Longitudinal databases and registries – why? [email protected]

Longitudinal databases and registries – why?

[email protected]


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.


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)

Survival in SLE Nephritis

Austin, Klippel, Balow, et al, NEJ Med 314:614, 1986







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







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









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


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



2. Document improvements in patient outcomes over the years by evidence, not eminence.


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


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


2.0

1.5

1.0

0.5

0.0

MH

AQ


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


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


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%


Mtx in RA Care - 1985-2000Jyvaskyla, 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





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





Documents

Longitudinal databases and registries – why? [email protected]