Transcript eSlide - P6780 ACC Epstein Presentation

Effect of Genotyping Warfarin Patients on Outcomes:
Results from The National Community-based MedcoMayo Warfarin Effectiveness Study (MM-WES)
Robert S Epstein MD MS, Thomas P. Moyer PhD, Ronald E. Aubert PhD,
Dennis J. O’Kane PhD, Fang Xia PhD, Robert R. Verbrugge PhD,
Brian F. Gage MD MS, J. Russell Teagarden DMH, RPh
Medco Health Solutions, Franklin Lakes, NJ;
Mayo Clinic, Rochester, MN;
Washington University, St Louis MO
Manuscript is “in press” in Journal of American College of Cardiology
Medco is a registered trademark of Medco Health Solutions, Inc.
© 2010 Medco Health Solutions, Inc. All rights reserved.
Disclosures for Robert Epstein MD
Financial disclosures:
None
Honoraria:
None
Support:
Medco and Mayo Clinic Center for Individualized Therapy
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Background
Warfarin exhibits large inter-individual dosing requirements
Warfarin is a leading cause of morbidity and mortality
Two genes account for ~33% of variance in dosing
 Cytochrome P450 2C9 (CYP2C9) – pharmacokinetics
 VKORC1 – pharmacodynamics
Meta-analysis of 3 clinical trials of warfarin genotyping showed
a 32% decrease in major bleeding (RR 0.68, CI 0.22-2.06)*
*Eckman MH, Rosand J, Geenberg SM, Gage BF: Cost-effectiveness of using pharmacogenetic
information in warfarin dosing for patients with nonvalvular atrial fibrillation. Ann Int Med
2009;150(2):73-83.
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Study hypothesis & design:
Hypothesis:
The use of CYP2C9/VKORC1 testing will reduce the
risk of hospitalization during the first 6 months of
warfarin treatment
Design:
Prospective observational cohort study with national
community based sampling (quasi-experimental)
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Inclusion/exclusion criteria
Inclusion Criteria:
Males, females 40-75 year of age
‘New starts’ to warfarin
Physician approval & Patient informed consent
Exclusion Criteria:
Known hypersensitivity reaction to warfarin
Patients residing in Olmsted County MN
Recent hospital stay >7 days in length
Short-term use of warfarin
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Study groups*
Medco-Mayo
Warfarin Effectiveness Study
Primary Comparison
Comparison of External
Controls
Historical control
Intervention
group
External
historical control
External
concurrent control
July 2006 –
June 2007
n=2688
July 2007 –
February 2009
n=896
July 2006 –
June 2007
n=2688
July 2007 –
February 2009
n=2688
23 Benefit Plan Sponsors
56 Benefit Plan Sponsors
*6 month follow-up on all patients initiating warfarin in all groups
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Methods for Outcomes Comparisons
Unadjusted comparisons – Kaplan-Meier and log-rank tests
Adjusted comparisons – propensity scores to handle
participant/non-participant differences, indications for therapy,
specific concomitant drugs, medical conditions, prior history of
hospitalization or history of bleed/thromboemboli.
ANALYSES
Intention-to-treat – all outcomes even if adverse event
preceded genotype
Per-protocol – only those outcomes counted if post-genotype
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Flow of the genotyping arm
Medco identified
‘new starts’ to
warfarin on any
given day of
the week
Medco contacted
‘new starts’ to
solicit verbal
informed consent
Medco contacted
physician for
clinical information
and consent for
patient to receive
genotype test
First half of
enrollment – Medco
arranged for home
blood draw –
received written
informed consent,
sent blood to Mayo
Mayo completed lab test –
supplied report to physician
and results to Medco
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Sample Mayo Clinic Laboratory Report
Sample Lab Report: Warfarin Genotype Results
Medco Health Solutions
Mayo/Medco Warfarin Protocol
Attn: Accounts Payable
100 Parsons Pond Drive
Franklin Lakes, NJ 07417
Patient Name:
SMITH, JOHN
Received Date:
Accession #:
DOE, JANE
Birth Date:
Medical Rec #:
Client Accn #:
A1234567
09/13/1942 Age:65 Gender:F
1234
123456789
Ordering Phys:
Collect Date:
11/07/2007
11/08/2007
7:19 AM
10:40 AM
---------------------------------------------------------------------------------------------------------------
Test Requested
Result
Units
Perform Site *
------------------------------Rapid DNA Extraction
Comment
Genomic DNA was extracted.
MCR
============================================================================
CYP2C9 + VKORC1 Genotype, Warfarin
CYP2C9 430C>T(*2)
C/T
CYP2C9 1075A>C(*3)
A/C
CYP2C9 1076T>C(*4)
T/T
CYP2C9 1080C>G(*5)
C/C
CYP2C9 818delA(*6)
A/A
VKORC1 -1639G>A
A/A
============================================================================
Ref Range
-------
MCR
MCR
MCR
MCR
MCR
MCR
Interpretation:
This genotype is rare and has very high sensitivity to warfarin.
Warfarin dose decrease and frequent INR monitoring should be
considered.
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Participants from 49 US states
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Results: Baseline characteristics
Characteristic
Mean age, yrs (SD)
Male(%)
Medications (%)
Amiodarone
Statins
Sulfamethoxazole
Fluconazole
NSAID
Clopidogrel
Steroids
Conditions (%)
GI bleed
Atrial fibrillation
Pulmonary embolism
Deep vein thrombosis
Hypertension
Diabetes
Prior hospitalizations (%)
Any cause
Bleeding or thromboembolism
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Historical control
(n=2688)
65.2 (8.0)
60.5%
Intervention group
(n= 896)
65.2 (8.3)
60.5%
P-value
0.921
1.000
4.0%
14.5%
4.4%
2.4%
19.6%
10.8%
12.4%
3.2%
16.9%
5.2%
2.6%
19.9%
10.2%
13.6%
0.313
0.071
0.268
0.803
0.865
0.574
0.354
3.6%
40.4%
11.0%
24.6%
47.0%
15.3%
4.0%
41.1%
11.8%
25.8%
54.2%
11.6%
0.539
0.709
0.501
0.489
<0.001
0.007
54.4%
23.6%
52.8%
24.8%
0.405
0.469
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Results: (n=424)
Warfarin Rxs within 21 days post-genotyping
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Warfarin
sensitivity
% patients
Mean weekly
dose change (SE)
P-value
< Normal
29.0%
+6.65 mg (1.98)
<0.01
Normal
28.1%
+1.10 mg (1.40)
0.50
Mild
11.6%
+3.21 mg (3.41)
0.21
Moderate
25.0%
-3.65 mg (1.56)
<0.01
High
4.0%
-10.14 mg (3.18)
0.04
Very high
2.4%
-17.33 mg (4.54)
<0.01
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Results: Unadjusted 6 mo. hospitalization rates
>=1 hospitalization per 100 patients/6months
28%
Historical control (n=2688)
↓
Intervention group (n=896)
25.52
27%
18.45
↓
8.13
5.97
All cause
p-value
Bleed or thromboembolism
<0.001
0.039
Intention to treat (ITT)
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Results: All-cause hospitalization rate
Intention-to-treat analyses*
All cause
Hospitalization risk
30%
IG
HC
25%
20%
HR: 0.69 (CI: 0.58, 0.82)
p<0.001
15%
10%
5%
0%
0
10
20
30
40
50 60
70
80
90 100 110 120 130 140 150 160 170 180
Days after treatment onset
*Adjusted for age, comorbid conditions, drugs, propensity score, indications, prior GI bleed or
VTE, history of prior hospitalization
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Results:
Hospitalization rate for bleed / thromboembolism. Intention-to-treat analysis*
Bleed or thromboembolism
Hospitalization risk
10%
8%
6%
IG
HC
HR: 0.72 (CI: 0.53, 0.97)
p=0.029
4%
2%
0%
0
10
20
30
40
50 60
70
80
90 100 110 120 130 140 150 160 170 180
Days after treatment onset
*Adjusted for age, comorbid conditions, drugs, propensity score, indications, prior GI bleed or VTE,
history of prior hospitalization
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Results:
External control group comparison
Hospitalization rates (unadjusted)
External Pre
External Post
22.8%
7.8%
22.7%
7.2%
 Any cause
 Bleeds/thromboemboli
p=ns
p=ns
Hospitalization rates (adjusted) H.R. (95% CI)
 Any cause
 Bleeding or thromboemboli
HR 0.98 (0.88-1.1)
HR 0.92 (0.76-1.1)
No difference in hospitalization rates over the
same 2 time periods in the external controls
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Limitations
Non-randomized trial design
Hawthorne effect
Administrative Claims Data for endpoints
Time to genotyping
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Conclusions
Genotyping warfarin patients resulted in ~30% reduction in
hospitalizations for all-cause & for bleeds/thromboemboli
Genotyping closer to therapy initiation improved outcomes
Physicians modified warfarin prescribing through the
introduction of the Mayo genotype laboratory report
Physicians adoption of genotype testing was high (75%)
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