Dabigatran Vs. Warfarin in Patients with Atrial Fibrillation. Journal Club. Jad Skaf 11/12/2009. BACKGROUND. Warfarin. Substantial risk of major bleedings (approximately 1.2% per year).
Substantial risk of major bleedings (approximately 1.2% per year)
Albers GW, Dalen JE, Laupacis A, Manning WJ, Petersen P, Singer DE. Antithrombotic therapy in atrial fibrillation. Chest 2001; 119:194S–206S.
Even within the controlled setting of a clinical trial, it has not been possible to stay within the therapeutic window more than 50% of the time.Cairns JA, Connolly SJ. Nonrheumatic atrial fibrillation. Risk of stroke and role of antithrombotic therapy. Circulation 1991; 84:469–481.
In summary, therapy with VKAs is complex, potentially dangerous, and unpleasant, and this has resulted in considerable difficulty in convincing physicians and patients to adhere to current practice guidelines, with a resulting undertreatment in a considerable proportion of patients at risk.
Frykman V, Beerman B, Ryden L, Rosenqvist M. Management of atrial fibrillation: discrepancy between guideline recommendations and actual practice exposes patients to risk for complications. Eur Heart J 2001; 22:1954–1959.
-Atrial fibrillation Clopidogrel Trial with Irbesartan for
prevention of Vascular Events ACTIVE-W trial
-ACTIVE-A trial, comparing clopidogrel
and aspirin with aspirin alone in patients with
contraindication to warfarin
of factors II, VII, IX, and X
Direct Xa inhibition:
Indirect via antithrombin: Fondaparinux
Indirect via antithrombin: UFH, LMWH
Direct Thrombin Inhibition: Hirudin
-Dabigatran with or without concomitant
aspirin compared with warfarin alone in
patients with nonvalvular atrial fibrillation
Am J Cardiol 2007;100:1419-26.
-Dabigatran etexilate versus enoxaparin
for prevention of VTE after total hip
Is Dabigatran non-inferior to Warfarin for
preventing stroke or other systemic
Embolism in patients with AF ?
- Clinical trials are increasingly being required to show benefits on clinical end-points rather than surrogate end-points
- The incremental benefits of newer treatments are getting smaller
Trials to show that the new treatment has an effect similar to that of the standard, rather than outright superiority.
ASSENT (Assessment of the Safety and Efficacy of a New Thrombolytic)-2
GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries)-III
COBALT(Continuous Infusion Versus Double-Bolus Administration of Alteplase)
- A trial that successfully demonstrates superiority has simultaneously demonstrated assay sensitivity. However, a noninferiority trial that successfully finds the effects of the treatments to be similar has demonstrated no such thing.
- A well-executed clinical trial that correctly demonstrates the treatments to be similar can not be distinguished, on the basis of the data alone, from a poorly executed trial that fails to find a true difference.
- Therefore, a noninferiority trial must rely on an assumption of assay sensitivity on the basis of information external to the trial, such as the quality control procedures or the reputation of the investigator.
Poor Compliance with the study medication
Poor diagnostic criteria
Excessive variability of measurements
Biased end-point assessment.
Analysis of noninferiority trials
Specifying the noninferiority margin
-Specify the equivalence margin on the basis of a clinical notion of a minimally important effect.
-The equivalence margin is often chosen with reference to
the effect of the active control in historical placebo
A phase 3, multicenter, prospective, open-label,
randomized trial with blinded evaluation of all outcomes
(PROBE design),designed to compare two fixed doses
Of dabigatran, each administered in a blinded manner,
With open-label use of warfarin in patients who had
Atrial fibrillation and were at increased risk for stroke.
.There is ECG documented AF on the day of screening or randomization
.The patient has had a symptomatic episode of paroxysmal or persistent AF
documented by 12-lead ECG within 6 m before randomization
.There is documentation of symptomatic or asymptomatic paroxysmal or persistent AF on 2 separate occasions, at least 1 day apart, one of which is within 6 m before randomization. In this case, AF may be documented by 12
lead ECG, rhythm strip, pacemaker/ICD electrogram, or Holter ECG.
.The duration of AF should be at least 30 s.
.Electrograms (not marker channels or mode switch episodes) from pacemakers and defibrillators can be used to document only 1 episode of paroxysmal or persistent AF2.)
2.) In addition to documented AF, patients must have one of the following:
a. History of previousStroke, TIA, or systemic embolism
b. EF <40% documented by echocardiogram, radionuclide or contrast angiogram in the last 6 m
c. Symptomatic heart failure, New York Heart Association class 2 or higher in the last 6 m
d. Age ≥75 y
e. Age ≥65 y and one of the following: i) Diabetes mellitus on treatment
ii) Documented CAD
iii) HTN requiring medical treatment
3.) Age >18 y at entry
4.) Written, informed consent
Severe heart-valve disorder.
Stroke within 14 days or severe stroke within 6 months before screening.
A condition that increased the risk of hemorrhage.
Creatinine Cl < 30 ml/min.
Active liver disease.
Dabigatran 110 mg BID
Dabigatran 150 mg BID
Warfarin 1,3,5 mg
Men 64.3 %
CHADS2 score 32.6
Long Term VKA 50.1 %
Men 63.3 %
CHADS2 score 30.9
Long Term VKA 48.6 %
Men 63.2 %
CHADS2 score 32.2
Long Term VKA 50.2 %
1ary outcome: stroke or systemic embolism1ary safety outcome: major hemorrhage
2ary outcomes: stroke, systemic embolism, death
Q3m / 1st year
Q4m / 2nd year
The primary efficacy variable is the time to the first occurrence of
Stroke (including hemorrhagic) or systemic embolism using the Cox
Proportional hazard model.
The null hypothesis:
Hazard ratio of dabigatran vs warfarin is larger than or equal to the specified
noninferiority margin δ = 1.46
Meta Analysis of trials of vitamin K antagonists
as compared with control therapy in patients
with atrial fibrillation, with the margin defined
according to the upper bound of the 95%
confidence interval for the relative risk of the
primary outcome in the control group versus
the warfarin group.
Cox regression was used to calculate relative
risks, confidence intervals, and P values. Chi
square testing was used to compare rates of
medication discontinuation and adverse events.
Dabigatran 110 mg BID
Dabigatran 150 mg BID
Warfarin 1,3,5 mg
Stroke: 182 (1.53 % / yr)
Hgic Stroke: 0.12%
Stroke: 169 (1.99 % / yr)
Hgic Stroke: 0.38%
Stroke: 134 (1.11 % / yr)
Hgic Stroke: 0.10%
The 150-mg dose of dabigatran was also superior to warfarin (relative risk, 0.66;
95% confidence interval [CI], 0.53 to 0.82; P<0.001), but the 110-mg dose was not
(relative risk, 0.91; 95% CI, 0.74 to 1.11; P = 0.34).
Cumulative Hazard Rates for the Primary Outcome of Stroke or Systemic Embolism, According to Treatment Group
Both dabigatran doses were non-inferior to warfarin with respect to the primary efficacy outcome of stroke or systemic embolism.
In addition, the 150-mg dose of dabigatran was superior to warfarin with respect to stroke or systemic embolism, and the 110-mg dose was superior to warfarin with respect to major bleeding.
Declared a delta of 1.46 (relative risk) as the margin of non-inferiority!
Translated this says that a 46% difference in the rate of stroke or arterial clot is clinically non-significant!
This choice was justified on the basis of trials comparing warfarin to PLACEBO as analyzed in a 10-year-old meta-analysis*.
It is obvious that an ex-post difference between a therapy and placebo in superiority trials does not apply to non-inferiority trials of two active agents.
This just means that the RR point estimate for 110 mg versus warfarin is statistically significantly different from a RR of 1.46
It does NOT mean that the comparison between the two drugs on stroke and arterial clot is highly clinically significant, but misleadingly suggests so.
This creates an artificial and exaggerated impression of the difference between these two agents.
But here again, the 95% CI is narrower than the margin of non-inferiority, and had the results gone the other direction, as in Scenarios 3 and 4, (in favor of warfarin), we would have still claimed non-inferiority, even though warfarin would have been statistically significantly "better than" dabigatran! So it is unfair to claim superiority on the basis of a statistically significant result favoring dabigatran
This is the problem that is likely to crop up when you make your margin of non-inferiority excessively wide, which you will do if you wish to stack the deck in favor of your therapy.
Imagine the reverse. If dabigatran was the existing agent for prevention of stroke in A-fib, and warfarin was the new kid on the block. If the makers of warfarin had designed this trial AND GOTTEN THE EXACT SAME DATA, they would have said (look at the left of the figure and the dashed red line there) that warfarin is non-inferior to the 110 mg dose of dabigatran, but that it was not non-inferior to the 150 mg dose of dabigatran. They would NOT have claimed that dabigatran was superior to warfarin, nor that warfarin was inferior to dabigatran, because the 95% CI of the difference between warfarin and dabigatran 150 mg crosses the pre-specified margin of non-inferiority. And to claim superiority of dabigatran, the 95% CI of the difference would have to fall all the way to the left of the dashed red line on the left. (See Piaggio, JAMA, 2006.)