Nuovi Anticoagulanti orali:
dai criteri di scelta all’esperienza sul campo
RIVAROXABAN
Dr. Elisabetta Toso
SOC Cardiologia
Ospedale Cardinal Massaia - Asti
THE RIVAROXABAN
HISTORY
FDA
Approves Rivaroxaban
For NVAF, DVT and PE
Oral Inhibitors
Antistasin
(FXa inhibitor)
ROCKET-AF
EINSTEIN-DVT
EUROPE
Approves Rivaroxaban
For ACS
Rivaroxaban
EINSTEIN-PE
ATLAS TMI 51 ACS
Xabans i.v.
1905-1980
1980-1990
2000
2011-2012
Years
2013
DABIGATRAN
150 bid or 110 bid
APIXABAN
5 bid or 2.5 bid
RIVAROXABAN
20 or 15 od
EDOXABAN
30 or 60 od
Name
Pradaxa
Eliquis
Xarelto
Lixiana
Target
Direct IIa
inhibitor
Factor Xa
inhibitor
Factor Xa
inhibitor
Factor Xa
inhibitor
Bioavailability
7%
80%
80%
40%
Half-life (T ½)
12-17 h
12 h
7-11 h
8-10
T max h
2-4 h
3-4 h
2-4 h
1-5 h
Clearence
80% renal
25% renal
75% biliary
60% renal
33% biliary
40% renal
Drug interaction
Amiodarone ()
Quinidine ()
Verapamil ()
Diltiazem ()
Ketoconazolo()
Ritonavir()
Ketokonazole()
Quinidine()
Quinidine()
Verapamil()
P-gp competition
CYP3A4 inhibition
DABIGATRAN
Coagulation
tests
aPTT
ECT
RIVAROXABAN
EDOXABAN
Anti-Fxa
chromogenic
assays
PT
Anti-Fxa
chromogenic
assays
PT
Anti-Fxa
chromogenic
assays
PCC 25 U/Kg
aPCC 50 IE/Kg
rFVIIa 90 mcg/Kg
Bleedings
management
Antidote
APIXABAN
IDARUCIZIMAB
(Boehringer Ing.)
RE-Verse AD study
ANDEXANET ALFA
(Portola)
ANNEXA- A study
Indications
Prophylaxis
Treatment
VTE
NVAF
VTE
ACS
10 mg od
15 or 20 mg od
15 mg bid 21 days

20 mg od
2.5 mg bid +
antiplatelets
ROCKET AF
14264 patients
Mean age 73 y, 80% persistent AF, mean CHADS2 score 3.5
Stroke or systemic embolism
Warfarin
(2.4%/y)
Rivaroxaban
(2.1%/y)
Days
Patel et al. NEJM 2011
ROCKET AF – all-cause mortality
Rivaroxaban
(N=7,061)
Warfarin
(N=7,082)
n
(% per year)
n
(% per year)
Hazard ratio
(95% CI)
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)
Endpoints
All-cause mortality
Hazard ratio
and 95% CIs
0.2
0.5
1
Favours
rivaroxaban
2
5
Favours
warfarin
Safety population – on-treatment analysis
Patel MR et al, NEJM 2011.
ROCKET AF – bleeding analysis
Rivaroxaban
(N=7,111)
Warfarin
(N=7,125)
n (% per year)
n (% per year)
Hazard ratio
(95% CI)
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)*
55 (0.5)
84 (0.7)
0.67 (0.47,0.93)*
27 (0.2)
55 (0.5)
0.50 (0.31,0.79)*
1,185 (11.8)
1,151 (11.4)
1.04 (0.96,1.13)
Parameter
Intracranial
haemorrhage
Fatal bleeding
Non-major clinically
relevant bleeding
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
Hazard ratio
and 95% CIs
0.2
0.5
1
Favours
rivaroxaban
2
5
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.
www.fda.gov
¨ nt er Br eit har dt 1* , H elm ut Baum gar t ner 2, Scot t D. Ber kowit z 3, A nne S. H ellkam p 4,
Gu
Jonat han P. Piccini 4, Susanna R. St evens4, Yuliya Lokhnygina4, Manesh R. Pat el 4,
Jonat han L. H alper in 5, Daniel E. Singer 6, Gr aem e J. H ankey 7, W er ner H acke8,
Richar d C. Becker 4, Chr ist opher C. N essel 9, Kennet h W . Mahaffey 10, Keit h A . A . Fox 11,
and Rober t M. Califf 12, for t he RO CKET A F St eer ing Com m it t ee & Invest igat or s
Valvular Heart Disease 1992 pts (14%)
90% mitral regurgitation (only 3% post-rheumatic)
1
Stroke or SE
Major Bleedings
Department of Cardiovascular Medicine, Division of Electrophysiology, University Hospital Mu
¨ nster, Von-Esmarch-Str asse 117, Mu
¨nster D-48149, Germany; 2Department of
Cardiovascular Medicine, Division of Adult Congenital and Valvular Heart Disease, University Hospital Mu
¨nster, Mu
¨ nster, Germany; 3Bayer Healthcare Pharmaceuticals, L.P., W hippany,
NJ, USA; 4Duke Clinical Research Institute, Duke University Medical Center, Durham, NC, USA; 5The Cardiovascular Institute, Mount Sinai Medical Center, New York, NY,USA; 6Clinical
Epidemiology Unit, General MedicineDivision,Massachusetts General Hospital,and Harvard Medical School,Boston, MA,USA; 7School of Medicine and Pharmacology, TheUniversity of
Western Australia, Perth, Australia; 8Ruprecht-Karls-University, Heidelberg, Germany; 9Johnson & Johnson Pharmaceutical Research & Development, Raritan, NJ, USA; 10Department of
Medicine, Stanford University, Stanfor d, CA, USA; 11University of Edinburgh, and Royal Infirmary of Edinburgh, Edinburgh, UK; and 12Duke Translational Medicine Institute, Duke
University Medical Center, Durham, NC, USA
6,14
2,43
Received 27 February 2014; revised 11 June 2014; accepted 16 July 2014
2,01
• Rivaroxaban
• Warfarin
% Events/100 pts/y
% Events/100 pts/y
P 0,76
P 0,01
4,20
We investigated clinical characteristics and outcomes of patients with significant valvular disease (SVD) in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and
Embolism Trial in Atrial Fibrillation (ROCKET AF) trial.
.....................................................................................................................................................................................
M et hods
ROCKET AFexcluded patientswith mitral stenosisor artificial valveprostheses.Weused Cox regression to adjust comparand r esul t s
isonsfor potential confounders.Among14 171patients,2003(14.1%) hadSVD;theywereolder andhadmorecomorbidities
than patients without SVD. The rate of stroke or systemic embolism with rivaroxaban vs. warfarin was consistent among
patients with SVD [2.01 vs. 2.43%; hazard ratio (HR) 0.83, 95% confidence interval (CI) 0.55–1.27] and without SVD
(1.96 vs.2.22%;HR0.89, 95%CI 0.75–1.07;interaction P¼ 0.76). However,ratesof major and non-major clinically relevant
bleedingwith rivaroxabanvs.warfarin werehigher in patientswith SVD (19.8%rivaroxaban vs.16.8%warfarin;HR1.25,95%
CI 1.05–1.49) vs. those without (14.2%rivaroxaban vs. 14.1%warfarin; HR1.01, 95%CI 0.94–1.10; interaction P¼ 0.034),
even when controlling for risk factors and potential confounders. In intracranial haemorrhage, there was no interaction
between patients with and without SVD where the overall rate waslower amongthose randomized to rivaroxaban.
.....................................................................................................................................................................................
Conclusions
Many patients with ‘non-valvular atrial fibrillation’ have significant valve lesions. Their risk of stroke is similar to that of
A im s
Downloaded from http://eurheartj.oxfordjournals.org/ at BIBLIOTECHE BIOMEDICHE UNIVERSITA' DEGLI STUDI DI TORINO on September
Clinical char act er ist ics and out com es wit h
r ivar oxaban vs. war far in in pat ient s wit h
non-valvular at r ial fibr illat ion but under lying
nat ive m it r al and aor t ic valve disease
par t icipat ing in t he ROCKET AF t r ial
Breithardt G. et al Eur Heart Journal 2014
• 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 DISEASE
HYPERTROPHIC CARDIOMYOPATHY
ELECTRICAL CARDIOVERSION
Electrical Cardioversion on warfarin
Sintomatic cerebrovascular complications
13/ 5247 pts
0.24%
0.7%
0.5%
0.4%
0.3%
0
1841 pts
664 pts
521 pts
275 pts
1946 pts
Electrical Cardioversion on NOACs
Sintomatic cerebrovascular complications
CHADS 3.5
1.6%
9/1708 pts
0,52%
CHADS 2.1-2.2
0.8%
CHADS 2.1
0.30%
0
647 pts
672 pts
Nagarakanti R et al Circulation 2011
265 pts
Piccinini et al JACC 2013
265 pts
Flaker G. et al JACC 2014
Rivaroxaban vs. vitamin K antagonists
for cardioversion in atrial fibrillation
1504
Riccar do Cappat o 1†, Michael D. Ezekowit z 2†* , Allan L.
Klein 3, A. John
Cam m 4,
X-VERT
Trial
patients,
141 Centres
across 16Le
countries
Chang-Sheng
Ma5, Jean-Yves
Heuzey 6, Mar io Talajic 7, Maur ´ıcio Scanavacca8,
Panos E. Var das9, Paulus Kir chhof 10,11,12, Melanie Hem m r ich 13, Vivian Lanius14,
Isabelle Ling Meng13,Finland
Pet er W ildgoose15, Mart in van Eickels13, and Stefan H. Hohnlose
UK
on behalf of the X -VeRT Investigators
Italy:
•
•
•
•
Canada
USA
Botto GL
Calò L
Cappato R
Capucci A
Netherlands
Denmark
Arrhythmia and
Electrophysiology Center, University
of Milan, IRCCSPoliclinico San Donato, San Donato Milanese, Milan, Italy; 2TheSidney Kimell Medical College at Thomas
Germany
Belgium
University,1999 Sproul
Rd,Suite 25,Broomall, PA 19008,USA; 3Department of Cardiovascular Medicine,Cleveland Clinic Heart and Vascular Institute, Cleveland, OH,USA; 4D
France
Clinical Sciences, St George’s, University of London, London, UK; 5Cardiology Division, Beijing AnZhen Hospital, Capital Medical University, Beijing, China; 6Division of Cardio
Portugal
ˆ pital Europe´enGeorgesPompidou, Universite´ ParisVRene´ -Descartes, Paris, France; 7Department of Medicine, Research Center,Montreal Heart Institute, U
Arrhythmology,Ho
de Montre´al, Montreal,
Canada; 8Arrhythmia Clinical Greece
Unit of Heart Institute (InCor), University of Sa˜ o Paulo Medical School, Sa
˜ o Paulo, Brazil; 9Department of Cardiology, H
Spain
10
China
University Hospital, Heraklion (Crete),Greece; Centrefor Cardiovascular Sciences, School of Clinical and Experimental Medicine,University of Birmingham, Birmingham, UK;
NHSTrust, Birmingham, UK; 12Department of Cardiovascular Medicine, Hospital of the University of Mu¨ nster, Mu¨ nster, Germany; 13Global Medical Affairs, Bayer HealthCar
Germany; 14Global Research and Development Statistics,Bayer HealthCare, Berlin, Germany; 15Janssen Scientific Affairs, LLC,Raritan,NJ,USA;and 16Department of Cardiology
of Clinical Electrophysiology, J.W. Goethe University, Frankfurt, Germany
1
• Gaita F
• Grimaldi M
• Gulizia MM
X-VeRT isthefirst prospectiverandomized trial of anovel oral anticoagulant in patientswith atrial fibrillation unde
• Themistoclakis S
elective cardioversion.
Received 23 July 2014; revised 7 August 2014; accepted 11 August 2014
Singapore
A im s
............................................................................................................................................................................
South Africa
M et hods
Weassigned1504patientsto
rivaroxaban(20 mgoncedaily,15 mgifcreatinineclearancewasbetween30and49 m
and r esult s
or dose-adjustedvitaminKantagonists(VKAs) ina2:1ratio.Investigatorsselectedeither anearly(target periodof1–
after randomization) or delayed (3–8 weeks)
cardioversion
efficacyoutcomewasthecompo
Cappato
R. strategy.Theprimary
et al. Eur Heart
Journal 2014
stroke, transient ischaemic attack, peripheral embolism, myocardial infarction, and cardiovascular death. The p
Randomized, open-label, parallel-group,
active-controlled multicentre study
Inclusion criteria:
R
2:1
Cardioversion
strategy
1–5 days
VKA
Rivaroxaban
20 mg od*
Delayed
R
2:1
≥21 days
(max. 56 days)
VKA
Rivaroxaban 20
mg od*
42 days
VKA
Rivaroxaban
20 mg od*
42 days
End of study treatment
Early#
Cardioversion
Rivaroxaban 20
mg od*
Cardioversion
Age ≥18 years, non-valvular AF lasting >48 h or unknown duration, scheduled for cardioversion
OAC
30-day
follow-up
VKA
*15 mg if CrCl 30–49 ml/min; VKA with INR 2.0–3.0;
#protocol recommended only if adequate anticoagulation or immediate TEE
Ezekowitz MD et al. Am Heart J 2014;167:646–652;
X-VeRT: clinical characteristics
Total
(N=1504)
Rivaroxaban
(n=1002)
VKA
(n=502)
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
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±1.6
Age, mean SD, years
Previous stroke/TIA or SE, %
Cappato R et al. Eur Heart J 2014
X-VeRT: Stroke or TIA
768/872 early CV performed
399/632 delayed CV performed
1,08%
0,9%
0.7%
0.2%
567 pts
277 pts
321 pts
78 pts
Cappato R et al. Eur Heart J 2014
X-VeRT: time to cardioversion
Patients cardioverted as scheduled
p<0.001
Delayed cardioversion
Patients (%)
Rivaroxaban: 841/1002 pts (84%)
Warfarin: 385/502 pts (77%)
1 patient with
inadequate
anticoagulation
95 patients with
inadequate
anticoagulation
Rivaroxaban: 321/417 pts (77%)
Warfarin: 78/215 pts (36.3%)
Cappato R et al. Eur Heart J 2014
X-VeRT: time to cardioversion
Median time to cardioversion
100
80
Days
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)
Rivaroxaban
VKA
60
p<0.001
p=0.628
40
22
days
20
0
Early
30
days
Delayed
Cappato R et al. Eur Heart J 2014
Thanks for your attention!
Thrombosis Research Global Forum 2014, Berlin 6-8 November