Sex Differences Among Patients With High Risk Receiving Ticagrelor With or Without Aspirin After Percutaneous Coronary Intervention: A Subgroup Analysis of the TWILIGHT Randomized Clinical Trial

Key Points

Question  Is sex associated with differences in treatment outcomes for early aspirin withdrawal with continuation of ticagrelor after percutaneous coronary intervention (PCI) in patients at high risk for bleeding or ischemic events?

Findings  In this prespecified subgroup analysis of a randomized clinical trial including 7119 patients, women had a higher bleeding risk compared with men, which was mostly attributable to baseline differences, whereas ischemic events were similar between sexes. In this high-risk PCI population, benefits of early aspirin withdrawal with continuation of ticagrelor were generally comparable in women and men.

Meaning  These findings have important implications for antiplatelet regimens after PCI and should motivate dedicated studies to further explore the benefits of this approach in women.

Importance  Shortened dual antiplatelet therapy followed by potent P2Y12 receptor inhibitor monotherapy reduces bleeding without increasing ischemic events after percutaneous coronary intervention (PCI).

Objective  To explore sex differences and evaluate the association of sex with outcomes among patients treated with ticagrelor monotherapy vs ticagrelor plus aspirin.

Design, Setting, and Participants  This was a prespecified secondary analysis of TWILIGHT, an investigator-initiated, placebo-controlled randomized clinical trial conducted at 187 sites across 11 countries. Study participants included patients who underwent successful PCI with drug-eluting stents, were planned for discharge with ticagrelor plus aspirin, and who had at least 1 clinical and at least 1 angiographic feature associated with high risk of ischemic or bleeding events. Data were analyzed from May to July 2020.

Interventions  At 3 months after PCI, patients adherent to ticagrelor and aspirin without major adverse event were randomized to either aspirin or placebo for an additional 12 months along with ticagrelor.

Main Outcomes and Measures  The primary end point was Bleeding Academic Research Consortium (BARC) type 2, 3, or 5 bleeding at 12 months after randomization. The primary ischemic end point was a composite of death, myocardial infarction, or stroke.

Results  Of 9006 enrolled patients, 7119 underwent randomization (mean [SD] age, 63.9 [10.2] years; 5421 [76.1%] men). Women were older (mean [SD] age, 65.5 [9.6] years in women vs 63.4 [10.3] years in men) with higher prevalence of chronic kidney disease (347 women [21.2%] vs 764 men [14.7%]). The primary bleeding end point occurred more often in women than men (hazard ratio [HR], 1.32; 95% CI, 1.06-1.64; P = .01). After multivariate adjustment, incremental bleeding risk associated with female sex was no longer significant (adjusted HR, 1.20; 95% CI, 0.95-1.52; P = .12). Ischemic end points were similar between sexes. Ticagrelor plus placebo vs ticagrelor plus aspirin was associated with lower risk of BARC type 2, 3, or 5 bleeding in women (adjusted HR, 0.62; 95% CI, 0.42-0.92; P = .02) and men (adjusted HR, 0.57; 95% CI, 0.44-0.73; P < .001; P for interaction = .69). Ischemic end points were similar between treatment groups in both sexes.

Conclusions and Relevance  These findings suggest that the higher bleeding risk in women compared with men was mostly attributable to baseline differences, whereas ischemic events were similar between sexes. In this high-risk PCI population, the benefits of early aspirin withdrawal with continuation of ticagrelor were generally comparable in women and men.

Trial Registration  ClinicalTrials.gov Identifier: NCT02270242

Prolonged dual antiplatelet therapy (DAPT) with a P2Y12 receptor inhibitor and aspirin has been proven to decrease the risk of ischemic events after percutaneous coronary intervention (PCI) but is also associated with an increase in bleeding.¹ Recently, the Ticagrelor With Aspirin or Alone in High-Risk Patients After Coronary Intervention (TWILIGHT) study² has shown that monotherapy with a potent P2Y12 inhibitor after a short period of DAPT compared with continued DAPT leads to reduced bleeding without an increase in ischemic events among patients at high risk for bleeding or ischemic events after PCI. Whether these effects vary in relation to sex remains unknown. This distinction is clinically relevant as women have an increased risk for bleeding after PCI compared with men.^3,4 While these associations may reflect differences in baseline risk factors (eg, older age, kidney impairment) that are more common in women, other reports suggest an independent biological association of female sex with hemorrhagic risk. Accordingly, we performed a prespecified secondary analysis to explore sex differences in the TWILIGHT population and to evaluate the association of sex with outcomes among patients treated with ticagrelor monotherapy vs ticagrelor plus aspirin.

The TWILIGHT trial was a placebo-controlled randomized clinical trial conducted in 187 sites across 11 countries. The trial rationale, design, and main findings have been reported previously.^2,5 The Icahn School of Medicine at Mount Sinai designed and sponsored the trial supported by an investigator-initiated grant from AstraZeneca. National regulatory agencies and institutional review boards or ethics committees of participating centers approved the trial protocol (Supplement 1). An independent data safety monitoring board provided external oversight to ensure safety of all trial participants. All patients provided written informed consent prior to participation. The TWILIGHT trial was conducted from July 2015 to July 2019.

To be eligible for enrollment, a patient had to have undergone successful PCI with at least 1 locally approved drug-eluting stent (DES) with a plan for discharge with ticagrelor plus aspirin. In addition, at least 1 clinical and at least 1 angiographic feature for high risk of ischemic or bleeding events were required. The clinical features for high risk included age 65 years or older, female sex, troponin-positive acute coronary syndrome (ACS), established vascular disease, diabetes treated with medication, and chronic kidney dysfunction (CKD; defined as an estimated glomerular filtration rate <60 mL/min/1.73 m² or creatinine clearance <60 mL/min). The angiographic features for high risk included multivessel coronary artery disease (CAD), total stent length greater than 30 mm, treatment of a thrombotic target lesion, a bifurcation lesion treated requiring at least 2 stents, an obstructive left main or proximal left anterior descending coronary artery lesion, and treatment of a calcified target lesion with atherectomy. Key exclusion criteria included presentation with ST-segment elevation myocardial infarction, cardiogenic shock, ongoing long-term treatment with oral anticoagulants, or contraindication to aspirin or ticagrelor.

After the index PCI, all patients received open-label ticagrelor (90 mg twice daily) and enteric-coated aspirin (81 to 100 mg daily). At 3 months after hospital discharge, patients who had been adherent to treatment and had not experienced a major bleeding event (Bleeding Academic Research Consortium [BARC] type 3b or higher) or an ischemic event (stroke, myocardial infarction [MI], or coronary revascularization) were eligible to be randomized to either aspirin or matching placebo for an additional 12 months along with continuation of open-label ticagrelor. Follow-up was performed by telephone at 1 month after randomization and in person at 6 and 12 months after randomization. After 12 months of protocol-mandated therapy, patients were switched to a standard-of-care antiplatelet regimen at the discretion of their treating physician, followed by a final telephone follow-up 3 months later.

The primary end point was the first occurrence of BARC type 2, 3, or 5 bleeding between randomization and 12 months after randomization. The primary ischemic end point was a composite of death from any cause, nonfatal MI, or nonfatal stroke. Secondary bleeding end points included BARC type 3 or 5 bleeding⁶; Thrombolysis in Myocardial Infarction (TIMI) major bleeding⁷; Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) moderate, severe, or life-threatening bleeding⁸; or major bleeding as defined by the International Society of Thrombosis or Hemostasis (ISTH).⁹ Other ischemic end points included cardiovascular death, MI, ischemic stroke, and definite or probable stent thrombosis. MI was defined according to the third universal definition,¹⁰ and revascularization and stent thrombosis were classified according to the Academic Research Consortium.¹¹ All clinical events were adjudicated by an independent external committee, the members of which were unaware of the treatment group assignments.

Baseline clinical and procedural characteristics were summarized by sex as well as by sex and randomized treatment assignment using means and SDs for continuous variables and numbers and frequencies for categorical variables. The cumulative incidences of the primary and secondary end points were estimated by the Kaplan-Meier method. Patients without a primary end point between randomization and 1 year were censored at the time of death, last known contact, or 365 days, whichever came first. Hazard ratios (HRs) and 95% CIs were generated with Cox proportional-hazards models. Associations of sex with bleeding and ischemic outcomes were examined using Cox regression. Models were adjusted for variables displaying baseline differences or other known biological confounders, including age (years), non-White race (including Black, Asian, or other), region of enrollment, insulin-treated diabetes, CKD, hypercholesteremia, anemia, smoking status, hypertension, previous MI, previous PCI or previous coronary artery bypass graft, multivessel CAD, indication for PCI, radial artery access, whether a left anterior descending coronary artery lesion was treated, whether left circumflex artery was treated, number of lesions treated, lesion calcification, and minimum stent diameter (millimeters).

Treatment outcomes of ticagrelor monotherapy vs ticagrelor plus aspirin were evaluated by sex, and formal interaction testing using Cox regression was performed to assess for association modification. Bleeding end points were analyzed in the intention-to-treat population (7119 individuals), and ischemic end points were analyzed in the per-protocol population (7039 individuals). Patients who underwent randomization and did not fulfill enrollment criteria, were not eligible for randomization, or who never received protocol-mandated therapy were excluded from the per-protocol analysis (80 participants). P values were 2-sided, and statistical significance was set at P < .05. All analyses were performed using Stata statistical software version 16.0 (StataCorp). Data were analyzed from May to July 2020.

A total of 9006 patients were enrolled, of whom 7119 underwent randomization (eFigure in Supplement 2). Of randomized patients, 1698 (23.9%) were women, and the mean (SD) age was 63.9 (10.2) years. Baseline clinical and procedural characteristics are reported in Table 1. Women, compared with men, were older (mean [SD] age, 65.5 [9.6] years vs 63.4 [10.3] years) and more likely to have a race other than White with a higher prevalence of insulin-dependent diabetes, CKD (347 women [21.2%] vs 764 men [14.7%]), anemia, and hypertension. Conversely, women were less likely to be current smokers and to have a history of MI, PCI, or coronary artery bypass graft surgery (Table 1). Women were more likely than men to have undergone PCI for an ACS indication. Compared with men, women were less likely to have multivessel CAD. There were no significant differences with regard to lesion morphology between sexes. However, women had lower total stent length and minimum stent diameter (Table 1).

Baseline clinical and procedural characteristics according to sex and randomized treatment assignment are reported in Table 2. Among men, baseline clinical characteristics were well balanced between treatment groups except for a higher rate of current smoking in men randomized to ticagrelor plus aspirin. Among women, compared with patients randomized to ticagrelor plus placebo, those randomized to ticagrelor plus aspirin were more likely to have insulin-dependent diabetes, CKD, and hypercholesterolemia (Table 2).

The incidences of bleeding end points at 1 year are reported in Figure 1A. The primary end point of BARC type 2, 3, or 5 bleeding occurred more often in women than men (114 women [6.8%] vs 277 men [5.2%]; HR, 1.32; 95% CI, 1.06-1.64; P = .01). Similarly, women experienced higher rates of BARC type 3 or 5 bleeding (34 women [2.0%] vs 69 men [1.3%]; HR, 1.57; 95% CI, 1.04-2.37; P = .03). There were no statistically significant differences between sexes in TIMI major bleeding, GUSTO moderate or severe bleeding, or ISTH major bleeding (Figure 1A). Following multivariate adjustment, the association between female sex and increased bleeding risk was no longer significant (BARC type 2, 3, or 5 bleeding: adjusted HR, 1.20; 95% CI, 0.95-1.52; P = .12).

The rates of ischemic end points at 1 year are reported in Figure 1B. No significant differences between women and men were found in the incidence of the composite of death, MI, or stroke; the composite of cardiovascular death, MI, or ischemic stroke; or the individual end points of all-cause death; cardiovascular death; MI; ischemic stroke; and definite or probable stent thrombosis. After multivariate adjustment, these results were largely unchanged.

Bleeding and ischemic outcomes by sex and randomized treatment assignment are shown in Table 3. Ticagrelor plus placebo vs ticagrelor plus aspirin was associated with lower risk of BARC type 2, 3, or 5 bleeding in women (42 patients [5.0%] vs 72 patients [8.6%]; adjusted HR, 0.62; 95% CI, 0.42-0.92; P = .02) and in men (99 patients [3.7%] vs 178 patients [6.6%]; adjusted HR, 0.57; 95% CI, 0.44-0.73; P < .001) without significant interaction between randomized treatment assignment and sex (P for interaction = .69) (Figure 2A). The strategy of aspirin withdrawal was associated with an absolute risk reduction of 3.6% (95% CI, −6.0% to −1.2%) in the incidence of BARC type 2, 3, or 5 bleeding in women and 2.9% (95% CI, −4.1% to −1.7%) in men. The reductions in TIMI major bleeding were not statistically significant in either sex. The reductions in BARC type 3 or 5 bleeding, GUSTO moderate or severe bleeding, and ISTH major bleeding were consistent for both women and men with no significant interactions between randomized treatment assignment and sex for these end points (Table 3).

The rates of the composite of death, MI, or stroke were similar in the group randomized to ticagrelor plus placebo and the group randomized to ticagrelor plus aspirin in woman (29 patients [3.5%] vs 29 patients [3.5%]; adjusted HR, 1.04, 95% CI, 0.61-1.77; P = .88) and men (106 patients [4.0%] vs 108 patients [4.1%]; adjusted HR, 1.06, 95% CI, 0.80-1.39; P = .69) with no significant interaction between randomized treatment assignment and sex (P for interaction = .95) (Figure 2B). Similar results were found for the other ischemic end points, except for all-cause death, which was similar in both treatment groups in men (31 patients [1.2%] vs 33 patients [1.2%]; adjusted HR, 1.00; 95% CI, 0.61-1.64; P > .99) but lower in women treated with ticagrelor plus placebo vs ticagrelor plus aspirin (3 patients [0.4%] vs 12 patients [1.4%]; adjusted HR, 0.17; 95% CI, 0.04-0.78; P = .02), with significant interaction between randomized treatment assignment and sex (P for interaction = .03). The absolute risk reduction for all-cause death was 1.1% (95% CI, −2.0% to −0.2%) in women and 0.1% (95% CI, −0.7% to 0.5%) in men.

In this prespecified subgroup analysis of the TWILIGHT randomized clinical trial, substantial differences in baseline characteristics were observed between sexes, including significantly older age and a higher prevalence of risk factors for bleeding and ischemic events in women compared with men. Bleeding events occurred more often in women, whereas ischemic risk was similar between sexes. After adjustment for baseline characteristics, the incremental bleeding risk associated with female sex was no longer significant, suggesting excess bleeding risk beyond the immediate periprocedural time period in women was associated with differences in comorbid conditions rather than an independent biological association. Withdrawing aspirin while continuing ticagrelor after 3 months of DAPT in patients at high risk for bleeding or ischemic events after PCI with DES implantation was associated with a reduction in bleeding and preserved ischemic benefits in women and men. A significant interaction between randomized treatment assignment and sex was observed owing to significant reduction of mortality associated with ticagrelor monotherapy vs ticagrelor plus aspirin among women but not men.

Increased bleeding risk in women compared with men after PCI or ACS has been documented previously.^4,12-14 In some studies, the increased risk of bleeding was mostly attributed to known risk factors, such as women’s older age, higher rate of CKD, and lower body mass index. For example, an analysis from the PROMETHEUS study including patients with ACS after PCI treated with clopidogrel and prasugrel found an increased risk of bleeding in women that was attenuated and no longer significant after adjustment for differences in baseline risk.¹² These results are in keeping with our analysis, in which the increased bleeding risk in women was no longer significant after adjustment for age, CKD, anemia, and other differences in baseline risk between sexes. However, with regard to BARC type 3 or 5 bleeding, the risk attenuation was minimal, with a decrease of the HR from 1.57 to 1.49, suggesting additional unknown or unmeasured factors that may contribute to women’s increased risk for serious bleeding. Indeed, in previous studies,^4,13,14 the risk of bleeding after PCI or ACS remained significantly greater in women than men after multivariate adjustment. In contrast, a sex-specific subanalysis of the LEADERS FREE trial is one of the few studies that have not found sex differences in long-term bleeding risk after PCI between individuals with similar risk of BARC types 3 to 5 bleeding even before adjustment for baseline risk factors.¹⁵ The LEADERS FREE trial¹⁶ enrolled only patients at high risk for bleeding, and differences in measured but also unmeasured confounders for bleeding risk between sexes may have been less prominent in this study population compared with others. In addition, DAPT duration was reduced to 1 month after PCI.

To reduce the risk of bleeding after PCI, several studies have been performed to investigate the efficacy and safety of shortening of DAPT by early aspirin withdrawal.^17-20 For example, the SMART-CHOICE¹⁸ and TICO¹⁹ randomized clinical trials reported decreased bleeding and similar ischemic risk with P2Y12 monotherapy after 3 months of DAPT vs 12 months of DAPT, with no interaction between treatment strategy and sex. However, both study populations were of modest size, which limits statistical power, particularly in subgroup analyses. In the large GLOBAL LEADERS trial,²⁰ 23 months of ticagrelor monotherapy after 1 month of DAPT vs 12 months of DAPT followed by 12 months of aspirin monotherapy was associated with a lower risk of bleeding in men but not in women at 1 year, while at 2 years, there was no difference in the efficacy and safety of the 2 antiplatelet strategies between sexes.³ Although these 1-year outcomes may appear to be at odds with those from TWILIGHT, it is important to note that between 1 month and 1 year after PCI, GLOBAL LEADERS²⁰ compared the effects of 2 different antiplatelet agents (ticagrelor vs clopidogrel), as well as aspirin withdrawal, in many patients. In secondary analyses, it appeared that their results were driven by an increased risk of bleeding with ticagrelor monotherapy compared with standard DAPT (clopidogrel plus aspirin) in women with stable CAD, and suggested that potent P2Y12 inhibitors, such as ticagrelor, should be used with caution in women with stable CAD.³ The use of clopidogrel in patients with stable CAD in the comparator group is only 1 of the differences between GLOBAL LEADERS and TWILIGHT that may have contributed to the conflicting results. Other differences pertain to the trial design (open-label vs double-blind), the study population (all comers vs patients with high risk), modes of bleeding ascertainment (site-reported vs adjudicated), and protocol adherence.²

The results from TWILIGHT are consistent with pharmacodynamic effects of the aspirin withdrawal strategy. The TWILIGHT platelet substudy²¹ found that markers sensitive to cyclo-oxygenase-1 blockade, including platelet reactivity in response to arachidonic acid and collagen stimuli, were higher in the absence of aspirin; however, the antithrombotic potency of ticagrelor monotherapy was similar to that of ticagrelor plus aspirin with respect to ex vivo blood thrombogenicity. Although a sensitivity analysis to control for sex was performed and showed similar results,²¹ further investigations are needed to investigate sex-specific aspects of blood thrombogenicity and platelet reactivity associated with shortening of DAPT by early aspirin withdrawal.

Of note in the TWILIGHT study, rates of all-cause mortality were similar in men regardless of treatment assignment, but lower in women randomized to ticagrelor plus placebo vs ticagrelor plus aspirin with a significant interaction between randomized treatment assignment and sex. Although this differential mortality benefit associated with aspirin withdrawal in women compared with men cannot be considered definite, it may deserve some consideration. One possible explanation is that avoidance of bleeding may lead to a greater mortality benefit in women vs men. Although the association of post-PCI bleeding with mortality is well documented,^22-24 data on the impact of sex on this association are limited and conflicting. While a post hoc analysis from the PARIS registry did not find any sex differences in the mortality risk associated with actionable bleeding after PCI,²⁵ an analysis from the Blue Cross Blue Shield of Michigan Cardiovascular Consortium registry suggested that women had greater in-hospital mortality associated with bleeding compared with men²⁶. Conversely, an analysis from the SWEDEHART registry in patients hospitalized with MI found increased 1-year mortality associated with in-hospital bleeding in men vs women.²⁷ Similar results were reported in a subanalysis of the EARLY-ACS trial, in which the risk of 30-day mortality associated with bleeding was higher in men than women.²⁸ Further research is needed to investigate sex-specific aspects in bleeding-associated mortality risk. Notwithstanding the possibility of a difference in relative benefit by sex, even a similar relative risk reduction for bleeding, coupled with the higher rate of bleeding in women compared with men, would be expected to magnify the absolute benefit of aspirin withdrawal in women. Indeed, in TWILIGHT, the absolute risk reduction for BARC type 2, 3, or 5 bleeding was greater in women compared with men. This finding is reinforced by the suggestion of a potential late mortality benefit in women. Taken together, the results of this analysis suggest that strong consideration should be given to early withdrawal of aspirin in women after PCI, especially if they are being treated with ticagrelor-based DAPT.

This study has some limitations. Although this subgroup analysis was prespecified, our findings should be considered hypothesis-generating only and require confirmation in future studies. Randomization was not stratified by sex, and we did not account for multiplicity, thereby increasing the chance for a type I error. The female subgroup was modest in size, and there were substantial differences in baseline risk between sexes but also some imbalances in patient characteristics between sex-specific treatment groups, including insulin-dependent diabetes and CKD. Despite multivariate adjustment for baseline differences, residual confounding cannot be excluded. Neither of the sex-specific subgroups was individually powered to draw definitive conclusions on the effect of ticagrelor monotherapy vs ticagrelor plus aspirin on the bleeding and ischemic end points. Furthermore, our findings are specific to a PCI population at high risk for bleeding or ischemic events and may not apply to the broad population of patients undergoing PCI. Additionally, our analyses considered only patients who tolerated an initial 3 months of DAPT with ticagrelor plus aspirin without any major adverse events.

In this prespecified subgroup analysis of the TWILIGHT randomized clinical trial, bleeding events after PCI occurred more often in women, whereas ischemic risk was similar between sexes. After adjustment for baseline characteristics, the incremental bleeding risk associated with female sex was no longer significant. In this high-risk PCI population, the benefits of early aspirin withdrawal with continuation of ticagrelor were generally comparable in women and men. These findings have important implications for antiplatelet regimens after PCI and should motivate dedicated studies to further explore the benefits of early aspirin withdrawal in women.

Accepted for Publication: April 1, 2021.

Published Online: May 15, 2021. doi:10.1001/jamacardio.2021.1720

Corresponding Author: Roxana Mehran, MD, The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, PO Box 1030, New York, NY 10029 (roxana.mehran@mountsinai.org).

Author Contributions: Dr Mehran had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Vogel, Baber, Sartori, Kornowski, Krucoff, Kunadian, Moliterno, Mehran.

Acquisition, analysis, or interpretation of data: Vogel, Baber, Cohen, Sartori, Sharma, Angiolillo, Farhan, Goel, Zhang, Briguori, Collier, Dangas, Dudek, Escaned, Gil, Han, Kaul, Krucoff, Kunadian, Mehta, Moliterno, Ohman, Sardella, Witzenbichler, Gibson, Pocock, Huber, Mehran.

Drafting of the manuscript: Vogel, Baber, Kunadian, Sardella.

Critical revision of the manuscript for important intellectual content: Vogel, Baber, Cohen, Sartori, Sharma, Angiolillo, Farhan, Goel, Zhang, Briguori, Collier, Dangas, Dudek, Escaned, Gil, Han, Kaul, Kornowski, Krucoff, Kunadian, Mehta, Moliterno, Ohman, Witzenbichler, Gibson, Pocock, Huber, Mehran.

Statistical analysis: Baber, Sartori, Zhang, Collier, Pocock.

Administrative, technical, or material support: Farhan, Goel, Moliterno, Mehran.

Supervision: Baber, Sartori, Sharma, Briguori, Dangas, Ohman, Huber, Mehran.

Conflict of Interest Disclosures: Dr Baber reported receiving personal fees from Amgen, AstraZeneca, and Boston Scientific during the conduct of the study. Dr Cohen reported receiving grants and personal fees from AstraZeneca, Medtronic, and Abbott Vascular and grants from Boston Scientific outside the submitted work. Dr Sharma reported receiving personal fees from Abbott Vascular, Boston Scientific, and Cardiovascular Systems and serving on an advisory board for Boston Scientific outside the submitted work. Dr Angiolillo reported receiving grants and personal fees from Abbott, Amgen, Aralez, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Bristol Myers Squibb, CeloNova, Chiesi, Daiichi-Sankyo, Eli Lilly, Haemonetics, Janssen, Merck, PhaseBio, PLx Pharma, Pfizer, Sanofi, and The Medicines Company; personal fees from St Jude Medical; and grants (paid to his institution) from Amgen, AstraZeneca, Bayer, Biosensors, CeloNova, CSL Behring, Daiichi-Sankyo, Eisai, Eli Lilly, Gilead, Idorsia, Janssen, Matsutani Chemical Industry, Merck, Novartis, Osprey Medical, Renal Guard Solutions, and the Scott R. MacKenzie Foundation. Dr Briguori reported receiving grants from Mount Sinai during the conduct of the study. Dr Collier reported serving on data monitoring committees sponsored by AstraZeneca, Boston Scientific, Daiichi-Sankyo, Devax, Infraredx, Medtronic, Pfizer, and Zoll. Dr Dangas reported receiving grants from AstraZeneca, personal fees from AstraZeneca and Biosensors, and owning stock in Medtronic outside the submitted work. Dr Escaned reported receiving personal fees from Abbott, Philips, Boston Scientific, Medtronic, Abiomed, Terumo, and Biosensors. Dr Krucoff reported receiving grants and personal fees from Abbott Vascular, Biosensors, Boston Scientific, Celonova, Medtronic, OrbusNeich. Dr Kunadian reports receiving personal fees/honoraria from Bayer, AstraZeneca, Abbott, Amgen, Daichii Sankyo. Dr Mehta reported receiving grants from AstraZeneca during the conduct of the study. Dr Moliterno reported receiving grants from AstraZeneca during the conduct of the study. Dr Ohman reported receiving grants from Chiesi and Portola and personal fees from Cytokinetics, Abiomed, Pfizer, 3D Communications, ACI Clinical, Biotie, Cara Therapeutics, Cardinal Health, Faculty Connection, Imbria, Impulse Medical, Janssen Pharmaceuticals, Medscape, Milestone Pharmaceuticals, XyloCor, and Otsuka outside the submitted work. Dr Witzenbichler reported personal fees from Mount Sinai Hospital during the conduct of the study. Dr Gibson reported receiving grants and personal fees from Angel Medical, Bayer, CSL Behring, Johnson & Johnson, Janssen, AstraZeneca, Portola Pharmaceuticals, personal fees from the Medicines Company, Eli Lilly, Gilead Sciences, Novo Nordisk, WebMD, UpToDate Cardiovascular Medicine, Amarin Pharma, Amgen, Boehringer Ingelheim, Chiesi, Merck, PharmaMar, Sanofi, Somahlution, Verreseon Corporation, Boston Scientific, Impact Bio, MedImmume, Medtelligence, MicroPort, PERT Consortium, and GE Healthcare; owning stock in nference; serving as chief executive officer of Baim Institute, and receiving grants (paid to Baim Institute) from Bristol Myers Squibb. Dr Pocock reported receiving grants and personal fees from AstraZeneca outside the submitted work. Dr Huber reported receiving personal fees from AstraZeneca and Bayer. Dr Mehran reported receiving grants and personal fees (paid to the institution) from Abbott, Abiomed, Bayer, Beth Israel Deaconess, Bristol Myers Squibb, Chiesi, Concept Medical Research, Medtronic, Novartis and DSI Research; grants from Applied Therapeutics, AstraZeneca, Cerecor, CSL Behring, OrbusNeich, and Zoll; personal fees from Boston Scientific, California Institute for Regenerative Medicine, Cine-Med Research, Janssen Scientific Affairs, American College of Cardiology, and WebMD; personal fees paid to the institution from CardiaWave, Duke University, and Idorsia Pharmaceuticals; serving as a consultant or committee or advisory board member for Society for Cardiovascular Angiography and Interventions, the American Medical Association, and Regeneron Pharmaceuticals; and owning stock in ControlRad, Elixir Medical, and STEL outside the submitted work. No other disclosures were reported.

Funding/Support: This work was supported by an investigator-initiated grant from AstraZeneca.

Role of the Funder/Sponsor: The funder 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.

Meeting Presentation: This paper was presented at the Scientific Session of the American College of Cardiology; May 15, 2021; virtual conference.

Data Sharing Statement: See Supplement 3.