Canadian Society of Internal Medicine Annual Meeting 2016 Montreal, QC

Canadian Society of Internal Medicine Annual Meeting 2016 Montreal, QC DEBATE: DOAC vs Good Old Warfarin André Roussin MD, FRCP, CSPQ CHUM and ICM/MHI Associate professor University of Montreal A. Roussin MD

Canadian Society of Internal Medicine Annual Meeting 2016 Montreal, QC The following presentation represents the views of the speaker at the time of the presentation. This information is meant for educational purposes, and should not replace other sources of information or your medical judgment. Andre Roussin MD, FRCP, CSPQ; September 2016 A. Roussin MD

Canadian Society of Internal Medicine Annual Meeting 2016 Montreal, QC Conflict Disclosures Advisor or advisory boards: Bayer, BI, BMS, Leo, Merck, Pfizer, Sanofi Research funding: Astra-Zeneca and Bayer Speaker: Bayer, BI, BMS, Leo, Merck, Pfizer and Sanofi Andre Roussin MD, FRCP, CSPQ; September 2016 A. Roussin MD

DEBATE: DOAC vs Good Old Warfarin Objectives Recognize the benefits and harms associated with DOACs for the prevention and treatment of thromboembolic events Recognize the benefits and harms associated with warfarin for the prevention and treatment of thromboembolic events Compare and contrast the benefits and harms of DOACs versus warfarin in complex patients with multiple comorbidities A. Roussin MD

DOAC vs VKA (warfarin) Pharmacological aspects Warfarin DOAC Onset of action Slow (5 days) and unpredictable Rapid (2 hours) and predictable Dosing Variable and difficult Fixed, according to creatinine Food interactions Numerous None (except rivaroxaban: meal) Drug interactions Very long list Few CKD No impact Impact if severe (Clear < 25-30) Liver disease Impact on warfarin and coagulation factors Contra-indicated Child-Pugh B + C A. Roussin MD

DOAC vs VKA (warfarin) "Strategic" aspects Warfarin DOAC Routine monitoring Necessary Useless AC effect duration Bleeding Surgery Antidote 2 to 5 days 1 day to activity to 25% PCC (Beriplex or Octaplex ) with Vit K Idarucizumab for Dabi. Andexanet for Api. / Rivaro. PCC (Beriplex or Octaplex )? Daily cost of medication $0.45 average $2.80 (riva) to $3.20 (dabi and api) Strategic costs Rx cost + INR/visits + costs of Stroke (AF), bleeding (AF + VTE) and days of supplemetary hospitalization (AF + VTE) Rx cost + QALY A. Roussin MD

DOAC vs Warfarin for AF Stroke or Systemic embolism Relative risk (IC 95 %) RE-LY [Dabigatran 150 mg] 0,66 (0,53-0,82) ROCKET AF [Rivaroxaban] 0,88 (0,75-1,03) ARISTOTLE [Apixaban] 0,80 (0,67-0,95) ENGAGE AF-TIMI 48 [Edoxaban 60 mg] 0,88 (0,75-1,02) All 0,81 (0,73-0,91) p = < 0,0001 N = 58 541 0,5 DOAC better 1 VKA better 2 Heterogeneity p = 0,13 Ruff CT et all. Lancet. A. Roussin 2013. MD

DOAC vs Warfarin for AF Major bleeding Study DOAC Relative risk (IC 95 %) ROCKET-AF RE-LY Rivaroxaban à 20 mg qd Dabigatran à 150 mg bid Dabigatran à 110 mg bid ENGAGE ARISTOTLE Édoxaban à 60 mg qd Édoxaban à 30 mg qd Apixaban* à 5 mg bid 0,1 DOAC better 1 VKA better 2 Connolly SJ et coll., RE-LY. N Engl J Med. 2009;361:1139-1151; Connolly SJ et coll., poure-ly. N Engl J Med. 2011;363(19):1875-1876 (mise à jour); Patel MR et coll. ROCKET AF. N Engl J Med. 2011;365:883-891; Granger CB et coll., ARISTOTLE. N Engl J Med. 2011; 365:981-992. Giugliano RP et coll., ENGAGE AF-TIMI 48. N Engl J Med. 19 nov. 2013. A. Roussin MD

DOAC vs Warfarin for AF Intracranial bleeding All DOACs reduce the rate of intracranial blededing compared to warfarin. Study DOAC Relative risk (IC 95 %) ROCKET-AF RE-LY ENGAGE ARISTOTLE Rivaroxaban 20 mg qd Dabigatran 150 mg bid Dabigatran 110 mg bid Édoxaban 60 mg qd Édoxaban 30 mg qd Apixaban 5 mg bid 0,1 DOAC better 1 2 VKA better Connolly SJ et coll., RE-LY. N Engl J Med. 2009;361:1139-1151; Connolly SJ et coll., poure-ly. N Engl J Med. 2011;363(19):1875-1876 (mise à jour); Patel MR et coll. ROCKET AF. N Engl J Med. 2011;365:883-891; Granger CB et coll., ARISTOTLE. N Engl J Med. 2011; 365:981-992. Giugliano RP et coll., ENGAGE AF-TIMI 48. N Engl J Med. 19 nov. 2013. A. Roussin MD

DOAC vs Warfarin: GI bleeding (for AF) DOACs are associated with similar or higher risk of GI bleeding than warfarin (AF patients) DOAC No. of éven. (% an) Warfarin HR Dabigatran 110 Dabigatran 150 137 (1.15) 126 (1.07) 1.08 188 (1.56) 126 (1.07) 1.48 Rivaroxaban* Apixaban 224 (3.15) 154 (2.16) 105 (0.76) 119 (0.86) 1.46 0.89 0.0 0.5 1.0 1.5 2.0 DOAC better VKA better *Rivaroxaban: *% and not %/yr are reported; RR, not reported, was calculated: http://www.spc.univ-lyon1.fr/mfcalc Connolly SJ, et al. N Engl J Med 2010; 363(19):1875-1876, suppl app. Patel MR, et al. N Engl J Med. 2011; 365:883 91. Granger CB, et al. N Engl J Med. 2011; 365:981 92. A. Roussin MD

DOAC vs Warfarin for AF Total mortality DOACs reduced the rate of total mortality compared to warfarin. Study DOAC Relative risk(ic 95 %) ROCKET-AF Rivaroxaban 20 mg qd RE-LY Dabigatran 150 mg bid Dabigatran 110 mg bid ENGAGE ARISTOTLE Édoxaban 60 mg qd Édoxaban 30 mg qd Apixaban 5 mg bid 0,1 DOAC better 1 2 VKA better Connolly SJ et coll., RE-LY. N Engl J Med. 2009;361:1139-1151; Connolly SJ et coll., poure-ly. N Engl J Med. 2011;363(19):1875-1876; Patel MR et coll. ROCKET AF. N Engl J Med. 2011;365:883-891; Granger CB et coll., ARISTOTLE. N Engl J Med. 2011; 365:981-992. Giugliano RP et coll., ENGAGE AF-TIMI 48. N Engl J Med. 19 nov. 2013. A. Roussin MD

Peri-procedural bleeding Dabigatran vs Warfarin 4591 patients had an invasive procedure during RELY Healey et al. Circulation 2012; 126: 343-348 A. Roussin

DOACs for VTE Phase III studies UHF or LMWH As effective with less bleeding than VKA Front line Fontana P et al. EHJ 2014 A. Roussin MD

VTE treatment options: AT 10 Warfarin, UFH, LMWH and DOACs Warfarin LMWH Rather than VKA 2B or DOAC 2C DOAC Rather than VKA 2B LMWH sc or UHF iv or sc. or fondaparinux sc Warfarin INR 2 3 rather than LMWH 2C Transition treatment offering immediate AC CANCER, (6 months ) LMWH monotherapy Rivaroxaban 15 mg BID for 21 days, then 20 mg DOD LMWH (UHF) for 5-10 days, then dabigatran 150/110 mg BID Apixaban 10 mg BID for 7 days, then 5 mg BID 6 months then 2.5 mg BID Special cases- UFH UHF if CrCl < 30 ml/min, increased bleeding risk, need for rapid reversal or if thrombolysis contemplated A. Roussin MD

DOACS and VTE for acute phase Non head-to-head comparisons APIXABAN 1 RIVAROXABAN 2,3 DABIGATRAN 4,5 Trial design: double-blind Yes No Yes Use of LMWH and/or UFH lead-in No No Yes Duration of treatment 6 months 3, 6, or 12 months 6 months Non-inferior efficacy vs. comparator* (recurrent or fatal VTE) Yes DVT Yes Major bleeding vs. comparator* ns ns Major or CRNM bleeding vs. comparator* PE Yes Yes ns ns Dosing BID BID then QD BID Head-to-head studies have not been conducted, therefore comparative safety and efficacy have not been established. *Comparator was LMWH or UFH followed by either a vitamin K antagonist (warfarin or acenocoumarol) in the rivaroxaban trials or warfarin in the other NOAC trials. BID, twice daily; CRNM, clinically relevant non-major; QD, once daily; LMWH, low molecular weight heparin; NOAC, novel oral anticoagulant; UFH, unfractionated heparin; VTE, venous thromboembolism 1. Agnelli G et al. N Engl J Med 2013;369:799-808; 2. The EINSTEIN Investigators. N Engl J Med 2010;363:2499-510; 3. The EINSTEIN-PE Investigators. N Engl J Med 2012;366:1287-1297; 4. Schulman et al. N Engl J Med. 2009;361:2342 2352; 5. Schulman et al. Circulation;2014:129:764-772. 15

DOACs and VTE prolonged phase Non head-to-head comparisons APIXABAN 1 RIVAROXABAN 2 DABIGATRAN 3 Trial design: double-blind Yes Yes Yes Comparator Placebo Placebo Placebo Duration of treatment 12 months 6 or 12 months 6 months Dosing BID QD BID Dose(s) of NOAC studied 2.5 mg and 5 mg 20 mg 150 mg Superior efficacy (recurrent or fatal VTE) vs comparator Yes Yes Yes Major bleeding vs comparator ns ns ns Major or clinically-relevant non-major bleeding vs comparator ns Head-to-head studies have not been conducted, therefore comparative safety and efficacy have not been established BID, twice daily; NOAC, novel oral anticoagulant; ns, not significant; QD, once daily. 1.Agnelli et al. N Engl J Med 2013;368:699-708. 2.The EINSTEIN Investigators. N Engl J Med. 2010;363:2499-2510. 3.Schulman et al. N Engl J Med. 2013; 368:709-718. 16

Real life: FDA 2014: 134,414 patients Dabigatran and Warfarin for AF 2010 à 2012 Medicare 1 >134 000 patients 0.86 1.28 0.92 0.80 0.34 RE-LY 2 4 >18 000 patients 0.88 1.48 1.27 0.75 0.41 In the USA, the licensed doses for dabigatran etexilate are 150 mg BID and 75 mg BID for the prevention of stroke and systemic embolism in adult patients with nonvalvular AF. Numbers on bars denote hazard ratios vs warfarin; MI = myocardial infarction 1. http://www.fda.gov/drugs/drugsafety/ucm396470.htm. Accessed on August 2014; 2. Connolly SJ et al. N Engl J Med 2009;361:1139 51; 3. Connolly SJ et al. N Engl J Med. 2010;363:1875 6; 4. Pradaxa : EU SPC 2014

Real life: Quebec registry, 12,840 patients Dabigatran and Warfarin for AF INESSS 2013

In this combined analysis of real-world observational comparison studies with VKA, dabigatran was associated with: Lower risk of ischaemic stroke, major bleeding, intracranial bleeding and mortality Higher risk of GI bleeding Similar risk of myocardial infarction. Carmo J et al TH 2016

Dabigatran vs VKA for AF Ischemic Stroke

Dabigatran vs VKA for AF Major bleeding

Dabigatran vs VKA for AF Intracranial bleeding

Dabigatran vs VKA for AF Mortality

Dabigatran vs VKA for AF Gastrointestinal bleeding

Dabigatran vs VKA for AF Myocardial infarction

Real-world EVIdence on Stroke prevention In patients with atrial Fibrillation in the US Objective: To assess the real-world effectiveness and safety of newly-initiated rivaroxaban or apixaban compared to warfarin in NVAF patients 38,831 patients Rivaroxaban vs Warfarin 18, 591 patients Apixaban vs Warfarin Coleman CI et al, ESC 2016: P2576

Rivaroxaban vs Warfarin Rivaroxaban was associated with a significant* 47% reduction in ICH vs. warfarin 29% non-significant decrease in ischaemic stroke vs. warfarin Significant* 39% reduction in the combined endpoint of ICH and ischemic stroke vs. warfarin Rivaroxaban Warfarin HR (95% CI) Rate (%/year) Rate (%/year) rivaroxaban vs. warfarin HR (95% CI) rivaroxaban vs. warfarin ICH 0.49 0.96 0.53 (0.35 0.79) Ischemic stroke 0.54 0.83 0.71 (0.47 1.07) Combined 0.95 1.6 0.61 (0.45 0.82) *p<0.05 Coleman CI et al, ESC 2016: P2576 Favors rivaroxaban Favors warfarin

Apixaban vs Warfarin Apixaban was associated with a significant* 62% reduction in ICH vs. warfarin 13% non-significant increase in ischemic stroke vs. warfarin Non-significant 37% reduction in the combined endpoint of ICH and ischemic stroke vs. warfarin Apixaban Warfarin HR (95% CI) Rate (%/year) Rate (%/year) apixaban vs. warfarin HR (95% CI) apixaban vs. warfarin ICH 0.38 0.97 0.38 (0.17 0.88) Ischemic stroke 0.56 0.51 1.13 (0.49 2.63) Combined 0.89 1.44 0.63 (0.35 1.12) *p<0.05 Coleman CI et al, ESC 2016: P2576 Favors apixaban Favors warfarin

Lip G et al. Int J Clin Pract 2016; 70: 752-763

Lip G et al. Throm Haemost 2016

Using a large US insurance database, we identified privately insured and Medicare Advantage patients with nonvalvular atrial fibrillation who were users of apixaban, dabigatran, rivaroxaban, or warfarin between October 1, 2010, and June 30, 2015. We created 3 matched cohorts using 1:1 propensity score matching: Apixaban versus warfarin (n = 15 390) Dabigatran versus warfarin (n = 28 614) Rivaroxaban versus warfarin (n = 32 350) Yao X et al. J Am Heart Assoc. 2016

CONCLUSIONS Apixaban was associated with lower risks of both stroke and major bleeding Dabigatran was associated with similar risk of stroke but lower risk of major bleeding Rivaroxaban was associated with similar risks of both stroke and major bleeding in comparison to warfarin

"Strategic" messages DOACs vs VKA vs UHF/LMWH The benefit / risk ratio is better for AF (efficacy + ICH) and for VTE (bleeding) CKD (clear < 25-30 ml/min) and mechanic valves are the major limiting factors for DOACs For cancer related VTE, LMWH are superior to VKA and possibly to DOACs For HIV related VTE, dabigatran and VKA are the best choices For pregnancy, LMWH are superior to VKA and DOACs

REFERENCES 2016 34

THROMBOSIS CANADA: «App»

References: "App" www.thrombosiscanada.ca @ThrombosisCan