Nuovi Anticoagulanti orali: dai criteri di scelta all’esperienza sul campo RIVAROXABAN Dr. Elisabetta Toso SOC Cardiologia Ospedale Cardinal Massaia - Asti

Years Xabans i.v. THE RIVAROXABAN HISTORY Antistasin (FXa inhibitor) 2000 Oral Inhibitors Rivaroxaban FDA Approves Rivaroxaban For NVAF, DVT and PE ROCKET-AF EINSTEIN-DVT EINSTEIN-PE 2013 ATLAS TMI 51 ACS EUROPE Approves Rivaroxaban For ACS

Indications Prophylaxis Treatment NVAF 15 or 20 mg od VTE 10 mg od ACS 2.5 mg bid + antiplatelets VTE 15 mg bid 21 days  20 mg od

Warfarin(2.4%/y) Rivaroxaban(2.1%/y) patients Mean age 73 y, 80% persistent AF, mean CHADS2 score 3.5 Patel et al. NEJM 2011 ROCKET AF Days Stroke or systemic embolism

ROCKET AF – all-cause mortality Safety population – on-treatment analysis Hazard ratio and 95% CIs Favours rivaroxaban Favours warfarin Endpoints Rivaroxaban (N=7,061) Warfarin (N=7,082) Hazard ratio (95% CI) n (% per year) All-cause mortality208 (1.9)250 (2.2)0.85 (0.70,1.02) Vascular death170 (1.5)193 (1.7)0.89 (0.73, 1.10) Non-vascular death21 (0.2)34 (0.3)0.63 (0.36, 1.08) Unknown cause17 (0.2)23 (0.2)0.75 (0.40, 1.41) Patel MR et al, NEJM 2011.

Parameter Rivaroxaban (N=7,111) Warfarin (N=7,125) Hazard ratio (95% CI) n (% per year) Principal safety endpoint 1,475 (14.9)1,449 (14.5)1.03 (0.96,1.11) Major bleeding395 (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)* Transfusion183 (1.6)149 (1.3)1.25 (1.01,1.55)* Critical organ bleeding91 (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 bleeding27 (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) Safety population – on-treatment analysis; *Statistically significant ROCKET AF – bleeding analysis Major bleeding from gastrointestinal site (upper, lower and rectal): rivaroxaban=224 events (3.2%); warfarin=154 events (2.2%); p<0.001* Hazard ratio and 95% CIs Favours rivaroxaban Favours warfarin Patel MR et al, NEJM 2011.

What about Rivaroxaban and.. VALVULAR HEART DISEASE HYPERTROPHIC CARDIOMYOPATHY ELECTRICAL CARDIOVERSION

NOACs for VALVULAR HD ESC AF Guidelines European Heart Journal 2012 Patients with prosthetic heart valves should not take dabigatran/rivaroxaban/apixaban nor should pts with AF that is caused by a heart valve problem.

Breithardt G. et al Eur Heart Journal 2014 Valvular Heart Disease 1992 pts (14%) 90% mitral regurgitation (only 3% post-rheumatic) Stroke or SEMajor Bleedings P 0,76 Rivaroxaban Warfarin P 0,01 % Events/100 pts/y 2,01 2,43 6,14 4,20 % Events/100 pts/y

In HCM pts CHA 2 DS 2 VASC score to calculate stroke risk is not recommended There are no data on the use of NOACs in HCM pts

What about Rivaroxaban and.. VALVULAR HEART DISEASE HYPERTROPHIC CARDIOMYOPATHY ELECTRICAL CARDIOVERSION

Electrical Cardioversion on warfarin 664 pts 1841 pts 521 pts275 pts1946 pts 0.7% 0.5% 0.4% 0.3% 0 13/ 5247 pts 0.24% Sintomatic cerebrovascular complications

Electrical Cardioversion on NOACs 647 pts672 pts 0.8% 265 pts 0.30% 0 Sintomatic cerebrovascular complications Flaker G. et al JACC 2014Nagarakanti R et al Circulation pts 1.6% Piccinini et al JACC /1708 pts 0,52% CHADS CHADS 2.1 CHADS 3.5

Cappato R. et al. Eur Heart Journal 2014 X-VERT Trial 1504 patients, 141 Centres across 16 countries Germany France Netherlands UK South Africa Canada Belgium China Denmark Finland Spain Portugal USA Singapore Greece Italy: Botto GL Calò L Cappato R Capucci A Gaita F Grimaldi M Gulizia MM Themistoclakis S

30-day follow-up OAC Randomized, open-label, parallel-group, active-controlled multicentre study Early # Delayed Cardioversion strategy 1–5 days R Rivaroxaban 20 mg od* VKA 2:12:1 2:12:1 ≥21 days (max. 56 days) Rivaroxaban 20 mg od* VKA R Inclusion criteria: Age ≥18 years, non-valvular AF lasting >48 h or unknown duration, scheduled for cardioversion Ezekowitz MD et al. Am Heart J 2014;167:646–652; *15 mg if CrCl 30–49 ml/min; VKA with INR 2.0–3.0; # protocol recommended only if adequate anticoagulation or immediate TEE 42 days Rivaroxaban 20 mg od* VKA Rivaroxaban 20 mg od* VKA End of study treatment Cardioversion

Total (N=1504) Rivaroxaban (n=1002) VKA (n=502) Age, mean SD, years64.9 ± ±10 Male, % Persistent Hypertension, % Renal function/CrCI, % ≥80 ml/min Prior OAC use for ≥6 weeks, % Previous stroke/TIA or SE, % CHADS 2 score, mean SD1.4±1.11.3±1.11.4±1.1 CHA 2 DS 2 -VASc score, mean SD2.3±1.6 Cappato R et al. Eur Heart J 2014 X-VeRT: clinical characteristics

X-VeRT: Stroke or TIA 768/872 early CV performed 567 pts 0.7% 277 pts 1,08% 399/632 delayed CV performed 321 pts 0.2% 78 pts 0,9% Cappato R et al. Eur Heart J 2014

p< patient with inadequate anticoagulation 95 patients with inadequate anticoagulation Patients cardioverted as scheduled X-VeRT: time to cardioversion Cappato R et al. Eur Heart J 2014 Rivaroxaban: 841/1002 pts (84%) Warfarin: 385/502 pts (77%) Patients (%) Delayed cardioversion Rivaroxaban: 321/417 pts (77%) Warfarin: 78/215 pts (36.3%)

Median time to cardioversion Days EarlyDelayed p=0.628 p<0.001 Rivaroxaban VKA 22 days 30 days X-VeRT: time to cardioversion Cappato R et al. Eur Heart J 2014 The time between randomization and CV was similar or shorter in Rivaroxaban vs Warfarin Early median 1 (1-2 ) vs 1 (1-3) Delayed 22 (21-26) vs 30 (23-42)

Thrombosis Research Global Forum 2014, Berlin 6-8 November Thanks for your attention!