Tailored-therapy of ACE-inhibitors in Coronary Artery Disease: Pharmacogenetic Profiling of Treatment Benefit

Abstract

To optimally treat patients, and to develop ways to guide ACE-inhibitor treatment, it remains essential to identify those patients most likely to benefit from therapy. New research to elucidate such heterogeneity is necessary. If feasible, guided-therapy of ACE-inhibitors will have a large impact on clinical practice by increasing patient's benefit of drug prescriptions and reducing healthcare costs: to get the right drug to the right patient. The quest for the Holy Grail: tailoring drug therapies to individual patients. The purpose of this thesis was to investigate a new approach to guide ACE-inhibitor therapy using patient specific genetic characteristics (19). We studied the feasibility of pharmacogenetic profiling of the treatment benefit of ACE-inhibitor therapy. We focused on the common genetic variation in the candidate genes of the direct pharmacodynamic pathway of ACE-inhibitors: the renin-angiotensin-system and kallikrein-bradykinin system. These studies were conducted within the randomized placebo-controlled EUROPA-trial studying the ACE-inhibitor perindopril versus placebo in ten thousand patients with stable coronary artery disease. The main research questions we examined were as follows: - Is the treatment benefit (reduction of cardiovascular events) of ACE-inhibitor therapy modified by genetic variation between patients? - Is the level of blood pressure and blood pressure reduction by ACE-inhibitor therapy modified by genetic variation between patients? - Can we develop a pharmacogenetic profile to individualize ACE-inhibitor therapy and optimize patients' benefit in stable coronary artery disease