Newer Anti-Anginal Agents and Anticoagulants

Transcription

1 Newer Anti-Anginal Agents and Anticoagulants Satish Gadi, MD FACC FSCAI Interventional Cardiologist, Cardiovascular Institute of the South (CIS) Baton Rouge Clinical Assistant Professor, Tulane University School of Medicine

2 Burden of Chronic Angina in the U.S. 9.1 million American adults have chronic angina 1 500, 000 new cases diagnosed per year Approx. 50% of pts presenting with MI at the hospital have preceding angina 2

3

4

5

6

7

8

9

10 Resting HR and Beta-blocker Tx

11

12 RANOLAZINE: Late Na current Inhibitor

13 RANOLAZINE: Key Clinical Trials CARISA N = 823 Ranolazine Vs Placebo + Standard therapy for Chronic Angina ERICA N = 565 Ranolazine Vs Placebo + Amlodipine for Chronic Angina MERLIN TIMI-36 N = 6560 Non-STE ACS pts Ranolazine Vs Placebo + Standard Care

14 ERICA / CARISA Efficacy Summary

15 MERLIN: Components of Primary Endpoint

16 IVABRADINE Prototype of a new class of drugs, the I f Inhibitors A new concept for a drug providing anatomical (sinus node cell) and functional (I f channel) selectivity

17 The I f Current f = funny Described in 1979 by Brown, Di Francesco, and Noble Present only in the sinus node and retina Important for pacemaker depolarization a.k.a. heart rate Mixed ion channel, conducts Na + and K + Controlled by sympathetic and parasympathetic systems

18

19 Ivabradine, contrary to b-blockers, maintains cardiac contractility

20 Effects of Ivabradine on HR

21 Expected clinical benefits from pure HR reduction Stable Angina / Ischemia CAD and LV dysfunction CHF

22 Ivabradine Vs beta-blockers

23

24

25 NOVEL ORAL ANTICOAGULANTS

26 Why New Anticoagulants? LIMITATION Slow onset and offset of action Genetic variation in metabolism Multiple food and drug interactions Narrow therapeutic window CONSEQUENCE Overlap with parenteral agent; prolonged time to procedures Variable dose requirements; increased monitoring Frequent coagulation monitoring Frequent coagulation monitoring; increased propensity for adverse events

27

28

29 How do we determine stroke risk? CHADS2 (Gage, et al.: JAMA 2001) Congestive heart failure - 1pt Hypertension - 1pt Age > 75-1 pt Diabetes - 1pt Stroke or TIA - 2 pts 0 points low risk ( strokes per 100 patient years) 1-2 points moderate risk ( strokes per 100 patient years) > 3 points high risk ( strokes per 100 patient years)

30 Lip Y, et al. Chest 2010, 137(2):263

31 CHADS 2 vs. CHA 2 DS 2 VASc CHADS 2 score 0: 1.4% events CHA 2 DS 2 -VASc 0: 0 events CHA 2 DS 2 -VASc score 1: 0.6% events CHA 2 DS 2 -VASc score 2: 1.6% events Recommended approach: anticoagulation when Isch stroke risk > 0.9%/year

32 The problem with Warfarin??

33

34

35 Warfarin Effective Reversible Inexpensive Slow onset of action Regular monitoring Food interaction Medication interaction Difficult titration-regular dose adjustments

36

37

38

39 Dabigatran 150 mg Vs Warfarin

40

41 Rivaroxaban

42

43 ROCKET AF: Primary Efficacy Outcome

44

45 Apixaban

46

47

48

49 EDOXABAN

50 Study Design 21,105 PATIENTS AF on electrical recording within last 12 m CHADS 2 2 RANDOMIZATION 1:1:1 randomization is stratified by CHADS 2 score 2 3 versus 4 6 and need for edoxaban dose reduction* Double-blind, Double-dummy Warfarin (INR ) High-dose Edoxaban 60* mg QD Low-dose Edoxaban 30* mg QD *Dose reduced by 50% if: - CrCl ml/min - weight 60 kg - strong P-gp inhibitor 1º Efficacy EP = Stroke or SEE 2º Efficacy EP = Stroke or SEE or CV mortality 1º Safety EP= Major Bleeding (ISTH criteria) Non-inferiority Upper 97.5% CI <1.38 CI = confidence interval; CrCl = creatinine clearance; ISTH=International Society on Thrombosis and Haemostasis; P-gp = P-glycoprotein; SEE=systemic embolic event Ruff CR et al. Am Heart J 2010; 160:

51 Compared to well-managed warfarin (TTR 68.4%) once-daily edoxaban: Non-inferior for stroke/see (both regimens) - High dose stroke/see on Rx (trend ITT) Both regimens significantly reduced: - Major bleeding (20%/53%) - ICH (53%/70%) - Hem. stroke (46%/67%) - CV death (14%/15%) Superior net clinical outcomes No excess in stroke or bleeding during transition oral anticoagulant at end of trial 51

52 Dosing Schedules Atrial Fibrillation Agent Dabigatran 75mg, 150mg Apixaban 2.5mg, 5mg Rivaroxaban 10mg, 15mg, 20mg Dosing Recommendations CrCl > 30 cc/min: 150 mg, BID CrCl 15 to 30 cc/min: 75 mg, BID Avoid < 15 cc/min CrCl > 15 cc/min: 5 mg, BID Any 2 ( > 80 yrs, < 60 kg, SCr > 1.5mg/dL: 2.5 mg, BID) Avoid < 15 cc/min CrCl > 50 cc/min: 20 mg, Qday CrCl cc/min: 15 mg, Qday Avoid CrCl < 15 cc/min