Category: Pulmonary Embolism

Go Ahead, Age-Adjust the D-Dimer

If you include D-dimer as part of your practice to exclude pulmonary embolism, you’re probably already aware background levels gradually increase with age.  This results in further deterioration of the already poor specificity.  Happily, this publication in JAMA demonstrates it’s probably safe to gradually increase your cut-off level for D-dimer with age without sacrificing sensitivity.

These authors enrolled 3,324 patients in a cohort with ultimate prevalence for PE of 19.0%.  Of these, 2,898 fell into the “pulmonary embolism unlikely” group and underwent D-dimer testing.  817 met the traditional D-dimer <500 μg/L cut-off and no CTA was performed.  An additional 337 patients met their “age-adjusted cutoff” – “10 x patient age” for those aged greater than 50 years.  Only one patient with a negative D-dimer met their final adjudicated outcome of eventual venous thromboembolism.  The authors, therefore, conclude this strategy of age-adjusted D-dimer cut-off is safe.

However, a handful of patients were lost to follow-up, and the confidence interval for 3-month VTE, considering the sample size, ranges from 0.1-1.7% in their age-adjusted cohort.  Additionally, 7 patients died and 7 patients were evaluated for suspected VTE during the follow-up period.  Only 1 was judged by their 3 experts to have been due to VTE, but this consensus measure for their primary outcome could have profound effects on their ultimate conclusion.  Six different D-dimer assays were also used across their multi-center study, which hinders external generalizability.

But, in the end, it’s probably reasonable.  The harms and costs secondary to testing and treating false-positives and small VTE still likely outweigh any additional misses through this strategy.  Considering this comes from JAMA, it’s likely defensible in the face of peer-review to begin using age-adjusted cut-offs immediately.

“Age-Adjusted D-Dimer Cutoff Levels to Rule Out Pulmonary Embolism”
https://jama.jamanetwork.com/article.aspx?articleid=1841967

A “Positive” Primary Outcome for PEITHO

Yet, by “positive”, as we all too often see, the underlying data comes with a surprise twist.

The Pulmonary Embolism Thrombolysis (PEITHO) trial evaluates single-dose tenecteplase added to conventional heparin therapy for the treatment of “intermediate risk” acute pulmonary embolism.  This includes patients with pulmonary embolism, right ventricular dysfunction on imaging, and elevated cardiac biomarkers.  For the primary endpoint of death or hemodynamic deterioration within 7 days, 2.6% of patients in the immediate thrombolysis group met this outcome vs. 5.6% of patients in the usual treatment arm (OR 0.44, p=0.02).

Unfortunately, this composite outcome obfuscates the difference between treatment arms is limited solely to hemodynamic deterioration.  The downside to thrombolysis – major extracranial bleeding (11.5% by ISTH definition) and hemorrhagic stroke (2.0%) – occurred five times as frequently in the treatment arm.  As a result, the overall 7-day and 30-day mortality were statistically identical.  Ultimately, then, this study paints the treatment decision as a choice between cardiovascular instability and life-threatening bleeding complications.

A couple interesting tidbits from the supplementary appendix:

  • The criteria for myocardial injury was a troponin I >0.06 μg/L or troponin T >0.01 μg/L.  These may be relatively inclusive thresholds.
  • Not all placebo patients developing hemodynamic collapse received subsequent thrombolysis; likewise, almost half of those who received open-label thrombolysis had no hemodynamic collapse.
  • Half the deaths in the placebo arm were “sudden unexplained” or “other”, compared with bleeding or stroke complications in the thromboysis arm.

How does this study fit in with the other recent evidence regarding thrombolysis of non-massive pulmonary embolism, e.g. MOPETT and TOPCOAT?  It means we know there are patients who will benefit – both in short-term hemodynamics and long-term functional status.  However, we’re still trying to minimize the number harmed by parsing out the best candidates and choosing the correct dose.  There’s a lot of room for disagreement and practice variation during continued investigation, with practice ranging from standard anticoagulation and monitoring to, as Jeff Kline promotes, full-dose thrombolysis with tenecteplase.  At the moment, I fall into the half-dose camp – but always re-evaluating new evidence.

“Fibrinolysis for Patients with Intermediate-Risk Pulmonary Embolism”

Shared Decision-Making to Reduce Overtesting

Medicine, like life, is full of uncertainty.  Every action or inaction has costs and consequences, both anticipated and unintended.  Permeating through medical culture for many reasons, with the proliferation of tests available, has been a decreased tolerance for this uncertainty and the rise of “zero-miss” medicine.  However, there are some tests that carry with them enough cost and risk, the population harms of the test outweigh the harms of the missed diagnoses.  CTPA for pulmonary embolism is one of those tests.

In this study, these authors attempt to reduce testing for pulmonary embolism by creating a shared decision-making framework to discuss the necessity of testing with patients.  They prospectively enrolled 203 patients presenting to the Emergency Department with dyspnea and, independent of their actual medical evaluation, attempted to ascertain their hypothetical actions were they to be evaluated for PE.  Specifically, they were interested in the “low clinical probability” population whose d-Dimer was elevated above the abnormal threshold – but still below twice-normal the threshold.  For these “borderline” abnormal d-Dimers, the authors created a visual decision tool describing their estimate of the benefit and risk of undergoing CTPA given this specific clinical scenario.

After viewing the benefits and risks of CTPA, 36% of patients in this study stated they would hypothetically decline testing for PE.  Most of the patients (85%) who planned to follow-through with the CTPA did so because they were concerned regarding a possible missed diagnosis of PE, while the remaining hoped the CT would at least also provide additional information regarding their actual diagnosis.  The authors conclude, based on a base case of 2.6 million possible PE evaluations annually, this strategy might save 100,000 CTPAs.

I think the approach these authors promote is generally on the right track.  The challenge, however, is the data used to discuss risks with patients.  From their information graphics, the risks of CTPA – cancer, IV contrast reaction, kidney injury and false positives – are all fair to include, but can be argued greatly regarding their clinical relevance.  Is a transient 25% increase in serum creatinine in a young, healthy person clinically significant?  Is it the same as a cancer diagnosis?  Is it enough to mention there are false-positives from the CTPA without mentioning the risk of having a severe bleeding event from anticoagulation?  Then, in their risk of not having the CTPA information graphic, they devote the bulk of that risk to a 15% chance of the CT identifying a diagnosis that would have otherwise been missed.  I think that significantly overstates the number of additional, clinically important findings requiring urgent treatment that might be identified.  Finally, the risks presented are for the “average” patient – and may be entirely inaccurate across the heterogenous population presenting for dyspnea.

But, any quibbles over the information graphic, limitations, and magnitude of effect are outweighed by the importance of advancing this approach in our practice.  Paternalism is dead, and new tools for communicating with patients will be critical to the future of medicine.

“Patient preferences for testing for pulmonary embolism in the ED using a shared decision-making model”
http://www.ncbi.nlm.nih.gov/pubmed/24370071

Ultrasound First For Pulmonary Embolism?

Akin to the ultrasound first for appendicitis protocol currently in use, the authors of a recently published study in CHEST propose using ultrasound before CTPA in patients where the diagnosis of pulmonary embolism is being considered.

Their protocol consisted of bedside thoracic and lower extremity ultrasounds to identify either a confirmatory DVT or an alternative diagnosis that would account for the patient’s current presentation. In both the ED and inpatient settings,  ICU physicians evaluated this protocol’s performance in 100 patients. The 54 patients who were determined, due to an alternative diagnosis found on ultrasound, not to require further testing, none of them were found to have a pulmonary embolism on confirmatory CT. Of the remaining 40 patients (42%) whose ultrasound revealed no convincing alternative diagnosis or lower extremity DVTs, 12 were found to have pulmonary embolisms on their confirmatory CTPA. The authors conclude that though further studies are needed, an ultrasound first strategy will reduce the number of CTs obtained to rule out pulmonary embolism.

Though I am not opposed to the utilization of ultrasound as a bedside tool, using it to rule out pulmonary embolisms is a flawed paradigm. The proposed protocol is not one which rules out PE, it in fact does just the opposite. This protocol takes advantage of the high specificity of ultrasound for the diagnosis of pneumonia, pulmonary edema, and DVT. It employs the strategy of ruling in an alternative diagnosis or a lower extremity DVT. If no convincing diagnosis is discovered the patient will then move on to the more traditional rule out strategy of CTPA. This study essentially uses bedside ultrasound to address the  two most heavily weighted criteria on the Well’s Score, “an alternative diagnosis that is less likely than pulmonary embolism” and  “signs and symptoms of deep venous thrombosis”. In no way is this protocol fatally flawed. It has the potential to add a great deal to clinical decision making. Unfortunately it does not address the more serious epidemic in the current management of pulmonary embolisms. That is the egregious over-testing and subsequent over-diagnosis of pulmonary embolism in the ultra low risk patient.

“Ultrasound Assessment of Pulmonary Embolism in Patients Receiving Computerized Tomography Pulmonary Angiography”
journal.publications.chestnet.org/article.aspx?articleid=1763837

For more nihilism, emergency medicine and the art of doing nothing see emnerd.com and @CaptainBasilEM

Ultrasound First For Pulmonary Embolism?

Akin to the ultrasound first for appendicitis protocol currently in use, the authors of a recently published study in CHEST propose using ultrasound before CTPA in patients where the diagnosis of pulmonary embolism is being considered.

Their protocol consisted of bedside thoracic and lower extremity ultrasounds to identify either a confirmatory DVT or an alternative diagnosis that would account for the patient’s current presentation. In both the ED and inpatient settings,  ICU physicians evaluated this protocol’s performance in 100 patients. The 54 patients who were determined, due to an alternative diagnosis found on ultrasound, not to require further testing, none of them were found to have a pulmonary embolism on confirmatory CT. Of the remaining 40 patients (42%) whose ultrasound revealed no convincing alternative diagnosis or lower extremity DVTs, 12 were found to have pulmonary embolisms on their confirmatory CTPA. The authors conclude that though further studies are needed, an ultrasound first strategy will reduce the number of CTs obtained to rule out pulmonary embolism.

Though I am not opposed to the utilization of ultrasound as a bedside tool, using it to rule out pulmonary embolisms is a flawed paradigm. The proposed protocol is not one which rules out PE, it in fact does just the opposite. This protocol takes advantage of the high specificity of ultrasound for the diagnosis of pneumonia, pulmonary edema, and DVT. It employs the strategy of ruling in an alternative diagnosis or a lower extremity DVT. If no convincing diagnosis is discovered the patient will then move on to the more traditional rule out strategy of CTPA. This study essentially uses bedside ultrasound to address the  two most heavily weighted criteria on the Well’s Score, “an alternative diagnosis that is less likely than pulmonary embolism” and  “signs and symptoms of deep venous thrombosis”. In no way is this protocol fatally flawed. It has the potential to add a great deal to clinical decision making. Unfortunately it does not address the more serious epidemic in the current management of pulmonary embolisms. That is the egregious over-testing and subsequent over-diagnosis of pulmonary embolism in the ultra low risk patient.

“Ultrasound Assessment of Pulmonary Embolism in Patients Receiving Computerized Tomography Pulmonary Angiography”
journal.publications.chestnet.org/article.aspx?articleid=1763837

For more nihilism, emergency medicine and the art of doing nothing see emnerd.com and @CaptainBasilEM

Which Pulmonary Emboli Are Missed?

Apparently, as many as one-third of them!

This is a retrospective study from a Spanish hospital evaluating all patients presenting through the Emergency Department who subsequently received a chest CTA revealing pulmonary embolism.  These diagnoses were further classified as having received the diagnosis of PE on initial presentation, during hospitalization, or on a return visit to the Emergency Department.  66% of patients diagnosed with PE were diagnosed on the initial visit, while 22% were diagnosed only after hospital admission, and 12% on Emergency Department revisit.  This leads to the authors conclusions that delayed diagnosis of acute PE is frequent despite current diagnostic strategies.

While it’s only a single center study, and the frequency of missed diagnoses may not be generalizable, it’s still a reasonable investigation.  The characteristics of patients with missed PE fit the typical spectrum from other, prior studies: confounding comorbidities and diagnostic findings.  Patients with delayed diagnosis had fewer typical features, were more likely to have COPD or asthma, more likely to have fever, and more likely to have pulmonary infiltrates.  The authors state there were no mortality differences between early and delayed PE diagnosis, but the study is too small and heterogenous to truly put much faith in this observation.  Of note, 41% of patients who were initially discharged from the ED had unilateral subsegmental clot, a far greater proportion than either other diagnostic group.

It certainly makes sense that patients with dyspnea and other potential causes will have their diagnosis delayed until their lack of response to therapy results in reassessment.  These authors suggest we ought to be more aggressive in our evaluation for PE in the Emergency Department; I tend to feel the delayed diagnosis in confounding situations is appropriate, and suspect some of these represent subclinical disease.  “Zero-miss” is only appropriate if the harms from the disease outweigh the harms of testing and treatment – and follow-up re-evaluation or additional testing during acute hospitalization are reasonable pathways to diagnosis in a subset of patients.

“Clinical features of patients inappropriately undiagnosed of pulmonary embolism”
http://www.ncbi.nlm.nih.gov/pubmed/24060320

Replace Us With Computers!

In a preview to the future – who performs better at predicting outcomes, a physician, or a computer?

Unsurprisingly, it’s the computer – and the unfortunate bit is we’re not exactly going up against Watson or the hologram doctor from the U.S.S. Voyager here.

This is Jeff Kline, showing off his rather old, not terribly sophisticated “attribute matching” software.  This software, created back in 2005-ish, is based off a database he created of acute coronary syndrome and pulmonary embolism patients.  He determined a handful of most-predictive variables from this set, and then created a tool that allows physicians to input those specific variables from a newly evaluated patient.  The tool then finds the exact matches in the database and spits back a probability estimate based on the historical reference set.

He sells software based on the algorithm and probably would like to see it perform well.  Sadly, it only performs “okay”.  But, it beats physician gestalt, which is probably better ranked as “poor”.  In their prospective evaluation of 840 cases of acute dyspnea or chest pain of uncertain immediate etiology, physicians (mostly attendings, then residents and midlevels) grossly over-estimated the prevalence of ACS and PE.  Physicians had a mean and median pretest estimate for ACS of 17% and 9%, respectively, and the software guessed 4% and 2%.  Actual retail price:  2.7%.  For PE, physicians were at mean 12% and median 6%, with the software at 6% and 5%.  True prevalence: 1.8%.

I don’t choose this article to highlight Kline’s algorithm, nor the comparison between the two.  Mostly, it’s a fascinating observational study of how poor physician estimates are – far over-stating risk.  Certainly, with this foundation, it’s no wonder we’re over-testing folks in nearly every situation.  The future of medicine involves the next generation of similar decision-support instruments – and we will all benefit.

“Clinician Gestalt Estimate of Pretest Probability for Acute Coronary Syndrome and Pulmonary Embolism in Patients With Chest Pain and Dyspnea.”
http://www.ncbi.nlm.nih.gov/pubmed/24070658

Subsegmental Pulmonary Emboli Are Just As Deadly?

A couple weeks back, I posted my algorithm regarding (not) evaluating patients with chest pain for pulmonary embolism.  As has been written multiple times – most recently in this BMJ article – the evidence for overdiagnosis is rather overwhelming, and I’m trying to come up with strategies to do my small part to reduce it.

These Dutch authors, however, perform a retrospective analysis of prospectively-collected data and conclude “patients with symptomatic [subsegmental pulmonary embolism] appear to mimic those with segmental or more proximal PE as regards their risk profile and short term clinical course.”  If correct, it would imply there are no “clinically insignificant” PE – which flies in the face of our evidence of overdiagnosis.

These authors found 116 SSPE, 632 proximal PE, and 2980 patients without PE.  They found the folks with proximal and SSPE, by almost every measure, had significantly more thromboembolic risk factors – particularly malignancy – than the folks without PE.  Unsurprisingly, given the identical VTE risk profile between proximal and SSPE, there was essentially no difference in rate of recurrent VTE in the proximal and SSPE groups during 3 month follow-up – 4 patients (3.6%) with SSPE and 14 patients (2.5%) for proximal PE.  Given an absence of risk factors, the patients without PE at baseline had only 1.1% incidence of VTE during the follow-up period.  For all-cause mortality, the risk was 10.3% for SSPE, 6.3% for proximal PE, and 5.4% for patients without PE at baseline.  1.6% of both the SSPE and proximal PE group suffered major bleeding complications from anticoagulation.

So, there is some truth to the authors’ conclusion that SSPE has a clinical course similar to proximal PE.  However, the clinical significance of SSPE is almost certainly confounded by co-occurrence of comorbid conditions.  It is reasonable to suggest true PE and SSPE are poor prognostic indicators of background disease burden, and not the salient pathologic diagnosis.  Anticoagulation may not be the most important course of action; rather, identifying and treating the underlying cause, if present.

This article ought not support any argument regarding the necessity of diagnosis and treatment of sub-segmental PE, except in the context of a broader approach to a patient.

“Risk profile and clinical outcome of symptomatic subsegmental acute pulmonary embolism”
www.ncbi.nlm.nih.gov/pubmed/23736701

The EM Lit of Note PE Decision Tree

A couple weeks back I posted regarding a study where even intermediate- and high-risk patients with suspected PE had negative CTA in the presence of low d-Dimers.  Based on that post, I’ve put together a rough decision tree encapsulating how I (currently) prefer to approach the diagnosis of pulmonary embolism:
Note that “Scan for PE” really means to be “offer patient scan for PE”, considering relevant diagnostic uncertainty and risks in a shared decision-making process.  “Other reason why d-Dimer would be elevated” takes into account clinical judgement regarding the uselessness of d-Dimer as an acute-phase reactant or inflammatory marker; many “sick” patients will have elevated d-Dimers, obviating its value as a one-way screen-out.  Also, this chart does not account for any medicolegal liability risks – a wonderful perk of practicing in Texas.
Follow-up:  Seth Trueger and John Greenwood pointed out on the original that there are some specific moderate- and high-risk cases that satisfy PERC criteria, and perhaps the risk-stratification step should occur before application of PERC, as is traditionally done.  Fair enough!  They also note the EMCrit flow-chart begins with an exhortation of “Did you really care about PE?” – which, I’d say, is approximated by my value judgement of “Bad miss?” after starting to consider PE.  Finally, Scott Weingart chimed in to suggest, for patients in whom you’re playing the minimal-harm game for unexciting pulmonary emboli, a bedside ultrasound to quickly check for an occult DVT that might cause them to come back with clinically significant pulmonary venous thrombosis.

How I (Hardly Ever) Scan For Pulmonary Embolism

There’s probably no diagnosis in the Emergency Department that confounds residents more than the practice variation between attendings regarding the evaluation for pulmonary embolism.  Some folks send d-Dimers with reckless abandon on patients with near-zero pretest probability, others make emotional decisions to “take PE off the table” when faced with no other explanation, and then there’s a group that only very rarely pursues the diagnosis.

I rarely pursue the diagnosis – mostly because the epidemiological evidence suggests we’re only harming folks by making additional diagnoses of pulmonary embolism.  Therefore, in a patient who is otherwise physiologically intact, a diagnosis of pulmonary embolism is more likely to result in iatrogenic bleeding risk rather than treatment benefit.  And, then, there’s the backwards fashion in which I use d-Dimer: I order it at the same time as the CTA in an otherwise intermediate- or high-risk patient, and then cancel the CTA if the d-Dimer is normal.

I use this strategy based on this prospectively collected data from the Kaiser system, published obscurely in The Permanente Journal several years back.  These authors evaluated 744 patients over 16 months who underwent CTA for rule-out PE, 347 of which had latex agglutination d-Dimer levels less than 1.0 µg/mL.  In this cohort of 347, there were seven positive scans – six of which were ultimately found to be false positives.  A handful of patients were lost, but the remainder had zero events in the three-month follow-up period.

So – d-Dimer negative, cancel the CTA, regardless of the pretest probability.  So far, so good!

“Computed Tomography Angiography in Patients Evaluated for Acute Pulmonary Embolism with Low Serum D-dimer Levels: A Prospective Study”
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2911823/