Antihypertensive drugs and risk of cancer: network meta-analyses and trial sequential analyses of 324168 participants from randomised trials

Background The risk of cancer from antihypertensive drugs has been much debated, with a recent analysis showing increased risk with angiotensin-receptor blockers (ARBs). We assessed the association between antihypertensive drugs and cancer risk in a comprehensive analysis of data from randomised clinical trials. Methods We undertook traditional direct comparison meta-analyses, multiple comparisons (network) meta-analyses, and trial sequential analyses. We searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials from 1950, to August, 2010, for randomised clinical trials of antihypertensive therapy (ARBs, angiotensin-converting-enzyme inhibitors [ACEi], beta blockers, calcium-channel blockers [CCBs], or diuretics) with follow-up of at least 1 year. Our primary outcomes were cancer and cancer-related deaths. Findings We identified 70 randomised controlled trials (148 comparator groups) with 324168 participants. In the network meta-analysis (fixed-effect model), we recorded no difference in the risk of cancer with ARBs (proportion with cancer 2.04%; odds ratio 1.01, 95% CI 0.93-1.09), ACEi (2.03%; 1.00, 0.92-1.09), beta blockers (1.97%; 0.97, 0.88-1.07), CCBs (2.11%; 1.05, 0.96-1.13), diuretics (2.02%; 1.00, 0.90-1.11), or other controls (1.95%, 0.97, 0.74-1.24) versus placebo (2.02%). There was an increased risk with the combination of ACEi plus ARBs (2.30%, 1.14, 1.02-1.28); however, this risk was not apparent in the random-effects model (odds ratio 1.15, 95% CI 0.92-1.38). No differences were detected in cancer-related mortality for ARBs (death rate 1.33%; odds ratio 1.00, 95% CI 0.87-1.15), ACEi (1.25%; 0.95, 0.81-1.10), beta blockers (1.23%; 0.93, 0.80-1.08), CCBs (1.27%; 096, 0.82-1.11), diuretics (1.30%; 0.98, 0.84-1.13), other controls (1.43%; 1.08, 0.78-1.46), and ACEi plus ARBs (1.45%; 1.10, 0.90-1.32). In direct comparison meta-analyses, similar results were recorded for all antihypertensive classes, except for an increased risk of cancer with ACEi and ARB combination (OR 1.14, 95% CI 1.04-1.24; p=0.004) and with CCBs (1.06, 1.01-1.12; p=0.02). However, we noted no significant differences in cancer-related mortality. On the basis of trial sequential analysis, our results suggest no evidence of even a 5-10% relative risk (RR) increase of cancer and cancer-related deaths with any individual class of antihypertensive drugs studied. However, for the ACEi and ARB combination, the cumulative Z curve crossed the trial sequential monitoring boundary, suggesting firm evidence for at least a 10% RR increase in cancer risk. Interpretation Our analysis refutes a 5.0-10.0% relative increase in the risk of cancer or cancer-related death with the use of ARBs, ACEi, beta blockers, diuretics, and CCBs. However, increased risk of cancer with the combination of ACEi and ARBs cannot be ruled out.