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

Abstract

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% vs1·6%, 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.

GPCRs and cancer

“…Of note, ARBs have been associated with reduced cancer occurrence in patients with essential hypertension and a longer exposure to ARBs has been related with major benefits in cancer patients [119] . Nevertheless, ARBs did not show the ability to reduce considerably cancer development in a meta-analysis of randomized controlled trials [120] .…”

The renin-angiotensin system meets the hallmarks of cancer

“…Also these results need to be taken with caution since beta-blockers and ACEIs were used in the control group of two out of the five trials included in this analysis; hence the results could be from a cancer-protecting effect of these two groups of RAS blockers. 42 A retrospective study analysing 287 patients with advanced non-small-cell lung cancer undergoing first-line platinum-based chemotherapy to examine the use of longterm medication with ACEI and ARB found that patients receiving ACEIs/ARBs had a remarkable estimated survival advantage of 3.1 months (HR 0.56, p = 0.03). 43 Similar data have been observed in other types of cancer.…”

Does Outcome Reporting Bias “Cause” Cancer? Risks Associated with Hidden Data on Angiotensin Receptor Blockers

“…They found no significant increase in the risk of cancer in the ARB treatment group (Table 2). Comparison of the analyses by Sipahi and others 2 and by the ATC 3 reveals a striking difference in the raw numeric data for cancer outcomes from 5 trials that were included in both meta-analyses: LIFE, ONTARGET, PROFESS, TRAN-SCEND, and TROPHY. This difference was due to the exclusion from the ATC analysis 3 of patients with known cancer at baseline.…”

“…For VALIANT and Val-HeFT, only cancer-related mortality was reported in the final publications, and CHARM did not differentiate between benign and malignant neoplasms when reporting outcomes. [1][2][3] Therefore, none of these trials were included in the primary outcome of the meta-analysis by Sipahi and others. 2 However, for the ATC analysis, 3 the incidence of cancer for all of these trials (VALUE, VALIANT, Val-HeFT, and CHARM) was made available and was included in the pooled analysis.…”

“…1 Subsequently, 3 meta-analyses have been published pooling different combinations of outcome data (see publication timeline in Figure 1). In June 2010, Sipahi and others 2 published a meta-analysis of 5 trials, with a total of 61 590 patients, implicating ARBs as a class associated with an increased incidence of cancer (OR 1.08, 95% CI 1.01-1.15) over an average 4-year follow-up. In April 2011, another metaanalysis, covering 15 trials with a total of 134 000 patients and published by the ARB Trialists Collaboration (ATC), reported no statistically significant difference in the incidence of cancer in the ARB treatment group (OR 1.00, 95% CI 0.95-1.04).…”