AER 4.3 CRT Supplement

Volume 4 • Issue 3 • Winter 2015 • Promotional Supplement

www.AERjournal.com

Optimisation of Cardiac Resynchronisation Therapy with MultiPoint™ Pacing Proceedings of a satellite symposium held at the EHRA Cardiostim Conference in Milan, Italy on 23 June 2015, funded by St Jude Medical Reviewers: ` Antonio Curnis, David O’Donnell, Axel Kloppe and Žarko Calovic `

Radcliffe Cardiology

Lifelong Learning for Cardiovascular Professionals

Quadra Assura MP™ CRT-D with MultiPoint™ Pacing

18%

Relative reduction in all-cause mortality1

53% Lower risk of hospitalization 87% Lower hospitalization costs compared to Bipolar LV leads 26% Absolute improvement in CRT response rate 2

3

4

SJMprofessional.com

1. Turakhia, M. P., Cao, M., Fischer, A., Arnold, E., Sloman, L. S., Dalal, N. & Gold, M. R., (2014). Reduced Mortality with Quadripolar Versus Bipolar Left Ventricular Leads in Cardiac Resynchronization Therapy. Presented at Heart Rhythm Society (HRS) 2014, San Francisco CA. PO01-51. This data is from a retrospective data analysis and has limitations.

2. Forleo, G. B., Panattoni, G., Bharmi R., Dalal, N., Pollastrelli, A., Rocca, D. D.,…Romeo, F., (2014). Hospitalization Rates and Associated Cost Analysis of Quadripolar versus Bipolar CRT-D: a comparative analysis of single-center prospective Italian registry. Presented at Heart Rhythm Society (HRS) 2014, San Francisco CA. AB39-02.

3. Corbisiero, R., Armbruster, R. & Muller, D., (2014). Reduced Costs Post CRT with Quadripolar LV leads compared to Bipolar LV leads. Heart Rhythm Society (HRS) 2014, San Francisco CA. PO01-195.

4. Pappone C., Calovic, Z., Culo, A., McSpadden, L. C., Ryu, K., Baldi, M.,…Santinelli, V. (2013). Multisite Left Ventricular Pacing in a Single Coronary Sinus Branch Improves 3-Month Echocardiographic and Clinical Response to Cardiac Resynchronization Therapy. Journal of Cardiac Failure, 19(8), S26.

Rx Only Brief Summary: Prior to using these devices, please review the Instructions for Use for a complete listing of indications, contraindications, warnings, precautions, potential adverse events and directions for use.

Unless otherwise noted, ™ indicates that the name is a trademark of, or licensed to, St. Jude Medical or one of its subsidiaries. ST. JUDE MEDICAL and the nine-squares symbol are trademarks and service marks of St. Jude Medical, Inc. and its related companies. © 2015 St. Jude Medical, Inc. All Rights Reserved.

SJM-QD-1115-0036a | Item approved for international use only.

Supported by St Jude Medical

Optimisation of Cardiac Resynchronisation Therapy with MultiPoint™ Pacing ` `4 Reviewers: Antonio Curnis, 1 David O’Donnell, 2 Axel Kloppe 3 and Žarko Calovic 1. Brescia, Italy; 2. Austin Hospital, Melbourne, Australia; 3. Medical Clinic II, Cardiology and Angiology, Bergmannsheil Bochum, Germany; 4. Department of Arrhythmology, IRCCS Policlinico San Donato, San Donato Milanese, Italy

Abstract Cardiac resynchronisation therapy (CRT) using biventricular pacing is an established therapy for impairment of left ventricular (LV) systolic function in patients with heart failure (HF). Although technological advances have improved outcomes in patients undergoing biventricular pacing, the optimal placement of pacing leads remains challenging, and approximately one third of patients have no response to CRT. This may be due to patient selection and lead placement. Electrical mapping can greatly improve outcomes in CRT and increase the number of patients who derive benefit from the procedure. MultiPoint™ pacing (St Jude Medical, St Paul, MN, US) using a quadripolar lead increases the possibility of finding the best pacing site. In clinical studies, use of MultiPoint pacing in HF patients undergoing CRT has been associated with haemodynamic and clinical benefits compared with conventional biventricular pacing, and these benefits have been sustained at 12 months. This article describes the proceedings of a satellite symposium held at the European Heart Rhythm Association (EHRA) Europace conference held in Milan, Italy, in June 2015.

Keywords Heart failure, cardiac resynchronisation, MultiPoint pacing Disclosure: Dr Curnis has received fees from Medtronic Inc, Biotronik,St Jude Medical, Boston Scientific, Sorin Liva Nova and Spectranetics; Dr O’Donnell has received fellowship support from Medtronic Inc and St Jude Medical, advisory booard fees from St Jude Medical and Metronic and speakers fees from Medtronic Inc, St Jude Medical, Boston Scientific, Boehringer Ingelheim and Merit Medical; Dr Kloppe has received consulting fees from Medtronic Inc and St Jude Medical, and lecture fees from Medtronic Inc, Boston Scientific and St. Jude Medical; Dr Calovic has received speakers fees from St Jude Medical Received: 11 November 2015 Accepted: 24 November 2015 Citation: Arrhythmia & Electrophysiology Review 2015;4(3):Suppl 1. Access at: www.AERjournal.com

Support: This supplement is based on the proceedings of a St Jude Medical satellite symposium held at the EHRA Europace conference, Milan, Italy in June 2015. This report was written by a medical writer, Katrina Mountfort, and the participants all reviewed and approved this supplement before publication. St Jude Medical reviewed the supplement for technical accuracy and sponsored the development of this supplement in Arrhythmia & Electrophysiology Review.

Cardiac resynchronisation therapy (CRT) with biventricular pacing is an effective therapy in patients with advanced heart failure (HF) symptoms (New York Heart Association [NYHA] Class III or IV), an ejection fraction (EF) of 35 % or less and an intraventricular conduction delay (IVCD) of 120 ms or more.1–3 CRT has also been shown to be effective for the prevention of HF in relatively asymptomatic patients with wide QRS.4 However, CRT is underutilised among eligible patients.5 Approximately one-third of patients do not respond to CRT due to various factors, including anatomic difficulties and suboptimal lead placement. To increase the effectiveness of CRT, several experts

have hypothesised that pacing at multiple left ventricular (LV) sites may provide more effective resynchronisation. A new approach involving MultiPoint™ pacing with the use of a single quadripolar lead (Quartet™ lead; St Jude Medical, St Paul, MN, US) has recently been proposed. This lead integrates four pacing electrodes, increasing the options in device programming. In order to present an overview of research to date on this technology, a satellite symposium, supported

by St Jude Medical and chaired by Dr Antonio Curnis (Brescia, Italy), was held at the European Heart Rhythm Association (EHRA) Europace conference held in Milan, Italy, in June 2015. n

Electrical Mapping to Optimise Heart Failure Outcomes Following Cardiac Resynchronisation Therapy David O’Donnell, Austin Hospital, Melbourne, Australia Dr O’Donnell began by stating that the response to CRT is suboptimal and a significant proportion of the poor response to CRT is due to poor positioning of the LV leads. In a typical left bundle branch block (LBBB), the response to routine CRT is 60 to 70 %, with an 8 % improvement in EF. Most physicians consider this a good response rate. However, if CRT is electrically mapped, outcomes can be further improved to yield an 80 % response rate and 12 % improvement in EF.

smaller group are becoming eligible for CRT, meaning that a significant number of patients with HF are missing out on a treatment that may benefit them. Prior to electrical mapping, patients with atypical LBBB had a poor chance of responding to CRT. Randomised studies show response rates of around 40 % and EF improvements of 3%. Electrically mapped CRT nearly doubles the response in these patients (response rate 75 % and an 11 % improvement in EF).6

In order to improve CRT outcomes, we need to consider the factors that influence the response. These include patient selection: an increasingly

Patients with other conduction abnormalities, including a narrow QRS, right bundle branch block (RBBB) and non-specific IVCDs (NIVCD) have

© RADCLIFFE CARDIOLOGY 2015

3

Supported by St Jude Medical also typically been excluded from CRT. Many consider that traditional CRT is ineffective for these patients; in cases of narrow QRS, response rate is negligible with no improvement in EF.7 However, with electrically mapped CRT, the response rate is 65 % and the EF improves by 8 %.

The same is true of RBBB/NIVCD, where electrically mapped CRT can give responses of 60 % with an EF improvement of 6 %.8 Correct lead placement is also essential to optimise responses to CRT. Dr O’Donnell explained the challenges of optimising myocardial cell-to-cell transmission in CRT using the analogy of transmitting a message to a group of soldiers in such a way that each soldier receives the message as quickly as possible. However, CRT presents unique challenges such as scar (some soldiers do not pass on the message); conduction block (some soldiers only pass the message in one direction); functional block (some soldiers pass the message slowly or incompletely); and intrinsic conduction (some soldiers utilise intrinsic communication systems).

In other words, we need to focus on where to put the leads, the electrical conduction and the electrical map. In the same way that golf clubs and tennis racquets have a ‘sweet spot’ for an optimal shot, Dr O’Donnell suggested that there is a sweet spot in CRT. However, at present, we do not know where or how big it is. The remarkable improvement experienced by some patients with anterior leads suggests that in some people, the sweet spot is clearly bigger than others and in a broad left bundle with notching, it may be 2 to 3 cm, and the lead positioning is less crucial; whereas in cases of narrow QRS, it may be as small as 2 mm. This raises the questions: how close do we have to place the leads to achieve 90 % of the effect? If we do not find the right spot, are we making these patients worse? Large studies suggest that 10 to 15 % of patients deteriorate following CRT.9 Dr O’Donnell presented his ideas as a series of concepts. Concept 1 is that there are better and there are worse places to pace in the heart. Others argue that this is incorrect and support their arguments with data that show the LV lead location does not impact on mortality or measures of response to CRT.10 Interpretations of the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT) data have also led to the conclusion that the lead position is unimportant.11 However, this study concluded that, anatomically, it is difficult to determine where to put the lead, but areas of scar or the apical region should be avoided. This leads to Concept 2: anatomical placement is ineffective for finding the sweet spot. Therefore, if the sweet spot exists, it must be electrical.

The reasons that anatomical placement fails is evident if we look at the different forms of septal activation in LBBB – a slide was presented of 20 different anatomical specimens of LBBB in 20 different patients – so it is unreasonable to expect that placing the lead in the same position in everyone will be beneficial.

A study of electrical activation in LBBB shows that there are multiple types of activation, and most people consider the typical LB that travels down the septum in a U shape but this activation pattern occurs in less than 50 % of all LBBB.12 A recent study of patients with LBBB found that the type of bundle block significantly influences response to CRT; an absence of ECG markers of residual LB conduction was predictive of a greater improvement in LV function with CRT.6 A study found that markers of electrical dyssynchrony, including the electrical delay at the LV pacing site (QLV) are predictive of response to

4

CRT. Activation was measured as the time that the intrinsic electrical wave front detected in the RV lead takes to travel to the LV lead,8 a simple process that takes only seconds. If RV and LV electrograms are on time with each other, it is difficult to resynchronise the entire area effectively. Such patients are termed non-responders. In a typical non-responder, intrinsic RV–LV = 20 ms, QRSd = 145 ms, QLV = 15 %.

In a typical responder intrinsic RV–LV = 120 ms, QRSd = 145 ms, QLV = 82 %, i.e., a large electrical delay. There was moderate correlation between intrinsic RV–LV electrical delay and delta LV versus absolute change in LVEF (p=0.03).8 Many groups have validated this study. Electrical delay in the LV lead has been shown to be correlated with the haemodynamic response to CRT expressed as an intra-individual percentage change in the maximum rate of rise of LV pressure over baseline (dP/dt, derived from the mitral regurgitation Doppler profile).13–15 Later activated areas are associated with higher stroke volume16 and improved LV synchrony as determined by tissue Doppler imaging (TDI).17 The seminal electrical mapping study by Gold et al. found that a measured QLV interval is an electrical marker of delayed LV lead position and that long QLV is associated with better echocardiogram and clinical outcomes.18 The LV end-systolic volume and quality of life (QOL) response rates were statistically significant in the QLV quartiles used.

Another study examined the impact of electrical and anatomical location of the LV lead in relation to baseline QRS morphology on the CRT outcome.19 The best response was seen in a patient with an LB and an LV lead late in the QRS complex. Interestingly, patients with a non-left bundle and a narrow QRS had a similar benefit if the lead was placed in the correct spot. In other words, there is a statistical difference between having the wrong patient with the lead in the right spot and the right patient with the lead in the wrong spot.

It can therefore be concluded that patient selection is important for successful outcomes in CRT, but it is only one component of a complex picture.

In the Targeted Left Ventricular Lead Placement to Guide Cardiac Resynchronization Therapy (TARGET) study, patients (n=220) underwent baseline echocardiographic speckle-tracking two-dimensional radial strain imaging and were then randomised 1:1 into two groups. In group 1 (TARGET), the LV lead was positioned at the latest site of peak contraction that was free from scar and non-apical. Group 2 (control) patients underwent standard unguided CRT. Patients were classified by the relationship of the LV lead to the optimal site as concordant (at optimal site), adjacent (within 1 segment), or remote (≥2 segments away). The primary endpoint was a 15 % reduction in LV end-systolic volume at 6 months. Secondary endpoints were clinical response (one improvement in NYHA functional class), all-cause mortality and combined all-cause mortality and HF-related hospitalisation. Response rates were higher in TARGET patients (83 % versus 65 %; p=0.003), and superior improvements in ESV and QOL were also reported.20 The major finding of this study was the importance of lead placement exactly at the latest zone, not merely adjacent to the latest zone (see Figure 1).

These study data can be summarised in Concept 3: electrical mapping is effective and improves outcomes for patients undergoing CRT. Dr O’Donnell proceeded to describe how electrical mapping is used in his institution: following lead placement, activation is measured from proximal to distal, which shows an activation wave front. By using the electrical map to achieve a more distal lead placement, improvements can be gained. In the ongoing ‘moving the LV lead quad lead’ study,

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

Optimisation of Cardiac Resynchronisation Therapy with MultiPoint™ Pacing

There is a reluctance among cardiologists to move leads and, in these situations, a quadripolar lead is useful. A recent multicentre study of consecutive implants and a quadripolar lead has shown that the mean difference in intrinsic electrical activation of the usable electrodes was 30 ms (3 to 55 ms). Quadripolar leads reduce phrenic nerve stimulation, reduce high thresholds and are user friendly; however, the most compelling argument for their use is the fact that resynchronisation parameters can be improved by 20 ms by picking the best versus worst electrode.

Figure 1: TARGET Study – Combined Endpoint of Death and Heart Failure-related Hospitalisation According to Left Ventricular Lead Position 50 Per cent combined endpoint

in patients where the lead was moved, QLV at final position was 89 % whereas in patients where the lead was not moved, QLV in final position was 77 %,21 leading to Concept 3b; electrical mapping is effective and improves outcomes for patients undergoing CRT. However, electrical mapping requires moving the lead if it is not in the late zone.

Concordant Adjacent Remote

40 30 20 10 0

Log rank p<0.0001 0

200

With permission from Khan et al., 2012.20

The optimal pacing site appears to be determined by the fastest pathway of activation from the LV and RV electrodes.22 If it takes longer to move from one side of the heart than from another, the answer is to move the leads. The greater the difference in timings left–right versus right–left, the worse the outcomes, i.e., delta LV. In a recent study, the RV-paced delay (RVp-LV) and LV-paced delay (LVp-RV) were measured during RV-only pacing and LV-only pacing, respectively. The timing difference between the LVp-RV and RVp-LV was termed the delta LV. Results showed that significant intrinsic electrical delay and shorter delta-LV both predicted response, even when LV leads were implanted in the targeted mechanically delayed segment. Such assessments

400 Days

600

of electrical dyssynchrony may be used to determine optimal lead positions and response to CRT.23 In conclusion, electrical mapping is very effective but is not yet easy. Anatomical LV lead placement does not enable optimal patient outcomes but electrical mapping can guide LV placement and improve outcomes for patients undergoing CRT. Increased experience will improve our expertise at mapping CRT. However, by using the lead with the most poles and the device with the most programming options, we can future proof our patients. n

Clinical Evidence Demonstrating the Benefit of MultiPoint Pacing Cardiac Resynchronisation Therapy Axel Kloppe, Bergmannsheil Bochum, Germany Dr Kloppe began his presentation by discussing a 2008 multicentre single-blind crossover study that randomised patients with congestive HF (n=40) either to triventricular (one RV and two LV leads) or biventricular (one RV and one LV lead) stimulation. The primary endpoint was quality of ventricular resynchronisation (Z ratio). The study did not find a significant change in Z ratio but concluded that CRT with triple-site ventricular stimulation was safe and resulted in a significantly higher LVEF and smaller LV end-systolic volume and diameter.24 Since this study, quadripolar leads have been developed. A 2013 study (n=21) compared biventricular and multisite pacing with a quadripolar LV lead. Using an acute pacing protocol, four configurations of multisite and simultaneous RV pacing were tested. In the majority (84 %) of patients, MultiPoint pacing improved LV dP/dt(max) compared with biventricular pacing.25 Only three patients with MultiPoint pacing (one who was a super-responder) experienced no significant additional effect from MultiPoint pacing.

In a prospective multicentre study (n=40), a CRT defibrillator incorporating a quadripolar lead was programmed to deliver MultiPoint pacing with eight different configurations of timing delays. The configuration that yielded the best echocardiographic measurement for each patient was defined as ‘optimal MultiPoint pacing’. The endpoint was analysis of contractility expressed as global radial strain of the opposing walls and stroke volume LV output tract velocity timed intervals (LVOT VTIs).

Compared with conventional CRT, the mean peak radial strain was significantly higher for the optimal MultiPoint pacing configuration (18.3

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

± 7.4 versus 9.3 ± 5.3 %; p<0.001).26 The median delay between LV1 and LV2 was 55 ms, and between LV2 and RV was 20 ms. In a subanalysis, no difference was seen between ischaemic and nonischaemic patients.

The proportion of patients who exhibited improvements in LVOT VTI with at least one MultiPoint pacing intervention over conventional CRT is shown in Figure 2, and suggests that low and non-responders might derive more benefit from MultiPoint pacing.

Most recently, a study by Pappone et al. investigated MultiPoint pacing in 44 consecutive patients in an acute setting. Following CRT implantation, consecutive patients (n=44) were randomised to receive biventricular pacing with either conventional LV pacing (CONV) or MultiPoint pacing (see Figure 3). In each case, an optimal pacing configuration was determined based on intra-operative pressure-volume (PV) loop measurements. The primary endpoint was reduction in LV end-systolic volume (LVESV) of ≥15 %. The delay between LV1 and LV2 was 26 ± 15 ms and between LV2 and RV was 10 ± 9 ms. After 3 months, 50 % of CONV patients and 76 % of MultiPoint pacing patients were classified as responders. ESV reduction, EF increase and NYHA class reduction relative to baseline were significantly greater in the MultiPoint pacing group than in the CONV group. In terms of aetiology, non-ischaemic patients had a significant reduction in LVESV compared with ischaemic patients, but no differences were seen in other parameters. A significant increase in MultiPoint pacing group in contractility, stroke volume and EF was seen with MultiPoint pacing. In addition, the best MultiPoint pacing improved acute diastolic function, i.e., change from baseline.27 In 2015, Pappone published 12-month

5

Supported by St Jude Medical Figure 2: Proportion of Patients who Exhibited Improvement in Left Ventricular Output Tract Velocity Timed Intervals with at Least One MultiPoint Pacing Intervention Over Conventional Cardiac Resynchronisation Therapy

% Patients with at least 1 MPP improving over BiV baseline

80 70 60 50 40 30 20 10 0

≥10 %

≥15 %

≥20 %

≥25 %

Threshold for VT improvement over BiV baseline BiV = biventricular, MPP = MultiPoint pacing. Source: Rinaldi et al., 2014.25

Figure 3: Design of the MultiPoint Pacing Pressure-volume Loop Study Enrolment (n=44)

CRT implant (n=44)

MPP group Randomisation 1 patient lost to follow-up

• Echo exam (LVESV, LVEDV, LVEF) • NYHA class assessment

• Quartet LV lead and CRT device with MPP feature • PV loop measurments during pacing protocol CONV group

(n=44) 3 months (n=21)

• Echo exam (blinded observer) • NYHA class assessment

• Patients programmed to optimal pacing configuration

3 months

1 patient lost to follow-up (n=19)

• Echo exam (blinded observer) • NYHA class assessment

In an ongoing study (n=19), Kloppe et al. measured the acute effect of conventional pacing (SSP) and MultiPoint pacing on dP/dt(max) compared with baseline. A significant increase was observed with MultiPoint pacing relative to SSP but wide inter-patient response to the two interventions was observed. At the recent Heart Rhythm Society meeting, preliminary data were presented from a multicentre prospective study (n=313) that received MultiPoint pacing or biventricular pacing. In the MultiPoint pacing group, EF increased significantly compared with biventricular (42±8 % versus 35 ± 10 %; p<0.001).30

(n=22)

2 patient deaths from non-cardiac causes 12 months

Another recent study compared biventricular pacing and MultiPoint pacing in a group of 29 patients with a high QRS. The effect of MultiPoint pacing, by means of simultaneous pacing from distal and proximal dipoles, was investigated at any available site, an average of 3.2 pacing sites per patients, and a total of 92 measurements. An increase in LV electrical delay (Q-LV) at any site was seen even with MultiPoint pacing relative to biventricular pacing when taking the best and worst sites.

Q-LV was measured at each location, along with the increase in LVdP/ dtmax (maximum rate of rise of LV pressure) obtained by biventricular pacing and MultiPoint pacing. The effect of MultiPoint pacing, by means of simultaneous pacing from distal and proximal dipoles, was investigated at all available sites. Compared with biventricular pacing at any LV site, MultiPoint pacing yielded a small but consistent increase in haemodynamic response. A correlation between the increase in haemodynamics and Q-LV on MultiPoint pacing was observed for all measurements, including those taken at the best and worst sites. The MultiPoint pacing-induced improvement in contractility was associated with significantly greater narrowing of the QRS complex than conventional biventricular pacing. A good correlation was observed between electrical delay and haemodynamic improvement.29

12 months (n=21)

CRT = cardiac resynchronisation therapy; LVEDV = left ventricular end-diastolic volume; LVEF = left ventricular ejection fraction; LVESV = left ventricular end-systolic volume; MPP = MultiPoint Pacing; NYHA = New York Heart Association; PV = pressure-volume. Adapted from Pappone et al., 2014.27

data from this study, showing sustained improvements; these are discussed in the final presentation.28

In conclusion, a growing body of clinical data have demonstrated that CRT with MultiPoint pacing can significantly improve acute cardiac contractility and haemodynamic parameters compared with conventional pacing. MultiPoint pacing can further augment the well-described systolic benefits of CRT, likely by better synchronising LV contraction and/or recruiting additional LV myocardial tissue.

The MultiPoint pacing-induced improvement in contractility was associated with significantly greater narrowing of the QRS complex than conventional biventricular pacing, However, much remains poorly understood, including the optimal timing of LV1 to LV2 to RV. n

Management of Non-responders to Cardiac Resynchronisation Therapy with MultiPoint Pacing ` IRCCS Policlinico San Donato, San Donato Milanese, Italy Žarko `Calovic, ` Dr Calovic ` started by examining the percentage of non-responders to CRT. A 2010 evaluation of different studies concluded that agreement is poor among different studies, since different response criteria are used, and concluded that 30 to 50 % of patients do not respond to CRT.31 Strategies for dealing with non-responders include electrogram-based delay optimisation, which is fast, simple and non-invasive, but has not been associated with any benefit in the FREEDOM or SMART-AV trials.32,33 Echo-based delay optimisation is time-consuming, measurements may be inconsistent and its clinical benefit is questionable. Targeting the LV lead to the latest activation has been shown to be effective20

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but coronary sinus anatomy may prevent access to the ideal location.

The limitations of these strategies have led to the development of MultiPoint pacing LV pacing.

A 2000 study of HF patients with LBBB showed that dual-site pacing gave a greater improvement in systolic function compared with single-site pacing.34 Subsequent studies investigated triple-site pacing24 and concluded that multiple LV pacing sites capture a larger area and reduce dyssynchrony, but involve increased procedure times and increased contrast exposure, as well as lower implant success and the requirement for a Y adaptor or second LV lead connected to the atrial port of the device.

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

Optimisation of Cardiac Resynchronisation Therapy with MultiPoint™ Pacing

The use of MultiPoint pacing involves a lead with four poles with an ability to pace from three ventricular sites with programmable delays.

In a scarred heart, we often see dispersal of the wave fronts of the electrical current. Pacing at two points simultaneously overcomes these obstacles. As previously discussed, numerous studies have demonstrated the acute and mid-term benefits of MultiPoint pacing in improving electrical propagation, acute haemodynamics and dyssynchrony.25–28,35–37 Remaining unanswered questions include: what are the long-term benefits of MultiPoint pacing? Can MultiPoint pacing help patients already receiving CRT? Determining the optimal pacing vector and inter-ventricular delay can be challenging in conventional CRT. With MultiPoint pacing, the addition of a second LV pulse with another programmable delay gives even more programming options. The MultiPoint pacing loop study evaluated two methods of MultiPoint pacing vector combination selection and multiple delay combinations. In this patient cohort, an empirical method of selecting MultiPoint pacing pacing vectors based on maximising anatomical spacing between LV1 and LV2 cathodes resulted in the best dP/dt response more often than an electrical delay-based selection method. Moreover, pacing with 5 ms LV1–LV2 delay produced the best dP/dt response more often than pacing with 40 ms LV1–LV2.27 Recently, Pappone published 12-month follow-up data from this study.28,38 The trend observed at 3 months was sustained; LVESV and EF were significantly improved in the MultiPoint pacing group relative to the CONV group. A clinical benefit was also seen: improvement of more than two NYHA classes was seen in a much higher proportion of MultiPoint pacing patients compared with conventional pacing. According to the definition of response (ESV reduction of ≥15 % and alive status at 12 months), 67 % of the overall patient population were responders, with a 76 % responder rate in the MultiPoint pacing group compared with 57 % in the CONV group. This was further subdivided into superresponders (ESV reduction ≥30 %), responders (ESV reduction ≥15 and <30 %), non-responders (ESV reduction ≥0 and <15 %) and negative responders (ESV increase). The MultiPoint pacing group showed a lower rate of negative responders (10 versus 25 %) and a higher rate of super responders (33 versus 14 %) compared with the CONV group (see Figure 4).38 An example of acute haemodynamic measurements and echo measurements were given in a super responder: these included a decrease in EDV from 310 ml at baseline to 235 ml at 3 months and 211 ml at 12 months. The decrease in EF was 35 % at baseline and 41 % at both 3 and 12 months.38 Dr Calovic next posed the question: can MultiPoint pacing improve the response in patients receiving conventional CRT? At CRT implant

Figure 4: Twelve-month Cardiac Resynchronisation Therapy Response Rate in the MultiPoint Pacing Pressure-volume Loop Study Response definition: ESV reduction ≥15 % and Alive Status

All patients (n=42) 17 %

24 %

Super-responders Responders Non-responders

17 %

Negative responders

43 % CONV group (n=21) 24 %

`

` 19 %

14 %

MPP group (n=21) 9% 14 %

33 %

43 % 43 %

CONV = conventional left ventricular pacing; ESV = end-systolic volume; MPP = MultiPoint pacing. Source: Pappone et al., 2015.38

programmed with simultaneous biventricular pacing, patients were assessed by an echo exam (LVESV, LVEDV, LVEF) as well as undergoing NYHA class assessment. At 12 months, patients underwent follow-up assessments and CRT programming was switched to MultiPoint pacing.

Further follow-up assessments were performed at 16 months. Following the switch, the two non-responders to conventional CRT both became responders with MultiPoint pacing while experiencing an additional reduction in ESV of -33 % and -20 % and an improvement in EF of +15 % and +4 % at 16 months relative to the 12-month exam. Five of the six responders to conventional CRT remained responders with MultiPoint pacing, with four patients experiencing additional ESV change of at least -10 %. In terms of NYHA class changes, all patients were Class II pre-implant, all improved to Class II at 12 months and after 4 months of MultiPoint pacing, four patients improved to Class I while the remaining five patients remained in Class II.39 In conclusion, MultiPoint LV pacing in a single coronary sinus branch results in significant improvements in acute haemodynamic function and long-term CRT response relative to conventional biventricular pacing. Non-responders to conventional CRT may benefit from activating MultiPoint pacing and may be converted to responders. In addition, CRT responders may experience additional LV remodeling and/or increased LV function beyond that received from the conventional therapy. n

Summary and Concluding Remarks Although technological advances have improved outcomes in patients undergoing biventricular pacing, the optimal placement of pacing leads remains challenging and there is a need to improve response rates to CRT and optimise patient selection. MultiPoint pacing using a quadripolar lead increases the possibility of finding the best pacing site. In clinical studies, use of MultiPoint pacing in HF patients undergoing CRT has been associated with increased

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

haemodynamic and clinical benefits compared with conventional pacing, particularly in patients with the least improvement from biventricular pacing. Use of MultiPoint pacing results in a smaller number of non-responders and further improvements in those that do respond. While data have shown that benefits are sustained at 12 months, there is a need for further long-term studies to investigate the performance and reliability of MultiPoint pacing. n

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14.

Epstein AE, DiMarco JP, Ellenbogen KA, et al. 2012 ACCF/AHA/ HRS focused update incorporated into the ACCF/AHA/HRS 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society.

J Am Coll Cardiol 2013;61:e6–75.

Bristow MR, Saxon LA, Boehmer J, et al. Cardiacresynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med 2004;350:2140–50.

Cleland JG, Daubert JC, Erdmann E, et al. The effect of cardiac resynchronization on morbidity and mortality in heart failure.

N Engl J Med 2005;352:1539–49.

Moss AJ, Hall WJ, Cannom DS, et al. Cardiac-resynchronization therapy for the prevention of heart-failure events. N Engl J Med 2009;361:1329–38.

Curtis AB, Yancy CW, Albert NM, et al. Cardiac resynchronization therapy utilization for heart failure: findings from IMPROVE HF. Am Heart J 2009;158:956–64.

Perrin MJ, Green MS, Redpath CJ, et al. Greater response to cardiac resynchronization therapy in patients with true complete left bundle branch block: a PREDICT substudy.

Europace 2012;14:690–5.

Zareba W, Klein H, Cygankiewicz I, et al. Effectiveness of Cardiac Resynchronization Therapy by QRS Morphology in the Multicenter Automatic Defibrillator Implantation TrialCardiac Resynchronization Therapy (MADIT-CRT). Circulation 2011;123:1061–72.

O‘Donnell D, Lin T, Swale M, et al. Long-term clinical response to cardiac resynchronisation therapy under a multidisciplinary model. Intern Med J 2013;43:1216–23.

Ploux S, Eschalier R, Whinnett ZI, et al. Electrical dyssynchrony induced by biventricular pacing: implications for patient selection and therapy improvement. Heart Rhythm 2015;12:782–91.

Saxon LA, Olshansky B, Volosin K, et al. Influence of left ventricular lead location on outcomes in the COMPANION study. J Cardiovasc Electrophysiol 2009;20:764–8.

Singh JP, Klein HU, Huang DT, et al. Left ventricular lead position and clinical outcome in the multicenter automatic defibrillator implantation trial-cardiac resynchronization therapy (MADIT-CRT) trial. Circulation 2011;123:1159–66.

Regoli F, Auricchio A. The role of invasive mapping in the electrophysiology laboratory. Europace 2009;11(Suppl. 5):v40–5.

Singh JP, Fan D, Heist EK, et al. Left ventricular lead electrical delay predicts response to cardiac resynchronization therapy.

Heart Rhythm 2006;3:1285–92.

Zanon F, Baracca E, Pastore G, et al. Determination of the longest intrapatient left ventricular electrical delay may predict acute hemodynamic improvement in patients after cardiac resynchronization therapy. Circ Arrhythm Electrophysiol

2014;7:377–83.

15. Gold MR, Leman RB, Wold N, et al. The effect of left ventricular electrical delay on the acute hemodynamic response with cardiac resynchronization therapy. J Cardiovasc Electrophysiol 2014;25:624–30.

16. van Geldorp IE, Delhaas T, Hermans B, et al. Comparison of a non-invasive arterial pulse contour technique and echo Doppler aorta velocity-time integral on stroke volume changes in optimization of cardiac resynchronization therapy.

Europace 2011;13:87–95.

17. Lane RE, Chow AW, Mayet J, et al. The interaction of interventricular pacing intervals and left ventricular lead position during temporary biventricular pacing evaluated by tissue Doppler imaging. Heart 2007;93:1426–32.

18. Gold MR, Birgersdotter-Green U, Singh JP, et al. The relationship between ventricular electrical delay and left ventricular remodelling with cardiac resynchronization therapy. Eur Heart J 2011;32:2516–24.

19. Kandala J, Upadhyay GA, Altman RK, et al. QRS morphology, left ventricular lead location, and clinical outcome in patients receiving cardiac resynchronization therapy. Eur Heart J 2013;34:2252–62.

20. Khan FZ, Virdee MS, Palmer CR, et al. Targeted left ventricular lead placement to guide cardiac resynchronization therapy: the TARGET study: a randomized, controlled trial. J Am Coll Cardiol 2012;59:1509–18.

21. Lin T, Crosby P, Sugumar H, et al. Implant electrical characteristics predict response to cardiac resynchronization therapy, WJCD, 2014;4:513–21.

22. Mafi Rad M, Blaauw Y, Debie L, et al. Evaluation of left ventricular endocardial cardiac resynchronization therapy in a non-responder with ventricular arrhythmias, Indian Pacing Electrophysiol J, 2014;14:32–6.

23. Leclercq C, Gadler F, Kranig W, et al. A randomized comparison of triple-site versus dual-site ventricular stimulation in patients with congestive heart failure. J Am Coll Cardiol 2008;51:1455–62.

24. Thibault B, Dubuc M, Khairy P, et al. Acute haemodynamic comparison of multisite and biventricular pacing with a quadripolar left ventricular lead. Europace 2013;15:984–91.

25. Rinaldi CA, Leclercq C, Kranig W, et al. Improvement in acute contractility and hemodynamics with multipoint pacing via a left ventricular quadripolar pacing lead. J Interv Card Electrophysiol 2014;40:75–80.

26. Pappone C, Calovic Z, Vicedomini G, et al. Multipoint left ventricular pacing improves acute hemodynamic response assessed with pressure-volume loops in cardiac resynchronization therapy patients. Heart Rhythm 2014;11:394–401.

27. Pappone C, Calovic Z, Vicedomini G, et al. Multipoint left ventricular pacing in a single coronary sinus branch improves

28.

29.

30.

31.

32.

33.

34.

35.

36.

37.

38.

mid-term echocardiographic and clinical response to cardiac resynchronization therapy. J Cardiovasc Electrophysiol 2015;26:58–63.

Zanon F, Baracca E, Pastore G, et al. Multipoint pacing by a left ventricular quadripolar lead improves the acute hemodynamic response to CRT compared with conventional biventricular pacing at any site. Heart Rhythm 2015;12:975–81.

Forleo GB, Santini L, Potenza D, et al. Impact of multi-point left ventricular pacing on QRS duration and left ventricular ejection fraction. Preliminary results from a multicenter prospective study. Presented at HRS, Boston, May 2015 Abstract no p004-183.

Fornwalt BK, Sprague WW, BeDell P, et al. Agreement is poor among current criteria used to define response to cardiac resynchronization therapy. Circulation 2010;121:1985–91.

Abraham WT. Results from the FREEDOM Trial – Assess the Safety and Efficacy of Frequent Optimization of Cardiac Resynchronization Therapy. SP08. Late-Breaking Clinical Trials, HRS 2010. Denver, Colorado, US. Ellenbogen KA, Gold MR, Meyer TE, et al. Primary results from the SmartDelay determined AV optimization: a comparison to other AV delay methods used in cardiac resynchronization therapy (SMART-AV) trial: a randomized trial comparing empirical, echocardiography-guided, and algorithmic atrioventricular delay programming in cardiac resynchronization therapy. Circulation 2010;122:2660–8.

Pappone C, Rosanio S, Oreto G, et al. Cardiac pacing in heart failure patients with left bundle branch block: impact of pacing site for optimizing left ventricular resynchronization.

Ital Heart J 2000;1:464–9.

Shetty AK, Sohal M, Chen Z, et al. A comparison of left ventricular endocardial, multisite, and multipolar epicardial cardiac resynchronization: an acute haemodynamic and electroanatomical study. Europace 2014;16:873–9.

Thibault B, Dubuc M, Karst E, et al. Design of an acute dP/ dt hemodynamic measurement protocol to isolate cardiac effect of pacing. J Card Fail 2014;20:365-72.

Rinaldi CA, Kranig W, Leclercq C, et al. Acute effects of multisite left ventricular pacing on mechanical dyssynchrony in patients receiving cardiac resynchronization therapy. J Card Fail 2013;19:731-8.

Pappone C, Calovic Z, Vicedomini G, et al. Improving cardiac resynchronization therapy response with multipoint left ventricular pacing: Twelve-month follow-up study. Heart Rhythm 2015;12:1250–8.

Pappone A, Calovic Z, Cuko A, et al. Multipoint left ventricular pacing provides additional echocardiographic benefit to responders and non-responders to conventional cardiac resynchronization therapy. Eur Heart J 2015; Suppl A: A12-A17.

Brief Summary: Prior to using these devices, please review the Instructions for Use for a complete listing of indications, contraindications, warnings, precautions, potential adverse events and directions for use. Unless otherwise noted, ™ indicates that the name is a trademark of, or licensed to, St. Jude Medical or one of its subsidiaries. ST. JUDE MEDICAL and the nine-squares symbol are trademarks and service marks of St. Jude Medical, Inc. and its related companies. © 2015 St. Jude Medical, Inc. All Rights Reserved.

SJM-MLP-1015-0027 | Item approved for International use.

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