Introduction
The ARIES-HM3 clinical trial is a landmark international, randomized, double-blind, placebo-controlled study examining the role of aspirin in patients with advanced heart failure supported by the fully magnetically levitated HeartMate 3 (HM3) left ventricular assist device (LVAD). Aspirin, used as an antiplatelet agent alongside vitamin K antagonists (VKAs), has been standard therapy to reduce thrombotic complications in continuous-flow LVAD patients, though without conclusive evidence for efficacy and safety. This comprehensive review summarizes multiple ARIES-HM3 publications to clarify aspirin’s impact on hemocompatibility events, bleeding risk, and clinical outcomes, stratified by time and patient characteristics.
Trial Design and Primary Findings
The trial enrolled 628 patients across 51 centers in 9 countries from July 2020 to September 2022, randomizing them 1:1 to aspirin (100 mg daily) or placebo, both with VKA therapy. The primary composite endpoint was survival free of major nonsurgical hemocompatibility-related adverse events (HRAEs) including stroke, pump thrombosis, major bleeding, or arterial peripheral thromboembolism at 12 months.
Analysis of 589 patients with median 14-month follow-up demonstrated that aspirin omission was noninferior to aspirin use regarding event-free survival (74% placebo vs 68% aspirin; absolute difference 6.0%, P < .001). Importantly, aspirin avoidance significantly reduced nonsurgical bleeding (relative risk 0.66, P = .002) without increasing thromboembolic events, a finding consistent across demographic subgroups. This robust evidence supports omitting aspirin in HM3 LVAD patients managed with VKAs to improve bleeding outcomes safely.
Impact of Anticoagulation Quality (TTR) on Outcomes
A key analysis investigated how the quality of VKA management, assessed by the Time in Therapeutic Range (TTR), affected outcomes in 554 patients. Patients with TTR ≥56% had higher success rates for the primary endpoint (77% vs 66.9%, P = .01) and fewer bleeding events at 12 months (26.4 vs 49.2 events per 100 patient-years) without increased stroke risk. Aspirin use and TTR did not interact in influencing outcomes, and bleeding risk decreased steadily with increasing TTR. Predictors of low TTR included female sex and Black race, highlighting the need for tailored anticoagulation management. This analysis underscores the critical role of optimal VKA control for minimizing bleeding risks in LVAD patients.
Influence of Comorbidities: Atrial Fibrillation, Diabetes, and Obesity
Among 589 patients, 78% had one or more of atrial fibrillation (AF), diabetes mellitus (DM), or obesity (Ob). The presence of these comorbidities did not modify the beneficial effect of aspirin elimination on the primary endpoint. Patients with all three conditions receiving aspirin showed increased HRAEs (difference 30.6%), suggesting possible harm. Additionally, aspirin avoidance reduced nonsurgical bleeding similarly regardless of these comorbidities. Thromboxane-B2 levels confirmed effective platelet inhibition with aspirin. These findings support aspirin omission as safe and beneficial even in patients with complex metabolic and arrhythmic profiles.
Pharmacological Background Therapies and Hemocompatibility
Analysis of background pharmacologic therapies showed that use of renin-angiotensin-aldosterone system (RAAS) inhibitors, common in heart failure treatment, was associated with higher rates of primary endpoint success but did not significantly alter the impact of aspirin on outcomes. Other HF-related therapies and cardiovascular drugs also did not influence aspirin’s effect. This insight suggests potential avenues to further optimize hemocompatibility beyond antithrombotic therapy in LVAD-supported patients.
Aspirin Use in Patients with Atherosclerotic Vascular Disease
A secondary analysis of 589 patients assessed the effect of aspirin in those with prior atherosclerotic vascular disease (history of PCI, CABG, stroke, or peripheral vascular disease, present in 41%). Aspirin avoidance remained safe, with no increased thrombotic risk, and significantly reduced nonsurgical major bleeding in this subgroup (rate ratio 0.52 for placebo vs aspirin). This challenges the standard practice mandating aspirin in vascular disease and supports its removal in conjunction with adequate anticoagulation.
Summary Table of Key Outcomes by Follow-up Timepoint
| Study Aspect | Follow-up/ Timing | Findings |
|---|---|---|
| Primary ARIES-HM3 Trial | Median 14 months | Aspirin avoidance noninferior for survival free of HRAEs; bleeding reduced by 34% |
| Anticoagulation Quality (TTR) | 12 months | Higher TTR ≥56% linked to better endpoint success and fewer bleedings; no stroke increase |
| Comorbidities (AF, DM, Obesity) | 12 months | Aspirin avoidance benefits consistent regardless of presence of comorbidities |
| Pharmacological Therapy Impact | 1 month (therapy status) | RAAS inhibitors linked to improved outcome; no interaction with aspirin effect |
| Atherosclerotic Vascular Disease Subgroup | 12 months | Aspirin avoidance safe; bleeding decreased without thrombosis increase |
Clinical Implications and Future Directions
The ARIES-HM3 trial series provides high-quality evidence that omitting aspirin from antithrombotic protocols in HM3 LVAD patients treated with VKAs is safe, reduces bleeding risk, and does not elevate thrombotic events. This paradigm shift could improve quality of life and clinical outcomes in a population traditionally burdened by bleeding complications. Optimal anticoagulation management measured by TTR remains critical to reducing bleeding. Patient subgroups with metabolic and vascular comorbidities also benefit from aspirin omission.
Furthermore, the independent beneficial association of RAAS inhibitors on hemocompatibility presents potential therapeutic enhancement targets.
Continued research into personalized anticoagulation strategies, pharmacologic background therapy impact, and long-term outcomes will further refine care for LVAD patients.
References
Reference:
Connors JM, Gustafsson F, Uriel N, Pagani FD, Jorde UP, Katz JN, Netuka I, Zimpfer D, Nemeh H, Ransom JM, Agarwal R, Byku M, Givertz MM, Hall S, Kanwar MK, Cogswell R, Sheikh FH, Phancao A, Ravichandran A, Conway J, Adler E, Chung ES, Grinstein J, Dirckx N, Chakouri N, Mehra MR. Withdrawal of aspirin in patients with left ventricular assist device treated with vitamin K antagonists: impact of anticoagulation quality in the randomized ARIES-HM3 trial. Eur Heart J. 2025 Nov 7:ehaf745. doi: 10.1093/eurheartj/ehaf745 . Epub ahead of print. PMID: 41206679 .
Uriel N, Netuka I, Jorde UP, Pagani FD, Katz JN, Connors JM, Ivak P, Zimpfer D, Pya Y, Conway J, Gustafsson F, Nathan S, Scandroglio AM, Hayward C, D’Alessandro DA, Collins M, Dirckx N, Mehra MR. Impact of Atrial Fibrillation, Diabetes Mellitus and Obesity on Outcomes with Aspirin Avoidance and Hemocompatibility with a Left Ventricular Assist Device: An analysis from the ARIES-HM3 Trial. J Card Fail. 2025 Nov 25:S1071-9164(25)01029-2. doi: 10.1016/j.cardfail.2025.11.488 . Epub ahead of print. PMID: 41308860 .
Katz JN, Connors JM, Pagani FD, Jorde UP, Gustafsson F, Uriel N, Netuka I, Byku M, Anyanwu A, Keebler M, Nathan S, Selzman CH, Alexis JD, Sulemanjee N, Atluri P, D’Allesandro D, Porter S, Lee FS, Mehra MR; ARIES Investigators. Hemocompatibility Outcomes With Pharmacological Therapy Following LVAD Implantation: Insights From the ARIES-HM3 Trial. JACC Heart Fail. 2025 Nov 17:102769. doi: 10.1016/j.jchf.2025.102769 . Epub ahead of print. PMID: 41258850 .
Mehra MR, Netuka I, Uriel N, Katz JN, Pagani FD, Jorde UP, Gustafsson F, Connors JM, Ivak P, Cowger J, Ransom J, Bansal A, Takeda K, Agarwal R, Byku M, Givertz MM, Bitar A, Hall S, Zimpfer D, Vega JD, Kanwar MK, Saeed O, Goldstein DJ, Cogswell R, Sheikh FH, Danter M, Pya Y, Phancao A, Henderson J, Crandall DL, Sundareswaran K, Soltesz E, Estep JD; ARIES-HM3 Investigators. Aspirin and Hemocompatibility Events With a Left Ventricular Assist Device in Advanced Heart Failure: The ARIES-HM3 Randomized Clinical Trial. JAMA. 2023 Dec 12;330(22):2171-2181. doi: 10.1001/jama.2023.23204 . PMID: 37950897 ; PMCID: PMC10640705 .
Gustafsson F, Uriel N, Netuka I, Katz JN, Pagani FD, Connors JM, Jorde UP, Zimpfer D, Pya Y, Conway J, Anyanwu A, Scandroglio AM, Sulemanjee N, Atluri P, Keebler M, Selzman CH, Alexis JD, Hayward C, Henderson J, Dirckx N, Gazzola C, Mehra MR; ARIES Investigators. Aspirin and Hemocompatibility After LVAD Implantation in Patients With Atherosclerotic Vascular Disease: A Secondary Analysis From the ARIES-HM3 Randomized Clinical Trial. JAMA Cardiol. 2025 Mar 1;10(3):235-242. doi: 10.1001/jamacardio.2024.4849 . Erratum in: JAMA Cardiol. 2025 Jun 1;10(6):635. doi: 10.1001/jamacardio.2025.1212 . PMID: 39774588 ; PMCID: PMC11904737 .
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This comprehensive overview consolidates the ARIES-HM3 trial outcomes across multiple facets, organized by follow-up timelines, highlighting aspirin’s role in LVAD patient management and potential clinical practice shifts.