(Microsoft PowerPoint - Gronda Edoardo.ppt [modalit\340

Le conferme dalla real life superano
gli studi registrativi
E. Gronda, MD, FESC
Cardiology and Research Unit
IRCCS MultiMedica Sesto S. Giovanni
Cardiovascular Department
MultiMedica Group.
Rate
(% / yr)
Years
Atrial Fibrillation Investigators, Arch Intern Med 1994;154:1449.
Di Pasquale G, et al, Current presentation and management of 7148 patients with atrial fibrillation in cardiology and
internal medicine hospital centers: The ATA AF study, Int J Cardiol (2012),
In the real world : WHY ?
Why don’t old patients, running the highest risk for stroke,
receive OA treatment?
Fears for:
•
•
•
•
Bleeding
Negative interaction with age
Lack of laboratory control
Lack of compliance in therapy persistence
Major and Fatal Bleeding are High with VKA in
NVAF Patients in Real World
Study drug
Patients
(n)
Rate of major
bleeding
(%/year)
Fatal bleeding
(%)
Warfarin starters1
125,195
3.8
1.6#
Warfarin starters2
820
6.5
2.3#
VKA starters3
682
6.0
1.0
Warfarin users4
261
5.3*
0.4#
10,757
7.2
0.3#
Coumarin derivative
users5
#Values
are calculated (not reported); *In the first year.
1. Gomes T et al. CMAJ. 2013;185(2):E121-127; 2. Beyth RJ et al. Am J Med. 1998;105(2):91-99;
3. Steffensen FH et al. J Intern Med. 1997;242(6):497-503; 4. Gitter MJ et al. Mayo Clin Proc.
1995;70(8):725-733;
5. Linkins LA et al. Ann Intern Med. 2003;139(11):893-900;
Granger C B , and Armaganijan L V
Circulation 2012;125:159-164
Copyright © American Heart Association
Information on AF pt characteristics, management, and
outcome has limitation
- largely drawn from RCTs, which are highly selected
- information gathered from hospital sources or on the
occasion of an event, therefore not
reflective of th
status of stable outpatient with AF
- not contemporary as epidemiology and practice are
evolving
There is a need for data which are:
- contemporary, international, end representative
Registries and “administrative databases” provide
complementary information “from real world”
About registry event adjudication statistics
The new era of clinical research: Using data for multiple purposes
The CLARICOR study
1. The most common errors were false-positive attributions from
the
registry in cases that were ruled non-events by
the adjudication committee.
2. This is not surprising because clinical diagnoses tend to err on the
more serious side of classification, whereas an Adjudication
Committee applies rigorous criteria that would exclude
borderline cases.
3. A similar issue with estimation of death from cardiovascular
causes was observed, although this is less concerning, given the
known
difficulty of determining cause of death with even the
best
data available.
CALIFF RM American Heart Journal
August 2014
Rivaroxaban Safety Profile in Real World was
Consistent with Results from ROCKET AF
mean CHADS2-Score 3.0#
mean CHADS2-Score 3.5
Rivaroxaban
n=7,111
Event rate (%/year)
4
3
3.6
2
1
Event rate (%/year)
ROCKET
US DoD PMSS2
AF1
n=27,467
4
3
2.9
2
1
0
0
Major bleeding**
Major bleeding*
Clinical endpoint
% (n)
Clinical endpoint
% (n)
ICH
0.8 (55)
ICH
0.1 (36)
Fatal Bleeding
0.4 (27)
Fatal Bleeding
<0.1 (14)
Major GI Bleeding
3.2 (224)
Major GI Bleeding
1.5 (423)
Median duration of treatment exposure was 590 days
Rivaroxaban users were followed for 455 days
Results are not intended for direct comparison
*Major bleeding definitions according to ISTH; **Major bleeding was defined by the Cunningham algorithm3; #refers to mean CHADS2 among patients who
experienced MB
1. Patel MR et al. N Engl J Med 2011; 365(10):883-891; 2. Tamayo S et al. Clin Cardiol 2015; 38(2):63-68; 3. Cunningham A et al. Pharmacoepidemiol Drug Saf
2011; 20(6): 560-566
Major Bleeding Rates with Rivaroxaban in Real World
Studies were Consistent with Findings from ROCKET AF
mean CHADS2-Score 2.4
mean CHADS2-Score 3.5
n=7,111
4
3.6
3
2
Event rate (%/year)
Event rate (%/year)
Rivaroxaban
3
3.1
2
1
1
0
0
Major bleeding*
n=1,204
4
US DoD PMSS3
mean CHADS2-Score 2.2
Event rate (%/year)
Prospective Registry
Dresden NOAC Registry2
Clinical Trial
ROCKET AF1
Retrospective Database
n=27,467
2.9
2.9
Major bleeding#
Results are not intended for direct comparison
US DoD PMSS = US Department of Defense Post-Marketing Surveillance Study
*Major bleeding definitions according to ISTH; # modified ISTH definition (additionally included surgical revision from bleeding)
**Major bleeding was defined by the Cunningham algorithm4
1. Patel MR et al. N Engl J Med 2011; 365(10):883-891; 2. Beyer-Westendorf et al. Blood 2014;124(6); 955-962; 3. Tamayo S et al. Clin Cardiol. 2015;38(2):63-68;
4. Cunningham A et al. Pharmacoepidemiol Drug Saf. 2011;20(6):560-566
Rivaroxaban, Dabigatran and Warfarin:
Findings on Risk of Major Bleeding in Real World
Two retrospective analyses of U.S. Department of Defense
records1,2
Rivaroxaban PMSS1
Dabigatran PMSS2
n=25,586
4
3
2.9
2
1
Event rate (%/year)
Event rate (%/year)
n=27,467
3.7
3.1
0
Rivaroxaban
ICH
Fatal bleeding
Major GI bleeding
Rivaroxaban
(%)
0.1
<0.1
1.5
ICH
Fatal bleeding
Major GI bleeding
Dabigatran
(%/year)
0.27
Not reported
2.54
Warfarin
(%/year)
0.56
Not reported
2.37
Major bleeding was defined by the Cunningham algorithm in both studies3
1. Tamayo S et al. Clin Cardiol. 2015;38(2):63-68;
2. http://us.boehringer-ingelheim.com/news_events/press_releases/press_release_archive/2014/11-17-14-us-department-defense-study-supports-favorablebenefit-risk-profile-pradaxa-dabigatran-etexilate-mesylate-reducing-stroke-risk-non-valvular-atrial-fibrillation.html;
3. Cunningham A et al. Pharmacoepidemiol Drug Saf. 2011;20(6):560-566.
70
Conservative = no treatment/ compression/
tamponade/ transfusion
Approach (%)
60
50
40
Case fatality rate (%)
Dresden NOAC Registry: Outcomes of Major Bleedings may be Better
with Rivaroxaban than those reported for VKAs
10
9
8
7
6
5
4
3
2
1
0
30
VKA
20
Rivaroxaban
2
10
Most MB cases could be treated conservatively, rarely
requiring procoagulants1
rFVII
FFP + PCC
PCC only
FFP only
Vit K
RBC
Surg/Interv
Conserva ve
0
1
With Rivaroxaban Case-fatality rate
was 6.3% at day 90 after bleedingrelated hospitalization compared to
9.1% with VKA1,2
Different studies report Case fatality
rates of VKA-related major bleeding
of 13% - 18%3-5
1. Beyer-Westendorf J et al. Blood. 2014;124(6):955-962; 2. Michalski F et al. Thromb Haemostat 2015; 114(4) epub 3. Gomes et al., CMAJ. 2013;185(2):E121E127: 4. Linkins et al. Ann Intern Med. 2003;139(11):893-900; 5. Halbritter et al. J Thromb Haemost. 2013;11(4):651-659
German prospective, non-interventional NOA registry
Rates, management and outcome of rivaroxabanrelated bleeding events analysed (n=1776)
Characterizing Major Bleeding in Patients With Nonvalvular Atrial Fibrillation:
A Pharmacovigilance Study of 27 467 Patients Taking Rivaroxaban
Tamayo S et al Clinical Cardiology DOI:10.1002/clc.22373
Patient Characteristics
MB
Age
78.4 (±7.7)
No MB
vs
75.7 (±9.7) years
More prevalent comorbidities
vs
HBP
75.8%
95.6%
CAD
64.2%
vs
36.7%
HF
48.5%
vs
23.7%
38.7%
vs
16.7 %
vs
36.6% (9878/26 989)
CKD
Concomitant medication of interest
29.1% (139/478)
CHADS2
MB, n=478
3.0 ± 1.2
No MB, n=26 989
2.2 ± 1.3
Greater Net Clinical Benefit of Rivaroxaban vs.
Warfarin in a Real World AF Population
HAS-BLED ≤2
Background/rationale
Evaluate the net clinical benefit (NCB)* of
rivaroxaban compared with warfarin for
stroke prevention in patients with AF using
real-World stroke/ICH event rates
CHA2DS2-VASc=0
Warfarin
Rivaroxaban
CHA2DS2-VASc=1
Warfarin
Results
Event rates (± warfarin treatment) collected
from the Danish AF registry
Results adjusted for rivaroxaban using relative
risk of events from ROCKET AF
Conclusion
Rivaroxaban demonstrated a NCB
for stroke prevention in patients with AF,
which may be greater than the NCB achieved
with warfarin treatment across low- and highrisk stroke/bleeding risk groups
Rivaroxaban
CHA2DS2-VASc=2–9
Warfarin
Rivaroxaban
–1.0
0
1.0
2.0
3.0
Net clinical benefit favours drug
–1.0
0
1.0
2.0
3.0
Net clinical benefit favours drug
HAS-BLED ≥3
CHA2DS2-VASc=1
Warfarin
Rivaroxaban
CHA2DS2-VASc=2–9
Warfarin
Rivaroxaban
*To quantify the balance between risk of IS and risk of ICH
Banerjee A et al. Thromb Haemost 2012;107(3):584-589
Stroke/ Embolia Sistemica
Wallentin L et al.Circulation. 2013;127:2166-76.
doi: 10.1161/CIRCULATIONAHA.112.142158
TAXUS data integrity and quality
Tamayo S et al Clinical Cardiology DOI:10.1002/clc.22373
Data quality assurance
1Outcome variables and covariates recorded on a standardized CRF
2Reporting bias minimized by verifying source data from at least 10% of the sites.
350% of the sites underwent random visits to monitor study conduct.
4Selection bias minimized by requiring investigators to document consecutive patients
prescribed rivaroxaban, with no omissions.
Data management and administrative organization
1.XANTUS study major bleeding, stroke, systemic embolism, TIA, and myocardial
infarction
2.Adjudicated centrally (blinded adjudication committee)
3.Data verification at study sites for identification of any relevant outcomes not
submitted for adjudication.
4.The XANTUS study had one centralized database to receive results.
XANTUS: Patient Flow
Major events, specifically
major bleeding, stroke, SE, TIA
and MI, adjudicated centrally
by an independent CAC blinded
to individual patient data
Screened
(N=10,934)
Enrolled
(N=6785)
Primary analysis population:
defined as all patients who had
taken at least one dose of
rivaroxaban
Rivaroxaban 20 mg od
(n=5336)
4149 patients excluded*
Patient decision (n=1222)
Administrative reason (n=456)
Availability of drug (n=18)
Medical guidelines (n=399)
Price of drug (n=473)
Medical reasons (n=442)
Internal hospital guidelines (n=30)
Type of health insurance (n=183)
Other (n=1454)
1 patient
Did not take any rivaroxaban (n=1)
Safety population
(N=6784)
Rivaroxaban 15 mg od
(n=1410)
Another dose
(n=35)#
*Reasons for not continuing in the study included, but were not limited to, patient decision, administrative or medical
reasons. Some patients could have more than one reason for exclusion; #other dose includes any initial daily rivaroxaban
dose besides 15/20 mg od (excluding missing information, n=3)
1. Camm AJ et al, Eur Heart J 2015; doi: 10.1093/eurheartj/ehv466
XANTUS: Baseline Demographics –
Distribution of Stroke Risk Factors
Mean score±SD = 2.0±1.3
Mean score±SD = 3.4±1.7
35,0
35,0
30,4 30,0
Prop
portion of patients (%)
Prop
portion of patients (%)
30,0
25,0
20,0
16,4
15,0
10,4
9,1
10,0
23,3
25,0
20,7
19,4
20,0
15,0
12,3 11,6
10,1
10,0
5,0
3,3
5,0
30,0
2,6
0,5
0,0
0,0
0
1
2
3
4
5
CHADS2 score
*3 patients had missing CHA2DS2-VASc scores
1. Camm AJ et al, Eur Heart J 2015; doi: 10.1093/eurheartj/ehv466
6
0
1
2
3
4
5
CHA2DS2-VASc score*
6–9
XANTUS: Event-Free Rate (Kaplan–Meier) for
Treatment-Emergent Primary Outcomes
In total, 6522 (96.1%) patients did not experience any of the
outcomes of treatment-emergent all-cause death, major bleeding
or stroke/SE
1. Camm AJ et al, Eur Heart J 2015; doi: 10.1093/eurheartj/ehv466
XANTUS: Cumulative Rates (Kaplan–Meier) for
Treatment-Emergent Primary Outcomes
1. Camm AJ et al, Eur Heart J 2015; doi: 10.1093/eurheartj/ehv466
ARISTOTLE (average CHADS2 2,1) OUTCOMES
The rate of death from any cause was 3.09% and 3.94%, respectively (hazard ratio,
0.89; 95% CI, 0.80 to 0.99; P = 0.047 as compared to 3.52% in the warfarin group.
The rate of major bleeding was 2.13% per year in the apixaban group, as compared with
3.09% per year in the warfarin group (hazard ratio, 0.69; 95% CI, 0.60 to 0.80; P<0.001).
The rate of hemorrhagic stroke was 0.24% per year in the apixaban group, as compared
with 0.47% per year in the warfarin group (hazard ratio, 0.51; 95% CI, 0.35 to 0.75;
P<0.001)
The rate of ischemic or uncertain type of stroke was 0.97% per year in the apixaban
group and 1.05% per year in the warfarin group (hazard ratio, 0.92; 95% CI, 0.74 to
1.13; P = 0.42).
XANTUS: Outcomes According to Dosing
(20/15 mg od)
Major bleeding, all-cause death and thromboembolic events (stroke/SE/TIA/MI)
occurred at higher incidence rates for the 15 mg od versus the 20 mg od dose
Inciden
nce rate, %/year*
4,0
3,7
15 mg dose
3,5
20 mg dose
3,1
3,0
2,5
2,3
2,0
1,6
1,8
1,4
1,5
1,0
0,5
0,0
Thromboembolic events
*Events per 100 patient-years
Camm AJ et al, Eur Heart J 2015; doi: 10.1093/eurheartj/ehv466;
Major bleeding
All-cause death
In Real World AF Patients Stayed Longer on
Rivaroxaban Than on Warfarin
Two retrospective U.S. database analyses
Matched sample included 3,654
Rivaroxaban and 14,616 Warfarin patients1
HR 0.66 (95% CI 0.60–0.72);
p<0.0001
Rivaroxaban
90
Warfarin
80
70
100
Patient persistence (%)
Patient persistence (%)
100
7,259 Rivaroxaban patients were matched
1:1 with Warfarin patients2
HR 0.63 (95% CI 0.59–0.68);
p<0.001
Rivaroxaban
90
Warfarin
80
70
60
50
40
60
0
30
60
90
120 150 180
Time to non-persistence (days)
0
60
120
180
240
300
Time to non-persistence (days)
Patients were significantly more persistent with Rivaroxaban than with Warfarin
1. Laliberté F et al. Curr Med Res Opin. 2014;30(7):1317-1325; 2. Nelson WW et al. Curr Med Res Opin. 2014;30(12):2461-2469
360
BMJ 2015;350:h1857
doi: 10.1136/bmj.h1857
Dresden NOAC Registry: Higher Treatment Persistence
with Rivaroxaban than with Dabigatran
Two analyses of the prospective Dresden NOAC registry
341 AF patients treated with Dabigatran2
100
Event-free survival for
treatment discontinuation (%)
Event-free survival for
treatment discontinuation (%)
1,204 AF patients treated with Rivaroxaban1
15/20 mg OD Rivaroxaban
80
U.S. database
60
40
0
120
240
360
480
600
720
100
150 mg BID Dabigatran
110 mg BID Dabigatran
All patients
80
60
40
0
120
240
360
480
600
720
Time (days)
Time (days)
Median follow-up: 544 days
Median follow-up: 671 days
The rate for Rivaroxaban
discontinuation was 13.6%/year
840
960
Rate of Dabigatran discontinuation
was 25.8%/yr and therefore higher
than rates reported in RE-LY3
1. Beyer-Westendorf J et al. Europace 2015;17(4):530-538; 2. Beyer-Westendorf J et al. Thromb Haemost. 2015;113(6):1247-1257;
3. Connolly SJ et al. N Engl J Med. 2009;361(12):1139-1151
Conclusion
• Only ~6% of all bleeding events were
major;
• >60% of these were managed
conservatively
• Outcomes with rivaroxaban are at least no
worse than with VKA
German prospective, non-interventional
NOA registry Rates, management
and outcome of rivaroxaban-related bleeding
events analysed (n=1776)
Similar Risk of Gastrointestinal Bleeding with
Rivaroxaban Compared to Warfarin in Real World
Population based retrospective cohort study1
Patients: 4,907 Dabigatran, 1,649 Rivaroxaban, 39,607 Warfarin
Analysis (reference: warfarin)
All patients
Adjusted HR (95% CI)
Patients < 65 years
Adjusted HR (95% CI)
Patients > 65 years
Adjusted HR (95% CI)
Dabigatran
Rivaroxaban
n = 44,514
n = 41,256
1.21 (0.96 - 1.53)
n = 34,038
1.34 (0.98 - 1.83)
n = 10,476
1.07 (0.75 - 1.53)
0.98 (0.36 - 2.69)
n = 32,099
1.03 (0.33 - 3.18)
n = 9,157
0.62 (0.18 - 2.08)
Results are similar to a recent observational study from the US that reported no statistically significant differences in real world
rates of bleeding between rivaroxaban and warfarin (HR for Major bleeding 1.08, 95% CI 0.71-1.64)2
The rate of GI bleeding was highest among Dabigatran users and lowest among Rivaroxaban users
(9,0%/year Dabigatran, 3.4%/year, Rivaroxaban, 7.0%/year Warfarin)1
1. Chang et al. BMJ 2015;350:h1585 doi:10.1136/bmj.h1585; 2. Laliberté F et al. Curr Med Res Opin. 2014;30(7):1317-1325