Burden of ProofProof of Principle

Quantification, Replication and Validation…

Standards of Evidence in Outcomes Research

W. Robert Simons

2

Quantification, Replication and Validation…

Standards of Evidence in Outcomes Research

Outcomes research consists of an abundance of studies in a single data source

Despite the rigour of methodologies as well as the source of publication, they remain a single study

The guidelines such as NICE, PBAC, SMC, AMCP, etc. have gradients for the level of clinical evidence (e.g., multiple head-to-head RCTs, placebo controlled, non-randomised or indirect comparisons)

Outcomes research with less rigourous standards imparts uncertainty

3

Overview

Quantification, Replication, Validation by Example

Prevalence, direct medical expenditures and indirect productivity losses as measured by work force participation, absenteeism and income loss in Rheumatoid Arthritis patients: 2004, 2005 and 2006

Heart rate and all-cause death

HbA1c, Treatment and Risk of Diabetic-related Complications

Pain Management and Adverse Events

HDL-C and mortality

New Longitudinal Outcomes Research Analytical Technique

Annihilation of stagnant study cohorts

The Economic Consequences of Rheumatoid Arthritis: Analysis of Medical Expenditure Panel Survey (MEPS) 2004, 2005 and 2006 Data

Methods

Medical expenditure panel survey 2004-2006

Multiple linear and semi-log regressions were applied to estimate total and annual medical expenditures and income loss associated with RA

Outcomes

Prevalence

Direct medical expenditures

Indirect productivity losses

Work force participation

Absenteeism

Income loss

4

Study Results: Prevalence

MEPS correctly reproduced 2004-2006 US census records for the US population, validating the weights

RA prevalence in the US was 0.40% in 2004, 0.44% in 2005 and 0.43% in 2006

5

Direct Economic Cost: Incremental Health Expenditures

6

2004 2005 2006

RA Healthcare Expenditures (per person) $4422.25 $2901.59 $1882.42

Healthcare Expenditures:

Overall Health vs Excellent Health

Poor Health $9752.26 $8802.82 $7824.23

Fair Health $3731.77 $4305.90 $3354.11

Good Health $570.81 $967.45 $640.20

Very Good Health -$181.17 $147.68 $120.11

Productivity Loss: Workforce Production, Absenteeism and Income Loss

7

WORKFORCE PARTICIPATION BY RA STATUS

NUMBER (%) OF

EMPLOYED NON-RA

PATIENTS

NUMBER (%) OF

EMPLOYED RA

PATIENTS

NUMBER (%) OF

EMPLOYED NON-RA

PATIENTS

NUMBER (%) OF

EMPLOYED RA

PATIENTS

NUMBER (%)

OF

EMPLOYED

NON-RA

PATIENTS

NUMBER (%) OF EMPLOYED RA

PATIENTS

YEAR 2004

N= 34,403

YEAR 2005

N= 33,645

YEAR 2006

N= 34,145

<20 504(4.3) 1(100%) 433(3.9) 1(25) 502(4.4) 0(0)

20-39 6422(69.2) 6(35.3) 6141(68.6) 8(72.7) 5970(69.2) 6(54.5)

40-64 6709(70.5) 28(36.8) 6841(69.8) 34(39.5) 7018(71) 33(44)

65-79 597(20.2) 2(6.5) 496(18.7) 2(5.5) 680(22.1) 2(4.8)

80+ 34(3.8) 0(0) 35(3.8) 0(0) 38(3.7) 1(7.8)

DAYS ABSENT FROM WORK BY RA STATUS

NON-RA PATIENTS RA PATIENTS NON-RA PATIENTS RA PATIENTSNON-RA

PATIENTSRA PATIENTS

YEAR 2004 (p = 0.0021) YEAR 2005 (p = 0.0004) YEAR 2006 (p = 0.0006)

MEAN STDSTD

ERRORMEAN STD

STD

ERRORMEAN STD

STD

ERRORMEAN STD

STD

ERRORMEAN STD

STD

ERRORMEAN STD

STD

ERROR

4.06 13.81 0.126 12.17 30.75 5.61 3.77 12.85 0.118 10.71 23.91 3.88 3.84 14.24 0.130 9.14 18.74 3.08

INCOME LOSS

2004 2005 2006

Income Loss Due to RA -$3,525.50* -$2,206.96* -$1,211.97*RA = Rheumatoid Arthritis

* Statistically significant at 1%

Heart Rate and All-cause Mortality

9

Heart Rate: BackgroundBiology

Semi-logarithmic relationship between heart rate and life expectancy among mammals

Man is the exception

*Source: Levine (1997)

Heart Rate vs. Life Expectancy

10

BackgroundEpidemiology Singh (2001)

Systematic review of thirteen large epidemiological studies

Increasing risk of all-cause death with increases in RHR irrespective of age, sex, and ethnic origin

Cucherat (2007) Meta-analysis and meta-regression of sixteen placebo-

controlled randomised clinical trials (coefficient = 0.0249)

Intervention affecting heart rate significantly changes all-cause mortality

Validating results from Cucharet Coronary Artery Surgery Study (CASS)

The Copenhagen City Heart Study (CCHS)

General Practice Research Network (GPRN).

11

Cucharet

(multinational)

GPRN

(Australia) 300 GPs

(2% sample)

CCHS

(Denmark)

CASS

(Canada)

Singh

(multinational)

Number of studies or patients

16 intervention studies in post-MI patients

11,000

CAD patients

Longitudinal GP visits,

19,698

Random population sample

Panel survey: 1976-78,

81-83, 91-94, 2001-03.

24,913

Post cardiac surgery

13 epidemiological studies across multiple countries in healthy people

116,539

Follow-up mean

1.37 years 2.2 years 12 years 14.7 years 5 to 36 years

Quality of evidence

Highest Validates Cucharet with Australian data

Validates GPRN

Replicates CASS

Reproduces Cucharet

Reproduces Cucharet

Strongest

Results consistent with Cucharet

A Comparison of the Literature

Background

12

Methods

Compare apples to apples Singh – results converted to odds-ratios (ORs) and meta-

analysed

Cucherat uses a regression (coefficient relating incremental changes in heart rate to the probability of death) as well as meta-analyses (odds-ratio)

CASS— Weibull survival regression with heart rate as a predictor

CCHS— Weibull as well as GEE (coefficient analogous to Cucherat’s regression coefficient

GPRN— GEE (coefficient analogous to Cucherat’s coefficient)

Odds ratios (ORs) produced from all sources of evidence

13

Methods

Table 1 of the Cucherat 2007 Publication

Plug the initial heart rate reported at baseline and the absolute change in heart rate from baseline for each of the 16 clinical trials into the CASS, CCHS and GPRN equations for all cause mortality

HEART

RATES

FROM

CUCHERAT

CARDIOVASCULAR

RISK EQUATIONS

CASS

CCHS

GPRN

RIP

ODDS

RATIOS

REPORTED

IN

CUCHERAT

Odds Ratios

14

Meta-analysis of Singh's Study

Study Name Statistics for Each Study

Events / Total

Odds Ratio P-Value HR < 75 BPM HR >= 75 BPM

Chicago Western Electric 0.601 0.000 97/756 225/1143

Chicago Peoples Gas 0.587 0.000 124/700 143/533

Chicago HA Detection Project in Industry

0.749 0.014 167/3532 140/2252

Framingham Heart Study 0.667 0.000 149/8000 332/12000

Robert Koch Institute 0.978 0.001 296/3640 120/1039

Israeli Male Industrial 0.507 0.001 38/1349 74/1368

Overall Results 0.650 0.000

Results

15

Meta-Analysis of Cucherat’s Study

Groups by HR Reduction

LevelsStudy Name

Statistics for Each Study

Events/Total

Odds ratio Active Control

Low

CRIS 1.059 30/531 29/542

MDPIT 0.995 166/1232 167/1234

Australian / Swedish

0.962 45/263 47/266

Taylor 0.924 60/632 48/471

Wilhelmsson 0.477 7/114 14/116

DAVIT 0.793 95/878 119/897

Tretile Overall 0.914

Medium

BHAT 0.715 138/1916 188/1921

EIS 1.325 57/858 45/883

APSI 0.489 17/298 34/309

Multicenter Int’l 0.782 102/1533 127/1520

Baber 1.072 28/355 27/365

Hjalmarson 0.623 40/698 62/697

Tretile Overall 0.782

High

Hansteen 0.654 25/278 37/282

Julian 0.808 64/873 52/583

Wilcox 0.935 36/259 19/129

Norweigian 0.599 98/945 152/939

Tretile Overall 0.685

Complete Overall 0.806

16

Comparative Weibull Regressions with Heart Rate at Baseline as a Covariate

Results

CASS CCHS

1981-83

CCHS

1991-93

VARIABLES DEATH DEATH DEATH

INTERCEPT 4.25157 4.95531 5.84813

HEART RATE -0.00694 -0.00683 -0.00717

AGE CATEGORY (50-59 YEARS)

-0.34182 -0.61060 -0.95736

AGE (60-69 YEARS) -0.76160 -0.98391 -1.58453

AGE (70-79 YEARS) -1.31332 -1.38566 -2.00030

MALE -0.13709 -1.81236 -2.52007

HYPERTENSION -0.10415 -0.25346 -0.35017

DIABETES -0.42727 -0.11786 -0.06230

FORMER SMOKER -0.11330 -0.30669 -0.20382

PRESENT SMOKER -0.40022 -0.08434 -0.12511

1 DISEASED VESSEL -0.47763

2 DISEASED VESSELS -0.73045

3 DISEASED VESSELS -0.98794

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Comparative Weibull Regressions (Continued)

Results

CASS CCHS

1981-83

CCHS

1991-93

VARIABLES DEATH DEATH DEATH

EJECTION FRACTION 0.02202

BETA-BLOCKER USE 0.01453

MODERATE ACTIVITY -0.03356 -0.00608 -0.11371

MILD ACTIVITY -0.10955

SEDENTARY -0.20079 -0.16128 -0.31471

ANTIPLATELET USE -0.01053

DIURETIC USE -0.32735 -0.17573 -0.22675

LIPID LOWERING DRUGS

-0.00184

ANTIHYPERTENSIVE MEDICATION

-0.14423 -0.13021

CARDIAC MEDICATION

-0.28235 -0.26095

TRANQUILIZERS -0.07124 -0.9259

LOG (SCALE) -0.09403 -0.58841 -0.42485

18

Results of GEE Analysis for All-Cause Mortality and Heart Rate

ResultsSystolic Blood Pressure Diastolic Blood Pressure

VARIABLES ESTIMATE PROB > | Z | ESTIMATE PROB > | Z |

(Intercept) -4.2618 <.0001 -4.6057 <.0001

Heart Rate 0.0268 0.0006 0.0400 <.0001

Age, 50 -2.7663 0.0005 -2.6555 0.0011

Age, 60 -1.2923 0.0002 -1.2836 0.0003

Age, 70 -0.7384 0.0004 -0.7677 0.0007

Male 0.3751 0.0142 0.4305 0.0044

Smoking, Present smoker 0.1921 0.4922 0.2238 0.4384

Smoking, Former smoker 0.0687 0.7335 0.0805 0.7039

Rate Product Pressure -0.0001 0.2379 -0.0003 0.0027

Systolic Blood Pressure> 150 mmHg

0.2370 0.0421 **** *****

Diastolic Blood Pressure > 100 mmHg

***** ***** 0.2278 0.2994

Angina -0.0051 0.9831 -0.0034 0.9890

Hypertension -0.5227 0.0098 ***** *****

Diabetes 0.1094 0.6602 0.0480 0.8537

Coronary Artery Disease -0.8599 0.1606 -0.8459 0.1601

Use of Beta Blockers 0.0489 0.8383 0.0870 0.7141

Use of Diuretics 0.2585 0.4413 0.2848 0.3928

Use of Lipid Low Agents -0.6587 0.0449 -0.6899 0.0449

19

Precision and Comparability of Coefficient Estimates

Regression

Coefficients

(GEE/Meta regression)

Weibull

Survival Analyses

Cucherat0.0249

(P=0.008) longitudinal HR

GPRN0.0268

(P=0.0006) longitudinal HR

CASS-0.00694

(P<0.001) baseline HR

CCHS0.0159

(P<0.001) longitudinal HR

-0.00683

(P<0.001) baseline HR

Results

20

Validating ORs from Cucherat with Three Epidemiological Studies

Risk Levels

Number of Trials

Ave. Base Reduction*

Cucherat

(P=0.017)

CASS CCHS GPRN

Low 6 4.7 0.91 0.88 0.91 0.90

Medium 6 10.0 0.78 0.78 0.78 0.80

High 4 16.2 0.69 0.69 0.69 0.71

* Ave. Base Reduction: Absolute HR reduction (mean, bpm)

Results

21

Recap

Cucharet 16 intervention studies Quantifies relationship

Unable to control for BP

Establishes correlation

CCHS & CASS & GPRN Replicate odds ratios from Cucharet

All 3 control for BP and other co-variates

Singh 13 studies closely replicate Odds Ratio from Cucharet

MET THE BURDEN

PROVED THE PRINCIPLE

22

Accidental?

…..Dumb Luck?

23

Validated Diabetic-Risk EquationsReplication in Quantification

UK1 GERMANY2 USA3

Patient Population Size 2,137 3,190 497,716

Effect of Rx on Glycemic Control

-0.99% -0.92% -0.89%

Effect of Glycemic Control on Risk of Complication -0.388% -0.414% -0.436%

1. Simons WR, Kemo R and Bolinder B. A five year longitudinal analysis of the health benefits of transitioning toward

insulin sooner in newly diagnosed type 2 diabetics. Value Health 3 2000. [no.5]DB3.

2. Simons WR, Vinod HD, Gerber RA and Bolinder B. Does rapid transition to insulin therapy in subjects with newly

diagnosed type 2 diabetes mellitus benefit glyceamic control and diabetic related complications? A Germany

population-based study. Exp Clin Endocrinol Diabetes 2006; 114:520-526.

3. Simons WR. The quantification of the relationship between t pharmacological intervention, HbA1c and diabetic related

complications: A USA validation study. ISPOR 2009

Diabetes

24

Comparative Odd-Ratio Plot for Adverse Events Associated with Opioid Use in

Post- Surgical Patients

HCUP (2005) and Premier (2005)

HP H

P HP

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P

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Pain Management in Post Surgical Patients

25

Selected Variables

Estimates Confidence Intervals P-Value

Intercept -45.08 -62.76 -27.40 <0.01

HDL-C -1.60 -3.14 -0.05 0.04

LDL-C 0.30 <0.01 0.60 <0.05

Log Age 9.54 5.59 13.49 <0.01

Angina 0.87 -0.01 1.76 0.05

Diabetes 1.16 0.09 2.23 0.03

GEE Analysis Death in Patients With HDL-C Less Than 1.0

mmol/L Despite Taking a Statin With IHD

26

Validation of Epidemiological Studies (PTC) and GPRN HDL-C Mortality Equations

PTC reports that a 0.33 mmol/L increase in HDL-C is associated with about a third (33%) lower IHD mortality.

That increase in HDL-C used in the HDL-C Mortality Equations from GPRN with bootstrapping reduces the hazard ratios by 29% [95% CI: -0.34 – -0.23], 30% [95% CI: -0.35 - -0.24] and 32% [95% CI: -0.38 - -0.26] for baseline HDL-C levels of 0.992 mmol/L, 0.9 mmol/L and 0.8 mmol/L, respectively.

GPRN HDL-C Mortality Equation replicates 22 epidemiological studies with HDL-C and mortality.

PTC = Prospective Trialists’ Collaborative

27

Replication of quantification

Validation

Reconciliation

……Standard of Evidence

28

MET THE BURDEN

PROVED THE PRINCIPLE

New Longitudinal Outcomes Research Analytical Technique

Redefining Outcomes Research

Key analytical change

Annihilation of stagnant study cohorts

Blood pressure readings are linked to the time of actual drug usage

Patients are allowed to transition or titrate

Patients are not confined to a single study cohort

All data are used in the analyses

Objectives

Quantify and compare the effectiveness of various ARBs in achieving treatment goal, as well as reduction in systolic and diastolic blood pressure

Differentiate effectiveness in a number of special patient populations (e.g. African American, diabetic, obese, overweight patients)

30

Results: Changes in Systolic and Diastolic Blood Pressure and Goal Attainment

31

Systolic Blood Pressure Diastolic Blood Pressure Goal Attainment

Parameter Estimate95% Confidence

LimitsEstimate

95% Confidence

Limits

Marginal

Effect

95% Confidence

Limits

Intercept 83.6875 83.0091 84.3660 46.8458 46.3319 47.3598 0.8424 0.8206 0.8642

Olmesartan 20mg -8.1876 -8.5582 -7.8170 -4.5671 -4.7823 -4.3519 0.2110 0.2012 0.2208

Losartan 50mg -5.4167 -5.7248 -5.1086 -3.2733 -3.4447 -3.1019 0.1393 0.1313 0.1474

Valsartan 80mg -6.4975 -6.8079 -6.1871 -3.6587 -3.8313 -3.4862 0.1687 0.1604 0.1769

Valsartan 160mg -5.9001 -6.6767 -5.1235 -3.5958 -3.9918 -3.1999 0.1348 0.1155 0.1542

Irbesartan 150mg -6.5180 -6.9856 -6.0504 -3.7411 -4.0010 -3.4811 0.1683 0.1559 0.1808

Olmesartan 20mg/HCTZ -10.1896 -10.7997 -9.5796 -5.6991 -6.0601 -5.3380 0.2404 0.2239 0.2568

Losartan 50mg/HCTZ -7.4682 -8.0013 -6.9351 -4.1043 -4.3960 -3.8125 0.1653 0.1516 0.1790

Valsartan 80mg/HCTZ -8.9511 -9.4101 -8.4920 -4.8933 -5.1580 -4.6287 0.2094 0.1972 0.2215

Valsartan 160mg/HCTZ -7.3538 -7.6920 -7.0156 -4.2095 -4.4036 -4.0154 0.1733 0.1645 0.1821

Irbesartan 150mg/HCTZ -8.4265 -9.1942 -7.6588 -4.8096 -5.2699 -4.3492 0.2080 0.1876 0.2285

Olmesartan 40mg -7.2622 -7.9972 -6.5273 -4.2729 -4.6471 -3.8987 0.1672 0.1492 0.1851

Losartan 100mg -5.8477 -6.4724 -5.2229 -3.4239 -3.7699 -3.0780 0.1473 0.1319 0.1627

Valsartan 320mg -5.5594 -6.6048 -4.5140 -3.4439 -4.0317 -2.8561 0.1280 0.1034 0.1525

Irbesartan 300mg -6.5013 -7.3308 -5.6718 -3.6268 -4.0703 -3.1832 0.1602 0.1393 0.1812

Olmesartan 40mg/HCTZ -9.7413 -10.4462 -9.0364 -5.6391 -6.0794 -5.1988 0.2116 0.1937 0.2295

Losartan 100mg/HCTZ -7.1166 -7.8399 -6.3932 -4.1585 -4.5702 -3.7467 0.1515 0.1340 0.1690

Valsartan 320mg/HCTZ -6.7834 -8.1713 -5.3955 -3.8899 -4.7517 -3.0282 0.1608 0.1237 0.1979

Irbesartan 300mg/HCTZ -7.4217 -8.3696 -6.4738 -3.9916 -4.5360 -3.4471 0.1738 0.1490 0.1986

Results: Special Patient Populations

32

African American Diabetic Obese Overweight

SBP

Parameter

Estimates

(95% CI)

DBP

Parameter

Estimates

(95% CI)

Goal

Attainment

Marginal

Effects

(95% CI)

SBP

Parameter

Estimates

(95% CI)

DBP

Parameter

Estimates

(95% CI)

Goal

Attainment

Marginal

Effects

(95% CI)

SBP

Parameter

Estimates

(95% CI)

DBP

Parameter

Estimates

(95% CI)

Goal

Attainment

Marginal

Effects

(95% CI)

SBP

Parameter

Estimates

(95% CI)

DBP

Parameter

Estimates

(95% CI)

Goal

Attainment

Marginal

Effects

(95% CI)

Olmesartan-7.37

(-8.84,-5.91)

-3.95

(-4.77, -3.13)

0.190

(0.153,0.227)

-8.00

(-8.37,-7.64)

-4.47

(-4.68,-4.26)

0.159

(0.132,0.185)

-7.15

(-7.66,-6.65)

-4.14

(-4.43,-3.84)

0.186

(0.173,0.199)

-7.61

(-8.02,-7.21)

-4.35

(-4.59,-4.12)

0.192

(0.182,0.203)

Losartan-4.73

(-5.92,-3.53)

-3.10

(-3.75,-2.46)

0.138

(0.109,0.167)

-5.29

(-5.58,-4.99)

-3.23

(-3.40,-3.06)

0.106

(0.087,0.126)

-4.73

(-5.14,-4.32)

-2.99

(-3.23,-2.75)

0.125

(0.114,0.136)

-5.12

(-5.47,-4.76)

-3.12

(-3.32,-2.92)

0.134

(0.125,0.143)

Valsartan-4.46

(-5.85,-3.07)

-3.17

(-3.88,-2.46)

0.128

(0.095,0.160)

-6.26

(-6.54,-5.97)

-3.60

(-3.76,-3.45)

0.137

(0.116,0.158)

-5.92

(-6.34,-5.50)

-3.47

(-3.72,-3.23)

0.150

(0.138,0.161)

-6.24

(-6.58,-5.89)

-3.59

(-3.78,-3.40)

0.159

(0.150,0.168)

Irbesartan-4.13

(-6.26,-1.99)

-3.21

(-4.37,-2.04)

0.114

(0.056,0.172)

-6.42

(-6.88,-5.97)

-3.68

(-3.93,-3.43)

0.162

(0.135,0.189)

-5.96

(-6.59,-5.34)

-3.47

(-3.82,-3.12)

0.151

(0.134,0.168)

-6.25

(-6.74,-5.77)

-3.66

(-3.93,-3.40)

0.160

(0.147,0.173)

Olmesartan

HCTZ

-9.71

(-11.49,-7.92)

-5.36

(-6.30,-4.43)

0.205

(0.158,0.252)

-10.01

(-10.60,-9.42)

-5.61

(-5.98,-5.24)

0.159

(0.121,0.197)

-8.98

(-9.67,-8.28)

-5.28

(-5.68,-4.89)

0.216

(0.198,0.234)

-9.30

(-9.86,-8.74)

-5.41

(-5.73,-5.09)

0.218

(0.203,0.232)

Losartan

HCTZ

-6.65

(-8.35,-4.96)

-3.93

(-4.83,-3.04)

0.146

(0.107,0.185)

-7.28

(-7.79,-6.77)

-3.92

(-4.20,-3.64)

0.115

(0.081,0.149)

-6.72

(-7.38,-6.05)

-3.96

(-4.34,-3.57)

0.153

(0.135,0.170)

-6.85

(-7.41,-6.29)

-4.00

(-4.31,-3.69)

0.155

(0.141,0.170)

Valsartan

HCTZ

-7.32

(-8.42,-6.21)

-4.00

(-4.68,-3.32)

0.164

(0.136,0.192)

-7.72

(-7.99,-7.44)

-4.34

(-4.50,-4.19)

0.123

(0.101,0.145)

-7.29

(-7.68,-6.90)

-4.04

(-4.28,-3.80)

0.173

(0.162,0.184)

-7.58

(-7.91,-7.26)

-4.28

(-4.47,-4.09)

0.180

(0.171,0.189)

Irbesartan

HCTZ

-6.25

(-8.83,-3.66)

-4.35

(-6.17,-2.53)

0.160

(0.096,0.224)

-8.09

(-8.81,-7.36)

-4.51

(-4.94,-4.08)

0.124

(0.079,0.169)

-6.86

(-7.71,-6.01)

-3.99

(-4.52,-3.46)

0.166

(0.142,0.189)

-7.61

(-8.32,-6.91)

-4.40

(-4.83,-3.97)

0.189

(0.169,0.209)

Amlodipine-5.06

(-6.52,-3.60)

-2.86

(-3.69,-2.03)

0.068

(0.033,0.103)

-6.20

(-6.76,-5.63

-3.64

(-3.97,-3.31)

0.029

(-0.011,0.068)

-1.39

(-1.84,-0.94)

-0.67

(-0.92,-0.42)

0.067

(0.049,0.084)

-3.74

(-4.18,-3.29)

-2.35

(-2.61,-2.09)

0.087

(0.073,0.101)

Global Health Economics& Outcomes Research

Raising the Bar in Outcomes Research to Obtain MarketAccess, Favorable Pricing and Support Core Brand Messages