Since the Australian Prescriber editorial on this subject1, information has continued to accumulate about the risks and benefits of calcium channel blockers. Although mostly reassuring, some questions remain about their suitability as first-line drugs in mild hypertension and about their appropriateness in certain patients (e.g. diabetics).
These questions relate mainly to the dihydropyridine subgroup which includes a variety of different drugs and formulations. Short-acting nifedipine preparations were the first to achieve clinical popularity. They were rapidly absorbed and capable of inducing reflex sympathetic stimulation and an increased heart rate. They were subsequently replaced by various slow-release formulations and drugs with slower absorption, a longer duration of action and less of a tendency to activate the sympathetic nervous system. These longer-acting drugs became widely used for the management of all grades of hypertension.2
Soon after short-acting nifedipine was released, it was found to provoke angina occasionally and even myocardial infarction. However, broader concerns were raised by a series of studies published in 1995-96. The first of these was a case-control study which revealed that patients taking calcium channel blockers had a higher risk of myocardial infarction than those taking diuretics (risk ratio 1.62) or beta blockers (risk ratio 1.57). This increased risk was regardless of whether the patients had a history of heart disease.3 A similar finding was observed in another cohort of elderly hypertensives in the U.S.A. Soon afterwards, a meta-analysis of randomised trials showed that patients with acute myocardial infarction or unstable angina, who had been previously treated with nifedipine, were at an increased risk of death.4
These findings principally involved short-acting nifedipine since it dominated practice in the U.S.A. at the time the data were collected. Subgroup analysis showed that the risk of adverse events was largely confined to patients receiving doses >60 mg per day, well in excess of what would now be considered prudent. Another pivotal study revealed that the risk was largely confined to individuals receiving nifedipine monotherapy.5 Amongst those receiving combination therapy (usually a beta blocker or diuretic), no increase in risk was observed.
Following these reports, other studies were published describing increased risks of cancer, suicide and gastrointestinal haemorrhage amongst users of calcium channel blockers.6 As with much pharmacoepidemiological data, the results have been difficult to interpret because of problems in separating the effects of the drug from the consequences of the diseases being treated. In general, the associations described so far have been relatively weak and inconsistent. While the evidence of harm was not compelling, these studies did call attention to a lack of medium- or long-term safety data that was striking for such widely used drugs.
A particular concern raised by the calcium channel blocker 'controversy' stems from how often these drugs are used in low-risk patients with mild-moderate hypertension. The risks and benefits of treatment in such patients are so finely balanced that even a very low incidence of serious adverse effects can negate the benefits of treatment. Even the best epidemiological studies usually lack the power to detect these small risks. Only large morbidity-mortality studies can confirm that a preventive intervention in low-risk patients is accomplishing more good than harm. Calcium channel blocker therapy in mild-moderate hypertension became established without the reassurance provided by such trials.
Information from large randomised trials of newer calcium channel blockers has at last become available. In the Systolic Hypertension in Europe (Syst-Eur) trial, the long-acting drug nitrendipine reduced the incidence of stroke and a favourable trend was noted in the incidence of myocardial infarction.7 On the other hand, the Appropriate Blood Pressure Control in Diabetes (ABCD) trial, which compared nisoldipine and enalapril, was stopped early. This was because of an excess of myocardial infarctions (25 versus 5) amongst the patients taking the calcium channel blocker.8,9 It is unclear if this is an adverse effect of calcium channel blockers or a beneficial effect of enalapril. More large studies will be required to establish the risk benefit profile in a range of important patient groups. The 40 000 patient ALLHAT trial which will be completed within the next 3 years will provide useful data.
In summary, the data presently available provide credible evidence that harm may result from the use of short-acting nifedipine in high doses. There is also a strong suggestion that ACE inhibitors may be preferable to dihydropyridines for the initial management of hypertension in patients with diabetes. Conversely, there is no substantive evidence of harm from the newer drugs or formulations and these are likely to remain an important part of the regimens for moderate and severe hypertension. Their value in isolated systolic hypertension has also been established. For mild hypertension, where a single drug may suffice, current evidence supports the guidelines which recommend starting treatment with beta blockers or diuretics which have had a beneficial effect in large morbidity-mortality trials.10
- Moulds RF. Calcium antagonists: the current controversy [editorial]. Aust Prescr 1996;19:35.
- Scholz H. Pharmacological aspects of calcium channel blockers. Cardiovasc Drugs Ther 1997;10(3 Suppl):869S-872S.
- Psaty BM, Heckbert SR, Koepsell TD, Siscovick DS, Raghunathan TE, Weiss NS, et al. The risk of myocardial infarction associated with antihypertensive drug therapies. JAMA 1995;274:620-5.
- Furberg CD, Psaty BM, Meyer JV. Nifedipine. Dose-related increase in mortality in patients with coronary heart disease. Circulation 1995;92:1326-31.
- Stason WB, Schmid CH, Niedzwiecki D, Whiting GW, Luo D, Ross SD, et al. Safety of nifedipine in patients with hypertension: a meta-analysis. Hypertension 1997;30:7-14.
- Stanton AV. Calcium channel blockers. The jury is still out on whether they cause heart attacks and suicide [editorial]. Br Med J 1998;316:1471-3.
- Staessen JA, Fagard R, Thijs L, Celis H, Arabidze GG, Birkenhager WH, et al. Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. The Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Lancet 1997;350:757-64.
- Estacio RO, Jeffers BW, Hiatt WR, Biggerstaff SL, Gifford N, Schrier RW. The effect of nisoldipine as compared with enalapril on cardiovascular outcomes in patients with non-insulin-dependent diabetes and hypertension. N Engl J Med 1998;338:645-52.
- Cutler JA. Calcium channel blockers for hypertension - uncertainty continues [editorial]. N Engl J Med 1998;338:679-81.
- The sixth report of the Joint National Committee on prevention, detection, evaluation and treatment of high blood pressure. Arch Intern Med 1997;157:2413-46.