CORRESPONDENCE: LETTER TO THE EDITOR
Is the Relationship Between Beta-Blocker–Induced Heart Rate Lowering and Cardiovascular Outcomes the Result of Confounding by Indication?
Robert A. Phillips, MD, PhD*
* UMass Memorial Medical Center, Heart and Vascular Center of Excellence, 55 Lake Avenue North, Room S3-836, Worcester, Massachusetts 01655 (Email: Robert.phillips{at}umassmemorial.org).
In a meta-analysis of beta-blocker trials for the treatment of hypertension, Bangalore et al. (1) report that there is an inverse relationship between achieved heart rate at the end of the trials and risk of myocardial infarction and cardiovascular death. The authors suggest that the heart rate decrease associated with beta-blockers leads to increased central aortic pressure, and that this phenomenon is the cause of increased adverse events associated with lower heart rate. However, this study and conclusion are subject to several sources of residual confounding, including indication bias. It is well known in cardiovascular trials that patients who require higher doses of medication are almost always those with the worst cardiovascular disease; the converse is also true. In their limitation section, the authors note that they were unable to determine the dose of beta-blocker used. However, based on the pharmacology of beta-blockers, it is highly likely that the achieved heart rate is closely correlated with the dose of beta-blocker that was required to achieve blood pressure control. In addition, many of the trials that the authors included in their meta-analysis were conducted before the era of ambulatory blood pressure monitoring, and therefore included patients with white coat hypertension, who are at low risk for cardiovascular events. In these low-risk patients, blood pressure would most likely have been controlled with a low dose of beta-blockers, and therefore they would have had higher heart rates and few cardiovascular events.
Although these potential confounding factors are difficult to test in a post-hoc fashion, the authors should have the data to answer the question of the relationship between achieved heart rate and achieved blood pressure, as well as the relationship between achieved heart rate and percentage of patients achieving goal blood pressure. If these analyses demonstrate an inverse relationship between heart rate and measures of blood pressure control, then it would suggest that the authors' findings simply reflect the fact that more difficult to control patients require higher doses of antihypertensive medication—in this case, a beta-blocker.
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Footnotes
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Please note: Dr. Phillips receives research support from King Pharmaceuticals Research and Development, Inc., and from Forest Laboratories.
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References
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1. Bangalore S, Sawhney S, Messerli FH. Relation of beta-blocker–induced heart rate lowering and cardioprotection in hypertension J Am Coll Cardiol 2008;52:1482-1489.[Abstract/Free Full Text]
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- Franz H. Messerli and Sripal Bangalore
J. Am. Coll. Cardiol. 2009 53: 2106-2107.
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