Evidence Based Management Hypertension in High Risk Patients Dr Rajesh Jain MD Project Manager Diabetes Prevention Control Project National Health Mission,Uttar Pradesh

01_India_RAAS Disclosures No Conflict of Interest

Both ACEi and ARBs reduce blood pressure Only ACEi (and especially perindopril) reduce all cause and cardiovascular mortality and the risk if pneumonia

Meta-analysis of ARBs and ACE inhibitors trials conducted before 2006 01_India_RAAS Meta-analysis of ARBs and ACE inhibitors trials conducted before 2006 ARBs vs comparators (11 trials, n=55,050) ACE inhibitors vs comparators (39 trials, n=150,943) Global death CV death RRR (%) +8%* RRR (%) Stroke MI -8 -6 -4 -2 2 4 6 8 -2 -4 +1% +1% -8% -6 -6% -8 -10 -9%  Followed by the VALUE study a meta analysis was initiated and published in the lancet in the year 2006 to see the differential benefits between the ACE-Is and ARBs and results were startling where ARBs were found to increase MI by a significant +8% -12 -12%  -14 Global death CV death Stroke MI -14%  * P=0.03 ** P=0.0005; *** P<0.00001 Adapted from Strauss MH, Hall AS. Circulation. 2006;114:838-854. 4 4

BP-independent effect 01_India_RAAS ACE inhibitors vs ARB Unique Differences Data from meta-regression analyses ACE inhibitors BP-independent effect Stroke RRR = -2% (8% to -13%) HF RRR = 5% (15% to -5%) Stroke p=0.6 CHD RRR = 9% (14% to 3%) HF p=0.6 ARBs CHD p=0.002 Stroke RRR = 1% (18% to -20%) HF RRR = 17% (38% to -12%) As showed by the meta-regression analyses performed by the Blood Pressure Treatment Trialist Collaboration, both ACE inhibitors and ARBs exert similar blood pressure (BP) dependent protection against stroke and heart failure (HF). However, for ACE inhibitors, but not for ARBs, there is evidence of blood-pressure independent effects on the risk of major coronary disease events. CHD RRR = -8% (17% to -39%) 30% 20% 10% 0% 10% 20% 30% Risk Decrease Risk Increase J Hypertens. 2007;25:951-958.

Main results Eur Heart J 2012 01_India_RAAS ACE-Is, thanks to the Coversyl based studies ASCOT, ADVANCE and EUROPA faired much better than the ARBS in preventing death among hypertensive patients!... Infact ARBs did not reduce death in any of the hypertension studies conducted between the year 2000 till date! Van Vark LC, Bertrand M, Akkerhuis KM, et al. Eur Heart J. Online 17 Apr 2012.

Secondary prevention of CAD by ACEIs 01_India_RAAS Secondary prevention of CAD by ACEIs QUIET HOPE 50 4% Risk increase RR 1.04 (0.89–1.22) P=0.6 20 Placebo Quinapril 20 mg % Patients 22% Risk reduction RR 0.78 (0.70–0.86) P=0.001 40 15 30 Ramipril 10 mg 20 Placebo 10 10 Four major trials have been conducted in high-risk CAD patients with normal LV function. HOPE demonstrated the benefit of ramipril 10 mg in high-risk stable CAD patients without LV dysfunction or heart failure. The primary outcome (CV death, MI, and stroke) was reduced 15% after 1 year and 22% at the end of the study.1 EUROPA, conducted in lower-risk patients with stable CAD and no heart failure, demonstrated a 20% reduction with perindopril 8 mg in the primary outcome (CV death, MI, and cardiac arrest).2 Thus, HOPE and EUROPA demonstrated comparable benefits with long-term treatment. In contrast, PEACE demonstrated a neutral effect of trandolapril 4 mg on the primary outcome (CV death, MI, and revascularization) in lower-risk patients with stable CAD and no LV dysfunction.3 QUIET was conducted in 1750 patients who had undergone coronary angioplasty or atherectomy at baseline.4 Subjects were randomized to quinapril 20 mg or placebo. This study also demonstrated a neutral effect for the ACE inhibitor studied. Various reasons have been suggested for the difference in outcome—including the low-risk population, the drug or dose used, and notably, the study was underpowered to provide evidence of a reduction in hard outcomes such as MI and CV death.4,5 These issues as they relate to the optimal use of ACE inhibition in high-risk CAD patients without LV dysfunction are discussed in following slides. PEP: CV death, MI, cardiac arrest, revascularization, hospitalization for UA 5 PEP: CV death, MI, stroke Time (years) Time (years) 1 2 3 1 2 3 4 EUROPA PEACE 30 14 Placebo 4% Risk reduction HR 0.96 (0.88–1.06) P=0.43 20% Risk reduction RR 0.80 (0.71–0.91) P=0.0003 % Patients 12 25 10 20 Trandolapril 4 mg 8 Placebo Perindopril 8 mg 15 6 4 10 2 PEP: CV death, MI, cardiac arrest 5 PEP: CV death, MI, revascularization Time (years) Time (years) 1 2 3 4 5 1 2 3 4 5 6 HOPE Study Investigators. N Engl J Med. 2000;342:145-53. PEACE Trial Investigators. N Engl J Med. 2004;351:2058-68. EUROPA Investigators. Lancet. 2003;362:782-8. Pitt B et al. Am J Cardiol. 2001;87:1058-63. 1. HOPE Study Investigators. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular high-risk patients. N Engl J Med. 2000;342:145-153. 2. EUROPA Investigators. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: Randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet. 2003;362:782-788. 3. PEACE Trial Investigators. Angiotensin-converting-enzyme inhibition in stable coronary artery disease. N Engl J Med. 2004;351:2058-68. 4. Pitt B, O’Neill B, Feldman R, Ferrari R, Schwartz L, Mudra H, et al, for the QUIET Study Group. The Quinapril Ischemic Event Trial (QUIET): Evaluation of chronic ACE inhibitor therapy in patients with ischemic heart disease and preserved left ventricular function. Am J Cardiol. 2001;87:1058-1063. 5. Pitt B. ACE inhibitors for patients with vascular disease without left ventricular dysfunction–May they rest in PEACE? N Engl J Med. 2004;351:2115-2117.

BP reduction from basal 01_India_RAAS QUIET 4.4 PEACE 4.2 5.0 EUROPA 4.0 HOPE 3.5 4.0 Δ SBP (mm Hg) 3.0 2.0 1.0 0.0 4.0 QUIET 3.1 PEACE 3.0 EUROPA 2.6 HOPE 2.6 Δ DBP (mm Hg) 3.0 In QUIET and PEACE blood pressure (BP) reduction from baseline was similar, if not more important, that in HOPE and EUROPA. Despite this effect on BP, HOPE and EUROPA were positive, while PEACE and QUIET were negative trials in terms of cardiovascular outcomes. Thus, cardiovascular protection cannot be fully explained by the blood pressure (BP) lowering effect of ACE inhibition. 2.0 1.0 0.0 HOPE Study Investigators. N Engl J Med. 2000;342:145-53. PEACE Trial Investigators. N Engl J Med. 2004;351:2058-68. EUROPA Investigators. Lancet. 2003;362:782-8. Pitt B et al. Am J Cardiol. 2001;87:1058-63.

Endothelium Weight: 1.5 kg, surface: >800 m2 01_India_RAAS Endothelium The endothelium is a lining of the vessel, which is made up of a continuous layer of cells, rather like tiles on a floor. The average human endothelium weigths around 1.5 kg, with a surface area of more that 800 m2. The human endothelium is capable of producing more that 250 biologically active substances that help regulate vascular structure and function. Like almost every cell of the body, endothelium undergoes a life/death cycle, which includes the process of programmed cell suicide or apoptosis, matched by a consequent regeneration. Weight: 1.5 kg, surface: >800 m2 Produces >250 active substances Undergoes the life and death cycle

Atheroma formation and progression: a struggle between death and regeneration Endothelial cells undergo suicide (apoptosis) and regenerate, every 3 months When a mismatch occurs and apoptosis exceed regeneration, the endothelium loses its continuity causing: - Progression of atherosclerosis - Acute coronary syndrome - Myocardial infarction

Incubated (72 h) with serum from 01_India_RAAS PERTINENT substudy Isolation of human endothelium Incubated (72 h) with serum from Healthy subjects EUROPA patients Effect of perindopril on endothelial cell apoptosis was determined in the PERTINENT substudy of the EUROPA study. Isolated human endothelial cells were incubated with serum from EUROPA patients with stable coronary artery disease and with serum from healthy age-matched controls. These experiments were designed to mimic the effects of circulating blood on endothelial function by measuring eNOS protein expression and activity, and the rate of apoptosis. ecNOS Apoptosis To mimic the effects of circulating blood on endothelial function

PERTINENT Analysis in cultured HUVECs Apoptosis Effects of HUVEC incubation with serum from: PERTINENT Analysis in cultured HUVECs Controls CAD PERTINENT patients baseline 1 year 20 P<0.01 Apoptosis P<0.05 10 Controls n=45 Placebo n=44 Treated n=43 Placebo n=44 Treated n=43 #P=controls vs baseline *P=perindopril vs placebo Ceconi C et al. Cardiovasc Res. 2006

Endothelial apoptosis and atherosclerosis Normal rate of apoptosis: 3% Excess rate of apoptosis Maintenance of endothelial layer Endothelium continuity Protection against atherosclerosis Onset of atherosclerotic Plaque erosion and rupture

Myocardial infarction

ACEi and apoptosis: a class effect? 01_India_RAAS ACEi and apoptosis: a class effect? (after 1 week’s treatment) 10.0 7.5 8.8 9.5 4.3 6 12 10 4 2 8 10.7 0.8 perindoprill ramipril quinapril trandolapril enalapril control LPS infusion P<0.001 * % Apoptosis 10.0 7.5 8.8 9.5 4.3 6 12 10 4 2 8 10.7 0.8 perindoprill ramipril quinapril trandolapril enalapril control LPS infusion P<0.001 * % Apoptosis * * In one of the studies apoptosis was induced in the isolated rat aortic endothelial cells by endotoxic shock with bacterial lipopolysaccharides (LPS). All ACE inhibitors reduced the rate of endothelial apoptosis compared with vehicle, but this reached significance only for perindopril. * P<0.001 vs LPS Ceconi C et al. Cardiovasc Drugs Ther. 2007;21:423-429.

How does perindopril reduce endothelial apoptosis? 01_India_RAAS How does perindopril reduce endothelial apoptosis? By reducing angiotensin-II and TNF-α (pro-apoptotic) By enhancing bradykinin (anti-apoptotic)

What about endothelial regeneration ? 01_India_RAAS Bone marrow produces endothelial progenitor cell (EPC) to be incorporated into vessels

CC CV

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Stable Angina Patients 01_India_RAAS Stable Angina Patients 0.5 1 1.5 2 2.5 3 3.5 4 4.5 EPC cells (u/mm3) baseline 10 days 1 month 3 months 6 months Time * In the first study in patients with angina, perindopril treatment was associated with increased level of endothelial progenitor cels in comparison with placebo. This effect was aparent starting from the 3rd month of treatment. Perindopril Placebo

Protection against ACS 01_India_RAAS ACE inhibition (with perindopril) reduces death and improves life of the endothelium Protection against ACS

Servier Choosing optimal combination What about ARBs? Do ARBs have the same effects on the endothelium ? Are ARBs equivalent to ACE inhibitors? NO

ARBs have little (or no) effect on bradykinin Do not reduce endothelial apoptosis Do not improve endothelial regeneration

ANG II AT1 AT3 6 AT2 VASOCONSTRICTION WATER RETENTION PROLIFERATION ANTI APOPTOSIS VASODILATATION NO WATER RETENTION ANTI PROLIFERATION PRO APOPTOSIS SEVERAL OTHER EFFECTS

ANG II AT1 AT3 6 AT2 VASOCONSTRICTION WATER RETENTION PROLIFERATION ARB’s AT1 AT3 6 AT2 VASOCONSTRICTION WATER RETENTION PROLIFERATION ANTI APOPTOSIS VASODILATATION NO WATER RETENTION ANTI PROLIFERATION PRO APOPTOSIS SEVERAL OTHER EFFECTS

Perindopril, but not valsartan, decreases endothelial cell apoptosis in post-AMI patients Normal controls Perindopril 8 mg Valsartan 160mg 25 20 * 15 Apoptotic nuclei (%) 10 5 Baseline Day 30 Baseline Day 30 Baseline Day 30 *p=0.05 vs baseline Cangiano E, Ferrari R. Am J Cardiovasc Drugs. 2011;11:189-198.

Servier Choosing optimal combination Perindopril, but not valsartan, improves EPC production * * * 7 * 6 5 4 EPC (u/mm3) 3 2 In another study in patients with myocardial infarction, we studied effect of perindopril and an ARB valsartan on EPC. In comparison with the ARB, treatment with perindopril resulted in significant increase in EPC starting from the 7th day of treatment. Differential effects on the EPC in coronary artery disease patients could contribute to the differential effects of ACE inhibitors and ARBs in coronary protection. 1 baseline 3 days 5 days 7 days 10 days Time Perindopril 8 mg Valsartan 160mg

Conclusion 01_India_RAAS The goal of hypertension treatment is to reduce blood pressure and the risk of CV mortality ACEi and ARBs both control blood pressure

ACEi are far better than ARBs in CAD prevention and reduction of overall mortality If the medical community continues to ignore this evidence and to prescribe ARBs for hypertension, patients will be deprived of the benefits of ACEi

Between all ACEi, Perindopril has the most evidence for cardiac protection through the entire cardiovascular continuum

Morbi-mortality trials on perindopril along the cardiovascular disease continuum (n=50 822) 01_India_RAAS Post-stroke patients n=6 105 Patients with stable CAD n=12 218 Post-AMI patients n=1 252 Benefits of perindopril across the cardiovascular disease continuum, from treatment of hypertension to prevention of cardiovascular events in established cardiovascular disease, have been demonstrated in well-conducted randomized clinical trials. Hypertensive patients n=19 257 Diastolic HF n=850 Patients with diabetes n=11 140

Servier Choosing optimal combination Risk of pneumonia with use of ACEi compared with ARBs BMJ 2012 Caldeira et al

ARBs are not just ACEi without the cough! The cough is not always deleterious Consider the evidence vs perception

ACEi but not ARBs reduce the risk of pneumonia This finding discourages the withdrawal of ACEi in patients with tolerable cough at risk of CAD and pneumonia

Perception is not always reality