Fast track — ArticlesAntihypertensive drugs and risk of cancer: network meta-analyses and trial sequential analyses of 324 168 participants from randomised trials
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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