Disclosures

1. Evidence Based ManagementHypertension in High Risk PatientsDr Rajesh Jain MDProject Manager Diabetes Prevention Control Project National Health Mission,Uttar Pradesh

2. Disclosures • No Conflict of Interest

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

4. 8 6 4 2 0 -2 -4 -6 -8 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) Globaldeath CVdeath RRR (%) RRR (%) +8%* Stroke MI 0 -2 -4 +1% +1% -8% -6 -6% -8 -9%  -10 -12 -12% -14 -14% Globaldeath CVdeath Stroke MI * P=0.03 ** P=0.0005; *** P<0.00001 Adapted from Strauss MH, Hall AS. Circulation. 2006;114:838-854.

5. ACE inhibitors vs ARB Unique Differences Data from meta-regression analyses ACE inhibitors BP-independent effect Stroke RRR = -2% (8% to -13%) RRR = 5% (15% to -5%) HF Strokep=0.6 RRR = 9% (14% to 3%) CHD HFp=0.6 ARBs CHD p=0.002 RRR = 1% (18% to -20%) Stroke RRR = 17% (38% to -12%) HF CHD RRR = -8% (17% to -39%) 30% 20% 10% 0% 10% 20% 30% Risk Decrease Risk Increase J Hypertens. 2007;25:951-958.

6. Main results Eur Heart J 2012 n=76 615 n=82 383 Van Vark LC, Bertrand M, Akkerhuis KM, et al. Eur Heart J. Online 17 Apr 2012.

7. Secondary prevention of CAD by ACEIs QUIET HOPE 50 4% Risk increase RR 1.04 (0.89–1.22) P=0.6 Placebo 20 % Patients Quinapril 20 mg 22% Risk reduction RR 0.78 (0.70–0.86) P=0.001 40 15 30 Ramipril 10 mg 20 Placebo 10 10 PEP: CV death, MI, cardiac arrest, revascularization, hospitalization for UA 5 PEP: CV death, MI, stroke 0 Time(years) Time(years) 0 1 2 0 3 1 2 3 4 0 EUROPA PEACE 30 Placebo 4% Risk reduction HR 0.96 (0.88–1.06) P=0.43 14 20% Risk reduction RR 0.80 (0.71–0.91) P=0.0003 % Patients 12 25 10 Trandolapril 4 mg 20 8 Placebo 15 Perindopril 8 mg 6 10 4 PEP: CV death, MI, cardiac arrest 2 5 PEP: CV death, MI, revascularization 0 Time(years) Time (years) 0 0 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.

8. BP reduction from basal QUIET 4.4 PEACE 4.2 5.0 EUROPA 4.0 HOPE 3.5 4.0 ΔSBP (mm Hg) 3.0 2.0 1.0 0.0 QUIET 3.1 PEACE 3.0 4.0 EUROPA 2.6 HOPE 2.6 ΔDBP (mm Hg) 3.0 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.

9. Endothelium • Weight: 1.5 kg, surface: >800 m2 • Produces >250 active substances • Undergoes the life and death cycle

10. 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

11. PERTINENT substudy Incubated (72 h) with serum from Isolation of human endothelium Healthy subjects EUROPA patients ecNOSApoptosis To mimic the effects of circulating blood on endothelial function

12. ApoptosisEffects of HUVEC incubation with serum from: PERTINENTAnalysis in cultured HUVECs Controls CAD PERTINENT patients baseline 1 year P<0.01 20 Apoptosis P<0.05 10 0 Treatedn=43 Treatedn=43 Controlsn=45 Placebon=44 Placebon=44 #P=controls vs baseline *P=perindopril vs placebo Ceconi C et al. Cardiovasc Res. 2006

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

15. Myocardial infarction

16. P<0.001 P<0.001 P<0.001 P<0.001 12 12 P<0.001 P<0.001 10.7 10.7 10 10 P<0.001 P<0.001 10.0 10.0 9.5 9.5 8.8 8.8 8 8 7.5 7.5 6 6 * * % Apoptosis % Apoptosis 4 4 4.3 4.3 2 2 0.8 0.8 0 0 control control ramipril ramipril quinapril quinapril perindoprill perindoprill enalapril enalapril trandolapril trandolapril LPS infusion LPS infusion ACEi and apoptosis: a class effect? (after 1 week’s treatment) * * * P<0.001 vs LPS Ceconi C et al. Cardiovasc Drugs Ther. 2007;21:423-429.

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

18. What about endothelial regeneration ? Bone marrowproduces endothelial progenitor cell (EPC) to be incorporated into vessels

19. CV CC

21. * 4.5 * 4 3.5 3 2.5 EPC cells (u/mm3) 2 1.5 1 0.5 0 baseline 10 days 1 month 3 months 6 months Time Stable Angina Patients Perindopril Placebo

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

23. What about ARBs? Do ARBs have the same effects on the endothelium ? Are ARBs equivalentto ACE inhibitors? NO

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

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

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

27. 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.

28. Perindopril, but not valsartan, improves EPC production * * * * 7 6 5 4 EPC (u/mm3) 3 2 1 0 baseline 3 days 5 days 7 days 10 days Time Valsartan 160mg Perindopril 8 mg

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

30. 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

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

32. Morbi-mortality trials on perindopril along the cardiovascular disease continuum(n=50 822) Post-stroke patients n=6 105 Patients with stable CAD n=12 218 Post-AMI patients n=1 252 Hypertensive patients n=19 257 Diastolic HF n=850 Patients with diabetes n=11 140

33. Risk of pneumonia with use of ACEi compared with ARBs BMJ 2012 Caldeira et al

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

35. 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

36. Perception is not always reality