The latest results on the use of convalescent plasma in Covid-19 are now out from the RECOVERY trial as a pre-print. As you know we have already covered the trial quite extensively and thus far we know the following for hospitalised patients with COVID-19
- Drugs that improve survival
- Dexamethasone if the patient has an oxygen requirement)
- Tocilizumab (for those with more severe disease)
- Drugs that don’t improve survival
- Drugs we are still recruiting to in the trial
- REGN monoclonal antibodies
- Dimethyl Fumarate
The results out this week relate to the pre-print of the convalescent plasma arm of the study.
What type of trial is this?
We have covered the methodology in previous posts, but in essence this is a platform adaptive trial. Whilst the entry criteria and outcome measures (survival at 28 days) are consistent, the drugs tested can come and go into the trial as results show success or failure, and as new drugs become available for assessment. I won’t go over the details of the trial again here, just look at some of our past posts (listed below). There are now over 38000 patients in the trial and in my trust we have recruited well over 500 of them.
Remind me about the patients.
It’s worth remembering that this is hospitalised patients with COVID-19. My view is that this is very important when we think about the phase of disease. At the point of hospital admission patients are in the phase of disease where it appears that it is the abnormal immune response doing the damage. It is not the viraemic phase and thus antivirals (of which convalescent plasma may be considered one), may not be as effective as we might hope. A reminder that the outcome measure is survival 28 days post recruitment.
What about the results.
Disappointingly, but perhaps not surprisingly, convalescent plasma did not improve survival. There was no significant difference in 28-day mortality between the two groups: 1398 (24%) of 5795 patients allocated convalescent plasma and 1408 (24%) of 5763 patients allocated usual care died within 28 days (rate ratio [RR] 1.00; 95% confidence interval [CI] 0.93 to 1.07; p=0.93).
The study also looked at a number of subgroups which again showed no significant benefits.
These results are consistent with other trials and the accompanying meta-analysis demonstrates no benefit to convalescent plasma across a range of trials.
We previously covered a trial of convalescent plasma that showed no mortality benefit, but in that trial the donors were not screened for the levels of anti SarsCoV2 antibodies. In this trial donors were screened for high levels of antibodies and so we should be assured that if it was going to work then we should have seen some signal in the results.
What is also very interesting is the very large difference in mortality between patients depending on whether they were seronegative or seropositive for their own antibodies. Those who were seronegative had a much higher mortality and so we might have expected them to do better with convalescent plasma, but this was not the case. The trial is still recruiting to the monoclonal antibody arm of the trial which may produce a different result as the antibodies will be more specific to Sars CoV2 but only time will tell. As far as I know the patients own antibodies on admission are not currently used as a prognostic tool in clinical practice, but I think that this may become an area for future research. Patients with low levels of serum antibodies were older and had more comorbidities so it may be an association, but clearly it is a very interesting finding from the study.
There is no doubt that the news will be disappointing to many, and there will be many patients who will have received convalescent plasma outside of trials in the international community. This trial result is further evidence that in a pandemic we should be strengthening the practice of evidence based medicine through science and research. Evidence based medicine took a bit of a bashing in the early part of the pandemic, but it is making a rather impressive comeback through trials such as RECOVERY. It’s not a perfect trial and we have a number of concerns about outcomes, but for now this is the best evidence we have on convalescent plasma and other therapies for hospitalised patients.
The bottom line.
Convalescent plasma should not be a standard of care for hospitalised patients with COVID-19.
- Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. https://www.medrxiv.org/content/10.1101/2021.03.09.21252736v1
- RECOVERY Collaborative Group. Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): preliminary results of a randomised, controlled, open-label, platform trial | medRxiv 2021.02.11.21249258; doi: https://doi.org/10.1101/2021.02.11.21249258
- Evidence-based medicine and COVID-19: what to believe and when to change | Emergency Medicine Journal Carley S, Horner D, Body R, et al Evidence-based medicine and COVID-19: what to believe and when to change Emergency Medicine Journal 2020;37:572-575.
- RECOVERY trial closes recruitment to colchicine treatment for patients hospitalised with COVID-19 https://www.recoverytrial.net/news/recovery-trial-closes-recruitment-to-colchicine-treatment-for-patients-hospitalised-with-covid-19
- Simon Carley, “JC: RECOVERY trial shows Tocilizumab effective for COVID19. St Emlyn’s,” in St.Emlyn’s, February 11, 2021, https://www.stemlynsblog.org/jc-recovery-trial-shows-tocilizumab-effective-for-covid19-st-emlyns/.
- Simon Carley, “The RECOVERY platform trial: No benefit to Hydroxychloroquine in Covid-19. St Emlyn’s,” in St.Emlyn’s, June 6, 2020, https://www.stemlynsblog.org/the-recovery-platform-trial-no-benefit-to-hydroxychloroquine-in-covid-19-st-emlyns/.
- Simon Carley, “Dexamethasone, COVID-19 and the RECOVERY trial. St Emlyn’s,” in St.Emlyn’s, June 28, 2020, https://www.stemlynsblog.org/dexamethasone-covid-19-and-the-recovery-trial-st-emlyns/.
- Simon Carley, “JC: Lopinavir/Ritonavir in the treatment of COVID-19,” in St.Emlyn’s, December 23, 2020, https://www.stemlynsblog.org/jc-lopinavir-ritonavir-in-the-treatment-of-covid-19/.
- Simon Carley, “JC: Convalescent plasma in COVID 19 patients.,” in St.Emlyn’s, November 21, 2020, https://www.stemlynsblog.org/jc-convalescent-plasma-in-covid-19-patients/.
- Simon Carley, “Colchicine does not improve mortality in COVID19. St Emlyn’s,” in St.Emlyn’s, March 5, 2021, https://www.stemlynsblog.org/cochicine-does-not-improve-mortality-in-covid19-st-emlyns/.
- Dan Horner, “Tocilizumabulous? A special offer on IL-6 with Tocilizumab.,” in St.Emlyn’s, February 26, 2021, https://www.stemlynsblog.org/tocilizumabulous-a-special-offer-on-il-6-with-tocilizumab/.