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 attacknot 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 levelsa question answered decisively by trials of statins in patients with coronary heart disease.46
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 (2030%) 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,46 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,1315 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)10a finding consistent with epidemiological expectations of greater benefits from larger blood pressure reductions,1315 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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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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