Biosimilars of low molecular weight heparins: Relevant background information for your drug formulary.

Biosimilars of low molecular weight heparins (LMWHs) are more alike the originator than different branded LMWHs. The latter differ largely in molecular weight, anti-FXa/anti-FIIa ratio and antithrombin binding. The Food and Drug Administration and European Medicines Agency guidelines are sufficient for the clinical use of high quality LMWHs. However, the Food and Drug Administration guideline lacks the results of a phase I clinical trial in the approval process. Most information about biosimilars is available for enoxaparin given that many biosimilars of enoxaparin have received market access. The guidelines of many International Thrombosis Societies for LMWH biosimilars are too stringent, not updated and impractical for formulary uptake discussions. This review gives background information on critical factors for the formulary uptake process of LMWHs with special attention for the use of the System of Objectified Judgment Analysis/Infomatrix model.

Cost-Effectiveness of Dabigatran Compared to Vitamin-K Antagonists for the Treatment of Deep Venous Thrombosis in the Netherlands Using Real-World Data.

BACKGROUND: Vitamin-K antagonists (VKAs) present an effective anticoagulant treatment in deep venous thrombosis (DVT). However, the use of VKAs is limited because of the risk of bleeding and the necessity of frequent and long-term laboratory monitoring. Therefore, new oral anticoagulant drugs (NOACs) such as dabigatran, with lower rates of (major) intracranial bleeding compared to VKAs and not requiring monitoring, may be considered. OBJECTIVES: To estimate resource utilization and costs of patients treated with the VKAs acenocoumarol and phenprocoumon, for the indication DVT. Furthermore, a formal cost-effectiveness analysis of dabigatran compared to VKAs for DVT treatment was performed, using these estimates. METHODS: A retrospective observational study design in the thrombotic service of a teaching hospital (Deventer, The Netherlands) was applied to estimate real-world resource utilization and costs of VKA monitoring. A pooled analysis of data from RE-COVER and RE-COVER II on DVT was used to reflect the probabilities for events in the cost-effectiveness model. Dutch costs, utilities and specific data on coagulation monitoring levels were incorporated in the model. Next to the base case analysis, univariate probabilistic sensitivity and scenario analyses were performed. RESULTS: Real-world resource utilization in the thrombotic service of patients treated with VKA for the indication of DVT consisted of 12.3 measurements of the international normalized ratio (INR), with corresponding INR monitoring costs of €138 for a standardized treatment period of 180 days. In the base case, dabigatran treatment compared to VKAs in a cohort of 1,000 DVT patients resulted in savings of €18,900 (95% uncertainty interval (UI) -95,832, 151,162) and 41 (95% UI -18, 97) quality-adjusted life-years (QALYs) gained calculated from societal perspective. The probability that dabigatran is cost-effective at a conservative willingness-to pay threshold of €20,000 per QALY was 99%. Sensitivity and scenario analyses also indicated cost savings or cost-effectiveness below this same threshold. CONCLUSIONS: Total INR monitoring costs per patient were estimated at minimally €138. Inserting these real-world data into a cost-effectiveness analysis for patients diagnosed with DVT, dabigatran appeared to be a cost-saving alternative to VKAs in the Netherlands in the base case. Cost savings or favorable cost-effectiveness were robust in sensitivity and scenario analyses. Our results warrant confirmation in other settings and locations.

Pharmacogenetic differences between warfarin, acenocoumarol and phenprocoumon.

Coumarin oral anticoagulant drugs have proven to be effective for the prevention of thromboembolic events. World-wide, warfarin is the most prescribed drug. In Europe, acenocoumarol and phenprocoumon are also administered. Yet it has been proven that variant alleles of the VKORC1 and CYP2C9 genotypes influence the pharmacokinetics and pharmacodynamics of these drugs. The combination of these two variant genotypes is a major cause of the inter-individual differences in coumarin anticoagulant drug dosage. Individuals who test positive for both variant genotypes are at increased risk of major bleeding. The impact of the CYP2C9 and VKORC1 genotype is most significant during the initial period of coumarin anticoagulant therapy. The effect of VKORC1 allelic variants is relatively similar for all three VKAs. The CYP2C9 polymorphism is associated with delayed stabilisation for coumarin anticoagulants. The effects of CYP2C9 polymorphisms on the pharmacokinetics and anticoagulant response are least pronounced in the case of phenprocoumon. In the long term, patients using phenprocoumon have more often international normalised ratio (INR) values in the therapeutic range, requiring fewer monitoring visits. This leads us to conclude that in the absence of pharmacogenetic testing, phenprocoumon seems preferable for use in long-term therapeutic anticoagulation. Pharmacogenetic testing before initiating coumarin oral anticoagulants may add to the safety of all coumarin anticoagulants especially in the elderly receiving multiple drugs.

The influence of NSAIDs on coumarin sensitivity in patients with CYP2C9 polymorphism after total hip replacement surgery.

OBJECTIVE: To determine the influence of NSAIDs on the international normalized ratio (INR) in patients with cytochrome P450 (CYP)-2C9 enzyme variants starting acenocoumarol (an oral coumarin) therapy during the first 7 days after total hip replacement surgery. METHODS: In this prospective study, an age-dependent protocol was used for the initiation of the acenocoumarol dose. Low-molecular-weight heparin was given for 5 days. The study included 100 patients undergoing total hip replacement surgery. After the inclusion of the last patient, polymerase chain reaction CYP2C9 mutation testing was performed for all patients. Drug-use evaluation of NSAIDs and other potential coumarin-drug interactions was also performed. RESULTS: Eleven patients had an INR on 1 or more days >4.9. There were 52 patients who were using NSAIDs. Patients with a CYP2C9 mutation had a mean INR curve similar to patients without the mutation when NSAIDs were not coadministered. Within the group of patients heterozygous for a CYP2C9 mutation (n=30) only concomitant use of a NSAID resulted in an INR >4.9 (0% vs 38.9%, p<0.05). CONCLUSION: In the group of patients with a CYP2C9 variant (*2 or *3 alleles), only concomitant use of a NSAID resulted in INRs >4.9. The cost effectiveness of CYP2C9 screening before elective surgery has yet to be determined.

Thromboprophylaxis in total hip-replacement surgery in Europe: acenocoumarol, fondaparinux, dabigatran and rivaroxban.

This paper reviews the clinical and pharmacoeconomic studies that have been conducted within Europe for patients undergoing elective hip-replacement surgery. Additionally, we offer a perspective on the possible future clinical use of new agents in orthopedic surgery, such as dabigatran and BAY 59-7939 (rivaroxban). Low-molecular weight heparins are standard therapy for patients requiring thromboprophylaxis and, therefore, we compare these with the other agents: vitamin K antagonists, fondaparinux and the direct oral inhibitors (thrombin or factor Xa inhibitors). The most evidence on the cost-effectiveness and efficacy is available for the low-molecular weight heparins and fondaparinux. Their major limitation is that they require parenteral administration. Only fondaparinux has undergone an extensive pharmacoeconomic evaluation. The direct thrombin inhibitors and direct factor Xa inhibitors are possibly the drugs of the future, but it must be borne in mind that they are still in Phase III clinical trials and, therefore,their safety and efficacy profile is not completely understood, neither are the pharmacoeconomic aspects.