In a meta-analysis published in The Oncologist, researchers found that second-generation Bruton's tyrosine kinase (BTK) inhibitors had a better cardiovascular safety profile than the first-generation BTK inhibitor ibrutinib for patients with B-cell malignancies. This led to fewer reported key cardiac events and treatment-limiting toxicities.
“First-generation BTKs not only inhibit the BTK itself but enzymes found in other cells, including the C-terminal SRC kinase, which is important for atrial remodeling and arrhythmogenesis,” said study co-author Moaath Mustafa Ali, MD, MPH, a medical oncologist/hematologist with Cleveland Clinic Cancer Institute. “This is the cause of cardiac side effects. These medications also interfere with coagulation, resulting in an increased risk of bleeding. Second-generation BTK inhibitors were intended to more specifically target cancer cells to reduce these off-target side effects.”
The study authors suggested that these findings could inform clinical decision-making, especially among patients at greater risk for cardiovascular disease.
Background and Study Methods
Treatment with ibrutinib has been associated with significant cardiotoxicity, so the second-generation agents were developed to try to mitigate some of these cardiovascular risks.
Researchers conducted a systemic review and meta-analysis of six comparator studies to assess the cardiac safety profiles of both first- and second-generation BTK inhibitors (n = 14,455). The studies were found through a thorough search of Medline, Embase, and Cochrane for studies that compared first- and second-generation BTK inhibitors.
The primary outcomes of the analysis were the incidence of atrial fibrillation and cardiac events, calculated using a random-effects model.
Researchers used a funnel plot to evaluate potential publication bias, which was corrected with the Duval and Tweedie trim-and-fill method.
Key Findings
Ibrutinib was associated with a significantly higher risk of atrial fibrillation (odds ratio [OR] = 2.50; 95% confidence interval [CI] = 1.97–3.17), total cardiac events (OR = 1.53; 95% CI = 1.18–1.99), and heart failure (OR = 2.08; 95% CI = 1.13–3.83) than second-generation BTK inhibitors. There was a more-than-three-fold greater treatment discontinuation rate for cardiac events among patients receiving ibrutinib vs second-generation BTK inhibitors (OR - 3.32; 95% CI = 1.46–7.55).
“We found that the first-generation medication had a 2.5-fold higher risk of development of atrial fibrillation, two-fold increased risk of heart failure, and almost a four-fold risk of hypertension,” said Dr. Mustafa Ali. “One of the biggest takeaways from the meta-analysis is that patients on ibrutinib had a three-fold higher rate of discontinuing therapy due to a cardiac event.”
No significant difference was noted in all-cause mortality.
“Once ibrutinib becomes available as a generic, my expectation is that we’ll see an increase in its use due to its lower cost, so there’s an important question about the merits of doing so,” Dr. Mustafa Ali noted.
He recommended that whenever prescribing a BTK inhibitor, physicians should keep a close eye on EKGs, cardiovascular risk factors, and blood pressure management and monitoring to mitigate the cardiovascular risks of these agents in patients with B-cell malignancies.
DISCLOSURES: For full disclosures of the study authors, visit academic.oup.com.
