Longitudinal databases and registries why

1
Longitudinal databases and registries why?
t.pincus_at_vanderbilt.edu
2
Longitudinal databases and registries why?

• Randomized trials have many limitations,
  especially patient selection, short time frame
• Document improvements in patient outcomes over
  5-20 years.
• How do we know if treatment improves outcomes,
  eg, survival?

3

• 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

4
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
27721,1984.
5

• 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. 1983287569.

6
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 27864,
1984.
7
Longitudinal databases and registries why?

• Randomized trials have many limitations,
  especially patient selection, short time frame
• How do we know if treatment improves outcomes,
  eg, survival?
• Document improvements in patient outcomes over
  the years by evidence, not eminence.

8
Some Pragmatic Limitations of Randomized
Controlled Clinical Trials in Chronic Diseases J
Clin Epidemiol 411037,1988 Arthritis Rheum
48313, 2003

• Relatively short observation period
• Inclusion and exclusion criteria - most patients
  ineligible in most trials
• Surrogate markers - may be suboptimal for actual
  outcomes, e.g., T cell counts vs. AIDS, tender
  joints vs. surgical replacement
• Inflexible dosage schedules and concomitant drug
  therapies

9
Standard Composite Treatment Effect
Felson, Anderson, Meenan. Arthrit Rheum.
1990331449.
10
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)
Pincus, Marcum, Callahan. J Rheumatol.
1992191885.
11
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

12
Estimated Continuation of Courses of 2nd-Line
Therapy
All Courses Over 60 Months
Initial Course Over 12 Months
Methotrexate (61) Hydroxychloroquine
(130) Penicillamine (55) Parenteral gold
(207) Oral gold (5) Azathioprine (19)
Months
Pincus, Marcum, Callahan. J Rheumatol.
1992191885.
13
Survival in SLE Nephritis
Austin, Klippel, Balow, et al, NEJ Med 314614,
1986
14
Some Pragmatic Limitations of Randomized
Controlled Clinical Trials in Chronic Diseases J
Clin Epidemiol 411037,1988 Arthritis Rheum
48313, 2003

• Relatively short observation period
• Inclusion and exclusion criteria - most patients
  ineligible in most trials
• Surrogate markers - may be suboptimal for actual
  outcomes, e.g., T cell counts vs. AIDS, tender
  joints vs. surgical replacement
• Inflexible dosage schedules and concomitant drug
  therapies

15
ATTRACT trial clinical inclusion criteria
138
Criteria
? 6 tender joints and ? 6 swollen joints
42
96
2 of 3 Morning stiffness ? 45 min ESR ? 28 mm /
hour CRP ? 2.0 mg / dL
21
77
19
21
MTX dose ? 12.5 mg / week
48
15
16
14
7
4
29
5
Meet ATTRACT criteria
Do not meet ATTRACT criteria
Sokka and Pincus Arthrits Rheum 48213, 2003
16
Etanercept in Early RA (ERA) ACR Responses at
52 Weeks
100
p NS
Etanercept 25 mg (n 207)
MTX, mean 19 mg (n 217)
80
72
65
p NS
60
49
p NS
Patients
43
40
25
22
20
0
ACR20
ACR50
ACR70
Bathon JM et al. N Engl J Med. 20003431586-1593
17
Number of patients who meet ERA clinical
inclusion criteria 1st visit patients who did
not take methotrexate
Sokka and Pincus Arthritis Rheum 48213, 2003
18
of Patients with RA who meet Criteria for
Inclusion in Clinical Trials
TP Recent Clinic onset RA 1998-2001 200
1 Number of Patients 146 300 1. gt 6 Swollen
Joints 42.5 63.4 2. gt 6 Tender
Joints 25.3 50.4 3. ESR gt 28 25.0 49.3 4.
AM Stiffness gt 45 mins 45.9 50.9 123 or
4 22.0 34.1 123 and 4 11.3 18.3 Sokka
and Pincus, submitted for publication
19
Some Pragmatic Limitations of Randomized
Controlled Clinical Trials in Chronic Diseases J
Clin Epidemiol 411037,1988 Arthritis Rheum
48313, 2003

• Relatively short observation period
• Inclusion and exclusion criteria - most patients
  ineligible in most trials
• Surrogate markers - may be suboptimal for actual
  outcomes, e.g., T cell counts vs. AIDS, tender
  joints vs. surgical replacement
• Inflexible dosage schedules and concomitant drug
  therapies

20
Measures of activity and damage in patients with
RA over 5 years
75 50 25 0 25 50 75
Grip strength
Sedimentation rate
Percentage improvement
Ritchie articular index
Morning stiffness
Pain VAS
Haemoglobin
Radiological score
Percentage deterioration
VAS 10 cm visual analogue scale
Mulherin D, et al. Br J Rheumatol.
1996351263-1268.
21
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
Worse
Erosions
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
Arthritis Care Res 10381,1997
Pain - Visual Analog Scale
Helplessness
-1.5
-1.3
-1.1
-0.9
-0.7
-0.5
-0.3
-0.1
0.1
0.3
0.5
Effect Size
22
Some Pragmatic Limitations of Randomized
Controlled Clinical Trials in Chronic Diseases J
Clin Epidemiol 411037,1988 Arthritis Rheum
48313, 2003

• Relatively short observation period
• Inclusion and exclusion criteria - most patients
  ineligible in most trials
• Surrogate markers - may be suboptimal for actual
  outcomes, e.g., T cell counts vs. AIDS, tender
  joints vs. surgical replacement
• Inflexible dosage schedules and concomitant drug
  therapies

23
Some Pragmatic Limitations of Randomized
Controlled Clinical Trials in Chronic Diseases J
Clin Epidemiol 411037,1988 Arthritis Rheum
48313, 2003

• 5. Variables other than randomization, such as
  education, clinical care site, etc., may affect
  outcome more than randomization group
• Statistically significant results not necessarily
  clinically important, and vice versa
• Rare toxicities not seen in fewer than 10,000
  subjects
• Balance of efficacy and toxicity may be unclear

24
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25
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26
Some Intrinsic Limitations of Controlled Clinical
Trials in Chronic Diseases J Clin Epidemiol
411037,1988 Arthritis Rheum 48313, 2003

• Control group does not remove bias 1st DMARD vs
  requirement to fail 2 DMARDs
• 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?
• Results reported for groups of patients ignore
  individual variation most people preferis that
  true for all?
• Loss of placebo effect when patent given
  randomized versus best therapy

27
Infliximab MTX (ATTRACT)ACR Responses at 30
and 54 Weeks
C
Placebo MTX (n 88)
3 mg/kg q8w (n 86)
Infliximab MTX
3 mg/kg q4w (n 86)
70
10 mg/kg q8w (n 87)
p lt 0.001
p lt 0.001
60
10 mg/kg q4w (n 81)
50
p lt 0.001
40
p lt 0.001
Patients
p lt 0.001
30
p lt 0.001
20
10
0
Week 30
Week 54
Week 30
Week 54
Week 30
Week 54
ACR50
ACR70
ACR20
vs placebo. ATTRACT Anti-Tumor Necrosis
Factor Trial in Rheumatoid Arthritis with
Concomitant Therapy.
Maini R et al. Lancet. 19993541932-1939.
Lipsky PE et al. N Engl J Med.
20003431594-1602.
28
ACR Core Data Set Measure changes - 12 Months
Leflunomide (LEF) vs Methotrexate (MTX)vs
Placebo (PBO)
Measure LEF PBO MTX Effect Relative Size
Efficiency Tender Jts -7.7 -3.0 -6.6 -0.59
1.00 Swollen Jts -5.7 -2.9 -5.4 -0.44
0.56 MD Global -2.8 -1.0 -2.4 -0.68
1.33 ESR -6.3 2.6 -6.5 -0.41 0.48 FN-
HAQ -0.45 0.03 -0.26 -0.80
1.84 FN-MHAQ -0.29 0.07 -0.15 -0.69
1.37 Pain -2.2 -0.4 -1.7 -0.65 1.21 Pt
Global -2.1 0.1 -1.5 -0.81 1.88
Strand V, et al. Arch Intl Med. 1999
1592542-2550 Tugwell P, et al. Arthritis
Rheum. 2000 43506-514.
29
Longitudinal databases and registries why?

• Randomized trials have many limitations,
  especially patient selection, short time frame
• Document improvements in patient outcomes over
  the years by evidence, not eminence.
• How do we know if treatment improves outcomes,
  eg, survival?

30
Progression of the Larsen score in the 1970s vs.
1980s
26
12
Disease duration (years)
Sokka T, Kaarela K, Mottonen T, Hannonen P. Clin
Exp Rheumatol 1999
31
Cross-Sectional Data in Patients With RA Cohort
2 in 1985 and Cohort 4 in 2000 Swollen Joint
Count Scores
2000
1985
20 16 12 8 4 0
20 16 12 8 4 0
Swollen Joint Count 28
Swollen Joint Count 28
0
5
10
15
20
0
5
10
15
20
Disease Duration (Years)
Disease Duration (Years)
Pincus, Sokka, Kautiainen, Arth Rheum 521009,
2005
32
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
521009-1019, 2005
33
Cross-Sectional Data in Patients With RA Cohort
2 in 1985 and Cohort 4 in 2000
Multidimensional Health Assessment Questionnaire
(MDHAQ) scores
2000
1985
2.0 1.5 1.0 0.5 0.0
2.0 1.5 1.0 0.5 0.0
MHAQ
MHAQ
0
5
10
15
20
0
5
10
15
20
Disease Duration (Years)
Disease Duration (Years)
Pincus, Sokka, Kautiainen, Arth Rheum 521009,
2005
34
Cross-Sectional Data in RA PatientsCohort 2-
1985 and Cohort 4-2000 Larsen X-Ray score, of
maximum 2000
1985
RF-
RF
Pincus, Sokka, Kautiainen, Arth Rheum 521009,
2005
35
Median clinical status measures in two cohorts of
patients with RA seen in 1984-86 (1985) and
1999-2001 (2000).
Pincus, Sokka, Kautiainen, Arth Rheum 521009,
2005
36
DMARDs used in the 1985 and 2000 TP cohorts
Pincus, Sokka, Kautiainen, Arth Rheum 521009,
2005
37
Mtx in RA Care - 1985-2000 Jyvaskyla, Finland
Nashville,TN
38
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
39
Is rheumatoid arthritis becoming less severe? A
Silman, P Davies, HLF Currey, SJW Evans J
Chronic Dis 36891-897, 1983
40
Longitudinal databases and registries why?

• Randomized trials have many limitations,
  especially patient selection, short time frame
• Document improvements in patient outcomes over
  the years by evidence, not eminence.
• How do we know if treatment improves outcomes,
  eg, survival?

41
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 4314, 2000

42
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43
Methotrexate and mortality in patients with
rheumatoid arthritis a prospective study

• H K Choi, MA Hernan, JD Seeger, JM Robins, F
  Wolfe
• The Lancet 3591173, 2002

44
Response to methotrexate treatment is associated
with reduced mortality in patients with severe
rheumatoid arthritis

• Improvement gt50 20-50 lt20 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
• ratio
• Confidence (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
  4314, 2000

45
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 64207-211, 2005

46
Methotrexate continuation in TP clinic standard
care 1990-2003
Yazici,Y. et al. Ann Rheum Dis 64, 207-211
(2005).
47
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
12026,1994 Functional status on patient
questionnaire lt vs gt 91.5 with ease 2.91
of Involved Joints gt vs lt 18 joints 3.01 CV
disease 312,000 pts 12 yrs Neaton et al,
Arch Int Med 15256,1992 Serum cholesterol gt245
vs lt182 mg/Dl 2.91 Systolic blood pressure gt142
vs lt118 mmHg 3.01 Diastolic blood pressure gt92
vs lt76 mmHg 2.91 Smoking gt26 vs 0
cigarettes/day 2.91 Data adjusted for age, sex,
education, disease duration
48
Longitudinal databases and registries why?

• Randomized trials have many limitations,
  especially patient selection, short time frame
• Document improvements in patient outcomes over
  the years by evidence, not eminence.
• How do we know if treatment improves outcomes,
  eg, survival?

49
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