Search

Direct-acting oral anticoagulant (DOAC) use has increased dramatically since their introduction because of the growing evidence of proven efficacy and enhanced safety compared with warfarin and the low-molecular-weight heparins in the general population. Unfortunately, there is a dearth of quality data regarding the safety and efficacy of the DOACs in patients awaiting organ transplant and those who received a solid organ transplant. This review aims to evaluate the available literature and considerations regarding anticoagulation use in transplant recipients, focusing on preoperative, perioperative, and postoperative DOAC use.

The introduction of newer anticoagulants requires clinicians to fully appreciate, interpret, and correctly apply the use of coagulation assays, such as the prothrombin time (PT), activated partial thromboplastin time (APTT), and anti-factor Xa assays. For oral vitamin K antagonists, the international normalized ratio (INR) is a predictor of anticoagulation intensity. However, for direct oral anticoagulants (DOACs), the PT or INR and APTT are unable to quantify the level of anticoagulation intensity as there is a poor correlation between plasma concentration of DOAC with these routine coagulation assays and that significant anticoagulant effect may still be present despite normal or near normal results for these routine assays. In the USA, there are 5 DOACs available including dabigatran, a direct thrombin inhibitor and 4 direct factor Xa inhibitors (FXaI), each with varying indications, doses, pharmacodynamic, and pharmacokinetic characteristics. A thorough understanding of these properties aids in the management of the periprocedural or bleeding patient. In this first section of this manuscript, we will review the laboratory tests that are commonly performed for assessing a patient’s coagulation status with known DOAC exposure. The second section will describe 3 real-world challenging case studies in DOAC-treated patients, with a focus on presenting clinical queries, interpretation of baseline laboratory tests with interpretations, followed by the case discussion to combine interpretation of appropriate laboratory tests with clinical patient considerations in an effort to guide clinical decision-making.

Durable left ventricular assist device (LVAD) recipients require long-term anticoagulation to prevent thromboembolic complications. Their management is complicated by the risk of bleeding, which may require rapid anticoagulation reversal. We conducted a narrative review of data published from January 2007 to September 2018, analyzing anticoagulation reversal strategies in patients with durable, continuous-flow LVADs. The aim of this review is to provide guidance for reversal strategies in patients with LVADs experiencing bleeding complications or needing urgent surgical procedures, incorporating four-factor prothrombin complex concentrate (4F-PCC). Most data were from small, retrospective studies. Data for 4F-PCC use were more robust for heart transplant than for other surgical procedures or bleeding management. In patients undergoing heart transplant, 4F-PCC reversed warfarin more rapidly and reduced total blood product use versus other reversal strategies. Most surgical procedures were conducted without excess bleeding when utilizing 4F-PCCs. Time to warfarin reversal was shorter when managing intracranial hemorrhage with 4F-PCC. No differences in thromboembolic rates between 4F-PCC and control groups were observed. Overall, the use of 4F-PCC resulted in more rapid and predictable warfarin reversal in LVAD patients with no apparent risk of thromboembolism. Well-designed, larger prospective trials are required to better define 4F-PCC use in patients with LVADs.

Background Both andexanet alfa and 4F-PCC reversal strategies have been associated with thrombotic events. It remains unclear whether the risk is associated with the reversal agent or the lack of re-initiation of anticoagulation. Objective The aim of this study was to describe anticoagulant (AC) re-initiation patterns in patients presenting with major bleeding while on a FXai requiring reversal, and to describe associated post-reversal thrombotic events. Methods This was a single-center retrospective cohort study. Patients were included if they received FXai reversal with andexanet alfa or 4F-PCC for major bleeding. Results Fifty-seven patients met inclusion criteria; of these patients, 34 received andexanet alfa and 23 patients received 4F-PCC. Most patients were prescribed AC for atrial fibrillation. The most common indications for reversal were intracranial hemorrhage 68%, followed by gastrointestinal bleeding 19%. AC was re-initiated at either prophylactic or therapeutic doses in 59% in the andexanet alfa recipients and 65% in the 4F-PCC recipients within 30 days. In those who restarted AC within 30 days, the median time to re-initiate AC was three days [IQR: 1–3]. Thrombotic events occurred in 3% of patients in the andexanet alfa group and 13% in the 4F-PCC group (7% overall rate). None were receiving anticoagulation at the time of the event. Conclusion Anticoagulation was restarted in approximately half of the patients who received a reversal agent for a life-threatening bleed. The thrombotic risk was 7% at the 30 day follow up period. Continuous assessment of bleeding and thrombosis is important for post-reversal management of patients with major bleeding events.

Background Four‐factor prothrombin complex concentrate (4F‐PCC) dosing is based on INR and actual body weight (ABW), with maximum doses not to exceed the dose used in patients weighing >100 kg (Kcentra PI). There are limited data comparing the efficacy of 4F‐PCC between patients with low body weight ≤100 kg (LoWT) and high body weight >100 kg (HiWT). Methods We conducted a retrospective cohort study of patients on warfarin who received 4F‐PCC for life‐threatening major bleeding or requiring emergent surgery between January 2015 to June 2018 at three academic medical centers. These data were combined with a dataset from 2 randomized Phase 3b clinical trials. Results We included 388 patients who received 4F‐PCC, 318 (82%) were LoWT, and 70 (18%) were HiWT. Indication for 4F‐PCC for life‐threatening bleeding and emergent surgery was 266 (69%) and 122 (31%) patients, respectively. The most common bleeding type was intracranial hemorrhage (41%), followed by gastrointestinal (36%). The median dose was 2283 units (25 units/kg), and 2.1% of patients required a repeat dose. Conclusion In those >100 kg, we found no difference in achieving international normalized ratio (INR) ≤1.3, hemostasis in intracranial hemorrhage, or thrombosis. In‐hospital mortality occurred 15% in LoWt versus 6% in HiWT (CI 1.8%–17%, p = 0.034). Achievement of INR ≤ 1.5 was significantly lower in the LoWT group compared to the HiWT group (80% versus 91%, CI −20% to −2.5%, p = 0.03).

Patients on oral anticoagulation commonly undergo surgery or other invasive procedures. Periprocedural management of oral anticoagulants involves a careful balance of the thromboembolic risk and bleeding risk. To standardize clinical practice at our institution, we developed a guideline for periprocedural management for patients taking oral anticoagulants that incorporates published data and expert opinion. In this article, we present our clinical practice guideline as a decision support tool to aid clinicians in developing a consistent strategy for managing periprocedural anticoagulation and for safely bridging anticoagulation in patients who require it.

Continuous flow left ventricular assist devices (CF-LVAD) require therapeutic anticoagulation which is often interrupted for procedures or bleeding. Prior to the availability of four factor prothrombin complex concentrate (4F-PCC) in the United States, warfarin was held and its effects reversed by vitamin K or fresh frozen plasma. We evaluated the use of 4F-PCC for temporary warfarin reversal in patients with CF-LVADs and assessed outcomes. This analysis is a retrospective study of CF-LVAD patients who received 4F-PCC for warfarin reversal in the setting of bleeding or need for urgent or elective procedures. Primary outcome assessments included feasibility of administration in elective versus emergent situations, safety measured as incidence of thrombotic events, and change in INR after administration. In total, 37 CF-LVAD patients received 49 4F-PCC administrations. The average 4F-PCC dose was 1842 units (range 518–4292 units), or 22 units/kg (range 5.8–58 units/kg). 4F-PCC significantly decreased the mean INR from 2.9 to 1.7 (p

Background The HeartMate 3 left ventricular assist system is engineered to avoid pump thrombosis, yet bleeding complications persist. We investigated the safety of low-intensity anti-coagulation in patients with the HeartMate 3. Methods The M inimal A nticoa G ulation E valuatio N T o a U gment he M ocompatibility (MAGENTUM 1) pilot study is a prospective, single-arm study of low-intensity warfarin anti-coagulation in patients implanted with the HeartMate 3 pump. After standard warfarin anti-coagulation (international normalized ratio [INR] 2.0 to 3.0) and aspirin for 6 weeks post-implant, patients were transitioned to a lower INR target range of 1.5 to 1.9. The primary end-point was a composite of survival free of pump thrombosis, disabling stroke (modified Rankin score [MRS] >3), or major bleeding (excluding peri-operative bleeding) with at least 6-month post-implant follow-up. Time in therapeutic range (TTR) was measured to assess anti-coagulation target efficacy using the Rosendaal method. A safety algorithm to monitor for signs of pump thrombosis was developed and implemented. Results We enrolled 15 patients (mean age 57.3 ± 13.3 years), 13 men with advanced heart failure (67% with INTERMACS Profiles 2 or 3), irrespective of therapeutic goal of bridge-to-transplant or destination therapy. The primary end-point was met in 14 of 15 (93 ± 6%) patients; 1 patient developed recurrent gastrointestinal bleeding . The TTR during the reduced anti-coagulation phase (6 weeks to 6 months) was 75.3 ± 8.6%. No thrombotic events occurred. Conclusions This pilot study suggests low-intensity anti-coagulation targeting an INR between 1.5 and 1.9 is achievable and safe with the HeartMate 3 cardiac pump in the short-term phase, 6-months post-implant. A large-scale trial is now warranted.

Background Diagnosing heparin‐induced thrombocytopenia (HIT) in patients with end‐stage renal disease (ESRD) can be difficult, as they are frequently exposed to heparin and have multiple etiologies for thrombocytopenia. Objective To correlate 4T scores, IgG heparin–platelet factor 4 (PF4‐heparin) ELISA results, and serotonin release assay (SRA) results in patients with ESRD. Methods We performed a retrospective review of patients with ESRD (creatinine clearance 0.4 but negative SRA, who were not treated for HIT, there were no adverse outcomes documented such as new or progressive thrombosis. Conclusion In our ESRD population, 4T scores and PF4 testing were not predictive of a clinical diagnosis of HIT.

In patients with submassive pulmonary embolism, the use of catheter-directed thrombolysis (CDT), using low-dose alteplase is associated with improvement in overall hemodynamics. The data for use of CDT in patients with heparin-induced thrombocytopenia are limited. We report a case of CDT in a patient with HIT using bivalirudin anticoagulation. Data of the use of bivalirudin and argatroban for systemic anticoagulation with CDT are limited.

Andexanet alfa is a recombinant factor Xa decoy molecule capable of reversing direct and indirect factor Xa-inhibiting anticoagulants. We present an adult patient on apixaban for nonvalvular atrial fibrillation who required urgent reoperative aortic surgery for an aortic root pseudoaneurysm. Apixaban was reversed with andexanet alfa. A second dose of andexanet alfa was required before surgical incision for persistently elevated antifactor Xa levels. Intraoperative management required use of cardiopulmonary bypass (CPB). No major adverse cardiovascular, cerebrovascular, hemorrhagic, or thromboembolic events were observed.

Gastrointestinal bleeding (GIB) occurs in up to 40% of patients with continuous-flow (CF) left ventricular assist devices (LVADs). We sought to identify targets to improve hospital resource utilization and decrease readmissions after GIB. We performed a single-center, retrospective analysis of LVAD-associated GIB resulting in hospital admission between July 2011 and April 2014. Follow-up data were collected through March 2015. We analyzed 57 admissions for GIB in 23 patients. One or more diagnostic imaging study was performed in 47% of admissions, with a definite or probable source of GIB identified in 23%. A total of 76 endoscopies were performed (≥ 1 endoscopy in 79% of admissions, ≥ 2 in 42%). Definite or probable bleeding sources were identified in 25% and 12% of endoscopies, respectively. Patients who underwent multiple endoscopies were no more likely to have a bleeding source identified (OR 1.48; 95% CI 0.50–4.32; p = 0.59) and had longer hospital stays (11.1 vs. 7.8 days, p

Patients with durable mechanical circulatory support are at increased risk of thromboembolic and bleeding complications. Current guidelines recommend that these patients receive chronic anticoagulation with warfarin to maintain a target international normalized ratio (INR) as specified by device manufacturers. Limited data exist regarding management of subtherapeutic INRs in this setting. To standardize clinical practice at our institution, we assembled a multidisciplinary task force including members from various specialties to develop a guideline for managing subtherapeutic INRs that incorporates published data and expert opinion. In this article, we present our clinical practice guideline as a decision support tool to aid clinicians in developing a consistent strategy for managing subtherapeutic INRs and for safely bridging anticoagulation in patients receiving mechanical circulatory support.

Recipients of left ventricular assist system (LVAS) require long-term anticoagulation with warfarin to prevent thromboembolic complications. We discuss a successful case of the use of four factor prothrombin complex concentrate (4F-PCC) for temporary warfarin reversal in a patient with a HeartMate 3 LVAS requiring robotic assisted laparoscopic prostatectomy.

Unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) are highly utilized throughout inpatient and ambulatory care settings for many indications, including the treatment of venous thromboembolism, thromboprophylaxis, and acute coronary syndromes. In this chapter, we review the evidence-based recommendations and pharmacology of both UFH and LMWH with a detailed description of their mechanisms of action, pharmacokinetics, and pharmacodynamics. We highlight approved indications and dosing as well as common unapproved uses of these agents. We review important monitoring considerations for each agent in addition to considerations that should be evaluated when treating certain patient populations. Finally, we discuss various reversal strategies and complications that can arise from their use.

Patients on oral anticoagulation (OAC) requiring an invasive procedure or surgery may require interruptions to their anticoagulation regimen depending on patient- and procedure-specific factors. The risks of both thromboembolism and procedural-related bleeding need to be considered as well as provider and patient preferences. Though some dental procedures allow for continuation of OAC, other procedures may require that their anticoagulation regimen be continued at a minimized intensity, held, or switched to a temporary “bridging” agent. A plan specific to each event requires coordination with the patient, the provider overseeing the patient’s anticoagulation regimen (e.g., primary care provider, cardiologist, or other specialist) and the provider performing the surgery or invasive procedure. This chapter will focus on the periprocedural management of anticoagulants.

Bivalirudin may cause a falsely prolonged international normalized ratio (INR) that complicates the discontinuation of bivalirudin when used as a bridge to warfarin. To prospectively validate our novel bivalirudin to warfarin transition nomogram, adult patients who received bivalirudin as a bridge to warfarin between July 2015 and June 2016 were prospectively evaluated, utilizing our predictive nomogram. The major outcome of our analysis was the correlation between the predicted change in INR upon bivalirudin discontinuation based on the nomogram, and the actual change in INR upon bivalirudin discontinuation. The major outcome was analyzed using the Pearson’s correlation test. A Pearson’s correlation coefficient >0.6 was considered to be a strong correlation. Bivalirudin was used as a bridge to warfarin in 29 patients. The majority of patients (86%) included in the analysis had a ventricular assist device. The median initial bivalirudin rate was 0.07 mg/kg/h and the mean increase in INR when starting bivalirudin was 0.6. The mean final weight-based bivalirudin rate was 0.08 mg/kg/h and the mean change in INR after stopping bivalirudin was 0.7. The Pearson correlation coefficient between the predicted change in INR upon bivalirudin discontinuation and the actual change in INR upon bivalirudin discontinuation was 0.86 (p

Summary of Objectives The HeartMate 3 Left Ventricular Assist System has demonstrated absence of confirmed de-novo pump thrombosis and reduction in stroke. However, bleeding related adverse events persist under standard anticoagulation targeting a INR range of 2.0-3.0. In an initial experience we demonstrated safety of transition to low intensity anticoagulation (INR target 1.5-1.9, n=15, follow up of at least 6 months). Whether complete cessation of anticoagulation maintains “thromboresistance” in the HeartMate 3 pump remains unknown. Methods We previously reported on a strategy of low-intensity warfarin anticoagulation in patients implanted with HeartMate 3 (J Heart Lung Transplant. 2018;37(5):579-586). Following completion of this study phase, a staged trial was approved by the single site's ethics committee and registered as NCT03704220. All patients enrolled in the low intensity warfarin study (target INR of 1.5-1.9) were considered eligible for enrollment in the “anticoagulation withdrawal” study, if they were continuing on long-term support. All patients had to meet safe eligibility criteria including pump speed reduction to facilitate aortic valve opening (to avoid root thrombus), absence of thrombus in the pre-pump cardiac system, and absence of signs of poor unloading at reduced device speed. Careful surveillance for pump thrombosis was algorithmically mandated with biomarker and serial pump log file analyses. If enrolled, they were withdrawn from warfarin therapy and followed for survival free of pump thrombosis, disabling stroke or major bleeding for at least 3 months as the primary safety end point. Endpoints Enrollment and follow up in the low intensity anticoagulation study has been reported (n=15); 13 men, mean age 57 years (18-72), with intended goal of therapy of either BTT or DT, INTERMACS Profile mean 3 (2-5), Cardiac Index mean 1.62 l/min/m2. Of 10 patients followed beyond 1 year on reduced anticoagulation, 5 patients have qualified for complete withdrawal of anticoagulation and the safety endpoint analysis will be completed prior to the ISHLT meeting in March 2019. This pivotal study is the first indication-independent anticoagulation withdrawal study in the HeartMate 3 designed to establish thrombo-resistance for the device and form the rationale for a large scale multicenter trial.

Clinical uncertainty exists regarding which assay should be designated as the standard monitoring coagulation test for intravenous unfractionated heparin (UFH). Several studies have compared the use of activated partial thromboplastin time (aPTT) and antifactor-Xa (anti-Xa) and have come out with varying results. The correlation between these 2 tests varied, markedly from strong to weak. Some have demonstrated that monitoring with anti-Xa heparin assay leads to fewer dose adjustments, resulting in fewer laboratory tests, while others have not. In the current study, we evaluated the correlation between aPTT and anti-Xa values to guide clinical management of UFH, with the intention to develop a new correlation nomogram.

Patients receiving durable mechanical circulatory support (MCS) require life-long anticoagulation with a vitamin K antagonist (VKA). Due to alternations in hemostasis, concomitant therapy with antiplatelet agents and critical illness, they are at increased risk of thromboembolic and bleeding complications compared with the general population managed on VKAs. To prevent thrombotic events, current guidelines recommend that patients with MCS receive long-term anticoagulation with a VKA to maintain a target international normalized ratio (INR) as specified by device manufacturers, but limited data exist regarding specific routine management of anticoagulation therapy and its potential complications. To optimize anticoagulation management and minimize risk in these patients, we have centralized anticoagulation management in a collaborative approach between the inpatient hemostatic and antithrombotic (HAT) stewardship service and between ambulatory anticoagulation management service (AMS) and the advanced heart disease team. Patients are followed by these three services beginning when the device is implanted and extending the duration that patients have the device. The teams include multiple clinicians from cardiac surgery, cardiology, hematology, pharmacy, nursing, case management, nutrition, and psychiatry, therefore, in order to standardize practice among clinicians without compromising patient centered decision making, we assembled an interdisciplinary team to create multiple treatment guidelines. In addition to a centralized and collaborative approach, our guidelines ensure seamless transitions of care between the inpatient and outpatient settings. We believe our approach has demontrated a positive improvement in the care of these challenging patients. In this article, we present our comprehensive centralized anticoagulation management approach for patients with left ventricular assist systems (LVAS).

Available options for the treatment of advanced heart failure have expanded to include the use of mechanical circulatory assist devices to improve quality of life in those both eligible and ineligible for heart transplant. Although there have been significant advancements in device technologies, anticoagulation protocols, and multidisciplinary team management, bleeding and thrombosis are the most common adverse effects. Management strategies for pump thrombosis and their outcomes vary considerably among mechanical circulatory support centers and include intensification of antithrombotic therapy (medical) and device exchange (surgical). We describe a successful case of medical therapy for pump thrombosis with bivalirudin monotherapy.

Treatment of venous thromboembolism (VTE) has been confined to parenteral agents and oral vitamin K antagonists for decades; however, with the approval of the direct oral anticoagulants (DOACs), clinicians now have more options. This study aims to evaluate the real world prescribing practices of all oral anticoagulants for VTE at a single center. A retrospective cohort analysis of all adult patients diagnosed with acute onset VTE was conducted. Of the 105 patients included in the analysis, 45 (43 %) patients received warfarin and 60 (57 %) patients received a DOAC. Rivaroxaban and apixaban were the most common DOACs initiated. There were significantly more patients in the warfarin group with an eCrCl of