Heterogeneity of treatment effect of higher dose dexamethasone by geographic region in patients with COVID-19 and severe hypoxemia - A post hoc evaluation of the COVID STEROID 2 trial (preprint)

Background: The COVID-STEROID 2 trial found high probability of benefit with dexamethasone 12 mg vs. 6 mg daily among patients with COVID-19 and severe hypoxemia. There was suggestion of heterogeneity of treatment effects (HTE)between patients enrolled from Europe vs. India on the primary outcome. Whether there was HTE by geographical region for the remaining prespecified patient-important outcomes is unclear. Methods: We evaluated HTE by geographical region (Europe vs. India) for all secondary outcomes assessed in the trial with analyses adjusted for stratification variables. The results are presented as risk differences (RDs) or mean differences (MDs) with 99% confidence intervals (CIs) and P-values from interaction tests. Results: We found HTE for mortality at day 28 (RD for Europe -8.3% (99 % CI: -17.7 to 1.0) vs. RD for India 0.1% (99% CI: -10.0 to 10.0)), mortality at day 90 (RD for Europe -7.4% (99% CI: -17.1 to 2.0) vs. RD for India -1.4% (99% CI:-12.8 to 9.8)), mortality at day 180 (RD for Europe -6.7% (99%CI:-16.4 to 2.9) vs. RD for India -1.0% (99%CI:-12.3 to 10.3)), and number of days alive without life support at day 90 (MD for Europe 6.1 days (99% CI:-1.3 to 13.4) vs. MD for India 1.7 days (99% CI:-8.4 to11.8)). For serious adverse reactions, the direction was reversed (RD for Europe -1.0% (99% CI:-7.1 to 5.2) vs. RD for India -5.3% (99% CI: -16.2 to 5.0). For HRQoL outcomes, MD in EQ-5D-5L index values was 0.08(99%CI: -0.01 to 0.16) for Europe and 0.02(99%CI:-0.10 to 0.14) for India. For EQ VAS, MD was 4.4(95%CI:-3.1 to 11.9) for Europe and 2.6(99%CI:-9.0 to 14.2) for India. P values for all tests of interaction were [≥]0.12. Conclusions: In this post hoc exploratory analysis, we found that higher dose dexamethasone may have lower beneficial effects for patients in India as compared with those in Europe without an increase in serious adverse reactions.

Liver injury in hospitalized patients with COVID-19: An International observational cohort study (preprint)

Background: Using a large dataset, we evaluated prevalence and severity of alterations in liver enzymes in COVID-19 and association with patient-centred outcomes. Methods: We included hospitalized patients with confirmed or suspected SARS-CoV-2 infection from the International Severe Acute Respiratory and emerging Infection Consortium (ISARIC) database. Key exposure was baseline liver enzymes (AST, ALT, bilirubin). Patients were assigned Liver Injury Classification score based on 3 components of enzymes at admission: Normal; Stage I) Liver injury: any component between 1-3x upper limit of normal (ULN); Stage II) Severe liver injury: any component >= 3x ULN. Outcomes were hospital mortality, utilization of selected resources, complications, and durations of hospital and ICU stay. Analyses used logistic regression with associations expressed as adjusted odds ratios (OR) with 95% confidence intervals (CI). Results: Of 17,531 included patients, 46.2% (8099) and 8.2% (1430) of patients had stage 1 and 2 liver injury respectively. Compared to normal, stages 1 and 2 were associated with higher odds of mortality (OR 1.53 [1.37-1.71]; OR 2.50 [2.10-2.96]), ICU admission (OR 1.63 [1.48-1.79]; OR 1.90 [1.62-2.23]) and invasive mechanical ventilation (OR 1.43 [1.27-1.70]; OR 1.95 (1.55-2.45).Stages 1 and 2 were also associated with higher odds of developing sepsis (OR 1.38 [1.27-1.50]; OR 1.46 [1.25-1.70]), acute kidney injury (OR 1.13 [1.00-1.27]; OR 1.59 [1.32-1.91]), and acute respiratory distress syndrome (OR 1.38 [1.22-1.55]; OR 1.80 [1.49-2.17]). Conclusions: Liver enzyme abnormalities are common among COVID-19 patients and associated with worse outcomes.