Endotoxin mediated circulatory collapse remains a theoretical target in the treatment of sepsis.
But, eritoran won’t be one of the agents used to ameliorate its effects.
After a phase II trial found sepsis patients randomized to eritoran had 37.5% mortality compared with 56.3% in the placebo group, the manufacturer sponsored a multi-national, multi-center phase III trial enrolling 1,951 patients. And, in short – no mortality benefit overall, and no individual subgroups of severe sepsis with any indication of benefit. The authors comments speak wistfully of the early favorable results before finally concluding: “Eritoran joins a long list of other experimental sepsis treatments that do not improve outcomes in clinical trials in these critically ill patients.”
Interestingly, the study concluded in 2010 – meaning it took 2 1/2 years for the results to reach publication. The reader will have to derive their own interpretation regarding whether this had anything to do with being negative results from a manufacturer-sponsored trial.
“Effect of Eritoran, an Antagonist of MD2-TLR4, on Mortality in Patients With Severe Sepsis”
Chovstek Sign – Forget It
This entertaining brief communication refers to Chvostek sign – the twitching of the facial muscles after tapping the facial nerve purportedly associated with hypocalcemia.
This neurologist notes, after one of his residents presented with bilateral Chvostek sign, he convenience sampled other residents and medical students on the wards – and 6 out of 11 exhibited Chvostek sign. He otherwise notes 25-43% of healthy individuals exhibit this sign and 29% of patients with hypocalcemia do not. He bluntly states Chvostek sign should simply be retired as a clinically relevant entity.
Stick with the Trousseau sign!
“Chvostek sign, frequently found in healthy subjects, is not a useful clinical sign”
http://www.neurology.org/content/80/11/1067.full
New Pediatrics Otitis Media Recommendations
The content of these recommendations is what made the rounds in various news outlets – the first begrudging revelations that antibiotics are possibly unnecessary for many of acute otitis media. This isn’t news to us, of course, but it’s entertaining to see the precise moment the Rock of Gibraltar starts to make its slow course corrections.
As far as clinical policy statements go, however, this is beautifully constructed. For every actionable statement, these authors offer a concise summary of the benefits, harms, value judgements, intentional vagueness, patient preferences, and exclusions. Whether I agree with the hairs they split on each recommendation is almost overwhelmed by how pleasant it is to understand the basis of their reasoning.
My big irritation: their implication that symptom severity or temperatures greater than 102.2F are somehow specific for bacterial disease more likely to benefit from antibiotics. Odd – or am I missing a notable piece of literature? Please point it out if so!
The other new item of interest is the “Strong Recommendation” for analgesic treatment in cases of AOM. Thank goodness!
“The Diagnosis and Management of Acute Otitis Media”
www.ncbi.nlm.nih.gov/pubmed/23439909
Back For More With Cangrelor
Two negative studies weren’t enough to stop the Medicines Company from CHAMPION PHOENIX, the third attempt at demonstrating cangrelor is useful during PCI.
Cangrelor is a direct-acting platelet adenosine diphosphate inhibitor – same as prasugrel and clopidogrel – that differs in its half-life and route of administration. Rather than clopidogrel, which is a long-acting oral loading dose during STEMI, cangrelor is a continuous intravenous inhibitor that wears off after minutes. This has some theoretical advantages, such as when multiple lesions are found on invasive angiography and coronary bypass need not be delayed for the antiplatelet effects of clopidogrel to wear off.
So, PHOENIX follows up CHAMPION PCI and CHAMPION PLATFORM, each of which were negative for their primary combined endpoint of death, myocardial infarction, or ischemia-driven revascularization. In fact, these studies were stopped at their interim analysis for futility, as they were unlikely to show superiority given the planned enrollment.
So, why does PHOENIX succeed where others have failed? Well, they changed the primary endpoint to a new composite – death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis. And, PHOENIX shows a 0.8% vs 1.4% advantage to cangrelor for stent thrombosis – which accounts for most of the new advantage in primary outcome. In previous CHAMPION studies, stent thrombosis was 0.2% vs. 0.3% and 0.2% vs. 0.6%. So, truly, cangrelor succeeds here mostly because the clopidogrel group fares so much more poorly, rather than on its own merits. Considering 25.7% of the clopidogrel group received only 300mg rather than 600mg, and 36.6% received their clopidogrel during or after PCI, it’s no wonder they had greater stent thrombosis in this study.
It’s pretty clear the Medicines Company learned from its two negative studies and rigged the third one to succeed – and kept it just underpowered enough that severe or moderate bleeding with cangrelor didn’t reach statistical significance (0.6% vs. 0.3% p = 0.09). This reinforces a bias frequently seen in sponsored trials – failure at first begets further trials, while initial success doesn’t lead to confirmatory RCTs that might cast doubts upon the authenticity of the golden goose.
“Effect of Platelet Inhibition with Cangrelor during PCI on Ischemic Events”
www.ncbi.nlm.nih.gov/pubmed/23473369
Dabigatran & CES1 SNP rs2244613
This piece of literature is incredibly important – not because of the specific clinical question it addresses, but, rather, because of the fundamental principle in medicine it illustrates.
In large, heterogenous populations – frequently clinical trials – the risks and benefits are not evenly distributed throughout the cohort. However, when the primary outcome reported, this is based on the aggregate results. This leads us to one of the primary flaws in evidence-based medicine, that statistical power typically comes at the expense of external validity to the individual patient.
This retrospective evaluation of the cohort from RE-LY, the trial comparing dabigatran to warfarin for the prevention of stroke in atrial fibrillation, evaluates genetic polymorphisms and their association with primary and safety outcomes. In short, each minor allele of CES1 SNP rs2244613 was associated with lower trough concentrations and statistically significant interaction between treatment with warfarin and bleeding – hazard ratio 0.59 (0.46 – 0.76) for carriers and hazard ratio 0.96 (0.81 – 1.14) for noncarriers. No difference in the primary stroke prevention outcome was apparent – but outcomes were infrequent and the study was underpowered to detect such a difference.
My take on these results is simple – the 32.1% of patients who are carriers for the rs2244613 allele account for most of the bleeding benefit seen in RE-LY, and the non-carriers have no bleeding advantage compared with warfarin. We ought to be specifically tailoring and reducing the dabigatran treatment population to this subgroup with the most favorable risk profile – and we need to be developing tools that support this kind of individualized treatment throughout medicine.
“Genetic Determinants of Dabigatran Plasma Levels and Their Relation to Bleeding”
www.ncbi.nlm.nih.gov/pubmed/23467860
The Sad Reality of Chest Pain Observations
Chest pain observation units run by the Emergency Department are fairly popular – and it’s easy to see why. It eliminates the need to fight a hospitalist for admission, allows for complete coverage of medicolegal liability, captures another set of billing codes for ED revenue, and keeps the cardiologists happy with a steady stream of interpretation and consultation revenue.
Duke University has one of these such chest pain observation units, and this study is a retrospective evaluation of the subgroup of patients aged less than 40 years. Of the 2,231 patients observed for suspected acute coronary syndrome, 362 met eligibility based on age. Of these 362 patients, median age 36, 238 underwent stress testing and the remainder underwent serial enzymes.
From this cohort, there was a single true positive – defined as a patient who underwent a coronary angiogram with an intervention performed.
There were, however, 14 false positives – indeterminate or positive stress tests and one set of positive biomarkers, leading to five negative invasive coronary angiograms.
The authors sum it up quite nicely: “The extremely risk- adverse physician cannot totally exclude the possibility of ACS based on age, but it seems that routine observation for such patients may cause the potential for as much harm as good.”
“Utility of Observation Units For Young Emergency Department Chest Pain Patients”
www.ncbi.nlm.nih.gov/pubmed/22975283
“ePlacebo”-Controlled Trials?
This is a bit of a fascinating application of clinical informatics – using retrospective patient cohorts and propensity matching techniques to reduce the need for placebo groups in future trials.
This is work done by Pfizer on their own internal database, to address the ethical and financial concerns regarding recruiting large populations for new clinical trials. For example, if you’re testing a new diabetes medication – do you really need a new control group, or can you sort of re-use the control group you had from the previous trial? The answer of course, has traditionally been no – but their answer is yes-and-no. Using their database of over 24,000 trials, they were able to identify 4,075 placebo-controlled groups, with varying degrees of data integrity, crossover, and parallel status. They then suggest these groups could be used, when appropriate, as comparators in future studies in the same domain.
This is certainly an interesting application of clinical informatics – creating temporal databases of clinical trial patients with the potential to augment the evaluation of new medications. What’s nice is that these authors appropriately recognize the limitations of such a database, noting it may only supplement, not replace placebo arms in future trials.
“Creation and implementation of a historical controls database from randomized clinical trials”
www.ncbi.nlm.nih.gov/pubmed/23449762
Stroke or Stroke Mimic? Who Cares!
Suppose you’re “lucky” enough to be taken to an experienced stroke center if you have stroke-like symptoms. After all, they see strokes every day, are experts in the diagnosis of stroke, and have given thousands of patients thrombolytics. However, how often might they be wrong, you ask?
Oh, they estimate about 1 in every 50. But, truthfully, it’s probably much worse.
This is a multi-center observational cohort that purports to identify the percentage of patients treated with tPA and subsequently diagnosed with stroke mimics. Out of the 5518 patients in their cohort, 100 were identified as stroke mimics. Two of the 100 had sICH by NINDS criteria, but none died. Therefore, these authors confirm, tPA is safe even when they’re wrong, and the collateral damage of racing to tPA is low.
Of course, their methodology for identifying a stroke mimic is hugely skewed towards maintaining the diagnosis of ischemic stroke. Only patients in whom clinical details did not suggest a vascular etiology or a clear alternative diagnosis were labeled mimics. Patients with nonspecific features, non-contradictory imaging, or lacking definite evidence favoring stroke mimic remained as diagnoses of acute stroke.
So, even at experienced stroke research institutions – 1 in 50 with the most generous of criteria. What’s the chance real-world performance approaches anything close to this level of diagnostic skill?
The authors, of course, declare multiple financial conflicts of interest with the manufacturer of tPA.
“Safety of Thrombolysis in Stroke Mimics : Results From a Multicenter Cohort Study”
www.ncbi.nlm.nih.gov/pubmed/23444310
Does Size Matter? (Chest Tube Size)
That is, apparently, the question being asked by the trauma folks at Los Angeles County Hospital. Traditionally, traumatic pneumothorax with accompanying hemothorax is routinely treated by the largest chest tube possible. Theoretically, smaller chest tubes will clog with debris or blood clot, requiring additional thoracostomy tubes or interventions.
However, these authors note several simulations of chest tube drainage indicating tubes as small as 14 French may be adequate. They also hypothesize these larger chest tubes are as painful as tragically possible, and the tradition of large chest tubes results in undue suffering.
The answer…remains unsettled. There was no difference observed in their analysis of chest tubes of maximum size versus smaller-than-maxiumum size. But, a 28-32 Fr chest tube is still a pretty darn large tube. I’m not surprised that pain and drainage characteristics were not different. If they really wanted to push the envelope, they ought to look at the truly small tubes – at least, if their goal is clinically relevant pain reduction.
“Does size matter? A prospective analysis of 28–32 versus 36–40 French chest tube size in trauma”
www.ncbi.nlm.nih.gov/pubmed/22327984
The NICE Traffic Light Fails
Teasing out serious infection in children – while minimizing testing and unnecessary interventions – remains a challenge. To this end, the National Institute for Health and Clinical Excellence in the United Kingdom created a “Traffic Light” clinical assessment tool. This tool, which uses colour, activity, respiratory, hydration, and other features to give a low-, intermediate-, or high-risk assessment.
These authors attempted to validate the tool by retrospectively applying it to a prospective registry of over 15,000 febrile children aged less than 5 years. The primary outcome was correctly classifying a serious bacterial infection as intermediate- or high-risk. And the answer: 85.8% sensitivity and 28.5% specificity. Meh.
108 of the 157 missed cases of SBI were urinary tract infections – for which the authors suggest perhaps urinalysis could be added to the NICE traffic light. This would increase sensitivity to 92.1%, but drop specificity to 22.3% – if you agree with the blanket categorization of UTI as SBI.
Regardless, the AUC for SBI was 0.64 without the UA and 0.61 with the UA – not good at all.
“Accuracy of the “traffic light” clinical decision rule for serious bacterial infections in young children with fever: a retrospective cohort study”
www.ncbi.nlm.nih.gov/pubmed/23407730