Comparative study of acute coronary syndrome in postmenopausal women and age-matched men: A prospective cohort study in Southern India.

Background: Acute coronary syndrome (ACS) differs in women and men with respect to risk factors, clinical presentation, complications and outcome. The major reason for the differences has been the effect of estrogen which protects women from coronary artery disease (CAD) till menopause. Women develop CAD one decade later than men. Hence, we compared the profile of ACS in postmenopausal women with age-matched men to see, does the difference still exist. Materials and
Methods: Comparative prospective study of 50 postmenopausal women as study group and fifty age-matched men as a control group diagnosed with ACS, who were admitted in a medical college hospital from December 2013 to September 2015. Chi-square test and Student's t-test have been used to find the significant association of study parameters between women and men.
Results: Chest pain was the main complaint in the majority of the women (76%) and men (88%). Radiation of chest pain (60%) and sweating (72%) were significantly present in men compared to women (24% and 26%, respectively), whereas breathlessness was significantly present in women (40%) compared to men (16%). Women had later presentation to the hospital after symptom onset compared to men. Women had a higher respiratory rate (22.02 cycles/min) compared to men (20 cycles/min) and more crepitations compared to men. Men had more ventricular tachycardia (14%) and intracerebral hemorrhage (4%), whereas women had all other complications more than or same as men and higher in-hospital mortality (14%) compared to men (8%).
Conclusion: Postmenopausal women with ACS had more atypical presentation of symptoms, later presentation to hospital, more tachypnea, more crepitations, more complications, and higher in-hospital mortality compared to men of the same age group. The difference in the profile of ACS continues to exist even after menopause and age matching.

INTRODUCTION

Acute coronary syndrome (ACS) in women is different from men with respect to risk factors, clinical presentation, complications, and outcome. ACS in women compared to men presents at a later age, has more atypical presentation, longer time to hospital presentation after symptom onset, increased morbidity and mortality.[12] The greater age in women compared to men is presumably due to premenopausal exposure to endogenous estrogen.[1] In females, coronary artery disease (CAD) is found more around the time of menopause when the estrogen in plasma begins to decline.[2]

Comparative studies on ACS between women and men have been reported from the Western world.[345678910111213] Studies on ACS in women in India have also been reported.[14151617] Most of the previous studies have compared the differences between women and men but have included both pre- and post-menopausal women. Furthermore, in most studies, men outweigh women by a significant number. In most studies, women are older compared to men; thus age being a significant confounding factor. Studies comparing the profile of ACS in postmenopausal women and age-matched men among patients of Indian/south Indian ethnicity, to the best of our knowledge, are lacking. The major reason for the differences between men and women for ACS has been the effect of estrogen; hence we compared only postmenopausal women with age-matched men to evaluate the differences.

MATERIALS AND METHODS

This comparative prospective study of 50 postmenopausal women as a study group and 50 age-matched men as a control group (in 1:1 ratio) was undertaken on patients of ACS admitted in the coronary care unit under the Department of Internal Medicine in a Medical College hospital in Southern Karnataka, India from December 2013 to September 2015. The total sample size was 100 based on the data of admissions of ACS patients to the hospital from the previous year. It was an in-hospital follow-up study, and the patients were followed up for a period ranging from 2 to 12 days with an average of 6 days depending on the response to treatment and hemodynamics and then referred to a percutaneous coronary intervention (PCI) capable centre for coronary angiography and revascularization if indicated or discharged.

Postmenopausal women above 45 years of age and men more than 45 years of age diagnosed with ACS (as per European society of cardiology guidelines),[18] were included in the study. Patients with chronic coronary syndrome, premenopausal women with ACS, postmenopausal women on hormone replacement therapy, postmenopausal women <45 years of age and men <45 years of age were excluded from the study. Informed consent was obtained from all the subjects included in the study. Ethical clearance was obtained from the institute ethical committee. Age matching was done, and groups of patients with age 45–54 years, 55–64 years, 65–74 years, and more than 75 years were created.

At the time of admission, a complete history was taken, and a meticulous physical examination was done. In the emergency department, a 12-lead electrocardiogram was done within 10 min of arrival and repeated if necessary. Cardiac enzymes such as creatinine kinase myocardial band isoform (CK-MB) and troponin T were done at the time of admission and repeated if required. Echocardiogram was done during the stay in the hospital. Routine investigations such as complete blood count, urine microscopy, fasting, and postprandial blood sugar, blood urea, serum creatinine, fasting lipid profile were done during the admission. Patients of ST-elevation myocardial infarction (STEMl), non-STEMI, and unstable angina were treated with antiplatelet drugs (aspirin and clopidogrel), statins, anticoagulants (unfractionated/low molecular weight heparin) beta-blockers, angiotensin-converting enzyme inhibitors, aldosterone antagonists, and nitrates (as indicated). Reperfusion therapy with streptokinase was given to every patient of STEMI who presented with chest pain within 12 h and who did not have any contraindications to thrombolysis. Hemodynamically compromised patients were treated with normal saline or inotropes as indicated. Mechanical ventilation was used in patients with left ventricular (LV) failure with pulmonary edema if required. The two groups were compared based on the presenting complaints, time to hospital presentation after symptom onset, risk factors for CAD, clinical features on presentation, lipid profile, echo parameters, cardiac biomarkers, complications, and outcome. Subgroup analysis was performed, and all parameters were further compared after age matching into groups.

Statistical analysis

Microsoft Excel 2019 was used to create the tables and figures. Statistical analysis was performed using IBM SPSS Statistics for Windows, version 23 (IBM Corp., Armonk, N.Y., USA). For data comparison, Chi-square test and Fisher's exact test were used for categorical data and Student's t-test for continuous variables. Differences were considered statistically significant when P < 0.05.

RESULTS

Baseline characteristics and comparison of symptoms between women and men

The mean age of postmenopausal women in the study was 60.5 ± 8.9 years and of men was 60.8 ± 9.75 years [Table 1]. The patients in both groups were further subdivided into four subgroups of age 45–54 years, 55–64 years, 65–74 years, and more than 75 years with equal women and men in each group. When the symptoms on presentation between the two groups were compared, chest pain was the predominant symptom among both women and men. But when the characteristics of typical angina were compared, radiation of chest pain and sweating associated with chest pain were significantly present in men (60% and 72%) compared to women (24% and 26%), respectively (P = 0.000265 and < 0.05, respectively).

Table 1

Comparison of baseline characteristics, symptoms, time to hospital presentation, risk factors, clinical features at presentation, diagnosis and investigations between women and men

	Women	Men	P
Age (years), n (%)
45-54	17 (34)	17 (34)
55-64	21 (42)	21 (42)
65-74	10 (20)	10 (20)
≥75	2 (4)	2 (4)
Mean±SD	60.5±8.9	60.8±9.75
Symptoms, n (%)
Chest pain	38 (76)	44 (88)	0.11
Radiation	12 (24)	30 (60)	0.000265
Sweating	13 (26)	36 (72)	<0.05
Breathlessness	20 (40)	8 (16)	0.00753
Fatigue	5 (10)	3 (6)	0.460
Vomiting	1 (2)	3 (6)	0.307
Giddiness	2 (4)	0	0.153
Others	5 (10)	3 (6)	0.460
Time to hospital, n (%)
≤30 min	5 (10)	5 (10)	1.0
30-60 min	0	4 (8)	0.04
1-2 h	3 (6)	10 (20)	0.03
2-12 h	15 (30)	16 (32)	0.828
12-24 h	3 (6)	8 (16)	0.11
24-48 h	8 (16)	1 (2)	0.01
2-7 days	8 (16)	5 (10)	0.372
7-14 days	5 (10)	0	0.02
≥15 days	3 (6)	1 (2)	0.307
Risk factors, n (%)
Hypertension	17 (34)	16 (32)	0.821
Diabetes	14 (28)	7 (14)	0.085
Previous MI	2 (4)	9 (18)	0.025
Smoking	0	36 (72)	<0.01
Heavy alcohol	0	7 (14)	<0.01
Family h/o IHD	9 (18)	8 (16)	0.79
Overweight	9 (18)	12 (24)	0.46
Obesity	12 (24)	28 (56)	0.001
BMI, mean±SD	23.3±4.29 (17.5-36)	26.12±4.4 (19.5-40)	0.0016
Clinical features, n (%)
Pulse rate	87.8±15.32 (42-126)	84.2±17 (50-160)	0.268
SBP	147±33.8 (70-220)	146±33.5 (70-220)	0.882
DBP	85±17.3 (50-110)	89±21.35 (50-180)	0.305
RR	22.02±4.8 (14-35)	20±3.8 (14-30)	0.023
Crepitations, n (%)	18 (36)	9 (18)	0.042
Investigations/diagnosis
TC, mean±SD	202±36.9 (134-220)	194±33.7 (113-289)	0.260
TG, mean±SD	179±60 (78-320)	174±63 (72-345)	0.685
LDL, mean±SD	95±18.8 (56-145)	89.5±26.7 (32-174)	0.236
HDL, mean±SD	40.5±7.6 (25-56)	37.3±9 (23-65)	0.05
Elevated CKMB, n (%)	33 (66)	37 (74)	0.382
Elevated troponin T, n (%)	31 (62)	37 (74)	0.198
RWMA present, n (%)	31 (62)	35 (70)	0.398
LVEF <50%, n (%)	21 (42)	27 (54)	0.229
Unstable angina, n (%)	17 (34)	12 (24)	0.270
NSTEMI, n (%)	9 (18)	8 (16)	0.79
AW-STEMI, n (%)	12 (24)	18 (36)	0.19
IW-STEMI, n (%)	12 (24)	12 (24)	1.0

MI=Myocardial infarction, H/O=History of, BMI=Body mass index, LDL=Low density lipoprotein cholesterol, HDL=High density lipoprotein cholesterol, CKMB=Creatinine kinase MB isoform, RWMA=Regional wall motion abnormality, AW=Anterior wall, IW=Inferior wall, STEMI=ST elevation myocardial infarction, NSTEMI=Non-ST elevation myocardial infarction, LVEF=Left ventricular ejection fraction, SBP=Systolic blood pressure, DBP=Diastolic blood pressure, IHD=Ischemic heart disease, SD=Standard deviation, RR=Respiratory rate, TC=Total cholesterol, TG=Triglycerides

Breathlessness, an atypical symptom of ACS was significantly present in women (40%) compared to men (16%) (P = 0.00753). Other atypical symptoms such as fatigue, giddiness, nausea, abdominal discomfort and diarrhoea were more common among women than men, though they did not reach statistical significance [Table 1].

Subgroupanalysis showed that radiation of chest pain and sweating was statistically significant among men in the age group of 55–64 years compared to women of the same age group. Although sweating and radiation were seen more commonly among men in all age groups, they did not reach statistical significance [Table 2]. Breathlessness and fatigue were statistically significant among women in the age group of 45–54 years compared to men of the same age group. Although this trend was seen in all age groups, statistical significance was not achieved [Table 2].

Table 2

Comparison of symptoms and time to hospital presentation between postmenopausal women and age matched men

	45-54 years			55-64 years			65-74 years			≥75 years
	Women	Men	P	Women	Men	P	Women	Men	P	Women	Men	P
Symptom
Chest pain	13	12	0.87	13	20	0.83	10	10	1	2	2	1
Radiation	3	7	0.26	4	14	0.04	3	7	0.29	2	2	1
Sweating	5	9	0.36	4	15	0.03	2	8	0.11	2	2	1
Breathlessness	7	1	0.05	7	3	0.25	5	2	0.32	1	2	0.65
Fatigue	4	0	0.05	0	0		1	2	0.59	0	1	0.36
Vomiting	1	0	0.32	0	1	0.32	0	2	0.17	0	0
Giddiness	1	0	0.32	1	0	0.32	0	0		0	0
Others	1	1	1	3	2	0.17	1	0	0.32	0	0
TTHP
≤30 min	1	1	1	2	1	0.57	2	2	1	0	1	0.36
30-60 min	0	0	0	1	0.32	0	2	0.17	0	1	0.36
1-2 h	1	1	1	0	7	0.01	1	2	0.59	1	0	0.36
2-12 h	6	3	0.37	6	7	0.8	3	4	0.74	0	2	0.22
12-24 h	1	4	0.2	0	2	0.16	2	2	1	0	0
24-48 h	2	1	0.58	4	0	0.05	2	0	0.17	0	0
2-7 days	0	2	0.16	4	0	0.05	2	1	0.59	2	2	1
7-14 days	2	0	0.16	2	0	0.16	1	0	0.32	0	0
≥15 days	1	1	1	2	0	0.16	0	0		0	0

TTHP=Time to hospital presentation

Time to hospital presentation after symptom onset

We found that 8% of men presented to hospital within 30–60 min of symptom onset compared to none of the women (P = 0.04) and 20% men presented within 1–2 h compared to 6% women (P = 0.03). Women had a later presentation to hospital after symptom onset with 16% women presenting within 24–48 h compared to only 2% men (P = 0.01) and 10% women presenting within 7–14 days compared to none of the men (P = 0.02) [Table 1].

Subgroup analysis showed the statistically significant differences between men and women mainly in the 55–64 years age group with more men presenting within 1–2 h and more women presenting within 24–48 h and 2–7 days [Table 2]. Although this trend of later presentation to the hospital among women was maintained across all age groups, statistical significance was not achieved [Table 2].

Risk factors for coronary artery disease

Previous myocardial infarction (MI), smoking, heavy alcohol consumption, and obesity were significant risk factors among men compared to postmenopausal women, while hypertension was the most common risk factor among women [Table 1]. Both hypertension and diabetes were seen more among women compared to men, however not statistically significant. Subgroup analysis showed that smoking was statistically significant among men compared to women across most age groups, while heavy alcohol consumption and obesity were significantly more among men in the 45–54 years age group [Table 3].

Table 3

Comparison of risk factors and body mass index between postmenopausal women and age matched men

Risk factor	45-54 years			55-64 years			65-74 years			≥75 years
	Women	Men	P	Women	Men	P	Women	Men	P	Women	Men	P
HTN	4	6	0.57	6	4	0.56	6	5	0.8	1	1	1
DM	2	2	1	9	2	0.05	1	3	0.36	2	0	0.22
Previous MI	0	1	0.32	1	2	0.57	1	5	0.14	0	1	0.36
Smoking	0	10	0.004	0	14	<0.001	0	10	0.006	0	2	0.22
Heavy alcohol	0	4	0.05	0	1	0.32	0	2	0.17	0	0
F/H/O CAD	0	0		2	3	0.67	7	4	0.46	0	1	0.36
Overweight	1	4	0.2	6	7	0.8	2	1	0.59	0	0
Obesity	3	12	0.04	4	10	0.16	4	3	0.74	1	1	1
BMI	21.75±3.27	26.11±3.35	<0.01	24.3±3.56	27.54±4.99	<0.01	24.27±6.1	26.08±4.44	0.46	21±2.79	21.5±1.98	0.85

HTN=Hypertension, DM=Diabetes mellitus, MI=myocardial infarction, F/H/O=Family history of, BMI=Body mass index, CAD=Coronary artery disease

Clinical findings at presentation

Postmenopausal women were found to have a higher respiratory rate compared to men (P = 0.023) and more crepitations on auscultation compared to men (P = 0.04) [Table 1]. Although women also had a higher pulse rate and systolic blood pressure, statistical significance was not achieved. Similarly, men had a higher diastolic blood pressure compared to women, but not statistically significant. Although subgroup analysis also showed a higher respiratory rate and more crepitations among women across various age groups, statistical significance could not be reached [Table 4].

Table 4

Comparison of clinical features at presentation and lipid profile between postmenopausal women and age matched men

	45-54 years			55-64 years			65-74 years			≥75 years
	Women	Men	P	Women	Men	P	Women	Men	P	Women	Men	P
C/F
Pulse rate	84.5±15.37	79.38±14.36	0.32	88±14.86	90.83±22.9	0.63	93.38±15.96	78.21±8.19	0.95	84±20	86.8±10.9	0.87
SBP	150.77±22.89	138.92±38.1	0.89	145.26±40.17	150.31±38.55	0.68	146.15±33.7	147.69±24.55	0.9	140±40.46	142±24.89	0.99
DBP	90±15.11	86.92±31.98	0.72	81.05±17.91	90.73±20.25	0.98	84.61±17.61	87.69±12.35	0.99	80±24.49	92±13.03	0.6
RR	21.26±5.07	19.7±4.8	0.36	21.89±4.5	19.78±3.18	0.08	22.92±4.73	20.4±3.6	0.19	22±5.4	21.2±5.02	0.87
Crepitations	4	2	0.45	7	3	0.25	5	2	0.32	2	2	1
Lipid profile
TC	211.5±31.22	188.53±26.81	0.97	198.94±33.69	191±41.87	0.5	187.38±30.46	205.54±23.58	0.15	177±26.76	190.6±36.97	0.71
TG	194.36±59.08	196.33±79.36	0.97	194.94±61.6	179±62.2	0.4	136.38±36.67	159.15±48.27	0.25	150.75±49.4	147±43	0.94
LDL	93.14±8.79	91.61±20.24	0.83	97.72±19.61	92.33±25.35	0.43	93.68±21.99	87.85±35.4	0.69	96.75±27.54	81.75±28.7	0.654
HDL	38.42±7.94	37.84±8.12	0.83	41.85±8.35	37.31±9.23	0.1	43.54±7.91	35.08±6.77	0.01	44.5±10.15	40.6±15.14	0.79

C/F=Clinical features, SBP=Systolic blood pressure, DBP=Diastolic blood pressure, RR=Respiratory rate, TC=Total cholesterol, TG=Triglycerides, LDL=Low density lipoprotein cholesterol, HDL=High density lipoprotein cholesterol

Dyslipidemia and body mass index

When the lipid parameters were compared, we found that the mean total cholesterol, triglycerides and low density lipoprotein (LDL) cholesterol were higher among postmenopausal women compared to men, though statistical significance was not reached. On the other hand, high-density lipoprotein (HDL) cholesterol, the good cholesterol, was lower among men compared to women (P = 0.05) [Table 1]. Subgroup analysis showed a similar trend, though statistical significance was mainly seen in the 65–74 years age group with men having a lower HDL cholesterol compared to postmenopausal women of the same age group (P = 0.01) [Table 4].

The mean body mass index was higher among men compared to postmenopausal women (P = 0.0016) [Table 1]. Subgroup analysis also showed a similar trend of events, while statistically significant findings were seen in the 45–54 year and 55–64 year age groups [Table 3]. These findings correlate with a higher prevalence of overweight and obesity among men compared to women as discussed previously [Tables 1 and 3].

Cardiac biomarkers, echocardiography findings, and subtype of acute coronary syndrome

Cardiac biomarkers such as CKMB and troponin T were increased above the normal range more among men compared to postmenopausal women, though not statistically significant. Echocardiographic parameters such as regional wall motion abnormality (RWMA) and LV systolic dysfunction were more commonly seen among men compared to postmenopausal women, though not statistically significant [Table 1]. Postmenopausal women had a higher prevalence of non-ST elevation ACS (NST-ACS) compared to men, whereas men had a higher prevalence of STEMI, especially anterior wall STEMI, though statistical significance was not reached [Table 1].

Complications and outcome

Among complications, men had more ventricular tachycardia (14%) and intracerebral hemorrhage (4%) compared to women (4% and 0%, respectively). Women in this study had all other complications more than or same as men, but none of the values reached statistical significance [Figure 1].

Figure 1

Comparison of complications between women and men. LVF = Left ventricular failure, CS = Cardiogenic shock, VT = Ventricular tachycardia, AF = Atrial fibrillation, CHB = Complete heart block, AV = Atrio-ventricular, ICH = Intracerebral hemorrhage

The in-hospital mortality was more among postmenopausal women (7 deaths [14%]) compared to men (4 deaths [8%]), but among patients who survived, men developed more LV systolic dysfunction but was not statistically significant [Figure 2].

Figure 2

Comparison of outcome between women and men

DISCUSSION

The current study presents the profile of ACS in postmenopausal women compared with age-matched men. Although chest pain was the predominant symptom of ACS in both women and men, the characteristics of the pain were different between the groups. The classical symptoms of angina such as sweating and radiation of chest pain to the left arm and neck were more common among men, while women presented with atypical symptoms such as breathlessness, fatigue, giddiness, nausea, and diarrhea. These findings were consistent with previous studies.[456]

When the time to hospital presentation after symptom onset was evaluated, we found that postmenopausal women presented to hospital much later compared to men of the same age group. This finding was consistent with previous studies.[1920] Thus, we could find that delay in seeking treatment among women persisted even after menopause and age matching. This is explained by the frequency of more atypical symptoms among women.

Considering risk factors, our study showed that previous MI and smoking were less significant risk factors among women compared to men which was consistent with previous studies.[1021] Women had a higher prevalence of hypertension and diabetes mellitus which was consistent with previous studies by Tan et al.,[22] Hochman et al.,[10] and Gottlieb et al.[8] Contrary to the study by Tan et al.,[22] we found that obesity was significantly more among men than postmenopausal women. This could be explained by age matching, as in most studies, women are older than men resulting in more chances of developing obesity. We found that women presented with a higher respiratory rate and more crepitations on examination. This was consistent with more dyspnea among women.

Study of lipid parameters showed that women had a higher LDL cholesterol and triglycerides, which was consistent with previous studies.[22] But contrary to previous studies,[22] we found that postmenopausal women had a higher HDL cholesterol compared to age-matched men. This could be explained by age matching, as women in most studies are older than men.

When the type of ACS was compared between the groups, we found that women were less likely than men to present with STEMI and more likely to present with NST-ACS. This was in accordance with previous studies.[710] Women overall had more complications than men, which was consistent with previous studies.[1013] The in-hospital mortality was also higher among women compared to men which was also consistent with previous studies.[132324]

Limitations of the study

This was a small-scale study including only 100 participants. Larger scale studies are required to generalize the results. In view of the small sample size, age matching resulted in very few patients in various age groups resulting in very few parameters reaching statistical significance.

This study was done in a non-PCI capable hospital. If there was the availability of catheterization laboratory and cardiac surgery facility, the results, especially complications and outcomes could have been different. Furthermore, the gender differences with respect to coronary angiographic findings could throw more light in the context of including only postmenopausal women and age matching.

There was no use of newer antiplatelets such as prasugrel and ticagrelor, newer thrombolytics such as alteplase, reteplase, or tenecteplase, or anticoagulants such as bivaluridin or fondaparinux, which could have influenced the results, especially the complications and outcome.

The study included a short follow-up period. Long-term follow-up could indicate the long-term outcome of the patients.

Interpretation and generalizability

The results of this study should be interpreted in the context of the study been done in a non-PCI capable hospital. In India, even today, most of the hospitals do not have the facility of catheterization laboratory (cath lab), and medical management still remains the most common mode of treatment of ACS. The results can still be generalizable to the underdeveloped/developing parts of the world with scare cath lab facilities. Similar kinds of studies in PCI-capable centers can confirm or rebute the results, especially regarding the outcome. Most of the aspects of the study except complications and outcome can still be generalizable to most parts of the world. However, ethnic considerations still apply, and similar studies in other parts of the world, in other ethnic groups are required to generalize the results.

CONCLUSION

Postmenopausal women with ACS have more atypical presentation of symptoms, later presentation to hospital after symptom onset, more tachypnea, more crepitations, less likely to have obesity and past history of MI, less likely to be smokers and heavy alcohol consumers compared to men.

Women were also found to have a higher total, LDL cholesterol and triglycerides, and a higher HDL cholesterol compared to men of the same age group. Echocardiographic parameters such as RWMA and LV systolic dysfunction were lower among women compared to mem. Women were more likely to present with non-ST-ACS and less likely to present with STE-AWMI compared to men.

Postmenopausal women were found to have more complications and higher in-hospital mortality compared to men of the same age group. Thus, our study shows that even after menopause and age matching, the differences in the profile of ACS between women and men continue to exist.

A high index of suspicion of ACS should be borne in mind by the treating physician while evaluating a potential atypical symptom in a postmenopausal woman, and timely diagnosis and management can decrease the morbidity and mortality.

Community education of such symptoms can reduce the prehospital delay which is an important determinant of morbidity and mortality in ACS. Aggressive management and proper monitoring of postmenopausal women with ACS can identify and decrease the complications which are more common compared to age-matched men.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.