The Andexxa Showpiece

Every so often a masterclass performance arises in the medical literature. A performance transcending the boundaries of what was once thought possible. A shining exemplar of human achievement.

This is a trial, published in the New England Journal of Medicine, with the following features:

  • Conducted by an institute sponsored by pharma.
  • Designed by the first author, a consultant for pharma, and two employees of pharma.
  • Written by a medical writer employed by pharma.
  • Replete with authors reporting multiple financial conflicts of interest with pharma.
  • Substantially modified trial procedures and outcomes two and three years into the trial.
  • Introduced an interim stopping rule whose analysis was performed by an unblinded statistician affiliated with the funded institute.
  • Stopped the trial early based on the new interim stopping rule.
  • Used a surrogate composite primary endpoint.
  • Allowed the “usual care” arm to include patients who did not receive an active treatment comparator.
  • Permitted discrepancies in the baseline characteristics favoring the experimental arm.

And, this is solely the reported mechanisms by which pharma has placed their hands on the scales of this trial. It ought to be quite clear these procedures were carefully designed to ensure the (financial) success of this trial, and its ultimate publication is virtually an advertorial for the product in question.

The culprit this go-around? AstraZeneca née Alexion née Portola for Andexxa – better known as “andexanet alfa” (even though the FDA declined their drug naming for this label, properly known as “Coagulation Factor Xa [Recombinant], Inactivated-zhzo”). The trial is ANNEXA-I, which purports to be a comparison between Andexxa and Prothrombin Concentrate Complexes.

As alluded to above, this trial was not designed to permit Andexxa to fail. With Andexxa sales climbing and approaching $200M annually, it is obviously impermissible to allow a trial to offer a hint of doubt – especially considering Portola/Alexion/AstraZeneca have been investing in “expert guidelines” aimed at elevating Andexxa above PCCs as first-line treatment for Factor Xa-associated bleeding.

So – naturally, Andexxa “succeeds”. On the composite endpoint of “good hemostatic efficacy” – hematoma volume change < 35%, NIHSS change < 7 points, and no use of rescue therapy between 3-12 hours – Andexxa outperformed “usual care” by 13.4%, 67.0% to 53.1%. The primary limiting factor to this composite endpoint was the sub-endpoint of hematoma volume change of < 35%. And, as this composite favours Andexxa, the trial was stopped early – and the favorable press releases roll in. Ideally, this is the point at which our sponsors would like us to stop further analysis and critique.

Interestingly, the main paper presents an efficacy analysis consisting of 452 patients. However, between the initiation of the interim analysis and cessation of trial procedures, the authors enrolled an additional 78 patients. The authors report findings from all 530 in their safety analysis, but exclude them from the primary efficacy analysis – consigning the full cohort analysis to a supplementary appendix. There is no obvious reason to do so – other than the fact the larger cohort demonstrates less favorable results for Andexxa, with the hemostatic efficacy composite dropping from 67.0% to 63.9%. As is frequently cautioned regarding stopping trials early, doing so inflates the confidence intervals, diminishes the precision of an effect size estimate, and precludes the natural propensity of regression to the mean.

Then, there are the trial procedures. Prior to a protocol amendment excluding subdural hematomas, the Andexxa group included 13 patients with SDH, as compared with only 4 in “usual care”. Subdural hematomas, generally speaking, have far less sinister an outcome than intracerebral hemorrhage – an imbalance favoring the Andexxa cohort. Then, bizarrely, only 85% of the “usual care” cohort received anticoagulation reversal using PCCs. Very little data is included regarding these 60 patients receiving “non-PCC” care at the discretion of their treating clinicians. What sort of selection bias led clinicians to withhold an active treatment for ICH? Without concrete data, it is impossible to do more than speculate, but it seems logical to theorize these patients must have been disadvantaged by their lack of treatment.

Next, there are The Downsides. Treatment with Andexxa very clearly causes increased arterial thrombotic events. Ischemic strokes occurred in 6.5% of those treated with Andexxa, as compared to 1.5% receiving “usual care”. Myocardial infarctions occurred in 4.2% of those treated with Andexxa, as compared to 1.5% of those receiving “usual care”. A smaller excess of pulmonary embolism was seen in the “usual care” arm, however.

Lastly, there are the patient-oriented outcomes. Naturally, with a trial stopped early due to a composite surrogate, the authors are quick to mention the trial is underpowered to evaluate these endpoints. However, the overall outcomes of patients included in this trial are grim – and they are more grim for those treated with Andexxa. At 30 days, only 28% of patients treated with Andexxa achieved a modified Rankin scale of 0 to 3, compared with 31% in the “usual care” cohort. Similarly, 27.8% of patients treated with Andexxa had died at 30 days, as compared with 25.5% of those receiving “usual care”.

So, there you have it – such a “success” story of a trial it needed to be stopped early, and we still have no clear evidence Andexxa ought to be favored over “usual care”. The authors merrily cite INTERACT1, the trial upon which the “hematoma growth” surrogate is “validated” – and they will rely on this heavily for marketing purposes. In the end, we have exactly what we ought to have expected from a trial designed to stand on its head to deliver for its product, and we as clinicians are ever-poorer for it.

Andexanet for Factor Xa Inhibitor-Associated Acute Intracerebral Hemorrhage

Stayin’ Alive Below 65

Just a quick note looking at this lovely trial hypotension trial, evaluating potential use of lower mean arterial pressure targets in elderly patients receiving vasopressors.

Quick summary: Less is more. With a primary outcome of 90-day mortality, outcomes were no worse in patients randomized to a MAP target of 60-65 mmHg rather than “usual care” (≥65 mmHg) – 41.0% vs. 43.8% (-2.85%, 95%CI -6.75 to 1.05). Stated in formal terms, however, the trial failed to demonstrate a statistically significant difference between the treatment arms, and the confidence interval crosses unity. That said, I certainly agree with the accompanying editorial – it should be considered likely there is a potential advantage to “permitting” hypotension, rather than being hedging against intermittent dips. This trial wouldn’t go so far as to say the 65 mmHg is not the MAP target – patients in the “permissive” cohort still had a mean MAP on vasopressors of 66.7 mmHg, while those in the usual care arm trended higher at 72.6 mmHg – but, additional work looking at lower targets is reasonable.

There are, of course, minor oddities to be observed when considering how (or if) to generalize these data. While 78% of patients received norepinephrine, the second-most popular vasopressor was metaraminol, a predominately alpha agonist, used in almost a third of those randomized. Interestingly, fewer than half the patients enrolled were in “septic shock” by Sepsis-3 definitions, while only another quarter were noted to have “sepsis (not in shock)”. Finally, while the findings are generally consistent across all age cohorts, the mean age is ~75, and nearly 75% of those screened were excluded for one of many reasons.

This study is a lovely demonstration of a rather straightforward underlying principle – MAP is not a measure of tissue perfusion, and is used rather as a surrogate for the ultimately-important microvascular circulation. Making big tubes run at a higher pressure at the expense of clamping down little tubes may be harmful – hence the rationale for this trial, and future ones.

As another random aside, I might make a note here for aspiring researchers – the guidelines will frequently tell you where knowledge gaps exist. The 2012 Surviving Sepsis guidelines gave the MAP >65 target a “1C” recommendation, with “1” meaning consensus for the recommendation was strong, but “C” meaning the evidence was weak. Looking at guideline recommendations and their accompanying level of evidence provides: 1) clues as to which clinical questions are important enough to be addressed by guidelines, and 2) the gaps in the evidence. Guideline authors will even, frequently, explicitly call out certain clinical questions for further study. I wouldn’t go so far as to call it a roadmap to clarifying the important questions in your specialty, but it certainly could be fertile.

“Effect of Reduced Exposure to Vasopressors on 90-Day Mortality in Older Critically Ill Patients With Vasodilatory Hypotension”
https://jamanetwork.com/journals/jama/fullarticle/2761427

Let’s Sell Andexxa

Have you heard the Good News (from Portola) about andexanet?

It’s an ever-changing landscape of anticoagulants and reversal agents in the Emergency Department – though, it’s not so much as a whirlwind as it is a creeping ooze. The latest developments have all been covered ad nauseum over the past few years – dabigatran, idarucizumab, factor Xa inhibitors, and coagulation factor Xa (recombinant) inactivated-zhzo (andexanet alfa). This final product, trade name Andexxa, has generally been held in a dim view over the past year by many, including yours truly, Rebel EM, the Skeptic’s Guide to Emergency Medicine, EmCrit, first10EM, the American Society of Hematology, and both the European Medicines Agency and the Food and Drug Administration’s own clinical reviewers.

There is, however, a competing viewpoint in which Andexxa is Tier 1 therapy for treatment of major bleeding in the context of of direct Xa inhibitor use – such as this recent “Recommendations of a Multidisciplinary Expert Panel” piece in Annals of Emergency Medicine. What aspect of their review differs so greatly in their affinity for Andexxa?

The expert panel meeting was convened with funds from unrestricted educational grants from Portola Pharmaceuticals and Boehringer Ingelheim to the American College of Emergency Physicians.

And, to no great surprise, the convened panel reflects the funding source:

Dr. Baugh has worked as a consultant for Janssen Pharmaceuticals and previously received research funding from Janssen Pharmaceuticals and Boehringer Ingelheim as a coinvestigator. Dr. Cornutt has received speaker’s fees from Boehringer Ingelheim. Dr. Wilson has worked as a consultant for Janssen Pharmaceuticals, Boehringer Ingelheim, BMS/Pfizer Pharmaceuticals, and Portola Pharmaceuticals, and has also received research funding from them. Dr. Mahan has served on the speaker’s bureau and as a consultant for Boehringer Ingelheim, Janssen Pharma, Portola Pharma, and BMS/Pfizer and as a consultant to Daiichi-Sankyo, WebMD/Medscape, and Pharmacy Times/American Journal of Managed Care. Dr. Pollack is a scientific consultant to Boehringer Ingelheim, Janssen Pharma, Portola Pharma, and BMS/Pfizer; he also received research support from Boehringer Ingelheim, Janssen Pharma, Portola Pharma, Daiichi-Sankyo, CSL Behring, and AstraZeneca. Dr. Milling’s salary is supported by a grant from the National Heart, Lung, and Blood Institute. He serves on the executive committee for the ANNEXA-4 and ANNEXA-I trials, the steering committee for the LEX-209 trial, and the publications committee for the Kcentra trials. He has received consulting fees or research funding from CSL Behring, Portola, Boehringer Ingelheim, Genentech, and Octapharma. He received speaker’s fees from Janssen. Dr. Peacock has received research grants from Abbott, Boehringer Ingelheim, Braincheck, CSL Behring, Daiichi-Sankyo, Immunarray, Janssen, Ortho Clinical Diagnostics, Portola, Relypsa, and Roche. He has served as a consultant to Abbott, AstraZeneca, Bayer, Beckman, Boehringer-Ingelheim, Ischemia Care, Dx, Immunarray, Instrument Labs, Janssen, Nabriva, Ortho Clinical Diagnostics, Relypsa, Roche, Quidel, and Siemens. He has provided expert testimony on behalf of Johnson & Johnson and has stock and ownership interests in AseptiScope Inc, Brainbox Inc, Comprehensive Research Associates LLC, Emergencies in Medicine LLC, and Ischemia DX LLC. Dr. Rosovsky has served as an advisor or consultant to Janssen, BMS, and Portola and has received institutional research support from Janssen and BMS. Dr. Sarode has served as a consultant for CSL Behring and Octapharma and advisor to Portola Pharmaceuticals. Dr. Spyropoulos is a scientific consultant to Janssen, Bayer, Boehringer Ingelheim, Portola, and the ATLAS Group; he also has received research support from Janssen and Boehringer Ingelheim. Dr. Woods is a scientific consultant to Boehringer Ingelheim. Dr. Williams serves as a consultant to Janssen Pharmaceuticals, Boehringer Ingelheim, and Portola Pharmaceuticals.

This work is effectively an advertorial, masquerading as serious academic literature, and part of a well-executed marketing and promotional campaign by the manufacturers of these drugs – particularly Portola, which is having difficulty getting Andexxa on formulary due its cost and controversial clinical data. This publication in Annals is just one of many sponsored products:

The further afield these pseudo-guidelines permeate, the more likely the product – the $25k or $50k a dose Andexxa – is incorporated into hospital formularies and local practice. These also have implications for risk-management assessments, in which the costs – passed along to the patient or payor – are far outweighed by the potential liability of a decision to make the drug unavailable for treatment.

It should be clear from all the non-conflicted opinion the role of Andexxa is yet to be clearly established, with true RCT evidence unfortunately years away. To state otherwise – and to make Tier 1 recommendations – is simply misleading.

“Anticoagulant Reversal Strategies in the Emergency Department Setting: Recommendations of a Multidisciplinary Expert Panel”
https://www.annemergmed.com/article/S0196-0644(19)31181-3/fulltext

2019 Early Management of Acute Ischemic Stroke

Well, it’s 2019 – for another couple months – so there’s still time to update your Early Management of Acute Ischemic Stroke.

For what would otherwise sound to be a potentially underwhelming interval update, there is, in fact, a ton to unpack in here. Institutional stroke committees and regional EMS systems thrive on constant change, after all. Most of the changes are “clarity”, but there are many new recommendations, some of which are bland – promoting the use of EMS for stroke symptoms, for example – whereas others are even potentially controversial.

Some of the meat:

  • Expert opinion-based recommmendations to bypass local hospitals in preference of thrombectomy-capable facilities for patients ineligible for IV thrombolysis, but with symptoms of large vessel occlusions.
  • Several new recommendations promoting telestroke as a reasonable means of patient evaluation, even if it’s just telephone consultation.
  • A handful of new recommendations incorporating the use of MRI for stroke assessment, based on WAKE-UP, including the use of IV thrombolysis beyond 4.5 hours.
  • Two new recommendations regarding multimodal imaging in acute ischemic stroke. The first, non-controversial recommendation includes the use of CT perfusion or MRI-DWI for assessment of patients between 6 and 24 hours from symptom onset. However, when symptom onset is less than 6 hours, the new recommendation is to perform endovascular intervention based just on vessel status and ASPECTS. Throw out the high-value care guided by REVASCAT, SWIFT PRIME, EXTEND-IA, and ESCAPE and just treat based on the smaller effect sizes seen in THRACE and MR-CLEAN!
  • Surprisingly, explicit recommendation to withhold thrombolysis of mild non-disabling stroke based on PRISMS.
  • Thrombolysis with tenecteplase makes its first appearance as a reasonable alternative to alteplase.
  • A new recommendation to cover initiation of short-term dual antiplatelet therapy for minor stroke not treated with alteplase.
  • An entire massive new section with recommendations regarding in-hospital imaging modalities to help regarding secondary prevention of ischemic stroke.

There’s something in here for just about everyone!

“Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke.”
https://www.ncbi.nlm.nih.gov/pubmed/31662117

ATS + IDSA CAP 2019

As the authors of this document lead off, it has been more than 10 years since the last American Thoracic Society/Infectious Diseases Society of America community-acquired pneumonia guideline – and much has changed. And, reflecting this, Much Has Changed.

A few interesting tidbits:

  • Do not obtain blood cultures in the outpatient setting, and blood cultures are recommended as inpatients only for severe CAP and when MRSA and P. aeruginosa are being covered. This, of course, is likely moot given our current triage of potential sepsis.
  • Basic outpatient CAP should be amoxicillin, doxycycline, or macrolide (based on local resistance) monotherapy. Add in comorbidities, and combination therapy or monotherapy with a respiratory fluoroquinolone is indicated.
  • Procalcitonin is not reliable to augment clinical judgment when CAP is suspected.
  • The Pneumonia Severity Index is the preferred decision instrument to augment clinical judgement regarding hospitalization.
  • Inpatient antibiotics are universally ß-lactam plus macrolide, or monotherapy with a respiratory fluoroquinolone. Empiric MRSA and P. aeruginosa coverage is suggested only if prior infection, not in those with risk factors alone.
  • No routine empiric anerobic coverage for suspected aspiration pneumonia.
  • No routine steroids for CAP, even severe.
  • Various recommendations regarding nfluenza and suspicion of CAP – treat with both antiviral and antibiotic therapy.
  • No follow-up chest x-ray documenting resolution of infiltrates is necessary in the outpatient setting if the patient is clinically improved.

Details, doses, and rationale within – many caveats, conditional recommendations, and need for additional research.

“Diagnosis and Treatment of Adults with Community-acquired Pneumonia: An Official Clinical Practice Guideline of the American Thoracic Society and Infectious Diseases Society of America”
https://www.atsjournals.org/doi/10.1164/rccm.201908-1581ST

More Cardiac Stress Test Futility

Once upon a time, it was believed important to perform cardiac stress testing in patients with chest pain and potential acute coronary syndrome. Intuitively, this makes little sense – a stress test may identify obstructive coronary disease, but this is rarely the culprit for acute coronary syndrome, and certainly only rarely the cause of chest symptoms in a patient at low-risk for coronary artery disease. Unfortunately, the American College of Cardiology/American Heart Association have had a nonsensical recommendation for noninvasive testing within 72 hours of an index visit on the books for quite some time – leading, to put it mildly, to a test or two.

This observational data set evaluates the outcomes of patients in the Kaiser Southern California system who were referred for outpatient stress testing following an encounter in the Emergency Department. They tracked 7,988 patients for a month after their ED encounter, 2,497 of whom underwent stress testing within 3 days, 4,695 within 4 to 30 days, and 796 who never showed up for their referred testing. Most stress tests were exercise or pharmacologic stress ECG, with the minority stress echocardiograms or myocardial perfusion imaging.

Patients undergoing testing were not devoid of risk factors: an average age of 55 years, most were overweight, and over half had at least one risk factor for coronary artery disease. Within 30 days, fewer than 1% were diagnosed with an acute MI, and a handful of those underwent PCI or CABG. There were tiny differences between groups, as none of the patients who skipped their stress test underwent subsequent revascularization. There were no deaths in any cohort.

The narrow view here in this article is there is no apparent benefit to undergoing stress testing within 72 hours as compared with a longer timeframe. The wider view is yet another piece of information showing the general disutility of stress testing. These are not randomized cohorts, nor is 30-days a long enough window to detect any potential benefits to the stress test – as measured by decreased morbidity or mortality as relating to a timelier PCI or CABG. However, even these interventions were rare enough the effect size from any benefit is bound to be so small as to represent low-value care. It is absolutely reasonable to suggest the Bayesian pendulum for the valuation of stress testing is swinging the other direction – and those who advocate for stress tests ought to generate data to support its targeted use, rather than for the opposition to generate data contrary to its assumed routine utility.

“Evaluation of Outpatient Cardiac Stress Testing After Emergency Department Encounters for Suspected Acute Coronary Syndrome”

https://www.sciencedirect.com/science/article/pii/S019606441930054X

IDSA Influenza – Class A, Level III

The last time the IDSA updated their influenza practice guidelines, it was the time of the 2009 H1N1 influenza pandemic. Fittingly, we are entering another season of H1N1 – and we have new guidelines, incorporating all the new evidence gathered in the meantime.

And, unfortunately, that is to say: we don’t really have any new, high-quality evidence.

The grading system for their recommendations includes two categories. Strength of recommendation:

  • A: Good evidence to support a recommendation for or against use
  • B: Moderate evidence to support a recommendation for or against use
  • C: Poor evidence to support a recommendation

Quality of evidence:

  • I: Evidence from 1 or more properly randomized controlled trials
  • II: Evidence from 1 or more well-designed clinical trials, without randomization; from cohort or case-controlled analytic studies (preferably from >1 center); from multiple time-series; or from dramatic results from uncontrolled experiments
  • III: Evidence from opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees

It would follow, then, for an “A” strength recommendation, this ought to reflect I or II quality of evidence – but a bizarrely staggering number of their recommendations are A-III, effectively self-contradicting. Most of their “Which Patients Should Be Tested for Influenza?” recommendations are A-III. The critical “Which Patients With Suspected or Confirmed Influenza Should Be Treated With Antivirals?” section features another batch of A-III recommendations, followed by several C-I and C-IIIs.

A long story short, this is simply paradoxical, making level A recommendations from class III evidence in the form of manufacturer sponsored trials, indirectly-sponsored meta-analyses, and observational data. Many authors of this piece are neck deep in reported financial and professional conflicts of interest with industry, which almost certainly eases any pain felt by distributing such internally invalid recommendations. After decades of controversy and hundreds of millions of dollars in profit for Genetech/Roche, we’re still bumbling along with our original momentum lacking a full understanding of the effectiveness and value of these medications.

“Clinical Practice Guidelines by the Infectious Diseases Society of America: 2018 Update on Diagnosis, Treatment, Chemoprophylaxis, and Institutional Outbreak Management of Seasonal Influenza”
https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciy866/5251935

Metronidazole is Out for C. Diff

Time to update USMLE, ABEM, ABIM, and every other standardized test given in medicine – the old standby, metronidazole, has been downgraded for the treatment of Clostridium difficile infection.

This update from the Infectious Disease Society of America, published last month, refreshes clinical practice guidelines for C. diff. The article covers a few different topics, including the population to be tested, the criteria for diagnosis, and a whole host of management and prevention factors. As with any comprehensive guideline, there is the occasional discordance between the strength of the recommendation and the quality of the underlying evidence, so the generalizability of their recommendations may have limitations.

However, tucked into all the various nuances (which are all mostly worth looking over, of course), is one of the most profound changes – metronidazole has been demoted from first-line for C. diff infection. The co-first line agents are now oral vancomycin or oral fidaxomicin. The authors effectively cite the continued use of metronidazole as anachronistic dogma, with vancomycin repeatedly demonstrated as having greater effectiveness. Cure rates with oral vancomycin range from 80-97%, while metronidazole is a rung down at 70-84%. Unfortunately, the cost of oral vancomycin and fidaxomicin remains highly burdensome – leaving a role for metronidazole, but not preferred as before.

It should be noted virtually every author of the guideline has some sort of relationship with a pharmaceutical company, including the manufacturer of fidaxomicin.  That said, oral vancomycin is generic – if still expensive – and has been around a long time.

“Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 Update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA)”
http://www.idsociety.org/Guidelines/Patient_Care/IDSA_Practice_Guidelines/Infections_By_Organ_System-81567/Gastrointestinal/Clostridium_difficile/

The qSOFA Story So Far

What do you do when another authorship group performs the exact same meta-analysis and systematic review you’ve been working on – and publishes first? Well, there really isn’t much choice – applaud their great work and learn from the experience.

This is primarily an evaluation of the quick Sequential Organ Failure Assessment, with a little of the old Systemic Inflammatory Response Syndrome thrown in for contextual comparison. These studies included those in the Intensive Care Unit, hospital wards, and Emergency Departments. Their primary outcome was mortality, reported in these studies mostly as in-hospital mortality, but also 28-day and 30-day mortality.

The quick synopsis of their results, pooling 38 studies and 383,333 patients, mostly from retrospective studies, and mostly from ICU cohorts:

  • qSOFA is not terribly sensitive, particularly in the settings in which it is most relevant. Their reported overall sensitivity of 60.8% is inflated by its performance in ICU patients, and in ED patients sensitivity is only 46.7%.
  • Specificity is OK, at 72.0% overall and 81.3% in the ED. However, the incidence of mortality from sepsis is usually low enough in a general ED population the positive predictive value will be fairly weak.
  • In their comparative cohort for SIRS, which is frankly probably irrelevant because SIRS is already well-described, the expected results of higher sensitivity and lower specificity were observed.

Their general conclusion, to which I generally agree, is qSOFA is not an appropriate general screening tool. They did not add much from a further editorial standpoint – so, rather than let our own draft manuscript for this same meta-analysis and systematic review languish unseen, here is an abridged version of the Discussion section of our manuscript written by myself, Rory Spiegel, and Jeremy Faust:

This analysis demonstrates qualitatively similar findings as those observed in the original derivation study performed by Seymour et al. We find our pooled AUC, however, to be lower than the 0.81 reported in their derivation and validation cohort, as well as the 0.78 reported in two external validation cohorts. The meaning of this difference is difficult to interpret, as the clinical utility of this instrument is derived from its use as a binary cut-off, rather than an ordinal AUC. Our sensitivity and specificity from our primary analysis, respectively, compare favorably to their reported 55% and 84%. We also found qSOFA’s predictive capabilities remained robust when exposed to our sensitivity analyses. When only studies at low risk for bias were included, qSOFA’s performance improved.

While our evaluation of SIRS is limited by restricting the comparison solely to those studies which contemporaneously reported qSOFA, our results are broadly consistent with results previously reported. The SIRS criteria at the commonly used cut-off benefits from superior sensitivity for mortality in those with suspected infection, while its specificity is clearly lacking due to its impaired capability to distinguish between clinically important immune system dysregulation and normal host responses to physiologic stress. The important discussion, therefore, is whether and how to incorporate each of these tools – and others, such as the Modified Early Warning Score or National Early Warning Score – into clinical practice, guidelines, and quality measures.

The current approach to sepsis revolves around the perceived significant morbidity and mortality associated with under-recognized sepsis, favoring screening tools whose purpose is minimizing missed diagnoses. Current sepsis algorithms typically rely upon SIRS, depending on its maximal catchment at the expense of over-triage. Such maximal catchment almost certainly represents a low-value approach to sepsis, considering the in-hospital mortality of patients in our cohort with ≥2 SIRS criteria is not meaningfully different than the overall mortality of the entire cohort. The subsequent fundamental question, however, is whether qSOFA and its role in the new sepsis definitions provides a structure for improvement.

Using qSOFA as designed with its cut-off of ≥2, it should be clear its sensitivity does not support its use as an early screening tool, despite its simplicity and exclusion of laboratory measures. However, in a cohort with suspected infection and some physiologic manifestations of sepsis, e.g., SIRS, the true value of qSOFA may be in prioritizing a subgroup for early clinical evaluation. In a healthcare system with unlimited resources, it may be feasible to give each patient uncompromising evaluation and care. Absent that, we must hew towards an idealized approach, where our resources are directed towards those highest-yield patients for whom time-sensitive interventions modify downstream outcomes.

Less discussed are the direct, patient-oriented harms resulting from falsely-positive screening tools and over-enrollment into sepsis bundles. Recent data suggests benefits from shorter time-to-antibiotics administration intervals are realized primarily in critically ill patients. As such, utilization of overly sensitive tools, such as the SIRS criteria, would lead to over-triage and over-treatment, leading to potential iatrogenic harms in excess of net benefits. These harms include effects on individual and community patterns of antibiotic resistance, as exposure to broad-spectrum antibiotics leads to induction of extended-spectrum beta-lactamase resistance in gram-negative pathogens or vancomycin- and carbapenem-resistance in enterococci. Unnecessary antibiotic exposures lead to excess cases of C. difficile infections. The aggressive fluid resuscitation mandated by sepsis bundles leads to metabolic derangement and potential respiratory impairment. Further research should assess the extent of these harms, and in what measure they counterbalance those benefiting from time-sensitive interventions.

This meta-analysis has several limitations. First, we were limited by the relative dearth of high quality prospective data; most of the studies included in our analysis were retrospective. Second, we restricted our prognostic analyses to mortality alone, rather than diagnosis of sepsis. We chose to analyze only mortality because of competing sepsis definitions among expert bodies and government-issued guidelines. Among them, however, mortality is a common feature, the most objective metric, and manifestly the most important patient-centered outcome. Our analysis would not capture other important sequelae of sepsis, including amputation, loss of neurologic and/or independent function, chronic pain, and prolonged psychiatric effects of substantial critical illness. Third, we do not know whether patients included in these studies were septic on presentation, or developed sepsis later in their hospitalization. This may degrade the accuracy assessment of both SIRS and qSOFA. Fourth, while we know that qSOFA alone may miss some cases of sepsis that SIRS might detect, we do not know how many would, in reality, have been deprived of antibiotics and other necessary treatments. In other words, the fate of “qSOFA negative” patients who were evaluated and treated by physicians qualified to detect and treat critical illness via clinical acumen is not known; nor it should not be presumed that all such patients would have necessarily been deprived of timely treatment. Our analysis and comparison of SIRS is definitively incomplete, and not the most reliable estimate of its diagnostic characteristics, but provided for incidental comparison.

The prudent clinical role for qSOFA, however, is as yet undefined, and these data do not offer insight regarding its superiority to clinician judgment for determining a cohort at greatest risk for poor outcomes. Compared with SIRS, at least, those patients identified by qSOFA likely better represent the subset of patients for whom aggressive early treatment confers a particular advantage, and may drive high-value care in the sepsis arena. Future research should assist clinicians in further individualizing initial treatment of sepsis for those stratified to differing levels of risk for poor outcome, as well as to account for the iatrogenic harms and system costs.

“Prognostic Accuracy of the Quick Sequential Organ Failure Assessment
for Mortality in Patients With Suspected Infection: A Systematic Review and Meta-analysis”
http://annals.org/aim/fullarticle/2671919/prognostic-accuracy-quick-sequential-organ-failure-assessment-mortality-patients-suspected

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