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!

The Holiday Shift Expectation

Emergency physicians work holidays. It’s just part of the job description. I’ll be in the Emergency Department tomorrow, myself.

Which holidays are typically the lightest – according to this retrospective review from a single pediatric Emergency Department?

  • Probably no different: Washington’s Birthday, Memorial Day, Columbus Day, New Year’s Day
  • Probably lighter: Martin Luther King Day, Labor Day
  • Almost definitely lighter: Thanksgiving Day, Christmas Day

Hopefully we’ll all have good shifts together tomorrow!

“Predicting Flow in the Pediatric Emergency Department: Are Holidays Lighter?”
https://www.ncbi.nlm.nih.gov/pubmed/27253652

No, All Bacteria Do Not Require Antibiotics

The natural world is replete with bacteria.

Humans have existed on this planet for millennia.

In the ages before antibiotics, many humans succumbed to bacterial infections – while, of course, the vast majority survived.

This is not a profoundly reliable observational study, but it does help reinforce this basic concept. This report is a secondary analysis of the GRACE-10 study, which involved primary care patients recruited with a diagnosis of acute cough. The original study was a randomized, placebo-controlled trial for non-specific lower respiratory tract infection, as part of a genomics analysis for evaluation of antibiotic resistance.

This analysis, however, looks solely at the placebo arm, and examines the symptom course and resolution of those who were ultimately diagnosed with a bacterial cause of their LRTI and compares the with those who were not. Of the 834 patients included in their analysis (those with complete symptom diaries), 162 were thought to have a bacteria pathogen based on respiratory culture, nasal swab, or whole blood antibody titers.

S pneumoniae and H influenzae were the most common bacterial pathogens, with most of the remainder the “atypicals” for community-acquired pneumonia. And, at the end of the day: virtually everyone did fine. Patients with a confirmed bacterial pathogen in the setting of their LRTI improved slightly more slowly than those without, had more re-visits in follow-up due to worsening or new symptoms, and a greater percentage were placed on antibiotics in follow-up (12% vs. 6%). The remainder eradicated their bacterial pathogens without antibiotics – you know, the way humans and other contemporary mammals survived for eons.

Now, some of these cases positive for LRTI may be colonization and not pathogenic infection, while some of the negative cases were not diagnosed due to lack of sensitivity. But, regardless, the overall point of this article is probably valid – some bacterial infections will worsen, but in the generally healthy population, a delayed-antibiotic strategy might be valid as an attempt to improve antibiotic stewardship.

“Disease Course of Lower Respiratory Tract Infection With a Bacterial Cause”

http://www.annfammed.org/content/14/6/534.full

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