Month: June 2017

Questioning the Benefit of Non-Invasive Testing for Chest Pain

Welcome to the fascinating world of instrumental variable analysis!

This is a retrospective cohort analysis of a large insurance claims database attempting to glean insight into the value of non-invasive testing for patients presenting to the Emergency Department with chest pain. Previous version of the American Heart Association guidelines for the evaluation of so-called “low risk” chest pain have encouraged patients to undergo some sort of objective testing with 72 hours of initial evaluation. These recommendations have waned in more recent iterations of the guideline, but many settings still routinely recommend admission and observation following an episode of chest pain.

These authors used a cohort of 926,633 unique admissions for chest pain and analyzed them to evaluate any downstream effects on subsequent morbidity and resource utilization.  As part of this analysis, they also split the cohort into two groups for comparison based on the day of the week of presentation – hence the “instrumental variable” for the instrumental variable analysis performed alongside their multivariate analysis. The authors made assumptions that individual patient characteristics would be unrelated to the day of presentation, but that downstream test frequency would. The authors then use this difference in test frequency to thread the eye of the needle as a pseudo-randomization component to aid in comparison.

There were 571,988 patients presenting on a weekday, 18.1% and 26.1% of which underwent some non-invasive testing within 2 and 30 days of an ED visit, respectively. Then, there were 354,645 patients presenting on a weekend, with rates of testing 12.3% and 21.3%. There were obvious baseline differences between those undergoing testing and those who did not, and those were controlled for using multivariate techniques as well as the aforementioned instrument variable analysis.

Looking at clinical outcomes – coronary revascularization and acute MI at one year – there were mixed results: definitely more revascularization procedures associated with exposure to non-invasive testing, no increase in downstream diagnosis of AMI. The trend, if any, is actually towards increased diagnoses of AMI. The absolute numbers are quite small, on the order of a handful of extra AMIs per 1,000 patients per year, and may reflect either the complications resulting from stenting or a propensity to receive different clinical diagnoses for similar presentations after receiving a coronary stent.  Or, owing to the nature of the analysis, the trend may simply be noise.

The level of evidence here is not high, considering its retrospective nature and dependence on statistical adjustments.  It also cannot determine whether there are longer-term consequences or benefits beyond its one-year follow-up time-frame. Its primary value is in the context of the larger body of evidence.  At the least, it suggests we have equipoise to examine which, if any, patients ought to be referred for routine follow-up – or whether the role of the ED should be limited to ruling out an acute coronary syndrome, and the downstream medical ecosystem is the most appropriate venue for determining further testing when indicated.

“Cardiovascular Testing and Clinical Outcomes in Emergency Department Patients With Chest Pain”

http://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2633257

Diving to Save Lives

Hyperbaric oxygen therapy is easily as controversial a topic in Emergency Medicine as any. Many physicians and scientists believe HBOT is an essential treatment for carbon monoxide poisoning, with a goal toward restoring normal intracellular physiology as rapidly as possible. Other skeptics, however, point to the paucity of high-quality evidence in support of a logistically complex and expensive intervention.

This is a retrospective review from Taiwan evaluating outcomes of 25,737 patients recorded in their national health database as suffering from carbon monoxide poisoning. Of these, 7,278 patients received HBOT while the remaining 18,459. There were many significant and relevant differences between cohorts, with those not receiving HBOT tending to be older and have more medical comorbidities. On this substrate, unsurprisingly, the authors find a survival advantage – persisting through multivariate statistical adjustment – to receiving HBOT, with an adjusted hazard ratio of 0.74 (95% CI 0.67-0.81).

Despite the size of their sample, it is unlikely these data reflect a true treatment effect from HBOT. In a retrospective cohort such as this, the pervasive differences between groups almost certainly suggests confounding features influencing treatment decisions. Off the limited structured data recorded in this database, it is unlikely any statistical adjustment or matching technique will provide a better reliable estimate of any true mortality benefit – nor is a mortality benefit one of the expected outcomes of HBOT.

The authors also spend some time reporting the survival advantages associated with receiving HBOT more than once over the first month following the poisoning event. These positive findings are, effectively, the definition of survivorship bias – mortality directly affects the ability to receive multiple treatments. You can’t dive the dead, of course, so simply surviving to undergo additional treatments is erroneously associated with a benefit.

The authors eventually state “The results provide important references for decision making in the treatment of COP” – but, unfortunately, they tell us very little. The level of evidence supporting or refuting treatment with HBOT remains poor until an RCT of sufficient scale can be performed.

“Hyperbaric oxygen therapy is associated with lower short- and long-term mortality in patients with carbon monoxide poisoning”
https://www.ncbi.nlm.nih.gov/pubmed/28427969

The Door-to-Lasix Quality Measure

Will [door-to-furosemide] become the next quality measure in modern HF care? Though one could understand enthusiasm to do so ….

No.

No one would understand such enthusiasm, despite the hopeful soaring rhetoric of the editorial accompanying this article. That enthusiasm will never materialize.

The thrills stacked to the ceiling here are based on the data in the REALITY-AHF registry, a multi-center, prospective, observational cohort designed to collect data on treatments administered in the acute phase of heart failure treatment in the Emergency Department.  Twenty hospitals, mixed between academic and community, in Japan participated.  Time-to-furosemide, based on the authors’ review of prior evidence, was prespecified as particular data point of interest.

They split their cohort of 1,291 analyzed patients between “early” and “non-early” furosemide administration, meaning within 60 minutes of ED arrival and greater than 60 minutes. Unadjusted mortality was 2.3% in the early treatment group and 6% in the non-early – and similar, but slightly smaller, differences persisted after multivariate adjustment and propensity matching. The authors conclude, based on these observations, the association between early furosemide treatment and mortality may be clinically important.

Of course, any observational cohort is not able to make the leap from association to causation.  It is, however, infeasible to randomize patients with acute heart failure to early vs. non-early furosemide – so this is likely close to the highest level of evidence we will receive.  As always, any attempt at adjustment and propensity matching will always be limited by unmeasured confounders, despite incorporating nearly 40 different variables. Finally, patients with pre-hospital diuretic administration were excluded, which is a bit odd, as it would make for an interesting comparison group on its own.

All that said, I do believe their results are objectively valid – if clinically uninterpretable. The non-early furosemide cohort includes both patients who received medication in the first couple hours of their ED stay, as well as those whose first furosemide dose was not given until up to 48 hours after arrival.  This probably turns the heart of the comparison into “appropriately recognized” and “possibly mismanaged”, rather than a narrow comparison of simply furosemide, early vs. not.  Time may indeed matter – but the heterogeneity of and clinical trajectory of patients treated between 60 minutes and 48 hours after ED arrival defies collapse into a dichotomous “early vs. non-early” comparison.

And this certainly ought not give rise to another nonsensical time-based quality metric imposed upon the Emergency Department.

“Time-to-Furosemide Treatment and Mortality in Patients Hospitalized With Acute Heart Failure”

http://www.onlinejacc.org/content/69/25/3042

No Pictures of Poop Needed

I like this article – not because of any specific quality improvement reason relating to their intervention, but because it reminded me of something of which I perform too many.

It’s an easy trap to fall into, the – “well, let’s just see how much poop is in there” for diagnostic reassurance and to help persuade the family you’re doing relevant testing in the Emergency Department. However, here are the relevant passages from their introduction:

In a 2014 clinical guideline, the North American and European Societies of Pediatric Gastroenterology, Hepatology, and Nutrition found that the evidence supports not performing an AXR to diagnose functional constipation.

and

Recent studies showed that AXRs performed in the ED for constipation resulted in increased return visits to the ED for the same problem.

I feel some solace in knowing that 50 to 70% of ED visits for constipation may include an abdominal radiograph as part of their workflow – meaning I’m just, at least, part of the herd.

So, regardless of the point of their article – that a plan-do-act cycle of education and provider feedback successfully cut their rate of radiography from 60% to 20% – this is yet another misleading and/or unnecessary test to delete from our practice routine.

“Reducing Unnecessary Imaging for Patients With Constipation in the Pediatric Emergency Department.”
https://www.ncbi.nlm.nih.gov/pubmed/28615355

The FAST Is Wrong, Bob

What happens when you routinely do an unnecessary test that rarely changes management? Essentially, nothing.

So, here is a randomized, controlled trial demonstrating precisely that.

This trial looks at the Focused Assessment with Sonography in Trauma exam, as performed in pediatric blunt trauma patients. The FAST, if you recall, is generally indicated primarily for hypotensive blunt trauma patients – that is, it has supplanted diagnostic peritoneal lavage as a non-invasive alternative. It does not routinely provide a diagnosis, but it helps guide initial management and may triage a patient to emergency laparotomy rather than resuscitation and further testing.  Therefore, in a stable pediatric trauma patient, the pretest likelihood of a significant finding – free fluid relating to hemorrhage from trauma – is quite low. Furthermore, because many significant intra-abdominal injuries to solid and hollow organs are missed by ultrasound, a negative FAST has poor negative likelihood ratios and should not substantial affect decisions for advanced imaging as otherwise clinically indicated.

So, then, this trial is a bit of an odd duck with respect to any expected difference observed – and that’s precisely what they found in their “coprimary outcomes”. Among the 925 patients randomized to trauma team assessment alone or trauma team assessment supplemented by Emergency Physician FAST, there was no significant difference in imaging, Emergency Department length of stay, missed intra-abdominal injuries, or total hospital charges. The authors hypothesized, based on adult data, there might be savings at least in ED LOS – though, I might rather suggest adding in one more non-diagnostic test to the acute evaluation is more likely to mildly prolong LOS.

There are also issues generalizing this study setting, where ~53% of patients in each cohort received CTs, to other institutions. Interestingly, mean time to CT was over 2 1/2 hours, suggesting a great deal of observation and reassessment drove imaging decisions rather than the initial evaluation. Then, after expert review, EPs incorrectly identified a positive FAST in 10 out of 23 cases – and missed 11 true positives, as well.  The FAST, even at this academic medical center where it is done as routine, cannot be relied upon.

The sum of this evidence is: no change in practice. A stable patient is, by definition, stable for imaging as indicated – and the FAST is an unnecessary part of the initial clinical evaluation.

“Effect of Abdominal Ultrasound on Clinical Care, Outcomes, and Resource Use Among Children With Blunt Torso Trauma”

http://jamanetwork.com/journals/jama/article-abstract/2631528

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

What Does a Sepsis Alert Gain You?

The Electronic Health Record is no longer simply that – a recording of events and clinical documentation.  Decision-support has, for good or ill, morphed it into a digital nanny vehicle for all manner of burdensome nagging.  Many systems have implemented a “sepsis alert”, typically based off vital signs collected at initial assessment. The very reasonable goal is early detection of sepsis, and early initiation of appropriately directed therapy. The downside, unfortunately, is such alerts are rarely true positives for severe sepsis in broadest sense – alerts far outnumber the instances in a change of clinical practice results in a change in outcome.

So, what to make of this:

This study describes a before-and-after performance of a quality improvement intervention to reduce missed diagnoses of sepsis, part of which was introduction of a triage-based EHR alert. These alerts fired during initial assessment based on abnormal vital signs and the presence of high-risk features. The article describes baseline characteristics for a pre-intervention phase of 86,037 Emergency Department visits, and then a post-intervention phase of 96,472 visits. During the post-intervention phase, there were 1,112 electronic sepsis alerts, 265 of which resulted in initiation of sepsis protocol after attending physician consultation.  The authors, generally, report fewer missed or delayed diagnoses during the post-intervention period.

But, the evidence underpinning conclusions from these data – as relating to improvements in clinical care or outcomes, or even the magnitude of process improvement highlighted in the tweet above – is fraught. The alert here is reported as having a sensitivity of 86.2%, and routine clinical practice picked up nearly all of the remaining cases that were alert negative.  The combined sensitivity is reported to be 99.4%.  Then, the specificity appears to be excellent, at 99.1% – but, for such an infrequent diagnosis, even using their most generous classification for true positives, the false alerts outnumbered the true alerts nearly 3 to 1.

And, that classification scheme is the crux of determining the value of this approach. The primary outcome was defined as either treatment on the ED sepsis protocol or pediatric ICU care for sepsis. Clearly, part of the primary outcome is directly contaminated by the intervention – an alert encouraging use of a protocol will increase initiation, regardless of appropriateness. This will not impact sensitivity, but will effectively increase specificity and directly inflate PPV.

This led, importantly, for the authors to include a sensitivity analysis looking at their primary outcome. This analysis looks at the differences in overall performance if stricter rules for a primary outcome might be entertained. These analyses evaluate the predictive value of the protocol if true positives are restricted to those eventually requiring vasoactive agents or pediatric ICU care – and, unsurprisingly, even this small decline in specificity results in dramatic drops in PPV – down to 2.4% for the alert alone.

This number better matches the face validity we’re most familiar with for these simplistic alerts – the vast majority triggered have no chance of impacting clinical care and improving outcomes. It should further be recognized the effect size of early recognition and intervention for sepsis is real, but quite small – and becomes even smaller when the definition broadens to cases of lower severity. With nearly 100,000 ED visits in both the pre-intervention and post-intervention periods, there is no detectable effect on ICU admission or mortality. Finally, the authors focus on their “hit rate” of 1:4 in their discussion – but, I think it is more likely the number of alerts fired for each each case of reduced morbidity or mortality is on the order of hundreds, or possibly thousands.

Ultimately, the reported and publicized magnitude of the improvement in clinical practice likely represents more smoke and mirrors than objective improvements in patient outcomes, and in the zero-sum game of ED time and resources, these sorts of alerts and protocols may represent important subtractions from the care of other patients.

“Improving Recognition of Pediatric Severe Sepsis in the Emergency Department: Contributions of a Vital Sign–Based Electronic Alert and Bedside Clinician Identification”

http://www.annemergmed.com/article/S0196-0644(17)30315-3/abstract

PCCs for Non-Warfarin ICH?

This quick post comes to you from the EMedHome weekly clinical pearl, which was forwarded along to me with a “Good stuff?” open-ended question.

The “good stuff” referred to a series of articles discussing the “CTA spot sign”, referring to a radiologic marker of ongoing extravasation of blood following an intracranial hemorrhage. As logically follows, ongoing bleeding into a closed space has been associated with relatively increased hematoma growth and poorer clinical outcomes.

However, the post also highlighted – more in an informational sense – an article highlighting potential use of prothrombin concentrate complexes for treatment of bleeding, regardless of anticoagulation status. We are all obviously familiar with their use in warfarin-related and factor Xa-associated ICH, but this article endeavors to promote a hypothesis for PCC use in the presence of any ICH with ongoing radiologically apparent bleeding.

The evidence produced to support their hypothesis? A retrospective 8 patient cohort of patients with ICH and CTA spot sign, half of whom received PCCs and half who did not. Given the obvious limitations regarding this level of evidence, along with problems of face validity, there is no reason to revisit their results. The EMedHome pearl seemed to suggest we ought to be aware of this therapy in case a specialist consultant requested it. Now, you are aware – expensive, unproven, and not indicated without a substantially greater level of evidence to support its use.

“Role of prothrombin complex concentrate (PCC) in Acute Intracerebral Hemorrhage with Positive CTA spot sign: An institutional experience at a regional and state designated stroke center”
https://www.ncbi.nlm.nih.gov/pubmed/27915393

Angiotensin II for Refractory Shock

If you blockade the angiotensin receptor system, you have a treatment for hypertension. If you agonize that same system, it logically follows you may have a corresponding treatment for hypotension. So, this is ATHOS-3, a phase 3 trial of synthetic human angiotensin II infusion in patients with catecholamine-resistant shock.

Roughly speaking, this is a trial evaluating the effectiveness of angiotensin for improving hemodynamic parameters in adult patients in vasodilatory shock – defined by the trialists as based on sufficient cardiac index, intravascular volume measurements, and persistent hypotension. Enrolled patients also needed to display ongoing hemodynamic derangement despite “high-dose vasopressors”. Exclusion criteria abound. The primary outcome was achievement of mean arterial pressure targets at 3 hours after initiation of angiotensin or placebo infusion.

Over the ~1.5 year study period, 404 patients were screened to ultimately initiate study protocol in 321. There’s little ambiguity with respect to the primary outcome – 69.9% of patients met MAP targets in the angiotensin cohort compared with 23.4% with placebo. Improvement in MAP led to corresponding downtitration of catchecholamine vasopressors in the intervention cohort. The intervention cohort displayed improvements in the cardiovascular SOFA, but no difference in overall SOFA at 48 hours. Mortality was quite high, regardless of group assignment, and no reliable difference was noted. Adverse events were common in each group with, again, no reliable differences detected.

This trial is mostly just interesting from a scientific awareness standpoint. The beneficial or harmful effects of angiotensin infusion are not established by these data. The enrolled population – approximately one patient every four months per site, on average – cannot be reliably generalized. As with any sponsored trial replete with conflict of interest among the authors – and particularly those with slow enrollment due to extensive exclusions – skepticism is particularly warranted. That said, this novel vasopressor clearly warrants additional study and comparative effectiveness evaluation.

“Angiotensin II for the Treatment of Vasodilatory Shock”
http://www.nejm.org/doi/full/10.1056/NEJMoa1704154