Category: Medication Safety

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

Back Pain is a Pain

The authors’ bottom line:

“Adding baclofen, metaxalone, or tizanidine to ibuprofen does not appear to improve functioning or pain any more than placebo plus ibuprofen by 1 week after an ED visit for acute low back pain.”

There were 320 patients with atraumatic back pain randomized to one of four arms in a 1:1:1:1 manner at two urban Emergency Departments, with follow-up one week later. As noted above, the differences in improvement on the Roland-Morris Disability Questionnaire were similarly scattershot across groups. The waterfall graph probably shows this best:

Notes:

  • The prescribed dose of ibuprofen was only 600mg every eight hours. I’m more a 500mg naproxen twice daily sort of guy, but this wouldn’t necessarily obscure differences between groups.
  • Half of patients continued to complain of back pain at seven days, including a third for whom it was moderate or severe.
  • Adverse events were rare in all groups.

Pretty dismal and disappointing, as so many of our patients in the ED are coming in because they’re already taking some over-the-counter analgesic without perceived relief. There is clearly an unmet need for something to fill the void, hence our attempted use of all these unproven adjuncts. Unfortunately, these folks are stuck – it’s going to be 2-3 days until they will be able to return to their usual activities, if not more, and none of these are adding any value.

“A Randomized, Placebo-Controlled Trial of Ibuprofen Plus Metaxalone, Tizanidine, or Baclofen for Acute Low Back Pain”

https://www.ncbi.nlm.nih.gov/pubmed/30955985

OK, Google: Discharge My Patient

Within my electronic health record, I have standardized discharge instructions in many languages. Many of these, I can read or edit with some fluency – such as Spanish – and those of which I have no facility whatsoever – such at Vietnamese. These function adequately for general reading material regarding any specific diagnosis made in the Emergency Department.

However, frequently, additional free text clarification is necessary regarding a treatment plan – whether it be time until suture removal, specifics about follow-up, or clarifications relevant to an individual patient. This level of language art is beyond my capacity in Spanish, let alone any sort of logographic or morphographic writing.

These authors performed a simple study in which they processed 100 free-text Emergency Department discharge instructions through the Google Translate blender to produce Spanish- and Chinese-language editions. The accuracy of the Spanish translation was 92%, as measured by the number of sentences preserving meaning and readability. Chinese fared less well, at 81%. Finally, authors assessed the errors for clinically relevant and potential harm – and found 2% of Spanish instructions and 8% of Chinese met their criteria.

Of course, there are a couple potential strategies to mitigate these potential issues – including back-translating the text from the foreign language back into English, as they did as part of these methods, or spending time verbally confirming the clarity of the written instructions with the patient. Instructions can also be improved prior to instruction by avoiding abbreviations and utilizing simple sentence structures.

Imperfect as they may be, using a translation tool is still likely better than giving no written instruction at all.

“Assessing the Use of Google Translate for Spanish and Chinese Translations of Emergency Department Discharge Instructions”
https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2725080

More Bad News for Influenza Antivirals

Deep in the throes of influenza season, I’m sure the oseltamivir is flying off the shelves around the country. In Japan, however, it’s baloxavir that’s flying off the shelves. Unfortunately, as was presaged by the data from their definitive clinical trial, resistance to baloxavir is rapidly increasing.

And, now, tucked into this retrospective look at “early” versus “late” oseltamivir treatment in the critically ill – additional data regarding its general futility. In this 1,330 patient ICU cohort of patients who received osteltamivir within 48 hours of symptom onset (“early”) or later (“late”), overall mortality was 46.8% – and no different between the two groups. There are obvious issues here with regards to confounding and baseline differences, but it should be apparent a beneficial treatment … provides some benefit.

The authors did observe an absolute 10% survival advantage associated with “early” treatment in those infected with A/H3N2 – but as this accounted for a minority of their cases, overall, the entire cohort was a wash. This is consistent with another review specific to data from the 2009A/H1N1 pandemic. Mortality in included studies was only 8%, but no survival advantage was seen in those treated with oseltamivir. While universal and indiscriminate treatment with neuraminidase inhibitors is engrained in the conflict-of-interest-infested IDSA guidelines, one can only hope these data points encourage additional prospective evaluation into the true narrow value of our tools for the treatment of influenza.

“Effect of early oseltamivir treatment on mortality in critically ill patients with different types of influenza: a multi-season cohort study”

https://www.ncbi.nlm.nih.gov/pubmed/30753349