P2Y12 receptor inhibitors in ACS

22 Jul

So what to make of all these articles?

These data indicate that clopidogrel is better than placebo in reducing risk for vascular events in patients with ACS, without an increase in life threatening bleeding. It must be said however, that the studies looking at clopidogrel vs placebo are older and most patients didn’t underwent PCI, indicating that the treatment might be different than it is nowadays. Furthermore there is little evidence that clopidogrel has any benefit in mortality reduction.  The review from Aradi, et al (2013) showed a slightly significant benefit (OR 0.9. CI95%: 0.87-0.99), but none of the articles that were reviewed showed a significant benefit by itself.

The newer prasugrel and ticagrelor seem to give an additional benefit over clopidogrel, but prasugrel has been shown to give more CABG-related bleeding. Prasugrel showed no benefit over clopidogrel in patients with a previous stroke or TIA, patients older than 75 years or patients underneath 60 kg. However, this was with a maintance dose of 10mg, instead of the 5 mg given nowadays in (Dutch) hospitals to patients > 75 y or < 60 kg. To my knowledge, it remains unknown if this regimen is beneficial over clopidogrel in this group.  In patients with a history of stroke or TIA the outcome was significantly worse and that is why in this group prasugrel is contraindicated.

Ticragelor has a faster on- and offset of platelet function inhibition than clopidogrel, which might make it the better drug for patients undergoing CABG. It can give side effects like bradycardia and dyspnea, but these seem to happen rarely.

Although not important in the acute setting in the ED, patients are at higher risk for cardiovascular events in the period immediately after stopping clopidogrel (which might also be the case with prasugrel and ticagrelor).  More research should is needed to identify strategies to reduce these events.

My conclusions are different than a comment recently published in the NTVG (a Dutch Medical Journal) http://www.ntvg.nl/publicatie/clopidogrel-plus-acetylsalicylzuur-een-dodelijke-combinatie/volledig

, which came to the conclusion that clopidogrel as addition to aspirin has proven itself in reducing MI in patients with a stent or ACS, but has no benefit in mortality reduction. A reason for this would be an increase in major bleeding. Their opinion was that clopidogrel in these patients should be withheld. Although I don’t think the evidence for this is black (or white) and more of a grey area, I can only encourage the discussion.

Off course there are major limitations to these studies.

– Most studies are funded by the Pharmaceutical Companies, which might lead to a conflict of interest.

– A lot of data came from post hoc subgroup analysis, aka “data dredging.“ Then you retrospectively look at the

data and look at all kinds of different subgroups. And the more you look, the more you will find!

– Several different outcomes were combined (like cardiovasc death, MI and stroke = cardiovascular events), instead of looking at them separately.  (I mean, what would have happened if you put another outcome in the mix. It might change the outcome.)

– There is heterogenousy between the patients of different studies.

Finally, I am wondering what to do with those chest pain patients with normal EKG’s and enzymes who get admitted. Do these patients benefit from P2Y12 receptor inhibitors, or does the risk outweigh the benefit? As you know the biggest group of these patients don’t have an ACS. They might have reflux, for example.I would say that these patients should be looked at individually (as you should do with every patient!) and not be protocolized. A risk-benefit analysis before giving the P2Y12 receptor is of great importance!

A big new, prospective, unsponsored study looking at this group of patients would be very interesting to see if they have any benefit from these medications!

Until next time! Like to hear your thoughts on the subject!


reference list will follow


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