Dabigatran – In Annals of Internal Medicine

My short review article warning the internists of the dangers associated with rushing into overuse of dabigatran was published today in Annals of Internal Medicine.


It was actually originally entitled “Dabigatran – Sinking Into Uncharted Waters,” but the editor changed it after the Italian cruise ship disaster.


Dabigatran — Uncharted Waters and Potential Harms”
http://www.annals.org/content/early/2012/05/23/0003-4819-157-1-201207030-00467

The Third International Stroke Trial: IST-3

The Cochrane systematic review of the 11 complete trials of rt-PA for thrombolysis encompasses 3,977 total patients.  IST-3 enrolled 3,035, nearly doubling our cohort of randomized data.  Unfortunately, this influx of new data does very little to resolve any of the outstanding issues regarding stroke care.

Before even looking at the results, it’s particularly important to wade through the dense study design and methods – and realize this is a non-blinded study in which patients were enrolled if the treating clinician was “uncertain of the benefits or harms of TPA”.  Considering this study began back in 2003, prior to ECASS III, a large chunk of their enrolled patients fell into the 3-4.5 hour time frame, with the remaining majority falling into the up to six hour limit.  The other major area of interest this study was intended to evaluate was the efficacy and safety in patients aged >80 years of age, of which they enrolled 1,616.  And, in a shocking twist, this study actually manages to enroll TPA and control cohorts with nearly identical baseline variables.

IST-3 is negative for the primary endpoint, which is the proportion of patients functionally independent at six months (Oxford Handicap Score 0-2, a scoring system similar to the Modified Rankin Score), with a 95% CI of 0.95 to 1.35.  On ordinal secondary analysis, there are non-significant trends towards improvements in OHS favoring rt-PA, which is probably what you’ll hear when people refer to IST-3 as “positive.”

Then, regarding the patients aged >80, there is a trend towards benefit with TPA, CI 0.97-1.88.  Unfortunately, in a neutral study, that means there is actually a trend towards harm in ages <80, CI 0.67-1.26.  Likewise, between 4.5-6 hours, there is a trend towards benefit with TPA, CI 0.89-1.93.  Therefore, between 3 and 4.5 hours, there is a trend towards harm with TPA, CI 0.50-1.07.  TPA is also essentially neutral or trends towards harm up until NIHSS 14, with more pronounced benefit shown in severe strokes.

Interestingly enough, the “blinded” phase of the study trended towards favoring control, CI 0.42-1.98, while the open phase favored TPA, CI 0.89-1.45.

So, what does this all mean?  It means, there’s still plenty of shades of grey open for interpretation and discussion.  Indeed, when added into the systematic review, IST-3 brings several of the previously significant benefits back into the nonsignificant range.  To me, this reinforces what I’ve been arguing for awhile – that the focus shouldn’t be on massive expansion of TPA eligibility, but specifically targeting those who have the best benefit/harm profile.

As with any major stroke trial, many of the investigators have financial associations with Boehringer Ingelheim.

“The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the third international stroke trial [IST-3]): a randomised controlled trial”
http://www.lancet.com/journals/lancet/article/PIIS0140-6736(12)60738-7/fulltext

Azithromycin – Not Guilty of Murder

The FDA has announced it is reviewing the safety of azithromycin in lieu of a recent NEJM article documenting an association between azithromycin and cardiovascular death.  In theory, azithromycin has been implicated in QT-prolongation and pro-arrhythmic effects, leading to torsades de pointes and polymorphic ventricular tachycardia.  The authors of this study therefore hypothesized an association between azithromycin use and cardiovascular death.

This is a retrospective study of computerized data generated from the Tennessee Medicaid program between 1992 and 2006, linking deaths to any concurrent antibiotic prescriptions.  The authors data-mined for a cohort aged 30 to 74 years of age, had no “life threatening non-cardiovascular illness”, did not abuse drugs, and did not reside in a nursing home.  They compared azithromycin prescriptions to non-prescription controls, as well as amoxicillin, ciprofloxacin, and levofloxacin cohorts.  And, after a little statistical maneuvering, they report a death rate of 85.2 per 1,000,000 courses of antibiotics with azithromycin, which compares to a death rate of 29.8 with no antibiotic and 31.5 with amoxicillin.

So, for every ~20,000 prescriptions of azithromycin written, there is one additional death from cardiovascular causes.  This is another one of those cases where the severity of the absolute difference doesn’t quite match the relative difference – it is likely any efficacy difference between a macrolide and a second-line agent results in greater morbidity than the magnitude of effect found in this study.

Then, azithromycin is frequently prescribed for upper and lower respiratory tract infections – conditions that, in the absence of other specific signs, might be non-infectious cardiovascular disease misdiagnosed as having an infectious etiology.  In their non-propensity matched cohorts, 50% more azithromycin prescriptions were written for respiratory symptoms than amoxicillin.  The propensity matching in their statistical analysis attempts to account for this, but 30% of their azithromycin prescriptions had no documented indication – which I think means there’s likely a hidden statistical difference in underlying pathophysiology secondary to unknown indications.

Finally, this runs contrary to a 2005 article “Azithromycin for the Secondary Prevention of Coronary Events” published in NEJM – at one point, it was theorized that azithromycin would be protective for coronary events.  For 4,000 patients who took azithromycin weekly for a year, there was no difference in cardiovascular outcomes as compared to placebo (CI -13% to +13% relative risk reduction).

There are lots of reasons not to prescribe azithromycin, but this study isn’t the one that should change your practice.

“Azithromycin and the Risk of Cardiovascular Death”
http://www.nejm.org/doi/full/10.1056/NEJMoa1003833

Codeine, Potentially Unpredictably Lethal

Frequently used in the pediatric population, codeine is a narcotic analgesic in prodrug form.  In the body, codeine is metabolized to morphine through the CYP2D6 pathway.  In the general population, it is estimated that approximate 10% of codeine undergoes conversion to morphine.

We’re generally familiar with the concept that a certain percentage of the population is ineffective at metabolizing codeine, and therefore receives no additional analgesic effect.  However, the flip side, as these authors report, is a CYP2D6 genotype of over-metabolizers.  In this case series, the over-metabolism of codeine in three post-surgical children likely resulted in supra-therapeutic conversion to morphine, leading to respiratory arrest.

The short summary – when possible, avoid medications that are unpredictably metabolized – such as codeine.

“More Codeine Fatalities After Tonsillectomy in North American Children”
www.ncbi.nlm.nih.gov/pubmed/22492761

Mobile Stroke Units – Probably Not Helpful

Door to needle times too long?  Well, take the needle to the patient, then.

This is an interesting idea that, unfortunately, probably isn’t a good idea.  They loaded a CT scanner, a stroke physician, a paramedic, and a mobile laboratory into a truck, and sent it out to meet acute stroke patients in the field.  The primary endpoint of the study – alarm to thrombolysis time – was great, with a mean time from alarm to therapy decision of 35 minutes.

The authors are very excited about the concept – as they feel the accelerated time scale in terms of acute stroke thrombolysis represents a paradigm shift in management.  Unfortunately, the patient-oriented outcomes – which were not part of the primary endpoint – don’t support their enthusiasm.

All their safety and therapeutic outcomes are underpowered, but, out of their 47 intervention patients and 53 control (in-hospital thrombolysis) patients, 12 vs. 6 were treated stroke mimics and 3 vs. 0 were dead within 7 days.  Comorbidities and stroke severity should have favored the intervention group, so, these outcomes are surprising.  But, it is underpowered, so more data is needed.

“Diagnosis and treatment of patients with stroke in a mobile stroke unit versus in hospital: a randomised controlled trial.”
http://www.ncbi.nlm.nih.gov/pubmed/22497929

The Dexamethasone Dose for Croup is 0.15mg/kg

Unfortunately, this is still probably not the trial that convinces everyone.  In fact, it’s been over 15 years since the original single-center trials/reports showing that 0.15mg/kg of dexamethasone was every bit as effective as 0.6mg/kg of dexamethasone.  This makes intuitive sense, considering the steroid equivalencies, and the doses used in studies that have established prednisolone as an adequate treatment for croup, as well.

Regardless, this is a very small – 30-odd patients – with mild croup, randomized to dexamethasone at 0.15mg/kg vs. placebo.  The point of this study was not to test the efficacy of dexamethasone, but rather to show that, despite it’s long half-life, it had immediate effects.  And, I think it’s fair to say this study demonstrates those significant effects in reduction in croup score, gaining statistical significance by 30 minutes.

I don’t know where the attachment came from in terms of the 0.6mg/kg dose of dexamethasone, but it’s just preposterously high.

“How fast does oral dexamethasone work in mild to moderately severe croup? A randomized double-blinded clinical trial.”
http://www.ncbi.nlm.nih.gov/pubmed/22313564

Rivaroxaban and Pulmonary Embolism

This is rivaroxaban, an oral Factor Xa inhibitor, part of the wave of potential warfarin replacements.  This is their phase III EINSTEIN-PE trial, which is a non-inferiority comparison against warfarin for the long-term outpatient management of pulmonary embolism.

Overall, it was slightly less effective at prevention of recurrent venous thromboembolism (2.1% vs 1.8%), but slightly safer with regards to bleeding episodes (10.3% vs. 11.4%).  Adherence to therapy was reasonable compared to other trials regarding the amount of time patients spent with therapeutic INR between 2.0 and 3.0.  So, really, it’s pretty much a wash.
But, of course, when you have a new and expensive therapy that’s essentially similar to the old, cheap option, the conclusion is: “Our findings in this study involving patients with pulmonary embolism, along with those of our previous evaluation involving patients with deep-vein thrombosis, support the use of rivaroxaban as a single oral agent for patients with venous thromboembolism.”  
Of course, if you were expecting a different conclusion from an open-label, manufacturer-sponsored study, you are unfortunately mistaken.
So, make sure your hematology group is on board with PCCs, because there doesn’t seem to be any other possible option for reversing life-threatening bleeding – and rivaroxaban is coming, whether it should be or not.
“Oral Rivaroxaban for the Treatment of Symptomatic Pulmonary Embolism”

Is It Reasonable to Keep Using Vasopressin in Shock?

The authors of this meta-analysis seem to think so.
Unfortunately, they identify a very heterogenous set of evidence for analysis, which reduces the statistical power of every comparison.  They identify only a couple studies of vasopressin vs. placebo, and most of their studies are vasopressin vs. an increased dose of norepinephrine.
It’s hard to generate any unreasonable conclusion from this data – the error bars cross one, so you can either take this as permission to drop vasopressin from your usage patterns because its use has no measurable mortality benefit, or you can continue to use vasopressin because it doesn’t seem to be harmful, and allows you to reduce the dose of norepinephrine.
I’d really like to see more vasopressin vs. control – there’s only one reasonably sized vasopressin vs. placebo trial – and it heavily, but non-significantly, favors control with a risk ratio for mortality of 1.94 (0.74 to 5.10).
More to be done!
“Vasopressin for treatment of vasodilatory shock: an ESICM systematic review and meta-analysis”

Ketamine + Propofol = Ketofol

Combining propofol, a beloved agent for procedural sedation for its rapid onset, quick recovery times, and titratable levels of sedation with ketamine, the world’s safest agent for unmonitored anesthesia, has been shown in case series to be as safe and effective as expected.

This small, randomized trial is a direct comparison between ketofol and propofol, with the primary outcome measure being the proportion of patients experiencing an adverse respiratory event using the standardized Quebec Criteria.  The authors are testing the hypothesis that use of ketofol will result in fewer adverse respiratory events, which they believe to be one of the weaknesses of propofol, and one of the strengths of ketamine.

With ~120 patients in each group, there is essentially no clinical or statistical difference between outcomes of the two groups.  Clinicians provided transient assisted ventilation for three ketofol patients and one propofol patient – which is not statistically different.  Secondary outcomes were similar, although a handful of ketofol patients experienced recovery agitation, some of which required treatment.

It seems odd to me that the authors would be testing the respiratory adverse events of ketofol – both ketamine and propofol are so profoundly safe, with already extremely low rates of assisted ventilation, and unplanned intubation rates of ~1 in 5,000 or more.  Ketofol has been similarly already shown to be extremely safe in terms of respiratory events, primarily in retrospective case series.  They’ve essentially set themselves up to test something that’s almost already conclusively expected to generate insignificant differences.  What is more interesting to clinicians now, when considering agents for sedation, is the secondary effects – hypotension, hypersalivation, vomiting, myoclonus, agitation – and how that affects procedural success and time to disposition.  Ketofol is a great combination – but its value seems to be in the mitigation of the non-airway adverse events.

“Ketamine-Propofol Combination (Ketofol) Versus Propofol Alone for Emergency Department Procedural Sedation and Analgesia:  A Randomized Double-Blind Trial”
http://www.ncbi.nlm.nih.gov/pubmed/22401952

Please Stop Using Azithromycin Indiscriminantly

There is a time and a place for a macrolide with a long half-life, and it is not empirically for pharyngitis.

And, it’s even less appropriate empirically for pharyngitis now that it’s been overused to the point where it’s nearly in the drinking water – because it can no longer be considered second-line for group A streptococcus for your penicillin allergic patients.

This is a case report and evidence review from Pediatrics that discusses two cases of rheumatic fever, both of which presented after treatment of GAS pharyngitis with azithromycin.  While rheumatic fever has been almost completely wiped out – there are so few of the RF emm types in circulation, that it’s almost nonexistent in the United States – there are still sporadic cases.  Macrolides are listed as second-line therapy for GAS, but single-institution studies have shown macrolide resistant streptococcus in up to 48% of patients.  Macrolide resistance varies greatly worldwide, from a low of 1.1% in Cyprus to 97.9% in Chinese children.

Why is macrolide resistance so high?  Azithromycin is the culprit; because it has such a long-half life, it spends a long time in the body at just below its mean inhibitory concentration, and preferentially selects for resistant strains.

Please stop using azithromycin.  Use doxycycline, or another alternative, when possible.  There has never been reported resistance to pencillin in GAS.

“Macrolide Treatment Failure in Streptococcal Pharyngitis Resulting in Acute Rheumatic Fever”
http://www.ncbi.nlm.nih.gov/pubmed/22311996