Not finding a difference doesn’t prove equivalence

Image from http://www.physio-control.com/

The recent LINC trial was a randomised controlled trial comparing a mechanical chest compression device (LUCAS) with manual CPR(1). “No significant difference” was found for any of the main outcome measures considered.

So do you think the LINC trial demonstrated that mechanical CPR using the LUCAS device is equivalent, or at least not inferior, to manual CPR?

This was an interesting and important trial for those of us who manage prehospital cardiac arrest patients. In some social media discussions, it appears to have been interpreted by some as evidence that they are equivalent resuscitative techniques or that LUCAS is not inferior to manual CPR.

LINCdata

However, unless you see a p-value less than 0.05 in the table above, (issues of multiple hypotheses testing aside) no evidence of anything was demonstrated; not of difference and certainly not of equivalence. When faced with 2-sided p values >5%, investigators often conclude that there is “no difference” between the treatments, leading to an assumption among readers that the treatments are equivalent. A better conclusion is that there is “no evidence” of a difference between treatments (see opinion piece by Sackett, 2004(2)). In order to determine if treatments are equivalent, equivalence must be tested directly.

How can we test for equivalence?
First, we must define equivalence. It is crucial that this definition is provided a priori i.e. defined before the data are examined. As the focus of the LINC study was on superiority the investigators did not offer an a priori definition of equivalence. However, the CIRC study(3), conducted some time earlier and similar in design, did. (This study examined an alternative mechanical CPR device, the Zoll AutoPulse).

When establishing equivalence between treatments, instead of the more customary null hypothesis of no difference between treatments, the hypothesis that the true difference is equal to a specified ‘delta’ (δ) is tested (4).

To analyse the LINC results to look for equivalence, we can derive our delta values from the CIRC study, which as we’ve said did offer an a priori definition of equivalence. For the purpose of illustration, we will use the risk-difference stopping boundaries calculated for the CIRC study, rather than the odds ratio based equivalence margins, on the grounds of greater simplicity and clinical appropriateness. Therefore, we set our equivalence margins at -δ=-1.4% and δ=1.6%, meaning, where LUCAS fared no worse than manual CPR by 1.4% and no better by 1.6%, we will consider the two techniques equally efficacious. Thus, we will declare equivalence between LUCAS and manual CPR if the 2-sided 95% CI for the treatment difference lies entirely within -1.4% and 1.6%, and noninferiority if the one-sided 97.5% CI for the treatment difference (equivalent to the lower limit of the two-sided 95% CI) lies above -1.4%. (5).

These concepts and how they differ from a traditional comparison are more readily appreciated graphically (Fig. 1).

Figure 1. Two one-sided test procedure and the equivalence margin in equivalence/noninferiority testing between LUCAS and manual CPR

1a Traditional comparative study, such as the LINC trial, shows results with confidence intervals that show no evidence of a difference as they encompass 0.

LINCtradcomp

1b. Using equivalence margins (-δ and δ) derived from a similar study (CIRC), we show that the LINC trial does not demonstrate that LUCAS and manual CPR are equally efficacious, since the 95% CI do not lie completely within the equivalence margins.

LINCequiv
1c. The one sided CI lies above -δ for some outcomes, allowing us to declare non-inferiority on those measures.
LINCnoninf

Conclusion
The presentation of the LINC trial’s results shows no evidence of a difference in outcomes between mechanical and manual CPR, which is not the same as showing they are equivalent or that mechanical CPR is non-inferior. However if we re-examine their data using equivalence margins (-δ, δ) derived from a similar study (CIRC), there is some evidence that the LUCAS device is not inferior to manual CPR (but not necessarily equivalent) with respect to longer term good neurological outcome.

References

1. Rubertsson S, Lindgren E, Smekal D, er al. Mechanical Chest Compressions and Simultaneous Defibrillation vs Conventional Cardiopulmonary Resuscitation in Out-of-Hospital Cardiac Arrest
JAMA. 2014 Jan 1;311(1):53-61

2. Sackett D. Superiority trials, non-inferiority trials, and prisoners of the 2-sided null hypothesis
Evid Based Med 2004;9:38-39 [Open Access]

3. Lerner EB, Persse D, Souders CM, et al. Design of the Circulation Improving Resuscitation Care (CIRC) Trial: a new state of the art design for out-of-hospital cardiac arrest research
Resuscitation. 2011 Mar;82(3):294-9

4. Dunnett CW, Gent M. Significance testing to establish equivalence between treatments, with special reference to data in the form of 2X2 tables. Biometrics. 1977 Dec;33(4):593-602

5. Piaggio G, Elbourne DR, Pocock SJ, et al. Reporting of noninferiority and equivalence randomized trials: extension of the CONSORT 2010 statement. JAMA. 2012;308(24):2594-604. [Open Access]

Does RV enlargement on echo predict PE?

A nice paper from Annals of Emergency Medicine showing the test characteristcs of some of the common signs we look for on basic 2D echo that suggest the presence of (sub)massive pulmonary embolism:

Right Ventricular Dilatation on Bedside Echocardiography Performed by Emergency Physicians Aids in the Diagnosis of Pulmonary Embolism
Ann Emerg Med. 2014 Jan;63(1):16-24


STUDY OBJECTIVE: The objective of this study was to determine the diagnostic performance of right ventricular dilatation identified by emergency physicians on bedside echocardiography in patients with a suspected or confirmed pulmonary embolism. The secondary objective included an exploratory analysis of the predictive value of a subgroup of findings associated with advanced right ventricular dysfunction (right ventricular hypokinesis, paradoxical septal motion, McConnell’s sign).

METHODS: This was a prospective observational study using a convenience sample of patients with suspected (moderate to high pretest probability) or confirmed pulmonary embolism. Participants had bedside echocardiography evaluating for right ventricular dilatation (defined as right ventricular to left ventricular ratio greater than 1:1) and right ventricular dysfunction (right ventricular hypokinesis, paradoxical septal motion, or McConnell’s sign). The patient’s medical records were reviewed for the final reading on all imaging, disposition, hospital length of stay, 30-day inhospital mortality, and discharge diagnosis.

RESULTS: Thirty of 146 patients had a pulmonary embolism. Right ventricular dilatation on echocardiography had a sensitivity of 50% (95% confidence interval [CI] 32% to 68%), a specificity of 98% (95% CI 95% to 100%), a positive predictive value of 88% (95% CI 66% to 100%), and a negative predictive value of 88% (95% CI 83% to 94%). Positive and negative likelihood ratios were determined to be 29 (95% CI 6.1% to 64%) and 0.51 (95% CI 0.4% to 0.7%), respectively. Ten of 11 patients with right ventricular hypokinesis had a pulmonary embolism. All 6 patients with McConnell’s sign and all 8 patients with paradoxical septal motion had a diagnosis of pulmonary embolism. There was a 96% observed agreement between coinvestigators and principal investigator interpretation of images obtained and recorded.

CONCLUSION: Right ventricular dilatation and right ventricular dysfunction identified on emergency physician performed echocardiography were found to be highly specific for pulmonary embolism but had poor sensitivity. Bedside echocardiography is a useful tool that can be incorporated into the algorithm of patients with a moderate to high pretest probability of pulmonary embolism.

Etomidate – there is always a downside

By Norwegian intensivist/anaesthetist/HEMS Physician Dr Per Bredmose.

[Warning – Rant level: Viking]

Etomidate has for a long time been known in some countries as the “drug of choice” for RSI in unstable/fragile patients. This is due to the fact that induction with etomidate is fairly cardiovascularly stable. However, there is a down side: a subsequent suppression of adrenal function. This was initially discovered after etomidate was used for sedation infusions on ICU.

It has for a long time been debated whether this is a side effect with clinical implications after a single dose induction… and yes it has.

A recent Japanese study demonstrates this(1). This is a large propensity based study. Now, propensity based statistics are pretty complex to explain. In short, it is an advanced method to strengthen the statistics when comparing groups in non-cross over studies.

In this study 2616 patients receiving etomidate for induction and a volatile agent for maintenance are included.
This showed an increased OR for 30-days mortality with a factor of 2.5 and 1.5 times greater chance for a major cardiovascular event in hospital. Interestingly enough, there were no significant differences in either perioperative vasopressor use or infections complications during hospital stay.

What does this mean?
In my mind and experience, it strengthens the fact that there is no wonder drug. And also that there seems to be a reason for why etomidate is de-registered in many countries.
Also, it tells me that for a safe prehospital RSI we need physicians capable of clinical judgment and “decision making” to tailor an (any) induction agent to the specific individual patient. In my mind, there is no room for an etomidate-only (dose / weight) induction protocol!

1. Komatsu R, You J, Mascha EJ, Sessler DI, Kasuya Y, Turan A.
Anesthetic induction with etomidate, rather than propofol, is associated with increased 30-day mortality and cardiovascular morbidity after noncardiac surgery.
Anesth Analg. 2013 Dec;117(6):1329-37

How You Train is How You Fight

Simulation makes us more effective. I think it’s good to consider how one would deal with emergency situations in every day life, and practice the response. There are ALWAYS learning points.

My four year old son Kal brought along his rubber red bellied black snake on a New Year’s Day bush walk with my family. Too good an opportunity to miss, so we practiced managing a snakebite scenario. What we did and what we learned are summarised in this three minute video:

 
This was a worthwhile exercise. Learning points were:

1. Carry a knife to help cut up the teeshirt (if you don’t carry bandages)

2. Call for help early – it takes several minutes to apply the pressure immobilisation bandage, so ideally these things are done in parallel rather than series.

3. Know how to get your coordinates from your smart phone. Several free apps are available.
On an Apple iPhone, they are displayed on the ‘Compass’ app but ONLY if you have enabled location services (Settings->Privacy->Location Services->Compass)

location services compass-10

 

 

 

 

 

 

 

 

 

Learn more about pressure immobilisation technique and its indications from the Australian Resuscitation Council