Category: Medication Safety

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

Disutility, Thy Name is ANEXXA-4

About two and a half years ago, we were introduced to andexanet alfa (Andexxa), a modified recombinant form of factor Xa designed as a reversal option for factor Xa inhibitors. The mechanism of action is simple: andexanet mimics native factor Xa, providing the various Xa inhibitors (rivaroxaban, apixaban, edoxiban, betrixiban, and enoxaparin) an alternative target. When sufficient Xa inhibitor is bound to andexanet, the native version is freed to return to its normal work in hemostasis.

The problem, however, is the reversal is not durable. The half-life of andexanet is approximately 1 hour, after which point the factor Xa inhibitor levels rise and hemostasis is again impaired. This necessitates a bolus and an infusion. A bolus and infusion that costs ~$3,000 per 100mg vial – and requires 900mg for a “low dose” protocol or 1,800mg for a “high dose” protocol. And, it all vanishes to dust when the infusion completes.

The first NEJM publication regarding andexanet featured just the first 67 patients from ANNEXA-4, an open-label, single-arm descriptive study of patients given andexanet for major bleeding. Now, presented at the International Stroke Conference 2019 in Honolulu, we have the results from the full 352 patient cohort – and they’re every bit as uninspiring as the preview.

Nearly all patients were receiving rivaroxaban (half-life 7 to 13 hours) or apixaban (half-life 12 hours), with a handful on enoxaparin. As in the preview, the bolus of andexanet effectively dropped circulating levels of the factor Xa inhibitor down to negligible amounts. Again, as seen before, after cessation of the bolus, factor Xa levels returned to a level consistent with their terminal half-lives. Case in point: “At 4, 8, and 12 hours after andexanet infusion, the median value for anti–factor Xa activity was reduced from baseline by 32%, 34%, and 38%, respectively, for apixaban and by 42%, 48%, and 62%, respectively, for rivaroxaban.” This is just normal metabolism, not andexanet magic.

Death occurred in 14% of patients within 30 days, and there were thrombotic events in 10%. Hemostasis at 12 hours, their primary outcome, was 82% “in 204 of 249 patients who could be evaluated”. Specifically, they excluded a third of their population because they were effectively enrolled in error, as they met bleeding criteria but not Factor Xa inhibitor level criteria. This is similar to the idarucizumab open-label demonstration, in which many patients who were not actually coagulopathic were treated with anticoagulation reversal. This represents tremendous waste and cost.

Finally, the nail in the coffin, this admission in the abstract and the text: “Overall, there was no significant relationship between hemostatic efficacy and a reduction in anti–factor Xa activity during andexanet treatment.” The primary outcome wasn’t even correlated with their intervention!

As you can tell from the tone of this post, I am profoundly unimpressed with the value demonstrated here. There’s no evidence this is clinically useful, nor a potentially preferred strategy to use of prothrombin concentrate complexes to replete missing factor. The company and the FDA effectively admit the same:

The most important limitation of this trial is that it did not include a randomized comparison with a control group. At the time of study initiation, it was determined that a randomized, controlled trial would have logistic and ethical challenges, given the perceived risks of placebo assignment in this highly vulnerable population. However, continued use of unapproved agents, despite a lack of rigorous clinical data, has changed the equipoise for a trial. Thus, under the guidance of the FDA and as a condition of accelerated approval in the United States, the sponsor is conducting a randomized trial (ClinicalTrials.gov number, NCT03661528) that is expected to begin later this year.

I’m sure more will be made to unpack even further unfavorable details as time passes – and, until further reliable evidence can be presented, I’d pass on andexanet, as well.

“Full Study Report of Andexanet Alfa for Bleeding Associated with Factor Xa Inhibitors”

https://www.nejm.org/doi/full/10.1056/NEJMoa1814051


The Beginning of the End of Heparin for ACS?

We’ve been routinely starting anticoagulation therapy on patients diagnosed with an acute coronary syndrome for a couple decades. The evidence from the preceding era is clear – patients treated with anticoagulation plus aspirin are at much lower risk for subsequent ischemic events than those treated with aspirin alone.

However, these trials are not generalizable to most modern care for ACS. For example, the FRISC and ATACS trial discharged patients with nSTEMI or unstable angina with continued anticoagulation for weeks to months. Revascularization procedures were performed only as rescue therapy, rather than the routine early invasive strategies in use today. Dual anti-platelet and other adjunctive therapies were unavailable. So – do we actually still need the heparin?

These authors retrospectively evaluated the association between parenteral anticoagulation therapy and in-hospital death and in-hospital major bleeding. There were 6,804 patients included in their 4-year, multi-center data set, about two-thirds of whom did not receive parenteral anticoagulation prior to PCI. There were small, probably unimportant differences reported between groups, excepting one feature: time to intervention. Time to intervention was a median of 1 day in those managed without anticoagulation versus a median of 3 days in those managed with. Overall, there was no difference in in-hospital death, nor 30-day, 1-year, or 3-year death for those included in long-term follow-up. A handful of cases suffered bleeding complications, with a small absolute excess in those managed with anticoagulation.

This is neither prospective nor a randomized trial, and there could certainly be unexamined confounding baseline characteristics favoring one treatment group over the other. The authors also note bleeding complications could be ameliorated by use of fondaparinux rather than heparinoids, but this would still be moot if there is still no benefit to anticoagulation. Finally, in-hospital mortality is a fabulous patient-oriented endpoint, but it does not tell the entire story with regard to any additional morbidity potentially resulting from anticoagulation being withheld. We should not change practice based on this level of evidence, but these data should prompt further examination and potentially prospective evaluation.

“Association of Parenteral Anticoagulation Therapy With Outcomes in Chinese Patients Undergoing Percutaneous Coronary Intervention for Non–ST-Segment Elevation Acute Coronary Syndrome”

https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2719425

Dentist, Dealer?

In the Emergency Department, we appreciate all the various sources of opiates in our healthcare system. We are, after all, effectively the last-resort after-hours refill destination – and patients with dental complaints are not uncommon.

These authors performed a retrospective, claims-based analysis of adolescents and young adults with exposures to opiates via a dental provider. In this database, there were 754,002 patients with continuous enrollment during the study period, 97,462 of whom received at least one prescription for an opiate. Of these, 29,791 (30.6%) received a prescription from a dental clinician. As compared with a randomly-selected opiate non-exposed cohort, the difference between subsequent healthcare encounters with an opioid abuse-related diagnosis was profound: 5.6% of the exposed cohort, compared with 0.4% of those unexposed.

It’s the same sort of high-level analysis with vast gulfs of inference as the “Emergency Physicians Are The Problem” article in the NEJM a few months back. It has obvious face validity, however, that an exposure to a potentially dependence-forming medication can result in downstream harms. Dental providers are not obviously any greater problem than other surgical specialties, but, yes, we are all similarly responsible for appropriate prescribing practices.

I also incidentally applaud these authors for their use of absolute risk differences – it would have been all too easy to breathlessly report relative risks, considering the low prevalence of opioid-abuse among “controls”.

“Association of Opioid Prescriptions From Dental Clinicians for US Adolescents and Young Adults With Subsequent Opioid Use and Abuse”
https://jamanetwork.com/journals/jamainternalmedicine/article-abstract/2717503

New Anti-Flu, Just Like the Old Anti-Flu

Mitigating the harm of influenza pandemic is certainly an important endeavor. Despite the clinical importance, however, we’ve simply been kicking the oseltamivir can down the road for over a decade. Given the ongoing controversy over its usefulness, this is suboptimal – and winter, of course, is coming.

The newest agent to the scene is baloxavir marboxil, being developed in Japan. Baloxavir is a selective inhibitor of influenza endonuclease, rather than a neuraminidase inhibitor like oseltamivir. This recent article details the phase 2 dose-ranging study and subsequent phase 3 placebo and oseltamivir-controlled trial, CAPSTONE-1.

There were 1,436 patients enrolled in CAPSTONE-1, 1,064 of whom were ultimately confirmed to have influenza A or B. Most of the patients (~85%) had influenza A. The results are – well, “favorable”, by which I mean most likely “profitable”. Symptom duration in the infected population was attenuated by the the same length of time as oseltamivir, which in turn was about a day shorter than placebo. Various measures of viral expression were improved by baloxavir, which seemed to virtually eliminate detectable infective activity within the first 24 hours. There were a small number of extra treatment-related adverse events in the baloxavir cohort, but there were only a handful in each cohort overall, and it remains to be seen in further surveillance the true incidence.

As anyone who has been afflicted by influenza can tell you, a day’s shorter illness is no small feat.  of course, this is just a single, sponsored trial, with all the advantages to the “home team”, as it were.  Whether treatment with baloxavir can be demonstrated to decrease clinically important deterioration remains to be seen – as has been a persistent struggle for other antivirals, given the low rate of complications, overall.  Then, even with rigorous screening, a third of those treated did not have influenza.  Real-world use would almost certainly include a greater proportion of patients without influenza.  Lastly, baloxavir-treated patients were observed to develop resistance mutations in substantial numbers, leading to questions whether this medication will provide durable efficacy in widespread use.

“Baloxavir Marboxil for Uncomplicated Influenza in Adults and Adolescents”
https://www.nejm.org/doi/full/10.1056/NEJMoa1716197

Tenecteplase vs. Alteplase For … Stroke Mimics?

Bless their little hearts.

It’s almost as though this is a submission fo the IgNobel Prize, rather than a serious scientific manuscript. “How well does a medicine work when the patient doesn’t have the disease?” is basically a joke, right?

Not in the magical world of stroke neurology, replete with its array of meretricious interventions.

This is a secondary analysis of NOR-TEST, a phase III trial comparing alteplase with tenecteplase. A few folks believe tenecteplase has superior fibrinolysis to alteplase, and therefore ought to be potentially favored in acute ischemic stroke. NOR-TEST, for what it’s worth, could not detect any statistically significant difference between the two.

What is notable in this trial, of course, is the 17% rate of stroke mimics. And, this is a Very Important publication comparing the safety of these two medications when given to patients inappropriately. And, of course, there is no difference. There were three cases of intracerebral hemorrhage and three cases of extracranial bleeding, none of whom – you know – died, but were clearly all unnecessary iatrogenic injury.

Some more interesting notes, at least, from their analysis of stroke mimics. The average NIHSS in this entire study was 4, with the IQR for mimics 2-6 and for acute ischemia 2-8. There’s no useful evidence to suggest thrombolysis is superior to placebo in this sort of mild stroke cohort, but, here we are. Absent this evidence, some neurologists make an argument based on the Get With the Guidelines-Stroke registry, observing many patients with mild stroke are ultimately unable to be discharged to home due to persistent disability. In the NOR-TEST cohort of mimics, however, only 79% were assessed to have mRS 0-1 at 3 months, while their treated stroke cohort achieved mRS 0-1 only 60% of the time.  It would seem the base rate of mimic- or mild-stroke disability is effectively as observed in the GWTG-Stroke registry, regardless of treatment.

In sum, these authors have basically provided us with an unwitting glimpse into how acute stroke treatment has gone utterly off the rails in Norway.  Now, I wonder if they’re related to the group trying to push tPA in less than 20 minutes ….

“Safety and predictors of stroke mimics in The Norwegian Tenecteplase Stroke Trial (NOR-TEST)”

https://www.ncbi.nlm.nih.gov/pubmed/30019629

The Fluoroquinolone/Aortic Dissection Association

We’ve been hearing about elevated incidence of connective-tissue disorders in patients having been prescribed fluoroquinolones for quite some time, primarily in the context of tendonopathies. Now, with aortic dissection.

The differences are quite small, but probably real. This retrospective case-crossover from Taiwan included 1,213 patients hospitalized with aortic pathology, and compared their fluoroquinolone exposure with those who did not experience aortic dissection despite similar disease risk scores from a national database. Using their time-period referent design, patients were about twice as likely to have been exposed to a fluoroquinolone in the aortic pathology group.

This isn’t the only recent look at the association between fluoroquinolone exposure and aortic pathology. Combine this with the profound impact on gastrointestinal flora these broad-spectrum antibiotics have, and the reasons are just piling up to avoid fluoroquinolones whenever clinically reasonable.

“Oral Fluoroquinolone and the Risk of Aortic Dissection”
https://www.ncbi.nlm.nih.gov/pubmed/30213330

tPA in Under 20 Minutes is Recklessness

In my book, “safe” translates to a lack of attributable harm. Therefore, going as fast as possible while still claiming safety – should mean no excess harms resulting from the rush.

There’s no way to precisely tell whether or not this is the case here in Helsinki, where the stroke neurologists have cut their door-to-needle time for thrombolysis to under 20 minutes. The results as described here, however, are not promising, and the authors agree with my impression:

“Our findings support the safety of highly optimized door-to-needle times.”

Ha ha! Of course they don’t.

This is a retrospective review of 1,015 stroke code patients arriving over a two-year period between 2013 and 2015. This institution, incorporating elements of pre-hospital assessment into their initial evaluation, have had door-to-needle times below 20 minutes since 2011. How do they perform?

Of the 1,015, there were 150 (14.8%) patients with misdiagnosis on the initial assessment. Of these, 90 were ultimately diagnosed with a stroke mimic, 59 were eventually diagnosed with a stroke or TIA, and one small basal ganglia hemorrhage was missed. These initial misdiagnoses led, as you might imagine, to both unnecessary treatment and delays to the correct treatment. The most profound effects of these delays were in the context of stroke mimics, whose median delay until a correct diagnosis was 39 hours. Thirteen stroke mimics received thrombolysis, and diagnostic inertia from the initial misdiagnosis led 13 more to have median delays of up to 56 hours for the initiation of condition-specific treatment.

Now, there are limitations here that likely tilt these statistics in favor of the institution. There is no described standard follow-up evaluation to confirm cerebral ischemia, and likely some of those with TIA (146 patients) or who received tPA (331 patients) and improved could further be lumped in with the stroke mimics based on their clinical evaluation and whether they ever underwent MRI. Conversely, even though these authors are speeding headlong in order to give tPA, we can’t actually attribute all these misdiagnoses to their rushed evaluation. It is likely some of these cases would remain clinically challenging, even with a few extra minutes of careful consideration.

However, if they are trying to prove their implementation is safe, this comparison group is exactly what is necessary. They’ve shown their protocol is results in a substantial number of misdiagnosis and documented patient harms; the onus is on this team to prove their pursuit of a handful fewer minutes to tPA is not a contributing factor.  Finally, any possible advantage to shaving a handful of minutes off door-to0-needle times pales in comparison to these obvious misses.

“Diagnosing cerebral ischemia with door-to-thrombolysis times below 20 minutes”
http://n.neurology.org/content/early/2018/07/11/WNL.0000000000005954