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Long-term outcomes after percutaneous coronary intervention versus coronary artery bypass grafting in women, a meta-analysis
Journal of Cardiothoracic Surgery volume 19, Article number: 666 (2024)
Abstract
Background
Despite the advances in the last decades for treatment of ischemic heart disease, women continue to experience poorer prognosis than men and currently, there is a gap in knowledge regarding the optimal revascularization strategy in women.
Objective
Compare the long-term outcomes of percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) for the treatment of stable ischemic heart disease in women.
Methods
A systematic search was conducted including randomized clinical trials (RCTs) comparing PCI with drug-eluting stents with CABG. The primary outcome were the composite outcomes of death, stroke or myocardial infarction (MI) and death, stroke, MI or repeat revascularization. Secondary outcomes included the individual components of the primary outcomes. Pooled hazard ratios with 95% confidence intervals were calculated in a fixed- effects meta-analysis using the inverse of variance method. Risk of bias and sensitivity analyses were also conducted.
Results
Six multicenter, RCTs were included after eligibility assessment. Median follow-up was 6.25 years (IQR: 5- 2.5). A significant benefit for CABG over PCI was observed for the primary composite outcomes of death, stroke, MI (HR = 1.24; 95% CI 1.01–1.52; p = 0.037) and death, stroke, MI or repeat revascularization (HR = 1.60; 95% CI 1.25–2.03; p < 0.000).
Conclusion
In the present study-level metanalysis, CABG is associated with a lower risk of major adverse cardiovascular events than PCI at long term follow-up in women.
Background
Despite the advances in the last decades for treatment of ischemic heart disease, women continue to experience poorer prognosis than men. The cause is multifactorial, including biological factors, clinical delay in diagnosis and atypical presentation, among others [1, 2]. Given that currently there is a gap in knowledge regarding the optimal revascularization strategy in women, we conducted a meta-analysis to compare the long-term outcomes of percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) for the treatment of stable ischemic heart disease in women.
Methods
This meta-analysis was developed following the recommendations of the PRISMA statement [3] and the Cochrane Handbook for Systematic Reviews of Interventions [4].
Ethics
Given the nature of this study, patient consent was not required.
Systematic search
A systematic search was conducted of the Cochrane Library, EMBASE, MEDLINE, Web of Science and conference abstracts in English language from database conception until June 2023. The search terms were:
(“Percutaneous Coronary Intervention” AND “drug eluting stent”) AND (“coronary artery bypass”) AND (“female” OR “male” OR “men” OR “women” OR “sex”) AND (“randomized controlled trial“[Publication Type]) AND (English [Language]).
This study was registered in PROSPERO (International Prospective Register of Systematic Reviews) (CRD42022323279).
Eligibility criteria
Eligible studies met the following PICOs criteria (participants, interventions, comparators, outcomes and study design):
-
a)
Population: Women with stable ischemic heart disease undergoing revascularization.
-
b)
Intervention: Myocardial revascularization.
-
c)
Comparison intervention: PCI with drug eluting stent (DES) or CABG for myocardial revascularization.
-
d)
Outcomes: At least 1 or more of the following outcomes or their composite at the longest follow-up available; Survival, myocardial infarction (MI), stroke and repeat revascularization. Outcomes had to be reported as crude events in each group or estimates (risk ratio, odds ratio, risk difference, mean difference) with 95% confidence intervals.
-
e)
Study design: Randomized clinical trials (RCT) comparing PCI with DES vs. CABG.
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f)
Exclusion criteria: Studies with less than 5 years of follow-up.
Quality assessment
Strength of evidence, consistency, precision, directness and publication bias was evaluated using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) system [5].
Outcomes and data extraction
The primary outcome was the composite outcome of death, stroke or myocardial infarction and death, stroke, myocardial infarction or repeat revascularization. Secondary outcomes included the individual components of the primary outcome. Authors, publication date, type of study, number of events, sample size, sex, age, type of devices employed for PCI and technical aspects of CABG were extracted. For the cases were estimate effects with 95% confidence intervals (CI) were not available, the method proposed by Tierney, J et al. to estimate hazard ratios (HR) with 95% CI was employed [6]. Only intention- to- treat analysis data was extracted.
Data analysis
The estimates for each endpoint were combined using a fixed- effects meta-analysis by means of the inverse of variance method to determine the pooled HR of PCI compared to CABG. Heterogeneity between studies was evaluated using the I2 statistic (An I2 value < 25% was considered low; I2 between 25 and 75% moderate and I2 > 75% high heterogeneity) and the Q test (p < 0.10 for significant heterogeneity). Sensitivity analysis using the leave-one-out method and subgroup analyses examining the influence of left main disease (LM) dedicated RCTs on the primary endpoints were also performed. In order to confirm the consistency of the results regarding of the analysis method, a random- effects analyses for the primary endpoints were also performed. Forest plots were used to illustrate the pooled estimates. Risk of bias was assessed using the RoB 2 tool [7]. Funnel plots represented publication bias and heterogeneity for the primary endpoints. Two- sided P values of 0.05 were considered statistically significant. Adjustment for multiple testing was not performed. Statistical analyses were performed using Stata 17 (StataCorp, 2021. College Station, TX).
Results
Six multicenter, RCTs were included after eligibility assessment (Fig. 1) [8,9,10,11,12,13,14]. The overall quality of evidence using the GRADE system for the primary endpoints was moderate (Supplementary Table 1), mainly due to some concerns regarding risk of bias and indirectness (Supplementary Figs. 1 and 2). Median follow-up was 6.25 years (IQR: 5–10). The weighted median age of the patients at the time of inclusion was 65.1 years (IQR: 63.2–66) and the weighted median perioperative risk estimated with the EuroSCORE was 2.8% (IQR: 2.7–3.8). First generation DES were employed in the SYNTAX, PRECOMBAT and FREEDOM trials, and second-generation DES in the BEST, NOBLE and EXCEL trials. The median of arterial grafts employed was 1 (IQR 1–2). Characteristics of included studies are resumed in Table 1. Different definitions of events were employed for each RCT, which are summarized in supplementary Table 2.
The SYNTAX trial compared the composite of death, stroke, MI and repeat revascularization. 1800 patients were included, 903 in the PCI arm and 897 in the CABG arm; of those, 23.6% (n = 213) and 21.1% (n = 189) were women, respectively [8]. After completion of 5-year follow up, the study was continued as the SYNTAXES trial, which evaluated survival at 10-year follow-up [9].
The PRECOMBAT trial included patients with LM disease, and evaluated the composite of death, stroke, MI and repeat revascularization up to 10 years of follow-up. 300 patients were included in each arm, with 24% (n = 72) and 23% (n = 69) female patients for PCI and CABG, respectively [10].
The FREEDOM was designed to compare the composite of death, stroke and MI in patients with diabetes and multivessel coronary artery disease (CAD), and reported outcomes at 5 years of follow-up. 953 patients were included in the PCI arm and 947 in the CABG arm. 26.8% (n = 255) and 30.5% (n = 289) were women in each arm, respectively [11]. After study completion, the study continued as the FREEDOM Follow-On study, evaluating survival at 7.5 years of follow-up [15].
The BEST trial included 880 patients with multivessel CAD and compared the composite of death, MI and repeat revascularization up to 5-year follow-up. 30.6% (n = 134) were female patients in the PCI arm and 26.5 (n = 117) in the CABG arm [12].
The NOBLE and EXCEL trials included 1184 and 1905 patients with LM CAD, respectively, and reported outcomes at 5 years of follow up. The primary endpoint of NOBLE was the composite of death, stroke, MI and repeat revascularization while EXCEL evaluated a primary endpoint of death, stroke and MI. In the NOBLE trial, 20% (n = 116) and 24% (n = 140) were women in the PCI and CABG arms respectively. In the EXCEL trial 23.8% (n = 226) were women in the PCI arm and 22.5% (n = 215) in the CABG arm [13, 14].
Death, stroke, MI
Five studies reported the composite endpoint of death, stroke or MI [8, 10,11,12, 14]. 25.1% (n = 1779) were female and 74.9% (n = 5306) male patients. In the pooled analysis, we observed a significant benefit favoring CABG over PCI (HR = 1.24; 95% CI 1.01–1.52; p = 0.037; I2 = 0.0%) (Fig. 2). In the sensitivity analysis, the SYNTAX, FREEDOM and EXCEL studies had a significant influence in the composite outcome (Supplementary Fig. 3). In the subgroup analyses stratified by LM or multivessel RCT, no significant differences were found when evaluating only LM dedicated RCTs (HR = 1.18; 95% CI 0.79–1.76; p = 0.41; I2 = 48.4%). Additionally, no significant interaction between subgroups was observed (p = 0.781) (Supplementary Fig. 4).
Death, stroke, MI, repeat revascularization
The composite of death, stroke, MI or repeat revascularization was reported in 4 studies [8, 10, 12, 13]. 23.5% (n = 1050) and 76.5% (n = 3414) were women and men, respectively. A significant benefit of CABG over PCI was observed in the pooled analysis (HR = 1.60; 95% CI 1.25–2.03; p < 0.000; I2 = 25.7%) (Fig. 3). In the sensitivity analysis, the estimate from the SYNTAX trial significantly influenced the composite outcome (Supplementary Fig. 5). Results were consistent in the subgroup analysis for LM RCT’s (HR = 1.49; 95% CI 1.01–2.21; p = 0.05; I2 = 73.5%) and no significant between-subgroup interaction was observed (p = 0.663) (Supplementary Fig. 6). Results were similar in the random- effects analysis for each of the composite endpoints (Supplementary Figs. 7–8).
Individual components of the primary outcomes
Death was reported in four studies (n = 4277) [9, 10, 12, 15], 26.3% (n = 1125) were women and 73.7% (n = 3152) men. In the pooled analysis, no significant difference between PCI and CABG was observed (HR = 1.02; 95% CI 0.82–1.25; p = 0.884; I2 = 0.0%) (Fig. 4A). Three studies reported the incidence of MI, repeat revascularization and stroke (n = 3280) [8, 10, 12]. 24.2% (n = 794) were women and 75,8% (n = 2486) were men. A significant benefit of CABG over PCI was observed in the pooled analysis for MI and repeat revascularization (MI HR = 2.15; 95% CI 1.06–4.35; p = 0.034; I2 = 0.0%) (Repeat revascularization HR = 2.55; 95% CI 1.69–3.86; p < 0.000; I2 = 0.0%), respectively (Fig. 4B and C). Regarding stroke, we observed no significant differences between treatments in the pooled analysis (HR = 0.55; 95% CI 0.25–1.21; p = 0.137; I2 = 0.0%) (Fig. 4D).
Discussion
We have conducted a study-level metanalysis including all contemporary RCTs with at least 5 years of follow up comparing PCI versus CABG in women (Central figure). Our main findings are the following:
-
1)
There is a significant benefit of CABG over PCI in for the composite outcome of death, MI, stroke and death, MI, stroke and repeat revascularization.
-
2)
Women were largely underrepresented in contemporary RCTs, with less than 30% of included patients.
The benefit of CABG over PCI in the composite endpoint was mainly driven by a reduction in MI and repeat revascularization events in CABG patients, without significant differences in death or stroke. Even though the main cause of ischemic heart disease in both sexes is atherosclerosis, women present different patterns of disease, usually less extensive with smaller vessel lumen, tortuous anatomy and high risk for coronary artery dissection, making revascularization procedures more technically demanding. In this setting, CABG might offer several advantages to overcome these challenges: restores distal flow irrespective of lesion characteristics, protects from proximal plaque progression in the treated vessel, and complete revascularization is often achieved at the time of the index procedure [16,17,18,19]. In addition, conduit patency in CABG grafts ranges from 50% at 10 years for saphenous vein grafts to 98% at 20 years for left internal thoracic artery grafts, with evidence of reduction in major adverse cardiovascular events when multiple arterial grafting is employed [20,21,22,23]. On the other hand, DES restenosis at 8 month follow up may be present in 12.2–14.6% of patients in large registries, with an incidence of repeat revascularization and target lesion failure within 5 years of 12.2 to 13.3% and 7.7–9.5%, respectively [24, 25].
The influence of guideline directed medical therapy in long term outcomes is out of the scope of this study given the lack of patient-level data. Nonetheless, two RCTs reported long term medication therapy according to sex, showing that women overall had worse adherence to medical therapy, and specifically, women who underwent CABG had significantly lower adherence to antiplatelet and statin therapy [9, 10].
Our results are in concordance with two previous metanalyses which reported similar findings in women and men. Nevertheless, the patient-level metanalysis by Stomi, Y et al. included only 3 RCT’s with a median follow up of 4.9 years and the study-level metanalysis by Gul, B et al. included studies with less than 5 years of follow-up [26, 27]. To our knowledge, our study is the first to include all contemporary RCT’s with long-term results.
Current guidelines in myocardial revascularization do not have sex-specific recommendations while the supporting evidence is not equal among women and men [28, 29]. The development, progression, clinical manifestations and response to treatment of ischemic heart disease is different between sex and it should be acknowledged that current recommendations may be biased regarding women.
Limitations
Several limitations should be accounted when interpreting the data form the present study:
First, even though we only included RCTs with DES, stent technology, conduit selection, medical therapy, interventional and surgical techniques have improved over the last decade and may not reflect current practice. Second, the evaluation of CAD has also evolved, incorporating intracoronary physiology and imaging as tools to determine the functional significant of coronary stenoses. The use of intracoronary imaging to guide PCI has demonstrated better outcomes compared to angiography guidance alone. In the aforementioned trials, the overall use of intracoronary imaging was low, even though the impact of imaging-guided PCI is more pronounced in patients with complex and multivessel CAD [30, 31]. Third, patient-level data was not available, thus further subgroup analyses and adjustment could not be performed. Fourth, stratified randomization by sex was not performed in the included RCTs, as a result, the balance of each group cannot be ensured. Finally, different definitions for clinical endpoints were used in each RCT, which may be a source of bias. Given the continuous evolution of both surgical and percutaneous revascularization techniques, furthers studies integrating contemporary practices are warranted.
Conclusion
In the present study-level metanalysis, CABG is associated with a lower risk of major adverse cardiovascular events than PCI at long term follow-up in women.
Data availability
The data underlying this article are available in the article and in its online supplementary material.
Abbreviations
- CABG:
-
Coronary artery bypass grafting
- CAD:
-
Coronary artery disease
- DES:
-
Drug eluting stent
- HR:
-
Hazard ratio
- LM:
-
Left main coronary artery
- MI:
-
Myocardial infarction
- OPCABG:
-
Off-pump coronary artery bypass grafting
- PCI:
-
Percutaneous coronary intervention
- RCT:
-
Randomized clinical trial
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Conception: DPC, PC, AT. Data acquisition: DPC, AT, LM. Data analysis and interpretation: DPC, MCA, COB, JCC. Manuscript preparation DPC, PC, LM. Manuscript revision AAA, FRL, LMC, MCA, COB. Manuscript approval: All authors.
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Pérez-Camargo, D., Campelos-Fernández, P., Travieso, A. et al. Long-term outcomes after percutaneous coronary intervention versus coronary artery bypass grafting in women, a meta-analysis. J Cardiothorac Surg 19, 666 (2024). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s13019-024-03167-y
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DOI: https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s13019-024-03167-y