The FDA fails to silence the ARB/cancer debate
The FDA conducted a safety review of ARBs last July after a meta-analysis published in the June issue of Lancet Oncology showed that ARBs could increase the rates of new cancers by 8 to 11 percent. While there are currently seven FDA-approved ARBs, the study only looked at three: telmisartan (Micardis; Boehringer Ingelheim), losartan (Cozaar; Merck) and candesartan (Atacand; Astra Zeneca).
Lead author of the meta-analysis Ilke Sipahi, MD, of the University Hospitals Case Medical Center in Cleveland, told Cardiovascular Business that “while we concluded that these drugs are associated with a modestly increased risk of cancer, if 10 million people are administered these drugs in one country, if you divide that by 105, you will see that you are potentially causing 100,000 excess cancers by preferring this medication over other medications.”
However, the data surrounding the benefits and risks of ARBs continue to clash. While previous data have shown that certain ARBs could reduce the risk of MI and stroke, Sipahi said that ARBs may not be all that much better than other blood pressure pills.
To further examine the link between cancer and ARBs, FDA conducted a trial-level meta-analysis of clinical trials that included patients randomized to an ARB treatment and those who were randomized to a non-ARB treatment. The analysis included 31 trials and more than 156,000 patients, greater than the 62,000 patients within the previous analysis conducted by Sipahi et al.
The agency concluded that ARB medications are not associated with an increased risk of cancer, cancer-related death, breast cancer, lung cancer or prostate cancer. Within the 31 trials analyzed, 84,461 patients received ARBs and 71,355 patients received non-ARB comparators. The average follow-up was 39 months.
However, Sipahi called the FDA analysis "unsatisfactory," because the agency did not fully examine the relationship between cumulative exposure to ARBs and cancer risk. He said that this is the most important factor when one is examining the risk of cancer with drug therapy or other environmental agents, like radiation.
Compared with Sipahi and colleagues who found that 105 patients would need to be treated with ARBs to cause one excess case of cancer, the FDA reported the rate of incident cancer events in the ARB group to be 1.82 per 100 patient-years. This rate in the non-ARB comparator group was 1.84 per 100 patient-years.
The FDA reported the relative risk of patients taking ARBs to be 0.99.
Sipahi called the agency's analysis incomplete due to the fact that the agency only conducted a trial-level examination rather than a patient-level analysis. He said that a trial-level assessment "does not enable the investigation of the cumulative exposure-risk relationship." He called the FDA's approach "surprising," particularly because the agency has the authority to collect individual patient data from industry sponsors of the trials.
“The FDA has completed its review of controlled trial data on more than 155,000 patients randomized to ARBs or other treatments--the largest evaluation of such data to date--and finds no evidence of an increased risk of cancer in patients who take an ARB,” said Mary Ross Southworth, PharmD, deputy director for safety in the Division of Cardiovascular and Renal Drugs in the FDA’s Center for Drug Evaluation and Research.
However, Sipahi rebutted saying that the FDA review mixed data from previous trials with high levels of cumulative-exposure to ARBs for long durations (ONTARGET, TRANSCEND and LIFE trials that showed excess cancer risk) with low exposure trials that used lower doses of ARBs, had high non-compliance rates to the study drugs or had shorter follow-ups and did not show a cancer risk. Sipahi argued that the "dilution of the data in this manner makes the excess cancer risk for ARBs disappear."
While data are still contradictory, the FDA said that it is has "determined that any concern about a relationship between ARB use and development of cancer has been resolved by this analysis." However, Sipahi offered that the new data from the DIRECT trial, which administered a high dose ARB (32 mg of candesartan) for five years, showed a "statistically significant excess in cancers with the ARB," similar to other high-exposure trials.
Sipahi implored the FDA to conduct a detailed patient-level analysis to assess the exposure-risk relationship and cancer risk with each particular ARB. Additionally, he said that the excess cancer risk must be clarified first before one can begin to determine the benefits of the drug class. Sipahi concluded that the agency has done an "unsatisfactory job so far defining the cumulative exposure cancer risk relationship with ARBs. Only a patient-level analysis of the existing data looking at whether there is an increase in cancer with an increase in exposure--higher dose and duration of exposure--will clarify these remaining questions.”
The FDA has recommended that physicians report any adverse events to their MedWatch program. A full list of approved ARBs is available here.