Infarction risk found with calcium channel blocker

British Medical Journal, March 14, 1998 by Deborah Josefson

Hypertensive patients with diabetes who are treated with the long acting calcium channel blocker nisoldipine are five times more like]y than patients treated with the angiotensin converting enzyme inhibitor enalapril to have a heart attack. These unexpected findings caused one arm of a study to be stopped and have raised renewed concerns over the safety of calcium channel blockers.

The appropriate blood pressure control in diabetes trial was led by Raymond Estacio and Robert Schrier from the University of Colorado Health Science Center (New England Journal of Medicine 1998;338:645-52). The researchers enrolled 470 patients with non-insulin dependent diabetes mellitus who were divided into two cohorts--one with high blood pressure and one with normal blood pressure. These cohorts were randomised to receive either intensive treatment of blood pressure, with the goal of dropping diastolic pressures by 10 mm Hg, or moderate treatment with no change in baseline diastolic blood pressures.

The normotensive cohort was subdivided into three groups--half of the cohort received placebo while the remaining half was equally divided into one group that received nisoldipine and one that received enalapril. The hypertensive participants were similarly randomised to receive intensive or moderate blood pressure control, and they were divided into a group receiving nisoldipine and one receiving enalapril.

In both cohorts the primary end point of the study was the effect of blood pressure modification on renal function as measured by 24 hour creatinine clearance. The secondary end points included the effects of blood pressure control on complications such as retinopathy, proteinuria, neuropathy, and cardiovascular events.

Five subjects in the enalapril group died of cardiovascular disease compared with 10 in the nisoldipine group. Moreover, in the group receiving the angiotensin converting enzyme inhibitor only five had heart attacks, none of which were fatal. In contrast, 25 patients in the nisoldipine cohort developed infarcts, three of which were fatal. This finding was even more alarming when taken in the light of the slightly increased baseline risk of patients assigned to the angiotensin converting enzyme inhibitor group, who had higher overall cholesterol concentrations and a worse ankle brachial index (a pulse measurement known to be an independent predictor of coronary disease).

The trial's monitoring committee recommended terminating the nisoldipine arm of the study after noting a relative risk ratio of 9.5 (95% confidence interval 2.3 to 21.4) for fatal to non-fatal myocardial infarcts in patients receiving treatment:.

Cautious interpretation

The authors point out that because the findings were based on a secondary end point of the study, the results should be interpreted cautiously: "For example, the apparent increased risk of heart attacks in patients receiving nisoldipine may be due to the protective effects of enalapril rather than the deleterious effects of the calcium channel blocker." They conclude: "None the less there was a significantly lower incidence of myocardial infarction in the enalapril group despite the potentially higher baseline risk of cardiovascular events in that group .... Not only were patients assigned to enalapril less likely to have myocardial infarction, but the time to first event was longer than in the nisoldipine group."

The authors state that an angiotensin converting enzyme inhibitor is the preferred anti-hypertensive agent, rather than a dihydropyridine calcium channel blocker, for the prevention of cardiovascular complications, specifically myocardial infarctions, in patients with non-insulin dependent diabetes.

Bayer, the manufacturer of nisoldipine, said that the difference in the effects of treatment was not seen in the larger group of diabetic patients with normal blood pressure. A statement said: "It is important to note that overall mortality was virtually identical in both groups. The findings are based on an analysis of a secondary end point and require further analysis. They are not an indication of either drug's potentially harmful effects."

This is not the first time that concerns have been raised over the safety of calcium channel blockers. In 1995 a study found the short acting calcium channel blockers such as nifedipine were associated with an increased risk of heart attack (JAMA 1995;274:620-5). This effect was thought to be limited to the short acting dihydropyridine subtypes, and the new study is the first to suggest that long acting calcium channel blockers may share this cardiovascular risk. Calcium channel blockers have also been recently associated with increased risks of suicide and depression, gastrointestinal haemorrhage, and even cancer. The MIDAS study (JAMA 1995;274:620-5) also found more adverse cardiovascular events such as angina and stroke in patients given calcium channel blockers compared with those taking diuretics.

A recent study on systolic hypertension in elderly people has found, however, that a long acting calcium channel blocker of the dihydropyridine class is effective in reducing the risk of stroke competed with placebo. Moreover, there is some evidence that non-dihydopyridine calcium channel blockers such as verapamil and diltiazem may decrease the risk of recurrent heart attacks in some patients.