In the present population-based drug utilization analysis, the trend in ED anticoagulant prescription for VTE in China was investigated. Retrospective data from four major Chinese cities were retrieved and analyzed as representatives. Between 2016 and 2019, a total of 4609 prescriptions on anticoagulants were prescribed in the ED. LMWH remained the mainstream anticoagulant for patients with VTE in the ED. Increased use of dabigatran and rivaroxaban was presented based on the study results. In contrast, warfarin became less prescribing during the study period. Regarding cost, LMWH contributed more than 60% of the total cost of anticoagulants prescribed for emergent VTE. During the study period, rivaroxaban accounted for the majority of the cost of oral anticoagulants. Expenses on dabigatran were on the rise. To the best of our knowledge, our study is the first drug utilization analysis on ED anticoagulant prescriptions in China.
The general incidence of VTE regardless of time period and setting is estimated to be 1 to 2 per 1000 people per year. 16–19 Once VTE is diagnosed, rapid-onset anticoagulation should be initiated to relieve the symptoms and prevent thrombus propagation and embolization.20 Our results revealed that LMWH is still the fundamental anticoagulant in the ED, constituting 74.6–80% of overall ED anticoagulant prescriptions during the study period. Pharmacologically, LMWH are fragments of unfractionated heparin with an average molecular weight of approximately 5000 Da. Since the long heparin chains are fractionated, LMWH hardly inhibits the activities of thrombin (Factor II).21 In addition, it neither binds to macrophages or endothelial cells nor possesses a strong affinity for heparin-binding plasma proteins.22 Therefore, LMWH is more predictable in its efficacy than other drugs because of its better bioavailability, longer half-life, and dose-independent clearance and has been recommended by the American College of Chest Physicians (ACCP) ninth edition guidelines as the first-line agent for the initial anticoagulation of VTE patients.8 After administering initial anticoagulation, long-term anticoagulation should be followed. Before the extensive application of DOACs, LMWH was usually followed by subsequent oral warfarin to maintain a stable international normalized ratio (INR) between 2.0 and 3.0 in the long term.20 However, the prescriptions of warfarin were not proportional to LMWH in the current study. The authors assume that this deviation can be explained by the bridging period. When following traditional anticoagulation, warfarin should overlap LMWH for a bridging period. The median bridging length was expected to be eight days (IQR 6–11 days) in accordance with clinical trials, although it is sometimes shorter in clinical practice. During the bridging period, patients may turn to outpatients for subsequent treatment after initial LMWH anticoagulation, resulting in fewer warfarin prescriptions.
Cost has been demonstrated to have an impact on patients’ selection of anticoagulants.9 In the present study, parenteral anticoagulant LMWH accounted for over 60% of the overall cost of ED anticoagulants. The average expense of LMWH was 89.75 yuan per prescription, based on the current findings. Given its acceptability in price, nonetheless, the authors assumed that the reasonable expense may not explain the high usage of LMWH, which was recommended as the first-line anticoagulant in most VTE events per the most recent guidelines.9 For the selection of oral anticoagulants, the average cost affected patients’ choice more remarkably. Our results suggested that warfarin provided 61.9% of the overall oral anticoagulant utilization with 1.4% − 3.1% of the total yearly cost (13.73 yuan per prescription). Despite the inconvenience and higher bleeding risks, more than 60% of the overall patients still had warfarin as their anticoagulation choice. Rivaroxaban (326.26 yuan per prescription) and dabigatran (385.00 yuan per prescription) accounted for over 90% of the total cost of oral anticoagulants in combination, notwithstanding that they were less prescribed than warfarin. The authors assumed that patients who placed a higher value on cost had a higher possibility of choosing warfarin. Nonetheless, as influences beyond price were not examined in the present study, the impact of cost on the selection of anticoagulants should be considered cautiously.
Since the introduction of DOACs, the treatment of VTE has dramatically changed. The results from scaled clinical trials indicated that DOACs are not inferior to standard therapy for the initial treatment of PE and symptomatic DVT.23,24 The risk for major bleeding was significantly decreased with DOACs compared to standard therapy.23–25 Real-world studies essentially confirmed the findings of Phase III clinical trials.26 Due to their predictable pharmacokinetics and pharmacodynamics, DOACs are exempt from the need for regular monitoring of the INR. DOACs are associated with shorter hospitalizations, fewer hospitalizations, and outpatient and ED visits and are recommended as the first choice for initial anticoagulation for patients with VTE unless contraindicated.11 Our results showed that the prescriptions of DOACs increased extensively over the past years. This finding is in line with several drug utilization studies.14,15,27 Prescriptions on warfarin decreased by over 25% within the four-year period. Dabigatran and rivaroxaban accounted for approximately 60% of the total ED oral anticoagulant prescriptions in 2019. The trend in oral anticoagulants is in line with the published literature.15 On the other hand, the main concerns regarding DOAC use in the ED are contraindications and drug-drug interactions. The therapeutic effectiveness and safety issues of DOACs among the particular population were not examined in the mentioned clinical trials. Patients with liver or renal impairment, pregnancy, active malignancy, expectations of surgery, and other extreme clinical statuses are not capable of DOACs. In addition, a number of medications can interact with the blood concentration of DOACs. Given the complexity of ED patients, prescribing DOACs for acute PE and symptomatic DVT is at risk of poorer clinical outcomes. For patients contraindicated or underlyingly contraindicated to DOACs, LMWH is preferred for initial anticoagulation because of its safety. Additionally, this agent must be injected subcutaneously by a healthcare worker. With LMWH, from the doctors' perspective, even patients with poor compliance are expected to receive a standard treatment. This advantage of LMWH may decrease the risks for overdose or missed dose, especially for those who cannot take care of themselves. In addition to the above considerations, the selection of anticoagulants is also based on patients' preferences.
Our study has several limitations. Given its retrospective nature and data retracting limitations, more detailed information concerning demographics (e.g., patients' age, education, income, exact diagnosis (PE or DVT)) and prescriptions (e.g., dosage, course) was lacking in our analysis. The imbalanced inclusion of medical settings may result in selection bias. Furthering analyses are expected to investigate the trend in ED-VTE anticoagulant prescription.