Medication Safety – Page 11 – Emergency Medicine Literature of Note

Just Poop, It Doesn’t Matter How

Hepatic encephalopathy, a consequence of bacterial overgrowth and impaired ammonia metabolism, contributes to (as these authors say) nearly $2B in healthcare costs due to hospitalization in the United States alone. Typical, goal-oriented, modern therapy? Lactulose, a non-digestible sugar, resulting in increased bowel movement frequency.

These authors, appropriately, challenge established dogma – noting, perhaps, there are more effective strategies for clearing the bowels. As anyone who has undergone colonoscopy is aware, 4 liters of polyethylene glycol solution is the preferred – and highly-effective – bowel-cleansing method. These authors, therefore, compare standard lactulose therapy with a forced high-volume intake of PEG solution.

With 50 patients randomized in generally similar distribution to either lactulose or PEG, the PEG solution group more rapidly cleared mentation within 24 hours – with 21 of 25 randomized to PEG making at least 1 point improvement on the hepatic encephalopathy scoring algorithm, compared with 13 of 25 in the lactulose cohort. Victory! Of course, this sample is too small to truly account for any adverse effects. 8 serious adverse events occurred, include 3 deaths, although the authors feel none were related to the differences between treatment strategies. And, oddly, diarrhea was noted to be a more frequent adverse event in the PEG group.

Why is this odd? Because increased frequency of bowel movements is critical to treatment success in HES – and, frankly, if they’re not seeing enough stool output in the lactulose group, they might be doing it wrong. There’s no specific mention of outputs in the lactulose group, but, ideally, treatment of HES involves a rapid titration of lactulose to adequate stool volume, not a rigid treatment dose. As such, I might suggest this is a bit of a straw-man comparator between PEG and lactulose, with regard to tests of superiority.

But, I applaud simply thinking outside the box. Lactulose use has become somewhat dogmatic for the treatment of HES, when, clearly, the answer is just – poop, it doesn’t matter how.

Thanks to Rick Pescatore for forwarding this along.

“Lactulose vs Polyethylene Glycol 3350-Electrolyte Solution for Treatment of Overt Hepatic Encephalopathy”
http://www.ncbi.nlm.nih.gov/pubmed/25243839

Merry Christmas!

If you truly must read literature on Christmas, then I direct you to thebmj, and a selection of articles from its Christmas issue:

“Televised medical talk shows—what they recommend and the evidence to support their recommendations: a prospective observational study”
http://www.bmj.com/content/349/bmj.g7346

“CARTOONS KILL: casualties in animated recreational theater in an objective observational new study of kids’ introduction to loss of life”
http://www.bmj.com/content/349/bmj.g7184

“When somebody loses weight, where does the fat go?”
http://www.bmj.com/content/349/bmj.g7257

“Are some diets “mass murder”?”
http://www.bmj.com/content/349/bmj.g7654

Ketamine For You! And You and You and You!

Over the last decade, ketamine has shifted from pariah status to celebrity, increasingly popular for procedural sedation, delayed-sequence intubation, treatment of intracranial hypertension, and even status epilepticus. There is also a smattering of trials demonstrating its use for inpatient post-operative patients as an opiate-sparing mechanism – but how well does it work in the Emergency Department?

These authors from Brown evaluated use of ketamine for adjunctive pain control in a small, three-arm prospective, blinded comparison between “usual care”, and two doses of ketamine. Patients with severe acute pain received 0.1 mg/kg of morphine up to 10mg, followed either by placebo injection, 0.15 mg/kg ketamine, or 0.3 mg/kg ketamine. Patients were then followed for need of rescue medication.

With only 20 patients in each group, the potential for type I and type II errors are substantial. All groups derived substantial pain relief from treatment. Patients in the two ketamine groups, however, derived a greater degree of relief – and required a lower gross amount of rescue analgesia. The authors eke only a few “statistically significant” p-values out of their tiny samples, but, regardless, the underlying differences likely appropriately reflect an expected acute analgesic effect from ketamine.

Unfortunately, the largest limitation of the small sample concerns the incidence of adverse events. The largest dose of ketamine, 0.3 mg/kg, had clearly distressing effects – half the patients felt dizzy – while both ketamine groups included a handful of patients with nausea, vomiting, and confusion. On the flip side, two patients in the standard-care group suffered possible morphine-related hypotension and respiratory depression as a result of rescue analgesia.

Ketamine may have a role in acute analgesia in the Emergency Department. However, appropriate dosing and ideal patient selection remain unclear.

“Low-dose Ketamine Improves Pain Relief in Patients Receiving Intravenous Opioids for Acute Pain in the Emergency Department: Results of a Randomized, Double-blind, Clinical Trial”
http://www.ncbi.nlm.nih.gov/pubmed/25377395

No Good Ever Comes of Dabigatran

Is anyone actually still using this drug? If so, why? There has been nothing but an endless progression of bad news associated with this medication – from Boehringer Ingelheim settling a massive lawsuit, the authors from RE-LY admitting they “missed” additional adverse events for a second time, and, now, further evidence describing flawed real-world effectiveness contrary to its supposed demonstrated efficacy.

The RE-LY trial showed non-inferiority for dabigatran at stroke prevention in non-valvular atrial fibrillation, but appeared to place patients at significantly lower risk of bleeding compared with warfarin. One of the critiques of RE-LY, however, is the patients were not appropriately representative of the general population at-risk for atrial fibrillation. By omitting chronic kidney disease and enrolling a generally white population in Europe, the generalizability of their findings is ultimately impaired.

And, thus, we see the fruits of such critiques. This is a retrospective cohort of Medicare beneficiaries prescribed either dabigatran or warfarin for atrial fibrillation. Based on propensity matched samples of 1,302 dabigatran users and 8,102 warfarin users, major bleeding of the dabigatran cohort exceeded that of the warfarin cohort – 9.0% (95% CI 7.8 – 10.2) versus 5.9% (95% CI 5.1 – 6.6). Risks were increased in the elderly, blacks, those with chronic kidney disease, and those on concomitant anti-platelet therapy.

So, we have a lesson – one of effectiveness versus efficacy, or one that’s an indictment of the original RE-LY study protocol. Medications should not be expected to perform the same in general use as they do in clinical trials – even those with tens of thousands of patients, such as RE-LY. Independent, confirmatory study ought be mandatory to ensure the safety of the public.

“Risk of Bleeding With Dabigatran in Atrial Fibrillation”

http://archinte.jamanetwork.com/article.aspx?articleid=1921753

Addendum:
Walid Gellad on Twitter points out this study in Circulation, published last week to much lesser fanfare, which uses a larger Medicare sample to come to the opposite conclusion – that dabigatran is better than, and safer than, warfarin. Which is correct? A subject for continued debate, to be certain. The correct answer is probably somewhere in between – dabigatran is safer for some, but more dangerous for others. However, given the lack of reversal – wouldn’t a Factor Xa inhibitor be a better choice, regardless?

Ondansetron vs. Metoclopramide in Hyperemesis

I hate to say it, but this is one of the first randomized trials I’ve stumbled across from Obstetrics and Gynecology – so, even though it’s not terribly profound, I felt compelled to cover it.

This is a double-blind, randomized trial of women admitted to observation with hyperemesis gravidarum. They received either 4mg of ondansetron or 10mg of metoclopramide every 8 hours for 24 hours, and patient were tracked for vomiting episodes and self-reported nausea. With regard to these co-primary outcomes, there was no difference between study drugs – most had full resolution, and most in each group had 2 episodes of vomiting or fewer. However, secondary outcomes and adverse effects – drowsiness, xerostomia, and persistent ketonuria – favored ondansetron.

The authors therefore conclude ondansetron ought probably be favored – all else being equal. But, for these authors, all else is not equal – ondansetron is markedly more expensive. Therefore, the ultimate conclusion of these authors is rather in favor of metoclopramide, considering their similar efficacy.

Of other interesting note, one patient, despite admission and supportive care, had 23 episodes of vomiting during the study period. Oy.

“Ondansetron Compared With Metoclopramide for Hyperemesis Gravidarum
A Randomized Controlled Trial”
http://www.ncbi.nlm.nih.gov/pubmed/24807340

Early P2Y12 Antagonists Just Don’t Seem Useful

When undergoing an early invasive strategy for myocardial infarction, the guidelines and trials typically support dual platelet inhibition. Most commonly, this regimen consists of aspirin and clopidogrel. However, the P2Y12 receptor antagonists ticagrelor and prasugrel have been promoted as options due to incremental increased platelet inhibition over clopidogrel. The theoretical benefits of early dual platelet inhibition include spontaneous lysis and prevention of re-thrombosis, as well as decreased early in-stent thrombosis. Unfortunately, the ACCOAST trial demonstrated early prasugrel was associated only with increased bleeding and no associated cardiovascular endpoint benefits.

Now we have ATLANTIC, with a similar treatment strategy, utilizing ticagrelor.

Which is also negative.

Negative for the “co-primary” endpoints of ST-segment resolution or pre-PCI TIMI flow grade, at least. The authors, however, focus on two other endpoints: bleeding, and in-stent thrombosis. These authors note, contrary to ACCOAST, there was no detectable difference in bleeding between the pre-hospital and in-hospital groups. They also note, as expected but not witnessed in ACCOAST, there was a reduction in short-term “definite” in-stent thrombosis. Therefore, the authors – by which I mean AstraZeneca and their ghostwriters – clearly present this secondary outcome (Figure 2) and conclude pre-hospital ticagrelor is safe.

Interestingly, there was a 1% absolute difference favoring pre-hospital ticagrelor in “definite” in-stent thrombosis at 30 days – but a 0.2% absolute difference favoring in-hospital ticagrelor in “definite or probable” in-stent thrombosis. For their definition, “probable” in-stent thrombosis included any death at 30 days for a patient receiving a stent. I’m not sure the expanded definition accurately reflects underlying stent thrombosis, but it is a fair combined endpoint to report for completeness.

There are a few differences between this trial and ACCOAST, however. In ACCOAST, patients were diagnosed with NSTEMI based on elevated troponin levels, and all were scheduled for coronary angiography 2 to 48 hours later. In ATLANTIC, patients were diagnosed prehospital with STEMI – and required to undergo PCI within 120 minutes. This reduced time of exposure to multiple anticoagulants may explain discrepancy in bleeding events between the trials. The in-stent thrombosis rate was also much higher in the peri-PCI antiplatelet group in ATLANTIC compared with ACCOAST, leading to the possibility of detecting a difference in in-stent thrombosis.

Details aside, however – it’s simply not clear there’s any advantage to utilizing these agents outside the peri-PCI environment. Regardless, I expect we will see more resources devoted to similar trials in slightly different populations, attempting to ferret out some subgroup and primary outcome definition capable of demonstrating a statistically significant benefit.

“Prehospital Ticagrelor in ST-Segment Elevation Myocardial Infarction”
http://www.nejm.org/doi/full/10.1056/NEJMoa1407024

United Kingdom Revisiting Safety of tPA

This odd and tragic saga continues: nearly 20 years after the original NINDS publication, we’re still going around and around with re-reviews of the same evidence. The recent news of this past week is the Medicines and Healthcare products Regulatory Agency in the United Kingdom will set up an expert panel to reevaluate the evidence in support of tPA for stroke. In light of a recent positive Cochrane Review, a positive individual patient meta-analysis, and a paucity of substantial new data – I cannot imagine what new insight will be uncovered.

This seems to have been brought about by correspondence, written by a British stroke neurologist, in The Lancet, describing the same series of arguments skeptics have been making for the last decade and a half. There are concerns over inadequate blinding of investigators, noting the alteplase infusion may be visually different from placebo, or that patients treated with alteplase possibly had observable minor bleeds from venipuncture sites. The manufacturer-sponsored nature of ECASS, ECASS II, and ECASS III is again cited, along with baseline imbalance regarding prior strokes favoring the treatment group in ECASS III. ATLANTIS is also mentioned as a negative trial, stopped early by interim futility analysis. He further mentions the lack of difference between <3h and 3-4.5h windows in observational registries, suggesting the underlying time-dependent hypothesis behind treatment with alteplase is flawed. And, most interestingly, he provides a funnel plot of outcomes by treatment center from NINDS, suggesting certain centers suspiciously had disproportionately positive findings.

Again, these are many of the same arguments made by other experts in their critiques of the evidence behind thrombolysis for stroke. As such, the responses – headlined by Peter Sandercock and Joanna Wardlaw – provide some of the same rebuttals as previously seen. Essentially, what it boils down to – again – is you either trust the data, or you don’t. And, given the suppressed evidence associated with Boehringer Ingelheim’s dabigatran product, not trusting the data remains a reasonable standpoint.

Whether the the MHRA enquiry will change any regulatory statutes is another issue entirely, and Ian Hudson states there will be a fair re-appraisal. However, Prof. Simon Brown points us to this interesting blog entry covering Mr. Hudson’s prior time at GlaxoSmithKline. This journalistic endeavor covers his potential role in overlooked safety concerns regarding paroxetine, as well as other conflicts of interest, and implies the enquiry is unlikely to be truly balanced.

Not to sound like a broken record, but only one thing will settle this debate, once and for all – a large, multi-center, randomized trial conducted independently from the manufacturers of alteplase and otherwise biased institutions. And, since the chance of that happening is basically nil – I imagine another decade from now, we’ll still be picking apart stroke research and debating the quality of the evidence.

“Questions about authorisation of alteplase for ischaemic stroke”
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(14)61385-4/fulltext

http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(14)61386-6/fulltext

http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(14)61387-8/fulltext

http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(14)61388-X/fulltext

The Scandal of Dabigatran – A Summary

We’ve been desperate for a more elegant solution to anticoagulation than rat poison for seemingly an eternity. Now, we have them: direct thrombin and factor Xa inhibitors. The studies supporting their use seem favorable.

But, as the old story goes – and as previously reported on this blog many times – Boehringer Ingelheim has been selectively reporting only the most favorable aspects of their flagship drug, dabigatran. Increased cardiovascular events have been downplayed through study design not powered to detect a difference. Issues with fixed dose therapy – and lack of a range of options for patients with renal impairment – rear their ugly head in multiple case reports.

Then, the most damning – the recent legal action reveals Boehringer Ingelheim, after selling dabigatran as not requiring monitoring nor having a reliable assay to monitor its effects, was hiding information on both counts. There is, in fact, substantial individual-patient variability in dabigatran efficacy and bleeding risk, and the HEMOCLOT test is, in fact, a reliable method of measuring activity. Review of internal documents shows employees were aware many patients might benefit from routine monitoring of levels – but this would eliminate one of its selling points (and cost savings) over warfarin. These e-mails also specifically address the potential damaging effect on sales if said information were released in the scientific literature.

Clearly, yet another case where first-mover status into a lucrative market trumped patient-safety concerns. If you wonder where the rampant skepticism regarding conflict-of-interest comes from on this blog – this is a beautifully flagrant example.

“Dabigatran: how the drug company withheld important analyses”
http://www.bmj.com/content/349/bmj.g4670 (free fulltext)

Previous EM Lit of Note Posts:
“Rivaroxaban Can Be Reversed, But Not Dabigatran” – Sept 2011
“Scattering Tacks In The Road” – Jan 2012
“Dabigatran — Uncharted Waters and Potential Harms” (Annals of Internal Medicine) – May 2012
“Dabigatran – It’s Everywhere!” – Sept 2012
“Not-So Routine Surgery on Dabigatran” – Sept 2012
“Dabigatran: Hidden Danger in the Home” – Nov 2012
“Dabigatran & CES1 SNP rs2244613” – Mar 2013

The Return of Metoprolol – for Anterior STEMI

Beta-blockade early in the course of myocardial infarction was once fashionable – until COMMIT demonstrated an excess of early cardiogenic shock detracting from subsequent late, favorable effects. This led to beta-blockade initiation being deferred until after hemodynamic stability established.

This study, METOCARD-CNIC, is a trial of early intravenous metoprolol prior to primary PCI in patients with anterior STEMI. 270 patients were randomized over two years to receive IV metoprolol pre-reperfusion versus standard initiation following PCI. These two publications describe a surrogate outcome based on infarct size seen in follow-up MRI, and patient-oriented outcomes of 2-year MACE and heart failure progression. And, overall, it’s a good thing – infarct size at 1 week was reduced from 32.0 to 25.6 grams, and long-term MACE at median 2-year follow up was reduced from 18.3% to 10.8%.

However, long-term MRI follow-up at twelve months showed infarcted myocardium measured at 15.7 grams in the intervention group versus 18.2 grams in the control – no longer statistically significant. And, the patient-oriented outcome of MACE is a combined endpoint of death, heart failure admission, reinfarction, and malignant arrhythmias – with most of the separation in groups coming from heart failure admissions and malignant arrhythmias, as opposed to hard endpoints.

But, at the minimum, this is worth continuing to investigate. There are likely patients, such as this anterior STEMI cohort, with Killip Class II or lower at presentation, that reasonably have a greater chance of benefit than harm from early metoprolol. This is also quite small study – but taken in the context of the prior evidence, an argument could be made to cautiously re-introduce this treatment strategy, ideally as part of prospective investigation.

“Effect of Early Metoprolol on Infarct Size in ST-Segment−Elevation Myocardial Infarction Patients Undergoing Primary Percutaneous Coronary Intervention”
http://www.ncbi.nlm.nih.gov/pubmed/24002794

“Long-Term Benefit of Early Pre-Reperfusion Metoprolol Administration in Patients With Acute Myocardial Infarction”
http://www.ncbi.nlm.nih.gov/pubmed/24694530

End-Tidal CO2 Monitoring Unhelpful in Sedation

Capnography during procedural sedation has rapidly become standard practice in the interests of “safety” – despite decades of Emergency Medicine experience safely performing sedation without. The theory: earlier detection of inadequate ventilation allows for intervention and prevention of hypoxemic episodes. In the most prominent randomized trial, there was a 17% absolute reduction in transient hypoxemic events. Critics appropriately point out, however, that transient events are hardly a meaningful patient-oriented outcome.

This trial, in which sedation was performed by nurses in an outpatient gynecology setting in the Netherlands, describes 427 patients randomized either to capnography or “routine monitoring”. Supplemental oxygen was not used in this setting, as these practioners considered it to obscure the additive value of pulse oximetry. Essentially by definition, all patients were female, and the median age was 24 with few co-morbidities.

Overall, 25.7% of patients in the capnography group developed hypoxemic episodes versus 24.9% of patients in the control group. There were also no differences in numbers of patients with profound hypoxemia (<81%) or prolonged hypoxemia (>60 seconds), although patients with hypoxemia in the capnography group had more frequent prolonged episodes than the control group (14.0% vs. 3.7%). Likely as a result, patients in the capnography group underwent airway positioning maneuvers more frequently (49.5% vs. 32.1%).

It’s a stretch to say this is information is generalizable to Emergency Department sedation. It is, at least, a useful window into what many skeptics have been saying all along – the additive value of capnography in sedation is low, and, rather, the extra information leads to additional interventions and procedural interruptions without measurable benefit. Procedural success in this setting was not adversely impacted by the frequent interruptions, however.

“Capnography During Deep Sedation with Propofol by Nonanesthesiologists: A Randomized Controlled Trial”
http://www.ncbi.nlm.nih.gov/pubmed/24836471