Study Results Show Greater Hypertension, Cardiovascular Risks With Ibrutinib

Use of ibrutinib (Imbruvica) significantly increased the risk of early onset hypertension (HTN) and was associated with long-term risk of developing other major cardiotoxic events in patients with B-cell malignancies, according to findings of a retrospective study (N = 562).

More than three-fourths (78.3%; n = 440) of patients treated with ibrutinib developed new or worsening HTN over a median of 30 months. Investigators said that 84.8% of those patients had HTN with at least a probable association with ibrutinib.

Ibrutinib is associated with dramatic efficacy against B-cell malignancies, but its links to cardiotoxicity are not clearly understood, which is why investigators undertook this study. They said more needs to be known about the long-term incidence, severity, and impact of ibrutinib use on HTN.

Among patients who did not have a history of HTN, 71.6% developed the condition during treatment with ibrutinib (467 cases observed vs 39 Framingham risk model—predicted cases per 1000 person-years).

Overall, 205 patients (37.6%) developed high-grade HTN, defined as systolic blood pressure (SBP) >160/100 mm Hg, including 17.7% who did not have baseline HTN. Of those with baseline HTN (n = 347), worsening was observed in 286 (82.4%).

Existing HTN was defined as a documented SBP ≥130 mm Hg at 2 visits within 3 months prior to ibrutinib initiation or a history of HTN with the current use of at least 1 blood pressure—lowering medication.

New HTN was defined as SBP ≥130 mm Hg at 2 visits within 3 months. An elevation in HTN grade by Common Terminology Criteria for Adverse Events or an increase in antihypertensive therapy constituted worsened HTN.

Investigators also studied the correlation between ibrutinib-linked HTN and development of other major adverse cardiovascular events (MACE), such as arrhythmias, myocardial infarction, stroke, heart failure, and cardiovascular death. A further focus of investigation involved the preventive and modulatory effects of antihypertensives on ibrutinib-related HTN by drug class.

New or worsened HTN correlated with increased MACE (HR, 2.17; 95% CI, 1.08-4.38; Figure). Among patients who developed HTN, the rate of MACE, including atrial fibrillation, and ventricular arrhythmias during ibrutinib was “disproportionately elevated,” investigators said, concluding that HTN development may translate to a higher risk of subsequent cardiotoxic events.

Investigators noted MACE among 93 patients (16.5%), including 84 (19.1%) with new or worsened HTN versus 9 (8.2%) with stable or no HTN. The most common cardiovascular complication during ibrutinib treatment was atrial fibrillation, which occurred in 73 patients (13%).

Figure. Cumulative Incidence of MACE Stratified by HTN Status During Ibrutinib Use

No single antihypertensive class was associated with prevention or control of ibrutinib-related hypertension, the authors added. However, use of an antihypertensive after HTN development was associated with a lower risk of MACE (HR, 0.40; 95% CI, 0.24-0.66).

Dickerson T, Wiczer R, Waller A, et al. Hypertension and incident cardiovascular events following ibrutinib initiation I [published online October 3, 2019]. Blood. doi: 10.1182/blood.2019000840.