Byron Hoogwerf, M.D., FACP, FACE, Cleveland Clinic Foundation, Cleveland, Ohio, U.S.A.
Therapy with angiotensin converting enzyme inhibitors (ACE-I) has a well-established role in the treatment of diabetic nephropathy and in the treatment of patients with heart failure. Information from the heart failure studies suggested that there was a reduction in the risk for cardiovascular events (fatal or non-fatal MI) that was independent of any benefit on heart failure. In addition, this benefit appeared to be independent of any blood pressure reduction effect.
Heart Outcomes Prevention (HOPE) Study
The Heart Outcomes Prevention Study (HOPE) was double blind placebo controlled trial designed to assess whether ramipril 10 mg (vs. placebo) would reduce the risk for cardiovascular events in subjects at high risk for coronary disease events. The participants included a population of patients who had evidence of atherosclerotic vascular disease or diabetes with atherosclerotic vascular disease or (in the absence of clinical evidence of cardiovascular disease) one other cardiovascular risk factor. The diabetic population was a subset of patients specified for analyses at the beginning of the trial. The use of ramipril was associated with a significant reduction in the combined endpoint (non-fatal MI, stroke, cardiovascular death) as well as for each of these end-points individually. This was true for all participants in the study as well as for the diabetic patients (see slide sets for event rates/Kaplan Meier curves). Event rates were comparable in the diabetic patients and non-diabetic patients.
Whereas there were slightly lower mean blood pressure levels , most of the beneficial effect on MI and stroke reduction associated with ramipril use was independent of the blood pressure effect.
Event rates were slightly lower in patients without prior coronary heart disease (CHD, all with diabetes) vs. those with prior CHD. The incremental reduction in events with ramipril was comparable in patients both with and without CHD. In subsequent analyses, albuminuria was a continuous and graded risk factor for CHD events in both diabetic and non-diabetic participants. Patients with diabetes and elevated serum creatinine (>1.4 mg/dl) on placebo had higher event rates than those with serum creatinine levels (<1.4 mg/dl). Ramipril use had a greater incremental benefit in patients with creatinine >1.4 than in patients with values <1.4, although the absolute risk with ramipril treatment was higher in the elevated creatinine group.
Finally, the effects of ACE-I are in addition to other strategies associated with a reduction in risk for CHD (e.g. lipid lowering, aspirin use, or beta blocker use).
Perindopril Protection against Recurrent Stroke Study (PROGRESS)
The PROGRESS trial was a secondary prevention trial designed to assess whether perindopril 4.0 mg (vs. placebo) + indapamide would reduce the risk for stroke in subjects with a prior stroke or transient ischemic attack. There was a 28% reduction in the risk for recurrent stroke with perindopril use. The greatest effect was perindopril use in combination with indapamide (43% reduction) vs. perindopril alone (5% reduction (P=NS). Most of the beneficial effect on stroke reduction appears to be related to blood pressure reduction.
United Kingdom Prospective Diabetes Study (UKPDS)
The blood pressure treatment arm of the UKPDS used the ACE-I, captopril, and the beta blocker, atenolol, in the intensive treatment blood pressure arm. The intensive blood pressure treatment was associated with a reduction in the risk for microvascular and macrovascular diabetes endpoints. However, for comparable blood pressure reduction, there were no differences in clinical endpoints between captopril and atenolol treatment strategies based on intent to treat analyses. When outcomes in this trial were analyzed by in trial blood pressure levels, for every 10 mmHg reduction in blood pressure, there was a 12% reduction in fatal/non-fatal MI. It is not clear whether there was a beneficial effect of either the ACE-I or beta blocker beyond the reduction in blood pressure.
There are several other trials that included ACE-I and diabetic patients as a part of the treatment strategy. In general, there is a beneficial effect on cardiovascular endpoints in these studies.
Implications of the ACE-I trials for a prevention trial with omega-3 fatty acids
The ACE-inhibitor trials provide strong evidence that patients with established CHD and cerebrovascular disease benefit from the use of ACE-inhibitors. Furthermore, the HOPE study data indicate that patients with diabetes and other CHD risk factors benefit from ACE-I therapy. Therefore, it is likely that diabetic patients eligible for a primary prevention trial will likely all be candidates for ACE-I therapy based on current clinical trial data and current guidelines. This will have an effect on the event rate calculations for such patients, as the projected event rates will be more than 20% lower than may be derived from other populations of diabetic patients.
There is clearly some benefit of blood pressure reduction with ACE-I on reduction in atherosclerotic disease events. It is not yet clear whether the beneficial effects of ACE-I reported for ramipril in the HOPE study are applicable to all ACE-inhibitors (class effect). Clinical trials currently in progress may help to address this question. Until these clinical trial data are available, any trial design needs to address the blood pressure effects of ACE-I use, as well as the pleiotrophic effects. Until more is known about whether this is class-effect specific, ACE-I type and dose should be carefully recorded for trial participants.
The HOPE Study Investigators. Effects of an Angiotensin-Converting-Enzyme Inhibitor, Ramipril, on Death from Cardiovascular Causes, Myocardial Infarction and Stroke in High Risk Patients. New Engl J. Med. 2000;342:145-153
Mann JFE, Gerstein HC, Pogue J, Bosch J, Yusuf S for the HOPE Investigators. Renal Insufficiency as a Predictor of Cardiovascular Outcomes and the Impact of Ramipril: The HOPE Randomized Trial. Ann Intern Med 2001;134:629-636
Gerstein HC. Mann JF. Yi Q. Zinman B. Dinneen SF. Hoogwerf B. Halle JP. Young J. Rashkow A. Joyce C. Nawaz S. Yusuf S. HOPE Study Investigators. Albuminuria and risk of cardiovascular events, death, and heart failure in diabetic and nondiabetic individuals. JAMA. 2001;286:421-6
United Kingdom Prospective Diabetes Study Group. Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39: BMJ 1998;317:713-720
Adler AI, Stratton IM, Neil AW et al on behalf of the UK Prospective Diabetes Study Group Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study BMJ 2000;321:412-419