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Brief Communication

Discontinuation of Aspirin in Heartmate 3 Left Ventricular Assist Device

Lim, Hoong Sern; Ranasinghe, Aaron; Mascaro, Jorge; Howell, Neil

Author Information
doi: 10.1097/MAT.0000000000000859

The combination of aspirin and warfarin is commonly used for thromboprophylaxis in left ventricular assist devices (LVADs) therapy. However, this combination is associated with significantly increased risk of major bleeding.1 The Heartmate 3 (HM3) LVAD, engineered to minimize the risk of thrombosis,2 has low risk of pump thrombosis.3 On the basis of these findings, we amended our institutional practice following HM3 implant with the discontinuation of aspirin therapy after >3 months or following a bleeding complication. This study reports the result of this change in practice in our institution.

This is a retrospective analysis of a prospective audit included consecutive patients who underwent HM3 LVAD implant from November 2015 to October 2017 at the University Hospital Birmingham, United Kingdom (Supplemental Digital Content, http://links.lww.com/ASAIO/A314). All our patients had LVAD implanted with the intention of bridging to heart transplantation or candidacy.

Intravenous unfractionated heparin was initiated in all patients within 48 hours of HM3 LVAD implant in the absence of significant bleeding. Warfarin was then initiated 24 hours after initiation of heparin in the absence of bleeding and titrated to a target international normalized ratio (INR) range of 2.0–3.0. Low-molecular weight heparin (LMWH) enoxaparin was used if INR fell below 1.5 (2.0 if atrial fibrillation) at a dose of 1 mg/kg twice daily. Patients were followed up in accordance to our protocol in a specialist LVAD clinic (Supplemental Digital Content, http://links.lww.com/ASAIO/A314). Aspirin (75 mg OD) was initiated within 7 days of implant and continued thereafter in combination with warfarin. However, aspirin was discontinued in patients with bleeding complications, and patients were maintained on warfarin monotherapy (INR, 2.0–3.0). Aspirin was discontinued after >3 months and maintained on warfarin monotherapy.

The end-point for this study was survival free from thromboembolic and bleeding complications requiring intervention. Strokes (n = 2) and cardiothoracic bleeding complications within 2 weeks of LVAD implant were excluded.

This study included 43 consecutive patients after the exclusion of 7 patients who died before discharge. Characteristics are shown in Table 1. All 43 patients started with aspirin and warfarin therapy (median duration of 77 [62–116] days). Three patients were maintained on aspirin and warfarin therapy by choice after discussion, i.e., 40 patients were converted to warfarin monotherapy (median duration of 316 [145–390] days). Fifteen patients were maintained on warfarin monotherapy for >12 months. There was no significant difference in mean INR of median lactate dehydrogenase levels for the 3 consecutive months before and after discontinuation of aspirin (Figure 1A, B). Doppler blood pressure, pump speed, and flow were 92 (86–98) mm Hg, 5,800 (5,600–6,000) RPM, and 5.2 ± 0.2 liters per minute, respectively.

Table 1.
Table 1.:
Patient Characteristics (n = 43)
Figure 1. Serial changes in INR and LDH
Figure 1. Serial changes in INR and LDH:
A: Serial international normalized ratio (INR) 3 months before (black diamonds) and after (white diamonds) discontinuation of aspirin. Error bars indicate 2 standard deviations. B: Serial lactate dehydrogenase (LDH) (IU/L) 3 months before (black diamonds) and after (white diamonds) discontinuation of aspirin. Error bars indicate 2 standard deviations.

Overall survival (conditional on survival to hospital discharge) at 12 months was 91%. None of the patients were transplanted during this period. Eight patients suffered nine events. Eight of these events occurred on aspirin and warfarin: three recurrent/persistent epistaxis requiring intervention/transfusion, three gastrointestinal (GI) bleed, one fatal retroperitoneal bleed, and one intracerebral bleed. One patient suffered GI bleed on warfarin monotherapy, and this patient also had prior GI bleed on aspirin and warfarin. Hence, of the seven patients who survived their bleeding complications, only one patient had recurrence of bleeding on warfarin monotherapy. There were no pump thrombosis or ischemic strokes with or without aspirin. Twelve-month event-free survival was significantly better on warfarin monotherapy compared with aspirin and warfarin (97% vs. 65%, p = 0.018). Details of the fatal retroperitoneal bleed and stroke are described in the Supplementary Material (Supplemental Digital Content, http://links.lww.com/ASAIO/A314).

Recent studies with HM3 LVAD reported no suspected or confirmed pump thrombosis,4 but bleeding complications were comparable to HM2 LVADs. Crow et al.5 noted that the observed rates of bleeding in patients with LVADs were higher than would be expected from anticoagulation therapy alone. Left ventricular assist device-related hemostatic abnormalities6,7 may interact with the intensity of anticoagulation and antiplatelet therapy to increase the risk of bleeding.

Since the change in practice, an analysis of the Multicenter study of MagLev Technology in patients Undergoing Mechanical Circulatory Support Therapy with HeartMate 3 (MOMENTUM 3) trial showed that the absence of antiplatelet therapy was associated with increased risk of adverse events.8 These discordant results may be related to differences in patient characteristics. Patients in MOMENTUM 3 had a median age that was 10 years older than our cohort and destination therapy was the primary intention in the majority of patients. In addition, the pump speeds in our cohort were relatively high compared with other reports.9

This study has a number of limitations. First, this is a relatively small, nonrandomized, single-center study with relatively short follow-up. Second, the timing of discontinuation of aspirin was variable, and in some cases, occurred in response to bleeding complications. The latter may introduce selection bias in favor of warfarin monotherapy. Third, the risk of bleeding may be highest in the first few months in part because of labile INR levels, which may confound the results of this study. We did not find significant differences in early INR between patients with and without bleeding complications. Nonetheless, confounding cannot be excluded. Finally, it is not possible to determine if bleeding complications can be further reduced with warfarin monotherapy at the outset. This should be examined in future studies.

In conclusion, discontinuation of aspirin (warfarin monotherapy) did not appear to be associated with an increased incidence of thromboembolism in the short term. These findings should be evaluated in future studies.

References

1. Warfarin Antiplatelet Vascular Evaluation Trial Investigators. Oral anticoagulant and antiplatelet therapy and peripheral arterial disease. N Engl J Med 2007.357: 217–227.
2. Schmitto JD, Hanke JS, Rojas SV, Avsar M, Haverich A. First implantation in man of a new magnetically levitated left ventricular assist device (HeartMate III). J Heart Lung Transplant 2015.34: 858–860.
3. Mehra MR, Naka Y, Uriel N, et al. A fully magnetically levitated circulatory pump for advanced heart failure. N Engl J Med 2016.376: 440–450.
4. Netuka I, Sood P, Pya Y, et al. Fully magnetically levitated left ventricular assist system for treating advanced HF: A multicenter study. J Am Coll Cardiol 2015.66: 2579–2589.
5. Crow S, John R, Boyle A, et al. Gastrointestinal bleeding rates in recipients of non-pulsatile and pulsatile left ventricular assist devices. J Thorac Cardiovasc Surg 2009.137: 208–215.
6. Uriel N, Pak SW, Jorde UP, et al. Acquired von Willebrand syndrome after continuous-flow mechanical device support contributes to a high prevalence of bleeding during long-term support and at the time of transplantation. J Am Coll Cardiol 2010.56: 1207–1213.
7. Demirozu ZT, Radovancevic R, Hochman LF, et al. Arteriovenous malformation and gastro-intestinal bleeding in patients with the HeartMate II left ventricular assist device. J Heart Lung Transplant 2011.30: 849–853.
8. Uriel N, Colombo PC, Cleveland JC, et al. Hemocompatibility-related outcomes in the MOMENTUM 3 Trial at 6 months. A randomized controlled study of a fully magnetically levitated pump in advanced heart failure. Circulation 2017.135: 2003–2012.
9. Uriel N, Adatya S, Maly J, et al. Clinical hemodynamic evaluation of patients implanted with a fully magnetically levitated left ventricular assist device (Heartmate 3). J Heart Lung Transplant 2017.36: 28–35.
Keywords:

ventricular assist device; anticoagulation; lactate dehydrogenase

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