JC: Non-invasive ventilation for COVID 19 patients. The Recovery RS trial. St Emlyn’s

I remember back at the beginning of the pandemic when we were seeing lots of patients arriving in the ED in extremis. The now familiar picture of the deeply hypoxic patient with terrible chest X-rays was still very much a new experience and we were struggling to know how to treat our patients. In the early phase of the pandemic the sort of patient described above would have been intubated and ventilated in the ED and then transferred to the ICU. Non-invasive therapies were considered too dangerous owing to the risks of generating aerosols in an environment that was not safe for staff. So the decision was between high flow oxygen delivered by a range of face masks OR endotracheal intubation. The non-invasive step was simply not widely used in the very early days and this was a real problem for us. There were a number of patients who were considered not suitable for endotracheal intubation, but who were also really sick and objectively needing ventilatory support that if it had been COPD/pneumonia we might well have used non-invasive methods.

Oh how things changed quickly as we learned from colleagues in those countries hit early (notably Italy).

The use of non-invasive ventilation has become widespread as we have learned more about risks and on the basis of experiential data from thousands of patients treated in the UK. Segregation of high-risk areas, PPE and the sheer necessity of running out of capacity to intubate and ventilate patients meant that non-invasive ventilation became a core treatment for our patients, but there are still doubts. For example, one concern was that patients would be left too long on non-invasive ventilation leading to worsening lung damage.

As part of the RECOVERY platform trial (which we have covered extensively on the blog) a randomised controlled trial was started of non-invasive ventilation for hospitalised patients with COVID-19. That trial has now appeared in pre-print form and has been presented on the critical care reviews website (which is fantastic btw and a regular must visit site for anyone interested in critical or emergency care).

The abstract is below, but as we always say, please read the full paper yourself and come to your own conclusions.

What type of study is this?

The RECOVERY-RS (respiratory support) trial is three arm trial of a subset of patients in the RECOVERY platform adaptive trial. It’s a randomised controlled trial which is the appropriate method to test an intervention. Patients were randomised using an online system that was able to adapt to whatever non-invasive techniques were available at each site, However, all sites had to recruit to the conventional face mask arm as an option.

Patients were recruited at 48 sites in the UK, although recruitment was available at 75 hospitals. These numbers are considerably less than the wider RECOVERY trial as not all sites had the capability to perform the trial (in our case it was because of difficulties in cohorting patients in the early stages of the pandemic).

Tell me about the patients.

The wider RECOVERY trial recruits from all hospitalised patients with COVID-19, but in this trial patients were only eligible if they had evidence of respiratory failure which was defined as a peripheral oxygen saturation of <95% on an FiO2 of 40% or more. They also had to be suitable candidates for intubation if the therapy failed, so those patients considered very poor prognosis were probably not included. This may have also influenced issues such as age and comorbidities in the recruited groups.

What interventions were trialled?

The three arms of the trial were:

1. CPAP: Continuous Positive Airway Pressure adminstered by face mask or hood
2. HFNO: High Flow Nasal Oxygen
3. Conventional Oxygen therapy

Some patients crossed over therapies and some had NIV as a bridging technique to intubation. It should also be noted that for obvious reasons this trial was not blinded to patients or to the staff treating them and of course this can cause bias in the findings, though it is clearly impossible to avoid this.

What about the outcomes?

The principle outcome was defined as death or tracheal intubation within 30 days of randomisation. The decision to perform tracheal intubation was left at the discretion of the treating clinicians which is appropriate in my opinion as it’s a complex multifactorial decision, and thus this trial represents a pragmatic approach which will more likely represent future practice.

What did they find?

The headline results are important. 1272 patients were recruited (5 patient had double randomisation in error). 13 patients were unable to be analysed (withdrawn or lost) leaving 1259 for analysis.

• Conventional O2 therapy 467 patients
• HFNO 384 patients
• CPAP 248 patients

However, the analysis of data is slightly confusing as the numbers above do not add up to the same numbers below

The patient group is interesting as the age of participants is somewhat younger than the wider cohort of patients with COVID-19 (average age was 57.4). I suspect this is due to the necessity to have intubation and ventilation as a treatment option for the trial. Sadly advancing age is associated with reasons why this may not be a consideration in severely unwell patients.

As for the primary outcome the results are quite stark.

For CPAP vs. conventional O2 therapy, 137/377 (36.3%) of patients (CPAP) were intubated or dead at 30 days vs. 158/356 (44.4%) in the O2 group. This was clinically and statistically significant with a number need to treat of 12.

For HFNO vs. conventional O2 therapy, 184/414 (44.4%) of patients (HFNO) were intubated or dead at 30 days vs. 166/368 (45.1%) in the O2 group. This was not clinically or statistically significant.

So on the basis of these results it appears that CPAP is much more advantageous than HFNO, which will come as a surprise to many.

However, there is more complex data in the secondary outcomes and especially if you split the composite outcome. The main advantage of CPAP was seen in reducing the need for intubation. In terms of mortality the result is less impressive. Mortality for CPAP at 30 days was 63/378 (16.7%) vs. 69/359 (19.2%) for O2 therapy and 78/415 (18.8%) in the HFNO group. None of the comparisons of mortality was statistically significant.

It may be that the trial is underpowered to detect a difference, or it may be that the 30 day outcome is too short, but on this data the lack of a mortality impact is disappointing. However, if CPAP reduces the need for intubation and ventilation without affecting mortality that is still a big win for hard pressed ICU departments and (almost certainly) better for patients too.

The analysis in the paper also include data which are adjusted for known covariates such as age, sex, obesity, etc. Adjusting for these covariates did not substantially change the findings of the study.

There were a small number of adverse events linked to CPAP use.

Other concerns and comments.

The decision to stop the trial early was a pragmatic one which is understandable, but disappointing as it may have revealed more important data on the secondary outcomes such as mortality. As an open label trial it is prone to bias and especially with regard to the combined outcome which included tracheal intubation. It is entirely possible, likely perhaps, that patients on NIV would have been delayed in the decision to intubate as they were receiving ventilatory support, and indeed the data on timings to intubation supports this theory.

We don’t know the number of patients screened in the trial and as previously mentioned the demographics of patients in this trial are different from the general population of patients we saw admitted to hospital in the first year of the pandemic (although in the latest waves the age has come down significantly).

There was a fair degree of crossover in the study which may have influenced the results.

The bottom line.

This trial is the largest RCT of NIV in COVID-19 patients and it’s therefore important. Whilst the finding that CPAP reduces the need for intubation is not surprising I think a number of clinicians will be surprised that there was no impact of HFNO on the primary outcome.

Even though there is no mortality benefit seen in this trial it seems that CPAP should be advocated for our patients, but HFNO should not.

vb

Simon Carley and Chris Gray

UPDATE – New UK guidance has acknowledged the new evidence and now states the following with regard to HFNO

References and links.

1. Aspirin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. https://www.medrxiv.org/content/10.1101/2021.06.08.21258132v1.full.pdf
2. 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
3. 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/.
4. 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/.
5. 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/.
6. 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/.
7. 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/.
8. 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/.
9. Simon Carley, “JC: Aspirin is not effective for hospitalised COVID19 patients. St Emlyn’s,” in St.Emlyn’s, June 8, 2021, https://www.stemlynsblog.org/jc-aspirin-does-not-work-in-hospitalised-covid19-patients-st-emlyns/.
10. Simon Carley, “REGN monoclonal antibodies work in selected hospitalised COVID-19 patients. St Emlyn’s,” in St.Emlyn’s, June 27, 2021, https://www.stemlynsblog.org/regn-monoclonal-antibodies-work-in-selected-hospitalised-covid-19-patients-st-emlyns/.