Review: Angiotensin-converting enzyme inhibitors and coronary heart disease prevention

Abstract

A number of large randomised controlled trials have shown that angiotensin-converting enzyme (ACE) inhibitors, compared with placebo or other blood pressure-lowering drugs, improve coronary heart disease outcomes (fatal and non-fatal myocardial infarction, and coronary revascularisation) in diverse patient groups, e.g. in primary and secondary prevention, those with and without left ventricular dysfunction, and among hypertensive and non-hypertensive subjects. An updated meta-regression analysis which included five major trials in patients with established coronary artery disease (CAD) (EUROPA, INVEST, ACTION, PEACE and CAMELOT) concluded that ACE inhibitor (ACE-I) therapy has clear benefits in secondary prevention, but there are important and unexplained differences between trials in clinical outcome, baseline cardiovascular risk, blood pressure changes and trial design which deserve further discussion of the underlying mechanisms and clinical interpretation. For example, in placebo-controlled trials the biggest (20—22%) reductions in primary end points (including mortality) have been observed with perindopril and ramipril, whereas trials using trandolapril and quinapril had no effect on survival or recurrent CAD events. This review summarises and compares the major findings of these recent trials, and provides further analysis of the underlying mechanisms and clinical significance of secondary CAD prevention with ACE-I therapy.

Keywords

angiotensin-converting enzyme inhibitor CHD hypertension angina blood pressure reduction

Get full access to this article

View all access options for this article.

References

Atkinson AB , Lever AF , Brown JJ , Robertson JIS. Combined treatment of severe intractable hypertension with captopril and diuretic . Lancet 1980;2:105-07.

Pfeffer MA , Braunwald E. , Moye LA et al. on behalf of the SAVE investigators. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after

myocardial infarction: results of the Survival And Ventricular Enlargement (SAVE) trial. N Engl J Med 1992;327:669-77.

The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991;325:293-302.

Yusuf S. , Sleight P. , Pogue J. , Bosch J. , Davies R. , Dagenais G. Effects of an angiotensin converting enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000;342:145-53.

Acute Infarction Ramipril Efficacy (AIRE) Study Investigators. Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. Lancet 1993;342:821-8.

Rutherford JD , Pfeffer MA , Moye LA Effects of captopril on ischaemic events after myocardial infarction. Results of the Survival and Ventricular Enlargement Trial. Circulation 1994;90:1731-8.

Kasiske BL , Kalil RS , Ma JZ , Liao M. , Keane WF Effect of antihypertensive therapy on the kidney in patients with diabetes: a meta-regression analysis. Ann Intern Med 1993;118:129-38.

Lewis EJ , Hunsicker LG , Bain RP , Rohde RD , the Collaborative Study Group. The effect of angiotensin converting enzyme inhibition on diabetic nephropathy. N Engl J Med 1993;329:1456-62.

10.

The EUCLID study group. Randomised placebocontrolled trial of lisinopril in normotensive patients with insulin-dependent diabetes and normoalbuminuria or microalbuminuria. Lancet 1997;349:1787-92.

11.

Strippoli GFM , Craig M. , Deeks JJ , Schena FP , Craig JC Effects of angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists on mortality and renal outcomes in diabetic nephropathy:systematic review. Br Med J 2004;329:828-39.

12.

Blood Pressure Lowering Treatment Trialists Collaboration. Effects of different BP-lowering regimens on major cardiovascular events: results of prospectively-designed overviews of randomised trials. Lancet 2003;362:1527-35.

13.

Pitt B. , O'Neill B. , Feldman R. , on behalf of QUIET study Group. The QUinapril Ischaemic Event Trial (QUIET): Evaluation of chronic ACE inhibitor therapy in patients with ischaemic heart disease and preserved left ventricular function. Am J Cardiol 2001;87:1058-63.

14.

The EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease 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;362:782-8.

15.

The PEACE trial investigators. Angiotensin Converting Enzyme inhibition in stable coronary artery disease . N Engl J Med 2004;351:2058-68.

16.

Dahlof B. , Sever PS , Poulter NR et al. on behalf of ASCOT investigators. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): A multicentre randomised controlled trial. Lancet 2005;366:895-906.

17.

Pepine CJ , Handberg EM , Cooper-DeHoff RM , Marks RG , Kowey P. , Messerli FH A calcium antagonist vs. a non-calcium antagonist hypertension treatment strategy for patients with coronary artery disease. The international Verapamil-Trandolapril study (INVEST): a randomised controlled trial.JAMA 2003;290:2805-16.

18.

Verdecchia P. , Beboldi G. , Angeli F. Angiotensin-converting enzyme inhibitors and calcium channel blockers for coronary heart disease and stroke prevention .Hypertension 2005;46:386-92.

19.

Poole-Wilson PA , Lubsen J. , Kirwan BA Effect of long-acting nifedipine on mortality and cardiovascular morbidity in patients with stable angina requiring treatment (ACTION trial): randomised controlled trial. Lancet 2004;364:849-57.

20.

Nissen SE , Tuzcu EM , Libby P. et al. CAMELOT investigators. Effect of antihypertensive agents on cardiovascular events in patients with coronary disease and normal blood pressure, the CAMELOT study: a randomised controlled trial. JAMA 2004;292:2217-26.

21.

Yusuf S. , Pogue J. ACE Inhibition in stable coronary artery disease. N Engl J Med 2005;352:937-8.

22.

Cashin-Hemphill L. , Holmvang G. , Chan RC , Pitt B. , Dinsmore RE , Lees RS , for the QUIET investigators. Angiotensin-converting enzyme inhibition as anti-atherosclerotic therapy: no answer yet. Am J Cardiol 1999;83:43-7.

23.

Dagenais GR , Pogue J. , Fox K. , Simoons ML , Yusuf S. Angiotensin-converting-enzyme inhibitors in stable vascular disease without left ventricular systolic dysfunction or heart failure: a combined analysis of three trials.Lancet 2006;368:581-8.

24.

Poulter NR , Wedel H. , Dahlof B. et al. Role of blood pressure and other variables in the differential cardiovascular event rates noted in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOTBPLA). Lancet 2005;366:907-13.

25.

Liu L. , Zhang Y. , Liu G. , Li W. , Zhang X. , Zanchetti A. The felodipine event reduction (FEVER) study: a randomised long-term placebo-controlled trial in Chinese hypertensive patients. J Hypertens 2005;23:2157-72.

26.

The Heart Outcomes Prevention Evaluation (HOPE) study investigators. Effects of ramipril on cardiovascular outcomes in people with diabetes mellitus: results of HOPE study and MICRO-HOPE substudy. Lancet 2000;355:253-9.

27.

Daly C. , Fox KM , Remme WJ , Bertrand ME , Ferrari R. , Simoons M. , on behalf of E the EUROPA investigators. The effect of perindopril on ca R rdiovascular morbidity and mortality in of perindopril on cardiovascular morbidity and mortality in patients with diabetes in the EUROPA study: results from the PERSUADE substudy. Eur Heart J 2005 ;26:1369-78.

28.

Deckers JW , Goedhart DM , Bertrand ME et al. Treatment benefit by perindopril in patients with stable coronary artery disease at different levels of risk. Eur Heart J 2005;26 (suppl 1):622.

29.

Sleight P. , Yusuf S. , Pogue J. , Tsuyuki R. , Diaz R. , Probstfield J. , for the Heart Outcomes Prevention Evaluation (HOPE) Study Investigators. Blood pressure reduction and cardiovascular risk in HOPE study. Lancet 2001;358:2130-1.

30.

Svensson P. , de Faire U. , Sleight P. , Yusuf S. , Ostergren J. Comparative effects of ramipril on ambulatory and office blood pressures: a HOPE substudy . Hypertension 2001;36:E28-E32.

31.

Mourad J-J. , Safar ME , O'Rourke MF

Who is fooling us?

Lancet 2002;360:89.

32.

Palatini P. , Thijs L. , Staessen JA et al. Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Predictive value of clinic and ambulatory heart rate for mortality in elderly subjects with systolic hypertension. Arch Intern Med 2002;162:2313-21.

33.

Disegni E. , Goldbourt U. , Reicher-Reiss H. et al. The predictive value of admission heart rate on mortality in patients with acute myocardial infarction. J Clin Epidemiol 1995;48:1197-205.

34.

Diaz A. , Bourassa MG , Guertin MC , Tardif JC Long term prognostic value of resting heart rate in patients with suspected or proven coronary artery disease. Eur Heart J 2005;26:967-74.

35.

Lubsen J. , Wagener G. , Kirwan B. -A, de Brouwer S. , Poole-Wilson PA Effect of long-acting nifedipine on mortality and cardiovascular morbidity in patients with symptomatic stable angina and hypertension: the ACTION trial . J Hypertens 2005;23:641-8.

36.

Fagard RH Benefits and safety of long-acting calcium antagonists in coronary artery disease: the ACTION trial. J Hypertens 2005 ;23:489-91.

37.

Remme WJ Prevention of cardiovascular events by perindopril in patients with stable coronary disease does not depend on blood pressure and its reduction - Results from the EUROPA study. Circulation 2004;110(suppl III):III-628.

38.

Mancini GBJ , Henry GC , Macaya C. et al. Angiotensin converting enzyme inhibition with quinapril improves endothelial vasomotor dysfunction in patients with coronary artery disease. The TREND (Trial on Reversing Endothelial Dysfunction) study. Circulation 1996;94:258-65.

39.

Dzau VJ , Bernstein K. , Celermajer D. et al. Working group on Tissue Angiotensin: the relevance of tissue angiotensin converting enzyme: manifestations in mechanistic and end point data. Am J Cardiol 2001;88:1L-20L.

40.

Rader DJ , Jacoby DS Renin-angiotensin system and atherothrombotic disease. Arch Intern Med 2003;163:1155-64.

41.

Sauer WH , Baer JT , Berlin JA , Kimmel SE Class effect of angiotensin converting enzyme inhibitors on prevention of myocardial infarction. Am J Cardiol. 2004 ;94:1171-3.

42.

Pilote L. , Abrahamowicz M. , Rodrigues E. , Eisenberg MJ , Rahme E.

Mortality rates in elderly patients who take different angiotensin converting enzyme inhibitors after acute myocardial infarction: a class effect?

Ann Intern Med 2004;141:102-12.

43.

Ghiadoni L. , Magagna A. , Versari D. et al. Different effect of antihypertensive drugs on conduit artery endothelial function. Hypertension 2003;41:1281-6.

44.

Zhuo J. , Mendelsohn F. , Ohishi M. Perindopril alters vascular angiotensin converting enzyme, AT1 receptor and nitric oxide synthase expression in patients with coronary heart disease . Hypertension 2002;39(part 2):634-8.

45.

Antony I. , Lerebours G. , Nitenberg A. Angiotensin converting enzyme inhibition restores flow-dependent and cold pressor test-induced dilations in coronary arteries of hypertensive patients . Circulation 1996;94:3115-22.

46.

Fogari R. , Mugellini A. , Zoppi A. et al. Losartan and perindopril effects on plasma plasminogen activator inhibitor-1 and fibrinogen in hypertensive type 2 diabetic patients. Am J Hypertens 2002;15:316-20.

47.

Ceconi C. , Fox KM , Remme WJ , Simoons ML , Bertrand M. , Kluft C. Effect of perindopril in patients with stable coronary artery disease:results on inflammatory and thrombosis markers of the PERTINENT study. Eur Heart J 2005;26(suppl 1):623.

48.

Mann JF , Yi QL , Sleight P. et al. HOPE Investigators. Serum potassium, cardiovascular risk and effects of an ACE inhibitor:results of the HOPE study. Clin Nephrol 2005;63:181-7.