Would You Rather....

The Gist:  Composite endpoints, a sneaky way to skew data, are common in medical literature.  These outcomes often represent disease states across a spectrum, making it difficult to parse out what the intervention may mean for a given patient.  Check out this article by Peter Kleist, the Jan 2013 mini-JC with Dr. David Newman (if you're an EMRAP subscriber), and SMARTEM (particularly on coronary CT or stress testing). 

Composite endpoint:  multiple single end-points that are combined into a 'single outcome.'

FOAM,  SMARTEM, EM Lit of Note, and Twitter discussions can provide one with a cognitive toolkit and skeptical lens to look beyond abstracts and evaluate papers/assertions critically.  Recently, however, I was privy to a debate on PCI versus medical management for coronary artery disease.  I realized that a lack of understanding about composite endpoints abounds.  Dr. Newman showed me that death, MI, and cardiac catheterization aren't the same (silly as it sounds now) so I feel inclined to spread this wisdom. 

Understanding the problem with composite endpoints reminds me of a game my rugby teammates and I played when we traveled for games, 'Would you rather.."  The object is to pose a question with two very similar, difficult choices that often expose weaknesses or fears.  Questions are often gross or entertaining (and many are juvenile).  They are along the lines of:  "Would you rather travel a thousand years back and meet your ancestors or travel a thousand years forward and meet your grandchildren?" or "Would you rather sleep in a bed of cockroaches or a bed of maggots?"  This game would lose all appeal if the dilemma had a clear answer, "Would you rather get a cut on your arm or have your leg sawed in half?"  When this perspective is applied to the components of a composite endpoint, the weakness is exposed.  Like the last question, they're not equal.   

@lwestafer The fastest way for me to stop reading an abstract is to put the word "composite" in it
— Steve Carroll, DO (@embasic) January 16, 2013

Inspired by @lwestafer- search for "composite" in abstracts in last 10 years- NEJM 543 Annals EM 18- not scientific- coincidence? #ithinknot
— Steve Carroll, DO (@embasic) January 16, 2013

One Annals EM hit was for "dental composite"- NEJM abstracts frequently mention "primary outcome" and "composite" in same sentence #facepalm
— Steve Carroll, DO (@embasic) January 16, 2013

The Debated Paper:  FAME 2 Trial

• Looked at PCI versus medical management in patients who had a stenosis of at least one major coronary artery that rendered a fractional flow reserve of <0.80.
• Primary end-point: composite death from any cause, nonfatal MI, or unplanned hospitalization leading to urgent revascularization during the first 2 years (the triple composite endpoint).  
• Urgent revascularization:  Patient with persistent or increasing chest pain admitted to the hospital with revascularization during that hospitalization). 
• Results:  more patients in the medical management group had a primary end-point compared with the PCI group, 12.7% vs 4.2%.  That's an 8.5% absolute reduction in the PCI group.  
• The rate of death did not differ between the groups (0.2%, n=1 in PCI group; 0.7% n=3 in medical management group)
• The rate of MI did not differ between the groups. (3.4%, n=15 in PCI group; .3% n=14 in medical management group)
• The rate of urgent revascularization was significantly less in the PCI group at 1.6% (n=7) compared with the medical management group at 11.1% (n=49).
• Where did the 8.5% reduction in primary end-point come from?  Revascularization, a subjective outcome.  Who gets revascularized?
• Whomever the cardiologists choose, and this may differ between cardiologists.  It's not necessarily rooted in disease. 
• When these patients come into the ED, is a physician more likely to take a patient to the cath lab who just had a cath?  Or, is a physician more likely to take a patient who has been trying medical management.
• Are all of these outcomes the same or do they  represent different portions on a spectrum? I see one firm endpoint in this composite (death), and then a spectrum.  Furthermore, while MIs are unfavorable, there are varying degrees of badness even within this singular end-point.  

That's one article.  What about composite endpoints across the literature?

• Cordoba et al conducted a systematic review of RCTs published in 2008 that used a composite endpoint as a primary outcome (search via PubMed). 
• The definition of the endpoint changed between the abstract, methods, and results section in 33% (n=13) of articles
• 70% (n=28) of trials had a primary composite endpoint comprised of components of dissimilar significance (ex. death and hospital admission).
• A meta-analysis of cardiovascular therapeutic interventions from 2002-2003 demonstrated that 32% (n=37) of studies did not report the effects of the individual components of the endpoints, obscuring the impact of components of different clinical significance. 
• Freemantle et al (full text) looked at trials with mortality as part of a composite primary outcome in 9 high impact journals and found that only 11% (n=19) trials had both significant composite and mortality outcomes.  The below figure, demonstrates the difference in treatment effects using the composite and component portions in several trials of glycoprotein IIb/IIIa inhibitors in ACS.   

 

• Would you rather die or develop diabetes?  - The DREAM Trial 

So, are composite endpoints rooted in malevolence?

• Composite endpoints may allow a trial to enroll a fewer number of patients, thereby decreasing cost and increasing feasibility.  When attempting to measure rare events, it could be difficult to power a study so that an intervention could achieve statistical significance. To borrow an example from Tomlinson et al, if an outcome is expected to occur at a 5% annual rate and the trial is planned to last five years, more than 2,500 patients are needed to establish a hazard ratio of 0.75 with p<0.05. 
• We need and like studies to evaluate interventions and cost and feasibility are important so it's likely that there's some sort of trade-off here. 
• Some interventions may have a few important outcomes.  For example, some people argue that when evaluating a cardiovascular medication, looking at cardiovascular events such as deaths due to cardiac events, non-fatal strokes, and non-fatal MIs is theoretically reasonable.

So, then, what do we do with these composite endpoints? 

• Pick them apart.  The FOAM website, theNNT has the following philosophy on composite endpoints:  "Generally speaking there is no need to use composite endpoints. In many cases the use of composite endpoints (e.g. ‘death, MI, or revascularization’ in studies of coronary treatments) obfuscates the patient-oriented utility of an intervention (Tomlinson, 2010). In addition, composite endpoints are very often made up of components with considerably varying patient-interest. At TheNNT our sense is that separating these endpoints into separate outcomes helps to clarify the degree to which an intervention may be beneficial based on the value system of an individual patient. We therefore separate all composite endpoints into their constituent parts for NNT calculations."
• Be sensitive for detecting these in literature and ask some key questions:
• Does the composite endpoint really measure a disease?
• Are the components of the composite have the same clinical significance (or do they cover a broad spectrum of disease)?
• Does the composite endpoint camouflage a single negative outcome bundled in the composite?
• Are the individual components of the composite endpoint valid? Are they of importance for patients?
• Are the results clinically meaningful? Do they provide a basis for therapeutic decisions? Does each single endpoint support the overall result?
•  Educate those around you.

Update:  Stolker JM et al. Re-Thinking Composite Endpoints in Clinical Trials: Insights from Patients and Trialists. Circulation. 2014. PMID: 25200210

• Composite endpoints are commonplace, especially in cardiology literature. It takes massive power to find mortality/major mobidity benefits for many interventions; thus, many studies are powered for a primary composite outcome, often: death, myocardial infarction (MI), and revascularization. This cardiology survey data highlights that both patients and trial researchers appreciate the inequity between death and revascularization. The shocker? Patients rated MI and stroke worse than death, whereas researchers rated MI and stroke as 1/3 to 1/2 as important as death. Both clinical trialists and patients rated revascularization as a minor event, in contradistinction to the equal weight placed in the composite primary outcome in many trials.