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Systematic Review and Meta-analyses Investigating Whether Risk Stratification Explains Lower Rates of Coronary Angiography Among Women With Non–ST-Segment Elevation Acute Coronary Syndrome

Worrall-Carter, Linda PhD, BEd, Med(Prelim), RN; McEvedy, Samantha LLB; Kuhn, Lisa PhD, MHSc (Nursing), RN; Scruth, Elizabeth PhD, MPH, RN; MacIsaac, Andrew MD, FRACP; Rahman, Muhammad Aziz PhD, MPH, MBBS

Journal of Cardiovascular Nursing: March/April 2017 - Volume 32 - Issue 2 - p 112–124
doi: 10.1097/JCN.0000000000000300
ARTICLES: Systematic Reviews

Background: Guidelines recommend that all non–ST-segment elevation acute coronary syndrome (NSTEACS) patients with high-risk features receive a coronary angiogram. We hypothesised that the widely reported gender disparity in the use of angiography might be the result of women more frequently being stratified into the lower-risk category.

Objectives: The aim of the study was to review studies reporting risk stratification of NSTEACS patients by gender, compare risk profiles, and assess impact on use of coronary angiography.

Methods: PubMed, Scopus, and EMBASE databases were searched on June 17, 2014, using MeSH terms/subheadings and/or key words with no further limits. The search revealed 1230 articles, of which 25 met our objective.

Results: Among the 28 risk-stratified populations described in the 25 articles, women were more likely to be stratified as high-risk in 13 studies; men were more likely to be stratified as high-risk in 3 studies. After meta-analyses, women had a 23% higher odds of being stratified as high-risk than did men (P = .001). Lower-risk patients were more likely to receive an angiogram in 15 study populations.

Conclusions: Contrary to our hypothesis, this review showed that women with NSTEACS are more likely than men to be considered high-risk when stratified using a range of risk assessment methods. Lower rates of angiography in women form part of a broader treatment-risk paradox, which may involve gender bias in the selection of patients for invasive therapy.

Linda Worrall-Carter, PhD, BEd, Med(Prelim), RN Founder and CEO, Her Heart Ltd; Director, St Vincent’s Centre for Nursing Research (SVCNR) and The Cardiovascular Research Centre (CvRC), Australian Catholic University; and St Vincent’s Hospital, Melbourne, Australia.

Samantha McEvedy, LLB Research Associate, SVCNR, Australian Catholic University, Melbourne, Australia.

Lisa Kuhn, PhD, MHSc (Nursing), RN Research Fellow, Deakin University, Melbourne, Australia.

Elizabeth Scruth, PhD, MPH, RN Clinical Practice Consultant, Regional Quality and Regulatory Services, Kaiser Permanente, Oakland, California.

Andrew MacIsaac, MD, FRACP Director of Cardiology Services and Deputy Chief Medical Officer, St Vincent’s Hospital and The University of Melbourne, Melbourne, Australia.

Muhammad Aziz Rahman, PhD, MPH, MBBS Senior Research Fellow, SVCNR and CvRC, Australian Catholic University; and The Mary MacKillop Institute for Health Research, Melbourne, Australia.

The authors have no conflicts of interest to disclose.

Correspondence Linda Worrall-Carter, PhD, BEd, Med(Prelim), RN, St Vincent’s Centre for Nursing Research and The Cardiovascular Research Centre, Australian Catholic University, Level 4, 486 Albert St, East Melbourne, Victoria 3002, Australia (lindaworrallcarter@herheart.org.au).

Cardiac catheterization, or coronary angiography, is often referred to as the criterion standard for the investigation of acute coronary syndrome (ACS).1,2 A diagnostic coronary angiogram provides an opportunity to evaluate coronary plaque and determine the degree of coronary artery stenosis. If indicated by the presence of significant narrowing of the coronary arteries or complicated plaque, revascularization via percutaneous coronary intervention (balloon angioplasty and stent or coronary artery bypass graft) is performed, thereby reducing the risk of subsequent cardiac events.3

While there has been a marked increase in the use of cardiac catheterization for males and females of all ages in the last 20 years, national and international studies continue to report lower rates of angiography in women than in men.4–8 This phenomenon has been substantiated via a systematic review that found that across 8 studies women were 14% to 55% less likely to receive diagnostic angiography than men, although there was no gender difference in rates of referral for coronary revascularization once angiography had been performed and coronary anatomy was known.9 Our own retrospective analyses of all Victoria, Australia, hospital ACS admissions in a 2-year period confirmed that women diagnosed with non–ST-segment elevation ACS (NSTEACS) had 32% lower odds of receiving an angiogram than men after adjusting for age, comorbidity, and other confounders.8 A 2013 study by Roe et al7 aggregating data from 39 hospitals around Australia further found that, even after they had been properly identified as having high-risk features, women with NSTEACS were 13% less likely to receive an angiogram than men, although it is important to note that lower rates of angiography in women are not ubiquitous across all hospitals.10

It has been suggested that lower rates of angiography in women are directly related to gender differences in the use of secondary prevention medications in women.9 Some have contended that the disparity is due to an androcentric gender bias in the diagnosis and treatment of coronary heart disease that could be considered a form of discrimination.9,11 However, a growing body of work from the WISE (Women’s Ischemia Syndrome Evaluation) study suggests that biological differences in the pathophysiology and etiology of coronary heart disease in women may be at the root of the gender bias in the treatment of ACS.12,13 While evidence-based guidelines are clear regarding the use of an early invasive strategy, commencing with diagnostic angiography, for patients with NSTEACS stratified as high-risk features, the strategies used in the treatment of lower-risk NSTEACS can be classified into 2 approaches: early invasive or conservative.2,14–16 The conservative approach for the treatment of lower-risk NSTEACS involves medical therapy only, and patients are referred for angiography only if medical therapy fails to reduce their symptoms, or if they are subsequently proven to be high-risk through the utilization of other methods of diagnostic imaging and tests.17

In light of these considerations, an understanding of gender differences in the risk stratification profile for NSTEACS patients may explain why angiography is used less frequently in women. If women are more likely to be classified as low to intermediate risk, it would explain their lower rates of invasive coronary intervention. Therefore, this review aimed to analyze studies that report risk stratification of NSTEACS patients by gender in order to test the hypothesis that women were less likely than men to be stratified into the high-risk category.

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Methods

Literature Search

The review was conducted following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines.18 PubMed, Scopus, and EMBASE were selected as the primary databases. After consulting with university librarians, we developed the following search terms using MeSH terms/subheadings and/or keywords as appropriate: (non-ST-segment elevation OR non ST segment elevation OR non-ST elevation OR non ST elevation OR NSTEMI OR non STEMI OR NSTEACS OR NSTE-ACS) AND (Women OR female OR sex OR gender) AND (Risk assessment OR risk score OR risk stratif*). The asterisk represents a truncation so that words stemming from that root (eg, stratify, stratification) are included. No further limits were applied to the search that was conducted on June 17, 2014 (Figure 1).

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Study Selection

Our focus for this systematic review was to identify studies reporting risk stratification of patients with NSTEACS by gender. First, articles were screened for relevance by 2 reviewers based on titles and abstracts. Articles were selected for further consideration if they reported results for NSTEACS (separate from STEMI) and included reference to risk scores or risk stratification of patients. Studies were considered eligible if all patients received cardiac catheterization or if patients received invasive therapy according to standard practice in the study setting or if patients were randomized into invasive versus conservative therapy. However, studies limited to patients with specific conditions other than NSTEACS (eg, renal failure, diabetes), studies testing the effect of specific medications (eg, antiplatelet, clopidogrel), and those using biomarkers only (eg, troponin, N-terminal pro–B-type natriuretic peptide) to measure risk were excluded. Remaining articles were considered in detail to determine whether they reported risk stratification of NSTEACS patients by gender.

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Data Extraction

Data from included studies were extracted onto a standardized template by 1 reviewer and independently confirmed by a second reviewer, with any discrepancies resolved through discussion. A data extraction spreadsheet was used to extract the following information: study description, author, study year, study design, registry name, study population, sample size (by gender), and key findings related to the hypothesis (ie, method of risk stratification, proportion of high-risk by gender, use of cardiac catheterization).

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Statistical Analyses

Statistical analyses were performed using MedCalc for Windows version 13.3.3 (MedCalc software, Ostend, Belgium). Odds ratios and 95% confidence intervals comparing the probability of women being classified as high-risk to the probability of men being classified as high-risk for 28 risk stratification populations were calculated. One study population was represented twice in the meta-analysis because 2 different methods were used to stratify risk.19 Meta-analyses were carried out using the Comprehensive Meta-analysis package, version 2 (Biostat, Englewood, New Jersey), and are summarized in chronological order in a forest plot, which indicates the risk stratification method and cutoff values used to denote high-risk in the study (Figure 2). The random-effects model was utilized rather than the fixed-effects approach, as differences in included studies precluded the assumption of a common effect size. Sensitivity analyses were performed by recalculating the overall odds ratio with each study removed from the overall sample to determine the impact of studies with large numbers; the direction of the effect did not vary. Secondary analyses were conducted after grouping studies by risk stratification method to confirm that the effect was not being driven by 1 particular risk scoring method.

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Assessment of Quality of Reviewed Studies

Level of quality of reviewed studies was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.20

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Risk Stratification Methods in Reviewed Studies

Eight risk stratification methods were used across the 25 articles: Global Registry of Acute Cardiac Events (GRACE),21 Thrombolysis in Myocardial Infarction (TIMI),22 Platelet glycoprotein IIb-IIIa in Unstable angina: Receptor Suppression Using Integrilin Therapy (PURSUIT),23 National Health Data Dictionary,24 Synergy Between PCI With Taxus and Cardiac Surgery (SYNTAX),25 Physician’s Risk Assessment (PRA),26,27 Agency for Health Care Policy and Research,28 and a combined method using PREDICT software and involving GRACE risk score plus elevated troponin plus ST-segment deviation.16 Some studies compared more than 1 risk stratification method, and cutoff values for high-risk were not always consistent (even for studies using the same risk stratification method); these are noted in the legend on the forest plot (Figure 2). Each of the risk stratification methods included in this review and meta-analyses utilizes a series of diagnostic variables to estimate risk, which have been summarized in Table 1. The GRACE, TIMI, and PURSUIT risk scores have been validated and have been included as level B recommendations in the American College of Cardiology/American Heart Association and European guidelines since 2007. All 3 risk scores have been shown to confer additional prognostic value over and above physician risk assessment alone.29 Variables used in the Agency for Health Care Policy and Research and combined methods offer some concordance with GRACE, TIMI, and PURSUIT with age, ST-segment deviation, and elevated cardiac biomarkers most consistently used across the various risk models.30 We note that PURSUIT is the only method that includes male gender as a marker of increased risk. SYNTAX is not included in Table 1 because it differs substantially from the other methods, being a scoring system to rank the complexity of the coronary anatomy following angiography.25

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Results

The literature search from PubMed, Scopus, and EMBASE elicited 2456 articles, of which 1226 were removed as duplicates. Abstracts for the remaining 1230 articles were assessed for relevance by 2 separate researchers to determine whether they were eligible for inclusion in the review, of which 147 articles were reviewed in detail. Any areas of disagreement between the 2 researchers were resolved by discussion. In total, 1205 articles were excluded for the following reasons: the focus of the study was not relevant to the hypothesis (n = 1083), did not report risk stratification of NSTEACS by gender (n = 117), or were abstracts only (n = 5). Detailed results are presented as a flowchart in Figure 1. Twenty-five articles reported details of risk stratification in patients with NSTEACS by gender,19,26,27,31–52 although it was not necessarily the main focus of the study, and profiling by gender often required some recalculation (eg, proportions, P values) from baseline data provided within the articles. Study characteristics and key findings for the 25 articles are summarized in Table 2. Two articles reported the results from 2 different registries,49,52 and 1 article stratified patients using 2 different scoring methods19; thus, there were 28 risk-stratified populations across the 25 included studies. The proportion of women ranged from 23% to 40% and was 32% on average, which is broadly what we would expect because it reflects the well-established higher incidence of ACS in men compared with women.53

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Risk Stratification by Gender

Women were more likely to be stratified as high-risk in 13 populations.34,35,37,39–42,47,49,50,52 Most of the studies where women were more likely to be high-risk used the GRACE risk score and defined high-risk as either the highest tercile (6 studies) or a GRACE risk score of 141 or greater (3 studies). One study in which women were more likely to be high-risk used a TIMI score of 5 to 7; 2 studies used the PURSUIT high-risk definition; and 1 study used a combination of GRACE score 141 or greater and elevated troponin plus ST-segment deviation to define high risk. In 3 risk-stratified populations, men were more likely to be high-risk than women.32,33,46 Two of those studies were atypical because low-risk NSTEACS was excluded from their study populations. One study where men were more likely to be high-risk used the National Health Data Dictionary to define high-risk; 1 study used a SYNTAX score ≥of 13 or greater (an angiographic scoring system that ranks the complexity of the coronary anatomy); and the third study stratified patients as either higher or lower risk, with two-thirds of patients falling into the high-risk category, that is, high to intermediate risk. In all remaining studies, the proportion of women and men stratified as high-risk was statistically similar.19,26,27,31,36,38,43–45,48,51 Meta-analyses including all 28 study populations revealed that women with NSTEACS had a 23% higher odds of being stratified as high-risk than men (odds ratio, 1.23; 95% confidence interval, 1.09–1.40) (Figure 2).

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Use of Angiography

Consistent with the widely reported gender disparity in the use of angiography, Huang et al38 noted coronary angiography was performed in 65% of women compared with 74% of men. Similarly, in the study by Jedrzkiewicz et al,39 women had a 25% lower probability of being selected for cardiac catheterization (P < .001) after adjusting for confounders. However, in the study by Kerr et al,40 rates of angiography did not differ significantly by gender. Other reviewed studies did not report rates of angiography by gender, but many did report whether patients in low-, intermediate-, and high-risk groups received an angiogram. A curious “treatment-risk paradox” was identified in 15 study populations, whereby patients with higher risk scores had significantly lower rates of cardiac catheterization (Table 3). When patients were stratified according to PRA, the use of coronary angiography was more likely to increase in line with the physician’s estimate of risk.26,27 Nevertheless, in both studies, which used PRA, more than one-quarter of patients classified as high-risk by physicians did not receive an angiogram, despite the fact that invasive therapy is recommended in guidelines for all high-risk patients except in the presence of serious comorbidities. In the study conducted by Lee et al,43 the most frequent reason patients were not referred for angiography (reported by 68% of treating physicians) was that the patient was not considered high-risk enough and/or current clinical trial evidence did not support an early invasive strategy for the individual patient. However, when the TIMI risk score was calculated, a large proportion of patients (59%) who were not treated invasively turned out to be intermediate to high-risk, suggesting that their risk had been underestimated. Looking at this by gender, 33% of women who would have been stratified as intermediate to high-risk using TIMI scores did not receive cardiac catheterization because they were not considered to be high-risk enough, compared with 23% of men.

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Quality Level of the Selected Studies

We used the Cochrane GRADE approach to rate the quality of the included studies.20 Grading was undertaken independently by 2 authors. The GRADE approach was designed to be used in evaluating clinical trials/interventions being systematically reviewed, and therefore, observational studies have a default rating of “low.” Although upgrading and downgrading of studies can occur in some circumstances, all of the studies in this current review remained in the low-quality category.54 The 2 randomized controlled trials included in the review were also rated “low,” because risk stratification was not the outcome under study but was reported as a baseline characteristic or sample grouping.46,48

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Discussion

Results of this review did not support the hypothesis that women with NSTEACS were less likely than men to be stratified as high-risk. Rather, in many study populations (particularly those using the GRACE, TIMI, or PURSUIT risk scores), women were more likely to present with features that designated them as high-risk (such as older age, electrocardiogram changes, and/or elevated biomarkers) and thus be stratified into the high-risk category. Furthermore, meta-analyses revealed that, overall, women had a 23% higher odds of being stratified as high-risk than men. Thus, the evidence does not substantiate the notion that the gender disparity in the use of angiography in this patient group can be explained by lower risk in women. The review also revealed an interesting treatment-risk paradox in several studies, where patients with higher-risk NSTEACS were less likely than lower-risk patients to receive the most effective invasive cardiac procedures.

Risk stratification is key to the management of ACS, and guidelines provide a paradigm for the classification of NSTEACS patients into high, intermediate, or low risk of short-term adverse outcomes (death or myocardial [re]infarction).2,14,15 Stratifying the patient’s risk is an important aspect of decision making with regard to secondary prevention, helping clinicians to decide on either an invasive or conservative strategy. Gender is now a part of this decision-making process, because the most recent international guidelines include a level B recommendation that a conservative approach be used in very low-risk women.2,14 This is because there is some evidence to suggest that very low-risk women appear to have an increased odds for death, myocardial infarction, or rehospitalization for ACS following an invasive as opposed to a conservative approach (whereas outcomes between invasive and conservative strategies in low-risk men have been found to be similar).14,55,56 Female gender has also been associated with a higher risk of retroperitoneal bleeding, a potentially life-threatening complication of catheterization; however, it is important to note that major complications from cardiac catheterization are rare, and mortality related to the procedure is negligible.1

The treatment-risk paradox in the use of cardiac catheterization has been documented and discussed by a number of scholars.6,34,39,40,47,52,57–59 Reasons proposed for this dissociation between risk and treatment propensity, whereby catheterization is not used in high-risk patients, include failure to recognize high-risk features, knowledge gaps regarding guideline recommendations, skepticism about the applicability of trial evidence, a lack of appreciation for the risk-benefit ratio in women, concerns about performing invasive procedures in patients at increased risk of treatment complications, and absolute contraindications being present but not documented.43,50,57,58 It has also been noted that early invasive therapy is more likely to be used in patients with scant comorbidity and that there has been a lack of representation of patients with multimorbidity in clinical trials, which may deter the use of invasive therapies in more complex patients.42,60 Thus, on the one hand, a woman may be deemed too high-risk for invasive therapy because of complex comorbidities or contraindications, and on the other, her level of risk and potential benefits may be underestimated because of a lack of confidence in evidence-based guidelines, both resulting in lower rates of angiography for women.

A number of studies have concluded that underestimation of patient risk is a key contributing factor to the underuse of an invasive therapy in high-risk patients, including women.6,39,50 Prospective risk stratification is essential to estimate patient prognosis, to aid in clinical decision making, and to ensure quality control.46 Evidence from this review suggests that the risk stratification process is not routinely applied in decision making regarding referral for invasive therapy. Risk stratification requires accurate and comprehensive integration of numerous prognostic factors, which may be difficult in practice without the use of validated risk scores.27,61,62 The TIMI, GRACE, and PURSUIT risk assessment instruments have been validated in all types of ACS63 and are endorsed in international guidelines,2,14 but they are not widely used in practice, and contemporary risk stratification has been described as suboptimal.27 A recent UK study found that only 27% of emergency departments routinely use objective clinical risk stratification instruments.64 The authors concluded that, although the use of troponin as a diagnostic test and risk stratification instrument appears to be universal, further risk stratification is inconsistent. This may have led to an overreliance on the presence of pain and elevated troponin when evaluating patients, an approach seemingly endorsed by the Australian guideline’s simplified risk assessment algorithm, which relies on pain, electrocardiogram changes, and elevated troponin.15 Research has shown that women with ACS are significantly less likely to report chest pain or discomfort compared with men and that almost 2 in 5 women with ACS present without chest pain or discomfort.65 Consequently, diagnosis of NSTEACS in women can be particularly challenging,14 and overreliance on a simplified assessment of pain and troponin as diagnostic instruments in the stratification of risk for NSTEACS, without consideration of other high-risk features, may also be contributing to the underestimation of risk in women and thus to lower rates of angiography.

The risk stratification process involves the exercise of clinical judgement and may include the utilization of risk-scoring instruments that seek to make the diagnostic process more objective. It has been noted that risk scores are useful instruments that require stronger evidence showing a benefit in terms of optimizing therapies, reducing costs, or improving patient outcomes.30 The results of this review indicate that the inclusion of additional prognostic factors through the use of risk scores would lead to more women being classified high-risk than men and therefore should result in greater use of angiography in women. However, there appear to be a number of barriers to the adoption of risk assessment instruments. Risk scores may be difficult to implement without an electronic decision-making instrument,33,40 although a number of these do exist, and a GRACE risk prediction instrument has recently been developed for smart devices.66 Other possible barriers include the overlay of clinical judgement and conflicting information and uncertainty about the link between clinical risk scores and underlying coronary anatomy, in particular the presence or absence of significant obstructive coronary lesions.67,68 Angiographic results for women are more likely to show normal coronary arteries, or mild disease, unsuitable for stenting.5,48,69,70 In such cases, physicians may feel that the patient could have been spared an expensive, invasive procedure and, consequently, be more hesitant to carry out angiograms in women and to think of them as lower risk. We suspect that this is the phenomenon described as “not-high-enough risk” in the study by Lee et al.43 Existing risk-scoring systems are well validated; however, the outcomes they predict (eg, in-hospital death, 30-day complications) may not be those that clinicians are most interested in when deciding whether to refer the patient for angiography. Although the accuracy of risk scores in predicting the angiographic severity of ACS remains worthy of further research,67,71 several of the studies we reviewed noted a significant association between higher risk score and greater coronary artery disease (CAD) severity.19,31,36,45 In the last few years, there have been efforts to develop clinical prediction instruments to identify patients with a low likelihood of obstructive CAD, and coronary computed tomographic (CT) angiography has emerged as an alternative imaging technique for coronary anatomy and CAD diagnosis.72 Computed tomographic (CT) angiography provides an opportunity to noninvasively investigate plaque morphology that may yield a better understanding of the severity of CAD in lower-risk women or those with stable disease as opposed to acute high-risk cases.73,74

Nurses in the community have an important role to play in educating women with the right messages about heart disease prevention and enabling them to become their own best advocates. The key messages are that heart disease affects women as well as men and that anyone older than 45 years (or 35 years for Aboriginal/Torres Strait Islanders) should ask their family doctors/general practitioners for an annual assessment of their absolute risk of cardiovascular disease.75 Women also need to be regularly reminded of their modifiable risk factors (smoking, cholesterol, blood pressure, diabetes, physical inactivity, body mass index ≥25 kg/m2, and depression or social isolation).14,75 Therefore, a healthy diet and regular exercise are paramount, although pharmacological support is available if needed. Nurses also need to raise awareness that women are more likely to experience atypical symptoms of ACS. These include jaw pain, nausea, unexplained shortness of breath, sweating, back/shoulder pain, and epigastric pain.14,76 Risk stratification and subsequent utilization of appropriate invasive or noninvasive diagnostic tests should be promoted within hospitals and applied without gender bias. Nurses therefore need to be familiar with the risk stratification process and encourage more widespread use of risk-scoring instruments in clinical practice to help ensure equitable use of secondary prevention therapies.

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Limitations

A limitation of this review is that we were unable to find any studies directly examining the relationship between gender, risk stratification, and the use of coronary angiography; hence, we were unable to present the results regarding use of cardiac catheterization within the risk group by gender. Therefore, we recognize that the relationship between risk stratification and lower rates of angiography may involve factors aside from gender. The lack of studies may be due to the relatively recent incorporation of risk scores as a method of risk stratification in American College of Cardiology Foundation/American Heart Association and European guidelines. However, it also reflects the need for further research assessing the prevalence, efficacy, and efficiency of various methods of risk stratification in hospital settings and more fully understand the role of gender within the broader treatment-risk paradox. Observational study cohorts included in the review may lack generalizability because of possible patient selection bias in different studies. However, the representation of women in studies included in our review is unlikely to affect the findings.

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Conclusions

Contrary to our hypothesis, this review showed that women with NSTEACS are more likely than men to be high-risk when stratified using a range of risk assessment methods. Lower rates of angiography in women form part of a broader treatment-risk paradox, which may involve gender bias in the selection of patients for invasive therapy.

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What’s New and Important

* Women with non–ST-segment elevation acute coronary syndrome (NSTEACS) are less likely to receive coronary angiography than men, although they have 23% higher probability of being stratified as high-risk.

* Patients stratified as high-risk are less likely to receive coronary angiography than those without high-risk features.

* Both issues are contrary to guidelines for using coronary angiography among patients with NSTEACS.

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Keywords:

acute coronary syndrome; angiogram; meta-analyses; risk stratification; women

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