Safety Of Prothrombin Complex Concentrates Research Articles

Goal-Directed Use of Prothrombin Complex Concentrates in Liver Transplantation: Is a Plasma-Free Procedure Feasible?

Background: Fresh frozen plasma (FFP) transfusions have been the mainstay of hemostatic intervention for the treatment of bleeding and coagulation abnormalities arising during liver transplantation (LT) for decades. However, numerous clinical studies showed that FFP has many side effects, including the risk of pathogen transmission, transfusion-associated circulatory overload (TACO), transfusion-related immunomodulation (TRIM), and transfusion-related acute lung injury (TRALI). These adverse events are particularly challenging in patients undergoing LT, who often suffer from severe portal hypertension, poor renal function and coexisting cardiac disease.The aims of this review are to summarize the pharmacological properties of currently available PCCs, to represent the theoretical benefits and the possible risks related to the use of these drugs in patients undergoing LT, and, finally, to review the current literature on the topic in order to highlight the evidence that currently supports PCC use in LT patients. Methods: The current literature on the topic was reviewed in order to highlight the evidence that currently supports PCC use in LT patients. Results: Prothrombin complex concentrates (PCCs) may offer several advantages when compared to FFP. Indeed, PCCs have been shown to reduce the risk of TACO, which during liver transplantation may deteriorate portal hypertension, increase intraoperative bleeding, and possibly reduce survival rates. One of the major concerns for PCC use is thrombogenicity. However, currently available PCCs are much safer as they contain inactivated forms of the vitamin K-dependent coagulation factors and protein C, protein S, antithrombin and/or heparin. Nowadays, the use of PCCs to correct coagulation abnormalities that occur during LT is an increasingly widespread practice. However, it is not yet clear what level of evidence supports this practice, and what the risks associated with it are. Conclusions: Administration of PCC in LT patients to correct haemostatic abnormalities seems to be well-tolerated, but the relationship between PCC use and thromboembolic events in the postoperative period remains unclear. Adequately powered, methodologically sound trials are urgently required for more definitive conclusions about the efficacy and safety of PCCs in a broad phenotype of LT recipients.

Prothrombin complex concentrate (PCC) for treatment of trauma-induced coagulopathy: systematic review and meta-analyses

BackgroundTrauma-induced coagulopathy (TIC) is common in trauma patients with major hemorrhage. Prothrombin complex concentrate (PCC) is used as a potential treatment for the correction of TIC, but the efficacy, timing, and evidence to support its use in injured patients with hemorrhage are unclear.MethodsA systematic search of published studies was performed on MEDLINE and EMBASE databases using standardized search equations. Ongoing studies were identified using clinicaltrials.gov. Studies investigating the use of PCC to treat TIC (on its own or in combination with other treatments) in adult major trauma patients were included. Studies involving pediatric patients, studies of only traumatic brain injury (TBI), and studies involving only anticoagulated patients were excluded. Primary outcomes were in-hospital mortality and venous thromboembolism (VTE). Pooled effects of PCC use were reported using random-effects model meta-analyses. Risk of bias was assessed for each study, and we used the Grading of Recommendations Assessment, Development, and Evaluation to assess the quality of evidence.ResultsAfter removing duplicates, 1745 reports were screened and nine observational studies and one randomized controlled trial (RCT) were included, with a total of 1150 patients receiving PCC. Most studies used 4-factor-PCC with a dose of 20–30U/Kg. Among observational studies, co-interventions included whole blood (n = 1), fibrinogen concentrate (n = 2), or fresh frozen plasma (n = 4). Outcomes were inconsistently reported across studies with wide variation in both measurements and time points. The eight observational studies included reported mortality with a pooled odds ratio of 0.97 [95% CI 0.56–1.69], and five reported deep venous thrombosis (DVT) with a pooled OR of 0.83 [95% CI 0.44–1.57]. When pooling the observational studies and the RCT, the OR for mortality and DVT was 0.94 [95% CI 0.60–1.45] and 1.00 [95% CI 0.64–1.55] respectively.ConclusionsAmong published studies of TIC, PCCs did not significantly reduce mortality, nor did they increase the risk of VTE. However, the potential thrombotic risk remains a concern that should be addressed in future studies. Several RCTs are currently ongoing to further explore the efficacy and safety of PCC.

A meta‐analysis of andexanet alfa and prothrombin complex concentrate in the treatment of factor Xa inhibitor–related major bleeding

BackgroundAndexanet alfa (andexanet) and prothrombin complex concentrate (PCC) are both reversal agents for major bleeding in patients using factor Xa inhibitors (FXaIs). Our aim was to evaluate the current evidence for the effectiveness and safety of andexanet and PCC in a systematic review and meta‐analysis. ObjectivesPrimary objective was hemostatic effectiveness. Secondary objectives were thromboembolic event rate and mortality. MethodsA systematic review was performed in PubMed and Embase. Studies describing the effectiveness and/or safety of PCC or andexanet in patients with major bleeding using FXaIs were included. Meta‐analysis was performed using a random‐effects model. ResultsSeventeen PCC studies, 3 andexanet studies, and 1 study describing PCC and andexanet were included, comprising 1428 PCC‐treated and 396 andexanet‐treated patients. None of the included studies had control groups, hampering a pooled meta‐analysis to compare the two reversal agents. Separate analyses for andexanet and PCC were performed. In subgroup analysis, the pooled proportion of patients with effective hemostasis in studies that used Annexa‐4 criteria demonstrated a hemostatic effectiveness of 0.85 (95% confidence interval [CI], 0.80‐0.90) in PCC and 0.82 (95% CI, 0.78‐0.87) in andexanet studies. The pooled proportion of patients with thromboembolic events was 0.03 (95% CI, 0.02‐0.04) in PCC and 0.11 (95% CI, 0.04‐0.18) in andexanet studies. ConclusionBased on the available evidence with low certainty from observational studies, PCC and andexanet demonstrated a similar, effective hemostasis in the treatment of major bleeding in patients using FXaIs. Compared to PCC, the thromboembolic event rate appeared higher in andexanet‐treated patients.

Efficacy and Safety of Prothrombin Complex Concentrate in Patients Treated with Rivaroxaban or Apixaban Compared to Warfarin Presenting with Major Bleeding

IntroductionBleeding is the major complication of anticoagulant therapy. Reversal of vitamin K antagonists (VKAs) in patients with major bleeding events (MBE) including intracranial haemorrhage (ICH) is achieved with prothrombin complex concentrate (PCC) and intravenous vitamin K. Administration of PCC or activated PCC is approved UK strategy for treating MBE associated with rivaroxaban or apixaban, pending approval of a specific reversal agent. In all cases there is concern regarding the incidence of thrombotic events.MethodsIn this respective review, the efficacy and safety of 4-factor PCCs for the management of MBE in 344 patients receiving rivaroxaban, apixaban or warfarin were compared from January 2016 to April 2018.All patients had full blood count, coagulation screen (INR for VKA) and biochemistry profile at presentation and prior to receiving PCC. Patients on rivaroxaban or apixaban had samples taken for drug level but did not wait for the results to administer PCC. Concomitant antiplatelet or nonsteroidal anti-inflammatory drugs, length of stay, thromboembolic events, re-bleeding at the same site and 30-day mortality were documented from medical records.ResultsTable 1: Baseline characteristics of the 344 patientsOverall median (range) dose of PCC was 2000 units of Factor IX (500-5000). As expected, AF was more frequently the indication for apixaban and rivaroxaban (36/40, 90% and 29/40, 72.5%) than it was for warfarin (165/264, 62.5%). Patients with metallic heart valves or left ventricular thrombus received only warfarin. ICH was the most common indication for PCC in all three anticoagulant groups (137/344, 39.8%) followed by gastrointestinal bleeding (93/344, 27%). ICH was more frequently the indication for PCC in patients receiving rivaroxaban (25/40, 62.5%) and apixaban (21/40, 52.5%) compared to warfarin (91/264, 34.5%), p=0.003. Patients on warfarin more frequently received PCC for musculoskeletal bleeding (12.9%) compared to those on rivaroxaban (5%) and apixaban (5%), p=0.003. There were no differences in the other bleeding sites based on type of anticoagulant.No differences were observed in hemoglobin, platelet count and fibrinogen in patients based on type of anticoagulant or site of bleeding. Median (range) rivaroxaban and apixaban levels at time of receiving PCC were 230ng/ml (47-759) and 159ng/ml (45-255) respectively. Median INR pre- and post-PCC in patients on warfarin were 3.4 (1.9-15.4) and 1.2 (1.0-1.9) respectively. A significantly higher proportion of patients on apixaban (17/40, 42.5%) or rivaroxaban (14/40, 35%) received tranexamic acid compared to warfarin (51/264, 19.2%), p=0.001. Vitamin K was given to 227/264, 86% of patients on warfarin with median dose 5mg (range 1mg-10mg). There was no difference in number of red cell units, platelet or FFP used in the three anticoagulant groups. Overall 30-day mortality rate was 24.7% (85/344) and did not differ according to type of anticoagulant (p=0.17). Recurrent bleeding occurred in 18% overall, warfarin 15.8%, rivaroxaban 20% and apixaban 30.8%, p=0. 07. Recurrent thrombosis occurred in 4.1% (14/344) patients within 30 days of receiving PCC with no difference in three anticoagulant groups, p=0.83 (warfarin 4.2%, rivaroxaban 5.1% and apixaban 2.5%). Nearly half of the patients (48.1%), restarted anticoagulation in a median 13.5 days (6-44). Anticoagulation was restarted in a significantly higher proportion of patients on warfarin (138/264, 52.3%) compared to (10/40, 25%) on rivaroxaban and (13/40, 32.5%) on apixaban, p=0.001.In patients with ICH there were no differences in age or sex between groups. There were no differences in concomitant use of antiplatelet treatment, recurrent bleeding (overall 17.8%, warfarin 17.8%, rivaroxaban 20% and apixaban 15%, p=0.90) or 30-day mortality (overall 30-day mortality was 35%; warfarin 31.9%, rivaroxaban 44% and apixaban 38.1%, p=0.50). None of the patients with ICH on rivaroxaban or apixaban had thrombotic events and only 2/91 (2.2%) patients on warfarin had ischemic strokes within 30 days post PCC. Overall 30.6% of patients with ICH restarted anticoagulation with a median 15 days (10-42).In conclusion, there was no difference in the safety (thrombosis) and efficacy (30-day mortality and re-bleeding) in use of PCC to treat MBE in patients on warfarin, rivaroxaban and apixaban. Some differences may reflect indications for anticoagulation. [Display omitted] DisclosuresJayakody Arachchillage:Octapharma: Other: Sponsored to attend an educational meeting; Mitsubishi Phama: Other: Sponsored to attend an educational meeting; Bayer: Other: Sponsored to attend educational meetings. Laffan:Roche: Consultancy, Speakers Bureau; Pfizer: Honoraria.

Efficacy and Safety of Prothrombin Complex Concentrate (PCC) for Direct Oral Anticoagulant Reversal: A Single Institutional Experience

BackgroundAn increasing number of patients (pts) requiring anticoagulation are treated with oral factor Xa inhibitors (DOAC) as an alternative to vitamin K antagonists. Prior to the recent approval of coagulation factor Xa (recombinant), inactivated-zhzo in May 2018, four factor prothrombin complex concentrates (4PCC) have been used to reverse the effects of DOACs. We retrospectively analyzed our institutional experience with 4 PCC for reversal of apixaban and rivaroxaban to determine the indications for 4PCC use and outcomes.MethodsAfter IRB approval, pts receiving 4PCC, from Feb 2016 to January 2018 were identified from our pharmacy database and pts receiving PCC for reversal of apixiban and rivaroxaban were selected. Consenting pts medical records (MR) were reviewed for demographics and indications for DOAC and 4PCC as well as outcomes of 4PCC use. Pts were excluded if they had discontinued DOAC greater than 7 days before receiving 4PCC or if they were started on alternative forms of anticoagulation at a therapeutic dose prior to receiving PCC.Primary endpoint was clinical efficacy (clinical improvement or stability) or ability to undergo required procedure) and secondary endpoint was safety (thromboembolism and death) up to 35 days post-infusion of 4PCC. Stability for intracranial hemorrhages (ICH) was determined by clinical improvement and if head imaging performed, no change in head CT or MRI scan, whereas stability for other bleeds was determined by hemoglobin stability and opinions of providers in the MR. Primary efficacy outcome for pts undergoing surgery was based on MR comments by the performing surgeon and use of other hemostatic agents and red blood cell transfusions.Results49 (32 male) pts, median age of 74 (31-95) years, met our study criteria and received 4PCC for reversal of apixaban (n=29) and rivaroxaban (n=20). Indications for anticoagulation were atrial fibrillation (n=35) and thrombosis (n=14). Of the 14 pts with thrombosis, 11 had deep vein thrombosis while 3 had thrombosis at other sites (arterial graft thrombus, aortic thrombus, and portal vein thrombosis). 4PCC was administered in the emergency department (n=36), intensive care unit (n=10), or the general medical wards (n=3). Indications for 4PCC included bleeding (n=40), procedure/surgery (n=6), and hemodynamic instability with clinical suspicion for bleeding (n=3). Bleeding location is reported in table 1. All procedure/surgery performed for clinical symptoms not related to hemorrhage were non-elective procedures and included exploratory laparotomy (n=4), laparoscopic cholecystectomy (n=1), and incision and drainage of abdominal wall abscess (n=1). Median PCC dose was 42 (10.3-63.3) IU/kg.Outcomes32/40 (80%) pts had stability or an improvement in bleeding, while 5 pts had bleeding that did not improve. 3 pts, all with ICH, had a bleed that worsened 8 (6-8) hours after PCC but then spontaneously stabilized 24 (8-24) hours later. Of those presenting with clinical bleeding, 3 pts received FFP within 3 hours prior to treatment with 4PCC, 2 pts received FFP within 12 hours after 4PCC, and 2 pts received FFP within 3 hours before and 12 hours after 4PCC. Of 40 pts receiving PCC for bleeding, 14 also had a procedure to help achieve hemostasis (Table 2).All 6 pts were able to undergo procedure/surgery. 5/6 patients achieved adequate hemostasis. One pt had no mention of unanticipated bleeding in the MR but received 8 units of FFP intraoperatively after 4PCC.6/49 (12%) pts had a thrombotic complication within 35 days of receiving PCC (median 4 days; (range 1-31) including arterial graft thrombus (n=1), superficial venous thrombus (n=1), bilateral soleal vein thrombosis (n=1), internal jugular vein and innominate vein thrombosis (n=1) stroke (n=1), and progression of preexisting portal vein thrombosis (n=1). All-cause mortality was 20%. 3/10 deaths were in pts who never achieved neurologic recovery after ICH and one pt had stroke-like symptoms leading to death 30 days after 4PCC (administered for ICH).ConclusionIn this cohort, 80% of pts demonstrated clinical stability/improvement of hemorrhage. All pts were able to undergo surgical procedures; however 17% required additional FFP to achieve hemostasis. Thromboembolism occurred in 12% of patients. No deaths could definitely be attributed to 4PCC; however, 30% of deaths could be attributable to the underlying hemorrhagic episode. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Efficacy and Safety of Prothrombin Complex Concentrate in Patients Undergoing Major Cardiac Surgery

IntroductionAdministration of coagulation factors after major cardiac surgery, with or without cardiopulmonary bypass, may be a strategy for reducing risk of bleeding and requirement for allogeneic blood transfusions. However, transfusion of large volumes of fresh frozen plasma (FFP) is restricted by the competing problem of heart failure, a common complication following cardiac surgery in patients with existing cardiac decompensation. Prothrombin complex concentrate (PCC) has a smaller volume of administration than FFP for a similar amount of coagulation factors, making it an attractive option in this situation. However, patients undergoing complex cardiac surgery may also have prothrombotic conditions and have a high risk of both venous and arterial thrombosis including ischemic neurological complications. We performed a retrospective analysis to investigate whether the use of PCC is safe and effective compared with FFP to treat coagulopathy in patients undergoing isolated coronary artery bypass graft (CABG), valve surgery (with or without concomitant CABG) and major aortic procedures. If the patient was on warfarin, this was stopped at least 5 days before the surgery and appropriate bridging was followed. For patients on dual antiplatelet therapy, P2Y12 receptor inhibitors such as Clopidogrel and Prasugrel were stopped 5-7days before the surgery and Aspirin was allowed to continue. The decision to use PPC or FFP was based on individual patient characteristics such as complexity of the surgery and previous history of increased bleeding during surgery and also ability to tolerate volume.MethodsOne hundred and seventy consecutive adult patients who underwent major cardiac surgery between January 2015 and December 2015 were studied. Among them, 87 received PCC (male/female = 55/32, mean age= 56 years) and 83 received FFP (male/female = 56/27, mean age = 58 years) to control coagulopathy. The decision on need for coagulation factor treatment and the choice of treatment was made by the treating team of the patient. Those who received both PCC and FFP were excluded. Blood loss within first 12 hours and 24hours from the end of operation, total use of allogeneic blood and platelet transfusion and patient outcomes in terms of thrombotic complications both venous and arterial, incidence of acute kidney injury and 30 day mortality were compared in the two groups. Antiplatelet drug effect on bleeding was also assessed.ResultsThere was no significant difference in the amount of bleeding at the first 12 hours from the end of the operation in the two groups (p=0.25) :median and 95% confidence interval [CI] were 825mL [926-1317] and 787mL [804-1067] patients received PPC or FFP respectively. However, total blood loss within 24hours was significantly higher in patients who received PPC (median [CI] (1575mL [1658-2263]) compared to FFP (median [CI] (1213mL [1244-1641]), P=0.0034. There was no difference in the mean blood loss between patients continued Aspirin at the time of surgery and those who were not on Aspirin in either groups. The use of allogeneic blood (P=.001) and platelets (P=0.03) was significantly higher in patients receiving FFP compared to PPC. A significantly higher number of patients treated with FFP (9.6% vs 3.5%, p=0.002) developed cardiac failure related to circulatory overload. There was no difference in thrombotic events in the two groups: one patient from each group (1.1%) developed venous and arterial thrombosis respectively following surgery. Thirty day mortality rate was similar in the patients receiving FFP or PPC (4%) and none were directly related to surgery. There was no difference in the acute kidney injury in the two groups.ConclusionsThis retrospective analysis suggests that PCC may be an alternative to FFP in patients undergoing major cardiac surgery. Although there was a higher amount of bleeding within 24hours of surgery in patients treated with PCC, this may reflect the complexity, duration and the individual patient risk of bleeding due to selection bias. The use of PPC may reduce the number of allogeneic blood and platelet transfusion in these patients and reduce risk of circulatory overload. There was no increased risk of thrombosis with use of PCC. However, randomized controlled studies powered to evaluate efficacy and safety in patients receiving PCC versus FFP for coagulopathic bleeding after major cardiac surgery are warranted. DisclosuresLaffan:CSL: Other: Travel support; Octapharma: Speakers Bureau.

Safety and efficacy of prothrombin complex concentrate as first-line treatment in bleeding after cardiac surgery.

BackgroundBleeding after cardiac surgery requiring surgical reexploration and blood component transfusion is associated with increased morbidity and mortality. Although prothrombin complex concentrate (PCC) has been used satisfactorily in bleeding disorders, studies on its efficacy and safety after cardiopulmonary bypass are limited.MethodsBetween January 2005 and December 2013, 3454 consecutive cardiac surgery patients were included in an observational study aimed at investigating the efficacy and safety of PCC as first-line coagulopathy treatment as a replacement for fresh frozen plasma (FFP). Starting in January 2012, PCC was introduced as solely first-line treatment for bleeding following cardiac surgery.ResultsAfter one-to-one propensity score–matched analysis, 225 pairs of patients receiving PCC (median dose 1500 IU) and FFP (median dose 2 U) were included. The use of PCC was associated with significantly decreased 24-h post-operative blood loss (836 ± 1226 vs. 935 ± 583 ml, p < 0.0001). Propensity score–adjusted multivariate analysis showed that PCC was associated with significantly lower risk of red blood cell (RBC) transfusions (odds ratio [OR] 0.50; 95 % confidence interval [CI] 0.31–0.80), decreased amount of RBC units (β unstandardised coefficient −1.42, 95 % CI −2.06 to −0.77) and decreased risk of transfusion of more than 2 RBC units (OR 0.53, 95 % CI 0.38–0.73). Patients receiving PCC had an increased risk of post-operative acute kidney injury (AKI) (OR 1.44, 95 % CI 1.02–2.05) and renal replacement therapy (OR 3.35, 95 % CI 1.13–9.90). Hospital mortality was unaffected by PCC (OR 1.51, 95 % CI 0.84–2.72).ConclusionsIn the cardiac surgery setting, the use of PCC compared with FFP was associated with decreased post-operative blood loss and RBC transfusion requirements. However, PCC administration may be associated with a higher risk of post-operative AKI.Electronic supplementary materialThe online version of this article (doi:10.1186/s13054-015-1172-6) contains supplementary material, which is available to authorized users.

Retrospective evaluation of the clinical use of prothrombin complex concentrate for the reversal of anticoagulation with vitamin K antagonists

Anticoagulation reversal is a time-sensitive intervention for the prevention of life-threatening hemorrhagic events occurring with bleeding or surgery. Recommendations for the most effective and well tolerated reversal agent in these settings remain controversial. Several clinical guidelines for the management of intracerebral hemorrhage support use of prothrombin complex concentrates (PCCs) for the rapid reversal of warfarin-associated coagulopathy despite limited clinical data. The purpose of this investigation was to evaluate the efficacy and safety of PCC for the rapid reversal of anticoagulation by vitamin K antagonists for life-threatening bleeding or emergent surgery and to assess adherence to a hospital-based protocol. A retrospective chart review was conducted of adult patients receiving PCC for the reversal of anticoagulation. Patients were assessed according to indication for anticoagulation reversal. The primary outcome measure was adequacy of international normalized ratio reversal. Other outcomes included cessation of bleeding, thrombotic complications, and adherence to an institutional-based guideline for the use of PCC. ICU and hospital length of stay and 30-day mortality was assessed. There were 70 patients included in this study. Mean international normalized ratio was reduced from 3.1 to 1.6 following administration of at least one dose of PCC. Cessation of bleeding occurred in 65.7% of patients. Clinical assessment was unclear in 18.6%. Thrombotic complications were observed in 7.1% of patients. The 30-day mortality rate was found to be 14.3%. These data demonstrate that PCC is a well tolerated and effective method for anticoagulation reversal associated with a relatively high 30-day survival rate.

Prothrombin Complex Concentrates Compared with Frozen Plasma for Urgent Reversal of Vitamin K Antagonists: A Single Centre Retrospective Review

▪Background: Vitamin K antagonists (VKAs) are associated with a risk of major bleeding requiring urgent reversal with frozen plasma (FP) or prothrombin complex concentrates (PCC) and concurrent vitamin K administration. Several treatment guidelines currently recommend PCC over FP for urgent reversal in VKA-associated bleeding. Four-factor PCC (Octaplex®, Beriplex®) has been available in Canada since 2008 with a change in national dosing recommendations in 2012. We conducted a retrospective study to determine the efficacy and safety of PCC in comparison with FP in patients presenting with bleeding and requiring VKA reversal.Methods: We retrospectively reviewed all consecutive bleeding episodes requiring VKA reversal at Vancouver General Hospital (VGH) for 2 cohorts of patients: i) those who received FP (July 28, 2008 to July 27, 2010); and ii) those who received PCC, during two time periods (July 28, 2008 to July 27, 2010; and September 1, 2011 to December 31, 2012) during which Canadian national dosing recommendations had changed. The PCC data however were pooled as no significant differences between the early and later PCC cohorts were found. Details of VKA reversal were reviewed, including patient demographics, bleeding type, indication for VKA therapy, dose of PCC or FP, admission hematologic parameters, INR value subsequent to completion of PCC or FP infusion, time to complete infusion, transfusion requirements, vitamin K dose and route of administration, transfusion reactions, thrombotic events (within 30 days) and mortality during hospitalization. The primary outcome was the proportion of patients achieving a target INR defined as ≤1.5 following the initial order of PCC or FP. Subject characteristics were compared using two-sided t-tests for continuous and Chi-square analysis for categorical variables. Predictors of mortality were analyzed with binary logistic regression.Results: A total of 201 bleeding episodes occurred in 191 patients. PCC was used in 89 episodes (44%). The most common indication for VKA was atrial fibrillation (81%). Mean PCC dose was 1489 U (range 500-3000 U). Mean FP dose was 3.1 U (range 1-10 U). Target INR was achieved in 86% of episodes in the PCC group versus 60% with FP (p<0.001). Mean time to complete the reversal agent was 4.4 hours with PCC versus 8.7 hours with FP (p<0.001). There was no significant difference in thromboembolic events between FP and PCC with 4 thromboembolic events occurring in each treatment group: 2 strokes, 1 myocardial infarction, and 1 recurrent deep vein thrombosis occurred in the PCC cohort. No transfusion-related reactions occurred in the PCC group compared with 12.6% with FP (p<0.001). Mortality was significantly higher in the PCC group (25% vs. 11%, p=0.010); however, intracranial bleeding (ICH) was more common in the PCC group (62% vs. 31%, p<0.001) and was the only independent predictor of mortality. Vitamin K was not administered in 20% of episodes, including 17% of episodes of ICH.Conclusion: PCC is effective in the urgent reversal of VKA with faster and more complete INR reversal, significantly fewer transfusion reactions and no increase in thromboembolic events in comparison to FP. Along with vitamin K, PCC should be the agent of choice for VKA reversal in bleeding patients. DisclosuresChipperfield:Boehringer Ingelheim: Honoraria. Yenson:Octapharma Canada: Unrestricted Education Grant Other; Alexion Pharmaceuticals: Honoraria.

Initial Experience with 4-Factor PCC for the Reversal of Warfarin: Patterns of Use and Safety Outcomes

Major bleeding among patients receiving oral anticoagulants is common and is reported to occur in up to 6.5% of patients per year. Vitamin K antagonists (VKA) remain the most frequently prescribed class of anticoagulants for conditions such as atrial fibrillation, mechanical heart valves and venous thromboembolism. The products used for the reversal of VKA-associated coagulopathy include Vitamin K, fresh frozen plasma (FFP), activated recombinant factor VII (rFVIIa), and Prothrombin Complex Concentrates (PCC).Kcentra® (CSL Behring Gmbh, Marburg, Germany) is a 4-factor PCC that contains all of the vitamin K-dependent proteins (Factors II,VII, IX, X, Protein C and S). While Kcentra® has been in use in Europe and other parts of the world for several years, it was only recently approved in the United States for warfarin reversal during acute major bleeding (April, 2013) or when there is a need for an urgent invasive procedure (December 2013).We conducted a retrospective study to evaluate the use of 4-factor PCC in a community-based tertiary care center. The efficacy and safety of PCCs has been established in large multi-center trials. However, there is limited data from outside of carefully conducted clinical trials. In particular, there is a paucity of data regarding the use of 4-factor PCC in the community setting, specifically from the United States. We developed protocols for the reversal of warfarin for life-threatening bleeding and emergent surgery. All patients get vitamin K and they receive Kcentra® if the INR is ≥ 2. If the INR is < 2 they receive plasma. The dose of Kcentra® is based on pre-treatment INR (25 u/kg for INR 2 to < 4, 35 u/kg for INR 4-6 and 50 u/kg for INR >6).We identified 33 patients from July 2013 to April 2014 that were treated with 4-factor PCC (18 males and 15 females). The mean age was 71.06 +/- 14.04 years (Range 42-94). Kcentra® was used appropriately, per our institutional protocol for VKA reversal, in 28/33 (84.35%) cases. Four of the patients, who were treated inappropriately, did not have a drug history on admission and were subsequently found to have an elevated INR due to liver dysfunction. The leading indications for PCC use were intracranial hemorrhage (49%), reversal of elevated INR prior to surgery (21%) and gastrointestinal bleeding (15%). 73% of patients had a pre-reversal INR in the range of 2-4, 12% had INR of 4-6 and15% of patients presented with an INR of >6. The indications for warfarin use included atrial fibrillation (50% patients), prosthetic valve (21.4%) and prior deep vein thrombosis and pulmonary embolism in 18% patients. 40% patients were also receiving concomitant antiplatelet therapy.The mean administered dose of Kcentra® was 2461 +/- 825 units (Range 1375-4715). Among patient treated for reversal of VKA-related coagulopathy, the pre-treatment INR was 4.6 (range 2-17) and mean post-treatment INR was 1.32 (range 1.1-1.9). Post-treatment INR of ≤ 1.5 was attained in 24/33 (73%) patients. Post-treatment INR was not available for one patient. There was only one case of thrombosis within 72 hours of treatment (myocardial infarction). 28/33 patients (85%) were alive at 24 hours.Based on experience from our limited number of patients, we have found Kcentra® to be effective in the rapid reversal of INR in the setting of VKA associated coagulopathy. Kcentra® was successfully used for a wide variety of indications in our patient population. Arterial and venous thromboembolic complications have previously been reported in patients receiving 4-factor PCC. We found a low complication rate in our patients with only one patient developing a thrombotic phenomenon (acute coronary event) within 72 hours of administration of Kcentra®. In conclusion, based on our experience, we have found Kcentra® to be a safe and effective agent for reversal of VKA associated coagulopathy. DisclosuresNo relevant conflicts of interest to declare.

Use of Prothrombin Complex Concentrates and Fibrinogen Concentrates in the Perioperative Setting: A Systematic Review

The use of prothrombin complex concentrates (PCCs) and fibrinogen concentrates (FIBCs) to achieve hemostasis in the perioperative setting as alternatives to allogeneic blood products remains controversial. To examine the efficacy and safety of PCCs and FIBCs, we conducted a systematic review-in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis statement-to compare the use of these transfusion alternatives in bleeding surgical patients. We performed a literature search of English articles published between July 1997 and July 2012 in MEDLINE via PubMed, The Cochrane Library, and CINAHL. Five randomized trials and 15 nonrandomized studies with a comparator group were included in the final review. Studies were sorted into 1 of the following 3 clinical settings: cardiac surgery, non-cardiac surgery, and reversal of warfarin anticoagulation. Risk of bias was assessed using the Cochrane risk of bias tool. With the exception of 2 randomized controlled trials, the existing body of literature on the use of PCCs and FIBCs in the perioperative setting was assessed to have a high degree of methodological bias. Overall, prospective studies in the cardiac surgery grouping suggested that patients receiving FIBC and/or PCCs required less allogeneic blood transfusion and had less chest tube drainage. In studies of warfarin reversal, PCCs more rapidly corrected the International Normalized Ratio compared to plasma; however, in the setting of intracranial hemorrhage, functional outcomes were poor regardless of the reversal strategy. With regards to safety outcomes, reporting was not uniform and raises concerns of underreporting. Adequately powered, methodologically sound trials would be required for more definitive conclusions to be drawn about the efficacy of PCCs and FIBC over conventional blood components for the treatment of perioperative coagulopathy in bleeding patients.

Recombinant activated factor VII and prothrombin complex concentrates have different effects on bleeding and arterial thrombosis in the haemodiluted rabbit

Recombinant activated factor VII (rFVIIa) is indicated in bleeding patients when a life-threatening haemorrhage occurs. Prothrombin complex concentrates (PCCs) are also used for this indication in several countries, without any evidence-based rationale. Our objective was to compare the efficacy and safety of PCC and rFVIIa in a model of bleeding and thrombosis in haemodiluted rabbits. Forty-eight rabbits were randomly allocated into four groups: a control group and three treatment groups, in which animals were haemodiluted with hydroxyethyl starch 130/0.4 then administered either placebo, 160 µg kg(-1) rFVIIa, or 25 IU FIX kg(-1) PCC. The primary endpoint was hepatosplenic (HS) blood loss. Secondary endpoints were: (i) ear immersion bleeding time (IBT); (ii) thrombosis risk assessed by cyclic flow reductions (CFRs) of the carotid artery; and (iii) activated partial thromboplastin time (aPTT), and progress of thrombin activity. Haemodilution increased HS blood loss by 80% from 8 g (5-16) (control group) to 14 g (8-45) (placebo group) (P<0.01). HS blood loss was not different in animals receiving either rFVIIa [10 g (7-22)] or PCC [15 g (4-33)] (P<0.05) compared with the placebo group. Ear IBT was reduced with both rFVIIa and PCC. CFRs disappeared after haemodilution and were not restored with any treatment. Although PCC nearly doubled the total amount of thrombin generated, no significant change in the total amount of thrombin was seen in animals treated with rFVIIa. Neither rVIIa nor PCC reduced HS blood loss, whereas they both controlled the bleeding time, without increasing the thrombosis risk.

The Efficacy and Safety of Prothrombin Complex Concentrate In Patients Requiring Urgent Reversal of Warfarin, A Retrospective Canadian Experience

AbstractAbstract 3344 Background:Major bleeding remains the most frequent adverse effect of oral anticoagulant therapy. A rapid method of reversal is required for patients on warfarin who suffer acute bleeding or require emergency surgery. Octaplex is a prothrombin complex concentrate recently recommended for use by the National Advisory Committee for Blood and Blood Products of Canada (Canadian Blood Services) at a dose of 1000 IU of factor IX activity. It ensures rapid INR correction by providing vitamin K-dependent factors without a large volume load. The main goal of this study was to investigate both the efficacy and safety of Octaplex use in a tertiary care center in Quebec, Canada. Materials and Methods:A retrospective review was conducted on the charts of patients who received Octaplex for urgent warfarin reversal between 1 January 2009 and 31 October 2009. Data collected included INRs pre and post Octaplex administration, and documentation of any adverse events. Results:We identified 146 occasions when Octaplex was administered for urgent INR reversal. A total of 118 patients were included in the study with a median age of 77. The three most frequent indications for Octaplex were: 1) gastrointestinal bleeding, 2) intracranial hemorrhage, and 3) pre-procedural INR reversal. The majority of patients (90.7%) were treated with Octaplex at a dose of 1000 IU of factor IX activity, with a range of 500 IU to 5000 IU. The average mean pre-and post INRs were 4.00 and 1.65, respectively. Overall, 89.8% (130/146) of patients corrected to an INR < 2.0, of which 51.5% (67/130) corrected to an INR < 1.5. Although 8.2% (12/146) of patients were considered to have a poor response (post INR > 2.1), these patients tended to have a higher mean pre-INR value (5.28 vs. 2.69) and still achieved important absolute drops in INR (range 1.1–9.3, mean 2.91). Only 4 patients (2.7%) did not experience a reversal of their INR. Seventeen patients received second doses of Octaplex, 70.6% (12/17) of whom achieved a post INR < 1.5 and 94.1% (16/17) achieved a post INR < 2.0. There were 8 reported thrombotic events amongst 118 patients: 3 myocardial infarctions, 3 DVTs, 1 ischemic limb and 1 intracardiac clot. All patients with these adverse events had other co-morbities that could have also contributed to these toxicities. Conclusion:Octaplex is efficient and appears to be safe in the urgent reversal of INR in patients taking vitamin K antagonists. Disclosures:No relevant conflicts of interest to declare.