Angiotensin Receptor Blockers, Cancer, and Smoking

Concern that antihypertensive drugs might be associated with increased risk of cancer has a long history, beginning with a report that linked use of reserpine with breast cancer. That report was not supported by subsequent surveys. Case control associations have also suggested that diuretics were related to renal cancer. Calcium channel blockers had been associated with cancer, again with little support after other studies were analyzed. In the very large Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), no association was found between cancer and the three drug limbs of the trial: a thiazide-type diuretic, an angiotensin-converting enzyme (ACE) inhibitor, and a calcium channel blocker. A recent meta-analysis that reports an association between exposure to angiotensin II receptor blockers (ARBs) and increased risk for cancer, especially lung cancer, continues this research. Given the widespread use of antihypertensive drugs over long periods for so many patients, it is reasonable to continue surveillance for possible long-term risk that might not appear during the early phases of drug development, availability, and use for approved indications. ARBs with specificity for the angiotensin II type 1 receptor have become valuable, widely used, and effective therapy for hypertension and congestive heart failure (CHF). ARBs reduce activity of the renin-angiotensin system without potentiation of kinins or other mechanisms that account for the well-recognized adverse reaction, cough, that is clearly associated with ACE inhibitors. Welldesigned double-blinded trials support the conclusion that ACE inhibitor–associated cough often leads to discontinuation of ACE therapy. If continued blockade of the renin-angiotensin system is needed, particularly for treatment of CHF, switch from an ACE inhibitor to an ARB has been beneficial. A report from analysis of a large meta-analysis of ARB trials, finding a small but statistically significant association between ARB use and cancer immediately raises concern about the safety of ARBs. Does the association represent a causative mechanism or can it be explained by the limitations inherent in retrospective analysis? Could a hidden flaw account for the apparent association between ARB exposure and cancer, especially lung cancer, for which the only significant association was found. It was acknowledged by Sipahi and colleagues that their meta-analysis did not include smoking as a covariate due to lack of sufficient baseline information from the studies. This brief review will focus on the issue of smoking as a possible confounder in the ARB-cancer association because cigarette smoking is so highly linked to incidence of lung cancer. We reviewed available outcome trials in which ARBs were compared with either a placebo or an alternate therapy for baseline rates of current smoking or past smoking. The results are given in the Table. The baseline rates for current smoking varied from approximately 10% to 17% in these From the Center for Cardiovascular Health, Mount Sinai School of Medicine, New York, NY Address for correspondence: Lawrence R. Krakoff, MD, Professor of Medicine, Center for Cardiovascular Health, Mount Sinai School of Medicine, Box 1030, One Gustave Levy Place, New York NY 10029-6574 E-mail: lawrence.krakoff@mssm.edu Manuscript received July 14, 2010; accepted July 22, 2010