Direct Oral Anticoagulant Therapy With the HeartMate 3 LVAD: A Pilot Study

HeartMate 3 (HM3) Left Ventricular Assist System (LVAS) is a centrifugal, fully magnetically levitated, continuous-flow pump designed to facilitate hemocompatibility by reducing shear stress on blood elements and to optimize pump washout by intrinsic pulsatility.

The Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy with HeartMate 3 (MOMENTUM 3) trial 2-year data demonstrated an absence of confirmed pump thrombosis requiring pump exchange and marked reduction in stroke rates. On the backdrop of conventional anticoagulation protocols used in the study, observed bleeding complication rates in HM 3 were reduced, yet there is a need for further improvement as the overall intensity of conventional anti-thrombotic therapy represents a major contributor to non-surgical bleeding-related outcomes.

The HM3 LVAS Instructions for Use (IFU) recommend maintaining patients on Warfarin and Aspirin for long-term anticoagulation therapy. Recent results of The Minimal AnticoaGulation EvaluatioN To aUgment heMocompatibility (MAGENTUM 1) pilot study has demonstrated substantially lower-intensity anticoagulation (INR range 1.5 - 1.9) is achievable and supports the safety of lower targets with select patients implanted with the HeartMate 3 beyond 1 year with no thromboembolic complications or pump thrombosis. The observed outcomes were similar to those with the higher intensity anticoagulation targets and further support a signal of enhanced intrinsic thromboresistance of the HM3.

Direct oral anticoagulants (DOACs) are a class of drugs which directly exert therapeutic effect on specific coagulation factors. Broadly, they can be categorized as direct thrombin inhibitors (dabigatran) and factor Xa inhibitors (apixaban, rivaroxaban, and edoxaban) or FXai. Warfarin, which inhibits vitamin K dependent synthesis of coagulation factors in a manner that prevents activation of these factors, has wide inter-individual variation in metabolism and a narrow therapeutic window, as well as both food-drug and drug-drug interactions; the result is that patients taking warfarin require frequent monitoring of the anticoagulant effect to maintain safety and efficacy. The DOAC directly enter the blood to bind to the activated coagulation factor target; they have predictable pharmacokinetics, little interindividual variation in metabolism, few drug-drug interactions, and no interactions with foods. The large phase 3 RCT in both AF and VTE established both efficacy and safety-without the need for monitoring. The FXai may provide better anticoagulation than the oral direct thrombin inhibitor due to their action earlier in the coagulation cascade prior to the generation of thrombin which may ameliorate the likelihood of initiation of the feedback loop resulting in >1000-fold increase in thrombin production. Of the studied FXai , apixaban has the lowest major bleeding complication rate and has not been shown to increase GI-bleeding. It also has the least dependence on renal clearance.

Consequently, with the documented enhanced hemocompatibility of the HeartMate 3 and the potential for reduced major bleeding with apixaban in indicated patient populations, the investigators provide the rationale that patients with the HM3 are in clinical equipoise to be randomized in a feasibility study of a new antithrombotic strategy testing apixaban with or without aspirin compared to the current standard of care warfarin and aspirin in a rigorously structured study to evaluate safety in stable patients with the HM3 device.