William J. Culpepper, PhD

DMT Use and its Clinical Impact in the
VHA
William J. Culpepper II, PhD, MA
Associate Director for Epidemiology & Outcomes
MS Center of Excellence – East
and
Assistant Professor, Department of Neurology
University of Maryland School of Medicine
Disclosures - Support

This continuing education activity is managed and accredited by
Professional Education Service Group. The information presented in
this activity represents the opinion of the author(s) or faculty. Neither
PESG, nor any accrediting organization endorses any commercial
products displayed or mentioned in conjunction with this activity.

This work was supported by an Investigator Initiated grant from Berlex
Laboratories, Inc. (Currently Bayer healthcare, Inc.) and the VHA
Multiple Sclerosis Center of Excellence – East
Disclosures - Faculty

William J Culpepper II, PhD, MA



Grant/research support : IIR from Berlex Laboratories, Inc.
Grant/research support: IIR from Novartis Pharmaceutical
Corporation
CMS Staff Disclosures

Professional Education Services Group staff have no financial
interest or relationships to disclose
Learning Objectives

Provide overview of MS disease modifying
therapy (DMT) use and the associated
clinical impact

Present and discuss screening guidelines in
patients treated with mitoxantrone

Present and discuss effectiveness of DMT
Overview
FDA approved DMTs
 Importance of surveillance
 Methods for surveillance within the VHA
 FDA screening guidelines for mitoxantrone
 Effectiveness of DMTs in the VHA
Multiple Sclerosis Surveillance Registry
 Plans for prospective surveillance

FDA Approved DMT : Injectable
Drug Name
(YR approved)
Mode of Administration
Indication
for Use
Betaseron®
INFβ-1b (1993)
SC injection, every other day
RRMS,
SPMS
Avonex®
INFβ-1a (2002)
SC injection, 3/week
RRMS,
SPMS
Rebif®
INFβ-1a (1996)
IM injection, 1/week
RRMS,
SPMS
SC injection, daily
RRMS
Copaxone®
glatiramer acetate
(1996)
AEs : injection site reaction, flu-like symptoms, malaise, impaired
liver function, Nab and lack of efficacy, depression, allergic reactions,
seizures
FDA Approved DMT : Infusion
Drug Name
(YR approved)
Mode of Administration
Indication
for Use
Novantrone®
mitoxantrone (2000)
IV infusion every 3m (lifetime
maximum 140 mg/m2)
RRMS,
SPMS
Tysabri®
natalizumab (2006)
IV infusion 300mg every 4
weeks
RRMS
AEs: cardiac toxicity; impaired LVEF, CHF, acute myelogenous
leukemia (AML), PML, death
FDA Approved DMT : Oral
Drug Name
(YR approved)
Mode of Administration
Indication
for Use
Gilenya®
fingolimod (2012)
0.5 mg tablet once a day
RRMS
Aubagio®
teriflunomide (2012)
7 or 14mg tablet once a day
RRMS
120mg table 2x day for 1-week
240mg tablet 2x day thereafter
RRMS
Tecfidera®
dimethyl fumarate
(2013)
AEs: opportunistic infections (possible death); bradycardia
Impaired liver function, macular swelling
DMT Surveillance

Given the side-effect profile of existing
DMTs surveillance is essential



For patient safety by minimizing AEs and
SAEs
To assess efficacy and effectiveness
To develop criteria whereby DMT can be
tailored to for individual patients
DMT Surveillance Methods in
the VHA



Retrospective – review of Rx and claims data to
assess system- and patient-level outcomes (e.g.,
utilization, costs, QIs)
Retrospective/Current – patient surveys to
ascertain current (and past) DMT use and patientlevel outcomes (e.g., disability, relapses)
Prospective – Multiple Sclerosis Assessment Tool
in CPRS to assess ongoing DMT use, side-effects,
and patient-level outcomes (e.g., disability,
relapses)
DMT Surveillance Examples

Mitoxantrone

Retrospective review of Rx and claims data to



Assess for cardiac screening
Development of AML
Injectable DMTs

Survey of current and past DMT use to assess


Adherence
Clinical outcomes
Mitoxantrone Surveillance

Reviewed Rx data from FY1998 – 2010


445 patients 1998 - 2007
Ascertained (from Rx and claims data)





Total number of treatments and total dose
Frequency and timing of ECHO/MUGA
Occurrence of CHF
Occurrence of AML
Deaths
Mitoxantrone Surveillance
Mitoxantrone Surveillance
445 patients had at least one infusion
 43 patients died within 1-year of first dose
and were excluded from further analysis
 Mean treatment duration was 26 ± 14 mo.
 301 (75%) received at least 1 LVEF screen




137 (35%) screened within 4 mo of 1st dose
68 (17%) screened within 5-12 mo of 1st dose
92 (23%) screened beyond 12 mo of 1st dose
Mitoxantrone Surveillance

Acute Myelogenous Leukemia (AML)

ICD9 codes: 104 – 208 & 238
6 MS patients with AML post MTX
 All 6 cases occurred in men
 OR for AML given MTX: 0.99 [.44 to 2.40]
 AML-MS patients had marginally
significant higher cumulative dose 66.6 vs.
44.2 mg/m2

Mitoxantrone Surveillance

Deaths (FY1998 – FY2010)


From BIRLs & Vital Status file
A total of 86 (19%) patients ever treated
with MTX died


43 died within 10 mo of 1st dose
43 additional patients died > 1 yr of 1st dose
4
died after being diagnoses with CHF
 None of the 6 AML patients had died by end of the
study period (FY2010)
Mitoxantrone Surveillance
Cardiac-related issues occurred in 46 (10%)
of MS patients treated with MTX
 AML occurred in 6 (1.3%) of MS patients
treated with MTX
 Our findings similar to results from Marriott
et al. (2010)1



12% developed cardiac dysfunction/disease
0.8% developed AML
1 Marriott et al. Evidence Report: Safety and efficacy of mitoxantrone (Novantrone) in the treatment of multiple
sclerosis. Neurology 2010; 74: 1463-70.
Mitoxantrone Surveillance

Rates of MTX-related cardiac events and AML
are similar to other reports in the literature


Rates of cardiac events in the VHA may be
underestimated as rates of ECHO/MUGA are lower
than recommended by current guidelines
Even though MTX no longer used to treat MS in
the VHA, continued surveillance is warranted



To detect new and worsening cardiac disease
To detect new cases of AML
To initiate treatment as soon as possible
DMT Surveillance
A survey was developed to create the MS
Surveillance Registry (MSSR)
 Survey included





Demographic and clinical characteristics
DMT use history
Patient-reported disability and QoL
Surveyed stratified random sample of VHA
users with confirmed MS
DMT Surveillance

DMT use questions provided longitudinal
history of




DMT use
Switching / stopping
Duration of DMT use
Developed DMTuse Ratio (DMT-R)

Time on DMT / Disease duration from Dx
DMT Surveillance

DMT Validation


Patient-reported
compared with
PBM data
Comparisons
restricted to FY99
through time of
survey (FY2008)
Comparison
Agreement
1st DMT used
79 %
2nd DMT used
83 %
3rd DMT used
91 %
Average 1st – 3rd
85 %
Rebif
94 %
Betaseron
89 %
Copaxone
89 %
Avonex
88 %
Average all DMT
90 %
DMT Surveillance



Analyses limited to patients with relapsing disease
(n = 1,002)
116 (12%) never used any DMT
886 patients attempted DMT



137 (14%) quit at some point
749 (74%) continued DMT (some which switched
DMTs)
VHA doing a better job than most systems
adhering to DMT practice guidelines
DMT Surveillance
Patients that quit DMT had tried a mean of
2.4±0.9 DMTs compared to 1.53±0.7
among DMT users
 DMT users compared to those that quit




Were younger (p < 0.01)
Had shorter disease duration (p = 0.07)
Had greater proportion of AA patients (0.82 vs.
0.70; p < 0.05)
DMT Surveillance
Reason for Switching / Quitting
Quit DMT On DMT
(n = 137) (n = 749)
Too many injections
16 (12%)
16 (2%)
Injection-site reactions
25 (19%)
21 (3%)
Flu-like symptoms
27 (21%)
39 (5%)
Developed Progressive disease
18 (14%)
11 (1%)
Impaired liver function
6 (5%)
0
Developed N-Ab
8 (6%)
2 (<1%)
Was not effective
30 (23%)
42 (6%)
DMT Surveillance

The Million Dollar Question…


Only 2 studies on DMT “effectiveness”



Are DMTs effective?
Brown et al. Neurology 2007; 69: 1498-1507.
Shirani et al. JAMA 2012; 308(3): 247-56.
Results are contradictory

Methodological differences and uncontrolled
confounding contribute to discrepant findings
DMT Surveillance

Brown et al. 2007




MS patients from Nova Scotia’s drug insurance
program
1980 – 2004
1998 DMTs available
Effectiveness assessed through multiple
regression to determine EDSS increase avoided
per treatment year
DMT Surveillance
Brown et al. Neurology 2007
N
EDSS baseline
Disease duration (onset) yr
DMT duration yr
Switched DMTs
Quit
Pre-DMT EDSS change/yr
EDSS increase avoided/ TX-Yr

RRMS
SPMS
390
2.12±0.85
8.0±5.1
2.96±1.71
16%
2%
0.10
0.103
200
4.43±1.47
10.2±5.2
3.65±1.66
25%
5%
0.31
0.065
To prevent a 0.5-point increase in the EDSS
would require 5-years of DMT treatment
DMT Surveillance

Shirani et al. 2012


Patients with RRMS
British Columbia MS Database (1985 – 2004)
•


Total sample = 2,656 patients
998 patients excluded (e.g., < 2 EDSS)
•

DMT first available in 1995
Comparisons with study participants not provided
Cox proportional Hazard Model
•
Time to sustained EDSS - 6
DMT Surveillance
Shirani et al. JAMA 2012
INF-β
N
Age at baseline
EDSS baseline
Disease duration (onset) yr
FU yr
868
38.1
2.1
5.8±6.6
5.2

After controlling for age, gender, disease duration, baseline
EDSS the adjusted Hazard ratio was



Contemporary Historical
Control
Control
829
959
41.3
38.4
2.0
2.0
8.3±8.5
7.7±7.9
4.5
10.5
1.30 [0.92 – 1.83] comparing INF-β with contemporary controls
0.77 [0.58 – 1.02] comparing INF-β with historical controls
Concluded INF-β not associated with reduction in
disability progression
DMT Surveillance

Greenberg et al. Arch Neurology 2012

In BC, RRMS patients not started on DMT at
DX
•

Incomplete control for confounding by indication
No discussion of differences or distribution by
treatment group of the 998 excluded patients
EDSS-6 as endpoint does not account for
variability in EDSS less than 6
 TX group had shortest disease duration

DMT Surveillance

DMT Effectiveness in the MSSR


Multiple Linear Regression
Outcome
•

Predictor
•

Patient Determined Disease Steps
DMT-R
Control Variables
•
•
Age, gender, race, number of comorbidities
DX before 1994, disease duration, smoking
DMT Surveillance

DMT use ratio (DMT-R)

DMT treated as a “class” like in Brown (2007)
DMT-R
Frequency
0.0
215 (21.5%)
.0001 - .2734
155 (15.5%)
.2735 - .5333
197 (19.7%)
.5334 - .8750
224 (22.4%)
.8751 – 1.000
208 (20.8%)
DMT Surveillance
Variable
B ( SE)
95 % CI
LB
UB
t
p
DMT-R = 0.0
.094
.21
-.323
.511
.442
.659
DMT-R = .0001 to .2734
.570
.23
.116
1.024
2.463
.014
DMT-R = .2735 to .5333
.485
.21
.067
.902
2.278
.023
DMT-R = .5334 to .8750
.346
.20
-.039
.731
1.762
.078
YR DX (1= before 1994)
.402
.16
.091
.713
2.535
.011
Current Age (yrs)
.138
.06
.025
.251
2.401
.017
Age2
-.001
.01
-.002
.000
-2.016
.044
Gender (1=male)
.492
.14
.222
.763
3.570
.000
Comorbidities (total #)
.220
.03
.154
.287
6.502
.000
Intercept = -0.37
1.49 (95%CI : -3.29, 2.56), p = .81
DMT Surveillance

After controlling for age, gender, comorbidities



Patients using DMT more than 87% of disease duration
had 0.57-point lower PDDS score than patients using
DMT less than 27% of the time since diagnosis
0.48-point lower than patients using DMT between
27% and 53% of the time since diagnosis
Patients diagnosis prior to availability of 1st DMT
(1994) had a 0.40-point higher PDSS
•

Suggesting that delaying initiation of DMT minimizes DMT
effectiveness
PDDS increases 0.22-points for each comorbid
condition
DMT Surveillance

These results suggest…

DMT is effective in slowing/preventing
disability progression
•



Up to ½-point over a mean 14.6 yr FU
Dose-effect response was shown
Delaying DMT associated with increased
disability
Presence of comorbidities associated with
increased disability independent of DMT use
DMT Use and it’s Clinical
Impact in the VHA

10 DMTs currently available

Several more likely over the next year
Newer, oral and infused DMTs have a more
serious side-effect profile
 DMT surveillance is/will be essential to



Address AEs and SAEs in a timely manner
Determine criteria to define optimal responders
DMT Use and it’s Clinical
Impact in the VHA

MTX surveillance efforts suggest



CHF and AML in MTX users in the VHA are
comparable to reports in literature
However, current screening is less than
recommended by FDA guidelines
Ongoing screening and monitoring of past
MTX users is critical as existing data indicates
delayed onset of CHF and AML are possible
DMT Use and it’s Clinical
Impact in the VHA

Injectable DMTs in MSSR

VHA has done well in initiating DMT
•
•
88% of relapsing MS patients initiated on DMT
74% maintained on a DMT
 Injectable DMTs appear to effective if initiated
early and with patient compliance
Given cost and unknown impact of long-term use
 Remains unclear whether DMT should be discontinued
after transition to SPMS w/o relapses
DMT Use and it’s Clinical
Impact in the VHA

Prospective Surveillance
 Multiple

Sclerosis Assessment Tool
To provide “real-time” clinical detail
 MS
Surveillance Registry (MSSR)
Add in extant data (IP/OP utiliz, $, & Rx)
 Merged with MSAT data

 Will allow us to track and summarize patients by DMT
used

For the MSAT / MSSR to be a functional tool, it is
critical that the MSAT be used in ALL MSCoE clinics
Epidemiology & Outcomes Team








Joel Culpepper, PhD, MA
Mitch Wallin, MD, MPH
Shan Jin, PhD
Heidi Maloni, RN, PhD
Z McDowell, PhD
Joshua Moore
Sean Burke, MD
Chris Bever, MD
Obtaining CME/CE Credit

If you would like to receive continuing
education credit for this activity, please
visit:

http://www.pesgce.com/PVA2013

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