Therapy Management for Adults Undergoing LVAD Placement

A 71-year-old man with ischemic cardiomyopathy has worsening heart failure and requires inotrope therapy. He takes warfarin owing to his history of atrial fibrillation. He is determined not to be a candidate for transplantation but is approved for left ventricular assist device (LVAD) implantation.

How is antithrombotic therapy managed in adults undergoing LVAD placement?

Consensus guidelines from the International Society for Heart and Lung Transplantation have been published on general recommendations for anticoagulation and antiplatelet therapy after LVAD implantation. However, significant institutional variation exists.^1,2  The indications for LVAD placement (bridge-to-transplant or long-term use, i.e., destination therapy) and institutional preference dictate which pump is implanted, but the approach to antithrombotic therapy is similar for all pump designs. The figure shows a typical approach to perioperative management of antithrombotic therapy in adults undergoing LVAD placement.

Preoperative Management

Most patients with heart failure require anticoagulation and/or antiplatelet therapy because of a history of atrial fibrillation, thrombosis, or ischemic heart disease. Clinical trials have shown that prior to LVAD implantation as a bridgeto-transplant, 50 to 60 percent of patients were anticoagulated with heparin, and 30 percent used aspirin.^3,4  Although surgical approaches are evolving, a median sternotomy or thoracotomy is required to insert the inflow cannula into the left ventricle and the outflow cannula into the aorta. Oral anticoagulation and thienopyridine antiplatelet agents (e.g., clopidogrel) are typically discontinued prior to surgery.¹  Prothrombin complex concentrates have been used to reverse the anticoagulant effect of warfarin prior to urgent LVAD surgery without increased thromboembolic events in retrospective case series.⁵  Depending on the indication for anticoagulation, unfractionated heparin can be used to limit the time off anticoagulation prior to surgery.

Intraoperative Management

Cardiopulmonary bypass is required for LVAD implantation. Unfractionated heparin remains the most common anticoagulant during cardiopulmonary bypass owing to the short half-life, familiarity with use, and reversibility with protamine sulfate. Institutional variation exists, but anesthesiologists typically target the protamine dose to normalize the activated clotting time (ACT). For patients with a history of heparin-induced thrombocytopenia (HIT) in whom it is not feasible to wait for disappearance of the heparin-PF4 antibodies, anticoagulation during cardiopulmonary bypass with a direct thrombin inhibitor has been reported.⁶  To decrease the risk of HIT, some institutions have used bivalirudin as the parenteral anticoagulant instead of unfractionated heparin.⁷  During cardiopulmonary bypass using bivalirudin, ACT goals between 300 to 450 seconds have been suggested.⁶  Typically bivalirudin would be discontinued approximately 15 minutes prior to completion of cardiopulmonary bypass, or ultrafiltration could be considered in the setting of severe renal failure to remove the anticoagulant effect prior to surgical closure.⁶ 

Postoperative Management

The balance between thrombosis prevention and avoiding major bleeding can be challenging, as bleeding has been reported in 6 to 69 percent of LVAD patients postoperatively.²  Antithrombotic therapy needs to be adjusted accordingly. It is controversial whether antiplatelet treatment is required and what the dose of therapy should be. Consensus guidelines recommend starting aspirin 24 to 72 hours postoperatively.¹  Despite these recommendations, antiplatelet therapy varies dramatically in the literature.²  Some European centers have avoided antiplatelet therapy in patients with the HeartMate II^TM LVAD with similar rates of bleeding and thrombotic complications (2-year rates of freedom from bleeding, ischemic stroke, and pump thrombosis of 81 ± 6%, 96 ± 2%, and 94 ± 3%, respectively).⁸ 

However, the PREVENT trial and the U.S. Food and Drug Administration approval studies for the HeartWare^TM HVAD^TM (Medtronic, Minneapolis, MN) and HeartMate 3^TM (Abbott Laboratories) have recommended aspirin. A trial of HeartMate II^TM patients randomized to aspirin or placebo is ongoing (NCT02836652). Therefore, it is unknown whether aspirin is required or if differences in pump design mandate alterations in antiplatelet therapy.

Anticoagulation with heparin is recommended to begin once chest tube output has decreased. Although recommended, 29 percent of patients in the HeartMate II^TM trials did not receive heparin bridging.⁹  A retrospective analysis of these patients reported similar thrombotic outcomes, but higher rates of transfusion for bleeding in the patients treated with heparin (16% no heparin vs. 32% therapeutic heparin).⁹  Due to the concern for post-operative hemorrhage and long-term gastrointestinal bleeding, the field shifted away from heparin bridging and reduced anticoagulation targets. An increased incidence of pump thrombosis in HeartMate II^TM patients¹⁰  has led to a re-evaluation of that strategy, including the use of heparin bridging. The PREVENTion of HeartMate II Pump Thrombosis trial involved nine strategies believed to influence the risk of thrombosis, including surgical techniques, antithrombotic therapy, pump speed, and blood pressure management strategies. Ninety-five percent of patients received unfractionated heparin. Patients who received heparin bridging maintained pump speeds of at least 9,000 revolutions per minute, and those who had all implant techniques followed experienced significantly fewer pump thrombosis events at six months (1.9% vs. 8.9%; p<0.01).¹¹ 

Consensus guidelines suggsuggest starting unfractionated heparin with a lower goal range and gradually increasing the anticoagulation target during subsequent days (e.g., postoperative day 1-2 activated partial thromboplastin time [aPTT] goal of 40-60 seconds, and increase aPTT goal to 60-80 seconds on post-operative day 2-3).¹  Hospitals have switched to anti-Xa monitoring of unfractionated heparin and have found a significant discordance between aPTT and anti-Xa activities in LVAD patients that worsens when international normalized ratio (INR) is greater than 1.8.¹²  A randomized feasibility trial of aPTT or anti-Xa management of unfractionated heparin after LVAD implantation recently began (NCT03143569).

Vitamin K antagonists (VKA) are the standard of care for long-term anticoagulation in adult LVAD patients.¹  In the United States, patients typically begin warfarin treatment once the chest tubes have been removed. The direct oral anticoagulants have been used in a limited number of LVAD patients. One of the key randomized studies in question¹³  was stopped early due to an increased rate of thromboembolism in the arm treated with direct oral anticoagulants. Therefore, VKA therapy is the standard long-term anticoagulant for LVAD patients.

Anticoagulation goals for VKA treatment vary between reported studies, but guidelines suggest an INR target of 2.0 to 3.0.¹  Study outcomes vary due to small sample sizes, but thrombotic events have been reported to inversely correlate to INR with the highest event rates occurring with INR lower than 1.5 and increased event rates with INR between 1.5 and 1.9.¹⁴  Maintaining a therapeutic INR in LVAD patients is challenging. Warfarin dosing prior to surgery provides an idea of required dosing, but one study found that 54 percent of patients on long-term warfarin treatment required a change in warfarin dosing after LVAD placement, with most patients requiring a decrease in dose.¹⁵  The time-intherapeutic range (TTR) for LVAD patients has been reported at between 31 to 51 percent, which is significantly worse than other conditions.^16-18  LVAD patients with TTR greater than 60 percent have been suggested to have less bleeding and fewer thrombotic complications.¹⁸  Studies have shown that patient self-testing can improve TTR¹⁷ ; however, Medicare requires 90 days of warfarin therapy prior to covering home testing.

LVAD patients require antithrombotic therapy to prevent thromboembolic complications. New pumps have been designed, but the most effective antithrombotic therapy remains debated. Until additional research becomes available, individual patient management can be guided by consensus opinion, extrapolation from other devices, and institutional practice.