SHA24/041004

Treatment of Angina: Drugs vs Intervention Fausto J. Pinto, MD, PhD, FESC, FACC Lisbon University, Portugal

Fausto J. Pinto, MD, PhD, FESC, FASE, FACC, FSCAI 

Disclosures:



Consultancy, advisory boards and lecture fees:

Astra Zeneca, Bayer, Bial, Boehringher Ingelheim, Covidien, GE, Irokio, Menarini, Pfizer, Servier

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Chronic ischemic heart disease : a changing scenario  Increase in general population life expectancy (1 in 3 men and women aged over 65 years have some form of cardiovascular disease including angina)  Significant increase in risk factors such as obesity, lipids, smoking diabetes, etc. (incidence of CAD has been shown to rise by as much as 55% among adult diabetic patients)  Increase in revascularization procedures (resistant and recurrent angina)  Frequent comorbidities (30% of primary care practice CAD patients have an altered cardiac function)

Jackson G. Angina. 4th ed. London, UK: Informa Healthcare; 2008. Management of stable angina pectoris. Recommendations from the Task Force of the ESC. Eur Heart J. 2006;27:1341-1381. K. Kotseva et al. Lancet. 2009;373:929-940. Marso SP and Stern DM. Diabetes and cardiovascular disease. Integrating science and clinical medicine. Philadelphia, PA: Lippincott Williams & Wilkins; 2004. Gibbons RJ, et al. J Am Coll Cardiol. 2003;41:159-168. - Malergue M.C, et al. P470: Prevalence of left ventricular systolic dysfunction in stable coronary artery disease patients. 8th International Congress on Coronary Artery Disease, Prague, Czech Republic, 10/2009.

Clinical patterns of stable coronary artery disease The Heart and Soul study (n=937)

Angina

38%

Exerciseinduced ischemia (by ETT)

38% of outpatients with stable CAD have angina or ischemia or both

Gehi AK, et al. Arch Intern Med. 2008;168:1423-1428.

Many patients continue to experience angina after ACS The MERLIN-TIMI 36 trial (n=5460) Rate of angina reported at 4 months after ACS (%) 60

50

50.2

49.8% of patients reported angina at 4 months after ACS

40 29.5

30 20

15.6

10

4.7

0 No angina

Monthly angina

Arnold SV, et al. Circ Cardiovasc Qual Outcomes. 2009;2:344-353.

Weekly angina

Daily angina

Ischemia or angina or both increase the risk of cardiovascular events The Heart and Soul Study (n=937) Survival rate (%)

100

No angina, no ischemia Angina alone

90

Ischemia alone 80 Angina and ischemia 70

60

50 0

Among patients with CAD, angina confers a 3-fold risk of cardiovascular events versus absence of angina

5

10

Gehi AK, et al. Arch Intern Med. 2008;168:1423-1428.

15

20

25

30

35

40

Months

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Annual event rates in stable CAD outpatients is high Annual event rates in stable CAD outpatients, REACH registry: CAD outpatients (n=38602), 1-year follow-up

1.4

Non-fatal MI

6.44

UA 1.4

CABG PCI

3 of 20 patients with established CAD had a major event or had been hospitalized within a year

3.8 4.9

CHF CV death

1.8

Death/MI/ Stroke/Hosp*

15.2 0

PG Steg, et al. JAMA. 2007;297:1197-1206.

5

10

15

Atherothrombosis reduces life expectancy by around 8-12 years in patients aged over 60 years Average remaining life expectancy at age 60 (men)

Year s

20 18 16 14 12 10 8 6 4 2 0 Healthy

History of CV disease

Peeters, et al. Eur Heart J. 2002;23:458-466. Analysis of data from the Framingham Heart Study.

History of AMI

Acute Coronary Syndrome without CAD (normal coronary angiography) 35 30 25 20 15

Men Women

10 5 0 MI with ST

MI without ST

Unstable angina

Hochman JS, et al GUSTO Iib. N Engl J Med. 1999;341:226-232.

Angina and CAD Observed prevalence

CAD50 Prevalence (%)

100

Expected (Guideline Probabilities)

Men (n=7113, 1619 with CAD50)

80

60 0.5

1.6

0.4

40 0.4

1.1 20 1.3 0

30- 4039 39

5059

60- 70+ 69

Asymptomatic

0.5

30- 4039 39

0.1

0.2

50- 60- 70+ 30- 4059 69 39 39

Nonanginal Chest Pain

0.3

0.3 0.0 5059

60- 70+ 69

Atypical Angina

30- 4039 39

5059

Typical Angina

60- 70+ 69

Age (years)

Chen VY, et al. Circulation. 2011;124:2423-2432.

Angina and CAD Observed prevalence

CAD50 Prevalence (%)

100

Expected (Guideline Probabilities)

Women (n=5684, 716 with CAD50)

80

60 0.2 0.2

40 0.2 20 1.5 0

30- 4039 39

5059

60- 70+ 69

Asymptomatic

1.7

30- 4039 39

1.3

0.9 0.3

0.3

50- 60- 70+ 30- 4059 69 39 39

Nonanginal Chest Pain

0.2 5059

0.2 0.2 60- 70+ 69

Atypical Angina

30- 4039 39

5059

Typical Angina

60- 70+ 69

Age (years)

Chen VY, et al. Circulation. 2011;124:2423-2432.

Angina and CAD: an elusive link!

1. Most patients with typical angina do not have coronary atherosclerotic obstructions 2. Prevalence of coronary atherosclerotic obstruction in patients with typical angina and without is similar 3. Female patients have a lower prevalence of coronary atherosclerotic obstruction than male patients 4. Prevalence of coronary atherosclerotic obstructions is agerelated in both sexes Chen VY, et al. Circulation. 2011;124:2423-2432.

INFLAMMATION CORONARY STENOSIS

Thrombosis MYOCARDIAL ISCHEMIA

ENDOTHELIAL VASOSPASM DYSFUNCTION MICROVASCULAR DYSFUNCTION

Mechanisms contributing to myocardial ischemia in man: a preliminary list…

Myocardial ischaemia Myocardial ischemia‌ complex mechanism Vasospasm Thrombus Atherosclerosis

O2 Supply

O2 Demand

Afterload Heart rate Contractility Preload

Myocardial Ischaemia Ischaemia Left ventricular remodeling

Acute coronary syndrome

Myocardial chronic ischemia

Usual management: The “haemodynamic pipeline Approach” • Vasodilators

(Nitrates, Nicorandil) • Beta-blockers • Calcium channel blockers • Revascularization

Myocardial ischemia result in major disturbances of energy production

Anaerobic Fatty acid

glycolysis

oxidation

Uncoupling between glycolysis and glucose oxidation.

Cell acidosis

Increase in FA oxidation inhibits glucose oxidation.

Calcium overload

Increase need of ATP for homeostasis.

Stanley WC, et al. Cardiovasc Res. 1997;34:25-33. Pilz S, et al. Clin Chem Lab Med. 2008;46:429-434.

Therapeutic perspectives for agents modulating cardiac energy metabolism

Heart Metab. 2008;38:5-14,

Significant improvement of ergometric parameters versus placebo Ns (Npt)

E (IC)

Trimetazidine

TED

170 (15744)

0.38 (0.23; 0.55)

Trimetazidine

T1

126 (13598)

0.46 (0.29; 0.64)

Trimetazidine

T0A

111 (11652)

0.45 (0.20; 0.70)

All anti-anginal agents All anti-anginal agents All anti-anginal agents

TED T1 T0A

158 (13791) 117 (12440) 105 (10905)

0.32 (0.26; 0.38) 0.47 (0.39; 0.56) 0.38 (0.29; 0.47)

Dihydropyridines Dihydropyridines Dihydropyridines

TED T1 T0A

170 (15744) 126 (13598) 111 (11652)

0.34 (0.27; 0.41) 0.52 (0.42; 0.62) 0.42 (0.32; 0.53)

Long-acting nitrates Long-acting nitrates Long-acting nitrates

TED T1 T0A

170 (15744) 126 (13598) 111 (11652)

0.30 (0.22; 0.38) 0.40 (0.28; 0.53) 0.31 (0.18; 0.44)

Nicorandil Nicorandil Nicorandil

TED T1 T0A

170 (15744) 126 (13598) 111 (11652)

0.32 (0.04; 0.60) 0.43 (0.10; 0.77) 0.75 (0.09; 0.81)

Ranolazine Ranolazine Ranolazine

TED T1 T0A

2 (966) 2 (966) 2 (966)

0.29 (0.09; 0.50) 0.33 (-0.03; 0.69) 0.31 (0.09; 0.53)

Ns (NPT): Number of studies (nb of patients) involved in the network E (IC): Estimate of the difference between treatment effects (corresponding credibility interval)

-0.1

0.0 0

0.1 -12

Favours placebo

0.2

0.3 -36

0.4

0.5 -60

0.6

0.7 0.8 seconds

Favours active comparators

Danchin N, et al. Eur Heart J. 2011;32 (Suppl. 1):572.

0.9

Optimizing energy metabolism with Trimetazidine MR: a key target in all stages of ischemic heart disease

Beadle G. and Frenneaux M. Heart 2010;96:824-830.

Guidelines

Metabolic antianginal drugs may be used in combination with conventional agents, as their primary effect is not through reduction in HR or BP, or as substitution therapy when conventional drugs are not tolerated

Role of HR in the pathophysiology of CAD Increasing heart rate Vascular damage Atherosclerosis

Increased O2 demand Decreased supply

Progression of atherosclerosis

Ischemia

Major CV events

Short term

Long term

Plaque rupture

Heart rate as a predictor of major cardiovascular events in stable CAD patients The TNT study (n=9580) Major cardiovascular events (%)

Major CV event: CAD death, nonfatal MI, resuscitated cardiac arrest, stroke Ho JE, et al. Am J Cardiol. 2010;105:905-911.

Inadequate control of heart rate in patients with stable angina The Euro Heart Survey; 2005 patients Patients (%) in different HR ranges according to HR-lowering treatment at baseline

35 CCBs

30

BBs

25 20 15 10 5 0 ≤62

63-70

Daly C et al. Postgrad Med J 2010;86:212-217.

71-76

77-82

≼83

Resting HR (bpm)

Ivabradine further reduces HR in patients already receiving β-blocker Heart rate (bpm) 68

67

66

66

66 64

Ivabradine 5 mg bid

Placebo + atenolol

62

Ivabradine + atenolol

60 60 (- 7 bpm) 58

Ivabradine 7.5 mg bid

58 (- 9 bpm)

56

Ivabradine 7.5 mg bid (90% of patients) or 5 mg bid (10%) 54 Baseline

Tardif JC, et al. Eur Heart J. 2009;30:540-548.

M2

M4

Combining ivabradine with beta-blocker provides additional anti-ischemic efficacy P<0.05

Workload on treadmill testing, METs

Ivabradine + bisoprolol Bisoprolol

P=0.004

Bisoprolol 5 mg

Amosova E. et al. Cardiovasc Drugs Ther 2011.

Bisoprolol 5 mg + Ivabradine (5-7.5 mg)

After 2 months

Baseline

After 2 months

Baseline

P=0.141

Bisoprolol 5 mg Bisoprolol 5 mg + Bisoprolol 5 mg

Effect of ivabradine on hospitalization for fatal/nonfatal MI Angina and HR >70 bpm (n = 712)

Angina (n = 1507) Event rate (%) 15

Event rate (%) 15

HR = 0.58 P=0.021

10

Placebo

42%

5

HR = 0.27 P=0.002

10

Placebo

5

73%

Ivabradine 0

Ivabradine

0 0

0.5

1 Years

1.5

Fox K, et al. Eur Heart J. 2009; 30:2337-2345.

2

0

0.5

1 Years

1.5

2

www.escardio.org/guidelines

www.escardio.org/guidelines

www.escardio.org/guidelines

COURAGE TRIAL

Boden WE et al. N Engl J Med 2007;356:1503-1516

COURAGE TRIAL Conclusion

â&#x20AC;˘ As an initial management strategy in patients with stable coronary artery disease, PCI did not reduce the risk of death, myocardial infarction, or other major cardiovascular events when added to optimal medical therapy

Boden WE et al. N Engl J Med 2007;356:1503-1516

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Fractional Flow Reserve for the Determination of Hemodynamicall Significant Stenosis Fractional Flow Reserve > 0.80

Fractional Flow Reserve < 0.80

ESC Textbook of Cardiovascular Medicine, J.C. Camm, T.F. L端scher, P.W. Serruys eds., Oxford University Press 20092nd Edition,

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FAME Study Conclusion â&#x20AC;˘ Routine measurement of FFR in patients with multivessel CAD who are undergoing PCI with drugeluting stents significantly reduces the rate of the composite end point of death, nonfatal myocardial infarction, and repeat revascularization at 1 year Tonino PAL et al. N Engl J Med 2009;360:213-224

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FFR vs. Angiography for Guiding PCI in Patients with Multivessel CAD â&#x20AC;&#x201C; Economic Evaluation

Fearon W F et al. Circulation 2010;122:2545-2550

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www.escardio.org/guidelines

64 yo male with angina clII and abnl Treadmill test

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64 yo male with angor clII and abnl Treadmill test

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Basal IVUS

â&#x20AC;˘Lipid lake in ulcerated plaque fjp

Fractional Flow Reserve

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Angioplastia de lesão da DA com controlo anatómico e fisiológico

Angioplastia

• DES (Everolimus) 3,0 x 16 mm implantado a 14 atm.

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Fractional Flow Reserve â&#x20AC;&#x201C; Post LAD PCI

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COURAGE vs FAME 

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In the COURAGE study, optimal medical treatment only and PCI in addition to medical treatment were investigated in patients with multivessel disease and moderately severe coronary disease. In most patients, bare metal stents were used.

The FAME study had broader inclusion criteria, including unstable patients and non–ST-segment elevation MI, and decreased left ventricular function, including patients who had undergone a previous PCI. fjp

Major Adverse Event Rate

Pijls, N. H. J. et al. J Am Coll Cardiol 2012;59:1045-1057

Conclusion Chronic ischemic heart disease is a significant clinical burden IHD may result from a number of mechanisms, including atherosclerotic obstructions, coronary vasomotor dysfunction, endothelial dysfunction, platelet dysfunction, etc.

Addressing the individual consequences of ischemia is essential to ensure an optimal management of IHD

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