Critique date: Mon, 03/22/2004 - 1:05pm
Article Citation
Citation:
Olsson SB, SPORTIF III Investigators . Stroke prevention with the oral direct thrombin inhibitor ximelagatran compared with warfarin in patients with non-valvular atrial fibrillation (SPORTIF III): randomised controlled trial. Lancet. 2003;362:1691-98.
Clinical Bottom Lines
Ximelagatran, a novel oral fixeddose direct thrombin inhibitor, is at least as effective for the prevention of stroke and systemic embolism and causes less bleeding than warfarin, INR 2-3, in patients with AF at high-risk of stroke.
There is a small but significant increased risk of elevated hepatic transaminases with ximelagatran, so liver enzymes must be monitored during the first 6 months.
The major advantage of ximelagatran is that it is an oral anticoagulant whose intensity does not need to be monitored.
Methods
Patient Population:
3407 patients (mean age 70 [SD 9], 69% men, 88% white) enrolled at 259 hospitals or doctor's offices in 23 countries, with persistent or paroxysmal AF and one or more of the following stroke risk factors: hypertension, history of stroke or TIA, symptomatic CHF or left ventricular dysfunction, age > 75, age > 65 and either coronary disease or diabetes mellitus.
Significant Exclusions:
mitral stenosis or prior valvular heart surgery; transient AF; recent stroke; increased bleeding risk (history of intracranial bleed, GI bleed in past year, recent peptic ulcer, recent surgery or trauma, poorly controlled hypertension); active infective endocarditis; atrial myxoma; acute coronary syndrome; chronic anticoagulation for disorders other than AF; planned cardioversion or major surgery; recent treatment with platelet-inhibitors or fibrinolytic agents; regular use of NSAIDs; renal insufficiency; active liver disease; severe anemia or thrombocytopenia; pregnancy; substance abuse.
Intervention/Exposure:
Multicenter, open-label, RCT
Randomization to either oral ximelagatran, 36mg twice daily (N=1704) or warfarin dose-adjusted for INR 2-3 (N=1703). Concomitant aspirin treatment up to 100mg daily was permitted.
Outcome Measures:
Primary outcomes
stroke (ischemic or hemorrhagic), and systemic embolic events. All primary events were reviewed by an independent, masked Central Event Adjudication Committee.
Secondary outcomes
composites of major and minor bleeding; treatment discontinuation; ischemic stroke, TIA, and systemic embolism; death, stroke, systemic embolism, and acute myocardial infarction. Major bleeding was defined as: fatal bleeding, overt bleeding with > 2 g/L hemoglobin drop or requiring transfusion of > 2 units, or bleeding involving critical sites (intracranial, intraspinal, intraocular, retroperitoneal, pericardial, atraumatic intra-articular).
Analysis
intention-to-treat (ITT)
Participant Follow-up:
81% ximelagatran, 85% warfarin
Conclusion
Results:
Â
XimelagatranÂ
N=1704
% per year
Warfarin
N=1703
% per year
ARR or Difference
(95% CI)
p-value
ITT Analyses
Â
Â
Â
Â
Primary outcomes
1.6%
2.3%Â
0.7 (-0.1 to 1.4)
0.10
Primary outcomes or death
4.2%
5.1%Â
-0.9 (-2.1 to 0.3)
0.15
Mortality
3.2%
3.2%
?
?
Fatal stroke
0.4%
0.4%
?
?
Non-fatal disabling stroke
0.2%
0.3%
?
?
On-Treatment Analyses
Â
Â
Â
Â
Composite mortality, stroke, embolism, and MI
4.2%
4.9%
-0.7 (-1.9 to 0.5)
0.26
Major bleeding
1.3%
1.8%
-0.5 (-1.2 to 0.2)
0.23
Major or minor bleeding
25.8%
29.8%Â
-4.0 (-6.9 to -1.1)
0.006
ALT >3x normal
6%
1%
?
<0.0001
ARR=absolute risk reduction, MI=myocardial infarction, ALT=alanine aminotransferase
At baseline, both groups had similar numbers of patients with each of the known major risk factors for stroke and embolus.
Rates of death, fatal stroke, non-fatal disabling stroke, and composites of mortality, stroke, embolism, and MI were similar in both groups. There was a trend towards lower yearly primary outcome event rates with ximelagatran [see table].
Major bleeding occurred in about 1.5% of each group; but minor bleeding events were significantly reduced from 28% with warfarin to 24.5% with ximelagatran.
Rates of adverse events were similar in both groups, with the exception of increased ALT levels in the ximelagatran group.
ALT elevations with ximelagatran occurred after 2 to 6 months of treatment, and returned to baseline in all subjects without clinical effects either spontaneously or after discontinuation of treatment. Of those with elevated ALT, 48 of the 107 (44.9%) taking ximelagatran and 4 of the 14 (28.6%) taking warfarin discontinued treatment. 4 developed jaundice due to either hepatic metastasis or cholelithiasis.
Adherence was high in both groups: in the warfarin group, INR values were therapeutic 2-3 for 66% of the follow-up period; in the ximelagatran group, medication adherence by pill counts was 94%.
Concerns Regarding Methodology, Applicability to Older Adults, etc.:
Idraparinux, oral factor Xa inhibitors, and clopidogrel plus aspirin are also currently being tested against warfarin for stroke prevention in A Fib.
Funding Source and Role:
AstraZeneca pharmaceuticals. Five of the 11 members of the Executive Steering Committee, two of whom were among the eight voting members, were AstraZeneca employees; expenses and honoraria were paid for the other members.
Created By:
Hans Stohrer, MD, Fellow, Mt. Sinai School of Medicine
This is a review of the validity of a single study; the ‘bottom lines’ do not reflect comparison with the rest of the literature on this subject.