Ceftriaxone: It’s Not For Stroke

Negative trials are just as important – if not moreso – than positive trials.  Without negative trials, well-meaning clinicians continue with unproven and unverified treatments, incurring unnecessary costs and exposing patients to unneeded potential adverse effects.

This prospective trial of 2,550 patients randomized patients post-stroke to four days of prophylactic ceftriaxone versus no treatment, using an open-label, masked endpoint design.  The theory – some of the mortality and disability post-stroke may be in excess as result of infectious (primarily respiratory) complications.  The fact – no.  There was no difference in functional outcome at any modified Rankin Score ordinal cut-off, nor mortality.  There were actually not fewer cases of pneumonia in the ceftriaxone group, but urinary tract infections were significantly suppressed.  Clostridium difficile infection occurred only in two cases, both in the ceftriaxone group.

As a random aside, the median NIHSS in this trial was 5 – and 37% of patients achieved mRS 0-1.  This is rather surprisingly low, considering the SITS-MOST cohort and pooled placebo groups from RCTs with median NIHSS’ ~12 had achieved mRS 0-1 in 38% and 33% of the time, respectively.  A window into the lack of generalizability of the thrombolysis RCTs?  Perhaps – or just a curiosity.

Oh, but, back to the point – it does not appear to have clinical utility to routine use ceftriaxone as antibiotic prophylaxis after acute ischemic stroke.

“The Preventive Antibiotics in Stroke Study (PASS): a pragmatic randomised open-label masked endpoint clinical trial”
http://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(14)62456-9.pdf

Should Men and Women Use Different Troponin Cut-Offs?

Much ado is made regarding potential differences in symptoms between men and women presenting with acute coronary symptoms.  Little is mentioned, however, about potential differences in laboratory thresholds between the sexes.  Considering women, on average, have decreased myocardial mass than men, any ischemic insult simply damages a smaller absolute quantity of myocardium.  Less damaged tissue, then, ought to lead to lower circulating biomarkers.

Why haven’t we tried this before?  Because the limit of detection of conventional troponin assays are above the clinically important thresholds for delineating such small quantities of circulating molecules.  However, with the advent of highly-sensitive troponins with reasonable precision below  the conventional troponin cut-off of 50 ng/L, it’s now a reasonable concept for investigation.

These authors conducted a yearlong prospective evaluation of all patients with suspected acute coronary syndrome, collecting conventional and highly-sensitive troponins on each.  Treating clinicians and initial adjudication of myocardial infarction were blinded to the results of the hsTnI.  Following conclusion of the study, records and unmasked hsTnI values were provided for independent adjudication and diagnosis changes accordingly.

Initially, 19% of men were diagnosed with Type 1 MI based on conventional troponin testing.  After using a gender-specific cut-off for men of 34 ng/L, only a handful of additional cases were re-classified – rising to 21%.  For women, 11% were initially diagnosed with Type 1 MI.  Using a gender-specific cut-off for hsTnI of 16 ng/L, however, doubled the diagnosis cohort to 22%.

Of course, simply lowering the threshold for any assay increases the rate of diagnosis.  In order to answer the question of whether the re-classified cases were clinically appropriate, all patients were also followed for survival free from death or MI.  While women not diagnosed with MI at initial presentation did well throughout the follow-up period, the women reclassified as MI using the hsTnI threshold suffered the same dismal outcomes as those initially diagnosed with MI.

I like this concept, and this is promising preliminary data.  It remains to be seen whether treatment, including increased treatment intensity for women, based on the gender-specific cut-offs changes clinical outcomes – or whether splitting these little nanograms worth of hairs is just overdiagnosis.  The good news: a clinical trial is ongoing.  I look forward to their results.

“High sensitivity cardiac troponin and the under-diagnosis of myocardial infarction in women: prospective cohort study”
http://www.bmj.com/content/350/bmj.g7873 (free fulltext)


Unreliable Information About Drug Use? In the ED? Never!

This simple observational series illuminates the likely truths behind our anecdotal experience – patients are either clueless or deliberately misleading regarding their ingestion of foreign substances.

For the purposes of this investigation, “drug use” is not restricted to illicit substances – these authors also explored the reliability of reporting of prescription medications.  In this prospective, year-long enrollment, 55 patients were selected randomly from a larger cohort to have a urine sample submitted for liquid chromatography/mass spectrometry.  The LC/MS assay utilized was capable of detecting 142 prescriptions, over-the-counter drugs, and drugs of abuse and their metabolites.  A drug whose level of detection was lower than 2 half-lives was reported as discordant with patient self-reporting.

All told, 17 out of 55 patients provided accurate medication histories, based on those detected on LC/MS.  Over half the patients under-reported – including a patient with 7 unreported drugs detected – while 29% over-reported a drug not subsequently detected.  Interestingly, illicit drugs were the least likely to be mis-reported, although, that may simply be a reflection of the higher prevalence of prescription and OTC medications.

Such observations are limited by the accuracy of the assay utilized, which has not been validated.  However, it ought come as no surprise many patients either intentionally or unintentionally misrepresent all possible drug exposures.  While not all omissions are clinically relevant, certainly, non-compliance and misinformation may have important implications for diagnosis and treatment.

“The Accuracy of Self-Reported Drug Ingestion Histories in Emergency Department Patients”
http://www.ncbi.nlm.nih.gov/pubmed/25052325

Prednisone … for Pneumonia?

The utility of antibiotics for eradication of bacterial pathogens from the lower respiratory tract is a given.  Use of steroids – also known for their immunosuppressive properties – not so much.

But, one can imagine clinical utility for steroids in acute infection.  Not every function of the immune system results in desirable patient-oriented effects.  Immunologic host responses include release of many inflammatory cytokines responsible for organ dysfunction, and steroids are already part of accepted therapy for several specific manifestations of pneumonia.  Based on prior results in smaller trials, these authors suspected use of steroids might be of benefit – both in mortality and in time to symptom resolution.

With 785 patients allocated in blinded fashion to 50 mg of prednisone daily or placebo, patients receiving prednisone reached “clinical stability” in a median of 3 days, compared to 4.4 days for the placebo cohort.  Hospital length-of-stay was reduced to 6 days from 7, and intravenous antibiotic use was cut by a day.  There were few important adverse effects overall, and the only consistent harm apparent in these data was increased hyperglycemia associated with corticosteroid use.

The accompanying editorial in The Lancet states adjunctive therapy with steroids is a therapy whose time has come, based on healthcare savings due to resource utilization.  In the context of other published studies, this observed reduction in time to vital sign normalization is valid.  However, whether the effect of steroids is truly beneficial or akin to simply masking the underlying clinical state by suppression of pro-inflammatory cytokine release is less certain.  Use of anti-pyretics blunts outward signs of systemic inflammatory response syndrome, and beta-blockers likewise reduce the tachycardia resulting from physiologic stress without specifically treating the underlying process.  It is hard to associate the outcomes measured in this trial with actual expedited clinical cure.

Reductions in length-of-stay and IV antibiotic use are reasonable patient-oriented and system-oriented outcomes, however, so the decision ultimately rests with the magnitude of harms – and the harms are certainly real.  Previous studies have suggested increased early recurrence or persistence of pneumonia, in addition to uncontrolled hyperglycemia.  These authors hoped to measure a 25% reduction in mortality – which was a bit of an odd expectation, given the ~2-4% expected absolute mortality – and no such suggestion of benefit was observed.

Simply put, this is not ready for prime-time or guideline-level adoption.  It is certainly worthy of further study, but steroids should not be used routinely outside the scope of prospective monitoring.

“Adjunct prednisone therapy for patients with community- acquired pneumonia: a multicentre, double-blind, randomised, placebo-controlled trial”
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(14)62447-8/abstract

NIHSS Scores are Not Created Equal

This is hardly news to anyone with a clinical practice, but it’s a topic rarely addressed in stroke trials – that patients with identical NIHSS can have a wide range of downstream disability.

This is a retrospective analysis of the VISTA registry, which collates non-thrombolysis acute stroke trial data, and is generally useful for identifying predictors of long-term prognosis and outcomes.  These authors used six hypothesized “profiles” of stroke syndromes with distinct constellations of disabilities, and matched a total of 10,271 patients from their database to one of the six.  Using their most disabling stroke subtype profile as reference, the authors noted three different syndromes – with median NIHSS 10, 9, and 7 – all had similar likelihood of favorable outcomes.  However, even though the NIHSS and good outcomes were similar, the disabilities and clinical profile associated with one of these cohorts translated to twice as likely to be deceased at 90 days.  In essence – similar "numbers", but very different outcomes.

There’s nothing here usable for direct knowledge translation – but, it does hearken back to my oft-repeated statements regarding the heterogeneity of stroke syndromes, outcomes, and likelihood of benefit or harm from pharmacologic revascularization.  Quite simply, data sources such as this – and those including patients from thrombolysis trials – ought be better utilized to predict patient-specific outcomes.

“National Institutes of Health Stroke Scale Item Profiles as Predictor of Patient Outcome”
http://www.ncbi.nlm.nih.gov/pubmed/25503546

You’re Damn Screwed on Ticagrelor

If you’re unlucky enough to suffer intracranial bleeding, your unluckiness is compounded if you’re concurrently taking any sort of anticoagulation.  Some agents have relatively-effective reversal options – typically prothrombin concentrate complexes or fresh frozen plasma.  Anti-platelet agents, however, tend to irreversibly bind and inactivate platelets – and the only theoretical reversal strategy is transfusion with new, unblemished platelets.

That definitely won’t work for ticagrelor.

This brief letter in the NEJM details the unfortunate case of a man suffering a hemorrhagic transformation following a stroke while on ticagrelor.  As part his treatment, these authors transfused the patient a total of 17 units of platelets.  After said transfusion, the platelet-reactivity index barely rose from 0% to approximately 10% immediately following the transfusion – but then returned to 0% an hour later, and remained unchanged at 0% seven hours later when rechecked.  As you might expect, with 0% platelet activity, the patient expired as a result of his intracranial bleeding.

If you can manage not to waste blood products in such futile action, please do so.  Also, beware!

“Inefficacy of Platelet Transfusion to Reverse Ticagrelor”
http://www.ncbi.nlm.nih.gov/pubmed/25564918