HOPE for Stroke

The Heart Outcomes Prevention Evaluation Study (HOPE) was a landmark trial demonstrating beneficial effects of the angiotensin converting enzyme ramipril on cardiovascular events and disease progression. Several lines of evidence suggest that ACE inhibitors may also lower the risk of ischemic vascular events. ACEIs reduce proliferation of vascular smooth muscle, enhance endogenous fibrinolysis, stabilize plaques and decrease angiotensin II mediated atherosclerosis, plaque rupture and vascular occlusion. These effects suggest that they may reduce transient ischemic events through mechanisms that are independent of reduction in blood pressure. The results of the HOPE trial support this hypothesis.

The primary outcome of HOPE was the composite end point of myocardial infarction, stroke or cardiovascular death, and individual components were analyzed separately. Reduction in blood pressure was modest; however, the relative risk of any stroke was reduced by 32% in the ramipril group compared with the placebo group, and the relative risk of fatal stroke was reduced by 61%.

Benefit was seen at all values of diastolic and systolic blood pressure, confirming that the beneficial effects of ramipril were not confined to those with 'high' blood pressure. The reduction in strokes was consistent across the various subgroups examined, including patients receiving antiplatelet treatment and lipid-lowering drugs. The benefits were also consistent across subgroups defined by the presence or absence of previous stroke, coronary artery disease, peripheral arterial disease, diabetes or hypertension.

These results support those of the PROGRESS trial (perindopril protection against recurrent stroke study), which found that perindopril in combination with indapamide reduced the risk of recurrent strokes by 28% in patients with previous cerebrovascular disease.2,3 The initial blood pressure in this study was higher than in HOPE, and, therefore, was lowered more substantially. Taken together, results from both studies suggest that ACE inhibitors are of benefit in both primary and secondary prevention, even in patients without hypertension. The authors conclude that patients who are at high risk of stroke should be treated with ramipril, irrespective of their initial blood pressure levels and in addition to other preventive treatments such as blood pressure lowering agents and aspirin.

Critics of the study point out that the absolute risk reduction and number needed to treat are not available and do not necessarily support the authors' conclusions.

Source

1. Bosch J, Yusuf S, Pogue J, et al. Use of ramipril in preventing stroke: double blind randomised trial. BMJ 2002; 324:1-5.
2. Neal B, MacMahon S. PROGRESS (perindopril protection against recurrent stroke study): rationale and design. J Hypertens 1995; 13: 1869-73.
3. 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; 358:1033-41.

Special commentaries by:
Pierre Larochelle¹,
Ellen P. Burgess²,
Ernesto L. Schiffrin³,
Simon Kouz⁴, and
Michael Adams⁵

¹Assistant Director, Clinical Research Centre,
Centre Hospitalier de l'Université de Montréal-Campus Hôtel-Dieu,
Professor of Pharmacology,
Université de Montréal, Montreal, Quebec.

²Active Staff & Director, Foothills Medical Centre,
Associate Professor of Medicine,
University of Calgary, Calgary, Alberta.

³Director, Multidisciplinary Hypertension Group,
Hypertension & Lipid Clinic and Clinical Research Institute of Montreal, and
Professor of Medicine, Université de Montréal, Montreal, Quebec.

⁴Chief, Cardiology Service & Director,
Clinical Research Unit in Cardiology,
Centre Hospitalier Régional de Lanaudière, Joliette, Quebec.

⁵Head, Department of Pharmacology and Toxicology,
Queen's University, Kingston, Ontario.

Did the Results of the HOPE Trial Come as a Surprise?
Dr. Ernesto L. Schiffrin. Not at all. Our research group has been conducting numerous studies on ACE inhibitors for a number of years.

Introduction
The publication of the landmark Heart Outcomes Prevention Evaluation (HOPE) Study¹ in the New England Journal of Medicine in January 2000 was greeted by a great deal of excitement in the medical community. In essence, the trial confirmed beyond a doubt the cardiac and renal protective benefit of ACE inhibition and extended the patient base in whom ACE inhibition has been proven effective. Our understanding of the cardioprotective nature of ACE inhibitors has been built over the years by the various mega-studies that have been conducted, dating back to the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS),² published in 1987, which showed a 31% survival advantage for ACE inhibition in New York Heart Association (NYHA) class IV heart failure patients. Thirteen years and more than a dozen large trials later, the HOPE study has confirmed that patients need not be so sick--indeed, need only be considered at risk for cardiovascular events--for ACE inhibition to show similar benefits. Looking down the list, from CONSENSUS to HOPE and several landmark trials in between, one would be hard pressed to find a class of agents with a wealth of compelling evidence comparable to that accumulated for ACE inhibitors.

Main Results and Significance
The HOPE study investigators found that 17.

Tawfic Nessim Abu-Zahra, BSc MSc

Since their introduction into clinical practice 20 years ago, angiotensin converting enzyme (ACE) inhibitors have proven to be safe, well-tolerated drugs, effective in the treatment of a variety of cardiovascular disorders. Large clinical trials have established the efficacy of ACE inhibitors in treating hypertension, in reducing the incidence of myocardial infarction, and in decreasing mortality from heart failure in patients with left ventricular dysfunction.^1-5 Additionally, evidence suggests that ACE inhibitors reduce the occurrence and progression of nephropathy in patients with diabetes mellitus.^6,7 In two recently published clinical trials of the Heart Out- comes Prevention Evaluation (HOPE) study and the Microalbuminuria, Cardiovascular and Renal Outcomes (MICRO HOPE) substudy, investigators have demonstrated that the ACE inhibitor ramipril (Altace) significantly reduces the rates of death, myocardial infarction, and stroke in a broad range of high-risk patients, including those with diabetes and the elderly.^8,9 A brief interview was conducted with Dr. Hertzel C. Gerstein, the principal MICRO HOPE investigator, for the purpose of writing this article. His comments have been included here.

ACE is responsible for the conversion of angiotensin I to angiotensin II (Ang II), the principle hormone mediating the effects of the renin-angiotensin-aldosterone system (RAAS). (Please see Figure 1.