Cost-effectiveness of folic acid therapy for primary prevention of stroke in patients with hypertension

Stroke is the second leading cause of death worldwide and the total number of deaths from stroke reached 6.55 million in 2019 [1]. As 77% of strokes are first events, effective primary prevention for stroke is essential to halt or reverse its rising burden [2]. Previous trials and meta-analyses have indicated that supplementation with folic acid might be an effective therapy for the primary prevention of stroke [3‐5]. The recent China Stroke Primary Prevention Trial (CSPPT) enrolled a total of 20,702 patients with hypertension without a history of stroke or myocardial infarction (MI). Patients were randomly assigned in a 1:1 ratio to receive 1 tablet containing 10 mg of enalapril and 0.8 mg of folic acid daily (single-pill compound, the enalapril-folic acid group) or 1 tablet containing 10 mg of enalapril daily (the enalapril group). After a median treatment duration of 4.5 years, the hazard ratio (HR) for occurrence of first stroke comparing enalapril-folic acid versus enalapril was 0.79 (95% CI: 0.68 to 0.93), with a 21% reduction in relative risk of first stroke, demonstrating that enalapril-folic acid was more effective for the primary prevention of stroke compared with enalapril alone [6]. A recent meta-analysis including 22 folic acid trials for the primary prevention of cardiovascular disease (CVD) events among Chinese populations, demonstrated an even greater risk reduction [7].

As one of the most common causes of long-term disability, stroke has a substantial impact on the total cost of healthcare worldwide, especially in developing countries [8, 9]. Although the benefits of folic acid treatment for hypertensive patients are evident, it is unknown whether folic acid treatment provides these health benefits at an acceptable cost to society. Given the large population of patients who might benefit from such therapy, this information is critical for physicians, patients, and policy holders to make informed decisions regarding preventive therapies. To address this gap in knowledge, we used data from the CSPPT to perform a formal health assessment of the cost-effectiveness of enalapril-folic acid versus enalapril alone for the primary prevention of stroke in hypertensive patients.

The CSPPT is the first, large-scale, randomized, controlled trial to demonstrate that treatment with enalapril-folic acid resulted in a significant reduction of primary stroke compared with treatment with enalapril alone for patients with hypertension [6, 10]. The results from this prospectively designed health economic analysis carried out alongside the CSPPT revealed that the ICER for enalapril-folic acid versus enalapril was $44,127.13 (284,620.00 RMB) per QALY gained during the 4.5-year follow-up period and $26,066.13 (168,126.54 RMB) per QALY gained over the remaining lifetime. These results were robust to a broad range of sensitivity analyses over a series of alternative assumptions, with an acceptability rate of 74.5% at the WHO-recommended WTP threshold of $37,663 (242,928 RMB) per QALY gained. In terms of the general population, these results suggest that enalapril-folic acid therapy is a cost-effective strategy for primary stroke prevention in hypertensive patients in China.

The subgroup analyses revealed some heterogeneity in the ICER estimates. The results indicated that, lifetime enalapril-folic acid treatment generally yielded ICERs below the “cost-effective” (< 3 times the GDP/capita) threshold for most patients, and some patients were even in the “highly cost-effective” range, such as patients with higher-risk factor levels (diabetes, baseline SBP ≥ 180 mm Hg, total cholesterol ≥ 6.2 mmol/L, or folate < 5.6 ng/mL). In a resource-constrained healthcare environment, targeting therapy to these subgroups of patients would be a highly efficient strategy for maximizing health benefits while minimizing the incremental costs of therapy. On the other hand, there were several subgroups of patients (e.g., female patients, aged < 55 or ≥ 65 years, MTHFR CT genotype, SBP < 160 mm Hg, total cholesterol < 5.2 mmol/L, folate ≥ 10.5 ng/mL, or homocysteine ≦ 10.0 μmol/L), for whom lifetime enalapril-folic acid therapy is “not cost-effective” (ICERs > 3 times the GDP/capita). These results reflect that for younger female patients with the MTHFR CT genotype and lower-risk factor levels, prolonged enalapril-folic acid therapy is not an economical strategy. Since the reduced sample sizes in each subgroup may lead to greater uncertainty, further studies are warranted to confirm the clinical and cost-effectiveness of enalapril-folic acid therapy for patients with different levels of risk factors of stroke at baseline.

This study should be interpreted in light of several important limitations. First, our study extrapolated 4.5 years of in-trial data to a lifetime horizon to capture the full benefits of the enalapril folic-acid treatment strategy and assumed that the impact of enalapril folic-acid treatment on the long-term risk of stroke was maintained throughout a patient’s life. However, our scenario analysis results show that even when enalapril-folic acid has no effect after 10 years—an unlikely assumption given the age range of patients in the CSPPT—it would still have an 84% probability of being cost-effective. Second, although microsimulation models have the advantage of simulating the complexity between individual risk factors and disease trajectories compared with the Markov model, they are still limited by the quality of data used to construct these models and their underlying model assumptions [20]. Third, although many of the key inputs were derived directly from the CSPPT, a few parameters (such as annual probabilities of first CHD, the utilities of primary stroke and CHD, mortality rates after stroke and CHD events) were estimated based on external studies or databases, which may have introduced uncertainty into the final results. Therefore, all model inputs were evaluated over a wide range of values in the sensitivity analyses, to examine their influence on the robustness of the model results. Fourth, this cost-effectiveness analysis was based on a single randomized trial with restrictive recruitment and limited follow-up. The results need to be validated in other trials since the clinical event rates may change with time. Finally, our study was carried out in a Chinese population without mandatory folic acid fortification. In addition to China, there are other countries with a high prevalence of low blood folic acid concentrations [21], and populations living in such low-folate regions may also benefit from supplemental folic acid treatment. However, whether our current findings can be extrapolated to populations in other countries, especially those with different ethnicities, and varying genetic and clinical characteristics, requires further research.

Based on empirical data from the CSPPT, we discovered that enalapril-folic acid therapy is a more cost-effective strategy for primary stroke prevention than enalapril alone among most hypertensive patients in China. Males between the ages of 55 and 65 who have a higher risk of stroke (e.g. diabetes, higher SBP, higher total cholesterol, higher HDL-C, lower folate, and higher homocysteine levels at baseline) drive the outcomes. Some subgroups with a potential lower risk of stroke may not be cost-effective. However, under the Patients Aid Program which offers a significant reduction in drug price, enalapril-folic acid therapy probably would be cost-effective in more patients of more subgroups. Although our findings should be interpreted with caution, as China bears the largest hypertensive population and stroke incidence of any country, these findings can inform health care policy and treatment guidelines. Finally, our study may also serve as a model for other countries with similar economic status and demographic characteristics, especially those whose populations have low folate intake.