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.
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.
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.
eFigure 1. Observed vs Expected Kaplan-Meier Rates of Stent Thrombosis or Myocardial Infarction Within the DAPT Study Population, by Quantile of Increasing Risk
eFigure 2. Observed vs Expected Kaplan-Meier Rates of GUSTO Moderate or Severe Bleeding Within the DAPT Study Population, by Quantile of Increasing Risk
eFigure 3. Observed vs Expected Kaplan-Meier Rates of Stent Thrombosis or Myocardial Infarction Within the PROTECT Population, by Quantile of Increasing Risk
eFigure 4. Observed vs. Expected Kaplan-Meier Rates of GUSTO Moderate or Severe Bleeding Within the PROTECT Population, by Quantile of Increasing Risk
eFigure 5. Distribution of Predicted Reduction in Ischemic Events (A) and Bleeding (B) With Continuation of Dual Antiplatelet Therapy From 12-30 Months Among Randomized DAPT Study Patients, Based on Ischemic and Bleeding Models
eFigure 6. Scatter Plot of Predicted Benefit vs Harm With Continued Thienopyridine Between 12-30 Months Among Randomized DAPT Study Patients, Based on Ischemic and Bleeding Models
eTable 1. Candidate Predictors
eTable 2. Additional Outcomes Between 12-30 Months Since Enrollment Stratified by DAPT Score Quartile
eTable 3. Observed Outcomes Between 12-30 Months Since Enrollment Stratified by DAPT Score Group for all Randomized Patients (N = 11 648)
eTable 4. Observed Outcomes Between 12-30 Months Since Enrollment When Divided into 2 DAPT Score Groups Among Patients Treated With Everolimus-Eluting Stents (N=4703)
Yeh RW, Secemsky EA, Kereiakes DJ, Normand ST, Gershlick AH, Cohen DJ, Spertus JA, Steg PG, Cutlip DE, Rinaldi MJ, Camenzind E, Wijns W, Apruzzese PK, Song Y, Massaro JM, Mauri L, for the DAPT Study Investigators. Development and Validation of a Prediction Rule for Benefit and Harm of Dual Antiplatelet Therapy Beyond 1 Year After Percutaneous Coronary Intervention. JAMA. 2016;315(16):1735-1749. doi:10.1001/jama.2016.3775
Dual antiplatelet therapy after percutaneous coronary intervention (PCI) reduces ischemia but increases bleeding.
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).
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.
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.
clinicaltrials.gov Identifier: NCT00977938.
The optimal duration of dual antiplatelet therapy with aspirin and thienopyridine after percutaneous coronary intervention (PCI) with stents is the subject of debate. Among patients who complete 1 year of dual antiplatelet therapy after PCI without an ischemic or bleeding event, continuing therapy decreases stent thrombosis and myocardial infarction but increases bleeding.1,2 Continuing dual antiplatelet therapy thus involves a careful assessment of the trade-offs between reduced ischemia and increased bleeding for individual patients.
However, assessing the balance between ischemia and bleeding risks can be challenging for clinicians and patients. Factors related to recurrent ischemic events and bleeding in patients undergoing PCI overlap substantially, making it difficult to determine optimal treatment.3 Although subgroup analyses have been helpful in determining groups with larger absolute benefits from continuing therapy (eg, patients presenting with myocardial infarction),4,5 there remain patients within these broad categories who may also experience serious bleeding events. Most data estimating ischemia and bleeding risk following PCI have focused on early risks, including periprocedural events.6,7 It remains unclear which patients are at high risk for late ischemic events and may thus benefit most from longer-term dual antiplatelet therapy vs those who are at high risk for late bleeding events and may thus be harmed.
The goal of this study was to identify factors predicting whether the expected benefit of reduced ischemia would outweigh the expected increase in bleeding associated with continued dual antiplatelet therapy beyond 1 year for individual patients, using data from the Dual Antiplatelet Therapy (DAPT) Study. These factors were used to develop a decision tool to help select the duration of therapy for individual patients being evaluated 1 year after stenting.
This secondary analysis of the DAPT Study was approved by the institutional review board of Partners HealthCare. The Patient-Related Outcomes With Endeavor vs Cypher Stenting (PROTECT) protocol was approved by ethical boards in accordance with local regulations. All patients in both studies provided written informed consent. The DAPT Study, conducted from August 2009 to May 2014 in 11 countries, enrolled patients after PCI with either drug-eluting stents (DES) or bare metal stents (BMS) and treated them with open-label thienopyridine plus aspirin for 12 months; at 12 months, eligible patients who were free from major bleeding and ischemic events and adherent to therapy remained taking aspirin and were randomized to continued thienopyridine vs placebo for 18 months.8 The full enrollment and randomization criteria are listed in the eAppendix in the Supplement. Patients receiving long-term anticoagulation therapy, those with planned surgical procedures necessitating discontinuation of antiplatelet therapy for more than 14 days, and those with a life expectancy of less than 3 years were excluded from enrollment. At 12 months, only those patients who were adherent with thienopyridine therapy and free from myocardial infarction, stroke, repeat coronary revascularization, stent thrombosis, and moderate or severe bleeding by the GUSTO (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Arteries) criteria9 during the first 12 months after enrollment were randomized.
As permitted by regulatory authorities, race and ethnicity data were collected via patient self-report. Race categories were prespecified as American Indian or Alaska Native, Asian, black or African American, Native Hawaiian or other Pacific Islander, white, and other. Ethnicity was collected as Hispanic or Latino and not Hispanic or Latino. This information was collected to assess potential heterogeneous treatment effects among different subgroups.
The primary follow-up period of the study was 12 to 30 months after the index procedure (or 18 months after randomization). Details of the study design and results have been described previously.1,2,8 As the results of the study were consistent across DES- and BMS-treated cohorts,2 all randomized patients were included in this analysis.
The goal of this study was to distinguish patients within the DAPT Study who derived the greatest benefit from those who experienced the most harm from continuation of dual antiplatelet therapy more than 1 year after PCI, considering individual patient characteristics and their independent associations with ischemic and bleeding events. This study sought to stratify outcomes based on a single multivariable risk score.10 This entailed (1) identifying factors associated with ischemic and bleeding risks, (2) choosing those that selectively predicted either ischemic or bleeding risk to generate a simplified risk score, and (3) assessing the randomized treatment results observed in the trial, stratified by the new risk score. An ideal score would identify patients with simultaneous high ischemic risk (and corresponding high benefit with continued thienopyridine) and low bleeding risk (and corresponding low risk of harm with continued therapy), and vice versa. In addition, the ability of the score to stratify ischemic and bleeding risk within an external sample was assessed.
The primary ischemic end point was a composite of myocardial infarction or definite or probable stent thrombosis (as defined by the Academic Research Consortium),11 and the primary bleeding end point was moderate or severe bleeding (as defined by the GUSTO criteria).9
A total of 37 candidate variables potentially associated with ischemic or bleeding events based on a comprehensive literature review and clinical plausibility were identified. Variables included sociodemographic variables, cardiovascular history, noncardiovascular medical comorbidities, anatomical and procedural factors, and concomitant medical therapy. (Candidate Variables for Model Building in the eAppendix in the Supplement).
Clinical and procedural characteristics were compared between patients experiencing events from 12 through 30 months and those without events, using Fisher exact or t tests as appropriate. Cox regression was used to develop 2 separate models within the DAPT randomized study population (derivation cohort), the first to predict ischemic events and the second to predict bleeding events after randomization. Data were censored at the time of a myocardial infarction or stent thrombosis for the ischemia model; a moderate or severe bleed for the bleeding model; or at the time of death, last known contact, or 30 months, whichever was earliest. Candidate variables that differed in bivariable comparisons at a significance level of less than .30 were incorporated. Stepwise selection was then performed, using the .05 significance level. To identify possible heterogeneous treatment effects, simple Cox regression models were developed for each outcome including treatment group, variable of interest, and their interaction term. Interactions terms significant at a P value less than .15 were entered into the stepwise selection process with other candidate variables.
Proportionality was evaluated for all variables in the models. Model discrimination was assessed using the c statistic. Calibration was assessed through the examination of calibration plots and using the corrected Nam and D’Agostino goodness-of-fit test.12,13 The primary models were internally validated using bootstrap resampling for 200 iterations.14 For each resampling, the stepwise selection process was rerun, and the discrimination of the bootstrap model was assessed in the bootstrap sample and the full data set. The mean difference between these bootstrap model values was defined as the “optimism,” and was subtracted from the final reported discrimination of the models.15
For each patient, the predicted risk (cumulative incidence) of an ischemic event from 12 through 30 months was estimated, assuming treatment with continued thienopyridine plus aspirin beyond 12 months and separately assuming treatment with aspirin alone beyond 12 months; similarly, bleeding event risks were predicted under these 2 assumptions. The difference between these 2 predicted values represented the predicted absolute risk reduction in combined myocardial infarction or stent thrombosis anticipated with continued thienopyridine from the ischemic model, and the predicted absolute risk increase in moderate or severe bleeding anticipated with continued thienopyridine from the bleeding model. The absolute difference between the predicted ischemic reduction and bleeding increase was defined as the “benefit-risk difference,” and estimated for each patient.
A linear regression model was created, using benefit-risk difference as the outcome and all predictors that were selected in the ischemia and bleeding models. Variables that statistically accounted for more than 1% of the observed variation in estimated benefit-risk difference were included in a simplified clinical prediction score. To facilitate ease of use, continuous variables (such as age and stent diameter) were categorized based on reference to prior studies or at median values and confirmation that the gradient of effect was maintained when transformed, and all variables were assigned an integer score of 1 or 2 (or −1 to −2) based on β coefficients (Development of a Predictive Score in the eAppendix in the Supplement). The range of potential scores was between −2 and 10.
The derivation cohort was divided into approximate quartiles based on the score, and Kaplan-Meier event rates from 12 through 30 months were compared within each score quartile by randomized treatment group. Additionally, event rates were examined among patients receiving only everolimus-eluting stents (EES). Based on these results, clinically relevant score groupings were created, defining patients more likely to benefit from thienopyridine continuation (high score group) vs those more likely to be harmed (low score group). The absolute risk differences in ischemic and bleeding event rates associated with continued thienopyridine vs placebo across high vs low score groups were compared using a Z test for interaction.
The risk models and the clinical prediction score were externally validated within the PROTECT trial, conducted from June 2007 through July 2014 in 36 countries, in which patients undergoing PCI were randomized to receive sirolimus-eluting (SES) vs zotarolimus-eluting stents (ZES) and were followed up for 5 years.16 This trial was selected for validation due to its large inclusive population of stent-treated patients, with similar definitions and adjudicated outcomes as those used in the DAPT Study. Those patients not sustaining myocardial infarction, stent thrombosis, or a moderate/severe bleeding event within the first 12 months in the PROTECT trial served as the validation cohort (n = 8136). Two forms of validation were conducted: (1) evaluation of the DAPT Study–derived ischemic and bleeding models and (2) evaluation of prediction score performance in stratifying risks of ischemic and bleeding events. First, for the validation of the models, because PROTECT trial patients were not randomized to different durations of dual antiplatelet therapy, dual antiplatelet therapy duration was likely confounded by treatment indication and was therefore not included in the validation. The anticipated statistical effect of omitting this variable in the validation would be to yield a conservative estimate of each model’s performance, given that randomized treatment group is strongly associated with both bleeding and ischemic events. Models were validated via the estimation of c statistics and goodness-of-fit tests by applying the function derived in the DAPT Study to PROTECT patients from 12 through 30 months after PCI, limited to patients not sustaining myocardial infarction, stent thrombosis, or a moderate/severe bleeding event within the first 12 months. Because PROTECT had lower overall ischemic and bleeding event rates than the DAPT Study, the calibration of the models was assessed after accounting for this difference in baseline hazard,17 and then the goodness of fit of the recalibrated model was assessed.
Second, the ability of the clinical prediction score to stratify ischemic and bleeding risk was evaluated by comparing overall rates of myocardial infarction, stent thrombosis, and moderate or severe bleeding among patients with a high vs low score in the validation cohort.
A 2-tailed α of .05 was used to define the significance threshold for all comparisons. All analyses were performed at the Harvard Clinical Research Institute, using SAS (SAS Institute), version 9.4.
A total of 11 648 patients undergoing PCI with coronary stents were randomized in the DAPT Study and included in this analysis (derivation cohort) (Figure 1). Of these, patients receiving EES were 40.3%; paclitaxel-eluting stents, 22.9%; ZES, 10.9%; SES, 9.6%; BMS, 14.4%; receiving more than 1 stent type, 1.8%. From 12 through 30 months after their index procedure, 348 patients (3.0%) developed myocardial infarction or stent thrombosis (myocardial infarction without stent thrombosis, 251; stent thrombosis, 97) and 215 patients (1.8%) developed moderate or severe bleeding (moderate, 142; severe, 72; 2 different events adjudicated as moderate and severe, 1). Thirty-three patients had both an ischemic and bleeding event in follow-up. Patients who had an ischemic event in follow-up had higher rates of cardiovascular risk factors (including diabetes, hypertension, peripheral arterial disease, renal insufficiency/failure, and smoking), had higher rates of cardiovascular disease (including history of congestive heart failure [CHF], low ejection fraction, prior myocardial infarction, and prior PCI), and were more likely to have been randomized to placebo compared with patients without an ischemic event (Table 1). Patients with a bleeding event were older, had a lower prevalence of smoking, had a higher prevalence of hypertension, prior CHF, renal insufficiency/failure, peripheral arterial disease, atrial fibrillation, prior stroke/transient ischemic attack, prior PCI, and history of cancer, and were more likely to have been randomized to continued thienopyridine compared with patients without a bleeding event.
In multivariable Cox regression, significant predictors of both ischemic and bleeding events included randomized treatment group, peripheral arterial disease, hypertension, and renal insufficiency/failure. Variables that predicted only the risk of ischemic events included history of PCI or myocardial infarction prior to the index procedure, stent diameter less than 3 mm, myocardial infarction at presentation, history of CHF or left ventricular ejection fraction lower than 30%, paclitaxel-eluting stent, vein graft stent, cigarette smoking within the year prior to index procedure, and diabetes mellitus (Table 2). No tested interactions between covariates and randomized treatment for ischemic events were retained in the model. The ischemic model had moderate discrimination (c statistic, 0.70 [95% CI, 0.68-0.73]) and was well calibrated (goodness-of-fit P = .81).
Increasing age was a significant independent predictor of bleeding, but not of ischemic events (Table 2). No tested interactions between covariates and randomized treatment for bleeding were retained in the model. The bleeding model showed similar discrimination to the ischemia model (c statistic, 0.68 [95% CI, 0.65-0.72]) and was well calibrated (goodness-of-fit P = .34). After bootstrap internal validation, optimism-corrected c statistics for both the ischemia (0.68 [95% CI, 0.65-0.70]) and bleeding models (0.66 [95% CI, 0.62-0.70]) were similar.
A simplified risk score was generated to predict the difference between the anticipated reduction in ischemic events and the anticipated increase in bleeding events with continued thienopyridine (ie, the benefit-risk difference) (Development of a Predictive Score in the eAppendix in the Supplement). The score, ranging from −2 to 10, assigned points as follows: for patients younger than 65 years, 0 points; for age 65 to younger than 75 years, −1; for patients 75 years or older, −2; for vein graft stent, 2; for current cigarette smoker or within past year, 1; for diabetes mellitus, 1; for myocardial infarction at presentation, 1; for stent diameter less than 3 mm, 1; for history of CHF or left ventricular ejection fraction lower than 30%, 2; for prior PCI or prior myocardial infarction, 1; and for paclitaxel-eluting stent, 1 (Figure 2). Among the derivation cohort, a higher score quartile was associated with higher rates of myocardial infarction or stent thrombosis (interaction P < .001), whereas lower score quartiles were associated with higher rates of moderate or severe bleeding (interaction P = .006). In addition, higher score quartiles were associated with larger observed risk reductions in myocardial infarction or stent thrombosis with randomization to continued thienopyridine (P = .001), and lower score quartiles were associated with greater observed risk increases in bleeding (P = .04, Table 3).
When separated into groups (high score group [score, ≥2] vs low score group [score, <2]), among patients in the high score group (n = 5917), randomization to continued thienopyridine was associated with larger reductions in myocardial infarction or stent thrombosis (2.7% for continued thienopyridine vs 5.7% for placebo; risk difference [RD], −3.0% [95% CI, −4.1% to −2.0%], P < .001) compared with those in the low score group (n = 5731; 1.7% for continued thienopyridine vs 2.3% for placebo; RD, −0.7% [95% CI, −1.4% to 0.09%], P = .07; interaction P < .001). Conversely, randomization to continued thienopyridine was associated with smaller increases in bleeding among the high score group (1.8% for continued thienopyridine vs 1.4% for placebo; RD, 0.4% [95% CI, −0.3% to 1.0%], P = .26) compared with the low score group (3.0% for continued thienopyridine vs 1.4% for placebo; RD, 1.5% [95% CI, 0.8% to 2.3%], P < .001; interaction P = .02) (Figure 3; eTable 3 in the Supplement).
The risk reduction in major adverse cardiovascular and cerebrovascular events (defined as the composite of death, myocardial infarction, and stroke) with continued thienopyridine was significantly greater among the high score group (4.9% for continued thienopyridine vs 7.6% for placebo; RD, −2.7% [95% CI, −4.0% to −1.5%]; P < .001) vs the low score group (3.7% for continued thienopyridine vs 3.8% for placebo; RD, −0.2% [95% CI, −1.2% to 0.86%]; P = .73; interaction P = .001). The all-cause mortality rate was 2.1% for continued thienopyridine vs 2.1% for placebo for the high score group (RD, 0.01% [95% CI, −0.73% to 0.76%]; P = .99) compared with 1.7% for continued thienopyridine vs 0.9% for placebo for the low score group (RD, 0.73% [95% CI, 0.13% to 1.33%], P = .02; interaction P = .14 [nonsignificant]) .
After restricting the population to those treated with EES (n = 4703), the rates of myocardial infarction or stent thrombosis were 2.9% for continued thienopyridine vs 4.7% for placebo (RD, −1.89% [95% CI, −3.70% to −0.08%], P = .04) among the high score group (n = 1869) and were 1.7% for continued thienopyridine vs 2.2% for placebo (RD, −0.50% [95% CI, −1.55% to 0.56%], P = .33; interaction P = .18 [non-significant]) among the low score group (n = 2834). The corresponding rates of bleeding were 1.8% for continued thienopyridine vs 1.2% for placebo (RD, 0.52% [95% CI, −0.63% to 1.67%], P = .38) for the high score group and 3.0% for continued thienopyridine vs 1.4% for placebo in the low score group (RD, 1.67% [95% CI, 0.55% to 2.78%], P = .003; interaction P = .15 [nonsignificant]). (Figure 4, eTable 4 in the Supplement). All-cause mortality occurred in 2.5% for continued thienopyridine vs 1.8% for placebo (P = .31) among the high score group, and 1.9% for continued thienopyridine vs 0.7% for placebo (P = .01, interaction P = .54 [nonsignificant]) among the low score group.
Among 8136 patients who did not have a myocardial infarction, stent thrombosis, or moderate/severe bleeding within the first 12 months after PCI in the PROTECT trial (validation cohort), the models used to derive the predictive score (excluding the variable reflecting randomization to continued thienopyridine vs placebo) showed modestly reduced discrimination (c statistic: ischemic model, 0.64 [95% CI, 0.58 to 0.70]; bleeding model, 0.64 [95% CI, 0.55 to 0.73]). These results were overall similar within the ZES and SES populations of the validation cohort (c statistic: ischemic model, 0.62 [95% CI, 0.52 to 0.72] in the ZES group and 0.64 [95% CI, 0.57 to 0.72] in the SES group; bleeding model, 0.63 [95% CI, 0.51 to 0.76] in the ZES group and 0.65 [95% CI, 0.53 to 0.76]in the SES group). Because the PROTECT trial enrolled a lower-risk population than the DAPT Study, both ischemic and bleeding event rates were overestimated. After recalibration to the baseline event rates observed in the PROTECT trial, the models were well fit (P = .81 for the ischemia model, P = .91 for the bleeding model) (eAppendix in the Supplement).
Within the validation cohort, the rate of myocardial infarction or stent thrombosis from 12 through 30 months after PCI was greater among the high-score patients (n = 2848) compared with the low-score patients (n = 5288; 1.5% high-score patients vs 0.7% low-score patients; hazard ratio [HR], 2.01 [95% CI, 1.29 to 3.13], P = .002). Rates of moderate or severe bleeding were not significantly different by score (0.4% in the high-score patients vs 0.5% in the low-score patients; HR, 0.69 [95% CI, 0.33 to 1.42], P = .31).
This study developed a clinical prediction score based on ischemic and bleeding risk factors to help identify patients with greater expected benefit vs greater expected harm from continuation of dual antiplatelet therapy from among patients who had completed 1 year of dual antiplatelet therapy after coronary stent treatment without a major ischemic or bleeding event. For patients randomized in the DAPT Study (derivation cohort) with clinical predictive scores of 2 or higher (high score group; 50.8%), continued thienopyridine was associated with an absolute risk reduction in myocardial infarction or stent thrombosis that was 8.2 times greater than the absolute risk increase in moderate or severe bleeding. Conversely, among patients with scores lower than 2 (low score group; 49.2%), randomization to continued thienopyridine was associated with an absolute increase in bleeding that was 2.4 times the absolute reduction in myocardial infarction or stent thrombosis. Within the PROTECT trial (validation cohort), the high score group was observed to have significantly greater ischemic risk and no significant difference in bleeding risk, compared with the low score group. Despite prior evidence suggesting that ischemic and bleeding risk are strongly correlated,3,18 these results suggest that it may be possible to identify individual patients with discordant ischemic risks and bleeding risks.
Numerous randomized trials evaluating duration of dual antiplatelet therapy after coronary stenting have demonstrated a trade-off between reductions in ischemia and increases in bleeding associated with longer durations of treatment.19- 23 Although clinical trial results are expected to be applied to the population represented by enrollment criteria, in the setting of discordant risks and benefits of treatment, tailoring therapies to individual patient profiles to maximize benefits and minimize harms affords an opportunity to further optimize outcomes.
A number of limitations should be considered in interpreting these findings. The results of this study should be interpreted with the understanding that patients enrolled in clinical trials may not represent those cared for in routine practice on the basis of the inclusion and exclusion criteria of the trial, as well as other unmeasured differences between study participants and nonparticipants. Patients taking oral anticoagulants were not enrolled in the DAPT Study, and they make up 4% to 7% of all PCI patients.24- 26 Patients who interrupted therapy for more than 14 days or sustained a major bleeding or ischemic event in the first year after PCI were also not randomized in the DAPT Study, and represented 22.7% of enrolled patients. Similarly, in a recent large registry of patients undergoing coronary stenting, discontinuation of antiplatelet therapy for more than 14 days occurred in 11.5% of patients; cessation due to a clinical event or nonadherence in 9.7%; and major bleeding in 1.4%; whereas myocardial infarction occurred in 2.2% and target-vessel revascularization in 5.1%—altogether representing approximately 30% of all PCI patients.26 Although there remains a sizable proportion of patients undergoing PCI who do not have events that would have disqualified them from randomization in the DAPT Study, the patients used to derive the clinical prediction score make up a group of patients that may not be representative of those seen in clinical practice.
Variables in the predictive score included patient and procedural characteristics that have demonstrated an association with either ischemic or bleeding events after PCI in prior studies. For instance, prior PCI, presentation with myocardial infarction, current smoking, and diabetes have each been predictive of stent thrombosis occurring within the first year after PCI.27 Similarly, advanced age, renal disease and history of peripheral arterial disease have correlated with both in-hospital and 30-day bleeding after PCI.28,29 In this study, peripheral arterial disease, renal insufficiency, and hypertension were predictive of both ischemic and bleeding events. Because these factors did not help identify discordant bleeding and ischemic risk, they were not included in the predictive score.
On the other hand, certain variables uniquely predicted either bleeding risk or anti-ischemic benefit: advanced age was predictive of increased bleeding only, whereas presentation with myocardial infarction, history of CHF, and prior PCI were predictive of myocardial infarction or stent thrombosis but not bleeding. Deaths not preceded by myocardial infarction or stent thrombosis were not considered in the creation of the prediction model because such deaths may not be directly modified by dual antiplatelet therapy. This may explain why age was not a significant predictor of the composite ischemia end point.
The median predictive score was 2, and patients with a score of 2 or higher (the high score group) had a clinically meaningful reduction in ischemic events (number needed to treat to benefit [NNTB], 34) with a smaller effect on bleeding events when randomized to continued thienopyridine (number needed to treat to harm [NNTH], 272), whereas those with scores less than 2 (the low score group) had a larger increase in bleeding events (NNTH, 64) and a smaller reduction in ischemic events (NNTB, 153). Nonetheless, scores ranging from −2 to 10 likely define a continuous gradient of risk and benefit. The model used to derive the point values for variables required an assumption that bleeding and ischemic events were of equal weight. However, examination of the results stratified by score quartile allows assessment of different score cutoffs with varied weighting of bleeding and ischemic events, as well as examination of the association of the score with other relevant end points, including bleeding events not classified as moderate or severe. The ischemic and bleeding events as defined in this analysis may not have an equivalent effect on patient outcomes, including mortality, and the results may have been different had other ischemic and bleeding end points been chosen.
Although the statistical test for interaction did not show a difference in the effect of continuation of long-term dual antiplatelet therapy on mortality in high vs low score groups, it is of interest that the numerical difference in all-cause mortality was concentrated among patients in the low score group. After analyzing the results of 12 randomized trials enrolling 56 799 patients, the US Food and Drug Administration recently concluded that there was no evidence of an increase in either cancer or mortality with extended thienopyridine treatment.30 Whether different subgroups of patients may in fact have greater mortality with continuation of long-term dual antiplatelet therapy has been suggested31 and may be a topic of future inquiry.
Paclitaxel-eluting stents were found to be associated with higher risk of myocardial infarction or stent thrombosis. Although these results are consistent with those of other studies,32 stent type was not randomized in the DAPT Study. As these stents are rarely used, the use of this predictive score going forward is unlikely to utilize this variable. In addition, among the stents used in the DAPT Study, only EES are widely used today. Among the EES subgroup (n = 4703), tests for interaction comparing treatment effect among high vs low score groups were not significant. However, interaction testing is generally underpowered in clinical trials and more underpowered when performed within a subset of patients. Approximately half of the risk reduction for myocardial infarction attributed to continued thienopyridine therapy in the DAPT Study was not attributable to stent thrombosis,1 and bleeding risk should not be influenced by stent type. Therefore, the ability of the prediction rule to stratify patient risks for myocardial infarction unrelated to stent thrombosis and for bleeding should not vary by stent type.
The incorporation of more variables into the individual bleeding and ischemia models may have improved discrimination, at the expense of parsimony. In addition, the estimation of risks based on the use of the separate ischemic and bleeding model coefficients rather than use of the simplified score could improve the ability to predict such events, and provide the opportunity for clinicians to identify patients with concordantly high ischemic and bleeding risks, in addition to those with discordant risks (Estimation of Ischemic and Bleeding Risk in the eAppendix in the Supplement).
Although the development of the score was prespecified, the analysis should be considered exploratory. Thus, use of this prediction score should be cautious until further validation is performed, and optimal clinical and procedural care to reduce overall bleeding and ischemic risks should be practiced independent of a patient’s score. Preexisting anemia, prior bleeding, and granular measures of atherosclerosis extent and severity were not available and may in part explain the modest discrimination of the ischemia and bleeding prediction. In addition, patients receiving ticagrelor or other antiplatelet combinations could have a different risk-benefit relationship. The score is relevant to patients with characteristics similar to those enrolled in the DAPT Study, and its generalizability to other patient populations not studied in the trial may be limited. Although BMS-treated patients were included, the score is not applicable to patients for whom a BMS is selected due to high risk of bleeding or nonadherence. The end points considered in developing the score, although well defined and adjudicated, are heterogeneous in severity. Although the PROTECT trial served as an external population for validation, it was not a randomized trial of dual antiplatelet therapy duration, and the observed duration of therapy was likely influenced by patient risk factors. Therefore, these data could only be used to evaluate whether the score stratified patient ischemic or bleeding risk, and not actual benefit or harm with long-term dual antiplatelet therapy. These results would ideally be replicated in a similarly designed, large randomized trial of different durations of dual antiplatelet therapy among PCI patients. Use of the clinical score has not been demonstrated to improve patient outcomes.
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.
Corresponding Authors: Robert W. Yeh, MD, MSc, Smith Center for Outcomes Research in Cardiology, Beth Israel Deaconess Medical Center, 185 Pilgrim Rd, Boston, MA 02215 (firstname.lastname@example.org); and Laura Mauri, MD, MSc, Division of Cardiovascular Medicine, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115 (email@example.com).
Published Online: March 29, 2016. doi:10.1001/jama.2016.3775.
Correction: This article was corrected for an update to the conflict of interest disclosures for Drs Yeh and Mauri and corrected for errors in the Supplement and the bar graph of Figure 2 on May 24, 2016.
Author Contributions: Drs Yeh and Mauri had full access to all of 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: Yeh, Secemsky, Kereiakes, Cohen, Mauri.
Acquisition, analysis, or interpretation of data: Yeh, Secemsky, Kereiakes, Normand, Gershlick, Spertus, Steg, Cutlip, Rinaldi, Camenzind, Wijns, Apruzzese, Song, Massaro, Mauri.
Drafting of the manuscript: Yeh, Secemsky, Kereiakes, Apruzzese, Mauri.
Critical revision of the manuscript for important intellectual content: Kereiakes, Normand, Gershlick, Cohen, Spertus, Steg, Cutlip, Rinaldi, Camenzind, Wijns, Song, Massaro.
Statistical analysis: Yeh, Secemsky, Kereiakes, Normand, Apruzzese, Song, Massaro, Mauri.
Obtained funding: Yeh, Normand, Mauri.
Administrative, technical, or material support: Cutlip, Mauri.
Study supervision: Yeh, Kereiakes, Mauri.
Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Yeh reports receiving personal fees from Abbott Vascular, Boston Scientific, and Merck; research salary from Harvard Clinical Research Institute. Dr Kereiakes reports receiving personal fees from Abbott Vascular, Boston Scientific, and sanofi-aventis. Dr Gershlick reports receiving personal fees from AstraZeneca, Eli Lilly, Daiichi-Sankyo, Medtronic, Abbott Vascular, and Boston Scientific. Dr Cohen reports receiving grant funding and personal fees from Abbott Vascular, Medtronic, AstraZeneca, and Eli Lilly, and grant funding from Daiichi-Sankyo. Dr Spertus reports ownership of equity interest in Health Outcomes Sciences and having a patent for ePRISM. Dr Steg reports receiving personal fees from Amarin, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, GlaxoSmithKline, Eli Lilly, Merck Sharpe and Dohme, Novartis, Regeneron, Janssen, Pfizer, Regado, and Roche; grants and personal fees from Sanofi and Servier; personal fees and nonfinancial support from The Medicines Company; and serving on the steering committee for CSL Behring. Dr Cutlip reports receiving grant funding from Medtronic and Boston Scientific and Celonova. Dr Rinaldi reports serving on the advisory boards of Abbott Vascular, Boston Scientific, and Volcano. Dr Wijns reports receiving grant funding from Medtronic, Boston Scientific, Terumo, MiCell, Microport, St Jude Medical, Stentys, AstraZeneca, Biotronik, and Abbott Vascular; and serving as a nonexecutive board member and shareholder of Argonauts Partners, Celyad, and Genae. Dr Massaro reports receiving personal fees from Harvard Clinical Research Institute. Dr Mauri reports receiving grant funding from Abbott Vascular, Boston Scientific, Cordis, Bristol-Myers Squibb, and Daiichi Sankyo; grants and personal fees from Medtronic, Eli Lilly, sanofi-aventis, Boehringer Ingelheim, Biotronik; personal fees from Amgen, Recor, AstraZeneca, and St Jude Medical. No other disclosures were reported.
Funder/Sponsor: This article was sponsored by Harvard Clinical Research Institute, grant K23 HL 118138 from the National Heart, Lung, and Blood Institute (Dr Yeh); grant 1RO1FD003870-01 from the US Department of Health and Human Services. The 8 stent and pharmaceutical manufacturers who contributed to the funding of the 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 funded the DAPT Study were participating members in the design of the trial, the conduct of the study, and in the collection of the data. Specifically, the DAPT Study included patients contributed from each of 4 industry-designed and conducted postmarket studies. The funders had no role in the management, analysis, and interpretation of the data. 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 study design or the decision to submit the manuscript for publication, but were given the opportunity to review and approve the manuscript prior to submission.
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 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 (Hopital Saint Louis), Erwan Bressollette (Nouvelle Clinique Nantaise), Emmanuel Teiger (CHU Henri Mondor), P. Gabriel Steg (Hospital 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 (Vivantes-Humboldt 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).
Additional Contributions: We thank Joanna Suomi, MSC (Harvard Clinical Research Institute), for her assistance with the preparation of this article. She was compensated for her contribution.