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Figure 1.
Frequency of Events and Death Among Randomized Patients in the Dual Antiplatelet Therapy (DAPT) Study
Frequency of Events and Death Among Randomized Patients in the Dual Antiplatelet Therapy (DAPT) Study

Shown are cumulative rates of cardiovascular and bleeding events and subsequent risk of death. The number of each event represents the number of patients experiencing the event. Multiple types of events could be experienced by the same patient. For patients with more than one of the same type of event, only the earliest event contributed to the analysis. Other cardiovascular deaths were defined as any cardiovascular death not preceded by a myocardial infarction (MI), stent thrombosis (ST), or ischemic stroke. These events primarily consisted of sudden cardiac deaths (n = 40), heart failure–related deaths (n = 9), and fatal ventricular arrhythmias (n = 4). GUSTO indicates Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Arteries.

Figure 2.
Cumulative Incidence of Death After Ischemic and Bleeding Events
Cumulative Incidence of Death After Ischemic and Bleeding Events

Shown is the cumulative incidence of death based on Kaplan-Meier estimates. MI indicates myocardial infarction; ST, stent thrombosis.

Table 1.  
Baseline Characteristics at Index Coronary Stenting by Ischemic and Bleeding Event Statusa
Baseline Characteristics at Index Coronary Stenting by Ischemic and Bleeding Event Statusa
Table 2.  
Procedural and Lesion Characteristics at Index Coronary Stenting by Ischemic and Bleeding Event Status
Procedural and Lesion Characteristics at Index Coronary Stenting by Ischemic and Bleeding Event Status
Table 3.  
Risk of Mortality After Ischemic and Bleeding Events During the 21-Month Postrandomization Period
Risk of Mortality After Ischemic and Bleeding Events During the 21-Month Postrandomization Period
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Koskinas  KC, Räber  L, Zanchin  T,  et al.  Clinical impact of gastrointestinal bleeding in patients undergoing percutaneous coronary interventions.  Circ Cardiovasc Interv. 2015;8(5):e002053.PubMedGoogle ScholarCrossref
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Original Investigation
May 2017

Mortality Following Cardiovascular and Bleeding Events Occurring Beyond 1 Year After Coronary Stenting: A Secondary Analysis of the Dual Antiplatelet Therapy (DAPT) Study

Author Affiliations
  • 1Division of Cardiology, Massachusetts General Hospital, Boston
  • 2Harvard Medical School, Boston, Massachusetts
  • 3Center for Clinical Biometrics, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts
  • 4Smith Center for Outcomes Research in Cardiology, Beth Israel Deaconess Medical Center, Boston, Massachusetts
  • 5Baim Institute for Clinical Research, Boston, Massachusetts
  • 6Division of Cardiology, Beth Israel Deaconess Medical Center, Boston, Massachusetts
  • 7Christ Hospital Heart and Vascular Center, Cincinnati, Ohio
  • 8Lindner Center for Research and Education, Cincinnati, Ohio
  • 9Saint Luke’s Mid America Heart Institute, Kansas City, Missouri
  • 10University of Missouri–Kansas City School of Medicine, Kansas City, Missouri
  • 11Université Paris-Diderot, Institut National de la Santé et de la Récherche Médicale U-1148, Hôpital Bichat, Paris, France
  • 12Département Hospitalo-Universitaire Fibrosis, Inflammation, and Remodeling, Assistance Publique, Hôpitaux de Paris, Paris, France
  • 13National Heart and Lung Institute, Institute of Cardiovascular Medicine and Science, Royal Brompton Hospital, Imperial College, London, England
  • 14Division of Cardiology, Brigham and Women’s Hospital, Boston, Massachusetts
  • 15Boston University School of Public Health, Boston, Massachusetts
JAMA Cardiol. 2017;2(5):478-487. doi:10.1001/jamacardio.2017.0063
Key Points

Question  What is the prognosis of ischemic and bleeding events occurring beyond 1 year after coronary stenting?

Findings  Among 11 648 individuals who underwent randomization in the Dual Antiplatelet Therapy (DAPT) Study, ischemic events occurred in 4%, 11% died, and the cumulative incidence of death after an ischemic event was 0.5%. Bleeding events occurred in 2%, 18% died, and the cumulative incidence of death after a bleeding event was 0.3%.

Meaning  Among patients surviving 1 year after coronary stenting, ischemic events were more frequent than bleeding events, and both events were associated with high risk of mortality.

Abstract

Importance  Early cardiovascular and bleeding events after coronary stenting are associated with high risk of morbidity and mortality.

Objective  To assess the prognosis of cardiovascular and bleeding events occurring beyond 1 year after coronary stenting.

Design, Setting, and Participants  This secondary analysis is derived from data from the Dual Antiplatelet Therapy (DAPT) Study, a multicenter trial involving 220 US and international clinical sites from 11 countries. The study dates were August 2009 to May 2014. Individuals who underwent coronary stenting and completed 12 months of thienopyridine plus aspirin therapy without ischemic or bleeding events remained on an aspirin regimen and were randomized to continued thienopyridine therapy vs placebo for 18 additional months. Individuals were then followed up for 3 additional months while receiving aspirin therapy alone. The analysis began in August 2015.

Exposures  Ischemic events (myocardial infarction not related to stent thrombosis, stent thrombosis, and ischemic stroke) and bleeding events (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Arteries [GUSTO] classification moderate or severe bleeding).

Main Outcomes and Measures  Ischemic events (myocardial infarction not related to stent thrombosis, stent thrombosis, and ischemic stroke) and bleeding events (GUSTO classification moderate or severe bleeding). Death at 21 months after randomization (33 months after coronary stenting).

Results  In total, 25 682 individuals older than 18 years with an indication for coronary stenting were enrolled, and 11 648 (mean age, 61.3 years; 25.1% female) were randomized. After randomization, 478 individuals (4.1%) had 502 ischemic events (306 with myocardial infarction, 113 with stent thrombosis, and 83 with ischemic stroke), and 232 individuals (2.0%) had 235 bleeding events (155 with moderate and 80 with severe bleeding). Among individuals with ischemic events, 52 (10.9%) died. The annualized mortality rate after an ischemic event was 27.2 (95% CI, 20.3-35.7) per 100 person-years. The cumulative incidence of death after an ischemic event among the total randomized study population was 0.5% (0.3% with myocardial infarction, 0.1% with stent thrombosis, and 0.1% with ischemic stroke). Among individuals with bleeding events, 41 (17.7%) died. The annualized mortality rate after a bleeding event was 21.5 (95% CI, 15.4-29.1) per 100 person-years. The cumulative incidence of death after a bleeding event among the total randomized study population was 0.3% (0.1% with moderate and 0.2% with severe bleeding).

Conclusions and Relevance  In patients treated with dual antiplatelet therapy for at least 1 year after coronary stenting, ischemic events were more frequent than bleeding events, and both events were associated with high risk of mortality.

Trial Registration  clinicaltrials.gov Identifier: NCT00977938

Introduction

Advances in the management of patients with coronary artery disease undergoing percutaneous coronary intervention (PCI) have reduced cardiovascular events around the time of the procedure and within the first year after PCI.1,2 However, the risk of recurrent ischemia related to atherosclerosis progression and thrombosis in stented and nonstented coronary arteries persists indefinitely, despite treatment and risk factor modification.3,4 Antiplatelet medications, including aspirin and P2Y12 inhibitors, have become the standard of care as they decrease the risk of myocardial infarction (MI) and stent thrombosis (ST) within the first year after PCI.5,6 While recent randomized trials7-9 have shown the benefits of treatment beyond 1 year, these findings have been counterbalanced by risks of bleeding, which are of particular concern with long-term therapy.

Although the prognosis following early ischemic and bleeding events has been well described,4,10-12 data for events occurring beyond 1 year after PCI are limited.13 This scarcity may result from smaller size and duration of PCI trials,14-16 while larger observational studies often lack systematic follow-up or independent event adjudication.11,12

We sought to assess the cumulative incidence of death after ischemic and bleeding events occurring among patients in the Dual Antiplatelet Therapy (DAPT) Study beyond 1 year after coronary stenting.

Methods
Study Population

The DAPT Study (described previously8,17) was a randomized, double-blind trial comparing 12 vs 30 months of dual antiplatelet therapy in individuals undergoing PCI with a drug-eluting stent or a bare metal stent. The study involved 220 US and international clinical sites from 11 countries. After coronary stenting, 25 682 enrolled patients older than 18 years were prescribed thienopyridine plus aspirin therapy for 12 months. At 12 months, treatment-adherent patients who had no major adverse cardiovascular or cerebrovascular events, recurrent revascularization, or moderate or severe bleeding continued taking aspirin and were randomized to continued thienopyridine therapy vs placebo for 18 additional months. Randomized treatment was then discontinued, and patients were followed up for 3 additional months while receiving aspirin therapy alone. During the 21-month postrandomization period, all potential cardiovascular and bleeding events were adjudicated by a clinical events committee masked to treatment assignment. This study was conducted in accordance with the Declaration of Helsinki. The institutional review board at each institution approved the study, and all participating patients provided written informed consent. For the present secondary analysis, we examined all 11 648 randomized individuals.

Outcomes and Exposures

The primary outcome was death at 21 months after randomization (33 months after coronary stenting). The primary exposures were ischemic and bleeding events occurring 12 to 33 months after coronary stenting. Ischemic events included MI not related to ST, definite or probable ST as defined by the Academic Research Consortium,18 and ischemic stroke. While cardiovascular death as adjudicated in the DAPT Study included deaths that were associated with a concurrent ischemic event and deaths that could not be attributed to a noncardiovascular cause, only cardiovascular deaths related to MI, ST, or ischemic stroke were considered ischemic events in the present study. Bleeding events included moderate or severe bleeding as defined by the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Arteries (GUSTO) classification.19 As a secondary bleeding end point, bleeding events were classified based on the Bleeding Academic Research Consortium (BARC) 2, 3, or 5 definitions.20 Intracranial hemorrhage (ICH) was classified as a BARC 3c bleeding event or hemorrhagic stroke as defined previously.17

Statistical Analysis

Categorical variables were reported as counts and percentages, and continuous variables were reported as means (SDs). Between-group differences were assessed using Fisher exact test or χ2 test for categorical variables and t test or Wilcoxon rank sum test for continuous variables.

Among the randomized study population, we examined (1) the rate of ischemic and bleeding events after randomization, (2) the mortality risk among patients with each of these events, and (3) the cumulative incidence of mortality after each event. Patients experiencing multiple ischemic and bleeding events contributed data to both the ischemic events group and the bleeding events group; however, for patients with more than one of the same type of event, only the earliest event was included. We used Kaplan-Meier methods to estimate the cumulative incidence of death after an ischemic or bleeding event among those experiencing these events. Follow-up started at the time of the event and continued until death or study completion. Patients who died on the same day as the event were included in the analysis. To quantify the total population at risk of death after an event, we used Kaplan-Meier methods to estimate the cumulative incidence of death after the event among all randomized patients, with follow-up starting at the time of randomization.

Cox proportional hazards regression models with time-dependent covariates for exposure status were created for each exposure to evaluate the independent association of ischemic events or bleeding events with mortality. The time-updated model allowed for patients to contribute both unexposed (ie, before event) and exposed (ie, after event) person-time. A propensity score was calculated for each ischemic and bleeding event using all collected covariates, including the randomization arm, and each Cox proportional hazards regression model was stratified by propensity score quintile to control for confounding.

A two-sided P < .05 was considered statistically significant. Statistical analyses were performed using a software program (SAS, version 9.3; SAS Institute Inc).

Results
Incidence and Mortality Risk of Ischemic Events

Among 11 648 randomized patients (mean age, 61.3 years; 25.1% female), 478 (4.1%) had 502 ischemic events by 21 months. Of these 502 events, 306 (61.0%) were MI not related to ST, 113 (22.5%) were ST, and 83 (16.5%) were ischemic stroke. In addition, 88 patients had cardiovascular deaths that were not due to MI, ST, or ischemic stroke. Of these cardiovascular deaths, 63 (71.6%) had identifiable causes, including sudden cardiac death (n = 40), heart failure (n = 9), ventricular arrhythmia (n = 4), and other events (n = 10).

Patients with ischemic events had a higher prevalence of cardiovascular risk factors and prior cardiovascular disease (Table 1). They also more often initially presented with non–ST-segment elevation MI, had smaller minimum stent diameters, and received more paclitaxel-eluting stents (Table 2). Patients with ischemic events were more often randomized to placebo (283 patients [59.2%]) than to continued thienopyridine therapy (195 patients [40.8%]) (P < .01).

The median follow-up time after an ischemic event was 275.0 days (interquartile range [IQR], 90.0-456.0 days). Among the 478 patients with ischemic events, 52 (10.9%) died, and 41 deaths (78.8%) were attributable to cardiovascular causes. In comparison, of the 11 082 patients without a cardiovascular event, 82 (0.7%) died (P < .001). The cumulative incidence of death after an ischemic event among the total randomized study population was 0.5% (0.3% with MI, 0.1% with ST, and 0.1% with ischemic stroke) (Figure 1). The cumulative incidence of death for all cardiovascular events, including cardiovascular deaths that were not due to MI, ST, or ischemic stroke, was 1.3%. Death after ST or ischemic stroke primarily occurred within 1 month of presentation, whereas death after MI not related to ST occurred throughout the follow-up period (median survival time, 67.5 days; IQR, 4.0-281.0 days) (Figure 2). Nine ischemic events were immediately fatal, which occurred mainly among patients with ST (n = 8).

The unadjusted annualized mortality rate after an ischemic event was 27.2 (95% CI, 20.3-35.7) per 100 person-years. Controlling for demographic characteristics, comorbid conditions, and procedural factors, the occurrence of an ischemic event was associated with a 12.6-fold (95% CI, 9.0-17.6) increased hazard of mortality compared with the absence of such event. Risks of death associated with ST (hazard ratio [HR], 14.6; 95% CI, 8.2-25.9) and ischemic stroke (HR, 13.1; 95% CI, 7.2-23.8) were greater in magnitude compared with MI not related to ST (HR, 9.1; 95% CI, 6.1-13.6) (Table 3). Risks of death within the first 30 days after an ischemic event and more than 30 days after the event are summarized in eTable 1 in the Supplement.

Incidence and Mortality Risk of Bleeding Events

Among randomized patients, 232 (2.0%) had 235 bleeding events. Of all bleeding events, 155 (66.0%) were moderate, and 80 (34.0%) were severe. Intracranial hemorrhage occurred in 47 of 11 648 (0.4%), of whom 23 (0.4%) were randomized to continued thienopyridine therapy and 24 (0.4%) were randomized to placebo (P = .88).

Patients with bleeding events had lower body mass index, were older, and demonstrated a higher prevalence of cardiovascular risk factors and prior cardiovascular disease (Table 1). They also had higher rates of prior cancer, were less likely to have initially presented with non–ST-segment elevation MI at the time of PCI, and were more often randomized to continued thienopyridine therapy (140 [60.3%]) than to placebo (92 [39.7%]) (P < .01) (Table 2).

The median follow-up time after a bleeding event was 281.5 days (IQR, 98.5-445.0 days). Among 232 patients with a bleeding event, 41 deaths (17.7%) occurred, whereas among 11 416 patients without a bleeding event, 181 deaths (1.6%) occurred (P < .001). Of deaths after a bleeding event, 22 (53.7%) were attributable to cardiovascular causes (9 related to MI, ST, or ischemic stroke). The frequency of death after a moderate bleeding event was 9.7% and after a severe bleeding event was 32.5% (Figure 1). The cumulative incidence of death after a bleeding event was 0.3% (0.1% with moderate and 0.2% with severe bleeding). Results according to BARC definitions are summarized in eTable 2 in the Supplement. Of 47 patients with ICH, 14 (29.8%) died, with a cumulative incidence of death after an ICH of 0.1%. Death after moderate or severe bleeding occurred predominantly within 1 month of the event (Figure 2), with a median survival time of 16.0 days (IQR, 3.0-81.0 days). Three of the 235 bleeding events were immediately fatal.

The unadjusted annualized mortality rate after a moderate or severe bleeding event was 21.5 (95% CI, 15.4-29.1) per 100 person-years. Controlling for demographic characteristics, comorbid conditions, and procedural factors, a bleeding event was associated with an 18.1-fold (95% CI, 12.6-26.0) increased hazard for death compared with the absence of a bleeding event. There was a greater hazard of death after severe bleeding events (HR, 36.3; 95% CI, 23.3-56.6) compared with moderate (HR, 8.0; 95% CI, 4.7-13.7) bleeding events. Similar results were obtained when applying BARC bleeding definitions (Table 3). Risks of death within the first 30 days after a bleeding event and more than 30 days after the event are summarized in eTable 1 in the Supplement.

Incidence and Mortality Risk Among Patients With Multiple Ischemic or Bleeding Events

Among randomized patients, 101 (0.9%) had multiple events, whereas 558 (4.8%) had a single event. Of those with multiple events, 41 (0.4%) had more than 1 ischemic event, 9 (0.1%) had more than 1 bleeding event, and 51 (0.4%) experienced both ischemic and bleeding events. Among patients with both events, 24 (47.1%) had an ischemic event first, 14 (27.4%) had a bleeding event first, and 13 (25.5%) had both ischemic and bleeding events at the time of presentation. Patients with multiple events had a mortality rate of 23.8% compared with 9.3% among those with a single event (P < .01). Mortality among patients with more than 1 ischemic event was 12.2%, among those with more than 1 bleeding event was 22.2%, and among those with both ischemic and bleeding events was 33.3%.

Discussion

This post hoc analysis of randomized patients from the DAPT Study is the largest to date to examine the incidence and prognosis of very late ischemic and bleeding events after coronary stenting. From this analysis, we note the following observations. Among treatment-adherent patients who were event free for 1 year after coronary stenting, ischemic and bleeding events occurring between 12 and 33 months were associated with high risk of mortality. Ischemic events were more common than bleeding events, and death after either category of event accounted for an elevated mortality risk (27.2 deaths for ischemic events and 21.5 deaths for bleeding events per 100 person-years of follow-up, respectively). The risk of death after MI not related to ST was sustained throughout follow-up, whereas the mortality risk after bleeding events was greatest within 30 days of the event. A minority of randomized patients (0.9%) experienced more than 1 ischemic or bleeding event, and mortality was increased among patients with multiple events compared with a single event (23.8% vs 9.3%). The most common cause of death after an ischemic event or a bleeding event was cardiovascular. Overall, the cumulative incidence of death after an ischemic event was 0.5%, and the cumulative incidence of death after a bleeding event was 0.3%.

This study broadens our understanding of the clinical effect of ischemic and bleeding events by focusing on adjudicated events occurring beyond 1 year after coronary stenting. While a diverse group of patients was enrolled in the DAPT Study,21 including patients with or without MI at the time of the index procedure,22 randomization was limited to those patients who were treatment adherent and event free during the first year of follow-up. Despite this restriction, it is noteworthy that ischemic and bleeding events occurring beyond 1 year were associated with substantial mortality risk.

We observed a ratio of ischemic events to bleeding events of 2.1:1 and a ratio of MIs to bleeding events of 1.3:1. These findings are similar to the ratio of events that occurred among this study population in the first 12 months after enrollment in the DAPT Study.8 Other studies7,11 examining late events after MI or PCI have found comparable ratios of cardiovascular events to bleeding events, whereas analyses that included earlier events have demonstrated higher rates of bleeding.13 Prior analyses have also demonstrated that cardiovascular and bleeding events may differ depending on the timing of initiation of dual antiplatelet therapy.23

In our analysis, very late ischemic events and very late bleeding events were associated with high hazards of mortality, even after adjusting for measured patient factors. Significant mortality risks have been similarly observed for events occurring earlier after PCI.11-13,24,25 Moderate bleeding, the most frequent bleeding event in the present study, was associated with a risk of mortality similar to that of MI as seen in prior analyses11,25 and had mortality risks comparable to those events occurring around the time of the procedure10 and within the first year after PCI.12 Conversely, severe (including fatal) bleeding occurred less commonly herein but was associated with a grave risk of death. Patients infrequently experienced ICH (0.4%), and rates of events occurred equally between randomized groups.

Of all ischemic events, MI not related to ST occurred most commonly and was associated with a sustained risk of death throughout the study period. This result differed from bleeding events, which were primarily followed by death within 1 month. These temporal relationships are the inverse of those seen in a prior analysis that involved earlier events after acute coronary syndromes.26 We hypothesize that these disparate findings are largely because of differing types of events. Bleeding events in the present analysis were mainly nonprocedure-related spontaneous bleeds, which have been associated with higher short-term mortality compared with procedure-related bleeding.24 Spontaneous MIs unrelated to the stented artery constituted most ischemic events in our study rather than periprocedural or ST-related MIs. Unlike spontaneous MIs, ST was associated with immediate mortality risk. The sustained risk associated with spontaneous MI may occur via the development of risk factors for future mortality, such as left ventricular dysfunction and arrhythmias,11 risks expected to persist beyond the time frame of the present study.

Few patients had both ischemic and bleeding events, which highlights the need to adapt dual antiplatelet therapy duration according to individual patient characteristics. A prediction rule for patient benefit and harm has been developed from the present study population27 and may be useful in optimizing care for individual patients.28

Strengths and Limitations

This analysis has several strengths. It included patients with a range of comorbidities and procedural complexity. In addition, all events and outcomes were independently adjudicated. However, the results must also be interpreted in the context of the study design. Patients with a history of significant bleeding or treated with oral anticoagulation were excluded. While ischemic events were more common than bleeding events in the first year as reasons for exclusion from randomization, our analysis is only relevant to determining the prognosis after late events occurring among treatment-adherent patients who have survived event free in the first 12 months after coronary stenting. Fortunately, most patients undergoing PCI have excellent outcomes, without ischemic or bleeding events, recurrent procedures, or treatment nonadherence during the first year of follow-up.29 In addition, the incidences of ischemic and bleeding events depend on the definitions used. We found similar risks of mortality whether using GUSTO19 or BARC20 definitions for bleeding events in that more severe events were associated with higher mortality and less severe events were associated with less subsequent mortality. We excluded cardiovascular deaths not adjudicated to be preceded by MI, ST, or ischemic stroke and, in doing so, excluded 40 sudden cardiac deaths from classification as ischemic events in this study. While it is possible that many of these events were related to ischemia in the absence of documented MI or ST, their exclusion provides a conservative estimate of the proportion and number of ischemic events.

Conclusions

Among patients who survived to 12 months after coronary stenting event free, ischemic events were more frequent than bleeding events, yet both events were associated with high risk of mortality. The risk of death after very late MIs was sustained, whereas death after bleeding events primarily occurred within 30 days. These findings emphasize the need to adapt therapy to individual patient characteristics to avoid very late ischemic and bleeding events among patients after coronary stenting.

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Article Information

Accepted for Publication: December 20, 2016.

Corresponding Author: Laura Mauri, MD, MSc, Division of Cardiology, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115 (lmauri1@partners.org).

Published Online: March 15, 2017. doi:10.1001/jamacardio.2017.0063

Author Contributions: Drs Secemsky and Mauri had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Secemsky, Yeh, Kereiakes, Steg, D’Agostino, Mauri.

Acquisition, analysis, or interpretation of data: Secemsky, Kereiakes, Cutlip, Cohen, Steg, Cannon, Apruzzese, Massaro, Mauri.

Drafting of the manuscript: Secemsky, Kereiakes, Apruzzese, Mauri.

Critical revision of the manuscript for important intellectual content: Secemsky, Yeh, Kereiakes, Cutlip, Cohen, Steg, Cannon, D’Agostino, Massaro, Mauri.

Statistical analysis: Secemsky, Apruzzese, D’Agostino, Massaro, Mauri.

Obtained funding: Cohen, Mauri.

Administrative, technical, or material support: Kereiakes, Cannon, Mauri.

Study supervision: Kereiakes, Steg, Cannon, Mauri.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Yeh reported receiving research grant funding from Abiomed and Boston Scientific and reported serving on an advisory board for or as a consultant to Abbott and Boston Scientific. Dr Kereiakes reported receiving research funding from and serving as a consultant to Abbott Vascular, Boston Scientific, and Sanofi. Dr Cutlip reported receiving grant funding from Medtronic, Boston Scientific, and CeloNova. Dr Cohen reported receiving grant funding and personal fees from Medtronic and AstraZeneca and reported receiving grant funding from Abbott Vascular, Eli Lilly, and Daiichi Sankyo. Dr Steg reported receiving research grant funding from Merck, Sanofi, and Servier and reported receiving speaking or consulting fees from Amarin, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, CSL Behring, Daiichi Sankyo, GlaxoSmithKline, Janssen, Eli Lilly, Merck, Novartis, Pfizer, Regeneron, Sanofi, Servier, and The Medicines Company. Dr Cannon reported receiving grant funding and personal fees from Arisaph, Boehringer Ingelheim, Merck, Takeda, Amgen, and Bristol-Myers Squibb; reported receiving personal fees from AstraZeneca, GlaxoSmithKline, Lipimedix, Pfizer, Sanofi, Regeneron, Kowa, and Alnylam; and reported receiving grant funding from Janssen and Daiichi Sankyo (all outside of the submitted work). Dr Massaro reported receiving personal fees from the Harvard Clinical Research Institute. During the conduct of the study, Dr Mauri reported receiving grant funding from Abbott, Boston Scientific, Cordis, Medtronic, Eli Lilly/Daiichi Sankyo, and Sanofi/Bristol-Myers Squibb. Outside of the submitted work, Dr Mauri reported receiving consulting fees from Amgen and St Jude Medical; reported serving on the steering committee for Biotronik and Corvia; reported being a lecturer for AstraZeneca, Sanofi, and Daiichi Sankyo; and reported being an investigator for Boehringer Ingelheim and ReCor. No other disclosures were reported.

Funding/Support: This analysis was sponsored by the Harvard Clinical Research Institute; by grant K23 HL 118138 from the National Heart, Lung, and Blood Institute (Dr Yeh); and by grant 1R01FD003870-01 from the US Department of Health and Human Services. Eight stent and pharmaceutical manufacturers who contributed to the funding of the Dual Antiplatelet Therapy (DAPT) Study included Abbott Vascular (Xience everolimus-eluting stent), Boston Scientific (TAXUS paclitaxel-eluting and PROMUS everolimus-eluting stents), Cordis (Cypher sirolimus-eluting stent), Medtronic (Endeavor zotarolimus-eluting stent), Bristol-Myers Squibb, Sanofi, Eli Lilly, and Daiichi Sankyo.

Role of the Funder/Sponsor: The stent manufacturers who contributed to the funding of the DAPT Study (Abbott Vascular, Boston Scientific, Cordis, and Medtronic) were participating members in the design of the trial, the conduct of the study, and the collection of the data. Specifically, the DAPT Study included patients from each of 4 industry-designed and industry-conducted postmarket studies. The funders had no role in the management, analysis, and interpretation of the data. The Harvard Clinical Research Institute was responsible for the scientific conduct of the DAPT Study and independent analysis of the data. For this substudy, the funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Group Information: The DAPT Study Investigators include the following. United States: Aaron Kaplan (Dartmouth Hitchcock Medical Center), Abdel Ahmed (Altru Health System), Abdel-Hamid Ahmed (Altru Health System), Abdulhay Albirini (Genesis HealthCare System), Abel Moreyra (University of Medicine and Dentistry of New Jersey), Abram Rabinowitz (South Texas Cardiovascular), Adhir Shroff (Jesse Brown VA Medical Center), Alan Moak (Penn Presbyterian Medical Center), Alice Jacobs (Boston Medical Center), Ameer Kabour (Mercy St Vincent’s Medical Center), Amit Gupta (North Mississippi Medical Center), Anand Irimpen (Tulane Medical Center), Andrew Rosenthal (Bayfront Medical Center), Andrew Taussig (Florida Hospital), Angelo Ferraro (Sacred Heart Medical Center), Anil Chhabra (Cardiovascular Research), Anthony Pucillo, (Westchester Medical Center), Anthony Spaedy (Missouri Heart Center), Anthony White (NEA Baptist Clinic), Antonis Pratsos (Bryn Mawr Hospital), Arif Shakir (Midwest Regional Medical Center), Arnold Ghitis (Diagnostic Cardiology Associates), Arvind Agarwal (Valley Hospital), Ash Jain (California Cardiovascular Consultants Medical Associates), Atul Chawla (Iowa Heart Center), Aylmer Tang (Chambersburg Hospital), Barbara Barker (Arizona Regional Medical Center), Barry Bertolet (Cardiology Associates Research), Barry Uretsky (Arkansas VA Medical Center), Bernard Erickson (Central Minnesota Heart Center at St Cloud Hospital), Bhola Rama (Frederick C. Smith Clinic), Brent McLaurin (AnMed Health), Brian Dearing (Thomas Hospital), Brian Negus (Chattanooga Heart Institute), Brian Price (King's Daughters Medical Center), Brigitta Brott (University of Alabama at Birmingham), Brijesh Bhambi (Bakersfield Heart), Bruce Bowers (Cardiopulmonary Research Science and Technology Institute), Bruce Watt (North Central Heart Institute), Bryan Donohue (University of Pittsburgh Medical Center Shadyside Hospital), C. David Hassel (Jacksonville Heart Center), Charles Croft (Holmes Regional Medical Center), Charles Lambert (Pepin Heart Hospital), Charles O'Shaughnessy (North Ohio Heart Center), Charles Shoultz (Providence Health Center), Chin Kim (Florida Hospital), Christopher Caputo (North Florida Regional Medical Center), Christopher Nielson (Medical University of South Carolina Hospital), Christopher Scott (University of Tennessee Medical Center), Christopher Wolfe (Providence St Peter Hospital), Clark McKenzie (St John's Mercy Cardio Research), Claude Brachfeld (Promise Regional Medical Center), Craig Thieling (Hattiesburg Clinic PA), Daniel Fisher (UMASS Memorial Medical Center), Daniel Lee (Bay Regional Medical Center), Daniel Simon (University Hospitals Case Medical Center), David Churchill (Washington Regional Medical Center), David Dobies (Genesys Regional Medical Center), David Eich (Sentara Norfolk General Hospital), David Goldberg (New England Heart Institute), David Griffin (Good Samaritan Hospital), David Henderson (Cardiology Research Associates), David Kandzari (Piedmont Heart Institute), David Lee (Bakersfield Memorial Hospital), David Lewis (South Central Wisconsin Heart), David Mego (Little Rock Cardiology Clinic), David Paniagua (Michael E. DeBakey VA Medical Center), David Rizik (Scottsdale Health Care), David Roberts (Sacramento Heart and Vascular Institute), David Safley (St Luke's Hospital), Dawn Abbott (Rhode Island Hospital), Dean Kereiakes (Christ Hospital), Dinesh Shaw (Christus St Frances Cabrini Hospital), Dogan Temizer (Good Samaritan Hospital), Donald Canaday (Inland Cardiology Associates), Donald Cutlip (Beth Israel Deaconess Medical Center), Donald Myears (St John's Medical Research Institute), Donald Westerhausen (Midwest Cardiovascular Research & Education Foundation), Douglas Ebersole (Watson Clinic Center for Research), Douglas Netz (Nebraska Heart Institute), Drew Baldwin (Tulane University Medical School), Dustin Letts (Carolina Heart Specialists), Edward Harlamert (Clarian North Medical Center), Edward Kosinski (Connecticut Clinical Research), Edward Portnay (Cardiology Associates of Fairfield County), Ehtisham Mahmud (UCSD Medical Center), Elie Korban (Jackson-Madison County General Hospital), Eric Hockstad (Kansas City Heart Foundation), Ernesto Rivera (Amarillo Heart Group), Fayaz Shawl (Washington Adventist Hospital), Fayez Shamoon (St Michael's Medical Center), Francis Kiernan (Hartford Hospital), G. Ramon Aycock (Cardiology Consultants), Gary Schaer (Rush University Medical Center), Geoffrey Kunz (New Mexico Heart Institute PA), George Kichura (St John's Mercy Cardiovascular Research), George Myers (Redmond Regional Medical Center), George Pilcher (St Vincent's Healthcare), George Tadros (North Memorial Medical Center), Georges I. Kaddissi (Our Lady of Lourdes Medical Center), Govind Ramadurai (Heartland Cardiovascular Center), Greg Eaton (Medcentral Health System), Gregory Elsner (Care Group), Gregory Mishkel (St John's Hospital), Gregory Simonian (Hackensack University Medical Center), Guy Piegari (Berks Cardiologists), Henry Chen (Heart Center PC), Henry Liberman (Emory University Hospital Midtown), Herbert Aronow (Michigan Heart & Vascular Institute), Hoshedar P. Tamboli (Bay Area Cardiology Associates), Imran Dotani (McFarland Clinic PC), Jairo Marin (St Joseph's Hospital), James F. Fleischhauer (Cardiology Consultants), James Hopkins (Christiana Hospital), James Leggett (Over Lake Hospital Medical Center), James Mills (Duke Raleigh Hospital), James Phillips (Palmetto Richland Memorial Hospital), James Revenaugh (J. L. Sorenson Heart & Lung), James Tift Mann (Wake Heart Research Institute), James Wilson (Texas Heart Institute), Jan Pattanayak (Asheville Cardiology Associates), Janah Aji (Cooper University Hospital), Janet Strain (Valley Hospital), Jay Patel (Hamilton Cardiology Associates), Jeffrey Carr (East Texas Medical Center), Jeffrey Moses (Columbia Presbyterian Hospital), Jen-Cheng Chen (Straub Clinic and Hospital), Jerome Williams (Mid Carolina Cardiology), Jerry Greenberg (Aurora Denver Cardiology Associates), Joel Cohn (Ingham Regional Medical Center), John Douglas (Emory University Hospital), John Gordon (Sharp Memorial Hospital), John Griffin (Alegent Health Research Center), John Griffin (Cardiovascular Associates), John Hawkins (St John's Medical Research Institute), John Katopodis (Tallahassee Research Institute), John Lopez (Loyola University Medical Center), John Marshall (Northeast Georgia Medical Center), John Wang (Union Memorial Hospital), Jonathan Waltman (St Joseph Hospital), Jorge Saucedo (University of Oklahoma Health Science Center), Joseph Galichia (Galichia Heart Hospital), Miles McClure (Mid-Michigan Heart and Vascular Center), Joseph Kozina (Mercy General Hospital), Joseph Stella (Heart Care Research Foundation), Joseph Tuma (Black Hills Cardiovascular Research), Joshua Kieval (Palm Beach Heart Research Institute), Kartik Giri (Cardiovascular Associates of Delaware Valley), Kasi Ramanathan (Northwest Ohio Cardiology Consultants), Kathleen Allen (Presbyterian Heart Group), Keith Atassi (Northwest Indiana Cardiovascular Physicians PC), Kenneth Baran (St Paul Heart Clinic), Kenneth Khaw (Our Lady of Lourdes Medical Center), Kevin Clayton (Munson Medical Center), Kevin Croce (Brigham and Women’s Hospital), Kimberly Skelding (Geisinger Medical Center), Kiritkumar Patel (St Joseph Mercy Oakland), Kirk Garratt (Lenox Hill Hospital), Kishore Harjai (Donald Guthrie Foundation), Kollagunta Chandrasekhar (Winter Haven Hospital), Kumar Kalapatapu (Westchester Medical Center), Lang Lin (Morton Plant Hospital), Larry Dean (University of Washington), Lawrence Barr (Midwest Heart Foundation), Lee MacDonald (Swedish Medical Center), Louis Cannon (Cardiac and Vascular Research Center of North Michigan), Lowell Satler (Washington Hospital Center), Luis Gruberg (Stony Brook University Medical Center), Luis Tami (Memorial Regional Hospital), Mahesh Bikkina (St Joseph's Regional Medical Center), Mahesh Shah (Shah Associates), Mahmoud Atieh (Pinehurst Medical Clinic), Manish Chauhan (Cardiovascular Specialists of Texas), Marc Litt (Jacksonville Heart Center), Marc Unterman (St Joseph’s Hospital Atlanta), Marcel Lechin (College Station Medical Center), Marcel Zughaib (Providence Hospital), Mark Fisch (Clarian North Medical Center), Mark Grabarczyk (Greenville Memorial Hospital), Mark Greenberg (Moses Hospital), Mark Lurie (Torrance Memorial Medical Center), Mark Rothenberg (Palm Beach Heart Research Institute), Martha Stewart (Cardiology Consultants), Matthew Purvis (Medical Center of the Rockies), Matthew Hook (Wake Heart Research Institute), Massoud Leesar (University of Cincinnati), Maurice Buchbinder (Foundation for Cardiovascular Medicine), Maurice Weiss (Jersey Shore University Medical Center), Mayra Guerrero (Henry Ford Hospital), Mazen Abu-Fadel (University of Oklahoma Health Science Center), Michael Ball (Care Group), Michael Chang (Mercy General Hospital), Michael Cunningham (University Hospitals Case Medical Center), Michael Del Core (Cardiac Center of Creighton University Medical Center), Michael Jones (Central Baptist Hospital), Michael Kelberman (St Elizabeth Medical Center), Michael Lim (St Louis University), Michael Ragosta (University of Virginia), Michael Rinaldi (Carolinas Medical Center), Michael Rosenberg (Advocate Good Shepherd Hospital), Michael Savage (Thomas Jefferson University Hospital), Michael Tamberella (Carolina Heart Specialists), Miles McClure (Mid-Michigan Heart and Vascular Center), Mirle Kellett (Maine Medical Center), Mladen Vidovich (University of Illinois Hospital), Mohamed Effat (University of Cincinnati), Mohd Ayoub Mirza (Carilion Medical Center), Muhammad Khan (North Dallas Research Associates), Nabil Dib (Mercy Gilbert Medical Center), Nathan Laufer (Heart and Vascular Center of Arizona), Neal Kleiman (Methodist Hospital), Niam Farhat (North Ohio Heart Center), Nima Amjadi (Texas Heart and Vascular), Norberto Schechtmann (MIMA Century Research Associates), Nydia Bladuell (WellStar Kennestone Hospital), Ofsman Quintana (Doctors Hospital at Renaissance), Osvaldo Gigliotti (Seton Heart Institute), Patricia Best (Mayo Clinic), Patrick Flaherty (Little Rock Cardiology Clinic), Patrick Hall (Providence Hospital), Paul Gordon (Miriam Hospital), Paul Gurbel (Sinai Center for Thrombosis Research), Paul Ho (Kaiser Foundation Hospitals), Paul Luetmer (Aspirus Heart and Vascular Institute), Paul Mahoney (Sentara Norfolk General Hospital), Paul Mullen (Memorial Hospital at Gulfport), Paul Teirstein (Scripps Green Hospital), Paul Tolerico (York Hospital), Periakaruppan Ramanathan (Northwest Ohio Cardiology Consultants), Peter Kerwin (Midwest Heart Foundation), Peter Ver Lee (Northeast Cardiology Associates), Phillip Kraft (Beaumont Hospital Troy), R. Michael Wyman (Torrance Memorial Medical Center), Rafael Gonzalez (Scott & White Health Care Round Rock), Raghunandan Kamineni (Salem Hospital), Rajesh Dave (Spirit Physician Services), Rajesh Sharma (St Anthony Central Hospital), Rakesh Prashad (Ocala Research Institute), Ramon Aycock (Cardiology Consultants), Ramon Quesada (Baptist Hospital), Randy Goodroe (Grand Strand Regional Medical Center), Raymond Magorien (Ohio State University Medical Center), Renzi Randolph (Winchester Medical Center), Richard Bach (Washington University School of Medicine in St Louis), Richard Kettelkamp (Cardiologists LC), Richard Paulus (King's Daughters Medical Center), Richard Waters (St Joseph's Medical Center), Richard Zelman (Cape Cod Research Institute), Ricky Ganim (Kingwood Medical Center), Riyaz Bashir (Temple University), Robert Applegate (Wake Forest University), Robert Feldman (MediQuest Munroe Regional Medical Center), Robert Frankel (Maimonides Medical Center), Robert Hibbard (Bryan LGH Medical Center), Robert Jobe (Wake Heart Research Institute), Robert Jumper (Cardiology Associates of Fairfield County), Robert Maholic (Hamot Medical Center), Robert Siegel (Arizona Regional Medical Center), Robert Smith (Tyler Cardiovascular Consultants), Robert Stoler (Baylor Heart & Vascular Hospital), Robert Watson (Abington Medical Specialist), Robert Wheatley (Centennial Heart), Roger Gammon (Austin Heart Research), Roger Hill (St Bernard's Medical Center), Rohit Sundrani (Cardiovascular Consultants), Ronald Caputo (St Joseph Hospital Cardiology Associates), Ronald Jenkins (Kootenai Medical Center), Ronald Stella (Heart Care Research Foundation), Samir Germanwala (Longview Regional Medical Center), Samir Hadeed (Conemaugh Valley Memorial Hospital), Samuel Ledford (Chattanooga Heart Institute), Sandeep Dube (Indiana Heart Hospital), Saurabh Gupta (Oregon Health and Science University), Scott Davis (Baptist Health Medical Center), Scott Martin (Covenant Medical Center), Sergio Waxman (Lahey Clinic Medical Center), Simon Dixon (William Beaumont Hospital), Srihari Naidu (Winthrop University Hospital), Srinivasa Potluri (Heart Hospital Baylor Plano), Stephen Cook (Novant Clinical Research Institute), Stephen Cook (Sacred Heart General Hospital), Stephen Crowley (Aurora Denver Cardiology Associates), Stephen Kirkland (Forsyth Medical Center), Stephen McIntyre (Martin Memorial Health Systems), Stephen Thew (Heart Clinics Northwest PS), Steve Lin (St Joseph Hospital), Steve Marshalko (Bridgeport Hospital), Steven Guidera (Doylestown Hospital), Steven Hearne (Delmarva Heart Research Foundation), Steven Karas (MIMA Century Research Associates), Steven Manoukian (Sarah Cannon Research Institute), Steven Rowe (Cox Medical Centers), Steven Yakubov (Ohio Health Research Institute), Stewart Pollock (Rockingham Memorial Hospital), Subhash Banerjee (VA North Texas Health Care Center), Suhail Allaqaband (Sinai Medical Center), Sung Choi (California Pacific Medical Center Research), Suresh Mulukutla (University of Pittsburgh Medical Center), Stylianos Papadakos (Lenox Hill Hospital), Tanvir Bajwa (Sinai Medical Center), Tayo Addo (University of Texas Southwestern Medical Center), Theodore Schreiber (DMC Harper University Hospital), Thomas Haldis (MeritCare Hospital Pharmacy), Thomas Mathew (Slocum Dickson Medical Group), Thomas McGarry (Oklahoma Foundation for Cardiovascular Research), Thomas Nygaard (Cardiovascular Group), Thomas Pow (Great Lakes Heart and Vascular Institute), Timothy Larkin (Midwest Heart Specialists), Todd Caulfield (Providence St Vincent Medical Center), Tomasz Stys (Sanford Research), Tommy Lee (Stanford Medical Center), Vafa Mansouri (St Thomas Hospital), Vankeepuram Srinivas (Weiler Hospital), Vishal Gupta (Borgess Research Institute), Walt Marquardt (Mercy General Hospital), William Ballard (Piedmont Heart Institute), William Bachinsky (Pinnacle Health), William Colyer (University of Toledo Medical Center), William Dillon (Louisville Cardiology Medical), William Felten (Mid-Michigan Medical Center), William French (LA Biomed Research Institute), William Kuehl (Asheville Cardiology Associates), William Nicholas (Freeman West Hospital), William Nicholson (York Hospital), William Phillips (Central Maine Medical Center), Yazan Khatib (1st Coast Cardiovascular Institute), Youssef Al-Saghir (1st Coast Cardiovascular Institute), Zafir Hawa (North Kansas City Hospital), Zaki Masud (Kaleida Health), Zubair Jafar (Hudson Valley Heart Center). Australia: David Muller (St Vincent’s Hospital Sydney), Ian Meredith (Monash Heart Southern Health), Jamie Rankin (Royal Perth Hospital), Matthew Worthley (Royal Adelaide Hospital), Nigel Jepson (Prince of Wales Eastern Heart), Peter Thompson (Sir Charles Gardiner Hospital), Randall Hendriks (Fremantle Hospital), Robert Whitbourn (St Vincent’s Hospital Melbourne), Steven Duffy (Alfred Hospital). Czech Republic: Josef Stasek (FN Hradec Kralove), Kamil Novobilsky (Mestská nemocnice Ostrava), Robert Naplava (Centrum pro choroby srdce), Zdenek Coufal (KNTB a.s.). France: Bruno Vaquette (Hôpital Saint Louis), Erwan Bressollette (Nouvelle Clinique Nantaise), Emmanuel Teiger (CHU Henri Mondor), P. Gabriel Steg (Hôpital Bichat), Pierre Coste (Groupe Hospitalier Sud), Riadh Rihani (Hôpital Saint Philibert). Germany: Harold Darius (Vivantes-Klinikum Neukoelln), Martin W. Bergmann (Asklepios Klinik St Georg), Peter Radke (UK-SH), Philipp Sebastian (Elbe-Kliniken Stade GmbH), Ruth Strasser (Universitaetsklinikum Dresden), Stefan Hoffmann (Vivantes Klin. Friedrichshain), Steffen Behrens (VivantesHumboldt Klinikum), Sven Moebius-Winkler (Herzzentrum Leipzig GmbH), Wolfgang Rutsch (Helios Klinikum Emil von Behring). Hungary: Geza Lupkovics (Zala Megyei Korhaz), Ivan Horvath (Pecsi Tudomanyegyetem Klinikai Kozpont), Sandor Kancz (Gottsegen Gyorgy Orszagos Kardiologiai Intezet), Tamas Forster (Szegedi Tudomanyegyetem SZ-GY), Zsolt Koszegi (Josa Andras Oktato Korhaz Nonprofit Kft). New Zealand: Gerry Devlin (Waikato Hospital), Hamish Hart (North Shore Hospital), John Elliott (Christchurch Hospital), John Ormiston (Mercy Angiography), Malcolm Abernathy (Wakefield Hospital), Nick Fisher (Nelson Hospital), Patrick Kay (Middlemore Hospital), Scott Harding (Wellington Hospital), Warwick Jaffe (Ascot Integrated Hospital). Poland: Andrzej Hoffmann (Wielospecj. Szpital Miejski im), Cezary Sosnowski (Instytut Kardiologii Kardynala Wyszynskiego), Jaroslaw Trebacz (NZOZ Centr. Med. Beluga-Med), Pawel Buszman (Polsko-Amerykanskie Kliniki Serca), Slawomir Dobrzycki (Uniwer. Szpital Klin. Bialystok), Zdzislawa Kornacewicz-Jach (SPSK nr 2 Pomor. AM Szczecin). Romania: Adrian Corneliu Iancu (Institutul Inimii Niculae Stancioiu Cluj-Napoca), Carmen Doina Ginghina (Inst. Urgenta Boli Cardiovasculare), Costel Matei (Institutul de Urgentapentru Boli Cardiovas), Dan Dobreanu (Institutul de Boli Cardiovasculare si), Filip Romi Bolohan (Centrul Clinic de Urgenta de Boli Cardi), Maria Dorobantu (Spitalul Clinic de Urgenta Bucuresti). United Kingdom: Adam Jacques (St Peter's Hospital), Ajay Jain (London Chest Hospital), Ameet Bakhai (Barnet Hospital), Anthony Gershlick (Glenfield Hospital), Dawn Adamson (Coventry and Warwickshire UH), David Newby (Royal Infirmary of Edinburgh), Dirk Felmeden (Torbay Hospital), Ian Purcell (Freeman Hospital), John Edmond (Weston General Hospital), John Irving (Ninewells Hospital & MS), Mark de Belder (James Cook Hospital), Michael Pitt (Heartland Hospital), Paul Kelly (Basildon University Hospital), Peter O’Kane (Bournemouth Hospital), Piers Clifford (Wycombe General Hospital), Venkatesan Suresh (Derriford Hospital).

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