Aspirin and Hemocompatibility Events With a Left Ventricular Assist Device in Advanced Heart Failure: The ARIES-HM3 Randomized Clinical Trial

Abstract

Importance: Left ventricular assist devices (LVADs) enhance quality and duration of life in advanced heart failure. The burden of nonsurgical bleeding events is a leading morbidity. Aspirin as an antiplatelet agent is mandated along with vitamin K antagonists (VKAs) with continuous-flow LVADs without conclusive evidence of efficacy and safety.

Objective: To determine whether excluding aspirin as part of the antithrombotic regimen with a fully magnetically levitated LVAD is safe and decreases bleeding.

Design, setting, and participants: This international, randomized, double-blind, placebo-controlled study of aspirin (100 mg/d) vs placebo with VKA therapy in patients with advanced heart failure with an LVAD was conducted across 51 centers with expertise in treating patients with advanced heart failure across 9 countries. The randomized population included 628 patients with advanced heart failure implanted with a fully magnetically levitated LVAD (314 in the placebo group and 314 in the aspirin group), of whom 296 patients in the placebo group and 293 in the aspirin group were in the primary analysis population, which informed the primary end point analysis. The study enrolled patients from July 2020 to September 2022; median follow-up was 14 months.

Intervention: Patients were randomized in a 1:1 ratio to receive aspirin (100 mg/d) or placebo in addition to an antithrombotic regimen.

Main outcomes and measures: The composite primary end point, assessed for noninferiority (-10% margin) of placebo, was survival free of a major nonsurgical (>14 days after implant) hemocompatibility-related adverse events (including stroke, pump thrombosis, major bleeding, or arterial peripheral thromboembolism) at 12 months. The principal secondary end point was nonsurgical bleeding events.

Results: Of the 589 analyzed patients, 77% were men; one-third were Black and 61% were White. More patients were alive and free of hemocompatibility events at 12 months in the placebo group (74%) vs those taking aspirin (68%). Noninferiority of placebo was demonstrated (absolute between-group difference, 6.0% improvement in event-free survival with placebo [lower 1-sided 97.5% CI, -1.6%]; P < .001). Aspirin avoidance was associated with reduced nonsurgical bleeding events (relative risk, 0.66 [95% confidence limit, 0.51-0.85]; P = .002) with no increase in stroke or other thromboembolic events, a finding consistent among diverse subgroups of patient characteristics.

Conclusions and relevance: In patients with advanced heart failure treated with a fully magnetically levitated LVAD, avoidance of aspirin as part of an antithrombotic regimen, which includes VKA, is not inferior to a regimen containing aspirin, does not increase thromboembolism risk, and is associated with a reduction in bleeding events.

Trial registration: ClinicalTrials.gov Identifier: NCT04069156.

Figure 1.. Flow of Patients in the Randomized Trial of Placebo Compared to Aspirin With a Vitamin K Antagonist in Patients With a Fully Magnetically Levitated Left Ventricular Assist Device

Patients were followed up until 12 months for the evaluation of the primary end point in the primary end point set. Patients who continued receiving the treatment group medication (placebo or aspirin) at 12 months were eligible for continued follow-up beyond 12 months. Reasons for patient withdrawal are shown in eTable 1 in Supplement 2. Details on patient transition to open-label aspirin use can be found in eTables 2 and 3 in Supplement 2. ^aMedian (IQR) of 14.2 (9.0-21.4) months. ^bMedian (IQR) of 14.3 (7.2-20.6) months. ^cConcluded follow-up at 12 months (n = 53). ^dConcluded follow-up at 12 months (n = 55).

Figure 2.. Estimates of the Probability of Death or Nonsurgical Major Hemocompatibility-Related Adverse Events and Nonsurgical Bleeding Events

The probability of death or nonsurgical major hemocompatibility-related adverse event reflects the failure of the primary end point. In this 24-month time-to-event analysis, patients in the placebo group experienced decreased probability of primary end point failure at 12 months (25.8 for placebo vs 32.4 for aspirin) and 24 months (36.9 for placebo vs 45.9 for aspirin; log-rank P = .03). Decreased primary end point failure was driven by decreased nonsurgical bleeding at 12 months (23.1 for placebo vs 29.7 for aspirin) and at 24 months (30.0 for placebo vs 42.4 for aspirin; log-rank P = .01). Hazard ratios were calculated by Cox proportional hazard modeling with treatment group as the only effect. Adjusted hazards models are provided in eFigure 10 in Supplement 2. Median (IQR) follow-up was 14.2 (9.0-21.4) months in the placebo group and 14.3 (7.2-20.6) months in the aspirin group.

Figure 3.. Principal Secondary End Point Details and Safety End Points

With the avoidance of aspirin, the relative risk of bleeding (the principal secondary end point, including recurrent bleeding) was reduced with no change in safety end points. Bleeding event reduction is observed in both moderate and severe bleeding categories as well as gastrointestinal bleeding. Bleeding events included those that occur while hospitalized or that led to hospitalization or urgent care and required medical intervention. Details on classification as moderate or severe are available in Supplement 2. Events are shown as events per 100 patient-years (to account for first and recurrent events). The relative risk is depicted as a forest plot with 95% CIs and P values. Time-to-event analyses of stroke (eFigure 5 in Supplement 2), overall survival (eFigure 6 in Supplement 2), thrombotic components (eFigure 11 in Supplement 2), and bleeding components of the primary end point (eFigure 12 in Supplement 2) are provided in the Supplement 2. Adjusted hazard models of major adverse events are shown in eFigure 10 in Supplement 2. ^aAn ischemic stroke with hemorrhagic conversion event is counted within both the composite “bleeding components of the primary end point” and “thrombotic components of the primary end point.” ^bExcludes ischemic stroke with hemorrhagic conversion.

Figure 4.. Subgroup Analysis of the Primary End Point (Primary Analysis Population)

There were no significant interactions on the primary end point for most subgroups, including age, sex, race and ethnicity, obesity, disease severity, history of diabetes, ischemic etiology of heart failure, history of coronary stenting, thrombosis history, history of atrial fibrillation, coronary artery bypass surgery, or left ventricular assist device (LVAD) surgical implant method. Patients with a history of bleeding or stroke were noted to experience more benefit from aspirin avoidance. The dashed line represents the noninferiority margin of −10% for the success difference. ^aInteraction testing of primary end point subgroups was completed by general linearized modeling with terms for treatment group, subgroup, and their interaction. ^bSurgical techniques include sternotomy, referring to full median sternotomy, and thoracotomy, referring to left thoracotomy combined with right thoracotomy or hemisternotomy. ^cDisease severity defined by Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profiles, which range from 1 to 7; a profile of 1 represents the most severe illness and a profile of 7 the least severe illness.