Ofatumumab versus Teriflunomide in Multiple Sclerosis.

BACKGROUND: Ofatumumab, a subcutaneous anti-CD20 monoclonal antibody, selectively depletes B cells. Teriflunomide, an oral inhibitor of pyrimidine synthesis, reduces T-cell and B-cell activation. The relative effects of these two drugs in patients with multiple sclerosis are not known. METHODS: In two double-blind, double-dummy, phase 3 trials, we randomly assigned patients with relapsing multiple sclerosis to receive subcutaneous ofatumumab (20 mg every 4 weeks after 20-mg loading doses at days 1, 7, and 14) or oral teriflunomide (14 mg daily) for up to 30 months. The primary end point was the annualized relapse rate. Secondary end points included disability worsening confirmed at 3 months or 6 months, disability improvement confirmed at 6 months, the number of gadolinium-enhancing lesions per T1-weighted magnetic resonance imaging (MRI) scan, the annualized rate of new or enlarging lesions on T2-weighted MRI, serum neurofilament light chain levels at month 3, and change in brain volume. RESULTS: Overall, 946 patients were assigned to receive ofatumumab and 936 to receive teriflunomide; the median follow-up was 1.6 years. The annualized relapse rates in the ofatumumab and teriflunomide groups were 0.11 and 0.22, respectively, in trial 1 (difference, -0.11; 95% confidence interval [CI], -0.16 to -0.06; P<0.001) and 0.10 and 0.25 in trial 2 (difference, -0.15; 95% CI, -0.20 to -0.09; P<0.001). In the pooled trials, the percentage of patients with disability worsening confirmed at 3 months was 10.9% with ofatumumab and 15.0% with teriflunomide (hazard ratio, 0.66; P = 0.002); the percentage with disability worsening confirmed at 6 months was 8.1% and 12.0%, respectively (hazard ratio, 0.68; P = 0.01); and the percentage with disability improvement confirmed at 6 months was 11.0% and 8.1% (hazard ratio, 1.35; P = 0.09). The number of gadolinium-enhancing lesions per T1-weighted MRI scan, the annualized rate of lesions on T2-weighted MRI, and serum neurofilament light chain levels, but not the change in brain volume, were in the same direction as the primary end point. Injection-related reactions occurred in 20.2% in the ofatumumab group and in 15.0% in the teriflunomide group (placebo injections). Serious infections occurred in 2.5% and 1.8% of the patients in the respective groups. CONCLUSIONS: Among patients with multiple sclerosis, ofatumumab was associated with lower annualized relapse rates than teriflunomide. (Funded by Novartis; ASCLEPIOS I and II ClinicalTrials.gov numbers, NCT02792218 and NCT02792231.).

Effect of ofatumumab versus placebo in relapsing multiple sclerosis patients from Japan and Russia: Phase 2 APOLITOS study.

BACKGROUND: Ofatumumab, the first fully human anti-CD20 monoclonal antibody, has been developed as a treatment for relapsing multiple sclerosis (RMS) which can be self-administered at home. OBJECTIVE: To investigate the efficacy and safety of ofatumumab in RMS patients from Japan and Russia. METHODS: APOLITOS included a 24-week, double-blind, placebo-controlled core-part followed by an open-label extension-part. Patients were randomized (2:1) to subcutaneous ofatumumab 20 mg or placebo. Primary outcome was the number of gadolinium-enhancing (Gd+) T1 lesions per scan over 24 weeks. RESULTS: Sixty-four patients were randomized (ofatumumab, n = 43; placebo, n = 21). Primary endpoint was met; ofatumumab reduced Gd + T1 lesions versus placebo by 93.6% (p < 0.001) and the results were consistent across regions (Japan/Russia). Ofatumumab reduced annualized T2 lesion and relapse rate versus placebo by week 24. Both groups showed benefit from ofatumumab in the extension-part. Incidence of adverse events was lower with ofatumumab versus placebo (69.8% vs 81.0%); injection-related reactions were most common. No deaths, opportunistic infections, or malignancies were reported. CONCLUSION: Ofatumumab demonstrated superior efficacy versus placebo, with sustained effect through 48 weeks in RMS patients from Japan/Russia. Switching to ofatumumab after 24 weeks led to rapid radiological and clinical benefits. Safety findings were consistent with pivotal trials.

Efficacy and safety of ofatumumab in recently diagnosed, treatment-naive patients with multiple sclerosis: Results from ASCLEPIOS I and II.

BACKGROUND: In the phase III ASCLEPIOS I and II trials, participants with relapsing multiple sclerosis receiving ofatumumab had significantly better clinical and magnetic resonance imaging (MRI) outcomes than those receiving teriflunomide. OBJECTIVES: To assess the efficacy and safety of ofatumumab versus teriflunomide in recently diagnosed, treatment-naive (RDTN) participants from ASCLEPIOS. METHODS: Participants were randomized to receive ofatumumab (20 mg subcutaneously every 4 weeks) or teriflunomide (14 mg orally once daily) for up to 30 months. Endpoints analysed post hoc in the protocol-defined RDTN population included annualized relapse rate (ARR), confirmed disability worsening (CDW), progression independent of relapse activity (PIRA) and adverse events. RESULTS: Data were analysed from 615 RDTN participants (ofatumumab: n = 314; teriflunomide: n = 301). Compared with teriflunomide, ofatumumab reduced ARR by 50% (rate ratio (95% confidence interval (CI)): 0.50 (0.33, 0.74); p < 0.001), and delayed 6-month CDW by 46% (hazard ratio (HR; 95% CI): 0.54 (0.30, 0.98); p = 0.044) and 6-month PIRA by 56% (HR: 0.44 (0.20, 1.00); p = 0.049). Safety findings were manageable and consistent with those of the overall ASCLEPIOS population. CONCLUSION: The favourable benefit-risk profile of ofatumumab versus teriflunomide supports its consideration as a first-line therapy in RDTN patients.ASCLEPIOS I and II are registered at ClinicalTrials.gov (NCT02792218 and NCT02792231).

Clinical assessment of AF pattern is poorly correlated with AF burden and post ablation outcomes: A CIRCA-DOSE sub-study.

BACKGROUND: Contemporary guidelines recommend that atrial fibrillation (AF) be classified into paroxysmal and persistent AF based on clinical assessment, with these categorizations forming the basis of therapeutic recommendations. While pragmatic, clinical assessment may introduce misclassification errors, which may impact treatment decisions. We sought to determine the relationship between AF classification, baseline AF burden, and post-ablation arrhythmia outcomes. DESIGN: The current study is a sub-analysis of a prospective, parallel-group, multicenter, single-blinded randomized clinical trial. All 346 patients enrolled in CIRCA-DOSE received an implantable cardiac monitor a median of 72 days prior to ablation. AF was classified as low burden paroxysmal, high burden paroxysmal, or persistent based on clinical assessment prior to device implantation. Prior to ablation patients were re-classified using the same definitions based on device monitoring data. Correlation between classifications, AF burden, and post-ablation arrhythmia outcomes were assessed. RESULTS: There was poor agreement between clinical and device-based AF classification (Cohen's kappa: 0.192). AF classification derived from pre-ablation continuous monitoring reflected baseline and post-ablation AF burden with greater accuracy and with less overlap between the AF classes (P < 0.01 for all categorical comparisons). Patients objectively classified as "Low Burden" paroxysmal by continuous monitoring data had significantly greater freedom from recurrent AF/AT/AFL compared to those classified as "High Burden" paroxysmal (hazard ratio [HR] 0.57 for AF/AT/AFL recurrence) or persistent AF (HR 0.19 for AF/AT/AFL recurrence). CONCLUSIONS: Classification of AF pattern based on pre-ablation continuous cardiac rhythm monitoring better predicted AF burden and freedom from recurrent AF post ablation. Despite the use of standardized definitions, classification of AF based on clinical assessment did not predict baseline AF burden, post ablation AF burden, or freedom from recurrent AF post ablation. TRIAL REGISTRATION: ClinicalTrials.govNCT01913522.

Relationship between Time-to-ROSC and Survival in Out-of-hospital Cardiac Arrest ECPR Candidates: When is the Best Time to Consider Transport to Hospital?

OBJECTIVE: Extracorporeal cardiopulmonary resuscitation (ECPR) may improve outcomes for refractory out-of-hospital cardiac arrest (OHCA). Transport of intra-arrest patients to hospital however, may decrease CPR quality, potentially reducing survival for those who would have achieved return-of-spontaneous-circulation (ROSC) with further on-scene resuscitation. We examined time-to-ROSC and patient outcomes for the optimal time to consider transport. METHODS: From a prospective registry of consecutive adult non-traumatic OHCA's, we identified a hypothetical ECPR-eligible cohort of EMS-treated patients with age ≤ 65, witnessed arrest, and bystander CPR or EMS arrival < 10 minutes. We assessed the relationship between time-to-ROSC and survival, and constructed a ROC curve to illustrate the ability of a pulseless state to predict non-survival with conventional resuscitation. RESULTS: Of 6,571 EMS-treated cases, 1,206 were included with 27% surviving. Increasing time-to-ROSC (per minute) was negatively associated with survival (adjusted OR 0.91; 95%CI 0.89-0.93%). The yield of survivors per minute of resuscitation increased from commencement and started to decline in the 8th minute. Fifty percent and 90% of survivors had achieved ROSC by 8.0 and 24 min, respectively, at which times the probability of survival for those with initial shockable rhythms was 31% and 10%, and for non-shockable rhythms was 5.2% and 1.6%. The ROC curve illustrated that the 16th minute of resuscitation maximized sensitivity and specificity (AUC = 0.87, 95% CI 0.85-0.89). CONCLUSION: Transport for ECPR should be considered between 8 to 24 minutes of professional on-scene resuscitation, with 16 minutes balancing the risks and benefits of early and later transport. Earlier transport within this window may be preferred if high quality CPR can be maintained during transport and for those with initial non-shockable rhythms.

Strategies for multivessel revascularization in patients with diabetes.

BACKGROUND: In some randomized trials comparing revascularization strategies for patients with diabetes, coronary-artery bypass grafting (CABG) has had a better outcome than percutaneous coronary intervention (PCI). We sought to discover whether aggressive medical therapy and the use of drug-eluting stents could alter the revascularization approach for patients with diabetes and multivessel coronary artery disease. METHODS: In this randomized trial, we assigned patients with diabetes and multivessel coronary artery disease to undergo either PCI with drug-eluting stents or CABG. The patients were followed for a minimum of 2 years (median among survivors, 3.8 years). All patients were prescribed currently recommended medical therapies for the control of low-density lipoprotein cholesterol, systolic blood pressure, and glycated hemoglobin. The primary outcome measure was a composite of death from any cause, nonfatal myocardial infarction, or nonfatal stroke. RESULTS: From 2005 through 2010, we enrolled 1900 patients at 140 international centers. The patients' mean age was 63.1±9.1 years, 29% were women, and 83% had three-vessel disease. The primary outcome occurred more frequently in the PCI group (P=0.005), with 5-year rates of 26.6% in the PCI group and 18.7% in the CABG group. The benefit of CABG was driven by differences in rates of both myocardial infarction (P<0.001) and death from any cause (P=0.049). Stroke was more frequent in the CABG group, with 5-year rates of 2.4% in the PCI group and 5.2% in the CABG group (P=0.03). CONCLUSIONS: For patients with diabetes and advanced coronary artery disease, CABG was superior to PCI in that it significantly reduced rates of death and myocardial infarction, with a higher rate of stroke. (Funded by the National Heart, Lung, and Blood Institute and others; FREEDOM ClinicalTrials.gov number, NCT00086450.).

The Designed Ankyrin Repeat Protein Antiviral Ensovibep for Nonhospitalized Patients With Coronavirus Disease 2019: Results From EMPATHY, a Randomized, Placebo-Controlled Phase 2 Study.

Background: The coronavirus disease 2019 (COVID-19) pandemic was characterized by rapid evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants, affecting viral transmissibility, virulence, and response to vaccines/therapeutics. EMPATHY (NCT04828161), a phase 2 study, investigated the safety/efficacy of ensovibep, a multispecific designed ankyrin repeat protein (DARPin) with multivariant in vitro activity, in ambulatory patients with mild to moderate COVID-19. Methods: Nonhospitalized, symptomatic patients (N = 407) with COVID-19 were randomized to receive single-dose intravenous ensovibep (75, 225, or 600 mg) or placebo and followed until day 91. The primary endpoint was time-weighted change from baseline in log10 SARS-CoV-2 viral load through day 8. Secondary endpoints included proportion of patients with COVID-19-related hospitalizations, emergency room (ER) visits, and/or all-cause mortality to day 29; time to sustained clinical recovery to day 29; and safety to day 91. Results: Ensovibep showed superiority versus placebo in reducing log10 SARS-CoV-2 viral load; treatment differences versus placebo in time-weighted change from baseline were -0.42 (P = .002), -0.33 (P = .014), and -0.59 (P < .001) for 75, 225, and 600 mg, respectively. Ensovibep-treated patients had fewer COVID-19-related hospitalizations, ER visits, and all-cause mortality (relative risk reduction: 78% [95% confidence interval, 16%-95%]) and a shorter median time to sustained clinical recovery than placebo. Treatment-emergent adverse events occurred in 44.3% versus 54.0% of patients in the ensovibep and placebo arms; grade 3 events were consistent with COVID-19 morbidity. Two deaths were reported with placebo and none with ensovibep. Conclusions: All 3 doses of ensovibep showed antiviral efficacy and clinical benefits versus placebo and an acceptable safety profile in nonhospitalized patients with COVID-19.

Serum Neurofilament Light Trajectories and Their Relation to Subclinical Radiological Disease Activity in Relapsing Multiple Sclerosis Patients in the APLIOS Trial.

INTRODUCTION: Several studies have described prognostic value of serum neurofilament light chain (sNfL) at the group level in relapsing multiple sclerosis (RMS) patients. Here, we aimed to explore the temporal association between sNfL and development of subclinical disease activity as assessed by magnetic resonance imaging (MRI) at the group level and evaluate the potential of sNfL as a biomarker for capturing subclinical disease activity in individual RMS patients. METHODS: In the 12-week APLIOS study, patients (N = 284) received subcutaneous ofatumumab 20 mg. Frequent sNfL sampling (14 time points over 12 weeks) and monthly MRI scans enabled key analyses including assessment of the group-level temporal relationship of sNfL levels with on-study subclinical development of gadolinium-enhancing (Gd +)T1 lesions. Prognostic value of baseline sNfL ("high" vs. "low") level for subsequent on-study clinical relapse or Gd + T1 activity was assessed. Individual patient-level development of on-study Gd + T1 lesions was compared across three predictors: baseline Gd + T1 lesion number, baseline sNfL ("high" vs. "low"), and time-matched sNfL. RESULTS: In patients developing Gd + T1 lesions at week 4 (absent at baseline), sNfL levels increased during the month preceding the week-4 MRI scan and then gradually decreased back to baseline. High versus low baseline sNfL conferred increased risk of subsequent on-study clinical relapse or Gd + T1 activity (HR, 2.81; p < 0.0001) in the overall population and, notably, also in the patients without baseline Gd + T1 lesions (HR, 2.48; p = 0.0213). Individual patient trajectories revealed a marked difference in Gd + T1 lesions between patients with the ten highest vs. lowest baseline sNfL levels (119 vs. 19 lesions). Prognostic value of baseline or time-matched sNfL for on-study Gd + T1 lesions was comparable to that of the number of baseline MRI Gd + T1 lesions. CONCLUSIONS: sNfL measurement may have utility in capturing and monitoring subclinical disease activity in RMS patients. sNfL assessments could complement regular MRI scans and may provide an alternative when MRI assessment is not feasible. CLINICALTRIALS: GOV: NCT03560739. CLASSIFICATION OF EVIDENCE: This study provides class I evidence that serum neurofilament light may be used as a biomarker for monitoring subclinical disease activity in relapsing multiple sclerosis patients, as shown by its elevation in the weeks preceding the development of new gadolinium-enhancing T1 lesion activity.

Genetic testing in monogenic early-onset atrial fibrillation.

A substantial proportion of atrial fibrillation (AF) cases cannot be explained by acquired AF risk factors. Limited guidelines exist that support routine genetic testing. We aim to determine the prevalence of likely pathogenic and pathogenic variants from AF genes with robust evidence in a well phenotyped early-onset AF population. We performed whole exome sequencing on 200 early-onset AF patients. Variants from exome sequencing in affected individuals were filtered in a multi-step process, prior to undergoing clinical classification using current ACMG/AMP guidelines. 200 AF individuals were recruited from St. Paul's Hospital and London Health Sciences Centre who were ≤ 60 years of age and without any acquired AF risk factors at the time of AF diagnosis. 94 of these AF individuals had very early-onset AF ( ≤ 45). Mean age of AF onset was 43.6 ± 9.4 years, 167 (83.5%) were male and 58 (29.0%) had a confirmed family history. There was a 3.0% diagnostic yield for identifying a likely pathogenic or pathogenic variant across AF genes with robust gene-to-disease association evidence. This study demonstrates the current diagnostic yield for identifying a monogenic cause for AF in a well-phenotyped early-onset AF cohort. Our findings suggest a potential clinical utility for offering different screening and treatment regimens in AF patients with an underlying monogenic defect. However, further work is needed to dissect the additional monogenic and polygenic determinants for patients without a genetic explanation for their AF despite the presence of specific genetic indicators such as young age of onset and/or positive family history.

The Future REvascularization Evaluation in patients with Diabetes mellitus: optimal management of Multivessel disease (FREEDOM) trial: clinical and angiographic profile at study entry.

BACKGROUND: The optimal revascularization strategy for diabetic patients with multivessel coronary artery disease (MVD) remains uncertain for lack of an adequately powered, randomized trial. The FREEDOM trial was designed to compare contemporary coronary artery bypass grafting (CABG) to percutaneous coronary intervention (PCI) with drug-eluting stents in diabetic patients with MVD against a background of optimal medical therapy. METHODS: A total of 1,900 diabetic participants with MVD were randomized to PCI or CABG worldwide from April 2005 to March 2010. FREEDOM is a superiority trial with a mean follow-up of 4.37 years (minimum 2 years) and 80% power to detect a 27.0% relative reduction. We present the baseline characteristics of patients screened and randomized, and provide a comparison with other MVD trials involving diabetic patients. RESULTS: The randomized cohort was 63.1 ± 9.1 years old and 29% female, with a median diabetes duration of 10.2 ± 8.9 years. Most (83%) had 3-vessel disease and on average took 5.5 ± 1.7 vascular medications, with 32% on insulin therapy. Nearly all had hypertension and/or dyslipidemia, and 26% had a prior myocardial infarction. Mean hemoglobin A1c was 7.8 ± 1.7 mg/dL, 29% had low-density lipoprotein <70 mg/dL, and mean systolic blood pressure was 134 ± 20 mm Hg. The mean SYNTAX score was 26.2 with a symmetric distribution. FREEDOM trial participants have baseline characteristics similar to those of contemporary multivessel and diabetes trial cohorts. CONCLUSIONS: The FREEDOM trial has successfully recruited a high-risk diabetic MVD cohort. Follow-up efforts include aggressive monitoring to optimize background risk factor control. FREEDOM will contribute significantly to the PCI versus CABG debate in diabetic patients with MVD.

The Morphology of Coronary Artery Disease in South Asians vs White Caucasians and Its Implications.

South Asians (SAs) experience a higher prevalence and earlier onset of coronary artery disease and have worse outcomes compared with White Caucasians (WCs) following invasive revascularisation procedures, a mainstay of coronary artery disease (CAD) management. We sought to review the differences in the CAD pattern and risk factors between SA and WC patients and to discuss their potential impact on the development of coronary disease, acute coronary syndrome, and revascularisation outcomes. SAs have a more diffuse pattern with multivessel involvement compared with WCs. However, less is known about other morphologic characteristics, such as calcification of atherosclerotic plaque and coronary diameter in SA populations. Despite a similar coronary calcification burden, higher noncalcified plaque composition, elevated thrombosis, and inflammatory markers likely contribute to the disease pattern. Although the current evidence on the role of coronary vessel size remains inconsistent, smaller diameters in SAs could play a potential role in the higher disease prevalence. This is especially important given the impact of coronary artery diameter on revascularisation outcomes. In conclusion, SAs have a unique CAD risk profile composed of traditional and novel risk factors. Our findings highlight the need for additional awareness of health professionals of this specific risk profile and potential therapeutic targets, as well as the need for further research in this vulnerable population.

Prognostic Value of Serum Neurofilament Light Chain for Disease Activity and Worsening in Patients With Relapsing Multiple Sclerosis: Results From the Phase 3 ASCLEPIOS I and II Trials.

Objective: This study aims to confirm the prognostic value of baseline serum neurofilament light chain (sNfL) for on-study disease activity and worsening in patients with relapsing MS (RMS). Background: Previous post-hoc studies suggested that sNfL could be a prognostic biomarker in RMS. In the phase 3 ASCLEPIOS I/II trials in which ofatumumab demonstrated better efficacy outcomes than teriflunomide, treatment with ofatumumab also led to significantly reduced sNfL levels compared to teriflunomide treatment. Design/Methods: In this study, we report protocol-planned analyses from the pooled ASCLEPIOS I/II trials (N=1882). Per protocol, patients were stratified by median baseline sNfL levels (9.3 pg/ml) into high (>median) and low (≤median) categories to prognosticate: annualized rate of new/enlarging T2 (neT2) lesions in year 1 and 2, annualized relapse rate, annual percentage change in whole brain (WB) and regional brain volume [thalamus, white matter (WM), cortical gray matter (cGM)], and disability outcomes. Similar analyses were performed for the recently diagnosed (within 3 years), treatment-naive patients (no prior disease-modifying therapy) subgroup. Results: High versus low sNfL at baseline was prognostic of increased on-study T2 lesion formation at year 1 (relative increase: ofatumumab +158%; teriflunomide +69%, both p<0.001), which persisted in year 2 (+65%, p=0.124; +46%, p=0.003); of higher annual percentage change of WB volume (ofatumumab, -0.32% vs. -0.24%, p=0.044, and teriflunomide, -0.43% vs. -0.29%, p=0.002), thalamic volume (-0.56% vs. -0.31%, p=0.047 and -0.94% vs. -0.49%, p<0.001), and WM volume (-0.30% vs. -0.19%, p=0.083 and -0.38% vs. -0.18%, p=0.003) but not of cGM volume (-0.39% vs. -0.32%, p=0.337 and -0.49% vs. -0.46%, p=0.563). A single sNfL assessment at baseline was not prognostic for on-study relapses or disability worsening. Results were similar in the subgroup of recently diagnosed, treatment-naive patients. Conclusion: This study confirms that baseline sNfL levels are prognostic of future on-study lesion formation and whole brain and regional atrophy in all RMS patients, including recently diagnosed, treatment-naive patients.

Population Pharmacokinetic-B Cell Modeling for Ofatumumab in Patients with Relapsing Multiple Sclerosis.

BACKGROUND: Ofatumumab, a fully human anti-CD20 monoclonal antibody indicated for the treatment of relapsing forms of multiple sclerosis (RMS), binds to a unique conformational epitope, thereby depleting B cells very efficiently and allowing subcutaneous administration at lower doses. OBJECTIVES: The aims were to characterize the relationship between ofatumumab concentration and B cell levels, including the effect of covariates such as body weight, age, or baseline B cell count, and use simulations to confirm the chosen therapeutic dose. METHODS: Graphical and regression analyses previously performed based on data from a dose-range finding study provided the B cell depletion target used in the present work. All available adult phase 2/3 data for ofatumumab in RMS patients were pooled to develop a population pharmacokinetics (PK)-B cell count model, using nonlinear mixed-effects modeling. The population PK-B cell model was used to simulate B cell depletion and repletion times and the effect of covariates on PK and B cell metrics, as well as the dose response across a range of subcutaneous ofatumumab monthly doses. RESULTS: The final PK-B cell model was developed using data from 1486 patients. The predetermined B cell target was best achieved and sustained with the 20-mg dose regimen, with median B cell count reaching 8 cells/µL in 11 days and negligible repletion between doses. Only weight had a significant effect on PK, which did not translate into any clinically relevant effect on B cell levels. CONCLUSION: The PK-B cell modeling confirms the dose chosen for the licensed ofatumumab regimen and demonstrates no requirement for dose adjustment based on adult patient characteristics.

Effect of ofatumumab on pregnancy, parturition, and lactation in cynomolgus monkeys.

Knowledge of the impacts of the anti-CD20 monoclonal antibody ofatumumab on the developing immune system is limited. This study examined the effects of intravenous ofatumumab on pregnancy, parturition, and lactation, and on pre- and postnatal survival and development in cynomolgus monkeys, an established model for developmental toxicity assessment. Pregnant cynomolgus monkeys (n = 42) were randomized to receive vehicle only (control group; n = 14), low-dose ofatumumab (n = 14), or high-dose ofatumumab (n = 14). Survival, clinical outcomes, and clinical pathology investigations were evaluated regularly until lactation day (maternal animals) and postnatal day 180±1 (infants). Anatomic pathology was investigated in euthanized infants and unscheduled terminations of maternal animals and infants. Ofatumumab treatment was not associated with maternal toxicity or embryotoxicity and had no effect on the growth and development of offspring. As expected, B-cell depletion occurred in maternal animals and their offspring, with a reduced humoral immune response in infants of mothers on high-dose ofatumumab. Both effects were reversible. In the high-dose group, perinatal deaths of 3 infants were attributed to infections, potentially secondary to pharmacologically induced immunosuppression. The no-observed adverse-effect level for initial/maintenance ofatumumab doses was 100/20 mg, and 10/3 mg/kg for pharmacological effects in infant animals, which are associated with exposures significantly higher than those following therapeutic doses in humans. In this study with cynomolgus monkeys, ofatumumab treatment was not associated with maternal toxicity or embryotoxicity and had no effect on the growth and development of offspring.

Rapid complete reversal of systemic hypoperfusion after intra-aortic balloon pump counterpulsation and survival in cardiogenic shock complicating an acute myocardial infarction.

BACKGROUND: In patients with cardiogenic shock (CS) complicating an acute myocardial infarction, a strategy of early revascularization (ERV) versus initial medical stabilization (IMS) improves survival. Intra-aortic balloon counterpulsation (IABC) provides hemodynamic support and facilitates coronary angiography and revascularization in CS patients. METHODS AND RESULTS: We evaluated 499 patients with record of systemic hypoperfusion status as an early response to IABC from the SHOCK trial (n = 185) and registry (n = 314) to determine the association between rapid complete reversal of systemic hypoperfusion (CRH) after 30 minutes of IABC and in-hospital, 30-day and 1-year mortality. Rapid complete reversal of systemic hypoperfusion was highly associated with lower in-hospital mortality (29% versus 65%, P < .001) in all patients. In the SHOCK trial, among patients assigned to ERV versus IMS, 30-day mortality was 26% versus 29%, respectively, with CRH and 61% versus 81%, respectively, without CRH after commencing IABC. The corresponding 1-year mortality rates were 35% versus 52% for ERV and 69% versus 87% for IMS (interaction P ≥ .25 at both time points). After adjusting for important correlates of outcome (left ventricular ejection fraction, age, and randomization to ERV), a significant association remained between CRH and registry and trial in-hospital mortality (odds ratio 0.23, 95% CI 0.14-0.39, P < .001) and trial 1-year mortality (odds ratio .28, 95% CI 0.12-0.67, P < .001). CONCLUSIONS: In CS patients, CRH after commencing IABC was independently associated with improved in-hospital, 30-day and 1-year survival regardless of early revascularization. In CS patients, CRH with IABC is an important early prognostic feature.

Temporal changes in the management and outcome of Canadian diabetic patients hospitalized for non-ST-elevation acute coronary syndromes.

BACKGROUND: There are limited data on the contemporary management and outcomes of non-ST-elevation acute coronary syndrome (NSTE-ACS) patients with diabetes in the "real world." We sought to evaluate (1) the temporal changes in the medical and invasive management and (2) in-hospital outcome of NSTE-ACS patients with and without diabetes. METHODS: We included Canadian patients hospitalized for NSTE-ACS enrolled in 4 consecutive, prospective, multicenter registries: Canadian ACS-I (n = 3259; 1999-2001), ACS-II (n = 1,956; 2002-2003), Global Registry of Acute Coronary Events (GRACE/GRACE2 [n = 7,561; 2004-2007]) and Canadian Registry of Acute Coronary Events (n = 1,326; 2008). Participants were stratified by the presence or absence of preexisting diabetes on admission. Temporal changes in patient management and outcomes were evaluated across the 4 registries. Multivariable analyses were performed to determine the independent prognostic significance of diabetes. RESULTS: Of the 14,102 NSTE-ACS patients, 4,046 (28.7%) had previously diagnosed diabetes. Patients with diabetes were older; were more likely to have prior cardiac history including myocardial infarction, revascularization, and heart failure; and had worse Killip class and higher GRACE risk score (all P < .001). Over time, there were significant increases in the use of in-hospital coronary angiography and revascularization. However, diabetic patients were less likely to undergo coronary angiography (52.5% vs 57%, P < .001) or revascularization (28.4% vs 33.4%, P < .001). The underuse of invasive procedures in diabetic patients was seen in all registries and was persistent over time. Overall, compared with the group without diabetes, diabetic patients had higher unadjusted rates of in-hospital mortality (3.0% vs 1.6%, P < .001). In multivariable analysis adjusting for components of the GRACE risk score, diabetes remained an independent predictor of in-hospital death (adjusted odds ratio 1.66, 95% CI 1.30-2.11, P < .001). CONCLUSIONS: Over the last decade, NSTE-ACS patients with diabetes continue to be treated more conservatively, despite evidence that they would derive similar or even greater benefits from aggressive treatment. This underutilization of evidence-based therapies among diabetic patients with NSTE-ACS in the "real world" may partly explain their worse outcome.

Acute Myocarditis Following mRNA-1273 SARS-CoV-2 Vaccination.

Myocarditis has been described previously as a rare side effect of both influenza and smallpox vaccines. In this report, we present a case of acute perimyocarditis in a young, healthy man after vaccination with the mRNA-1273 severe acute respiratory syndrome coronavirus -2 (SARS-CoV-2; Moderna) vaccine. He presented with chest pain and decompensated heart failure 3 days after administration of his second dose, and his symptoms resolved by 9 days post-inoculation. This case highlights a rare but potentially serious side effect of this mRNA vaccine that primary care physicians and cardiologists should be aware of in order to identify and appropriately manage these patients.

La myocardite a auparavant été considérée comme un effet secondaire rare des vaccins antigrippaux et antivarioliques. Dans ce rapport, nous présentons le cas d'un homme, jeune et en bonne santé, atteint d'une périmyocardite aiguë après avoir reçu le vaccin à ARNm-1273 contre le coronavirus du syndrome respiratoire aigu sévère 2 (SARS-CoV-2, de l'anglais severe acute respiratory syndrome coronavirus-2; Moderna). Il a éprouvé une douleur thoracique et présenté une décompensation cardiaque 3 jours après l'administration de la seconde dose. Les symptômes se sont résorbés 9 jours après l'inoculation. Ce cas illustre un effet secondaire rare, mais potentiellement sérieux, de ce vaccin à ARNm, que les médecins de premier recours et les cardiologues doivent connaître pour être en mesure de détecter et prendre en charge adéquatement ces patients.

Lifestyle modification program, LIFE is LIGHT, in patients with type 2 diabetes mellitus and obesity: Results from a 48-week, multicenter, non-randomized, parallel-group, open-label study.

BACKGROUND: Obesity is a potential risk factor for development of type 2 diabetes mellitus (T2DM). To achieve long-term weight reduction in patients with T2DM and obesity using comprehensive lifestyle management program (LMP). MATERIALS AND METHODS: This 48-week interventional, multicenter, parallel-group, open-label study included patients aged ≥18 years with T2DM and a body mass index (BMI) of 27-40 kg/m2. The primary objective was to demonstrate a clinically significant weight reduction (≥5%) from baseline in intensive lifestyle modification (ILM) and standard treatment (ST) groups. RESULTS: The ILM group (N = 100) received recommendations for dietary and physical activity, and behavioral counseling. The ST group (N = 30) was managed in accordance with routine T2DM clinical practice. The patients in ST group were older (60.6 ± 8.9 vs. 54.6 ± 10.2 years in ILM group); overall more than 60% were women. At Week 48, the mean reduction in body weight was 5.8% (95% confidence interval [CI]: -6.9, -4.6) and 1.2% (95% CI: -2.6, 0.2) (p < 0.001) in the ILM and ST group, respectively. At Week 48, a weight loss of ≥5% was achieved by 50% of patients in the ILM group versus 13.3% in the ST group (p = 0.002). The decreases in BMI, waist-to-hip ratio and glycated hemoglobin (HbA1c) was significantly greater in the ILM versus ST group with between-group differences of -1.63 (p ≤ 0.001), -0.03 (р ≤ 0.001) and -0.69% (p = 0.002), respectively. CONCLUSION: A clinically significant weight reduction (≥5%) was demonstrated in patients with obesity and T2DM with use of a comprehensive LMP, along with improvements in BMI, waist-to-hip ratio, and HbA1c.

Long COVID-19: A Primer for Cardiovascular Health Professionals, on Behalf of the CCS Rapid Response Team.

It is now widely recognized that COVID-19 illness can be associated with significant intermediate and potentially longer-term physical limitations. The term, "long COVID-19" is used to define any patient with persistent symptoms after acute COVID-19 infection (ie, after 4 weeks). It is postulated that cardiac injury might be linked to symptoms that persist after resolution of acute infection, as part of this syndrome. The Canadian Cardiovascular Society Rapid Response Team has generated this document to provide guidance to health care providers on the optimal management of patients with suspected cardiac complications of long COVID-19.

Examining Coronary Revascularization Practice Patterns for Diabetics: Perceived Barriers, Facilitators, and Implications for Knowledge Translation.

BACKGROUND: The FREEDOM trial provided robust evidence that coronary artery bypass grafting (CABG) was superior to percutaneous coronary intervention (PCI) for coronary revascularization in patients with diabetes mellitus (DM) and multivessel coronary artery disease (MV-CAD). The present study examined practice pattern changes and perceived barriers and facilitators to implementing FREEDOM trial evidence in British Columbia (BC). METHODS: Using a population-based database of cardiac procedures in BC, PCI:CABG ratios from 2007-2014 were compared before and after publication of the FREEDOM trial in the 4 tertiary cardiac centres that provided both CABG and PCI. Surveys of barriers and facilitators to implementation of evidence in practice were completed by 57 health care providers (HCPs) attending educational outreach sessions conducted in 2016-17 at 5 tertiary cardiac centres in BC. RESULTS: The overall PCI:CABG ratio declined from 1.59 (95% confidence interval [CI] 1.48-1.70, range 1.16-1.86) before publication to 0.88 (95% CI 0.75-1.01, range 0.56-0.82) after publication (P < 0.01). This decline from before to after publication was significant in 3 centres, but not in the fourth centre (from 1.62 to 1.49; P = 0.61). Barriers were identified at the levels of evidence (applicability, credibility), HCP (awareness/knowledge, practice behaviours), patient (knowledge/misconceptions, preferences), and systems (siloing of care, financial disincentives, resource limitations, geography). Facilitators were additional studies/guidelines, education/dissemination, shared decision making, a heart team approach, changes to remuneration models, and increased resources. CONCLUSIONS: Following publication of the FREEDOM trial, the proportion of patients with DM and MV-CAD undergoing CABG increased in BC; however, practice patterns varied across cardiac centres. HCPs attributed these practice variations to multilevel barriers and facilitators. Future knowledge translation strategies should be multifaceted and tailored to identified determinants.