Medication Safety – Page 15 – Emergency Medicine Literature of Note

The Curious Story of Diclegis

For no particular reason, I’ve recently become familiarized with the story of Diclegis (Diclectin in this study, and in Canada). For use in pregnancy-induced nausea and vomiting, Diclegis is a delayed-release combination formulation of 10mg each of doxylamine and pyridoxine. It was approved by the FDA in April of 2013, and has rapidly become first-line therapy.

The surprising bit – this is precisely the same drug our mothers took in pregnancy. It was introduced in the 1950s as Bendectin, and it was estimated as many as 30% of pregnant women took this combination pill in the 1970s. However, in the early 1980s, the manufacturer was the target of innumerable lawsuits alleging fetal malformation – and in 1983, voluntarily withdrew the drug from the market. This choice was made solely due to the costs of defending against litigation, and not a reflection of the safety of the drug. The physicians who had published data suggesting fetal risk were eventually discredited, and even the FDA noted in 1999 that Bendectin was not withdrawn for reasons of safety or effectiveness.

So – now it’s back, and, unsurprisingly, it works better than placebo. This manufacturer-sponsored, double-blind, placebo-controlled trial demonstrated improvement with Diclectin in almost every measure. And, 48% of Diclegis users asked for compassionate use of the study drug following conclusion of the study (although, so did 32% of placebo). I’ve also discovered my new favorite disease-severity scoring system: the PUQE Score.

The downside: it costs ~$160 for 30 pills.

A brief perusal of the internet shows doxylamine, a sedating, first-generation antihistamine costs as low as 3 cents per tablet. Pyridoxine, vitamin B6, costs as little as 6 cents per tablet. Diclectin costs ~$5 per tablet. You could pay for Diclegis – after all, it is a special “delayed-release” formulation where doxlyamine reaches peak concentration 6 hours after ingestion. Or, you could do what obstetricians have been telling their patients to do for the last several decades: make your own equivalent dosing from the component medications at a fraction of the cost.

It certainly seems prudent to try the cheaper option, first.

“Effectiveness of delayed-release doxylamine and pyridoxine for nausea and vomiting of pregnancy: a randomized placebo controlled trial”
http://www.ncbi.nlm.nih.gov/pubmed/20843504

Bivalrudin Trumps Heparin (Or Not)(Who Knows?)

10 out of 10 physicians employed by the Medicines Company approved this message.

Straight out of Jeff Drazen’s unbiased news pipeline, a treatment you might now start seeing more of in the Emergency Department: bivalrudin (Angiomax) for anticoagulation prior to PCI in the setting of STEMI. In this trial, 2,231 patients across Europe were randomized pre-hospital (or at non-PCI hospitals) to either bivalrudin or heparin plus optional glycoprotein IIb/IIIa inhibitor. The primary outcome, as typical of these sorts of trials, is another muddled composite: death from any cause, re-infarction (MI), or major bleeding not related to CABG.

Oh, wait, that was the original primary outcome. In December of 2012, over three-quarters of the way through the enrollment period, the Medicines Company dropped re-infarction (MI) from the primary outcome. It may or may not be a coincidence re-infarction due to stent thrombosis favored the control intervention, but I will leave that speculation up to the astute reader. Regardless, the new final composite endpoint favored bivalrudin: 5.1% to 8.5%. However, this outcome also depends on their own unique definition of “major bleeding”, which is different from TIMI and GUSTO. If the TIMI and GUSTO definitions are used, the trend towards reduced bleeding with bivalrudin is still there, but the absolute differences become trivial and the overall primary outcome (original or eventual) is a wash. Finally, this may all simply be a straw-man comparison for the safety outcome, as it’s reasonable to ask whether 69% of cases ought to be receiving prehospital glycoprotein IIb/IIIa inhibitor (an AHA Class IIb recommendation).

However, better questions may be – as are a recurring theme for the NEJM – do you trust the results of an open-label trial sponsored by the manufacturer, designed by the manufacturer, with data stored and dispensed to the academic oversight group by the manufacturer? Are you less or more convinced when four authors are employed by the manufacturer, and the manufacturer employed a scientific communications firm for “editorial support”? Why is NEJM publishing a trial that changed its primary outcome in clinicaltrials.gov – even, as the authors claim, to “reduce the necessary sample size”?

Physicians ought to be outraged at this transparent and unbalanced pharma shill – but, such occurrences have become so commonplace, it’s hard to not just surrender to lassitude. Bivalrudin doubtless has an advantage in some specific subgroup, but with this sort of offal clogging the evidence, we’ll never really know.

“Bivalirudin Started during Emergency Transport for Primary PCI”
www.ncbi.nlm.nih.gov/pubmed/24171490

Ischemic Stroke – Shaken, Not Stirred

It’s always mildly entertaining when stroke neurologists flip hats – from espousing the success of tPA to promoting the Next Big Thing. This is when you hear tPA’s greatest proponents admitting “only 20% to 30% of patients have complete recanalization within 2 hours of intravenous tPA” or “one third of those with any recanalization experience reocclusion.”

Ah, sigh.

But, regardless, this study is about the Next Big Thing – which is a transcranial sonothrombolysis helmet. This safety evaluation of 20 patients starts with IV tPA as indicated, and then continues with this operator-independent 2-MHz pulsed-wave ultrasound through a special headband. The theory, of course, is there will be gaseous microbubbles at the site of occlusion that increase efficacy of tPA and further prevent reocclusion. This safety study had a primary endpoint of 10% symptomatic intracranial hemorrhage with a power of 0.80.

Good news! There were no episodes of sICH. But, however, 6 out of 20 (30%) had asymptomatic ICH. And, then, in the ultimate safety outcome – there were 4 deaths resulting from the 14 other serious adverse events. These deaths were mostly progression of cerebral edema and related consequences, and the authors state they were unrelated to the study device.

The first author is on the scientific advisory board for the device manufacturer – which is not disclosed in the text. The second author holds the patent for the device and is Chair of their scientific advisory board. The Texas Board of Regents is the asignee for the patent for the device, and is one of two sponsoring institutions. And, as the authors note, “other limitations include possible selection bias and investigators unblinded to treatment.”

The median NIHSS was 15, so some poor outcomes are to be expected – but, still, I think this is only convincingly safe if you have financial conflicts of interest.

“CLOTBUST-Hands Free – Pilot Safety Study of a Novel Operator-Independent Ultrasound Device in Patients With Acute Ischemic Stroke”
http://www.ncbi.nlm.nih.gov/pubmed/24159060

Direct Vascular Toxicity From PPIs

Proton-pump inhibitors have been the mainstay of many gastroesophageal disorders. 21 million people in the U.S. received a prescription for PPIs in 2009, associated with a cost of $13 billion globally.

Unsurprisingly, there are signals of harm from PPIs that are not completely understood. It is recognized gastric pH is part of the body’s natural immune defense mechanism, and increased pH as a result of PPI use increases susceptibility to infection. Additionally, some concerns have been documented regarding CPY2C19 inhibition, resulting in decreased clopidogrel activity. However, multiple studies also point to increased vascular risk with PPIs that do not significantly inhibit CPY2C19.

These authors further explore the hypothesis the mechanism of PPI vascular risk has nothing to do with CPY2C19. They find, through high-throughput chemical screening, that PPIs directly inhibit dimethylarginine dimethylaminohydrolase (DDAH). This enzyme metabolizes asymmetrical dimethyarginine (ADMA), which is further responsible for inhibiting nitric oxide synthase (NOS). In clinical terms, inhibition of NOS is a bad thing, and consistent with multiple clinical studies demonstrating increased ADMA activity is associated with cardiovascular death.

The in vivo portion of this study is limited by mouse model, but they do show a dose-dependent decrease in tissue nitric oxide associated with omeprazole administration. The end clinical result of this would be increased oxidative stress, reduced vasodilator function, and otherwise impaired vasoprotective mechanisms.

It’s an interesting translational study uncovering a reasonable hypothesis for the recurrent themes of observed PPI harms. It also tailors neatly into the prior clinical trial evidence suggesting PPI use in upper GI bleeding decreases bleeding-related deaths, while increasing non-bleeding deaths, resulting in no net mortality benefit.

The International Consensus and the American College of Gastroenterology guidelines say PPIs “may” be considered prior to endoscopy to downstage lesion severity, while NICE states PPIs should not be offered prior endoscopy for non-variceal UGIB. The most recent Cochrane Review on the topic show no patient-oriented benefits to PPI prior to endoscopy. I think it’s very reasonable to make an individualized decision whether the risks and costs associated with PPI use outweigh the benefits of acute clot stabilization in UGIB.

“Unexpected Effect of Proton Pump Inhibitors: Elevation of the Cardiovascular Risk Factor Asymmetric Dimethylarginine”
www.ncbi.nlm.nih.gov/pubmed/23825361

Bar-Code Scanners in the ED

Welcome to the Emergency Department of the Future. Soft chimes play in the background. Screaming children are appropriately muffled. There is natural light and you can hear the ocean. Patients and doctors alike are polite and respectful, and a benign happiness seems to radiate from all directions. A young nurse wafts through the patient care areas with a handheld barcode scanner, verifying and dispensing medications in a timely and accurate fashion.

Everything about that vision is coming to your Emergency Department, everything except the chimes, the quiet, the politeness, and the happiness. The bar-code scanners, however, perhaps.

This is a pre- and post- study from The Ohio State University regarding their use of handheld scanners for medication verification (BCMA). Our hospital system uses these throughout the inpatient services to verify and provide decision-support for nurses at the final step of the medication delivery process. However, given the chaotic nature of the Emergency Department, we have not yet implemented them in that environment. Ohio State, on the other hand, has forged ahead – requiring all medication administrations be verified by bar-code scanner, excepting a small number of “emergency” medications that may be given via override. They also excluded patients in their resuscitation areas from this requirement.

Across the 2,000 medication administrations observed in the pre- and post- implementation periods, there were reductions in essentially all types various drug administration errors, leading to 63/996 errors in pre- and 12/982 in the post-. Therefore, these authors conclude – hurrah!

However, none of these errors were serious – and only one even met criteria for “possible temporary harm”. The majority of errors were “wrong dose”, and involved sedatives, narcotics, and nausea medications the most. Certainly, the potential for prevention of a significant drug event may be reduced with this system, but it would require much greater statistical power to detect such an effect. These authors do not touch much upon any unintended consequences of their implementation – such as delays in treatment, changes in LOS, or qualitative frustration with the system. A better accounting for these effects would assist in fully assessing the utility of this intervention in the Emergency Department.

“Effect of Barcode-assisted Medication Administration on Emergency Department Medication Errors”
http://www.ncbi.nlm.nih.gov/pubmed/24033623

Colchicine for Pericarditis: Do It

Anti-inflammatory treatment is the mainstay of therapy for pericarditis. Aspirin, NSAIDs, steroids – and now, colchicine. Used to treat inflammation related to gouty attacks, useful in other types of serositis, colchicine has been suggested as having value in pericarditis, as well.

This is a seven-year double-blind, randomized controlled trial between colchicine and placebo, added to usual therapy – which, in this case, was usually aspirin. Primary outcome was “incessant or recurrent pericarditis” – and, there’s no doubt in this trial the colchicine is successful and mostly harmless. With standard anti-inflammatory treatment 37% of patients suffered incessant or recurrent pericarditis within the 18-month follow-up period, compared with 16.7% of patients receiving colchicine. Colchicine had beneficial effect on symptom persistence at 72 hours – 40.0% vs. 19.2% – and was superior with remission at one week – 58.3% vs. 85.0%.

Adverse effects and drug discontinuation rates were essentially identical within the bounds of their relatively small sample size. I don’t see any particular reason to exclude appropriate patients from colchicine for acute pericarditis.

“A Randomized Trial of Colchicine for Acute Pericarditis”
http://www.ncbi.nlm.nih.gov/pubmed/23992557

Language Barriers as Overdose Risk

This is a simple study, but demonstrates an incredibly important risk – the effect on language barriers on subsequent prescription dosing errors.

These authors followed up English-speaking and Spanish-speaking parental dyads being prescribed acetaminophen at discharge from the Emergency Department. The discharge instructions were observed, and, following discharge, the parents were asked to repeat back their understanding of the correct weight-based dose of acetaminophen for their child.

English-speaking parents: 25% dosing errors
Spanish-speaking parents: 54% dosing errors

Firstly, these are both too high – despite a standardized chart given to parents. Observation of discharged indicated providers only explicitly identified the dose of acetaminophen for parents 37% of the time.

Secondly, it’s clear an extra level of care needs to be taken when language barriers present themselves. The dosing error risk remained significant whether adjusted for health literacy, income, or preferred language of discharge instructions.

We can, and need, to do better.

“Parental Language and Dosing Errors After Discharge From the Pediatric Emergency Department”
http://www.ncbi.nlm.nih.gov/pubmed/23974717

Letter in Stroke

My correspondence regarding this article was published in Stroke a couple days ago. I’d like to say the author response is earth-shattering and insightful, but while it is not, they were kind enough to respectfully reply.

Sadly, the correspondence and response is available only to subscribers – but I have PDFs available for educational purposes….

“Letter by Radecki Regarding Article, ‘Safety of Thrombolysis in Stroke Mimics: Results From a Multicenter Cohort Study'”http://stroke.ahajournals.org/content/early/2013/08/08/STROKEAHA.113.002040.full.pdf+html

tPA Proponents Want to Have It Both Ways

I’m sure I sound like a bit of a broken record – yet again covering further attempts by the stroke neurology literature to continue expanding use of tPA for acute stroke beyond its initial, narrowly selected treatment population. This observational, retrospective review from SITS-ISTR would like you to know:

“…this is the first observational study demonstrating that intravenous alteplase therapy within 4.5 to 6 hours of stroke onset for patients compliant with other EU approval criteria resulted in comparable rates of SICH, mortality, and functional independence to treatment initiated within 3 hours. This observation persisted in the multivariate analysis after adjustment for baseline imbalances.”

No difference in outcomes between 0-3h, 3-4.5h, and 4.5-6h – in both guideline-compliant and protocol-violation cohorts, and both adjusted and unadjusted results. The authors, all receiving honoraria or grant support from Boehringer Ingelheim would like you to believe this analysis, also funded by Boehringer Ingelheim, supports a benefit for tPA up to six hours.

…but didn’t we just cover Jeff Saver’s JAMA article that “proved” an obvious time-to-treatment effect, favoring faster treatment?

Which of these observational, retrospective, registry reviews provides us the truth? Is there a time-to-treatment effect that decays benefit with time, or, as this registry suggests, no difference between any time frames?

I suppose it depends on your specific professional conflicts-of-interest.

“Results of Intravenous Thrombolysis Within 4.5 to 6 Hours and Updated Results Within 3 to 4.5 Hours of Onset of Acute Ischemic Stroke Recorded in the Safe Implementation of Treatment in Stroke International Stroke Thrombolysis Register (SITS-ISTR)”
www.ncbi.nlm.nih.gov/pubmed/23689267‎

Dermabond … The Tongue?

In an addition to the pages of possibly brilliant innovations, this is a case report of an attempt to use 2-octyl cyanoacrylate (Dermabond) on the tongue. The authors document a gaping laceration to the tongue on a pediatric patient – and a family that refused consent for sedation and suture repair. So, even though Dermabond is not recommended for use on mucosal surfaces – onward!

After extensive drying, the authors document secure and successful closure. However, at the 24 hour wound check, the glue had begun to detach, requiring removal of the first application and a second treatment. No further complications were encountered, and a 14-day revisit showed complete resolution of the injury.

I agree with these authors – the tongue is not a trivial repair, particularly in the unruly youth. The risk is probably minimal – although, the tissue adhesive could be problematic if it comes detached. The laceration itself is documented in images – and, while it’s possible the still images don’t tell the story, I’m not sure it necessitated any repair at all.

I appreciate the novel use, but it’s unclear if this is a technique worth much enthusiasm in revisiting.

“Pediatric Tongue Laceration Repair Using 2-Octyl Cyanoacrylate (Dermabond)”
www.ncbi.nlm.nih.gov/pubmed/23827167