WOMAN-2: What Does the Robot Say?

Following on the success of Toy Story 2, Inside Out 2, and Avatar 2, we have WOMAN-2, yet another trial featuring emergency medicine’s third-favorite medication: tranexamic acid. However, where those sequels succeeded, WOMAN-2 is more like Miss Congeniality 2 – the one we’re not going to talk about again.

But, don’t take it from me – take it from the ChatGPT Agent I created!

The WOMAN-2 trial serves as a benchmark for evaluating interventions targeting postpartum hemorrhage (PPH) in women with anemia, but it underscores the challenges of translating promising pharmacological hypotheses into clinical practice. The study meticulously implemented randomization and blinding protocols, ensuring that biases from enrolment and allocation processes were minimized. Baseline characteristics were well-matched, providing a solid foundation for evaluating the intervention’s effect.

However, the trial’s design reveals critical limitations that may have compromised its ability to detect meaningful clinical benefits. The reliance on clinical judgment rather than standardized measurement tools for diagnosing PPH introduces variability, potentially diluting the observed treatment effect. Furthermore, the timing of tranexamic acid administration—after cord clamping—raises questions about its pharmacological plausibility in rapidly evolving hemorrhagic scenarios. Subgroup analyses suggest the intervention’s effect may differ in high-risk populations, such as those with antepartum hemorrhage, but the evidence is inconclusive.

The null findings for both primary and secondary outcomes should prompt reflection on trial methodology and clinical priorities. The absence of adverse events is reassuring, yet the lack of demonstrable efficacy highlights the complexity of addressing PPH in anemic populations. A focus on earlier interventions and systemic prevention of anemia may hold greater promise. Additionally, future trials should prioritize precision in outcome measurement and incorporate emerging technologies to minimize subjective assessment variability.

While the study’s funding sources were disclosed transparently, the authors’ broader involvement in tranexamic acid research warrants attention to ensure interpretations remain unbiased. Overall, the WOMAN-2 trial reinforces the urgency of optimizing anemia management and refining therapeutic strategies for PPH, underscoring the need for innovation in both clinical practice and research methodologies.

Well, there you have it – unbiased evaluation by the robot, featuring that bland robotic voice common to all its very average, very “correct” output. Interestingly, it can be trained and/or instructed to copy your writing “style”, and the output is grossly similar – but with an added layer of tryhard treacle slathered upon it.

In my brief experimentations with the Agent, it seems clear the augmentation feasible does not include writing – at least, enjoyable writing. It is superficially very competent at enumerating questions from a template, however, such as study population, primary outcomes, and specific sources of bias. For example, this agent actually executes the ROB2 questionnaire on an RCT before using that output as the foundation for its summary paragraphs. Probably good enough to give an “at a glance” summarization, but not nearly sufficient to put the research into context.

Agent aside, we’re here because WOMAN-2 is the sequel, obviously, to WOMAN – a “positive” trial, also “negative”. In WOMAN, it was positive for the endpoint of post-partum hemorrhage and death due to bleeding, but negative for the patient-oriented outcomes of overall mortality. Here in WOMAN-2, the small effect size previously seen in WOMAN has entirely vanished, leading to further questions. Where TXA seems to be most effective are instances in which it is given early – and subsequent trials “I’M Woman” and “WOMAN-3” will address these possibilities. The other possibility is, such as with gastrointestinal bleeding, certain clinical scenarios feature specific fibrinolytic activation pathways where the mild effect of TXA simply can’t move the needle.

So, nothing here changes what most of us do in the modern world – and those who have Bayesian ideas regarding the efficacy of TXA are likely going to keep using it in sub-Saharan Africa. If you are going to keep using TXA routinely, use it early and in the highest-risk populations – as the likelihood of a clinically meaningful benefit will otherwise disappear like a whisper in the wind.

“The effect of tranexamic acid on postpartum bleeding in women with moderate and severe anaemia (WOMAN-2): an international, randomised, double-blind, placebo-controlled trial”

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(24)01749-5/fulltext

In: Dexamethasone, Out: Prednisone

Move over ketamine and TXA, there’s another medication gradually approaching do-it-all darling status in Emergency Medicine: dexamethasone.

Sore throats?

Croup?

Headaches?

Non-specific aches?

Well, yes to all of the above, in the appropriate clinical context –

But, most prominently, as featured in this brief report, for asthma – particularly childhood asthma.

It’s NHAMCS – so it is representative data being transformed into rough weighted estimates – between 2010-2021, but we see its use increasing from 3.5% of asthma visits to 17.3% – and the rates are over double that in children.

A heartening trend for a simpler administration and adherence strategy – and non-inferior, overall, while entirely reasonable to judiciously select a higher-risk patient in whom it might be plausible to prescribe prednisone/prednisolone instead.

“Trends in dexamethasone treatment for asthma in U.S. emergency departments”
https://onlinelibrary.wiley.com/doi/full/10.1111/acem.14997

The Andexxa Showpiece

Every so often a masterclass performance arises in the medical literature. A performance transcending the boundaries of what was once thought possible. A shining exemplar of human achievement.

This is a trial, published in the New England Journal of Medicine, with the following features:

  • Conducted by an institute sponsored by pharma.
  • Designed by the first author, a consultant for pharma, and two employees of pharma.
  • Written by a medical writer employed by pharma.
  • Replete with authors reporting multiple financial conflicts of interest with pharma.
  • Substantially modified trial procedures and outcomes two and three years into the trial.
  • Introduced an interim stopping rule whose analysis was performed by an unblinded statistician affiliated with the funded institute.
  • Stopped the trial early based on the new interim stopping rule.
  • Used a surrogate composite primary endpoint.
  • Allowed the “usual care” arm to include patients who did not receive an active treatment comparator.
  • Permitted discrepancies in the baseline characteristics favoring the experimental arm.

And, this is solely the reported mechanisms by which pharma has placed their hands on the scales of this trial. It ought to be quite clear these procedures were carefully designed to ensure the (financial) success of this trial, and its ultimate publication is virtually an advertorial for the product in question.

The culprit this go-around? AstraZeneca née Alexion née Portola for Andexxa – better known as “andexanet alfa” (even though the FDA declined their drug naming for this label, properly known as “Coagulation Factor Xa [Recombinant], Inactivated-zhzo”). The trial is ANNEXA-I, which purports to be a comparison between Andexxa and Prothrombin Concentrate Complexes.

As alluded to above, this trial was not designed to permit Andexxa to fail. With Andexxa sales climbing and approaching $200M annually, it is obviously impermissible to allow a trial to offer a hint of doubt – especially considering Portola/Alexion/AstraZeneca have been investing in “expert guidelines” aimed at elevating Andexxa above PCCs as first-line treatment for Factor Xa-associated bleeding.

So – naturally, Andexxa “succeeds”. On the composite endpoint of “good hemostatic efficacy” – hematoma volume change < 35%, NIHSS change < 7 points, and no use of rescue therapy between 3-12 hours – Andexxa outperformed “usual care” by 13.4%, 67.0% to 53.1%. The primary limiting factor to this composite endpoint was the sub-endpoint of hematoma volume change of < 35%. And, as this composite favours Andexxa, the trial was stopped early – and the favorable press releases roll in. Ideally, this is the point at which our sponsors would like us to stop further analysis and critique.

Interestingly, the main paper presents an efficacy analysis consisting of 452 patients. However, between the initiation of the interim analysis and cessation of trial procedures, the authors enrolled an additional 78 patients. The authors report findings from all 530 in their safety analysis, but exclude them from the primary efficacy analysis – consigning the full cohort analysis to a supplementary appendix. There is no obvious reason to do so – other than the fact the larger cohort demonstrates less favorable results for Andexxa, with the hemostatic efficacy composite dropping from 67.0% to 63.9%. As is frequently cautioned regarding stopping trials early, doing so inflates the confidence intervals, diminishes the precision of an effect size estimate, and precludes the natural propensity of regression to the mean.

Then, there are the trial procedures. Prior to a protocol amendment excluding subdural hematomas, the Andexxa group included 13 patients with SDH, as compared with only 4 in “usual care”. Subdural hematomas, generally speaking, have far less sinister an outcome than intracerebral hemorrhage – an imbalance favoring the Andexxa cohort. Then, bizarrely, only 85% of the “usual care” cohort received anticoagulation reversal using PCCs. Very little data is included regarding these 60 patients receiving “non-PCC” care at the discretion of their treating clinicians. What sort of selection bias led clinicians to withhold an active treatment for ICH? Without concrete data, it is impossible to do more than speculate, but it seems logical to theorize these patients must have been disadvantaged by their lack of treatment.

Next, there are The Downsides. Treatment with Andexxa very clearly causes increased arterial thrombotic events. Ischemic strokes occurred in 6.5% of those treated with Andexxa, as compared to 1.5% receiving “usual care”. Myocardial infarctions occurred in 4.2% of those treated with Andexxa, as compared to 1.5% of those receiving “usual care”. A smaller excess of pulmonary embolism was seen in the “usual care” arm, however.

Lastly, there are the patient-oriented outcomes. Naturally, with a trial stopped early due to a composite surrogate, the authors are quick to mention the trial is underpowered to evaluate these endpoints. However, the overall outcomes of patients included in this trial are grim – and they are more grim for those treated with Andexxa. At 30 days, only 28% of patients treated with Andexxa achieved a modified Rankin scale of 0 to 3, compared with 31% in the “usual care” cohort. Similarly, 27.8% of patients treated with Andexxa had died at 30 days, as compared with 25.5% of those receiving “usual care”.

So, there you have it – such a “success” story of a trial it needed to be stopped early, and we still have no clear evidence Andexxa ought to be favored over “usual care”. The authors merrily cite INTERACT1, the trial upon which the “hematoma growth” surrogate is “validated” – and they will rely on this heavily for marketing purposes. In the end, we have exactly what we ought to have expected from a trial designed to stand on its head to deliver for its product, and we as clinicians are ever-poorer for it.

Andexanet for Factor Xa Inhibitor-Associated Acute Intracerebral Hemorrhage

Don’t Use Lytics in Mild Stroke, Part 3

Well, PRISMS demonstrated unfavorable results.

MARISS tried to ascertain predictors of poor outcome in mild stroke, and intravenous thrombolysis was not associated with an effect on the primary outcome.

Now, again, we examine thrombolysis in “mild” stroke, in this case, NIHSS ≤3 – and fail.

Like MARISS, this is a retrospective dredge of patients selected by the treating clinicians to receive either intravenous thrombolysis or, in this case, dual-antiplatelet therapy with clopidogrel and aspirin. The population included for analysis is the Austrian Stroke Unit Registry from 2018 until 2019, an original cohort of 53,899 patients. Of these, 29,252 were NIHSS ≤3, but exclusions meant nearly 25,000 were left out – primarily those whose strokes were the result of atrial fibrillation, or whose treating clinicians chose platelet monotherapy instead of dual antiplatelet therapy.

The remaining ~4,000 were analyzed both in their unadjusted cohorts, as well as propensity scored cohorts comprised of roughly 20% of the original. In the unadjusted cohorts, efficacy and safety outcomes were universally worse in those selected for thrombolysis – but, of course, were generally more severe stroke syndromes. After propensity score matching, these differences generally disappeared – except a preponderance of sICH in the thrombolysis cohort.

The authors here conclude there’s no evidence of superiority for thrombolysis in mild stroke, and their results fit broadly with those from other cohorts. It’s observational and unreliable, but it ought to be a very reasonable stance to withhold thrombolysis for mild strokes pending trials conclusively demonstrating which, if any, mild strokes do improve with thrombolysis.

IV Thrombolysis vs Early Dual Antiplatelet Therapy in Patients With Mild Noncardioembolic Ischemic Stroke

The Opiates in Back Pain Conundrum

We do love to give out opiates in the emergency department. Kidney stone? Opiates. Broken arm? Opiates. Gunshot wound? Opiates. Sore throat? Dexamethasone. And opiates.

So of course we’re here with opiates for your back pain.

In this modern day, we are far, far more judicious than in times of yore, back when pharma had lobbied for pain to become the “fifth vital sign”. But, nonetheless, those patients who are struggling to manage despite non-opiate analgesia frequently end up with some sort of small supply to try and resolve an acutely painful condition.

The OPAL trial, published in The Lancet, is yet another in a series of trials decrying the disutility of virtually anything for back pain – in the context of prior work diminishing the efficacy of skeletal muscle relaxants, as well as even acetaminophen added to ibuprofen. In this trial, patients with “acute” low back pain were prescribed an oxycodone-based opiate or matching placebo, and their functional recovery was assessed in follow up. Unfortunately, no advantage was seen for patients randomized to oxycodone, while there were small, but likely real, risks for opiate misuse at later intervals.

However, does this trial apply to the emergency department?

  • Patients were eligible if they had low back pain for up to 3 months. This is not exactly “acute” – especially since early versions of the protocol excluded patients whose back pain had been ongoing for less than 2 weeks.
  • Modified-release oxycodone-naloxone was the opiate of choice in this Australian trial. The naloxone itself does not exert much influence on the analgesic effect, but the preparation itself differs from preparation used commonly in the emergency department.
  • The follow-up interval was at six weeks, a good patient-oriented timeframe for long-term clinical resolution. However, emergency department treatment tends to choose opiate analgesia with the goal of short-term mobilization and return to activity, so 48- or 72- hour relief or functioning may be more relevant.

The most notable problem with this trial is not, in fact, the trial itself. Rather, the issue remains the paucity of true short-term data regarding any added benefit for the minimally effective quantity of opiates usually dispensed from the emergency department. Spring into action, team!

“Opioid analgesia for acute low back pain and neck pain (the OPAL trial): a randomised placebo-controlled trial”

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

Settling the Thrombolysis Before Thrombectomy Question

… taking a quick break from combating misinformation in our age of public health emergency to note this important non-COVID-19 article from the New England Journal of Medicine. Today’s question: is alteplase necessary prior to endovascular thrombectomy in acute ischemic stroke?

“It depends”.

This isn’t the first study to hit the light of day, but the largest. Previously, the “Randomized Study of Endovascular Therapy with Versus Without Intravenous Tissue Plasminogen Activator in Acute Stroke with ICA and M1 Occlusion (SKIP)” was presented at the International Stroke Conference earlier this year. Their study enrolled 204 patients and found no clinically important differences, particularly with respect to their primary outcome of mRS 0-2. Symptomatic intracranial hemorrhage was increased by a couple percent in those with bridging therapy, and there was a small excess of deaths – but, of course, none of these were “statistically significant”.

This study is three times the size, with 656 enrolled. Specifically, these are patients with large-vessel, anterior circulation occlusions for whom treatment can be initiated within 4.5 hours – the role for which alteplase is currently enshrined in the guidelines. And, these results are remarkably consistent with the prior observations. The mRS scores were, again, virtually identical. There was, again, an 2% absolute increase in sICH favoring the direct to endovascular therapy group, likely contributing to an observed ~1% excess deaths in the alteplase cohort.

The only element in “favor” of alteplase bridging is the surrogate outcome of successful reperfusion. There was a 4.6% excess of successful reperfusion before thrombectomy in the alteplase cohort, an advantage maintained to final angiographic recanalization at 24-72 hours. However, this small difference simply has minimal reliable effect on clinical outcomes – reperfusion is not synonymous with tissue salvage.

The net result of these observations ought to be the exclusion of thrombolytic therapy prior to endovascular intervention for those patients with immediate catheterization lab availability. Many patients, however, have prolonged transport times prior to endovascular intervention, and this study does not address this situation. However, prior studies likely demonstrate tenecteplase is more effective at obtaining early reperfusion in patients with large vessel occlusion, and probably should be the thrombolytic of choice in a “drip and ship” situation – if not all situations.

At this point, at least, the onus ought to rather be on proving clinical advantage to alteplase/tenecteplase prior to endovascular intevention. Given the consistent costs and harms of thrombolytic therapy, it is time to prove its value, rather than the converse.

“Endovascular Thrombectomy with or without Intravenous Alteplase in Acute Stroke”
https://www.nejm.org/doi/full/10.1056/NEJMoa2001123

Let’s Sell Andexxa

Have you heard the Good News (from Portola) about andexanet?

It’s an ever-changing landscape of anticoagulants and reversal agents in the Emergency Department – though, it’s not so much as a whirlwind as it is a creeping ooze. The latest developments have all been covered ad nauseum over the past few years – dabigatran, idarucizumab, factor Xa inhibitors, and coagulation factor Xa (recombinant) inactivated-zhzo (andexanet alfa). This final product, trade name Andexxa, has generally been held in a dim view over the past year by many, including yours truly, Rebel EM, the Skeptic’s Guide to Emergency Medicine, EmCrit, first10EM, the American Society of Hematology, and both the European Medicines Agency and the Food and Drug Administration’s own clinical reviewers.

There is, however, a competing viewpoint in which Andexxa is Tier 1 therapy for treatment of major bleeding in the context of of direct Xa inhibitor use – such as this recent “Recommendations of a Multidisciplinary Expert Panel” piece in Annals of Emergency Medicine. What aspect of their review differs so greatly in their affinity for Andexxa?

The expert panel meeting was convened with funds from unrestricted educational grants from Portola Pharmaceuticals and Boehringer Ingelheim to the American College of Emergency Physicians.

And, to no great surprise, the convened panel reflects the funding source:

Dr. Baugh has worked as a consultant for Janssen Pharmaceuticals and previously received research funding from Janssen Pharmaceuticals and Boehringer Ingelheim as a coinvestigator. Dr. Cornutt has received speaker’s fees from Boehringer Ingelheim. Dr. Wilson has worked as a consultant for Janssen Pharmaceuticals, Boehringer Ingelheim, BMS/Pfizer Pharmaceuticals, and Portola Pharmaceuticals, and has also received research funding from them. Dr. Mahan has served on the speaker’s bureau and as a consultant for Boehringer Ingelheim, Janssen Pharma, Portola Pharma, and BMS/Pfizer and as a consultant to Daiichi-Sankyo, WebMD/Medscape, and Pharmacy Times/American Journal of Managed Care. Dr. Pollack is a scientific consultant to Boehringer Ingelheim, Janssen Pharma, Portola Pharma, and BMS/Pfizer; he also received research support from Boehringer Ingelheim, Janssen Pharma, Portola Pharma, Daiichi-Sankyo, CSL Behring, and AstraZeneca. Dr. Milling’s salary is supported by a grant from the National Heart, Lung, and Blood Institute. He serves on the executive committee for the ANNEXA-4 and ANNEXA-I trials, the steering committee for the LEX-209 trial, and the publications committee for the Kcentra trials. He has received consulting fees or research funding from CSL Behring, Portola, Boehringer Ingelheim, Genentech, and Octapharma. He received speaker’s fees from Janssen. Dr. Peacock has received research grants from Abbott, Boehringer Ingelheim, Braincheck, CSL Behring, Daiichi-Sankyo, Immunarray, Janssen, Ortho Clinical Diagnostics, Portola, Relypsa, and Roche. He has served as a consultant to Abbott, AstraZeneca, Bayer, Beckman, Boehringer-Ingelheim, Ischemia Care, Dx, Immunarray, Instrument Labs, Janssen, Nabriva, Ortho Clinical Diagnostics, Relypsa, Roche, Quidel, and Siemens. He has provided expert testimony on behalf of Johnson & Johnson and has stock and ownership interests in AseptiScope Inc, Brainbox Inc, Comprehensive Research Associates LLC, Emergencies in Medicine LLC, and Ischemia DX LLC. Dr. Rosovsky has served as an advisor or consultant to Janssen, BMS, and Portola and has received institutional research support from Janssen and BMS. Dr. Sarode has served as a consultant for CSL Behring and Octapharma and advisor to Portola Pharmaceuticals. Dr. Spyropoulos is a scientific consultant to Janssen, Bayer, Boehringer Ingelheim, Portola, and the ATLAS Group; he also has received research support from Janssen and Boehringer Ingelheim. Dr. Woods is a scientific consultant to Boehringer Ingelheim. Dr. Williams serves as a consultant to Janssen Pharmaceuticals, Boehringer Ingelheim, and Portola Pharmaceuticals.

This work is effectively an advertorial, masquerading as serious academic literature, and part of a well-executed marketing and promotional campaign by the manufacturers of these drugs – particularly Portola, which is having difficulty getting Andexxa on formulary due its cost and controversial clinical data. This publication in Annals is just one of many sponsored products:

The further afield these pseudo-guidelines permeate, the more likely the product – the $25k or $50k a dose Andexxa – is incorporated into hospital formularies and local practice. These also have implications for risk-management assessments, in which the costs – passed along to the patient or payor – are far outweighed by the potential liability of a decision to make the drug unavailable for treatment.

It should be clear from all the non-conflicted opinion the role of Andexxa is yet to be clearly established, with true RCT evidence unfortunately years away. To state otherwise – and to make Tier 1 recommendations – is simply misleading.

“Anticoagulant Reversal Strategies in the Emergency Department Setting: Recommendations of a Multidisciplinary Expert Panel”
https://www.annemergmed.com/article/S0196-0644(19)31181-3/fulltext

Counterpoint: Topical Anesthetics for Corneal Abrasions

We’ve seen a few articles recently discussing the potential utility of topical anesthetics for analgesia for corneal abrasions. The general point: there’s no consistent, modern evidence of harm, so why should we cling to older ways?

Counterpoint from the corneal specialist community: cling to old ways.

In this long correspondence, the authors detail the physiologic basis for their opposition to topical anesthetics as it relates to stimulation of endothelial growth. They follow this up with a three question survey regarding the practice, distributed to “an international community of cornea trained specialists”.

The clear winner in each of their three questions: “strongly disagree” with provision of topical anesthetics for acute corneal abrasions.

Interestingly, they also conflate these results with lack of justification for a clinical trial to further explore the safety and efficacy of such use:

“Often when there is a difference in clinical practice or clinical equipoise, there is an opportunity for a clinical trial. However, it is our hypothesis that within the ophthalmology community, there is not equipoise with respect to our practice of not prescribing topical anesthetics after traumatic corneal abrasions.”

I think it’s clear these specialists are making valid points regarding the potential for topical anesthetic abuse, but their citations hardly support their practice stance. I do agree, at least, regarding the lack of utility of clinical trials – but not because their use is so dangerous it cannot be tested. Rather, any clinical trial simply would be of low value as adverse events would be so rare it would be unlikely to reliably detect a difference between management strategies. It is clear topical anesthetic use will not be safe in all clinical situations, but it is rather more appropriate to provide guidance on the proper use of topic anesthetics than to simply ban them completely while continuing to cite the same anachronistic, limited evidence.

“Cornea Specialists Do Not Recommend Routine Usage of Topical Anesthetics for Corneal Abrasions”
https://www.ncbi.nlm.nih.gov/pubmed/31445551

Add Clopidogrel to Aspirin, Temporarily

In the Emergency Department, we’re not necessarily spending a lot of our time sending home patients with minor stroke or high-risk transient ischemic attack – or, even if we are, we’re usually not doing it independently. That said, our scope of practice always seems to be expanding, observation units are frequently run by emergency physicians, and hospitals are looking to take advantage of opportunities to discharge patients rather than admit.

Regardless, this is a meta-analysis supporting the findings of CHANCE, looking specifically at the short-term use of aspirin and clopidogrel after a minor stroke or high-risk TIA. CHANCE enrolled 5,170 patients, while this meta-analysis effectively combines these with POINT, while also tossing in the patients from FASTER.

The main takeaway here is the combination of the evidence from the long-term treatment observing it was effectively a wash between stroke prevention and bleeding complications, and the observation that stroke risk was highest immediately following the index event. A reasonable interpretation, as highlighted by the guidelines, is to use dual-antiplatelet therapy short-term after the index event. The evidence does not specifically describe the optimal duration, but anywhere between 10 and 21 days seems reasonable.

Just wanted to toss this one out there with a little more prominence, as this isn’t particularly new, but I also wouldn’t want it to be overlooked.

“Clopidogrel plus aspirin versus aspirin alone for acute minor ischaemic stroke or high risk transient ischaemic attack: systematic review and meta-analysis”
https://www.bmj.com/content/363/bmj.k5108

“Guideline: Starting dual antiplatelet therapy ≤ 24 h after high-risk TIA or minor ischemic stroke is recommended.”
https://www.ncbi.nlm.nih.gov/pubmed/30986828