Author + information
- Received February 15, 2016
- Revision received April 14, 2016
- Accepted May 28, 2016
- Published online September 12, 2016.
- Giuseppe Gargiulo, MDa,b,
- Sara Ariotti, MDa,c,
- Andrea Santucci, MDa,
- Raffaele Piccolo, MDa,
- Andrea Baldo, MDa,
- Anna Franzone, MDa,
- Giulia Magnani, MDa,
- Marcello Marino, MDa,
- Giovanni Esposito, MD, PhDb,
- Stephan Windecker, MDa and
- Marco Valgimigli, MD, PhDa,c,∗ ()
- aDepartment of Cardiology, Bern University Hospital, University of Bern, Bern, Switzerland
- bDepartment of Advanced Biomedical Sciences, Federico II University of Naples, Naples, Italy
- cThoraxcenter, Erasmus Medical Center, Rotterdam, the Netherlands
- ↵∗Reprint requests and correspondence:
Dr. Marco Valgimigli, Bern University Hospital, Department of Cardiology, CH-3010 Bern, Switzerland.
Objectives The aim of this study was to assess the impact of sex on 2-year outcomes after percutaneous coronary intervention (PCI) in patients randomly allocated to 24-month versus 6-month dual-antiplatelet therapy (DAPT).
Background The optimal duration of DAPT after PCI is highly debated. Whether sex per se should drive decision making on DAPT duration remains unclear.
Methods The primary efficacy endpoint of PRODIGY (Prolonging Dual Antiplatelet Treatment After Grading Stent-Induced Intimal Hyperplasia Study) was the composite of death, myocardial infarction, or cerebrovascular accident at 24-month follow-up. The key safety endpoint was type 2, 3, or 5 bleeding according to the Bleeding Academic Research Consortium criteria.
Results Women (n = 459 [23.3%]) were older and more likely to have hypertension, lower creatinine clearance, and acute coronary syndrome but had a lower severity of coronary artery disease. After adjustment, prolonged DAPT, compared with 6-month treatment, did not reduce the primary endpoint in both men (adjusted hazard ratio: 1.080; 95% confidence interval: 0.766 to 1.522; p = 0.661) and women (adjusted hazard ratio: 1.013; 95% confidence interval: 0.588 to 1.748; p = 0.962) (interaction p = 0.785). No sex disparity was identified across multiple secondary ischemic endpoints, including overall or cardiovascular mortality, myocardial infarction, and stent thrombosis. There was also no clear sex-related effect on clinically relevant bleeding, including Bleeding Academic Research Consortium type 3 or 5, TIMI (Thrombolysis in Myocardial Infarction), and GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) scales.
Conclusions The present findings suggest that men and women undergoing PCI have similar adjusted 2-year ischemic and bleeding outcomes, despite being characterized by different clinical presentation. Sex failed to emerge as a treatment modifier with respect to DAPT duration, suggesting that decision making on DAPT duration in female patients should weigh ischemic versus bleeding risks.
Percutaneous coronary intervention (PCI) is the most frequently performed revascularization procedure for coronary artery disease (CAD) in both male and female patients. Sex influences age, cardiovascular risk factors, clinical presentation, and angiographic features, including extension of disease and vessel size. However, the impact of sex on clinical outcomes after PCI remains debated. Although female sex has been identified as an independent predictor of adverse outcomes after PCI in some studies (1–4), it had no or minimal impact on outcomes in others (5–10).
Dual-antiplatelet therapy (DAPT) is the cornerstone of antithrombotic treatment in patients undergoing PCI, although its optimal duration remains controversial (11–17). Whether sex should be taken into account when selecting the DAPT regimen is still unknown. Female sex per se was recently proposed as a single covariate to identify patients in whom short DAPT duration would be advisable (18). Yet the evidence appraising the role of sex in the choice of the optimal DAPT duration is limited.
The aim of this subanalysis of the PRODIGY (Prolonging Dual Antiplatelet Treatment After Grading Stent-Induced Intimal Hyperplasia Study) randomized trial was to compare 2-year clinical outcomes in male and female patients and to assess the impact of sex in the setting of an all-comer population undergoing PCI and with a randomly allocated short (6-month) or prolonged (24-month) DAPT regimen, consisting of clopidogrel and aspirin.
The present study is a pre-specified analysis of PRODIGY (NCT00611286). The design and main findings have been previously reported (11,19). Briefly, all-comer PCI patients (n = 2,013) were randomized to 4 types of stent (bare-metal, zotarolimus-eluting, paclitaxel-eluting, or everolimus-eluting stents) with varying anti-intimal hyperplasia potency and belonging to both the first and second generations of drug-eluting stent at 3 Italian sites. At 30 days, patients (n = 1,970) were randomly allocated to either 6 or 24 months of DAPT. Selection criteria were broad, reflecting routine clinical practice. Randomization to 6- or 24-month DAPT was stratified by center, ongoing ST-segment elevation myocardial infarction (MI), the presence of diabetes mellitus, and need for intervening on at least 1 in-stent restenotic lesion. The study was conducted in accordance with the principles of the Declaration of Helsinki. The ethics committees of the 3 participating centers independently approved the protocol, and all participants gave written informed consent.
All patients received aspirin (80 to 160 mg orally indefinitely) and clopidogrel (75 mg/day) according to the randomization scheme as follows: for either 6 months in the short-DAPT arm or 24 months in the prolonged-DAPT arm, irrespective of the previously implanted stent type or indication for PCI.
The randomized patients returned for study visits at 30 days and then every 6 months up to 2 years. During follow-up visits, patients were examined and assessed for adverse events and asked about antiplatelet therapy compliance, and 12-lead electrocardiographic recordings were obtained.
The primary efficacy endpoint of the PRODIGY trial was the composite of death, MI, or cerebrovascular accident (CVA), while the key safety endpoint included Bleeding Academic Research Consortium (BARC) type 2, 3, or 5 bleeding. The net effect on the combined ischemic and bleeding complications was obtained by 2 net adverse clinical event endpoints that were generated by combining the primary efficacy endpoint of death, MI, or CVA with either the primary safety endpoint of BARC type 2, 3, or 5 bleeding or BARC type 3 or 5 events. Other endpoints included each component of the primary efficacy endpoint, cardiovascular death, stent thrombosis (ST) defined on the basis of the Academic Research Consortium criteria, and BARC type 3 or 5 bleeding. Other safety endpoints included bleeding events adjudicated according to the TIMI (Thrombolysis in Myocardial Infarction) and GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) scales. All study endpoint definitions were previously reported.
All endpoints were confirmed on the basis of documentation collected at each hospital and were centrally adjudicated by the clinical events committee, whose members were unaware of the patients’ treatment group assignments. The time frame of interest for the primary endpoint was from 30 days (i.e., after the primary endpoint randomization) to 24 months.
Categorical variables are expressed as frequency (percentage), whereas continuous variables are expressed as median (interquartile range). Continuous variables were compared between randomized groups using the Wilcoxon rank sum test, whereas for binary variables, the chi-square test was used. Multiple imputation (the iterative Markov-chain Monte Carlo algorithm [fully conditional specification or chained equations imputation] implemented in SPSS [IBM, Armonk, New York] was used to create 5 datasets with imputation of missing values on the basis of their potential predictors) was used for missing values of creatinine levels at baseline (n = 21) and ejection fraction (n = 136).
Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated for male versus female (values >1 indicated increased hazard in the male group) and 24-month versus 6-month DAPT (values >1 indicated increased hazard with 24-month DAPT) with a proportional hazards model. Cox regression was used for multivariate analysis. Clinical and angiographic characteristics that were imbalanced at a nominal 5% significance level between the 2 groups were identified and included the final adjusted model; these included age, hypertension, smoking, baseline creatinine level, prior MI, clinical presentation, multivessel intervention and total American College of Cardiology/American Heart Association score.
Interaction testing was performed to determine whether the effect of DAPT duration was consistent irrespective of sex on the primary and secondary endpoints of the study. This was performed with likelihood ratio tests of the null hypothesis that the interaction coefficient was zero. A 2-sided p value <0.05 was considered to indicate statistical significance. All analyses were based on the intention-to-treat principle and were performed with SPSS version 23.0.
Among 1,970 patients randomized to 6- versus 24-month DAPT at 30 days from PCI, 1,511 (76.7%) were men, and 459 (23.3%) were women. Baseline characteristics are summarized in Table 1, while Table 2 describes baseline characteristics of the 2 randomized arms of DAPT regimens (24 vs. 6 months) in male and female patients. Compared with men, women were older, had a higher prevalence of hypertension, had lower creatinine clearance, presented more frequently with acute coronary syndrome, were less likely smokers, and had a lower prevalence or extension of CAD with less need for multivessel intervention (Table 1). Overall, baseline characteristics were well balanced in patients randomized to 24-month or 6-month DAPT in both male and female subgroups (Table 2).
At 2 years, crude events and unadjusted HRs showed that women had higher rates of death, MI, and the composite of ischemic events or ischemic and bleeding events (Table 3). The primary efficacy endpoint (death, MI, or CVA) occurred in 58 women (12.6%) and 140 men (9.3%) (HR: 0.716; 95% CI: 0.527 to 0.972; p = 0.032) (Table 3). After multivariate adjustment for baseline imbalances, no significant difference was noted between men and women in the primary efficacy endpoint (adjusted HR: 0.912; 95% CI: 0.658 to 1.262; p = 0.577) (Table 3). Consistent results were observed across all other ischemic or bleeding endpoints between sexes (Table 3). In an age-matched sensitivity analysis, major adverse cardiovascular events and net adverse clinical events were not affected by sex (all interaction p values > 0.05) (Figure 1) or by stent type (Online Table 1).
In both randomized DAPT groups, the primary endpoint was similar in female and male patients after adjustment (24-month DAPT: adjusted HR: 0.923; 95% CI: 0.586 to 1.453; p = 0.729; 6-month DAPT: adjusted HR: 0.828; 95% CI: 0.515 to 1.331; p = 0.436; p for interaction = 0.785) (Figure 2, Online Table 2). Accordingly, event rates did not differ with respect to DAPT duration in male (adjusted HR: 1.080; 95% CI: 0.766 to 1.522; p = 0.661 (Figure 3, Table 4) and female (adjusted HR: 1.013; 95% CI: 0.588 to 1.748; p = 0.962) (Figure 3, Table 4) patients.
The key safety endpoint of BARC type 2, 3, or 5 bleeding occurred in 30 women (6.5%) and 77 men (5.1%). Men treated with longer DAPT experienced higher rates of bleeding events (adjusted HR: 3.506; 95% CI: 2.013 to 6.104; p < 0.0001) (Table 4), whereas women did not (adjusted HR: 0.827; 95% CI: 0.382 to 1.794; p = 0.631) (Table 4), with positive interaction testing (p for interaction = 0.002). This difference appeared to be driven mainly by BARC 2 bleeding events (men: adjusted. HR: 6.651; 95% CI: 2.592 to 17.065; p < 0.0001; women: adjusted HR: 0.764; 95% CI: 0.240 to 2.431; p = 0.649; p for interaction = 0.003) (Table 4). Accordingly, when bleeding was assessed in terms of BARC type 3 or 5, prolonged versus short DAPT did not differ with respect to clinical outcomes in men (adjusted HR: 1.969; 95% CI: 0.965 to 4.019; p = 0.063) (Figure 3, Table 4) or women (adjusted HR: 0.971; 95% CI: 0.331 to 2.851; p = 0.957) (Figure 3, Table 4) separately appraised, with negative interaction testing (p for interaction = 0.237). Assessing the impact of sex across TIMI and GUSTO bleeding scales provided consistent results (Table 4).
According to major adverse cardiovascular event and BARC results, the rates of net adverse clinical events did not show a significant interaction between DAPT duration and sex (BARC type 2, 3, or 5: p for interaction = 0.091; BARC type 3 or 5: p for interaction = 0.753) (Figure 4, Table 4). No relevant interaction was found between age or stent type and sex in DAPT arms (Online Tables 3 and 4).
In the present analysis from the PRODIGY trial, we assessed the impact of sex on clinical outcomes in all-comer patients undergoing PCI and receiving different durations of DAPT. The main findings can be summarized as follows. 1) Twenty-four-month DAPT duration was not associated with ischemic benefits in male and female patients, consistent with the overall PRODIGY results. 2) Male but not female patients had a significantly increased risk for bleeding events with prolonged DAPT according to the key safety endpoint of BARC type 2, 3 or 5 bleeding. However, the rate of bleeding did not differ between male and female patients when treated with 6- or 24-month DAPT duration after exclusion of BARC type 2 events.
This is the first dedicated sex-based analysis of a randomized trial comparing a short with a prolonged DAPT regimen. Our analysis suggests that the overall results of the PRODIGY trial can be extended with confidence to both sexes.
PRODIGY was designed to detect a 40% reduction in the composite endpoint of death, MI, or CVA in the prolonged-DAPT arm but failed to support such a benefit in largely unselected patients (25.6% with stable CAD and 74.4% with acute coronary syndrome) undergoing PCI with a balanced mixture of stent types, including both first- and second-generation drug-eluting stents. Overall, these results are consistent with those of other trials exploring the impact of DAPT prolongation (12,14–17), which either showed no benefit of prolonged DAPT or benefit on recurrent MI and very late ST but no significant impact on death or cardiovascular death. The PEGASUS–TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin–Thrombolysis In Myocardial Infarction 54) study was the only trial to observe a significant reduction of stroke in patients treated with 60 mg but not in those taking a 90-mg twice-daily ticagrelor regimen compared with aspirin only (20). All studies consistently observed increases in bleeding events, depending on study power and bleeding endpoint definitions.
When taken together, currently available studies suggest that decision making regarding DAPT duration toward either shorter or longer than the conventional 12-month time frame should involve a “patient-by-patient” approach, aiming at balancing ischemic versus bleeding risks. With that respect, whether sex per se should be taken into account in tailoring patient’s therapy is still unclear.
Although many studies support sex differences in cardiovascular outcomes (1–4), an equally large body of evidence suggests that women treated for CAD are older and have a higher prevalence of comorbidities, and as a result significant differences in outcomes between male and female patients are no longer demonstrated following adjustment for these baseline differences (5–10). Consistent with the latter studies, the results of the current analysis show that in an all-comer population of patients treated with stent implantation, men and women feature similar ischemic as well as clinically relevant bleeding risks when baseline confounders are accounted for in the multivariate model.
Age is a major confounder when analyzing outcomes stratified for sex (21,22). Hence, in our analysis, we also compared women and men on the basis of age subcategories, which confirmed the results of the adjusted analysis.
Some evidence suggests that women undergoing PCI are at increased risk for bleeding. Hence, it could be speculated that DAPT prolongation should be avoided in women, who are on average older (18). However, the increased bleeding risk in women compared with men appears to be restricted largely to the periprocedural period, with sex failing to predict long-term bleeding risk (7,10,23,24). This is consistent with our study findings, which suggest that clinically relevant bleeding occurring from 30 days onward after intervention is not affected by sex.
The DAPT trial showed that DAPT prolongation significantly reduced both MI and definite or probable ST in men but not in women (sex interaction 0.03 and 0.04 for MI and ST, respectively). However, the sex interaction for bleeding (GUSTO moderate or severe) or major adverse cardiovascular and cerebrovascular events was not significant (25). Sex subgroup analysis in the ARCTIC Interruption trial did not show differences between sexes in the primary (composite of all-cause death, MI, stroke or transient ischemic attack, urgent coronary revascularization, and ST) and secondary (composite of ST or urgent revascularization) endpoints (26). Similarly, the DES-LATE trial confirmed consistency between men and women for the primary endpoint (composite of cardiac death, MI, or stroke 24 months after randomization) (27), as did the PEGASUS–TIMI 54 trial (20).
Hence, the results of our dedicated analysis are consistent with the results of subgroup analysis of other major DAPT studies and support the concept that sex is not a treatment modifier with respect to DAPT duration.
Although this was a pre-specified analysis of the PRODIGY trial, sex was not used for stratification at the time of randomization. The female study population was smaller compared with the male group, as observed in most trials investigating patients with CAD. Yet this analysis suffered from both type I and type II errors. This study should be regarded as exploratory and hypothesis generating.
Women undergoing PCI differed from their male counterparts in that they were typically older, more often had hypertension and reduced renal function, but less frequently were smokers and had a lower degree of CAD complexity. However, after adjustment, 2-year ischemic and clinically relevant bleeding outcomes did not differ. DAPT prolongation did not mitigate the high risk at baseline; indeed, compared with short-term DAPT, a prolonged DAPT regimen did not benefit both male and female patients, suggesting that sex should not be a primary covariate to be considered in decision making on DAPT duration after coronary stenting.
WHAT IS KNOWN? Contrasting evidence exists on the optimal DAPT duration and on the impact of sex on long-term clinical outcomes after PCI.
WHAT IS NEW? Women and men have similar rates of long-term ischemic and bleeding events. Prolonged DAPT did not reduce ischemic events in both sexes.
WHAT IS NEXT? Sex should not be a primary covariate to be considered in decision making on DAPT duration after coronary stenting.
For supplemental tables, please see the online version of this article.
Dr. Gargiulo is supported by research grants from the European Association of Percutaneous Cardiovascular Intervention and from the CardioPath PhD program (Federico II University). Dr. Piccolo is supported by a research grant from Veronesi Foundation-Cardiovascular Research. Dr. Franzone is supported by a research grant from the Italian Society of Cardiology. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- Bleeding Academic Research Consortium
- coronary artery disease
- confidence interval
- cerebrovascular accident
- dual-antiplatelet therapy
- hazard ratio
- myocardial infarction
- percutaneous coronary intervention
- stent thrombosis
- Received February 15, 2016.
- Revision received April 14, 2016.
- Accepted May 28, 2016.
- 2016 American College of Cardiology Foundation
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