Month: May 2017

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”
http://thelancet.com/journals/lancet/article/PIIS0140-6736(17)30885-1/fulltext

Double Coverage, Cellulitis Edition

The Infectious Disease Society Guidelines are fairly reasonable when it comes to cellulitis. Non-suppurative cellulitis – that is to say, without associated abscess or purulent drainage – is much less likely to be methicillin-resistant s. aureus. The guidelines, therefore, recommend monotherapy with a ß-lactam, typically cephalexin. Conversely, with a suppurative focus, trimethoprim-sulfamethoxazole monotherapy is an appropriate option. However, it’s reasonable to estimate current practice involves prescribing both agents somewhere between one fifth and a quarter of cases – presumably both wasteful and potentially harmful. This trial, therefore, examines this practice by randomizing patients to either double coverage or cephalexin plus placebo.

The short answer: no difference. The rate of clinical cure was a little over 80% of both cohorts in the per-protocol population. Of those with follow-up and treatment failure, over half progressed to abscess or purulent drainage on re-evaluation – and about two-thirds were cultured out as s. aureus. There was no reliable evidence, however, co-administration of TMP-SMX prevented this progression.

The really fun part of this article, however ties into the second line of their abstract conclusion:

“However, because imprecision around the findings in the modified intention-to-treat analysis included a clinically important difference favoring cephalexin plus trimethoprim-sulfamethoxazole, further research may be needed.”

This hedging stems from the fact 17.8% were excluded from the enrolled cohort for inclusion in the per-protocol analysis – and, depending on the modified intention-to-treat analysis definition, there was actually up to a 7.3% difference in failure rate favoring double coverage (76.2% vs 69.0%). This resulted from almost twice as many patients in the cephalexin monotherapy cohort taking <75% of antimicrobial therapy, missing follow-up visits, or other protocol deviations.

The best Bayesian interpretation of this finding is probably – and this is where frequentism falls apart – simply to ignore it. The pre-study odds of dramatic superiority of double coverage are low enough, and the outcome definition for the modified intention to treat cohort in question is broad enough, this finding should not influence the knowledge translation of this evidence. Stick with the IDSA soft-tissue guidelines – and one antibiotic at a time, please.  It is important to recognize – and educate patients – that about 1 in 6 may fail initial therapy, and these failures to not necessarily reflect inappropriately narrow antibiotic coverage nor therapeutic mismanagement.

“Effect of Cephalexin Plus Trimethoprim-Sulfamethoxazole vs Cephalexin Alone on Clinical Cure of Uncomplicated Cellulitis”
http://jamanetwork.com/journals/jama/article-abstract/2627970

Blood Cultures Save Lives and Other Pearls of Wisdom

It’s been sixteen years since the introduction of Early Goal-Directed Therapy in the Emergency Department. For the past decade and a half, our lives have been turned upside-down by quality measures tied to the elements of this bundle. Remember when every patient with sepsis was mandated to receive a central line? How great were the costs – in real, in time, and in actual harms from these well-intentioned yet erroneous directives based off a single trial?

Regardless, thanks to the various follow-ups testing strict protocolization against the spectrum of timely recognition and aggressive intervention, we’ve come a long way. However, there are still mandates incorporating the vestiges of such elements of care –such as those introduced by the New York State Department of Health. Patients diagnosed with severe sepsis or septic shock are required to complete protocols consisting of 3-hour and 6-hour bundles including blood cultures, antibiotics, and intravenous fluids, among others.

This article, from the New England Journal, looks retrospectively at the mortality rates associated with completion of these various elements. Stratified by time-to-completion following initiation of the 3-hour bundle within 6 hours of arrival to the Emergency Department, these authors looked at the mortality associations of the bundle elements.

Winners: obtaining blood cultures, administering antibiotics, and measuring serum lactate
Losers: time to completion of a bolus of intravenous fluids

Of course, since blood cultures are obtained prior to antibiotic administration, these outcomes are co-linear – and they don’t actually save lives, as facetiously suggested in the post heading. But, antibiotic administration was associated with a fraction of a percent of increased mortality per hour delay over the first 12 hours after initiation of the bundle. Intravenous fluid administration, however, showed no apparent association with mortality.

These data are fraught with issues, of course, relating to their retrospective nature and the limitations of the underlying data collection. Their adjusted model accounts for a handful of features, but there are still potential confounders influencing mortality of those who received their bundle completion within 3 hours as compared to those who did not.  The differences in mortality, while a hard and important endpoint, are quite small.  Earlier is probably better, but the individual magnitude of benefit will be unevenly distributed around the average benefit, and while a delay of several hours might matter, minutes probably do not.  The authors are appropriately reserved with their conclusions, however, only stating these observational data support associations between mortality and antibiotic administration, and do not extend to any causal inferences.

The lack of an association between intravenous fluids and mortality, however, raises significant questions requiring further prospective investigation. Could it be, after these years wandering in the wilderness with such aggressive protocols, the only universally key feature is the initiation of appropriate antibiotics? Do our intravenous fluids, given without regard to individual patient factors, simply harm as many as they help, resulting in no net benefit?

These questions will need to be addressed in randomized controlled trials before the next level of evolution in our approach to sepsis, but the equipoise for such trials may now exist – to complete our journey from Early Goal-Directed to Source Control and Patient-Centered.  The difficulty will be, again, in pushing back against well-meaning but ill-conceived quality measures whose net effect on Emergency Department resource utilization may be harm, with only small benefits to a subset of critically ill patients with sepsis.

“Time to Treatment and Mortality during Mandated Emergency Care for Sepsis”

http://www.nejm.org/doi/full/10.1056/NEJMoa1703058

You’ve Got (Troponin) Mail

It’s tragic, of course, no one in this generation will understand the epiphany of logging on to America Online and being greeted by its almost synonymous greeting “You’ve got mail!” But, we and future generations may bear witness to the advent of something almost as profoundly uplifting: text-message troponin results.

These authors conceived and describe a fairly simple intervention in which test results – in this case, troponin – were pushed to clinicians’ phones as text messages. In a pilot and cluster-randomized trial with 1,105 patients for final analysis, these authors find the median interval from troponin result to disposition decision was 94 minutes in a control group, as compared with 68 minutes in the intervention cohort. However, a smaller difference in median overall length of stay did not reach statistical significance.

Now, I like this idea – even though this is clearly not the study showing generalizable definitive benefit. For many patient encounters, there is some readily identifiable bottleneck result of greatest importance for disposition. If a reasonable, curated list of these results are pushed to a mobile device, there is an obvious time savings with regard to manually pulling these results from the electronic health record.

In this study, however, the median LOS for these patients was over five hours – and their median LOS for all patients receiving at least one troponin was nearly 7.5 hours. The relative effect size, then, is really quite small. Next, there are always concerns relating to interruptions and unintended consequences on cognitive burden. Finally, it logically follows if this text message derives some of its beneficial effect by altering task priorities, then some other process in the Emergency Department is having its completion time increased.

I expect, if implemented in a typically efficient ED, the net result of any improvement might only be a few minutes saved across all encounter types – but multiplied across thousands of patient visits for chest pain, it’s still worth considering.

“Push-Alert Notification of Troponin Results to Physician Smartphones Reduces the Time to Discharge Emergency Department Patients: A Randomized Controlled Trial”
http://www.annemergmed.com/article/S0196-0644(17)30317-7/abstract

Correct, Endovascular Therapy Does Not Benefit All Patients

Unfortunately, that headline is the strongest takeaway available from these data.

Currently, endovascular therapy for stroke is recommended for all patients with a proximal arterial occlusion and can be treated within six hours. The much-ballyhooed “number needed to treat” for benefit is approximately five, and we have authors generating nonsensical literature with titles such as “Endovascular therapy for ischemic stroke: Save a minute—save a week” based on statistical calisthenics from this treatment effect.

But, anyone actually responsible for making decisions for these patients understands this is an average treatment effect. The profound improvements of a handful of patients with the most favorable treatment profiles obfuscate the limited benefit derived by the majority of those potentially eligible.

These authors have endeavored to apply a bit of precision medicine to the decision regarding endovascular intervention. Using ordinal logistic regression modeling, these authors used the MR CLEAN data to create a predictive model for good outcome (mRS score 0-2 at 90 days). These authors subsequently used the IMS-III data as their validation cohort. The final model displayed a C-statistic of 0.69 for the ordinal model and 0.73 for good functional outcome – which is to say, the output is closer to a coin flip than a informative prediction for use in clinical practice.

More importantly, however, is whether the substrate for the model is anachronistic, limiting its generalizability to modern practice. Beyond MR CLEAN, subsequent trials have demonstrated the importance of underlying tissue viability using either CT perfusion or MRI-based selection criteria when making treatment decisions. Their model is limited in its inclusion of just a measure of collateral circulation on angiogram, which is only a surrogate for potential tissue viability. Furthermore, the MR CLEAN cohort is comprised of only 500 patients, and the IMS-III validation only 260. This sample is far too small to properly develop a model for such a heterogenous set of patients as those presenting with proximal cerebrovascular occlusion. Finally, the choice of logistic regression can be debated, simply from a model standpoint, given its assumptions about underlying linear relationships in the data.

I appreciate the attempt to improve outcomes prediction for individual patients, particularly for a resource-intensive therapy such as endovascular intervention in stroke. Unfortunately, I feel the fundamental limitations of their model invalidate its clinical utility.

“Selection of patients for intra-arterial treatment for acute ischaemic stroke: development and validation of a clinical decision tool in two randomised trials”
http://www.bmj.com/content/357/bmj.j1710

An Uninsightful Look at Traumatic ICH in Ground Level Falls

The ground is ubiquitous. There are many ways to injure oneself, but the typical readily available impact surface is the ground. The ground is particularly pernicious, it seems, in the elderly and those in assisted care facilities. Thus, we have a great number of patients for whom imaging decisions must be made in elderly patients who have fallen from, apparently, “ground-level”.

Many of these same elderly patients have multiple medical comorbidities, including those for whom antiplatelet or anticoagulant therapy is indicated. These patients are, then, at elevated risk for intracranial hemorrhage despite the apparent low mechanism of injury. Wouldn’t it be lovely if we had better descriptive data with which to estimate and determine those at greatest risk?

Unfortunately, this fundamentally flawed observational study design tells us quite little. These authors included every patient whose electronic health record included antiplatelet and anticoagulant medications, and subsequently had intracranial imaging ordered. The EHR, then, prospectively prompted clinicians to indicate “ground-level fall” as their mechanism of injury. Of 668 patients on antiplatelets, 29 (4.3%) demonstrated ICH on CT. Of 180 patients on anticoagulants, 3 (1.7%) suffered ICH. Another 91 were on some sort of combined treatment, and 1 (1.1%) suffered ICH.

And this tells us nothing, other than the risk of ICH is non-zero. Even from a simple frequentist statistical standpoint, the sample sizes are small enough the confidence intervals around these numbers are quite wide. Then, there is the problem of their screening methods – which starts after the decision has been made to perform CT. Unless it is specifically protocolized all patients with ground-level fall are mandated to perform CT, decisions to initiate imaging would depend on the selection bias of individual clinicians. Individual perceptions of the risk of ICH on antiplatelet and anticoagulant medications dramatically impact the rate of imaging – so this ultimately only tells us the risk for ICH in their uniquely selected population.  Additionally, without structured follow-up of those not imaged, neither the numerator nor the denominator are reliable in this estimate.

These patients fall out of all of our decision support instruments, and it would be lovely to have better information regarding their true risk and specific predisposing factors in order to be better stewards of imaging resources and costs. These data unfortunately do not add much to our decision-making substrate.

“Risk of Intracranial Hemorrhage in Ground Level Fall with Antiplatelet or Anticoagulant Agents”

http://onlinelibrary.wiley.com/doi/10.1111/acem.13217/abstract

Use HEART, Or Whatever

The HEART score receives a lot of favorable press these days. It generally has face validity. It is probably superior in terms of discriminatory ability versus our venerable candidates such as TIMI and GRACE. It has been well-evaluated in multiple practice settings with reliable predictive value.

But, the final question for a decision instrument distilling a complex clinical scenario down to a five-question substrate for guiding evaluation and disposition – does it safely improve practice?

The answer is no – if you’re Dutch, in these Dutch hospitals.

In a stepped-wedge, cluster-randomized trial, these authors evaluated the effect of using HEART on patient outcomes and healthcare resource utilization. The three HEART risk categories carry general practice recommendations, in which low-risk (0-3) suggest early discharge, intermediate-risk (4-6) noninvasive testing, and high-risk (7-10) early invasive strategies. The comparator, “usual care” was, well, as usual.

With two cohorts comprising approximately 1,800 patients each, there were probably no reliable differences in care or outcomes demonstrated. The HEART low-risk cohort had a 2.0% 30-day incidence of MACE, which is similar to the safety profile described in other studies. However, the real goal of this evaluation was to determine acceptability and impact on resource utilization – and those results are decidedly mixed. Similar rates of early discharge from the ED, ED observation, inpatient admission, and downstream outpatient utilization were observed between the HEART cohort and usual care.

But, this answer from above – no impact on practice – is argued by these authors to be mostly related to non-adherence to the protocol recommendations. Most importantly, they note nearly a third of their low-risk patients were kept for prolonged ED or chest pain unit observation, and a handful more were admitted. The authors suggest there may be room for improvement in resource utilization, but they encountered entrenched cultural practice barriers.

This study was conducted between July 2013 and August 2014 – a long time ago, before most had heard of HEART. It is reasonable to suggest clinicians would now be more comfortable using this score for early discharge from the Emergency Department than during the trial period. It is probably also reasonable to suggest a more robust cultural effort backing practice change would improve adherence to recommendations – a collective departmental agreement associated with educational initiatives. Finally, usual care entailed early discharge of nearly 50% of all patients with chest pain, so your local baseline will affect whether a HEART-based protocol demonstrates improvement.

While these results in this trial are generally negative, what we see here is probably the floor for the effect of HEART on practice. At a minimum, it is as safe as advertised, and probably has room to demonstrate more robust beneficial effects on practice.

“Effect of Using the HEART Score in Patients With Chest Pain in the Emergency Department”

https://www.ncbi.nlm.nih.gov/pubmed/28437795

Symptoms Over Science

There’s a reason general primary care has evolved to diagnose and treat uncomplicated urinary tract infections over the phone: the patient is the authority, not any test we order.

We’ve tried relying upon some constellation of the urinalysis, the urine microscopic examination, and, finally, the urine culture. Each of these has limitations, although, in many settings, the culture result has been the gold standard. However, this culture result, some quantification of the number of colony-forming units, is also somewhat of an arbitrary diagnostic – an arbitrary numerical cut-off must be used, with its own implications for sensitivity and specificity.

This brief clinical microbiology article evaluates the urine culture as a gold standard for the diagnosis of UTI by comparing it with polymerase chain reaction-based methods for measuring the presence of pathogenic bacteria. Based on 86 asymptomatic women and 220 general practice women complaining of UTI symptoms, these authors compared the number of positive culture results with positive PCR results. Of this sample, 149 had positive cultures for e. coli, while 211 patients had positive PCR for e. coli. Finally, combining the culture results – which identified other pathogens, as well – with the PCR for e. coli, 216 of 220 symptomatic women had pathogenic bacteria identified. In the control cohort, there were similar numbers of positive culture and PCR results – ~10% in each, which these authors feel accurately reflects the general rate of asymptomatic bacteruria in the general population.

These data correlate nicely with similar findings demonstrating a negative urine culture does not exclude clinical improvement while on antibiotics, and thus the reasonable conclusion we ought simply treat appropriate symptomatic patients without specifically relying on testing.

“Women with symptoms of a urinary tract infection but a negative urine culture: PCR-based quantification of Escherichia coli suggests infection in most cases”
http://www.clinicalmicrobiologyandinfection.com/article/S1198-743X(17)30209-4/abstract