Category: Medication Safety

Prescribing Opiates to the Entire House

Opiate prescribing has blossomed into an appropriately huge issue in the current medical landscape. A fair bit of thought now goes into evaluating individuals for their potential for use and misuse – including even state-mandated prescription database review.

But, this interesting analysis suggests it should not only be the individual recipient considered when prescribing – but the impact on the health of the entire household. These authors compared administrative health care claims from 12,695,280 patients with a family member prescribed opiates against 6,359,639 patients whose family members were prescribed a non-opiate analgesic. Within one year, 11.68% of family members of those prescribed an opiate subsequently received their own, compared with 10.60% in the non-opiate cohort. After statistical adjustment, the absolute difference narrowed somewhat, and the authors also report their sensitivity analysis cannot rule out invalidation of their findings by an unmeasured confounder.

Regardless, this fits with my anecdotal experience – where many patients coming in for musculoskeletal pain have used a family member’s leftover opiate medication for breakthrough pain control. Despite the underlying limitations from this statistical analysis, it certainly seems to have face validity. It is reasonable to consider not just the individual patient being prescribed opiates, but also the risk to the household as being a gateway to subsequent opiate prescribing for family members.

“Association of Household Opioid Availability and Prescription Opioid Initiation Among Household Members”
https://jamanetwork.com/journals/jamainternalmedicine/article-abstract/2664515

The Acetaminophen/Ibuprofen Ascendancy

The new hotness of the day is the piece out of JAMA comparing our various oral analgesic treatment options for acute pain the Emergency Department. This relatively mundane line of research has been relatively fertile over the last few years, so, what do we have in store here?

This was a double-blind, placebo-controlled trial of four different analgesic combinations for acute extremity pain. To enter the trial, one of the criteria was receipt of an imaging study, which served twofold: an assumed proxy for more serious injuries and pain, and because it increased ED length-of-stay enough to reduce patients lost to follow-up for their primary outcome. The primary outcome, then, was reduction in pain on a 0 to 10 numerical rating scale at the 2-hour mark, with an interim 1-hour mark recorded as well.

The study drugs were as follows: 400 mg of ibuprofen and 1000 mg of acetaminophen; 5 mg of oxycodone and 325 mg of acetaminophen; 5 mg of hydrocodone and 300 mg of acetaminophen; or 30 mg of codeine and 300 mg of acetaminophen. Approximately 100 patients per arm were targeted from their sample size calculations, and they ultimately randomized 416 into generally similar groups with respect to final diagnoses.

The outcomes are essentially a wash – raising a question of whether there is any advantage to opiate therapy for this indication.  In our beautiful public health tapestry of increasing opiate misuse and addiction, any opportunity to reduce opiate prescribing is important.  There are some reasonable takeaways with respect to the relative efficacy of ibuprofen/acetaminophen, oxycodone/acetaminophen,  hydrocodone/acetaminophen and codeine/acetaminophen combinations, but their clinical relevance is highly questionable considering the doses tested in this study.  This is, unfortunately, essentially a straw-man comparison between an adequate dose of non-opiate analgesia compared with the least-adequate preparation of each of the commonly used combination opiate products.  A proper comparison in patients with severe pain ought to use a more typical maximal dose, which would probably be twice as much of each of the combination opiate products.

There are a few other small oddities relating to this study, of course. As an unavoidable consequence of the study setting, 60% of their study cohort identified as Latino and another 31% identified as black. There are potential genetic differences in pharmacokinetics relating to ethnicity, as well as cultural factors relating to the cohort enrolled at the study site, so the generalization of these data requires some caution. The study protocol states patients were to be asked whether they were satisfied with their pain control and side effects were to be recorded (nausea, vomiting, itchiness, etc.), but these are not reported in the final manuscript or supplement. Finally, these data are also limited, essentially, to sprains, fractures, and contusions. This represents an important slice of outpatients seeking analgesia, but may not be applicable to other types of pain.

Overall, however, this is reasonable evidence to support strategies of combination non-opiate therapy in patients without contraindications to both acetaminophen and ibuprofen.  It should not, however, be offered as evidence of the disutility of commonly used combination opiate preparations.

“Effect of a Single Dose of Oral Opioid and Nonopioid Analgesics on Acute Extremity Pain in the Emergency Department”

https://jamanetwork.com/journals/jama/article-abstract/2661581

And, The Safest Pediatric Sedation Drug Is …

Ketamine.

This ought not surprise virtually anyone, considering the vast body of experience physicians have performing safe, effective procedural sedation with ketamine. However, medicine is prone to its dogmatic confirmation bias, so I applaud these authors for this important report.

This is a prospective, observational, multi-center cohort specifically evaluating all episodes of procedural sedation for serious adverse events and important interventions. These authors recorded medication cocktails used for sedation, any adjunctive use of medication, the procedure performed, fasting status, and underlying health risks, and then tracked the outcomes of each procedure performed.

Ultimately, they included 6,295 children and sedation events in this study. The most commonly used sedation medications were ketamine, propofol, and combinations of ketamine, propofol, and fentanyl. Serious events were rare, occurring in about 1% of sedations – and, likewise, so were important interventions. Furthermore, the vast majority of events and interventions were simply temporary use of positive pressure ventilation in response to periods of apnea. Importantly, no patients required intubation or unplanned hospital admission. Oxygen desaturation was tracked separately from serious events and, along with vomiting, occurred in approximately 5% of sedation procedures.

With regard to other contributing factors to serious events or interventions, any deviation from ketamine monotherapy increased such risks. Whether it be combining ketamine with another opiate or benzodiazepine, or whether propofol were used alone or in combination, all increased the risk of serious events a small absolute amount over the baseline. Several figures included in the manuscript describe the various risk factors associated with serious outcomes with generally predictable associations, including increased risks with periprocedural opiate use, and decreased vomiting when ketamine were excluded.

Overall, even though the short answer to the question posed in the title is “ketamine”, the slightly longer answer is “any choice is probably fine”. Even though the relative risks are increased, the absolute risks are small – and the severity of interventions required, despite their labeling, were essentially benign.

“Risk Factors for Adverse Events in Emergency Department Procedural Sedation for Children”
https://www.ncbi.nlm.nih.gov/pubmed/28828486

Morphine Not a Good Adjunct For Pediatric Pain

Treating acute musculoskeletal pain in the Emergency Department is a common occurrence – and even on the docket as a time-to-analgesia quality measure. Where we frequently see failures and delays, however, are in children, with much written regarding oligoanalgesia and the dragging of feet before any sort of pain management. Furthermore, adults are frequently managed with opiate therapy, which, despite its various pitfalls, may be considered to stand above the commonly used ibuprofen and acetaminophen monotherapy in children.

So, does it work better to combine an oral non-steroidal analgesic with opiate therapy in children? Or, perhaps, is even an opiate alone better with regard to adverse effects? That is the question asked by this three-arm, double-blinded, placebo-controlled, randomized trial. Children with painful musculoskeletal injuries were randomized either ti 10mg/kg oral ibuprofen, 0.2mg/kg oral morphine, or the combination of both.

The winner is: not children. With 91 analyzed in the ibuprofen-only arm, 188 in the morphine-only arm, and 177 in the combination arm, there were no reliable differences between analgesia between groups. More disappointingly, the average pain score on the visual analogue scale was ~60mm across all groups, and no group improved more than 20mm within an hour. The authors considered a VAS score of <30mm at 60 minutes to represent adequate pain control, and less than a third from each group achieved this. There were no serious adverse events in any group, but 20% of those receiving morphine complained of mild adverse events, mostly nausea and abdominal pain, compared with 7% of the ibuprofen-only arm.

So, still at square one for oral analgesia – but, at least, this negative trial helps inform our avoidance of the intervention tested here.

“Oral Analgesics Utilization for Children With Musculoskeletal Injury (OUCH Trial): An RCT”
http://pediatrics.aappublications.org/content/early/2017/10/09/peds.2017-0186

Azithromycin Ruins Everything

For some reason – and by “some reason”, I mean extensive evaluation of immunomodulatory properties – there is an obsession with azithromycin use for more than simply its anti-bacterial indications. It has been hypothesized to diminish inflammation and have antiviral properties, and, of course, functions as a floor wax and dessert topping.

This is a randomized, controlled trial of azithromycin versus placebo in pre-school children with acute wheezing as a primary diagnosis. The primary outcome was time to resolution of respiratory symptoms, and secondary outcomes included any use of short-acting beta-agonists, adverse events, and time to any repeat exacerbation of wheezing.  These authors enrolled 300 before funding ran out, and were able to follow-up 222 with completed symptom diaries. Patients were generally similar between the two groups, and over 80% of each cohort had prior episodes of wheezing, and a similar percentage used or was prescribed a beta-agonist at discharge from the Emergency Department.

The winner: nothing and no one. Azithromycin did not improve any outcomes versus placebo, and should not be used for suspected viral wheezing in the hopes of anti-inflammatory symptom improvement until better evidence of benefit emerges.

“Treatment of preschool children presenting to the emergency department with wheeze with azithromycin: A placebo-controlled randomized trial”
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0182411

The Futility of NSAIDs for Back Pain?

This article filled with reproach for non-steroidal anti-inflammatories was highlighted in a New England Journal of Medicine Journal Watch and on Twitter – a wistful treatise remarking on the general ineffectiveness of pharmacologic analgesics. “Nothing works!” accompanied by a general gnashing of teeth and writhing on invisible flames.

But – does this meta-analysis actually reach such a conclusion? Examine the first few words in their conclusion:

NSAIDs are effective for spinal pain …

Off to a good start! But, the catch:

… but the magnitude of the difference in outcomes between the intervention and placebo groups is not clinically important.

These authors pool the results of 35 randomized, placebo-controlled trials for “spinal pain”, which is to say undifferentiated pain relating anatomically to any part of the spine. These trials comprised 6,065 participants – or, if you do the math, an average of 173 patients per trial, nearly all of them performed over a decade ago. The pooled effects of these trials all favored NSAIDs – but, as the authors mention, the absolute magnitude of effect on pain scales was a the edge of their threshold for clinical significance. The authors defined a difference of 10 points on a 100-point scale as clinically important, but most of their pooled results landed between -7 and -16, favoring NSAIDs over placebo. With these small samples, generally moderate GRADE quality, and moderate to high heterogeneity between the pooled results, there is a lot of fuzziness around their ultimate conclusion.

These authors do many, other, exploratory analyses, and it is reasonable to suggest the limitations inherent to each render any conclusions unreliable. Adverse events, as reported, were similar between groups – excepting for increased gastrointestinal adverse events, most of which were non-serious. The authors report this difference as a relative risk of 2.5 for GI side effects in their comparison, but the absolute differences are on the order of an excess of 1 in 100.

This is probably much ado about nothing. Their perspective is not inaccurate, per se, but these trials do find a consistent benefit to NSAIDs. The value judgment here on clinical effectiveness probably misses the mark, particularly considering these are inexpensive, readily available, with few adverse effects in short-term use. I would probably argue it is easier to defend a position they still have utility in multi-modal pain control regimens, rather than to conclude they be consigned to the rubbish bin.

“Non-steroidal anti-inflammatory drugs for spinal pain: a systematic review and meta-analysis”

https://www.ncbi.nlm.nih.gov/pubmed/28153830

 

Idarucizumab, the Sequel

There’s nothing hotter than idarucizumab, the reversal agent for dabigatran. It’s so hot, the New England Journal of Medicine once published a farcical 91 patient interim analysis of a planned 500 patient enrollment.  Now, two years later, we have the full cohort and it’s, well, more of the same, with all the flaws previewed in the previous iteration.

To recap, there are no viable reversal options for dabigatran besides this antibody fragment. And, in full sucker-born-every-minute fashion, Boehringer Ingelheim is both good cop and bad cop, selling us both the poison and the antidote.

There are 503 patients enrolled in this open-label study with two arms: Group A, with uncontrolled bleeding, or Group B, anticoagulated and requiring an urgent procedure. The primary outcome is, essentially, utterly unrelated to any of the context of enrollment – “maximum percentage reversal of the anticoagulant effect of dabigatran within 4 hours after the administration of idarucizumab”, which is frankly already well-documented in the healthy-volunteer pharmacokinetic studies.

Theoretically, the interesting portion here is supposed to be the clinical relevance of the reversal effect – which is measured by secondary outcomes of subjective assessment of median time to cessation of bleeding in Group A or by periprocedural hemostasis in Group B. The most striking result in the interim result was a median time to cessation of bleeding of 11.4 hours – a concerningly high number calling into question the entire purpose of reversal. In this new publication, the median time to reversal is now reported as 2.5 hours. This also, oddly, differs from nearly identical cohort results presented to the American Heart Association – explicitly broken down as shown below:

Then, compare with this slide passed along by @bloodman from #ISTH2017 in Berlin:

Considering this was an easily critiqued result – and essentially the most clinically relevant – it’s not surprising the sponsor and their funded- and fee-supported collaborators solved the issue in the most expeditious fashion possible: exclude >55% of Group A from time-to-bleeding assessment.  Just toss out the patients who didn’t have cessation of bleeding within 24 hours, or – despite inclusion criteria of “signs and symptoms of (overt) uncontrolled bleeding” – the “bleeding location could not be identified”.

Most (93.4%) of patients in Group B were assessed as having normal hemostasis during their procedures, which occurred a median of 1.6 hours after completion of idarucizumab infusion. That said, many of the procedures were minimally invasive (catheter placement for dialysis, lumbar puncture, cutaneous abscess drainage) and likely favorably influenced both the fraction reported having normal hemostasis, as well as driving down the time to the intended procedure.

About 10% of the cohort had normal hemostasis at baseline as judged by the central laboratory, meaning they were likely not taking the dabigatran as reported or suspected – a smaller percentage than the interim analysis, where almost 25% were not. Whether this reflects better enrollment screening, or simply moving the goalposts again, cannot be reliably discerned from the results provided. Adverse events relating to the study drug, likewise, are difficult to parse without a true unexposed comparator.  Most of the cohort was elderly, with multiple comorbid conditions, in addition to their serious bleeding event or need for urgent procedural intervention. A handful of early thrombotic events and hypersensitivity-type reactions occurred, demonstrating there may yet be some consequential, but poorly quantified, risk to idarucizumab administration.

But, hand-wringing aside, we’re in the same place we were yesterday. Idarucizumab clearly and effectively removes dabigatran from circulation, unlike andexanet alfa and Factor-Xa inhibitors, and this ought to be occasionally clinically useful. I would certainly exhaust all potential supportive and expectant management options first, as well as try to definitively confirm dabigatran as the culprit for abnormal hemostasis. Ultimately, the best way to avoid idarucizumab? Don’t use dabigtran in the first place.

“Idarucizumab for Dabigatran Reversal — Full Cohort Analysis”

http://www.nejm.org/doi/full/10.1056/NEJMoa1707278

Icatibant … Can’t?

In a small, problematic, Phase 2 trial, icatibant – a selective bradykinin B2 receptor antagonist – seemed promisingly efficacious for the treatment of angiotensin-converting enzyme inhibitor-induced angioedema. Considering the catastrophic and potentially fatal complications relating to airway angioedema, the prospect of having an effective rescue medication is of substantial clinical importance.

Sadly, and first picked up by Bryan Hayes, the phase 3 trial was a wash. Published with great fanfare in the Journal of Allergy and Clinical Immunology: In Practice, this multi-center study enrolled 121 patients with presumed, and at least moderately severe, ACE-I-induced angioedema. The primary efficacy endpoint was the subjective “time to meeting discharge criteria”, which was guided by a scoring system consisting of difficulty breathing, difficulty swallowing, voice change, and tongue swelling. Secondary endpoints included time to onset of symptom relief, rescue therapy, and other safety considerations.

Almost all patients received some “conventional” therapy prior to randomization, with most (>80%) receiving antihistamines or corticosteroids and approximately one-fifth receiving epinephrine. The median time to doses of conventional therapy were ~3.5 hours, and enrolled patients received either icatibant or placebo ~3.3 hours afterwards.

The picture is worth all the words:

No difference.

Laudably – although this ought to be the default, without special recognition – the sponsor and these COI-afflicted authors unabashedly published these neutral findings with little sugarcoating. I will defer, then, to their closing sentence:

In conclusion, icatibant was no more effective than placebo in treating at least moderately severe ACE-Ieinduced angioedema in this phase III trial.

“Randomized Trial of Icatibant for Angiotensin-Converting Enzyme Inhibitor Induced Upper Airway Angioedema”
http://www.sciencedirect.com/science/article/pii/S2213219817301721

An Uninsightful Look at Traumatic ICH in Ground Level Falls

The ground is ubiquitous. There are many ways to injure oneself, but the typical readily available impact surface is the ground. The ground is particularly pernicious, it seems, in the elderly and those in assisted care facilities. Thus, we have a great number of patients for whom imaging decisions must be made in elderly patients who have fallen from, apparently, “ground-level”.

Many of these same elderly patients have multiple medical comorbidities, including those for whom antiplatelet or anticoagulant therapy is indicated. These patients are, then, at elevated risk for intracranial hemorrhage despite the apparent low mechanism of injury. Wouldn’t it be lovely if we had better descriptive data with which to estimate and determine those at greatest risk?

Unfortunately, this fundamentally flawed observational study design tells us quite little. These authors included every patient whose electronic health record included antiplatelet and anticoagulant medications, and subsequently had intracranial imaging ordered. The EHR, then, prospectively prompted clinicians to indicate “ground-level fall” as their mechanism of injury. Of 668 patients on antiplatelets, 29 (4.3%) demonstrated ICH on CT. Of 180 patients on anticoagulants, 3 (1.7%) suffered ICH. Another 91 were on some sort of combined treatment, and 1 (1.1%) suffered ICH.

And this tells us nothing, other than the risk of ICH is non-zero. Even from a simple frequentist statistical standpoint, the sample sizes are small enough the confidence intervals around these numbers are quite wide. Then, there is the problem of their screening methods – which starts after the decision has been made to perform CT. Unless it is specifically protocolized all patients with ground-level fall are mandated to perform CT, decisions to initiate imaging would depend on the selection bias of individual clinicians. Individual perceptions of the risk of ICH on antiplatelet and anticoagulant medications dramatically impact the rate of imaging – so this ultimately only tells us the risk for ICH in their uniquely selected population.  Additionally, without structured follow-up of those not imaged, neither the numerator nor the denominator are reliable in this estimate.

These patients fall out of all of our decision support instruments, and it would be lovely to have better information regarding their true risk and specific predisposing factors in order to be better stewards of imaging resources and costs. These data unfortunately do not add much to our decision-making substrate.

“Risk of Intracranial Hemorrhage in Ground Level Fall with Antiplatelet or Anticoagulant Agents”

http://onlinelibrary.wiley.com/doi/10.1111/acem.13217/abstract

Dexamethasone Dilemma

Look! On Twitter! Two highly-respected medical minds taking the same trial publication and producing two, very different responses:

The controversy stems from a small study examining the relatively common practice of treating pharyngitis with an oral steroid – usually dexamethasone – for its anti-inflammatory effect. Most pharyngitis does not require antibiotics, and physicians understandably prefer to try something to provide relief from suffering.

This study enrolled 576 patients in a randomized, placebo-controlled, double-blind trial in an outpatient general practice setting. Patients were provided either 10mg of oral dexamethasone or an identical lactose placebo. Patients could only enter into the trial if immediate antibiotics were not prescribed, but physicians were allowed to give a “delayed” prescription for failure to improve.

The trial is statistically negative for the primary outcome, complete resolution of sore throat at 24 hours. Of those assigned to dexamethasone, 22.6% had complete symptom resolution at 24 hours, compared with 17.7% of placebo, an absolute risk difference of 4.7% (-1.8 to 11.2)[sic]. The effect size is slightly larger at 48 hours, 8.7%, which does reach statistical significance – and thus the NNT noted above by Ian Stiell. Nearly all the other secondary outcomes – resource utilization, subsequent antibiotic use, use of pain relief – favor dexamethasone, but generally range in effect size between 1-4%.

Does the failure to meet statistical significance for the primary outcome refute this therapy as effective? Not hardly – but it certainly calls into question whether the difference is reproducible or clinically meaningful. Plug these data into Ioannidis’ framework regarding the reliability of research findings, and we see this is precisely the sort of work where both conclusions are reasonable. Is there a signal for a symptomatic benefit? Absolutely. The strength of the signal, however, is not strong enough to overcome whatever pre-study odds you placed on the treatment being successful. If, like many, you feel this is a treatment likely beneficial, this study appears confirmatory. If, like many, you feel systemic steroids for symptomatic pharyngitis is inane, this study does little to change your view of the inadequate risk/benefit ratio.

Another possible interpretation of these data is the possibility of variable effects within subgroups, where the entire small effect size seen in these data results from a more substantial effect size in some fraction of the cohort. For example, the mean duration of symptoms was ~3.9 days, with a SD of ~1.7 days. Could the recency of symptoms be associated with likelihood of benefit? Any secondary analyses such as these, particularly in a small trial like this, would only serve as fodder for future investigations.

I have seen, however, other folks using this as an opportunity to link to the recent BMJ publication regarding adverse events and corticosteroid exposures. Without delving into that publication in detail, it would be a mistake to generalize those data to this population. That said, systemic corticosteroids are certainly not harmless. These authors rather ludicrously state “Short courses of oral steroids have been shown to be safe, in the absence of contraindications” – justified by a citation from 1982.

The final answer is somewhere in between our two friends above. Dexamethasone will help some patients with symptom relief from pharyngitis, and it will harm some.  Teasing out a prediction of the optimal risk/benefit for a patient is substantially challenging – and wide practice variation is justifiable from these data, as long as it is acknowledged the uncertainty in the evidence base.

“Effect of Oral Dexamethasone Without Immediate Antibiotics vs Placebo on Acute Sore Throat in Adults”
http://jamanetwork.com/journals/jama/fullarticle/2618622