When and How to Use the Newly Approved Oral Anticoagulants to Treat Acute Deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE) Ian del Conde, MD

Transcription

1 When and How to Use the Newly Approved Oral Anticoagulants to Treat Acute Deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE) Ian del Conde, MD December 12, 2015 Disclosures CONSULTANT Merck; New Haven Pharmaceuticals ADVISORY BOARD Merck, IC Sciences SPEAKER S BUREAU Johnson & Johnson, BMS, Pfizer 1

2 NOAC New Oral Anticoagulant Novel Oral Anticoagulant Non-Vitamin K Oral Anticoagulant Phase-III Trials of NOACs in VTE Dabigatran(Pradaxa): Rivaroxaban(Xarelto): Apixaban(Eliquis): Edoxaban(Savaysa): RECOVER EINSTEIN AMPLIFY HOKUSAI 2

3 NOAC Road Map: DVT/PE Mechanism of action Kidney and liver metabolism Warfarin Vs. NOAC Pharmacology Treatment of acute DVT/PE Extended Duration with NOACs Differentiating among NOACs 3

4 New Oral Anticoagulants (NOACs) Factor Xa Rivaroxaban(Xarelto ) Apixaban(Eliquis ) Edoxaban(Savaysa ) Thrombin Dabigatran(Pradaxa ) NOACS Differ in Kidney and Liver Metabolism 20% 65% 80% 35% 73% 65% 27% 50% Europace 2013; 15:

5 Warfarin Vs. NOAC Pharmacology Feature Warfarin NOACs Onset Slow Rapid Dosing Variable Fixed Food interactions Yes No Drug Interactions Many Few INR Monitoring Yes No Half-Life Long Short Reversal Agents Sortof Yes and more coming Comparison of the Designs of the Phase III Acute VTE Trials Drug RE-COVER EINSTEIN AMPLIFY HOKUSAI Dabigatran (Pradaxa) Rivaroxaban (Xarelto) Apixaban (Eliquis) Edoxaban (Savaysa) n Design 2 X blind Prosp; open 2 X blind 2 X blind Hypothesis noninf noninf noninf noninf Indication VTE DVT or PE VTE VTE Heparin bridge Duration (months) Yes No No Yes 6 3, 6, , 6, 12 5

6 Comparison of the Designs of the Phase III Acute VTE Trials Drug RE-COVER EINSTEIN AMPLIFY HOKUSAI Dabigatran (Pradaxa) Rivaroxaban (Xarelto) Apixaban (Eliquis) Edoxaban (Savaysa) n Design 2 X blind Prosp; open 2 X blind 2 X blind Hypothesis noninf noninf noninf noninf Indication VTE DVT or PE VTE VTE Heparin bridge Duration (months) Yes No No Yes 6 3, 6, , 6, 12 EINSTEIN-PE Symptomatic Recurrent VTE (Efficacy) Rivaroxaban Clinically significant bleeding Rivaroxaban Major bleeding (2ary endpoint) HR 0.29, p<0.003) Rivaroxaba 6

7 Pooled Analysis: RE-COVER (Pradaxa) Trials (n=5,107) Parameter HR (95% CI) Recurrent VTE 1.09 ( ) Major Bleeding 0.73 ( ) Any Bleeding 0.70 ( ) Circulation 2014; 129: AMPLIFY: Eliquis10 mg BID x 7d; then 5 mg BID 2/3 reduction p<0.001 Agnelli G. NEJM 2013;369:

8 HOKUSAI (Savaysa) Efficacy (n=8,240) Edoxaban(%) N=4118 Warfarin(%) N=4122 Hazard Ratio (95% CI) Recurrent VTE Overall ( ) DVT Patients ( ) PE Patients ( ) Severe PE (n=938) ( ) NEJM 2013; 369: LESS Intracranial Hemorrhage 57% risk reduction Blood. 2014;124(15):2450 8

9 LESS Major Bleeding 28% risk reduction Blood. 2014;124(15):2450 LESS Total Bleeding 24% risk reduction Blood. 2014;124(15):2450 9

10 Acute VTE Treatment All 4 NOACs are noninferior to LMWH/warfarin for efficacy. Meta-analysis (n=24,455): 40% lower major and 64% lower fatal bleeding than LMWH/warfarin. (van der Hulle, T. JTH. 2014; 12: ) Edoxaban: pre-specified submassive PE subgroup showed superiority. NOACS in Extended Treatment To Prevent Recurrent VTE 10

11 RIETE: Recurrent VTE Martinez C. Thromb Haemost 2014;112;2:255 Rivaroxaban(Xarelto) for Extended Therapy EINSTEIN Study Xarelto 20 mg QD Placebo NEJM 2010; 363:

12 EINSTEIN: Extended Treatment Placebo Xarelto20 mg QD Xarelto Rivaroxaban Major or clinical significant bleeding Xarelto: 6% Placebo: 1.2% AMPLIFY-EXTENSION Eliquis 2.5 mg BID Eliquis 5 mg BID Placebo 12

13 Apixaban is Very Effective in Reducing Recurrent VTE Symptomatic Recurrent VTE, or VTE-related Death Placebo = 8.8% Eliquis2.5 mg = 1.7% Eliquis5 mg = 1.7% Eliquis apixaban Apixaban(Eliquis) Extended Treatment AMPLIFY Extension Apixaban 2.5 mgbid Apixaban 5 mgbid Placebo Eliquis2.5 mg BID is as effective as 5 Recurrent VTE 3.8% 4.2% 11.6% mg BID in preventing recurrent VTE, Major bleeding 3.2% 4.3% 2.7% but it is almost as safe as placebo. NEJM 2013; 368:699 13

14 What have we learned? 1) Compared to LMWH/warfarin, NOACS are: Easier to use; monitoring not necessary Comparable in efficacy Safer Less risk of ICH, major, and fatal bleeding 2) It is possible to eliminate initial heparin therapy in some cases Initial heparin/lmwh NOT NEEDED: Xarelto, Eliquis. Initial heparin/lmwh NEEDED: Pradaxa, edoxaban Differentiating NOACs OBJECTIVE Minimize inflammation (with heparin loading) Maximize Convenience (once daily dosing) Avoid injectible heparin initially Minimize Bleeding Submassive PE (superior to warfarin) NOAC Pradaxa/Savaysa Xarelto/Savaysa Xarelto/ Eliquis Eliquis Savaysa 14

15 Practical Approach to the Use of New Oral Anticoagulants Reversal of NOACS 15

16 How long to delay surgery or procedures after last NOAC dose Half Life Low-risk Surg. High-risk Surg. Pradaxa hrs 1 day 2 days Xarelto 5-13 hrs 1 day 2 days Eliquis 8-15 hrs 1 day 2 days Delay an additional 1-2 days if: -Age > 75 yrs -CrCl< 30 or AKI - Very high-risk procedure 16

17 Summary The new oral anticoagulants are equally effective, but safer than LMWH/coumadin for VTE. No head-to-head comparisons among the NOACs; nor are any expected. For VTE treatment, NOACs offer improved convenience, and improved safety with reductions in major/fatal bleeding. Thank You Ian Del Conde, MD, FACC Vascular Medicine and Cardiology 17