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
Tirupakuzhi Vijayaraghavan, B. K.; Granholm, A.; Myatra, S. N.; Jha, V.; Hammond, N.; Micallef, S.; Munch, M. W.; Kjaer, M.-B. N.; Moller, M. H.; Lange, T.; Perner, A.; Venkatesh, B.
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BackgroundThe 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. MethodsWe 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. ResultsWe 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. ConclusionsIn 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.
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