Sex-Related 30-Day and Long-Term Mortality in Acute Myocardial Infarction Patients Treated with Percutaneous Coronary Intervention

Abstract

Background:

The data on sex as an independent risk factor for death in acute myocardial infarction (MI) patients are still contrasting. The aim was to assess how sex influences 30-day and long-term all-cause mortality in MI patients undergoing percutaneous coronary intervention (PCI).

Materials and Methods:

Data from 3624 MI patients undergoing PCI at our institution from January 2009 to December 2014, 30.6% were women, were analyzed. A propensity-matched analysis was performed to adjust for differences in the baseline characteristics between men and women. The effect of sex on 30-day and long-term mortality was observed. Multivariate logistic regression modeling was used for 30-day mortality and Cox regression analysis for long-term mortality. The median follow-up time was 27 months (25th, 75th percentile: 9, 48).

Results:

Women had a significantly higher unadjusted 30-day (5.9% in men vs. 9.5% in women; p < 0.0001) and long-term mortality (13.5% in men vs. 19.0% in women; p < 0.0001). In a propensity-matched analysis, female sex was not associated with a higher 30-day (adjusted odds ratio: 1.46; 95% confidence interval: 0.97–2.19) or long-term mortality (hazard ratio 1.02; 95% CI 0.81–1.28). Age older than 77 years, cardiogenic shock, PCI of left anterior descending artery (LAD), thrombolysis in myocardial infarction (TIMI) flow less than 3 after PCI, hypertension, dyslipidemia, and P2Y12 receptor antagonists were identified as independent predictors of 30-day and long-term mortality. In addition, renal failure requiring dialysis predicted long-term mortality.

Conclusion:

Older age, comorbidities, worse clinical presentation, and adjunctive pharmacotherapy rather than sex may explain the higher mortality rate in women with MI undergoing PCI.

Introduction

Higher mortality rates are observed among women admitted with acute coronary syndrome in comparison to men.^{1

–12} Despite the increased attention, this relationship is poorly understood.^1,3,13 The data on sex as an independent prognostic factor for death are conflicting.^{1

–5,7,10,12

–16} Underuse of evidence-based treatment and delayed reperfusion are observed in women.^1,13,17 Women present more often with non-ST-elevation myocardial infarction and less frequently with ST-elevation myocardial infarction (STEMI) compared with men.¹ They often delay seeking medical care compared with men, probably because they more often experience atypical symptoms.^1,13,17 Only a limited number of studies reported results about the medium or long-term mortality in women with myocardial infarction (MI) receiving modern treatment and these are almost exclusively limited to STEMI patients^2,16,18,19 or MI patients treated either conservatively or with percutaneous coronary intervention (PCI).²⁰ Changes in PCI practice and quality initiatives aimed at reducing pain-to balloon times may have influenced these sex-related differences over time.^2,17 The aim of our study was to assess sex differences in 30-day and long-term outcomes in a retrospective cohort of MI patients undergoing PCI.

Materials and Methods

The present study is a single-center analysis of consecutive 3624 MI patients treated in a tertiary referral hospital with a 24/7 primary PCI service from January 2009 to December 2014. Patients were treated according to the guidelines for MI management.^21,22 Angioplasty strategy, PCI of other coronary arteries, and concomitant medication were at the discretion of the operator. Patients were followed until January 31, 2015. Median follow-up time was 27 months (25th, 75th percentile: 9, 48). Data on dates of death were provided by the Slovenian National Cause of Death Registry. The study was approved by the local ethics committee.

Definitions

To assess the baseline clinical characteristics of the study cohort, we collected data concerning sex, diabetes, hypertension, dyslipidemia, laboratory values, all performed interventions, stents, lesions, interventions, coronary flow before and after procedure and outcome.

MI definition was based on the guidelines.^21,22 Cardiogenic shock was defined according to clinical and hemodynamic criteria, including hypotension (systolic blood pressure ≤90 mm Hg for ≥30 minutes or need for supportive measures to maintain systolic blood pressure of >90 mm Hg) and evidence of end-organ hypoperfusion.

Multivessel PCI was defined as PCI of at least two major coronary arteries or PCI of the left main coronary artery and at least one major coronary artery. Unsuccessful PCI was defined as PCI with thrombolysis in myocardial infarction (TIMI) flow 0/1 after PCI. Anemia was defined as hemoglobin level <118 g/L for women and <133 g/L for men on admission. Glomerular filtration rate (GFR) was calculated with the four-variable modification of diet in renal disease formula.²³ The first serum creatinine level on admission was used for calculations of GFR.

Outcomes

The endpoints were all-cause 30-day and long-term mortality in male and female patients. Long-term mortality was defined as mortality during the observation period. Data on all essential patient and procedure characteristics were at least 94.8% complete and ascertainment of endpoints was 100% complete. Patients with missing data were excluded from the analysis.

Statistical methods

Differences between men and women in baseline clinical, angiographic, and procedural characteristics were compared using the independent samples t test or the Mann–Whitney U test for continuous variables, and the chi-square test for categorical variables, as appropriate.

Greedy matching technique was then used to match a female patient to a male patient with the nearest propensity score to permit comparison of female patients with male patients with similar characteristics.²⁴ The filter included age, diabetes, STEMI, bivalirudin, PCI of LM coronary artery, cardiogenic shock, multivessel PCI, and TIMI 3 after PCI. The IBM SPSS algorithm was used. This applies the greedy matching technique, which orders and sequentially matches observations to the nearest propensity score until no matches are possible (propensity scores differ above the default threshold—a calliper of 0.15 of the standard deviation of the logit of the propensity score). Propensity matching involved 1110 women and 2514 men. A male match was found for 1005 women, 105 women remained without an appropriate male match. After propensity matching, the sample included 2010 patients (1005 women and 1005 men). Cumulative incidence rates of unadjusted long-term mortality were estimated by the Kaplan–Meier method and compared by the log-rank test. Multivariate logistic regression modeling was used to calculate adjusted odds of 30-day mortality, and multivariable Cox regression was calculated for long-term mortality. Covariates used in all regression analysis were as follows: age, hypertension, hyperlipidemia, diabetes, cardiogenic shock, P2y12 receptor antagonists, PCI of left anterior descending artery (LAD), drug eluting stents, TIMI flow after PCI, renal failure requiring dialysis, and sex. In addition, several Cox models were built according to age to identify which age boundary is of importance. Data were analyzed with the SPSS 22.0 software for Windows (IBM Corp., Armonk, NY). All p values were two-sided; p values less than 0.05 were considered statistically significant.

Results

Descriptive data for patients

Out of 3624 MI patients 1110 (30.6%) were female. Women were on average almost 7 years older (62.7 ± 11.8 in men vs. 69.3 ± 11.7 in women; p < 0.0001). Significantly more women had diabetes (11.7% in women vs. 14.5% in men; p = 0.022). On the contrary, they had less hyperlipidemia (33.4% in men vs. 29.9% in women; p = 0.041), suffered less STEMI (58.6% in men vs. 53.8% in women; p = 0.008), and were less frequently treated with bivalirudin (14.6% in men vs. 10.4% in women; p < 0.0001). They tend to present more often in cardiogenic shock (4.0% in men vs. 5.3% in women; p = 0.09), and more PCI of the left main coronary artery was performed in women (2.8% in men vs. 4.5% in women; p = 0.022). Basic clinical and angiographic characteristics are shown in Table 1. After propensity matching, there were no longer any apparent differences between women and men (see Supplementary Tables S1 and S2; Supplementary Data are available online at www.liebertpub.com/jwh).

Table 1.

Basic Patients' Characteristics

	Men (N = 2514)	Women (N = 1110)	All patients (N = 3624)	p
Age, years^a	62.7 (11.8)	69.3 (11.7)	64.7 (12.2)	<0.0001
Diabetes, N (%)^b	295 (11.7)	161 (14.5)	456 (12.6)	0.022
Hypertension, N (%)^b	999 (39.7)	471 (42.4)	1470 (40.6)	0.18
Dyslipidemia, N (%)^b	839 (33.4)	332 (29.9)	1171 (32.3)	0.041
Anemia, N (%)^b	705 (29.4)	294 (27.7)	999 (28.9)	0.31
RF requiring dialysis, N (%)^b	28 (1.2)	6 (0.6)	34 (1.0)	0.13
STEMI, N (%)^b	1472 (58.6)	587 (53.8)	2069 (57.1)	0.008
Cardiogenic shock, N (%)^b	104 (4.1)	60 (5.4)	164 (4.5)	0.09
CPR, N (%)^b	142 (5.6)	53 (4.8)	195 (5.4)	0.30
P2Y12, N (%)^b	2225 (88.6)	964 (86.8)	3189 (88.1)	0.13
Bivalirudin, N (%)^b	367 (14.6)	115 (10.4)	482 (13.3)	<0.0001
GPIIb/IIIa, N (%)^b	1194 (47.5)	541 (48.7)	1735 (47.9)	0.49
PCI LMCA, N (%)^b	74 (2.8)	50 (4.5)	124 (3.4)	0.022
PCI LAD, N (%)^b	961 (38.2)	446 (40.2)	1407 (38.2)	0.27
PCI LCX, N (%)^b	446 (17.7)	201 (18.1)	647 (17.9)	0.81
PCI RCA, N (%)^b	785 (31.2)	367 (33.1)	1152 (31.8)	0.28
Multivessel PCI, N (%)^b	341 (13.6)	170 (15.3)	511 (14.1)	0.18
Unsuccessful PCI, N (%)^b	93 (3.7)	49 (4.4)	142 (3.9)	0.31
Radial approach, N (%)^b	419 (16.7)	175 (15.8)	584 (16.4)	0.53
IABP, N (%)^b	48 (1.9)	26 (2.3)	73 (2.0)	0.52
DES, N (%)^b	928 (36.9)	404 (36.4)	1332 (36.8)	0.79
TIMI3 before PCI, N (%)^b	276 (11.0)	138 (12.4)	414 (11.4)	0.21
TIMI3 after PCI, N (%)^b	1940 (77.3)	865 (77.9)	2805 (77.5)	0.70

Mean (standard deviation); comparison made using the t-test.

Comparison made using the chi-square test.

DES, drug eluting stent; GPI, GPIIb-IIIa receptor inhibitors; IABP, intra-aortic balloon pump insertion; LAD, left anterior descendent artery; LCX, circumflex artery; LMCA, left main coronary artery; Multivessel PCI, PCI of more than one major coronary artery; N, number; P2Y12, P2Y12 receptor antagonists; PCI, percutaneous coronary intervention; RCA, right coronary artery; RF, renal failure; STEMI, ST-elevation myocardial infarction; TIMI, thrombolysis in myocardial infarction; TIMI3 before PCI, TIMI grade flow before PCI; TIMI3 after PCI, TIMI3 grade flow after PCI; Unsuccessful PCI, TIMI grade flow after PCI = 0/1.

Mortality

30-Day mortality

Women had a significantly higher 30-day unadjusted mortality [148 men (5.9%) died vs. 110 women (9.5%); p < 0.0001] (Table 2). Unadjusted women-to-men odds ratio (OR) for mortality was 1.76 (95% confidence interval [CI] 1.36–2.27; p < 0.0001). After the propensity-matched adjustment, 30-day mortality was similar in both groups (Table S2). Multivariate logistic regression modeling did not identify the female sex as a prognostic factor for 30-day mortality (adjusted OR: 1.46; 95% CI: 0.97–2.19). Age older than 77 years (adjusted OR: 2.47; 95% CI: 1.77–3.99; p < 0.0001), cardiogenic shock (adjusted OR: 11.15; 95% CI: 8.00–20.70; p < 0.0001), PCI of LAD (adjusted OR: 2.19; 95% CI: 1.43–3.37; p < 0.0001), TIMI flow less than 3 after PCI (adjusted OR: 2.27; 95% CI: 1.40–3.68; p = 0.001), dyslipidemia (adjusted OR: 2.15; 95% CI: 1.15–4.01; p = 0.016), hypertension (adjusted OR: 1.71; 95% CI: 1.09–2.68; p = 0.019), and P2Y12 receptor antagonists (adjusted OR: 0.38; 95% CI: 0.23–0.62; p < 0.0001) were identified as independent predictors of 30-day mortality.

Table 2.

Mortality in Male and Female Myocardial Infarction Patients Undergoing Percutaneous Coronary Intervention

	Men (N = 2514)	Women (N = 1110)	All patients (N = 3624)	p
30-Day, N (%)^a	148 (5.9)	110 (9.9)	258 (7.1)	<0.0001
Long-term mortality, N (%)^a	338 (13.5)	211 (19.0)	550 (15.2)	<0.0001

Comparison made using the chi-square test.

Long-term mortality

Women had a significantly higher unadjusted long-term mortality [338 (13.5%) men died versus 211 (19.0%) women; p < 0.0001] (Table 2 and Fig. 1A). In a propensity-matched analysis, sex was no longer associated with a higher long-term mortality (HR 1.04; 95% CI: 0.84–1.27; Table S2 and Fig. 1B). Age older than 77 years (HR 2.33; 95% CI: 1.86–2.93; p < 0.0001), cardiogenic shock (HR 4.41; 95% CI: 3.05–6.37; p < 0.0001), TIMI flow less than 3 after PCI (HR 1.66; 95% CI: 1.26–2.17; p < 0.0001), PCI of LAD (HR 1.70; 95% CI: 1.33–2.17; p < 0.0001), dyslipidemia (HR 1.78; 95% CI: 1.29–2.46; p = 0.001), hypertension (HR 1.41; 95% CI: 1.10–1.80; p = 0.006), RF requiring dialysis (HR 2.84; 95% CI: 1.25–6.43; p = 0.012), and P2Y12 receptor antagonists (HR 0.45; 95% CI: 0.34–0.60; p < 0.0001) independently predicted long-term mortality.

FIG. 1.

Long-term all-cause mortality in male and female MI patients. (A) Unadjusted long-term mortality; (B) long-term mortality after propensity matching. Women = green line; Men = blue line. Color images available online at www.liebertpub.com/jwh

Discussion

We retrospectively analyzed men and women with MI who underwent PCI. Women were found to have a higher 30-day and long-term unadjusted mortality. However, in a propensity-matched analysis, no difference was found between women and men in either 30-day or long-term mortality.

Women were almost 7 years older than men, had more comorbidities, and tended to have more hemodynamic impairment, which is in accordance with previous observations.^{1

–6,9,10,13
–15,25

–29} Higher unadjusted women's short-term mortality in MI patients has also been previously described.^{1
–3,5,8,9,11,16,17,25,30} However, data on sex as an independent prognostic factor for death were still conflicting.^{1,2,10,12,14,15} Short-term mortality was not independently linked to the female sex after adjustment for age, comorbidities, and clinical picture on admission in most studies for MI,^{2

–6,13,16,18,25,30
–32} but some had noticed that the female sex was linked with a higher mortality.^9,12,33

The same was true for long-term mortality. The majority of studies showed a sex difference in long-term mortality rates,^10,16,33 but some showed no sex difference.^9,18,28

Higher mortality in women was mainly attributed to older age, worse risk-factor profiles, greater comorbidities, delays in presentation, and treatment differences.^2,13 Alternative explanations for differences in mortality may relate to sex-specific biology, pathophysiology of MI, psychosocial stressors, and potential intrinsic differences in angiogenesis and collateralization between men and women.^1
–3,13,34 After the propensity-matched adjustment in our study, sex was not an independent predictor for either 30-day or long-term mortality in MI patients undergoing PCI. Sex-related differences in survival were no longer apparent, suggesting that additional comorbidities, adjunctive pharmacotherapy, and age account for sex-related differences in mortality.

Age, cardiogenic shock, STEMI, hypertension, dyslipidemia, PCI of LAD, and TIMI flow less than 3 after PCI predicted worse and P2Y12 receptor antagonists predicted better 30-day and long-term mortality. The correlation of these factors with the outcome in MI patients is well known.^22,35

–38 In addition, renal failure requiring dialysis predicted worse long-term outcome, which is also well established.^22,35 Although diabetes is one of the main risk factors for MI it was not associated with mortality. This is also consistent with the previous findings.^7,39

This data strongly support the concept that the worse outcomes observed with female sex mainly result from the greater prevalence of known prognostic factors for mortality, rather than the female sex per se.

The result of our study may be relevant for treatment of women with MI in everyday practice. Women with MI more often experience atypical symptoms such as back, neck, and jaw pain, nausea, vomiting dyspnea, indigestion, palpitations, dizziness, fatigue, loss of appetite, and syncope.^1,14 They are older than men, with multiple risk factors and comorbidities, and therefore at high risk.¹³ Moreover, healthcare professionals can be misled by this atypical presentation and underestimate the possibility of MI in women.⁸ Women usually have a longer time interval from the onset of chest pain to presenting to the hospital, thus the “sense of urgency” may be lost by the triage personnel resulting in a less urgent triage, classification, and subsequent delay.¹⁴ Therefore, particular attention should be paid to women with MI to provide them with the equal quality of treatment as men.

Limitations

This was an observational and a single-center study. Our data encompassed all-cause mortality only, which is certainly considered to be a limitation of the study. The data about Killip class, heart rate, blood pressure on admission, and evidence-based medical therapy after PCI were not available for a sufficient number of patients to be considered in the evaluation. Finally, the data on bleeding and smoking were not collected.

Conclusion

Women represent almost one third of patients with MI undergoing PCI. Short-and long-term mortality risks were increased with female sex. After propensity-matched adjustment for age, clinical, and procedural characteristics, there was no difference in mortality. Worse outcomes observed with female sex mainly result from the greater prevalence of known prognostic factors for mortality, rather than the female sex per se.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

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