Genomic Testing Making Inroads in Cardiology

Adoption of pharmacogenomic testing has trailed behind optimistic projections, particularly in the field of cardiology. But now two recent studies published in The Lancet by the Thrombolysis in Myocardial Infarction Study Group are demonstrating that genetic information can improve risk assessment for coronary artery disease and can identify patients most likely to benefit from preventive statin therapy. Furthermore, pharmacogenomic testing can identify atrial fibrillation patients who are at greater risk for bleeding events early in treatment and would benefit from novel anticoagulant therapy instead of widely-prescribed warfarin. “There are many conditions for which genetic testing can fit very nicely into routine cardiology practice,” Jessica Mega, M.D., lead author of both studies, tells DTET. “Cardiologists are personalizing medicine all the time for patients, by taking into account other variables like diabetes status, creatinine levels, or age. There has been this hesitation around genetic information, but I believe that is eroding.”
Genetics IDs Cardiac Risk, Those to Benefit From Statins A genetic risk score identifies individuals at increased risk for heart attack or death from coronary artery disease, according to a study published online March 4 in The Lancet. The researchers say the composite score further identifies those individuals who will derive the most clinical benefit from initiating statin therapy. “Clinical, biochemical, and imaging parameters have been used to stratify cardiovascular risk and potentially to tailor therapy,” writes Mega, who is currently on leave from Harvard University to work on a project with Google X. “Our present analysis suggests that genetics might also have such a role.” The Brigham and Women’s Hospital-based researchers conducted a meta-analysis of 48,421 individuals (3,477 events) participating in five different trials. A genetic risk score was developed based on 27 previously identified single nucleotide polymorphisms associated with heart disease. Individuals were stratified into low (quintile 1), intermediate (quintiles 2 to 4), and high (quintile 5) risk groups. Participants classified as having intermediate or high genetic risk had more than a 30 percent and 70 percent increase in the risk of cardiovascular death or a heart attack, respectively, compared to the lowest risk group. Those with the highest risk though, showed the greatest benefit from statin therapy. Benefits were seen in both primary and prevention of recurrent cardiovascular events. “Debate continues about the use of statins in people at lower risk of coronary heart disease events, especially in primary prevention populations, which is driven by concerns about safety and cost-effectiveness in an extremely broad population,” write the authors. “For that reason, an understanding of the absolute risk reductions achieved with statin therapy in different subgroups could be useful.”
Genetic Variants Raise Warfarin Safety Concerns Patients with genetic polymorphisms in CYP2C9 and VKORC1 are more likely to experience early bleeding upon initiation of warfarin treatment, according to a study published online March 11 in The Lancet. Pharmacogenomic testing can identify atrial fibrillation patients with these variants tied to bleeding risk and can allow clinicians to tailor therapy selection and improve safety outcomes. “Bleeding complications are the most important concern related to warfarin therapy because of the narrow therapeutic range and high degree of variability between individuals,” writes Mega and internationally-based colleagues. “Although these genetic variants affect the warfarin dose required, their effects on clinical outcomes, namely bleeding, remain debated, and payment for genotyping is controversial.” While the U.S. Food and Drug Administration label for warfarin states that genetic variants in the CYP2C9 and VKORC1 genes can assist in optimizing warfarin dosage, a “conclusive link” between these gene variants and bleeding outcomes remains debated. Newer anticoagulants with lower rates of associated bleeding are now available, but are significantly more expensive than warfarin. ENGAGE AF-TIMI 48 was a randomized, double-blinded clinical trial in which patients with atrial fibrillation were assigned to warfarin (dosed to achieve a target international normalized ratio of 2.0 to 3.0), or to higher-dose (60 mg) or lower-dose (30 mg) edoxaban once daily. The trial prespecified genetic analysis for a subgroup of patients (n=14,348). In the current study, the authors assessed genotypes and bleeding events for those taking warfarin and edoxaban. Of the genotyped patients, 4,833 were assigned to warfarin and the majority (61.7 percent) were classified as normal responders, while 35.4 percent were sensitive responders and 2.9 percent were classified as highly sensitive responders. In the first 90 days of therapy, sensitive and highly sensitive responders spent significantly greater proportions of time over-anticoagulated and had increased risks of bleeding with warfarin (31 percent increased risk for sensitive responders and more than 2.6 times greater risk for highly sensitive responders), compared with normal responders. Among participants taking warfarin, 334 had an overt bleeding event in the first 90 days. The researchers say that genotype added “independent information beyond clinical risk scoring.” “Although the increased risk of any overt bleeding was most apparent in the first 90 days, we found a long-term excess of serious bleeding subtypes ... in sensitive and highly sensitive responders receiving warfarin,” write the authors. “Heightened response to even small doses of warfarin might, therefore, make some individuals vulnerable to over-anticoagulation and bleeding from fluctuations in diet, drug–drug interactions, and other environmental factors at any time.” Among patients randomized to either dose of edoxaban, genotype was not significantly associated with an increased risk of bleeding. But for those taking edoxaban, bleeding risk was cut in the first 90 days among sensitive and highly sensitive responders, compared with those taking warfarin. “Warfarin will continue to be used because of low cost and wide availability,” the researchers say. “In cases where there is a plan to use warfarin, genotyping could identify close to 40 percent of patients in whom there is an early increased risk of over-anticoagulation and bleeding with use of standard dosing practices. ... This risk could be substantially mitigated by using edoxaban.” The study was funded by Daiichi Sankyo, the developer of edoxaban. Takeaway: Evidence supporting incorporation of genomic testing into routine cardiology practice is mounting. Genomic data can lead to better risk assessment therapy selection to reduce risk of future events, while mitigating safety concerns.