Association of Convalescent Plasma Treatment with Reduced Mortality and Improved Clinical Trajectory in Patients Hospitalized with COVID-19 in the Community Setting

Abstract

Background: Convalescent plasma (CP) quickly emerged as one of the first investigational treatment options for COVID-19. Evidence supporting CP for treating patients hospitalized with COVID-19 has been inconclusive, leading to conflicting recommendations regarding its use. The primary objective was to perform a comparative effectiveness study of CP for all-cause, in-hospital mortality in patients with COVID-19. Methods: The matched, multicenter, electronic health records-based, retrospective cohort study included 44,770 patients hospitalized with COVID-19 in one of 176 HCA Healthcare-affiliated community hospitals across the United States from March 2 to October 7, 2020. Coarsened exact matching (1:k) was employed resulting in a sample of 3,774 CP and 10,687 comparison patients. Results: Examining mortality using a shared frailty model and controlling for concomitant medications, calendar date of admission, and days from admission to transfusion demonstrated a significant association of CP with lower risk of mortality compared to the comparison group (aHR = 0.71, 95% CI 0.59-0.86, p<0.001). Examination of patient risk trajectories, represented by 400 clinico-demographic features from our Real-Time Risk Model (RTRM), indicated that patients who received CP recovered more quickly. The time from admission to CP transfusion was significantly associated with risk of mortality and stratification revealed that CP within 3 days after admission, but not 4-7 days, was associated with a significant reduction in mortality risk (aHR = 0.53, 95% CI 0.47-0.60, p<0.001). CP serology level was inversely associated with mortality when controlling for interaction with days to transfusion (HR = 0.998, 95% CI 0.997-0.999, p = 0.013) but was not significant in a univariable analysis. Conclusion: Utilizing this large, diverse, multicenter cohort, we demonstrate that CP is significantly associated with reduced risk of in-hospital mortality. These observations demonstrate the utility of real-world evidence and suggest the need for further evaluation prior to abandoning CP as a viable therapy for COVID-19. Funding: This research was supported, in whole, by HCA Healthcare and/or an HCA Healthcare affiliated entity including Sarah Cannon and Genospace.

COVID-19 convalescent plasma and randomized clinical trials: explaining conflicting outcomes and finding signals of efficacy

“…Another PSM from the Washington DC area found a reduction in mortality with CCP use at both days 14 and 28, which reached statistical significance at the earlier date (47). Finally, a very large study from 176 community hospitals affiliated with Healthcare Corporation of America confirmed substantial mortality reduction in hospitalized patients receiving CCP within 3 days from admission (48).…”

“…Depending on the statistical model, the RR for 30-day mortality in high-titer CCP compared to low-titer CCP recipients ranged from 0.64 – 0.67, with an upper 95% confidence bound of 0.91 (8). Similarly, the large retrospective PSM study from Hospital Corporation of America (HCA) Healthcare-affiliated hospitals reported a 0.2% decreased risk of mortality for every 1 unit of S/Co serology level (40).…”

Is SARS‐CoV‐2 viral clearance in nasopharyngeal swabs an appropriate surrogate marker for clinical efficacy of neutralising antibody‐based therapeutics?

“…54 Unfortunately, most PSM studies did not assess this parameter at all. [55][56][57][58][59][60][61][62][63][64][65][66] 3) and provide proof of principle.…”

Early administration of COVID‐19 convalescent plasma with high titer antibody content by live viral neutralization assay is associated with modest clinical efficacy

“…In contrast, the PennCCP2 trial (US) 44 found a benefit in the primary clinical endpoint of disease severity and 28-day mortality, and a double-blind RCT study by O'Donnell et al, (US and Brazil) 45 found CCP was not associated with significant improvement in day 28 clinical status, but was associated with significantly improved survival. Observational studies [46][47][48][49][50][51][52][53][54] have reported mixed findings, but generally suggest that efficacy is more likely with high titer CCP in earlier and less severe disease, [46][47][48][49][50][51][52][53] or when used in those with impaired immunity. [55][56][57] Interpretation of RCT data, including those in recent metaanalyses, 58,59 is made challenging for multiple reasons: 1) the use of either untitered plasma or plasma qualified by serologic testing alone,…”

“…In contrast, the PennCCP2 trial (US) 44 found a benefit in the primary clinical endpoint of disease severity and 28‐day mortality, and a double‐blind RCT study by O'Donnell et al, (US and Brazil) 45 found CCP was not associated with significant improvement in day 28 clinical status, but was associated with significantly improved survival. Observational studies 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 have reported mixed findings, but generally suggest that efficacy is more likely with high titer CCP in earlier and less severe disease, 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 or when used in those with impaired immunity. 55 , 56 , 57 …”