Rivaroxaban in SPAF: Efficacy, safety and cardio-vascular profile. Hans Rickli, St.Gallen

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1 Rivaroxaban in SPAF: Efficacy, safety and cardio-vascular profile Hans Rickli, St.Gallen

2 HADS 2 Distribution Across SPAF Trials % HADS 2 Score Dabigatran and apixaban: evaluated across a spectrum of stroke risk categories Rivaroxaban: evaluated in patients at high risk of stroke onnolly N Engl J Med 2009;361:1139; Patel N Engl J Med :883; Granger N Engl J Med 2011;365:981; Ruff Am Heart J 2010;160:635

3 Patient haracteristics Across SPAF Trials % of Study Patients * # # *HF or LVEF 40%; #HF or LVEF 35% With over patient-years of exposure, the RKET AF trial provides the largest prospective experience involving high-risk elderly patients with AF using oral anticoagulation with rivaroxaban onnolly N Engl J Med 2009;361:1139; Patel N Engl J Med :883;Granger N Engl J Med 2011;365:981; Ruff Am Heart J 2010;160:635

4 RKET AF Rivaroxaban vs warfarin Patient characteristics haracteristic Rivaroxaban (N=7,131) Warfarin (N=7,133) HADS 2 score, mean ± SD 3.48 ± ± , n (%) 925 (13.0) 934 (13.1) 3, n (%) 3,058 (42.9) 3,158 (44.3) 4, n (%) 2,092 (29.3) 1,999 (28.0) 5, n (%) 932 (13.1) 881 (12.4) 6, n (%) 123 (1.7) 159 (2.2) o-existing conditions, n (%) Previous stroke/tia or SE 3,916 (54.9) 3,895 (54.6) ongestive heart failure 4,467 (62.6) 4,441 (62.3) Hypertension 6,436 (90.3) 6,474 (90.8) Diabetes mellitus 2,878 (40.4) 2,817 (39.5) Previous MI 1,182 (16.6) 1,286 (18.0) Peripheral vascular disease 401 (5.6) 438 (6.1) hronic obstructive pulmonary disease 754 (10.6) 743 (10.4) rl, median (25th, 75th), ml/min 67 (52, 88) 67 (52, 86) ITT population Patel MR et al. N Engl J Med 2011;365:

5 cumulative event rate (%) RKET AF: Efficacy 6 Primary endpoint: stroke or systemic embolism Warfarin 2.2% events/year Rivaroxaban 1.7% events/year 20 mg 1x/day (rl ml/min: 15 mg 1x/day) HR=0.79 ( ) p=0.02 (for superiority) years RRR: relative risk reduction; HR: Hazard Ratio; NNT = Number Needed to Treat Stroke prevention in non valvular atrial fibrillation. Patel MR. NEJM 2011 n=14'143 (as-treated safety population).

6 RKET AF Primary efficacy endpoint - components Rivaroxaban (N=7,061) Warfarin (N=7,082) Endpoints n (% per year) n (% per year) HR (95% I) HR and 95% Is Primary efficacy endpoint 189 (1.7) 243 (2.2) 0.79 (0.65, 0.95)* All-cause stroke 184 (1.7) 221 (2.0) 0.85 (0.70,1.03) Haemorrhagic stroke 29 (0.3) 50 (0.4) 0.59 (0.37,0.93)* Ischaemic stroke 149 (1.3) 161 (1.4) 0.94 (0.75,1.17) Unknown stroke type 7 (0.1) 11 (0.1) 0.65 (0.25,1.67) Non-NS systemic embolism 5 (0.04) 22 (0.2) 0.23 (0.09, 0.61)* Safety population on-treatment analysis *Statistically significant Favours rivaroxaban Favours warfarin Patel MR et al. N Engl J Med 2011;365:

7 RKET AF Rivaroxaban vs warfarin Results: Safety Parameter Rivaroxaban (N=7,111) n (% per year) Warfarin (N=7,125) n (% per year) HR (95% I) Principal safety endpoint 1,475 (14.9) 1,449 (14.5) 1.03 (0.96,1.11) HR and 95% Is Major bleeding 395 (3.6) 386 (3.4) 1.04 (0.90,1.20) Haemoglobin drop ( 2 g/dl) 305 (2.8) 254 (2.3) 1.22 (1.03,1.44)* Transfusion 183 (1.6) 149 (1.3) 1.25 (1.01,1.55)* ritical organ bleeding 91 (0.8) 133 (1.2) 0.69 (0.53,0.91)* Intracranial haemorrhage 55 (0.5) 84 (0.7) 0.67 (0.47,0.93)* Fatal bleeding 27 (0.2) 55 (0.5) 0.50 (0.31,0.79)* Non-major clinically relevant bleeding 1,185 (11.8) 1,151 (11.4) 1.04 (0.96,1.13) Major bleeding from gastrointestinal site (upper, lower and rectal): rivaroxaban = 224 events (3.2%); warfarin = 154 events (2.2%); p<0.001* Safety population on-treatment analysis. *Statistically significant Patel MR et al. N Engl J Med 2011;365: Favours Favours rivaroxaban warfarin

8 RKET AF: Subanalysis efficacy omparison of patients without prior stroke/tia vs. patients with prior stroke/tia umulative event rate - stroke/se (%) Primary efficacy endpoint: Stroke or SE With prior stroke/tia: Warfarin Without prior stroke/tia: Warfarin With prior stroke/tia: Rivaroxaban Without prior stroke/tia: Rivaroxaban Intention-to-treat population Months from randomization Hankey GJ et al. Lancet Neurol 2012;11(4):

9 RKET AF: Subanalysis secondary prevention Results omparison of patients without prior stroke vs. patients with prior stroke Efficacy endpoints Without prior stroke or TIA (n=6,729) With prior stroke or TIA (n=7,414) Endpoint Rivaroxaban Events/yr (nr*) Warfarin Events/yr (nr*) HR (95% I) Rivaroxaban Events/yr (nr*) Warfarin Events/yr (nr*) HR (95% I) p-value Any stroke or non-ns systemic embolism ( ) ( ) Any stroke ( ) ( ) Haemorrhagic stroke ( ) ( ) Ischaemic or unknown stroke ( ) ( ) Safety on-treatment population.these results support the use of rivaroxaban as an alternative to warfarin for prevention of recurrent as well as initial stroke. * nr=number of events Hankey GJ et al. Lancet Neurol 2012;11(4):

10 RKET AF: Subanalysis Safety omparison of patients without prior stroke/tia vs. patients with prior stroke/tia Safety endpoints Rivaroxaban Events/yr (nr*) Warfarin Events/yr (nr*) Without prior stroke or TIA With prior stroke or TIA HR (95% I) p-value Principal safety bleeding endpoint (785) (690) (743) (706) 1.10 ( ) 0.96 ( ) 0.08 Major bleeding 4.10 (217) 3.13 (178) 3.69 (203) 3.22 (183) 1.11 ( ) 0.97 ( ) 0.36 Fatal bleeding 0.22 (12) 0.26 (15) 0.48 (27) 0.49 (28) 0.46 ( ) 0.54 ( ) 0.74 Intracranial haemorrhage 0.39 (21) 0.59 (34) 0.68 (38) 0.80 (46) 0.57 ( ) 0.74 ( ) 0.47 Intracerebral haemorrhage 0.24 (13) 0.45 (26) 0.52 (29) 0.54 (31) 0.46 ( ) 0.84 ( ) 0.16 Extracerebral 0.18 (10) haemorrhage 0.17 (10) Non-major clinically relevant bleeding (620) (565) 0.30 (17) 0.35 (20).equally safe in both subgroups (585) (566) 0.61 ( ) 0.50 ( ) 1.10 ( ) 0.99 ( ) Safety on-treatment population Favours rivaroxaban Favours warfarin * nr=number of events; 17 intracranial haemorrhages were considered both intracerebral and extracerebral. Includes intraparenchymal and intraventricular haemorrhage. ne intraparenchymal haemorrhage that occurred with extracerebral haematoma was classified as traumatic. Includes subarachnoid haemorrhage, subdural haematoma, and epidural haematoma. Hankey GJ et al. Lancet Neurol 2012;11(4):

11 RKET AF Subanalysis heart failure omparison of patients without HF vs. patients with HF Safety endpoints by treatment and HF utcome With HF Without HF Hazard ratio (95% I) p-value (interaction) Major or NMR bleeding 1.05 ( ) 1.05 ( ) 0.99 Haemorrhagic stroke 0.38 ( ) 0.91 ( ) Intracranial haemorrhage 0.63 ( ) 0.72 ( ) Rivaroxaban better Warfarin better. similar treatment-related outcomes in patients with and without HF and across HF subgroups. Van Diepen S et al. irc Heart Fail 2013;6(4):

12 V Death, MI, or unstable angina (%) RKET AF Subanalysis ischaemic cardiac outcomes: omparison of pts without MI (83%) vs. patients with MI (17%) Primary efficacy endpoint: V death, MI, and UA With prior MI: Warfarin Without prior MI: Warfarin With prior MI: Rivaroxaban Without prior MI: Rivaroxaban Prior MI was common and associated with substantial risk for subsequent cardiac events No significant difference between VKA and rivaroxaban group Safety on-treatment population Days from randomization V=cardiovascular; MI=myocardial infarction; UA=unstable angina Mahaffey KW et al. Eur Heart J 2014 Jan;35(4):233-41

13 Rate of all-cause mortality RKET AF: Subanalysis Type of AF Results Higher risk of death and stroke in patients with persistent vs. paroxysmal atrial fibrillation All-cause mortality 0,12 0,10 Adjusted HR paroxysmal (95% I ) = 0.79 ( ) p= ,08 0,06 Persistent AF Paroxysmal AF 0,04 0,02 0,00 Months since randomization No. at risk Persistent 11,485 11,255 10,962 8,113 4,975 2,134 Paroxysmal 2,490 2,451 2,404 1,830 1, Benjamin A. Steinberg1*, European Heart Journal doi: /eurheartj/ehu359

14 Lip YH, Windecker S et. al EHJ 2014.

15 Management of pts with PI and need of anticoagulation in nonvalvular atrial fibrillation HA 2 DS 2 -VASc < 1 HA 2 DS 2 -VASc > 2 HAS-BLED > 3 HAS-BLED < 2 DAPT IIa IIa SAD AS IIa IIb B (N)A* + DAPT for 1 month, then (D)A + SAPT (6-) 12 months (N)A* + DAPT for (3-)6 months then (D)A + SAPT up to 12 months (N)A* + lopidogrel up to 12 months Legende: DAPT: dual antiplatelet therapy (ASS 100mg und lopidogrel) SAPT: single antiplatelet therapy (lopidogrel) DA-dose reduction in pts with Triple-therapy: 2x110mg Dabigatran/d, 15mg Rivaroxaban/d, 2x2.5mg Apixaban/d SAD: stable coronary artery disease Adapted: 2014 ES/EATS Guidelines on myocardial Revascularization. European Heart Journal (2014) 35,

16 % patients All AS patients -Triple therapy at discharge (ASA and VKA/NA and P2Y12 inhibitors) N= ,0 6,0 5,0 4,0 3,0 2,0 1,0 0,0 Trend: Increased number of patients with triple tx at discharge since 1997

17 patients Trends in triple antithrombotic therapy at discharge in AS patients with atrial fibrillation at admission (n=294) 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Increasing rate of ombination of newer P2Y12 inhibitors together with A - In hospital bleeding, in hospitaloutcome, at 1 yr? Increasing rate of triple tx with NAs A or NA & Prasugrel or Ticagrelor NA & ASA & lopidogrel A & ASA & lopidogrel Unpublished data

18 pen question: Potential Role (Risks and benefits) of NAs in AS no interaction with (dual) antiplatelet therapy on both efficacy and bleeding in the AF trials with NA it might be assumed that the respective advantages of the NA over VKA are maintained in dual or triple therapy. In addition, there was also no interaction between SAPT vs. DAPT in the AS trials with the NAs apixaban and rivaroxaban Not enough data of the AMIS-plus population to make any conclusion more data needed!

19 Summary I RKET provides the largest prospective experience involving high-risk elderly patients with AF comparing Warfarin vs. Rivaroxaban Efficacy: Significantly fewer cases of haemorrhagic stroke were observed in patients on rivaroxaban Safety: less fatal/intracranial bleedings and more gastrointestinal bleedings in patients on rivaroxaban

20 Summary II Subanalysis: onsistent efficacy and safety of rivaroxaban compared with warfarin in pts without prior stroke and with prior stroke similar treatment-related outcomes in patients with and without HF and across HF subgroups Prior MI was common (17%) and associated with substantial risk for subsequent cardiac events Persistent Afib subgroup associated with higher subsequent all-cause mortality rate

21 Summary III An increasing number of AS patients with Afib in Switzerland gets triple antithrombotic therapy with NAs In contrast of to the guidelines a substantial number of AS Afib patients is treated with Prasugrel or Ticagrelor in combination with anticoagulation (VKA or NAs) ngoing Rivaroxan Study (PINEER-PI) is addressing the safety aspects of this clinically important question (PI in Afib)

22 Back-up information

23 RKET AF Rivaroxaban vs warfarin Patient characteristics haracteristic Rivaroxaban (N=7,131) Warfarin (N=7,133) Age, median (25th, 75th), years 73 (65, 78) 73 (65, 78) Female, % Body mass index, median, kg/m Blood pressure, median, mm Hg Systolic Diastolic linical presentation, n (%) Type of AF Persistent 5,786 (81.1) 5,762 (80.8) Paroxysmal 1,245 (17.5) 1,269 (17.8) Newly diagnosed/new onset 100 (1.4) 102 (1.4) Previous ASA use 2,586 (36.3) 2,619 (36.7) Previous VKA use 4,443 (62.3) 4,461 (62.5) ITT population Patel MR et al. N Engl J Med 2011;365:

24 RKET AF Rivaroxaban vs warfarin Secondary endpoints Endpoints Rivaroxaban (N=7,061) n (% per year) Warfarin (N=7,082) n (% per year) HR (95% I) omposite of stroke, nonns SE, vascular death omposite of stroke, non-ns SE, vascular death and MI 346 (3.1) 410 (3.6) 0.86 (0.74, 0.99)* 433 (3.9) 519 (4.6) 0.85 (0.74, 0.96)* omponents of major secondary endpoints All-cause stroke 184 (1.7) 221 (2.0) 0.85 (0.70, 1.03) Non-NS SE 5 (0.04) 22 (0.2) 0.23 (0.09, 0.61)* MI 101 (0.9) 126 (1.1) 0.81 (0.63, 1.06) Vascular death 170 (1.5) 193 (1.7) 0.89 (0.73, 1.10) All-cause mortality 208 (1.9) 250 (2.2) 0.85 (0.70, 1.02) Safety population on-treatment analysis. *Statistically significant Patel MR et al. N Engl J Med 2011;365:

25 Nonvalvular Atrial Fibrillation L.H.H DE/EN STEP 1 - Stroke risk HA 2 DS 2 -VASc = 1 HA 2 DS 2 -VASc 2 STEP 2 - Bleeding risk Low to intermediate (e.g. HAS-BLED = 0-2) High (e.g. HAS-BLED 3) Low to intermediate (e.g. HAS-BLED = 0-2) High (e.g. HAS-BLED 3) STEP 3 - linical setting Stable AD AS Stable AD AS Stable AD AS Stable AD AS If PI is performed If PI is performed If PI is performed If PI is performed 0 Triple or dual therapy* Triple or dual therapy* Triple or dual therapy* Triple or dual therapy* 4 weeks A or DAPT Triple therapy A Dual therapy A Triple or dual therapy* Triple therapy A A A A STEP 4 Antithrombotic therapy 6 months 12 months A Dual therapy** A A or or DAPT Dual therapy** A or or DAPT Dual therapy** A A or Dual therapy** A or Triple or dual therapy* A Dual therapy** A or Dual therapy** A or Lifelong Monotherapy*** Monotherapy*** Time from PI/AS Lip YH, Windecker S et. al EHJ ral Anticoagulation A Aspirin mg daily lopidogrel 75 mg daily

26 L.H.H DE/EN onsensus recommendation - AF & AS / stable AD 1. In AF patients, stroke risk must be assessed using the HA2DS2-VASc score, and bleeding risk using the HAS-BLED score. (lass I ). 2. Where a NA is combined with clopidogrel and/or low-dose ASA, the lower tested dose for stroke prevention (dabigatran 110 mg b.i.d., rivaroxaban 15 mg qd or apixaban 2.5 mg b.i.d.) may be considered (lass IIb ). 3. In patients with AF and stable vascular disease the patient should be managed with A alone (i.e. whether NA or a VKA) (lass IIa B). 4. Novel P2Y12 receptor inhibitors (prasugrel and ticagrelor) should not be part of a triple therapy regimen in patients with AF (lass III ). Lip YH, Windecker S et. al EHJ 2014.

27 L.H.H DE/EN onsensus recommendation - AF & stable AD 1. Stable AD and AF at low-bleeding risk (HAS-BLED 0 2) triple therapy (A, ASA mg qd, clopidogrel 75 mg qd) for at least 4 weeks (no longer than 6 months) after PI (lass IIa ). followed by dual therapy with A (NA or VKA) and clopidogrel 75 mg/d (or ASA mg/d) for up to 12 months (lass IIa ). HA2DS2-VASc=1 at low-bleeding risk (HAS-BLED 0 2), DAPT (ASA mg and clopidogrel 75 mg), or dual therapy (A: NA or VKA) and clopidogrel 75 mg/d should be considered (lass IIa ). Dual therapy of A (i.e. NA or a VKA) and clopidogrel 75 mg/day may be considered as an alternative to initial triple therapy in selected patients with HA2DS2-VASc 2 (lass IIb ). 2. Stable AD and AF at high-bleeding risk (HAS-BLED >3) triple therapy (A, ASA mg, clopidogrel 75 mg) or dual therapy consisting of A (NA or VKA) and clopidogrel 75 mg/day for 4 weeks followed by dual therapy with A and clopidogrel 75 mg/d (or ASA mg/d) for up to 12 months (lass IIa ). HA2DS2-VASc=1 at high-bleeding risk (HAS-BLED >3) DAPT (ASA mg and clopidogrel 75 mg/day, or dual therapy consisting of A (NA or VKA) and clopidogrel 75 mg/day may be considered (lass IIb ) for 12 months. Lip YH, Windecker S et. al EHJ 2014.

28 L.H.H DE/EN onsensus recommendation - AF & stable AD 3. Long-term antithrombotic therapy with A (NA or VKA) (beyond 12 months) is recommended in all patients (lass I B). ombination A plus single antiplatelet therapy (clopidogrel 75 mg/day or ASA mg/day)] may be considered in very selected cases, e.g. stenting of the left main, proximal left anterior descending, proximal bifurcation, recurrent MIs, etc. (lass IIb, ). 4. Gastric protection with PPIs should be considered in patients with A plus antiplatelet therapy (lass IIa, ). Lip YH, Windecker S et. al EHJ 2014.

29 RKET-AF: Wirksamkeit Ref.: Fachinformation XARELT