Prasugrel Dose De-escalation Therapy After Complex Percutaneous Coronary Intervention in Patients With Acute Coronary Syndrome: A Post Hoc Analysis From the HOST-REDUCE-POLYTECH-ACS Trial

Key Points

Question  Is prasugrel dose de-escalation therapy feasible for patients after acute coronary syndrome (ACS) in complex percutaneous coronary intervention (PCI)?

Findings  In this post hoc analysis of 2271 patients with ACS who were receiving PCI from the HOST-REDUCE-POLYTECH-ACS trial, although complex PCI was associated with an increased risk of ischemic adverse events after ACS, prasugrel dose de-escalation therapy as compared with conventional therapy did not show an increased risk of ischemic adverse events but reduced the risk of minor bleeding at 1 year, albeit with wide 95% CIs.

Meaning  These results suggest that prasugrel dose de-escalation therapy can be a feasible option for appropriate patients with ACS, irrespective of PCI complexity.

Importance  De-escalation of dual-antiplatelet therapy through dose reduction of prasugrel improved net adverse clinical events after acute coronary syndrome (ACS), mainly through the reduction of bleeding without an increase in ischemic outcomes. However, whether such benefits are similarly observed in those receiving complex procedures is unknown.

Objective  To investigate whether the benefits of prasugrel dose de-escalation therapy are maintained in the complex percutaneous coronary intervention (PCI) subgroup.

Design, Setting, and Participants  This was a post hoc analysis of the HOST-REDUCE-POLYTECH-ACS trial, a randomized, open-label, adjudicator-blinded, multicenter trial performed at 35 hospitals in South Korea. Study participants included patients with ACS who were receiving PCI. Data were collected from September 30, 2014, to December 18, 2015, and analyzed from September 17, 2020, to June 15, 2021.

Interventions and Exposures  Patients were randomized to a prasugrel dose de-escalation (5 mg daily) at 1 month post-PCI group or a conventional (10 mg daily) group. Complex PCI was defined as having at least 1 of the following features: 3 or more stents implanted, 3 or more lesions treated, bifurcation PCI, total stent length 60 mm or larger, left main PCI, or heavy calcification.

Main Outcomes and Measures  The main analysis end points were MACE (major adverse cardiac event, a composite of cardiovascular death, nonfatal myocardial infarction, stent thrombosis, and repeat revascularization) at 1 year for ischemic outcomes, and BARC (Bleeding Academic Research Consortium) class 2 or higher bleeding events at 1 year for bleeding outcomes.

Results  Of 2271 patients (mean [SD] age, 58.9 [9.0] years; 2024 [89%] male patients) for whom full procedural data were available, 705 patients received complex PCI, and 1566 patients received noncomplex PCI. Complex PCI was associated with higher rates of ischemic outcomes but not with bleeding outcomes. Prasugrel dose de-escalation did not increase the risk of MACE (hazard ratio [HR], 0.88; 95% CI, 0.47-1.66; P = .70 in complex PCI; HR, 0.81; 95% CI, 0.45-1.46; P = .48 in noncomplex PCI; P for interaction = .84) but decreased BARC class 2 or higher bleeding events (HR, 0.25; 95% CI, 0.10-0.61; P = .002 in complex PCI; HR, 0.62; 95% CI, 0.38-1.00; P = .05 in noncomplex PCI; P for interaction = .08), albeit with wide 95% CIs.

Conclusions and Relevance  In this post hoc analysis of patients with ACS, prasugrel dose de-escalation compared with conventional therapy was not associated with an increased risk of ischemic outcomes but may reduce the risk of minor bleeding events at 1 year, irrespective of PCI complexity.

Trial Registration  ClinicalTrials.gov Identifier: NCT02193971

In patients with acute coronary syndrome (ACS) receiving percutaneous coronary intervention (PCI), a potent P2Y12 inhibitor–based dual antiplatelet therapy (DAPT) is currently recommended as standard therapy.¹ However, the benefits of potent P2Y12 inhibitors on ischemic outcomes come at the cost of increased bleeding risk.^2,3 Considering that bleeding events are associated with a higher risk of mortality, we should not overlook the bleeding risk when deciding on the DAPT strategy.⁴ In a recent randomized trial,⁵ a de-escalation strategy of antiplatelet therapy by reducing the dose of prasugrel at 1 month post-PCI reduced net adverse clinical outcomes compared with maintaining the conventional dose of prasugrel. The benefit was driven by a significant reduction of bleeding without any increase in ischemic events. However, whether such benefits are similarly observed in those receiving complex PCI is unknown.

Plaque burden and lesion complexity in coronary artery disease lead to procedural complexity and are associated with increased risk of adverse outcomes after PCI.^6,7 Previous studies have reported specific procedural features related to higher risks of short- and long-term thrombotic events after PCI.^8-10 In addition, a pooled analysis of randomized clinical trials demonstrated the benefits of a prolonged duration of DAPT after complex PCI,¹¹ suggesting that patients receiving complex PCI may require a more potent antiplatelet therapy regimen. Thus de-escalation therapy may even increase the risk of ischemic outcomes. We sought to investigate the efficacy and safety of prasugrel dose de-escalation therapy after complex PCI in patients with ACS.

This study was a post hoc analysis of the HOST-REDUCE-POLYTECH-ACS (Harmonizing Optimal Strategy for Treatment of coronary artery diseases-comparison of Reduction of Prasugrel Dose or Polymer Technology in ACS patients) trial, which was a randomized, parallel-group, open-label, adjudicator-blinded, multicenter trial performed at 35 centers in Korea (trial protocol Supplement 1). The HOST-REDUCE-POLYTECH-ACS trial had a 2 × 2 factorial design testing 2 independent hypotheses. The trial explored whether the reduction of prasugrel maintenance dose beyond 1 month post-PCI was noninferior to the maintenance of conventional dose in patients with ACS for net adverse clinical events and whether polymer technology (durable vs biodegradable) would affect patient-oriented clinical outcomes. The main results of the trial have been published.^5,12 The current study is a nonprespecified post hoc analysis of the prasugrel randomization arm. Patients eligible for the trial were patients with ACS with at least 1 culprit coronary lesion in a native coronary artery. Patients who had clinically significant stenosis and underwent PCI were screened to participate in the trial. Major exclusion criteria were hypersensitivity or contraindication to heparin, aspirin, clopidogrel, prasugrel, ticagrelor, contrast media, any major or active bleeding, childbearing potential, life expectancy less than 1 year, and condition that may result in protocol noncompliance. Randomization was performed after the initial coronary angiography and before PCI. Data were collected from September 30, 2014, to December 18, 2014. Patients who did not meet the core indication for full-dose prasugrel were also excluded from the prasugrel randomization process. Exclusion criteria included age 75 years or older, body weight of less than 60 kg, or history of transient ischemic attack or stroke.

All patients were to receive 100 mg daily of aspirin and 10 mg of prasugrel daily for the first month. Then, patients who were randomized to the dose de-escalation group received a reduced dose of prasugrel, 5 mg, while those who were randomized to the conventional group continued to receive prasugrel, 10 mg, daily; DAPT was recommended for at least 1 year after PCI. The study protocol was approved by the institutional review board or ethics committee at each participating center, and all patients provided written informed consent.

Complex PCI was defined as having at least 1 of the following features: 3 or more stents implanted, 3 or more lesions treated, bifurcation PCI, total stent length 60 mm or greater, left main PCI, or heavy calcification.^6-11 Bifurcation PCI was defined as bifurcation PCI requiring 2 stents, and heavy calcification was defined by a qualitative evaluation showing readily identifiable radio-opacities in the vascular wall during angiography.^9,11 The current study investigated the effect of PCI complexity on clinical outcomes in patients who had ACS and evaluated the efficacy and safety of prasugrel dose de-escalation therapy after complex PCI in patients with ACS.

Although the primary outcome of the main trial was net adverse clinical events, a composite of both ischemic and bleeding events,⁵ the current study separately evaluated the effects of prasugrel dose de-escalation on ischemic and bleeding outcomes considering the prognostic effects of complex PCI. The main analysis end points were major adverse cardiac event (MACE, a composite of cardiovascular death, nonfatal myocardial infarction [MI], stent thrombosis, and repeat revascularization) at 1 year for ischemic outcomes and BARC (Bleeding Academic Research Consortium) class 2 or higher bleeding events at 1 year for bleeding outcomes.

Categorical variables were summarized by counts and percentages, with comparisons by the χ² test, while continuous variables were summarized by means and SDs, with comparisons with the t test. The cumulative incidence of each clinical outcome was calculated using Kaplan-Meier estimates at 1 year, and the log-rank test was used to estimate the group differences. Cox proportional hazards regression model was used to calculate the hazard ratio (HR) and 95% CI. The validity of the proportional hazards assumption was tested with Schoenfeld residuals, and Cox proportional hazards models for all clinical outcomes satisfied the proportional hazards assumption. For the comparison of outcomes according to PCI complexity, a multivariate Cox proportional hazards regression model was used to calculate adjusted HR and its 95% CI. The following variables were included for adjustment: age, diabetes, chronic kidney disease, ejection fraction, current smoking, and clinical diagnosis. Formal interaction testing was performed to evaluate the consistency of the effect of prasugrel dose de-escalation compared with conventional therapy between the complex and noncomplex PCI groups. As the prasugrel dose was changed after the first month, landmark analysis at 1 month was performed for sensitivity analysis. All analyses were performed based on the intention-to-treat approach. All P values were 2-sided, and P < .05 was considered statistically significant. The statistical package R, version 4.0.3 (R Foundation for Statistical Computing) was used for statistical analysis.

The study flow is shown in Figure 1. Among a total of 2338 patients successfully randomized to the prasugrel study arm, 2271 patients (mean [SD] age, 58.9 [9.0] years; 2024 [89.1%] male patients) for whom complete procedural data were available were analyzed in this study. A total of 705 patients (31.0%) received complex PCI and 1566 patients (69.0%) received noncomplex PCI (Figure 1; eTable 1 in Supplement 2). Patients who underwent complex PCI were older and had lower left ventricular ejection fraction, higher prevalence of diabetes, and higher prevalence of chronic kidney disease than those who underwent noncomplex PCI. PRECISE-DAPT (PREdicting bleeding Complications In patients undergoing Stent implantation and subsEquent Dual Anti Platelet Therapy) score was higher in the complex PCI group than in the noncomplex PCI group (mean [SD], 14.6 [9.1] vs 12.6 [7.0]; P < .001). ST-segment elevation MI was more frequent in the noncomplex PCI group. More stents were used in complex PCI than in noncomplex PCI.

In the patients who received complex PCI (705 patients), 349 patients were allocated to the prasugrel dose de-escalation group and 356 patients to the conventional group (Figure 1 and Table 1). The de-escalation group had a higher prevalence of diabetes and a lower prevalence of prior revascularization, while the de-escalation group had a higher frequency of ST-segment elevation MI. In those who received noncomplex PCI (1566 patients), 794 patients were allocated to the prasugrel dose de-escalation group and 772 patients to the conventional group (Figure 1 and Table 1). Baseline characteristics were well balanced in the 2 groups, except for the prior history of MI.

Patients who underwent complex PCI showed a higher risk of MACE than those who underwent noncomplex PCI (5.6% vs 2.9%; HR, 2.00; 95% CI, 1.30-3.07; P = .002; adjusted HR, 1.76; 95% CI, 1.12-2.77; P = .01) (Figure 2; eTable 2 in Supplement 2). The difference was mainly driven by a higher risk of repeat revascularization in patients with complex PCI. However, complex PCI was not associated with the risk of bleeding events (BARC class 2 or higher bleeding, HR, 0.97; 95% CI, 0.63-1.49; P = .88; adjusted HR, 0.93; 95% CI, 0.59-1.49; P = .78) (Figure 2; eTable 2 in Supplement 2).

Among the complex PCI features in those receiving complex PCI, 3 or more stents implanted, and 3 or more lesions treated were strongly associated with increased risk of MACE (eFigure 1 and eTable 3 in Supplement 2). Other features showed a trend toward a higher risk of MACE but were not statistically significant. In contrast, there was no association between the individual complex PCI features and the risk of bleeding (eFigure 1 and eTable 3 in Supplement 2).

The effects of prasugrel dose de-escalation on clinical outcomes in complex PCI are presented in Figure 3 and Table 2. There were no statistically significant differences between the prasugrel dose de-escalation and conventional groups in MACE (5.3% vs 6.0%; HR, 0.88; 95% CI, 0.47-1.66; P = .70). The rates of each ischemic outcome were also comparable between the 2 groups. In contrast with the ischemic outcomes, the risk of BARC class 2 or higher bleeding was lower in the prasugrel dose de-escalation group (HR, 0.25; 95% CI, 0.10-0.61; P = .002). Landmark analyses at 1 month also showed consistent results (eFigure 2 in Supplement 2). In noncomplex PCI, the rates of MACE were comparable between the prasugrel dose de-escalation and conventional groups (2.6% vs 3.2%; HR, 0.81; 95% CI, 0.45-1.46; P = .48) (eFigure 3 in Supplement 2; Table 2). Bleeding risk was numerically lower in the prasugrel dose de-escalation group (HR, 0.62; 95% CI, 0.38-1.00; P = .05 for BARC class 2 or higher bleeding) (eFigure 3 in Supplement 2 and Table 2), which was corroborated by a landmark analysis at 1 month showing a lower risk of BARC class 2 or higher bleeding in the prasugrel dose de-escalation group (HR, 0.44; 95% CI, 0.24-0.79; P = .006) (eFigure 4 in Supplement 2). The interactions for the prasugrel dose de-escalation therapy between the complex PCI group and the noncomplex PCI group were not present for ischemic outcomes. However, marginal interaction was present for BARC class 2 or higher bleeding events (P for interaction = .08; Table 2).

The effects of prasugrel dose de-escalation according to each complex PCI feature are presented in eFigure 5 and eTable 4 in Supplement 2. Prasugrel dose de-escalation did not increase the risk of MACE regardless of the individual complex PCI features or the degree of PCI complexity (the number of complex PCI features). For bleeding, prasugrel dose de-escalation showed lower trends of bleeding risk regardless of the individual complex PCI features and the number of complex PCI features.

The current study evaluated the efficacy and safety of prasugrel dose de-escalation therapy after complex PCI in patients with ACS. The major findings were as follows. First, complex PCI as compared with noncomplex PCI in patients with ACS was associated with a higher risk of the ischemic outcome, defined as MACE, mainly driven by a higher risk of repeat revascularization. Second, even with a higher risk of ischemic outcome after complex PCI, prasugrel dose de-escalation therapy was not associated with a significant increase in the risk of MACE compared with conventional therapy. This was consistent regardless of the type and degree of PCI complexity. Fourth, prasugrel dose de-escalation therapy reduced the risk of bleeding compared with conventional therapy in the complex PCI group. These results suggest that prasugrel dose de-escalation could be a reasonable option in appropriate patients with ACS, even after complex PCI if the risk trade-off favors reducing the risk of bleeding.

The HOST-REDUCE-POLYTECH-ACS trial demonstrated that prasugrel dose de-escalation therapy reduced the risk of net adverse clinical outcomes compared with conventional therapy in patients with ACS after PCI.⁵ This result was achieved by reducing the risk of bleeding without increasing the risk of ischemic outcomes. Because the HOST-REDUCE-POLYTECH-ACS trial included relatively lower-risk patients with ACS primarily owing to the exclusion of patients who did not meet the core indication for full-dose prasugrel, it could be argued that the benefits observed in the main trial may not hold up in higher-ischemic-risk patients. Patients with ACS undergoing complex PCI might be the very patients who may not benefit from a decreased intensity of potent P2Y12 inhibitor therapy because they possess a heightened risk of ischemic events. Previous studies reported that the risk of ischemic outcome was strongly associated with specific procedural features during PCI,^8-10,13 and PCI complexity was related to the risk of adverse outcomes after PCI.^11,14 Consistent with the previous results, the current study demonstrated that the risk of MACE was 2-fold higher in patients with ACS after complex PCI than after noncomplex PCI. This higher risk of ischemic outcome might be explained by the innate nature of patients who were undergoing complex PCI. Patients who underwent complex PCI were older and had lower left ventricular ejection fraction and higher prevalence of diabetes and chronic kidney disease than those who underwent noncomplex PCI. These features are associated with a more extensive disease burden and lesion complexity,^15-18 leading to more stents used in complex PCI, platelet activation, and ischemic outcomes.^8,11

Consistent with the results of the HOST-REDUCE-POLYTECH-ACS trial, we found that in patients with ACS, prasugrel dose de-escalation compared with conventional therapy was not associated with an increased risk of ischemic outcomes but may reduce the risk of minor bleeding events at 1 year, irrespective of PCI complexity. These results were corroborated by similar findings in a landmark analysis at 1 month, which excluded the period of using the full dose of prasugrel in both prasugrel dose de-escalation and conventional groups. What was even more reassuring was the fact that the ischemic event rates were numerically lower in the prasugrel dose de-escalation group than in the conventional group among patients who underwent complex PCI. The neutral effects on ischemic outcomes were also consistent irrespective of the individual type of complex PCI features and the number of complex PCI features. However, it should be noted that the current analysis was underpowered to draw any definitive conclusion, and considering the wide range of 95% CIs of ischemic outcomes, the present results should be taken as only hypothesis generating. These findings were somewhat different from a previous study that reported the benefits of longer-term DAPT on ischemic outcomes in patients receiving complex PCI and that the effects were proportional to the number of complex PCI features.¹¹ There may be several explanations for these differences. First, although complex PCI has a higher risk of ischemic outcomes, prasugrel dose de-escalation therapy might be enough to prevent stent-related events in patients with ACS. The superior efficacy and safety of contemporary stents compared with first-generation drug-eluting stent or bare-metal stent might be associated with these results.^19,20 Second, 1 month of intensive antiplatelet therapy can be more crucial for the recovery from balloon-induced injury or dissection and endothelization of stents, thereby stabilizing the patients. In the early phase after PCI in patients with ACS, the thrombotic risk is prominent because patients with ACS have a thrombotic milieu, and treated lesions have to recover from balloon-induced injury or dissection and be covered by endothelium,^2,3,21 which may be especially important in those receiving complex PCI. The current study maintained the conventional dose of prasugrel, 10 mg, daily during the first month in both groups, which may have been enough to stabilize treated lesions in both groups. Third, the duration of DAPT can be more important than the potency of DAPT in the setting of ACS. Because most of the patients maintained DAPT for 1 year in this study, this maintenance can be a sufficient condition to prevent the ischemic outcome, as previous studies have reported.^11,14

Prasugrel dose de-escalation reduced the risk of bleeding in the current study. This was not affected by the individual complex PCI features or the degree of PCI complexity. Considering that the bleeding events are associated with a 7-fold higher risk of mortality, we should not overlook the risk of bleeding when deciding the intensity of DAPT therapy.²² Although the reduced bleeding risk in the current study was mainly driven by minor bleeding (BARC class 2), the prognostic importance and effect of minor bleeding on mortality have been reported in a previous study.²³ The effect of prasugrel dose de-escalation on reducing bleeding risk showed marginal interaction (the risk of BARC class 2 or higher: HR, 0.25; 95% CI, 0.10-0.61; P = .002 in complex PCI; HR, 0.62; 95% CI, 0.38-1.00; P = .05 in noncomplex PCI; P for interaction=.08) between the complex PCI than noncomplex PCI groups in this study. Because PCI complexity was not associated with the risk of bleeding, this may be owing to the fact that patients who may be more sensitive to reduction of bleeding risk were enrolled in the complex PCI group. Although we excluded older patients (owing to the core indications of prasugrel), patients with complex PCI were older, had a higher prevalence of chronic kidney disease, and had a higher PRECISE-DAPT score than those with noncomplex PCI.²⁴ The current results extend the previous trial findings by demonstrating consistent findings for prasugrel dose de-escalation in patients receiving complex PCI. Overall, the present results suggest that prasugrel dose de-escalation therapy can be a feasible option for appropriate patients with ACS even after complex PCI.

There are several limitations to the current analysis. First, this is a post hoc analysis of the HOST-REDUCE-POLYTECH-ACS trial, and there is a chance for type I error owing to the multiple testing for the results of BARC class 2 or higher bleeding events. However, we believe that the present findings, although hypothesis generating at best, raise important questions on whether prasugrel dose de-escalation therapy can be a feasible option by reducing the risk of bleeding in patients with ACS who are receiving complex PCI. Second, the current analyses were not prespecified, and randomization was not stratified by lesion complexity. The fact that this trial was from an all-Asian population that may be more prone to bleeding and that the clinical benefit with de-escalation was mostly driven by a reduction in minor bleeding leaves the evaluation of ischemic events in this post hoc analysis underpowered with a possibility of type II error. These results are exploratory at best and need to be interpreted with caution. However, the direction of the effect was largely consistent with the main trial outcomes, and ischemic events showed numerically lower rates in the de-escalation group than in the conventional group. Third, this study was from a dedicated East Asian population. There is a possibility that thrombogenicity, P2Y12 receptor inhibition, and bleeding risk may be different according to race and ethnicity.²⁵ Therefore, we should be cautious in extrapolating the current results to non-Asian patients. Finally, the HOST-REDUCE-POLYTECH-ACS trial was an open-label randomized trial where the investigators and patients were not blinded to the medication. Therefore, there is a possibility of patient self-reporting bias. However, the clinical events were adjudicated by an independent committee blinded to the randomization.

In this analysis of a randomized clinical trial of patients with ACS, prasugrel dose de-escalation therapy was not associated with an increased risk of ischemic outcomes but reduced the risk of minor bleeding events irrespective of PCI complexity. These results suggest that prasugrel dose de-escalation therapy could be a feasible option in patients with ACS even after complex PCI. However, further studies are warranted to confirm these results owing to the underpowered nature of the post hoc analyses.

Accepted for Publication: January 3, 2022.

Published Online: March 9, 2022. doi:10.1001/jamacardio.2022.0052

Corresponding Author: Kyung Woo Park, MD, PhD, MBA, Department of Internal Medicine, Cardiovascular Center, Seoul National University Hospital, 101 Daehak-ro, Jongro-gu, Seoul 03080, Republic of Korea (kwparkmd@snu.ac.kr); Kook Jin Chun, MD, PhD, Cardiovascular Center, Pusan National University Yangsan Hospital, 20 Geumo-ro, Mulgeum-eup, Yangsan-si, Gyeongsangnam-do 50612, Republic of Korea (ptca82@gmail.com).

Author Contributions: Prof Park and Dr Hwang 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. Drs Hwang and Lim contributed equally to this work.

Concept and design: Hwang, Lim, Park, Koo, Yong Hoon Kim, Oh, H. Kim.

Acquisition, analysis, or interpretation of data: Hwang, Lim, Park, Chun, Han, Yang, H. Kang, J. Kang, Cho, Hong, S. Kim, Jo, W. Kim, S. Lee, Young Dae Kim, J. Lee.

Drafting of the manuscript: Hwang, Park, Cho, Yong Hoon Kim, S. Lee, Oh.

Critical revision of the manuscript for important intellectual content: Hwang, Lim, Park, Chun, Han, Yang, H. Kang, Koo, J. Kang, Hong, S. Kim, Jo, W. Kim, Young Dae Kim, J. Lee, H. Kim.

Statistical analysis: Hwang, Yang, J. Kang.

Obtained funding: H. Kim.

Administrative, technical, or material support: Lim, Park, Han, Yang, H. Kang, Koo, Cho, Hong, S. Kim, Jo, Yong Hoon Kim, W. Kim, S. Lee, Young Dae Kim, J. Lee, H. Kim.

Supervision: Lim, Park, Chun, Koo, J. Kang, Jo, Oh, J. Lee, H. Kim.

Conflict of Interest Disclosures: Prof Park reported grants from Daiichi Sankyo, Boston Scientific, Terumo, Biotronik, Qualitech Korea, and Dio during the conduct of the study, and speaker's fees from Sanofi, Bristol Myers Squibb, Bayer, Pfizer, Daiichi Sankyo, and AstraZeneca outside the submitted work. Dr H. Kim reported research grants or speaker’s fees from Daiichi Sankyo, Boston Scientific, Terumo, Biotronik, Dio, Medtronic, Abbott Vascular, Edwards Life Science, Amgen, and Behringer Ingelheim outside of the submitted work. No other disclosures were reported.

Funding/Support: This research was supported by Daiichi Sankyo, Boston Scientific, Terumo, Biotronik, Qualitech Korea, and Dio. This post hoc analysis was supported by Abbott Vascular and a research grant of the MR KOPRE study (Research ID: 620112830). This research was partially supported by a grant from Seoul National University Hospital (Research ID: 03-2021-0030).

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Group Information: The HOST-RP-ACS investigators appear in Supplement 3.

Data Sharing Statement: See Supplement 4.