Transcript Journal Club

Journal Club
Dabigatran Vs. Warfarin
in Patients with Atrial Fibrillation
Jad Skaf
11/12/2009
BACKGROUND
Warfarin
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.
Dietary intake of vitamin K; hepatic dysfunction; changes in the gut flora;
patient compliance; and alcohol intake.
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.
- Vitamin K epoxide reductase complex subunit 1 (VKORC1).
- Cytochrome P450 2C9 (CYP2C9)
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.
40%
Hence the Search for Newer Anticoagulants to decrease
Cardio-vascular Events esp. in patients with AF
CLOPIDOGREL
-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
VKA inhibit the synthesis
of factors II, VII, IX, and X
Direct Xa inhibition:
Rivaroxaban, Apixaban
Indirect via antithrombin:
Fondaparinux
Indirect via antithrombin:
UFH, LMWH
Direct Thrombin Inhibition:
Hirudin
Bivalirudin
Argatroban
Dabigatran
Dabigatran Etexilate (PRADAXA)
•
•
•
•
•
Direct, competitive
inhibitor of thrombin.
Bioavailability - 6.5%,
80% of the given dose is
excreted by the kidneys
Half-life - 12 to 17 hrs
Does not require regular
monitoring
-Dabigatran with or without concomitant
aspirin compared with warfarin alone in
patients with nonvalvular atrial fibrillation
PETRO Study
Am J Cardiol 2007;100:1419-26.
-Dabigatran etexilate versus enoxaparin
for prevention of VTE after total hip
replacement
Lancet 2007;370:
Question ?
Is Dabigatran non-inferior to Warfarin for
preventing stroke or other systemic
Embolism in patients with AF ?
Non Inferiority Trials (NIT)
Indications:
- Clinical trials are increasingly being required to show
benefits on clinical end-points rather than surrogate endpoints
- 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
GUSTO
COBALT
(Assessment of the Safety and Efficacy of a New Thrombolytic)-2
(Global Use of Strategies to Open Occluded Coronary Arteries)-III
(Continuous Infusion Versus Double-Bolus Administration of Alteplase)
NIT Weaknesses
Assay Sensitivity
- 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
measuremen
ts
Biased endpoint
assessment.
NIT Weaknesses
Assay Sensitivity
Analysis of noninferiority trials
Blinding
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
controlled trials.
ITT
alternative?
CONCLUSION - NIT
• There are inherent problems with NIT that make their
results clearly less credible than those of a placebocontrolled trial.
• However, it is not always possible to include a placebo
treatment for ethical reasons, and there will always be a
need for clinical trials to test new treatments that are
either no more effective than the standard (but which
may offer some other advantage, such as better safety
or more convenient dosing) or offer such a small
increase in efficacy that the size of a superiority trial
would be prohibitive.
• Be aware of the issues and account for them
appropriately.
Journal club questions
• What is the question?
• Why does it matter?
• How does it fit with what already is known? What
does it add to literature?
• Study design, methods and findings.
• How generalisable is the data=Validity?
• Strengths and weaknesses
• Can the information change the current
practice? How can you imply the findings into
your practice?
The Randomized Evaluation of
Long-Term Anticoagulation
Therapy (RE-LY)
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.
INCLUSION Criteria
1.) AF
.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:
Stroke,
. EF <40%
Symptomatic heart failure
a. History of previous
b
TIA, or systemic embolism
documented by echocardiogram, radionuclide or contrast angiogram in the last 6 m
c.
higher in the last 6 m
d.
, New York Heart Association class 2 or
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
EXCLUSION Criteria
• 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.
• Pregnancy.
18113
Dabigatran 110 mg BID
(2005-2007)
Dabigatran 150 mg BID
Warfarin 1,3,5 mg
6015
Age 71.4±8.6
2 Years
6076
6022
Age 71.6±8.6
Men 64.3 %
Age 71.5±8.8
Men 63.3 %
CHADS2 score 32.6
Men 63.2 %
CHADS2 score 30.9
Long Term VKA 50.1 %
CHADS2 score 32.2
Long Term VKA 48.6 %
Long Term VKA 50.2 %
1ary outcome: stroke or systemic embolism
1ary safety outcome: major hemorrhage
2ary outcomes: stroke, systemic embolism, death
INR
• INR measured at least monthly.
• The time that the INR was within the therapeutic range was
calculated with the use of the method of Rosendaal et al.
• These data were reported back to the participating centers with
advice for optimal INR control.
• Concomitant use of aspirin (at a dose of <100 mg per day) or other
antiplatelet agents was permitted.
14d 1m 3m
Q3m / 1st year
Q4m / 2nd year
Statistical Analysis
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
This noninferiority margin was derived from a
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.
95%
18113
Dabigatran 110 mg BID
(2005-2007)
Dabigatran 150 mg BID
Warfarin 1,3,5 mg
6015
6022
20.7 %
6076
16.6%
21.2 %
Stroke: 182 (1.53 % / yr)
Hgic Stroke: 0.12%
Stroke: 169 (1.99 % / yr)
Stroke: 134 (1.11 % / yr)
Hgic Stroke: 0.38%
Hgic Stroke: 0.10%
In Stroke or systemic embolism prevention:
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
CONCLUSION
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.
Weaknesses of Re-Ly
Declared a delta of 1.46 (relative risk) as the margin of noninferiority!
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.
•
•
•
•
P. Petersen, G. Boysen and J. Godtfredsen et al., Placebo-controlled, randomised trial of warfarin and ASA for
prevention of thromboembolic complications in chronic atrial fibrillation: the Copenhagen AFASAK study, Lancet 1
(1989), pp. 175–179.
Boston Area Anticoagulation Trial for Atrial Fibrillation Investigators, The effect of low-dose warfarin on the risk of
stroke in nonrheumatic atrial fibrillation, N Engl J Med 323 (1990), pp. 1505–1511.
Stroke Prevention in Atrial Fibrillation Investigators, Stroke prevention in atrial fibrillation study. Final results,
Circulation 84 (1991), pp. 527–539.
European Atrial Fibrillation Trial Study Group, Secondary prevention in non-rheumatic atrial fibrillation after
transient ischemic attack or minor stroke, Lancet 342 (1993), pp. 1255–1262.
P-value for noninferiority ???
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 noninferiority, 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.)
Does that make any sense ?