e19016 Background: Bruton tyrosine kinase (BTK) inhibitors are an important therapeutic option for patients with CLL/SLL. The first-generation BTK inhibitor, ibrutinib (ibru), is associated with an increased risk of hypertension. Zanubrutinib (zanu) is a next-generation BTK inhibitor designed to maximize BTK occupancy and minimize toxicity with fewer off-target effects. This analysis evaluated the risk of developing hypertension based on initiation of antihypertensives (anti-HTN) in ALPINE (NCT03734016). Methods: Anti-HTN use in the zanu (n=324) and ibru (n=324) treatment arms was assessed. The definition of anti-HTN was based on Standardized Drug Grouping; concomitant anti-HTN were adjudicated by an independent hypertension specialist blinded to BTK inhibitor assignment. Time to initiating new anti-HTN and time to adding a new class of anti-HTN were assessed using the Kaplan-Meier method. Comparisons of time-to-onset endpoints were analyzed based on the log-rank test. Results: At baseline, patient characteristics were generally balanced between zanu and ibru arms (median age, 66.7 vs 67.1 y; male, 65.1% vs 71.4%; history of hypertension, 50.9% vs 50.0%; type 2 diabetes mellitus, 10.1% vs 8.9%). Among patients not on anti-HTN at baseline, 20.7% (n=35/169) of zanu- and 28.7% (n=51/178) of ibru-treated patients initiated anti-HTN during the study. Among all patients, fewer patients in the zanu arm initiated new anti-HTN (28.4% [n=92/324] vs 32.4% [n=105/324]) and the anti-HTN were initiated later (hazard ratio [HR], 0.77; P-value=.071). Additionally, statistically fewer patients in the zanu arm compared with the ibru arm started anti-HTN in a new class (24.1% [n=78/324] vs 29.3% [n=95/324]) and the anti-HTN were started later (HR, 0.72; P-value=.034). The event rates for initiation of new anti-HTN or a new class of anti-HTN were consistently lower in the zanu vs ibru arm at each timepoint (Table). Conclusions: In ALPINE, initiation of new anti-HTN or a new class of anti-HTN occurred less frequently in the zanu arm vs the ibru arm in patients with CLL/SLL. Adoption of anti-HTN occurred sooner with ibru than zanu. These findings should be considered when initiating BTK inhibitor therapy in patients with CLL/SLL who have an elevated cardiovascular risk. Clinical trial information: NCT03734016 . [Table: see text]