Gender differences in the incidence of chronic thromboembolic pulmonary hypertension after acute pulmonary embolism: A meta-analysis

Abstract

Background:

To explore the role of gender in the incidence of chronic thromboembolic pulmonary hypertension after acute pulmonary embolism.

Methods:

Two researchers search the PubMed Database, Embase Database and Cochrane Library Database from their establishment to October 2022, using Endnote software for document management and RevMan5.3 software for the meta-analysis of the included literature. A total of 11 studies are selected, including 5788 acute pulmonary embolism events and 391 patients (179 males and 212 females) with chronic thromboembolic pulmonary hypertension (CTEPH) under the stated conditions. The results show that there is no statistically significant difference in the incidence of CTEPH between males and females after PE (P = .28), with combined OR of 0.89 and 95% CI 0.72–1.10.

Results and conclusions:

Gender is found to be absent as a factor in the incidence of CTEPH after acute pulmonary embolism. This may indicate that gender is not a risk factor for CTEPH and that female patients are not necessarily more likely to have a higher incidence than male patients. As such, accurate judgments should be made on the possible complications of all patients after acute pulmonary embolism, which will be conducive to early detection and intervention in the treatment of CTEPH.

1. Introduction

1.1. Background

Chronic thromboembolic pulmonary hypertension (CTEPH) is defined as an increase in pulmonary vascular resistance resulting from unresolved thromboembolic material in the pulmonary vascular bed, increased pulmonary vascular resistance due to intraluminal thrombotic tissue and fibrous stenosis, or complete occlusion of the pulmonary arteries, resulting in a persistent increase in pulmonary artery pressure which leads to right ventricular failure and death.^[1] CTEPH is considered a serious complication after acute pulmonary embolism (PE), but it is also the only possible cure in pulmonary endarterectomy.^[2] Acute PE is a major event that leads to CTEPH, and embolism can lead to vascular stenosis, vascular endothelial damage and vasoconstriction,^[3] which in turn can lead to abnormal vascular remodeling and may also be associated with a variety of factors including fibrinolytic system abnormalities and fibrinogen damage, endothelial dysfunction and neovascular defects, abnormal gene expression, platelet dysfunction and inflammation.^[2] A recent population-based study conducted in the United Kingdom suggests that women may be more likely to develop CTEPH than men,^[4] while a global registry of expected CTEPH rates observed in the United States and most European countries, with the exception of Japan which has a higher female prevalence, showed gender-balanced results.^[5] Therefore, it is still unknown whether sex hormones or gender differences are a risk factor for CTEPH after PE. The systematic evaluation of gender differences in the incidence of CTEPH after acute PE is currently lacking. Based on data extracted from the relevant literature retrieved from the PubMed, Embase and Cochrane Library databases, this study conducted a meta-analysis on gender differences in the incidence of CTEPH after acute PE.

2. Methods

2.1. Data sources

Comprehensive and systematic searches were conducted using the online databases PubMed (updated to October 2022), Cochrane Library (updated to October 2022) and Embase (updated to October 2022). Search terms included free words as well as MeSH subject words. English literature was searched using the terms “Pulmonary Embolism,” “pulmonary,” “embolism,” “PulmonaryEmbolism,” “pulmonary,” “embolisms,” “pulmonary embolisms,” “Pulmonary Embolism,” “embolism pulmonary,” “embolisms” pulmonary,” “pulmonary thromboembolisms,” “pulmonary thromboembolism,” “thromboembolism pulmonary,” “thromboembolisms pulmonary,” “chronic thromboembolic pulmonary hypertension,” “CTEPH.” “Secondary Attack Rate,” “Attack Rate,” “Secondary Rate,” “Secondary Attack,” “Secondary Attack Rates,” “Incidence Proportion,” “Incidence Proportions,” “Proportion,” “Incidence,” “Cumulative Incidence,” “Cumulative Incidences,” “Incidence,” “Cumulative,” “Person-time Rate,” “Person-time Rates” and so on. The scheme was registered in the System Review Prospective Register (Prospero: CRD42022306821). Figure 1 shows the study incorporation process.

Figure 1.

Documentation incorporation process.

2.2. Research selection criteria

Studies of CTEPH events after acute PE were included if the following criteria were met: patients with CTEPH complicated by acute PE; pulmonary angiography confirmed by PE (CTPA) or ventilation perfusion (V/Q) lung scan in adult patients (≥18 years of age); right heart catheterization confirming anterior capillary pulmonary hypertension and ≥ CTPA or V/Q scan showing a segmental perfusion defect. Studies were excluded if they met any of the following criteria: patients had no history of acute PE; patients did not have concurrent CTEPH after developing acute PE; patients without follow-up; and The study was not published in English or was published repeatedly.

2.3. Data extraction

This study eventually included 11 articles. The necessary data was extracted independently by the 3 researchers, and any disagreement was resolved through discussion. At the initial screening, by reading the titles and abstracts of each article, irrelevant articles were excluded according to the standards. When sifting through, the full articles were read to exclude any in which the outcome data could not be extracted. The 3 researchers extracted the data independently. Any disagreement was resolved through discussion until a consensus was reached or the third researcher was consulted upon the completion of the second screening. The data extraction of the included literature was carried out. The content of the data extraction included first author of article, publication year, study type, study population, age range, sample size, number of male and female patients with acute PE, number of male and female patients with CTEPH after acute PE, and follow-up time.

2.4. Literature quality assessment

As the literature included prospective cohort studies and retrospective studies, the NOS scale was used for assessment. Newcastle–Ottawa scale (NOS) and the quality assessment scale set by the Agency for Healthcare Research and Quality (AHRQ, Rockville, MD) are two of the most widely used scales to evaluate observational studies (NOS for longitudinal study and case–control study; AHRQ for cross-sectional study). We defined a high-quality study as attaining over 70% on the respective rating scale, which means 7 or more out of 9 scores for the NOS. The quality of the literature was assessed by 2 researchers, and any disagreement was settled through discussion with the third researcher.

2.5. Statistical processing

For the included literature, all statistical analyses were meta-analyzed using RevMan version 5.3 and Stata version 12.0 provided by the Cochrane Collaboration Network. The number of male and female patients with CTEPH after acute PE in clinical events was compared to the odds ratio (OR) as an effect indicator, and the confidence interval was 95% (95% CI); literature heterogeneity was assessed by I²: if the included literature was statistically non-heterogeneous (P > .01, I² < 50%), it was studied by the fixed effect model; and if it was statistically heterogeneous (P < .01, I² > 50%), the sources of heterogeneity were understood by the random effect model and sensitive or subgroup analyses. Publication bias was evaluated by funnel plot, Egger’s test, and Begg’s test. Meta-analyses were performed after converting the data to ± patterns if the data was median (or extreme).

3. Results

A total of 11 studies with 5788 acute PE patients were included. The baseline characteristics of the included cohort are shown in Table 1. The studies were published from 2004 to 2021. Seven were prospective cohort studies and the remaining 4 were retrospective studies. We scored according to the NOS scale. After evaluation, 5 studies scored 8 points and the remaining 6 scored 7 points. The evaluation of the NOS scale in the included studies is shown in Table 2.

Table 1.

Baseline characteristics of included articles.

Author	Year of publication	Research type	Study population	Age years (mean/median)	Sample size	Male	Female	Number of male patients with CTEPH	Number of female patients with CTEPH	Follow-up time (years)
Vittorio Pengo[6]	2004	PC	Patients with consecutive acute PE	61.2	305	125	180	9	9	7.9
Frederikus A. Klok[7]	2010	RC	Patients with consecutive acute PE	56.0	866	410	456	1	3	2.8
David Martί[8]	2010	PC	Patients with consecutive acute PE	63.4	110	48	62	6	4	2.0
Laurent Guérin[9]	2014	PC	Patients with acute PE	61.0	23	146	63	83	2	5
F.A. Klok[10]	2014	PC	Patients with acute PE	44.5	134	75	59	4	2	0.6
Suqiao Yang[11]	2015	PC	Patients with acute PE	61.6	614	298	316	3	7	3.3
Chih-Hsin Hsu[12]	2019	RC	Patients with acute PE	63.8	200	83	117	2	6	3.0
Farid Rashidi[13]	2020	PC	Patients with acute PE	58.3	475	280	195	8	14	1.0
Gudula J. A. M. Boon[14]	2021	PC	Patients with acute PE	56.0	314	167	174	7	2	2.0
Carlos Aranda[15]	2020	RC	Patients with acute PE	51.8	241	121	120	7	7	2.0
C. Martinez[16]	2018	RC	Patients with acute PE	61.1	2356	1137	1219	130	153	3.5

CTEPH = chronic thromboembolic pulmonary hypertension, PC = prospective cohort study, PE = pulmonary embolism, RC = retrospective cohort study.

Table 2.

Evaluation of NOS scale of included articles.

Author	Selection				Comparability	Outcome			Scores
	Representativeness of the cohort	Selection of the non exposed cohort	Ascertainment of exposure	Demonstration that outcome of interest was ont present at start of study	Comparability of cases and controls on the basis of the design or analysis	Assessment of outcome	Was follow-up long enough for outcomes to occur	Adequacy of follow up of cohorts
Vittorio Pengo[6]	1	1	1	1	1	1	1	1	8
Frederikus A. Klok[7]	1	1	1	1	1	1	1	0	7
David Martί[8]	1	1	1	1	1	1	1	1	8
Laurent Guérin[9]	1	1	1	1	1	1	1	1	8
F.A. Klok[10]	0	1	1	1	1	1	1	1	7
Suqiao Yang[11]	0	1	1	1	1	1	1	1	7
Chih-Hsin Hsu[12]	0	1	1	1	1	1	1	1	7
Farid Rashidi[13]	0	1	1	1	1	1	1	1	7
Gudula J. A. M. Boon[14]	1	1	1	1	1	1	1	1	8
Carlos Aranda[15]	0	1	1	1	1	1	1	1	7
D. Martinez[16]	1	1	1	1	1	1	1	1	8

NOS = Newcastle–Ottawa scale.

We investigated gender differences in the incidence of CTEPH based on the number of people who developed CTEPH after a PE event published in each study. The total sample size of male patients with acute PE was 2807 and that of female patients was 2981. The average age was 44 to 64 years, and the average follow-up was 3 years. The numbers of patients with CTEPH following an acute PE event were 179 in men and 212 in women, and low heterogeneity (I² = 20%) was shown in the meta-analysis, so the fixed effect model was used. There were 7 studies in which the cumulative incidence of CTEPH after PE was higher in women than in men, and the remaining was higher in men than in women. (Supplementary Materials S1, http://links.lww.com/MD/K913) The meta-analysis results showed that the gender difference of CTEPH after PE events was not statistically significant (P = .28), with combined OR of 0.89 and 95% CI 0.72–1.10, as shown in Figure 2.

Figure 2.

Meta-analysis of gender differences in patients with CTEPH after PE event. CTEPH = chronic thromboembolic pulmonary hypertension, PE = pulmonary embolism.

The funnel plots are shown in Figure 3. The plots of Egger’s test and Begg’s test are displayed in Supplementary Materials S2, http://links.lww.com/MD/K914. The funnel plot is symmetrical at the time of visual examination, indicating no risk of publication bias, and the points in the figure basically fall in the funnel plot, indicating that there was no heterogeneity. Further to this, the findings of Egger’s test (P = .982) and Begg’s test (P = .876) both supported this finding.

Figure 3.

Funnel chart for meta-analysis.

The people in each study were different. The region, diet and living habits may lead to different probability of CTEPH between male and female. Therefore, We performed a subgroup analysis of the occurrence of CTEPH in Asian and European populations, where there was no heterogeneity (I² = 0%) shown in the subgroup analysis, so the fixed effect model was used. The results showed that female was more likely to develop CTEPH than male in Asia (P = .01), with combined OR of 0.41 and 95% CI 0.21–0.81, while there was no significant difference between male and female in Europe (P = .81), with combined OR of 0.97 and 95% CI 0.78–1.22, as shown in Figure 4.

Figure 4.

Subgroup analysis of CTEPH after PE event. CTEPH = chronic thromboembolic pulmonary hypertension, PE = pulmonary embolism.

Table 3 shows the diagnostic methods and anticoagulation strategies used in all studies. Among the 11 included studies, 9 studies diagnosed CTEPH by pulmonary ventilation/perfusion scan (V/Q scan). There are also right heart catheters, enhanced computed tomography CT, and CTPA. C. Martinez’s study did not mention diagnosis. Almost all studies that included anticoagulation strategies would first use heparin for a week, and then give vitamin K antagonists for at least 6 months. In 3 studies, the treatment duration was 3 months. In addition, other risk factors for CTEPH were summarized in Supplementary materials S3, http://links.lww.com/MD/K915, where the incidence of CTEPH is higher in cases with previous PE and previous deep venous thrombosis (DVT), based on the data in the table; CTEPH was confirmed in 240 (10.7%) of the 2241 cases with a history of PE and in 81 (5.3%) of the 1527 cases with a history of DVT.

Table 3.

Diagnostic methods and anticoagulation strategies for CTEPH in the included studies.

	Year	Diagnostic method	Anticoagulants	Treatment duration
C. Martinez	2018	NA	NA	NA
Carlos Aranda	2020	CT pulmonary angiography	Low molecular weight heparin, Vitamin K Antagonists	≥6 mo
Chih-Hsin Hsu	2019	right heart catheterization, V/Q scan	Low molecular weight heparin	≥6 mo
David Marti	2010	V/Q scan	Low molecular weight heparin, Vitamin K Antagonists	≥3 mo
F.A. Klok	2014	enhanced computed tomography CT, V/Q scan, CT pulmonary angiography	Low molecular weight heparin, Vitamin K Antagonists, Factor Xa inhibitor rivaroxaban	≥3 mo
Farid Rashidi	2020	CT pulmonary angiography, right heart catheterization, V/Q scan	Enoxaparin, warfarin	≥3 mo
Frederikus A. Klok	2010	CT pulmonary angiography, V/Q scan	Low molecular weight heparin, Vitamin K Antagonists	≥6 mo
Gudula J. A. M. Boon	2021	V/Q scan, right heart catheterization	NA	NA
Laurent Guérin	2014	V/Q scan	NA	NA
Suqiao Yang	2015	right heart catheterization, V/Q scan	Vitamin K Antagonists	≥6 mo
Vittorio Pengo	2004	CT pulmonary angiography, V/Q scan	Low molecular weight heparin	≥6 mo

CTEPH = chronic thromboembolic pulmonary hypertension.

4. Discussion

CTEPH after acute PE events is not a rare complication. The incidence rate of acute PE is not low. The meta-analysis of Meng Z shows that the overall incidence rate of CTEPH is 3.13% (95% CI: 2.11–4.63%).^[17] However, this incidence may be biased. Martí D’s research shows that many patients with CTEPH are clinically asymptomatic or have few symptoms, and it is difficult to diagnose such patients using current diagnostic methods.^[8] We should pay attention to asymptomatic or oligosymptomatic patients.^[17] The European Society of Cardiology predicts PE by predicting early mortality. According to the guidelines and the studies included, the current diagnosis of CTEPH includes echocardiography, V/Q scan, right heart catheter, enhanced computed tomography CT, CT pulmonary angiography (CTPA), and so on.^[18–21] Although there are many inspection methods, the early diagnosis of CTEPH is also a major clinical challenge in the European CTEPH registry, with data suggesting a median diagnostic delay of 14 months for CTEPH.^[22] We suggest that telephone monitoring follow-up and cardiopulmonary exercise testing should be included in the plan for the early detection of CTEPH in the follow-up of acute PE.^[23]

Multiple risk factors are currently known to influence the incidence of CTEPH developing from acute PE, including red blood cell distribution width values, LP (a), advanced age and high brain natriuretic peptide plasma levels. Xu W’s study showed that elevated red blood cell distribution width values can predict the risk of CTEPH after acute PE to a certain extent.^[24] Xi Q’s study revealed that increased red blood cell distribution width is an independent predictor of the development of CTEPH after acute PE, which may help to determine the outcome and treatment strategy of patients with acute PE.^[25] Ignatescu M’s study showed that the median LP (a) plasma level in CTEPH patients was significantly higher than that in the control group.^[26] Wei L’s study showed that the incidence of CTEPH was higher after PE, and advanced age and high brain natriuretic peptide were risk factors for the development of CTEPH,^[27] but whether gender is a risk factor for the development of CTEPH from acute PE remained inconclusive. In addition, Wei L’s study showed that gender was not statistically significant in the incidence of CTEPH after PE.^[27] And a recent population-based study in the UK suggests that women may be more likely to develop CTEPH than men.^[4]

A total of 11 articles^[6–16] were included in this study, and a funnel plot study was performed. The results of the present study demonstrate that there was no significant gender difference in the occurrence of CTEPH after a PE event (P = .28), with OR of 0.89 and 95% CI 0.72–1.10. According to the funnel plots, Egger’s test and Begg’s test, indicating no risk of publication bias and no heterogeneity. It follows that gender may not be a risk factor for developing CTEPH after PE. In subgroup analysis, it was found that Asian female was more likely to develop CTEPH than Asian male, and this result was not significantly different among Europeans. A limited number of studies have investigated gender as a risk factor. In Tosun H’s study found that male had a 4.59-fold increased risk of developing CTEPH.^[28] However, Yu Y’s study showed that female (OR = 2.39) was associated with a higher risk of CTEPH.^[29] In this paper, however, no difference is found. The result among Asians is obviously different and there is no heterogeneity, further studies are needed to analyze other factors in different populations. Although Chen TX’s study showed that almost all cardiopulmonary exercise testing parameters in patients with CTEPH were significantly different between genders, the overall trend of cardiopulmonary impairment was consistent between male and female CTEPH patients. They considered that this might be due to differences in motor ability between genders affecting hemodynamics, but the specific mechanism remained unclear.^[30] The study of Japanese scholar Ayako S showed that HLA-B*5201 is correlated with CTEPH. They considered that HLA-B*5201 positive type is Japan-specific CTEPH, HLA-B*5201 negative type is CTEPH related to DVT, and HLA-B*5201 positive CTEPH patients are mainly female, which means that in Japan, women have a higher frequency of CTEPH.^[31] This is similar to the higher female prevalence observed in Japan in the global registry of expected CTEPH, but the United States and most European countries show gender-balanced results.^[5] Therefore, as gender did not increase the risk of developing CTEPH according to our meta-analysis, the authors suggest that the development of CTEPH after PE may also be related to factors such as region, race, physical status, diet, living habits, different exercise capacity between genders, red blood cell distribution width and LP (a) plasma levels, while gender may be responsible for the different factors.

Our results also suggest that both previous PE and previous DVT are independent risk factors for developing CTEPH. CTEPH may be reduced if thrombolysis or surgical intervention is performed in time after PE. Yang S et al suggested that high-risk PE appears to be protective against CTEPH after timely intervention. Nearly all patients with high-risk PE have been treated with thrombolytic therapy, resulting in a more complete dissolution of the embolus than in patients who initially received anticoagulation, and therefore thrombolytic therapy may reduce the incidence of CTEPH after PE.^[11] All patients required lifelong anticoagulation for the prevention of recurrent venous thromboembolism and/or in situ thrombosis. The vast majority of patients are treated with vitamin K antagonists (VKA).^[32] In a small observational study of 92 PE patients followed for 18 months by echocardiography and CTPA, the potential role of low-quality anticoagulation in the development of CTEPH after PE was briefly presented.^[33] However, in the study by Boon GJAM et al,^[14] poor control of initial anticoagulation with VKA for acute PE was not more prevalent in PE patients diagnosed with CTEPH compared with PE patients who did not develop CTEPH. Boon GJAM et al^[14] gave two explanations for this result. First, none of the patients in their study met the criteria for “poor anticoagulation” and therefore a causal relationship between poor control of VKA and CTEPH anticoagulation after acute PE can not be excluded. Second, diagnostic misclassification makes it possible for even high-quality anticoagulation to prevent CTEPH because it already exists before the initiation of anticoagulation.^[34] Anticoagulation therapy is primarily intended to prevent recurrent venous thromboembolism or in situ pulmonary thrombosis, rather than to treat CTEPH itself.^[35] However, the effect of heparin on preventing or delaying the occurrence of CTEPH in patients with PE still needs to be further confirmed. Pulmonary thromboendarterectomy remains the only potential treatment option for CTEPH. Balloon pulmonary angioplasty can be used for inoperable CTEPH due to the presence of distal disease unsuitable for surgical intervention or inoperable comorbidities, or persistent or recurrent CTEPH after pulmonary thromboendarterectomy.^[32] In addition, C. Martinez’s study indicate that the incidence of CTEPH on the basis of chronic obstructive pulmonary diseases was 29.93% (82/274), which may suggest that patients with chronic obstructive pulmonary diseases and cardiovascular disease are at increased risk for CTEPH. Patients with cancer do not appear to have a significant impact on the development of CTEPH, but because of the small sample size in the articles, further confirmation of malignancy as a risk factor for the development of CTEPH is needed.

Our meta-analysis has several limitations. First, the inclusion of both cohort and retrospective studies, and the low number and insufficient sample sizes of included studies, mean that high-quality multi-center, prospective cohort studies are still required to determine the exact incidence of CTEPH after acute PE in men and women. Second, there is a lack of follow-up in the included article samples. Although the number of patients without follow-up and how to deal with them are clarified in the article, it will still have an impact on the exact incidence of CTEPH after acute PE in men and women. Finally, due to the difficulty in the early diagnosis and detection of CTEPH, some hidden patients may go undetected.

In conclusion, our meta-analysis suggests that gender may not be a risk factor for CTEPH in PE patients, but this conclusion still needs to be supported by high-quality studies with more sample data.

Author contributions

Conceptualization: Mingdi Chen, Chunhe Li, Zhenzhen Zheng, Riken Chen.

Data curation: Yuanqiang Lai, Minshan Chen.

Formal analysis: Yuanqiang Lai, Minshan Chen.

Funding acquisition: Chunhe Li, Xiaojuan Chen, Riken Chen.

Investigation: Yuanqiang Lai, Mingdi Chen, Chunhe Li, Yuanzhi Lai.

Methodology: Yuanqiang Lai, Minshan Chen, Mingdi Chen.

Project administration: Mingdi Chen, Chunhe Li, Xiaojuan Chen.

Resources: Yuanqiang Lai, Minshan Chen.

Software: Mingdi Chen.

Supervision: Chunhe Li, Yuanzhi Lai, Zhenzhen Zheng.

Validation: Xiaojuan Chen, Riken Chen.

Visualization: Xiaojuan Chen, Yuanzhi Lai, Zhenzhen Zheng, Riken Chen.

Writing – original draft: Yuanqiang Lai, Minshan Chen.

Writing – review & editing: Yuanqiang Lai, Minshan Chen, Xiaojuan Chen, Yuanzhi Lai, Zhenzhen Zheng, Riken Chen.