Title: Ximelagatran, an Oral Direct Thrombin Inhibitor, Compared With DoseAdjusted Warfarin for Primary and
1(No Transcript)
2Ximelagatran, an Oral Direct Thrombin
Inhibitor, Compared With Dose-Adjusted Warfarin
for Primary and Secondary Stroke Prevention in
Patients With Atrial Fibrillation
- Gregory W. Albers, MDOn behalf of the SPORTIF
Investigators
FINANCIAL DISCLOSUREResearch support and
consultant AstraZeneca
3Anticoagulation in Atrial FibrillationStroke
Risk Reductions
Hart et al. Ann Intern Med. 1999131492-501.
4Warfarin for Atrial Fibrillation Limitations
Lead to Inadequate Treatment
Adequacy of Anticoagulation inPatients with AF
in Primary Care Practice
INR above target6
No warfarin65
INR intarget range15
Subtherapeutic INR 13
Samsa et al. Arch Intern Med. 2000160967-973.
5XimelagatranOral Direct Thrombin Inhibitor
- Prompt onset and offset of anticoagulation
- Wider therapeutic margin than warfarin
- Predictable pharmacokinetics
- Low potential for food and drug interactions
- No dose adjustment
- No coagulation monitoring
Eriksson et al. Drug Metab Dispos.
200331294-305. Sarich et al. J Am Coll
Cardiol. 200341557-564.
6Stroke Prevention Using anORal Direct Thrombin
Inhibitor in Atrial FibrillationThe SPORTIF III
and V Trials
Patients with Nonvalvular AF and Risk Factors for
Stroke n7,329
SPORTIF III 23 nations open-label
(n3,407) SPORTIF V US, Canada double-blind (n3,
922)
7Design of SPORTIF III and V
- Randomized, open-label treatment allocation (III)
- Randomized, double-blind, sham INR (V)
- Patients with AF and ?1 additional stroke risk
factor - Multiple levels of blinded event assessment
- Local study-affiliated neurologists
- Central Events Adjudication Committee
- Exposure (each study)
- Minimum 12 months/patient
- ?4,000 patient-years aggregate
- ?80 primary events
8Outcome Analyses
- Primary analysis
- Prevention of all strokes (ischemic or
hemorrhagic) and systemic embolic events, based
on intention-to-treat - Sensitivity analyses
- Primary events all-cause mortality
- Primary events, on-treatment approach
- Safety
- Pooled analysis of SPORTIF III V, pre-specified
9Statistical Design
Ximelagatran superior
Warfarin superior
Superiority
Non-inferiority
Non-inferiority
Equivalence
0
2
Absolute Difference in Event RatesSPORTIF III
and V
10Patient Characteristics SPORTIF V
Warfarin
lt1
1-5
gt5
AF Duration(years)
Ximelagatran
Paroxysmal
Persistent
AF Pattern
lt65
65-75
gt75
Age
Female
Male
Gender
Percent
11Patient CharacteristicsSPORTIF VStroke Risk
Factors
Warfarin
Prior stroke/TIA
Ximelagatran
?75 years
LV dysfunctionor CHF
Hypertension
gt65 years CAD
gt65 years diabetes
Percent
12SPORTIF VINR Values Warfarin Group
13SPORTIF ProgramStroke and Systemic Embolism
Intention-to-treat Analysis
SPORTIF
7
III
V
6
Warfarin
5
Ximelagatran
4
Cumulative Event Rate (year)
3
2
1
0
0
3
6
9
12
15
18
21
24
Months
14SPORTIF ProgramPrimary AnalysesIntention-to-trea
t Analysis
Ximelagatran Better
Warfarin Better
-0.66
SPORTIF III
p0.10
0.45
p0.13
SPORTIF V
-1
0
1
2
3
4
-2
-3
-4
Difference in Absolute Event Rates(Ximelagatran
Warfarin)
15Consistency of Efficacy ResultsPatients ?75
YearsPooled Analysis SPORTIF Program
Ximelagatran better
Warfarinbetter
Cumulativeevent rate
Stroke/systemic embolism(ITT)
2.2 vs 2.3
Stroke/systemic embolism/ death (ITT)
5.8 vs 6.9
Stroke/systemic embolism (OT)
1.8 vs 2.1
Event Rate Difference (/year)
16Consistency of Efficacy Results in WomenPooled
Analysis SPORTIF Program
Ximelagatran better
Warfarinbetter
Cumulativeevent rate
Stroke/systemic embolism(ITT)
2.2 vs 2.0
Stroke/systemic embolism/ death (ITT)
4.0 vs 4.5
Stroke/systemic embolism(OT)
1.5 vs 1.8
Event Rate Difference (/year)
17SPORTIF IIIHemorrhage
p0.007
29.8
25.8
Event Rate ( per year)
pNS
pNS
1.8
1.3
0.4
0.2
MajorBleeding
Major MinorBleeding
ICH
18SPORTIF VHemorrhage
plt0.0001
Event Rate ( /year)
p0.16
pNS
19SPORTIF ProgramStroke Subtypes
Intention-to-treat Analysis
20SPORTIF ProgramAll Strokes and Systemic
EmbolismIntention-to-treat Analysis
Event Rate (/year)
3.3
2.8
1.3
1.3
PrimaryPrevention 8968 pt-years
SecondaryPrevention 2265 pt-years
21SPORTIF VLiver Enzyme ElevationALT gt3 x ULN
22SPORTIF Program Net Clinical Benefit Primary
Events Major Bleeding DeathOn-treatment
Analysis
RRR 26p0.02
RRR 16p0.04
Event Rate ( per year)
All Patients
?75 Years
23Conclusions
In high-risk patients with atrial fibrillation,
ximelagatran offers
- Fixed oral dosing without coagulation monitoring
- Effectiveness comparable to well-controlled
warfarin in preventing stroke and systemic
embolic events - Less bleeding than warfarin
- Elevated liver enzymes in 6 of patients
- A promising treatment option for prevention of
thromboembolism
24AcknowledgmentsSPORTIF Executive Steering
Committee
G Albers (USA) H C Diener (Germany) L Frison
(Sweden) M Grind (UK) J Halperin (USA) J Horrow
(USA) M Nevinson (UK) B Olsson (Sweden) P
Petersen (Denmark) S Partridge (UK) A Vahanian
(France)
25AcknowledgmentsSPORTIF Program
Data Safety Monitoring Board R Hart (USA) G
Boysen (Denmark) D DeMets (USA) D Julian
(UK) Data Safety Monitoring Board Statistical
Center D DeMets (USA) J Feyzi (USA) R Bechhofer
(USA) Central Event Adjudication Committee R
von Kummer (Germany) D Mucha (Germany) G Gahn
(Germany) A Schmeisser (Germany) A Müller
(Germany) H Reichmann (Germany) T Schwarz
(Germany) O Wunderlich (Germany)
26AcknowledgmentsSPORTIF V Steering Committee
Co-Chairs G Albers (USA) J Halperin
(USA) Members J Andrews (Canada) J
Blackshear (USA) S Connolly (Canada) R
Ekeland (USA) G Flaker (USA) J Ghali
(USA) M Grind (UK) J Horrow (USA) M
Nevinson (UK) J Teitelbaum (Canada) A Vieira
(Sweden)
27Stroke Prevention Using theOral Direct Thrombin
InhibitorXimelagatran in Patients With
Nonvalvular Atrial Fibrillation
SPORTIF III and V
- Gregory W. Albers, MD On behalf of the SPORTIF
Investigators