Overview

Coronary heart disease (CHD) is the most

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 several partner

organizations charged the University of

California, San Francisco (UCSF)-Stanford

Evidence-based Practice Center (EPC) with the

development of an initial review of evidencebased 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. 

The three major aims of this project were to

(1) determine whether any of the 42 specific

subtopic areas have been adequately addressed in

systematic reviews or definitive individual

studies, (2) summarize the information from the

evidence-based studies identified that address

the subtopics, and (3) describe the feasibility of

further research for each subtopic.

Key Questions

1. Are there accurate non-invasive approaches

to evaluating suspected coronary disease in

women? (3 subtopics, 1.01-1.03)

1.01 exercise tolerance testing, with and

without perfusion imaging

1.02 exercise echocardiogram

1.03 coronary artery calcification score

2. Are there effective treatments for women

with coronary heart disease? (15 subtopics

2.01-2.12 with secondary and primary

prevention considered separately as

appropriate)

2.01 aspirin

a. secondary prevention

b. primary prevention

2.02 beta-blockers

a. secondary prevention

b. primary prevention

2.03 angiotensin converting enzyme 

inhibitors

a. secondary prevention

b. primary prevention

2.04 calcium channel blockers

2.05 nitrates

2.06 heparin, including low molecular 

weight heparin

2.07 glycoprotein IIb/IIIa inhibitor drugs

2.08 thrombolysis

2.09 ticlopidine

2.10 clopidogrel

Evidence Report/Technology Assessment

Number 80

Results of Systematic Review of Research on

Diagnosis and Treatment of Coronary Heart

Disease in Women

Summary

Agency for Healthcare Research and Quality

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES • Public Health Service
2.11 angioplasty or stenting

2.12 coronary artery bypass surgery

3. What are the risk factors for coronary heart disease in

women and does modifying these risk factors result in

reduced risk for coronary heart disease events? (20

subtopics labeled 3.01-3.12 with subtopic as a risk factor

for CHD or treatment/modification of a risk factor for

CHD prevention considered separately where

appropriate)

3.01 hypertension

a. as a risk factor

b. treatment

3.02 diabetes 

a. as a risk factor

b. treatment

3.03 hyperlipidemia (LDL-, HDL-cholesterol, 

triglycerides, lipoprotein (a))

a. as a risk factor

b. treatment

3.04 elevated homocysteine

a. as a risk factor

b. treatment

3.05 C-reactive protein

a. as a risk factor

b. treatment

3.06 cigarette smoking 

a. as a risk factor

b. smoking cessation

3.07 obesity

a. as a risk factor

b. weight reduction

3.08 inactivity

a. as a risk factor

b. exercise

3.09 age

3.10 age at menopause

3.11 ethnicity

3.12 socioeconomic status

4. Are accurate tests (defined in #1), effective treatments

(defined in #2), or risk factor modifications (defined in

#3) underutilized in women (or among women of various

race/ethnic populations) compared to men?

5. What is the prognostic value of biochemical markers for

diagnosis of acute myocardial infarction or unstable

angina in women? (3 subtopics labeled 5.01-5.02)

5.01 troponin

5.02 creatinine kinase myocardial bands including 

isoforms

5.03 myoglobin

Methodology

Data Sources 

To assemble a bibliographic database of systematic reviews

and articles that might provide definitive primary data, we

searched MEDLINE®, the Cochrane Database and DARE

from 1985 to July 2001, reviewed the bibliographies of

retrieved articles and sought suggestions for additional articles

from an expert Advisory Board and Peer Reviewers. 

Inclusion Criteria 

To be categorized as an article that provided evidence

regarding a key question, the article had to address the

subtopic and contain data specific to women. For subtopics

with CHD events as the outcome (effects of risk factors, risk

factor modification, and treatment), we required that the

outcome be CHD events or mortality. For key question 1, the

gold standard test to which noninvasive test results were

compared was required to be angiographic evidence of

coronary disease. When systematic reviews were not available

to address the subtopic, we also searched for clinical trials,

prospective cohort, and cross-sectional studies as appropriate. 

Search Terms 

We conducted a separate search for evidence regarding each

of the 42 subtopics using the same search terms for CHD

outcomes (i.e., cardiovascular diseases or heart diseases or heart

or cardiovas* or cardiac* or coronary or myocardial) and for

systematic reviews (i.e., publication type: meta-analysis or

meta-analy* or metaanaly* or metanaly* or review or overview

and systematic or methodologic* or evidence*) and added

terms specific to each subtopic. 

Data Abstraction

One UCSF-Stanford EPC physician investigator reviewed

all identified titles and excluded those that clearly 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 remaining eligible articles was reviewed independently

by two UCSF-Stanford EPC physician investigators using a

standardized abstraction form to classify eligibility and rate

quality as fair or good based on predefined criteria. 

Evaluation of Evidence Provided by Identified

Articles

We reviewed and summarized in detail the findings of each

systematic review and clinical trial identified. A general

summary of the overall findings from prospective cohort and

cross-sectional studies pertinent to each subtopic is also

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provided. Finally, we summarized the answer to each subtopic

question, graded the evidence as none, weak, fair or good,

compared results in women and men and recommended a

new or updated systematic review if feasible. 

Results of Literature Searches

The searches identified 6,403 citations. After review of titles

and abstracts, 810 articles were retrieved and reviewed in full

text. The 162 articles that provided evidence in women are

characterized with regard to study design and quality as

follows:

Good Fair

Total Quality Quality

Systematic review 32 17 15

Randomized trial 25 17 8

Prospective cohort 66 59 7

Cross-sectional 39 25 14

Total 162 118 44

In total, we reviewed the full text of 272 systematic reviews

and 55 randomized trials; only 32 systematic reviews and 25

randomized trials contained evidence on the key question in

women. In general, most authors of systematic reviews and

randomized trials that we identified did not perform subgroup

analyses in women or ethnic minorities, even though a

substantial proportion of participants were women or

minorities. 

Of the articles that provide evidence to address one of the

key questions in women, only 35 percent are systematic

reviews or randomized trials. The remaining cohort and crosssectional studies provide some evidence, but the study designs

are susceptible to bias due to confounding.

Findings

General

• We found no data in women to address 13 of the subtopic

questions, weak data to address 15, fair data for eight, and

good data to address six. 

• In general, no evidence addressed differences in the

accuracy of diagnostic tests, strength of risk factors, effects

of treatment, and prognostic value of markers for ischemia

in women of different races or ethnicity. The only evidence

regarding differences by ethnicity suggests that AfricanAmerican women may benefit more from treatment of

hypertension than white women.

Non-invasive diagnostic testing

Fair evidence suggests that the accuracy of exercise EKG

and exercise thallium testing for CHD in women is low. The

accuracy of exercise echocardiography appears to be higher,

but data are limited.

Weak evidence suggests that the absence of coronary

calcification may be useful for ruling out disease in both men

and women.

Treatments

• Fair or good evidence suggests that beta-blockers, aspirin,

and angiotensin converting enzyme inhibitors reduce risk

for CHD events in women with known heart disease. 

• Good evidence suggests that nitrates do not reduce risk for

CHD events in women with known heart disease. 

• Fair evidence suggests that glycoprotein IIb/IIIa inhibitor

drugs given to women undergoing percutaneous

revascularization result in a reduced risk of CHD events

and need for revascularization, but treatment in women

suffering acute coronary syndromes may result in increased

mortality. This was the only treatment for which there was

evidence of a possible interaction by gender: men treated

with IIb/IIIa drugs during acute coronary syndromes

appear to benefit.

• Evidence regarding the efficacy of important treatments

such as calcium channel blockers, heparin, ticlopidine,

clopidogrel, coronary artery bypass surgery, percutaneous

angioplasty and coronary stenting in women is weak.

Risk factors and risk factor modification

• Fair or good evidence suggests that hyperlipidemia,

diabetes and hyperhomocysteinemia are risk factors for

CHD in women. 

• Only weak evidence links most of the risk factors of

interest and CHD risk in women. This is primarily

because all of the studies addressing the strength of risk

factors are observational and very few good-quality

systematic reviews have been completed. 

• Risk factors for CHD seem to be equally strong in men

and women with the possible exceptions of age, diabetes,

and certain lipoproteins. 

• Fair or good evidence suggests that smoking cessation after

MI and treatment of hypertension and of hyperlipidemia

lower risk for CHD events in women. 

• No evidence was found for the effectiveness of other

interventions to modify risk factors in women.

Differences in utilization

• Weak evidence suggests that men are more likely than

women to undergo diagnostic testing and treatment for

CHD, but that women are more likely than men to be

treated for hypertension. 

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• Differences in utilization of tests and treatment might be

explained by differences in severity of disease or

comorbidities between men and women or by overuse of

tests and treatments in men.

Biochemical Markers

• No evidence was found to address the diagnostic value of

troponins, creatine kinase or myoglobin in women with

ischemia. 

Future Research

We believe that a new or updated systematic review is

feasible and would be provide clinically important information

for the following subtopics:

• Exercise tolerance testing

• Exercise echocardiogram

• Aspirin for secondary prevention

• Beta-blockers for secondary prevention

• Hypertension as a risk factor

• Diabetes as a risk factor

• Hyperlipidemia as a risk factor

• Hyperlipidemia treatment

• Homocysteine as a risk factor

• Smoking as a risk factor

• Smoking cessation

• Obesity as a risk factor

• Age as a risk factor

• Differences in utilization between men and women

The major limitation in performing these systematic reviews

will be the availability of data on women and minority

populations. Women typically comprise 20 to 30 percent of

participants in randomized trials, but risk estimates for women

are infrequently published. Thus, investigators attempting to

systematically review the medical literature must attempt to

contact investigators and obtain unpublished risk estimates.

For a variety of reasons, these subgroup analyses are often not

available. Thus, even though the National Institutes of Health

and other funding agencies appear to have succeeded in

assuring that some proportion of women and minorities are

included in randomized trials, data from such participation are

not generally available. We recommend that, in addition to

demanding 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 primary and secondary outcome data by subgroup

be published or archived. Similarly, we recommend that

funding agencies that support systematic reviews require

inclusion of subgroup estimates in women and minorities

whenever possible. 

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. 80, Results of Systematic

Review of Research on Diagnosis and Treatment of Coronary

Heart Disease in Women. 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-E034

May 2003

ISSN 1530-440X