Rivaroxaban:
importanti evidenze nelle
diverse tipologie di
paziente reale
Assume that NAOs have been on the market for 5 year
➢A new drug comes to the market. Compared to NAOs, the new drug has:
- cheaper
- antidote
- requirement for monthly monitoring to adjust dose
- many food and drug interactions
- 25% increased relative risk of stroke/systemic embolism
- nearly 50% increased relative risk of major bleeding
- approx. 2.5 times the rate of ICH
- 10% increased relative risk of mortality
➢Would Warfarin be approved by regulatory authorities now?
An effective antithrombotic treatment could combine in any
single patient …..
Efficacy
at preventing stroke in
AF and at treating DVT
or PE
Adherence
taken as instructed for
the prescribed period
of time
Treatment
goal
Safety/tolerability
profile similar to control
treatment
Convenience
easy to take and
to administer i.e.
number of doses
Compliance with od versus bid regimens is generally
better for chronic conditions
Number of studies that directly assessed compliance
Number of studies
od > bid*
*Patient compliance (assessed in study) with od regimen is
significantly better than with bid regimen
#No significant difference in patient compliance (assessed in study)
between od and bid regimens
‡Patient compliance (assessed in study) with bid regimen is
significantly better than with od regimen
od = bid#
od < bid‡
Pubmed search; March 2001–2011
CV medication adherence:
od is associated with higher adherence than bid
p<0.01
100
93
86
p<0.01
85
74
Patient adherence (%)
OD
p<0.01
76
BID
50
50
Adherence calculated by
three measures, in order
of increasing strictness:
•Taking – Number of
bottle cap openings
divided by the
prescribed number of
doses.
•Regimen – Percentage
of days with the
appropriate number of
doses taken.
•Timing – Percentage of
0
Taking
Regimen
Timing
near optimal interadministration intervals.
Adherence definition
Coleman CI. Curr Med Res Opin. 2012;28(5):1–12
“Du gust is megl che one”
“One gust is megl che du”
Baseline Demographics ROCKET AF
Pengo V. Journal of Thrombosis and Haemostasis, 18: 1979–1987
Quali pazienti
 Il paziente anziano
 Il paziente con Insufficienza Renale
 Il paziente con pregresso evento ischemico
 Il paziente sottoposto a cardioversione elettrica
Rivaroxaban nel paziente anziano
1- Subanalysis elderly patients
Rationale
 To determine the efficacy and safety of rivaroxaban compared with
warfarin among elderly patients (>75 years old) with AF compared with
patients <75 years
 6,229 patients were ≥75 years
▪ Mean CHADS2 3.7 vs 3.3
▪ Female 46% vs. 35%
▪ Prior stroke/TIA 42% vs 65%
Halperin JL et al. presented at AHA 2012
ROCKET AF
subanalysis elderly patients – Results
Age (Years)
Stroke/SE
(n=14.171)
Major Bleeding
(n=14.236)
<75
HR 0.95 (0.76-1.19)
HR 0.96 (0.78-1.19)
≥75
HR 0.80 (0.63-1.02)
HR 1.11 (0.92-1.34)
p*=0.31
p*=0.34
Rivaroxaban
better
* p-value for interaction
Halperin JL et al. presented at AHA 2012
Warfarin
better
Rivaroxaban
better
Warfarin
better
ROCKET AF
subanalysis elderly patients - Conclusion
 Elderly patients had
‐ higher absolute rates of stroke and systemic embolism
‐ higher absolute rates of major bleeding
‐ similar absolute rates of haemorrhagic stroke
 The overall relative effects of rivaroxaban vs. warfarin were consistent
among elderly (and younger) patients for both efficacy and safety
Halperin JL et al. presented at AHA 2012
Rivaroxaban nel paziente
con Insufficienza Renale
http://eurheartj.oxfordjournals.org/cgi/content/full/ehr342
European Heart Journal
Baseline demographics
CrCl 30–49 ml/min
Characteristic
CrCl ≥50 ml/min
Rivaroxaban
15 mg od
(N=1474)
Warfarin
(N=1476)
Rivaroxaban
20 mg od
(N=5637)
Warfarin
(N=5640)
79 (75–82)
79 (75–83)
71 (63–76)
71 (63–76)
55.0
55.9
35.6
35.4
BMI, median (IQR),
kg/m2
25.1 (22.7–28.0)
25.2 (22.8–27.9)
29.2 (26.1–33.0)
28.9 (26.0–32.7)
SBP, median (IQR),
mm Hg
130 (120–140)
130 (120–140)
130 (120–140)
130 (120–140)
Prior ASA use (%)
35.9
37.4
36.4
36.5
Prior VKA use (%)
62.7
61.3
62.2
62.9
Age, median (IQR), yrs
Female (%)
ASA, acetylsalicylic acid; IQR, interquartile range; VKA, vitamin K antagonist
Safety population (minus 9 pts in warfarin arm with no CrCl data)
2 - ROCKET AF: stroke or non-CNS embolism among
patients with CrCl 30–49 ml/min
8
Cumulative event rate (%)
7
6
Warfarin
5
4
Rivaroxaban
3
HR (95% CI): 0.84 (0.57, 1.23)
2
1
0
0
120
240
360
480
600
720
840
Days since randomization
No. at risk:
Rivaroxaban
Warfarin
1,434
1,439
1,226
1,261
1,103
1,140
1,027
1,052
Event rates are % per year; Based on Protocol Compliant on Treatment Population
Fox KA et al. Eur Heart J 2011; 32 (19): 2387-2394
806
832
621
656
442
455
275
272
ROCKET AF: safety outcomes among
patients with CrCl 30–49 ml/min
Clinical endpoint
(% per year)
Rivaroxaban Warfarin
(N=7,111)
(N=7,116)
CrCl ≥50 ml/min‡
CrCl 30–49 ml/min§
HR (95% CI)
Rivaroxaban
vs warfarin
P
(interaction)
Principal safety
outcome*
14.24
17.82
13.67
18.28
1.04 (0.96–1.13)
0.98 (0.84–1.14)
0.45
Major bleeding
3.39
4.49
3.17
4.70
1.07 (0.91–1.26)
0.95 (0.72–1.26)
0.48
Haematocrit or
haemoglobin drop
2.54
3.76
2.03
3.28
1.25 (1.03–1.52)
1.14 (0.83–1.58)
0.65
Transfusion
1.49
2.34
1.16
2.00
1.28 (0.99–1.65)
1.17 (0.77–1.76)
0.71
Critical organ
0.83
0.76
1.13
1.39
0.74 (0.55–0.99)
0.55 (0.30–1.00)
0.39
Fatal bleeding
0.23
0.28
0.43
0.74
0.55 (0.32–0.93)
0.39 (0.15–0.99)
0.53
0.44
0.71
0.71
0.88
0.62 (0.42–0.92)
0.81 (0.41–1.60)
0.51
Intracranial
haemorrhage
0.01
0.1
1
10
Based on safety population on treatment
‡
§
*Composite of major plus non-major clinically relevant bleeding; Rivaroxaban 20 mg od; Rivaroxaban 15 mg od
Fox KA et al. Eur Heart J 2011; 32 (19): 2387-2394
ROCKET AF: bleeding sites among
patients with CrCl 30–49 ml/min
CrCl 30–49 ml/min
Warfarin
(N=1,476)
Rivaroxaban
20 mg
(N=5,637)
Warfarin
(N=5,640)
2.88
1.77
1.79
1.12
Intracranial haemorrhage#
0.71
0.88
0.44
0.71
Macroscopic haematuria
0.05
0.18
0.28
0.19
Bleeding associated with
non-cardiac surgery
0.24
0.42
0.15
0.19
Intra-articular
0.00
0.23
0.18
0.17
Epistaxis
0.19
0.09
0.10
0.13
Major bleeding
(% per year)
Gastrointestinal (upper, lower,
and rectal)*
Rivaroxaban
15 mg
(N=1,474)
CrCl ≥50 ml/min
*p=0.02 (rivaroxaban vs warfarin in CrCl 30–49 ml/min); p=0.0002 (rivaroxaban vs warfarin in CrCl ≥50 ml/min)
#p=0.02 (rivaroxaban vs warfarin in CrCl ≥50 ml/min)
Fox KA et al. Eur Heart J 2011; 32 (19): 2387-2394
Ictus emorragico (TF receptor)
Mackmann, Anesth Analg. 2009 May; 108(5):1447-52
The role of tissue factor and factor VIIa in hemostasis.
ROCKET AF
renally impaired patients - Conclusion
 Patients with AF and moderate renal insufficiency have higher rates of
stroke and bleeding than those with normal renal function in both
treatment arms
 Dose adjustment in ROCKET-AF yielded results consistent with the overall
trial in comparison with dose-adjusted warfarin
Raccomandazioni dell’ESC nei pazienti con IR
Raccomandazioni dell’EHRA nei pazienti con IR
Backgroun: Vitamin K-Antagonists Induce Vascular Damage
Price et al,
Arterioscler Thromb Vasc Biol 18 (1998): 1400-1407
Schurgers et al,
Blood 109 (2007): 2823-2831
Brodsky et al,
Kidney Int 109 (2011): 181-189
Krüger et al,
Arterioscler Thromb Vasc Biol 33 (2013): 2618-2624
Change in GFR (CKD-EPI) Assigned to D110, D150 or Warfarin
0
*p< 0.005 vs warfarin
Change from Baseline
-1
-2
*
*
-3
DE 110mg bid
DE 150mg bid
Warfarin
*
-4
0
3
6
9
12
15
18
21
24
27
30
Months
Available
patients
DE 110mg bid
DE 150mg bid
Warfarin
3 months
6 months
12 months
24 months
30 months
5130
5171
5243
5000
5005
5146
4686
4696
4895
3368
3434
3519
1672
1685
1703
Michael Böhm, ESC 2014, Barcelona, 30 Aug - 3 Sep 2014
Il paziente con pregresso
evento ischemico (TIA/Ictus)
4 - ROCKET AF
subanalysis: secondary prevention - Rationale
 The aim of this prespecified subanalysis was to investigate whether the efficacy and safety of
rivaroxaban compared with warfarin is consistent among the subgroups of patients with and
without previous stroke or TIA and the entire ROCKET AF study population
 Because treatment effects might differ between patients with prior stroke/TIA patients
because there may be a higher risk of recurrence of stroke and higher risk of bleeding
events
 Cohorts:
‐
History of stroke/TIA (stroke cohort) versus
‐
No history of stroke/TIA (non-stroke cohort)
 7468 (52%) patients had a previous stroke (n=4907; 65%) or TIA (n=2561; 34%)
Hankey G. Lancet Neurology epub ahead of print March 7, 2012
ROCKET AF – subanalysis: secondary pre-vention –
Results: Primary efficacy outcome
Cumulative event rate – stroke or
systemic embolism (%)
Kaplan–Meier survival curve showing time to the primary outcome (stroke or systemic embolism)
7
Previous stroke/
TIA, warfarin
6
Previous stroke/
TIA, rivaroxaban
5
No previous stroke/
TIA, warfarin
No previous stroke/ TIA,
rivaroxaban
4
3
2
1
0
0
6
12
18
Months from randomisation
Intention-to-treat population
Hankey G. Lancet Neurology epub ahead of print March 7, 2012
24
30
ROCKET AF – subanalysis: secondary pre-vention –
Safety outcome (Safety on-treatment*)
HR
(95% CI)
Rivaroxaban
Warfarin
Events/yr (nr*)
Events/yr (nr*)
Principal safety
bleeding endpoint
16.69 (785)
13.31 (690)
15.19 (743)
13.87 (706)
1.10 (0.99-1.21)
0.96 (0.87-1.07)
0.08
Major bleeding
4.10 (217)
3.13 (178)
3.69 (203)
3.22 (183)
1.11 (0.92-1.34)
0.97 (0.79-1.19)
0.36
Fatal bleeding
0.22 (12)
0.26 (15)
0.48 (27)
0.49 (28)
0.46 (0.23-0.90)
0.54 (0.29-1.00)
0.74
Intracranial
haemorrhage†
0.39 (21)
0.59 (34)
0.68 (38)
0.80 (46)
0.57 (0.34-0.97)
0.74 (0.47-1.15)
0.47
Intracerebral
haemorrhage‡
0.24 (13)
0.45 (26)
0.52 (29)
0.54 (31)
0.46 (0.24-0.89)
0.84 (0.50-1.41)
0.16
Extracerebral
haemorrhage§
0.18 (10)
0.17 (10)
0.30 (17)
0.35 (20)
0.61 (0.28-1.32)
0.50 (0.23-1.07)
0.73
12.93 (620)
10.78 (565)
11.78 (585)
10.98 (566)
1.10 (0.98-1.23)
0.99 (0.88-1.11)
0.20
Non-major clinically
relevant bleeding
No previous stroke or TIA
Previous stroke or TIA
0.1
Safety on-treatment population
*nr=number of events
Hankey G. Lancet Neurology epub ahead of print March 7, 2012
0.2
0.5
Favours rivaroxaban
1
2
4
10
Favours warfarin
p-value*
ROCKET AF
subanalysis: secondary prevention - Conclusion


Efficacy and safety results in patients with prior stroke/TIA were
consistent
‐
With patients without prior stroke/TIA and
‐
With the entire ROCKET AF study population
Overall bleeding rates were similar
‐
in both treatment arms and
‐
in patients with and without prior stroke/TIA
 Fatal bleedings as well as ICH were less frequent in the rivaroxaban arm,
but this difference did not reach statistical significance
 These results support the use of rivaroxaban as an alternative to warfarin
for both primary and secondary stroke prevention in AF
Hankey G. Lancet Neurology epub ahead of print March 7, 2012
Rivaroxaban e cardioversione
elettrica
X-VeRT: study population
Screening
(N=1584)
Randomized
(N=1504)
Rivaroxaban
(n=1002)
Excluded (n=80)
•Screening failure (n=71)
•Withdrawal by patient (n=7)
•Adverse event (n=2)
2:1
Rivaroxaban
(n=988)
Rivaroxaban
(n=978)
Cappato R et al. Eur Heart J 2014: doi: 10.1093/eurheartj/ehu367;
Cappato R. ESC Congress 2014. Oral presentation 4945
VKA
(n=502)
VKA
(n=499)
VKA
(n=492)
X-VeRT: randomized, open-label, parallel-group, active-
R
1–5 days
2:1
VKA
Cardioversion
strategy
Rivaroxaban
20 mg od*
Delayed
R
≥21 days
(max. 56 days)
2:1
VKA
Rivaroxaban
20 mg od*
42 days
VKA
Rivaroxaban
20 mg od*
42 days
End of study treatment
Early#
Rivaroxaban
20 mg od*
Cardioversion
Inclusion criteria:
Age ≥18 years, non-valvular AF lasting >48 h
or unknown duration, scheduled for
cardioversion
Cardioversion
controlled multicentre study
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; www.clinicaltrials.gov. NCT01674647
OAC
30-day
follow-up
X-VeRT: primary efficacy endpoints
Rivaroxaban
(N=978)
Primary efficacy endpoint
Stroke
Haemorrhagic stroke
VKA
(N=492)
%
n*
%
n*
0.51
5
1.02
5
0.20
2
0.41
2
0.20
2
Ischaemic stroke
0
Risk ratio
(95% CI)
0.50 (0.15–1.73)
0
0.41
2
TIA
0
0
Non-CNS SE
0
0.20
1
MI
0.10
1
0.20
1
Cardiovascular death
0.41
4
0.41
2
*Number of patients with events; patients may have experienced more than one primary efficacy event
mITT population
Cappato R et al. Eur Heart J 2014: doi: 10.1093/eurheartj/ehu367
X-VeRT: time to cardioversion by cardioversion
strategy
Median time to cardioversion
100
Rivaroxaban
VKA
Patients cardioverted as scheduled*
p<0.001
p<0.001
60
p=0.628
40
22
days
20
30
days
Patients (%)
Days
80
1 patient with
inadequate
anticoagulation
95 patients with
inadequate
anticoagulation
0
Early
Delayed
Delayed cardioversion
*Reason for not performing cardioversion as first scheduled from 21–25 days primarily due to
inadequate anticoagulation (indicated by drug compliance <80% for rivaroxaban or weekly INRs
outside the range of 2.0–3.0 for 3 consecutive weeks before cardioversion for VKA)
Cappato R et al. Eur Heart J 2014: doi: 10.1093/eurheartj/ehu367
Clinical implications: rivaroxaban in the cardioversion
setting
• Based on data from X-VeRT, rivaroxaban can be regarded as
an effective and safe alternative to VKAs in patients with AF
scheduled for cardioversion irrespective of:
I.
Early (with or without a TEE-guided approach) or delayed
cardioversion strategy
II. Cardioversion (electrical or pharmacological) strategy
• Results demonstrate that rivaroxaban may overcome critical
limitations of VKA treatment in the setting of cardioversion,
including a significant reduction in time to cardioversion
Cappato R et al. Eur Heart J 2014: doi: 10.1093/eurheartj/ehu367;
Cappato R. ESC Congress 2014. Oral presentation 4945
Rivaroxaban e CVE
Conclusioni
 Rivaroxaban è un farmaco efficace e sicuro e che garantisce un’ottima
compliance e maneggevolezza
 Rivaroxaban mantiene un beneficio clinico netto favorevole anche in diverse
sottopopolazioni di pazienti fragili (anziani, IR, pregresso ictus)
 Rivaroxaban può essere utilizzato con assoluta sicurezza per le CVE