Symptoms of acute coronary syndrome in women with diabetes: An integrative review of the literature

Symptoms of acute coronary syndrome in women with diabetes: An integrative review of the literature Sharon A. Stephen, RN, GNP, PhD, Blair G. Darney, MPH, and Anne G. Rosenfeld, PhD, RN, CNS, FAAN, FAHA

OBJECTIVE: To review studies comparing multiple acute coronary syndrome (ACS) symptoms in white and Latina women with and without diabetes. METHODS: This empirical integrative review summarizes 8 studies and identifies the limitations of research to date. RESULTS: There are conflicting results about acute coronary syndrome (ACS) symptoms in women with diabetes. Differences were found in associated ACS symptoms and symptom characteristics; however, some studies found no differences in frequency of chest pain by diabetic status. Diabetes is an independent predictor of “atypical” presentation of acute myocardial infarction in women, and research to date suggests that shortness of breath may be an important ACS symptom in women with diabetes. CONCLUSIONS: There is a paucity of literature on ACS symptoms in women, particularly Latina women, with diabetes, and results are inconclusive. Future research should examine the full range of ACS symptoms in multiethnic samples of women with diabetes. (Heart Lung® 2008;37:179 –189.)

D

iabetes incidence has increased dramatically in the white1 and Latino2 populations in the United States. Cardiovascular disease, notably coronary heart disease (CHD), is the most common and lethal complication of diabetes,3 particularly in women. Although CHD deaths have decreased 27% in women without diabetes, they have increased 23% in women with diabetes.4 In addition, Latinos have a higher burden of type 2 diabetes and subsequent complications, such as CHD, than do whites.5-8 Acute coronary syndrome (ACS), which includes myocardial infarction (MI) and unstable angina,9,10 is the most common clinical manifestation of CHD in those with and without diabetes. Women with ACS are less likely than men to present with chest From School of Nursing, Oregon Health & Science University, 3455 S.W. US Veterans Hospital Rd., Mail Code SN-5N, Portland, OR 97239-2941. Corresponding author: Anne G. Rosenfeld, PhD, RN, CNS, FAAN, FAHA, School of Nursing, Oregon Health and Science University, 3455 S.W. United States Veterans Hospital Rd., Mail Code SN-5N, Portland, OR 97239-2941. 0147-9563/$ – see front matter Copyright © 2008 by Mosby, Inc. doi:10.1016/j.hrtlng.2007.05.006

HEART & LUNG

VOL. 37, NO. 3

pain and may experience different or “atypical” acute MI symptoms.11 However, little is known about the range of ACS symptoms experienced by women with diabetes, a high-risk group for ACS morbidity and mortality. To date, most work has focused on the presence or absence of chest pain in persons with diabetes.12,13 Studies that explore a broad array of ACS symptoms often include diabetes as a control variable, obscuring its possible role in symptom presentation.14,15 An understanding of the range of ACS symptoms in white and Latina women with diabetes is a first step to help women and their health care providers recognize early symptoms and take action to seek medical care quickly, thus decreasing morbidity and mortality from CHD. Published research reports of ACS symptoms in white and Latina women with diabetes have not been synthesized. The purpose of this article was to review published studies that compared ACS symptoms in women with and without diabetes. Latinas are included because of the high and growing burden of diabetes in the Latina population. The term Latino/a is used to refer to persons of Western Hemisphere Latin American ancestry.16 Other terms

www.heartandlung.org

179

Acute coronary syndrome in women with diabetes

are used when the primary investigators do so (eg, Cuban, Mexican American), but these groups are included in the definition of Latino/a. This paper summarizes findings, provides a critique of study methods, discusses limitations of research to date, and presents recommendations for future research.

BACKGROUND AND SIGNIFICANCE Both incident and prevalent cases of diabetes are increasing in the United States population.1-3 Nearly 10 million women, or 8.8% of women ⬎20 years old, have diabetes.3 Diabetes prevalence is 2 to 4 times greater in Latinos compared with nonHispanic whites.17 Prevalence reaches 1 in 3 in Mexican-American women ⬎60 years old, a subgroup of Latinas,6,18 compared with 1 in 5 in the general population ⬎60 years old.3

Diabetes, coronary heart disease, sex, and ethnicity Between 65% and 80% of persons with diabetes die from cardiovascular disease.17,19,20 Diabetes is a CHD equivalent in both men and women21-23; however, women experience a differential potency not explained by other cardiac risk factors.24-27 Research has shown that diabetes deletes the female cardiovascular survival advantage, although the extent of the interaction between diabetes and sex is not fully understood.25,28-31 Women with diabetes bear higher morbidity and mortality from CHD than do men with diabetes.32-34 At the onset of diabetes-related cardiovascular complications, women have higher out-of-hospital mortality than do men, and those who reach the hospital are more likely to die from an initial cardiac event.35 Women with diabetes who survive an initial cardiac event are at high risk for postevent complications (recurrent MI, heart failure, and death).22,36-38 Low cardiovascular and all-cause mortality have been documented in the Latino population compared with whites,39,40 as have good outcomes after a cardiovascular event.41,42 The phenomenon of good outcomes despite a high risk-factor burden in the Latino population is termed the “Hispanic paradox.” However, recent longitudinal findings have not supported the Hispanic paradox.43-48 Latinas with diabetes had similar mortality rates (all-cause and CHD) as white women in the San Luis Valley Diabetes Study.45 In the Corpus Christi Heart Project, Mexican-American women bore the greatest burden of CHD death46 and experienced the highest case-fatality rate after hospitalization for MI com-

180

www.heartandlung.org

Stephen et al

pared with Mexican-American men and white men and women.47 Similarly, the San Antonio Heart Study reported that Latinos with diabetes were at much higher risk of CHD mortality than whites with diabetes.43 Unfortunately, Latinas have been underrepresented in cardiovascular research, so the magnitude of disparities in treatment and outcomes based on ethnicity and sex together is not known.49

Symptom recognition and treatment-seeking delay There is a growing body of research on the meaning, management, and symptoms of type 2 diabetes in white50 and Latina women.51-54 Remarkably, there has been little attention to acute cardiac symptoms in the context of diabetes. Diabetes and female sex are risk factors for MI without chest pain12,55; lack of chest pain may make symptom recognition more difficult. In addition, patients with diabetes may misinterpret their symptoms as changes in blood glucose levels and thus misattribute cardiac symptoms to their diabetes.56 Failure to recognize ACS symptoms may lead to treatment-seeking delay57-59 and thus contribute to the high cardiovascular morbidity and mortality in women with diabetes.60 Reports demonstrate that patients with diabetes delay longer than patients without diabetes57,61 and that women with ACS symptoms delay longer than do men.62-64 Likewise, ethnicity and race are predictors of treatment-seeking delay.41,65,66 Women with diabetes, particularly Latinas, may be at high risk of delay. Treatmentseeking delay for ACS symptoms is dangerous; delay increases the risk of out-of-hospital death and interferes with receiving timely reperfusion therapies.67

METHODS This article is based on an empirical integrative review method.68,69 An empirical integrative review is a summary of the literature in which relevant empirical studies are summarized and analyzed and conclusions are drawn.69 This review is limited to English-language published research reports that compared a range of ACS symptoms in men and women with and without diabetes. First, a search of medical and nursing literature in the MEDLINE (1966 to 2006) and CINAHL (1982 to 2006) databases was executed. Keywords included “acute coronary syndrome,” “myocardial infarction,” “unstable angina,” “coronary heart disease,” “coronary artery disease,” “diabetes mellitus,” “symptoms,” “chest pain,” “Latinas/Hispanics,” and “women.” Next, an-

MAY/JUNE 2008

HEART & LUNG

Stephen et al

Acute coronary syndrome in women with diabetes

cestry searching was performed by hand and citation analysis was performed with a computerized database.70 The first and second investigators independently reviewed all 8 studies, using a matrix to systematically critique study designs, samples, measures, results, and findings. These independent reviews were then combined and discrepancies discussed with participation of the third investigator until consensus was achieved.

Literature review: ACS symptoms in women with diabetes The literature on ACS symptoms in women with diabetes is sparse; 8 studies were found that examined multiple presenting symptoms of ACS in men and women with and without diabetes15,61,71-76 (Table I). Not all studies reported analyses by sex and diabetic status. Only 1 study reported findings for women with diabetes,72 and only 1 study reported findings for Latinos,15 despite broad search and inclusion criteria. The range of ACS in these studies varied from a narrow definition—first MI—to the inclusion of patients with unstable angina and MI. All of the studies were descriptive, and some of the studies relied solely on pooled registry data or chart review data. Only 1 study employed qualitative methods. Differences were found in associated ACS symptoms and symptom characteristics; however, some studies found no differences in frequency of chest pain by diabetic status. The overall results were conflicting and inconclusive about whether diabetic status affects women’s ACS symptom experience. In the only study reviewed to report subgroup analyses of women with diabetes, Cˇulic´ et al72 found that diabetes is an independent predictor of “atypical” presentation of acute MI in women. Sex differences were found in the location of pain: women reported more back, arm, neck, and jaw pain than men.72 In analyses adjusted for age, cardiac enzyme levels, smoking, hypertension, diabetes, and hypercholesterolemia, men were less likely to report any nonpain symptoms (odds ratio [OR] 0.74 and 95% CI 0.57 to 0.95) as well as dyspnea (OR 0.66 and 95% CI 0.55 to 0.81) and nausea (OR 0.62 and 95% CI 0.51 to 0.81]) compared with women.72 Similarly, men were more likely than women to report any pain associated with acute MI (OR 1.59 [95% CI 1.18 to 2.13]).72 Patients with diabetes also reported less pain (OR 0.71 and 95% CI 0.52 to 0.97) and more nonpain symptoms (OR 1.31 and 95% CI 1.11 to 1.66) compared with patients without diabetes (adjusted for age, sex, cardiac enzyme levels, smoking, hyperten-

HEART & LUNG

VOL. 37, NO. 3

sion, and hypercholesterolemia).72 These findings were in women with acute MI, a narrow spectrum of ACS. Results have been mixed in ACS samples that were not limited to acute MI. Coronado et al reported that diabetes was an independent predictor of painless presentation in the acute MI subgroup but not in the total ACS group.71 More women had painless presentation compared with painful presentation in this sample (53% vs 42%, P ⫽ .007); however, female sex was not an independent predictor of painless presentation of ACS in multivariate analysis.71 The frequency of diabetes was significantly higher with painless compared with painful presentation (35% vs 26%, P ⫽ .01).71 Mackenzie and Neibert61 found that patients with unstable angina and diabetes reported less pain intensity compared with patients without diabetes (P ⫽ .09). In contrast, several investigators73-76 found no difference in ACS symptoms by diabetic status. Thuresson et al76 found that the presence or absence of diabetes was not a factor in any of the descriptions of the ACS symptoms except for a trend for decreased arm pain in patients with diabetes. The words used by patients to describe their ACS symptoms were further categorized as describing either the sensory component (such as burning) or the emotional component (such as frightening).76 No differences were found in the sensory or emotional component descriptor words used to describe the ACS symptom experience by diabetic status.76 However, another study found that patients with diabetes were more likely to feel very threatened by their symptoms (44.9% vs 36.4%, P ⬍.05).74 Although several studies found no differences in frequency of chest pain with ACS between patients with and without diabetes,15,73-76 differences were found in symptom location,15,61 quality,73 radiation,61,76 and associated symptoms.15,72,73 Shortness of breath was identified by several studies61,71,72,74 as an important ACS symptom in women and/or persons with diabetes.

Limitations of research to date The little research to date on women’s ACS symptoms in the context of diabetes has several limitations. Investigators have identified selection bias as a key limitation.71 Chest pain is often an inclusion criterion in this body of research,15,71,73,76 thus excluding those without chest pain, painless presentation, or “atypical” symptoms. For example, DeVon et al reported that 97% of their sample reported chest pain, but chest pain was among the inclusion criteria, and this finding is thus likely a result of

www.heartandlung.org

181

www.heartandlung.org

Study Meshack et al 1998

Sample N ⫽ 589 (203 women; 296 M-A 50 M-A women with DM and 38 white women with DM); DM prevalence ⫽ 39%

Setting/country Critical care or Intermediate cardiac unit/ USA

Design/measures Descriptive, cross-sectional; structured interview (presence of 12 symptoms during event); chart data collected 4 to 5 days after admission

Inclusion Hospitalized with acute cardiac ischemia (AMI, UA, chest pain)

Limitations Excluded asymptomatic (n ⫽ 34); no subgroup analyses by ethnicity, sex, and DM status; recall bias

Strengths Included Latinas; range of symptoms; multiple data sources

Findings ●

●

●

●

●

Richman et al 1999

MacKenzie and Neibert 2001

N ⫽ 216 (19 women with DM); DM prevalence ⫽ 24%

MAY/JUNE 2008

N ⫽ 64 (12 women with DM) DM prevalence ⫽ persons with DM oversampled to achieve equal groups (n ⫽ 32 each)

ED/USA

CCU/Canada

Rule-in AMI; present to ED with ⱖ1 of the following: chest pain, SOB, nausea, Abdominal pain, diaphoresis

Descriptive, cross-sectional; mixed methods; semistructured interview, pain intensity scale, body diagram, and chart data collected within 24 hours of admission to CCU

UA and MI

No subgroup analyses by sex and DM status; narrow spectrum of ACS; excluded persons with no symptoms (silent MI); included persons with acute HF changes in MI diagnostic procedures since data collected No subgroup analyses by sex and DM status; selection bias (DM oversampled: 75 patients ineligible because of absence of DM); approximately 75% of persons with and without DM had previous CHD, thus not a naive sample; qualitative data quantified for analyses

Multiple data sources

●

●

Qualitative and quantitative methods; data collected soon after event

●

●

●

●

●

Patients with DM and UA reported less pain intensity than those without DM (P ⫽ .02) No difference in pain intensity between MI patients with and without DM (P ⱖ .05) Patients with DM and UA or MI were more likely to report midsternal chest pain (P ⫽ .04) and chest pain that radiated to the back of the left arm (P ⫽ .01) than those without DM Patients with DM and UA or MI reported more shortness of breath (53.1% vs 31.3%; NS) In patients with DM and UA or MI, shortness of breath was a factor in deciding to seek care Continued

Stephen et al

HEART & LUNG

Descriptive, cross-sectional; close-ended questionnaire and chart data collected at presentation

Chest pain the most common symptom (83.2% of total sample; NS difference between DM [80.4%, n ⫽ 230] and no DM [84.6%, n ⫽ 359]) No significant difference in frequency of chest pain by diabetic status (P ⬎ .05) Patients with DM reported more upper back pain and lower frequency of indigestion (P ⬎ .05) than those without DM Women reported less chest pain (P ⬎ .05) and more “atypical” symptoms (P ⬎ .05; fatigue, dyspnea, dizziness, palpitations, cough, and upper back pain) M-A women reported more chest pain that white women (P ⬍ .05) but less chest pain than M-A and white men (P ⬍ .05) No difference in frequency of chest pain or associated symptoms by diabetic status (P ⱖ .05) Chest pain absent in more patients with than without DM (NS)

Acute coronary syndrome in women with diabetes

182

Table I ACS symptoms in women with diabetes: evidence from 8 studies

Stephen et al

HEART & LUNG

Table I Continued Study

VOL. 37, NO. 3

Cuˇlic´ et al 2002

Kentsch et al 2003

N ⫽ 1996 (601 [30%] women and 243 [12%] women with DM); DM prevalence ⫽ women 40.4% and men 22.1%; P ⬍ .0001

N ⫽ 1042 (330 women; 155 women with DM) DM prevalence: women more likely to be in DM group; P ⬍ .0001

N ⫽ 2541 (1058 women, 410 women with DM); DM prevalence ⫽ 30%

Setting/country CCU/Croatia

ICC/Germany

ED/USA

Design/measures

www.heartandlung.org

Descriptive, cross-sectional (enrollment spanned 4.5 years); structured interview (recall symptoms at onset of MI, including prodromal symptoms, pain at MI, location of pain) and chart data collected 3 (median) days after MI Secondary analysis of pooled data from 2 large registries (N ⫽ 19,828); analysis included only those with data on multiple symptoms; structured interview (symptom severity and location) Secondary analysis of multisite registry; chart data and standard criteria used to classify subjects as painful or painless presentation

Inclusion First MI

Limitations

Strengths

Narrow spectrum of ACS (confirmed MI only); recall bias; protocol drift

Analyses reported by sex and DM status; multiple data sources; sample naïve to cardiac symptoms; large sample; controlled for enzyme levels, smoking, hypertension, hypercholesterolemia

Findings ●

●

●

●

ST-elevation MI; present within 96 hours of pain or 1 week after MI

ACS diagnosis

No subgroup analysis by sex and DM status; narrow spectrum of ACS (confirmed STelevation MI only); potentially confusing pooled data reporting strategy; more patients with DM had a previous MI than those without DM (22.6% vs 15.8%; P ⬍ .05)

Large sample; multiple symptoms

Chart data only; grouped variety of symptoms into pain/painless; no subgroup analyses by sex and DM status

Large sample

●

●

●

●

●

●

●

DM an independent predictor of “atypical” acute MI presentation (absence of pain [P ⫽ .002] & nonpain symptoms [P ⫽ .005]) in women with DM and first MI Men and women with DM reported less pain with MI (OR ⫽ 0.71 [0.52– 0.97]) and had more nonpain symptoms (OR ⫽ 1.31 [1.11–1.66]) than those without DM (adjusted results) Women reported more back, arm, neck, and jaw pain, and more dyspnea and nausea than men Women reported more nonpain symptoms than men No difference in frequency or intensity of chest pain by diabetic status Patients with DM reported significantly more dyspnea than those without DM (29.5% vs 19.5%; P ⬍ .01) Patients with DM more likely to feel “very threatened” by their symptoms (P ⬍ .05)

Women more likely to have painless (53%) compared with painful (42%) ACS presentation (⫽ .007) Frequency of diabetes greater with painless compared with painful presentation (35% vs 26%; P ⫽ .01). Shortness of breath most common chief complaint in the painless presentation group (72%) DM independent predictor of painless presentation in acute MI subgroup but not in total ACS group Continued

183

Acute coronary syndrome in women with diabetes

Coronado et al 2004

Sample

www.heartandlung.org

Study

Sample

Setting/country

Design/measures

DeVon et al 2005

N ⫽ 100 (50 women, 23 women with DM); DM prevalence ⫽ 40%

CCUs and Intermediate cardiac units of 2 hospitals/ USA

Secondary analysis; descriptive, crosssectional; structured interview and chart at least 12 hours after admission

Thuresson et al 2005

N ⫽ 1939 (480 women, 82 women with DM); DM prevalence ⫽ approximately 15%

Critical care Cardiac unit/ Sweden

MAY/JUNE 2008

Multihospital descriptive, crosssectional; closeended questionnaire (symptom severity and sensory/emotional descriptor words) and chart data collected during hospital stay (timing not specified)

Inclusion UA diagnosis admitted by way of ED

Out-of-hospital onset of chest pain/discomfort, ACS, and admission to CCU

Limitations

Strengths

Group differences (previous angiogram [P ⫽ .04] and CHD history [P ⫽ .03] more frequent in patients with DM); excluded those without chest pain; no subgroup analyses by sex and DM status; recall bias; sample not naïve to cardiac symptoms (high Proportion of CHD in total sample); included patients with HF

Multiple data sources (interview and chart)

Excluded those without chest pain; excluded those who did not present with painful symptoms or admitted to noncritical bed; no subgroup analyses by sex and DM status; large number of statistical tests required significance level P ⫽ .01

Large sample; compared symptom severity with characteristics multiple data sources (questionnaire and chart); controlled for cardiac risk factors

Findings ●

●

●

●

●

●

●

●

Similar frequency and severity (P ⱖ .05) of chest pain in those with and without DM (however, chest pain was an inclusion criterion) No differences in symptoms of UA by diabetic status. Patients with DM reported weakness as second most common symptom and more likely to describe chest pain as squeezing (P ⫽ .02) or aching (P ⫽ .04) than patients with DM Patients with DM reported higher frequency of hyperventilation (P ⫽ .04) and lower frequency of nausea (P ⫽ .04) than patients without DM Women reported more tiredness/ weakness, anxiety/fear, vomiting, back pain, left arm pain, and neck or jaw pain than men (P ⫽ ⱖ .01). No difference in chest pain or other ACS symptoms by DM status Patients without DM had more arm pain than those with DM (left arm [P ⫽ .02]; right arm [P ⫽ .03]) No differences in emotional/sensory words used to describe symptoms by DM status

Acute coronary syndrome in women with diabetes

184 Table I Continued

Atypical ⫽ term used by investigators to describe a variety of ACS symptom presentations, including absence of chest pain; CCU ⫽ critical care unit; DM ⫽ diabetes; ED ⫽ emergency department; HF ⫽ heart failure; M-A ⫽ Mexican-American; NS ⫽ not significant; SOB ⫽ shortness of breath; UA ⫽ unstable angina

Stephen et al

HEART & LUNG

Stephen et al

Acute coronary syndrome in women with diabetes

selection bias.73 In addition, many studies do not control for history of CHD61,71,73,74,76 and heart failure.71,73-76 Interpretation of symptoms may be altered by a history of CHD or heart failure. Three of the 8 studies focused exclusively on MI, a narrow spectrum of ACS. In addition, duration of diabetes was not included as a covariate in these studies; however, investigators have recognized the potential impact of duration of diabetes on symptoms and recommended including these data in future research.73,75 Variation in symptom measurement is another key limitation of the studies reviewed here. Datacollection methods included checklists,15,73 chart review,71 structured interview,72,74,75 and semistructured interview.61,76 Forced-choice questionnaires, common in symptom research, may not capture the range of symptoms experienced. Mackenzie and Neibert61 conducted a qualitative study, but then quantified their results for analysis. One study used chart data only,71 but most collected symptom data directly from patients. The use of different instruments makes comparisons across studies difficult and precluded performing a meta-analysis. The small sample sizes of some of the studies reviewed here have resulted in several limitations. Investigators were not able to examine, or did not report, subgroup differences by sex, ethnicity, and diabetic status; only 1 study reviewed here presented results for women with diabetes.72 Alarmingly, only 1 study presented results by ethnicity,15 resulting in the sparsest data for populations at highest risk for diabetes and ACS. Inadequate power to detect differences in ACS symptoms was another result of small sample sizes. If differences in ACS symptoms exist between women with and without diabetes, it is possible that research to date has not been able to capture the difference. Last, diabetes, sex, race, and ethnicity are often control variables in analyses, making it difficult to assess their combined effects.15 Future research should present subgroup analyses and interaction effects of sex, ethnicity, and diabetic status.

Strengths of research to date Despite the limitations discussed above, existing research on ACS symptoms in women with diabetes is useful. Pooling the studies reviewed here, data for 1032 women with diabetes and ACS are available. However, only Cuˇlic´ et al72 provided subgroup analyses for women with diabetes (n ⫽ 243). These studies cover the spectrum of ACS in a broad sample, including European and Canadian women.

HEART & LUNG

VOL. 37, NO. 3

Most studies collected symptom data directly from patients soon after their ACS event, and some studies included a wide range of symptoms72,74-76 and included women who presented without chest pain.61,71,72,75 The one study that performed analyses of “atypical” MI symptom frequency (defined by the investigators as absence of pain and nonpain symptoms) by sex found that diabetes is an independent predictor of “atypical” presentation of acute MI in women.72 The sample was presumably naive to acute ischemic symptoms (only first MIs were included), and group sizes were adequate to provide subgroup analyses by sex and diabetic status.72 In addition, the statistical analyses controlled for factors such as age, cardiac risk factors, and size of MI.72 Most of the studies in this review included multiple sources of data.15,61,72,73,75,76 Some studies had large samples but failed to report subgroup analyses.71,74 Thuresson et al76 provided data comparing ACS symptom severity and characteristics, in addition to frequency, between patients with and without diabetes.76 Mackenzie and Neibert61 reported the only study to employ both quantitative and qualitative methods. Qualitative interview data provided depth and detail about the shortness of breath experienced by patients with diabetes: Patients with diabetes described shortness of breath as a factor in their decision to seek help.61 Finally, Meshack et al15 provided the only report of ACS symptoms in Latina women. This study extended the knowledge about the frequency of selected ACS symptoms in Latina women and found that the frequency of chest pain in women varied by ethnic status.15

SUMMARY The largest study to date that presents subgroup analyses, by Cuˇlic´ et al,72 found that diabetes was an independent predictor of “atypical” presentation of acute MI in women. Several studies reported that patients with diabetes had less pain compared with patients without diabetes61,71,72,75; 1 study reported that diabetes was an independent predictor of painless presentation for ACS,71 but analyses of women were not presented. These 8 studies point to differences in ACS symptoms with a greater prevalence of “atypical” symptoms in patients with diabetes.61,71,72 In addition, the absence of chest pain was more common in patients with diabetes.71,75 Only 1 study could be found that reported ACS symptoms in Latinas,15 but diabetes was a control variable. However, the literature suggests that ACS symptoms may vary by race and ethnicity.15,65,77,78 Data

www.heartandlung.org

185

Acute coronary syndrome in women with diabetes

on ACS symptoms in women with diabetes are inadequate, but Cuˇlic´ et al’s72 large study suggests that nonpain or “atypical” symptoms (such as shortness of breath) may be common in women with diabetes and MI.

Chest pain, shortness of breath, and blood glucose levels Despite existing evidence that women with diabetes may present without chest pain,12 this review of studies that investigated multiple symptoms highlights the weakness of our evidence base about the range of symptoms in white and Latina women with diabetes. Most work to date has focused on the presence or absence of chest pain, the hallmark symptom of ACS in men.12 However, McSweeney et al’s11 seminal description of women’s prodromal and acute MI symptoms documented that only 57% of women with MI presented with acute chest pain. Restricting eligibility to presenting with chest pain has eliminated many women with and without diabetes from ACS symptom study protocols. MI without chest pain, regardless of diabetic status, is an independent predictor of 30-day mortality12,55; painless presentation has also been identified as an independent predictor of hospital mortality in patients with ACS.71 Shortness of breath has been documented as among the most common acute symptoms of ACS in women.11 In addition, women with diabetes and symptoms suggestive of CHD (but not documented ACS and therefore not included in our review) reported high frequency of shortness of breath.79 The literature suggests that shortness of breath may be a defining ACS symptom for women with diabetes.56,61,71,72,74 However, shortness of breath may be confounded by heart failure because the initial ACS diagnosis in patients with diabetes may be made when these patients present in acute heart failure. In addition, heart failure is an independent predictor of painless presentation of ACS.71 Symptom interpretation is especially complicated in the context of multiple symptoms and multiple chronic illnesses. Symptoms, such as chest pain or discomfort and shortness of breath, may not be identified as cardiac in origin because of other concurrent symptoms. Similarly, abnormalities in blood glucose levels may confound the interpretation of ACS symptoms.56 None of the studies reviewed reported data on blood glucose levels. Glucose levels are important because increased blood glucose is an independent predictor of CHD mortality.80

186

www.heartandlung.org

Stephen et al

This review must be interpreted with the following limitations: no firm conclusions can be drawn based on available evidence; there is possible publication bias because only published research reports were included; and it is possible that published research was omitted, but our review methodology followed standard and rigorous procedure.68

IMPLICATIONS Building on the strengths of the studies reviewed here, future research should seek to describe the range of ACS symptoms experienced by women with diabetes. In particular, symptom characteristics, such as location, radiation, quality, severity, interpretation, and response, must be described. Study samples should include the full spectrum of ACS but should be limited to those naive to ACS symptoms and those without previous known heart failure. Study samples must also include those who have often been excluded from research to date: treatment-seeking delay ⬎6 hours, lack of chest pain, and painless presentation or “atypical” symptoms. In addition, study samples should be racially and ethnically diverse, and studies that include Latinas should collect data on acculturation, country of origin, and region and length of residence in the United States to begin to describe the impact on outcomes81 and the heterogeneity of the Latina population.82 Data-collection strategies must allow the full range of ACS symptoms to be documented. Researchers should seek to fully describe chest pain and associated symptoms, moving beyond a presence-or-absence dichotomy to explore quality of chest discomfort and other symptoms as well as patient interpretation and response to symptoms. In addition, studies must include blood glucose levels and type and duration of diabetes. Quantitative studies need to be large enough to permit subgroup analyses and interaction effects of sex, ethnicity, and diabetic status. In-depth qualitative studies may be best suited to capturing rich descriptions of the full array of ACS symptoms in women with diabetes. Significant gaps remain in our knowledge of ACS symptoms in women with diabetes. In contrast with the extensive research on diabetes management, there has been very little research focused on ACS symptoms in women with diabetes, despite the fact that CHD is the primary complication of the disease. Evidence is especially weak for nonwhite women and for those who present without chest pain. The

MAY/JUNE 2008

HEART & LUNG

Stephen et al

Acute coronary syndrome in women with diabetes

range of ACS symptoms in women with diabetes or their responses to symptoms and treatment-seeking delay processes has yet to be understood. The literature is inconclusive about possible differences in ACS symptoms in women with and without diabetes. Women with diabetes and ACS may experience a range of symptoms other than chest pain, and the absence of chest pain may contribute to difficulty attributing their symptoms to a cardiac cause. Research to date suggests that shortness of breath may be an important symptom in women with diabetes and ACS.56,61,72,74 Future research should examine the full range of ACS symptoms in multiethnic samples of women with diabetes, including the role of shortness of breath, blood glucose levels, and duration of diabetes. This work was supported by postdoctoral fellowship funding from the National Institute of Nursing Research, National Institutes of Health, Grant No. 5 T32 NR007061 (S. A. S.) and by Oregon Health & Science University School of Nursing intramural funding.

REFERENCES

12.

13.

14. 15.

16.

17.

1. Fox CS, Pencina MJ, Meigs JB, Vasan RS, Levitzky YS, D’Agnostino RB. Trends in the incidence of type 2 diabetes mellitus from the 1970s to the 1990s. The Framingham Heart Study. Circulation 2006;113:2914-8. 2. Burke JP, Williams K, Gaskill SP, Hazuda HP, Haffner SM, Stern MP. Rapid rise in the incidence of type 2 diabetes from 1987 to 1996. Results from the San Antonio heart study. Arch Intern Med 1999;159:1450-6. 3. Centers for Disease Control and Prevention. National diabetes fact sheet: General information and national estimates on diabetes in the United States, 2005. United States Department of Health and Human Services. Available at: http:// www.cdc.gov/diabetes/pubs/factsheet05.htm. Accessed: June 30, 2006. 4. Gu K, Cowie CC, Harris MI. Diabetes and decline in heart disease mortality in US adults. JAMA 1999;281:1291-7. 5. Carter JS, Pugh JA, Monterrosa A. Non-insulin-dependent diabetes mellitus in minorities in the United States. Ann Intern Med 1996;125:221-32. 6. Stern MP, Mitchell BD. Diabetes in Hispanic Americans. In: National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases, editor. Diabetes in America. 2nd ed. Bethesda, MD: National Institutes of Health; NIH No. 95-1468. 1995:631-59. 7. American Diabetes Association. Diabetes statistics for Latinos. Available at: www.diabetes.org/utils/printhtispage.jsp? PageID⫽STATISTICS_233187. Accessed: May 4, 2005. 8. Haffner SM, Mitchell BD, Stern MP, Hazuda HP. Macrovascular complications in Mexican Americans with type 2 diabetes. Diabetes Care 1991;14:665-71. 9. Cannon CP, Battler A, Brindis RG, Cox JL, Ellis SG, Every NR, et al. American College of Cardiology key data elements and definitions for measuring the clinical management and outcomes of patients with acute coronary syndromes. A report of the American College of Cardiology Task Force on Clinical Data Standards (Acute Coronary Syndromes Writing Committee). J Am Coll Cardiol 2001;38:2114-30. 10. Luepker RV, Apple FS, Christenson RH, Crow RS, Fortmann SP, Goff D, et al. Case definitions for acute coronary heart

HEART & LUNG

11.

VOL. 37, NO. 3

18.

19. 20.

21.

22.

23.

24.

25.

26.

disease in epidemiology and clinical research studies: a statement from the AHA Council on Epidemiology and Prevention; AHA Statistics Committee; World Heart Federation Council on Epidemiology and Prevention; the European Society of Cardiology Working Group on Epidemiology and Prevention; Centers for Disease Control and Prevention; and the National Heart, Lung, and Blood Institute. Circulation 2003;108:2543-9. McSweeney JC, Cody M, O’Sullivan P, Elberson K, Moser DK, Garvin BJ. Women’s early warning symptoms of acute myocardial infarction. Circulation 2003;108:2619-23. Canto JG, Shlipak MG, Rogers WJ, Malmgren JA, Frederick PD, Lambrew CT, et al. Prevalence, clinical characteristics, and mortality among patients with myocardial infarction presenting without chest pain. JAMA 2000;283:3223-9. Brieger D, Eagle KA, Goodman S, Steg PG, Budaj A, White K, et al. Acute coronary syndromes without chest pain, an underdiagnosed and undertreated high-risk group. Insights from the Global Registry of Acute Coronary Events. Chest 2004;126:461-9. Chen W, Woods SL, Puntillo KA. Gender differences in symptoms associated with acute myocardial infarction: a review of the research. Heart Lung 2005;34:240-7. Meshack AF, Goff DC, Chan W, Ramsey D, Linares A, Reyna R, et al. Comparison of reported symptoms of acute myocardial infarction in Mexican Americans versus non-Hispanic Whites (The Corpus Christi Heart Project). A J Cardiol 1998;82:1329-32. Suarez L, Ramirez AG. Hispanic/Latino health and disease. In: Huff RM, Kline MV, editors. Promoting health in multicultural populations. A handbook for practitioners. Thousand Oaks, CA: Sage; 1999. Engelgau MM, Geiss LS, Saaddine JB, Boyle JP, Benjamin SM, Gregg EW, et al. The evolving diabetes burden in the United States. Ann Intern Med 2004;140:945-50. Flegal KM, Ezzati TM, Harris MI, Haynes SG, Juarez RZ, Knowler WC, et al. Prevalence of diabetes in Mexican Americans, Cubans, and Puerto Ricans from the Hispanic Health and Examination Survey (HHANES), 1982-84. Diabetes Care 1991;14:628-38. O’Keefe JHJ, Miles JM, Harris WH, Moe RM, McCallister BD. Improving the adverse cardiovascular prognosis of type 2 diabetes. Mayo Clin Proc 1999;74:171-80. Geiss LS, Herman WH, Smith PJ. Mortality in non-insulindependent diabetes. In: National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases, editor. Diabetes in America 2nd ed. Bethesda, MD: National Institutes of Health; NIH No. 95-1468; 1995:233-58. Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laasko M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 1998;339:229-34. Malmberg K, Yusuf S, Gerstein HC, Brown J, Zhao F, Hunt D, et al. Impact of diabetes on long-term prognosis in patients with unstable angina and non-Q-wave myocardial infarction. Results of the OASIS (Organization to Assess Strategies for Ischemic Syndromes) registry. Circulation. 2000;102:1014-9. Grundy SM, Benjamin IJ, Burke GL, Chait A, Eckel RH, Howard BV, et al. Diabetes and cardiovascular disease. A statement for healthcare professionals from the American Heart Association. Circulation 1999;100:1134-46. Natarajan S, Liao Y, Cao G, Lipsitz SR, McGee DL. Sex differences in risk for coronary heart disease mortality associated with diabetes and established coronary heart disease. Arch Intern Med 2003;163:1735-40. Becker A, Bos G, DeVegt F, Kostense PJ, Dekker JM, Nijpels G, et al. Cardiovascular events in type 2 diabetes: comparison with nondiabetic individuals without and with prior heart disease. Eur Heart J 2003;24:1406-13. Hu G, Jousilahti P, Qiao Q, Peltonen M, Katoh S, Tuomilehto J. The gender-specific impact of diabetes and myocardial infarction at baseline and during follow-up on mortality from

www.heartandlung.org

187

Acute coronary syndrome in women with diabetes

27.

28. 29. 30. 31. 32. 33.

34.

35. 36. 37.

38.

39.

40.

41.

42.

43.

44.

all causes and coronary heart disease. J Am Coll Cardiol 2005;45:1413-8. Whiteley L, Padmanabhan S, Hole D, Isles C. Should diabetes be considered a coronary heart disease risk equivalent? Results from 25 years of follow-up in the Renfrew and Paisley Survey. Diabetes Care 2005;28:1588-93. Barrett-Connor EL, Cohn BA, Wingard DL, Edelstein SL. Why is diabetes mellitus a stronger risk factor for fatal ischemic heart disease in women than in men? JAMA 1991;265:627-31. Brandenburg SL, Lindenfeld J, Reusch JEB, Regensteiner JG. Cardiovascular risk in women with type 2 diabetes. Med Clin North Am 2003;87:955-69. Mak KH, Haffner SM. Diabetes abolishes the gender gap in coronary heart disease. Eur Heart J 2003;24:1385-6. Kannel WB, Wilson PWF. Risk factors that attenuate the female coronary disease advantage. Arch Intern Med 1995; 155:57-61. Crowley AS. Gender differences in long-term survival after acute myocardial infarction in patients with diabetes mellitus. Ann Emerg Med 2002;40:S1 (abstract). Wei M, Gaskill SP, Haffner SM, Stern MP. Effects of diabetes and level of glycemia on all-cause and cardiovascular mortality. The San Antonio Heart Study. Diabetes Care 1998;21: 1167-72. Botkin NF, Spencer FA, Goldberg RJ, Lessard D, Yarzebski J, Gore JM. Changing trends in the long-term prognosis of patients with acute myocardial infarction: a populationbased perspective. Am H J 2006;151:199-205. Miettinen H, Lehto S, Salmoaa V, Mahonen M, Niemela M, Haffner SM, et al. Impact of diabetes on mortality after the first myocardial infarction. Diabetes Care 1998;21:69-75. Abbott RD, Donahue RP, Kannel WB, Wilson PF. The impact of diabetes on survival following myocardial infarction in men vs women. JAMA 1988;260:3456-60. Aguilar D, Solomon SD, Kober L, Rouleau JL, Skali H, McMurrary JJ, et al. Newly diagnosed and previously known diabetes mellitus and 1-year outcomes of acute myocardial infarction. The Valsartan in Acute Myocardial Infarction (VALIANT) trial. Circulation 2004;110:1572-78. Mukamal KJ, Nesto RW, Cohen MC, Muller JE, Maclure M, Sherwood JB, et al. Impact of diabetes on long-term survival after acute myocardial infarction. Comparability of risk with prior myocardial infarction. Diabetes Care. 2001;24:1422-7. Goff DC, Ramsey DJ, Labarthe DR, Nichaman MZ. Acute myocardial infarction and coronary heart disease mortality among Mexican Americans and non-Hispanic whites, Texas, 1980 through 1989. Ethn Dis 1993;3:64-9. Rewers MJ, Shetterly SM, Hoag S, Baxter J, Marshall J, Hamman RF, et al. Is the risk of coronary heart disease lower in Hispanics than in non-Hispanic whites? The San Luis Valley Diabetes Study. Ethn Dis 1993;3:44-54. Canto JG, Taylor HA, Rogers WJ, Sanderson B, Hilbe J, Barron HV. Presenting characteristics, treatment patterns, and clinical outcomes of nonblack minorities in the National Registration of Myocardial Infarction 2. Am J Cardiol 1998;82: 1013-8. Cohen MG, Granger CB, Ohman EM, Stebbins AL, Grinfeld LR, Cagide AM, et al. Outcome of Hispanic patients treated with thrombolytic therapy for acute myocardial infarction. Results from the GUTO-I and -III trials. J Am Coll Cardiol 1999;34:1729-37. Hunt KJ, Williams K, Resendez RG, Hazuda HP, Haffner SM, Stern MP. All-cause and cardiovascular mortality among diabetic participants in the San Antonio Heart Study: evidence against the “Hispanic paradox.” Diabetes Care 2002;25:1557-63. Hunt KJ, Resendez RG, Williams K, Haffner SM, Stern MP, Hazuda HP. All-cause and cardiovascular mortality among Mexican-Americans and non-Hispanic white older participants in the San Antonio Heart Study— evidence against the “Hispanic Paradox.” Am J Epidemiol 2003;158:1048-57.

188

www.heartandlung.org

Stephen et al 45. Swenson CJ, Trepka MJ, Rewers MJ, Scarbro S, Hiatt WR, Hamman RF. Cardiovascular disease mortality in Hispanics and non-Hispanic whites. Am J Epidemiol 2002;156:919-28. 46. Pandey D, Labarthe DR, Goff DC Jr, Chan W, Nichaman MZ. Community-wide coronary heart disease mortality in Mexican Americans equals or exceeds that in non-Hispanic whites: the Corpus Christi Heart Project. Am J Med 2001;110: 81-7. 47. Goff DCJ, Ramsey DJ, Labarthe DR, Nichaman MZ. Greater case-fatality after myocardial infarction among Mexican Americans and women than among non-Hispanic whites and men. Am J Epidemiol 1994;139:474-83. 48. Goff DC, Nichaman MZ, Chan W, Ramsey DJ, Labarthe DR, Oritz C. Greater incidence of hospitalized myocardial infarction among Mexican Americans than non-Hispanic whites. The Corpus Christi Heart Project, 1988-1992. Circulation 1997;95:1433-40. 49. Kaiser Family Foundation. Racial/ethnic differences in cardiac care: the weight of the evidence. Kaiser Family Foundation. Available at: http://www.kff.org/uninsured/loader. cfm?url⫽/commonspot/security/getfile.cfm&PageID⫽ 14167. Accessed May 18, 2005. 50. Fisher L, Chesla CA, Skaff MM, Gilliss C, Mullan JT, Bartz RJ, et al. The family and disease management in Hispanic and European-American patients with type 2 diabetes. Diabetes Care 2000;23:267-72. 51. Adams CR. Lessons learned from urban Latinas with type 2 diabetes mellitus. J Transcult Nurs 2003;14:255-65. 52. Alcozer F. Secondary analysis of perceptions and meanings of type 2 diabetes among Mexican-American women. Diabetes Educ 2000;26:785-95. 53. Chesla CA, Skaff MM, Bartz RJ, Mullan JT, Fisher L. Differences in personal models among Latinos and European Americans. Diabetes Care 2000;23:1780-5. 54. Garcia AA. Symptom prevalence and treatments among Mexican-Americans with type 2 diabetes. Diabetes Educ 2005;31: 543-54. 55. Dorsch MF, Lawrance RA, Sapsford RJ, Durham N, Oldham J, Greenwood DC, et al. Poor prognosis of patients presenting with symptomatic myocardial infarction but without chest pain. Heart 2001;86:494-8. 56. Mayer D, Rosenfeld AG. Symptom interpretation in women with diabetes and myocardial infarction: a qualitative study. Diabetes Educ 2006;32:918-24. 57. Mak KH, Topol EJ. Emerging concepts in the management of acute myocardial infarction in patients with diabetes mellitus. J Am Coll Cardiol 2000;35:563-8. 58. Zerwic JJ, Ryan CJ, DeVon HA, Drell MJ. Treatment seeking for acute myocardial infarction symptoms. Differences in delay across sex and race. Nurs Res 2003;52:159-67. 59. Dracup K, Moser DK, Eisenberg M, Meischke H, Alonzo AA, Braslow A. Causes of delay in seeking treatment for heart attack symptoms. Soc Sci Med 1995;40:379-92. 60. Lefler LL, Bondy KN. Women’s delay in seeking treatment with myocardial infarction. A meta-synthesis. J Cardiovasc Nurs 2004;19:251-68. 61. MacKenzie G, Neibert MB. Diabetes and myocardial infarction or unstable angina: do patients with diabetes report pain and symptoms differently than patients without diabetes? Can J Cardiovasc Nurs 2001;11:25-34. 62. Gibler WB, Armstrong PW, Ohman EM, Weaver WD, Stebbins AL, Gore GM, et al. Persistence of delays in presentation and treatment for patients with acute myocardial infarction: the GUSTO-I and GUSTO-III experience. Ann Emerg Med 2002; 39:123-30. 63. De Luca G, Suryapranata H, Ottervanger JP, Antman EM. Time delay to treatment and mortality in primary angioplasty for acute myocardial infarction: every minute of delay counts. Circulation 2004;109:1223-5. 64. Murphy SA, Chen C, Cannon CP, Antman EM, Gibson CM. Impact of gender on angiographic and clinical outcomes after

MAY/JUNE 2008

HEART & LUNG

Stephen et al

65.

66.

67.

68. 69. 70.

71.

72.

73.

Acute coronary syndrome in women with diabetes

fibrinolytic therapy in acute myocardial infarction. Am J Cardiol 2002;90:766-70. Lee H, Bahler R, Chung C, Alonzo A, Zeller RA. Prehospital delay with myocardial infarction: the interactive effect of clinical symptoms and race. Appl Nurs Res 2000;13:125-33. Henderson SO, Magana RN, Korn CS, Genna T, Bretsky PM. Delayed presentation for care during acute myocardial infarction in a Hispanic population of Los Angeles county. Ethn Dis 2002;12:38-44. Giugliano RP, Braunwald E. Selecting the best reperfusion strategy in ST-elevation myocardial infarction. It’s all a matter of time. Circulation 2003;108:2828-30. Whittemore R, Knafl KA. The integrative review: updated methodology. J Adv Nurs 2005;52:546-53. Whittemore R. Combining evidence in nursing research. Nurs Res 2005;54:56-62. Conn VS, Isaramalai S-A, Rath S, Jantarakupt P, Wadhawan R, Dash Y. Beyond MEDLINE for literature searches. J Nurs Scholar 2003;35:177-82. Coronado BE, Pope JH, Griffith JL, Beshansky JR, Selker HP. Clinical features, triage, and outcomes of patients presenting to the ED with suspected acute coronary syndromes but without pain: a multicenter study. Am J Emerg Med 2004;22: 568-74. Cuˇlic´ V, Eterovic D, Miric D, Silic N. Symptom presentation of acute myocardial infarction: influence of sex, age, and risk factors. Am Heart J 2002;144:1012-7. DeVon HA, Penckofer SM, Zerwic JJ. Symptoms of unstable angina in patients with and without diabetes. Res Nurs Health 2005;28:136-43.

HEART & LUNG

VOL. 37, NO. 3

74. Kentsch M, Rodemerk U, Gitt AK, Schiele R, Wienbergen H, Schubert J, et al. Angina intensity is not different in diabetic and non-diabetic patients with acute myocardial infarction. Z Kardiol 2003;92:817-24. 75. Richman PB, Brogan GX, Nashed AN, Thode HC. Clinical characteristics of diabetic vs nondiabetic patients who “rulein” for acute myocardial infarction. Acad Emerg Med 1999;6: 719-23. 76. Thuresson M, Jarlov MB, Lindhal B, Svensson L, Zedigh C, Herlita J. Symptoms and type of symptom onset in acute coronary syndrome in relation to ST elevation, sex, age, and a history of diabetes. Am Heart J 2005;150:234-42. 77. McSweeney JC, O’Sullivan P, Cody M, Lefler LL. Black women’s symptoms of coronary heart disease. Circulation 2005; 112:II-391(abstr). 78. Richards SB, Funk M, Milner KA. Differences between blacks and whites with coronary heart disease in initial symptoms and in delay in seeking care. Am J Crit Care 2000;9:237-44. 79. Funk M, Naum JB, Milner KA, Chyun D. Presentation and symptom predictors of coronary heart disease in patients with and without diabetes. A J Emerg Med 2001;19:482-7. 80. Cao JJ, Hudson M, Jankowski M, Whitehouse F, Weaver WD. Relation of chronic and acute glycemic control on mortality in acute myocardial infarction with diabetes mellitus. Am J Cardiol 2005;96:183-6. 81. Lerman-Garber I, Villa AR, Caballero E. Diabetes and cardiovascular disease. Is there a true Hispanic paradox? Rev Invest Clin 2004;56:282-96. 82. Caban A, Walker EA. A systematic review of research on culturally relevant issues for Hispanics with diabetes. Diabetes Educ 2006;32:584-95.

www.heartandlung.org

189