Category: Medication Safety

A Muddled Look at ED CPOE

Computerized Provider Order Entry – the defining transition in medicine over the last couple decades.  Love it or hate it, as UCSF’s CEO says, the best way to characterize the industry leader is that it succeeds “not because it’s so good, but because others are so bad.”  A fantastic sentiment for a trillion-dollar industry that has somehow become an unavoidable reality of medical practice.

But, it’s not all doom and gloom.  This systematic review of CPOE in use in the Emergency Department identified 22 articles evaluating different aspects of EDIS – and some were even helpful!  The main area of benefit – which has been demonstrated repeatedly in the informatics literature – was a reduction in medication prescribing errors, overdoses, and potential adverse drug events.  There was no consensus regarding changes in patient flow, length of stay, or time spent in direct patient care.  Then, on the flip side, some CPOE interventions were harmful – the effect of order set use as decision-support was implementation dependent, with some institutions seeing increased testing while others saw decreases.

A muddled look at a muddled landscape with, almost certainly, a muddled immediate future.  There are a lot of decisions being made in boardrooms and committees regarding the use of these systems, and not nearly enough evaluation of the unintended consequences.

“May you live in interesting times,” indeed.

“The Effect of Computerized Provider Order Entry Systems on Clinical Care and Work Processes in Emergency Departments: A Systematic Review of the Quantitative Literature”
www.ncbi.nlm.nih.gov/pubmed/23548404

Back For More With Cangrelor

Two negative studies weren’t enough to stop the Medicines Company from CHAMPION PHOENIX, the third attempt at demonstrating cangrelor is useful during PCI.

Cangrelor is a direct-acting platelet adenosine diphosphate inhibitor – same as prasugrel and clopidogrel – that differs in its half-life and route of administration.  Rather than clopidogrel, which is a long-acting oral loading dose during STEMI, cangrelor is a continuous intravenous inhibitor that wears off after minutes.  This has some theoretical advantages, such as when multiple lesions are found on invasive angiography and coronary bypass need not be delayed for the antiplatelet effects of clopidogrel to wear off.

So, PHOENIX follows up CHAMPION PCI and CHAMPION PLATFORM, each of which were negative for their primary combined endpoint of death, myocardial infarction, or ischemia-driven revascularization.  In fact, these studies were stopped at their interim analysis for futility, as they were unlikely to show superiority given the planned enrollment.

So, why does PHOENIX succeed where others have failed?  Well, they changed the primary endpoint to a new composite – death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis.  And, PHOENIX shows a 0.8% vs 1.4% advantage to cangrelor for stent thrombosis – which accounts for most of the new advantage in primary outcome.  In previous CHAMPION studies, stent thrombosis was 0.2% vs. 0.3% and 0.2% vs. 0.6%.  So, truly, cangrelor succeeds here mostly because the clopidogrel group fares so much more poorly, rather than on its own merits.  Considering 25.7% of the clopidogrel group received only 300mg rather than 600mg, and 36.6% received their clopidogrel during or after PCI, it’s no wonder they had greater stent thrombosis in this study.

It’s pretty clear the Medicines Company learned from its two negative studies and rigged the third one to succeed – and kept it just underpowered enough that severe or moderate bleeding with cangrelor didn’t reach statistical significance (0.6% vs. 0.3% p = 0.09).  This reinforces a bias frequently seen in sponsored trials – failure at first begets further trials, while initial success doesn’t lead to confirmatory RCTs that might cast doubts upon the authenticity of the golden goose.

“Effect of Platelet Inhibition with Cangrelor during PCI on Ischemic Events”
www.ncbi.nlm.nih.gov/pubmed/23473369

Dabigatran & CES1 SNP rs2244613

This piece of literature is incredibly important – not because of the specific clinical question it addresses, but, rather, because of the fundamental principle in medicine it illustrates.

In large, heterogenous populations – frequently clinical trials – the risks and benefits are not evenly distributed throughout the cohort.  However, when the primary outcome reported, this is based on the aggregate results.  This leads us to one of the primary flaws in evidence-based medicine, that statistical power typically comes at the expense of external validity to the individual patient.

This retrospective evaluation of the cohort from RE-LY, the trial comparing dabigatran to warfarin for the prevention of stroke in atrial fibrillation, evaluates genetic polymorphisms and their association with primary and safety outcomes.  In short, each minor allele of CES1 SNP rs2244613 was associated with lower trough concentrations and statistically significant interaction between treatment with warfarin and bleeding – hazard ratio 0.59 (0.46 – 0.76) for carriers and hazard ratio 0.96 (0.81 – 1.14) for noncarriers.  No difference in the primary stroke prevention outcome was apparent – but outcomes were infrequent and the study was underpowered to detect such a difference.

My take on these results is simple – the 32.1% of patients who are carriers for the rs2244613 allele account for most of the bleeding benefit seen in RE-LY, and the non-carriers have no bleeding advantage compared with warfarin.  We ought to be specifically tailoring and reducing the dabigatran treatment population to this subgroup with the most favorable risk profile – and we need to be developing tools that support this kind of individualized treatment throughout medicine.

“Genetic Determinants of Dabigatran Plasma Levels and Their Relation to Bleeding”
www.ncbi.nlm.nih.gov/pubmed/23467860

Stroke or Stroke Mimic? Who Cares!

Suppose you’re “lucky” enough to be taken to an experienced stroke center if you have stroke-like symptoms.  After all, they see strokes every day, are experts in the diagnosis of stroke, and have given thousands of patients thrombolytics.  However, how often might they be wrong, you ask?

Oh, they estimate about 1 in every 50.  But, truthfully, it’s probably much worse.

This is a multi-center observational cohort that purports to identify the percentage of patients treated with tPA and subsequently diagnosed with stroke mimics.  Out of the 5518 patients in their cohort, 100 were identified as stroke mimics.  Two of the 100 had sICH by NINDS criteria, but none died.  Therefore, these authors confirm, tPA is safe even when they’re wrong, and the collateral damage of racing to tPA is low.

Of course, their methodology for identifying a stroke mimic is hugely skewed towards maintaining the diagnosis of ischemic stroke.  Only patients in whom clinical details did not suggest a vascular etiology or a clear alternative diagnosis were labeled mimics.  Patients with nonspecific features, non-contradictory imaging, or lacking definite evidence favoring stroke mimic remained as diagnoses of acute stroke.

So, even at experienced stroke research institutions – 1 in 50 with the most generous of criteria.  What’s the chance real-world performance approaches anything close to this level of diagnostic skill?

The authors, of course, declare multiple financial conflicts of interest with the manufacturer of tPA.

“Safety of Thrombolysis in Stroke Mimics : Results From a Multicenter Cohort Study”
www.ncbi.nlm.nih.gov/pubmed/23444310

Informatics for Wrong-Patient Ordering

It seems intuitive – if, perhaps, the electronic health record has an updated problem list, and the EHR knows the typical indication of various medications, then the EHR would be able to perform some cursory checks for concordance.  If the orders and the problems are not concordant – then, as these authors propose, perhaps the orders are on the wrong patient?

This study is a retrospective analysis of the authors’ EHR, in which they had previously implemented alerts of this fashion in the interests of identifying problem lists that were not current.  However, after data mining their 127,320 alerts over a 6-year period, they noticed 32 orders in which the order was immediately cancelled on one patient and re-ordered on another.  They then conclude that their problem list alert also has the beneficial side-effect of catching wrong-patient orders.

A bit of a stretch – but, it’s an interesting application of surveillance intelligence.  The good news is, at least, that their problem list intervention is successful (pubmed) – because a 0.25 in 1000 patient alert yield for wrong-patient orders would be abysmal!

“Indication-based prescribing prevents wrong-patient medication errors in computerized provider order entry (CPOE)”
www.ncbi.nlm.nih.gov/pubmed/23396543

JAMA & Procalcitonin

Someday, I’ll publish another article summary that doesn’t involve a conflict-of-interest skewering.  I’m really not as angry as Rob Orman says I am.  This article, at least, is directly relevant to the Emergency Department.

There’s been significant research into biomarkers for infectious/inflammatory processes, with the goal of identifying a sufficiently sensitive assay to use as a “rule-out” for serious infection.  The goal is to use such an assay to prevent the overuse of antibiotics without increasing morbidity/mortality.  This is a good thing.

Procalcitonin is the latest darling of pediatrics and intensive care units.  However, to call the literature “inconclusive” is a bit of an understatement – which is why I was surprised to see an article in JAMA squarely endorsing procalcitonin-guided antibiotic-initiation strategies.  After all, I’ve previously covered negative trials in this blog (pubmed, pubmed).  However, these authors seem to have intentionally narrowed their trial selection to exclude these trials – and publish no methods regarding their systematic selection of articles.

The disclosures for all three authors includes “BRAHMS/Thermofisher”.  Who is this, you might ask?  Google points me to: http://www.procalcitonin.com – where BRAHMS/Thermofisher will sell you one of seven procalcitonin assays.  JAMA, third-ranked medicine journal in Impact Factor, reduced to advertising masquerading as peer-reviewed science.

“Clinical Outcomes Associated With Procalcitonin Algorithms to Guide Antibiotic Therapy in Respiratory Tract Infections”http://www.ncbi.nlm.nih.gov/pubmed/23423417

How to Fix Your Clinical Trial

Don’t like your study results?  Just drop the patients who inconveniently don’t benefit from treatment.  That’s what these authors have documented as occurring at Pfizer during the trials of gabapentin for off-label treatment of migraine prophylaxis, bipolar disorder, and neuropathic pain.

As part of legal proceedings against Pfizer, internal gabapentin study documents became available for public review.  These authors collected these internal study documents and attempted to correlate the study methods and enrollment between the internal documents and subsequent journal publications.  What these authors found were important irregularities between study protocols and published results.

Specifically, the authors identified at least two studies that randomized patients, but then failed to report their enrollment in subsequent publications.  In addition, even when patients were reported – the intention-to-treat analysis was altered to further exclude additional patients.  They also noted missing pre-specified safety analysis in nearly all publications, despite their present in original study protocols.

Clinicaltrials.gov and other transparency campaigns are steps in the right direction – but, clearly, those steps can be only of limited effectiveness if this sort of unethical results massaging remains rampant.

“Differences in Reporting of Analyses in Internal Company Documents Versus Published Trial Reports: Comparisons in Industry-Sponsored Trials in Off-Label Uses of Gabapentin”

Statistics For tPA & Profit

IST-3 broke new ground for misleading statistics in stroke trials with its secondary ordinal analysis, demonstrating “benefit” in the presence of an overall negative, open-label, randomized trial of over 3,000 patients.  Now, who here can decipher the Cochran-Mantel-Haenszel test?  Team Genentech/Boehringer Ingelheim is hoping you can’t.

This is a retrospective, observational cohort from the Virtual International Stroke Trials Registry looking for a way around the pesky “contraindications” to tPA treatment that currently prevent large groups of patients from receiving treatment.  These authors pulled non-treated “controls” from the cohort along with tPA-treated patients who had at least one contraindication or warning to tPA use and compared mRS outcomes at 90 days.  The control group was significantly older and sicker – though their strokes were milder (NIHSS 12 [SD 9] vs. NIHSS 14 [SD 8]) – but the authors adjusted only for age and NIHSS.  Their conclusion?

“Many of the warnings and contraindications of alteplase may not be justified and licences, guidelines, and protocols should be adjusted to accommodate recent data from registries and real-world experience.”

As the authors correctly note earlier in the paper, observational data combined from heterogenous trials spread over many years is likely rife with differences in care and selection bias.  This alone renders their results invalid as anything but hypothesis-generating, rather than practice-changing.

The other issue is their primary outcome and statistical tool of choice:

“The primary outcome measure was the mRS at 90 days, analyzed across the whole distribution of scores with the use of the Cochran–Mantel–Haenszel test,”

Here’s an example of an unadjusted mRS distribution “favoring” alteplase:

Just at first glance, looks pretty much the same – perhaps even favors placebo (top bar).  How the heck is this significantly positive towards tPA?  Well, the CMH takes into all ordinal levels – even the perturbations between disability/living death/death at the bottom of the scale – as opposed to just the clinically relevant mRS 0-1 or mRS 0-2 that were primary outcomes in other stroke trials.  So, the statistical significance in this test has nothing to do with the clinical efficacy of the treatment in question.  Then, the adjusted OR of 1.29 (95% CI 1.00 – 1.66) is somehow based on a mélange of “dichotomized outcomes at 90 days (mRS 0–1, mRS 0–2, NIHSS 0–1, and mortality)”.

I’m afraid this simply looks like the authors dragged the VISTA data through every permutation of statistical tools possible until they found a test and a combined endpoint for logistic regression that came out in favor of tPA.  And, then, sold it as practice-altering.

Disheartening.

Here’s the disclosures, for your reading pleasure:
BF has received modest honoraria for participation in clinical trials (Sanofi-Aventis). AVA has served as PI of CLOTBUST trial partially funded by Genentech, and currently serves as PI of CLOTBUSTER funded by Cerevast Therapeutics and consultant to Genentech. EB is an employee of Boehringer Ingelheim. JCG, CW, PL, and NKM have no relevant conflicts of interest. AM has served as a consultant for Boehringer Ingelheim, received speaker’s honoraria from Boehringer Ingelheim, and congress expenses from Lundbeck. NW has received expenses from Boehringer Ingelheim for his role as member of the steering committee in relation to the ECASS III trial with alteplase and served as a consultant to Thrombogenics as chairman of the DSMB. SITS International (chaired by NW) received a grant from Boehringer Ingelheim and from Ferrer for the SITS-MOST/SITS- ISTR. His institution has also received grant support toward administrative expenses for coordination of the ECASS III trial. NW has also received lecture fees from Boehringer Ingelheim and from Ferrer. AS and KRL have received research grants, modest honoraria for participation in clinical trials, and have a consultancy or advisory board relationship with manufacturers from drugs (including Boehringer Ingelheim). KRL administered the grant from Genentech for support of this study.

“Thrombolysis in Stroke Despite Contraindications or Warnings?”
stroke.ahajournals.org/…/STROKEAHA.112.674622.abstract

Lidocaine for Renal Colic

Just when you think you’ve heard it all – something new and different.  This is a randomized, blinded trial of morphine vs intravenous lidocaine for the management of flank pain associated with ureterolithiasis.  Why, do you ask?  Because, in Iran, they don’t have ketorolac as an option for renal colic.

Patients were enrolled based on clinical symptoms, and ureterolithiasis was confirmed by plain radiographs.  240 patients in generally well-balanced groups were enrolled; all patients received 0.15mg/kg IV metoclopramide for nausea, and then the groups were randomized to 0.1mg/kg of morphine vs. 1.5 mg/kg of intravenous lidocaine.  Pain outcomes were measured by visual analog scale at 5, 10, 15, and 30 minutes – and the short answer is, they both worked, and neither treatment had terribly significant side effects.

I am all for expanding the toolbox for Emergency Medicine, however unusual the idea might be.  After all, every so often, you might need an alternative agent for that extra-special patient who is allergic to ketorolac, morphine, acetaminophen, ondansetron, fentanyl, and the color blue….

“Effectiveness of intravenous lidocaine versus intravenous morphine for patients with renal colic in the emergency department”