1.1 Evaluation method
This study started with the payer and used a cost-effectiveness analysis to construct a Markov model. The model was used to compare the cost and effectiveness of warfarin, rivaroxaban, and dabigatran (110 mg and 150 mg) in the prevention of stroke and myocardium infarction in patients with non-valvular AF (NVAF).
1.2 Model specification
An individual-level simulation model was built to predict the clinical events and outcomes of each patient over time under different treatment regimens. According to the natural history of disease development, the survival status of patients with NVAF was divided into four conditions: mild (no event of AF or no sequelae of events), moderate (moderate disability survival), severe (need help to survive) and death. Clinical manifestations in the model simulation were ischemic stroke (IS), intracranial hemorrhage (ICH), extracranial hemorrhage (ECH), myocardial infarction (MI) and death. At the beginning of the cycle, all patients were of mild status. With the cycle running, clinical events occurred, and individuals switched between states. The flow chart of the model is shown in Fig. 1. The model cycle was one year, and the study period was 30 years with a discount rate of 3%.
1.3 Hypothesis
We assumed the following hypothesis: 1) patients can experience any but only one clinical event in each cycle, 2) the conversion rate of each event in the model does not change with time, 3) assuming extracranial hemorrhage and MI have only two outcomes, namely patients with mild illness or death, 4) severely ill status is a state of irrecoverable disability and entirely in need of survival. It is assumed that once an individual enters the state of a severely ill condition, there are only two outcomes: maintenance and death, and 5) ignoring the occurrence of clinical events may lead to changes in costs due to drug withdrawals and others.
1.4 Data sources
1.4.1 Therapeutic effect and conversion rate
Transition probability refers to the probability that a patient moves from one state to various states in one cycle. To obtain the closest conversion rate of the Chinese population, Re-ly15, XANTUS16, ROCKET AF17 trials, and relevant literature were considered18-20. All included subjects were Chinese or subgroup analysis of the Asian population. The Re-ly trial selected 541 AF patients from the Chinese subgroup, which was a randomized efficacy comparison warfarin and dabigatran (110 mg or 150 mg, twice daily) in long-term anticoagulant therapy. The XANTUS trial included 2,273 Chinese (including Hong Kong and Taiwan), which was a prospective real-world observation study, comparing different doses of rivaroxaban in NVAF patients. Results are shown in Table 1
Table 1
Base-case model variables and ranges used in a sensitivity analysis
Variable | Value | Range | Reference |
Probabilities |
Probability of ischemic stroke caused by different drugs |
Warfarin | 0.04 | 0.023–0.0453 | 15, 18, 20 |
Rivaroxaban | 0.0193 | NA | 18 |
Dabigatran110mg | 0.0183 | 0.0167–0.0189 | 15, 18 |
Dabigatran150mg | 0.0137 | NA | 20 |
Probability of ischemic stroke outcome by severity |
Light | 0.091 | 0.091–0.133 | 21 |
Moderate | 0.425 | 0.348–0.425 | 21 |
Severe | 0.402 | 0.402–0.417 | 21 |
Die(in 30day) | 0.082 | 0.082–0.101 | 21 |
Probability of ICH caused by different drugs | | | |
Warfarin | 0.0121 | 0.0057–0.0294 | 15, 17, 18 |
Rivaroxaban | 0.00257 | 0.0021–0.0033 | 17, 18 |
Dabigatran110mg | 0.00359 | 0.0028–0.0039 | 15, 18 |
Dabigatran150mg | 0.0027 | NA | 15 |
Probability of ICH outcome by severity |
Light | 0.12 | NA | 16, 21 |
Moderate | 0.27 | NA | 16, 21 |
Severe | 0.43 | NA | 16, 21 |
Die | 0.18 | NA | 16, 21 |
Probability of ECH caused by different drugs | | | |
Warfarin | 0.027 | NA | 19 |
Rivaroxaban | 0.03 | NA | 16 |
Dabigatran110mg | 0.007 | NA | 19 |
Dabigatran150mg | 0.0217 | NA | 16 |
Probability of ECH outcome by severity |
Die | 0.0147 | 0.01–0.04 | 21 |
Probability of MI caused by different drugs | | | |
Warfarin | 0.0098 | NA | 21 |
Rivaroxaban | 0.0098 | NA | 21 |
Dabigatran110mg | 0.0072 | NA | 15 |
Dabigatran150mg | 0.0074 | NA | 15 |
Probability of MI outcome by severity |
Death | 0.166 | 0.158–0.174 | 21, 22 |
All-cause mortality by different drugs | | | |
Warfarin | 0.026 | 0.0258–0.0261 | 15, 17 |
Rivaroxaban | 0.0164 | NA | 17 |
Dabigatran110mg | 0.0333 | NA | 15 |
Dabigatran150mg | 0.0219 | NA | 15 |
Cost |
Price (specification/yuan) | | Range of daily dose | |
warfarin | 3 mg/0.53 | 1.5 mg-6 mg/d | |
Rivaroxaban | 20 mg/34.6 | 15–20 mg qd | |
Dabigatran110mg | 110 mg/16.63 | 110–150 mg bid | |
Dabigatran150mg | 150 mg/21.39 | 110–150 mg bid | |
Cost of examination and service | 76.55 | NA | |
Frequency about examination/Annual | | | |
warfarin | 21 | NA | 23 |
Rivaroxaban and Dabigatran | 1 | NA | |
Total cost(drug and examination) | | | |
Warfarin | 1801 | 1704.28-1994.45 | |
Rivaroxaban | 12705.55 | 10208.95-20224.55 | |
Dabigatran110mg | 12216.45 | 12166.45-15691.25 | |
Dabigatran150mg | 15691.25 | 12166.45-15691.25 | |
Event | | | |
Stroke | 9607 | 6053.2-19066.8 | |
ICH | 18524.6 | 13764-27459.2 | |
ECH | 8650.9 | 6166-17893.6 | |
MI | 27552.5 | 12833.7-39317.5 | |
Health utility values in each state |
Light | 0.76 | 0.7–0.9 | 24 |
Moderate | 0.39 | 0.1–0.5 | 24 |
Severe | 0.16 | 0.0-0.32 | 24 |
ICH | 0.8 | 0.79–0.84 | 25 |
ECH | 0.8 | 0.79–0.84 | 25 |
MI | 0.84 | 0.67–0.96 | 26 |
ICH = Intracranial hemorrhage; ECH = Extracranial hemorrhage; MI = Myocardial infarction |
1.4.2 Cost
The state of NVAF event-free costs were the average annual direct medical costs of the four treatment measures, including medical service costs, medication costs, and related examination costs. The medical service charge was 50 yuan per time for general outpatient service in the tertiary hospital of Beijing. The drug cost referred to the public price from the Beijing Sunshine Drug Procurement platform. The coagulation function monitoring cost was 26.55 yuan/test. Warfarin's coagulation function monitoring frequency was based on the 2015 guidelines for stroke prevention and treatment in patients with AF in China23. INR is monitored 21 times a year, and the monitoring frequency for NOACs is once a year. The average hospital expenses for acute events were obtained from the 2018 China Health Statistics Yearbook, as shown in Table 1.
The dose of warfarin was adjusted based on INR, and the daily dose fluctuated between 1.5 mg − 6 mg, resulting in a change in drug costs. The recommended dosage of rivaroxaban for an adult with NVAF was between 15–20 mg/d. There are three dosage strengths of 10 mg, 15 mg, and 20 mg for rivaroxaban, and the cost of 20 mg/day of rivaroxaban was used in our analysis. The dosage of dabigatran was adjusted from 220 mg/d to 300 mg/d according to the risk of bleeding, as shown in table
1.4.3 Value of health utility
The quality-adjusted life year (QALY) was adopted as the health utility index in this analysis. The value of health utility was derived from a similar population investigation and published literature. Assuming that QALY is 1 for health and 0 for death, EQ-5D was used to calculate the quality of life under specific condition, and the health utility values in each state are shown in Table 1.