New Age Anticoagulants: Bleeding Considerations

Transcription

1 Ontario Regional Blood Coordinating Network March 23, 2012 New Age Anticoagulants: Bleeding Considerations Bill Geerts, MD, FRCPC Thromboembolism Specialist, Sunnybrook HSC Professor of Medicine, University of Toronto National Lead, VTE Prevention, Safer Healthcare Now!

2 Outline The new oral anticoagulants Evidence of benefit Limitations of new anticoagulants Laboratory monitoring Peri-procedure management Management of bleeding

3 Traditional Anticoagulants XII XI IX VIII VII X heparin AT LMWH AT V warfarin II I Fibrin clot

4 The Potential of New Oral Anticoagulants Simple dosing regimens/fixed doses Rapid onset No dietary restrictions Predictable anticoagulation No routine coagulation monitoring Less laborintensive Less impact on daily life Improved compliance Reduced administrative costs Improved quality of life Improved efficacy and safety

5 The new oral anticoagulants apixaban (Eliquis ) dabigatran (Pradax ) rivaroxaban (Xeralto )

6 New Oral Anticoagulants XII XI IX VIII X VII Oral Xa inhibitors rivaroxaban apixaban others heparin LMWH V warfarin II I Oral IIa inhibitors dabigatran others Fibrin clot

7 Approved in Canada Today apixaban dabigatran rivaroxaban Orthopedic prophylaxis Stroke prevention in AF Not yet VTE treatment No No # ACS No No No Other indications* No No No * medical/surgical thromboprophylaxis, mechanical heart valves, cancer, pregnancy # ODB supported

8 Property - 1 warfarin new oral anticoag Pharmacodynamics Indirect inhibition Direct inhibition Onset of action Slow (4-7 days) Rapid (1-3 hrs) Dosing Variable ( mg) Fixed Drug interactions Several (CYP 2C9) Apparently fewer (P-gp, CYP 3A4) Lab monitoring Regularly Less frequent Half-life Long (40 hrs) Shorter (8-15 hrs)

9 Property - 2 warfarin new oral anticoag Renal elimination No Yes Offset Slow (4-5 days) Short (1-2 days+) Antidote Yes, rapid No Years experience 60 <3 Drug cost/month $5 $123 (dabi) $82 (riva)

10 Property dabigatran rivaroxaban apixaban Target Thrombin Factor Xa Factor Xa Bioavailability <6.5% (+ variable) ~90% ~66% P-gp interaction Yes Yes Yes Time to peak 1-2 hrs 2-4 hrs 1-2 hrs Half-life hrs 9-12 hrs 8-15 hrs Plasma prot binding 33% 90% 87% Dosing Twice daily Once daily Twice daily Hepatic metabolism Very little 33% (CYP3A4, 2J2) 75% (CYP3A4) Renal elimination >80% 33% active 25% Specific antidote No No No

11 Orthopedic thromboprophylaxis apixaban (Eliquis ) dabigatran (Pradax ) rivaroxaban (Xeralto )

12 The Future of Thromboprophylaxis 1. Oral route 2. One drug/one dose for (almost) all patients at risk 3. Relatively inexpensive 4. Used routinely for duration of risk

13 Rivaroxaban after THA/TKA RECORD 1-4 (N=12,383) Outcome Enoxaparin N=6,200 Rivaroxaban N=6,183 P VTE 402 (9.4%) 180 (4.2%) <0.001 Major bleeding 17 (0.3%) 27 (0.4%) > Clinically-important outcomes (death, MI, stroke, symptomatic VTE + major bleeding) > 139 (2.2%) 96 (1.6%) Turpie Blood 2008;112:36A

14 Thromboprophylaxis Use in Orthopedic Surgery (Canada)

15 VTE Treatment apixaban (Eliquis ) dabigatran (Pradax ) rivaroxaban (Xeralto )

16 Treatment of Acute VTE current approach LMWH Warfarin INR 2-3 rivaroxaban rivaroxaban 15 mg BID x 3 weeks 20 mg QD dabigatran LMWH dabigatran 150 mg BID 5-10 days

17 Stroke prevention in atrial fibrillation apixaban (Eliquis ) dabigatran (Pradax ) rivaroxaban (Xeralto )

18 Dabigatran in AF (RE-LY) warfarin Dabigatran 110 mg BID Dabigatran 150 mg BID P=0.3 % per year P<0.001 P=NS 1.7% 1.5% 1.1% Stroke or embolism P= % 2.7% 3.1% Major bleeding Connolly NEJM 2009;361:1139

19 Apixaban in AF (ARISTOTLE) AF + >1 risk factor for stroke 18,201 patients in 39 countries Stroke or systemic embolism warfarin Major bleeding warfarin apixaban 5 mg PO BID Apixaban apixaban 5 5 mg mg PO PO BID BID Months Months Granger NEJM 2011;365:981

20 New Oral Anticoagulants: Strengths Oral administration Few drug interactions Less variability No laboratory monitoring Rapid onset of action Won t cause HIT Greater patient convenience Potential major impact on clinical practice: greater proportion of patients get prophylaxis

21 New OACs: Limitations Few studies, selected patients, careful follow-up Renal clearance (dabi >> riva > apix) No proven reversal agent Compliance in routine practice will be less than in trials Little real-world experience Who to monitor and how? Greater cost Mistakes in practice Long-term complications

22 January 12, 2012 During the 1 st quarter of 2011, FDA has received: 932 serious AEs linked to dabigatran 505 hemorrhages (warfarin 176) 120 deaths 120 hemorrhagic strokes 543 hospitalizations We believe FDA and the manufacturer should reevaluate dosing in the elderly or those with moderate renal impairment to determine optimal dosing and monitoring requirements.

23 The Goal of the New OACs

24 The New OACs in 2012? Convenience Uncertainties Cost

25 Laboratory Monitoring of New Oral Anticoagulants apixaban (Eliquis ) dabigatran (Pradax ) rivaroxaban (Xeralto )

26 Lab Monitoring is Sometimes Necessary Bleeding event High risk for bleeding Acute thromboembolic event Pre-procedure safety elective, urgent Extremes of weight is the dose appropriate? Renal dysfunction Potential drug interactions Adherence check, patient education tool Suspected overdose

27 Problems with Monitoring New Oral Anticoagulants 1. No validated tests 2. Each drug has unique effect on clotting tests 3. Generally poor correlation between drug levels and test results 4. Reagent - analyzer variability 5. Timing of test is critical 6. Target ranges not established 0 24

28 Laboratory Monitoring Drug dabigatran Lab monitoring aptt (poor at supratherapeutic doses) ECT Hemoclot linear relation TT (Too sensitive - is any drug present?) rivaroxaban PT (INR) (riva-specific ISI) AXa with specific riva calibrator apixaban PT (INR) (?apix-specific ISI) AXa with specific apix calibrator At high concentrations, all of the new OAC prolong both the PT and aptt

29 Laboratory Monitoring New OAC Assessment of reversal dabigatran rivaroxaban aptt PT Monitoring of blood level dabigatran Factor Xa inhibitors Hemoclot test Anti-Xa

30 Periprocedure Management with a New OAC apixaban (Eliquis ) dabigatran (Pradax ) rivaroxaban (Xeralto )

31 Pre-Procedure Use of Dabigatran Renal Function (CrCL, ml/min) Half-life (hr) (range) How far in advance of procedure should dabigatran be stopped? (12-23) 1-2 days (15-25) 3 days (consider aptt before) < 30 * More than 25 Approx 5 days (check aptt before) * Use of dabigatran contra-indicated

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33 Pre-Procedure Use of Rivaroxaban Renal Function (CrCL, ml/min) Half-life (hr) (range) How far in advance of procedure should rivaroxaban be stopped? >30 12 (11-13) 1-2 days (consider INR before) <30 *? 3 days (check INR before) * Use of rivaroxaban contra-indicated

34 When is it safe to do surgery? dabigatran Normal aptt? rivaroxaban Normal INR **Develop your own institutional policy pending real data

35 When is safe for a spinal/epidural? No one knows!

36 Urgent Surgery in Patient on Dabigatran 78 year old woman on dabigatran for AF (CHADS 2 = 3). Took dabigatran 150 mg this morning. In ER with aptt = 52 seconds, INR = 1.8, creatinine = 132. A. Bowel obstruction requiring OR B. Hip fracture

37 Post-Procedure Management Dictated almost entirely by bleeding risk Consider starting a prophylaxis dose until bleeding risk : dabigatran mg QD rivaroxaban 10 mg QD Or LMWH until bleeding risk

38 Bleeding and Emergency Reversal of a New OAC apixaban (Eliquis ) dabigatran (Pradax ) rivaroxaban (Xeralto )

39 when prescribing a drug with side effects that include lifethreatening hemorrhage, reversal is not desirable, it is essential. Cotton NEJM 2012;366:864

40 Management of Bleeding on New Oral Anticoagulants No specific antidotes for any

41 Management of Bleeding in Patients Receiving a New Anticoagulant - 1 Always: Assess the source and severity of bleeding Assess coagulation aptt, PT, platelets - Normal aptt, PT = no significant drug on board Stop the anticoagulant Good urine output (esp for dabigatran) Implement mechanical hemostasis if possible packing, clipping, embolization, surgery Consider hemodialysis for dabigatran

42 Management of Bleeding in Patients Receiving a New Anticoagulant - 2 Don t use: Plasma, cryo unless factor deficiency too Consider: Antifibrinolytics (tranexamic acid) - No data, may help and unlikely to harm a bleeding patient If really desperate: 1) RFVIIa 50 IU/kg for riva 2) PCC (Octaplex, Beriplex) II, VII, IX, X 3) FEIBA activated II, VII, IX, X

43 Option Plasma Risk/problems Large volume, risks of infusion, not proven rviia Arterial/venous TE, cost, 2 hour half-life, not proven PCC apcc No effect on PTT with dabigatran, not proven Arterial/venous TE, not widely available, not proven

44 Reversal with PCC rivaroxaban dabigatran dabigatran 150 mg PO BID or rivaroxaban 20 mg QD x 2½ days in 12 healthy volunteers Eerenberg Circulation 2011

45 Patient with bleeding on dabigatran CBC, creatinine aptt If aptt >40 sec, consult TE or Transfusion Medicine Mild bleeding Moderate-severe Bleeding * Life-threatening Bleeding * Local hemostatic measures Hold 1 or more doses of dabigatran Manage bleeding (compression, surgery) Fluid diuresis Transfuse RBCs or platelets if needed (follow Sunnybrook guidelines) Oral charcoal if dose <2 hrs before Contact Transfusion Medicine Consider tranexamic acid (1 G IV followed by 1 G infusion over 8 hours) Hemodialysis might be helpful *DO NOT TRANSFUSE plasma or cryo to reverse aptt

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47 Management of Bleeding in Patients Receiving a New Anticoagulant - 3 Institutional Perspective: Develop a written local policy post on Intranet Transfusion Medicine mandate Enforce it Investigate and database each event Use events as educational opportunities Look for new evidence use it to modify local policy Report bleeding events to Health Canada