Elsevier

The Lancet Oncology

Volume 11, Issue 7, July 2010, Pages 627-636
The Lancet Oncology

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Angiotensin-receptor blockade and risk of cancer: meta-analysis of randomised controlled trials

https://doi.org/10.1016/S1470-2045(10)70106-6Get rights and content

Summary

Background

Angiotensin-receptor blockers (ARBs) are a widely used drug class approved for treatment of hypertension, heart failure, diabetic nephropathy, and, recently, for cardiovascular risk reduction. Experimental studies implicate the renin-angiotensin system, particularly angiotensin II type-1 and type-2 receptors, in the regulation of cell proliferation, angiogenesis, and tumour progression. We assessed whether ARBs affect cancer occurrence with a meta-analysis of randomised controlled trials of these drugs.

Methods

We searched Medline, Scopus (including Embase), Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and the US Food and Drug Administration website for studies published before November, 2009, that included any of the seven currently available ARBs. Randomised controlled trials with an ARB given in at least one group, with a follow-up of at least 1 year, and that enrolled at least 100 patients were included. New-cancer data were available for 61 590 patients from five trials. Data on common types of solid organ cancers were available for 68 402 patients from five trials, and data on cancer deaths were available for 93 515 patients from eight trials.

Findings

Telmisartan was the study drug in 30 014 (85·7%) patients who received ARBs as part of the trials with new cancer data. Patients randomly assigned to receive ARBs had a significantly increased risk of new cancer occurrence compared with patients in control groups (7·2% vs 6·0%, risk ratio [RR] 1·08, 95% CI 1·01–1·15; p=0·016). When analysis was limited to trials where cancer was a prespecified endpoint, the RR was 1·11 (95% CI 1·04–1·18, p=0·001). Among specific solid organ cancers examined, only new lung-cancer occurrence was significantly higher in patients randomly assigned to receive ARBs than in those assigned to receive control (0·9% vs 0·7%, RR 1·25, 1·05–1·49; p=0·01). No statistically significant difference in cancer deaths was observed (1·8% vs 1·6%, RR 1·07, 0·97–1·18; p=0·183).

Interpretation

This meta-analysis of randomised controlled trials suggests that ARBs are associated with a modestly increased risk of new cancer diagnosis. Given the limited data, it is not possible to draw conclusions about the exact risk of cancer associated with each particular drug. These findings warrant further investigation.

Funding

None.

Introduction

Antagonists of the angiotensin II type-1 receptor (ie, angiotensin-receptor blockers, ARBs) are a widely used class of drugs. The first ARB, losartan, was approved for clinical use in 1995, followed by six other drugs, including valsartan, candesartan, irbesartan, telmisartan, olmesartan, and eprosartan. These drugs are used for treatment of highly prevalent conditions such as hypertension, heart failure, and diabetic nephropathy.1, 2, 3 Most recently, telmisartan was approved for lowering the risk of cardiovascular events in high-risk patients who are unable to take angiotensin-converting enzyme (ACE) inhibitors. Many large, randomised controlled trials of ARBs have supported their clinical indications.4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23

Currently, there are no major safety concerns with ARBs, apart from their use in pregnancy, renal-artery stenosis, and chronic kidney disease. Although preclinical carcinogenicity studies in rats and mice have been negative,24, 25, 26 experimental studies implicate the renin-angiotensin system, particularly angiotensin II type-1 and type-2 receptors (AT1R and AT2R), in the regulation of cellular proliferation, angiogenesis, and tumour progression.27 However, clinical trials of ARBs have mainly assessed their effects on cardiovascular and renal endpoints and have usually not reported incidence of cancers. In 2003, the Candesartan in Heart failure Assessment of Reduction in Mortality and Morbidity (CHARM) programme, assessing ARBs in heart failure, reported an unexpected finding of significantly higher fatal cancers in the candesartan group than with placebo.5 Because the results of several other large ARB trials have become available since the publication of the CHARM trial, we decided to do a meta-analysis of randomised controlled trials of these drugs, to examine their effect on occurrence of new cancers. Our secondary objectives were to determine whether ARBs affect the occurrence of specific solid-organ cancers and cancer deaths.

Section snippets

Data collection

The aim of this meta-analysis was to include all publicly available data for development of cancers from randomised controlled trials of ARBs. We did systematic searches of Medline, Scopus (including Embase and several other journal groups from a wide range of disciplines), Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and the public website of the US Food and Drug Administration (FDA), through November, 2009. The search terms and other search

Results

Characteristics of the randomised controlled trials included in the analyses are summarised in table 1. Both patients and investigators were masked to treatment allocation in all trials. For the primary outcome of cancer occurrence, telmisartan was the main ARB used as the study drug (in 30 014 [85·7%] patients). There was no notable imbalance within trial groups with regard to age, sex, ethnic origin, smoking status, and history of previous cancer. Overall, very few patients had a history of

Discussion

In this meta-analysis, we found that ARBs are associated with a modestly increased risk of new cancer occurrence. To the best of our knowledge, this analysis incorporated all publicly available data on new cancer occurrence from randomised trials of ARBs. Information was from peer-reviewed publications and data posted on the FDA website, a valuable source for meta-analyses.44 A strength of this meta-analysis is the inclusion of data from randomised controlled trials only, thereby reducing the

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