Category: Medication Safety

tPA Means: Blinders On, Full Power!

IST-3, despite its pro-tPA bias, was a negative trial for the primary endpoint.  But, that hasn’t stopped folks from looking at secondary outcomes and slicing it into subgroups and claiming – victory!

The root of the issue is:  in a negative trial, when you pull out a subgroup with positive outcomes, naturally there must be a counterweight subgroup with worse outcomes.  The trouble with the true believers/sponsored representatives is they focus only on the positive subgroup for hypothesis generation, and neglect the negative bits.

This latest rehash of IST-3 focuses on patients with high predicted risk of sICH or poor functional outcome.  These authors reviewed all the published prognostication tools and developed their own from the patient data in IST-3.  For what it’s worth, most of the tools performed approximately the same:  fair to poor.  The best AUC for prediction of sICH was 0.68 and the best AUC for prediction of post-tPA poor outcome was 0.80.

Then, these authors stratified the groups into low-, medium-, and high-risk for sICH or poor functional outcome with tPA, and compared the outcomes to the placebo group in IST-3.  For these subgroups, these authors found patients stratified as high-risk by the various scores tended to have better outcomes when treated with tPA compared with placebo.  Thus they conclude: “These data suggest that intravenous rtPA has an absolute beneficial effect in patients at a high predicted risk of sICH or poor functional outcome.”

… which is a fine and reasonable hypothesis given their baseline assumptions.  However, they never acknowledge the biases of IST-3 or the greater context of a negative trial – the counterweight that tPA is thereby futile or harmful in those at low- or medium-risk for poor outcome.

Of course, when most authors are funded by Boehringer Ingelheim to fly about the world and describe the wonders of tPA, it’s no surprise they choose to focus only on the conclusions that might lead to more tPA use, rather than narrowed, more appropriate tPA use.

“Targeting Recombinant Tissue-Type Plasminogen Activator in Acute Ischemic Stroke Based on Risk of Intracranial Hemorrhage or Poor Functional Outcome: An Analysis of the Third International Stroke Trial”
https://stroke.ahajournals.org/content/early/2014/03/06/STROKEAHA.113.004362.abstract

The “Standard of Care”

A guest post by William Paolo (@paolomd1), the Program Director of Emergency Medicine at SUNY Upstate.
“Standard of care” is a legal term whose colloquial medical usage, outside of tort law, has been unfortunately adopted by the medical infrastructure into its cultural lexicon.  The implications of its usage, when related amongst physicians, is the suggestion that there is an accepted, established, and parsimonious rendering of medical care that all reasonable providers would, under similar circumstances, judiciously employ.  It serves as an idealistic touchstone resting upon the foundations of summated evidence via which clinicians measure their individual and collective performances.  Actions that deviate from the collective wisdom are deemed inappropriate, negligent, and worthy of derision for failing to practice within the established evidentiary parameters of the authoritative collective guild.  Undermining this concept are the radical disparities of an agreed upon standard among clinical specialists and varying geographical norms that disrupt the foundations of a standardized standard of care.   The very term itself is normative, proposing what ought to be rather than what currently is, based upon a leap of logic that has never been fully supported by medical empiricism as expressed within the evidentiary literature.  The standard therefore may be determined by the collective, but more often it is determined by a scant few individuals utilizing the argument from authority to prescribe practice patterns.  The difficulty lies in prospectively determining what current “standard of care” actually results in patient harm, as the medical story is replete with examples of injury obvious only in retrospect.
The PROWESS study was released in 2001 in which activated protein C as manufactured and distributed by Eli-Lilly under the name Xigris was evaluated for the treatment of severe sepsis.   1690 people with septic shock requiring vasopressors were randomized to receive either activated protein-C or placebo.  The primary end point was death from any cause 28 days after infusion. Because of the results the phase 3 trial was stopped early having demonstrated an absolute mortality reduction of 6% yielding a number needed to treat of 17.   As is now widely known there were multiple issues with the original study and the subsequent 2012 PROWESS-Shock study demonstrated no benefit and potential harms of Xigris.  In 2014 it is easy to appreciate the issues of harm and need for reproduction and verification of PROWESS to overcome equipoise however physicians in 2001 had a very well done study (as most industry supported research is—though it is also done well to bias in their favor) that was stopped early due to patient benefit.  One could not fault a 2001 physician for referring to activated protein C as the new standard of care for sepsis—or can we?
Standard of care forces physicians to adopt an intellectually closed approach to evidence presuming that science has settled particular questions regarding clinical conundrums.  Retrospectively the foolishness of this position is obvious as the inexorable progress of empiricism wrought through experimentation recurrently dismantles accepted evidentiary norms.  The “standard” of current epochal standard care has no more underlying claim to absolute truth-value than previous erroneous medical misadventures exemplified by the various theories of humorism.  The problem, as it were, is one of perspective as it is difficult discern objective truths when temporally related to the perpetuation of often faulty ideas and attitudes.  Only the march forward of time and accumulated wisdom is able to dismantle that which seemed once intuitively and evidentially obvious in a given medical period.  The reasonable intellectual position to therefore adopt, as a profession, is one of radical agnosticism towards absolute truth claims and delineations of care as defined by standards.  This is not to say that we should fall into nihilism and presume that all of our current care will one day be proven mistaken and therefore be paralyzed by the knowledge of transformation.   The story of medical science, as all of science, is replete with advancements and misadventures with a clear arrow of progression. “Standard of care” adopts a position of unsupported truth-value without the reason necessary for its nuanced interpretation.  Though we may continue to utilize it as a profession it would be preferable to hand it, in its entirety, back to the lawyers who endowed us with it at the beginning.

“Efficacy and safety of recombinant human activated protein C for severe sepsis.”
http://www.ncbi.nlm.nih.gov/pubmed/11236773

Dexamethasone. Think About It.

Many aspects of medicine are simply based on momentum and routine.  One of those routines, in my anecdotal experience, is the use of 5-day courses of steroids for mild/moderate asthma exacerbations.  However, why give multiple doses when one will suffice?  Why not dexamethasone?

Unfortunately, this meta-analysis doesn’t really bring any new knowledge into play.  These authors attempt to pool the results from all the pediatric randomized trials comparing dexamethasone vs. short-course prednisone for the outpatient management of asthma with exacerbation.  No included individual trial showed a relapse rate with dexamethasone significantly worse than prednisone – and, unsurprisingly, the pooled results reflect that same finding.  The only recorded adverse effect – vomiting in the ED or at home – was seen less frequently with dexamethasone, although the overall incidence in both arms was minimal.

But, there are only six trials, most of which are fewer than 100 patients.  These trials are also a mix of oral and intramuscular, single and multiple dose, and dose ranges from 0.3 mg/kg to 1.7 mg/kg (“max 36 mg”!).  There were also methodologic problems with blinding, allocation, and other outcomes issues with each included study.

Based on this low-quality evidence, it would be reasonable to say dexamethasone use is not adequately described in the literature.  It would, likewise, be reasonable to go ahead and make use of dexamethasone in this setting, with the recognition of these limitations.  Personally, I fall on the dexamethasone side of the argument – for children, as well as adults.  When feasible, I use an approximately prednisone-equivalent oral dosing at 0.15 mg/kg up to a maximum dose of 12mg in both populations.

And I would love to see a high-quality trial to settle matter, once and for all.

“Dexamethasone for Acute Asthma Exacerbations in Children: A Meta-analysis”
http://www.ncbi.nlm.nih.gov/pubmed/24515516

Sources of Nonmedical Opiates

Making an even three consecutive posts on opiate abuse makes a week of it; this ought to be the last, unless further profound insights are hot-off-the-presses.

This study – actually a minor Research Letter in JAMA Internal Medicine – evaluates self-reported behavioral patterns in nonmedical drug use in the United States.  This accompanies another study looking at the risk factors for unintentional opiate-related deaths, which, helpfully, adds a little context.

This survey extrapolates out to approximately 12 million nonmedical opiate users aged greater than 12 years in the United States.  A slight majority of users were male, and most had annual incomes less than USD$50,000.  Most interesting, however, is Table 2, which describes how the source of opiates varies with increasing frequency of use.  Individuals who reported nonmedical use of opiates fewer than 30 days out of the year received their opiates predominantly for free from a friend or relative.  As frequency of use increased, opiates were less frequently received from a friend for free – and more likely to be received from a physician or purchased from friends, family, or drug dealers.  As the accompanying study notes, increasing prescription and increasing mean daily use of opiates were associated with increased risk of death – so it would appear the population at highest risk of death also has the greatest extent of physician contact for opiates.

But, just as important as it may be to evaluate an individual risk for opiate misuse when prescribing, it is also important to note the majority of nonmedical use was obtained via diversion activities.  Every opiate prescribed enters an ecosystem of illicit exchange – presumably under-recognized by physicians, else I would expect far fewer prescriptions.  Judicious – and sparing – use of opiates is far more likely to benefit society than harm.

“Sources of Prescription Opioid Pain Relievers by Frequency of Past-Year Nonmedical Use: United States, 2008-2011”
http://archinte.jamanetwork.com/article.aspx?articleid=1840031

Nonsensical Opiate Overuse in Adolescent Headache

The title says it all.

This is an observational cohort analysis of linked medical and pharmacy records for commercially insured patients across 14 health plans.  Patients were identified by age 13-17 with, allegedly, new-onset atraumatic headache from claims database abstraction – limited, of course, by the nature of querying such a database.  8,373 patients were identified from their two year study period as meeting these criteria.

And 46% were prescribed opiates.

52% of those received more than one prescription for opiates, including 11% who received 5 or more prescriptions for opiates during the study period.

This study came about because the insurer contacted the American Academy of Pediatrics with a query regarding the appropriate frequency of use of opiates for headache.  The answer ought to be a tiny fraction, as third-line or rescue therapy.

Considering all the problems this country has with prescription opiate abuse, it is maddening to see physicians inoculating such a vulnerable population with medication whose harms almost certainly outweigh the benefits.

“Opioid Use Among Adolescent Patients Treated for Headache”
http://www.jahonline.org/article/S1054-139X(13)00834-3/abstract

Gently Euthanizing the Elderly

It is well-known the elderly are at higher risk for medication adverse effects.  It is, likewise, recognized opiates are one of the most dangerous prescription medications in use.  Therefore, the prudent thing to do would be avoid opiate use in the elderly – and, certainly, not be irresponsible regarding multiple, concurrent prescriptions for opiates.

However, as this 20% random sample of Medicare beneficiaries demonstrates, an estimated 5.2M Americans covered by this insurance source received opiates – with approximately 85% of this cohort aged greater than 55.  Most patients who received opiates filled more than one prescription – including a full 7% who received >4 prescriptions, from >4 different providers.  This last group received a mean number 15 opiate prescriptions in a single calendar year.  Unsurprisingly, increased opiate prescriptions were associated with increased subsequent hospitalizations.  While there is no mortality data in this report, I don’t think it’s a stretch to speculate the illness-adjusted outcomes would be much poorer.

The use of opiates for pain control for acute and chronic illness is a necessary evil, particularly in the elderly.  This study, given its limitations, cannot precisely elucidate whether the opiates provided represented irresponsible prescribing – but it supports much of what we anecdotally observe regarding the fragmented healthcare process.  Whether the magnitude of the problem is as great as these authors seem to suggest, there should be no argument we have plenty of room for improvement in treating some of our most vulnerable patients.

“Opioid prescribing by multiple providers in Medicare: retrospective observational study of insurance claims”
http://www.bmj.com/content/348/bmj.g1393

Again on Giving tPA to TIAs

When I suggested to Jeff Saver in JAMA his analysis of the Get With the Guidelines Registry may have become unbalanced due to the presence of TIAs within the tPA cohort, he went back to the NINDS data and identified seven patients from the placebo arm with TIAs.  Because 3 were in the 58 to 90 minute cohort and 4 were in the 91 to 180 minute cohort, he concludes there is an equal distribution of TIAs – and thus confounders – across all time periods.  This, of course, is nonsense – he is generalizing a handful of patients from the placebo arm from NINDS, a carefully controlled trial run by stroke neurologists, to the GTWG-Stroke registry, a cohort of community hospitals rushing to hit time-based stroke quality measures.  The contemporary evidence, such as this observational series from Japan, is that most TIAs present early in their symptom course – and earlier, if symptoms are more severe.

These authors retrospectively identified 464 patients admitted to 13 stroke centers in Japan with ultimate diagnosis of TIA based on complete clinical resolution of symptoms.  233 of them (55%) presented within the first three hours and the next 65 (15%) within six hours.  The common elements for the TIAs presenting earliest were the greatest severity of symptoms, primarily motor and speech disturbances.  A full 42% of their cohort had persistent symptoms upon arrival.

In the brave new world of tPA, hospitals are falling over themselves to treat these patients with thrombolytics – patients that ultimately would experience full clinical resolution of symptoms without intervention, and receive only the risks associated with tPA administration.  These patients ultimately make their way into the GWTG-Stroke registry, and come out the back end analysis looking like tPA miracles, “proving” time-to-treatment matters with tPA.  As “code stroke” protocols become more widespread, we will see even further such collateral damage.

“Factors Associated With Onset-to-Door Time in Patients With Transient Ischemic Attack Admitted to Stroke Centers”
http://www.ncbi.nlm.nih.gov/pubmed/24262324

Droperidol Never Killed Anyone

The bearer of a black box and the scourge of Pharmaceutical and Therapeutics committees, droperidol has a long history – a history where, for the most part, it is used safely for decades.

This is a small case series from a prospective trial of treatment for acute agitation in the Emergency Department.  In this study, patients requiring treatment for agitation received 10mg of IM droperidol as an initial dose, followed by a second dose within 15 minutes as needed, and further doses of droperidol as needed and in consultation with a toxicologist.  An ECG was obtained, and continuous telemetry monitoring was applied as soon as safely possible.

42 patients qualified for droperidol in this study, 29 of whom received 10mg of droperidol, 11 received 20mg, 3 received 30mg, and 3 received 40mg.  Of these, 4 patients receiving 10mg or 20mg had prolonged QT observed on ECG – to a maximum of 534ms.  The authors write, then, in their conclusion: “QT prolongation was observed with high-dose droperidol.”

A more accurate conclusion, however, would probably be: “In a limited case series, no dose-dependent relationship between droperidol and QT prolongation was observed.  QT prolongation of uncertain clinical significance was noted in a small number, but confounding co-ingestants limit the reliability of this finding.”

There ought to be, at this point, little legitimate concern over the clinical significance of the QT prolonging effects of these medicines in nearly all clinical situations.  Thanks to Ariel Cohen for sending this in!

“High dose droperidol and QT prolongation: analysis of continuous 12-lead recordings”
http://www.ncbi.nlm.nih.gov/pubmed/24168079

My ACEP tPA Policy Critique

As some of you are aware, there is controversy regarding the use of tPA for acute ischemic stroke.  To this end, ACEP has opened up public comment for their recent relevant Clinical Policy Statement.

The comment form, however, is a bit of an odd and onerous format.  To spark discussion, to provide inspiration – and for public feedback/comment/correction – here are a few points from the initial draft of my response:
Page 225, Line 3, author list:
Area of Content / Concept – Conflict of Interest in Guideline Development Group (GDG)
The Institute of Medicine publishes recommendations regarding the composition and conflict of interest disclosures of a Clinical Practice Guideline (CPG) writing panel.  This tPA policy statement falls short on several accounts, most importantly:
Standard 2.1:  
The disclosures listed by the authors only narrowly address their direct financial relationships, but do not describe non-commercial, intellectual, and patient/public activities pertinent to the scope of the CPG.  For instance, authors do not fully describe their relationships with FERNE, a pharmaceutical-supported organization, nor other indirect and intellectual activities relevant to the CPG.
Standard 2.3:
The recommendation states members of the GDG should not participate in marketing activities or advisory board of entities whose interests are affected by the recommendations.  This standard does not appear to be met.
Standard 2.4:
Whenever possible, GDG members should not have COI.  If this is not possible, members with COIs should represent only a minority.  The chair, or co-chair, should not have COI.  This standard does not appear to have been met.
Standard 3.1:
The GDG should be multidisciplinary with methodological experts, clinicians, and patients.  The GDG members appear to be primarily clinicians and administrators, rather than patients and methodologic experts.
Standard 7:
The external review process is only briefly described, and the guideline was not open to public comment until this 60-day period.
Additional comments on the integrity of CPG come from a recent BMJ article, “Ensuring the integrity of clinical practice guidelines:  a tool for protecting patients.”  The recommendations from this publication are similar to the IOM recommendations, with the addition the GDG members ought to represent diverse viewpoints regarding the topic in question.  It does not appear this CPG represented any point of view other than a pro-tPA viewpoint.  The ACEP tPA clinical policy was evaluated using the “red flag” methodology by this article and found to be lacking.
Based on the COIs identified in this GDG, the output lacks face validity.
Page 227, Line 23:
Area of Content / Concept – Patient Management Recommendations
The guideline specifies offering IV tPA to acute ischemic stroke patients within 3 hours to be a Level A recommendation.  A Level A recommendation, according to the methodology of the CPG, states this indicates “Generally accepted principles for patient management that reflect a high degree of clinical certainty.”
The evidentiary table cites several articles as Class I evidence specifically relevant to the 3 hour timeframe (NINDS, ECASS II, and ATLANTIS B 0-3).  NINDS, by all accounts, shows benefit, while the effect size is debated by many based on the baseline characteristics of the treatment groups.  ECASS II is a negative trial; it is inappropriate to apply a subgroup analysis consisting of the 158 patients treated within 3 hours as the same level of Class I evidence.  The ATLANTIS B publication cited is also a very small subgroup analysis of a heavily modified trial stopped early for futility, and should not be considered the same level of Class I evidence.
Notably missing from this evidentiary table is ATLANTIS Part A – cited in the text, but apparently not considered as contributory to the CPG.  This is randomized, placebo-controlled evidence stopped early due to patient harms in the tPA cohort.  This merits inclusion in the evidentiary table as evidence of the harms of IV tPA.
The Lees meta-analysis, among others performed prior to 2010, is appropriately level II evidence.  However, it should be noted there are significant methodologic concerns associated with performing a meta-analysis that includes trials stopped early by their sponsors for futility or harms alongside trials allowed by their sponsors to run to their conclusion.  The evidentiary table notes “some of the analyzed studies were industry supported.”  To be more precise, all of the listed studies have substantial COI with industry – including employees of the sponsoring corporations listed among study authors – except NINDS, where the COI is minimized.
The remaining observational evidence is not relevant to a Level A recommendation.  The Hill and Wahlgren Phase IV studies are not placebo-controlled and only offer substantially limited, indirect, adjusted comparisons to a non-tPA treated population regarding safety and effectiveness.
My point, therefore, is NINDS is unique in support of tPA.  It is irresponsible to base a Level A treatment recommendation on a single positive study with a disputed effect size, whose results cannot be considered externally valid to current stroke practice.  NINDS – along with most evidence cited here – describes use in controlled trial environments of academic stroke centers supported by stroke neurologists.  There is insufficient evidence to support its general effectiveness, compared with standard treatment, in community Emergency Medicine.  Additionally, the observational evidence cited in the evidentiary table clearly describes a heterogenous acute stroke population, with varying levels of sICH risk, mortality risk, and capacity to benefit.  A CPG should not make a global recommendation for treating such a heterogenous disease without providing tools for physicians to communicate individualized risks and benefits.  Unfortunately, the placebo-controlled data are of insufficient quantity and quality to guide therapy.
A demonstration of the dangers of basing treatment decisions on small trials and small effect sizes is based in statistical theory.  Dr. Ioannidis demonstrates how “Most published research findings are false”, a hypothesis apparently borne out by “A decade of reversal:  an analysis of 146 contradicted medical practice.”
Furthermore, a Level A recommendation constitutes “generally accepted principles” with a “high degree of clinical certainty”.  If this were, indeed, the case, tPA for acute ischemic stroke would not be a controversial therapy 18 years past its introduction.  Respected U.S. Emergency Medicine experts in critical appraisal and knowledge translation, e.g., Jerome Hoffman, David Schriger, David Newman, Anand Swaminathan, and many others feel tPA for stroke remains an unproven and inadequately described therapy for acute ischemic stroke.  Indeed, Dr. Swaminathan ably debates Dr. Jagoda, one of the authors of this Clinical Policy in podcast, hosted by Scott Weingart.

Citation:  http://emcrit.org/podcasts/tpa-for-ischemic-stroke-debate/

Lest ACEP consider these objections simply a vocal minority or lunatic fringe, it should be noted active debate continues in the international literature as well.  Just last year, the BMJ posted a “Head to Head” debate regarding the proven efficacy of tPA in acute ischemic stroke.  An unscientific poll accompanying the article reported a slim majority of respondents did not feel tPA was proven effective.

Citation:  http://www.bmj.com/content/347/bmj.f5215

Additionally, there remains disagreement between international professional societies regarding the use of tPA in acute ischemic stroke.  While several countries endorse its use, others, such as Australia and New Zealand, remain concerned the strength of the evidence does not support widespread use.

Citations:
http://bit.ly/1nY6P18
http://bit.ly/1gRpYRs

In summary, the evidence does not support a Level A recommendation for tPA for ischemic stroke within 3 hours.

There is no reasonable justification for anything higher than a Level B recommendation – and even then, a caveat stating this has never been demonstrated as efficacious compared to usual therapy outside of controlled clinical trial environments.  Physicians may consider offering this therapy based on comfort, diagnostic certainty, supporting resources, and institutional commitment, but it should not be considered the standard of care.

Page 227, Line 28:
Area of Content / Concept – Patient Management Recommendations
The Level B recommendation given to IV tPA is inappropriate given the lack of unbiased evidence in support of treatment beyond the 3 hour time window.  This therapy is not approved in the U.S. and the Class I evidence regarding the 3-4.5 hour time window is conflicting.  ECASS, ECASS II, and ECASS III are manufacturer-sponsored studies of which only ECASS III demonstrated benefit.  ATLANTIS, also manufacturer-sponsored, enrolled patients similar to the NINDS criteria and showed harms beyond 5 hours, futility in the 3-5 hour window, and no usable insights in the 0-3 hour timeframe.  As Clark and Madden note, “Keep the three hour tPA window: the lost study of Atlantis” – ECASS III alone is not enough to refute prior evidence of either futility or harm.  There is a reason why the FDA still has not approved IV tPA beyond 3 hours.
ECASS III is also flawed regarding a baseline imbalance of prior stroke included in the placebo arm.  The absolute difference in percentage of patients with prior stroke is identical to the effect size offered by IV tPA.  Even more concerning regarding the internal validity of the findings, ECASS III offers this COI statement:
Supported by Boehringer Ingelheim.
Dr. Hacke reports receiving consulting, advisory board, and lecture fees from Paion, Forest Laboratories, Lundbeck, and Boehringer Ingelheim and grant support from Lundbeck; Dr. Brozman, receiving consulting and lecture fees from Sanofi- Aventis and consulting fees and grant support from Boehringer Ingelheim; Dr. Davalos, receiving consulting fees from Boeh- ringer Ingelheim, the Ferrer Group, Paion, and Lundbeck and lecture fees from Boehringer Ingelheim, Pfizer, Ferrer Group, Paion, and Bristol-Myers Squibb; Dr. Kaste, receiving consulting and lecture fees from Boehringer Ingelheim; Dr. Larrue, receiv- ing consulting fees from Pierre Fabre; Dr. Lees, receiving con- sulting fees from Boehringer Ingelheim, Paion, Forest, and Lund- beck, lecture fees from the Ferrer Group, and grant support from Boehringer Ingelheim; Dr. Schneider, receiving consulting fees from the Ferrer Group, D-Pharm, BrainsGate, and Stroke Treat- ment Academic Industry Round Table (STAIR) and lecture fees from Boehringer Ingelheim and Trommsdorff Arzneimittel; Dr. von Kummer, receiving consulting fees from Boehringer Ingel- heim and Paion and lecture fees from Boehringer Ingelheim and Bayer Schering Pharma; Dr. Wahlgren, receiving consulting fees from ThromboGenics, lecture fees from Ferrer and Boehringer Ingelheim, and grant support from Boehringer Ingelheim; Dr. Toni, receiving consulting fees from Boehringer Ingelheim and lecture fees from Boehringer Ingelheim, Sanofi-Aventis, and Novo Nordisk; and Drs. Bluhmki, Machnig, and Medeghri, being employees of Boehringer Ingelheim.
As I did not mention it previously, the meta-analysis by Lees also supplies this relevant COI statement:
KRL, RvK, DT, MK, and WH report honoraria from Boehringer Ingelheim for their roles in conduct of the ECASS trials. KRL reports honoraria from Lundbeck and Thrombogenics. DT reports honoraria from Novo-Nordisk, Pfizer, Sanofi-Aventis, and Boehringer Ingelheim. EB is an employee of Boehringer Ingelheim. RvK and JCG report being consultants to Lundbeck. GWA reports being a consultant to Lundbeck and Boehringer Ingelheim. SMD reports honoraria from Boehringer Ingelheim.
Confident translation in policy of clinical trial evidence having this level of COI is simply not reasonable.

Finally, it should also be noted the updated meta-analysis by Wardlaw accompanying the publication of IST-3 no longer shows a statistically significant benefit for alive and independent for the 3-6h time frame – moving from OR 1.17 (1.00 – 1.36) to OR 1.07 (0.96 – 1.20).  This ought to be viewed as regression to the mean as the sample size continues to increase.  Considering thrombolytic trials for myocardial infarction enrolled 140,000 patients, rather than the ~3500 tPA patients from the trials included in the Wardlaw meta-analysis, this should serve as a warning regarding the inadequacy of current evidence.

In summary, treatment beyond 3 hours can only be recommended based on “expert” (e.g., the sponsored mouthpieces of industry) opinion, should be considered only as part of prospective research, and absolutely not be recommended or implied to be standard of care.
Page 232, Line 28:
Area of Content / Concept – NINDS Exclusion Criteria
There is no mention of oral anticoagulation in these treatment recommendations, other than reference to the NINDS exclusion criteria regarding PTT and PT.
The safety of tPA given concomitant use of coumadin and the novel oral anticoagulants (direct thrombin inhibitors, factor Xa inhibitors) is not established.  Contradictory findings from meta-analyses and systematic reviews suggest increased risk of bleeding, even with INR <1.6.  Any CPG recommending offering IV tPA is remiss in excluding mention of these commonly prescribed medications in the population most at risk for stroke.
tPA cannot yet be considered safe when considered in the setting of anticoagulation, despite the NINDS inclusion criteria, in the absence of high-quality data on the subject.
Citations:

All NSAIDs are Created Equally . . . Right?

A guest post by Anand Swaminathan (@EMSwami) of EM Lyceum and Essentials of EM fame.

It’s been more than 10 years since Merck made headlines regarding the increased risk of atherothrombotic events with it’s drug rofecoxib (Vioxx) and 3 years since the almost $1 billion settlement regarding the drug. Over this time period, physicians have questioned the use of all non-steroidal anti-inflammatory drugs (NSAIDs) in patients with increased risk of coronary artery disease. Rofecoxib and its brethren were developed in the 1990’s as alternatives to the traditional NSAIDs (tNSAIDs). These newer drugs only inhibited COX-2 and theoretically would lead to less gastrointestinal bleeding since inhibition of COX-1 is believed to lead to this side effect. Based on this pathophysiologic theory and strong marketing, the drugs became widely prescribed. Unfortunately for our patients, saving the gut may compromise the heart. Or is it actually that all NSAIDs, regardless of which COX they inhibit, raises the risk?

This research group performed a meta-analysis of a large number of trials looking at both NSAIDs vs. placebo (280 trials) and one NSAID vs. another NSAID (474 trials). All of the studies look at length of use of at least four weeks but many had longer treatment durations. So, what did they find? When compared to placebo, coxibs (COX-2 inhibitors), diclofenac and ibuprofen all increased the risk of major coronary events but naproxen did not:
Coxibs RR (CI)
Diclofenac RR (CI)
Ibuprofen RR (CI)
Naproxen RR (CI)
Major Vascular Events
1.37 (1.14 – 1.66)
1.41 (1.12 – 1.78)
1.44 (0.89 – 2.33)
0.93 (0.69-1.27)
Major Coronary Events
1.76 (1.31-2.37)
1.70 1.19-2.41)
2.22 (1.10 – 4.48)
0.84 (0.52 – 1.35)
Gastrointestinal Complications
1.81 (1.17-2.81)
1.89 (1.16-3.09)
3.97 (2.22-7.10)
4.22 (2.71-6.56)

Additionally, it didn’t matter which coxib they looked at: all of them increased major coronary events. The coxibs did, however, do what they were supposed to do; the risk of gastrointestinal bleeding was lower in comparison to tNSAIDs like ibuprofen and naproxen.

Does this change what we should do? Can we give NSAIDs to older patients without fearing a major coronary event or death from an MI? The numbers here are small but important. For every 1000 patients allocated to a coxib, three more had major vascular events and one of these events would be fatal. That’s an absolute increase of 0.1% in comparison to placebo. Small increased risk but avoidable. Why not give naproxen instead? In fact, NSAIDs like ibuprofen interfere with the binding of aspirin negating its cardioprotective effects if the two are taken together. Naproxen doesn’t have this issue.
The relative safety in terms of major vascular events associated with naproxen versus ibuprofen was recently written about by the FDA and reported by the Associated Press here –

http://hosted.ap.org/dynamic/stories/U/US_PAIN_RELIEVERS_SAFETY?SITE=AP&SECTION=HOME&TEMPLATE=DEFAULT

I think the bottom line here isn’t much of a surprise. If you can, avoid NSAIDs in patients with cardiac risk factors. Ibuprofen isn’t a safe alternative. If you need to give an NSAID for whatever reason, use naproxen and use short courses of therapy.
“Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomized trials”