STOCKHOLM – Genetic profiling can identify the roughly one-fourth of patients with stable coronary artery disease who will not obtain clinical benefit from ACE inhibitor therapy, as well as a far larger group of superresponders.
“Our findings open the route to individualize therapy by pharmacogenetic profiling. Such individualized therapy could revolutionize drug therapy by enabling physicians to prescribe drugs only to those patients most likely to benefit from the therapy. This would not only increase efficacy, but also decrease unnecessary treatment of patients and avoid unwanted side effects, thereby decreasing overall costs,” Dr. Jasper J. Brugts said at the congress.
Although developing the pharmacogenetic profile entailed a huge multinational research effort, the resultant gene test – which focuses on three single nucleotide polymorphisms on two genes – is simple. But, pharmacogenetic profiling to target ACE inhibitor therapy is not yet ready for use in clinical practice. Further confirmatory studies need to be done first, added Dr. Brugts of Erasmus University, Rotterdam, the Netherlands.
He and his coworkers developed their pharmacogenetic score for predicting clinical outcomes in perindopril-treated patients who have stable CAD by analyzing data from the landmark placebo-controlled, randomized EUROPA (European Trial on Reduction of Cardiac Events With Perindopril in Stable Coronary Artery Disease) trial. In that study, perindopril provided a 20% reduction in the relative risk of cardiac death or MI, compared with placebo, during 4.2 years of follow-up.
The investigators were able to isolate DNA from 9,454 of the 12,218 EUROPA participants. They analyzed 12 candidate genes and 52 haplotype-tagging single nucleotide polymorphisms (SNPs) lying within the pharmacogenetic pathway of ACE inhibitors.
In a multivariate analysis, three SNPs emerged as having a significant negative association with treatment benefit. Two are located on the angiotensin II type 1 receptor gene; the third is on the bradykinin type 1 receptor gene. The greater the number of unfavorable alleles in these SNPs that a patient possessed, the lesser the treatment benefit of perindopril.
In the overall EUROPA study, for example, the absolute risk of cardiac death or MI during follow-up was 9.9% with placebo, vs. 8.0% with perindopril, meaning that the ACE inhibitor provided a 20% relative risk reduction. But in patients with none of the unfavorable alleles, the event rate was 12.2% with placebo, compared with 6.3% with perindopril – a 55% relative risk reduction.
These data illustrate an easily overlooked key point about clinical trial data, according to Dr. Brugts: “The treatment effect that is observed for the total group in a clinical trial does not necessarily count for the patient sitting in front of you at your desk. The risk reduction varies from patient to patient.”
Altogether, 74% of EUROPA patients who were included in the pharmacogenetic study were identified as perindopril responders via blinded genetic profiling. They averaged a 33% relative risk reduction vs. placebo, compared with the 20% figure for the overall study.
In contrast, 26% of study participants had a “nonresponder” genetic profile based upon the three SNPs. They averaged a 26% higher event rate than did placebo-treated patients with the same pharmacogenetic score, although this increased risk did not reach statistical significance.
The pharmacogenetic profile has held up in a preliminary confirmatory analysis of 1,051 patients with cerebrovascular disease who were randomized to perindopril or placebo in the previously reported PROGRESS trial (Lancet 2001;358:1033-41), Dr. Brugts continued.
The pharmacogenetic research is funded by the Netherlands Heart Foundation. He said he had no conflicts of interest.