Cardiac Effort Provides a Reproducible Remote Assessment of 6-Minute Walk Test

Rationale: 'Cardiac Effort' (CE), the total number of heart beats used during the 6-minute walk test (6MWT) divided by walk distance (beats/m), improves reproducibility in the 6MWT and correlates with right ventricular function in pulmonary arterial hypertension (PAH). The SARS-CoV-2 pandemic made in-office 6MWT challenging. We aimed to determine 1) whether a chestbased accelerometer could estimate 6MWT distance in the clinic and remotely;2) the reproducibility of CE measured during a remote 6MWT;and 3) the safety of remote 6MWT. We also compared measures of heart rate (HR) derived from electrocardiogram (ECG) and wrist-based photoplethysmography (PPG) during the 6MWT in PAH. Methods: This was a singlecenter, prospective observational study with IRB approval completed October 2020-April 2021. Group 1 PAH subjects on stable therapy for >90 days completed 4-6 total 6MWT during a 2 week period to assess reproducibility;we anticipated no clinical change during this short interval. The first and last 6MWT were performed in the clinic;2-4 remote 6MWT were completed at participant's discretion. Participants did not wear masks but did wear the MC10 Biostamp nPoint sensors to measure ECG HR and accelerometry. Two blinded readers estimated 6MWT distance using raw accelerometry data. We measured PPG HR with a wrist Nonin 3150 pulse oximeter during clinic 6MWT only. Averages of clinic variables and remote variables were used for paired Student's t test, Bland-Altman Plot, or Pearson correlation. Results: We enrolled 20 participants: 80% female;60% connective tissue disease;and 65% on initial combination therapy with ambrisentan and tadalafil. There was a wide range in baseline, clinicperformed 6MWT distance (220 -570 m). The median length of the remote 'hallway' was 40 ft. For clinic walks, there was 0.10% average difference between the directly observed and Biostamp accelerometry-estimated 6MWT distance with a strong correlation of r=0.99, p<0.0001 (figure 1). The 6MWT distance estimated using Biostamp in the clinic was greater than what was estimated remotely, 405 m vs. 389 m, p=0.007. There was no clear difference between clinic or remote CE, 1.83 beats/m vs 1.93 beats/m, p=0.14, or Borg Dyspnea Index, 3.5 vs 3.4, p=0.35. There were no safety concerns. PPG undercounted total HR expenditure during 6MWT compared to Biostamp (629 vs 719, p<0.0001). Conclusion: Remote 6MWT was feasible, appeared safe, and 6MWT distance was shorter than clinic distance. CE calculated by ECG HR and accelerometer-estimated distance provides a reproducible remote assessment of exercise tolerance, comparable to the clinic measured value. (Figure Presented).

Endothelin antagonism and sodium glucose Co-transporter 2 inhibition. A potential combination therapeutic strategy for COVID-19.

The novel coronavirus 2019 (COVID-19) infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a global pandemic that requires a multi-faceted approach to tackle this unprecedent health crisis. Therapeutics to treat COVID-19 are an integral part of any such management strategy and there is a substantial unmet need for treatments for individuals most at risk of severe disease. This perspective review provides rationale of a combined therapeutic regimen of selective endothelin-A (ET-A) receptor antagonism and sodium glucose co-transporter-2 (SGLT-2) inhibition to treat COVID-19. Endothelin is a potent vasoconstrictor with pro-inflammatory and atherosclerotic effects. It is upregulated in a number of conditions including acute respiratory distress syndrome and cardiovascular disease. Endothelin mediates vasocontractility via endothelin (ET-A and ET-B) receptors on vascular smooth muscle cells (VSMCs). ET-B receptors regulate endothelin clearance and are present on endothelial cells, where in contrast to their role on VSMCs, mediate vasodilation. Therefore, selective endothelin-A (ET-A) receptor inhibition is likely the optimal approach to attenuate the injurious effects of endothelin and may reduce ventilation-perfusion mismatch and pulmonary inflammation, whilst improving pulmonary haemodynamics and oxygenation. SGLT-2 inhibition may dampen inflammatory cytokines, reduce hyperglycaemia if present, improve endothelial function, cardiovascular haemodynamics and cellular bioenergetics. This combination therapeutic approach may therefore have beneficial effects to mitigate both the pulmonary, metabolic and cardiorenal manifestations of COVID-19. Given these drug classes include medicines licensed to treat heart failure, diabetes and pulmonary hypertension respectively, information regarding their safety profile is established. Randomised controlled clinical trials are the best way to determine efficacy and safety of these medicines in COVID-19.

muLTi-Arm Therapeutic study in pre-ICu patients admitted with Covid-19-Experimental drugs and mechanisms (TACTIC-E): A structured summary of a study protocol for a randomized controlled trial.

OBJECTIVES: To determine if a specific intervention reduces the composite of progression of patients with COVID-19-related disease to organ failure or death as measured by time to incidence of any one of the following: death, invasive mechanical ventilation, ECMO, cardiovascular organ support (inotropes or balloon pump), or renal failure (estimated Cockcroft Gault creatinine clearance <15ml/min). TRIAL DESIGN: Randomised, parallel arm, open-label, adaptive platform Phase 2/3 trial of potential disease modifying therapies in patients with late stage 1/stage 2 COVID-19-related disease, with a diagnosis based either on a positive assay or high suspicion of COVID-19 infection by clinical, laboratory and radiological assessment. PARTICIPANTS: Patients aged 18 and over, with a clinical picture strongly suggestive of COVID-19-related disease (with/without a positive COVID-19 test) AND a risk count (as defined below) >3 OR ≥3 if risk count includes "Radiographic severity score >3". A risk count is calculated by the following features on admission (1 point for each): radiographic severity score >3, male gender, non-white ethnicity, diabetes, hypertension, neutrophils >8.0 x109/L, age >40 years and CRP >40 mg/L. Patients should be considered an appropriate subject for intervention with immunomodulatory or other disease modifying agents in the opinion of the investigator and are able to swallow capsules or tablets. The complete inclusion and exclusion criteria as detailed in the Additional file 1 should be fulfilled. Drug specific inclusion and exclusion criteria will also be applied to the active arms. Patients will be enrolled prior to the need for invasive mechanical ventilation, cardiac or renal support. Participants will be recruited across multiple centres in the UK including initially at Cambridge University Hospitals NHS Foundation Trust and St George's University NHS Foundation Trust. Other centres will be approached internationally in view of the evolving pandemic. INTERVENTION AND COMPARATOR: There is increasing evidence of the role of immunomodulation in altering the course of COVID-19. Additionally, various groups have demonstrated the presence of pulmonary shunting in patients with COVID-19 as well as other cardiovascular complications. TACTIC-E will assess the efficacy of the novel immunomodulatory agent EDP1815 versus the approved cardio-pulmonary drugs, Dapagliflozin in combination with Ambrisentan versus the prevailing standard of care. EDP1815 will be given as 2 capsules twice daily (1.6 x 1011 cells) for up to 7 days with the option to extend up to 14 days at the discretion of the principal investigator or their delegate, if the patient is felt to be clinically responding to treatment, is tolerating treatment, and is judged to be likely to benefit from a longer treatment course. Ambrisentan 5mg and Dapagliflozin 10mg will be given in combination once daily orally for up to maximum of 14 days. Patients will be randomised in a 1:1:1 ratio across treatments. Each active arm will be compared with standard of care alone. Additional arms may be added as the trial progresses. No comparisons will be made between active arms in this platform trial. MAIN OUTCOMES: The primary outcome is the incidence (from baseline up to Day 14) to the occurrence of the any one of the following events: death, invasive mechanical ventilation, extra corporeal membrane oxygenation, cardiovascular organ support (inotropes or balloon pump), or renal failure (estimated Cockcroft Gault creatinine clearance <15ml/min). RANDOMISATION: Eligible patients will be randomised using a central web-based randomisation service (Sealed Envelope) in a 1:1:1 ratio, stratified by site to one of the treatment arms or standard of care. BLINDING (MASKING): This is an open-label trial. Data analysis will not be blinded. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): There is no fixed sample size for this study. There will be an early biomarker-based futility analysis performed at a point during the study. If this biomarker futility analysis is not conclusive, then a second futility analysis based on clinical endpoints will be performed after approximately 125 patients have been recruited per arm. Provisionally, further analyses of clinical endpoints will be performed after 229 patients per active arm and later 469 patients per arm have been recruited. Further additional analyses may be triggered by the independent data monitoring committee. TRIAL STATUS: TACTIC-E Protocol version number 1.0 date May 27th, 2020. Recruitment starts on the 3rd of July 2020. The end trial date will be 18 months after the last patient's last visit and cannot be accurately predicted at this time. TRIAL REGISTRATION: Registered on EU Clinical Trials Register EudraCT Number: 2020-002229-27 registered: 9 June 2020. The trial was also registered on ClinicalTrials.gov (NCT04393246) on 19 May 2020. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.