Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Analysis of atrial sensed far-field ventricular signals:A reassessment

Accurate detection of the spontaneous far-field ventricular signal may be used to determine the ventricular activation, and hence, the interval from atrial stimulus to the ventricular R wave (AR interval) using a standard atrial pacing lead. This can be useful in developing a physiological atrial rate responsive (AAIR) pace-maker and in further improving DDD(R) pacing algorithms. In order to better characterize the atrial sensed far-field ventricular signal, 200 consecutive patients undergoing pacemaker implantation were studied. The amplitude of the far-field ventricular signal was significantly smaller than that of the atrial deflection. In all recordings, the slew rate oft he atrial deflection was larger than that of the far-field ventricular signal. Subdivision of the recordings by electrode position, pocket location, or QRS duration on the surface ECG resulted in significantly different signal characteristics. The amplitude and slew rate of the far-field ventricular signal were significantly smaller in bipolar versus unipolar sensing. Atrial sensed far-field ventricular recordings could also be obtained in the case of ventricular pacing. Our results indicate that accurate sensing of the far-field ventricular signal from an atrial pacing lead is conceivable in most patients. The different signal characteristics in relation to parameters, such as electrode position, sensing mode, and pocket location, may be useful in determining the optimal conditions for signal sensing