Atrial Fibrillation Risk With Cancer Drugs Underestimated

M. Alexander Otto, PA, MMS

April 07, 2023

Atrial fibrillation (AF) is a known and serious side effect of some cancer treatments, but it is underreported in cancer drug trials, French investigators say in a new report.

As a result, oncologists likely underestimate the risk of atrial fibrillation when new cancer drugs come to market, they say.

The team came to these conclusions after conducting a meta-analysis of 191 phase 2 or 3 clinical trials that included 26,604 patients. The trials investigated 15 anticancer drugs used as monotherapy.

The meta-analysis showed that the annualized incidence rate of AF ranged from 0.26 cases per 100 person-years ― about the same as placebo ― to 4.92 cases, a nearly 20 times' higher risk.

Rates were the highest for ibrutinib, clofarabine, and ponatinib.

The study was published on March 28 in JACC: CardioOncology, a journal of the American College of Cardiology.

Actual rates of AF are probably higher than what they found in this meta-analysis, the authors suspect, because most oncology trials only identify and report severe cases of AF that require immediate medical attention. Less severe cases can also lead to serious complications, including strokes, but they go unreported, say investigators led by Joachim Alexandre, MD, PhD, a member of the cardio-oncology program at the University of Caen Normandie Hospital Center, France.

"These findings suggest a global and systemic underreporting and/or underidentification of cardiotoxicity among cancer clinical trial participants," and AF reporting is "particularly affected," they said.

Call for Routine Monitoring

The root of the problem is the lack of routine rhythm monitoring in cancer trials. This in turn "leads to a significant underestimation of AF incidence" and rates "markedly lower than those observed among real-life" patients, the authors point out.

To address the issue, Alexandre and his team called for routine cardiac monitoring in trials to capture the true incidence of AF and to "clearly define which anticancer drugs are significantly associated" with the condition.

Approached for comment, Michael Fradley, MD, medical director of cardio-oncology at the University of Pennsylvania, Philadelphia, agreed.

"It's incredibly important" to "identify the drugs most likely to cause arrhythmias and determine the best prevention and treatment strategies. Unfortunately, systematic evaluation of arrhythmias in cancer clinical trials has often been lacking," Fradley told Medscape Medical News.

The investigators say the issue is particularly pressing for drugs known to be associated with AF. For Bruton's tyrosine kinase inhibitors such as ibrutinib, for instance, they call for standardize AF detection in trials "not only on 12-lead ECGs" for symptomatic AF but also with "longer-term ambulatory monitoring or insertable cardiac monitors to detect subclinical AF."

Fradley thought there might also be a role for newer wearable technologies that can detect arrhythmias through a skin patch or by other means.

Details of the Meta-Analysis

The investigators pulled the 191 studies they used in their meta-analysis from the database.

The trials covered anticancer drugs used as monotherapy up to September 18, 2020. Almost half were randomized trials, but only seven had placebo arms. Trials involving hematologic cancers outnumbered those involving solid tumors.

The 15 drugs examined were dacarbazine, abiraterone, clofarabine, azacitidine, ibrutinib, nilotinib, ponatinib, midostaurin, ipilimumab, aldesleukin, lenalidomide, pomalidomide, rituximab, bortezomib, and docetaxel.

The annualized incidence AF rates per 100 person-years were 4.92 cases for ibrutinib, 2.38 cases for clofarabine, and 2.35 cases for ponatinib.

The lowest AF rates were for ipilimumab (0.26 cases), rituximab (0.27), and nilotinib (0.29).

For placebo, the annualized rate was 0.25 cases per 100 person-years.

The team says caution is warranted regarding their estimations for clofarabine and midostaurin (0.65 cases) because no trials were registered after September 2009, when adverse event reporting became mandatory. As a result, estimates may be artificially low.

One of the limits of the study is that it focused on monotherapy in an age when combination treatment is generally the rule for cancer, the authors note.

No external funding was reported for the study. Alexandre has received honoraria for presentations and consulting fees from Bayer, BMS, Pfizer, Amgen, and Bioserenity.

JACC: CardioOncol. Published online March 28. Full text

M. Alexander Otto is a physician assistant with a master's degree in medical science and a journalism degree from Newhouse. He is an award-winning medical journalist who worked for several major news outlets before joining Medscape. Alex is also an MIT Knight Science Journalism fellow. Email:

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