Anticoagulation Beyond Coumadin

Transcription

1 Anticoagulation Beyond Coumadin Saturday, September 21, 2013 Crystal Mountain Resort and Spa Pratik Bhattacharya MD, MPH Stroke Neurologist, Michigan Stroke Network; Assistant Professor of Neurology; Wayne State University

2 Disclosures I have no relevant disclosures. I receive research support from: Ethel and James Flinn foundation Genentech.

3 Non Valvular Atrial Fibrillation Four to five fold increased risk for ischemic stroke. Risk of Atrial fibrillation increases with age. 30% of strokes in patients over the age of 80. Meta-analysis: Vitamin K antagonists reduce stroke risk compared to aspirin by 39% CHADS2 score. Hart et al Ann Intern Med 2007.

4 Targets for Anticoagulation

5 The problems with Coumadin Narrow therapeutic range Hard to maintain TTR (Time in Therapeutic Range) Frequent monitoring of blood Variable response Dietary adjustments Medication interactions.

6 Comparative Pharmacokinetics Parameter Dabigatran Rivoroxaban Apixaban Target Factor IIa (thrombin) Factor Xa Factor Xa Tmax 2h h 3 h Half life 12-17h 9-13h 8-11h Elimination Renal dosing 80%renal; 20% bile; no liver metabolism CrCl>30:150 mg bid CrCl15-29: 75 mg bid 2/3 renal; 1/3 liver 25% renal, 55% fecal; 15% liver CrCl>50:20 mg/d CrCl15-50:15 mg/d Dosing Bid Daily bid Assay for detection Drug interactions aptt; Thrombin time; Ecarin clotting time P-glycoprotein inhibitors PT; Anti Xa assay calibrated for rivoroxaban CYP3A4P/P glycoprotein inhibitors 5mg bid; 2.5 mg bid if 2 or more of: Cr>1.5; age>80; weight <60Kg PT; Anti Xa assay calibrated for Apixaban CYP3A4P/P glycoprotein inhibitors

7 Potential Drug interactions P-glycoprotein inhibitors Amiodarone Ceftriaxone Macrolides Cyclosporine Diltiazem Dipyridamole Hydrocortisone Ketoconazole Nicardipine/ nifedipine Propranolol Quinine, Quinidine Ritonavir, saquinavir, nelfinavir Tamoxifen Tacrolimus Verapamil P glycoprotein inducers Rifampin Clotrimazole Phenytoin Phenobarbital St. John s Wort

8 Recent Clinical Trials Randomized Evaluation of Long-Term Anticoagulation Therapy (RELY) trial. (Dabigatran) Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) Apixaban for Reduction of Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial

9 RE-LY (Dabigatran) Randomized, open label trial. 2 doses of Dabigatran (110 and 150) vs. dose adjusted Warfarin. 1:1:1 NVAF and at least one risk factor for stroke patients; median follow up of 2 years. About 20% of each arm was also taking aspirin Time in Therapeutic Range for Warfarin was 64% Primary outcome (non-inferiority): stroke or systemic embolism. Primary safety outcome: major bleeding Connoly et al N Engl J Med 2009

10 RE-LY: Outcomes OUTCOME Warfarin Dabigatran 110 vs warfarin P value Dabigatran 150 vs warfarin P value Stroke or embolism 1.7% 1.5% 0.91( ) <0.001 */ % 0.66( ) <0.001*/ <0.001 Hemorrhagic stroke 0.38% 0.12% 0.31( ) < % 0.26 ( ) <0.001 Ischemic stroke 1.2% 1.34% 1.11( ) % 0.76( ) 0.03 Vascular death 2.69% 2.43% 0.90( ) % 0.85( ) 0.04 Major bleed 3.36% 2.71% % 0.31 GI bleeding 1.02% 1.12% % <0.001 Minor bleeding 16.37% 13.16% < % Net benefit# 0.92 ( ) ( ) 0.04 *P for noninferiority # composite of benefit and harm. Slightly higher risk of MI with dabigatran; Increased dyspepsia due to acidic preparation

11 Explanation of Dabigatran Effects Dyspepsia and Increased GI bleeding: tartaric acid core of dabigatran pellets in the capsule. Decreased ICH/ major bleeding: only inhibits thrombin; sparing other hemostatic mechanisms. Dabigatran does not cross the Blood brain barrier Stable pharmacokinetics: twice a day dosing.

12 RE-LY stroke subset 3623 patients had prior stroke/ TIA: Warfarin: 1195; Dabigatran 110: 1195; Dabigatran 150: 1233 Similar results to the overall study group. OUTCOME Warfarin Dabigatran 110 mg Dabigatran 150 mg Stroke or embolism 2.78% 2.32% 0.84( ) 2.07% 0.75( ) Hemorrhagic stroke 0.77% 0.08% 0.11( ) 0.20% 0.27( ) Ischemic stroke 1.75% 2.19% 1.26( ) 1.75% 1.00( ) Vascular Death 3.0% 1.90% 0.63( ) 2.97% 0.98 ( ) Major bleeding 4.15% 2.74% 0.66( ) 4.15% 1.01 ( ) Life threatening bleed 2.57% 1.47% 0.57( ) 2.03% 0.79 ( ) GI bleeding 1.41% 1.39% 0.99( ) 2.32% 1.67( ) Net clinical benefit 8.73% 7.12% 0.81( ) 8.70% 1.01( ) Pulmonary embolism rates were not reported in this subgroup analysis. Diener et al. Lancet Neurol 2010

13 ROCKET AF (Rivoroxaban) Multicenter, randomized, double blind, double dummy at 1178 sites in 45 countries Included NVAF with CHADS2 of 2 or more (moderate to high stroke risk) 14,264 patients; median follow up 707 days Mean CHADS2 score was 3.5. Rivoroxaban 20 mg daily. (15 mg if CrCl low) Primary outcome: Stroke (ischemic and hemorrhagic) and systemic embolism. Safety outcome: Major bleeding or minor but clinically significant bleeding Patel et al N Engl J Med 2011

14 ROCKET AF outcomes OUTCOME Warfarin Rivoroxaban P value Primary outcome Intention to treat 2.4% 2.4% 0.88( ) <0.001/0.12 During treatment 2.2% 1.7% 0.79( ) 0.02 Ischemic stroke 1.4% 1.3% 0.94 ( ) 0.58 Hemorrhagic stroke 0.4% 0.26% 0.59( ) 0.02 Myocardial infarction 1.12% 0.91% 0.81( ) 0.12 Vascular death 1.71% 1.53% 0.89( ) 0.29 Safety outcome 14.5% 14.9% 0.44 Major bleeding 3.4% 3.6% 0.58 GI bleeding 2.2% 3.2% <0.001 Patel et al N Engl J Med 2011

15 ARISTOTLE (Apixaban) Randomized, double-blind, double dummy, noninferiority trial comparing apixaban and warfarin. Patients with NVAF and at least one stroke risk factor patients in 1034 sites in 39 countries. Mean CHADS2 score was 2.1 Median follow up duration 1.8 years. Primary outcome: stroke or systemic embolism Safety outcome: major bleeding Granger et al N Engl J Med 2011

16 ARISTOTLE: Outcomes OUTCOME Warfarin Apixaban P value Primary outcome 1.6% 1.3% 0.79( ) 0.01 Ischemic stroke 1.05% 0.97% 0.92 ( ) 0.42 Hemorrhagic stroke 0.47% 0.24% 0.51( ) <0.001 Myocardial infarction 0.61% 0.53% 0.88( ) 0.37 Stroke/embolism/MI or death from any cause 5.49% 4.85% 0.88 ( ) 0.01 Major bleeding 3.09% 2.13% 0.69( ) <0.001 GI bleeding 0.86% 0.76% 0.89( ) 0.37 Any bleeding 25.8% 18.1% 0.71( ) <0.001 Net clinical outcome 7.2% 6.13% 0.85( ) <0.001 Granger et al N Engl J Med 2011

17 Comparison of Study Designs RE-LY (dabigatran) ROCKET AF (Rivoroxaban) ARISTOTLE (Apixaban) Dose 110/150 mg bid 20 mg/d (or 15) 5 mg bid (or 2.5) Inclusions Afib and risk factor for embolization Afib and CHADS2 of 2 or more Afib and CHADS2 of 1 or more Exclusions CrCl<30 CrCl<30 Creatinine >2.5 CrCl<25 Outcomes Primary Composite of systemic embolism and stroke (I + H) Composite of systemic embolism and stroke (I + H) Mortality All cause All cause All cause Major Bleeding ISTH ISTH ISTH Randomization 1:1:1 1:1 1:1 Blinding NO Yes (sham INRs and double dummy) Composite of systemic embolism and stroke (I + H) Yes (sham INRs and double dummy)

18 Stroke or systemic embolism Comparison of Outcomes with Newer Anticoagulants (numbers represent the Hazard ratios) Dabigatran vs Warfarin 110mg bid 150mg bid Rivoroxaban vs Warfarin Apixaban vs Warfarin * * Major bleeding 0.80* * Intracranial hemorrhage 0.30* 0.41* 0.67* 0.42* All-cause mortality * Ischemic stroke * 0.92 Hemorrhagic stroke 0.31* 0.26* 0.59* 0.51* Myocardial infarction GI bleeding * 0.89

19 IV TPA EXPERIENCE IN PATIENTS ON DABIGATRAN Thrombin time and Ecarin clotting time are most predictive. Elevated aptt may be indicative. Doses 12 hours apart. Some believe: if closer to 12 hours since the last dose and normal aptt, may be okay to give tpa. However guideline says 48 hours. 5 case reports: dabigatran history was not available (also personal experience) 1 had asymptomatic hemorrhage. 1 case report: Patient enrolled in the RELY-ABLE trial developed a stroke. tpa given 7 hours after the last dose. ptt case report: tpa given 6 hours after dabigatran dose; ptt 37. Fatal ICH. De smedt et al Cerebrovasc Dis 2010; Matute et al Thromb Hemostat 2011; Naranjo et al Cerebrovascular dis 2011; Lee et al J Stroke Cerebrovasc Dis 2012.

20 What if a person who needs anticoagulation; develops bleeding on a newer anticoagulant? Aspirin + plavix Coumadin (dose adjusted to INR) Lower dose of the newer anticoagulant.

21 Dabigatran toxicity aptt and TT easiest to assess whether or not the patient is anticoagulated. No specific antidote Due to its short duration of effect drug discontinuation is usually sufficient to reverse any excessive anticoagulant activity. In case of potential overdose, early administration of activated charcoal and subsequent charcoal filtration. Dabigatran can also be dialyzed in patients with renal impairment. In instances of life-threatening bleeding, where conventional measures have non-specific prohaemostatic agents such as recombinant activated factor VII and prothrombin complex concentrates can be considered. Van Ryn et al Thrombosis and Hemostasis 2010

22 Knowing Who To Call May Save Precious Time and Precious Life Questions? Pratik Bhattacharya