Enoxaparin for outpatients with COVID-19: 90-day results from the randomised, open-label, parallel-group, multinational, phase III OVID trial.

INTRODUCTION The benefits of early thromboprophylaxis in symptomatic COVID-19 outpatients remain unclear. We present the 90-day results from the randomised, open-label, parallel-group, investigator-initiated, multinational OVID phase III trial. METHODS Outpatients aged 50 years or older with acute symptomatic COVID-19 were randomised to receive enoxaparin 40 mg for 14 days once daily vs. standard of care (no thromboprophylaxis). The primary outcome was the composite of untoward hospitalisation and all-cause death within 30 days from randomisation. Secondary outcomes included arterial and venous major cardiovascular events, as well as the primary outcome within 90 days from randomisation. The study was prematurely terminated based on statistical criteria after the predefined interim analysis of 30-day data, which has been previously published. In the present analysis, we present the final, 90-day data from OVID and we additionally investigate the impact of thromboprophylaxis on the resolution of symptoms. RESULTS Of the 472 patients included in the intention-to-treat population, 234 were randomised to receive enoxaparin and 238 no thromboprophylaxis. The median age was 57 (Q1-Q3: 53-62) years and 217 (46 %) were women. The 90-day primary outcome occurred in 11 (4.7 %) patients of the enoxaparin arm and in 11 (4.6 %) controls (adjusted relative risk 1.00; 95 % CI: 0.44-2.25): 3 events per group occurred after day 30. The 90-day incidence of cardiovascular events was 0.9 % in the enoxaparin arm vs. 1.7 % in controls (relative risk 0.51; 95 % CI: 0.09-2.75). Individual symptoms improved progressively within 90 days with no difference between groups. At 90 days, 42 (17.9 %) patients in the enoxaparin arm and 40 (16.8 %) controls had persistent respiratory symptoms. CONCLUSIONS In adult community patients with COVID-19, early thromboprophylaxis with enoxaparin did not improve the course of COVID-19 neither in terms of hospitalisation and death nor considering COVID-19-related symptoms

Enoxaparin for outpatients with COVID-19: 90-day results from the randomised, open-label, parallel-group, multinational, phase III OVID trial

INTRODUCTION The benefits of early thromboprophylaxis in symptomatic COVID-19 outpatients remain unclear. We present the 90-day results from the randomised, open-label, parallel-group, investigator-initiated, multinational OVID phase III trial. METHODS Outpatients aged 50 years or older with acute symptomatic COVID-19 were randomised to receive enoxaparin 40 mg for 14 days once daily vs. standard of care (no thromboprophylaxis). The primary outcome was the composite of untoward hospitalisation and all-cause death within 30 days from randomisation. Secondary outcomes included arterial and venous major cardiovascular events, as well as the primary outcome within 90 days from randomisation. The study was prematurely terminated based on statistical criteria after the predefined interim analysis of 30-day data, which has been previously published. In the present analysis, we present the final, 90-day data from OVID and we additionally investigate the impact of thromboprophylaxis on the resolution of symptoms. RESULTS Of the 472 patients included in the intention-to-treat population, 234 were randomised to receive enoxaparin and 238 no thromboprophylaxis. The median age was 57 (Q1-Q3: 53-62) years and 217 (46 %) were women. The 90-day primary outcome occurred in 11 (4.7 %) patients of the enoxaparin arm and in 11 (4.6 %) controls (adjusted relative risk 1.00; 95 % CI: 0.44-2.25): 3 events per group occurred after day 30. The 90-day incidence of cardiovascular events was 0.9 % in the enoxaparin arm vs. 1.7 % in controls (relative risk 0.51; 95 % CI: 0.09-2.75). Individual symptoms improved progressively within 90 days with no difference between groups. At 90 days, 42 (17.9 %) patients in the enoxaparin arm and 40 (16.8 %) controls had persistent respiratory symptoms. CONCLUSIONS In adult community patients with COVID-19, early thromboprophylaxis with enoxaparin did not improve the course of COVID-19 neither in terms of hospitalisation and death nor considering COVID-19-related symptoms

Sex-Based Differences in Bleeding Risk After Percutaneous Coronary Intervention and Implications for the Academic Research Consortium High Bleeding Risk Criteria.

Background Female sex was not included among the high bleeding risk (HBR) criteria by the Academic Research Consortium (ARC) as it remains unclear whether it constitutes an HBR condition after percutaneous coronary intervention. We investigated whether female sex associates with HBR and assessed the performance of ARC HBR criteria separately in women and men. Methods and Results Among all consecutive patients undergoing percutaneous coronary intervention between 2009 and 2018, bleeding occurrences up to 1 year were prospectively collected and centrally adjudicated. All but one of the originally defined ARC HBR criteria were assessed, and the ARC HBR score generated accordingly. Among 16 821 patients, 25.6% were women. Compared with men, women were older and had lower creatinine clearance and hemoglobin values. After adjustment, female sex was independently associated with access-site (adjusted hazard ratio, 2.14; 95% CI, 1.22-3.74; P=0.008) but not with overall or non-access-site 1-year Bleeding Academic Research Consortium 3 or 5 bleeding. This association remained consistent when the femoral but not the radial approach was chosen. The ARC HBR score discrimination, using the original criteria, was lower among women than men (c-index 0.644 versus 0.688; P=0.048), whereas a revised ARC HBR score, in which age, creatinine clearance, and hemoglobin were modeled as continuous rather than dichotomized variables, performed similarly in both sexes. Conclusions Female sex is an independent predictor for access-site bleeding but not for overall bleeding events at 1 year after percutaneous coronary intervention. The ARC HBR framework shows an overall good performance in both sexes, yet is lower in women than men, attributable to dichotomization of age, creatinine clearance, and hemoglobin values, which are differently distributed between sexes. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02241291

Electrocardiographic Diagnosis of Life-Threatening STEMI Equivalents: When Every Minute Counts.

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Comparative Outcomes After Percutaneous Coronary Intervention in Unconscious and Conscious Patients With Out-of-Hospital Cardiac Arrest.

BACKGROUND Up to 70% of out-of-hospital cardiac arrest (OHCA) patients have a relevant coronary stenosis which may need revascularization. The short- and long-term ischemic and bleeding risk of unconscious and conscious OHCA patients undergoing percutaneous coronary intervention (PCI) is largely unknown. OBJECTIVES This study sought to compare the occurrence of 1-year outcomes after PCI between OHCA patients, stratified on the basis of state of consciousness, with patients with acute coronary syndrome (ACS) not preceded by OHCA. METHODS The study assessed the unadjusted and adjusted risk of cardiovascular events in a prospective single-center cohort of 9,303 consecutive PCI patients. RESULTS At 1 year, all-cause mortality was higher in unconscious (49.5%) but not in conscious OHCA (8.9%) patients than in ACS patients (8.0%), and both unconscious and conscious OHCA patients were more likely than ACS patients to experience definite stent thrombosis (4.4% and 3.5% vs 1.3%) and Bleeding Academic Research Consortium 3 or 5 bleeding (17.8% and 9.0% vs 5.1%). The higher hazards were largely determined by events occurring in the first 30 days. After multivariable adjustment, only unconscious OHCA patients remained at increased risk of death (adjusted HR: 3.27; 95% CI: 2.65-4.05), definite stent thrombosis (adjusted HR: 2.40; 95% CI: 1.30-4.43), and Bleeding Academic Research Consortium 3 or 5 bleeding (adjusted HR: 2.51; 95% CI: 1.82-3.47) at 1 year. CONCLUSIONS At 1 year after PCI, unconscious OHCA patients were at higher risk of death, definite stent thrombosis, and bleeding, while conscious OHCA patients had similar hazards compared with an all-comer ACS population without OHCA. Dedicated PCI strategies for OHCA patients taking into account their state of consciousness after resuscitation are warranted

Acute Coronary Occlusion in Patients With Non-ST-Segment Elevation Out-of-Hospital Cardiac Arrest.

BACKGROUND According to current guidelines, hemodynamic status should guide the decision between immediate and delayed coronary angiography (CAG) in out-of-hospital cardiac arrest (OHCA) patients without ST-segment elevation. A delayed strategy is advised in hemodynamically stable patients, and an immediate approach is recommended in unstable patients. OBJECTIVES This study sought to assess the frequency, predictors, and clinical impact of acute coronary occlusion in hemodynamically stable and unstable OHCA patients without ST-segment elevation. METHODS Consecutive unconscious OHCA patients without ST-segment elevation who were undergoing CAG at Bern University Hospital (Bern, Switzerland) between 2011 and 2019 were included. Frequency and predictors of acute coronary artery occlusions and their impact on all-cause and cardiovascular mortality at 1 year were assessed. RESULTS Among the 386 patients, 169 (43.8%) were hemodynamically stable. Acute coronary occlusions were found in 19.5% of stable and 24.0% of unstable OHCA patients (P = 0.407), and the presence of these occlusions was predicted by initial chest pain and shockable rhythm, but not by hemodynamic status. Acute coronary occlusion was associated with an increased risk of cardiovascular death (adjusted HR: 2.74; 95% CI: 1.22-6.15) but not of all-cause death (adjusted HR: 0.72; 95% CI: 0.44-1.18). Hemodynamic instability was not predictive of fatal outcomes. CONCLUSIONS Acute coronary artery occlusions were found in 1 in 5 OHCA patients without ST-segment elevation. The frequency of these occlusions did not differ between stable and unstable patients, and the occlusions were associated with a higher risk of cardiovascular death. In OHCA patients without ST-segment elevation, chest pain or shockable rhythm rather than hemodynamic status identifies patients with acute coronary occlusion

Impact of clinical presentation on bleeding risk after percutaneous coronary intervention and implications for the ARC-HBR definition.

BACKGROUND The identification of bleeding risk factors in patients undergoing percutaneous coronary intervention (PCI) is essential to inform subsequent management. Whether clinical presentation per se affects bleeding risk after PCI remains unclear. AIMS We aimed to assess whether clinical presentation per se predisposes to bleeding in patients undergoing PCI and if the Academic Research Consortium (ARC) High Bleeding Risk (HBR) criteria perform consistently in acute (ACS) and chronic (CCS) coronary syndrome patients. METHODS Consecutive patients undergoing PCI from the Bern PCI Registry were stratified by clinical presentation. Bleeding events at one year were compared in ACS versus CCS patients, and the originally defined ARC-HBR criteria were assessed. RESULTS Among 16,821 patients, 9,503 (56.5%) presented with ACS. At one year, BARC 3 or 5 bleeding occurred in 4.97% and 3.60% of patients with ACS and CCS, respectively. After adjustment, ACS remained associated with higher BARC 3 or 5 bleeding risk (adjusted HR 1.21, 95% CI: 1.01-1.43; p=0.034), owing to non-access site-related occurrences, which accrued mainly within the first 30 days after PCI. The ARC-HBR score had lower discrimination among ACS compared with CCS patients, and its performance slightly improved when ACS was computed as a minor criterion. CONCLUSIONS ACS presentation per se predicts one-year major bleeding risk after PCI. The ARC-HBR score discrimination appeared lower in ACS than CCS, and its overall performance improved numerically when ACS was computed as an additional minor risk criterion

Validation of high bleeding risk criteria and definition as proposed by the academic research consortium for high bleeding risk.

AIMS To validate the set of clinical and biochemical criteria proposed by consensus by the Academic Research Consortium (ARC) for High Bleeding Risk (HBR) for the identification of HBR patients. These criteria were categorized into major and minor, if expected to carry in isolation, respectively, ≥4% and <4% Bleeding Academic Research Consortium (BARC) 3 or 5 bleeding risk within 1-year after percutaneous coronary intervention (PCI). High bleeding risk patients are those meeting at least 1 major or 2 minor criteria. METHODS AND RESULTS All patients undergoing PCI at Bern University Hospital, between February 2009 and September 2018 were prospectively entered into the Bern PCI Registry (NCT02241291). Age, haemoglobin, platelet count, creatinine, and use of oral anticoagulation were prospectively collected, while the remaining HBR criteria except for planned surgery were retrospectively adjudicated. A total of 16 580 participants with complete ARC-HBR criteria were included. After assigning 1 point to each major and 0.5 point to each minor criterion, we observed for every 0.5 score increase a step-wise augmentation of BARC 3 or 5 bleeding rates at 1 year ranging from 1.90% among patients fulfilling no criterion, through 4.01%, 5.98%, 7.42%, 8.60%, 12.21%, 12.29%, and 17.64%. All major and five out of six minor criteria, conferred in isolation a risk for BARC 3 or 5 bleeding at 1 year exceeding 4% at the upper limit of the 95% confidence intervals. CONCLUSION All major and the majority of minor ARC-HBR criteria identify in isolation patients at HBR

Enoxaparin for primary thromboprophylaxis in symptomatic outpatients with COVID-19 (OVID): a randomised, open-label, parallel-group, multicentre, phase 3 trial

Background: COVID-19 is a viral prothrombotic respiratory infection. Heparins exert antithrombotic and anti-inflammatory effects, and might have antiviral properties. We aimed to investigate whether thromboprophylaxis with enoxaparin would prevent untoward hospitalisation and death in symptomatic, but clinically stable outpatients with COVID-19. Methods: OVID was a randomised, open-label, parallel-group, investigator-initiated, phase 3 trial and was done at eight centres in Switzerland and Germany. Outpatients aged 50 years or older with acute COVID-19 were eligible if they presented with respiratory symptoms or body temperature higher than 37·5°C. Eligible participants underwent block-stratified randomisation (by age group 50–70 vs >70 years and by study centre) in a 1:1 ratio to receive either subcutaneous enoxaparin 40 mg once daily for 14 days versus standard of care (no thromboprophylaxis). The primary outcome was a composite of any untoward hospitalisation and all-cause death within 30 days of randomisation. Analysis of the efficacy outcomes was done in the intention-to-treat population. The primary safety outcome was major bleeding. The study was registered in ClinicalTrials.gov (NCT04400799) and has been completed. Findings: At the predefined formal interim analysis for efficacy (50% of total study population), the independent Data Safety Monitoring Board recommended early termination of the trial on the basis of predefined statistical criteria having considered the very low probability of showing superiority of thromboprophylaxis with enoxaparin for the primary outcome under the initial study design assumptions. Between Aug 15, 2020, and Jan 14, 2022, from 3319 participants prescreened, 472 were included in the intention-to-treat population and randomly assigned to receive enoxaparin (n=234) or standard of care (n=238). The median age was 57 years (IQR 53–62) and 217 (46%) were women. The 30-day risk of the primary outcome was similar in participants allocated to receive enoxaparin and in controls (8 [3%] of 234 vs 8 [3%] of 238; adjusted relative risk 0·98; 95% CI 0·37–2·56; p=0·96). All hospitalisations were related to COVID-19. No deaths were reported during the study. No major bleeding events were recorded. Eight serious adverse events were recorded in the enoxaparin group versus nine in the control group. Interpretation: These findings suggest thromboprophylaxis with enoxaparin does not reduce early hospitalisations and deaths among outpatients with symptomatic COVID-19. Futility of the treatment under the initial study design assumptions could not be conclusively assessed owing to under-representation of older patients and consequent low event rates