Let’s Get Inappropriate With AHA Guidelines

How do you hide bad science?  With meta-analyses, systematic reviews, and, the granddaddy of the them all, guidelines.  Guidelines have become so twisted over the recent history of medicine the Institute of Medicine had to release a statement on how to properly create them, and a handful of folks have even gone so far as to imply guidelines have become so untrustworthy a checklist is required for evaluation in order to protect patients.

Regardless, despite this new modern era, we have yet another guideline – this time from the American Heart Association – that deviates from our dignified ideals.  This guideline is meant to rate appropriate use of advanced imaging in all patients presenting to the Emergency Department with chest pain.  This includes, for their purposes, imaging to evaluate nSTEMI/ACS, suspected PE, suspected syndromes of the aorta, and “patients for whom a leading diagnosis is problematic or not possible”.

My irritation, as you might expect, comes at the expense of ACS and “leading diagnosis is problematic or not possible”.  The guidelines weighing the pros and cons of the various options for imaging PE and the aorta are inoffensive.  However, their evaluation of chest pain has one big winner: coronary CT angiograms.  The only time this test is not appropriate in a patient with potential ACS is when the patient has a STEMI.  They provide a wide range of broad clinical scenarios to assist the dutiful reader – all of which are CCTA territory – including as every low/intermediate risk nonischemic EKG and troponin-negative syndrome, explicitly even TIMI 0 patients.

Their justification of such includes citation of the big three – ACRIN-PA, ROMICAT II, and CT-STAT – showing the excellent negative predictive value of the test.  Indeed, the issues with the test – middling specificity inflicted upon low disease prevalence, increased downstream invasive angiography and revascularization of questionable value – are basically muttered under the breath of the authors.  Such dismissive treatment of the downsides of the test are of no surprise, considering Harold Litt, of ACRIN-PA and Siemens, is part of the writing panel for the guideline.  I will, again, point you to Rita Redberg’s excellent editorial in the New England Journal of Medicine, refuting the foundation of such wanton use of CCTA in the emergency evaluation of low-risk chest pain.

The “leading diagnosis is problematic or not possible” category is just baffling.  Are we really trying to enable clinicians to be so helpless as to say, “I don’t know!  Why think when I can scan?”  The so-called “triple rule-out” is endorsed in this document for this exact scenario – so you can use a test whose characteristics for detection of each entity under consideration are just as degraded as your clinical acumen.

Fantastically, both the Society of Academic Emergency Medicine and the American College of Emergency Physicians are somehow co-signatories to this document.  How can we possibly endorse such fragrant literature?

“2015 ACR/ACC/AHA/AATS/ACEP/ ASNC/NASCI/SAEM/SCCT/SCMR/ SCPC/SNMMI/STR/STS Appropriate Utilization of Cardiovascular Imaging in Emergency Department Patients With Chest Pain”

The Value-Add of Ultrasound to STONE Score

There are a few major questions to be addressed in patients with suspected renal colic:
  • Is there an infection?
  • If there is a stone, will it pass spontaneously or require urologic intervention?
  • If I make a clinical diagnosis without CT, will I miss an important alternative diagnosis mimicking stone?
The STONE score addresses the last question – using a weighted decision instrument to classify patients with suspected stone into low-, moderate-, and high-risk cohorts for ureteral stone disease.  There are some issues with face validity for STONE, and likewise the validation has shown its performance to be somewhat inexact.  However, it helps reinforce gestalt and aids in shared decision-making.

This study adds in point-of-care ultrasound to assess the degree of hydronephrosis.  The hope of these authors was the presence of hydronephrosis would improve the performance of the STONE score by identifying the few patients with stones at the low- and moderate- end, while also using moderate or greater hydronephrosis to predict the need for subsequent urologic intervention.

The answer: only marginally.

Generally, the most useful positive likelihood ratios are above 10, and the most useful negative likelihood ratios are below 0.1.  In this study, only one LR potentially met that criteria.  The presence of moderate or greater hydronephrosis in a patient with a low likelihood of stone disease had a +LR of ~20 for both the presence of stone and for stone disease requiring urologic intervention – but this +LR was based on only a handful of patients, and the 95% CIs range from 4 to 110.

Lastly, did the presence of hydronephrosis rule out any important alternative diagnoses?  No.  Out of 835 patients, there were 54 with an important alternative diagnosis.  There were 11 patients with hydronephrosis plus an important alternative, including 3 appendicitis, 1 cholecystitis, 2 diverticulitis.  The presence of moderate or severe hydronephrosis was helpful, but would not obviate imaging for an alternative diagnosis if indicated.

“STONE PLUS: Evaluation of Emergency Department Patients With Suspected Renal Colic, Using a Clinical Prediction Tool Combined With Point-of-Care Limited Ultrasonography”

Is the 6-Hour CT for SAH Debate Over?

There has been a fair bit of back and forth about the validity of early CT in the setting of “thunderclap headache” to obviate a lumbar puncture in the search for aneurysmal subarachnoid hemorrhage.  David Newman and Kevin Klauer debated this subject a few years ago – and that was in all-comers, not simply those in the few hours following onset.

This most recent meta-analysis and systematic review gathers together all the published literature regarding early CT and the incidence of SAH on follow-up.  Including 8,907 patients from five publications, based on a few assumptions from retrospective studies, there were up to 13 missed cases of aneurysmal SAH occurring despite a negative CT within 6 hours of onset.  Worst-case sensitivity based on these data, then, was 0.987 (95% CI 0.971-0.994).

The prevalence of SAH in patients presenting with true thunderclap headache is estimated at ~10%.  The post-test odds, then, after a negative CT, are on the order of 0.1% – in line with David Newman’s posit of requiring 1000 LPs to catch one missed SAH.  The problem, then, lies in taking the next step in Bayesian reasoning – how likely is the positive LP to be true SAH?  If prevalence has dropped to 1 in 1000 after a negative CT, and the specificity of LP for SAH is only 65%, even a positive result barely budges the likelihood of disease.

How do you consent a patient for an invasive procedure in a setting in which a positive result has only the tiniest fraction of a chance of being real – and the treatments based on findings of follow-up examinations may be more likely to harm the patient than the magnitude of benefit associated with detection of a true positive?

“Sensitivity of Early Brain Computed Tomography to Exclude Aneurysmal Subarachnoid Hemorrhage: A Systematic Review and Meta-Analysis”

CTCA in the ED, Getting Less Sexy By The Day

As I’ve written before, the CT coronary angiograms is a funny test.  The idea of having a non-invasive method of detecting previously unknown coronary artery disease is compelling.  The practical application, however, has been limited by a low specificity – further exacerbated by those encouraging its use in a population with low pretest probability.

However, the few major studies regarding it tend to view CTCA in a favorable light – the result of comparing CTCA-based strategies to modern over-triage and over-testing of potential acute coronary syndrome.  These studies, ACRIN-PA and ROMICAT, showed significant improvements in direct discharge from the ED and in length-of-stay, not so much due to being a superior strategy of benefit to patients, but by obviating unnecessary care inflicted upon them.

The general gist of this trial is framed in the “era of high-sensitivity troponins” – referring to new developments in assays allowing a safer rapid rule-out in the Emergency Department.  This trial, as opposed to the others, also occurs in the Netherlands, a setting in which direct discharge from the ED is no anathema.  The “standard care” arms of ACRIN-PA and ROMICAT-2 had discharge rates from the ED of ~20% or less, while this trial discharges nearly 60%.  Yet, despite such recklessness displayed in this trial, these patients are ultimately just as safe.  And, when such an insanity-reduction initiative is undertaken, the advantages of CTCA diminish.

And, frankly, nearly all low-risk patients can be discharged safely from the Emergency Department.  The appropriate urgent follow-up test, if any, is a trickier proposition – and CCTA may yet be appropriate for some.  However, as a routine, ED-based strategy, it should probably be considered low-value care.

“Coronary CT Angiography for Suspected ACS in the Era of High-Sensitivity Troponins”

Give More tPA, Pretty Please?

There’s been another scientific update from Genentech-by-proxy, this time lamenting the low utilization for tPA in ischemic stroke patients.  This guideline panel from the AHA notes administering tPA in a safe and timely fashion to stroke patients is a non-trivial organizational exercise, but, what really gets their goat are the various exclusion criteria.  These criteria – minor symptoms, elevated blood pressure, acute trauma, etc. – are aimed at reducing the overall harms of tPA use, but to “help” as many patients as possible, the stroke neurologists believe it is necessary to break all the eggs.

This document, most prominently, is an entertaining exercise in linguistic calisthenics.  Clearly, these authors would like to treat as many patients as possible with tPA.  In their pursuit of these justifications, absent evidence, they torture the English language into providing he most diverse possible assortment of non-committal positivity.  To wit:
  • “There should be no exclusion …”
  • “Intravenous alteplase treatment is reasonable …”
  • “Intravenous alteplase administration for ischemic stroke may be considered …”
  • “…  it is reasonable that urgent intravenous alteplase treatment not be delayed …”
  • “Intravenous alteplase may be considered on a case-by-case basis.”
  • “Intravenous alteplase may be reasonable …”
  • “Use of intravenous alteplase in carefully selected patients … may be considered …”
  • “In acute ischemic stroke patients … intravenous alteplase may be carefully considered …”
  • “… administration of intravenous alteplase is reasonable and probably recommended …
  • “Intravenous alteplase treatment is probably recommended …”
  • “Patients … may benefit from intravenous alteplase …”
  • “… intravenous alteplase treatment appears safe and may be beneficial …”
  • “… intravenous alteplase may be as effective … and may be a reasonable option …”
  • “Intravenous alteplase is probably indicated …”
I.e., this scientific update may be a reasonably probably carefully considered option.  Or, as I've heard Jerry Hoffman say, each instance of the word "may" should be paired with its logical partner – "may not" – for the appropriately even-handed reading.

Other gems:
The risk of symptomatic intracranial hemorrhage in the SM population is quite low; thus, starting intravenous alteplase is probably recommended in pref- erence over delaying treatment to pursue additional diagnostic studies (Class IIa; Level of Evidence B).
The authors devote half a page to overstating the safety margin of tPA in stroke mimics by focusing on a single 100-patient cohort.  The clinical anecdotes of the two patient suffering sICH, and being lucky enough to survive, in this cohort are provided as apparently definitive reassurance.

For patients with mild but disabling stroke symptoms, intravenous alteplase is indicated within 3 hours from symptom onset of ischemic stroke. There should be no exclusion for patients with mild but nonetheless disabling stroke symptoms in the opinion of the treating physician from treatment with intravenous alteplase because there is proven clinical benefit for those patients (Class I; Level of Evidence A).
The pursuit of treating mild, but nonetheless disability symptoms is not new – and not specifically offensive.  However, they give this recommendation “Class I, Level of Evidence A”, which is the strongest level of support, based on, apparently, multiple randomized clinical trials or meta-analyses.  Except, however, their justification in the text for this recommendation is merely:
Alteplase may be beneficial for milder stroke cases judged as potentially disabling despite low NIHSS scores. The NINDS trialists explored 5 different definitions of minor stroke in a post hoc analysis and found benefit for alteplase across all definitions. However, data are not available on the effect of alteplase for milder stroke cases judged as not potentially disabling at presentation. Because nearly 3000 such cases of ischemic stroke were excluded from the 2 NINDS trials for mild symptoms, any analysis of mild symptoms within the 2 NINDS trials is difficult to interpret.
Why let the true level of evidence affect the final recommendation categorization?

If left to my own devices, this post could meander onward for an eternity.  I will, then, now step aside to allow the motivated reader to move along to source document itself.

“Scientific Rationale for the Inclusion and Exclusion Criteria for Intravenous Alteplase in Acute Ischemic Stroke”

Still Making Sense of High-Sensitivity Troponin

Figuring out the value of a troponin measurement is both simple, and complicated.  Big numbers are still straightforward and trouble.  Small numbers – and even smaller still – are increasingly difficult to parse.

What does seem to be true, at least: the closer to zero, the better.

This is a multi-center evaluation of a 0- and -1hour troponin delta strategy, based on a hs-cTnT from Roche.  These authors prospectively enrolled 1,458 patients with chest pain of peak intensity within 6 hours.  Samples were then taken at 0, 1, 2, and then at least 4 hours after presentation.  The outcome of interest was an independently adjudicated final diagnosis of acute myocardial infarction.  And, this study probably shows just about what every similar study has shown: initial sensitivity is ~90%, with marginal increases as additional time points are added, while specificity suffers predictably due to the nature of the assay.

However, there are a couple concerning potential sources of bias.  The authors enrolled 1,458 patients – but exclude 176 of them from analysis for a variety of reasons.  In a study trying to catch rare events to demonstrate near-100% sensitivity, over 10% of patients dropping out is an important consideration.  There were also issues with slow enrollment, compared to previous studies, and the patient flow diagram is extremely sparse.  Over two years, the centers involved likely had many thousands of chest pain presentations.  No information regarding the missed enrollments is presented.

There are also issues with the adjudication downstream, which was based on the results of various follow-up examinations as well as, oddly enough, a different troponin assay: s-cTnI-ultra.  213 (17%) patients received a final diagnosis of AMI, while 167 (13%) received a diagnosis of unstable angina.  The clinical significance of their definition of unstable angina remains unclear to me – myocardial ischemia without cellular injury associated with chest pain at rest.  The authors reference these UA patients as being at low risk for poor long term outcomes, which seems clinically discontinuous with the sort of “critical near-occlusion” working definition I’m familiar with for true UA.  Regardless, the safety of their strategy is only reasonable if UA is a relatively benign catch-all diagnosis for troponin-negative chest pain, so I will accept their categorization.

There were also diverse and perverse conflicts-of-interest described with the manufacturer of the assay involved.

Regardless, as previously stated, these data are consistent with prior demonstrations – so, yes, using these assays at presentation, or as 1- or 2-hour deltas in the Emergency Department, will result in a very low miss rate when paired with low pretest likelihoods of disease.  Furthermore, anything missed by these assays will be such a minute injury pattern as to be extremely low-risk for short term cardiac mortality.

Yes, Virginia, you can discharge chest pain.

“Multicenter Evaluation of a 0-Hour/1-Hour Algorithm in the Diagnosis of Myocardial Infarction With High-Sensitivity Cardiac Troponin T”