Nov. 26, 2020
One of the keys to delivering personalized medicine is the use of information from the genome — the set of chromosomes in an individual — and its variation to guide medical decision-making. By identifying individual genetic profiles, the hope is that therapies can be targeted, dosages can be optimized and side effects can be reduced.
Patients who undergo percutaneous coronary intervention (PCI) are commonly prescribed anti-platelet agents such as clopidogrel for up to one year after the procedure to reduce the risk of stent thrombosis. Clopidogrel is a prodrug, absorbed by the intestine and converted to its active metabolite in the liver via two oxidative steps that involve the cytochrome P450 superfamily enzyme system, of which the CYP2C19 enzyme is the most important component.
Individuals who have a loss-of-function (LOF) variant of the CYP2C19 gene are unable to fully metabolize the prodrug into the active metabolite, reducing its effectiveness and increasing the risk of ischemic events. The most common LOF alleles are CYP2C19*2 and CYP2C19*3, occurring in approximately 30% of the U.S. population. Studies have shown that patients who carry these LOF alleles have an increased incidence of ischemic events when they take clopidogrel compared with those without the alleles who take clopidogrel.
This risk is mediated by many factors, not just genotype, including systemic factors such as diabetes mellitus and chronic kidney disease as well as technical factors such as arterial and stent size and flow. It is unknown whether routinely genotyping for CYP2C19 LOF alleles and prescribing anti-platelet therapy based on the results can reduce the incidence of ischemic events.
To test this hypothesis, the largest genotype-guided cardiovascular trial was designed and initiated by researchers at Mayo Clinic in collaboration with an international network of sites to determine if anti-platelet therapy guided by CYP2C19 genetic metabolizer status could reduce the incidence of ischemic events after PCI.
The Tailored Antiplatelet Initiation to Lessen Outcomes Due to Decreased Clopidogrel Response after Percutaneous Coronary Intervention (TAILOR-PCI) study was a multicenter (40 centers in the U.S., Canada, Mexico and South Korea), randomized, prospective clinical trial. Patients undergoing PCI for stable or unstable angina were randomized to a genotype-guided strategy (n = 2,652), in which patients without CYP2C19 LOF alleles received 75 mg of clopidogrel daily and patients with the LOF alleles received 90 mg of ticagrelor twice daily. Ticagrelor is not a prodrug and is not dependent on CYP2C19 metabolic activation for therapeutic effect. The standard therapy (n = 2,650) group received 75 mg of clopidogrel once daily without prospective genotyping.
To test the hypothesis that altering anti-platelet therapy based on CYP2C19 LOF status would lead to improved outcomes, the primary analysis was conducted only in the 1,849 patients with LOF alleles, 903 in the genotype-guided group compared with 946 in the standard therapy group. The primary endpoint was a composite of cardiovascular death, myocardial infarction, stroke, stent thrombosis and severe recurrent ischemia at 12 months. Investigators hypothesized that genotype-guided therapy would reduce the incidence of the primary endpoint in the genotype-guided group by 50% compared with the standard therapy group.
At the end of the trial, the composite endpoint occurred in 3.9% (35/903) of the genotype-guided group, and in 5.7% (54/946) of the standard therapy group (p = 0.056). The genotype-guided strategy yielded a 34% reduction in cardiovascular events, but did not reach the 50% reduction target, and was not statistically beneficial compared with standard therapy.
Based on the statistically not significant p-value of 0.056, if one assumed that genotype-guided therapy had no effect in reducing ischemic events as compared with standard therapy, then less than 3% of studies would have an effect of 34% reduction in ischemic events as observed in TAILOR-PCI ― therefore making it highly probable that genotype-guided treatment was associated with improved outcomes.
"Although these results fell short of the effect size that we predicted, they nevertheless provide a signal that offers support for the benefit of genetically guided therapy, with approximately one-third fewer adverse events in the patients who received genetically guided treatment compared with those who did not," said Naveen L. Pereira, M.D., cardiologist at Mayo Clinic in Rochester, Minnesota, and co-principal investigator of the study with Michael Farkouh, M.D., from the Peter Munk Cardiac Centre, University of Toronto.
While the primary outcome was not statistically different between treatment groups at 12 months, interestingly a post hoc analysis revealed a 79% reduction in adverse events in the first three months in the genotype-guided group compared with those in the standard therapy group, which may indicate a particularly high-risk window of time after stenting. Similarly, a pre-specified analysis demonstrated a 39% (p = 0.01) reduction in cumulative or multiple ischemic events per patient with genotype-guided therapy.
It is assumed that a more modest effect of genetic testing, which would have translated to enrolling more patients, may have resulted in the trial achieving its primary endpoint. When the TAILOR-PCI trial was designed in 2012, around 10% to 12% of patients who received a stent could be expected to have a major adverse cardiovascular event within a year. Over the course of the trial, the standard of care evolved through greater use of drug-coated stents and other treatments, which reduced the expected rate of adverse events in a year to about 5%. This change in technology substantially improved care for patients, but at the same time may have made it more difficult for the trial to reach its goal of a 50% reduction in adverse events with the number of patients enrolled.
For more information
Mayo Clinic Cardiovascular Research Center. study.TAILOR-PCI Mayo Clinic.