Work

Epidemiology and management patterns of chronic thromboembolic pulmonary hypertension in China

Year: 2025

Type: article

Abstract: To the Editor: Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare but serious condition characterized by obstruction of the pulmonary arteries due to thromboembolic events and subsequent vascular remodeling, which leads to pulmonary hypertension (PH). Classified as Group 4 in the 2022 PH guidelines by the European Society of Cardiology and the European Respiratory Society, CTEPH poses significant risks, including progressive PH, right ventricular dysfunction, and mortality if left untreated. Despite established diagnostic and treatment guidelines, the exact national prevalence of CTEPH remains largely unknown due to the absence of organized registries, with estimates ranging from 3 to 30 cases per million people. Although CTEPH is commonly thought to follow acute pulmonary embolism (PE), epidemiological data reveal a discrepancy; studies suggest that only 0.1% to 3.8% of PE patients may develop CTEPH.[1,2] Recent reports indicate that 65.6% of CTEPH patients have a history of acute PE, although this proportion varies across regions.[3] Treatment options include pulmonary endarterectomy (PEA), riociguat, and balloon pulmonary angioplasty (BPA). CTEPH significantly impacts patients’ quality of life, causing symptoms such as shortness of breath and fatigue, which lead to increased healthcare utilization and economic burden. In China, limited awareness and delayed diagnosis further complicate the management of CTEPH, underscoring the need for studies that address the disease’s burden and enhance recognition among healthcare providers. Therefore, this systematic review aimed to estimate the prevalence of CTEPH using data from PE patients and to investigate the characteristics and management patterns of CTEPH in the Chinese population. This study adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and was registered in the PROSPERO database (Ref. CRD42024510051). An electronic search of databases, including PubMed, EMBASE, Web of Science, Cochrane, the Chinese Biomedical Database (CBM), China National Knowledge Infrastructure (CNKI), and the Wanfang Digital Resource Database, was conducted in August 2023. No restrictions were applied regarding language or publication status. Due to the limited epidemiological evidence, we applied Gall’s methodology (2017) to indirectly calculate the prevalence of CTEPH in the general Chinese population.[4] This approach involved estimating overall CTEPH prevalence based on the proportion of CTEPH among PE patients, the prevalence of PE in the general population, and the proportion of CTEPH cases associated with prior PE. Diagnosis of PE and CTEPH was based on the definitions used in the original studies. Inclusion criteria varied between the prevalence and characteristics investigations. For the prevalence study, we included observational studies involving the general population and PE patients in China, which reported PE prevalence, the proportion of CTEPH among PE patients, and the number of CTEPH cases with and without a history of PE. For the characteristics investigation, we included prognostic and cross-sectional studies on CTEPH patients in China, focusing on venous thromboembolism (VTE) history, comorbidities, demographics, risk factors, disability rates, and treatment patterns. Exclusion criteria included interventional studies, case reports, abstracts, reviews, conference proceedings, and literature not published in English or Chinese. Both study selection and data extraction were performed by two independent reviewers, with discrepancies resolved through discussion. For dichotomous outcomes, rates were extracted, and pooled proportions with 95% confidence intervals (CIs) were calculated using a random-effects model in R software (version 4.3.1, https://www.r-project.org/). For continuous outcomes, means and standard deviations (SDs) were pooled similarly. The prevalence of CTEPH was estimated using the following formula: Zprevalence of CTEPH =P1proportion of CTEPH following PE×P2prevalence of PE P3proportion of CTEPH cases with a history of PE These proportions were obtained through meta-analysis. For characteristics related to comorbidities and treatment, the results were described narratively. Heterogeneity was assessed using the Cochrane Q test and I2 statistic, with substantial heterogeneity indicated by an I2 ≥50% and a P-value <0.1 from the Q test. Publication bias was evaluated using a funnel plot and Egger’s test, but only when there were more than 10 studies. The risk of bias in studies estimating CTEPH prevalence was independently assessed by two reviewers using the Joanna Briggs Institute (JBI) critical appraisal checklist for prevalence studies. Ultimately, 31 studies on CTEPH and 5 studies on PE were included [Supplementary Figures 1 and 2, https://links.lww.com/CM9/C403]. To estimate the prevalence of CTEPH in China, 18 studies were analyzed [Supplementary reference list 1, https://links.lww.com/CM9/C403]. The quality assessment revealed that 83% (15/18) of studies lacked an appropriate sample frame, 50% (9/18) did not enroll an adequate sample size, and 78% (14/18) failed to measure the condition reliably [Supplementary Table 1, https://links.lww.com/CM9/C403]. The pooled proportion of CTEPH following PE (P1) was found to be 5.36% (95% CI: 3.04–7.67%, Supplementary Figure 3, https://links.lww.com/CM9/C403), based on seven studies involving 1843 patients. Two prevalence representations of PE were identified: P2a (0.09% among hospitalized patients, from five studies, 95% CI: 0.08–0.10%, Supplementary Figure 4, https://links.lww.com/CM9/C403) and P2b (0.0071% among the general population, from one study). The proportion of CTEPH cases with a history of PE (P3) was 56.50% (95% CI: 48.61–64.38%, Supplementary Figure 5, https://links.lww.com/CM9/C403). Using these values, the overall prevalence of CTEPH was estimated at 85 cases per million in hospitalized populations (Za) and 6.74 cases per million in the general population (Zb), translating to approximately 9729 individuals with CTEPH in China [Table 1]. Table 1 - Definitions and values of variables in formula used to calculate prevalence of CTEPH among general population in China. Variable Definition Rate (95% CI) Source Sample size P1 Proportion of CTEPH following PE 5.36% (95% CI 3.04 to 7.67%) Gong 2015, Yang 2015, Bian 2015, Guo 2016, Xi 2016, Xu 2022, Xu 2016 1843 P2a Prevalence of PE among hospitalized population 0.09% (95% CI 0.08 to 0.10%) Yang 2011, Li 2016, Liu 2011, Wang 2017, Zhang 2019 55,028,750 P2b Prevalence of hospitalized PE among general population 0.0071% Zhang 2019 NA P3 Proportion of CTEPH cases with a history of PE 56.50% (95% CI 48.61 to 64.38%) Deng 2020, Du 2019, Han 2013, Shu 2007, Wang 2018, Xie 2019 1221 Za Prevalence of CTEPH among hospitalized population 85 cases per million (95% CI 42 to 128 cases per million) P1×P2a/P3 NA Zb Prevalence of CTEPH among general population 6.74 cases per million P1×P2b/P3 NA CI: Confidence interval; CTEPH: Chronic thromboembolic pulmonary hypertension; NA: not applicable; PE: Pulmonary embolism; SD: Standard deviation; SE: Standard error. For references of studies listed in Source column, please see Supplementary reference list 1, https://links.lww.com/CM9/C403. 95% CI of prevalence of CTEPH among general population calculated using delta method SE=p22p32Var(p1)+p12p32Var(p2)+p12p22Var(p3)p34 95% CI: Z ± 1.96SE. The 30 studies provided insights into the baseline clinical characteristics of CTEPH patients [Supplementary references list 2, https://links.lww.com/CM9/C403]. The average age was 57.55 years, with 47.02% of patients being female. The mean body mass index (BMI) was 23.99 kg/m2, and 39.02% had a history of smoking. Notably, 56.50% had a history of PE, while 61.38% were classified as World Health Organization (WHO) functional class III/IV, with an average time from symptom onset to diagnosis of 24.63 months [Supplementary Table 2, https://links.lww.com/CM9/C403]. Egger’s tests for mean age, BMI, female proportion, smoking history, and WHO functional class III/IV showed no significant publication bias across the studies (P >0.05, Supplementary Figures 6–10, https://links.lww.com/CM9/C403). Common comorbidities included diabetes mellitus (2.00–33.33%), hypertension (8.33–75.00%), coronary heart disease (6.35–16.67%), and chronic obstructive pulmonary disease (COPD, 2.78–27.27%). Comorbidities associated with the onset of CTEPH included varicose veins in the lower limbs (63.64%) and deep vein thrombosis (DVT; 31.25% to 96.88%; Supplementary Table 3, https://links.lww.com/CM9/C403). Additionally, common risk factors identified for CTEPH included pulmonary artery systolic pressure (PASP) and intermediate- to high-risk PE [Supplementary Table 4, https://links.lww.com/CM9/C403]. Mortality rates associated with CTEPH were reported in seven studies, ranging from 6.94% to 45.45%. Among these, three studies reported additional estimated survival rates: 1-year survival rate was from 93.3% to 97.1%, 3-year survival rate was from 84.6% to 93.3%, 5-year survival rate was from 73.4% to 86.9%, 7-year survival rate was 82.0%, and 8-year survival rate was 66.6%, respectively [Supplementary Table 5, https://links.lww.com/CM9/C403]. Unfortunately, data on disability rates and socioeconomic burdens were not available. Treatment patterns revealed that 11.11% to 35.14% of patients received PEA, and 10.29% to 40.95% were treated with BPA. Medical therapy alone was documented in 30.29% to 88.89% of cases. Among patients using specific medications, a significant proportion received a combination of conventional anticoagulants and other therapies [Supplementary Table 6, https://links.lww.com/CM9/C403]. Compared to global trends of 3 to 30 cases per million, our study found a higher prevalence of CTEPH among hospitalized patients in China. This discrepancy may stem from prior studies that primarily focused on acute PE cases, while CTEPH can also develop from sub-acute and chronic PE, as well as in individuals without a history of PE. Our analysis included a broader range of PE patients, although it may overestimate the prevalence of CTEPH due to the higher likelihood of inpatient cases. Furthermore, the estimation of prevalence in the general population is based on a single study, which requires further validation through larger epidemiological investigations. Our study also reveals a significant delay in diagnosis, with many patients presenting at advanced stages of the disease. This underscores the urgent need to increase awareness for early detection of CTEPH. The absence of standardized guidelines for multimodal therapy, coupled with limited evidence on approved medications such as riociguat, underscores the need for improved treatment strategies and further research in this area. Several limitations of our study should be noted. First, the imprecision inherent in the calculation formula, along with notable heterogeneity due to diverse patient characteristics and study designs, may have impacted the results. Additionally, the lack of tailored prevalence studies further complicates the accuracy of our findings. Risk factor analysis was based on descriptive data rather than pooled data, which hinders a more precise predictive assessment of these factors. The relatively small sample sizes in the studies examining risk factors may contribute to data instability, emphasizing the need for caution in interpreting the results. This also highlights the importance of future research involving larger sample sizes. In conclusion, our study highlights the complexity of the CTEPH landscape in China, stressing the need for greater awareness, specialized databases, and enhanced clinical standards. Ongoing studies are expected to provide further insights into the management patterns and outcomes of CTEPH in the Chinese population. Acknowledgements The authors would like to acknowledge Miss Xue Zhou, Miss Yang Zhang, and Dr. Sitong Dong from Systematic Review Solutions Ltd for their medical writing and editorial support, which was funded by MSD China. Funding This study was supported by the National Key Research and Development Program of China (No. 2023YFC2507200), Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (CIFMS) (No. 2021-I2M-1-049), National High Level Hospital Clinical Research Funding (No. 2022-NHLHCRF-LX-01-0203), and National Natural Science Foundation of China (Nos. 82241029, 81970058). Conflicts of interest Y Wu and J Zou are employees of MSD China, while Jean-François Richard is an employee of Merck & Co. The other authors declare no competing interests.

Source: Chinese Medical Journal

DOI: 10.1097/cm9.0000000000003580