ESC: genetic substudies of large trials question value of clopidogrel genotyping

Genetic substudies across a broad range of large clinical trials that used clopidogrel  raise questions about the clinical utility of clopidogrel genotyping. The substudies come from large and important trials like PLATO, TRITON-TIMI 38, CURE, and ACTIVE A.

Update:

A genetic substudy of PLATO finds that ticagrelor is superior to clopidogrel irrespective of genetic subtype. Therefore, according to Lars Wallentin and colleagues in their presentation at the ESC in Stockholm and in a simultaneous publication in the Lancet, “use of ticagrelor instead of clopidogrel eliminates the need for presently recommended genetic testing before dual antiplatelet treatment.” The PLATO investigators analyzed the role of CYP2C19 and ABCB1 polymorphisms in more than 10,000 patients enrolled in PLATO. Among patients with any CYP2C19 variation the primary endpoint of PLATO occurred in 8·6% of patients treated with ticagrelor versus 11·2% of patients treated with clopidogrel. A similar pattern occurred with ABCB1.

In a Lancet press release, Wallentin said that the “findings emphasise that ticagrelor will be a simple and reliable treatment to further improve survival and reduce the risk of recurrences in almost all patients with acute coronary syndrome without the need for any specific tests of its activity before or during routine treatment.”

In a second study appearing in the Lancet, Jessica Mega and colleagues genotyped ABCB1 in nearly 3000 patients enrolled in the TRITON-TIMI 38 trial comparing prasugrel to clopidogrel. They also examined the combined effect of ABCB1 variants and CYP2C19 variants and found that a majority of people have a genetic variation that may reduce the efficacy of clopidogrel. In sharp contrast to the PLATO investigators, they conclude that “as clinicians, professional societies, and patients integrate information about genetic factors affecting the response to thienopyridines, the roles of both ABCB1 and CYP2C19 should be considered.”

In an accompanying comment in the Lancet, Betti Giusti and Rosanna Abbate observe that both studies “confirmed the independent role of the CYP2C19 loss-of-function alleles as a determinant of major adverse cardiovascular events in these patients on clopidogrel… whereas they did not show any effects of CYP2C19 genetic variants in patients on prasugrel or ticagrelor.”

In a third paper, published online in the New England Journal of Medicine, Guillaume Paré and colleagues genotyped patients who had been enrolled in the  CURE and ACTIVE A trials and found no reduction in the effect of clopidogrel among patients with a loss-of-function CYP2C19 genotype, although patients with a gain-of-function genotype received greater benefit from clopidogrel.

“The bottom line,” according to Sanjay Kaul, is that “routine genetic testing to define platelet responsiveness to P2Y12 receptor antagonists cannot be recommended at the present time.” Here are his further comments:

In the 2 placebo-controlled studies (CURE and ACTIVE A), CYP2C19 loss-of-function variants did not modify the efficacy and safety of clopidogrel. Similarly, in the active control study (PLATO), CYP2C19 loss-of-function variants or ABCB1 TT variant did not modify the efficacy and safety of ticagrelor compared with clopidogrel. The TRITON analysis showed that variants in the ABCB1 TT and CYP2C19 loss-of-function allele are associated with adverse cardiovascular outcomes in patients treated with clopidogrel, but not prasugrel. Although prasugrel vs. clopidogrel results are not presented by Mega et al (at least not in the primary report), I find it interesting that amongst the CT/CC carriers for the ABCB1 variant, the MACE event rate was numerically higher in prasugrel-treated (8.7%) compared with clopidogrel-treated patients (7.8%). The data for the TT homozygotes appear to be going in the right direction (12.9% clopidogrel vs. 11% prasugrel).

When one estimates the predictive accuracies of the genetic testing for major adverse CV outcomes (MACE), the positive predictive values (PPV) for CYP2C19 loss-of-function variants amongst clopidogrel-treated patients range from 8% in CURE, 10% in PLATO, 11% in TRITON and 22% in ACTIVE A. The corresponding PPV for ABCB1 TT variant ranges from 10% in PLATO to 13% in TRITON. In other words, the predictive accuracy of these genetic polymorphisms is low for MACE and even lower for bleeding and stent thrombosis (presumably because of low prevalence of these events). These data, therefore provide support for the recent ACC/AHA clinical alert on clopidogrel that concluded “the evidence base is insufficient to recommend either routine genetic or platelet function testing at the present time”. The overwhelming majority of events cannot be predictable solely on the basis of genetic testing. Thus, improvement in prediction of future cardiovascular events in patients receiving antiplatelet therapy will likely benefit from development of a global risk assessment score based on traditional demographic, clinical, and procedural risk factors, genetics, and biological information rather than any single test result.

This post is republished with permission from CardioExchange, a new website for cardiovascular healthcare professionals from the New England Journal of Medicine.CardioBrief readers who are healthcare professionals are invited to join the site.

Here are the press releases from the Lancet:
TICAGRELOR IS BETTER THAN CLOPIDOGREL TO PREVENT BLOOD CLOTS REGARDLESS OF GENETIC PROFILE, THUS ELIMINATING NEED FOR GENETIC TESTING (embargo 0800H New York time Sunday 29 August)

A study published Online First and in an upcoming Lancet shows that anticlotting treatment using ticagrelor is better than clopidogrel, regardless of the presence of genetic variations that leads to variable efficacy of clopidogrel. Thus use of ticagrelor in patients with acute coronary syndromes eliminates the need for genetic testing that is considered necessary to avoid a poor response when treating with clopidogrel. The Article is written by Professor Lars Wallentin, Uppsala University, Sweden, and colleagues.

For patients with acute coronary syndromes, dual antiplatelet (anticlotting) treatment with aspirin and a thienopyridine (clopidogrel or prasurgrel) is recommended to prevent recurrences such as new heart attacks and clotting of implanted stents in the coronary arteries (stent thrombosis). The effects of the most commonly used drug, clopidogrel are variable and affected by genetic variations in the genes CYP2C19 (responsible for activating the drug) and ABC1B (responsible for its absorption). Patients with a genetically determined poor response to clopidogrel, therefore, had inadequate protection against new cardiovascular events. Ticagrelor operates through a completely different mechanism and has been proven to give more pronounced and consistent platelet (clotting) inhibition, with quicker action. There are no known genetic variants affecting ticagrelor metabolism, although the authors of this new work say that ABC1B, since it is responsible for absorption, could have an effect.

In this new work, the authors used data from the PLATO (PLATelet inhibition and patient Outcomes) study. In PLATO, ticagrelor reduced events of the primary composite endpoint of cardiovascular death, heart attack, or stroke by 16% and stent thrombosis with 34% without any difference in overall major bleeding, but with an 19% increase of spontaneous major bleeding during long-term treatment. In this first substudy from the PLATO genetics programme, the researchers investigated the role of CYP2C19 and ABCB1 polymorphisms on efficacy and safety outcomes both between and within the ticagrelor and clopidogrel arms of the PLATO study.

A total of 10 285 patients provided samples for genetic analysis. The primary outcome occurred less often with ticagrelor versus clopidogrel, irrespective of CYP2C19 genotype: 8·6% versus 11·2% in patients with any genetic variation (either or both copies); and 8·8% versus 10·0% in those without any variation. For the ABCB1 genotype, event rates for the primary outcome were also consistently lower in the ticagrelor than in the clopidogrel group for all genotype groups (8·8% vs 11·9% for the high-expression genotype). The study verified the effect of the genetic loss-of-function variation in the clopidgorel group since the event rate for the primary outcome at 30 days was higher in patients with any than in those without any loss-of-function variation (5·7% vs 3·8%).

In the main PLATO trial, ticagrelor treatment was associated with a 19% increase in spontaneous bleeding events. In the clopidogrel group the bleeding rates were higher in the group with any gain-of-function variation. However, the researchers recorded no significant interaction of any CYP2C19 variation when comparing bleeding risks between the treatment groups. Accordingly, spontaneous bleeding events were higher with ticagrelor treatment regardless of CYP2C19 variation.

The authors conclude: “Ticagrelor is a more efficacious treatment for acute coronary syndromes than is clopidogrel, irrespective of CYP2C19 and ABCB1 polymorphisms. Use of ticagrelor instead of clopidogrel eliminates the need for presently recommended genetic testing to identify poor responders to clopidogrel before start of dual antiplatelet treatment.”

“These findings emphasise that ticagrelor will be a simple and reliable treatment to further improve survival and reduce the risk of recurrences in almost all patients with acute coronary syndrome without the need for any specific tests of its activity before or during routine treatment. The study also shows the importance of evaluating treatments not only in a diffuse large group of patients but also in relation to the individual response based on genetic or other sources of variation,” adds Professor Wallentin*, the leader of the PLATO study.

GENETIC VARIATION IN KEY CELL PUMPING MECHANISM REDUCES EFFECTS OF CLOPIDOGREL TREATMENT (BUT NOT PRASUGREL), LEAVING THOSE AFFECTED AT INCREASED RISK OF CARDIOVASCULAR EVENTS

A study published Online First and in an upcoming Lancet shows that patients with a genetic variation affecting a key protein pump in drug transport do not respond as well to the anticlotting drug clopidogrel—as such, patients with this variation at are at increased risk of cardiovascular events with standard clopidogrel treatment. However, no association exists between this genetic variation and another anticlotting drug, prasugrel. This, and other work on a separate genetic variation, shows that more than half the population have a genetic profile making them less amenable to clopidogrel treatment, and the authors of this new work say such profiling should be considered when looking at anticlotting regimens in patients requiring anticlotting treatment. The Article is by Dr Jessica Mega, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA, and colleagues.

Both clopidogrel and prasugel are prodrugs, meaning that they are metabolically activated once inside the body. Both are used to prevent blood clots forming in patients with coronary artery diseases, peripheral vascular disease, and cerebrovascular disease.

Previous work has already identified CYP2C19 as another genetic variation affecting clopidogrel (but not prasugrel) metabolism. In this case, patients with the variation in CYP2C19 have inadequate clopidogrel activation (but not prasugrel). In this study, Mega and co-workers look at another part in the chain vital for drug absorption: ABCB1 is a gene that encodes P-glycoprotein, a protein pump which transports molecules across cell membranes. The pump is found, among other places, on the epithelial cells lining the gut wall. The researchers aimed to discover whether variation in the ABCB1 gene caused further problems in clopidogrel metabolism, in addition to those caused by CYP2C19. They looked at the population studied in the TRITON-TIMI 38 trial published in 2007 (which compared clopidogrel and prasugrel treatment in patients with acute coronary syndromes) as the basis for their analysis. The primary endpoint in this study was cardiovascular death, heart attack, or stroke.

Participants in TRITON-TIMI 38 had three possible variants for ABCB1 3435C→T: TT, CT, and CC (C=cystosine and T=thymine, both building blocks of DNA). The researchers showed that patients on clopidogrel with the TT variation had a 72% increased risk of hitting the primary endpoint compared with CT/CC collectively. No association was recorded with prasugrel and ABCB1 variation. The authors speculate that prasugrel is metabolised more rapidly, mitigating the effects of the variation.

The authors also showed that the ABCB1 and CYP2C19 variations have separate but complementary effects on the response to clopidgrel. Collectively, patients with either variation or both were twice as likely to hit the primary end point as those with neither. The authors say: “When both ABCB1 and CYP2C19 were taken into account, in this population following an acute coronary syndrome and percutaneous coronary intervention, nearly half the population carried a genotype associated with increased risk of major adverse events during treatment with standard doses of clopidogrel.”

They conclude: “As clinicians, professional societies, and patients integrate information about genetic factors affecting the response to these drugs, the roles of both ABCB1 and CYP2C19 should be considered.”

In a linked Comment covering both the Wallentin and Mega genetics papers, Dr Betti Giusti and Dr Rosanna Abbate, University of Florence-Careggi Hospital, Florence, Italy, say: “The issue is not to choose the lesser of the evils, but the better of the goods—by identifying the therapeutic strategy that, in consideration of individual characteristics, warrants the higher benefit/risk ratio.”

They conclude: “Prospective studies evaluating different antiplatelet treatments tailored to individual characteristics of patients—genetic profile, residual platelet reactivity, drug–drug interactions, and traditional and procedural risk factors—are urgently needed to identify therapeutic strategies that will provide the best benefit for the single patient in this high-risk clinical setting.”

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