Therapeutic versus prophylactic anticoagulation for patients admitted to hospital with COVID-19 and elevated D-dimer concentration (ACTION): an open-label, multicentre, randomised, controlled trial.

BACKGROUND: COVID-19 is associated with a prothrombotic state leading to adverse clinical outcomes. Whether therapeutic anticoagulation improves outcomes in patients hospitalised with COVID-19 is unknown. We aimed to compare the efficacy and safety of therapeutic versus prophylactic anticoagulation in this population. METHODS: We did a pragmatic, open-label (with blinded adjudication), multicentre, randomised, controlled trial, at 31 sites in Brazil. Patients (aged ≥18 years) hospitalised with COVID-19 and elevated D-dimer concentration, and who had COVID-19 symptoms for up to 14 days before randomisation, were randomly assigned (1:1) to receive either therapeutic or prophylactic anticoagulation. Therapeutic anticoagulation was in-hospital oral rivaroxaban (20 mg or 15 mg daily) for stable patients, or initial subcutaneous enoxaparin (1 mg/kg twice per day) or intravenous unfractionated heparin (to achieve a 0·3-0·7 IU/mL anti-Xa concentration) for clinically unstable patients, followed by rivaroxaban to day 30. Prophylactic anticoagulation was standard in-hospital enoxaparin or unfractionated heparin. The primary efficacy outcome was a hierarchical analysis of time to death, duration of hospitalisation, or duration of supplemental oxygen to day 30, analysed with the win ratio method (a ratio >1 reflects a better outcome in the therapeutic anticoagulation group) in the intention-to-treat population. The primary safety outcome was major or clinically relevant non-major bleeding through 30 days. This study is registered with ClinicalTrials.gov (NCT04394377) and is completed. FINDINGS: From June 24, 2020, to Feb 26, 2021, 3331 patients were screened and 615 were randomly allocated (311 [50%] to the therapeutic anticoagulation group and 304 [50%] to the prophylactic anticoagulation group). 576 (94%) were clinically stable and 39 (6%) clinically unstable. One patient, in the therapeutic group, was lost to follow-up because of withdrawal of consent and was not included in the primary analysis. The primary efficacy outcome was not different between patients assigned therapeutic or prophylactic anticoagulation, with 28 899 (34·8%) wins in the therapeutic group and 34 288 (41·3%) in the prophylactic group (win ratio 0·86 [95% CI 0·59-1·22], p=0·40). Consistent results were seen in clinically stable and clinically unstable patients. The primary safety outcome of major or clinically relevant non-major bleeding occurred in 26 (8%) patients assigned therapeutic anticoagulation and seven (2%) assigned prophylactic anticoagulation (relative risk 3·64 [95% CI 1·61-8·27], p=0·0010). Allergic reaction to the study medication occurred in two (1%) patients in the therapeutic anticoagulation group and three (1%) in the prophylactic anticoagulation group. INTERPRETATION: In patients hospitalised with COVID-19 and elevated D-dimer concentration, in-hospital therapeutic anticoagulation with rivaroxaban or enoxaparin followed by rivaroxaban to day 30 did not improve clinical outcomes and increased bleeding compared with prophylactic anticoagulation. Therefore, use of therapeutic-dose rivaroxaban, and other direct oral anticoagulants, should be avoided in these patients in the absence of an evidence-based indication for oral anticoagulation. FUNDING: Coalition COVID-19 Brazil, Bayer SA.

Therapeutic versus prophylactic anticoagulation for patients admitted to hospital with COVID-19 and elevated D-dimer concentration (ACTION): an open-label, multicentre, randomised, controlled trial

BACKGROUND: COVID-19 is associated with a prothrombotic state leading to adverse clinical outcomes. Whether therapeutic anticoagulation improves outcomes in patients hospitalised with COVID-19 is unknown. We aimed to compare the efficacy and safety of therapeutic versus prophylactic anticoagulation in this population. METHODS: We did a pragmatic, open-label (with blinded adjudication), multicentre, randomised, controlled trial, at 31 sites in Brazil. Patients (aged ≥18 years) hospitalised with COVID-19 and elevated D-dimer concentration, and who had COVID-19 symptoms for up to 14 days before randomisation, were randomly assigned (1:1) to receive either therapeutic or prophylactic anticoagulation. Therapeutic anticoagulation was in-hospital oral rivaroxaban (20 mg or 15 mg daily) for stable patients, or initial subcutaneous enoxaparin (1 mg/kg twice per day) or intravenous unfractionated heparin (to achieve a 0·3­0·7 IU/mL anti-Xa concentration) for clinically unstable patients, followed by rivaroxaban to day 30. Prophylactic anticoagulation was standard in-hospital enoxaparin or unfractionated heparin. The primary efficacy outcome was a hierarchical analysis of time to death, duration of hospitalisation, or duration of supplemental oxygen to day 30, analysed with the win ratio method (a ratio >1 reflects a better outcome in the therapeutic anticoagulation group) in the intention-to-treat population. The primary safety outcome was major or clinically relevant non-major bleeding through 30 days. This study is registered with ClinicalTrials.gov (NCT04394377) and is completed. FINDINGS: From June 24, 2020, to Feb 26, 2021, 3331 patients were screened and 615 were randomly allocated (311 [50%] to the therapeutic anticoagulation group and 304 [50%] to the prophylactic anticoagulation group). 576 (94%) were clinically stable and 39 (6%) clinically unstable. One patient, in the therapeutic group, was lost to follow-up because of withdrawal of consent and was not included in the primary analysis. The primary efficacy outcome was not different between patients assigned therapeutic or prophylactic anticoagulation, with 28 899 (34·8%) wins in the therapeutic group and 34 288 (41·3%) in the prophylactic group (win ratio 0·86 [95% CI 0·59­1·22], p=0·40). Consistent results were seen in clinically stable and clinically unstable patients. The primary safety outcome of major or clinically relevant non-major bleeding occurred in 26 (8%) patients assigned therapeutic anticoagulation and seven (2%) assigned prophylactic anticoagulation (relative risk 3·64 [95% CI 1·61­8·27], p=0·0010). Allergic reaction to the study medication occurred in two (1%) patients in the therapeutic anticoagulation group and three (1%) in the prophylactic anticoagulation group. INTERPRETATION: In patients hospitalised with COVID-19 and elevated D-dimer concentration, in-hospital therapeutic anticoagulation with rivaroxaban or enoxaparin followed by rivaroxaban to day 30 did not improve clinical outcomes and increased bleeding compared with prophylactic anticoagulation. Therefore, use of therapeutic-dose rivaroxaban, and other direct oral anticoagulants, should be avoided in these patients in the absence of an evidence-based indication for oral anticoagulation.

Clinical findings and prognosis of patients hospitalized for acute decompensated heart failure: Analysis of the influence of Chagas etiology and ventricular function.

AIMS: Explore the association between clinical findings and prognosis in patients with acute decompensated heart failure (ADHF) and analyze the influence of etiology on clinical presentation and prognosis. METHODS AND RESULTS: Prospective cohort of 500 patients admitted with ADHF from Aug/2013-Feb/2016; patients were predominantly male (61.8%), median age was 58 (IQ25-75% 47-66 years); etiology was dilated cardiomyopathy in 141 (28.2%), ischemic heart disease in 137 (27.4%), and Chagas heart disease in 113 (22.6%). Patients who died (154 [30.8%]) or underwent heart transplantation (53[10.6%]) were younger (56 years [IQ25-75% 45-64 vs 60 years, IQ25-75% 49-67], P = 0.032), more frequently admitted for cardiogenic shock (20.3% vs 6.8%, P<0.001), had longer duration of symptoms (14 days [IQ25-75% 4-32.8 vs 7.5 days, IQ25-75% 2-31], P = 0.004), had signs of congestion (90.8% vs 76.5%, P<0.001) and inadequate perfusion more frequently (45.9% vs 28%, P<0.001), and had lower blood pressure (90 [IQ25-75% 80-100 vs 100, IQ25-75% 90-120], P<0.001). In a logistic regression model analysis, systolic blood pressure (P<0.001, OR 0.97 [95%CI 0.96-0.98] per mmHg) and jugular distention (P = 0.004, OR 1.923 [95%CI 1.232-3.001]) were significant. Chagas patients were more frequently admitted for cardiogenic shock (15%) and syncope/arrhythmia (20.4%). Pulmonary congestion was rare among Chagas patients and blood pressure was lower. The rate of in-hospital death or heart transplant was higher among patients with Chagas (50.5%). CONCLUSIONS: A physical exam may identify patients at higher risk in a contemporaneous population. Our findings support specific therapies targeted at Chagas patients in the setting of ADHF.

Prognosis and risk stratification in patients with decompensated heart failure receiving inotropic therapy.

Objectives: The prognostic significance of transient use of inotropes has been sufficiently studied in recent heart failure (HF) populations. We hypothesised that risk stratification in these patients could contribute to patient selection for advanced therapies. Methods: We analysed a prospective cohort of adult patients admitted with decompensated HF and ejection fraction (left ventricular ejection fraction (LVEF)) less than 50%. We explored the outcomes of patients requiring inotropic therapy during hospital admission and after discharge. Results: The study included 737 patients, (64.0% male), with a median age of 58 years (IQR 48-66 years). Main aetiologies were dilated cardiomyopathy in 273 (37.0%) patients, ischaemic heart disease in 195 (26.5%) patients and Chagas disease in 163 (22.1%) patients. Median LVEF was 26 % (IQR 22%-35%). Inotropes were used in 518 (70.3%) patients. In 431 (83.2%) patients, a single inotrope was administered. Inotropic therapy was associated with higher risk of in-hospital death/urgent heart transplant (OR=10.628, 95% CI 5.055 to 22.344, p<0.001). At 180-day follow-up, of the 431 patients discharged home, 39 (9.0%) died, 21 (4.9%) underwent transplantation and 183 (42.4%) were readmitted. Inotropes were not associated with outcome (death, transplant and rehospitalisation) after discharge. Conclusions: Inotropic drugs are still widely used in patients with advanced decompensated HF and are associated with a worse in-hospital prognosis. In contrast with previous results, intermittent use of inotropes during hospitalisation did not determine a worse prognosis at 180-day follow-up. These data may add to prognostic evaluation in patients with advanced HF in centres where mechanical circulatory support is not broadly available.

Left cardiac sympathetic denervation for treatment of symptomatic systolic heart failure patients: a pilot study.

AIMS: To evaluate the feasibility, safety, and potential beneficial effects of left cardiac sympathetic denervation (LCSD) in systolic heart failure (HF) patients. METHODS AND RESULTS: In this prospective, randomized pilot study, inclusion criteria were New York Heart Association (NYHA) functional class II or III, left ventricular ejection fraction (LVEF) ≤40%, sinus rhythm, and resting heart rate >65 b.p.m., despite optimal medical therapy (MT). Fifteen patients were randomly assigned either to MT alone or MT plus LCSD. The primary endpoint was safety, measured by mortality in the first month of follow-up and morbidity according to pre-specified criteria. Secondary endpoints were exercise capacity, quality of life, LVEF, muscle sympathetic nerve activity (MSNA), brain natriuretic peptide (BNP) levels and 24 h Holter mean heart rate before and after 6 months. We studied clinical effects in long-term follow-up. Ten patients underwent LCSD. There were no adverse events attributable to surgery. In the LCSD group, LVEF improved from 25 ± 6.6 to 33 ± 5.2 (P = 0.03); 6 min walking distance improved from 167 ± 35 to 198 ± 47 m (P = 0.02). Minnesota Living with Heart Failure Questionnaire (MLWHFQ) score physical dimension changed from 21 ± 5 to 15 ± 7 (P = 0.06). The remaining analysed variables were unchanged. During 848 ± 549 days of follow-up, in the MT group, three patients either died or underwent cardiac transplantation (CT), while in the LCSD group six were alive without CT. CONCLUSIONS: LCSD was feasible and seemed to be safe in systolic HF patients. Its beneficial effects warrant the development of a larger randomized trial. Trail registration: NCT01224899.

Beneficial effects of high doses of growth hormone in the introduction and optimization of medical treatment in decompensated congestive heart failure.

BACKGROUND: Optimizing oral therapy in patients with unstable decompensated and/or dobutamine-dependent congestive heart failure (CHF) is a challenge. METHODS AND RESULTS: We investigated the effects of high doses of recombinant human growth hormone (GH) in 6 patients with cardiac cachexia and unstable decompensated CHF (5 dobutamine-dependent), including its influence in the optimization of oral CHF treatment. Patients received 8 IU of subcutaneous GH per day for median 26 (range 61) days. GH improved the systolic systemic blood pressure (SSBP, in mm Hg) from median 85 (range 34) to 100 (20) (p<.01), and the left ventricular (LV) ejection fraction (in %) from median 23 (range 22) (pretreatment) to 28 (18) (posttreatment) and 38 (28) (later) (p<.007). The NYHA functional class improved from IV to I in 2 patients, from IV to II in 3, and from IV to II-III in one. All patients were discharged from the hospital. It was possible in the hospital to initiate and after discharge to optimize long-term CHF treatment from 37.5 to 50 mg of carvedilol in 5 patients and with higher doses of captopril (from 50 to 150 mg) in all patients. Three patients are alive after 67, 75, and 11 months of follow-up. The remaining 3 patients died from a pulmonary abscess at 9 months, septicemia at 21 months, and progressive heart failure due to unplanned withdrawal of carvedilol at 36 months. CONCLUSION: The use of GH in patients with decompensated CHF and cardiac cachexia provided clinical stability without the need for inotropic drugs permitting introduction of nonpreviously tolerated drugs. This could represent a new option for optimizing long-term CHF therapy and discharging hospitalized patients who are dobutamine-dependent.