Ravi Sarode

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.

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.

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

Rapid warfarin reversal: a 3-factor prothrombin complex concentrate and recombinant factor VIIa cocktail for intracerebral hemorrhage

2270 per patient or an annual savings of

Thrombotic Thrombocytopenic Purpura: 2012 American Society for Apheresis (ASFA) Consensus Conference on Classification, Diagnosis, Management, and Future Research

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.

Consensus on the standardization of terminology in thrombotic thrombocytopenic purpura and related thrombotic microangiopathies.

OBJECT Intracerebral hemorrhage (ICH) is the most serious bleeding complication of vitamin K antagonist (VKA) therapy, carrying a high mortality. Rapid reversal of VKA in ICH is critical. Plasma therapy, the standard of care in the US, is not optimal. The ideal prothrombin complex concentrate (PCC) containing all vitamin K-dependent factors (VKDFs) is not available in the US. Therefore, the authors developed a Trauma Coumadin Protocol (TCP) consisting of a 3-factor PCC available in the US (which contains insufficient factor VII [FVII]) with a low-dose recombinant FVIIa to rapidly reverse VKA. METHODS Forty-six patients treated with the TCP were retrospectively analyzed. Fourteen patients had pre- and post-TCP plasma samples collected to assess their VKDF increment. Eleven patients had measurable intraparenchymal hematomas, which were evaluated for expansion. RESULTS The mean pre- and post-TCP international normalized ratios (INRs) were 3.4 (median 2.9) and 1.0 (median 0.9), respectively. Once corrected, INR was maintained at < 1.3 during a patients hospital stay. The pre-TCP median values of FII, FVII, FIX, and FX were 28%, 21%, 45%, and 20%, respectively; post-TCP median values increased to 144%, 417%, 102%, and 143%, respectively. Four of the 11 patients with measurable intraparenchymal hemorrhage had expansion at 24 hours after TCP. One patient probably (8 hours post-TCP) and 1 patient possibly (3 days post-TCP) had thrombotic complications. CONCLUSIONS The TCP was very effective in rapidly reversing VKA-associated coagulopathy; however, this protocol should be used cautiously in patients at high risk for thrombosis.

Role of ADAMTS13 in the management of thrombotic microangiopathies including thrombotic thrombocytopenic purpura (TTP)

The American Society for Apheresis (ASFA) conducted a 1 day consensus conference on Thrombotic Thrombocytopenic Purpura (TTP) during its annual meeting in Atlanta, GA, on April 10, 2012. The authors of this article, a subcommittee of ASFAs Clinical Applications Committee, developed several questions with regard to definitions, classification, pathophysiology, diagnosis, management, and future research in TTP. These questions were provided to the seven invited speakers who are the experts in the field of TTP. Two moderators conducted the proceedings of the conference which was attended by more than 100 participants. After each presentation, there was an open discussion that included moderator‐selected written questions submitted by the audience. A medical writer‐generated transcript of the proceedings as well as each presentation was made available to the authors. Each summary was reviewed and approved by the respective speaker before submission of this article. The subcommittee also developed seven key questions for blinded, electronic polling conducted by the moderators to generate a consensus amongst the speakers. This article includes these presentation summaries as well as results of the electronic poll. J. Clin. Apheresis 29:148–167, 2014.

Five hematologic tests and treatments to question

Essentials An international collaboration provides a consensus for clinical definitions. This concerns thrombotic microangiopathies and thrombotic thrombocytopenic purpura (TTP). The consensus defines diagnosis, disease monitoring and response to treatment. Requirements for ADAMTS‐13 are given.

Effects of platelet and plasma transfusion on outcome in traumatic brain injury patients with moderate bleeding diatheses

The clinical presentation of thrombotic thrombocytopenia purpura (TTP) and other thrombotic microangiopathies (TMAs) can often be similar. The role of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) in diagnosing TTP is accepted by most researchers but continues to be debated in a few studies. We report the experience of our single‐centre academic institution, where ADAMTS13 is used to diagnose TTP and guide plasma exchange (PLEX). Patients presenting to our institution with thrombotic microangiopathy (60 patients) between January 2006 and December 2012 were divided into two groups based on ADAMTS13 activity and clinical history. Patients with ADAMTS13 activity <10% were included in the TTP (n = 30) cohort while patients with activity >11% were classified as ‘other microangiopathies’ (TMA, n = 30). PLEX was only initiated in patients with a high likelihood of TTP and discontinued when the baseline ADAMTS13 activity was >11%. Patients with severe ADAMTS13 deficiency (TTP group) showed significant presenting differences: lower platelet counts, less renal dysfunction, higher presence of neurological abnormalities, and greater haemolysis markers as compared to non‐deficient patients (TMA group). Most importantly, patients without severe ADAMTS13 deficiency were safely managed without increased mortality despite receiving no PLEX or discontinuing PLEX after a short course (upon availability of ADAMTS13 results). In conclusion, ADAMTS13 can be used to diagnose TTP and guide appropriate PLEX therapy.

Atypical presentations of thrombotic thrombocytopenic purpura: a review.

Choosing Wisely(®) is a medical stewardship initiative led by the American Board of Internal Medicine Foundation in collaboration with professional medical societies in the United States. The American Society of Hematology (ASH) released its first Choosing Wisely(®) list in 2013. Using the same evidence-based methodology as in 2013, ASH has identified 5 additional tests and treatments that should be questioned by clinicians and patients under specific, indicated circumstances. The ASH 2014 Choosing Wisely(®) recommendations include: (1) do not anticoagulate for more than 3 months in patients experiencing a first venous thromboembolic event in the setting of major, transient risk factors for venous thromboembolism; (2) do not routinely transfuse for chronic anemia or uncomplicated pain crises in patients with sickle cell disease; (3) do not perform baseline or surveillance computed tomography scans in patients with asymptomatic, early-stage chronic lymphocytic leukemia; (4) do not test or treat for heparin-induced thrombocytopenia if the clinical pretest probability of heparin-induced thrombocytopenia is low; and (5) do not treat patients with immune thrombocytopenia unless they are bleeding or have very low platelet counts.