Review of Newer Antiplatelets, Antithrombotics and Reversal

Transcription

1 Review of Newer Antiplatelets, Antithrombotics and Reversal Ravi Sarode, MD Professor of Pathology Chief of Pathology and Medical Director of Clinical Laboratory Services Director, Transfusion Medicine and Hemostasis UT Southwestern Medical Center, Dallas, TX SVIN Hollywood, FL, November 7, 2014

2 Disclosures Consultant CSL Behring Advisor Octapharma Off label use of drugs PCC and rfviia

3 Please don t show coagulation cascade!!!

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

5 Evolution of Oral Anticoagulation Therapy Warfarin to Dabigatran to Rivaroxaban to Apixaban to..

6 Target Specific Oral Anticoagulants Dabigatran Etexilate (Pradaxa) Rivaroxban (Xarelto) Apixaban (Eliquis) MOA Direct Thrombin inhibitor Direct FXa inhibitor Direct FXa inhibitor Manufacturer Boehringer Ingelheim Bayer Bristol Myers and Sqibb Indications 1. Reduce risk of stroke and TE in NV-AF 2. Treatment and prophylaxis of DVT/PE 1. Reduce risk of stroke and TE in NV-AF 2. Rx of DVT and PE 3. DVT prophylaxis 1. Reduce risk of stroke and TE in NV- AF 2. Rx DVT and PE 3. DVT prophylaxis

7 RE-LY Study Connolly NEJM 2009 (n=) 110 mg Dabi (6015) 150 mg Dabi (6076) Warfarin (6022) P=value D/C at 1 yr (%) Primary outcome Stroke/TE (%/yr) * 1.69 *<0.001 MI (%/yr) * <0.48 Intracranial Bleed 27 (0.23)* 36 (0.30)* 87 (0.74) <0.001 Extracranial bleed 299 (2.51) 342 (2.84) 315 (2.67) NS GI Bleed 133 (1.12) 182 (1.51)* 120 (1.02) *<0.001 Life-threatening Bleed 145 (1.220)* 175(1.45)** 212(1.8) *<0.001 and **<0.04 No information on how these bleeds were managed!

8 ROCKET-AF Patel NEJM 2011 Outcome Primary outcome (Stroke/TE) %/yr Rivaraxoban (20 mg OD) Warfarin P value <0.001 Major bleeding %/yr NS ICH GI Bleed Hb >2 g RBC Tx Critical bleeding Fatal bleeding No information on how these bleeds were managed!

9 ARISTOTLE Granger NEJM 2011 Outcome Primary outcome (Stroke/TE) %/yr Apixaban (5 mg bid) Warfarin P value <0.01 Major bleeding %/yr NS ICH <0.001 GI Bleed NS Major or clinically relevant non-major bleeding <0.001 Any bleeding <0.001 Net clinical outcomes stroke, TE, or major bleed <0.001

10 FDA approved TSOAs but never asked How bleeds with TSOAs were managed? How to detect drug levels if needed? What is the therapeutic level? Is there a reversal agent for urgent surgery or serious bleeding? Is patient s weight important? Assessment of compliance?

11 FDA

12 Warfarin Dabigatran Rivaroxaban Apixaban Onset of action 2-5 days hrs 1-4 hrs 3-4 hrs Dosing Once a day Twice a day Once a day Twice a day Bioavailability (%) % Prodrug No Yes No No Variability Common Uncommon Uncommon Unknown Therapeutic Index Narrow Not known Not known Not known Diet/ drugs Not known + Monitoring needed Yes No No No Test to monitor INR???Anti-Xa assay Elimination half life?anti-xa assay h hrs 6-9 hrs 12 hrs Renal Excretion Liver 85% renal 33% renal 25% urine Antidote PCC/FFP/Vit K None None None

13 How to Manage Bleeding?

14 Hemostasis and Thrombosis Research Society (HTRS) Discontinue the drug Supportive care Activated charcoal for dabigatran Dialysis or PLEX PCC either 3 or 4 factor nonactivated may be used Did not recommend rfviia or plasma Kaatz et al, AJH 2012

15 Removal of Drugs Dabigatran Rivaroxaban Apixaban Within 2-3 hrs Dialysis Activated charcoal?? 65% free yes 65% Bound No 87% bound No PLEX No Yes Yes Line placement Problem Problem Problem PLEX = Plasma exchange

16 Experimental Reversal of TSOAs Prothrombin Complex Concentrate (PCC) 3 factor PCCs = Bebulin, Profilnine 4 factor PCC = Kcentra Activated PCC = FEIBA rfviia Variable efficacy in controlling bleeding after rat tail clipping, head trauma, etc Ex vivo studies in human volunteers rviia less effective than PCCs Anticoagulants, Clinics in Lab Med Sep 2014

17 Rationale for PCC Use Prothrombin gene mutation - increased levels of FII or prolongs t/2 With thrombophilia have levels >125% Probably generates more thrombin PCC - 50U/kg will increase FII and X significantly Generate more IIa neutralize DTI Generate more Xa neutralize DXaI Coagulation factors get activated in-vivo in minutes hence avoid apcc

18 FVII FII FIX (%) FX Factor Levels Over Time Mean infusion 200IU/min; Mean dose 3750 IU (150 ml) Pre Beriplex Minutes: Post-Infusion Time Hours: Post-Infusion PK Healthy Volunteer Study 1001 Ostermann et al. Thromb Haemost 2007; 98: 790 7

19 rfviia PCC

20 Scheduled Surgeries Discontinue 24 hrs before 48 hrs before for procedures with high risk for bleeding Longer for patients with compromised renal function TT should be normal before surgery for dabigatran PT should be normal with no detectable anti FXa activity for direct FXa inhibitors

21 Bleeding Management at UTSW Hospitals Tests to assess TSOAs effects TT or PTT if normal no DTI anti-xa assay (LMWH or Rivaroxaban assay) Hemostatic strategy STOP the drug Topical hemostatic agents for epistaxis PCC (KCentra) = 4000 Units (fixed dose) Check above tests 30 min later Assess clinical effect may repeat PCC

22 TSOAs vs VKA 22

23 Newer Antiplatelet Drugs

24 Nature Review Cardiology 2014

25 Nature Review Cardiology 2014

26 Oral APAs Features ASA Ticlopidine Clopidogrel Prasugrel Ticagrelor MOA COX-1 P2Y12 P2Y12 P2Y12 P2Y12 Prodrug No Yes Yes Yes NO Onset of action Minutes 4-7 days <24 hr <24 hr faster Steady state of inhibition Hours 8-11 days 3-7 days 3-5 days Hours Half-line (hr) Reversible (days) Bleeding risk PLT Tx for Urgent surgery No 1 dose 1 dose 1 dose No PLT Tx for Urgent Eye/Neurosurgery or ICH One dose Two doses Two dose Two doses Two doses Elective surgery No wait 7 days 5 days 5 days 5 days MOA = mechanism of action; P2Y12 = ADP receptor;

27 PLT Function Testing for APAs Agonists PF-100 TM CT (sec) WBA/ VerifyNow AA = arachidonic acid; ADP = adenosine diphosphate; ASA = aspirin; Coll = collagen; CT = closure time; EPI = epinephrine; LTA = light transmission aggregometry; N = normal; ND = not done; PFA-100 TM = PLT function analyzer; WBA = whole blood aggregation. LTA Interpretation EPI >200 ND ASA Effect ADP N Clopidogrel Ticlopidine Prasugrel Ticagrelor ADP N N N P2Y12 resistant AA ND 0/ / ASA effect AA ND N N ASA resistant

28 Vorapaxar (Zontivity) Selective potent PAR-1 inhibitor that blocks thrombin-mediated platelet activation without interfering with thrombin action on fibrinogen. Rapidly absorbed with high bioavailability VERY long half-life of ~311 h (13 days ) Metabolized by CYP3A4 in the liver.

29 Significant Bleeding Complications TRACER trial 120 : NSTE-ACS were randomly assigned to receive either vorapaxar (40mg loading dose and a 2.5 mg daily maintenance dose) or placebo in addition to APA therapy. A significant 35% increase in mod/severe bleeding (7.2% versus 5.2%; P<0.001) and three fold increase in ICH (1.1% versus 0.2%; P<0.001) terminated early. TRA 2P-TIMI 50 trial - secondary prevention of ischemic events in patients with known atherothrombotic disease (MI, ischaemic stroke, PAD) Ischemic benefit was hampered by a significantly increased Mod/severe bleeding (4.2% versus 2.5%; P=0.001) and a two fold increase in ICH (1.0% versus 0.5%; P<0.001) terminated early

30 FDA Approved in May 2014 For clinical use at 2.5mg once daily for the reduction of thrombotic cardiovascular events in patients with a history of MI or PAD It must be used in addition to standard-of-care antiplatelet therapy because no studies have investigated vorapaxar monotherapy. Higher bleeding risk! Vorapaxar is contraindicated in patients with a history of stroke, transient ischemic attack, or ICH and in those with active pathological bleeding How to manage severe bleeding? rfviia

31 Pharmacologic Agents for Reversing Effects of Antiplatelet Drugs rfviia DDAVP

32 In vitro Thrombin Generation by rfviia ASA and plavix treated platelets Studied various does of rfviia and standard conc. of AA, ADP and Collagen Measured Lag Time, peak and total thrombin generation rfviia in 10, 20, 104 and 200 µg/kg corrected TG in absence of TF This effect can be important in pts on APA undergoing urgent surgery or bleeding Recommendation µg/kg Altman et al, JTH 2006

33 DDAVP for ASA Treated Patients VWF release Elective Cholecystecomy pts Randomized to get ASA or ASA+DDAVP and control group Pre-op BT 7.4 in ASA vs 5.0 in control Post-DDAVP BT 5.5 4/6 in ASA required blood; 5/6 had post-op bleeding episodes None in DDAVP group Recommendation: 0.3 µg/kg IV Flordal and Sahlin BJS 1993

34 Take Home Messages TSOAs related bleeds Stop the drug 50 U/kg PCC Antiplatelet therapy related bleed Stop the drug P2Y12 antagonists 2 doses of PLT Jehovah's witness rfviia 20µg/kg DDAVP 0.3 µg/kg infusion

35 New Agents are going to kick.