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], β 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 324,168 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), β 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), β blockers (1·23%; 0·93, 0·80-1·08), CCBs (1·27%; 0·96, 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, β blockers, diuretics, and CCBs. However, increased risk of cancer with the combination of ACEi and ARBs cannot be ruled out.