Author + information
- Received December 7, 2016
- Revision received February 6, 2017
- Accepted February 12, 2017
- Published online May 1, 2017.
- Eric A. Secemsky, MD, MSca,b,c,d,
- Robert W. Yeh, MD, MScc,d,
- Dean J. Kereiakes, MDe,
- Donald E. Cutlip, MDc,
- P. Gabriel Steg, MDf,g,
- Joseph M. Massaro, PhDc,
- Patricia K. Apruzzese, MAc,
- Laura Mauri, MD, MScb,c,∗ (, )
- Dual Antiplatelet Therapy Study Investigators
- aDivision of Cardiology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts
- bDivision of Cardiology and Center for Clinical Biometrics, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts
- cBaim Institute for Clinical Research, Boston, Massachusetts
- dSmith Center for Outcomes Research in Cardiology, Beth Israel Deaconess Medical Center, Boston, Massachusetts
- eThe Christ Hospital Heart and Vascular Center and The Lindner Center for Research and Education, Cincinnati, Ohio
- fUniversité Paris-Diderot, INSERM U-1148, Hôpital Bichat, Département Hospitalo-Universitaire Fibrosis, Inflammation, and Remodelling, Assistance Publique–Hôpitaux de Paris, Paris, France
- gNational Heart and Lung Institute, Institute of Cardiovascular Medicine and Science, Royal Brompton Hospital, Imperial College, London, United Kingdom
- ↵∗Address for correspondence:
Dr. Laura Mauri, Division of Cardiology, Harvard Medical School, Brigham and Women’s Hospital, 75 Francis Street, Boston, Massachusetts 02115.
Objectives This study sought to determine whether patients with peripheral arterial disease (PAD) experience different reductions in ischemic event and increases in bleeding events with extended duration dual antiplatelet therapy versus those without PAD.
Background Patients with PAD have increased ischemic and bleeding risks after coronary stenting.
Methods The DAPT (Dual Antiplatelet Therapy) study randomized 11,648 patients free from ischemic and bleeding events 12 months after coronary stenting to continued thienopyridine plus aspirin therapy for an additional 18 months versus aspirin therapy alone. The effects of continued thienopyridine on myocardial infarction (MI) or stent thrombosis, major adverse cardiovascular and cerebrovascular events (death, MI, or stroke) and bleeding (GUSTO [Global Utilization of t-PA and Streptokinase for Occluded Coronary Arteries] moderate or severe) were assessed among those with versus without PAD.
Results Among 11,648 randomized patients, 649 (5.57%) had PAD. Between 12 and 30 months, randomized patients with PAD had higher rates of MI/stent thrombosis (6.03% vs. 2.92%; p < 0.001), major adverse cardiovascular and cerebrovascular events (11.65% vs. 4.62%; p < 0.001), and bleeding (4.86% vs. 1.74%; p < 0.001). Continued thienopyridine versus placebo was associated with consistent treatment effects for MI/stent thrombosis (with PAD, HR: 0.63; 95% CI: 0.32 to 1.22; without PAD, HR: 0.53; 95% CI: 0.42, 0.66; interaction p = 0.631), major adverse cardiovascular and cerebrovascular events (with PAD, HR: 1.06; 95% CI: 0.67 to 1.67; without PAD, HR: 0.70; 95% CI: 0.59 to 0.84; interaction p = 0.103), and bleeding (with PAD, HR, 1.82; 95% CI: 0.87 to 3.83; without PAD, HR: 1.66; 95% CI: 1.23 to 2.24; interaction p = 0.811).
Conclusions Among patients undergoing coronary stenting, those with PAD have more ischemic and bleeding events versus those without PAD. Extended duration dual antiplatelet therapy is associated with consistent ischemic benefit and bleeding harm among patients with and without PAD.
Peripheral arterial disease (PAD), the systemic manifestation of atherosclerotic disease, affects more than 8.5 million Americans and 200 million people worldwide (1). Of those with PAD, approximately 2 of 3 have concomitant coronary artery disease, and up to 1 of 3 with coronary artery disease have PAD (2). Furthermore, patients with PAD have a 60% increased risk for myocardial infarction (MI) and a 2- to 6-fold increased risk of cardiovascular death (3). Those who require percutaneous coronary intervention (PCI) are at heightened risk of post-procedure events, with a 6-fold increased odds of stent thrombosis (4), 20% to 60% increased risk of bleeding (5,6), and a 2-fold greater risk of death (2).
Antiplatelet therapy with either aspirin or a P2Y12 inhibitor reduces the risk of MI, stroke, and vascular death among those with PAD (7,8). Yet, the ischemic benefits of prolonged dual antiplatelet therapy for patients with PAD may be counterbalanced by the increased risk of bleeding. For instance, among 3,096 patients with PAD from the CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance) trial (9), those randomized to aspirin and clopidogrel for 28 months versus aspirin alone experienced a 40% reduction in MI but a 2-fold increased hazard of bleeding. As such, current guidelines assign a Class IIb recommendation for use of combination aspirin and clopidogrel therapy to reduce the risk of ischemic events only among those with symptomatic PAD at high cardiovascular risk and low bleeding risk (10).
Similarly, among the general population of patients undergoing PCI, dual antiplatelet therapy for >12 months reduces the risk of MI and stent thrombosis, but increases the risk of moderate or severe bleeding (11). For patients with PAD, who are at greater risk of both ischemic and bleeding events, the optimal duration of dual antiplatelet therapy after PCI is uncertain. Findings from two recent analyses involving patients with PAD and either a prior history of MI (12) or PCI (13) conflict as to whether there is a greater benefit with longer term dual antiplatelet therapy in patients with PAD than in the rest of the PCI population.
The Dual Antiplatelet Therapy (DAPT) study, which enrolled 25,682 patients after coronary stenting and randomized 11,648 patients who were compliant with thienopyridine therapy and who remained free from ischemic and bleeding events after 12 months of dual antiplatelet therapy treatment, compared the effects of 30 months versus 12 months of dual antiplatelet therapy. Treatment with 30 months of dual antiplatelet therapy was associated with significant reductions in MI and stent thrombosis but increases in moderate or severe bleeding (14,15). Using these data, we sought to determine whether patients with PAD in the DAPT Study experienced different reductions in ischemic event and increases in bleeding events with extended duration dual antiplatelet therapy relative to those without PAD.
The DAPT study (NCT00977938), described previously (14,15), was a randomized, double-blind, placebo-controlled trial comparing 30 months versus 12 months of thienopyridine therapy (clopidogrel or prasugrel) in addition to aspirin therapy in subjects undergoing coronary stenting with either drug-eluting or bare metal stents. Adults who were candidates for dual antiplatelet therapy were enrolled and treated with open-label aspirin plus thienopyridine therapy for 12 months after coronary stenting (enrollment period, 0 to 12 months). At 12 months, treatment-compliant patients who had not had a major adverse cardiovascular or cerebrovascular event (MACCE), repeat revascularization, or moderate or severe bleeding event continued taking aspirin and were randomly assigned to either continued thienopyridine or placebo for an additional 18 months (randomization period, 12 to 30 months). At 30 months after the index coronary stenting procedure, randomized treatment was discontinued and all patients were continued on aspirin and followed for an additional 3 months. Over the 21-month post-randomization period, all potential cardiovascular and bleeding events were adjudicated. For this secondary non-prespecified analysis, PAD status was identified at the time of the index coronary stenting procedure by the investigational site and was based on documented medical history. The institutional review board at each participating institution approved the study, and all patients provided written informed consent.
Effectiveness endpoints included the incidence of Academic Research Consortium MI or definite/probable stent thrombosis (16), MACCE (composite of all-cause death, MI, or stroke), and death. Bleeding-related deaths were defined as any death that was possibly, probably, or definitely related to a prior bleeding event. Fatal bleeding was adjudicated as a Bleeding Academic Research Consortium Type 5 bleed. MI/stent thrombosis was used as a combined endpoint to distinguish the impact on ischemic events. The individual components of this endpoint were also reported to be consistent with the primary outcomes from the DAPT Study. The safety endpoint included the incidence of moderate or severe bleeding as assessed according to the GUSTO [Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Arteries] classification (17).
Categorical variables were reported as counts and percentages, and continuous variables as mean ± SD. Between-group differences were assessed using Fisher exact or chi-square tests for categorical variables and Student t tests or Wilcoxon rank sum tests for continuous variables.
Rates of endpoints by PAD status were determined for enrolled patients 12 months post-stenting. Fisher exact tests were used for comparisons between groups. Cumulative incidences of endpoints occurring between 12 and 30 months after stenting among patients in the randomized group, stratified by PAD status, were calculated using Kaplan-Meier methods. Log-rank tests were used for comparisons between groups.
Multivariable models were used to determine the independent association between PAD status and adverse events in both the enrollment (logistic regression) and randomization (Cox proportional hazards regression) periods. All models were adjusted for potential confounders selected a priori based on clinical judgment and published data review, and included age (years), female sex, non-white race, Hispanic or Latino, weight (kg), body mass index (kg/m2), enrollment region, current cigarette smoker or within past year, hypertension, diabetes, congestive heart failure, stroke/transient ischemic attack, previous PCI, previous MI, renal insufficiency/failure, treatment with clopidogrel versus prasugrel at randomization, presentation with acute coronary syndrome, drug-eluting stent type at index coronary stenting, in-stent restenosis lesion, modified American College of Cardiology/American Heart Association lesion class, total stent length (mm), minimum stent diameter <3 mm, number of stents, number of treated vessels, extreme tortuosity, heavy calcification, vessel type (native coronary versus bypass graft), and number of treated lesions.
To measure the consistency of randomized treatment effect between patients with and without PAD, patients were stratified by PAD status and by randomization arm. Log-rank tests were used for within-group comparisons. Cox proportional hazards regression models were created and included the terms PAD status, randomization arm, and randomized treatment-by-PAD status as the interaction term. Potential confounders, as listed, were then included in these models to measure adjusted multiplicative interaction terms. In addition, tests for interaction on the additive scale were performed. An interaction p value of <0.05 was prespecified as indication of a potential differential (i.e., lack of consistent) effect of treatment across subgroups.
For all Cox proportional hazards regression models, an assessment of whether the proportional hazards assumption was met was performed using log–log-survival plots and the Kolmogorov-type supremum test using 1,000 simulations. The assumption was met for the endpoints of bleeding and death. While the proportional hazards assumption p value was significant at <0.05 for the outcomes of MI/stent thrombosis and MACCE in the randomized population, inspection of the log-log survival curves indicated that they were relatively parallel to mitigate concern. The lack of proportionality seemed to occur due to hazards not being proportional at the early stage of the study, but then becoming approximately parallel after the early stage.
In an exploratory analysis to determine whether the DAPT Score (18) identified PAD patients at high risk of ischemia and low risk of bleeding, patients with PAD were stratified by a score of <2 versus 2 or greater. A DAPT Score of <2 predicts patients who have a greater likelihood of experiencing more bleeding events than ischemic events after coronary stenting. A DAPT Score of 2 or greater predicts patients who have a greater likelihood of experiencing more ischemic events than bleeding events after coronary stenting (18). For the enrollment period, rates of events at 12 months among those in each group were compared using Fisher exact tests. For the randomization period, cumulative incidences of events at 30 months among those in each group were compared using log-rank tests. Due to the limited number of events that occurred during the randomization period, patients were not stratified by randomized treatment arm.
For all analyses, a 2-sided p value of <0.05 was considered significant. All statistical analyses were conducted at Baim Institute for Clinical Research with the use of SAS software version 9.2 (SAS Institute Inc., Cary, North Carolina).
Of 25,682 enrolled patients, 1,745 (6.79%) had a diagnosis of PAD at the time of index coronary stenting and 23,937 (93.21%) did not have a diagnosis of PAD (Figure 1). Of all enrolled patients, 5,844 (22.76%) were not eligible for randomization (most commonly because of ischemic events), and 8,190 (31.89%) were eligible but not randomized (most commonly because of withdrawal of consent). At 12 months after enrollment, 11,648 patients (45.35% of all enrolled) underwent randomization: 649 with PAD (5.57% of the randomized population) and 10,999 without PAD (94.43% of the randomized population). Clinical follow-up was available at 30 months for 94.30% of those with PAD and 95.16% of those without PAD. Rates of compliance with randomized treatment at 30 months was 89.48% for those with PAD and 92.63% for those without PAD.
Baseline characteristics among randomized patients with and without PAD at the time of index stenting are shown in Table 1. Of all randomized patients, those with PAD were on average older, more often women, had more cardiovascular risk factors and prior cardiovascular disease, and had a higher frequency of cancer. In addition, PAD patients presented less often for coronary stenting with a myocardial infarction, but more often had left main and bypass graft disease, in-stent restenosis, and lesions with heavy calcification. Patients with PAD were more likely to have received clopidogrel than prasugrel after stenting (clopidogrel: 72.57% with PAD vs. 68.11% without PAD; p = 0.017). In patients with PAD, clinical, procedural and lesion characteristics were overall similar between randomized treatment arms (Table 1).
Impact of PAD on clinical events during the enrollment period
Among enrolled patients at 12 months after stenting, those with versus without PAD had more than 2-fold the rate of MI/stent thrombosis events (6.19% vs. 2.67%; p < 0.001), MACCE (9.05% vs. 4.11%; p < 0.001), and death (2.98% vs. 1.19%; p < 0.001) (Table 2). In addition, patients with PAD had more bleeding events during the enrollment period (5.73% vs. 2.51% without PAD; p < 0.001).
Controlling for demographics, comorbid conditions and procedural characteristics, the presence of PAD was independently associated with an increased risk of cardiovascular (MI/stent thrombosis: adjusted odds ratio [OR]: 1.68; 95% CI: 1.30 to 2.16; p < 0.001; MACCE: adjusted OR: 1.45; 95% CI: 1.17 to 1.78; p < 0.001) and bleeding (adjusted OR: 1.67; 95% CI: 1.30 to 2.15; p < 0.001) events at 12 months after stenting. There was no association between PAD and death at 12 months (adjusted OR: 1.28; 95% CI: 0.89 to 1.84; p = 0.182).
Impact of PAD on clinical events during the randomization period
From 12 to 30 months after stenting, randomized patients with PAD, compared with those without PAD, had more than twice the frequency of MI/stent thrombosis (6.03% vs. 2.92%; p < 0.001), MACCE (11.65% vs. 4.62%; p < 0.001), and death (5.91% vs. 1.44%; p < 0.001) (Table 2). Additionally, randomized patients with PAD had more bleeding events (4.86% vs. 1.74%; p < 0.001). Bleeding-related deaths among those with PAD were infrequent (n = 3; 0.50% of those randomized with PAD) and did not differ relative to those without PAD (n = 23; 0.22% of those randomized without PAD; p = 0.169). Fatal bleeds (Bleeding Academic Research Consortium Type 5) occurred in 1 randomized patient with PAD versus 11 randomized patients without PAD.
After controlling for potential confounders, the baseline presence of PAD was independently associated with an increased hazard of MACCE at 30 months after stenting (adjusted hazard ratio [HR]: 1.68; 95% CI: 1.27 to 2.23; p < 0.001), but not MI/stent thrombosis (adjusted HR: 1.41; 95% CI: 0.96 to 2.08; p = 0.081). In addition, a history of PAD was independently related to increased bleeding (adjusted HR: 1.91; 95% CI: 1.24 to 2.96; p = 0.004) and death (adjusted HR: 2.47; 95% CI: 1.62 to 3.76; p < 0.001).
Effect of randomized treatment by PAD status
From 12 to 30 months after stenting, patients with a history of PAD randomized to continued thienopyridine versus placebo had consistent risk reductions of MI/stent thrombosis relative to those without PAD (with PAD, HR: 0.63; 95% CI: 0.32 to 1.22; without PAD, HR: 0.53; 95% CI: 0.42 to 0.66; unadjusted interaction p = 0.631; adjusted interaction p = 0.369) (Figures 2 and 3, Table 3). Continued thienopyridine versus placebo also had a similar effect in patients with versus without PAD on MACCE (with PAD, HR: 1.06; 95% CI: 0.67 to 1.67; without PAD, HR: 0.70; 95% CI: 0.59 to 0.84; unadjusted interaction p = 0.103; adjusted interaction p = 0.106) and death (with PAD, HR: 1.73; 95% CI: 0.89 to 3.35; without PAD, HR: 1.17; 95% CI: 0.85 to 1.60; unadjusted interaction p = 0.297, adjusted interaction p = 0.435) (Figures 2 and 3, Table 3).
For the safety endpoint of bleeding, risk increases associated with continued thienopyridine compared with placebo were similar between patients with and without PAD (with PAD, HR: 1.82; 95% CI: 0.87 to 3.83; without PAD, HR: 1.66; 95% CI: 1.23 to 2.24; interaction p = 0.811; adjusted interaction p = 0.943) (Figures 2 and 3, Table 3). There was also consistency in the risks of the individual components of the bleeding endpoint (GUSTO moderate and GUSTO severe bleeding) associated with continued thienopyridine versus placebo (Table 3).
PAD and the DAPT score
Among 1,745 enrolled patients with PAD, 753 (43.15%) had a DAPT score of <2 and 992 (56.85%) had a score of 2 or greater. Compared with patients with a DAPT score of 2 or greater, those with a score of <2 had lower frequencies of stent thrombosis/MI (4.52% vs. 7.46% with score ≥2; p = 0.012) and MACCE (7.17% vs. 10.48% with score ≥2; p = 0.018) at 12 months after stenting (Figure 4). Rates of bleeding at 12 months did not differ between DAPT score groups (5.58% for score <2 vs. 5.85% for score ≥2; p = 0.836). Among the 649 randomized patients with PAD, 282 (43.45%) had a DAPT score of <2 and 367 (56.55%) had a score of 2 or greater. A DAPT score of <2 identified randomized patients with PAD who had a lower risk of MACCE between 12 and 30 months after stenting (8.52% vs. 14.05% with score ≥2; p = 0.030), but did not differentiate those at risk for MI/stent thrombosis (5.31% vs. 6.59% with score ≥2; p = 0.457). Absolute rates of bleeding were higher among those with a DAPT score of <2 (6.66%) relative to a score of 2 or greater (3.47%), but this comparison did not reach statistical significance (p = 0.064).
The present analysis of the DAPT Study evaluates the impact of PAD on adverse events after coronary stenting and the treatment effect of 30 months versus 12 months of dual antiplatelet therapy among patients with and without PAD. The principal findings are that treatment with dual antiplatelet therapy for 30 months among those with PAD who were treatment-compliant and free from events 12 months after coronary stenting corresponded with consistent risk reductions in ischemia and consistent risk increases in bleeding relative to those without PAD. A history of PAD was associated with greater rates of ischemia and bleeding after coronary stenting. These risks were present both at 12 months among all enrolled and at 30 months among those who survived the first year event free.
Risk of ischemic and bleeding events among patients with PAD
Patients with PAD are at increased risk for cardiovascular events, and these risks persist despite treatment with more potent antiplatelet therapies (8). Similarly, adverse events are common among patients with PAD who undergo coronary stenting (2), a relationship that was reaffirmed by the current analysis. We observed a more than doubling of the rates of MI/stent thrombosis, MACCE, and bleeding for those with versus without PAD, risks that remained associated after adjustment for potential confounders. This finding is particularly notable for those who underwent randomization, as these patients were at lower risk having already survived 12 months event free. The relationship between PAD and adverse events is likely multifactorial and involves elements such as an increased inflammatory state (19), disease comprising more than 1 vascular bed (20), and concomitant risk factors for recurrent ischemia and bleeding, such as advanced age and renal dysfunction (5,21). Although PAD has been associated with high on-treatment platelet reactivity and possibly lower antiplatelet responsiveness (22), this would not explain the higher baseline risk of ischemic events we observed, because patients with PAD were responsive to continued antiplatelet therapy in terms of reduced ischemic events, similar to subjects without PAD.
Treatment effects of extended dual antiplatelet therapy in patients with PAD
Our study found that among randomized patients with PAD who were treatment compliant and survived for 12 months after stenting without events, there was consistency in the reduction in ischemic events and increase in bleeding events with extended duration dual antiplatelet therapy relative to patients without PAD. These associations were present despite patients with PAD having a higher prevalence of risk factors for both post-procedure ischemia and bleeding, including advanced age, female sex, diabetes, previous PCI, and history of heart failure (4,5). Compared with earlier studies of patients with PAD, such as the subanalysis of 3,096 patients with PAD in the CHARISMA trial (9), we similarly observed reductions in MI and increases in bleeding associated with extended dual antiplatelet therapy. Importantly, because the overall rates of these events were greater among those with PAD relative to those without, our results emphasize that high ischemic and bleeding risks remain present for patients with PAD despite greater attention to risk modification and medical therapies.
In addition, our analysis contributes to the few studies that have examined the effectiveness and safety of extended dual antiplatelet therapy among stented patients with PAD. In a recent analysis of 246 patients with PAD enrolled in PRODIGY (Prolonging Dual Antiplatelet Treatment After Grading Stent-Induced Intimal Hyperplasia Study) (13), treatment with 24 months versus 6 months or less of dual antiplatelet therapy after coronary stenting was associated with a 50% risk reduction in the composite of death, stroke, or MI that was not observed in patients without PAD. An additional risk of bleeding was not detected. However, the lack of bleeding risk with prolonged dual antiplatelet therapy contradicts findings from prior studies (9,11,20,23), and may be related to limited statistical power. In a larger substudy from the PEGASUS-TIMI 54 trial (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) (12), 1,143 patients with known PAD and a history of MI were randomized to ticagrelor plus aspirin versus aspirin alone. At 3 years, patients with versus without PAD experienced consistent reductions in cardiovascular events and increases in bleeding events with prolonged ticagrelor, findings analogous to our results.
Therefore, because continued dual antiplatelet therapy for patients with PAD is associated with similar reductions in ischemia and increases in bleeding as compared with the general population of stented patients, these risks and benefits need to be weighed when deciding who should continue treatment at 1 year after stenting. This is similar to the decision making required for all stented patients (24) as well as for those with symptomatic PAD who may benefit from dual antiplatelet therapy over monotherapy (10).
Within the PAD cohort, we did not observe a difference in rates of MACCE between randomization arms, although the rate of death, a component of MACCE, was numerically greater among those continued on thienopyridine. Higher rates of death with continued thienopyridine were also observed in the full cohort of patients in the DAPT Study (14,15). This relationship was not primarily mediated by bleeding events, but by an imbalance in cancer related mortality (25). Nonetheless, review of multiple prior randomized trials of thienopyridine therapy has not shown an increase in cancer or mortality (26).
Use of the DAPT score among patients with PAD
Because there was a heterogeneous treatment effect with extended dual antiplatelet therapy among patients with PAD, it may be challenging to discern those most likely to derive overall clinical benefit. In an exploratory analysis involving the DAPT Score, a novel decision tool developed for this purpose (18), a score of 2 or greater identified stented patients with PAD who experienced more post-procedure ischemic events but no increase in bleeding events. These patients may, therefore, obtain greater benefit than harm with extended dual antiplatelet therapy. However, these findings require further validation.
The results of this study must be interpreted in the context of its design. PAD status was determined solely on the basis of clinical history, and under-reporting or over-reporting cannot be excluded. Details regarding the method of diagnosis, location of disease, and presence of symptoms were not available for this analysis. Similarly, we did not have access to data on limb-related outcomes for those with lower extremity disease. Finally, comparisons between randomized treatment arms and tests of interaction in this subset were post hoc, have limited statistical power, and are subject to risks of multiple testing.
Patients with PAD undergoing coronary stenting are at heightened risk of both ischemic and bleeding events post-procedure. Among randomized patients with PAD free of events and compliant with dual antiplatelet therapy 12 months after stenting, treatment with 30 months versus 12 months of dual antiplatelet therapy resulted in consistent reductions in ischemic events and increases in bleeding events relative to patients without PAD. As such, extending dual antiplatelet therapy more than 1 year after coronary stenting may be of benefit to select patients with PAD who are at high risk of recurrent ischemia and low risk of bleeding, similar to the general population of stented patients.
WHAT IS KNOWN? Patients with PAD have elevated risks of ischemic and bleeding events. Extending dual antiplatelet therapy with aspirin and a P2Y12 inhibitor for more than 12 months after stenting reduces ischemic events while increasing bleeding events in the general population, but treatment effects between those with and without PAD are unclear.
WHAT IS NEW? This study demonstrated that patients with PAD are at high risk of both ischemic and bleeding events after coronary stenting. Continued dual antiplatelet therapy to 30 months after coronary stenting provides consistent reductions in ischemic events and consistent increases in bleeding events among patients with PAD relative to those without PAD.
WHAT IS NEXT? Further investigation is needed to identify the subset of stented patients with PAD who have the greatest ischemic risk and lowest bleeding risk in order to optimize duration of dual antiplatelet therapy.
Sponsored by the Baim Institute for Clinical Research (formerly known as Harvard Clinical Research Institute); and supported by the National Heart, Lung and Blood Institute (K23 HL 118138), Abbott, Boston Scientific Corporation, Cordis Corporation, Medtronic, Inc., Bristol-Myers Squibb Company/Sanofi Pharmaceuticals Partnership, Eli Lilly and Company, and Daiichi Sankyo Company Limited, and the U.S. Department of Health and Human Services (1RO1FD003870-01).
Dr. Yeh has received research grants from Abiomed and Boston Scientific; and advisory board/consulting for Abbott and Boston Scientific. Dr. Kereiakes has received research funding and consultant to Abbott Vascular, Boston Scientific, and Sanofi. Dr. Cutlip has received grant funding from Medtronic, Boston Scientific, and Celonova. Dr. Steg has received research grants from Merck, Sanofi, and Servier; and speaking or consulting fees from Amarin, AstraZeneca, Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, CSL-Behring, Daiichi Sankyo, GlaxoSmithKline, Janssen, Lilly, Merck Novartis, Pfizer, Regeneron, Sanofi, Servier, and The Medicines Company. Dr. Massaro has received personal fees from Baim Institute for Clinical Research. Dr. Mauri has received grants from Abbott, Boston Scientific, Cordis, Medtronic, Eli Lilly/Daiichi Sankyo, and Sanofi/Bristol-Myers Squibb, during the conduct of the study; outside the submitted work she reports consulting fees from Amgen and St. Jude Medical; serves on the steering committee for Biotronik and Corvia; is a lecturer for AstraZeneca, Sanofi, Daiichi-Sankyo; and is an investigator for Boehringer Ingelheim and ReCor. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- confidence interval
- major adverse cardiovascular or cerebrovascular event(s)
- myocardial infarction
- peripheral arterial disease
- percutaneous coronary intervention
- Received December 7, 2016.
- Revision received February 6, 2017.
- Accepted February 12, 2017.
- 2017 American College of Cardiology Foundation
- Saw J.,
- Bhatt D.L.,
- Moliterno D.J.,
- et al.
- Hirsch A.T.,
- Haskal Z.J.,
- Hertzer N.R.,
- et al.
- van Werkum J.W.,
- Heestermans A.A.,
- Zomer A.C.,
- et al.
- Mehta S.K.,
- Frutkin A.D.,
- Lindsey J.B.,
- et al.
- Ducrocq G.,
- Wallace J.S.,
- Baron G.,
- et al.
- Hiatt W.R.,
- Fowkes F.G.,
- Heizer G.,
- et al.
- Cacoub P.P.,
- Bhatt D.L.,
- Steg P.G.,
- Topol E.J.,
- Creager M.A.
- Gerhard-Herman M.D.,
- Gornik H.L.,
- Barrett C.,
- et al.
- Bittl J.A.,
- Baber U.,
- Bradley S.M.,
- Wijeysundera D.N.
- Bonaca M.P.,
- Bhatt D.L.,
- Storey R.F.,
- et al.
- Franzone A.,
- Piccolo R.,
- Gargiulo G.,
- et al.
- Mauri L.,
- Kereiakes D.J.,
- Yeh R.W.,
- et al.
- Cutlip D.E.,
- Windecker S.,
- Mehran R.,
- et al.
- Brevetti G.,
- Giugliano G.,
- Brevetti L.,
- Hiatt W.R.
- Bhatt D.L.,
- Peterson E.D.,
- Harrington R.A.,
- et al.
- Leunissen T.C.,
- Peeters Weem S.M.,
- Urbanus R.T.,
- et al.
- Levine G.N.,
- Bates E.R.,
- Bittl J.A.,
- et al.
- Mauri L.,
- Elmariah S.,
- Yeh R.W.,
- et al.
- ↵Food and Drug Administration. Plavix (clopidogrel): drug safety communication. Long-term treatment does not change risk of death. Available at: http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm471531.htm?source=govdelivery&utm_medium=email&utm_source=govdelivery. Accessed November 6, 2015.