Ryan Radecki

Stopping the Alteplase Indication Creep

Ever since the narrow approval and strict inclusion criteria of the first trials for alteplase in stroke, our benevolent corporate overlords have been doing their utmost to expand its indications – all while continuing to unilaterally boost its price. This includes sponsoring “expert” convocations to whittle down contraindications, as well as sponsoring, and then cancelling, trials destined to futility.

This is another example of the latter.

This is the remnants of PRISMS, a trial testing the alteplase versus aspirin in a randomized, placebo-controlled trial of mild stroke. In this trial, “mild stroke” included a NIHSS of ≤5 and the absence of any disabling deficits. That is to say, rather, every patient entered in this trial met, in theory, the primary outcome of an mRS of 0-1 at entry. The trial expected to find an advantage to treatment of 9% and incidence of sICH of 2%, a NNT of 11, NNH of 50, and a requirement of 948 patients for the statistical power to validate such findings.

The trial, however, was stopped after 313 patients due to “slow enrollment”. Of these, 32 were lost to follow-up, leaving 281 available for 90-day assessment without imputation. The bulk of patients ranged in NIHSS 1 to 3, with sensory symptoms, facial palsy, and dysarthria the most frequently represented stroke symptoms. Of those with 90-day follow-up, 83.1% of the aspirin arm achieved mRS 0-1, compared with 77.5% of those randomized to alteplase. Conversely, 3.4% of these mild strokes were ultimately mRS 4-6 – a typical definition of “poor outcome” – in the aspirin arm, compared with 10% of those randomized to alteplase. The 5 patients with sICH following alteplase administration contributed to these poor outcomes, compared with none following administration of aspirin.

So, very clearly, there is no evidence here to support a presumption of benefit from alteplase administration, but quite clearly evidence of harm. The authors – with hardly any conflict-of-interest to speak of – go to great lengths to assure us:

“The findings from the current trial cannot be extrapolated to all patients with lower stroke severity based on an NIHSS score of 0 to 5.”

Please continue, they say, treating this population despite the virtual absence of evidence. Even more comically, they also conclude this ought not be the last word in this patient population:

“… the very early study termination precludes any definitive conclusions, and additional research may be warranted.”

Although these authors go to great lengths to assure us there was no tomfoolery at work in the sponsor’s decision to terminate the trial, it strains credibility to suggest Genentech would be so willing to abandon potential profit relating to an expanded indication. Such decisions to cut their losses would hardly be warranted if an expectation of potential return were in store.

At the very least, this clearly shows not only diminishing returns, but likely harms relating to the use of alteplase in minor stroke. Given the sparse RCT data in this realm – NINDS, for example, included only 58 cases with a NIHSS below 5, and nearly 3,000 patients were actively excluded from other RCTs – these data still ought to move the needle of equipoise with regard to treating a spectrum of low NIHSS, but potentially disabling, deficits. It would be entirely defensible not to treat this population while awaiting robust trial evidence in support.

Also: 13% stroke mimics!

“Effect of Alteplase vs Aspirin on Functional Outcome for Patients With Acute Ischemic Stroke and Minor Nondisabling Neurologic Deficits”

https://jamanetwork.com/journals/jama/fullarticle/2687354

More Snapshots of Awful Antibiotic Use

Is there ever any good news these days? Geopolitical disasters, unwarranted pharmaceutical price increases – and physicians can’t even manage to get the evaluation for group A strep right.

This is a “successful” quality improvement paper wrapped around depressing and embarrassing data from a typical primary care pediatrics practice. These authors, primarily pediatric infectious disease specialists, were dismayed by the rate of guideline-non-compliant group A streptococcal testing and treatment in their group.

How bad?

The base rate of unnecessary GAS testing was 64% of all rapid strep tests performed. The base rate of inappropriate antibiotic prescribing – driven primarily by treating positive results in those who should never have been tested (e.g., likely non-pathogenic colonization) – was 49%.

After their multifaceted year-long intervention, they were able to achieve the amazing results of: 40% unnecessary testing … and the same, inappropriate 49% for antibiotic prescribing. When restricted to selection of antibiotic, at least, first-line antibiotics used 87% of the time.

Is this really the best we can possibly do, even after intent focus on practice improvement? And for a disease entitiy with such limited benefit for antibiotic in most modern settings?

“Improving Guideline-Based Streptococcal Pharyngitis Testing: A Quality Improvement Initiative”
http://pediatrics.aappublications.org/content/early/2018/06/18/peds.2017-2033

Again With the Failings of CTPA

Most of the unhinged ramblings on this blog involve lamenting the excessive sensitivity of CT pulmonary angiograms for the diagnosis of pulmonary embolism. “Excessively sensitive for PEs of uncertain clinical signifiance!” and “Too many false positives in an inappropriately selected population!” gloomily drones the author (We can’t all, and some of us don’t).

Now, again, come the baffling attacks from the right – the CTPA isn’t sensitive enough:

“The negative predictive value of CTPA for VTE varies according to pretest prevalence of PE, and is likely to be insufficient to safely rule out VTE as a stand-alone diagnostic test amongst patients at the highest pretest probability of VTE. Prospective studies are required to validate the appropriate diagnostic algorithm for this subgroup of patients.”

Foundational quibbles in the narrative induced by their meta-analysis:

Sure, maybe, in the cohort of studies before 2006 – but since then, the number of VTE “missed” by CTPA is less than 1%.
A VTE “missed” by CTPA includes lower extremity DVT concurrently diagnosed by duplex ultrasound. Whether a CTPA should be impugned for failing to include the legs is a separate debate regarding the adequacy of its Natural State of Being.
Again, a VTE “missed” by CTPA includes all VTE (including LE DVT) diagnosed in the three-month follow-up period, a timeframe certainly adequate for individuals at high-risk for VTE to develop thrombosis anew.
“High” clinical probability in this study refers to those patients with ≥40% pretest likelihood of disease, which is tremendously infrequently encountered in clinical practice.

Clearly, these authors are far from convincing me CTPA is guilty of relevant concerns for inadequate sensitivity in these modern times. One problem at a time, please; queue up, now.

“Outcomes following a negative computed tomography pulmonary angiography according to pulmonary embolism prevalence: a meta-analysis of the management outcome studies”
https://www.ncbi.nlm.nih.gov/pubmed/29645405

Another Failure for Tamsulosin

As has been described more than once on this blog, the evidence favoring use of tamsulosin for renal colic has been grossly overstated. The vast majority of the trial evidence collated by the Cochrane Review has been distorted by small trials and those biased by pharmaceutical manufacturers. Every time a reasonably-designed randomized-controlled trial has been performed, the magnitude of effect has been dramatically lower – or non-existent.

This, the STONE trial, included 512 patients with ureteral stones of fewer than 9mm in greatest diameter. Split into a single-center phase with patient-reported passage, and a multi-center phase with CT follow-up for passage, there were no clear advantages to tamsulosin. Of all the outcomes compared, both passage and surrogates for stone-related disability, there were no differences except one – in the CT follow-up phase, tamsulosin displayed a 6% absolute advantage in stone passage. Absent other correlated patient-oriented outcomes, it is reasonable to consider this as a chance finding – or, at least, of inadequate effect size to reliably affect clinical practice.

Considering these results generalize to the vast majority of symptomatic stones, if you’ve still been prescribing tamsulosin routinely, it is time for a rethink.

“Effect of Tamsulosin on Passage of Symptomatic Ureteral Stones”

https://www.ncbi.nlm.nih.gov/pubmed/29913020

Comparing Unnecessary ED Chest Pain Testing

Since my last post regarding the disutility of coronary CT angiograms for the evaluation of acute chest pain in the Emergency Department was so popular, here’s more: a randomized trial testing CCTA versus stress echocardiogram.

The problem: no specific functional or anatomic testing is routinely necessary in the ED.

And, hidden in this comparison are broad results typical of testing in a “low to intermediate” population with a Diamond-Forrester pre-test probability of 28% and a TIMI score of 0 to 1. Effectively, it’s unimportant to describe their comparison because the incidence of their safety outcomes over a median follow-up of 733 days is so low its virtually impossible to detect a difference. Any Major Adverse Cardiovascular Event occurred in only 4.5% of all patients – but, restricted to the endpoints relevant to the testing performed, only 3.0% had a nonfatal myocardial infarction or cardiac arrest. Any differences in throughput and resource utilization between arms will be related to specific process and protocol implementation unique to the trial institution, so even their findings with respect to their primary outcome are not likely to be generalizable.

But, back to the futility of any test – only 10% of those enrolled were referred for cardiac catheterization, and only half of those received an intervention as a result. Another 10% or so received new or increased pharmacotherapy – likely overlapping with the population undergoing catheterization. Therefore, probably 85% of patients enrolled clearly received no specific benefit from these tests, 5% probably had some benefit, 5% were harmed (excess revascularization, serious complications), and 5% are equivocal.

And, all of this on the foundational premise these tests need to be performed widely, and in the ED. True disease is rare in this population, and the timeliness of diagnosis of CAD does not need to be made at the index visit. This is not high-value medical care.

“Coronary Computed Tomography Angiography Versus Stress Echocardiography in Acute Chest Pain: A Randomized Controlled Trial”

https://www.ncbi.nlm.nih.gov/pubmed/29909113

Treating Influenza with Antibiotics & Other Stories

Every time I review an article espousing the benefits of a protocol based on the use of procalcitonin to improve antibiotic stewardship, I usually say something along the lines of: “We don’t need this test, it only looks like we need it because our baseline antibiotic prescribing is hysterically shameful.”

Well, here’s another piece of evidence describing the basis for that statement.

This is a secondary analysis of observational data collected from the Influenza Vaccine Effectiveness Network. All patients were eligible for inclusion in the study if they presented with an acute cough of duration fewer than 7 days. Patients all received influenza testing as part of disease surveillance, as well as any other testing indicated.

Of 14,987 patient visits analyzed, 6,136 (41%) were associated with an antibiotic prescription. Of these, 2,494 patients (52%) received diagnoses for “potentially indicated” antibiotics – pharyngitis, sinusitis, and otitis media – while 2,522 (41%) fell into a category of “antibiotics not indicated” – viral upper respiratory infection, bronchitis, allergy or asthma, clinical influenza, or “other”. So, as far as the coded diagnosis is reliable, it is likely half of prescribed antibiotics are simply unnecessary.

Then, of the 14,987 analyzed, 3,381 had laboratory-confirmed influenza. Excluding those receiving a diagnosis of pneumonia, there were 945 who received a prescription for antibiotics. Finally, there were an estimated 860 patients with a diagnosis of pharyngitis and a negative test for Group A Strep, 327 (38%) of whom received antibiotics.

And, let’s not even get into whether patients received an appropriate narrow-spectrum antibiotic (44%).

There are limitations to the precision and clinical context of using diagnosis codes to classify antibiotic prescribing as appropriate or not, but these results are broadly consistent with the prior literature. Before we start deferring our prescribing decisions to something like a PCT assay, there’s a huge opportunity to simply Do The Right Thing, first. Once the low-hanging fruit has been resolved, then we can worry about tweezing out the uncertain cases in a narrow cohort with potential limited application of PCT or other infectious disease differentiation engine.

“Outpatient Antibiotic Prescribing for Acute Respiratory Infections
During Influenza Seasons”
https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2683951

The Rate of Resuscitation in Pediatric DKA

A few children experience cognitive impairment and cerebral edema following the resuscitation phase of diabetic ketoacidosis. For many years, there has been suspicion the rapid volume replacement with isotonic crystalloids precipitated cerebral edema, leading to protocols requiring conservative rates of fluid administration.

Probably unnecessarily so.

This 2×2 randomized trial tested “fast” versus “slow” fluid resuscitation, as well as isotonic 0.9% saline versus 0.45% saline. “Fast” resuscitation repleted a 10% body weight fluid deficit with half of the fluid in the first 12 hours, while the “slow” resuscitation repleted a 5% fluid deficit at a steady rate over 48 hours. A little more than three hundred patients were included in each arm, with the primary outcome being a decline in mental status as measured by the Glasgow Coma Score. Persistent cognitive impairment, “clinically apparent brain injury”, and other adverse events were tracked as secondary outcomes.

Effectively, there is no discernable difference in outcomes between the four groups. Deterioration of mental status and clinically apparent brain injury were rare – occurring, essentially, around the expected 0.5-1.0% rate regardless of resuscitation speed or fluid selection. Serious adverse events were uncommon and similar across groups, without reliable signals of inferiority to any specific resuscitation strategy.

Whatever you’ve been doing these last few years, at least, hasn’t been “wrong”. Unfortunately, having failed to identify this as a preventable trigger for cerebral injury in DKA, the search for its cause must go on.

“Clinical Trial of Fluid Infusion Rates for Pediatric Diabetic Ketoacidosis”
https://www.nejm.org/doi/full/10.1056/NEJMoa1716816

Predicting Cellulitis Treatment Failure

To (mostly) no one’s surprise, in descending order:

Tachypnea at triage
Chronic skin ulcers
History of MRSA
Recurrent cellulitis
Chronic kidney disease
Diabetes mellitus

Adjusted ORs for failure topped out at ~6.3, and descend into statistical noise from there.

However, reliably unpacking and generalizing these data is far more challenging, considering the variety of permutations for treatment and treatment failure. Of the initial 500 consecutive non-purulent skin-and-soft-tissue infections enrolled, patients were managed with all manner of combinations of inpatient and outpatient oral and intravenous antibiotics (including 6 patients with both). Treatment failure in the 288 managed primarily as outpatient, as evaluated from 48 hours to 14 days after the initial ED visit, could result in a change of oral agent, change to outpatient intravenous antibiotics, or hospitalization. While the validity of the predictive features of treatment failure is probably not affected by the specifics of their clinical setting, the rate of failure of oral antibiotics – almost 30% – is likely unique to their population and practice pathway.

At least, in contrast to my last cellulitis article, only 3 patients were subsequently judged by an infectious disease specialist to have a misdiagnosis of cellulitis.

“Predictors of Oral Antibiotic Treatment Failure for Non-Purulent Skin and Soft Tissue Infections in the Emergency Department”
https://www.ncbi.nlm.nih.gov/pubmed/29869364

That Time Dermatology Saved the Day!

Thanks to the insightful teaching of Seinfeld, we know dermatology’s scope exceeds that of “Pimple Popper, MD“. However, when an article published reviewed the rate of misdiagnosis of cellulitis in the hospital, pegged the costs half a billion dollars per year, and suggested a dermatologist be involved in every case where the skin ain’t look right – I was skeptical.

This publication details the results of a trial in which patients admitted with a diagnosis of cellulitis were randomized to either consultation of with a dermatologist within 24-hour of admission or to routine medical care. And, by consultation with a dermatologist – actually just one dermatologist, the senior author on the paper. Over the five year-study period, this dermatologist screened 1,300 patients for potential inclusion, yielding 175 for randomization. The primary outcome, a little unclear from the clinicaltrials.gov registration, is either antibiotic usage or inpatient length-of-stay.

Regardless, the dermatology consultation appeared to improve medical care, although the magnitude of the benefit is more difficult to pin down. The dermatologist identified approximately an excess of one-quarter of the cases to be “pseudocellulitis” – venous stasis dermatitis, erythema migrans, contact dermatitis, or some such ilk – leading to changes in therapy based on misdiagnosis. Both length-of-stay and antibiotic-free days displayed modest absolute gains in those evaluated by dermatology. The author further tabulated her other recommendations for treatment, including wound care, steroid treatment, and additional testing, and suggests there are many peripheral benefits to specialist involvement.

This is all fairly reasonable at face validity, although it is nearly impossible to generalize this single-institution, single-dermatologist, low-enrollment study to general practice. Given the scarcity of dermatology specialists in many settings, it would take some substantial innovation to find a cost-effective and high-value protocol for utilization.

“Effect of Dermatology Consultation on Outcomes for Patients With Presumed Cellulitis”
https://jamanetwork.com/journals/jamadermatology/fullarticle/2672582

And Here’s Why CTCA Is Useless

In the Emergency Department, that is, at least.

A few years ago, there were several major studies evaluating the safety of a CT coronary angiogram-based study for the evaluation of chest pain in the Emergency Department. These studies consistently found the CTCA is sensitive for coronary artery plaque – and, thus, patients with troponin-negative chest pain syndromes and clear coronary arteries could be discharged from the ED.

The constant challenge, however, has been specificity – not only with respect to whether the CT can accurately detect stenoses, but the clinical relevance of the stenoses. Non-obstructive, moderate, and high-grade stenoses detected on CTCA all trigger further evaluation – either non-invasive or invasive, with subsequent interventions of uncertain clinical value.

This small propensity-matched study from a cohort of 25,251 patients undergoing CTCA picked out 234 pairs of patients, matching those who had an acute coronary syndrome during follow-up with those who did not. And, yes, those with ≥50% or ≥70% stenosis were more likely to suffer an ACS, but not my much. The vast majority – 62% – of those with an ACS in follow-up had non-obstructive coronary disease. Indeed, just over half of patients with an ACS even had their culprit lesion identified on the initial CTCA. The degree of stenosis was mildly predictive of future ACS, but plaque burden between those who suffered an event and those who did not was similar. The most predictive feature, however, was composition of non-obstructive plaque, including fibrofatty features and necrotic core.

This is why CTCA is unhelpful in the Emergency Department. It does, yes, accurately detect patients without coronary disease – but this target “low-risk” population already has such a low pretest likelihood of poor outcome the added value is nil. Then, the “true positives” from these studies – stenoses and interventions – are not equivalent to ACS prevented.

Friends don’t let friends do CTCA in the ED – it doesn’t add value or prevent adverse outcomes.

“Coronary Atherosclerotic Precursors of Acute Coronary Syndromes”
http://www.onlinejacc.org/content/71/22/2511