Category: Medication Safety

Another Expensive “Miracle”

Coronary artery disease – one of many self-inflicted wounds of Western society – fuels some of the largest pharmaceutical and device blockbusters of our time. Statins, stents, and the entire organization of our health system around STEMI care are all linked to coronary disease.

This JAMA article and its breathless lay coverage focus on a clinical trial for evolocumab (Repatha), one of the new proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. This trial, featuring evolocumab added to a statin versus a statin alone, evaluated this therapy using one of the most surrogate of surrogate markers: nominal change in percent coronary atheroma volume at 78 weeks.

As the press releases indicate, this trial was a massive success – the $14,000-per-dose PCSK9 inhibitor was positive for its primary endpoint. Patients taking just a statin continued to have excellent LDL levels and their coronary atheroma volume, as measured by intravascular ultrasound, was essentially unchanged. The evolocumab cohort, however, had even better LDL levels and … coronary atheroma volume was essentially unchanged. But, the difference between +0.05% and -0.95% is statistically significant, and therefore, the trial was a success.

There were, of course, in this trial with only 968 patients, no signals of clinically relevant benefit nor obvious reliable harm. Considering the fierce debate regarding whether statins are already overprescribed, despite being ubiquitously inexpensive, I do not see any reason to look forward to this $14,000 drug entering more widespread use.

“Effect of Evolocumab on Progression of Coronary Disease in Statin-Treated Patients: The GLAGOV Randomized Clinical Trial”
http://jamanetwork.com/journals/jama/fullarticle/2584184

More Coverage of Inappropriate Antibiotic Prescribing

If this feels like déjà vu, it might be because it is.

This short research letter in JAMA Internal Medicine describes patterns of antibiotic prescribing for three common conditions: otitis media, sinusitis, and pharyngitis. In all of these cases – in the infrequent occasion antibiotics are necessary – the appropriate first-line antibiotic is amoxicillin/penicillin. These authors estimate, based on treatment failures, allergies, and complicated disease, approximately 80% of antibiotic prescriptions for these conditions should be the first-line agents.

How did we do? Well, better in pediatrics than adults, but first-line prescribing ranged from a low of 37% to a high of 67%. The most commonly used inappropriate antibiotics were macrolides (invariably azithromycin) and fluoroquinolones. Macrolides are usually inappropriate due to high levels of resistance among common pathogens, and fluroquinolones are simply too broad-spectrum to be appropriate.

The catch, unfortunately, is the data source: the National Ambulatory Medical Care Survey, warts and all, from 2010 to 2011. The authors state they expect practice patterns have not changed much in the last five years, but it’s still a little challenging to generalize this to current practice.

Finally, as a nice corollary, this Medical Letter article was featured in JAMA regarding fluoroquinolones and their increasingly detected serious adverse effects. When antibiotics are truly necessary, physicians should try and choose one of the many alternatives presented in the article.

“Frequency of First-line Antibiotic Selection Among US Ambulatory Care Visits for Otitis Media, Sinusitis, and Pharyngitis”
http://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2571613

Finding the Holes in CPOE

Our digital overlords are increasingly pervasive in medicine. In many respects, the advances of computerized provider order-entry are profoundly useful: some otherwise complex orders are facilitated, serious drug-interactions can be checked, along with a small cadre of other benefits. But, we’ve all encountered its limitations, as well.

This is a qualitative descriptive study of medication errors occurring despite the presence of CPOE. This prospective FDA-sponsored project identified 2,522 medication errors across six hospitals, 1,308 of which were related to CPOE. These errors fell into two main categories: CPOE failed to prevent the error (86.9%) and CPOE facilitated the error (13.1%).

CPOE-facilitated errors are most obvious. For example, these include instances in which an order set was out-of-date, and a non-formulary medication order resulted in delayed care for a patient; interface issues resulting in mis-clicks or misreads; or instances in which CPOE content was simply erroneous.

More interesting, however, are the “failed to prevent the error” issues – which are things like dose-checking and interaction-checking failures. The issue here is not specifically the CPOE, but that providers have become so dependent upon the CPOE to be a reliable safety mechanism that we’ve given up agency to the machine. We are bombarded by so many nonsensical alerts, we’ve begun to operate under an assumption that any order failing to anger our digital nannies must be accurate. These will undoubtedly prove to be the most challenging errors to stamp out, particularly as further cognitive processes are offloaded to automated systems.

“Computerized prescriber order entry– related patient safety reports: analysis of 2522 medication errors”
http://jamia.oxfordjournals.org/content/early/2016/09/27/jamia.ocw125

Which is Safer – Rivaroxaban or Dabigatran (or Neither?)

The world of anticoagulation turned upside-down with dabigatran, and continued with the Factor Xa inhibitors: rivaroxaban, apixaban, and edoxaban. While RE-LY and its ilk showed, in the settings of controlled clinical trials, that these new agents were potentially superior, or at least non-inferior, to warfarin – which is best? Do we have any idea?

Unfortunately, such comparative effectiveness work is sadly lacking, and we are forced to try and glean safety data indirectly following approval. This study pools Medicare beneficiaries using the new agents for stroke prevention in the setting of nonvalvular atrial fibrillation, and attempts to observe “real world” outcomes.

The winner on stroke prevention: rivaroxaban, by a hair. The winner on bleeding: dabigatran, by a long shot, both intra-cranial and extra-cranial. Overall mortality, then, slightly favored dabigatran.

These data are retrospective and tortured by statistical matching methods, so their reliability is hardly bulletproof. What this does raise are more questions about the appropriate usage of these new agents – and further emphasizes the importance of prospectively performed patient-centered effectiveness research.

“Stroke, Bleeding, and Mortality Risks in Elderly Medicare Beneficiaries Treated With Dabigatran or Rivaroxaban for Nonvalvular Atrial Fibrillation”

http://archinte.jamanetwork.com/article.aspx?articleid=2560376

Imprecise Dosing of Liquid Medications

“Many parents are overdosing their kids, study says”. Is this true? Are parents poisoning their own children, as the headline implies?

Of course not; this is not in fact a study regarding overdose incidence at all. It is, quite simply, a measurement precision study.

This study involves 2,110 parents randomly assigned to measure doses of liquid medication in various quantities using either a cup, a 0.2mL syringe, or a 0.5mL syringe. Approximately a quarter of parents were >20% off with their measurement, and 2.9% doubled the instructed dose. Taking these results as a surrogate for overdose depends on the therapeutic range for a medication – so, while the headline is not technically incorrect, the implication is an exaggeration.

With regard to measurement and dosing errors, there were a few important trends to note. Health literacy had a large influence on dosing errors – regardless of whether teaspoons or mL were used in the instructions. Then, the cup: avoid the cup when possible. Almost three-quarters of parents committed measurement or dosing errors when asked to provide a 2.5mL dose in the cup. Stick to the syringe and target round numbers (5mL) to minimize errors.

With regard to the premise of overdose – for medications with a wide therapeutic range, these data are not quite as clinically relevant. However, for high-risk medications, more time and effort should be taken to demonstrate proper dosing with parents.

“Liquid Medication Errors and Dosing Tools: A Randomized Controlled Experiment”
http://pediatrics.aappublications.org/content/early/2016/09/08/peds.2016-0357

But Where is the Antidote to the Poison @NEJM?

Andexanet alfa is the long-awaited antidote for the Factor Xa inhibitors – rivaroxaban, apixaban, edoxaban, and their ilk. This publication, featured at the European Stroke Congress and in the New England Journal of Medicine, is Portola’s latest update regarding its utility. Is it better than their previous update – their failure to receive initial FDA approval – or just another “incomplete” like their publication last fall?

This is ANNEXA-4, an open-label, single-group study purporting to evaluate the efficacy and safety of andexanet for clinical hemostasis in actively bleeding patients with concomitant use of Factor Xa inhibitors. Or, more specifically, these are interim results – the first 67 of 250 planned for enrollment. The clinical efficacy endpoint is a complex series of adjudicated judgements regarding the cessation of bleeding, hematoma expansion, or change in hematocrit, depending on the type of bleeding enrolled. The primary safety endpoint is death or thrombotic event within 30 days – stroke, myocardial infarction, venous thromboembolism, etc.

There is virtually nothing positive to relate here. The authors, of course, relate that somewhere around 80% of the 47 patients included in their efficacy analysis obtained “good” or “excellent” hemostasis with 12 hours following their andexanet infusion. But, these essentially arbitrary labels at a potentially clinically unimportant timepoint tells us virtually nothing regarding its value versus observation, or an alternative treatment such as prothrombin concentrate complexes.

On the negative side, the list is endless. There is the baffling offensiveness of publishing what amounts to a quarter of a trial in the New England Journal of Medicine.  The mean time to andexanet bolus was nearly 5 hours, raising concern regarding the acuity and severity of bleeding in enrolled patients.  The vague, patient-oriented endpoints are meaningless – with or without a comparator – and thus, this boils down to basically a pharmacokinetic observational study. Even then, the pharmacokinetics don’t appear terribly favorable – andexanet dramatically reduces Factor Xa activity during infusion, but pops back to therapeutic anticoagulation following cessation. A concerning 18% had thrombotic events within 30 days – but, again, without any control group, little can be concluded regarding safety.

Finally, clearly, the NEJM has given up publishing the conflicts-of-interest for the authors because it would sum up to half the journal – this article directs the reader to the disclosure forms on the web. For the eagle-eyed reader, however, they can pick out this text as part of the author affiliations: “Portola Pharmaceuticals, San Francisco (J.T.C., A.G., M.D.B., G.L., P.B.C., S.G., J.L., B.L.W.)”. Yes, eight of the authors are employees of Portola Therapeutics, the manufacturer. Better even, are their ICJME form disclosures. John Curnutte, the Head of Research and Development, has checked the box stating he has no relevant conflicts of interest with the work under consideration for publication – but, you know, outside the submitted work he happens to be an employee for Portola. In fact, from what I can tell, every employee authoring this article declared they have no COI with the work under consideration for publication.

Inconceivable!

Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors
http://www.nejm.org/doi/full/10.1056/NEJMoa1607887

Tylenol & Case of the Flawed Fetus

If you’re like most folks advising pregnant patients on pain and fever control, you’ve advised against ibuprofen and recommended acetaminophen. It is, after all, considered to be generally safe throughout pregnancy, in contrast to the alternatives.

I’m afraid I do not know precisely what to make of this study, but it is the latest in a context of several other studies linking maternal acetaminophen use during pregnancy with behavioral issues in young children. These authors link surveys of pregnant women performed over a decade ago with follow-up surveys of their children, with specific emphasis on identifying potential cofounders for their observed association.

The ultimate conclusion is fairly clear from just the title, with the subtitle of “Evidence Against Confounding”. An association is clearly observed between those they identify with likely or confirmed usage of acetaminophen and increased behavioral and attention difficulties in childhood. However, the evidence against confounding is rather incomplete. There are small differences in maternal psychiatric illness, maternal smoking, and maternal alcohol use favoring normally behaved children – and, while these authors attempt to control for these factors, this still introduces some element of statistical tomfoolery. There are also several non-genetic and non-prenatal risk factors for ADHD, and these authors are able only to collect a handful of these – absent completely any observations of the home environment of the children evaluated. Finally, no dose-response relationship is ultimately measured, as well.

I would, of course, ultimately advise minimal medication exposure in pregnancy, regardless. If pain control is necessary, it is not clear this risk – if true – is specifically of greater magnitude than those associated with alternative analgesia. For, this does not yet change practice.

“Association of Acetaminophen Use During Pregnancy With Behavioral Problems in Childhood”

http://archpedi.jamanetwork.com/article.aspx?articleid=2543281

Shaking Out Stroke Mimics

In a world of continued aggressive guideline- and pharmaceutical-sponsored expansion of stroke treatment with thrombolytics, this article fills and important need – better codifying the predictors of stroke mimics. While other editorials espouse the need to be fast without being sure, this is frankly irresponsible medicine – and, in resource-constrained environments, unsustainable.

These authors at two academic centers performed a retrospective clinical and imaging review of 784 patients evaluated for potential acute cerebral ischemia. Patients were excluded if they had signs of acute stroke on initial non-contrast imaging, and if they did not subsequently undergo MRI. Based on review of the totality of clinical information for each patient, 41% of this cohort were deemed stroke mimics. The authors scoring system, then derived 6 variables – and 3 or more were present, the chance of stroke mimic being cause of the current presentation was 87.2%. Their criteria:

  • Absence of facial droop
  • Age <50 y/o
  • Absence of atrial fibrillation
  • SBP <150 mm Hg
  • Presence of isolated sensory deficit
  • History of seizure disorder

When the rate of tPA administration to stroke mimics is ~15%, and 30-40% of patients evaluated for stroke are stroke mimics – there is a lot of waste and potential harm occurring here. These authors suggest the use of this score could potentially halve these errant administrations for 94% sensitivity, or cut errant administrations down to 2% with 90% sensitivity. Considering the patients for which stroke/stroke mimic is an ambiguous diagnosis, it is reasonably likely the symptoms are of lesser severity – and in the range for which tPA is of most tenuously “proven” value. While their rule has not been prospectively validated, some of these elements certainly have face validity, and can be incorporated into current practice at least as a reminder.

“FABS: An Intuitive Tool for Screening of Stroke Mimics in the Emergency Department”

http://stroke.ahajournals.org/content/early/2016/08/04/STROKEAHA.116.013842.abstract

Dawn of the Stat Acupuncture Consult

For thousands of years, a smattering of herbology, naturopathy, and non-pharmacologic treatment formed the mainstay of medical practice. With recent seismic shifts away from vaccines and other pillars of medical therapy – will we remember the 20th century as the apex of the pharmacologic era of medicine?

This is a randomized, unblinded trial comparing morphine against acupuncture for acute pain syndromes in the Emergency Department. Patients were recruited with, essentially, severe pain without serious underlying illness – sprains, low back pain, headaches, renal colic and dysmenorrhea. Patients were treated with either 0.1mg/kg morphine with additional 0.05mg/kg doses every 5 minutes or protocolized acupuncture performed by an experienced practioner (who also happened to be an Emergency Medicine physician).

There were three hundred patients included in this trial, and there were a few differences between groups – the morphine group tended to have more abdominal pain, while the acupuncture group skewed towards low back pain. Regardless, the acupuncture group achieved similar – or better – pain relief than the morphine treatment arm. There were no major adverse events in either arm, although a little more than half of the morphine cohort experienced the typical minor effects of drowsiness or nausea.

Could it be prime-time for acupuncture? Probably not – one, small, single-center trial does not generalized across all practice settings. Additional validation should be performed – and, most importantly, a placebo effect needs to be excluded. However, this is quite the powerful placebo effect – and, at a minimum, should inspire further research on methods for triggering these same perceptual effects within the context of our current treatment modalities.

“Acupuncture vs intravenous morphine in the management of acute pain in the ED”
http://www.ajemjournal.com/article/S0735-6757(16)30422-3/abstract

The Downside of Antibiotic Stewardship

There are many advantages to curtailing antibiotic prescribing. Costs are reduced, fewer antibiotic-resistant bacteria are induced, and treatment-associated adverse events are eliminated.

This retrospective, population-based study, however, illuminates the potential drawbacks. Using electronic record review spanning 10 years of general practice encounters, these authors compared infectious complication rates between practices with low and high antibiotic prescribing rates. Spanning 45.5 million person-years of follow-up after office visits for respiratory tract infections, there is both reason for reassurance and reason for further concern.

On the “pro” side, cases of mastoiditis, empyema, bacterial meningitis, intracranial abscess and Lemierre’s syndrome were no different between those who prescribed high rates (>58%) and those with low rates (<44%). However, there is a reasonably clear linear relationship with excess follow-up encounters for both pneumonia and peritonsilar abscess. Incidence rate ratios were 0.70 compared with reference for pneumonia and 0.78 compared with reference for peritonsillar abscess. However, the absolute differences can best be described as “large handful” and “small handful” of extra cases per 100,000 encounters

There are many rough edges and flaws relating to these data, some of which are probably adequately defeated by the massive cohort size. I think it is reasonable to interpret this article as accurately reflecting true harms from antibiotic stewardship. More work should absolutely be pursued in terms of strategies to mitigate these potential downstream complications, but I believe the balance of benefits and harms still falls on the side of continued efforts in stewardship.

“Safety of reduced antibiotic prescribing for self limiting respiratory tract infections in primary care: cohort study using electronic health records”

http://www.bmj.com/content/354/bmj.i3410