STREAM-2: Half-Dose Tenecteplase or Primary Percutaneous Coronary Intervention in Older Patients With ST-Segment-Elevation Myocardial Infarction: A Randomized, Open-Label Trial.

BACKGROUND: ST-segment-elevation myocardial infarction (STEMI) guidelines recommend pharmaco-invasive treatment if timely primary percutaneous coronary intervention (PCI) is unavailable. Full-dose tenecteplase is associated with an increased risk of intracranial hemorrhage in older patients. Whether pharmaco-invasive treatment with half-dose tenecteplase is effective and safe in older patients with STEMI is unknown. METHODS: STREAM-2 (Strategic Reperfusion in Elderly Patients Early After Myocardial Infarction) was an investigator-initiated, open-label, randomized, multicenter study. Patients ≥60 years of age with ≥2 mm ST-segment elevation in 2 contiguous leads, unable to undergo primary PCI within 1 hour, were randomly assigned (2:1) to half-dose tenecteplase followed by coronary angiography and PCI (if indicated) 6 to 24 hours after randomization, or to primary PCI. Efficacy end points of primary interest were ST resolution and the 30-day composite of death, shock, heart failure, or reinfarction. Safety assessments included stroke and nonintracranial bleeding. RESULTS: Patients were assigned to pharmaco-invasive treatment (n=401) or primary PCI (n=203). Median times from randomization to tenecteplase or sheath insertion were 10 and 81 minutes, respectively. After last angiography, 85.2% of patients undergoing pharmaco-invasive treatment and 78.4% of patients undergoing primary PCI had ≥50% resolution of ST-segment elevation; their residual median sums of ST deviations were 4.5 versus 5.5 mm, respectively. Thrombolysis In Myocardial Infarction flow grade 3 at last angiography was ≈87% in both groups. The composite clinical end point occurred in 12.8% (51/400) of patients undergoing pharmaco-invasive treatment and 13.3% (27/203) of patients undergoing primary PCI (relative risk, 0.96 [95% CI, 0.62-1.48]). Six intracranial hemorrhages occurred in the pharmaco-invasive arm (1.5%): 3 were protocol violations (excess anticoagulation in 2 and uncontrolled hypertension in 1). No intracranial bleeding occurred in the primary PCI arm. The incidence of major nonintracranial bleeding was low in both groups (<1.5%). CONCLUSIONS: Halving the dose of tenecteplase in a pharmaco-invasive strategy in this early-presenting, older STEMI population was associated with electrocardiographic changes that were at least comparable to those after primary PCI. Similar clinical efficacy and angiographic end points occurred in both treatment groups. The risk of intracranial hemorrhage was higher with half-dose tenecteplase than with primary PCI. If timely PCI is unavailable, this pharmaco-invasive strategy is a reasonable alternative, provided that contraindications to fibrinolysis are observed and excess anticoagulation is avoided. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02777580.

Identifying the highest risk vascular patients: Insights from the XATOA registry.

BACKGROUND: Patients with coronary and peripheral artery disease (PAD) have a residual risk of major adverse cardiovascular and limb events despite standards of care. Among patients with coronary artery disease (CAD) and/or PAD selected for low dose rivaroxaban (2.5 mg BID) and aspirin, we sought to determine the highest risk vascular patients. METHODS: Xarelto pluc Acetylsalicylic acid: Treatment patterns and Outcomes in patients with Atherosclerosis (XATOA) is a single-arm registry of CAD and/or PAD patients. All participants were initiated on low dose rivaroxaban (2.5 mg BID) and aspirin. We report the incidence risk of major adverse cardiovascular events (MACE) or major adverse limb events (MALE) and major bleeding. A classification and regression tree analysis determined independent subgroups. RESULTS: Between November 2018 and May 2020, 5,808 participants were enrolled in XATOA; 5,532 were included in the full analysis. The median follow-up (interquartile range) was 462 (371-577) days. The incidence risk per 100 patient-years of MACE or MALE was highest among participants with polyvascular disease (2 or more vascular beds affected, n = 2,889). The incidence risk was 9.16 versus 2.48 per 100 patient-years in polyvascular and nonpolyvascular patients respectively. Other subgroups of high-risk patients included participants 75 years or older, with a history of diabetes, heart failure, or chronic renal insufficiency (CRI). Rates of major bleeding were low overall. A classification and regression tree analysis showed that polyvascular disease was the most dominant factor separating higher from lower risk participants, and this was heightened with CRI or diabetes. CONCLUSION: Patients with polyvascular disease represent a substantial subset of patients in clinical practice and should be prioritized to receive maximal medical therapy including low dose rivaroxaban (2.5 mg BID) and aspirin.

Effects of complete revascularization according to age in patients with ST-segment elevation myocardial infarction and multivessel disease (COMPLETE-AGE).

BACKGROUND: In ST-segment elevation myocardial infarction (STEMI), complete revascularization with percutaneous coronary intervention (PCI) reduces major cardiovascular events compared with culprit-lesion-only PCI. Whether age influences these results remains unknown. METHODS: COMPLETE was a multinational, randomized trial evaluating a strategy of staged complete revascularization, consisting of angiography-guided PCI of all suitable nonculprit lesions, versus a strategy of culprit-lesion-only PCI. In this prespecified subgroup analysis, treatment effect according to age (≥65 years vs <65 years) was determined for the first coprimary outcome of cardiovascular (CV) death or new myocardial infarction (MI) and the second coprimary outcome of CV death, new MI, or ischemia-driven revascularization (IDR). Median follow-up was 35.8 months (interquartile range [IQR]: 27.6-44.3 months). RESULTS: Of 4,041 patients randomized in COMPLETE, 1,613 were aged ≥ 65 years (39.9%). Higher event rates were observed for both coprimary outcomes in patients aged ≥ 65 years comparted with those aged < 65 years (11.2% vs 7.9%, HR 1.49, 95% CI 1.22-1.83; 14.4% vs 11.8%, HR 1.28, 95% CI 1.07-1.52, respectively). Complete revascularization reduced the first coprimary outcome in patients ≥ 65 years (9.7% vs 12.5%, HR 0.77; 95% CI, 0.58-1.04) and < 65 years (6.7% vs 9.1%, HR 0.72; 95% CI, 0.54-0.96)(interaction P = .74). The second coprimary outcome was reduced in those ≥ 65 years (HR 0.56, 95% CI, 0.43-0.74) and < 65 years (HR 0.48, 95% CI, 0.37-0.61 (interaction P = .37). A sensitivity analysis was performed with consistent results demonstrated using a 75-year threshold (albeit attenuated). CONCLUSIONS: In patients with STEMI and multivessel CAD, complete revascularization compared with culprit-lesion-only PCI reduced major cardiovascular events regardless of patient age and could be considered as a revascularization strategy in older adults.

Effect of Peripheral Interventions in Patients with Peripheral Artery Disease Receiving Rivaroxaban and Aspirin: Analyses from the XATOA Registry.

OBJECTIVE: To assess the characteristics and clinical outcomes of patients with lower extremity peripheral artery disease (PAD) in XATOA receiving dual pathway inhibition (DPI) with rivaroxaban 2.5 mg twice daily plus aspirin according to lower extremity revascularisation (LER) history. METHODS: XATOA is an international, multicentre, prospective, single arm registry study. This subanalysis investigated patients with lower extremity PAD according to LER history. Patients with coronary artery disease, PAD, or both, receiving DPI were followed for 12 or more months. Baseline characteristics and clinical outcomes were assessed according to LER history. A time dependency analysis assessed outcomes by time between the most recent LER procedure and the start of DPI. A multivariate analysis assessed the influence of patient characteristics on clinical outcomes. RESULTS: In XATOA (n = 5 532), 2 820 (51.0%) patients had lower extremity PAD, of whom 1 736 (61.6%) had prior LER and 1 084 (38.4%) had no prior LER. Baseline characteristics were generally similar between patients with or without prior LER. A higher proportion of patients with prior LER experienced any treatment emergent clinical events compared with those without prior LER (15.0% vs. 9.4%, respectively), with greater differences observed between incidence rates of limb events, including major adverse limb events (9.06 vs. 4.09 events per 100 patient years, respectively). Similar rates of myocardial infarction, stroke, and major bleeding were observed in both subgroups. Clinical event rates were generally higher in patients who had previous LER for six months or less compared with patients who had previous LET for more than six months before starting DPI, regardless of LER type. Multivariate analyses showed that prior LER was predictive of limb events. CONCLUSION: This subanalysis of XATOA found that prior LER was associated with increased rates of limb events, consistent with results of COMPASS and VOYAGER PAD. Rates of bleeding were also low regardless of LER history and consistent with the findings from these trials.

A Controlled Trial of Rivaroxaban after Transcatheter Aortic-Valve Replacement.

BACKGROUND: Whether the direct factor Xa inhibitor rivaroxaban can prevent thromboembolic events after transcatheter aortic-valve replacement (TAVR) is unclear. METHODS: We randomly assigned 1644 patients without an established indication for oral anticoagulation after successful TAVR to receive rivaroxaban at a dose of 10 mg daily (with aspirin at a dose of 75 to 100 mg daily for the first 3 months) (rivaroxaban group) or aspirin at a dose of 75 to 100 mg daily (with clopidogrel at a dose of 75 mg daily for the first 3 months) (antiplatelet group). The primary efficacy outcome was the composite of death or thromboembolic events. The primary safety outcome was major, disabling, or life-threatening bleeding. The trial was terminated prematurely by the data and safety monitoring board because of safety concerns. RESULTS: After a median of 17 months, death or a first thromboembolic event (intention-to-treat analysis) had occurred in 105 patients in the rivaroxaban group and in 78 patients in the antiplatelet group (incidence rates, 9.8 and 7.2 per 100 person-years, respectively; hazard ratio with rivaroxaban, 1.35; 95% confidence interval [CI], 1.01 to 1.81; P = 0.04). Major, disabling, or life-threatening bleeding (intention-to-treat analysis) had occurred in 46 and 31 patients, respectively (4.3 and 2.8 per 100 person-years; hazard ratio, 1.50; 95% CI, 0.95 to 2.37; P = 0.08). A total of 64 deaths occurred in the rivaroxaban group and 38 in the antiplatelet group (5.8 and 3.4 per 100 person-years, respectively; hazard ratio, 1.69; 95% CI, 1.13 to 2.53). CONCLUSIONS: In patients without an established indication for oral anticoagulation after successful TAVR, a treatment strategy including rivaroxaban at a dose of 10 mg daily was associated with a higher risk of death or thromboembolic complications and a higher risk of bleeding than an antiplatelet-based strategy. (Funded by Bayer and Janssen Pharmaceuticals; GALILEO ClinicalTrials.gov number, NCT02556203.).

Patients acceptance and comprehension to written and verbal consent (PAC-VC).

BACKGROUND: Acute myocardial infarction (AMI) research is challenging as it requires enrollment of acutely ill patients. Patients are generally in a suboptimal state for providing informed consent. Patients' understanding to verbal assents have not been previously examined in AMI research. Patients Acceptance and Comprehension to Written and Verbal Consent (PAC-VC) compared patients' understanding and attitudes to verbal and written consents in AMI RCTs. METHODS: PAC-VC recruited patients from 3 AMI trials using both verbal N = 12 and written N = 6 consents. We compared patients' understanding using two survey questionnaires. The first questionnaire used open-ended questions with multiple choice answers. The second questionnaire used a 5-point Likert scale to measure patients understanding and attitudes to the consent process. Overall answers average scores were categorized into three groups: Adequate understanding (71-100) %, Partial understanding (41-70)% and Inadequate understanding (0-40)%. RESULTS: Responses showed patients with verbal assent had adequate understanding to most components of informed consent, close to those of written consent. Most patients did not read written information entirely and believed that it is not important to make a final decision. Patients favoured to have written information be part of the consent but not necessarily presented during the initial consent process. Patients felt less pressured in the verbal assent arm than those of written consent. CONCLUSION: Patients had adequate understanding to most components of verbal assent and comparable to those of written consent. Utilizing verbal assents in the acute care setting should be further assessed in larger trials.

Longitudinal surface-based spatial Bayesian GLM reveals complex trajectories of motor neurodegeneration in ALS.

Longitudinal fMRI studies hold great promise for the study of neurodegenerative diseases, development and aging, but realizing their full potential depends on extracting accurate fMRI-based measures of brain function and organization in individual subjects over time. This is especially true for studies of rare, heterogeneous and/or rapidly progressing neurodegenerative diseases. These often involve small samples with heterogeneous functional features, making traditional group-difference analyses of limited utility. One such disease is amyotrophic lateral sclerosis (ALS), a severe disease resulting in extreme loss of motor function and eventual death. Here, we use an advanced individualized task fMRI analysis approach to analyze a rich longitudinal dataset containing 190 hand clench fMRI scans from 16 ALS patients (78 scans) and 22 age-matched healthy controls (112 scans). Specifically, we adopt our cortical surface-based spatial Bayesian general linear model (GLM), which has high power and precision to detect activations in individual subjects, and propose a novel longitudinal extension to leverage information shared across visits. We perform all analyses in native surface space to preserve individual anatomical and functional features. Using mixed-effects models to subsequently study the relationship between size of activation and ALS disease progression, we observe for the first time an inverted U-shaped trajectory of motor activations: at relatively mild motor disability we observe enlarging activations, while at higher levels of motor disability we observe severely diminished activation, reflecting progression toward complete loss of motor function. We further observe distinct trajectories depending on clinical progression rate, with faster progressors exhibiting more extreme changes at an earlier stage of disability. These differential trajectories suggest that initial hyper-activation is likely attributable to loss of inhibitory neurons, rather than functional compensation as earlier assumed. These findings substantially advance scientific understanding of the ALS disease process. This study also provides the first real-world example of how surface-based spatial Bayesian analysis of task fMRI can further scientific understanding of neurodegenerative disease and other phenomena. The surface-based spatial Bayesian GLM is implemented in the BayesfMRI R package.

Two-year clinical outcomes after successful transcatheter aortic valve implantation with balloon-expandable versus self-expanding valves: A subanalysis of the GALILEO trial.

BACKGROUND: Midterm data comparing clinical outcomes after successful implantation of self-expanding and balloon-expandable transcatheter heart valves (THV) are limited. We aimed to compare 2-year outcomes after successful transcatheter aortic valve implantation (TAVI) with the Edwards balloon-expandable or the Medtronic self-expanding THV. METHODS: Two-year outcomes were analyzed according to the implanted THV in the GALILEO trial. Major adverse cardiac and cerebrovascular events (MACCE) was a composite of all-cause death or thromboembolic events including stroke, myocardial infarction, symptomatic valve thrombosis, systemic embolism, deep-vein thrombosis, or pulmonary embolism. RESULTS: Among 1644 patients recruited in 136 centers across 16 countries between 2015 and 2018, 499 received a self-expanding and 757 patients received a balloon-expandable THV. Patients treated with a self-expanding THV were more likely to be female, and had higher surgical risk, lower hemoglobin levels, and more frequent valve-in-valve procedures than those with a balloon-expandable THV. After multivariable adjustment, there were no significant differences in major clinical outcomes between self-expanding versus balloon-expandable THV: MACCE (17.0% vs. 13.4%, adjusted-hazard ratios [HR] 1.18, 95% confidence intervals [CI]: 0.82-1.69); all-cause death (11.4% vs. 9.3%, adjusted-HR 1.26; 95% CI: 0.78-2.05); cardiovascular death (8.5% vs. 4.0%, adjusted-HR 1.53; 95% CI: 0.82-2.86), any stroke (5.1% vs. 3.7%, adjusted-HR 0.86; 95% CI: 0.43-1.73); major or life-threatening bleeding (5.9% vs. 6.8%, adjusted-HR 0.93; 95% CI: 0.53-1.63). CLINICAL TRIAL REGISTRATION: https://www. CLINICALTRIALS: gov. NCT02556203. CONCLUSIONS: Two-year follow-up data from the GALILEO trial indicate that successful TAVI either with self-expanding or balloon-expandable THVs according to physician discretion did not show difference in rates of MACCE.

Is There a Sex Gap in Surviving an Acute Coronary Syndrome or Subsequent Development of Heart Failure?

BACKGROUND: We hypothesized that disparities between sexes in the management of myocardial infarction (MI) may have changed over time, and thus altered the prognoses after MI, especially the risk for the development of heart failure. METHODS: Using a large population-based cohort of patients with MI between April 1, 2002, and March 31, 2016, we examined the incidence, angiographic findings, treatment (including revascularization), and clinical outcomes of patients with a first-time MI. To elucidate the differences between sexes, a series of multivariable models were created to explore all MI and non-ST-segment-elevation MI (NSTEMI) versus ST-segment-elevation MI (STEMI) over time. RESULTS: Between 2002 and 2016, 45 064 patients (13 878 [30.8%] women) were hospitalized with a primary diagnosis of first-time MI (54.9% NSTEMI and 45.1% STEMI). Women were older (median age, 72 versus 61 years), had more comorbidities, and had lower rates of diagnostic angiography than did men (women, 74%, versus men, 87%). When angiography was performed, women had a lower proportion of left main, 2-vessel disease with proximal left anterior descending or 3-vessel disease compared with men (33.4% versus 40.9%, P<0.0001), and a higher frequency of 1-vessel disease or nonobstructive coronary artery disease (39.6% versus 29.1%, P<0.0001). Women had a higher unadjusted rate of in-hospital mortality than did men in both patients with STEMI (women, 9.4%, versus men, 4.5%) and patients with NSTEMI (women, 4.7%, versus men, 2.9%). After adjustment, this difference remained significant in STEMI (adjusted odds ratio, 1.42 [95% CI, 1.24-1.64]) but not in NSTEMI (adjusted odds ratio, 0.97 [95% CI, 0.83-1.13]). After discharge, women developed heart failure after STEMI (women, 22.5%, versus men, 14.9%) as well as after NSTEMI (women, 23.2%, versus men, 15.7%). The adjusted relative risk for women versus men of developing the outcomes of mortality and heart failure remained similar across years, although the differences were nonsignificantly attenuated over 5 years of follow-up. CONCLUSIONS: Although some attenuation of differences in clinical outcomes over time has occurred, women remain at higher risk than men of dying or developing heart failure in the subsequent 5 years after STEMI or NSTEMI, even after accounting for differences in angiographic findings, revascularization, and other confounders.

Rivaroxaban Plus Aspirin Versus Aspirin Alone in Patients With Prior Percutaneous Coronary Intervention (COMPASS-PCI).

BACKGROUND: The COMPASS trial (Cardiovascular Outcomes for People using Anticoagulation Strategies) demonstrated that dual pathway inhibition (DPI) with rivaroxaban 2.5 mg twice daily plus aspirin 100 mg once daily versus aspirin 100 mg once daily reduced the primary major adverse cardiovascular event (MACE) outcome of cardiovascular death, myocardial infarction, or stroke, as well as, mortality, in patients with chronic coronary syndromes or peripheral arterial disease. Whether this remains true in patients with a history of percutaneous coronary intervention (PCI) is unknown. METHODS: In a prespecified subgroup analysis from COMPASS, we examined the outcomes of patients with chronic coronary syndrome with or without a previous PCI treated with DPI versus aspirin alone. Among patients with a previous PCI, we studied the effects of treatment according to the timing of the previous PCI. RESULTS: Of the 27 395 patients in COMPASS, 16 560 patients with a chronic coronary syndrome were randomly assigned to DPI or aspirin, and, of these, 9862 (59.6%) had previous PCI (mean age 68.2±7.8, female 19.4%, diabetes mellitus 35.7%, previous myocardial infarction 74.8%, multivessel PCI 38.0%). Average time from PCI to randomization was 5.4 years (SD, 4.4) and follow-up was 1.98 (SD, 0.72) years. Regardless of previous PCI, DPI versus aspirin produced consistent reductions in MACE (PCI: 4.0% versus 5.5%; hazard ratio [HR], 0.74 [95% CI, 0.61-0.88]; no PCI: 4.4% versus 5.7%; HR, 0.76 [95% CI, 0.61-0.94], P-interaction=0.85) and mortality (PCI: 2.5% versus 3.5%; HR, 0.73 [95% CI, 0.58-0.92]; no PCI: 4.1% versus 5.0%; HR, 0.80 [95% CI, 0.64-1.00], P-interaction=0.59), but increased major bleeding (PCI: 3.3% versus 2.0%; HR, 1.72 [95% CI, 1.34-2.21]; no PCI: 2.9% versus 1.8%; HR, 1.58 [95% CI, 1.15-2.17], P-interaction=0.68). In those with previous PCI, DPI compared with aspirin produced consistent (robust) reductions in MACE irrespective of time since previous PCI (as early as 1 year and as far as 10 years; P-interaction=0.65), irrespective of having a previous myocardial infarction (P-interaction=0.64). CONCLUSIONS: DPI compared with aspirin produced consistent reductions in MACE and mortality but with increased major bleeding with or without previous PCI. Among those with previous PCI 1 year and beyond, the effects on MACE and mortality were consistent irrespective of time since last PCI. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01776424.

Mechanisms of rumination change in adolescent depression (RuMeChange): study protocol for a randomised controlled trial of rumination-focused cognitive behavioural therapy to reduce ruminative habit and risk of depressive relapse in high-ruminating adolescents.

BACKGROUND: Adolescent-onset depression often results in a chronic and recurrent course, and is associated with worse outcomes relative to adult-onset depression. Targeting habitual depressive rumination, a specific known risk factor for relapse, may improve clinical outcomes for adolescents who have experienced a depressive episode. Randomized controlled trials (RCTs) thus far have demonstrated that rumination-focused cognitive behavioral therapy (RFCBT) reduces depressive symptoms and relapse rates in patients with residual depression and adolescents and young adults with elevated rumination. This was also observed in a pilot RCT of adolescents at risk for depressive relapse. Rumination can be measured at the self-report, behavioral, and neural levels- using patterns of connectivity between the Default Mode Network (DMN) and Cognitive Control Network (CCN). Disrupted connectivity is a putative important mechanism for understanding reduced rumination via RFCBT. A feasibility trial in adolescents found that reductions in connectivity between DMN and CCN regions following RFCBT were correlated with change in rumination and depressive symptoms. METHOD: This is a phase III two-arm, two-stage, RCT of depression prevention. The trial tests whether RFCBT reduces identified risk factors for depressive relapse (rumination, patterns of neural connectivity, and depressive symptoms) in adolescents with partially or fully remitted depression and elevated rumination. In the first stage, RFCBT is compared to treatment as usual within the community. In the second stage, the comparator condition is relaxation therapy. Primary outcomes will be (a) reductions in depressive rumination, assessed using the Rumination Response Scale, and (b) reductions in resting state functional magnetic resonance imaging connectivity of DMN (posterior cingulate cortex) to CCN (inferior frontal gyrus), at 16 weeks post-randomization. Secondary outcomes include change in symptoms of depression following treatment, recurrence of depression over 12 months post-intervention period, and whether engagement with therapy homework (as a dose measure) is related to changes in the primary outcomes. DISCUSSION: RFCBT will be evaluated as a putative preventive therapy to reduce the risk of depressive relapse in adolescents, and influence the identified self-report, behavioral, and neural mechanisms of change. Understanding mechanisms that underlie change in rumination is necessary to improve and further disseminate preventive interventions. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03859297 , registered 01 March 2019.

Use of antithrombotic therapy for secondary prevention in patients with stable atherosclerotic cardiovascular disease: Insights from the COordinated National Network to Engage Cardiologists in the antithrombotic Treatment of patients with CardioVascular Disease (CONNECT-CVD) study.

BACKGROUND: Although acetylsalicylic acid is the most commonly used antithrombotic agent for the secondary prevention of cardiovascular events, residual atherothrombotic risk has prompted a guideline recommendation for the addition of dual antiplatelet therapy (DAPT) or dual pathway inhibition (DPI) in high vascular risk patients. Accordingly, the CONNECT CVD quality enhancement initiative provides a contemporary "snapshot" of the clinical features and antithrombotic management of atherosclerotic cardiovascular disease (ASCVD) patients in Canada. METHODS: Canadian cardiologists (49 cardiologists from six provinces) undertook a retrospective chart audit of 10 ASCVD patients in their outpatient practice who met the Cardiovascular Outcomes for People Using Anticoagulation Strategy-like criteria from May 2018 to April 2019. RESULTS: Of the 492 (two cardiologists provided 11 patients) enroled, average age was 70 years, 25% were female, 39% had diabetes and 20% had atrial fibrillation. Prior revascularisation was common (percutaneous coronary artery intervention 61%, coronary artery bypass graft 39%), with 31% having multivessel disease. A total of 47% of patients had a Reduction of Atherothrombosis for Continued Health bleeding score of ≥11 (~2.8% risk of serious bleeding at 2 years). Single antiplatelet therapy (SAPT) alone was most commonly used (62%), while 22% were on DAPT alone. In total, 22% were on oral anticoagulation (OAC), with 16% being on non-vitamin K oral anticoagulant alone, 5% on DPI and 1% received triple therapy. CONCLUSIONS: In contemporary Canadian clinical practice of stable ASCVD patients, a large number of patients receive antithrombotic therapy other than SAPT. Further efforts are required to guide the appropriate selection of patients in whom more potent antithrombotic therapies may safely reduce residual risk.

Antithrombotic Therapy in Patients With Atrial Fibrillation and Acute Coronary Syndrome Treated Medically or With Percutaneous Coronary Intervention or Undergoing Elective Percutaneous Coronary Intervention: Insights From the AUGUSTUS Trial.

BACKGROUND: The safety and efficacy of antithrombotic regimens may differ between patients with atrial fibrillation who have acute coronary syndromes (ACS), treated medically or with percutaneous coronary intervention (PCI), and those undergoing elective PCI. METHODS: Using a 2×2 factorial design, we compared apixaban with vitamin K antagonists and aspirin with placebo in patients with atrial fibrillation who had ACS or were undergoing PCI and were receiving a P2Y12 inhibitor. We explored bleeding, death and hospitalization, as well as death and ischemic events, by antithrombotic strategy in 3 prespecified subgroups: patients with ACS treated medically, patients with ACS treated with PCI, and those undergoing elective PCI. RESULTS: Of 4614 patients enrolled, 1097 (23.9%) had ACS treated medically, 1714 (37.3%) had ACS treated with PCI, and 1784 (38.8%) had elective PCI. Apixaban compared with vitamin K antagonist reduced International Society on Thrombosis and Haemostasis major or clinically relevant nonmajor bleeding in patients with ACS treated medically (hazard ratio [HR], 0.44 [95% CI, 0.28-0.68]), patients with ACS treated with PCI (HR, 0.68 [95% CI, 0.52-0.89]), and patients undergoing elective PCI (HR, 0.82 [95% CI, 0.64-1.04]; Pinteraction=0.052) and reduced death or hospitalization in the ACS treated medically (HR, 0.71 [95% CI, 0.54-0.92]), ACS treated with PCI (HR, 0.88 [95% CI, 0.74-1.06]), and elective PCI (HR, 0.87 [95% CI, 0.72-1.04]; Pinteraction=0.345) groups. Compared with vitamin K antagonists, apixaban resulted in a similar effect on death and ischemic events in the ACS treated medically, ACS treated with PCI, and elective PCI groups (Pinteraction=0.356). Aspirin had a higher rate of bleeding than did placebo in patients with ACS treated medically (HR, 1.49 [95% CI, 0.98-2.26]), those with ACS treated with PCI (HR, 2.02 [95% CI, 1.53-2.67]), and those undergoing elective PCI (HR, 1.91 [95% CI, 1.48-2.47]; Pinteraction=0.479). For the same comparison, there was no difference in outcomes among the 3 groups for the composite of death or hospitalization (Pinteraction=0.787) and death and ischemic events (Pinteraction=0.710). CONCLUSIONS: An antithrombotic regimen consisting of apixaban and a P2Y12 inhibitor without aspirin provides superior safety and similar efficacy in patients with atrial fibrillation who have ACS, whether managed medically or with PCI, and those undergoing elective PCI compared with regimens that include vitamin K antagonists, aspirin, or both. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02415400.

Using resting-state intrinsic network connectivity to identify suicide risk in mood disorders.

BACKGROUND: Little is known about the neural substrates of suicide risk in mood disorders. Improving the identification of biomarkers of suicide risk, as indicated by a history of suicide-related behavior (SB), could lead to more targeted treatments to reduce risk. METHODS: Participants were 18 young adults with a mood disorder with a history of SB (as indicated by endorsing a past suicide attempt), 60 with a mood disorder with a history of suicidal ideation (SI) but not SB, 52 with a mood disorder with no history of SI or SB (MD), and 82 healthy comparison participants (HC). Resting-state functional connectivity within and between intrinsic neural networks, including cognitive control network (CCN), salience and emotion network (SEN), and default mode network (DMN), was compared between groups. RESULTS: Several fronto-parietal regions (k > 57, p < 0.005) were identified in which individuals with SB demonstrated distinct patterns of connectivity within (in the CCN) and across networks (CCN-SEN and CCN-DMN). Connectivity with some of these same regions also distinguished the SB group when participants were re-scanned after 1-4 months. Extracted data defined SB group membership with good accuracy, sensitivity, and specificity (79-88%). CONCLUSIONS: These results suggest that individuals with a history of SB in the context of mood disorders may show reliably distinct patterns of intrinsic network connectivity, even when compared to those with mood disorders without SB. Resting-state fMRI is a promising tool for identifying subtypes of patients with mood disorders who may be at risk for suicidal behavior.

Canadian spontaneous coronary artery dissection cohort study: in-hospital and 30-day outcomes.

AIMS: Spontaneous coronary artery dissection (SCAD) was underdiagnosed and poorly understood for decades. It is increasingly recognized as an important cause of myocardial infarction (MI) in women. We aimed to assess the natural history of SCAD, which has not been adequately explored. METHODS AND RESULTS: We performed a multicentre, prospective, observational study of patients with non-atherosclerotic SCAD presenting acutely from 22 centres in North America. Institutional ethics approval and patient consents were obtained. We recorded baseline demographics, in-hospital characteristics, precipitating/predisposing conditions, angiographic features (assessed by core laboratory), in-hospital major adverse events (MAE), and 30-day major adverse cardiovascular events (MACE). We prospectively enrolled 750 SCAD patients from June 2014 to June 2018. Mean age was 51.8 ± 10.2 years, 88.5% were women (55.0% postmenopausal), 87.7% were Caucasian, and 33.9% had no cardiac risk factors. Emotional stress was reported in 50.3%, and physical stress in 28.9% (9.8% lifting >50 pounds). Predisposing conditions included fibromuscular dysplasia 31.1% (45.2% had no/incomplete screening), systemic inflammatory diseases 4.7%, peripartum 4.5%, and connective tissue disorders 3.6%. Most were treated conservatively (84.3%), but 14.1% underwent percutaneous coronary intervention and 0.7% coronary artery bypass surgery. In-hospital composite MAE was 8.8%; peripartum SCAD patients had higher in-hospital MAE (20.6% vs. 8.2%, P = 0.023). Overall 30-day MACE was 8.8%. Peripartum SCAD and connective tissue disease were independent predictors of 30-day MACE. CONCLUSION: Spontaneous coronary artery dissection predominantly affects women and presents with MI. Despite majority of patients being treated conservatively, survival was good. However, significant cardiovascular complications occurred within 30 days. Long-term follow-up and further investigations on management are warranted.

Amygdala-prefrontal cortex white matter tracts are widespread, variable and implicated in amygdala modulation in adolescents.

The amygdala is critically involved in processing emotion. Through bidirectional connections, the prefrontal cortex (PFC) is hypothesized to influence amygdala reactivity. However, research that elucidates the nature of amygdala-PFC interactions - through mapping amygdala-prefrontal tracts, quantifying variability among tracts, and linking this variability to amygdala activation - is lacking. Using probabilistic tractography to map amygdala-prefrontal white matter connectivity in 142 adolescents, the present study found that white matter connectivity was greater between the amygdala and the subgenual cingulate, orbitofrontal (OFC), and dorsomedial (dmPFC) prefrontal regions than with the dorsal cingulate and dorsolateral regions. Then, using a machine-learning regression, we found that greater amygdala-PFC white matter connectivity was related to attenuated amygdala reactivity. This effect was driven by amygdala white matter connectivity with the dmPFC and OFC, supporting implicit emotion processing theories which highlight the critical role of these regions in amygdala regulation. This study is among the first to map and compare specific amygdala-prefrontal white matter tracts and to relate variability in connectivity to amygdala activation, particularly among a large sample of adolescents from a well-sampled study. By examining the association between specific amygdala-PFC tracts and amygdala activation, the present study provides novel insight into the nature of this emotion-based circuit.

Applying contemporary antithrombotic therapy in the secondary prevention of chronic atherosclerotic cardiovascular disease.

For 4 decades, antithrombotic therapy with aspirin has been a cornerstone of secondary prevention for patients with chronic atherosclerotic cardiovascular disease (ASCVD). Unfortunately, despite the use of evidence-based therapies, patients with ASCVD continue to have recurrent major adverse cardiovascular events including death, myocardial infarction, and stroke-at a rate of approximately 2%-4% per year. To combat this continuing risk, several recent trials have evaluated the efficacy and safety of more intensive antithrombotic strategies through prolonged dual antiplatelet therapy (DAPT), combining a P2Y12 receptor antagonists and low-dose aspirin, or alternatively applying a dual pathway inhibition approach, combining low-dose non-vitamin K antagonist anticoagulant and low-dose aspirin. Both combination strategies have been shown to reduce recurrent ischemic events but at the cost of increased bleeding events. The clinical application of these antithrombotic strategies requires clinicians to assess and balance the risk of recurrent ischemic and bleeding events in an individual patient. Furthermore, clinicians may also need to adapt their antithrombotic strategies to achieve best patient outcomes, as ASCVD is a progressive disease and the risks of cardiovascular ischemic and bleeding events may shift over time. This state-of-the-art article reviews evidence from the trials and provides a practical approach to the application of DAPT and dual pathway antithrombotic therapy in the long-term management of patients with chronic ASCVD.

Developmental changes in resting-state functional networks among individuals with and without internalizing psychopathologies.

BACKGROUND: Three well-established intrinsic connectivity networks (ICNs) involved in cognitive-affective processing include the cognitive control network (CCN), default mode network (DMN), and salience and emotional network (SEN). Despite recent advances in understanding developmental changes in these ICNs, the majority of research has focused on single seeds or networks in isolation with limited age ranges. Additionally, although internalizing psychopathologies (IPs), such as anxiety and depression, are often characterized by maladaptive cognitive-affective processing styles, it is not clear how IP history influences age-related changes in brain networks. METHOD: The current study aimed to characterize the normative development of the CCN, DMN, and SEN across a large age-span (7-29 year olds) of typically developing (TD) individuals (n = 97). We also explore how age may impact differences in network connectivity between TD individuals and patients with IPs (n = 136). RESULTS: Among TD individuals, DMN and CCN connectivity strengthened with age, whereas connectivity between the SEN and ventromedial prefrontal cortex weakened across development. When exploring group (IP vs. TD) differences, the IP group was characterized by greater connectivity between the CCN and cerebellum and between the SEN and caudate from childhood to early adulthood, relative to TD individuals. In addition, patients with IPs, versus TD individuals, exhibited reduced connectivity between the SEN and medial frontal gyrus from adolescence to adulthood. CONCLUSIONS: The current findings shed light on differential age-related changes in brain network patterns among psychiatrically free, TD individuals and those with internalizing disorders, and may provide plausible targets for novel mechanism-based treatments that differ based on developmental stage.

Amygdala habituation and uncinate fasciculus connectivity in adolescence: A multi-modal approach.

Despite prior extensive investigations of the interactions between the amygdala and prefrontal cortex, few studies have simultaneously considered activation and structural connectivity in this circuit, particularly as it pertains to adolescent socioemotional development. The current multi-modal study delineated the correspondence between uncinate fasciculus (UF) connectivity and amygdala habituation in a large adolescent sample that was drawn from a population-based sample. We then examined the influence of demographic variables (age, gender, and pubertal status) on the relation between UF connectivity and amygdala habituation. 106 participants (15-17 years) completed DTI and an fMRI emotional face processing task. Left UF fractional anisotropy was associated with left amygdala habituation to fearful faces, suggesting that increased structural connectivity of the UF may facilitate amygdala regulation. Pubertal status moderated this structure-function relation, such that the association was stronger in those who were less mature. Therefore, UF connectivity may be particularly important for emotion regulation during early puberty. This study is the first to link structural and functional limbic circuitry in a large adolescent sample with substantial representation of ethnic minority participants, providing a more comprehensive understanding of socioemotional development in an understudied population.