Background
The relationship between gender and post-acute coronary syndrome (ACS) outcomes has been extensively investigated.1 Nevertheless, the underlying causes of these outcome disparities remain incompletely understood. Prior investigations have produced mixed and inconclusive results.2
Heart failure (HF) is a significant public health issue affecting millions of individuals worldwide, with a considerable impact on morbidity and mortality.3,4 ACS continues to be a major cause of HF, potentially playing a significant role in the long-term outcomes of these patients.3,4
It is well established that ACS is associated with a high risk of developing HF, with substantial variability in patient outcomes.5 Studies suggest that differences may exist in the underlying pathophysiology and risk factors between men and women that influence the development of HF and clinical outcomes.6–8
In this framework, it remains uncertain whether the survival of ACS patients with new-onset HF at follow-up might differ by gender.
We sought to investigate the risk of new-onset HF and long-term outcomes in men and women with ACS undergoing percutaneous coronary intervention (PCI) by querying a large-scale multicentre registry.
Methods
We retrospectively analysed the ACTION-ACS, a pooled international large ACS database involving interventional large-volume academic centres based in Poland and recently one in Italy: the Department of Cardiology and Structural Heart Diseases, Medical University of Silesia, Katowice, and the Nicolaus Copernicus University, Bydgoszcz, Poland, and more recently the Clinical Interventional Cardiology, University of Sassari, Sassari, Sardinia Island, Italy. Information on the follow-up events was site reported and adjudicated by a trained physician-investigator. Details were previously reported.9 Data from patients with ACS undergoing PCI from 2009 to 2017 were analysed. All patients were prescribed dual antiplatelet therapy (DAPT) consisting of acetylsalicylic acid, 75–100 mg daily, and a P2Y12 inhibitor for at least 1 year according to guidelines. The included patients in the present study did not have a diagnosis of HF at baseline.
Study endpoints
The primary prespecified endpoint was new-onset HF, which was addressed at the 5 year follow-up. The diagnosis of acute HF was based on clinical symptoms or signs and radiographic evidence of pulmonary congestion. Acute HF was defined as Killip class ≥ 2. The secondary endpoints included all-cause mortality, myocardial infarction (MI), repeat PCI and acute ischaemic stroke. MI was defined according to its fourth universal definition.10 Reinterventions with PCI were performed in two specific scenarios: directly in response to the recurrence of ACS, where the decision for reintervention was based on clinical evaluations consistent with an ACS event, and following the detection of inducible ischaemia during screening examinations, such as ergometric testing or echocardiography stress tests.
Statistical analysis
We performed an adjusted analysis based on the propensity score (PS). The PS is the probability that each individual patient is included in the treatment group and was estimated via logistic regression based on the available baseline covariates. Potential confounders were entered into the PS model based on the known clinical and/or statistical relevance of associations (P < 0.01) observed at univariate analysis. Missing data were present in <5% of the inspected variables. Matching was performed with the use of a 1:1 nearest neighbour matching algorithm with a calliper width equal to 0.2 of the standard deviation of the logit of the PS. The covariate balance was assessed by exploring the standardized mean differences between unadjusted and adjusted populations and the distribution of the PS. The standardized differences were estimated for all the baseline covariates before and after matching to assess the pre-match imbalance and the post-match balance. Standardized differences of <10.0% for a given covariate indicate a relatively small imbalance. In the matched cohort, categorical variables were compared by χ2 or Fisher's exact tests, as appropriate. Categorical variables are reported as n (%) and continuous variables as means ± standard deviation or median plus interquartile range if the data distribution is not normal. Continuous data were analysed by the independent-samples t-test or the Mann–Whitney test.
The Cox proportional-hazards regression analyses were performed on the matched pairs. The results of the Cox regression at the 5 year follow-up are presented as a hazard ratio (HR) with a 95% confidence interval (CI). Cumulative incidence curves were generated for the endpoints of interest, and a landmark survival analysis was conducted, setting 1 year as the landmark time for HF and mortality outcomes. A P value < 0.05 was considered statistically significant for all analyses. For the subgroup analyses, the P interaction was calculated, and a value of <0.10 was considered significant. The statistical analysis was performed using R 4.0 statistical software (R Foundation for Statistical Computing, Vienna, Austria).
Results
From an initial cohort of 6120 unmatched patients, a total of 3334 matched patients with ACS were analysed (Figure S1). The remainder was excluded because long-term outcomes were not complete. Standardized differences were <10.0%, indicating a relatively small imbalance (Figure S2). All ACS patients with non-ST-segment elevation myocardial infarction (NSTEMI) (88.8%) or ST-segment elevation myocardial infarction (STEMI) (11.2%) had acute myocardial injury with clinical evidence of acute myocardial ischaemia according to the fourth universal definition of MI.10 The clinical characteristics in the male and female groups after matching were balanced and are illustrated in Table 1.
Table 1 Baseline characteristics in the matched population.
| Male | Female | ||
| CV risk factors | |||
| Age (years) | 0.37 | ||
| ≤75 | 1317 (79) | 1296 (77.7) | |
| >75 | 350 (21) | 371 (22.3) | |
| Dyslipidaemia | 1042 (63) | 1044 (63) | 0.971 |
| BMI, median (Q1, Q3) | 28.73 (25.83, 31.64) | 29 (25.7, 32.35) | 0.127 |
| Hypertension, n (%) | 1316 (78.9) | 1358 (81.5) | 0.07 |
| Anaemia, n (%) | 278 (17) | 294 (18) | 0.491 |
| GFR, median (Q1, Q3) | 85.02 (71, 96.31) | 84.62 (65.19, 103.18) | 0.83 |
| DM, n (%) | 1030 (62) | 980 (59) | 0.08 |
| Clinical history of CAD | |||
| CAD (%) | 396 (24) | 418 (25) | 0.39 |
| Previous PCI (%) | 734 (44) | 705 (42.3) | 0.31 |
| Previous CABG | 275 (16.50) | 257 (15.40) | |
| Clinical presentation | |||
| Two-vessel disease, n (%) | 509 (31) | 515 (31) | 0.85 |
| Three-vessel disease, n (%) | 283 (17) | 263 (15.8) | 0.35 |
| GRACE risk > 140, n (%) | 288 (17) | 256 (15) | 0.14 |
| Cardiac arrest, n (%) | 18 (1) | 13 (1) | 0.47 |
| HF therapy on admission | |||
| Beta-blocker, n (%) | 100 (6) | 92 (5.50) | 0.55 |
| ACE inhibitor, n (%) | 88 (5.30) | 89 (5.30) | 0.93 |
| Leucocytes, median (Q1, Q3) | 7.37 (6.10, 9.10) | 7.4 (6.09, 9.3) | 0.90 |
| Invasive access, n (%) | |||
| Radial access, n (%) | 1457 (87) | 1481 (89) | 0.21 |
Primary endpoint
All investigated patients developed HF with a reduced ejection fraction (EF). In comparison to females, male patients had a significantly higher risk of HF at 5 years [17.9% vs. 14.8%, HR (95% CI) = 1.22 (1.03–1.44), P = 0.02] (Figure 1A). By landmark analysis, the cumulative rate difference in HF between males and females emerged during the first year and was maintained thereafter (Figure 1B). EF was significantly lower in the male cohort [49 (44–54) vs. 55 (50–60), P < 0.001] (Figure 1C).
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Prespecified subgroup analyses
Several prespecified subgroups were explored. They included age, diabetes, hypertension, dyslipidaemia, glomerular filtration rate (GFR), coronary artery disease (CAD), anaemia, Global Registry of Acute Coronary Events (GRACE) score and multivessel disease (MVD). The estimates were directionally consistent in showing an increase in HF risk in males across subgroups without significant interactions (Figure 2).
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Secondary endpoints
Mortality
At 5 year follow-up, all-cause mortality was significantly higher in the male cohort as compared with the female cohort [15.50% vs. 12.70%, HR (95% CI) = 1.23 (1.02–1.47), P = 0.02] (Figure 3A). On landmark analysis, differences in mortality emerged after the first year and were maintained thereafter (Figure 3B).
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Ischaemic endpoints
MI risk was comparable without significant differences between groups [10.40% vs. 9.40%, HR (95% CI) = 1.03 (0.83–1.27), P = 0.78] (Figure 4). Likewise, PCI risk was comparable between groups [26.3% vs. 26.5%, HR (95% CI) = 1.0 (0.88–1.14), P = 0.93] (Figure S3). Ischaemic stroke risk was also not significant in males versus females [5.00% vs. 4.90%, HR (95% CI) = 1.05 (0.77–1.42), P = 0.74].
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Discussion
The main findings of this large-scale analysis encompassing 3334 ACS propensity-matched patients up to 5 years are the following: (i) Compared with females, male patients experienced significantly higher risk of new-onset HF episodes; (ii) landmark survival analysis demonstrated a sustained higher cumulative incidence of HF in males at 1 year follow-up and beyond; (iii) the greatest HF risk in male gender was consistent across all predefined subgroups; and (iv) a significant increase in mortality was observed in males, with landmark analysis indicating that this heightened risk occurred predominantly post 1 year period.
Previous large-scale studies have yielded varied findings.11–13 Some reports have proposed that disparities in outcomes may be attributed to older age and a lower rate of coronary interventions in women.14 Conversely, other studies have indicated that the differences may be ascribed to variances in the pathophysiology of coronary heart disease in women.15
To the best of our knowledge, the current work is one of the largest scale analyses of propensity-matched patients in the long term after ACS, with a focus on gender differences in clinical outcomes.
Our current work expands previous evidence by addressing HF and other outcomes by gender over the long term. The salient findings of the current study were generated in the long term, not restricted to hospitalization or 30 days. In another recent analysis based on administrative data, the HF rates were higher in females at 30 days, but no long-term data were available.2
However, the outcomes at shorter follow-up may have been influenced by other concomitant factors occurring during the hospital stay, thus being more prone to confounders.
In our propensity-matched study, there was an excess mortality in men as compared with women without significant differences in ischaemic outcomes. By landmark analysis, mortality tended to diverge after 1 year follow-up. Thus, time-related factors could play a role in influencing the prognosis of ACS patients, and the subsequent development of HF could emerge as a significant contributor to long-term mortality.
Post-ischaemic left ventricular remodelling, a recognized precursor to HF, initiates soon after MI due to tissue loss and persists over time after myocardial injury.16 This is a dual-phase process.17,18 Initially, remodelling is confined to the infarcted region, correlating directly with the extent of the infarction. Subsequently, the process extends to remote myocardial areas, driven by interactions of mechanical, neurohormonal and genetic factors. This latter stage of maladaptive remodelling is not inevitable and seems to be influenced mainly by increased wall stress and neurohormonal activation.19 Left ventricular remodelling appears to be gender related. Indeed, men have an increased risk of HF with reduced EF, and clinical and experimental studies suggest the presence of important differences in cardiac remodelling between females and males.20,21
A plausible explanation for increased HF in males is that studies have shown that men are more likely to develop eccentric hypertrophy, a type of cardiac remodelling characterized by an increase in left ventricular volume and dilation of the heart chambers.22,23 This may result in a reduced EF, which is a significant risk factor for congestive HF. In contrast, women may be more prone to develop concentric remodelling, which implies an increase in wall thickness without a significant change in chamber size. This response, while increasing the risk of acute haemodynamic collapse in the early stages, tends to limit dilation and is associated with more favourable long-term prognoses.7,8
Hormonal differences between men and women could also affect the risk of HF post-ACS in younger age groups. Oestrogens have been shown to exert protective effects on the cardiovascular system. They can help maintain vascular function, reduce inflammation and promote vasodilation.24 Pre-menopausal women, who have higher oestrogen levels, may experience some degree of cardioprotection. On the other hand, testosterone, the primary male sex hormone, may have some adverse cardiovascular effects. High testosterone levels have been associated with an increased risk of adverse cardiovascular events.25 Genetic factors might contribute to the inherent differences in HF risk between men and women. Some genetic variants and polymorphisms have also been associated with an increased risk of HF.26 These genetic predispositions may differ between men and women, potentially influencing their susceptibility to HF following ACS.
An additional possible strength of the current large-scale analysis is the employment of PS matching. Among adjustment methods, a matching algorithm is the most robust method aimed at mitigating selection bias by balancing the distribution of covariates between male and female groups, resembling a randomized design, thereby reducing the impact of confounding variables on the estimated treatment effect.27
The pivotal findings of the current study reinforce the need for improved risk stratification as well as therapeutic optimization to reduce HF-related outcomes such as mortality after ACS.
In summary, our findings demonstrate that long-term disparities in outcomes exist between genders following ACS, with a heightened risk of HF observed in males, potentially serving as the primary contributor to the increased mortality rate identified in the male population.
Limitations
This was an observational study, so residual confounding due to unmeasured variables cannot be completely excluded. On the other hand, a propensity matching score was built to generate a quasi-randomized design to mitigate the risk carried by confounders. A final balance of the covariate distribution was achieved.
Conclusions
After experiencing ACS, men face a greater long-term risk of developing new-onset HF compared with women. This discrepancy remained consistent across all examined subgroups. HF emerges as the primary independent contributor to long-term gender disparities among ACS patients and mortality. Efforts aimed at identifying and modifying HF gender-related prognosis following ACS should be a key point for the future, with the aim of improving prognosis.
Conflict of interest statement
The authors have no conflicts of interest to disclose.
Funding
None.
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Abstract
Aims
A paucity of studies addressed sex‐related differences in clinical outcomes in the long term following acute coronary syndrome (ACS) treated with percutaneous coronary intervention (PCI). In these patients, it remains uncertain whether heart failure (HF) might exert a differential impact on the prognosis in the long term.
Methods
We queried a large‐scale database of ACS patients undergoing PCI. The primary endpoint was new‐onset HF. Secondary endpoints included mortality, myocardial infarction, re‐PCI and ischaemic stroke. Propensity score matching was generated to balance group characteristics. A total of 3334 patients after propensity score matching were analysed. Follow‐up was assessed at the 5 year term.
Results
At 5 year follow‐up, HF risk increased significantly in males versus females {17.9% vs. 14.8%, hazard ratio [HR] [95% confidence interval (CI)] = 1.22 [1.03–1.44], P = 0.02}. At 5 year follow‐up, mortality was significantly higher in the male cohort as compared with the female cohort [HR (95% CI) = 1.23 (1.02–1.47), P = 0.02]. On landmark analysis, differences in mortality emerged after the first year and were maintained thereafter. Ischaemic outcomes were comparable between cohorts.
Conclusions
Following ACS, males experienced a greater long‐term risk of developing new‐onset HF as compared with females. This difference remained consistent across all prespecified subgroups. Mortality was significantly higher in males. No differences were observed in ischaemic outcomes. New‐onset HF emerges as a primary contributor to long‐term gender disparities after ACS and a strong predictor of mortality in men with HF.
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Details
1 Clinical and Experimental Cardiology, Clinical and Interventional Cardiology, University of Sassari, Sassari, Italy, SIRIO MEDICINE Research Network, Sassari, Italy
2 Department of Cardiology, Republican Clinical Hospital, Baku, Azerbaijan, Department of Family Medicine, Azerbaijan Medical University, Baku, Azerbaijan
3 Department of Cardiology and Structural Heart Diseases, Medical University of Silesia, Katowice, Poland
4 Clinical and Experimental Cardiology, Clinical and Interventional Cardiology, University of Sassari, Sassari, Italy
5 Department of Cardiology and Internal Medicine, Nicolaus Copernicus University, Bydgoszcz, Poland