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:
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.
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.
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.
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.
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.
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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.
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.
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.
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.
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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.
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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.