Medication Safety – Page 14 – Emergency Medicine Literature of Note

Open the Data

There is a committee within the Institute of Medicine charged with examining the issues associated with data sharing after randomized controlled trials.

Data-sharing, without question, reflects a dire need. From companies behaving badly – such as Merck with Vioxx, or Roche with Tamiflu – to inadvertent errors in analysis, protecting the health of patients requires more than simple peer review of documents prepared for pharmaceutical corporations by medical communication professionals.

Jeff Drazen, in this editoral, makes a call for feedback to the IOM. Oddly, his main concern is – how long ought the original authors of a study be allowed exclusive access to trial data? Would open data disincentivize researchers to perform clinical investigations, knowing their academic and commercial benefit would likely be curtailed? On the flip side, we have seen publication of trial data be massively delayed – see ATLANTIS Part A, withheld for seven years – by pharmaceutical companies concerned with protecting their business interests.

It is a complicated and subtle issue, to be sure, but appropriate transparency is almost certainly an improvement over the current situation. Full details, and how to leave feedback, are at:
http://www.iom.edu/activities/research/sharingclinicaltrialdata.aspx

“Open Data”
http://www.nejm.org/doi/full/10.1056/NEJMe1400850 (open access)

Can We Escape Antibiotics in Sore Throat?

Yes. And no.

It is well-established complications of acute sore throat are incredibly rare. The likelihood of a patient developing the most concerning of suppurative complications – a peritonsillar abscess or “quinsy” – is less than a fraction of a percent. Rheumatic fever is virtually eliminated in the United States. Yet, as we see from this British cohort, over half of patients visiting primary care received a prescription for antibiotics.

This is study reports on a combination of several, prospectively gathered cohorts presenting with acute sore throat to British primary care practices. Comprising 14,610 adults, only 5,243 escaped the physicians office without an antibiotic prescription, while the remainder received immediate or delayed antibiotics. Suppurative complications across all cohorts – peritonsillar abscess, sinusitis, otitis media, and cellulitis – ranged from 0.1% to 0.6%.

Unfortunately, this is not a randomized trial – the patients who were given antibiotics by their physician had much more severe initial clinical presentations. This means, unfortunately, there is no information in this data set describing the actual protective effect of antibiotics without making statistical contortions. The main value, however, is in describing the futility of clinical judgement for selecting patients for antibiotics. Of all the various clinical features recorded prospectively for each patient, only severe ear pain and severely inflamed tonsils were significant predictors of suppurative complications – with ORs of 3.02 and 1.92, respectively. However, these still constituted hundreds of patients with symptoms who otherwise did not progress. High scores on the Centor and FeverPAIN criteria were similarly, minimally predictive.

In the end, it is ultimately apparent antibiotics confer some protective effect. The absolute benefit, however, will represent just a handful of patients out of thousands. The authors sum it up just as nicely as I might:

“Since a policy of liberal antibiotic prescription for sore throat to prevent complications is highly unlikely to be cost effective, and clinicians cannot rely on clinical targeting to predict most complications, clinicians will need to rely on strategies such as safety netting or delayed prescription in managing the low risk of suppurative complications.”

“Predictors of suppurative complications for acute sore throat in primary care: prospective clinical cohort study”
http://www.bmj.com/content/347/bmj.f6867 (open access)

ACEP Clinical Policy on tPA Up For Comment

At ACEP13, the Council voted to reconsider the clinical policy statement regarding tPA for acute ischemic stroke. As part of that resolution, the policy was to be opened up for a sixty-day public comment period.

And, the moment you’ve all been waiting for – it’s up! Follow this link to read more, download the clinical policy statement, and leave your comments:

http://www.acep.org/commentform/IVtPA-Stroke/

Ignore This Fixed-Dose Philosophy For Morphine

Emergency physicians are legendary for poor control of pain in the Emergency Department, with many factors challenging optimal care. One solution – and one I’ve taught in the ED – is to use a weight-based approach to dosing. This works out to 0.1-0.15 mg/kg of morphine or equivalent as an initial starting dose.

These authors gather 300 patients – 100 non-obese, 100 obese, and 100 morbidly obese – who all received a 4mg intravenous dose of morphine for median initial pain levels of ~8 on a scale to 10. Upon reassessment a median of ~1 hour after administration, the median pain level in all groups had fallen to 2 or 3. This somewhat tailors along with other work, which observed substantial numbers of patients with adequate response following even doses of morphine of less than 4mg. The authors therefore conclude:

“BMI does not predict the analgesic response to a single dose of intravenous morphine in the ED. This is true even for patients who are morbidly obese. We suggest using fixed doses rather than weight-based doses of morphine for acute pain in obese patients.”

However, this retrospective study fails to capture and control for many of the other factors associated with opiate response, including age, substance abuse history, pre-hospital pain control – along with all the other contextual factors lost through chart abstraction. Additionally, patients at Maricopa Medical Center in Phoenix are not hardly generalizable to, well, nearly anywhere in the world.

Ultimately, this limited study leads to an erroneous, and potentially harmful conclusion that weight-based doses are unnecessary. Aggressive, titrated or weight-based, pain control is not in any fashion refuted by this work.

“Analgesic response to morphine in obese and morbidly obese patients in the emergency department.”
http://www.ncbi.nlm.nih.gov/pubmed/23314209

FDA: The Black Knight

… specifically, the Black Knight from Monty Python, apparently reduced to nibbling impotently at the feet of pharmaceutical corporations as they sail through the approval process.

This study in JAMA reviews the characteristics of novel therapeutics approved by the FDA between 2005 and 2012. These authors identified 188 novel agents approved for 206 indications, and describe an entire host of fascinating data regarding the trials supporting approval. A few of the most damning pearls:

37% of indications were approved on the basis of a single trial.
The median number of patients per trial was 760.
49% of trials used only surrogate outcomes.
Surrogate outcome trials constitute sole basis of approval for 91 indications.
Only 48% of cancer trials were randomized, and only 27% were double-blinded.
40 trials were part of accelerated approval, 39 of which used surrogate outcomes, with a median number of patients of 157.

The data go on and on.

Considering many landmark trials could not be independently reproduced, even with the help of the original researchers; most published research findings are false; and half of what you know is wrong – we might as well just dump poison in our water supply. It’s cheaper than suffering the next blockbuster drug for which pharmaceutical companies engineer an indication through distorted trial design.

“Clinical Trial Evidence Supporting FDA Approval of Novel Therapeutic Agents, 2005-2012“
http://jama.jamanetwork.com/article.aspx?articleid=1817794 (open access)

“Author Insights: Quality of Evidence Supporting FDA Approval Varies”
http://newsatjama.jama.com/2014/01/21/author-insights-quality-of-evidence-supporting-fda-approval-varies/

More Bleeding Nightmares

Do you like managing bleeding on aspirin? How about aspirin plus clopidogrel? What would you say to aspirin + clopidogrel + vorapaxar?

Vorapaxar, a selective antagonist for protease-activated receptor 1, is the next proposed layer of anti-thrombotic prevention for high-risk cardiovascular patients. Just this week, back from the dead, it received a favorable review from an FDA panel tasked with examining its application for approval.

The subject of both TRACER and TRA 2°P-TIMI 50, vorapaxar may soon bless your Emergency Department with a roughly 60% increase (2% vs. 3.5%) the risk of GUSTO moderate or severe bleeding. What’s most fascinating about this drug is, technically, both trials were negative for the primary endpoint, and TRACER was stopped early after interim safety review. However, a pre-specified and pre-allocated subgroup from TRA 2°P-TIMI 50 for patients with recent MI – and no history of stroke – showed benefit.

Of course, as is standard for these sorts of cardiovascular trials, it showed benefit primarily in the questionable combined endpoints – and, likewise, was only safe in the narrowest slicing and dicing of favorable endpoints and bleeding outcomes.

It should be of no surprise to anyone most authors are being substantially enriched by multiple drug companies. I’m certain whatever foot-in-the-door Merck receives will be enough to extract the necessary healthcare dollars from the system for minimal benefit – a net NNT for mortality of ~450.

Oh, and as the great Tom Deloughery (@bloodman) writes:

“Hmmm – a competitive platelet inhibitor with a T1/2 of ~300hrs! So, sounds like it will inhibit any platelets you give for the next 12 days … I guess Dr. Radecki will be holding direct pressure for a long time!”

“Vorapaxar for secondary prevention of thrombotic events for patients with previous myocardial infarction: a prespecified subgroup analysis of the TRA 2°P-TIMI 50 trial”
http://www.ncbi.nlm.nih.gov/pubmed/22932716

Remember: Tamiflu is Still Junk

It’s that season of the year again, and with the fatalities from the H1N1 strain returning to the news folks are clamoring for Tamiflu (oseltamivir).

And, there’s still no evidence it has any protective effect at reducing complications from seasonal influenza. In these two studies, a systematic review and a meta-analysis, some small reductions in symptom duration in mild illness were outweighed by drug adverse events such as nausea, vomiting, and diarrhea. There is no evidence of any decrease in severe complications of influenza.

Unfortunately, the heterogeneity of trials, irregularities in baseline characteristics, and incomplete peer review all impair knowledge translation of this relatively expensive outpatient medication. You’re all hopefully aware of the BMJ’s ongoing open data campaign regarding Tamiflu. The last update from July seemed to indicate independent access to higher-quality trial data had finally been achieved. If there is a durable, beneficial effect attributable to osletamivir, perhaps we will soon know. Given the lack of transparency to date, I’m not optimistic.

“The value of neuraminidase inhibitors for the prevention and treatment of seasonal influenza: a systematic review of systematic reviews.”
http://www.ncbi.nlm.nih.gov/pubmed/23565231

“Effectiveness of oseltamivir in adults: a meta-analysis of published and unpublished clinical trials.”
http://www.ncbi.nlm.nih.gov/pubmed/22997224

Biphasic anaphylactic reactions – How long should we observe?

A guest post by Anand Swaminathan (@EMSwami) of EM Lyceum and Essentials of EM fame.

ED Nurse: “You want to watch that allergic reaction for 6 hours? Seems like a long time.”

ED MD: “Yeah, I know but I want to make sure they don’t have a biphasic anaphylactic response.”

ED Nurse: “When does that usually happen?”

ED MD: “Well, uh . . . I’m not sure . . . hey did anyone see that 90 year old with dizziness yet? I should go see her now.”

If this conversation seems familiar, you’re not alone. We’ve all been taught that patients with allergic reactions have a risk of recurrent reaction. What we fear, is an anaphylactic episode that improves, the patient goes home and then has recurrent anaphylaxis and dies. As a result, many of us have been taught that if the patient resolves, you watch them for 4-6 hours and if they remain okay, they can go home.

However, when you look at the literature, it shows that the biphasic reaction can be delayed. It can occur anywhere from 5 minutes up to 3-4 days out. So what is the optimal duration of observation?

Enter this retrospective, chart review from the University of British Columbia. The researchers found 2,819 patients with allergic reactions at two institutions (496 classified as anaphylaxis) and the scoured databases for representations within 7 days. They further separated out those patients with clinically important biphasic reactions. Overall, there were five patients (0.18%) who had clinically important biphasic anaphylactic responses in seven days. Of these, two had immediate biphasic anaphylaxis during their initial Emergency Department visit and three experienced a delayed response up to six days out of their initial visit. Two of the biphasic reactions were in patients initially presenting with anaphylaxis (0.40%) and three were in patients presenting with simple allergic reactions (0.13%). There were no deaths identified.

The study has the typical limitations of any retrospective chart review. One major concern is that patients presented to EDs other than the original two sites. The researchers did, however, check the regional database for representations and checked the provincial database for mortality.

Although the study isn’t perfect, it suggests that the biphasic response may be lower than previously thought. Prior studies have shown biphasic reaction rates ranging from 3 – 20% (Tole 2007). As a result, some authors have recommended observation for up to 24 hours after an anaphylactic reaction. The truth is that there are no consistent recommendations about observation. The authors conclude that,

“although extended observation would be justified in patients with severe or protracted anaphylaxis, the added costs and resource use involved in routine prolonged monitoring of patients whose symptoms have resolved may worsen ED crowding while likely adding little to individual patient safety.”

While it’s hard to recommend changing practice based on a retrospective study, this is the largest study done on the subject and offers very reassuring numbers. The bottom line is that clinically important biphasic reactions are rare (less than 1%) and can occur days after the initial reaction. There is no 100% safe observation period. After symptom relief, and decision for discharge, patients should be given epinephrine auto injectors and taught how to use them. Any potential inciting allergens should be removed and follow up should be arranged with an allergist. With a clinically important biphasic response rate < 0.5%, extended observation seems to be unnecessary.

Hear more at http://thesgem.com/2013/12/sgem57-should-i-stay-or-should-i-go-biphasic-anaphylactic-response/

References

Grunau BE et al. Incidence of Clinically Important Biphasic Reactions in Emergency Department Patients with Allergic Reactions or Anaphylaxis. Ann of EM 2013. ePub http://dx.doi.org/10.1016/j.annemergmed.2013.10.017

Tole JW, Lieberman P. Biphasic Anaphylaxis: Review of Incidence, Clinical Predictors and Observation Recommendations. Immunol Allergy Clin N Am 2007; 27: 309-26.
http://www.ncbi.nlm.nih.gov/pubmed/17493505

tPA for TIA?!

A guest post by Anand Swaminathan (@EMSwami) of EM Lyceum and Essentials of EM fame.

Over the last year, the debate over the use of alteplase in acute ischemic stroke has continued to heat up. The issue really boiled over in June after BMJ reporter Jeanne Lenzer wrote a scathing evaluation of clinical guidelines after the publication of the new ACEP Clinical Policy on the use of alteplase in ischemic stroke. Now, to muddy the waters further, enter the discussion of giving alteplase to transient ischemic attacks (TIAs).

That’s right, this week, the American Journal of Emergency Medicine published a case report discussing the administration of alteplase to a patient that the treating physicians agreed had a TIA. Before we get into the article itself, let’s take a stroll back in time to 1995.

On December 14^th, 1995, the NEJM published the NINDS trial and ushered in the era of alteplase for acute ischemic stroke. One of the major exclusions in the study, and one that few have argued with, was “rapidly improving or minor symptoms.” In essence, NINDS sought to exclude patients with TIAs. The reason for this is elegantly stated by Dr. David Liebeskind (UCLA Stroke Center):

“Thrombolysis is not a rational or evidence-based therapeutic option for transient ischemia irrespective of vascular status . . . The prevailing obsession with arterial occlusion has erroneously focused attention on clots rather than ischemia . . . Imaging of occlusion without consideration of clinical details or pahtophysiolgical mechanisms may therefore be misleading.” (Stroke 2010).

From a pathophysiological and outcome standpoint, there is no good reason to administer alteplase to a patient with a TIA regardless of imaging. If the patient has an NIHSS of 0, there is no room for improvement, only harm.

In spite of this, the authors of the above case report recount the story of a 37-year-old woman who presented with a TIA. Her presenting NIHSS was 0. CT angiogram showed a “near total occlusion of the M2 segment of the MCA.” There is no report about the presence of an ischemic penumbra. After the CTA was completed, the patients’ symptoms returned but then rapidly resolved. At this point, the physicians decided to administer alteplase in spite of the absence of symptoms. She was then transferred to a stroke center for consideration of neurointerventional care (a therapy proven not to work. See NEJM March 2013). Interestingly, the authors base their decision to treat on imaging findings but never discuss the resolution of these findings after therapy (i.e. no mention of repeat CTA or MRI/MRA).

What does this tell us about alteplase for TIA? Not much. This is a case report and gives us no information about causality of treatment. It doesn’t even show efficacy of concept because pathophysiologically the idea of giving alteplase to a TIA doesn’t make sense. The authors talk about weighing risks and benefits outside of standard indications and contraindications. But what they have done is give a potentially dangerous, life-threatening medication to a patient with no disability at the time of administration. They have taken on all the risk of the drug without any potential benefit.

What this report really shows is the concept of “indication creep.” Earlier this year, the TREAT task force recommended that patients with rapidly resolving symptoms (but some continued deficit) should be considered for thrombolytic treatment (Stroke 2013). This recommendation wasn’t based on any literature but rather an expert consensus from a meeting sponsored by Genentech (Boehringer-Ingelheim in Europe). This case report is simply the logical extension of an illogical idea: if thrombolytics should be given to a patient with rapidly resolving symptoms, why not give it to one with no symptoms but imaging abnormalities?

The authors conclude by pointing the finger at EM physicians stating that we, “have been historically slow in adopting thrombolytic therapy for CVA.” We haven’t embraced this treatment because we don’t see definitive evidence that it works and we do see the potential harms. A month ago at ACEP, a group of EPs voted 75% to 25% to reconsider the ACEP clinical policy on tPA. The authors go on to suggest that this patient did well and required no further treatments because she received “off-label” thrombolytics. This link violates everything we know about research. Just because something happens after you do something, doesn’t mean the thing you did caused the outcome. Domhnall Brannigan told a wonderful story during his lecture at SMACC last year about a patient who presented with stroke-like symptoms and nausea. Dr. Brannigan gave the patient ondansetron for the nausea and minutes later the patient had resolution of his symptoms. None of us, though, are rushing to give ondansetron for ischemic CVA. The proposition by these authors is just as ludicrous.

“TPA for TIA: The case for “off-label” use of thrombolytics.”
http://www.ajemjournal.com/article/S0735-6757(13)00747-X/fulltext

References

Sobel RM, Wu DT, Hester K, Anda K. tPA for TIA: The case for “off-label” use of thrombolytics. Am J EM 2013; 06 November 2013 (10.1016/j.ajem.2013.10.046

The National Institute of Neurological Disorders and Stroke, rt-PA Stroke Study Group. Tissue Plasminogen Activator for Acute Ischemic Stroke. NEJM 1995; 333(24): 1581-7.

Liebskind DS. No-Go to tPA for TIA. Stroke 2010; 41(12): 3005-6.

The Re-examining Acute Eligibility for Thrombolysis (TREAT) Task Force. Levine SR, Khatri P, Broderick JP, Grotta JC et al. Review, historical context, and clarifications fo the NINDS rt-PA stroke trials exclusion criteria: part 1: rapidly improving stroke symptoms. Stroke 2013; 44: 2500-2505

tPA for TIA?!

A guest post by Anand Swaminathan (@EMSwami) of EM Lyceum and Essentials of EM fame.

References

Sobel RM, Wu DT, Hester K, Anda K. tPA for TIA: The case for “off-label” use of thrombolytics. Am J EM 2013; 06 November 2013 (10.1016/j.ajem.2013.10.046

The National Institute of Neurological Disorders and Stroke, rt-PA Stroke Study Group. Tissue Plasminogen Activator for Acute Ischemic Stroke. NEJM 1995; 333(24): 1581-7.

Liebskind DS. No-Go to tPA for TIA. Stroke 2010; 41(12): 3005-6.