Pharmacogenetics in Cardiovascular Disorders
Pharmacogenetics in Cardiovascular Disorders
Atrial fibrillation (AF) is a common cardiac arrhythmia that can lead to ischemic stroke in approximately 15 % of cases. The major risk factors leading to this are a previous history of stroke or transient ischemic attack (TIA), left ventricular dysfunction, hypertension, age ≥75 years, and diabetes mellitus. Warfarin is, to date, the recommended drug for long-term anticoagulation in patients with AF who have previously experienced ischemic stroke, TIA, or systemic embolism (considered at high risk for a TIA). For people at moderate (defined by the presence of heart failure, hypertension, age ≥75 years, and diabetes mellitus) or low risk for such events, the use of aspirin or warfarin or long-term aspirin treatment are recommended, respectively.
Warfarin is an antagonist of vitamin K and prevents coagulation and thromboembolism by inhibiting the activation of vitamin K-dependent clotting factors (Fig. 1). It was originally idealized as mouse venom more than 50 years ago. For this reason, its application in the human therapeutic field approximately 40 years ago raised initial doubts. Nevertheless, warfarin is now one of the most widely used anticoagulants.
(Enlarge Image)
Figure 1.
Mechanism of action of warfarin, dabigatran, rivaroxaban, and apixaban in relation to the coagulation cascade. Warfarin is a vitamin K antagonist and interferes with its cycle. In particular, warfarin binds to the oxidized vitamin K (KO) reductase enzyme, so that it cannot be recycled. The resulting lack of reduced vitamin K (KH2) limits the carboxylation of coagulation factors such as prothrombin precursor. Dabigatran targets thrombin directly, while rivaroxaban and apixaban target factor Xa
Warfarin is metabolized in the liver and by the cytochromes P450 (CYP). Different forms of these enzymes catalyze metabolism of warfarin at different sites, a process known as stereoselective metabolism.
The response to this drug is highly variable and ranges from non-response (and consequent thromboembolism) to bleeding, and the dose requirement can vary up to tenfold; furthermore, warfarin is known to interact with other drugs and foods. For these reasons, each individual's coagulation needs to be monitored frequently, and the dosage needs to be adjusted in a timely manner.
For the prediction of the optimal therapy, two uniform loading doses of 10 mg/day are given, followed by maintenance doses of 5 mg/day for Western ancestry individuals and 2–3 mg/day for individuals of Asian ancestry, given the high frequency of the VKORC1 haplotype. Debate continues as to the best loading dose, which also depends on the age of the patient. The dose for each patient is then adjusted by monitoring the prothrombin time and the international normalized ratio (INR). These are measures of the extrinsic pathway of coagulation and estimate the tendency of blood to clot. An INR <2 can be associated with thromboembolism, while an INR >4 is usually associated with the risk of bleeding.
Polymorphisms both in warfarin target (vitamin K epoxide reductase VCORK1, rs9934438, and rs9923231) and in its principal metabolizer (CYP2C9, rs1799853 or R144C and rs1057910 or I135L) have been shown to have strong effects in the determination of the correct dose (Table 1).
The combination of the knowledge of the genotypes for these polymorphisms and clinical information can explain up to half the inter-individual dosage variations for warfarin. In fact, a recent well powered study demonstrated how algorithms that considered CYP2C9 and VCORK1 genotypes with the prediction of warfarin dosages are successful compared with parallel controls for which genotypes are not considered (percentage of out-of-range INR 31 vs. 42 % at month 1; 30 vs. 42 % at month 3; percentage of time in therapeutic range 69 vs. 58 % and 71 vs. 59 %, respectively, all p-values were lower than 10).
Recently, novel drugs have been synthesized, targeting thrombin directly (dabigatran) and factor Xa (rivaroxaban and apixaban), and compared with warfarin in several clinical trials. A recent study comparing the different clinical trials performed on such drugs concluded that all these drugs are at least as efficacious as warfarin, with similar bleeding events. These drugs can be an alternative for patients who do not wish to adhere to the monitoring required for warfarin dose adjustment, or for those patients whose therapeutic effect is not optimal, despite adjustments.
2 Warfarin
Atrial fibrillation (AF) is a common cardiac arrhythmia that can lead to ischemic stroke in approximately 15 % of cases. The major risk factors leading to this are a previous history of stroke or transient ischemic attack (TIA), left ventricular dysfunction, hypertension, age ≥75 years, and diabetes mellitus. Warfarin is, to date, the recommended drug for long-term anticoagulation in patients with AF who have previously experienced ischemic stroke, TIA, or systemic embolism (considered at high risk for a TIA). For people at moderate (defined by the presence of heart failure, hypertension, age ≥75 years, and diabetes mellitus) or low risk for such events, the use of aspirin or warfarin or long-term aspirin treatment are recommended, respectively.
Warfarin is an antagonist of vitamin K and prevents coagulation and thromboembolism by inhibiting the activation of vitamin K-dependent clotting factors (Fig. 1). It was originally idealized as mouse venom more than 50 years ago. For this reason, its application in the human therapeutic field approximately 40 years ago raised initial doubts. Nevertheless, warfarin is now one of the most widely used anticoagulants.
(Enlarge Image)
Figure 1.
Mechanism of action of warfarin, dabigatran, rivaroxaban, and apixaban in relation to the coagulation cascade. Warfarin is a vitamin K antagonist and interferes with its cycle. In particular, warfarin binds to the oxidized vitamin K (KO) reductase enzyme, so that it cannot be recycled. The resulting lack of reduced vitamin K (KH2) limits the carboxylation of coagulation factors such as prothrombin precursor. Dabigatran targets thrombin directly, while rivaroxaban and apixaban target factor Xa
Warfarin is metabolized in the liver and by the cytochromes P450 (CYP). Different forms of these enzymes catalyze metabolism of warfarin at different sites, a process known as stereoselective metabolism.
The response to this drug is highly variable and ranges from non-response (and consequent thromboembolism) to bleeding, and the dose requirement can vary up to tenfold; furthermore, warfarin is known to interact with other drugs and foods. For these reasons, each individual's coagulation needs to be monitored frequently, and the dosage needs to be adjusted in a timely manner.
For the prediction of the optimal therapy, two uniform loading doses of 10 mg/day are given, followed by maintenance doses of 5 mg/day for Western ancestry individuals and 2–3 mg/day for individuals of Asian ancestry, given the high frequency of the VKORC1 haplotype. Debate continues as to the best loading dose, which also depends on the age of the patient. The dose for each patient is then adjusted by monitoring the prothrombin time and the international normalized ratio (INR). These are measures of the extrinsic pathway of coagulation and estimate the tendency of blood to clot. An INR <2 can be associated with thromboembolism, while an INR >4 is usually associated with the risk of bleeding.
Polymorphisms both in warfarin target (vitamin K epoxide reductase VCORK1, rs9934438, and rs9923231) and in its principal metabolizer (CYP2C9, rs1799853 or R144C and rs1057910 or I135L) have been shown to have strong effects in the determination of the correct dose (Table 1).
The combination of the knowledge of the genotypes for these polymorphisms and clinical information can explain up to half the inter-individual dosage variations for warfarin. In fact, a recent well powered study demonstrated how algorithms that considered CYP2C9 and VCORK1 genotypes with the prediction of warfarin dosages are successful compared with parallel controls for which genotypes are not considered (percentage of out-of-range INR 31 vs. 42 % at month 1; 30 vs. 42 % at month 3; percentage of time in therapeutic range 69 vs. 58 % and 71 vs. 59 %, respectively, all p-values were lower than 10).
Recently, novel drugs have been synthesized, targeting thrombin directly (dabigatran) and factor Xa (rivaroxaban and apixaban), and compared with warfarin in several clinical trials. A recent study comparing the different clinical trials performed on such drugs concluded that all these drugs are at least as efficacious as warfarin, with similar bleeding events. These drugs can be an alternative for patients who do not wish to adhere to the monitoring required for warfarin dose adjustment, or for those patients whose therapeutic effect is not optimal, despite adjustments.
Source...