Disclosures. Learning Objectives. Financial: none. Off label discussion: Recommendations in lieu of data

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1 Kathryn Hassell, MD Professor of Medicine, Division of Hematology University of Colorado Denver Disclosures Financial: none Off label discussion: Prothormbin complex concentrates for DOAC reversal Use of DOACs for HIT Recommendations in lieu of data Learning Objectives Assess the need for attempted reversal of direct oral anticoagulants (DOACs) for acute bleeding Weigh factors impacting reintroduction of anticoagulation after a bleeding episode Interpret available clinical and lab data when considering a diagnosis of HIT, and understand data regarding use of DOACs Consider risks and benefits of extended medical prophylaxis

2 75 year old man on rivaroxaban (Xarelto) for a fib, hx of stroke presents at 1 p.m. with bright red blood per rectum. Last rivaroxaban dose at dinner last night. Stable vital signs Initial CBC normal except Hb of 12.5 gm/dl (last month in clinic it was 14.2 gm/dl) Estimated GFR 50 ml/min What are you going to do about his anticoagulation? A. Give idarucizumab (Praxibind) B. Nothing the drug is going away already C. Give a prothrombin complex concentrate (PCC, e.g. K-Centra) D. Give fresh frozen plasma Control of Bleeding FIX the HOLE Systemic measures to reduce bleeding until the hole can be fixed Permissive hypotension, low-volume resuscitation Attention to systemic factors which impact hemostasis; adverse outcome predicted by ph < 7.2, temp <34 o C, ISS>25, SBP<30 mmhg Coagulation doesn t work well outside the physiological range (e.g. acidosis, hypothermia) Cosgriff, J Trauma 42:857, 1997 How Much Anticoagulation Is Present? Single dose of aspirin permanently inhibits platelet function Will only increase functional platelets by 10%/dy Acute solution? Platelet transfusion Warfarin therapy reduces pool of clottable factors Will take 3-5 days to rebuild all coagulation factors, even with vitamin K supplementation Acute solution? FFP and prothrombin complex concentrates (PCCs) to temporarily replete coagulation factors

3 DOAC: Consider Half-Life and Timing Half-life of DOACs Harder, Thromb J 12:22, 2014 Our patient Dabigatran (Pradaxa) Rivaroxaban (Xarelto) Apixaban (Eliquis) Betrixaban (Bevxxya) 7-17 hrs hrs 8-15 hrs hrs Rivaroxaban levels after 20 mg dose Comparable to LMWH Caveats to Judging Presence of DOACs Prolonged half-life due to: Inappropriate dosing for level of renal function New severe AKI Increased drug activity due to introduction interacting medications Cannot use regular coagulation tests (PT, aptt, thrombin time) to prove drug is gone Ebner, Stroke 48:2457, 2017 Cannot assume drug is present if coags are abnormal - affected by other things Do We Need to Reverse DOACs? Average time to attempted reversal comes hours after last dose was taken It s already going away, so did reversal matter? (no RCTs) Warfarin reversal takes at least that long No increased fatal bleeding in all studies for those on DOACs as compared to warfarin Over 25,000 people exposed for up to two years and/or in a post-op setting Many were yrs old, 35% also on ASA DeLoughery, Am J Hem 86:586, 2011 Eerenberg, Circulation 124:1508, 2011 Sardar, J Am Geriat Soc 62:857, 2014 Shatzel, J Intern Med Oct 5. doi: /joim.12697

4 ICH Outcome: Anticoagulation Doesn t Matter Italian multi-cohort prospective study of consecutive ICH patients 163 on VKA 54 on DOACs 97 on antiplatelet agents 167 on no therapy No difference in initial size of hemorrhage, risk or volume of expansion, or death No difference with anticoagulant reversal Attempted in 50% of VKA, 20% of DOACs Franco, International Society of Thrombosis and Hemostasis Congress, July 2017, ASY 10.1 PCCs for Anticoagulant Reversal Prothrombin Complex Concentrates (PCC) (activated, 4-factor) Typical dosing ~25 U/kg (up to 50 U/kg if INR>6) Second dose sometimes given For warfarin (meta-analysis): more rapid correction of INR, less volume overload, reduced all-cause mortality in intracranial hemorrhage (ICH) FDA-approved for reversal for patients with acute major bleeding, second dose not recommended Chai-Adisaksopha,Thromb Haemost 2016 Oct 28;116(5):879 DOAC Specific Reversal Idarucizumab: monoclonal antibody binding dabigatran FDA-approved for emergent/urgent surgery, lifethreatening or uncontrolled bleeding 2 50 ml iv doses, total of 5 gms, not >15 min apart Andexanet alpha: recombinant inactive form of factor Xa for rivaroxaban, apixaban, edoxaban, enoxaparin Short-acting Not yet available Samuelson and Cuker, Blood Reviews 31:77, 2017

5 PCCs for DOAC Reversal Most data from normal human subjects, measuring markers of capacity for thrombin generation Largest cohort study 2017 (n=84) 69% with effective management of major bleeding (mostly ICH, GI), e.g. Stable Hb, no more intervention by 48 hrs Visible bleeding stopped for 4 hrs Stable ICH volume at 12 hrs, neuro fctn not worse at 30 dy 2.3% developed ischemic stroke Majeed, Blood 2017 Aug 23 doi: /blood Khorsand, J Thromb Haemost 14:211, year old man on rivaroxaban with rectal bleeding What are you going to do about his anticoagulation? A. Give idarucizumab Wrong drug B. Nothing the drug is going away already It s been 18 hours since his last dose Given half-life of drug and adequate renal function, no proven benefit to reversal C. Give a PCC No data to support improved outcomes D. Give fresh frozen plasma Will also be inhibited by drug Shatzel, J Intern Med 2017 Oct 5. doi: /joim His Hb remains above 12.0 gm/dl, no additional rectal bleeding observed. No active bleeding on colonoscopy that evening; diverticula noted. On rounds the next day, he is very anxious about having another stroke. When and how will you resume his anticoagulation? A. Wait for 14 days, then initiate warfarin B. Wait for 14 days, then resume rivaroxaban C. Restart within 1-2 days with iv heparin and if no bleeding, start rivaroxaban or apixaban D. Restart within 1-2 days with LMWH and if no bleeding, start rivaroxaban or apixaban E. Resume rivaroxaban or apixaban within 1-2 days

6 Resumption of Anticoagulation as Long-Term Therapy Retrospective Medicare dataset analysis of a fib patients with major bleeding Risk of recurrent major bleeding events is NOT increased if anticoagulation resumed compared to withholding it Subset analysis for recurrent bleeding Warfarin: HR 1.56 ( ) Dabigatran: HR of 0.65 ( ) Included both GI and CNS bleeding Hernandez, Stroke 48:, 2017 Resumption of Anticoagulation as Long-Term Therapy However, significant reduction in risk of stroke and all-cause mortality if resumed anticoagulation (HR ) Hernandez, Stroke 48:, 2017 Withholding anticoagulation does not reduce the recurrence of bleeding Anticoagulation doesn t cause bleeding However, at risk for recurrent thromboembolic events Resuming Anticoagulation after GIB Most data from warfarin therapy (retrospective cohorts), some DOAC therapy No increase in risk of recurrent bleeding if resumed after 7 days though at a median of 4 days 3-fold reduction in all-cause mortality in those who resumed Significant reduction in rate of thromboembolism Steark, BMJ 351:h5876, 2015 Colantino, Cleveland Clin J Med 82:245, 2015 Kido Ann Pharmacotherapy 2017 Jun 1:

7 Resuming DOAC after GI Bleeding Increased GI bleeding risk with some DOACs? Kido Ann Pharmacotherapy 2017 Jun 1: However, meta-analysis suggests no increase risk of GIB with DOACs compared to warfarin Few data, but generally recommended to start DOAC at discharge or within 7 days Milling, Am J Emerg Med 34:19, 2016 Resuming Anticoagulation After CNS Bleeding Recent systematic review and meta-analysis 8 studies, average age yrs, 5306 pts 1899 restarted on anticoagulation - No increased risk of recurrent CNS bleeding with resumption of anticoagulation - Reduced risk of recurrent thrombotic events: 0.34 ( ) Murthy, Stroke 48:1594, 2017 Resuming Anticoagulation After CNS Bleeding 5 studies: consequences of restarting Same or lower Lower Lower Recommended timing ranges from ASAP (stable volume of bleed on CT) to >14 dys Becattini, Vasc Pharm 84:15, 2016; Kuramatsu, JAMA 313:824, 2015

8 75 year old man on rivaroxaban with rectal bleeding, now stable ~2 days later, worried about stroke When and how will you resume his anticoagulation? A. Wait for 14 days, then initiate warfarin Data suggest possible increased risk of recurrent GIB with warfarin as compared to DOACs B. Wait for 14 days, then resume rivaroxaban Data support resumption within 7 days C. Restart within next 1-2 days with iv heparin and if no bleeding, start rivaroxaban or apixaban If nervous, challenge with reversible anticoag first D. Restart within next 1-2 days with LMWH and if no bleeding, initiate warfarin or resume DOAC LMWH is also basically irreversible E. Resume rivaroxaban or apixaban within 1-2 days Kido Ann Pharmacotherapy 2017 Jun 1: Other Dilemmas HITting Patients Platelet count Classic HIT HIT with Reexposure Unlikely HIT Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 γ γ HIT: Clinical Diagnosis Clinical Criteria: the 4 Ts score Thrombocytopenia Points (0, 1, or 2), Maximum = Nadir (x10 9 /L) <10 Fall >50% 30-50% <30% Timing Recent heparin 1 dy 1 dy No prev heparin 5-10 dys Unclear or >10 dys 4 days Thrombosis, ASR, skin lesions New event after heparin Progressive or new thrombosis/event None Other cause for plt None Possible Definite Probability of HIT: High: 6-8 Moderate: 4-5 Low: 0-3 Arepally, Ann Rev Med 61:77, 2010

9 Big Challenge: HIT ELISA Testing Many patient populations have (+) HIT ELISA with heparin exposure but don t have HIT Up to 50-75% of those who undergo bypass, but clinical HIT in ~1% Up to 75% of those who have LVAD, but clinical HIT in 4.2%, though some case series report 10% Example of an ICU population (n=320) By day 10, 17.2% have (+) HIT ELISA 27.8% had fall in platelets <100 Only 7 pts (2.2%) had a fall beginning on 4 th day Only 2 of these actually had HIT (0.6% of all pts) Selleng, Thromb Haemost 116:843; Selleng, J Thromb Thrombolysis 39:60 Confirmatory HIT Testing Do antibodies found by ELISA do anything? they don t hurt most people Higher titers >2.000 more likely to be relevant Many labs do reflexive functional testing: serotonin release assay (SRA) Seen as gold standard, done in reference lab Literature often uses >50-90% release = positive Often labs list >20% as positive, but some labs choose >50-75% to improve specificity.so how golden is the standard? Integrate into the big picture Nagler, Thromb Haemost 116:823, 2016 Treatment of Suspected HIT Stop all forms of heparin Excellent review of alternatives (LVADs, CVVH, etc): Selleng, Thromb Haemost 116:843, 2016 Treat with an anticoagulant even if no thrombosis 2017 meta-analysis: all forms of iv direct thrombin inhibitors (argatroban, lepirudin, bivalirudin) equally safe and effective Fondaparinux (Arixtra) acceptable Higher rates of bleeding (10-22%) in some case series Sun Int J Hematol 106:476, 2017; Arepally Blood 129:2864, 2017

10 HIT and DOACs Not heparin no cross-reactivity Sufficient anticoagulation? Literature review Analysis of 64 cases + 16 pts at single institution Most experience with rivaroxaban Most used as primary therapy or while still thrombocytopenic Risk of thrombosis 2.2% Risk of bleeding 0% Acute treatment doses? Certainly if thrombosis present Probably even if no thrombosis yet? Warkentin Blood 130:1104, 2017 Treatment of (Suspected) HIT Treat with an anticoagulant, even without clot All forms of iv direct thrombin inhibitors (argatroban, lepirudin, bivalirudin) equally safe and effective Fondaparinux (Arixtra) acceptable Higher rates of bleeding (10-22%) in some case series Continue acute anticoagulation until platelets stable and/or >150K Don t stop even if INR becomes therapeutic (warfarin) Sustain anticoagulation if HIT confirmed HIT but no thrombosis: 4 weeks per guidelines HIT with thrombosis: 3 months Sun Int J Hematol 106:476, 2017; Arepally Blood 129:2864, 2017 Other Dilemmas VTE prophylaxis for medically ill patients: How long is long enough?

11 Medical Inpatient Prophylaxis No gold standard risk assessment model Some lack external validation, others complex Others are very complicated (up to 86 variables) No clearly superior agent Camden Am J Health Sys Pharm 71:909, 2014 Stuck Thromb Haemost 117:801, 2017 LMWH most commonly used; FDA-approved for up to 14 days for medical patients Unfractionated heparin still used in some institutions Typical duration is until discharge A New Era? FDA Approval of Betrixaban Approved for adults hospitalized for acute medical illness at risk for thromboembolic complications due to restricted mobility or other risk factors Recommended duration: 35 to 42 days Short- vs. Extended-Duration Hospitalization associated with 20% attributable risk for VTE in North America Prior studies: EXCLAIM: Enoxaparin for 14 days vs. 28 days ADOPT: Enoxaparin for 6 days vs. apixaban 2.5 mg bid for 30 days MAGELLAN: Enoxaparin for 10 days vs. rivaroxaban 10 mg/day for 35 days Liew J Thromb Thrombolysis 43:291, 2017

12 Short- vs. Extended-Duration Meta-analysis of trials NNT = 313 (DVT), 625 (PE) Liew J Thromb Thrombolysis 43:291, 2017 Short- vs. Extended-Duration No difference in VTE-related or all cause mortality Concern has been bleeding > benefit NNH = 196 if exclude betrixaban trial NNH = 244 if include betrixaban Liew J Thromb Thrombolysis 43:291, 2017 Is Betrixaban Different? APEX 7513 medically ill 40+ yr olds, inpatient 96+ hrs, typical risk factors for VTE Cohort 1: 5621 pts Cohort 2: 1892 pts with (+) d-dimer or 75 yrs old Enoxaparin 40 mg/day x 10±4 days vs. betrixaban 160 mg then 80 mg/day x days Average hospital LOS: 10 days (7-14) Composite endpoint: asymptomatic DVT (US), symptomatic DVT, non-fatal PE, fatal VTE Cohen NEJM 375:534, 2017

13 Is Betrixaban Different? Results Overall: 5.3% with betrixaban vs. 7% with enoxaparin (p=.006) Asymptomatic/symptomatic DVT, PE, fatal VTE No difference in benefit based on D-dimer testing done at local labs (Some) benefit without harm Major Bleeding Cohort 1 Cohort 2 Cohort 1 Cohort 2 Enoxaparin 8.5% 7.1% 0.7% 0.6% Betrixaban 6.9% 5.6% 0.6% 0.7% Cohen NEJM 375:534, 2017 Betrixaban for Medical Prophylaxis Equivalent to enoxaparin in first 10 days, better than nothing out to day 42 Cohen NEJM 375:534, 2017 Hospital Anticoagulation (in the DOAC Era) Bleeding in the DOAC patient No clinical evidence of harm related to irreversibility Reversal rarely needed by the time the patient presents and reversal is attempted, drug likely to be going away Can t really judge presence or absence of drug by common coag tests Specific antidotes available and/or coming

14 Hospital Anticoagulation (in the DOAC Era) Resumption of anticoagulation after major bleeding (GI, CNS) Evidence demonstrates reduction in future thrombotic events without increase in recurrent bleeding events Can be done in relatively short period of time after bleeding stabilizes (days not weeks) No reason to avoid DOACs (Ir)reversibility not a significant issue Some data suggest better outcomes re: recurrence bleeding DOACs Hospital Anticoagulation (in the DOAC Era) Heparin-induced thrombocytopenia Less common than you think (<1% even in the ICU) and won t occur with use of DOACs Pattern/timing of thrombocytopenia is key (along with the other features of the 4Ts) Positive ELISA HIT Be cautious about what the lab means by positive SRA If you test, you need to treat, until the tests are negative DOACs show promise (dosing?) Hospital Anticoagulation (in the DOAC Era) Prophylaxis for the medically ill New FDA approval for extended prophylaxis after discharge with a DOAC Because you can, does that mean you should? Risk reduction in VTE (5.3% instead of 7%...) without increased risk of bleeding Easy to take but covered? Cost effective? Ideally target a higher-risk population Local D-dimer testing didn t discern Risk assessment models untested for this

15 Questions?