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Key Points: Question: Does ivermectin, with a maximum targeted dose of 600 μg/kg daily for 6 days, compared with placebo, shorten symptom duration among adult (≥30 years) outpatients with symptomatic mild to moderate COVID-19? Findings: In this double-blind, randomized, placebo-controlled platform trial including 1206 US adults with COVID-19 during February 2022 to July 2022, the median time to sustained recovery was 11 days in the ivermectin group and 11 days in the placebo group. In this largely vaccinated (84%) population, the posterior probability that ivermectin reduced symptom duration by more than 1 day was less than 0.1%. Meaning: These findings do not support the use of ivermectin among outpatients with COVID-19. Importance: It is unknown whether ivermectin, with a maximum targeted dose of 600 μg/kg, shortens symptom duration or prevents hospitalization among outpatients with mild to moderate COVID-19. Objective: To evaluate the effectiveness of ivermectin at a maximum targeted dose of 600 μg/kg daily for 6 days, compared with placebo, for the treatment of early mild to moderate COVID-19. Design, Setting, and Participants: The ongoing Accelerating COVID-19 Therapeutic Interventions and Vaccines 6 (ACTIV-6) platform randomized clinical trial was designed to evaluate repurposed therapies among outpatients with mild to moderate COVID-19. A total of 1206 participants older than 30 years with confirmed COVID-19 experiencing at least 2 symptoms of acute infection for less than or equal to 7 days were enrolled at 93 sites in the US from February 16, 2022, through July 22, 2022, with follow-up data through November 10, 2022. Interventions: Participants were randomly assigned to receive ivermectin, with a maximum targeted dose of 600 μg/kg (n = 602) daily, or placebo (n = 604) for 6 days. Main Outcomes and Measures: The primary outcome was time to sustained recovery, defined as at least 3 consecutive days without symptoms. The 7 secondary outcomes included a composite of hospitalization, death, or urgent/emergent care utilization by day 28. Results: Among 1206 randomized participants who received study medication or placebo, the median (IQR) age was 48 (38-58) years, 713 (59.1%) were women, and 1008 (83.5%) reported receiving at least 2 SARS-CoV-2 vaccine doses. The median (IQR) time to sustained recovery was 11 (11-12) days in the ivermectin group and 11 (11-12) days in the placebo group. The hazard ratio (posterior probability of benefit) for improvement in time to recovery was 1.02 (95% credible interval, 0.92-1.13; P =.68). Among those receiving ivermectin, 34 (5.7%) were hospitalized, died, or had urgent or emergency care visits compared with 36 (6.0%) receiving placebo (hazard ratio, 1.0 [95% credible interval, 0.6-1.5]; P =.53). In the ivermectin group, 1 participant died and 4 were hospitalized (0.8%); 2 participants (0.3%) were hospitalized in the placebo group and there were no deaths. Adverse events were uncommon in both groups. Conclusions and Relevance: Among outpatients with mild to moderate COVID-19, treatment with ivermectin, with a maximum targeted dose of 600 μg/kg daily for 6 days, compared with placebo did not improve time to sustained recovery. These findings do not support the use of ivermectin in patients with mild to moderate COVID-19. Trial Registration: ClinicalTrials.gov Identifier: NCT04885530 This platform randomized clinical trial examines the effectiveness of ivermectin at a targeted dose of 600 μg/kg daily compared with placebo for the treatment of early mild to moderate COVID-19. [ABSTRACT FROM AUTHOR]

Key Points: Question: Does 50 mg of fluvoxamine twice daily for 10 days, compared with placebo, shorten symptom duration among adult (aged ≥30 years) outpatients with symptomatic mild to moderate COVID-19? Findings: In this platform randomized clinical trial conducted during a period of predominance for the Delta and Omicron variants in the US, including 1288 adult outpatients with COVID-19 treated with fluvoxamine vs placebo, the hazard ratio was 0.96 (95% credible interval, 0.86-1.06) for time to sustained recovery with a posterior P =.21 for the probability of improvement. This did not meet the prespecified threshold of greater than 0.95 for posterior probability. Meaning: These findings do not support the use of fluvoxamine at this dose and duration in patients with mild to moderate COVID-19. Importance: The effectiveness of fluvoxamine to shorten symptom duration or prevent hospitalization among outpatients with mild to moderate symptomatic COVID-19 is unclear. Objective: To evaluate the efficacy of low-dose fluvoxamine (50 mg twice daily) for 10 days compared with placebo for the treatment of mild to moderate COVID-19 in the US. Design, Setting, and Participants: The ongoing Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV-6) platform randomized clinical trial was designed to test repurposed medications in outpatients with mild to moderate COVID-19. A total of 1288 participants aged 30 years or older with test-confirmed SARS-CoV-2 infection and experiencing 2 or more symptoms of acute COVID-19 for 7 days or less were enrolled between August 6, 2021, and May 27, 2022, at 91 sites in the US. Interventions: Participants were randomized to receive 50 mg of fluvoxamine twice daily for 10 days or placebo. Main Outcomes and Measures: The primary outcome was time to sustained recovery (defined as the third day of 3 consecutive days without symptoms). There were 7 secondary outcomes, including a composite outcome of hospitalization, urgent care visit, emergency department visit, or death through day 28. Results: Among 1331 participants who were randomized (median age, 47 years [IQR, 38-57 years]; 57% were women; and 67% reported receiving ≥2 doses of a SARS-CoV-2 vaccine), 1288 completed the trial (674 in the fluvoxamine group and 614 in the placebo group). The median time to sustained recovery was 12 days (IQR, 11-14 days) in the fluvoxamine group and 13 days (IQR, 12-13 days) in the placebo group (hazard ratio [HR], 0.96 [95% credible interval, 0.86-1.06], posterior P =.21 for the probability of benefit [determined by an HR >1]). For the composite outcome, 26 participants (3.9%) in the fluvoxamine group were hospitalized, had an urgent care visit, had an emergency department visit, or died compared with 23 participants (3.8%) in the placebo group (HR, 1.1 [95% credible interval, 0.5-1.8], posterior P =.35 for the probability of benefit [determined by an HR <1]). One participant in the fluvoxamine group and 2 participants in the placebo group were hospitalized; no deaths occurred in either group. Adverse events were uncommon in both groups. Conclusions and Relevance: Among outpatients with mild to moderate COVID-19, treatment with 50 mg of fluvoxamine twice daily for 10 days, compared with placebo, did not improve time to sustained recovery. These findings do not support the use of fluvoxamine at this dose and duration in patients with mild to moderate COVID-19. Trial Registration: ClinicalTrials.gov Identifier: NCT04885530 This randomized, placebo-controlled platform trial compares the use of low-dose fluvoxamine (50 mg twice daily) for 10 days compared with placebo in outpatients with mild to moderate COVID-19. [ABSTRACT FROM AUTHOR]

Importance: The effectiveness of ivermectin to shorten symptom duration or prevent hospitalization among outpatients in the US with mild to moderate symptomatic COVID-19 is unknown.Objective: To evaluate the efficacy of ivermectin, 400 μg/kg, daily for 3 days compared with placebo for the treatment of early mild to moderate COVID-19.Design, Setting, and Participants: ACTIV-6, an ongoing, decentralized, double-blind, randomized, placebo-controlled platform trial, was designed to evaluate repurposed therapies in outpatients with mild to moderate COVID-19. A total of 1591 participants aged 30 years and older with confirmed COVID-19, experiencing 2 or more symptoms of acute infection for 7 days or less, were enrolled from June 23, 2021, through February 4, 2022, with follow-up data through May 31, 2022, at 93 sites in the US.Interventions: Participants were randomized to receive ivermectin, 400 μg/kg (n = 817), daily for 3 days or placebo (n = 774).Main Outcomes and Measures: Time to sustained recovery, defined as at least 3 consecutive days without symptoms. There were 7 secondary outcomes, including a composite of hospitalization or death by day 28.Results: Among 1800 participants who were randomized (mean [SD] age, 48 [12] years; 932 women [58.6%]; 753 [47.3%] reported receiving at least 2 doses of a SARS-CoV-2 vaccine), 1591 completed the trial. The hazard ratio (HR) for improvement in time to recovery was 1.07 (95% credible interval [CrI], 0.96-1.17; posterior P value [HR >1] = .91). The median time to recovery was 12 days (IQR, 11-13) in the ivermectin group and 13 days (IQR, 12-14) in the placebo group. There were 10 hospitalizations or deaths in the ivermectin group and 9 in the placebo group (1.2% vs 1.2%; HR, 1.1 [95% CrI, 0.4-2.6]). The most common serious adverse events were COVID-19 pneumonia (ivermectin [n = 5]; placebo [n = 7]) and venous thromboembolism (ivermectin [n = 1]; placebo [n = 5]).Conclusions and Relevance: Among outpatients with mild to moderate COVID-19, treatment with ivermectin, compared with placebo, did not significantly improve time to recovery. These findings do not support the use of ivermectin in patients with mild to moderate COVID-19.Trial Registration: ClinicalTrials.gov Identifier: NCT04885530. [ABSTRACT FROM AUTHOR]

A study to evaluate the perception that ambulatory patients with cardiac disease associated with survival and compared this with previously available model data is conducted. Results reveal that active patients with cardiac problems had positive perceptions of their survival rates, which could affect decisions for future therapies and called for further study.

Importance: Exercise limitation is a cardinal manifestation of heart failure with reduced ejection fraction (HFrEF) but is not consistently improved by any of the current guideline-directed medical therapies.Objective: To determine whether omecamtiv mecarbil, a novel direct myosin activator that improves cardiac performance and reduces the risk for cardiovascular death or first HF event in HFrEF, can improve peak exercise capacity in patients with chronic HFrEF.Design, Setting, and Participants: Phase 3, double-blind, placebo-controlled randomized trial of patients with HFrEF (left ventricular ejection fraction ≤35%), New York Heart Association class II-III symptoms, N-terminal pro-B-type natriuretic peptide level of 200 pg/mL or greater, and baseline peak oxygen uptake (V̇o2) of 75% or less of predicted. Patients were randomized in a 2:1 ratio (omecamtiv mecarbil to placebo) between March 2019 and May 2021 at 63 sites in North America and Europe, with the last patient visit occurring on November 29, 2021.Interventions: Omecamtiv mecarbil (n = 185) or matching placebo (n = 91), given orally twice daily at a dose of 25 mg, 37.5 mg, or 50 mg based on target plasma levels, for 20 weeks.Main Outcomes and Measures: The primary end point was a change in exercise capacity (peak V̇o2) from baseline to week 20. Secondary end points included total workload, ventilatory efficiency, and daily physical activity as determined by accelerometry.Results: Among 276 patients who were randomized (median age, 64 years; IQR, 55-70 years; 42 women [15%]), 249 (90%) completed the trial. The median left ventricular ejection fraction was 28% (IQR, 21-33) and the median baseline peak V̇o2 was 14.2 mL/kg/min (IQR, 11.6-17.4) in the omecamtiv mecarbil group and 15.0 mL/kg/min (IQR, 12.0-17.2) in the placebo group. Mean change in peak V̇o2 did not differ significantly between the omecamtiv mecarbil and placebo groups (mean, -0.24 mL/kg/min vs 0.21 mL/kg/min; least square mean difference, -0.45 mL/kg/min [95% CI, -1.02 to 0.13]; P = .13). Adverse events included dizziness (omecamtiv mecarbil: 4.9%, placebo: 5.5%), fatigue (omecamtiv mecarbil: 4.9%, placebo: 4.4%), heart failure events (omecamtiv mecarbil: 4.9%, placebo: 4.4%), death (omecamtiv mecarbil: 1.6%, placebo: 1.1%), stroke (omecamtiv mecarbil: 0.5%, placebo: 1.1%), and myocardial infarction (omecamtiv mecarbil: 0%, placebo: 1.1%).Conclusions and Relevance: In patients with chronic HFrEF, omecamtiv mecarbil did not significantly improve exercise capacity over 20 weeks compared with placebo. These findings do not support the use of omecamtiv mecarbil for treatment of HFrEF for improvement of exercise capacity.Trial Registration: ClinicalTrials.gov Identifier: NCT03759392. [ABSTRACT FROM AUTHOR]

Importance: Adoption of guideline-directed medical therapy for patients with heart failure is variable. Interventions to improve guideline-directed medical therapy have failed to consistently achieve target metrics, and limited data exist to inform efforts to improve heart failure quality of care.Objective: To evaluate the effect of a hospital and postdischarge quality improvement intervention compared with usual care on heart failure outcomes and care.Design, Setting, and Participants: This cluster randomized clinical trial was conducted at 161 US hospitals and included 5647 patients (2675 intervention vs 2972 usual care) followed up after a hospital discharge for acute heart failure with reduced ejection fraction (HFrEF). The trial was performed from 2017 to 2020, and the date of final follow-up was August 31, 2020.Interventions: Hospitals (n = 82) randomized to a hospital and postdischarge quality improvement intervention received regular education of clinicians by a trained group of heart failure and quality improvement experts and audit and feedback on heart failure process measures (eg, use of guideline-directed medical therapy for HFrEF) and outcomes. Hospitals (n = 79) randomized to usual care received access to a generalized heart failure education website.Main Outcomes and Measures: The coprimary outcomes were a composite of first heart failure rehospitalization or all-cause mortality and change in an opportunity-based composite score for heart failure quality (percentage of recommendations followed).Results: Among 5647 patients (mean age, 63 years; 33% women; 38% Black; 87% chronic heart failure; 49% recent heart failure hospitalization), vital status was known for 5636 (99.8%). Heart failure rehospitalization or all-cause mortality occurred in 38.6% in the intervention group vs 39.2% in usual care (adjusted hazard ratio, 0.92 [95% CI, 0.81 to 1.05). The baseline quality-of-care score was 42.1% vs 45.5%, respectively, and the change from baseline to follow-up was 2.3% vs -1.0% (difference, 3.3% [95% CI, -0.8% to 7.3%]), with no significant difference between the 2 groups in the odds of achieving a higher composite quality score at last follow-up (adjusted odds ratio, 1.06 [95% CI, 0.93 to 1.21]).Conclusions and Relevance: Among patients with HFrEF in hospitals randomized to a hospital and postdischarge quality improvement intervention vs usual care, there was no significant difference in time to first heart failure rehospitalization or death, or in change in a composite heart failure quality-of-care score.Trial Registration: ClinicalTrials.gov Identifier: NCT03035474. [ABSTRACT FROM AUTHOR]

The article focuses on the advancements in mechanical circulatory support devices for late-stage heart failure, highlighting progressive improvements in device durability and patient outcomes. Topics discussed include the ARIES-HM3 study, demonstrating the noninferiority of avoiding aspirin therapy in patients with a HeartMate 3 LVAD, leading to a substantial reduction in major bleeding events without compromising survival or thrombotic outcomes.

Importance: In patients with heart failure and reduced ejection fraction (HFrEF), treatment with sacubitril-valsartan reduces N-terminal pro-b-type natriuretic peptide (NT-proBNP) concentrations. The effect of sacubitril-valsartan on cardiac remodeling is uncertain.Objective: To determine whether NT-proBNP changes in patients with HFrEF treated with sacubitril-valsartan correlate with changes in measures of cardiac volume and function.Design, Setting, and Participants: Prospective, 12-month, single-group, open-label study of patients with HFrEF enrolled in 78 outpatient sites in the United States. Sacubitril-valsartan was initiated and the dose adjusted. Enrollment commenced on October 25, 2016, and follow-up was completed on October 22, 2018.Exposures: NT-proBNP concentrations among patients treated with sacubitril-valsartan.Main Outcomes and Measures: The primary outcome was the correlation between changes in log2-NT-proBNP concentrations and left ventricular (LV) EF, LV end-diastolic volume index (LVEDVI), LV end-systolic volume index (LVESVI), left atrial volume index (LAVI), and ratio of early transmitral Doppler velocity/early diastolic annular velocity (E/e') at 12 months.Results: Among 794 patients (mean age, 65.1 years; 226 women [28.5%]; mean LVEF = 28.2%), 654 (82.4%) completed the study. The median NT-proBNP concentration at baseline was 816 pg/mL (interquartile range [IQR], 332-1822) and 455 pg/mL (IQR, 153-1090) at 12 months (difference, P < .001). At 12 months, the change in log2-NT-proBNP concentration was correlated with changes in LVEF (r = -0.381 [IQR, -0.448 to -0.310]; P < .001), LVEDVI (r = 0.320 [IQR, 0.246 to 0.391]; P < .001), LVESVI (r = 0.405 [IQR, 0.335 to 0.470]; P < .001), LAVI (r = 0.263 [IQR, 0.186 to 0.338]; P < .001), and E/e' (r = 0.269 [IQR, 0.182 to 0.353]; P < .001). At 12 months, LVEF increased from 28.2% to 37.8% (difference, 9.4% [95% CI, 8.8% to 9.9%]; P < .001), while LVEDVI decreased from 86.93 to 74.15 mL/m2 (difference, -12.25 mL/m2 [IQR, -12.92 to -11.58]; P < .001) and LVESVI decreased from 61.68 to 45.46 mL/m2 (difference, -15.29 mL/m2 [95% CI, -16.03 to -14.55]; P < .001). LAVI and E/e' ratio also decreased significantly. The most frequent adverse events were hypotension (17.6%), dizziness (16.8%), hyperkalemia (13.2%), and worsening kidney function (12.3%).Conclusions and Relevance: In this exploratory study of patients with HFrEF treated with sacubitril-valsartan, reduction in NT-proBNP concentration was weakly yet significantly correlated with improvements in markers of cardiac volume and function at 12 months. The observed reverse cardiac remodeling may provide a mechanistic explanation for the effects of sacubitril-valsartan in patients with HFrEF.Trial Registration: ClinicalTrials.gov Identifier: NCT02887183. [ABSTRACT FROM AUTHOR]

Importance: There are few effective treatments for heart failure with preserved ejection fraction (HFpEF). Short-term administration of inorganic nitrite or nitrate preparations has been shown to enhance nitric oxide signaling, which may improve aerobic capacity in HFpEF.Objective: To determine the effect of 4 weeks' administration of inhaled, nebulized inorganic nitrite on exercise capacity in HFpEF.Design, Setting, and Participants: Multicenter, double-blind, placebo-controlled, 2-treatment, crossover trial of 105 patients with HFpEF. Participants were enrolled from July 22, 2016, to September 12, 2017, at 17 US sites, with final date of follow-up of January 2, 2018.Interventions: Inorganic nitrite or placebo administered via micronebulizer device. During each 6-week phase of the crossover study, participants received no study drug for 2 weeks (baseline/washout) followed by study drug (nitrite or placebo) at 46 mg 3 times a day for 1 week followed by 80 mg 3 times a day for 3 weeks.Main Outcomes and Measures: The primary end point was peak oxygen consumption (mL/kg/min). Secondary end points included daily activity levels assessed by accelerometry, health status as assessed by the Kansas City Cardiomyopathy Questionnaire (score range, 0-100, with higher scores reflecting better quality of life), functional class, cardiac filling pressures assessed by echocardiography, N-terminal fragment of the prohormone brain natriuretic peptide levels, other exercise indices, adverse events, and tolerability. Outcomes were assessed after treatment for 4 weeks.Results: Among 105 patients who were randomized (median age, 68 years; 56% women), 98 (93%) completed the trial. During the nitrite phase, there was no significant difference in mean peak oxygen consumption as compared with the placebo phase (13.5 vs 13.7 mL/kg/min; difference, -0.20 [95% CI, -0.56 to 0.16]; P = .27). There were no significant between-treatment phase differences in daily activity levels (5497 vs 5503 accelerometry units; difference, -15 [95% CI, -264 to 234]; P = .91), Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (62.6 vs 61.9; difference, 1.1 [95% CI, -1.4 to 3.5]; P = .39), functional class (2.5 vs 2.5; difference, 0.1 [95% CI, -0.1 to 0.2]; P = .43), echocardiographic E/e' ratio (16.4 vs 16.6; difference, 0.1 [95% CI, -1.2 to 1.3]; P = .93), or N-terminal fragment of the prohormone brain natriuretic peptide levels (520 vs 533 pg/mL; difference, 11 [95% CI, -53 to 75]; P = .74). Worsening heart failure occurred in 3 participants (2.9%) during the nitrite phase and 8 (7.6%) during the placebo phase.Conclusions and Relevance: Among patients with HFpEF, administration of inhaled inorganic nitrite for 4 weeks, compared with placebo, did not result in significant improvement in exercise capacity.Trial Registration: ClinicalTrials.gov Identifier: NCT02742129. [ABSTRACT FROM AUTHOR]

Importance: The natriuretic peptides are biochemical markers of heart failure (HF) severity and predictors of adverse outcomes. Smaller studies have evaluated adjusting HF therapy based on natriuretic peptide levels ("guided therapy") with inconsistent results.Objective: To determine whether an amino-terminal pro-B-type natriuretic peptide (NT-proBNP)-guided treatment strategy improves clinical outcomes vs usual care in high-risk patients with HF and reduced ejection fraction (HFrEF).Design, Settings, and Participants: The Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure (GUIDE-IT) study was a randomized multicenter clinical trial conducted between January 16, 2013, and September 20, 2016, at 45 clinical sites in the United States and Canada. This study planned to randomize 1100 patients with HFrEF (ejection fraction ≤40%), elevated natriuretic peptide levels within the prior 30 days, and a history of a prior HF event (HF hospitalization or equivalent) to either an NT-proBNP-guided strategy or usual care.Interventions: Patients were randomized to either an NT-proBNP-guided strategy or usual care. Patients randomized to the guided strategy (n = 446) had HF therapy titrated with the goal of achieving a target NT-proBNP of less than 1000 pg/mL. Patients randomized to usual care (n = 448) had HF care in accordance with published guidelines, with emphasis on titration of proven neurohormonal therapies for HF. Serial measurement of NT-proBNP testing was discouraged in the usual care group.Main Outcomes and Measures: The primary end point was the composite of time-to-first HF hospitalization or cardiovascular mortality. Prespecified secondary end points included all-cause mortality, total hospitalizations for HF, days alive and not hospitalized for cardiovascular reasons, the individual components on the primary end point, and adverse events.Results: The data and safety monitoring board recommended stopping the study for futility when 894 (median age, 63 years; 286 [32%] women) of the planned 1100 patients had been enrolled with follow-up for a median of 15 months. The primary end point occurred in 164 patients (37%) in the biomarker-guided group and 164 patients (37%) in the usual care group (adjusted hazard ratio [HR], 0.98; 95% CI, 0.79-1.22; P = .88). Cardiovascular mortality was 12% (n = 53) in the biomarker-guided group and 13% (n = 57) in the usual care group (HR, 0.94; 95% CI; 0.65-1.37; P = .75). None of the secondary end points nor the decreases in the NT-proBNP levels achieved differed significantly between groups.Conclusions and Relevance: In high-risk patients with HFrEF, a strategy of NT-proBNP-guided therapy was not more effective than a usual care strategy in improving outcomes.Trial Registration: clinicaltrials.gov Identifier: NCT01685840. [ABSTRACT FROM AUTHOR]

Importance: Iron deficiency is present in approximately 50% of patients with heart failure with reduced left ventricular ejection fraction (HFrEF) and is an independent predictor of reduced functional capacity and mortality. However, the efficacy of inexpensive readily available oral iron supplementation in heart failure is unknown.Objective: To test whether therapy with oral iron improves peak exercise capacity in patients with HFrEF and iron deficiency.Design, Setting, and Participants: Phase 2, double-blind, placebo-controlled randomized clinical trial of patients with HFrEF (<40%) and iron deficiency, defined as a serum ferritin level of 15 to 100 ng/mL or a serum ferritin level of 101 to 299 ng/mL with transferrin saturation of less than 20%. Participants were enrolled between September 2014 and November 2015 at 23 US sites.Interventions: Oral iron polysaccharide (n = 111) or placebo (n = 114), 150 mg twice daily for 16 weeks.Main Outcomes and Measures: The primary end point was a change in peak oxygen uptake (V̇o2) from baseline to 16 weeks. Secondary end points were change in 6-minute walk distance, plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, and health status as assessed by Kansas City Cardiomyopathy Questionnaire (KCCQ, range 0-100, higher scores reflect better quality of life).Results: Among 225 randomized participants (median age, 63 years; 36% women) 203 completed the study. The median baseline peak V̇o2 was 1196 mL/min (interquartile range [IQR], 887-1448 mL/min) in the oral iron group and 1167 mL/min (IQR, 887-1449 mL/min) in the placebo group. The primary end point, change in peak V̇o2 at 16 weeks, did not significantly differ between the oral iron and placebo groups (+23 mL/min vs -2 mL/min; difference, 21 mL/min [95% CI, -34 to +76 mL/min]; P = .46). Similarly, at 16 weeks, there were no significant differences between treatment groups in changes in 6-minute walk distance (-13 m; 95% CI, -32 to 6 m), NT-proBNP levels (159; 95% CI, -280 to 599 pg/mL), or KCCQ score (1; 95% CI, -2.4 to 4.4), all P > .05.Conclusions and Relevance: Among participants with HFrEF with iron deficiency, high-dose oral iron did not improve exercise capacity over 16 weeks. These results do not support use of oral iron supplementation in patients with HFrEF.Trial Registration: clinicaltrials.gov Identifier: NCT02188784. [ABSTRACT FROM AUTHOR]

Importance: Abnormal cardiac metabolism contributes to the pathophysiology of advanced heart failure with reduced left ventricular ejection fraction (LVEF). Glucagon-like peptide 1 (GLP-1) agonists have shown cardioprotective effects in early clinical studies of patients with advanced heart failure, irrespective of type 2 diabetes status.Objective: To test whether therapy with a GLP-1 agonist improves clinical stability following hospitalization for acute heart failure.Design, Setting, and Participants: Phase 2, double-blind, placebo-controlled randomized clinical trial of patients with established heart failure and reduced LVEF who were recently hospitalized. Patients were enrolled between August 2013 and March 2015 at 24 US sites.Interventions: The GLP-1 agonist liraglutide (n = 154) or placebo (n = 146) via a daily subcutaneous injection; study drug was advanced to a dosage of 1.8 mg/d during the first 30 days as tolerated and continued for 180 days.Main Outcomes and Measures: The primary end point was a global rank score in which all patients, regardless of treatment assignment, were ranked across 3 hierarchical tiers: time to death, time to rehospitalization for heart failure, and time-averaged proportional change in N-terminal pro-B-type natriuretic peptide level from baseline to 180 days. Higher values indicate better health (stability). Exploratory secondary outcomes included primary end point components, cardiac structure and function, 6-minute walk distance, quality of life, and combined events.Results: Among the 300 patients who were randomized (median age, 61 years [interquartile range {IQR}, 52-68 years]; 64 [21%] women; 178 [59%] with type 2 diabetes; median LVEF of 25% [IQR, 19%-33%]; median N-terminal pro-B-type natriuretic peptide level of 2049 pg/mL [IQR, 1054-4235 pg/mL]), 271 completed the study. Compared with placebo, liraglutide had no significant effect on the primary end point (mean rank of 146 for the liraglutide group vs 156 for the placebo group, P = .31). There were no significant between-group differences in the number of deaths (19 [12%] in the liraglutide group vs 16 [11%] in the placebo group; hazard ratio, 1.10 [95% CI, 0.57-2.14]; P = .78) or rehospitalizations for heart failure (63 [41%] vs 50 [34%], respectively; hazard ratio, 1.30 [95% CI, 0.89-1.88]; P = .17) or for the exploratory secondary end points. Prespecified subgroup analyses in patients with diabetes did not reveal any significant between-group differences. The number of investigator-reported hyperglycemic events was 16 (10%) in the liraglutide group vs 27 (18%) in the placebo group and hypoglycemic events were infrequent (2 [1%] vs 4 [3%], respectively).Conclusions and Relevance: Among patients recently hospitalized with heart failure and reduced LVEF, the use of liraglutide did not lead to greater posthospitalization clinical stability. These findings do not support the use of liraglutide in this clinical situation.Trial Registration: clinicaltrials.gov Identifier: NCT01800968. [ABSTRACT FROM AUTHOR]

Importance: Small studies suggest that low-dose dopamine or low-dose nesiritide may enhance decongestion and preserve renal function in patients with acute heart failure and renal dysfunction; however, neither strategy has been rigorously tested.Objective: To test the 2 independent hypotheses that, compared with placebo, addition of low-dose dopamine (2 μg/kg/min) or low-dose nesiritide (0.005 μg/kg/min without bolus) to diuretic therapy will enhance decongestion and preserve renal function in patients with acute heart failure and renal dysfunction.Design, Setting, and Participants: Multicenter, double-blind, placebo-controlled clinical trial (Renal Optimization Strategies Evaluation [ROSE]) of 360 hospitalized patients with acute heart failure and renal dysfunction (estimated glomerular filtration rate of 15-60 mL/min/1.73 m2), randomized within 24 hours of admission. Enrollment occurred from September 2010 to March 2013 across 26 sites in North America.Interventions: Participants were randomized in an open, 1:1 allocation ratio to the dopamine or nesiritide strategy. Within each strategy, participants were randomized in a double-blind, 2:1 ratio to active treatment or placebo. The dopamine (n = 122) and nesiritide (n = 119) groups were independently compared with the pooled placebo group (n = 119).Main Outcomes and Measures: Coprimary end points included 72-hour cumulative urine volume (decongestion end point) and the change in serum cystatin C from enrollment to 72 hours (renal function end point).Results: Compared with placebo, low-dose dopamine had no significant effect on 72-hour cumulative urine volume (dopamine, 8524 mL; 95% CI, 7917-9131 vs placebo, 8296 mL; 95% CI, 7762-8830 ; difference, 229 mL; 95% CI, -714 to 1171 mL; P = .59) or on the change in cystatin C level (dopamine, 0.12 mg/L; 95% CI, 0.06-0.18 vs placebo, 0.11 mg/L; 95% CI, 0.06-0.16; difference, 0.01; 95% CI, -0.08 to 0.10; P = .72). Similarly, low-dose nesiritide had no significant effect on 72-hour cumulative urine volume (nesiritide, 8574 mL; 95% CI, 8014-9134 vs placebo, 8296 mL; 95% CI, 7762-8830; difference, 279 mL; 95% CI, -618 to 1176 mL; P = .49) or on the change in cystatin C level (nesiritide, 0.07 mg/L; 95% CI, 0.01-0.13 vs placebo, 0.11 mg/L; 95% CI, 0.06-0.16; difference, -0.04; 95% CI, -0.13 to 0.05; P = .36). Compared with placebo, there was no effect of low-dose dopamine or nesiritide on secondary end points reflective of decongestion, renal function, or clinical outcomes.Conclusion and Relevance: In participants with acute heart failure and renal dysfunction, neither low-dose dopamine nor low-dose nesiritide enhanced decongestion or improved renal function when added to diuretic therapy.Trial Registration: clinicaltrials.gov Identifier: NCT01132846. [ABSTRACT FROM AUTHOR]

IMPORTANCE Small studies suggest that low-dose dopamine or low-dose nesiritide may enhance decongestion and preserve renal function in patients with acute heart failure and renal dysfunction; however, neither strategy has been rigorously tested. OBJECTIVE To test the 2 independent hypotheses that, compared with placebo, addition of low-dose dopamine (2 µg/kg/min) or low-dose nesiritide (0.005 µg/kg/min without bolus) to diuretic therapy will enhance decongestion and preserve renal function in patients with acute heart failure and renal dysfunction. DESIGN, SETTING, AND PARTICIPANTS Multicenter, double-blind, placebo-controlled clinical trial (Renal Optimization Strategies Evaluation [ROSE]) of 360 hospitalized patients with acute heart failure and renal dysfunction (estimated glomerular filtration rate of 15-60 mL/min/1.73 m²), randomized within 24 hours of admission. Enrollment occurred from September 2010 to March 2013 across 26 sites in North America. INTERVENTIONS Participants were randomized in an open, 1:1 allocation ratio to the dopamine or nesiritide strategy. Within each strategy, participants were randomized in a double-blind, 2:1 ratio to active treatment or placebo. The dopamine (n = 122) and nesiritide (n = 119) groups were independently compared with the pooled placebo group (n = 119). MAIN OUTCOMES AND MEASURES Coprimary end points included 72-hour cumulative urine volume (decongestion end point) and the change In serum cystatin C from enrollment to 72 hours (renal function end point). RESULTS Compared with placebo, low-dose dopamine had no significant effect on 72-hour cumulative urine volume (dopamine, 8524 mL; 95% CI, 7917-9131 vs placebo, 8296 mL; 95% CI, 7762-8830 ; difference, 229 mL; 95% CI, -714 to 1171 mL; P = .59) or on the change in cystatin C level (dopamine, 0.12 mg/L; 95% CI, 0.06-0.18 vs placebo, 0.11 mg/L; 95% CI, 0.06-0.16; difference, 0.01; 95% CI, -0.08 to 0.10; P = .72). Similarly, low-dose nesiritide had no significant effect on 72-hour cumulative urine volume (nesiritide, 8574 mL; 95% CI, 8014-9134 vs placebo, 8296mL; 95% CI, 7762-8830; difference, 279 mL; 95% CI, -618 to 1176 mL; P = .49) or on the change in cystatin C level (nesiritide, 0.07 mg/L; 95% CI, 0.01-0.13 vs placebo, 0.11 mg/L; 95% CI, 0.06-0.16; difference, -0.04; 95% CI, -0.13 to 0.05; P = .36). Compared with placebo, there was no effect of low-dose dopamine or nesiritide on secondary end points reflective of decongestion, renal function, or clinical outcomes. CONCLUSION AND RELEVANCE In participants with acute heart failure and renal dysfunction, neither low-dose dopamine nor low-dose nesiritide enhanced decongestion or improved renal function when added to diuretic therapy. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01132846 [ABSTRACT FROM AUTHOR]

Importance: Studies in experimental and human heart failure suggest that phosphodiesterase-5 inhibitors may enhance cardiovascular function and thus exercise capacity in heart failure with preserved ejection fraction (HFPEF).Objective: To determine the effect of the phosphodiesterase-5 inhibitor sildenafil compared with placebo on exercise capacity and clinical status in HFPEF.Design: Multicenter, double-blind, placebo-controlled, parallel-group, randomized clinical trial of 216 stable outpatients with HF, ejection fraction ≥50%, elevated N-terminal brain-type natriuretic peptide or elevated invasively measured filling pressures, and reduced exercise capacity. Participants were randomized from October 2008 through February 2012 at 26 centers in North America. Follow-up was through August 30, 2012.Interventions: Sildenafil (n = 113) or placebo (n = 103) administered orally at 20 mg, 3 times daily for 12 weeks, followed by 60 mg, 3 times daily for 12 weeks.Main Outcome Measures: Primary end point was change in peak oxygen consumption after 24 weeks of therapy. Secondary end points included change in 6-minute walk distance and a hierarchical composite clinical status score (range, 1-n, a higher value indicates better status; expected value with no treatment effect, 95) based on time to death, time to cardiovascular or cardiorenal hospitalization, and change in quality of life for participants without cardiovascular or cardiorenal hospitalization at 24 weeks.Results: Median age was 69 years, and 48% of patients were women. At baseline, median peak oxygen consumption (11.7 mL/kg/min) and 6-minute walk distance (308 m) were reduced. The median E/e' (16), left atrial volume index (44 mL/m2), and pulmonary artery systolic pressure (41 mm Hg) were consistent with chronically elevated left ventricular filling pressures. At 24 weeks, median (IQR) changes in peak oxygen consumption (mL/kg/min) in patients who received placebo (-0.20 [IQR, -0.70 to 1.00]) or sildenafil (-0.20 [IQR, -1.70 to 1.11]) were not significantly different (P = .90) in analyses in which patients with missing week-24 data were excluded, and in sensitivity analysis based on intention to treat with multiple imputation for missing values (mean between-group difference, 0.01 mL/kg/min, [95% CI, -0.60 to 0.61]). The mean clinical status rank score was not significantly different at 24 weeks between placebo (95.8) and sildenafil (94.2) (P = .85). Changes in 6-minute walk distance at 24 weeks in patients who received placebo (15.0 m [IQR, -26.0 to 45.0]) or sildenafil (5.0 m [IQR, -37.0 to 55.0]; P = .92) were also not significantly different. Adverse events occurred in 78 placebo patients (76%) and 90 sildenafil patients (80%). Serious adverse events occurred in 16 placebo patients (16%) and 25 sildenafil patients (22%).Conclusion and Relevance: Among patients with HFPEF, phosphodiesterase-5 inhibition with administration of sildenafil for 24 weeks, compared with placebo, did not result in significant improvement in exercise capacity or clinical status.Trial Registration: clinicaltrials.gov Identifier: NCT00763867. [ABSTRACT FROM AUTHOR]

Larry A. Allen and G. Michael Felker respond to a letter to the editor about their article "Discordance Between Patient-Predicted and Model-Predicted Life Expectancy Among Ambulatory Patients With Heart Failure" in a previous issue.

Importance: The effect of montelukast in reducing symptom duration among outpatients with mild to moderate COVID-19 is uncertain., Objective: To assess the effectiveness of montelukast compared with placebo in treating outpatients with mild to moderate COVID-19., Design, Setting, and Participants: This randomized clinical trial (Accelerating COVID-19 Therapeutic Interventions and Vaccines [ACTIV]-6) was conducted from January 27 through June 23, 2023, during the circulation of Omicron subvariants. Participants aged 30 years or older with confirmed SARS-CoV-2 infection and 2 or more acute COVID-19 symptoms for less than 7 days were included across 104 US sites., Interventions: Participants were randomized 1:1 to receive montelukast, 10 mg once daily, or matched placebo for 14 days., Main Outcomes and Measures: The primary outcome was time to sustained recovery (defined as ≥3 consecutive days without symptoms). Secondary outcomes included time to death; time to hospitalization or death; a composite of health care utilization events (hospitalization, urgent care clinic visit, emergency department visit, or death); COVID-19 clinical progression scale score; and difference in mean time unwell. A modified intention-to-treat approach was used for the analysis., Results: Among 1250 participants who were randomized and received the study drug or placebo, the median age was 53 years (IQR, 42-62 years), 753 (60.2%) were female, and 704 (56.3%) reported receiving 2 or more doses of a SARS-CoV-2 vaccine. Among 628 participants who received montelukast and 622 who received placebo, differences in time to sustained recovery were not observed (adjusted hazard ratio [AHR], 1.02; 95% credible interval [CrI], 0.92-1.12; P = .63 for efficacy). Unadjusted median time to sustained recovery was 10 days (95% CI, 10-11 days) in both groups. No deaths occurred, and hospitalizations were reported for 2 participants (0.3%) in each group; the composite of health care utilization events was reported for 18 participants (2.9%) in the montelukast group and 18 (2.9%) in the placebo group (AHR, 1.01; 95% CrI, 0.45-1.84; P = .48 for efficacy). Five participants (0.4%) experienced serious adverse events (3 [0.5%] in the montelukast group and 2 [0.3%] in the placebo group)., Conclusions and Relevance: In this randomized clinical trial of outpatients with mild to moderate COVID-19, treatment with montelukast did not reduce duration of COVID-19 symptoms. These findings do not support the use of montelukast for the treatment of mild to moderate COVID-19., Trial Registration: ClinicalTrials.gov Identifier: NCT04885530.

Importance: The effect of higher-dose fluvoxamine in reducing symptom duration among outpatients with mild to moderate COVID-19 remains uncertain., Objective: To assess the effectiveness of fluvoxamine, 100 mg twice daily, compared with placebo, for treating mild to moderate COVID-19., Design, Setting, and Participants: The ACTIV-6 platform randomized clinical trial aims to evaluate repurposed medications for mild to moderate COVID-19. Between August 25, 2022, and January 20, 2023, a total of 1175 participants were enrolled at 103 US sites for evaluating fluvoxamine; participants were 30 years or older with confirmed SARS-CoV-2 infection and at least 2 acute COVID-19 symptoms for 7 days or less., Interventions: Participants were randomized to receive fluvoxamine, 50 mg twice daily on day 1 followed by 100 mg twice daily for 12 additional days (n = 601), or placebo (n = 607)., Main Outcomes and Measures: The primary outcome was time to sustained recovery (defined as at least 3 consecutive days without symptoms). Secondary outcomes included time to death; time to hospitalization or death; a composite of hospitalization, urgent care visit, emergency department visit, or death; COVID-19 clinical progression scale score; and difference in mean time unwell. Follow-up occurred through day 28., Results: Among 1208 participants who were randomized and received the study drug, the median (IQR) age was 50 (40-60) years, 65.8% were women, 45.5% identified as Hispanic/Latino, and 76.8% reported receiving at least 2 doses of a SARS-CoV-2 vaccine. Among 589 participants who received fluvoxamine and 586 who received placebo included in the primary analysis, differences in time to sustained recovery were not observed (adjusted hazard ratio [HR], 0.99 [95% credible interval, 0.89-1.09]; P for efficacy = .40]). Additionally, unadjusted median time to sustained recovery was 10 (95% CI, 10-11) days in both the intervention and placebo groups. No deaths were reported. Thirty-five participants reported health care use events (a priori defined as death, hospitalization, or emergency department/urgent care visit): 14 in the fluvoxamine group compared with 21 in the placebo group (HR, 0.69 [95% credible interval, 0.27-1.21]; P for efficacy = .86) There were 7 serious adverse events in 6 participants (2 with fluvoxamine and 4 with placebo) but no deaths., Conclusions and Relevance: Among outpatients with mild to moderate COVID-19, treatment with fluvoxamine does not reduce duration of COVID-19 symptoms., Trial Registration: ClinicalTrials.gov Identifier: NCT04885530.

Importance: Persistent congestion is associated with worse outcomes in acute heart failure (AHF). Mineralocorticoid receptor antagonists administered at high doses may relieve congestion, overcome diuretic resistance, and mitigate the effects of adverse neurohormonal activation in AHF., Objective: To assess the effect of high-dose spironolactone and usual care on N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels compared with usual care alone., Design, Setting, and Participants: This double-blind and placebo (or low-dose)-controlled randomized clinical trial was conducted in 22 US acute care hospitals among patients with AHF who were previously receiving no or low-dose (12.5 mg or 25 mg daily) spironolactone and had NT-proBNP levels of 1000 pg/mL or more or B-type natriuretic peptide levels of 250 pg/mL or more, regardless of ejection fraction., Interventions: High-dose spironolactone (100 mg) vs placebo or 25 mg spironolactone (usual care) daily for 96 hours., Main Outcomes and Measures: The primary end point was the change in NT-proBNP levels from baseline to 96 hours. Secondary end points included the clinical congestion score, dyspnea assessment, net urine output, and net weight change. Safety end points included hyperkalemia and changes in renal function., Results: A total of 360 patients were randomized, of whom the median age was 65 years, 129 (36%) were women, 200 (55.5%) were white, 151 (42%) were black, 8 (2%) were Hispanic or Latino, 9 (2.5%) were of other race/ethnicity, and the median left ventricular ejection fraction was 34%. Baseline median (interquartile range) NT-proBNP levels were 4601 (2697-9596) pg/mL among the group treated with high-dose spironolactone and 3753 (1968-7633) pg/mL among the group who received usual care. There was no significant difference in the log NT-proBNP reduction between the 2 groups (-0.55 [95% CI, -0.92 to -0.18] with high-dose spironolactone and -0.49 [95% CI, -0.98 to -0.14] with usual care, P = .57). None of the secondary end point or day-30 all-cause mortality or heart failure hospitalization rate differed between the 2 groups. The changes in serum potassium and estimated glomerular filtration rate at 24, 48, 72, and 96 hours. were similar between the 2 groups., Conclusions and Relevance: Adding treatment with high-dose spironolactone to usual care for patients with AHF for 96 hours was well tolerated but did not improve the primary or secondary efficacy end points., Trial Registration: clinicaltrials.gov Identifier: NCT02235077.

Importance: Phosphodiesterase-5 inhibition with sildenafil compared with a placebo had no effect on the exercise capacity or clinical status of patients with heart failure with preserved ejection fraction (HFpEF) in the PhosphodiesteRasE-5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic Heart Failure with Preserved Ejection Fraction (RELAX) clinical trial. Metabolic impairments may explain the neutral results., Objective: To test the hypothesis that profiling metabolites in the RELAX trial would clarify the mechanisms of sildenafil effects and identify metabolites associated with clinical outcomes in HFpEF., Design, Setting, and Participants: Paired baseline and 24-week plasma samples of 160 stable outpatient individuals with HFpEF enrolled in the RELAX clinical trial were analyzed using flow injection tandem mass spectrometry (60 metabolites) and conventional assays (5 metabolites)., Interventions: Sildenafil (n = 79) or a placebo (n = 81) administered orally at 20 mg, 3 times daily for 12 weeks, followed by 60 mg, 3 times daily for 12 weeks., Main Outcomes and Measures: The primary measure was metabolite level changes between baseline and 24 weeks stratified by treatments. Secondary measures included correlations between metabolite level changes and clinical biomarkers and associations between baseline metabolite levels and the composite clinical score., Results: No metabolites changed between baseline and 24 weeks in the group treated with a placebo; however, 7 metabolites changed in the group treated with sildenafil, including decreased amino acids (alanine and proline; median change [25th-75th], -38.26 [-100.3 to 28.19] and -28.24 [-56.29 to 12.08], respectively; false discovery rate-adjusted P = .01 and .03, respectively), and increased short-chain dicarboxylacylcarnitines glutaryl carnitine, octenedioyl carnitine, and adipoyl carnitine (median change, 6.19 [-3.37 to 14.18], 2.72 [-3 to 12.57], and 10.72 [-11.23 to 29.57], respectively; false discovery rate-adjusted P = .01, .04, and .05, respectively), and 1 long-chain acylcarnitine metabolite (palmitoyl carnitine; median change, 7.83 [-5.64 to 26.99]; false discovery rate-adjusted P = .03). The increases in long-chain acylarnitine metabolites and short-chain dicarboxylacylcarnitines correlated with increases in endothelin-1 and creatinine/cystatin C, respectively. Higher baseline levels of short-chain dicarboxylacylcarnitine metabolite 3-hydroxyisovalerylcarnitine/malonylcarnitine and asparagine/aspartic acid were associated with worse clinical rank scores in both treatment groups (β, -96.60, P = .001 and β, -0.02, P = .01; after renal adjustment, P = .09 and .02, respectively)., Conclusions and Relevance: Our study provides a potential mechanism for the effects of sildenafil that, through adverse effects on mitochondrial function and endoplasmic reticulum stress, could have contributed to the neutral trial results in RELAX. Short-chain dicarboxylacylcarnitine metabolites and asparagine/aspartic acid could serve as biomarkers associated with adverse clinical outcomes in HFpEF.

A surgical technique for secondary emplacement of an orbital implant is described in which a spherical implant encased in a scleral homograft is placed in the orbit through a transconjuctival incision and sutured to the superior part of the periosteum.

A case of acrodermatitis enteropathica is presented that is the first to manifest punctal stenosis, the fourth to show corneal changes, and the sixth to survive into adulthood.