Elsevier

The Lancet Oncology

Volume 12, Issue 1, January 2011, Pages 65-82
The Lancet Oncology

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Antihypertensive drugs and risk of cancer: network meta-analyses and trial sequential analyses of 324 168 participants from randomised trials

https://doi.org/10.1016/S1470-2045(10)70260-6Get rights and content

Summary

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.

Funding

None.

Introduction

The article by Sipahi and colleagues1 showing an increased risk of cancer with angiotensin-receptor blockers (ARBs) has once again raised questions about the association of antihypertensive drugs and cancer. The carcinogenic potential of antihypertensive drugs has been debated for more than three decades,2 ever since reports of an increased risk of breast cancer with rauwolfia derivatives in women older than 50 years.3, 4 β blockers,5 calcium-channel blockers (CCBs),6 and diuretic drugs7 have all been associated with increased cancer risk.

The debate has been fuelled by conflicting data, mostly from observational studies with inherent selection and ascertainment bias. The rate of cancer and cancer-related mortality are low, making the design of well-powered randomised trials to test the association expensive. Traditional meta-analyses are limited by only direct comparison of a few comparators. Moreover, even if an association is detected on a direct comparison analysis, the interpretation of the results is challenging because of multiplicity of testing. Additionally, in a randomised trial, monitoring boundaries can be drawn for interim analyses that can dictate whether to stop a trial (either for benefit or for futility) or not, in view of the interim results. No such analysis on cumulative data for cancer risk has been done so far.

We aimed to assess the association between antihypertensive drugs and the risk of cancer in a comprehensive analysis of data from randomised clinical trials with both direct8 and indirect (network)9 meta-analyses and trial sequential analyses (TSA).10

Section snippets

Search strategy and selection criteria

We (SB, SK, and HM) searched PubMed, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) with the terms: “angiotensin receptor blockers”, “angiotensin receptor antagonists”, “ARBs”, “angiotensin converting enzyme inhibitors”, “ACE inhibitors”, “beta blockers”, “beta-receptor antagonist”, “beta adrenergic antagonists”, “calcium antagonists”, “calcium channel blockers”, and “diuretics”, and with the names of individual medications (webappendix p 1), in human beings from 1950, to

Results

We identified 70 randomised controlled trials with 148 comparator groups that met our inclusion criteria (webappendix pp 11–16). Of the 70 trials, 62 trials were two-grouped trials and eight were three-grouped trials. Figure 1 shows the network of available treatment comparisons.

Table 1 summarises the baseline characteristics and quality analysis. The 70 trials enrolled 324 168 participants with a mean follow-up of 3·5 years (range 1–9). Webappendix pp 2–5 shows other baseline characteristics,

Discussion

The results of this meta-analysis refute a 5·0–10·0% RR increase in either cancer or cancer-related death with most antihypertensive drug classes. However, our analyses suggest an association between the ACEi and ARB combination and cancer risk. In-vitro studies have implicated both AT1-receptor blockade (such as that with an ARB) and AT2-receptor stimulation on cellular proliferation, angiogenesis, and tumour progression, thus suggesting a mechanistic basis for possible increased risk of

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