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Interactive CardioVascular and Thoracic Surgery 15 (2012) 733–740 What is the optimal anticoagulation in patients with a left Michele Rossi*, Giuseppe Filiberto Serraino, Federica Jiritano and Attilio Renzulli Department of Cardiac Surgery, Magna Graecia University, Catanzaro, Italy * Corresponding author. Department of Cardiac surgery, Magna Graecia University, Viale Europa. Germaneto, 88100 Catanzaro, Italy. Tel: +39-096-13647058; fax: +39-096-13647142; e-mail: [email protected] (M. Rossi).
Received 6 March 2012; received in revised form 17 May 2012; accepted 31 May 2012 A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was whether there isan optimal antithrombotic management for patients supported with axial-flow left ventricular assist devices (LVADs). Altogether, morethan 758 papers were found using the reported search, of which 17 represented the best evidence to answer the clinical question. Theauthors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers aretabulated. These included seven prospective and three retrospective cohort studies with a total of 538 patients with axial-flow left ven-tricular assist device (LVAD) (HeartMate II, Jarvik 2000, INCOR, Thoratec assist device) implanted across the world as destination therapyor bridge to transplantation. We conclude that there is a substantial alteration of the prothrombotic profile in patients with axial-flowLVADs. These abnormalities appeared to be reversible with the removal of the device and are likely to be responsible for the high inci-dence of non-surgical bleeding episodes reported. Warfarin seems to offer a lower thromboembolic risk compared with unfractionedheparin or low molecular weight heparin. There are reports that suggest that managing axial-flow LVAD without anticoagulation, aftermajor bleeding complications, is possible but in all probability, these papers are subject to publication bias as poor outcomes are un-likely to have been reported. All patients with axial-flow LVAD, showed severely impaired platelet function at point of care tests. Theuse of warfarin (INR target 2.5), in association with aspirin at 100 mg/day, or with point-of-care tests titrated antiplatelet therapy toinhibit 70%, seems to have the best bleeding-thrombosis, and in many cases a very small dose of aspirin of 25 mg twice a day and adose of clopidogrel of 35 mg/day, were sufficient to achieve a reduction of the maximum aggregation to less than 30%. Finally, wewould like to emphasize that such recommendations are addressed only to patients with axial-flow LVAD.
Keywords: Left ventricular assist device • Oral anticoagulation • Antiplatelet agents • Antithrombotic therapy resolve. You wonder what the current anticoagulation strategies are around the world and resolve to check the literature.
A best evidence topic was constructed according to a structured protocol. This is fully described in the ICVTS [ Medline 1950 to March 2012 using OVID interface (left ventricu- lar assist device/or LVAD.mp.) and (antithrombotic therapy/oranticoagulation.mp.) In [ patients with axial-flow left ventricular assist device] what is[the best anticoagulation strategy] to [optimize mortality andmorbidity]? 758 papers were found using the reported search. From these, 17 papers were identified. That provided the best evidence toanswer the question. They are presented in Table You are at a ventricular assist device (VAD) conference and thespeaker is talking about the problems that they have beenhaving with non-surgical bleeding at their institution. You are surprised as in your institution you have not had many bleedingcomplications, but have had a few serious ventricular assist Uriel et al. in a retrospective analysis of 79 patients with device (VAD) thromboses, which all required thrombolysis to axial-flow LVAD, anticoagulated with a combination of warfarin, The Author 2012. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.
M. Rossi et al. / Interactive CardioVascular and Thoracic Surgery journal, countryStudy type(level ofevidence) Uriel et al., 2010, Seventy-nine HM II were reviewed 2 CVAs, 1 popliteal arteryembolism and 2 embolicevents after treatment with IVIgGn Stern et al., 2010, Thirty-three patients undergoing GI bleeding after 63 ± 62(range 8–241) days of support.
heparin (target PTT of 60–80 s) recorded in the VAD group binding capacity and ristocetincofactor activity were lower inVAD compared to HTXrecipients M. Rossi et al. / Interactive CardioVascular and Thoracic Surgery journal, countryStudy type(level ofevidence) Crow et al., 2010, Blood samples were collected Ann Thorac Surg, before and after CF-LVAD aggregation as well as a loss of in all patients after LVAD to warfarin after drain removal patient had AvWS aspirin was(INR target 2.5 ± 0.5) + aspirin pump thrombosis (one afterdiscontinuation of warfarin) One died due to mesentericischaemia 4 months afterimplantation; 1 died due tosepsis after 40 months episodes. One patient had atransient ischaemic attack(INR 1.6) M. Rossi et al. / Interactive CardioVascular and Thoracic Surgery journal, countryStudy type(level ofevidence) Coumadin (0–8 mg daily dose) Despite high shear stresses Int J Artif Organs, implanted for destination therapy John et al., 2008, Forty-five patients (mean age 57.24 Warfarin (from POD 3–5) with postoperative heparin and 14 patients and 1.5–2.0 for theothers; aspirin from POD 2–3at 81 mg/day Forty-one had a mean INR ofless than 2.0; of those 41patients, 21 had a mean INRof less than 1.6 the remaining 31 patients who without any thromboembolicreceived only warfarin, 4 had thrombus (INR, 1.3 at the time usedof presentation) therapy with aspirin andclopidogrel was startedbetween the second and thefifth POD AA,/50% with epinephrine and the effective dose of clopidogrel/30% with ADP. Collagen M. Rossi et al. / Interactive CardioVascular and Thoracic Surgery journal, countryStudy type(level ofevidence) events was 0.09 and 0.2 perpatient-year respectively Thereafter, IV heparin (PTT60– monitored through measurement drains were removed and total peak levels). Antiplatelet therapy 75 mg three times daily. Assoon as the patients weremoved to the regular ward,the intravenous heparin wasreplaced by subcutaneousLMWHs at a therapeutic levelof 1 mg/kg, twice daily One patient had a fatal lateintestinal bleeding Five minor TIA. FourThrombus-related pumpdysfunction. One severe strokewith concomitant intracranialbleeding fatal to the patient every 6 h. Aspirin was startedat 2–10 mg/kg/min after plt >150 000 mm3. Dosage wasincreased in larger children by162–325 mg for each 100 000plt above 150 000.
Pentoxifylline 400 mg × 3/dailywas used in >6-years old Eight deaths (29%): 4 embolic,1 graft failure, 2 anoxic braindamage and 1 postexplantheart failure (21%); 7 strokes (25%) and 3visceral emboli (11%) M. Rossi et al. / Interactive CardioVascular and Thoracic Surgery journal, countryStudy type(level ofevidence) thromboembolism,haemorrhage or drivelineinfection Ann Thorac Surg, matched volunteers using TEG Although antigen levels of von collagen adenosine diphosphateWillebrand factor were 80% threefold higher in volunteers(P < 0.001) In all VAD implantation except The risk of cerebrovascular 62 seconds. Warfarin wasintroduced on postoperativeday (POD) 10 INR 2.5–3.5.
Aspirin 81–325 mg and/orclopidogrel 75 mg daily wasstarted 48 h after implantation M. Rossi et al. / Interactive CardioVascular and Thoracic Surgery journal, countryStudy type(level ofevidence) PTT: partial thromboplastin time; BVAD: biventricular assist device; ADP: adenosine diphosphate; POD: post operative day.
aspirin and dipyridamole, reported an incidence of gastrointes- effect on platelet activation, independently of length of support, tinal (GI) bleeding events of 44.3%. Anticoagulant use was not antiplatelet and anticoagulation regimens used.
statistically different between bleeders and non-bleeders, with John et al. in their series of 45 patients supported with an average INR at time of bleeding of 1.67 ± 0.53.
HM II, successfully reduced the intensity of anticoagulation (avoid- Stern et al. ] similarly reported an incidence of GI bleeding ing postoperative heparin infusion, decreasing the therapeutic INR of 40% in the HeartMate II (HM II) axial-flow LVAD, group versus to 1.5–2.0 and introducing aspirin at 81 mg/day from post op day 0% in the pulsatile one. The anticoagulation protocol consisted 2–3), without any increase in thromboembolic events.
of a low-dose of aspirin and dipyridamole and warfarin (INR of Attisani et al. [] successfully used a platelet aggregation test 2.0–3.0). Interestingly, 3 bleeding patients uneventfully withheld (PAT) to reduce the dose of antiplatelet in 14 patients supported with the INCOR LVAD and anticoagulated with warfarin (INR Demirozu et al. [in a large series of 172 patients, supported target 2.8–3.2). They showed that 82% required a dose of aspirin with HM II and anticoagulated with warfarin aspirin and dipyrid- of 25 mg twice a day and 90% a dose of clopidogrel of 35 mg/ amole, reported a GI bleeding rate of 32%. They demonstrated day, to reduce the maximum aggregation <30%. They reported the presence of an arteriovenous malformation in 31% of the no GI bleeding episodes and a rate of major and minor thromboembolic events of 0.09 and 0.2 per patient-year, Geisen et al. [demonstrated that their axial-flow LVAD patients developed impaired coagulation secondary to acquired Meuris et al. in 10 patients supported with the INCOR LVAD implanted as bridge-to-transplantation, suggested the use Crow et al. ], in a multicenter prospective study, investigated of the low molecular weight heparin (LMWH) (1 mg/Kg twice the impact of continuous flow LVAD support on the haemostatic daily) and triple antiplatelet therapy (aspirin at 80 mg two times profile in 37 patients. All LVAD recipients developed AvWS after daily; clopidogrel at 75 mg daily; and dipyridamole 75 mg three the device implantation, but only 10 had bleeding complica- times daily) as an alternative to oral anticoagulants. PAT was tions. The anticoagulation protocol consisted of warfarin (INR used to reduce platelet aggregation levels to at least 30%. They target 1.5–2.0) and aspirin. INR levels between bleeders and reported 1 severe stroke with concomitant fatal intracranial non-bleeders were similar. Point of care test for the evaluation bleeding and 4 Thrombus-related pump dysfunction.
of platelet function was not used. They conclude that the loss of Copeland et al. [], similarly in children with LVAD used IV high-molecular-weight von Willebrand factor multimers alone heparin associated with point-of-care titrate antiplatelet therapy consisting of: Aspirin 2–10 mg/kg/min increased in larger chil- Meyer et al. ] showed the reversibility of AvWS in 26 patients dren by 162–325 mg for each 100 000 platelets above 150 000; supported with axial-flow LVAD implanted as bridge to trans- dipyridamole, IV at 0.1 mg/kg/h in children <6 years old, 50 mg plantation after the removal of the device. During LVAD support (age 6–10 years) or 100 mg (>10 years) by mouth every 6 h; pen- they reported an incidence of bleeding of 0.17 per patient-year toxifylline 400 mg per os three times daily(age > 6). This experi- using warfarin (INR target 2.5 ± 0.5) and Aspirin 100 mg/day. If a ence was worrisome, with 20% incidence of reoperation for patient was diagnosed with AvWS, aspirin was stopped. One bleeding and 25% of stroke (2 fatal).
patient had fatal mesenteric ischaemia. Platelet function analyser Saito et al. [in an animal model, successfully supported showed severe impairment in all patients on LVAD support.
the systemic circulation with continuos flow LVAD without any Jennings et al. [] reported that their outpatient HM II cohort (16 patients) spent 32% of the average time below the thera- Pereira et al. reported 2 axial-flow LVAD patients who stopped peutic INR range (2.0–3.0) with only one incidence of TIA and anti-thrombotic therapy for more than a year because of recurrent no incidence of GI bleeding episodes. The authors did not GI bleeding episodes, without any thrombotic complications.
Steinlechner et al. [], simultaneously used thrombelastography Slaughter et al. [showed that, despite high shear stresses (TEG), rotation thromboelastometry (ROTEM), platelet function associated with a high-speed axial flow pump, there was no analyser (PFA-100) and multiplate, on 12 patients supported with M. Rossi et al. / Interactive CardioVascular and Thoracic Surgery continuous flow LVAD. They showed markedly impaired platelet support contributes to a high prevalence of bleeding during long-term function independently from the effect of the anticoagulation support and at the time of transplantation. J Am Coll Cardiol 2010;56:1207–13.
therapy with warfarin (INR target 2.5–3.5) and aspirin 100 mg/day.
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Reliable long-term non-pulsatile circulatory support without anticoagu- Conflict of interest: none declared.
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