Nuovi Anticoagulanti orali: dai criteri di scelta all’esperienza sul campo

RIVAROXABAN

Dr. Elisabetta TosoSOC Cardiologia

Ospedale Cardinal Massaia - Asti

2011-2012Years

1980-1990

Xabans i.v.

THE RIVAROXABAN HISTORY

1905-1980

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

NVAF15 or 20 mg od

VTE10 mg od

ACS2.5 mg bid +antiplatelets

VTE15 mg bid 21 days

20 mg od

Warfarin Warfarin (2.4%/y)(2.4%/y)

RivaroxabanRivaroxaban(2.1%/y)(2.1%/y)

14264 patientsMean age 73 y, 80% persistent AF, mean CHADS2 score 3.5

Patel et al. NEJM 2011Patel et al. NEJM 2011

ROCKET AFROCKET AF

DaysDays

Stroke or systemic embolism

ROCKET AF – all-cause mortality

Safety population – on-treatment analysis

Hazard ratio and 95% CIs

0.2 0.5 1 2 5Favours

rivaroxabanFavours warfarin

Endpoints

Rivaroxaban (N=7,061)

Warfarin (N=7,082)

Hazard ratio (95% CI)

n(% per year)

n(% per year)

All-cause mortality 208 (1.9) 250 (2.2) 0.85 (0.70,1.02)

Vascular death 170 (1.5) 193 (1.7) 0.89 (0.73, 1.10)

Non-vascular death 21 (0.2) 34 (0.3) 0.63 (0.36, 1.08)

Unknown cause 17 (0.2) 23 (0.2) 0.75 (0.40, 1.41)

Patel MR et al, NEJM 2011.Patel MR et al, NEJM 2011.

Parameter

Rivaroxaban (N=7,111)

Warfarin (N=7,125)

Hazard ratio (95% CI)n (% per year) n (% per year)

Principal safety endpoint

1,475 (14.9) 1,449 (14.5) 1.03 (0.96,1.11)

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)*

Critical 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)

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

0.2 0.5 1 2 5Favours

rivaroxabanFavours warfarin

Patel MR et al, NEJM 2011.Patel MR et al, NEJM 2011.

What about Rivaroxaban and..

VALVULAR HEART DISEASEHYPERTROPHIC 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.

www.fda.gov

Breithardt G. et al Eur Heart Journal 2014

Valvular Heart Disease 1992 pts (14%)90% mitral regurgitation (only 3% post-rheumatic)

Stroke or SE Major Bleedings

P 0,76

• Rivaroxaban • Warfarin

P 0,01

% E

vent

s/10

0 pt

s/y

2,01

2,43

6,14

4,20

% E

vent

s/10

0 pt

s/y

• In HCM pts CHA2DS2VASC 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 DISEASEHYPERTROPHIC CARDIOMYOPATHY

ELECTRICAL CARDIOVERSION

Electrical Cardioversion on warfarin

664 pts1841 pts 521 pts 275 pts 1946 pts

0.7%

0.5%

0.4%0.3%

0

13/ 5247 pts0.24%

Sintomatic cerebrovascular complications

Electrical Cardioversion on NOACs

647 pts 672 pts

0.8%

265 pts

0.30%

0

Sintomatic cerebrovascular complications

Flaker G. et al JACC 2014Nagarakanti R et al Circulation 2011

265 pts

1.6%

Piccinini et al JACC 2013

9/1708 pts0,52%

CHADS 2.1-2.2

CHADS 2.1

CHADS 3.5

Cappato R. et al. Eur Heart Journal 2014

X-VERT Trial1504 patients, 141 Centres across 16 countries

GermanyFrance

Netherlands

UK

South Africa

Canada Belgium

China

Denmark

Finland

SpainPortugal

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

Cardioversionstrategy

1–5 daysR

Rivaroxaban 20 mg od*

VKA2:1

2:1

≥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

42 days

Rivaroxaban 20 mg od*

VKA

Rivaroxaban 20 mg od*

VKA

End

of

stud

y tr

eatm

ent

Car

dio

vers

ion

Car

dio

vers

ion

Total(N=1504)

Rivaroxaban(n=1002)

VKA(n=502)

Age, mean SD, years 64.9 ±10 64.9±10 64.7±10

Male, % 72.7 72.6 73.1

Persistent 53.9 55.9 50.0

Hypertension, % 66.2 65.0 68.7

Renal function/CrCI, % ≥80 ml/min

60.2 61.5 57.6

Prior OAC use for ≥6 weeks, % 42.8 42.3 43.8

Previous stroke/TIA or SE, % 7.7 6.7 9.8

CHADS2 score, mean SD 1.4±1.1 1.3±1.1 1.4±1.1

CHA2DS2-VASc score, mean SD 2.3±1.6 2.3±1.6 2.3±1.6Cappato 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<0.001

1 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%)

Pati

ents

(%

)

Delayed cardioversion

Rivaroxaban: 321/417 pts (77%)Warfarin: 78/215 pts (36.3%)

Median time to cardioversion

Day

s

0

20

40

60

80

100

Early Delayed

p=0.628

p<0.001

RivaroxabanVKA

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!