A Review of Direct-acting Oral Anticoagulants and Their Use in Solid Organ Transplantation.

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.

Comparison of 4F-PCC in obese and nonobese patients with life-threatening bleeding or requiring emergent surgery.

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).

Heparin-induced thrombocytopenia in end-stage renal disease: Reliability of the PF4-heparin ELISA.

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 < 15 mL/min or on renal replacement therapy [RRT]) who underwent PF4-heparin ELISA testing from October 2015 to September 2019. True-positive PF4s required an intermediate to high 4T score (≥4), a positive SRA, and receipt of treatment for a HIT diagnosis. False-positive PF4s were defined as a positive PF4 with a negative SRA, low 4T score (<4), or lack of treatment for HIT. Indeterminant cases were classified on the basis of clinical assessment by the treating team (eg, hematology or vascular medicine). RESULTS: Of 254 patients with ESRD (92% on RRT), 29 patients (11.4%) had a positive PF4. Eleven (37.9%) had a confirmed diagnosis of HIT: 10 patients who met all of the above criteria, and one who met the 4T criteria and was treated for HIT but did not have SRA testing due to high clinical suspicion and a positive PF4 test. False-positive PF4 values occurred in 8 patients (27.5%). Of 10 (34.5%) indeterminant cases of patients with a negative SRA but intermediate to high 4T and positive PF4, only 3 patients were treated for HIT, whereas the other 7 were judged not to have HIT as assessed by the treating clinician. In patients with an intermediate to high 4T score and PF4 optical density > 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.

Development of an Institutional Periprocedural Management Guideline for Oral Anticoagulants.

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.

Prothrombin Complex Concentrate for Warfarin Reversal in Patients with Continuous-Flow Left Ventricular Assist Devices: A Narrative Review.

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.

Evaluation of Antifactor-Xa Heparin Assay and Activated Partial Thromboplastin Time Values in Patients on Therapeutic Continuous Infusion Unfractionated Heparin Therapy.

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.

Andexanet Alfa for Urgent Reversal of Apixaban Before Aortic Surgery Requiring Cardiopulmonary Bypass: A Case Report.

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.

Development of Multidisciplinary Anticoagulation Management Guidelines for Patients Receiving Durable Mechanical Circulatory Support.

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).

Resource utilization and hospital readmission associated with gastrointestinal bleeding in patients with continuous-flow left ventricular assist devices.

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 < 0.02). Readmission rates for GIB at 30 and 90 days were 33% and 53%, respectively. A decrease in antiplatelet regimen at discharge was associated with lower rate of readmission for GIB (OR 0.16; 95% CI 0.03-0.82; p = 0.03) or any cause (OR 0.21; 95% CI 0.05-0.85; p = 0.04) at 30 and 90 days. GIB in patients with CF-LVADs is associated with significant in-hospital resource utilization and high rates of readmission. Imaging and endoscopy are common, but have low diagnostic yield and infrequently result in successful intervention. Strategies to reduce resource utilization and prevent readmission are warranted.

Four factor prothrombin complex concentrate for warfarin reversal in patients with left ventricular assist devices.

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 < 0.0001) in 47 of 49 administrations; two patients did not have post infusion INR testing. No cases of new confirmed or suspected pump thrombosis, stroke, venous thromboembolism, arterial thrombosis, or myocardial infarction were observed within 30 days of administration of 4F-PCC. 4F-PCC administration for temporary warfarin reversal was demonstrated to be feasible, effective, and, safe in CF-LVAD patients and judged to be 96% effective in patients for whom data were available. We observed no thrombotic events attributed to use of 4F-PCC.

Evaluation of low-intensity anti-coagulation with a fully magnetically levitated centrifugal-flow circulatory pump-the MAGENTUM 1 study.

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 Minimal AnticoaGulation EvaluatioNTo aUgment heMocompatibility (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.

Development of an Outpatient Guideline for Optimal Anticoagulation Bridging in Patients With Durable Mechanical Circulatory Support.

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.

Use of systemic bivalirudin with catheter-directed thrombolysis in a patient with heparin-induced thrombocytopenia: A case report.

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.

Prospective evaluation of a bivalirudin to warfarin transition nomogram.

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 < 0.001). After bivalirudin discontinuation, 68% of patients had a therapeutic INR. The results of this prospective analysis successfully validated our novel bivalirudin to warfarin transition nomogram. There was a very strong correlation between the predicted change and actual change in INR upon bivalirudin discontinuation.

Evaluation of anticoagulation selection for acute venous thromboembolism.

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 <60 ml/min compared to patients who received a DOAC (77.8 % vs. 15 %; P < 0.05). There were significantly less patients in the warfarin group with serum aminotranferase concentrations three times the upper limit of normal compared to those who received a DOAC (15.6 % vs. 55 %; P < 0.05). Patients who received a DOAC had less days on parenteral anticoagulation compared to patients who received warfarin (median 2.5 days [IQR 0-4] vs. 6 days [IQR 5-7], p < 0.05). Patients who received a DOAC had a shorter hospital length of stay compared to patients who received warfarin (median 3 days [IQR 2-4] vs. 8 days [IQR 6-10], p < 0.05). This analysis showed that DOACs are being prescribed more than warfarin for treatment of new onset VTE. Renal and liver function may influence the agent prescribed. Utilization of DOACs may decrease the hospital length of stay.