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Long considered a safe class of drugs, angiotensin-receptor II blockers have suddenly become investigational targets as troubling signals of increased risk of cancer and cardiovascular deaths have emerged.

First, on June 11, the Food and Drug Administration announced that it is conducting a safety review of data from two trials that showed an increased rate of cardiovascular deaths in patients with type 2 diabetes.

Then, results of a meta-analysis of randomized, controlled trials published on June 14 showed an association between ARBs and a modestly increased risk of new cancer diagnoses.

Investigators performed the meta-analysis examining cancer risk because several large ARB trials have been completed since 2003, when “an unexpected finding” of significantly higher fatal cancers in patients taking candesartan was observed, wrote Dr. Ilke Sipahi and colleagues at Case Western Reserve University in Cleveland (Lancet 2003;362:759–66).

They designed a meta-analysis of the published randomized controlled trials of ARBs to examine their effect on the occurrence of new cancers and, as secondary outcomes, specific solid-organ cancers and cancer deaths, they wrote.

The meta-analysis included studies before November 2009 in which an ARB was given in at least one group. Nine trials were included overall. Among those trials, five reported new cancer occurrence, five reported common types of specific solid-organ cancers, (i.e., lung, prostate, and breast), and eight reported cancer deaths (Lancet Oncol. 2010 [doi:10.1016/S1470-2045(10)70142-6]).

For the primary outcome of cancer recurrence, patients who were randomized to ARB treatment had a 7.2% risk of new cancer occurrence, compared with a 6.0% risk among control groups, a statistically significant increase, the authors reported. An analysis of three of the trials in which cancer was a prespecified end point also showed a significant increase in risk of cancer with ARBs, they wrote.

Because the ARB telmisartan (Micardis) was used as the study drug in 86% of the patients randomized to an ARB, the investigators conducted a meta-analysis of three of the trials looking at this drug that showed an increase in new cancer occurrence of borderline significance. Analyses looking specifically at patients on background ACE inhibitor therapy and looking at patients without concomitant ACE inhibitor treatment also showed significant increases in new cancer occurrences.

For the secondary outcome of the occurrence of specific solid-organ cancers, the “meta-analysis showed an increase in relative risk for the occurrence of new lung cancer in patients randomized to an ARB compared with controls,” the authors wrote. “This effect was also seen in the subgroup of patients who received background ACE inhibitor therapy.”

When evaluating for cancer deaths, “there was no significant difference in cancer deaths between patients randomized to ARBs and those randomized to control for the duration of the follow-up,” the authors wrote.

The clinical significance of the “modest but significant” increased risk of new cancer occurrence is unknown, the authors conceded. “The finding of a 1.2% increase in absolute risk of cancer over an average of 4 years needs to be interpreted in view of the estimated 41% lifetime cancer risk,” they wrote.

Importantly, “it is not possible to draw conclusions about the exact risk of cancer associated with each particular [ARB],” the authors stated, nor is it known whether the remaining four ARBs are associated with an increased risk of new cancers.

The mechanism for the possible increase in new cancer occurrences associated with ARBs is uncertain, the authors noted. Although experimental studies using cancer cell lines and mouse models have implicated the renin-angiotensin system in the regulation of cell proliferation, tumor growth, angiogenesis, and metastasis, and evidence shows that both angiotensin II type-1 blockade with ARB and direct stimulation of angiotensin II type-2 are capable of stimulating tumor angiogenesis in vivo, “the relevance of these observations in human malignancy is largely unknown.”

In an accompanying editorial, Dr. Steven Nissen said that the meta-analysis has its strengths, particularly its size, the thoroughness of the literature search, and the application of appropriate filters to exclude potentially unreliable data, but “there are also important weaknesses, which the investigators acknowledge—including the post hoc nature of this investigation and the fact that the trials were not designed to explore cancer outcomes.

The study also raises crucial drug safety questions for practitioners and regulators, such as whether we should be concerned about all ARBs or only telmisartan, how this uncertainty can best be resolved, and what actions practitioners should take while this concern undergoes further examination and analysis, he said (Lancet Oncol. 2010 [doi:10.1016/S1470-2045(10)70142-X]).

Until regulators review and report the possible link between ARBs and cancer, “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 [ACE] inhibitors. ARBs can be reserved for patients with intolerance to ACE inhibitors,” suggested Dr. Nissen, chair of cardiovascular medicine at the Cleveland Clinic.

He added that selective use of ARBs will also save money, “since nearly all ARBs are proprietary while ACE inhibitors are generic.”

“This is a disturbing report about a very popular and well tolerated class of antihypertensive drugs that will likely have a chilling effect on the use of these agents,” said Dr. John Flack, professor of medicine and physiology and chairman of the department of internal medicine at Wayne State University, Detroit. However, “although there seems to be a signal of modestly increased cancer risk, as well as data suggesting biological plausibility, there is also an issue of competing risks. In selected patients, such as those with diabetic nephropathy, there is risk reduction associated with using these agents,” he said in an interview.

However, given the significant limitations of meta-analyses in attempting to determine causality, Dr. Flack is not inclined to stop using ARBs. “Does it or should it cause ARBs to be used only in ACE intolerant patients? Maybe. An obvious next step would be to try and determine the association of ACE inhibitors, which mechanistically work in the RAS system, with cancer risk,” he said.