Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

DIFFERENCES IN CLINICAL CHARACTERISTICS BETWEEN BIPOLAR PATIENTS WITH CURRENT PSYCHOTIC SYMPTOMS AND THOSE WHO HAVE NEVER BEEN PSYCHOTIC

Background: Psychotic symptoms are common in bipolar disorder (BD). Data suggest that BD patients with or without psychotic symptoms may differ from each other with regards to some clinical features of BD (e.g., age at onset, suicidality, psychiatric comorbidity, number of hospitalizations). However, the literature in this area is relatively scarce and not always conclusive. Therefore, the objective of the current study was to investigate whether the presence of psychotic symptoms is associated with clinical characteristics of patients with BD. Subjects and methods: We enrolled 365 hospitalized patients who were diagnosed with BD according to the ICD-10 criteria. After we excluded 196 patients without current psychotic symptoms but psychotic mood episodes in their medical history, our final sample consisted of 169 patients (i.e., 89 BD patients presenting with current psychotic symptoms and 80 BD patients who were hospitalized in the same period, but who did not have psychotic symptoms either currently or during their previous hospitalizations). Clinically available data were collected, systematized and statistically processed according to the aims of the study. Results: Early age of onset, bipolar-I diagnosis, comorbid personality disorder, number of hospitalizations and suicidality were significantly more common in the psychotic group compared to the never-psychotic group. On the contrary, sedative/hypnotics dependence was more frequent in the never-psychotic group. Conclusions: Our results support the notion that the presence of psychotic symptoms in the context of BD may be associated with various other clinical features of this disease

Associations between untreated depression and secondary health care utilization in patients with hypertension and/or diabetes

Purpose. We determined the prevalence of untreated depression in patients with hypertension (HT) and/or diabetes (DM) and estimated the extra health care use and expenditures associated with this comorbidity in a rural Hungarian adult population. We also assessed the potential workload of systematic screening for depression in this patient group.Methods. General health check database from a primary care programme containing survey data of 2027 patients with HT and/or DM was linked to the outpatient secondary care use database of National Institute of Health Insurance Fund Management. Depression was ascertained by Beck Depression Inventory score and antidepressant drug use. The association between untreated depression and secondary healthcare utilization indicated by number of visits and expenses was evaluated by multiple logistic regression analysis controlled for socioeconomic/lifestyle factors and comorbidity. The age-, sex- and education-specific observations were used to estimate the screening workload for an average general medical practice.Results. The frequency of untreated depression was 27.08%. The untreated severe depression (7.45%) was associated with increased number of visits (OR 1.60, 95% CI 1.11?2.31) and related expenses (OR 2.20, 95% CI 1.50?3.22) in a socioeconomic status-independent manner. To identify untreated depression cases among patients with HT and/or DM, an average GP has to screen 42 subjects a month.Conclusion. It seems to be reasonable and feasible to screen for depression in patients with HT and/or DM in the primary care, in order to detect cases without treatment (which may be associated with increase of secondary care visits and expenditures) and to initiate the adequate treatment of them

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

Long-term (180-Day) outcomes in critically Ill patients with COVID-19 in the REMAP-CAP randomized clinical trial

Importance The longer-term effects of therapies for the treatment of critically ill patients with COVID-19 are unknown. Objective To determine the effect of multiple interventions for critically ill adults with COVID-19 on longer-term outcomes. Design, Setting, and Participants Prespecified secondary analysis of an ongoing adaptive platform trial (REMAP-CAP) testing interventions within multiple therapeutic domains in which 4869 critically ill adult patients with COVID-19 were enrolled between March 9, 2020, and June 22, 2021, from 197 sites in 14 countries. The final 180-day follow-up was completed on March 2, 2022. Interventions Patients were randomized to receive 1 or more interventions within 6 treatment domains: immune modulators (n = 2274), convalescent plasma (n = 2011), antiplatelet therapy (n = 1557), anticoagulation (n = 1033), antivirals (n = 726), and corticosteroids (n = 401). Main Outcomes and Measures The main outcome was survival through day 180, analyzed using a bayesian piecewise exponential model. A hazard ratio (HR) less than 1 represented improved survival (superiority), while an HR greater than 1 represented worsened survival (harm); futility was represented by a relative improvement less than 20% in outcome, shown by an HR greater than 0.83. Results Among 4869 randomized patients (mean age, 59.3 years; 1537 [32.1%] women), 4107 (84.3%) had known vital status and 2590 (63.1%) were alive at day 180. IL-6 receptor antagonists had a greater than 99.9% probability of improving 6-month survival (adjusted HR, 0.74 [95% credible interval {CrI}, 0.61-0.90]) and antiplatelet agents had a 95% probability of improving 6-month survival (adjusted HR, 0.85 [95% CrI, 0.71-1.03]) compared with the control, while the probability of trial-defined statistical futility (HR >0.83) was high for therapeutic anticoagulation (99.9%; HR, 1.13 [95% CrI, 0.93-1.42]), convalescent plasma (99.2%; HR, 0.99 [95% CrI, 0.86-1.14]), and lopinavir-ritonavir (96.6%; HR, 1.06 [95% CrI, 0.82-1.38]) and the probabilities of harm from hydroxychloroquine (96.9%; HR, 1.51 [95% CrI, 0.98-2.29]) and the combination of lopinavir-ritonavir and hydroxychloroquine (96.8%; HR, 1.61 [95% CrI, 0.97-2.67]) were high. The corticosteroid domain was stopped early prior to reaching a predefined statistical trigger; there was a 57.1% to 61.6% probability of improving 6-month survival across varying hydrocortisone dosing strategies. Conclusions and Relevance Among critically ill patients with COVID-19 randomized to receive 1 or more therapeutic interventions, treatment with an IL-6 receptor antagonist had a greater than 99.9% probability of improved 180-day mortality compared with patients randomized to the control, and treatment with an antiplatelet had a 95.0% probability of improved 180-day mortality compared with patients randomized to the control. Overall, when considered with previously reported short-term results, the findings indicate that initial in-hospital treatment effects were consistent for most therapies through 6 months