Abatacept, Cenicriviroc, or Infliximab for Treatment of Adults Hospitalized With COVID-19 Pneumonia: A Randomized Clinical Trial.

Importance: Immune dysregulation contributes to poorer outcomes in COVID-19. Objective: To investigate whether abatacept, cenicriviroc, or infliximab provides benefit when added to standard care for COVID-19 pneumonia. Design, Setting, and Participants: Randomized, double-masked, placebo-controlled clinical trial using a master protocol to investigate immunomodulators added to standard care for treatment of participants hospitalized with COVID-19 pneumonia. The results of 3 substudies are reported from 95 hospitals at 85 clinical research sites in the US and Latin America. Hospitalized patients 18 years or older with confirmed SARS-CoV-2 infection within 14 days and evidence of pulmonary involvement underwent randomization between October 2020 and December 2021. Interventions: Single infusion of abatacept (10 mg/kg; maximum dose, 1000 mg) or infliximab (5 mg/kg) or a 28-day oral course of cenicriviroc (300-mg loading dose followed by 150 mg twice per day). Main Outcomes and Measures: The primary outcome was time to recovery by day 28 evaluated using an 8-point ordinal scale (higher scores indicate better health). Recovery was defined as the first day the participant scored at least 6 on the ordinal scale. Results: Of the 1971 participants randomized across the 3 substudies, the mean (SD) age was 54.8 (14.6) years and 1218 (61.8%) were men. The primary end point of time to recovery from COVID-19 pneumonia was not significantly different for abatacept (recovery rate ratio [RRR], 1.12 [95% CI, 0.98-1.28]; P = .09), cenicriviroc (RRR, 1.01 [95% CI, 0.86-1.18]; P = .94), or infliximab (RRR, 1.12 [95% CI, 0.99-1.28]; P = .08) compared with placebo. All-cause 28-day mortality was 11.0% for abatacept vs 15.1% for placebo (odds ratio [OR], 0.62 [95% CI, 0.41-0.94]), 13.8% for cenicriviroc vs 11.9% for placebo (OR, 1.18 [95% CI 0.72-1.94]), and 10.1% for infliximab vs 14.5% for placebo (OR, 0.59 [95% CI, 0.39-0.90]). Safety outcomes were comparable between active treatment and placebo, including secondary infections, in all 3 substudies. Conclusions and Relevance: Time to recovery from COVID-19 pneumonia among hospitalized participants was not significantly different for abatacept, cenicriviroc, or infliximab vs placebo. Trial Registration: ClinicalTrials.gov Identifier: NCT04593940.

Abatacept for Treatment of Adults Hospitalized with Moderate or Severe Covid-19.

Background: We investigated whether abatacept, a selective costimulation modulator, provides additional benefit when added to standard-of-care for patients hospitalized with Covid-19. Methods: We conducted a master protocol to investigate immunomodulators for potential benefit treating patients hospitalized with Covid-19 and report results for abatacept. Intravenous abatacept (one-time dose 10 mg/kg, maximum dose 1000 mg) plus standard of care (SOC) was compared with shared placebo plus SOC. Primary outcome was time-to-recovery by day 28. Key secondary endpoints included 28-day mortality. Results: Between October 16, 2020 and December 31, 2021, a total of 1019 participants received study treatment (509 abatacept; 510 shared placebo), constituting the modified intention-to-treat cohort. Participants had a mean age 54.8 (SD 14.6) years, 60.5% were male, 44.2% Hispanic/Latino and 13.7% Black. No statistically significant difference for the primary endpoint of time-to-recovery was found with a recovery-rate-ratio of 1.14 (95% CI 1.00-1.29; p=0.057) compared with placebo. We observed a substantial improvement in 28-day all-cause mortality with abatacept versus placebo (11.0% vs. 15.1%; odds ratio [OR] 0.62 [95% CI 0.41- 0.94]), leading to 38% lower odds of dying. Improvement in mortality occurred for participants requiring oxygen/noninvasive ventilation at randomization. Subgroup analysis identified the strongest effect in those with baseline C-reactive protein >75mg/L. We found no statistically significant differences in adverse events, with safety composite index slightly favoring abatacept. Rates of secondary infections were similar (16.1% for abatacept; 14.3% for placebo). Conclusions: Addition of single-dose intravenous abatacept to standard-of-care demonstrated no statistically significant change in time-to-recovery, but improved 28-day mortality. Trial registration: ClinicalTrials.gov ( NCT04593940 ).

Rationale and design of a multicenter randomized clinical trial of vestibulodynia: understanding pathophysiology and determining appropriate treatments (vestibulodynia: UPDATe).

BACKGROUND: Limited data are available to establish evidence-based management protocols for vestibulodynia (VBD), a chronic vulvar pain condition that affects approximately 14 million women in the U.S. For the purposes of the study, our group subdivided VBD subtypes that may benefit from different types of treatment: 1) VBD peripheral (VBD-p), characterized by pain localized to the vulvar vestibule and 2) VBD central (VBD-c), characterized by VBD alongside one or more other chronic overlapping pain conditions (e.g. irritable bowel syndrome, temporomandibular disorder, and fibromyalgia syndrome) that affect remote body regions. Here, we describe the rationale and design of an NIH-funded multicenter clinical trial comparing the effectiveness of topical and/or systemic medication for alleviating pain and normalizing pain- relevant biomarkers among women with VBD-p and VBD-c. METHODS: Participants will be randomly assigned to one of four parallel arms: peripheral treatment with 5% lidocaine + 0.5 mg/ml 0.02% oestradiol compound cream + oral placebo pill, 2) central treatment with the tricyclic antidepressant nortriptyline + placebo cream, 3) combined peripheral cream and central pill treatments, or 4) placebo cream and placebo pill. The treatment phase will last 16 weeks, with outcome measures and biomarkers assessed at 4 time points (0, 8, 16, and 24 weeks). First, we will compare the efficacy of treatments in alleviating pain using standardized tampon insertion with a numeric rating scale and self-reported pain on the short form McGill Pain Questionnaire. Next, we will compare the efficacy of treatments in improving perceived physical, mental, and sexual health using standardized questionnaires. Finally, we will measure cytokines and microRNAs in local vaginal and circulating blood samples using multiplex assays and RNA sequencing, and determine the ability of these biomarkers to predict treatment response. CONCLUSION: This is the first multicenter randomized controlled trial to evaluate the efficacy of peripherally and centrally acting medications currently used in clinical practice for treating unique VBD subtypes based on distinct clinical and biological signatures. ADMINISTRATIVE INFORMATION: Vestibulodynia UPDATe is a multi-centre, two-by-two factorial designed randomized, double-blind, placebo-controlled trial registered at clinical trials.gov (NCT03844412). This work is supported by the R01 HD096331 awarded to Drs. Nackley, Rapkin, Geller and Carey by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD).Key messagesPeripheral lidocaine and oestradiol and centrally-targeted nortriptyline medications are used for the treatment of pain in women with VBD, but there is a lack of data from well-powered RCTs.This two-by-two factorial RCT will test the efficacy of these medications in VBD subtypes characterized by distinct clinical characteristics and biomarker profiles.We hope that results will provide clinicians with scientific evidence of therapeutic efficacy in distinct VBD subtypes in an effort to direct and optimize treatment approaches.

Infliximab for Treatment of Adults Hospitalized with Moderate or Severe Covid-19.

Background: Immune dysregulation contributes to poorer outcomes in severe Covid-19. Immunomodulators targeting various pathways have improved outcomes. We investigated whether infliximab provides benefit over standard of care. Methods: We conducted a master protocol investigating immunomodulators for potential benefit in treatment of participants hospitalized with Covid-19 pneumonia. We report results for infliximab (single dose infusion) versus shared placebo both with standard of care. Primary outcome was time to recovery by day 29 (28 days after randomization). Key secondary endpoints included 14-day clinical status and 28-day mortality. Results: A total of 1033 participants received study drug (517 infliximab, 516 placebo). Mean age was 54.8 years, 60.3% were male, 48.6% Hispanic or Latino, and 14% Black. No statistically significant difference in the primary endpoint was seen with infliximab compared with placebo (recovery rate ratio 1.13, 95% CI 0.99-1.29; p=0.063). Median (IQR) time to recovery was 8 days (7, 9) for infliximab and 9 days (8, 10) for placebo. Participants assigned to infliximab were more likely to have an improved clinical status at day 14 (OR 1.32, 95% CI 1.05-1.66). Twenty-eight-day mortality was 10.1% with infliximab versus 14.5% with placebo, with 41% lower odds of dying in those receiving infliximab (OR 0.59, 95% CI 0.39-0.90). No differences in risk of serious adverse events including secondary infections. Conclusions: Infliximab did not demonstrate statistically significant improvement in time to recovery. It was associated with improved 14-day clinical status and substantial reduction in 28- day mortality compared with standard of care. Trial registration: ClinicalTrials.gov ( NCT04593940 ).

Prophylactic Mechanical Circulatory Support Use in Elective Percutaneous Coronary Intervention for Patients With Stable Coronary Artery Disease.

BACKGROUND: Mechanical circulatory support (MCS) devices can be used in high-risk percutaneous coronary intervention (PCI). Our objective was to describe trends and outcomes of prophylactic MCS use in elective PCI for patients with stable coronary artery disease in the American College of Cardiology National Cardiovascular Data Registry's CathPCI registry. METHODS: Among 2 108 715 consecutive patients with stable coronary artery disease undergoing elective PCI in the CathPCI registry between 2009 and 2018, we examined patterns of prophylactic use of MCS. Propensity score models with inverse probability of treatment weighting compared effectiveness (in-hospital death, cardiogenic shock, or new heart failure) and safety (stroke, tamponade, major bleeding, or vascular complication requiring treatment) between patients treated with intra-aortic balloon pump versus other MCS (Impella or extracorporeal membrane oxygenation). RESULTS: Overall, 6905 (0.3%) patients underwent elective PCI with prophylactic MCS. MCS use trended up from 0.2% of elective PCIs in 2009 to 0.6% in 2018 (P<0.0001), driven by other MCS (P<0.0001), whereas intra-aortic balloon pump use remained low and constant (P=0.12). In-hospital major adverse cardiac events and cardiovascular complications occurred in 7.1% and 18.8% of elective PCI patients with prophylactic MCS use and 0.5% and 2.3% of patients without prophylactic MCS use. Intra-aortic balloon pump use was associated with a higher risk of major adverse cardiac events (9.6% versus 6.0%, adjusted odds ratio, 1.59 [95% CI, 1.32-1.91]) but lower risk of complications (18.2% versus 19.1%, adjusted odds ratio, 0.88 [95% CI, 0.77-0.99]) than use of other MCS. CONCLUSIONS: The use of prophylactic MCS has increased over time for elective PCI in patients with stable coronary artery disease. Intra-aortic balloon pump was associated with higher major adverse cardiac events but lower risk of procedural complications compared with other MCS.

Differential Longitudinal Outcomes Following Percutaneous Coronary Intervention to the Left Internal Mammary Artery and Other Bypass Grafts of the LAD: Findings From the NCDR.

OBJECTIVES: Limited studies of percutaneous coronary intervention (PCI) of the left internal mammary artery (LIMA) graft exist. We compared outcomes of different bypass grafts to the left anterior descending (LAD) coronary artery. METHODS: Participants ≥65 years old in the CathPCI Registry who underwent PCI of a bypass graft to the LAD between 2009 and 2014 were included. Individuals were divided by graft type: LIMA; saphenous vein graft (SVG); or other. Clinical characteristics and outcomes using Medicare claims data for mortality, rehospitalization for myocardial infarction (MI), stroke, or unplanned repeat revascularization at 1 year were examined. RESULTS: There were 10,051 PCIs performed on grafts to the LAD: 6797 SVGs (67.6%), 3011 LIMA grafts (30.0%); and 243 other (2.4%). Procedural success rates (SVG 92.9%, LIMA 91.1%, other 93.4%; P=.65) and in-patient mortality rates (SVG 3.0%, LIMA 2.7%, other 2.1%; P=.61) were similar. However, dissection rates were higher in LIMA interventions (SVG 0.7%, LIMA 2.8%, other 2.5%; P<.001). At 1 year, mortality, MI, and repeat revascularization were lower in arterial grafts (mortality: SVG 16.6%, LIMA 14.8%, other 11.8% [P<.001]; MI: SVG 9.9%, LIMA, 6.6%, other 8.1% [P<.001]; revascularization: SVG 14.4%, LIMA 9.5%, other 10.4% [P<.001]). After multivariable adjustment, LIMA patients had lower rates of MI (hazard ratio, 0.71; 95% confidence interval, 0.60-0.84) and repeat revascularization (hazard ratio, 0.68; 95% confidence interval, 0.59-0.79) compared with the SVG group. Mortality was not significantly different. CONCLUSIONS: Despite similar procedural success rates compared with SVG and other graft types, LIMA interventions were independently associated with lower rates of recurrent MI and repeat revascularization at 1 year.

Establishment of normative ranges of the healthy human immune system with comprehensive polychromatic flow cytometry profiling.

Existing normative flow cytometry data have several limitations including small sample sizes, incompletely described study populations, variable flow cytometry methodology, and limited depth for defining lymphocyte subpopulations. To overcome these issues, we defined high-dimensional flow cytometry reference ranges for the healthy human immune system using Human Immunology Project Consortium methodologies after carefully screening 127 subjects deemed healthy through clinical and laboratory testing. We enrolled subjects in the following age cohorts: 18-29 years, 30-39, 40-49, and 50-66 and enrolled cohorts to ensure an even gender distribution and at least 30% non-Caucasians. From peripheral blood mononuclear cells, flow cytometry reference ranges were defined for >50 immune subsets including T-cell (activation, maturation, T follicular helper and regulatory T cell), B-cell, and innate cells. We also developed a web tool for visualization of the dataset and download of raw data. This dataset provides the immunology community with a resource to compare and extract data from rigorously characterized healthy subjects across age groups, gender and race.

Association of Physician Variation in Use of Manual Aspiration Thrombectomy With Outcomes Following Primary Percutaneous Coronary Intervention for ST-Elevation Myocardial Infarction: The National Cardiovascular Data Registry CathPCI Registry.

Importance: Following negative randomized clinical trials, US guidelines downgraded support for routine manual aspiration thrombectomy (AT) during primary percutaneous coronary intervention (pPCI) for ST-segment elevation myocardial infarction (STEMI). However, some PCI operators continue to endorse a clinical benefit with AT use despite the lack of supportive data. Objective: To examine temporal trends and comparative outcomes of AT use during pPCI for STEMI. Design, Setting, and Participants: Retrospective cohort study of the National Cardiovascular Data Registry (NCDR) CathPCI Registry from July 1, 2009, to June 30, 2016, to assess temporal trends and in-hospital outcomes associated with AT use. To evaluate outcomes through 180 days, a subanalysis was conducted among Centers for Medicare and Medicaid Services-linked patients from July 1, 2009, through December 31, 2014. The comparative effectiveness analysis was performed using instrumental variable analyses to account for treatment selection bias. The instrumental variable was operator's preference to use AT during pPCI. Data were analyzed between February 1, 2017, and April 1, 2018. Exposures: Aspiration thrombectomy use during pPCI for STEMI. Main Outcomes and Measures: Primary outcomes included in-hospital stroke and death. Secondary outcomes included heart failure, stroke, all-cause rehospitalization, and death through 180 days of follow-up. Results: Among all pPCIs performed (683 584), the mean (SD) age of patients was 61.7 (12.8) years, 489 257 were male (71.6%), and 596 384 were white (87.2%). Among patients undergoing pPCI, AT use increased from 2009 through 2011, with peak use of 13.8%. This was followed by a decline of more than 9%, reaching 4.7% by mid-2016. Overall, AT was used in 10.8% of pPCIs (lowest operator group median, 0%; highest operator group median, 33.8%). After instrumental variable analysis, AT use was associated with no difference in in-hospital death (adjusted absolute risk difference, -0.18%; 95% CI, -0.53% to 0.16%; P = .29) and a small increase in in-hospital stroke (adjusted RD, 0.14%; 95% CI, 0.01%-0.30%; P = .03). Among Centers for Medicare and Medicaid Services-linked patients, AT use was not associated with differences in death, heart failure, stroke, or rehospitalization at 180 days. Conclusions and Relevance: In this large, nationwide analysis, AT use during STEMI pPCI declined by more than 50% since 2011, with use as of mid-2016 at less than 5%. Selective AT use was associated with a small excess risk of in-hospital stroke and no difference in other outcomes through 180 days of follow-up.

Usefulness of Antithrombotic Therapy in Patients With Atrial Fibrillation and Acute Myocardial Infarction.

To examine patterns of preadmission and discharge antithrombotic therapies in coronary artery disease (CAD) and atrial fibrillation (AF) patients admitted for acute myocardial infarction (AMI), we performed a retrospective analysis of the Acute Coronary Treatment and Intervention Outcomes Network Registry-Get With the Guidelines (ACTION Registry-GWTG), which captures consecutive AMI patients treated at participating US hospitals. We included patients with CAD, AF, and CHA2DS2-VASc score ≥2 admitted for AMI (07/01/2013-09/30/2016). In the 15,034 AMI patients with previous AF and CAD, median age was 75; 32% were female. Preadmission, 32% of patients were on P2Y12 inhibitors, 36% were anticoagulated, 72% were on aspirin, and 5% were on triple therapy. At discharge post-AMI, 73% were prescribed P2Y12 inhibitors and 41% anticoagulation. Discharge anticoagulation use did not vary directly with CHA2DS2-VASc score; 16% of previously anticoagulated patients had discontinued anticoagulation at discharge. In patients receiving anticoagulants at discharge, 27% used nonvitamin K antagonist oral anticoagulants. Triple therapy was prescribed in 23% at discharge; 27% of these were with nonvitamin K antagonist oral anticoagulants and 14% with prasugrel or ticagrelor. P2Y12 inhibitors and anticoagulants without aspirin were used in 2%. In conclusion, patients with previous CAD and AF are undertreated for both recurrent ischemic events and stroke prevention. After AMI hospitalization, P2Y12 inhibition was preferentially selected over oral anticoagulation.

Relationship Between Operator Volume and Long-Term Outcomes After Percutaneous Coronary Intervention.

BACKGROUND: Although many studies show an inverse association between operator procedural volume and short-term adverse outcomes after percutaneous coronary intervention (PCI), the association between procedural volume and longer-term outcomes is unknown. METHODS: Using the National Cardiovascular Data Registry CathPCI registry data linked with Medicare claims data, we examined the association between operator PCI volume and long-term outcomes among patients ≥65 years of age. Operators were stratified by average annual PCI volume (counting PCIs performed in patients of all ages): low- (<50 PCIs), intermediate- (50-100), and high- (>100) volume operators. One-year unadjusted rates of death and major adverse coronary events (MACEs; defined as death, readmission for myocardial infarction, or unplanned coronary revascularization) were calculated with Kaplan-Meier methods. The proportional hazards assumption was not met, and risk-adjusted associations between operator volume and outcomes were calculated separately from the time of PCI to hospital discharge and from hospital discharge to 1-year follow-up. RESULTS: Between July 1, 2009, and December 31, 2014, 723 644 PCI procedures were performed by 8936 operators: 2553 high-, 2878 intermediate-, and 3505 low-volume operators. Compared with high- and intermediate-volume operators, low-volume operators more often performed emergency PCI, and their patients had fewer cardiovascular comorbidities. Over 1-year follow-up, 15.9% of patients treated by low-volume operators had a MACE compared with 16.9% of patients treated by high-volume operators ( P=0.004). After multivariable adjustment, intermediate- and high-volume operators had a significantly lower rate of in-hospital death than low-volume operators (odds ratio, 0.91; 95% CI, 0.86-0.96 for intermediate versus low; odds ratio, 0.79; 95% CI, 0.75-0.83 for high versus low). There were no significant differences in rates of MACEs, death, myocardial infarction, or unplanned revascularization between operator cohorts from hospital discharge to 1-year follow-up (adjusted hazard ratio for MACEs, 0.99; 95% CI, 0.96-1.01 for intermediate versus low; hazard ratio, 1.01; 95% CI, 0.99-1.04 for high versus low). CONCLUSIONS: Unadjusted 1-year outcomes after PCI were worse for older adults treated by operators with higher annual volume; however, patients treated by these operators had more cardiovascular comorbidities. After risk adjustment, higher operator volume was associated with lower in-hospital mortality and no difference in postdischarge MACEs.

Association of Patient Perceptions of Cardiovascular Risk and Beliefs on Statin Drugs With Racial Differences in Statin Use: Insights From the Patient and Provider Assessment of Lipid Management Registry.

Importance: African American individuals face higher atherosclerotic cardiovascular disease risk than white individuals; reasons for these differences, including potential differences in patient beliefs regarding preventive care, remain unknown. Objective: To evaluate differences in statin use between white and African American patients and identify the potential causes for any observed differences. Design, Setting, and Participants: Using the 2015 Patient and Provider Assessment of Lipid Management (PALM) Registry data, we compared statin use and dosing between African American and white outpatient adults who were potentially eligible for primary or secondary prevention statins. A total of 138 US community health care practices contributed to the data. Data analysis was conducted from March 2017 to May 2018. Main Outcomes and Measures: Primary outcomes were use and dosing of statin therapy according to the 2013 American College of Cardiology/American Heart Association guideline by African American or white race. Secondary outcomes included lipid levels and patient-reported beliefs. Poisson regression was used to evaluate the association between race and statin undertreatment, a category combining people who were not taking a statin or those taking a dose intensity lower than recommended. Results: A total of 5689 patients (806 [14.2%] African American) in the PALM registry were eligible for statin therapy. African American individuals were less likely than white individuals to be treated with a statin (570/807 [70.6%] vs 3654/4883 [74.8%]; P = .02). Among those treated, African American patients were less likely than white patients to receive a statin at guideline-recommended intensity (269 [33.3%] vs 2145 [43.9%], respectively; P < .001; relative risk, 1.07 [95% CI, 1.00-1.15]; P = .05, after adjustment for demographic and clinical factors). The median (interquartile range) low-density lipoprotein cholesterol levels of patients receiving treatment were higher among African American than white individuals (97.0 [76.0-121.0] mg/dL vs 85.0 [68.0-105.0] mg/dL; P < .001). African American individuals were less likely than white individuals to believe statins were safe (292 [36.2%] vs 2800 [57.3%]; P < .001) or effective (564 [70.0%] vs 3635 [74.4%]; P = .008) and were less likely to trust their clinician (663 [82.3%] vs 4579 [93.8%]; P < .001). Group differences in statin undertreatment were not significant after adjusting for demographic, clinical, and clinician factors, socioeconomic status, and patient beliefs (final adjusted relative risk, 1.03 [95% CI 0.96-1.11]; P = .35). Conclusions and Relevance: African American individuals were less likely to receive guideline-recommended statin therapy. Demographic, clinical, socioeconomic, belief-related, and clinician differences contributed to observed differences and represent potential targets for intervention.

Appropriateness and Outcomes of Percutaneous Coronary Intervention at Top-Ranked and Nonranked Hospitals in the United States.

OBJECTIVES: This study sought to compare the appropriate use and outcomes of percutaneous coronary intervention (PCI) between top-ranked and nonranked hospitals. BACKGROUND: The U.S. News & World Report "Best Hospitals" rankings are an influential consumer-directed publication of hospital quality, and are commonly used in promotional campaigns by hospital systems. METHODS: Hospitals in the National Cardiovascular Data Registry CathPCI registry between July 1, 2014, and June 30, 2015, were classified as top-ranked if they were included in the 2015 U.S. News & World Report 50 best "Cardiology and Heart Surgery" hospitals. The remaining were classified as nonranked. We compared in-hospital mortality, post-procedural bleeding, post-procedural acute kidney injury, and the proportion of appropriate PCI procedures between top-ranked and nonranked hospitals. RESULTS: A total of 509,153 PCIs at 654 hospitals were included, of which 55,550 (10.9%) were performed at 44 top-ranked hospitals. After adjusting for patient case mix, PCIs performed at top-ranked hospitals had similar odds of in-hospital mortality (adjusted odds ratio [aOR]: 0.96; 95% confidence interval [CI]: 0.83 to 1.12; p = 0.64), acute kidney injury (aOR: 1.10; 95% CI: 0.98 to 1.22; p = 0.099), and bleeding (aOR: 1.15; 95% CI: 0.99 to 1.31; p = 0.052). Top-ranked hospitals had a slightly lower proportion of appropriate PCI compared with nonranked hospitals (89.2% vs. 92.8%; OR: 0.56; 95% CI: 0.45 to 0.69; p < 0.001). CONCLUSIONS: PCI performed at top-ranked hospitals was not associated with superior outcomes compared with PCI at nonranked hospitals. The inclusion of metrics based on clinical data may be important for hospital quality rankings.

Outcomes of PCI in Relation to Procedural Characteristics and Operator Volumes in the United States.

BACKGROUND: Professional guidelines have reduced the recommended minimum number to an average of 50 percutaneous coronary intervention (PCI) procedures performed annually by each operator. Operator volume patterns and associated outcomes since this change are unknown. OBJECTIVES: The authors describe herein PCI operator procedure volumes; characteristics of low-, intermediate-, and high-volume operators; and the relationship between operator volume and clinical outcomes in a large, contemporary, nationwide sample. METHODS: Using data from the National Cardiovascular Data Registry collected between July 1, 2009, and March 31, 2015, we examined operator annual PCI volume. We divided operators into low- (<50 PCIs per year), intermediate- (50 to 100 PCIs per year), and high- (>100 PCIs per year) volume groups, and determined the adjusted association between annual PCI volume and in-hospital outcomes, including mortality. RESULTS: The median annual number of procedures performed per operator was 59; 44% of operators performed <50 PCI procedures per year. Low-volume operators more frequently performed emergency and primary PCI procedures and practiced at hospitals with lower annual PCI volumes. Unadjusted in-hospital mortality was 1.86% for low-volume operators, 1.73% for intermediate-volume operators, and 1.48% for high-volume operators. The adjusted risk of in-hospital mortality was higher for PCI procedures performed by low- and intermediate-volume operators compared with those performed by high-volume operators (adjusted odds ratio: 1.16 for low versus high; adjusted odds ratio: 1.05 for intermediate vs. high volume) as was the risk for new dialysis post PCI. No volume relationship was observed for post-PCI bleeding. CONCLUSIONS: Many PCI operators in the United States are performing fewer than the recommended number of PCI procedures annually. Although absolute risk differences are small and may be partially explained by unmeasured differences in case mix between operators, there remains an inverse relationship between PCI operator volume and in-hospital mortality that persisted in risk-adjusted analyses.

Metformin for Treatment of Overweight Induced by Atypical Antipsychotic Medication in Young People With Autism Spectrum Disorder: A Randomized Clinical Trial.

IMPORTANCE: Atypical antipsychotic medications are indicated for the treatment of irritability and agitation symptoms in children with autism spectrum disorder (ASD). Unfortunately, these medications are associated with weight gain and metabolic complications that are especially troubling in children and with long-term use. OBJECTIVE: To evaluate the efficacy of metformin for weight gain associated with atypical antipsychotic medications in children and adolescents with ASD (defined in the protocol as DSM-IV diagnosis of autistic disorder, Asperger disorder, or pervasive developmental disorder not otherwise specified), aged 6 to 17 years. DESIGN, SETTING, AND PARTICIPANTS: A 16-week, double-blind, placebo-controlled, randomized clinical trial was conducted at 4 centers in Toronto, Ontario, Canada; Columbus, Ohio; Pittsburgh, Pennsylvania; and Nashville, Tennessee. In all, 209 potential participants were screened by telephone, 69 individuals provided consent, and 61 participants were randomized to receive metformin or placebo between April 26, 2013, and June 24, 2015. INTERVENTIONS: Metformin or matching placebo titrated up to 500 mg twice daily for children aged 6 to 9 years and 850 mg twice daily for those 10 to 17 years. MAIN OUTCOMES AND MEASURES: The primary outcome measure was change in body mass index (BMI) z score during 16 weeks of treatment. Secondary outcomes included changes in additional body composition and metabolic variables. Safety, tolerability, and efficacy analyses all used a modified intent-to-treat sample comprising all participants who received at least 1 dose of medication. RESULTS: Of the 61 randomized participants, 60 participants initiated treatment (45 [75%] male; mean [SD] age, 12.8 [2.7] years). Metformin reduced BMI z scores from baseline to week 16 significantly more than placebo (difference in 16-week change scores vs placebo, -0.10 [95% CI, -0.16 to -0.04]; P = .003). Statistically significant improvements were also noted in secondary body composition measures (raw BMI, -0.95 [95% CI, -1.46 to -0.45] and raw weight, -2.73 [95% CI, -4.04 to -1.43]) but not in metabolic variables. Overall, metformin was well tolerated. Five participants in the metformin group discontinued treatment owing to adverse events (agitation, 4; sedation, 1). Participants receiving metformin vs placebo experienced gastrointestinal adverse events during a significantly higher percentage of treatment days (25.1% vs 6.8%; P = .005). CONCLUSIONS AND RELEVANCE: Metformin may be effective in decreasing weight gain associated with atypical antipsychotic use and is well tolerated by children and adolescents with ASD. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01825798.

Coronary CT Angiography Versus Standard Emergency Department Evaluation for Acute Chest Pain and Diabetic Patients: Is There Benefit With Early Coronary CT Angiography? Results of the Randomized Comparative Effectiveness ROMICAT II Trial.

BACKGROUND: Cardiac computed tomography angiography (CCTA) reduces emergency department length of stay compared with standard evaluation in patients with low- and intermediate-risk acute chest pain. Whether diabetic patients have similar benefits is unknown. METHODS AND RESULTS: In this prespecified analysis of the Rule Out Myocardial Ischemia/Infarction by Computer Assisted Tomography (ROMICAT II) multicenter trial, we randomized 1000 patients (17% diabetic) with symptoms suggestive of acute coronary syndrome to CCTA or standard evaluation. The rate of acute coronary syndrome was 8% in both diabetic and nondiabetic patients (P=1.0). Length of stay was unaffected by the CCTA strategy for diabetic patients (23.9 versus 27.2 hours, P=0.86) but was reduced for nondiabetic patients compared with standard evaluation (8.4 versus 26.5 hours, P<0.0001; P interaction=0.004). CCTA resulted in 3-fold more direct emergency department discharge in both groups (each P≤0.0001, P interaction=0.27). No difference in hospital admissions was seen between the 2 strategies in diabetic and nondiabetic patients (P interaction=0.09). Both groups had more downstream testing and higher radiation doses with CCTA, but these were highest in diabetic patients (all P interaction≤0.04). Diabetic patients had fewer normal CCTAs than nondiabetic patients (32% versus 50%, P=0.003) and similar normalcy rates with standard evaluation (P=0.70). Notably, 66% of diabetic patients had no or mild stenosis by CCTA with short length of stay comparable to that of nondiabetic patients (P=0.34), whereas those with >50% stenosis had a high prevalence of acute coronary syndrome, invasive coronary angiography, and revascularization. CONCLUSIONS: Knowledge of coronary anatomy with CCTA is beneficial for diabetic patients and can discriminate between lower risk patients with no or little coronary artery disease who can be discharged immediately and higher risk patients with moderate to severe disease who warrant further workup. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov/. Unique identifier: NCT01084239.

Use of Coronary Computed Tomographic Angiography Findings to Modify Statin and Aspirin Prescription in Patients With Acute Chest Pain.

Coronary CT angiography (CCTA) is used in patients with low-intermediate chest pain presenting to the emergency department for its reliability in excluding acute coronary syndrome (ACS). However, its influence on medication modification in this setting is unclear. We sought to determine whether knowledge of CCTA-based coronary artery disease (CAD) was associated with change in statin and aspirin prescription. We used the CCTA arm of the Rule Out Myocardial Infarction using Computed Angiographic Tomography II multicenter, randomized control trial (R-II) and comparison cohort from the observational Rule Out Myocardial Infarction using Computed Angiographic Tomography I cohort (R-I). In R-II, subjects were randomly assigned to CCTA to guide decision making, whereas in R-I patients underwent CCTA with results blinded to caregivers and managed according to standard care. Our final cohort consisted of 277 subjects from R-I and 370 from R-II. ACS rate was similar (6.9% vs 6.2% respectively, p = 0.75). For subjects with CCTA-detected obstructive CAD without ACS, initiation of statin was significantly greater after disclosure of CCTA results (0% in R-I vs 20% in R-II, p = 0.009). Conversely, for subjects without CCTA-detected CAD, aspirin prescription was lower with disclosure of CCTA results (16% in R-I vs 4.8% in R-II, p = 0.001). However, only 68% of subjects in R-II with obstructive CAD were discharged on statin and 65% on aspirin. In conclusion, physician knowledge of CCTA results leads to improved alignment of aspirin and statin with the presence and severity of CAD although still many patients with CCTA-detected CAD are not discharged on aspirin or statin. Our findings suggest opportunity for practice improvement when CCTA is performed in the emergency department.

Potential for coronary CT angiography to tailor medical therapy beyond preventive guideline-based recommendations: insights from the ROMICAT I trial.

BACKGROUND: Coronary CT angiography (CCTA) is used in the emergency department to rule out acute coronary syndrome in low-intermediate risk patients. OBJECTIVES: We evaluated the potential of CCTA to tailor aspirin (ASA) and statin therapy in acute chest pain patients. METHODS: We included all patients in the ROMICAT I trial who underwent CCTA before admission. Results of CCTA were blinded to caretakers. We documented ASA and statin therapy at admission and discharge and determined change in medications during hospitalization, agreement of discharge medications with contemporaneous guidelines, and agreement with the presence and severity of coronary artery disease (CAD) as determined by CCTA. RESULTS: We included 368 patients (53 ± 12 years; 61% male). Baseline medical therapy at presentation included 27% on ASA and 24% on statin. Most patients who qualified for secondary prevention were on ASA and statin therapy at discharge (95% and 80%, respectively), whereas among those qualifying for primary prevention therapy, only 59% of patients were on aspirin and 33% were on statin at discharge. Excluding secondary prevention patients, among those with CCTA-detected CAD, only 66/131 (50%) were on ASA at discharge and only 53/131 (40%) were on statin. Conversely, in those without CCTA-detected CAD, 54/156 (35%) were on ASA and 20/151 (13%) were on statin at discharge. CONCLUSION: There are significant discrepancies between discharge prescription of statin and ASA with the presence and extent of CAD. CCTA presents an efficient opportunity to tailor medical therapy to CAD in patients undergoing CCTA as part of their acute chest pain evaluation.

An electronic surveillance tool for catheter-associated urinary tract infection in intensive care units.

BACKGROUND: Traditional methods of surveillance of catheter-associated urinary tract infections (CAUTIs) are error-prone and resource-intensive. To resolve these issues, we developed a highly sensitive electronic surveillance tool. OBJECTIVE: To develop an electronic surveillance tool for CAUTIs and assess its performance. METHODS: The study was conducted at a 947-bed tertiary care center. Patients included adults aged ≥18 years admitted to an intensive care unit between January 10 and June 30, 2012, with an indwelling urinary catheter during their admission. We identified CAUTIs using 4 methods: traditional surveillance (TS) (ie, manual chart review by ICPs), an electronic surveillance (ES) tool, augmented electronic surveillance (AES) (ie, ES with chart review on a subset of cases), and reference standard (RS) (ie, a subset of CAUTIs originally ascertained by TS or ES, confirmed by review). We assessed performance characteristics to RS for reviewed cases. RESULTS: We identified 417 candidate CAUTIs in 308 patients; 175 (42.0%) of these candidate CAUTIs were selected for review, yielding 32 confirmed CAUTIs in 22 patients (RS). Compared with RS, the sensitivities of TS, ES, and AES were 43.8% (95% confidence interval [CI], 26.4%-62.3%), 100.0% (95% CI, 89.1%-100.0%), and 100.0% (95% CI, 89.1%-100.0%). Specificities were 82.5% (95% CI, 75.3%-88.4%), 2.8% (95% CI, 0.8%-7.0%), and 100.0% (95% CI, 97.5%-100.0%). CONCLUSIONS: Electronic CAUTI surveillance offers a streamlined approach to improve reliability and resource burden of surveillance.

Sensitive troponin assays in patients with suspected acute coronary syndrome: Results from the multicenter rule out myocardial infarction using computer assisted tomography II trial.

BACKGROUND: Sensitive troponin (Tn) assays have been developed for the evaluation of patients with suspected acute coronary syndrome (ACS). We sought to compare the performance of a commercially available sensitive Tn I (sTnI) and precommercial highly sTnI (hsTnI) method to conventional Tn (cTn) assays. METHODS: Among patients with acute chest pain but normal cTn in the emergency department of 6 centers, sTnI and hsTnI were measured at baseline, 2 and 4 hours after presentation. Diagnostic accuracy of sTnI and hsTnI relative to cTn for diagnosis during index hospitalization as well as their associations with coronary artery disease in patients randomized to coronary computed tomographic angiography (CTA) was assessed. RESULTS: Overall, 322 patients were enrolled, of whom 161 had a CTA; 28 had ACS (8.7%), including 21 with unstable angina pectoris (UAP). Both sTnI and hsTnI values at baseline and second draw had significantly higher sensitivity for ACS and UAP than cTn and had significantly greater area under the receiver operator characteristic curve than cTn at first and second draws. Compared with cTn, 29% of ACS cases previously categorized as UAP were reclassified to acute myocardial infarction with sTnI or hsTnI. An hsTnI below limit of detection had 100% negative predictive value for ACS or significant coronary artery stenosis in those randomized to CTA. CONCLUSIONS: In patients with acute chest discomfort, use of sTnI and hsTnI methods led to significant improvement in the early diagnostic accuracy for ACS, reclassifying one-third of UAP to myocardial infarction. Very low values for hsTnI excluded underlying coronary artery disease.

Use of coronary artery calcium scanning beyond coronary computed tomographic angiography in the emergency department evaluation for acute chest pain: the ROMICAT II trial.

BACKGROUND: Whether a coronary artery calcium (CAC) scan provides added value to coronary computed tomographic angiography (CCTA) in emergency department patients with acute chest pain remains unsettled. We sought to determine the value of CAC scan in patients with acute chest pain undergoing CCTA. METHODS AND RESULTS: In the multicenter Rule Out Myocardial Infarction using Computer-Assisted Tomography (ROMICAT) II trial, we enrolled low-intermediate risk emergency department patients with symptoms suggesting acute coronary syndrome (ACS). In this prespecified subanalysis of 473 patients (54±8 years, 53% men) who underwent both CAC scanning and CCTA, the ACS rate was 8%. Overall, 53% of patients had CAC=0 of whom 2 (0.8%) developed ACS, whereas 7% had CAC>400 with 49% whom developed ACS. C-statistic of CAC>0 was 0.76, whereas that using the optimal cut point of CAC≥22 was 0.81. Continuous CAC score had lower discriminatory capacity than CCTA (c-statistic, 0.86 versus 0.92; P=0.03). Compared with CCTA alone, there was no benefit combining CAC score with CCTA (c-statistic, 0.93; P=0.88) or with selective CCTA strategies after initial CAC>0 or optimal cut point CAC≥22 (P≥0.09). Mean radiation dose from CAC acquisition was 1.4±0.7 mSv. Higher CAC scores resulted in more nondiagnostic CCTA studies although the majority remained interpretable. CONCLUSIONS: In emergency department patients with acute chest pain, CAC score does not provide incremental value beyond CCTA for ACS diagnosis. CAC=0 does not exclude ACS, nor a high CAC score preclude interpretation of CCTA in most patients. Thus, CAC results should not influence the decision to proceed with CCTA, and the decision to perform a CAC scan should be balanced with the additional radiation exposure required. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01084239.