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

Thrombosis in Myeloproliferative Neoplasms: A Single Center Experience of Using Whole Blood Platelet Aggregation Studies for Risk Assessment and Thromboprophylaxis

Thromboembolic complications are the most common causes of morbidity and mortality in patients with Philadelphia chromosome-negative myeloproliferative neoplasms (MPN); and prevention of these complications remains a significant clinical challenge. Effective thromboprophylaxis in MPN patients generally requires use of anti-platelet therapy, commonly aspirin; however, there are no standardized or universally accepted guidelines regarding the dose of aspirin. This study evaluates the usefulness of whole blood platelet aggregation (WBPA) studies to identify patients at risk for thrombosis and to achieve safe and effective long term thromboprophylaxis. One hundred and thirty-two consecutive patients were enrolled into this study. WBPA studies were performed at diagnosis in 125 patients to identify those with platelet hyperactivity (deemed to be at risk for thrombosis) and repeated 4 weeks after commencement of anti-platelet therapy to ascertain the efficacy. In patients with incomplete drug effect, treatment was revised and the study repeated until optimum effect was achieved. Results of the WBPA studies and anti-platelet therapy requirements were correlated with the underlying driver mutations and various international prognostic score of thrombosis for essential thrombocythemia (IPSET- Thrombosis) sub-groups. WBPA studies showed varying degrees of platelet hyper-activity in 115 patients. Based on these results, the patients were commenced on anti-platelet therapy comprising aspirin (dose ranging from 100mg twice or thrice weekly to 400mg daily) and clopidogrel (75mg daily) alone or in combination with aspirin or odorless garlic. None of the patients developed thrombosis during the follow up period ranging from 1-23 years (median 8yrs), while on the prescribed, individualized anti-platelet therapy. No significant differences were noted in terms of aspirin dose requirements between the JAK-2 positive and CALR or MPL positive patients, and, among the four IPSET-Thrombosis sub-groups. Patients with normal (9) or hypo (1) – activity were not given any anti-platelet therapy at diagnosis. Conclusion Routine use of WBPA studies enables safe and effective risk-adapted thromboprophylaxis in MPN patients, irrespective of the underlying driver mutation and their risk predicted by the IPSET- thrombosis criteria

Beta 2 glycoprotein I is a substrate of thiol oxidoreductases

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