Intermediate-Value CTCA?

Pervasive use of CT coronary angiography has been an unnecessary feature of the evaluation of patient with low-risk chest pain for the better part of a decade now. The argument behind its use – a normal examination confers a durable protective effect – is obviously nonsensical, as this bestows agency upon the test itself. Obviously, in a low-risk population with rare adverse outcomes, there can be no reasonable expectation of value in testing.

The sensible idea, then, is to use CTCA in those patients at intermediate risk. In this trial, the stratification used was GRACE score, and the 1,748 participants in this trial were a mean of 62 years of age, and a GRACE score of 115 (SD ± 35). Patients were eligible by symptoms of an acute coronary syndrome, supported by ECG changes, an elevated troponin, or a history of ischemic heart disease. Patients were then were randomized to receive CTCA in the ED or “standard of care only”. The primary outcome was, naturally, the glorious typical cardiology trial outcome of death or non-fatal myocardial infarction at one year.

Over half of patients included demonstrated troponin levels exceeding the 99th percentile, nearly two-thirds had an abnormal ECG, and a third had known coronary artery disease. Approximately a quarter had previously undergone angiography, with a number also receiving PCI. The vast majority presented with chest pain as their initial complaint.

Most patients randomized to CTCA underwent CTCA; a small number of those randomized to standard care also underwent CTCA within 30 days, as well. About a quarter of patients in this cohort demonstrated normal coronary arteries – a fairly surprising development considering the combination of age, risk factors, elevated troponin, and abnormal electrocardiogram necessary for inclusion. Most patients with normal coronary arteries were predictably managed by medical means alone. The remaining patients demonstrated either non-obstructive coronary disease or obstructive coronary artery disease, with concordant trends towards subsequent invasive coronary angiography.

However, after all of that, even with the added information provided by CTCA, there was no difference in mortality or non-fatal myocardial infarction at one year. Delving into the complexities of subsequent resource utilization, it was noted patients undergoing CTCA were less likely to ultimately undergo invasive coronary angiography, 54.0% vs 60.8%. Similarly, patients with the initial CTCA were less likely to undergo subsequent non-invasive testing, 19.4% vs. 26.2%. Other differences in medical or preventive management did not differ by study arm.

So, a small decrease in invasive testing counterbalanced by the large baseline investment in non-invasive testing – without any clear patient-oriented benefit on health outcomes. CTCA certainly has a role in the evaluation of patients with chest pain and possible CAD, but certainly not as a routine investigation in the ED.

“Early computed tomography coronary angiography in patients with suspected acute coronary syndrome: randomised controlled trial”
https://www.bmj.com/content/374/bmj.n2106

Why Isn’t tPA in Minor Stroke Questioned?

A couple months back, this little report – MaRISS – was published with minimal fanfare in Stroke. Considering the effort necessary to fund and conduct a prospective study, it’s rather remarkable these data are so uninformative.

The stated purpose of this study:

“The objective of this study is to describe multidimensional outcomes, identify predictors of worse outcomes, and explore the effect of thrombolysis in this population.”

Reading between the lines – and considering the study and virtually every author here are sponsored by Genentech – the hoped-for outcome was likely some observational support for the pervasive practice of treating mild stroke with alteplase. Considering all the bias of their study design, it’s actually rather surprising they were unable to do so.

To be included in MaRISS, patients with mild stroke were approached after initial treatment, within 24 hours of hospital admission. However, it is grossly obvious the vast majority of patients meeting eligibility criteria were not even approached. Their “CONSORT diagram” doesn’t actually describe their study population prior to the “consented” step of the process – meaning it only describes those patients dropping out or excluded subsequent to consent. How many patients with mild stroke were admitted to participating hospitals during the study period? How many patients were approached, but declined participation? This information is conspicuously and irresponsibly absent.

The resulting convenience sample, then, ultimately reflects the selection biases of those enrolling. For example, out of 1,765 patients included, only 3 (0.3%) developed symptomatic intracranial hemorrhage. This clearly indicates these data are flawed, as the PRISMS trial demonstrated a 3.3% rate of sICH, and even the Get With the Guidelines-Stroke registry of minor stroke shows a 1.8% rate of sICH. The authors provide the understated: “it is possible that individuals with early complication from thrombolytic treatment were not enrolled.”

Sometimes, possibilities are near certainties – and this is one of those cases.

Regardless, the authors then attempt to discern a beneficial effect of alteplase by comparing their treated (57%) and untreated (43%) final study population. Again, the bias of these authors is quite clear because they create eight different adjustment models and use mRS, Barthel Index, European Quality of Life 5 Dimensions, a Visual Analogue Scale version of stroke assessment, and the Stroke Impact Scale to create an 8 x 5 grid of tests for alteplase to display its superiority. In only one of these boxes was their model able to shake out a benefit for alteplase – and, of course, this chance finding gets escalated into the abstract with “a suggestion of efficacy was noted in the NIHSS 3–5 subgroup.” Nor was any effect on outcomes from time-to-treatment with alteplase identified.

So, an observational trial unable to obtain a representative sample nor describe a hoped-for treatment effect. What little remains is a page and a half of mostly previously-described associations of clinical features with poor functional outcomes, fractionally moving the science forward. If anything, these data ought to enhance calls for better prospective clinical trials versus placebo in minor stroke – if anyone weren’t already entrenched in their clinical opinions.

“Predictors of Outcomes in Patients With Mild Ischemic Stroke Symptoms”

https://www.ahajournals.org/doi/10.1161/STROKEAHA.120.032809

All Glory to the MSU

It has apparently become time for the mobile stroke unit to go from niche to prime-time. Previously consigned to the pages of Stroke and similar journals, the latest and most comprehensive trial now graces the pages of the New England Journal of Medicine.

A flagship study for a flagship journal. Not to mention, a positive study – almost too good to be true.

Which, of course, means it probably isn’t.

In brief, the BEST-MSU trial presented is a series of nested protocols and substudies under the umbrella of purpose to test and refine the deployment of a mobile stroke unit. Amongst its many substudies are those testing time-to-tPA administration, early administration of reversal agents for intracerebral hemorrhage, and whether an on-board neurologist can be replaced by a telemedicine neurologist. The trial design is one of those “one week on, one week off” non-randomized designs – not truly randomized, but generally hoping these temporal controls generate basically similar patient populations. The primary outcome is “utility weighted modified Rankin Scale score” at 90 days, a probably-unnecessary rejiggering of what amounts to chasing a mRS 0-1.

The clear and obvious winner: mobile stroke units, the manufacturer of which two authors are consultants. In fact, MSUs were profoundly better – 55% of modified intention-to-treat patients ultimately achieved mRS 0-1 during MSU deployment weeks, compared with only 44% of those treated during traditional EMS response weeks. This treatment effect was basically driven by an 11% absolute excess of patients achieving mRS of 0.

The dramatic enhancement of treatment provided by MSU? 97.5% of those in the MSU cohort received tPA, compared with a mere 80% in the EMS cohort – and those receiving tPA did so within 60 minutes of symptom onset for 30% of those in the MSU cohort, compared with 2.6% of those with EMS. Proponents of MSUs would point to this dramatic improvement in outcomes to be associated with such “hyperacute” stroke treatment.

And, effectively, that is the principle upon which interpretation of this trial hinges. Nearly 17% of patients in the MSU cohort analysis received a final diagnosis of “stroke reversed by tPA”, as compared to 9% in the EMS cohort. There were a few more patients in the MSU cohort whose pre-existing mRS scores were 0, as well as a small excess of NIHSS 0-5, but it’s fairly clear most of the effect size on the primary outcome is driven by those final diagnoses of “stroke reversed by tPA”. This concept of “stroke reversed by tPA” is not specifically defined anywhere in the protocol or paper, somewhat limiting appraisal, unfortunately.

The traditional definition used by neurologists for “stroke reversed by tPA”, also sometimes known as “aborted stroke”, is usually equivalent to “neuroimaging negative cerebral ischemia”. NNCI occurs when patients have resolution of clinical symptoms of stroke, yet follow-up MRI shows no diffusion-weighted imaging lesions. The tPA, therefore, has saved all the brain and there is no indication there was ever any injury. However, this concept is controversial, and both emergency physicians and neurologists believe this to be relatively rare – and that these NNCI are in fact stroke mimics whose presence in study cohorts systematically bias the outcomes.

Another clue regarding those “stroke reversed by tPA” patients comes from the BEST-MSU substudy evaluating the feasibility of teleneurology versus on-board vascular neurologist. When the vascular neurologist was on-board, only 4% were “stroke reversed by tPA”, along with 10% stroke mimics. With the teleneurologist, 26% became “stroke reversed by tPA”, along with 12% stroke mimics. The sample sizes in this substudy were small, but it does not take much imagination to hypothesize there is a diagnostic accuracy component driving the “stroke reversed by tPA” final diagnoses.

There are also various issues with their CONSORT diagram. There were 10,443 stroke alerts, with 8,928 excluded as non-stroke, stroke with exclusions, or stroke mimics. Then, even though the time periods for enrollment were equal, the MSU cohort accumulated 886 enrollments versus 629 in the EMS cohort. This excess in enrollment accumulation in the MSU group is curious, and raises suspicions regarding the presence of a systematic bias towards study enrollment and treatment during MSU deployment weeks. The study protocol then trims down these enrollment cohorts into the modified-intention-to-treat population with a retrospective adjudication of tPA eligibility, further reducing the size of each cohort by approximately 30% – many of whom actually did receive tPA. This unbalanced, retrospectively tweaked cohort represents the mITT population for their primary analysis.

So, the final perspective on the utility of these multi-million dollar technological marvels comes down to, after minor whinging about their study population, the values in Table 5 of their Supplementary Appendix: did early tPA “reverse” strokes – or did their enthusiasm for MSU bias their cohort towards early treatment of stroke mimics?

“Prospective, Multicenter, Controlled Trial of Mobile Stroke Units”
https://www.nejm.org/doi/full/10.1056/NEJMoa2103879

Still Alive!

While the blog has become a bit sparse – owing to the demands of a new environment down in New Zealand – I’ve got plenty of new content to share.

I’m still writing bimonthly for ACEPNow:

Then, every month there’s a new Annals of Emergency Medicine Journal Club:

Finally, the Annals of Emergency Medicine Podcast is available on your choice of platform:

Enjoy!

It’s a Stroke – of the Eye?

As we are well aware, a brain globally deprived of oxygen, for even the briefest moments, suffers irreversible damage. Cerebrovascular events, those depriving a smaller distribution of the brain of oxygen, do so likewise – excepting the potential for recovery provided by the so-called “ischemic penumbra”. There is great heterogeneity between stroke syndromes and potential for recovery, but perfusion- and tissue-based treatments quite clearly demonstrate some protective effect of collateral circulation.

Does the eye work like that? That is the working theory – or, at least, working wishes and hopes of the neurology and neuro-ophthalmology community.

There is typically only one blood vessel supplying the inner retina – the central retinal artery. If this vessel becomes occluded, widespread ischemia is inevitable. The outer retina is supplied by the choriocapilaris, derived from separate branches of the ophthalmic artery. A further, non-trivial percentage of individuals have a cilioretinal artery, supplying a part of the macula. These other vessels may provide some additional perfusion to parts of the eye, with intact survival approaching 90 minutes in animal studies. Widespread, irreversible damage seems complete by four hours.

So, is there a window of opportunity for early thrombolysis? The American Heart Association thinks so: “The current literature suggests that treatment with intravenous tissue plasminogen activator may be effective.”

This “current literature” of which they speak is primarily a citation from last year’s Stroke, a single-center cohort study and updated patient-level meta-analysis. In the “cohort” portion, this site treated 16 patients with CRAO with alteplase within 4.5 hours, and compared them with 87 others who received “Standard of Care”. Patients in this treatment cohort did better than those who were not – hardly surprising, considering those treated had fewer signs of damage to the retina on initial fundoscopic examination.

The “patient-level meta-analysis” includes 238 patients from studies dating back to the 1980s. The 9 patients for whom treatment was provided within 90 minutes displayed better outcomes than those treated in later time windows, as well as those patients whose outcomes describe the “natural history” of the disease. The guideline authors’ interpretation of these data: “An updated meta-analysis including these modern cohorts again demonstrated a strong effect with treatment within 4.5 hours.”

Little heed is paid to the 5 patients within their meta-analysis reported as having intracranial hemorrhage, 1 with angioedema, and 1 with extracranial hemorrhage.

CRAO is devastating, and there is no known effective treatment. Thrombolysis may be beneficial, but treatment is associated with well-established harms. Along with all the stroke mimics and low-NIHSS patients currently being treated, it’s not surprising these authors contort themselves into recommendations overstating the strength of the evidence. Clinical trials are underway – wait and see.

“Management of Central Retinal Artery Occlusion”
https://www.ahajournals.org/doi/pdf/10.1161/STR.0000000000000366

“Intravenous Fibrinolysis for Central Retinal Artery Occlusion”
https://www.ahajournals.org/doi/10.1161/STROKEAHA.119.028743

Minor Stroke is Our Favorite Stroke

While most facilities are using non-contrast CT, CT angiograms, and/or CT perfusion as part of their initial triage of possible stroke, there are a few using rapid MRI-based protocols. MRI is vastly superior to CT for its specificity for stroke, quite useful in reducing early diagnostic closure and unnecessary treatment with thrombolytics.

One of these MRI-based stroke systems has published a brief, retrospective look at their tPA cohort – focusing, in this report, on the particularly controversial “minor stroke”. Specifically, they teased out patients with presenting NIHSS 0-6, tried to classify them as “clearly disabling”, “potential disabling”, and “non-disabling”. Then, they looked at 90-day outcomes from these groups, trying to discern any useful conclusions regarding the efficacy and safety of tPA in these patients.

Over the 2015-17 study period, there were 1,440 patients evaluated for potential stroke treatment. Of these, 792 fell into their “minor stroke” definition – only 255 of which received a provisional diagnosis of acute ischemic stroke. The remainder were diagnosed as stroke mimics, transient ischemic attacks, or intracranial hemorrhage. Of these 255, about 80% were able to be evaluated with MRI as their primary mode of evaluation, and about 3/5ths were treated with tPA. Ultimately, they end up with 119 patients in their primary comparison, looking at features and outcomes of 30 patients with “clearly disabling” deficits and 89 without.

How effective is tPA in this cohort? Who knows! This study doesn’t answer that question in the slightest. There is no untreated population with 90-day outcomes gathered for comparison. The authors mostly use this study to tout MRI-based screening technology, along with descriptive statistics of frequent perfusion abnormalities present in their untreated cohort. The general gist of their discussion is akin to the oculostenotic reflex in cardiac catheterization – if a stenosis is seen, it will be treated, regardless of known benefit. For using MRI to screen for stroke, they tend to wax optimistically the identification of these perfusion abnormalities in non-disabling strokes might better encourage acute treatment.

This ought to be considered nonsense, as tPA treatment of non-disabling strokes remains bereft of evidence of value. And, just to describe the scope of the problem – of the 305 patients treated with IV tPA, 75 did not have “clearly disabling” deficits. A full quarter of the tPA treatment population based on wishes and hopes! There was one upside to screening with MRI, at least: 454 of those 792 with “minor stroke” received a diagnosis of stroke mimic. I shudder to think of the unnecessary carnage at hospitals without the capacity to exclude stroke mimics with such ease.

Non-disabling stroke should never be treated with thrombolysis in clinical practice, not after PRISMS, nor after looking at the NIHSS 0-5 group in IST-3. The new European Stroke Organization guidelines recommend against thrombolysis. Just stop!

“Prevalence of Imaging Targets in Patients with Minor Stroke Select for IV tPA Treatment Using MRI”
https://n.neurology.org/content/96/9/e1301

Antibiotics, With or Without Delay!

This is a trial addressing a practice to which I’m not opposed, and recommended by some other experts: delayed antibiotic prescribing. Delayed prescribing, providing patients with an antibiotic to fill “just in case they get worse”, has seemingly reasonable fundamental components. An encounter with a patient is a single snapshot in time, frequently without a clear picture of the ongoing clinical course. Early bacterial illness may not be clearly apparent as infection, with subsequent days bringing the diagnosis into clearer focus. In the interests of respecting patients’ time and healthcare resource utilization, why not provide a provisional antibiotic prescription to be filled by the patient if they self-assess clinical worsening?

This specific delayed antibiotic prescribing trial was performed in children presenting with an acute, uncomplicated respiratory infection – which, by their inclusion criteria included acute otitis media, pharyngitis, rhinosinusitis, or acute bronchitis. These authors randomized 436 children to one of three arms: immediate antibiotics, delayed antibiotics, or no antibiotics. Parents whose children were enrolled in the delayed antibiotics arm were instructed to start the antibiotic if their children worsened or did not start feeling better within a few days to weeks, depending on the underlying illness at time of enrollment. The primary outcome for the trial was severity and duration of acute symptoms over the following month.

The good news – the trial was a “success”. Children randomized to the delayed antibiotics strategy reported similar numbers of symptom days as those randomized to the immediate antibiotics arm. Whether it was pharyngitis, otitis media, rhinosinusitis or bronchitis, children remained symptomatic – for 4 to 10 days – regardless of their treatment arm. Delayed antibiotic prescribing, then, was not clinically harmful with respect to the primary illness.

With respect to antibiotic use and adverse effects, within 30 days of enrolment nearly the entire immediate antibiotic arm used their prescriptions. In contrast, only 25% of those randomized to delayed antibiotics did so, along with 12% of those who had no antibiotic prescribed. As to be expected, those with fewer antibiotic exposures suffered fewer gastrointestinal side effects. Unscheduled primary care utilization was uncommon and similar across all treatment groups.

So, “success”!

Except for that other niggling, less-heralded study arm: the no antibiotics arm.

The authors conclude by saying “DAP compared to IAP led to greatly reduced antibiotic use and fewer gastrointestinal adverse effects associated with antibiotic intake.” While this is not untrue, the actual final conclusion might more appropriately be: “No practical advice can be provided regarding the appropriateness of a delayed antibiotic strategy, as this trial best demonstrates the no antibiotic strategy most likely the best choice.”

The entire premise of a delayed strategy is, in the context of clinical uncertainty, there is a substantial likelihood the underlying illness will ultimately require antibiotics for successful resolution. In this trial, the authors have selected a scenario where that is not the case – and, therefore, haven’t produced terribly generalizable information regarding delayed antibiotic prescribing strategies.

The authors have, at least, provided some useful insight into human behavior with respect to delayed antibiotics and the rate at which they are filled. But, mostly, they have best demonstrated, yet again, the vast majority of children evaluated for respiratory illnesses are best treated with supportive care and time, rather than antibiotics.

“Delayed Antibiotic Prescription for Children With Respiratory Infections: A Randomized Trial”
https://pediatrics.aappublications.org/content/early/2021/02/09/peds.2020-1323

APPAC II

The original APPAC was one of the first trials systematically testing an antibiotics-first strategy for appendicitis, demonstrating its feasibly and safety as an alternative to immediate surgery. Based on these and other data, reasonable differences of opinion exists regarding the favored approach. In Finland, however, where the original APPAC was performed, they’ve already moved on from the “if” question and onto “how best”.

In APPAC II, the “how best” question involves whether the initial treatment for uncomplicated appendicitis (no perforation, appendicolith, or tumor) need be intravenous, or whether a completely oral antibiotic strategy is noninferior. The intravenous strategy was comprised of two days of ertapenem, followed by five days of levofloxacin plus metronidazole, while the oral strategy was comprised of seven days of moxifloxacin monotherapy. All patients were hospitalized for observation for at least 20 hours, the minimum time necessary for two doses of intravenous antibiotics. The primary endpoint was treatment success at 1 year, defined as avoidance of surgery or recurrent appendicitis.

There were approximately 300 patients enrolled in each group, based on sample size estimates derived from their non-inferiority margin of -6% and an expected success rate of 73%. At one year follow-up, the success rate for the intravenous cohort was 73%, as compared with 70% for oral antibiotics. However, this did not meet their pre-defined margin for non-inferiority, as the difference of −3.6% had a one-sided 95% CI lower bound of -9.7%. This leads us into our favorite statistical wasteland, the land of not-non-inferior, yet also not inferior, nor equivalent.

These are interesting data, and, cutting through the statistical chicanery, it is most likely the outcomes in each arm are virtually indistinguishable. It is hard to tell, however, the advantage of adopting the oral strategy, as implemented, in the face of even a small amount of potential harm. Because all patients were hospitalized and observed inititally, the oral strategy does not avoid unnecessary bed utilization. It is not clear whether this initial hospitalization could be avoided; this initial timeframe constituted the greatest percentage of treatment failures, although this can also be potentially confounded by conservative clinical judgement and readily available operative resources.

The choice of moxifloxacin monotherapy as the comparator is interesting, as it is not strictly equivalent to levofloxacin plus metronidazole with respect to its anaerobic efficacy. It is rather baffling not to simply use levofloxacin plus metronidazole as the oral therapy in each group. The authors cite several publications demonstrating the viability of moxifloxacin monotherapy for intra-abdominal infections, but it seems to muddle the comparison unnecessarily.

In the end, these represent yet another interesting permutation in the approach to the non-surgical management of appendicitis. From a pragmatic standpoint, it seems rather mooted until such data exist showing patients can be managed without hospitalization. Then, if an acute emergency department evaluation is being performed, this provides plenty of opportunity to give at least a single intravenous dose of antibiotics, if warranted, rather than hewing dogmatically to oral-only – admitting fluoroquinolones have identical oral and intravenous bioavailability. These data raise as many follow-up questions as answers, unfortunately.

Finally, tucked into this publication is an even more interesting tidbit: APPAC III. Characterizing diverticulitis as “left-sided appendicitis”, and noting the relative inessential nature of antibiotics for diverticulitis, this currently-enrolling trial tests antibiotics versus placebo for uncomplicated appendicitis. In a world where others are slow to move beyond mandatory operative intervention, this group is testing zero intervention at all – fascinating!

“Effect of Oral Moxifloxacin vs Intravenous Ertapenem Plus Oral Levofloxacin for Treatment of Uncomplicated Acute Appendicitis”
https://jamanetwork.com/journals/jama/fullarticle/2775227

Whirlwind COVID-19 Therapy Tour

Just a brief post collating some of the high-level evidence on therapies approved or under investigation for COVID-19. I’d written this up for another audience, and it could be obsolete as soon as I post – and hopefully mooted in just a few months!

Hydroxychloroquine:
No. What a farce.
https://www.nejm.org/doi/full/10.1056/NEJMoa2022926
https://www.nejm.org/doi/full/10.1056/NEJMoa2021801
https://www.nejm.org/doi/full/10.1056/NEJMoa2016638
https://www.nejm.org/doi/full/10.1056/nejmoa2019014

Remdesivir:
A controversial repurposing of an antiviral previously trialled against ebola. Consistent benefits have been difficult to replicate. ACTT-1 in the U.S. showed a small length-of-stay and mortality benefit, but SOLIDARITY by the WHO found none.
https://www.nejm.org/doi/full/10.1056/NEJMoa2007764
https://www.medrxiv.org/content/10.1101/2020.10.15.20209817v1

Dexamethasone:
The best reliable evidence for benefit so far, with face validity in treating inflammation-mediated lung disfunction. For “moderate to severe” COVID-19, which is effectively anyone with hypoxia requiring supplemental oxygen.
https://www.nejm.org/doi/full/10.1056/NEJMoa2021436

Convalescent plasma:
Over 250,000 people in the U.S. have been treated with plasma donated by persons recovered from COVID-19. However, minimal evidence of efficacy exists. It certainly does not work in the very ill, but is still being explored in those early in the disease process.
https://www.nejm.org/doi/full/10.1056/NEJMoa2031304

Bamlanivimab:
This is the Eli Lilly neutralizing antibody, approved for emergency use in the U.S. This is a monoclonal antibody to the SARS-CoV-2 spike protein. Interestingly, this product failed in ACTIV-3, hospitalized inpatients. The interim results leading to FDA approval are from BLAZE-1, preventing deterioration of mild disease at high-risk for progression.
https://www.fda.gov/media/143603/download

Casirivimab plus imdevimab:
This is the Regeneron “antibody cocktail” given to President Trump. These are both monoclonal antibodies to different, non-overlapping domains of the SARS-CoV-2 spike protein. These are also similarly targeted at high-risk outpatients with mild disease with the goal of preventing progression.
https://www.fda.gov/media/143892/download

JAK (Janus kinase) inhibitor:
Baricitinib is approved as second-line therapy for moderate-to-severe rheumatoid arthritis. Per FDA EUA data, this conferred mortality benefit when given in tandem with remdesivir in ACTT-2. However, few patients in this trial received steroids, limiting generalizability.
https://www.fda.gov/media/143823/download

Tocilizumab:
This is an IL-6 inhibitor currently approved for moderate-to-severe rheumatoid arthritis. Mixed results have been observed with tocilizumab, and current use is primarily as a salvage in the mechanically ventilated. However, there is not much face validity for its effectiveness when added to dexamethasone.
https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2772187
https://www.nejm.org/doi/full/10.1056/NEJMoa2028836

Ivermectin:
Antiparasitic agent theorized to reduce severity of COVID-19 through inhibition of viral protein transport. Widely used in the developing world due to its availability and low cost; virtually no useful data available.
https://journal.chestnet.org/article/S0012-3692(20)34898-4/fulltext
https://www.researchsquare.com/article/rs-109670/v1

Lopinavir and rotonavir:
Antiviral combination therapy typically used for HIV-1. No clinical benefit detected in the RECOVERY trial, and adverse effects led to discontinuation in other trials.
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)32013-4/fulltext
https://www.nejm.org/doi/full/10.1056/NEJMoa2001282

The NIH also features fairly good tables of agents under ongoing evaluation, if you’re interested in seeing more extensive summaries of evidence for each:
https://www.covid19treatmentguidelines.nih.gov/tables/table-2/
https://www.covid19treatmentguidelines.nih.gov/tables/table-3a/

The Futility of Mask Wearing?

The parade of COVID-19 papers is relentless enough (fluvoxamine, anyone?) it’s almost impossible to try and keep up, but this one is a little different. This trial, rather than just another inflammatory mediator striving for its day in the sun, tries to inform something we can all do every day: wear a mask.

So, this is the mask trial everyone’s been talking about – in which 4,862 patients completed a study where the intervention arm was given 50 masks and asked to wear them outside the home. The primary outcome at 1 month was SARS-CoV-2 infection, as measured by seroconversion, PCR, or hospital clinical diagnosis.

At the end of the day, this was a “negative” trial – there was no statistically significant difference in SARS-CoV-2 infection between the mask (1.8%) and control (2.1%) participants. C’est la vie.

While the findings of this trial are being covered by news outlets in a variety of ways, the more important takeaways from this research are what it does not show:

  • It does not show masks are ineffective for preventing the wearer from becoming infected with SARS-CoV-2. The 95% confidence interval for the between group difference is -1.2 to 0.4 percentage points. This can be strictly interpreted, in a frequentist sense, to indicate a range of possible true effect sizes from this study. Most of these true effect sizes favor the intervention, but, most likely not to the effect size meeting the authors’ definition of a clinically meaningful difference.
  • It does not have invalid results because of imperfect adherence with mask use. Research results need to be applicable to the world in which we live. A pragmatic trial taking into account individual behaviors reflects (and likely even overstates) their typical real-world use, and this can greatly inform public policy.
  • It does not, finally, inform any aspect of current mask recommendations, which are designed, primarily, to prevent the wearer from spreading infection. This is why surgeons wear masks while operating – it isn’t for their own protection, but for the patient.

There are also additional points to make regarding the right censoring of outcomes. Patients received their final testing kits at one month, but sensitivity limitations inherent to both PCR and lateral flow immunoassays could have missed infections present at time of final testing. This would have the effect of attenuating the observed effect size. Other limitations of these tests are clearly applicable, but their inaccuracies ought to be evenly distributed between groups. Many others have also pointed out issues with study attrition, and its inevitable effect on outcomes.

Lastly, a fair bit of discussion on Twitter pertains to whether this study ought to have been published at all, considering it may be disseminated with headlines lacking the nuance of the study findings. I certainly do not have a problem with letting light shine upon data, and it being the responsibility of authors and editors to educate through their contextual presentation. I would also go as far to say if this trial had been clearly positive (instead of just inconclusive based on their sample and power), it would have been potentially a strong motivator for mask use. We should be wary of the scientific harms of publication bias and encourage the completion and dissemination of “negative” studies.

“Effectiveness of Adding a Mask Recommendation to Other Public Health Measures to Prevent SARS-CoV-2 Infection in Danish Mask Wearers: A Randomized Controlled Trial”
https://www.acpjournals.org/doi/10.7326/M20-6817