Category: Medication Safety

FFP Vs. PCCs for Warfarin Reversal – Special Advertising Supplement

It is generally well-known, the advantages of Prothrombin Concentrate Complexes over Fresh Frozen Plasma.  They are a smaller-volume infusion, more rapidly reverse the anticoagulant effect, and lack some of other disadvantages of hemostatic product use.  This study, therefore, a Phase 3b open-label trial of PCCs vs. FFP for anticoagulation reversal before urgent surgery, is essentially of questionable utility.  Is it emergency surgery?  Then use the immediate reversal agent.  Is it semi-elective?  Well, why not wait a bit?

So, why even run a trial for the use of PCCs in the non-emergent realm?  Well, it rapidly becomes clear how this study was conceived by review of the “Role of the funding source”:

This research was funded by CSL Behring. A steering committee of academic medical experts and representatives of the funder oversaw the design and conduct of the study. The funder participated in the selection of the board members. The funder was responsible for data collection, management, and analysis of the data according to a predefined statistical analysis plan. Preparation and review of the Article and the decision to submit for publication was done by a publication steering committee that included academic medical experts and representatives of the funder. Medical writing assistance was paid for by the funder. JNG and RS had full access to all the data in the study and took responsibility for the integrity and accuracy of the data analysis.

The goal: “indication creep” – an entirely obvious corporate landgrab, essentially sponsored, conducted, and written by CSL Behring to expand the use of PCCs beyond emergency reversal.  Indeed, it’s hard to even dignify this Lancet content with a summary.  The exclusion criteria were extensive.  The trial was modified after a letter from the FDA.  Some of the reported outcome numbers in the paper don’t match their ClinicalTrials.gov entry.  Almost all the differences in outcomes were subjective or surrogates for patient-oriented measures.  The authors conclusion:

“[T]hese data show that 4F-PCC is an effective and superior alternative to plasma in terms of haemostatic efficacy and rapid INR reduction for the rapid reversal of VKA therapy before urgent procedures.”

But, despite all these differences “favoring” PCCs, the surgical hemostasis was identical in practical terms – the difference in blood loss between cohorts was only 12 mL on average, only a handful of patients in each cohort required any sort of transfusion, and the total number of units transfused was nearly identical.  In fact, half of the FFP patients never had full INR reversal – with apparently no clinically important consequence.  Surgical cases went to the OR much faster with PCCs – so, as above, in an emergent or semi-emergent instance, PCCs are a great option.  Absent such a rush, however, ignore this Special Advertising Supplement masquerading as science in a supposedly reputable journal.

“Four-factor prothrombin complex concentrate versus plasma for rapid vitamin K antagonist reversal in patients needing urgent surgical or invasive interventions: a phase 3b, open-label, non-inferiority, randomised trial”
http://www.ncbi.nlm.nih.gov/pubmed/25728933

Rampant Underreported Research Misconduct

It is not surprising to hear clinical trials sometimes struggle with data integrity and quality issues.  Such undertakings can be logistically challenging, and certainly any substantial scope of effort leads to the occasional cutting of corners.

However, there are also millions (or billions) of dollars in revenue, along with multiple professional reputations, at stake.  This creates fertile territory for the more nefarious sort of data corruption.  In some instances, the Food and Drug Administration performs site monitoring as evaluation for misconduct.  And, as this study indicates, the FDA sometimes discovers serious issues – issues almost always swept under the rug.

Using a variety of methods, including Freedom of Information Act requests, FDA.gov site exploration, and other FDA published warnings, these authors compiled a list of 421 serious irregularities identified by FDA audit.  However, heavily redacted language in many of the documents discovered precluded linkage to clinical trials – resulting in only 57 published trials that could be linked to serious violations.  These 57 trials resulted in 78 identifiable publications – only 3 of which mentioned or addressed the issues raised by the FDA.  Those three specifically noted data excluded due to protocol errors, data falsification, or inappropriate monitoring.  The remaining 75 publications did not.

A couple examples:

  • 8 of 16 FDA inspections of sites for RECORD 4, a rivaroxaban trial for DVT prophylaxis, identified unblinding, falsification of records, and randomization improprieties.  The associated study publications do not mention such issues.
  • A clinical site in China falsified data regarding apixiban in ARISTOTLE.  Excluding such data from the final study report would eliminate any apparent mortality benefit, but publications continue reporting mortality benefit analyses based on the entire data set.

The lack of transparency and apparent action regarding what is certainly just the tip of the iceberg is staggering.  How is it our own drug safety organization fails to protect patients on such a scale?  Is it any wonder so few clinical trial results hold up on re-examination?

“Research Misconduct Identified by the US Food and Drug Administration”
http://www.ncbi.nlm.nih.gov/pubmed/25664866

Irresponsible Use of NOACs in End-Stage Renal Disease

Frequent readers may have noted this blog is somewhat skeptical regarding the novel oral anticoagulants, with particular criticism reserved for dabigatran.*  The bleeding risks, particularly for dabigatran, are profoundly increased in renal impairment – while the Factor Xa inhibitors simply do not have sufficient safety data to describe their risks in this population.

So, in dialysis patients with zero renal function – wouldn’t it perhaps be safest to continue using our present, time-tested, warfarin anticoagulation strategy?

This review of the Fresenius Medical Care database of end-stage renal patients on dialysis captured 8,064 patients with non-valvular atrial fibrillation who were initiated on anticoagulation between 2010 and 2014.  During this time, 5.9% of patients receiving new anticoagulation were initiated on dabigatran or rivaroxaban, with the remainder started on warfarin or aspirin.  And, dabigatran or rivaroxaban use increased the incidence of minor bleeding, major bleeding, and bleeding-associated mortality – with relative risk increases ranging from ~1.3 for minor bleeding to ~1.7 for hemorrhagic death.  Even rates for ischemic stroke were low in all groups, and no meaningful protective difference for thromboembolic events was observed.  Small baseline differences between the various anticoagulant cohorts are present, but they are probably clinically unimportant.

More bleeding?  More death?  It seems clear it is not responsible medicine to initiate the NOACs in a dialysis population.

“Dabigatran and Rivaroxaban Use in Atrial Fibrillation Patients on Hemodialysis”
http://www.ncbi.nlm.nih.gov/pubmed/25595139

*Disclosure: I provided legal consultation pertaining to dabigatran, with funds paid to my institution.

Inappropriately Promoted tPA “Drip and Ship” Safety

“More community hospitals are giving a powerful clot-busting medication to stroke victims, improving their chances of survival and recovery, new research shows.”

This statement comes from the American Heart Association press release regarding this synopsis of the Get-With-the-Guideline Registry.  Part of this statement is true – more community hospitals are using tPA for acute ischemic stroke.  In this review of 44,667 patients treated with tPA over the past decade, 23.5% received tPA outside of a specialized stroke or academic center.

The second half of this press statement is false.

Patients treated by the “drip and ship” method, as community administration of tPA is described, did not have an improved chance of survival.  Patients treated at community hospitals were younger, had less-severe strokes, and had fewer prior strokes – yet their in-hospital mortality was 10.9%, compared with 9.7%.  Additionally, their rate of symptomatic intracranial hemorrhage was 5.7% compared with 5.2%, and they had 1.8% serious tPA-related complications, compared with 1.6%.  These small absolute differences are magnified when adjustments are made for baseline comorbidities, and, in fact the OR for in-hospital mortality increases to 1.23 or 1.33, depending on the precise statistics pursued.  So, of course, the logical leading sentence of the Discussion is:

“In this study of >40000 patients with acute ischemic stroke treated with IV thrombolysis throughout the United States, drip and ship thrombolysis was …. safe.”

A better leading sentence to their Discussion might rather suggest the “drip and ship” model is, in fact, less safe than typical thrombolysis.  Further, they might better suggest the “drip and ship” model should be curtailed while further investigation into additive risks are performed, or to confirm the effects noted from this somewhat dodgy registry data.  But, these authors focus more on explaining away this inconsistency with their narrative than calling for safer, narrower administration of tPA.  After all, these authors are well-funded by industry – including one affiliated with MGH TeleHealth, providing telestroke-enabled thrombolysis:

Dr Sheth is a member of the Get with the Guidelines (GWTG)- Stroke Clinical Workgroup, and he is a Co-Principal Investigator and Executive Committee member for Glyburide Advantage in Malignant Edema and Stroke-Remedy Pharmaceuticals (GAMES-RP), a phase II–trial to prevent swelling in patients with large stroke, funded by Remedy Pharmaceuticals, Inc. Dr Smith is a member of the GWTG- Stroke Workgroup. Dr Kleindorfer discloses speaking engagements. Dr Fonarow is a member of the GWTG Steering Committee; receipt of research support (to the institution) from Patient-Centered Outcomes Research Institute, and he is an employee of the University of California that holds a patent on retriever devices for stroke. Dr Schwamm is the chair of the GWTG-Stroke Clinical Workgroup, a principal investi- gator of the National Institutes of Health–funded MR WITNESS (A Study of Intravenous Thrombolysis With Alteplase in MRI-Selected Patients) trial of extended window thrombolysis for which Genentech provides supplemental site payments and alteplase free of charge, a member of the international steering committee of the Desmoteplase in Acute Ischemic Stroke (DIAS) 3 and 4 trials of extended window thrombolysis, and the director of Massachusetts General Hospital (MGH) TeleHealth. The MGH provides a broad array of telehealth services to hospitals in New England, including telestroke-enabled thrombolysis. Dr Grau-Sepulveda reports no conflicts.

Perhaps the new ACEP Clinical Policy statement can explicitly address such settings in their “systems in place” language.

“Drip and Ship Thrombolytic Therapy for Acute Ischemic Stroke”

Icatibant for ACE-Inhibitor Angioedema

Oropharyngeal angioedema can be one of the true Emergency Department airway disasters.  Massive and rapidly progressive edema can engulf all usable landmarks and views, necessitating surgical intervention.  No one enjoys these cases – least of all the patient.

This small trial, replete with heavy sponsor involvement, details the utility of icatibant, a selective bradykinin receptor antagonist, for treatment of ACE inhibitor-induced angioedema.  27 patients were randomized either to icatibant or steroids plus an antihistamine.  The mean times to symptom relief were reduced substantially by use of icatibant – with reported total symptom resolution reduced from 27 hours to 8 hours.

Of course, for the three placebo patients meeting the protocol definition of worsening clinical status, the authors arbitrarily set their time to symptom resolution to 61.8 hours – exaggerating (unnecessarily) the difference measured for the primary outcome.  Finally, bizarrely, 4 of these 27 patients were lost to follow-up – all in the placebo cohort.  What sort of effect this would have on the integrity of the results is uncertain.

But, all such misbehaviors aside, icatibant probably works, along with C1-esterase inhibitor and ecallantide.  However, each use of these medications costs between ~$7,000-$10,000 per administration.  Therefore, restraint is necessary to prevent indication creep – and such medications should not be given to all perioral angioedema presentations, and be reserved only as a final option to fend off impending upper airway obstruction.

“A Randomized Trial of Icatibant in ACE-Inhibitor–Induced Angioedema”
http://www.ncbi.nlm.nih.gov/pubmed/25629740

Which Review of Tamiflu Data Do You Believe?

Ever since its introduction, there have been skeptics regarding the utility of oseltamivir and other neuraminidase inhibitors for the treatment of influenza.  Roche has profited tremendously off strategic stockpiling by many governments as a response to pandemic influenza – yet, nearly all the data comes from Roche-conducted trials, and the data has been persistently cloaked from independent review.  This past year, after much strife and public shaming, the Cochrane Collaboration received some access to clinical trial reports to conduct an independent review.  This review found, on average, adults receiving early treatment with oseltamivir benefited by reduction in symptom duration from 7 days to 6.3 days.  No benefit was found for reduction in respiratory infectious complications or hospitalization, the truly critical need during influenza outbreaks.

However, a second group also conducted an independent review – the “Multiparty Group for Advice on Science”.  Their results, based on an individual-patient meta-analysis, are published in the Lancet and offer similar – yet wildly different – conclusions.  They find, as did the Cochrane group, approximately a 17-hour reduction in symptoms in the intention-to-treat population across the eight Roche trials evaluated.

Similar to the Cochrane review, they perform secondary analyses for “lower respiratory tract infection”(e.g., bronchitis or pneumonia) and hospitalization, stratified by ITT and ITT-infected populations.  Most prominently emphasized are the results for the ITT-infected population, in which the antibiotics for LRTI were provided to 4.2% in the oseltamivir cohort, compared with 8.7% in placebo.  Likewise, 0.9% of patients were hospitalized for any cause compared with 1.7% of placebo.  The authors therefore conclude oseltamivir use decreased infectious complications of influenza.

These numbers, however, are entirely different from the Cochrane review.  The Cochrane review found a 1.4% hospital admission rate in the oseltamivir cohort and 1.8% in the placebo cohort.  Broken down by trial, the admit rates for the oseltamivir cohort in the MUGAS analysis compared with the Cochrane review:

  • M76001: 7/965 vs. 9/965
  • WV15670: 1/241 vs. 1/484
  • WV15671: 1/210 vs. 6/411
  • WV15707: 2/17 vs. 2/17
  • WV15812+: 6/199 vs. 9/199
  • WV15819+: 6/360 vs. 9/362
  • WV16277: 2/226 vs. 2/225

The differences in WV15670 and WV15671 appear to stem, at least in part, due to the MUGAS analysis being restricted to only trial patients taking 75mg twice daily, and not 150mg twice daily.  However, it is otherwise entirely unclear how the Cochrane group found extra hospitalizations in the other trials the MUGAS group did not – particularly considering the hospitalization numbers in the placebo cohorts were essentially identical.  Might it be partly a result of the MUGAS group receiving their data directly from a Roche web portal, while the Cochrane group reviewed the individual clinical study reports?

Rather, might it be revealing to pry into the genesis of the “Multiparty Group for Advice on Science”?  Is it an unbiased, independent clearinghouse for re-analysis of trial data?  Do they have a long track record of respected publications in multiple disciplines?  Unfortunately, neither of these conjectures are true – making it increasingly likely they are a puppet foundation fraught with conflict-of-interest.  MUGAS and the present work were funded by an unrestricted grant from Roche.  Furthermore, MUGAS, along with the European Scientific Working group on Influenza (ESWI), are projects of Semiotics, a scientific branding and communication company specializing in influenza.  The stated goal of Semiotics is promoting corporate science and ensuring its place on top of the policy agenda – and MUGAS is one of their “brands”.  This ought to very clearly demonstrate MUGAS is not a scientific enterprise, and rather an organization tasked with the sort of advocacy as best represents the needs of its sponsors.

Any bias might also be clear just in the style used to present results.  These authors present the tiny absolute differences in hospitalization and infectious complications in forest plot figures using only relative risk, rather than absolute risk.  This serves to inflate the apparent effect size.  Conversely, they present the increased incidence of adverse effects in a table culminating in adjusted absolute risk, with the opposite effect.  This manner of presentation persists in their Discussion, highlighting a “significant 63% reduction in risk of hospitalization”, compared with “absolute increases of 3.7% for nausea and 4.7% for vomiting.”

So – the results of an analysis performed by a “brand”, highlighting results discordant with a prior unbiased analysis.  Where is the peer review vetting such discrepancies?  With so many professional reputations and so much revenue at stake – which report do you believe?

“Oseltamivir treatment for influenza in adults: a meta-analysis of randomised controlled trials”
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(14)62449-1/abstract

Additional editorial content:
“The BMJ Today: The FDA and CDC’s disagreement over Tamiflu, and the spy who isn’t”
http://blogs.bmj.com/bmj/2015/02/05/the-bmj-today-the-fda-and-cdcs-disagreement-over-tamiflu-and-the-spy-who-isnt/

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

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

The Wholesale Revision of ACEP’s tPA Clinical Policy

ACEP has published a draft version of their new Clinical Policy statement regarding the use of IV tPA in acute ischemic stroke.  As before, the policy statement aims to answer the questions:

(1) Is IV tPA safe and effective for acute ischemic stroke patients if given within 3 hours of symptom onset?
(2) Is IV tPA safe and effective for acute ischemic stroke patients treated between 3 to 4.5 hours after symptom onset?

Most readers of this blog are familiar with the mild uproar the previous version caused, and this revision opens by stating “changes to the ACEP clinical policies development process have been implemented, the grading forms used to rate published research have continued to evolve, and newer research articles have been published.”  Left unsaid, in presumably a bit of diplomacy, were the conflicts of interest befouling the prior work.  Notably absent from this work is any involvement from the American Academy of Neurology.

What’s new, with a new methodology-focused rather than conflicted-expert-opinion approach?  Most obviously, there’s a new Level A recommendation – focused on the only consistent finding across all tPA trials: clinicians must consider a 7% incidence of symptomatic intracranial hemorrhage, compared with 1% in the placebo cohorts.  The previously Level A recommendation to treat within 3 hours has been downgraded to Level B.  Treatment up to 4.5 hours remains Level B.  Finally, a new Level C recommendation includes a consensus statement recommending shared decision-making between the patient and a member of the healthcare team regarding the potential benefits and harms.

Most of the reaction on Twitter has been, essentially, a declaration of victory.  And, in a sense, it is certainly a powerful statement regarding the ability for like-minded patient advocates and evidence purists to coalesce through alternative media and initiate a major change in policy.  To critique this new effort is a bit of punishing the good for lack of manifesting perfect, but there are a number of oddities worth providing feedback to the writing committee:

  • The authors provide a curious statement:  “The 2012 IV tPA clinical policy recommendation to ‘offer’ tPA to patients presenting with acute ischemic stroke within 3 hours of symptom onset was consistent with other national guidelines. Unfortunately, the essence of the term ‘offer’ may have been lost to readers and has therefore been avoided in this revision.”  I rather find “offer” a lovely term, in the sense it expresses a cooperative process for proceeding forward with a mutually agreed upon treatment strategy.  Rather than discard the term, clarification might have been reasonable.
  • They mention ATLANTIS as Class III evidence with regard to the 3-4.5 hour question.  I can see how its classification may be downgraded given the multiple protocol revisions.  That said, its inability to find a treatment benefit in spite of extensive sponsor involvement ought be a more powerful negative weighting than currently acknowledged.  Given the biases favoring the treatment group in ECASS III (given a Class II evidence label), the cumulative evidence probably does not support a Level B recommendation for the 3-4.5 hour window.
  • One of my Australian colleagues in private communication brings up a small letter from Bradley Shy, previously covered on this blog, mentioning a statistical change to ECASS III.  This statement could acknowledge this post-publication correction and its implications regarding the aforementioned imbalance between groups.
  • The authors fail to acknowledge the heterogeneity of acute ischemic stroke syndromes and patient substrates, and the utter paucity of individualized risk or benefit assessment tools – in no small consequence of the small sample sizes of the few trials rated as Class I or Class II evidence.  This is a powerful platform with which to state clinical equipoise exists for continued placebo-controlled randomization.  As we see from the endovascular trials, the acute recanalization rate of IV tPA is as low as 40% – with many patients re-occluding following completion of the infusion.  Patients need to be selected less broadly with respect to likelihood of benefit compared with supportive care.  I believe tPA helps some patients, but it should be a goal to dramatically reduce the costs and collateral damage associated with rushing to treat mimics and patients without a favorable balance of risks and benefits.  For these authors to recommend treatment in “carefully selected patients” and “shared decision-making”, more guidance should be provided – and absent the evidence to support such guidance, they should be calling for more trials!

The comment period is open until March 13, 2015.

“Clinical Policy: Use of Intravenous tPA for the Management of Acute Ischemic Stroke in the Emergency Department DRAFT”
http://www.acep.org/Clinical-Policy-Comment-form-Intravenous-tPA/

Addendum 01/18/2015:
The SAEM EBM interest group is compiling comments on the evidence for feedback to the SAEM board of directors.  These are my additional comments after having had additional time to digest:

  • I agree with sICH as a Level A recommendation.  Both RCTs and observational registries tend to support such a recommendation.  Whether the pooled risk estimates are usable in knowledge translation to individual patients is less clear.  The risk of sICH is highly variable depending on individual patient substrate.  There are several risk stratification instruments described in the literature, but none are specifically recommended/endorsed/prospectively validated in large populations.
  • It is uncertain regarding the NINDS data whether their intention is to present pooled Part 1 and Part 2.  The prior clinical policy used only Part 2 for their NNT calculation, giving rise to an NNT of 8 instead of 6.  It appears they are pooling the data from both parts here.  Either is fine as long as it’s explicitly stated – the primary outcome differed, but the enrollment and eligibility should have been the same.
  • ECASS seems to be missing from their evidentiary table.  The ECASS 3-hour cohort data is available as a secondary analysis.  However, such would probably be Class III data of no real consequence for the recommendation.
  • Level B is probably an acceptable level of recommendation for tPA within the 0-3 hour window.  “Moderate clinical certainty” is reasonable, mostly on the strength of the Class III data.  However, the “systems in place to safely administer the medication” is not clearly addressed in the text.  Most of the published clinical trial and observational evidence involves acute evaluation by stroke neurology.  Does the primary stroke center certification practically replicate the conditions in which patients were enrolled in these trials/registries?  Perhaps this should be split out into a separate recommendation regarding the required setting for safe/timely/accurate administration.
  • Level B is difficult to justify for the 3 to 4.5 hour time window.  There is Class II evidence from ECASS III (downgraded due to potential for bias) demonstrating a small benefit.  The authors then cite Class III trial evidence from IST-3 and ATLANTIS in which no benefit was demonstrated.  Then, they cite the individual patient meta-analysis having similar effect size to ECASS III – because many of the patients in that subgroup come from ECASS III.  Basically, there’s only a single piece of Class II evidence and then inconsistent Class III evidence, which doesn’t meet criteria state for a Level B recommendation (1 or more Class of Evidence II studies or strong consensus of Class of Evidence III studies).  
  • With both Level B recommendations, the authors also reference “carefully selected” patients, but do not cite evidentiary basis regarding how to select said patients other than listing the enrollment criteria of trials.  If the “careful selection” is strict NINDS or ECASS III criteria, this should be explicitly stated in the recommendation.
  • The Level C recommendations to have shared decision-making with patients and surrogates ought to be obvious standard medical practice, but I suppose it bears repeating given the publications regarding implied consent for tPA.  They mention two publications regarding review and development of such tools, but there is no evidence supporting their efficacy or effectiveness in use.  Frankly, calling them a starting point in such a heterogenous population is along the lines of the broken clock that’s right twice a day.  I would rather say their dependence on group-level data minimizes their practical utility, and clinician expertise will be the best tool for individual patient risk assessment.

Feel free to add your comment and I will incorporate them into my feedback to SAEM.

Opiates Are a Gateway Drug … to Opiates

By definition, essentially, all prescription drug abuse starts with a prescription.  Diversion and misuse cannot occur without a physician – well-meaning or not – at the start of the chain.  And, not only are physicians the pipeline for maintaining supply in the community – they’re also one of the sources for minting new abusers.

This simple retrospective study looked at Emergency Department patients receiving treatment for an acutely painful condition.  Patients were then distilled down into those without prior use of opioids within the previous one year – the so called “opioid naive” for the purposes of this classification.  Approximately half of these patients received an opiate prescription at discharge.

Two interesting observations:

  • Those receiving, and filling, a prescription for opiates were far more likely than those who did not receive a prescription – 17% vs. 10% – to fill another prescription for opiates in a 60-day time period one year later.
  • Those receiving, but not filling, a prescription for opiates had only an 8% prevalence of filling another prescription for opiates a year later.

Within the limitations of the selection biases inherent to a such a retrospective evaluation – the message is reasonable: beware the downstream harms of every opiate prescription provided.

“Association of Emergency Department Opioid Initiation With Recurrent Opioid Use”
http://www.ncbi.nlm.nih.gov/pubmed/25534654