Angiogenic Gene Therapy for Refractory Angina: Results of the EXACT Phase 2 Trial.

BACKGROUND: XC001 is a novel adenoviral-5 vector designed to express multiple isoforms of VEGF (vascular endothelial growth factor) and more safely and potently induce angiogenesis. The EXACT trial (Epicardial Delivery of XC001 Gene Therapy for Refractory Angina Coronary Treatment) assessed the safety and preliminary efficacy of XC001 in patients with no option refractory angina. METHODS: In this single-arm, multicenter, open-label trial, 32 patients with no option refractory angina received a single treatment of XC001 (1×1011 viral particles) via transepicardial delivery. RESULTS: There were no severe adverse events attributed to the study drug. Twenty expected severe adverse events in 13 patients were related to the surgical procedure. Total exercise duration increased from a mean±SD of 359.9±105.55 seconds at baseline to 448.2±168.45 (3 months), 449.2±175.9 (6 months), and 477.6±174.7 (12 months; +88.3 [95% CI, 37.1-139.5], +84.5 [95% CI, 34.1-134.9], and +115.5 [95% CI, 59.1-171.9]). Total myocardial perfusion deficit on positron emission tomography imaging decreased by 10.2% (95% CI, -3.1% to 23.5%), 14.3% (95% CI, 2.8%-25.7%), and 10.2% (95% CI, -0.8% to -21.2%). Angina frequency decreased from a mean±SD 12.2±12.5 episodes to 5.2±7.2 (3 months), 5.1±7.8 (6 months), and 2.7±4.8 (12 months), with an average decrease of 7.7 (95% CI, 4.1-11.3), 6.6 (95% CI, 3.5-9.7), and 8.8 (4.6-13.0) episodes at 3, 6, and 12 months. Angina class improved in 81% of participants at 6 months. CONCLUSIONS: XC001 administered via transepicardial delivery is safe and generally well tolerated. Exploratory improvements in total exercise duration, ischemic burden, and subjective measures support a biologic effect sustained to 12 months, warranting further investigation. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04125732.

Dyspnea-Related Ticagrelor Discontinuation After Percutaneous Coronary Intervention.

BACKGROUND: Nearly 20% of patients on ticagrelor experience dyspnea, which may lead to treatment discontinuation in up to one-third of cases. OBJECTIVES: The authors sought to evaluate the incidence, predictors, and outcomes of dyspnea-related ticagrelor discontinuation after percutaneous coronary intervention (PCI). METHODS: In the TWILIGHT (Ticagrelor With Aspirin or Alone in High-Risk Patients After Coronary Intervention) trial, after 3 months of ticagrelor plus aspirin, patients were maintained on ticagrelor and randomized to aspirin or placebo for 1 year. The occurrence of dyspnea associated with ticagrelor discontinuation was evaluated among all patients enrolled in the trial. A landmark analysis was performed at 3 months after PCI, that is, the time of randomization. Predictors of dyspnea-related ticagrelor discontinuation were obtained from multivariable Cox regression with stepwise selection of candidate variables. RESULTS: The incidence of dyspnea-related ticagrelor discontinuation was 6.4% and 9.1% at 3 and 15 months after PCI, respectively. Independent predictors included Asian race (lower risk), smoking, prior PCI, hypercholesterolemia, prior coronary artery bypass, peripheral artery disease, obesity, and older age. Among 179 patients who discontinued ticagrelor because of dyspnea after randomization, ticagrelor monotherapy was not associated with a higher risk of subsequent ischemic events (composite of all-cause death, myocardial infarction, or stroke) compared with ticagrelor plus aspirin (5.0% vs 7.1%; P = 0.566). CONCLUSIONS: In the TWILIGHT trial, dyspnea-related ticagrelor discontinuation occurred in almost 1 in 10 patients and tended to occur earlier rather than late after PCI. Several demographic and clinical conditions predicted its occurrence, and their assessment may help identify subjects at risk for therapy nonadherence.

EXACT Trial: Results of the Phase 1 Dose-Escalation Study.

BACKGROUND: New therapies are needed for patients with refractory angina. Encoberminogene rezmadenovec (XC001), a novel adenoviral-5 vector coding for all 3 major isoforms of VEGF (vascular endothelial growth factor), demonstrated enhanced local angiogenesis in preclinical models; however, the maximal tolerated dose and safety of direct epicardial administration remain unknown. METHODS: In the phase 1 portion of this multicenter, open-label, single-arm, dose-escalation study, patients with refractory angina received increasing doses of encoberminogene rezmadenovec (1×109, 1×1010, 4×1010, and 1×1011 viral particles) to evaluate its safety, tolerability, and preliminary efficacy. Patients had class II to IV angina on maximally tolerated medical therapy, demonstrable ischemia on stress testing, and were angina-limited on exercise treadmill testing. Patients underwent minithoracotomy with epicardial delivery of 15 0.1-mL injections of encoberminogene rezmadenovec. The primary outcome was safety via adverse event monitoring over 6 months. Efficacy assessments included difference from baseline to months 3, 6 (primary), and 12 in total exercise duration, myocardial perfusion deficit using positron emission tomography, angina class, angina frequency, and quality of life. RESULTS: From June 2, 2020 to June 25, 2021, 12 patients were enrolled into 4 dosing cohorts with 1×1011 viral particle as the highest planned dose. Seventeen serious adverse events were reported in 7 patients; none were related to study drug. Six serious adverse events in 4 patients were related to the thoracotomy, 3 non-serious adverse events were possibly related to study drug. The 2 lowest doses did not demonstrate improvements in total exercise duration, myocardial perfusion deficit, or angina frequency; however, there appeared to be improvements in all parameters with the 2 higher doses. CONCLUSIONS: Epicardial delivery of encoberminogene rezmadenovec via minithoracotomy is feasible, and up to 1×1011 viral particle appears well tolerated. A dose response was observed across 4 dosing cohorts in total exercise duration, myocardial perfusion deficit, and angina class. The highest dose (1×1011 viral particle) was carried forward into phase 2. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT04125732.

Ticagrelor with and without aspirin in patients with a prior coronary artery bypass graft undergoing percutaneous coronary intervention: the TWILIGHT-CABG study.

BACKGROUND: Prior coronary artery bypass graft surgery (CABG) patients undergoing percutaneous coronary intervention (PCI) are often older and present with multiple comorbidities. Ticagrelor monotherapy after a short course of dual antiplatelet therapy (DAPT) has emerged as an effective bleeding-avoidance strategy among high-risk patients. AIMS: We aimed to examine the effects of ticagrelor with or without aspirin in prior CABG patients undergoing PCI within the TWILIGHT trial. METHODS: After 3 months of ticagrelor plus aspirin, patients were randomised to either aspirin or placebo, in addition to ticagrelor, for 12 months and compared by prior CABG status. The primary endpoint was Bleeding Academic Research Consortium (BARC) type 2, 3 or 5 bleeding. The key secondary endpoint was all-cause death, myocardial infarction (MI), or stroke. RESULTS: Out of 7,119 patients, a total of 703 (10.8%) patients had prior CABG within the randomised cohort. Prior CABG patients had more comorbidities and a higher incidence of BARC type 2, 3, or 5 bleeding and death, MI or stroke at 1 year after randomisation, compared with patients without prior CABG. Ticagrelor monotherapy was associated with significantly less BARC 2, 3, or 5 bleeding among prior CABG patients compared with DAPT (4.9% vs 9.6%, hazard ratio [HR] 0.50, 95% confidence interval [CI]: 0.28 to 0.90; pinteraction=0.676) and similar rates of death, MI or stroke (10.0% vs 8.7%, HR 1.14, 95% CI: 0.70 to 1.87; pinteraction=0.484). When comparing target vessel type, treatment effects were consistent among graft- and native-vessel interventions. CONCLUSIONS: In high-risk patients with prior CABG, ticagrelor monotherapy reduced bleeding without compromising ischaemic outcomes compared with ticagrelor plus aspirin.

Clinical Outcomes in Patients With ST-Segment Elevation MI and No Standard Modifiable Cardiovascular Risk Factors.

BACKGROUND: The author recently reported ∼50% excess early mortality in patients with first-presentation ST-segment elevation myocardial infarction (STEMI) without standard modifiable cardiovascular risk factors (SMuRFs); the cause of this is not clear. OBJECTIVES: The aim of this study was to examine differences in infarct characteristics and clinical outcomes in patients with versus without SMuRFs (dyslipidemia, hypertension, diabetes mellitus, and smoking). METHODS: Individual-level data were pooled from 10 randomized percutaneous intervention (PCI) trials in which infarct size was measured within 1 month by either cardiac magnetic resonance or technetium-99m sestamibi single-photon emission computed tomography imaging. First-presentation STEMI was classified into 2 groups according to the presence or absence of at least 1 SMuRF. RESULTS: Among 2,862 patients, 524 (18.3%) were SMuRF-less. After adjusting for study effect, SMuRF-less patients had more frequent poor pre-PCI flow Thrombolysis In Myocardial Infarction 0/1 compared with patients with at least 1 SMuRF (72.0% vs 64.1%; OR: 1.35; 95% CI: 1.08-1.70). There were no independent associations between the presence or absence of SMuRFs at baseline and infarct size (estimate = -0.35; 95% CI: -1.93 to 1.23), left ventricular ejection fraction (estimate = -0.06; 95% CI: -1.33 to 1.20), or mortality at 30 days (HR: 0.46; 95% CI: 0.19-1.07) and 1 year (HR: 0.74; 95% CI: 0.43-1.29). CONCLUSIONS: First-presentation STEMI patients with no identifiable baseline SMuRFs had a higher risk of Thrombolysis In Myocardial Infarction flow grade 0/1 pre-PCI. However, after adjustment, there were no significant associations between SMuRF-less status and infarct size, left ventricle ejection fraction, or mortality.

Cangrelor Use Patterns and Transition to Oral P2Y12 Inhibitors Among Patients With Myocardial Infarction: Initial Results From the CAMEO Registry.

Background In clinical trials, cangrelor has been shown to reduce percutaneous coronary intervention-related ischemic complications without increasing major bleeding. This study was performed to examine cangrelor use and transition to oral P2Y12 inhibitors in routine clinical practice. Methods and Results The CAMEO (Cangrelor in Acute Myocardial Infarction: Effectiveness and Outcomes) registry is a multicenter, retrospective observational study of platelet inhibition strategies for patients with myocardial infarction undergoing percutaneous coronary intervention. In phase 1, data were collected on consecutive patients with myocardial infarction (n=482) treated with any P2Y12 inhibitor to understand cangrelor use by hospital. In phase 2, data were collected in a 2:1 (cangrelor-: non-cangrelor-treated) ratio of patients with myocardial infarction (n=873). In phase 1, cangrelor use varied across hospitals (overall, 50.4% [range, 6.0%-100%]). Of patients receiving cangrelor in both phases (n=819), 3.3% received either the bolus or infusion only. Cangrelor was infused for a median of 121 (76-196) minutes; and 38.3% received an infusion for <2 hours. Most patients transitioned from cangrelor to ticagrelor (ticagrelor, 85.3%; clopidogrel, 9.5%; prasugrel, 5.2%). Many patients (16.4%) had a >1-hour gap between cangrelor cessation and oral P2Y12 inhibitor initiation; this was highest among those transitioned to clopidogrel (56.6% versus 34.5% prasugrel versus 10.8% ticagrelor; P<0.001). Only 27.3% were dosed with cangrelor and transitioned to an oral P2Y12 inhibitor in a fashion consistent with the pivotal trials and US Food and Drug Administration label. Conclusions This multicenter registry demonstrated interhospital variability in how cangrelor was administered and transitioned to an oral P2Y12 inhibitor. These findings highlight opportunities for optimization of cangrelor dosing, infusion duration, and transition of care from the catheterization laboratory to the ward setting.

Rationale and design of the safe and timely antithrombotic removal - ticagrelor (STAR-T) trial: A prospective, multi-center, double-blind, randomized controlled trial evaluating reductions in postoperative bleeding with intraoperative removal of ticagrelor by the drugsorb™-ATR device in patients undergoing cardiothoracic surgery within 48 hours from last ticagrelor dose.

BACKGROUND: Ticagrelor is often administered to patients with acute coronary syndromes. However, when these patients require urgent or emergent cardiothoracic (CT) surgery the presence of ticagrelor significantly increases surgical bleeding. The goal of the current trial is to evaluate the effectiveness and safety of the DrugSorb-ATR hemoadsorption device for the intraoperative removal of ticagrelor to reduce postoperative bleeding in the above patient population. The Safe and Timely Antithrombotic Removal - Ticagrelor (STAR-T) Trial is a multi-center, double-blind, randomized, controlled trial enrolling patients who require cardiothoracic surgery on cardiopulmonary bypass (CPB) within 48 hours of last ticagrelor dose. METHODS: Subjects will be randomized 1:1 to receive either the DrugSorb-ATR device or an identical sham device during CPB. The study will enroll up to 120 subjects at 20 U.S centers, and the primary outcome is the composite of fatal perioperative bleeding, moderate/severe/massive bleeding according to the Universal Definition of Perioperative Bleeding in Cardiac Surgery (UDPB), and 24 hours chest tube drainage. The components of the composite are hierarchically ranked according to clinical significance and the primary analysis will utilize the Win Ratio method. Percent change in ticagrelor levels before and after CPB (drug removal) will be the key secondary endpoint. An independent Clinical Events Committee will adjudicate all clinical endpoints including safety endpoints relating to postoperative thrombotic events. Subjects will be followed through 30 days after the index operation. CONCLUSIONS: The results from STAR-T, if positive, will potentially support FDA market approval for DrugSorb-ATR, and provide a solution to an important unmet clinical need.

Bridging Antiplatelet Therapy After Percutaneous Coronary Intervention: JACC Review Topic of the Week.

Patients undergoing early surgery after coronary stent implantation are at increased risk for mortality from ischemic and hemorrhagic complications. The optimal antiplatelet strategy in patients who cannot discontinue dual antiplatelet therapy (DAPT) before surgery is unclear. Current guidelines, based on surgical and clinical characteristics, provide risk stratification for bridging therapy with intravenous antiplatelet agents, but management is guided primarily by expert opinion. This review summarizes perioperative risk factors to consider before discontinuing DAPT and reviews the data for intravenous bridging therapies. Published reports have included bridging options such as small molecule glycoprotein IIb/IIIa inhibitors (eptifibatide or tirofiban) and cangrelor, an intravenous P2Y12 inhibitor. However, optimal management of these complex patients remains unclear in the absence of randomized controlled data, without which an argument can be made both for and against the use of perioperative intravenous bridging therapy after discontinuing oral P2Y12 inhibitors. Multidisciplinary risk assessment remains a critical component of perioperative care.

Epicardial delivery of XC001 gene therapy for refractory angina coronary treatment (The EXACT Trial): Rationale, design, and clinical considerations.

BACKGROUND: Patients with refractory angina (RA) have poor quality of life and new therapies are needed. XC001 is a novel adenoviral vector expressing multiple isoforms of vascular endothelial growth factor (VEGF) promoting an enhanced local angiogenic effect. METHODS: The Epicardial Delivery of XC001 Gene Therapy for Refractory Angina Coronary Treatment (EXACT) trial is a 6-month (with 6-month extension) phase 1/2, first-in-human, multicenter, open-label, single-arm, dose-escalation study to evaluate the safety, tolerability, and preliminary efficacy of XC001 in patients with RA. The trial will enroll 33 patients in an initial (n = 12) ascending dose-escalation phase (1 × 109, 1 × 1010, 4 × 1010, and 1 × 1011 viral particles), followed by phase 2 (n = 21) assessing the highest tolerated dose. Patients must have stable Canadian Cardiovascular Society (CCS) class II-IV angina on maximally tolerated medical therapy without options for conventional revascularization, demonstrable ischemia on stress testing, and angina limiting exercise tolerance. XC001 will be delivered directly to ischemic myocardium via surgical transthoracic epicardial access. The primary outcome is safety via adverse event monitoring through 6 months. Efficacy assessments include difference from baseline to month 6 in time to 1 mm of ST segment depression, time to angina, and total exercise duration; myocardial blood flow at rest, and stress and coronary flow reserve by positron emission tomography; quality of life; CCS functional class; and angina frequency. CONCLUSIONS: The EXACT trial will determine whether direct intramyocardial administration of XC001 in patients with RA is safe and evaluate its effect on exercise tolerance, myocardial perfusion, angina and physical activity, informing future clinical investigation. CLINICAL TRIAL REGISTRATION: NCT04125732.

Coronary revascularization and circulatory support strategies in patients with myocardial infarction, multi-vessel coronary artery disease, and cardiogenic shock: Insights from an international survey.

Cardiogenic shock (CS) complicating acute myocardial infarction (MI) is associated with high mortality. In the absence of data to support coronary revascularization beyond the infarct artery and selection of circulatory support devices or medications, clinical practice may vary substantially. METHODS: We distributed a survey to interventional cardiologists and cardiothoracic surgeons through relevant professional societies to determine contemporary coronary revascularization and circulatory support strategies for MI with CS and multi-vessel coronary artery disease (CAD). RESULTS: A total of 143 participants completed the survey between 1/2019 and 8/2019. Overall, 55.2% of participants reported that the standard approach to coronary revascularization was single vessel PCI of the infarct related artery (IRA) with staged PCI of non-culprit lesions. Single vessel PCI of the IRA only (28.0%), emergency multi-vessel PCI (11.9%), and coronary artery bypass grafting (CABG) (4.9%) were standard approaches at some centers. A plurality of survey respondents (46.9%) believed initial PCI with staged CABG for multi-vessel CAD would be associated with the most favorable outcomes. A minority of respondents believed PCI-only strategies (23.1%) and CABG alone (6.3%) provided optimal care, and 23.1% were unsure of the best strategy. After PCI for CS, Impella (76.9%), intra-aortic balloon pump (IABP) (12.8%), and extra-corporeal membrane oxygenation (ECMO) (7.7%) were preferred. After CABG, IABP (34.3%), Impella (32.2%), and ECMO (28%) were preferred. CONCLUSIONS: This survey indicates substantial heterogeneity in clinical care in CS. There is evidence of provider uncertainty and clinical equipoise regarding the optimal management of patients with MI, multi-vessel CAD, and CS. SHORT ABSTRACT: We sought to determine contemporary practice patterns of coronary revascularization and circulatory support in patients with MI, multi-vessel coronary artery disease (CAD), and cardiogenic shock. A survey was distributed to interventional cardiologists and cardiothoracic surgeons through relevant professional societies. Survey respondents identified substantial heterogeneity in clinical care and evidence of provider uncertainty and clinical equipoise regarding the optimal management of patients with MI, multi-vessel CAD, and CS.

Comparative Efficacy and Safety of Oral P2Y12 Inhibitors in Acute Coronary Syndrome: Network Meta-Analysis of 52 816 Patients From 12 Randomized Trials.

BACKGROUND: New randomized, controlled trials have become available on oral P2Y12 inhibitors in acute coronary syndrome. We aimed to evaluate current evidence comparing the efficacy and safety profile of prasugrel, ticagrelor, and clopidogrel in acute coronary syndrome by a meta-analysis of randomized controlled trials. METHODS: We performed a network meta-analysis and direct pairwise comparison analysis of efficacy and safety outcomes from 12 randomized controlled trials including a total of 52 816 patients with acute coronary syndrome. RESULTS: In comparison with clopidogrel, ticagrelor significantly reduced cardiovascular mortality (hazard ratio [HR], 0.82 [95% CI, 0.72-0.92]) and all-cause mortality (HR, 0.83 [95% CI, 0.75-0.92]), whereas there was no statistically significant mortality reduction with prasugrel (HR, 0.90 [95% CI, 0.80-1.01] and HR, 0.92 [95% CI, 0.84-1.02], respectively). In comparison with each other, there were no significant differences in mortality (HR prasugrel versus ticagrelor, 1.10 [95% CI, 0.94-1.29] and 1.12 [95% CI, 0.98-1.28]). In comparison with clopidogrel, prasugrel reduced myocardial infarction (HR, 0.81 [95% CI, 0.67-0.98]), whereas ticagrelor showed no risk reduction (HR, 0.97 [95% CI, 0.78-1.22]). Differences between prasugrel and ticagrelor were not statistically significant. Stent thrombosis risk was significantly reduced by both ticagrelor and prasugrel versus clopidogrel (28%-50% range of reduction). In comparison with clopidogrel, both prasugrel (HR, 1.26 [95% CI, 1.01-1.56]) and ticagrelor (HR, 1.27 [95% CI, 1.04-1.55]) significantly increased major bleeding. There were no significant differences between prasugrel and ticagrelor for all outcomes explored. CONCLUSIONS: Prasugrel and ticagrelor reduced ischemic events and increased bleeding in comparison with clopidogrel. A significant mortality reduction was observed with ticagrelor only. There was no efficacy and safety difference between prasugrel and ticagrelor. Registration: URL: https://www.crd.york.ac.uk/PROSPERO/; Unique identifier: CRD42019155648.

Effect of Smoking on Outcomes of Primary PCI in Patients With STEMI.

BACKGROUND: Smoking is a well-established risk factor for ST-segment elevation myocardial infarction (STEMI); however, once STEMI occurs, smoking has been associated with favorable short-term outcomes, an observation termed the "smoker's paradox." It has been postulated that smoking might exert protective effects that could reduce infarct size, a strong independent predictor of worse outcomes after STEMI. OBJECTIVES: The purpose of this study was to determine the relationship among smoking, infarct size, microvascular obstruction (MVO), and adverse outcomes after STEMI. METHODS: Individual patient-data were pooled from 10 randomized trials of patients with STEMI undergoing primary percutaneous coronary intervention. Infarct size was assessed at median 4 days by either cardiac magnetic resonance imaging or technetium-99m sestamibi single-photon emission computed tomography. Multivariable analysis was used to assess the relationship between smoking, infarct size, and the 1-year rates of death or heart failure (HF) hospitalization and reinfarction. RESULTS: Among 2,564 patients with STEMI, 1,093 (42.6%) were recent smokers. Smokers were 10 years younger and had fewer comorbidities. Infarct size was similar in smokers and nonsmokers (adjusted difference: 0.0%; 95% confidence interval [CI]: -3.3% to 3.3%; p = 0.99). Nor was the extent of MVO different between smokers and nonsmokers. Smokers had lower crude 1-year rates of all-cause death (1.0% vs. 2.9%; p < 0.001) and death or HF hospitalization (3.3% vs. 5.1%; p = 0.009) with similar rates of reinfarction. After adjustment for age and other risk factors, smokers had a similar 1-year risk of death (adjusted hazard ratio [adjHR]: 0.92; 95% CI: 0.46 to 1.84) and higher risks of death or HF hospitalization (adjHR: 1.49; 95% CI: 1.09 to 2.02) as well as reinfarction (adjHR: 1.97; 95% CI: 1.17 to 3.33). CONCLUSIONS: In the present large-scale individual patient-data pooled analysis, recent smoking was unrelated to infarct size or MVO, but was associated with a worse prognosis after primary PCI in STEMI. The smoker's paradox may be explained by the younger age and fewer cardiovascular risk factors in smokers compared with nonsmokers.

Meta-Analysis of Intraocular Bleeding With Dual Antiplatelet Therapy Using P2Y12 Inhibitors Prasugrel or Ticagrelor.

Intraocular bleeding is a devastating clinical event due to its potentially blinding nature. It is not known if determine if dual antiplatelet therapy using aspirin and potent P2Y12 inhibitors increases this risk. We searched MEDLINE and ClinicalTrials.gov for randomized controlled trials that were phase III, randomly assigned patients to dual antiplatelet therapy with either aspirin and a potent P2Y12 inhibitor or aspirin and clopidogrel, had follow-up of 6 months, and at least 200 patients. Corresponding authors were contacted for intraocular bleeding data. Inverse-variance, weighted, fixed-effects meta-analysis was undertaken, with random-effects meta-analysis performed as a sensitivity analysis. Four trials enrolling 42,850 patients were included. The median follow-up ranged from 12 to 14 months. There was overall low risk of bias. Pooled analysis demonstrated no statistically significant increase in the risk of intraocular bleeding with dual antiplatelet therapy using potent P2Y12 inhibitors compared with clopidogrel (risk ratio 0.89, 95% confidence interval 0.58 to 1.36). There was no significant heterogeneity observed across trials (I2 statistic 0%, p = 0.98). The use of random-effects meta-analysis did not change the effect estimate or confidence intervals, and the results appeared similar when stratified by potent P2Y12 inhibitor (p = 0.97). In conclusion, this collaborative meta-analysis of dual antiplatelet trials does not suggest that the risk of intraocular bleeding is increased with the use of potent P2Y12 inhibitors compared with clopidogrel. Our results suggest that these potent P2Y12 inhibitors may continue to be used cautiously where indicated as part of dual antiplatelet therapy, even in those at high risk of spontaneous intraocular bleeding.

P2Y12 Inhibitor Switching in Response to Routine Notification of CYP2C19 Clopidogrel Metabolizer Status Following Acute Coronary Syndromes.

Importance: Physician behavior in response to knowledge of a patient's CYP2C19 clopidogrel metabolizer status is unknown. Objective: To investigate the association of mandatory reporting of CYP2C19 pharmacogenomic testing, provided to investigators with no direct recommendations on how to use these results, with changes in P2Y12 inhibitor use, particularly clopidogrel, in the Randomized Trial to Compare the Safety of Rivaroxaban vs Aspirin in Addition to Either Clopidogrel or Ticagrelor in Acute Coronary Syndrome (GEMINI-ACS-1) clinical trial. Design, Setting, and Participants: The GEMINI-ACS-1 trial compared rivaroxaban, 2.5 mg twice daily, with aspirin, 100 mg daily, plus open-label clopidogrel or ticagrelor (provided), in patients with recent acute coronary syndromes (ACS). The trial included 371 clinical centers in 21 countries and 3037 patients with ACS. Data were analyzed between May 2017 and February 2019. Interventions: Investigators were required to prestipulate their planned response to CYP2C19 metabolizer status. In response to a regulatory mandate, results for all patients were reported to investigators approximately 1 week after randomization. Main Outcomes and Measures: Reasons for switching P2Y12 inhibitors and occurrence of bleeding and ischemic events were collected. Results: Of 3037 patients enrolled (mean [SD] age, 62.8 [9.0] years; 2275 men [74.9%], and 2824 white race/ethnicity [93.0%]), investigators initially treated 1704 (56.1%) with ticagrelor and 1333 (43.9%) with clopidogrel. Investigators prestipulated that they would use CYP2C19 metabolizer status to change P2Y12 inhibitor in 48.5% of genotyped clopidogrel-treated patients (n = 642 of 1324) and 5.5% of genotyped ticagrelor-treated patients (n = 93 of 1692). P2Y12 inhibitor switching for any reason occurred in 197 patients and was more common in patients treated with ticagrelor (146 of 1704 [8.6%]) compared with clopidogrel (51 of 1333 [3.8%]). Of patients initially treated with ticagrelor, only 1 (0.1% overall; 0.7% of all who switched) was switched based on CYP2C19 status. Of patients initially treated with clopidogrel, 23 (1.7% overall,;45.1% of all who switched) were switched owing to metabolizer status. Of 48 patients (3.6%) with reduced metabolizer status treated initially with clopidogrel, 15 (31.3%) were switched based on metabolizer status, including 48.1% (13 of 27) in which switching was prestipulated. Conclusions and Relevance: Physicians were evenly split on how to respond to knowledge of CYP2C19 metabolizer status in clopidogrel-treated patients. Mandatory provision of this information rarely prompted P2Y12 inhibitor switching overall, including a minority of patients with reduced metabolizer status. These findings highlight the clinical equipoise among physicians regarding use of this information and the reluctance to use information from routine genotyping in the absence of definitive clinical trial data demonstrating the efficacy of this approach. Clinical Trial Registration: ClinicalTrials.gov identifier: NCT02293395.

Does prior coronary angioplasty affect outcomes of surgical coronary revascularization? Insights from the STICH trial.

BACKGROUND: The STICH trial showed superiority of coronary artery bypass plus medical treatment (CABG) over medical treatment alone (MED) in patients with left ventricular ejection fraction (LVEF) ≤35%. In previous publications, percutaneous coronary intervention (PCI) prior to CABG was associated with worse prognosis. OBJECTIVES: The main purpose of this study was to analyse if prior PCI influenced outcomes in STICH. METHODS AND RESULTS: Patients in the STICH trial (n = 1212), followed for a median time of 9.8 years, were included in the present analyses. In the total population, 156 had a prior PCI (74 and 82, respectively, in the MED and CABG groups). In those with vs. without prior PCI, the adjusted hazard-ratios (aHRs) were 0.92 (95% CI = 0.74-1.15) for all-cause mortality, 0.85 (95% CI = 0.64-1.11) for CV mortality, and 1.43 (95% CI = 1.15-1.77) for CV hospitalization. In the group randomized to CABG without prior PCI, the aHRs were 0.82 (95% CI = 0.70-0.95) for all-cause mortality, 0.75 (95% CI = 0.62-0.90) for CV mortality and 0.67 (95% CI = 0.56-0.80) for CV hospitalization. In the group randomized to CABG with prior PCI, the aHRs were 0.76 (95% CI = 0.50-1.15) for all-cause mortality, 0.81 (95% CI = 0.49-1.36) for CV mortality and 0.61 (95% CI = 0.41-0.90) for CV hospitalization. There was no evidence of interaction between randomized treatment and prior PCI for any endpoint (all adjusted p > 0.05). CONCLUSION: In the STICH trial, prior PCI did not affect the outcomes of patients whether they were treated medically or surgically, and the superiority of CABG over MED remained unchanged regardless of prior PCI. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov; Identifier: NCT00023595.

Days Alive and Out of Hospital: Exploring a Patient-Centered, Pragmatic Outcome in a Clinical Trial of Patients With Acute Coronary Syndromes.

Background Cardiovascular clinical trials have traditionally incorporated separate time-to-first-event analyses for their primary efficacy and safety comparisons, but this framework has a number of limitations, including limited patient-centeredness and a traditional requirement for central adjudication. Days alive and out of the hospital (DAOH) has the potential to provide additional insight. Methods and Results TRILOGY ACS (Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes) was a randomized, multinational clinical trial that compared the effect of prasugrel versus clopidogrel in patients stabilized after non-ST segment elevation acute coronary syndrome treated without revascularization; the trial had a neutral result. DAOH was calculated for each patient using site-submitted adverse event reporting data. We described patterns of DAOH overall, and among younger adults (<75 years old), older adults (≥75 years old), and frail/prefrail patients over 12 months follow-up and used Poisson regression to compare DAOH for patients randomized to prasugrel versus clopidogrel. Of 9249 patients in the overall trial population, 500 (5.4%) died, and 2504 (27.1%) were hospitalized 4150 times over 12 months' follow-up; the mean±SD DAOH was 317±86. The distribution of DAOH over 12 months was left-skewed, with median DAOH 363 days. Among younger adults, older adults, and frail/prefrail patients, mean DAOH were 323, 293, and 304 days, respectively. There were no differences in DAOH by treatment arm in the overall population (rate ratio, 1.00; 95% CI, 0.99-1.01) or any subgroup. Conclusions These results support the feasibility of determining DAOH, a patient-centered outcome that can potentially overcome many of the disadvantages of the traditional time-to-composite-event framework in the clinical trial setting. Clinical Trial Registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT00699998.

Outcomes of Patients Receiving Downstream Revascularization After Initial Medical Management for Non-ST-Segment Elevation Acute Coronary Syndromes (From the TRILOGY ACS Trial).

Patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS) are sometimes treated with medical management alone rather than an invasive strategy. Among those medically managed without revascularization and discharged, a proportion will require revascularization later on, but little is known about this population. In TRILOGY ACS, 9,326 patients with NSTE ACS who were selected for medical management alone were randomized to treatment with prasugrel or clopidogrel and discharged without revascularization. Patient characteristics and ischemic and bleeding outcomes through 30 months were compared between patients who underwent downstream revascularization after the index hospitalization and those who did not. A total of 662 patients (7.1%) underwent later revascularization by percutaneous coronary intervention (73.1%), coronary artery bypass graft surgery (26.4%), or the two (0.5%). Median time to revascularization was 121 days (twenty-fifth, seventy-fifth percentiles: 41, 326). Revascularized patients were younger, more likely to be male, and had higher rates of hyperlipidemia, diabetes mellitus, prior myocardial infarction, and prior revascularization compared with those not revascularized. Europe and North America had the highest rates of revascularization. During the follow-up period, those who underwent revascularization had a higher rate of the composite outcome of cardiovascular death, myocardial infarction, or stroke occurring after revascularization compared with those not revascularized (hazard ratio [HR] 2.73 [95% confidence interval {CI} 2.21 to 3.38], p < 0.001) as well as a higher rate of each of the individual outcomes. Major bleeding was also higher in those who underwent revascularization (GUSTO severe or life-threatening: HR 2.61 [95% CI 1.02 to 6.67], p = 0.045; TIMI major: HR 2.24 [95% CI 1.12 to 4.48], p = 0.022). There was no evidence that bleeding and ischemic outcomes varied by treatment with clopidogrel versus prasugrel. In conclusion, among patients initially medically managed after NSTE ACS, a small proportion later require revascularization and have a high rate of ischemic and major bleeding outcomes compared with those not requiring downstream revascularization.

Predicting the risk of bleeding during dual antiplatelet therapy after acute coronary syndromes.

OBJECTIVES: Dual antiplatelet therapy (DAPT) with aspirin + a P2Y12 inhibitor is recommended for at least 12 months for patients with acute coronary syndrome (ACS), with shorter durations considered for patients with increased bleeding risk. However, there are no decision support tools available to predict an individual patient's bleeding risk during DAPT treatment in the post-ACS setting. METHODS: To develop a longitudinal bleeding risk prediction model, we analy sed 9240 patients with unstable angina/non-ST segment elevation myocardial infarction (NSTEMI) from the Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes (TRILOGY ACS) trial, who were managed without revasculari sation and treated with DAPT for a median of 14.8 months. RESULTS: We identified 10 significant baseline predictors of non-coronary artery bypass grafting (CABG)-related Global Use of Strategies to Open Occluded Arteries (GUSTO) severe/life-threatening/moderate bleeding: age, sex, weight, NSTEMI (vs unstable angina), angiography performed before randomi sation, prior peptic ulcer disease, creatinine, systolic blood pressure, haemoglobin and treatment with beta-blocker. The five significant baseline predictors of Thrombolysis In Myocardial Infarction (TIMI) major or minor bleeding included age, sex, angiography performed before randomi sation, creatinine and haemoglobin. The models showed good predictive accuracy with Therneau's C-indices: 0.78 (SE = 0.024) for the GUSTO model and 0.67 (SE = 0.023) for the TIMI model. Internal validation with bootstrapping gave similar C-indices of 0.77 and 0.65, respectively. External validation demonstrated an attenuated C-index for the GUSTO model (0.69) but not the TIMI model (0.68). CONCLUSIONS: Longitudinal bleeding risks during treatment with DAPT in patients with ACS can be reliably predicted using selected baseline characteristics. The TRILOGY ACS bleeding models can inform risk -benefit considerations regarding the duration of DAPT following ACS. TRIAL REGISTRATION: ClinicalTrials.gov identifier: https://clinicaltrials.gov/ct2/show/NCT00699998.