Rethinking Antithrombotic Therapy for LVADS: Is Less More?

Left ventricular assist devices (LVADs) are surgically implanted mechanical pumps used as an advanced therapy for end-stage heart failure to reduce symptoms, improve quality of life, and extend patients’ lives, either as destination therapy (long-term therapy) or as a bridge to heart transplantation. LVADs have evolved substantially over the past few decades, from early-generation pulsatile devices, which required intensive antithrombotic therapy to prevent pump thrombosis, to continuous-flow devices such as HeartMate II (Abbott) and current-generation centrifugal-flow devices, with HeartMate 3 (Abbott) as the primary option in the US. The engineering improvements in LVADs have led to a lower incidence of pump thrombosis, but significant concern remains regarding bleeding complications often seen in patients with LVADs.

This has prompted recent exploration of shifting antithrombotic therapy to a less intensive approach. In addition, direct oral anticoagulants (DOACs) are being studied as alternatives to warfarin sodium (Jantoven; Upsher-Smith), which has been the standard for anticoagulation therapy for LVADs since their inception.

Lower INR Goals

The HeartMate 3 has shown a lower incidence of pump thrombosis events compared with its predecessor HeartMate II, as evidenced by the pivotal MOMENTUM 3 trial (NCT02224755).¹ This observation, coupled with increased bleeding risk—especially with higher international normalized ratios (INRs)—has led to the exploration of INR targets lower than the standard range of 2 to 3. The landmark MAGENTUM 1 trial (NCT03078374) prospectively evaluated an INR goal range of 1.5 to 1.9 in 15 patients with a HeartMate 3 without added thromboembolic risk factors.² There were no thrombotic events at 12 months, and only 1 patient had a bleeding event. In another retrospective analysis, 26 patients with a HeartMate 3 who had an INR goal range of 1.8 to 2.2 showed only 1 possible thrombotic event over a 12-month period.³

Although these studies have small sample sizes and relatively short duration follow-up results, they suggest that lower INR target ranges may be reasonable and preferable for select patients with a HeartMate 3 device, particularly those with a history of significant bleeding events.

Less Bridging

Although bridging anticoagulation with unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) to therapeutic INR on a vitamin K antagonist is current practice for all durable LVADs (HeartWare [HeartWare International], HeartMate II, HeartMate 3), early studies evaluating bridging with UFH in the early postoperative period following LVAD implantation of pre–HeartMate 3 devices showed an increase in bleeding rates with mixed results in protection from thromboembolic events.^4,5 Furthermore, outpatient bridging with LMWH in pre–HeartMate 3 devices showed a significant increase in risk of bleeding events.^6,7 With HeartMate 3, a recent study investigating a no-bridge approach in the early postimplantation period demonstrated a statistically significant bleeding rate reduction from approximately 33% to 4% (P = .005).⁸ In addition, a recent analysis of the MOMENTUM 3 trial did not show a significant difference in bleeding or thrombotic events between patients with a HeartMate 3 device who were bridged and those who were not.⁹

Although the data are currently limited, less intensive bridging or forgoing bridging in HeartMate 3 recipients may be reasonable, especially given the lower thromboembolic potential observed compared with previous-generation devices.

Aspirin Deprescribing

Antiplatelet therapy has been an essential component of antithrombotic therapy for durable LVADs since the days of early-generation devices. It is still included in antithrombotic regimens for HeartMate II and HeartWare devices; however, improved hemocompatibility in regard to lower incidence of pump thrombosis events observed with HeartMate3 led investigators to study an aspirin-free regimen, given continued concern about significant postimplantation bleeding events.

The landmark ARIES-3 trial (NCT04069156) was a randomized, double-blind, placebo-controlled trial comparing aspirin with placebo in addition to a vitamin K antagonist, with the primary outcome being event-free survival from a hemocompatibility-related event.¹⁰ Bleeding events were assessed as a secondary measure.

Results demonstrated that an aspirin-free regimen was noninferior to standard therapy with a vitamin K antagonist plus aspirin and was associated with less nonsurgical bleeding without an increase in pump thrombosis events. This study has led to the deprescribing of aspirin in patients with HeartMate 3 devices, as well as updated FDA-approved manufacturer device labeling and clinical practice guidelines.^11,12

Potential for DOACs

Anticoagulation with warfarin is standard of care for all durable LVADs, but management can be challenging given the need for frequent INR monitoring, dietary restrictions, and many drug-drug interactions among its disadvantages. The advent of DOACs was revolutionary for the treatment of venous thromboembolism and atrial fibrillation, but their safety and efficacy for preventing pump thrombosis in durable LVADs are unclear.

To date, only a few small studies have investigated DOACs in patients with a HeartMate 3 device. The DOT-HeartMate3 study (NCT04974684) randomly assigned 45 patients to 3 different groups: apixaban with aspirin, without apixaban without aspirin, or a vitamin K antagonist with aspirin.¹³ Primary end points of pump thrombosis, disabling stroke, or major bleeding did not occur in any of the 3 groups at 6 months.¹³

The DOAC LVAD study (NCT04865978) randomly assigned 30 patients to either apixaban or warfarin in addition to aspirin, with results showing no hemocompatibility-related adverse events or deaths at 24 weeks in the apixaban group compared with 2 major gastrointestinal bleeds in the warfarin group.¹⁴ A longer 2-year follow-up analysis also favored fewer events with apixaban compared with warfarin, but the study was not adequately powered to produce confident results.¹⁴

The ongoing ApixaVAD study is investigating low-dose apixaban (2.5 mg twice daily) compared with a vitamin K antagonist.¹⁵ An interim analysis at 6 months revealed similar event-free survival between the apixaban and vitamin K antagonist groups, with no significant difference in thrombotic or bleeding events.¹⁵

It is important to emphasize that these studies have small sample sizes, carefully selected patients, are single-center in design, and mostly demonstrate short-term results; however, the data remain encouraging and are continuing to evolve.

Conclusion

Antithrombotic therapy currently remains an essential component of pharmacotherapy for patients with durable LVADs, but the balance between prevention of thrombotic events and avoidance of bleeding remains a challenge. Several recent small studies exploring less intensive approaches to antithrombotic therapy show promise, but several limitations, including small sample sizes, short duration of follow-up, and careful patient selection, prevent generalization of these results. Data from larger, more robust studies is needed to draw more confident conclusions, but the path forward appears to be moving toward a “less is more” approach.

REFERENCES

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