Time in the Therapeutic Range Conflict Disclosure Information. 'As The Clot Thickens' A NOAC (Novel Anticoagulant Update)

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1 Conflict Disclosure Information Kevin J. Pistawka NOAC S New Oral Anti-Coagulants Dr. K. Pistawka - KGH FINANCIAL DISCLOSURE Grants/Research Support: None Research Trial involvment RELY, RELYABLE Speakers Bureau/Honoraria: Most Consulting Fees: None Investments: None Other: None? What is AF What do I need before I prescribe? Who shouldn t get a NOAC?? What is valvular AF What are major advantages? Which drug? Which dose? How do I switch over? Patient needs OR? How to manage Antedote / Bleeding mgmt. What about concommitant ASA Hazard functions of death and events of the vessels of the brain INR=international normalized ratio Hart RG, et al. J Thromb Thrombolysis 2008;25:26-32 Time in the Therapeutic Range 1

2 RE-LY Rivaroxaban (xarelto) Apixiban (eliquis) Dabigatran (pradax) Cumulative incidence Stroke or Systemic Embolism (n=18 113) HR = 0.90 (95% CI ) p = 0.29 (superiority) p < (non-inferiority) Follow-up (months) (TTR = 64%) Warfarin Dabigatran 110 mg Dabigatran 150 mg HR = 0.65 (95% CI ) p < (superiority) Connolly SJ, et al. N Engl J Med. 2009; 361: Connolly SJ, et al. N Engl J Med 2010; 363(19): Cumulative event rate (%) ROCKET AF Primary Efficacy Endpoint Stroke or Systemic Embolism HR 0.79 (0.66, 0.96) p<0.001 (non-inferiority) Warfarin Rivaroxaban Days since randomization Number of subjects at risk Rivaroxaban Warfarin Per-protocol population as treated population 2.2%/yr. 1.7%/yr P (non-inferiority)<0.001 Apixaban 212 patients, 1.27% per year Warfarin 265 patients, 1.60% per year HR 0.79 (95% CI, ); P (superiority)=0.011 No. at Risk Apixaban Warfarin % RRR Patel et al. N Engl J Med Sep 8;365(10): Prospective, observational Patients with DDDR/ +/- ICD s +/- AF Excluded if on warfarin 2486 pts., CHADS = 1 or more (2.2) Mean follow-up 1.4 yrs. Longest total AT/AF on any given day Three groups: No AF All episodes < 5.5 hrs. Episodes > 5.5 hrs. 2

3 Annual risk lower than traditional Typical CHADS 2 = 4.0% TRENDS pts. 2.4% Analysis based on 40 events Role of AC not certain for these patients Clinical trials underway. Consider AC if Asymptomatic AF > 5.5 hrs. Trends analysis > 24 hrs CCS 2014 Guidelines Update ú Shorter duration if high risk (recent CVA). PAC s < 30 sec. not AF AF CHADS 2 or more CHADS 1?? CHADS 65 CHF 1 HT 1 Age >75 1 D.M. 1 Prior Stroke CCS Non Valvular Atrial Fibrillation! Stroke Prevention Recommendations! CCS Update! "! Skaynes AC et al. Can J Cardiol. 2012; ! 14! 3

4 CHADS score Bleeding risk assessment HasBleed Private insurance coverage? Hemoglobin / Renal function Reasonably compliant/educated patient BC Pharmacare INR stabilty > 1/3 out of range Can t get to lab? Cardioversion planned Bleeds per 100 patient-years AF cohort of the Euro Heart Survey 0 HAS-BLED score Number of patients Number of bleeding events Clinical characteristic Points Hypertension (SBP >160 mmhg) 1 Abnormal renal or liver function Stroke 1 Bleeding 1 Labile INRs 1 Elderly (age >65 years) 1 Drugs or alcohol Cumulative score Range , Pisters R et al, Background Initial Warfarin/placebo trials excluded rheumatic mitral stenosis and AF since CVA risk > 15% / yr. Rely Trial exclusions Prosthetic valve -any Hemodynamically relevant valve disease ú Rheumatic MS ú MR with CHF/ with large LA > 5.5cm. Valvular AF Mitral +/- Aortic tissue prosthesis Mechanical valves MV repair Rheumatic MS Severe renal disease Dialysis/ GFR < 30ml/min Valvular AF Mitral +/- Aortic tissue prosthesis Mechanical valves MV repair Rheumatic MS? Triple Rx. recent stents on ASA /Plavix Pregnancy Mechanical valves??? REALIGN study Recently published Dabigatran inferior to warfarin Do not use NOAC with mechanical valves. 4

5 New OACs Trials Intracranial Hemorrhage Convenience no lab testing No impact from diet Little impact from drug interactions Ketoconazole/rifampin Reduced ICH Fairly consistent 50% reduction seen with all 3 drugs Quick onset/ offset of action TRIAL OAC Agent HR (95% CI) P Value # ARISTOTLE Apixaban 5mg BID RE-LY New OACs are consistently associated with a lower risk of intracranial hemorrhage Dabigatran 110mg BID Dabigatran 150mg BID ROCKET AF Rivaroxaban 20mg QD P < P < P < P = 0.02 Not head-to-head comparisons New Anticoagulant Better Warfarin Better Connolly SJ, et al. N Engl J Med. 2009; 361: Patel MR, et al. N Engl J Med. 2011; 365: Granger CB, et al. N Engl J Med. 2011; 365: New OAC Renal Elimination No head to head comparisons exist/planned Questions to ask CHADS score - apixiban/dabigitran if higher? Renal function not dabigatran if impaired/labile Other drug regimen other bid drugs.? Prior DVT/PE rivaroxaban +/- dabigatran Patient preference Importance of registry data (post-marketing) Renal elimination ~ Apixaban: 27% ~ Dabigatran: 85% ~ Rivaroxaban: 33% ELIQUIS TM (apixaban). PM, Bristol-Myers Squibb/Pfizer Canada. PRADAX TM (dabigatran). PM, Boehringer Ingelheim Canada Ltd. XARELTO (rivaroxaban). PM, Bayer Canada. Low dose dabigatran (110mg./day) If preventing bleed more impt than CVA prevention Low dose for: ú Age > 80 - recent change to > 75 ú High bleed risk Low dose Xarelto (15mg/d) If abnormal renal function (CrCl 30-50ml/min) Low dose apixiban (2.5mg. Bid) If 2 of 3 present: ú Age > 80 ú Weight < 60 kg. ú Creatinine > 133 Stop warfarin 2-3 days before Monitor INR daily Initiate new OAC when: - INR < 2: start apixaban or dabigatran - INR 2.5: start rivaroxaban Starting new OAC will depend on renal function and prescribing information for new OAC Schulman S, Crowther MA. Blood. 2012; 119:

6 Question 8 Bridging essential To balance onset of warfarin (~ 5 days) and half-life of new OAC 1. Initiate warfarin, continue new OAC for at least 2 days 2. Discontinue new OAC once INR is > While on concomitant therapy, test INR just prior to the next dose of the NOAC Schulman S, Crowther MA. Blood 2012; 119: ELIQUIS TM (apixaban). PM, Bristol-Myers Squibb/Pfizer Canada. PRADAX TM (dabigatran). PM, Boehringer Ingelheim Canada Ltd. XARELTO (rivaroxaban). PM, Bayer Canada. ASK 1) CHADS 2) BLEEDING RISK OF SURGERY 3) RENAL FUNCTION 4) WHICH DRUG? 5) CURRENT RHYTHM TODAY How should the periprocedural period be managed in patients receiving new OACs? Thrombotic Risk Stratification for Perioperative in AF High risk Moderate risk Low risk Suggested Risk Stratification for Perioperative Anticoagulant CHADS 2 score of 5 or 6 Recent (within 3 mo) stroke or TIA Rheumatic valvular heart disease CHADS 2 score of 3 or 4 CHADS 2 2 (no prior stroke or TIA) Procedural Bleeding Risks Low (2-day risk of major bleed 0% 2%) Cholecystectomy Abdominal hysterectomy GI endoscopy +- biopsy Pacemaker/defibrillator insertion Simple dental extractions Knee/hip replacement and shoulder/foot/hand surgery Dilatation and curettage Skin cancer excision Hemorrhoid surgery Cataract/no cataract eye surgery High (2-day risk of major bleed 2% 4%) Heart valve replacement Coronary artery bypass Abdominal aortic aneurysm repair Neurosurgical/urologic/head and neck/abdominal/breast cancer surgery) Bilateral knee replacement Transmural prostate resection Kidney biopsy Vascular and general surgery Any major operation Spyropoulos AC & Doukatis JD. Blood. 2012; 120(15): Spyropoulos AC & Doukatis JD. Blood. 2012; 120(15): Postoperative Management of New Anticoagulants Pradaxa - Discontinuation before surgery Renal function (CLCR, ml/min) Half-life (hours) a Timing of discontinuation after last dose of dabigatran before surgery Standard risk of bleeding High risk of bleeding b > (11 22) 24 hours 2-4 days > 50 to (12 34) 24 hours 2-4 days > 30 to (13 23) at least 48 hrs. 4 days ( days > 5 days Drug Dabigatran 150 mg* A suggested approach Low Bleeding Risk Surgery High Bleeding Risk Surgery Resume 1 day after surgery (24 h postoperative) Rivaroxaban 20 mg OD Resume 1 day after surgery (24 h postoperative) Apixaban 5 mg BID Resume 1 day after surgery (24 h postoperative) Resume 2-3 days after surgery (48-72 h postoperative) Resume 2-3 days after surgery (48-72 h postoperative) Resume 2-3 days after surgery (48-72 h postoperative) *For patients at high-risk, consider administering reduced dose of dabigatran to 110 mg OD on the evening after surgery and on the following day (first postoperative day) after surgery Consider a reduced dose of rivaroxaban 10 mg OD or apixaban 2.5 mg BID in patients with this risk Spyropoulos AC & Doukatis JD. Blood. 2012; 120(15):

7 Key Messages Patient or referring physicians should notify the surgeon that patient is taking a new OAC Assessment of patient and procedural-related risk of thrombosis and bleeding must be done to develop a procedural strategy Most minor procedures, such as dental, dermatological, and ophthalmologic, can be safely undergone while a patient is on new OAC Do not use LMWH with NOAC s perioperatively If switching to IV UFH Give 12 hrs after pradaxa if normal renal function. Give 24 hrs. after pradaxa if abn. Renal function. May consider for DVT/PE Rx. Spyropoulos AC & Doukatis JD. Blood. 2012; 120(15): Measure PT/PTT PTT - Dabigratran PT Apixiban/ Rivoroxaban Local bleeding measures Blood transfusions prn Consider platelets if on plavix or thrombocyotpenia present Consider Octiplex/ FEIBA Consider dialysis for Dabigatran Early development stages for: Fab to dabigitran - Imitation factor Xa (Andexanet) ú Return of anti-factor Xa activity within 2 hrs. ú Reversible inhibitor for apixiban and rivaroxaban Studies so far in healthy volunteers No real clinical bleeding data Antedote time frame?? 2015/6 Illusion on antedote with warfarin Dealing with change/ protocols 7

8 AVERROES Cumulative risk Stroke or Systemic Embolism HR 0.45 (95% CI, ) p<0.001 Aspirin 3.7 % Apixaban 1.6% Cumulative risk HR 1.13 (95% CI, ) p=0.57 Major Bleeding Apixaban 1.46% Aspirin 1.2% Months Months Mean CHADS 2 score at baseline: 0 1: 36%; 2: 36%; 3+: 28% Connolly SJ, et al. N Engl J Med. 2011; 364: Aristotle Trial subanalysis Major bleed with death < 30 days RR 0.5 with apixiban 36 vs. 71ps. If major bleed on apixiban vs. warfarin note: Less hospitalization Less medical/surgical intervention Less transfusion Fewer changes thrombotic Rx. 40% of trial patients where on ASA in NOAC studies. No randomized NOAC/ASA data available Would consider for all recent coronary events ie. NSTEMI (< 1 year) Would consider stopping ASA in patients with clinically stable CAD / Atherosclerotic disease. Consider low dose NOAC if on antiplatelet?? No randomized evidence ablation reduces stroke risk Registry data favourable?? Selection bias. Currently role of ablation for QOL Randomized trials underway.? Role for low dose NOAC after ablation OCEAN Trial underway Optimal AC post- catheter AF ablation 8