JOURNAL CLUB – FEBRUARY 2022

Journal Club Podcast for February 2022

Prof Peter Cameron Dr Myles Sri Ganeshan Dr Eanna Mac Suibhne

Editor: Dr David McCreary

Welcome to the Journal Club Podcast for February 2022 (yes, published in March...sometimes it takes a while for our timetables to sync!). You can listen to the podcast above and have a read at our summary below, courtesy of our senior registrar for research, Dr Eanna Mac Suibhne.

In February, I was joined by Professor Peter Cameron, Academic Director for the Alfred Emergency and Trauma Centre, and our new Research Fellow, Dr Myles Sri Ganeshan. We reviewed 2 more COVID-related papers, the first regarding Molnupiravir as an option for outpatient management of COVID and another concerning rapid antigen tests. We also reviewed papers exploring ketamine nebulisation for pain, and the risks of not anticoagulating patients with subsegmental PEs. As always, have a read of the papers for yourselves and draw your own conclusions. But read on to get a snapshot of what we discussed.

PAPER 1: MOLNUPIRAVIR FOR ORAL TREATMENT OF COVID-19 IN NON-HOSPITALIZED PATIENTS

READ IT HERE

CLINICAL QUESTION: Is Molnupiravir superior to placebo in preventing hospitalisation and death through day 29 in patients with mild to moderate COVID-19?

FINDINGS In the interim analysis, the Molnupiravir group had a lower risk of hospitalisation or death through day 29, 7.3% (28/385) compared to 14.1% (53/377) in the placebo group. There was a statistically significant treatment difference of 6.8%. However, the treatment difference was much lower in the full trial. In the full trial, the Molnupiravir group noted that 6.8% (48/709) of participants were hospitalised or died through day 29. The Placebo group noted that 9.7% (68/699) participants were hospitalised or died through day 29. There was a statistically significant treatment difference of 2.9% in favour of the intervention.

AUTHORS' CONCLUSIONS In this trial, oral Molnupiravir was found to be effective for the treatment of COVID-19, without evident safety concerns, when initiated within 5 days after the onset of signs or symptoms in this population of non-hospitalised, unvaccinated adults who were at risk for progression to severe disease.

JOURNAL CLUB THOUGHTS Some strengths of this study were that the primary outcome was both clinically relevant and patient-oriented. It was a double-blind, parallel-group, randomised, placebo-controlled trial that minimised bias. This was also an international study with enrolment at more than 100 sites in 20 countries which increased the external validity. However, the trial is markedly underpowered, and some benefits may be due to gender differences in the experimental and placebo groups. The primary outcome is a composite, and the two components (hospitalisation and death) do not have equal importance. An independent review board opted to stop the trial early for benefit, in the absence of predetermined stop criteria. It is also notable that vaccinated patients were excluded; this limits the generalisability of the results in a population where the vast majority is vaccinated. Finally, based on animal models, Molnupiravir may be teratogenic and is not recommended during pregnancy. Potential teratogenicity is a major issue and compliance with contraceptive methods may be difficult to attain particularly for men.

PAPER 2: COMPARISON OF NEBULIZED KETAMINE AT THREE DIFFERENT DOSING REGIMENS FOR TREATING PAINFUL CONDITIONS IN THE EMERGENCY DEPARTMENT: A PROSPECTIVE, RANDOMIZED, DOUBLE-BLIND CLINICAL TRIAL

READ IT HERE

CLINICAL QUESTION: Which dose of nebulised ketamine is most effective for pain relief?

FINDINGS This was a prospective, randomised, double-blinded trial comparing 3 doses of nebulised ketamine (0.75 mg/kg, 1 mg/ kg, and 1.5 mg/kg) administered through breath-actuated nebulisation to patients with moderate to severe acute and chronic pain in an adult emergency department. The primary outcome was the difference in pain scores on an 11-point numeric rating scale at 30 minutes in each group. 120 subjects (40 per group) were enrolled. All doses demonstrated clinically significant pain reduction. However, there was no additional benefit to higher doses of ketamine. To add context to the chosen secondary outcomes (adverse events and need for rescue analgesia), the authors compared their results to previous studies done on IV ketamine and morphine. Clinical pain reductions were on par with the degree of pain relief seen with IV ketamine and morphine.

AUTHORS' CONCLUSIONS The authors concluded that they found no difference between the 3 doses of ketamine administered through breath-actuated nebuliser for short term treatment of moderate to severe pain in the emergency department.

JOURNAL CLUB THOUGHTS It is always useful to have another option when it comes to analgesia in the ED. However, in terms of generalisability, access to breath actuated nebulised ketamine devices is limited. The study had numerous limitations including convenience sampling and a small sample size. In addition, the authors did not provide a breakdown of the conditions being treated while analgesia was provided. Finally, it would have been interesting to see this study done in a paediatric population, as the non-invasive aspect of treatment is especially appealing.

Paper 3: Risk for Recurrent Venous Thromboembolism in Patients With Subsegmental Pulmonary Embolism Managed Without Anticoagulation

Read it here

CLINICAL QUESTION: Are patients with subsegmental pulmonary embolism (SSPE) at low risk for recurrent venous thromboembolism (VTE) and need clinical surveillance, or is anticoagulation indicated?

FINDINGS In the study, patients with isolated subsegmental PE but no DVT on ultrasound were managed without anticoagulation. The primary outcome was recurrent VTE during 90-day follow-up which occurred in 8 patients with a cumulative incidence of 3.1%. Study recruitment ended early because the predefined stopping rule was met when 292 of the projected 300 patients were enrolled. Overall, 266 patients were included in the study. Other notable results were that patients with multiple isolated SSPE had a higher incidence of recurrent VTE compared to those with single isolated SSPE (5.7% vs 2.1%, respectively), and patients over 65 years of age had a higher rate of recurrent VTE compared to those 65 years or under (5.5% vs 1.8%). In total, 4 patients had recurrent proximal PE and 4 patients had DVT. No patients had a fatal recurrent PE.

AUTHORS' CONCLUSIONS Patients with isolated single or multiple SSPE, who did not have proximal DVT, had higher than expected rates of recurrent VTE. This has implications for the treatment of these patients with anticoagulation in clinical practice.

JOURNAL CLUB THOUGHTS Despite the small numbers included in this study, the results would make you think twice before skipping anticoagulation in the management of patients with isolated single or multiple SSPE. This study addressed a clinically important question and adds to the existing research which has been retrospective until this point. The background rates of SSPEs in the community are unknown, and with more and more CTPAs being performed, there are increased rates of SSPEs being diagnosed of questionable clinical significance. The subgroup analysis, which is to be interpreted with caution, suggests that the rate of recurrent VTE may be greater in older versus younger patients and in those with multiple versus single isolated SSPE. These factors, if present, could assist when considering anticoagulation.

Guidelines from the American College of Chest Physicians suggest clinical surveillance over anticoagulation in a select group of patients with SSPE but there is only low-level evidence to guide this recommendation. The opinion at the journal club swayed towards anticoagulating this patient group and involving our haem/thrombosis colleagues in the discussion.

PAPER 4: SARS-COV-2 RAPID ANTIGEN TESTING IN THE HEALTHCARE SECTOR: A CLINICAL PREDICTION MODEL FOR IDENTIFYING FALSE NEGATIVE RESULTS

READ IT HERE

CLINICAL QUESTION: What parameters can be used to identify false-negative rapid antigen tests, and could these facilitate the development of a clinical prediction model?

FINDINGS In this multicentre trial, patients with documented paired results of rapid antigen tests (RAT) and RT-PCR were retrospectively analysed in respect to clinical findings. Variables included demographics, laboratory values, and specific symptoms. Three different models were evaluated using Bayesian logistic regression. The initial dataset included 4,076 patients. Overall, the sensitivity and specificity of RAT was 62.3% and 97.6%, respectively. 2,997 cases with negative RAT results (false negative (FN): 120; true negative: 2,877) were evaluated further. The best-performing model for predicting FN RAT results containing 10 variables yielded an area under the curve of 0.971. The most important variables for model performance with respect to Bayesian factor were leucocyte count, fever, respiratory rate, dyspnoea, and musculoskeletal symptoms.

AUTHORS' CONCLUSION FN RAT results can be accurately identified through ten routinely available variables. In addition to RAT testing in the clinical setting, implementation of a prediction model can provide useful information to guide decision making when initiating appropriate hygiene measures and therefore helps avoiding nosocomial infections.

JOURNAL CLUB THOUGHTS The rapidly changing face of COVID and the development of new variants means that the utility of these results may shortly expire. The study predates the evolution of the omicron variant which, at the time of writing, is the predominant variant and, as such, questions the effectiveness of the proposed model. There were a few issues with the methodology including the data being collected retrospectively which limits data quality, especially regarding symptom assessment. There was also a significant number of missing values and data in the final results. Additionally, the reference standard of PCR testing isn't itself 100% sensitive.

REFERENCES

1. Bernal AJ, Silva MMG da, Musungaie DB, Kovalchuk E, Gonzalez A, Reyes VD, et al. Molnupiravir for Oral Treatment of Covid-19 in Nonhospitalized Patients. New Engl J Med. 2021;386(6):509–20.

2. Dove D, Fassassi C, Davis A, Drapkin J, Butt M, Hossain R, et al. Comparison of Nebulized Ketamine at Three Different Dosing Regimens for Treating Painful Conditions in the Emergency Department: A Prospective, Randomized, Double-Blind Clinical Trial. Ann Emerg Med. 2021;78(6):779–87.

3. Gal GL, Kovacs MJ, Bertoletti L, Couturaud F, Dennie C, Hirsch AM, et al. Risk for Recurrent Venous Thromboembolism in Patients With Subsegmental Pulmonary Embolism Managed Without Anticoagulation: A Multicenter Prospective Cohort Study. Ann Intern Med. 2022;175(1):29–35.

4. Leiner J, Pellissier V, Nitsche A, König S, Hohenstein S, Nachtigall I, et al. SARS-CoV-2 rapid antigen testing in the healthcare sector: A clinical prediction model for identifying false negative results. Int J Infect Dis. 2021;112:117–23.