As reported by Cardiovascular Business, June 16, 2010.

Experts Clash on ARBs Potential Link to Cancer

By Kaitlyn Dmyterko

Angiotensin-receptor blockers (ARBs) are commonly administered as a treatment to high-blood pressure, heart failure (HF) and other complex patient conditions and have been shown to reduce incidence of stroke, MI and HF. However, a new analysis featured in Lancet Oncology this week suggests that the use of these drugs may increase the rates of new cancers in patients by 8-11 percent.

The analysis pooled data from nine randomized controlled trials that were published before November 2009, had a follow-up of at least one year and included at least 100 patients. The researchers assessed whether or not the use of ARBs affected cancer occurrence.

Today, the ARB market consists of seven FDA-approved drugs: olmesartan, telmisartan, losartan, candesartan, valsartan, irbesartan and eprosartan. However, the studies in the Lancet analysis focused mainly on the assessment of telmisartan (Micardis; Boehringer Ingelheim), losartan (Cozaar; Merck) and candesartan (Atacand; AstraZeneca).

The study's lead author, Ilke Sipahi, M.D., of the University Hospitals Case Medical Center in Cleveland, told Cardiovascular Business News that the ONTARGET trial (25,620 patients) showed a “statistically significant excess in cancers” in patients who received the ARB candesartan plus an ACE inhibitor compared to those administered an ACE inhibitor alone.

And, when examining the LIFE trial, which administered losartan to 9,193 patients, researchers found a "statistically significant excess in lung cancer," while the CHARM-Overall trial, which administered candesartan to 7,599 patients, showed an increase in the risk of fatal cancers, Sipahi said in an interview.

However, William B. White, M.D., president-elect of the American Society of Hypertension (ASH), told Cardiovascular Business News, “The analysis was not definitive and that it actually asks more questions than it gives answers.

“You have to be careful because this analysis is not really a comparison of one drug versus another,” said White, who also is chief of the division of hypertension and clinical pharmacology at the University Of Connecticut School of Medicine in Farmington, Conn.

White said that studies within the meta-analysis were not projected to specifically evaluate rates of cancer and that each study populations within the nine evaluated studies were “vastly different.” For example, some looked at patients with HF, some with hypertension and some with hypertension and vascular disease. “There was a lot of heterogeneity,” said White.

While Sipahi agreed that not all the trials were performed primarily to look at cancer, three trials in the analysis—LIFE, TROPHY and TRANCEND—enrolled over 40,000 patients to specifically examine cancer risk and its association with ARBs.

Additionally, Sipahi said that while the trial populations did differ, the majority of patients in the trials were in their upper 60s, were mostly white and the cohorts were “not that heterogeneous.” However, smoking status did vary from 9-21 percent across the evaluated, randomized, large-scale, clinical trials, said Sipahi.

White said that because lung cancer takes a “very long time to develop—an estimated 20-40 years—it would be highly unlikely that a drug could actually either stimulate the growth of one of these or could cause cancer.”

While Sipahi acknowledged that “cancer is a slow phenomenon, it doesn't always take 40 years to develop. People get testicular cancer at age 10 and kids have brain tumors at age three. Perhaps these drugs are increasing the growth of pre-existing tumors and they become prominent and cause symptoms that end in the clinical diagnosis of cancer.”

But, White said that the analysis “lacks clarity and that it should not be emphasized in practice at this time.” He added that ASH would not recommend that a patient stop taking ARBs or other anti-hypertension drugs because of these study findings.

Because data were pooled and not taken from individual cases, “there could be underlying confounders that could cause the problem than the actual drug itself,” explained White.

If there was a higher percentage of patients who were smokers in the cohort administered an ARB plus an ACE inhibitor, this could be the potential cause of the higher rates of lung cancers found, he said. “You have to evaluate these kinds of studies with substantial caution because of the way they are done and because of the lack of knowledge related to individual patients in their findings.”

When asked whether an analysis of the other seven FDA-approved ARBs would produce similar results, White said that they could also depict very different results because different studies often go in complete opposite directions.

During the current analysis, the ONTARGET trial, where patients were administered both ARB and ACE inhibitors, showed a higher risk of lung cancer in patients, while the PROFESS study, which administered the same ARB (telmisartan) without ACE inhibitors showed a lower incidence of lung cancer.

"Two studies using the same drug showed opposite findings…that’s why these findings are not what I would consider robust," said White. “The relative increase in cancer risk is about 1.1 percent which is a very small margin and is certainly not enough of a signal for me to say that the results are in any way definitive.”

White added that the benefits of ARBs should not be forgotten and are “absolutely well defined.” He estimated that telmisartan has the same potential as an ACE inhibitor to reduce incidence of MI and stroke, 25-27 percent and 35-40 percent, respectively.

Additionally, White said that there have been declines in the rates of HF in older patients who are administered ARBs plus ACE inhibitors. And, these reductions he said, are higher than the increased risk of cancer found within the analysis.

However, Sipahi contended that these data are concerning. Today, almost 80 million prescriptions for ARBs are administered to what he estimates to be more than 10 million patients per year. During the analysis, he and colleagues found that to cause one excess cancer case 105 patients would need to be treated with ARBs.

“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,” he said.

If ARBs were a superior class of drug that decreased mortality, MI, or stroke, than this would be a different story, but Sipahi offered that “these drugs are not superior to existing blood pressure pills. Even dummy pills can do as well as ARBs in certain patients.”

While White said that ARBs are the best tolerated class of antihypertensives, they do produce similar results as beta blockers and calcium channel blockers.

Sipahi said that further review of this data needs to be taken up with the FDA to make recommendations of the future for these drugs and how this will affect the medical community.