Category: Medication Safety

Again With No Antibiotics, This Time for UTI

Frequent readers of this blog may have noticed a bit of an anti-antibiotic tendency.  Diverticulitis!  Strep throat!  All manner of upper respiratory symptoms!

How about urinary tract infections?

This German study randomized ambulatory women with urinary tract infection symptoms and positive findings on urine dipstick to either fosfomycin plus placebo tablets for three days, or simply ibuprofen for three days.  Patients were then reassessed after three days, and those with treatment failure were provided an additional course of antibiotics.  “Co-primary” endpoints were antibiotics utilization and the AUC of sums of daily symptom scores.

The results are, like last week’s URI trial, a little mixed.  The authors included 484 patients in their intention-to-treat analysis, and 77% of them ultimately had culture-positive UTIs.  A lot – 69% – of patients randomized to ibuprofen had spontaneous resolution of their symptoms and avoided antibiotic use for their UTI.  However, obviously, those who did not improve spontaneously, and ultimately were given antibiotics, did worse than their fosfomycin counterparts – and the symptom scores clearly favored the antibiotic cohort.  Furthermore, 5 of 241 of patients randomized to ibuprofen advanced to pyelonephritis, and one more patient suffered ulcer-related bleeding due to ibuprofen.

I’m not sure how many women would opt for the trial of ibuprofen as part of a shared decision-making conversation, were practice to be based on this specific trial.  That said, it does raise a bit of an interesting question regarding potential strategies to reduce antibiotic use.  Would a 24- or 48-hour “waiting period” help?  If routine urine cultures weren’t already grossly low-value care, could waiting for those results help triage appropriate use of antibiotics?  Could a different symptom adjunct, such as pyridium, help reduce the difference in symptom scores while awaiting spontaneous resolution?

Regardless, it is is yet again an insight into the general effectiveness of the human body’s natural antibacterial defense mechanisms.  How much of modern medicine is critically important – and how much is simply are mildly harmful minor ameliorations of mostly self-limited disease processes?

“Ibuprofen versus fosfomycin for uncomplicated urinary tract infection in women: randomised controlled trial”
http://www.bmj.com/content/351/bmj.h6544

The Antibiotic Mandatory Waiting Period?

It has become generally accepted within the medical community the vast majority of cases of pediatric otitis media will resolve without antibiotics.  However, the tradition of treating OM with antibiotics is slow to wane, fueled by momentum and parental expectations.  Some success has been achieved with delayed-prescription strategies, where parents are provided with antibiotics, but encouraged to wait a few days and observe for spontaneous improvement.

These authors applied the same school of thought to benign upper respiratory tract infections – sinusitis, pharyngitis, and bronchitis.  They randomized 398 patients with common URTI-spectrum symptoms to one of four treatment strategies:  immediate antibiotic initiation; antibiotics provided immediately, but patient encouraged to wait-and-see a few days for spontaneous improvement; antibiotics available for pick-up three days later, if desired; and no antibiotics.  The primary outcome was duration and severity of symptoms, with various secondary outcomes of absenteeism, satisfaction, and antibiotic utilization.

The results of this study are a little bit mixed.  The patients initiating antibiotics immediately had shorter symptoms duration than any other strategy.  The sample sizes are small, and the standard deviation of symptoms in each cohort is huge, but it’s probably reasonable to estimate antibiotic use truncated moderate or severe symptoms by about a day or a day and a half from a 5-6 day illness duration.  Twelve of 98 randomized to no prescription ultimately crossed over to antibiotics.

But the remainder, despite their randomization to benign neglect, improved regardless, without any detectable difference in safety outcomes.  After all, the majority of these infections are either viral, or self-limited bacterial infections handled by the body’s natural immune system without complications.

The interesting outcomes, however, were the two delayed-antibiotic strategies.  Compared to the 91% antibiotic usage rate of the immediate antibiotic group, the patient-initiated and delayed-collection strategies resulted in 33% and 23% antibiotic usage rates, respectively.  Symptom duration, as to be expected, was mildly attenuated, falling between immediate antibiotic use and no antibiotics.

Is this the happy medium strategy needed to finally divorce ourselves from our addiction to unnecessary care for URTI disease?  “Choosing Wisely” as a general philosophy doesn’t seem to have had the desired effect – how about an executive action to mandate the same waiting period for antibiotics as we have for guns?

“Prescription Strategies in Acute Uncomplicated Respiratory Infections: A Randomized Clinical Trial”
http://www.ncbi.nlm.nih.gov/pubmed/26719947

The Opiate Overdose Train

There is a certain inalterability about trains.  Their travel is predictable and linear.  Slowing and stopping are extended affairs.  It’s hard for a train to make a sharp turn.

Apparently, opiate prescribing is like that.

This study reviewed administrative data from a health insurer to identify patients receiving long-term opiate therapy.  Patients were then included for analysis if they had a visit to an Emergency Department or a hospitalization related to heroin or opiate overdose.  These same patients were then followed for up to 2 years following the index overdose, and their opiate prescribing tracked.

With a median follow-up of 299 days, opiates were dispensed to 91% of patients following opiate overdose – 7% of whom went to to repeated overdose, many of whom had multiple overdose events.  Some patients had their opiate quantities curtailed, but the majority received the same – or even more – opiates after the overdose event.

Certainly, some of this prescribing is still appropriate – our tools for managing severe pain are grossly inadequate, and in hospice settings, inadvertent overdose is an acceptable hazard of control of malignant pain.  But, just as certain, there is a cohort suffering the harms of shocking irresponsibility.

We’ve been getting bombarded with information regarding the harms of opiate prescribing for several years now; why are we still inflicting such great harm on the healthcare-seeking public?

“Opioid Prescribing After Nonfatal Overdose and Association With Repeated Overdose”
http://annals.org/article.aspx?articleid=2479117

The Disutility of Acetaminophen for Influenza

Wait … what?

This headline: “Acetaminophen Appears To Be Ineffective Against Flu.”

Hopefully, when you saw that either in the ACEP member daily news e-mail, or on the Reuters distribution, you had the same befuddled reaction as me.  Even better, the coverage includes this fascinating fearmongering from one of the authors:

“What this study does is raise some very serious questions about the real evidence base for using acetaminophen routinely for anyone that has the flu.”

Actually, it doesn’t.

This is a randomized, double-blind, placebo-controlled study of patients with suspected influenza, treating with five days of either scheduled acetaminophen or placebo.  The primary outcome was the area under the cure for quantitative PCR influenza log(10) viral load from baseline to day 5.  Patients were admitted to a clinical trials unit for the first 48 hours, then followed up in clinic at day 5 and day 14.  Secondary outcomes included symptom scores for health and temperatures of each patient.  The authors based their power calculation on the standard deviation for PCR viral load, and estimated to have 80% power to detect a difference greater than that standard deviation, they would need 80 patients with influenza.

Over the course of two influenza seasons, 2011 and 2012, they were able to enroll: 46

More specifically, they enrolled 46 patients with PCR-confirmed influenza.  The other 34 patients had false-positives on the rapid assay used for enrollment, and could not be included in their primary outcome analysis.  Because of their inadequate sample size, it is therefore mostly nonsensical to comment on their failure to find statistical differences in their outcomes.  However, there do not appear to be any potentially clinically important clues hiding in plain sight.

Bafflingly, one of their discussion points notes “These findings raise questions about the anti-pyretic efficacy of paracetamol in influenza and other respiratory infections.”  The mean temperature in the 80 patients randomized to placebo never even exceeded a 38°C “fever” threshold.  Then, the mean temperature was actually normal on day 2-5.  To suggest acetaminophen fails to normalize fever in respiratory infection compared with placebo, fever ought be relatively ubiquitous in the study population.  Otherwise, there simply isn’t any clinical feasibility of detecting a difference.

Finally, what makes the questions about the use of acetaminophen most bizarre, the study was actually undertaken to confirm the safety of acetaminophen.  Their clinical trial registration states:

“Paracetamol is recommended for the routine treatment of fever and systemic symptoms in influenza. However, this recommendation is contrary to evidence which suggests that the presence of fever is protective in infections. This study aims to investigate whether the regular use of an antipyretic (paracetamol) during acute infection with influenza may prolong viral shedding and clinical symptoms.”

Setting aside the inability of their sample size to actually address their outcomes – their conclusions are based on a failure to detect a difference.  Therefore, their original concerns over potential harms from the anti-pyretic nature of acetaminophen ought to have been allayed!

Quite a long way from the headline at the top of this post.

“Randomized controlled trial of the effect of regular paracetamol on influenza infection”
http://www.ncbi.nlm.nih.gov/pubmed/26638130

More Futile “Quality”, vis-à-vis, Alert Fatigue

The electronic health record can be a wonderful tool.  As a single application for orders, results review, and integrated documentation storehouse, it holds massive potential.

Unfortunately, much of the currently realized potential is that of unintended harms and inefficiencies.

Even the most seemingly innocuous of checks – those meant to ensure safe medication ordering – have gone rogue, and no one seems capable of restraining them.  These authors report on the real-world effectiveness of adverse drug alerts related to opiates.  These were not public health-related educational interventions, but, simply, duplicate therapy, drug allergy, drug interaction, and pregnancy/lactation safety alerts.  These commonly used medications frequently generate medication safety alerts, and are reasonable targets for study in the Emergency Department.

In just a 4-month study period, these authors retrospectively identified 826 patients for whom an opiate-related medication safety alert was triggered, and these 4,742 alerts constituted the cohort for analysis.  Of these insightful, timely, and important contextual interruptions, these orders were overridden 96.3% of the time.  And, if only physicians had listened, these overridden alerts would have prevented: zero adverse drug events.

In fact, all 8 opiate-related adverse drug events could not have been prevented by alerts – most of which were itching, anyway.  The authors do attribute 38 potentially prevented adverse drug events to the 3.7% of accepted alerts – although, again, these would probably mostly just have been itching.

Thousands of alerts.  A handful of serious events not preventable.  A few episodes of itching averted.  This is the “quality” universe we live in – one in which these alerts paradoxically make our patients less safe due to sheer volume and the phenomenon of “alert fatigue”.

“Clinically Inconsequential Alerts: The Characteristics of Opioid Drug Alerts and Their Utility in Preventing Adverse Drug Events in the Emergency Department”
http://www.ncbi.nlm.nih.gov/pubmed/26553282

The Macrolide Scourge, Updated

We’ve had a couple prior alerts regarding the potential cardiovascular risks of macrolides.  These have been taken with quite the grain of salt, particularly considering macrolides were, at one point, prescribed in a trial thought to be cardioprotective.

This meta-analysis is probably the most reasonable data to date on the subject.  These authors (of which there are 17) gather 33 studies comprising 20,779,963 participants.  These studies show, reasonably consistently, small increases in ventricular arrhythmias and sudden cardiac death.  The relative risks reported are 2.52 for VT and 1.31 for SCD, and there was not much reliable variation between different macrolide antibiotics.
However, these relative risks translate into just a handful of additional cases per million prescriptions.  The number needed to harm with cardiovascular death is about 25,000.  On the flip side, across the included studies, the all-cause mortality was unchanged.  So, yes, perhaps macrolides are not entirely benign – but neither is the underlying condition for which they are prescribed.
Overall, this study doesn’t add much to our insight into appropriate macrolide usage.  There may be particular subgroups for whom they may be best avoided, but, the alternative agent must be equally effective against the existing pathology – and not have its own particular undesired interaction.

Of course, if macrolides are used in context where their benefit is minimal or zero – then there is only harm.

“The Role of Macrolide Antibiotics in Increasing Cardiovascular Risk”

The Great Reveal of Andexanet Alfa

The brave new world of “bleeding that doesn’t stop” is a little closer to ending today.  However, this is definitely just the smallest of baby steps in that direction – and hardly as straightforward and simple as the authors’ conclusion:

“Andexanet reversed the anticoagulant activity of apixaban and rivaroxaban in older healthy participants within minutes after administration and for the duration of infusion, without evidence of clinical toxic effects.”

This is ANNEXA-A and ANNEXA-R, two healthy-volunteer studies evaluating the utility of Andexanet Alfa for reversal of Factor Xa inhibitors.  Andexanet is a recombinant Xa decoy protein with a higher afinity for the Xa inhibitors than endogenous Factor Xa, having the net effect of restoring thrombin production.  In these studies, the 40-odd participants in each were housed at the study site for 8 days, loaded with either apixaban or rivaroxaban, and then assigned in a 3:1 or 2:1 ratio to receive either Andexanet or placebo.  Then, the participants were assigned to single-bolus dosing or bolus plus infusion.

The general gist of the outcomes is best visualized by the following graphic:

Andexanet, as expected, rapidly binds circulating Factor Xa.  However, there are two quite obvious, clinically important considerations.  First, reversal is very short-acting if only the bolus is given.  Then, it seems clear while the Factor Xa inhibitor is bound, it cannot be eliminated – and there is a rebound phenomenon to near-baseline levels once the infusion is stopped.  It appears this may be a very tricky drug to use in certain clinical scenarios, considering the duration of required reversal – especially if full and permanent effects are desired.

And, as noted before, this is just baby steps.  This handful of healthy volunteers did not have any specific adverse events related to the infusion, but the small numbers prevent any reliable conclusions regarding safety.  This is also just a pharmacokinetic study without clinical outcomes, and we don’t truly know its real-world effectiveness based on this publication.

It is quite an interesting innovation, but it still lands somewhere between “promising” and “minimally useful” – and almost certainly expensive.

“Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity”
http://www.nejm.org/doi/full/10.1056/NEJMoa1510991

Death From Pills

Now that physicians can be convicted of murder for irresponsible opiate prescribing, it’s worth reviewing precisely how we’re fulfilling our felonious destiny.

This is a brief look at the prescription drug-related deaths in San Diego County for the year 2013.  These authors identified each patient death, performed a pharmacy query for all the medications prescribed in the year prior, and then compiled descriptive statistics regarding the providers and specialties involved.  The results are disturbing, yet unsurprising.

  • Primary care provided the bulk of prescriptions related to the 254 deaths, whether opiates, benzodiazepines, or sleep aids.
  • Regarding opiates, 190 patients amassed 2,350 prescriptions totaling 205,700 pills – over 1,000 per patient.
  • Emergency providers were not terribly over-represented, and provided among the fewest pills per prescription, at 22.9.
  • The sample sizes of many subspecialties were small, but the 22 orthopedists captured by this analysis provided an average 169 pills each refill.
  • “Doctor shoppers” constituted 28% of patients, but received 51% of the total prescriptions.  Various surgical specialties seemed to be their primary target.

As irritating as unnecessary antibiotic prescriptions and their ilk may be, this is far more gruesome and disappointing a spectacle.

“Who is prescribing controlled medications to patients who die from prescription drug abuse?”
http://www.ncbi.nlm.nih.gov/pubmed/26476578

A Mostly Uninformative Back Pain Trial in JAMA

There were almost 3 million visits to U.S. Emergency Departments last year for low back pain – and, yet, it is fair to say we manage these visits poorly.  Patients typically continue to have pain at discharge, at long-term follow-up, and we inject a vast number of opiates into circulation in the course of treatment.

This trial, appropriately, looks at a few of our most common prescriptions: scheduled NSAID (naprosyn), an anticholinergic smooth-muscle relaxant (cyclobenzaprine), and an opiate (oxycodone-acetaminophen).  Patients presenting to Montefiore hospital in the Bronx were randomized into three arms, and medications distributed in placebo-controlled, blinded fashion.

However, the primary outcome was not exactly what you might expect.  These authors used a questionnaire describing functional impairment, and used the change in impairment from enrollment to 1 week as their primary outcome.  This is an interesting choice as, while it doesn’t encounter some of the subjectiveness of pain scales, level of function is a technically surrogate outcome for pain relief.  Then, since it can be reasonably suggested the simple passage of time is the curative element in most cases of acute low back pain, it reasonable to expect such disability to regress to the mean, regardless of therapy, by one week.  I wonder if these authors did not inadvertently choose an outcome likely to show no difference.

And, that is precisely what they found.  At 1 week and – in another odd timeframe choice – 3 months.

However, that’s not the entirety of the story.  They measured many different outcomes, including adherence, utilization of the as-needed study medication, desire for same medication, days of return to work, and self-reported pain.  None of these secondary outcomes can be parsed reliably, but the general signal throughout is one of increased relief with the use of opiates.  It should be noted the authors’ conclusion is worded carefully – simply stating these data “do not support the use” of the therapies tested.  I am all for the avoidance of opiates, but the outcome measurement in this study probably obfuscates any potential benefit, and may rather mask their utility.

Lastly, these authors screened 2,588 patients with a complaint of low back pain in order to identify 390 meeting their inclusion criteria.  Radicular pain, traumatic pain, long-standing back pain, and elderly patients were all excluded – and, clearly, make up the bulk of visits to the Emergency Department.  These data apply to only a very small subset of patients, and they were enrolled at a single center.  The generalizability of their findings is not ideal.

It’s not a sexy topic, but its prevalence certainly makes it an important one.  If a fraction of the hundreds of millions of dollars devoted to the development of me-too blockbuster copycat drugs were devoted to such common issues, we would have far better data to guide the bulk of our practice.  I love that these authors did this trial – I just wish their measurements and timeframes differed.

“Naproxen With Cyclobenzaprine, Oxycodone/Acetaminophen, or Placebo for Treating Acute Low Back Pain: A Randomized Clinical Trial”
http://jama.jamanetwork.com/article.aspx?articleid=2463257

Better Less than More for tPA

Ah, but this is not one of those rants about the inefficacy of tPA.  This is just an amuse-bouche of a mention of an article from Stroke, regarding a line of investigation in Asian countries.

In these countries, particularly Korea and Japan, there is some substantial thought given to “low dose” tPA being just as effective, with a lower risk of intracranial hemorrhage.  Interestingly, approximately 40% of acute stroke patients in Asian countries is at this lower dose, 0.6 mg/kg compared with the typical 0.9 mg/kg.  This study is a retrospective evaluation of registry data from 13 academic stroke centers, comparing 3-month outcomes on the modified Rankin Scale.

There were, essentially, two entertaining bits from this article:

  • The rate of symptomatic ICH in centers contributing at least 100 patients during the study period ranges from 3.7% on the low side up to 13.0% on the high.
  • Given the constraints of the study, they were unable to demonstrate any reliable difference between the two doses.  In fact, as you can see from the figure below, retrospective data can be adjusted, propensity matched, or essentially tortured to show whatever advantage preferred:

Should we be using low-dose?  And why stop at 0.6 mg/kg – why not 0.3 mg/kg?  And, further down the rabbit hole, back to the ideal dose of … none.  Ah, but I kid, I kid ….

“Low-Versus Standard-Dose Alteplase for Ischemic Strokes Within 4.5 Hours: A Comparative Effectiveness and Safety Study”
http://www.ncbi.nlm.nih.gov/pubmed/26243232