It’s not very often I read an article and decide to I’d like to incorporate it into my practice. EMCrit covered this last month, but I reserved judgement until I had a chance to read the primary literature for myself.
This is the MOPETT trial – half-dose (?”safe dose”) tPA for “moderate” pulmonary embolism. We already know what to do for “massive” PE – full-dose thrombolytics when not otherwise contraindicated. However, the data for full-dose thrombolytics in “submassive” PE is less conclusive.
These authors enrolled relatively ill PE patients – tachypneic, hypoxic, tachycardic patients with >70% thrombotic occlusion of lobar or main pulmonary arteries – but did not apply regularly applied measures of “submassive” – RV dysfunction, elevated troponins, elevated BNP. Their primary outcome was long-term development of pulmonary hypertension, with mortality and bleeding as their secondary outcomes. They dosed tPA at 50mg, rather than 100mg – 10mg bolus and 40mg infusion.
Their two cohorts were rather well matched. Outcomes favored the thrombolysis group, with 16% subsequent pulmonary hypertension compared with 57% in the control group. Mortality, recurrent pulmonary embolism, and bleeding complications were similar and at rates too low to detect a difference given the power of the study.
I’d like to start doing this. I wish they published the troponin/BNP/RV dysfunction rates in the two cohorts to provide better context with the other submassive literature. I also would have preferred to see this study registered with clinicaltrials.gov. But, in a nice change, none of the authors declare any conflicts of interest!
“Moderate Pulmonary Embolism Treated With Thrombolysis (from the “MOPETT” Trial)”
www.ncbi.nlm.nih.gov/pubmed/23102885
Category: Pulmonary Embolism
Lactate – Is There Any Death It Doesn’t Predict?
Turns out – apparently, no!
Continuing the run on pulmonary embolism articles, we find that – in addition to all the things we know prognosticates increased mortality in PE patients – elevated plasma lactate levels also predict poor outcomes. This is generally unsurprising, because elevated lactate levels are associated with increased mortality, even in unselected ED patients. What is interesting, however, is that lactate levels >2 mmol/L were more associated with 30-day mortality than shock/hypotension, hypoxia, or right-ventricular dysfunction. It’s a small cohort, but it’s a reasonable finding, regardless.
However, what’s sort of odd regarding the Editor’s Summary for this article is that it specifically mentions the lactate level does not outperform a simplified pulmonary embolism severity index clinical tool. The “truth” is that an AUC of 0.84 is better than an AUC of 0.71 – but that (0.72 to 0.95) and (0.60 to 0.83) overlap. Rather than trash the lactic acid level compared with the PESI, it might have been more accurate to simply state the current study was underpowered to confirm the advantage of lactic acid over PESI, and further research is necessary.
Can you buy stock in lactate level assays? It’s clearly the new favorite all-purposes prognostication tool.
“Prognostic Value of Plasma Lactate Levels Among Patients With Acute Pulmonary Embolism: The Thrombo-Embolism Lactate Outcome Study”
http://www.ncbi.nlm.nih.gov/pubmed/23306454
http://www.ncbi.nlm.nih.gov/pubmed/23306454
Inadequate “Overuse” Reduction Strategies
This study was featured in Academic Emergency Medicine as one of their CME articles – theoretically, an article with additional value presented with incentives to motivate a closer reading of the content. I don’t mean to imply this is somehow a bad article – but it’s just interesting to step back out of the tunnel vision of statistics and boggle at the inadequacy of the current state of medicine.
This is a prospective study of patients evaluated for pulmonary embolism attempting to evaluate how many patients were “inappropriately” scanned. This definition of “inappropriate” scanning was determined by patients who were either PERC negative or had low-risk Wells’ score followed by a negative d-Dimer. Overall, of 152 patients, 11.8% were ultimately diagnosed with PE. However, the authors state that application of the PERC rule might have eliminated 9.2% of these scans while Wells’/d-Dimer would have obviated 13.8%.
While I certainly don’t discount the beneficial effect of even small reductions in the number of individuals evaluated for pulmonary embolism, these are still terrible numbers. 90% of CT scans for PE are negative? And using these decision instruments gets us to ~75% negative scans? This would be comically wasteful performance and innovative performance improvement in any other industry.
We pretty clearly need to do better.
“Overuse of Computed Tomography Pulmonary Angiography in the Evaluation of Patients with Suspected Pulmonary Embolism in the Emergency Department”
www.ncbi.nlm.nih.gov/m/pubmed/23167851/
Who Are the PE Positive PERC Negatives?
This little letter, tucked away in the Correspondence section of Annals delves into the Pulmonary Embolism Rule-Out Criteria – a decision instrument of some controversy in Emergency Medicine. Specifically, this letter addresses a case report from a previous issue of Annals of, essentially, a large pulmonary embolus diagnosed in a young patient who was otherwise PERC negative.
The authors from Carolinas Medical Center have a registry of 1,880 PE+ patients with which to evaluation, and they performed a retrospective application of the PERC rule. Overall, 6% of this cohort was PE positive and PERC-negative. When compared with the patients with PE who were PERC-positive, there are a few statistically significant differences – pleuritic chest pain was more common in PERC-negative patients with PE, along with pregnancy or post-partum status. Unfortunately, these statistically significant relative differences reflect only small absolute differences of essentially clinically irrelevant magnitude. The only mildly interesting tidbit from the letter is the statistic that none of PERC-negative PEs died within 30 days, compared with 5.7% of the PERC-positive cohort.
The authors suggest a couple weak clinical implications from the data, but these are limited by the retrospective nature of the analysis. It is enough to remember that PERC-negative does not actually “rule-out” PE – it is simply a collection of negative likelihood ratios working against a pretest probability, resulting in clinical equipoise regarding the expect benefits vs. harms of CT pulmonary angiogram and the resultant harms of treatment in physiologically uninteresting PE.
“Clinical Features of Patients With Pulmonary Embolism and a Negative PERC Rule Result”
www.ncbi.nlm.nih.gov/pubmed/23260692
Next Up – Apixaban!
The latest installment of propaganda in the NEJM comes from Pfizer and Bristol-Meyers Squibb, the joint venture behind apixaban. Along with rivaroxaban, apixaban is an oral Factor Xa inhibitor, another option in the procession of potential warfarin replacements. The Xa inhibitors, while they’ve had their problems, improve upon their main competitor – dabigatran – because they can be reversed in the emergency setting using prothrombin concentrate complexes (PCCs). Dabigatran, as we all know, has no practical reversal strategy.
This is AMPLIFY-EXT, the extended treatment option from AMPLIFY – where apixaban is continued for an additional 12 months for prophylaxis against recurrent venous thromboembolism. In isolation, looks great! The placebo group had an 8.8% VTE recurrence in the study period vs. 1.7% in either of the two apixaban doses. And, major bleeding in the placebo group exceeded the apixaban groups – 0.5% vs. 0.2% and 0.1%. More effective and safer than a sugar pill!
So, what’s the problem? Well, this is the third apixaban trial to be published in the NEJM in the last two years. The first one, apixaban for acute coronary syndrome, showed no benefit and increased bleeding. The next, apixaban for stroke prevention in non-valvular atrial fibrillation (ARISTOTLE), showed non-inferiority to warfarin – but the rate of major bleeding in that study was 2.1% per year. Then, the NEJM also has a recent article regarding aspirin for the prevention of recurrent VTE – where the placebo group only had a VTE recurrence risk of 6.5% rather than the 8.8% observed in AMPLIFY-EXT.
You can’t directly compare trial populations, of course, but it doesn’t make any sense that bleeding would be reduced compared to placebo. And, it’s a straw man comparison with placebo – the correct comparison is rather head-to-head against a potentially efficacious agent, such as low-dose aspirin. After all, low-dose ASA is pennies a day, rather than the ~$10 per day for apixaban.
Can’t blame the pharmaceutical companies for selling, can only blame the suckers for buying.
“Apixaban for Extended Treatment of Venous Thromboembolism”
http://www.nejm.org/doi/full/10.1056/NEJMoa1207541
Send Your PE Patient to MRI!
Well, not exactly…but this is at least a “proof of concept” for cardiovascular magnetic resonance and the diagnosis of pulmonary embolism.
Obviously, helical CT has become the standard diagnostic modality for pulmonary embolism due to its rapid acquisition time and high sensitivity. Unfortunately, contrast-enhanced scans through the thorax carry with them short- and long-term health risks. So, what about MRI?
This small case series of twelve PE+ patients and twelve healthy controls undergoing CMR showed fair discriminatory power for pulmonary embolism. On a per-patient basis, sensitivity was 100% – but to best evaluate a diagnostic test, it’s probably important to consider a higher-resolution measure. On a per-lobe basis, sensitivity was only 71% – with a kappa of only 0.69 for the reading radiologists.
And, then there’s the minor issue that CMR is a 20-minute scan with 10 minutes of post-processing, so even when this is ready for prime-time, it’s still going to have some practical limitations.
“Pulmonary Perfusion Imaging: New Insights Into Functional Consequences of Pulmonary Embolism Using a Multicomponent Cardiovascular Magnetic Resonance Imaging Protocol”
www.ncbi.nlm.nih.gov/pubmed/23194944
When Positive D-Dimers are Negative
This is the latest article from Jeff Kline, published in Thrombosis and Haemostasis (don’t you all subscribe to that, too?), concerning pulmonary embolism and d-Dimer.
Wouldn’t it be great if the d-Dimer wasn’t a dichotomous cut-off? Where, if a patient were of sufficiently low pre-test probability, a d-Dimer value that was nearly negative still contributed adequately to a negative likelihood ratio to reduce the probability of a significant pulmonary embolism? Well, that’s the theory behind this article – which looks at d-Dimer measurements combined with age, Wells’ score, and Revised Geneva scores.
There are a lot of complex tables in this article breaking down the various potential cut-off values for d-Dimer along with different pre-test probabilities, and the concept presented is that potentially higher cut-off values of d-Dimer can be used without missing PEs larger than sub-segmental. This is presented in context that a higher cut-off might allow reductions in imaging, which seems fair.
However, the most interesting thing in this article to me is Figure 3 – which is d-Dimer concentration compared with fractional obstruction of pulmonary vascular tree. It is, unfortunately, pretty clear there’s not a great linear relationship between dimer and pulmonary obstruction. Most low d-Dimers had < 5% obstruction of the vascular tree, but at least one patient with a “negative” d-Dimer had 20% obstruction. Beyond that, patients were just as likely to have 90% obstruction with modestly elevated d-Dimers than with massively elevated d-Dimers.
“D-dimer threshold increase with pretest probability unlikely for pulmonary embolism to decrease unnecessary computerized tomographic pulmonary angiography”
www.ncbi.nlm.nih.gov/pubmed/22284935
Failings of Modern Medicine
A brilliant piece that eloquently states many of the ideas espoused on this blog, focusing on pulmonary embolism as the poster child for over-testing, over-diagnosis, and lack of sound evidence underlying treatment.
These authors, in the Archives of Internal Medicine, accurately describe the chimeric nature of pulmonary embolism – historically described as a dreaded disease, diagnosed clinically from the manifestations of pulmonary infarction, to the modern manifestation of filling defects noted on CTA during an episode of pleuritic chest pain. They discuss the handful of patients who benefited from the first heparinization for treatment, and argue the disease for which anticoagulation is the treatment is not the disease we are diagnosing today.
This article covers so many excellent points, and ties the clinical problems so tightly into the underlying principles, that it’s almost the sort of must-read article to which medical students should be exposed – in order to bring about that frightening moment of maturity in medicine in which you realize the emperor is distinctly lacking in clothes.
Lovely work!
“The Diagnosis and Treatment – of Pulmonary Embolism: A Metaphor for Medicine in the Evidence-Based Medicine Era”
www.ncbi.nlm.nih.gov/pubmed/22473672
Nephropathy Was As Common as PE after CTPA
It’s Jeff Kline Week at EMLitOfNote, with the second Carolinas paper this week – and, as a Patient Safety and Quality Fellow, I just can’t help but cite articles that deal with the consequences of otherwise well-meaning practice.
This small study followed 174 patients undergoing CTPA demonstrated a yield of 7% for PE. On the other hand, this same cohort demonstrated a yield of 14% for contrast-induced nephropathy – as defined by an increase in serum Cr of 0.5 mg/dL or >25%. Three of the 24 patients with CIN progressed to severe renal failure, two of whom died. The proportion of CIN and renal failure were similar to the outcomes observed in the additional 459 patients they followed for CT imaging on other contrast protocols.
So, the rate of CIN is not insignificant – particularly compared to the rate of diagnosis of PE at this institution. It seems to be suggested by this study, although not shown, that the relative risk of death conferred by receiving contrast and developing CIN might even exceed the number of adverse events that might have occurred from PE if left undiagnosed or untreated.
“Prospective Study of the Incidence of Contrast-induced Nephropathy Among Patients Evaluated for Pulmonary Embolism by Contrast-enhanced Computed Tomography”
http://www.ncbi.nlm.nih.gov/pubmed/22687176
National Quality Measure for Pulmonary Embolism
The overuse of CTA in the Emergency Department and the over-diagnosis of pulmonary emboli of non-physiologic significance has been demonstrated as a significant societal harm. In response to this, the National Quality Forum has been looking at developing a quality measure aimed at reducing CTA use in the Emergency Department.
The NQF estimated 7 to 25% of CTAs in the ED might be unnecessary. From Jeff Kline’s shop at Carolinas, they prospectively gathered data on all their potential pulmonary emboli and attempted to determine which scans were “inappropriate.” For their purposes, a scan was “inappropriate” if it was a low-risk patient with a negative D-dimer assay, or it was a low-risk patient without D-dimer testing. 11% were D-dimer negative and 22% were low-risk without D-dimer testing performed, which sums to 32% potentially avoidable imaging.
Of the 1,205 “potentially avoidable” scans, there were 58 positives. The clinical significance of these potential misses is uncertain. Whether this represents an acceptable miss rate for a quality measure in a liability prone environment is another matter entirely.
“Evaluation of Pulmonary Embolism in the Emergency Department and Consistency With a National Quality Measure”
www.ncbi.nlm.nih.gov/pubmed/22664742