Hypertension and incident cardiovascular events after next-generation BTKi therapy initiation

Abstract

Background Post-market analyses revealed unanticipated links between first-generation Bruton’s tyrosine kinase inhibitor (BTKi) therapy, ibrutinib, and profound early hypertension. Yet, whether this is seen with novel selective second (next)-generation BTKi therapy, acalabrutinib, is unknown. Methods Leveraging a large cohort of consecutive B cell cancer patients treated with acalabrutinib from 2014 to 2020, we assessed the incidence and ramifications of new or worsened hypertension [systolic blood pressure (SBP) ≥ 130 mmHg] after acalabrutinib initiation. Secondary endpoints were major cardiovascular events (MACE: arrhythmias, myocardial infarction, stroke, heart failure, cardiac death) and disease progression. Observed incident hypertension rates were compared to Framingham heart-predicted and ibrutinib-related rates. Multivariable regression and survival analysis were used to define factors associated with new/worsened hypertension and MACE, and the relationship between early SBP increase and MACE risk. Further, the effect of standard antihypertensive classes on the prevention of acalabrutinib-related hypertension was assessed. Results Overall, from 280 acalabrutinib-treated patients, 48.9% developed new/worsened hypertension over a median of 41 months. The cumulative incidence of new hypertension by 1 year was 53.9%, including 1.7% with high-grade (≥ 3) hypertension. Applying the JNC 8 cutoff BP of ≥ 140/90 mmHg, the observed new hypertension rate was 20.5% at 1 year, > eightfold higher than the Framingham-predicted rate of 2.4% (RR 8.5, P < 0.001), yet 34.1% lower than ibrutinib (12.9 observed-to-expected ratio, P < 0.001). In multivariable regression, prior arrhythmias and Black ancestry were associated with new hypertension (HR 1.63, HR 4.35, P < 0.05). The degree of SBP rise within 1 year of treatment initiation predicted MACE risk (42% HR increase for each + 5 mmHg SBP rise, P < 0.001). No single antihypertensive class prevented worsened acalabrutinib-related hypertension. Conclusions Collectively, these data suggest that hypertension may be a class effect of BTKi therapies and precedes major cardiotoxic events.

Established and Emerging Cancer Therapies and Cardiovascular System: Focus on Hypertension—Mechanisms and Mitigation

“…127 Importantly, the study demonstrated there was no single antihypertensive treatment which was found to prevent this hypertensive effect. 127 These opposing data presented support the need for further larger clinical trials and real-world studies to properly ascertain the true hypertensive effects of the newer generation BTKi treatments. hypertension is limited.…”

How We Manage Patients with Indolent B-Cell Malignancies on Bruton’s Tyrosine Kinase Inhibitors: Practical Considerations for Nurses and Pharmacists

“…Unlike most AEs, which have the highest onset in the first year of BTK inhibitor therapy, the incidence of new onset hypertension increases over the course of treatment [ 79 ]. In addition, higher rates of hypertension have been reported in real-world studies, with up to 78% of patients receiving ibrutinib and 49% receiving acalabrutinib having new or worsened hypertension [ 80 , 81 , 82 ]. Risk factors for the development of new hypertension based on multivariable analysis include prior arrhythmias and Black ancestry [ 82 ].…”

“…In addition, higher rates of hypertension have been reported in real-world studies, with up to 78% of patients receiving ibrutinib and 49% receiving acalabrutinib having new or worsened hypertension [ 80 , 81 , 82 ]. Risk factors for the development of new hypertension based on multivariable analysis include prior arrhythmias and Black ancestry [ 82 ]. In real-world studies, new or worsened hypertension was also associated with increased risk of major adverse cardiovascular events (MACE) [ 82 ].…”

“…Risk factors for the development of new hypertension based on multivariable analysis include prior arrhythmias and Black ancestry [ 82 ]. In real-world studies, new or worsened hypertension was also associated with increased risk of major adverse cardiovascular events (MACE) [ 82 ]. Although no single class of antihypertensive agent has been associated with the prevention or control of BTK inhibitor-related hypertension, the initiation of any antihypertensive agent was associated with a lower risk of MACE [ 82 ].…”

Luteolin Attenuates Hypertension via Inhibiting NF-κB-Mediated Inflammation and PI3K/Akt Signaling Pathway in the Hypothalamic Paraventricular Nucleus

“…Hypertension, as characterized by elevated blood pressure (140/90 mmHg), is a leading powerful risk factor for cardiovascular diseases [ 1 , 2 ]. Unfortunately, the cure rate of hypertension in the world is still unsatisfactory.…”