Study Design 5/2/2018. Complex NOAC Cases. Outcomes Overall Population. Key Inclusion and Exclusion Criteria

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1 /2/218 Med Work: Complex OAC Cases Kori Leblanc, PharmD Cardiovascular Pharmacotherapy Specialist and Research Coordinator Department of Pharmacy - University Health etwork Assistant Professor, Leslie Dan Faculty of Pharmacy Frank Age: 7 Weight: 77 kg PAST MEDICAL HISTORY Hyperlipidemia Hypertension PAD -Intermittent claudication -ABI <.9 -GERD Ex-smoker, quit years ago CURRET TREATMETS Rivaroxaban 2. mg BID EC ASA 81 mg Ramipril 1 mg daily Amlodipine mg daily Pantoprazole mg daily Rosuvastatin 2 mg at bedtime Presents for his annual physical. ECG done in clinic shows AFIB at a rate of 9bpm. Frank is completely asymptomatic. RELEVAT FIDIGS ECG: Atrial fibrillation : 9 irregular BP: 1/8 LDL: 2. LABS DATE: 1 week ago CBC: WL Cr: 1 umol/l CrCl: ~1 ml/min 28,27 patients with CAD or PAD, 7,7 with PAD x 2 partial factorial design Study Design days (excluding pts randomized -1 days post-cabg) on Rivaroxaban placebo bid and Aspirin 1 mg od 8% adherence (2,2 [8%] excluded) n=17,98 Anticipated - year follow-up (~2,2 primary events*) n=9,797 *. per 1 person-yrs Aspirin event rate 9% power to detect 2% lower risk with 2 comparisons of rivaroxaban COMPASS Trial EJM 217 Bosch et al Can J Cardiol 217;:127- Eikelboom et al Engl J Med 217;77:119-1 Key Inclusion and Exclusion Criteria Coronary or peripheral artery disease (MI/angina/PCI/CABG) Patients with CAD must also have Age 6 years, or Age <6 years and documented atherosclerosis or revascularization involving 2 vascular beds or 2 additional risk factors (e.g., current smoker, diabetes, egfr<6 ml/min, HF, non-lacunar ischemic stroke 1 month ago) Criteria for PAD Claudication, previous amputation or revascularization Carotid revascularization Asymptomatic carotid disease with >% stenosis Key Exclusion eed for dual antiplatelet, other non-aspirin antiplatelet, or oral anticoagulant therapy Stroke 1 month, history of hemorrhagic or lacunar stroke Severe HF (EF<%, YHA class ) egfr <1 ml/min Bosch et al Can J Cardiol 217;:127- Eikelboom et al Engl J Med 217;77:119-1 Outcomes Overall Population Primary CV death, stroke or myocardial infarction (MI) For PAD subgroup above plus MALE (major adverse limb events) Secondary CHD death, ischemic stroke, MI, or acute limb ischemia CV death, ischemic stroke, MI, or acute limb ischemia Mortality Safety and net clinical benefit ISTH major bleeding (modified to include presentation to an acute care facility or hospitalization as major) Primary plus fatal or critical organ bleeding Bosch et al Can J Cardiol 217;:127- Eikelboom et al Engl J Med 217;77:

2 *CV Death/MI/Stroke /2/218 Characteristic Selected Baseline Characteristics Rivaroxaban + ASA Rivaroxaban Aspirin =9,12 =9,117 =9,126 Age, years (mean) Blood pressure, mm Hg 16/77 16/78 16/78 Total cholesterol, mmol/l CAD PAD Previous MI Heart Failure Previous Stroke Diabetes Lipid-lowering agent(s) ACE-I or ARB Beta-blocker Primary Outcome: CV Death/Stroke/MI Median follow-up 2 (max. 7) months Eikelboom et al Engl J Med 217;77:119-1 Outcome CV death Stroke MI Primary Outcome Components Riva + Aspirin =9,12 16 (1.7%) 8 (.9%) 178 (1.9%) Aspirin =9,126 2 (2.2%) 12 (1.6%) 2 (2.2%) Rivaroxaban + Aspirin vs. Aspirin (9% CI).78 (.6-.96).8 (.-.76).86 (.7-1.) p.2 <.1.1 PAD Subgroup: Primary Efficacy Outcome* Eikelboom et al Engl J Med 217;77:119-1 PAD Limb Outcomes PAD Major Bleeding R + A =2,92 Outcome MALE* (1.2) Major amputation (.2) R =2,7 (1.) 8 (.) A =2, 6 (2.2) 17 (.7) Riva + Aspirinvs. Aspirin P (9% CI).. (.-.8). (.11-.8).1 Riva vs. Aspirin (9% CI).6 (.1-.96).6 (.2-1.8) *Major Adverse Limb Events (MALE): Severe limb ischemia leading to an intervention (angioplasty, bypass surgery, amputation, thrombolysis) Major Amputation above forefoot due to vascular cause P..7 Outcome R + A =2,92 77 Major Bleeding** (.1) Fatal on-fatal ICH on-fatal other critical organ* (.2) (.2) 1 (.) R =2,7 79 (.2) (.2) (.1) 18 (.7) A =2, 8 (1.9) (.1) 8 (.) 8 (.) Riva + Aspirin vs. Aspirin (9% CI) P 1.61 ( ).9 Riva vs. Aspirin (9% CI) 1.68 ( ) P (.6-.7). 2.1 (.9-.96) **Modified ISTH Criteria: fatal, symptomatic into a critical organ, surgical site requiring reoperation, requiring acute facility intervention.6 Anand et al Lancet 218;91:

3 Probability of stroke or systemic embolism within 1 year (9% Cl) /2/218 Outcomes by Renal Function % per 1 patient-years Danish Cohort Study Patient-level data from ational Registries: 12, 72 VAF Patients 6 Stroke and Systemic Embolism Rivaroxaban* 6 Major Bleeding Rivaroxaban*.7.9 o Renal Disease ( =127,88) on-end-stage Chronic Kidney Disease (=87) Hazard Ratio (9% Cl) p Value Hazard Ratio (9% Cl) p Value Disease Requiring Renal- Replacement Therapy (=91) Hazard Ratio (9% Cl) p Value Stroke/SE ( ) < ( ) < Fatal Bleeding:.7% vs..28%, p= Bleeding ( ) < (2.8-.7) <.1 renal status at baseline Engl J Med 212;67:62-. DOI: 1.16/EJMoa119 n=176 n=17 n=6 n=67 CrCl -9 ml/min * CrCl ml/min: 2 mg daily CrCl -9 ml/min: 1 mg daily CrCl ml/min n=176 n=17 n=6 n=67 CrCl -9 ml/min CrCl ml/min Fox et al Eur Heart J 211;2:287-9 Pharmacodynamic/Pharmacokinetic Profiles of the OACs Adjusted Dose Criteria of OACs Dabigatran (Pradax ) *66% excreted in the urine with approximately % unchanged BCRP = breast cancer resistance protein; CYP = cytochrome P; R = not reported; P-gp = P-glycoprotein Rivaroxaban (Xarelto ) Apixaban (Eliquis ) Edoxaban (Lixiana ) Dosing frequency Twice daily Once daily Twice daily Once daily Distribution volume (L) Bioavailability 7% 8% 66% 62% 1 2 Hrs to C max (delayed by food) Half-life 12 1 h 1 h 8 1 h 1 1 h CYP metabolism one 66% 1% <% Protein binding % >9% 87% % Transporters P-gp P-gp/BCRP P-gp P-gp Renal elimination 8% %* 2% % Adapted from: Gonzalez-Quesada CJ, et al. Am J Cardiovasc Drugs 21; 1: OAC Usual Dose Adjusted Dose Criteria Apixaban mg BID 2. mg BID at least 2 of: age 8 yrs, weight 6 kg, creatinine 1 µmol/l Edoxaban 6 mg once daily mg once daily Rivaroxaban 2 mg once daily 1 mg once daily Weight 6 kg, creatinine clearance - ml/min, or concomitant use of some P-glycoprotein inhibitors Creatinine clearance -9 ml/min Dabigatran 1 mg BID 11 mg BID patients 8 yrs of age consider this dose for those at higher risk of bleeding, including those 7 yrs of age or older with at least one risk factor for bleeding (e.g. CrCl - ml/min, P-glycoprotein inhibitor, concomitant antiplatelet therapy etc.) Use of Reduced Dose in OAC trials Outcomes in Patients with Worsening Renal Function (WRF): Stroke/SE ARISTOTLE 2,, EGAGE AF,6 ROCKET AF 1 RE-LY 7,8 A 1. Interaction p=. WRF x treatment Rivaroxaban vs. warfarin (9% Cl) Total Patients Mean CHADS2 Score Patients with moderate renal impairment umber of patients studied with Reduced Dose 17% # 19% 21%* 2% 2. mg BID: 28 mg daily : mg daily: mg BID: WRF = decrease of 2% or more Rivaroxaban 1 2. *CrCl -9 ml/min (Cockroft-Gault); # egfr ml/min (Cockcroft-Gault); CrCl ml/min (Cockroft-Gault); egfr,< ml/min; ǁ renal impairment defined as serum creatine levels 1. mg/dl; data given for dose adjusted arm of high-dose (6/) group 1.Fox KAA et al, Eur Heart J 211;2:287 29; 2. Granger GB et al, Engl J Med 211;6: ;. Hohnloser SH et al, Eur Heart J 212;: ;. Apixaban FDA medical review;. Giugliano RP et al, Engl J Med 21;69:29 21; 6. Bohula EA et al, Circulation 216;1:2-6; 7. Connolly SJ et al, Engl J Med 29;61: ; 8. Hijazi Z et al, Circulation 21;129: Creatinine Clearance: % decrease from screening Stroke/SE:.2 vs. 1. per 1 pt-yrs. (.27-.9) Fordyce CB. Circulation 216;1

4 Probability of major or MCR bleeding within 1 year (9% Cl) /2/218 Outcomes in Patients with Worsening Renal Function (WRF): Bleeding B 2. Rivaroxaban vs. warfarin (9% Cl) Interaction p=.61 WRF x treatment. The superior efficacy and safety of apixaban as compared with warfarin were similar in patients with normal, poor, and worsening renal function. 1.. Rivaroxaban o difference in major or non-major clinically relevant (MCR) bleeding among WRF patients randomized to rivaroxaban vs. warfarin* WRF = decrease of 2% or more. 1 2 Creatinine Clearance: % decrease from screening The efficacy and safety profile of dabigatran compared to warfarin was similar irrespective of renal function changes over time dabigatran 11mg showed a greater RRR in major bleeding in patients with stable renal function. JAMA Cardiol. 216;1():1-6. doi:1.11/jamacardio DOI: Reference: YMHJ ASA/OAC in Stable Vascular Disease: What do we know? o. of Dose- Reduction Criteria o. of Patients one 1 6 (77) 1 Age 8 years Weight 6 kg only Creatinine 1 µmol/l 966 (2) 166 (1) 126 (6) 9 (2) ASA decreases the risk of mortality and CV events in CAD patients is also effective in decreasing CV events and mortality in CAD patients 1,2, Similar effect on mortality Superior prevention of MI and stroke vs ASA More bleeding Adding ASA to OAC increases major bleeding 2 8 (.) 1 Hurlen M, EJM 22;7(1) 2 van Es RF, Lancet 22;6 Anand S, JAMA 1999;282 Increased Bleeding Risk with OAC + Antiplatelet Combination Therapy OAC Bleeding risk increases -6% with OAC + antiplatelet combination therapy 1- Parameter MB OAC + ASA vs. OAC alone ( 9% Cl) Apixaban 1 ASA at baseline 1.1 ( ) Dabigatran 2 ASA at baseline 1.6 ( ) Edoxaban ASA at baseline 1.6 ( ) Rivaroxaban ASA at baseline 1.2 ( ) Comparative Bioavailability Standards: Formulations Used for Systemic Effects For the majority of drugs, with the exception of subsequententry biologic products, the following standards obtained in single dose cross-over comparative bioavailability studies determine bioequivalence: a) The 9% confidence interval of the relative mean area under the concentration vs. time curve to the time of the last quantifiable concentration (AUCT) of the test to reference product should be within 8.% to 12.% inclusive. b) The relative mean maximum concentration (Cmax) of the test to reference product should be between 8.% and 12.% inclusive. 1. Hylek et al. J Am Coll Cardio. 21;6:211-7; 2. Dans et al. Circulation. 21;127:6-;. Xu et al. J Am Heart Assoc. 216;(2);. Goodman et al. J Am Coll Cardiol. 21;6:

5 /2/218 Pradaxa Formulation Dabigatran etexilate limited solubility yields a bioavailability of only -7% This solubility is ph-dependent (DE practically insoluble under alkaline conditions) branded DE capsules are filled with drug pellets each consisting of a tartaric acid core that is coated with a drug layer ph Impact Administration with PPI: Less than % decrease in bioavailability Clinical Data from RE-LY: Generics TEVA-DABIGATRA 8 healthy volunteers 1mg dose tested Fasting conditions APO-DABIGATRA 11 healthy volunteers 1 mg dose tested fasting conditions Both generics are supplied in capsule form: TEVA-DABIGATRA contains tartaric acid pellets APO-DABIGATRA capsules do not Triple Antithrombotic Therapy: Threats and Opportunities Capodano & Angiolillo JACC Cardiol CV Interv 217;in press RCT Evidence WOEST 1 (n=7) Less bleeding* with dual tx (clopidogrel+oac) ot powered for efficacy; 2% ACS ISAR-TRIPLE 2 (n=61) Less bleeding with 6 weeks of triple tx ot powered for efficacy; 2% ACS PIOEER AF REDUAL PCI 1 Dewilde et al Lancet 21;81: Fiedler et al J Am Coll Cardiol 21;6: from Canada (.1%) 212 patients with VAF Coronary stenting o prior stroke/tia o recent GI bleeding, anemia, CrCl< ml/min ~2% with ACS Patients With Atrial Fibrillation Undergoing Coronary Stent Placement R A 72 D hours O after M sheath removal I Z E Time in the Therapeutic Range (TTR): 6% Primary endpoint: TIMI major + minor + bleeding requiring medical attention Secondary endpoint: CV death, MI, and stroke (any type) * 1 mg daily if CrCl 9 ml/min Gibson et al Am Heart J 21;169:72-78.e 1,6, or 12 months Pre randomization MD Choice Rivaroxaban 2. mg BID Clopidogrel 7 mg daily Aspirin 7-1 mg daily 1,6, or 12 months Pre randomization MD Choice VKA (target IR 2-) Clopidogrel 7 mg daily Aspirin 7-1 mg daily Rivaroxaban 1 mg daily* Clopidogrel 7 mg daily Triple Therapy months: 1 (16%), 6 (%), 12 (9%) Rivaroxaban 1 mg daily* Aspirin 7-1 mg daily VKA (target IR 2-) Aspirin 7-1 mg daily Open label VKA () Clopidogrel (9%), Ticagrelor (%), Prasugrel (1%) End of treatment 12 months WOEST Like ATLAS Like Triple Therapy

6 TIMI Major, TIMI Minor, or Bleeding Requiring Medical Attention Probability of event Cardiovascular Death, Myocardial Infarction, or Stroke Patients with outcome event Probability of event /2/218 First Occurrence of Clinically Significant Bleeding Events First Occurrence of CV Death, MI or Stroke Mean age 7±9 (% 7) years, 26% female, 28% CrCl -<6 ml/min Median CHADS 2 2, CHA 2 DS 2 -VASc, HAS-BLED DES 66%, BMS 2%, Both 2% p<.1 p<.18 Riva + DAPT 26.7% 18.% 16.8% ~17% power to detect a 2% relative difference Riva + P2Y 12 Riva + DAPT 6.% 6.%.6% Riva + P2Y 12 =.6 (9% CI.-.8) = ARR.9 = (9% 8.7 Riva CI.7-.76) + DAPT v. =.9 (9% ARR CI:.7-.76) T = 9.9 = 12 =.6 (9% CI:.-.8) p <.1 p <.18 ARR=9.9 T = 11 ARR=8.7 T=11 T=12 Riva + P2Y 12 v. Riva + P2Y 12 vs. =1.8 (9% CI: ) p=.7 Riva + DAPT vs. =.9 (9% CI:.9-1.8) p=.77 o. at risk Days o. at risk Days VKA Riva + DAPT P2Y 12 VKA Riva + DAPT Gibson et al Engl J Med 216;7:22- Riva + P2Y 12 Riva + DAPT Gibson et al Engl J Med 216;7:22- Time to All-cause Death or First Recurrent Hospitalization* *Adverse events leading to hospitalization classified by consensus panel blinded to treatment group as potentially related to either cardiovascular (CV), bleeding, or other causes Evaluation of Dual Therapy With Dabigatran vs. Triple Therapy With in AF Patients That Undergo a PCI With Stenting 2,72 patients with VAF Open-label undergoing PCI with stenting Randomization Key excl. 12 hours CrCl< post-pci* ml/min R Dabigatran 1 mg BID + P2Y12 inhibitor x 6-12 months Dabigatran 11 mg BID + P2Y12 inhibitor x 6-12 months 2, (IR 2..) + P2Y12 inhibitor + ASA 1 x 6-12 months 1 Clopidogrel 88% Ticagrelor 12% Mean duration of anticoagulant therapy ~12 months Follow-up: ~1 months TTR 6% ~1% with ACS Primary Endpoint - Safety: Major or Clinically Relevant on-major Bleeding In the Secondary initial protocol, Endpoint a sample - Efficacy: size of 8,2 Composite patients had of been Death, planned MI, Stroke/SE to allow for a or co-primary Unplanned end-point comparison of thromboembolic event rates in revascularization each dual-therapy group vs. triple-therapy group; however, enrollment of this number of patients in a timely fashion was determined to be infeasible Gibson et al Circulation 217;1:2- * 72 hrs preferred; study drug administered 6 hrs after sheath removal 1 ASA should be discontinued at 1 month (BMS) or months (DES ~8%) 2 P2Y12 inhibitor can be discontinued or switched to ASA 1 mg/day from month 12 Pts 8 yrs outside of U.S. randomized to dabigatran 11 mg BID or warfarin Cannon et al Clin Cardiol 216;9:-6 and Engl J Med 217;77: Primary Endpoint: Time to first ISTH Major or Clinically Relevant on-major Bleeding Event Mean age ~71 (17% 8 [7 in Japan]) years, ~2% female Median CHA 2DS 2-VASc -, HAS-BLED ~ :.2 (9% CI:.2-.6) on-inferiority p<.1 Superiority p<.1 TIMI Major:.8% vs. 1.% p=.1 + P2Y12 inh + ASA (n=981) Dabigatran 11 mg BID + P2Y12 inhibitor (n=981) 26.9% vs. 1.% ARR: 11.% ICH: 1.% vs..%; p=.6 T ~ Time to first event (days) :.72 (9% CI:.8-.88) on-inferiority p<.1 Superiority p=.2 TIMI Major:.9% vs. 2.1% p=.28 + P2Y12 inh + ASA (n=76) Dabigatran 1 mg BID + P2Y12 inhibitor (n=76) 2.7% vs. 2.2% ARR:.% ICH: 1.% vs..1%; p=.7 T ~ Time to first event (days) Death, MI, Stroke/Systemic Embolism, or Unplanned Revascularization Dabigatran 1 mg BID 11.8% vs.12.8%.89 ( ) : 1. (9% CI: ) on-inferiority p= Dabigatran (combined doses) + P2Y12 inhibitor (n=17) 1. + P2Y12 inhibitor + ASA (n=981) 2 P Value Event Dabi 11 Dabigatran (combined doses) mg BID 2 + P2Y12 inhibitor (9% CI) (n=17) MI (.) 29 (.) (.9 2.1) Stent 1 (1.) 8 + (.8) P2Y12 inhibitor ASA.1 1 thrombosis (n=981) (.79.) Dabigatran 11 mg BID 1.2% vs.1.% 1.1 (.9-1.) Time to first event (days) Cannon et al Engl J Med 217; 77:11-2 Cannon et al Engl J Med 217; 77:11-2 6

7 /2/218 Dual vs. Triple Therapy Major and Minor Bleeding Events Relative weight* (19.%) (.%) (1.7%) (2.%) (17.%) (2.7%) (High heterogeneity) *based on the inverse of the observed variance of the treatment effect within studies and between studies Major Adverse Cardiovascular Events Relative weight* (11.1%) (17.6%) (.9%) (.2%) (1.7%) (17.1%) Implications Assessing appropriateness of antithrombotic combinations is challenging Dual therapy strategy is looking favoured More to come: (Moderate heterogeneity) DerSimonian and Laird method for random effects Piccini & Jones Engl J Med 217;77: Antiplatelet Guidelines AF and PCI for ACS or high-risk 1 elective PCI In patients with AF undergoing PCI for ACS or elective PCI with high-risk features: Practical tip: The duration of treatment with DAPT in patients with ACS (or those undergoing high-risk PCI) who also have AF with a low risk of stroke should depend on a balanced assessment of the risk of coronary thrombotic events and bleeding. Patients at lower risk of coronary thrombotic events and higher risk of bleeding can be considered for shorter-duration DAPT and patients at higher risk of coronary thrombotic events and lower risk of bleeding should be considered for longer duration of DAPT. Age < 6 and CHADS 2 = ASA + P 2Y 12 inhibitor 2 (ticagrelor, prasugrel preferred over clopidogrel for ACS) Duration after PCI: Up to 12 Months ASA +/- P 2Y 12 inhibitor AF and PCI for ACS or high-risk 1 elective PCI Age > 6 or CHADS 2 > 1 Reduced OAC + ASA + clopidogrel ASA: stop 1 day post PCI or any time up to 6 months Followed by: clopidogrel + OAC Duration after PCI: Up to 12 months OAC 6 +/- SAPT *If CHADS 2 = 1 and Age <6 another option for initial treatment (especially if high-risk for ischemic events) is DAPT alone using ASA + ticagrelor or ASA + prasugrel, similar to the recommendation for CHADS 2 = patient. Regimens evaluated in the context of triple therapy include rivaroxaban 2. mg BID or warfarin. If warfarin is to be used, recommended IR target is OAC options evaluated in the context of a dual pathway strategy include rivaroxaban 1 mg daily (plus clopidogrel) or dabigatran 11 mg/1 mg BID (plus clopidogrel). 218 CCS Antiplatelet Guidelines 218 CCS Antiplatelet Guidelines Mehta SR Can J Cardiol 218: Mehta SR Can J Cardiol 218: 7

8 /2/218 Obesity? Renal blood flow and CrCl are increased Higher doses needed in VKA studies Weight not an exclusion in OAC studies Dabi: Case reports of treatment failures with in very obese (BMI kg/m 2 ) Riva: effective across BMIs; not directly compared with warfarin Edox: in VTE studies, 611 pts >1kg and no difference in efficacy or safety ISTH recommends: use VKA if BMI kg/m2 (or weight >12) ARISTOTLE: Analysis by BMI Sandu RK. European Heart Journal (216) 7, Ongoing Monitoring and Adherence Steffel J. Eur H J (218) 9,