Safety of Calcium Channel Blockers in Cardiovascular Disease
To the Editor:
I read with interest the report by Michels et al1 and the accompanying editorial2 and wondered about reversed bias in publication when the research is newsworthy. As is the case with many observational studies, the quality of data is diminished by lack of ascertainment for drug exposure and confounding bias.
On the basis of the results of Table 3A, the authors conclude that there is an increased risk of myocardial infarction (MI) among those exposed to calcium channel blockers. However, covariate adjustment does not appear to include adjustment for previous MI, even though Table 2 clearly demonstrates an increased prevalence of previous MI among these subjects. Furthermore, casual inspection of Table 3A suggests a similar increase in risk of MI among those exposed to β-blockers, with a statistically significant increase in those taking diuretics and β-blockers. The group with the highest risk consists of those subjects taking a combination of diuretics, β-blockers, and calcium channel blockers. Not surprisingly, when the history of previous cardiovascular disease is removed (Table 3B), no association with increased risk of MI is found. The observation that the risk of calcium channel blocker therapy is mostly imparted from the groups of subjects treated with combination therapy with diuretics and β-blockers (Tables 3A and 3B) highlights the complexity and unreliability of these analyses.
The only conclusion that can be reliably reached is that calcium channel blockers are prescribed more frequently in sicker individuals. Because of the strength of this association, reliable adjustment to remove confounding bias cannot be completed. Given the lack of knowledge as to which of the calcium channel blockers was taken, if any, the results of this large observational study are rendered nongeneralizable to the current standard of practice.
- Copyright © 1998 by American Heart Association
Michels KB, Rosner BA, Manson JE, Stampfer MJ, Walker AM, Willett WC, Hennekens CH. Prospective study of calcium channel blocker use, cardiovascular disease, and total mortality among hypertensive women: the Nurses’ Health Study. Circulation. 1998;97:1540–1548.
Califf RM, Kramer JM. What have we learned from the calcium channel blocker controversy? Circulation. 1998;97:1529–1531.
We agree with Dr Langer—and, in fact, began our discussion section with the statement—that in our cohort, a greater proportion of women prescribed calcium channel blockers had risk factors for cardiovascular disease. Furthermore, we also stated that residual confounding by indication is likely to remain, and results from observational studies on these issues have to be interpreted with considerable caution. Specifically, it remains unclear whether any observed increased risks are real, are due to chance, or represent residual confounding by indication.
We also wish to clarify our analytical strategy, which may have been unclear due to a typographical error that occurred in typesetting our article: in Tables 1 and 3A, the symbols “†” and “‡” were erroneously exchanged. When read correctly, the footnote for Table 3A indicates that 296 women with prior myocardial infarction (MI) were excluded from the analysis for the end point of MI. We only presented results on first events. The 296 women excluded from the analysis of MI had been confirmed by medical records to have suffered a prior MI. As described in the Methods section, women who reported a prior MI but for whom this diagnosis could not be confirmed were not excluded from the analysis presented in Table 3A, but their self-report of MI was adjusted for in the analysis. The analysis presented in Table 3B excluded all women with self-reported MI and, additionally, all women who reported stoke, CABG/PTCA, or angina pectoris.