Transcript Thoughts about the New Anticoagulants

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.
3
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
6
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
8
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
9
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
11
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)
12
Supervision
• Built-in supervision warfarin’s greatest advantage
• Lack of supervision greatest weakness of new agents
13
What is the Evidence That
Less Supervision
Has
Positive Results?
14
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
15
Supervision Improves At Least
• Building factories in Bangladesh
• Parking trains in Quebec
• Taking pills (anywhere)
16
Physician Supervision Less Effective
17
Physician Supervision Less Effective
18
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
19
PROBE tested
20
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
21
PROBE tested
• Ximelagatran
– At risk atrial fibrillators
– Stroke & systemic embolism
• SPORTIF lll PROBE
– unblinded trial, blinded adjudicators
– Questionnaire
• SPORTIF V
– Double blind, double dummy
22
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
23
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
24
Re-Ly
• PROBE trials are
–
–
–
–
Easier
Less expensive
Produce more positive results
Acceptable !!
N Engl J Med 2009;361:1139-1151
25
Dabgatran in Atrial Fibrillation
• Trial design was invalid
• Probable overestimate of efficacy
• Probable overestimate of warfarin strokes
prevented / bleeds caused
26
Re-Ly
• Published IC bleeding advantage nullified
by % noncompliance of
CHADS 2 score
27
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?
28
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.
29
Patients Poorly Managed on
Warfarin do Poorly on New Agents
30
Effect by
INR Time in Therapeutic Range
31
Dabigatran Effect by
INR Time in Therapeutic Range
32
Effect of TTR on rivaroxaban
Rocket
33
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
34
Effect of TTR on apixaban
ARISTOTLE
35
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
36
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
37
Venous Thromboembolic Disease
• Compliance not an issue in hospital
• Compliance probably better
– Treating rather than preventing events
– With short term treatment
38
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
39
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
40
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
41
If well managed warfarin is optimal,
how do we manage it well?
•
•
•
•
•
•
•
•
•
•
•
•
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’
42
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
43
Ontario College of Family Physicians
51st Annual Scientific Assembly
New oral Anticoagulants
November 30, 2013
Dr John Blakely
44