DOACs. What s in a name? or TSOACs. Blood Clot. Darra Cover, Pharm D. Clot Formation DOACs work here. Direct Oral AntiCoagulant

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1 DOACs NOACs or TSOACs Generic Name DOACs Brand Name Mechanism of Action Direct Xa Inhibitor Direct Thrombin Inhibitor Dabigatran Pradaxa X Rivaroxaban Xarelto X Darra Cover, Pharm D Apixaban Eliquis X Edoxaban Savaysa X Objectives Explain how the different DOAC s work to anticoagulate Explore DOAC differences by looking at their pharmacokinetics, indications, pharmacodynamics Give an overview of DOAC reversal strategies Apply all of the information to choosing DOACs for different patient characteristics. Platelet Clot Formation Fibrin DOACs work here Blood Clot What s in a name? Direct Oral AntiCoagulant Fibrin Formation: Chemistry at Work New Oral AntiCoagulant Novel Oral AntiCoagulant Target Specific Oral AntiCoagulant 1

2 Xa Inhibitors Efficacy of DOACs Rivaroxaban (Xarelto ) Apixaban (Eliquis ) Edoxaban (Savaysa ) When compared to gold standard for the FDA indications listed. All have similar or greater efficacy to the comparator in their respective clinical trials Effective Dabigatran: Thrombin Inhibitor Safety of DOACs When compared to gold standard for the FDA indications listed. All have decreased risk of major bleeding as compared to their comparator in their respective clinical trials All carry the same warning for increased risk of thrombotic events if discontinued without another anticoagulant on board Safe Indications: Warfarin and DOACs Uses Reduction in risk of stroke and systemic embolism in nonvalvular AF Warfarin Coumadin Edoxaban Savaysa Apixaban Eliquis Rivaroxaban Xarelto Dabigatran Pradaxa X X X X X Treatment of DVT and PE X X X X X Reduction in the risk of DVT/PE recurrence X X X X Prevention of DVT in hip or knee replacement surgery X X X Anticoagulation for valvular related AF Anticoagulation for prosthetic heart valves X X Cost Comparison.. One month of atrial fibrillation therapy = $376 Pradaxa $399 Xarelto $400 Eliquis $330 Edoxaban Expensive 2

3 Atrial Fibrillation: Dose Comparison Dabigatran and Edoxaban frequency advantage Dabigatran - Pradaxa Drug Interactions P-glycoprotein inducers Food Effects None Take without regard to meals Full glass of water Administration Original Container; Tightly closed Avoid Moisture 4 month expiration after opening VTE Treatment: Dose Comparison Active Compound Dabigatran and Edoxaban 5 10 days of parenteral anticoagulant Edoxaban QD treatment Apixaban only 7 day oral ramp up vs 21 day for rivaroxaban Tablet Can be crushed G-Tube = Ok J-Tube = NOT Ok Peak Effect: hours T ½: 5 9 hours (healthy); hours (elderly) Elimination: 66% renal (1/3 unchanged) 28% fecal Prodrug Dabigatran - Pradaxa Capsule Cannot be crushed or opened up Peak Effect: hours T ½: hours Elimination: 85% renal 6% fecal 9% hepatic CYP 450 not involved w/ hepatic metabolism CrCl (ml/min) anti Xa activity % % < % Afib CrCl ml/min give 15 mg daily VTE tx No renal dose adjustment. Do not use if CrCl less than 30 ml/min 3

4 Hepatic elimination CYP-450 3A4 Parameter (% relative to normal) Mild Moderate Exposure AUC 15% 127% Cmax 0 27% Xa inhibition AUC 8% 159% Effect max 0 24% PT increase AUC 6% 114% Effect max 2% 41% Avoid use in patients w/ moderate or severe hepatic impairment Active Compound Tablet Can be crushed G-Tube = Ok J-Tube =?? Peak Effect: 3 4 hours T ½: Actual T ½ is 6 hours; apparent half life is 9 14 hour Elimination: 27% renal; 50% fecal Hepatic Metabolism CYP3A4/5 Drug Interactions Renal dysfunction P-glycoprotein inducers/inhibitors and strong CYP3A4 inducers/inhibitors Avoid P-glycoprotein inhibitor and moderate CYP3A4 inhibitors if CrCl < 80 ml/min *diltiazem, verapamil, dronedarone Food Effects and administration Body Weight Fasting Fed Cmax (mcg/l) Tmax (H) AUC mcg h/l

5 Dose Adjust for atrial fibrillation if patient has 2 of the following 3 characteristics: Renal dysfunction SCr > = 1.5 or HD Actual body weight < = 60 Kg Age > = 80 Years Old No renal dose adjustment for VTE treatment indications. **Can use in HD** Active Compound Tablet No information on crushing or administering via GT or JT Peak Effect: 1 2 hours T ½: Actual T ½ is hours Elimination: 50% renal; 50% bile Food Effects None Hepatic impairment: No dosage adjustments in patients with mild or moderate hepatic impairment Severe hepatic impairment was an exclusion criteria from trials Food Effects None Take without regard to meals Full glass of water Event Rate (% per year) Renal Function, CrCl (ml/min) Edoxaban 60 mg* Warfarin 50 or less Greater than 50 to less than ** 1.2 Greater than 80 to less than Greater than *** All patients with CrCl of 95 ml/min or less**** * Some patients received a dose reduction to 30 mg ** Significant difference in favor of edoxaban *** Significant difference in favor of warfarin **** Indicated population Drug Interactions Strong P-glycoprotein inhibitors and strong CYP3A4 inhibitors: ketoconazole AUC 200%, clarithromycin Decrease dosage 50% if on a 10 mg or 5 mg BID regimen Avoid using if patient a 2.5 mg BID candidate Avoid using Strong inducers of PGP and CYP3A4: Rifampin Renal impairment dose for Afib and VTE therapy Do not use CrCl < 15 ml/min CrCl ml/min decrease dose by 50% to 30 mg Effect of low body weight Decrease dose by 50% for VTE therapy if less than 60 kg 5

6 Hepatic impairment: No dosage adjustments in patients with mild hepatic impairment Moderate to Severe hepatic impairment not recommended 65 year old diabetic male with new onset atrial fibrillation. Current medications: metformin, lisinopril, tramadol, ASA, metoprolol SCr 3.2 CrCl 33mL/min hepatic function normal for age. Drug Interactions PGP substrate Doses for VTE were reduced if edoxaban was used with a moderate to strong PGP inhibitor: verapamil, azithromycin, ketoconazole, clarithromycin. 65 year old female with crones disease. Partial colectomy. No dose change for Afib dosing Anticoagulants 27 year old male who broke his leg 3 weeks ago while skiing. His leg has increased swelling with redness and tenderness. Found to have DVT. No current medications Renal and hepatic function normal for age. Life Savers Mechanical Heart Valves Genetic Blood Clotting Disorders Atrial Fibrillation Vein Thrombosis Pulmonary Embolism Big Risk Severe Nose Bleeds GI Bleeds Subdural Hematomas Hemorrhagic Strokes 6

7 When Trouble Arises. Reversal Strategies: Activated Charcoal Dialysis Reversal with Clotting Factors Target Specific Reversal Agents Feiba (Activated Prothrombin Complex Concentrate) Contains activated factor VII and inactivated factors II,VII,IX,X When Trouble Arises. Reversal with Clotting Factors FFP Kcentra Feiba Target Specific Reversal Idarucizumab specific for dabigatran Mechanism Monoclonal antibody fragment Binds directly to dabigatran with an affinity that is 350 times higher than that of thrombin Binds both free and thrombin-bound dabigatran Kcentra (Prothrombin Complex Concentrate) Contains inactivated factors II,VII,IX,X Idarucizumab for Dabigatran Reversal Patients enrolled 90% prescribed dabigatran for stroke prevention in atrial fibrillation Group A 51 patients 18 patients intracranial bleed 20 patients GI bleed 9 patients Bleed due to trauma 11 patients Other Group B 49 patients Variety of indications for surgery Most common (9 patients) Bone fracture Pollack et.al. NEJM June

8 Idarucizumab for Dabigatran Reversal Endpoints Primary Maximum percentage reversal of the anticoagulant effect of dabigatran at any time from the start of the first infusion to 4 hours after the second infusion Assessed by dilute thrombin time or ecarin clotting time at a central laboratory Questions? Secondary Proportion of patients who had complete normalization of dilute thrombin time or ecarin clotting time in the first 4 hours Reduction in the concentration of unbound dabigatran Results Idarucizumab for Dabigatran Reversal Median maximum percentage reversal in both groups was 100% (95% CI 100 to 100) Dilute thrombin time was normalized in 98% of patients in group A and 93% in group B Ecarin clotting time was normalized in 89% of patients in group A and 88% in group B Idarucizumab lowered dabigatran concentrations from 132 ng/ml in group A and 114 ng/ml in group B to les than 20 ng/ml Child-Pugh Grading of Chronic Liver Disease Score Bilirubin (mg/dl) >3 Albumin > <2.8 Ascites None Mild Moderate Encephalopathy None Prothrombin time (seconds longer than control) Mild hepatic impairment = < 6 points; Moderate hepatic impairment = 6-10 points; Severe hepatic impairment = > 10 points >6 Results Idarucizumab for Dabigatran Reversal In the patients that cessation of bleeding could be determined, 11.4 hours was the median cessation 18 deaths overall (9 in each group) Death within 96 hours after treatment appeared to be due to the primary event Later deaths appear to be due to coexisting conditions Thrombotic events occurred in five patients ranging from 2 to 26 days after treatment None of these patients were anticoagulated at time of event References Apixaban. DrugPoints Summary. Micromedex 2.0. Truven Health Analytics, Inc. Greenwood Village, CO. Available at: Accessed September 2, Apixaban. Drug Facts and Comparisons. Facts & Comparisons eanswers. Wolters Kluwer Health, Inc. Philadelphia, PA. Available at: September 2, Edoxaban. DrugPoints Summary. Micromedex 2.0. Truven Health Analytics, Inc. Greenwood Village, CO. Available at: September 2, Edoxaban. Drug Facts and Comparisons. Facts & Comparisons eanswers. Wolters Kluwer Health, Inc. Philadelphia, PA. Available at: September 2, Savaysa. [package insert]. Tokyo, Japan: Daiichi-Sankyo;

9 References Rivaroxaban. DrugPoints Summary. Micromedex 2.0. Truven Health Analytics, Inc. Greenwood Village, CO. Available at: Accessed September 2, Rivaroxaban. Drug Facts and Comparisons. Facts & Comparisons eanswers. Wolters Kluwer Health, Inc. Philadelphia, PA. Available at: September 2, Dabigatran. DrugPoints Summary. Micromedex 2.0. Truven Health Analytics, Inc. Greenwood Village, CO. Available at: September 2, Dabigatran. Drug Facts and Comparisons. Facts & Comparisons eanswers. Wolters Kluwer Health, Inc. Philadelphia, PA. Available at: September 2,