Blood pressure lowering and ACE inhibition for the avoidance of cardiac and cerebral events

S. MacMahon* and J. Chalmers

Institute for International Health, University of Sydney, P.O. Box 576, 2042 Sydney, New South Wales, Australia

* Corresponding author. Tel.: +61-2-9351-0099; fax: +61-2- 9351-0008
E-mail address: s.macmahon{at}iih.usyd.edu.au

See doi:10.1016/S1095-668X(02)00804-7for the article to which this editorial refers.

It is now well established that the level of blood pressure, whether systolic or diastolic, is an important determinant of the risks of both stroke and heart attack—not only among those with high blood pressure but also among those with average or below average blood pressure levels.1 However, while numerous clinical trials have demonstrated that blood pressure lowering treatments reduce the risks of stroke and of heart attack in hypertensives,2,3 until recently there has been little evidence about the effects of such therapy in non-hypertensives. Since many individuals at very high risk of stroke or heart attack do not have hypertension, there is a considerable interest in determining whether there are benefits of blood pressure lowering agents for high-risk individuals with average or below average blood pressure levels. This question mirrors another posed a decade ago about the effects of blood cholesterol lowering in high-risk patients with average or below average cholesterol levels—a question answered decisively by trials of statins in patients with coronary heart disease.4–6

Over the past 2 years, two major trials have been completed that have demonstrated important benefits of ACE inhibitor-based regimens for patients at high risk of coronary events or stroke, whether hypertensive or non-hypertensive. The Heart Outcomes Protection Evaluation (HOPE) study was designed to determine the effects of treatment with ramipril among individuals with a history of vascular disease or diabetes.7 Its results showed clear benefits of treatment for both coronary events7 and stroke.8 The Perindopril Protection Against Recurrent Stroke Study (PROGRESS) was designed to determine the effects of a regimen involving perindopril, with the discretionary use of the diuretic, indapamide, among individuals with a history of cerebrovascular disease.9 Once again, the results of that study demonstrated clear benefits of blood pressure lowering treatment for stroke10 and, as reported in this issue, clear benefits for both coronary events and congestive heart failure.11 In both HOPE and PROGRESS, the relative reductions in stroke and coronary disease risk were of broadly similar magnitude (20–30%) and, collectively, these studies demonstrate that ACE-inhibitor-based treatment is effective not only in the secondary prevention of major vascular events, but also in the primary prevention of such events, at least among high risk patients. Moreover, the demonstration of this duality of benefits for stroke and heart attack establishes a third category of interventions, in addition to antiplatelet therapy12 and statins,4–6 that avert catastrophic events in both the cardiac and cerebral vasculature of high risk patients. These three interventions provided concurrently to such patients would be expected to reduce the risks of major vascular events by more than half.

Both HOPE and PROGRESS demonstrated separately significant reductions in the risk of stroke among hypertensive and non-hypertensive patients.8,10 This is consistent with expectations from epidemiological evidence demonstrating continuous associations of blood pressure with the risk of stroke,13–15 although the risk reduction observed in HOPE is somewhat larger than that which would have been predicted for the blood pressure reductions observed. PROGRESS provided strong evidence of a greater reduction in stroke risk with combination therapy (with both perindopril and indapamide) than with single drug therapy (with perindopril alone)10—a finding consistent with epidemiological expectations of greater benefits from larger blood pressure reductions,13–15 as well as with evidence from randomized trials that have directly compared more and less aggressive blood pressure lowering therapy.3 In PROGRESS, the overall reduction in stroke risk was almost exactly that predicted for the blood pressure reductions achieved16 (a 4mmHg reduction in diastolic blood pressure and a 9mmHg reduction in systolic blood pressure). For both combination therapy and single drug therapy there was substantial overlap between the 95% confidence intervals of the observed effects10 and the effects predicted from the achieved blood pressure reductions (Fig. 1). 16



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Fig. 1 Effects of ACE inhibitor-based treatment on the risks of stroke, major coronary events and congestive heart failure in HOPE and PROGRESS. {blacksquare}=point estimates of treatment effect. These are proportional in size to the number of events that occurred. Horizontal lines represent 95% confidence intervals. *Major coronary events=non-fatal myocardial infarction or death from coronary heart disease. ¶Risk reduction for this outcome is derived from the relative risk calculated from data provided to the Blood Pressure Lowering Treatment Trialists' Collaboration. §Congestive heart failure in HOPE=all cases of heart failure, whether or not these required hospitalization. Congestive heart failure in PROGRESS=heart failure causing death or hospitalisation or requiring open-label treatment with ACE inhibitor±diuretic.

 
For coronary heart disease, the observed effects in both trials appeared to be somewhat greater than those predicted for the blood pressure reductions achieved. In previous trials of blood pressure lowering regimens (based primarily on diuretics or beta-blockers), a reduction in diastolic blood pressure of 5–6mmHg (with a corresponding reduction in systolic blood pressure of about 10–12mmHg) reduced coronary heart disease risk by 16%.2 In HOPE7 and earlier trials of ACE inhibitor monotherapy,17 the risk of coronary heart disease was reduced by about 20%, yet reductions in blood pressure were very modest. In PROGRESS, the 26% reduction in major coronary events was about twice as large as that which would have been predicted from the previous trials given the blood pressure reductions achieved. Moreover, the reduction of 35% in major coronary events among those treated with both perindopril and indapamide might reflect independent, additive benefits of blood pressure lowering and ACE inhibition, although the confidence interval for this estimate of treatment effect is too wide to allow definitive conclusions. For congestive heart failure, both studies demonstrated substantial reductions in incidence among patients assigned active treatment, thereby extending the evidence provided by earlier trials of ACE inhibitor-based therapy among patients with left ventricular dysfunction.17

The absolute benefits of treatment observed in HOPE and PROGRESS are large by any standard. In HOPE, the treatment of 100 patients for 4 years resulted in the avoidance of four major vascular events (stroke, myocardial infarction or vascular death). In PROGRESS, the treatment of 100 patients with both perindopril and indapamide for the same period resulted in the avoidance of eight major vascular events. Importantly, these benefits were achieved with very few side effects requiring treatment withdrawal: in PROGRESS, after an initial screening phase for short-term treatment intolerance, there were only 2% more withdrawals from active treatment than placebo by the end of follow-up. The benefits and safety of ACE inhibitor-based therapy for high-risk patients, therefore, compare very favourably with the established mainstays of secondary vascular disease prevention— namely, antiplatelet therapy with aspirin or clopidogrel and cholesterol lowering with statins. Such demonstrably worthwhile effects should result in treatment with ACE inhibitor-based therapy being considered routinely for all patients with established vascular disease. Globally, if such therapy were made widely available to patients with vascular disease, several million serious vascular events could be avoided each year.

References

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  3. Blood Pressure Lowering Treatment Trialists' Collaboration. Effects of ACE inhibitors, calcium antagonists, and other blood-pressure-lowering drugs: results of prospectively designed overviews of randomised trials. Lancet. 2000;356:1955–1964.[CrossRef][ISI][Medline]
  4. Sacks F, Pfeffer M, Moyle L et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med. 1996;335:1001–1009.[Abstract/Free Full Text]
  5. Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and broad range of initial cholesterol levels. N Engl J Med. 1998;339:1349–1357.[Abstract/Free Full Text]
  6. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360:7–22.[CrossRef][ISI][Medline]
  7. The Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med. 2000;342:145–153.[Abstract/Free Full Text]
  8. Bosch J, Yusuf S, Pogue J et al. Use of ramipril in preventing stroke: double blind randomised trial. Br Med J. 2002;324:1–5.[Abstract/Free Full Text]
  9. PROGRESS Management Committee. Blood pressure lowering for the secondary prevention of stroke: rationale and design for PROGRESS. J Hypertens. 1996;14(Suppl 2):S41–S46.[ISI]
  10. PROGRESS Collaborative Group. Randomised trial of a perindopril-based blood pressure lowering regimen among 6,105 individuals with previous stroke or transient ischaemic attack. Lancet. 2001;358:1033–1041.[CrossRef][ISI][Medline]
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  12. Antithrombotic Trialists' Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. Br Med J. 2002;324:71–86.[Abstract/Free Full Text]
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  14. Prospective Studies Collaboration. Cholesterol, diastolic blood pressure, and stroke: 13 000 strokes in 450 000 people in 45 prospective cohorts. Lancet. 1995;346:1647–1653.[ISI][Medline]
  15. Eastern Stroke and Coronary Heart Disease Collaborative Research Group. Blood pressure, cholesterol, and stroke in eastern Asia. Lancet. 1998;352:1801–1807.[CrossRef][ISI][Medline]
  16. Rodgers A, MacMahon S, Gamble G et al. on behalf of the UKTIA Collaborative Group. Blood pressure and risk of stroke in patients with cerebrovascular disease. Br Med J. 1996;313:147.[Free Full Text]
  17. Flather M, Yusuf S, Kober L et al. Long-term ACE-inhibitor therapy in patients with heart failure or left-ventricular dysfunction: a systematic overview of data from individual patients. ACE-Inhibitor Myocardial Infarction Collaborative Group. Lancet. 2000;355:1575–1581.[CrossRef][ISI][Medline]

Related articles in EHJ:

Effects of a perindopril-based blood pressure lowering regimen on cardiac outcomes among patients with cerebrovascular disease
PROGRESS Collaborative Group
EHJ 2003 24: 475-484. [Abstract] [Full Text]  




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