Category: Pulmonary Embolism

Defensive Medicine is Defensive

Sometimes, people order a CTA chest to evaluate for pulmonary embolism because they’ve used the available evidence to risk-stratify the patient for a pulmonary embolism, and it’s an important diagnosis to make.  Sometimes, people order CTAs of the chest to evaluate for pulmonary embolism out of defensive practice, in order to avoid missing a pulmonary embolism.

There are some holes in this paper, considering how few patients in their cohort received the study intervention.  However, the general statistical gist was is that physicians who indicated that defensive medicine played a role in their ordering decisions had a much lower yield on their CTA for PE.  Conversely, elevated Wells/Geneva scores were associated with higher yield CTA.  Positive d-Dimers and patient request were non-significantly positively associated with increased CTA yield.

Not precisely an earthshaking paper, but it does weakly reinforce what we probably already suspected – defensive medicine harms the patient and the healthcare system.

“Ordering CT pulmonary angiography to exclude pulmonary embolism: defense versus evidence in the emergency room”
www.ncbi.nlm.nih.gov/pubmed/22584801

Rivaroxaban and Pulmonary Embolism

This is rivaroxaban, an oral Factor Xa inhibitor, part of the wave of potential warfarin replacements.  This is their phase III EINSTEIN-PE trial, which is a non-inferiority comparison against warfarin for the long-term outpatient management of pulmonary embolism.

Overall, it was slightly less effective at prevention of recurrent venous thromboembolism (2.1% vs 1.8%), but slightly safer with regards to bleeding episodes (10.3% vs. 11.4%).  Adherence to therapy was reasonable compared to other trials regarding the amount of time patients spent with therapeutic INR between 2.0 and 3.0.  So, really, it’s pretty much a wash.
But, of course, when you have a new and expensive therapy that’s essentially similar to the old, cheap option, the conclusion is: “Our findings in this study involving patients with pulmonary embolism, along with those of our previous evaluation involving patients with deep-vein thrombosis, support the use of rivaroxaban as a single oral agent for patients with venous thromboembolism.”  
Of course, if you were expecting a different conclusion from an open-label, manufacturer-sponsored study, you are unfortunately mistaken.
So, make sure your hematology group is on board with PCCs, because there doesn’t seem to be any other possible option for reversing life-threatening bleeding – and rivaroxaban is coming, whether it should be or not.
“Oral Rivaroxaban for the Treatment of Symptomatic Pulmonary Embolism”

PERC – Still (Mostly) Useless

…except, perhaps, in a risk-management sense – but, only if we keep beating it down into its narrowest application due to its terrible specificity.

This most recent Annals publishes a systematic review of the Pulmonary Embolism Rule-Out Criteria, a decision instrument recommended in ACEP’s pulmonary embolism clinical guidelines as a reasonable tool to risk-stratify a patient into a so-called “zero-risk” population that does not require any testing – not even a D-dimer.  And, I think they do a reasonable job including studies and summarizing the data, especially considering the width of the error bars on a lot of these studies.

The key points – pooled sensitivity is 97% when applied to a low-risk (Wells, Geneva, gestalt, whichever) population with a negative LR of 0.18.  This means, if you had someone who you already didn’t think had a PE and they meet PERC criteria, it helps you with your medicolegal documentation, since it’s in ACEP’s guidelines.  The negative LR is strong enough to be helpful – but when you’re already looking at single-digit percentage risk for PE, the absolute reduction in risk is quite small.

The important point to hammer home is the positive LR is only 1.23, which makes it the D-dimer of decision instruments.  Please don’t justify further work-up just because they fail PERC – it barely moves the needle with its terrible specificity.  You need to have another clinical justification for further work-up in pulmonary embolism.

As an aside, in this era of over-testing and over-diagnosis of PE, the diagnosis of PE isn’t necessarily the ideal endpoint – what we should be following are patient-oriented outcomes such as death/heart failure in untreated PE in PERC-negative patients to truly make it a valid tool.

“Diagnostic Accuracy of Pulmonary Embolism Rule-Out Criteria: A Systematic Review and Meta-analysis”
http://www.ncbi.nlm.nih.gov/pubmed/22177109

Early Heparin Does Not Save Lives in Pulmonary Embolism

Or, if it does, this is not the article that shows it.  It tries to show it – and Rick Bukata, who I love, includes it as part of his PE review in this month’s Emergency Physician’s Monthly.  It’s a year and a half old, but I had to pull it because I’ve presented other articles showing the diagnosis and treatment of pulmonary embolism isn’t changing mortality.

This is from the Mayo clinic, and it’s observational, retrospective cohort data, which is red flag #1 for drawing practice-changing conclusions.  They reviewed charts on 400 symptomatic pulmonary embolism identified on CTPA that were subsequently admitted to the hospital and anticoagulated with systemic heparin.  In their introduction, they set out to show that outcomes are improved in pulmonary embolism if you initiate heparin in the Emergency Department.  In the end, their conclusion is essentially summarized by this graphic:

Seems pretty convincing, eh?

And, it’s true, there was a significant association between heparin in the ED and 30-day survival.  There was also, however, a significant association between 30-day survival and: tachycardia, Wells score, leukocytosis, elevated troponin, malignancy, recent surgery, ICU admission, and hemorrhagic events.  So, did patients die because they didn’t get heparin, or did they die because they were more acutely ill – and/or had a hemorrhagic event after initiating heparin?  The big one for me is the difference between positive (>0.01 ng/mL) troponins – 26.4% in their survivors and 47.8% in the non-survivors.  Considering the criteria for diagnosis of submassive pulmonary embolism – patients who occupy a different level of risk for poor outcomes – includes elevated troponins indicative of right heart strain, I think this study doesn’t properly support anything it tries to imply regarding the time to heparin and survival.

“Early Anticoagulation Is Associated With Reduced Mortality for Acute Pulmonary Embolism”
www.ncbi.nlm.nih.gov/pubmed/20081101

The PERC Rule Mini-Review

Journal club this month at my institution involved the literature behind the derivation and validation of the PERC (Pulmonary Embolism Rule-Out Criteria) Rule.  So, as faculty, to be dutifully prepared, I read the articles and a smorgasbord of supporting literature – only to realize I’m working the conference coverage shift.  Rather than waste my notes, I’ve turned them into an EMLit mega-post.

Derivation
The derivation of the PERC rule in 2004 comes from 3,148 patients for whom “an ER physician thought they might have Pulmonary Embolism”.  Diagnosis was confirmed by CTA (196 patients), CTA + CTV (1116), V/Q (1055) + duplex U/S (372), angiography (11), autopsy (21), and 90-day follow-up (650).  348 (11% prevalence) were positive for PE.  They then did a regression analysis on those patients and came up with the PERC rule, the eight-item dichotomous test for which you need to answer yes to every single question to pass.

The test case for the derivation came from 1,427 “low-risk” patients that were PE suspects, and as such, had only a d-Dimer ordered to rule-out PE – and in whom a CTA was performed when positive.  114 (8% prevalence) had PE.  There was also an additional test case of “very low-risk”, 382 patients from another dyspnea study who were enrolled when “an ED physician thought PE was not the most likely diagnosis.”  9 (2.3%) of the very low-risk cohort had PE.

Performance on their low-risk test set was a sensitivity of 96% (CI 90-99%) with a specificity of 27%.  On their very low-risk test set, sensitivity was 100% (59-100%) with a specificity of 15%.

Validation
Multicenter enrollment of 12,213 with “possible PE”.  8,183 were fully enrolled.  51% underwent CTA, 6% underwent V/Q, and everyone received 45-day follow up for a diagnosis of venous thromboembolism.  Overall, 6.9% of their population was diagnosed with pulmonary embolism.

Of these, 1,952 were PERC negative – giving rise to a 95.7% sensitivity (93.6-97.2%).  However, the authors additionally identify a “gestalt low-risk” group of 1,666 that had only 3.0% prevalence of PE, apply the PERC rule to that, and come up with sensitivity of 97.4% (95.8 – 98.5%).

The authors then conclude the PERC rule is valid and obviates further testing when applied to a gestalt low-risk cohort in which the prevalence is less than 6%.

Other PERC Studies
Retrospective application of PERC to another prospective PE database in Denver.  Prevalence of PE is 12% of 134 patients.  Only 19 patients were PERC negative, none of whom had PE.  Sensitivity is 100% (79-100%).

Retrospective application of PERC to patients receiving CT scans in Schenectady.  Prevalence of PE was 8.45% of 213.  48 were PERC negative, none of whom had PE.  Sensitivity is 100% (79-100%).

Effectiveness study of PERC in an academic ED (Carolinas).  183 suspected PE patients, PERC was applied to 114, 65 of whom were PERC negative.  16 of the PERC negative underwent CTA, all negative.  14 day follow-up of the remaining 49 also indicated no further PE diagnosis.  No sensitivity calculation.

Retrospective application of PERC to prospective PE cohort in Switzerland.  Prevalence of PE was 21.3% in 1,675 patients.  In the 221 patients who were PERC negative, 5.4% had PE (3.1 – 9.3%) for a sensitivity of 96.6 (94.2 – 98.1%).  The subset of PERC negative who were also low-risk by Geneva Score actually had a higher incidence of PE at 6.4%.

Summary
So, PERC can only be applied to a population you think is low-risk for PE – for which you can use clinical gestalt or Wells’ – because it looks like Wells low-risk is 1.3% (0.5-2.7%) to 2% (0-9%).  But, you can’t use Geneva because that prevalence is closer to 8% for low-risk – and that’s essentially what the Swiss study shows.

But in this already very low-risk population, the question is, what is the role of PERC?  Clinical gestalt in their original study actually worked great.  Even though clinicians were only asked to risk stratify to <15%, they risk stratified to 3.0% prevalence of PE.  Which, of course, means our estimation of the true risk of pulmonary embolism is absolutely bonkers.  If you take a gestalt or Wells’ low-risk population, apply PERC, and it’s negative – your population that nearly universally didn’t have a PE still doesn’t have a PE, and it doesn’t get you much in absolute risk reduction.  You probably shouldn’t have even considered PE as a diagnosis other than for academic and teaching reasons if they’re Wells’ low-risk and PERC negative.

Then, if you take the flip side – what happens if your patient is PERC positive?  You have a low-risk patient whose prevalence for PE is probably somewhere between 1 and 5%, and now you’ve got a test with a positive LR of 1.24 – it barely changes anything from a statistical standpoint.  Then, do you do a d-Dimer, which has a positive LR between 1.6 and 2.77?  Now you’ve done a ton of work and painted yourself into a corner and you have to get a CTA on a patient whose chance of having a PE is still probably less than 10%.

That’s where your final problem shows up.  CTA is overrated as a diagnostic test for pulmonary embolism.  In PIOPED II, published 2006 in NEJM, CTA had 16 false positives and 22 true positives in their low risk cohort – 42% false positive rate – and this is against a reference standard for which they estimated already had a 9% false positive and 2% false negative rate.  CTA is probably better now than it once was, but it still has significant limitations in a low-risk population – and I would argue the false positive rate is even higher, given the increased resolution and ability to discern more subtle contrast filling defects.

So, this is what I get out of PERC.  Either you apply it to someone you didn’t think had PE and it’s negative and you wonder why you bothered to apply it in the first place – or you follow it down the decision tree and you end up at a CTA for whom you can flip a coin to believe whether the positive result is real or not.

And, I don’t even want to get into the clinical relevance of diagnosis and treatment of those tiny subsegmental PEs we’re “catching” on CTA these days.

“Clinical criteria to prevent unnecessary diagnostic testing in emergency department patients with suspected pulmonary embolism”
www.ncbi.nlm.nih.gov/pubmed/15304025

“Prospective multicenter evaluation of the pulmonary embolism rule-out criteria”
www.ncbi.nlm.nih.gov/pubmed/18318689

“Assessment of the pulmonary embolism rule-out criteria rule for evaluation of suspected pulmonary embolism in the emergency department”
www.ncbi.nlm.nih.gov/pubmed/18272098

“The Pulmonary Embolism Rule-Out Criteria rule in a community hospital ED: a retrospective study of its potential utility”
www.ncbi.nlm.nih.gov/pubmed/20708891

“Prospective Evaluation of Real-time Use of the Pulmonary Embolism Rule-out Criteria in an Academic Emergency Department”
www.ncbi.nlm.nih.gov/pubmed/20836787

“The pulmonary embolism rule-out criteria (PERC) rule does not safely exclude pulmonary embolism”
www.ncbi.nlm.nih.gov/pubmed/21091866

“Multidetector Computed Tomography for Acute Pulmonary Embolism”
www.ncbi.nlm.nih.gov/pubmed/16738268

“D-Dimer for the Exclusion of Acute Venous Thrombosis and Pulmonary Embolism”
www.ncbi.nlm.nih.gov/pubmed/15096330

http://www.mdcalc.com/perc-rule-for-pulmonary-embolism

Physicians Will Test For PE However They Damn Well Please

Another decision-support in the Emergency Department paper.

Basically, in this study, an emergency physician considered the diagnosis of pulmonary embolism – and a computerized intervention forced the calculation of a Wells score to help guide further evaluation.  Clinicians were not bound by the recommendations of the Wells calculator to guide their ordering.  And they sure didn’t.  There were 229 patients in their “post-intervention” group, and 26% of their clinicians said that evidence-based medicine wasn’t for them, and were “non-compliant” with their testing strategy.

So, did the intervention help increase the number of positive CTAs for PE?  Officially, no – their trend from 8.3% positive to 12.7% positive didn’t meet significance.  Testing-guideline complaint CTA positivity was 16.7% in the post-intervention group, which, to them, validated their intervention.

It is interesting that a low-risk Wells + positive d-Dimer or high-risk Wells cohort had only a 16% positive rate on a 64-slice CT scanner – which doesn’t really match up with the original data.  So, I’m not sure exactly what to make of their intervention, testing strategy, or ED cohort.  I think the take home point is supposed to be, if you you can get evidence in front of clinicians, and they do evidence-based things, outcomes will be better – but either this just was too complex a clinical problem to tackle to prove it, or their practice environment isn’t externally valid.

Overdiagnosis of Pulmonary Embolism

Another over-testing over-diagnosis article effectively illustrating issues endemic to our current medical culture.

They do a retrospective national database review regarding the impact of the introduction of CTPA protocol for rule-out PE, and note that we’ve diagnosed three times as many PEs in 2006 as we did in 1998.  And, by detecting more PEs, we managed to reduce mortality attributed to PE…along the same gradually decreasing trendline that was present prior to the introduction of CTPA.

Figure 2 is the truly damning graphic – look at all those extra PEs we’re finding and treating for effectively no substantial benefit.  Their secondary analysis was in-hospital anticoagulation complications on patients with any diagnosis of PE, which has jumped 71%.  Thank goodness we can put them on dagibatran now instead of coumadin and not be able to reverse their life-threatening bleeding episodes….

Again, we are testing people who shouldn’t be testing, finding disease of uncertain clinical significance, and harming them with overtreatment – and let’s not even start with the costs.

http://www.ncbi.nlm.nih.gov/pubmed/21555660

Testing For Pulmonary Embolism is More Harmful Than Helpful

This is, in my opinion, the most conceptually important article I have read in the few months I’ve been posting to this blog.

This is where Dr. Newman and Dr. Schriger, outstanding clinicians and analysts of data, present a compelling case regarding the diagnosis and treatment of pulmonary embolism.  In brief, the authors try to estimate, based on the limited evidence, both the benefits and harm of diagnosis and treatment of pulmonary embolism.  In their review, very few patients were found to benefit from treatment of pulmonary embolism – the existing evidence is weakly supportive of anticoagulation.  Additionally, they show a great many patients were harmed by excessive testing and treatment of clinically unimportant pulmonary embolisms.

This is, while a complicated opinion piece, a lovely summation in a nutshell of the concept that finding more “disease” does not equal better outcomes.  And, depending on the risks of testing and treatment – the barbaric contrast, radiation, and rat poison that diagnosis of PE typically entails – more people would be alive today if we all stopped testing for pulmonary embolism.

This is not unique to pulmonary embolism – this is partly the same issue we encounter with overtesting our low-risk chest pain patients, particularly with CTA.  What this means – and, of course, subject to legal challenge in our bizarre society – is that with our current methods of detection and treatment, society would be better off as a whole if we missed a few pulmonary embolisms in order to find and treat the few clinically relevant ones.  The only shame in this article is that not nearly enough people will read it and take it to heart.

http://www.ncbi.nlm.nih.gov/pubmed/21621091