DIRECT ORAL ANTICOAGULANTS

Transcription

1 2017 Cardiovascular Symposium DIRECT ORAL ANTICOAGULANTS ERNESTO UMAÑA, MD, FACC

2 ORAL ANTICOAGULANTS Vitamin K Antagonists (VKAs): Warfarin Non Vitamin K Antagonists Direct oral anticoagulants Novel Oral anticoagulants (NOACs) Factor Xa Inhibitors Rivaroxaban Apixaban Edoxoban Direct thrombin inhibitor Dabigatran

3 ANTICOAGULANTS MECHANISM OF ACTION

4 Stroke Prevention in Atrial Fibrillation -Efficacy of Warfarin -Meta-Analysis of Antithrombotic Therapy in A Fib Adjusted-dose warfarin compared with placebo or control Study Year AFASAK I 1989; 1990 SPAF I 1991 BAATAF 1990 CAFA 1991 SPINAF 1992 EAFT 1993 Relative Risk Reduction (95% CI) All trials (n=6) N=2,900 Ann Intern Med 2007; 146: % 50% 0-50% -100% Favors Warfarin Favors Placebo or Control

5 ADVANTAGES OF NOACS OVER VKAS FOR THROMBOEMBOLIC PREVENTION IN PATIENTS WITH NON-VALVULAR AF WARFARIN High maintenance Vitamin k Narrow therapeutic index Many drug interactions Delayed pharmacodynamics onset NOACs Predictable effect without need for monitoring Fewer food and drug interactions More predictable halflife/elimination Improved efficacy/safety ratio

6 DEFINITION OF NON-VALVULAR ATRIAL FIBRILLATION AND ELIGIBILITY FOR NON-VITAMIN K ANTAGONIST ORAL ANTICOAGULANTS

7 NOACS APPROVED FOR PREVENTION OF SYSTEMIC EMBOLISM OR STROKE IN PATIENTS WITH NON-VALVULAR AF Dabigatran Apixaban Rivaroxaban Edoxoban Action Direct thrombin inhibitor Activated factor Xa inhibitor Activated factor Xa inhibitor Activated factor Xa inhibitor Dose 150mg BID 75mg BID 110mg BID (EU) 5mg BID 2.5mgBID 20mg QD 15mg QD 60mg QD 30mg QD 15mg QD Phase III clinical trial RE-LY ARISTOTLE AVERROES ROCKET-AF ENGAGE-AF

8 METABOLISM OF NOACS Heidbuchel H, Verhamme P, Alings M, et al. European Heart Rhythm Association practical guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation. Europace 2013; 15:

9 Oral bioavailability (%) RE-LY Dabigatran ROCKET AF Rivaroxaban ARISTOTLE Apixaban Half life (h) Renal elimination (%) ENGAGE-AF Edoxoban Liver metabolism Time to maximal inhibition (h) Study treatment No Yes Yes Minimal Dabigatran 110 mg BID Dabigatran 150mg BID Rivaroxoban 20mg daily (15mg daily with egfr ml/min) Apixaban 5mg BID (2.5 mg in age > 80, weight < 60, creat > 1.5) Edoxoban 30mg daily Edoxoban 60mg daily

10 STROKE OR SYSTEMIC EMBOLIC EVENTS Ruff CT et al. Lancet 2014; 383:

11 MAJOR BLEEDING Ruff CT et al. Lancet 2014; 383:

12 SAFETY OUTCOMES - BLEEDING

13 EFFECT ON NOAC PLASMA LEVELS (AUC) FROM DRUG DRUG INTERACTIONS AND CLINICAL FACTORS, AND RECOMMENDATIONS TOWARDS NOAC DOSE ADAPTATION

14 EFFECT ON NOAC PLASMA LEVELS (AUC) FROM DRUG DRUG INTERACTIONS AND CLINICAL FACTORS, AND RECOMMENDATIONS TOWARDS NOAC DOSE ADAPTATION

15 EFFECT ON NOAC PLASMA LEVELS (AUC) FROM DRUG DRUG INTERACTIONS AND CLINICAL FACTORS, AND RECOMMENDATIONS TOWARDS NOAC DOSE ADAPTATION

16 EFFECT ON NOAC PLASMA LEVELS (AUC) FROM DRUG DRUG INTERACTIONS AND CLINICAL FACTORS, AND RECOMMENDATIONS TOWARDS NOAC DOSE ADAPTATION

17 CHRONIC RENAL DISEASE Creatinine clearance of 60 ml/min may even be an independent predictor of stroke and systemic embolism. Oral anticoagulation may convey a greater relative benefit in patients with mild to moderate CKD compared with normal renal function. Data is less clear in patients with severe renal impaiment and on those with end-stage kidney disease and dialysis - both stroke and bleeding risks are elevated. Some date have suggested that VKAs may be harmful, although others have concluded that VKA therapy has positive net clinical benefit. Prospective data are not available in end-stage CKD patients, either with VKA, or with NOAC. Registry data have shown a higher risk of hospitalization or death from bleeding in dialysis patients started on NOAC compared with VKA. The net clinical effect of oral anticoagulation requires careful assessment in patients with severe impairment of kidney function

18 CHRONIC RENAL DISEASE

19 NOAC RENAL DOSING (AF) DABIGATRAN 150MG BID 75MG BID IF CrCl CONTRAINDICATED IF CrCl<15 (In Europe CrCl < 30) EDOXABAN CONTRAINDICATED IF CrCl>95 60MG DAILY IF CrCl MG DAILY IF CrCl CONTRAINDICATED IF CrCl<15 APIXABAN 5MG BID 2.5MG BID IF 2 OF THE FOLLOWING PRESENT: WT < 60 KG AGE > 80 YEARS SCR > 1.5 MG/DL RIVAROXABAN 20MG DAILY 15MG DAILY IF CrCl CONTRAINDICATED IF CrCl< 15

20 OTHER FACTORS RELATED TO DOSING

21 BLEEDING

22 MAJOR BLEEDING Ruff CT et al. Lancet 2014; 383:

23 FACTORS ASSOCIATED TO INCREASED BLEEDING RISK

24 MAJOR BLEEDING REQUIRING HOSPITALIZATION (PER 100 PERSON YEAR) AND ADJUSTED HAZARD RATIOS FOR ANTICOAGULANT INITIATION

25 MAJOR BLEEDING REQUIRING HOSPITALIZATION (PER 100 PERSON YEAR) AND ADJUSTED HAZARD RATIOS FOR ANTICOAGULANT INITIATION

26 ANTIDOTES

27 BLEEDING WHILE USING A NOAC

28 CONVERTING FROM OTHER ANTICOAGULANTS TO NOAC Vitamin K to NOAC Rivaroxaban: start when INR is < than 3 Edoxoban: start when INR is < 2.5 Apixaban: start when INR is < 2 Dabigatran: start when INR is < 2 Parental anticoagulation to NOAC Heparin: start NOAC when heparin is stopped Low molecular weight heparin: when next dose of LMWH was indicated

29 CONVERTING FROM NOAC TO WARFARIN Owing to the slow onset of action of VKAs, it may take 5 10 days before an INR in therapeutic range is obtained, with large individual variations. Therefore, the NOAC and VKA should be administered concomitantly until the INR is in a range that is considered appropriate

30 ATRIAL FIBRILLATION AND CORONARY ARTERY DISEASE

31 The WOEST Trial= What is the Optimal antiplatelet and anticoagulant therapy in patients with oral anticoagulation and coronary StenTing Cumulative incidence of bleeding 50 % 40 % 30 % 20 % 44.9% Triple therapy group Double therapy group 19.5% 10 % 0 % p<0.001 HR= %CI[ ] n at risk: Days Primary Endpoint: Total number of TIMI bleeding events

32 % WOEST PRIMARY ENDPOINT: BLEEDING EVENTS TIMI CLASSIFICATION p< TIMI Minimal 11.2 p< p= p< TIMI Minor TIMI Major Any TIMI bleeding Double therapy group Triple therapy group

33 Long-term treatment of patients on NOAC therapy after revascularization or ACS. Hein Heidbuchel et al. Europace 2015;17:

34 PIONEER AF-PCI Trial design: Patients with AF and PCI randomized to: Group 1: Rivaroxaban 15 mg daily plus P2Y12 inhibitor for 12 months (n = 709). Group 2: Rivaroxaban 2.5 mg twice daily plus DAPT for 1-12 months (n = 709). Group 3: warfarin plus DAPT for 1-12 months (n = 706). % (p < for group 1 or 2 vs. group 3) Results Clinically significant bleeding: 16.8% in group 1 vs. 18.0% in group 2 vs. 26.7% in group 3 (HR 0.59, p < for group 1 vs. 3); (HR 0.63, p < for group 2 vs. 3) Stent thrombosis: 0.8% in group 1 vs. 0.9% in group 2 vs. 0.7% in group 3 (HR 1.20, p = 0.79 for group 1 vs. 3; HR 1.44, p = 0.57 for group 2 vs. 3) Rivaroxaban 15 mg daily, P2Y12 for 12m Rivaroxaban 2.5 mg daily, DAPT for 1-12 months Warfarin, DAPT for 1-12 months Conclusions Among patients with nonvalvular AF who underwent PCI, a rivaroxaban-based strategy was associated with a lower frequency of clinically significant bleeding compared with a warfarin/dapt strategy Stent thrombosis appeared to be similar between the three groups Gibson CM, et al. N Engl J Med 2016;375:

35 RE-DUAL PCI Dabigatran ; ongoing AUGUSTUS - Apixaban ; ongoing EVOLVE-AF-PCI Edoxaban; to start

36 Flowchart for the initiation or re-initiation of anticoagulation after TIA/stroke or intracerebral haemorrhage. Hein Heidbuchel et al. Europace 2015;17:

37 SURGICAL PROCEDURES AND TIME TO HOLD ANTICOAGULATION Doherty et al. JACC 2017 Periprocedural Anticoagulation Pathway

38 HELPFUL TOOL ACC AnticoagEvaluator Iphones Android base smartphones Web Version Calculate a patient's stroke risk (CHA2DS2-Vasc), bleed risk (HAS-BLED and concomitant meds), and renal function (Cockroft-Gault Equation) Improve accurate use of DOACs with adjusted dosage based on prescribing information, fine-tuned for renal and other patient characteristics Determine appropriate therapy for a patient by reviewing Synthesized individualized risk for antithrombotic therapy options based on clinical trials (e.g., ACTIVE-A, RE-LY, ROCKET-AF, ARISTOTLE, ENGAGE- AF) Relevant safety information and full prescribing information for all therapy options

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