AIMS:Dipstick urine testing is often performed in primary and secondary care, although the results may not be routinely inspected or acted upon. We aimed to examine the prognostic value of semiquantitative urine dipstick proteinuria (DP) assessments in patients with heart failure (HF) and reduced ejection fraction. METHODS:This retrospective analysis utilized data from GALACTIC-HF, a randomized trial that investigated the efficacy and safety of the cardiac myosin activator, omecamtiv mecarbil, compared with placebo in patients with HF with reduced ejection fraction. The primary outcome was the composite of a first HF event (hospitalization or urgent visit for HF) or cardiovascular death, and secondary outcomes were a HF event, cardiovascular death, and all-cause death. Cox proportional hazard models were used to examine the relationship between DP levels and clinical outcomes. RESULTS:Baseline DP data were available for 7790 patients, of whom 5910 (75.9%) had a negative test or trace proteinuria, 995 (12.8%) had 1+, and 885 (11.4%) had ≥2+ proteinuria. The incidence rate of the primary outcome (per 100 person-years) increased significantly with increasing DP: negative/trace (21.8, 95% confidence interval 20.8-22.7); 1+ (34.8, 31.8-38.0); and ≥2+ (38.1, 34.7-41.9). Similar trends were observed for the components of the primary outcome and all-cause mortality. The association between greater DP and worse outcomes was stronger in patients with preserved (≥60 ml/min/1.73 m2) estimated glomerular filtration rate compared with reduced estimated glomerular filtration rate (<60 ml/min/1.73 m2). CONCLUSION:In GALACTIC-HF, higher DP levels were independently associated with increased risk of adverse clinical outcomes in patients with reduced ejection fraction. TRIAL REGISTRATION:GALACTIC-HF ClinicalTrials.gov Identifier: NCT02929329; EudraCT number, 2016-002299-28.

BACKGROUND AND AIMS:The frequency and prognostic significance of abnormalities in serum magnesium concentrations have not been described in a contemporary heart failure (HF) population. The authors evaluated the prognostic significance of magnesium concentrations in patients with HF with reduced ejection fraction (HFrEF) enrolled in GALACTIC-HF trial. METHODS:GALACTIC-HF was a randomized, double-blind, multicentre, event-driven trial that investigated the efficacy and safety of omecamtiv mecarbil compared with placebo in HF patients with left ventricular ejection fraction ≤ 35%. The primary outcome was the composite of a first worsening HF event or cardiovascular death. RESULTS:A total of 6147 outpatients had baseline serum magnesium data. Of these, 1082 (17.6%) had magnesium concentrations below .75 mmol/L, 4410 (71.7%) had concentrations within the normal range, and 655 (10.7%) had concentrations above .95 mmol/L. The incidence rate (per 100 person-years) for the primary composite outcome was highest in patients with hypermagnesaemia (34.9, 95% confidence interval 31.2-39.0), while rates were similar between those with hypomagnesaemia (21.5, 19.4-23.8), and normal magnesium (20.9, 19.9-22.0). Similar trends were observed for the components of the primary outcome and all-cause death. The incidence rate of sudden death and ventricular tachyarrhythmia did not differ among the three magnesium groups, but the risk of death from worsening HF was highest in patients with hypermagnesaemia. CONCLUSIONS:In GALACTIC-HF, 10.7% of outpatients with HFrEF had hypermagnesaemia, which was associated with a higher risk of the primary outcome compared with normal magnesium concentrations. Abnormal magnesium levels were not associated with a higher risk of sudden death or ventricular tachyarrhythmias. These findings do not support routine correction of hypomagnesaemia.

Phase II clinical trials play an important role in drug development, providing key data that guide decision-making for promising therapeutic candidates. An important objective of phase II is to establish proof of concept by demonstrating that the drug produces its intended biological effects in the target population. Phase II trials also evaluate pharmacokinetics, pharmacodynamics, safety, and dose-response relationships. Ultimately, the goal is to generate the evidence needed to inform go/no-go decisions for further development. However, as we will discuss, phase II studies have inherent limitations and cannot fully predict phase III outcomes. In this JACC: Basic to Translational Science and Heart Failure Collaboratory position paper, we examine the value and constraints of phase II programs, using prior examples of heart failure trials, with the goal of providing insights that will help investigators and sponsors to derisk go/no-go decisions.

Neuen, Brendon L.; Catanese, Benjamin; Chang, Annamarie; Heise, Mark; Tricoci, Pierluigi; Felker, G. Michael; Mahaffey, Kenneth W.; Wolf, Myles; Chertow, Glenn M.; the POSIBIL6ESKD Investigators Author Information

BACKGROUND:Previous studies have shown important but sometimes heterogeneous differences between women and men with heart failure (HF). OBJECTIVES:This study aims to investigate sex differences in the phenotype and journey of men and women in a large contemporary acute heart failure (AHF) cohort. METHODS:The authors analyzed 6,545 AHF patients (40% women) enrolled in RELAX-AHF-2 (Efficacy, Safety and Tolerability of Serelaxin When Added to Standard Therapy in AHF). RESULTS:Women were older (78 vs 72 years; P < 0.001) and had higher ejection fraction (45% vs 35%; P < 0.001). During hospitalization, women received lower diuretic doses (furosemide equivalent through day 5: 200 vs 240 mg intravenous; P < 0.001) and achieved lower weight loss (relative; P = 0.026), with slightly lower diuretic response (-0.33 vs -0.36 kg/40 mg furosemide at day 5; P = 0.011) and similar sign and symptom improvement by day 5 compared with men (all adjusted P > 0.05). More women experienced worsening renal function by day 5 (WRF; adjusted HR: 1.24 [95% CI: 1.06-1.46]; P = 0.009). Women experiencing WRF had increased risk of 180-day cardiovascular death and rehospitalizations for HF or renal failure (RF) and of rehospitalizations for HF/RF compared with men and women without WRF (adjusted P for interaction: P < 0.001). Incidence of other outcomes was similar in women and men (all P > 0.20). CONCLUSIONS:During an AHF hospitalization, women received lower doses of loop diuretic agents and achieved less weight loss with slightly lower diuretic response compared with men, despite similar symptom relief and postdischarge outcomes. Early incident WRF was more frequent in women and was associated with worse 180-day outcomes. (Efficacy, Safety and Tolerability of Serelaxin When Added to Standard Therapy in AHF [RELAX-AHF-2]; NCT01870778).

Phase II clinical trials play an important role in drug development, providing key data that guide decision-making for promising therapeutic candidates. An important objective of phase II is to establish proof of concept by demonstrating that the drug produces its intended biological effects in the target population. Phase II trials also evaluate pharmacokinetics, pharmacodynamics, safety, and dose-response relationships. Ultimately, the goal is to generate the evidence needed to inform go/no-go decisions for further development. However, as we will discuss, phase II studies have inherent limitations and cannot fully predict phase III outcomes. In this JACC: Basic to Translational Science and Heart Failure Collaboratory position paper, we examine the value and constraints of phase II programs, using prior examples of heart failure trials, with the goal of providing insights that will help investigators and sponsors to derisk go/no-go decisions.

The effect of metformin on reducing symptom duration among outpatient adults with COVID-19 has not been studied. To assess metformin compared with placebo for symptom resolution during acute infection with SARS-CoV-2. The Accelerating COVID-19 Therapeutic Interventions and Vaccines platform evaluated repurposed medications for mild to moderate COVID-19. Between September 19, 2023, and May 1, 2024, participants 30 years or older with confirmed SARS-CoV-2 infection and 2 or more COVID-19 symptoms for 7 days or less were included at 90 US sites. Participants were randomized to receive metformin (titrated to 1500 mg, daily) or placebo for 14 days. The primary outcome was time to sustained recovery (3 consecutive days without COVID-19 symptoms) within 28 days of receiving the study drug. Secondary outcomes included time to clinic visit, emergency department (ED) visit, hospitalization, or death. Safety events of interest were hypoglycemia and lactic acidosis. Among 2991 participants who were randomized and received study drug, the median age was 47 (IQR, 38-58) years; 1895 (63.4%) were female, 25 (0.8%) were American Indian of Alaska Native, 77 (2.6%) were Asian, 350 (11.7%) were Black, African American, or African, 1392 (46.5%) identified as Hispanic or Latino, 8 (0.3%) were Native Hawaiian or other Pacific Islander, 2395 (80.1%) were White, and 2044 (68.3%) reported 2 or more doses of a SARS-CoV-2 vaccine. Among 1443 (48.2%) participants who received metformin and 1548 (51.8%) who received placebo, differences in time to sustained recovery were not observed (adjusted hazard ratio, 0.96; 95% credible interval [CrI], 0.89-1.03; P for efficacy = .11). The median time to sustained recovery was 9 days (95% CI, 9-10) for metformin and 10 days (95% CI, 9-10) for placebo. No deaths were reported; 103 participants reported clinic visits, ED visits, or hospitalization: 54 in the metformin group and 49 in the placebo group (hazard ratio, 1.25; 95% CrI, 0.82-1.78; P for efficacy = .13). Overall, 35 (1.2%) reported ED visits or hospitalization (1.1% in the metformin and 1.3% in the placebo group). Seven participants who received metformin and 3 who received placebo experienced a serious adverse event over 180 days. There were 4 episodes of participant-reported hypoglycemia in the placebo group and 2 in the metformin group. In this randomized clinical trial, metformin was not shown to shorten the time to symptom resolution in low-risk adults with COVID-19. The median days to symptom resolution was numerically but not significantly lower for metformin. Safety was not a limitation in the study population. ClinicalTrials.gov Identifier: NCT04885530

Importance:The effect of metformin on reducing symptom duration among outpatient adults with COVID-19 has not been studied. Objective:To assess metformin compared with placebo for symptom resolution during acute infection with SARS-CoV-2. Design, Setting, and Participants:The Accelerating COVID-19 Therapeutic Interventions and Vaccines platform evaluated repurposed medications for mild to moderate COVID-19. Between September 19, 2023, and May 1, 2024, participants 30 years or older with confirmed SARS-CoV-2 infection and 2 or more COVID-19 symptoms for 7 days or less were included at 90 US sites. Interventions:Participants were randomized to receive metformin (titrated to 1500 mg, daily) or placebo for 14 days. Main Outcomes and Measures:The primary outcome was time to sustained recovery (3 consecutive days without COVID-19 symptoms) within 28 days of receiving the study drug. Secondary outcomes included time to clinic visit, emergency department (ED) visit, hospitalization, or death. Safety events of interest were hypoglycemia and lactic acidosis. Results:Among 2991 participants who were randomized and received study drug, the median age was 47 (IQR, 38-58) years; 1895 (63.4%) were female, 25 (0.8%) were American Indian of Alaska Native, 77 (2.6%) were Asian, 350 (11.7%) were Black, African American, or African, 1392 (46.5%) identified as Hispanic or Latino, 8 (0.3%) were Native Hawaiian or other Pacific Islander, 2395 (80.1%) were White, and 2044 (68.3%) reported 2 or more doses of a SARS-CoV-2 vaccine. Among 1443 (48.2%) participants who received metformin and 1548 (51.8%) who received placebo, differences in time to sustained recovery were not observed (adjusted hazard ratio, 0.96; 95% credible interval [CrI], 0.89-1.03; P for efficacy = .11). The median time to sustained recovery was 9 days (95% CI, 9-10) for metformin and 10 days (95% CI, 9-10) for placebo. No deaths were reported; 103 participants reported clinic visits, ED visits, or hospitalization: 54 in the metformin group and 49 in the placebo group (hazard ratio, 1.25; 95% CrI, 0.82-1.78; P for efficacy = .13). Overall, 35 (1.2%) reported ED visits or hospitalization (1.1% in the metformin and 1.3% in the placebo group). Seven participants who received metformin and 3 who received placebo experienced a serious adverse event over 180 days. There were 4 episodes of participant-reported hypoglycemia in the placebo group and 2 in the metformin group. Conclusions and Relevance:In this randomized clinical trial, metformin was not shown to shorten the time to symptom resolution in low-risk adults with COVID-19. The median days to symptom resolution was numerically but not significantly lower for metformin. Safety was not a limitation in the study population. Trial Registration:ClinicalTrials.gov Identifier: NCT04885530.

BACKGROUND:Aortic stenosis leads to increased afterload, which may be detrimental in a failing left ventricle and has been associated with an increased risk of hospitalizations due to heart failure and mortality in chronic heart failure. The prevalence and impact of aortic stenosis in acute heart failure are less well described. This post hoc analysis aimed to evaluate the prevalence and prognostic impact of aortic stenosis in a large cohort of patients hospitalized due to acute heart failure. METHODS AND RESULTS:All patients from the Relaxin in Acute Heart Failure 2 (RELAX-AHF-2) trial with data available on aortic stenosis severity were included in the present analysis (n = 6241). Patients with severe aortic stenosis were ineligible for RELAX-AHF-2. Baseline characteristics, in-hospital outcomes and 180-day clinical outcomes were compared between patients with and without aortic stenosis. Mild or moderate aortic stenosis was present in 454 (7.3%) patients. Patients with aortic stenosis were older, more commonly female, had more comorbidities, and had higher left ventricular ejection fractions compared to patients without aortic stenosis. Mild or moderate aortic stenosis was associated with a higher risk of cardiovascular mortality or readmission for heart or renal failure (unadjusted hazard ratio (HR) 1.32, 95% CI 1.11-1.57). This association was maintained when adjusting for age and sex, but not after comprehensive multivariable adjustment (adjusted HR 1.04, 95% CI 0.82-1.32). CONCLUSION:The presence of mild or moderate aortic stenosis reflects an increased risk profile in patients with acute heart failure, but it is not an independent predictor of poor clinical outcomes.

Rare cardiovascular diseases, while individually uncommon, collectively affect millions of people worldwide and are associated with significant morbidity, mortality, and economic burden. Despite this considerable impact, most rare cardiovascular diseases lack approved treatments. Developing therapies for rare cardiovascular diseases requires overcoming a unique set of challenges. This includes barriers to accurate patient diagnosis (and therefore to trial cohort generation), small cohort sizes, the choice of effective clinical trial endpoints, unique ethical and regulatory concerns, and the often-substantial costs of such therapies (which may limit public access to treatment). Despite such challenges, the past decade has witnessed a significant increase in the successful development of rare cardiovascular disease therapies. This review provides an overview of the challenges, while also highlighting potential strategies to advance the field.

AIMS:Little is known regarding the clinical and financial implications of varying inpatient and outpatient management strategies for worsening heart failure (WHF). This analysis aimed to compare clinical outcomes, home-time, and healthcare expenditure following various types of inpatient and outpatient WHF events in US clinical practice. METHODS AND RESULTS:We examined US Medicare beneficiaries 65 years and older discharged from a hospitalization for heart failure (HF) in the Get With The Guidelines-Heart Failure registry from 2010 to 2018. Patients developing subsequent WHF within 12 months were divided into four mutually exclusive groups by type of first event: HF hospitalization, emergency department (ED) visit with ED discharge, observation stay, and outpatient intravenous (IV) diuretic clinic visit. Following each type of WHF event, mortality, home-time (days alive and out of any healthcare institution), and healthcare costs were compared over the subsequent 12 months. Among 181 827 eligible patients discharged alive from a HF hospitalization across 553 US hospitals, 61 159 (33.6%) patients had a subsequent WHF event within 12 months. Of these, 48 612 were managed with HF hospitalization (79.5%), 8139 (13.3%) with an ED visit, 1767 (2.9%) with an observation stay, and 2641 (4.3%) with an outpatient IV diuretic visit. Rates of 12-month mortality were highest following HF hospitalization (cumulative incidence rate [IR] 48.8; 95% confidence interval [CI] 48.3-49.3), lowest following observation unit stay (IR 29.9; 95% CI 27.7-32.0), and intermediate following ED discharge (IR 41.2; 95% CI 40.1-42.3) and outpatient IV diuretic visit (IR 39.3; 95% CI 37.4-41.2). Median (25th-75th) 12-month home-time was lowest following HF hospitalization (251 [47-351] days) and highest following observation unit stays (354 [206-365] days). For the index WHF event itself, median total per-patient costs were highest for HF hospitalization (US$11 335) and lowest for outpatient IV diuretic visit (US$259). Over the 12 months following the WHF event, when accounting for costs of all patients including those who died within 12 months, the median total per-patient costs were highest following outpatient IV diuretic visits (US$29 173). Among patients surviving 12 months after WHF, median total per-patient costs following an outpatient IV diuretic visit (US$29 931) versus HF hospitalization (US$30 971) were similarly high. CONCLUSIONS:In this nationwide analysis of older US adults, high rates of death and substantial reductions in home-time occurred following WHF regardless of inpatient or outpatient management, but were worse following HF hospitalization. Outpatient IV diuretic administration was the least expensive initial management strategy, but over the subsequent 12 months, associated costs were similar or higher than costs following HF hospitalization.

Background:The effect of metformin on preventing long-term COVID-19 symptoms among low-risk adults has not been studied. The objective of this study was to Assess metformin compared with placebo during acute SARS-CoV-2 infection on the presence of COVID-19 symptoms 180 days later. Methods:The ACTIV-6 platform evaluated repurposed medications for mild to moderate COVID-19. Between September 19, 2023 and May 1, 2024, 2983 outpatient adults ≥30 years with confirmed SARS-CoV-2 infection and ≥2 COVID-19 symptoms for ≤7 days were included from 90 sites. Participants were randomized to metformin (titrated to 1500 mg daily) or placebo for 14 days. Post-acute sequelae of SARS-CoV-2 or death (PASCD) was ascertained by asking whether participants had symptoms they attributed to COVID-19 on day 180. Secondary outcomes included clinician diagnosis of long COVID. For the primary outcome, the single-sided threshold for efficacy was 0.975. Results:Among 2983 participants, the median age was 47 years (interquartile range [IQR] 38-57); 63% were female; 47% Hispanic/Latino; 83% reported ≥1 prior COVID-19 infections or SARS-CoV-2 vaccines. There were no deaths. Overall, 96 (3.2%) reported COVID-19 symptoms on day 90, 101 (3.4%) on day 120, and 79 (2.6%) on day 180. The covariate-adjusted risk of PASCD on day 180 was lower in the metformin group (-0.008; 95% credible interval [CrI] -0.022 to 0.006; posterior probability of efficacy [PPE] 0.83), compared with the placebo group with an adjusted risk ratio of 0.79 (95% CrI 0.474 to 1.230). The risk of clinician diagnosis of long COVID (secondary outcome) on day 180 was lower in the metformin group (-0.007; 95% CrI -0.015 to 0.001; PPE 0.96), with a relative risk of 0.495 (95% CrI 0.155 to 0.995). Conclusions:The posterior probability of efficacy for metformin preventing the primary endpoint did not exceed the prespecified threshold of 0.975 for declaring efficacy. Secondary outcomes were numerically better with metformin. Trial Registration:ClinicalTrials.gov ( NCT04885530 ).