Ontario College of Family Physicians
51st Annual Scientific Assembly
New oral Anticoagulants
November 30, 2013
Dr John Blakely
1
Faculty/Presenter Disclosure
• Faculty: Dr. John Blakely
• Program: 51st Annual Scientific Assembly
• Relationships with commercial interests:
- None
2
Disclosure of Commercial
Support
• This program has received no financial or in kind support or
benefits from anyone in any form.
Potential for conflict(s) of interest:
- I run an anticoagulant clinic.
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Mitigating Potential Bias
• The presentation is about data
• Opinion is clearly identified
4
Disclosures
• 51 years running anticoagulant clinics
• Dosing sessions about 1,600 / month
• Mean INR 107 consecutive clinics 2.53
• INR SD 0.5
• IC Bleed rate ≈ 2 / 1000 patient years (4?)
5
Disclosures
• Little experience with warfarin–NOAC
transitions & NOAC bleeding
• Major interest in logic of trials analysis
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New Oral Anticoagulants
• Read the EU executive summary
• Check renal function (q 3 – 6 months)
• Check compliance with pill counts
7
Backwards Presentation
• Conclusions first
• Then supporting evidence
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New Anticoagulants in Atrial Fibrillation
• Dabigatran – should not have been approved
for atrial fibrillation
• Rivaroxaban, apixaban
– atrial fibrillation -should have been
approved for institutional use (only)
• New agents unlikely to solve poor INR control
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New Anticoagulants in VTE
• Rivaroxaban OK in orthopedic thrombprophylaxis
• Bioequivlence overstated in VTE
10
Assessing Treatment Value
• Efficacy
– Demonstration of anticoagulant effect
• Requires double blind double dummy trial
• Effectiveness
– Prevention of strokes in practice
• Requires practice conditions; ‘hard’ endpoints
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Supervision
• Warfarin requires considerable supervision
• “It would be good to have an
anticoagulant that did not need regular
supervision”
• NO!!!
Supervision improves compliance
(& all human activities)
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Supervision
• Built-in supervision warfarin’s greatest advantage
• Lack of supervision greatest weakness of new agents
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What is the Evidence That
Less Supervision
Has
Positive Results?
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Supervision Improves At Least
• Tuberculosis treatment
– primary drug resistance
– acquired drug resistance
– relapse.

N Engl J Med 1994; 330:1179-1184April 28, 1994
DOI: 10.1056/NEJM199404283301702
• Emergency Physicians

compliance with guidelines

Tidsskr Nor Laegeforen. 2008 May 15;128(10):1179-81.

European Journal of Vascular and Endovascular Surgery : the Official Journal of the European
Society for Vascular Surgery[2007, 34(1):1-9]
• Obstetric services in Norway.
• Exercise therapy
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Supervision Improves At Least
• Building factories in Bangladesh
• Parking trains in Quebec
• Taking pills (anywhere)
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Physician Supervision Less Effective
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Physician Supervision Less Effective
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PROBE
• Prospective Randomized Open trial with
Blinded End-point assessments
• Introduced in 1992 without validation as it
was ‘‘self evident that results would be the
same as double blind.‘‘
Blood Pressure 1992, Vol. 1, No. 2 , Pages 113-119
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PROBE tested
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Impact of double-blind vs. open study
design on the observed treatment effects of
new oral anticoagulants in atrial fibrillation:
a meta-analysis
• Thirteen studies, 61,620 patients. (All phase II or III trials eligible)
• Embolism & stroke PROBE produced 14% overestimate
• 1/6 chance of equal efficacies producing the result observed
• Hemorrhagic stroke 67% overestimate
• Warfarin management ?
J Thromb Haemost; 2013 Jul;11(7):1240-50
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PROBE tested
• Ximelagatran
– At risk atrial fibrillators
– Stroke & systemic embolism
• SPORTIF lll PROBE
– unblinded trial, blinded adjudicators
– Questionnaire
• SPORTIF V
– Double blind, double dummy
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SPORTIF lll
Method
PROBE
Mean INR
2.4
TTR
68%
Strokes/Yr ximelagatan 1.6%
Strokes/Yr warfarin
2.2%
Excess strokes
37.5%
SPORTIF V
Double Blind
2.5
66%
1.6%
1.2%
- 25%
PROBE efficacy overestimate 43%
p = 0.003
Lancet 2003; 362:1691-98
JAMA 2005; 293, 6
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PROBE trial Design
(unblinded trial, blinded adjudicators)
• SPORTIF: PROBE overestimated the double blind
result by 43% (V published February 9, lll Nov 22 2005)
• Re-Ly (PROBE) recruiting began December 22 2005
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Re-Ly
• PROBE trials are
–
–
–
–
Easier
Less expensive
Produce more positive results
Acceptable !!
N Engl J Med 2009;361:1139-1151
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Dabgatran in Atrial Fibrillation
• Trial design was invalid
• Probable overestimate of efficacy
• Probable overestimate of warfarin strokes
prevented / bleeds caused
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Re-Ly
• Published IC bleeding advantage nullified
by % noncompliance of
CHADS 2 score
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Compliance
In ‘real life’ (practice) compliance is the key
Rivaroxaban & apixaban have not been tested.
Do unsupervised anticoagulants prevent as
many strokes as well managed warfarin?
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The Compliance Trap
• Most (83%) patients believe they take every pill
• Properly questioned, only 64% of these actually do
• “Compliance assumption trap”
may be a significant cause of stroke
.
Dtsch Med Wochenschr. 2007 Jan 26;132(4):139-44.
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Patients Poorly Managed on
Warfarin do Poorly on New Agents
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Effect by
INR Time in Therapeutic Range
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Dabigatran Effect by
INR Time in Therapeutic Range
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Effect of TTR on rivaroxaban
Rocket
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Loss of Riveroxaban Efficacy
with Decrease in TTR
(p =.016)
Ratio excess events over 4th quartile
1.60
1.40
event rate
1.20
1.00
Series1
0.80
Series2
0.60
0.40
0.20
0.00
1
2
3
quartile
4
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Effect of TTR on apixaban
ARISTOTLE
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Effect of TTR on apixaban
Centre
TTR
<58%
Apixaban
Warfarin
Events/100 Events/100
pt-yrs
pt-yrs
1.75
2.28
58 - 65
1.30
1.61
65 - 72
1.21
1.55
> 72
0.83
1.02
The heart.org Aug 28 2011
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New Anticoagulants in Atrial Fibrillation
• Dabigatran – data unreliable, overestimate
• Rivaroxaban & apixaban
– OK when supervised exactly as warfarin
– Validated supervision likely rare
– Not tested in practice
– Probably ideal for institutional use
– Poor remedy for poor INR control
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Venous Thromboembolic Disease
• Compliance not an issue in hospital
• Compliance probably better
– Treating rather than preventing events
– With short term treatment
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Assessing Treatment Value
• Efficacy
– Demonstration of anticoagulant effect
• Requires double blind double dummy trial
• Effectiveness
– Prevention of strokes in practice
• Requires practice conditions; ‘hard’ endpoints
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Extended Use of Dabigatran, Warfarin, or
Placebo in Venous Thromboembolism
• Recurrence
–
–
–
–
–
(RESONATE)
dabigatran
1.8%
warfarin group 1.3%
hazard ratio with dabigatran, 1.44; 95%
P=0.01 for noninferiority
1/9 chance equal efficacies would produce result
– “p -0.01” is statistical distance between result
& committee decision ≤ 285% (3.7% ) worse is non-inferior
N ENGL J MED 2013; 368:709-718February 21, 2013DOI: 10.1056/NEJMOA1113697
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Re-Cover
Dabigatran VS Warfarin in
Treatment of Acute Venous
Thromboembolism
P < 0.001 for the prespecified non-inferiority margin
• “Dabigatran Can Replace Warfarin in Venous Thromboembolism”
• 1/3 chance that equal efficacies would produce the observation
NEJM.ORG Dec 10 2009
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If well managed warfarin is optimal,
how do we manage it well?
•
•
•
•
•
•
•
•
•
•
•
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Cumulative record of INRs, doses, indication, review date, INR
target, tab strength
Written warfarin safe practice instructions & dosing calendar.
Insist on a dosette™ box for warfarin (identifies missed doses;
take them ‘now’).
Dosing algorithm. Aim for the target, not the bottom of the range.
One tablet strength only. Give weekly doses as combinations of
whole & half tablets
Know about changes in concomitant therapy within a week
Standard questions for out of range INRs
Bridge therapy protocol
Don’t stop warfarin for dentistry, screening colonoscopy, minor
superficial surgery
INR turnaround ≤ 24 hour, positive contact every INR
Most INR perturbations are ‘one off’. Use ‘one off’ corrections.
Modify maintenance dose if change understood or 2 – 3
consecutive ‘one offs’
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Summary
• The ‘PROBE’ trial design overestimates efficacy
• Anticoagulant effect is not enough. Warfarin
alternatives must be effective unsupervised
• New anticoagulants are not a fix for poorly
managed warfarin
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Ontario College of Family Physicians
51st Annual Scientific Assembly
New oral Anticoagulants
November 30, 2013
Dr John Blakely
44