Clinical Context

Patients with cancer are at risk for a large number of potential adverse events (AEs) during treatment and even years thereafter, and the current study highlights the risk for atrial fibrillation (AF) among patients with a history of cancer. Atrial fibrillation accounts for nearly 5% of cardiovascular (CV) AEs in clinical trials of cancer treatment, and previous research has found that the diagnosis of cancer is associated with a 47% increase in the risk for incident AF. Another study of women with breast cancer found that the diagnosis of AF within 30 days of the diagnosis of cancer was associated with more than a 2-fold increase in the risk for death at 1 year.

Many factors can increase the risk for AF among patients with cancer, including higher levels of inflammation, immune dysregulation, and electrolyte abnormalities. Higher stages of cancer are also associated with higher risks for AF, but the application of anticancer drugs might also contribute to AF among patients with cancer, and the current study by Alexandre and colleagues uses clinical trial data to assess the significance of this potential association.

Study Synopsis and Perspective

Atrial fibrillation is a known and serious AE of some cancer treatments, but it is underreported in cancer drug trials, French investigators said in a new report.

As a result, oncologists likely underestimate the risk for AF when new cancer drugs come to market, they said.

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 (PY): 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: Cardio-Oncology, a journal of the American College of Cardiology.^[1]

Actual rates of AF are probably higher than what they found in this meta-analysis, the authors suspected, 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, said investigators led by Joachim Alexandre, MD, PhD, a member of the cardio-oncology program at the University of Caen Normandie Hospital Center, Caen, France.

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

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 pointed 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, Pennsylvania, 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 said the issue is particularly pressing for drugs known to be associated with AF. For Bruton tyrosine kinase inhibitors, they called 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.

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

The trials covered anticancer drugs used as monotherapy up to September 18, 2020. Almost half were randomized trials, but only 7 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 PY 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 PY.

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 AE 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 noted.

No external funding was reported for the study. Alexandre has received honoraria for presentations and consulting fees from Amgen Inc.; Bayer AG; Bioserenity; Bristol-Myers Squibb Company; and Pfizer Inc.

Implications for the Healthcare Team

• Atrial fibrillation accounts for nearly 5% of CV AEs in clinical trials of cancer treatment, and previous research has found that the diagnosis of cancer is associated with a 47% increase in the risk for incident AF. Another study of women with breast cancer found that the diagnosis of AF within 30 days of the diagnosis of cancer was associated with more than a 2-fold increase in the risk for death at 1 year, and cancer stage correlates positively with the risk for AF.
• Atrial fibrillation was generally more common after treatment with anticancer drugs vs placebo in the current analysis of clinical trials of cancer. The drugs associated with the highest rates of AF included ibrutinib, clofarabine, and ponatinib.
• The healthcare team should have a low threshold for routine testing for AF among patients with a history of cancer, particularly if they were treated with specific anticancer drugs

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