Abstract
Background
Moderate to high risk medical inpatients are at increased risk of Venous Thromboembolism (VTE). The present study aims to investigate the cost-effectiveness and cost-utility of using Enoxaparin compared to Heparin in VTE prophylaxis in medical inpatients, from Iranian payer’s perspective.
Methods
Decision tree modeling technique was used to evaluate cost-effectiveness and cost-utility of the compared interventions. The main considered outcomes were Life Years Gained (LYG) for Cost-Effectiveness Analysis (CEA) and Quality-Adjusted Life Years (QALY) for Cost-Utility Analysis (CUA). Costs and consequences of the interventions were evaluated for a three-month period and reported as Incremental Cost-Effectiveness Ratios (ICERs). One-way and Probabilistic Sensitivity Analysis (PSA) were conducted to evaluate the robustness of the model due to uncertainty in the input data.
Results
In base case scenario (i.e. public tariff), incremental cost was $10.32, and incremental QALY and incremental LYG were 0.0001 and 0.0002 per patients respectively. Base case ICERs were 60,376 USD/QALY and 71,077 USD/LYG per patient. The results of the sensitivity analysis showed the robustness of the model.
Conclusion
As the estimated ICER per QALY is more than three times the reported Gross Domestic Product (GDP) per capita by world bank for Iran in 2017 ($5415), the use of Enoxaparin for VTE prophylaxis in medical in patients doesn’t seem to be a cost-effective intervention compared to the use of Heparin in Iran.
Keywords: Economic evaluation, Enoxaparin, Heparin, Venous thromboembolism, Medical inpatients
Introduction
Venous Thromboembolism (VTE) is the third prevalent cardio-vascular disease after Myocardial Infarction (MI) and stroke [1]. It occurs following clot formation in veins. VTE encompasses Deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE) [2].
The annual global prevalence and incidence of VTE is estimated to be between 104 to 183 and 142 to 300 per 100,000 people, respectively [1].
Despite obtained developments in VTE treatment, it is estimated that about 7% of hospitalized PE patients die due to the event. According to estimation by US surgeon general’s call to action to prevent DVT and PE, 100,000 to 180,000 deaths occur annually due to PE. PE is the most important preventable mortality cause in hospitalized patients [3].
Age, surgical operations with high risk of VTE, acute trauma, having a history of VTE, obesity, and immobility are some of the VTE risk factors [4].
VTE pharmaceutical prophylaxis is used in moderate or high risk patients. Heparin, Low Molecular Weight Heparin (LMWH) such as Enoxaparin and oral anti-coagulants such as Rivaroxaban and Warfarin are used in prophylaxis [5]. Heparin and Enoxaparin show their anti-coagulant effect through binding to anti-thrombin and inactivating xa coagulant factor [6].
Considering the high prevalence of VTE in Iran as well as lack of a national precise prophylaxis guide line, it is necessary to evaluate the cost-effectiveness of the use of different medical strategies to prevent VTE in Iran [7]. The present study aims to compare the cost-effectiveness and cost-utility of the use of Enoxaparin with Heparin as two most available and routine medicines for VTE prophylaxis in medical inpatients in Iran from the payer’s perspective.
Methods
This part includes population, model structure, clinical data, costs, economic evaluation and outcomes, and sensitivity analysis.
Population
The population of the present study was 2 hypothetical cohorts of 1000 medical inpatients with moderate to high risk of VTE, based on Caprini criteria [8]. One group received 40 mg of Enoxaparin once a day and the other group received 5000 IU of Heparin twice a day to prevent VTE [9].
Model structure
As VTE is an acute event, a decision tree modeling technique was used to evaluate cost-effectiveness and cost-utility of the compared interventions. The possible transitions (branches and nodes) are presented in Fig. 1. Microsoft Excel 2010 software was used to analyse the model.
Fig. 1.
The decision tree diagram. MB-pro: Major Bleeding in prophylaxis, MB-Tx: Major Bleeding in Treatment, No-MB: No Major Bleeding
The incidence of VTE within the first week of hospitalization (the average reported hospitalization period) was investigated in the model. To include the costs and consequences of the short-term treatment period for VTE, a three-month period was considered [10, 11]. Major bleeding and resultant death have been considered as main adverse events due to taking Heparin or Enoxaparin during VTE prophylaxis and anti-coagulants (such as Warfarin) during VTE treatment. To include time in the model, it was assumed that death following major bleeding occurs in the middle of the one-week prophylaxis or the three-month treatment period. Fatal PE was considered to occur immediately.
The face validity of the model was evaluated by the clinical expert. The internal validity was evaluated by replacing different numbers for input data to check whether it can affect the final data. The external validity was evaluated by comparing the result of the current study with other literatures.
Clinical data
Table 1 shows clinical data used in the model [12–14].
Table 1.
Clinical data used in the model. Relative risks, probabilities, and utility weights were sourced from references [12–14] respectively
| Relative Risk (95%CI) | |
| Major bleeding in prophylaxis with Enoxaparin comparing to Heparin | 0.48 (0.23–1.00) |
| VTE in prophylaxis with Enoxaparin comparing to Heparin | 0.83 (0.56–1.24) |
| Probability (95% CI) | |
| Major bleeding in prophylaxis with Heparin | 0.012 (0.008–0.017) |
| Death due to major bleeding in prophylaxis | 0.09 (0.03–0.19) |
| VTE in prophylaxis with Heparin (Proportion of DVT equals to 0.97) | 0.024 (0.018–0.031) |
| Death due to PE | 0.0377 (0.0110–0.0838) |
| Major bleeding in treatment | 0.007 (± 10%) |
| Death due to major bleeding in treatment | 0.104 (0.083–0.129) |
| Utility Weight (95% CI) | |
| Population norm | 0.92 (0.92–0.92) |
| Major bleeding in prophylaxis | 0.92 (0.92–0.92) |
| DVT (1 month) | 0.81 (0.55–0.94) |
| PE (1 month) | 0.75 (0.45–0.91) |
| ICHa | 0.15 (0.00–0.65) |
| ECHb (1 week) | 0.65 (0.15–0.86) |
Major bleeding in treatment includes ICH and ECH
aICH: Intra Cranial Hemorrhage
bECH: Extra Cranial Hemorrhage
Costs
Direct costs of interventions include cost of medicine, admission and hospitalization, physician’s visit, laboratory and para-clinical tests. The costs were based on US Dollar (USD) considering an exchange rate of 42,000 Iranian Rial for each USD as reported by the central bank of Iran [15]. As the analysis was performed from the payer’s perspective, the indirect costs were not considered in the model. As VTE is an acute condition, direct non-medical costs were assumed equal for both interventions and ignored in the economic evaluation.
Prophylaxis and treatment costs are presented in Table 2 [16–20].
Table 2.
| Costs for one person | Public tariff($) | Private tariff($) | 80% public and 20% private tariff($) |
|---|---|---|---|
| Prophylaxis with Heparin | 491.8 | 1222 | 637.8 |
| Prophylaxis with Enoxaparin | 504.4 | 1234.7 | 650.5 |
| Treatment of major bleeding during VTE prophylaxis | 205.8 | 529.3 | 270.5 |
| DVT diagnosis | 34.3 | 142.5 | 56 |
| PE diagnosis | 34.3 | 142.3 | 55.9 |
| VTE treatment (DVT or PE) | 220 | 539.2 | 283.9 |
| Treatment of major bleeding during VTE treatment | 774 | 1998.3 | 1018.9 |
To value the identified costs, the last published tariff book by the Iranian ministry of health and medical sciences was used [21]. Three different sets of tariffs (i.e. public (base-case), private, and 80% public and 20% private tariff) were evaluated separately. Costs of the medications sourced from the Iran food and drug administration [22].
Economic evaluation and outcomes
The main considered outcomes were Life Years Gained (LYG) for Cost-Effectiveness Analysis (CEA) and Quality-Adjusted Life Years (QALY) for Cost-Utility Analysis (CUA). The final results reported as Incremental Cost-Effectiveness Ratios (ICERs) for QALY and LYG. ICER can be obtained from dividing the incremental costs by incremental effects (Incremental effects refer to incremental QALY or incremental LYG) [23].
According to WHO recommendation, alternatives with an ICER for QALY of less than one Gross Domestic Product (GDP) per capita can be considered as highly cost-effective alternatives. Those with an ICER between one to three times the GDP per capita can be considered as cost-effective alternatives and the ICERs more than three times the GDP per capita are not considered as cost-effective alternatives [24].
Sensitivity analysis
One-way sensitivity analysis and Probabilistic Sensitivity Analysis (PSA) were used to evaluate the robustness of the model due to uncertainty in the input data and the probability of being cost-effective was reported using the Cost-Effectiveness Acceptability Curve (CEAC).
Results
The results of different scenarios are presented in Table 3.
Table 3.
Final results of different scenarios
| Tariff | Cost (USD per patient) | Effect (Per patient) | Incremental results (per patient) | |||||
|---|---|---|---|---|---|---|---|---|
| Heparin | Enoxaparin | QALY | LYG | ICER for QALY | ICER for LYG | |||
| Heparin | Enoxaparin | Heparin | Enoxaparin | |||||
| Public | 500.43 | 510.75 | 0.244 | 0.2441 | 0.2654 | 0.2656 | 60,376.31 | 71,076.65 |
| Private | 1245 | 1251.55 | 0.244 | 0.2441 | 0.2654 | 0.2656 | 38,260.55 | 45,041.37 |
| 80% public and 20% Private | 649.34 | 658.92 | 0.244 | 0.2441 | 0.2654 | 0.2656 | 55,953.16 | 65,869.60 |
Figure 2a and b show Tornado charts for one-way sensitivity analyses. The evaluated data and examined range are presented in the mentioned charts.
Fig. 2.
a Tornado chart for incremental cost/ QALY per patient (public tariffs). RR: Relative Risk, MB-pro: Major Bleeding in prophylaxis, Enox: Enoxaparin, VS: Versus, Hep: Heparin, P: Probability, UW: Utility Weight. b Tornado chart for incremental cost/ LYG per patient (public tariffs). RR: Relative Risk, MB-pro: Major Bleeding in prophylaxis, Enox: Enoxaparin, VS: Versus, Hep: Heparin, P: Probability
According to the presented Tornado charts, ICER for QALY is mostly affected by the four following factors: relative risk of major bleeding in prophylaxis with Enoxaparin compared to Heparin, relative risk of VTE in prophylaxis with Enoxaparin compared to Heparin, probability of death due to major bleeding in prophylaxis, and Enoxaparin cost.
Considering the estimated results for LYG, the ICER was particularly sensitive to relative risk of major bleeding in prophylaxis with Enoxaparin compared to Heparin, probability of death due to major bleeding in prophylaxis, Enoxaparin cost, and probability of major bleeding in prophylaxis with Heparin, respectively.
Scatter plots of conducted PSA are presented in Fig. 3a and b.
Fig. 3.
a PSA scatter plot for incremental cost/ QALY ratio (public tariffs). b PSA scatter plot for incremental cost/ LYG ratio (public tariffs)
In these figures, 96% of the 5000 iterations are located in the upper right zone revealing that the use of Enoxaparin compared to Heparin in VTE prophylaxis in medical inpatients is both more costly and more effective. A few points located in the upper left corner, represent a negative incremental QALY or incremental LYG.
Considering the conducted PSA, average incremental cost per QALY and incremental cost per LYG were estimated to be $95,444 (95% Confidence Interval [CI]: $ -186,538 to $ +550,567) and $35,530 (95% [CI]: $ -120,380 to $ +643,345), respectively.
Cost-Effectiveness Acceptability Curve (CEAC) demonstrates the probability of cost-effectiveness of one intervention compared to the alternative, over a range of ceiling values (λ) (the Willingness To Pay (WTP) for an additional unit of effectiveness such as QALY) [25].
Figure 4 represents the CEAC based on QALY for VTE prophylaxis with Enoxaparin compared to Heparin.
Fig. 4.
CEAC for prophylaxis with Enoxaparin compared to Heparin
The CEAC shows that when the WTP per QALY is more than the cross-over point ($71,655), the probability of prophylaxis with Enoxaparin being cost-effective is more compared to prophylaxis with Heparin. With ceiling ratio more than $115,000, the probability of cost-effectiveness of the Enoxaparin is more than 70%.
Discussion
The present study for the first time surveyed cost-effectiveness and cost-utility of using Enoxaparin compared to Heparin in VTE prophylaxis in medical inpatients in Iran.
Findings of the present study revealed that in the base-case scenario (public tariff), Enoxaparin has a cost-utility of $60,376 per additional QALY ($38,260 with private tariff and $55,953 with 80% public and 20% private tariffs) and a cost-effectiveness of $71,077 per additional LYG ($45,041 with private tariff and $65,870 with 80% public and 20% private tariffs) in VTE prophylaxis in medical inpatients compared to Heparin. In base case scenario incremental cost was $10.32, and incremental QALY and incremental LYG were 0.0001 and 0.0002 per patients respectively. A lower incremental cost can be found in private section, despite the higher total cost of health services in this section (Table 3).
The results of the study are particularly sensitive to relative risk of major bleeding in prophylaxis with Enoxaparin compared to Heparin; therefore, uncertainty in the mentioned factor needs to be considered in decision making.
The PSA demonstrated the robustness of the results, as more than 96% of the points in the PSA scatter plot were located in the upper right zone.
Taking into account the threshold recommended by WHO for cost-effectiveness of interventions, the estimated ICER for QALY in the present study is more than three times the reported Gross Domestic Product (GDP) per capita by world bank for Iran in 2017 ($5415). Consequently, the use of Enoxaparin for VTE prophylaxis in medical inpatients seems to be not a cost-effective intervention compared to the use of Heparin in Iran [26].
Some other studies reported the cost-effectiveness of the use of Enoxaparin in comparison with Heparin for thromboprophylaxis in other countries. Wilbur et al. (2011) study showed that VTE prophylaxis using LMWH costs more and results in lower DVT risk and adverse effects compared to the use of Heparin [27]. Mc Garry et al. (2004) study revealed that VTE prophylaxis using LMWH involves lower cost and is more effective; however, in sensitivity analysis both medicines were considered identical in terms of effectiveness and bleeding risk [28].
Limitations and generalizability
The current study was performed from the payer’s perspective. Consequently, the evaluation of indirect costs was not pertinent to the analysis. The target population of the current study was medical inpatients. Considering other patients such as surgical, ICU and trauma patients may result in different consequences. Utility weights used in the model, are sourced from published literature, as they have not been evaluated in Iranian population.
Due to difference in payment system, considered perspective, some treatment strategies, and pharmaceutical costs, the results of these studies can’t be generalized to our country.
Conclusion
Taking into account the results of the study, using Enoxaparin compared to Heparin in VTE prophylaxis in moderate to high risk medical inpatients in Iran can’t be considered a cost-effective intervention. This can be mainly due to the considerable higher acquisition cost of Enoxaparin compared to Heparin in Iran as well as low difference between clinical outcomes of the compared alternatives. The sensitivity analysis showed that uncertainty in the input data does not change the final decision.
The outcomes of this research can be beneficial for decision-makers in health-care policy to develop national guidelines.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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