You Can’t Spell “Insanity” Without tPA

When you think you’ve seen it all – a call to administer tPA to acute stroke patients without a prior non-contrast CT.

Indeed, in this “Views & Reviews” article, the authors ask explicitly the question: “Is the administration of alteplase to patients with primary ICH that harmful?”  After much stimulating confabulation, the authors bafflingly conclude: “we cannot argue with confidence that alteplase administration to patients with ICH is harmful”.

Perhaps they’ve never treated patients with alteplase personally, and they further mis-cite or misinterpret the evidence regarding the influence of cerebral microbleeds on symptomatic intracranial hemorrhage.  Despite the clear evidence from multiple meta-analyses that cerebral microbleed burden prior to alteplase administration leads to substantially increased risk of ICH and neurologic worsening, these authors sum up this evidence as “either no increased risk of symptomatic ICH or an increased risk that does not necessarily preclude an overall benefit from alteplase.”


Even better, the entire purpose of their intellectual exercise boils down to discarding the inconvenience of pre-lytic CT so that alteplase can be delivered pre-hospital.  Yes, rather than clinically correlating the presentation with maximal vascular and perfusion information to consider the safest, most potentially effective (if any) reperfusion therapy – these authors are promoting administration of a $6000 medication in a pre-hospital setting with a paucity of diagnostic expertise or technology available.

Good plan.

“And why not thrombolysis in the ambulance (at least for some)?”

Excitement and Ennui in the ED

It goes without saying some patient encounters are more energizing and rewarding than others.  As a corollary, some chief complaints similarly suck the joy out of the shift even before beginning the patient encounter.

This entertaining study simply looks for any particular time differential relating to physician self-assignment on the electronic trackboard between presenting chief complaints.  The general gist of this study would be that time-to-assignment reflects a surrogate of a composite of prioritization and/or desirability.

These authors looked at 30,382 presentations unrelated to trauma activations, and there were clear winners and losers.  This figure of the shortest and longest 10 complaints is a fairly concise summary of findings:

Despite consistently longer self-assignment times for certain complaints, the absolute difference in minutes is still quite small.  Furthermore, there are always issues with relying on these time stamps, particularly for higher-acuity patients; the priority of “being at the patient’s bedside” always trumps such housekeeping measures.  I highly doubt ankle sprains and finger injuries are truly seen more quickly than overdoses and stroke symptoms.

Vaginal bleeding, on the other hand … is deservedly pulling up the rear.

“Cherry Picking Patients: Examining the Interval Between Patient Rooming and Resident Self-assignment”

High Blood Pressure is Not a Crime

And you don’t need to be sent to “time out” – i.e., referred to the Emergency Department – solely because of it.

This is a retrospective, single-center report regarding the incidence of adverse events in patients found to have “hypertensive urgency” in the outpatient setting.  This was defined formally as any systolic blood pressure measurement ≥180 mmHg or diastolic measurement ≥110 mmHg.  Their question of interest was, specifically, whether patients referred to the ED received clinically-important diagnosis ("major adverse cardiovascular events"), with a secondary interest in whether their blood pressure was under better control at future outpatient visits.

Over their five-year study period, there were 59,535 patient encounters meeting their criteria for “hypertensive urgency”.  Astoundingly, only 426 were referred to the Emergency Department.  Of those referred to the ED, 2 (0.5%) received a MACE diagnosis within 7 days, compared with 61 (0.1%) of the remaining 58,109.  By 6 months, MACE had equalized between the two populations – now 4 (0.9%) in the ED referral cohort compared with 492 (0.8%) in those sent home.  Hospital admission, obviously, was higher in those referred to the ED, but apparently conferred a small difference in blood pressure control in follow-up.

The authors go on to perform a propensity-matched comparison of the ED referrals to the sent home cohort, but this is largely uninsightful.  The more interesting observation is simply that these patients largely do quite well – and any adverse events probably happen at actuarial levels rather than having any specific relationship to the index event.

I appreciate how few patients were ultimately referred to the Emergency Department in this study; fewer than 1% is an inoffensive number.  That said, zero percent would be better.

“Characteristics and Outcomes of Patients Presenting With Hypertensive Urgency in the Office Setting”

Futility, Thy Name is ATTACH-2

Intracranial hemorrhage tends to have a poor prognosis – the cascade of inflammation, vasospasm, and necrosis leaves the vast majority with some residual disability.  INTERACT-2 offered some glimpse of hope, at least, from a surrogate standpoint – finding that patients with “intensive” blood pressure control showed reduced hematoma growth.  It seems logical that reduced hematoma growth would directly correlate with improved clinical outcomes, and there was a reasonable suggestion this was present, as well.

And, so, ATTACH-2.

This trial randomized patients with ICH to “standard” 140-179 mmHg blood pressure control versus “intensive” 110-139 mmHg blood pressure control, with a primary outcome of modified Rankin scale of 4 to 6.  All patients were treated using nicardipine by continuous infusion, and generally achieved their blood pressure targets within 2 hours of randomization.  They included 500 in each arm of the trial before stopping prematurely when a pre-specified threshold for futility was crossed.

Since I’ve used the word “futility” twice so far, you’ve probably already discerned the result.  At 90 day follow-up, there were 38.7% with mRS 4-6 in the intensive group versus 37.7% in the standard group.  No other long-term clinical outcomes seemed to reflect an advantage to one arm or the other.  In both adjusted and unadjusted analyses, there were a few interesting tidbits.  Hematoma expansion was, indeed, attenuated by intensive control.  However, as a counterweight, the intensive treatment group was more likely to suffer neurologic deterioration within 24 hours (11.0% vs. 8.0%) and more likely to suffer a serious adverse event within 3 months (25.6% vs. 20.0%).

It certainly seemed plausible such intensive lowering might be of value – but, instead, we have an excellent example where patient-oriented outcomes trump surrogates, and the adverse effects from treatment seem to counterbalanced any benefit picked up along the way.

“Intensive Blood-Pressure Lowering in Patients with Acute Cerebral Hemorrhage”

ENCHANTED – Positive or Negative?

I am probably the last person to comment on ENCHANTED, the trial testing low-dose vs. standard-dose tPA in “Asians”.  When it was released, to some fanfare in the New England Journal of Medicine, I had little to say – it is, frankly, a rather bland contribution to the science.  What has been fascinating, however, is the unusually divergent interpretation of the results.  To wit, the accompanying editorial in the NEJM states:
“ENCHANTED provides no compelling evidence for using low-dose alteplase for acute ischemic stroke in Asian or other populations on the basis of safety considerations or clinical outcomes.”
This is a relatively reasonable interpretation of the results – hinging on the word “compelling”.  No one’s hearts are to be set a-flutter over these results, but that does a disservice to the ultimate clinical question of which dose is appropriate.  The lay press, however, is here to clear things up – or is it?

“ENCHANTED: Low-Dose tPA Now a Viable Option in Stroke?” 
“ENCHANTED results challenge reduced alteplase dose in Asian stroke patients”
“Low-Dose tPA Not as Effective, Even for Asians”
“Lower Dose of Clot-Busting Drug Reduces Brain Bleeding”
“Low-dose alteplase fails to prove noninferiority to standard dose, shows some benefit in stroke”
“Low-Dose Alteplase Not as Effective as Standard-Dose in Acute Ischemic Stroke”

The question, simply, comes down to how easily one interprets “non-inferiority” – a point made nicely by Rory Spiegel in his post – and, further, how one interprets these findings in a Bayesian sense.  The prevailing opinion going into this trial was that low-dose tPA was safer and similarly efficacious in certain ethnic subpopulations on the Asian continent.  The nonsignificant difference (OR 1.09; 95% CI 0.95 to 1.25) in patients having excellent outcomes (mRS 0-1) and the even smaller difference (OR 1.03; 95% CI 0.89 to 1.19) in those having good outcomes (mRS 0-2) does nothing to move the needle on the prevailing clinical hypothesis.  If there is unlikely to be a profound difference in clinical outcomes, what of the safety outcomes?  Here, low-dose alteplase is obviously a winner – significant reductions in hemorrhage and a corresponding decrease in 90-day mortality (p=0.07).

If ECASS failed gloriously due to adverse effects at 1.1 mg/kg, subsequent trials found some favorable risk/benefit at 0.9 mg/kg, and the (supposed) clinical efficacy seems preserved with even greater safety at 0.6 mg/kg, it seems logical to expand interest in lower doses of tPA.  I disagree with those who would dismiss this trial as an unimportant “failure”.

“Low-Dose versus Standard-Dose Intravenous Alteplase in Acute Ischemic Stroke”