AimDescribe the distinguishing features of heart failure (HF) patients with reduced ejection fraction (HFrEF) in the VICTORIA (Vericiguat Global Study in Patients with Heart Failure with Reduced Ejection Fraction) trial.Methods and resultsKey background characteristics were evaluated in 5050 patients randomized in VICTORIA and categorized into three cohorts reflecting their index worsening HF event. Differences within the VICTORIA population were assessed and compared with PARADIGM‐HF (Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) and COMMANDER HF (A Study to Assess the Effectiveness and Safety of Rivaroxaban in Reducing the Risk of Death, Myocardial Infarction, or Stroke in Participants with Heart Failure and Coronary Artery Disease Following an Episode of Decompensated Heart Failure). VICTORIA patients had increased risk of mortality and rehospitalization: New York Heart Association class (40% class III), atrial fibrillation (45%), diabetes (47%), hypertension (79%) and mean estimated glomerular filtration rate of 61.5 mL/min/1.73 m2. Baseline standard of HF care was very good: 60% received triple therapy. Their N‐terminal pro‐B‐type natriuretic peptide was 3377 pg/mL [interquartile range (IQR) 1992–6380]. Natriuretic peptides were 30% higher level in the 67% patients with HF hospitalization <3 months, compared to those within 3–6 months of HF hospitalization and those randomized after recent outpatient intravenous diuretic therapy. Overall the median MAGGIC (Meta‐Analysis Global Group in Chronic Heart Failure) risk score in VICTORIA was 23 (IQR 18–27) as compared to the MAGGIC risk score in PARADIGM‐HF of 20 (IQR 16–24).ConclusionsVICTORIA comprises a broadly generalizable high‐risk population of three unique clinical strata of worsening chronic HFrEF despite very good HF therapy. VICTORIA will establish the role of vericiguat, a soluble guanylate cyclase stimulator, in HFrEF.

Background Thrombo-inflammation may contribute to morbidity and mortality in Covid-19. We hypothesized that therapeutic-dose anticoagulation may improve outcomes in non-critically ill patients hospitalized for Covid-19. Methods In an open-label adaptive multiplatform randomized controlled trial, non-critically ill patients hospitalized for Covid-19, defined by the absence of critical care-level organ support at enrollment, were randomized to a pragmatic strategy of therapeutic-dose anticoagulation with heparin or usual care pharmacological thromboprophylaxis. The primary outcome combined survival to hospital discharge and days free of organ support through 21 days, which was evaluated with Bayesian statistical models according to baseline D-dimer. Results The trial was stopped when prespecified criteria for superiority were met for therapeutic-dose anticoagulation in groups defined by high (≥2-fold elevated) and low (<2-fold elevated) D-dimer. Among 2219 participants in the final analysis, the probability that therapeutic anticoagulation increased organ support-free days compared to thromboprophylaxis was 99.0% (adjusted odds ratio 1.29, 95% credible interval 1.04 to 1.61). The adjusted absolute increase in survival to hospital discharge without organ support with therapeutic-dose anticoagulation was 4.6% (95% credible interval 0.7 to 8.1). In the primary adaptive stopping groups, the final probabilities of superiority for therapeutic anticoagulation were 97.3% in the high D-dimer group and 92.9% in the low D-dimer group. Major bleeding occurred in 1.9% and 0.9% of participants randomized to therapeutic anticoagulation and thromboprophylaxis, respectively. Conclusions In non-critically ill patients with Covid-19, an initial strategy of therapeutic-dose anticoagulation with heparin increases the probability of survival to hospital discharge with reduced use of organ support.

BackgroundThe rapid diagnostic tests for malaria (RDT) constitute a fast and opportune alternative for non-complicated malaria diagnosis in areas where microscopy is not available. The objective of this study was to validate a RDT named Parascreen™ under field conditions in Iquitos, department of Loreto, Peru. Parascreen™ is a RDT that detects the histidine-rich protein 2 (HRP2) antigen from Plasmodium falciparum and lactate deshydrogenase from all Plasmodium species.MethodsParascreen™ was compared with microscopy performed by experts (EM) and polymerase chain reaction (PCR) using the following indicators: sensitivity (Se), specificity (Sp), positive (PV+) and negative predictive values (PV-), positive (LR+) and negative likehood ratio (LR-).Results332 patients with suspected non-complicated malaria who attended to the MOH health centres were enrolled between October and December 2006. For P. falciparum malaria, Parascreen™ in comparison with EM, had Se: 53.5%, Sp: 98.7%, PV+: 66.7%, PV-: 97.8%, LR+: 42.27 and LR-: 0.47; and for non-P. falciparum malaria, Se: 77.1%, Sp: 97.6%, PV+: 91.4%, PV-: 92.7%, LR+: 32.0 and LR-: 0.22. The comparison of Parascreen™ with PCR showed, for P. falciparum malaria, Se: 81.8%, Sp: 99.1%, PV+: 75%, PV-: 99.4, LR+: 87.27 and LR-: 0.18; and for non-P. falciparum malaria Se: 76.1%, Sp: 99.2%, PV+: 97.1%, PV-: 92.0%, LR+: 92.51 and LR-: 0.24.ConclusionsThe study results indicate that Parascreen™ is not a valid and acceptable test for malaria diagnosis under the field conditions found in the Peruvian Amazon. The relative proportion of Plasmodium species, in addition to the genetic characteristics of the parasites in the area, must be considered before applying any RDT, especially after the finding of P. falciparum malaria parasites lacking pfhrp2 gene in this region.

ImportanceRandomized clinical trials (RCTs) of therapeutic-dose heparin in patients hospitalized with COVID-19 produced conflicting results, possibly due to heterogeneity of treatment effect (HTE) across individuals. Better understanding of HTE could facilitate individualized clinical decision-making.ObjectiveTo evaluate HTE of therapeutic-dose heparin for patients hospitalized for COVID-19 and to compare approaches to assessing HTE.Design, Setting, and ParticipantsExploratory analysis of a multiplatform adaptive RCT of therapeutic-dose heparin vs usual care pharmacologic thromboprophylaxis in 3320 patients hospitalized for COVID-19 enrolled in North America, South America, Europe, Asia, and Australia between April 2020 and January 2021. Heterogeneity of treatment effect was assessed 3 ways: using (1) conventional subgroup analyses of baseline characteristics, (2) a multivariable outcome prediction model (risk-based approach), and (3) a multivariable causal forest model (effect-based approach). Analyses primarily used bayesian statistics, consistent with the original trial.ExposuresParticipants were randomized to therapeutic-dose heparin or usual care pharmacologic thromboprophylaxis.Main Outcomes and MeasuresOrgan support–free days, assigning a value of −1 to those who died in the hospital and the number of days free of cardiovascular or respiratory organ support up to day 21 for those who survived to hospital discharge; and hospital survival.ResultsBaseline demographic characteristics were similar between patients randomized to therapeutic-dose heparin or usual care (median age, 60 years; 38% female; 32% known non-White race; 45% Hispanic). In the overall multiplatform RCT population, therapeutic-dose heparin was not associated with an increase in organ support–free days (median value for the posterior distribution of the OR, 1.05; 95% credible interval, 0.91-1.22). In conventional subgroup analyses, the effect of therapeutic-dose heparin on organ support–free days differed between patients requiring organ support at baseline or not (median OR, 0.85 vs 1.30; posterior probability of difference in OR, 99.8%), between females and males (median OR, 0.87 vs 1.16; posterior probability of difference in OR, 96.4%), and between patients with lower body mass index (BMI &amp;lt;30) vs higher BMI groups (BMI ≥30; posterior probability of difference in ORs &amp;gt;90% for all comparisons). In risk-based analysis, patients at lowest risk of poor outcome had the highest propensity for benefit from heparin (lowest risk decile: posterior probability of OR &amp;gt;1, 92%) while those at highest risk were most likely to be harmed (highest risk decile: posterior probability of OR &amp;lt;1, 87%). In effect-based analysis, a subset of patients identified at high risk of harm (P = .05 for difference in treatment effect) tended to have high BMI and were more likely to require organ support at baseline.Conclusions and RelevanceAmong patients hospitalized for COVID-19, the effect of therapeutic-dose heparin was heterogeneous. In all 3 approaches to assessing HTE, heparin was more likely to be beneficial in those who were less severely ill at presentation or had lower BMI and more likely to be harmful in sicker patients and those with higher BMI. The findings illustrate the importance of considering HTE in the design and analysis of RCTs.Trial RegistrationClinicalTrials.gov Identifiers: NCT02735707, NCT04505774, NCT04359277, NCT04372589

We investigated the etiology of acute diarrhea among Peruvian military recruits undergoing three months of basic combat training near the Amazonian city of Iquitos. From January through September 2002, 307 of 967 recruits were seen at the Health Post for diarrhea (attack rate [AR] = 31.8%, incidence = 1.28 95% confidence interval [CI] = 1.14-1.43] episodes/person-year). Shigella spp. were the most common bacterial pathogen recovered from recruits experiencing diarrhea episodes. These bacteria were isolated from 89 (40%) of 225 diarrheal stools examined (AR = 7.6%, incidence = 0.30 [95% CI = 0.24-0.38] episodes/person-year). Most (83 of 90; 92%) of the Shigella isolates were S. flexneri, of which 57 (69%) were serotype 2a. Seventy-six percent of Shigella isolates were resistant to sulfamethoxazole/trimethoprim and all were sensitive to ciprofloxacin. Peruvian soldiers may be an excellent population in which to test the efficacy of S. flexneri vaccines in advanced development.