First-Generation BTK Inhibitors Associated with Higher Risk of Cardiac Events

In a meta analysis of head-to-head comparisons of first- and second-generation Bruton’s tyrosine kinase (BTK) inhibitors the former had a significantly increased risk of cardiac events such as atrial fibrillation or heart failure as well as a notably increased risk of treatment discontinuation due to cardiac issues. The study results were published in Oncologist.

Background

While BTK inhibitors have revolutionized the care of patients with B-cell malignancies, these drugs have been associated with high rates of cardiotoxicity. Some patients also experienced bleeding or thrombocytopenia.

“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,” says 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.”

Study design

To guide clinical decision-making, researchers were looking to compare the cardiac safety profile of early therapies such as ibrutinib to newer iterations of BTK inhibitors such as acalabrutinib, zanubrutinib and orelabrutinib. They conducted a systematic review and meta-analysis encompassing 14,455 patients in six direct-comparison studies.

The primary outcomes included incidence of atrial fibrillation and total cardiac events. Secondary outcomes included incidence of heart failure, hypertension, coronary artery disease, bleeding, ventricular tachycardia, all-cause mortality, treatment discontinuation due to atrial fibrillation and treatment discontinuation due to any cardiac issues.

Study outcomes

“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,” says 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.”

Treatment discontinuation is an obvious concern, as stopping therapy prematurely impacts disease control and overall survival. The evidence shows patients with preexisting heart issues or risks should be prescribed second-generation therapy.

These side effects most commonly emerge within two to four months of initiating therapy, with atrial fibrillation occurring at variable timepoints, so patients who are not experiencing cardiac or bleeding events on first-generation therapy are generally kept on those medications. Patients who are newly diagnosed with marginal zone lymphoma or CLL will usually now be prescribed a second-generation therapy.

First-generation BTK inhibitors may continue to be used in developing countries as well as in cases where cost is a major factor. “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.” says Dr. Mustafa Ali.

The study co-author also pointed out that it’s unknown whether all the cases of cardiac events are attributable to the medication. Anything that stresses the body can trigger atrial fibrillation in older patients so this may be a factor in some cases.

Regardless of which BTK inhibitor a patient is on, Dr. Mustafa Ali recommends that physicians:

• Conduct a baseline EKG for patients going on these drugs and repeat it every three to six months specifically in the first year of treatment.
• Order a baseline echocardiogram before starting treatment for patients with a known history of structural heart disease, heart failure, or multiple cardiovascular risk factors.
• Assess the patient's ejection fraction if a new arrhythmia is detected on an ECG or if clinical symptoms of heart failure develop during treatment.
• Be mindful of blood pressure management and monitoring.
• Look at the root cause of high blood pressure.
• If high blood pressure or atrial fibrillation is recurrent, refractory and severe, consider switching from a first-generation to a second-generation BTK inhibitor instead of using medications alone to control it.
• Avoid non-dihydropyridine calcium channel blockers such as diltiazem or verapamil due to drug-drug interactions with ibrutinib.