INTERACT2: ICH Half-Truths

There have been dueling schools of thought regarding atraumatic intracerebral hemorrhage: let the brain autoregulate its own blood supply and don’t artificially lower the blood pressure, or use intravenous agents to lower blood pressure because there’s evidence it decreases hematoma expansion.  However, until now, there’d been no evidence that decreased hematoma size correlated with meaningful patient-oriented outcomes.

So, what are they saying about INTERACT2, the open-label, randomized trial of intensive BP control (SBP <140 mmHg) versus guideline-concordant BP control (<180 mmHg)?

@medwireNews INTERACT2 contradicts “longstanding dogma”, supports intensive BP reduction in ICH #eurostroke2013 

@MedscapeNeuro INTERACT2: Intensive Blood Pressure Lowering Benefits ICH 

@IctusClnic #ESCLondon2013 Surely INTERACT2 will have a great impact in blood pressure management after intracranial hemorrhage.


The primary outcome was reduction in death or major disability (modified Rankin scale 3 to 6) at 90 days.  Unadjusted outcome was statistically negative, 52.0% to 55.6% (OR 0.87, 95% CI 0.75 to 1.01), but favoring intensive BP control.  Their secondary outcomes, which uses the conceptually messy tool of ordinal analysis, essentially magnified the effect of that 3.6% absolute difference in mRS outcomes and goes on to show that folks with less disability end up happier and more functional.

However, the baseline functional characteristics favored the intensive BP group, with median NIHSS score of 10 vs. 11.  68% of the cohort was from China – which has uncertain effects on external validity.  Over seven different intravenous antihypertensives – including the most popular agent, urapidil – were used for BP lowering, further muddling precise treatment guidance.  Most ICH was small volume hemorrhage, and BP treatment didn’t seem to have much different on hematoma expansion – so it’s hard to say why the intensive control group seemed to have a trend towards superiority.

And, finally, even though approximately half of the 1436 assigned to guideline-recommended treatment group had baseline systolic BP >180 mmHg, only 303 of them received an anti-hypertensive agent within 1 hour of study assignment.  It might be more appropriate to describe this study as “intensive” vs. “poorly guideline-concordant” BP control – would outcomes have been more favorable if more of the guideline-concordant group actually had their systolic BP lowered below 180 mmHg?

In any event, to call this a practice-changing paradigm is a only a half-truth.  It does appear safe, at least, to make a brisk and reasonable effort to lower BP in atraumatic, intracerebral hemorrhage.  Whether “intensive” control is needed with a nicardipine infusion, such as in the upcoming Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH) II trial, is still uncertain.

“Rapid Blood-Pressure Lowering in Patients with Acute Intracerebral Hemorrhage”

Misleading Claims for Coronary CTA

The authors of this article make several discrete claims regarding the utility of coronary CT angiography – simply stated right in the title of the article:  “Routine coronary computed tomographic angiography reduces unnecessary hospital admissions, length of stay, recidivism rates, and invasive coronary angiography in the Emergency Department triage of chest pain”.  And, essentially all the assertions made in this observational, retrospective review are suspect.

Reduces unnecessary hospital admissions:
The article in no fashion addresses “unnecessary” hospital admissions.  After all, of their selected cohort of patients, a tiny fraction – 9 of 1,788 – ruled-in for acute MI.  A total of 42 underwent revascularization, but this is a measure reflecting only the aggressiveness of their local cardiology groups.  It would seem the real problem regarding “unnecessary” admissions is an inability to select patients with appropriate clinical probability for further evaluation.

Reduces length of stay:
There is a less than 1 hour reduction in length of stay only for discharged ED patients.  A true accounting of the LOS and congestion of chest pain patients ought to include admitted patients who depart the ED for their hospital observation bed soon after their initial biomarker result – but that would probably make their overall result contrary to their chosen narrative.  The reduction in length of stay is also influenced by the authors exclusion of patients who had ED LOS less than 3 hours – as the authors simply decide no adequate evaluation of low-risk chest pain patients could be performed in that timeframe.

Reduces recidivism rates:
The reduction in recidivism rates may have reached statistical significance, but the absolute difference was only 20 patients, most of whom were discharged from the Emergency Department.

Reduces invasive coronary angiography:
There is a reduction in coronary angiography – mostly, from what I can tell, in that the handful of patients with multi-vessel disease detected on CCTA were referred to CABG, and the use of invasive coronary angiography was obviated.  The absolute difference was only 19 angiography episodes – an avoidance of a handful of $2000-$3000 procedures at the cost of nearly a thousand $700-$1200 CCTAs.

Finally, their abstract conclusion claims it reduces healthcare resource utilization:
The authors never explicitly define this endpoint – which is probably for the best, as I count 960 non-invasive and 8 invasive tests in their CCTA cohort versus 368 non-invasive and 27 invasive tests in their “standard evaluation” cohort.  The admission rate, however, is more than halved from 40% to 14%.  A reduction in resource utilization would be contrary to general consensus from trials of CCTA versus standard care.

Most disturbingly, this article reports “Disclosures: none”.  However, a simple internet search reveals multiple authors having prior relationships with Siemens and GE Healthcare.  Perhaps by some narrowest definition this isn’t untruthful, but it is certainly misleading.

“Routine coronary computed tomographic angiography reduces unnecessary hospital admissions, length of stay, recidivism rates, and invasive coronary angiography in the Emergency Department triage of chest pain”

The EM Lit of Note PE Decision Tree

A couple weeks back I posted regarding a study where even intermediate- and high-risk patients with suspected PE had negative CTA in the presence of low d-Dimers.  Based on that post, I’ve put together a rough decision tree encapsulating how I (currently) prefer to approach the diagnosis of pulmonary embolism:
Note that “Scan for PE” really means to be “offer patient scan for PE”, considering relevant diagnostic uncertainty and risks in a shared decision-making process.  “Other reason why d-Dimer would be elevated” takes into account clinical judgement regarding the uselessness of d-Dimer as an acute-phase reactant or inflammatory marker; many “sick” patients will have elevated d-Dimers, obviating its value as a one-way screen-out.  Also, this chart does not account for any medicolegal liability risks – a wonderful perk of practicing in Texas.
Follow-up:  Seth Trueger and John Greenwood pointed out on the original that there are some specific moderate- and high-risk cases that satisfy PERC criteria, and perhaps the risk-stratification step should occur before application of PERC, as is traditionally done.  Fair enough!  They also note the EMCrit flow-chart begins with an exhortation of “Did you really care about PE?” – which, I’d say, is approximated by my value judgement of “Bad miss?” after starting to consider PE.  Finally, Scott Weingart chimed in to suggest, for patients in whom you’re playing the minimal-harm game for unexciting pulmonary emboli, a bedside ultrasound to quickly check for an occult DVT that might cause them to come back with clinically significant pulmonary venous thrombosis.

The War on Blood Cultures

There are two problems with blood cultures.  The first question is with regard to the likelihood you’ll get a true positive result.  That question is covered by this JAMA Rational Clinical Examination.

The second question regards whether the true positive result is clinically meaningful.  This retrospective review of 639 cellulitis patients – 325 without medical comorbidities and 314 with – evaluated for changes in therapy as a result of positive cultures.  46 cultures returned positive – with half being judged due to contaminants.    Of the 23 true positives, 5 resulted in a change of antibiotic therapy – only 2 of which expanded the initial antibiotic choice to include coverage for a new pathogen.  Both changes in therapy occurred in the immunosuppressed group.

Yet another example of the incredibly low yield of an expensive test.  We’re clearly simply asking a question for which we already have the answer.

“Blood culture results do not affect treatment in complicated cellulitis”

More Endovascular Junk Science

So far, we’ve seen nothing but poor outcomes in endovascular cerebral reperfusion trials.  The MERCI devices were simply dysfunctional and lethal and, despite advances with newer devices, we’re still waiting for a decisive trial demonstrating clear benefit.  But, the money is out there for the taking if the science will support it – and thus, more “science”.

This is a study involving authors sponsored by Stryker who do a retrospective review of cases at two hospitals, comparing infarct volume and short-term outcomes of patients who underwent either endovascular intervention, conventional thrombolysis, or no treatment for their large-vessel acute ischemic stroke.  The accompanying editorial probably sums up their limitations best:
“Retrospective, nonrandomized nature of the study; the comparison between 2 hospitals in the same health care system in which endovascular interventions were performed in one and not the other, which may have resulted in some unintentional differences in overall care; the combining of data among patients who received intravenous thrombolysis with those who received no reperfusion therapy, which may have diluted treatment responses; … and the lack of long-term clinical outcomes that could be correlated with the imaging findings.”

So, they have a collection of patients for whom it is in no way appropriate to compare outcomes and generalize any sort of conclusions – and that’s precisely what they do.  And, specifically, after reporting full-cohort baseline characteristics, their conclusions are based on subgroups of that cohort – and using an imaging surrogate outcome measure!

I’d tell you these authors conclude patients with an NIHSS of 14 or higher may be the best candidates for endovascular reperfusion therapy – but then I’d be further perpetuating this “science”.  Again, what they claim may be true – but they’re overestimating the ability of their data to claim it.

“Comparison of Final Infarct Volumes in Patients Who Received Endovascular Therapy or Intravenous Thrombolysis for Acute Intracranial Large-Vessel Occlusions”

Autopulse Advertisement in Critical Care Medicine

We’ve all seen folks come in via EMS with mechanical devices performing automated chest compressions.  These probably do a lovely job of freeing up paramedics from performing uninterrupted CPR, but their relationship to outcomes has been typically uncertain.

This meta-analysis and systematic review, however, reports these devices are superior to manual chest compression – with an OR of 1.6 towards increased return of spontaneous circulation.  Considering the copious evidence towards improved outcomes by minimizing interruptions during CPR, this would be an important finding, and tailors nicely with the expected advantage of mechanical compression devices.

However, this COI statement covering each of the four authors might also be in some fashion related to the positive results reported here:
“Dr. Westfall has received modest research grant support from ZOLL Medical Corporation. Mr. Krantz has received significant research grant support from ZOLL Medical Corporation. Mr. Mullin has served as a consultant for ZOLL Medical Corporation. Dr. Kaufman is an employee of ZOLL Medical Corporation.”

Unsurprisingly, these authors also demonstrate one of the overlooked evils of meta-analyses – the obfuscation of source COIs.  This JAMA article from 2011 does a lovely job describing this critical problem, and, as expected, these conflicted authors ignore the pervasive sponsorship bias present in their selected review.  Additionally, half the articles are only conference abstracts, suffering from results and methods not subject to the same level of rigorous peer review.

It really ought to be rather embarrassing for the editors of this journal to be approving such a clearly flawed vehicle – essentially blatant advertising for their $15,000 medical device – for publication.  No better, Journal Watch Emergency Medicine gives this article a bland and un-insightful thumbs-up.

“Mechanical Versus Manual Chest Compressions in Out-of-Hospital Cardiac Arrest: A Meta-Analysis”‎

Negative CTs and Pediatric Abdominal Trauma

I am biased – I helped set the Pediatric Emergency Care Applied Research Network up back as a research assistant peon before medical school – so it always pleases me to report on PECARN’s newest outputs.

This is a preplanned sub-analysis of their massive observational pediatric blunt trauma study.  Their pediatric blunt trauma decision instrument, unfortunately, turned out to not be terribly useful.  This data on the outcomes of patients with negative abdominal CT scans, at least, ought to help us.

Of the 3,819 patients enrolled with normal abdominal CTs following blunt trauma, 6 went on to have clinically significant abdominal injuries requiring intervention.  They provide a lot of detail about the patient population, but their conclusion is pretty simple: don’t routinely admit these trauma patients for observation to try and catch that 0.02%.  If there’s no other indication for admission, they may be discharged with appropriate symptom return precautions.

“A Multicenter Study of the Risk of Intra-Abdominal Injury in Children After Normal Abdominal Computed Tomography Scan Results in the Emergency Department”

Simple SBI Prediction – Hopeless

It remains a noble endeavour to attempt to identify the risk of serious bacteria infections in children.  That said, many have tried, and many have failed.

These authors from the Netherlands and the United Kingdom try, yet again.  They note the best performing decision instrument incorporates 26 variables – which they feel is unworkably unwieldy in a clinical setting – and attempt to derive their own, tighter instrument.  Unfortunately, the clinical variables that shake out of their prediction methodology all have odds ratios less than 6 – leading to a prediction model that can be calibrated only either for horrible sensitivity or horrible specificity.  The sensitive model will lead to over-testing of an otherwise well population, and the specific model will essentially pick up only the cases that were clinically obvious.

It’s becoming pretty clear over the years that attempting to reduce the number of discrete clinical variables in the febrile SBI decision-instrument is a dead-end strategy.  Complex clinical problems simply defy dimension reduction.  Furthermore, the true test of a decision instrument also ought not just be statistical evaluation in a vacuum, but comparison with clinical judgement.

“Clinical prediction model to aid emergency doctors managing febrile children at risk of serious bacterial infections: diagnostic study”

Fewer CTs, More Ultrasounds in Children

It’s pretty clear that children shouldn’t be receiving CT scans, whenever possible.  Despite this, the rate of CT for the diagnosis of pediatric appendicitis continues to rise.

This is a retrospective review from the Medical University of South Carolina that describes their implementation of an imaging protocol designed to encourage ultrasound use.  They report before-and-after statistics for their protocol – and, unsurprisingly, they’re pro-ultrasound.

Their protocol is generally simple – if it’s clinical appendicitis, consult surgery.  If it’s uncertain, do ultrasound first – if ultrasound equivocal, do CT.  If the patient appears unwell, skip ultrasound and do CT to evaluate for perforation.  Their institution started out with 82% of patients undergoing appendectomy having received CT, with this percentage dropping to 20% following implementation of the protocol.  Their negative appendectomy rate was stable at 5% after implementation, as well.  They also note the cost of a pediatric CT is $6500 compared with ultrasound at $1100.

The main disadvantage of their protocol was the low sensitivity exhibited by ultrasound – 61% – and the length of stay resulting from patients who required both ultrasound and CT – nearly 8 hours.  Considering ultrasound sensitivity depends on the experience of the operator, efforts to implement this strategy might benefit from upgrading local ultrasound capabilities.

“Clinical Practice Guidelines for Pediatric Appendicitis Evaluation Can Decrease Computed Tomography Utilization While Maintaining Diagnostic Accuracy”‎

Prophylactic Platelet Transfusions Needed?

Every so often, we’re referred a patient from the hematology clinic for prophylactic platelet transfusion when their infusion center is full.  As these authors state, it is common practice to routinely prophylactically transfuse platelets in the presence of severe thrombocytopenia.

And, the abstract conclusion here is:  “The results of our study support the need for the continued use of prophylaxis with platelet transfusion and show the benefit of such prophylaxis for reducing bleeding, as compared with no prophylaxis.”

This conclusion is the dubious interpretation of a combined endpoint of uncertain clinical significance.  Their primary endpoint was the summation of WHO 2, 3 and 4 bleeding.  Nearly all their bleeding was WHO 2 – essentially, troublesome, but self-limited bleeding not requiring transfusion.  With regards to major bleeding, the per-protocol rates were 5/258 in the no-prophylaxis group and 1/230 in the prophylaxis group – falling short of statistical significance, but reasonably clinically significant.

There was a 0.2 unit PRBCs per patient difference in transfusion between the prophylaxis group and the no prophylaxis group.  There was, obviously, a 1.3 unit platelets per patient difference between groups.  Hospitalization days were similar.  No patient died from bleeding.  One patient in the prophylaxis group suffered a transfusion-related anaphylactic event.

So, yes – platelet transfusions reduce bleeding.  I’m just not certain these authors have demonstrated the net benefit – given 66 patients receiving prophylactic transfusions, 1 fewer non-fatal important bleeding event.  Clinically insignificant net PRBC difference, significantly higher usage of platelet transfusions.  I think there is plenty of room to debate cost and benefit – particularly considering interesting hypothesis-generating subgroup variation.

The authors declared multiple conflicts-of-interest, although it’s not clear to me if any of them would be relevant to the current study.

“A No-Prophylaxis Platelet-Transfusion Strategy for Hematologic Cancers”