Diltiazem

Hansson L, Hedner T, Lund-Johansen P, et al. Randomised trial of effects of calcium antagonists compared with diuretics and beta-blockers on cardiovascular morbidity and mortality in hypertension: the Nordic Diltiazem (NORDIL) study. Lancet 2000; 356:359-65.

* BACKGROUND Although the effectiveness of older antihypertensives (eg, diuretics and [Beta]-blockers) in preventing complications from hypertension has long been established, the effectiveness of newer agents such as calcium-channel blockers has not been demonstrated. As demonstrated by the Antihypertensive and Lipid-lowering Treatment to Prevent Heart Attack Trial study,[1] the ability of a medication to lower blood pressure may not translate into fewer complications. Although calcium-channel blockers lower blood pressure, questions remain regarding their safety and ability to prevent complications. Since calcium-channel blockers are also more expensive, it is fair to ask if the added expense to patients is worth it.

* POPULATION STUDIED Patients aged between 50 and 74 years were recruited from primary health care centers in Norway and Sweden. Inclusion criteria included 2 or more diastolic blood pressures of [is greater than or equal to] 100 mm Hg on 2 or more occasions. If patients were on treatment, the medications were stopped and the 2 elevated diastolic blood pressure readings had to be at least 1 week apart.

* STUDY DESIGN AND VALIDITY his was an open label comparison of antihypertensives. Randomization was conducted using a central randomization center where treatment was assigned. There was no mention of allocation concealment. The groups were similar at baseline. Almost 11,000 patients were initially assigned to receive either diltiazem (180-360 mg/day) or a diuretic or [Beta]-blocker. Additional drugs were added in a stepwise fashion to control the blood pressure. An intention-to-treat analysis was used. Mean follow-up was 4.5 years. Only 52 (0.5%) of the patients were lost to follow-up, but there was complete information on fatal events for 31 of the 52.

This was a large well-designed study. The relatively short follow-up of patients coupled with the low frequency of outcomes makes it more difficult to find a difference between diltiazem and the other agents, should one actually exist. However, because of the large number of patients the study had sufficient power to find such a difference, allowing us to feel confident in the equivalence of the different approaches.

* OUTCOMES MEASURED A committee using preset criteria and whose members were blinded to the treatment assessed the end points. The primary outcome was the combined rates of fatal and nonfatal stroke, fatal and nonfatal myocardial infarction, and other cardiovascular death. Secondary outcomes were the individual rates of fatal and nonfatal stroke and fatal and nonfatal myocardial infarction, and overall mortality.

* RESULTS Overall, the combined outcome of stroke, myocardial infarction, or cardiovascular death was the same in both groups (relative risk [RR]=1.0; 95% confidence interval [CI], 0.87-1.15). Overall mortality was also the identical for both groups. Taken individually, there was no difference in the incidence of myocardial infarction, though there were fewer strokes in the diltiazem-treated patients (RR=0.80; 95% CI, 0.65-0.99). However, the rate of events was relatively low in both groups (yes=0.64% per patient year in the diltiazem group vs 0.79% per patient year in the diuretic/[Beta]-blocker group). Subgroup analysis in patients with type 2 diabetes revealed no difference in end points. There were 4 adverse effects that differed significantly between the 2 groups: the diltiazem group experienced more headaches but less fatigue, dyspnea, and impotence.

RECOMMENDATIONS FOR CLINICAL PRACTICE

Another study published in the same issue of Lancet[2] also showed no difference between sustained-release nifedipine and diuretics/[Beta]-blockers. These 2 studies found no difference in the effectiveness of these agents. However, an unpublished meta-analysis is purported to show a higher risk of heart failure, heart attack, and major cardiovascular events with calcium-channel blockers compared with diuretics, [Beta]-blockers, clonidine, or ACE inhibitors.[3] Until this question is resolved, the effective less expensive agents remain the best choice for most patients with hypertension.

REFERENCES

[1.] The Antihypertensive and Lipid-lowering Treatment to Prevent Heart Attack Trial (ALLHAT) Collaborative Research Group. Major cardiovascular events in patients with hypertension randomized to doxazosin vs chlorthalidone: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2000; 283:1967-75.

[2.] Brown MJ, Palmer CR, Sastaigne A, et al. Morbidity and mortality in patients randomised to double-blind treatment with a long-acting calcium-channel blocker or diuretic in the International Nifedipine GITS study: Intervention as a goal in hypertensive treatment (INSIGHT). Lancet 2000; 356:366-72.

[3.] Josefson D. News: Calcium-channel blockers inferior to cheaper drugs. BMJ 321:590.

Alan Adelman, MD, MS Pennsylvania State University Hershey E-mail: aadelman@psu.edu

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