SK Clinical Guideline 2 Dabigatran ( Pradax ) and Bleeding Patients

Transcription

1 SK Clinical Guideline 2 Dabigatran ( Pradax ) and Bleeding Patients A Cnsensus-Based Guidance Dcument * This guidance dcument was created by the Prvincial Transfusin Medicine Service, with input frm key medical specialists in Saskatn, Regina as well as acrss the cuntry - after cnsideratin f the best-available evidence. Nte that existing medical evidence is limited and thus this issue will require cntinued review as mre data becmes available and as mre clinical experience using dabigatran accumulates. 1.0 Intrductin Dabigatran is an ral direct thrmbin inhibitr apprved fr use in patients with nn-valvular atrial fibrillatin and VTE prphylaxis fllwing hip r knee replacement surgery. Direct thrmbin inhibitrs (DTIs) exert their anticagulant effect by directly attaching t and inhibiting bth free and fibrin-bund thrmbin. 2.0 Purpse The purpse f this dcument is t prvide guidance in the management f patients wh experience bleeding cmplicatins while n dabigatran. It is nt intended t guide the selectin f alternate ral anticagulants. 3.0 Bleeding Risks In studies f atrial fibrillatin, the verall bleeding risk assciated with dabigatran was similar t warfarin, including the elevated bleeding risk assciated with increased patient age. There was a significantly higher incidence f gastrintestinal bleeding and a significantly lwer incidence f intracranial hemrrhage in the patients taking dabigatran (cmpared t warfarin). The main cncern regarding bleeding n dabigatran is that there is n specific antidte fr reversal f the anticagulant effect. 4.0 Pharmackinetics Dabigatran is rapidly absrbed with peak dabigatran levels achieved within 2-4 hurs. Biavailability is lw apprximately 6% The half-life f dabigatran is hurs, and steady-state cncentratins are reached within tw t five days after multiple dses. Dabigatran is renally eliminated s clearance is significantly influenced by renal functin, and any deteriratin in renal functin will prlng the half-life. Versin April 25, f 6

2 5.0 Labratry Testing and Dabigatran Addendum t the Saskatchewan Transfusin Resurce Manual 5.1 Indicatins fr labratry testing: Currently, rutine therapeutic mnitring is nt indicated. 5.2 Situatins where labratry testing may be useful t assess fr residual drug effect: The bleeding patient Preperative setting Patient wh may have been expsed t trauma 5.3 Labratry assays: Labratry assays may be bradly categrized int generally available tests and specialized labratry assays Generally available tests: These include a prthrmbin time (PT/INR), activated partial thrmbplastin time (aptt), thrmbin time (TT). Dabigatran prlngs these assays; hwever, the degree f prlngatin des NOT reliably predict plasma dabigatran levels nr des it prvide an accurate assessment f risk f surgical hemrrhage in patients n dabigatran. The infrmatin prvided by these assays is limited t whether there is residual dabigatran effect r nt. Nte: A nrmal PT r aptt des nt exclude the presence f residual dabigatran. The thrmbin time is typically very sensitive and, again, nly prvides infrmatin n presence r absence f residual drug Specialized labratry assays: These include ecarin cltting time (ECT) and dilute thrmbin time (dtt). When apprpriately calibrated, the ECT and dtt generally prvide reliable infrmatin n plasma dabigatran levels. Hwever, these assays are nt widely available. In additin there is currently n infrmatin n plasma dabigatran levels and risk f hemrrhage and/r the safety f surgical r ther invasive interventins. 6.0 Cnsensus-Based Prtcl fr Bleeding Management Ntes: There are n knwn specific agents t reverse the drug. Plasma will nt reverse the drug as dabigatran will inhibit thrmbin in transfused plasma. The nly knwn way t remve the drug is dialysis, but this has limited efficacy and may nt be practical in an actively bleeding anticagulated patient. There is very little data t help guide us in managing bleeding cmplicatins n the drug: There is n readily available labratry test t quantify the degree f anticagulatin: Standard cagulatin tests (PTT, PT/INR) d nt accurately reflect drug levels. Thrmbin Time (TT) is the mst sensitive t the drug. Fibringen activity testing may nt be reliable n dabigatran. Versin April 25, f 6

3 Addendum t the Saskatchewan Transfusin Resurce Manual 6.1 Fr minr bleeding: Evaluate drug adherence and timing f last dse, current renal functin (i.e., estimated creatinine clearance), whether anatmical defects may explain hemrrhage. Review results f lcally-available cagulatin tests: If aptt and TT are nrmal (r aptt alne in the absence f TT availability), n drug is present. Re-evaluate fr ther cause f bleeding. Use lcal measures t cntrl the bleeding. (i.e. mechanical cmpressin, tranexamic acid 10 mg/kg iv r 25 mg/kg p, etc.) Keep well-hydrated t prmte diuresis. Dabigatran is 80% renally-cleared. Replace fluids and use bld prducts if needed. Use clinical judgment t hld r cntinue dabigatran. Stpping the drug will decrease the cntinued bleeding risk. But the risk f strke and the severity f the bleeding shuld be weighed. Cnsider additinal factrs, such as duratin f the drug effects (1-2 days in patients with nrmal renal functin, but can be > 5 days in patients with impaired renal functin) and the nset f actin when restarting (peak activity within 2 4 hurs). Cntact reginal/ prvincial Transfusin Medicine Medical Directr fr further cnsultatin. 6.2 Fr severe r life-threatening bleeding: Stp dabigatran. Assess adherence and timing f last dse. If last dse within the previus 2 hurs cnsider administratin f activated charcal. Lab testing: CBC, aptt, INR, TT (if available), fibringen (if available), creatinine (kidney functin), electrlytes (including calcium, which is necessary fr adequate hemstasis). If aptt and TT are nrmal (r aptt alne in the absence f TT availability), n drug is present. If aptt is nrmal and TT is prlnged, there is likely drug present, but the patient is unlikely t be therapeutically anticagulated. Re-evaluate fr ther cause f bleeding. If aptt and TT are prlnged, then anticagulant effect is present. Determine drug half-life based n time frm last dse and creatinine clearance. Repeat testing every 4 6 hurs until bleeding has stpped. Cntrl the bleeding site and prvide supprtive care f patient. Use lcal measures (i.e. cmpressin, wund packing, tpical/ral/iv tranexamic acid). Cntact surgery r interventinal radilgy fr pssible emblizatin. Cnsider dialysis; may be able t remve 30-60% f the drug. (Best with a charcal filter.) Versin April 25, f 6

4 Addendum t the Saskatchewan Transfusin Resurce Manual Perfrm bld transfusin as necessary and when apprpriate prducts are available, use the fllwing transfusin cnsideratins: Red bld cells (RBCs): Transfuse RBCs per institutinal guidelines r t keep Hgb > 90 g/l. Plasma: After the 4th unit f RBCs alne, start giving RBCs and plasma n a 1:1 rati (t avid dilutinal cagulpathy). Platelets: give 1 adult dse after 8 units RBCs/4 units plasma. Cryprecipitate: Cnsider 8 units f cry if nging bleeding after 8 RBCs/4 plasma/1 platelet dse. Please nte that neither plasma nr cryprecipitate is expected t reverse the anti-cagulant effect f dabigatran. Cntact reginal/prvincial transfusin medicine medical directrs fr further cnsultatin. 6.3 Exceptinal Measures Special hemstatic bld prducts - either the activated prthrmbin cmplex cncentrate called FEIBA (preferred) r activated Factr VII ( NiaStase; preferred if FEIBA is nt available) shuld be cnsidered if bleeding is life threatening and all ther measures t cntrl bleeding have failed. These agents d nt actually reverse the drug; they vercme its effects. Thus, the crrect dse is unknwn. There is insufficient data in the medical literature t supprt the immediate, upfrnt use f such agents Thrmbsis is a ptential side effect f all agents, but much mre s with Factr VIIa. Prthrmbin cmplex cncentrates (PCCs, Beriplex, / Octaplex ) are less likely t reverse dabigatran hwever, are als less likely t cause thrmbtic side effects. Cntact reginal/prvincial Transfusin Medicine Medical Directr fr further cnsultatin. Saskatn & Nrthern SK: Transfusin Medicine Medical Directr - Saskatn Health Regin, (306) Regina & Suthern SK: Physician n call fr hematlgy/bld transfusin - Regina Qu Appelle Health Regin Bld Transfusin Service, (306) Versin April 25, f 6

5 7.0 Selected References Addendum t the Saskatchewan Transfusin Resurce Manual Cnnlly SJ, et al. Dabigatran versus Warfarin in Patients with Atrial Fibrillatin. NEJM. Sep 17, (RE-LY) Eikelbm JW, et al. Risk f Bleeding With 2 Dses f Dabigatran Cmpared With Warfarin in Older and Yunger Patients With Atrial Fibrillatin: An Analysis f the Randmized Evaluatin f Lng-Term Anticagulant Therapy (RE-LY) Trial. Circulatin. 2011; 123: Kaatz S, et al. Guidance n the emergent reversal f ral thrmbin and factr Xa inhibitrs. Am J Hematl Published nline in Wiley Online Library (DOI: /ajh.23202). RxFiles Trial Summary (Review) Nv FDA Website. Pradaxa (dabigatran etexilate mesylate): Drug Safety Cmmunicatin - Safety Review f Pst-Market Reprts f Serius Bleeding Events. Dec 7, Find the mst up-t-date versin f the Saskatchewan Transfusin Resurce Manual and related dcuments at Versin April 25, f 6

6 Addendum t the Saskatchewan Transfusin Resurce Manual Patient with Bleeding n Dabigatran Therapy Initiate standard resuscitatin measures, as indicated. Check labs: CBC, Cag s (including TT, where available), Renal functin, Lytes (including Ca ++ ). Stp Dabigatran, determine time f last dse. Cnsider ral charcal if 2 hurs frm last dse. Cnsult Transfusin Medicine Medical Directr(s) as needed. Mild Bleeding (clinically determined r EBL<750mL r <15%) Mderate Bleeding (clinically determined r EBL 750mL 2000 ml r 15-40%) Life-Threatening Bleeding (clinically determined r EBL>2000mL r >40% Delay r discntinue dabigatran as apprpriate Lcal hemstatic measures (mechanical cmpressin, tranexamic acid 10 mg/kg iv r 25 mg/kg p) Keep well-hydrated Mild Bleed measures PLUS: Lcal hemstatic measures (surgical interventins) Fluid replacement Transfusin as needed Mderate Bleed measures PLUS: Cnsider hemdialysis Cnsider FEIBA, Factr VIIa Cnsult TM Medical Directr Prvincial Transfusin Medicine Medical Directrs: Saskatn & Nrthern SK: Saskatn Health Regin - (306) (ask fr transfusin medicine medical directr) Regina & Suthern SK: Regina Qu Appelle Health Regin Bld Transfusin Service (306) (ask fr physician n call fr hematlgy/ bld transfusin) *Adaptable nly under the authrity f the Prvincial Transfusin Medicine Medical Directrs. Versin April 25, f 6