JC – Prasugrel vs Clopidogrel in ACS

Critical appraisal of NEJM paper on Clopidogrel vs Prasugrel for the treatment of non STEMI

So why did we choose this paper if it’s about something that we don’t ordinarily prescribe. Well, partly because it’s current, but also because there are some nice questions that we can develop here to help people learning critical appraisal. I’m not going to put it in the featured section of the blog, but you should be able to find it in the JC archives.

So, the paper itself. Basically this is an RCT comparing Prasugel vs Clopidogrel for patients with ACS but without need for revascularisation. Here’s the abstract, but if you’re interested in the Critical Appraisal questions later I’d suggest that you read the entire article.

 

9326 patients were randomised between the two treatments and outcomes were assessed at 30 months. So for starters this is quite a large trial conducted over a long period of time which as a starter is a good indicator that we might be able to get a decent answer.

As an RCT we should look at the interventions which were either 30mg of Prasugrel daily or 300mg Clopidogrel daily, but most importantly we should consider what the outcomes are. Ideally outcomes should be clinically focused and clearly relevant to the patient (and the clinician of course). The outcome are interesting here and there are some further questions on this later.

The primary end point is death from cardiovascular causes, non fatal MI or non-fatal stroke which is interesting as it does not contain some of the know complications of this kind of therapy. I would argue that the outcome of death from all causes is a better outcome and to be fair to the authors they do report this. In my opinion death is somewhat important and therefore I think this is where we should focus.

So what did they find after 30 months? Well in terms of death the rate in the Prasugrel group was 385/4663 (8.3%) whereas death occurred in 409/4663 (8.8%) in the Clopidogrel group. That’s a 0.5% difference which if you’re smart and read our post a few weeks ago equates to an NNT of 200 (which is a pretty big number). The confidence intervals around those estimates are pretty wide though so it looks as though there is little difference between the two therapies to be honest.

Now, as we have said there are not that many things that we can learn from this paper from an EM perspective as the decision to prescribe these two drugs probably rests with the patient’s cardiologist or family physician. However, from a critical appraisal point of view this is a good study as it allows us to ask a couple of questions that might crop up in exams. Courtesy of Alison S, we have a couple of questions that are worthy of consideration, so read the paper and then have a bash at the following.

What do you understand by the term ‘composite outcome’

In simple terms a composite outcome is where we consider a number of outcomes in a group to define that something has happened to the patient. In this study the composite outcome is defined as the cardiovascular grouping of relates to cardiovascular death, MI or stroke. Now firstly I’d say this is a bit rubbish as their secondary end point is death from all causes. Surely it must be better to have death from all causes, particularly when the two drugs being compared are known to have risks (primarily bleeding), but the authors and the reviewers of the NEJM presumably know better…..maybe.

What are the pros and cons of using composite outcomes in clinical trials

You may come across composite outcomes in diagnostic and therapeutic trials. As with all things in life there are pros and cons to using them and although this list is not exhaustive it might help if you are ever faced with this question in an exam.

1. Composite outcomes are useful if sample size is an issue. By defining a number of outcomes you may need fewer people in the study (as multiple outcomes are possible).

2. Composite outcomes are great if a true gold standard is not available. Think PE here….although CTPA is good we know that some -ve CTPA patients still die of PE. By combining PE with follow up for 3/12 (a composite outcome) we can try and avoid this known problem.

3. Composite outcomes allow a number of related factors to be grouped in a sensible way. In this study stroke and MI are both in the composite because they are both CVS outcomes. That seems sensible.

4. Composite outcomes can mislead as you score the same regardless of which you get. So in this study death from CVS cause is weighted the same as stroke or another MI…..! Clearly that’s not right from a patient perspective and it can be misleading to link them like this. It is possible that in one arm of the study all patients die, in the other they all have strokes.., but at the same frequency. A composite outcome might suggest that they are therefore the same (they are not).

5. Composite outcomes are often quite difficult to communicate to patients and colleagues. You really need to think hard about whether you truly understand the inherent complexities that exist in their interpretation.

There is a nice review in the BMJ on the use of composite outcomes if you want to learn more.

 

Before you go please don’t forget to…

 

 

Posted by Simon Carley

Professor Simon Carley MB ChB, PGDip, DipIMC (RCS Ed), FRCS (Ed)(1998), FHEA, FAcadMed, FRCEM, MPhil, MD, PhD is Creator, Webmaster, owner and Editor in Chief of the St Emlyn’s blog and podcast. He is Professor of Emergency Medicine at Manchester Metropolitan University and a Consultant in adult and paediatric Emergency Medicine at Manchester Foundation Trust. He is co-founder of BestBets, St.Emlyns and the MSc in emergency medicine at Manchester Metropolitan University. He is an Education Associate with the General Medical Council and is an Associate Editor for the Emergency Medicine Journal. His research interests include diagnostics, MedEd, Major incidents & Evidence based Emergency Medicine. He is verified on twitter as @EMManchester

  1. One further problem with composite outcomes – their use assumes that whatever you are testing has the same effect/predictive value on all the compositor parts….so death from MI/non-fatal MI are reasonably combined, but do we really understand the pathophysiology of antiplatelets in cerebrovascular disease enough to be sure that they will have the same effect on hearts and heads?

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