Does early detection of atrial fibrillation reduce the risk of thromboembolic events? Rationale and design of the Heartline study.

BACKGROUND: The impact of using direct-to-consumer wearable devices as a means to timely detect atrial fibrillation (AF) and to improve clinical outcomes is unknown. METHODS: Heartline is a pragmatic, randomized, and decentralized application-based trial of US participants aged ≥65 years. Two randomized cohorts include adults with possession of an iPhone and without a history of AF and those with a diagnosis of AF taking a direct oral anticoagulant (DOAC) for ≥30 days. Participants within each cohort are randomized (3:1) to either a core digital engagement program (CDEP) via iPhone application (Heartline application) and an Apple Watch (Apple Watch Group) or CDEP alone (iPhone-only Group). The Apple Watch Group has the watch irregular rhythm notification (IRN) feature enabled and access to the ECG application on the Apple Watch. If an IRN notification is issued for suspected AF then the study application instructs participants in the Apple Watch Group to seek medical care. All participants were "watch-naïve" at time of enrollment and have an option to either buy or loan an Apple Watch as part of this study. The primary end point is time from randomization to clinical diagnosis of AF, with confirmation by health care claims. Key secondary endpoint are claims-based incidence of a 6-component composite cardiovascular/systemic embolism/mortality event, DOAC medication use and adherence, costs/health resource utilization, and frequency of hospitalizations for bleeding. All study assessments, including patient-reported outcomes, are conducted through the study application. The target study enrollment is approximately 28,000 participants in total; at time of manuscript submission, a total of 26,485 participants have been enrolled into the study. CONCLUSION: The Heartline Study will assess if an Apple Watch with the IRN and ECG application, along with application-facilitated digital health engagement modules, improves time to AF diagnosis and cardiovascular outcomes in a real-world environment. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04276441.

External validation of the ADA score for predicting thrombosis among acutely ill hospitalized medical patients from the APEX Trial.

The ADA (Age-D-dimer-Albumin) score was developed to identify hospitalized patients at an increased risk for thrombosis in the coronavirus infectious disease-19 (COVID-19) setting. The study aimed to validate the ADA score for predicting thrombosis in a non-COVID-19 medically ill population from the APEX trial. The APEX trial was a multinational, randomized trial that evaluated the efficacy and safety of betrixaban vs. enoxaparin among acutely ill hospitalized patients at risk for venous thromboembolism. The study endpoints included the composite of arterial or venous thrombosis and its components. Metrics of model calibration and discrimination were computed for assessing the performance of the ADA score as compared to the IMPROVE score, a well-validated VTE risk assessment model. Among 7,119 medical inpatients, 209 (2.9%) had a thrombosis event up to 77 days of follow-up. The ADA score demonstrated good calibration for both arterial and venous thrombosis, whereas the IMPROVE score had adequate calibration for venous thrombosis (p > 0.05 from the Hosmer-Lemeshow test). For discriminating arterial and venous thrombosis, there was no significant difference between the ADA vs. IMPROVE score (c statistic = 0.620 [95% CI: 0.582 to 0.657] vs. 0.590 [95% CI: 0.556 to 0.624]; ∆ c statistic = 0.030 [95% CI: -0.022 to 0.081]; p = 0.255). Similarly, for discriminating arterial thrombosis, there was no significant difference between the ADA vs. IMPROVE score (c statistic = 0.582 [95% CI: 0.534 to 0.629] vs. 0.609 [95% CI: 0.564 to 0.653]; ∆ c statistic = -0.027 [95% CI: -0.091 to 0.036]; p = 0.397). For discriminating venous thrombosis, the ADA score was modestly superior to the IMPROVE score (c statistic = 0.664 [95% CI: 0.607 to 0.722] vs. 0.573 [95% CI: 0.521 to 0.624]; ∆ c statistic = 0.091 [95% CI: 0.011 to 0.172]; p = 0.026). The ADA score had a higher sensitivity (0.579 [95% CI: 0.512 to 0.646]; vs. 0.440 [95% CI: 0.373 to 0.507]) but lower specificity (0.625 [95% CI: 0.614 to 0.637] vs. 0.747 [95% CI: 0.737 to 0.758]) than the IMPROVE score for predicting thrombosis. Among acutely ill hospitalized medical patients enrolled in the APEX trial, the ADA score demonstrated good calibration but suboptimal discrimination for predicting thrombosis. The findings support the use of either the ADA or IMPROVE score for thrombosis risk assessment. The applicability of the ADA score to non-COVID-19 populations warrants further research.Clinical Trial Registration: http://www.clinicaltrials.gov . Unique identifier: NCT01583218.

Discontinuing vs continuing ACEIs and ARBs in hospitalized patients with COVID-19 according to disease severity: Insights from the BRACE CORONA trial.

BACKGROUND: We explored the effect of discontinuing versus continuing angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) on clinical outcomes in patients with COVID-19 according to baseline disease severity. METHODS: We randomized 659 patients with a confirmed diagnosis of COVID-19 and classified them as having mild or moderate COVID-19 disease severity at hospital presentation using blood oxygen saturation and lung imaging. The primary outcome was the mean ratio of number of days alive and out of the hospital at 30 days according to disease severity. RESULTS: At presentation, 376 patients (57.1%) had mild and 283 (42.9%) had moderate COVID-19. In patients with mild disease, there was no significant difference in the number of days alive and out of the hospital between ACEI/ARB discontinuation (mean 23.5 [SD 6.3] days) and continuation (mean 23.8 [SD 6.5] days), with a mean ratio of 0.98 (95% CI 0.92-1.04). However, in patients with moderate disease, there were fewer days alive and out of the hospital with ACEI/ARB discontinuation (mean 19.6 [SD 9.5] days) than continuation (mean 21.6 [SD 7.6] days), with a mean ratio of 0.90 (95% CI 0.81-1.00; P-interaction = .01). The impact of discontinuing versus continuing ACEIs/ARBs on days alive and out of hospital through 30 days differed according to baseline COVID-19 disease severity. CONCLUSIONS: Unlike patients with mild disease, patients with moderate disease who continued ACEIs/ARBs had more days alive and out of hospital through 30 days than those who discontinued ACEIs/ARBs. This suggests that ACEIs/ARBs should be continued for patients with moderate COVID-19 disease severity. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov (NCT04364893).

Effect of azithromycin and hydroxychloroquine in patients hospitalized with COVID-19: Network meta-analysis of randomized controlled trials.

Chloroquine or its derivative hydroxychloroquine (HCQ) combined with or without azithromycin (AZ) have been widely investigated in observational studies as a treatment option for coronavirus 2019 (COVID-19) infection. The network meta-analysis aims to summarize evidence from randomized controlled trials (RCTs) to determine if AZ or HCQ is associated with improved clinical outcomes. PubMed and Embase were searched from inception to March 7, 2021. We included published RCTs that investigated the efficacy of AZ, HCQ, or its combination among hospitalized patients with COVID-19 infection. The outcomes of interest were all-cause mortality and the use of mechanical ventilation. The pooled odds ratio was calculated using a random-effect model. A total of 10 RCTs were analyzed. Participant's mean age ranged from 40.4 to 66.5 years. There was no significant effect on mortality associated with AZ plus HCQ (odds ratio [OR] = 0.562 [95% confidence interval {CI}: 0.168-1.887]), AZ alone (OR = 0.965 [95% CI: 0.865-1.077]), or HCQ alone (OR = 1.122 [95% CI: 0.995-1.266]; p = 0.06). Similarly, based on pooled effect sizes derived from direct and indirect evidence, none of the treatments had a significant benefit in decreasing the use of mechanical ventilation. No heterogeneity was identified (Cochran's Q = 1.68; p = 0.95; τ2 = 0; I2 = 0% [95% CI: 0%-0%]). Evidence from RCTs suggests that AZ with or without HCQ was not associated with a significant effect on the mortality or mechanical ventilation rates in hospitalized patients with COVID-19. More research is needed to explore therapeutics agents that can effectively reduce the mortality or severity of COVID-19.

Worldwide differences of hospitalization for ST-segment elevation myocardial infarction during COVID-19: A systematic review and meta-analysis.

BACKGROUND: Discrepant data were reported about hospital admissions for ST-segment elevation myocardial infarction (STEMI) during COVID-19 pandemic. We reviewed studies reporting STEMI hospitalizations during COVID-19 pandemic, investigating whether differences in COVID-19 epidemiology or public health-related factors could explain discrepant findings in different countries. METHODS: Search through MedLine, Embase, Scopus, Web-of-Science, Cochrane Register of Controlled Trials, of studies comparing STEMI admissions during COVID-19 pandemic with a reference period, without language restrictions, as registered in PROSPERO International Prospective Register of Systematic Reviews. Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines were followed. Data independently extracted by multiple investigators were pooled using a random-effects model. Health-related metrics were from publicly-available sources. RESULTS: We included 79 articles (111,557 STEMI cases, from 57 countries). During peak COVID-19 pandemic, overall incidence rate-ratio (IRR) of STEMI hospitalizations over reference period decreased (0.80; 95% CI 0.76-0.84; p < 0.05). Although wide variations and significant heterogeneity were detected among studies (I2 = 89%; p < 0.0001), no significant differences were observed by report methodology (survey vs registry), or observation/reference period. However, large differences emerged at country level not explained by COVID-related epidemiological data, nor by public health strategies. Instead, IRRs for STEMI admissions were inversely related to hospital bed availability in each country (p < 0.05). CONCLUSIONS: During COVID-19 pandemic hospitalization for STEMI significantly decreased, although to a smaller extent than initially reported. Large variability emerged across countries, unrelated to COVID-related epidemiology or social containment measures. Disparities in healthcare organization likely contributed, indicating that proper organization of emergency medicine should be preserved during pandemics.

Safety and efficacy of different prophylactic anticoagulation dosing regimens in critically and non-critically ill patients with COVID-19: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: The clinical impact of different prophylactic anticoagulation regimens among hospitalized patients with coronavirus disease 2019 (COVID-19) remains unclear. We pooled evidence from available randomized controlled trials (RCTs) to provide insights on this topic. METHODS AND RESULTS: We searched for RCTs comparing treatment with an escalated-dose (intermediate-dose or therapeutic-dose) vs. a standard-dose prophylactic anticoagulation regimen in critically and non-critically ill COVID-19 patients requiring hospitalization and without a formal indication for anticoagulation. The primary efficacy endpoint was all-cause death, and the primary safety endpoint was major bleeding. Seven RCTs were identified, including 5154 patients followed on an average of 33 days. Compared to standard-dose prophylactic anticoagulation, escalated-dose prophylactic anticoagulation was not associated with a reduction of all-cause death [17.8% vs. 18.6%; risk ratio (RR) 0.96, 95% confidence interval (CI) 0.78-1.18] but was associated with an increase in major bleeding (2.4% vs. 1.4%; RR 1.73, 95%CI 1.15-2.60). Compared to prophylactic anticoagulation used at a standard dose, an escalated dose was associated with lower rates of venous thromboembolism (2.5% vs. 4.7%; RR 0.55, 95%CI 0.41-0.74) without a significant effect on myocardial infarction (RR 0.80, 95%CI 0.47-1.36), stroke (RR 0.94, 95%CI 0.43-2.09), or systemic arterial embolism (RR 1.20, 95%CI 0.29-4.95). There were no significant interactions in the subgroup analysis for critically and non-critically ill patients. CONCLUSIONS: Our findings provide comprehensive and high-quality evidence for the use of standard-dose prophylactic anticoagulation over an escalated-dose regimen as routine standard of care for hospitalized patients with COVID-19 who do not have an indication for therapeutic anticoagulation, irrespective of disease severity. STUDY REGISTRATION: This study is registered in PROSPERO (CRD42021257203).

Effect of Discontinuing vs Continuing Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers on Days Alive and Out of the Hospital in Patients Admitted With COVID-19: A Randomized Clinical Trial.

Importance: It is unknown whether angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) have a positive, neutral, or negative effect on clinical outcomes in patients with coronavirus disease 2019 (COVID-19). Objective: To determine whether discontinuation compared with continuation of ACEIs or ARBs changed the number of days alive and out of the hospital through 30 days. Design, Setting, and Participants: A randomized clinical trial of 659 patients hospitalized in Brazil with mild to moderate COVID-19 who were taking ACEIs or ARBs prior to hospitalization (enrolled: April 9-June 26, 2020; final follow-up: July 26, 2020). Interventions: Discontinuation (n = 334) or continuation (n = 325) of ACEIs or ARBs. Main Outcomes and Measures: The primary outcome was the number of days alive and out of the hospital through 30 days. Secondary outcomes included death, cardiovascular death, and COVID-19 progression. Results: Among 659 patients, the median age was 55.1 years (interquartile range [IQR], 46.1-65.0 years), 14.7% were aged 70 years or older, 40.4% were women, and 100% completed the trial. The median time from symptom onset to hospital admission was 6 days (IQR, 4-9 days) and 27.2% of patients had an oxygen saturation of less than 94% of room air at baseline. In terms of clinical severity, 57.1% of patients were considered mild at hospital admission and 42.9% were considered moderate. There was no significant difference in the number of days alive and out of the hospital in patients in the discontinuation group (mean, 21.9 days [SD, 8 days]) vs patients in the continuation group (mean, 22.9 days [SD, 7.1 days]) and the mean ratio was 0.95 (95% CI, 0.90-1.01). There also was no statistically significant difference in death (2.7% for the discontinuation group vs 2.8% for the continuation group; odds ratio [OR], 0.97 [95% CI, 0.38-2.52]), cardiovascular death (0.6% vs 0.3%, respectively; OR, 1.95 [95% CI, 0.19-42.12]), or COVID-19 progression (38.3% vs 32.3%; OR, 1.30 [95% CI, 0.95-1.80]). The most common adverse events were respiratory failure requiring invasive mechanical ventilation (9.6% in the discontinuation group vs 7.7% in the continuation group), shock requiring vasopressors (8.4% vs 7.1%, respectively), acute myocardial infarction (7.5% vs 4.6%), new or worsening heart failure (4.2% vs 4.9%), and acute kidney failure requiring hemodialysis (3.3% vs 2.8%). Conclusions and Relevance: Among patients hospitalized with mild to moderate COVID-19 and who were taking ACEIs or ARBs before hospital admission, there was no significant difference in the mean number of days alive and out of the hospital for those assigned to discontinue vs continue these medications. These findings do not support routinely discontinuing ACEIs or ARBs among patients hospitalized with mild to moderate COVID-19 if there is an indication for treatment. Trial Registration: ClinicalTrials.gov Identifier: NCT04364893.

Continuing versus suspending angiotensin-converting enzyme inhibitors and angiotensin receptor blockers: Impact on adverse outcomes in hospitalized patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)--The BRACE CORONA Trial.

Angiotensin-converting enzyme-2 (ACE2) expression may increase due to upregulation in patients using angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARBs). Because renin-angiotensin system blockers increase levels of ACE2, a protein that facilitates coronavirus entry into cells, there is concern that these drugs could increase the risk of developing a severe and fatal form of COVID-19. The impact of discontinuing ACEI and ARBs in patients with COVID-19 remains uncertain. DESIGN: BRACE CORONA is a pragmatic, multicenter, randomized, phase IV, clinical trial that aims to enroll around 500 participants at 34 sites in Brazil. Participants will be identified from an ongoing national registry of suspected and confirmed cases of COVID-19. Eligible patients using renin-angiotensin system blockers (ACEI/ARBs) with a confirmed diagnosis of COVID-19 will be randomized to a strategy of continued ACEI/ARB treatment versus temporary discontinuation for 30 days. The primary outcome is the median days alive and out of the hospital at 30 days. Secondary outcomes include progression of COVID-19 disease, all-cause mortality, death from cardiovascular causes, myocardial infarction, stroke, transient ischemic attack, new or worsening heart failure, myocarditis, pericarditis, arrhythmias, thromboembolic events, hypertensive crisis, respiratory failure, hemodynamic decompensation, sepsis, renal failure, and troponin, B-type natriuretic peptide (BNP), N-terminal-proBNP, and D-dimer levels. SUMMARY: BRACE CORONA will evaluate whether the strategy of continued ACEI/ARB therapy compared with temporary discontinuation of these drugs impacts clinical outcomes among patients with COVID-19.

COVID-19 and Thrombotic or Thromboembolic Disease: Implications for Prevention, Antithrombotic Therapy, and Follow-Up: JACC State-of-the-Art Review.

Coronavirus disease-2019 (COVID-19), a viral respiratory illness caused by the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), may predispose patients to thrombotic disease, both in the venous and arterial circulations, because of excessive inflammation, platelet activation, endothelial dysfunction, and stasis. In addition, many patients receiving antithrombotic therapy for thrombotic disease may develop COVID-19, which can have implications for choice, dosing, and laboratory monitoring of antithrombotic therapy. Moreover, during a time with much focus on COVID-19, it is critical to consider how to optimize the available technology to care for patients without COVID-19 who have thrombotic disease. Herein, the authors review the current understanding of the pathogenesis, epidemiology, management, and outcomes of patients with COVID-19 who develop venous or arterial thrombosis, of those with pre-existing thrombotic disease who develop COVID-19, or those who need prevention or care for their thrombotic disease during the COVID-19 pandemic.

Pharmacological Agents Targeting Thromboinflammation in COVID-19: Review and Implications for Future Research.

Coronavirus disease 2019 (COVID-19), currently a worldwide pandemic, is a viral illness caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The suspected contribution of thrombotic events to morbidity and mortality in COVID-19 patients has prompted a search for novel potential options for preventing COVID-19-associated thrombotic disease. In this article by the Global COVID-19 Thrombosis Collaborative Group, we describe novel dosing approaches for commonly used antithrombotic agents (especially heparin-based regimens) and the potential use of less widely used antithrombotic drugs in the absence of confirmed thrombosis. Although these therapies may have direct antithrombotic effects, other mechanisms of action, including anti-inflammatory or antiviral effects, have been postulated. Based on survey results from this group of authors, we suggest research priorities for specific agents and subgroups of patients with COVID-19. Further, we review other agents, including immunomodulators, that may have antithrombotic properties. It is our hope that the present document will encourage and stimulate future prospective studies and randomized trials to study the safety, efficacy, and optimal use of these agents for prevention or management of thrombosis in COVID-19.