Personalized Medicine and Antiplatelet Therapy: Ready for Prime Time?
Personalized Medicine and Antiplatelet Therapy: Ready for Prime Time?
The concept of personalized medicine is receiving significant attention due to the greater awareness of the influence of genes to the drug effects. Single nucleotide polymorphisms (SNPs) in the DNA are the most frequent form of sequence variations in the human genome and appear to affect the efficacy and safety of many drugs. The term 'pharmacogenetics' was coined over 40 years ago with an ultimate goal of using the genetic makeup of an individual to predict drug response and efficacy. We are just at the beginning of a new era in personalized cardiovascular therapies. However there is little doubt that, in the near future, pharmacogenetic testing will become a valuable tool for a drug and dose selection and thus result in a more desirable benefit/risk ratio for drugs prescribed to patients.
Over the past decades, the platelet has emerged as a major pathway involved in cardiovascular diseases. The platelet as a 'drug target' has spawned a variety of new drugs that have been shown in large-scale randomized trials to improve patient outcomes in acute coronary syndromes and following percutaneous revascularization procedures. Until recently aspirin, centred on the tromboxane pathway, was the only antiplatelet agent considered to be the gold standard for effectiveness in both primary and secondary prevention of atherothrombotic diseases. Although it continues to be used as the gold standard antiplatelet therapy, adenosine diphosphate (ADP) receptor antagonists and phosphodiesterase inhibitors in combination therapy appear to exert synergistic effects and provide added benefits among high-risk patients for cardiovascular disease.
Nevertheless an important lesson that has emerged from number of trials is that antiplatelet potency per se does not necessarily guarantee enhanced clinical benefit or tolerability for a given patient. This may in part be due to the substantial interindividual variation in platelet response to ADP. The mechanism underlying such variation has recently become clearer (Figure 1). Specifically the wide inter-subject variabilities to antiplatelet agents such as clopidogrel, may be genetically mediated and arises from altered drug metabolism or transport. In the current review, we will focus on the key molecular mechanisms involved in the pharmacological action of oral antiplatelet drugs, the environmental and genetic factors that may impact antiplatelet therapies. We will also provide an update on recent advances in personalized medicine of relevance to arterial thrombosis and antiplatelet drugs. Finally, we will provide our perspectives of pharmacogenetic testing for drugs used to treat cardiovascular diseases.
(Enlarge Image)
Figure 1.
Factors influencing the variability of antiplatelet drug response.
Abstract and Introduction
Introduction
The concept of personalized medicine is receiving significant attention due to the greater awareness of the influence of genes to the drug effects. Single nucleotide polymorphisms (SNPs) in the DNA are the most frequent form of sequence variations in the human genome and appear to affect the efficacy and safety of many drugs. The term 'pharmacogenetics' was coined over 40 years ago with an ultimate goal of using the genetic makeup of an individual to predict drug response and efficacy. We are just at the beginning of a new era in personalized cardiovascular therapies. However there is little doubt that, in the near future, pharmacogenetic testing will become a valuable tool for a drug and dose selection and thus result in a more desirable benefit/risk ratio for drugs prescribed to patients.
Over the past decades, the platelet has emerged as a major pathway involved in cardiovascular diseases. The platelet as a 'drug target' has spawned a variety of new drugs that have been shown in large-scale randomized trials to improve patient outcomes in acute coronary syndromes and following percutaneous revascularization procedures. Until recently aspirin, centred on the tromboxane pathway, was the only antiplatelet agent considered to be the gold standard for effectiveness in both primary and secondary prevention of atherothrombotic diseases. Although it continues to be used as the gold standard antiplatelet therapy, adenosine diphosphate (ADP) receptor antagonists and phosphodiesterase inhibitors in combination therapy appear to exert synergistic effects and provide added benefits among high-risk patients for cardiovascular disease.
Nevertheless an important lesson that has emerged from number of trials is that antiplatelet potency per se does not necessarily guarantee enhanced clinical benefit or tolerability for a given patient. This may in part be due to the substantial interindividual variation in platelet response to ADP. The mechanism underlying such variation has recently become clearer (Figure 1). Specifically the wide inter-subject variabilities to antiplatelet agents such as clopidogrel, may be genetically mediated and arises from altered drug metabolism or transport. In the current review, we will focus on the key molecular mechanisms involved in the pharmacological action of oral antiplatelet drugs, the environmental and genetic factors that may impact antiplatelet therapies. We will also provide an update on recent advances in personalized medicine of relevance to arterial thrombosis and antiplatelet drugs. Finally, we will provide our perspectives of pharmacogenetic testing for drugs used to treat cardiovascular diseases.
(Enlarge Image)
Figure 1.
Factors influencing the variability of antiplatelet drug response.
