Ritonavir (RTV) may increase the risk for bradycardia among critically ill patients with coronavirus 2019 (COVID-19), according to the results of a prospective preliminary study published in Circulation: Arrythmia and Electrophysiology.1
During the first month of the COVID-19 outbreak, 41 patients who were admitted to the intensive care unit at Amiens University Hospital in France and tested positive for the virus were administered 2 daily doses of lopinavir (LPV; 200 mg) and RTV (50 mg) for a period of 10 days. Patients were monitored with a 5-lead electrocardiograph for all hemodynamic parameters. Bradycardia was defined as a low heart rate (<60 beats per minute) for at least 24 hours. Plasma concentrations of LPV and RTV were measured every 72 hours by high-performance liquid chromatography and tandem mass spectrometry.
Although none of the included patients had pre-existing nodal pathology, 9 patients (22%) experienced bradycardia during the course of the disease. The following parameters differed in patients with vs without bradycardia: age (median, 73; interquartile range [IQR], 62-80 vs median, 62; IQR, 54-68, respectively; P =.009), lymphocyte count (median, 500; IQR, 265-1050 vs median, 710; IQR, 600-800, respectively; P =.006), and RTV plasma concentrations at 72 hours (median, 1249 ng/ml; IQR, 820-1374 vs median, 652 ng/ml; IQR, 406-1176, respectively; P =.036). RTV plasma did not correlate with LPV concentration.
Other demographic parameters, chronic medication use, electrocardiograph parameters at admission, and other biologic data were comparable in patients with vs without bradycardia.
Among patients with bradycardia, 8 had sinus bradycardia and 1 had a third-degree atrioventricular block. Treatment with LPV/RTV was believed to be the cause for bradycardia, as this phenomenon occurred in all patients in whom it was observed within 48 hours of treatment initiation and was resolved after dose reduction or discontinuation of LPV/RTV treatment.
Study limitations include the fact that its result contradict those of another study conducted in China, in which no instance of bradycardia was detected in patients with COVID-19 treated with RTV.2 However, the patients in the Chinese study were older and sicker, their heart rate was not continuously monitored, and their RTV plasma concentrations were not measured.
“Intensivists should be aware of this potential side effect in order to closely monitor LPV/RTV plasma levels notably in elderly patients,” concluded the study authors.
1. Beyls C, Martin N, Hermida A, et al. Lopinavir-ritonavir treatment for COVID-19 infection in intensive care unit: risk for bradycardia. [Published online July 9, 2020] Circ Arrhythmia Elec. doi:10.1161/CIRCEP.120.008798
2. Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, Ruan L, Song B, Cai Y, Wei M, et al. A trial of lopinavir–ritonavir in adults hospitalized with severe Covid-19. N Engl J Med 2020; NEJMoa2001282.