Is The Road to Hell Paved With D-Dimers?

Ah, D-dimers, the exposed crosslink fragments resulting from the cleaving of fibrin mesh by plasmin. They predict everything – and nothing, with poor positive likelihood ratios for scads of pathologic diagnoses, and limited negative likelihood ratios for others.  Little wonder, then, routine D-dimer assays were part of the PESIT trial taking the diagnosis of syncope off the rails. Now, does the YEARS study threaten to make a similar kludge out of the diagnosis of pulmonary embolism?

On the surface, this looks like a promising study. We are certainly inefficient at the diagnosis of PE. Yield for CTPA in the U.S. is typically below 10%, and some of these diagnoses are likely insubstantial enough to be false positives. This study implements a standardized protocol for the evaluation of possible PE, termed the YEARS algorithm. All patients with possible PE are tested using D-dimer. Patients are also risk-stratified for pretest likelihood of PE by three elements: clinical signs of deep vein thrombosis, hemoptysis, or “pulmonary embolism the most likely diagnosis”. Patients with none of those “high risk” elements use a D-dimer cut-off of 1000 ng/mL to determine whether they proceed to CTPA or not. If a patient has one of more high-risk features, a traditional D-dimer cut-off of 500 ng/mL is used. Of note, this study was initiated prior to age-adjusted D-dimer becoming commonplace.

Without going into interminable detail regarding their results, their strategy works. Patients ruled out solely by the the D-dimer component of this algorithm had similar 3 month event rates to those ruled out following a negative CTPA. Their strategy, per their discussion, reduces the proportion managed without CTPA by 14% over a Wells’-based strategy (CTPA in 52% per-protocol, compared to 66% based on Wells’) – although less-so against Wells’ plus age-adjusted D-dimer. Final yield for PE per-protocol with YEARS was 29%, which is at the top end of the range for European cohorts and far superior, of course, to most U.S. practice.

There are a few traps here. Interestingly, physicians were not blinded to the D-dimer result when they assigned the YEARS risk-stratification items. Considering the subjectivity of the “most likely” component, foreknowledge of this result and subsequent testing assignment could easily influence the clinician’s risk assessment classification. The “most likely” component also has a great deal of inter-physician and general cultural variation that may effect the performance of this rule. The prevalence of PE in all patients considered for the diagnosis was 14% – a little lower than the average of most European populations considered for PE, but easily twice as high as those considered for possible PE in the U.S. It would be quite difficult to generalize any precise effect size from this study to such disparate settings. Finally, considering the D-dimer assay continuous likelihood ratios, we know the +LR for a test result of 1000 ± ~500 is probably around 1. This suggests using a cut-off of 1000 may hinge a fair bit of management on a test result representing zero informational value.

This ultimately seems as though the algorithm might have grown out of a need to solve a problem of their own creation – too many potentially actionable D-dimer results being produced from an indiscriminate triage-ordering practice. I remain a little wary the effect of poisoning clinical judgment with the D-dimer result, and expect it confounds the overall generalizability of this study. As robust as this trial was, I would still recommend waiting for additional prospective validation prior to adoption.

“Simplified diagnostic management of suspected pulmonary embolism (the YEARS study): a prospective, multicentre, cohort study”
http://thelancet.com/journals/lancet/article/PIIS0140-6736(17)30885-1/fulltext

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

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 Intravenous Contrast Debate

Does intravenous contrast exposure increase the likelihood of developing renal insufficiency? The consensus opinion has been, generally, “yes”. However, evaluated under a closer lens, it is apparent some of these data come from high-dose use during angiography, from exposure to high-osmolar contrast material not routinely used in present day, and weak evidence from observational cohort studies.

The modern take is, increasingly, potentially “no”. However, it is virtually impossible to conclusively study the effect of intravenous contrast exposure. A prospective, controlled trial would require patients for whom a contrast study was believed important to their medical care be randomized to not receiving the indicated study, leading to all manner of potential harms. Therefore, we are reduced to looking backwards and comparing patients undergoing a contrasted study with those who do not.

This study is probably the best style of this type of evidence we are going to get. This is a propensity-matched analysis of patients undergoing contrast CT, non-contrast CT, and those not undergoing CT at all. Between 5,000 and 7,000 patients comprised each cohort, and these were stratified by baseline comorbidities, medications administered, illness severity indicators, and baseline renal function. After these various adjustments and weighting, the authors did not observe any effect on subsequent acute kidney injury relating to the administration of intravenous contrast – limited to patients with a creatinine of 4.0 mg/dL or below at baseline.

I think this is basically a reasonable conclusion, given the approach. There has been a fair bit of observational content regarding the risk of AKI after a contrast CT, but it is impossible separate the effect of contrast from the effects of the concurrent medical illness requiring the contrast CT. Every effort, of course, should be taken to minimize the use of advanced imaging – but in many instances, the morbidity of a missed diagnosis almost certainly outweighs the risk from intravenous contrast.

“Risk of Acute Kidney Injury After Intravenous Contrast Media Administration”
http://www.annemergmed.com/article/S0196-0644(16)31388-9/abstract

Chest X-Ray Utility in Syncope Lost in Translation

Again, straight out of the ACEP Daily News briefing: “Patients Presenting To ED With Complaints Of Syncope Should Still Undergo Routine Chest X-Rays, Research Suggests.”

This accurately reports the lead of the linked lay medical press article: “ED Patients With Syncope Should Undergo Chest X-Rays

But, it does not accurately reflect the authors’ discussion or conclusions regarding the utility of chest x-ray in syncope.

This is a retrospective evaluation of patients presenting with syncope and having a chest x-ray between 2003 and 2006 – a secondary analysis of the “Boston Syncope Criteria” study. There were 575 patients included in their analysis, 116 of whom had a defined adverse event within 30 days. Of the patients with positive findings on CXR, 15 of those 18 went on to have an adverse event – and I presume this association led to the perpetuation of this headline.

However, in the greater context: only 18 patients out of 575 had abnormal CXR findings, and even the vast majority of patients with adverse events had normal normal CXR findings. Then, an obvious selection bias should be clear with regard to obtaining CXR in those patients with the appropriate clinical indications – such as a suspicion for CHF or pneumonia. Patients go on to have adverse events because of the morbidity associated with concomitant clinical syndromes, of which the findings on CXR are only one small part of their evaluation.

In short, no, CXR is so low-yield it need not be performed anywhere remotely near routinely in syncope. It may be performed to evaluate a specific presenting symptom related to a syncopal event, but, if anything, these data should indicate it ought be performed less frequently.

“Utility of Chest Radiography in Emergency Department Patients Presenting with Syncope”
http://westjem.com/original-research/utility-of-chest-radiography-in-emergency-department-patients-presenting-with-syncope.html

No CT Before LP?

There are a couple schools of thought regarding the need for a CT before an LP in the setting of infectious cerebral disease. The traditionalist school of thought: herniation. The pragmatist school: no big deal.

This article falls on the side of “no big deal”, which was probably the bias of the authors prior to its conception. These authors looked at comatose children in Malawi with suspected malaria. They analyzed the mortality outcomes of 1,827 patients, including 1,470 who received an LP and 357 who did not. Unadjusted mortality was higher in those who did not receive an LP, for which the authors attempted to adjust using propensity-based analyses, or by directly comparing those who had documented brain swelling on MRI or with papilledema. Using their admittedly small numbers in their retrospective cohort, they did not find any signals of harm relating to overall mortality or herniation precipitated by LP within 12 hours of procedure.

We probably will only ever get this level of evidence regarding the safety of LP in the critically ill with elevated ICP secondary to infection. Adverse events are rare, regardless, and it will always be difficult to shake out the confounding features of the malignant infection. I tend to agree with these authors that LP is safe in a stable patient without localizing neurologic signs, but it is entirely reasonable to take the opposite view.

“Safety of lumbar puncture in comatose children with clinical features of cerebral malaria”
http://www.neurology.org/content/early/2016/10/28/WNL.0000000000003372

The Impending Pulmonary Embolism Apocalypse

After many years of intense effort, our work in recognizing overdiagnosis and over-treatment of pulmonary embolism has been paying off. With the PERC, with adherence to evidence-based guidelines, and with a responsible approach to resource utilization, it is reasonable to suggest we’re making headway into over-investigating this diagnosis.

Prepare for all that hard work to be obliterated.

This is a prospective study of patients admitted to the hospital for syncope, evaluating each in a systematic fashion for the diagnosis of PE. Consecutive admissions with first-time syncope, who were not currently anticoagulated, underwent risk-stratification using Wells score, D-dimer testing if indicated, and ultimately either CT pulmonary angiograms or V/Q scanning. The top-line result, the big scary number you’re likely seeing circulating the medical and lay news: “among 560 patients hospitalized for a first-time fainting episode, one in six had a pulmonary embolism.”

Prepare for perpetual arguments with the admitting hospitalist for the next several eternities: “Could you go ahead an get a CTPA? You know, 17% of patients with syncope have PE.”

I’d like to tell you they’re wrong, and this study is somehow flawed, and you’ll be able to easily refute their assertions. Unfortunately, yes, they are wrong, and this study is flawed – but it won’t make it any easier to prevent the inevitable downstream overuse of CT.

The primary issue here is the almost certain inappropriate generalization of these results to dissimilar clinical settings. During the study period, there were 2,584 patients presenting to the Emergency Department with a final diagnosis of syncope. Of these, 1,867 were deemed to have an obvious or non-serious alternative cause of syncope and were discharged home. Thus, less than a third of ED visits for syncope were admitted, and the admission cohort is quite old – with a median age for admitted patients of 80 (IQR 72-85). There is incomplete descriptive data given regarding their comorbidities, but the authors state admission criteria included “severe coexisting conditions” and “a high probability of cardiac syncope on the basis of the Evaluation of Guidelines in Syncope Study score.” In short, their admission cohort is almost certainly older and more chronically ill than many practice settings.

Then, there are some befuddling features presented that would serve to inflate their overall prevalence estimate. A full 40.2% of those diagnosed with pulmonary embolism had “Clinical signs of deep-vein thrombosis” in their lower extremities, while 45.4% were tachypneic and 33.0% were tachycardic. These clinical features raise important questions regarding the adequacy of the Emergency Department evaluation; if many of these patients with syncope had symptoms suggestive of PE, why wasn’t the diagnosis made in ED? If even only the patients with clinical signs of DVT were evaluated prior to admission, those imaging studies would have had a yield for PE of 65%, and the prevalence number seen in this study would drop from 17.3% to 10.3%. Further evaluation of either patients with tachypnea or tachycardia might have been similarly high-yield, and further reduced the prevalence of PE in admitted patients.

Lastly, any discussion regarding a prevalence study requires mention of the gold-standard for diagnosis. CTPA confirmed the diagnosis of PE in 72 patients in this study. Of these, 24 involved a segmental or sub-segmental pulmonary artery – vessels in which false-positive results typically represent between one-quarter to one-half. Then, V/Q scanning was used to confirm the diagnosis of PE in 24 patients. Of these, the perfusion defect represented between 1% and 25% of the area of both lungs in 12 patients. I am not familiar with the rate of false-positives in the context of small perfusion defects on V/Q, but, undoubtedly a handful of these would be as well.  Add this to the inadequate ED evaluation of these patients, and suddenly we’re looking at only a handful of true-positive occult PE in this elderly, chronically ill cohort with syncope.

My view of this study is that its purported take-home point regarding the prevalence of PE in syncope is grossly misleading, yet this “one in six” statistic is almost guaranteed to go viral among those on the other side of the admission fence.  This study should not change practice – but I fear it almost certainly will.

“Prevalence of Pulmonary Embolism among Patients Hospitalized for Syncope”

http://www.nejm.org/doi/full/10.1056/NEJMoa1602172

Don’t CTPA With Your Gut Alone

Many institutions are starting to see roll-out of some sort of clinical decision-support for imaging utilization. Whether it be NEXUS, Canadian Head CT, or Wells for PE, there is plenty of literature documenting improved yield following implementation.

This retrospective evaluation looks at what happens when you don’t obey your new robot overlords – and perform CTPA for pulmonary embolism outside the guideline-recommended pathway. These authors looked specifically at non-compliance at the low end – patients with a Wells score ≤4 and performed with either no D-dimer ordered or a normal D-dimer.

During their 1.5 year review period, there were 2,993 examinations and 589 fell out as non-compliant. Most – 563 – of these were low-risk by Wells and omitted the D-dimer. Yield for these was 4.4% positivity, compared with 11.2% for exams ordered following the guidelines. This is probably even a high-end estimate for yield, because this includes 8 (1.4%) patients who had subsegmental or indeterminate PEs but were ultimately anticoagulated, some of whom were undoubtedly false positives. Additionally, none of the 26 patients that were low-risk with a normal D-dimer were diagnosed with PE.

Now, the Wells criteria are just one tool to help reinforce gestalt for PE, and it is a simple rule that does not incorporate all the various factors with positive and negative likelihood ratios for PE. That said, this study should reinforce that low-risk patients should mostly be given the chance to avoid imaging, and a D-dimer can be used appropriately to rule-out PE in those where PE is a real, but unlikely, consideration.

“Yield of CT Pulmonary angiography in the emergency Department When Providers Override evidence-based clinical Decision support”
https://www.ncbi.nlm.nih.gov/pubmed/27689922

When Is An Extremity CTA Necessary?

Here’s another piece regarding low-value testing in trauma, focusing on another topic: the use of CT angiograms for evaluation of extremity vascular injury.

This single-center, retrospective series looks at use of the extremity computed tomography angiogram in the setting of orthopedic and multi-system trauma. For what it’s worth, at least, there were only 275 scans identified during their 10-year study period. However, the bad news, of course: only 16 (6%) of those scans identified an injury requiring treatment.

Of greatest interest to those trying to eradicate low-value care comes the entirely unsurprising observation that 109 (40%) of patients received CTAs despite the absence of hard or soft signs of vascular injury – and all were normal. Additionally, all 16 cases requiring treatment had diminished or absent distal pulses on presentation.

I do anedcotally see the clinical examination being devalued, especially in trauma – it shouldn’t be!

“When are CT angiograms indicated for patients with lower extremity fractures? A review of 275 extremities”
http://journals.lww.com/jtrauma/Abstract/publishahead/When_are_CT_angiograms_indicated_for_patients_with.99386.aspx

All Glory to the Triple-Rule-Out

The conclusions of this study are either ludicrous, or rather significant; the authors are either daft, or prescient. It depends fundamentally on your position regarding the utility of CT coronary angiograms.

This article describes a retrospective review of all the “Triple-Rule-Out” angiograms performed at a single center, Thomas Jefferson University Hospital, between 2006 and 2015. There were no specific circumstances under which the TRO were performed, but, grossly, the intended population were those who were otherwise being evaluated for an acute coronary syndrome but “was suspected of having additional noncoronary causes of chest pain”.

This “ACS-but-maybe-not” cohort totaled 1,192 patients over their 10 year study period. There were 970 (81.4%) with normal coronary arteries and no significant alternative diagnosis identified. The remaining, apparently to these authors, had “either a coronary or noncoronary diagnosis that could explain their presentation”, including 139 (11.7%) with moderate or severe coronary artery disease. In a mostly low-risk, troponin-negative population, it may be a stretch to attribute their symptoms to the coronary artery disease – but I digress.

The non-coronary diagnoses, the 106 (8.6%) with other findings, range from “important” to “not at all”. There were, at least, a handful of aortic dissections and pulmonary emboli picked up – though we can debate the likelihood of true positives based on pretest odds. However, these authors also credit the TRO with a range of sporadic findings as diverse as endocarditis, to diastasis of the sternum, and 24 cases of “aortic aneurysm” which were deemed important mostly because there were no priors for comparison.

The authors finally then promote TRO scans based on these noncoronary findings – stating that, if a traditional CTCA were performed, many of these diagnosis would likely be missed. Thus, the paradox. If you are already descending the circles of hell, and are using CTCA in the Emergency Department – then, yes, it is reasonable to suggest the TRO is a valid extension of the CTCA. Then again, if CTCA in the acute setting is already outside the scope of practice, and TRO is an abomination – carry on as if this study never existed.

“Diagnostic Yield of Triple-Rule-Out CT in an Emergency Setting”
http://www.ncbi.nlm.nih.gov/pubmed/27186867