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Reversing New and Existing Anticoagulants: What is the Role of Prothrombin Complex Concentrates in Patient Blood Manag

Reversing New and Existing Anticoagulants: What is the Role of Prothrombin Complex Concentrates in Patient Blood Management?. Presented by: Dr. Lynn Boshkov, MD Prof. Pathology, Medicine & Pediatrics Director Hemostasis & Thrombosis Associate Director Transfusion Medicine

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Reversing New and Existing Anticoagulants: What is the Role of Prothrombin Complex Concentrates in Patient Blood Manag

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  1. Reversing New and Existing Anticoagulants: • What is the Role of Prothrombin Complex Concentrates in Patient Blood Management? Presented by: Dr. Lynn Boshkov, MD Prof. Pathology, Medicine & Pediatrics Director Hemostasis & Thrombosis Associate Director Transfusion Medicine Oregon Health & Science University, Portland Oregon, USA E-mail: boshkovl@ohsu.edu At: SABM Annual Meeting 2012 Pittsburgh, PA Sept 22, 2012 9:15-10:30

  2. Structure of this talk: • Urgent warfarin reversal issues are complex and product • recommendations are evolving ‘tho data is still only grade 2C. • Why giving plasma +/- Vit K can be problematic—volume, • time, and INR issues • An overview of 3- and 4-component PCCs and why we need • them for warfarin reversal • Why the bloom is off rVIIa for warfarin reversal • Concerns re: safety of PCCs?—will they clot your patient solid? • New anti-IIa and anti-Xa anticoagulants are here as alternatives • to warfarin —how do we monitor and urgently reverse them? • Will PCCs likely be useful here? • Anecdotal cases of very off-label use of PCCs as a procoagulant • tool in difficult-to-manage non-warfarin clinical scenarios

  3. Disclosures: None; confess to bias to 4-component PCCs after seeing them in action as site investigator for the Octaplex trial (Lex-205) Off-label uses (US): Multiple: 3 component PCCs, rVIIa, FEIBA…and, of course, 4 component PCCs (as yet unlicensed in the US)

  4. Recommended recent reviews and articles re: reversal of Vit K antagonists and newer anticoagulants: • Focus on warfarin: • Goodnough LT and Shander A, How I treat warfarin-associated coagulopathy • in patients with intracerebral hemorrhage, 117:6091-6099, Blood 2011. • Streiff MB, Prothrombin complex concentrates for reversal of vitamin K • antagonists: Assessing the risk, ThrombHaemost106: 389-390, 2011. • Dentali F et al, Safety of prothrombin complex concentrates for rapid anticoagu- • lation reversal of vitamin K antagonists, ThrombHaemost106: 425-438, 2011. • Drager WE, Using prothrombin complex concentrates to rapidly reverse oral • anticoagulant effects, Ann Pharmacother 45: 1016-20, 2011. • Focus on warfarin and the new anti-IIa and anti-Xa agents in clinical practice: • Bauer KA, Reversal of antithrombotic agents, Am J Hematol 87:S119- • S126, 2012 • Dzik W, Reversal of drug-induced anticoagulation: old solutions and new • problems, Transfusion 52: 45S-55S, 2012 • Ageno W et al, Oral Anticoagulant Therapy in: Antithrombotic Therapy • and Prevention of Thrombosis, 9th ed: American College of Chest Physicians • Evidence-Based Clinical Practice Guidelines, Chest 141 (2 Suppl) Feb 2012.

  5. Focus on anticoagulant agents with novel mechanisms of action in pretrials and early trials: • Weitz JI et al, New Antithrombotic Drugs in: Antithrombotic Therapy and • Prevention of Thrombosis, 9th ed: American College of Chest Physicians • Evidence-Based Clinical Practice Guidelines, Chest 141 (2 Suppl) Feb 2012. • UpToDate articles: • Valentine KA et al, Correcting excess anticoagulation after warfarin, • www.uptodate.com, Literature review through: Aug 2012. This topic last • updated: Aug 29, 2012 • Freeman WD et al, Management of warfarin-associated intracerebral • hemorrhage, www.uptodate.com, Literature review through: Aug 2012. This • topic last updated: April 2, 2012 • Leung LLK, Anticoagulants other than heparin and warfarin, • www.uptodate.com Literature review through: Aug 2012. This topic last • updated: Sept 5, 2012

  6. Focus of this talk will be the treatment of major bleeding • associated first with warfarin and by extension with newer • oral anticoagulants with anti-IIa and anti-Xa activity • Major Bleeding (ISTH 2005—regardless of INR): • Fatal bleeding • Symptomatic bleeding in a critical area or organ including • intracranial, intraspinal, introcular, retroperitoneal, intra- • articular, pericardial, or intramuscular with compartment • syndrome • Drop in Hb level of >/= 2 g/dl (1.24 mmol/l) • Need to transfused 2 or more units of whole blood or • RBCs

  7. Structure of this talk: • Urgent warfarin reversal issues are complex and product • recommendations are evolving ‘tho data is still only grade 2C. • Why giving plasma +/- Vit K can be problematic—volume, • time, and INR issues • An overview of 3- and 4-component PCCs and why we need • them for warfarin reversal • Why the bloom is off rVIIa for warfarin reversal • Concerns re: safety of PCCs?—will they clot your patient solid? • New anti-IIa and anti-Xa anticoagulants are here as alternatives • to warfarin —how do we monitor and urgently reverse them? • Will PCCs likely be useful here? • Anecdotal cases of very off-label use of PCCs as a procoagulant • tool in difficult-to-manage non-warfarin clinical scenarios

  8. We subvert almost every step in normal hemostasis to prevent and treat thrombosis: 1-On the venous side: 2-On the arterial side: DVT, PE MI, CVA, afibCVA • Anticoagulants• Antiplatelet agents • (Fibrinolytics) • Anticoagulants • • Fibrinolytics

  9. And unfortunately patients sometimes bleed….. • NY Times on-line: January 5, 2006 • “Blood Thinners a Danger in Sharon's Treatment” • “The huge strokesuffered by Prime Minister Ariel Sharonof Israel, caused by uncontrolled bleeding into the brain, will probably bedevastating and nearly impossible to treat because Mr. Sharon has been on blood thinners….” • “Before operating, doctors gave Mr. Sharon a drug to counteract the effects of the blood thinner ….” • Sharon was coumadinized • In 2006 the drug to “counteract the effects of the • blood thinner” was almost certainly rVIIa; • today it would almost certainly be a PCC

  10. Recommendations for reversal of major bleeding on warfarin have been: • Relatively rapidly evolving due to emergence of “new” • agents (rVIIs, 4 component PCCs) • Controversial due to relatively poor quality of evidence • as to benefit, comparative efficacy, and risk/benefit in • of these agents esp in heterogenous patient populations • (Are valves = DVTs or even other valves??? Are • vaculopaths = non-vasculopaths??? Are kids = adults???) • Confounded by lack of availability of agents such as • 4 component PCCs in the US • And even “the Bible” has been inconstant….

  11. August 2008 New in 2008 (Adapted from Tony Giulivi)

  12. “Although FFP can be given in this situation, immediate and full correction can only be achieved by the use of factor concentrates because the amount of FFP required to fully correct the INR is considerable.”CHEST 2008; 133: 175S

  13. (From: Goodnough & Shander, Blood, 2011)

  14. And the Feb 2012 Chest again revised recommendations…….. • Plasma seems condemned • rVIIa removed • role of 3-component PCCs (and US • MDs) left in limbo…..

  15. What’s a poor US hematologist to do?? Well, let’s look at some basics and try to make our own decision with the materials on hand….

  16. Structure of this talk: • Urgent warfarin reversal issues are complex and product • recommendations are evolving ‘tho data is still only grade 2C. • Why giving plasma +/- Vit K can be problematic—volume, • time, and INR issues • An overview of 3- and 4-component PCCs and why we need • them for warfarin reversal • Why the bloom is off rVIIa for warfarin reversal • Concerns re: safety of PCCs?—will they clot your patient solid? • New anti-IIa and anti-Xa anticoagulants are here as alternatives • to warfarin —how do we monitor and urgently reverse them? • Will PCCs likely be useful here? • Anecdotal cases of very off-label use of PCCs as a procoagulant • tool in difficult-to-manage non-warfarin clinical scenarios

  17. Basics #1: General tools / interventions for reversal of • emergency bleeding on ANY anticoagulant: • Direct neutralizing agents: • ex. protamine (for standard heparin +/- LMWH) • Not available or applicable for VKAs • Give/replete missing coagulation factors: • plasma, PCCs have II,VII,IX, X so should be useful • for VKAs • --fibrinogen (cryo, concentrates) not useful for VKAs) • Promote synthesis of Vit K dependent factors: • give Vit K –but all factors won’t respond equally • temporally and it will take hrs before any effect • and days for full effect • Use factor “bypass” agents off-label:rVIIa, FEIBA

  18. Basics #2: Consider clinical issues involved: • Urgency :mins? hrs? • Volume tolerance:ICH on warfarin + 4 ‘U’ plasma • Optimal dose(s), routes, timing • t ½ of the coagulation factors / agents involved • Will redosing or a combination of interventions be necessary? • How tomonitor correction of coagulopathy? • Risk of thrombosis? • Especially: rVIIa and FEIBA in underlying thrombotic vasculopathy • but worries about PCCs too—reason they’re not yet • licensed inUS • Risk to patient of anticoagulant reversal/interruption? • “Faced with a choice between bleeding and thrombosis choose • bleeding—it’s easier to treat….”—Dr. Jack Hirsh

  19. Some authorities have suggested different target INRs for • reversal of VKA’s with either plasma or PCCs depending on • the degree of bleeding and the thrombotic risk: • (Shulman NEJM 349:675, 2003 referenced in UpToDate article on “Correcting • excess anticoagulation after warfarin) • Moderate bleeding and high thrombotic risk: Target INR 2.0-2.1 • Serious bleeding and mod thrombotic risk: Target INR 1.5 • Serious or life-threatening bleeding and low thrombotic risk: • Target INR 1.0

  20. Basics #3: Where coumadin works: XI XIa IX X Xa X II IIa Fibrinogen Fibrin X-L Fibrin Extrinsic/ “PT” Intrinsic/ “PTT” Tissue Factor Release T. F. IXa VIIaVIIIa Va XIII • Coumadin:VitK antagonist [ II, VII, IX, X= • dysfunctional]

  21. So ideally for immediate coumadin reversal we • would rapidly give a balanced mix of II, VII, IX • and X (not forgetting the other Vit K dependent proteins = • C and S) • Plasma has this mix BUT: • 1) At an INR of 2.0-3.0 levels of Vit K dep factors are • about 20%--how much plasma do we need to give to • bring factor levels to 50-100%? • Can we give plasma fast enough esp given the variable • t ½’s of the different Vit K dep-factors? Factor t ½ (hr) F II 60 F VII 4-6 F IX 22 F X 35

  22. Basics #4: Vit K-dep factor levels at an INR of 2.0-3.0 are about 15-25% but there is non-linearity of the INR and the degree of factor def’y—its much easier to correct the INR from 3.0 to 2.2 with plasma than to go below 2.2: ???? (Adapted from Dzik, Transfusion 2012)

  23. Due to this non-linearity:1. With each ~250 ml unit of plasma increasing factor • levels ~ 4% in a 70 kg adult, it should take a lot of • plasma (~3-4 L) to take coagulation factors from 20 to • 80-100% (INR 2.2 to 1.2-1.0)--if 80-100% is our object. • --for minor bleeding 30-40% may be enough but can plasma • reallydo the job for major bleeding? • A concentrated source of II, VII, IX and X (i.e. a 4- • component PCC) would appear strongly desirable • in major bleeding 2. Factor levels are about 30-40% at an INR of 1.4-1.8 and • giving 2-4 units of plasma for an INR of 1.3 – 1.8 should • do almost nothing for the INR -- exactly what was found by Abdel-Wahab OI, et al. Transfusion 46: • 1279-85, 2006.

  24. In conclusion: It’s hard to give plasma fast enough if you are aiming for 50-80% factor levels to correct major bleeding in a therapeutically coumadinized patient If the INR is >4.0 factor levels are 5-10%--and if the patient is 100 kg--the problem of giving enough plasma fast enough is worse 3. Due to the t ½ of the Vit K dep factors correcting FVII is a real problem 4. PT INR will prolong/correct faster than the PTT and due to the VII problem redosing of factors may be necessary

  25. Treating bleeding on warfarin: one US approach • Problem: Vit K deficiency Factor t ½ (hr) F II 60 F VII 4-6 F IX 22 F X 35 Isssues to keep in mind: 1.PT INR prolongs/correct faster than PTT→ target PT INR < 2.0 2.Vit Kgive IV (over 30-60 min)--SQ absorption erratic adult: INR 2-4.5: 2.5 mg; INR 4.5-10: 5mg; INR>10: 5-10mg [anaphylaxis ~ 3:10,000; can give 2.5-5 mg PO if not emergent] 3.Earliest effect 4-6 hr; 2-3 days to full effect give plasma too [ Large doses needed quickly: 15-20 ml/kg or 4-5 ‘U’ in an adult] (1 ‘U’ plasma →↑ factor levels ~ 3-5%-- at INR 2.0-3.0 baseline levels 20-30%) 4. In truly emergent situation (ICH)  give 3 component PCC and small amount rVIIa or consider FEIBA (but concern re: thrombosis)

  26. Caveat if you are using plasma : • You’ll probably need to give a lot: 15-20 ml/kg minimum • One suggested protocol (UpToDate): • Determine the target INR: • Moderate bleeding and high thrombotic risk: Target INR 2.0-2.1 • Serious bleeding and mod thrombotic risk: Target INR 1.5 • Serious or life-threatening bleeding and low thrombotic risk: Target INR 1.0 • Determine your patient’s prothrombin complex percentage by the current INR: • INR > 4.0: 5 – 10 % of normal • INR 1.9-3.2: 15 – 20 % of normal • INR 1.4-1.8: 30 – 40 % of normal • INR 1.0: 100% of normal • Determine the dose of plasma (or PCC) from the following formula: • Dose = (target INR level [as %] – present INR level [as %] x body wt (kg) • This is the ml of FFP or the IU of PCC needed • As an example, in a 70 kg pt with PE 3 mos prior presenting with major GIB • and INR of 7.5 (5% of normal activity), the target INR would be 1.5 (40% of • normal) and the dose would be: (40-5) x 70 = 2450 of FFP (~10 units) or • 2450 IU of PCC • And prepare to have a long-drawn out reversal likely • complicated by TACO (txn associated circulatory overload)

  27. Or if you are in the US reach for the 3-component • PCC you can get and use it with a bit of rVIIa: • Need 2450 IU of PCC = about 250 ml which can be infused over about 20 mins

  28. Structure of this talk: • Urgent warfarin reversal issues are complex and product • recommendations are evolving ‘tho data is still only grade 2C. • Why giving plasma +/- Vit K can be problematic—volume, • time, and INR issues • An overview of 3- and 4-component PCCs and why we need • them for warfarin reversal • Why the bloom is off rVIIa for warfarin reversal • Concerns re: safety of PCCs?—will they clot your patient solid? • New anti-IIa and anti-Xa anticoagulants are here as alternatives • to warfarin —how do we monitor and urgently reverse them? • Will PCCs likely be useful here? • Anecdotal cases of very off-label use of PCCs as a procoagulant • tool in difficult-to-manage non-warfarin clinical scenarios

  29. Problem: Currently licensed PCCs (prothrombin complex concentrates) in the US are used to treat hemophilia B = FIX def’y and are definitely NOT ideal for warfarin reversal: NOTE: Very little FVII (Slide adapted from Michael Recht, MD PhD)

  30. So if you give these 3-component PCCs for warfarin reversal • you ideally need to give some FVII too…. • OHSU has a “one-size fits all” approach to major bleeding • requiring full reversal of coumadin: • 1. Give Profilnine 4000 U (or 50 U/kg if patient tiny or • huge—average American is 100 kg so 4000 U is 40 U/kg) • 2. Give 1 mg of rVIIa also to replete FVIIa (this is 10 mcgm/kg if you’re 100 kg) • 3. To sustain the reversal give Vit K IV 5-10 mg.

  31. Cost of various factors per OHSU Regional Hemophilia Center— Giving Profilnine and rVIIa like this is not horribly $$$$ FEIBA: $1.3392/iuSo for 50 U/kg x 70 kg = 3500 IU x $1.3392 / IU = $ 4, 687 Profilnine: • $.4491/iuSo for 4000 IU x $0.4491 / IU = $ 1,796---------- NovoSeven RT: (different pricing for each vial size) --- Total cost 4000Profilnine + 1 mg rVIIa = 1000mcg = $1.1863/mcg = $ 1, 186-------------------------------- ~ $ 3000 2000mcg = $1.1693/mcg 5000mcg = $1.1654/mcg 8000mcg = $1.4579/mcg (though because of the obvious price hike for this vial size, on principle, we do not purchase)

  32. Things are much easier outside the US: (From Goodnough & Shander, Blood 2011)

  33. Octaplex, a “balanced”PCC has recently been licensed in • Canada for use in warfarin reversal; data being gathered; • US trial (Lex-205) has just been completed and is in • analysis stage… • Beriplex, another 4-componenet “balanced” PCC has • also recently completed theirUS trial….

  34. FFP vs Octaplex • FFP • Large volume (15 mL/kg; 770-1500 mL) • Risk of TRALI, TACO and anaphylaxis • Requires ABO group • Needs to be thawed • Not virally inactivated • PCC • Pooled, virally inactivated • Prion reduction process • Lyophilized • Small volume 40-80 mL • Procoagulant (Slide adapted from Tony Giulivi, MD)

  35. In vivo animal model (rat): PCC vsrVIIa; in vitro human plasma….

  36. PCC vsrVIIa for reversal of coumadin anticoagulation: PT correction in rats PCC FVIIa Saline Dickneite G. Thromb Res. 2008;122(1):117-23. Epub 2007 Oct 31 (Slide adapted from Tony Giulivi, MD)

  37. PCCs vsrVIIa for reversal of coumadin anticoagulation: effect on blood loss in rats Note: PCC but not rVIIa impacted blood loss in the animal model c Dickneite G. Thromb Res. 2008;122(1):117-23. Epub 2007 Oct 31 (Slide adapted from Tony Giulivi, MD)

  38. PCCs in People: The European ExperienceJ ThrombHaemost 2008; 6: 622-31 • 15 center in Europe (8 countries) over 1 yr • Beriplex P/N • Adults, INR>2, needing emergency surgery or bleeding • 25 IU/kg (2-4), 35 IU/kg (4-6), 50 IU/kg (>6) • Vitamin K a bit diverse (75% IV, 75% 10mg) (Slide from Tony Giulivi, MD)

  39. The European ExperienceJ Thromb Haemost 2008; 6: 622-31 (Slide adapted from Tony Giulivi, MD) 41

  40. (From: Dzik, Transfusion, 2012)

  41. Structure of this talk: • Urgent warfarin reversal issues are complex and product • recommendations are evolving ‘tho data is still only grade 2C. • Why giving plasma +/- Vit K can be problematic—volume, • time, and INR issues • An overview of 3- and 4-component PCCs and why we need • them for warfarin reversal • Why the bloom is off rVIIa for warfarin reversal • Concerns re: safety of PCCs?—will they clot your patient solid? • New anti-IIa and anti-Xa anticoagulants are here as alternatives • to warfarin —how do we monitor and urgently reverse them? • Will PCCs likely be useful here? • Anecdotal cases of very off-label use of PCCs as a procoagulant • tool in difficult-to-manage non-warfarin clinical scenarios

  42. That animal data on the rVIIavs PCC in VKA looked nasty: • rVIIa looked like it reversed the INR but not necessarily the • blood—were we treating ourselves in giving it? • I didn’t think so, because it had seemed to work for me on • many occasions, some spectacular • And Guy Young had TEG data that it worked….. • And various august bodies had recommended it….

  43. (From: Goodnough & Shander, Blood, 2011)

  44. Case #1: 5 ½ wk boy with severe Vit K deficiency and ICH* • Called ~ 5 AM Jan 2, 2006 by PICU Attending • Baby had presented with 2 wks loose stools, 1 wk cutaneous bruising, • new blood-tinged vomitus and BRBPR • Hct 19, platelets 602 • PT INR > 15, PTT >200—repeated x 2 • CT head: large ICH with major shift •  urgent correction coagulopathy and neurosurgery needed • Had received dose of oral Vit K at birth • Shotgun interventions: (after verifying normal fibrinogen) • Megadose rVIIa (200 mcgm/kg) • Vit K 2 mg IV • Plasma and RBCs—but volume tolerance an issue • Called in special coag tech to do assays to sort this out… *Flood VH et al, Hemorrhagic Disease of the Newborn Despite Vitamin K Prophylaxis at Birth, Pediatr Blood Cancer 2008 50: 1075-77

  45. Course of correction of coagulopathy: HCT PT INR PTT (28-42) ( 0.9-1.2) (26.0-36.0) 4 Jan 2006 13:00 21.3 1.15 38.9 3 Jan 2006 10:00 23.5 1.22 39.8 measured FX 0.62 3 Jan 2006 03:50 25.7 1.14 40.2 3 Jan 2006 00:30 25.3 1.07 36.5 2 Jan 2006 19:40 22.9 0.99 33.6 2 Jan 2006 16:15 23.7 0.89 32.2 2 Jan 2006 13:10 19.6 0.83 35.4  return to PICU  plasma 15 ml/kg 2 Jan 2006 11:30 18.5 0.98 57.3  to OR ~10:00; IV Vit K ~9:00 2 Jan 200607:45 27.2 0.89 39.7  Megadose rVIIa 2 Jan 200604:55 19.6 >15 >200**~ 7:00 ** Final factor assays: Vit K factors: FII, VII, IX: all < 0.01; FX 0.05 Other factors: FV 0.74; FVIII 0.88 weaning plasma drip / boluses

  46. However a RCT published in Blood Aug 2010 seems to have settled the issue

  47. rVIIa in coumadinized patients corrects the INR and normalizes the TEG and thrombin generation assays in humans—but they still bleed—just like the rats did!!!!! : (From Dzik, Transfusion, 2012)

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