Personalized Medicine in Cardiovascular Diseases

Two patients, John Doe and John Smith, had been taking clopidogrel in the similar standard dose for 1 year since the first occurrence of heart attack. However, suddenly John Doe had the recurrent heart attack. After some examinations, it is found out that John Doe had received the clopidogrel in an insufficient dose or, in other words, the dose had to be increased. The examination result also indicated that the genetic factor contributed to this condition.

Responses to medicine differ from one person to another. Some factors may be the cause of such response difference to medicine, including genetic, age, sex, environment, and disease. As such, administering uniform therapy or medicine to all patients to treat a specific disease will not guarantee the same result.

Therefore, a disease suffered by patients should be treated using a personalized approach to match the unique condition of the patients. This is known as personalized medicine.

The correlation between genetic factors and cardiovascular disease remains a hot talk in researches around the world. Genetic variations in the enzymes used in the metabolism of medicine may result in different enzyme activities. The enzymes secreted may metabolize medicine into an active substance as expected, but may otherwise result in substances that generate adverse effects. As such, genetic analysis is necessary prior to starting a therapy in order to identify whether or not the genes will affect the medicine taken by the patients. The analysis is conducted to determine the type and dose of medicine to take, which will further contribute to the effect of medication and the patient' s recovery.

Clopidogrel and cardiovascular disease

Clopidogrel is among the most familiar medicines used for treating patients with cardiovascular disease. One of the causes of cardiovascular diseases is blood clot in your arteries, blocking blood flow to the whole body. Clopidogrel is an anticoagulation medicine that works by inhibiting blood clot in the blood vessels, thus prevents heart attack and stroke caused by blood vessel clogging. Clopidogrel is given to the persons with high risk of heart attack and stroke or who have just had these events, including those with the risk of blood circulation problem, acute coronary syndrome, or atrial fibrillation.

Metabolism of clopidogrel

Clopidogrel is a prodrug, defined as a medicine that remains dormant before being activated by the liver into active drug that works actively and can generate effects to the body. Cytochrome P450 (CYP) is a group of enzymes (isoenzymes) that holds a significant role in metabolism or that transforms medicine into active metabolite. Among the enzymes in the liver that function to transform medicine into active metabolite is CYP2C19. As such, if someone experiences a genetic mutation, CYP2C19 will affect the ability of his/her CYP2C19 enzyme to transform clopidogrel into an active metabolite. The result of such genetic mutation is the decrease, increase, or loss of enzyme activity. When someone experiences genetic mutation of CYP2C19, dose increase or even alternative therapies may be necessary if he/she is consuming clopidogrel.

'Boxed Warning' in administering clopidogrel

In March 2010, the Food and Drug Administration (FDA) agreed upon a ' boxed warning' to be embedded on clopidogrel label, providing information on the potentials of reduced effectiveness in patients with dysfunction in the ability to transform medicine into active form.

The boxed warning is based on the view that the anticoagulation effect of clopidogrel is highly dependent on the activity of the CYP enzyme, which is why patients with degraded CYP2C19 function due to genetic mutation cannot metabolize clopidogrel properly, leading to a high rate of cardiovascular event following acute coronary syndrome and percutaneous coronary intervention (PCI) as compared to patients with normal CYP2C19.

The warning also informs that laboratory analysis is available to help identify patients with genetic mutation and therefore alternative medication strategies should be considered in those belonging to poor metabolizer (PM) group. The term poor metabolizer refers to individuals with genetic mutation that results in the loss of the whole functions of enzymes or the enzymes cannot function in metabolizing clopidogrel.