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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 anti-inflammatory 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
0.5
1
1.5
2
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
Effect in Standard Units
*Composite of grip strength (adjusted for disease duration and trial length), tender joint count (adjusted for initial TJC and blinding and ESR
Standard Composite Treatment Effect*
Felson, Anderson, Meenan. Arthrit Rheum. 1990;33:1449.
Estimated Continuation of Courses of 2nd Line Therapies Over 60 Months in RA Patients
1.0
0.8
0.6
0.4
0.2
00 10 20 30 40 50 60
Months
Es
tim
ate
d C
on
tin
ua
tio
n
Pincus, Marcum, Callahan. J Rheumatol. 1992;19:1885.
Azathioprine (56)Hydroxychloroquine (228)Methotrexate (253)Oral gold (84)Parenteral gold (269)Penicillamine (193)
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
Azathioprine (56)Hydroxychloroquine (228)Methotrexate (253)Oral gold (84)Parenteral gold (269)Penicillamine (193)
100
80
60
40
20
00 10 20 30 40 50 60
Months
Est
imat
ed C
on
tin
uat
ion
(%
)
Pincus, Marcum, Callahan. J Rheumatol. 1992;19:1885.
All Courses Over 60 Months
Estimated Continuation of Courses of 2nd-Line Therapy
Initial Course Over 12 Months
Months
Es
tim
ate
d C
on
tin
ua
tio
n (
%)
20
40
60
80
100
00 1 2 3 4 5 6 9 1
17 8 10 1
2
Methotrexate (61)Hydroxychloroquine (130)Penicillamine (55)Parenteral gold (207)Oral gold (5)Azathioprine (19)
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
6 tender joints and 6 swollen joints
2 of 3:Morning stiffness 45 minESR 28 mm / hourCRP 2.0 mg / dL
MTX dose 12.5 mg / week
Criteria:138
96
21 77
48151614
Do not meet ATTRACT criteria
Meet ATTRACT criteria
7 4 295
1921
42
Sokka and Pincus Arthrits Rheum 48:213, 2003
16
Etanercept in Early RA (ERA): Etanercept in Early RA (ERA): ACR Responses at 52 WeeksACR Responses at 52 Weeks
% P
ati
ents
0
20
40
60
80
6572
43
49
2225
100
ACR20 ACR50 ACR70
Etanercept 25 mg (n = 207)MTX, mean 19 mg (n = 217)
Bathon JM et al. N Engl J Med. 2000;343:1586-1593
p = NS
p = NS
p = NS
Number of patients who meet ERA clinical inclusion criteria – 1st visit patients who
did not take methotrexate
12 tender joints and 10 swollen joints
Positive rheumatoidfactor or erosions
Morning stiffness 45 minor ESR 28 mm / hour
Criteria:19
9
2 2
0 00 0
Do not meet ERA criteria
Meet ERA criteria
8 7 22
78
10
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 2001Number of Patients 146 3001. > 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 22.0% 34.1% 1+2+3 and 4 11.3% 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
Percentage improvement
Percentage deterioration
Ritchie articular index
Morning stiffness
Radiological score
VAS = 10 cm visual analogue scale
HaemoglobinPain VAS
Grip strength
Sedimentation rate
Measures of activity and damage in patients with RA
over 5 years
Mulherin D, et al. Br J Rheumatol. 1996;35:1263-1268.
75
50
25
0
–25
–50
–75
-1.5-1.5 -1.3-1.3 -1.1-1.1 -0.9-0.9 -0.7-0.7 -0.5-0.5 -0.3-0.3 -0.1-0.1 0.10.1 0.30.3 0.50.5
MalalignmentMalalignment
Limited MotionLimited Motion
Joint Space NarrowingJoint Space Narrowing
Changes in Measures in 100 Patients with RheumatoidChanges in Measures in 100 Patients with Rheumatoid Arthritis Over 5 Years Determined by Effect SizesArthritis Over 5 Years Determined by Effect Sizes
TendernessTenderness
SwellingSwelling
PainPain on Motion on Motion
Radiographic MeasuresRadiographic Measures
Joint Count MeasuresJoint Count Measures
Laboratory MeasuresLaboratory Measures
Clinical MeasuresClinical Measures
Patient Questionnaire MeasuresPatient Questionnaire Measures
DeformityDeformity
ErosionsErosions
Erythrocyte Sedimentation RateErythrocyte Sedimentation Rate
Rheumatoid Factor TiterRheumatoid Factor Titer
HemoglobinHemoglobin
Morning StiffnessMorning Stiffness
Grip StrengthGrip Strength
Walk TimeWalk Time
Button TimeButton Time
Functional Status - MHAQFunctional Status - MHAQ
Global StatusGlobal StatusPain - Visual Analog ScalePain - Visual Analog Scale
HelplessnessHelplessness
EEffect Sizeffect Size
Arthritis Care ResArthritis Care Res10:381,199710:381,1997
BetterBetter
WorseWorse
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
5. 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
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 failureVersus 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
27
Infliximab + MTX (ATTRACT):Infliximab + MTX (ATTRACT):ACR Responses at 30 and 54 WeeksACR Responses at 30 and 54 Weeks
0
10
20
30
40
50
60
70
Week 30 Week 54 Week 30 Week 54 Week 30 Week 54
ACR50 ACR70ACR20
% P
atie
nts
Maini R et al. Lancet. 1999;354:1932-1939. Lipsky PE et al. N Engl J Med. 2000;343:1594-1602.
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)
Infliximab + MTXp < 0.001* p < 0.001*
p < 0.001*
p < 0.001*
p < 0.001*
p < 0.001*
*vs placebo. ATTRACT = Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy.
CC
ACR Core Data Set Measure changes - 12 Months: Leflunomide (LEF) vs Methotrexate (MTX)
vs Placebo (PBO)
ACR Core Data Set Measure changes - 12 Months: Leflunomide (LEF) vs Methotrexate (MTX)
vs Placebo (PBO)
Strand V, et al. Arch Intl Med. 1999; 159:2542-2550;Tugwell P, et al. Arthritis Rheum. 2000; 43:506-514.
Measure: LEF PBO MTX Effect Relative Size Efficiency
Tender Jts -7.7 -3.0 -6.6 -0.59 1.00Swollen Jts -5.7 -2.9 -5.4 -0.44 0.56MD Global -2.8 -1.0 -2.4 -0.68 1.33ESR -6.3 +2.6 -6.5 -0.41 0.48FN- HAQ -0.45 +0.03 -0.26 -0.80 1.84FN-MHAQ -0.29 +0.07 -0.15 -0.69 1.37Pain -2.2 -0.4 -1.7 -0.65 1.21Pt Global -2.1 +0.1 -1.5 -0.81 1.88
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
0
12
24
36
0 1 2 3 4 5 6 7 8
Lar
sen
scor
e 0-
100
1970's 1980's
Disease duration (years)
12%
Sokka T, Kaarela K, Mottonen T, Hannonen P. Clin Exp Rheumatol 1999
26%
20001985
0 5 10 15
Disease Duration (Years)
20
16
12
8
4
0
Sw
oll
en J
oin
t C
ou
nt
28
Disease Duration (Years)
Sw
oll
en J
oin
t C
ou
nt
28
20 0 5 10 15 20
20
16
12
8
4
0
Cross-Sectional Data in Patients With RA: Cohort #2 in 1985 and Cohort #4 in 2000:
Swollen Joint Count Scores
Pincus, Sokka, Kautiainen, Arth Rheum 52:1009, 2005
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
20001985
0 5 10 15
Disease Duration (Years)
2.0
1.5
1.0
0.5
0.0
MH
AQ
Disease Duration (Years)
MH
AQ
2.0
1.5
1.0
0.5
0.020 0 5 10 15 20
Cross-Sectional Data in Patients With RA: Cohort #2 in 1985 and Cohort #4 in 2000:
Multidimensional Health Assessment Questionnaire (MDHAQ)
scores
Pincus, Sokka, Kautiainen, Arth Rheum 52:1009, 2005
Cross-Sectional Data in RA Patients:Cohort #2- 1985 and Cohort #4-2000: Larsen X-Ray score,% of maximum
2000
0
5
10
15
20
25
30
0 5 10 15
Disease duration
La
rso
n s
co
re f
or
ha
nd
s, %
of
ma
x
RF+
RF-
0
5
10
15
20
25
30
0 5 10 15
Disease duration
La
rso
n s
co
re f
or
ha
nd
s, %
of
ma
x0
5
0
RF
positive
RF+
RF-
1985
Pincus, Sokka, Kautiainen, Arth Rheum 52:1009, 2005
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) 49 (15 , 73) 0.38
Gripstr,mmHg(30-300) 82 (65 ,115) 120 (91, 166) <0.001
Walk time,secs(0-20) 8.6 (7.0,11.8) 7.4 (6.6 8.7) 0.018
Buttontest,scs(0-300) 50 (39 ,71) 40 (32 , 52) <0.001Pincus, Sokka, Kautiainen, Arth Rheum 52:1009, 2005
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
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%
Standard mortality 1.47 1.85 4.11 5.56 2.60 ratioConfidence (0.84- (0.97- (2.56- (3.29- (2.05- interval 2.10) 2.73) 5.66) 7.83) 3.15)
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
Methotrexate continuation in TP clinic standard care – 1990-2003
Duration of methotrexate therapy (years)
0 1 2 3 4 5
Cu
mu
lative
pro
ba
bility o
f co
ntin
ua
tio
n o
f th
era
py (
%)
0
10
20
30
40
50
60
70
80
90
100
Yazici,Y. et al. Ann Rheum Dis 64, 207-211 (2005).
RA – 75 pts – 15 yrs - Pincus et al, Ann Int Med 120:26,1994Functional status on patient questionnaire < vs > 91.5% “with ease” 2.9:1# of Involved Joints > vs < 18 joints 3.0:1
CV disease – 312,000 pts – 12 yrs – Neaton et al, Arch Int Med 152:56,1992Serum cholesterol >245 vs <182 mg/Dl 2.9:1Systolic blood pressure >142 vs <118 mmHg 3.0:1Diastolic blood pressure >92 vs <76 mmHg 2.9:1Smoking >26 vs 0 cigarettes/day 2.9:1
Data adjusted for age, sex, education, disease duration
Relative Risk of Death Over 12-15 Years in rheumatoid arthritis (RA) and
cardiovascular (CV) disease according to baseline severity indicators
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?