Wednesday, September 17, 2014

Are a Third of Research Conclusions Wrong?

As I covered last year, half of what you’ve been taught in medicine is wrong – we just don’t know which half.

And, it turns out, sometimes even the same authors taking a second look at the same data as before, can come up with new – and wildly different – conclusions.

This is a review of 37 randomized-controlled trials published after 1966 paired with 37 “re-analyses” of the same data.  These trials span the entire medical domain, from mycophenolate therapy after cardiac transplantation to homeopathy for fibrosis.  Of these 37 re-analyses, 32 of them involved authors from the original research group.  These re-analyses differed by changing statistical techniques, outcome definitions, or other study interpretation methods.

Following re-analysis, 13 (35%) changed the original conclusions – either suggesting more, fewer, or even entirely different patients should be treated.  The implication regarding the reliability of our evidentiary basis for medical practice is obviously profound – if even just the original authors and data can result in conflicting conclusions.

In his editorial, Harlan Krumholz argues the solution is clear: open the data.  Independent verification of findings – whether by erasing bias or undesired mathematical pathology – is critical to ensuring the most complete understanding of the evidence base.  If our highest duty is to our patients, we must break down the barriers created by self-interest and institutional policies in order to promote data sharing – and serve patients by improving the clarity and transparency of medical practice.

“Reanalyses of Randomized Clinical Trial Data”

Monday, September 15, 2014

Emergency PCI for STEMI is Dead?

This somewhat befuddling study tries desperately to create a problem where there probably truly wasn’t – but as soon as the conflict-of-interest disclosures come up, it’s clear why.

This is the 1-year outcomes from STREAM, a prospective, open-label, parallel-group trial enrolling participants with acute STEMI, but unlikely to undergo primary PCI within 1 hour of diagnosis.  Participants were then randomized to either still undergo emergency PCI, or to fibrinolysis followed by urgent or emergency rescue PCI.  The initial 1-month composite outcome, despite an excess of deaths secondary to intracranial hemorrhage in the fibrinolysis group, did not demonstrate any disadvantage to fibrinolysis with delayed PCI.  There was actually a 2% absolute decrease in the composite outcome favoring fibrinolysis – and thus the 1-year follow-up, hoping this small advantage in morbidity would translate into a measurable mortality advantage.

This was, however, not the case – as cardiac mortality was 4.0% with fibrinolysis vs. 4.1% with PCI.  Adding in the ICH and other non-cardiac deaths, the all-cause mortality rose to 6.7% with fibrinolysis vs. 5.9% with PCI.  Baseline characteristics probably favored the fibrinolysis group, so there’s actually a reasonable chance the mortality disadvantage owed to the fibrinolysis strategy might indeed be durable if properly powered and balanced.

Ostensibly, the authors claim to be addressing a problem of resource scarcity.  Using their fibrinolysis strategy, they seem to suggest, allows elimination of the expensive healthcare delivery models predicated on timely PCI.  However, a full 36% of patients failed to re-establish flow and still required emergency rescue angiography.  Then, all remaining patients still underwent urgent angiography, with greater than 95% receiving a stent.  So, in essence, the trade-off for increased flexibility in the timing of angiography is the added expenditure of tenecteplase – and possibly an increase in long-term mortality.

Certainly, there are many remote or resource austere settings where revascularization by thrombolysis is appropriate.  However, Boehringer Ingelheim and their sponsored collaborators have produced this scientific work simply in a transparent attempt at promoting an expansion of the pharamacoinvasive group (read: sell more tenecteplase) – and, frankly, failing.

"STEMI Patients Randomized to a Pharmaco-Invasive Strategy or Primary PCI: The STREAM 1-Year Mortality Follow-Up"

Friday, September 12, 2014

Why Should Patients Be Denied Access to Results?

Interestingly, even though patients have long had full access to their medical record – laborious as it might be to obtain – just recently the Department of Health and Human Services issued a ruling stating patients could directly obtain their laboratory results from medical laboratories.

The real question – why did this take so long?  Are lab results, excepting a few exceptional cases, truly dangerous?  And, are patients not essentially the true owner of their medical testing?  Certainly, where the patient has directly purchased diagnostics, there should be no obstacle in providing them with information.  One can make a technical case that, when the results are purchased by a third-party – government or health insurance provider – those entities are the true owner of the result, but that hardly holds up to ethical scrutiny.

Regardless, this step is just one part of what is increasingly a growing movement towards transparency in medicine.  I think this is a good thing – patients ought be involved at each step of testing and interpretation, and, ideally should be provided with their results in real time.  It is outdated paternalism in medicine patients cannot be trusted with their own test results; is it reasonable to expect patients are a “threat” to themselves by using alternative information sources to self-educate?  If this is truly so, the answer is not to hide the results – but rather to improve how we as professionals educate patients, and improve the lines of communication.

“Direct-to-Patient Laboratory Test Reporting” (free fulltext)

Wednesday, September 10, 2014

Appropriate Resource Utilization Can Be Taught!

At least, that is the implication of this paper – and even though it’s probably not the most reliable demonstration of such an effect, its observations are likely valid.

This is a very convoluted study design aiming to comment upon whether residents trained in “conservative” practice environments differed from residents trained in “aggressive” practice environments.  However, “conservative” and “aggressive” were defined by utilizing a Medicare database to calculate the “End-of-Life Visit Index”.  Residents trained in a region where elderly patients received greater frequency of inpatient and outpatient care at the end-of-life were judged to have trained in an “aggressive” environment.

Then, to measure whether residents themselves had tendencies towards “conservative” or “aggressive” management, the authors reviewed American Board of Internal Medicine board certification examination questions.  Questions regarding management strategy were divided into "conservative" or "aggressive" strategies, based on the correct answers.  Finally, examinees were measured on how many correct and incorrect answers were provided on these questions featuring the two management strategies.  Correlating these test answers with the end-of-life environment presumes to measure an association between training and practice.

After all these calisthenics – yes, residents training in the lower-intensity environments were more likely to perform better on the “conservative” management questions.  Thus, the authors make the expected extrapolation: trainees apparently learn to mimic inappropriately aggressive care.

This is probably true.  Whether this study – with its limitations and surrogates – adequately supports such conclusions is another matter entirely.

“The Association Between Residency Training and Internists’ Ability to Practice Conservatively”

Monday, September 8, 2014

Patient Satisfaction: It’s Door-to-Room Times (Duh)

As customer satisfaction becomes rapidly enshrined as our reimbursement overlord, we are all eager to improve our satisfaction scores.  And, by scores, I mean: Press Ganey.

So, as with all studies attempting to describe patient satisfaction, we unfortunately depend on the validity of the proprietary Press Ganey measurement instrument.  This limitation acknowledged, these authors at Oregon Health and Science University have conducted a single-center study, retrospectively linking survey results with patient characteristics, and statistically evaluating associations using a linear mixed-effects model.  They report three survey elements:  overall experience, wait time before provider, and likelihood to recommend.

Which patients were most pleased with their experience?  Old, white people who didn’t have to wait very long.  Every additional decade in age increased satisfaction, every hour wait decreased satisfaction, and there was a smattering of other mixed effects based on payor source, ethnicity, and perceived length of stay.  What’s interesting about these results – despite the threats to validity and limitations inherent to a retrospective study – is how much the satisfaction outcomes depend upon non-modifiable factors.  You can actually purchase patient experience consulting from Press Ganey, and they’ll come teach you and your nurses a handful of repackaged common-sense tricks – but I’m happy to save your department the money:  door-to-room times.

Or change your client mix.


“Associations Between Patient and Emergency Department Operational Characteristics and Patient Satisfaction Scores in an Adult Population”

Friday, September 5, 2014

Still Adrift in Ignorance Over Blood Cultures

While supervising residents, one of the frequent diagnostic suggestions in undifferentiated febrile patients is: blood cultures.  As an Emergency Physician, the utility of blood cultures – short of diagnosing endocarditis or another primary hematogenous source – is vanishingly small.  After all, the source of infection is nearly universally somewhere else – lung, urine, CSF, skin & soft tissue – and relying on the blood to give you the answer two days later is an unreliable and impractical proposition.

This study is yet another attempt at identifying patients with high likelihood of bacteremia, retrospectively analyzing 5,499 patients at Odense University Hospital for whom blood cultures were drawn.  This cohort, representing roughly half of all patients presenting to the Emergency Department, had positive blood culture results 7.6% of the time.  CRP, temperature, and SIRS criteria were evaluated as potential predictive variables – and, unfortunately, the positive likelihood ratios of each were only between 2 and 3, and the negative likelihood ratios associated with each were all 0.4.  The authors combine these criteria and promote their absence as a rule-out, with a negative predictive value of 99.5% – but, common sense ought obviate trying to diagnose bacteremia in an afebrile patient with no SIRS criteria, and the NPV performance is more related to the low prevalence of disease than the utility of their criteria.

Really, the most interesting element of this study: the massive volume of blood cultures performed, with 92% of them true negative or false positive.  Costs for blood cultures vary by facility, and range from $15-$50, with patient charges typically a significant multiplier beyond.  A low yield might be important if the diagnoses were changing management and improving outcomes, but the vast majority of culture results are clinically unimportant.  These authors have not described particularly strong positive predictors – but they’ve illustrated the massive scope of the problem.

“How do bacteraemic patients present to the emergency department and what is the diagnostic validity of the clinical parameters; temperature, C-reactive protein and systemic inflammatory response syndrome?”

Wednesday, September 3, 2014

Early P2Y12 Antagonists Just Don't Seem Useful

When undergoing an early invasive strategy for myocardial infarction, the guidelines and trials typically support dual platelet inhibition.  Most commonly, this regimen consists of aspirin and clopidogrel.  However, the P2Y12 receptor antagonists ticagrelor and prasugrel have been promoted as options due to incremental increased platelet inhibition over clopidogrel.  The theoretical benefits of early dual platelet inhibition include spontaneous lysis and prevention of re-thrombosis, as well as decreased early in-stent thrombosis.  Unfortunately, the ACCOAST trial demonstrated early prasugrel was associated only with increased bleeding and no associated cardiovascular endpoint benefits.

Now we have ATLANTIC, with a similar treatment strategy, utilizing ticagrelor.

Which is also negative.

Negative for the “co-primary” endpoints of ST-segment resolution or pre-PCI TIMI flow grade, at least.  The authors, however, focus on two other endpoints: bleeding, and in-stent thrombosis.  These authors note, contrary to ACCOAST, there was no detectable difference in bleeding between the pre-hospital and in-hospital groups.  They also note, as expected but not witnessed in ACCOAST, there was a reduction in short-term “definite” in-stent thrombosis.  Therefore, the authors – by which I mean AstraZeneca and their ghostwriters – clearly present this secondary outcome (Figure 2) and conclude pre-hospital ticagrelor is safe.

Interestingly, the there was a 1% absolute difference favoring pre-hospital ticagrelor in “definite” in-stent thrombosis at 30 days – but a 0.2% absolute difference favoring in-hospital ticagrelor in “definite or probable” in-stent thrombosis.  For their definition, “probable” in-stent thrombosis included any death at 30 days for a patient receiving a stent.  I’m not sure the expanded definition accurately reflects underlying stent thrombosis, but it is a fair combined endpoint to report for completeness.

There are a few differences between this trial and ACCOAST, however.  In ACCOAST, patients were diagnosed with NSTEMI based on elevated troponin levels, and all were scheduled for coronary angiography 2 to 48 hours later.  In ATLANTIC, patients were diagnosed prehospital with STEMI – and required to undergo PCI within 120 minutes.  This reduced time of exposure to multiple anticoagulants may explain discrepancy in bleeding events between the trials.  The in-stent thrombosis rate was also much higher in the peri-PCI antiplatelet group in ATLANTIC compared with ACCOAST, leading to the possibility of detecting a difference in in-stent thrombosis.

Details aside, however – it’s simply not clear there’s any advantage to utilizing these agents outside the peri-PCI environment.  Regardless, I expect we will see more resources devoted to similar trials in slightly different populations, attempting to ferret out some subgroup and primary outcome definition capable of demonstrating a statistically significant benefit.

“Prehospital Ticagrelor in ST-Segment Elevation Myocardial Infarction”

Monday, September 1, 2014

The Most Dangerous Holiday!

Here in the United States, it is Labor Day – a Federal holiday established in 1886 by U.S. President Grover Cleveland.  We, apparently, have Canada to thank for this innovation.

But, what was actually news to me – Labor Day is actually the highest-volume holiday for pediatric trauma, outpacing all other holidays.  I’d have thought 4th of July – with it’s various explosive devices – would be the most popular pediatric trauma holiday, but, between 1997 and 2006, Labor Day takes the lead, followed by Memorial Day, and 4th of July as a close third.  Halloween, Easter, Thanksgiving, New Year’s and Christmas round out the list, in that order.

Most common documented products associated with injuries on Labor Day included:  Football, bicycles, stairs/ramps, playgrounds, and beds.  Contrast with Christmas:  Stairs, beds, skiing, tables, knives, and sofas.  And the article provides lists of appropriately seasonal injury mechanisms for each other holiday.

So – beware Labor Day!  The most dangerous holiday of the year!

“Epidemiology of Pediatric Holiday-Related Injuries Presenting to US Emergency Departments”

Friday, August 29, 2014

United Kingdom Revisiting Safety of tPA

This odd and tragic saga continues: nearly 20 years after the original NINDS publication, we’re still going around and around with re-reviews of the same evidence.  The recent news of this past week is the Medicines and Healthcare products Regulatory Agency in the United Kingdom will set up an expert panel to reevaluate the evidence in support of tPA for stroke.  In light of a recent positive Cochrane Review, a positive individual patient meta-analysis, and a paucity of substantial new data – I cannot imagine what new insight will be uncovered.

This seems to have been brought about by correspondence, written by a British stroke neurologist, in The Lancet, describing the same series of arguments skeptics have been making for the last decade and a half.  There are concerns over inadequate blinding of investigators, noting the alteplase infusion may be visually different from placebo, or that patients treated with alteplase possibly had observable minor bleeds from venipuncture sites.  The manufacturer-sponsored nature of ECASS, ECASS II, and ECASS III is again cited, along with baseline imbalance regarding prior strokes favoring the treatment group in ECASS III.  ATLANTIS is also mentioned as a negative trial, stopped early by interim futility analysis.  He further mentions the lack of difference between <3h and 3-4.5h windows in observational registries, suggesting the underlying time-dependent hypothesis behind treatment with alteplase is flawed.  And, most interestingly, he provides a funnel plot of outcomes by treatment center from NINDS, suggesting certain centers suspiciously had disproportionately positive findings.

Again, these are many of the same arguments made by other  experts in their critiques of the evidence behind thrombolysis for stroke.  As such, the responses – headlined by Peter Sandercock and Joanna Wardlaw – provide some of the same rebuttals as previously seen.  Essentially, what it boils down to – again – is you either trust the data, or you don’t.  And, given the suppressed evidence associated with Boehringer Ingelheim’s dabigatran product, not trusting the data remains a reasonable standpoint.

Whether the the MHRA enquiry will change any regulatory statutes is another issue entirely, and Ian Hudson states there will be a fair re-appraisal.  However, Prof. Simon Brown points us to this interesting blog entry covering Mr. Hudson’s prior time at GlaxoSmithKline.  This journalistic endeavor covers his potential role in overlooked safety concerns regarding paroxetine, as well as other conflicts of interest, and implies the enquiry is unlikely to be truly balanced.

Not to sound like a broken record, but only one thing will settle this debate, once and for all – a large, multi-center, randomized trial conducted independently from the manufacturers of alteplase and otherwise biased institutions.  And, since the chance of that happening is basically nil – I imagine another decade from now, we’ll still be picking apart stroke research and debating the quality of the evidence.

“Questions about authorisation of alteplase for ischaemic stroke”

Wednesday, August 27, 2014

Emergency Department or Return-to-Daycare Department?

Have you ever seen a child brought to the Emergency Department for pinkeye?  Not only that, but specifically to fulfill the requirement they receive a prescription for antibiotic ointment in order to return to daycare?  You would not be alone, my friends.

In this convenience sample of 303 surveyed parents, 26% reported taking their child to an Urgent Care, and 25% reported taking their child to an Emergency Department, rather than primary care, for minor ailments – including pinkeye.

These parents were also asked several questions regarding how they dealt with illness in children outside the home, where they would take the child for care, and what sort of requirements were placed upon them by daycare.  Most parents would send their children to daycare with a minor upper respiratory infection, but, fever, ringworm, and gastroenteritis were not accepted.  Most parents would either keep the child at home or seek primary care, but at least 10% of those surveyed would utilize some urgent or emergent services.  Significant predictors of utilizing emergency services for minor pediatric ailments were requirements for a “return to daycare” note or a parent “work excuse”, African American ethnicity, single/divorced parents, and those with tenuous job situations.

As such, the authors recommend improved guideline adoption by child care facilities to allow improved management of infectious disease – and reduced resource utilization from harried parents.

“Emergency Department and Urgent Care for Children Excluded From Child Care”