Anticoagulation management strategies in heart transplantation

Journal Pre-proof Anticoagulation management strategies in heart transplantation

John Rizk, Mandeep Mehra PII:

S0033-0620(20)30032-3

DOI:

https://doi.org/10.1016/j.pcad.2020.02.002

Reference:

YPCAD 1043

To appear in:

Progress in Cardiovascular Diseases

Received date:

29 January 2020

Accepted date:

3 February 2020

Please cite this article as: J. Rizk and M. Mehra, Anticoagulation management strategies in heart transplantation, Progress in Cardiovascular Diseases(2020), https://doi.org/10.1016/ j.pcad.2020.02.002

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© 2020 Published by Elsevier.

Journal Pre-proof

Anticoagulation Management Strategies in Heart Transplantation John Rizk, RPh, MSc,a Mandeep Mehra, MD, MSc, FRCPb From the aArizona State University, Edson College, Phoenix, Arizona; bBrigham and Women's Heart & Vascular Center and Harvard Medical School, Boston, Massachusetts.

Corresponding Author: Dr. Mandeep R. Mehra at the Brigham and Women’s Hospital Heart and Vascular Center, Center for Advanced Heart Disease, 75 Francis Street, Boston, MA 02115 or at

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[email protected]; Fax: 617-264-5265; Tel: 617-732-8534; Twitter Handle:

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@MRMehraMD

Journal Pre-proof ABSTRACT Anticoagulation before, during, and after heart transplantation (HT) presents unique challenges to clinicians. Bleeding and thrombotic morbidity continues to affect this patient population throughout all phases of the HT journey. Reversal is commonly required since patients are commonly bridged to HT with left ventricular assist devices, which require chronic anti platelet and anticoagulation. Caution must be exercised in patients requiring cardiopulmonary bypass during surgery who are at risk of complications from heparin induced thrombocytopenia. The reported incidence of venous thromboembolism following HT is high, particularly during the first post-HT year,

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most likely due to surgery, biopsies, specific immunosuppression (mTOR inhibitors) and immobilization. It is crucial to maintain long-term oral anticoagulation after the first venous

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thromboembolism event, especially when risk factors exist. A major issue, and one for which there remains considerable debate, is the optimal treatment of such complications, particularly upper

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extremity venous thrombosis. For both warfarin and the thrombin inhibitors or Factor Xa inhibitors, the

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clinician must determine potential drug interactions based on the HT drug regimen, and then develop a

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patient-specific management strategy. Key Words: Heart Transplantation

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Venous Thromboembolism

Reversal

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Anticoagulation

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Heparin Induced Thrombocytopenia

Abbreviations: 3F-PCC, 3-factor prothrombin complex concentrates; 4F-PCC, 4-factor prothrombin complex concentrates; ACC, American College of Cardiology; ACCP, American College of Chest Physicians; aFXa, anti-factor Xa; CNIs, calcineurin inhibitors; CIEDs, cardiac implantable electronic devices; CPB, cardiopulmonary bypass; CDT, catheter-directed thrombolysis; CrCl, creatinine clearance; CVC, central venous catheter; CsA, cyclosporine; CYP2C9, cytochrome P450 2C9; CYP3A4, cytochrome P450 3A4; DVT, deep venous thrombosis; DOACs, direct oral anticoagulants; EIA, Enzyme-linked Immunosorbent Assay; FFP, fresh frozen plasma; HT, heart transplantation; HT, heart failure; HIPA, heparin-induced platelet activation assay; HIT, Heparin-Induced Thrombocytopenia; IVC, inferior vena cava; LVAD, left ventricular assist device; LMWH, low-molecular-weight heparin; lower-extremity deep vein thrombosis (LEDVT); P-gp, P-glycoprotein; PE, pulmonary embolism; PF4, platelet factor 4; SRA, serotonin release assay; Tac, tacrolimus; TPE, therapeutic plasma exchange; TTR, time in therapeutic range; UFH, unfractionated heparin; UEDVT, upper-extremity deep vein thrombosis; VTE, venous thromboembolism; VKA, vitamin K antagonist.

Journal Pre-proof Introduction Heart transplantation (HT) is utilized as the choice of therapy in well selected candidates with advanced heart failure (HF) that fail medical therapy [1]. Before a donor heart organ becomes available, many patients require bridging support with a left ventricular assist device (LVAD). LVAD supported candidates are exposed to longterm anti-platelet and anticoagulation therapy and suffer complications of bleeding or thrombosis during the journey of support [2,3]. Unfractionated heparin (UFH) is used during cardiopulmonary bypass (CPB) while performing a HT procedure. Occasionally, the perioperative period is challenged by the presence of HeparinInduced Thrombocytopenia (HIT) Type II [4], and there are no well-defined guidelines for optimal

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anticoagulation management in such patients with HIT.

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Venous thromboembolism (VTE) is significantly more common in solid organ recipients than in individuals from the general population [5-17]. Following HT, 7-12% of recipients experience VTE [16-19], and often require

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prophylactic and therapeutic anticoagulation at different stages of their journey. Consensus guidelines for optimal management of VTE in HT patients are lacking [20]. Thus, we review the role of anticoagulation

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reversal and management in LVAD supported patients when a HT procedure is planned, use of optimal strategies intra-and-perioperatively when heparin induced thrombocytopenia contraindicates conventional

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therapy, and finally after HT when a compelling indication for anticoagulation becomes manifest.

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Reversal of Anticoagulation

Patients with an LVAD are often treated with anticoagulation prior to HT to prevent pump thrombosis, VTE,

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and stroke. In adults, vitamin K antagonists (VKA) are the standard long-term anticoagulants after LVAD implantation, with aspirin serving as the antiplatelet therapy of choice [3]. Aspirin is ideally initiated 24-72

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hours after surgery and VKA treatment typically begins once the chest tubes have been removed (target INR = 2-3) [21,22]. Full and immediate anticoagulation reversal is required prior to HT. Thus, administration of vitamin K alone is not sufficient in correcting coagulopathy in patients who are called in for HT [23]. Before the introduction of 4-factor prothrombin complex concentrates (4F-PCC), fresh frozen plasma (FFP) and low-dose3-factor prothrombin complex concentrates (3F-PCC) were used for warfarin reversal before HT. 4F-PCC offers the advantage of reversing the anticoagulation effects of VKA therapy faster and with smaller volumes than FFP [24,25]. However, a 2019 retrospective study showed significantly higher risk of thromboembolic events in patients receiving 4F-PCC compared to FFP (17.7% vs 2.7%, p≤0.001) for urgent warfarin reversal *26+, raising a significant concern for use of such products in the perioperative period. Consensus guidelines from the American College of Cardiology (ACC) recommend the use FFP for the immediate reversal of anticoagulation only when 4-factor PCC is not available [23]. 4F-PCC is derived from

Journal Pre-proof human plasma that contains factors II, VII, IX, X, protein C, protein S, antithrombin III, and heparin. The dose of 4F-PCC depends on the current INR and the patient’s body weight (if INR 2 to 4: 25 U/kg, INR 4 to 6: 35 U/kg, INR >6: 50 U/kg; dose capped at 5,000 U in patients over 100 kg), and it should be co-administered with vitamin K. Since 4F-PCC contains heparin, its use is contraindicated in patients with HIT [27]. A recent single-center, retrospective cohort study of 106 patients evaluating HT patients pre- and postimplementation of a PCC-based preoperative warfarin reversal protocol for HT revealed that the use of PCC considerably decreases the need for FFP compared with the traditional approach of vitamin K and FFP (6 units versus 8 units, p = 0.002) [28]. Of the PCC cohort, 47 received 3F-PCC and 10 received 4F-PCC. All patients

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receiving 4F-PCC achieved an INR < 1.5 at the time of surgery, whereas 35 of 47 (74.5%) patients receiving 3FPCC achieved this INR goal. Additionally, the study reported a significant reduction in reversal time in the 4F-

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PCC group compared to the 3F-PCC group (1.1 ± 1.0 hours versus 3.4 ± 3.3 hours, p < 0.001). In this study,

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patients who had a baseline INR between 1.6 and 3.4 were given 4F-PCC at a dose of 10 U/kg and patients with a baseline INR between 4 and 6 were given 20 U/kg, along with 10 mg of IV vitamin K. If the INR remained

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above 1.5 after 15 minutes, a second dose of 4F-PCC 500 U was administered. A third and last dose of 4F-PCC 500 U was considered if INR remained above target 15 minutes after the second dose. This step-wise approach

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allowed use of significantly lower doses of 4F-PCC than other studies [24] and the FDA-labeled dose [27], which may be important in avoiding VTE events. Larger randomized trials investigating the appropriateness of

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study, may be considered.

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this dosing protocol are warranted, but until then, a cautious approach using low sequential doses as in this

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Heparin-Induced Thrombocytopenia

HT patients are exposed to heparin mainly during LVAD implantation and subsequently the HT procedure. Heparin is used during HT surgery to maintain patency of the CPB circuit and to prevent blood clots. HIT type II is a life-threatening complication of heparin therapy that is caused by IgG antibodies binding with negatively charged complexes of heparin and soluble platelet protein platelet factor 4, PF4 (which is positively charged) [29]. The incidence of HIT following solid organ transplant is very low. HT recipients are at the highest risk of developing HIT with an incidence of 3.6% [4], compared to 1-3% in the general population [31]. Hourigan et al have shown that >90% (10 of 11 patients) of HIT events occur before HT in patients with a HIT antibody [32]. The diagnosis of HIT requires clinical and serological findings. The clinical scoring system known as the “4 Ts,” based on Thrombocytopenia, Timing, Thrombosis, and oTher causes of thrombocytopenia serves as a tool to assess the probability of HIT II. Laboratory tests include immunological assays (Enzyme-linked Immunosorbent

Journal Pre-proof Assay [EIA]), which quantify platelet factor 4 (PF4)/heparin-specific antibodies, and functional assays [serotonin release assay (SRA) and heparin-induced platelet activation (HIPA) assay], which detect the presence of platelet-activating heparin-dependent antibodies [33]. Accurate diagnosis of HIT II in transplant patients is of the utmost importance and should account for both clinical and laboratory findings. An intermediate-to-high pretest clinical score using the 4T’s scoring system along with a positive EIA + SRA/HIPA is indicative of HIT II. Overdiagnosis of HIT II can lead to an increased risk of intra-operative bleeding and increased healthcare costs as a result of switching to non-heparin anticoagulants, and even in delisting from the transplant list [34].

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Optimal intraoperative anticoagulation management strategies in patients with HIT undergoing CPB remain uncertain, with no widely accepted guidelines [35]. Patients with HIT are at high risk for VTE complications and

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this poses a problem to CPB patients who require full anticoagulation. The American College of Chest

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Physicians (ACCP) guideline for the treatment and prevention of HIT supports heparin re-exposure in patients with a previous history of HIT, particularly if the adverse event did not occur within the last 100 days and anti-

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heparin/PF4 antibody testing is negative at the time of surgery [36,37]. This approach is based on the idea that antibodies are typically undetectable after that period, heparin re-exposure time during the operation is brief,

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the HIT reaction is slow, and that intravenous protamine sulfate can rapidly reverse the anticoagulant effects of heparin [36,37]. In these cases, the use of heparin should be restricted to the operative period and all other

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exposure avoided [36,37].

In patients with an established acute (i.e., thrombocytopenia and detectable anti-PF4/heparin) or sub-acute

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(i.e., platelet count have normalized but anti-PF4/heparin IgG antibodies are still detectable) HIT, the guideline recommends the use of bivalirudin over other non-heparin anticoagulants or heparin plus antiplatelet agents

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[37]. The use of non-heparin anticoagulants such as lepirudin and danaparoid during cardiac surgery has been shown to be associated with an increased risk of bleeding particularly in patients with renal insufficiency [37]. Other strategies include delaying surgery until HIT antibodies decrease to negative titers/levels, plasmapheresis to remove the HIT antibody, and using UFH with a short-acting potent antiplatelet agent such as a prostacyclin analog (such as epoprostenol or iloprost) or a glycoprotein (GP) IIb/IIIa inhibitor (tirofiban) in order to attenuate the HIT reaction [36-42]. A 2008 case-series by Selleng et al presented evidence that it is safe to use UFH in potential HT patients with subacute HIT, provided that they test negative by a sensitive functional assay using washed platelets [43]. HIT antibodies are transient, generally disappearing within 50-80 days [44]. Thus, waiting until antibodies are cleared is not always a plausible option, particularly for patients requiring high urgency HT. In addition, nonheparin anticoagulants bear a considerable bleeding risk, especially if administered to a patient with

Journal Pre-proof thrombocytopenia, and lack reversal agents [41]. The use of intra-operative heparin could be made possible using therapeutic plasma exchange (TPE), which eliminates heparin-PF4 antibodies and recovers platelet counts. Ramu et al. described a case-series of 4 patients requiring CPB with acute HIT, 2 of whom underwent HT [45]. Upon diagnosis, all patients had a positive HIT EIA and 2 had a positive SRA. The strategy in this study involved pre-operative TPE until HIT EIA turned negative, followed by intra-operative heparin. Post-operatively, patients were treated with non-heparin anticoagulants (bivalirudin or argatroban) bridged with warfarin. This strategy was successful in achieving its goal of avoiding non-heparin anticoagulants intra-operatively while preventing complications such as thrombosis and bleeding. Complications associated with plasmapheresis

A proposed algorithm is outlined in Figure 1.

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Thrombosis before HT

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(infections, hypocalcemia, large volume shifts, hemodynamic instability) were not reported in this small series.

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Patients awaiting HT in high-urgency status have risk factors that make them particularly susceptible to VTE. Almost all of these patients are immobile during the pre-operative period, and prolonged immobility leads to

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reduced blood flow, venous stasis, and propensity for VTE. The need and presence of a central venous

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catheter (CVC) is a significant risk factor for the development of a VTE. In addition, cardiac implantable electronic devices (CIEDs), such as transvenous implantable cardioverters, used prior to HT have the potential to form thrombi [46], particularly Upper-Extremity Deep Vein Thrombosis (UEDVT) [18], due to the endocardial

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leads that are recognized as foreign bodies.

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Pre-operative VTE due to Central Venous Catheters Catheter-related thrombosis occurs most commonly in the upper extremity where most long-term indwelling

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catheters are placed [47]. The use of a CVC is associated with a 14.0-fold increase in the risk of UEDVT (95% CI, 5.9-33.2) [48]. There is evidence to suggest that the incidence of CVC-associated UEDVT is on the rise [49], conceivably due to an increase in the clinical use of CVC and improved diagnosis. The optimum management of catheter-related thrombosis is controversial, and for patients with end-stage HF waiting for a suitable donor heart, the treatment strategy will depend on whether or not they continue to need the indwelling catheter. For those who will no longer need a CVC, guidelines from the ACCP recommend removing the catheter after 3–5 days of anticoagulation therapy with warfarin or low-molecular-weight heparin (LMWH). Although the length of a time a patient should be anticoagulated after catheter removal is unclear, the guideline recommends 3 months of anticoagulation, but clinicians often individualize therapy duration depending on prothrombotic risk factors and clot size and location [50,51].

Journal Pre-proof High urgency patients awaiting HT who likely continue to need an indwelling catheter may be candidates for considering the ACCP guidelines that recommend continuation of anticoagulation as long as the CVC remains [50]. Patients with catheter-related thrombosis can initially be placed on UFH or LMWH for 5-7 days, followed by 3 to 12 months of anticoagulation with warfarin or LMWH [50,51]. If CVC is left in place after the anticoagulation course is complete, the ACCP recommends continued anticoagulation treatment at a prophylactic dose until the catheter is removed. In patients with an UEDVT, catheter-directed thrombolysis

Thrombosis after HT

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(CDT) is not recommended as initial therapy [50].

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Solid organ transplant recipients are at a higher risk of developing a VTE than the usually reported rates

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encountered in the general population [5-17], which account for one to two cases per 1000 persons in non-HT patients [52-54]. HT recipients have a six-fold higher risk than the general population of developing a VTE [17],

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which poses an increased risk of death and graft loss.

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Incidence

Estimates of the overall incidence of VTE [deep venous thrombosis (DVT) and pulmonary embolism (PE)] after

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HT range from 7 to 12% [16-19], with variable follow-up duration among studies. Expectedly, the aggregate incidence of VTE after HT does not seem to be influenced by distinct populations or geographic location. A U.S.

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retrospective study of 1258 HT patients by Elboudwarej et al included the largest population, and reported a VTE incidence of 9.3% [18], which is similar to the 8.5% incidence reported in a Spanish study of 635 HT

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patients by Alvarez-Alvarez et al [17]. Similarly, a French study by Forrat et al found that the probability of developing VTE post-HT was 9.86 per 100 patients per year [19]. Moreover, there is seemingly no effect of gender on the development of VTE. Thibodeau et al. reported the highest incidence of VTE events of 12%, which occurred in HT patients taking sirolimus as an adjunctive immunosuppressant. In contrast, HT patients who did not receive sirolimus as part of their immunosuppression regimen had the lowest VTE incidence of 7% (p =0.03) [16]. Furthermore, Elboudwarej et al compared the incidence rate of lower extremity DVT (LEDVT) and UEDVT and found that they were proportionately nearly similar (55.5% vs. 44.4%), but the incidence of PE was higher for those with LEDVT (23.1% vs 7.7%, p=0.04) [18]. Table 1 includes a detailed description of these studies. In all these studies, thromboprophylaxis with subcutaneous UFH or LMWH and/or compression stockings, and aspirin was given to patients who required prolonged bed rest (>24 hours). Thibodeau et al also report using clopidogrel as part of the prophylaxis regimen [16]. The high overall rate of VTE after HT indicates that the current regimens for thromboprophylaxis may be inadequate and warrant a reappraisal.

Journal Pre-proof Anticoagulation Management Post-VTE Guidelines for optimal management of VTE in HT and lung transplant patients are lacking [20]. The primary treatment at the time of VTE in these studies was heparin, enoxaparin, or argatroban, regardless of the DVT type [17,18]. For acute DVT or PE, guidelines from the ACCP recommend starting with parenteral anticoagulant therapy (LMWH, fondaparinux, IV UFH, or subcutaneous UFH) over no such initial treatment, or anticoagulation with rivaroxaban [50]. However, the use of direct oral anticoagulants (DOACs) in HT recipients is controversial due to fluctuating renal function observed in this population, especially early after HT. Subcutaneous enoxaparin could be the preferred agent especially during the early period because of the need

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to perform routine surveillance endomyocardial biopsies, but the use of LMWH may be limited by renal insufficiency. Patients can then be switched to warfarin for long-term anticoagulation. Endomyocardial

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biopsies are high-bleeding risk procedures, and if enoxaparin is used, it should be stopped at least 24 hours

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before each biopsy and resumed on the same day post procedure. Patients placed on warfarin should hold the drug 5 days prior to biopsy, then should be bridged with enoxaparin upon re-initiation if there is a high risk for

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VTE [55,56]. When anticoagulation therapy is contraindicated for LEDVT, the use of an inferior vena cava (IVC)

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filter can be considered, although this approach should be only a last resort [57]. Risk Factors for VTE

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VTE events following HT can be provoked by transient major risk factors. Approximately 40% of VTE episodes occur within the first 30 days after a hospital admission [17]. There is evidence that the risk of VTE is highest

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during the first 12 months after HT (45.1 episodes per 1,000 patient-years), then declines sharply beyond this time (8.7 episodes per 1,000 patient-years) [17]. Repeat endomyocardial biopsies, particularly during the first

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year post-HT, make this patient population susceptible to VTE. Early post-HT VTE can also be due to the use of clotting factors (factor VII and factor IX complex) post-surgery [18]. HT patients have perturbed hemostasis [58,59]; the net effects of this being platelet aggregation and development of coronary artery disease [59]. Emergency transplantation, which refers to the highest level of waiting list priority, is a classic risk factor for VTE [17]. Additional factors such as older age, obesity, renal dysfunction, use of mTOR inhibitors (such as sirolimus and everolimus), lower BMI (cardiac cachexia), and low cholesterol levels have also been shown to contribute to an increased risk of VTE [16,17,18]. VTE recurrence

Journal Pre-proof The incidence rate of VTE recurrence is reported to be 30.5 (95% CI 13.2-60.2) episodes per 1000 patientyears, and is mostly seen in patients who discontinue oral anticoagulation [17]. Evidence suggests that only 4% of patients on an anticoagulant regimen experience a VTE recurrence [17]. Although oral anticoagulation with warfarin reduces the rate of recurrent VTE, studies did not note a reduction in mortality in patients with symptomatic VTE on warfarin (RR 0.89, 95% CI 0.66 to 1.21, P = 0.46), and the risk for major bleeding remains [60]. A multicenter, double-blind trial by Becattini et al showed that aspirin reduces the risk of recurrence in patients with VTE who had discontinued anticoagulant treatment (5.9% vs. 11.0% per year; hazard ratio, 0.55; 95% CI, 0.33 to 0.92), with no increase in the risk of major bleeding [61].

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Guidelines for Anticoagulation Adjustment

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For decades, warfarin has remained the standard therapy in HT patients requiring oral anticoagulation. The use of warfarin can be a challenge given the need for repeated biopsies, frequent anticoagulation

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interruptions, sporadic availability of donor organs, difficulty to maintain optimal time in therapeutic range (TTR), drug-drug interactions, food-drug interactions, and vomiting and diarrhea secondary to

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immunosuppressants causing vitamin K and other electrolyte losses [62-64]. TTR on warfarin in HT patients is

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expected is to be poor [64], predisposing patients to increased risk of thrombotic events or major bleeding [65].

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Transitioning to a DOAC is a potential alternative and these agents are preferred to VKA for many reasons [4850,57]. Pharmacokinetic advantages of DOACs compared to VKA include a faster onset of action, lower inter-

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and intra-patient variability, lack of routine laboratory monitoring, reduced risk of intracranial bleeding, and fewer drug and food interactions [66]. In addition, several studies have shown that DOACs are non-inferior to

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warfarin in the treatment of VTE, with no significant difference in all-cause mortality of VTE-related mortality [67-71]. However, the safety and efficacy of DOACs in the HT population is unknown. Like LMWH, the use of DOACs can be limited by fluctuating renal function, a pertinent issue for HT patients. It may be a good practice to avoid using DOACs in the immediate post-transplant period until a stable renal function is achieved. A prospective, observational study by Ambrosi et al. reported a series of heart transplant recipients taking cyclosporine (CsA) or tacrolimus (Tac) and treated with rivaroxaban. The study observed two cases of rivaroxaban overdosing among 11 heart transplant recipients within the 28 first days of rivaroxaban initiation, discouraging the use of rivaroxaban in transplanted patients with a creatinine clearance (CrCl) <30 ml/min, and caution in patients with moderate renal failure (30 > CrCl < 60 ml/min) [72]. Apixaban is the least renally eliminated DOAC [73], and may be the preferred DOAC for this population due to this advantage. However, there are no studies to evaluate the effect of CsA or Tac on apixaban pharmacokinetics. In contrast,

Journal Pre-proof dabigatran is the most renally eliminated DOAC and is contraindicated when CrCl <30 mL/min [74]. Additional factors such as drug-drug interactions, routine biopsies, and the limited availability of reversal agents may further limit their use. Drug interactions by VKA versus DOAC versus LMWH All oral anticoagulants are subject to interactions with other drugs, requiring careful monitoring and often therapy adjustments. Warfarin is exclusively hepatically metabolized, with S-warfarin (the more potent enantiomer) metabolized mainly via cytochrome P450 2C9 (CYP2C9), with a smaller contribution by cytochrome P450 3A4 (CYP3A4). Therefore, warfarin is subject to increased or decreased serum

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concentration with inhibitors or inducers of the cytochrome system [75,76]. Interactions between warfarin

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and common antimicrobials used in transplant patients, such as azole antifungal agents and sulfamethoxazole/trimethoprim, have high potential to increase INR and bleeding events. A retrospective,

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single-center study by Ha et al. recommended empirical reduction in warfarin dosing by 20%-30% for patients whose INRs were therapeutic at the start of these antimicrobials, followed by INR monitoring over the first 48

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hours for consideration of dosing adjustment [77].

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While DOACs offer the advantage of less drug interactions than warfarin, the potential for drug interactions remains. All four DOACs (rivaroxaban, apixaban, edoxaban, dabigatran) are substrates of P-glycoprotein (P-gp),

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a plasma membrane protein found in the intestine and liver that actively exports drugs out of the cell. Concomitant use of a DOAC with a potent P-gp inhibitor can remarkably increase the concentration of the

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DOAC [78]. In addition, both rivaroxaban and apixaban are metabolized by the liver CYP system, and their concentrations are increased by CYP3A4 inhibitors and decreased by CYP3A4 inducers. This can be troubling

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especially since all transplant recipients are placed on calcineurin inhibitors (CNIs), antihypertensives, and many on antifungals [64]. The CNIs, CsA and Tac, are substrates and inhibitors of CYP3A4 and P-gp pathways [79]. CsA is a potent P-gp inhibitor and a moderate CYP3A4 inhibitor, whereas Tac is a weaker P-gp and CYP3A4 inhibitor [79]. Hence, drug interactions between rivaroxaban/apixaban and CsA are expected to be clinically more significant than with rivaroxaban/apixaban and Tac. In spite of that, a single-center, retrospective study of 39 solid organ transplant patients (including 5 HT recipients) showed that the concomitant use of a CNI with rivaroxaban (n = 29) or apixaban (n = 10) resulted in a limited (<20%) increase in CNI trough concentration, an effect that is unlikely to result in a CNI dose change [80]. Therefore, the benefits and risks of using DOACs in HT patients should be prudently evaluated on a case-by-case basis. Enoxaparin is an attractive option for the treatment of VTE [62]. While anti-factor Xa (aFXa) levels are not routinely performed, some institutions warrant mandatory monitoring of aFXa levels on all transplant patients

Journal Pre-proof treated with therapeutic doses of enoxaparin considering that bleeding secondary to treatment have occurred [81]. Singer et al studied the incidence of supratherapeutic aFXa levels in lung transplant recipients receiving Tac [81]. 12 of 18 patients (67%; 95% CI: 43% - 91%) receiving standard enoxaparin dosing of 1 mg/kg twicedaily had supratherapeutic aFXa activity levels, but none of the 8 patients (0%; 95% CI 0 – 37%) receiving lower non-standard dosing of 0.8 mg/kg twice-daily developed supratherapeutic levels (p = 0.002). When the dose of enoxaparin was reduced from 1 mg/kg twice-daily to 0.8 mg/kg twice-daily, all patients fell within the recommended therapeutic range [Absolute Risk Reduction: 67%, (95% CI: 45% to 88%)]. The study noted no correlation between Tac levels and aFXa levels. These results are consistent with another retrospective, singlecenter study of 96 organ transplant patients (including 8 HT patients), which showed that patients with

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supratherapeutic aFXa had higher doses than those within the therapeutic range (0.89 mg/kg vs. 0.77 mg/kg; p

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= 0.002), though no major bleeds occurred [82]. The immunosuppression drug regimen in these patients included Tac (n = 88, 92%), CsA (n = 11, 12%), and sirolimus (n = 3, 3%), and no specific interactions were

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identified. Table 2 outlines a summary of anticoagulation therapy recommendations in HT patients.

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Conclusions

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Anticoagulation before, during, and after HT presents unique challenges to clinicians. Bleeding and thrombotic morbidity continues to affect this patient population throughout all phases of the HT journey. In LVAD patients, the intensity of antithrombotic therapy should be individualized based on device type, risk of

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thrombosis and bleeding, availability of anticoagulants, institutional preferences, and results of laboratory testing. Caution must be exercised in patients requiring CPB surgery at risk of HIT. The reported incidence of

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VTE following HT is high, particularly during the first post-transplant year, most likely due to surgery, biopsies, specific immunosuppression (mTOR inhibitors) and immobilization. It is crucial to maintain long-term oral

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anticoagulation after the first VTE event, especially when risk factors exist. A major issue, and one for which there remains considerable debate, is the optimal treatment of VTE, particularly UEDVT. For both warfarin and the DOACs, the clinician must determine potential drug interactions based on the HT recipient drug regimen, and then develop a patient-specific management strategy.

Disclosures: J.R. has no relevant conflicts to disclose. M.R.M. reports consulting income from Abbott, Medtronic, Janssen, Bayer, Portola, FineHeart, NupulseCV, Leviticus, Mesoblast and Triple Gene.

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Figure 1. Proposed algorithm for the management of HIT Type II in heart transplant candidates; AC = Anticoagulant, HT = Heart Transplant, TPE = Therapeutic Plasma Exchange

Table 1: Studies evaluating incidence of VTE post-heart transplantation

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Table 2: Summary of recommendations for anticoagulation therapy in Heart Transplantation

Journal Pre-proof Conflict of interest Disclosures: J.R. has no relevant conflicts to disclose. M.R.M. reports consulting income from Abbott,

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Medtronic, Janssen, Bayer, Portola, FineHeart, NupulseCV, Leviticus, Mesoblast and Triple Gene.

Journal Pre-proof Table 1: Studies evaluating incidence of venous thromboembolism post-heart transplantation Investigators

Design

Baseline characteristics

VTE incidence

Risk factors for VTE

Prophylaxis regimen

VTE treatment

Outcome

Results

Alvarez20 Alvarez et al.

Retrospective, single center, observational study

n = 635 (all OHT) from 1991-2013

62 VTE episodes in 54 patients (8.5%)

VTE: <1 year after HT: Chronic renal dysfunction (≥2 mg/dl), older age, obesity (≥30 kg/m2), emergency HT.

Enoxaparin sodium 2,000-4,000 IU daily Bemiparin sodium 2,500-3,5000 IU daily Nadroparin calcium 2,850-5,700 IU daily

Upon diagnosis: LMWH n=26 (52%) UFH n=24 (48%) IV thrombolysis n=1 (2%) IVC filter implantation n=1 (2%) Venous embolectomy n=1 (2%)

Incidence, recurrence, and predisposing factors of VTE among HT patients

Incidence rates (episodes per 1,000 patient-years): VTE=12.7 DVT=8.4 PE=7.0

Follow-up time after transplant: median 8.4 years Mean age:54.6 ± 12.4 years

>1year after HT: mTOR inhibitors

Females: 107 (17%)

VTE recurrence: Anticoagulation discontinuation

Median time from HT to VTE=2.6 years (IQR, 0.1-9 years)

After early post-VTE phase: Oral acenocoumarol n=47 (94%) DOAC n=0

Incidence rate of VTE (episodes per 1,000 patient-years): First Post-HT year=45.1 Beyond Year 1=8.7

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Country: Spain

Patients with VTE who received prophylaxis: Hospitalized=18/25 (72%) Ambulatory=3/32 (9%)

n = 329 (all OHT) n = 67 (20%) on sirolimus n = 134 control group from 1999-2010 Follow-up time after transplant: mean > 3 years

Sirolimus use, lower BMI, lower total cholesterol levels

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Mean age: Sirollimus group: 50 ± 13 years Control: 54 ± 11 years

Cumulative incidence of VTE 8.5%

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Retrospective, single center, observational study

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Thibodeau et al.19

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Incidence rate of VTE recurrence after first VTE episode(episodes per 1,000 patientyears)=30.5

Patients who developed VTE: Sirolimus group: ASA: 7/8 (87.5%) Clopidogrel: 2/8 (25%) Warfarin: Not described Control group: ASA: 2/9 (22.2%) Clopidogrel: 0/9 Warfarin: Not described

VTE treatment: Not described

Sirolimus use and incidence of VTE in HT patients

Median time from VTE to VTE recurrence=1.7 years Sirolimus is associated with an increased risk of VTE in HT recipients. 22 VTE episodes in 17 patients. Sirolimus group: 8/67 (12%) vs. control 9/134 (7%)

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Patient without VTE: Not described

Females: Sirolimus: 16 (24%) Control: 25 (19%)

Elboudwarej et al.21

Retrospective, single center, observational study

Country: USA n = 1258 (all OHT) from 1994-2011 Follow-up time after transplant: 5.4 ± 4.3 years Mean age: UEDVT: 58.7 ± 11.9 years LEDVT: 58.9 ± 10.8 years No DVT/PE: 55.6 ± 12.0 years PE: 57.9 ± 10.8 years Females:

117 VTE (9.3%) episodes (65 LEDVT and 52 UEDVT)

UEDVT: Higher donor age, lower recipient BMI, TAC/MMF LEDVT: Higher recipient age, higher recipient BMI, TAC/MMF, CSA/MMF, PSI PE: UNOS status 1 (38%), CSA/MMF, PSI.

Subcutaneous UFH and/or compression stockings (frequency not described) All patients receive ASA 81 mg/day unless contraindicated

UEDVT (n=52): No trt: 7 (13.4%) UFH, enoxaparin, or argatroban: 25 (48.1%) Warfarin: 11 (21.2%) IVC filter: 0 UFH + IVC Filter: 0 UFH + Warfarin: 3 (5.8%) UFH + ASA: 1 (1.9%) UFH + SE: 1 (1.9%) Warfarin + IVC Filter: 1 (1.9%) ASA + Clopidogrel: 1 (1.9%) Unknown: 1 (1.9%)

Rate of VTE and incidence of PE-related mortality among HT patients.

DVT: 117 (9.3%); 65/117 (55.5%) with LEDVT and 52/117 (44.4%) with UEDVT PE: n=24 (1.9%), 7 deaths. Median time from transplant to DVT: 4.46 months

Journal Pre-proof n = not described. UEDVT: 33% LEDVT: 29% No DVT/PE: 24% PE: 17% Country: USA

Retrospective, single center, observational study

n = 285 (all OHT) from 1984-1988 Follow-up time after transplant: 41.8±1.7 months.

9.86 per 100 patients per year

No significant predictor

Preventive anticoagulant treatment not prescribed unless 1 thrombotic complication has already occurred. Low dose ASA (250 mg) systematically given, unless contraindicated.

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Evaluate the frequency of TE complications after HT and their impact on early and late mortality

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Mean age: 47.6 (5-66) years

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Females: n=49 (17.2%)

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Country: France

TE: 9.86 per 100 patients per year, probability of fatal complications: 3.97% per year. Mean interval between transplant and death: 1247 days vs. non-TE deaths 29.5 days. TE deaths represented 5.1% of total mortality at the first year post-HT but 57, 30, 67 and 73% at the second, third, fourth, and fifth years, respectively.

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Abbreviations: Body Mass Index (BMI), Cyclosporine (CSA), Direct Oral Anticoagulant (DOAC), Deep Vein Thrombosis (DVT), Heart Transplantation (HT), Inferior Vena Cava (IVC), Low Molecular Weight Heparin (LMWH), Lower Extremity Deep Vein Thrombosis (LEDVT), Mycophenolate Mofetil (MMF), mammalian target of rapamycin (mTOR), Orthotopic Heart Transplant (OHT), Pulmonary Embolism (PE), Proliferation signal inhibitors (PSI), Tacrolimus (TAC), Thromboembolism (TE), Treatment (trt), Upper Extremity Deep Vein Thrombosis (UEDVT), United Network for Organ Sharing (UNOS), Venous Thromboembolism (VTE).

Anticoagulant Dabigatran

Rivaroxaban

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Forrat et al.

LEDVT (n=65): No trt: 9 (13.8%) UFH, enoxaparin, or argatroban: 28 (43%) Warfarin: 10 (15.3%) IVC filter: 10 (15.3%) UFH + IVC Filter: 1 (1.5%) UFH + Warfarin: 3 (4.6%) UFH + ASA: 0 UFH + SE: 0 Warfarin + IVC Filter: 2 (3%) ASA + Clopidogrel: 0 Unknown: 1 (1.5%) VTE treatment: Not described

Recommendations  Avoid use when CrCl <30 mL/min.  Avoid use due to potent P-gp inhibition of CsA and increased risk of bleeding in studies.  Avoid when used in combination with potent P-gp inhibitors or inducers.  No studies evaluating effect on CNI trough levels.  Not recommended in HT patients.  Use is discouraged in HT patients with CrCl <30 mL/min.  Consider use when CrCl >30 mL/min, with frequent monitoring of renal function in HT patients.  If used, monitor CNI trough levels initially, but not necessarily in the long-term.

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    

Warfarin

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LMWH (Enoxaparin)

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Edoxaban

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Apixaban

Avoid when used in combination with potent inhibitors or inducers of both CYP3A4 and P-gp. Preferred DOAC in HT due to low renal elimination. If used, monitor CNI trough levels initially, but not necessarily in the long-term. Avoid when used in combination with potent inhibitors or inducers of both CYP3A4 and P-gp. Use not recommended; clinical trials with edoxaban excluded patients taking cyclosporine. Not studied with tacrolimus – unknown effect. Avoid when used in combination with potent P-gp inhibitors or inducers. No studies evaluating effect on CNI trough levels. No correlation between tacrolimus, cyclosporine, sirolimus levels and anti-factor Xa levels. 0.8 mg/kg twice-daily could be the preferred dose. Monitor anti-factor Xa levels (aim for levels between 0.6 – 1.0 IU/mL). Obtain venous blood samples after 3rd or 4th enoxaparin dose and adjust dose accordingly. Use can be limited by fluctuating renal function. Not recommended if frequent surveillance endomyocardial biopsies are expected. Closely monitor INR when used with azole antifungal agent, TMP/SMX, steroids, tacrolimus. Monitor INR/PT at least 2 times weekly when used with azathioprine (≥100 mg). Switch to DOAC in patients with poor time in therapeutic range (TTR) or if considered noncompliant.

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Table 2. Summary of recommendations for anticoagulation therapy in Heart Transplantation