Inhaled nitric oxide lowers mortality risk in Black patients with COVID-19
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Key takeaways:
- Black vs. white patients with COVID-19 receiving inhaled nitric oxide had more improvement in systemic oxygenation.
- The risk for mortality after receipt of this therapy was lowered in Black patients.
Black ICU patients with COVID-19 receiving high-dose inhaled nitric oxide had a decreased risk for 28-day and 90-day mortality, according to results published in American Journal of Respiratory and Critical Care Medicine.
“Prior literature has shown that the nitric oxide system is suppressed in Black individuals and this suppression may play a role in their increased burden of cardiopulmonary disease,” Pankaj Arora, MD, associate professor in the division of cardiovascular disease at the University of Alabama at Birmingham, told Healio. “Augmenting the nitric oxide system in Black individuals may overcome this suppression and improve outcomes.”
Notably, Arora said the African-American Heart Failure Trial previously demonstrated a mortality benefit linked to nitric oxide augmentation in Black patients with heart failure, and this led to the recommendation of this treatment for this population in heart failure guidelines.
“Similarly, the findings from our study support that high-dose inhaled nitric oxide [iNO] may be used in Black patients with acute respiratory distress syndrome [ARDS] to reduce their risk of death and improve systemic oxygenation,” Arora added. “Therefore, it is vital for clinicians to recognize that regulation of biological systems, such as the nitric oxide system, may vary in white and Black individuals and targeting this system in Black individuals may have a greater therapeutic yield.”
In a post-hoc analysis of the NOSARSCOVID trial, Arora and colleagues evaluated 110 self-identified white patients (median age, 63 years; 30.9% women) and 43 self-identified Black patients (median age, 63 years; 39.5% women) with COVID-19 receiving mechanical ventilation in the ICU to find out if the impact of high-dose iNO on systemic oxygenation and mortality differs based on race.
As Healio previously reported, adults on mechanical ventilation for COVID-19 pneumonia showed improvements in oxygenation with high-dose iNO.
Within the cohort of white patients, 49 patients received the treatment and 61 acted as control patients. In the cohort of Black patients, 23 patients received treatment and 20 acted as controls.
Between the two sets of patients, Black patients had a greater change in the ratio of arterial oxygen partial pressure to fractional inspired oxygen (PaO2/FiO2) at hour 48 on iNO (79.1 mm Hg; 95% credible interval [CrI], 12.4-139.2 vs. 21.3 mm Hg; 95% CrI, –6.5 to 48.8) and a higher probability of an increase in this measure at the 48-hour mark (99.3% vs. 93.2%) compared with white patients, according to researchers.
“We found that the improvement in systemic oxygenation noted in the primary trial was mainly attributed to the improvement in systemic oxygenation in Black patients,” Arora said.
In terms of mortality, a higher proportion of Black patients vs. white patients died by day 28 (39.5% vs. 23.6%), but Black patients had a reduced risk for 28-day mortality with iNO therapy (RR = 0.46; 95% CrI, 0.13-1.49). For white patients, researchers did not find a link between iNO and a decreased 28-day mortality risk (RR = 1.04; 95% CrI, 0.44-2.42).
Black patients receiving iNO also had a higher probability for a risk ratio less than one vs. white patients receiving nitric oxide (89.2% vs. 46.9%).
Compared with white patients, a greater proportion of Black patients died by day 90 (46.5% vs. 26.4%); however, researchers again observed a decreased risk for this outcome at 90 days with iNO among Black patients (RR = 0.35; 95% CrI, 0.11-1.04). There was no relationship between the therapy and a 90-day mortality risk reduction among white patients (RR = 1.05; 95% CrI, 0.45-2.34).
Similar to the probability results observed for 28-day mortality, Black patients vs. white patients receiving iNO had a higher probability for a risk ratio less than 1 for 90-day mortality (96.2% vs. 45.2%).
“Our study highlights the need to include a diverse patient population in clinical trials,” Arora told Healio. “Race may serve as a proxy for genetic ancestry and reflect differences in the regulation of biological systems. Therefore, it is important to recognize that the treatment effect of therapies may show heterogeneity by racial groups.
“Keeping this in mind, future studies should focus on exploring the differences in the biological system by race and developing therapies that target these differences to improve patient outcomes and reduce health disparities,” Arora said.
Reference:
- New study finds high-dose inhaled nitric oxide decreases the risk of death among critically ill Black patients with COVID-19. https://www.uab.edu/news/research/item/13967-new-study-finds-high-dose-inhaled-nitric-oxide-decreases-the-risk-of-death-among-critically-ill-black-patients-with-covid-19. Published Feb. 9, 2024. Accessed Feb. 29, 2024.
Perspective
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The findings from this study raise interesting questions for how we understand and treat ARDS. Studies have shown racial disparities in survival in patients with ARDS. Many of these differences are attributable to social determinants of health factors; however, there may be underlying physiological differences in genetics that may play a role in explaining at least some of these disparities. Although subgroups have been shown to potentially benefit from inhaled nitric oxide (iNO) therapy in ARDS — namely, also demonstrated by the same group in a research letter from 2023 that hint at subgroups that may benefit — this is one of the first articles to demonstrate potential benefits in treatment, as well as a potential mechanism, that differ across races. This may sway intensivists to be more likely to attempt iNO therapy in Black patients if a hospital system already supports this and they have iNO access.
In context, doctors have noticed that there are racial disparities in surviving ARDS. Furthermore, there have also been racial disparities in recruiting a diverse group of patients. It’s been difficult for doctors to identify exactly which patients would be responders and which patients would be nonresponders to iNO. Some doctors have thought that iNO improves numbers (eg, oxygen numbers) without actually changing mortality. It’s unclear whether these earlier studies were too small to see the effect or whether they weren’t explicitly robustly compared.
This is still early work, so it may not have a major shift in clinical practice yet. Access to iNO therapy is somewhat limited given its expense (up to 17 times more expensive than inhaled epoprostenol, per Torbic et al); once patients with severe ARDS require iNO or inhaled epoprostenol therapy, they’re already very sick. iNO is already considered salvage therapy. However, for those doctors who believe that iNO improves numbers without improving mortality — while we are waiting for stronger results — it might be a reason for them to consider offering iNO in very severe cases of ARDS when they run out of options.
Before we can take this early work into mainstream practice, the future would likely involve a more robust study that would actively recruit a greater population of patients across all races and ethnicities. The white patient group (n = 110) was 255% larger than the Black patient group (n = 43), so more robust studies across hospitals would build the case that this should change clinical practice. If we can identify a specific group of patients that would highly benefit, we can strategically help those very severe cases.
References:
Shetty NS, et al. Am J Respir Crit Care Med. 2023;doi:10.1164/rccm.202311-2112LE.
Torbic H, et al. J Crit Care. 2013;doi:10.1016/j.jcrc.2013.03.006.
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