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”

D-Dimer, It’s Not Just a Cut-Off

It’s certainly simpler to have a world where everything is black or white, right or wrong, positive or negative. Once upon a time, positive cardiac biomarkers meant acute coronary syndrome – now we have more information and shades of grey in between. The D-dimer, bless its heart, is probably like that, too.

This is a simple study that pooled patients from five pulmonary embolism studies to evaluate the diagnostic performance characteristics of the D-dimer assay. Conventional usage is simply to deploy the test as a dichotomous rule-out – a value below our set sensitivity threshold obviates further testing, while above consigns us to the bitter radiologic conclusion. These authors, perhaps anticipating a more sophisticated diagnostic strategy, go about trying to calculate interval likelihood ratios for the test.

Using over 6,000 patients as their substrate for analysis, these authors determine the various likelihood ratios for D-dimer levels between 250 ng/mL and greater than 5,000 ng/mL, and identify intervals of gradually increasing width, starting at 250 and building up to 2,500. Based on logistic regression modeling, the fitted and approximate iLR range from 0.0625 for those with D-dimer less 250 ng/mL and increasing to 8 for levels greater than 5,000. Interestingly, a D-dimer between 1,000 and 1,499 had an iLR of roughly 1 – meaning those values basically have no effect on the post-test likelihood of PE.

The general implication of these data would be to inform more precise accounting of the risk for PE involving the decision to proceed to CTPA. That said, with our generally inexact tools for otherwise estimating pretest likelihood of disease (Wells, Geneva, gestalt), these data are probably not quite ready for clinical use. I expect further research to develop more sophisticated individual risk prediction models, for which these likelihood ratios may be of value.

“D-Dimer Interval Likelihood Ratios for Pulmonary Embolism”

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”

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”

An Oddly Dire Look at CIN after CTPA

This is an abstract that sucked me in – not because of the concept of the study – but because of its quoted incidence of adverse outcomes.  23.7% incidence of contrast-induced nephropathy following a CT pulmonary angiogram!  12.5% incidence of renal failure!  12.8% in-hospital mortality!

But, no.

The study itself is a comparison between three different prophylaxis methods for the prevention of CIN after CTPA – N-acetylcysteine plus normal saline, bicarbonate plus NS, or NS alone.  The simple summary: no difference between groups.

But, getting back to those dire numbers – roughly double the typically reported incidence of CIN.  They’re a mirage.  In reality, they assigned the primary outcome to all 26 (9.3%) of patients lost to follow-up.  Therefore, the starting point for their outcomes of interest are in a more reasonable range: 15.2% CIN, 2.6% renal failure, and 3.0% in-hospital mortality.

This, again, leads us back to the question: how much renal impairment is attributable to the CTPA, and how much to the underlying disease processes leading patients to require a CTPA in the first place?  Yield for PE on their CTPA cohort was 31.9%, which, in itself, elevates the comorbid burden of the population and could contribute to heart failure and renal injury.  There is no control group not receiving CTPA – for obvious clinical reasons – so it is hard to estimate the additive injury resulting directly from the CTPA.

But, at least, the big numbers displayed in their abstract a little misleading.

“The high risk of contrast induced nephropathy in patients with suspected pulmonary embolism despite three different prophylaxis: A randomized controlled trial”

The “Don’t Anticoagulate Pulmonary Embolism” Guideline

We’ve expressed a lot of angst around these parts regarding the homogenous treatment of acute pulmonary embolism.  With the advent of angiography, and then computed tomography with ever-increasing levels of sensitivity, the physiologic spectrum of disease for pulmonary embolism has massively increased.

In olden times, pulmonary embolism actually presented as pulmonary infarction with the “classic” triad of pleuritic pain, hemoptysis, and signs of deep venous thrombosis.  Now, nearly 10% are virtually incidental subsegmental PE of uncertain clinical significance – yet, recommendations for treatment remained systemic anticoagulation.

Until now.

This new guideline states patients with subsegmental PE, without another identifiable VTE source, and at low risk for recurrent VTE, have the option of watchful waiting.  They cite no new groundbreaking evidence, but generally recognize the low rates of recurrent VTE in retrospective and observational studies.  They also recognize a diagnosis of subsegmental PE is quite likely to be a false-positive, as covered in my last ACEPNow column, unless the following conditions are met:

We suggest that a diagnosis of subsegmental PE is more likely to be correct (i.e. a true-positive) if: (1) the CT pulmonary angiogram (CTPA) is of high quality with good opacification of the distal pulmonary arteries; (2) there are multiple intraluminal defects; (3) defects involve more proximal sub-segmental arteries (i.e. are larger); (4) defects are seen on more than one image; (5) defects are surrounded by contrast rather than appearing to be adherent to the pulmonary artery; (6) defects are seen on more than one projection; (7) patients are symptomatic, as opposed to PE being an incidental finding; (8) there is a high clinical pre-test probability for PE; and D-Dimer level is elevated, particularly if the increase is marked and otherwise unexplained.

Patients discharged without anticoagulation should be provided prospective guidance on seeking care for new or progressive symptoms.  These recommendations are appropriately GRADE category 2C, reflecting moderate/weak certainty and a low level of evidence – but, it at least provides a framework to have a reasonable conversation and shared decision-making with a patient.

It also appropriate raises a question about testing for PE:  if a patient has a PE meeting criteria for non-treatment, does it need to be found in the first place?  Should the acceptable miss rate for PE – assuming the quoted prevalence of subsegmental disease – be ~10%?

“Antithrombotic Therapy for VTE Disease: CHEST Guideline”

Welcome to Yesterday, Have You Heard of PERC?

I usually like these sorts of articles regarding the yield and utilization of CT pulmonary angiograms.  They’re fun to dissect, useful to marvel at the inefficiency of our usage, and finally to feed my editorial hyperbole.  But, not this time.

This is a retrospective study from the University of Michigan comprising six months of CTPA data from 2013.  These authors reviewed charts on 602 consecutive patients and calculated modified Wells and PERC for each, and describe the appropriateness and yields of various cohorts.

Rather than detail these statistics and outcomes – other than to note their overall yield of 61 positives reported out of 602 scans – I’d rather just focus on the 108 patients scanned who were PERC negative.  PERC has been around since 2004, and it’s been percolating into various guidelines and evidence-based algorithms since.  Hello, it’s 2015: why are almost 20% of CTs at an academic medical center PERC-negative?

The authors state two PERC-negative patients had positive CT findings; given the pretest probability, I wouldn’t be surprised if one or both were ultimately false-positives.  Come on, man.

“CT Pulmonary Angiography: Using Decision Rules in the Emergency Department”

The Battle for Age-Adjusted D-Dimer

Around these parts, we are fans of the age-adjusted D-dimer.  Jeff Kline proposes their use in his algorithm for the diagnosis of PE.  We embed decision-support in our EHR to encourage their use.  But, this new review from Annals of Emergency Medicine describes its test characteristics in the Kaiser Permanente population – and reports the age-adjusted D-dimer is not infallible.

These authors look retrospectively at 31,094 patients over 50, with a chest- or respiratory-related complaint, for whom a D-dimer was ordered.  14,434 of these patients had a D-dimer above the “customary” level of 500 ng/dL, and clinicians ordered 12,486 imaging studies to evaluate for PE.  Of these, 507 were diagnosed with PE.  This gives a 4.1% yield for CTPA – which, frankly, is disturbingly low – but another topic for another day.

The 500 ng/dL threshold was sensitive for 497 of the 507, while using an age-adjusted D-dimer would have reduced sensitivity to 471 of the 507.  Thus, using an age-adjusted D-dimer in this retrospective cohort may potentially have introduced an additional 26 missed PEs.  The savings, however, amount to 2,924 fewer CTPAs – or, roughly, 100 CTs per missed PE.

The contemporaneous Twitter response:

@EBMgoneWILD @ZackRepEM So age-adjusted D-dimer is dead? 26 misses to save $290K in costs = dead.

— Robert McNamara (@RobertMcNamar12) September 4, 2015

I don’t think so – but questions abound, many of which need be directly addressed by our specialty.  What is an acceptable miss rate for pulmonary embolism?  What is an acceptable miss rate of the pulmonary emboli in this age-adjusted range, just above our prior test threshold?  Does the net harm reduction from reduced testing outweigh the harms of missing those PEs?  Do those PEs convey the same level of morbidity or mortality if the diagnosis is missed or delayed?  How does the radiologic false-positive rate trend for PEs whose D-dimers are just over the test threshold?  And, finally – the age-adjusted D-dimer is not a static construct – would other age-adjustment formulas strike a better balance between sensitivity and specificity?

When all the questions are posed, I believe the summative value shows it reduces physiologic harms from testing, harms from healthcare costs, and harms from false-positives.  But, like everything we do, the age-adjusted D-dimer is still deserving of continued questioning and refinement.

“An Age-Adjusted D-dimer Threshold for Emergency Department Patients With Suspected Pulmonary Embolus: Accuracy and Clinical Implications.”

Your CTPA is Lies

There are a few moments you pat yourself on the back in Emergency Medicine.  The good save.  Shared decision-making that goes well.  And, the small victory when you’ve utilized an evidence-based pathway for pulmonary embolism, and received positive results for the leviathan of over-utilization and over-diagnosis: the CT pulmonary angiogram.

Well, it’s time to deduct about 1.25 fingers from that pat on the back you give yourself, because, unfortunately, radiology PE overcalls may be more rampant than initially thought.

This is a retrospective, single-center study reviewing a year’s worth of CTPA for pulmonary embolism, a total of 937 studies.  Of the studies included, 174 (18.6%) were initially read as positive.  Then, each positive study was reviewed by a panel of three, specially trained chest radiologists, with their consensus read used as the gold standard for diagnosis.  And so: 45 (25.9%) were subsequently judged to be incorrectly read by the original radiologist – a quarter of positive studies! – with those patients almost certainly consigned to at least short-term anticoagulation as a result.

In a light moment in the discussion, the authors helpfully contribute the following commentary:

Furthermore, many pulmonary CTA examinations in our institution are ordered by the emergency department before assessment by the admitting medical team.

My heart goes out to the poor Scottish EM physicians, for whom their radiology colleagues apparently have quite the low opinion for appropriate testing.  However, the authors’ attention may be better spent further discussing their own false-positive rate, which is double the ~11% rate of other similar reviews.  They also do not provide any accompanying data on the rate of false-negatives, although, in theory, these should be less clinically important.

So, think twice about doing your little happy dance for a positive CT – if your pretest likelihood was low, and the PE is subsegmental, there’s a substantial chance the stars have aligned in just the wrong constellation.

“Overdiagnosis of Pulmonary Embolism by Pulmonary CT Angiography”

Gestational Age and D-Dimer Levels

In general, the utility of D-dimer for the evaluation of venous thromboembolism declines with gestational age.  The typical cut-offs for the 95th percentile, depending on your assay, become less and less relevant as pregnancy progresses.  Wouldn’t it be nice, perhaps, if we had reliable data?

So, well, here’s something:

One glaring hole in this data is the broad inclusion criteria of “healthy” women.  No testing was specifically performed to exclude asymptomatic venous thromboembolism, so the possibility exists of inclusion of small, subsegmental pulmonary emboli, or of non-occlusive lower extremity deep venous thrombosis.  The effect on this data would be to increase the 95% percentile, and to widen the 95th percentile confidence interval.

Jeff Kline has proposed gradually increasing cut-offs of 750, 1000, and 1250 ng/mL for the first, second, and third trimester, respectively (based on a standard cut-off of 500 ng/mL).  This sample is much larger than the one cited by Kline in his “PE in pregnancy” algorithm, but his appear to be reasonable, sensitive cut-offs.  By far, the most important aspect of evaluating pulmonary embolism in pregnancy is simply to communicate the uncertainty, and to inform and share decision-making with the patient along the way.

“Gestation-specific D-dimer reference ranges: a cross-sectional study”