ICR 8. 2 by Radcliffe Cardiology

Established: June 2006

Frequency: Bi-annual

Current issue: Autumn 2013

Aims and Scope • • • •

Interventional Cardiology Review aims to assist time-pressured physicians to stay abreast of key advances and opinion in interventional cardiology practice. The journal endeavours, through its pertinent teaching reviews, to support the continuous medical education of both specialist and general cardiologists. Interventional Cardiology Review comprises balanced and comprehensive articles written by leading authorities, addressing the most pertinent developments in the field. Interventional Cardiology Review provides comprehensive update on a range of salient issues to support physicians in developing their knowledge and effectiveness in day-to-day clinical practice.

Structure and Format • • • •

Interventional Cardiology Review is a bi-annual journal comprising teaching reviews, editorials, and case reports. The structure and degree of coverage assigned to each category of the journal is determined by the Editor, with the support of the Editorial Board. Articles are fully referenced, providing a comprehensive review of existing knowledge and opinion. Each edition of Interventional Cardiology Review is replicated in full online at www.icrjournal.com

Editorial Expertise Interventional Cardiology Review is supported by various levels of expertise: • Overall direction from an Editor, supported by an Editorial Board comprising leading authorities from a variety of related disciplines. • Invited contributors who are recognised authorities from their respective fields. • Peer review – conducted by experts appointed for their experience and knowledge of a specific topic. • An experienced team of Editors and Technical Editors.

Peer Review • • •

On submission, all articles are assessed by the Editor and Editorial Board to determine their suitability for inclusion. The Editor, following consultation with the Editorial Board, identifies appropriate reviewers, who are selected on the basis of their specialist knowledge in the relevant area. Following review, papers are either accepted without modification, accepted pending modification, in which case the manuscripts are returned to the author(s) to incorporate required changes, or rejected outright. The Editor reserves the right to accept or reject any proposed amendments.

Submissions and Instructions to Authors • • • •

Contributors are identified and invited by the Editor with guidance from the Editorial Board. Following acceptance of an invitation, the author(s) and Editor formalise the working title and scope of the article. Subsequently, the Editor provides an ‘Instructions to Authors’ document and additional submission details. The journal is always keen to hear from leading authorities wishing to discuss potential submissions, and will give due consideration to any proposals. Please contact the Editor for further details. The ‘Instructions to Authors’ information is available for download at www.icrjournal.com

Reprints All articles included in Interventional Cardiology Review are available as reprints (minimum order 1,000). Please contact Jonathan McKenna at jonathan.mckenna@radcliffepublishing.com

Distribution and Readership Interventional Cardiology Review is distributed bi-annually through controlled circulation to senior professionals in the field in Europe.

Copyright and Permission Radcliffe is the sole owner of all articles and other materials that appear in Interventional Cardiology Review unless otherwise stated. Permission to reproduce an article, either in full or in part, should be sought from the publication’s Editor.

Online All manuscripts published in Interventional Cardiology Review are available free-to-view at www.icrjournal.com. Also available at www.radcliffecardiology.com are manuscripts from other journals within Radcliffe’s cardiovascular portfolio – including Arrhythmia & Electrophysiology Review. n

Radcliffe Cardiology

Lifelong Learning for Cardiovascular Professionals

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Radcliffe Cardiology

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Coronary Interventions Cardiogenic Shock

Evidence-based Management of Cardiogenic Shock After Acute Myocardial Infarction Ka rl W erda n, 1 Ma rtin R uss, 2 M i c h a e l B u e r k e , 3 Ro l a n d Pr o n d z i n s k y 4 a n d S e b a s t i a n D i e t z 1 1. Halle(Saale); 2. Dachau; 3. Siegen, 4; Merseburg, Germany

Abstract Guidelines for evidence-based management of patients with cardiogenic shock after acute myocardial infarction focuses on early revascularisation of the occluded coronary artery as well as on support of cardiac failure and improvement of impaired organ perfusion. Also of great importance is effective treatment of shock complications, especially acute respiratory failure and other forms of multiple organ dysfunction syndrome (MODS). Cardiovascular therapy has to be accompanied by best general intensive care of these critically ill patients with high mortality. Most lives can be saved by early revascularisation, and this class I recommendation has a high level of evidence. So far, most of the other guideline recommendations are of low evidence level, in most cases based on expert opinions. Recently, the Intra-aortic Balloon Pump in Cardiogenic Shock II (IABP SHOCK II) trial with 600 patients has shown that adjunctive IABP therapy – for long a class I recommendation – does not reduce 30-day and six-month motality.

Keywords Cardiogenic shock, myocardial infarction, IABP SHOCK II trial, multiple organ dysfunction syndrome, guideline, German-Austrian cardiogenic shock guideline, percutaneous coronary intervention, dobutamine, norepinephrine, lung protective ventilation, blood glucose Disclosure: Karl Werdan was the coordinator of the German-Austrian S3 guideline, “Cardiogenic Shock Due to Myocardial Infarction: Diagnosis, Monitoring and Treatment” and Martin Russ and Michael Buerke were also authors of this guideline. The remaining authors have no conflicts of interests to declare. Received: 20 August 2013 Accepted: 15 September 2013 Citation: Interventional Cardiology Review, 2013;8(2):73–80 Correspondence: Karl Werdan, Department of Medicine III, Department of Medicine and Heart Centre, University Clinics Halle(Saale), Martin-Luther-University Halle-Wittenberg, Ernst-Grube-Str. 40, D-06120 Halle (Saale), Germany. E: karl.werdan@uk-halle.de

Cardiogenic Shock, One of the Unresolved Problems in Cardiology

Which Patient with Cardiogenic Shock After Acute Myocardial Infarction Will Survive?

Provided the patient with acute myocardial infarction (AMI) reaches the hospital, he has a more than 90 % probability to survive.1 However, when cardiogenic shock develops, either initially or in the course of the infarction, only one in two patients is alive one year later.2,3 It really seems that all the progress in the treatment of myocardial infarction (MI) within the last ten years has bypassed these 5–10 % of patients suffering from cardiogenic shock complicating myocardial infarction – the publication of the most important evidence-based progress in treatment of cardiogenic shock after acute myocardial (CSAMI) patients – the earliest possible reperfusion of the culprit lesion of the occluded infarct coronary artery by percutaneous coronary intervention (PCI) or aortocoronary bypass (ACB) – is already 14 years old.4 This disappointing situation explains the urgent search for better treatment concepts 5 to lower this unacceptably high mortality of patients with cardiogenic shock complicating myocardial infarction.

Cardiogenic shock is not only a problem of the heart. One main cause of the high mortality among patients with CSAMI is the development of prolonged shock leading to systemic inflammatory response syndrome (SIRS) and even sepsis,3,7–9 with consecutive development of deleterious multiple organ dysfunction syndrome (MODS).10,11 Consequently, CSAMI is not just a disease of the heart, but a disease of the critically ill intensive care unit (ICU) patient with SIRS and MODS. This has to be taken in mind when trying to improve prognosis and reduce mortality by simply increasing cardiac output and stabilising blood pressure.

About 80 % of cardiogenic shocks after AMI are due to left ventricular pump failure; the rest consists of severe mitral regurgitation due to papillary muscle dysfunction or rupture, ventricular septal rupture, cardiac rupture, shock due to right ventricular infarction and other rare causes. 6 In this article we will mainly focus on cardiogenic shock due to left ventricular failure after AMI.

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Figure 1 shows the time course of cardiac index, brain-type natriuretic peptide (BNP), interleukin-6 (IL-6) and Acute Physiology and Chronic Health Evaluation II (APACHE II) score in surviving and non-surviving patients with cardiogenic shock due to left ventricular failure complicating MI. Of course one would expect that haemodynamic measures like cardiac index would discriminate best between survivors and non-survivors. And indeed, cardiac index in survivors was significantly higher than in non-survivors, but only less than 1 L x min-1 x m-2 and only within the first 24 hours (see Figure 1A). The heart failure marker BNP was even without any prognostic relevance within the first 96 hours (see Figure 1B). On the other hand, IL-6 serum levels as a marker of SIRS were much higher in non-survivors (see Figure 1C) as was also the severity of disease score APACHE II, a measure of MODS (see Figure

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Evidence-based Management of Cardiogenic Shock After Acute Myocardial Infarction

muscle dysfunction or rupture, ventricular septal defect and pericardial rupture).6,15 Important in case of shock following right ventricular infarction is revascularisation as early as possible, an adequate increase in right ventricular preload (central venous pressure 15–20 mmHg) with careful watching of left ventricular dysfunction, increasing right ventricular inotropy with dobutamine and – in case of bradycardia – acutely given atropine and eventually pacing. Treatment of choice of shock due to mechanical AMI complications usually is early cardiac surgery, with pre-operative haemodynamic stabilisation by IABP implementation.

Complications of Cardiogenic Shock After Acute Myocardial Infarction Arrhythmias Arrhythmias in the course of acute myocardial infarction6 and especially in CSAMI patients15 – either pre-existing, triggering cardiogenic shock or as a consequence of acute heart failure (6–32 %)39 – can further aggravate cardiac dysfunction. Electrical cardioversion/defibrillation and amiodarone are therapies of choice in case of haemodynamically relevant recent onset atrial fibrillation and ventricular tachycardias.15

Multiple Organ Dysfunction Syndrome The cardiogenic shock – especially if prolonged – triggers a drastic hypoperfusion of vital organs with the consequence of development of SIRS (see below) and MODS. Consequently best prophylaxis of MODS development and best therapy of MODS is rapid restoration of a sufficient organ perfusion. Scores like APACHE II (see Figure 1)/III, SAPS II and SOFA characterise the severity of MODS, which is an important determinant of mortality (see Figure 1).11,40 Concerning the organs involved in MODS, the lungs (ARDS) play a prominent role (see above). Treatment of acute renal failure can be compensated by either continuous renal replacement therapy (CRRT) or by intermittent haemodialysis, with a weak recommendation (↑) for CRRT because of better tolerability in haemodynamically unstable patients.15 Other organ dysfunctions consist those of the gastrointestinal tract and the liver, the critical illness neuropathy, myopathy, encephalopathy and autonomous dysfunction as well as the endocrine and the metabolism.15 Despite the postulated relative adrenal insufficiency in shock, no convincing data exist about a beneficial role of low dose hydrocortisone in CSAMI. No information is available for CSAMI about the role of selective decontamination of the digestive tract (SDD), which may be useful in septic shock.38

Systemic Inflammatory Response Syndrome Patients with CSAMI have increased serum levels of pro-inflammatory mediators like IL-6 (see Figure 1), C-reactive protein and many others,8,9 even as high as in septic shock. This clearly indicates a high state of SIRS in these patients, which is of prognostic relevance. Consequently, the TRIUMPH (The Tilarginine Acetate Injection in a Randomized International Study in Unstable MI Patients With Cardiogenic Shock) trial41 tested tilarginine (L-NG-monomethylarginine [L-NMMA]), a non-selective nitric oxide synthase (NOS)-inhibitor in 398 patients with MI and refractory cardiogenic shock despite an establishment of an open infarct artery. Tilarginine did neither reduce 30-day mortality in comparison with placebo (48 versus 42 %; risk ratio 1.14; 95 % CI 0.92–1.41; p=0.31), six-month mortality nor improve any other morbidity measure. At present, no effective specific anti-inflammatory therapy is available in CSAMI patients.

Sepsis, Severe Sepsis and Septic Shock In one of every six CSAMI patients, sepsis/severe sepsis with organ failure or septic shock develops during the first days of shock development.7

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Positive blood cultures revealed Staphylococcus aureus (32 %), Klebsiella pneumoniae and Pseudomonas aeruginosa as the dominant pathogens, particularly in patients with prolonged IABP support or multiple central catheters.42 In the SHOCK trial, septic patients had an inadequately low SVR for patients with cardiogenic shock (1,051 [862–1,486] versus 1,402 [1,088–1,807] dyn × s × cm-5) and a twofold higher mortality.7 To diagnose sepsis as early as possible, careful monitoring of clinical and haemodynamic sepsis signs in these patients is mandatory; and if sepsis is suspected or is confirmed by increased procalcitonin levels (cut-off 2 ng/ml), blood cultures should be immediately drawn and sepsis therapy immediately started according to the sepsis guidelines – according to the three hour sepsis bundle, within three hours the following should be completed:38 • • • •

measure lactate level; obtain blood cultures prior to administration of antibiotics; administer broad spectrum antibiotics (within one hour); and administer 30 mL/kg crystalloid for hypotension or lactate 4 mmol/L.

Especially in CSAMI patients, fluid administration must be carefully monitored and titrated.

Intensive Care for the Patient with Cardiogenic Shock After Acute Myocardial Infarction Nutrition – Enteral Nutrition is Preferred! Enteral nutrition is preferred over parenteral nutrition. Critically ill patients of 20–30/30–70/>70 years in the catabolic acute phase need a daily caloric intake of no more than 25/22.5/20 kcal/kg, with the shock stage even decreasing energy turnover. Hyperalimentation of the CSAMI patient of >25 kcal/kg/day should be avoided.15

Blood Glucose – Keep a “Middle Way”! The initially propagated beneficial effect of normalising blood glucose levels (4.4–6.1 mmol/L / 60–110 mg/dL) by continuous insulin infusion in intensive care patients could not be confirmed in later studies as the NICE-SUGAR (Normoglycemia in Intensive Care Evaluation–Survival Using Glucose Algorithm Regulation) study,43 which also pointed to the risk of hypoglycaemia with this concept. On the other hand, high blood glucose levels in heart attack patients indicate an unfavourable prognosis.44 As compromise, the German-Austrian guideline14 gives a weak recommendation (↑) to keep blood glucose values below 150 mg × dL-1/<8.3 mmol × L-1 by means of insulin (E 99 in Figure 3 and 8). The formerly used glucose-insulin-potassium infusions given to AMI patients show no benefit in AMI patients44 and shall not be given to CSAMI patients (E 100 in Figure 3).

Which Haemoglobin Threshold Can be Accepted in Cardiogenic Shock After Acute Myocardial Infarction Patients? A lot of controversy does exist at what haemoglobin (Hb) threshold red blood cells should be transfused in intensive care patients, especially in those with cardiac disease and in older patients in whom increased oxygen requirement of the heart may be assumed.15 Based on intense discussions of the experts, the German-Austrian guideline gives the weak recommendation (↑) that red cell concentrate transfusions should be given in CSAMI patients when haemoglobin values are <7.0 g × dL-1 /4.3 mmol × L-1 or haematocrit <25 % and the values be brought up to 7.0–9.0 g × dL-1/4.3–5.6 mmol × L-1 or ≥25 % (E 101 in Figure 3); in older patients with CSAMI a fall of the haematocrit below 30 % should be avoided (E 102).15

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Coronary Interventions Cardiogenic Shock Mandatory Prophylactic Measures Thrombosis prophylaxis with heparin shall be given by the intravenous route, at least during shock phase (see above) (E 103/104).15 As most CSAMI patients have risk factors for gastroenteral bleeding, stress ulcer prophylaxis, mostly done with proton pump inhibitors,45 should be applied (E 107).15 Bicarbonate is often used in shock patients with blood acidosis. However, no proven benefit was achieved in two studies with blood acidosis not lower than 7.15,46,47 but with possible harm (retention of sodium ion [Na+] and fluid, increase in lactate and carbon dioxide partial pressure [pCO2], as well as a fall in ionized serum calcium). Therefore, the German-Austrian guideline recommends (↑) that bicarbonate should not be used for treatment of hypoperfusion-induced lactic acidosis with a blood pH ≥7.15 with the intention to stabilise haemodynamics or reduce vasopressors (E 108).15

In the IABP SHOCK II trial having included 600 patients with CSAMI,3 treatment was standardised according to the German-Austrian S3 guideline,14,15 which was provided to the investigators of all 37 participating centres located in Germany. Guideline adherence in this trial is presently under investigation.

Limitations of Evidence-based Management of Cardiogenic Shock after Acute Myocardial Infarction

What About Guideline Adherence Under Cardiologists Treating Patients with Cardiogenic Shock After Acute Myocardial Infarction?

Most of the given guideline recommendations are based on low evidence levels (see Figures 2 and 3): results from non-randomised trials, expert opinions and recommendations deduced from guidelines for noncardiogenic shock ICU patient groups. Only a few recommendations are based on data from large randomised trials or meta-analyses, like the benefit of early revascularisation and the neutral result of IABP therapy. A lot of work will have to be done in the future, to give evidence-based management of cardiogenic shock a better fundament. This should include standardised and consented nursing guidelines for these patients.

We all know that guideline knowledge is no guarantee for guideline adherence.48,49 With respect to the treatment of CSAMI patients, we can be sure that early revascularsation – a class I recommendation of all guidelines6,13,14 has a very high adherence, and the recommendation of the German-Austrian guideline14 of lung protective ventilation a low one37 (see above). However, systematic research on this topic is scarce in CSAMI patients.

Though hospital mortality of CSAMI patients is very high, long-term prognosis of the surviving patients is encouraging – after one year, more than half are in New York Heart Association (NYHA) class I or II,16,50 and many are completely asymptomatic.51 Optimisation of postintensive and rehabilitation care could help to improve prognosis and quality of life of these patients even further. n

1. 2. 3. 4.

5. 6.

7. 8.

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Nabel EG, Braunwald E, A tale of coronary artery disease and myocardial infarction, N Engl J Med, 2012;366:54–63. Hochman JS, Sleeper LA, Webb JG, et al., Early revascularization and long-term survival in cardiogenic shock complicating acute myocardial infarction, JAMA, 2006;295:2511–5. Thiele H, Zeymer U, Neumann FJ, et al., Intraaortic Balloon Support for Myocardial Infarction with Cardiogenic Shock, N Engl J Med, 2012;367(14):1287–96. Correspondence: 2013;368(1):80–1. Hochman JS, Sleeper LA, Webb JG, et al., Early revascularization in acute myocardial infarction complicated by cardiogenic shock. SHOCK investigators. Should We Emergently Revascularize Occluded Coronaries for Cardiogenic Shock, N Engl J Med, 1999;341:625–34. Reynolds HR, Hochman JS, Cardiogenic Shock: Current Concepts and Improving Outcomes, Circulation, 2008;117:686–97. Task Force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology (ESC), Steg PG, James SK, et al., ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation, Eur Heart J, 2012;33(20):2569–619. Kohsaka S, Menon V, Lowe AM, et al., Systemic inflammatory response syndrome after acute myocardial infarction complicated by cardiogenic shock, Arch Int Med, 2005;165;1643–50. Prondzinsky R, Unverzagt S, Lemm H, et al., Interleukin -6, -7, -8 and -10 predict outcome in acute myocardial infarction complicated by cardiogenic shock, Clin Res Cardiol, 2012;101(5):375–84. Prondzinsky R, Unverzagt S, Lemm H, et al., Acute myocardial infarction and cardiogenic shock: prognostic impact of cytokines: INF-γ, TNF-α, MIP-1β, G-CSF, and MCP-1β, Med Klin Intensivmed Notfmed, 2012;107(6):476–84. Hochman JS, Cardiogenic shock complicating acute myocardial infarction: expanding the paradigm, Circulation, 2003;107(24):2998–3002. Prondzinsky R, Lemm H, Swyter M, et al., Intra-aortic balloon counterpulsation in patients with acute myocardial infarction complicated by cardiogenic shock: the prospective, randomized IABP SHOCK Trial for attenuation of multiorgan dysfunction syndrome, Crit Care Med, 2010;38(1):152–60. Werdan K, Do not get in RAGE in cardiogenic shock: it is detrimental!, Crit Care Med, 2012;40(5):1669–70. O’Gara PT, Kushner FG, Ascheim DD, et al., 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, Circulation, 2013;127:529–55. Werdan K, Ruß M, Buerke M, et al., Cardiogenic Shock Due to Myocardial Infaction: Diagnosis, Monitoring and Treatment – A German-Austrian S3 Guideline, Dtsch Arztebl Int, 2012;109(19):343–51. Revised version in preparation. Werdan K, Ruß M, Buerke M, et al., [“German-Austrian S3 guideline: “Diagnosis, monitoring and therapy of cardiogenic shock due to myocardial infarction“], Kardiologe, 2011;5:166–224. Revised version in preparation. Hochman JS, Sleeper LA, White HD, et al., One-year survival following early revascularization for cardiogenic shock, JAMA, 2001;285;190–2. Arntz HR, Bossaert LL, Danchin N, Nikolaou N, European Resuscitation Council Guidelines for Resuscitation 2010: Section 5. Initial management of acute coronary syndromes, Resuscitation, 2010;81:1353–63. Nolan JP, Soar J, Postresuscitation care: entering a new era, Curr Opin Crit Care, 2010;16:216–22.

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19. Demondion P, Fournel L, Golmard JL, et al., Predictors of 30-day mortality and outcome in cases of myocardial infarction with cardiogenic shock treated by extracorporeal life support, Eur J Cardiothorac Surg, 2013 [Epub ahead of print]. 20 Fincke R, Hochman JS, Lowe AM, et al., Cardiac Power is the Strongest Hemodynamic Correlate of Mortality in Cardiogenic Shock: A Report From the SHOCK Trial Registry, J Am Coll Cardiol, 2004;44:340–8. 21. Mendoza DD, Cooper HA, Panza JA, Cardiac power output predicts mortality across a broad spectrum of patients with acute cardiac disease, Am Heart J, 2007;153:366–70. 22. Sakr Y, Reinhart K, Vincent JL, et al., Does dopamine administration in shock influence outcome? Results of the Sepsis Occurrence in Acutely Ill Patients (SOAP) Study, Crit Care Med, 2006;34:589–97. 23. De Backer D, Biston P, Devriendt J, et al., Comparison of Dopamine and Norepinephrine in the treatment of shock, N Engl J Med, 2010; 362:779–89. 24. Fuhrmann JT, Schmeisser A, Schulze MR, et al., Levosimendan is superior to enoximone in refractory cardiogenic shock complicating acute myocardial infarction, Crit Care Med, 2008;36:2257–66. 25. Mebazaa A, Nieminen MS, Filippatos GS, et al., Levosimendan vs. dobutamine: outcomes for acute heart failure on betablockers in SURVIVE, Eur J Heart Fail, 2009;11(3):304–11. 26. Metra M, Nodari S, D’Aloia A, et al., Beta-blocker therapy influences the hemodynamic response to inotropic agents in patients with heart failure: A randomized comparison of dobutamine and enoximone before and after chronic treatment with metoprolol or carvedilol, J Am Coll Cardiol, 2002;40:1248–58. 27. Werdan K, Ruß M, Buerke M, The intra-aortic balloon pump. In: Tubaro M, Danchin N, Filippatos G, et al., (eds), The ESC Textbook of Intensive and Acute Cardiac Care, Oxford, UK: Oxford University Press, 2011;277–88. 28. Werdan K, Gielen S, Ebelt H, Hochman JS, Mechanical circulatory support in cardiogenic shock, Eur Heart J, 2013 [Epub ahead of print]. 29. Sjauw KD, Engstrom AE, Vis MM, et al., A systematic review and meta-analysis of intra-aortic balloon pump therapy in ST-elevation myocardial infarction: should we change the guidelines?, Eur Heart J, 2009;30:459–68. 30. Unverzagt S, Machemer MT, Solms A, et al., Intra-aortic balloon pump counterpulsation (IABP) for myocardial infarction complicated by cardiogenic shock, Cochrane Database Syst Rev, 2011;(7) CD007398. 31. Prondzinsky R, Unverzagt S, Russ M, et al., Hemodynamic effects of intra-aortic balloon counterpulsation in patients with acute myocardial infarction complicated by cardiogenic shock: the prospective, randomized IABP SHOCK trial, Shock, 2012;37:378–84. 32. Sheu JJ, Tsai TH, Lee FY, et al., Early extracorporeal membrane oxygenator assisted primary percutaneous coronary intervention improved 30-day clinical outcomes in patients with ST-segment elevation myocardial infarction complicated with profound cardiogenic shock, Crit Care Med, 2010;38:1810–7. 33. Ouweneel DM, Henriques JPS, Percutaneous cardiac support devices for cardiogenic shock: current indications and recommendations, Heart, 2012;98:1246–54. 34. Peura JL, Colvin-Adams M, Francis GS, et al., Recommendations for the Use of Mechanical Circulatory Support: Device Strategies and Patient Selection – A Scientific Statement of the American Heart Association, Circulation, 2012;126:2648–67. 35. Cheng JM, den Uil CA, Hoeks SE, et al., Percutaneous left ventricular assist devices vs. intra-aortic balloon pump

counterpulsation for treatment of cardiogenic shock: a metaanalysis of controlled trials, Eur Heart J, 2009;30:2102–8. 36. Kouraki K, Schneider S, Uebis R, et al., Characteristics and clinical outcome of 458 patients with acute myocardial infarction requiring mechanical ventilation. Results of the BEAT registry of the ALKK-study group, Clin Res Cardiol, 2011;100:235–9. 37. Schneck M, Holder K, Nuding S, et al., [Lung protective ventilation and hospital survival in coronary care patients], Med Klin Intensivmed Notfmed, 2013;108(4):363. 38. Dellinger P, Levy MM, Rhodes A, et al., Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock: 2012, Crit Care Med, 2013;41:580–637. 39. Benza RL, Tallaj JA, Felker GM, et al., The impact of arrhythmias in acute heart failure, J Card Fail, 2004;10:279–84. 40. Kellner P, Prondzinsky R, Pallmann L, et al., Predictive value of outcome scores in patients suffering from cardiogenic shock complicating AMI: APACHE II, APACHE III, Elebute-Stoner, SOFA, and SAPS II, Med Klin Intensivmed Notfmed, 2013 [Epub ahead of print]. 41. The TRIUMPH Investigators, Alexander JH, Reynolds HR, et al., Effect of tilarginine acetate in patients with acute myocardial infarction and cardiogenic shock: the TRIUMPH randomized controlled trial, JAMA, 2007;297:1657–66. 42. Kohsaka S, Menon V, Iwata K, et al., Microbiological Profile of Septic Complication in Patients With Cardiogenic Shock Following Acute Myocardial Infarction (from the SHOCK Study), Am J Cardiol, 2007;99:802–4. 43. Finfer S, Chittock DR, Su SY, et al., Intensive versus conventional glucose control in critically ill patients, N Engl J Med, 2009;360:1283–97. 44. Cobb LA, Killip T, Lambrew CT, et al., Glucose-insulin-potassium infusion and mortality in the CREATE-ECLA trial, JAMA, 2005; 293(4):437–46; Letters and authors’ reply: 2005;293:2596–8. 45. Conrad SA, Gabrielli A, Margolis B, et al., Randomized, doubleblind comparison of immediate-release omeprazole oral suspension versus intravenous cimetidine for the prevention of upper gastrointestinal bleeding in critically ill patients, Crit Care Med, 2005;33:760–5. 46. Cooper DJ, Walley KR, Wiggs BR, Russell JA, Bicarbonate does not improve hemodynamics in critically ill patients who have lactic acidosis. A prospective, controlled clinical study, Ann Intern Med, 1990;112:492–8. 47. Mathieu D, Neviere R, Billard V, et al., Effects of bicarbonate therapy on hemodynamics and tissue oxygenation in patients with lactic acidosis: a prospective, controlled clinical study, Crit Care Med, 1991;19:1352–6. 48. Michota FA Jr, Amin A, Bridging the gap between evidence and practice in acute decompensated heart failure management, J Hosp Med, 2008;3(6 Suppl):S7–15. 49. Tjandrawidjaja MC, Fu Y, Al-Khalidi H, et al., APEX-AMI Investigators. Failure of investigator adherence to electrocardiographic entry criteria is frequent and influences clinical outcomes: lessons from APEX-AMI, Eur Heart J, 2007;28(23):2850–7. 50. Sleeper LA, Ramanathan K, Picard MH, et al., Functional status and quality of life after emergency revascularization for cardiogenic shock complicating acute myocardial infarction, J Am Coll Cardiol, 2005;46:266–73. 51. Ammann P, Straumann E, Naegeli B, et al., Long-term results after acute percutaneous transluminal coronary angioplasty in acute myocardial infarction and cardiogenic shock, Int J Cardiol, 2002;82:127–31.

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Coronary Interventions Acute Coronary Syndrome

The Role of the Transradial Approach for Complex Coronary Interventions in Patients with Acute Coronary Syndrome S a s k o Ke d e v Professor of Medicine, University Clinic of Cardiology, Medical Faculty, University of St Cyril and Methodius, Skopje, Macedonia

Abstract Despite advances in antithrombotic and antiplatelet therapy, bleeding complications remain an important cause of morbidity and mortality in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI). A significant proportion of such bleedings are related to the access site, and adoption of transradial access (TRA) may reduce these complications. In patients with ST-segment elevation myocardial infarction (STEMI), TRA reduced cardiac mortality in comparison with the femoral approach (TFA). High-risk patients such as women, obese patients and elderly subjects who are at increased risk for vascular complications and bleeding, might particularly benefit from the TRA. However, specific radial expertise providing procedural time and a success rate comparable to those with the TFA are strongly recommended before using this technique in the emergency setting.

Keywords Transradial approach, acute coronary syndrome, percutaneous coronary intervention, non-ST-segment elevation acute coronary syndromes, ST-segment elevation myocardial infarction, cardiogenic shock, left main culprit Disclosure: The author has no conflicts of interest to declare. Received: 15 May 2013 Accepted: 20 June 2013 Citation: Interventional Cardiology Review, 2013;8(2):81–6 Correspondence: Sasko Kedev, Professor of Medicine, University Clinic of Cardiology, Medical Faculty, University of St Cyril and Methodius, Vodnjanska 17, 1000 Skopje, Macedonia. E: skedev@gmail.com

An invasive strategy including percutaneous coronary intervention (PCI) improves clinical outcomes in patients with ST-segment elevation myocardial infarction (STEMI) and in high-risk patients with non-ST-segment elevation acute coronary syndrome (NSTEACS). 1,2 The femoral approach (TFA) is the preferred and most widely used percutaneous access site in most cardiac catheterisation laboratories worldwide. However, being a relatively deep and terminal vessel, the femoral artery may expose the patient to frequent bleeding and vascular complications,3,4 especially in the setting of acute coronary syndrome (ACS) where potent antithrombotic drugs are frequently used.5,6 Since its initial description as a safe and feasible access route for cardiac catheterisation,7,8 the transradial access (TRA) has increasingly been used for PCI. The main advantage over the TFA is a reduced risk of access site bleeding and major vascular complications, particularly in the presence of multiple and more powerful antiplatelet and antithrombotic agents.9 This is mainly ascribed to the more favourable anatomy of the radial artery that runs superficially, separated from major neurovascular structures, thus allowing shorter times to haemostasis and ambulation as compared with the TFA.10 More recently, the radial approach has been shown to confer mortality benefits for STEMI patients and a reduction in mortality, myocardial infarction (MI) and stroke for patients undergoing the procedure at high-volume radial centres.11–13 Reported access failure for radial procedures in primary PCI (PPCI) is low with an access crossover rate between 3.8 %14 and 9.6 %13 with

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negligible time delay by expert operators. There are several reasons leading to failure – inability to cannulate, severe radial artery spasm (RAS) and anatomical variations. In some of these difficult transradial cases, ulnar artery cannulation has been proposed as a reasonable and useful alternative to the TRA if performed by an experienced radial operator, before crossover to the TFA.15,16

Bleeding Complications in Acute Coronary Syndrome Peri-PCI procedural bleeding complications have been consistently associated with worse outcomes and increased short- and longterm mortality.6,17 Access site-related bleeding, accounting for as many as 30–50 % of all causes of bleeding in patients with ACS, has repeatedly been found to be the major contributor for bleeding events. 9,18–20 Due to the firm link between bleeding, ischaemic events and mortality, more attention has recently been focused on bleeding avoidance strategies.21 Despite the development of new more potent, selective and safe antithrombotics, the use of TRA remains likely the best way to significantly influence access site-related bleeding risk.22–25 Recently, the REgistro regionale AngiopLastiche dell’Emilia-Romagna (REAL) Registry of 11,068 STEMI patients undergoing PPCI, showed that TRA was associated with a decreased two-year mortality rate compared with the traditional TFA (8.8 versus 11.4 %, hazard ratio [HR] 1.303; p=0.025).12 The observed difference in death was not explained by the incidence of MI or stroke, which did not differ between groups. By

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Coronary Interventions Acute Coronary Syndrome Figure 1: Complete Thrombotic Occlusion of Unprotected Left Main in Patient Presenting with ST-segment Elevation Myocardial Infarction and Cardiogenic Shock – Right Radial Approach

Figure 2: Right Radial Access for Primary Percutaneous Coronary Intervention with 6F Extra Backup Guiding Catheter – Manual Thromboaspiration (Arrow) and Intra-aortic Balloon Pump Counterpulsation (Arrow) Through the Right Femoral Access

contrast, TRA was associated with a significant and marked reduction of in-hospital major bleeding or vascular events.

compare the radial (500 patients) and femoral approaches (501 patients) for primary/rescue PCI. In this nearly all-comers study, the TRA was associated with significantly lower rates of clinically relevant

The available clinical evidence summarised in recent meta-analyses demonstrated a significant reduction in mortality, major adverse cardiac events (MACE), major bleeding events and major access site complications associated with the TRA.24,25 Therefore, the use of the TRA for high-risk patients with ACS certainly has a key role in the prevention of access site bleeding complications.

access site bleeding (2.6 versus 6.8 %; p=0.002) and subsequent 30-day mortality (5.2 versus 9.2 %; p=0.020) in comparison with TFA. The reduction in cardiac mortality and clinically relevant access site bleeding by 60 % with a significant decrease in the need for transfusion in the radial arm of the RIFLE-STEACS, support the link between mortality and ‘clinically relevant’ access site bleeding. Furthermore, there were no differences in the symptom-to-balloon and door-to-balloon times between the two study groups. Vascular approach crossover was 9.6 % in the radial arm and 2.8 % in the femoral arm with negligible time delay by expert operators.13

Randomised Controlled Trials and Registries of Transradial Access Versus the Femoral Approach in Acute Coronary Syndrome The radial versus femoral access for coronary angiography and intervention in patients with acute coronary syndromes (RIVAL) is the largest randomised comparison of radial and femoral artery access of 7,021 patients with ACS; 1,958 with a pre-randomisation diagnosis of STEMI; and 5,063 patients with NSTEACS.11 In patients with STEMI, TRA significantly reduced the primary outcome: death, MI, stroke or non-coronary artery bypass graft surgery (CABG)-related major bleeding within 30 days (3.1 versus 5.2 %; HR 0.60; p=0.026) and mortality alone (1.3 versus 3.2 %; HR 0.39; p=0.006). In patients presenting with NSTEACS, there were no significant differences in any of these outcomes. In both STEMI and NSTEACS patients, TRA reduced major vascular access site complications (1.4 versus 3.7 %; HR 0.37; p<0.0001), and major bleeding as defined by the Acute Catheterization and Urgent Intervention Triage strategy (ACUITY) definition (1.9 versus 4.5 %; HR 043; p<0.0001). In STEMI patients, the reduction in the primary and secondary composite outcomes was driven mainly by a reduction in mortality with a directionally consistent reduction in MI. No such benefit was observed in patients with NSTEACS. Access site crossover was higher in the radial group compared with the femoral group (7.6 versus 2.0 %; HR 3.82; p<0.0001), and this was consistent in both STEMI and NSTEACS cohorts. 26 The Radial Versus Femoral Randomized Investigation in ST Elevation Acute Coronary Syndrome (RIFLE-STEACS) is the first large randomised clinical trial of 1,001 patients with STEMI specifically designed to

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Recently, A Prospective Randomized Trial of Radial vs. Femoral Access in Patients with ST-Segment Elevation Myocardial Infarction (STEMIRADIAL) showed that TRA was associated with a significantly lower incidence of major bleeding and access site complications, and a significantly better net clinical benefit – composite of death, MI and stroke, and major bleeding (4.6 versus 11.0 %; p=0.0028) Moreover, TRA significantly reduced intensive coronary care unit (ICU) stay (p=0.0016) and contrast volume (p<0.01) compared with TFA.27 The post hoc analysis of the Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction Trial (HORIZON-AMI),22 showed improved event-free survival in patients undergoing primary PCI by the TRA and confirmed the advantage of the TRA with regard to haemorrhagic complications also in patients treated with bivalirudin. Based on data derived from the RIFLE-STEACS and STEMI subgroup of RIVAL, in the latest 2012 European Society of Cardiology (ESC) STEMI Guidelines recommendations, TRA is preferred over TFA if performed by an experienced operator (Class IIa, Level B).28 In a cohort of 21,339 patients suffering from STEMI in the Swedish Coronary Angiography and Angioplasty Registry (SCAAR), the adjusted one-year cumulative risk of death was lower in patients treated via TRA (odds ratio [OR] 0.78, 0.64–0.96; p=0.018).29

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Figure 3 and 4: Final Result of Transradial Access Percutaneous Coronary Intervention with Drug-eluting Stent of Unprotected Left Main Culprit in Patient Presenting with ST-segment Elevation Myocardial Infarction and Cardiogenic Shock 3

A recent meta-analysis of nine randomised controlled studies involving 2,977 patients suggested that the TRA is associated with a 47 % reduction in mortality and a 38 % reduction in major adverse cardiac events in STEMI patients undergoing PCI.24 Similarly, analysis of the North American National Cardiovascular Data Registry – CathPCI® Registry – that included 90,879 patients who underwent either primary or rescue PCI for STEMI showed that TRA was independently associated with the reduction of in-hospital mortality (OR 0.76, 95 % confidence interval [CI] 0.57–0.99) and of bleeding (OR 0.62, 95 % CI 0.53–0.72).30 Finally, the analysis of 46,128 PPCI cases recorded in the British Cardiovascular Intervention Society database over a five-year period, suggested that TRA was independently associated with a lower 30-day mortality (HR 0.71, p<0.05), in-hospital major adverse cardiac and cerebrovascular events (MACCE) (HR 0.73, p<0.05), major bleeding (HR 0.37, p<0.01) and access site complications (HR 0.38, p<0.01).31 However, the 0.7 % absolute reduction in major bleeding and 0.3 % absolute reduction in access site-related complications associated with TRA use cannot fully explain the scale of the mortality benefit associated with TRA in PPCI.31 Additional unmeasured factors may contribute to the benefit of TRA PCI. Although some access site complications will not result in significant blood loss, they may lead to systemic inflammation, activation of prothrombotic pathways and activation of the clotting cascade. This could further increase the risk of cardiovascular events even though the initial insult is not haemodynamically significant.32,33 Bleeding or access site complications can also lead to withdrawal of antiplatelet agents, increasing the risk of ischaemic complications.

High-risk Subgroups for Bleeding and Vascular Complications Patients undergoing PCI in the context of ACS are expected to receive a combination of potent multiple antithrombotic drugs that

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may lead to an increased risk of bleeding and subsequent morbidity and mortality. Women are at higher risk of bleeding and other adverse outcomes after PCI than men.34,35 In a recent observational study, routine TRA was associated with reduced bleeding risk in women.36 Unfortunately, muscular arterial hyper-reactivity, procedural discomfort and small artery diameter increases the risk of first radial access failure (9.6 % in women versus 1.6 % in men). However, successful radial access does not allow the operator to use more aggressive combinations of anticoagulants and antiplatelet agents in this group, given that women remain at higher non-access site bleeding risk.37,38 Elderly patients are also at high risk for bleeding and vascular complications post-PCI. Lower limb peripheral artery disease (PAD), tortuosity of the iliac arteries and aneurysms of the abdominal aorta may represent relative or absolute contraindications to TFA. As a result of PAD in the elderly, radial access appears to be as feasible as femoral access. In two randomised trials, the TRA was associated with fewer vascular complications in elderly patients.39,40

Cardiogenic Shock and Left Main Culprit in Acute Coronary Syndrome Cardiogenic shock has a poor outcome compared with less severe presentations of ACS. The Should We Emergently Revascularize Occluded Coronaries for Cardiogenic Shock (SHOCK) trial40 showed the importance of revascularisation to improve outcomes, but the recent Intraaortic Balloon Pump in Cardiogenic Shock II (IABP-SHOCK II) trial41 failed to show any marginal benefit of adding haemodynamic support with intra-aortic balloon counterpulsation in the setting of shock. Cardiogenic shock is associated with a doubling of the risk of bleeding compared with the absence of shock.42 There may be a safety advantage of using the radial artery for the coronary intervention and reserving the femoral artery for larger devices in patients with cardiogenic shock (see Figures 1–4).

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Coronary Interventions Acute Coronary Syndrome Rodriguez-Leor analysed their single-centre registry experience with radial access in cardiogenic shock patients. From a 1,400-patient experience, 122 (8.7 %) developed cardiogenic shock with 80 undergoing transfemoral and the remaining 42 undergoing transradial catheterisation. Mortality (64.3 versus 32.5 %, p<0.001), serious access site complications (11.9 versus 2.5 %, p<0.03), access site complications requiring blood transfusion (7.1 versus 0.0 %, p<0.04) and MACCE (death, infarction, stroke, serious bleeding and postanoxic encephalopathy) (73.8 versus 43.8 %, p<0.001) were greater in patients treated by the femoral route. After multivariate analysis, initial TRA was associated with lower mortality (OR 0.39; 95 % CI 0.15–0.97) compared with an initial TFA.43 Bernat et al. evaluated outcomes of 197 STEMI patients with signs of cardiogenic shock who were treated with primary PCI at two highvolume centres. The TRA was used successfully in 55 % of cases where at least one radial artery was weakly palpable. TRA emerged as an independent predictor of survival with more than half of the patients treated successfully. Mortality at one-year was 44 % in the radial group and 64 % in the femoral group (p=0.0044).44 Romagnoli et al. analysed 241 consecutive patients (91 % with ACS and left main culprit in 26 % of cases) receiving IABP support during PCI in four high-volume centres. Patients were further divided in two groups – 116 patients receiving double femoral access (FF) and 125 receiving both radial and femoral (RF) approaches. NACEs were more frequent in the FF group when compared with the RF group (67 versus 41 %, p<0.01). In particular, this difference originated from an increase of access site-related bleeding (21 versus 7 %, p<0.01) and cardiac death (41 versus 25 %, p<0.01).45 These data show that a radial-femoral access strategy is safer than a femoral-femoral access strategy, and this safety advantage is associated with reduced mortality.45

Left Main Culprit A significant involvement of the left main coronary artery occurs in 4–7 % of patients presenting with an acute myocardial infarction (AMI).46,47 These critically ill patients frequently present with cardiogenic shock or cardiac arrest and are at high risk for in-hospital major cardiac adverse events.48,49 Primary PCI for an AMI due to an unprotected left main coronary artery (ULMCA) culprit lesion is a rare procedure, frequently associated with adverse clinical outcomes. The incidence of AMI due to an ULMCA culprit lesion is reported to be 0.8–5.4 %.50 Patients undergoing primary PCI for an AMI due to an ULMCA culprit lesion and presenting with cardiogenic shock have a high 30-day mortality compared with patients without cardiogenic shock, with the estimated 30-day all-cause mortality of 55 % for patients with cardiogenic shock and 15 % for patients without cardiogenic shock. A hybrid approach of initial revascularisation by primary PCI and elective surgery afterwards remains an alternative treatment option. Treating patients with cardiogenic shock or after cardiac arrest is one of the most challenging PCI procedures due to the nature of the clinical presentation while targeting a coronary lesion associated with a very large area of the myocardium at risk. These haemodynamically unstable patients have an extensive amount of ischaemic myocardium. Immediate mechanical haemodynamic support may prevent from further multi-organ failure.

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Whether newer and more powerful circulatory assist devices (Impella®, TandemHeart®, Extracorporeal Membrane Oxygenation [ECMO]) will result in better outcomes is the subject of ongoing clinical evaluation before widespread adoption.51 Most PCIs in high-risk ACS patients can be performed by TRA through conventional 6 French (Fr) guiding catheters, including complex cases, left main bifurcations and cardiogenic shock. However, a stepwise approach to learning is proposed and high-risk ACS-PCI is recommended as the last step. Ultimately, the treatment of patients in shock requires an individualised approach. Although the radial pulse may return with vasopressor administration, there may be clinical situations in which radial access is not possible and femoral access must be used. From the available evidence supporting the safety of the TRA over the TFA, a ‘radial first’ strategy likely still applies in most patients, even those with large STEMI and shock if performed by a skilled and experienced radial operator. Haemodynamic support devices can be placed via the femoral route and temporary pacemakers can be placed through the forearm or femoral veins (see Figures 1–4).52

Ulnar Artery Access The TRA may be difficult or associated with increased risk of complications in the presence of significant radial artery abnormalities, severe loops and curvatures, after failed radial artery cannulation and when the radial artery was repeatedly used previously. Transulnar artery cannulation (TUA) has been proposed as an alternative access for interventions in patients with a small-calibre radial artery or a thin radial pulse and stronger pulsation of the ulnar artery. Larger studies have further confirmed the safety and effectiveness of TUA as an alternative wrist approach to TRA for coronary interventions.16,53 The procedural success, advantages and complication rates for transulnar interventions appear similar to those from the TRA.15,53 Adding the ulnar artery access expertise could further reduce the crossover rate to TFA and lower the intrinsic risk of bleeding and vascular complications associated with the TFA. When the TRA is not possible or fails, the TUA may be considered as a safe alternative before reverting to the TFA.16 The TUA is a viable option for the high-volume radial centres, when performed by the expert radial operators who are skilled in ulnar artery cannulation.53

Limitations of the Transradial Access for Complex Percutaneous Coronary Intervention in Acute Coronary Syndrome Longer procedure duration and radiation exposure during the learning curve, and the potential influence on radial artery patency have slowed down acceptance of the TRA. Technique of TRA requires a specific set of skills, and is associated with a significant learning curve. With appropriate training, similar success rates with the TRA and TFA may be achieved even in complex ACS cases. The learning curve is highly individual and more experienced operators may become proficient sooner. To achieve the best results in TRA interventions, individual operators and institutional teams should aim at maintaining the highest feasible rate of TRA. After the learning curve has been completed, for over

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50 % TRA in routine practice, a minimum of 80 procedures per year per operator is recommended.54 A stepwise approach to learning is proposed according to clinical characteristics and PCI difficulty. ACS-PCI is proposed as the last step (NSTEACS and STEMI patients), due to multifaceted clinical settings and PCI complexity. The highest level of competency is obtained when patients requiring complex clinical management can be managed with timely and technically proficient control of PCI, irrespective of vascular access anatomy.54 The TRA is associated with very low incidence (0.2 %) of major vascular complications.10 Haematomas are usually minor, affecting only subcutaneous tissue. Unlike groin bleeding, subcutaneous bleeding after TRA is rapidly noticed and can be controlled by local compression. Major vascular complications like compartment syndrome are completely avoidable. Radial artery occlusion (RAO) is the most common complication, affecting 1.5–33.0 % shortly after the procedure, depending on the antithrombotic regimen, sheath size and protocol for haemostasis.55 Although usually asymptomatic, RAO is an important consequence of TRA, as it prohibits future ipsilateral TRA. Preserving radial artery patency is of paramount importance. Proper anticoagulation, downsizing of material (sheathless catheters) and shorter and less forceful ‘patent haemostasis’ of the radial artery with the emphasis on maintaining adequate arterial flow, considerably reduces the risk of RAO. It is important to remember that almost all potential complications are preventable by accurate preprocedural evaluation, meticulous technique and optimal post-procedural management. The incidence of RAS has varied considerably (4–30 %) depending on its definition, study population and the expertise of the operators.54 Spasm is the second most common cause of radial access failure after anatomical variations. The incidence of moderate/severe RAS is low in centres with a default TRA (2.7 %). Its development and procedural failure (0.7 %) appears strongly related to the numbers of puncture attempts and the use of larger-bore sheaths.56

Technical Recommendations for Complex Percutaneous Coronary Intervention in Acute Coronary Syndrome Challenging anatomy must be avoided to minimise the risk of complications and shorten the duration of both the procedure and radiation exposure. For this reason, a systematic preliminary angiogram of the forearm arteries through the radial introducer is recommended. The final choice of procedure will depend on the level of expertise of the operator, and the equipment required. In patients with cardiogenic shock, TRA procedures can be performed if the radial artery is palpable while leaving two potential femoral accesses for IABP counterpulsation or more complex cardiac-assist devices (see Figures 1–4). The right side is usually more ergonomic to the operator; however, the left radial approach might be more convenient in the learning phase

Keeley EC, Boura JA, Grines CL, Primary angioplasty versus intra-venous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomised trials, Lancet, 2003;361:13–20.

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because of similar catheter handling when compared to the femoral approach. Even if dedicated catheter shapes are available, traditional femoral shapes accommodate the radial approach easily. Coaxial alignment with the target coronary artery is mandatory and requires different handling for the right radial versus femoral approach. The choice of guiding catheter (diameter, shape, size) is essential for adequate back-up. Most PCIs can be performed through 6 Fr guiding catheters, including complex cases, thrombus aspiration, post-CABG and left main bifurcations. In selected patients of large stature, larger catheters (7 or even 8 Fr) or sheathless guiding catheters can be considered, allowing for large-lumen guiding catheters to be used in a small radial artery. However, these catheters, though useful in selected cases, are more difficult to handle in complex procedures due to lower back-up. RAO should be prevented during and after the procedure with systematic assessment of the arterial patency.57 Spasm prevention with 3–5 milligrams (mg) verapamil administered intra-arterially through the sheath is routinely recommended. Specific early and delayed post-procedural attention to forearm haematomas is mandatory.

Conclusion Considerable evidence supports conversion to TRA for most PCI procedures in ACS, with an emphasis on decreasing access site bleeding and vascular complications without compromising procedural outcome. Beside the development of new more selective and safe antithrombotic agents, the use of TRA remains likely the best way to significantly affect access site-related bleeding risk. A high-risk subset of patients for bleeding and vascular complications such as complex STEMI patients, women and the elderly, might particularly benefit from the TRA whenever appropriately available and performed by skilled operators. Complications arising from the TRA are infrequent, negligible and mostly avoidable compared with TFA complications. Certain limitations to the TRA such as longer radiation exposure during the learning curve and the potential influence on radial artery patency have slowed down acceptance of this technique. Therefore, the modern interventional cardiologist should go through a high-volume radial training programme, and after developing the optimal radial expertise, adopt ‘the TRA first’ whenever possible. Adding the ulnar artery access expertise could further reduce the crossover rate to TFA, and lower the intrinsic risk of bleeding and vascular complications associated with TFA. Femoral approach will likely remain the viable alternative for patients not eligible for the wrist access and accessory access for larger devices in patients with cardiogenic shock. Complex PCIs in patients with ACS, cardiogenic shock and left main culprit, should be performed only by experienced high-volume radialists. Finally, it is important to remember that the choice of access site is only one aspect of improving the patient’s outcome. All interventions should be performed according to the highest available standards, providing the best care for each individual patient without sacrificing procedural success and long-term prognosis. n

Mehta SR, Cannon CP, Fox KA, et al., Routine vs selective invasive strategies in patients with acute coronary syndromes: a collaborative meta-analysis of randomized trials, JAMA, 2005;293:2908–17.

Doyle BJ, Ting HH, Bell MR, et al., Major femoral bleeding complications after percutaneous coronary intervention: incidence, predictors, and impact on long-term survival among 17,901 patients treated at the Mayo Clinic from 1994

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transfemoral approach for coronary angiography and intervention in patients above 75 years of age, Catheter Cardiovasc Interv , 2008;72:629–35. Hochman JS, Sleeper LA, Webb JG, et al., Early revascularization in acute myocardial infarction complicated by cardiogenic shock. SHOCK Investigators. Should We Emergently Revascularize Occluded Coronaries for Cardiogenic Shock, N Engl J Med, 1999;341:625–34. Thiele H, Zeymer U, Neumann FJ, et al., Intraaortic balloon support for myocardial infarction with cardiogenic shock, N Engl J Med, 2012;367:1287–96. Mehta SK, Frutkin AD, Lindsey JB, et al., Bleeding in patients undergoing percutaneous coronary intervention: the development of a clinical risk algorithm from the National Cardiovascular Data Registry, Circ Cardiovasc Interv, 2009;2:222–9. Rodriguez-Leor O, Fernandez-Nofrerias E, Carrillo X, et al., Transradial percutaneous coronary intervention in cardiogenic shock: a single-center experience, Am Heart J, 2013;165:280–5. Bernat I, Abdelaal E, Plourde G, et al., Early and late outcomes after primary percutaneous coronary intervention by radial or femoral approach in patients presenting in acute ST-elevation myocardial infarction and cardiogenic shock, Am Heart J , 2013;165(3):338–43. Romagnoli E, De Vita M, Burzotta F, et al., TCT-31 Clinical Benefit of Radial Versus Femoral Approach in Percutaneous Coronary Intervention with Intra-Aortic Balloon Pump Support, J Am Coll Cardiol , 2012;60/17/Suppl B9–10. Goldberg S, Grossman W, Markis JE, et al., Total occlusion of the left main coronary artery. A clinical, hemodynamic and angiographic profile, Am J Med, 1978;64:3–8. Spiecker M, Erbel R, Rupprecht HJ, Meyer J, Emergency angioplasty of totally occluded left main coronary artery in acute myocardial infarction and unstable angina pectoris-institutional experience and literature review, Eur Heart J, 1994;15:602–7. de Feyter PJ, Serruys PW, Thrombolysis of acute total occlusion of the left main coronary artery in evolving myocardial infarction, Am J Cardiol, 1984;53:1727–8. Quigley RL, Milano CA, Smith LR, et al., Prognosis and management of anterolateral myocardial infarction in patients with severe left main disease and cardiogenic shock. The left main shock syndrome, Circulation, 1993;88:II65–70. Vis MM, Beijk MA, Grundeken MJ, et al., A systematic review and meta-analysis on primary percutaneous coronary intervention of an unprotected left main coronary artery culprit lesion in the setting of acute myocardial infarction, JACC Cardiovasc Interv, 2013;6:317–24. Basra SS, Loyalka P, Kar B, Current status of percutaneous ventricular assist devices for cardiogenic shock, Curr Opin Cardiol, 2011;26:548–54. Gilchrist IC, Rao SV, Improving outcomes in patients with cardiogenic shock. achieving more through less, Am Heart J, 2013;165(3):256–7. Kedev S, Zafirovska B, Dharma S, Petkoska D, Safety and feasibility of transulnar catheterization when ipsilateral radial access is not available, Catheter Cardiovasc Interv , 2013 [Epub ahead of print]. Hamon M, Pristipino C, Di Mario C, et al., Consensus document on the radial approach in percutaneous cardiovascular interventions: position paper by the EAPCI and Working Groups on Acute Cardiac Care and Thrombosis of the European Society of Cardiology, EuroIntervention, 2013;8:1242–51. Geijer H, Persliden J, Radiation exposure and patient experience during percutaneous coronary intervention using radial and femoral artery access, Eur Radiol, 2004;14:1674–80. Goldsmit A, Kiemeneij F, Gilchrist IC, et al., Radial artery spasm associated with transradial cardiovascular procedures: Results from the RAS registry, Catheter Cardiovasc Interv , 2013 [Epub ahead of print]. Pancholy SB, Patel TM, Effect of duration of hemostatic compression on radial artery occlusion after transradial access, Catheter Cardiovasc Interv, 2012;79:78–81.

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Coronary Interventions Bioresorbable Scaffolds

The Role of Bioresorbable Scaffolds in Meeting the Challenges of Bifurcations Ax el Sc h m e r m u n d a n d H o l g e r E g g e b r e c h t Cardioangiologisches Centrum Bethanien, Frankfurt, Germany

Abstract Side branches are frequently related to periprocedural complications. Considering any side branches >1 millimetres (mm), side branch occlusion or reduced flow may occur in approximately 10 % of interventional procedures. First data indicate that bioresorbable vascular scaffolds (BVS) behave similar compared with modern drug-eluting stents (DES) with regard to compromising or occluding sizeable side branches. Although technically more demanding compared with modern DES, it appears to be feasible to dilate side branches after crossing BVS cells. Preliminary data suggest at least balloon diameters up to 2.5 mm can be used, but safety remains unclear. Instead of kissing balloon dilatation, rather sequential balloon dilatation should be employed. Anecdotic evidence suggests BVS can be used even in relatively complex coronary anatomy, e.g. bifurcations distal to chronic total occlusion. Certainly more data are needed. As of today, BVS offer promise not only for the treatment of simple coronary lesions but also bifurcations. Given successful side branch protection, they might allow for restoring the native coronary anatomy in the sense of restitutio ad integrum.

Keywords Bioresorbable vascular scaffold, coronary bifurcation, side branch occlusion, periprocedural myocardial infarction Disclosure: The authors have no conflicts of interest to declare. Received: 28 August 2013 Accepted: 14 September 2013 Citation: Interventional Cardiology Review, 2013;8(2):87–9 Correspondence: Axel Schmermund, Cardioangiologisches Centrum Bethanien, Im Prüfling 23, D-60389, Frankfurt, Germany. E: A.Schmermund@ccb.de

It is estimated that 15–20 % of all coronary interventional procedures involve side branches.1 Side branches are frequently related to periprocedural complications. Side branch occlusion or compromise appears to be the underlying cause of approximately 30 % of periprocedural myocardial infarctions.2 Periprocedural infarction in turn is an important predictor of midterm mortality3. Considering any side branches >1 millimetres (mm), clinical studies including complex lesions in the modern drug-eluting stent (DES) era have demonstrated side branch occlusion or reduced flow in approximately 10 % of interventional procedures.2 The above noted does not comprise the left main bifurcation, which can also be regarded as a side branch anatomy. Significant left main disease is observed in 3–5 % of patients undergoing coronary angiography.4 Increasingly, interventional procedures are considered an alternative to surgical revascularisation in unprotected left main disease. As a result of the fast-evolving technical advances, it is impossible to obtain a durable appraisal of the interventional techniques compared with surgery. Yet, recent data suggest interventional left main procedures can markedly improve patient outcome compared with medical treatment.5 The Medina classification is used to describe the distribution of stenoses between main vessel and side branch in the bifurcation lesion.6 In short, a stenosis can affect the proximal portion of the main vessel (proximal to the side branch) or its distal portion, or it can affect the side branch itself. Combinations of either two of these locations are possible as well as stenoses in all three locations. For example, a lesion with stenoses pertaining to the proximal as well as the distal portion of the main vessel, but sparing the side branch, is classified as Medina (1,1,0).

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Contemporary Interventional Bifurcation Treatment Operators contemplating a bifurcation lesion intervention need to determine if the side branch in question is important and needs to be protected. This will in large part depend on its diameter. However, other factors also need to be considered such as the patient’s overall condition, whether there is diffuse coronary atherosclerosis or not, and which angulation of the side branch is encountered before and after rewiring. In general, side branches with a diameter ≥2 mm should be protected. Stent implantation in the main vessel may lead to side branch compromise or occlusion due to plaque shift or other mechanisms. Long-term results have been improved with the use of DES compared with bare metal stents (BMS).1 However, even in the DES era it may be very difficult to rewire the side branch once it has been occluded, in particular if the DES in the main branch has a diameter <3 mm and is not well-suited for a wire to re-cross the stent struts. Open-cell or helical stent design will generally allow for a better re-crossing profile compared with a closed-cell design.7 The predominant technique used for bifurcation interventions employs provisional side branch stenting.8,9 The main branch is treated by implantation of a DES. The side branch is rewired (through the stent struts of the DES) and dilatation with a non-compliant balloon is performed. Side branch stent implantation only follows if deemed necessary due to dissection, plaque shift or other forms of severe side branch compromise. The geometry of the main vessel stent is protected either by a kissing balloon approach or by balloon inflation in the main branch after completion of side branch treatment. If a second stent needs to be implanted in the side branch, final kissing balloon inflation is usually performed.9 These basic principles are

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The Role of Bioresorbable Scaffolds in Meeting the Challenges of Bifurcations

An important question relates to the necessity of performing side branch dilatation. Will this be needed in a sizeable number of BVS interventions? A recent analysis from the ABSORB-EXTEND (A Continuation in the Clinical Evaluation of the ABSORB Bioresorbable Vascular Scaffold [BVS] System in the Treatment of Subjects With de Novo Native Coronary Artery Lesions) single-arm trial compared the rate of side branch occlusion in 435 patients treated by using BVS implantation to a historic control group of 237 patients with DES (Abbott XIENCE® V) implantation in the SPIRIT first and SPIRIT II (A Clinical Evaluation of the XIENCE V® Everolimus Eluting Coronary Stent System in the Treatment of Patients With de Novo Native Coronary Artery Lesions) trials.19 The angiographic analysis documented a mean of 2.8 side branches in the BVS group and 2.9 in the DES group. Side branch occlusion occurred in 6.0 % in the BVS group and in 4.1 % in the DES group (p=0.09). The incidence of side branch occlusion appeared to depend on side branch vessel diameter. Whereas occlusion was clearly more frequent in small side branches with an angiographic diameter ≤0.5 mm, no statistic difference was observed in larger side branches (see Figure 4).19 These data suggest that with regard to important side branches, the occlusion rates are similar between BVS and modern DES, and the necessity to perform a bifurcation procedure should be comparable.

Conclusion In summary, first data indicate that BVS behave similar compared with modern DES with regard to compromising or occluding side branches >0.5 mm. Smaller side branches might be compromised more often by BVS implantation compared with DES. It appears to be feasible to dilate side branches after crossing BVS cells, even though it may be technically more demanding compared with bifurcation procedures using solely DES. The safety of side branch dilatations remains open, but preliminary data suggest at least balloon diameters up to 2.5 mm can be used. Instead of kissing balloon dilatation, rather sequential balloon dilatation should be employed. It remains to be seen if BVS will also allow for treatment of rather complex bifurcation lesions. To our knowledge, no reports have

1. 2.

6. 7.

Iakovou I, Ge L, Colombo A, Contemporary stent treatment of coronary bifurcations, J Am Coll Cardiol , 2005;46:1446–55. Popma JJ, Mauri L, O’Shaughnessy C, et al., Frequency and clinical consequences associated with sidebranch occlusion during stent implantation using zotarolimus-eluting and paclitaxel-eluting coronary stents, Circ Cardiovasc Interv, 2009;2:133–9. Kini AS, Lee P, Marmur JD, et al., Correlation of postpercutaneous coronary intervention creatine kinase-MB and troponin I elevation in predicting mid-term mortality, Am J Cardiol , 2004;93:18–23. El-Menyar AA, Al Suwaidi J, Holmes DR Jr, Left main coronary artery stenosis: state-of-the-art, Curr Probl Cardiol, 2007;32:103–93. Bittl JA, He Y, Jacobs AK, et al., Bayesian methods affirm the use of percutaneous coronary intervention to improve survival in patients with unprotected left main coronary artery disease, Circulation, 2013;127:2177–85. Medina A, Suárez de Lezo J, Pan M, A new classification of coronary bifurcation lesions, Rev Esp Cardiol, 2006;59:183. Ormiston JA, Webster MW, El Jack S, et al., Drug-eluting stents for coronary bifurcations: bench testing of provisional side-branch strategies, Catheter Cardiovasc Interv, 2006;67:49–55.

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10.

11.

12.

13.

Figure 3: Bioresorbable Vascular Scaffold After 2.5 mm Side Branch Dilatation with Sequential Main Vessel Post-dilatation

Abbreviation as in Figure 1. Picture courtesy of Abbott Vascular.

Figure 4: Incidence of Post-procedural Side Branch Occlusion Stratified by Reference Diameter of Side Branches Incidence of post-procedural side branch occlusion (%)

has been rewired, crossing the BVS cells with a balloon appears to be rather simple. However, it is currently unclear up to what size balloons can be inflated without disrupting the cells of the BVS or impacting its radial strength. Certainly, there is a risk that kissing balloon inflation will damage the main vessel BVS, and it should probably be avoided. If deemed absolutely necessary, moderate balloon sizing and inflation pressures should be chosen. Preferentially, if yearning to protect the BVS from malapposition, sequential balloon inflation should be performed first in the side branch and then in the main vessel (see Figures 1–3).

p for interaction=0.08

BVS

p=0.36

p=0.03

EES 10.5 9.5

7.3 p=0.61 5

3.9 1.7

2.2

(N=276) (N=102)

(N=357) (N=218)

(N=576) (N=362)

RVD≤0.5 mm

0.5<RVD≤1.0 mm

RVD>1.0 mm

Whereas BVS implantation compared with DES implantation is associated with more side branch occlusion in side branches with a small diameter, there is no difference in side branches with a diameter >1.0 mm. BVS = bioresorbable vascular scaffold; DES = drugeluting stent; EES = Everolimus-eluting stent; RVD = reference vessel diameter. Source: Reproduced with permission from Muramatsu, et al.19

so far been published related to BVS left main interventions. Certainly, more data are needed. As of today, BVS offer promise not only for the treatment of simple coronary lesions but also bifurcations. Given successful side branch protection, they might allow for restoring the native coronary anatomy in the sense of restitutio ad integrum. n

Niemelä M, Kervinen K, Erglis A, et al., Randomized comparison of final kissing balloon dilatation versus no final kissing balloon dilatation in patients with coronary bifurcation lesions treated with main vessel stenting: The Nordic-Baltic Bifurcation Study III, Circulation, 2011;123:79–86. Zimarino M, Corazzini A, Ricci F, et al., Late Thrombosis After Double Versus Single Drug-Eluting Stent in the Treatment of Coronary Bifurcations: A Meta-Analysis of Randomized and Observational Studies, JACC Cardiovasc Interv, 2013;6:687–95. Morino Y, Yamamoto H, Mitsudo K, et al., Functional formula to determine adequate balloon diameter of simultaneous kissing balloon technique for treatment of bifurcated coronary lesions: clinical validation by volumetric intravascular ultrasound analysis, Circ J, 2008;72:886–92. Serruys PW, Garcia-Garcia HM, Onuma Y, From metallic cages to transient bioresorbable scaffolds: change in paradigm of coronary revascularization in the upcoming decade?, Eur Heart J, 2012;33:16–25. Serruys PW, Ormiston JA, Onuma Y, et al., A bioabsorbable everolimus-eluting coronary stent system (ABSORB): 2-year outcomes and results from multiple imaging methods, Lancet, 2009;373:897–910. Okamura T, Serruys PW, Regar E, Cardiovascular flashlight. The fate of bioresorbable struts located at a side

14.

15. 16. 17.

18.

19.

branchostium: serial three-dimensional optical coherence tomography assessment, Eur Heart J , 2010;31:2179. Gutiérrez-Chico JL, Gijsen F, Regar E, et al., Differences in neointimal thickness between the adluminal and the abluminal sides of malapposed and side-branch struts in a polylactide bioresorbable scaffold: evidence in vivo about the abluminal healing process, JACC Cardiovasc Interv, 2012;5:428–35. van Geuns RJ, BVS Summit Berlin, Sept 21, 2013. Smits P, PCR focus group, March 8, 2013. Gogas BD, van Geuns RJ, Farooq V, et al., Three-dimensional reconstruction of the post-dilated ABSORB everolimus-eluting bioresorbable vascular scaffold in a true bifurcation lesion for flow restoration, JACC Cardiovasc Interv, 2011;4:1149–50. Naganuma T, Basavarajaiah S, Latib A, et al., Use of BVS in a chronic total occlusion with bifurcation lesion, Int J Cardiol , 2013;167:e129–31. Muramatsu T, Onuma Y, García-García HM, et al., Incidence and short-term clinical outcomes of small side branch occlusion after implantation of an everolimus-eluting bioresorbable vascular scaffold: an interim report of 435 patients in the ABSORB-EXTEND single-arm trial in comparison with an everolimus-eluting metallic stent in the SPIRIT first and II trials, JACC Cardiovasc Interv, 2013;6:247–57.

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Coronary Interventions Bioresorbable Scaffolds

How to Select the Most Appropriate Patient and Lesion to be Treated with a Coronary Bioresorbable Vascular Scaffold C ha ris C ostopoul o s, 1, 2, 3 A z e e m L a t i b 1, 2 a n d A n t o n i o Co l o m b o 1, 2 1. Interventional Cardiology Unit, San Raffaele Scientific Institute, Milan, Italy; 2. Interventional Cardiology Unit, EMO GVM Centro Cuore Columbus, Milan, Italy; 3. Department of Cardiology, Imperial College University, London, UK

Abstract Bioresorbable vascular scaffolds (BVS) are an exciting novel treatment for coronary artery disease (CAD) as their eventual resorption renders the artery free from a permanent metallic cage. Clinical trials regarding these novel devices have demonstrated promising results, although their use in this context has largely been restricted to simple lesions. More recently, BVS use has expanded to patients with more complex lesions including those with long diffuse disease, and results from several registries are awaited with regard to their efficacy in ‘real-world’ patients. Although any patient who requires percutaneous treatment for CAD could benefit from BVS implantation, there are certain cohorts of patients and lesions in whom BVS could be of particular benefit. In this review, we attempt to identify which patient and lesion cohort is most suitable for treatment with these novel devices.

Keywords Bioresorbable vascular scaffold, target lesion revascularisation, major adverse cardiac events Disclosure: The authors have no conflicts of interest to declare. Received: 5 August 2013 Accepted: 18 August 2013 Citation: Interventional Cardiology Review, 2013;8(2):90–2 Correspondence: Antonio Colombo, EMO GVM Centro Cuore Columbus, 48 Via M. Buonarroti, 20145 Milan, Italy. E: info@emocolumbus.it

Although the introduction of metallic stents has revolutionised the percutaneous treatment of coronary artery disease (CAD) and has been demonstrated to improve clinical outcomes as compared with plain old balloon angioplasty (POBA), the permanent presence of a metallic cage that stays on the vessel wall beyond its intended purpose of preventing acute recoil, is associated with a number of drawbacks. The recent introduction of bioresorbable vascular scaffolds (BVS) offers the potential of dealing with these drawbacks as these devices allow positive remodelling and restoration of normal vasomotor vessel function.1,2 They also offer the potential of reducing restenosis and stent thrombosis rates because they tend to be more biocompatible as compared with conventional metallic drug-eluting stents (DES), whilst also maintaining access for coronary bypass grafting in the future if required. Until recently, the use of BVS has largely been in the context of clinical trials, but an increasing number of ‘real-world’ patients are being treated with these scaffolds. Despite the fact that most, if not all, patients can be treated with these devices, it is clear that certain patient cohorts have more to gain than others from BVS use, especially if these innovative devices fulfil their expected potential. In view of their higher cost and challenges in implantation technique as compared with conventional DES, the selective use of BVS is appropriate especially in the current climate.

Bioresorbable Vascular Scaffolds Available for Clinical Use Recent years have seen a huge expansion in the development of BVS many of which are undergoing preclinical or clinical assessment. One of these, the ABSORB™ BVS (Abbott Vascular, Santa Clara, California, US) is currently available with the DESolve™ BVS (Elixir Medical,

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Sunnyvale, California, US) being available for clinical use later in the year. The ABSORB BVS is made from semicrystalline poly-L-lactic acid (PLLA) coated with an amorphous poly-D, L-lactide (PDLA) polymer eluting everolimus. Degradation of the scaffold is mainly through hydrolysis, a process that takes approximately two years to complete. The efficacy of the currently used ABSORB BVS (revision 1.1) has been assessed in the multicentre, single-arm ABSORB Cohort B trial, which recruited 101 patients with single- or two-vessel de novo disease, all of which received a 3 x 18 millimetre (mm) BVS. Patients were divided into two groups for follow-up purposes with group 1 being assessed at six months and two years and group 2 at one and three years, respectively. Scaffold area was shown to progressively increase during follow-up with no differences in late lumen loss (LLL) (0.29 ± 0.16 mm versus 0.25 ± 0.22 mm, p=0.439) being noted between small vessels (<2.5 mm) and large vessels (≥2.5 mm) at two-year angiographic follow-up.3 At 18 months follow-up in the entire cohort, there were three non-ST elevation myocardial infarctions (MIs) and four ischaemia-driven target lesion revascularisations (TLR).4 In the ABSORB EXTEND study, aiming to recruit 1,000 patients, in which the recruitment of patients with disease in smaller vessels (>2.0 mm) as well as those with long lesions is allowed, the ischaemia-driven TLR and major adverse cardiac events (MACE) rates at one-year has been reported as 1.8 and 4.2 %, respectively. Definite/probable stent thrombosis (ST) rate was 0.9 %.5 Data from the treatment of real-world patients is also emerging. In the prospective, single-centre, BVS Expand registry in which the liberal use of BVS is permitted with the exception of patients with ST-elevation MI (STEMI) and restenotic lesions, the use of BVS was associated with one MI and one non-target vessel revascularisation (TVR) at 30-day follow-up in a cohort of

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Coronary Interventions Bioresorbable Scaffolds Young patients are also attractive candidates for BVS for exactly the same reasons as mentioned above. Patients that require a dedicated two-stent technique for the treatment of a coronary bifurcation may also fare better with a BVS especially when a mini-crush or T-stenting technique is undertaken (see Figure 2). It is important when considering BVS for this indication to ensure that the side branch diameter is ≥2.5 mm as this is the smallest BVS available, and that the main branch can accommodate ≈450 µm of struts on the other side of the carina, which will result after a mini-crush technique. Although BVS use in this setting can be slightly challenging, it can be achieved by ensuring adequate predilatation with a balloon of the same diameter as the BVS intended to be implanted. This applies for any lesion to be treated with BVS as it helps to ensure complete BVS expansion. The advantage of using BVS for a dedicated two-stent strategy is that the ‘congestion’ of struts after a mini-crush technique is undertaken stops being an issue as the scaffold undergoes hydrolysis. It is important to note here that we do not advocate the use of a ‘culotte’ technique with BVS as these result in relatively long segments of BVS overlap. Although BVS can be used for most lesions, there are certain occasions that these should be avoided or at least used with caution. However, this does not include patients with heavily calcified lesions, as currently available tools such as rotational atherectomy, scoring, cutting and ultra-high pressure balloons can ensure that a calcified lesion is well-prepared for BVS implantation. This is a principle that applies also to conventional DES. In our experience, excellent results can be obtained with BVS in such lesions when meticulous lesion preparation as well as post-dilatation have been performed. Occasions where BVS use may not be appropriate includes the treatment of lesions where vessel diameter is <2.5 mm not only because a 2.25 mm BVS is not available but also

Serruys PW, Onuma Y, Dudek D, et al., Evaluation of the second generation of a bioresorbable everolimus-eluting vascular scaffold for the treatment of de novo coronary artery stenosis: 12-month clinical and imaging outcomes, J Am Coll Cardiol , 2011;58:1578–88. Haude M, Progress with Drug-Eluting Magnesium Resorbing Stents (BIOTRONIK Dreams Program): DREAMS 2-Year Results, Presented at: Transcatheter Cardiovascular Therapeutics (TCT) Conference, Miami, FL, US, 15 October 2012. Diletti R, Farooq V, Girasis C, et al., Clinical and intravascular imaging outcomes at 1 and 2 years after implantation of absorb everolimus eluting bioresorbable

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because the thicker struts of currently available devices may lead to significant lumen reductions. They should also not be used when vessel diameter is >4.0 mm as the largest available BVS is 3.5 mm and the maximum recommended balloon diameter that can be used for this is 4.0 mm (0.5 mm tolerance). In our opinion, they should also be used with caution in STEMI until evidence with regards to BVS use in this context becomes available. Finally, although the use of BVS can theoretically allow shorter periods of dual-antiplatelet therapy (DAPT) due to the inherent biocompatibility of the device, it is not yet known whether this is possible or not. Thus, for patients in whom a DES is required and DAPT cannot be given for more than six months it is perhaps judicious to use a second generation metallic DES for which a shorter DAPT period is possible such as the XIENCE PRIME or XIENCE V® (Abbott Vascular, Santa Clara, California, US) or the Endeavor Resolute (Medtronic, Santa Rosa, California, US).

Conclusion BVS have the potential of revolutionising the percutaneous treatment of CAD as their greater biocompatibility and eventual resorption offer the possibility of further improving clinical outcomes whilst maintaining the future option of further revascularisation if necessary. In our experience, BVS can be used in a wide-range of lesions with good procedural and early outcome results. Patients that may especially benefit from this technology include those with multivessel disease, diffusely diseased vessels, bifurcation lesions and those of younger age. They should, however, be avoided in patients with too large (>4.0 mm) or too small (<2.5 mm) vessels for currently available devices. They should also be used with caution in patients with STEMI and in those that may require shorter DAPT durations until further evidence becomes available. n

vascular scaffolds in small vessels. Late lumen enlargement: does bioresorption matter with small vessel size? Insight from the ABSORB cohort B trial, Heart, 2013;99:98–105. Serruys PW, Onuma Y, on behalf of the ABSORB A & B investigators, ABSORB Cohort B: 6 m, 12 m, 18 m and 24 m follow-up, Presented at: PCR focus group on bioresorbable vascular scaffolds, Rotterdam NL, The Netherlands, 8–9 March 2012. Serruys PW, BVS Extend: An Interim Report on the 12-Month Clinical Outcomes from the First 450 Patients Registered, Presented at: EuroPCR, Paris, France, 21–24 May 2013.

Van Geuns R, BVS Expand: First result of wide clinical applications of Bioresorbable Vascular Scaffold, Presented at: EuroPCR, Paris, France, 21–24 May 2013. Dudek D, Rzeszutko A, Lekston A, et al., Bioresorbable Vascular Scaffolds (BVS) in Patients with Acute Coronary Syndrome. The Muticenter Registry in Poland: POLAR ACS, Presented at: EuroPCR, Paris, France, 21–24 May 2013. Widimsky P, Bioresorbable vascular scaffolds in acute STEMI: Prague-19 study, Presented at: EuroPCR, Paris, France, 21–24 May 2013. Abizaid A, First report on the Pivotal DESolve Nx trial, Presented at: EuroPCR, Paris, France, 21–24 May 2013.

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Coronary Interventions Bioresorbable Scaffolds

Personal Experience with Bioresorbable Scaffolds in Bifurcations R oberto D i l e t t i a n d N i c o l a s M Va n M i e g h e m Department of Interventional Cardiology, Thoraxcenter, Erasmus Medical Center, Rotterdam, The Netherlands

Abstract Bioresorbable scaffolds represent a promising new technology in the field of percutaneous coronary interventions. The concept of the eventual resorption of the scaffold pertains to multiple theoretical advantages that may hold true particularly in bifurcation lesions – no permanent caging of the coronary artery, avoidance of acquired device malapposition and delayed hypersensitivity reactions, no permanent metallic stent protrusion in the main branch, etc. The worldwide experience with the use of bioresorbable scaffolds is limited. In our experience of selected bifurcation lesions, a provisional approach using one-scaffold has excellent results. Two-scaffold techniques appeared feasible. Our data support the exploration of the use of bioresorbable scaffolds in more challenging coronary substrates like bifurcations. Prospective registries and ideally randomised trials should assess whether the theoretical benefits of bioresorbable vascular scaffolds (BVS) in bifurcation lesions can produce sustainable good clinical outcomes.

Keywords Bioresorbable scaffolds, percutaneous coronary interventions, bifurcation lesions Disclosure: The authors have no conflicts of interest to declare. Received: 19 August 2013 Accepted: 2 September 2013 Citation: Interventional Cardiology Review, 2013;8(2):93–5 Correspondence: Nicolas M Van Mieghem, Department of Interventional Cardiology, Thoraxcenter, Erasmus Medical Center, Room Bd 171, ‘s Gravendijkwal 230 3015 CE Rotterdam, The Netherlands. E: n.vanmieghem@erasmusmc.nl

Since Andreas Gruentzig presented his pioneering work in 1977, ‘three revolutions’ in percutaneous coronary interventions (PCI) have characterised the field of interventional cardiology. Plain old balloon angioplasty (POBA) was refined by the introduction of bare metal stenting (BMS) (second revolution) to address the issue of acute vessel recoil and unacceptably high rates of restenosis. Drug-eluting stents (DES) (third revolution) further decimated the burden of target vessel revascularisation into the low single-digit figures. The bioresorbable scaffold technology such as the Absorb™ Bioresorbable Vascular Scaffold (Absorb BVS, Abbott Vascular, Santa Clara, California, US) may represent the fourth revolution in PCI as the implanted scaffolds provide transient vessel support and drug delivery, which is followed by substantial polymer degradation at two-years post-implantation, with a complete disappearance of the BVS strut ‘footprint’ in the vessel wall within a four year period.1 This concept precludes permanent caging of the coronary artery, may avoid persistent or acquired device malapposition and delayed hypersensitivity reactions to contemporary stent platforms and/ or drug polymers, which may solve the smouldering yet clinically devastating problem of late stent thrombosis.2

with both increased atherogenesis and restenosis at the ostium of the side branch but also delayed vascular healing and incomplete neointimal coverage making the side branch more vulnerable to (very) late stent thrombosis.12–15

Flow-limiting atherosclerotic disease at bifurcations of coronary arteries, remain a challenging substrate for PCI. POBA in bifurcations was characterised by a relatively low success rate and a high incidence of restenosis.3,4 BMS improved acute procedural success yet was still associated with reserved long-term clinical outcomes irrespective of the applied stenting technique.5–11

On the 1st September 2012, the BVS was commercially launched in the Netherlands. The Erasmus Medical Center immediately started with the BVS Expand Registry to prospectively follow up procedural and clinical data in a wider pallet of coronary lesions including bifurcations, chronic total occlusions and calcified lesions.16,19

Even in the DES era overall long-term clinical results in bifurcations seem suboptimal. The pathophysiology may appear paradoxical

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Bioresorbable vascular scaffolds (BVS) may be interesting in bifurcation lesions as it precludes permanent side branch jailing after complete scaffold bioresorption. Okamura et al. recently described serially the appearance of a coronary artery side branch ostium after BVS implantation in the main vessel. At six-months the BVS struts were overhanging the side branch ostium but at two-year follow-up the struts proximal to the side branch were fully incorporated into the vessel wall and the struts located distally were replaced by a smooth membranous neocarina.

Current Experience with Bioresorbable Vascular Scaffold in Bifurcation Lesions BVS has been intensely investigated in two cohort studies (ABSORB Cohort A and B) enrolling patients with relatively simple coronary lesion complexity.16–18

Analogous to the mainstream bifurcation stenting paradigm, the provisional one-scaffold technique is considered the approach of first choice. One scaffold is implanted in the main vessel followed, if necessary,

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Personal Experience with Bioresorbable Scaffolds in Bifurcations

Figure 3: Treatment of a Diagonal Branch (D) Acutely Occluded at the Ostium

In order to have optimal ostial coverage, the bioresorbable vascular scaffold (BVS) is placed with some struts protruding into the left anterior descending (LAD). The use of BVS provides the advantage of the future resorption of the protruded segment. LAD = left anterior descending.

In a variable percentage (up to 30 %) of cases treated with a provisional approach a cross-over to a two-stent technique is required. The T-stenting and small protrusion (TAP) approach26,27 is a relatively new technique, ensuring complete coverage of the side branch ostium minimising stent overlap. Technically, the TAP technique is less challenging compared with reverse culotte and reverse crush, and is feasible in a variation of bifurcation angulations (at variance of reverse T-stenting that can only be optimally performed in bifurcations with 90° angulation). TAP technique may be challenging with BVS as re-crossing and dilatation of scaffold struts into the side branch are necessary. A potential disadvantage of the TAP technique is the presence of struts protruding into the main vessel lumen that occasionally impair laminar blood flow in the main vessel. Interestingly, in this setting, BVS may have the unique advantage of a complete coverage of the side branch ostium with an eventual complete disappearing of the protruding struts over time. 1.

Onuma Y, Serruys PW, Perkins LE, et al., Intracoronary optical coherence tomography and histology at 1 month and 2, 3, and 4 years after implantation of everolimus-eluting bioresorbable vascular scaffolds in a porcine coronary artery model: an attempt to decipher the human optical coherence tomography images in the ABSORB trial, Circulation, 2010;122(22):2288–300. 2. Serruys PW, Garcia-Garcia HM, Onuma Y, From metallic cages to transient bioresorbable scaffolds: change in paradigm of coronary revascularization in the upcoming decade?, Eur Heart J, 2012;33(1):16–25b. 3. George BS, Myler RK, Stertzer SH, et al., Balloon angioplasty of coronary bifurcation lesions: the kissing balloon technique, Cathet Cardiovasc Diagn, 1986;12(2):124–38. 4. Pinkerton CA, Slack JD, Van Tassel JW, Orr CM, Angioplasty for dilatation of complex coronary artery bifurcation stenoses, Am J Cardiol, 1985;55(13 Pt 1):1626–8. 5. Colombo A, Al-Lamee R, Bifurcation lesions: an inside view, Circ Cardiovasc Interv, 2010;3(2):94–6. 6. Yamashita T, Nishida T, Adamian MG, et al., Bifurcation lesions: two stents versus one stent--immediate and follow-up results, J Am Coll Cardiol, 2000;35(5):1145–51. 7. Lefèvre T, Louvard Y, Morice MC, et al., Stenting of bifurcation lesions: classification, treatments, and results, Catheter Cardiovasc Interv, 2000;49(3):274–83. 8. Sheiban I, Albiero R, Marsico F, et al., Immediate and long-term results of “T” stenting for bifurcation coronary lesions, Am J Cardiol, 2000;85(9):1141–4, A9. 9. Karvouni E, Di Mario C, Nishida T, et al., Directional atherectomy prior to stenting in bifurcation lesions: a matched comparison study with stenting alone, Catheter Cardiovasc Interv, 2001;53(1):12–20. 10. Al Suwaidi J, Berger PB, Rihal CS, et al., Immediate and longterm outcome of intracoronary stent implantation for true bifurcation lesions, J Am Coll Cardiol, 2000;35(4):929–36.

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Finally, in ostial lesions (e.g. aorto-ostial, ostium left anterior descending lesions, ostium circumflex lesions and bifurcations medina 0,0,1) BVS can be an interesting product as complete ostium coverage can be achieved with only temporary strut protrusion into the aorta or main vessel (see Figure 3).

Conclusion Bioresorbable vascular scaffolds may represent the fourth revolution in PCI. In particular coronary subsets BVS may represent a paradigm shift. So far, published data on BVS use in bifurcations is scarce. Our personal experience with a provisional approach as first choice shows favourable procedural and acute clinical success creating a window of opportunities to expand the use of BVS towards more challenging coronary substrates. Prospective registries and ideally randomised trials should assess whether the theoretical benefits of BVS in bifurcation lesions can produce sustainable good clinical outcomes. n

11. Thuesen L, Kelbaek H, Kløvgaard L, et al., Comparison of sirolimus-eluting and bare metal stents in coronary bifurcation lesions: subgroup analysis of the Stenting Coronary Arteries in Non-Stress/Benestent Disease Trial (SCANDSTENT), Am Heart J, 2006;152(6):1140–5. 12. Colombo A, Moses JW, Morice MC, et al., Randomized study to evaluate sirolimus-eluting stents implanted at coronary bifurcation lesions, Circulation, 2004;109(10):1244–9. 13. Tanabe K, Hoye A, Lemos PA, et al., Restenosis rates following bifurcation stenting with sirolimus-eluting stents for de novo narrowings, Am J Cardiol, 2004;94(1):115–8. 14. Pan M, de Lezo JS, Medina A, et al., Rapamycin-eluting stents for the treatment of bifurcated coronary lesions: a randomized comparison of a simple versus complex strategy, Am Heart J, 2004;148(5):857–64. 15. Iakovou I, Schmidt T, Bonizzoni E, et al., Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents, JAMA, 2005;293(17):2126–30. 16. Serruys PW, Onuma Y, Ormiston JA, et al., Evaluation of the second generation of a bioresorbable everolimus drugeluting vascular scaffold for treatment of de novo coronary artery stenosis: six-month clinical and imaging outcomes, Circulation, 2010;122(22):2301–12. 17. Gomez-Lara J, Brugaletta S, Diletti R, et al., A comparative assessment by optical coherence tomography of the performance of the first and second generation of the everolimus-eluting bioresorbable vascular scaffolds, Eur Heart J, 2011;32(3):294–304. 18. Serruys PW, Onuma Y, Dudek D, et al., Evaluation of the second generation of a bioresorbable everolimus-eluting vascular scaffold for the treatment of de novo coronary artery stenosis: 12-month clinical and imaging outcomes, J Am Coll Cardiol, 2011;58(15):1578–88. 19. Ormiston JA, Serruys PW, Regar E, et al., A bioabsorbable everolimus-eluting coronary stent system for patients

20.

21.

22.

23.

24. 25. 26.

27.

with single de-novo coronary artery lesions (ABSORB): a prospective open-label trial, Lancet, 2008;371(9616):899–907. Okamura T, Onuma Y, Garcia-Garcia HM, et al., 3-Dimensional optical coherence tomography assessment of jailed side branches by bioresorbable vascular scaffolds: a proposal for classification, JACC Cardiovasc Interv, 2010;3(8):836–44. van Geuns RJ, Gogas BD, Farooq V, et al., 3-Dimensional reconstruction of a bifurcation lesion with double wire after implantation of a second generation everolimus-eluting bioresorbable vascular scaffold, Int J Cardiol, 2011;153(2):e43–5. Gogas BD, van Geuns RJ, Farooq V, et al., Three-dimensional reconstruction of the post-dilated ABSORB everolimus-eluting bioresorbable vascular scaffold in a true bifurcation lesion for flow restoration, JACC Cardiovasc Interv, 2011;4(10):1149–50. Adriaenssens T, Byrne RA, Dibra A, et al., Culotte stenting technique in coronary bifurcation disease: angiographic follow-up using dedicated quantitative coronary angiographic analysis and 12-month clinical outcomes, Eur Heart J, 2008;29(23):2868–76. Ruzsa Z, van der Linden M, Van Mieghem NM, et al., Culotte stenting with bioabsorbable everolimus-eluting stents, Int J Cardiol, 2013 [Epub ahead of print]. Iakovou I, Ge L, Colombo A, Contemporary stent treatment of coronary bifurcations, J Am Coll Cardiol, 2005;46(8):1446–55. Burzotta F, Gwon HC, Hahn JY, et al., Modified T-stenting with intentional protrusion of the side-branch stent within the main vessel stent to ensure ostial coverage and facilitate final kissing balloon: the T-stenting and small protrusion technique (TAP-stenting). Report of bench testing and first clinical Italian-Korean two-centre experience, Catheter Cardiovasc Interv, 2007;70(1):75–82. Naganuma T, Latib A, Basavarajaiah S, et al., The long-term clinical outcome of T-stenting and small protrusion technique for coronary bifurcation lesions, JACC Cardiovasc Interv, 2013;6(6):554–61.

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are. eclare.

Coronary Interventions Bifurcations

Technical Aspects of Provisional Stenting in Percutaneous Treatment of Complex Bifurcation Lesions Fra n c e s c o B u r z o t t a a n d Ca r l o Tra n i Institute of Cardiology, Catholic University of the Sacred Heart, Rome, Italy

Abstract Drug-eluting stent (DES) implantation using the ‘provisional’ approach is the gold standard for percutaneous treatment of patients with unselected bifurcated lesions. Nevertheless, many operators still consider the provisional approach unsuitable for coronary patients with complex bifurcation anatomies. Yet, the provisional approach may be so differently carried out that its procedural outcome is often unpredictable. Some technical refinements may help to anticipate or manage procedural difficulties, which may occur during the management of complex patients. We sought to overview the issues related with DES selection as well as some technical points, which may increase the effectiveness of provisional stenting. In particular, the DES characteristics influencing bifurcation interventions and the technical refinements, which may be considered during a provisional stenting procedure are discussed. Indeed, main vessel stent sizing, proximal optimisation, side branch protection modality, side branch rewiring, kissing balloon and side branch rescue techniques are all pivotal to increase the safety and efficacy of the provisional strategy especially in the setting of complex anatomies and patients.

Keywords Percutaneous coronary interventions, bifurcated lesions, stent Disclosure: Francesco Burzotta has been involved in advisory board meetings for Medtronic. Carlo Trani has no conflicts of interest to declare. Received: 29 August 2013 Accepted: 5 September 2013 Citation: Interventional Cardiology Review, 2013;8(2):96–9 Correspondence: Francesco Burzotta, Department of Cardiovascular Sciences, Catholic University of the Sacred Heart, 00168 Rome, Italy. E: f.burzotta@rm.unicatt.it

Diseased coronary bifurcations are frequently treated by percutaneous coronary interventions (PCI), and in these complex lesions the adoption of the most suitable treatment technique and the selection of the most appropriate coronary stent are of primary importance. Clinical evidence suggests that drug-eluting stent (DES) implantation using a provisional approach is the gold standard for unselected bifurcated lesions.1,2 In particular, an accumulated body of evidence shows that the systematic adoption of ‘complex’ techniques with intentional implantation of DES in both main vessel (MV) and side branch (SB) is associated with worse clinical results compared with the provisional approach.3,4 Of note, the double stenting techniques do not appear to be beneficial even in the more challenging anatomies.3 On the other hand, a series of technical issues (DES selection and sequence of procedural steps) may greatly influence the results of provisional stenting and its suitability for complex bifurcation anatomies. In this manuscript we sought to overview the tips and tricks useful to manage coronary bifurcated lesions by systematic ‘provisional’ stenting.

Approaching the Bifurcation – Branch Wiring and Lesion Preparation The provisional SB stenting approach is an ‘A technique’ (A for across the SB) of the Main, Across, Distal, Side (MADS) classification5 adopted by the European Bifurcation Club (EBC) in 2007. A 6 French size (Fr) guide catheter is generally appropriate and this increases the overall safety of the procedure since the radial approach may liberally be practised and large sheaths may not be needed. As a first step in a bifurcation PCI, it is usually advisable to wire both branches, MV

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and SB, with two 0.014” coronary guidewires. Details regarding the wiring techniques for complex bifurcated lesions have been recently summarised by our group.6 According to our experience, the practice of wiring the more complex branch first and keeping the two wires separated over the operative table by a simple sterile drape sheet minimises the risk of wire twisting (see Figure 1). After wiring, the MV is pre-dilated if required (according to operator’s preference or after the direct stenting failure). Regarding the SB preparation, there is a general consensus that SB dilation before MV stenting should be avoided in most of the cases since balloon dilation may cause SB dissections, which may cause an obstacle during subsequent rewiring. However, this concept has been recently challenged by the results of a randomised trial by Pan and colleagues7 showing improved result after MV stenting in patients with SB ostial disease randomised to SB pre-dilation versus no pre-dilation. Thus, in case of true bifurcations with critical stenosis of a relevant SB, preventive SB dilation should probably be considered (with liberal use of non-compliant balloons). Some authors may recommend the use of scoring balloons or debulking devices in the case of (fibro)calcific SB ostial disease.

Issues Related with Stent Implantation in the Main Vessel After wiring both branches and pre-dilation, when appropriate, the stent is deployed in the MV across the SB. As a first point, it must be emphasised that with the systematic provisional approach, careful evaluation of the ‘operative’ MV axis is mandatory. Indeed,

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Provisional Stenting Tricks

branches, Circ Cardiovasc Interv, 2012;5(5):657–62. 10. Stankovic G, Darremont O, Ferenc M, et al., Percutaneous coronary intervention for bifurcation lesions: 2008 consensus document from the fourth meeting of the European Bifurcation Club, EuroIntervention , 2009;5(1):39–49. 11. Foin N, Sen S, Allegria E, et al., Maximal expansion capacity with current DES platforms: a critical factor for stent selection in the treatment of left main bifurcations?, EuroIntervention, 2013;8(11):1315–25. 12. Basalus MW, van Houwelingen KG, Ankone MJ, et al., Microcomputed tomographic assessment following extremely oversized partial postdilatation of drug-eluting stents, EuroIntervention, 2010;6:141–8. 13. Vassilev D, Gil RJ, Koo BK, et al., The determinants of side branch compromise after main vessel stenting in coronary bifurcation lesions, Kardiol Pol , 2012;70(10):989–97. 14. Brunel P, Lefevre T, Darremont O, Louvard Y, Provisional T-stenting and kissing balloon in the treatment of coronary bifurcation lesions: results of the French multicenter “TULIPE” study, Catheter Cardiovasc Interv , 2006;68(1):67–73. 15. Burzotta F, Trani C, Sianos G, Jailed balloon protection: a new technique to avoid acute side-branch occlusion during provisional stenting of bifurcated lesions. Bench test report and first clinical experience, EuroIntervention, 2010;5(7):809–13. 16. Singh J, Patel Y, Depta JP, et al., A modified provisional

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17.

18.

19.

20.

21.

22.

stenting approach to coronary bifurcation lesions: clinical application of the “jailed-balloon technique”, J Interv Cardiol , 2012;25(3):289–96. Niemelä M, Kervinen K, Erglis A, et al., Randomized comparison of final kissing balloon dilatation versus no final kissing balloon dilatation in patients with coronary bifurcation lesions treated with main vessel stenting: the Nordic-Baltic Bifurcation Study III, Circulation , 2011;123(1):79–86. Gwon HC, Hahn JY, Koo BK, et al., Final kissing ballooning and long-term clinical outcomes in coronary bifurcation lesions treated with 1-stent technique: results from the COBIS registry, Heart , 2012;98(3):225–31. Koo BK, Park KW, Kang HJ, et al., Physiological evaluation of the provisional side-branch intervention strategy for bifurcation lesions using fractional flow reserve, Eur Heart J, 2008;29:726–32. Burzotta F, Trani C, Todaro D, et al., Prospective evaluation of myocardial ischemia related to post-procedural sidebranch stenosis in bifurcated lesions treated by provisional approach with drug-eluting stents, Catheter Cardiovasc Interv , 2012;79(3):351–9. Di Mario C, Iakovou I, van der Giessen WJ, Foin N, Adrianssens T, Tyczynski P, Ghilencea L, Viceconte N, Lindsay AC, Optical coherence tomography for guidance in bifurcation lesion treatment, EuroIntervention, 2010;6 Suppl J:J99-J106. Alegría-Barrero E, Foin N, Chan PH, et al., Optical coherence

23.

24.

25.

26.

27.

28.

tomography for guidance of distal cell recrossing in bifurcation stenting: choosing the right cell matters, EuroIntervention , 2012;8(2):205–13. Ormiston JA, Webster MW, Ruygrok PN, et al., Stent deformation following simulated side-branch dilatation: a comparison of five stent designs, Catheter Cardiovasc Interv, 1999;47:258–64. Kinoshita T, Kobayashi Y, De Gregorio J, et al., Difference in security of stent jail between Palmaz-Schatz, NIR, and Multi-Link stents: the effect of balloon inflation through stent struts, Catheter Cardiovasc Interv, 1999;48:230–4. Mortier P, De Beule M, Van Loo D, et al., Finite element analysis of side branch access during bifurcation stenting, Med Eng Phys, 2009;31:434–40. Mylotte D, Hovasse T, Ziani A, et al., Non-compliant balloons for final kissing inflation in coronary bifurcation lesions treated with provisional side branch stenting: a pilot study, EuroIntervention , 2012;7(10):1162–9. Burzotta F, Trani C, Talarico GP, et al., Resolute zotarolimuseluting stent to treat bifurcated lesions according to the provisional technique: a procedural performance comparison with sirolimus- and everolimus-eluting stents, Cardiovasc Revasc Med , 2013;14(3):122–7. Aminian A, Dolatabadi D, Lalmand J, Small balloon inflation over a jailed wire as a bailout technique in a case of abrupt side branch occlusion during provisional stenting, J Invasive Cardiol , 2010;22(9):449–52.

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Coronary Interventions Platelet Reactivity Testing

Current Concepts in the Clinical Utility of Platelet Reactivity Testing J e a n - Ph i l i p p e Co l l e t Professeur des Universités-Praticien Hospitalier, Paris, France

Abstract The pharmacodynamic effect of clopidogrel varies among individuals; approximately a third will have high on-treatment platelet reactivity (HTPR) to adenosine diphosphate and may benefit from more intensive antiplatelet therapy. Platelet reactivity testing has an important role in monitoring the therapeutic efficiency of clopidogrel and the safety of more potent drugs that confer an increased bleeding risk, because it provides a direct measure of the biological effect of these drugs. Numerous studies have demonstrated an association between HTPR and the risk of cardiac events in acute coronary syndrome (ACS) or after percutaneous coronary intervention (PCI). While the prognostic value of platelet reactivity testing following PCI has been demonstrated repeatedly in cohort studies and meta-analyses, randomised controlled studies investigating the clinical utility of the technique to guide treatment decisions failed to improve clinical outcomes of clopidogrel-treated patients undergoing stent implantation. Available data suggest that platelet function monitoring may be carried out in clopidogrel-treated patients with a higher risk of thrombotic events. These include patient risk factors such as body mass index (BMI), type 2 diabetes, and those prior unexpected ischemic events such as stent thrombosis, as well as procedural risk factors. As we move towards conclusively defining a therapeutic window associated with both cardiovascular (upper threshold) and bleeding risk (lower threshold) for antiplatelet agents, platelet reactivity testing will become a central tool in the practice of personalised strategies.

Keywords Clopidogrel, platelet reactivity testing, percutaneous coronary intervention, VerifyNow® Disclosure: Jean-Philippe Collet has no conflicts of interest to declare. Acknowledgement: Radcliffe Cardiology provided medical writing assistance in the development of this article. Received: 8 August 2013 Accepted: 11 September 2013 Citation: Interventional Cardiology Review, 2013;8(2):100–6 Correspondence: Jean-Philippe Collet, Professeur des Universités-Praticien Hospitalier, Institut de Cardiologie – INSERM U 937, ACTION, Groupe Hospitalier Pitié-Salpêtrière, Paris, France. E: jean-philippe.collet@psl.aphp.fr

Support: The publication of this article was supported by Accumetrics, Inc.

The role of platelets in coronary artery thrombosis is well-established.1 They also play a critical role in a number of cardiovascular conditions including stroke, peripheral vascular disease and diabetes, and may be involved in the pathology underlying atherosclerotic changes.1 Antiplatelet agents such as clopidogrel, a platelet P2Y12 receptor antagonist, and aspirin are used for the prevention of thrombotic conditions in patients with acute coronary syndrome (ACS) or when undergoing percutaneous coronary intervention (PCI).2 Dual antiplatelet therapy (DAPT), with the combination of aspirin (75–325 milligrams [mg] daily) and clopidogrel (75 mg daily after a loading dose of 300/600 mg) has become the widely accepted regimen for stent-placement procedures. Use of these drugs is widespread – clopidogrel is one of the largest selling drugs worldwide.3 However, despite antiplatelet therapy following PCI with stent implantation, 1–5 % of patients develop stent thrombosis (ST), a feared complication that results in myocardial infarction (MI) in 80 % and mortality in up to 40 % of cases.4,5 Individuals receiving clopidogrel exhibit a wide variability in platelet responsiveness, resulting from a variable level of P2Y12 inhibition.6,7 A significant number (up to a third) of patients have no measurable effect of the medication, often referred to as having high on-treatment platelet activity (HTPR) to adenosine diphosphate (ADP).8 The presence of HTPR has been associated with

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increased rates of adverse effects, including cardiovascular death, MI and ST in patients undergoing PCI.9–11 Although less common, low response to aspirin has also been observed and has been associated with adverse effects.12–14 Alternative therapeutic options, such as prasugrel and ticagrelor, have been shown to be successful for ACS patients irrespective of HTPR status.15–18 These new therapeutic options have also demonstrated superiority to clopidogrel for the prevention of ischaemic events in patients undergoing PCI for ST-elevation MI (STEMI).19 However, these therapies may confer a higher risk of bleeding and are not available everywhere due to economic constraints. Another option is increasing the dose of clopidogrel; a randomised clinical trial found that a double-dose clopidogrel regimen is associated with a reduction in cardiovascular events and ST when PCI is performed, but also an elevated risk of major bleeding.20 A ‘one-size-fits-all approach’ is therefore not appropriate in antiplatelet therapy and personalised strategies appear attractive, identifying those patients who would benefit most from therapeutic adjustment. A subset of patients demonstrate low on-treatment platelet reactivity or a hyper-response to clopidogrel, which has been associated with an increased risk of haemorrhagic complications following coronary

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Current Concepts in the Clinical Utility of Platelet Reactivity Testing

stent placement21 and after neurointerventional procedures.22–24 There is a need for larger studies to define thresholds for clopidogrel hyperresponse and examine the clinical effects of dose adjustments or treatment interruption in the setting of coronary artery bypass graft (CABG) surgery in particular.

Figure 1: The VerifyNow ® Assay

Platelet reactivity testing enables the identification of patients with an inadequate response to antiplatelet agents who might benefit from a more intense antiplatelet regimen, as well as those exhibiting hyper-responsiveness. While large studies and registries have clearly defined a threshold for hypo-response,25,26 there remains a need to definitively define a threshold for hyper-response and the clinical effects of antiplatelet dosage adjustment. This article aims to discuss advances in platelet reactivity testing and to review clinical studies investigating their use.

Platelet Reactivity Testing In addition to its role in disorders associated with platelet dysfunction,27 platelet reactivity testing is a crucial component of the management of cardiovascular disease in order to identify patients at higher risk for poor clinical outcome related to their response to antiplatelet drugs. The measurement of platelet aggregation at baseline following administration of DAPT is subject to considerable variability, therefore on-treatment platelet reactivity is the preferred means of platelet reactivity testing.28 However, it is a poorly standardised process. Several studies have shown large inter-laboratory variation in platelet reactivity testing practice.29 Platelet reactivity has been historically measured with light transmittance aggregometry (LTA), but this method is technically complex, time-consuming, requires sample manipulation, and is subject to operator-induced error.30 Point-of-care tests have been developed that are more practical and facilitate the clinical management of patients. The VerifyNow® P2Y12 assay was designed to overcome the limitations of conventional optical platelet aggregation assays. It produces results in five minutes and requires no pipetting or sample preparation, reducing the risk of error. The VerifyNow System (Accumetrics Inc, San Diego, CA, US) is a pointof-care assay that measures agonist-induced platelet aggregation by turbidimetric based optical detection, using a four-channel disposable cartridge (see Figure 1). In the channels, platelets are activated by the presence of agonists and bind to fibrinogen-coated beads, causing agglutinates to drop out of solution. The change in optical density is then measured.31 Results are reported as P2Y12 reaction units (PRU), a BASE (base PRU) value, and a percentage of inhibition calculated from the BASE and PRU. A lower PRU value corresponds to a higher degree of P2Y12 receptor inhibition and thus a decreased possibility of platelet activation and aggregation. Advantages of the VerifyNow system include simplicity, sensitivity, speed and user-friendliness.32,33 The VerifyNow assay correlates well with LTA and with other point-of-care assay devices,34,35 and has been validated in a head-to-head comparison of platelet function tests.30

Clinical Studies Involving Platelet Reactivity Testing Testing platelet reactivity following the administration of antiplatelet agents aims to determine how the drugs affect their biological targets, which is likened to the risk for secondary ischaemic/bleeding events. It is important to evaluate the levels of platelet reactivity that may correlate with thrombotic events and to create a clinically meaningful cut-off value of platelet reactivity. According to the VerifyNow package insert,

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Protective Sheath

Finger Grip

Vacutainer® Spike Staging Well Sample Well

Humidity Indicator (on back) Mixing Chamber/Detection Well

the highest combination of sensitivity and specificity for identifying a measureable effect of a P2Y12 inhibitor is a PRU of 208.36 To date, cut-off values have mainly been investigated in patients undergoing PCI. However, platelet reactivity testing has been employed in numerous clinical indications (see Table 1).

Peripheral Angioplasty Procedures Clopidogrel resistance, defined as ≥235 PRU, significantly affected clinical outcomes after peripheral angioplasty procedures.37,38

Coronary Artery Bypass Graft Surgery A strategy based on pre-operative platelet reactivity testing to determine the timing of CABG surgery in clopidogrel-treated patients was associated with the same amount of bleeding observed in clopidogrel-naive patients and 50 % shorter waiting time than recommended in the current guidelines.39 These results led to an upgrade in the guidelines, to base timing of surgery on platelet function monitoring rather than the arbitrary use of a specified period of delay.40

Neurovascular Applications Clopidogrel resistance, defined using a PRU cut-off value of 235, was associated with increased periprocedural thromboembolic complications following neurovascular stenting.41 Flow diversion with the Pipeline™ Embolization Device (PED) is an important treatment option for cerebral aneurysm, but it is associated with the risk of thromboembolic complications. A study of pre-procedure platelet reactivity testing using VerifyNow found that a PRU value of <60 or >240 was the strongest

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Coronary Interventions Platelet Reactivity Testing Table 1: Clinical Settings Where Platelet Reactivity Testing has Proven Beneficial Setting

Significant Findings

Reference

Pipeline Embolization

Pre-procedure PRU value of <60 or >240

Device procedures

was the strongest independent predictor of

(pre-operative use)

all and major peri-operative thromboembolic and haemorrhagic complications

Peripheral angioplasty

PRU >235 was associated with significantly

procedures

more repeat interventions after peripheral

PRU >234 was optimal for predicting clinical

to clopidogrel treatment

outcomes of peripheral angioplasty and

after peripheral

stenting

endovascular procedures Post-clopidogrel platelet

PRU >235 was predictive of cardiovascular

response after PCI and

events

drug-eluting stent implantation Coronary artery bypass

A platelet function measurement-based

graft surgery

strategy reduced bleeding and waiting

The level of platelet function inhibition as measured by a point-of-care assay is an independent predictor for the risk of major adverse cardiac events after PCI.43 A recent systematic review and meta-analysis concluded that initiating intensified antiplatelet therapy on the basis of platelet reactivity testing in patients after PCI is associated with a significant reduction in cardiovascular mortality, ST and MI (p<0.01 for all).44 A study of patients with ACS assessed the cost-effectiveness of universal clopidogrel, ticagrelor or prasugrel (given to all patients) or PRA-driven ticagrelor or prasugrel (given to patients with a PRU of >230 on the VerifyNow assay; the remainder received clopidogrel). PRA-driven ticagrelor and prasugrel were found to be cost-effective over five years compared with universal clopidogrel (incremental cost-effectiveness ratio US$40,100 and US$49,143/quality-adjusted life-year, respectively); however, universal ticagrelor and prasugrel were not cost-effective (incremental cost-effectiveness ratio US$61,651 and US$96,261/quality-adjusted life-year, respectively).45 Thus, platelet reactivity testing has the potential to decrease the healthcare costs associated with ACS.

angioplasty procedures Platelet responsiveness

Percutaneous Coronary Intervention

time in clopidogrel-treated patients undergoing CABG Coronary angiography

PRU ≥275 (Asian population) after

administration of antiplatelet agents is related to silent embolic cerebral infarctions after coronary angiography Neurovascular stenting

Clopidogrel resistance defined using a PRU

cut-off value of >235 was associated with increased periprocedural thromboembolic complications Aspirin resistance

Patients with aspirin resistance as measured 12, 81

after PCI

by a point-of-care assay have an increased risk of myonecrosis following non-urgent PCI

CABG = coronary artery bypass graft; PCI = percutaneous coronary intervention; PRU = P2Y12 reaction units.

Figure 2: Failure Rate for Normal and High On-treatment Platelet Reactivity

Death, MI or ST

0.20

On-treatment platelet reactivity High Normal

0.15

14.7 %

Log-Rank p<0.001

0.10 7.0 % 0.05

0 No. at risk Normal High

1,908 1,133

100

200 1,561 872

300 400 Time (days) 956 434

500

600

700

552 351

Kaplan–Meier curve for probability of death, MI or ST by platelet reactivity. High on-treatment platelet reactivity (blue lines) was defined as PRU values ≥230 and normal (red lines) as PRU values <230. Dashed lines = 95 % confidence intervals for each group. MI = myocardial infarction; ST = stent thrombosis. Source: Brar, et al., 2011.10

independent predictor of all major peri-operative thromboembolic and haemorrhagic complications after PED procedures.23 In defining optimal cut-off values, it is also important to distinguish between a cardiovascular and neurovascular patient – those with a history of stroke have a greater risk of haemorrhage on more potent antiplatelet therapy and may benefit from platelet reactivity within a more narrow window.42

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Defining optimal cut-offs has proved challenging in clinical studies of antiplatelet therapy following PCI. A study assessed post-clopidogrel HTPR using VerifyNow following PCI with drug-eluting stent implantation and established a cut-off of ≥235 PRU.46 Stratifying patients according to HTPR based on this threshold proved strongly predictive of cardiovascular events. A recent meta-analysis of clinical outcomes after PCI confirmed this finding and found that every 10-U increase in PRU was associated with a significantly higher rate of the primary endpoint (hazard ratio [HR] 1.04; 95 % confidence interval (CI) 1.03–1.06; p<0.0001). A PRU cut-off of 230 was the strongest predictor of death, MI or ST (p<0.001). A PRU value ≥230 was associated with a higher rate of a composite primary endpoint of death, MI or ST (HR 2.10; 95 % CI 1.62–2.73; p<0.0001), as well as the individual endpoints of death (HR 1.66; 95 % CI 1.04–2.68; p<0.04), MI (HR 2.04; 95 % CI 1.51–2.76; p<0.001) and ST (HR 3.11; 95 % CI 1.50–6.46; p<0.002) (see Figure 2).10 As mentioned previously, according to the VerifyNow package insert, the highest combination of sensitivity and specificity for identifying a measureable effect of a P2Y12 inhibitor is a PRU of 208.36 However, among clinical studies, a consensus has not yet been reached on optimal cut-off values. One small study of patients with stable angina suggested that a cut-off of ≤15 % inhibition or >213 PRU may be optimal for the identification of patients with HTPR.47 Another study of patients with stable coronary artery disease (CAD) found that cut-off levels of 256 PRU and 26.5 % inhibition identified carriers of reduced-function cytochrome P450 2C19 (CYP2C19) allele on antiplatelet therapy, which is associated with a higher rate of clinical risk.48,49 As the prevalence of the CYP2C19 variant is higher in Asian population compared with the prevalence in Westerners, PRU ≥275 has predicted clinical events more accurately in this population.50,51 For low-risk patients, lower PRU values (180–210) have been used.18,52 However, the recommended cut-off of 208 was found to be significantly associated with the risk of ST at 30 days (HR 3.9, p=0.005) in the Assessment of Dual AntiPlatelet Therapy With Drug Eluting Stents (ADAPT-DES) registry study (n=8,583), which included a higher risk population (~50 % with ACS).26 A recent study found that HTPR decreases from baseline to one month, a trend that is partly influenced by genotype. The study found that HTPR at one month was the strongest predictor of adverse outcomes.53

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While platelet activity appears to correlate with the risk of cardiovascular events and ST following PCI, studies investigating the use of platelet reactivity testing to guide treatment have had mixed results.18,44,54,55 The Gauging Responsiveness With A VerifyNow Assay-Impact On Thrombosis And Safety (GRAVITAS) trial investigated a strategy based on high-dose clopidogrel in patients with HTPR (defined as ≥230 PRU).25 However, this strategy of a fixed higher dose, regardless of the achieved level of platelet inhibition, did not reduce cardiovascular death, MI and ST after PCI compared with standard-dose clopidogrel.25 However, a subsequent analysis of GRAVITAS data found that achievement of <208 PRU was significantly and independently associated with a markedly lower risk of cardiovascular events at 60 days (adjusted HR 0.23; 95 % CI, 0.05–0.98; P=0.047).56 The lower cut-off may be due to the fact that this trial enrolled a relatively low-risk population. Consequently the trial showed low overall event rates. Furthermore, patients were randomised to single or double-dose clopidogrel rather than targeting to a specific inhibition level. Other studies have suggested that a triple dose may be needed in patients exhibiting variants in the CYP2C19 gene.57 The Testing Platelet Reactivity In Patients Undergoing Elective Stent Placement on Clopidogrel to Guide Alternative Therapy With Prasugrel (TRIGGER-PCI) trial, a randomised trial of prasugrel versus clopidogrel in patients with HTPR after PCI, was terminated early after a preliminary, blinded analysis indicated that the trial would not meet its primary endpoints. The rate of adverse ischaemic events was very low in the sample cohort, making it difficult to achieve statistical significance.54 However, the study enrolment was biased towards very low risk populations – approximately 30 % of the study population did not go on to randomisation after it was established that they had HTPR on clopidogrel. The Assessment by a double Randomization of a Conventional antiplatelet strategy versus a monitoring-guided strategy for drug-eluting stent implantation and, of Treatment Interruption versus Continuation one year after stenting (ARCTIC) trial randomised patients scheduled for coronary stenting to platelet function monitoring with the VerifyNow and adjusting antiplatelet therapy accordingly versus no monitoring and conventional clopidogrel therapy. HTPR was defined as ≥230 PRU or a percent inhibition <15 %. In the monitoring arm, serial platelet function tests (before stent implantation and during the maintenance phase) and treatment adjustments using a predefined treatment algorithm were performed. In addition to treatment intensification due to high on-treatment platelet reactivity, patients could be switched back from prasugrel to clopidogrel after PCI if low on-treatment platelet reactivity was measured. Despite halving the rate of high platelet reactivity to adenosine diphosphate, the primary endpoint of death, MI, ST, stroke or urgent revascularisation was similar after one year with the two strategies (HR 1.13, 95 % CI 0.98–1.29; p=0.10).58 The risk level of the population, the cut-off value used to define HTPR, the heterogeneity in treatment adjustment (or lack of adjustment) in deemed non-responders, the rare use of prasugrel, which became available late after study initiation, and the lack of impact of treatment adjustment on other major determinants of platelet reactivity (such as treatment compliance) may account for the lack of benefit. However, ARCTIC is the only study that has evaluated by randomisation to the use of a platelet function test. It was appropriately powered to test the hypothesis of treatment monitoring. One-third of the randomised patients had an ACS, and one-year mortality was 2 %. Eight of 10 patients deemed non-responders were reloaded with clopidogrel and were given a glycoprotein IIb/IIIa inhibitor; 22 % of patients with

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Table 2: Risk Factors for Future Thrombolytic Events in Patients Following Percutaneous Coronary Intervention Risk Factor Advanced age (>65 years)

Reference 82, 83

Diabetes

82–85

ACS at presentation

Previous MI

83, 86, 87

Unstable angina

85, 86

Adherence to antiplatelet medication

Diffuse disease

85, 87

Complex anatomy

82, 84, 85, 87, 88

Bifurcations

Vessel size

82, 84, 85, 87

Long lesions

84, 85, 87

Stent type

4, 90

Multiple stents

84–87

Concomitant medications

67, 68

Renal insufficiency

Current smoker

83, 84

Hypertension

ACS = acute coronary syndrome; MI = myocardial infarction.

high on-treatment platelet reactivity were on prasugrel at the end of the study. The rate of poor response was halved after treatment adjustment for both P2Y12 inhibition and aspirin pathway, further highlighting an aggressive approach.

Perspectives Personalised therapeutic strategies based on platelet reactivity testing have yet to improve clinical outcomes in low-risk groups, perhaps due to the already low event rates observed in this patient population. However, it has been hypothesized that the approach may be more beneficial in high-risk patient populations.8,54 In addition to responsiveness to antiplatelet medication, there are numerous risk factors for future cardiovascular (CV) events following PCI; these are summarised in Table 2. Risk factors for non-response to antiplatelet therapy include advanced age,59 type 2 diabetes,60 particularly if treated with insulin,61 overweight patients,62 genetic factors49,63–66 and concomitant medications, particularly proton pump inhibitors.67,68

The Concept of a Therapeutic Window for Antiplatelet Therapy The concept of a therapeutic window of P2Y12 reactivity defining the upper threshold as HPTR associated with ischaemic events and a lower threshold based on bleeding risk has been suggested.28 A study using the VerifyNow assay established a therapeutic window of 86–238 PRU at a one month time-point that minimised both ischaemic and bleeding events (see Figure 3). At the time of PCI, the suggested cut-offs were 95 PRU for hyper- and 214 for hypo-response.53 There is a need to target high-risk patients groups to optimise the clinical utility of platelet reactivity testing. Recent American and European guidelines have included Class IIb recommendations for platelet reactivity testing in high-risk patients if the results may impact on patient management.69,70 Adjusting medication based on the results of platelet reactivity testing is already being carried out in some outpatient ST clinics and hundreds of US hospitals.71 It must be stressed that this approach has not been conclusively validated, though it is logical based on the desire to observe evidence of treatment success in patients treated with antiplatelet agents.

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combined with platelet reactivity testing. Clinical trials using a combined genotyping and phenotyping approach are underway to better define the role of such tests in guiding antiplatelet therapy in clinical practice. The advent of the stronger P2Y12 inhibitors such as prasugrel and ticagrelor and their increased cost and bleeding risk compared with

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clopidogrel, will necessitate the establishment of a therapeutic window to achieve optimal and cost-effective platelet inhibition while minimising bleeding risk.2,3 As we move towards conclusively defining a therapeutic window for antiplatelet agents, platelet reactivity testing will become a central tool in the practice of personalised antiplatelet strategies. n

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gov/ct2/show/NCT01477775 (accessed 12 September 2013). 81. Chen WH, Lee PY, Ng W, et al., Aspirin resistance is associated with a high incidence of myonecrosis after non-urgent percutaneous coronary intervention despite clopidogrel pretreatment, J Am Coll Cardiol , 2004;43:1122–6. 82. Urban P, Gershlick AH, Guagliumi G, et al., Safety of coronary sirolimus-eluting stents in daily clinical practice: one-year follow-up of the e-Cypher registry, Circulation , 2006;113:1434–41. 83. Ergelen M, Uyarel H, Osmonov D, et al., Early stent thrombosis in patients undergoing primary coronary stenting for acute myocardial infarction: incidence, a simple risk score, and prognosis, Clin Appl Thromb Hemost , 2010;16:33–41. 84. Baran KW, Lasala JM, Cox DA, et al., A clinical risk score for prediction of stent thrombosis, Am J Cardiol , 2008;102:541–5. 85. Bezerra H, Perin E, Berger P, et al., Outcomes of unselected recipients of sirolimus-eluting stents: the Cypher stent U.S. post-marketing surveillance registry, J Invasive Cardiol , 2010;22:48–55. 86. Madan P, Elayda MA, Lee VV, et al., Predicting major adverse cardiac events after percutaneous coronary intervention: the Texas Heart Institute risk score, Am Heart J , 2008;155:1068–74. 87. Lasala JM, Cox DA, Dobies D, et al., Drug-eluting stent thrombosis in routine clinical practice: two-year outcomes and predictors from the TAXUS ARRIVE registries, Circ Cardiovasc Interv , 2009;2:285–93. 88. Costa JR Jr, Sousa A, Moreira AC, et al., Incidence and predictors of very late (>or=4 years) major cardiac adverse events in the DESIRE (Drug-Eluting Stents in the Real World)Late registry, JACC Cardiovasc Interv , 2010;3:12–8. 89. van Werkum JW, Heestermans AA, Zomer AC, et al., Predictors of coronary stent thrombosis: the Dutch Stent Thrombosis Registry, J Am Coll Cardiol , 2009;53:1399–409. 90. Rinaldi MJ, Kirtane AJ, Piana RN, et al., Clinical, procedural, and pharmacologic correlates of acute and subacute stent thrombosis: results of a multicenter case-control study with 145 thrombosis events, Am Heart J , 2008;155:654–60.

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are. eclare.

Coronary Interventions Coronary Chronic Total Occlusion

Challenges in Complicated Coronary Chronic Total Occlusion Recanalisation Nicolaus Reifart Main Taunus Heart Institute, Bad Soden, Germany

Abstract Percutaneous coronary intervention for chronic total occlusions (CTOs) is still today a challenge even for experienced operators. In the hands of the most experienced the success rate increased from about 60 to 90 % in the past 10 years; paralleled by a long-term patency with drugeluting stents exceeding 90 %. These results are comparable or even superior to surgical revascularisation. Thanks to Japanese and European CTO club online registries and live courses we are able to rapidly understand and adopt new strategies, techniques and materials to master morphology deemed untreatable 10 years ago. Several of the persistent challenges and solutions unique to CTO interventions are discussed.

Keywords Chronic total coronary occlusion, revascularisation, technique, results, complications Disclosure: The author has no conflicts of interest to declare. Received: 2 September 2013 Accepted: 19 September 2013 Citation: Interventional Cardiology Review, 2013;8(2):107–11 Correspondence: Nicolaus Reifart, Main Taunus Heart Institute, 65812 Bad Soden, Germany. E: n.reifart@reifart-partner.de

Definition and Prevalence Chronic coronary occlusions (CTOs) are defined as lesions with Thrombolysis in Myocardial Infarction (TIMI) 0 flow older than three months (either angiographically proven or with high clinical likelihood).1 According to a recent Canadian registry, CTOs are detected in about 30 % of patients with symptomatic coronary artery diseases (CAD).2 Likewise a very large German monitor controlled registry found that 27.5 % of 45,722 consecutive patients with CAD had a non-acute total occlusion.3

poor proof of viability or residual ischaemia. A meta-analysis of 7,288 patients observed over a weighted average follow-up of six years confirms that successful attempts appear to be associated with an improvement in mortality and with a reduction for the need for CABG as compared with failed recanalisation.14 In summary, patients who are symptomatic or ischaemic despite optimal medical therapy as well as those with relevant viable territory (>5 % of myocardium) should deserve revascularisation.

Current Challenges Indication of Chronic Coronary Occlusion Percutaneous Coronary Intervention The overriding principle in medicine is to improve symptoms and/or prognosis. Thus revascularisation of CTO is indicated only in the presence of angina or ischaemia related to the respective territory.4 It has been shown that upon successful reopening angina will improve, functional tests will be normalised, left ventricular (LV) function will improve and coronary artery bypass graft (CABG) will be avoided.5–10,11 Improved LV dysfunction correlates with the presence of myocardial viability in the respective LV segments,12 and it has been shown to attain better prognosis. In about 60 % of CTO patients it appears sufficient to simply prove that no Q-waves are present in the territory of the occluded vessel in order to achieve recovery of the LV function upon recanalisation.8 The EuroCTO registry 2008–2010 of 4,820 patients clearly elucidates that more than 80 % of the CTO patients had no prior ST-elevation myocardial infarction (STEMI) in the region of the occluded vessel, and we might deduct a prognostic impact of successful CTO percutaneous coronary intervention (PCI) in these patients. Frankly, we do not yet know if we are improving life-expectancy. In the Occluded Artery Trial (OAT) patients with a recent myocardial infarction (MI) of 3–28 days there was no advantage of the interventional approach in terms of survival and there were more recurrent MIs than with the conservative approach.13 However, this trial is dealing with a different subset of patients that had infarctions and only

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Operator Experience Ten to 20 years ago most of the reports of CTO results included ‘well selected cases’ and used a more liberal definition including recent occlusions so that the success rates of >60 % are overestimated.10,15,16 Even experienced non-CTO operators, as the SYNTAX participants, still today achieve success rates of about 50 % only, a figure not far from CABG either.17 The classical predictors of failure until the late 1990s included no stump, occlusion at side branch, orthograde collaterals (caput medusae) and occlusion age >3 months. Severe calcifications, marked tortuosity or long occlusions were considered undoable. Material and strategies, namely retrograde approach, were recently refined predominantly by a few Japanese pioneers. Unfortunately, most centres still do not restrict the recanalisations of CTO to a few selected operators, which results in insufficient experience (<30/year) and less favourable outcomes. Only high-volume CTO operators will be able to deal with difficult morphology and achieve success rates >80 % even in unselected cases. Since 2006 the EuroCTO club has been collecting clinical and procedural data of all consecutive CTO procedures – and in an online registry (www.ercto. org) since 2008. During these seven years data of more than 14,000 CTO procedures by more than 35 ERCTO operators were collected. The overall success rate increased from 75 to 85 %, in 2012 reaching 91 % in the hands of the most experienced who enrolled >100 procedures annually (see Figure 1). The result of the EuroCTO club online registry depicts a

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Coronary Interventions Coronary Chronic Total Occlusion Figure 1: Success Rate of Experienced European Operators 2008–2012 According to Their Level of Experience Variance analysis p<0.001

100

Percent

88 89

86 78

89 91

The most important prerequisite is operator and team experience in CTO procedures. The operator should be skilful, trained specifically in CTO intervention, be patient, persistent and yet cautious. Every operator should select patients according to their level of expertise or seek for expert backup or refer those beyond their reach to CTO masters.

Patient Preparation

It is mandatory to carefully review the film for best views, occlusion entry and exit, and possible mistakes of previous unsuccessful attempts.

20 0

Crucial Steps to Success

2008

>150/<200 procedures

2009

2010

>200/<300 procedures

2011

2012

>300 procedures

The mean success rate in 2012 was 85 %, in those with an annual caseload >100 it was >90 %.

clear relation of caseload and success even in highly experienced CTO operators (see Figure 1). Furthermore in this survey a retrograde approach was chosen in 12 % of cases with a success rate of 65 %, underscoring that this is a good strategy after antegrade failure.

The patient’s glomerular filtration rate (GFR) (millilitre/minute [ml/min]) should be considered as a limit to dye consumption that should not exceed 4–8 times the nominal number of GFR in ml.23 An activated clotting time (ACT) measurement has to be accomplished every 30–40 minutes (min) to keep the level above 250 seconds (sec) and all lines need to be flushed every 10–20 min to avoid clotting and embolisation that is life-threatening if it occurs at the contralateral access. Since wire exits are not uncommon during the process of recanalisation IIb/IIIa inhibitors should be avoided.

Operators With and Without Retrograde Experience This European registry more recently depicted that the success rate of the less experienced operators who do not apply the retrograde approach is about 80 % as opposed to 90 % of those who do.18 Similarly in 2009 a US retrospective analysis of 636 consecutive CTO procedures (overall success 69 %) confirmed that less experienced operators who did not adopt the novel retrograde strategy had a lower success rate than those who did (59 versus 75 %).19

Morphology An analysis of the registry data 2008–2010 comprising 1,914 consecutive patients of then 16 centres revealed as independent predictors of antegrade failure: blunt stump, occlusion length >20 millimetres (mm), severe calcification and previously failed attempt (76 versus 83 %).20 Noteworthy is that the success rate of a second attempt was 85 % if a different operator had failed before (n=636) and 69 % if it was the same operator who failed before (n=260).21 In the Japanese J-CTO registry from 12 enrolling centres 498 patients with 528 CTOs the success rate was 88.6 % for first attempt and 65.8 % for retry cases, which confirms the European experience.22 Other independent predictors of lower success rates in this registry were calcification, bending, blunt stump and occlusion length >20 mm. The retrograde approach was chosen in 26 % of cases, and was successful without trying antegrade first in 79 %, and after futile antegrade attempt in 68–74 %, similar to European results. In summary, complex morphology, that until recently was deemed impossible to negotiate is barely influencing success rates nowadays. According to contemporary experience the most important factor inversely influencing success independent from the approach is severe calcification. No doubt other factors like tortuosity, absence of stump, length of occlusion and failed recanalisation will cumber the procedure, but are by no means a reason to deny an attempt by experienced operators.20,22 There is only one exception to this rule, chronically occluded vessels with no visible distal target should not be addressed at all because the ‘blind penetration’ bears an unpredictable risk of perforation and life-threatening tamponade.

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Access Route and Guiding Catheters Although radial approach is feasible, 90 % of experienced operators prefer femoral access mainly because they are used to it and because this access allows for use of larger guiding catheters. For chronic occlusions a good passive support with coaxial alignment and sufficient lumen to host several wires, an anchor balloon and a microcatheter or Corsair® or even sometimes intravascular ultrasound (IVUS) guidance is crucial. This can only be achieved with larger guiding catheters (7 and 8 French [Fr]). For the left coronary system extra backup-type catheters (Voda left, extra backup, geometric left, left support) are preferable. For the right coronary artery we prefer left Amplatz 0.75–2.00 shapes, hockey stick upon gentle superior origin of the right coronary artery (RCA), Judkins shape for slightly inferior origin and internal mammary artery (IMA) or Shepherd’s Crook Replacement (SCR) type guiding for upward origin of RCA. For the RCA I strongly recommend guides with side-holes to prevent aorto-ostial disssections or progressive spiral dissections caused by forceful dye injection into a subintimal space. It is absolutely mandatory to visualise the vessel distal to the occlusion to avoid blind poking or immensely dangerous dilatation of a false wire exit. When the distal vessel is not filled by orthograde collaterals or these collaterals disappear during manipulation, contralateral injection is a must. The contralateral approach can also be achieved easily by puncturing the same groin with a 4–6 Fr catheter, which may overcome an operators inhibition to insert a second sheath in the other groin. Over the wire kink resistant microcatheters ease wire manipulation and allow atraumatic rapid exchange or reshaping of the wires and its use is therefore strongly recommended.

Wires and Handling The most popular current strategy is to start with the atraumatic tapered and highly lubricious Fielder XT®, which according to the EuroCTO registry will be successful in 39 % of cases. The second most popular selection – especially in old and calcified occlusions that are not very tortuous is to select stiffer tapered wires, like the Confianza 9 Pro® early in the process to minimise the risk of large dissection as well as shorten and simplify the procedure. Another recent line of action is to start with a soft tapered polymer wire (e.g. Fielder XT),

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stepping up quite early (Confianza 9 Pro or Miracle 6g®) and then step down to a softer wire again. The three fundamental elements of wire handling are rotating, pushing and pulling the wire. It is important to feel the resistance at the wire tip, when pulling the wire, since a wrong channel often exerts much higher resistance than the correct lumen. Any wire has the tendency to follow the outer part of the vessel curve, which can often cause the tip to exit the lumen. It is therefore preferable to direct the wire-curve towards the inner part of the vessel bend.

Figure 2: (A) Extreme Iliac Tortuosity that Could Not be Overcome by a Single Kink Resistant 7 Fr Sheath and a Regular Guidewire (0.035). No Guiding Catheter Could be Inserted into the Coronary Ostium Because of Serious Friction (B) Only After Inserting a Second 5 Fr Long Sheath and Placing Three Extra Stiff 0.035 Amplatz Guidewires, the Iliac was Well-straightened and the Intervention Continued Successfully A

Parallel Wire Technique First described in 1995 this is still the best technique to correct a false wire position.24 If the first wire has entered a false lumen, it is left in place to mark the dissection channel and a second wire (typically the same stiffness or stiffer and often tapered) with a slightly different tip curve to allow creating a slightly different course supported by an over-the-wire (OTW) (balloon) catheter, is passed along the same path parallel to the first wire, with care taken to avoid wire twisting. This technique allows for penetration towards the distal cap more centrally, avoiding the false channel that is marked by the wire left in situ. Occasionally, three or more wires are used in parallel.

How to Overcome Specific Challenges Tortuous Access The most common approach for CTO-PCI is via the groin. However, in some elderly patients catheter manipulation via femoral approach is barred by tremendous friction due to severe kinking of the iliac artery, most probably because of atherosclerotic vessel remodelling.25 A common solution is to use a larger rigid kink resistant long sheath with a stiff guidewire. Nevertheless in rare cases the kinking cannot be overcome and the friction remains high that the investigator has to puncture the contralateral side or switch to a transradial approach, which might be extremely difficult as well because the atherosclerotic disease is often generalised, and last but not least in more than 70 % of the cases we do need two arterial catheters for contralateral injections. Finally up to 1 % of the CTO procedures may fail because of insurmountable access problems. Inserting two parallel sheaths and extra stiff guidewires into the same common femoral artery is a simple novel technique not only to ease contralateral access but also to overcome serious iliac tortuosity that otherwise prevents diagnostic or therapeutic percutaneous interventions. With this technique the external and common iliac will be straightened impressively and the friction reduced tremendously thus enabling easy guiding catheter manipulations and intervention (see Figure 2A and B).26

No Stump, Ostial Occlusion or Occlusion at Take-off Without a doubt recanalisation is much easier if a stump can be identified, and tapered stumps are more favourable than blunt stumps, which are more likely to be experienced in very old occlusions. If no stump can be identified, some operators primarily prefer a retrograde approach via collaterals although antegrade wiring may still be successful in >50 % of cases. This is why I do start antegrade in almost all ‘no stump-cases’. Several techniques were developed to help identify the correct antegrade entry. If a side branch is available at the suspected takeoff, IVUS may be used to guide the wire entry. Less expensive strategies are the Sesame-open technique that requires a wire left in the side branch at take-off. The wire not only may serve as a marker for the take-off but also sometimes lever the side branch and enlarge the bifurcation angle and thus demask a tiny stump. A more aggressive approach is the side

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branch technique, an attempt to break the proximal cap with a balloon inflated in the main vessel and side branch across the take-off. This technique may successfully open the entry in 30–40 % of cases with a risk of subintimal dissection requiring re-entry with a tapered stiff wire. If I do not succeed antegradely within 5–10 minutes of fluoroscopy time or a dissection occurs with the risk of extending distally I do stop the antegrade approach and search my cine runs for optimal collaterals to continue retrograde.

Heavy Calcification About 60 % of chronic occlusions involve calcification that can be detected during angiography. The EuroCTO registry ERCTO grades calcification as: • • • •

absent; mild (spots of calcium); moderate (<50 % of vessel circumference involved); and severe (>50 % of vessel circumference calcified) – severe calcification was an independent predictor of lower success rate.

Although some operators prefer to start antegrade with a soft tapered polymer wire (e.g. Fielder XT) to probe invisible microchannels, in my experience this is a waste of time in 90 % of cases since in most cases it is only possible to break up the rocky proximal cap with a tapered stiff wire like Confianza 9 or 12. I do recognise that in 10 % of cases even severe calcification may mainly be located outside the former vessel lumen and what initially appeared like a rock-hard barrier is quite easy to cross with a moderately stiff wire. After having entered the CTO I continue with the same wire if the course is straight and switch to a softer steerable wire (e.g. Ultimate 3g or Pilot 150) if the course is tortuous. The distal cap is always softer than the proximal but often still requires to be punctured preferably at its centre. If the distal vessel cannot be re-entered correctly one should avoid extensive manipulations that can easily shear off collaterals and prohibit visualisation of the distal vessel. Instead of losing distal patency and time the operator should leave the antegrade wire in place and switch to retrograde wire crossing or reversed controlled antegrade and retrograde subintimal tracking (CART). In general it is easier to enter a calcified CTO from retrograde than antegrade because the distal cap is always softer.

Balloon Failure After successful antegrade wire crossing it may be impossible to follow with a small balloon even after having increased the guiding support with an anchoring wire or balloon in a proximal side branch.

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Coronary Interventions Coronary Chronic Total Occlusion Figure 3: (A) Short CTO Proximal to Anastomosis of LIMA to LAD and Short Stenosis More Distal. Extreme Tortuosity Due to Curved LIMA and Three Angles of 180 Degrees (B) Corsair, Straightening First and Second Bend and a Lubricious Wire (Fielder XT ® ) Enabled Retrograde Crossing of the Occlusion (C) Final Result After PCI of Both LAD Lesions with DES A

CTO = chronic total occlusion; DES = drug-eluting stents; LAD = left anterior descending; LIMA = left internal mammary artery; PCI = percutaneous coronary intervention.

Rotablator may be successful but it is not wise to pull the wire and a change for a rotawire unless all other options failed. The options that will be successful in >70 % are Tornus®, twisted in counter-clockwise, or Corsair, twisted in clockwise and counter-clockwise, although the latter is more fragile and operators should avoid extensive rotations on the same spot indicating that the device might be captured and break. In about 10 % of the balloon failures Tornus and Corsair will fail as well. In these cases Laser is the best option; however, it is available only in a few institutions. Then it is worth trying to increase the lumen of the channel by paralleling a second stiff wire, but staying strictly parallel along the whole occlusion is not easy either. Before giving up we try to advance a micocatheter as close as possible and then exchange the CTO wire for a rotablator wire and then rotablator with a 1.25 burr.

No wonder that up until 2010 IVUS and Multislice Computed Tomography (MSCT) were used in 1.5 % (IVUS) and 4.0 % (MSCT) of cases only by the members of the EuroCTO club. With a redoubling of the retrograde approach in 2012 the use of IVUS increased to a still modest 12.5 %. No doubt IVUS appears helpful to identify the take-off of the occluded vessel when no stump is discernible, to facilitate re-entry after having created a large false channel and to identify the position of the retrograde wire in the dissection channel as well as to measure the vessel diameter and safely select the proper balloon size. MSCT is used to depict long and tortuous occlusions and to locate calcifications not visible angiographically29,30 – definitely helpful information if the first attempt to recanalise failed. Since only a few studies with small numbers are reported so far, the importance of MSCT with its adverse additional X-ray exposure and additional costs remains unsolved.

Tortuous Coronary Artery

Retrograde Approach

Tortuosity in the ERCTO registry is defined as none (straight: no bend >70 °, slight: one bend >70 °, moderate: two bends >70 ° or one bend >90 °, severe: two bends >90 °or one bend >120 °).

If a vigorous antegrade attempt to open the vessel failed a second attempt then mostly a retrogradely approach is recommendable in most patients. Until recently, it was strongly suggested to schedule the retrograde attempt a few weeks after the antegrade failure.31 Many operators, including me, nowadays favour to switch ad hoc after 10–15 min of unsuccessful antegrade wiring with different wires and wiring techniques well before the distal vessel gets affected by enlarged false channels.

The best strategy to overcome tortuosity is to use a Corsair, which thanks to its flexibility, kink resistance and lubricious surface render optimal steerability even to non-polymer wires. Polymer wires should be selected in very tortuous anatomy as depicted in Figure 3 (A–C). Sometimes progress can only be achieved by keeping more than one wire in place to straighten the vessel.

Dissection Almost all recanalisations to some extent involve a wire exit and re-entry, and thus limited dissection with subintimal stenting. This limited mistreatment of the coronary appears not to unfavourably influence short and long-term results. However, intentional extended subintimal tracking, what I view as Ramboplasty and stenting as practised with STAR-like techniques, not only may amputate side branches but also bear the risk of unacceptable reocclusion rates of more than 50 %.27 Therefore if a subintimal wire cannot be steered back to the lumen after 10–15 mm, one should consider either switching to retrograde or to a more sophisticated re-entry technique like IVUS-guided re-entry or the BridgePoint Stingray® system.28

Complementary Imaging as Solution to Challenges Unlike in the US and Japan complementary imaging is still unpopular in Europe firstly because the predominant philosophy is to keep procedures simple and secondly because of restricted reimbursement.

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The first report of retrograde recanalisation of a CTO was published by a French group in 1996.32 In 2005, Katoh opened an important new window, pioneering the modern era of retrograde CTO recanalisation with the CART technique.33 The novelties introduced in this procedure were the targeted septal collateral crossing and the connection of an antegrade and retrograde subintimal channel. To facilitate this approach several tools were newly developed like the channel dilator Corsair, a long wire for externalisation (ASAHI RG3®), Short (90–95 centimetres [cm]) or shortened guiding catheters (GCs) are sometimes necessary especially in long epicardial connections. Monitoring of anticoagulation during the procedure is very important. An ACT should be measured every 30 min and should be maintained over 300 sec until the end of the procedure is foreseeable, to avoid any thrombotic complications in the donor artery, which are potentially lethal. Septal collaterals are most often used (about 75 % of cases) followed by epicardial collaterals that are in general larger but more tortuous and more difficult to traverse. Stronger and straight collaterals are easier to be crossed than invisible and tortuous connections, but it is not

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rare to discover that the collateral that appeared less favourable was quite easy to cross. There are three main techniques to cross and dilate the occlusion: • R etrograde marker wire at the distal end of occlusion as a target for the antegrade stiff and tapered wire. • Retrograde penetration of occlusion with wire and Corsair and externalisation of a long wire like Rotablator Wire or ASAHI RG3 via guiding catheter exiting the ‘antegrade sheath’ followed by antegrade stenting. • Connecting both false wire channels either via retrograde subintimal dilation (CART technique) or antegrade subintimal dilation (reverse-CART technique) followed by antegrade stenting. Since the retrograde approach is generally more difficult and time consuming all CTO procedures should be started in an antegrade way with very few exceptions. The more complex nature is documented by the EuroCTO club registry 2008–2010 with a procedural time of antegrade approach 87 min, dye consumption 268 millilitres (ml) in 4,299 patients versus 154 min and 383 ml dye consumption in 501 patients with retrograde approach. As patients selected for retrograde approach are generally more awkward and the procedure is more tricky, the current success rate is roughly 15 % lower than antegrade. To make matters worse the retrograde approach is handicapped by a 2–3 fold higher rate incidence of severe in-hospital complications.

superselective dye injection via the retrograde Corsair. This is best done by a 3 ml syringe with Luer-lock and forceful injection. To prove proper position in the vessel and avoid detrimental forceful intramural injection one should be able to aspirate blood before injecting dye. Connecting an antegrade and retrograde dissection again should aim at limiting the extension of a subintimal track to avoid long subintimal stenting. Antegrade IVUS is very helpful to identify the optimal balloon size for retrograde CART and the optimal position for re-entry (where both wires are closest).

Complications In-hospital complications are rare, but not negligible – quite similar to PCI of non-occluded vessels in the EuroCTO online registry 2008– 2010 (N=4,820 patients) death occurred in 0.30 %, any MI in 2.70 %, emergency CABG in 0.21 % and cardiac tamponade in 0.45 % of cases.

Retrograde Challenges

As mentioned earlier the complication rate with retrograde approach exceeds that of antegrade by at least 2–3 times (major adverse cardiac events [MACE] 4.5 %)34 and according to G. Werner infarctions defined as CK rise to >3 times upper limit were 3.1 % following antegrade and 7.1– 20.0 % following retrograde approach via septal or epicardial collaterals.35 Some of the complications of retrograde approach are quite unusual like collateral perforation, septum haematoma, aortic dissection, dissection and thrombotic occlusion of the collateral donating vessel or severe wire entrapment. In general I assume that complications after retrograde approach do occur more often than reported in registries and I strongly recommend adopting this technique only after extensive proctoring.

The most difficult part is the successful transition of collaterals, which might only be possible in 60–70 % of CTO patients. The most favourable collaterals are the well visible straight interseptals and the worst are the tiny cork screw like epicardials. Although ‘surfing’ collaterals may be successful even if the vessel course is not clearly depicted angiographically, it is recommendable to take advantage of

In summary CTO PCI is probably the most challenging percutaneous intervention, but almost every vehement assignment in CTO may nowadays be mastered with high success rates, low complication rates and good long-term results, provided that indication, operator experience and strategy are fit and proper. n

Di Mario C, Werner GS, Sianos G, et al., European Perspective in Recanalisation of Chronic Total Occlusions: Consensus Document from the EuroCTO-club, Eurointervention , 2007;3(1):30–43. 2. Werner GS, Gitt AK, Zeymer U, et al., Chronic total coronary occlusions in patients with stable angina pectoris: impact on therapy and outcome in present day clinical practice, Clin Res Cardiol , 2009;98(7):435–41. 3. Reifart NSG, Levenson B, Effect of chronic total coronary occlusion on treatment strategy in 2008: analysis of a monitor controlled registry (QUIK), Submitted for publication, 2011. 4. Wijns W, Kolh P, Danchin N, et al., Guidelines on myocardial revascularization, Eur Heart J , 2010;31(20):2501–55. 5. Pfisterer ME, Buser P, Osswald S, et al., Time dependence of left ventricular recovery after delayed recanalization of an occluded infarct-related coronary artery: findings of a pilot study, J Am Coll Cardiol , 1998;32(1):97–102. 6. Sirnes PA, Myreng Y, Mølstad P, et al., Improvement in left ventricular ejection fraction and wall motion after successful recanalization of chronic coronary occlusions, Eur Heart J, 1998; 19(2):273–81. 7. Melchior JP, Doriot PA, Chatelain P, et al., Improvement of left ventricular contraction and relaxation synchronism after recanalization of chronic total coronary occlusion by angioplasty, J Am Coll Cardiol, 1987;9(4):763–8. 8. Surber R, Schwarz G, Figulla HR, Werner GS, Resting 12-lead electrocardiogram as a reliable predictor of functional recovery after recanalization of chronic total coronary occlusions, Clin Cardiol , 2005;28(6):293–7. 9. Warren RJ, Black AJ, Valentine PA, et al., Coronary angioplasty for chronic total occlusion reduces the need for subsequent coronary bypass surgery, Am Heart J , 1990;120(2):270–4. 10. Bell MR, Berger PB, Bresnahan JF, et al., Initial and long-term outcome of 354 patients after coronary balloon angioplasty of total coronary artery occlusions, Circulation , 1992;85(3):1003–11. 11. Kirschbaum SW, Baks T, van den Ent M, et al., Evaluation of left ventricular function three years after percutaneous recanalization of chronic total coronary occlusions, Am J Cardiol, 2008;101(2):179–85. 12. Senior R, Kaul S, Lahiri A, Myocardial viability on echocardiography predicts long-term survival after

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revascularization in patients with ischemic congestive heart failure, J Am Coll Cardiol , 1999;33:1848–54. 13. Hochman JS, Lamas GA, Buller CE, et al., Coronary intervention for persistent occlusion after myocardial infarction, N Engl J Med , 2006;355(23):2395–407. 14. Joyal D, Afilalo J, Rinfret S, Effectiveness of recanalization of chronic total occlusions: a systematic review and metaanalysis, Am Heart J, 2010;160(1):179–87. 15. Prasad A, Rihal CS, Lennon RJ, et al., Trends in outcomes after percutaneous coronary intervention for chronic total occlusions: a 25-year experience from the Mayo Clinic, J Am Coll Cardiol , 2007;49(15):1611–8. 16. Suero JA, Marso SP, Jones PG, et al., Procedural outcomes and long-term survival among patients undergoing percutaneous coronary intervention of a chronic total occlusion in native coronary arteries: a 20-year experience, J Am Coll Cardiol , 2001;38(2):409–14. 17. Serruys PW, SYNTAX trial: Chronic total occlusion subsets, Presented at: Cardiovascular Research Technologies, Washington DC, US, 4-6 March 2009. 18. Galassi AR, Updates from the EuroCTO Club, Presented at: CTO Summit 2013, New York, US, February 2013. 19. Thompson CA, Jayne JE, Robb JF, et al., Retrograde techniques and the impact of operator volume on percutaneous intervention for coronary chronic total occlusions an early U.S. experience, JACC Cardiovasc Interv , 2009;2(9):834–42. 20. Galassi AR, Tomasello SD, Reifart N, et al., In-hospital outcomes of percutaneous coronary intervention in patients with chronic total occlusion: insights from the ERCTO (European Registry of Chronic Total Occlusion) registry, Eurointervention , 2011;7(4):472–9. 21. Reifart N, Percutaneous Revascularisation of Coronary Chronic Total Occlusion – Outcomes and development of strategies 2006–2010, Interventional Cardiology Review, 2011;6(2):128–33. 22. Morino Y, Abe M, Morimoto T, et al., Predicting successful guidewire crossing through chronic total occlusion of native coronary lesions within 30 minutes: the J-CTO (Multicenter CTO Registry in Japan) score as a difficulty grading and time assessment tool, JACC Cardiovasc Interv , 2011;4(2):213–21. 23. Laskey WK, Jenkins C, Selzer F, et al., Volume-to-creatinine clearance ratio: a pharmacokinetically based risk factor for

prediction of early creatinine increase after percutaneous coronary intervention, J Am Coll Cardiol , 2007;50(7):584–90. 24. Reifart N, The parallel wire technique for chronic total occlusions. Interventional Course Frankfurt, 1995: p. personal communication. 25. Nasser TK, Mohler ER 3rd, Wilensky RL, Hathaway DR, Peripheral vascular complications following coronary interventional procedures, Clin Cardiol , 1995;18(11):609–14. 26. Reifart N, The Parallel Sheath Technique in Severe Iliac Tortuosity, Eurointerv , 2013: p. in print. 27. Valenti R, Vergara R, Migliorini A, et al., Predictors of reocclusion after successful drug-eluting stent-supported percutaneous coronary intervention of chronic total occlusion, J Am Coll Cardiol , 2013;61(5):545–50. 28. Werner GS, The BridgePoint devices to facilitate recanalization of chronic total coronary occlusions through controlled subintimal reentry, Expert Rev Med Device s, 2011;8(1):23–9. 29. Mollet NR, Hoye A, Lemos PA, et al., Value of preprocedure multislice computed tomographic coronary angiography to predict the outcome of percutaneous recanalization of chronic total occlusions, Am J Cardiol, 2005;95(2):240–3. 30. Kaneda H, Saito S, Shiono T, et al., Sixty-four-slice computed tomography-facilitated percutaneous coronary intervention for chronic total occlusion, Int J Cardiol, 2007;115(1):130–2. 31. Di Mario C, Werner GS, Sianos G, et al., European perspective in the recanalisation of Chronic Total Occlusions (CTO): consensus document from the EuroCTO Club, Eurointervention , 2007;3(1):30–43. 32. Silvestri M, Parikh P, Roquebert PO, et al., Retrograde left main stenting, Cathet Cardiovasc Diagn, 1996;39:396–9. 33. Surmely JF, Tsuchikane E, Katoh O, et al., New concept for CTO recanalization using controlled antegrade and retrograde subintimal tracking: the CART technique, J Invasive Cardiol, 2006;18(7):334–8. 34. Rathore S, Katoh O, Matsuo H, et al., Retrograde Percutaneous Recanalization of Chronic Total Occlusion of the Coronary Arteries, Circulation: Cardiovascular Interventions, 2009;2(2):124–32. 35. Werner G, The retrograde aproach increases complications and adds little to CTO angioplasty, Presented at: Transcatheter Cardiovascular Therapeutics, Washington, US, 21–25 September 2010.

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The Anatomic–Functional Duality of So-called ‘Significant’ Atherosclerotic Stenosis – Update on Invasive Diagnostic Strategies in Coronaropathy G é ra r d F i n e t a n d G i l l e s Ri o u f o l Department of Coronary Artery and Valvular Diseases and Interventional Cardiology, Cardiovascular Hospital – Hospices Civils de Lyon and Claude Bernard University, INSERM U1060 (CARMEN), Lyon, France

Abstract So-called ‘significant’ atherosclerotic coronary stenosis is defined by a simple binary morphological index of tightness – percent diameter stenosis (%DS >50 %). Invasive diagnosis of atherosclerotic coronary lesions classically comprises two consecutive stages, which can be fairly accurately described as angiographic visual perception and functional deduction. This anatomic–functional duality should be seen as not so much antithetic as causal and finally quite complex. The present update seeks to: define the ambiguous relationship between functional impact and morphology in atherosclerotic coronary stenosis; to specify the means of invasive diagnosis complementing coronary angiography to compensate the anatomic and functional limitations intrinsic to the latter (cross-sectional intravascular ultrasound [IVUS] and optical coherence tomography [OCT] imaging and fractional flow reserve [FFR] determined by pressure guide); and to bring these preliminary considerations to bear on the design of algorithms to guide the use of complementary invasive diagnostic exploration and draw up a novel diagnostic strategy in interventional cardiology (first-line coronary angiography).

Keywords Fractional flow reserve, coronary angiography, intravascular ultrasound, percutaneous coronary intervention, clinical decision-making Disclosure: The authors have no conflicts of interest to declare. Received: 14 August 2013 Accepted: 3 September 2013 Citation: Interventional Cardiology Review, 2013;8(2):112–7 Correspondence: Gérard Finet, Hôpital Cardiologique, Groupement Hospitalier Est, 28 Avenue du Doyen Lépine, 69500 Bron Cedex, France. E: gerard.finet@univ-lyon1.fr

“Nothing comes to us except falsified and altered by our senses.” Michel de Montaigne (1533–1592) Coronary angiography (CA) has been performed in cardiology centres for more than 50 years. The diagnosis it provides soon became the gold standard in coronaropathy. It is a purely anatomic diagnosis, and this approach has made a deep mark on cardiology, although the need for a prior non-invasive functional approach was quickly admitted and developed.1,2 Nevertheless, our view of the functional impact of coronary stenosis was quickly reduced to a hypothetico-deductive inference drawn from a simple morphological index. So-called ‘significant’ atherosclerotic coronary stenosis is defined by a simple binary morphological index of tightness – percent diameter stenosis (%DS >50 %) – to which the most recent guidelines on myocardial revascularisation still refer for clinical decision-making.3 A ‘stenosis’ is visualised as a pathological focal anatomic entity on imaging, and its functional impact on myocardial perfusion (i.e. its significance) is then, still to the present day, inferred by a process of hypothetico-deductive reasoning. Interventional cardiologists presently dispose of at least three complementary techniques supplementing CA: intravascular ultrasound (IVUS) and optical coherence tomography (OCT), and pressure guide to determine fractional flow reserve (FFR). The present update seeks to: • define the ambiguous relationship between functional impact and morphology in atherosclerotic coronary stenosis;

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• specify the means of invasive diagnosis, both anatomical and functional, complementing CA in order to compensate for the anatomic and functional limitations intrinsic to the latter; and • bring these preliminary considerations to bear on the design of different diagnostic exploration strategies in interventional cardiology.

The Ambiguous Relationship Between Anatomy and Functional Impact in Atherosclerotic Coronary Stenosis Haemodynamic impact is determined by many purely morphologic factors such as minimum lumen area, upstream arterial reference area, lesion length, wall lesion irregularity, lesion entry and exit angles, and vascular remodelling, but also by haemodynamic (flow and pressure) and rheological factors (haematocrit and blood viscosity). 4 However, the overall ischaemic impact of coronary stenosis on underlying myocardial perfusion is the outcome of even more complex interactions, involving the effect of any spread of atherosclerosis to the epicardial arterial segment as a whole, and of changes in arteriolar resistive microcirculation, collateral circulation and myocardial tissue itself.5 Given the underlying physiopathological complexity, it seems highly reductive to see the haemodynamic impact of obstructive coronary artery stenosis as a simple change in relative diameter between an upstream segment considered to be normal and the minimum stenosis diameter (% DS).2

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The 1974 Gould et al. study of a dog model of progressive quantified circumflex artery obstruction, statistically determined the degrees of stenosis associated with significant flow change at rest or under hyperaemia.6 Experimental hyperaemia is induced by 10 seconds total coronary artery obstruction. This was later replaced by a pharmacological effect, at first using papaverine, quickly changed to a continuous intravenous perfusion, or as is still used today, an intracoronary bolus injection of adenosine.7 At rest, an 85 % reduction in lumen diameter reduces coronary flow, while the hyperaemic response is affected as of 45 % stenosis and becomes significant as of 60 %. Gould therefore suggested that obstructive coronary stenosis becomes haemodynamically significant under effort or, more generally, under hyperaemia when diameter is reduced by 60 % or more. Cut-off quickly came to be set at a 50 % binary threshold, which became the functional index for significant coronary stenosis. This index has held sway for more than 40 years, although already criticised in the 1980s.8 Percent stenosis does seem to predict haemodynamic impact in a dog model in which the arterial network as a whole is strictly normal except for the mechanical obstruction. However, even in his princeps animal model, Gould reported variability in measurements, presaging greater uncertainty in patient-to-patient and artery-to-artery values.9 A clear discrepancy soon emerged between degree of stenosis (%DS) and maximal hyperaemia or coronary flow reserve (CFR) in several human studies using invasive or computed tomography (CT) coronary arteriograms.10,11 Indices such as CFR or myocardial microvascular resistance index fail to answer the question as to whether an epicardial coronary stenosis in itself accounts for observed myocardial ischaemia.2 CFR assesses the ratio of myocardial blood flow to hyperaemic flow; it cannot be compared to a patient’s normal value, so that normal CFR is poorly defined and highly variable from patient to patient.12 Moreover, the technique involves several limitations and above all is not specific to epicardial coronary stenosis exploration. The index of myocardial resistance (IMR) expresses only the resistance of intramyocardial microvasculature.13,14 Myocardial resistance pathologically elevated by microangiopathy or myocardial fibrosis cannot be improved by any epicardial coronary revascularisation.9 Thus only a physiopathological index specific to epicardial stenosis, and more precisely to the epicardial compartment itself, can be of use in indicating revascularisation. Such an index of epicardial circulation physiology should take account of normal and pathological (stenotic) epicardial flow rates. It also needs to: • be independent of haemodynamic loading and rheological conditions; • take possible collateral function into account; and • take account of any myocardial pathology. This is what FFR succeeds in assessing precisely, lesion by lesion and more generally coronary artery by coronary artery.15,16

The Intrinsic Limitations of Coronary Angiography X-ray CA has been in use for more than 50 years; it gives planar projection images, leading to a confusion of planes. It provides only a densitometric luminogram by iodine contrast injection. Its spatial resolution has not improved over the 50 years, and the development

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of digital flat panels enhanced the images only by increasing the contrast resolution and eliminating geometric distortions. Visual and even computer-assisted quantitative analysis has never been very precise.17 The most widely used quantitative parameter is variation in %DS according to differential diameter between a reference segment and the minimum lesional diameter. In one study, only 60 out of 884 angiographically normal reference segments (6.8 %) were normal on intravascular ultrasound;18 moreover, the detection and quantification of minimum lumen diameter is imprecise.19 Detection and quantification of left coronary artery lesions on CA alone are also inaccurate.20 Finally, CA does not provide precise anatomic information on the different types of atherosclerotic lesion and their complications; it is thus impossible to detect plaques, quantify plaque burden, specify plaque composition, or detect intraparietal or adventitial haematoma or certain dissections. Even in analysing the lumen itself, intraluminal densitometric variations are ambiguous – endoluminal thrombus, calcified protrusion, highly excentric stenosis, flap and plaque rupture. Equivalent limitations in CT coronary angiography have also been described.21

The Need to Overcome the Morphologic Limitations of Coronary Angiography All of these morphologic limitations intrinsic to CA inspired the development of realtime high-resolution invasive complementary imaging techniques. These cross-sectional images provide full information from the lumen to the complete arterial wall. They enable precise quantification, with the possibility of three-dimensional (3D) reconstruction. Thus in the early 1990s, intravascular ultrasound (IVUS) began to complement the morphologic failings of CA by supplying cross-sectional imagery. Progressive advances have notably concerned improved spatial resolution by increasing the ultrasound frequency (90 micrometer [µm] at 40 megahertz [MHz]). Quantitative analysis thus gained in precision, overall assessment of the arterial wall and its impact on the lumen became clearly defined, and pathological mechanisms at work in the wall can now be rapidly detected and correctly described.22 Analysis of plaque composition is more limited, being based on simple acoustic reflectivity, providing only approximate assessment of the ternary aspect of the usual plaque components (anechogenic or hypoechogenic structures), which merely indicate the absence of a reflective ingredient such as calcium, collagen or elastin.23 IVUS resolves certain endo- or extra-luminal ambiguities with a more or less complex additional image; and precisely detects plaque rupture following acute coronary syndrome, parietal thrombus, intra-plaque or intra-adventitia haematoma and certain ambiguities in the distribution or protrusion of calcification. Alongside the development of complex coronary angioplasty, IVUS has become a tool for selecting, guiding and assessing percutaneous coronary intervention (PCI) with stent implantation.24 Long-term clinical outcome after IVUS-guided stent implantation and long-term mortality in stenting for unprotected left main coronary artery stenosis have improved significantly.25 Taken together, these advantages, completing classical CA diagnosis with precision, have been drawn up into a level IIa/IIb set of recommendations.26 Endocoronary imaging has recently seen the advent of OCT, based on a different physical principle from IVUS and providing much-improved spatial resolution of around 13 µm.27 Unfortunately, the physics underlying this technique means that the wavelengths used cannot penetrate deep in a plaque (not more than 0.5–1.0 millimetres [mm], depending on the type of tissue) thus the

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Coronary Interventions Coronary Stenosis for location purposes. While effort tests do not help with location, myocardial scintigraphy and stress echo are claimed to do so. However, using FFR and its ability to analyse stenosis-by-stenosis and, more generally, artery-by-artery, several reports have demonstrated the locational imprecision of these tests in multivessel disease.45,46 These findings have a real impact on strategy, if myocardial revascularisation is indicated only on positive results on these non-invasive tests and on their topographic analysis, only partial revascularisation of myocardial ischaemia will be achieved (see Figure 2). In acute coronary syndrome, the need for early treatment means that other lesions over and above the culprit lesion may be discovered, and frequently dilated without objective proof of ischaemia (see Figure 3).47

First-line Coronary Angiography – A Provocative Diagnostic Strategy? There is a new strategy that should be mentioned and can now be argued for; implementing CA in first-line without preliminary noninvasive testing (see Figure 4). This attitude may seem at first glance to be provocative, but now in 2013 that is not really the case.

present day however, it is coherent – the twofold limitations of CA can and should be corrected by FFR and IVUS.56 First-line coronary angiography after risk stratification by precise clinical assessment can be an effective strategy,57 with: • detection and anatomic analysis of focal or diffuse atherosclerotic coronary lesions; • precise functional assessment by artery-to-artery and lesion-tolesion measurement of FFR;5 • provocative tests in case of vasospastic or variant angina;58 • documented topographic decision-making for any revascularisation (by PCI or CABG);59 and finally • early comprehensive treatment with greater diagnostic certainty than achieved with non-invasive testing (whether single or successive) on a classic Bayesian approach to the diagnosis of coronary artery disease. Algorithms may be drawn up for a revascularisation strategy functionally determined by FFR and anatomically guided by IVUS.60

Conclusion In reality, non-invasive tests are rarely performed ahead of angioplasty. The accuracy of non-invasive functional tests is often poor.48–51 The various stress imaging techniques (stress echocardiography, perfusion scintigraphy and cardiac magnetic resonance imaging [MRI] stress testing), while known to show better diagnostic performance than conventional exercise electrocardiography (ECG),52 seem to be less effective for locating myocardial ischaemia than artery-by-artery FFR measurement.45,46,53–55 Even so, CA performed without non-invasive testing in patients at intermediate or high-risk of clinically significant coronary disease will involve intrinsic anatomic and especially functional limitations. A decade ago, this attitude would have been difficult to defend; in the

Topol EJ, Nissen SE, Our preoccupation with coronary luminology. The dissociation between clinical and angiographic findings in ischemic heart disease, Circulation, 1995;92(8):2333–42. 2. Gould KL, Does Coronary Flow Trump Coronary Anatomy?, JACC Cardiovasc Imaging, 2009;2:1009–23. 3. Wijns W, Kolh P, Danchin N, et al., Guidelines on myocardial revascularization, Eur Heart J , 2010;31:2501–55. 4. In: Gould KL, Coronary Artery Stenosis 1st Edition , New York, US: Elsevier Science Publishing,1991;4:41–52. 5. Kern MJ, Samady H, Current concepts of integrated coronary physiology in the catheterization laboratory, J Am Coll Cardiol, 2010;55;173–85. 6. Gould KL, Lipscomb K, Effects of coronary stenoses on coronary flow reserve and resistance, Am J Cardiol , 1974;34:48–55. 7. Rioufol G, Caignault JR, Finet G, et al., 150 microgram intracoronary adenosine bolus for accurate fractional flow reserve assessment of angiographically intermediate coronary stenosis, EuroIntervention, 2005;1(2):204–7. 8. Raphael MJ, Donaldson RM, A “significant” stenosis: thirty years on, Lancet, 1989;1(8631):207–9. 9. Gould KL, Kirkeeide RL, Buchi M, Coronary flow reserve as a physiologic measure of stenosis severity, J Am Coll Cardiol, 1990;15;459–74. 10. White CW, Wright CB, Doty DB, et al., Does visual interpretation of the coronary arteriogram predict the physiologic importance of a coronary stenosis?, N Engl J Med, 1984;310:819–24. 11. Meijboom WB, Van Mieghem CA, van Pelt N, et al., Comprehensive assessment of coronary artery stenoses: computed tomography coronary angiography versus conventional coronary angiography and correlation with fractional flow reserve in patients with stable angina, J Am Coll Cardiol, 2008;52:636–43. 12. Erbel R, Ge J, Bockisch A, et al., Value of intracoronary ultrasound and Doppler in the differentiation of angiographically normal coronary arteries: a prospective study in patients with angina pectoris, Eur Heart J, 1996;17;880–9.

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The interventional cardiologist is above all a clinician, whose diagnosis of coronary artery disease is greatly refined by the systematic anatomic and functional confirmation provided by the various forms of invasive exploration now available. Indeed, the interventional cardiologist has probably become a better pathologist of coronary disease, and certainly a physiopathologist. The nonredundant complementarity of pressure guides and IVUS (or OCT) in correcting the functional and anatomic uncertainties inherent to coronary angiography has, over the years, acquired major IA recommendation in the case of FFR and IIa/b-B/C recommendation as useful and effective in the case of IVUS. These important recent developments now guarantee unambiguous management adapted to each CAD patient’s individual case. n

13. Fearon WF, Balsam LB, Farouque HM, Novel index for invasively assessing the coronary microcirculation, Circulation, 2003;107:3129–32. 14. Melikian N, Vercauteren S, Fearon WF, et al., Quantitative assessment of coronary microvascular function in patients with and without epicardial atherosclerosis, EuroIntervention, 2010;5;939–45. 15. De Bruyne B, Baudhuin T, Melin JA, et al., Coronary flow reserve calculated from pressure measurements in humans. Validation with positron emission tomography, Circulation, 1994;89;1013–22. 16. De Bruyne B, Bartunek J, Sys SU, et al., Simultaneous coronary pressure and flow velocity measurements in humans. Feasibility reproducibility, and hemodynamic dependence of coronary flow velocity reserve, hyperemic flow versus pressure slope index, and fractional flow reserve, Circulation, 1996;94;1842–9. 17. Finet G., Liénard J, Parameters that influence accuracy and precision of quantitative coronary arteriography, Int J Cardiac imaging, 1996;12:271–87. 18. Mintz GS, Painter JA, Pichard AD, et al., Atherosclerosis in angiographically “normal” coronary artery reference segments: an intravascular ultrasound study with clinical correlations, J Am Coll Cardiol, 1 995;25(7):1479–85. 19. Liénard J, Sureda F, Finet G, The 6sigma quality approach for quantitative arteriography performance improvement, Int J Card Imaging, 2002;18:77–92. 20. Motreff P, Rioufol G, Gilard M, et al., Diffuse atherosclerotic left main coronary artery disease unmasked by fractal geometric law applied to quantitative coronary angiography: an angiographic and intravascular ultrasound study, EuroIntervention , 2010;5(6):709–15. 21. Nissen SE, Limitations of computed tomography coronary angiography, J Am Coll Cardiol, 2008;52:2145–7. 22. Mintz GS, Nissen SE, Anderson WD, et al., American College of Cardiology Clinical Expert Consensus Document on Standards for Acquisition, Measurement and Reporting of Intravascular Ultrasound Studies (IVUS). A report of the American College of Cardiology Task Force on Clinical Expert

Consensus Documents, J Am Coll Cardiol , 2001;37:1478–92. 23. Chopard R, Boussel L, Motreff P, et al., How reliable are 40 MHz IVUS and 64-slice MDCT in characterizing coronary plaque composition? An ex vivo study with histopathological comparison, Int J Cardiovasc Imaging , 2010;26(4):373–83. 24. Hong MK, Mintz GS, Lee CW, et al., Intravascular ultrasound predictors of angiographic restenosis after sirolimus-eluting stent implantation, Eur Heart J, 2006;27:1305–10. 25. Roy P, Steinberg DH, Sushinsky SJ, et al., The potential clinical utility of intravascular ultrasound guidance in patients undergoing percutaneous coronary intervention with drugeluting stents, Eur Heart J, 2008;29:1851–7. 26. Smith SC Jr, Feldman TE, Hirshfeld JW Jr, et al., ACC/AHA/ SCAI 2005 guideline update for percutaneous coronary intervention: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines (ACC/AHA/ SCAI Writing Committee to Update 2001 Guidelines for Percutaneous Coronary Intervention), Circulation , 2006;113(7):e166–286. 27. Bezerra HG, Attizzani GF, Sirbu V, et al., Optical coherence tomography versus intravascular ultrasound to evaluate coronary artery disease and percutaneous coronary intervention, JACC Cardiovasc Interv , 2013;6(3):228–36. 28. Park SJ, Kim YH, Park DW, et al., Impact of intravascular ultrasound guidance on long-term mortality in stenting for unprotected left main coronary artery stenosis, Circ Cardiovasc Interv, 2009;2:167–77. 29. Pijls NH, Van Gelber B, Van der Voort P, et al., Fractional flow reserve. A useful index to evaluate the influence of an epicardial coronary stenosis on myocardial blood flow, Circulation, 1995;92:3183–93. 30. Pijls NH, De Bruyne B, Peels K, et al., Measurement of fractional flow reserve to assess the functional severity of coronary-artery stenoses, N Engl J Med , 1996;334:1703–8. 31. In: Pijls HHJ, de Bruyne B, Coronary Pressure 2nd Editon , Dordrecht, The Netherlands: Kluwer Academic Publishers, 1997;10:189–220. 32. Tonino PAL, Fearon WF, De Bruyne B, et al., Angiographic

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College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/SCAI Writing Committee to Update the 2001 Guidelines for Percutaneous Coronary Intervention), Circulation, 2006;113:156–75. Topol EJ, Ellis SG, Cosgrove DM, et al., Analysis of coronary angioplasty practice in the United States with an insuranceclaims data base, Circulation, 1993;87:1489–97. Lin GA, Dudley RA, Lucas FL, et al., Frequency of stress testing to document ischemia prior to elective percutaneous coronary intervention, JAMA , 2008;300:1765–73. Melikian N, De Bondt P, Tonino P, et al., Fractional flow reserve and myocardial perfusion imaging in patients with angiographic multivessel coronary artery disease, JACC Interv, 2010;3:307–14. Jung PH, Rieber J, Störk S, et al., Effect of contrast application on interpretability and diagnostic value of dobutamine stress echocardiography in patients with intermediate coronary lesions: comparison with myocardial fractional flow reserve, Eur Heart J, 2008;29:2536–43. Cavender MA, Milford-Beland S, Roe MT, et al., Prevalence, predictors, and in-hospital outcomes of non-infarct artery intervention during primary percutaneous coronary intervention for ST-segment elevation myocardial infarction (from the National Cardiovascular Data Registry), Am J Cardiol , 2009;104:507–13. Ashley EA, Myers J, Froelicher V, Exercise testing in clinical medicine, Lancet , 2000;356:1592–7. Hung J, Chaitman BR, Lam J, et al., Noninvasive diagnostic test choices for the evaluation of coronary artery disease in women: a multivariate comparison of cardiac fluoroscopy, exercise electrocardiography and exercise thallium myocardial perfusion scintigraphy, J Am Coll Cardiol, 1984;4:8–16. Ciaroni S, Bloch A, Albrecht L, Vanautryve B, Diagnosis of coronary artery disease in patients with permanent cardiac pacemaker by dobutamine stress echocardiography or exercise thallium-201 myocardial tomography, Echocardiography, 2000;17:675–9. Alexánderson E, Mannting F, Gómez-Martín D, et al.,

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Technetium-99m-Sestamibi SPECT myocardial perfusion imaging in patients with complete left bundle branch block, Arch Med Res, 2004;35:150–6. Metz LD, Beattie M, Hom R, et al., The prognostic value of normal exercise myocardial perfusion imaging and exercise echocardiography: a meta-anlysis, J Am Coll Cardiol, 2007;49:227–37. Beleslin B, Dobric M, Sobic-Saranovic D, et al., Fractional flow reserve and myocardial viability as assessed by SPECT perfusion scintigraphy in patients with prior myocardial infarction, J Nucl Cardiol, 2010;17:817–24. Förster S, Rieber J, Ubleis C, et al., Tc-99m sestamibi single photon emission computed tomography for guiding percutaneous coronary intervention in patients with multivessel disease: a comparison with quantitative coronary angiography and fractional flow reserve, Int J Cardiovasc Imaging, 2010;26(2):203–13. Ragosta M, Bishop AH, Lipson LC, et al., Comparison between angiography and fractional flow reserve versus single-photon emission computed tomographic myocardial perfusion imaging for determining lesion significance in patients with multivessel coronary disease, Am J Cardiol, 2007;99:896–902. Rioufol G, Finet G, Functional versus anatomical stenosis evaluation: fractional flow reserve defeats intravascular ultrasound, JACC Cardiovasc Interv, 2011;4:812–3. Lipinski M, Froelicher V, Atwood E, et al., Comparison of treadmill scores with physician estimates of diagnosis and prognosis in patients with coronary artery disease, Am Heart J, 2002;143:650–8. Bugiardini R, Bairey Merz CN, Angina with “normal” coronary arteries: a changing philosophy, JAMA , 2005;293:477–84. Botman KJ, Pijls NH, Bech JW, et al., Percutaneous coronary intervention or bypass surgery in multivessel disease? A tailored approach based on coronary pressure measurement, Catheter Cardiovasc Interv , 2004;63:184–91. Park SJ, Ahn JM, Kang SJ, Paradigm shift to functional angioplasty new insights for fractional flow reserve and intravascular ultrasound-guided percutaneous coronary intervention, Circulation, 2011;124:951–7.

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Hypertension Renal Sympathetic Denervation

Catheter-based Renal Sympathetic Denervation – Long-term Symplicity™ Renal Denervation Clinical Evidence, New Data and Future Perspectives K a t rina Moun t f o r t , M e d i c a l Wr i t e r, R a d c l i f f e Ca r d i o l o g y

Based on Presentations at a Medtronic Sponsored Symposium held at EuroPCR 2013, Paris, France, on 21 May 2013 The article was reviewed for accuracy by the presenters: Felix Mahfoud,1 Roland Schmieder,2 Justin Davies,3 David E Kandzari,4 Joachim Weil5 and Robert Whitbourn6 1. Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes, Homburg/Saar, Germany; 2. Medizinische Klinik IV, Universitätsklinikum Erlangen, Erlangen, Germany; 3. Consultant Cardiologist, Hammersmith Hospital, Imperial College London, London, UK; 4. Chief Scientific Officer, Director, Interventional Cardiology, Piedmont Heart Institute, Atlanta, Georgia, US; 5. CardioMed Herzzentrum Nord, Sana Klinikum Lübeck, Akademisches Lehrkrankenhaus der Universität zu Lübeck, Lübeck, Germany; 6. Director, Cardiac Catheterization Labs and Coronary Intervention, The Cardiovascular Research Centre, University of Melbourne and Australian Catholic University, Melbourne, Australia

Abstract Hypertension is one of the most prevalent chronic diseases worldwide and the incidence of resistant hypertension is increasing. Catheter-based renal denervation (RDN) offers a new approach to reaching blood pressure goals by targeting the renal nerves. The technique has demonstrated significant and sustained reductions in blood pressure (BP) in the Symplicity HTN-1 and Symplicity HTN-2 clinical trials. The Global SYMPLICITY Registry aims to demonstrate safety and effectiveness in a ‘real-world’ patient population. Real-world RDN experience has emphasised that patient selection is crucial to successful outcomes; a multidisciplinary referral network is recommended to increase awareness of the procedure and identify patients who are likely to respond best to RDN. Further advances in catheter technology have led to the development of the multi-electrode Symplicity Spyral™ multi-electrode catheter; preliminary data from the feasibility study using the Symplicity Spyral catheter indicate clinical efficacy and procedural safety with reduced procedure times. The Symplicity Spyral catheter is not yet commercially available. The indications of RDN may also expand beyond resistant hypertension – encouraging data have been seen in patients with moderate treatment resistant hypertension. Furthermore, RDN may be beneficial in other clinical states characterised by sympathetic nervous system overactivation including heart failure and chronic kidney disease. Additional data are needed to evaluate the efficacy of RDN in these disease states.

Keywords Blood pressure, radiofrequency ablation, renal denervation, resistant hypertension, Symplicity Disclosure: All authors have served either in a consultancy or advisory capacity, or on a speakers’ bureau for Medtronic. Acknowledgements: The speaking panel acknowledge Radcliffe Cardiology for providing writing and editing support. Received: 20 July 2013 Accepted: 5 September 2013 Citation: Interventional Cardiology Review, 2013;8(2):118–23

Support: The publication of this article was supported by Medtronic. The views and opinions expressed are those of the speakers and not necessarily those of Medtronic.

Hypertension is one of the most important public health problems of the 21st century, with a global prevalence of around 30 %.1 In 2010, it accounted for 7.5 million deaths worldwide, representing 12.8 % of the global total.2 Furthermore, its prevalence is projected to rise to 1.5 billion hypertensive patients in 2025.3 Despite the availability of numerous safe and effective antihypertensive medications, the proportion of hypertensive patients achieving recommended blood pressure (BP) targets is only around 50 %.4 Resistant hypertension is generally defined as BP that remains high (>140/90 millimetres of mercury [mmHg]) despite the concomitant use of antihypertensive drugs from more than three drug classes, including a diuretic.5 Estimates of its prevalence vary widely, but data from observational studies and clinical trials suggest that 8–30 % of treated hypertension

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patients have resistant hypertension.6 Given that cardiovascular mortality doubles with each 20/10 mmHg increase in BP,7 resistant hypertension represents a serious global health challenge. New approaches to the treatment of patients with resistant hypertension are an important clinical need. Percutaneous catheterbased transluminal renal ablation (renal denervation [RDN]) is emerging as a novel treatment approach for resistant hypertension. Renal nerve activation contributes to the pathogenesis of hypertension as a result of renal vasoconstriction; renal blood flow and glomerular filtration rate (GFR) decrease; increased sodium reabsorption and renin release.8,9 RDN, involving a multiple application of radiofrequency (RF) energy using a catheter, has been shown to provide an effective and

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Long-term Symplicity™ Renal Denervation Clinical Evidence, New Data and Future Perspectives

Figure 1: Symplicity HTN-2, Changes in Office Blood Pressure Over 30 Months Initial RDN Group 0

12m

24m

Crossover Group

30m

12m

18m

24m

Table 1: Overview of the Symplicity™ Renal Denervation Clinical Trial Programme Trial

Description

Symplicity

Series of non-randomised 153

Status Completed, 3 year

HTN-1

pilot studies

follow-up data

Symplicity

1:1 randomisation

available -10

-10 -12

-10

-8

-10 -13

-20

-30

-28 -32

-40

HTN-2 -10

-13

-24

-24 -28

-29 -35

-40 SBP

-35

DBP

DBP = diastolic blood pressure; m = months; SBP = systolic blood pressure. Esler, 2013.20 Reproduced from slide 14, Kandzari presentation.

Completed enrolment, 2 year

-10

-20

-30

106

follow-up data available SYMPLICITY

Randomised controlled

HTN-3

trial (2:1)

530

Enrolment completed May 2013

SYMPLICITY-HF Feasibility study

Global

Prospective,

5,000 Enrolling

SYMPLICITY

non-interventional

Registry

registry

SYMPLICITY

Randomised controlled

HTN-Japan

trial (1:1)

SYMPLICITY HTN-4 SYMPLICITY

Enrolling

100

Enrolling

Randomised controlled

530–

To start in latter half of

trial (2:1)

580

2013

Single-arm trial

Planned

HTN-India

safe means of reducing sympathetic outflow to and from the kidneys without adversely affecting other functions of the kidney.10 It is a minimally invasive procedure, characterised by short recovery times and the absence of significant systemic side effects.11 The treatment has resulted in significant and sustained BP reductions over 36 months in the majority of patients with resistant hypertension12–14 and has been associated with improvements in health-related quality of life.15 A recent study also suggested that RDN is a cost-effective strategy for resistant hypertension.16 Several devices have been approved for RDN, the most established of which is the Symplicity™ renal denervation system (Medtronic, Inc). The Symplicity Flex™ catheter is specifically designed for the renal anatomy, being non-occlusive and 6 French guiding catheter compatible. The Symplicity G2™ generator utilises specific algorithms that ensure optimal delivery of RF energy to the renal artery. The procedure requires application of RF energy to 4–6 locations within each of the renal arteries to effect renal nerve interruption. The technique is straightforward to perform – treatment of renal arteries without angiographic stenosis with the Symplicity Flex catheter requires two minutes duration per treatment for a total bilateral denervation time of 8–12 minutes. Its use is supported by extensive worldwide experience, including a clinical evaluation programme. This review will present the clinical evidence in support of RDN, as well as considering future perspectives on the technique.

The Symplicity™ Renal Denervation Clinical Trial Programme Early clinical trial data showed that the use of the Symplicity RDN system was associated not only with reductions in systolic BP (SBP) and diastolic BP (DBP) but also with markers of hypersympathetic activity, such as reductions in muscle sympathetic activity and reductions in cardiac baroreflex sensitivity,11 as well as a reduction in renal noradrenaline spillover.17 The first human clinical trial, Renal Denervation in Patients With Uncontrolled Hypertension (Symplicity HTN-1) (n=153), was an aggregate of multiple studies of patients with resistant hypertension (office SBP ≥160 mmHg with at least three or more antihypertensive

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medications, including a diuretic) and normal renal function (GFR >45 millilitres per minute [ml/min]).12,17 At six months, 92 % of patients had an office BP reduction of ≥10 mmHg, with reductions in SBP and DBP of 25/11 mmHg, respectively (p<0.0001). Safety data were excellent – 97 % of patients had no complications. The four acute procedural complications included three pseudoaneurysms of the common femoral artery and one renal artery dissection, all managed without further sequelae. Three-year follow-up data showed no treatment-related vascular complications; no hypotensive events that required hospitalisation; no orthostatic hypotension; no electrolyte disturbances; and no significant changes in mean electrolytes or estimated GFR (eGFR).18 Of the short-term follow-up renal imaging performed, no evidence of renal artery stenosis or abnormalities was noted in treated arteries. The successful results of the Symplicity HTN-1 trial were expanded by the multicentre, prospective, randomised Renal Denervation in Patients With Uncontrolled Hypertension (Symplicity HTN-2) trial (n=106), in which patients with resistant hypertension and office SBP ≥160 mmHg (≥150 mmHg for patients with type 2 diabetes) were randomised to RDN immediately or after six months, without any change in the previous antihypertensive medication regimen. At six months, RDN was associated with BP reductions of 32/12 mmHg (p<0.0001),13 showing superiority over medication management alone, and similar results were reported at two years.19 Recently presented 30-month follow-up data showed durable BP reductions of 35/13 mmHg (p<0.01) in subjects available at data lock. At six months after randomisation, 46 of the 51 patients available for follow-up crossed over to RDN, 35 of which still met initial eligibility criteria. In the crossover group, a significant reduction in both SBP and DBP was of almost equal magnitude to that of the initial treatment cohort (see Figure 1).20 The Renal Denervation in Patients With Uncontrolled Hypertension (SYMPLICITY HTN-3) trial (n=530) is a multicentre, prospective randomised controlled study, which is blinded and includes a mask blinded (sham) procedure in the study design.21 It will address ambulatory blood pressure monitoring (ABPM) as both an entry criteria and a powered secondary endpoint. In addition, a feasibility

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Hypertension Renal Sympathetic Denervation concomitant use of oral sympatholytic drugs, and consider age, heart rate and BP above and below median.

study in heart failure (Renal Denervation in Patients With Chronic Heart Failure & Renal Impairment Clinical Trial [SYMPLICITY-HF], n=40), and a hypertension clinical trial in Japan (Renal Denervation by MDT-2211 System in Patients With Uncontrolled Hypertension [HTN-J], n=100) are underway. Further trials in India (Single-arm Study of Symplicity™ Renal Denervation System in Patients With Uncontrolled Hypertension in India) and the US (Renal Denervation in Patients With Uncontrolled Hypertension [SYMPLICITY HTN-4]) are planned (see Table 1). All of these trials, together with the Global Prospective Registry for Sympathetic Renal Denervation in Selected Indications Through 3-5 Years Registry (Global SYMPLICITY Registry) discussed below, will include over 320 sites and nearly 6,000 patients.

terms of interpreting BP measurements and in obtaining an accurate diagnosis of resistant hypertension.

In summary, clinical trials to date investigating the safety and efficacy of RDN with the Symplicity RDN system for patients with resistant hypertension have demonstrated significant and durable reductions in BP; procedural, intermediate and long-term safety as well as preservation of electrolyte and human homeostasis. Ongoing evaluation should confirm the effectiveness of RDN in selected and broader patient populations.

Safety endpoints will include vascular complications; renal artery perforation or dissections; renal artery re-interventions; new renal artery stenosis; hypertensive crisis; contrast nephropathy (acute eGFR drop of >25 % or new renal failure); new need for dialysis; and significant embolic event resulting in end-organ damage. Stroke, acute MI, end-stage renal disease, atrial fibrillation and mortality will also be investigated.

The Global SYMPLICITY Registry

As of January 2013, data were available for 617 patients, the majority (60 %) of which had been treated according to the European Society of Cardiology (ESC) consensus guideline paper on RDN.27 Preliminary six-month data demonstrated an excellent procedural and clinical safety profile, including significant reductions in both office and ambulatory BP compared to baseline.23 In summary, the enrolment and analyses of the Global SYMPLICITY Registry continue to meet the goals of establishing the procedural safety and efficacy of RDN.

In addition to the Symplicity clinical trials, the Global SYMPLICITY Registry, which will include ≥5,000 patients in more than 200 sites worldwide, is being conducted.22,23 Inclusion criteria are patients 18 years and older that are eligible for RDN and sign a patient consent form. The registry will also include patients with conditions characterised by an increase in sympathetic activity, including heart failure, chronic kidney disease, sleep apnoea and atrial fibrillation. The aims of this registry are to document the long-term safety and effectiveness of RDN; in everyday clinical practice; to monitor BP response in different nationalities and races; to identify patients who are likely to respond best to RDN and to monitor pleiotropic treatment effects, such as changes in glucose metabolism, renal and cardiac function. Secondary objectives include duration of BP lowering after treatment.23 The Global SYMPLICITY Registry is intended as an umbrella under which national registries, including the German Renal Denervation (GREAT) registry in Germany (n=1,000), the Korea Registry (n=102) and the South Africa Registry (n=400), will contribute data. The recommended follow-up schedule is three months, six months, one year, and each year up to five years after treatment.23 Baseline and follow-up assessments will include patient demographics; physical measurements; office and 24-hour ambulatory BP, medication logs; quality of life; and heart rate. Vascular safety in the renal artery will be assessed and right ventricular imaging will also be conducted for those patients who receive cardiac imaging as per their standard of care, since it has been shown that RDN reduces heart rate.24 Patient selection is crucial to the success of RDN therefore subgroup analysis from the registry will be performed to determine whether any patient group especially benefits from the procedure. This will include renal function (eGFR <60 versus >60 ml/min/1.73 square metres [m2]). The registry will also compare dippers (patients with lower BP at night) to non-dippers (characterised by an increased sympathetic activity and an indication of higher cardiovascular risk). Analyses will also focus on subgroups with left ventricular hypertrophy (LVH), an indicator of end-organ damage in arterial hypertension. The presence of LVH is associated with an increased rate of cardiovascular events and death independent of BP.25 Subgroup analysis will also include patients with type 2 diabetes, impaired glucose tolerance, hyperinsulinemia,

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Changes in medication will also be recorded. It is recommended that baseline medication is maintained in order to accurately assess the net effect of RDN on BP, although in practice patients tend to manage their medications themselves. Poor compliance to therapy is a well-known problem in resistant hypertension; a recent study involving toxicological urine analysis found that drug adherence in resistant hypertension was only 47 %.26 This leads to difficulties in

The Symplicity Spyral™ Multi-electrode Renal Denervation Catheter Renal denervation using the Symplicity Flex catheter has demonstrated efficacy and safety both in clinical trial and real-world settings; however, it would be desirable to minimise the amount of treatment time required during the procedure. The Symplicity Spyral multi-electrode renal denervation catheter was designed with the goal of reducing procedure time while maintaining similar clinical outcomes and reassurance of success as compared to the original proven Symplicity Flex catheter. The Symplicity Spyral catheter has a helical-shape, and the electrode array consists of four independently selectable RF electrodes radially spaced by approximately 90 degrees to each other. The electrodes deliver energy simultaneously, decreasing the time for the ablation cycle to one minute per artery (see Figure 2) and the commercial catheter can be used for arteries with diameters between 3 and 8 millimetres (mm) (‘one-size-fits-all’). Preclinical data using a porcine model showed that the ablation pattern achieved using the Symplicity multi-electrode catheter was consistent with the ablation pattern obtained with the Symplicity single-electrode catheter. At 28 days post-intervention, no difference in norepinephrine levels, a measure of renal sympathetic activity, was seen between the multi-electrode and single-electrode catheter; in both cases there was a significant reduction compared with the control kidneys. Histological evaluation also revealed no sign of injury to the renal artery.28 A feasibility study is underway to assess the efficacy of the Symplicity Spyral catheter in the acute setting. The feasibility study is expected to include up to 50 patients in total. The inclusion criteria are similar to those used in the Symplicity clinical trials. Initial results in 29 patients were presented at the 2013 EuroPCR meeting in Paris, France. The

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In summary, in data generated to date, the Symplicity Spyral catheter had a safety profile consistent with the safety results demonstrated by the Symplicity Flex catheter; had demonstrated preclinical and clinical efficacy data consistent with the Symplicity Flex catheter; and confers the advantage of shorter treatment duration.

Effectiveness of Renal Denervation in Mild to Moderate Resistant Hypertension The safety and efficacy of RDN for BP reduction in patients with severe resistant hypertension has been established. However, such patients represent only a small portion of the hypertensive community. Current studies are investigating the possibility of expanding the therapeutic indications for RDN, including the larger ‘mild to moderate’ resistant hypertension population. An ongoing observational non-randomised trial29 (n=54) included patients with office BP above 140/90 mmHg and below 160/100 mmHg; all had been on three medications, one of which was a diuretic. The objectives were to analyse the reduction in office BP, as well 24-hour ABPM. Preliminary data from this study show that the absolute reduction in office BP was 12.5/7.5 mmHg (17.6/8.8 mmHg in patients with available ABPM, n=36) after six months, numerically less than the reductions observed in the Symplicity HTN-1 and Symplicity HTN-2 clinical trials (see Figure 3).29 This is unsurprising given the lower baseline BP in the patient population. Heart rate dropped significantly from 67 to 63 beats per minute. In 37 % of the patients, antihypertensive medication was reduced during the follow-up period, despite the guidance of the study protocol not to do so. Antihypertensive medication was not increased in any patient. In 51 % of the patients, office BP was controlled (defined as <140/90 mmHg) after RDN. Furthermore, there was a substantial reduction in 24-hour ambulatory BP (14.1/6.6 mmHg) (see Figure 3). An increasing body of evidence suggests that reduction of 24-hour ambulatory BP may provide superior cardiovascular risk reduction to office BP.30 However, management decisions based on the interpretation of ABPM patterns are more complex than with office BP, and suitable educational processes are required. In summary, although this was a small study and lacked a control group, the data indicated that RDN resulted in a substantial reduction in both office and 24-hour ambulatory BP in mild to moderate resistant hypertension. These results will need to be confirmed in a larger study. The SYMPLICITY HTN-4 trial, which is planned to commence enrolment in the latter half of 2013, will address this patient cohort, as well as the broader patient population.

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Figure 2: Ablation Pattern in Symplicity Flex™ and Symplicity Spyral™ Catheters

Symplicity Flex ablation pattern

Symplicity Spyral ablation pattern Whitbourn, 2013,28 reproduced from the EuroPCR presentation, slide 3.

Figure 3: Absolute Change in Office Blood Pressure and 24-hour Ambulatory Blood Pressure in Patients (n=36) with Available Ambulatory Blood Pressure Monitoring Before and After Renal Denervation Office BP

24-hour ABPM

0 -2 Change in BP (mmHg)

mean BP at baseline was 182/94 mmHg, and participants were taking 4.7 medications. The mean procedure time for the Symplicity Spyral catheter (calculated as guide catheter removal – catheter insertion) was 21.2 minutes. Nearly all of the patients had an RF treatment time of one minute per artery; two patients received more than one treatment in a single artery. At one month, patients experienced an average office BP reduction of 16/7 mmHg from baseline (p<0.001), which was consistent to that achieved in the Symplicity-HTN trials. A reduction in heart rate of 4.3 beats per minute (p<0.047) and a decrease in pulse pressure of 8.8 mmHg (p=0.004) were also seen. The procedure had 96.6 % procedure success (defined as successful delivery of any RF in the absence of an in-hospital major adverse effect). One femoral pseudoaneurysm occurred in hospital at the access site requiring surgical intervention and one occurred at day three post-treatment requiring compression.28

-4 -6 -8 -10 -12 -14 -16 -18 -20

After 6 months: 17.6/-8.8 mmHg 14.1/6.6 mmHg

Schmieder, 2013,48 reproduced from the EuroPCR presentation, slide 16. ABPM = ambulatory blood pressure monitoring; BP = blood pressure; mmHg = millimetres of mercury.

New Therapeutic Indications for Renal Denervation Evolving applications for RDN in disease conditions sympathetic overactivity may expand its therapeutic The sympathetic nervous system has an impact on a cardiovascular and metabolic diseases,31 and possible

related to indications. number of

indications for RDN include the treatment of glycemic control,32 sleep apnoea,32 cardiac systolic and diastolic dysfunction,33,34 LVH,33 polycystic ovary syndrome34 and end-stage renal failure.35 The mechanisms that underlie heart failure may also benefit from RDN. In congestive heart failure, sympathetic overactivation that accompanies decreased cardiac output causes renin release, sodium and fluid retention, and reduces renal blood flow, leading to arterial constriction and increased heart rate. An increase in plasma levels of angiotensin II, partly mediated by renal sympathetic activation, acts on the central nervous system to further increase global sympathetic tone.36 Renal sympathetic activity causes norepinephrine activation; levels of plasma

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Hypertension Renal Sympathetic Denervation Figure 4: Improvement in Exercise Capacity in Patients with Heart Failure Following Renal Denervation Improvement in Exercise Capacity REACH-Pilot

Exercise distance (Metres)

320 300

∆ 27.1m p=0.03

280 260 240 220

ay p o

Pre

st 1w eek 2w eek s 1m ont h 2m ont hs 3m ont hs 4m ont hs 5m ont hs 6m ont hs

200

Davies et al., 2013,40 reproduced from slide 29 of the presentation.

SBP reduction 6 months after RDN (mmHg)

Figure 5: Baseline Systemic Blood Pressure and Blood Pressure Reduction Following Renal Denervation 40

R=-0.46, p<0.001

20 0 1. G

-20

2. G

-40

3. G

-60 1. Group: <160 mmHg 2. Group: 160–175 mmHg 3. Group: >175 mmHg

-80 -100

120

160

180

SBP at baseline (mmHg) mmHg = millimetres of mercury; RDN = renal denervation; SBP = systolic blood pressure. Weil, 2013,47 reproduced from the EuroPCR presentation, slide 8.

norepinephrine correlate with mortality in patients with congestive heart failure.37 Two mechanisms are thought to be responsible for fluid retention – a slow renal mechanism and a faster pathway whereby the splanchnic venous reservoir becomes activated and blood becomes immobilised.38 Another clinical feature of heart failure is overactivation of central chemoreceptors, modulated by sympathetic pathways, which causes breathlessness. Chemoreceptor sensitivity increases with worsening heart failure and high chemoreceptor activation is associated with increased mortality.39 Numerous effective drugs are available for the treatment of arterial constriction and diuretics can help in the management of fluid retention. However, there are few options for modifying the sensitivity of the chemoreceptors that control breathing. RDN offers the potential to modulate central chemoreceptors, improve fluid balance, reduce heart rate and cause a decrease in peripheral vascular resistance. A small pilot study (n=7) assessed the safety of RDN in patients with chronic heart failure and on maximal tolerated heart failure therapy.40 Patients were hospitalised for a day before the procedure and up

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to five days after, and were closely followed up. No procedural or post-procedural complications were observed during six months of follow-up. Improvements in both symptoms and exercise capacity were reported, and the resulting reduction in BP was negligible and remained stable. The six-minute walk distance was significantly increased at six months (∆=27.1 ± 9.7 m, p=0.03), with each patient experiencing an increase (see Figure 4). The procedure also resulted in dose reduction in some medications, in particular diuretic dosage, which was reduced in four of the seven patients. In a larger study of patients with advanced heart failure (n=51, 12 months), 26 patients were treated with RDN and standard pharmacotherapy and 25 patients received standard drug treatment with beta-blockers, angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) and diuretics. No acute or medium term complications were observed in the RDN group. The RDN group reported an increase in ejection fraction, a lower cumulative frequency of hospitalisations for heart failure, and also showed other interesting trends, such as a reduction in the N-terminal pro-hormone of brain natriuretic peptide (NT proBNP), a reliable indicator of the severity of heart failure.41 Several ongoing studies aim to assess the safety and efficacy of RDN in heart failure. These include the SYMPLICITY-HF trial (n=40), and the Renal Artery Denervation in Chronic Heart Failure (REACH) trial (n=100). In summary, RDN may offer the potential to expand its indications beyond resistant hypertension.

Building a Successful Renal Denervation Referral Network Following current consensus papers, around 10–15 % of current patients are suitable for RDN, and proper evaluation is important. Firstly, it is necessary to identify patients who have truly resistant hypertension, taking into account compliance issues. In patients with resistant hypertension, secondary causes of hypertension are common.42 Therefore a detailed screening process is required to identify patients with potentially curable forms of hypertension, since RDN has not been evaluated for efficacy in these patients.27 Ultimately, the success of RDN rests on building a referral network. Evaluation of patients for secondary hypertension and end-organ damage often requires different specialists. A multidisciplinary team is therefore recommended, including hypertension experts, radiologists, nephrologists, endocrinologists and both interventional and noninvasive cardiologists to exclude secondary causes of hypertension and make the right decision for each individual patient.43 The importance of the multidisciplinary approach has been stressed by hypertension experts and has proven successful in daily practice.27,44 It is important to identify the referring physicians, which may be a family practitioner rather than a specialist. Involvement of local physicians can help to spread awareness and knowledge about the procedure. In targeting appropriate patients for RDN, the new European Society of Hypertension (ESH) guidelines45 are useful – office BP ≥160 mmHg systolic (diabetics ≥150 mmHg); a stable drug regimen including a diuretic and three different antihypertensive drugs and age over 18 years. Currently, the only parameter identified that predicts response to RDN is baseline SBP – a correlation has been demonstrated between BP reduction after RDN at six months follow-up and SBP baseline values (see Figure 5).46

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The establishment of an RDN referral network maintains a streamlined patient evaluation. In a referral network established in Lubeck, Germany, 41 % of patients were excluded because they were taking less than three medications and 26 % were excluded because they had a SBP <160 mgHg. Twenty-six percent of all the patients seen were treated with RDN. The SBP at baseline was around 180 mmHg, the reduction in BP observed was about 26 mmHg. These real-world data are similar to those observed in clinical trials.47 In summary, patient selection is crucial to the success of a RDN programme. In order to optimise patient selection, it is important to build a multidisciplinary referral network by personal communication and quality of medical treatment.

Summary and Concluding Remarks RDN using the Symplicity RDN system represents an exciting and innovative development in the field of interventional medicine. It

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WHO, World Health Statistics 2012, 2012. Available at: http:// apps.who.int/iris/bitstream/10665/44844/1/9789241564441_ eng.pdf (accessed 8 September 2013). Murray CJ, Vos T, Lozano R, et al., Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 19902010: a systematic analysis for the Global Burden of Disease Study 2010, Lancet , 2012;380:2197–223. Kearney PM, Whelton M, Reynolds K, et al., Global burden of hypertension: analysis of worldwide data, Lancet , 2005;365:217–23. Egan BM, Zhao Y, Axon RN, US trends in prevalence, awareness, treatment, and control of hypertension, 19882008, JAMA , 2010;303:2043–50. Calhoun DA, Jones D, Textor S, et al., Resistant hypertension: diagnosis, evaluation, and treatment: a scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research, Circulation , 2008;117:e510–26. Pimenta E, Calhoun DA, Resistant hypertension: incidence, prevalence, and prognosis, Circulation , 2012;125:1594–6. Chobanian AV, Bakris GL, Black HR, et al., Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, Hypertension , 2003;42:1206–52. DiBona GF, The sympathetic nervous system and hypertension: recent developments, Hypertension , 2004;43:147–50. DiBona GF, Kopp UC, Neural control of renal function, Physiol Rev, 1997;77:75–197. Rippy MK, Zarins D, Barman NC, et al., Catheter-based renal sympathetic denervation: chronic preclinical evidence for renal artery safety, Clin Res Cardiol , 2011;100:1095–101. Schlaich MP, Sobotka PA, Krum H, et al., Renal denervation as a therapeutic approach for hypertension: novel implications for an old concept, Hypertension , 2009;54:1195–201. Symplicity HTN-1 Investigators, Catheter-based renal sympathetic denervation for resistant hypertension: durability of blood pressure reduction out to 24 months, Hypertension , 2011;57:911–7. Symplicity HTN-2 Investigators, Esler MD, Krum H, et al., Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial, Lancet , 2010;376:1903–9. Krum H, Schlaich M, Whitbourn R, et al., Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study, Lancet , 2009;373:1275–81. Lambert GW, Hering D, Esler MD, et al., Health-related quality of life after renal denervation in patients with treatmentresistant hypertension, Hypertension , 2012;60:1479–84. Geisler BP, Egan BM, Cohen JT, et al., Cost-effectiveness and clinical effectiveness of catheter-based renal denervation for resistant hypertension, J Am Coll Cardiol , 2012;60:1271–7. Esler MD, Krum H, Schlaich M, et al., Renal sympathetic denervation for treatment of drug-resistant hypertension: one-year results from the Symplicity HTN-2 randomized, controlled trial, Circulation , 2012;126:2976–82.

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has demonstrated significant and sustained reductions in BP in the Symplicity HTN-1 and Symplicity HTN-2 clinical trials. The Global SYMPLICITY Registry has also demonstrated safety and effectiveness in real-world clinical practice in the subjects for which data are available. New systems containing multi-electrodes has the potential to make RDN as easy and straightforward as the existing single-electrode catheter while reducing ablation time. Furthermore, the benefits of RDN may not be restricted to blood pressure lowering alone; the potential exists to expand its therapeutic indications. However, RDN is a relatively new technique and optimal patient selection is crucial. The joint expertise of different fields is required to identify patients who have truly resistant hypertension and are likely to respond to RDN. Clinical evidence to date suggests that a high baseline SBP is the best predictor of response. In conclusion, RDN is currently an effective and safe option if used in well-selected patients. As more clinical data become available, the approach to RDN is likely to become more accessible with an increase in indications. n

18. Böhm M, Three-Year Results from Symplicity HTN-1 and Symplicity HTN-2: What the Data Do (and Don’t) Tell Us, Presented at: Transcatheter Cardiovascular Therapeutics (TCT) Conference, Miami, FL, US, October 22-26, 2012 . 19. Esler M, Krum H, Schmieder R, Bohm M, Renal Sympathetic Denervation for Treatment of Resistant Hypertension: Two‐Year Update From the Symplicity HTN‐2 Randomized Controlled Trial, Presented at: 62nd Annual Scientific Session of the American College of Cardiology, San Francisco, CA, US, 9-11 March 2013. 20. Esler M, BP reductions with renal denervation durable to 30 months: Symplicity HTN-2, Presented at: ASH conference, San Francisco, US, 15-18 May 2013. 21. Kandzari DE, Bhatt DL, Sobotka PA, et al., Catheter-based renal denervation for resistant hypertension: rationale and design of the SYMPLICITY HTN-3 Trial, Clin Cardiol , 2012;35:528–35. 22. Global SYMPLICITY Registry, 2013. Available at: http:// clinicaltrials.gov/ct2/show/NCT01534299 (accessed 8 September 2013). 23. Mahfoud F, Update on global SYMPLICITY registry – Where to from here for renal denervation clinical studies?, Presented at: EuroPCR 2013, Paris, France, 21 May 2013. 24. Ukena C, Mahfoud F, Spies A, et al., Effects of renal sympathetic denervation on heart rate and atrioventricular conduction in patients with resistant hypertension, J Am Coll Cardiol, 2013;167(6):2846–51. 25. Pierdomenico SD, Cuccurullo F, Risk reduction after regression of echocardiographic left ventricular hypertrophy in hypertension: a meta-analysis, Am J Hypertens , 2010;23:876–81. 26. Jung O, Gechter JL, Wunder C, et al., Resistant hypertension? Assessment of adherence by toxicological urine analysis, J Hypertens, 2013;31:766–74. 27. Mahfoud F, Luscher TF, Andersson B, et al., Expert consensus document from the European Society of Cardiology on catheter-based renal denervation, Eur Heart J , 2013;34(28):2149–57. 28. Whitbourn R, Catheter-based Renal Sympathetic Denervation: Long-term Symplicity Clinical Evidence, New Data and Future Perspectives: Results from the Spyral Feasibility Study, Presented at: EuroPCR 2013, Paris, France, 21 May 2013. 29. Ott C, Mahfoud F, Schmid A, et al., Renal denervation in moderate treatment resistant hypertension, J Am Coll Cardiol , 2013, pii: S0735–1097(13)02539–4. 30. Myers MG, The great myth of office blood pressure measurement, J Hypertens, 2012;30:1894–8. 31. Grassi G, Seravalle G, Quarti-Trevano F, et al., Excessive sympathetic activation in heart failure with obesity and metabolic syndrome: characteristics and mechanisms, Hypertension , 2007;49:535–41. 32. Witkowski A, Prejbisz A, Florczak E, et al., Effects of renal sympathetic denervation on blood pressure, sleep apnea course, and glycemic control in patients with resistant hypertension and sleep apnea, Hypertension , 2011;58:559–65. 33. Brandt MC, Mahfoud F, Reda S, et al., Renal sympathetic denervation reduces left ventricular hypertrophy and

improves cardiac function in patients with resistant hypertension, J Am Coll Cardiol, 2012;59:901–9. 34. Schlaich MP, Straznicky N, Grima M, et al., Renal denervation: a potential new treatment modality for polycystic ovary syndrome?, J Hypertens , 2011;29:991–6. 35. Wang Y, Seto SW, Golledge J, Therapeutic effects of renal denervation on renal failure, Curr Neurovasc Res, 2013;10:172–84. 36. Sobotka PA, Krum H, Böhm M, et al., The role of renal denervation in the treatment of heart failure, Curr Cardiol Rep, 2012;14:285–92. 37. Francis GS, Cohn JN, Johnson G, et al., Plasma norepinephrine, plasma renin activity, and congestive heart failure. Relations to survival and the effects of therapy in V-HeFT II. The V-HeFT VA Cooperative Studies Group, Circulation , 1993;87(6 Suppl):VI40–8. 38. Fallick C, Sobotka PA, Dunlap ME, Sympathetically mediated changes in capacitance: redistribution of the venous reservoir as a cause of decompensation, Circ Heart Fail , 2011;4:669–75. 39. Ponikowski P, Anker SD, Chua TP, et al., Oscillatory breathing patterns during wakefulness in patients with chronic heart failure: clinical implications and role of augmented peripheral chemosensitivity, Circulation , 1999;100:2418–24. 40. Davies JE, Manisty CH, Petraco R, et al., First-in-man safety evaluation of renal denervation for chronic systolic heart failure: primary outcome from REACH-Pilot study, Int J Cardiol , 2013;162:189–92. 41. Táborský M, Lazárová ML, Václavík J, The effect of renal denervation in patients with advanced heart failure, Eur Heart J, 2012;33 (suppl): 517. 42. Faselis C, Doumas M, Papademetriou V, Common secondary causes of resistant hypertension and rational for treatment, Int J Hypertens, 2011;2011:236239. 43. Potthoff SA, Rump LC, Vonend O, The “resistant hypertension team”: focus on a multidisciplinary approach to hypertension, EuroIntervention , 2013;9 Suppl R:R48–53. 44. Choe HM, Bernstein SJ, Cooke D, et al., Using a multidisciplinary team and clinical redesign to improve blood pressure control in patients with diabetes, Qual Manag Health Care , 2008;17:227–33. 45. Mancia G, Fagard R, Narkiewicz K, et al., 2013 ESH/ESC Guidelines for the management of arterial hypertension: The Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC), J Hypertens , 2013;31:1281–357. 46. Mahfoud F, Cremers B, Janker J, et al., Renal hemodynamics and renal function after catheter-based renal sympathetic denervation in patients with resistant hypertension, Hypertension , 2012;60:419–24. 47. Weil J, Building a Successful Renal Denervation Referral Network, Presented at: EuroPCR 2013, Paris, France, 21 May 2013. 48. Schmieder RE, How effective is Renal Denervation in Less Severe Resistant Hypertension?, Presented at: EuroPCR 2013, Paris, France, 21 May 2013.

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Application in Hypertension of Renal Sympathetic Denervation – A Review Domi ni k Li nz, Felix Ma hfoud, Seba stia n Ew e n , S t e p h a n H S c h i r m e r, Ja n Re i l , Ch r i s t i a n U k e n a a n d M i ch ae l Bö h m Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes, Homburg/Saar, Germany

Abstract Afferent and efferent sympathetic nerves of the kidney located in the adventitia of the renal artery are involved in the regulation of blood pressure and play a pathophysiological role in the progression and maintenance of hypertension. Renal sympathetic denervation is a potent and safe catheter-based therapeutic approach for the treatment of patients with resistant hypertension. Clinical trials of renal sympathetic denervation have shown significant reduction in blood pressure, which was associated with a reduction in local renal norepinephrine spillover as well as a reduction of whole body sympathetic activation in resistant hypertensive patients.

Keywords Renal sympathetic denervation, hypertension, blood pressure, sympathetic nervous system Disclosure: Universitätsklinikum des Saarlandes has received scientific support from Medtronic/Ardian. Michael Böhm and Felix Mahfoud were investigators of the Symplicity HTN-1 and HTN-2 trials. Michael Böhm and Felix Mahfoud have received speaker honorarium and consultancy fees from Medtronic/Ardian, St. Jude and/or Cordis. The remaining authors have no conflicts of interest to declare. Received: 22 August 2013 Accepted: 2 September 2013 Citation: Interventional Cardiology Review, 2013;8(2):124–6 Correspondence: Dominik Linz, Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes, Kirrberger Str. 1, Geb. 40, D-66421, Homburg/Saar, Germany. E: Dominik.linz@uks.eu

The sympathetic nervous system regulates cardiac output, blood pressure (BP), heart rate and volume, electrolyte balance and composition of body fluids. The afferent signals to the brain are regulated by mechanosensitive baroreceptors, volume sensors and chemoreceptors located in the vessels and in many other organs, particularly in the heart, kidney, lung, brain and muscles. Sympathetic nervous system outflow is coordinated by the nucleus tractus solitarius, located in the midbrain.1 Efferent sympathetic signals regulate BP, heart rate and cardiac output through beta (β)-adrenergic receptors, and regulate peripheral resistance by vasoconstriction through alpha (α)-adrenergic receptors. In the kidney, sodium and water retention is stimulated by activation of β-adrenergic receptors in the proximal tubules.1

illustrating the diverse functional nature of various populations of renal receptors.3 In Figure 1, the interaction between efferent and afferent sympathetic activation and the kidney are shown. Activation of renal efferent sympathetic nerve fibres increases sodium and water retention, reduces renal blood flow and elevates renin release from juxtaglomerular apparatus, regulating BP. Renal nerves contain sensory afferent fibres, which enable communication with the central nervous system. Activation of renal afferent nerves itself elevate sympathetic nervous outflow to the kidney and other downstream organs (see Figure 1).

Renal Sympathetic Denervation Renal Sympathetic Nerves Renal sympathetic nerves regulate kidney function, volume homeostasis, cardiac output and BP control.2 Renal sympathetic activation results in volume retention, sodium reabsorption, reduction of blood flow and renin-angiotensin-aldosterone system activation.2 However, the kidney also has an extensive network of afferent unmyelinated fibres that transmit important sensory information to the central nervous system. 2,3 Afferent fibres from the kidney have been shown to travel along with the sympathetic nerves at the level of the kidney and then enter the dorsal roots and project to neurons at both spinal and supraspinal levels. Most of the brainstem regions involved in cardiovascular control including the hypothalamus receive inputs from the renal afferents, which carry information to the central nervous system from renal chemo- and mechano-receptors. 2,3 Direct electrical stimulation of the renal afferent nerves in animals can produce both sympathoinhibitory and sympathoexcitatory reflexes,

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Recently, a catheter-based approach has been developed for renal sympathetic denervation (RDN). RDN significantly lowers BP in patients with therapy-resistant hypertension. Both, a proof-of-concept trial (Symplicity HTN-14), including 50 patients and a multicentre, prospective, randomised trial (Symplicity HTN-25) including 106 patients with resistant hypertension (systolic BP ≥160 millimetres of mercury [mmHg], >150 mmHg for type 2 diabetes) despite receiving ≥3 antihypertensive drugs) demonstrated that RDN significantly lowered BP. Systolic BP in these clinical trials was reduced by 25–32 mmHg. Three hundred and forty-six uncontrolled hypertensive patients, separated according to daytime ambulatory BP monitoring into 303 with true resistant (office systolic BP 172 mmHg; 24-hour systolic BP 154 mmHg) and 43 with pseudoresistant hypertension (office systolic BP 161 mmHg; 24-hour systolic BP 121 mmHg), were analysed in another study.6 At three, six and 12 months follow-up, office systolic BP was reduced by 21/23/27 mmHg and office diastolic BP by 8/9/11 mmHg, respectively. In patients with true treatment resistance there was a significant reduction with

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Hypertension Renal Sympathetic Denervation 1. 2. 3. 4.

Sobotka PA, Mahfoud F, Schlaich MP, et al., Sympatho-renal axis in chronic disease, Clin Res Cardiol , 2011;100:1049–57. DiBona GF, Kopp UC, Neural control of renal function, Physiol Rev, 1997;77:75–197. Stella A, Zanchetti A, Functional role of renal afferents, Physiol Rev, 1991;71:659–82. Krum H, Schlaich M, Whitbourn R, et al., Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study, Lancet , 2009;373:1275–81. Symplicity HTN-2 Investigators, Esler MD, Krum H, et al., Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial, Lancet , 2010;376:1903–9. Mahfoud F, Ukena C, Schmieder RE, et al., Ambulatory blood pressure changes after renal sympathetic denervation in patients with resistant hypertension, Circulation , 2013;128:132–40. Kandzari DE, Bhatt DL, Sobotka PA, et al., Catheter-based

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renal denervation for resistant hypertension: rationale and design of the SYMPLICITY HTN-3 Trial, Clin Cardiol , 2012;35:528–35. 8. Hering D, Lambert EA, Marusic P, et al., Substantial reduction in single sympathetic nerve firing after renal denervation in patients with resistant hypertension, Hypertension, 2013;61:457–64. 9. Mahfoud F, Lüscher TF, Andersson B, et al., Expert consensus document from the European Society of Cardiology on catheter-based renal denervation, Eur Heart J , 2013;34:2149–57. 10. Ott C, Mahfoud F, Schmid A, et al., Renal denervation in moderate treatment resistant hypertension, J Am Coll Cardiol , 2013 [Epub ahead of print]. 11. Schlaich MP, Bart B, Hering D, et al., Feasibility of catheterbased renal nerve ablation and effects on sympathetic nerve activity and blood pressure in patients with end-stage renal disease, Int J Cardiol , 2013 [Epub ahead of print]. 12. Hering D, Mahfoud F, Walton AS, et al., Renal denervation in

moderate to severe CKD, J Am Soc Nephrol, 2012;23:1250–7. 13. Böhm M, Linz D, Urban D, et al., Renal sympathetic denervation: applications in hypertension and beyond, Nat Rev Cardiol , 2013;10:465–76. 14. Ukena C, Cremers B, Ewen S, et al., Response and nonresponse to renal denervation: who is the ideal candidate?, EuroIntervention , 2013;9 Suppl R:R54–7. 15. Ukena C, Mahfoud F, Linz D, et al., Potential role of renal sympathetic denervation for the treatment of cardiac arrhythmias, EuroIntervention , 2013;9 Suppl R:R110–6. 16. Mahfoud F, Ewen S, Ukena C, et al., Expanding the indication spectrum: renal denervation in diabetes, EuroIntervention , 2013;9 Suppl R:R117–21. 17. Ewen S, Ukena C, Linz D, et al., The sympathetic nervous system in chronic kidney disease, Curr Hypertens Rep, 2013;15:370–6. 18. Böhm M, Ewen S, Linz D, et al., Therapeutic potential of renal sympathetic denervation in patients with chronic heart failure, EuroIntervention , 2013;9 Suppl R:R122–6.

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Structural Heart Disease Hybrid Strategies

Concurrent Coronary Artery and Valvular Heart Disease – Hybrid Treatment Strategies in 2013 Kendra J Grubb, 1 Ta mi m N a z i f, 2 M a t h e w R Wi l l i a m s 1, 2 a n d I s a a c G e o r g e 1 1. Division of Cardiothoracic Surgery, College of Physicians and Surgeons; 2. Division of Cardiology, Columbia University Medical Center, New York, US

Abstract Concomitant coronary artery disease (CAD) and valvular heart disease is an increasingly common problem in the ageing population. Hybrid procedures combine surgical and transcatheter approaches to facilitate minimally invasive surgery or to transform a single highrisk open surgery into two less risky procedures. In ideal circumstances, this strategy may decrease the surgical risk in elderly, high-risk and reoperative surgical candidates, while improving patient comfort, convenience and cost-effectiveness. Hybrid procedures can be performed in a staged fashion or as a ‘one-stop’ procedure in a hybrid operating suite. Increasing evidence supports the safety and shortterm efficacy of hybrid valve repair or replacement and coronary revascularisation procedures. Nevertheless, important questions remain, including the optimal timing of the individual procedures and the optimal antiplatelet therapy after percutaneous coronary intervention. With ongoing advances in procedural techniques and anticoagulation strategies, as well as the accumulation of long-term outcomes data, hybrid approaches to concomitant CAD and valvular heart disease will likely become increasingly common.

Keywords Hybrid surgery, percutaneous coronary intervention, valvular heart disease, minimally invasive valve surgery Disclosure: The authors have no conflicts of interest to declare. Received: 18 April 2013 Accepted: 20 June 2013 Citation: Interventional Cardiology Review, 2013;8(2):127–30 Correspondence: Isaac George, New York Presbyterian Hospital – College of Physicians and Surgeons, Columbia University, Milstein Hospital Building, 7GN-435, 177 Fort Washington Avenue, New York, NY 10032, US. E: ig2006@columbia.edu

Concomitant coronary artery disease (CAD) and valvular heart disease is a common problem in the ageing population. It is estimated that the prevalence of mitral regurgitation and aortic stenosis in individuals over the age of 70 is 10 % and 4 %, respectively.1,2 Among patients presenting with symptomatic aortic stenosis, concurrent CAD occurs in over 50 % of those over 70 years of age and over 65 % of those over 80 years of age.3,4 However, elderly patients often have more co-morbidities, are more likely to have had a previous cardiac operation, and are less tolerant of complex cardiac surgery. Furthermore, the addition of coronary artery bypass grafting (CABG) at the time of valve surgery doubles the operative risk of the procedure.5–8 Interest in hybrid procedures, defined for the purpose of this review as surgical valve repair/replacement and percutaneous coronary intervention (PCI) (hybrid valve), has intensified with the emergence of minimally invasive surgical techniques, improved coronary stent technology, increased collaboration between cardiac surgeons and interventional cardiologists, and the introduction of hybrid operating suites. The complementary goals of minimising the morbidity of surgical procedures and optimising resource utilisation have driven development of new solutions for concurrent valvular and coronary heart disease.

of hybrid procedures are to facilitate minimally invasive surgery and to reduce overall operative morbidity and mortality by transforming a single, high-risk surgery into two less risky procedures. Minimally invasive valve surgery, via upper hemisternotomy for the aortic valve or right mini-thoracotomy for the mitral valve, has been shown to reduce operative pain, to require less blood transfusion, to provide a superior cosmetic result, and to be associated with faster recovery and a shorter hospital length of stay.5,10,11

Indications and Patient Selection

Hybrid procedures offer a reasonable alternative to traditional surgery for patients who meet the following basic criteria:

The primary purpose of a hybrid valve/PCI is to substitute PCI for bypass grafting with saphenous vein grafts (SVGs), particularly for lesions not in the left anterior descending (LAD) coronary artery.5 With the current excellent performance of drug-eluting coronary stents (DES), restenosis and thrombosis rates of DES may be less than the estimated rate of SVG failure of 20 % at 12 months.9,10 The two most common clinical objectives

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Reoperative coronary bypass grafting in a patient with valvular disease poses a particular challenge in cardiac surgery. The hybrid approach is of particular benefit in reoperative patients who have had prior CABG with patent grafts.5,9,12 The technical difficulty of accessing lateral wall targets, safely dissecting patent bypass grafts and obtaining exposure often precludes safe surgery, and these risks are not reflected in traditional scoring systems. Hybrid valve/PCI may be particularly useful in this regard and can dramatically simplify a challenging open valve and CABG surgery by substituting PCI for reoperative bypass grafting in lesions amenable to PCI.5

• non-LAD coronary lesions, not amenable to internal mammary bypass grafting; • PCI that is technically feasible and likely durable from a procedural standpoint; and

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Structural Heart Disease Hybrid Strategies Anticoagulation Management Regardless of the hybrid strategy employed, concern remains over the impact of clopidogrel, or other antiplatelet therapies, at the time of cardiac surgery. The early hybrid experience was associated with increased blood loss and higher transfusion rates, which was attributed to the use of clopidogrel at the time of the valve operation.18 The subsequent strategy of shortening the duration between stages offered the potential to circumvent the increased risk of bleeding based on the pharmacokinetics of clopidogrel. However, more contemporary data suggests the risk of surgical bleeding while on clopidogrel may be overestimated.25 Furthermore, the risk of bleeding may be significantly reduced with the introduction of novel anticoagulants and antiplatelet agents. Cangrelor (The Medicines Company, Parsippany, New Jersey, US), an intravenous adenosine diphosphate receptor antagonist with a short half-life and rapid onset, has been shown to be safe and effective during PCI. The Cangrelor versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition (CHAMPION) PHOENIX trial was a recently published, double-blinded, placebo-controlled trial of 11,145 patients undergoing urgent or elective PCI.26 The use of cangrelor was associated with a reduction in the rate of ischaemic events, including stent thrombosis, without an increase in severe bleeding. Although the effect of cangrelor in surgical patients is unknown, an intravenous antiplatelet agent with rapid onset that could be administered precisely at the time of PCI might prove to be highly beneficial with respect to the hybrid PCI/valve procedure.

Cost-effectiveness In the current era of closely scrutinised healthcare spending, the cost-effectiveness of hybrid procedures must be further evaluated prior to broad adoption. The available literature suggests the hybrid valve/PCI approach is safe and effective, and may be associated with lower blood transfusion rates, shorter lengths of stay, and ultimately lower cost.5,9,19,20 Further cost savings may be realised by

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Cosmi JE, Kort S, Tunick PA, et al., The risk of the development of aortic stenosis in patients with “benign” aortic valve thickening, Arch Intern Med, 2002;162(20):2345–7. Singh JP, Evans JC, Levy D, et al., Prevalence and clinical determinants of mitral, tricuspid, and aortic regurgitation (the Framingham Heart Study), Am J Cardiol, 1999;83(6):897–902. Iung B, Interface between valve disease and ischaemic heart disease, Heart, 2000;84(3):347–52. Kvidal P, Bergström R, Hörte LG, Ståhle E, Observed and relative survival after aortic valve replacement, J Am Coll Cardiol, 2000;35(3):747–56. Byrne JG, Leacche M, Vaughan DE, Zhao DX, Hybrid cardiovascular procedures, JACC Cardiovasc Interv, 2008;1(5):459–68. Hannan EL, Wu C, Bennett EV, et al., Risk index for predicting in-hospital mortality for cardiac valve surgery, Ann Thorac Surg, 2007;83(3):921–9. van Gameren M, Kappetein AP, Steyerberg EW, et al., Do we need separate risk stratification models for hospital mortality after heart valve surgery?, Ann Thorac Surg, 2008;85(3):921–30. Nowicki ER, Birkmeyer NJ, Weintraub RW, et al., Multivariable prediction of in-hospital mortality associated with aortic and mitral valve surgery in Northern New England, Ann Thorac Surg, 2004;77(6):1966–77. Umakanthan R, Leacche M, Zhao DX, et al., Hybrid options for treating cardiac disease, Semin Thorac Cardiovasc Surg, 2011;23(4):274–80. Solenkova NV, Umakanthan R, Leacche M, et al., The new era of cardiac surgery: hybrid therapy for cardiovascular disease, Innovations (Phila), 2010;5(6):388–93. Lamelas J, Sarria A, Santana O, et al., Outcomes of minimally invasive valve surgery versus median sternotomy in patients age 75 years or greater, Ann Thorac Surg, 2011;91(1):79–84. Masroor S, Berkowitz R, Nejad K, Alexander JC, Hybrid percutaneous coronary intervention and minimally invasive reoperative mitral valve surgery, J Card Surg, 2009;24(2):191–3. Angelini GD, Wilde P, Salerno TA, et al., Integrated left small thoracotomy and angioplasty for multivessel coronary artery revascularisation, Lancet, 1996;347(9003):757–8. Halkos ME, Rab ST, Vassiliades TA, et al., Hybrid coronary revascularization versus off-pump coronary artery bypass for the treatment of left main coronary stenosis, Ann Thorac Surg, 2011;92(6):2155–60.

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implementation of a single-stage approach, since only one hybrid suite and personnel team are utilised. Further study is necessary to truly delineate the cost-effectiveness of the hybrid valve/PCI approach.

Transcatheter Valve Replacement and Percutaneous Coronary Intervention Fully transcatheter approaches to valvular and coronary heart disease, including PCI and transcatheter aortic valve replacement (TAVR), are beyond the scope of this review.27 However, a truly hybrid strategy involving open surgery and TAVR has been proposed as a means of addressing aortic stenosis and CAD (particularly LAD lesions) in a patient who is inoperable due to anatomic factors, such as hostile chest, porcelain aorta, complex reoperation, or patent right internal mammary artery crossing anterior to the aorta. The hybrid strategy in this regard combines a TAVR (transfemoral, transapical or transaortic) and open or minimally invasive direct coronary bypass grafting through a left mini-thoracotomy.28–35 Further study is necessary to better understand the risks and benefits of this new hybrid approach.

Conclusion With advances in stent technology and surgical technique, a hybrid procedure offers a unique approach to complex valve and coronary pathology and may become a more common strategy as longer-term outcomes become available. As experience is gained with minimally invasive techniques, a broader range of patients may benefit from hybrid valve/PCI procedures. The hybrid operating room has enabled new strategies to address complex cardiac disease. The single-stage approach to concomitant coronary and valvular disease is an excellent alternative to traditional open surgery. By transforming a complex, high-risk, operation into two procedures, excellent outcomes can be achieved with potential cost savings from a single procedure room and team, quicker patient recovery and decreased length of stay without added risk of bleeding. Additional study is necessary to truly understand the benefit of this innovative approach. n

15. Halkos ME, Vassiliades TA, Douglas JS, et al., Hybrid coronary revascularization versus off-pump coronary artery bypass grafting for the treatment of multivessel coronary artery disease, Ann Thorac Surg, 2011;92(5):1695–701; discussion 1701–2. 16. Reicher B, Poston RS, Mehra MR, et al., Simultaneous “hybrid” percutaneous coronary intervention and minimally invasive surgical bypass grafting: feasibility, safety, and clinical outcomes, Am Heart J, 2008;155(4):661–7. 17. Kon ZN, Brown EN, Tran R, et al., Simultaneous hybrid coronary revascularization reduces postoperative morbidity compared with results from conventional off-pump coronary artery bypass, J Thorac Cardiovasc Surg, 2008;135(2):367–75. 18. Byrne JG, Leacche M, Unic D, et al., Staged initial percutaneous coronary intervention followed by valve surgery (“hybrid approach”) for patients with complex coronary and valve disease, J Am Coll Cardiol, 2005;45(1):14–8. 19. Brinster DR, Byrne M, Rogers CD, et al., Effectiveness of same day percutaneous coronary intervention followed by minimally invasive aortic valve replacement for aortic stenosis and moderate coronary disease (“hybrid approach”), Am J Cardiol, 2006;98(11):1501–3. 20. Greelish JP, Ailiwadi M, Balaguer JM, et al., Combined percutaneous coronary intervention and valve surgery, Curr Opin Cardiol, 2006;21(2):113–7. 21. Umakanthan R, Leacche M, Petracek MR, et al., Combined PCI and minimally invasive heart valve surgery for high-risk patients, Curr Treat Options Cardiovasc Med, 2009;11(6):492–8. 22. Santana O, Funk M, Zamora C, et al., Staged percutaneous coronary intervention and minimally invasive valve surgery: results of a hybrid approach to concomitant coronary and valvular disease, J Thorac Cardiovasc Surg, 2012;144(3):634–9. 23. Leacche M, Zhao DX, Umakanthan R, Byrne JG, Do hybrid procedures have proven clinical utility and are they the wave of the future? : hybrid procedures have no proven clinical utility and are not the wave of the future, Circulation, 2012;125(20):2504–10; discussion 2510. 24. Shannon J, Colombo A, Alfieri O, Do hybrid procedures have proven clinical utility and are they the wave of the future? : hybrid procedures have proven clinical utility and are the wave of the future, Circulation, 2012;125(20):2492–503; discussion 2503. 25. Fox KA, Mehta SR, Peters R, et al., Benefits and risks of

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the combination of clopidogrel and aspirin in patients undergoing surgical revascularization for non-ST-elevation acute coronary syndrome: the Clopidogrel in Unstable angina to prevent Recurrent ischemic Events (CURE) Trial, Circulation, 2004;110(10):1202–8. Bhatt DL, Stone GW, Mahaffey KW, et al., Effect of platelet inhibition with cangrelor during PCI on ischemic events, N Engl J Med, 2013;368(14):1303–13. Dewey TM, Brown DL, Herbert MA, et al., Effect of concomitant coronary artery disease on procedural and late outcomes of transcatheter aortic valve implantation, Ann Thorac Surg, 2010;89(3):758–67; discussion 767. Baumbach H, Adili S, Ursulescu A, Franke UF, Concomitant transapical transcatheter aortic valve implantation and minimally invasive direct coronary artery bypass, Innovations (Phila), 2011;6(6):389–90. Cheung A, Hon JK, Ye J, Webb J, Combined off-pump transapical transcatheter aortic valve implantation and minimally invasive direct coronary artery bypass, J Card Surg, 2010;25(6):660–2. Ferrari E, Sulzer C, Marcucci C, et al., Successful combined minimally invasive direct coronary artery bypass and transapical aortic valve implantation, Ann Thorac Surg, 2011;91(6):1979–82. Gotte JM, Rupp W, Schild A, et al., Hybrid approach combining off-pump CABG with transapical aortic valve implantation via median sternotomy, Thorac Cardiovasc Surg, 2012;60(6):425–7. Kolettis TN, Spargias K, Stavridis GT, Combined transapical aortic valve implantation with coronary artery bypass grafting in a young patient with porcelain aorta, Hellenic J Cardiol, 2009;50(1):79–82. Mellert F, Breuer J, Probst C, et al., Combined transapical aortic valve replacement and minimally invasive direct coronary bypass grafting--a new concept for selected highrisk patients, Heart Surg Forum, 2011;14(1):E61–3. Pasic M, Buz S, Unbehaun A, Hetzer R, Transcatheter aortic valve implantation combined with conventional heart surgery: hybrid approach for complex cardiac pathologic features, J Thorac Cardiovasc Surg, 2012;144(3):728–31. Wiegerinck EM, Cocchieri R, Baan J Jr, de Mol BA, Hybrid coronary artery bypass grafting and transaortic transcatheter aortic valve implantation, J Thorac Cardiovasc Surg, 2013;145(2):600–2.

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Structural Heart Disease Transcatheter Aortic Valve Implantation

Overcoming the Challenges of the Transfemoral Approach in Transcatheter Aortic Valve Implantation St e p h a n e N o b l e a n d M a r c o R o f f i Cardiology Division, University Hospital of Geneva, Geneva, Switzerland

Abstract Transcatheter aortic valve implantation (TAVI) is performed through a retrograde transfemoral approach in approximately 80–90 % of cases thanks to the improvements in delivery catheter profile, size and steerability compared with the first generation devices. The aim of this review article is to describe the challenges of transfemoral TAVI and the options to overcome them. The difficulties may be related to the access itself or the placement of the valve using the transfemoral route. Comprehensive patient screening using multislice computed tomography and crossover techniques to prevent bleeding should result in low complication rates even for fully percutaneous procedures. Horizontal ascending aorta and severely calcified aortic valves remain a challenge for retrograde valve crossing, device advancement and accurate positioning during deployment. The buddy balloon technique is a simple option in the case of difficult aortic valve crossing with a delivery catheter, whereas an antegrade approach using the transapical route is a reasonable alternative in such anatomy.

Keywords Transcatheter aortic valve implantation, transfemoral approach, vascular access, vascular complications, buddy balloon technique, horizontal aorta Disclosure: Stephane Noble is a proctor for Medtronic CoreValve. Marco Roffi has no conflicts of interest to declare. Received: 5 August 2013 Accepted: 3 September 2013 Citation: Interventional Cardiology Review, 2013;8(2):131–4 Correspondence: Stephane Noble, Interventional Cardiology Unit, University Hospital of Geneva, Geneva, Switzerland. E: Stephane.noble@hcuge.ch

Since the first human transcatheter aortic valve implantation (TAVI) performed through an antegrade transfemoral approach (i.e. femoral venous access, transseptal puncture advancement of the device to the left ventricle and antegradely through the aortic valve), the venous approach has been abandoned and different arterial access routes such as the transfemoral, transapical, subclavian or direct aortic have been developed. At present, TAVI is performed through a retrograde transfemoral approach in approximately 80–90 % of cases thanks to the improvements in delivery catheter profile, size and steerability compared with the first generation devices. Furthermore, transfemoral TAVI has the advantage of offering the option for a fully percutaneous procedure, performed under local anaesthesia with mild sedation, via a puncture of the common femoral artery using the Seldinger technique and a closure device used with a pre-closure technique to achieve haemostasis. The aim of this review article is to describe the challenges of transfemoral TAVI and the options to overcome them. The challenges may involve either the access itself or the valve insertion and implantation.

Challenges in the Vascular Approach of Transfemoral Transcatheter Aortic Valve Implantation In order to successfully perform transfemoral TAVI, the operators should not only have appropriate knowledge on the devices they use and good training in femoral access and management of its specific complications, but they should also perform comprehensive screening of patients and careful evaluation of vascular access. Genereux et al. showed in a post hoc analysis of the 419 transfemoral patients from the Placement of AoRTic TraNscathetER Valves trial (PARTNER

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A and B) that vascular complications adversely impacted 30-day and one-year outcomes.1 In this analysis, major vascular complications (the most frequent being vascular dissection, vascular perforation and access site haematoma) occurred in as often as 15.4 % of cases with the use of the first generation Edwards SAPIEN® valves (Edwards Lifesciences Corporation, Irvine, California, US) and were associated with bleeding events, transfusions and increased mortality. Importantly, major vascular complications were associated with more than a fourfold increase in 30-day mortality.1 However, as shown by the Vancouver single-centre experience (137 patients), the incidence of major vascular complications can be dramatically reduced over time. Indeed, major vascular complications (22/24 were iliofemoral) in this centre fell from 8 % in 2009 to 1 % in 2010, thanks to increased operator experience, sheath size reduction (22 and 24 French size [Fr] for the first Edwards SAPIEN generation as opposed to 19 and 18 Fr for the second generation) and improved screening using multislice computed tomography (MSCT). Furthermore, distinction between major and minor vascular complications is of importance since in the PARTNER trial, vascular subanalysis minor vascular complications, which occurred in 11.9 % of cases, were not associated with higher mortality, major bleeding, transfusions or need for dialysis at 30 days and one year.1

Vascular Screening Using angiography and MSCT comprehensive vascular screening should determine the degree and localisation of calcifications, the presence of relevant iliofemoral atherosclerotic disease, major tortuosity and the minimal lumen vessel diameter that must be

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Structural Heart Disease Transcatheter Aortic Valve Implantation Figure 1: A) Iliofemoral Tortuosity with a Marked Pigtail Inside the Vessel. B) Vessel Straightened by the Insertion of a 0.35’’ Hi-Torque SupraCore Wire (Abbott Vascular) into the Pigtail. Case from Our Experience

Figure 2: Example of Difficult Anatomy for Crossover Approach. A) EN Snare Endovascular Snare System (Merit Medical Systems, South Jordan, Utah, US) with its Three Loops Opened. B) Regular 0.035” Wire Grabbed by the EN Snare System. C) Mammary Catheter (6 Fr) Advanced in the Right Iliac Artery A

Different 18 Fr Sheaths Used for the Medtronic CoreValve Different 18 Fr sheaths are available when implanting a CoreValve® (Medtronic Inc, Minneapolis, Minnesota, US). The Cook sheath (Cook Medical, Indiana, US) is the most commonly used. It is robust enough to allow recapture of a partially deployed valve. The latter manoeuvre is more challenging when using the St Jude 18 Fr sheath (ST Jude Medical, Minnesota, US), which is softer and with a better profile, but has the tendency to invaginate during recapture of a partially deployed CoreValve. The recently available SoloPath™ Balloon Expandable sheath (Terumo Corporation, Japan) represents an interesting option in the presence of difficult vascular anatomy. The concept of this sheath is a reduced profile when folded (outer diameter of 13 Fr) allowing facilitated vessel entry, it is subsequently expanded by balloon inflation up to an inner and outer diameter of 19 Fr and 22 Fr, respectively. It provides enhanced manoeuvrability, utilises the natural elasticity of vessels and thus enables delivery through difficult anatomy.3,4 Also, it is designed to collapse upon withdrawal. The SoloPath sheath is an interesting option for borderline iliofemoral access in terms of vascular diameter. However, caution should be paid in the presence of tortuous vessels because of a possibly limited kinking resistance observed in our preliminary experience.

Lubrification with Propofol To facilitate large bore sheath insertion in calcified vascular access, lubrification of the sheath with sterile propofol may be of help. This tip and trick was also successfully described in the case of stent delivery failure in coronary arteries.5 Indeed, propofol is a short-acting intravenous hypnotic/amnestic agent with lubricating properties, as it is an emulsion of 1.0 % propofol, 10.0 % soybean oil, 1.2 % purified egg phospholipids, 2.25 % glycerol and sodium hydroxide.

Pre-closure Technique Using the Prostar 10XL Device Surgical femoral cut-down may at first glance seem safer than a fully percutaneous approach. However, surgery may be associated with adverse events such as haematoma, seroma, lymphoceles and infection, and may lengthen the intervention, the timing to ambulation and hospital stay.6 On the other hand, a fully percutaneous approach has been used for many years in the field of endovascular aortic aneurysm repair and has the advantage of being performed under local anaesthesia with mild sedation. At present, with the reduction of sheath size, many centres favour this latter approach. at least >6 millimetres (mm) to accommodate an 18 Fr sheath. MSCT is very important in assessing the distribution of vascular calcification. Indeed, in the presence of circumferential calcification and/or tortuosity, the minimum iliofemoral arterial diameter should be larger (preferably >6.5 mm). In the setting of tortuous iliofemoral vessels the feasibility of transfemoral approach can be determined by the ability to straighten the tortuous vessel with a stiff wire (see Figure 1). Vavuranakis et al. developed an index to define the significance of vessel tortuosity – the Total arterial Tortuosity/Access vessel Diameter ratio (TT/AD). This ratio corresponds to the sum of angles from the puncture site divided by the minimum femoral artery diameter at the puncture site. In their analysis, a TT/AD >27.7 predicts major vascular complications with 50.8 % sensitivity and 70.6 % specificity. This index, although not commonly used in clinical practice, supports the concept that larger arteries are less prone to vascular complications.2

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When using a percutaneous approach, a closure device – either the Prostar 10XL device (Abbott Vascular, Santa Clara, California, US) or three 6 Fr Perclose devices (Abbott Vascular)7 – should be inserted before the large sheath; the so-called pre-closure technique. Of note, both devices are only approved for closure of ≤10 Fr sheath holes by the Food and Drug Administration in the US. However, 24.9 % of the PARTNER A and B transfermoral procedures were performed with a fully percutaneous approach using the Prostar XL device. Furthermore, in 2009, Prostar 10XL received a CE Mark and Canada Health approvals to close puncture sites when sheaths up to 24 Fr are used. At the beginning of the procedure, the sutures of the Prostar device are deployed at the arteriotomy site without tying the knots. At the end of the procedure, the sutures of the pre-closing system are knotted while retrieving the large sheath using either the crossover balloon technique (see below) or with a crossover access to the

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Overcoming the Challenges of the Transfemoral Approach in Transcatheter Aortic Valve Implantation

external iliac artery ready in case of incomplete haemostasis. Failure of the Prostar XL device seems to be associated with obesity, small-diameter vessels with significant calcification or a high puncture site.8–10 The failure rate of the Prostar device has been reported to be between 7.4 and 15.0 % in TAVI and endovascular aortic aneurysm repair series.6,10–12 In a series of 142 patients from Paris, the rate of failure clearly decreased from early experience (14.3 %) to later experience (4.3 %) whereas the total failure rate was 9.4 %.10 Interestingly, in this series, all Prostar failures could be managed without surgical intervention, namely with prolonged balloon inflation (3.6 %) or covered stent implantation (3.6 %) and no Prostar failure led to a major vascular complication according to the Valve Academic Research Consortium (VARC) criteria.10

Figure 3: Final Angiography by Crossover Approach of the Case Shown in Figure 2. Arrow Showing the Puncture Site

Crossover Balloon Occlusion Technique Some operators routinely advance a peripheral balloon in the external or common iliac artery from the contralateral access and inflate it when retrieving the sheath and knotting the sutures – the so-called crossover balloon occlusion technique. This approach permits bleeding control and offers a bloodless field for percutaneous or surgical repair if needed.9,13 In our experience, the need to inflate a balloon to achieve haemostasis is rarely needed and we therefore do not use it prophylactically. However, we strongly advise having a diagnostic catheter in place in the external iliac artery using a contralateral approach. This can be easily done by advancing a 6 Fr internal mammary artery catheter over a 0.035” wire (usually a stiff Terumo wire, Terumo Inc, Japan). If the aortic bifurcation is narrow-angled and it is not possible to easily advance a wire into the contralateral limb, we advise snaring it (e.g. with EN Snare® Endovascular Snare System [Merit Medical Systems, South Jordan, Utah, US]) from the large bore introducer site. This technique may be the only way to ‘secure’ the contralateral limb in challenging cases (see Figure 2). From the 6 Fr mammary, a final angiogram is performed to document complete haemostasis at the Prostar site (see Figure 3).

Crossover Final Angiography It is essential to perform a final angiography of the vascular access by a crossover approach to verify the haemostasis and to exclude local complications such as dissection or vessel occlusion. Small leaks are not seen from the skin and they may contribute to the formation of a false aneurysm or become the source of delayed major bleeding. If small vascular leakages are seen, prolonged manual compression is usually effective in sealing the leak and a final angiographic check is required to confirm the sealing. Large leaks or tears often require covered stenting or surgical intervention. In this setting, proximal balloon occlusion is a valuable bridge to endovascular or surgical repair. In summary, careful patient screening associated with device size reduction and expertise in advanced percutaneous techniques should result in very low complication rates when using the transfemoral approach, even for fully percutaneous procedures. Most local complications can be treated by endovascular methods, surgery is rarely needed.

Challenges in Valve Crossing and Positioning During Transfemoral Transcatheter Aortic Valve Implantation Despite improvements in delivery catheter profile, size and steerability compared with the first generation devices, retrograde aortic valve

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crossing during transfemoral TAVI may be challenging especially in the presence of a severely calcified native aortic valve or horizontal ascending aorta. Sheiban et al. first reported the use of the buddy balloon technique to successfully deliver a transcatheter aortic valve through a severely calcified aortic valve. Despite repeated balloon valvuloplasty, several attempts to deliver a 23 mm Edwards SAPIEN device were unsuccessful, probably due to calcified spiculae and/or recoil. Finally the buddy balloon technique using a 23 x 40 mm NuCLEUS valvuloplasty balloon (NuMed, New York, US) inflated at low pressure was successful. The valvuloplasty balloon was used as a shoehorn to enable successful delivery of the Edwards SAPIEN valve.14 Balkin et al. also reported two cases of failure to cross highly calcified aortic valves with the Retroflex catheter, used to deliver the Edwards SAPIEN device.15 The buddy balloon technique using an 8 Fr 20 x 40 mm valvuloplasty balloon (OSYPKA AG, Rheinfelden, Germany) allowed successful valve crossing. At the congress of the European Association of Percutaneous Cardiovascular Interventions (EuroPCR) 2013, we presented a case of retrograde aortic valve crossing with the AccuTrak CoreValve device (Medtronic Inc, Minneapolis, Minnesota, US) requiring the buddy balloon technique to be successful.16 The difference with the previous reports is that we used a 6 Fr compatible 8 x 80 mm Admiral peripheral balloon (Medtronic Inc) instead of a valvuloplasty balloon. The difficulty of crossing the native aortic valve in this case was probably due to the horizontal orientation of the ascending aorta. The main advantage of using a 6 Fr compatible balloon is that we do not need to oversize our contralateral access since we routinely insert a 6 Fr introducer in the contralateral femoral side in order to be ready to perform

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Structural Heart Disease Transcatheter Aortic Valve Implantation a crossover balloon inflation technique in case of major vascular complication when the large sheath is retrieved. The buddy balloon technique is a simple and easy tip and trick for challenging retrograde valve crossing. Of note, the buddy wire technique was not effective in the report by Sheiban et al.,14 similarly as in our own experience. Finally, the buddy balloon technique may avoid excessive manipulations with the delivery system and wire, and potentially reduce the risk of left ventricle perforation by the wire and embolisation of calcific particles when struggling to cross the valve. Another option in such cases is to convert to transapical approach or even surgical aortic valve replacement. The former is the only TAVI approach using an antegrade crossing of the valve with the device, which is technically easier than the retrograde crossing required with all the other TAVI approaches.

5. 6.

Généreux P, Webb JG, Svensson LG, et al., Vascular complications after transcatheter aortic valve replacement: insights from the PARTNER (Placement of AoRTic TraNscathetER Valve) trial, J Am Coll Cardiol , 2012; 60(12):1043–52. Vavuranakis M, Kariori M, Voudris V, et al., Predictive Factors of Vascular Complications after Transcatheter Aortic Valve Implantation in Patients Treated with a Default Percutaneous Strategy, Cardiovasc Ther, 2013 [Epub ahead of print]. Dimitriadis Z, Scholtz W, Faber L, et al., Balloon expandable sheath for transfemoral aortic valve implantation: a viable option for patients with challenging access, J Interv Cardiol, 2013;26(1):84–9. Eggebrecht H, Kahlert P, Thielmann M, et al., Usefulness of a novel balloon-expandable vascular sheath for facilitated large-bore arterial access for transcatheter aortic valve implantation, EuroIntervention , 2011;6(7):893–4. Burri L, Toni M, Cook S, Propofol-dip for tricky stent delivery, Cardiovsacular Medicine , 2013;16(5):153–4. Etezadi V, Katzen BT, Naiem A, et al., Percutaneous

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Conclusions At present the transfemoral approach is the most commonly used approach for TAVI worldwide. Alternative access routes such as direct aortic, subclavian or transapical approaches are of interest when the iliofemoral arteries are diseased, highly calcified or extremely tortuous. Comprehensive patient screening using multislice computed tomography and crossover techniques may reduce complication rates when using transfemoral approach, even for fully percutaneous procedures. Horizontal ascending aorta remains a challenge for retrograde valve crossing and device advancement as well as for accurate positioning during deployment. The buddy balloon technique is a simple option in the case of difficult aortic valve crossing with a delivery catheter, whereas the antegrade approach using the transapical route is a reasonable alternative in such anatomy. n

suture-mediated closure versus surgical arteriotomy in endovascular aortic aneurysm repair, J Vasc Interv Radiol , 2011;22(2):142–7. 7. Kahlert P, Eggebrecht H, Erbel R, Sack S, A modified “preclosure” technique after percutaneous aortic valve replacement, Catheter Cardiovasc Interv , 2008;72(6):877–84. 8. Cockburn J, de Belder A, Brooks M, et al., Large calibre arterial access device closure for percutaneous aortic valve interventions: use of the Prostar system in 118 cases, Catheter Cardiovasc Interv , 2012;79(1):143–9. 9. Genereux P, Kodali S, Leon MB, et al., Clinical outcomes using a new crossover balloon occlusion technique for percutaneous closure after transfemoral aortic valve implantation, JACC Cardiovasc Interv , 2011;4(8):861–7. 10. Hayashida K, Lefèvre T, Chevalier B, et al., True percutaneous approach for transfemoral aortic valve implantation using the Prostar XL device: impact of learning curve on vascular complications, JACC Cardiovasc Interv , 2012;5(2):207–14. 11. Van Mieghem NM, Nuis RJ, Piazza N, et al., Vascular

12.

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14.

15. 16.

complications with transcatheter aortic valve implantation using the 18 Fr Medtronic CoreValve System: the Rotterdam experience, EuroIntervention , 2010;5(6):673–9. Thomas C, Steger V, Heller S, et al., Safety and Efficacy of the Prostar XL Vascular Closing Device for Percutaneous Closure of Large Arterial Access Sites, Radiol Res Pract , 2013;2013:875484. Sharp AS, Michev I, Maisano F, et al., A new technique for vascular access management in transcatheter aortic valve implantation, Catheter Cardiovasc Interv , 2010;75(5):784–93. Sheiban I, Infantino V, Bollati M, Buddy balloon to deliver a percutaneous aortic valve device: a percutaneous shoehorn?, Catheter Cardiovasc Inter v, 2009;74(5):805–7. Balkin J, Silberman S, Almagor Y, Buddy balloon for TAVI, Catheter Cardiovasc Interv , 2010 [Epub ahead of print]. Noble S, Roffi M, Challenging transfemoral self-expandable bioprosthesis insertion using the buddy balloon technique. Oral presentation in the session: Overcoming TAVI challenges, Presented at: EuroPCR 2013, Paris, France, 21 May 2013.

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Structural Heart Disease Transcatheter Aortic Valve Implantation

Basic Principles of Health Economics Applied – How to Assess if Transcatheter Aortic Valve Implantation is Worth the Investment Ma tthia s B r u n n 1 a n d I s a b e l l e D u ra n d - Z a l e s k i 2 1. Research Fellow, Paris Health Economics and Health Services Research Unit (URC Eco), Paris, France; 2. Director, Paris Health Economics and Health Services Research Unit (URC Eco) and Department of Public Health at Henri Mondor Hospital, Paris, France

Abstract This article attempts to present some highlights from the rich economic literature pertaining to interventional cardiology and transcatheter aortic valve implantation (TAVI). There are currently more questions than answers, not surprisingly given the pace of technological change in interventional cardiology. For clinicians who work in a strictly regulated environment and have limited control over their use of medical technologies, this article will hopefully shed some light on the motives for policy decisions. For clinicians who make decisions on the resources used to treat their patients, it aims to provide the means of looking for evidence that will allow for informed decisions from both clinical and economic perspectives.

Keywords Health economics, economic evaluation, cost-effectiveness, transcatheter aortic valve implantation Disclosure: The authors have previously received an unrestricted grant for the economic evaluation of the FRANCE registry from the French Ministry of Health, Edwards Lifesciences and Medtronic. Acknowledgements: The authors wish to thank Stephanie Harvard for her helpful suggestions on the manuscript. Received: 6 August 2013 Accepted: 17 August 2013 Citation: Interventional Cardiology Review, 2013;8(2):135–9 Correspondence: Matthias Brunn, URC Eco, Hotel Dieu, AP-HP, 1 Place du Parvis Notre Dame, 75004 Paris, France. E: matthias.brunn@urc-eco.fr

A Primer on Health Economics The objective of this technical paper is to provide a user-friendly primer on economic evaluation applied to aortic valve replacement. We will firstly present the general concepts of economic evaluation with a specific focus on the reasons why the results of academic research may not be relevant to the physicians in charge of managing a department or to hospital directors, and secondly illustrate those concepts with the practical example of transcatheter aortic valve implantation (TAVI). As cardiovascular diseases are a leading cause of mortality and make up around 10 % of total health expenditures in developed countries, any change in practice has an effect on medical expenditures. This explains the scrutiny to which interventional cardiology has been subjected, first on coronary interventions and later on the use of TAVI, which led in turn to questions about the effectiveness of this additional spending at the population level.

and outcomes expressed in a single medical unit; for example, lives saved, life years, or quality-adjusted life years (QALY). The latter takes into account the value that people would assign to a period of time lived in a certain condition (e.g. with the effects of a stroke). The final result of a cost-effectiveness analysis is often expressed as a ratio of cost to life years gained or cost to lives saved (termed incremental cost-effectiveness ratio [ICER]). A positive result means that the increase in costs results in a better medical outcome. The lower the cost-effectiveness ratio, the more efficient is the strategy. Comparing any two strategies yields one of the following four situations:

The general purpose of an economic evaluation in the field of healthcare is to relate the costs of a diagnostic or therapeutic strategy to its outcomes. The two components of the evaluation are thus a measure of effectiveness and an estimate of costs. Economic evaluation is currently both a decision tool and an evolving academic discipline.

• In very simple cases, the strategy of interest scores better on both outcome and cost, i.e. yields greater effectiveness at lower cost than the other strategy, it is superior (dominant). • If the strategy of interest yields lower effectiveness at higher cost, it is inferior (dominated). • If it yields greater effectiveness at higher cost, we need to decide whether the incremental costs are worth paying compared to the effectiveness gained. • If it yields lower effectiveness at lower cost we need to decide whether the achieved cost-savings are justified compared to the effectiveness lost.

The comparison of medical strategies that both use different resources and yield different outcomes requires a comparative approach on two criteria – the costs and the medical outcomes. Cost-effectiveness analyses compare strategies with costs expressed in monetary terms

In the case of the first two situations the decision is straightforward. In the last two situations a trade-off needs to be made between costs and effectiveness and strategies to be compared based on the cost-effectiveness ratio.1

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simulated the outcomes of their patient cohort (TAVI versus SAVR) over the period of only one year (based on the rationale that there was no significant survival difference in the PARTNER trial for these patients), leading to an ICER of €750,000/QALY (US$868,100).4 Conversely, Gada and colleagues modelled the outcomes in their analysis over the lifetime of the patients and found an ICER of US$53,000/QALY.17 Other choices to be made for such types of modelling analyses include what events will be considered in the follow-up (e.g. stroke, re-hospitalisations) and how quality of life will be taken into account. It is important to be aware that such assumptions always have to be made in modelling analyses, which is why it is worthwhile to carefully read the methods section of a publication before interpreting the results.

3. 4.

Laupacis A, Feeny D, Detsky AS, Tugwell PX, How attractive does a new technology have to be to warrant adoption and utilization? Tentative guidelines for using clinical and economic evaluations, CMAJ , 1992;146(4):473–81. Murray CJ, Lauer JA, Hutubessy RC, et al., Effectiveness and costs of interventions to lower systolic blood pressure and cholesterol: a global and regional analysis on reduction of cardiovascular-disease risk, Lancet , 2003;361(9359):717–25. Garber AM, Sox HC, The role of costs in comparative effectiveness research, Health Aff (Millwood), 2010;29(10):1805–11. Neyt M, Van Brabandt H, Devriese S, Van De Sande S, A costutility analysis of transcatheter aortic valve implantation in Belgium: focusing on a well-defined and identifiable population, BMJ Open , 2012;2(3). Goddard M, Hauck K, Smith PC, Priority setting in health - a political economy perspective, Health Econ Policy Law , 2006;1(Pt 1):79–90. Weinstein MC, Siegel JE, Gold MR, et al., Recommendations of the Panel on Cost-effectiveness in Health and Medicine, JAMA , 1996;276(15):1253–8. Gilard M, Eltchaninoff H, Iung B, et al., Registry of transcatheter aortic-valve implantation in high-risk patients, N Engl J Med , 2012;366(18):1705–15. Lefèvre T, Kappetein AP, Wolner E, et al., One year follow-up of the multi-centre European PARTNER transcatheter heart

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10.

11.

12.

13.

14.

Conclusion This article has attempted to present some highlights from the rich economic literature pertaining to interventional cardiology and TAVI. There are currently more questions than answers, not surprisingly given the pace of technological change in interventional cardiology. For clinicians who work in a strictly regulated environment and have limited control over their use of medical technologies, this article will hopefully shed some light on the motives for policy decisions. For clinicians who make decisions on the resources used to treat their patients, we have aimed to provide the means of looking for evidence that will allow for informed decisions from both clinical and economic perspectives. n

valve study, Eur Heart J, 2011;32(2):148–57. Thomas M, Schymik G, Walther T, et al., One-year outcomes of cohort 1 in the Edwards SAPIEN Aortic Bioprosthesis European Outcome (SOURCE) registry: the European registry of transcatheter aortic valve implantation using the Edwards SAPIEN valve, Circulation , 2011;124(4):425–33. Leon MB, Smith CR, Mack M, et al., Transcatheter aorticvalve implantation for aortic stenosis in patients who cannot undergo surgery, N Engl J Med, 2010;363(17):1597–607. Kodali SK, Williams MR, Smith CR, et al., Two-year outcomes after transcatheter or surgical aortic-valve replacement, N Engl J Med , 2012;366(18):1686–95. Sehatzadeh S, Doble B, Xie F, et al., Transcatheter Aortic Valve Implantation (TAVI) for Treatment of Aortic Valve Stenosis: An Evidence Update, Ont Heal Technol Assess Ser , 2013;13(1):1–40. Reynolds MR, Magnuson EA, Wang K, et al., Health-related quality of life after transcatheter or surgical aortic valve replacement in high-risk patients with severe aortic stenosis: results from the PARTNER (Placement of AoRTic TraNscathetER Valve) Trial (Cohort A), J Am Coll Cardiol , 2012;60(6):548–58. Chevreul K, Brunn M, Cadier B, et al., Cost of transcatheter aortic valve implantation and factors associated with higher hospital stay cost in patients of the FRANCE (FRench Aortic National CoreValve and Edwards) registry, Arch Cardiovasc Dis,

2013;106(4):209–19. 15. Reynolds MR, Magnuson EA, Wang K, et al., Costeffectiveness of transcatheter aortic valve replacement compared with standard care among inoperable patients with severe aortic stenosis: results from the placement of aortic transcatheter valves (PARTNER) trial (Cohort B), Circulation , 2012;125(9):1102–9. 16. Fairbairn TA, Meads DM, Hulme C, et al., The costeffectiveness of transcatheter aortic valve implantation versus surgical aortic valve replacement in patients with severe aortic stenosis at high operative risk, Heart , 2013;99(13):914–20. 17. Gada H, Kapadia SR, Tuzcu EM, et al., Markov model for selection of aortic valve replacement versus transcatheter aortic valve implantation (without replacement) in high-risk patients, Am J Cardiol , 2012;109(9):1326–33. 18. Watt M, Mealing S, Eaton J, et al., Cost-effectiveness of transcatheter aortic valve replacement in patients ineligible for conventional aortic valve replacement, Heart , 2012;98(5):370–6. 19. Doble B, Blackhouse G, Goeree R, Xie F, Cost-effectiveness of the Edwards SAPIEN transcatheter heart valve compared with standard management and surgical aortic valve replacement in patients with severe symptomatic aortic stenosis: a Canadian perspective, J Thorac Cardiovasc Surg , 2013;146(1):52–60.e3.

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No Racial Disparities in the Treatment of ST Elevation Myocardial Infarction – A Community-based Experience Abhijeet Basoor, Gagan Randhawa, John F Cotant, Nishit Choksi, Abdul R Halabi, Kiritkumar C Patel and Michele DeGregorio Division of Cardiology, Department of Internal Medicine, St. Joseph Mercy Oakland Hospital, Pontiac, Michigan, US

Abstract Whether racial disparities exist in the treatment of ST elevation myocardial infarction (STEMI) is not exactly known. We report a retrospective chart review of patients with first event of STEMI, in two groups separated by one decade. Results revealed that hospital mortality in the 2007 and 1997 groups for African Americans versus Caucasians was one of 22 versus 21 of 170, 95 % confidence interval (CI) -0.178 to 0.022, p=0.48 and four of 41 versus 39 of 402, 95 % CI -0.095 to 0.096, p=1.00, respectively. The mean length of stay (LOS) for African Americans and Caucasians in the 2007 and 1997 groups was 5.7 versus 4.1 days (p=0.09) and 7.3 versus 6.6 days (p=0.42), respectively. During follow-up, a total of 40 patients needed re-intervention in the 2007 group. The re-intervention rate in African American patients being 13.6 % (three of 22) versus 21.2 % (36 of 170) in Caucasians, 95 % CI -0.231 to 0.081, with p=0.57. In conclusion, there was no evidence of racial disparity in the treatment of STEMI in terms of hospital mortality, length of hospital stay and re-intervention rate.

Keywords ST elevation myocardial infarction, racial disparities, African Americans, Caucasians Disclosure: The authors have no conflicts of interest to declare. Received: 20 April 2013 Accepted: 30 July 2013 Citation: Interventional Cardiology Review, 2013;8(2):140–2 Correspondence: Abhijeet Basoor, Division of Cardiology, Medical Education – Fourth Floor, St. Joseph Mercy Oakland, 44405 Woodward Avenue, Pontiac, Michigan 48341, Michigan, US. E: drasbasoor@hotmail.com

In the US, over the past 30 years, advances in cardiovascular care have resulted in a dramatic decline in mortality and morbidity associated with ST elevation myocardial infarction (STEMI) and non-STEMI.1,2 The overall incidence of coronary heart disease (CHD) has decreased over the last four decades.3 There are various reports about disparities in healthcare and the higher mortality among African Americans in CHD.3–5 There are few reports looking at racial disparities in the treatment of STEMI. We present our community-based experience demonstrating the disparities among African Americans and Caucasians in the treatment of STEMI.

Hypothesis The study was designed to test the hypothesis that there is a disparity in the treatment of STEMI among African Americans and Caucasians.

Methods and Design A retrospective chart review on two STEMI population groups was performed – October 1995 to July 1997 (first) and October 2005 to July 2007 (second). Each of the two groups comprised patients with first event of STEMI in an 18-month timeframe at our community teaching hospital, St. Joseph Mercy Oakland, Pontiac, Michigan, US. The institutional Review Board approved this retrospective review protocol. Data collection included patient demographics, insurance status, co-morbidities, hospital length of stay (LOS) and their clinical outcome with complications if any. Based on the risk for CHD at different age for men and women, and recommendations for treatment for dyslipidaemia from the Adult

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Treatment Panel (ATP) III report,6 young population in our study was defined as: males <45 years of age and females <55 years of age. In the second group, population was characterised as obese if their body mass index (BMI) was greater than or equal to 30 kilograms/ square metres (kg/m2). Tobacco use was defined as any patient who had secondary diagnoses of history of tobacco use and/or tobacco use disorder. Racial disparities between African Americans and Caucasians were measured using their hospital mortality and LOS in the two population groups and re-intervention rate in the second group. Mortality was defined as any STEMI patient who was brought to the hospital and who died during the hospital stay either with or without invasive treatment. In the second group, re-intervention rate was calculated by review of follow-up heart catheterisation reports, if performed. In this group, all patient charts were retrieved for a minimum follow-up period of one year (until July 2008) in order to determine rate of re-intervention procedures. The other details relevant to the methods and statistical tests used can be found in our previously published report from this investigation.7

Results Patient Characteristics In the first group 1995–1997 (1997 group) a total of 455 subjects were included, with males comprising 64 % of the group (289 of 455). In the second group 2005–2007 (2007 group) there was a total of 206 patients, with males comprising 65 % of the group (134 of 206). The basic characteristics of the two groups are shown

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Original Contribution According to the findings of the National Conference on Cardiovascular Disease Prevention there has been a decrease in the difference in mortality rates between African Americans and the Caucasian population.3 There are other reports to suggest that the gap in CVD mortality between the various ethnic groups, poor and undereducated versus the wealthy and well-educated, has not lessened and may be widening.10 The last Cardiovascular Science and Health Care Disparities Minority Health Summit5 emphasised that racial/ethnic disparities in CVD exist and are indeed complex and multifactorial, and they occur at all levels of the medical care system. The report also mentioned that the largest difference is due to a higher mortality rate among minorities. Although among CHD there are various reports that disparities in patient care exist,11 in our STEMI populations there was no disparity among the African American and Caucasian races in terms of mortality, length of hospital stay and cardiac re-interventions (see Table 1 and

Fox KA, Steg PG, Eagle KA, et al., Decline in rates of death and heart failure in acute coronary syndromes, 1999-2006, JAMA , 2007;297:1892–900. Enas EA, Singh V, Munjal YP, et al., Reducing the burden of coronary artery disease in India: challenges and opportunities, Indian Heart J , 2008;60:161–17. Cooper R, Cutler J, Desvigne-Nickens P, et al., Trends and disparities in coronary heart disease, stroke, and other cardiovascular diseases in the United States: findings of the national conference on cardiovascular disease prevention, Circulation, 2000;102:3137–47. Mensah GA, Mokdad AH, Ford ES, et al., State of Disparities in Cardiovascular Health in the United States, Circulation, 2005;111:1233–41.

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Figure 1). Our results regarding no racial disparity in the management of STEMI are in concordance with other authors.12 In the author’s opinion, no racial disparity in the study is due to the systems of care in management of STEMI and to strict adherence to these treatment guidelines and protocol.

Limitations This was a retrospective review of patients with STEMI, with a relatively small number of patients studied.

Conclusion In the management of STEMI there was no evidence of disparity between African Americans and Caucasians in terms of length of hospital stay, hospital mortality and re-intervention rates. Larger studies are needed to confirm these findings in the treatment of STEMI, which are in contrast to various reports of the existence of racial disparity in CVD treatment. n

Yancy CW, Benjamin EJ, Fabunmi RP, Bonow RO, Discovering the full spectrum of cardiovascular disease: Minority Health Summit 2003: executive summary, Circulation, 2005;111:1339–49. Third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). final report, Circulation , 2002;106:3143–421. Basoor A, Cotant JF, Randhawa G, et al., High prevalence of obesity in young patients with ST elevation myocardial infarction, Am Heart Hosp J , 2011;9:E37–40. Boland LL, Folsom AR, Sorlie PD, et al., Occurrence of unrecognized myocardial infarction in subjects aged 45 to 65 years (the ARIC study), Am J Cardiol , 2002;90:927–31.

Roger VL, Go AS, Lloyd-Jones DM, et al., Heart disease and stroke statistics--2011 update: a report from the American Heart Association, Circulation, 2011;123:e18–209. 10. Davis SK, Liu Y, Gibbons GH, Disparities in Trends of Hospitalization for Potentially Preventable Chronic Conditions Among African Americans During the 1990s: implications and Benchmarks, Am J Public Health, 2003;93:447–55. 11. Fincher C, Williams JE, MacLean V, et al., Racial disparities in coronary heart disease: a sociological view of the medical literature on physician bias, Ethn Dis , 2004;14:360–71. 12. Jacobi JA, Parikh SV, McGuire DK, et al., Racial disparity in clinical outcomes following primary percutaneous coronary intervention for ST elevation myocardial infarction: influence of process of care, J Interv Cardiol , 2007;20:182–7.

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