New Studies Encourage Clopidogrel Genotyping

March 12, 2018

ORLANDO — Two new studies suggested that genotyping patients with acute coronary syndrome (ACS) or those undergoing percutaneous coronary intervention (PCI) to identify poor clopidogrel responders influences decision making on drug therapy by the interventionalist and may lead to benefits in outcomes.

The studies were presented here at the American College of Cardiology (ACC) 2018 Annual Scientific Session.

The Italian PHARMCLO trial, which was also published online March 11 in the Journal of the American College of Cardiology, showed that patients who received genotyping to guide the choice of medication were significantly less likely to experience a primary endpoint event — a composite of myocardial infarction (MI), stroke, cardiovascular death, and major bleeding — compared with patients who did not receive the genetic test.

"Selecting treatment on the basis of genetic data in addition to considerations concerning the patients' clinical characteristics may lead to a more personalized, and therefore more efficient, antiplatelet therapy, thus reducing both ischemic and bleeding risk," said Diego Ardissino, MD, Azienda Ospedaliero-Universitaria di Parma, Italy, the study's lead author.

However, Ardissino told theheart.org | Medscape Cardiology that the results of the PHARMCLO trial need to be interpreted with some caution because the study was stopped early, with only one quarter of the planned 3600 patients enrolled.

"Because of this the confidence intervals are very large and we can't estimate the size of the benefit accurately. So I would not recommend practice changes on the basis of these results," he said.

Ardissino explained that one of the ethical committees decided to stop the trial because of the lack of in vitro diagnosis certification for the genetic testing instrument used.

"This was very peculiar because the test had received CE mark approval and the same ethics committee had previously approved the trial at the start," he added. "I believe this was a big misunderstanding but we had to stop, and this is a great pity."    

Commenting on the PHARMCLO trial for theheart.org | Medscape Cardiology, Kim Eagle, MD, University of Michigan, Ann Arbor, who chaired the ACC press conference at which it was discussed, agreed that the study should be interpreted with caution.

"The stopping of this study early is very curious," Eagle said. "And despite the fact they had a far smaller sample than planned, they still showed quite a large beneficial effect on outcomes in the genetic tested group, many of whom received more potent antiplatelet agents."

"But this benefit included a reduction in bleeding as well as reduction in cardiac events, and I can't see how using a more potent antiplatelet agent could possibly bring about a reduction in bleeding," he noted. "So for me this makes it seem a little too good to be true and makes me question the broader result."

"So I don't think this trial is practice changing, and I wouldn't say we are there yet on genetic testing for antiplatelet drug choice," Eagle said. 

In a second study, known as ADAPT-PCI, genotyping patients undergoing PCI led to an increase in the use of more potent antiplatelet agents (prasugrel and ticagrelor), and a post hoc analysis suggested a higher clinical event rate in patients with the clopidogrel loss-of-function gene receiving clopidogrel than in those taking the higher-potency drugs.

"Our trial gives some insight into how genetic testing could be used in the real world," lead author, Sony Tuteja, MD, University of Pennsylvania, Philadelphia, said in an interview. "I think our results and those from the PHARMCLO study will encourage more use of such genetic testing to guide antiplatelet therapy."

There is a lot of skepticism about the value of genotyping for clopidogrel response, she added, "but if I had the loss-of-function genotype I certainly wouldn't want to be treated with clopidogrel."

Commenting on the trials' results, Deepak L. Bhatt, MD, Brigham & Women's Hospital, Boston, Massachusetts, said, "These recent studies nicely highlight the potential value of genotyping in personalizing antiplatelet therapy. There are a number of larger ongoing trials, such as TAILOR PCI, that will need to provide greater clarity to the field before we routinely change practice."

Reviewing previous data on this issue for theheart.org | Medscape Cardiology, Paul Gurbel, MD, Inova Heart and Vascular Institute, Falls Church, Virginia, noted that studies on personalization of antiplatelet therapy have shown mixed results. 

"Two previous studies using platelet function testing to guide therapy and using higher clopidogrel doses in poor responders did not show benefits, but the more recent TROPICAL ACS trial suggested that a personalized approach using prasugrel for high platelet reactivity may be safe and effective."

He added: "We now have evidence from two studies suggesting that genetically predicted platelet function analysis is feasible and can significantly influence treatment decisions of the interventional cardiologist, and may also improve outcomes."

A further study by Gurbel's group presented as a poster at the ACC meeting showed that bedside genotyping is feasible and confirmed the findings in the other two studies that genetic information can affect decision making by the interventionalist; 77% of patients were poor or intermediate clopidogrel metabolizers prescribed ticagrelor or prasugrel.

But he added that in contrast, the GEMINI-ACS-1 genetic substudy presented at last year's American Heart Association 2017 Scientific Sessions showed that genetic information did not affect physician decision making.

"In summary, personalization of antiplatelet therapy, whether by genetic analysis or determination of platelet function, is an area of continued interest," Gurbel said.

"Data from TROPICAL-ACS, and now from the new PHARMCLO trial, suggest potential clinical benefit when more potent agents are used to treat high platelet reactivity," he said. "Larger-scale trials are needed to confirm or refute these results, and we await the results of the TAILOR PCI, which is using bedside genetic assessment to personalize therapy."

PHARMCLO

In the PHARMCLO study, patients hospitalized for ACS were randomly assigned to standard of care or to bedside genotyping of three genes affecting clopidogrel metabolism: ABCB1, CYP2C19*2, and CYP2C19*17.

The trial was stopped after enrolling 888 of the planned 3600 patients.

Results showed that clopidogrel was used more frequently in the standard-of-care group (50.7% vs 43.3%), ticagrelor was used more frequently in the pharmacogenomic group (42.6% vs 32.7%; P = .02), and prasugrel was equally used in both groups.

The primary endpoint — a composite of cardiovascular death and the first occurrence of nonfatal MI, nonfatal stroke, and Bleeding Academic Research Consortium score of 3 to 5 defined major bleeding — occurred in 15.9% of patients in the pharmacogenomic group and in 25.9% of those in the standard-of-care group (hazard ratio, 0.58; 95% confidence interval, 0.43 - 0.78; P < .001).

Reductions were seen in both ischemic endpoints (13% in the pharmacogenomic group vs 21.4% in the standard-of-care group) and in bleeding endpoints (4.2% in the pharmacogenomic group vs 6.8% in the standard-of-care group).

ADAPT-PCI

In the ADAPT-PCI study, 504 patients having PCI with stent implantation were randomly assigned to genotype-guided antiplatelet therapy with a point-of-care test measuring just one gene (CYP2C19) or to usual care.

It was recommended that patients with the loss-of-function genotype receive more potent antiplatelet agents — ticagrelor or prasugrel — but this was not mandated, and the therapeutic choice was left to the interventional cardiologist.  

Results showed that these more potent agents were used more often in the genotype group: 30% vs 21%.  And in the 68 patients who were found to have the loss-of-function gene, 53% received ticagrelor or prasugrel, with 47% remaining on clopidogrel.

"We found that 71% of interventionalists followed the recommendations for therapy after the gene testing but 29% did not," Tuteja commented. "Reasons given for not using a more potent antiplatelet agent in a loss-of-function patient include having stable disease and concerns about cost."

Normal metabolizers were given prasugrel or ticagrelor in 22% of cases; reasons given included presence of more complicated disease, ACS, and location or size of stent.

Another factor predicting drug choice was whether the patient was receiving an antiplatelet agent before PCI.  "Those taking clopidogrel before the procedure were twofold more likely to remain on clopidogrel after.  And if patients were taking ticagrelor or prasugrel beforehand they almost always stayed on them regardless of their genotype," Tuteja noted.

"Our results show that interventionalists will consider genotype when choosing antiplatelet therapy if this information is available, but they also consider other factors when making the decision," she concluded.

Major adverse cardiac events did not differ between the genotype and usual care groups. However, in a post hoc analysis of the genotype group, patients with the loss-of-function allele receiving clopidogrel had a higher rate of the composite of major adverse coronary event /major bleeding/death than patients receiving ticagrelor or prasugrel (hazard ratio, 1.84; P = .03).

The PHARMCLO study was supported by Programma di Ricerca Regione-Università, Regione Emilia-Romagna, bando 2010–2012 Area 2 Ricerca per il Governo clinico, a program affiliated with Italy's regional health service. Ardissino and Tuteja report no disclosures.

American College of Cardiology (ACC) 2018 Scientific Session. Presentations 402-10, 404-08. Presented March 10 and 11, 2018.

J Am Coll Cardiol. Published online March 11, 2018. PHARMCLO abstract

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