Category: Medication Safety

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

Punching Holes in CIN

Contrast-induced nephropathy, the scourge of modern medical imaging. Is there any way to prevent it? Most trials usually show alternative treatments are no different than saline – but what about saline itself?  Does saline even help?

This most recent publication in The Lancet claims: no. This is AMACING, a randomized, controlled trial of saline administration versus usual care in patients undergoing contrast CT. These authors recruited patients “at risk” for CIN (glomerular filtration rate 30-59 mL per min/1.73m2), and those assigned to the IV hydration arm received ~25 mL/kg over either 8 or 24 hours spanning the timeframe of the imaging procedure. Their primary outcome was incidence of CIN, as measured by an increase in serum creatinine by 25% or 44 µmol/L within 2-6 days of contrast exposure.

Regardless, despite hydration, the same exact number of patients – 8 – in each group suffered downstream CIN. This gives an absolute between groups difference of -0.1%, and a 95% CI -2.25 to 2.06. This is still technically below their threshold of non-inferiority of 2.1%, but, as the accompanying editorial rightly critiques, it still allows for a potentially meaningful difference. Secondary outcomes measured included adverse events and costs, with no reliable difference in adverse events and obvious advantages in the non-treatment group with regards to costs.

This work, despite its statistical power limitations, fits in nicely with all the other work failing to find effective preventive treatment for CIN – sodium bicarbonate, acetylcysteine, et al. Then, it may also tie into the recent publications having difficulty finding an association between IV contrast and acute kidney injury. Do these preventive treatments fail because they are ineffective, or does the clinical entity and its suspected underlying mechanism not exist?  It appears a more and more reasonable hypothesis the AKI witnessed after these small doses of IV contrast may, in fact, be related to the comorbid illness necessitating imaging, and not the imaging itself.

“Prophylactic hydration to protect renal function from intravascular iodinated contrast material in patients at high risk of contrast-induced nephropathy (AMACING): a prospective, randomised, phase 3, controlled, open-label, non-inferiority trial”

http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)30057-0/abstract

The Emergency Narcotic Dispensary

Far and away, the most common initial exposure to narcotics is through a healthcare encounter. Heroin, opium, and other preparations are far less common than the ubiquitous prescription narcotics inundating our population. As opiate overdose-related morbidity and mortality climbs, increasing focus is rightly turned to the physicians supplying these medications.

This most recent article is from the New England Journal of Medicine, and is focused on the prescriptions provided in the Emergency Department. The Emergency Department is not one of the major prescription sources of narcotics, but may be an important source of exposure, regardless. Through a retrospective analysis of a 3-year cohort of Medicare beneficiaries, these authors defined two treatment groups: patients treated by a lowest-quartile of physician opiate prescribing rates, and those treated by a highest-quartile of physician opiate prescribing rates. The lowest quartile provided narcotics to approximately 7% of ED visits, while the highest to approximately 24%. In the subsequent 12 month period, those who received treatment by the highest-quartile of physician prescribing were more likely to fill at least an additional 6-month supply of another opiate. This adjusted odds ratio of 1.30 compared with the lowest-quartile includes a dose-response relationship with the two middle quartiles, as well.

The authors note this, essentially, means for every 48 patients prescribed an opiate above the lowest prescribing baseline, one additional patient then receives a long-term prescription they otherwise would not.  Their calculation is a little odd – factoring both the additional likelihood of a prescription and the absolute increase in subsequent prescription rates.  The true value likely lies between that and the NNH calculated from the absolute percentage difference – 0.35%, or ~280.  No reliable or specific harms were detected with regards to these patients – additional Emergency Department visits, deaths by overdose, or subsequent encounters for potential side effects were similar between the groups. It is reasonable, however, to expect these additional prescriptions have some small number of downstream harms.

There are many indirect effects measured here, including pinning the entire primary outcome observation on clinical “inertia” resulting from the initial Emergency Department prescription.  They also could not, by their methods, specifically attribute a prescription for opiates to any individual physician – they used the date of an index visit matched to a filled prescription to do so.

That said, the net effect here probably relates to less-restrictive prescribing resulting in prescriptions dispensed to patients for whom dependency is more likely. The effect size is small, but across the entire healthcare system, even small effect sizes result in potentially large absolute magnitudes of effect. The takeaway is not terribly profound – physicians should be judicious as possible with regard both their prescribing rate and the number of morphine equivalents prescribed.

Finally, the article concludes with a pleasing close-up photograph of a tiger.

“Opioid-Prescribing Patterns of Emergency Physicians and Risk of Long-Term Use”
http://www.nejm.org/doi/full/10.1056/NEJMsa1610524

Thrombolysis and the Aging Brain

The bleeding complications of thrombolysis are well-described, but frequently under-appreciated in the acute setting. Stroke patients often disappear upstairs after treatment in the Emergency Department quickly enough that we rarely see the neurologic worsening associated with post-thrombolysis hemorrhage.

Risk factors for post-tPA ICH are well-known, but often difficult to precisely pin down for an individual patient. This study pools patients from up to 15 studies to evaluate the effect of leukoariosis on post-tPA hemorrhage. Leukoariosis, essentially, is a cerebral small vessel disease likely related to chronic ischemic damage. It has been long-recognized as a risk factor for increased hemorrhage and poor outcome, independent of age at treatment.

In this study, authors pooled approximately 5,500 patients, half of which were identified to have leukoariosis. The unadjusted absolute risk of symptomatic ICH in those without leukoariosis was 4.1%, while the risk of those with was 6.6%. Then, looking at the 2,700 patients with leukoariosis, those with mild disease had an unadjusted absolute risk of 4.0%, compared with 10.2% for those with moderate or severe. Similar trends towards worse functional outcomes were also seen with regards to worsening leukoariosis.

The moral of the story: the baseline health of the brain matters. When discussing the risks, benefits, and alternatives for informed consent with a family, these substantial risks in those patients with leukoariosis should be clearly conveyed with regards to appropriateness of tPA when otherwise potentially indicated.

“Leukoaraiosis, intracerebral hemorrhage, and functional outcome after acute stroke thrombolysis”

http://www.neurology.org/content/early/2017/01/27/WNL.0000000000003605.abstract

More CLEAR!

Ah, the CLEAR trial – a trial evaluating the efficacy of intraventricular injections of alteplase for intracerebral hemorrhage with acute obstructive hydrocephalus. In other words, treating brain bleeds with an agent responsible for brain bleeds. It is not quite as nonsensical as it seems, however, as improved resolution of the intraventricular blood is linked to improved outcomes.

This trial, however, performed over the course of six years and enrolling 500 patients, fails to find anything reliable in favor of alteplase – a rather inconsequential end to a decade’s worth of build-up from the initial and phase II trial. At the end of the day, there was no significant difference between either treatment with regard to the primary outcome, patients attaining a mRS of 0-3.

It should also be noted the preliminary results from this trial were presented last year at the International Stroke Conference with breathless coverage:
“CLEAR III: tPA Clot Removal Hope for Intraventricular Hemorrhage”

Along with the lead author stating “This treatment saves lives. Our results suggest that physicians should begin to think about using it for stable hemorrhagic stroke patients.”

Which, now that we can all review the results together, is obviously not the case – nor is it their conclusion in the published article. These results do raise some questions – mortality was lower in the intervention group, and patients with improve clot evacuation also tended to do better – regarding potential subgroups for benefit. However, without further prospective data to confirm these signals, this intervention should continue to be reserved for controlled trials.

“Thrombolytic removal of intraventricular haemorrhage in treatment of severe stroke: results of the randomised, multicentre, multiregion, placebo-controlled CLEAR III trial”
https://www.ncbi.nlm.nih.gov/pubmed/28081952

Insight Is Insufficient

In this depressing trial, we witness a disheartening truth – physicians won’t necessarily do better, even if they know they’re not doing well.

This study tested a mixed educational and peer comparison intervention on primary care physicians in Switzerland, with an end goal of improving antibiotic stewardship for common ambulatory complaints. The “worst-performing” 2,900 physicians with respect to antibiotic prescribing rates were enrolled and randomized to the study intervention or none. The study intervention consisted of materials regarding appropriate prescribing, along with personalized feedback regarding where their prescribing rate ranked compared to the entire national cohort. The core of their hypothesis involved whether just this passive knowledge regarding their peer performance would exert normalizing influence over their practice.

Unfortunately, despite providing these physicians with this insight, as well as tools for improvement, the net effect of their intervention was effectively zero. There were some observations regarding changes in prescribing rates for certain age groups, and for certain types of antibiotics, but dredging through these secondary outcomes leads to only unreliable conclusions.

This is not particularly surprising data. These sorts of passive feedback mechanisms unhitched from material consequences have never previously been shown to be effective. There are other, more effective mechanisms – focused education, decision-support interventions, and shared decision-making – but, for a fragmented, national health system, this represented a relatively inexpensive model to test.

Try again!

“Personalized Prescription Feedback Using Routinely Collected Data to Reduce Antibiotic Use in Primary Care”

https://www.ncbi.nlm.nih.gov/pubmed/28027333

Opiates Versus NSAIDs, the Battle Continues

HealthDay says: “Opioids No Better Than Ibuprofen for Pain After Car Crash: Study”, leading with an assertion that prescription painkillers are no more effective than non-steroidal anti-inflammatory drugs. This was also picked up by the daily American College of Emergency Physicians e-mail newsletter.

So – no?

Despite the best of intentions, there is simply no reliable conclusion to be drawn from the cited publication. In the citation, the authors perform a propensity score-matching secondary analysis of prospectively collected observational data on patients discharged from the Emergency Department following a motor vehicle collision. There were 948 patients in their initial study cohort, with approximately half receiving a prescription at ED discharge. Propensity score matching then further excluded approximately 100 more, and finally patients lost to follow-up reduce their ultimate sample to 284. Their primary outcome was the presence of persistent self-reported moderate to severe pain six weeks after their MVC.

Unsurprisingly, with the wide confidence intervals mandated by their small sample, there was some overlap between the number in each group having persistent pain at six weeks. Thus, this leads the authors to make a guarded, but clearly anti-opiate, conclusion the evidence does not exist to recommend opiate therapy at ED discharge.

The bias in any underpowered study is to commit Type II error, which, as a reminder, is to retain the false null hypothesis in failing to detect an effect. Furthermore, as the authors note in their extensive methods section, in non-randomized studies, the measured and unmeasured confounders ultimately guide group assignment, which can bias the downstream results. The adjustments of propensity matching attempt to control for these, but tend to depend on large sample sizes and robust feature sets to reduce the magnitude of systematic bias – neither of which are present here. The need to impute missing data further reduces the reliability of under foundational data. Lastly, is their primary outcome relevant and related to the interventions examined? I am doubtful that six week persistent pain accurately reflects the scope of benefit (or lack thereof) relating to analgesic pharmacotherapy following MVC.

Avoiding the adverse effect of opiates is certainly important. However, this article should add little to the discussion – despite its lay medical press coverage.

“Persistent pain after motor vehicle collision: comparative effectiveness of opioids versus non-steroidal anti-inflammatory drugs prescribed from the emergency department—a propensity matched analysis”
http://journals.lww.com/pain/Abstract/publishahead/Persistent_pain_after_motor_vehicle_collision__.99393.aspx

No Guidance for Calf Clots from CACTUS

Treatment evidence regarding venous thromboembolism is not particularly sparse – except what to do about calf VTE. The most robust evidence is three decades old, and of little use for generalizing to modern diagnostic methods and direct oral anticoagulants.

This, then, is the CACTUS trial – a randomized, double-blind, placebo-controlled trial examining the need for treatment of isolated calf DVT with subcutaneous nadroparin. The primary outcome was a composite measure of extension of calf DVT to proximal veins, contralateral DVT, or symptomatic pulmonary embolism. Safety endpoints were bleeding, death, and treatment-related adverse events.

Sadly, this evidence is mostly bereft of guidance. Over the six-year course of this trial, they screened 746 patients and only enrolled 259 – 50% of their goal sample. There were four (3.3%) VTE in the nadroparin group compared with seven (5.4%) in the placebo cohort, and these differences failed to reach statistical significance. Furthermore, clinically significant bleeding occurred in one patient in the nadroparin group, along with one clinically significant adverse medication reaction (heparin-induced thrombocytopenia). Thus, the authors conclude: “Nadroparin was not superior to placebo in reducing the risk of proximal extension or venous thromboembolic events in low-risk outpatients with symptomatic calf DVT, but did increase the risk of bleeding.”

However, half the patients enrolled had deep muscular DVT, further reducing the risk profile of their already grossly underpowered cohort. Thus, the question remains open – and probably the most relevant evidence would come from an adequately powered trial comparing the natural course of disease to both oral antiplatelet agents and direct oral anticoagulants.
“Anticoagulant therapy for symptomatic calf deep vein thrombosis (CACTUS): a randomised, double-blind, placebo-controlled trial”

https://www.ncbi.nlm.nih.gov/pubmed/27836513

Thanks to Tom Deloughery (@bloodman) for his insights!