Something About Nothing: ROSC is a Meaningless Outcome (and The 2018 ACLS Update).

ROSC is not an outcome that matters.

“You have to get ROSC before you get anything else.”

“If patients don’t get ROSC they can’t live, so anything that increases ROSC is giving that patient a chance.”

It makes sense to think that ROSC is an important outcome, at least on a superficial level. Patients need to get ROSC at some point if they are going to have a  good neurologic outcome. It is true, but it is a half-truth and unless it is examined health care providers will continue to administer ineffective and perhaps harmful treatments.

Resuscitation is more than the sum of its parts.

Resuscitation can be deconstructed into a million small steps and surrogate outcomes but they only matter if they contribute to the end result- the patient walking out of the hospital neurologically intact. Outside of a research setting the focus of resuscitation needs to be on things that are proven to work and nothing else. Anything that dilutes this process, such as drugs with no proven efficacy, should be discarded. Drug administration should not be justified by only improving meaningless outcomes.

In simplest terms, the fallacy of ROSC being a meaningful outcome is similar to the adage that you have to spend money to make money. It may be true that you have to spend money to make money, but if you spend so much money on the money-making process before realizing any profits that you end up bankrupt and homeless then all you managed to do was ruin your life*.

To illustrate this point here is an example of the fictional Drug X in a trial versus placebo in VF/VT arrests.

ROSC trial 1
Drug X looks pretty promising at this point, doesn’t it?

Looking at the fictitious drug trial it certainly seems like drug X would be a welcome addition to the cardiac arrest algorithm. In VF/VT arrest Drug X is associated with 47% more patients achieving ROSC than when compared to placebo.

Cardiac arrest outcomes can be classified by looking at the neurologic outcomes of patients on the Modified Rankin Scale (mRS). There is some debate about what constitutes a “good” score on the scale with some proponents advocating for 0-2 as good and others saying it should be anything in the 0-3 range. For this article, we will use 0-2 as a “good” outcome.

mrs

When looking beyond a first-order outcome like ROSC and looking at the second-order effects of Drug X, like the mRS, a much different picture starts to emerge. Drug X did increase ROSC but it did not increase the number of people being discharged with a good neurologic status, in fact, it might even cause worse outcomes.

drug x neuro
Drug X does not look quite as enticing now.

When we look at the second order outcomes of a drug for cardiac arrest, we can classify it as helpful, harmful or no effect based on the available data. Some drugs may be a mix of helpful and harmful but in those cases, the benefits must outweigh the harms and make the drug helpful overall. If a drug is not helpful then it should not be given.

2018 Update:

The AHA released the 2018 version of the ACLS guidelines last week with an updated adult cardiac arrest algorithm. In a puzzling change, they added lidocaine back into the algorithm as an equivalent to amiodarone in VF/VT cardiac arrests. In the 2015 update, the AHA stated that if amiodarone was unavailable that lidocaine was an acceptable option.

The AHA states in the 2018 update that lidocaine should be given even though “no antiarrhythmic drug has yet been shown to increase long-term survival or to improve neurological outcome after VF/pVT cardiac arrest…” Maybe it was just bad editing, but the word “yet” does not belong in any evidence-based guidelines. If there is no evidence yet that it works, why are we still using it?

The AHA cites the 2016 ROC-ALPS study (Resuscitation Outcomes Consortium–Amiodarone, Lidocaine or Placebo Study) as the main driver for the renewed role lidocaine in their guidelines. The study showed that ROSC occurred more frequently in cardiac arrest patients in VF/VT that received lidocaine or amiodarone than those who received placebo. Without thinking about this too much it certainly seems like these drugs should be given to VF/VT cardiac arrest patients (as long as we do not look at second order outcomes). Let’s take a look at the data from the ROC-ALPS:

roc alps graph

 

The AHA also references the subgroup analysis of VF/VT arrests witnessed by EMS in the ROC-ALPS as a reason for endorsing the use of lidocaine and amiodarone stating:

“Amiodarone and Lidocaine Recommendation—Updated: Amiodarone or lidocaine may be considered for VF/pVT that is unresponsive to defibrillation. These drugs may be particularly useful for patients with witnessed arrest, for whom time to drug administration may be shorter.”

The subgroup looked at people that had a witnessed VF/VT arrest in the presence of EMS and compared those that received Amiodarone to those that were given lidocaine or placebo. At first glance, the subgroup analysis sounds promising for antiarrhythmics in EMS witnessed VF/VT arrests. The AHA points out that these drugs increased survival to discharge compared to EMS witnessed VF/VT arrests that received placebo. Unfortunately, the subgroup analysis has several issues that the AHA glossed over.

subgroup1.png
The data in the subgroup only had the outcome of survival to discharge – no mRS was available.

 

The sample size is important in any study and when it comes to changing guidelines the sample size should be a large number of people, and ideally multiple studies that replicate the results. This was not a large group of people; this was a total of 154 patients that had a witnessed VF/VT arrest in the presence of EMS. Out of the 154 patients, 41 of them survived to discharge. Changing a guideline on outcomes of a total of 41 people randomized to three different treatment arms is not a sound practice.

The 2018 AHA update does not mention that amiodarone outperformed lidocaine by more than a 15% increase in survival to discharge in this subgroup. Lidocaine, on the other hand, beat placebo in this cohort by just 7%. Why does the AHA believe the 7% increase in survival from lidocaine versus placebo is important but the 15% increase in survival regarding amiodarone versus lidocaine is negligible and not mentioned at all? If the subgroup data is to be taken at face value, ignoring a 15% increase in survival to discharge but emphasizing a 7% increase in survival to discharge is weird.

In the subgroup, if just 3 more of the 54 people who received placebo had survived to hospital discharge, placebo would have outperformed lidocaine. Conversely, if only 2 fewer people had survived in the lidocaine cohort, placebo would have outperformed lidocaine again. The small sample size makes it impossible to say if this is a real effect or if it is simply the effects of chance.


Resuscitation guidelines (at least from the AHA) are verging on becoming alternative medicine- a paradigm where things such as facts and evidence do not matter and drugs have to be conclusively be proven to not work before abandoning them. That isn’t how science works- the onus of responsibility is always on those making the claim that something works, not the other way around.

I do not think the AHA is acting out of malice or out of some non-disclosed financial interest from the makers of generic lidocaine. The AHA endorses drugs in cardiac arrest for no other reason that they increase ROSC, even when multiple studies show that the drugs do not improve the neurologic outcomes of these patients.  We can torture that data more until it confesses; subject our patients to more human experimentation engage is statistical witchcraft and cherry pick subgroups of subgroups all we want, but it isn’t going to change the fact that anti-arrhythmic drugs have never shown a real benefit in meaningful outcomes and yet we are still using them.

We need to demand that medicines show a positive change in meaningful outcomes and we need to come to terms with the fact that ROSC is not one of them.


*My wife says I am not good at analogies, so this might not actually make any sense but it is better than the other one I was going to use involving shoving a jet engine in a Honda Civic.

 

 

 

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out /  Change )

Google+ photo

You are commenting using your Google+ account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s