Ryan Radecki

FDA: The Black Knight

… specifically, the Black Knight from Monty Python, apparently reduced to nibbling impotently at the feet of pharmaceutical corporations as they sail through the approval process.

This study in JAMA reviews the characteristics of novel therapeutics approved by the FDA between 2005 and 2012. These authors identified 188 novel agents approved for 206 indications, and describe an entire host of fascinating data regarding the trials supporting approval. A few of the most damning pearls:

37% of indications were approved on the basis of a single trial.
The median number of patients per trial was 760.
49% of trials used only surrogate outcomes.
Surrogate outcome trials constitute sole basis of approval for 91 indications.
Only 48% of cancer trials were randomized, and only 27% were double-blinded.
40 trials were part of accelerated approval, 39 of which used surrogate outcomes, with a median number of patients of 157.

The data go on and on.

Considering many landmark trials could not be independently reproduced, even with the help of the original researchers; most published research findings are false; and half of what you know is wrong – we might as well just dump poison in our water supply. It’s cheaper than suffering the next blockbuster drug for which pharmaceutical companies engineer an indication through distorted trial design.

“Clinical Trial Evidence Supporting FDA Approval of Novel Therapeutic Agents, 2005-2012“
http://jama.jamanetwork.com/article.aspx?articleid=1817794 (open access)

“Author Insights: Quality of Evidence Supporting FDA Approval Varies”
http://newsatjama.jama.com/2014/01/21/author-insights-quality-of-evidence-supporting-fda-approval-varies/

The Great Sugar Wars of Pediatric Critical Care

A guest post by Rory Spiegel (@CaptainBasilEM) who blogs on nihilism and the art of doing nothing at emnerd.com.

Kids are just small adults, or so says the Control of Hyperglycemia in Pediatric Intesive Care (ChiPS) trial. This impressively large RCT of 1369 pediatric ICU patients (under 16 years old) requiring at least 12 hours of vasoactive support and mechanical ventilation, examined how controlling blood glucose levels affects outcomes. Subjects were randomized to either tight glucose control (72-126mg/dL) or conventional control (less than 216 mg/dL). Patients were followed for 30 days to see if mortality and rates of ventilator dependence differed between the two groups.

Simply put the trial was negative. Though the tight glucose control group received more insulin and had lower mean daily blood glucose levels during the first 10 days after randomization, there was no statistical difference between days alive and off the ventilator between the two groups. Patients in the tight glycemic control group were less likely to receive renal replacement therapy (an odds ratio of 0.64 CI 0.45-0.89), but conversely were far more likely to suffer an episode of severe hypoglycemia (below 36mg/dL) with an absolute difference of 4.8%.

Unfortunately thanks to the authors’ spectacular display of subgroup analysis there is nothing simple about this publication. 60% of the population was admitted to the ICU after cardiac surgery. The remaining 40% were there for other reasons, though further details were not specified. A multitude of endpoints in both the cardiac and non-cardiac subgroups were examined. As with the entire cohort, there was no difference in mortality or ventilator-free days in either subgroup. The authors did observe a decrease in length of stay and mean healthcare costs in the subgroup of patients who did not undergo cardiac surgery and were treated using the tight glycemic parameters.

Though the authors conclude that these findings are at best hypothesis building and should not be used to guide therapy, this subgroup analysis will inevitably be misinterpreted, suggesting that pediatric ICU patients who have not undergone cardiac surgery will benefit from a strict glycemic regimen. This is clearly not the case. What this trial amounts to is a negative study with both negative primary and secondary endpoints that upon subgroup analysis uncovered statistical differences equally likely to be caused by chance as by the aggressive glucose management.

This trial is a reminder of our continued insistence of applying disease-oriented outcomes with questionable efficacy over the long term to an acutely ill population. The NICE-SUGAR trial established that tight glucose control was detrimental in an acutely ill adult population, the ChiP trial has demonstrated these lessons can now be applied to our smaller counterparts.

“A Randomized Trial of Hyperglycemic Control in Pediatric Intensive Care” www.ncbi.nlm.nih.gov/pubmed/24401049

Dantrolene: Saving Canadian Pigs in Ventricular Fibrillation

Just a quick highlight of interesting translational research, this time aimed at improving survival post-ventricular fibrillation.

These authors hypothesized that, as VF is associated with impaired intracellular calcium cycling, perhaps blockade of an intracellular pathway may reduce refractoriness to defibrillation. The agent? Dantrolene – which acts upon the ryanodine receptor of the sarcoplasmic reticulum.

Twenty-six Yorkshire pigs had VF induced, subsequently received dantrolene or normal saline, and finally CPR and defibrillation. 85% of dantrolene-treated pigs were successfully defibrillated compared with 39% of controls, and all dantrolene-treated pigs remained in organized rhythm. An ex vivo rabbit-heart model also showed similar physiologic effects.

Perhaps dantrolene has a future as a component of ACLS protocols – only time, and further study, will tell.

“Dantrolene Improves Survival Following Ventricular Fibrillation by Mitigating Impaired Calcium Handling in Animal Models”
http://circ.ahajournals.org/content/early/2014/01/07/CIRCULATIONAHA.113.005443.abstract

More Bleeding Nightmares

Do you like managing bleeding on aspirin? How about aspirin plus clopidogrel? What would you say to aspirin + clopidogrel + vorapaxar?

Vorapaxar, a selective antagonist for protease-activated receptor 1, is the next proposed layer of anti-thrombotic prevention for high-risk cardiovascular patients. Just this week, back from the dead, it received a favorable review from an FDA panel tasked with examining its application for approval.

The subject of both TRACER and TRA 2°P-TIMI 50, vorapaxar may soon bless your Emergency Department with a roughly 60% increase (2% vs. 3.5%) the risk of GUSTO moderate or severe bleeding. What’s most fascinating about this drug is, technically, both trials were negative for the primary endpoint, and TRACER was stopped early after interim safety review. However, a pre-specified and pre-allocated subgroup from TRA 2°P-TIMI 50 for patients with recent MI – and no history of stroke – showed benefit.

Of course, as is standard for these sorts of cardiovascular trials, it showed benefit primarily in the questionable combined endpoints – and, likewise, was only safe in the narrowest slicing and dicing of favorable endpoints and bleeding outcomes.

It should be of no surprise to anyone most authors are being substantially enriched by multiple drug companies. I’m certain whatever foot-in-the-door Merck receives will be enough to extract the necessary healthcare dollars from the system for minimal benefit – a net NNT for mortality of ~450.

Oh, and as the great Tom Deloughery (@bloodman) writes:

“Hmmm – a competitive platelet inhibitor with a T1/2 of ~300hrs! So, sounds like it will inhibit any platelets you give for the next 12 days … I guess Dr. Radecki will be holding direct pressure for a long time!”

“Vorapaxar for secondary prevention of thrombotic events for patients with previous myocardial infarction: a prespecified subgroup analysis of the TRA 2°P-TIMI 50 trial”
http://www.ncbi.nlm.nih.gov/pubmed/22932716

Maddening Lack of Perspective in Endovascular Stroke Therapy

Despite three negative trials in the New England Journal of Medicine last year, accompanied by an editorial calling for a moratorium on reimbursement for endovascular therapy for acute stroke, proponents of this therapy forge ahead. The negative trials, at the very least, have encouraged researchers to recognize – where tPA advocates fail to see – that patient selection is key, and not all candidates eligible for endovascular therapy are likely to benefit.

However, these authors, despite their well-intentioned effort to better target endovascular interventions, completely miss the mark. This is a retrospective review of patients undergoing endovascular therapy between 2008 and 2012, stratified by selection protocols. In 2010, the institution switched from an “all-comers” strategy to an MRI diffusion-weighted imaging-guided protocol. The hypothesis: patients selected for endovascular therapy on the basis MRI-guided infarct characteristics would display better outcomes than the “all-comers” selection cohort.

And, their registry provides them the necessary substrate. Between 2008 and 2010, 85 patients with median NIHSS 17 underwent endovascular therapy with dismal outcomes: 9.5% mRS 0-2 at 30 days and 47.6% mortality. After implementation of the imaging-based protocol, only half of eligible patients qualified – and of the 92 patients with median NIHSS 15.5 who eventually underwent endovascular therapy under the new protocol, 23.9% had mRS 0-2 and mortality dropped to 19.7%. Victory! So say these authors.

However, there’s another cohort visible only by its absence in their tabular data – the post-protocol group that did not undergo endovascular therapy. These 87 patients, with a median NIHSS ~16.5, had imaging characteristics thought by these authors to not qualify for endovascular therapy. For this group, 23.1% had mRS 0-2 and 30% mortality. These outcomes are not statistically different from the endovascular group.

The authors do not in any manner address this inconsistency in their data set – and the seemingly favorable intervention of lack-of-intervention. Rather than the authors’ conclusion imaging could guide therapy – the better conclusion is that endovascular therapy was frighteningly harmful to many in the pre-protocol phase, and simply reducing the number of patients undergoing unnecessary intervention improved global outcomes. And, for just added perspective: the placebo group in NINDS, with median NIHSS 15, had 26% mRS 0-1 and 21% mortality at 3 months – and this is before the modern post-stroke care that does more to improve outcomes than tPA could ever claim.

The madness continues.

“Addition of Hyperacute MRI Aids in Patient Selection, Decreasing the Use of Endovascular Stroke Therapy”
http://stroke.ahajournals.org/content/early/2014/01/09/STROKEAHA.113.003880.short

The “Padding” on Obese Patients is not Protective in Blunt Trauma

Everyone has an anecdotal tale of a morbidly obese patient who suffered penetrating injury that transversed only adipose tissue, leaving the small person living beneath unharmed. However, these isolated incidents do not appear to apply to blunt trauma.

This study is a retrospective analysis of the National Trauma Data Bank, evaluating 32,780 morbidly obese (BMI >40) and non-obese patients matched 1:1 on age, sex, ISS, GCS, and blood pressure on arrival. Baseline characteristics – as much as could be gleaned retrospectively – showed no substantial imbalance between the two cohorts. And, by nearly every measure, patients with morbid obesity suffered poorer outcomes. ARDS, decubitus ulcers, infectious complications, and thromboembolic complications were all significantly more frequent in this population. These carried forward with increased hospital LOS and increased mortality – 3% vs. 2.2%

Unsurprising, and yet another manner in which obesity shortens lifespan and degrades quality of life.

“Morbid obesity predisposes trauma patients to worse outcomes: A National Trauma Data Bank analysis”
http://www.ncbi.nlm.nih.gov/pubmed/24368375

Shared Decision-Making to Reduce Overtesting

Medicine, like life, is full of uncertainty. Every action or inaction has costs and consequences, both anticipated and unintended. Permeating through medical culture for many reasons, with the proliferation of tests available, has been a decreased tolerance for this uncertainty and the rise of “zero-miss” medicine. However, there are some tests that carry with them enough cost and risk, the population harms of the test outweigh the harms of the missed diagnoses. CTPA for pulmonary embolism is one of those tests.

In this study, these authors attempt to reduce testing for pulmonary embolism by creating a shared decision-making framework to discuss the necessity of testing with patients. They prospectively enrolled 203 patients presenting to the Emergency Department with dyspnea and, independent of their actual medical evaluation, attempted to ascertain their hypothetical actions were they to be evaluated for PE. Specifically, they were interested in the “low clinical probability” population whose d-Dimer was elevated above the abnormal threshold – but still below twice-normal the threshold. For these “borderline” abnormal d-Dimers, the authors created a visual decision tool describing their estimate of the benefit and risk of undergoing CTPA given this specific clinical scenario.

After viewing the benefits and risks of CTPA, 36% of patients in this study stated they would hypothetically decline testing for PE. Most of the patients (85%) who planned to follow-through with the CTPA did so because they were concerned regarding a possible missed diagnosis of PE, while the remaining hoped the CT would at least also provide additional information regarding their actual diagnosis. The authors conclude, based on a base case of 2.6 million possible PE evaluations annually, this strategy might save 100,000 CTPAs.

I think the approach these authors promote is generally on the right track. The challenge, however, is the data used to discuss risks with patients. From their information graphics, the risks of CTPA – cancer, IV contrast reaction, kidney injury and false positives – are all fair to include, but can be argued greatly regarding their clinical relevance. Is a transient 25% increase in serum creatinine in a young, healthy person clinically significant? Is it the same as a cancer diagnosis? Is it enough to mention there are false-positives from the CTPA without mentioning the risk of having a severe bleeding event from anticoagulation? Then, in their risk of not having the CTPA information graphic, they devote the bulk of that risk to a 15% chance of the CT identifying a diagnosis that would have otherwise been missed. I think that significantly overstates the number of additional, clinically important findings requiring urgent treatment that might be identified. Finally, the risks presented are for the “average” patient – and may be entirely inaccurate across the heterogenous population presenting for dyspnea.

But, any quibbles over the information graphic, limitations, and magnitude of effect are outweighed by the importance of advancing this approach in our practice. Paternalism is dead, and new tools for communicating with patients will be critical to the future of medicine.

“Patient preferences for testing for pulmonary embolism in the ED using a shared decision-making model”
http://www.ncbi.nlm.nih.gov/pubmed/24370071

An Abbreviated IV Acetylcysteine Regime for Acute APAP Toxicity. Short, Sweet, and…. Safe?

A guest post by Rory Spiegel (@CaptainBasilEM) who blogs on nihilism and the art of doing nothing at emnerd.com.

Anyone who has perused the literature on APAP toxicity will notice the protocols we use to guide us in the diagnosis and treatment of acute APAP overdose are based primarily on ultra-conservative estimates of risk rather than true clinical data. As a result we are left with acetylcysteine (NAC) treatment regimes that, though effective are cumbersome and convoluted. The current IV NAC regime consists of 3 different weight-based doses over various time periods within the first 25 hours. This regime is costly and frequently causes vomiting and anaphylactoid reactions. In a move towards practicality, authors from the Royal Infirmary of Edinburgh (the birthplace of the Rumack-Matthew Nomogram) performed a RCT comparing this traditional dosing scheme to a far more rational one.

These authors propose the initial bolus dose of NAC to be infused over a longer period (2 hours vs 15 min) followed by a maintenance infusion delivered over 12 hours in contrast to the traditional 24. They theorized that these modifications would reduce the amount of adverse reactions, primarily due to the initial rate at which NAC is infused and at the same time, limit the duration of treatment required. In a 2X2 factorial design, the authors also examined the effects of ondansetron on the rates of adverse reactions in both the traditional and modified NAC regimes.

From September 2010 to December 2012, 222 patients underwent randomization at three different UK hospitals. The authors found that both the modified dosing regiment and ondansetron prophylaxis decreased the rate of vomiting and retching in patients undergoing treatment for acute APAP intoxication. More impressively the modified dose regime seemed to dramatically reduce the incidence of serious anaphylactoid reactions from a frighteningly high 31% to 5%.

As far as safety is concerned there was no difference between the traditional and modified dosing regimes in the number of patients with an elevation in AST levels or microRNA miR-122 harpega(a more sensitive marker of hepatic injury as per the authors’ claims). There was an interesting increase in both AST levels and microRNA miR-122 levels in those given ondansetron when compared to placebo. Though this did not translate into any long term hepatic injuries and it is unclear if this increase was just noise secondary to the small sample size, the authors warn against its prophylactic use before further studies are performed to assess its safety.

Given that the Rumack-Mathews Nomogram was designed to be highly sensitive at the cost of its specificity, and very few patients above treatment threshold go on to clinically relevant hepatic toxicity, it is hard to say how many of these patients actually benefited from treatment. In addition 30% of this population were under the 4 hr 200mg/L level and were only treated because of the recent changes in the UK guidelines to lower the treatment threshold to 100mg/L. Due to the poor specificity and small sample size, it is difficult to truly assess the safety of this refined protocol. Using surrogate endpoints thought to be more sensitive for hepatic injury like a 50% rise in AST (in contrast to the more traditional measurement of AST > 1000 IU) and microRNA miR-122, may provide us with some idea of efficacy, but does not answer the more pressing question. Are the patients treated with this modified regime at a higher risk for clinically relevant hepatic injury? This would require a much larger study population.

“Reduction of adverse effects from intravenous acetylcysteine treatment for paracetamol poisoning: a randomised controlled trial”
www.ncbi.nlm.nih.gov/pubmed/24290406

The Optimal Blood Pressure After OHCA Is …

… normal.

This article is a lot of science for not a lot of insight. These authors gathered 3,620 out-of-hospital cardiac arrest patients who were transported to the Emergency Department after return of spontaneous circulation. Patients that arrived to the Emergency Department with ROSC and a normal blood pressure had the best survival, with a linear decrease in survival for patients arriving with SBP below 90 mmHg.

However, the authors take this finding to the next step and conclude patients might benefit from more aggressive post-resuscitation blood pressure management. Yes – any subgroup association identified on retrospective data dredging may reveal a true finding – but, rather than implicitly hype the positive result, it would be more appropriate to significantly downplay the finding as of uncertain significance and only hypothesis generating for future study. After all, chances are – sick patients are sick, and those that persist in hypotension after OHCA are declaring themselves as such. Prehospital blood pressure management does not address the underlying pathophysiology of the arrest and, given what we know about coronary and cerebral vasoconstriction, is more likely to be deleterious than beneficial.

“The association between systolic blood pressure on arrival at hospital and outcome in adults surviving from out-of-hospital cardiac arrests of presumed cardiac aetiology.”
http://www.ncbi.nlm.nih.gov/pubmed/24333351

Stop Using the Antibiotic Sledgehammer

There’s an interesting cultural phenomenon regarding inpatient treatment of respiratory illnesses – a sense that monitoring and close evaluation for treatment failure isn’t enough, and we must immediately deploy the nuclear option when the admission decision is made. This includes nonsense use of intravenous administration when oral is equivalent and unnecessary use of broad-spectrum agents.

This comparative-effectiveness study evaluated the necessity of broad-spectrum agents versus narrow-spectrum antibiotics for the treatment of pediatric community-acquired pneumonia. 492 CAP admissions from four children’s hospitals in 2010 were retrospectively reviewed for outcomes, stratified by antibiotic choice. Narrow-spectrum antibiotic choices were penicillin-like agents +/- macrolide, while broad-spectrum included cephalosporins or fluoroquinolones.

In their propensity-matched cohort, with the acknowledged limitations of unmeasured baseline characteristics, there were no useful differences in outcomes. Most trends favored narrow-spectrum antibiotics, but these are at best statistical noise, and at worst reflect underlying unmatched treatment-episode confounders.

Current consensus-based recommendations are for initial treatment with narrow-spectrum agents – follow them. I’d also note 51% of the population received blood cultures – 2.8% of which were positive. I’m sure these were also entirely a waste of money.

“Comparative Effectiveness of Empiric Antibiotics for Community-Acquired Pneumonia”
http://www.ncbi.nlm.nih.gov/pubmed/24324001