Medication Safety – Page 9 – Emergency Medicine Literature of Note

Beaten Into Submission By Wrong-Patient Alerts

It’s a classic line: “Doctor, did you mean to order Geodon for room 12? They’re here for urinary issues.”

And, the rolling of eyes, the harried return to the electronic health record – to cancel an order, re-order on the correct patient, and return to the business at hand.

Unfortunately, the human checks in the system don’t always catch these wrong-patient errors, leading to potential serious harms. As such, this handful of folks decided to test an intervention intended to reduce wrong-patient orders: a built-in system delay. For every order, a confirmation screen is generated with contextual patient information. The innovation in this case, is the alert cannot be dismissed until a 2.5 second timer completes. The theory being, this extra, mandatory wait time will give the ordering clinician a chance to realize their error and cancel out.

Based on a before-and-after design, and observation of 3,457,342 electronic orders across 5 EDs, implementation of this confirmation screen reduced apparent wrong-patient orders from approximately 2 per 1,000 orders to 1.5 per 1,000. With an average of 30 order-entry sessions per 12-hour shift in these EDs, this patient verification alert had a measured average impact of a mere 2.1 minutes of time.

Which doesn’t sound like much – until it accumulates across all EDs and patient encounters, and, in just the 4 month study period, this system occupied 562 hours of extra time. This works out to 70 days of extra physician time in these five EDs. As Robert Wears then beautifully estimates in his editorial, if this alert were implemented nationwide, it would result in 900,000 additional hours of physician time per year – just staring numbly at an alert to verify the correct patient.

It is fairly clear this demonstration is a suboptimal solution to the problem. While this alert certainly reduces wrong-patient orders of a measurable magnitude, the number of adverse events avoided is much, much smaller. However, in the absence of an ideal solution, such alternatives as this tend to take root. As you imagine and experience the various alerts creeping into the system from every angle, it seems inevitably clear: we will ultimately spend our entire day just negotiating with the EHR, with zero time remaining for clinical care.

“Intercepting Wrong-Patient Orders in a Computerized Provider Order Entry System”
http://www.ncbi.nlm.nih.gov/pubmed/25534652

“‘Just a Few Seconds of Your Time.’ at Least 130 Million Times a Year”
http://www.ncbi.nlm.nih.gov/pubmed/25724623

Narcotic Overdoses Are Just Who We Expect

Deaths from narcotic overdose have jumped tremendously in the past years – to the point where naloxone distribution has become a life-saving public health initiative. But, far more effective than treatment of overdose is prevention – and this small retrospective evaluation of Medicaid enrollees provides an insight into those at risk.

Based on an analysis of 90,010 Medicaid beneficiaries prescribed long-term opiate therapy, these authors made the following observations:

Patients without overlapping narcotic prescriptions, and who did not fill prescriptions at more than 3 pharmacies: 0.63% overdose incidence
Patients with overlapping narcotic prescriptions, and who filled prescriptions at more than 3 pharmacies: 6.09% overdose incidence

Other strongly predictive features for overdose were:

Morphine equivalent opioid doses >50mg per day
Concurrent sedative use
History of alcohol abuse
Depression diagnosis

Considering the increasing morbidity and mortality associated with opioid use and abuse, studies such as these help proactively identify those at greatest risk for early intervention.

“Defining Risk of Prescription Opioid Overdose: Pharmacy Shopping and Overlapping Prescriptions Among Long-Term Opioid Users in Medicaid”
http://www.ncbi.nlm.nih.gov/pubmed/25681095

High-Dose Oral Steroids for Multiple Sclerosis Flare

I am always a fan of evidence supporting treatments that are safe, efficacious, and massively less expensive than conventional care. Even if multiple sclerosis flares are infrequently seen in the Emergency Department setting compared with, say, sepsis or chest pain, their care is part of the spectrum of our purview.

We’ve known all along oral steroids are just as useful as intravenous steroids for asthma. However, multiple sclerosis flares are typically treated with 1000mg of intravenous methylprednisolone. When’s the last time you gave that dose – or equivalent with another steroid – orally?

So, this is the COPOUSEP trial, and it is a non-inferiority investigation comparing three days of high-dose oral administration of methylprednisolone with intravenous. Enrolling 199, and reporting outcomes on 90 and 93 patients in the oral and IV groups, respectively, the authors find functional improvement in the most disabling aspect persisting at 28 days in 81% for oral and 80% of IV. Adverse effects tended to favor the intravenous cohort, with agitation and insomnia troubling the oral cohort in greater fashion than IV. Despite these adverse effects, given the costs and inconvenience of inpatient or infusion center treatment, it is certainly reasonable to encourage patients to pursue the oral option.

Oddly, the authors omit their intention-to-treat results from the paper, and provide only the per-protocol. The ITT results, supposedly, are available in a supplementary appendix – not yet available, apparently – and are similar to the per-protocol outcomes. Thus, I see no particular reason to omit the ITT, as such better reflects the efficacy and safety profile of pragmatic use; the authors should either present both together, or defer the per-protocol analysis to the appendix.

Nearly all individuals involved in the study declared conflicts of interest with multiple pharmaceutical companies, although I do not see how any would have untoward effect on the work in question.

“Oral versus intravenous high-dose methylprednisolone for treatment of relapses in patients with multiple sclerosis (COPOUSEP): a randomised, controlled, double-blind, non-inferiority trial”
http://www.ncbi.nlm.nih.gov/pubmed/26135706

Get on the Haloperidol Wagon

For many years, droperidol has been a valuable tool for nausea, vomiting, headache, and termination of psychosomatic contributors to patient distress. Alas, droperidol availability has been markedly diminished in the U.S. in recent years, depriving us of one of our most efficacious management tools.

But, we still have plenty of haloperidol. So, let’s use it for the same purposes.

What’s the difference between droperidol and haloperidol? From a pharmacologic standpoint, the metabolism of haloperidol to active and toxic metabolites is far more complex than droperidol. But, from a clinical standpoint, there is very little difference – they are both butyrophenones with similar receptor antagonism.

This paper is not terribly robust, but compares the use of haloperidol against metoclopramide for acute headache in the Emergency Department. After pre-treatment with 25mg of IV diphenhydramine, either 10mg of IV metoclopromide or 5mg IV haloperidol was administered in double-blinded fashion. Owing to the small sample size of 64 patients, all measures of pain reduction, nausea, restlessness, and sedation were statistically equivalent between groups, although 8 of 33 of the metoclopromide cohort required rescue medications, compared with just 1 of 31 in the haloperidol cohort. However, telephone follow-up of patients following discharge also found the sedation and restlessness symptoms were more persistent in the haloperidol group compared with metoclopramide.

But, regardless, most of these differences – or lack thereof – is all small sample-size theatre. However, in addition to anachronistic anesthesia research into post-operative nausea and vomiting, this reasonably reinforces what we already know: if you’ve been suffering the loss of droperidol, you ought now be using haloperidol.

“A Randomized Controlled Trial of Intravenous Haloperidol vs. Intravenous Metoclopramide for Acute Migraine Therapy in the Emergency Department.”
http://www.ncbi.nlm.nih.gov/pubmed/26048068

Let’s Reverse: Dabigatran

‘Round EMLoN headquarters, we’re big fans of a few medications. Oseltamivir. Ticagrelor. Alteplase. And, finally, dabigatran. After all, a blog needs content – and controversy begets content. Dabigatran, if you need any reminder, is an irreversible direct thrombin inhibitor, whose sponsored trial results continue to receive “updates” for additional “newly discovered” adverse events. It was also subject to a $650M legal settlement related to its under-emphasized risks to patients.

This pair of articles, presumably, addresses one critical issue with dabigatran – lack of effective reversal options. The first, published in the Lancet, relates to controlled pharmacokinetics of the monoclonal antibody fragment binding dabigatran, idarucizumab. Healthy volunteers, all men, were loaded with four days of dabigatran, and the four cohorts of 12 participants each were assigned to receive various doses of idarucizumab. By every measure of coagulation function, the two highest-dose cohorts effectively reversed dabigatran. However, given the small number of participants, it is impossible to claim idarucizumab is safe, even in the setting of only a handful of adverse events. Entertainingly, almost half the research participants complained of at least two subjective adverse symptoms during the dabigatran load.

The second article, in the NEJM, is bizarrely an interim analysis of the first 90 patients enrolled of a planned 300 patient phase III study of idarucizumab. The appropriateness of reporting a fraction of enrollment from a sponsored phase III study, let alone in the NEJM, is unfathomable. Regardless, the study enrolled patients requiring urgent reversal for life-threatening bleeding or urgent surgery. As in the Lancet publication, administration of idarucizumab reversed coagulation parameters almost instantly. There was, however, a small rebound in anticoagulation and dabigatran activity approximately 12 hours after the initial dose, suggesting a limit to the durability of the reversal in some patients.

Clinically, outcomes are a little difficult to evaluate without a specific control or comparison group. The patients generally did poorly – 18 of 90 died – but, probably as expected in an elderly, anticoagulated cohort confronted by acute medical issues. In the patients with life-threatening bleeding, time to resolution was 11.4 hours following administration of idarucizumab – not dissimilar to the use of prothrombin-concentrate complexes for warfarin or Factor Xa inhibitors. Of course, nearly a quarter of patients were enrolled despite what turned out to be normal initial coagulation profiles – inflating any measure of apparent reversal or bleeding time cessation. And, again, in such a small sample, without a control population, no obvious statement on safety may be made, even in the setting of just a handful of thromboembolic events.

In short, Boehringer Ingelheim, having scattered the nails in the street, is almost ready to sell you new tires. Certainly, whatever the adverse effects of idarucizumab, it is better than uncontrolled bleeding – and will doubtless be a welcome addition to many formularies. The costs, however, will be quite unwelcome – and without a method to readily detect dabigatran activity in the clinical setting, this expensive antidote will likely be uselessly given to many patients without the possibility of benefit, as seen in a quarter of patients here.

Finally, as a bit of an aside, the accompanying editorial is penned by a physician who receives consulting fees from both Boehringer Ingelheim and Portola specifically for his work on the antidotes for dabigatran and the Factor Xa inhibitors. Is it really so difficult to identify qualified editorialists without the most egregious possible COI?

“Safety, tolerability, and efficacy of idarucizumab for the reversal of the anticoagulant effect of dabigatran in healthy male volunteers: a randomised, placebo-controlled, double-blind phase 1 trial”
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)60732-2/abstract

“Idarucizumab for Dabigatran Reversal”
http://www.nejm.org/doi/full/10.1056/NEJMoa1502000

DIAS-3 – Desmoteplase Fails in the Extended Time Window

It seems to be the stroke neurologists’ greatest lament – the restricted time windows for tPA, either 3 or 4.5 hours, excluding so many patients from receiving the blessing of thrombolysis. There have been failed trials in the past in extended time windows, and, even, failed trials in the 3-5h time window. But, this is desmoteplase, and it is more fibrin specific than alteplase – and this follows up DIAS-2, which seemed to suggest benefit in patients with demonstrated arterial conclusion on vascular imaging.

It is, sadly, negative by the primary outcome of 90-day Rankin score (mRS 0-2), adding another tick mark to the list of failed contemporary trials for systemic thrombolysis. Safety outcomes, mercifully for the patients involved, were similar, with low rates of neurologic worsening associated with intracranial hemorrhage in each cohort.

The authors, as before, find and focus on a single positive subgroup: patients with ischemic injury volume of less than 25mL on MRI. There was, interestingly, no positive effect noted for patients whose ischemic injury volume was less than 25mL on CT – and the authors had no specific explanation for the discrepancy. However, given the recent successful endovascular trials, it is quite reasonable to suggest an imaging-based, tissue-salvage model is more appropriate than the simplistic time-based model suggested by NINDS. Unfortunately, tissue salvage is dependent upon recanalization – and rates were not significantly different between cohorts, 49% with desmoteplase vs. 42% with placebo. This is the persistent elephant neurologists fail to acknowledge – that systemic thrombolysis simply rarely works as advertised – greatly diminishing any possible beneficial effect.

The conflict-of-interest statement falls on what probably would have once been considered the extreme side, but now is tragically routine:

The funder was involved in the study design, data collection, data analysis, and data interpretation. Two employees of the funder provided medical writing assistance in the editing of the report. The corresponding author had full access to all study data; all other authors without funder affiliation had access to study data via the corresponding author and authors with funder affiliation had full access to all study data.

Interestingly, review of the ClinicalTrials.gov registration indicates the study was initially planned in 2008 to enroll 320 patients, with an end date in 2010. In 2010, the planned enrollment was increased to 400, and the study ultimately enrolled 492. Given the COI involved, it reasonable to suggest the funder was involved in ongoing analysis of the results with the intention of stopping the study at the precise moment a positive outcome – or ultimate futility – was detected. Despite the best efforts of Jeff Drazen and the NEJM to downplay potential distortions secondary to funding sources, clearly, our vigilance for such likely scientific misconduct should not be diminished.

“Safety and efficacy of desmoteplase given 3–9 h after ischaemic stroke in patients with occlusion or high-grade stenosis in major cerebral arteries (DIAS-3): a double-blind, randomised, placebo-controlled phase 3 trial”
http://www.ncbi.nlm.nih.gov/pubmed/25937443

Finally, an End to Tamulosin for Renal Colic?

Most urologic professional societies recommend “medical expulsive therapy” for ureterolithiasis, with an expectation of increased stone expulsion, improved time-to-passage, and reduced need for analgesia.

As I’ve covered before – breaking down a pro-tamulosin Cochrane Review – the evidence in support of this practice is junk. David Newman, Anand Swaminathan, and Salim Rezaie agree. The last time I posted, I posited there was probably some small benefit to a subgroup of patient with renal colic, but, alas, we would probably never have high-quality evidence.

I was wrong.

This study in The Lancet tested MET by randomizing patients with CT-confirmed ureterolithiasis to three arms – placebo, nifedipine, or tamulosin. The randomization algorithm balanced the arms between stone size and stone location. The primary outcome was need for urologic intervention at 4 weeks, with secondary outcomes of patient-reported time to stone passage and pain medication use.

With 1,167 patients randomized – 31 of which were excluded or lost to follow-up – there was no difference in need for urologic intervention between groups: 20% placebo, 19% tamulosin, 20% nifedipine. Secondary outcomes – measured by follow-up questionnaire – were likewise similar, with no differences detected in the number of pain medication nor days until stone passage.

Now, urologic intervention is a rather imprecise surrogate outcome for evaluating the efficacy of MET for promoting stone passage. And, only 62% of patients returned the surveys regarding the secondary outcomes of subjective stone passage and analgesic use. This is high-quality evidence, but hardly infalliable. The authors also state no subgroup showed benefit – which is not entirely true. MET was slightly beneficial (86% vs. 82%) for patients with lower ureteral tract stones, with a p-value of 0.099. Giving into the tyranny of p-values, yes, there’s no benefit – but using the p-value akin to a likelihood ratio, judged against the larger context of other (albeit, low-quality) trials showing benefit, I would not find it unreasonable to contest the totality of these authors’ conclusion.

Regardless, the empiric use of tamulosin has simply been an urban legend taken one step too far. Short of large stones in the lower urinary tract, the benefit is fleeting at best – and the magnitude of the benefit may be too low to matter.

“Medical expulsive therapy in adults with ureteric colic: a multicentre, randomised, placebo-controlled trial”
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)60933-3/abstract (oa)

Again With the Claim tPA is “Safe” in Mild Strokes

In yet another exercise in asking the wrong questions, these authors put forth a rather great deal of effort to regurgitate a vast quantity of mostly meaningless data.

Neurologists, generally those well-supported by Genentech and Boehringer Ingelheim (as in this article), are keen to expand the use of tPA beyond the license criteria. One of the easiest targets is the giant cohort of stroke patients excluded from treatment for low NIHSS. In some respects, it seems reasonable to discard an ordinal cut-off in a measure of stroke severity having a non-linear relationship with disability. But, when media coverage describes an expansion of tPA to mild stroke patients as “saving hundreds of millions of dollars” or “having no downside”, even the hypothetical best intentions have clearly gone awry.

This is a retrospective review of the Get With the Guidelines-Stroke registry, a voluntary, prospective quality improvement project used by hospitals in the U.S. Between 2010 and 2012, 7,621 patients were treated with IV tPA for AIS having an NIHSS of 5 or less, with 5,910 having data for analysis. Ranging from 192 patients with an NIHSS to 0 to 1,800 having NIHSS of 5, treatment complications were fairly consistent: 1.3% died, 1.8% suffered sICH, 0.2% suffered serious systemic hemorrhage, and 1.8% suffered other serious complications (e.g., angioedema).

So, of course, for a treatment with no demonstrated efficacy in this population, the authors conclude a number-needed-to-harm somewhere between 30 and 50 “provide[s] reassurance about the safety of IV rtPA in patients with low NIHSS scores”.

Interestingly, this data is essentially an update of the authors’ prior work, published using the 2003 to 2009 GTWG-Stroke registry data. That publication provided a helpful data supplement comparing outcomes of tPA-treated patients with non-tPA-treated patients with NIHSS 5 or less. Within the limitations of such a comparison, tPA treatment was associated with significantly increased odds of death, decreased discharges to home, and decreased ambulation at discharge. The authors have in no way muddled this article with such negativity, nor did they perform any sort of gross comparison between the ambulatory and independence outcomes in the present study with the prior, non-treated population – as they are essentially identical.

But, when you’re fed free money from your sponsors, including free airfare to Chicago, why report or suggest anything that might disrupt the narrative?

“Outcomes in Mild Acute Ischemic Stroke Treated With Intravenous Thrombolysis: A Retrospective Analysis of the Get With the Guidelines–Stroke Registry”
http://www.ncbi.nlm.nih.gov/pubmed/25642650

Ketamine vs. Morphine – Again

Everyone loves ketamine. It’s a floor wax and a dessert topping. Traditionally, however, it has primarily been used in procedural sedation and the pre-hospital setting. In the Emergency Department, severe pain is almost universally the domain of intravenous opiates. Of course, opiates tend to disagree with some patients and cause others to be yet more disagreeable, so the search for alternatives continues.

This trial, similar to prior work, randomized severe, acute pain to an intravenous dose of 0.3 mg/kg of ketamine or 0.1 mg/kg of morphine. And, again, pain relief between two groups was statistically similar – and probably clinically similar, as well. The main difference, unsurprisingly, was adverse effects. The ketamine cohort was associated with an absolute surplus of 20% of patients complaining of dizziness, a surplus of 27% complaining of disorientation, and a few extra complaining of mood changes. However, all the extra adverse effects regressed to the level of the morphine group within 30 minutes.

We should be entirely settled by now regarding the safety and efficacy of ketamine. It works, and it works well – but some patients clearly find it unpleasant. I don’t foresee ketamine displacing opiates as typical first-line therapy for the majority, but there are certain types of patients and pain for which this would be a lovely option. If your hospital does not yet support its use for acute pain, they are falling behind and doing their patients a disservice.

“Intravenous Subdissociative-Dose Ketamine Versus Morphine for Analgesia in the Emergency Department: A Randomized Controlled Trial”
http://www.ncbi.nlm.nih.gov/pubmed/25817884

Cellulitis Done … Strangely

The Infectious Disease Society of America updated their recommendations last year with very reasonable guidelines. Simple, uncomplicated cellulitis requires nothing more than penicillin or a first-generation cephalosporin. This recognizes the overwhelming preponderance of susceptible organisms implicated in such infections. Now, in the era of increasingly endemic methicillin-resistant S. aureus, the current prevailing worry is the rate of treatment failure for such inexpensive and old-fashioned first-line agents.

So, why are these authors testing clindamycin versus trimethoprim/sulfamethoxazole? Not only that, in addition to uncomplicated cellulitis, these authors are also testing these agents following abscess drainage – yet another uncertain indication for antibiotics.

But, so, yes – with 524 patients in the phase of the trial enrolling those with uncomplicated cellulitis, mixed abscess and cellulitis, and abscesses greater than 5 cm, the comparison was a wash. Clindamycin and TMP/SMX had small differences favoring the former, but not large enough to reach statistical significance. Each antibiotic has its own specific constellation of adverse effects and interactions, and with treatment failures at roughly 1 in 5 in the ITT population for each, other considerations are probably more important than any efficacy difference between the two.

Of the 296 patients for which cultures were obtained, 167 (31.9% of the total cohort) grew MRSA. Oddly, the methods state non-suppurative lesions were not cultured, and they report only 47% of patients had purulent drainage. Yet, cultures were obtained in 56%. What sort of culture swab was performed on simple cellulitis?

And, of course, as with every trial, every possible comorbidity was excluded. Someday, we’ll have the wherewithal to compare failure rates in our typical Emergency Department patient – the diabetic, obese, and renally insufficient!

The other arm of the trial, a “limited abscess” group comparing I&D plus antibiotics versus I&D plus placebo will be published separately.

“Clindamycin versus Trimethoprim–Sulfamethoxazole for Uncomplicated Skin Infections”
http://www.nejm.org/doi/full/10.1056/NEJMoa1403789