Genetic Testing Spots Clopidogrel Responders After PCI for STEMI

Liam Davenport

September 03, 2019

PARIS — Genetic testing to determine which ST-elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention (PCI) will respond to clopidogrel, and then giving standard P2Y12 inhibitor therapy to the remainder, could reduce bleeding rates without compromising outcomes, results of a European randomized trial demonstrate.

Standard care for primary PCI patients after STEMI is with ticagrelor (Brilinta/Brilique, AstraZeneca) and prasugrel (Effient/Efient, Eli Lilly/Daiichi Sankyo), as the drugs are considered more potent than clopidogrel.

However, this could be affected by the presence of loss-of-function alleles in the CYP2C19 gene, thus masking the benefit of clopidogrel, which is much cheaper than ticagrelor and prasugrel and has simpler dosing.

Jurriën M. ten Berg, MD, PhD, St. Antonius Hospital, Nieuwegein, Netherlands, and colleagues therefore examined whether a genetic test could be used to direct patients to either clopidogrel or the other agents based on their allele profile.

They randomized almost 2500 patients to standard care with ticagrelor or prasugrel or genotype-guided treatment with clopidogrel, or to ticagrelor or prasugrel if they had the loss-of-function allele.

Half of the genetic testing group was tested using a rapid onsite point-of-care test and the rest with blood samples sent to a central laboratory.

The results, presented here at the European Society of Cardiology (ESC) Congress 2019 and published simultaneously September 3 in the New England Journal of Medicine, showed that genotype-guided care was noninferior to standard care for a combined thrombotic and bleeding outcome.

Crucially, patients treated with clopidogrel or ticagrelor/prasugrel based on their genotype for CYP2C19 had a 13% reduction in combined major and minor bleeding events compared with those given standard care.

"Easy to Use"

ten Berg told a press conference that genotyping is "easy to use" with the point-of-care test.

"It has a turnover time of within 1 hour, so when the patient has had his PCI, you can take a swab, and when the patient arrives in the ward, you know the result and you can administer the correct P2Y12 inhibitor," he said.

"We now have a tool where physicians can reduce bleeding complications by using this genotype-guided strategy for selecting oral P2Y12 inhibitors in all patients with STEMI undergoing primary PCI without an increase in thrombotic risk," ten Berg added.

Although results from further trials are awaited, he believes that, if confirmed, they warrant a change in the ESC acute STEMI guidelines, which currently recommend that all patients are treated with ticagrelor or prasugrel, with clopidogrel given if they are not indicated or contraindicated.

In the meantime, he said, he and his colleagues will follow the genotype-guided protocol "in all the centers that participated in the trial, and probably other centers will follow."

Kurt Huber, MD, director of the Department of Cardiology and Intensive Care Medicine, Wilhelminen Hospital, Vienna, told theheart.org | Medscape Cardiology that this is "a very important trial."

He pointed out that ticagrelor and prasugrel not available in every country, as "it's a very expensive therapy." Consequently, clopidogrel is used in a larger proportion of patients without any testing.

He said that, when looked at in the context of other data, including those from China, showing that genetic testing "is extremely important, I think this is good outcome…and I'm sure that we'll change the guidelines."

Less Stent Thrombosis

The aim of the study was to optimize the management of STEMI patients after primary PCI.

"These patients are at risk for stent thrombosis but also spontaneous myocardial infarction," he said, noting that they are "therefore treated, most of the time, in the ambulance, with aspirin, heparin, and a P2Y12 inhibitor. This is the focus of interest of our study."

Ten Berg said the rationale behind the ESC guideline recommendation to use ticagrelor or prasugrel over clopidogrel is that is that they are more potent than clopidogrel, leading to less stent thrombosis and lower rates of spontaneous myocardial infarction.

"But there is a drawback to this stronger P2Y12 inhibition, in that it leads to more bleeding, and bleeding is related to mortality."

One aspect of the weaker potency of clopidogrel is that approximately 30% of white patients have a loss-of-function allele for CYP2C19, which is needed to convert clopidogrel to its active metabolite.

Although these patients consequently do not respond properly to clopidogrel, ten Berg said that "it has also been shown that if the patient is not a carrier of the loss-of-function allele, the effect of clopidogrel is similar to ticagrelor or prasugrel."

The researchers therefore developed a CYP2C19 genotype-guided strategy in which patients with no loss-of-function of allele were treated with clopidogrel and those with the allele were given ticagrelor or prasugrel.

To compare this with guideline-directed therapy with ticagrelor or prasugrel, they conducted a randomized, open-label, blinded trial in STEMI patients treated at 10 hospitals: eight in the Netherlands, one in Italy, and one in Belgium.

In all, 2488 STEMI patients undergoing primary PCI between May 2012 and April 2018 were randomized in a 1:1 fashion to no genetic testing and standard care with ticagrelor or prasugrel (n = 1246) or genetic testing and CYP2C19 genotype-guided care (n = 1242) for 12 months. Testing was performed either in a central lab or using a point-of care test.

For central testing, blood samples were taken in the treating hospital and sent to St. Antonius Hospital. The tests themselves were performed in 2 hours, with the results available in 2 days.

The point-of-care test, which was used in approximately half of cases, required a swab to be placed into a fully automated machine, with the result obtained within 1 hour.

In the genetic-testing group as a whole, 35% of patients were found to be carriers of the loss-of-function allele and assigned to ticagrelor or prasugrel, whereas 65% were not and were treated with clopidogrel.

The rate of adherence was 82.0% in the standard care group and 84.5% in the genetic-testing group, with complete follow-up available for 99.9% of patients at 1 year.

The results showed that the combined end point of all-cause death, myocardial infarction, definite stent thrombosis, stroke, and major bleeding on PLATO criteria occurred in 5.9% of standard-care patients and 5.1% who underwent genetic testing.

This gave an absolute difference of –0.7% for genotype-guided vs standard care (95% CI, –2.0 to 0.7; < .001 for noninferiority).

Further analysis demonstrated that there was no significant difference in the occurrence of the combined end point between the two groups (hazard ratio [HR], 0.87; 95% CI, 0.62 - 1.21; = .40).

However, the team found that genotype-guided care was associated with significantly lower rates of combined major and minor bleeding on the PLATO criteria than standard care, (9.8% vs 12.5%; HR, 0.78; 95% CI, 0.61 - 0.98; P = .04).

The results of per-protocol and sensitivity analyses were comparable to those in the primary analyses.

Fewer Bleeding Complications

After his presentation, Huber asked ten Berg why, in genetically tested patients in whom clopidogrel was working maximally, there were fewer bleeding complications than with standard care.

Ten Berg pointed out that, even when it is "fully active, you get platelet aggregation inhibition of about 50%."

"With ticagrelor or prasugrel, it's about 80%, so there is still a difference, even if the patient is, say, a good responder to clopidogrel."

Huber then asked whether the team had a chance to compare their results to those from the ISAR-REACT trial.

This study, which was just presented at the ESC Congress 2019, showed that, among patients hospitalized for acute coronary syndrome and scheduled for invasive coronary angiography, prasugrel was, unexpectedly, associated with better 1-year outcomes than ticagrelor.

Ten Berg said that, although he had not yet made the comparison, he highlighted that more than 90% of patients in the standard-treatment group of their study received ticagrelor, and prasugrel use was "very low."

"It's not being used, especially not in the Netherlands in many centers, but we might reconsider now based on ISAR-REACT."

Finally, ten Berg addressed the potential cost-effectiveness of using genetic testing to direct patients to specific oral P2Y12 inhibitors.

He pointed out that the using a central laboratory is "more cumbersome, of course, "and it is more costly."

However, the point-of-care test does not lead to delays in care, and it is "not very costly," at approximately $100 per patient.

But the approximate cost of ticagrelor or prasugrel in the Netherlands is around $1000, and clopidogrel is only $100, he said, so "it probably also saves money" and they are going to look at the question more closely in their trial data.

The study was funded by ZonMW, a Dutch governmental organization, and Spartan Biosciences provided the Spartan RX point-of-care system free of charge. Ten Berg reported research contracts with ASTRA and ZonMw, and consulting/royalties/owner/stockholder relationships with ASTRA, Boehringer, Bayer, Ferrer, Isorsia, Pfizer, and MSD.

New Engl J Med. Published online September 3, 2019. Abstract

European Society of Cardiology Congress 2019: Abstract 6047. Presented September 3, 2019.

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