Temporary Warfarin Research Articles

Assessment of Temporary Warfarin Reversal in Patients With Left Ventricular Assist Devices: the KVAD Study*

Patients with left ventricular assist devices (LVADs) require interruption of warfarin for invasive procedures, but parenteral bridging is associated with many complications. Four-factor prothrombin complex concentrate (4F-PCC) can temporarily restore hemostasis in patients undergoing anticoagulation with warfarin. This pilot study evaluated the strategy of using variable-dose 4F-PCC to immediately and temporarily reverse warfarin before invasive procedures without holding warfarin in patients with LVADs. The duration of effect of 4F-PCC on factor levels and time to reestablish therapeutic anticoagulation post procedure were assessed. Adult patients with LVADs and planned invasive procedures were enrolled from a single center. Warfarin was continued uninterrupted. The 4F-PCC dose administered immediately pre-procedure was based on study protocol. International normalized ratio (INR)- and vitamin K-dependent factor levels were collected before and during the 48 hours after 4F-PCC administration. The use of parenteral bridging, International Society for Thrombosis and Haemostasis major and clinically relevant nonmajor bleeding (CRNMB) and thromboembolic events at 7 and 30 days were collected. In 21 episodes of 4F-PCC reversal, median baseline INR was 2.7 (IQR 2.2-3.2). The median dosage of 4F-PCC administered was 1794 units (IQR 1536-2130). At 24 and 48 hours post 4F-PCC administration, median INRs were 1.8 (IQR 1.7-2.0) and 2.0 (IQR 1.9-2.4). Two patients required postoperative bridging. One patient experienced major bleeding within 72 hours, and 2 experienced CRNMB within 30 days. There were no thromboembolic events. Baseline and post 4F-PCC vitamin K-dependent factor levels corresponded with changes in INR values. The median time to achieve therapeutic INR post-procedure was 2.5 days (IQR, 1-4). Administration of 4F-PCC for temporary reversal of warfarin for invasive procedures in patients with LVADs allowed for continued warfarin dosing with minimal use of post-intervention bridging, limited bleeding and no thromboembolic events.

PB1031 Assessment of Coagulation Factor Levels in LVAD Patients Following Temporary Warfarin Reversal with 4F-PCC: KVAD Study

PB1031 Assessment of Coagulation Factor Levels in LVAD Patients Following Temporary Warfarin Reversal with 4F-PCC: KVAD Study

Evaluation of Patients with Ineffective Anticoagulation after Left Ventricular Assist Device (LVAD) Implantation: Early and mid term follow up

Reports about discontinuation of anticoagulant therapy in LVAD patients are very limited. We reported that our experience of discontinuation of warfarin and aspirin therapy due to bleeding and ineffective international normalized ratio (INR) in patients with LVAD. From June 2013 to June 2019, hundred and forty seven patients that underwent LVAD implantation at our department. We analyzed outcomes of patients in whom warfarin and aspirin therapy had to be discontinued due to bleeding and temporary warfarin resistance during ongoing support with LVAD. None of these patients received any anticoagulation therapy until their bleeding event was over. INR <2 was defined as ineffective INR. We collected baseline and follow-up data, including patient characteristics, history of atrial fibrillation, history of heparin-induced thrombocytopenia, renal function at time of discontinuation. We checked speed, flow rates and power consumption parameters of pump, lactate dehydrogenase (LDH), creatinine, total bilirubin and INR level daily. After patients were discharged from the hospital, they returned to our center for follow-up, device review and clinical assessment. Of thirty five (23.8%) patients, mean age was 41 ± 16 (19-65) years, mean follow up time was 645.7 ± 430 (52-1315) days. Thirty patients had to discontinue warfarin due to bleeding and ineffective INR due to warfarin resistance in five patients. Mean duration of ineffective INR was 24.5 ± 12.1 (9-45) days. In one of the patient with intracranial hemorrhage, pump thrombosis was encountered, and his pump had to be exchanged with an urgent operation. There were not any other adverse events in this patient population. Mean follow-up time after ineffective INR situation was 344 ± 417 (94-1240) days. No delayed rehemorrhages or pump complications were observed after resuming aspirin and warfarin therapy. Despite advances in device technology and treatment strategies, prospective, controlled studies are needed to determine the new anticoagulation regimen that most effectively balances bleeding and thrombosis in LVAD patients.

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.

Four Factor Prothrombin Complex Concentrate for Anticoagulation Reversal in an LVAS Patient Undergoing Robotic Prostatectomy: A Case Report

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.

Three-month cumulative incidence of thromboembolism and bleeding after periprocedural anticoagulation management of arterial vascular bypass patients

The objective of this study was to determine 3-month cumulative incidence of peri-procedural thromboembolism (TE) including graft occlusion, and peri-procedural bleeding for chronically anticoagulated vascular bypass graft (BG) patients requiring temporary warfarin interruption for an invasive procedure. Appropriate peri-procedural management of patients receiving chronic warfarin therapy to preserve lower extremity arterial BG patency is unknown. In a protocol driven, cohort study design, all BG patients referred to the Mayo Clinic Thrombophilia Center for peri-procedural anticoagulation (1997-2007) were followed forward in time to estimate the 3-month cumulative incidence of TE and bleeding. Decisions to provide "bridging" low molecular weight heparin (LMWH) were individualized based on estimated risk of TE and bleeding. There were 78 BG patients (69 ± 10 years; 38% women), of whom 73% had a distal autogenous and 53% had prosthetic BG; 45% received antiplatelet therapy. Peri-procedural LMWH was prescribed for 77% of patients and did not vary by BG distal anastomosis location or type. The 3-month cumulative incidence of TE was 5.1% (95% CI 1.4-12.6), including two BG occlusions, one DVT, and one myocardial infarction. Major bleeding occurred in 1 patient (1.28%, 95% CI 0.0-6.94). One patient died due to heart failure. TE and bleeding did not differ by bridging status. The 3-month cumulative incidence of TE among BG patients in whom warfarin is temporarily interrupted for an invasive procedure may be higher than in other "bridging" populations (atrial fibrillation, prosthetic heart valve, venous thromboembolism). This finding underscores the often tenuous nature of distal bypass grafts necessitating an aggressive approach to peri-procedural anticoagulation management.

Predictors of major bleeding in peri‐procedural anticoagulation management

Appropriate periprocedural management for chronically anticoagulated patients requires assessment of patient-specific thrombosis and bleeding risks. However, predictors of post-procedure bleeding are unknown. To determine the 3-month cumulative incidence and independent predictors of peri-procedural bleeding in chronically anticoagulated patients requiring temporary warfarin interruption for an invasive procedure. In a protocol driven, cohort study design, all patients referred to the Mayo Clinic Thrombophilia Center for peri-procedural anticoagulation management (1997-2007; n = 2182), were followed forward in time to determine the 3-month cumulative incidence of peri-procedural bleeding (Kaplan-Meier product limit) and potential predictors of bleeding (Cox proportional hazards). Decisions to 'bridge' with low-molecular-weight heparin were based on estimated thromboembolism and bleeding risk. Indications for chronic anticoagulation included venous thromboembolism (38%), atrial fibrillation (30%) and mechanical heart valves (27%). Of these, 1496 (69%) patients received bridging therapy. The 3-month cumulative incidence rates of major and overall bleeding were 2.1% and 5.1%, respectively. Major bleeding occurred more frequently in patients receiving bridging therapy (3% vs. 1%; P = 0.017). Independent predictors (hazard ratio; 95% confidence interval) of major bleeding included mitral mechanical heart valve (2.2; 1.1-4.3), active cancer (1.8; 1.0-3.1), prior bleeding history (2.6; 1.5-4.5) and re-initiation of heparin therapy within 24 h after the procedure (1.9; 1.1-3.4). Factors predisposing to peri-procedural bleeding are primarily patient-specific. Premature heparin re-initiation is an avoidable provider-specific variable to consider.

Periprocedural Anticoagulation Management of Patients With Venous Thromboembolism

Patients with venous thromboembolism (VTE) often require temporary warfarin interruption for an invasive procedure. The incidence of thromboembolism and bleeding related to periprocedural anticoagulation management of such patients is unknown. In a protocol-driven, inception cohort design study, all VTE patients (n=775) referred for periprocedural anticoagulation management (1997-2007) were followed-up to estimate the 3-month cumulative incidence of thromboembolism and bleeding. Patients were stratified by thrombus acuity (acute, <30 days; subacute, 31-90 days; or chronic > or =91 days). Decisions to provide "bridging" low-molecular-weight heparin were based on estimated thromboembolism and bleeding risk. Low-molecular-weight heparin was more often administered in acute (87%) and subacute (81%) VTE compared to chronic VTE (59%; P<0.001). The 3-month cumulative incidence of thromboembolism (1.8%), major hemorrhage (1.8%), and mortality (1.7%) were low and did not differ by management strategy. Active cancer was the only independent predictor of thrombotic recurrence (HR, 4.86; 95% CI, 1.6-14.5; P=0.005), major hemorrhage (HR, 6.8; 95% CI, 2.1-21.7; P=0.001), and death (HR, 32.7; 95% CI, 4.3-251.2; P=0.0008). Thromboembolism, bleeding, and death among VTE patients in whom anticoagulation is temporarily interrupted for an invasive procedure is low. Cancer patients require particular care given their propensity for both clotting and bleeding.

The management of anticoagulants in the periendoscopic period for patients with atrial fibrillation: a decision analysis

PURPOSE: The management of patients who undergo endoscopy while being treated with warfarin is challenging. We used decision analysis to determine the preferred strategy to manage anticoagulants in the periendoscopic period. METHODS: We designed a Markov model to estimate costs and quality-adjusted survival during a 10-year period in patients with nonvalvular atrial fibrillation undergoing screening colonoscopy. We compared six alternatives to the continue-warfarin strategy, which was to perform colonoscopy while the patient was taking full-dose warfarin. The hold-warfarin strategy was to stop warfarin 5 days before the colonoscopy. The repeat endoscopy strategy was to continue warfarin for a diagnostic colonoscopy, followed by a repeat procedure after cessation of warfarin if polypectomy was required. The dose-reduction strategy was to reduce the warfarin dose before colonoscopy. The low molecular weight heparin strategy was to administer subcutaneous low molecular weight heparin for 2 days before and 2 days after colonoscopy. The unfractionated heparin strategy was to administer intravenous unfractionated heparin for 2 days before and 2 days after the procedure. The vitamin K strategy was to hold warfarin for 4 days and to administer vitamin K if the international normalized ratio (INR) exceeded 2.0 the day before the procedure, or low molecular weight heparin if the INR was less than 1.5. RESULTS: For screening colonoscopy, assuming that polyps would be removed in 35% of examinations, the hold-warfarin and dose-reduction arms were both cost-effective strategies. The hold-warfarin arm was most cost-effective if the likelihood of polypectomy exceeded 60%, or if there was a low risk of stroke despite atrial fibrillation. The continue-warfarin strategy was preferred if the probability of polypectomy was 1% or less. CONCLUSION: Temporary warfarin cessation or halving the warfarin dose for several days before endoscopy was the preferred strategy for most patients. Periendoscopic heparin therapy was not cost-effective for patients with nonvalvular atrial fibrillation.

The management of anticoagulants in the periendoscopic period for patients with atrial fibrillation: a decision analysis

Purpose The management of patients who undergo endoscopy while being treated with warfarin is challenging. We used decision analysis to determine the preferred strategy to manage anticoagulants in the periendoscopic period. Methods We designed a Markov model to estimate costs and quality-adjusted survival during a 10-year period in patients with nonvalvular atrial fibrillation undergoing screening colonoscopy. We compared six alternatives to the continue-warfarin strategy, which was to perform colonoscopy while the patient was taking full-dose warfarin. The hold-warfarin strategy was to stop warfarin 5 days before the colonoscopy. The repeat endoscopy strategy was to continue warfarin for a diagnostic colonoscopy, followed by a repeat procedure after cessation of warfarin if polypectomy was required. The dose-reduction strategy was to reduce the warfarin dose before colonoscopy. The low molecular weight heparin strategy was to administer subcutaneous low molecular weight heparin for 2 days before and 2 days after colonoscopy. The unfractionated heparin strategy was to administer intravenous unfractionated heparin for 2 days before and 2 days after the procedure. The vitamin K strategy was to hold warfarin for 4 days and to administer vitamin K if the international normalized ratio (INR) exceeded 2.0 the day before the procedure, or low molecular weight heparin if the INR was less than 1.5. Results For screening colonoscopy, assuming that polyps would be removed in 35% of examinations, the hold-warfarin and dose-reduction arms were both cost-effective strategies. The hold-warfarin arm was most cost-effective if the likelihood of polypectomy exceeded 60%, or if there was a low risk of stroke despite atrial fibrillation. The continue-warfarin strategy was preferred if the probability of polypectomy was 1% or less. Conclusion Temporary warfarin cessation or halving the warfarin dose for several days before endoscopy was the preferred strategy for most patients. Periendoscopic heparin therapy was not cost-effective for patients with nonvalvular atrial fibrillation.

Low-dose oral vitamin K is safe and effective for outpatient management of patients with an INR>10

Background: Low-dose oral vitamin K effectively returns an international normalized ratio (INR) between 4.5 and 10.0 to an INR of 2.0–3.0 within 24 h in about 70% of patients. However, the efficacy of oral vitamin K for the treatment of higher INR values has only been studied in one small randomized trial. Treatment of markedly prolonged INR values with low-dose oral vitamin K is attractive because it has the potential to greatly simplify the management of such patients. Methods: In our tertiary care anticoagulation clinic patients with an INR of more than 10 were managed as outpatients with simple warfarin withdrawal and, where feasible, low-dose (2 mg) oral vitamin K. Only patients with additional complications such as bleeding or unexplained symptoms were admitted to hospital. Results: Eighty-five patients had 89 episodes of an INR value of more than 10.0. Fourteen patients were admitted to the hospital for management. In the other 75 episodes patients were managed as outpatients by warfarin withdrawal. In 24 episodes patients did not receive vitamin K. In 51 episodes patients were also given oral vitamin K. None of the patients given oral vitamin K experienced bleeding requiring medical intervention (95% confidence interval (CI) 0–6%). In contrast there were three clinically important bleeding episodes amongst the patients managed with simple warfarin withdrawal (95% CI 0–34%). Patients given vitamin K were also more likely to have an INR<5 by day 3 than those managed by withdrawal of warfarin alone. Two patients admitted to hospital and given intravenous vitamin K at higher doses became temporarily refractory to anticoagulation while there were no such complications in those treated with low-dose oral vitamin K. Conclusion: Low-dose (2 mg) oral vitamin K, coupled with temporary warfarin discontinuation, appears to be a safe and effective treatment for severe warfarin associated coagulopathy in non-bleeding patients.