The use of enoxaparin as bridge to therapeutic INR after LVAD implantation

This is a two-center retrospective analysis of 250 consecutive patients with end-stage heart failure undergoing either HVAD (HeartWare International Inc., Framingham, MA), HeartMate II or HeartMate III (Abbott Corporation; Plymouth, MN) LVAD implantation between January 2017 and December 2018 at The University of Kansas Health System in Kansas City, Kansas and at Ascension St. Vincent in Indianapolis, Indiana. Patients were stratified according to the anticoagulation strategy used in enoxaparin (Lovenox; Sanofi) or UFH groups and timing of bridging (index hospitalization [immediate postoperative] vs within 3-months follow-up [early postoperative]). Patients were bridged with LMWH either on index admission, during the 3 month follow up period (should that have been required) or both. Patients with suspected or confirmed heparin induced thrombocytopenia were excluded from the study. Patients were followed daily in the inpatient setting and in planned clinic visits per each institution protocol post LVAD implantation. Data were collected in a retrospective manner from KUMC and St. Vincent prospective LVAD registries and supplemented by chart review of patients’ electronic medical records.

All patients were initiated on anticoagulation with either LMWH or UFH within 24 h and preferably within 12 h post LVAD implantation. Anticoagulation initiation was delayed if there was concern for post-operative bleeding. Most patients post-implantation are initiated on UFH in case of early bleeding complications. The initial dose of LMWH was 0.5 mg/kg administered subcutaneously every 12 h. Unfractionated heparin was initiated as a continuous intravenous infusion using standard protocol with initial bolus at the discretion of the physician. Peak anti-Xa activity of 0.2 to 0.4 IU/ml and PTT level of 60–80 s were considered therapeutic. LMWH dose was adjusted accordingly when anti-Xa levels were not within the target range. Similarly, UFH infusion rate was titrated for a goal PTT level of 60–80 s, or as clinically tolerated. LMWH or UFH was continued until a target international normalized ratio (INR) of 2 to 2.5 was achieved with Warfarin. Warfarin was started when deemed appropriate from a surgical perspective which was generally in the evening of postoperative day 1. Anti-platelet therapy with Aspirin 81–325 mg/day was initiated on the day of implant unless deemed surgically unsafe due to bleeding concerns. Patients that have been deemed ready for discharge but had not yet achieved a therapeutic INR were either discharged on enoxaparin or transitioned to enoxaparin from UFH for discharge. Patients were followed daily while inpatient and per hospital protocol after discharge in an established VAD clinic for the first 3 months post discharge from index hospitalization. Those that were found to have a sub-therapeutic INR (after having achieved a therapeutic INR post operatively) during routine follow-up would either be either be prescribed therapeutic enoxaparin or admitted to the hospital for IV UFH therapy per physician discretion. Patients that were elected to be treated as outpatient had increased INR monitoring until therapeutic levels were achieved.

The primary efficacy outcome was defined as the occurrence of any cerebrovascular accident (ischemic and hemorrhagic) in the first 3 months post LVAD implantation. The primary safety outcome was defined as the occurrence of any clinically significant bleeding event prompting at least hospitalization for inpatient monitoring. Bleeding events that occurred in the immediate post-operative period from the first day of parenteral anticoagulation, deemed non-surgical in nature were also included in the analysis. Those included thoracic, retroperitoneal, gastrointestinal and any bleeding of unknown source. Bleeding for the purposes of this study was defined as any overt bleeding or acute drop in hemoglobin without an identifiable source requiring a transfusion of at least 1 unit of packed red blood cells within a 24-h period. The secondary outcome was defined the length of stay (LOS) during index hospitalization.

A total of 250 patients that underwent LVAD implantation with HVAD (n = 102), HeartMate II (n = 69) or HeartMate III (n = 79) were included in the analysis during their index hospitalization (Fig. 1). Patients in the UFH group were older in age (56.1 ± 11.96 years vs 51.9 ± 15.3 years, p = 0.02), more likely to be male (82% vs 67%, p = 0.03), Caucasian (80.7% vs 65.1%, p = 0.03) and have paroxysmal atrial fibrillation (41% vs 16%, p = 0.005). Patients in the enoxaparin group were more likely to have chronic kidney disease than those in the UFH arm (41.9% vs 15.9%, p < 0.01). Baseline characteristics are detailed in Table 1.

Among 246 individuals followed for 3 months post LVAD implantation, patients in the LMWH arm were significantly younger (52.7 years vs. 56.6 years, p = 0.02), and more likely to have obstructive sleep apnea (29.5% vs 17.5%, p = 0.03), permanent atrial fibrillation (7.7% vs 1.2%, p < 0.001) and chronic kidney disease (38.5% vs 12.2%, p < 0.01). Patients in the UFH group were more likely to be Caucasian (84.30% vs 64.10%, p = 0.001), have an HM III implanted (36% vs 21.7%, p = 0.07) and have paroxysmal atrial fibrillation (44.2% vs 20.5%, p < 0.01).