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20 July 2011
An FDA meta-analysis of 31 randomised controlled trials found that treatment with an angiotensin-2 receptor antagonist (A2RA) does not increase the risk of cancer.
Level of evidence:
Level 1 (good quality patient-oriented evidence) according to the SORT criteria.
Action
This meta-analysis provides reassurance that the use of A2RAs is not associated with an increased risk of cancer. However, when a renin-angiotensin system (RAS) drug is indicated, ACE inhibitors, not A2RAs, remain the usual first-line choice. The major benefit of A2RAs over ACE inhibitors is a slightly lower rate of cough. Hence, A2RAs are an alternative where a RAS drug is indicated, but an ACE inhibitor has to be discontinued because of an intolerable ACE inhibitor-induced cough.
What is the background to this?
In July 2010, the FDA initiated a safety review of A2RAs following a meta-analysis which reported a small but statistically significant increase in the risk of cancer with A2RAs. This meta-analysis by Sipahi, et al (see MeReC Rapid Review No. 1525) found that A2RAs were associated with a modest increase in the risk of new cancer occurrence compared with controls (7.2% vs. 6.0%, relative risk [RR] 1.08, 95% confidence interval [CI] 1.01 to 1.15, P=0.016) when five randomised controlled trials [RCTs] were analysed (n=61,590).
What does this study claim?
The FDA meta-analysis of 31 RCTs included 84,461 patients randomised to A2RAs and 71,355 patients randomised to non-A2RA comparators, with an average follow-up of 39 months. It found no evidence of an increased risk of cancer with A2RAs. The rate of incident cancer events was 1.82 per 100 patient-years in the A2RA group and 1.84 per 100 patient-years in the non-A2RA comparator group (RR 0.99, 95%CI 0.92 to 1.06).
There was also no evidence of an association between A2RAs and cancer-related death (RR 1.04, 95% CI 0.96 to 1.13), breast cancer (odds ratio [OR] 1.06, 95% CI 0.90 to 1.23), lung cancer (OR 1.07, 95% CI 0.89 to 1.29), or prostate cancer (OR 1.05, 95% CI 0.95 to 1.17).
So what?
The FDA have concluded that, based on their review and analysis of all currently available data regarding this potential safety signal, treatment with an A2RA does not increase the risk of cancer.
The FDA study is the largest meta-analysis of clinical trials exploring the association between A2RAs and cancer conducted to date. It included all drug sponsor-identified RCTs that met pre-specified criteria (>100 patients and >1 year duration) and included data on the occurrence of cancer or cancer death either as a pre-specified endpoint or an adverse event. The findings of the FDA meta-analysis dispute the earlier findings from the smaller meta-analysis by Sipahi, et al, and concur with results from three other studies which also do not suggest any increased risk of cancer related to the use of A2RAs. These other studies are a meta-analysis by Bangalore, et al (see MeReC Rapid Review No. 2491), a meta-analysis by the ARB Trialists Collaboration and an observational cohort study by Pasternak, et al.
An EMA review of the possible increased risk of cancer in patients taking A2RAs was also started in 2010, but no details about this have been published to date.
The FDA meta-analysis provides reassurance that the use of A2RAs is not associated with an increased risk of cancer. However, the general limitation which applies to all of these types of analyses is that these studies are relatively short, and therefore an association with an increase, reduction or no change in cancer incidence from a longer period of use cannot be determined. The MHRA’s Yellow Card scheme should be used to report potentially relevant clinical events.
When a RAS drug is indicated, ACE inhibitors, not A2RAs, remain the usual first-line choice. The major benefit of A2RAs over ACE inhibitors is a slightly lower rate of cough (with a number needed to harm [NNH] of around 30 over 56 months from the ONTARGET trial). Hence, A2RAs are an alternative where a RAS drug is indicated, but an ACE inhibitor has to be discontinued because of an intolerable ACE inhibitor-induced cough. The evidence around the use of RAS drugs has been summarised in the renin-angiotensin system drugs NPC e-learning materials and in a MeReC Bulletin from March 2010.
Further information can be found on NHS Evidence.
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