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

Abstract

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.

Conflict of interest statement

Declaration of Interests

Dr. Yeh reports personal fees from Abbott Vascular, Boston Scientific, and Merck, and research salary from Harvard Clinical Research Institute, outside the submitted work.

Dr. Secemsky has nothing to disclose.

Dr. Kereiakes has nothing to disclose.

Dr. Normand has nothing to disclose

Dr. Gershlick has nothing to disclose.

Dr. Cohen reports grants and personal fees from Abbott Vascular, Medtronic, Astra-Zeneca, and Eli Lilly, and grants from Daichii-Sankyo, outside the submitted work.

Dr. Spertus reports ownership of equity interest in Health Outcomes Sciences.

Dr. Steg reports personal fees from Amarin, AstraZeneca, Bayer, Boehringer-Ingelheim, Bristol-Myers-Squibb, Daiichi-Sankyo, GlaxoSmithKline, Lilly, Merck-Sharpe-Dohme, Novartis, CSL-Behring, Regeneron, Janssen, Pfizer, Regado, and Roche; grants and personal fees from Sanofi and Servier; and personal fees and non-financial support from The Medicines Company; outside the submitted work.

Dr. Cutlip reports grants from Medtronic and Boston Scientific, outside the submitted work.

Dr. Rinaldi reports serving on the advisory boards of Abbott Vascular and Boston Scientific.

Dr. Camenzind has nothing to disclose.

Dr. Wijns reports grants from Medtronic, during the conduct of the study; grants from Medtronic, Boston Scientific, Terumo, MiCell, Stentys, and Abbott Vascular, outside the submitted work; and non-executive Board member and shareholder of Argonauts Partners, Celyad and Genae Inc.

Ms. Apruzzese has nothing to disclose.

Mr. Song has nothing to disclose.

Dr. Massaro reports personal fees from Harvard Clinical Research Institute during the conduct of the study.

Dr. Mauri reports grants from Abbott, Boston Scientific, Cordis, Bristol-Myers Squibb, and Daiichi Sankyo; grants and personal fees from Medtronic, Eli Lilly and Company, Sanofi, Boehringer Ingelheim, Biotronik; personal fees from Amgen, Recor, Astra Zeneca, and St. Jude, outside the submitted work

Figures

Figure 1. DAPT Study patient flow diagram

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 PCI.

Figure 2. Clinical prediction ccore to stratify individual risk of benefit vs. harm with continuation of dual antiplatelet therapy beyond 1 year after PCI

A. Summation of points for factors included in score. B. Distribution of prediction scores among all patients randomized in the DAPT Study (n = 11,648). Abbreviations: CHF, congestive heart failure; LVEF, left ventricular ejection fraction; MI, myocardial infarction; PCI, percutaneous coronary intervention.

Figure 3. Observed rates of MI or stent thrombosis, MACCE, and moderate or severe bleeding, stratified by clinical prediction score group

Kaplan-Meier curves for continued thienopyridine vs. placebo for MI or ST, MACCE, GUSTO moderate or severe bleeding, and death at 12–30 months after PCI in randomized patients (Panels A, B), and those treated with everolimus-eluting stents only (Panels C, D), stratified by clinical prediction score. 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. The P values are based on the subgroup log-rank test. Abbreviations: MACCE, major adverse cardiovascular and cerebrovascular events; GUSTO, Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Arteries.

Figure 3. Observed rates of MI or stent thrombosis, MACCE, and moderate or severe bleeding, stratified by clinical prediction score group

Kaplan-Meier curves for continued thienopyridine vs. placebo for MI or ST, MACCE, GUSTO moderate or severe bleeding, and death at 12–30 months after PCI in randomized patients (Panels A, B), and those treated with everolimus-eluting stents only (Panels C, D), stratified by clinical prediction score. 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. The P values are based on the subgroup log-rank test. Abbreviations: MACCE, major adverse cardiovascular and cerebrovascular events; GUSTO, Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Arteries.

Figure 3. Observed rates of MI or stent thrombosis, MACCE, and moderate or severe bleeding, stratified by clinical prediction score group

Kaplan-Meier curves for continued thienopyridine vs. placebo for MI or ST, MACCE, GUSTO moderate or severe bleeding, and death at 12–30 months after PCI in randomized patients (Panels A, B), and those treated with everolimus-eluting stents only (Panels C, D), stratified by clinical prediction score. 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. The P values are based on the subgroup log-rank test. Abbreviations: MACCE, major adverse cardiovascular and cerebrovascular events; GUSTO, Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Arteries.

Figure 3. Observed rates of MI or stent thrombosis, MACCE, and moderate or severe bleeding, stratified by clinical prediction score group

Kaplan-Meier curves for continued thienopyridine vs. placebo for MI or ST, MACCE, GUSTO moderate or severe bleeding, and death at 12–30 months after PCI in randomized patients (Panels A, B), and those treated with everolimus-eluting stents only (Panels C, D), stratified by clinical prediction score. 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. The P values are based on the subgroup log-rank test. Abbreviations: MACCE, major adverse cardiovascular and cerebrovascular events; GUSTO, Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Arteries.