This observational Lancet study compared ~96,000 patients across 671 international hospitals with a positive COVID-19 diagnosis who received hydroxychloroquine (HCQ) +/- a macrolide (ie, azithro) or chloroquine +/- a macrolide (four total treatment arms) to a control arm that received none of the aforementioned therapies. The primary outcome was In-hospital mortality. The major secondary outcome was de-novo ventricular arrhythmias (we already know HCQ and azithro prolong the QT interval).
Patients were excluded if they received the aforementioned treatments > 48 hours after testing positive, received remdesivir, or were already on mechanical ventilation. The authors found that each of the four treatment arms were independently associated with an increased risk of in-hospital mortality AND de-novo ventricular arrhythmias when compared to the control.
Naturally, one would be skeptical given the observational nature of this study coupled with the fact that many institutions were selecting for the “sickest patients” (ie, those requiring ICU admission) to receive the therapies in question. Perhaps many of these individuals would have died regardless of the therapy they received? However, the authors used a Cox proportional hazard model to account for many of the confounding variables (patient demographics, comorbidities, other medications, disease severity, etc.) in addition to propensity score matching to support the results.
Limitations include a lack of randomization and consideration for more granular data (no description of how treatment regimens were dosed/timed in the first 48 hours, etc.). Given the observational design, one CANNOT infer causation either; however, the authors should be lauded for performing such a large, comprehensive review of international data registries regarding this controversial topic.
So yes, in conclusion, we really don’t have a great alternative currently. Plenty of work is being done regarding vaccine development, but in the interim, prevention is the best therapy.