The Rationale and Design of the Perindopril Genetic Association Study (PERGENE): A Pharmacogenetic Analysis of Angiotensin-Converting Enzyme Inhibitor Therapy in Patients with Stable Coronary Artery Disease

Abstract

Background Angiotensin-converting enzyme (ACE) inhibitors reduce clinical symptoms and improve outcome in patients with hypertension, heart failure, and stable coronary artery disease (CAD) and are among the most frequently used drugs in these patient groups. For hypertension, treatment is guided by the level of blood pressure. In the secondary prevention setting, there are no means of guiding therapy. Prior attempts to target ACE-inhibitors to those patients that are most likely to benefit have not been successful, mainly due to the consistency in the treatment effect in clinical subgroups. Still, for prolonged prophylactic treatment with ACE-inhibitors it would be best to target treatment to only those patients most likely to benefit, which would considerably lower the number needed to treat and increase cost-effectiveness. A new approach for such "tailored-therapy" may be to integrate information on the genetic variation between patients. Until now, pharmacogenetic research of the efficacy of ACE-inhibitor therapy in CAD patients is still in a preliminary stage. Methods The PERindopril GENEtic association study (PERGENE) is a substudy of the EUROPA trial, a randomized double-blind placebo-controlled multicentre clinical trial which demonstrated a beneficial effect of the ACE-inhibitor perindopril in reducing cardiovascular morbidity and mortality in 12.218 patients with stable coronary artery disease Cardiovasc Drugs Ther (2009) (mean follow-up 4.2 years). Blood tubes were received from patients at the beginning of the EUROPA trial and buffy coats were stored at −40°C at the central core laboratory. Candidate genes were selected in the renin-angiotensin-system and bradykinin pathways. Polymorphisms were selected based on haplotype tagging principles using the HapMap genome project, Seattle and other up-to-date genetic database platforms to comprehensively cover all common genetic variation within the genes. Selection also took into consideration the functionality of SNP's, location within the gene (promoter) and existing relevant literature. The main outcome measure of PERGENE is the effect of genetic factors on the treatment benefit with ACEinhibitors. The size of this pharmacogenetic substudy allows detection with a statistical power of 98% to detect a difference in hazard ratios (treatment effect) of 20% between genotypes with minor allele frequency of 0.20 (two-sided alpha 0.05). Conclusion The PERGENE study is a large cardiovascular pharmacogenetic study aimed to assess the feasibility of pharmacogenetic profiling of the treatment effect of ACE-inhibitor use with the perspective to individualize treatment in patients with stable coronary artery disease.

A pharmacogenetic analysis of determinants of hypertension and blood pressure response to angiotensin-converting enzyme inhibitor therapy in patients with vascular disease and healthy individuals

“…The PERindopril GENEtic association study (PERGENE) is a substudy of the EUROPA trial; the designs of both studies were previously described in detail [15,16]. In short, the EUROPA trial randomized 12 218 stable CAD patients to perindopril (8 mg/day) or placebo.…”

“…Therefore, we conducted a largescale pharmacogenetic association analysis in patients of the EUROPA trial randomized to the ACE inhibitor perindopril versus placebo [14,15]. To ensure comprehensive coverage of genetic variation in the related hormonal systems, a haplotype-tagging approach was used to select single-nucleotide polymorphisms (SNPs) in multiple RAAS and kallikrein-bradykinin system genes together [15].…”

“…Therefore, we conducted a largescale pharmacogenetic association analysis in patients of the EUROPA trial randomized to the ACE inhibitor perindopril versus placebo [14,15]. To ensure comprehensive coverage of genetic variation in the related hormonal systems, a haplotype-tagging approach was used to select single-nucleotide polymorphisms (SNPs) in multiple RAAS and kallikrein-bradykinin system genes together [15]. As hypertension is a strong intermediate phenotype of (cardio)vascular disease, we investigated two separate research question: whether genetic variation in the cascade of RAAS/bradykinin system genes is related to the prevalence of hypertension and determines the BP response to ACE inhibitor therapy.…”

Prediction of absolute risk reduction of cardiovascular events with perindopril for individual patients with stable coronary artery disease — Results from EUROPA

“…The design, rationale and outcomes of the EUROPA trial and the PERindopril GENetic association study (PERGENE) substudy have been described elsewhere [16,17]. Briefly, the EUROPA trial was a randomized, double blind study evaluating the effect of perindopril 8 mg once daily versus placebo on major cardiovascular adverse events (MACE) comprising cardiovascular death, myocardial infarction (MI), and resuscitated cardiac arrest in 12,218 patients with sCAD.…”

Genetic variation-optimized treatment benefit of angiotensin-converting enzyme inhibitors in patients with stable coronary artery disease

“…It is unclear whether this genetic variation modifies the clinical efficacy of ACE inhibitors. Several small studies have examined this interaction, but have yielded inconclusive results [18][19][20][21]. Most of these studies were short Supplemental digital content is available for this article.…”