Calcium antagonists: the current controversy

Most practitioners will be aware of the current vigorous debate about the use of calcium antagonists in a wide range of clinical situations.

Some of the issues are not new, but the catalyst for the recent debate has been the publication of a case control study from the U.S.A.¹ This compared patients who had suffered a myocardial infarction with those who had not, with respect to their prior use of various antihypertensive drugs. The study reported that the risk of myocardial infarction was significantly increased in patients treated with a calcium antagonist compared with those treated with a diuretic.

In the light of the undoubted benefits of calcium antagonists in lowering blood pressure in hypertensive patients and improving angina in patients with coronary heart disease, it is unlikely a single case control study would have provoked such concern if it were not for the fact that calcium antagonists can be harmful in some specific circumstances. Thus, might it be that they could be harmful in broader circumstances than previously suspected?

Issues which are particularly relevant to the current controversy are:

• All published clinical trials studying the efficacy of calcium antagonists in the treatment of hypertension and/or angina have studied end points other than mortality. There are as yet no studies proving that calcium antagonists used in any clinical setting significantly reduce mortality.
• The evidence in the case control study, and in subsequently published meta-analyses of the use of calcium antagonists in various clinical situations, mainly relates to the short -acting formulation of the dihydropyridine calcium antagonist, nifedipine.
• In neither the case control study nor the meta-analyses has the effect of concurrent treatment with a dihydropyridine calcium antagonist and a beta blocker been analysed separately from treatment with a calcium antagonist alone.
• When dihydropyridine calcium antagonists are used alone, and, in particular, without a beta blocker, in the treatment of angina, a small percentage of patients undoubtedly deteriorate rather than improve.
• Several studies in the past have investigated whether or not calcium antagonists used routinely long term after myocardial infarction significantly reduce mortality (as has been shown with beta blockers and ACE inhibitors).None of the studies showed any overall benefit, and several showed significant harm, from calcium antagonist treatment.
• There are theoretical reasons why calcium antagonists, particularly the short-acting dihydropyridine drugs, may be harmful in patients with ischaemic heart disease. For example, it is possible that the less atherosclerotic coronary arteries might vasodilate more than arteries with extensive atherosclerosis. This 'steal effect'² might increase ischaemia by diverting blood away from areas of cardiac muscle which already have compromised blood supplies. This effect might be greater with the shorter-acting, more rapid onset formulations.

Obviously, a major factor in the current debate is the fact that the overall market for calcium antagonist drugs is one of the largest for any drug group e.g. the cost to the Pharmaceutical Benefits Scheme in Australia for calcium antagonists in the financial year 1994/95 was approximately $124.6 million. Thus, the pharmaceutical industry has a major financial interest in the outcome of the current debate. In addition, most major cardiovascular research groups in the world receive large research grants from the pharmaceutical industry, thus raising questions about the objectivity of opinions expressed by the leaders of those research groups.

In the face of such controversy, it is difficult for individual practitioners to decide what to do. At present, there is consensus that there is not a strong case for stopping calcium antagonist treatment for patients in whom it has been apparently successful. Current guidelines³ for the initiation of treatment for either hypertension or angina also do not recommend calcium antagonists as first-line treatment and, in the case of the dihydropyridine calcium antagonists, emphasise the advisability of concurrent treatment with a beta blocker. If current guidelines in Australia relating to the use of calcium antagonists are followed, it is unlikely patients will be ill served.