Download Fatimah Al-Shehri,journal club presentation of amplfy study NGH

August 29, 2013Agnelli G., Buller H.R., Cohen A., et al.N Engl J Med 2013; 369:799-808
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Pharmacological class.
Indications:(FDA & non-FDA )
Mechanism of action.
Pharmacokinetics.
Contraindications.
Advantages and disadvantages comparing to warfarin .
Apixaban: is an oral anticoagulant .
 pharmacological class: Factor Xa inhibitor.
 Uses :
 Labeled Uses(FDA approved):
1-Stroke prophylaxis. Systemic embolism prophylaxis in patients with
non-valvular atrial fibrillation. In 28 December, 2012.
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Unlabeled Uses(non-FDA approved):
1-To reduce the risk of recurrent DVT and/or PE (in patients
completing 6-12 months of standard anticoagulation for venous
thromboembolism).
2- Postoperative DVT prophylaxis for arthroplasty of the knee.
3- Postoperative DVT prophylaxis for total hip replacement.
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Oral anticoagulants in the management of venous thromboembolism
John N. Makaryus, Jonathan L. Halperin & Joe F. Lau
Nature Reviews Cardiology 10, 397-409 (July 2013)
doi:10.1038/nrcardio.2013.73
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Absorption:
- The bioavailability is 50%.
-(C max) appear 3 to 4 hours.
-Apixaban is absorbed throughout the GIT with the distal small bowel and ascending colon
contributing about 55% of apixaban absorption.
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Distribution:
Plasma protein binding in humans is 87%. The Vd is 21 liters.
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Metabolism:
Approximately 25% is recovered in urine and feces as metabolites. Apixaban is metabolized
mainly via CYP3A4.
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Elimination:
Apixaban is eliminated in both urine and feces. Renal excretion accounts for about 27% of
total clearance. Biliary and direct intestinal excretion contributes to elimination of apixaban in
the feces.
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Contraindications:
Active pathological bleeding.
 Severe hypersensitivity reaction to Apixaban.
 Liver diseases.
 With other anticoagulants.
 Prosthetic valves.
 Mitral stenosis.
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Comparison between Apixaban and Warfarin :
Warfarin
Apixaban
Frequent monitoring of INR.
INR monitoring is not
required but kidney
function test required.
Food and drug
interaction
Any food containing vitamin k
should be taken consistently
,interact with many drugs.
less food and drug
interaction.
Onset of action:
Slow
Rapid .
Doses frequency.
Once daily
Twice daily.
Antidote.
Vitamin K
No antidote.
Less than apixaban.
Higher than warfarin .
More side effects especially
bleeding.
Less side effects .(less
bleeding ).
Items:
Follow up.
Costs.
Side
effects(bleeding).
1-Apixaban versus Enoxaparin for Thromboprophylaxis after Hip
Replacement:
Population :
5407 patients undergoing total hip replacement.
Intervention :
Apixaban 2.5 mg orally twice daily.
Comparator:
Enoxaparin at a dose of 40 mg subcut every 24 hours
Outcomes:
The primary efficacy outcome was the composite of asymptomatic or
symptomatic DVT,
nonfatal PE, or death from any cause during the treatment period.
Time:
60 days after the last dose
Among patients undergoing hip replacement, thromboprophylaxis with apixaban,
as compared with enoxaparin, was associated with lower rates of venous
thromboembolism, without increased bleeding.
N Engl J Med 2010;363:2487-98 ,december 23, 2010 vol. 363 no. 26
2- Apixaban versus Enoxaparin for Thromboprophylaxis in Medically Ill
Patients.
Population :
6528 subjects with CHF or RF or other medical disorders and at least
one additional risk factor for VT .
Intervention:
Apixaban at a dose of 2.5 mg twice daily for 30 days,
Comparator :
Enoxaparin, subcut at a dose of 40 mg once daily for 6 to 14 days.
Outcomes :
The primary efficacy outcome was the 30-day composite of death
related to VTE, PE , symptomatic DVT, or asymptomatic proximal-leg
DVT , as detected with the use of systematic bilateral compression
ultrasonography on day 30. The primary safety outcome was bleeding.
Time :
5 YEARS.
In medically ill patients, an extended course of thromboprophylaxis with apixaban
was not superior to a shorter course with enoxaparin. Apixaban was associated
with significantly more major bleeding events than was enoxaparin.
N Engl J Med 2011;365:2167-77.
Agnelli G., Buller H.R., Cohen A., et al.N Engl J Med 2013; 369:799-808
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Aim of the study :to compare the efficacy and safety of apixaban with the
efficacy and safety of conventional therapy in patients with DVT,PE or
both.
PICOT:
Population:
5395 patients with acute venous thromboembolism.
Intervention:
Apixaban 10 mg twice daily for 7 days, followed by 5 mg
twice daily for 6 months.
Control :
conventional therapy (subcut enoxaparin, followed by
warfarin).
Outcomes:
 The primary efficacy outcome was recurrent
symptomatic VTE or death related to VTE.
 The primary safety outcomes were bleeding major
bleeding +clinically relevent nonmajor bleeding .
Time :
From 2008-2012.) Mean Follow up period was 6 months).
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Null hypothesis: Apixaban would be inferior to
conventional therapy with respect of the primary
outcomes .
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Trial design: Randomized, double-blind ,double dummy
trial.
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Funding: (Funded by Pfizer and Bristol-Myers Squibb;
ClinicalTrials.gov number, NCT00643201).
 Randomization :
Usage of an interactive voice-response system and was stratified
according to the qualifying diagnosis of either:
1-Symptomatic proximal deep-vein thrombosis.
2- Symptomatic pulmonary embolism (with or
without deep-vein thrombosis).
Allocation and blinding:
Apixaban tablets +placebo
Enoxaparin injections and
placebo warfarin tablets.
Enoxaparin injections
and warfarin tablets + placebo
Apixaban tablets.
- 10 mg twice daiy for 7 days .
- 5mg twice daily for 6 months.
- Enoxaparin :1 mg/kg every 12
hours for at least 5 days.
- Warfarin begun concomitantly and
continued for 6 months .
Double blinded , double dummy study , used blinded INR monitoring with a
point-of-care device that generated an encrypted code for INR results.
Patients were eligible for inclusion in the study if
they were:
- 18 years of age or older and had objectively
confirmed, symptomatic proximal deep-vein
thrombosis or pulmonary embolism (with or without
deep-vein thrombosis).
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Active bleeding OR a high risk of bleeding.
Contraindications to treatment with enoxaparin &warfarin.
If they had cancer and long-term treatment with LMWH was
planned.
If their DVT or PE was provoked in the absence of a persistent
risk factor for recurrence.
If < 6 months of anticoagulant treatment was planned.
If they had another indication for long-term anticoagulation therapy,
dual antiplatelet therapy, treatment with aspirin at a dose of more
than 165 mg daily, or treatment with potent inhibitors of cytochrome
P-450 3A4.
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If they had received more than two doses of a once-daily
LMWH regimen, fondaparinux, or a vitamin K antagonist.
more than three doses of a twice-daily LMWH regimen; or
more than 36 hours of continuous intravenous heparin.
A hemoglobin level of < 9 mg/dl.
A platelet count of <100,000 per cubic millimeter,
A serum creatinine level of >2.5 mg/dl, or a calculated
CrCl of < 25 ml/min.
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Statistical analysis:
Intention to treat analysis .
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The 95% confidence interval for the relative risk was calculated with the use
of the Mantel–Haenszel method.
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The 95% confidence interval for the difference in risk was calculated
for the primary outcome with the use of the inverse-variance method.
Statistical testing for non-inferiority was performed with the method
of Farrington and Manning.
Time-to-event curves were calculated with the Kaplan–Meier method
Adverse effects : The rates of adverse events, including
elevations in liver-function tests, were similar in the two treatment
groups .
 On the basis of the results of this study, together
with those of the Apixaban for the Extended
Treatment of Deep Vein Thrombosis and
Pulmonary Embolism trials , apixaban provided a
simple, effective, and safe regimen for the initial
and long-term treatment of venous thromboembolism.
Validity (is the study valid?)
Yes/No
Comment:
1-Randomization:
1-Were patients randomized to
treatment groups?
Yes .
2-Were the treatment and the
control groups similar at the
beginning of the trial?
Yes .
Validity (is the study valid?)
Randomization was
preformed with the use of
interactive voice response
system.
Yes/No:
Comment:
2-Allocation:
Was the randomization concealed?
Yes .
It was double dummy
study.
Validity (is the study valid?)
Yes/No
Comment:
3-Blinding :
1-Were measures objective or were
the patients and clinicians kept
blind to which treatment was being
received? Who was blinded?
-
- Double blinded, double dummy
- Investigator ,patients all were
blinded.
2-Compliance: was it assessed
,How?
No .
It wasn't mentioned how did they
assess it .
3-Co-intervenstion?were groups
treated equally ?
Yes.
Any indications for antiplatelet
anticoagulant ,aspirin
Were excluded.
4-Contamination: was it mentioned?
No .
No contamination mentioned
.
Validity (is the study valid?):
Yes/No:
Comment:
Intension to treat analysis or not ?
1-Were all patients who entered the trial
accounted for ? And were they analyzed
in the groups to which they were
randomized?
It was ITT.
Sponsor?
1-How was the study funded?
It was funded by
Bristol-Myers
Squibb and Pfizer.
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The steering committee,
consisting of academic authors
& authors who were employees
of Pfizer, had final
responsibility for the study
design, oversight, & data
verification &analyses.
What are the study
results ?
Yes/No:
Comment:
1-What was the
primary endpoint?
-
the incidence of the adjudicated composite of
recurrent symptomatic VTE,
thromboembolism or death related to VTE.
2-What was the
secondary endpoint?
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Each component of the primary efficacy
outcome, as well as death from
cardiovascular causes and death from any
cause. Symptomatic recurrent VTE with
death from cardiovascular causes, with death
from any cause, or with death related to
venous thromboembolism plus major
bleeding.
What are the study results ?
Yes/No:
Comments:
3-Was there statistically
significant difference between
the treatments?
No .
For the primary outcome no
statistical difference .
4-Was it clinically significant?
No .
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How are the results expressed ?
FOR MAJOR BLEEDING :
EER=(Events in E group/total in E-group)=15/2691= 0.005=(0.6 %).
CER=(Events in C group/total in C group)=49/2704= 0.018(1.8 %).
RR=EER/CER= (0.33)
RRR=1-RR=(1-0.33)= (0.67)
ARR=CER-EER=(1.2)
NNH=[100/ARR=100/ 1.2]=83
For every 83 patients treated by apixaban 1 of them will experience
MAJOR BLEEDING .
.
How can we apply the study results
to our patients ?
Yes/No:
1- Will the intervention (Apixaban)
be feasible in my settings?
Yes.
2-Were the patients in this study
similar to my patients?
Yes.
comment:
Patients criteria matches the
Criteria of our patients.
How can we apply the study results to our Yes/No:
patients ?
Comment:
3-Will the potential benefits of treatments Yes.
outweigh the potential harms of
treatment for my patients?
Benefits: less bleeding.
4-Potential costs (Cost effectiveness,
direct vs. indirect costs ).
High
cost.
Its cost is more than warfarin
but the benefits outweigh the
cost.
5-Will my patients prefer this
intervention?
Yes.
No monitoring of INR .
No regular follow up is
needed. Better tolerated .
Less drug and food interation.
Medication :
1- Warfarin .
Price in $:
Price in SR:
1mg (80 RS )
2.5mg(110RS)
3mg(125 RS )
5mh(119 RS )
110mg (382 RS )
2-Dabigatran.
3-Rivaroxaban.
4- Apixaban.
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Limitations :
 This study was funded by Bristol-Myers Squibb and
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Pfizer. Many of the authors were affiliated with or
employed by Bristol-Myers Squibb, which introduces a
potential for bias.
The compliance was mentioned but it wasn't assessed .
 Strength
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:
Minimization of bias with the double-blind design.
Identical follow-up of all patients.
Central adjudication of all outcome events.
Study execution was rigorous, with minimal loss to follow-up, few
patients withdrawing consent, good adherence to study medication,
and well-managed warfarin therapy.