Category: Pulmonary Embolism

YEARS, But Wells

It’s the Monday after Thanksgiving, so it’s time to turn the brains back on – and notice an oddly robust cultivation of articles worthy of comment dropped just before the holiday. This is the first, the “Pulmonary Embolism Graduated D-Dimer” (PEGeD) study, a rather obtuse name for what is effectively a pretest likelihood-adjusted implementation of D-dimer. This is also, effectively, what was done with the YEARS protocol – so, what’s new?

In this iteration of the concept, the authors use the Wells score, stratifying patients to either low, moderate, or high probability. A few published work-up algorithms describe pathways of care in which low probability leads to PERC, while the higher-risk cohort undergoes D-dimer testing or directly to CTPA to rule out PE. In this algorithm, those with “low” probability still undergo D-dimer testing – but with a cut-off threshold of 1000 ng/mL warranting advanced imaging. The primary outcome was symptomatic, objectively-verified venous thromboembolism, including PE and deep venous thrombosis, at 90 days.

These authors enrolled a cohort of 2,017 patients between 2015 and 2018, with 1,752 in the “low” probability cohort, 218 “moderate”, and 47 “high”. Overall prevalence of PE on initial testing was 7% and advanced imaging was performed on 34%, for an imaging yield of 24%. The general finding of most importance to the practicing clinician is their observation that 1,285 low-risk patients had D-dimer <1000 ng/mL and 40 moderate-risk patients had D-dimer <500 ng/mL and none had VTE detected at 90 day follow-up. Helpfully, these authors even compare their yield directly to the YEARS protocol – and find about 40 fewer patients would have undergone imaging with PEGeD than YEARS, which makes it basically a wash. They also compare their strategy to an age-adjusted D-dimer, which is a bit odd, considering they are not competing strategies, but synergistic.

The idea of pretest-adjusted D-dimer has been around a very long time, dating back to at least 2012. There’s nothing magical about a cut-off of 1000 ng/mL other than Round Numbers, but it is a serendipitously reasonable starting point for this approach. The real elephant in the room, however, is there were only 87 PEs in their low-risk cohort, for a prevalence of 4.9%. This may yet even over-represent the prevalence of PE in community practice in certain settings (read: the United States). Considering the accepted miss rate for PE is considered to be at least 1%, owing to the likelihood of false-positives and harms from anticoagulation, it is likely an even more aggressive cut-off or imaging-elimination strategy should be pursued.

However, I certainly do not want to minimize this work – adding good, prospective data pushing imaging stewardship is of great importance, whatever minor shortcomings might be observed. At the very least, please considering using PEGeD or YEARS as the basis for your imaging algorithm – and add age-adjusted D-dimer on top for even better reductions in unnecessary imaging.

“Diagnosis of Pulmonary Embolism with d-Dimer Adjusted to Clinical Probability”
https://www.nejm.org/doi/full/10.1056/NEJMoa1909159

Pulmonary Embolism in Syncope, Forever

For about the zillionth time – the Prandoni observations of 16% prevalence of pulmonary embolism in syncope are not not generalizable.

This is the BASEL IX study (BAsel Syncope EvaLuation Study) whose primary purpose is to gather observational data regarding the outcomes of patients with syncope. These authors pulled a chunk of their data to address the question of whether PE was highly prevalent among those with syncope, as well as to describe the timing of such any downstream “missed” diagnoses.

The data presented comes from 1,895 patients enrolled in the main study, 1,397 of whom were eligible via being clinically stable enough to provide informed consent, and in whom a D-dimer result was available. Patients underwent clinical assessment by treating physicians without influence by the study.

Overall, only 14% underwent imaging for PE, with PE ultimately found in 1.4% of the cohort at initial presentation. About half the remaining patients who did not undergo imaging had normal D-dimer results and were retrospectively calculated to have low pre-test probability. By logical conclusion, however, that means half the remaining cohort was either non-low pretest or had elevated D-dimer – but still did not undergo imaging.

The follow-up period was up to two years in 83% of this cohort, and only 12 events occurred in follow-up, all in the non-low/elevated D-dimer group not undergoing initial imaging evaluation. Eight of these were PEs and 4 were cardiovascular deaths. The good news: the earliest subsequent PE diagnosis was 55 days, and earliest death was almost a year later.

So, no, again, no – no need to pursue PE in syncope unless otherwise clinically indicated, even if the patient may be at incidentally elevated risk.

“Prevalence of Pulmonary Embolism in Patients With Syncope”
http://www.onlinejacc.org/content/74/6/744.full

PE in Pregnancy & YEARS Protocol

So, I generally like the YEARS protocol. It’s an incremental step forwards towards incorporating a pretest likelihood of disease into the interpretation of the D-dimer result. At the least, considering our reckless overdiagnosis of pulmonary embolism, it doesn’t make the situation worse.

Now, pregnancy. There is a mild increase in risk for PE while pregnant, and subsequent puerperal risk is even higher. Unfortunately this leads to a paradox: the index of suspicion for PE during pregnancy is so high, the yield of testing is frighteningly low – on the order of 5% or less for those undergoing evaluation for PE. Little prospective data regarding safe exclusion of PE during pregnancy are available.

These investigators – the Artemis Study – applied the YEARS algorithm, to the diagnosis of PE during pregnancy, attempting generally to demonstrate its safety while describing its yield and test characteristics. The primary modification to the baseline YEARS algorithm was patients having clinical signs of deep-vein thrombosis underwent compression ultrasonography prior to being evaluated with D-dimer and potential CTPA.

They enrolled 498 patients in whom PE was considered a relevant clinical diagnosis, about half of whom met no “high-risk” YEARS criteria. About a fifth of the patients were first trimester, and the remainder were split between second and third. The news is good and bad, unfortunately. Overall, the incidence of PE in their cohort was only 4.0% – typical of our deranged gestalt for PE in pregnancy. In the first trimester, their algorithm excluded PE without CTPA in 65% of those enrolled – meaning only 26 CTPA were indicated to diagnose the 5 PEs in this cohort. This is a reasonable yield.

However, second and third trimester excluded only 46% and 32% of patients from CTPA – meaning 261 CTPAs would be allowed to diagnosis 15 PEs – a yield of only 5.7%. This is better than performing a CT on everyone, but it’s still abysmal. This results, effectively, from the gradual physiologic increase in D-dimer throughout pregnancy – from a median of 505 ng/mL in their first trimester cohort, to 730 and 1,120 in subsequent trimesters.

So, while their algorithm is clearly safe – only one DVT occurred within their 3-month follow-up period, basically the expected rate of occurrence in their enrolled cohort – it’s not the final answer with regard to pregnancy. The next likely step required is to use our observational data to test specific trimester-related normals and pretest-related multipliers to find the optimal cut-offs, such that second and third trimester performance may approach that of the first.

“Pregnancy-Adapted YEARS Algorithm for Diagnosis of Suspected Pulmonary Embolism”
https://www.nejm.org/doi/full/10.1056/NEJMoa1813865

Computer Says: Discharge that Pulmonary Embolism!

We’ve learned a couple important things about pulmonary emboli for the past five or so years. First, we diagnose too many of them. Second, all pulmonary emboli do not need to be hospitalized. Knowing, as they say, is half the battle. That’s a start – but it’s not enough.

This study involves important thing number two above, the hospitalization of PE. Kaiser Permanente, in its endless quest for value, has already published several studies demonstrating the safety of discharging patients with PE. However, hidden in the descriptive statistics from those studies are the unfortunate still-low percentages of patients discharged.

In this prospective, multi-center, “convenience-assigned” trial, a computerized decision-support tool was rolled out to support risk-stratification for patients diagnosed with PE. Based on the pulmonary embolism severity index (PESI), patients scoring in class I or II were encouraged to be discharged, while those with higher scores were nudged towards hospitalization. In their pre-post design, little change occurred at the control hospitals, while the percentage of patients with PE discharged from the intervention hospitals jumped from 17.4% to 28.0%. No issues regarding untoward 5-day recidivism or 30-day adverse events were detected.

This is a great step forwards, and, frankly, one of the most prominent examples of decision-support being actually useful to implement practice change.   That said, in the intervention hospitals, there were “physician champions” associated with the roll-out of the CDS intervention, which almost certainly increased update.  Then, 41.2% of patients were PESI class I or II, so there’s even further room for improvement above these topline results – but this is an at least solid effort.

“Increasing Safe Outpatient Management of Emergency Department Patients With Pulmonary Embolism”

http://annals.org/aim/article-abstract/2714293/increasing-safe-outpatient-management-emergency-department-patients-pulmonary-embolism-controlled

The Swiss, Ruling out PE in Pregnancy

Evaluating the average Joe/Jane for pulmonary embolism is rather straightforward – but let’s not go back into that morass of practice variation and low-value over-diagnosis. This is an a study looking at how to diagnose PE during pregnancy, which is fraught with its own unique issues.

Firstly, obviously, CTPA ought to be avoided whenever possible – and moreso when there is a chance of fetal exposure. When the benefits outweigh the risks, of course, it is reasonable to proceed. Then, use of D-dimer as a tool to inform the posterior probability of PE is challenged by its steady increase in pregnancy.  This combination of issues results in general uncertainty with regard to the approach.

This is their algorithm:

Over the course of eight years, at 11 centers, these authors included 395 patients in their study – 357 of whom were evaluated per-protocol. Only a handful were assessed as “high” risk, while the bulk underwent D-dimer testing with a test threshold of 500 µg/L on the Vidas assay. The D-dimer was virtually useless, with only 46 of 392 being excluded from further evaluation. Then, the bilateral lower extremity ultrasound was basically useless, with only 7 positives out of 349 performed – resulting in 342 CTPAs. There were 19 positive CTPA, and then two of the inconclusive CTPA were ultimately diagnosed with PE by V/Q scanning.

What a mess. For those keeping score at home, that’s 7.1% yield for their evaluation of PE, and all their extra hoops prevented little radiation exposure. From a diagnostic evaluation standpoint, of course, their protocol was entirely adequate with regard to missed PE – unsurprising because most patients received all the tests in their algorithm.

The ugliest observation here is their prevalence of 7.1% is actually far lower than the prevalence observed in the non-pregnant population in Europe. Step one in fixing this approach: just apply the same gestalt to this population as the remainder of ED presentations. Then, let’s adopt the YEARS protocol, at a minimum, and consider adopting trimester-adjusted cut-offs for D-dimer. The miss rate will not be zero – but, incorporating appropriate clinical judgment, the net harms from untreated PE will be balanced by the benefit of avoided radiation, anticoagulation, and over-diagnosis.

“Diagnosis of Pulmonary Embolism During Pregnancy: A Multicenter Prospective Management Outcome Study”
http://annals.org/aim/article-abstract/2708166/diagnosis-pulmonary-embolism-during-pregnancy-multicenter-prospective-management-outcome-study

Again With the Failings of CTPA

Most of the unhinged ramblings on this blog involve lamenting the excessive sensitivity of CT pulmonary angiograms for the diagnosis of pulmonary embolism. “Excessively sensitive for PEs of uncertain clinical signifiance!” and “Too many false positives in an inappropriately selected population!” gloomily drones the author (We can’t all, and some of us don’t).

Now, again, come the baffling attacks from the right – the CTPA isn’t sensitive enough:

“The negative predictive value of CTPA for VTE varies according to pretest prevalence of PE, and is likely to be insufficient to safely rule out VTE as a stand-alone diagnostic test amongst patients at the highest pretest probability of VTE. Prospective studies are required to validate the appropriate diagnostic algorithm for this subgroup of patients.”

Foundational quibbles in the narrative induced by their meta-analysis:

  • Sure, maybe, in the cohort of studies before 2006 – but since then, the number of VTE “missed” by CTPA is less than 1%.
  • A VTE “missed” by CTPA includes lower extremity DVT concurrently diagnosed by duplex ultrasound.  Whether a CTPA should be impugned for failing to include the legs is a separate debate regarding the adequacy of its Natural State of Being.
  • Again, a VTE “missed” by CTPA includes all VTE (including LE DVT) diagnosed in the three-month follow-up period, a timeframe certainly adequate for individuals at high-risk for VTE to develop thrombosis anew.
  • “High” clinical probability in this study refers to those patients with ≥40% pretest likelihood of disease, which is tremendously infrequently encountered in clinical practice.

Clearly, these authors are far from convincing me CTPA is guilty of relevant concerns for inadequate sensitivity in these modern times.  One problem at a time, please; queue up, now.

“Outcomes following a negative computed tomography pulmonary angiography according to pulmonary embolism prevalence: a meta-analysis of the management outcome studies”
https://www.ncbi.nlm.nih.gov/pubmed/29645405

Don’t Rely on the EHR to Think For You

“The Wells and revised Geneva scores can be approximated with high accuracy through the automated extraction of structured EHR data elements in patients who underwent CTPA in the emergency department.”

Can it be done? Can the computer automatically discern your intent and extract pulmonary embolism risk-stratification from the structured data? And, with “high accuracy” as these authors tout in their conclusion?

IFF:  “High accuracy” means ~90%. That means one out of every ten in their sample was misclassified as low- or high-risk for PE. This is clinically useless.

The Wells classification, of course, depends highly upon the 3 points assigned for “PE is most likely diagnosis.” So, these authors assigned 3 points positive for every case.  This sort of probably works in a population that was selected explicitly because they underwent CTPA in the ED, but is obviously a foundationally broken kludge.  Revised Geneva does not have a “gestalt” element, but there are still subjective examination features that may not make it into structured data – and, obviously, it performed just as well (poorly) as the Wells tool.

To put it mildly, these authors are overselling their work a little bit. The electronic health record will always depend on the data entered – and it’s setting itself up for failure if it depends on specific elements entered by the clinician contemporaneously during the evaluation. Tools such as these have promise – but perhaps not this specific application.

“Automated Pulmonary Embolism Risk Classification and Guideline Adherence for Computed Tomography Pulmonary Angiography Ordering”
https://onlinelibrary.wiley.com/doi/abs/10.1111/acem.13442

A Validation of YEARS?

A couple of years (ha ha!) ago, the results of the YEARS study were unveiled, a culmination of various ideas towards incorporating pretest probability into the use of the D-dimer for “ruling out” pulmonary embolism. The ideas were not unique to this research group in the Netherlands, but the implementation was – and many awaited some independent confirmation of their results.

This is a step towards that independent confirmation, a multi-center observational evaluation of the YEARS protocol. In this study, these authors collected the data necessary to determine the workup and outcomes via YEARS, but clinical practice was left unchanged. This is of particular importance because, unfortunately, this leaves a glaring hole in their enrollment criteria – YEARS did not have any carve outs for patients in whom D-dimer was not part of the evaluation for PE, whereas in these EDs, patients with high pretest likelihood typically went straight to imaging without D-dimers.

Overall, then, in these 17 Emergency Departments, 1,789 low- and intermediate-risk patients were evaluated for PE, with an overall prevalence of 4%. There were 7 (0.3%) patients determined to have potentially missed PE by three month chart review and follow-up phone calls, with a default assignment of “no PE” for the handful lost to follow-up. In their sample, usual practice led 45% undergoing CTPA and 9% undergoing V/Q. With YEARS criteria implemented, the imaging rate would have been 33% – at the cost of an additional 6 missed PEs. This miss rate, however, is still below the threshold of testing equipoise, balancing the morbidity of anticoagulation versus the morbidity of missing PE.

This is a helpful piece of evidence in support of YEARS, even if it leaves major questions unanswered regarding its use in high-pretest probability patients, to say the least. The imaging reduction estimation, as well, should be considered to be overstated by an observational trial, as the adoption of apparently aggressive new protocols would likely be slower than this theoretical maximum.

One small step forward.

“Multicenter Evaluation of the YEARS Criteria in Emergency Department Patients Evaluated for Pulmonary Embolism”
https://www.ncbi.nlm.nih.gov/pubmed/29603819

Nothing Excludes Pulmonary Embolism?

It’s hard to find a diagnostic pathway with greater variation than that of pulmonary embolism. On one hand, you have the YEARS protocol, in which D-dimer is the definitive gatekeeper without carve-outs or exclusions. On the other hand, you have an article like this – saying even CT pulmonary angiograms are inadequate to rule-out PE.

These authors re-analyzed the data from a previous prospective study enrolling 7,940 patients across 12 Emergency Departments. In this analysis, these authors focused in on the 257 patients for whom a “High risk” Wells score was assigned. Of these, 201 underwent reliable CTPA, 71 of which were read as positive and 130 of which were read as negative. Within 45 days, using chart review and telephone follow-up, the authors determined 16 of these patients were ultimately diagnosed with PE. They conclude the CTPA missed these diagnoses at the index visit, and should not be considered adequate for rule-out in a high-risk patient. They go on to cite the inadequate sensitivity of CTPA as demonstrated in PIOPED-II as justification for their stance.

Unfortunately, there’s not nearly enough information presented here to fully evaluate their findings. The authors are attempting to refute the utility of CTPA as a reliable mechanism for rule-out, but, despite such a small sample, no individual scan follow-up was attempted to overread the initial CT. Then, patients with high Wells scores are obviously at high risk for VTE; it almost certainly reasonable some of these downstream PE are independent events, a possibility towards which the authors are fairly dismissive. The authors report many of these patients were positive for DVT, making a subsequent PE as an independent event even more likely. The PIOPED-II study, landmark or not, was conducted in a comparatively medieval era of CTPA, and those sensitivity findings should not impact current data interpretation. Finally, the CTPA is famous not so much for false negatives as it is false positives. The authors do not account for the possibility some of these downstream diagnoses are false positives, and no characterization of the subsequent diagnoses are given – an important consideration in this era of over-diagnosis of subsegmental PE of uncertain clinical significance.

I certainly do not believe these data should change practice or our opinion of the CTPA as a reliable rule-out for a clinically important PE. More robust, prospective study is necessary to confirm the veracity of their conclusion of these false negatives.

“Ruling out Pulmonary Embolism in Patients with High Pretest Probability”

https://escholarship.org/uc/item/74h4h8qb

Using PERC & Sending Home Pulmonary Emboli For Fun and Profit

The Pulmonary Embolism Rule-Out Criteria have been both lauded and maligned, depending on which day the literature is perused. There are case reports of large emboli in patients who are PERC-negative, as well as reports of PE prevalence as high as 5% – in contrast to its derivation meeting the stated point of equipoise at <1.8%. So, the goal here is to be the prospective trial to end all trials and most accurately describe the impact of PERC on practice and outcomes.

This is a cluster-randomized trial across 14 Emergency Departments across France.  Centers were randomized to either a PERC-based work-up strategy for PE, or “conventional” in which virtually every patient considered for PE was tested using D-dimer. Interestingly, these 14 centers also crossed-over to the alternative algorithm approximately halfway through the study period, so every ED was exposed to both interventions – some of which used PERC first, and vice versa.

Overall, they recruited 1,916 patients across the two enrollment periods, and these authors focused on the 1,749 who received per-protocol testing and were not lost to follow-up. The primary outcome was any new diagnosis of venous thromboembolism at 3 month follow-up.  This was their measure of, essentially, clinically important missed VTE upon exiting their algorithm. The headline results here were, in their per-protocol population, that 1 patient was diagnosed with VTE in follow-up in the PERC group compared with none in the control cohort. This met their criteria for non-inferiority, and, just at face value, the PERC-based strategy is clearly reasonable. There were 48 patients lost to follow-up, however, but given the overall prevalence of PE in this population, it is unlikely these lost patients would have affected the overall results.

There are a few interesting bits to work through from the characteristics of the study cohort. The vast majority of patients considered for the diagnosis of PE were “low risk” by either Wells or simplified Revised Geneva Score. However, 91% of those in the PERC cohorts were “low risk”, as compared to 78% in the control cohort – which, considering the structure of this trial, seems unlikely to have occurred by chance alone. In the PERC cohort, about half failed to meet PERC and these patients – plus a few protocol violations – moved forward with D-dimer testing. In the conventional cohort, 99% were tested with D-dimer in accordance with their algorithm.

There were then, again, more odd descriptive results at this point.  The results of the D-dimer testing (≥0.5 µg/mL) were positive in 343 of the PERC cohort and 471 of the controls. However, physicians only moved forward with CTPA in 38% of the PERC cohort and 46% of the conventional cohort.  It is left entirely unaddressed why patients entered a PE rule-out pathway and ultimately never received a definitive imaging test after a D-dimer above threshold. For what it’s worth, then, the fewer patients undergoing evaluation for PE in the PERC cohort led to fewer diagnoses of PE, fewer downstream hospital admissions and anticoagulants, and their ED length of stay was shorter. The absolute numbers are small, but patients in the control cohort undergoing CTPA were more likely to have subsegmental PEs (5 vs. 1), which, again, ought to generally make sense.

So, finally, what is the takeaway here? Should you use a PERC-based strategy? As usual, the answer is: it depends. Firstly, it is almost certainly the case the PERC-based algorithm is safe to use. Then, if your current approach is to carpet bomb everyone with D-dimer and act upon it, yes, you may see dramatic improvements in ED processes and resource utilization. However, as we see here, the prevalence of PE is so low, strict adherence to a PERC-based algorithm is still too clinically conservative. Many elevated D-dimers did not undergo CTPA in this study – and, with three month follow-up, they obviously did fine. Frankly, given the shifting gestalt relating to the work-up of PE, the best cut-off is probably not PERC, but simply stopping the work-up of most patients not intermediate- or high-risk.

“Effect of the Pulmonary Embolism Rule-Out Criteria on Subsequent Thromboembolic Events Among Low-Risk Emergency Department Patients: The PROPER Randomized Clinical Trial”
https://jamanetwork.com/journals/jama/fullarticle/2672630