Disclosures. Speaker s bureau: Research grant: Advisory Board: Servier International, Bayer, Merck Serono, Novartis, Boehringer Ingelheim, Lupin

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1 Disclosures Speaker s bureau: Research grant: Advisory Board: Servier International, Bayer, Merck Serono, Novartis, Boehringer Ingelheim, Lupin Servier International, Boehringer Ingelheim Servier International, Novartis, Amgen Boehringer Ingelheim

2 New Paradigms in Chronic Ischaemia Roberto Ferrari

3 New Paradigms in Chronic CAD Shift in Epidemiology Role of revascularisation Role of pharmacotherapy (HR) Role of coronary microcirculation Role of coronary sinus narrowing

4 Is angina pectoris common in the era of PCI? Prevalence: 2-4%, 10-15% after 65 years Incidence: 0,5%, 100,000/year (25-74) men Mortality: 0,9 1,4%/year Morbidity: Important contribution Cost: 2,6% of total health expenditure

5 Shift in CAD epidemiology Decline incidence in younger Shift of the burden to elderly Prevalence of angina will increase with increasing age of population

6 Angina contributes to cardiovascular morbidity One year CV event rates : % of patients with events REACH Registry: JAMA 297, 2007

7 New Paradigms in Chronic CAD Shift in Epidemiology Role of revascularization Role of pharmacotherapy (HR) Role of coronary microcirculation Role of coronary sinus narrowing

8 Different phases and approaches to treat chronic CAD Beside lifestyle modification Revascularisation for Pharmacotherapy for Symptoms Prognosis? Symptoms Prognosis

9 Revascularisation with PCI is booming everywhere But this does not mean it will improve prognosis

10 Ischemia in humans is a rather personal entity Degree of coronary occlusion Pre-existence of collateral flow Pre-existence of metabolic turnover Genetic factors Intrinsic, defensive capacity of myocytes Ischemia is such a personal entity, thus allowing Hibernation Preconditioning Stunning Viability

11 Revascularisation improves death according to the amount of ischaemic burden (evaluated by SPECT)

12 COURAGE in the light of FAME 2007: Data from COURAGE suggests that in stable CAD, PCI guided by visual assessment does not provide additional benefit over full medical therapy and lifestyle improvements

13 FAME in the light of COURAGE 2012: FAME 2 shows superiority of PCI guided by FFR 0,8 plus optimal therapy over best available therapy alone

14 FAME 2 : FFR-Guided PCI versus Medical Therapy in Stable CAD Flow chart

15 FAME 2 : FFR-Guided PCI versus Medical Therapy in Stable CAD Primary outcomes

16 FAME 2 : FFR-Guided PCI versus Medical Therapy in Stable CAD Death from any cause

17 FAME 2 : FFR-Guided PCI versus Medical Therapy in Stable CAD Myocardial infarction

18 FAME 2 : FFR-Guided PCI versus Medical Therapy in Stable CAD Urgent revascularisation

19 Cumulative No. Of Events per 100 Patient-Yr FAME STUDY: CUMULATIVE EVENTS DURING 5-YEAR FOLLOW-UP N=31 N=38 N=23 FFR-guided PCI Angio-guided PCI Follow-Up (years) The Lancet online N.H.J. PIJLS (Eindhoven, NL), FP 1949

20 And so? What do we do when the ischaemic burden is low? Consider the patient! Consider that ischaemia is a personal entity! But..the real problem is that when you (and the patient) know that there is an obstruction!

21 As a consequence elective PCI over time USA China France Italy

22 New Paradigms in Chronic CAD Shift in Epidemiology Role of revascularization Role of pharmacotherapy (HR) Role of coronary microcirculation Role of coronary sinus narrowing

23 What do the ESC Guidelines suggest? ANGINA RELIEF First-line Short-acting nitrate + beta-blockers or calcium blockers -Consider CCB-DHP if low heart rate or intolerance/contraindications -Consider beta-blockers + CCB-DHP if CCS angina > 2 Second-line Ivabradine Long-acting nitrates Nicorandil Ranolazine Trimetazidine EVENT PREVENTION Lifestyle management Diet Regular physical exercise Control of risk factors Treatments Aspirin Statins ACE inhibitors Montalescot G et al. Eur Heart J.2013;34:

24 Clarification of the role of HR reduction in angina treatment HR reduction in chronic CAD with preserved EF is important for symptoms reduction but not for prognosis This is true for Ivabradine (SIGNifY) and for betablockers (several registries)

25 Patients with event (%) Primary composite end point Ivabradine n=654 (3.03% PY) Placebo n=611 (2.82% PY) HR = 1.08 [95% CI ] P=0.20 Ivabradine Placebo Numbers at risk Time from randomisation (months) Ivabradine Placebo

26 Patients with event (%) Primary composite end point (angina population: CCS class II, n=12 049) Ivabradine n=459 (3.37% PY) Placebo n=390 (2.86% PY) HR = 1.18 [95% CI ] P=0.018 Ivabradine Placebo Ivabradine Placebo Numbers at risk Time from randomisation (months)

27 Effect of ivabradine on symptoms (angina population: CCS class II, n=12 049) Patients (%) 24.8 P<0.01 Elective revascularization Ivabradine 2.8% Placebo 3.5% HR 0.82 (P=0.058)

28 The question is whether elevated heart rate is a. Marker or Risk Factor Observational value Related to mortality but is not the cause Therapeutic value Contributes to outcome If you reduce the risk factor, the prognosis improves

29 Symptoms Different meanings of heart rate increase according to different phases of the CV continuum Coronary thrombosis Myocardial infarction Myocardial ischemia Arrhythmia and loss of muscle Coronary artery disease Atherosclerosis Endothelial dysfunction Marker Marker HR Risk F Risk F Cardiac remodeling Ventricular dilation Congestive heart failure Prognosis Risk factors: Hypertension Dyslipidemia Insulin resistance Smoking End-stage heart disease

30 BB benefit is related to the extent of HR reduction Data from the 1980s!

31 Cardioprotection with beta-blockers Data obtained in the 1980 s In patients with MI in the prethrombolytic era and / or primary angioplasty and in the absence ACEi and statin therapy

32 But Modern therapy for AMI has changed the phenotype of the infarcted heart Arrhythmias and sudden death are rare Revascularisation reduces the necrotic area and the decline of EF

33 BB in angina without previous MI REACH registry analysis Cumulative incidence curve for the risk of non-fatal MI in patients with CAD wihtout prior MI cohort by betablocker use Bangalore S, et al. Circ Cardiovasc Qual Outcomes. 2014;7:

34 2014 Meta-analysis on 26,793 CAD patients Andersson C et al JACC

35 Beta-blockers Paradoxically, (like Ivabradine) BBs reduce mortality in heart failure, but not if ventricular function is conserved such as in angina (only a symptomatic effect) In heart failure, beta-blockers and Ivabradine paradoxically increase contractility by reducing remodelling

36 New Paradigms in Chronic CAD Shift in Epidemiology Role of revascularization Role of pharmacotherapy (HR) Role of coronary microcirculation Role of coronary sinus narrowing

37 The coronary arteries are not only these!

38 But also these!

39 Coronary microcirculation

40

41 Angina exists even in the absence of obstructive disease and its prevalence is increasing Data in patients with stable angina pectoris Angina with obstructive disease Angina with obstructive disease 73% 41% 54% 19% Angina without obstructive disease Angina without obstructive disease Jespersen L et al. Eur Heart J. 2012;33:

42 New Paradigms in Chronic CAD Shift in Epidemiology Role of revascularization Role of pharmacotherapy (HR) Role of coronary microcirculation Role of coronary sinus narrowing

43 Verheye S et al N Engl J Med 2015: 372;6

44 Verheye S et al N Engl J Med 2015: 372;6

45 Conclusion: today we have a better understanding on: Epidemiology OFCAD Role of revascularisation Role of pharmacotherapy (HR) Increasing role of coronary microcirculation Possible role of coronary sinus narrowing

46 END