Sex differences in patients seeking medical attention for prodromal symptoms before an acute coronary event

Article Outline

• Abstract
• Methods
  • Patient population
  • Data
  • Baseline characteristics
  • Definition of prodromes
  • Statistical analysis
• Results
  • Association between prodromal symptoms and long-term mortality after an acute coronary event
• Discussion
• Acknowledgment
• Appendix A
• References
• Copyright

Background

Patients with acute coronary syndromes (ACS) may experience nonspecific prodromal symptoms before their cardiac event. We used population-level data to determine the rate at which such patients seek medical attention for these symptoms, whether sex differences are present, and if an association between prodromes and 1-year mortality exists.

Methods

All patients with ACS in Alberta, Canada, between April 1, 1999, and March 31, 2001, were included. Prodromes reported during all physician visits in the 90 days before ACS presentation consisted of (1) pain (chest, arm, shoulder, neck, jaw, throat, or leg); (2) anxiety/fatigue; (3) gastrointestinal disturbances; (4) head-related conditions (dizziness, headache, visual disturbances); and (5) other (sweating, shortness of breath, heart racing, cough, numbness).

Results

Of 14,230 patients with ACS, 2,268 (15.9%, 45.6% women) sought medical attention for at least one prodrome, with pain and anxiety/fatigue most common. Prodromes were associated with increased cardiac investigations before ACS in both sexes. After adjustment for baseline characteristics, a significant interaction between sex and prodromes was found (P [interaction] = .011). Prodromes were associated with improved 1-year survival in women (adjusted hazard ratio [HR] 0.74, 95% CI 0.58-0.95, P = .016, risk-adjusted mortality 8.7% vs 11.1% [without prodromes], P < .001) but not in men (adjusted hazard ratio 0.92, 95% CI 0.76-1.12, P = .422, 9.9% [with prodromes] vs 9.1% [without prodromes], P = .358).

Conclusions

A small proportion of patients with ACS seek medical attention for prodromal symptoms in the 90 days before ACS. Seeking help for these symptoms is associated with improved survival in women but not in men.

Patients with acute myocardial infarction (AMI) may experience nonspecific prodromal symptoms in the weeks to months before their cardiac event. These include fatigue, shortness of breath, gastrointestinal (GI) disturbances, and anxiety, as well as chest discomfort.¹ Much of the work examining prodromes has been focused on women, who are known to experience more atypical symptoms with acute cardiac events. Indeed, using a specifically developed survey administered to 515 women with AMI from 5 sites in the United States, McSweeney et al² found that 95% of these women exhibited prodromal symptoms before AMI. However, whether patients seek medical attention for these symptoms and the timeframe over which prodromes may be experienced are unknown. In addition, data specific to sex differences in the occurrence of these early atypical warning symptoms as well as their impact on mortality after a coronary event are sparse. We therefore used population-level data to determine whether sex differences in seeking medical attention for prodromal symptoms exist in patients subsequently presenting to an emergency department (ED) with an acute coronary syndrome (ACS). We also assessed whether prior prodromal indicators were associated with long-term mortality.

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Methods 

Patient population 

All patients presenting to any 1 of 101 EDs associated with an acute care facility in the Province of Alberta, Canada, between April 1, 1999, and March 31, 2001, with confirmed ACS (a discharge diagnosis of AMI [410.x] or unstable angina [UA, 411.1] as defined by the International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM]) were included in the study population (see Appendix A, available online, for codes).

Data 

Data for the study consist of databases described previously and maintained by the Alberta Ministry of Health and Wellness.³ To examine our a priori hypotheses, the following data sources were used: (1) the Ambulatory Care Classification System (ACCS) database, which includes all ED visits, admission and discharge dates, diagnostic and therapeutic procedures performed, and discharge dispositions (eg, admitted to acute care hospitals, returned home alive, or died in the ED); (2) the hospital discharge database that contains comorbidity, diagnostic and treatment information together with timing of invasive tests and revascularization for patients admitted to an acute care hospital; (3) the Statistics Canada neighborhood (areawide) socioeconomic data, which are publicly available and include data on average and median household income; (4) physician claims data, which provides information on the care received by patients before their index cardiac event including dates of service and diagnostic and treatment information; and (5) the Alberta Health Care Insurance Plan Registry, which records the status (including death) of all residents of Alberta. These data are validated with the Alberta Bureau of Vital Statistics (Edmonton, Alberta, Canada).

Baseline characteristics 

The ACCS database contains up to 6 diagnostic and 10 procedure codes. To establish a more complete patient risk profile, we considered a comorbidity to be present if it was reported on any of the following: (1) on the index ACCS ED visit record; (2) in the inpatient admission (if it occurred) concurrent to the ED visit; or (3) in any physician visit in the year before the index ED visit (see Appendix A, available online, for specific codes).

Definition of prodromes 

Based on the data used by McSweeney et al⁴ in their validated survey, we established the following 5 groups of potential atypical prodromal symptoms as determined by ICD-9-CM diagnostic coding (see Appendix A available online) in the linked databases described above: (1) pain (an aggregate of chest, arm, shoulder, neck, jaw, throat, or leg complaints); (2) anxiety/fatigue (anxiety, sleep disturbances, weakness/fatigue); (3) GI disturbances (nausea/vomiting, loss of appetite, indigestion); (4) head-related conditions (dizziness, headache, visual disturbances); and (5) other (sweating, shortness of breath, heart racing, cough, numbness).

Previous work has suggested that women may experience atypical prodromes for at least 1 month or longer (even 4-6 months) before their index cardiac event.², ⁵ Therefore, in this study, patients were considered to have experienced a prodrome if they sought medical attention (ie, ED visits or physician office visits) for ≥1 of these symptom types in the 90 days preceding their acute ED presentation. Records were also scanned for the relationship between prodromes and the occurrence of cardiac testing (electrocardiogram, echocardiogram, stress test, nuclear, cardiac catheterization) or revascularization procedures (percutaneous coronary intervention and/or coronary artery bypass graft surgery) within the same time frame.

Statistical analysis 

Mean and SD (or median and interquartile ranges, as appropriate) are presented for continuous variables and were compared between groups using t tests and nonparametric Mann-Whitney tests, respectively. Categorical variables are presented as percentages, and comparisons were evaluated using χ² tests. Kaplan-Meier survival analysis from the onset of index event and multivariable Cox proportional hazards regression were used to examine whether the presence of prodromal symptoms was significantly associated with 1-year all-cause mortality. After confirming that the proportional hazards assumption was met, covariates considered in the adjustment procedures were all those available: age, sex, diabetes mellitus, histories of congestive heart failure, hypertension, cancer, renal disease, MI and/or peripheral vascular disease, metropolitan residence (ie, Calgary or Edmonton), and discharge diagnosis for the index ED visit (UA vs AMI). The interaction between prodromes and sex was also tested. Finally, risk-adjusted mortality rates (adjusting for all baseline characteristics presented in Table I as well as discharge diagnosis) at 1 year according to prodromal status were calculated using standard risk-adjustment techniques. Given the exceptional follow-up in this population, logistic regression modeling was applied to obtain the “expected” (E) 1-year mortality, which was the average of the predicted probabilities. The observed versus expected ratio was calculated in each sex/prodrome group (men/no prodromes; men/prodromes; women/no prodromes; women/prodromes) and then multiplied by 1-year mortality rate in the overall population. All analyses were carried out using SPSS statistical package 15.0 (Chicago, IL).

Table I. Selected baseline characteristics according to presence/absence of prodromes

	All	No prodromes	Prodromes	P
n	14,230	11,962	2268
Age, y (mean [±SD])	65.3 (13.5)	65.1 (13.6)	66.0 (13.1)	.009
Age group (%)				.058
<65 y	47.3	47.7	45.0
65-74 y	25.6	25.3	26.6
≥75 y	27.1	26.9	28.4
Female (%)	36.6	34.9	45.6	<.001
Diabetes (%)	15.6	15.6	15.4	.807
Hypertension (%)	36.0	34.8	42.2	<.001
CHF (%)	9.6	9.1	12.6	<.001
Prior MI (%)	23.7	23.0	27.3	<.001
CVD (%)	4.0	3.8	5.2	.002
Cancer (%)	6.0	5.6	8.2	<.001
Renal disease (%)	1.5	1.5	1.6	.839
PVD (%)	9.4	8.9	12.3	<.001
Patient residency (%)				.133
Calgary	32.8	33.0	31.5
Edmonton	20.0	20.1	19.4
Non-metro	47.2	46.8	49.1
Household incomequartiles, $CAD (%)				.924
<$39,086	25.0	25.0	25.3
$39,086-<$49,936	25.0	25.0	24.9
$49,936-<$63,646	25.0	24.9	25.4
≥$63,646	25.0	25.1	24.5
Medical care in physician office	–	–	69.8
ED diagnosis (%)				<.001
AMI	42.9	45.1	31.6
UA	57.1	54.9	68.4

CHF, Congestive heart failure; CVD, cerebrovascular disease; PVD, peripheral vascular disease; CAD, Canadian dollars.

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Results 

From April 1, 1999, to March 31, 2001, a total of 14,230 patients presented to EDs in the Province of Alberta with a diagnosis of ACS. Overall, 36.6% of these patients were female. A total of 2,268 patients (15.9%), with a higher representation in women than in men (19.8% vs 13.7%), sought medical attention for at least one prodromal symptom in the 90 days preceding their index cardiac event.

Table I demonstrates selected baseline characteristics of the study population according to whether or not patients sought medical attention for prodromes. Patients seeking medical attention for prodromes were more often older, female, were more likely to have a history of previous MI, hypertension, congestive heart failure, cerebrovascular or peripheral vascular disease, and malignancy, and were also more likely to present to the ED with UA compared to patients without prodromes. Table II then further subdivides these patients by sex. Among women, those seeking medical attention for prodromes were younger, more often hypertensive and had more comorbidities (including prior MI), and presented to the ED with UA relative to women without. Men seeking medical attention for prodromes had a similar set of characteristics. Among those with prodromal symptoms, women were more likely to be older (P < .001) and have a history of hypertension (P < .001), whereas men were more likely to have a history of malignancy (P = .03) and to have AMI as their index ED presentation (P < .001). Sex differences were also noted in that women with prodromes tended to have lower household incomes (P < .001). Most patients sought medical attention in physician offices rather than in EDs.

Table II. Selected baseline characteristics by sex for patients who did and did not seek medical attention for prodromes

	Women				Men
	All	No prodromes	Prodromes	P	All	No prodromes	Prodromes	P
n	5212	4178	1034		9018	7784	1234
Age, y (mean [±SD])	68.8 (13.2)	69.1 (13.2)	67.9 (13.0)	.010	63.2 (13.2)	63.0 (13.3)	64.3 (12.9)	.002
Age group (%)				.044				.033
<65 y	36.8	36.3	38.8		53.4	53.9	50.2
65-74 y	25.9	25.5	27.3		25.4	25.2	26.1
≥75 y	37.3	38.2	33.9		21.3	20.9	23.7
Diabetes (%)	16.5	16.7	15.9	.536	15.0	15.0	15.0	.981
Hypertension (%)	43.9	43.1	47.0	.023	31.5	30.4	38.2	<.001
CHF (%)	11.1	10.5	13.8	.005	8.8	8.3	11.8	<.001
Prior MI (%)	20.6	19.6	25.0	<.001	25.4	24.8	29.3	.001
CVD (%)	4.5	4.3	5.5	.096	3.6	3.5	4.9	.014
Cancer (%)	5.4	5.1	6.9	.023	6.3	5.9	9.3	<.001
Renal disease (%)	1.4	1.5	1.2	.431	1.6	1.6	1.9	.311
PVD (%)	10.7	10.0	13.5	.001	8.7	8.2	11.3	<.001
Patient residency (%)				.020				.629
Calgary	35.3	35.9	33.2		31.3	31.5	30.1
Edmonton	19.6	20.0	17.9		20.3	20.2	20.6
Non-metro	45.1	44.1	48.9		48.4	48.3	49.3
Household income quartiles, $CAD (%)				.361				.884
<$39,086	28.9	29.0	28.5		22.7	22.8	22.5
$39,086-<$49,936	25.2	25.3	24.8		24.9	24.9	25.0
$49,936-<$63,646	23.6	23.1	25.6		25.8	25.9	25.1
≥$63,646	22.3	22.6	21.1		26.5	26.4	27.4
Medical care in physician office		–	70.6			–	69.1
ED diagnosis (%)				<.001				<.001
AMI	36.7	39.3	26.4		46.5	48.2	35.9
UA	63.3	60.7	73.6		53.5	51.8	64.1

Table III describes the types of prodromes experienced. Pain and anxiety/fatigue were the most common complaints noted in the 90 days before the diagnosis of ACS. Pain-related complaints were more common in men, and head-related complaints were experienced more commonly in women. Table III also demonstrates the median time from seeking medical attention with a prodromal symptom to index presentation. In general, pain and anxiety/fatigue complaints were noted within 4 weeks of index presentation, whereas head-related, GI, and other complaints occurred within 6 weeks. There were no differences in times to event by sex.

Table III. Types of prodromal symptoms noted and median days from prodrome to presentation in the 3 months before index ED visit

n	All	Women	Men	P
	2268	1034	1234
Pain-related	1324 (58.4%)	564 (54.5%)	760 (61.6%)	<.01
Mediandays (IQR)	24 (8, 52)	24 (8, 51)	25 (8, 53)	.50
Anxietyand fatigue	1171 (51.6%)	542 (52.4%)	629 (51.0%)	.50
Mediandays (IQR)	27 (8, 53)	26.5 (10, 54)	27 (7, 53)	.97
Head-related	302 (13.3%)	163 (15.8%)	139 (11.3%)	<.01
Mediandays (IQR)	40 (17, 65)	40 (17, 67)	38 (17, 64)	.61
GI-related	82 (3.6%)	35 (3.4%)	47 (3.8%)	.65
Mediandays (IQR)	39.5 (16, 59.3)	35 (11, 49)	45 (18, 68)	.12
Other	298 (13.1%)	138 (13.3%)	160 (13.0%)	.80
Mediandays (IQR)	35 (14, 61)	35.5 (16, 61.5)	35 (12.3, 60.8)	.83

IQR, Interquartile range.

Although most patients experienced a single type of prodrome, as shown in Figure 1, almost one third of patients of either sex sought medical attention for another prodromal symptom complex in the 90 days before index presentation. Experiencing >2 types of prodromes in a single patient was rare.

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• Figure 1. 

  Numbers of prodromal symptom complexes for which medical attention was sought in the 90 days before ACS in men and women.

Table IV shows the relationship between prodromal complaints and the occurrence of cardiac investigations and revascularization before the index cardiac event. Patients who sought medical attention for prodromal symptoms also underwent more cardiac testing, particularly electrocardiograms, in the 90 days before their ACS presentation. In addition, a small proportion of patients underwent cardiac catheterization (with subsequent revascularization procedures in even fewer patients) during this period. Once again, cardiac catheterization was also more commonly noted in patients with prodromes. Although more men with prodromes underwent subsequent revascularization procedures than men without prodromes, this was not the case for women.

Table IV. Relationship between seeking medical attention for prodromes and cardiac investigations or revascularization procedures within 3 months of index presentation

ECG, Electrocardiogram; Echo, echocardiogram; Cath, cardiac catheterization; Revasc, revascularization procedure (percutaneous coronary intervention or bypass surgery).

Association between prodromal symptoms and long-term mortality after an acute coronary event 

As shown in Figure 2, patients who did not seek medical attention for prodromal symptoms tended to have higher 1-year mortality compared to those who did access health care resources for prodromes in the 90 days before the index coronary event (P [log rank] = .085). Notably (Figure 3, A), when this relationship was examined according to sex, women without prodromes were significantly more likely to die within 1 year compared to those with prodromes (P [log rank] < .001). By contrast, prodromal status had little association with mortality in men (Figure 3, B) (P [log rank] = 0.358). After adjustment for baseline characteristics, a statistically significant interaction between sex and presence of prodromes was observed (P [interaction] = .011). The presence of prodromes was also associated with improved survival in women (adjusted hazard ratio [HR] 0.74, 95% CI 0.58-0.95, P = .016, risk-adjusted mortality 8.7% vs 11.1%, P < .001). Risk-adjusted mortality rates were similar in men regardless of prodrome status (adjusted HR 0.92, 95% CI 0.76-1.12, P = .422, 9.9% [with prodromes] vs 9.1% [without prodromes], P = .358).

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• Figure 2. 

  One-year mortality for patients seeking medical attention for prodromes compared to those who did not experience prodromes or did not seek medical attention.

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• Figure 3. 

  A, One-year mortality in women seeking medical attention for prodromes compared to those who did not experience prodromes or did not seek medical attention. B, One-year mortality in men seeking medical attention for prodromes compared to those who did not experience prodromes or did not seek medical attention.

A sensitivity analysis was performed in the subgroup that had an ED diagnosis of AMI to exclude the possibility that improved survival with prodromes may be driven by an incorrect UA diagnosis in the ED. We found that the interaction between prodromes and sex in the prediction of 1-year mortality was retained (P [interaction] = 0.023). In women, those seeking medical attention for prodromes had a lower hazard of 1-year mortality than those without (adjusted HR 0.72, 95% CI 0.52-0.99, P = .042). In men, prodromes were not significantly associated with mortality (adjusted HR 0.86, 95% CI 0.67-1.09, P = .203).

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Discussion 

In this large population-based analysis, we found that prodromal symptoms prompting medical attention are experienced in about 16% of patients with ACS. Of the 5 types of symptom complexes examined, women experience only head-related prodromes more commonly than men, who in turn experienced pain-related symptoms more commonly than women. Multiple presentations with the same complaint were common in both sexes, and more than one prodrome type was noted in almost one third of patients. In addition, we have found an important, heretofore unreported association between seeking care for prodromal syndromes and improved 1-year survival that was confined to women.

Interest in prodromal symptoms dates back in the literature as far as 1937.⁶ Early investigators confirmed the importance of fatigue and pain symptoms as precursors to AMI.⁷ These older studies did not differentiate between men and women, but it was recognized that women tend to experience different symptoms with AMI than men, supporting the relevance of sex-specific studies. Previous investigators subsequently reported that a large proportion of women experience prodromal symptoms before AMI. In a survey of 914 consecutive patients admitted to a coronary care unit with suspected AMI, Hofgren et al⁸ reported that 70% of women and 58% of men experienced nonspecific symptoms in the week before admission. In a smaller survey of 40 women with AMI, McSweeney et al found that 92.5% experienced at least one prodromal symptom, with 87.5% actually reporting 3 or more symptoms. Most of the women in this study had experienced symptoms for 4 to 6 months.⁵ McSweeney et al then developed a validated, telephone-administered instrument⁴ and used this in 515 women several months after AMI. The most common prodromes reported were fatigue, sleep disturbances, dyspnea, indigestion, and anxiety,² which other investigators have subsequently confirmed.⁹, ¹⁰, ¹¹ In addition, 78% of patients experienced at least one prodromal symptom daily or several times per week in the 1 month before AMI.² These studies and others are limited by their retrospective nature and convenience sampling. Investigators have also focused mainly on patients with AMI rather than the full spectrum of ACS as we have done in the present analysis.

Little attention has been paid to whether patients actually seek medical attention for prodromal symptoms. In their survey of coronary care unit patients, Hofgren et al⁸ did find that 33% of patients with prodromes actually contacted a physician in the week before admission, with no sex difference noted. In our study, only 15.9% of patients subsequently experiencing an ACS consulted a physician for these atypical symptoms.

An interesting and important finding in our study is the association of prodromal symptoms with reduced mortality in women. To our knowledge, this has not been previously described and deserves further investigation and confirmation. We have also demonstrated that all patients with prodromes undergo more cardiac testing before their index event than patients without prodromes. Given the related time frames, these investigations may have been triggered by prodromal complaints. Importantly, however, no increase in revascularization procedures in women with prodromes occurred that might have influenced survival.

What, then, could account for the association between prodromes and better survival in women? We have previously shown that women have a survival advantage when affected with UA but lose that advantage with AMI.¹² This may be related to time to treatment. Indeed, many investigators have shown that women with ACS delay longer in seeking health care than men.¹³, ¹⁴, ¹⁵, ¹⁶, ¹⁷, ¹⁸, ¹⁹ There are also different influences on delay time between women and men. Women appear less likely to attribute their ACS symptoms to cardiac causes.²⁰ Women can also delay seeking medical attention because they are busy with competing social demands with a desire to not bother others, and/or a lack of awareness of cardiac risk or the severity of their symptoms.²¹ It is plausible that in our study, women with prodromal symptoms (many of whom received cardiac investigations) were then more likely to attribute their ACS symptoms to a cardiac cause and therefore seek emergency medical attention more promptly. In addition, given the tendency of women with ACS to present with atypical symptoms, it is also possible that ED physician knowledge of the antecedent cardiac workup could then have led to more aggressive assessment and treatment at the time of index ED presentation.

There are limitations to this study. First, we have clearly underestimated the prevalence of prodromal symptoms in this population because we only capture those patients who sought medical attention for these symptoms. Therefore, the sex-related differences that we have described here may differ if prodromes had been self-reported. Second, our study uses administrative data collected by the provincial ministry of health in Alberta. Although these data have the advantage of capturing the entire population receiving cardiac services, they do not contain the level of clinical detail captured by registries or in clinical trials. Our study is observational in nature, and there may be residual confounding as a result of this unavailable information. Hence, we cannot confirm if the improved outcomes we observed are due to patient characteristics or the medical attention they received. Finally, as the population of Alberta consists mainly of people of European descent with Chinese and South Asian the most common visible minorities, our findings may not be generalizable to other races and ethnicities.

In conclusion, despite literature indicating that most patients experience prodromes, our findings reveal that only a small proportion of patients with ACS actually seek medical attention for these symptoms. The association of prodromal symptoms and improved survival in women, if confirmed, suggests that patients with these complaints should be educated and encouraged to seek medical attention. The identification of prodromal symptoms by caregivers may represent an opportunity to initiate timely cardiac investigation. Further work is needed to determine whether the presence of prodromes reduces delay in seeking treatment at the time of ACS.

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We greatly appreciate the assistance of Yan Jin MA, Data Analyst, Canadian VIGOUR Centre (University of Alberta, Edmonton, Alberta, Canada) in data management and analysis. Although the study is based in part on data provided by Alberta Health and Wellness, the interpretation and conclusions contained herein are those of the researchers and do no necessarily represent the views of the Government of Alberta. Neither the Government nor Alberta Health and Wellness express any opinion in relation to this study.

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Appendix A 

ICD-9-CM codes for prodromes and baseline characteristics

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