Issue 130 Item 4 ACE Inhibitor Plus Diuretic May Halt Coronary Events

Stroke patients see 38% reduction in risk of nonfatal MIs, 26% drop in CHF risk. Blood pressuring lowering with an ACE inhibitor and diuretic prevents coronary events and congestive heart failure in individuals with prior stroke or transient ischemic attack, regardless of their baseline blood pressure.

This key finding of a new secondary analysis of the Perindopril Protection Against Recurrent Stroke Study (PROGRESS) was greeted enthusiastically at the 24th Congress of the European Society of Cardiology. PROGRESS randomized 6,105 hypertensive or nonhypertensive patients on standard secondary prevention regimens for prior stroke or TIA to placebo or 4 mg/day of the long-acting ACE inhibitor perindopril; 2.5 mg/day of the diuretic indapamide was added at the physician’s discretion.

The previously reported primary end point in PROGRESS was the risk of stroke during 4 years of follow-up. The rate was 10% with active treatment and 14% in the placebo arm, for a 28% reduction in relative risk in patients on perindopril-based blood pressure lowering (Lancet 358 [9287]:1033-41, 2001).

The new secondary analysis looked at clinical outcomes in the coronary rather than cerebral vasculature. The benefits were impressive: active treatment conferred a 26% reduction in the risk of developing congestive heart failure, a 38% reduction in nonfatal acute MI, and a 26% decrease in the combined end point of nonfatal MI or death due to coronary heart disease, reported Dr. Anushka Patel of the Institute for International Health at the University of Sydney (Australia).

Moreover, the combined end point of major fatal or nonfatal coronary events, need for coronary revascularization, or hospitalization for unstable angina was 21% lower with active treatment than with placebo.

“One stroke, coronary event, or case of heart failure would be avoided for every 10 patients treated with a combination of perindopril and indapamide for 5 years. These absolute benefits certainly compare very favorably with other treatments commonly used for secondary prevention of vascular disease,” Dr. Patel observed.

As was true for the cerebrovascular benefits cited in the first PROGRESS report, the coronary benefits were similar in both hypertensive and nonhypertensive patients, as well as in those with or without known coronary heart disease.

“The documented treatment benefits for perindopril and indapamide really describe a third category of intervention in addition to antiplatelet agents and statin therapy that avoids catastrophic events in both the cerebral and coronary vasculature in high-risk patients. Thus, treatment with these agents should be considered in all patients with a history of stroke or transient ischemic attack, regardless of their blood pressure level,” she asserted.

PROGRESS was sponsored by Servier, the National Health and Medical Research Council of Australia, and the Health Research Council of New Zealand. Average blood pressure lowering achieved with active therapy was 9/4 mm Hg.

Discussant Dr. Peter Sleight hailed PROGRESS as “a landmark trial” and sought to place it in context. “Before this trial there was a lot of argument about what you did with people after a stroke. Some people feared that dropping the blood pressure would cause cerebral ischemia. … Now we have very clear evidence for blood pressure lowering in these people who have had a previous cerebrovascular event,” said Dr. Sleight, professor of medicine at the University of Oxford (England).

“PROGRESS, like the Heart Outcomes Prevention Evaluation (HOPE) and Heart Protection Study (HPS), showed the value of lowering so-called normal values of blood pressure or cholesterol in patients who have known vascular disease and are therefore at extremely high risk. This reduces all vascular events, not just the presenting event,” he noted.

Perindopril is a relatively long-acting ACE inhibitor, but the benefits in PROGRESS likely reflect a drug-class effect. “I would guess myself that all ACE inhibitors work the same way,” Dr. Sleight said.

Blood pressure reduction probably accounts for much of the benefit in PROGRESS, but perhaps not all of it. Several lines of evidence suggest that ACE inhibitors’ stimulation of angiotensin-2 receptors in the brain may exert a protective effect against cerebral ischemia, he said.