EP Special Topics 2016 Anticoagulation Defibrillator Therapy CRT
NOACs, OACs, NVKD-ACs, DACs, DTIs
Disclosures No disclosures Will not discuss off-label uses Will refer to some drugs by both trade and generic names due to their novelty
Clearing Up the Confusion OAC: Oral Anticoagulant NOAC: Novel Oral AntiCoagulant NVKD-OAC: Non-Vitamin K-Dependent Oral Anticoagulant DAC: Direct Anticoagulant DTI: Direct Thrombin Inhibitor XaI: Factor Xa Inhibitor
Scope of the Problem 1 in 4 will develop atrial fibrillation AF causes 5x greater stroke risk Valvular AF 17x greater risk 15-20% of strokes due to AF AF strokes are particularly bad
Mechanisms of Action Warfarin
Limitations of Warfarin Limitation Clinical Implications Need for bridging with a rapidly acting Slow onset and o fg set of action anticoagulant Interindividual variability in Variability in dosing requirements anticoagulant e fg ect Narrow therapeutic index Need for routine coagulation monitoring Dietary precautions; need for routine coagulation Food and drug interactions monitoring Reduced synthesis of all Risk of skin necrosis in patients with protein C or S vitamin K–dependent proteins deficiency; potential for osteoporosis * Circulation: April 5, 2011 vol. 123 no. 13 1436-1450 Vitamin K antagonists appears to inhibit production of vitamin K– dependent proteins found in bone (osteocalcin synthesized by osteoblasts, matrix Gla protein found in bone, cartilage and soft tissue, and protein S synthesized by osteoblasts).
Food Vitamin K Content Vegetables Low Medium High Green beans Asparagus Broccoli Carrots Avocado Brussels sprouts Cauliflower Red Cabbage Cabbage Celery Green peas Collard greens Corn Endive (raw) Cucumber Kale (raw leaf) Egg plant Lettuce (iceberg) Lettuce (bibb, red leaf) Mushrooms Mustard greens (raw) Onions Parsley Green pepper Spinach Potato Turnip greens (raw) Pumpkin Watercress (raw) Sauerkraut (canned) Swiss chard Tomato
Food Vitamin K Content Fats & Oils Low Medium High Corn oil Margarine Mayonnaise Peanut oil Olive oil Canola oil Safflower oil Soybean oil Sesame oil Sunflower oil Beverages Low Medium High Coffee Cola Fruit juices Milk Tea, black Tea, green Water
Limitations of Warfarin 55% of warfarin-eligible patients receive it Elderly even less likely Other high-risk patients even less likely 28% discontinue warfarin by 1 year
Limitations of Warfarin High major-bleeding rates 20% in first year for CHADS-VASc ≥ 4 50-60% in target range (INR 2.0 to 3.0) In trials and registries - general population? Worse in elderly!
Limitations of Warfarin Limitation Clinical Implications Need for bridging with a rapidly acting Slow onset and o fg set of action anticoagulant Interindividual variability in Variability in dosing requirements anticoagulant e fg ect Narrow therapeutic index Need for routine coagulation monitoring Dietary precautions; need for routine coagulation Food and drug interactions monitoring Reduced synthesis of all Risk of skin necrosis in patients with protein C or S vitamin K–dependent proteins deficiency; potential for osteoporosis * Circulation: April 5, 2011 vol. 123 no. 13 1436-1450 Vitamin K antagonists appears to inhibit production of vitamin K– dependent proteins found in bone (osteocalcin synthesized by osteoblasts, matrix Gla protein found in bone, cartilage and soft tissue, and protein S synthesized by osteoblasts).
Warfarin Limitations Room for Improvement!
Mechanisms of Action Warfarin
Mechanisms of Action Novel Anticoagulants
Ximelagatran First NOAC Showed reduced risk of stroke No increased bleeding risk Abandoned due to liver toxicity
Dabigatran (Pradaxa) Administered as Dabigatran Etexilate Zero pharmacologic effect Converted to Dabigatran within 1 hr T 1/2 = 12 - 17 hours Thrombin Inhibitor (Factor II) 10% bioavailability 80% renal clearance
Dabigatran RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulant Therapy Trial) 18,113 patients, open label AF + 1 risk factor (CHADS2 ≥ 1) Non-inferiority trial Compared Dabigatran to warfarin INR goal 2.0-3.0 achieved 64% of the time 2 Dabigatran doses (110 mg BID & 150 mg BID)
Dabigatran RE-LY Trial Results Dabigatran 110 mg BID Non-inferior to warfarin in stroke reduction 20% reduction in major bleeding (p=0.003) Increased risk of GI bleeding (11.3 vs 5.8% p<0.001)
Dabigatran RE-LY Trial Results Dabigatran 150 mg BID 34% reduction in stroke and embolization No overall increase in major bleeding Increased risk of GI bleeding (11.8 vs 5.8% p<0.001)
Dabigatran Dosing Recommendations Recommended Dose is 150 mg BID CrCl 15-30: 75 mg BID CrCl < 15: Not recommended Dialysis: Not recommended Different doses/adjustments for DVT/PE prophylaxis
Rivaroxaban (Xarelto) Small molecule active drug Direct Factor Xa Inhibitor T 1/2 = 9-12 hours Peak plasma concentration 2.5-4 hrs (elderly 11-13 hrs) 50% bioavailability 66% urine excretion (36% unchanged)
Rivaroxaban ROCKET-AF Trial Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation 14,264 patients Double Blinded, randomized Rivaroxaban 20 mg Warfarin (INR 2.0 - 3.0 - achieved 58% of the time) CHADS2 Score ≥ 2.0 Half of patients had prior stroke - high-risk patient group
Rivaroxaban ROCKET-AF Results 12% relative reduction in stroke or embolization NOT statistically significant Non-inferior to warfarin Statistically significant reduction intracranial hemorrhage and bleeding death
Apixaban (Eliquis) Small molecule active drug Direct Factor Xa Inhibitor (like Rivaroxaban) Peak plasma concentrations at 2 hrs T 1/2 ≈ 12 hours 50% bioavailability 25% urine excretion Strong CyP-450 3A4 Inhibitors increase levels
Apixaban AVERROES Trial Apixaban Versus Acetylsalicylic Acid to Prevent Strokes Trial 5599 patients Apixaban 5 mg vs. ASA 81-325 mg Unsuitable for warfarin Stopped early due to clear Apixaban superiority Bleeding rates similar to ASA Apxiaban better tolerated than ASA (less discontinuations)
Apixaban ARISTOTLE Trial Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation Trial 18,201 patients Apixaban 5 mg Warfarin (INR 2.0 - 3.0 - achieved 58% of the time) AF + at least one risk factor (CHADS2 ≥ 1) Lower risk patients than ROCKET-AF
Apixaban ARISTOTLE Trial Results 21% relative reduction in stroke or embolization 31% relative reduction in overall bleeding 11% relative reduction in mortality Better tolerated than warfarin
Edoxaban (Savaysa) Small molecule active drug Direct Factor Xa Inhibitor (like Rivaroxaban/Apixaban) Peak plasma concentration at 1 - 1.5 hrs T 1/2 ≈ 8-10 hours 40% urine excretion 50% Bioavailability Strong CyP-450 3A4 Inhibitors increase levels
Edoxaban ENGAGE-AF - TIMI 48 Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation >20,000 patients Double Blind CHADS2 ≥ 2 (high risk) Warfarin (INR 2.0 - 3.0 - achieved 68.4% of the time) Bioprosthetic valves and repaired valves included
Edoxaban ENGAGE-AF Trial Results Edoxaban 30 mg daily 53% relative reduction in major bleeding 15% relative reduction in mortality 7% relative increase in stroke or embolization
Edoxaban ENGAGE-AF Trial Results Edoxaban 60 mg daily 20% relative reduction in major bleeding 14% relative reduction in mortality 21% relative reduction in stroke or embolization
Comparison of Anticoagulants Warfarin Dabigatran Rivaroxaban Apixaban Edoxaban Administration Once a day Twice a day Once a day Twice a day Once a day Vit K–dependent Thrombin Target Factor Xa Factor Xa Factor Xa factors (Factor II) Time to Peak 3–5 d 1 h 2.5–4 h 3 h 1–2 h E fg ect 5 mg BID 150 mg BID 20 mg QD 60 mg QD Dose Variable 2.5 mg 110 mg BID 15 mg (renal) 30 mg QD (CRI+risk) Half-Life 40 h 12–14 h 7–11 h 12 h 9–11 h CYP 3A4 Inhibitors CYP 3A4 Inhibitors CYP 3A4 Inhibitors Interactions Many P-Gp Transporter P-Gp Transporter P-Gp Transporter P-Gp Transporter Renal Clearance 0 80 35 25 40 Anticoagulant Required Not required Not required Not required Not required Monitoring Antidote Vitamin K Praxabind None None None Contraindicated Notes for CrCl > 95
NOAC Clinical Trials Stroke or Systemic Embolism /yr Hemorrhagic Stroke /yr Major Bleeding /yr Novel Novel Novel Warfarin HR p Warfarin HR p Warfarin HR p Agent Agent Agent Dabigatran 110 RE-LY 1.53 1.69 0.91 0.34 0.12 0.38 0.31 <0.001 2.71 3.36 0.80 0.003 mg twice a day Dabigatran 150 1.11 1.69 0.66 <0.001 0.10 0.3 0.26 <0.001 3.11 3.36 0.93 0.31 mg twice a day Rivaroxaban 20 ROCKET-AF 2.12 2.42 0.88 0.12 0.26 0.44 0.59 3.60 3.45 1.04 0.58 0.02 mg every day Apixaban 5 mg ARISTOTLE 1.27 1.60 0.79 0.01 0.24 0.4 0.51 <0.001 2.13 3.09 0.69 <0.001 twice a day Edoxaban 30 mg ENGAGE-AF 1.61 1.50 1.07 0.005 0.16 0.47 0.33 <0.001 1.61 3.43 0.47 <0.001 daily Edoxaban 60 mg 1.18 1.50 0.79 <0.001 0.26 0.47 0.38 <0.001 2.75 3.43 0.8 <0.001 daily
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