Novel Anticoagulation Agents DISCLOSURES James W. Haynes, MD Department of Family Medicine Univ of TN Health Science Center (Chattanooga) Objectives Understand mechanism of action behind the NOAC agents Understand FDA approved indications/dosing for each agent Understand the risks of using these agents DOSING ATRIAL FIBRILLATION TRIALS PEAK LEVELS 1
RE-LY Trial Compared dabigatran to warfarin in 18,113 patients with AF at risk for stroke (PROBE - Prospective, randomized, outcome blinded trial) The mean CHADS 2 2.1, and median follow-up duration was 2 years Randomly assigned to 1 of 2 blinded doses of dabigatran, 110 or 150 mg twice daily, or open-label, dose-adjusted warfarin to study primary outcome of stroke or systemic embolization. Event rates of 1.71% per year in the warfarin group; 1.54% per year in the dabigatran 110 mg twice daily group( P <.001 for noninferiority to warfarin); and 1.11% per year with dabigatran, 150 mg twice daily ( P <.001 for superiority to warfarin). Significantly lower rates of intracerebral hemorrhage were noted with both doses of dabigatran when compared with warfarin. RE-LY Trial The higher dose of dabigatran yielded a higher rate of GI Bleed but a similar rate of major bleeding as compared with warfarin All-cause mortality was lower with dabigatran (4.13% per year for warfarin; 3.75% per year for dabigatran, 110 mg twice daily; and 3.64% per year for dabigatran, 150 mg twice daily) but did not reach statistical significance ( P =.13 and P =.051 for the 110 and 150 mg twice daily doses, respectively) Following RE-LY, dabigatran, 150 mg twice daily, was approved to reduce the risk of stroke and systemic embolism in patients with NVAF worldwide Although patients with severe renal impairment (CrCl <30 ml/min) were excluded from RE-LY, the FDA approved a dose of 75 mg twice daily for patients with CrCl 15 to 30 ml/min, based on pharmacokinetic modeling ROCKET-AF Randomized, double-blind, double-dummy study carried out over a median follow-up of 1.9 years comparing rivaroxaban with warfarin in 14,264 patients with NVAF who were at increased risk for stroke The study included patients with high stroke risk with a mean CHADS2 score of 3.5, with 55% of patients having a prior stroke or transient ischemic attack (TIA) Study arm patients received fixed-dose rivaroxaban, 20 mg once daily ( for those with CrCl 30 49 ml/min) Rivaroxaban was superior to warfarin (hazard ratio [HR], 0.88; P =.015) in preventing stroke or systemic embolism Rivaroxaban reduced the frequency of hemorrhagic strokes compared with warfarin by 41% (HR, 0.59) ARISTOTLE 18,201 patients with NVAF and at least 1 additional risk factor for stroke (mean CHADS2, 2.1) were evaluated in a randomized, double-blind study comparing apixaban (5 mg twice daily [2.5 mg twice daily in highrisk patients]) with warfarin; median follow up was 1.8 yrs The lower dose was used for those with 2 or more of the following factors associated with increased drug exposure: age greater than 80 years, body weight less than 60 kg, or serum creatinine level greater than 1.5 mg/dl. About 19% of these patients had a previous TIA, stroke, or systemic embolism Apixaban was superior to warfarin in preventing stroke or systemic embolism (HR with apixaban, 0.79; 95% confidence interval [CI], 0.66 0.95; P <.001 for noninferiority; P =.01 for superiority) Apixaban also caused less bleeding and resulted in lower mortality (HR, 0.89; 95% CI, 0.80 0.99; P =.047) and reduced hemorrhagic stroke by 49% compared with warfarin ( P = <.001) Aristotle Relies on Rockets DOSING PEAK LEVELS 2
Vasa 2014, 43: 353-364 3
Acute DVT/PE All 3 agents were NON-INFERIOR to Warfarin Lower rates major bleeding Rivaroxaban, Apixaban fewer bleeding events Dabigatran non-inferior bleeding event rate VTE Recurrence Dabigatran NON-INFERIOR to Warfarin Lower bleeding risk All 3 superior to placebo prevention VTE recurrence Apixaban did not have significantly higher rates of long-term major bleeding (Dab + Riv did) DOSING PEAK LEVELS PEAK LEVELS (CrCl 15-30 ml/min) (CrCl 15-50 ml/min) (Age >80; Wt < 60 kg; scr >1.5) 4
inhibitor Stroke Prev Nonvalv -Recurrent VTE Prev (CrCl 15-30 ml/min) (CrCl 15-50 ml/min) (Age >80; Wt < 60 kg; scr >1.5) PEAK LEVELS 2 h 2-4 h 3 h (CrCl 15-30 ml/min) (CrCl 15-50 ml/min) (Age >80; Wt < 60 kg; scr >1.5) PEAK LEVELS 2 h 2-4 h 3 h 10 mg daily Use of Assays Dabigatran Thrombin Clotting Time (TCT) most sensitive assay to determine presence aptt if normal then Dabigatran not contributing significantly to bleeding Rivaroxaban PT if normal suggests level is not high; does not exclude presence No effect on TCT Apixiban Normal PT or aptt DOES NOT rule out significant anticoag effect NOTE: RECORDING LAST DOSE TIME IMPORTANT FOR INTERPRETATION Hip/Knee Surg* (CrCl 15-30 ml/min) (CrCl 15-50 ml/min) (Age >80; Wt < 60 kg; scr >1.5) PEAK LEVELS 2 h 2-4 h 3 h INCR: aptt, TCT 10 mg daily INCR Anti-factor Xa INCR or =: PT, aptt NO CHANGE: TCT INCR Anti-factor Xa INCR or =: PT, aptt NO CHANGE: TCT SWITCHING AGENTS SWITCHING TO(FROM) A NOAC Transition FROM Warfarin to NOAC Transition TO Warfarin from NOAC Dabigatran - Monitor INR closely - Start NOAC when INR < 2 - Parenteral Anticoag not necessary - Start Warfarin 1-3 days prior to d/c - Consider parenteral bridging if high risk Apixiban / Rivaroxaban - DO NOT overlap agents - STOP Agent START Warfarin when next dose due - Consider parenteral bridging if high risk 5
SWITCHING TO(FROM) A NOAC Transition FROM UFH/LMWH to NOAC - Start NOAC 2 hrs after UFH discontinued - Start NOAC at next sched LMWH dose Transition TO UFH/LMWH from NOAC - Start UFH/LMWH when next dose NOAC due Risk of major bleeding in different indications for new oral anticoagulants: Insights from a meta-analysis of approved dosages from 50 randomized trials International Journal of Cardiology, 2015-01-20, Volume 179, Pages 279-287 6
COST ~ 7K pt on warfarin or NOAC studied over 33 month period Out of pocket for patient - 5x higher Insurer costs - 15 x higher; ~ $900 / month Warfarin - most $4 lists ; NOACs $250-350/mo Advantages Convenience for patients No lab monitoring Lower rates of MAJOR bleeds No bridging therapy Potentially less HIT (decr use bridging therapy) Less drug / diet interactions Disadvantages No antidote / reversal agents Measuring Compliance / Drug concentration Dabigatran - aptt normal; little to none present Rivaroxaban - PT normal; little to no presence Higher GI bleeding rate Higher cost Contraindicated mechanical heart valves / severe renal impairment Other Issues Dabigatran - Dyspepsia (33%) P-gp transport system CYP3A4 enzyme system 7
Drug interactions Ideal Candidate < 65 NL Renal Function Uncontrolled INR w/ compliance Non-compliance monitoring NOT!!!!!! Mechanical Valves Dabigatran - incr risk bleeding and stroke vs. Warfarin Renal dysfunction - check at baseline (especially dabigatran) 8
QUESTIONS? Hip/Knee Surg* (CrCl 15-30 ml/min) (CrCl 15-50 ml/min) (Age >80; Wt < 60 kg; scr >1.5) PEAK LEVELS 2 h 2-4 h 3 h INCR: aptt, TCT 10 mg daily INCR Anti-factor Xa INCR or =: PT, aptt NO CHANGE: TCT INCR Anti-factor Xa INCR or =: PT, aptt NO CHANGE: TCT REFERENCES 1. Ferns SJ, Naccarelli GV. New Oral Anticoagulants Their role in stroke prevention in high-risk patients with Atrial Fibrillation. Med Clin N Am 2015, 99: 759-780 BACKGROUND 2. Vandiver JW, et al. Is a novel anticoagulant right for your patient? J Fam Prac, Jan 2014, 63(1): 22-28 3. Hirschl M, Kundi M. New oral anticoagulants in the treatment of acute venous thromboembolism a systematic review with indirect comparisons. VASA 2014, 43: 353-364 4. Shivanshu M, et al. Use of novel oral anticoagulation agents in atrial fibrillation: current evidence and future perspectives. Cardiovasc Diagn Ther 2014, 4(4): 314-323.,, -VTE Prev Hip/Knee Surg - VTE Proph after Hip/Knee Surg CrCl 15-30 ml/min CrCl 15-50 ml/min Age > 80; Wt < 60 Kg; scr > 1.5 BIOAVAILABILITY 3-7% 80-100% 50% PEAK PLASMA LEVELS 2 h 2-4 h 3 h HALF-LIFE 12-17 h 5-9 h 8-15 h RENAL ELIMINATION > 80% 66% 25-27% MONITORING None None None INCR: aptt, TCT INCR or =: PT INCR Anti-factor Xa INCR or =: PT, aptt NO CHANGE: INCR Anti-factor Xa INCR or =: PT, aptt NO CHANGE: TCT 9
RESULTS 10
-VTE Prev Hip/Knee Surg - VTE Proph after Hip/Knee Surg PEAK PLASMA LEVELS (CrCl 15-30 ml/min) (CrCl 15-50 ml/min) (Age >80; Wt < 60 kg; scr >1.5) 2 h 2-4 h 3 h HALF-LIFE 12 17 h 5 9 h 8-15 h Acute Bleeding Mild to Mod Stop Medication & Supportive Measures Acute Ingestion or Overdose Activated Charcoal if ingestion within 3 hours Severe Bleeding Hemodialysis for Dabigatran Most effective intervention 75-80 units/kg Activated Prothrombin Complex Concentrate (apcc) 11
Perioperative Use Primarily based on expert opinion 12