What Have We Learned from the Hope Study

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 17.8% of the placebo group reached the primary outcome of death from cardiovascular causes, compared to 14.0% of the ramipril group,

a 22% relative risk reduction (Figure 1). Ramipril therapy was associated with a reduction in each of the components of the composite endpoint, as well as each of the secondary endpoints.

In addition to having a positive effect on each endpoint, ACE inhibitor therapy was beneficial in each of the trial's many subgroups, including those with or without diabetes, with or without evidence of cardiovascular disease, older or younger than 65 years, and with or without hypertension at baseline.

Based on their observations and the statistical analysis of the trial data, the study investigators made a series of concluding statements in the New England Journal of Medicine article. They reported that the treatment benefits described above were observed among patients who were already taking a number of effective treatments, such as acetylsalicylic acid (ASA), beta-blockers, and lipid-lowering agents, indicating that the inhibition of angiotensin-converting enzyme offers an additional approach to the prevention of atherothrombotic complications.

the wealth of data accumulated prior to HOPE indicates that the benefits attributed to ramipril in HOPE can be interpreted as a class effect.

The findings of the HOPE study should have a dramatic impact on the treatment of patients considered to be at high risk for cardiovascular events. Already proven to be effective for the prevention of events in patients with left-ventricular dysfunction, patients post-MI and those with non-diabetic and diabetic nephropathy (type I), HOPE shows that ACE inhibitors should now be gold standard therapy in all at-risk patients. Although the results of one study using one agent are not always applicable to all the agents within the class, the wealth of data accumulated prior to HOPE indicates that the benefits attributed to ramipril in HOPE can be interpreted as a class effect. HOPE is the logical culmination of numerous ACE inhibitor trials in cardiac and renal protection.

Heart failure: evidence with ACE inhibitors
The HOPE investigators concluded that the reduction in heart failure noted in their study complements previous ACE inhibitor studies, "which demonstrated that treatment with angiotensin-converting-enzyme inhibitors prevents heart failure". There are a number of trials that have