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Calcium Channel Blockers and Hypertension

A number of readers have called Bandolier to ask if we would explain the current controversy about the association between calcium channel blockers and myocardial infarction in hypertension. This is a tall order, and one that we probably can't fill in its entirety. What Bandolier can do, however, is to give a synopsis of the evidence from the two recent publications [1,2] which precipitated the row.

Case-control study [1]

623 hypertensive patients in and around Seattle who were members of a group health co-operative who had a first fatal or non-fatal myocardial infarction were the cases. The 2032 controls were a stratified random sample of hypertensive patients matched for age sex and calendar year.

Excluded were people who had been members of the scheme for less than one year, who did not have a diagnosis of hypertension, who had a prior myocardial infarction or whose infarction was a complication of a procedure or surgery. Patients had to have been taking antihypertensive medicines for at least 30 days because preliminary analysis showed that recent starting of ß-blockers and calcium channel blockers was strongly associated with a risk of myocardial infarction.

Dose-response analysis was conducted by selecting patients taking the modal dose as the middle group, with those with lower or higher doses comprising the other two groups.

Results

A first analysis included only patients who were free of clinical cardiovascular disease.
There was a powerful association between myocardial infarction and calcium channel dose, alone or in combination with diuretics. The risk at the highest doses of calcium channel blockers was three times that at the lowest doses, with an NNT for myocardial infarction of about 35 (19 - 264) for CCB alone and 59 (28 - >500) with diuretics.

For every 35 (or 59) patients treated with high dose CCB, one would have a myocardial infarction over the next five years who would not have if they had not been given this treatment.

Analysis across all patients showed the same relationship, a relationship which was not apparent for other medicines, for example, ß-blockers.
These effects of higher rates of myocardial infarction with calcium channel blockers appeared to be consistent with a number of different compounds. For patients taking a calcium channel blocker, compared with those taking a ß-blocker, there was a 60% increased risk of myocardial infarction.

Systematic review of nifedipine [2]

Authors who were involved with the case-control study assessed dose-related increases of mortality in patients with coronary heart disease through a systematic review. They found 16 randomised controlled studies in which nifedipine was used in doses from 30 mg/day to over 100 mg/day. Twelve of the trials randomised patients with myocardial infarction, three included patients with unstable angina, and one evaluated patients with stable angina, some of whom had a prior infarction. In all there were over 8,000 patients. The outcome measure of the review was mortality.

Results

At doses between 30 and 50 mg/day there was no excess mortality. Four trials with 2,400 patients used 60 mg/day. The risk ratio was 1.18, and although the confidence intervals included 1, two of the trials were stopped early because of increased mortality or increased reinfarction. This may have led to an underestimate of the adverse mortality effect of the 60 mg/day dose. Four trials with almost 800 patients used 80 mg/day. The risk ratio was 2.8 (1.4 - 5.9) - a three-fold increased risk.

Comment

These two papers come from the same "stable". They are thoughtful and apparently well conducted. The discussions need to be read to get a full flavour of this complicated subject. Ongoing large scale trials will provide much more information on the effects of various hypertensive therapies, but in the meantime these papers provide food for thought where calcium channel blockers are prescribed in high doses. US guidelines recommend the use of diuretics and ß-blockers as first-line agents unless contraindicated, unacceptable or not tolerated.

References:

  1. BM Psaty, SR Heckbert, TD Koepsell et al. The risk of myocardial infarction associated with antihypertensive drug therapies. Journal of the American Medical Association 1995 274: 620-5.
  2. CD Furberg, BM Psaty, JV Meyer. Nifedipine. Dose-related increase in mortality in patients with coronary heart disease. Circulation 1995 92:1326-31.





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