Evidence published earlier this year found that angiotensin-receptor blockers (ARBs), a drug class commonly prescribed to treat hypertension and sometimes cardiovascular events, may have the potential to increase the rates of new cancers by 8 to 11 percent. Here, the experts face off, arguing about whether ARBs are an effective drug class or whether this excess risk of cancer should cause concern.

Participants:

•  Sverre E. Kjeldsen  MD, PhD, Chief Physician at the Ullevaal University Hospital in Oslo, and Adjunct Professor of Medicine at the Division of Cardiovascular Medicine at the University of Michigan, Ann Arbor
•  FDA Representative  Mary Ross Southworth, PharmD, Deputy Director for Safety, FDA’s Division of Cardiovascular and Renal Drugs
•  Ilke Sipahi  MD, Assistant Professor of Cardiovascular Medicine at University Hospitals Case Medical Center in Cleveland, and lead author of the Lancet Oncology meta-analysis

The meta-analysis, published in Lancet Oncology, pooled data from nine randomized controlled trials on ARBs and focused mostly on three of the seven FDA-approved ARBs: telmisartan (Micardis; Boehringer Ingelheim), losartan (Cozaar; Merck) and candesartan (Atacand; AstraZeneca). While these data portray ARBs in a rather negative light, a meta-analysis launched by the FDA in response to this Lancet Oncology analysis found no association between cancer and ARBs. Previously, ARBs have been shown to reduce hospital admissions and may be superior to ACE inhibitors to prevent stroke. However, the potential risk of cancer would obviously be problematic. While many backers say the cancer risk is unfounded and stand behind the drugs as a first-rate option to help reduce hypertension and cardiovascular disease, Sipahi and colleagues argue that safer, more effective drugs are out there that work just as well, or better than ARBs. Is this still an ongoing debate or did the FDA's meta-analysis silence the issue?

Q: ARBs are commonly prescribed to lower blood pressure, but what have the data shown about their benefits?

 Sipahi  TRANSCEND, a placebo-controlled trial, which sought to determine whether telmisartan reduced cardiovascular events, showed no statistically significant reduction in cardiovascular events. There was no reduction in MIs and the primary endpoint was not met. I would disagree with the claim that ARBs reduce cardiovascular events in patients at a high-risk of cardiovascular disease. While ARBs have the ability to reduce heart failure mortality, they have never been shown to reduce MIs, arguably the most important cardiovascular event. Despite these facts, the FDA has approved telmisartan for the reduction of cardiovascular risk. Additionally, ARBs are not superior to ACE inhibitors for the prevention of stroke like some have previously thought. While ARBs may be equivalent to ACE inhibitors for reducing stroke, they have absolutely no effect on MIs.

Annual Medicaid Claims & Expenditures for ACE Inhibitors & ARBs: 1991-2008
Year	Expenditures	ARB/ Spending %	ARB/ Claim $
1991	$179,228,516	0.0%
1992	$236,948,154	0.0%
1993	$270,943,988	0.0%
1994	$281,378,322	0.0%
1995	$312,848,726	0.4%	$38.24
1996	$296,581,719	2.0%	$41.10
1997	$312,588,794	8.7%	$43.72
1998	$365,062,415	15.3%	$46.00
1999	$438,141,415	20.4%	$48.37
2000	$530,752,819	25.5%	$50.73
2001	$678,945,950	28.7%	$53.18
2002	$804,525,700	33.7%	$55.59
2003	$898,430,207	41.6%	$58.78
2004	$1,001,525,549	46.6%	$62.18
2005	$1,000,142,045	51.5%	$65.51
2006	$390,270,946	46.0%	$61.36
2007	$368,784,282	57.7%	$84.33
2008	$309,842,354	65.1%	$81.98
Source: J Manag Care Pharm 2010;16[9]:671-679.

 Kjeldsen  ARBs were the first drugs to treat hypertension. The previously published VALUE trial, which tested the efficacy of valsartan to reduce cardiac morbidity and mortality in hypertension patients at a high cardiovascular risk, showed that ARBs were just as effective as amlodipine (Norvasc, Pfizer) (Hypertension 2006;48:385-391). Previous meta-analyses all have concluded that ARBs are as equally effective as other drugs (calcium-channel blockers [CCBs], ACE inhibitors and beta-blockers). Additionally, ARBs have a better tolerability and are preferred by both physicians and patients.

Q: Explain the 8 to 11 percent increased risk of new cancers found in the Lancet Oncology meta-analysis.

 Sipahi  Two hundred million people are administered ARBs globally. Our calculations show that ARBs cause one excess cancer in every 105 patients treated (Lancet Onc 2010;11[7]:627-636). This means that about two-and-a-half million excess cancers are caused globally by this drug class every four years. This is an incredible number. There is a lot at stake here, and this issue cannot be dispersed by a trial-level meta-analysis. We must research this issue more carefully or we have the potential to cause many excess cancers by preferring these drugs over others that work just as effectively, or more effectively, than ARBs. We also found that the cancer risk was increased with adequate exposure to the drugs—at least three years on the maximum daily tolerated doses.

 Kjeldsen  Sipahi et al did not include all possible ARB trials in the meta-analysis. When we included data from the VALUE trial, we found no difference in cancer incidence between ARBs and other treatments. VALUE compared outcomes of an ARB and calcium-channel blocker in hypertensive patients at a heightened risk of cardiovascular disease. We found that 510 of the 7,649 cases of cancer were reported with the ARB valsartan (Diovan, Norvartis) compared with 591 of the 7,669 cases of cancer with the CCB amlodipine. The 15,245 patients were followed for several years. These results argue against the increased cancer risk that Sipahi et al found. If the VALUE results were appropriately included in meta-analysis, the event numbers become 1,870 of 24,146 (7.7 percent) vs. 1,853 of 24,123 (7.7 percent), clearly showing no difference in cancer between ARBs and control therapies. Also, no agent is capable in causing cancer in such a short period of time, not even smoking.

 FDA  Sipahi et al's meta-analysis concluded that ARBs were associated with a small increased risk of cancer. Although the increased risk of cancer estimated by Sipahi et al was small, when that small percentage is multiplied by the millions of patients who take these drugs, the number of excess cancers is large. This is the reason that we analyzed this potential safety signal further. The FDA's large meta-analysis, which included data from 31 trials and 156,000 patients, found that the rate of cancer events was essentially the same in patients treated and not treated with ARBs, 1.82 per 100 patient-years in the ARB group and 1.84 per 100 patient-years in the non-ARB group.

Q: Regarding the FDA's review, were the results sufficient and will the analysis silence this debate?

 Sipahi  The FDA's investigation of ARBs lasted 10 months and unfortunately, the agency performed a very superficial and incomplete review. Cancer risk is observed only in trials where ARBs were administered at a high-dose and for longer durations of time. Results of the DIRECT trial, which were not included in our meta-analysis, showed a 69 percent increase of cancer when candesartan was administered in diabetic patients. Despite these types of results, the FDA's meta-analysis included trials with a low exposure and short follow-up of just one year. Thus, they diluted the data and were able to mask the excess risk of cancer.

 Kjeldsen  The FDA and the European Medical Association both came to the same conclusion—that ARBs do not cause an excess of cancer. This debate should end, as it is no longer an issue.

 FDA  Based on the analysis by Sipahi et al, there was never any reason to suspect that ARBs actually cause cancer. It would require many years to detect tumors that are newly formed; the concern raised by Sipahi et al's analysis was that ARBs increase the speed of tumor growth. However, this did not prove to be the case. Our analysis included only trials that had a follow-up of at least one-year, a reasonable amount of time to assess a drug as a cancer promoter. We consider our analysis to be more comprehensive than that of the one published in Lancet Oncology. We have no further plans to conduct additional analyses.

Q: What is the next step? Is more research necessary?

 Sipahi  More clinical trials are no longer necessary; what is needed is individual patient-level data. The FDA needs to revert back to the TRANSCEND and ON-TARGET trials to investigate when excess cancers occured. If the cancer risk is increased with increased exposure, this will be the smoking gun for the FDA to say that ARBs are actually causing cancer. The agency will need to go back to these longer duration trials and look at the exposure risk relationship, which they have not done.

 Kjeldsen  We certainly do not need any further studies to investigate this non-finding.

 FDA  The results of the trial-level meta-analysis are sufficient to demonstrate that the rate of events per person-year is similar in ARBs versus comparators. Had we found evidence of excess tumors in the ARB group, we would have conducted additional analyses.

While data are conflicting as to whether ARBs are superior to other agents in terms of preventing stroke and reducing cardiovascular events, will this potential risk of cancer lead physicians to stop administering this drug class to hypertensive and other patient populations? Sipahi argues that a patient-level analysis is needed to assess the exposure-risk relationship and cancer risk with each ARB. This must be clarified before we can look at the benefits of the drug class.