HOPE in PROGRESS -- A Tale of Two Trials: Blood Pressure Reduction or Drug Mechanism?

Introduction

Results published from the Heart Outcomes Prevention Evaluation (HOPE) study demonstrated that treatment with the angiotensin-converting enzyme inhibitor ramipril reduced cardiovascular morbidity and mortality in a broad range of high-risk cardiovascular patients. Inclusion criteria included age over 55 with a history of coronary artery disease, cerebrovascular disease, peripheral arterial disease or diabetes mellitus with at least one additional cardiovascular risk factor; approximately 50% of these patients were treated hypertensives.^[1] The overall reduction in morbidity and mortality could only partially be attributed to the modest mean reduction of office blood pressure (OBP) during the study (3/2 mm Hg). However, the drug dosing protocol used an unusual sequence, administering ramipril once daily, at bedtime, and measuring OBP during the day. Thus, the protocol for monitoring blood pressure in HOPE may have underestimated the 24-hour reduction in blood pressure.

A recently published substudy from the HOPE trial focused attention on the role of blood pressure reduction in producing clinical benefit.^[2] Thirty-eight patients with peripheral arterial disease enrolled in HOPE underwent 24-hour ambulatory blood pressure (ABP) monitoring before randomization and after 1 year. OBP was measured in the sitting position immediately before fitting the ABP monitoring equipment to the patient. Ramipril did, in fact, not significantly reduce OBP (8/2 mm Hg; p=NS) or day ABP (6/2 mm Hg; p=NS) after 1 year. However, even these numbers were larger than those recorded during HOPE. 24-Hour ABP was significantly reduced (10/4 mm Hg; p<0.03) mainly because of more pronounced blood pressure lowering effects during nighttime (17/8 mm Hg; p<0.001). The night-to-day ratio was also significantly lowered in the ramipril group. These data suggest that the significant effect on cardiovascular morbidity and mortality seen with the HOPE study, and also in the Microalbuminuria, Cardiovascular, and Renal Outcomes (MICRO-HOPE) substudy for renal protection,^[3] may have been far more dependent upon the effect of blood pressure reduction than has been recognized and may have contributed in a much greater way to the reduction of events and the stabilization of renal function.

On the other hand, the Perindopril Protection Against Recurrent Stroke Study (PROGRESS) studied the effects of blood pressure reduction on the rate of recurrent stroke.^[4] The study was designed and initiated by an independent research group in an effort to resolve clinical uncertainty about the efficacy and safety of routine blood pressure lowering for normotensive or mildly hypertensive individuals who had already experienced a stroke or transient ischemic attack. The PROGRESS protocol dictated that eligible subjects would receive open-label perindopril at a dose of 2 mg daily for 2 weeks, followed by 4 mg daily for another 2 weeks. Participants were then randomly assigned to continued active treatment or placebo (in addition to usual care) in a double-blinded fashion. Active treatment consisted of perindopril with the addition of indapamide to subjects for whom the treating physician judged there to be no specific contraindication. Placebo treated patients might then also receive placebo indapamide.

As predicted by the investigators, systolic and diastolic blood pressures were reduced by an average of 9.0±0.3/4.0±0.2 mm Hg among those receiving active treatment relative to placebo. This blood pressure reduction was maintained through an average follow-up of 3.9 years. Compared with those assigned to receive placebo, blood pressure reductions among those treated with combination drug therapy (12.3±0.5/5.0±0.3 mm Hg) were about twice as great as those receiving perindopril alone (4.9±0.6/2.8±0.3 mm Hg), and there were only small differences between the standardized blood pressure reductions seen between the hypertensive (9.5±0.6/3.9±0.3 mm Hg) and nonhypertensive groups (8.8±0.5/4.23±0.3 mm Hg).

Two subgroup analyses were prespecified -- combination vs. single drug therapy, and treatment effects among participants classified as hypertensive (>160/>90 mm Hg) at baseline compared to those classified as nonhypertensive. At the first visit, mean blood pressure of all participants was 147/86 mm Hg; the mean blood pressure was 159/94 mm Hg among those classified as hypertensive (n=2916; 48% of total), and 136/79 mm Hg in those classified as nonhypertensive. The standardized reductions in stroke risk were similar in hypertensive and nonhypertensive groups. Reductions in the risk of major vascular events were also similar for both groups. Combination therapy conferred similar advantages over single-drug therapy for both hypertensive (44%; 95% confidence interval [CI], 28-57) and nonhypertensive groups (42%; 95% CI, 19-58). Reductions with single-drug therapy were 10% (95% CI, -25 to 35) among hypertensives and 1% (95% CI, -34 to 25) among nonhypertensives.

The initial interpretation of the HOPE results suggested that blood pressure reduction could not alone account for the reduction in the cardiovascular event rate. However, the accuracy of the measurement of blood pressure reduction has been questioned and the results from the ABP substudy, although admittedly performed in only a small segment of the study population and only in individuals with peripheral vascular disease, certainly do suggest that blood pressure reduction may have been far greater than initially reported, and may in fact account for a greater reduction in events than previously thought. The HOPE study design tested the importance of interference with the renin-angiotensin-aldosterone system (RAAS) in reducing the subsequent cardiovascular event rate in high-risk patients; in this setting it is not possible to separate blood pressure reduction from RAAS inhibition. One may clearly infer that blood pressure reduction is of great importance, even if blood pressure is normal or only mildly elevated. On the other hand, the PROGRESS data clearly seem to indicate that the extent of blood pressure reduction is the critical variable, beyond RAAS interference alone, in reducing cardiovascular end points.

These studies illustrate the difficulty in defining what an "optimal" blood pressure is for an individual patient. The sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI) defines optimal blood pressure as ≤120/80 mm Hg, but, as long as tissue perfusion is adequate, may be even lower for some individuals.^[5] The need for cohorts of subjects in large clinical trials to have home or ABP measuring, when blood pressure may influence outcome, is endorsed by these two studies.

The mechanical effects of an increase in blood pressure should not be underestimated. A 2-mm Hg reduction in diastolic blood pressure in large populations, including normotensive subjects, may account for a 6% reduction in coronary heart disease and a 15% reduction in stroke.^[6] Mechanisms that increase oxidative stress by reducing nitric oxide production -- and hence, result in vascular and myocardial remodeling -- may be significantly altered by small changes in blood pressure or specific mechanisms of antihypertensive medications. Clearly, the importance of blood pressure reduction per se is of primary importance.

Am J Geriatr Cardiol. 2002;11(5) © 2002 Le Jacq Communications, Inc.

Cite this: HOPE in PROGRESS -- A Tale of Two Trials: Blood Pressure Reduction or Drug Mechanism? - Medscape - Sep 01, 2002.