Majed A. Refaai

Efficacy and Safety of a 4-Factor Prothrombin Complex Concentrate in Patients on Vitamin K Antagonists Presenting With Major Bleeding A Randomized, Plasma-Controlled, Phase IIIb Study

Background— Patients experiencing major bleeding while taking vitamin K antagonists require rapid vitamin K antagonist reversal. We performed a prospective clinical trial to compare nonactivated 4-factor prothrombin complex concentrate (4F-PCC) with plasma for urgent vitamin K antagonist reversal. Methods and Results— In this phase IIIb, multicenter, open-label, noninferiority trial, nonsurgical patients were randomized to 4F-PCC (containing coagulation factors II, VII, IX, and X and proteins C and S) or plasma. Primary analyses examined whether 4F-PCC was noninferior to plasma for the coprimary end points of 24-hour hemostatic efficacy from start of infusion and international normalized ratio correction (⩽1.3) at 0.5 hour after end of infusion. The intention-to-treat efficacy population comprised 202 patients (4F-PCC, n=98; plasma, n=104). Median (range) baseline international normalized ratio was 3.90 (1.8–20.0) for the 4F-PCC group and 3.60 (1.9–38.9) for the plasma group. Effective hemostasis was achieved in 72.4% of patients receiving 4F-PCC versus 65.4% receiving plasma, demonstrating noninferiority (difference, 7.1% [95% confidence interval, –5.8 to 19.9]). Rapid international normalized ratio reduction was achieved in 62.2% of patients receiving 4F-PCC versus 9.6% receiving plasma, demonstrating 4F-PCC superiority (difference, 52.6% [95% confidence interval, 39.4 to 65.9]). Assessed coagulation factors were higher in the 4F-PCC group than in the plasma group from 0.5 to 3 hours after infusion start (P<0.02). The safety profile (adverse events, serious adverse events, thromboembolic events, and deaths) was similar between groups; 66 of 103 (4F-PCC group) and 71 of 109 (plasma group) patients experienced ≥1 adverse event. Conclusions— 4F-PCC is an effective alternative to plasma for urgent reversal of vitamin K antagonist therapy in major bleeding events, as demonstrated by clinical assessments of bleeding and laboratory measurements of international normalized ratio and factor levels. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00708435.

Blood Transfusions, Thrombosis, and Mortality in Hospitalized Patients With Cancer

BACKGROUND Anemia is frequent in patients with cancer, but there are concerns regarding treatment with erythropoiesis-stimulating agents. Blood transfusions are commonly used as an alternative, but with little data regarding outcomes. METHODS In a retrospective cohort study, we investigated the associations between transfusions and venous thromboembolism, arterial thromboembolism, and mortality in hospitalized patients with cancer using the discharge database of the University HealthSystem Consortium, which included 504 208 hospitalizations of patients with cancer between 1995 and 2003 at 60 US medical centers. RESULTS Of the patients included, 70 542 (14.0%) received at least 1 red blood cell (RBC) transfusion and 15 237 (3.0%) received at least 1 platelet transfusion. Of patients receiving RBC transfusions, 7.2% developed venous thromboembolism and 5.2% developed arterial thromboembolism, and this was significantly greater than the rates of 3.8% and 3.1%, respectively, for the remaining study population (P < .001). In multivariate analysis, RBC transfusion (odds ratio [OR], 1.60; 95% confidence interval [CI], 1.53-1.67) and platelet transfusion (1.20; 1.11-1.29) were independently associated with an increased risk of venous thromboembolism. Both RBC transfusion (OR, 1.53; 95% CI, 1.46-1.61) and platelet transfusion (1.55; 1.40-1.71) were also associated with arterial thromboembolism (P < .001 for each). Transfusions were also associated with an increased risk of in-hospital mortality (RBCs: OR, 1.34; 95% CI, 1.29-1.38; platelets: 2.40; 2.27-2.52; P < .001). CONCLUSIONS Both RBC and platelet transfusions are associated with increased risks of venous and arterial thrombotic events and mortality in hospitalized patients with cancer. Further investigation is necessary to determine whether this relationship is causal.

Four-factor prothrombin complex concentrate versus plasma for rapid vitamin K antagonist reversal in patients needing urgent surgical or invasive interventions: a phase 3b, open-label, non-inferiority, randomised trial

BACKGROUND Rapid reversal of vitamin K antagonist (VKA)-induced anticoagulation is often necessary for patients needing urgent surgical or invasive procedures. The optimum means of VKA reversal has not been established in comparative clinical trials. We compared the efficacy and safety of four-factor prothrombin complex concentrate (4F-PCC) with that of plasma in VKA-treated patients needing urgent surgical or invasive procedures. METHODS In a multicentre, open-label, phase 3b randomised trial we enrolled patients aged 18 years or older needing rapid VKA reversal before an urgent surgical or invasive procedure. We randomly assigned patients in a 1:1 ratio to receive vitamin K concomitant with a single dose of either 4F-PCC (Beriplex/Kcentra/Confidex; CSL Behring, Marburg, Germany) or plasma, with dosing based on international normalised ratio (INR) and weight. The primary endpoint was effective haemostasis, and the co-primary endpoint was rapid INR reduction (≤1·3 at 0·5 h after infusion end). The analyses were intended to evaluate, in a hierarchical fashion, first non-inferiority (lower limit 95% CI greater than -10% for group difference) for both endpoints, then superiority (lower limit 95% CI >0%) if non-inferiority was achieved. Adverse events and serious adverse events were reported to days 10 and 45, respectively. This trial is registered at ClinicalTrials.gov, number NCT00803101. FINDINGS 181 patients were randomised (4F-PCC n=90; plasma n=91). The intention-to-treat efficacy population comprised 168 patients (4F-PCC, n=87; plasma, n=81). Effective haemostasis was achieved in 78 (90%) patients in the 4F-PCC group compared with 61 (75%) patients in the plasma group, demonstrating both non-inferiority and superiority of 4F-PCC over plasma (difference 14·3%, 95% CI 2·8-25·8). Rapid INR reduction was achieved in 48 (55%) patients in the 4F-PCC group compared with eight (10%) patients in the plasma group, demonstrating both non-inferiority and superiority of 4F-PCC over plasma (difference 45·3%, 95% CI 31·9-56·4). The safety profile of 4F-PCC was generally similar to that of plasma; 49 (56%) patients receiving 4F-PCC had adverse events compared with 53 (60%) patients receiving plasma. Adverse events of interest were thromboembolic adverse events (six [7%] patients receiving 4F-PCC vs seven [8%] patients receiving plasma), fluid overload or similar cardiac events (three [3%] patients vs 11 [13%] patients), and late bleeding events (three [3%] patients vs four [5%] patients). INTERPRETATION 4F-PCC is non-inferior and superior to plasma for rapid INR reversal and effective haemostasis in patients needing VKA reversal for urgent surgical or invasive procedures. FUNDING CSL Behring.

Suboptimal effect of a three‐factor prothrombin complex concentrate (Profilnine‐SD) in correcting supratherapeutic international normalized ratio due to warfarin overdose

BACKGROUND: Plasma transfusion is standard therapy for urgent warfarin reversal in the United States. “Four‐factor” prothrombin complex concentrate (PCC), available in Europe, has advantages over plasma therapy for warfarin reversal; however, only “three‐factor” PCCs (containing relatively low Factor [F]VII) are available in the United States.

A Massive Transfusion Protocol to Decrease Blood Component Use and Costs

HYPOTHESIS A massive transfusion protocol (MTP) decreases the use of blood components, as well as turnaround times, costs, and mortality. DESIGN Retrospective before-and-after cohort study. SETTING Academic level I urban trauma center. PATIENTS AND METHODS Blood component use was compared in 132 patients during a 2-year period following the implementation of an MTP; 46 patients who were treated the previous year served as historical control subjects. INTERVENTION Introduction of an MTP that included recombinant factor VIIa for patients with exsanguinating hemorrhage. MAIN OUTCOME MEASURES The amount of each blood component transfused, turnaround times, blood bank and hospital charges, and mortality rates. RESULTS After introduction of the MTP, there was a significant decrease in packed red blood cells, plasma, and platelet use. The turnaround time for the first shipment was less than 10 minutes, and the time between the first and second shipments was reduced from 42 to 18 minutes, compared with historical controls. The decreased use of blood products represented a savings of

An association between decreased cardiopulmonary complications (transfusion-related acute lung injury and transfusion-associated circulatory overload) and implementation of universal leukoreduction of blood transfusions.

2270 per patient or an annual savings of

Prospective monitoring of plasma and platelet transfusions in a large teaching hospital results in significant cost reduction

200, 000, despite increased costs for recombinant factor VIIa. There was no difference in mortality in either group; it remained around 50%. Thromboembolic complications did not increase, despite a significant increase in the use of recombinant factor VIIa. CONCLUSIONS The MTP resulted in a reduction in the use of blood components with improved turnaround times and significant savings. Mortality was unaffected. The use of recombinant factor VIIa did not increase thromboembolic complications in these patients.

Transfusion immunomodulation from a clinical perspective: an update.

BACKGROUND: Cardiopulmonary adverse events after transfusion include transfusion‐related acute lung injury (TRALI) and transfusion‐associated circulatory overload (TACO), which are potentially lethal and incompletely understood.

Outcomes after platelet transfusion in patients with heparin-induced thrombocytopenia

BACKGROUND: Plasma and platelets (PLTs) are often transfused to correct mild to moderately abnormal laboratory values. Our objective was to reduce unnecessary plasma and PLT transfusions to nonbleeding patients by prospective triage and education of end users in evidence‐based hemostasis and transfusion medicine practices.

Platelet Transfusion – The New Immunology of an Old Therapy

Accumulated evidence demonstrates that allogeneic blood transfusions have clinically significant effects on the recipient’s immune system. This transfusion immunomodulation effect is associated with an increased rate of cancer recurrence (uncertain causality) and post-operative infection (established causality). The exact mechanisms of transfusion immunomodulation are still unknown. Data suggests that transfusion immunomodulation is a biologic effect strongly associated with the infusion of allogeneic leukocytes. Soluble mediators that accumulate in transfused red cells and platelets during storage are also possible causes of post-transfusion complications. Some approaches can mitigate these effects. Most important is adopting more conservative transfusion practices. Leukoreduction (proven) and plasma depletion (proposed) are other methods to significantly reduce transfusion immunomodulation and its clinical sequela.