Rationale and design of the PARTHENOPE trial: A two-by-two factorial comparison of polymer-free vs biodegradable-polymer drug-eluting stents and personalized vs standard duration of dual antiplatelet therapy in all-comers undergoing PCI.

BACKGROUND: Over the past few decades, percutaneous coronary intervention (PCI) has undergone significant advancements as a result of the combination of device-based and drug-based therapies. These iterations have led to the development of polymer-free drug-eluting stents. However, there is a scarcity of data regarding their clinical performance. Furthermore, while various risk scores have been proposed to determine the optimal duration of dual antiplatelet therapy (DAPT), none of them have undergone prospective validation within the context of randomized trials. DESIGN: The PARTHENOPE trial is a phase IV, prospective, randomized, multicenter, investigator-initiated, assessor-blind study being conducted at 14 centers in Italy (NCT04135989). It includes 2,107 all-comers patients with minimal exclusion criteria, randomly assigned in a 2-by-2 design to receive either the Cre8 amphilimus-eluting stent or the SYNERGY everolimus-eluting stent, along with either a personalized or standard duration of DAPT. Personalized DAPT duration is determined by the DAPT score, which accounts for both bleeding and ischemic risks. Patients with a DAPT score <2 (indicating higher bleeding than ischemic risk) receive DAPT for 3 or 6 months for chronic or acute coronary syndrome, respectively, while patients with a DAPT score ≥2 (indicating higher ischemic than bleeding risk) receive DAPT for 24 months. Patients in the standard DAPT group receive DAPT for 12 months. The trial aims to establish the noninferiority between stents with respect to a device-oriented composite end point of cardiovascular death, target-vessel myocardial infarction, or clinically-driven target-lesion revascularization at 12 months after PCI. Additionally, the trial aims to demonstrate the superiority of personalized DAPT compared to a standard approach with respect to a net clinical composite of all-cause death, any myocardial infarction, stroke, urgent target-vessel revascularization, or type 2 to 5 bleeding according to the Bleeding Academic Research Consortium criteria at 24-months after PCI. SUMMARY: The PARTHENOPE trial is the largest randomized trial investigating the efficacy and safety of a polymer-free DES with a reservoir technology for drug-release and the first trial evaluating a personalized duration of DAPT based on the DAPT score. The study results will provide novel insights into the optimizing the use of drug-eluting stents and DAPT in patients undergoing PCI.

Independence of clinical events committees: A consensus statement from clinical research organizations.

BACKGROUND: Randomized clinical trials are the gold standard to assess the causal relationship between an intervention and subsequent outcomes, also known as clinical endpoints. In order to limit bias, central clinical events committees (CEC) are established to ensure consistent event reporting across participating centers, as well as complete and accurate ascertainment of endpoints. However, defining independence is challenging. METHODS: This consensus statement was generated by teleconferences and electronic communications among clinical research organizations from the United States, Europe and Australia. This document does not constitute regulatory guidance. RESULTS: An independent CEC is defined when the adjudicators are not primarily involved in designing, funding, sponsoring, organizing, conducting, analyzing or regulating the clinical trial for which they serve as an adjudicator, beyond their role as CEC member. Moreover, independence requires absence of conflicts of interest with the steering committee, sponsor, grant giver, manufacturer, coordinating center, other independent committees, core laboratories, medical monitor, safety physician, participating clinical sites, statistician or data manager, regulatory agencies or authorities, which could influence (or be perceived to influence) a member's objectivity in evaluating trial data. Such conflicts of interest include financial benefits, directing or advisory role (paid or unpaid), decision-making position, as well as being a direct relative. An independent adjudicator has no other role within a clinical trial. CONCLUSIONS: This consensus statement presents a standardized definition of an independent CEC to be considered by clinical research organizations, manufacturers, and investigators. In addition, it provides recommendations on best practices for implementation of an independent CEC.

Prosthetic valve endocarditis after transcatheter aortic valve replacement in low-risk patients.

OBJECTIVES: We sought to report details of the incidence, organisms, clinical course, and outcomes of prosthetic valve endocarditis (PVE) after transcatheter aortic valve replacement (TAVR) in low-risk patients. BACKGROUND: PVE remains a rare but devastating complication of aortic valve replacement. Data regarding PVE after TAVR in low-risk patients are lacking. METHODS: We performed a detailed review of all patients in the low-risk TAVR trials who underwent TAVR from 2016 to 2020 and were adjudicated to have definitive PVE by the independent Clinical Events Committee. RESULTS: We analyzed 396 low-risk patients who underwent TAVR (including 72 with bicuspid valves). PVE occurred in 11 patients at a median 379 days (210, 528) from TAVR. The incidence within the first 30 days was 0%; days 31-365, 1.5%; and after day 365, 2.8%. The most common organism identified was Streptococcus (n = 4/11). Early PVE (≤ 365 days) occurred in five patients, of whom three demonstrated evidence of embolic stroke and two underwent surgical aortic valve re-intervention. Late PVE (> 365 days) occurred in six patients, of whom thee demonstrated evidence of embolic stroke and only one underwent surgical aortic valve re-intervention. Of the six patients with evidence of embolic stroke, two died, two were discharged to rehabilitation, and two were discharged home with home care. CONCLUSIONS: PVE was infrequent following TAVR in low-risk patients but was associated with substantial morbidity and mortality. Embolic stroke complicated the majority of PVE cases, contributing to worse outcomes in these patients. Efforts must be undertaken to minimize PVE in TAVR.

Standardized classification and framework for reporting, interpreting, and analysing medication non-adherence in cardiovascular clinical trials: a consensus report from the Non-adherence Academic Research Consortium (NARC).

Non-adherence has been well recognized for years to be a common issue that significantly impacts clinical outcomes and health care costs. Medication adherence is remarkably low even in the controlled environment of clinical trials where it has potentially complex major implications. Collection of non-adherence data diverge markedly among cardiovascular randomized trials and, even where collected, is rarely incorporated in the statistical analysis to test the consistency of the primary endpoint(s). The imprecision introduced by the inconsistent assessment of non-adherence in clinical trials might confound the estimate of the calculated efficacy of the study drug. Hence, clinical trials may not accurately answer the scientific question posed by regulators, who seek an accurate estimate of the true efficacy and safety of treatment, or the question posed by payers, who want a reliable estimate of the effectiveness of treatment in the marketplace after approval. The Non-adherence Academic Research Consortium is a collaboration among leading academic research organizations, representatives from the U.S. Food and Drug Administration and physician-scientists from the USA and Europe. One in-person meeting was held in Madrid, Spain, culminating in a document describing consensus recommendations for reporting, collecting, and analysing adherence endpoints across clinical trials. The adoption of these recommendations will afford robustness and consistency in the comparative safety and effectiveness evaluation of investigational drugs from early development to post-marketing approval studies. These principles may be useful for regulatory assessment, as well as for monitoring local and regional outcomes to guide quality improvement initiatives.

Standardized End Point Definitions for Coronary Intervention Trials: The Academic Research Consortium-2 Consensus Document.

The Academic Research Consortium (ARC)-2 initiative revisited the clinical and angiographic end point definitions in coronary device trials, proposed in 2007, to make them more suitable for use in clinical trials that include increasingly complex lesion and patient populations and incorporate novel devices such as bioresorbable vascular scaffolds. In addition, recommendations for the incorporation of patient-related outcomes in clinical trials are proposed. Academic Research Consortium-2 is a collaborative effort between academic research organizations in the United States and Europe, device manufacturers, and European, US, and Asian regulatory bodies. Several in-person meetings were held to discuss the changes that have occurred in the device landscape and in clinical trials and regulatory pathways in the last decade. The consensus-based end point definitions in this document are endorsed by the stakeholders of this document and strongly advocated for clinical trial purposes. This Academic Research Consortium-2 document provides further standardization of end point definitions for coronary device trials, incorporating advances in technology and knowledge. Their use will aid interpretation of trial outcomes and comparison among studies, thus facilitating the evaluation of the safety and effectiveness of these devices.

Ticagrelor plus aspirin for 1 month, followed by ticagrelor monotherapy for 23 months vs aspirin plus clopidogrel or ticagrelor for 12 months, followed by aspirin monotherapy for 12 months after implantation of a drug-eluting stent: a multicentre, open-label, randomised superiority trial.

BACKGROUND: We hypothesised that ticagrelor, in combination with aspirin for 1 month, followed by ticagrelor alone, improves outcomes after percutaneous coronary intervention compared with standard antiplatelet regimens. METHODS: GLOBAL LEADERS was a randomised, open-label superiority trial at 130 sites in 18 countries. Patients undergoing percutaneous coronary intervention with a biolimus A9-eluting stent for stable coronary artery disease or acute coronary syndromes were randomly assigned (1:1) to 75-100 mg aspirin daily plus 90 mg ticagrelor twice daily for 1 month, followed by 23 months of ticagrelor monotherapy, or standard dual antiplatelet therapy with 75-100 mg aspirin daily plus either 75 mg clopidogrel daily (for patients with stable coronary artery disease) or 90 mg ticagrelor twice daily (for patients with acute coronary syndromes) for 12 months, followed by aspirin monotherapy for 12 months. Randomisation was concealed, stratified by centre and clinical presentation (stable coronary artery disease vs acute coronary syndrome), and blocked, with randomly varied block sizes of two and four. The primary endpoint at 2 years was a composite of all-cause mortality or non-fatal centrally adjudicated new Q-wave myocardial infarction as assessed by a core lab in a blinded manner. The key secondary safety endpoint was site-reported bleeding assessed according to the Bleeding Academic Research Consortium criteria (grade 3 or 5). Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01813435, and is closed to new participants, with follow-up completed. FINDINGS: Between July 1, 2013, and Nov 9, 2015, 15 968 participants were randomly assigned, 7980 to the experimental group and 7988 to the control group. At 2 years, 304 (3·81%) participants in the experimental group had died or had a non-fatal centrally adjudicated new Q-wave myocardial infarction, compared with 349 (4·37%) participants in the control group (rate ratio 0·87 [95% CI 0·75-1·01]; p=0·073]). There was no evidence for a difference in treatment effects for the primary endpoint across prespecified subgroups of acute coronary syndromes and stable coronary artery disease (p=0·93). Grade 3 or 5 bleeding occurred in 163 participants in the experimental group and 169 in the control group (2·04% vs 2·12%; rate ratio 0·97 [95% CI 0·78-1·20]; p=0·77). INTERPRETATION: Ticagrelor in combination with aspirin for 1 month followed by ticagrelor alone for 23 months was not superior to 12 months of standard dual antiplatelet therapy followed by 12 months of aspirin alone in the prevention of all-cause mortality or new Q-wave myocardial infarction 2 years after percutaneous coronary intervention. FUNDING: AstraZeneca, Biosensors, and The Medicines Company.

Standardized End Point Definitions for Coronary Intervention Trials: The Academic Research Consortium-2 Consensus Document.

The Academic Research Consortium (ARC)-2 initiative revisited the clinical and angiographic end point definitions in coronary device trials, proposed in 2007, to make them more suitable for use in clinical trials that include increasingly complex lesion and patient populations and incorporate novel devices such as bioresorbable vascular scaffolds. In addition, recommendations for the incorporation of patient-related outcomes in clinical trials are proposed. Academic Research Consortium-2 is a collaborative effort between academic research organizations in the United States and Europe, device manufacturers, and European, US, and Asian regulatory bodies. Several in-person meetings were held to discuss the changes that have occurred in the device landscape and in clinical trials and regulatory pathways in the last decade. The consensus-based end point definitions in this document are endorsed by the stakeholders of this document and strongly advocated for clinical trial purposes. This Academic Research Consortium-2 document provides further standardization of end point definitions for coronary device trials, incorporating advances in technology and knowledge. Their use will aid interpretation of trial outcomes and comparison among studies, thus facilitating the evaluation of the safety and effectiveness of these devices.

Proposed Standardized Neurological Endpoints for Cardiovascular Clinical Trials: An Academic Research Consortium Initiative.

Surgical and catheter-based cardiovascular procedures and adjunctive pharmacology have an inherent risk of neurological complications. The current diversity of neurological endpoint definitions and ascertainment methods in clinical trials has led to uncertainties in the neurological risk attributable to cardiovascular procedures and inconsistent evaluation of therapies intended to prevent or mitigate neurological injury. Benefit-risk assessment of such procedures should be on the basis of an evaluation of well-defined neurological outcomes that are ascertained with consistent methods and capture the full spectrum of neurovascular injury and its clinical effect. The Neurologic Academic Research Consortium is an international collaboration intended to establish consensus on the definition, classification, and assessment of neurological endpoints applicable to clinical trials of a broad range of cardiovascular interventions. Systematic application of the proposed definitions and assessments will improve our ability to evaluate the risks of cardiovascular procedures and the safety and effectiveness of preventive therapies.

Randomized placebo controlled trial evaluating the safety and efficacy of single low-dose intracoronary insulin-like growth factor following percutaneous coronary intervention in acute myocardial infarction (RESUS-AMI).

BACKGROUND: Residual and significant postinfarction left ventricular (LV) dysfunction, despite technically successful percutaneous coronary intervention (PCI) for ST-elevation myocardial infarction (STEMI), remains an important clinical issue. In preclinical models, low-dose insulin-like growth factor 1 (IGF1) has potent cytoprotective and positive cardiac remodeling effects. We studied the safety and efficacy of immediate post-PCI low-dose intracoronary IGF1 infusion in STEMI patients. METHODS: Using a double-blind, placebo-controlled, multidose study design, we randomized 47 STEMI patients with significantly reduced (≤40%) LV ejection fraction (LVEF) after successful PCI to single intracoronary infusion of placebo (n = 15), 1.5 ng IGF1 (n = 16), or 15 ng IGF1 (n = 16). All received optimal medical therapy. Safety end points were freedom from hypoglycemia, hypotension, or significant arrhythmias within 1 hour of therapy. The primary efficacy end point was LVEF, and secondary end points were LV volumes, mass, stroke volume, and infarct size at 2-month follow-up, all assessed by magnetic resonance imaging. Treatment effects were estimated by analysis of covariance adjusted for baseline (24 hours) outcome. RESULTS: No significant differences in safety end points occurred between treatment groups out to 30 days (χ2 test, P value = .77). There were no statistically significant differences in baseline (24 hours post STEMI) clinical characteristics or LVEF among groups. LVEF at 2 months, compared to baseline, increased in all groups, with no statistically significant differences related to treatment assignment. However, compared with placebo or 1.5 ng IGF1, treatment with 15 ng IGF1 was associated with a significant improvement in indexed LV end-diastolic volume (P = .018), LV mass (P = .004), and stroke volume (P = .016). Late gadolinium enhancement (±SD) at 2 months was lower in 15 ng IGF1 (34.5 ± 29.6 g) compared to placebo (49.1 ± 19.3 g) or 1.5 ng IGF1 (47.4 ± 22.4 g) treated patients, although the result was not statistically significant (P = .095). CONCLUSIONS: In this pilot trial, low-dose IGF1, given after optimal mechanical reperfusion in STEMI, is safe but does not improve LVEF. However, there is a signal for a dose-dependent benefit on post-MI remodeling that may warrant further study.

Intravascular ultrasound-guided versus angiography-guided percutaneous coronary intervention in unprotected left main coronary artery disease: A systematic review.

BACKGROUND: Significant unprotected left main coronary artery (ULMCA) disease is encountered in approximately 5 % of patients undergoing diagnostic coronary angiography. Intravascular ultrasound (IVUS) overcomes many of the known limitations of angiography and improves outcomes of patients undergoing percutaneous coronary interventions (PCI) in stable or complex coronary artery disease. The aim of this systematic review is to evaluate the evidence on IVUS-guidance versus angiography-guidance in ULMCA PCI, highlighting the chronological frequencies of event rates in line with the maturation of PCI technique and devices over time. METHODS: A comprehensive systematic search in Medline was performed to identify all studies that had assessed the effect of IVUS-guided versus angiography-guided ULMCA PCI on various primary and secondary endpoints. RESULTS: Seventeen studies (2 randomized, 10 non-randomized and 5 meta-analyses) were included in this systematic review. CONCLUSIONS: This systematic review on IVUS-guided versus angiography-guided PCI in patients with significant ULMCA disease strongly supports the hypothesis that IVUS-guided PCI is associated with a significant reduction in major adverse cardiac events composites, all-cause death, cardiac death, myocardial infarction and stent thrombosis. Ongoing, adequately powered trials will contribute significantly to the level of evidence.

Ticagrelor or Clopidogrel Monotherapy vs Dual Antiplatelet Therapy After Percutaneous Coronary Intervention: A Systematic Review and Patient-Level Meta-Analysis.

Importance: Among patients undergoing percutaneous coronary intervention (PCI), it remains unclear whether the treatment efficacy of P2Y12 inhibitor monotherapy after a short course of dual antiplatelet therapy (DAPT) depends on the type of P2Y12 inhibitor. Objective: To assess the risks and benefits of ticagrelor monotherapy or clopidogrel monotherapy compared with standard DAPT after PCI. Data Sources: MEDLINE, Embase, TCTMD, and the European Society of Cardiology website were searched from inception to September 10, 2023, without language restriction. Study Selection: Included studies were randomized clinical trials comparing P2Y12 inhibitor monotherapy with DAPT on adjudicated end points in patients without indication to oral anticoagulation undergoing PCI. Data Extraction and Synthesis: Patient-level data provided by each trial were synthesized into a pooled dataset and analyzed using a 1-step mixed-effects model. The study is reported following the Preferred Reporting Items for Systematic Review and Meta-Analyses of Individual Participant Data. Main Outcomes and Measures: The primary objective was to determine noninferiority of ticagrelor or clopidogrel monotherapy vs DAPT on the composite of death, myocardial infarction (MI), or stroke in the per-protocol analysis with a 1.15 margin for the hazard ratio (HR). Key secondary end points were major bleeding and net adverse clinical events (NACE), including the primary end point and major bleeding. Results: Analyses included 6 randomized trials including 25 960 patients undergoing PCI, of whom 24 394 patients (12 403 patients receiving DAPT; 8292 patients receiving ticagrelor monotherapy; 3654 patients receiving clopidogrel monotherapy; 45 patients receiving prasugrel monotherapy) were retained in the per-protocol analysis. Trials of ticagrelor monotherapy were conducted in Asia, Europe, and North America; trials of clopidogrel monotherapy were all conducted in Asia. Ticagrelor was noninferior to DAPT for the primary end point (HR, 0.89; 95% CI, 0.74-1.06; P for noninferiority = .004), but clopidogrel was not noninferior (HR, 1.37; 95% CI, 1.01-1.87; P for noninferiority > .99), with this finding driven by noncardiovascular death. The risk of major bleeding was lower with both ticagrelor (HR, 0.47; 95% CI, 0.36-0.62; P < .001) and clopidogrel monotherapy (HR, 0.49; 95% CI, 0.30-0.81; P = .006; P for interaction = 0.88). NACE were lower with ticagrelor (HR, 0.74; 95% CI, 0.64-0.86, P < .001) but not with clopidogrel monotherapy (HR, 1.00; 95% CI, 0.78-1.28; P = .99; P for interaction = .04). Conclusions and Relevance: This systematic review and meta-analysis found that ticagrelor monotherapy was noninferior to DAPT for all-cause death, MI, or stroke and superior for major bleeding and NACE. Clopidogrel monotherapy was similarly associated with reduced bleeding but was not noninferior to DAPT for all-cause death, MI, or stroke, largely because of risk observed in 1 trial that exclusively included East Asian patients and a hazard that was driven by an excess of noncardiovascular death.

Stent thrombosis and major clinical events at 3 years after zotarolimus-eluting or sirolimus-eluting coronary stent implantation: a randomised, multicentre, open-label, controlled trial.

BACKGROUND: We sought to compare the long-term safety of two devices with different antiproliferative properties: the Endeavor zotarolimus-eluting stent (E-ZES; Medtronic, Inc) and the Cypher sirolimus-eluting stent (C-SES; Cordis, Johnson & Johnson) in a broad group of patients and lesions. METHODS: Between May 21, 2007 and Dec 22, 2008, we recruited 8791 patients from 36 recruiting countries to participate in this open-label, multicentre, randomised, superiority trial. Eligible patients were those aged 18 years or older undergoing elective, unplanned, or emergency procedures in native coronary arteries. Patients were randomly assigned to either receive E-ZES and C-SES (ratio 1:1). Randomisation was stratified per centre with varying block sizes of four, six, or eight patients, and concealed with a central telephone-based or web-based allocation service. The primary outcome was definite or probable stent thrombosis at 3 years and was analysed by intention to treat. Patients and investigators were aware of treatment assignment. This trial is registered with ClinicalTrials.gov, number NCT00476957. FINDINGS: PROTECT randomised 8791 patients, of whom 8709 provided consent to participate and were eligible: 4357 were allocated to the E-ZES group and 4352 patients to the C-SES group. At 3 years, rates of definite or probable stent thrombosis did not differ between groups (1·4% for E-ZES [predicted: 1·5%] vs 1·8% [predicted: 2·5%] for C-SES; hazard ratio [HR] 0·81, 95% CI 0·58-1·14, p=0·22). Dual antiplatelet therapy was used in 8402 (96%) patients at discharge, 7456 (88%) at 1 year, 3041 (37%) at 2 years, and 2364 (30%) at 3 years. INTERPRETATION: No evidence of superiority of E-ZES compared with C-SES in definite or probable stent thrombosis rates was noted at 3 years. Time analysis suggests a difference in definite or probable stent thrombosis between groups is emerging over time, and a longer follow-up is therefore needed given the clinical relevance of stent thrombosis. FUNDING: Medtronic, Inc.

P2Y12 Inhibitor Monotherapy or Dual Antiplatelet Therapy After Complex Percutaneous Coronary Interventions.

BACKGROUND: It remains unclear whether P2Y12 inhibitor monotherapy preserves ischemic protection while limiting bleeding risk compared with dual antiplatelet therapy (DAPT) after complex percutaneous coronary intervention (PCI). OBJECTIVES: We sought to assess the effects of P2Y12 inhibitor monotherapy after 1-month to 3-month DAPT vs standard DAPT in relation to PCI complexity. METHODS: We pooled patient-level data from randomized controlled trials comparing P2Y12 inhibitor monotherapy and standard DAPT on centrally adjudicated outcomes after coronary revascularization. Complex PCI was defined as any of 6 criteria: 3 vessels treated, ≥3 stents implanted, ≥3 lesions treated, bifurcation with 2 stents implanted, total stent length >60 mm, or chronic total occlusion. The primary efficacy endpoint was all-cause mortality, myocardial infarction, and stroke. The key safety endpoint was Bleeding Academic Research Consortium (BARC) 3 or 5 bleeding. RESULTS: Of 22,941 patients undergoing PCI from 5 trials, 4,685 (20.4%) with complex PCI had higher rates of ischemic events. The primary efficacy endpoint was similar between P2Y12 inhibitor monotherapy and DAPT among patients with complex PCI (HR: 0.87; 95% CI: 0.64-1.19) and noncomplex PCI (HR: 0.91; 95% CI: 0.76-1.09; Pinteraction = 0.770). The treatment effect was consistent across all the components of the complex PCI definition. Compared with DAPT, P2Y12 inhibitor monotherapy consistently reduced BARC 3 or 5 bleeding in complex PCI (HR: 0.51; 95% CI: 0.31-0.84) and noncomplex PCI patients (HR: 0.49; 95% CI: 0.37-0.64; Pinteraction = 0.920). CONCLUSIONS: P2Y12 inhibitor monotherapy after 1-month to 3-month DAPT was associated with similar rates of fatal and ischemic events and lower risk of major bleeding compared with standard DAPT, irrespective of PCI complexity. (PROSPERO [P2Y12 Inhibitor Monotherapy Versus Standard Dual Antiplatelet Therapy After Coronary Revascularization: Individual Patient Data Meta-Analysis of Randomized Trials]; CRD42020176853).

P2Y12 Inhibitor or Aspirin Monotherapy for Secondary Prevention of Coronary Events.

BACKGROUND: Aspirin is the only antiplatelet agent with a Class I recommendation for long-term prevention of cardiovascular events in patients with coronary artery disease (CAD). There is inconsistent evidence on how it compares with alternative antiplatelet agents. OBJECTIVES: This study compared P2Y12 inhibitor monotherapy vs aspirin in patients with CAD. METHODS: We conducted a patient-level meta-analysis of randomized trials comparing P2Y12 inhibitor monotherapy vs aspirin monotherapy for the prevention of cardiovascular events in patients with established CAD. The primary outcome was the composite of cardiovascular death, myocardial infarction, and stroke. Prespecified key secondary outcomes were major bleeding and net adverse clinical events (the composite of the primary outcome and major bleeding). Data were pooled in a 1-step meta-analysis. RESULTS: Patient-level data were obtained from 7 trials. Overall, 24,325 participants were available for analysis, including 12,178 patients assigned to receive P2Y12 inhibitor monotherapy (clopidogrel in 7,545 [62.0%], ticagrelor in 4,633 [38.0%]) and 12,147 assigned to receive aspirin. Risk of the primary outcome was lower with P2Y12 inhibitor monotherapy compared with aspirin over 2 years (HR: 0.88; 95% CI: 0.79-0.97; P = 0.012), mainly owing to less myocardial infarction (HR: 0.77; 95% CI: 0.66-0.90; P < 0.001). Major bleeding was similar (HR: 0.87; 95% CI: 0.70-1.09; P = 0.23) and net adverse clinical events were lower (HR: 0.89; 95% CI: 0.81-0.98; P = 0.020) with P2Y12 inhibitors. The treatment effect was consistent across prespecified subgroups and types of P2Y12 inhibitors. CONCLUSIONS: Given its superior efficacy and similar overall safety, P2Y12 inhibitor monotherapy might be preferred over aspirin monotherapy for long-term secondary prevention in patients with established CAD. (P2Y12 Inhibitor or Aspirin Monotherapy as Secondary Prevention in Patients With Coronary Artery Disease: An Individual Patient Data Meta-Analysis of Randomized Trials [PANTHER collaborative initiative]; CRD42021290774).

Ticagrelor Monotherapy or Dual Antiplatelet Therapy After Drug-Eluting Stent Implantation: Per-Protocol Analysis of the GLOBAL LEADERS Trial.

Background In the GLOBAL LEADERS trial, ticagrelor monotherapy beyond 1 month compared with standard antiplatelet regimens after coronary stent implantation did not improve outcomes at intention-to-treat analysis. Considerable differences in treatment adherence between the experimental and control groups may have affected the intention-to-treat results. In this reanalysis of the GLOBAL LEADERS trial, we compared the experimental and control treatment strategies in a per-protocol analysis of patients who did not deviate from the study protocol. Methods and Results Baseline and postrandomization information were used to classify whether and when patients were deviating from the study protocol. With logistic regressions, we derived time-varying inverse probabilities of nondeviation from protocol to reconstruct the trial population without protocol deviation. The primary end point was a composite of all-cause mortality or nonfatal Q-wave myocardial infarction at 2 years. At 2-year follow-up, 1103 (13.8%) of 7980 patients in the experimental group and 785 (9.8%) of 7988 patients in the control group qualified as protocol deviators. At per-protocol analysis, the rate ratio for the primary end point was 0.88 (95% CI, 0.75-1.03; P=0.10) on the basis of 274 versus 325 events in the experimental versus control group. The rate ratio for the key safety end point of major bleeding was 1.00 (95% CI, 0.79-1.26; P=0.99). The per-protocol and intention-to-treat effect estimates were overall consistent. Conclusions Among patients who complied with the study protocol in the GLOBAL LEADERS trial, ticagrelor plus aspirin for 1 month followed by ticagrelor monotherapy was not superior to 1-year standard dual antiplatelet therapy followed by aspirin alone at 2 years after coronary stenting. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01813435.

PRECISE-DAPT score for bleeding risk prediction in patients on dual or single antiplatelet regimens: insights from the GLOBAL LEADERS and GLASSY.

AIMS: The five-item PRECISE-DAPT, integrating age, haemoglobin, white-blood-cell count, creatinine clearance, and prior bleeding, predicts bleeding risk in patients on dual antiplatelet therapy (DAPT) after stent implantation. We sought to assess whether the bleeding risk prediction offered by the PRECISE-DAPT remains valid among patients receiving ticagrelor monotherapy from 1 month onwards after coronary stenting instead of standard DAPT and having or not having centrally adjudicated bleeding endpoints. METHODS AND RESULTS: The PRECISE-DAPT was calculated in 14 928 and 7134 patients from GLOBAL LEADERS and GLASSY trials, respectively. The ability of the score to predict Bleeding Academic Research Consortium 3 or 5 bleeding was assessed and compared among patients on ticagrelor monotherapy (experimental strategy) or standard DAPT (reference strategy) from 1 month after drug-eluting stent implantation. Bleeding endpoints were investigator-reported or centrally adjudicated in GLOBAL LEADERS and GLASSY, respectively. At 2 years, the c-indexes for the score among patients treated with the experimental or reference strategy were 0.67 [95% confidence interval (CI): 0.63-0.71] vs. 0.63 (95% CI: 0.59-0.67) in GLOBAL LEADERS (P = 0.27), and 0.67 (95% CI: 0.61-0.73) vs. 0.66 (95% CI: 0.61-0.72) in GLASSY (P = 0.88). Decision curve analysis showed net benefit using the PRECISE-DAPT to guide bleeding risk assessment under both treatment strategies. Results were consistent between investigator-reported and adjudicated endpoints and using the simplified four-item PRECISE-DAPT. CONCLUSION: The PRECISE-DAPT offers a prediction model that proved similarly effective to predict clinically relevant bleeding among patients on ticagrelor monotherapy from 1 month after coronary stenting compared with standard DAPT and appears to be unaffected by the presence or absence of adjudicated bleeding endpoints.

Second-generation everolimus-eluting and paclitaxel-eluting stents in real-life practice (COMPARE): a randomised trial.

BACKGROUND: Everolimus-eluting and paclitaxel-eluting stents, compared with bare metal stents, reduced the risk of restenosis in clinical trials with strict inclusion and exclusion criteria. We compared the safety and efficacy of the second-generation everolimus-eluting and paclitaxel-eluting stents in real-life practice. METHODS: We randomly assigned 1800 consecutive patients (aged 18-85 years) undergoing percutaneous coronary intervention at one centre to treatment with everolimus-eluting or paclitaxel-eluting stents. The primary endpoint was a composite of safety and efficacy (all-cause mortality, myocardial infarction, and target vessel revascularisation) within 12 months. Patients were not told which stent they had been allocated. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT01016041. FINDINGS: Follow-up was completed in 1797 patients. The primary endpoint occurred in 56 (6%) of 897 patients in the everolimus-eluting stent group versus 82 (9%) of 903 in the paclitaxel-eluting stent group (relative risk 0.69 [95% CI 0.50-0.95], p value for superiority=0.02). The difference was attributable to a lower rate of stent thrombosis (6 [<1%] vs 23 [3%], 0.26 [0.11-0-64], p=0.002), myocardial infarction (25 [3%] vs 48 [5%], 0.52 [0.33-0.84], p=0.007), and target vessel revascularisation (21 [2%] vs 54 [6%], 0.39 [0.24-0.64], p=0.0001). Cardiac death, non-fatal myocardial infarction, or target lesion revascularisation occurred in 44 [5%] patients in the everolimus-eluting stent group versus 74 [8%] patients in the paclitaxel-eluting stent group, p value for superiority was 0.005. INTERPRETATION: The everolimus-eluting stent is better than the second generation paclitaxel-eluting stent in unselected patients in terms of safety and efficacy. On the basis of our results, we suggest that paclitaxel-eluting stents should no longer be used in everyday clinical practice. FUNDING: Unrestricted grants from Abbott Vascular and Boston Scientific.

Comparison of Investigator-Reported and Clinical Event Committee-Adjudicated Outcome Events in GLASSY.

BACKGROUND: Event adjudication by a clinical event committee (CEC) provides a standardized, independent outcome assessment. However, the added value of CEC to investigators reporting remains debated. GLASSY (GLOBAL LEADERS Adjudication Sub-Study) implemented, in a subset of the open-label, investigator-reported (IR) GLOBAL LEADERS trial, an independent adjudication process of reported and unreported potential outcome events (triggers). We describe metrics of GLASSY feasibility and efficiency, diagnostic accuracy of IR events, and their concordance with corresponding CEC-adjudicated events. METHODS: We report the proportion of myocardial infarction, bleeding, stroke, and stent thrombosis triggers with sufficient evidence for assessment (feasibility) that were adjudicated as outcome events (efficiency), stratified by source (IR or non-IR). Using CEC-adjudicated events as criterion standard, we describe sensitivity, specificity, positive and negative predictive value, and global diagnostic accuracy of IR events. Using Gwet AC coefficient, we examine the concordance between IR- and corresponding CEC-adjudicated triggers. There was sufficient evidence for assessment for 2592 (98.3%) of 2636 triggers. RESULTS: Overall, the adjudicated end point-to-trigger ratio was high and similar between IR- (88%) and non-IR-reported (87%) triggers. The global diagnostic accuracy and concordance between IR-reported and CEC-adjudicated outcome events was 0.70 (95% CI, 0.65-0.74) and 0.54 (95% CI, 0.45-0.62), respectively, for myocardial infarction; 0.77 (95% CI, 0.75-0.79) and 0.71 (95% CI, 0.68-0.74) for bleeding; 0.70 (95% CI, 0.62-0.79) and 0.59 (95% CI, 0.43-0.74) for stroke; 0.59 (95% CI, 0.52-0.66) and 0.39 (95% CI, 0.25-0.53) for stent thrombosis. For IR bleedings, the concordance with the CEC on type of events was generally weak. CONCLUSIONS: Implementing CEC adjudication in a pragmatic open-label trial with IR events is feasible and efficient. Our findings of modest global diagnostic accuracy for IR events and generally weak concordance between investigators and CEC support the role for CEC adjudication in such settings. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03231059.

P2Y12 inhibitor monotherapy or dual antiplatelet therapy after coronary revascularisation: individual patient level meta-analysis of randomised controlled trials.

OBJECTIVE: To assess the risks and benefits of P2Y12 inhibitor monotherapy compared with dual antiplatelet therapy (DAPT) and whether these associations are modified by patients' characteristics. DESIGN: Individual patient level meta-analysis of randomised controlled trials. DATA SOURCES: Searches were conducted in Ovid Medline, Embase, and three websites (www.tctmd.com, www.escardio.org, www.acc.org/cardiosourceplus) from inception to 16 July 2020. The primary authors provided individual participant data. ELIGIBILITY CRITERIA: Randomised controlled trials comparing effects of oral P2Y12 monotherapy and DAPT on centrally adjudicated endpoints after coronary revascularisation in patients without an indication for oral anticoagulation. MAIN OUTCOME MEASURES: The primary outcome was a composite of all cause death, myocardial infarction, and stroke, tested for non-inferiority against a margin of 1.15 for the hazard ratio. The key safety endpoint was Bleeding Academic Research Consortium (BARC) type 3 or type 5 bleeding. RESULTS: The meta-analysis included data from six trials, including 24 096 patients. The primary outcome occurred in 283 (2.95%) patients with P2Y12 inhibitor monotherapy and 315 (3.27%) with DAPT in the per protocol population (hazard ratio 0.93, 95% confidence interval 0.79 to 1.09; P=0.005 for non-inferiority; P=0.38 for superiority; τ2=0.00) and in 303 (2.94%) with P2Y12 inhibitor monotherapy and 338 (3.36%) with DAPT in the intention to treat population (0.90, 0.77 to 1.05; P=0.18 for superiority; τ2=0.00). The treatment effect was consistent across all subgroups, except for sex (P for interaction=0.02), suggesting that P2Y12 inhibitor monotherapy lowers the risk of the primary ischaemic endpoint in women (hazard ratio 0.64, 0.46 to 0.89) but not in men (1.00, 0.83 to 1.19). The risk of bleeding was lower with P2Y12 inhibitor monotherapy than with DAPT (97 (0.89%) v 197 (1.83%); hazard ratio 0.49, 0.39 to 0.63; P<0.001; τ2=0.03), which was consistent across subgroups, except for type of P2Y12 inhibitor (P for interaction=0.02), suggesting greater benefit when a newer P2Y12 inhibitor rather than clopidogrel was part of the DAPT regimen. CONCLUSIONS: P2Y12 inhibitor monotherapy was associated with a similar risk of death, myocardial infarction, or stroke, with evidence that this association may be modified by sex, and a lower bleeding risk compared with DAPT. REGISTRATION: PROSPERO CRD42020176853.

Ticagrelor Monotherapy Versus Dual-Antiplatelet Therapy After PCI: An Individual Patient-Level Meta-Analysis.

OBJECTIVES: The aim of this study was to compare ticagrelor monotherapy with dual-antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) with drug-eluting stents. BACKGROUND: The role of abbreviated DAPT followed by an oral P2Y12 inhibitor after PCI remains uncertain. METHODS: Two randomized trials, including 14,628 patients undergoing PCI, comparing ticagrelor monotherapy with standard DAPT on centrally adjudicated endpoints were identified, and individual patient data were analyzed using 1-step fixed-effect models. The protocol was registered in PROSPERO (CRD42019143120). The primary outcomes were the composite of Bleeding Academic Research Consortium type 3 or 5 bleeding tested for superiority and, if met, the composite of all-cause death, myocardial infarction, or stroke at 1 year, tested for noninferiority against a margin of 1.25 on a hazard ratio (HR) scale. RESULTS: Bleeding Academic Research Consortium type 3 or 5 bleeding occurred in fewer patients with ticagrelor than DAPT (0.9% vs. 1.7%, respectively; HR: 0.56; 95% confidence interval [CI]: 0.41 to 0.75; p < 0.001). The composite of all-cause death, myocardial infarction, or stroke occurred in 231 patients (3.2%) with ticagrelor and in 254 patients (3.5%) with DAPT (HR: 0.92; 95% CI: 0.76 to 1.10; p < 0.001 for noninferiority). Ticagrelor was associated with lower risk for all-cause (HR: 0.71; 95% CI: 0.52 to 0.96; p = 0.027) and cardiovascular (HR: 0.68; 95% CI: 0.47 to 0.99; p = 0.044) mortality. Rates of myocardial infarction (2.01% vs. 2.05%; p = 0.88), stent thrombosis (0.29% vs. 0.38%; p = 0.32), and stroke (0.47% vs. 0.36%; p = 0.30) were similar. CONCLUSIONS: Ticagrelor monotherapy was associated with a lower risk for major bleeding compared with standard DAPT, without a concomitant increase in ischemic events.