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Original Investigation |

Development and Validation of a Prediction Rule for Benefit and Harm of Dual Antiplatelet Therapy Beyond 1 Year After Percutaneous Coronary Intervention

Robert W. Yeh, MD, MSc1,2,3; Eric A. Secemsky, MD, MSc2,3,4; Dean J. Kereiakes, MD5,6; Sharon-Lise T. Normand, PhD2,7; Anthony H. Gershlick, MBBS8,9; David J. Cohen, MD, MSc10,11; John A. Spertus, MD, MPH10,11,12; Philippe Gabriel Steg, MD13,14,15; Donald E. Cutlip, MD2,3,16; Michael J. Rinaldi, MD17; Edoardo Camenzind, MD18; William Wijns, MD, PhD19; Patricia K. Apruzzese, MA3; Yang Song, MS3; Joseph M. Massaro, PhD3,20; Laura Mauri, MD, MSc2,3,21 ; for the DAPT Study Investigators
[+] Author Affiliations
1Smith Center for Outcomes Research in Cardiology, Beth Israel Deaconess Medical Center, Boston, Massachusetts
2Harvard Medical School, Boston, Massachusetts
3Harvard Clinical Research Institute, Boston, Massachusetts
4Cardiology Division, Massachusetts General Hospital, Boston
5Christ Hospital Heart and Vascular Center, Cincinnati, Ohio
6Lindner Center for Research and Education, Cincinnati, Ohio
7Harvard T. H. Chan School of Public Health, Boston, Massachusetts
8Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom
9National Institute for Health Research Leicester Cardiovascular Biomedical Research Unit, University Hospitals of Leicester NHS Trust, Glenfield Hospital, Leicester, United Kingdom
10Saint Luke’s Mid America Heart Institute, Kansas City, Missouri
11University of Missouri-Kansas City School of Medicine, Kansas City, Missouri
12Washington University in St Louis, School of Medicine, St Louis, Missouri
13Université Paris-Diderot, INSERM U-1148, Hôpital Bichat, Paris, France
14Département Hospitalo-Universitaire Fibrosis, Inflammation, and Remodeling, Assistance Publique, Hôpitaux de Paris, Paris, France
15National Heart and Lung Institute, Institute of Cardiovascular Medicine and Science, Royal Brompton Hospital, Imperial College, London, United Kingdom
16Beth Israel Deaconess Medical Center, Boston, Massachusetts
17Sanger Heart and Vascular Institute, Carolinas HealthCare System, Charlotte, North Carolina
18Institut Loraine du Coeur et des Vaisseaux, University Hospital of Nancy-Brabois, Vandoeuvre-les-Nancy, France
19Cardiovascular Center, Onze-Lieve-Vrouwziekenhuis Hospital, Aalst, Belgium
20Boston University School of Public Health, Boston, Massachusetts
21Brigham and Women’s Hospital, Boston, Massachusetts
JAMA. 2016;315(16):1735-1749. doi:10.1001/jama.2016.3775.
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Importance  Dual antiplatelet therapy after percutaneous coronary intervention (PCI) reduces ischemia but increases bleeding.

Objective  To develop a clinical decision tool to identify patients expected to derive benefit vs harm from continuing thienopyridine beyond 1 year after PCI.

Design, Setting, and Participants  Among 11 648 randomized DAPT Study patients from 11 countries (August 2009-May 2014), a prediction rule was derived stratifying patients into groups to distinguish ischemic and bleeding risk 12 to 30 months after PCI. Validation was internal via bootstrap resampling and external among 8136 patients from 36 countries randomized in the PROTECT trial (June 2007-July 2014).

Exposures  Twelve months of open-label thienopyridine plus aspirin, then randomized to 18 months of continued thienopyridine plus aspirin vs placebo plus aspirin.

Main Outcomes and Measures  Ischemia (myocardial infarction or stent thrombosis) and bleeding (moderate or severe) 12 to 30 months after PCI.

Results  Among DAPT Study patients (derivation cohort; mean age, 61.3 years; women, 25.1%), ischemia occurred in 348 patients (3.0%) and bleeding in 215 (1.8%). Derivation cohort models predicting ischemia and bleeding had c statistics of 0.70 and 0.68, respectively. The prediction rule assigned 1 point each for myocardial infarction at presentation, prior myocardial infarction or PCI, diabetes, stent diameter less than 3 mm, smoking, and paclitaxel-eluting stent; 2 points each for history of congestive heart failure/low ejection fraction and vein graft intervention; −1 point for age 65 to younger than 75 years; and −2 points for age 75 years or older. Among the high score group (score ≥2, n = 5917), continued thienopyridine vs placebo was associated with reduced ischemic events (2.7% vs 5.7%; risk difference [RD], −3.0% [95% CI, −4.1% to −2.0%], P < .001) compared with the low score group (score <2, n = 5731; 1.7% vs 2.3%; RD, −0.7% [95% CI, −1.4% to 0.09%], P = .07; interaction P < .001). Conversely, continued thienopyridine was associated with smaller increases in bleeding among the high score group (1.8% vs 1.4%; RD, 0.4% [95% CI, −0.3% to 1.0%], P = .26) compared with the low score group (3.0% vs 1.4%; RD, 1.5% [95% CI, 0.8% to 2.3%], P < .001; interaction P = .02). Among PROTECT patients (validation cohort; mean age, 62 years; women, 23.7%), ischemia occurred in 79 patients (1.0%) and bleeding in 37 (0.5%), with a c statistic of 0.64 for ischemia and 0.64 for bleeding. In this cohort, the high-score patients (n = 2848) had increased ischemic events compared with the low-score patients and no significant difference in bleeding.

Conclusion and Relevance  Among patients not sustaining major bleeding or ischemic events 1 year after PCI, a prediction rule assessing late ischemic and bleeding risks to inform dual antiplatelet therapy duration showed modest accuracy in derivation and validation cohorts. This rule requires further prospective evaluation to assess potential effects on patient care, as well as validation in other cohorts.

Trial Registration  clinicaltrials.gov Identifier: NCT00977938.

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Figure 1.
Flow of Patients Through the Dual Antiplatelet Therapy Study

BMS indicates bare metal stent; DES, drug-eluting stent; GUSTO, Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Arteries. A total of 11 648 randomized patients comprised the cohort used to derive a clinical prediction score to stratify individual risk of benefit and harm with continuation of dual antiplatelet therapy beyond 1 year after percutaneous coronary intervention.

aScreening for eligibility data are not available to report.

bPatients may have had more than 1 event.

cOther reasons include site terminated participation, randomization target met prior to patient follow-up, or patient not recognized as eligible by site.

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Figure 2.
Elements of Clinical Prediction Score and Distribution of Score Among Randomized DAPT Study Patients (Derivation Cohort, 11 648 Patients)

CHF indicates congestive heart failure; LVEF, left ventricular ejection fraction; MI, myocardial infarction; PCI, percutaneous coronary intervention. Variables reflect characteristics at the time of the index procedure. Cigarette smoking was defined as smoking within 1 year prior to index procedure.

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Figure 3.
Observed Rates of Outcomes From 12 Through 30 Months After Percutaneous Coronary Intervention Among Randomized Patients by Clinical Prediction Score Group in the Derivation Cohort

Moderate or severe bleeding was defined by Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Arteries criteria. The number at risk was defined as the number of patients who had not had the event of interest and who were available for subsequent follow-up.

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Figure 4.
Observed Rates of Outcomes From 12 Through 30 Months After Percutaneous Coronary Intervention Among Patients Treated With Everolimus-Eluting Stents Only by Clinical Prediction Score Group in the Derivation Cohort

Moderate or severe bleeding was defined by Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Arteries criteria. The number at risk was defined as the number of patients who had not had the event of interest and who were available for subsequent follow-up.

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