The Use of New Anticoagulants in the Elderly NOACs, DOACs,TOACs,TSOACs.

Transcription

1 The Use of New Anticoagulants in the Elderly NOACs, DOACs,TOACs,TSOACs. Chris E. Holmes MD, PhD Assistant Director, Thrombosis and Hemostasis Program University of Vermont

2 Dabigatran (Praxxada) Rivoraxaban (Xarelto) Apixaban (Eliquis) Edoxaban (Savaysa) Stroke Prevention, Atrial fibrillation BID QD BID QD VTE Treatment Acute Extended NO Immediate Start Twice daily Yes Immediate Start Once daily Yes Immediate Start Twice Daily Yes NO Immediate Start Once Daily No VTE Prevention Knee Hip Medical Controlled or randomized trials demonstrating efficacy Yes No Yes Yes No Yes Yes No No No No

3 Dabigatran Apixaban Edoxaban Rivaroxaban Action Direct thrombin inhibitor Activated factor Xa (FXa) inhibitor Activated factor Xa (FXa) inhibitor Activated factor Xa (FXa) inhibitor Afib Dosing Acute VTE dosing 150 mg BID 75 BID (CrCl 15-30) 150 mg bid after 5 days of parentral therapy 5 mg BID 2.5 mg BID* 10 mg BID for 7 days then 5 mg bid 60 mg QD **Boxed Warning for CrCl >95 30 mg QD (GFR 15-49) 60 mg QD after 5-10 days of initial parentral therapy 30 mg QD (GFR 15-49) 20 mg QD 15 mg QD (CrCL 25-49) 15 mg bid for 3 weeks then 20 mg daily Half Life hours 12 hours 9-11 hours 5-9 hours; hours (elderly) * If any two of the following: SCr 1.5; age 8o years; body weight < 60 kg

4 Primary Safety and Efficacy of NOACs in Atrial Fibrillation in the Elderly (age 75) RE-LY ROCKET-AF ARISTOTLE ENGAGE AF NOACs dabigatran rivaroxaban apixaban edoxaban Number of 18,113 14,264 18,201 21,105 patients Age (years) 72 (mean) 73 (median) 70 (median) 72 (median) Age % 43.2% 31.2% 40.2% Follow-up (years)

5 Primary Safety and Efficacy of NOACs for Atrial Fibrillation in the Elderly (age 75) Event rate (%/yr) Dabigatran 150mg Warfarin Riva Warfarin Apix Warfarin HD Edox LD Edox Warfarin Stroke/ SEE Major bleeding Stoke NNT 141 NNT 179 NNT 159 NNT= 244 NNH= 417 Major Bleeding NNH 137 NNH 200 NNT = 54 NNT= 122 NNT= 39 Kato, JACC 2014.

6 RCT s of NOACs vs Warfarin in Acute Therapy of VTE Author, year Schulman, 2009 Schulman, 2014 Bauersachs, 2010 Buller, 2012 Trial name RE-COVER I-II EINSTEIN DVT-PE Drug and dose Dabigatran Rivaroxaban Agnelli, 2013 AMPLIFY Apixaban Buller, 2013 HOKUSAI Edoxaban Initial regimen Heparin leadin Rivaroxaban 15 mg bd for 3 weeks Apixaban 10 mg bd for 1 week Heparin leadin N patients N pts 75 years (%) N pts CrCl 50 ml/min (%) (12) 167 (5.2) (18) 664 (8.0) (14) 327 (6.2) (12) 541 (6.6)

7 RCT s of NOACs vs Warfarin in Acute Therapy of VTE Pooled RR with 95% CI Age DOAC vs VKA Recurrent VTE or VTE related death ( ) 2.1% vs 3.8% ( ) 2.6% vs 2.6% Renal clearance, ml/min CrCl ( ) 2.9% vs 4.4% CrCl ( ) 2.5% vs 2.6% DOAC vs VKA Major bleeding 0.49 ( ) 2% vs 4.1% 0.62 ( ) 0.9% vs 1.4% 0.51 ( ) 1.8% vs 3.8% 0.60 ( ) 1.1% vs 1.6% Nick van Es et al. Blood 2014;124:

8 Efficacy of NOAC in Acute VTE by Age Recurrent VTE/VTE Death From Geldhof V et al Thrombosis Journal 2014

9 Safety of NOAC in Acute VTE by Age Major Bleeding * * Hokusai = Major plus clinically significant non-major bleeding Adapted drom Geldhof V et al Thrombosis Journal 2014

10 Absorption and Metabolism of NOACs

11 What drug interactions do I need to remember when prescribing NOACs? P-glycoprotein transporter involved in absorption and renal clearance plasma levels may be affected by P-gp inducers or inhibitors Cytochrome P450 CYP3A4 involved in hepatic clearance of rivaroxaban and apixaban plasma levels may be affected by CYP3A4 inducers of inhibitors Gnoth et al, J Pharmacol Exp Ther 2011;338: Mueck et al, Br J Clin Pharmacol 2013

12 Action to be taken in case of Drug-Drug Interactions Three levels of alert: Red contraindicated/not recommended for use Orange adapt NOAC dose dabigatran: 150 mg to 110 mg BID rivaroxaban: 20 mg to 15 mg QD apixaban: 5 mg to 2.5 mg BID Yellow consider dose reduction if two concomitant yellow interactions Where no data available, NOACs not recommended yet

13 Possible Drug-Drug Interactions Effect on NOAC Plasma Levels Dabigatran Apixaban Edoxaban Rivaroxaban Atorvastatin P-gp/ CYP3A4 +18% no data yet no effect no effect Digoxin P-gp no effect no data yet no effect no effect Verapamil P-gp/ wk CYP3A % no data yet + 53% (slow release) minor effect Diltiazem P-gp/ wk CYP3A4 no effect +40% No data minor effect Quinidine P-gp +50% no data yet +80% +50% Amiodarone P-gp % no data yet no effect minor effect Dronedarone P-gp/CYP3A % no data yet +85% no data yet Ketoconazole; itraconazole; voriconazole; posaconazole; P-gp and BCRP/ CYP3A % +100% no data yet up to +160% Red contraindicated; orange reduce dose; yellow consider dose reduction if another yellow factor present; hatching no data available; recommendation made from pharmacokinetic considerations

14 Possible drug-drug interactions Effect on NOAC plasma levels Interaction Dabigatran Apixaban Edoxaban Rivaroxaban Fluconazole CYP3A4 no data no data no data +42% Cyclosporin; tacrolimus Clarithromycin; erythromycin HIV protease inhibitors Rifampicin; St John s wort; carbamezepine; phenytoin; phenobarbital P-gp no data no data no data +50% P-gp/ CYP3A % no data no data % P-gp and BCRP/ CYP3A4 P-gp and BCRP/ CYP3A4/CYP2J2 no data strong increase no data up to +153% -66% -54% -35% Rifampin contraindicated up to -50% Antacids GI absorption % no data no effect no effect Red contraindicated; orange reduce dose; yellow consider dose reduction if another yellow factor present; hatching no data available; recommendation made from pharmacokinetic considerations

15 Factors Associated with Raised Plasma levels of NOACs Aged 80 years Aged 75 years Weight 60 kg Renal function Increased plasma level Increased plasma level Increased plasma level Increased plasma level Other increased bleeding risk Dabigatran Apixaban Edoxaban Rivaroxaban no data no data Pharmacodynamic interactions antiplatelet drugs, NSAIDs Systemic steroid therapy Other anticoagulants Recent surgery on critical organ (brain, eye) Thrombocytopenia (e.g. chemotherapy) HAS-BLED 3 Orange reduce dose; yellow consider dose reduction if another yellow factor present; hatching no data available; recommendation made from pharmacokinetic considerations

16 Table 2: Primary Efficacy and Safety Endpoints in the Elderly ( 75 yr) 7-13 NNT = Number needed to treat (if a positive result). NNH = Number needed to harm (if a negative result). Dabi = dabigatran, Rivaro = rivaroxaban, Apix = apixaban, HD edox = higher dose edoxaban regimen, LD edox = lower dose edoxaban regimen. - See more at: RE-LY ROCKET-AF ARISTOTLE EDOXABAN Event rate (%/yr) Dabi 110mg Dabi 150mg Warfarin NNT/NNH Rivaro Warfarin NNT/NN H Dabi 110mg Dabi 150mg Apix Warfarin NNT/NN H HD edox LD edox Warfarin HD edox NNT/NNH LD edox Stroke/ SEE Major bleeding

17 Are there patients who should not receive NOACs? Mechanical prosthetic heart valves - dabigatran inferior to warfarin Severe liver dysfunction Severe renal dysfunction Major drug-drug interactions Active Malignancy HIT Antiphospholipid antibody syndrome Very Elderly (limited representation in clinical trials)

18 Practical Start-up Provide oral and written patient education Baseline CBC, renal and liver function Consider co-medications taken by patient. Consider co-medications such as PPI to reduce risk for gastro-intestinal bleeding. Consider carrying an information card or wearing a medical alert bracelet Educate patient on importance of strict adherence to regimen discontinuation is dangerous. Encourage pill box *dabigatran can not be removed from packaging until immediately prior to use Schedule follow up visit 4

19 Do Patients on NOACs Need Routine Follow Up? Compliance Bleeding Side effects Co-medications Upcoming Procedures Blood sampling Interval Every 6-12 months Every 6-12 months Every 6-12 months Each visit Each visit Yearly 6-monthly 3-monthly on indication Comments Inspect remaining medication Stress importance of compliance Inform about compliance aids Nuisance bleeding prevention possible? Bleeding with risk or impact on QoL prevention possible? Need to revise dose? Continuation? Temporary cessation with bridging? Change of anticoagulant drug? Prescription or over-the counter drugs? Even temporary use can be risky Consider need for bridging, treatment stop, calendar completion and plan dictated into note Haemoglobin, renal, liver function Renal function if CrCl ml/min or if on dabigatran and aged >75 years or fragile If CrCl ml/min If intercurring condition may impact renal or hepatic function.

20 Do Patients Taking NOACs Need Routine Coagulation Testing? PT and PTT monitoring not recommended Drugs can impact these parameters Assessment of drug exposure may be needed in emergency situations: serious bleeding and thrombotic events/ urgent surgery renal or hepatic insufficiency potential drug-drug interaction Nonspecific assays Test Specific Assay Dabigatran Rivaroxaban Apixaban Edoxaban Hemoclot Anti-Xa Anti-Xa Anti-Xa aptt PT

21 How do we manage drug interruptions and restarts? Drug Patient Procedure Drug half-life Renal function Bleeding risk Route of clearance Concomitant drugs (e.g., aspirin) Thrombosis risk

22 Interventions not necessarily requiring discontinuation of anticoagulant Dental interventions Extraction of 1 to 3 teeth Paradontal surgery Incision of abscess Implant positioning Ophthalmology Cataract or glaucoma intervention Endoscopy without surgery Superficial surgery (e.g. abscess incision, small dermatological excision) Perform procedures at trough levels of NOAC. Consider scheduling intervention h after last intake and then restart 6 h later (i.e. skipping 1 dose with BID N OAC)

23 Classification of surgical interventions according to bleeding risk LOW RISK Stop at least 24 hours prior to procedure HIGH RISK Stop at least 48 hours prior to procedure Endoscopy with biopsy Prostate or bladder biopsy Electrophysiological study or radiofrequency catheter ablation Angiography Pacemaker or ICD implantation (unless complex anatomical setting e.g. congenital heart disease) Spinal or epidural anaesthesia; lumbar diagnostic puncture Thoracic surgery Abdominal surgery Major orthopedic surgery Liver biopsy Transurethral prostate resection Kidney biopsy

24 Last Intake of Drug Before Elective Surgical Intervention Creatinine clearance (CrCl) Dabigatran Apixaban Rivaroxaban Low risk High risk Low risk High risk Low risk High risk CrCl 80 ml/min 24 h 48 h 24 h 48 h 24 h 48 h CrCl ml/min 36 h 72 h 24 h 48 h 24 h 48 h CrCl ml/min* 48 h 96 h 24 h 48 h 24 h 48 h CrCl ml/min* Not indicated Not indicated 36 h 48 h 36 h 48 h CrCl <15ml/min No official indication for use Low risk = surgery with low risk of bleeding, high risk = surgery with high risk of bleeding Heidbuchel et al, 2013

25 Resumption of NOAC of Procedures Procedure Procedures with immediate and complete haemostasis: Atraumatic spinal/ epidural anaesthesia Clean lumbar puncture Procedures associated with immobilization Action Resume 6 8 h after surgery Initiate reduced venous or intermediate dose of LMWH 6 8 h after surgery if haemostasis achieved Procedures with post-operative risk of bleeding Restart NOACs 48 72h after surgery upon complete haemostasis Heidbuchel et al, 2013

26 Switching Between anticoagulant Regimens VKA to NOAC Parenteral anticoagulant to NOAC: Intravenous unfractioned heparin (UFH) Low molecular weight heparin (LMWH) NOAC to VKA INR <2.0: immediate INR : immediate or next day INR >2.5: use INR and VKA half-life to estimate time to INR <2.5 Start once UFH discontinued (t½=2h). May be longer in patients with renal impairment Start when next dose would have been given Administer concomitantly until INR in appropriate range Measure INR just before next intake of NOAC Re-test 24h after last dose of NOAC Monitor INR in first month until stable values ( ) achieved NOAC to parenteral anticoagulant NOAC to NOAC Aspirin or clodiprogel to NOAC Initiate when next dose of NOAC is due Initiate when next dose is due except where higher plasma concentrations expected (e.g. renal impairment) Switch immediately, unless combination therapy needed

27 How to deal with dosing errors? Missed dose: BID: take missed dose up to 6 h after scheduled intake. If not possible skip dose and take next scheduled dose. QD: take missed dose up to 12 h after scheduled intake. If not possible skip dose and take next scheduled dose. Double dose: BID: skip next planned dose and restart BID after 24 h. QD: continue normal regimen. Uncertainty about intake: BID: continue normal regimen. QD: take another dose then continue normal regimen. Overdose: Hospitalization advised.

28 Specific Antidotes to NOACs Idarucizumab PER977 Andexanet alpha Structure Humanized Fab fragment Synthetic small molecule Human rxa variant Target Dabigatran Universal FXa inhibitors Binding Non-competit. High affinity? Competitive Clinical studies Rapid complete reversal? Rapid, near complete reversal Lauw M, et al. Can J Cardiol 2014 (accepted).

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