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The multiple cardiovascular (CV) side effects of ibrutinib (Imbruvica) overlap, with some conferring high rates of mortality, researchers found.

Results from a statistical disproportionality analysis of , the World Health Organization's global drug monitoring database of more than 16 million individual case-safety reports from 130 countries, showed that CV-adverse drug reactions (ADRs) associated with ibrutinib were significantly over-reported compared with CV-ADR reports on all other drugs in the database.

A case/no case imbalance was observed between 3,072 suspected cases of ibrutinib-associated CV-ADRs and all of the approximately 377,000 CV-ADR cases reported since 2013, when ibrutinib was approved for use in the U.S. by the FDA.

As of January 2, 2018, there were 303 deaths related to seven broad CV entities associated with ibrutinib therapy, said Joe-Elie Salem, MD, PhD, of Sorbonne Université and Pitié-Salpêtrière Hospital in Paris, France, and Vanderbilt University Medical Center in Nashville, and colleagues.

A mortality rate of 21% was seen with ibrutinib-associated heart failure, with a rate of reporting (ROR) more than three times higher than that seen with other drugs (ROR 3.5, P<0.0001). This was a new finding, the researchers reported in the .

Conduction disorders, seen in 50 cases of atrioventricular block, were also identified as a new complication associated with ibrutinib, with a mortality rate of 18% (ROR 3.5%, P<0.0001).

"Defining these ibrutinib-associated toxicities is critical, especially because ibrutinib is increasingly used in a front-line setting and combined with other agents," the investigators wrote. "In future clinical trials of ibrutinib, cardiovascular events should be carefully adjudicated so that patients at risk of these complications can be more accurately identified and preventive strategies can be developed."

The analysis revealed fatalities in 18-19% of patients who had central nervous system (CNS) events during ibrutinib therapy (ROR 3.7 for hemorrhagic events; ROR 2.2 for ischemic events), and in 10.6% of patients who developed ventricular arrhythmias (VAs; ROR 4.7, P<0.0001 for all).

A mortality rate of 10% was associated with ibrutinib-associated supraventricular arrhythmias (SVAs), which were reported 23 times more frequently than other drugs (ROR 23.1, P<0.0001). The prognosis was significantly worse when patients on ibrutinib developed a CNS event and an SVA at the same time, with fatalities reported in 15 of 52 cases (28.8%), the investigators said.

Ibrutinib-associated hypertension was non-fatal, the analysis showed. No disproportionate rates of ibrutinib-associated CV-ADRs were reported for cardiac ischemia, myocarditis, venous thromboembolic events, QT prolongation, or valvular disorders.

Although SVA with atrial fibrillation was the first ibrutinib-associated CV-ADR to be significantly over-reported, 66% of the 363 cases of atrial fibrillation occurred without concomitant risk factors for heart failure such as SVA, VA, or hypertension, the researchers noted. They added that this suggests "a possible direct role for ibrutinib."

The investigators also identified almost 1,000 cases of suspected ibrutinib-associated SVA, with 11.9% associated with heart failure, 4.2% with ischemic events, and 3.4% with CNS hemorrhagic events. The SVA rates associated with ibrutinib increased over time, with most reported in 2017. Patients were mostly male and older than 70, and 24% were on concurrent beta-blocker therapy, while 6% were taking other types of antiarrhythmic drugs.

"Due to the frequent need for co-prescriptions of drugs for rate control, anticoagulant stroke prophylaxis, and bleeding risk complicated by multiple drug interactions ... there is a clear and pressing need to improve of these patients, requiring a better understanding of pathophysiology of SVA induced by ibrutinib," the researchers wrote.

All cancer types were affected by disproportionately higher reporting of CV-ADRs in patients treated with ibrutinib, the results showed. The most commonly affected were chronic lymphocytic leukemia (60% to 76%), lymphomas (20% to 24%), and Waldenstrom's macroglobulinemia (4% to 15%).

The analysis also revealed that CV-ADR reports occurred steadily in the year following initiation of ibrutinib therapy. Conduction disorders developed within the first 30 days of treatment, while the time to onset of atrial fibrillation, ventricular arrhythmias, or heart failure peaked after 2 to 3 months of treatment. Hypertension tended to occur 4 to 5 months after the first dose of ibrutinib.

Writing in an , Jutta Bergler-Klein, MD, of the Medical University of Vienna, noted that the first-in-class oral covalent inhibitor of Bruton's tyrosine kinase (BTK) "has evolved as a major cornerstone of contemporary treatment of ." She warned that "the net benefit of ibrutinib may be offset by sequential cardiovascular mortality, which will presumably rise further with continuous therapy required to tackle residual disease or relapse."

Like the study authors, Bergler-Klein pointed to results from a recent comparison of front-line therapy in older patients with untreated chronic lymphocytic leukemia. Although progression-free survival at 2 years was 87% in all treatment arms, the number of sudden deaths was higher in the ibrutinib-containing treatment arms than in the chemoimmunotherapy control group.

"Careful cardiac evaluation and electrocardiogram monitoring should be considered during ibrutinib therapy, because patients may be asymptomatic despite arrhythmias or developing heart failure," Bergler-Klein advised.

"The aim of the new cardio-oncology field is to support the life-saving oncology therapies in cardiac patients," she emphasized, adding: "Future trials should approach which cardiac therapies achieve optimal continuation of ibrutinib despite, for example, atrial fibrillation, hypertension, heart failure, or conduction disorders."