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Clinical Trial
. 2019 Nov 28;134(22):1919-1928.
doi: 10.1182/blood.2019000840.

Hypertension and incident cardiovascular events following ibrutinib initiation

Tyler Dickerson  1 , Tracy Wiczer  1 , Allyson Waller  1 , Jennifer Philippon  1 , Kyle Porter  2 , Devin Haddad  3 , Avirup Guha  3 , Kerry A Rogers  4 , Seema Bhat  4 , John C Byrd  4 , Jennifer A Woyach  4 , Farrukh Awan  4 , Daniel Addison  3
Affiliations
Clinical Trial

Hypertension and incident cardiovascular events following ibrutinib initiation

Tyler Dickerson et al. Blood. .

Abstract

Ibrutinib is associated with dramatic efficacy against B-cell malignancies. Yet, it has been linked with potentially limiting cardiotoxicity, including emerging reports of profound hypertension (HTN). The long-term incidence, severity, and impact of HTN development with ibrutinib are unknown. Therefore, in 562 consecutive patients treated with ibrutinib for B-cell malignancies from 2009 through 2016, we assessed the new/incident or worsened HTN (systolic blood pressure [BP] cutoff, 130 mm Hg). Observed incident HTN rates were compared with Framingham-heart-predicted incident HTN rates. We also evaluated the relationship of HTN to the development of other major adverse cardiovascular events (MACEs), including arrhythmia, myocardial infarction, stroke, heart failure, and cardiovascular death. Further, we assessed the effects of different antihypertensive classes on ibrutinib-related HTN. Overall, 78.3% of ibrutinib users developed new or worsened HTN over a median of 30 months. New HTN developed in 71.6% of ibrutinib users, with a time to 50% cumulative incidence of 4.2 months. Among those without preceding HTN, 17.7% developed high-grade HTN (BP >160/100 mm Hg). In multivariate regression, new or worsened HTN was associated with increased MACEs (hazard ratio [HR], 2.17; 95% confidence interval [CI], 1.08-4.38). No single antihypertensive class was associated with prevention or control of ibrutinib-related HTN. However, antihypertensive initiation was associated with a lower risk of a MACE (HR, 0.40; 95% CI, 0.24-0.66). Collectively, these data suggest that ibrutinib is associated with a substantial increase in the incidence and severity of HTN, and that HTN development carries a higher risk of subsequent cardiotoxic events.

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Conflict of interest statement

Conflict-of-interest disclosure: J.C.B. received research funding and consulted for Acerta Pharma and Pharmacyclics. F.A. received research funding from Innate Pharma and Pharmacyclics; has provided consulting services to Gilead Sciences, Pharmacyclics, Janssen, Abbvie, Sunesis, AstraZeneca, Genentech, and Novartis Oncology; and has served on the speakers’ bureau of Abbvie and AstraZeneca. K.A.R. received research funding from Genentech and served on an advisory board for Acerta Pharma. J.A.W. received research funding from Abbvie, Pharmacyclics, Janssen, Acerta, Loxo, Karyopharm, and Morphosys and has consulted for Janssen and Pharmacyclics. The remaining authors declare no competing financial interests.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Effect of ibrutinib on BP over the 60-month study period. (A) Change in mean BP. Error bars represent SD. The cumulative incidence of new (B) or worsened (C) HTN across time after initiation of ibrutinib therapy is also shown. (B) Time to 50% cumulative incidence, 4.2 months; median follow-up, 31.0 months. (C) Time to 40% cumulative incidence, 1.1 months; median follow-up, 29.3 months.
Figure 2.
Figure 2.
Cumulative incidence of MACEs, stratified by HTN status during ibrutinib use. Shown is overall incidence of grade 3 or more HTN occurrence at baseline, 3, 6, 9, and 12 months after ibrutinib initiation. Data reflect the JNC-8 HTN cutoff of 140/90 mm Hg for comparison with established HTN prediction models (includes only subjects aged 20-69 years without diabetes). Subjects without known discussion of parenteral history of HTN, were assigned a value of 1 (ie, 1 of 2 parents with HTN) in the Framingham model. JNC-8, Joint National Committee-8.
Figure 3.
Figure 3.
Cumulative incidence of MACEs, stratified by the presence or absence of new or worsened HTN development among patients treated with ibrutinib. Observed vs predicted cumulative new HTN at 1 year (A) along with the incidence of grade 3 or higher HTN during ibrutinib use in patients without preceding HTN at baseline, 3, 6, 9, and 12 months (B). Data reflect JNC-8 HTN cutoffs of 140/90 mm Hg for comparison to established HTN models.
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Comment in

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