More AF Surveillance Needed in Chemotherapy Trials, Meta-analysis Hints

The actual incidence of atrial fibrillation (AF) in real-world patients undergoing chemotherapy may be higher than expected due to a lack of systematic surveillance in clinical trials of cancer therapies, a safety meta-analysis suggests.

AF may present after the cancer diagnosis itself or during or after cancer treatment. Factors known to increase its incidence include systemic inflammation, immune dysregulation, electrolyte fluctuations, and impaired oxygenation, among others, Joachim Alexandre, MD, PhD (Normandie University, Caen, France), and colleagues note. It is unclear in many cases whether the treatment for cancer or the cancer itself is responsible for the increased AF risk.

The new meta-analysis found that two inhibitors of Bruton's tyrosine kinase (BTK)—ibrutinib and ponatinib—and an antimetabolite were most associated with annualized AF incidence in trials involving 15 chemotherapy agents, with AF incidence in those on the drugs far outpacing that of those on placebo.

“In our view, trials studying BTK inhibitors, which are associated with an increased risk of AF, should consider implementation of a standardized AF detection strategy based not only on 12-lead ECGs performed only in cases of AF-related symptoms, but also on longer-term ambulatory monitoring or insertable cardiac monitors to detect subclinical AF,” the investigators write.

Commenting on the findings for TCTMD, Daniel Addison, MD (The Ohio State University, Columbus), said while the ibrutinib association is not surprising, the magnitude of the increased risk is greater than what others have reported and has implications for clinical practice.

What all of this is telling us is that many patients are receiving drugs for which we really don't know the actual risk of atrial fibrillation or other cardiac arrhythmias until they're actually used in clinical practice. Daniel Addison

“I think many of us in the cardio-oncology community have long believed that BTK as a drug class may result in some increase in arrhythmias,” he added. “Most of the trials with BTK inhibitors used EKGs whenever the patient came to the office, but there was not really any systematic symptom-based or otherwise approach to actually look for arrhythmias.”

Addison said he believes the results of the meta-analysis are valid and that real-world rates of AF and other cardiac events with BTK inhibitors are probably much higher than what was seen in clinical trials.

As in the general population, AF in cancer patients is associated with increased death, ACS, heart failure, and stroke. Addison was the senior author of one recent analysis using the SEER-Medicare registry, which found that patients with incident AF occurring within 30 days of a breast cancer diagnosis had greater risks of all-cause mortality and CV mortality at 1 year compared with breast cancer patients without AF.

“What all of this is telling us is that many patients are receiving drugs for which we really don't know the actual risk of atrial fibrillation or other cardiac arrhythmias until they're actually used in clinical practice,” he added.

Ibrutinib Safety Concerns

For the study, published last week in JACC: CardioOncology, Alexandre and colleagues looked at the annualized incidence rate of AF reporting associated with exposure to drugs used as monotherapy in 191 phase II and III clinical cancer trials. Approximately half of the trials were randomized, allowing the investigators to also report the annualized incidence rate of AF reported in those receiving placebo. Some studies included children, with the mean age in all studies ranging from 7.5 to 78 years. Follow-up duration ranged from 2.7 to 138 months.

Classes of study drugs included alkylating agents, androgen deprivation therapy, antimetabolites, anthracyclines, kinase inhibitors, immune checkpoint inhibitors, monoclonal antibodies, a proteasome inhibitor, and a taxane. Of 26,604 patients exposed to one of 15 monotherapy regimens, 485 developed AF. None of the trials had any AF-specific detection strategy, with cases only being reported in those who were symptomatic and who had AF verified on an electrocardiogram.

The risk was highest with ibrutinib at an estimated 4.92 cases per 100-person years (95% CI 2.91-8.31), followed by clofarabine (2.38; 95% CI 0.66-8.55), and ponatinib (2.35; 95% CI 1.78-3.12). In contrast, the annualized incidence of those treated with placebo was 0.25 cases per 100 person-years.

Alexandre and colleagues found that while reporting of AF during cancer treatment seems to have increased since the US Food and Drug Administration mandated collection of adverse events in clinical trials in 2009, underreporting of cardiac adverse events in oncologic trials remains a problem that makes it more difficult to understand which drugs pose the greatest safety risks.

Just this week, the FDA placed a partial clinical hold on all trials of a developmental BTK drug for central nervous system lymphoma after reports of AF and two patient deaths.

In a prior study, Alexandre and colleagues had seen associations between 19 chemotherapy agents and AF using a different database. The reason for the discrepancy between that finding and the new meta-analysis, in which only three stood out prominently, they add, is unclear and may be related to underreporting issues.

“This is only going to be even more of an issue in coming years as the number of cancer drugs continues to increase across many populations,” Addison noted. “It’s possible that often people may just write [AF] off to patients being older, or having some other reason for the rhythm disorder, but this analysis shows it often may be related to the treatment they are given. One of the more interesting things that they showed is that the risk of atrial fibrillation with some of the other drugs was actually highest in younger patients who one would expect would have less comorbidities like high blood pressure and diabetes that could influence the risk of atrial fibrillation.”

The inclusion of the placebo arms in the AF calculations for these analyses, he added, helps dispel some of the uncertainty about the role of the cancer itself in the presentation of AF.