Evidence Report/Technology Assessment

Number 81

Diagnosis and Treatment of Coronary Heart Disease in 

Women: Systematic Reviews of Evidence on Selected 

Topics

Prepared for: 

Agency for Healthcare Research and Quality

U.S. Department of Health and Human Services

www.ahrq.gov

Contract No. 290-97-0013

Prepared by:

University of California, San Francisco-Stanford University Evidence-based Practice Center, 

Stanford, CA

Principal Investigator

Deborah Grady, MD, MPH

EPC Coordinator

Kathryn McDonald, MM

EPC Staff

Kara Bischoff

Aurelie Cabou

Christopher Gehrman

Kate Hoerster

Lily Chaput, MD, MPH

Margaret Kristof, MS, RN

Kathryn Melsop, MS

Dan H. Moore, PhD

AHRQ Publication No. 03-E037

May 2003

Topic Team Staff

Noninvasive Diagnostic Tests

Mary Beattie, MD

Louise Metz, MD

Kirsten Fleishmann, MD

Rita Redberg, MD 

Lipid Lowering Treatment

Judith Walsh, MD, MPH

Michael Pignone, MD, MPH

Paul Varosy, MD

Diabetes as Risk Factor

Alka Kanaya, MD

Lily Chaput, MD, MPH

Troponins

Paul Heindenreich, MD

Kathy McDonald, MM

UCSF/Mt. Zion Fishbon 

Library Staff

Gail Sorrough, MLIS

Gloria Won, MLIS
ii

This document is in the public domain and may be used and reprinted without permission except 

those copyrighted materials noted for which further reproduction is prohibited without the 

specific permission of copyright holders.

Suggested Citation:

Grady D, Chaput L, Kristof M. Diagnosis and Treatment of Coronary Heart Disease in Women: 

Systematic Reviews of Evidence on Selected Topics. Evidence Report/Technology Assessment 

No. 81. (Prepared by the University of California, San Francisco-Stanford Evidence-based 

Practice Center under Contract No 290-97-0013.) AHRQ Publication No. 03-E037. Rockville, 

MD: Agency for Healthcare Research and Quality. May 2003.

This report may be used, in whole or in part, as the basis for development of clinical practice 

guidelines and other quality enhancement tools, or a basis for reimbursement and coverage 

policies. AHRQ or U.S. Department of Health and Human Services endorsement of such 

derivative products may not be stated or implied.

AHRQ is the lead Federal agency charged with supporting research designed to improve the 

quality of health care, reduce its cost, address patient safety and medical errors, and broaden access 

to essential services. AHRQ sponsors and conducts research that provides evidence-based 

information on health care outcomes; quality; and cost, use, and access. The information helps 

health care decisionmakers—patients and clinicians, health system leaders, and policymakers—

make more informed decisions and improve the quality of health care services.
iii

Preface

The Agency for Healthcare Research and Quality (AHRQ), through its Evidence-Based 

Practice Centers (EPCs), sponsors the development of evidence reports and technology 

assessments to assist public- and private-sector organizations in their efforts to improve the 

quality of health care in the United States. The reports and assessments provide organizations 

with comprehensive, science-based information on common, costly medical conditions and new 

health care technologies. The EPCs systematically review the relevant scientific literature on 

topics assigned to them by AHRQ and conduct additional analyses when appropriate prior to 

developing their reports and assessments.

To bring the broadest range of experts into the development of evidence reports and health 

technology assessments, AHRQ encourages the EPCs to form partnerships and enter into 

collaborations with other medical and research organizations. The EPCs work with these partner 

organizations to ensure that the evidence reports and technology assessments they produce will 

become building blocks for health care quality improvement projects throughout the Nation. The 

reports undergo peer review prior to their release. 

AHRQ expects that the EPC evidence reports and technology assessments will inform 

individual health plans, providers, and purchasers as well as the health care system as a whole by 

providing important information to help improve health care quality.

We welcome written comments on this evidence report. They may be sent to: Director, 

Center for Practice and Technology Assessment, Agency for Healthcare Research and Quality, 

6010 Executive Blvd., Suite 300, Rockville, MD 20852.

Carolyn M. Clancy, M.D.

Director

Agency for Healthcare Research and Quality

The authors of this report are responsible for its content. Statements in the report 

should not be construed as endorsement by the Agency for Healthcare Research and 

Quality or the U.S. Department of Health and Human Services of a particular drug, 

device, test, treatment, or other clinical service.

Jean Slutsky, P.A., M.S.P.H.

Acting Director, Center for Practice and 

Technology Assessment

Agency for Healthcare Research and Quality

v

Structured Abstract 

Objectives. The Agency for Healthcare Research and Quality (AHRQ) and the National 

Institutes of Health Office of Research on Women's Health funded the University of California, 

San Francisco-Stanford Evidence-based Practice Center to perform systematic reviews and metaanalyses on four key topics related to coronary heart disease (CHD) in women: (1) accuracy of 

exercise myocardial perfusion imaging and echocardiography for diagnosis of CHD in women, 

(2) lipid lowering treatment to reduce risk of CHD in women, (3) diabetes as a risk factor for 

CHD in women, and (4) troponin as a prognostic factor for CHD in women. For each question, 

we also attempted to provide evidence stratified by race or ethnicity. We used standard methods 

to systematically review the medical literature to address each topic. The evidence identified was 

reviewed and graded, data were abstracted and the findings summarized for each topic. 

Search Strategy. We developed specific search terms for each of the four key topics and 

performed standardized searches of electronic databases. We also reviewed bibliographies and 

sought suggestions from our peer reviewers. Authors of studies that met selection criteria but did 

not report findings by gender were contacted and asked to provide gender-specific outcomes.

Selection Criteria. Inclusion and exclusion criteria were defined for each of the four systematic 

reviews. Titles and abstracts were reviewed by investigators who coded each for eligibility. The 

full text of eligible articles was reviewed independently by two physician investigators using 

standardized forms to classify eligibility, rate quality and abstract data. The findings of all 

eligible studies rated good or fair quality were included in the summary estimates.

Data Collection and Analysis. Titles and abstracts were entered and coded using EndNote®

(Niles Software, Inc ). Data from the standardized review forms were entered in an Access 

(Microsoft ® Corporation) database to allow tracking of eligibility, quality and study design. 

Abstracted data were also stored electronically in a database (EXCEL, Microsoft® Corporation). 

Main Results

Overall

• Findings from 82 otherwise eligible studies could not be included in the systematic reviews 

because data were not stratified by gender. We contacted the author of these studies twice 

requesting data for women and received data from 19 studies (23 percent).

• Little evidence was available regarding the key questions as they pertain to women of 

different races/ethnicities. For this reason, only the review of diabetes as a risk factor for 

CHD provides summary findings by ethnicity.
vi

Accuracy of exercise myocardial perfusion imaging and echocardiography for diagnosis of 

CHD in women

• We found 14 eligible studies that provided data on the accuracy of noninvasive tests in 893 

women. Ten studies examined the accuracy of myocardial perfusion imaging and four 

examined the accuracy of exercise echocardiography.

• In women, the overall accuracy of both exercise myocardial perfusion imaging and exercise 

echocardiography for diagnosis of CHD is low with positive likelihood ratios of 2.5 to 3 and 

negative likelihood ratios of about 0.3.

• The accuracy of exercise myocardial perfusion imaging for diagnosis of CHD is not 

clinically different in women compared to men.

• There is little difference in the accuracy of exercise myocardial perfusion imaging and 

exercise echocardiography for diagnosis of CHD in women.

• The accuracy of exercise myocardial perfusion imaging for diagnosis of CHD is similar 

whether thallium or sestamibi is used as the imaging agent.

Efficacy of lipid lowering to reduce risk of CHD in women

• Although 20 clinical trials of the effects of lipid lowering therapy included women, only nine 

published results by gender. By contacting study investigators, we were successful in 

obtaining data on women from two additional trials. Thus, we were able to analyze results 

from 11 trials that included 15,917 women. 

• In women with known CHD, treatment with lipid lowering therapy reduces risk of CHD 

mortality 26 percent, nonfatal myocardial infarction (MI) 36 percent and major CHD events 

21 percent. There was insufficient evidence to show that lipid lowering reduces rates of 

revascularization procedures and no evidence of a reduction of risk in total mortality.

• For women without CHD, there is insufficient evidence to determine whether lipid lowering 

reduces risk for any clinical outcome. 

Diabetes as a risk factor for CHD in women

• We found 17 eligible studies that included 43,944 women (4,522 with diabetes and 39,422 

without diabetes).

• Adjusted summary odds ratios (ORs) for CHD mortality and nonfatal MI due to diabetes are 

higher among women than men, but summary ORs for all-cause mortality are slightly higher 

in men than women. All of the differences between men and women are modest and not 

statistically significant.

• The summary odds ratio for CHD mortality due to diabetes is 2.9 (95% confidence interval 

[CI], 2.2-3.8) for women and 2.3 (95% CI, 1.9-2.8) for men. The summary OR for nonfatal 

MI due to diabetes is 1.7 (95% CI, 1.3-2.3) for women and 1.6 (95% CI, 1.1-2.2) for men. 

The summary OR for all-cause mortality due to diabetes is 1.9 (95% CI, 1.7-2.3) for women 

and 2.1 (95% CI, 1.7-2.7) for men.
vii

• Summary estimates for risk of CHD mortality due to diabetes for nonwhite men and women 

are similar to those for whites.

• The difference in relative risk for CHD outcomes between men and women is progressively 

attenuated with adjustment for major cardiovascular risk factors. This finding may be due to 

the fact that women with diabetes have more risk factors or more severe risk factor 

abnormalities in comparison to women without diabetes than is the case for men with and 

without diabetes.

Prognostic value of troponin for CHD in women

• We identified eight eligible cohort studies that provided data on 3,169 women and 4,070 

men. 

• Elevated troponin was observed in 35 percent of women and 39 percent of men with non-ST 

elevation acute coronary syndromes.

• Women with acute coronary syndromes were older and more likely to have diabetes and 

hypertension than men.

• An elevated troponin indicates a similar increase in risk of death for both women (summary 

OR 2.63; 95% CI 1.75-3.95) and men (OR 2.83; 95% CI 1.92-4.17).

• An elevated troponin indicates a greater increase in risk of nonfatal MI for women (summary 

OR 1.80; 95% CI 1.28-2.54) than men (OR 1.06; 95% CI 0.8-1.41).

Conclusions. The major problem in performing these systematic reviews was that data stratified 

by sex and race/ethnicity from completed studies are often not available. We recommend that, in 

addition to requiring participation of women and minorities in research, the National Institutes of 

Health, U.S. Food and Drug Administration, and other funding and regulatory agencies insist 

that outcome data by subgroup be published or archived and made easily available to metaanalysts.
ix

Contents

Summary .........................................................................................................................1

Evidence Report..........................................................................................................9

Chapter 1. Introduction................................................................................................. 11

 Organization ............................................................................................................ 11

Key Questions.......................................................................................................... 12 

References for Introduction..................................................................................... 15

Chapter 2. Systematic Review of the Accuracy of Exercise Myocardial 

Perfusion Imaging and Echocardiography for Diagnosis of Coronary Heart 

Disease in Women......................................................................................................... 17

Introduction.............................................................................................................. 17

Methodology............................................................................................................ 18

Data Sources...................................................................................................... 18

Search Terms ..................................................................................................... 18

Inclusion Criteria ............................................................................................... 19

Article Identification.......................................................................................... 19

Obtaining Unpublished Results......................................................................... 20

Quality Assessment ........................................................................................... 20

Data Abstraction................................................................................................ 21

Data Management and Archive ......................................................................... 21

Data Analysis..................................................................................................... 22

Results...................................................................................................................... 22

Study Identification ........................................................................................... 22

Description of Eligible Studies.......................................................................... 22

Findings ............................................................................................................. 23

Conclusions.............................................................................................................. 26

Future Research ....................................................................................................... 28

References................................................................................................................ 29

Chapter 3. Systematic Review of Lipid Lowering Treatment to Reduce 

Risk of Coronary Heart Disease in Women .................................................................. 35

Introduction.............................................................................................................. 35

Methodology............................................................................................................ 36

Data Sources...................................................................................................... 36

Search Terms ..................................................................................................... 36

Inclusion Criteria ............................................................................................... 36

Article Identification.......................................................................................... 37

Obtaining Unpublished Results......................................................................... 37

Quality Assessment ........................................................................................... 37

Data Abstraction................................................................................................ 38

Data Management and Archive ......................................................................... 38

Data Analysis..................................................................................................... 38

Results...................................................................................................................... 39

Results of Study Identification .......................................................................... 39
x

Description of Eligible Studies.......................................................................... 39

Findings ............................................................................................................. 40

Conclusions.............................................................................................................. 43

Future Research ....................................................................................................... 45

References................................................................................................................ 47

Chapter 4. Systematic Review of Diabetes as a Risk Factor for Coronary Heart

Disease in Women......................................................................................................... 51

Introduction.............................................................................................................. 51 

Methodology............................................................................................................ 51

Data Sources...................................................................................................... 51

Search Terms ..................................................................................................... 52

Inclusion Criteria ............................................................................................... 52

Definition of Outcomes ..................................................................................... 52

Article Identification.......................................................................................... 52

Obtaining Unpublished Results in Women....................................................... 53

Quality Assessment ........................................................................................... 53

Data Abstraction................................................................................................ 54

Data Management and Archive ......................................................................... 54

Data Analysis..................................................................................................... 54

Results...................................................................................................................... 55

Results of Study Identification .......................................................................... 55

Description of Eligible Studies.......................................................................... 56

Summary of Results........................................................................................... 56

Conclusions.............................................................................................................. 57

Future Research ....................................................................................................... 59

References................................................................................................................ 61

Chapter 5. Systematic Review of Troponin as a Prognostic Factor for CHD 

in Women....................................................................................................................... 67

Introduction.............................................................................................................. 67

Methodology............................................................................................................ 68

Data Sources...................................................................................................... 68

Search Terms ..................................................................................................... 68

Inclusion and Exclusion Criteria ....................................................................... 69

Article Identification.......................................................................................... 69

Data Abstraction................................................................................................ 69

Obtaining Unpublished Results......................................................................... 69

Quality Assessment ........................................................................................... 69

Data Management and Archive ......................................................................... 69

Data Analysis..................................................................................................... 70

Results...................................................................................................................... 70

Results of Study Identification .......................................................................... 70

Patient Characteristics....................................................................................... 71

Study Report Characteristics ............................................................................. 71

Quality of Study Reports................................................................................... 71

Findings ............................................................................................................. 71

Conclusions.............................................................................................................. 73
xi

Future Research ....................................................................................................... 74

References................................................................................................................ 75

Evidence Tables............................................................................................................. 89

Evidence Table 1. Diagnostic Testing: Characteristics of

 studies of exercise myocardial perfusion imaging............................................ 91

Evidence Table 2. Diagnostic Testing: Characteristics of studies of exercise 

echocardiography............................................................................................... 92

Evidence Table 3. Diagnostic Testing: Findings of exercise 

myocardial perfusion imaging and summary estimates of accuracy................. 93

Evidence Table 4. Diagnostic Testing: Summary estimates of 

accuracy of myocardial perfusion imaging from studies using 

sestamibi compared to studies using thallium................................................... 95

Evidence Table 5. Diagnostic Testing: Findings of studies of 

exercise echocardiography and summary estimates of accuracy ...................... 96

Evidence Table 6. Lipids: Characteristics of included trials............................ 97

Evidence Table 7. Lipids: Outcomes of eligible studies .................................. 99

Evidence Table 8. Lipids: Summary results.................................................... 100

Evidence Table 9. Diabetes: Characteristics of studies of coronary 

heart disease risk in diabetics vs. nondiabetics.................................................. 101

Evidence Table 10. Diabetes: Adjusted odds ratios for CHD 

mortality, nonfatal MI, and all-cause mortality by sex...................................... 103

Evidence Table 11. Diabetes: Summary odds ratios for CHD 

mortality, nonfatal myocardial infarction, and all-cause mortality 

by sex................................................................................................................. 104

Evidence Table 12. Diabetes: Summary odds ratios for CHD mortality by sex, 

quality of studies and sensitivity analysis.......................................................... 105

Evidence Table 13. Troponin: Characteristics of the study

population by gender ...................................................................................... 106

Evidence Table 14. Troponin: Characteristics of the study reports.................. 107

Evidence Table 15. Troponin: Outcomes for women....................................... 108

Evidence Table 16. Troponin: Outcomes for men............................................ 109

Bibliography .................................................................................................................. 111

Appendixes .................................................................................................................... 125

Appendix A. Peer Reviewers.................................................................................. 127

Appendix B. Quality Evaluation Forms ................................................................. 131

Appendix C. Data Abstraction Forms .................................................................... 137

Appendix D. Abbreviations and Acronyms............................................................ 157

Figures

Figure 1. Troponin: Death for women with and without an elevated troponin...... 79

Figure 2. Troponin: Death for men with and without an elevated troponin............ 80

Figure 3. Troponin: Death or myocardial infarction for women with and 

without an elevated troponin .......................................................................... 81

Figure 4. Troponin: Death or myocardial infarction for men with and 

without an elevated troponin .......................................................................... 82
xii

Figure 5. Troponin: Nonfatal infarction for women with and without an 

elevated troponin ............................................................................................ 83

Figure 6. Troponin: Nonfatal infarction for men with and without an elevated 

troponin........................................................................................................... 84

Figure 7. Troponin: Odds ratios and their summary for death for both men and 

women............................................................................................................. 85

Figure 8. Troponin: Odds ratios and their summary for death or myocardial 

infarction for both men and women................................................................ 86

Figure 9. Troponin: Odds ratios and their summary for nonfatal myocardial

infarction for both men and women................................................................ 87
Overview 

Coronary heart disease (CHD) is a common

disease and cause of death in women,

accounting for over 250,000 deaths in women

per year. Over the last two decades, multiple

important studies have helped define accurate

clinical tests, risk factors, preventive

interventions, and effective therapies for CHD.

Unfortunately, many of these studies have either

excluded women entirely or included only

limited numbers of women and minorities.

Thus, much of the evidence supporting

contemporary recommendations for testing,

prevention, and treatment of coronary disease in

women is extrapolated from studies conducted

predominantly in middle-aged men. The two

best approaches to obtain additional evidence on

diagnosis and treatment of CHD in women are

to conduct large studies that include adequate

numbers of women and minorities to answer the

research question or to perform systematic

reviews and meta-analyses summarizing effect

estimates by subgroup.

The Agency for Healthcare Research and

Quality (AHRQ) and the National Institutes of

Health Office of Research on Women's Health

funded the University of California, San

Francisco (UCSF)-Stanford Evidence-based

Practice Center (EPC) to review the evidence

regarding prevention, diagnosis, and

management of coronary heart disease in

women and minorities. In an initial phase of

this work, the UCSF-Stanford EPC conducted a

preliminary review of evidence on 42 topics

related to CHD in women, titled Results of

Systematic Review of Research on Diagnosis and

Treatment of Coronary Heart Disease in Women.1

Based on these reviews, we identified four key

questions for systematic review and metaanalysis. The results of these four reviews are

presented in this report.

Key Questions

1. What is the accuracy of noninvasive tests

for diagnosis of CHD in women: exercise

myocardial perfusion imaging (MPI) and

exercise echocardiography?

a. What are the summary estimates of

sensitivity, specificity and likelihood

ratios for exercise MPI and exercise

echocardiography in women?

b. What is the accuracy of exercise MPI

and exercise echocardiography in

women compared to men?

2. What is the effectiveness of treatment with

lipid lowering drugs for reducing CHD risk

in women with and without CHD?

a. What is the effectiveness of drug

treatment in reducing total mortality,

CHD mortality, CHD events or CHD

procedures in women with known

CHD and those without known CHD?

3. What is the relative risk for CHD in

women with type 2 diabetes?

a. What is the relative risk for CHD in

women with type 2 diabetes compared

to women without diabetes?

Evidence Report/Technology Assessment

Number 81

Diagnosis and Treatment of Coronary Heart

Disease in Women: Systematic Reviews of

Evidence on Selected Topics

Summary

Agency for Healthcare Research and Quality

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES • Public Health Service

1 Grady D, Chaput L, Kristof M. Results of Systematic Review of Research on Diagnosis and Treatment of Coronary Heart

Disease in Women. Evidence Report/Technology Assessment No. 80. (Prepared by the University of California, San

Francisco-Stanford Evidence-based Practice Center under Contract No 290-97-0013.) AHRQ Publication No. 03-0035.

Rockville, MD: Agency for Healthcare Research and Quality. May 2003.
b. Does the relative risk for CHD differ between women

and men with type 2 diabetes?

4. What is the prognostic value of troponin for CHD in

women?

a. What is the impact of troponin on risk for death

among women with non-ST elevation acute coronary

syndromes?

b. Does the prognostic value of troponin for mortality

differ between men and women?

c. What is the impact of troponin on risk for death or

myocardial infarction for women with non-ST

elevation acute coronary syndromes?

d. Does the prognostic value of troponin for mortality

or myocardial infarction differ between men and

women?

For each of the four questions, we also attempted to

identify and summarize evidence stratified by race or ethnicity. 

Methodology

We performed standardized searches of electronic databases

of publications relevant to the topic areas. We developed

specific search terms for each of the four key topics and

conducted a separate search for evidence regarding each. We

also reviewed the bibliographies of retrieved articles and

sought suggestions for additional articles from our expert peer

reviewers. For each topic area, we established clear inclusion

criteria that required that studies provide data regarding the

research question specific to women. 

For three of the key questions (noninvasive diagnostic tests,

lipid lowering and diabetes), two UCSF-Stanford EPC

investigators reviewed all identified titles and excluded those

that did not meet inclusion criteria. The abstracts of remaining

articles were reviewed by two UCSF-Stanford EPC physician

investigators, who independently classified eligibility. The full

text of the remaining eligible articles was reviewed

independently by two UCSF-Stanford EPC physician

investigators using standardized abstraction forms to classify

eligibility, rate quality as fair or good based on predefined

criteria, and abstract data for eligible studies. For the key

question regarding troponin, titles and abstracts were reviewed

by one UCSF-Stanford EPC investigator. Data were

abstracted from each eligible article by two independent

reviewers and entered on standardized electronic data forms. 

Accuracy of exercise myocardial perfusion

imaging and echocardiography for diagnosis

of CHD in women

We searched PubMed®, the Cochrane Database, and

DARE for articles in English and other languages published

from 1990 through January 2002. We used the following

search terms to identify cross-sectional studies in which the

accuracy of the exercise MPI or exercise echocardiography was

compared to angiographic findings:

(Note: An asterisk indicates truncation of the search term.)

• Exercise MPI: thallium radioisotopes,

radiopharmaceuticals, tomography emission-computed

single-photon, technetium TC 99M sestamibi,

organotechnetium compounds, Spect, Cardiolite, Mibi

AND exercise, exercise test, exercise tolerance, exercise*,

exercising, "stress test" AND diagnosis, diagnoses,

diagnostic, diagnosing, predictive values of test

• Exercise echocardiography: echocardio*, ultrasound,

ultrasonography

AND exercise, exercise test, exercise tolerance, exercise*,

exercising, "stress test"

AND diagnosis, diagnoses, diagnostic, diagnosing,

predictive values of test

• Outcomes: cardiovascular diseases, heart diseases,

myocardial ischemia, coronary disease

Searches for noninvasive diagnostic tests identified 3,136

titles. After eliminating ineligible studies by review of titles

and abstracts, we reviewed the full text of 326 articles and

found 14 eligible cross-sectional studies with data on women

that were included in the systematic review. Ten studies

examined the accuracy of MPI and four examined the

accuracy of exercise echocardiography. 

Efficacy of lipid lowering to reduce risk of

CHD in women

We searched PubMed®, the Cochrane Database, and

DARE for articles in English and other languages published

from 1966 through January 2002. We used the following

search terms to identify clinical trials: 

• Lipid lowering: hyperlipidemia and anticholesteremic

agents, antilipemic agents, simvastatin, lovastatin,

pravastatin, atorvastatin, fluvastatin, gemfibrozil,

cholestyramine, cholestpol, niacin

• Outcomes: cardiovascular diseases, heart diseases,

myocardial ischemia, coronary disease

Searches for clinical trials of lipid lowering treatment

identified 1,335 titles. After eliminating ineligible studies by

review of titles and abstracts, we reviewed the full text of 120

articles and found 11 eligible randomized trials that provided

data on women and were included in the systematic review.

Diabetes as a risk factor for CHD in women

We searched PubMed®, the Cochrane Database, and

DARE for articles in English and other languages published

from 1966 through January 2002. We used the following

search terms to identify cohort and cross-sectional studies:

2
• Diabetes: diabetes

• Outcomes: cardiovascular disease, myocardial infarction,

ischemic heart disease

Searches for diabetes as a risk factor for CHD in women

identified 4,578 titles. After eliminating ineligible studies by

review of titles and abstracts, we reviewed the full text of 233

articles. We found 17 studies that fulfilled all inclusion

criteria; 12 were prospective cohort studies and five were crosssectional analyses.

Prognostic value of troponin for CHD in

women

We searched MEDLINE® for articles in English and other

languages published from 1966 through January 2002. We

used the following search terms to identify clinical trials or

cohort studies:

• The text word troponin, and

• The text words angina or unstable or myocardial infarction

or ischemia. 

We also performed a search of EMBASE from 1990-1998,

but did not find any additional articles fulfilling the study

criteria. 

Searches identified 1,049 articles. We excluded 878 articles

based on title or abstracts and reviewed the full text of 171

articles. Of these, eight eligible studies provided data on

women and were included in the systematic review; six were

clinical trials and two were cohort studies. 

Findings 

Overall

• Data from many otherwise eligible studies could not be

included in the systematic reviews because the findings

were not stratified by sex. We identified 82 studies that

included women, but did not stratify the data by sex. We

contacted authors of these studies twice requesting data on

women but received data from only 19 studies (23

percent). 

• Little evidence was available regarding the key questions as

they pertain to women of different races/ethnicities. For

this reason, only the review of diabetes as a risk factor for

CHD provides summary findings by ethnicity. 

Accuracy of exercise myocardial perfusion

imaging and echocardiography for diagnosis

of CHD in women

• Although 34 eligible studies of the accuracy of exercise

myocardial perfusion imaging or exercise echocardiography

included women, only nine published results by sex. By

contacting study investigators, we were successful in

obtaining data on women from five additional studies.

Thus, we were able to analyze results from 14 studies that

included 893 women. Ten studies examined the accuracy

of myocardial perfusion imaging and four examined the

accuracy of exercise echocardiography.

• In women, the overall accuracy of both exercise myocardial

perfusion imaging and exercise echocardiography for

diagnosis of CHD is low with positive likelihood ratios of

2.5 to 3 and negative likelihood ratios of about 0.3.

• The accuracy of exercise myocardial perfusion imaging for

diagnosis of CHD is not clinically different in women

compared to men.

• There is little difference in the accuracy of exercise

myocardial perfusion imaging and exercise

echocardiography for diagnosis of CHD in women.

• The accuracy of exercise myocardial perfusion imaging for

diagnosis of CHD is similar whether thallium or sestamibi

is used as the imaging agent. 

Efficacy of lipid lowering to reduce risk of

CHD in women 

• Although 20 clinical trials of the effects of lipid lowering

therapy included women, only nine published results by

sex. By contacting study investigators, we were successful in

obtaining data on women from two additional trials. Thus,

we were able to analyze results from 11 trials that included

15,917 women. 

• In women with known CHD, treatment with lipid

lowering therapy reduces risk of CHD mortality 26

percent, nonfatal myocardial infarction (MI) 36 percent

and major CHD events 21 percent. There was insufficient

evidence to show that lipid lowering reduces rates of

revascularization procedures and no evidence of a

reduction of risk in total mortality.

• For women without CHD, there is insufficient evidence to

determine whether lipid lowering reduces risk for any

clinical outcome. 

Diabetes as a risk factor for CHD in women

• Although 36 eligible studies included women, only 10

published results by sex. By contacting study investigators,

we were successful in obtaining data on women from seven

additional studies. Thus, we were able to analyze results

from 17 studies that included 43,944 women (4,522 with

diabetes and 39,422 without diabetes). 

• Adjusted summary odds ratios (ORs) for CHD mortality

and nonfatal MI due to diabetes are higher among women

than men, but summary ORs for all-cause mortality are

slightly higher in men than women. All of the differences

are modest and not statistically significant. 

• The summary OR for CHD mortality due to diabetes is

2.9 (95% confidence interval [CI], 2.2-3.8) for women

and 2.3 (95% CI, 1.9-2.8) for men. The summary OR for

nonfatal MI due to diabetes is 1.7 (95% CI, 1.3-2.3) for

women and 1.6 (95% CI, 1.1-2.2) for men. The summary

3
OR for all-cause mortality due to diabetes is 1.9 (95% CI,

1.7-2.3) for women and 2.1 (95% CI, 1.7-2.7) for men.

• Summary estimates for risk of CHD mortality due to

diabetes for white men and women are similar to those for

all ethnicities combined.

• The difference in relative risk for CHD outcomes between

men and women is progressively attenuated with

adjustment for major cardiovascular risk factors. This

finding may be due to the fact that women with diabetes

have more risk factors or more severe risk factor

abnormalities in comparison to women without diabetes

than is the case for men with and without diabetes.

Prognostic value of troponin for CHD in

women

• We reviewed the full text of 171 articles and found three

eligible studies with data on women. Nine additional large

studies of the prognostic value of troponin included

women, but did not provide data stratified by sex. After

contacting authors, we obtained data for women from five

of these studies. Thus, we identified eight eligible studies

that provided data on 3,169 women and 4,070 men. 

• Elevated troponin was observed in 35 percent of women

and 39 percent of men with non-ST elevation acute

coronary syndromes.

• Women with acute coronary syndromes were older and

more likely to have diabetes and hypertension than men

with acute coronary syndromes.

• Elevated troponin indicates a similar increase in risk of

death for both women (summary OR 2.63; 95% CI, 1.75-

3.95) and men (summary OR 2.83; 95% CI, 1.92-4.17).

• Elevated troponin indicates a greater increase in risk of

nonfatal MI for women (summary OR 1.80; 95% CI,

1.28-2.54) than men (summary OR 1.06; 95% CI, 0.8-

1.41).

Future Research 

The major problem in performing these systematic reviews

was lack of availability of data on women and minority

populations. Many studies that include women did not

provide estimates stratified by sex. Attempts to obtain

unpublished data from women were time-consuming and only

modestly successful.

Recommendations for future research follow.

Overall

• Future studies that include women should publish or make

available outcomes stratified by sex and ethnicity. 

Accuracy of exercise myocardial perfusion

imaging and echocardiography for diagnosis

of CHD in women

• The quality of future studies of the accuracy of noninvasive

tests for the diagnosis of CHD should be improved by

excluding persons with known CHD, performing both the

noninvasive test and angiography in all participants and

assuring that the outcome of the noninvasive test is assessed

by personnel blinded to the results of angiography.

• Future research should address ways to improve accuracy of

noninvasive tests for CHD in both men and women.

Efficacy of lipid lowering to reduce risk of

CHD in women

• Future clinical trials should include adequate numbers of

women to determine the effect of lipid lowering in women

at high risk but without known CHD.

Diabetes as a risk factor for CHD in women

• Future prospective studies should present sex- and

race/ethnicity-specific fatal and nonfatal coronary disease

endpoints before and after adjustment for established

CHD risk factors. 

• Future studies should attempt to clarify the effect of

established risk factors, which cluster in women with

diabetes, compared to the effect of diabetes itself in

increasing risk for CHD among women with diabetes.

Prognostic value of troponin for CHD in

women

• Future studies are needed to verify and explore why the

prognostic value of elevated troponin results for nonfatal

MI is different in women compared to men. 

Availability of the Full Report

The full evidence report from which this summary was

taken was prepared for the Agency for Healthcare Research

and Quality (AHRQ) by the University of California, San

Francisco-Stanford Evidence-based Practice Center, under

Contract No. 290-97-0013. It is expected to be available in

May 2003. At that time, printed copies may be obtained free

of charge from the AHRQ Publications Clearinghouse by

calling 800-358-9295. Requesters should ask for Evidence

Report/Technology Assessment No. 81, Diagnosis and

Treatment of Coronary Heart Disease in Women: Systematic

Reviews of Evidence on Selected Topics. In addition, Internet

users will be able to access the report and this summary online

through AHRQ’s Web site at www.ahrq.gov.

AHRQ Pub. No. 03-E036

May 2003

ISSN 1530-440X
Evidence Report
11

Chapter 1: Introduction 

Coronary heart disease (CHD) is the most common cause of death in women. 

Approximately 1 in 2 women develop CHD and 1 in 3 die from it,1 accounting for over 

250,000 deaths in women per year.2 Despite the high prevalence of CHD in women, it 

has traditionally been thought of as a disease of middle-aged men, perhaps because 

women tend to develop CHD about a decade later in life than men.3 During the last two 

decades, multiple important studies have helped define accurate clinical tests, important 

risk factors, preventive interventions and effective therapies for CHD. Unfortunately, the 

majority of these studies have either excluded women entirely or included only limited 

numbers of women.4 Thus, much of the evidence that supports contemporary 

recommendations for testing, prevention and treatment of coronary disease in women is 

extrapolated from studies conducted predominantly in middle-aged men. Applying the 

findings of studies in men to management of CHD in women may not be appropriate 

since the symptoms of CHD, natural history and response to therapy in women differ 

from that in men.5 Because large studies that include adequate numbers of women and 

minorities to answer the research question are generally not feasible, systematic reviews 

of the literature may be the best option for maximizing management of CHD in women.

The Agency for Healthcare Research and Quality (AHRQ) and the National Institutes of 

Health Office of Research on Women's Health funded the University of California, San 

Francisco (UCSF)-Stanford Evidence-based Practice Center (EPC) for the development 

of an initial review of evidence-based research on five key topics, including 42 subtopic 

areas related to the diagnosis and management of coronary heart disease in women and 

minority race/ethnic groups.6 Based on the results of the initial report, four key questions 

were identified for systematic review and meta-analysis: (1) the accuracy of exercise 

myocardial perfusion imaging and exercise echocardiography for diagnosis of CHD in 

women; (2) the efficacy of lipid lowering to reduce risk of CHD in women; (3) the 

strength of diabetes as a risk factor for CHD in women, and (4) the prognostic value of 

elevated troponin for CHD in women. This report presents the results of these four 

systematic reviews.

Organization

The methods of conducting these systematic reviews were similar. However, the 

appropriate study designs, inclusion criteria, clinical outcomes and statistical methods 

differed. In addition, the audience for each of these systematic reviews will likely differ. 

For these reasons, we present the four systematic reviews sequentially to allow each 

systematic review to stand alone.
12

Key Questions

Recognizing the importance of the issues raised above, multiple groups have requested 

evidence-based research pertinent to diagnosis and management of CHD in women and 

minority populations. The groups include an ad hoc women's health coalition (American 

Heart Association, American College of Cardiology, American College of Obstetricians 

and Gynecologists, American Society of Echocardiography, Association of Black 

Cardiologists, Jacobs Institute of Women's Health, Mayo Clinic Women's Heart Clinic, 

Society for Women's Health Research, and WomenHeart: National Coalition for Women 

with Heart Disease), the American Association for Clinical Chemistry and the National 

Institutes of Health Office of Research on Women's Health. The Centers for Medicare &

Medicaid Services and Harvard Pilgrim Health Services have also expressed interest. 

Concern about sex and gender-based differences in diagnosis and treatment of CHD was 

also noted in the U.S. Senate Appropriations Committee's report accompanying the FY 

2000 Departments of Labor, Health and Human Services, and Education and Related 

Agencies Appropriations bill. Specifically, these groups have requested evidence related 

to the following four key questions:

1. What is the accuracy of noninvasive tests for diagnosis of CHD in women:

exercise myocardial perfusion-imaging (MPI) and exercise 

echocardiography?

a. What are the summary estimates of sensitivity, specificity and likelihood ratios 

for exercise MPI and exercise echocardiography in women?

b. What is the accuracy of exercise MPI and exercise echocardiography in 

women compared to men?

2. What is the effectiveness of treatment with lipid lowering drugs for reducing 

CHD risk in women with and without CHD?

a. What is the effectiveness of drug treatment in reducing total mortality, CHD 

mortality, CHD events or CHD procedures in women with known CHD and 

those without known CHD?

3. What is the relative risk for CHD in women with type 2 diabetes?

a. What is the relative risk for CHD in women with type 2 diabetes compared to 

women without diabetes?

b. Does the relative risk for CHD differ between women and men with type 2 

diabetes?

4. What is the prognostic value of troponin for CHD in women?

a. What is the impact of troponin on risk for death among women with non-ST 

elevation acute coronary syndromes?

b. Does the prognostic value of troponin for mortality differ between men and 

women?

c. What is the impact of troponin on risk for death or myocardial infarction for 

women with non-ST elevation acute coronary syndromes?
13

d. Does the prognostic value of troponin for mortality or myocardial infarction 

differ between men and women?

For each of the four questions, we also attempted to identify and summarize evidence 

stratified by race or ethnicity. 
14
15

References for Introduction

1. Grady D, Rubin SM, Petitti DB, et al. Hormone therapy to prevent disease and 

prolong life in postmenopausal women. Ann Intern Med 1992;117(12):1016-37.

2. American Heart Association. Heart Disease and Stroke Statistics--2002 Update. 

Dallas, Tex.: American Heart Association; 2001.

3. Lerner DJ, Kannel WB. Patterns of coronary heart disease morbidity and 

mortality in the sexes: a 26-year follow-up of the Framingham population. Am 

Heart J 1986;111(2):383-90.

4. Healy B. The Yentl syndrome. N Engl J Med 1991;325(4):274-6.

5. Wenger NK, Speroff L, Packard B. Cardiovascular health and disease in women. 

N Engl J Med 1993;329(4):247-56.

6. Grady D, Chaput L, Kristof M. Results of Systematic Review of Research on the 

Diagnosis and Treatment of Coronary Heart Disease in Women. Evidence 

Report/Technology Assessment No. 80. (Prepared by the University of California, 

San Francisco-Stanford Evidence-based Practice Center under Contract No 290-

97-0013.) AHRQ Publication No. 03-0035. Rockville, MD: Agency for 

Healthcare Research and Quality. May 2003.
17

Chapter 2. Systematic Review of the Accuracy of 

Exercise Myocardial Perfusion Imaging and

Echocardiography for Diagnosis of Coronary 

Heart Disease in Women

Introduction 

Multiple studies suggest that the accuracy of diagnostic testing for coronary heart disease 

(CHD) may be different in women compared to men.1-6 Many factors may account for a 

differential accuracy, including differences in the pre-test probability of disease, chest 

wall anatomy, left ventricular chamber size, ability to exercise maximally, catecholamine 

response to exercise or hormone levels.

One systematic review of the studies of the diagnostic accuracy of exercise 

electrocardiogram (ECG), exercise thallium and exercise echocardiogram in women 

included literature published up to 1995. The review examined five myocardial perfusion 

imaging (MPI) studies that included 842 women and three echocardiography studies that 

included 296 women.7 MPI studies all used thallium as the radionuclide; two studies 

used planar imaging and three used single photon emission computed tomography 

(SPECT). Weighted mean sensitivity and specificity for exercise ECG in women were 61 

and 70 percent; for exercise MPI 78 and 64 percent; and for exercise echocardiography 

86 and 79 percent. The findings suggested that exercise stress testing without imaging has 

limited accuracy in women and that planar MPI is more specific than SPECT. Exercise 

echocardiography appeared to be the most accurate test, but data were available from 

only three studies. This systematic review is now outdated and provides little information 

on the accuracy of currently used MPI techniques that almost universally employ SPECT 

with technetium or technetium plus thallium imaging. 

Another systematic review examined the accuracy of exercise echocardiography and 

exercise SPECT imaging in men and women based on literature published up to 1997.8

Weighted mean sensitivity and specificity for exercise MPI were 87 and 64 percent and 

for exercise echocardiography 85 and 77 percent. The authors concluded that exercise 

echocardiography and exercise SPECT have similar sensitivities for the detection of 

coronary artery disease, but exercise echocardiography has slightly higher specificity. 

The total number of subjects in this study was 5,436; 70 percent were men and separate 

estimates for accuracy in women were not provided. 

The purpose of this systematic review is to evaluate the accuracy of exercise 

echocardiography and MPI in women, to determine if there are differences in accuracy of 

these tests in men and women, and to assess test characteristics of exercise MPI with 

thallium compared to technitium sestamibi imaging.
18

Methodology 

Data sources 

We searched PubMed®, the Cochrane Database, and DARE for articles in English and 

other languages published from 1990 through January 2002. We also reviewed 

bibliographies and asked peer reviewers (Appendix A) to identify additional articles. The 

date limits of the search were chosen because both exercise echocardiography and 

exercise MPI using SPECT with thallium and sestamibi were in widespread use during 

this period.

Search Terms

We used the following search terms to identify cross-sectional studies in which the 

accuracy of the diagnostic tests of interest were compared to angiographic findings:

Limits publication dates 1990 to January 2002, human

 Not: practice guideline, letter, editorial, review, meta-analysis 

 Infant newborn, infant, preschool child, child

Predictor 1: thallium radioisotopes, radiopharmaceuticals, tomography emissioncomputed single-photon, technetium TC 99M sestamibi, 

organotechnetium compounds, Spect, Cardiolite, Mibi

AND

exercise, exercise test, exercise tolerance, exercise*, exercising, "stress 

test"

AND

diagnosis, diagnoses, diagnostic, diagnosing, predictive values of test

Predictor 2: echocardio*, ultrasound, ultrasonography

AND

exercise, exercise test, exercise tolerance, exercise*, exercising, "stress 

test"

AND

diagnosis, diagnoses, diagnostic, diagnosing, predictive values of test

Note -- all of the commas represent "OR" statements.

Outcomes cardiovascular diseases, heart diseases, myocardial ischemia,

coronary disease
19

Inclusion Criteria 

To be included, articles were required to fit the following criteria: 

1) Contained primary data on at least 10 women who underwent exercise ECG with 

radionuclide injection and SPECT imaging or exercise echocardiography.

2) Estimated accuracy of noninvasive tests using angiographic evidence of CHD as the 

gold standard.

3) Provided data to calculate true positives (TP), true negatives (TN), false positives 

(FP) and false negatives (FN) for the noninvasive tests.

4) Clear definition of positive noninvasive test and positive angiogram provided. 

5) Published between 1990 and January 2002. Articles published outside this date range 

that were recommended by peer reviewers were included.

We excluded studies that met the following criteria:

1) Noninvasive tests performed exclusively in patients after myocardial infarction (MI), 

percutaneous angioplasty, coronary artery bypass surgery or hospitalization for an 

unstable coronary syndrome. In these patients, noninvasive tests are done for the 

purpose of risk assessment rather than diagnosis.

2) Tests in which pharmacologic agents rather than exercise were used as the stressor. 

Use of pharmacologic stressors may significantly affect the accuracy of noninvasive 

testing; many different agents are used and protocols for their use vary substantially.

Article Identification 

An initial search using the terms listed above identified articles that potentially provided 

evidence. Two University of California, San Francisco (UCSF)-Stanford Evidence-based 

Practice Center (EPC) investigators reviewed the titles and excluded those that clearly did 

not provide data on humans or clearly did not address the question.

The abstracts of the remaining articles were reviewed independently by two UCSFStanford EPC physician investigators and coded using the categories listed below. 

Disagreements were discussed and consensus codes were entered into a database (Access, 

Microsoft Corporation).

T Test – the study clearly does not include data on exercise ECG with imaging 

or exercise echocardiography.

A Angiogram - the study clearly does not compare the results of the 

noninvasive test with the results of angiography. 

ND Not diagnostic - The study assesses noninvasive tests performed exclusively 

in patients after myocardial infarction, percutaneous angioplasty, coronary 

artery bypass surgery or hospitalization for an unstable coronary syndrome.

R Review – the study is a review that does not contain primary data.
20

NH No humans - the study clearly does not include data on humans.

E1 Eligible – the study may contain primary evidence regarding the research 

questions in women and will be reviewed in full-text.

Articles coded E1 were retrieved and the full text was reviewed independently by two 

UCSF-Stanford EPC physician investigators. Names of authors and titles of journals were 

obscured before articles were reviewed. 

Obtaining Unpublished Results in Women 

Some eligible studies included women in the study population, but did not report findings 

separately by gender. In these instances we attempted to contact authors of these studies 

to obtain estimates in women. If we did not receive a response after the first contact, a 

second attempt was made. We contacted 34 authors2, 9-41 and received data from 

five.11, 15, 17, 18, 24 

Quality Assessment 

The full text of each eligible study was reviewed independently by two UCSF-Stanford 

EPC physician investigators who completed a quality evaluation form (Appendix B). The 

studies included in this systematic review are cross-sectional. The three major quality 

issues affecting these studies are verification bias, biased outcome measurement and 

spectrum effect. Verification bias occurs when the decision to proceed to the gold 

standard is in part dependent on the results of the noninvasive test. Since positive 

noninvasive test results are more likely to be followed by an invasive test, this tends to 

increase the chance of detecting a true positive (TP) relative to a false negative (FN) and 

tends to increase the chance of detecting a false positive (FP) relative to a true negative 

(TN). Therefore, sensitivity may appear to be higher and specificity lower in the verified 

sample. Biased outcome measurement occurs when personnel performing or reading the 

results of the noninvasive test already know the results of angiography. Spectrum effect 

refers to the variation in test performance depending on the severity of disease in the 

population studied. Sensitivity and specificity appear higher when the persons studied 

either have severe disease or are healthy. For instance, in participants with significant 

coronary disease and healthy volunteers, the spectrum of disease is clear-cut, and both 

sensitivity and specificity will be higher compared to a population with intermediate prior 

probability of coronary disease, such as those with angina. Our quality assessment 

addresses verification bias and biased outcome measurement, and we recorded spectrum 

of disease to allow subgroup analyses.
21

To be categorized as good quality, articles were required to meet the following 

parameters:

• All participants who had the noninvasive test also had angiography. 

• The diagnosis of coronary artery disease on angiography was made by investigators 

blinded to the results of the noninvasive test

Studies that did not meet these criteria were considered fair quality. 

Data Abstraction 

Two UCSF-Stanford EPC physician investigators independently reviewed the full text of 

each eligible study and completed a data abstraction form (Appendix C). Data abstracted 

included characteristics of the study (design, inclusion and exclusion criteria, noninvasive 

tests performed, and setting), participant characteristics (number of women and men, 

mean age of participants, number with prior MI, number with revascularization, cardiac 

risk factors in the population, and indications for cardiac testing), and test characteristics 

(type of exercise, average duration of exercise, percent with adequate exercise, 

radionuclide and imaging protocols used, criteria for positive noninvasive test, and 

criteria for positive coronary angiogram). For each eligible study, the numbers of true 

positive, true negative, false positive and false negative tests were recorded or calculated 

as necessary. We also abstracted accuracy measures for all subgroups evaluated. 

Disagreements between abstractors were discussed and decided by consensus. For studies 

with multiple publications, only data from the most comprehensive or recent publication 

were used.

Data Management and Archive 

We entered all identified titles and abstracts in an EndNote® file (Niles Software, Inc.) 

that includes searchable key words as codes for eligibility. Information on all articles that 

were reviewed in full text was transferred from EndNote® to a database (Access, 

Microsoft® Corporation) that allows us to categorize each article by reason for exclusion. 

Quality assessment data for each eligible study were also entered in the database, 

allowing us to categorize eligible articles by quality.

Abstracted data were entered into a database (EXCEL, Microsoft® Corporation) for 

preparation of evidence tables and calculation of summary estimates, confidence intervals 

and tests of heterogeneity. 

The full-text articles that were retrieved, and the abstraction forms for each article are 

filed in Dr. Grady's offices at the UCSF Mt. Zion Women's Health Clinical Research 

Center. 
22

Data Analyses 

The primary outcomes of each study were expressed as sensitivity, specificity, positive 

likelihood ratio and negative likelihood ratio comparing the results of the noninvasive test 

to angiographic findings. Summary results were calculated as the mean of the appropriate 

proportion (sensitivity, specificity, likelihood ratios) weighted by the sample size of each 

individual study. The significance level for all p-values for the weighted means was set at 

0.05. All findings were assessed for heterogeneity using Z-tests. The significance level 

for tests of heterogeneity was 0.10. To avoid calculation problems associated with zero 

cells, 0.5 was added to all cells to calculate variances and standard deviations.42 Results 

for women vs. men were compared using the Q* statistic, the point on the summary ROC 

curve where sensitivity equals specificity.43

Publication bias usually occurs if small studies with unremarkable findings (poor 

accuracy) are not published while small studies with markedly positive findings (high 

accuracy) are published. We calculated the correlation between individual study sample 

size and sensitivity using Kendall’s Tau to assess potential publication bias.

Results 

Study Identification 

Our searches identified 3,136 titles. After eliminating ineligible studies by review of titles 

and abstracts, we reviewed the full text of 326 articles and found 14 eligible for inclusion 

in the systematic review.2, 6, 17, 18, 23, 24, 41, 44-50 Of the 10 studies included that examined 

exercise MPI as the noninvasive test, five used thallium,17, 41, 44-46 four used 

sestamibi18, 23, 47, 48 and one used both6 as radionuclide agents. 

Nine MPI studies that provided accuracy estimates in women were excluded from the 

systematic review: four used pharmacologic agents in addition to exercise;51-54 four 

reported some measures of accuracy, but did not report adequate data to allow calculation 

of all required estimates,5, 55-57 and one did not provide definitions of a positive 

noninvasive test or positive coronary angiogram.58

Four eligible studies examined the accuracy of exercise echocardiography as the 

noninvasive test.2, 24, 49, 50 One study of exercise echocardiography that provided accuracy 

estimates for women was excluded because it was published outside our date range. 59

Description of Eligible Studies 

The characteristics of the 10 studies assessing the accuracy of MPI that were included in 

the systematic review are shown in Evidence Table 1. The number of participants in each 
23

study ranged from 41 to 371 and 14 to 100 percent were women. The total number of 

participants was 1,249, including 549 women and 700 men. Three of the studies included 

only women. One study included both men and women, but provided data that allowed 

calculation of accuracy estimates only in women.

48 The mean age of participants ranged 

from 51 to 62 years. Eight of the studies included participants with prior MI. All 10 

studies used SPECT imaging; five used thallium only, four sestamibi only and one used 

both radionuclides. The definition of an abnormal test was very similar in nine of the 

studies (fixed or reversible perfusion defects, perfusion defects at rest or after exercise or 

decreased uptake at rest or after exercise). One study defined a positive test as reversible 

uptake defects in more than one of 22 coronary segments. All but one of the 10 studies 

defined 50 percent stenosis of one or more major coronary artery at angiography as the 

gold standard for the presence of coronary artery disease. Eight studies used treadmill 

exercise and two used bicycle exercise. Six of the MPI studies were judged fair quality 

and four were judged good quality. 

The characteristics of the four studies assessing the accuracy of echocardiography that 

were included in the systematic review are shown in Evidence Table 2. The number of 

participants in each study ranged from 70 to 340 and 15 to 100 percent were women. The 

total number of participants was 689, including 344 women and 345 men. Two of the 

studies included both men and women and 2 included only women.2, 49 The mean age of 

participants ranged from 55 to 66 years. One of the studies included participants with 

prior MI. Two of the studies defined an abnormal test as new or worse regional wall 

motion abnormalities after exercise and two defined a positive as regional wall motion 

abnormalities at rest or after exercise. All studies defined 50 percent stenosis of at least 

one major coronary artery at angiography as the gold standard for the presence of 

coronary artery disease. Two of the echocardiography studies were judged fair quality 

and two were judged good quality. 

Findings 

Exercise Myocardial Perfusion Imaging

In women, sensitivity of exercise MPI using either thallium or sestamibi ranged from 

0.61 to 1.0 with a mean weighted sensitivity of 0.77 (95% CI 0.72-0.83) (Evidence Table 

3). Specificity of exercise MPI in women ranged from 0.40-1.0, with a mean weighted 

specificity of 0.69 (95% CI 0.62-0.75). The mean weighted positive likelihood ratio for 

exercise MPI in women was 2.46 (95% CI 2.00-3.04) and the mean weighted negative 

likelihood ratio was 0.33 (95% CI 0.26-0.41). 

Based on the findings of the six studies that included men, the mean weighted sensitivity 

of exercise MPI in men was 0.93 (95% CI 0.90-0.95) (Evidence Table 3) and the mean 

weighted specificity was 0.57 (95% CI 0.47-0.67). The mean weighted positive 

likelihood ratio for exercise MPI in men was 2.17 (95% CI 1.73-2.73) and the mean 

weighted negative likelihood ratio was 0.13 (95% CI 0.09-0.19). 
24

We performed a subgroup analysis limited to the findings of the four good quality studies 

(Evidence Table 1). Mean weighted accuracy estimates from these analyses were not 

materially different from the overall mean summary estimates (Evidence Table 3). 

We performed two sensitivity analyses. One eligible study evaluated the accuracy of both 

thallium and sestamibi.6 The overall mean weighted results included only the accuracy 

estimates for sestamibi. A sensitivity analysis substituting the results for thallium 

produced similar overall results. We also repeated the analysis for women including the 

findings of one study that was excluded because no definitions of an abnormal test or 

abnormal angiogram were provided.58 Including the results of this study did not 

materially change the accuracy estimates. 

We calculated mean weighted accuracy estimates for men and women from studies that 

used sestamibi separately from those that used thallium (Evidence Table 4). Accuracy 

estimates in women for studies using sestamibi and those using thallium were very 

similar (p-value for the comparison of Q* statistics = 0.84) 

Exercise Echocardiography

In women, sensitivity for exercise echocardiography ranged from 0.77 to 0.88 with a 

mean weighted sensitivity of 0.81 (95% CI 0.74-0.87) (Evidence Table 5). Specificity for 

exercise echocardiography in women ranged from 0.37 to 0.84, with a mean weighted 

specificity of 0.73 (95% CI 0.66-0.79). The mean weighted positive likelihood ratio for 

exercise echocardiography in women was 2.95 (95% CI 2.28-3.79) and the mean 

weighted negative likelihood ratio was 0.26 (95% CI 0.19-0.36). 

Based on the findings of two studies of the accuracy of echocardiography that included 

men, the mean weighted sensitivity was 0.84 (95% CI 0.79-0.88) and the mean weighted 

specificity was 0.45 (95% CI 0.32-0.59) (Evidence Table 5). The mean weighted positive 

likelihood ratio for exercise echocardiography in men was 1.54 (95% CI 1.20-1.98) and 

the mean weighted negative likelihood ratio was 0.36 (95% CI 0.24-0.53). 

We performed subgroup analyses limited to the findings of the two good quality studies 

of the accuracy of exercise echocardiography in women (Evidence Table 1). The mean 

weighted sensitivity estimate from the good quality studies was similar to the overall 

mean sensitivity (0.82 vs. 0.81), but specificity was lower (0.60 vs. 0.73) (Evidence Table 

5). These differences resulted in a lower mean weighted positive likelihood ratio based on 

the good quality studies compared to the estimate based on all eligible studies (2.06 vs. 

2.95). Mean estimates of negative likelihood ratios did not differ when results were 

restricted to the good quality studies (Evidence Table 5). 

We performed a sensitivity analysis by adding the results of one study of the accuracy of 

exercise echocardiography that was published before our date range.59 Including the 

results of this study did not materially change the overall accuracy estimates. 
25

Accuracy of Exercise MPI vs. Echocardiography in Women

Based on 10 studies of the accuracy of exercise MPI and four of exercise 

echocardiography, the accuracy of each test for the diagnosis of CHD in women is 

similar (Evidence Tables 3 and 5). The mean weighted sensitivity, specificity and 

positive likelihood ratio for MPI are slightly lower than for echocardiography (sensitivity 

0.77 vs. 0.81; specificity 0.69 vs. 0.73, positive likelihood ratio 2.46 vs. 2.95), but the 

differences are small and not statistically different (p-value for the Q* statistic = 0.10). 

The accuracy of the two tests is also similar when analyses are restricted to good quality 

studies (Evidence Tables 3 and 5). The use of sestamibi instead of thallium also did not 

change the accuracy of MPI studies in women (Evidence Table 4). 

Accuracy of Noninvasive Testing in Women Compared to Men

The mean weighted sensitivity of MPI in women is somewhat lower than in men (0.77 

vs. 0.93), but the specificity is higher (0.69 vs. 0.57) (Evidence Table 3). The positive 

likelihood ratio is slightly higher in women compared to men (2.46 vs. 2.17) as is the 

negative likelihood ratio (0.33 vs. 0.13). These differences in the accuracy of MPI 

between men and women were statistically significant (p-value for the comparison of Q* 

statistics 0.028), but it is not clear whether higher sensitivity or higher specificity is 

preferable.

Comparison of mean weighted accuracy estimates between women and men may be 

biased if these data are derived from different studies that may have used somewhat 

different methods and definitions of positive tests. To avoid this problem, we calculated 

mean weighted accuracy estimates for men and women restricted to the findings of 

studies that included both genders (Evidence Table 3). Based on the findings of these 

studies, sensitivity of MPI is lower in women than in men (0.86 vs. 0.93), but specificity 

is the same (0.57 for both genders; p-value for the comparison of Q* statistics 0.012). 

This analysis suggests that exercise MPI is more accurate in men than in women, but the 

differences are small and not clinically meaningful.

The mean weighted sensitivity of echocardiography in women is similar to that in men 

(0.81 vs. 0.84), but the specificity is higher (0.73 vs. 0.45) (Evidence Table 5). The 

positive likelihood ratio was substantially higher in women than in men (2.95 vs. 1.54), 

and the negative likelihood ratio was slightly lower (0.26 vs. 0.36). However, given the 

small numbers of men included in the analyses, we could not calculate a Q* statistic or 

determine any statistically significant differences between men and women with regard to 

exercise echocardiography. 

Assessments for Heterogeneity and Publication Bias

There was no heterogeneity in any of the mean weighted estimates of accuracy. 

Publication bias usually occurs if small studies with unremarkable findings (poor 

accuracy) are not published while small studies with markedly positive findings (high 
26

accuracy) are published. We calculated the correlation between individual study sample 

size and sensitivity using Kendall’s Tau to assess potential publication bias. There was no 

evidence of publication bias in any of the summary estimates of accuracy. 

Conclusions 

In the last decade, both exercise echocardiography and exercise MPI have become widely 

available and commonly used for noninvasive diagnosis of coronary disease. It is 

important for both patients and providers to understand the accuracy of these tests and 

their limitations. We obtained results from 14 studies published between 1990 and 2002 

on the accuracy of these tests in women. Based on these data, the overall accuracy of both 

tests in women is low with positive likelihood ratios of 2.5 to 3 and negative likelihood 

ratios of about 0.3. 

There are several advantages of estimating accuracy of a diagnostic test using likelihood 

ratios rather than sensitivity and specificity. First, it is possible to achieve a high 

sensitivity for most diagnostic tests by accepting a low specificity; similarly, high 

specificity can be achieved by accepting low sensitivity. In contrast, both sensitivity and 

specificity must be high to achieve good likelihood ratios (positive LR = sensitivity/(1-

specificity) and negative LR = (1-sensitivity)/specificity). Secondly, likelihood ratios are 

a powerful tool to apply clinically using Bayes’ theorem; the post-test odds that a patient 

has the disease are estimated by multiplying the pre-test odds by the positive likelihood 

ratio. For instance, in a 55 year old woman with probable angina, the prior probability of 

CHD is about 30 percent.60 If her exercise MPI is positive, her posterior probability of 

CHD would be about 50 percent (prior odds 1:2.3 multiplied by positive LR of 2.5 equal 

posterior odds of 2.5:2.3 which is equivalent to posterior probability of about 50 percent). 

Similarly, if her exercise echocardiogram is positive, her posterior probability of having 

CHD would be about 55 percent. If either of these studies were negative, her posterior 

probability would be about 10 percent. Small differences in the posterior probabilities 

based on exercise MPI or echocardiogram do not have different clinical implications and 

suggest that the value of these tests is equivalent. 

The common conception that exercise testing in women should always be combined with 

imaging may not be true. A prior meta-analysis that evaluated the accuracy of exercise 

EKG in women found a mean weighted positive likelihood ratio of 2.25 and a negative 

likelihood ratio of 0.55.7 These accuracy estimates are very similar to those that we 

calculated for exercise MPI and echocardiogram and would result in very similar 

estimates of posterior probability of CHD. However, women who receive exercise EKG 

testing without imaging are more likely to have a normal EKG at baseline and thus may 

be less likely to have significant CHD. Thus, comparison of the accuracy of exercise 

EKG with exercise imaging studies or exercise echocardgiography may be biased unless 

patients are randomized to receive the different tests. 
27

The value of a diagnostic test result depends on the accuracy of the test, the prior 

probability of disease and the threshold for treatment. In women with low to intermediate 

prior probability of CHD, a positive exercise MPI or echocardiogram result in similar 

posterior probabilities that may warrant further testing. Our 55 year-old woman with 

angina, for example, has about a 50 percent probability of having CHD if she has a 

positive noninvasive test. Before labeling her as having CHD and beginning treatment, 

many clinicians may want to pursue angiography. An older woman in her mid sixties 

with angina has about a 50 percent prior probability of having CHD. If she has a negative 

noninvasive test, her posterior probability of having CHD is about 25 percent. Many 

clinicians may prefer a more accurate test (such as angiography) before declaring that this 

woman does not have CHD and forgoing treatment.

Our analysis found that the sensitivity of exercise MPI in women was lower than in men. 

While this difference was statistically significant, it was small and not clinically 

meaningful. Most of the studies included in our review reported a higher prevalence of 

CHD in men than in women. The prevalence of prior MI also was higher in men 

compared to women. This spectrum effect could account for the apparent lower 

sensitivity of MPI in women compared to men. Alternatively, the lower sensitivity in 

women may be due to differences in chest wall anatomy, left ventricular chamber size, 

ability to exercise maximally, catecholamine response to exercise or hormone levels. 

Comparison of the accuracy of exercise echocardiography in women and men was 

limited by the small number of studies that reported separate data for men. 

Evaluation of the accuracy of noninvasive tests requires a dichotomous outcome. The 

conventional “gold standard” for the presence of CHD is 50 percent or more stenosis of 

one or more of the major coronary arteries at angiography, and this is the definition that 

we used. However, coronary heart disease represents a continuum of disease that may not 

be best measured by angiography.

In addition to diagnosis of CHD, exercise MPI and exercise echocardiography are also 

performed to localize disease and to determine the extent of disease. Our analysis 

provides no data on the accuracy of noninvasive tests for these purposes. 

The value of our review is limited by the quality of the studies included and the number 

of persons included. Many of the studies included in this systematic review were rated 

only fair quality, often because it was not clear that personnel who interpreted the 

noninvasive test were blinded to the results of the angiogram. Prior knowledge of 

angiographic results could falsely increase the accuracy of the noninvasive test. In many 

of the studies included, only persons with a positive noninvasive test went on to have 

angiography. This verification bias may result in higher sensitivity and lower specificity 

than in studies in which all subjects undergo both tests. 

Unfortunately, most studies did not report the percent of maximum predicted heart rate 

achieved by subjects. Failure to achieve 85 percent of maximum predicted heart rate 

would likely result in a higher number of false negatives and lower sensitivity. Sensitivity 

might be lower in women if they are less likely than men to exercise adequately. 
28

Most of the studies of MPI and one of the studies of echocardiography included a 

substantial proportion of persons with prior myocardial infarction. Including persons with 

diagnosed disease likely increases sensitivity at the cost of specificity. Finally, we 

identified only 14 studies that met our inclusion criteria and the number of women 

included was limited. We identified many additional studies that included some women, 

but were unable to obtain data stratified by gender from the authors. 

Future Research 

Studies of the accuracy of noninvasive tests should publish all estimates of accuracy 

stratified by sex, or make these estimates available to public access. Stratification by sex 

would allow more precise estimates of the accuracy of noninvasive tests for CHD in 

women, but it is unlikely that this would result in a substantial improvement in the 

estimated accuracy of the tests. The major finding of this systematic review is that the 

accuracy of noninvasive tests for CHD in both men and women is low and that future 

research should address ways to improve accuracy. The quality of future studies of the 

accuracy of noninvasive tests for the diagnosis of CHD would be improved by excluding 

persons with known CHD, performing both the noninvasive test and angiography in all 

participants and assuring that the outcome of the noninvasive test is assessed by 

personnel blinded to the results of angiography. Finally, assessment of the value of 

diagnostic tests for estimating risk of future CHD events would have important longterm clinical implications.
29

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35

Chapter 3. Systematic Review of Lipid Lowering 

Treatment to Reduce Risk of Coronary Heart 

Disease in Women

Introduction

Coronary heart disease (CHD) is the leading cause of death in the United States and half 

of all deaths from CHD occur in women.1, 2 Among white women, the cumulative risk of 

developing CHD between 50 and 94 years of age is 46 percent and the cumulative risk of 

dying from CHD is 31 percent.3

Elevated total cholesterol, low density lipoprotein-C (LDL-C) and triglycerides, and low 

high density lipoprotein-C (HDL-C) are risk factors for CHD in women.4-6 Lipid 

lowering may be achieved with either diet or drugs, but few studies have addressed the 

effects of dietary interventions on clinical outcomes. Several randomized clinical trials 

have evaluated the effect of lipid lowering with drugs on risk of CHD events, both in 

persons with known cardiovascular disease and in those without CHD.7-11 Unfortunately, 

many of the clinical trials of lipid lowering treatments did not include women and others 

did not include adequate numbers of women to allow sex-specific analyses. Finally, some 

of the trials that did include women reported aggregate events (e.g. major coronary 

events) but did not report specific outcomes such as CHD death or nonfatal myocardial 

infarction (MI) separately. 

A previous systematic review of lipid lowering therapy in women included only studies 

published before 1995 and is now outdated.12 A more recent systematic review that 

included only trials of statin drugs found that both women and men treated with statins 

had a 30 percent reduction in risk of major CHD events.13 However, this review did not 

address outcomes other than major CHD events in women, did not stratify by primary or 

secondary prevention and did not include data from recent large trials.

The goal of this systematic review is to critically assess the available clinical trial 

evidence regarding drug treatment of hyperlipidemia for the prevention of CHD events 

and death in women. We will assess the effects of lipid lowering on total mortality, CHD 

mortality, nonfatal myocardial infarction (MI), CHD events and revascularization 

procedures in women with and without prior CHD.
36

Methodology 

Data sources

We searched PubMed®, the Cochrane Database, and DARE for articles published in 

English and other languages from 1966 through January 2002. We also reviewed 

bibliographies and asked peer reviewers (Appendix A) to identify additional articles. 

Search Terms 

Search terms were developed in collaboration with a medical librarian and included the 

following:

Limits publication dates 1966 to January 2002, human

Not: practice guideline, letter, editorial, review, meta-analysis, 

 infant, newborn, preschool child, child

Predictor hyperlipidemia and anticholesteremic agents, antilipemic agents, 

simvastatin, lovastatin, pravastatin, atorvastatin, fluvastatin, gemfibrozil, 

cholestyramine, cholestpol, niacin

Outcomes cardiovascular diseases, heart diseases, myocardial ischemia,

coronary disease

Inclusion Criteria 

To be included, articles were required to fit the following criteria: 

1) Randomized clinical trials of outpatients with or without known CHD.

2) Treatment duration of at least one year.

3) Study population classified as either primary (participants without prior CHD) or 

secondary prevention (participants with prior CHD).

4) Data on women provided.

5) Impact of lipid lowering with drug treatment assessed for at least one of the following 

clinical outcomes: total mortality, CHD mortality, nonfatal MI, CHD events or 

revascularization procedures. Coronary events included ischemic coronary syndromes 

and nonfatal myocardial infarction. CHD procedures included coronary bypass graft 

surgery and percutaneous coronary angioplasty or stenting. 

6) Published between January 1, 1966 and January 30, 2002. Articles published outside 

this date range recommended by peer reviewers were included.

We excluded studies that only provided evidence on the effect of treatment on changes in 

lipids, angiographic findings or other intermediate outcomes. For studies with multiple 

publications, only data from the most comprehensive or most recent publication were 

used.
37

Article Identification 

An initial search using the terms listed above identified articles that potentially provided 

evidence. Two University of California, San Francisco (UCSF)-Stanford Evidence-based 

Practice Center (EPC) physician investigators reviewed the titles and excluded those that 

clearly did not provide data on humans or clearly did not address the question.

The abstracts of the remaining articles were reviewed independently by two UCSFStanford EPC physician investigators and coded using the categories listed below. 

Disagreements were discussed and the following consensus codes were entered into a 

database (Access, Microsoft Corporation):

RQ Research question - the article clearly does not address the research 

question.

R Review – the study is a review that does not contain primary data.

NSD Not appropriate study design - The article is not a randomized clinical trial.

NH No humans - the study clearly does not include data on humans.

E1 Eligible – the study may contain primary evidence regarding the research 

question in women and will be reviewed in full-text.

Articles coded E1 were retrieved and the full text was reviewed independently by two 

UCSF-Stanford EPC investigators. Names of authors and titles of journals were obscured 

before articles were reviewed. 

Obtaining Unpublished Results 

Some eligible studies included women in the study population, but did not report findings 

separately by gender. In these instances we attempted to contact authors to obtain these 

data. If we did not receive a response after the first contact, a second attempt was made. 

We contacted 13 authors11, 14-27 and received data from two.16, 25, 26

Quality Assessment

The full text of each eligible study was reviewed independently by two UCSF-Stanford 

physician investigators, who completed a quality evaluation form (Appendix B). All of 

the studies included in this systematic review are randomized clinical trials. To be 

categorized as good quality, articles were required to meet the following additional 

parameters:

• Inclusion/exclusion criteria clear and appropriate.

• Randomization allocation concealed.

• Control group received placebo.

• Participants and research staff blinded to intervention.

• More than 75 percent complete followup.
38

All other trials were considered fair quality. Disagreements between reviewers regarding 

quality parameters were decided by discussion and consensus.

Data Abstraction 

Two UCSF-Stanford EPC physician investigators independently reviewed the full text of 

each eligible study and completed a data abstraction form (Appendix C). We abstracted 

information on the study population (primary prevention trials were defined as those that 

included individuals without known CHD; secondary prevention trials included 

individuals with known CHD), inclusion criteria, length of followup, numbers of men 

and women, participant characteristics such as age, other cardiovascular risk factors and 

cardiac medication use, baseline and followup lipoprotein values and all clinical 

outcomes that were measured. When possible, data were abstracted for men and women 

separately. Disagreements were discussed and decided by consensus. 

Data Management and Archive 

We entered all identified titles and abstracts in an EndNote® file (Niles Software, Inc.) 

that includes searchable key words as codes for eligibility. Information on all articles that 

were reviewed in full text was transferred from EndNote® to a relational database 

(Access, Microsoft® Corporation) that allows us to categorize each article by reason for 

exclusion. Quality assessment data for each eligible study were also entered in the Access 

database, allowing us to categorize eligible articles by quality. Selected data were 

transferred to a flatfile database (EXCEL, Microsoft® Corporation) for preparation of 

evidence tables and calculation of summary estimates, confidence intervals and tests of 

heterogeneity. 

The full-text articles that were retrieved, and the abstraction forms for each article are 

filed by topic and question in Dr. Grady's offices at the UCSF Mt. Zion Women's Health 

Clinical Research Center. 

Data Analyses 

The primary outcome of each clinical trial was expressed as the relative risk (RR) among 

treated compared to untreated study participants. Summary estimates of RR and 95 

percent confidence intervals (CI) were calculated using the Mantel-Haenszel method and 

both fixed and random effects models. Results of the fixed and random effects models 

were similar, and we report only the findings of the random effects model. To avoid 

calculation problems associated with zero cells, 0.5 was added to all cells to calculate 

variances and standard deviations.28 The significance level for all tests of outcome was 

set at 0.05. All findings were assessed for heterogeneity using a standard Chi-square test 

and Q statistic with critical value set at 0.10. All analyses were performed separately for 

the findings of primary and secondary prevention studies. Subgroup analyses were 

performed by type of drug treatment (statins vs. others), and by good vs. fair quality. 
39

Publication bias usually occurs if small studies with unremarkable findings (relative risks 

about 1.0) are not published while small studies with markedly positive findings (in this 

case, low relative risks) are published. We calculated the correlation between individual 

study weight (1/variance) and relative risk using a nonparametric correlation coefficient 

(Kendall’s Tau) with critical value set at 0.10 to assess potential publication bias. 

Statistically significant correlation of study weight and relative risk suggests publication 

bias.

Results 

Results of Study Identification 

Our searches identified 1,335 titles. After eliminating ineligible studies by review of titles 

and abstracts, we reviewed the full text of 120 articles. We identified 20 studies that fit all 

inclusion criteria, but only 9 provided outcomes stratified by sex.7-9, 11, 27, 29-39 We 

contacted the principal investigators of the studies that did not provide data for women to 

request this information.11, 14-27 We received data on women from two investigators.16, 25, 

26 Thus, 11 studies (represented by 19 articles) were found to be both eligible and to 

contain data stratified by sex for inclusion in the systematic review.7-9, 11, 16, 25-27, 29-39 One 

additional study did not meet inclusion criteria because it did not provide data on any of 

the clinical outcomes of interest and the study population was equally divided between 

persons with prior CHD and those without prior CHD and separate estimates for the 

effects of lipid lowering in primary and secondary prevention were not published.40

Description of Eligible Studies 

Characteristics of the 11 eligible trials are described in Evidence Table 6. The numbers of 

participants in each trial ranged from 151 to 20,536 and 15 to 50 percent of participants 

were women. The total number of women included in the trials was 15,917, but almost 

two thirds were from two studies.11, 39Information on the ethnicity of participants was not 

provided in most trials. Duration of treatment ranged from 2.8 to 6.1 years and averaged 

4.7 years. Seven of the trials were classified as secondary prevention and four were 

classified as primary prevention (Evidence Table 6). Eligibility criteria for 5 trials 

required at least mild hyperlipidemia,7, 16, 25, 26, 31, 39 four required a range of cholesterol 

levels that would include some participants in the normal range9, 11, 27, 34 and 2 included 

participants regardless of cholesterol levels.29, 30 Three trials assessed the effects of 

clofibrate29, 30 or colestipol31 and eight assessed the efficacy of treatment with statins 

(lovastatin,9, 25, 26 simvastatin,7, 11, 39pravastatin16, 27, 34).

All but one of the 11 trials included a placebo control group39 and all but two were 

adequately blinded.31, 39 In all but one of the trials,31 followup was greater than 75 percent 

complete. Overall, seven of the trials were rated good quality and four were rated fair 

(Evidence Table 6). 
40

The clinical outcomes evaluated were total mortality, CHD mortality, nonfatal MI, CHD 

events and revascularization (Evidence Tables 7 and 8). Most trials were designed to 

address clinical outcomes, but two were designed to evaluate change in intimal medial 

thickness of the carotid artery16, 25, 26 and included clinical events only as secondary 

outcomes. 

For studies with mixed populations (e.g. some participants had CHD and some did not), 

the trial was classified as primary or secondary prevention based on the status of the 

majority of participants. Participants in most of the trials classified as primary prevention 

were at high risk for CHD outcomes due to presence of CHD risk factors.

Three trials included participants with and without CHD. In the colestipol trial, only 20 

percent of participants had CHD and this trial was classified as a primary prevention 

study.31 In the Heart Protection Study, 65 percent of participants had known CHD and 

remaining 35 percent had peripheral vascular disease, cerebrovascular disease or 

diabetes.11 Because the majority of participants had CHD and those without CHD were 

also at very high risk for CHD events, this trial was classified as a secondary prevention 

study. A recently published trial included older participants with CHD and those at high 

risk for CHD in approximately equal numbers40 and did not present results stratified by 

history of CHD. Because of the equal distribution, we are unable to classify this study as 

either primary or secondary prevention. In addition, we could not include the results of 

this trial for any specific coronary disease endpoint because the results for women were 

only given for the composite outcome of cardiovascular events (CHD mortality, nonfatal 

MI, fatal stroke and nonfatal stroke). 

Findings 

For each outcome, we assessed the effects of lipid lowering separately for primary and 

secondary prevention studies. We also calculated summary estimates based on the 

findings of all eligible studies, those that used a statin as the lipid lowering agent and 

those that were rated good quality (Evidence Table 8). 

Seven trials assessed the effects of lipid lowering among women with CHD (secondary 

prevention)7, 8, 11, 16, 27, 29, 30, 32-37 and included a total of 8,244 women. Two of these trials 

used clofibrate as the intervention,29, 30 while five used a statin.7, 8, 11, 16, 27, 32-37 Both of 

the trials of clofibrate were rated fair,29, 30 while all of the statin trials were rated good 

quality. While seven trials provided data, three were small (22 to 124 women),

16, 29, 30 two 

were mid-sized (5768, 34, 35 and 827 women32, 33) and only two included more than 1,000 

women (1,51627, 36, 37 and 5,08211). Evidence was also limited because several of the trials 

reported results among women for only one or two of the five outcomes of interest (total 

mortality, CHD mortality, nonfatal MI, CHD events and revascularization).
41

Four trials assessed the effects of lipid lowering among women without prior CHD 

(primary prevention)9, 25, 26, 31, 38, 39 and included 7,673 women. One of these trials used 

colestipol as the intervention31 and the rest used a statin. Two trials31, 39 were rated fair 

and the other two good quality.9, 25, 26, 38 Three of these trials included about 1,000 women 

or less (441,25, 26 997,9, 38 and 1,18431) and one included 5,051.39 As with the secondary 

prevention trials, many of these trials reported results among women for only one or two 

of the five outcomes of interest.

Secondary Prevention

Total mortality. Two trials,7, 16, 32, 33 both using a statin as the intervention, reported the 

effect of lipid lowering on mortality among a total of 899 women with CHD (Evidence 

Table 7). One of these trials16 enrolled only 22 women, so that essentially all of the data 

regarding the effects of lipid lowering for secondary prevention of mortality in women 

comes from one trial that used a statin as the intervention.7, 32, 33 Neither of the two trials 

found a reduction in risk of mortality among women (Evidence Table 7), and the 

summary relative risk was 1.11 (95% CI 0.66-1.87) (Evidence Table 8). 

CHD mortality. Five trials reported the effect of lipid lowering on CHD mortality among 

1,646 women with CHD (Evidence Table 7). However, three of these trials were small,16, 

29, 30 and two,7, 8, 32-35 both using a statin as the intervention, provide most of the evidence 

regarding the effect of lipid lowering on CHD mortality in women with CHD. The 

findings of these two trials were consistent in showing a reduced risk of CHD death 

among women treated with lipid lowering compared to controls. The summary relative 

risk for secondary prevention of CHD mortality was 0.74 (95% CI 0.57-0.96), suggesting 

a 26 percent reduction in risk of CHD mortality (Evidence Table 8). 

Nonfatal MI. Five trials reported the effect of lipid lowering on risk for nonfatal MI in 

1,646 women with CHD (Evidence Table 7). Three of these trials were small16, 29, 30 and 

two trials, both using a statin as the intervention,7, 8, 32-35 provide most of the evidence 

regarding the effect of lipid lowering for secondary prevention of nonfatal MI in women. 

Both of these two trials showed a reduced risk for nonfatal MI and the summary relative 

risk was 0.64 (95% CI 0.50-0.82), suggesting a 36 percent reduced risk (Evidence Table 

8). 

CHD events. Four trials, all using a statin as the intervention, reported the effect of lipid 

lowering on CHD events in 8,001 women with CHD (Evidence Table 7). These trials 

consistently found a reduced risk of CHD events among women,7, 8, 11, 27, 32-37 with a 

summary relative risk of 0.79 (95% CI 0.72-0.88), suggesting a 21 percent reduced risk 

of CHD events among women with CHD (Evidence Table 8). 
42

Revascularization. Two trials, both using a statin as the intervention, reported the effect 

of lipid lowering for secondary prevention of revascularization procedures in 1,403 

women with CHD (Evidence Table 7). Both of these trials found a reduction in risk 

among treated women and the summary relative risk was 0.70 (95% CI 0.42-1.16). 

Although the summary relative risk suggests a 30 percent reduction in risk of 

revascularization, this finding was not statistically significant (Evidence Table 8). 

Drug class and study quality. Only two studies, including a total of 221 women, 

addressed the impact of lipid lowering drugs other than statins.29, 30 Thus, evidence on the 

effect of non-statin drugs is limited. However, the summary ORs were similar for all 

outcomes when findings were restricted to those studies using a statin. Both of the studies 

that used a non-statin drug were rated fair quality,29, 30and all five of the trials that used a 

statin were rated good quality. Thus, the summary ORs are also unchanged when the 

results are restricted to good quality studies.

Sensitivity analyses. One trial that we included with the secondary prevention studies 

enrolled a mixed population of persons with and without CHD and reported the effect of 

statin treatment on risk for CHD events.11 Because 65 percent of the participants had 

prior CHD and the rest had vascular disease or diabetes, we included the results of this 

trial as secondary prevention. We also performed a sensitivity analysis excluding the 

results of this trial. The summary relative risk for secondary prevention of CHD events 

excluding the results of this trial was essentially unchanged (summary relative risk 0.74; 

95% CI 0.61-0.91). We also performed a sensitivity analysis by adding the results of the 

cardiovascular disease outcomes from the PROSPER trial to the summary results for 

secondary prevention of CHD events.40 The summary relative risk for secondary 

prevention of CHD events including the results of this trial was essentially unchanged 

(summary relative risk 0.76; 95% CI 0.72-0.87). 

Primary Prevention

Total mortality. Four trials9, 25, 26, 31, 38, 39 reported the effect of lipid lowering on mortality 

among 7,673 women without prior CHD (Evidence Table 7). One of these trials31 used 

colestipol as the intervention, while the rest used a statin. One of the trials reported a 

lower risk of mortality in women treated with lipid lowering compared to controls, but 

the other three did not (Evidence Table 7). The summary relative risk for primary 

prevention of mortality was 0.95 (95% CI 0.62-1.46) (Evidence Table 8). 

CHD mortality. Three trials9, 25, 26, 31, 38 reported the effect of lipid lowering on CHD 

mortality among 2,622 women without prior CHD (Evidence Table 7). One of these 

trials31 used colestipol as the intervention, while the other two used a statin. One of the 

three trials reported a lower risk of CHD mortality in women treated with lipid lowering 

compared to controls,25, 26 but the others did not. The summary relative risk for primary 

prevention of CHD mortality was 1.07 (95% CI 0.47-2.40).
43

Nonfatal MI. Two trials9, 25, 26, 38 reported the effect of lipid lowering on risk for nonfatal 

MI in 1,646 women without prior CHD (Evidence Table 7). Both of these trials used a 

statin as the intervention, and both found a reduced risk of nonfatal MI among women 

treated with lipid lowering. The summary relative risk for primary prevention of nonfatal 

MI was 0.61 (95% CI 0.22-1.68). Although the summary relative risk suggests a 39 

percent reduction in risk of nonfatal MI among treated women, this finding was not 

statistically significant.

CHD events. Two trials, both using a statin as the intervention,9, 38, 39 reported the effect 

of lipid lowering on risk for CHD events in 6,048 women without prior CHD (Evidence 

Table 7). The results of these trials are inconsistent, and the summary relative risk for 

primary prevention of CHD events was 0.87 (95% CI 0.50-1.49).

Revascularization. Only one trial reported the effect of statin therapy for primary 

prevention of revascularization procedures in women9, 38 (Evidence Table 7). This trial 

found a relative risk of 0.87 (95% CI 0.33-2.31). 

Drug class and study quality. Evidence on the primary prevention effects of drugs other 

than statins is limited as only one trial addressed the impact of a non-statin drug.31 The 

summary ORs were similar for all outcomes when findings were restricted to those 

studies using a statin or to studies rated good quality.

Sensitivity analyses. We performed a sensitivity analysis by adding the results of the 

cardiovascular disease outcomes from the PROSPER trial to the summary results for 

primary prevention of CHD events.40 The summary relative risk for primary prevention 

of CHD events including the results of this trial was essentially unchanged (summary 

relative risk 0.97; 95% CI 0.84-1.12). 

Assessments for Heterogeneity and Publication Bias

There was no statistical evidence of heterogene ity in any of the overall summary 

estimates of the effect of lipid lowering on any outcome except for secondary prevention 

of revascularization (Evidence Table 8). There was no evidence of publication bias in any 

of the summary estimates. 

Conclusions 

Although 20 clinical trials of the effects of lipid lowering therapy included women, only 

nine published results by gender. By contacting study investigators, we were successful 

in obtaining data on women from two additional trials. Thus, we were able to analyze 

results from 11 trials that included 15,917 women. However, complete data on the five 

outcomes of interest were not available from each trial, limiting our ability to assess the 

effect of lipid lowering on some outcomes. Only three studies, including a total of 1,405 

women, addressed the impact of lipid lowering drugs other than statins. Thus, evidence 

on the effect of non-statin drugs is limited. 
44

In the secondary prevention setting, treatment with lipid lowering therapy reduced risk of 

CHD mortality, nonfatal MI and CHD events in women. Summary estimates suggest a 26 

percent reduction in risk of CHD mortality, a 36 percent reduction in risk of nonfatal MI 

and a 21 percent reduction in risk of a CHD event. There was no evidence of a reduction 

in risk of total mortality and insufficient evidence to document a reduction in risk of 

revascularization procedures. In the primary prevention setting, there was insufficient 

evidence of reduced risk of any clinical outcome in women. The summary relative risk 

for nonfatal MI was similar to that for secondary prevention (39 percent reduction vs. 36 

percent reduction for secondary prevention), but was not statistically significant. 

A prior systematic review of the findings of clinical trials of the effects of lipid lowering 

among persons without CHD used inclusion criteria and methods very similar to ours, but 

did not stratify the results by gender.41 Since 90 percent of the participants included in 

that review were men, the results primarily reflect the effects of lipid lowering in men. 

Among (mostly) men, primary prevention with lipid lowering resulted in about a 30 

percent reduced risk for both CHD events and CHD mortality41 Our findings suggest that, 

among persons without CHD, lipid lowering may not be as effective in women as in men 

without CHD. However, our power to observe a modest reduction in CHD risk was 

limited because the findings of only four primary prevention trials were available for 

inclusion in the meta-analysis.

We were unable to include findings from a recently published clinical trial of the effect of 

lipid lowering among 2,804 men and 3,000 women aged 70 to 82 years randomized to 

pravastatin or placebo and followed for a mean of 3.2 years.40 About half of the 

participants in this trial had vascular disease and the others had vascular risk factors. 

Results were reported for the effect of lipid lowering on cardiovascular events in women 

(CHD mortality, nonfatal MI, fatal stroke and nonfatal stroke); the relative risk among 

women treated with pravastatin was 0.96 (95% CI 0.79-1.18). We could not include these 

data because we could not categorize the trial as primary or secondary prevention and 

results in women were only given for cardiovascular events. Given the timeline for this 

review, we did not have time to contact the authors to request findings stratified by sex, 

primary vs. secondary prevention and clinical outcomes. However, in sensitivity analyses 

that included the results of this trial as either primary or secondary prevention of CHD 

events did not alter the findings. 

There were no clinical differences in the summary odds ratios when studies included 

were restricted to those that used a statin as the intervention or to good quality studies. 

This is likely because eight of the 11 included trials used a statin as the intervention, and 

seven of the 11 trials were rated good quality.

In summary, lipid lowering therapy appears to reduce risk of CHD mortality, nonfatal MI 

and CHD events 25 to 35 percent in women with prior CHD. There was inadequate 

evidence to document a reduction in risk of any clinical outcome among women without 

prior CHD. Data were limited, but the risk for total mortality was not lower in women 
45

treated with lipid lowering, regardless of whether they had prior CHD or not. The lack of 

reduction in risk for mortality in either primary or secondary prevention settings may be 

because lipid lowering does not affect total mortality in women or because there were 

few deaths, even after summarizing study findings.

Future Research 

Future randomized trials should include women in adequate numbers to assess the effects 

of lipid lowering on clinical outcomes. Studies that include women should report the 

effects of lipid lowering on all clinical outcomes stratified by sex and primary vs. 

secondary prevention. 

47

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Chapter 4. Systematic Review of Diabetes as a 

Risk Factor for Coronary Heart Disease in Women

Introduction 

Studies suggest that there may be a stronger association between type 2 diabetes and 

coronary heart disease (CHD) risk in women than in men. Estimates of coronary heart 

disease mortality in diabetic men have varied from 1 to 3-fold the rate in nondiabetic 

men,1-10 while estimates in diabetic women have ranged from 2 to 5-fold the rate in 

nondiabetic women.2, 5, 8, 10-12 Variations in study population, design, quality and findings 

make it difficult to evaluate the strength of diabetes as a risk factor for CHD in either sex. 

Two previous meta-analyses that included studies that did not adjust for major 

cardiovascular risk factors concluded that diabetes is a stronger risk factor for CHD 

mortality in women than in men.13, 14 However, it is unclear whether these reported sex 

differences are real or attributable to differences in other major risk factors for CHD 

between diabetic men and women.

The goal of this systematic review is to establish an accurate estimate of CHD risk among 

women with type 2 diabetes and to compare the risk of CHD in diabetic women to that in 

diabetic men. Our main analyses will include only studies that provide multivariateadjusted comparisons to determine the independent association between diabetes and 

coronary disease outcomes.

Methodology 

Data Sources

We searched PubMed®, the Cochrane Database, and DARE for studies in English or 

other languages published from 1966 through January 2002 . We also reviewed 

bibliographies and asked peer reviewers (Appendix A) to identify additional articles. In 

the case of multiple publications from a single study, we used the most comprehensive or 

recent publication.
52

Search Terms

Search terms were developed in collaboration with a medical librarian and include the 

following:

Limits publication dates 1966 to 2002, peer-reviewed articles

Predictor diabetes

Outcomes cardiovascular disease, myocardial infarction, ischemic heart disease

Inclusion Criteria

To be included, articles were required to fit the following criteria: 

1) Include both men and women and provide an estimate of the CHD risk associated 

with diabetes in both sexes.

2) Followup of the cohort for at least six months.

2) Data on one of the following outcomes: total mortality, CHD mortality, 

cardiovascular disease (CVD) mortality or nonfatal myocardial infarction (MI).

3) Inclusion of primarily type 2 diabetic participants (defined by self-report, use of 

diabetic medication, medical record diagnosis, positive oral glucose tolerance test or 

an elevated fasting glucose).

4) Inclusion of multivariate adjustment for confounders, including at least age, 

hypertension, hypercholesterolemia and smoking.

5) Inclusion of a nondiabetic, concurrent control group.

6) Published between January 1, 1966 and January 1, 2002. Articles published outside 

this date range that were recommended by peer reviewers (Appendix A) were 

included.

Definition of Outcomes

All included studies defined CHD mortality by the International Classification of 

Diseases, Ninth Revision (ICD-9) codes of 410 through 414 or by physician 

documentation of sudden cardiac death. Nonfatal MI was defined by definite 

electrocardiographic criteria using the Minnesota code, enzyme levels consistent with MI, 

self-report (with or without Rose questionnaire criteria), or medical record 

documentation. 

Article Identification

An initial search using the terms listed above identified articles that potentially provided 

evidence. Two University of California, San Francisco (UCSF)-Stanford Evidence-based 

Practice Center (EPC) investigators reviewed the titles and excluded those that clearly did 

not provide data on humans or clearly did not address the question.
53

The abstracts of the remaining articles were reviewed independently by two UCSFStanford EPC physician investigators and coded using the categories listed below. 

Disagreements were discussed and consensus codes were entered into a database (Access, 

Microsoft Corporation).

RQ Research question: the article clearly does not address the research question 

R Review – the study is a review that does not contain primary data

NH No humans - the study clearly does not include data on humans

O Outcome- the study clearly does not address the outcomes of interest 

P Predictor- the study clearly does not include type 2 diabetics

E1 Eligible – the study may contain primary evidence regarding the research 

questions in women and will be reviewed in full-text

Articles coded E1 were retrieved and the full text was reviewed independently by two 

UCSF-Stanford EPC physician investigators. Names of authors and titles of journals were 

obscured before articles were reviewed. 

Obtaining Unpublished Results in Women

Some eligible studies included women in the study population, but did not report findings 

separately by gender. In these instances we twice attempted to contact the authors of 

these studies to obtain these data. We contacted the authors of 26 articles, requesting the 

required information.4, 5, 8, 11, 15-36 Authors of seven studies15-21 provided the data 

necessary to satisfy inclusion criteria. Some authors were unable to recreate their original 

analyses 4, 11, 22, 23 or did not have the necessary variables in the dataset,24-26 and others did 

not provide the requested data.5, 8, 27-36

Quality Assessment

The full text of each eligible study was reviewed independently by two UCSF-Stanford 

physician investigators who completed a quality evaluation form (Appendix B). Most of 

the studies included in this systematic review are prospective cohort studies. The major 

quality issues with this study design are lack of information on potential confounders, 

inadequate duration of followup, non-blinded outcome adjudication and loss to followup.

To be categorized as good quality, articles were required to meet the following 

parameters:

• Prospective cohort design (vs. retrospective cohort or cross-sectional design)

• Type 2 diabetes defined by fasting plasma glucose or oral glucose-tolerance test (vs. 

other definitions of diabetes)

• Multivariate adjustment for potential confounders in addition to age, hypertension, 

hypercholesterolemia, and smoking

• At least 14 years of followup time (the median length of followup of all studies)

• Less than 10 percent loss to followup
54

Studies were considered to be of fair quality if they met the following parameters:

• Retrospective or cross-sectional study design

• Criteria other than fasting plasma glucose or oral glucose-tolerance test used to define 

 diabetes

• Adjusted for age, hypertension, hypercholesterolemia, and smoking only

• Follow-up time of less than 14 years

• More than 10 percent loss to followup

Data Abstraction 

Two UCSF-Stanford EPC physician investigators independently reviewed the full text of 

each eligible study and completed a data abstraction form (Appendix C). One author 

reviewed titles and abstracts of articles retrieved from the search and excluded case 

reports, letters, comments, reviews, and reports without primary data. Two UCSFStanford EPC physician investigators reviewed the 50 remaining manuscripts to 

determine study eligibility. Data were extracted on study quality, participant 

characteristics, length of followup, and outcomes (CHD mortality, nonfatal MI, and 

cardiovascular or all-cause mortality). Discrepancies between reviewers were resolved 

by consensus. For studies with multiple publications, only data from the most 

comprehensive or recent publication were used.

Data Management and Archive

We entered all identified titles and abstracts in an EndNote® (Niles Software, Inc) file 

that includes searchable key words as codes for eligibility. Information on all articles that 

were reviewed in full text was transferred from EndNote® (Niles Software, Inc) to a 

database (Access, Microsoft® Corporation) that allows us to categorize each article by 

reason for exclusion. Quality assessment data for each eligible study were also entered in 

the database (Access, Microsoft® Corporation), allowing us to categorize eligible articles 

by quality.

Abstracted data were entered into a database (EXCEL, Microsoft® Corporation) for 

preparation of evidence tables and calculation of summary estimates, confidence intervals 

and tests of heterogeneity. 

The full-text articles that were retrieved, and the abstraction forms for each article are 

filed by topic and question in Dr. Grady's offices at the UCSF Mt. Zion Women's Health 

Clinical Research Center.

Data Analysis

The primary outcome of each study was expressed as the most adjusted odds ratio (and 

95 percent confidence interval) for CHD events among persons with diabetes compared 

to those without diabetes. Summary estimates of odds ratio and 95 percent confidence 
55

intervals were calculated using a general variance-based (confidence interval) method37

that retains adjustment for confounding. We calculated summary odds ratios using both a 

fixed and random effects model.38 Results were similar using both models and we report 

only summary odds ratios based on the random effects model. The significance level for 

all summary relative risks was set at 0.05. All estimates were assessed for heterogeneity 

using a Chi square test with the significance level set at 0.10. 

Publication bias usually occurs if small studies with unremarkable findings (odds ratios 

for the association of diabetes and CHD risk around 1.0) are not published while small 

studies with markedly positive findings (high odds ratios) are published. We calculated 

the correlation between individual study weight (1/variance) and odds ratio using 

Kendall’s Tau (a nonparametric correlation coefficient) to assess potential publication 

bias. 

Summary estimates for men and women were compared using the Z-test, with a twotailed five percent level of significance. The main comparisons were repeated in 

subgroups defined by race/ethnicity (white, black, Latino, Japanese American, and Native 

American) and by study design (prospective cohort and cross-sectional analyses). 

Sensitivity analyses were performed to assess the effects of study quality and degree of 

adjustment for confounding on the outcome.

Results 

Results of Study Identification

Our searches identified 4,578 titles. Of the 233 articles that contained primary data, 50 

were duplicative publications, 46 did not include a nondiabetic control group, 44 did not 

provide information about the outcomes of interest and 26 did not perform analyses based 

on diabetes status. Eight studies did not provide data stratified by sex and used ineligible 

study designs,39-46 seven were hospital-based studies with followup less than six 

months,47-53 nine included only patients with prior MI.54-62 Seven studies were excluded 

because the study population consisted of a single sex only.63-69

Of the 36 remaining studies, ten met all inclusion criteria.12, 70-78 Twenty-two did not 

publish adequately adjusted risk estimates,4, 5, 15-31, 33-35 two did not report 95 percent 

confidence intervals or p-values for adjusted results,2, 8 and two provided only combined 

outcomes of nonfatal and fatal CHD.11, 36 We contacted the authors of these 26 articles 

twice requesting the required information.4, 5, 8, 11, 15-36 Authors of seven studies15-21

provided the data necessary to satisfy inclusion criteria. Some authors were unable to 

recreate their original analyses 4, 11, 22, 23 or did not have the necessary variables in the 

dataset,24-26 and others did not provide the requested data.5, 8, 27-36
56

Description of Eligible Studies

After receiving additional information from authors, 17 studies fulfilled all inclusion 

criteria (Evidence Table 9); 12 were prospective cohort studies12, 15, 20, 70-78 and five were 

cross-sectional analyses.16-19, 21 More than one publication provided data from the same 

cohort 70, 77 such that the meta-analysis includes adjusted findings from 14 distinct study 

populations. 

Followup time in the 12 prospective cohort studies ranged from 5 to 32 years (mean 

approximately 14 years). Most of the studies enrolled middle-aged participants; one study 

enrolled only subjects older than 65.19 The 14 study populations included 6,235 diabetic 

participants (48 percent women) and 71,306 nondiabetic control subjects (52 percent 

women). In 7 of the 17 studies,12, 15, 16, 18, 19, 71, 79 all diabetics were type 2; the remainder 

of the studies included a few type 1 diabetics, but the majority were 

type 2.20, 21, 70, 72, 144, 73-78

Summary of Results

Evidence Table 10 presents the multivariate-adjusted odds ratios (OR) by gender and 

ethnicity for CHD mortality, nonfatal MI, and all-cause mortality for each included study. 

Most of the studies show a higher OR for CHD mortality and for nonfatal MI due to 

diabetes among women compared to men. Outcomes for cardiovascular and all-cause 

mortality are mixed with approximately half of the studies showing a higher odds ratio 

for women than men. 

CHD Mortality

The overall summary OR for CHD mortality due to diabetes was 2.3 (95% CI, 1.9 - 2.8) 

for men and 2.9 (95% CI, 2.2 - 3.8) for women for all race/ethnic groups combined 

(Evidence Table 11). Although the overall summary OR for CHD mortality from diabetes 

for women was somewhat higher than for men, the summary estimates were not 

statistically different (p=0.19 for the comparison of ORs). In sensitivity analyses that 

included only studies of whites, a trend to statistically significant differences between the 

summary odds ratios for men and women was observed only when outcomes were 

inadequately adjusted for potential confounders (Evidence Table 12). For example, based 

on the results of studies that provided age-adjusted estimates, the summary OR was 

higher in women compared to men (3.42 vs. 2.07; p-value for difference = .05). 

Most studies that reported CHD mortality were performed in white subjects, limiting 

subgroup analyses by race to whites. Summary estimates for CHD mortality from eligible 

studies for white men and women were similar to those for all ethnicities combined 2.2 

(95% CI, 1.8-2.7) for men and 2.8 (95% CI, 2.1–3.7) for women. 
57

Nonfatal Myocardial Infarction and All-Cause Mortality

The summary OR for nonfatal MI due to diabetes was 1.6 (95% CI, 1.1-2.2) for menand 

1.7 (95% CI, 1.3-2.3) for women, a difference that was not statistically significant (p=.68 

for comparison of ORs in men and women) (Evidence Table 11). 

The summary OR for all-cause mortality due to diabetes was 2.1 (95% CI, 1.7-2.7) for 

men and 1.9 (95% CI, 1.7-2.3) for women, a difference that was not statistically 

significant (p=.50 for comparison of ORs in men and women) (Evidence Table 11). 

Despite summarizing estimates from 14 distinct study populations, we lacked power to 

perform subgroup analyses by race/ethnicity for CHD mortality and total mortality. We 

were able to derive summary estimates for nonfatal MI for Latinos only from two crosssectional analyses.18, 19 Diabetes did not significantly increase risk of nonfatal myocardial 

infarction for Latino men (summary OR 1.2; 95% CI, 0.6-2.4) or for Latina women (1.4; 

95% CI, 0.9-2.1). The summary estimates for Latino men and women were lower than 

those for non-Latino whites (OR 1.7; 95% CI 1.1-2.6 for men and 2.8; 95% CI 1.7-4.4 for 

women). 

Assessments for Heterogeneity and Publication Bias

There was no heterogeneity in the findings of the individual studies for CHD death, 

nonfatal MI and total mortality in women. There was no hetereogeneity in the findings of 

the studies for CHD mortality in men, but there was significant heterogeneity of the 

findings among men for nonfatal MI and total mortality (Evidence Table 11) that was not 

explained in subgroup analyses. 

There was no evidence of publication bias in any of the summary odds ratios. 

Conclusions 

Using estimates adjusted for age, hypertension, hypercholesterolemia and smoking, 

summary ORs for CHD mortality and nonfatal MI due to diabetes were higher among 

women than men, but ORs for all-cause mortality were slightly higher in men than 

women. All of the differences were modest and not statistically significant. 

Two prior meta-analyses have addressed the question of whether there is a sex-specific 

difference in risk for coronary outcomes related to diabetes.13, 14 The first meta-analysis 

included the results of 25 prospective, population-based studies that provided unadjusted 

data to examine gender differences in relative risk of CHD mortality and myocardial 

infarction associated with type 2 diabetes.13 The risk of CHD death was higher for 

diabetic women compared to men. However, many of the cohort studies included in this 

meta-analysis did not control for established risk factors for coronary disease. The second 

and more recent meta-analysis included the results of 10 studies and found that women 
58

with diabetes were at significantly higher risk of CHD mortality compared with men 

(2.58 vs. 1.85, p=.045 for the comparison of ORs)14. This meta-analysis included studies 

that adjusted only for age and included subjects with prior coronary disease. In a 

subgroup analysis excluding studies of patients with existing coronary disease, there was 

no significant difference between summary ORs for CHD death between men and women 

(1.9 in men vs. 2.4 in women, p=0.18). A third systematic review based on this evidence 

report was recently published.80

These results of the two prior systematic reviews are consistent with our findings, except 

that we found no statistically significant differences between summary ORs for CHD for 

men and women. This disparity is likely due to the fact that the prior reviews included 

studies in which outcomes were unadjusted, while our inclusion critieria required 

adjustment for major CHD risk factors. Our subgroup analyses suggest that the difference 

in relative risk for CHD mortality between men and women is attenuated with adjustment 

for major cardiovascular risk factors. This may be due to the fact that diabetic women 

have more risk factors or more severe risk factor abnormalities compared to nondiabetic 

women than do diabetic men compared to nondiabetic men.81 Alternatively, cardiac risk 

factors may have a stronger impact on CHD risk in women than in men or risk factors 

may be managed less aggressively in women than in men.82, 83Adjustment for additional 

risk factors that were not included in most of the analyses in studies in our meta-analysis, 

(HDL cholesterol, triglycerides, exercise, body mass index) or more specific adjustment 

using continuous measures of risk rather than risk categories, might eliminate the 

remaining disparity between men and women. These data suggest that most of the 

observed difference in risk for CHD due to diabetes in men and women is mediated by 

traditional cardiac risk factors that are likely modifiable. 

Four large prospective cohort studies did not meet criteria for inclusion in our metaanalysis.4, 8, 11, 36 These four studies had conflicting results; one showed a higher diabetesassociated relative risk for CHD mortality in men compared to women,36 another showed 

a higher relative risk among women,4 and the two remaining studies found no difference 

between the sexes.8, 11 It is unlikely that the addition of the results of these four studies 

would have changed our summary estimates significantly. The results of one large 

prospective cohort study in the United States was not included, since participants were all 

women.66 In a sensitivity analysis, we added the results of this study to our summary 

estimate for CHD mortality in white women. The resulting summary OR for CHD 

mortality was 2.83 (95% CI, 2.27-3.53), very similar to the summary estimate restricted 

to the results of studies that included both men and women (OR = 2.79; 95% CI, 2.11-

3.69).

It is now recommended that cardiovascular risk factors be treated as aggressively in 

diabetic patients without a history of CHD as in nondiabetic patients with a prior 

myocardial infarction.84 Based on the results of the present review, diabetes 

independently increases the risk of fatal CHD in both men and women without preexisting CHD by 2- to 3-fold. The fact that the summary OR for CHD mortality is 
59

attenuated more with adjustment for major risk factors in women than in men diabetics 

suggests that women with diabetes might benefit more from aggressive risk factor 

management than diabetic men.

As with any systematic review, we are limited to the variables measured and endpoints 

reported in each eligible study. We required that outcomes be adjusted for major CHD 

risk factors, but these variables were defined differently in the studies. Likewise, there 

were differences in definition of outcomes among studies. Some studies differentiated 

patients with impaired glucose tolerance from those with frank diabetes, while others 

included those with impaired glucose tolerance with nondiabetic subjects. Some studies 

did not completely distinguish participants with type 1 diabetes from those with type 2. 

These errors of misclassification may have caused us to underestimate summary ORs. 

Lastly, we were unable to analyze results based on race/ethnicity for most of the 

outcomes due to the absence of studies meeting our inclusion criteria in nonwhite 

populations. 

The advantage of the present systematic review is that it is restricted to the findings of 

studies controlled for age, hypertension, hypercholesterolemia, and smoking. The most 

accurate adjusted summary odds ratio for coronary heart disease mortality due to diabetes 

for all race/ethnic groups combined is 2.3 for men and 2.9 for women. The difference in 

odds ratios between men and women is modest and not statistically significant.

Future Research

Future prospective studies should present sex- and ethnicity-specific fatal and nonfatal 

coronary disease endpoints before and after adjustment with established CHD risk 

factors. Analyzing the effect of specific risk factors separately and in combination will 

help to clarify their role in the cardiovascular protection observed in women without 

diabetes. In addition, much remains to be learned about coronary outcomes among ethnic 

minority groups with diabetes. 
60
61

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67

Chapter 5. Systematic Review of Troponin as a 

Prognostic Factor for CHD in Women

Introduction 

Patients with acute coronary syndromes (defined as myocardial infarction (MI) or 

unstable angina) are at increased risk for subsequent acute myocardial infarction and 

death. Managing patients with known or suspected acute coronary syndromes consumes a 

large amount of resources. Approximately five million people undergo evaluation for 

acute coronary syndromes in emergency departments annually in the United States at an 

estimated cost of over six billion dollars.1 Several tests have been used to identify 

patients at high risk of a major cardiac event, including the electrocardiogram, blood tests 

of proteins (cardiac markers) released with myocardial injury and clinical characteristics 

obtained from the history and physical exam. Several characteristics were recently 

combined in a risk score by the Thrombolysis in Myocardial Infarction (TIMI) study 

group.2 These characteristics include age of 65 or greater, known coronary artery disease, 

at least three risk factors for coronary artery disease (family history, hypertension, 

diabetes, hypercholesterolemia, current smoker), ST-segment deviation of at least 0.5 

mm, recent severe angina, aspirin use in the last seven days and elevated cardiac markers 

(troponin, creatine kinase-MB fraction). In a recently published study based on data from 

Evidence Report Number 31 (Prediction of Risk for Patients with Unstable Angina),3 we 

found that troponin cardiac markers indicate substantial risk for death or subsequent 

myocardial infarction.4

Cardiac troponin immunoassays (troponin T and I) were approved in 1994 by the Food 

and Drug Administration as markers of acute myocardial infarction and risk stratification. 

The troponin complex is comprised of three proteins (C, I, and T) which together regulate 

the contraction of striated muscle (cardiac and non-cardiac). Troponin C binds calcium 

and regulates contraction, troponin I inhibits actomyosin adenosine triphosphatase, and 

troponin T binds the troponin complex to tropomyosin. Because cardiac troponin C has 

the same amino acid sequence as skeletal muscle it is not a specific marker for cardiac 

injury. In contrast, cardiac troponins I and T are easily distinguished from skeletal 

troponin I and T, and the detection of cardiac troponin in serum is highly specific for 

cardiac injury. Both I and T have a small molecular mass and are thus released rapidly 

following cellular injury. They typically are detected four to six hours following injury 

and peak at 12 to 18 hours. Troponin I assays are produced by multiple companies and 

there is no standard threshold for an elevated test. Although the troponin T assay is 

standardized (produced by a single company), there are several generations of assays that 

are progressively more sensitive. The American College of Cardiology currently 

recommends that each lab report a positive troponin if the value is greater than the 99th

percentile for normal controls. 
68

 Although all elevated troponin levels are now considered diagnostic of myocardial 

infarction in the appropriate clinical setting (per the American College of Cardiology and 

European Society of Cardiology), little is known about the prognostic value of an 

elevated troponin level for women. Because women with acute coronary syndromes are 

often older than men, they may be more likely to have congestive heart failure which 

often results in elevated troponin levels independent of acute coronary syndromes. Thus, 

the prognostic value of troponin for women may differ from the value for men.5 One 

recently published study found that women suspected of acute coronary syndromes but 

with a negative troponin test (<0.06 ng/ml) had a very low six month risk (1 percent) of 

future death or myocardial infarction.6 This was not the case for a similar group of men 

whose risk of events was 9 percent in those with a negative troponin test.

Thus we sought to answer the following question:

• What is the impact of troponin on risk for death or myocardial infarction for women 

and men with non-ST elevation acute coronary syndromes?

Women with suspected acute coronary syndromes are often older than men and are likely 

to have more risk factors for coronary disease.6, 7 Thus, it is possible that the prognostic 

value of troponin will be different for men and women. If substantial differences 

between men and women exist, then different risk assessments should be considered for 

men and women.

Methodology

Data Sources

We used the results of a previous search of troponin articles in unstable angina (through 

1999)3 and supplemented this with a second search (through 2002) to identify gender 

specific rates of cardiac outcome (death or myocardial infarction) for patients with nonST elevation acute coronary syndromes with and without elevated troponin levels. 

Because few published studies provided sex specific data, we also contacted a selected 

group of study authors directly. Peer reviewers (Appendix A) were asked to submit 

articles that provide evidence to address the questions.

Search Terms

We searched MEDLINE® (1966-2002) and reviewed cited references of retrieved articles 

to identify relevant published studies. Our search criteria were (1) the text word troponin, 

and (2) the text words angina or unstable or myocardial infarction or ischemia. We also 

performed a search of the EMBASE database from 1990-1998, but did not find any 

additional articles fulfilling the study criteria. We contacted experts in the field of cardiac 

markers to identify large unpublished cohort studies.
69

Inclusion and Exclusion Criteria 

To be included, articles were required to fit the following inclusion criteria:

1) Clinical trial or cohort study

2) Evaluate patients with suspected myocardial ischemia

3) Evaluate the prognostic value of troponin levels in patients with non-ST elevation 

acute coronary syndromes

4) Published between January 1, 1966 and January 30, 2002. 

We excluded studies that only included patients with myocardial infarction. We also 

excluded case-control studies, articles that did not report mortality, and articles with 

followup limited to hospitalization. 

Article Identification

Study selection was performed initially by title review (PAH). Candidate abstracts were 

then reviewed and selected for data retrieval. 

Data Abstraction 

Two independent reviewers abstracted data for each article on standardized electronic 

data forms. A third reviewer compared their results and settled any differences. At least 

one reviewer of the pair had clinical cardiology expertise and one had experience in 

critical appraisal. We recorded the outcomes of nonfatal myocardial infarction and death. 

These were combined to form the outcome of death or myocardial infarction. If outcomes 

at more than one time period were reported, we used the value closest to 30 days 

following presentation. 

Obtaining Unpublished Results 

A number of eligible studies included women in the study population, but did not report 

findings separately by sex. In these instances we attempted to contact authors of all large 

studies (defined as >300 patients or >10 deaths during followup) to obtain this data. We 

contacted ten authors regarding nine studies8-17 and received data from five 

studies.8-10, 12, 13, 16

Quality Assessment

We performed double abstractions for each article. For data obtained directly from 

authors we asked for confirmation of the data we received. We determined if the 

following quality indicators were present for the studies: clear listing of exclusion 

criteria, statement of whether providers were or were not blinded to the troponin results 

(for clinical trials), clear definition of myocardial infarction, classification of death 

outcome as cardiac death or total death. If less than three of these indicators (or the two 

applicable to cohort studies) were present, a study was classified as poor; otherwise it 

was considered to be good quality. 
70

Data Management and Archive

All abstracted and author provided data were entered and stored electronically (EXCEL, 

Microsoft® Corporation). A citation of each article reviewed was archived using 

EndNote® (Niles Software Inc.).

Data Analysis

We used standard random (DerSimonian-Laird) and fixed (Peto) effects methods to 

estimate summary odds ratios for the outcomes of death and myocardial infarction.18, 19

Because both fixed and random-effects summary estimates were similar, we report only 

the random-effects results. For studies with no events in a patient group, we added 0.5 to 

each cell of the study for the random-effects calculation. We tested homogeneity of 

study effect size using a standard Chi-square test with the Q statistic.19 Summary 

estimates for men and women were compared using the z statistic. Data are presented as 

summary odds ratios with 95% confidence intervals, with two-tailed P-values and 

statistical significance set at P < 0.05.

Results 

Results of study identification 

A total of 1,049 articles were identified with the MEDLINE® and EMBASE databases 

and citation reviews. We excluded 878 articles based on title or abstract because they did 

not evaluate the prognostic value of troponin in patients with non-ST elevation acute 

coronary syndromes. The remaining 171 articles were retrieved and reviewed, and 78 of 

these articles met all of the inclusion/exclusion criteria. 

Eligible articles were then reviewed to determine whether they reported relevant data for 

women. Only three of the 78 articles reported sex and troponin specific outcomes of 

death or myocardial infarction following hospitalization. The three included studies 

reported data for 407 women and 774 men. 

Since so few studies reported data for an analysis of prognostic value of troponin by sex, 

we contacted the authors of the nine largest of the 78 studies to request outcomes data 

partitioned by sex and troponin test results. We obtained unpublished gender specific 
71

data for 2,762 women and 3,296 men from the authors of five of the nine large 

studies. 8-10, 12, 13, 16 Two investigators reported on different topics for the same 

population.10, 16

Patient Characteristics 

Patient characteristics are displayed by sex in Evidence Table 13. Women were 

consistently older than men. Women were less likely to be smokers and have a history of 

myocardial infarction, but were more likely to have hypertension and diabetes than men.

Study Report Characteristics

Evidence Table 14 shows characteristics of the studies and the source of data used in the 

analysis (i.e., abstraction of data from publication or supplied directly by a study author). 

Most studies used the highest troponin value to determine if the threshold was reached. 

The thresholds used for troponin T ranged from 0.1 to 0.2 ng/ml. The majority of studies 

were clinical trials where the troponin evaluation was a sub-study. 

Quality of Study Reports

All eight included studies were rated as “good” quality. One study did not clearly list 

exclusion criteria.20 All trials noted that health care providers were blinded to the 

troponin results. All studies stated how myocardial infarction was defined and all 

reported whether deaths referred to total or cardiac deaths. 

Findings

Troponin Values

The frequency of elevated troponin and outcomes for women and men for each study are 

listed in Evidence Tables 15 and 16. Among 3,169 women, troponin was elevated in 

1,118 (35 percent). This value ranged from 18 percent in the 1998 study report by 

Antman9 to 49 percent for the study by Safstrom.6 Among 4,070 men, the troponin was 

elevated in 1,571 (39 percent). This value ranged from 18 percent in the study by 

Galvani21 to 64 percent for the study by Safstrom.6

Death

There were 103 deaths among 3,169 women (3.3 percent). Among 2,051 women with a 

negative troponin, 42 died (2.0 percent) compared to 61 (5.5 percent) who died following 

a positive troponin value (Figure 1). There were 129 deaths among 4,070 men (3.2 

percent). Among 2,499 men with a negative troponin, 47 died (1.9 percent) compared to 

82 (5.2 percent) who died following a positive troponin value (Figure 2). The summary 

odds ratio for death with an elevated troponin was 2.63 (95 % CI 1.75-3.95) for women 

and 2.83 (95% CI 1.92-4.17) for men (p=0.8 for difference in odds ratio between men 

and women).
72

Death or Myocardial Infarction

There were 256 deaths or nonfatal myocardial infarctions among 3,169 women (8.1 

percent). Among women with a negative troponin, 117 died or had a myocardial 

infarction (5.7 percent) compared to 139 (12.4 percent) who died or had a myocardial 

infarction following a positive troponin value (Figure 3). There were 366 deaths or 

myocardial infarctions among 4,070 men (9.0 percent). Among men with a negative 

troponin, 180 died or had a myocardial infarction (7.2 percent) compared to 186 (11.8 

percent) who died or had a myocardial infarction following a positive troponin value 

(Figure 4). The summary odds ratio for the combined endpoint of death or MI for patients 

with an elevated troponin was for 2.16 (95% CI 1.65-2.81) women and 1.50 (95% CI 

1.20-1.88) for men (p=0.04 for difference in odds ratio between men and women).

Nonfatal Myocardial Infarction

There were 153 nonfatal myocardial infarctions among 3,169 women (4.8 percent). 

Among women with a negative troponin, 75 had a nonfatal myocardial infarction (3.7 

percent) compared to 78 (7.0 percent) who had a nonfatal myocardial infarction 

following a positive troponin value (Figure 5). There were 237 nonfatal myocardial 

infarctions among 4,070 men (5.8 percent). Among men with a negative troponin, 133 

had a nonfatal myocardial infarction (5.3 percent) compared to 104 (6.6 percent) who had 

a nonfatal myocardial infarction following a positive troponin value (Figure 6). The odds 

ratio for death with an elevated troponin was for 1.80 (95% CI 1.28-2.54) women and 

1.06 (95% CI 0.8-1.41) for men (p=0.02 for difference in odds ratio between men and 

women).

Comparisons Between Men and Women

The summary odds ratios for death (Figure 7), death or myocardial infarction (Figure 8) 

and nonfatal myocardial infarction (Figure 9) were computed separately for women and 

men. There was no significant heterogeneity (p<0.05) for any of the six summary 

estimates (three per gender). These results show that women and men had a similar 

increase in risk of death associated with a positive troponin. However, the relationship 

between death or myocardial infarction and elevated troponin was stronger for women 

(p=0.05). This was due to a stronger risk of nonfatal myocardial infarction with a positive 

troponin for women than for men (p=0.02).
73

Conclusions

Few published data are available comparing the prognostic value of troponin for men and 

women. Although many analyses of troponin have included a large number of women, 

we identified only three studies that reported sex specific outcome data. Because several 

of the investigators from the larger studies provided sex specific data, we were able to 

calculate a more robust estimate of the impact of troponin on outcome for men and 

women.

Our study is consistent with prior investigations that found that women with acute 

coronary syndromes are older and have more comorbidities (hypertension, diabetes) than 

men. In addition, we found that women were less likely to have a prior history of 

myocardial infarction and less likely to be smokers. Unlike other studies we found that 

the frequency of elevated troponin levels was similar for men and women. 

We found that the prognostic value of troponin for predicting death was the same for both 

men and women (odds ratio near 3). However, for the combined outcome of death or MI, 

troponin had greater prognostic value in women than men. This was due to a smaller 

number of nonfatal myocardial infarctions in troponin negative women than troponin 

negative men. 

How does one reconcile the similar troponin prognostic value for death but a difference 

in prognostic value for nonfatal MI? One possibility is that men and women are treated 

differently. In the study by Safstrom,6 low risk women (troponin <0.06 ng/ml) were less 

likely to undergo revascularization with percutaneous coronary interventions or bypass 

grafting than men (22 percent vs. 46 percent, p<0.01). However for higher levels of 

troponin, the rate of revascularization in men and women was similar. In fact, 

revascularization was more common for women than for men (though not significantly) 

with a troponin value >= 0.2 ng/ml (39 percent vs. 36 percent). If revascularization is 

frequently complicated by small myocardial infarctions, there will be more nonfatal 

myocardial infarctions in men than in women due to higher rates of revascularization in 

men, yet fatal events would be similar. Unfortunately, we do not have data on 

revascularization by gender and troponin level for most of the included studies. 

Another possibility is that men are at an increased risk for nonfatal myocardial infarction 

(but not fatal infarction) compared to women. Men are known to have more severe 

coronary artery disease than women among those presenting with chest pain. Men may 

be more likely to develop myocardial infarction at a site unrelated to the culprit lesion 

responsible for the initial coronary syndrome. These infarctions would not be preceded 

by a positive troponin level. Our findings could be explained if these new infarctions are 

more likely to be survived than the initial coronary syndrome. If men are simply at 

higher risk of events in general, we would have expected to observe similar gender 

specific risk with elevated troponin for death and nonfatal myocardial infarction.
74

Our ability to observe differences between men and women in their risk associated with 

an elevated troponin would not have been possible without the data provided directly 

from authors of past studies. Less than a third of the patients’ data used in the analysis 

were available from published studies. Because each study had limited power to detect 

differences between men and women, the authors may be reluctant to use limited 

resources to analyze and publish inconclusive sub-group data. Thus, obtaining data 

directly from authors is often critical to determine results for sub-populations. 

Limitations

Although we observed a difference between men and women in the relationship between 

troponin and risk of nonfatal myocardial infarction, the cause of this difference could not 

be determined. The borderline statistical significance indicates that this difference may 

have occurred by chance.

Future Research

Future studies will be needed to verify and explore possible causes for the finding that 

troponin results prognosticate nonfatal MI differently in women compared to men. In 

addition, authors should be encouraged to report outcomes data by sex and ethnic subgroups or to make these analyses easily available.
75

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9.
Evidence Table 1. Diagnostic Testing: Characteristics of studies of exercise myocardial perfusion imaging

Reference Total N 

(% women)

Mean age 

(years)

Prior MI

N (% 

women)

Radionuclide Definition of 

abnormal test 

Definition of 

CHDa (%)

Exercise Qualityb

Kiat et al, 199023 53 (26) 56 24 (NA) MIBI Fixed or 

reversible PD

50 Treadmill Fair

Van Train et al, 199041 371 (14) NA 130 (NA) TI PD at rest or 

after exercise

50 Treadmill Fair

Gupta et al, 199217 93 (17) 58 37 (NA) TI Fixed or 

reversible PD

50 Treadmilll Fair

Sciammarella et al, 

199247

56 (20) 55 42 (45) MIBI Fixed or 

reversible PD

50 Treadmill Good

Chae et al, 199344 243 (100) 62 102 (42) TI PD at rest or 

after exercise

50 Treadmill Good

Mak et al, 199548 139 (18) 51 90 (NA) MIBI Fixed or 

reversible PD

50 Treadmill Good

Hambye et al, 199618 123 (31) 0 (0) MIBI Fixed or 

reversible PD

50 Bicycle Fair

Laurienzo et al, 

1997

45

82 (100) 51 NA (NA) TI Fixed or 

reversible PD

70 or 50 LM Treadmill Good

Taillefer et al, 1997648 (100) 58 8 (17) TI & MIBI Decreased 

uptake at rest 

or after 

exercise

50 Treadmill Fair

Astarita et al, 199846 41 (48) 59 0 (0) TI Reversible 

uptake defects 

in > 2/22 

segments

50 Bicycle Fair

N, number; MI, myocardial infarction; CHD, coronary heart disease; NA, not available; TI, thallous chloride TI 201 (thallium); PD, perfusion defect; MIBI, technetium Tc 99m sestamibi; 

LM, left main coronary artery

aPercent stenosis of any one major coronary artery at or above this cut-off used to define angiographic evidence of coronary disease.

b Quality classification described in section on quality assessment.

Note: Superscripted numbers correspond with citations on reference list for Chapter 2.

91
Evidence Table 2. Diagnostic Testing: Characteristics of studies of exercise echocardiography

Reference Total N 

(% women)

Mean age 

(years)

Prior MI

N (% 

women)

Definition of 

abnormal test

Definition of 

CHD (%)a

Exercise 

Used

Qualityb

Williams et al, 199449 70 (100) 60 0 (0) New or worse 

RWMA after 

exercise

50 Bicycle Good

Marwick et al, 19952161 (100) 60 0 (0) RWMA at rest 

or after exercise

50 Treadmill & 

bicycle

Fair

Luotolahti et al, 199624 118 (15) 55 57 (39) New or worse 

RWMA after 

exercise

50 Bicycle Fair

Roger et al, 199750 340 (28) 66 0 (0) RWMA at rest 

or after exercise

50 Treadmill Good

N, number; MI, myocardial infarction; CHD, coronary heart disease; RWMA, regional wall motion abnormality

a

 Percent stenosis of any one major coronary artery at or above this cut-off used to define angiographic evidence of coronary disease.

b Quality classification described in section on quality assessment.

Note: Superscripted numbers correspond with citations on reference list for Chapter 2.

92
Evidence Table 3. Diagnostic Testing: Findings of studies of exercise myocardial perfusion imaging and summary

estimates of accuracy.

Women Men

Reference Sensitivity

(95% CI)

Specificity

(95% CI)

LR+

 (95% CI)

LR-

 (95% CI)

Sensitivity

(95% CI)

Specificity

(95% CI)

LR+

 (95% CI)

LR-

 (95% CI)

Kiat et al, 199023 1.00

(0.72-1.00)

0.67

(0.09-0.99)

3.00

(0.82-11.00) a

0.92

(0.78-0.98)

0.50

(0.01-0.99)

1.84

(0.58-5.86)

0.16

(0.03-0.75)

Van Train et al, 199041 0.95

(0.83-1.00)

0.62

(0.32-0.87)

2.47

(1.27-4.82)

0.08

(0.02-0.30)

0.95

(0.92-0.97)

0.43

(0.29-0.58)

1.67

(1.31-2.13)

0.12

(0.06-0.22)

Gupta et al, 199217 0.85

(0.55-0.99)

0.67

(0.09-0.99)

2.54

(0.68-9.46)

0.23

(0.06-0.92)

0.81

(0.69-0.90)

0.86

(0.57-0.99)

5.67

(1.78-18.1)

0.22

(0.12-0.39)

Sciammarella et al, 

199247

1.00

(0.54-1.00)

0.40

(0.05-0.96)

1.67

(0.81-3.43) a

0.95

(0.83-1.00)

0.33

(0.04-0.78)

1.42

(0.80-2.51)

0.15

(0.03-0.75)

Chae et al, 199344 0.71

(0.63-0.78)

0.65

(0.54-0.75)

2.03

(1.47-2.79)

0.44

(0.33-0.59) b b b b

Mak et al, 199548 0.83

(0.62-0.95)

1.00

(0.02-1.00)

0.17

(0.05-0.55) b b b b

Hambye et al, 199618 0.61

(0.39-0.80)

0.67

(0.39-0.89)

1.83

(0.85-3.93)

0.59

(0.30-1.10)

0.94

(0.85-0.99)

0.82

(0.60-0.95)

5.15

(2.20-12.0)

0.08

(0.03-0.20)

Laurienzo et al, 

199745

0.86

(0.65-0.97)

0.80

(0.68-0.89)

4.32

(2.53-7.37)

0.17

(0.06-0.46) b b b b

Taillefer et al, 19976

 (using sestamibi)

(using thallium)

0.72

(0.53-0.86)

0.75

(0.57-0.89)

0.81

(0.54-0.96)

0.50

(0.25-0.50)

3.83

(1.44-10.2)

1.50

(0.89-2.54)

0.35

(0.19-0.64)

 0.50

 (0.23-1.07)

b

b

b

b

b

b

b

b

93
Evidence Table 3. Diagnostic Testing: Findings of studies of exercise myocardial perfusion imaging and summary

estimate s of accuracy. (continued)

Women Men

Reference Sensitivity

(95% CI)

Specificity

(95% CI)

LR+

 (95% CI)

LR-

 (95% CI)

Sensitivity

(95% CI)

Specificity

(95% CI)

LR+

 (95% CI)

LR-

 (95% CI)

Astarita et al, 199846 1.00

(0.29-1.00)

0.47

(0.23-0.72)

1.89

(1.05-3.39)

a

1.00

(0.77-1.00)

0.50

(0.16-0.84)

2.00

(1.02-3.92)

a

SUMMARY 

All eligible studiesc

Good quality 

studies

Studies including 

men and women

0.77

(0.72-0.83)

0.75

(0.69-0.81)

0.86

(0.77-0.92)

0.69

(0.62-0.75)

0.71

(0.69-0.78)

0.57

(0.43-0.70)

2.46

(2.00-3.04)

2.54

(1.95-3.32)

2.01

(1.46-2.76)

0.33

(0.26-0.41)

0.36

(0.28-0.46)

0.24

(0.14-0.42)

0.93

(0.90-0.95)

d

0.93

(0.90-0.95)

0.57

(0.47-0.67)

d

0.57

(0.47-0.67)

2.17

(1.73-2.73)

d

2.17

(1.73-2.37)

0.13

(0.09-0.19)

d

0.13

(0.09-0.19)

CI, confidence interval; LR+, likelihood ratio for a positive test; LR- likelihood ratio for a negative test

a Estimates not calculable because sensitivity or specificity = 100%.

bEstimates not available because these studies did not include men.

c

Includes results from the study by Taillefer for sestamibi.6

dEstimates not available because only one good quality study included men.

Note: Superscripted numbers correspond with citations on reference list for Chapter 2.

94
Evidence Table 4. Diagnostic Testing: Summary estimates of accuracy of myocardial perfusion imaging from studies using sestamibi 

compared to studies using thallium

Women Men 

Radionuclide Sensitivity

(95% CI)

Specificity

(95% CI)

LR+

 (95% CI)

LR-

(95% CI)

Sensitivity

(95% CI)

Specificity

(95% CI)

LR+

 (95% CI)

LR-

(95% CI)

Sestamibi6, 18, 23, 47, 48 0.77

(0.67-0.85)

0.70

(0.53-0.83)

2.57

(1.58-4.17)

0.33

(0.22-0.50)

0.94

(0.89-0.97)

0.70

(0.51-0.85)

3.12

(1.82-5.37)

0.09

(0.05-0.18)

Thallium6, 17, 41, 44-46 0.77

(0.72-0.82)

0.67

(0.60-0.74)

2.32

(1.87-2.88)

0.34

(0.27-0.44)

0.92

(0.89-0.95)

0.52

(0.40-0.64)

1.93

(1.51-2.46)

0.14

(0.09-0.22)

CI, confidence interval; LR+ = likelihood ratio for a positive test; LR- = likelihood ratio for a negative test

Note: Superscripted numbers correspond with citations on reference list for Chapter 2.

95
Evidence Table 5. Diagnostic Testing: Findings of studies of exercise echocardiography and summary estimates of accuracy

Women Men

Reference Sensitivity

(95% CI)

Specificity

(95% CI)

LR+

 (95% CI)

LR-

 (95% CI)

Sensitivity

(95% CI)

Specificity

(95% CI)

LR+

 (95% CI)

LR-

(95% CI)

Williams et al, 199449 0.88

(0.72-0.97)

0.84

(0.68-0.94)

5.42

(2.62-11.2)

0.14

(0.06-0.35) a a a a

Marwick et al, 199520.80

(0.68-0.89)

0.81

(0.72-0.88)

4.28

(2.79-6.57)

0.25

(0.15-0.42) a a a a

Luotolahti et al, 199624 0.77

(0.46-0.95)

0.80

(0.28-0.99)

3.85

(0.91-16.4)

0.29

(0.10-0.82)

0.96

(0.90-0.99)

0.60

(0.14-0.95)

2.39

(0.91-6.29)

0.07

(0.02-0.22)

Roger et al, 199750 0.79

(0.66-0.89)

0.37

(0.22-0.54)

1.26

(0.95-1.67)

0.56

(0.32-1.08)

0.78

(0.71-0.84)

0.44

(0.30-0.59)

1.39

(1.07-1.80)

0.50

0.33-0.76)

SUMMARY 

All eligible studies

Good quality 

studies

Studies including 

men and women

0.81

(0.74-0.87)

0.82

(0.73-0.89)

0.79

(0.68-0.88)

0.73

(0.66-0.79)

0.60

(0.48-0.71)

0.42

(0.27-0.58)

2.95

(2.28-3.79)

2.06

(1.53-2.77)

1.36

(1.02-1.81)

0.26

(0.19-0.36)

0.29

(0.18-0.47)

0.50

(0.28-0.89)

0.84

(0.79-0.88)

b

0.84

(0.79-0.88)

0.45

(0.32-0.59)

b

0.45

(0.32-0.59)

1.54

(1.20-1.98)

b

1.54

(1.20-1.98)

0.36

(0.24-0.53)

b

0.36

(0.24-0.53)

CI, confidence interval; LR+ = likelihood ratio for a positive test; LR- = likelihood ratio for a negative test

aEstimates not available because these studies did not include men.

bEstimates not available because only one good quality study included men and women.

Note: Superscripted numbers correspond with citations on reference list for Chapter 2.

96
Evidence Table 6. Lipids: Characteristics of Included Clinical Trials 

Study Name,

Year

N Women/

Total

(% Women)

Mean Age 

of Women

Percent 

with CHDa

Lipid Entry 

Criterion

Intervention Mean Follow 

Up

(years)

Outcomes 

in Women

Quality

Ratingb

Scottish Society 

of Physicians,

197129

124/717

(17)

54 100% None Clofibrate 6 CHD mortality

nonfatal MI

Fair

Newcastle Upon 

Tyne, 197130

97/497

(20)

54 100% None Clofibrate 5 CHD mortality

nonfatal MI

Fair

Colestipol Study,

197831

1184/2278

(52)

57 20% TC >250 mg/dl Colestipol 3 total mortality 

CHD mortality

Fair

4S, 19947, 32, 33 827/4444

(19)

61 100% TC 213-309 mg/dl Simvastatin 5.4 total mortality 

CHD mortality

nonfatal MI

revascularization

CHD eventsc

Good

ACAPS, 199425, 26 441/919

(48)

61 0% LDL 130-159 

mg/dl with any 

number of risk 

factors; LDL 160-

189 mg/dl with no 

or one risk factor

Lovastatin 2.8 total mortality 

CHD mortality

nonfatal MI

Good

PLAC II, 199416 22/151

(15)

NA 100% LDL in 60-90th

percentile for age 

and gender

Pravastatin 3 total mortality 

CHD mortality

nonfatal MI

Good

CARE, 19988, 34, 35 576/4159

(14)

61 100% TC <240 mg/dl 

and LDL-C 115-

174 mg/dl

Pravastatin 5 total mortality 

CHD mortality

nonfatal MI

revascularization

CHD eventsc

Good

LIPID, 199827, 36, 

37

1516/9014

(17)

62 100% TC 155-271 mg/dl Pravastatin 6.1 CHD eventsc Good

97
Evidence Table 6. Lipids: Characteristics of Included Clinical Trials (continued)

Study Name,

Year

N Women/

Total

(% Women)

Mean Age 

of Women

Percent 

with CHDa

Lipid Entry 

Criterion

Intervention Mean Follow 

Up

(years)

Outcomes 

in Women

Quality

Ratingb

AFCAPS/

TEXCAPS, 19989, 

38

997/6605

(15)

62 0% TC 180-264 mg/dl

LDL 130-190 

mg/dl and HDL 

<47 mg/dl

Lovastatin 5.2 total mortality 

CHD mortality

nonfatal MI

revascularization

CHD eventsc

Good

HPS, 200211 5082/20,536

(25)

NA 65% TC >135 mg/dl Simvastatin 5 CHD eventsc Good

ALLHAT, 200239 5051/10,355

(49)

NA 14% LDL 100-189 

mg/dl

Pravastatin 4.8 total mortality

CHD eventsc

Fair

4S, Scandinavian Simvastatin Survival Study; ACAPS, Asymptomatic Carotid Artery Progression Study; PLAC II, Pravastatin, Lipids and Atherosclerosis in the Carotid Arteries; CARE, 

Cholesterol and Recurrent Events trial; LIPID, Long-term Intervention with Pravastatin in Ischaemic Disease; AFCAPS/TEXCAPS, Air Force/Texas Coronary Atherosclerosis 

Prevention Study; HPS, Heart Protection Study; ALLHAT, Antihypertensive and Lipid-Lowering Treatment to Prevent heart Attack Trial.

N, number; CHD, coronary heart disease; mg/dl, milligrams per deciliter; MI, myocardial infarction; NA, not available; CVD, cardiovascular disease; TC total cholesterol; LDL, low 

density lipoprotein

aCHD defined as history of myocardial infarction or angina.

b

see Quality Assessment section in text.

c CHD events in, CARE, LIPID and ALLHAT defined as CHD mortality or nonfatal MI; in 4S as CHD mortality, non fatal MI or resuscitated cardiac arrest and in AFCAPS as CHD 

mortality, nonfatal MI or unstable angina or sudden cardiac death; in HPS as CHD mortality, nonfatal MI, stroke or revascularization.

Note: Superscripted numbers correspond with citations on reference list for Chapter 3

98
99

Evidence Table 7. Lipids: Outcomes of Eligible Studies

Outcome Study RR (95% CI)

Secondary Prevention 

Total Mortality 4S7, 32, 33

PLAC II16

1.11

1.18

(0.66, 1.5)

(0.03, 54.81)

CHD Mortality Scottish Society of Physicians29

Newcastle Upon Tyne30

4S7, 32, 33

PLAC II16

CARE8, 34, 35

0.17

0.20

0.79

1.18

0.80

(0.02, 1.34)

(0.04, 1.13)

(0.39, 1.6)

(0.03, 54.81)

(0.61, 1.05)

Nonfatal MI Scottish Society of Physicians29

Newcastle Upon Tyne30

4S7, 32, 33

PLAC II16

CARE8, 34, 35

0.75

0.43

0.66

1.18

0.51

(0.42, 1.33)

(0.08, 2.25)

(0.48, 0.90)

(0.48, 54.81)

(0.27, 0.94)

CHD eventsa4S7, 32, 33

CARE8, 34, 35

LIPID27, 36, 37

HPS11

0.68

0.60

0.87

0.81

(0.51, 0.91)

(0.37, 0.97)

(0.67, 1.13)

(0.72, 0.92)

Revascularizaion 4S7, 32, 33

CARE8, 34, 35

0.52

0.82

(0.31, 0.86)

(0.64, 1.20)

Primary Prevention 

Total Mortality Colestipol31

ACAPS25, 26

AFCAPS/TEXCAPS9, 38

ALLHAT39

0.92

0.09

1.53

0.98

(0.51, 1.69)

(0.01, 1.7)

(0.62, 3.81)

(0.83, 1.17)

CHD Mortality Colestipol31

ACAPS25, 26

AFCAPS/TEXCAPS9, 38

1.08

0.35

2.99

(0.44, 2.63)

(0.01, 8.47)

(0.12, 73.3)

Nonfatal MI ACAPS25, 26

AFCAPS/TEXCAPS9, 38

0.35

0.69

(0.04, 3.31)

(0.21, 2.28)

CHD eventsaAFCAPS/TEXCAPS9, 38

ALLHAT39

0.54

1.02

(0.22, 1.34)

(0.81, 1.28)

Revascularization AFCAPS/TEXCAPS9, 38 0.87 (0.33,2.31)

CHD, coronary heart disease; CI, confidence interval; MI, myocardial infarction; NA not available; RR, relative 

risk; 4S, Scandinavian Simvastatin Survival Study; ACAPS, Asymptomatic Carotid Artery Progression 

Study; PLAC II, Pravastatin, Lipids and Atherosclerosis in the Carotid Arteries; CARE, Cholesterol and 

Recurrent Events trial; LIPID, Long-term Intervention with Pravastatin in Ischaemic Disease; 

AFCAPS/TEXCAPS, Air Force/Texas Coronary Atherosclerosis Prevention Study; HPS, Heart Protection 

Study; ALLHAT, Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial.

aCHD events in CARE, LIPID and ALLHAT defined as CHD mortality or nonfatal MI; in 4S as CHD mortality, non fatal MI or 

resuscitated cardiac arrest; in AFCAPS as CHD mortality, nonfatal MI, unstable angina or sudden cardiac death, and in HPS as 

CHD mortality, nonfatal MI, stroke or revascularization. 

Note: Superscripted numbers correspond with citations on reference list for Chapter 3.
100

Evidence Table 8. Lipids: Summary Results

Outcome Secondary Prevention

 References RR (95% CI)

Primary Prevention

 References RR (95% CI)

Total mortality

All studies

 Statin drugs

 Good quality

7, 16, 32, 33

7, 16, 32, 33

7, 16, 32, 33

1.11 (0.66 1.87)

1.11 (0.66 1.87)

1.11 (0.66 1.87)

9, 25, 26, 31, 38, 39

9, 25, 26, 38, 39

9, 25, 26, 38

0.95 (0.62, 1.46)

0.87 (0.37, 2.00)a

0.45 (0.03, 7.00)a

CHD mortality

All studies

 Statin drugs

 Good quality

7, 8, 16, 29, 30, 32-35

7, 8, 16, 32-35

7, 8, 16, 32-35

0.74 (0.57, 0.96)

0.78 (0.60, 1.01)

0.78 (0.60, 1.01)

7, 16, 32, 33

7, 16, 32, 33

7, 16, 32, 33

1.07 (0.47, 2.40)

1.02 (0.11, 9.76)

1.02 (0.11, 9.76)

Nonfatal MI

All studies

Statin drugs

Good quality

7, 8, 16, 29, 30, 32-35

7, 8, 16, 32-35

7, 8, 16, 32-35

0.64 (0.50, 0.82)

0.63 (0.48, 0.83)

0.63 (0.48, 0.83)

9, 25, 26, 38

9, 25, 26, 38

9, 25, 26, 38

0.61 (0.22, 1.68)

0.61 (0.22, 1.68)

0.61 (0.22, 1.68)

CHD eventsb

All studies

Statin drugs

Good quality

7, 8, 11, 27, 32-37

7, 8, 11, 27, 32-37

7, 8, 11, 27, 32-37

0.79 (0.72, 0.88)

0.79 (0.72, 0.88)

0.79 (0.72, 0.88)

9, 38, 39

9, 38, 39

9, 38

0.87 (0.50, 1.49)

0.87 (0.50, 1.49)

0.54 (0.22, 1.30)

Revascularization

All studies

Statin drugs

Good quality

7, 8, 32-35

7, 8, 32-35

7, 8, 32-35

0.70 (0.42, 1.16)a

0.70 (0.42, 1.16)a

0.70 (0.42, 1.16)a

9, 38

9, 38

9, 38

0.87 (0.33,2.31)c

0.87 (0.33,2.31)c

0.87 (0.33,2.31)c

RR, relative risk; CI, confidence interval; CHD, coronary heart disease; MI, myocardial infarction; statin drugs included lovastatin, 

pravastatin or simvastatin; good quality is defined in the methods section.

aP-value for heterogeneity <0.10

b

 CHD events in CARE, LIPID and ALLHAT defined as CHD mortality or nonfatal MI; in 4S as CHD mortality, non fatal MI or 

resuscitated cardiac arrest; in AFCAPS as CHD mortality, nonfatal MI, unstable angina or sudden cardiac death, and in HPS as 

CHD mortality, nonfatal MI, stroke or revascularization. See Tables 1 and 2 for full names of studies.

cOnly one trial provided data on this outcome9, 38

Note: Superscripted numbers correspond with citations on reference list for Chapter 3.
Evidence Table 9. Diabetes: Characteristics of studies of coronary heart disease risk in diabetics vs. nondiabetic subjects

Mean Number of Subjects

Quality Followup Mean Age Diabetic Nondiabetic

Source Study Name or Location Score (years) (Range), y M F M F

Barrett-Connor et al, 70

1991a Rancho Bernardo, CA good 14.4 63(50-89) 207 127 893 1244 

Collins et al, 71

 1996 Asian Indian, Fiji fair 11 20+ 102 129 1077 1236

Fujimoto et al, 16, 17

 1987, 1991 King County, WA fair NA 62- 64 78 52 79 72

Howard et al, 21

 1995 Strong Heart Study fair 4.8 55-57 797 1412 1049 1291

Jousilahti et al, 72

 1999 WHO-MONICA fair 7-12 25-64 262 254 6828 7442

Keil et al, 73

 1993 Charleston Heart Study fair 30 50(35-74) 30 42 956 1153

Kleinman et al, 74

 1988 NHANES I fair 9 57,63b(40-77) 189 218 3151 3823

Lindeman et al, 19

 1998 Bernalillo County, NM fair NA > 65 115 73 330 321

101
Evidence Table 9. Diabetes: Characteristics of studies of coronary heart disease risk in diabetics vs. nondiabetic subjects (continued)

Mean Number of Subjects

Quality Followup Mean Age Diabetic Nondiabetic

Source Study Name or Location Score (years) (Range), y M F M F

Lowe et al, 75

 1997a and 

Pan et al, 761986a Chicago, IL fair 9-22 45,52b(35-64) 926 170 7975 7860

Niskanen et al, 15

 1998 Finland-Kuopio fair 15 55(45-64) 70 63 62 82

Rewers et al, 18

 1992 San Luis Valley, CO fair NA 25-74 186 521 243 571

Scheidt-Nave et al, 77

1990a Rancho Bernardo, CA good 14.4 50-89 159 157 591 732

Sievers et al, 20

 1998 Gila River, AZ fair 12.1 > 15 630 813 1542 1552

Vilbergsson et al, 12

 1998 Reykjavik Study good 17 52(34-79) 267 210 8861 9549

Wei et al, 78

 1998 San Antonio Heart Study fair 7.5 43,53b (25-64) 190 281 1910 2494

CI indicates confidence interval; NA indicates not available; WHO-MONICA indicates World Health Organization-Monitoring of Trends and Determinants in Cardiovascular Disease; 

NHANES I indicates National Health and Nutrition Examination Survey I

aDuplicate publication, but separate outcomes or subgroups reported in each article.

bValues represent mean age for nondiabetic and diabetic subjects, respectively.

Note: Superscripted numbers correspond with citations on reference list for Chapter 4.

102
Evidence Table 10. Diabetes: Adjusted odds ratios (95% confidence intervals) for coronary heart disease mortality, 

 nonfatal myocardial infarction (NFMI), and all-cause mortality by sex

Source Race/

Ethnicity

CHD Mortality

Male Female

OR (95% CI)

Nonfatal MI

Male Female

 OR (95% CI)

All-Cause Mortality

Male Female

 OR (95% CI)

Barrett-Connor, 701991 W 1.9(1.3-2.8) 3.3(2.0-5.6)

Scheidt-Nave, 771990 W 1.3 (0.8-2.1) 1.8 (1.0-3.0)

Collins, 711996 I

Me

3.2(1.3-2.0)

1.6(0.4-6.0)

20.7 (2.5-171)

5.4(1.2-24.3)

4.4 (2.7-6.9)

1.3 (0.7-2.5)

3.1 (1.7-5.8)

2.3 (1.2-4.6)

Fujimotoa, 

161987 JA 2.1 (1.3-3.3)

Fujimotoa, 

171991 JA 1.2 (0.8-1.9)

Howarda, 

211995 NA 1.59 (.74-3.21) 7.11(2.24-

22.58)

Jousilahti, 721999 W 2.4 (1.6-3.4) 4.3 (2.4-7.6)

Keil, 731993 W

B

0.8 (0.5-2.4)

2.5(0.3-18.7)

1.3 (0.4-4.5)

2.0 (0.9-4.5)

1.2 (0.7-2.0)

3.1 (1.4-7.2)

2.2 (1.1-4.2)

1.8 (1.1-2.8)

Kleinman,741988 W 2.8 (2.0-3.8) 2.5 (1.6-3.8) 2.3 (1.8-2.8) 2.0 (1.6-2.6)

Lindemana, 

191998 W 3.4 (1.2-5.5) 3.6 (1.3-10)

Lindemana, 191998 L 1.7 (0.9-3.3) 1.4 (0.5-3.7)

Lowe, 751997

Pan, 761986

W

B

W 3.8 (1.7-8.4) 4.7 (1.9-11.9)

1.9 (1.6-2.2)

1.8 (1.0-3.3)

Niskanena, 

151998 W 5.4(1.7-14.7) 5.2(1.8-15)

Rewers a, 

181992 W

L

1.7 (1.0-2.8)

0.9 (0.5-1.4)

2.7 (1.5-4.7)

1.4 (0.9-2.1)

Sieversa, 

201992 P 5.3 (2.2-13) 6.3 (0.8-50) 1.8 (1.4-2.4) 1.4 (1.0-2.0)

Vilbergsson, 121998 W 2.0 (1.5-2.6) 2.2 (1.7-2.8) 1.9 (1.6-2.3) 1.7 (1.3-2.1)

Wei, 781998 M 2.1 (1.3-3.5) 3.2 (1.9-5.4)

 

aMultivariate results received via personal communication with authors; OR indicates odds ratio; CI indicates confidence interval; W=white, B=black, I=East Indian, Me=Melanesian, 

 JA=Japanese- American, L=Latino, P=Pima Indian, M=multiple races, INA=Native American

 Note: Superscripted numbers correspond with citations on reference list for Chapter 4. 103
Evidence Table 11. Diabetes: Summary odds ratios for coronary heart disease (CHD) mortality, 

 nonfatal myocardial infarction (NFMI), and all-cause mortality by sex (comparing diabetics to nondiabetics) 

Outcome Men

Summary OR

(95%CI)

Women

Summary OR

(95%CI)

References p-valuea

 

 

OR indicates odds ratio; CI indicates confidence interval.

 aP Value for comparison of odds ratio estimates between men and women.

 bP Value for heterogeneity < .10.

 Race-ethnicity groups with only one study (n=1), were not meta-analyzed.

 Note: Superscripted numbers correspond with citations on reference list for Chapter 4.

CHD Mortality: (n=8) 2.33 (1.91-2.85) 2.92 (2.22-3.84) 12, 20, 70-74, 76 0.19

White (n=6) 2.22 (1.79-2.75) 2.79 (2.11-3.69) 12, 70, 72-74, 76 0.20

Black (n=1) 2.5 (0.3-18.7) 2.0 (0.9-4.5) 73 0.87

East Indian (n=1) 3.2 (1.3-2.0) 20.7 (2.5-171) 71 0.11

Melanesian (n=1) 1.6 (0.4-6.0) 5.4 (1.2-24.3) 71 0.24

Pima India (n=1) 5.3 (2.2-13) 6.3 (0.8-50) 20 0.88

Nonfatal MI: (n=5) 1.55 (1.11-2.17)b1.70 (1.27-2.28) 16-19, 21, 77 0.68

 White (n=3) 1.65 (1.06-2.56) 2.29 (1.59-3.30) 18,19,77 0.26

 Native American (n=1) 1.59 (0.74-3.21) 7.11 (2.24-22.58) 21 0.03

 Japanese American (n=1) 2.1 (1.3-3.3) 1.2 (0.8-1.9) 16,17 0.08

 Latino (n=2) 1.2 (0.6-2.4) 1.4 (0.9-2.1) 18,19 0.71

Mortality: (n=7) 2.13 (1.71-2.65)b1.94 (1.65-2.28) 12,15, 20, 71, 73, 74,75, 78 0.50

 White (n=5) 2.01 (1.59-2.54) 1.98 (1.65-2.38)

12,15, 73-75 0.92

 Black (n=2 male; n=1 female) 2.19 (1.28-3.73) 1.8 (1.1-2.8) 73,75 0.60

 East Indian (n=1) 4.4 (2.7-6.9) 3.1(1.7-5.8) 71 0.37

 Melanesian (n=1) 1.3 (0.7-2.5) 2.3 (1.2-4.6) 71 0.21

 Pima Indian (n=1) 1.8 (1.4-2.4) 1.4 (1.0-2.0) 20 0.24

104
Evidence Table 12. Diabetes: Summary odds ratios (95% confidence intervals) for coronary heart disease mortality by sex (diabetes vs. 

no diabetes) quality of studies and sensitivity analysis (white race only)

 Summary Odds Ratios (95% Confidence Interval)

Subgroup Men Women P-valuea References

Quality of Studiesb

 Good (n=2) 1.96 (1.56-2.47) 2.54 (1.73-3.72) .26 12,70

 Fair (n=4) 2.42 (1.71-3.42) 3.07 (1.97-4.80) .41 72,73,74,76

Level of Adjustment for

Potential Confoundingb

Age Adjusted only (n=4) 2.07 (1.39-3.08) 3.42 (2.55-4.59) .05 12,70,73,76

Unadjusted only (n=3) 2.16 (1.56-2.98) 3.22 (2.39-4.34) .08 70,73,74

OR indicates odds ratio; CI indicates confidence interval

aP value for comparison of odds ratio estimates between men and women.

b The studies inc luded in these subgroup analyses were eligible for inclusion because they provided outcomes adjusted for at least age, hypertension, hyperlipidemia and smoking; 

these studies also provided unadjusted and/or age-adjusted estimates which are used to calculate these summary estimates. 

Note: Superscripted numbers correspond with citations on reference list for Chapter 4.

105
Evidence Table 13. Troponin: Characteristics of the Study Populations by Gender

Author Year Patient

Cohort

Agea

(years)

History of MI (%) Hypertension (%) Diabetes Mellitus 

(%)

Smoking (%)

M F M F M F M F M F

Antman 199681996 ACS 58 61 45 30 35 56 12 20 39 34

Antman 199891998 ACS 61 64 42 35 59 68 29 41 31 19

Christenson10, 16 1996 ACS 62 69 25 25 39 60 16 26 38 23

Galvani21 1997 Unstable 

Angina

66 48 na na na

Hamm12 1999 Unstable 

Angina

61 20 37 12 41

Heeschen13 1999 ACS 64 46 55 21 69

Ravkilde20 1993 Unstable 

Angina

68 28 9 9 na

Safstrom62000 ACS 69 72 29 29 30 37 12 16 22 16

na=not available; ACS=suspected acute coronary syndrome (non-ST elevation); UA=unstable angina (MI excluded). MI=myocardial Infarction.

aMean or median.

Note: Superscripted numbers correspond with citations on reference list for Chapter 5.

106
Evidence Table 14. Troponin: Characteristics of the Study Reports

Study

Data 

Source

Definition 

of Positive 

Troponin

Study 

Type

Troponin Troponin 

Threshold

(ng/ml)

Exclusions 

Listed

Providers 

Blinded to 

Troponin

Antman 19968Author Any positive Clinical Trial I 0.4 Yes Yes

Antman 19989Author Any positive Clinical Trial T 0.2 Yes Yes

Christenson10, 16 Author Initial 

Positive

Clinical Trial T 0.1 Yes Yes

Galvani21 Publication Any positive Cohort I 3.1 Yes Yes

Hamm12 Author Any positive Clinical Trial T 0.1 Yes Yes

Heeschen13 Author Any positive Clinical Trial I 0.1 Yes Yes

Ravkilde20 Publication Any positive Cohort T 0.2 No Yes

Safstrom6Publication Any positive Clinical Trial T 0.2 Yes Yes

I=Troponin I protein; T=Troponin T protein; ng/ml=nanogram per milliliter

Note: Superscripted numbers correspond with citations on reference list for Chapter 5.

107
Evidence Table 15. Troponin: Outcomes for Women

Death (%) Death or MI (%)

Author

Total Troponin 

Positive (%)

Troponin

 Negative Positive

Troponin 

Negative Positive

Antman 19968471 179 (38) 5 (1.7) 10 (5.6) 18 (6.2) 19 (10.6)

Antman 19989194 35 (18) 3 (1.9) 2 (5.7) 6 (3.8) 7 (20.0)

Christenson10, 16 251 102 (41) 8 (5.4) 13 (12.7) 14 (9.4) 15 (14.7)

Galvani21 29 11 (38) 0 (0) 1 (9) 2 (11) 2 (18)

Hamm12 333 149 (45) 2 (1.1) 3 (2.0) 16 (8.7) 26 (17.4)

Heeschen13 1513 464 (31) 20 (1.9) 19 (4.1) 51 (4.9) 30 (8.2)

Ravkilde20 36 12 (33) 0 (0) 0 (0) 0 (0) 2 (17)

Safstrom6342 166 (49) 4 (2.3) 13 (7.8) 10 (5.7) 30 (18.1)

Total 3169 1118 (35) 42 (2.0) 61 (5.5) 117 (5.7) 139 (12.4)

MI = myocardial infarction

Note: Superscripted numbers correspond with citations on reference list for Chapter 5.

108
Evidence Table 16. Troponin: Outcomes for Men

Death (%) Death or MI (%)

Author

Total N Total 

Positive (%)

Troponin

 Negative Positive

Troponin 

Negative Positive

Antman 19968933 394 (42) 7 (1.3) 11 (2.8) 44 (8.2) 27 (6.9)

Antman 19989344 75 (22) 3 (1.1) 1 (1.3) 7 (2.6) 4 (5.3)

Christenson10, 16 554 187 (34) 12 (3.2) 20 (10.7) 33 (9.0) 25 (13.4)

Galvani 21 62 11 (18) 0 (0) 1 (9.1) 2 (3.9) 3 (27.3)

Hamm12 756 297 (39) 5 (1.1) 12 (4.1) 33 (7.2) 35 (11.8)

Heeschen13 709 180 (25) 14 (2.6) 8 (4.4) 32 (6.0) 18 (10.0)

Ravkilde20 91 32 (35) 1 (1.7) 3 (9.4) 3 (5.1) 4 (12.5)

Safstrom6621 395 (64) 5 (2.2) 26 (6.6) 26 (11.5) 70 (17.7)

Total 4070 1571 (39) 47 (1.9) 82 (5.2) 180 (7.2) 186 (11.8)

MI = myocardial infarction

Note: Superscripted numbers correspond with citations on reference list for Chapter 5.

109
111

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Appendix A

Peer Reviewers
128
129

Appendix A: Peer Reviewers

Expert Peer Reviewers

Overall Reviewers

Elizabeth Barrett-Connor, MD University of California, San Diego

JoAnn Manson, MD, DrPH Harvard Medical School, Brigham and

Women's Hospital

Lori Mosca, MD, MPH, PhD Columbia University 

Noninvasive Diagnostics:

C. Noel Bairey Merz, MD Cedars-Sinai Medical Center

Pamela S. Douglas, MD University of Wisconsin, Madison

Lipid lowering:

Vera Bittner, MD, MSPH University of Alabama at Birmingham

Robert H. Knopp, MD Northwest Lipid Research Clinic, University 

of Washington School of Medicine

Diabetes as a risk factor:

Trevor Orchard, MBBCh, MMedSi University of Pittsburgh

Troponin:

E. Magnus Ohman, MD University of North Carolina at Chapel Hill

Advice was also solicited from representatives of Partner Organizations, including:

Robert Christenson, PhD American Association for Clinical 

Chemistry

Sharonne N. Hayes, M.D., F.A.C.C. American College of Cardiology

Rosalind Fabunmi, Ph.D. American Heart Association

Mary Norine Walsh, MD

Mary Winston, Ed.D.

American College of Cardiology

American Heart Association
Appendix B

Quality Assessment Forms
132
133

Appendix B: Quality Assessment Forms

Noninvasive Diagnostics: Exercise MPI and Echocardiography Quality Evaluation 

Form

Reviewer 1: «Reviewer1»

Reviewer 2: «Reviewer2»

Topic Team: «Question»

Article: «Article»

Name: 

INCLUSION/EXCLUSION CRITERIA 

If answer is “NO” for any question 1-5 or "YES" for Q 6, skip to Q 7.

(Note: you may not be able to complete Q 4 until later if PI needs to be contacted)

YES NO

1. a Is the study design cross sectional?

 b Does it address the research question?

2. Does the article contain primary data on > 10 women who underwent exercise EKG with 

radionuclide injection and SPECT imaging or exercise echocardiography.

3. Does the article include coronary angiography as the "gold standard" for measuring the accuracy of 

these tests?

4A. Does the article present data on the accuracy of these tests that allow calculation of sensitivity, 

specificity, or likelihood ratios in women (one measure acceptable if all are not given, but raw data 

TP, TN, FP, FN preferred) (If YES, go to Q.5)

 If NO to 4A: 4B. Will PI be contacted, or has PI already been contacted? (if NO, go to Q.7)

 If YES to 4B: 4C. Was data received from PI? (if YES, include in review)

5. Was the paper published between January 1, 1990 and January 1, 2002?

6. Were non-invasive tests performed exclusively in patients after myocardial infarction, percutaneous 

angioplasty, coronary artery surgery or hospitalization for an unstable coronary syndrome? (If yes, 

exclude)

7. Based on your responses to questions 1-6, is this article eligible for the systematic review?

IF YES, complete Question 8 - 10 and Quality Evaluation.

IF NO, complete Questions 8 - 10 only.

MISCELLANEOUS

8. Does this article contain data on women only?

9. Does the investigator need to be contacted to receive further data on women?

10. Comments (continue on other side)

QUALITY EVALUATION Yes No Unclear Likely

11. Did all women who undergo the non-invasive test also undergo angiography?

12. Did only women with abnormal non-invasive tests undergo angiography?

13. Was the diagnosis of coronary artery disease on angiography made by 

investigators blinded to results of the non-invasive test?
134

Appendix B: Quality Assessment Forms (continued)

Treatment: Lipid Lowering Quality Evaluation Form

Reviewer 1: «Reviewer1»

Reviewer 2: «Reviewer2»

Topic Team: «Question»

Article: «Article»

INCLUSION/EXCLUSION CRITERIA 

If answer is “NO” for any question 1-5, STOP after completing Q 6, article does not qualify for 

review. One "no" response will disqualify article.

YES NO

1. Does the article assess the impact of lipid lowering on clinical outcomes: total mortality, CHD 

mortality, CHD events or CHD procedures?

• Is the study a randomized clinical trial?

• Is this publication a sub-study? __yes __no

• IF YES, which paper will be reviewed for this systematic review?

 __substudy __main __ both __ neither

• What is the ID# (or author/year/journal) of main paper? _________________

3. Does the article contain data on women that address the research question?

4. Does the study include treatment duration of at least one year?

5. Was the article published between January 1, 1966 and January 1, 2002?

6. Based on your responses to questions 1-5, is this article eligible for the systematic review?

IF YES, proceed to Question 7. IF NO, stop here. 

MISCELLANEOUS

7. Is the study: (select one only)

 ( ) primary prevention ( ) mixed

 ( ) secondary prevention ( ) cannot determine

8. Were any references found in this article that need to be reviewed?

 IF YES: list information on back of this page so that article can be obtained.

9. Does the investigator need to be contacted to receive further data on women?

10. Comments: (continue on other side)

QUALITY EVALUATION YES NO NOT 

CLEAR

11. Was there a control group that received placebo?

12. Were the participants blinded to the intervention?

13. Were the providers blinded to intervention?

14. Were the staff who assessed outcome blinded to intervention?

15. Was randomization allocation concealed?

16. Were the inclusion/exclusion criteria clear?

17. Was there > 75% complete follow up?
135

Appendix B: Quality Assessment Forms (continued)

Risk Factors: Diabetes Quality Evaluation Form

Reviewer 1: «Reviewer1»

Reviewer 2: «Reviewer2»

Topic Team: «Question»

Article: «Article»

INCLUSION/EXCLUSION CRITERIA YES NO

1. Is the study design a prospective or retrospective cohort, or cross sectional study? 

2. Does the article address the risk/rates of CHD mortality, a CHD event, or 

angiographic evidence of CHD in diabetic persons? 

3. Does the article include data specific to Type II diabetic participants?

4.a. Does the article include data on women, with outcomes specified by gender?

4. b. If NO, should PI be contacted?

5. Does the article include multivariate adjustment for confounders, including age, 

hypertension, hypercholesterolemia and tobacco use?

6. Does the article include a nondiabetic control group (studies with historical 

controls or standardized mortality ratios will be excluded)?

7. Was the paper published between January 1, 1966 and January 1, 2002?

If the answer to any of the above questions is NO, STOP.

QUALITY EVALUATION YES NO NA

8. Were the inclusion/exclusion criteria clear?

9. If article is a prospective cohort study, was there less than 25% loss to 

follow-up? 

10. Did the analysis include multivariate adjustment for potential 

confounders beyond the specified 4 variables: age, hypertension, 

hypercholesterolemia, tobacco? 

11. Was the outcome adjudicated blindly?

12. If a prospective cohort, was the length of follow up time at least 6 

months? 

13. Was diabetes defined based on any formal glucose testing (fasting 

plasma glucose or OGTT)?
Appendix C

Data Abstraction Forms
138
139

Appendix C: Data Abstraction Forms (continued)

DATA ABSTRACTION FORM: DIAGNOSTICS

REVIEWER DATE

ARTICLE NUMBER

Author

Title

Journal

Year

Country

Institution

Is there another article from this same database? Y or N

STUDY CHARACTERISTICS

Setting (University/Community/Both/Emergency Room?/Pre-op?)

Study design ( prospective, retrospective)

Exercise Echo done (Y/N)

Exercise SPECT done (Y/N)

Other tests done (Y/N), if Y, which?__________

POPULATION

Consecutive? Y N Unclear

Total n______

Number of Women_____

% follow up, all_____% follow up, women______

Mean age of all ______and of women________

Clinical indications, all: angina_____atypical chest pain____ asymptomatic____other_

Clinical indic, women: angina_____atypical CP_____asymptomatic______other_____

Inclusion criteria:

Exclusion criteria:

BL Characteristics Women Men All

Age Range

Cardiac Risks (%)

Diabetes

Smokers

HTN

Dyslipidemia 

(definition)

Cardiac Hx (%)

Angina

Prior MI

Prior CABG

Prior PTCA

TEST FACTORS

Exercise preformed: Bruce____Other treadmill_____Bike_____Step____Other_____

Percent with Adequate exercise: Women_____ All_____

Radionuclide used (if applicable): Tl______MIBI______Both______Other______
140

Imaging used: SPECT_____Echo_____Planar______Other_______ 

Criteria for positivity_____________________
141

Appendix C: Data Abstraction Forms (continued)

For Nuclear med Women Men All

+ ECG Criteria

+ Imaging Criteria

# w/ +ECG/+image

#w/+ECG/-image

# w/-ECG/+image

# w/-ECG/ -image

_

Positive reported at rest (Y/N) at exercise (Y/N)

If echo, WMA new (Y/N) or worse (Y/N)

If echo, cine loop or videotape reading?

If SPECT, visual (Y/N) quantitative (Y/N)

Number of non-diagnostic tests, all________ women______

Reasons for non-diagnostic tests, all: inadequate HR______technically difficult_______

Inadequate double product____ image uninterpretable (rest/stress/both)______

Reasons for non-diag, women: inadequate HR_____technically difficult______ 

Inadequate double product____image ininterpretable (rest/stress/both)_____

Reversibility examined (Y/N)

Protocol: Time _______Return for repeat images (Y/N) and if Y, when?

Baseline ECG abnormalities: LBBB______RBBB____dig effect_____LVH____ST/T__

GOLD STANDARD

Cath done on all (Y/N), if N # who received cath_____# of women who received cath___

Angiographic definition of dz: < 50%___>50%____>70%____>50% LM____other____

Time between exercise test and cath_____

Cath data Women Men All

% normal % w/ 

single vessel

% w/ 2 vessel

% w/3 vessel

% w/ L Main

SUBGROUPS

Was severe disease a subgroup (Y/N), and if so, how was it defined?__________

Other subgroups and definitions?

Data for Sens/Spec Women Men All

Participants

# with cath results

TP (+cath+test)

FP (-cath+test)

TN (-cath-test)

FN (-cath-test)
142

Appendix C: Data Abstraction Forms (continued)

Subgroup:

Data for Sens/Spec Women Men All

Participants

# with cath results

TP (+cath+test)

FP (-cath+test)

TN (-cath-test)

FN (-cath-test)

Subgroup:

Data for Sens/Spec Women Men All

Participants

# with cath results

TP (+cath+test)

FP (-cath+test)

TN (-cath-test)

FN (-cath-test)

Comments:
143

Appendix C: Data Abstraction Forms (continued)

Data Abstraction Form: Lipid Lowering

Reviewer_____________________________________________________________

First Author ___________________________________________________________

Study Number__________________________________________________________

Year of Publication_______________________________________________________

Directions: Complete this form after completing the quality review form which assesses study eligibility. 

Form does not need to be filled out on studies that are not eligible.

METHODS

Study Design

Randomized Clinical Trial Y ___________ N___________________

Participants

Source (eg community, hospital) ________________________________

Inclusion criteria

Age range___________________________________________

Total cholesterol _________________________________

LDL cholesterol__________________________________

HDL cholesterol__________________________________

Known CHD?________________________________________

Other________________________________________________

Exclusion criteria

(eg cancer, dementia)___________________________________

Primary/secondary prevention

Primary _____________________

Secondary ____________________

Mixed (if mixed, what is the % of each) ____________________________

Location (city, state, country) __________________________________________

Recruitment Start Date ___________________________________________

Intervention 

Drug

Name(s)____________________________________

Starting dose________________________________

Was the dose titratable?_________________________

Diet 

Type of diet(s)_______________________________

______________________________

Interventions common to control and intervention group

_________________________________________
144

Appendix C: Data Abstraction Forms (continued)

Outcomes

Primary outcome IF INDIVIDUAL 

Total mortality ______________________

CHD mortality ______________________

Non-fatal MI _______________________

Angina ____________________________

Revascularization ____________________

Cardiovascular death_________________

Stroke_____________________________

Other ______________________________

Primary Composite Outcome(s) MARK ALL THAT APPLY

Total mortality ______________________

CHD mortality ______________________

Non-fatal MI _______________________

Angina ____________________________

Revascularization ____________________

Cardiovascular death_________________

Stroke_____________________________

Other ______________________________

Secondary outcomes

Total mortality ______________________

CHD mortality ______________________

Non-fatal MI _______________________

Angina ____________________________

Revascularization ____________________

Cardiovascuar death__________________

Stroke_____________________________

Other (Individual) ______________________________

Other (Composite) ______________________________

Follow-up strategy and how often Frequency

Patient examination/clinic visit _________

Questionnaire _________

Telephone contact _________

Medical records _________

Death registry _________

Other____________________________ _________

Over what period of time were outcomes assessed (mean, range) 

Exact dates of follow-up__________________________

Mean length of follow-up_________________________

Follow up rate or percent__________________________

RESULTS

Participant Information

Women Men

Intervention

Control

Total number of patients
145

Appendix C: Data Abstraction Forms (continued)

Age

Average age intervention (I) ___________

Avg age I women ________

Average age I men___________

Average age placebo (P) ________________

Average age P women___________

Average age P men____________

Angina

Total (%) Women Men

Intervention

Control

Hypertension

Total (%) Women Men

Intervention

Control

Anti-hypertensives

Total (%) Women Men

Intervention

Control

Diabetes

Total (%) Women Men

Intervention

Control

Current smokers

Total (%) Women Men

Intervention

Control

Aspirin use

Total (%) Women Men

Intervention

Control

ACE inhibitor use

Total (%) Women Men

Intervention

Control

Beta blocker use

Total (%) Women Men

Intervention

Control
146

Appendix C: Data Abstraction Forms (continued)

Baseline Lipids 

Total LDL HDL Triglycerides

Intervention

Control

Baseline Lipids in women

Total LDL HDL Triglycerides

Intervention

Control

Outcomes

Follow-up Lipids 

Total LDL HDL Triglycerides

Intervention

Control

Follow-up Lipids in women

Total LDL HDL Triglycerides

Intervention

Control

All cause mortality

OVERALL Number of events Event rate (eg # per 1000 pt 

years) 

Number at risk

Intervention

Control

WOMEN Number of events Event rate (eg # per 1000 pt 

years) 

Number at risk

Intervention

Control

MEN Number of events Event rate (eg # per 1000 pt 

years) 

Number at risk

Intervention

Control

Relative Risk________________

Relative risk in women_________

Absolute risk reduction__________

Absolute risk reduction in women__________

NNT________________
147

Appendix C: Data Abstraction Forms (continued)

CHD death

OVERALL Number of events Event rate (eg # per 1000 pt 

years) 

Number at risk

Intervention

Control

WOMEN Number of events Event rate (eg # per 1000 pt 

years) 

Number at risk

Intervention

Control

MEN Number of events Event rate (eg # per 1000 pt 

years) 

Number at risk

Intervention

Control

Relative Risk________________

Relative risk in women_________

Absolute risk reduction__________

Absolute risk reduction in women__________

NNT________________

Nonfatal MI

OVERALL Number of events Event rate (eg # per 1000 pt 

years) 

Number at risk

Intervention

Control

WOMEN Number of events Event rate (eg # per 1000 pt 

years) 

Number at risk

Intervention

Control

MEN Number of events Event rate (eg # per 1000 pt 

years) 

Number at risk

Intervention

Control

Relative Risk________________

Relative risk in women_________

Absolute risk reduction__________

Absolute risk reduction in women__________

NNT________________
148

Appendix C: Data Abstraction Forms (continued)

Angina

OVERALL Number of events Event rate (eg # per 1000 pt 

years) 

Number at risk

Intervention

Control

WOMEN Number of events Event rate (eg # per 1000 pt 

years) 

Number at risk

Intervention

Control

MEN Number of events Event rate (eg # per 1000 pt 

years) 

Number at risk

Intervention

Control

Relative Risk________________

Relative risk in women_________

Absolute risk reduction__________

Absolute risk reduction in women__________

NNT________________

Revascularization

OVERALL Number of events Event rate (eg # per 1000 pt 

years) 

Number at risk

Intervention

Control

WOMEN Number of events Event rate (eg # per 1000 pt 

years) 

Number at risk

Intervention

Control

MEN Number of events Event rate (eg # per 1000 pt 

years) 

Number at risk

Intervention

Control

Relative Risk________________

Relative risk in women_________

Absolute risk reduction__________

Absolute risk reduction in women__________

NNT________________

Cardiovascular death

OVERALL Number of events Event rate (eg # per 1000 pt 

years) 

Number at risk

Intervention

Control
149

Appendix C: Data Abstraction Forms (continued)

WOMEN Number of events Event rate (eg # per 1000 pt 

years) 

Number at risk

Intervention

Control

MEN Number of events Event rate (eg # per 1000 pt 

years) 

Number at risk

Intervention

Control

Relative Risk________________

Relative risk in women_________

Absolute risk reduction__________

Absolute risk reduction in women__________

NNT________________

Stroke

OVERALL Number of events Event rate (eg # per 1000 pt 

years) 

Number at risk

Intervention

Control

WOMEN Number of events Event rate (eg # per 1000 pt 

years) 

Number at risk

Intervention

Control

MEN Number of events Event rate (eg # per 1000 pt 

years) 

Number at risk

Intervention

Control

Relative Risk________________

Relative risk in women_________

Absolute risk reduction__________

Absolute risk reduction in women__________

NNT________________

Other

OVERALL Number of events Event rate (eg # per 1000 pt 

years) 

Number at risk

Intervention

Control

WOMEN Number of events Event rate (eg # per 1000 pt 

years) 

Number at risk

Intervention

Control
150

Appendix C: Data Abstraction Forms (continued)

MEN Number of events Event rate (eg # per 1000 pt 

years) 

Number at risk

Intervention

Control

Relative Risk________________

Relative risk in women_________

Absolute risk reduction__________

Absolute risk reduction in women__________

NNT________________

Other

OVERALL Number of events Event rate (eg # per 1000 pt 

years) 

Number at risk

Intervention

Control

WOMEN Number of events Event rate (eg # per 1000 pt 

years) 

Number at risk

Intervention

Control

MEN Number of events Event rate (eg # per 1000 pt 

years) 

Number at risk

Intervention

Control

Relative Risk________________

Relative risk in women_________

Absolute risk reduction__________

Absolute risk reduction in women__________

NNT________________

Adverse event(s)

LFT abnormality 

How defined_________________________________

Number (%) Intervention________________________

Number (%) Control____________________________

Liver failure

How defined_________________________________

Number (%) Intervention________________________

Number (%) Control____________________________

CK abnormality

How defined_________________________________

Number (%) Intervention________________________

Number (%) Control____________________________

Rhabdomyolysis

How defined_________________________________

Number (%) Intervention________________________

Number (%) Control____________________________
151

Appendix C: Data Abstraction Forms (continued)

Renal failure

How defined_________________________________

Number (%) Intervention________________________

Number (%) Control____________________________

Breast cancer

How defined_________________________________

Number (%) Intervention________________________

Number (%) Control____________________________

Other

How defined_________________________________

Number (%) Intervention________________________

Number (%) Control____________________________

Other

How defined_________________________________

Number (%) Intervention________________________

Number (%) Control____________________________
152
153

Appendix C: Data Abstraction Forms (continued)

Data Abstraction Form: Diabetes

Reviewer: ____________________________ First Author: __________________

Study #: ______________________________ Year of Publication: ____________

METHODS:

Study design: _____ Prospective cohort study

_____ Retrospective cohort study

_____ Cross-sectional analysis 

_____ Case-Control study

_____ Randomized Clinical Trial, intervention type: ________________

Study name (acronym):_____________________________________________________

Patient Population (clinic, survey, volunteers...): ________________________________

Location (City/State/Country): ______________________________________________

Recruitment start date: ____________________________________________________

Type of diabetics studied: _____ Type 1 (Insulin-Dependent DM)

_____ Type 2 (NIDDM)

Type 2 diabetes defined by (check all that apply):

_____ self-report

_____ use of diabetic medication

_____ medical record diagnosis

_____ Positive Oral Glucose Tolerance Test, cut-off: ________________

_____ Elevated fasting Glucose, cut-off: __________________________

_____ Elevated HbA1c or glycohemoglobin, cut-off: ________________

_____ other: 

Outcomes:

Primary endpoint(s):

1. 

2.

Secondary endpoints(s):

1. 3.

2. 4.

Endpoint Definition: (check all that apply)

• Coronary heart disease death defined by: Cardiovascular disease death defined by:

_____ ICD-9 code 410-414 _____ ICD-9 code 400-459

_____ sudden CHD death _____ physician documentation

_____ Other: _____ other:

• MI defined by: Stroke death defined by:

_____ EKG changes _____ ICD-9 code 430-438

_____ Enzyme levels consistent with MI _____ physician documentation

_____ Other: _____ Other: 

Follow-up strategy (Check all that apply):

_____ patient examination/clinic visit

_____ questionnaire returned

_____ telephone contact

_____ medical records search

_____ death registry

_____ other: 
154

Appendix C: Data Abstraction Forms (continued)

Within what period of time were outcomes assessed (mean, range): _________________

Exact dates of follow-up: ________________________________

Follow-up rate or percent: ________________________________

RESULTS:

Participant Information:

Women Men

Number of (type 2) diabetics

Number of nondiabetic patients

Total number of patients

Race: (list all: # with DM, # without DM)

• 

• 

Age (mean, range): Diabetics

 Non-diabetics

• Are outcomes reported with crude numbers (y/n):

• Are outcomes adjusted by age alone (y/n)?

• Are outcomes adjusted for other variables (y/n)?

 List all variables:

Outcome: Coronary heart disease death Race: ____________

WOMEN MEN

With Diabetes

Without Diabetes 

Women:

Crude RR: ____________________ 95% CI or p-value: _________________________

Age-adjusted RR: __________________ “ _________________________

Multiply-adjusted RR: _______________ “ _________________________

Men:

Crude RR: ____________________ 95% CI or p-value: _________________________

Age-adjusted RR: ___________________ “ _________________________

Multiply-adjusted RR: _______________ “ _________________________

Outcome: Non-fatal Myocardial Infarction 

WOMEN MEN

With Diabetes

Without Diabetes 

Women:

Crude RR: ____________________ 95% CI or p-value: _________________________

Age-adjusted RR: __________________ “ _________________________

Multiply-adjusted RR: _______________ “ _________________________

Men:

Crude RR: ____________________ 95% CI or p-value: _________________________

Age-adjusted RR: ___________________ “ _________________________

Multiply-adjusted RR: _______________ “ _________________________
155

Appendix C: Data Abstraction Forms (continued)

Outcome: Cardiovascular Death 

WOMEN MEN

With Diabetes

Without Diabetes 

Women:

Crude RR: ____________________ 95% CI or p-value: _________________________

Age-adjusted RR: __________________ “ _________________________

Multiply-adjusted RR: _______________ “ _________________________

Men:

Crude RR: ____________________ 95% CI or p-value: _________________________

Age-adjusted RR: ___________________ “ _________________________

Multiply-adjusted RR: _______________ “ _________________________

Outcome: All-cause mortality 

WOMEN MEN

With Diabetes

Without Diabetes 

Women:

Crude RR: ____________________ 95% CI or p-value: _________________________

Age-adjusted RR: __________________ “ _________________________

Multiply-adjusted RR: _______________ “ _________________________

Men:

Crude RR: ____________________ 95% CI or p-value: _________________________

Age-adjusted RR: ___________________ “ _________________________

Multiply-adjusted RR: _______________ “ _________________________

Other outcome: ______________________________________ 

WOMEN MEN

With Diabetes

Without Diabetes 

Women:

Crude RR: ____________________ 95% CI or p-value: _________________________

Age-adjusted RR: __________________ “ _________________________

Multiply-adjusted RR: _______________ “ _________________________

Men:

Crude RR: ____________________ 95% CI or p-value: _________________________

Age-adjusted RR: ___________________ “ _________________________

Multiply-adjusted RR: _______________ “ _________________________
156

Appendix C: Data Abstraction Forms (continued)

Other outcome: ______________________________________ 

WOMEN MEN

With Diabetes

Without Diabetes 

Women:

Crude RR: ____________________ 95% CI or p-value: _________________________

Age-adjusted RR: __________________ “ _________________________

Multiply-adjusted RR: _______________ “ _________________________

Men:

Crude RR: ____________________ 95% CI or p-value: _________________________

Age-adjusted RR: ___________________ “ _________________________

Multiply-adjusted RR: _______________ “ _________________________

If Race information is provided, enter each outcome with crude number and RR per race:

Race: _________________________________________

Outcome: ______________________________________

WOMEN MEN

With Diabetes

Without DM

Women: Men:

Age-adj RR(CI): _____________________ Age-adj RR(CI): _______________________

Mult.-adj RR(CI): _____________________ Mult-adj RR(CI): _______________________

Race: _________________________________________

Outcome: ______________________________________

WOMEN MEN

With Diabetes

Without DM

Women: Men:

Age-adj RR(CI): _____________________ Age-adj RR(CI): _______________________

Mult.-adj RR(CI): _____________________ Mult-adj RR(CI): _______________________

Race: _________________________________________

Outcome: ______________________________________

WOMEN MEN

With Diabetes

Without DM

Women: Men:

Age-adj RR(CI): _____________________ Age-adj RR(CI): _______________________

Mult.-adj RR(CI): _____________________ Mult-adj RR(CI): _______________________

Race: _________________________________________

Outcome: ______________________________________

WOMEN MEN

With Diabetes

Without DM

Women: Men:

Age-adj RR(CI): _____________________ Age-adj RR(CI): _______________________

Mult.-adj RR(CI): _____________________ Mult-adj RR(CI): _______________________
Appendix D

Abbreviations and Acronyms
158
159

Appendix D: Abbreviations and Acronyms

ACE angiotensin converting enzyme 

AHRQ Agency for Healthcare Research and Quality

CABG coronary artery bypass grafting

CHD coronary heart disease

CKMB creatine kinase myocardial bands

CHF congestive heart failure

CVD cardiovascular disease

CI confidence interval

DTS Duke Treadmill Score

ECHO echocardiography

EKG electrocardiogram

EPC Evidence-based Practice Center

ETT exercise treadmill test

HDL High density lipoprotein

HDL-C High density lipoprotein cholesterol

ICD-9 International Classification of Diseases, Ninth Revision 

LDL Low density lipoprotein

LDL-C Low density lipoprotein cholesterol

LM Left main coronary artery

Lp(a) lipoprotein a

mg milligrams

MI myocardial infarction

MIBI technetium Tc 99m sestamibi

mm millimeter

mmol millimole

MPI myocardial perfusion-imaging

MRC/BHF Medical Research Council/British Heart Foundation 

MB myocardial bands

N number

NA not available

NFMI nonfatal myocardial infarction

ng nanograms

NHLBI National Heart Lung and Blood Institute

OR odds ratio

PCI percutaneous coronary intervention

PD perfusion defect

PTCA percutaneous coronary angioplasty

RWMA regional wall motion abnormality

RR relative risk

SPECT single photon emission computed tomography

TI thallous chloride TI 201 (thallium) 
160

Appendix D: Abbreviations and Acronyms (continued)

Names of studies:

4S Scandinavian Simvastatin Survival Study

ACAPS Asymptomatic Carotid Artery Progression Study 

AFCAPS/TEXCAPS Air Force/Texas Coronary Artherosclerosis Prevention Study

ALLHAT-LLT Antihypertensive and Lipid-Lowering treatment to prevent Heart 

Attack Trial - Lipid-Lowering Trial

CARE Cholesterol and Recurrent Events trial

HPS Heart Protection Study

LIPID Long-term Intervention with Pravastatin in Ischaemic Disease

NHANES I National Health and Nutrition Examination Survey I

PLAC I Pravastatin Limitation of Atherosclerosis in the Coronary 

Arteries 

PLAC II Pravastatin, Lipids and Atherosclerosis in the Carotid Arteries

PROSPER PROspective Study of Pravastatin in the Elderly at Risk

TIMI Thrombolysis in Myocardial Infarction

WHO-MONICA World Health Organization-Monitoring of Trends and 

Determinants in Cardiovascular Disease