Beta-Blocker Treatment in Ventilated COVID-19 patients – A Cox Regression with Time Dependent Covariate Analysis

Background: Patients with co-morbidities are particularly vulnerable to severe COVID-19 disease. Critically ill patients with COVID-19 frequently experience severe tachycardias and avoidance of these is important in some co-morbidities, for instance cardiovascular disease. There is growing interest in beta blockade in critical illness as their use been associated with improved outcomes in a variety of conditions. We report the real-world use of heart rate management in patients during the first wave of the COVID-19 pandemic. As retrospective data are prone to an Immortal Time Bias, we created a Cohort Trial such as might be used for a future prospective trial and used Time Dependent Covariate Analysis for its analysis.

Methods: Data for all PCR-proven COVID-19 patients ventilated in the Intensive Care Unit (ICU) were extracted from the hospital databases. To compensate for the risk of immortal time bias, we restricted analysis to 144 patients who achieved a heart rate (HR) of 90 beats per minute for more than 12 hours and were treated with norepinephrine. We recorded time from these ‘entry criteria’ to first beta blocker dose. Those patients who did not receive a beta blocker were given a nominal time to beta blocker beyond the censor day. Outcome was mortality censored at 28 days.

Results: In the study group, 83/144 patients (57.6%) received a beta blocker. The median interval from entry criteria to beta blocker was 7.91 days (IQR 3.89, 13.15) and median duration of treatment was 7.00 days (IQR 4.00, 14.00). Twenty-four beta blocker patients (28.9%) died within 28 days compared with 29 (47.5%) who did not (adjusted OR 0.43; 95% CI 0.20-0.95, P=0.036). Cox Regression with time-dependent covariate analysis revealed there was an increased, but not significant, risk of death with beta blocker delay (Hazard Ratio 1.42 p=0.264). Mortality was also reduced for each day treated with beta blockade (adjusted Odds Ratio 0.76, 95% CI 0.64-0.91; P=0.002).

Conclusions: In a retrospective analysis of critically ill ventilated patients with COVID-19 who developed a tachycardia >90 beats per minute and were treated with norepinephrine, beta blockade was associated with reduced mortality.