Anticoagulation in the 21 st Century Adam Karpman, D.O. Saint Francis Medical Center/Oklahoma State University Medical Center Disclosures: None Atrial Fibrillation Most common arrhythmia in clinical practice. Accounts for more hospitalizations than all other arrhythmia diagnoses combined. 1
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Risk Stratify Our Patients Stroke Risk in AF: CHADS2 Scoring system JAMA 2001; 285: 2864-71 3
Stroke Risk in patients with non-valvular AF not treated with anticoagulation according to CHA2DS2-VASc score CHA2DS2-VASc Score Patients (n-7329) Adjusted stroke rate (%/Y) 0 1 0 1 422 1.3 2 1230 2.2 3 1730 3.2 4 1718 4.0 5 1159 6.7 6 679 9.8 7 294 9.6 8 82 6.7 9 14 15.2 4
What about the risk of bleeding? Risk of Hemorrhage on Warfarin Stratification Score Risk factor Points Severe renal Dx 3 Anemia 3 Age > 75 2 Prior hemorrhage 1 Event Rates/100 patient yrs Score Event rates 0 to 3 (low) 0.76 4 (intermediate) 2.62 5 to 10 (high) 5.76 Hypertension 1 http://sparctool.com/ 5
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Warfarin Multiple interactions with foods and drugs Requires regular laboratory-guided adjustments of the dose Lowest risk of stroke and bleeding is achieved by maximizing the time in the optimum therapeutic range (TTR), with an INR of 2.0 3.0 There are large variations in TTR between individuals, sites, and countries, which affects patient outcomes Rates of bleeding and discontinuation are high New Agents for Atrial Fibrillation Oral direct inhibitors TF/VIIa Xa inhibitors IIa inhibitors Rivaroxaban Apixaban Edoxaban Betrixaban Darexaban Letaxaban Dabigatran AZD 0837 X Fibrinogen IX IXa VIIIa Va Xa II IIa Fibrin Adapted from: Weitz JI. J Thromb Haemost. 2005;3:1843. 7
Study Overview In a large, randomized trial, two doses of the direct thrombin inhibitor dabigatran were compared with warfarin in patients who had atrial fibrillation and were at risk for stroke At 2 years, the 110-mg dose of dabigatran was found to be noninferior, and the 150-mg dose superior, to warfarin with respect to the primary outcome of stroke or systemic embolism Cumulative Hazard Rates for the Primary Outcome of Stroke or Systemic Embolism, According to Treatment Group Connolly SJ et al. N Engl J Med 2009;361:1139-1151 8
Conclusion In patients with atrial fibrillation, dabigatran given at a dose of 110 mg was associated with rates of stroke and systemic embolism that were similar to those associated with warfarin, as well as lower rates of major hemorrhage Dabigatran administered at a dose of 150 mg, as compared with warfarin, was associated with lower rates of stroke and systemic embolism but similar rates of major hemorrhage Study Overview In this trial, 14,264 patients with atrial fibrillation were randomly assigned to receive either rivaroxaban or warfarin. In a per-protocol, as-treated analysis, rivaroxaban was noninferior to warfarin with respect to the primary end point of stroke or systemic embolism. 9
Cumulative Rates of the Primary End Point (Stroke or Systemic Embolism) in the Per-Protocol Population and in the Intention-to-Treat Population. Patel MR et al. N Engl J Med 2011;365:883-891 Conclusions In patients with atrial fibrillation, rivaroxaban was noninferior to warfarin for the prevention of stroke or systemic embolism. There was no significant between-group difference in the risk of major bleeding, although intracranial and fatal bleeding occurred less frequently in the rivaroxaban group. 10
Study Overview The oral direct factor Xa inhibitor, apixaban, was compared with warfarin in atrial fibrillation. Apixaban was superior to warfarin in preventing stroke or systemic embolism, caused less bleeding, and lowered mortality. Kaplan Meier Curves for the Primary Efficacy and Safety Outcomes. Granger CB et al. N Engl J Med 2011;365:981-992 Conclusions In patients with atrial fibrillation, apixaban was superior to warfarin in preventing stroke or systemic embolism, caused less bleeding, and resulted in lower mortality. 11
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AVERROES: Apixaban vs Aspirin in 5,599 Pts with Nonvalvular AF and 1 Additional Risk Factor for Stroke Unsuitable for Warfarin by Physician or Pt Preference Apixaban dose was 5 mg bid (94% of pts), or 2.5 mg bid in pts with 2 of the following criteria: age 80 years, weight 60 kg, or s. creatinine 1.5 mg/dl Stroke or systemic embolism Major bleeding 0.05 0.04 HR (95%CI) = 0.45 (0.32-0.62) P 0.001 Aspirin Apixaban 0.020 HR (95%CI) = 1.13 (0.74-1.75) 0.015 P=0.57 0.03 0.010 Aspirin 0.02 0.01 Apixaban 0.005 0.00 0 3 6 9 12 18 Months 0.000 0 3 6 9 12 18 Months Connelly SJ et al. N Engl J Med 2011;364:806-17. New Oral Anticoagulants Phase III AF Trials RE-LY ROCKET-AF ARISTOTLE ENGAGE AF- TIMI 48 Drug Dabigatran Rivaroxaban Apixaban Edoxaban Dose (mg) 150, 110 20 (15*) 5 (2.5*) 60, 30 Frequency BID QD BID QD N 18,113 14,266 18,206 >21,000 Design Open-label Double-blind Double-blind Double-blind AF criteria AF x 1 < 6 mos AF x 2 (>1 in <30d) AF or AFl x 2 <12 mos AF x 1 < 12 mos VKA naive 50% 38% 43% 40% goal *In pts with drug clearance; dabi dose concealed, but no sham INR monitoring New Oral Anticoagulants Phase III AF Trials Re-LY (dabigatran) ROCKET-AF (rivaroxaban) ARISTOTLE (apixaban) Age, yrs 71.5 mean 73 median 70 median Female 37% 40% 35% Hypertension 79% 91% 87% Diabetes 23% 40% 25% Prior MI 17% 17% 14% Heart failure 32% 62% 35% Prior stroke/tia 20% 55% 20% CHADS 2 mean - 0-1 - 2-3 2.2 32% 35% 33% 3.5-13% 87% 2.1 34% 36% 30% TTR, median 66% 58% 66% 13
Rates = per yr FU New Oral Anticoagulants: Phase III AF Trials Primary Endpoint - Stroke or Systemic Emboli Powered for non-inferiority P<0.001 for all NI comparisons RE-LY ROCKET AF ARISTOTLE 0.91 (0.74 1.11), P=0.34 0.66 (0.53 0.82), P<0.001 0.88 (0.75 1.03), P=0.12 0.79 (0.66 0.95), P=0.01 % % % Connolly SJ, et al. NEJM 2009;361:1139-51; Patel MR et al, NEJM 2011; Granger CB et al. NEJM 2011 New Oral Anticoagulants: Phase III AF Trials Major Bleeding Rates = per yr FU RE-LY ROCKET AF ARISTOTLE 0.80 (0.69 0.93), P=0.003 0.93 (0.81 1.07), P=0.31 1.04 (0.90 1.20), P=0.58 0.69 (0.60 0.80), P<0.001 % % % Connolly SJ, et al. NEJM 2009;361:1139-51; Patel MR et al, NEJM 2011; Granger CB et al. NEJM 2011 New Oral Anticoagulants: Phase III AF Trials Intracranial Hemorrhage Rates = per yr FU RE-LY ROCKET AF ARISTOTLE 0.31 (0.20 0.47), P<0.001 0.40 (0.27 0.60), P<0.001 0.67 (0.47 0.93), P=0.02 0.42 (0.30 0.58), P<0.001 % % % Connolly SJ, et al. NEJM 2009;361:1139-51; Patel MR et al, NEJM 2011; Granger CB et al. NEJM 2011 14
New Oral Anticoagulants: Phase III AF Trials All-cause Death Rates = per yr FU RE-LY ROCKET AF ARISTOTLE 0.91 (0.80 1.03), P=0.13 0.88 (0.77 1.00), P=0.051 0.92 (0.82 1.03), P=0.15 0.89 (0.80 0.998), P=0.047 % % % Connolly SJ, et al. NEJM 2009;361:1139-51; Patel MR et al, NEJM 2011; Granger CB et al. NEJM 2011 Rates = per yr FU New Oral Anticoagulants: Phase III AF Trials Myocardial Infarction RE-LY ROCKET AF ARISTOTLE 1.35 (0.98 1.87), P=0.07 1.38 (1.00 1.91, P=0.048 0.81 (0.63 1.06), P=0.12 0.88 (0.66 1.17), P=0.37 % % % Connolly SJ, et al. NEJM 2009;361:1139-51; Patel MR et al, NEJM 2011; Granger CB et al. NEJM 2011 What about DVT/PE? 15
Pradaxa Pradaxa Cumulative Risk of Recurrent Venous Thromboembolism or Related Death during 6 Months of Treatment among Patients Randomly Assigned to Dabigatran or Warfarin Schulman S et al. N Engl J Med 2009;361:2342-2352 16
Cumulative Risks of a First Event of Major Bleeding and of Any Bleeding among Patients Randomly Assigned to Dabigatran or Warfarin Schulman S et al. N Engl J Med 2009;361:2342-2352 Conclusion For the treatment of acute venous thromboembolism, a fixed dose of dabigatran is as effective as warfarin, has a safety profile that is similar to that of warfarin, and does not require laboratory monitoring Xarelto 17
Study Overview In the treatment of patients with acute pulmonary embolism, the efficacy of rivaroxaban, a factor Xa inhibitor, was similar to that of traditional anticoagulation therapy. There was less bleeding in the group receiving rivaroxaban, which supports its use in the treatment of this condition. Cumulative Rates of the Primary Efficacy and Safety Outcomes and Rates of Major Bleeding. The EINSTEIN PE Investigators. N Engl J Med 2012;366:1287-1297 Xarelto 18
Eliquis Kaplan Meier Cumulative Event Rates. Agnelli G et al. N Engl J Med 2013;368:699-708 Eliquis 19
Discussion adam.m.karpman@gmail.com 20