“The potential benefits associated with this approach are faster reperfusion, lower risk of hemorrhage, and earlier initiation of fibrinolytic therapy, possibly by first responders.”
Sounds lovely, yes? This is the pie-in-the-sky version of tPA, complete with flying cars and hoverbuses. It’s a “Clinical Implications of Basic Research” article from NEJM covering a Science article about shear-activated nanoparticles.
Essentially, in a mouse model of acute arterial thrombosis and pulmonary embolism, researchers bound tPA to aggregated nanoparticles. In normal vasculature, these aggregates remain unaffected. However, in regions of turbulence and shear associated with stenosis, the aggregates break apart, exposing the biochemically active tPA in greater quantities. The authors, taking cue from the current political season, promise potential 100-fold reductions in dosing of tPA associated with this serendipitously targeted approach rather than standard systemic therapy.
So, someday, instead of taking an aspirin and calling 911 – home thrombolytics?
“The Shear Stress of Busting Blood Clots”
www.ncbi.nlm.nih.gov/pubmed/23034026
Category: Medication Safety
“Say Anything”, Regardless of the Data
As we’ve learned from prior publications, the conclusions section of the abstract is the ideal location to “spin” your article to generate news releases. This article, from JAMA Neurology, compares thrombolysis to endovascular intervention for acute carotid artery occlusions and states “Intravenous thrombolysis should be administered as first-line treatment in patients with early cervical ICA occlusion.”
That’s a pretty strong statement, without qualifiers. And, it means it received press coverage from MedPage Today, the ACEP News network, etc.
And, they base that statement on retrospective review of a cohort of 21 patients, 13 of whom received thrombolysis and 8 of whom received endovascular intervention. The tPA patients did better, done and done, OR for early neurologic recovery 77 (95% CI 3 to 500). But, then, Table 2 is a mini-systematic review of prior studies – and it turns out the rate of neurologic recovery is more like 40-50% with endovascular treatment, not the 1 in 8 they found in their retrospective cohort. Indeed, the authors go on to state in the article “These findings are in contrast to the results of previous studies”, and have an entirely reasonable, non-conclusive discussion of their findings in context of the other daa.
But, if you want news coverage, say something “interesting” in your abstract.
“Stroke From Acute Cervical Internal Carotid Artery Occlusion”
http://www.ncbi.nlm.nih.gov/pubmed/23007611
Acetaminophen and Asthma
If this article strikes your fancy – then you’ll never look at acetaminophen the same way again.
Published in Pediatrics, this is a bit of a commentary summarizing epidemiological data in both children and adults related to the association between acetaminophen (paracetamol) use and asthma. Specifically, that there is one, based on the studies he reviews, including:
• A prospective childhood asthma study of 520,000 subjects suggesting a dose-response effect between acetaminophen and asthma in children, up to an increased OR for wheezing of 3.25 for children taking acetaminophen at least once a month.
• A meta-analysis of six pediatric studies with a pooled increased OR for wheezing of 1.95 related to acetaminophen use.
• A meta-analysis of six adult studies with up to an increased OR for asthma of 2.87 for adults taking acetaminophen weekly.
…and several others. The author does not suggest any specific mechanism through which acetaminophen increases airway reactivity, but he has changed his practice to reduce acetaminophen usage to the minimum. I can’t say I disagree with his hypothesis, and there does appear to be a preponderance of mounting evidence, although I wouldn’t say this is an area where I am intimately familiar with the literature.
“The Association of Acetaminophen and Asthma Prevalence and Severity”
www.ncbi.nlm.nih.gov/pubmed/22065272
Don’t Believe The Data
This NEJM study published a couple days ago addresses the effect of funding and methodological rigor on physicians’ confidence in the results. It’s a prospective, mailed and online survey of board-certified Internal Medicine physicians, in which three studies of low, medium, and high rigor were presented with three different funding sources: none, NIH award, or industry funding.
Thankfully, physicians were less confident and less likely to prescribe the study drug for studies that were of low methodological quality and were funded by industry. Or, so I think. The study authors – and the accompanying editorial – take issue with the harshness with which physicians judge industry funded trials. They feel that, if a study is of high methodological quality, the funding source should not be relevant, and we should “Believe the Data“. Considering how easy it is to exert favorable effects on study outcomes otherwise invisible to ClincalTrials.gov and the “data”, I don’t think it is safe or responsible to be less skeptical of industry-funded trials.
Entertainingly, their study probably doesn’t even meet their definition of high rigor, considering the 50% response rate and small sample size….
“A Randomized Study of How Physicians Interpret Research Funding Disclosures”
www.ncbi.nlm.nih.gov/pubmed/22992075
Not-So Routine Surgery on Dabigatran
This correspondence, published in Blood in March, was probably pretty easy to overlook.
A patient enrolled in RE-LY, the trial comparing dabigatran and warfarin for non-valvular atrial fibrillation, underwent open aortic valve replacement surgery. As instructed, he discontinued his dabigatran two days prior to the surgery.
Had a little bit of a bleeding problem.
After 26 units of RBCs, 5 packs of platelets, 22 units of FFP, 5 x 10 units of cryoprecipitate, two doses of protamine, two doses of tranexamic acid, and five doses of Factor VIIa, the patient was finally stable enough to be evacuated to the ICU for dialysis to remove the remaining dabigatran.
What’s most fabulously ironic about this correspondence is that the authors use this horrifying case to sprightly conclude Factor VIIa and hemodialysis are viable and effective reversal strategies for dabigatran-associated bleeding.
The patient – “The postoperative course was complicated by prolonged ventilation/Enterobacter pneumonia, asymptomatic nonocclusive femoral DVT (by surveillance ultrasonography [postoperative day (POD 7)]), and acute-on-chronic renal failure. Discharge to a rehabilitation facility occurred on POD56.” – probably disagrees.
Would you be surprised if I mentioned there’s a COI issue involving the authors and the manufacturer?
“Recombinant factor VIIa (rFVIIa) and hemodialysis to manage massive dabigatran-associated postcardiac surgery bleeding”
www.ncbi.nlm.nih.gov/pubmed/22383791
Dabigatran – It’s Everywhere!
Dabigatran, you may know it at Pradaxa, the first in a string of potential blockbuster oral anticoagulants, has a few problems. Lack of effective reversal options, poor prescriber understanding of drug-drug and GFR interactions, and reduced dosing options should make physicians wary of this medication.
Well, it’s not.
This is a dataset gleaned by an ongoing physician audit covering ~4800 U.S. practioners between 2007 and 2011, used to estimate prescription trends for the U.S. Warfarin prescriptions were reasonably stable between 2007 and 2010, but then have dropped approximately 20% over the course of 2011. The medication taking up the slack? Dabigatran.
If you accept the findings from RE-LY, then you’re probably OK with its use in non-valvular atrial fibrillation. Unfortunately, 37% of the prescriptions were off-label, outside the FDA approved indications. Then, within the remaining 63%, there’s no breakdown for whether it was valvular or non-valvular atrial fibrillation. So, the percentage of off-label use is probably even higher than found in the data.
It would seem to be prudent to be cautious with a new medication that’s already being investigated by the FDA for serious bleeding complications. Luckily for the manufacturer, that’s not happening, and prescription expenditures for dabigatran already exceed those for warfarin – over $160 million per quarter.
“National Trends in Oral Anticoagulant Use in the United States, 2007 to 2011”
http://www.ncbi.nlm.nih.gov/pubmed/22949490
“Propoven”
Medication shortages are affecting many hospitals – we’re low/out of prochlorperazine, injectable metaclopromide, etomidate, propofol, brevital – and one of the replacements we’ve recently been introduced to is “Propoven”, a European manufacture of propofol.
It has only minor differences from propofol, but it should be noted it requires strict sterile technique when handling and has more medium-chain fatty acids. An informational letter from Kabi describing a few of the differences is here:
Ketamine – Cure For Everything
There aren’t many medications I love using more than ketamine. I use it for adjunctive pain control, to control agitation, and for induction prior to intubation. Now, chances are, it’s probably useful in seizures.
This is a case report and review of the literature for the use of ketamine in the control of refractory status epilepticus. The literature is profoundly weak – the “review” is essentially a review of case reports. And, the patient outcomes describe in the case reports are replete with “All died” or “Survived but severely disabled.” However, this is primarily due to the serious cause of the underlying disorders – encephalitis, neurosyphilis, meningitis, anoxic brain injury – and less likely the ketamine, although this does not provide the evidence to that effect. The proposed mechanism is via NMDA receptor antagonism, which the author proposes works better by synergy with GABA antagonism, rather than either as monotherapy.
Seems like a fair physiologic mechanism, and it’s nice to have something additional to consider in refractory disease. Ketamine also was noted in this case report to counteract the hypotensive effects of midazolam and propofol, consistent with prior literature describing its beneficial effect on cerebral perfusion pressure. It’s pretty much a “I tried this and I like it” article, but I think it’s probably likable and not the last we’ve heard about ketamine for status.
“Early Ketamine to Treat Refractory Status Epilepticus”
Tramadol: A Myth of Safety
For me, tramadol lands squarely in the gap between oral analgesics I might use for “no pain” – ibuprofen, acetaminophen – and analgesics I might use for “real pain” – hydrocodone derivatives. The literature describing the analgesic properties of tramadol is bizarre, with multiple comparisons with placebo, nerve blocks, adjunctive epidural anesthesia, etc., and very few head-to-head comparisons to the sorts of medications we routinely use. When there are comparative efficacy reports, they typically conclude that tramadol is effective…just as effective as the NSAIDs its being compared with.
The theory I’ve heard people use when considering use of tramadol is that it has a better safety profile than hydrocodone and is less dependence-forming. These claims may be true, but I do not believe they are true to the extent that it is clinically relevant. Tramadol still generates an opioid withdrawal syndrome and, as this article describes, overdose/abuse still results in apnea with need for ventilatory support.
Additionally, tramadol is a GABA antagonist, lowering seizure threshold. Of the 525 patients overdosing primarily on tramadol retrospectively identified at this Iranian hospital, 19 experienced apnea and 242 (46.1%) experienced seizures. This is retrospective and co-ingestants cannot be fully ruled out, but the propensity for seizure is far more surprising than the incidence of apnea.
Tramadol has a role in pain control prescribing, but, in my practice, that role is tiny.
“Tramadol-induced apnea”
http://www.ncbi.nlm.nih.gov/pubmed/22809771
Predicting sICH in Thrombolysis
In contrast to the lunacy of IST-3, this is another piece of work that at least in the right direction – helping us avoid harming patients with thrombolysis.
These authors use the Get With The Guidelines registry as their derivation and validation group to develop a prediction rule for sICH in the setting of thrombolytic use for acute ischemic stroke with in 3 hours of symptom onset. Subsequently, they “externally validate” their rule by applying it retrospectively to the NINDS data set. At the end of it, they come up with a not-so-handy point scale with six clinical features and twenty discrete elements, but basically, these things are bad:
– Older patients
– More severe strokes
– Higher systolic blood pressure
– Elevated blood glucose
– Asian ethnicity
– Male gender
The C-statistic was .71 on their derivation cohort, .70 on their validation cohort, and .68 on the NINDS cohort – which is more or less just OK. In practical, clinical terms, their tool more or less discriminates between folks who are at 1-3% risk of ICH, and then 6-10% risk of ICH. And, I think it’s extremely valuable when discussing risks with our patients to not use blanket generalities, and attempt to tailor the discussion to the individual.
“Risk Score for Intracranial Hemorrhage in Patients With Acute Ischemic Stroke Treated