Nisoldipine vs. Enalapril on Cardiovascular Outcomes in NIDDM and Hypertension

Source: Estacio RO, et al. N Engl J Med 1998;338:645-652.

Cardiovascular disease is the leading cause of mortality in non-insulin dependent diabetes mellitus (NIDDM). As NIDDM and hypertension often coexist, effective blood pressure control is an important strategy in reducing cardiovascular risk. Widely used in management of hypertension, angiotensin converting enzyme inhibitors (ACEI) are known to increase survival after myocardial infarction (MI) and in congestive heart failure. ACEI also slow the progression of diabetic nephropathy. The most frequently prescribed antihypertensives in the country are calcium channel blockers (CCB), and other indications for their use include angina and pulmonary hypertension. However, there have been recent reports of increased risk of cardiovascular events associated with their use in non-diabetics. Because this remains a controversial issue with CCB use in hypertension, Estacio et al studied the incidence of cardiovascular events in NIDDM and hypertension by randomizing patients to either a CCB, nisoldipine, or an ACEI, enalapril, as part of the Appropriate Blood Pressure Control in Diabetes (ABCD) Trial.

The ABCD trial is a prospective, randomized study comparing: 1) the effects of moderate blood pressure control (target diastolic 80-89 mmHg) with intensive control (target diastolic 75 mmHg) on the incidence and progression of the complications of diabetes and 2) nisoldipine and enalapril as first-line antihypertensives in prevention and progression of complications of diabetes. The ABCD trial includes a cohort with hypertension (470 patients) and a cohort without hypertension (480 patients). The current study presents the analysis of a secondary end point, MI, only in the cohort with hypertension.

A total of 470 patients with hypertension (baseline blood pressure ³ 90 mmHg) were randomized to nisoldipine or enalapril. The baseline demographics, cardiovascular and diabetic complications, were similar in both groups over the entire follow-up period. After 67 months, a significant difference was noted between the two groups in the incidence of cardiovascular events; therefore, the study was unblinded. Using a multiple logistic regression model with adjustment for cardiac risk, nisoldipine was associated with a seven-fold higher incidence of fatal and nonfatal myocardial infarction compared with enalapril (P = 0.001; see Table). The rate of myocardial infarction was one per year in the enalapril group as compared with roughly five per year in the nisoldipine group. The higher incidence of myocardial infarction in the nisoldipine group was unaffected by the blood pressure levels.

Table

Logistic Regression Analysis of Cardiovascular Events with Nisoldipine and Enalapril

Nisoldipine Enalapril Adjusted Event
n = 235
n = 235
Risk Ratio
Fatal or nonfatal MI 
25
5*
7.0
Nonfatal MI
22
5*
5.9
Cerebrovascular accident 
11
2.2
CHF
6
1.3
Death from cardiovascular causes
10
1.4
Death from any cause
17
13
1.0
*P = 0.001

Comment by Kamaljit Sethi, MD

What does the higher incidence of acute MI with nisoldipine compared to enalapril in this study mean? Does enalapril reduce the risk of MI? Does nisoldipine increase the risk of MI, or is it a combination of both? The 10% incidence of MI over a five-year period with nisoldipine is similar to that reported in other studies with NIDDM. The authors acknowledge that the difference is hard to tell because MI was only a secondary end point in the ABCD trial. Additionally, the numbers in the trial are relatively small, although the very highly significant P value (P = 0.001) would suggest that the data will likely stand.

Many questions remain, but there are some answers. Using a common sense approach based on scientific data, it is possible to make a reasonable choice-will it be harm or benefit? Opting for benefit could mean using ACEI in diabetic hypertensives because risk reduction has been demonstrated in numerous studies. At this point, insofar as risk reduction for cardiovascular events is concerned, CCB can only remain challengers that have yet to prove themselves. It is clear that antihypertensives cannot be judged on blood pressure control alone, but on their ability to alter end-organ outcomes. Let's deal an ACE inhibitor and save a heart.

Dr. Sethi is Professor of Medicine, Georgetown University School of Medicine; Director, Georgetown Nephrology Section, DC General Hospital, Washington, DC.