Transcript Slide 1

Longitudinal databases
and registries – why?
[email protected]
Longitudinal databases and
registries – why?
1. Randomized trials have many
limitations, especially patient
selection, short time frame
2. Document improvements in patient
outcomes over 5-20 years.
3. How do we know if treatment
improves outcomes, eg, survival?
Traditional approaches to clinical expertise:
EMINENCE BASED MEDICINE - making the
same mistakes with increasing confidence
over an impressive number of years
ELOQUENCE BASED MEDICINE - a year-round
suntan and brilliant oratory may overcome
absence of any supporting data
ELEGANCE BASED MEDICINE - where the
sartorial splendor of a silk-suited sycophant
substitutes for substance
The modern alternative?
EVIDENCE BASED MEDICINE - the best
approach - requires information from clinical
observational data in addition to clinical trials
Eminence-based medicine- example
“patients with rheumatoid arthritis (RA)
usually respond to a conservative
program of nonsteroidal antiinflammatory drugs, rest, and physical
therapy…”
HE Paulus, HJ Williams, JR Ward, JC Reading,
MJ Egger, ML Coleman, CO Samuelson, Jr.,
RF Willkens, M Guttadauria, GS Alarcon,
SB Kaplan, EJ MacLaughlin, A Weinstein,
RL Wilder, MA Solsky, RF Meenan.
Arthritis & Rheumatism
27:721,1984.
Clinicians may all too easily
spend years writing “doing
well” in the notes of a patient
who has become
progressively crippled
before their eyes…
– Verna Wright.
Br Med J. 1983;287:569.
Evidence-based medicine- example
“these studies indicate severe
functional declines, work disability,
and excess mortality in a group of 75
RA patients, studied at 2 time points
9 years apart….”
T Pincus, LF Callahan, WG Sale,
AL Brooks, LE Payne, WK Vaughn
Arthritis & Rheumatism
27:864, 1984.
Longitudinal databases
and registries – why?
1.Randomized trials have many
limitations, especially patient
selection, short time frame
2.How do we know if treatment
improves outcomes, eg, survival?
3.Document improvements in patient
outcomes over the years by
evidence, not eminence.
Some Pragmatic Limitations of Randomized
Controlled Clinical Trials in Chronic Diseases
J Clin Epidemiol 41:1037,1988; Arthritis Rheum 48:313, 2003
1. Relatively short observation period
2. Inclusion and exclusion criteria - most
patients ineligible in most trials
3. Surrogate markers - may be suboptimal
for actual outcomes, e.g., T cell counts vs.
AIDS, tender joints vs. surgical
replacement
4. Inflexible dosage schedules and
concomitant drug therapies
Standard Composite Treatment Effect*
Effect in Standard Units
2
1.5
1
0.5
0
(n=28)
Plac
(n=25)
AUR
(n=11)
AntiM
(n=15)
AZA
(n=28)
Gold
(n=9)
MTX
(n=22)
DPen
(n=8)
SSZ
<.0001
<.0001
<.05
*Composite of grip strength (adjusted for disease duration and trial
length), tender joint count (adjusted for initial TJC and blinding and
ESR
Felson, Anderson, Meenan. Arthrit Rheum. 1990;33:1449.
Estimated Continuation
Estimated Continuation of Courses of 2nd Line
Therapies Over 60 Months in RA Patients
Azathioprine (56)
Hydroxychloroquine (228)
Methotrexate (253)
Oral gold (84)
Parenteral gold (269)
Penicillamine (193)
1.0
0.8
0.6
0.4
0.2
0
0
10
20
30
40
50
60
Months
Pincus, Marcum, Callahan. J Rheumatol. 1992;19:1885.
RA Cohort #2-15 US sites 1985-90
Participating Rheumatologists
•
•
•
•
•
•
•
•
F. Adams
TN
J. Barber
CA
W. Barth
DC
M. Britton
CA
G. Gordon PA
J. Huston
TN
J.T. John
TN
J. Johnson TN
•
•
•
•
•
•
•
A. Kennedy FL
R. Polk
ID
J. Raitt
CA
J. Reinertsen MN
E. Schned
MN
J. Sergent
TN
A. Whelton FL
Estimated Continuation of Courses of 2nd-Line
Therapy
Azathioprine (56)
Hydroxychloroquine (228)
Methotrexate (253)
Oral gold (84)
Parenteral gold (269)
Penicillamine (193)
100
80
60
40
20
0
0
10
20
30
Months
40
50
60
Estimated Continuation (%)
Estimated Continuation (%)
All Courses Over 60 Months Initial Course Over 12 Months
10
0
8
0
6
0
4
0
Methotrexate (61)
Hydroxychloroquine
(130)
Penicillamine (55)
Parenteral gold (207)
Oral gold (5)
Azathioprine (19)
2
0
0
0
1
2
3
4
5
6
7
Months
8 9 10 1
1
Pincus, Marcum, Callahan. J Rheumatol. 1992;19:1885.
1
2
Survival in SLE Nephritis
Austin, Klippel, Balow, et al, NEJ Med 314:614, 1986
Some Pragmatic Limitations of Randomized
Controlled Clinical Trials in Chronic Diseases
J Clin Epidemiol 41:1037,1988; Arthritis Rheum 48:313, 2003
1. Relatively short observation period
2. Inclusion and exclusion criteria - most
patients ineligible in most trials
3. Surrogate markers - may be suboptimal
for actual outcomes, e.g., T cell counts vs.
AIDS, tender joints vs. surgical
replacement
4. Inflexible dosage schedules and
concomitant drug therapies
ATTRACT trial clinical
inclusion criteria
138
Criteria:
 6 tender joints and
 6 swollen joints
42
2 of 3:
Morning stiffness  45 min
ESR  28 mm / hour
CRP  2.0 mg / dL
MTX dose
 12.5 mg / week
7
96
21
21
14
5
19
16
4
77
15
29
48
Meet ATTRACT criteria
Do not meet ATTRACT criteria
Sokka and Pincus Arthrits Rheum 48:213, 2003
Etanercept in Early RA (ERA):
ACR Responses at 52 Weeks
100
Etanercept 25 mg (n = 207)
MTX, mean 19 mg (n = 217)
p = NS
80
72
% Patients
65
p = NS
60
49
p = NS
43
40
22
25
20
0
ACR20
ACR50
ACR70
Bathon JM et al. N Engl J Med. 2000;343:1586-1593
16
Number of patients who meet ERA clinical
inclusion criteria – 1st visit patients who
did not take methotrexate
19
Criteria:
 12 tender joints and
 10 swollen joints
10
Positive rheumatoid
factor or erosions
2
8
Morning stiffness  45 min
or ESR  28 mm / hour
8
9
0
2
7
0
7
2
0
2
0
Meet ERA criteria
Do not meet ERA criteria
Sokka and Pincus Arthritis Rheum 48:213, 2003
% of Patients with RA who meet
Criteria for Inclusion in Clinical Trials
TP
Recent
Clinic onset RA
1998-2001 2001
Number of Patients
146
300
1. > 6 Swollen Joints
42.5%
63.4%
2. > 6 Tender Joints
25.3%
50.4%
3. ESR > 28
25.0%
49.3%
4. AM Stiffness > 45 mins 45.9%
50.9%
1+2+3 or 4
1+2+3 and 4
22.0%
11.3%
34.1%
18.3%
Sokka and Pincus, submitted for publication
Some Pragmatic Limitations of Randomized
Controlled Clinical Trials in Chronic Diseases
J Clin Epidemiol 41:1037,1988; Arthritis Rheum 48:313, 2003
1. Relatively short observation period
2. Inclusion and exclusion criteria - most
patients ineligible in most trials
3. Surrogate markers - may be suboptimal
for actual outcomes, e.g., T cell counts vs.
AIDS, tender joints vs. surgical
replacement
4. Inflexible dosage schedules and
concomitant drug therapies
Measures of activity and
damage in patients with RA
over 5 years
75
Percentage
50
improvement
25
0
–25
Percentage
deterioration –50
Grip strength
Sedimentation rate
Ritchie articular index
Morning stiffness
Pain VAS
Haemoglobin
Radiological score
–75
VAS = 10 cm visual analogue scale
Mulherin D, et al. Br J Rheumatol. 1996;35:1263-1268.
Changes in Measures in 100 Patients with Rheumatoid
Arthritis Over 5 Years Determined by Effect Sizes
Tenderness
Swelling
Joint Count Measures
Pain on Motion
Deformity
Better
Limited Motion
Joint Space Narrowing
Radiographic Measures
Erosions
Worse
Malalignment
Erythrocyte Sedimentation Rate
Laboratory Measures
Rheumatoid Factor Titer
Hemoglobin
Morning Stiffness
Clinical Measures
Grip Strength
Walk Time
Button Time
Patient Questionnaire Measures
Functional Status - MHAQ
Global Status
Pain - Visual Analog Scale
Arthritis Care Res
10:381,1997
-1.5
Helplessness
-1.3
-1.1
-0.9
-0.7
-0.5
-0.3
Effect Size
-0.1
0.1
0.3
0.5
Some Pragmatic Limitations of Randomized
Controlled Clinical Trials in Chronic Diseases
J Clin Epidemiol 41:1037,1988; Arthritis Rheum 48:313, 2003
1. Relatively short observation period
2. Inclusion and exclusion criteria - most
patients ineligible in most trials
3. Surrogate markers - may be suboptimal
for actual outcomes, e.g., T cell counts vs.
AIDS, tender joints vs. surgical
replacement
4. Inflexible dosage schedules and
concomitant drug therapies
Some Pragmatic Limitations of Randomized
Controlled Clinical Trials in Chronic Diseases
J Clin Epidemiol 41:1037,1988; Arthritis Rheum 48:313, 2003
Variables other than randomization, such
as education, clinical care site, etc., may
affect outcome more than randomization
group
6. Statistically significant results not
necessarily clinically important, and vice
versa
7. Rare toxicities not seen in fewer than
10,000 subjects
8. Balance of efficacy and toxicity may be
unclear
5.
Some Intrinsic Limitations of Controlled
Clinical Trials in Chronic Diseases
J Clin Epidemiol 41:1037,1988; Arthritis Rheum 48:313, 2003
1. Control group does not remove bias – 1st DMARD
vs requirement to “fail” 2 DMARDs
2. Balance of efficacy and toxicity may be unclear –
90% remission with 1% renal failure
Versus 50% improvement with no renal
failure – which is the better therapy?
3. Results reported for groups of patients – ignore
individual variation – most people prefer…is that
true for all?
4. Loss of “placebo effect” when patent given
“randomized” versus “best” therapy
Infliximab + MTX (ATTRACT):
ACR Responses at 30 and 54 Weeks
Placebo + MTX (n = 88)
3 mg/kg q8w* (n = 86)
3 mg/kg q4w* (n = 86)
10 mg/kg q8w* (n = 87)
10 mg/kg q4w* (n = 81)
70
p < 0.001*
p < 0.001*
% Patients
60
50
C
Infliximab +
MTX
p < 0.001*
40
p < 0.001*
p < 0.001*
30
p < 0.001*
20
10
0
Week 30
Week 54
ACR20
Week 30
Week 54
ACR50
Week 30
Week 54
ACR70
*vs placebo. ATTRACT = Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis
with Concomitant Therapy.
Maini R et al. Lancet. 1999;354:1932-1939.
Lipsky PE et al. N Engl J Med. 2000;343:1594-1602.
27
ACR Core Data Set Measure changes - 12 Months:
Leflunomide (LEF) vs Methotrexate (MTX)
vs Placebo (PBO)
Measure:
LEF
PBO MTX
Tender Jts
Swollen Jts
MD Global
ESR
FN- HAQ
FN-MHAQ
Pain
Pt Global
-7.7
-5.7
-2.8
-6.3
-0.45
-0.29
-2.2
-2.1
-3.0
-2.9
-1.0
+2.6
+0.03
+0.07
-0.4
+0.1
-6.6
-5.4
-2.4
-6.5
-0.26
-0.15
-1.7
-1.5
Effect Relative
Size Efficiency
-0.59
1.00
-0.44
0.56
-0.68
1.33
-0.41
0.48
-0.80
1.84
-0.69
1.37
-0.65
1.21
-0.81
1.88
Strand V, et al. Arch Intl Med. 1999; 159:2542-2550;
Tugwell P, et al. Arthritis Rheum. 2000; 43:506-514.
Longitudinal databases and
registries – why?
1. Randomized trials have many
limitations, especially patient
selection, short time frame
2. Document improvements in patient
outcomes over the years by
evidence, not eminence.
3. How do we know if treatment
improves outcomes, eg, survival?
Progression of the Larsen
score in the 1970’s vs. 1980’s
1970's
1980's
Larsen score 0-100
36
26%
24
12%
12
0
0
1
2
3
4
5
6
7
8
Disease duration (years)
Sokka T, Kaarela K, Mottonen T, Hannonen P. Clin Exp Rheumatol 1999
Cross-Sectional Data in Patients With RA:
Cohort #2 in 1985 and Cohort #4 in 2000:
Swollen Joint Count Scores
1985
2000
20
Swollen Joint Count 28
Swollen Joint Count 28
20
16
12
8
4
0
16
12
8
4
0
0
5
10
15
Disease Duration (Years)
20
0
5
10
15
Disease Duration (Years)
Pincus, Sokka, Kautiainen, Arth Rheum 52:1009, 2005
20
Patients seen for standard
rheumatoid arthritis care
have significantly better
articular, radiographic,
laboratory, and functional
status in 2000 than in 1985
T Pincus, T Sokka, H Kautiainen
Arthritis Rheum 52:1009-1019, 2005
Cross-Sectional Data in Patients With RA:
Cohort #2 in 1985 and Cohort #4 in 2000:
Multidimensional Health Assessment Questionnaire (MDHAQ)
scores
2000
2.0
2.0
1.5
1.5
MHAQ
MHAQ
1985
1.0
1.0
0.5
0.5
0.0
0.0
0
5
10
15
Disease Duration (Years)
20
0
5
10
15
20
Disease Duration (Years)
Pincus, Sokka, Kautiainen, Arth Rheum 52:1009, 2005
1985
30
RF-
25
RF+
20
15
10
5
0
0
5
10
Disease duration
15
2000
Larson score for hands, % of max
Larson score for hands, % of max
Cross-Sectional Data in RA Patients:
Cohort #2- 1985 and Cohort #4-2000:
Larsen X-Ray score,% of maximum
30
25
20
RF+
15
10
RF
55
positive
RF-
0
00
0
5
10
Disease duration
Pincus, Sokka, Kautiainen, Arth Rheum 52:1009, 2005
15
Median clinical status measures in two
cohorts of patients with RA seen in 1984-86
(“1985”) and 1999-2001 (“2000”).
Measure
1985
2000
p
Swollen joints(0-28)
12 (6,16)
5 (2,10)
<0.001
X-Ray (Larsen - 0-100) 20 (2,36)
3 (0,13)
<0.001
ESR
33 (16 , 50)
20 (9,33)
0.016
Hemoglobin (g/L)
129(116,138) 136 (128,143) 0.002
MHAQ (0-3)
1.0 (0.6 , 1.4) 0.4 (0.1 , 1.0) <0.001
Pain VAS (0-100)
52 (32 , 80)
Gripstr,mmHg(30-300) 82 (65 ,115)
Walk time,secs(0-20)
49 (15 , 73)
120 (91, 166) <0.001
8.6 (7.0,11.8) 7.4 (6.6 8.7)
Buttontest,scs(0-300) 50 (39 ,71)
0.38
40 (32 , 52)
Pincus, Sokka, Kautiainen, Arth Rheum 52:1009, 2005
0.018
<0.001
DMARDs used in the 1985 and 2000 TP cohorts
DMARD
1985 Cohort
2000 Cohort
N
%
N
%
Total number of patients
125
100.0%
150
100.0%
No DMARDs, no prednisone
46
36.8%
5
3.3%
Prednisone only
37
29.6%
15
10.0%
Methotrexate + any other drug
13
10.4%
115
76.7%
Prednisone + any other drug
64
51.2%
129
86.0%
Methotrexate only or + prednisone or
+hydroxychloroquine
13
10.4%
92
61.3%
Methotrexate + other traditional DMARDs
0
0
17
11.3%
IM gold or hydroxychloroquine or D-pen or
azathioprine or auranofin or cyclophosphamide
only or + prednisone
29
23.2%
10
6.7%
Leflunomide + any other drug
0
0
5
3.3%
Infliximab + any other drug
0
0
3
2.0%
Etanercept + any other drug
0
0
3
2.0%
Pincus, Sokka, Kautiainen, Arth Rheum 52:1009, 2005
Mtx in RA Care - 1985-2000
Jyvaskyla, Finland & Nashville,TN
Methotrexate as the
“anchor drug” for the
treatment of early
rheumatoid arthritis
T Pincus, Y Yazici, T Sokka,
D Aletaha, JS Smolen
Clin Exp Rheumatol, 21(S31):179-185, 2003
Is rheumatoid
arthritis becoming
less severe?
A Silman, P Davies,
HLF Currey, SJW Evans
J Chronic Dis 36:891-897, 1983
Longitudinal databases and
registries – why?
1. Randomized trials have many
limitations, especially patient
selection, short time frame
2. Document improvements in patient
outcomes over the years by
evidence, not eminence.
3. How do we know if treatment
improves outcomes, eg, survival?
Response to methotrexate
treatment is associated with
reduced mortality in patients with
severe rheumatoid arthritis
D Krause, B Schleusser,
G Herborn, R Rau.
Arthritis and Rheumatism 43:14, 2000
Methotrexate and mortality in
patients with rheumatoid
arthritis: a prospective study
H K Choi, MA Hernan, JD Seeger,
JM Robins, F Wolfe
The Lancet 359:1173, 2002
Response to methotrexate treatment is
associated with reduced mortality in
patients with severe rheumatoid arthritis
Improvement:
>50%
20-50%
<20%
D/C
Total
# Patients
99
70
52
35
256
% Deceased
21%
17%
52%
66%
34%
1.47
1.85
4.11
5.56
2.60
(0.842.10)
(0.972.73)
(2.565.66)
(3.297.83)
(2.053.15)
Standard
mortality
ratio
Confidence
interval
Krause, Schleusser, Herborn, Rau. Arth Rheum 43:14, 2000
Long term safety of
methotrexate in routine
clinical care: discontinuation
is unusual
and rarely the result
of laboratory abnormalities
Y Yazici, T Sokka, H Kautiainen,
C Swearingen, I Kulman, T Pincus
Ann Rheum Dis 64:207-211, 2005
Cumulative probability of continuation of therapy (%)
Methotrexate continuation in TP
clinic standard care – 1990-2003
100
90
80
70
60
50
40
30
20
10
0
0
1
2
3
4
5
Duration of methotrexate therapy (years)
Yazici,Y. et al. Ann Rheum Dis 64, 207-211 (2005).
Relative Risk of Death Over 12-15 Years in
rheumatoid arthritis (RA) and
cardiovascular (CV) disease according to
baseline severity indicators
RA – 75 pts – 15 yrs - Pincus et al, Ann Int Med 120:26,1994
Functional status on
patient questionnaire
# of Involved Joints
< vs > 91.5% “with ease”
> vs < 18 joints
2.9:1
3.0:1
CV disease – 312,000 pts – 12 yrs –
Neaton et al, Arch Int Med 152:56,1992
Serum cholesterol
Systolic blood pressure
Diastolic blood pressure
Smoking
>245 vs <182 mg/Dl
>142 vs <118 mmHg
>92 vs <76 mmHg
>26 vs 0 cigarettes/day
2.9:1
3.0:1
2.9:1
2.9:1
Data adjusted for age, sex, education, disease duration
Longitudinal databases and
registries – why?
1. Randomized trials have many
limitations, especially patient
selection, short time frame
2. Document improvements in patient
outcomes over the years by
evidence, not eminence.
3. How do we know if treatment
improves outcomes, eg, survival?