Is There an Increased Cancer Risk Associated With the Use of Angiotensin Receptor Blockers and Should It Affect Current Prescribing?

A recent meta‐analysis published in The Lancet Oncology by Sipahi and colleagues proposed that angiotensin receptor blockers (ARBs) are associated with a modest increased risk of new cancer diagnosis. ¹ This publication has raised several thought‐provoking questions.

ARBs are generally regarded as a safe class of antihypertensive drug, with precautions reserved for pregnant women and patients with renal artery stenosis and severe chronic kidney disease. Preclinical carcinogenicity studies using ARBs in rats and mice have been negative. ARBs result in antagonism of the angiotensin (Ang) II type 1 receptor with unopposed stimulation of the Ang type 2 receptor. Experimental studies have shown that Ang II type 1 and 2 receptors have been implicated in the regulation of cellular proliferation, angiogenesis, and tumor progression ² ; thus, a theoretic basis for neoplasia is present.

Studies with ARBs have mainly assessed the effects on cardiovascular and renal end points and have not focused on cancer risk or diagnosis. However, the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) study ³ and, more recently, the Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET)⁴ and Telmisartan Randomized Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease (TRANSCEND) ⁵ studies have shown an unexpected increase in cancer diagnoses. Based on these data, Sipahi and associates decided to conduct a meta‐analysis of the randomized controlled trials with ARBs to examine the effects on occurrence of new cancers and to determine whether ARBs affect the occurrence of specific solid organ cancers and cancer deaths.

Randomized controlled trials using an ARB published before November 2009 with at least 1 year of follow‐up and including at least 100 participants were included in the meta‐analysis. New cancer data were available for 61,590 patients from 5 trials. The 5 trials with new cancer data included ONTARGET, Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS), Losartan Intervention for Endpoint Reduction in Hypertension (LIFE), TRANSCEND, and CHARM‐Overall. ³ , ⁴ , ⁶ , ⁷ Only 3 of the 7 Food and Drug Administration (FDA)–approved ARBs (telmisartan, losartan, and candesartan) were included in the meta‐analysis. A total of 30,014 (85.7%) patients in the meta‐analysis received telmisartan. The main findings in the Sipahi report were an increased risk of new cancer diagnosis compared with controls (7.2% vs 6.0%; risk ratio, 1.0; P=.016), but only new lung cancer was significantly higher in patients receiving ARBs (0.9% vs 0.7%; risk ratio, 1.25; P=.01). Putting these findings into a rough perspective, 143 patients would need to receive an ARB for 4 years for there to be one excess cancer diagnosis.

How should the practicing physician interpret these findings? We suggest that one must consider these data with some caution because (1) cancer risk and diagnosis (and the protocol‐specified methods to achieve uniform diagnosis) were not the primary purpose of any of these studies; (2) sex, age, and smoking status could not be examined as such data were not available; and (3) telmisartan was used in 85% of all patients and data are not available for most of the marketed ARBs. Based on this meta‐analysis we would NOT suggest either stopping an ARB in any patient, nor switching to another FDA‐approved ARB until a fuller picture of the class is established.

We propose this approach for now because this is not the first time antihypertensive drugs and cancer risk have made the news, nor is it likely to be the last. In 1974, reserpine was reported to be associated with an increased risk of breast cancer, ⁸ which was subsequently found not to be the case. Diuretics were reported to have an increased risk of renal cell cancer in women and colon cancer in both sexes, ⁹ , ¹⁰ which was subsequently not borne out. Atenolol has also been reported to be associated with increased risks of malignancy. Calcium channel blockers have contradictory data, with some studies showing no increased risk of malignancy while others purport an increased risk of breast cancer. ¹¹ , ¹² Angiotensin‐converting enzyme inhibitors were suspected to show an increased risk of malignancy in some studies and yet thought to be protective against malignancy in other studies.

Taking into account this study ¹ and prior data, we have not changed our prescribing habits and are waiting until we have more information on the “real” cancer risk of this class of drugs. A reasonable level of vigilance is necessary when prescribing anything; however, common sense needs to be in the balance, too. There remain several unresolved aspects in this drama, and we suggest watching it unfold further and considering more evidence before rushing to a verdict.