New American Study Shows That The Antiemetic Drug Zofran Lowers Risk Of Mortality Of Severe COVID-19 Patients On Ventilators
A new study that analyzes real-world data utilizing artificial intelligence by researchers from AdventHealth Research Institute-Orlando, Oak Ridge National Laboratory-Tennessee and the University of Tennessee has found that the antiemetic drug Zofran (Ondansetron) lowers risk of mortality of severe COVID-19 patients on ventilators and is associated with increased survival of these mechanically ventilated COVID-19 patients.
A new study that analyzes real-world data utilizing artificial intelligence by researchers from AdventHealth Research Institute-Orlando, Oak Ridge National Laboratory-Tennessee and the University of Tennessee has found that the antiemetic drug Zofran (Ondansetron) lowers risk of mortality of severe COVID-19 patients on ventilators and is associated with increased survival of these mechanically ventilated COVID-19 patients.
There are many cheaper generic versions of Zofran sold under the names Dantron 8, (Not Dantron the carcinogenic drug) Emeset, Emistop, Onsia and Zetron.
The study findings were published on a preprint server and are currently being peer reviewed.
https://www.medrxiv.org/content/10.1101/2021.10.05.21264578v1
The current study combines a large amount of COVID-19-focused RWD from AdventHealth that was analyzed using a Bayesian statistics driven platform on a supercomputer at Oak Ridge National Laboratory (ORNL). This collaboration allowed us to leverage the data availability and computational capacities in a data-driven manner to generate causal network models to identify factors associated with disease severity, increased survival and mortality, including drugs that have the potential to improve outcomes in COVID-19 patients.
One of our key findings is that mortality has a dependency on the use of ondansetron, a widely used anti-emetic medication. After examining the interaction of ondansetron use with other variables of interest previously found to predict death, we found that the beneficial effect of ondansetron on mortality is specifically seen in patients on mechanical ventilator.
DISCUSSION
The goal of this study, representing a multi-institutional collaborative effort of collecting, structuring, and analyzing RWD through AI analytics, was to generate insights on COVID-19 mortality-associated factors and identify potential new therapeutic options for COVID-19 patients.
The study involved two stage data analytics: the primary discovery phase, involving Bayesian statistics-based analysis to generate causal networks of all patients to identify significant factors influencing mortality in the COVID-19 positive cohort (Table 1), from 12 months pre- to 28 days post PCR-based COVID-19 diagnosis; this was followed by confirmatory tests of the main findings on imputed and bootstrapped data, from multivariable regression analysis to LASSO logistic regression.
The Bayesian network findings were based on the analysis of demographic, clinical, and laboratory data from 16,277 PCR confirmed COVID-19 patients representing a subset of the 279,281 patients in the RECOVER-19 registry; the confirmatory logistic regression analyses were performed on data from the 3,082 hospitalized patients.
We identified ondansetron as the main factor associated with improved survival in mechanically ventilated COVID-19 patients. An initial unbiased search for predictors of mortality at any time and within any patient population found ondansetron as the only medication associated with decreased mortality (Table 2).
This association was initially identified within a specific inpatient population (< 60 years old) and when ondansetron was administered at disparate times (up to 7 days and > 28 days post COVID-19 diagnosis). Regarding the timing of administration, of the 737 patients who received ondansetron at any time during the first 30 days, the majority (84%) received it within the first week post SARS-CoV-2 positive PCR test. Patients who received ondansetron in the first week post PCR test had improved survival compared with patients who did not (p < 0.0001) (Figure 4).
Multivariable logistic regression by LASSO showed significant effects for age and ondansetron use on mortality within 30 days, but not an Age:Ondansetron interaction effect, meaning that the ondansetron effect applies to all age groups equally. However, it is the interaction term Ondansetron:onVentilator that is primarily selected by LASSO as a covariate of non-zero coefficient, rather than the main term Ondansetron.
This indicates that the beneficial effect of ondansetron is seen only in patients on ventilator. This key finding complements a study by Bayat et. al. that reported a reduction in 30-day all-cause mortality for all inpatients (including ICU) with early administration of ondansetron after admission [12].
Kaplan-Meier curve showing 30-day survival rates of hospitalized patients who received (blue) or did not receive (red) ondansetron in the first week post SARS-CoV-2 positive PCR test. Patients who received ondansetron had improved 30-day survival compared with patients who did not (p < 0.0001).
Ondansetron is a selective 5-HT3 serotonin-receptor antagonist with known effects against nausea and vomiting through both central and peripheral mechanisms [13]. It has been postulated that SARS-CoV-2 might have an indirect effect on enteroendocrine cells (EEC), triggering the release of neuroactive agents such as the emesis inducing serotonin [14].
Most studies showed that patients with COVID-19 have higher plasma serotonin levels and this correlates with increased IL-6 [15, 16], while others concluded they have decreased serotonin levels [17]. Considering serotonin’s role in regulating innate and adaptive immune responses [18], the observed beneficial effect of ondansetron might be due to the modulation of serotonin levels or could also be linked with a direct effect on the immune system [19] or on known COVID-19 comorbidities, such liver and kidney disease or complications, such as thrombosis [20-22]. There are also data suggesting that serotonin receptor signaling influences cellular activities that regulate entry of diverse virus families [23].
It is interesting to note that while we do not find convalescent plasma to be a significant predictor of death, patients on ondansetron and convalescent plasma were more likely to die (Table 5), suggesting a complex interaction between ondansetron, ventilator use, and convalescent plasma. It is now known that high-titer convalescent plasma does not improve COVID-19 survival or clinical outcomes when used in both inpatients [24, 25] and high-risk outpatients [26] and when a beneficial effect on the risk of death was observed it was not maintained for patients who had received mechanical ventilation [27].
As, early in the pandemic, convalescent plasma was usually reserved for patients with more severe COVID-19 pneumonia, this observed association might be explained by this confounding bias and not by a potential detrimental effect of convalescent plasma.
In our cohort, tocilizumab had a similar effect on mortality as ondansetron for mechanically ventilated patients, in line with published evidence from large, randomized control studies [28, 29].
Although being male is associated with COVID-19 mortality, we find that in the context of neoplastic disease this is reversed. Our results show a negative association between the interaction term Gender:Neoplastic_Disease and mortality. This may be due to an indirect ondansetron effect, since this is often prescribed to cancer patients undergoing chemotherapy, radiation therapy, and surgery.
So, while being male is positively associated with COVID-19 mortality, in cancer patients this may be modulated by ondansetron use. Also, the association of COVID-19 mortality with cancer is not straightforward. The COVID-19 mortality of cancer patients depends on the type of their cancer, with the main mortality drivers being age, gender, comorbidities, and hematological cancers [30-32].
In the present study, besides ondansetron and tocilizumab, other covariates interacting with ventilator use indicate that males on ventilator and patients with chronic obstructive pulmonary disease (COPD) on ventilator are more likely to die. The former of these two findings agrees with Nicholson et al., who showed that male COVID-19 patients on ventilator have a higher mortality rate than females (after correcting for co-morbidities) [33]. COPD is also an already established comorbidity associated with increased odds of hospitalization and death in COVID-19 patients [34, 35].
Looking at interactions between other covariates, we found that the CRP and BUN dyad, laboratory biomarkers that are found in prognostic models for COVID-19 mortality, are also associated with mortality in our cohort [36, 37]. Similarly, the previously observed mortality link of interacting factors ferritin and age [38] as well as higher D-dimer levels in males were also confirmed by our analyses [39]. The association between mortality with a combination of age and age-squared agrees with a previous finding that infection fatality ratio has a log-linear increase by age among individuals older than 30 years [40].
Although an FDA-approved drug for COVID-19, remdesivir was not found to increase survival in large, randomized control trials [41-43]. We find that age and remdesivir use interact to increase mortality. This has not been reported previously and may suggest that we see a similar confounding bias with convalescent plasma, since remdesivir was reserved for more severe patients earlier on.
Diagnostic code Z20.828 (“Contact with and (suspected) exposure to other viral communicable diseases”) was one of the 3 features with a significant relationship with decreased mortality in our analysis. This code was used in 2020 when a clinician suspected exposure to SARS-CoV-2 without a test result available.
In the RECOVER-19 registry, out of the approximately 200,000 unique patients seen with this diagnostic code in 2020, about 16,000 were found to be positive. We might see this mortality benefit because the SARS-CoV-2 positive patients with the Z20.828 code might have had a less severe form of COVID-19 (higher ambiguity without a positive test) or arrived earlier in the course of the disease and were designated patients under investigation (PUI), benefiting from early precautions. Generally, the patients admitted with a severe form of COVID-19 would have received another more definitive diagnostic code.
