TEC Assessment Index

Special Report: Cardiovascular Pharmacogenomics

Assessment Program
Volume 22, No. 7
November 2007

Executive Summary

Background

Pharmacogenomics is the study of genetic influences on drug response. One of the more active areas of research in this field involves pharmacogenomics of cardiovascular disease. Given the high prevalence of cardiovascular disease and the large numbers of persons using cardiovascular drugs, pharmacogenomics has the potential to improve health outcomes.

Objective

This Special Report will survey the literature in the field of pharmacogenomics in relation to cardiovascular disease. It will highlight the particular diseases and drugs that have been studied in this field, and point out any promising areas. Areas not addressed in this Report include cytochrome P450 testing for warfarin dosage adjustment and use of genetic testing for cardiovascular disease susceptibility or outcome.

Search Strategy

A MEDLINE® search (via PubMed) for relevant review articles was completed for the period up to June 2007. The search strategy included the terms “pharmacogenetics” or “pharmacogenomics” and “cardiovascular” as text words or subject terms. The bibliographies of these review articles were also examined for other relevant review articles.

Selection Criteria

Based on the content of the review articles, it was determined that areas of this field that had sufficient research publications to discuss were pharmacogenomics of 1) statins, 2) angiotensin converting-enzyme (ACE) inhibitors, 3) beta blockers, and 4) diuretics.

Discussion

Most studies addressing the pharmacogenomics of cardiovascular disease examine potential genetic interactions of commonly prescribed drugs for highly prevalent conditions such as hypertension, congestive heart failure, and hypercholesterolemia. Studies have focused on differential efficacy of drugs, rather than prediction of adverse effects. There are very few currently marketed tests with potential pharmacogenomic use for cardiovascular drugs. 

Pharmacogenomic effects of existing and largely safe drugs may not translate into clinically useful knowledge. Such effects may not be strong or predictable enough to be clinically useful. It is difficult to prove that a particular drug previously demonstrated to be safe and effective is not effective in a particular subgroup, and demonstration of a stronger than average clinical benefit in a particular genetically identified group of persons may not change clinical decision making. Regarding research on statins, results are by and large unreplicated, inconsistent, or show small effects on lipid response or cardiovascular outcomes. The major review article in this field examined 41 studies. Many studies evaluated lipid response, which may not correlate with cardiovascular outcomes. ACE inhibitors have been studied many times because a known common polymorphism, the I/D polymorphism, is associated with serum ACE levels. The I/D allele and its interaction with ACE inhibitor treatment have been studied in a wide range of patients with differing indications and clinical endpoints. However, two review articles concluded that no conclusive pharmacogenomic effects have been demonstrated. Relatively fewer studies have examined beta-blockers and diuretics. Although some studies have shown pharmacogenomic interactions, such studies need to be replicated in order to confirm the associations and to assess the generalizability of the associations to other populations.

In sum, the study of pharmacogenetic interactions for cardiovascular diseases is at an early stage of development, and there are no tests that appear close to clinical utility. The literature is characterized by many exploratory findings that have not been replicated or have been contradicted. Strong and consistent associations between particular genotypes and drug response will be required for pharmacogenomics findings to be translated into clinical practice. Clinical trials may be necessary to determine whether patient outcomes are actually improved by treatment directed by genetic information.

TEC Assessment Index

KEYWORDS: ACE inhibitor; adverse effects; alpha-adducin; analytic validity; angiotensin; angiotensin; anticoagulation; ApoE; arrhythmia; association; associational; atorvastatin; beta blockers; CAD; candidate; cardiac; cardiovascular; CETP; cholesterol; cholesterol ester transfer protein; CLIA; clinical utility; clinical validity; congestive heart failure; converting; coronary artery disease; CYP450; cytochrome; DD; deletion; diuretics; drug; EGAPP; enzyme; gene testing; genetic variation; genetics; genomics; germline; HDL; HMG CoA; hypertension; hypertensive; I/D; insertion; LDL; lipids; Lipitor; MI; microarray; molecular; monoclonal antibody; mutation; myocardial infarction; NAT2; p450; PCR; personalized medicine; pharmacodynamics; pharmacogenetics; pharmacogenomics; pharmacokinetics; polymorphism; predictive; procainamide; renin; side effects; single nucleotide polymorphisms; SNPs; statins; stroke; susceptibility; target; therapy; transcriptional; warfarin; wild type;