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Role of Prothrombin Complex Concentrates (PCCs) in Bleeding Management

Role of Prothrombin Complex Concentrates (PCCs) in Bleeding Management. Ravi Sarode, MD Professor of Pathology Director, Transfusion Medicine and Reference Hemostasis Lab UT Southwestern Medical Center, Dallas, TX Coordinating PI for Beriplex Bleeding and Surgical Studies . Disclosures.

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Role of Prothrombin Complex Concentrates (PCCs) in Bleeding Management

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  1. Role of Prothrombin Complex Concentrates (PCCs) in Bleeding Management Ravi Sarode, MD Professor of Pathology Director, Transfusion Medicine and Reference Hemostasis Lab UT Southwestern Medical Center, Dallas, TX Coordinating PI for Beriplex Bleeding and Surgical Studies

  2. Disclosures • Consultant CSL Behring • Advisor Octapharma • Off label use of PCC, FEIBA and rFVIIa

  3. Sites of action of Oral Anticoagulants TF + VIIa FIX FX FVIIIa FIXa Rivaroxaban Apixaban FXa Warfarin FII Dabigatran etexilate FIIa

  4. Warfarin Use and Bleeding Complications in the US • 2-3 million patients on warfarin for hypercoagulable states, stroke and cardiac conditions • Major side effect is bleeding • 15-20% per year 1 • 1-3% life-threatening and fatal2 • Upto 2% suffer ICH/SDH with up to 79% mortality3 • 1.5% (conservative estimate) suggest ~ 45,000 major bleeds per year requiring rapid reversal • Another 0.3% require urgent reversal for surgery 1. Beyth et al, Am J med, 1998, 2. Wintzen et al, Ann Neuro 1984, 3. Mathiesen et al ActaNeuro Scan, 1995

  5. Recommendations for Managing Elevated INRs or Bleeding in Patients Receiving VKA ACCP Chest Guidelines

  6. Serious Bleeding At Any INR

  7. Life-threatening Bleeding 2012 “For patients with VKA-associated major bleeding, we suggest rapid reversal of anticoagulation with four-factor PCC rather than with plasma (Grade 2C)”

  8. Patients Requiring Urgent Surgicalor other Invasive Procedures For an urgent surgical or invasive procedure, Low-dose (2.5 - 5.0 mg) IV or oral vitamin K (Grade 1C). For more immediate reversal of the VKA FFP or PCC plus low-dose IV or oral vitamin K (Grade 2C).

  9. Other Guidelines forWarfarin Reversal European and British guidelines - PCC only Canada – PCC preferred over plasma Australian guidelines include a 3-factor PCC with supplementation with plasma Until recently there were no PCCs approved in the US for Warfarin reversal Plasma remained standard of care

  10. Plasma Therapy for VKA • Pubmed and EMBASE search revealed no RCT to show efficacy of plasma in warfarin reversal or its comparison with PCC • Only retrospective studies comparing plasma with PCC • PCC is superior to FFP Ageno et al Am J Hematol 2009;84:584-588

  11. Rapid Reversal Critical • Retrospective study of warfarin related ICH in 69 patients • Multivariate analysis showed shorter time to plasma transfusion was the most important determinant of INR correction • Every 30 minutes delay for the first dose of plasma was associated with 20% decreased odds of INR correction within 24 hours (OR 0.8;95% CI 0.63-0.99) Goldstein, Stroke 2006

  12. Other Studies • INR correction was 4.6 times faster (p=<0.001) and extent of INR correction was greater (p=<0.05) with PCC than FFP in ICH. PCC patients had less clinical deterioration. (1) • Rapid reversal with PCC associated with lower incidence of intracerebral hematoma enlargement as compared with FFP. (2) • Fredriksson et al, Stroke, 1992; 2. Yasaka et al, ThrombHemost, 2003

  13. Limitations of Plasma in Urgent Warfarin Reversal • Requires ABO matching • Sample draw and send = 15 minutes • ABO typing = 15 minutes • FFP = Thawing 15-30 minutes • Issuing = 10 minutes • Transportation = 5-15 minutes • Transfusion = 15-30 minutes/unit • Best scenario = 90 minutes for first unit

  14. Comparison Between Plasma and PCC

  15. Side Effects

  16. Types of PCCs • Activated (aPCC) • FEIBA • Non-activated PCC • 4-factor PCC – all VKDF including PC and PS e.g. Beriplex (Kcentra) and Octaplex • 3-factor PCC – poor FVII content and probably no PC and PS

  17. Thrombosis and PCC • Non-activated PCC originally used for hemophilia B • Given daily for days • FII/X longer half lives - cumulative effects • aPCC used in Hemophilia A and B with inhibitors • contain FVIIa and Xa • continued use for days prothrombotic • PCC for warfarin reversal • one or two doses only

  18. PCC in the US • Only 3-factor PCCs were available until recently • Have very low FVII (<35 U/100 U of FIX) and contain no protein C and S • Kcentra, a 4F-PCC approved by the FDA in July 2013 for warfarin reversal in bleeding patients on VKA

  19. Efficacy and Safety of a 4 factor prothrombin complex concentrate (4F-PCC) in patients on vitamin K antagonists presenting with major bleeding: A randomized, plasma-controlled, Phase IIIb Study Ravi Sarode,1Truman J. Milling,2Majed A. Refaai,3Antoinette Mangione,4 Astrid Schneider,5and Joshua N. Goldstein6 Circulation: Aug 2013 DOI:10.1161/circulationaha.113.002283

  20. Study Design • Primary endpoint: • Hemostaticefficacy over 24 h as assessed by EAB • Co-primary endpoint: • INR reduction to ≤1.3 at 30 min post-infusion Prospective, randomised, open-label, active-controlled,non-inferiority, multicentre phase IIIb clinical study • Secondary endpoints: • Time to INR correction • Plasma levels of FII, VII, IX, X and proteins C and S • Safety and tolerability (incl. all-cause mortality) F, factor; EAB, Endpoint Adjudication Board; INR, international normalised ratio

  21. Study Methods • Patients (≥18 years) receiving VKAs and experiencing an acute major bleeding event were randomised (1:1) to receive 4-factor PCC (4F-PCC; Beriplex®P/N, CSL Behring) or plasma (active control) • Dose was based on baseline INR and body weight: • Infusion rate not exceeding 3 IU/kg/min (max: 210 IU/min) • All patients received vitamin K in addition to PCC or plasma • Hemostaticefficacy evaluated at 24 h after start of infusion • Rapid decrease in INR defined as INR ≤1.3 at 30 min after the end of infusion • AEs recorded up to day 10; SAEs recorded up to day 45 AE, adverse event; 4F-PCC, four-factor prothrombin complex concentrate; INR, international normalised ratio; IU, international unit; SAE, serious adverse event; VKA, vitamin K antagonist

  22. Demographics and Baseline Characteristics Intent-to-treat efficacy population; *two-sided p-value >0.05 (Wilcoxon-test) for between-group difference; 4F-PCC, four-factor prothrombin complex concentrate; INR, international normalised ratio; SD, standard deviation

  23. Primary Endpoint: HemostaticEfficacy • Blinded EAB evaluated hemostasison a 3-point scale of:1. excellent, 2. good and 3. poor/none • “Effective” hemostasisdefined as a rating of excellent or good 4F-PCC was non-inferior to plasma for haemostatic efficacy in the first 24 h post-infusion Intent-to-treat efficacy population CI, confidence interval; EAB, endpoint adjudication board; 4F-PCC, four-factor prothrombin complex concentrate; LL lower limit Non-inferiority: LL 95% CI >–10% for the group difference (4F-PCC – plasma)

  24. Co-primary Endpoint: Rapid INR Reduction • Rapid decrease in INR defined as INR ≤1.3 at 30 min after the end of infusion 4F-PCC was superior to plasma for rapid decreasein INR (≤1.3) at 30 min after the end of infusion Intent-to-treat efficacy population CI, confidence interval; 4F-PCC, four-factor prothrombin complex concentrate; LL lower limit Superiority: LL 95% CI >0 for the group difference (4F-PCC – plasma)

  25. Time to INR Correction • Patients receiving 4F-PCC achieved INR correction (≤1.3) more rapidly than those receiving plasma 4F-PCC, N=98 Plasma, N=104 1.0 0.9 0.8 0.7 0.6 Fraction of patients without INR correction 0.5 0.4 0.3 0.2 0.1 0.0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 Hours after start of infusion Intent-to-treat efficacy population 4F-PCC, four-factor prothrombin complex concentrate; INR, international normalised ratio

  26. Factor Levels To 6 hr Post-infusion 30 min from the start of infusion factor levels were significantly higher versusplasma (p values<0.0001) 4F-PCC (N=98) Plasma (N=104) FIX (%) P 0.5 1 3 6 FII (%) FVII (%) FX (%) Scheduled measuring time: hours after start of infusion (P=pre-infusion) Intent-to-treat efficacy population; F, factor; 4F-PCC, four-factor prothrombin complex concentrate

  27. Protein C and S Levels To 6 hr Post-infusion 30 min from the start of infusion protein levels were significantly higher versusplasma (p values<0.0001) 4F-PCC (N=98) Plasma (N=104) P 0.5 1 3 6 Protein C (%) Protein S (%) Scheduled measuring time: hours after start of infusion (P=pre-infusion) Intent-to-treat efficacy population; 4F-PCC, four-factor prothrombin complex concentrate

  28. Safety and Tolerability 8/10 PCC patients and 4/5 plasma patients died after placement on comfort care Intent-to-treat safety population; * as assessed by investigator; AE, adverse event; 4F-PCC, four-factor prothrombin complex concentrate; SAE, serious adverse event

  29. Possibly Related Adverse Events Intent-to-treat safety population AE, adverse event; 4F-PCC, four-factor prothrombin complex concentrate; SAE, serious adverse event; TEE, thromboembolic event; SAB, blinded safety adjudication board

  30. Conclusions 1 : Efficacy Endpoints • 4F-PCC was non-inferior to plasma for hemostaticefficacy in the first 24 h post-infusion start • 4F-PCC was superior to plasma for rapid INR reversal (≤1.3 at 30 min post-infusion end) • INR reversal was more rapid with 4F-PCC than plasma • Faster increment of FII, VII, IX, X and proteins C and S with 4F-PCC than plasma This is the first and largest randomised study to demonstrate the non-inferiority of 4F-PCC to plasma through clinical endpoints and to show superiority through bioanalytical endpoints F, factor; INR, international normalised ratio; 4F-PCC, four-factor prothrombin complex concentrate

  31. Conclusions 2 : Safety Endpoints • The safety profile was: • consistent with patients experiencing acute major bleeding • generally similar between the 4F-PCC and plasma groups • Of note, fluid overload (or similar cardiac events) occurred less frequently in the 4F-PCC than in the plasma group 4F-PCC, four-factor prothrombin complex concentrate

  32. New Oral Anticoagulants (NOACs) or Target Specific Oral Anticoagulants (TSOA)

  33. Status of new anticoagulants

  34. RE-LY Study Connolly et al NEJM 2009; 361:1139 No information on how these bleeds were managed!

  35. ROCKET StudyConnolly et al NEJM 2009; 361:1139

  36. These are my pharmacists at two hospitals! Hello Ravi – Eliquis is coming #$%^&……

  37. ARISTOTLE StudyGranger et al, NEJM 2011;365:981-92

  38. FDA approved NOACs – but never asked • How to detect drug levels if needed? • What is the therapeutic level? • How would you treat the bleeding? • Is there a reversal agent for urgent surgery or serious bleeding? • Is patient’s weight important?

  39. FDA

  40. ISTH-SSC Recommendations -2013 • PTT can be used to determine relative intensity of dabigatran in emergency or urgent situation • Each lab should know sensitivity for dabi using available calibrators • Normal TT indicates very low or undetectable concentration • Dilute TT with dabi calibrators can be used to determine drug level Baglin et al JTH 2013

  41. ISTH-SSC Recommendations - 2013 • PT can be used to determine relative intensity of rivaroxaban in emergency or urgent situation • Each lab should know sensitivity for rivaroxaban using available calibrators • Anti-Xa assays (without exogenous AT) can be used with plasma calibrators to determine drug levels Baglin et al JTH 2013

  42. How to Manage Bleeding?

  43. Removal of Drugs

  44. Experimental Dabigatran Reversal • Kidney injury bleeding model • PCC (Beriplex) showed dose-dependent reversal of bleeding time and amount of blood loss • Rat tail incision bleeding model – • aPCC(FEIBA) reversed bleeding time prolongation but no effect on PTT • rVIIa more effective than aPCC Ann Medicine Aug 2011

  45. Experimental Rivaroxaban Reversal • Rat mesenteric vessel cutting model • PCC (Beriplex) – normalized prolonged bleeding time • rFVIIa partially reversed thrombin generation • Baboons – rFVIIa partially reduced bleeding time and PT Ann Medicine Aug 2011

  46. Human Volunteer Study • Human volunteers randomized, doubled-blind, placebo-controlled study • Given Rivaroxaban and Dabigatran • Received PCC (50u/Kg) or saline • PCC completely corrected prolonged PT and thrombin generation for Rivaroxaban but not Dabigatran • These volunteers were not bleeding Eerenberg et al Circulation 2011

  47. rFVIIa • Patients on DTI can be considered to have an acquired inhibitor! • However, this inhibitor is present in finite amount unlike AHA • Therefore, 45-90 ug/kg could be used as a starting dose and further need should be assessed based on clinical response.

  48. FEIBA • Similar rationale as rFVIIa use in AHA • 50 U/kg could be the starting dose • Longer acting then rFVIIa and hence may have advantage on the floor in a bleeding patient • Monitor fibrinogen for consumption due to DIC and added bleeding risk

  49. PCC • Prothrombin gene mutation - increased levels of FII or prolongs t/2 • With thrombophilia have levels >125% • Probably generates more thrombin • Both 3 and 4 F PCC at50U/kg will increase FII significantly • Generate more IIa – neutralize DTI

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