June 14th, 2010

ARBs Under Fire: Perspectives from Nissen, Yancy, and Messerli

Angiotensin-receptor blockers have been the subject of recent critical scrutiny. Last week, the FDA announced it was conducting a safety review of olmesartan. Over the weekend, the Lancet Oncology published a meta-analysis that found a small but statistically significant increase in the risk of developing new cancers in subjects taking ARBs.

The authors of the Lancet Oncology paper, led by Ilke Sipahi of Case Western Reserve University, acknowledged several important limitations of their analysis. As most of the available cancer data was for one ARB, telmisartan, it was impossible to make conclusions about individual ARBs. There was no significant difference in cancer deaths or in the incidence of individual cancers, with the exception of lung cancer, where a small but significant difference was observed.

Steve Nissen 
In an accompanying comment, Steve Nissen wrote that the meta-analysis “is disturbing and provocative, raising crucial drug safety questions for practitioners and the regulatory community. Are [ARBs] associated with increased risk of incident malignancies? Should we be concerned about all ARBs or a single drug, telmisartan? How can this uncertainty best be resolved? What actions should practitioners take while this concern undergoes further examination and analysis?”

Nissen called on regulatory authorities to initiate a thorough review of “the possible association between ARB use and cancer, and promptly report their findings.” Until then, he writes, “we should use ARBs, particularly telmisartan, with greater caution. These drugs are often overprescribed, as a result of aggressive marketing and in the absence of evidence that they are better than angiotensin-converting enzyme (ACE) inhibitors. ARBs can be reserved for patients with intolerance to ACE inhibitors. More selective use of ARBs will also save money for healthcare systems, since nearly all ARBs are proprietary and ACE inhibitors are generic.”

CardioExchange asked Clyde Yancy, the president of the AHA, and Franz Messerli, the director of the Hypertension Program at St. Luke’s-Roosevelt Hospital, to comment on the FDA safety review and the Lancet Oncology meta-analysis. Here are their remarks:

Clyde Yancy
To begin, we must quickly acknowledge that ARBs as a drug class have proven, evidence-based indications to reduce the incidence of stroke, improve outcomes post-MI, improve outcomes in heart failure, and retard the progression of chronic kidney disease. Additionally, these drugs are especially effective in ACE-intolerant patients either due to intractable cough or a prior history of angioedema. Thus, the medical community has appropriate high regard for the benefits of ARBs.

What is notable in this FDA MedWatch alert is the patient cohort being considered; that this question has been raised in a diabetic patient population is of interest. The recent ACCORD BP trial done in diabetics raised the very real concern that the extent of blood pressure lowering is an issue. In diabetic patients, the lower the blood pressure, the better … to a certain point, after which risk does emerge. What will need to be done very carefully in this FDA analysis is a careful process of review that controls for the extent of BP control. If the nadir of BP control in those treated with olmesartan is below 119 mm Hg, real risk may have been possible. Beyond that, we must always respect the play of chance in any post hoc analysis from data not prospectively acquired to address the question being pursued in the analysis.

The Lancet Oncology raises yet another question about the safety of ARBs. In a meta-analysis done by investigators at Case Western, a review of >60,000 patients exposed to one of three ARBs in five clinical trials with very disparate patient populations revealed a very modest but statistically significant increased incidence of cancer, particularly lung cancer. The incidence of death due to cancer was not different, and the risk was quite small. I have spoken with the investigators and agree with them that this finding requires very cautious interpretation. Despite a careful analysis, a statistical quirk may still be the only relevant explanation. Moreover, true biological plausibility is lacking for this observation. At best this is a question, and a question only, to be addressed in new datasets or by evaluating even more data, both published and unpublished. In the accompanying editorial by Steve Nissen, he calls for more extensive data analysis of existing datasets. Drug safety is of paramount importance to all of us, but drug paranoia must be avoided as the evidence supporting both benefit and safety is compelling for ARBs.

Overall then, ARBs are safe when used for appropriate indications and when used according to now well-refereed guidelines. Indiscriminate use of any drug should be discouraged, and the same can be said for ARBs. But no person taking these compounds at present should be hesitant about continuing therapy, and importantly any thought to discontinue therapy should be reviewed with the prescribing physician.

Franz Messerli
Ever since the use of reserpine was associated with an increased risk of breast cancer more than 50 years ago, the question of antihypertensive drugs and cancer has not come to rest. Over the past decades, beta-blockers have been associated with lung cancer, calcium blockers with cancer in general, thiazide diuretics with renal cell carcinoma and colon cancer. (Grossman, Messerli, et al. 2001. Review.) In most instances, the risk is small and not supported by biochemical, experimental, or epidemiological data. The relationship between reserpine and breast cancer is statistically significant but of little clinical concern because reserpine is no longer used. The relationship between diuretic therapy and renal cell carcinoma is supported by a variety of clinical, biochemical, and experimental data and remains of concern, particularly in women.  

Blockers of the renin angiotensin system have experienced a remarkably favorable record in this regard, ever since a retrospective study from Scotland (Lever et al. 1998) showed that the use of ACE inhibitors potentially protects against cancer. In most studies and meta-analyses, the risk of cancer with RAS blockers was either equal or lower than with their comparator, including placebo. Thus, the present study by Sipahi showing a modestly increased risk of new cancer diagnosis with ARBs is unexpected and certainly warrants scrutiny and further investigation. There is little, if any, biological plausibility that a drug exposure of only a few years would increase the risk of new cancer diagnosis. Cigarette smoking, which is one of the most powerful risk factors for lung cancer, will require 10 years or longer exposure to significantly increase lung cancer risk. Thus, it’s exceedingly unlikely that short-term drug exposure (as happens in clinical trials) of ARBs would have a clinically meaningful effect.

Unfortunately, blood pressure still remains uncontrolled in many patients and exposes them to the risk of having a heart attack or stroke. To get blood pressure to goal, we need to extensively use all available antihypertensive drug classes. The news that some of these antihypertensives potentially could cause cancer is alarming for patients who are on these drugs and could motivate them to abruptly discontinue treatment. While we cannot avoid — nor want to avoid — sharing this information with our patients, it should be done prudently.

ARBs are better tolerated than ACE inhibitors, which cause a dry cough in about 15% of all patients and much more rarely angioedema, which can be fatal. The risk of angioedema is particularly high in African-American patients, in whom ARBs therefore are often preferred. 

An apparent weakness is that the study was driven by one ARB alone — telmisartan. I do not know whether data obtained with telmisartan can be generalized to ARBs as a class. Time-to-event findings are not available, which are exceedingly important in carcinogenesis studies.

2 Responses to “ARBs Under Fire: Perspectives from Nissen, Yancy, and Messerli”

  1. Question from a fellow

    Can someone comment as to why they feel this paper has achieved such attention, both in the lay press and medical community? Even the authors admit to the small nature of the increased risk (7·2% vs 6·0%). I think also the fact that only one solid malignancy shows an increased risk to my mind as a trainee suggests this could be a statistical aberation rather than a definitive causative relationship. Is that fair?

  2. I would like to refer you to an editorial Dr Michael Bloch and I wrote in The Journal of Clinical Hypertension, September 2010, “Meta-Analysis Concludes Angiotensin Receptor Blocker Use Increases the Risk of Developing Cancer: Concerns About the Science and The Message. I think it places alot of the recent concern with lack of science on this topic.

    Jan Basile

    Competing interests pertaining specifically to this post, comment, or both:
    Speakers Bureau and Consultant for Takeda, Forest, Novartis, and Daiichi-Sankyo