RAAS Blockade: Focus on ACEI This section will summarize the results of major trials that have provided insight into the disease process and powerfully demonstrate that blocking the RAAS impacts CVD and renal outcomes. Clinical trials of ACEIs and ARBs that are underway to further elucidate the benefit of the RAAS blockade will also be discussed.

Role of ACEI as established in clinical trials This diagram summarizes the effect of ACEIs on hypertension, restenosis, atherosclerosis, and aortic aneurysm, as established in clinical trials. Several trials using ACE inhibition in patients with atherosclerosis and preserved cardiac function have been conducted, but not all trials show beneficial effects on prevention. Potentially, ACE inhibitors may be more beneficial for high-risk patients, but offer less benefit for low-risk patients or those already receiving treatment with statins and antiplatelet agents.

Evolution of ACE inhibition for treating patients with CHD Over the past 2 decades, outcomes trials have demonstrated benefits of ACE inhibition in a wide range of patients with CVD. Observations made by investigators in the Studies of Left Ventricular Dysfunction (SOLVD), and confirmed in the Survival and Ventricular Enlargement (SAVE) trial, suggested that treatment with ACE inhibitors may reduce the risk of CV events and set the stage for the Heart Outcomes Prevention Evaluation (HOPE) study. This study demonstrated the efficacy of ACE inhibition in patients with vascular disease or with diabetes and at least one other CVD risk factor, but without heart failure or left ventricular (LV) dysfunction. Observations made in the HOPE trial with such high-risk patients, were subsequently supported in other trials.

EUROPA, HOPE, PEACE, QUIET: Effect of ACEIs on CV endpoints The effect of ACE inhibition on CV morbidity and mortality has been examined in more than 31,000 patients with stable vascular disease without LV dysfunction, in the HOPE, European Trial on Reduction of Cardiac Events With Perindopril in Stable Coronary Artery Disease (EUROPA), Prevention of Events With ACE Inhibition (PEACE), and QUinapril Ischemic Event Trial (QUIET) trials. HOPE and EUROPA demonstrated comparable benefits of long-term ACE inhibition with perindopril and ramipril in high-risk patients. In EUROPA, perindopril 8 mg reduced the primary outcome of CV death, MI, and cardiac arrest by 20%. In HOPE, ramipril 10 mg reduced the primary outcome of CV death, MI, and stroke by 22%. In contrast, the PEACE trial results demonstrated a neutral effect with trandolapril 4 mg: Various explanations have been proposed for the difference in the outcome in the PEACE study, including better risk-factor control at baseline, slowness in up-titration of trandolapril, greater loss of patients to follow-up, and insufficient power to detect reductions in MI and CV death.(1) In the QUIET trial, patients randomly allocated to quinapril 20 mg after undergoing coronary angioplasty or atherectomy, demonstrated a statistically insignificant reduction (13%) in the risk of CV death, MI, or resuscitated cardiac arrest compared with placebo. Abbreviations: CABG = coronary artery bypass graft, HR = hazard ratio, PCI = percutaneous coronary intervention, RRR = relative risk reduction Fox K et al. Eur Heart J. 2006;27:2154-7.

HOPE, EUROPA, PEACE: Reduction in all-cause mortality Dagenais et al conducted a combined analysis of the HOPE, EUROPA, and PEACE trials (N = 29,805), which indicated that ACE inhibition has a significant benefit on all-cause mortality in patients with stable vascular disease without LV dysfunction. Reduction in all-cause mortality was significant in the HOPE trial (17%, P < 0.005). The odds ratios favored ACEIs in the EUROPA and PEACE trials, although the CIs overlapped with unity. Pooling the results yielded a significant 14% reduction in all-cause mortality (P = 0.0004).

DREAM: Effect of ramipril on new diabetes or death/regression to normoglycemia in low-risk patients In the Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication (DREAM) trial, the use of ramipril (up to 15 mg per day) was studied in 5269 low-risk patients without CVD, but with impaired fasting glucose levels (after an 8-hour fast) or impaired glucose tolerance. The primary outcome was the incidence of diabetes or death, whichever came first; the secondary outcome was regression to normoglycemia. Median follow-up was 3 years. The ramipril and placebo groups had a similar incidence of diabetes or death. However, the Kaplan-Meier curves suggest a potential benefit of ramipril in the prevention of diabetes after 3.5 years. Participants receiving ramipril were significantly more likely to have regression to normoglycemia than those receiving placebo (P = 0.001). The effect of treatment on regression to normal glucose levels in this low-risk population suggests that ramipril may have favorable effects on glucose metabolism.

Beyond Current Strategies: Focus on Angiotensin Receptors