Genotype-guided strategy to select oral P2Y12 inhibitor in STEMI lowers bleeding risk

ESC 2019 Selection of an oral P2Y12 inhibitor based on a genetic test for a loss-of-function allele that makes people non-responsive to clopidogrel did not increase stent thrombosis and reduced bleeding events.

POPular Genetics –Genotype-guided oral P2Y12 inhibition in patients with ST-segment elevation myocardial infarction undergoing primary PCI

Presented at ESC Congress 2019 in Paris, France by Jurriën M. ten Berg (Nieuwegein, The Netherlands)

Because of the risk for stent thrombosis and myocardial infarction (MI) right after a patient has an MI, ESC recommendations state that patients should be treated with aspirin, heparin and P2Y12 inhibitors. P2Y12 inhibitors ticagrelor and prasugrel are stronger platelet inhibitors than clopidogrel, and they lead to less stent thrombosis (80% MI and 20% death) and spontaneous MI. The drawback is that ticagrelor and prasugrel also lead to more bleeding, which is related to mortality.

30% Of Caucasians show an inadequate response to clopidogrel, partly because of the CYP2C19 loss-of-function (LOF) allele. People who are not a carrier of the LOF alleles, clopidogrel is as effective as ticagrelor.

This study tested the hypothesis that a CYP2C19 genotype-guided strategy of oral P2Y12-inhibition (clopidogrel in patients with no LOF allele and ticagrelor/prasugrel in patients with LOF) vs. standard treatment with ticagrelor/prasugrel will be:

• non-inferior for a net clinical benefit of all-cause death, MI, stent thrombosis, stroke and PLATO major bleeding,
• superior in reducing combined PLATO major and minor bleeding (co-primary endpoints).

The POPular Genetics trial was non-commercially sponsored. It was a randomized open label, blinded study, conducted in 10 sites. 2488 patients with STEMI undergoing primary PCI were randomized 1:1 to genetic testing or not. Those not allocated to testing received ticagrelor or prasugrel for 12 months. Tested individuals who were carrier of the LOF (35%) received ticagrelor or prasugrel, and the non-carriers received clopidogrel for 12 months. The test can be done as a fully automated analysis of a buccal swap, and the results is obtained in 1 hour. Complete follow-up was available for 99.9% of participants.

Main results

• Rate of adherence was 82.0% in the group that did not get genetic testing and 84.5% in the genetically tested group.
• The genotype-guided group showed a lower rate of the first co-primary endpoint than those on standard treatment (5.1% vs. 5.9%, HR: 0.86, 95%CI: 0.62-1.21), which was significant for non-inferiority with P=0.0002.
• The genotype-guided groups showed a lower rate of PLATO major and minor bleeding, and was superior to standard treatment (12.5% vs. 9.8%, HR: 0.78, 95%CI: 0.61-0.98, P-sup=0.04).

Conclusions

This study shows that in a CYP2C19 genotype-guided strategy for oral P2Y12 inhibition vs. standard treatment with ticagrelor/prasugrel in patients with STEMI, genotyping is easy to use (can be done in the cathlab) and has fast results. Almost 2/3 of the patients could be treated with clopidogrel and importantly, no differences were seen in thrombotic event rates. The genotype-guided strategy yielded a reduction in bleeding event rates. Thus, physicians can now reduce bleeding complications by using a genotype-guided strategy to select oral P2Y12 inhibitors in patients with STEMI without increasing the thrombotic risk.

Discussion

This study received a lot of interest during the discussion in the press conference. Of course, the question was raised whether this study shows strong enough results to change the guidelines. Ten Berg answered that the fact that a reduction was seen in bleeding, is important for patients. It was not powered to detect superiority with regard to thrombotic risk, but these events were not increased. The TAILOR-PCI trial tests a similar hypothesis, so hopefully these results will confirm the current findings. It is likely that these results are awaited before guidelines will speak of it.

It was mentioned however, that these findings can be meaningful for example in countries where ticagrelor and prasugrel are not available for cost reasons. The point-of-care test is very easy to use, quick and not expensive. So this might be used to select which patients would benefit from more expensive treatment.

- Our reporting is based on the information provided at the ESC congress -

Watch our video about POPular Genetics This study was simultaneously published in NEJM