Phenprocoumon

Abstract: Long-term oral anticoagulation is indicated for several cardiovascular diseases, including the prevention of cardiac thromboembolism in patients with atrial fibrillation (AF),1 mechanical heart valves,2 and acute myocardial infarction (MI),3 as well as the secondary prevention of venous thromboembolism (VTE).4 For the past 60 years, oral vitamin K antagonists (eg, warfarin, acenocoumarol, phenprocoumon, fluindione) have been widely prescribed.5 However, their impact in preventing thromboembolism has been hampered by several limitations that compromise their effectiveness and safety and make them difficult to use (Table 1). Vitamin K antagonists have a delayed onset and offset of action that often prolong hospitalization, and thus increase healthcare costs. Their large interindividual variability in dose response and narrow therapeutic window demand regular monitoring of the international normalized ratio (INR) and result in complex individualized dosing. Despite careful dose adjustment, the INR is frequently outside the target therapeutic range, which increases the risk of thromboembolism and bleeding.6 Patients treated with a vitamin K antagonist require counseling about drug and food interactions, the need for routine monitoring, and the inherent risk of bleeding. To reduce some of the dose variability, an algorithm based on clinical and genetic data has been developed and validated for estimating the appropriate dose of warfarin,7 but evidence of the cost-effectiveness of pharmacogenetic testing to optimize warfarin dosing in routine clinical practice is lacking.8 View this table: Table 1. Limitations of Warfarin and Other Oral Vitamin K Antagonists As a consequence of the limitations of vitamin K antagonists, the quality of anticoagulant control is frequently suboptimal among those who receive the treatment, and many patients at risk of thromboembolism do not receive treatment; only 50% to 70% of patients with AF at risk of stroke who are eligible for anticoagulant therapy are treated with a vitamin K antagonist.9,– …

Abstract: Vitamin K antagonists belong to the group of most frequently used drugs worldwide. They are used for long-term anticoagulation therapy, and exhibit their anticoagulant effect by inhibition of vitamin K epoxide reductase. Each drug exists in two different enantiomeric forms and is administered orally as a racemate. The use of vitamin K antagonists is complicated by a narrow therapeutic index and an unpredictable dose-response relationship, giving rise to frequent bleeding complications or insufficient anticoagulation. These large dose response variations are markedly influenced by pharmacokinetic aspects that are determined by genetic, environmental and possibly other yet unknown factors. Previous knowledge in this regard principally referred to warfarin. Cytochrome P450 (CYP) 2C9 has clearly been established as the predominant catalyst responsible for the metabolism of its more potent S-enantiomer. More recently, CYP2C9 has also been reported to catalyse the hydroxylation of phenprocoumon and acenocoumarol. However, the relative importance of CYP2C9 for the clearance of each anticoagulant substantially differs. Overall, the CYP2C9 isoenzyme appears to be most important for the clearance of warfarin, followed by acenocoumarol and, lastly, phenprocoumon. The less important role of CYP2C9 for the clearance of phenprocoumon is due to the involvement of CYP3A4 as an additional catalyst of phenprocoumon hydroxylation and significant excretion of unchanged drug in bile and urine, while the elimination of warfarin and acenocoumarol is almost completely by metabolism. Consequently, the effects of CYP2C9 polymorphisms on the pharmacokinetics and anticoagulant response are also least pronounced in the case of phenprocoumon; this drug seems preferable for therapeutic anticoagulation in poor metabolisers of CYP2C9. In addition to these vitamin K antagonists, oral thrombin inhibitors are currently under clinical development for the prevention and treatment of thromboembolism. Of these, ximelagatran has recently gained marketing authorisation in Europe. These novel drugs all feature some major advantages over traditional anticoagulants, including a wide therapeutic interval, the lack of anticoagulant effect monitoring and a low drug-drug interaction potential. However, they are also characterised by some pitfalls. Amendments of traditional anticoagulant therapy, including self-monitoring of international normalised ratio values or prospective genotyping for individual dose-tailoring may contribute to the continuous use of warfarin, phenprocoumon and acenocoumarol in the future.

Abstract: Long-term oral anticoagulation is indicated for several cardiovascular diseases, including the prevention of cardiac thromboembolism in patients with atrial fibrillation (AF),1 mechanical heart valves,2 and acute myocardial infarction (MI),3 as well as the secondary prevention of venous thromboembolism (VTE).4 For the past 60 years, oral vitamin K antagonists (eg, warfarin, acenocoumarol, phenprocoumon, fluindione) have been widely prescribed.5 However, their impact in preventing thromboembolism has been hampered by several limitations that compromise their effectiveness and safety and make them difficult to use (Table 1). Vitamin K antagonists have a delayed onset and offset of action that often prolong hospitalization, and thus increase healthcare costs. Their large interindividual variability in dose response and narrow therapeutic window demand regular monitoring of the international normalized ratio (INR) and result in complex individualized dosing. Despite careful dose adjustment, the INR is frequently outside the target therapeutic range, which increases the risk of thromboembolism and bleeding.6 Patients treated with a vitamin K antagonist require counseling about drug and food interactions, the need for routine monitoring, and the inherent risk of bleeding. To reduce some of the dose variability, an algorithm based on clinical and genetic data has been developed and validated for estimating the appropriate dose of warfarin,7 but evidence of the cost-effectiveness of pharmacogenetic testing to optimize warfarin dosing in routine clinical practice is lacking.8 View this table: Table 1. Limitations of Warfarin and Other Oral Vitamin K Antagonists As a consequence of the limitations of vitamin K antagonists, the quality of anticoagulant control is frequently suboptimal among those who receive the treatment, and many patients at risk of thromboembolism do not receive treatment; only 50% to 70% of patients with AF at risk of stroke who are eligible for anticoagulant therapy are treated with a vitamin K antagonist.9,– …

Abstract: Coumarin derivatives combine 3 unfavorable properties which make them prone to potentially life threatening drug-drug interactions: (i) high protein binding; (ii) cytochrome P450 dependent metabolism; and (iii) a narrow therapeutic range. An entire list of drugs which are supposed to interact with coumarins (mostly with warfarin) comprises about 250 different compounds. Noteworthy are the interactions with cardiovascular or antilipidaemic drugs which are often coadministered with coumarins: amiodarone, propafenone and fibrates. Cardiovascular drugs which are obviously devoid or proven to be devoid of an interaction are angiotensin converting enzyme (ACE) inhibitors, calcium antagonists, beta-blockers and cardiac glycosides. There are several other drugs which enhance the hypoprothrombinaemic response to coumarins by various mechanisms: inhibitors of the elimination of the eutomer S-(-)-warfarin (e.g. miconazole, phenylbutazone), combined with protein binding displacement (e.g., sulfinpyrazone, phenylbutazone), synergistic hypoprothrombinaemia (e.g. cefazoline). Furthermore, bleeding complications may occur with drugs affecting platelet function [aspirin (acetylsalicylic acid) and several nonsteroidal anti-inflammatories (NSAIDs)]. Strong inducers of coumarin metabolism are rifampicin (rifampin) and carbamazepine. Biphasic interactions may occur where a drug first enhances the hypoprothrombinaemic response to a coumarin but has a sustained inducing effect on coumarin metabolism (e.g. phenytoin or sulfinpyrazone). The complex response of coumarins to concomitant drug therapy makes it difficult to predict the occurrence and degree of a deterioration of anticoagulant control in individual patients. For clinical practice, it seems advisable that one should monitor for changes in prothrombin time when adding or deleting any newly approved drug or any drug suspected (e.g. on the basis of this review) to cause an interaction to patients on coumarin therapy. The onset of the adverse prothrombin time response might be from between 1 to 2 days up to 3 weeks (in case of phenprocoumon) after starting a concomitant drug regimen. With amiodarone, an adverse prothrombin time response might occur up to 2 months after initiating therapy. For heparins, only a drug interaction with aspirin or nitroglycerin seems clinically relevant due to the possibility of coadministration during acute cardiac events. Both drugs are shown to enhance the activated partial thromboplastin time response to heparin.