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

Safety of 2-hour IIVs of tacrolimus in the HSCT unit

Pharmacy residents have the opportunity to complete a research project during their residency training, which provides them with skills on how to conduct and manage a research project. Projects often represent an area of interest and need that has been recognized by the host institution’s pharmacy department. Projects are presented as a poster at an annual CSHP Ontario Branch Residency Research Night, and many eventually go on to be published in a peer-reviewed journal.Background: Administering intravenous (IV) tacrolimus by 24-hour continuous IV infusion (CIV), as recommended by the product monograph, poses significant logistical challenges in the allogeneic hematopoietic stem cell transplantation (HSCT) unit because it requires a dedicated central venous catheter lumen. Consequently, at our institution, tacrolimus has been administered via two-hour intermittent IV infusions (IIV) every twelve hours in the HSCT unit. Administration by IIV is not the standard of practice and shorter infusion times are cautioned due to higher rates of nephrotoxicity, neurotoxicity and infusion-related reactions (IRRs), although there is a paucity of data to support this claim. The primary objective of this retrospective study was to evaluate the safety of a two-hour IIV of tacrolimus in an adult HSCT population. Efficacy was evaluated as a secondary endpoint. Methods and Patients: We performed a retrospective chart review of all patients who received IV tacrolimus at our institution from January 2002 – January 2016. We reviewed 104 patients who received 118 tacrolimus treatment courses by IIV (TTC) [median number of doses per TTC=22, range 1 – 158, interquartile range (IQR) = 28]. Primary outcomes collected include rates of nephrotoxicity, neurotoxicity and IRRs that occurred during TTC. The incidence of acute graft-versus-host disease (aGVHD) and disease relapse within 180 days of transplant were collected to evaluate efficacy. Results and Discussion: There were sixteen incidences (13.6%) of nephrotoxicity, defined as a doubling of serum creatinine from baseline. Nephrotoxicity resolved in all but six (5.1%) cases. Precipitating factor for nephrotoxicity unrelated to tacrolimus were identified by the physician in all six cases. There were 40 incidences (34.5%) of neurotoxicity [seizure, posterior reversible encephalopathy syndrome (PRES), tremor, paresthesia, visual disturbance], of which, eight (6.8%) were considered serious (seizure and/or PRES). All neurotoxicity reverted to baseline or resolved completely. One grade 2 infusion reaction occurred and resolved without discontinuation of tacrolimus. In the subset of patients who received tacrolimus for the prevention of aGVHD (n=41), seven patients (17.1%) developed grade II – IV aGVHD. Nine patients (8.7%) experienced relapse of their disease. Conclusions: We propose that a two-hour IIV of tacrolimus is a safe method of administration in the adult HSCT setting. Additional safety and efficacy data from other institutions will provide external validity to this conclusion

Effect of Antiplatelet Therapy on Survival and Organ Support–Free Days in Critically Ill Patients With COVID-19

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