Ruling Out PE in the ED: Critical Analysis of the PROPER Trial

This post is going to be an in-depth "journal club" style analysis of the PROPER trial.

In this week's JAMA, Freund et al report the results of the PROPER randomized controlled trial of the PERC (pulmonary embolism rule -out criteria) rule for safely excluding pulmonary embolism (PE) in the emergency department (ED) among patients with a "low clinical gestalt" of having PE.  All things pulmonary and all things noninferiority being pet topics of mine, I had to delve deeper into this article because frankly the abstract confused me.

This was a cluster randomized noninferiority trial, but for most purposes, the cluster part can be ignored when looking at the data.  Each of 14 EDs in France was randomized such that during the "PERC period" PE was excluded in patients with a "low gestalt clinical probability" (not yet defined in the abstract) if all of the 8 items of the PERC rule were excluded.  In the "control period" usual procedures for exclusion of PE were followed.  The primary end point was occurrence of a [venous] thromboembolic event (VTE) during 3 months of follow-up.  The delta (pre-specified margin of noninferiority) for the endpoint was 1.5%.  This is a pleasingly low number.  In our meta-research study of 163 noninferiority trials including those in JAMA from 2010-1016, we found that the average delta for those using an absolute risk difference (n=137) was 8.7%, almost 6 times higher!  This is laudable, but was aided by a low estimated event rate in the control group which means that the sample size of ~1900 was feasible given what I assume were relatively low costs of the study.  Kudos to the authors too, for concretely justifying delta in the methods section.

Better the Devil You Know: Thrombolysis for Pulmonary Embolism

In my view, the task of the expert is to render the complex simple.  And the expert does do this, except when reality goes against his bets and complexity becomes a tool for obfuscating an unwanted result.

In 2002, Konstantanidis compared alteplase plus heparin versus heparin alone for submassive pulmonary embolism (PE).  The simple message from this study was "alteplase now saves you from alteplase later" and the simple strategy is to wait until there is hemodynamic deterioration (shock) and then give alteplase.  Would that it were actually viewed so simply - I would not then get calls from stressed providers hemming and hawing about the septum bowing on the echo and the sinus tachycardia and the....

If you're a true believer, you think alteplase works - you want it to work.  So, you do another study, hoping that biomarkers better identify a subset of patients that will benefit from an up front strategy of thrombolysis.  Thus, the PEITHO study appeared in the April 10th, 2014 issue of the NEJM.  It too showed that fibrinolysis (with tenecteplase) now simply saved you from tenecteplase later.  But fibrinolysis now also causes stroke later with an increase from 0.2% in the control group versus 2.4% in the fibrinolysis group - and most of them were hemorrhagic.   Again, the strategic path is in stark relief - if your patient is dying of shock from PE, give fibrinolysis.  If not, wait - because less than 5% of them are going to deteriorate.

So we have vivid clarity provided by large modern randomized controlled trials guiding us on what to do with that subset of patients with PE that is not in shock.  For those that are in shock, most agree that we should give thrombolysis.

To muddy that clarity, Chatterjee et al report the results of a meta-analysis in the June 18th issue of JAMA in which they combine all trials they could find over the past 45 years (back to 1970!) of all patients with PE, regardless of hemodynamic status.  The result:  fewer patients died but more had bleeding.  We have now made one full revolution, from trying to identify subsets likely to benefit, to combining them all back together - I think I'm getting dizzy.

If the editorialist would look at his numbers as his patients likely would (and dispense with relative risk reductions), he would see that:

	Death	Bleeding in the brain	Other Major Bleeding
Blood Thinner	3.89%	0.19%	3.42
Clot Buster	2.17%	1.46%	9.24
Difference	1.72%	-1.27%	-5.82

For almost every life that is saved, there is almost one (0.74) case of bleeding in the brain and there are 3.4 more cases of major bleeding.  And bear in mind that these are the aggregate meta-analysis numbers that include patients in shock and those not in shock - the picture is worse if you exclude those in shock.

Better the devil you know.