This document summarizes several studies that validate the relationship between heart rate and mortality risk found in previous research. It analyzes data from the Copenhagen City Heart Study, General Practice Research Network study, and Coronary Artery Surgery Study to estimate mortality risk based on heart rate, finding results consistent with prior studies. Plugging heart rate data from 16 clinical trials into risk equations from these 3 studies produces odds ratios similar to those originally reported. This demonstrates the relationship between heart rate and mortality is reproducible across multiple studies and populations.

1. Burden of Proof
Proof of Principle
Quantification, Replication and Validation…
Standards of Evidence in Outcomes Research
W. Robert Simons

2. 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. 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

4. 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

5. 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

6. 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

7. 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 PATIENTS
NON-RA
PATIENTS
RA PATIENTS
YEAR 2004 (p = 0.0021) YEAR 2005 (p = 0.0004) YEAR 2006 (p = 0.0006)
MEAN STD
STD
ERROR
MEAN STD
STD
ERROR
MEAN STD
STD
ERROR
MEAN STD
STD
ERROR
MEAN STD
STD
ERROR
MEAN 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%

8. Heart Rate and
All-cause Mortality

9. 9
Heart Rate: Background
Biology
 Semi-logarithmic relationship between heart
rate and life expectancy among mammals
 Man is the exception
*Source: Levine (1997)
Heart Rate vs. Life Expectancy

10. 10
Background
Epidemiology
 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. 11
Cucharet
(multination
al)
GPRN
(Australia
) 300 GPs
(2% sample)
CCHS
(Denmark)
CASS
(Canad
a)
Singh
(multination
al)
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
Reproduc
es Cucharet
Strongest
Results
consistent with
Cucharet
A Comparison of the Literature
Background

12. 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. 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. 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. 15
Meta-Analysis of Cucherat’s Study
Groups by HR
Reduction
Levels
Study 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. 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

17. 17
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. 18
Results of GEE Analysis for All-Cause Mortality and Heart Rate
Results
Systolic 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. 19
Precision and Comparability of Coefficient Estimates
Regression
Coefficients
(GEE/Meta regression)
Weibull
Survival Analyses
Cucherat
0.0249
(P=0.008) longitudinal HR
GPRN
0.0268
(P=0.0006) longitudinal HR
CASS
-0.00694
(P<0.001) baseline HR
CCHS
0.0159
(P<0.001) longitudinal HR
-0.00683
(P<0.001) baseline HR
Results

20. 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. 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. 22
Accidental?
…..Dumb Luck?

23. 23
Validated Diabetic-Risk Equations
Replication 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. 24
Comparative Odd-Ratio Plot for Adverse Events Associated with Opioid Use in
Post- Surgical Patients
HCUP (2005) and Premier (2005)
H
P H
P H
P
H
P
H
P
H
P
H
P
H
P
H
P
H P
H
P
H
P
0
5
10
15
20
25
30
Dehydration
Dehydration
GastricPain
FecalImpaction
Post-OperativeIleus
Post-OperativeIleus
OtherBowlObstruction
Constipation
Constipation
VomitPost-GISurgery
NauseawithVomiting
NauseawithVomiting
NauseaOnly
VomitingOnly
VomitingOnly
AbdominalPain
Poisoning-Opiates
Poisoning-Opiates
Pruritus
Nauseaand/orVomiting
Nauseaand/orVomiting
Pain Management in Post Surgical
Patients

25. 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. 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. 27
Replication of quantification
Validation
Reconciliation
……Standard of Evidence

28. 28
MET THE BURDEN
PROVED THE PRINCIPLE

29. New Longitudinal
Outcomes Research
Analytical Technique

30. 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

31. Results: Changes in Systolic and Diastolic
Blood Pressure and Goal Attainment
31
Systolic Blood Pressure Diastolic Blood Pressure Goal Attainment
Parameter Estimate
95% Confidence
Limits
Estimate
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

32. Results: Special Patient Populations
3
2
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)

33. Global Health Economics
& Outcomes Research
Raising the Bar in Outcomes Research to Obtain Market
Access, Favorable Pricing and Support Core Brand Messages