Angiotensin receptor antagonists and increased risk of cancer. Further evidence against

The fear that drugs chronically administered for the treatment of hypertension and other cardiovascular diseases might increase the risk of cancer has surfaced several times in the past, particularly in relation to the use of diuretics [1–3]. Although no conclusive evidence has ever been obtained, the issue has again gained momentum a few months ago, this time in relation to angiotensin receptor antagonists, which have been reported to be associated with an increased risk of cancer in a meta-analysis of some trials comparing angiotensin receptor antagonists with other antihypertensive drug use [4]. The alarm generated in public opinion by these results was attenuated in the following months by the understanding that the claimed carcinogenic effect of angiotensin receptor antagonists was based on a number of patients and trials that incompletely and insufficiently represented the large body of evidence collected in the recent past with these drugs in a variety of cardiovascular diseases [5–11]. More importantly, other results and meta-analyses were published in which the incidence and risk of cancer was found to be similar for several angiotensin receptor antagonists and other antihypertensive drugs [2,12,13] confining the risk of carcinogenity associated with their continuing use to an unlikely possibility. This possibility is made even more unlikely by the results of a new meta-analysis published in this issue of the Journal of Hypertension[14]. This is because this meta-analysis has scientific merits that make its conclusion particularly solid. One, the number of trials and patients included amounted to about 140 000, which makes it one of the most comprehensive insights to this issue ever performed. Two, the database includes all major angiotensin receptor antagonists, and its size is particularly large for telmisartan, which allows a rebuttal of the hypothesis of a specific carcinogenic effect of this drug advanced in the original meta-analysis, but based, however, on a limited amount of data [4]. Three, the results show not only a similar incidence of cancer for patients treated with angiotensin receptor antagonists, angiotensin-converting enzyme (ACE) inhibitors or drugs other than blockers of the renin–angiotensin system (RAS), but it also shows that no increased risk exists when combined angiotensin receptor antagonist-ACE inhibitor treatment is employed, an issue that had been left somewhat undecided in a previous meta-analysis in which the combined blockade of the RAS obtained by concomitant use of an angiotensin receptor antagonist and an ACE inhibitor was reported to modestly but significantly increase the risk of cancer compared with use of either RAS blocker in monotherapy [13]. Four, the large database provides a reliable conclusion also with regard to the uniform absence of an increased risk for some of the most common cancer types (breast, prostate and lungs), refusing the original claim of a selectively marked increase in the risk of lung cancer with angiotensin receptor antagonists. Furthermore, and perhaps most importantly, this meta-analysis was based on methodological requirements that add to the reliability of the identified events. Just to quote a few, information on cancer was obtained systematically in all trials, in some instances with access to individual data. Also, in most trials, the diagnosis was centrally adjudicated (based on prespecified criteria and often with the availability of bioimaging and microscopic examinations), a central adjudication being the rule also in the remaining trials as far as fatal cancers or cancers requiring hospitalization were concerned. Finally, information was also available from all trials on the high rate of compliance to treatment (70% or greater), which ensures that the vast majority of the patients made use of the drugs throughout the treatment period. This is highly relevant to the results because compliance to treatment is notoriously low in patients with cardiovascular disease, particularly in hypertension [15,16]. We can, thus, safely conclude that current evidence by no means indicates any risk of cancer associated with use of angiotensin receptor antagonists, which patients can continue to take for their documented antihypertensive efficacy, cardiovascular protection and good tolerability profile [16,17]. This conclusion reflects in the clinical setting the absence of any mechanistic evidence of carcinogenicity in pathophysiological studies on experimental animals, which rather suggest that blockade of the angiotensin II effects may slow down tumor progression [18], possibly because of the favourable influence of this substance on tissue growth, vessel formation and cell replication [19–23]. The happy end of the angiotensin receptor antagonists-cancer story deserves two further comments of more general nature. The first comment concerns the rules scientific Journals should adopt when dealing with information on crucial public health issues that are going to have a worldwide echo, raise alarm and perhaps lead to immediate reactive action by health authorities. As discussed in the paper that is the object of this Editorial [14], the need of ‘full disclosure’ should be balanced by the one of releasing the information only if scientifically solid. We have seen in recent years several breaches of this rule (possibly originated by the desire to enhance the journal visibility and citation rate), which can hardly be balanced by the addition of a soul-saving critical Editorial. The second comment is the documented long delay (10 or more years) between exposure to a carcinogenic substance (smoking, asbestos, radiation, etc.) and the actual manifestation of an increased risk of cancer [24–26]. As properly acknowledged by the authors of the present meta-analysis [14], this makes all current trials on antihypertensive drugs unsuited to provide a final word on the issue, given that their duration rarely exceeds 5 years. Large-scale, long-term studies will, thus, have to be performed to properly address this important question, keeping in mind that their nature will probably have to be observational because trials with a controlled design can hardly be run over such long periods. This concerns, however, not just angiotensin receptor antagonists or antihypertensive drugs but the many drug treatments used in medicine, the efficacy of which is usually decided on the basis of controlled trials lasting only few years.