Wednesday, April 23, 2014

Target: Stroke – “Success!”

The use of tPA has evolved rapidly over the last decade.  However, despite its increasing use, proponents have been dismayed to see eligible patients were still receiving tPA within 60 minutes of ED arrival only one-third of the time.  Thus, “Target: Stroke”, a set of key strategies to improve door-to-needle time introduced in 2010.

The initiative, described in this retrospective analysis of the Get With the Guidelines-Stroke registry, is very clearly successful.  Even taking into account the limitations in data quality, there is a clear inflection point in late 2010 or early 2011 at which participating hospitals began generally improving their door-to-needle time.  By mid-2013, over 50% of eligible patients were receiving their tPA within 60 minutes.

If the authors stop there, we have a respectable paper describing a successful quality intervention.

However, they also go one step further and try to link the door-to-needle improvements to outcomes.  They observe decreases in mortality, symptomatic intracranial hemorrhage, and tPA complications, and heavily associate these observations with faster tPA use – without seriously acknowledging any alternative explanation.

But, we know there have been many changes in stroke care over the last decade.  Stroke units, swallow evaluations, temperature management, and many other advances in post-stroke care have reduced mortality and complications.  However, the authors state:
“The in-hospital mortality benefit associated with the post-intervention vs preintervention periods for patients with acute ischemic stroke treated with tPA was of greater magnitude than the improvement observed for those not treated with tPA and for patients with hemorrhagic stroke cared for during the same time frame in these hospitals, suggesting this finding was the result of more than just general improvements in stroke care and outcomes.”
… but, despite claiming this – and having clearly done the analysis – they do not provide us with this data to inspect and compare.

They also dangerously assert:
“Although there have been concerns that attempting to achieve shorter door-to-needle times may lead to rushed assessments, inappropriate patient selection, dosing errors, and greater likelihood of complications, our findings suggest that more rapid reperfusion therapy in acute ischemic stroke is feasible … with actual reductions in complications.”
… when it has been clearly observed in multiple reviews of stroke mimics, the baseline rate of intracranial hemorrhage in patients without stroke is less than 1%.  Therefore, it is entirely consistent with the existing evidence that rushing to therapy – and treating mimics – will ultimately reduce overall intracranial hemorrhage.

Regardless, it’s the expected interpretation from a group of authors with a conflicts-of-interest statement so long it’s almost comedic:
Dr Fonarow reported serving as a member of the Get With The Guidelines (GWTG) steering committee; receiving significant research support from the National Institutes of Health; and being an employee of the University of California, which holds a patent on retriever devices for stroke. Dr Smith reported serving as a member of the GWTG steering subcommittee. Dr Saver reported serving as a member of the GWTG science subcommittee; the University of California, his employer, receives funding in exchange for his services as a scientific consultant for CoAxia, Grifols, Brainsgate, Lundbeck, Ev3, and Stryker regarding trial design and conduct; and the University of California holds a patent on retriever devices for stroke. Dr Reeves reported receiving salary support from the Michigan Stroke Registry and serving as a member of several American Heart Association (AHA) GWTG subcommittees. Dr Bhatt reported serving on advisory boards for Elsevier Practice Update Cardiology, Medscape Cardiology, and Regado Biosciences; serving on the board of directors for Boston VA Research Institute and the Society of Cardiovascular Patient Care; serving as chair of the AHA GWTG steering committee; being a member of data and safety monitoring committees for Duke Clinical Research Institute, Harvard Clinical Research Institute, Mayo Clinic, and the Population Health Research Institute; receiving honoraria from the American College of Cardiology (editor, Clinical Trials, Cardiosource), Belvoir Publications (editor in chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees), Harvard Clinical Research Institute (clinical trial steering committee), HMP Communications (editor in chief, Journal of Invasive Cardiology), Population Health Research Institute (clinical trial steering committee), Slack Publications (chief medical editor, Cardiology Today’s Intervention), WebMD (continuing medical education steering committees); serving as associate editor for Clinical Cardiology, section editor (pharmacology) for the Journal of the American College of Cardiology; receiving research grants from Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic, Roche, sanofi-aventis, The Medicines Company; and performing unfunded research for FlowCo, PLx Pharma, Takeda. Dr Hernandez reported receiving AHA pharmaceutical roundtable grant 0675060N and a research grant from Johnson & Johnson; and receiving honoraria from AstraZeneca and Amgen. Dr Peterson reported receiving research grants from Lilly, Johnson & Johnson, Bristol-Myers Squibb, sanofi-aventis, and Merck-Schering Plough partnership; and serving as principal investigator of the data analytic center for the AHA/American Stroke Association’s (ASA) GWTG. Dr Schwamm reported being the principal investigator of an investigator-initiated study of extended-window intravenous thrombolysis funded by the National Institute of Neurological Disorders and Stroke ( for which Genentech provides alteplase free of charge to Massachusetts General Hospital as well as supplemental per-patient payments to participating sites; serving as chair of the AHA/ASA GWTG stroke clinical work group; serving as a stroke systems consultant to the Massachusetts Department of Public Health; and serving as a scientific consultant regarding trial design and conduct to Lundbeck (international steering committee, DIAS3, 4 trial) and Penumbra (data and safety monitoring committee, Separator 3D trial). Mr Zhao and Dr Xian reported not having any disclosures.
Target: Stroke is an initiative provided by the American Heart Association/ American Stroke Association (AHA/ASA). The GWTG-Stroke program also is provided by the AHA/ASA. The GWTG-Stroke program is currently supported in part by a charitable contribution from Janssen Pharmaceutical Companies of Johnson & Johnson. The GWTG-Stroke program has been funded in the past through support from Boeringher-Ingelheim, Merck, Bristol-Myers Squib/sanofi pharmaceutical partnership and the AHA pharmaceutical roundtable.
“Door-to-Needle Times for Tissue Plasminogen Activator Administration and Clinical Outcomes in Acute Ischemic Stroke Before and After a Quality Improvement Initiative”

Monday, April 21, 2014

Sadly Inadequate Cochrane Review of Renal Colic

With little fanfare (probably because this Tamiflu document was published the same week), the Cochrane Collaboration published a review of the efficacy of alpha-blockers for stone expulsion.  The authors strongly approve of this therapy.  They also grievously downplay the tragic disutility of the data reviewed.

Only 7 of 32 included studies had adequate blinding to treatment for physicians and patients.  Only 6 studies report a blinded mechanism for randomization.  8 studies did not report outcomes matching the methods.  They are, frankly, a catastrophic mix of tiny samples, non-peer-reviewed abstracts, and low-quality study design:
  • Abdel-Meguid 2010 - 150 patients from Saudi Arabia, could not access.
  • Agrawal 2009a - 102 patients from India, multiple interventions, no disclosures statement.
  • Al Ansari 2010 - 100 patients from Qatar, no disclosures statement.
  • Aldemir 2011 - 90 patients from Turkey, multiple interventions, no disclosures statement.
  • Autorino 2005 - 96 patients in Italy, no disclosures statement.
  • Ayubov 2007 - Only published as conference abstract.
  • Cervenakov 2002 - 104 patients in Slovak Republic, could not access.
  • Dong 2009 - Korean Journal of Urology not indexed in PubMed.
  • Erturhan 2007 - 120 patients from Turkey, multiple interventions, no disclosures statement.
  • Ferre 2009 - 77 patients from USA, funded by academic grant.
  • Han 2006 - Korean Journal of Urology not indexed in PubMed.
  • Hermanns 2009 - 90 patients from Switzerland, authors state no COI.
  • Hong 2008 - Only published as conference abstract, ”furosemide-based expulsive therapy”.
  • Kaneko 2010 - 71 patients from Japan, no disclosures statement.
  • Kim 2007b - Only published as conference abstract.
  • Kupeli 2004 - 78 patients from Turkey, multiple interventions, no disclosures statement.
  • Liatsikos 2007 - 73 patients from Greece, multiple interventions, no disclosures statement.
  • Lojanapiwat 2008 - 75 patients from Thailand, multiple interventions, Astellas supplied tamulosin.
  • Mukhtarov 2007 - Only published as conference abstract, multiple interventions.
  • Pedro 2008 - 76 patients from Minnesota, supported by Sanofi-Aventis.
  • Porpiglia 2004 - 86 patients from Italy, multiple interventions, no disclosures statement.
  • Porpiglia 2009 - 91 patients from Italy, multiple interventions, authors state no COI.
  • Sayed 2008 - 90 patients from Egypt, could not access.
  • Sun 2009 - 60 patients from China, no disclosures statement.
  • Taghavi 2005 - Only published as conference abstract, multiple interventions.
  • Vincendeau 2010 - 129 patients from France, multiple pharma COI.
  • Wang 2008 - 95 patients from Taiwan, multiple interventions, could not access.
  • Ye 2011 - 3,189 patients from China, multiple interventions, supported by Astellas.
  • Yencilek 2010 - 92 patients from Turkey, no disclosures statement.
  • Yilmaz 2005 - 114 patients from Turkey, multiple interventions, no disclosures statement.
  • Zehri 2010 - 65 patients from Pakistan, no disclosures statement.
  • Zhang 2009b - 314 patients from China, multiple interventions, no disclosures statement.
This is a classic case of “Garbage In, Garbage Out”, where pooling studies for statistical power in a systematic review obfuscates the heterogeneity and poor underlying data quality.  From what I can gather, only two of these trials – Pedro 2008 and Vincendeau 2010 – registered as clinical trials and subscribed to methods and follow-up of sufficient integrity.  Both of these studies showed no or minimal benefit to alpha-blockers.

Patients will have adverse effects from these medications.  They may, however, also derive some stone passage and symptomatic benefit – although the magnitude of benefit cannot be reliably known.  Ultimately, the evidence collated by this systematic review is not of sufficient quality to support the authors’ conclusion:
“The use of alpha-blockers in patients with ureteral stones results in a higher stone-free rate and a shorter time to stone expulsion.”  
This statement ought to be significantly tempered by a declaration of the limitations of the underlying data.  It is probably still reasonable to offer a generic alpha-blocker to patients, but the expectation of ever knowing the true value of the therapy is basically nil.

“Alpha-blockers as medical expulsive therapy for ureteral stones (Review)”

Friday, April 18, 2014

Pre-Hospital Furosemide – No, No, Also No

In Ottawa, pre-hospital care includes paramedics authorized to treat acute cardiogenic pulmonary edema in the setting of respiratory distress.  Their treatment, sensibly, includes nitroglycerin.  It also, insensibly, includes furosemide.

Decompensated heart failure, resulting in pulmonary edema and dyspnea, is indeed a sort of fluid overload.  However, these patients frequently are not hypervolemic – they may be euvolemic or even hypovolemic, with other underlying etiologies for decompensation than fluid retention.  This pushes the concept of a strategy for the treatment of acute cardiogenic pulmonary edema with furosemide even further down the nonsense pathway.  Yet, there it is.

This study, a retrospective review of presentations with pre-hospital furosemide administration and hospital diagnoses of acute decompensated heart failure, demonstrates essentially nothing.  The primary outcome was designed to detect serious adverse outcomes associated with furosemide administration, but their comparison groups – furosemide given to heart failure, furosemide given to misdiagnosed heart failure, and furosemide not given to heart failure – are clinically heterogeneous and require probably meaningless adjusted comparisons.  The authors find no significant difference, but this is simply a matter of sample size and study design – a treatment given to a group with no chance of benefit obviously suffers only harms.

Most damning, however, is the utter failure of pre-hospital providers to correctly diagnose heart failure.  Of the 272 cases of heart failure diagnosed on arrival to the ED, pre-hospital providers made the diagnosis in only 110 instances.  Then, pre-hospital providers incorrectly diagnosed an additional 58 cases with heart failure and administered furosemide – when the patient was diagnosed with pneumonia, COPD, or another alternative.

Just say no.

“Prehospital use of furosemide for the treatment of heart failure”

Wednesday, April 16, 2014

Go Ahead, Age-Adjust the D-Dimer

If you include D-dimer as part of your practice to exclude pulmonary embolism, you’re probably already aware background levels gradually increase with age.  This results in further deterioration of the already poor specificity.  Happily, this publication in JAMA demonstrates it’s probably safe to gradually increase your cut-off level for D-dimer with age without sacrificing sensitivity.

These authors enrolled 3,324 patients in a cohort with ultimate prevalence for PE of 19.0%.  Of these, 2,898 fell into the “pulmonary embolism unlikely” group and underwent D-dimer testing.  817 met the traditional D-dimer <500 μg/L cut-off and no CTA was performed.  An additional 337 patients met their “age-adjusted cutoff” – "10 x patient age" for those aged greater than 50 years.  Only one patient with a negative D-dimer met their final adjudicated outcome of eventual venous thromboembolism.  The authors, therefore, conclude this strategy of age-adjusted D-dimer cut-off is safe.

However, a handful of patients were lost to follow-up, and the confidence interval for 3-month VTE, considering the sample size, ranges from 0.1-1.7% in their age-adjusted cohort.  Additionally, 7 patients died and 7 patients were evaluated for suspected VTE during the follow-up period.  Only 1 was judged by their 3 experts to have been due to VTE, but this consensus measure for their primary outcome could have profound effects on their ultimate conclusion.  Six different D-dimer assays were also used across their multi-center study, which hinders external generalizability.

But, in the end, it’s probably reasonable.  The harms and costs secondary to testing and treating false-positives and small VTE still likely outweigh any additional misses through this strategy.  Considering this comes from JAMA, it’s likely defensible in the face of peer-review to begin using age-adjusted cut-offs immediately.

“Age-Adjusted D-Dimer Cutoff Levels to Rule Out Pulmonary Embolism”

Monday, April 14, 2014

A "Positive" Primary Outcome for PEITHO

Yet, by "positive", as we all too often see, the underlying data comes with a surprise twist.

The Pulmonary Embolism Thrombolysis (PEITHO) trial evaluates single-dose tenecteplase added to conventional heparin therapy for the treatment of “intermediate risk” acute pulmonary embolism.  This includes patients with pulmonary embolism, right ventricular dysfunction on imaging, and elevated cardiac biomarkers.  For the primary endpoint of death or hemodynamic deterioration within 7 days, 2.6% of patients in the immediate thrombolysis group met this outcome vs. 5.6% of patients in the usual treatment arm (OR 0.44, p=0.02).

Unfortunately, this composite outcome obfuscates the difference between treatment arms is limited solely to hemodynamic deterioration.  The downside to thrombolysis – major extracranial bleeding (11.5% by ISTH definition) and hemorrhagic stroke (2.0%) – occurred five times as frequently in the treatment arm.  As a result, the overall 7-day and 30-day mortality were statistically identical.  Ultimately, then, this study paints the treatment decision as a choice between cardiovascular instability and life-threatening bleeding complications.

A couple interesting tidbits from the supplementary appendix:
  • The criteria for myocardial injury was a troponin I >0.06 μg/L or troponin T >0.01 μg/L.  These may be relatively inclusive thresholds.
  • Not all placebo patients developing hemodynamic collapse received subsequent thrombolysis; likewise, almost half of those who received open-label thrombolysis had no hemodynamic collapse.
  • Half the deaths in the placebo arm were “sudden unexplained” or “other”, compared with bleeding or stroke complications in the thromboysis arm.
How does this study fit in with the other recent evidence regarding thrombolysis of non-massive pulmonary embolism, e.g. MOPETT and TOPCOAT?  It means we know there are patients who will benefit – both in short-term hemodynamics and long-term functional status.  However, we're still trying to minimize the number harmed by parsing out the best candidates and choosing the correct dose.  There's a lot of room for disagreement and practice variation during continued investigation, with practice ranging from standard anticoagulation and monitoring to, as Jeff Kline promotes, full-dose thrombolysis with tenecteplase.  At the moment, I fall into the half-dose camp – but always re-evaluating new evidence.

“Fibrinolysis for Patients with Intermediate-Risk Pulmonary Embolism”

Friday, April 11, 2014

Tamiflu, the Bell Tolls for Thee

Have you read the revised Cochrane Review regarding neuraminidase inhibitors for preventing and treating influenza?  If you have, I’m impressed; it’s 559 pages long.   There are almost 250 pages of outcomes and treatment comparisons.  It is serious business.

And, it needs to be – because these folks from the Cochrane Collaboration are going up against Roche and a spin machine supporting of billions of dollars in revenue and pandemic flu strategic stockpiling.  The question:  do oseltamivir and zanamivir provide symptomatic relief and prevent serious complications from influenza infection with a reasonable safety margin?

Covering 20 oseltamivir (9,623 participants) and 26 zanamivir (14,628 participants) trials under a new data-sharing agreement, these authors ultimately conclude any faith in neuraminidase inhibitors is unwarranted.  Each treatment provided an advantage of less than a day with regard to symptom resolution – reducing the average duration of symptoms from nearly 7 days to slightly over 6 days.  Neither treatment had any effect on hospitalizations.  Pneumonia definitions were not standardized across trials; a 1% relative risk reduction was seen in investigator-reported pneumonia, but no reduction was seen in studies with radiologic objective measures of pneumonia.  Importantly, both neuraminidase inhibitors – osletamivir especially – were associated with adverse effects.  Nausea & vomiting were the most prominent symptoms, but neuropsychiatric disturbances were increased in a dose-dependent fashion.

Even more damning, there was universal risk of bias across trials – particularly for osletamivir.  The quality of the outcome follow-up for post-treatment complications was poor, allocation was not always blinded, and there was evidence of selective reporting of results.  That any government or guideline organization would base massive public health expenditures on a pharmaceutical corporation’s incomplete reporting of low-quality trials is simply indefensible.

So, there is a small, debatably unimportant effect on symptom duration.  There is zero evidence supporting the routine use of these agents to reduce subsequent infection.  This evidence does not exclude an important effect in a selected sub-population, but the authors of this review feel the underlying mechanism of action does not support such use until an effect is verified.  Furthermore, with regard to follow-up trials, the overall incidence of bacterial complications from influenza is low enough a sample size of over 20,000 patients would be required to detect a clinically meaningful difference.

It must be said – there is likewise potential bias on the side of these authors, who have long been vilifying Roche in this battle over open drug data.  The next step, we hope, will be opening the data to all to review and verify their findings.  We can hope, through repeated battles such as this, the open data day will come where we are able to properly protect patients from inadequate trial evidence.

In the meantime – let us purge ourselves of mandates and patient expectations for Tamiflu before the next influenza season rears its ugly head.

“Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children”

Wednesday, April 9, 2014

The Whole Truth, and Anything But

The publication of clinical trials in high-impact journals represents one of the most effective forms of knowledge translation for new medical evidence.  Three of these journals – JAMA, the New England Journal, and the Lancet – perennially rank among the highest-impact.  As I’ve mentioned before, these journals have a higher responsibility to society at large to maintain scientific integrity, as most readers therefore accept the authors presented results and conclusions at face-value.

However, clinical trials are also required to report their results on  These authors review one year’s worth of clinical trials published in the three aforementioned journals and compared the high-impact results with those stashed away on  Of 91 trials identified, 156 primary and co-primary endpoints were identified, but only 132 were described in both sources – and only 61% were concordant between each source.  Of 2,089 secondary endpoints, 619 were described in both sources – and were only 55% concordant.

Furthermore, the authors identified six studies with primary outcomes noted on resulting in alternative trial interpretation.  These included changes in disease resolution or progression time, as well as results that achieved statistical significance in publication, but not on

The authors conclude:
“…possible explanations include reporting and typographical errors as well as changes made during the course of the peer review process …. journal space limitations and intentional dissemination of more favorable end points and results in publications."
We ought to expect better vetting of results by journal editors – particularly from sources frequently followed by the lay media.

“Reporting of Results in and High-Impact Journals”

Tuesday, April 8, 2014

A Blog-A-Versary Of Sorts

It’s been three years since I started this blog, during PGY-3 of residency.  If you can imagine, I started out by posting every weekday.

That lasted – looking back – a surprisingly long time.

I’d like to say nowadays is “quality” over of “quantity”, but I’ll let the astute reader judge for themselves.

What have I learned?
  • This is a viable form of academic scholarship that bypasses the bureaucracy and limited format of print journals.  Just a quick look around at the folks who have substantially augmented their careers with an online presence validates this opinion.
  • tPA – we love to hate this drug.  Many of my most-viewed posts concern new trials and publications regarding tPA use in acute stroke.  Other popular topics seem to be cardiovascular & resuscitation topics, along with highly-controversial articles from prominent journals.
  • Blogger and Google Analytics traffic stats still don’t match up, but revisions to Analytics have brought the numbers closer together.
  • As any writer will tell you – the best way to improve your writing is to write.  The best way to improve your critical appraisal is to read other experts – and then throw your own hat in the ring.  Many projects now – including this one – offer the opportunity for intermittent, mentored posts with higher visibility for someone just starting out.
  • Knowledge translation is more important now than ever before.  Creating new knowledge through research is the foundation of advancing the practice of medicine, but the conflicts-of-interest and distortions (sometimes inadvertent) pervading even peer-reviewed publications demand an ever-more-vital skeptical layer of peer review.
  • This current state of online discourse is not the end.  Twitter, blogs, podcasts, Google Hangouts, Global Journal Clubs – don’t forget how “new” these elements are, and watch for (or go create) the next innovation.
Thanks for reading; the pleasure is all mine.

Monday, April 7, 2014

Colloids Will Never Die

People love colloids.  Gross fluid resuscitation with crystalloids makes folks uncomfortable; the general dilutional effects and lack of oncotic pressure associated with crystalloids portends suboptimal volume replacement.

Yet, as we see again, the theoretical advantages of colloids are just that:  theoretical.

In this multi-center study from Europe, ICU patients were randomized – following initial resuscitation – to further resuscitation with crystalloids alone or crystalloids supplemented with albumin to a serum albumin target of 30g/L.  Groups were well-matched at baseline, in medical/surgical comorbidities, organ dysfunction, physiologic parameters, and pre-randomization resuscitation.  This excerpt from the authors’ conclusions condenses the results most simply:
“… the use of albumin in addition to crystalloids to correct hypoalbuminemia, as compared with the use of crystalloids alone, in patients with severe sepsis during their stay in the ICU did not provide a survival benefit at 28 or 90 days, despite improvements in hemodynamic variables.”
The last note is important, and reveals why this study will do nothing to change the use of natural and synthetic colloids for resuscitation:  clinicians love to make numbers look good, and colloids do that better than crystalloids.  Despite increased cost and no ultimate change in the primary outcome of mortality – or any secondary outcome of note – colloids improved hemodynamics in the short term.  Even though colloids are more costly, perhaps there are yet financial advantages to this small, early hemodynamic advantage?  Regardless, we are assured further research on this topic will continue apace.

My wife's contribution to this post:  other important colloids people love include whipped cream, gravy, ketchup, and Jello®.

“Albumin Replacement in Patients with Severe Sepsis or Septic Shock”

Friday, April 4, 2014

Ignorant About Costs, Interested in Learning

Survey after survey shows: physicians rarely have any idea about the costs of medical care.  And, this is unsurprising – as there is a complex divorce between hospital charges, reimbursements, and ultimate expenses shouldered by patients.  Considering all these variables, it is nigh impossible to clearly communicate the cost of care to an individual in a patient care setting.

But, a ballpark estimate would be nice.

So, how do physicians do with their ballpark estimates of the costs of routine tests and procedures in the Emergency Department?

Using CMS reimbursement rates from 2012 and 2013, this survey of 97 emergency physicians representing 11 EDs in the Salt Lake City area finds they’re usually nowhere close.  Of all the tests and procedures surveyed, only 17% of physician estimates were within ± 25% of the actual CMS reimbursement.  We would be awful on the Price is Right.

Interestingly, the estimates varied widely.  With regards to lab tests and radiology, physicians tended to over-estimate reimbursement by >50%, while under-appreciating the charges associated with CPT codes for administration of IV fluids and IV antibiotics.  I’m not sure how to describe the host of interesting information graphics and tables detailing the bewildering range of inaccuracy, but suffice to say – we could/should/need to do a lot better.

At least, however, physicians self-rated their knowledge of costs of care as low, and over 80% wished they knew more about the charges.  So, hope is not lost – and movements like (the aptly named) Costs of Care ought to receive ready and enthusiastic audience.

“Emergency physician knowledge of reimbursement rates associated with emergency medical care”