Trials of New Cancer Drugs Failing to Address Potential CV Risks

Clinical trials supporting US Food and Drug Administration approval of new anticancer treatments—such as biologic, targeted, or immune-based therapies—over the past several decades seem to have underreported cardiovascular events, complicating risk-benefit considerations when initiating treatment.

A review of 189 phase II and III trials of 123 therapies showed that rates of MACE and any CVD events were consistently lower when compared with population rates obtained through the Multi-Ethnic Study of Atherosclerosis (MESA), according to lead author Janice Bonsu, MPH (The Ohio State University Medical Center, Columbus, OH), and colleagues.

In fact, slightly more than half of the trials (51.3%) didn’t report any MACE events and more than one-third (37.6%) didn’t report a single CVD event.

Senior author Daniel Addison, MD (The Ohio State University Medical Center), noted that the issue wasn’t confined to any one drug class or cancer type, indicating a general lack of awareness that anticancer therapies can come with a heightened risk of cardiovascular complications.

“That creates its own problems because if we don’t really know truly what the rate is with those drugs when [they] come to patients and come to commercial or clinical use, we really don’t have a good basis to know truly what we should expect,” Addison told TCTMD.

“Clinical trialists who study these drugs and pharmaceutical companies should be more aware that heart events actually can happen,” he said. “They’re not just isolated to anthracyclines or radiation, but rather they can happen with many or most of the new drugs in some form.”

What might help, Addison added, is involving a cardiologist, particularly a cardio-oncologist or another physician with that type of training, in cancer trials to improve adjudication of cardiovascular events.

‘A Bit Sobering’

For the study, published online ahead of the February 18, 2020, issue of the Journal of the American College of Cardiology, the investigators reviewed data from trials that supported FDA approval of new anticancer therapies for adults between January 1998 and June 2018. The trials included 97,365 participants (median age 61; 46.0% women). Nearly three-quarters were treated with biologic, targeted, or immune-based therapies.

During a median follow-up of 30 months, MACE (MI, stroke, heart failure, coronary revascularization, A-fib, or CVD death) occurred in 792 patients in the intervention arms of the trials and 356 in the control arms (P < 0.01).

When trials that excluded patients with baseline CVD were left out of the analysis, the average incidence of MACE in the trials was 542 per 100,000 person-years, much lower than the rate of 1,408 per 100,000 person-years seen in the population-based cohort (P < 0.001). CVD event reporting lagged behind the cancer trials even when those that allowed patients with baseline heart disease were included.

That indicates, according to Nanette Bishopric, MD (MedStar Heart and Vascular Institute, Georgetown Lombardi Comprehensive Cancer Center, Washington, DC), that the cardiovascular risks of many of the newer cancer therapies are not really known.

Part of the issue is that the pharmaceutical companies, in seeking a clean trial result to establish the efficacy of a new anticancer agent, will exclude patients with significant comorbidities like CVD, commented Bishopric, who wrote an accompanying editorial with Marc Lippman, MD (Georgetown Lombardi Comprehensive Cancer Center). “When you eliminate cardiovascular risk factors or cardiovascular disease from your trial population, you’re not treating a true cross section of the population.”

That minimizes the trials’ value in terms of informing the medical community about the expected cardiovascular risks, which is “a bit sobering, and it’s a reminder that we still have a lot of work to do to assess cardiac risk and cardiovascular risk for these wonderful new drugs,” Bishopric said.

While the primary goal of these studies is to assess the impact of the intervention on cancer, “I think there needs to be a way to do follow-on studies at least or parallel studies addressing the question of cardiovascular risks,” she said, pointing out that if these treatments can effectively suppress the malignancy then they are creating a new population of patients who will potentially die of cardiovascular disease. That will be particularly important for cancer types that either progress slowly or respond well to current treatments, she added.

It’s likely that multicenter consortia with centralized data collection will be needed to truly assess cardiovascular risks of new anticancer drugs, Bishopric said, citing the TIMI group as a model that can be followed. “It needs to be a consortium because no one center is going to collect enough cases to get incidence rates, since thankfully for many of these study groups, the incidence is not so high.”

Underscoring the need to better grasp the heart risks of these treatments, Addison said more and more patients he sees express concerns about the potential harms of anticancer therapies.

“I think the number one concern for most patients is conquering their cancer, but I think after enduring that process they want to make sure that their heart doesn’t suffer some significant damage, or some process that might cost them down the road.”