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
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
Resting HR and Beta-blocker Tx
RANOLAZINE: Late Na current Inhibitor
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
ERICA / CARISA Efficacy Summary
MERLIN: Components of Primary Endpoint
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
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
Ivabradine, contrary to b-blockers, maintains cardiac contractility
Effects of Ivabradine on HR
Expected clinical benefits from pure HR reduction Stable Angina / Ischemia CAD and LV dysfunction CHF
Ivabradine Vs beta-blockers
NOVEL ORAL ANTICOAGULANTS
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
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 (1.2-3.0 strokes per 100 patient years) 1-2 points moderate risk (2.8-4.0 strokes per 100 patient years) > 3 points high risk (5.9-18.2 strokes per 100 patient years)
Lip Y, et al. Chest 2010, 137(2):263
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
The problem with Warfarin??
Warfarin Effective Reversible Inexpensive Slow onset of action Regular monitoring Food interaction Medication interaction Difficult titration-regular dose adjustments
Dabigatran 150 mg Vs Warfarin
Rivaroxaban
ROCKET AF: Primary Efficacy Outcome
Apixaban
EDOXABAN
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 2.0 3.0) High-dose Edoxaban 60* mg QD Low-dose Edoxaban 30* mg QD *Dose reduced by 50% if: - CrCl 30 50 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; 160:635-41. 3
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
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 15-50 cc/min: 15 mg, Qday Avoid CrCl < 15 cc/min