CTEPH is a serious long-term complication after acute pulmonary embolism. CTEPH occurs infrequently after PE, so diagnostic evaluation of CTEPH is not recommended for all PE survivors[17], however, screening and diagnostic evaluation of CTEPH, such as persistent dyspnoea and risk factors for CTEPH, are recommended for patients who are clinically suspected to have CTEPH. Several studies have shown that patients with pulmonary embolism and right heart dysfunction are more likely to have CTEPH [17, 18]. The initial treatment of acute pulmonary embolism also has a certain impact on the occurrence of residual right heart dysfunction and CTEPH. Similarly, compared with anticoagulation therapy alone, MATUSOV Y [19]reported that reperfusion therapy for intermediate- to high-risk pulmonary embolism was significantly beneficial for short-term and long-term right heart recovery and reduced the occurrence of CTEPH. In the European CTEPH registration study, the average diagnostic delay from the first symptom to diagnosis was 14 months [20], and delays in diagnosis and treatment of CTEPH significantly affect patient prognosis. The 2019 ESC Guidelines for the Diagnosis and Management of pulmonary embolism recommend CTEPH screening for patients with acute pulmonary embolism after 3–6 months[15]. In our study, APE patients with right heart dysfunction on CT or echocardiography were continuously included, and risk factors for suspected CTEPH were investigated according to the 3–6 month follow-up. These findings could help make treatment decisions for acute pulmonary embolism to reduce the adverse prognosis caused by acute pulmonary embolism and improve the early screening rate and diagnosis rate of CTEPH. Our study is the first to investigate risk factors for early onset of suspected CTEPH in a subgroup of APE patients with right heart dysfunction via CT or echocardiography.
In our study, among 128 patients with acute pulmonary embolism with right ventricular dysfunction indicated by imaging, 33 patients were found to develop suspected CTEPH at 3–6 months of follow-up, for an incidence rate of 25.8%. Among pulmonary embolisms that were haemodynamically stable, the incidence rate of suspected CTEPH was 28.4%. Only 5 patients in our study had no elevated biomarkers for right heart dysfunction, and 96% of patients had intermediate- to high-risk pulmonary embolism. KLOK F A et al. reported that 25% of patients with submassive pulmonary embolism still had right ventricular dysfunction or possible CTEPH at the 6-month follow-up [21]; the conclusion of our study was similar to that previously reported. All 20 patients were treated after initial thrombolytic therapy without CTEPH during follow-up. ASL FS et al. also showed that none of the patients with haemodynamic instability or reperfusion therapy were diagnosed with CTEPH during follow-up[17]. However, in patients with haemodynamically stable pulmonary embolism, there was no significant difference in treatment method between the groups (p > 0.05), which was consistent with the conclusions reached in previous studies [22] and may be related to less thrombolytic therapy in patients with stable haemodynamics. In the present study, the application of catheter-directed thrombolysis (CDT) in patients with intermediate-high risk pulmonary embolism was conducive to the recovery of right heart function and pulmonary artery pressure and to reducing CTEPH incidence[23, 24]. Our study screened out the risk factors that may cause CTEPH and conducted more active treatment in APE patients with risk factors to reduce the occurrence of CTEPH.
In our study, it was concluded that the time from symptom onset to treatment, the TRPV, and the sPESI were independent risk factors for CTEPH in patients with right heart dysfunction, as indicated by imaging (p < 0.05). Since all patients with haemodynamic instability are less likely to develop CTEPH after thrombolytic therapy and all patients with suspected CTEPH have haemodynamically stable pulmonary embolism, we separately analysed pulmonary embolism patients with stable haemodynamics. It was also concluded that longer duration from symptom onset to treatment, higher TRPV, and sPESI score ≥ 1 were independent risk factors for suspected CTEPH (p < 0.05). The best cut-off value for predicting suspected CTEPH was 8 days, and the average number of days was 13 days. Previous studies have indicated that a duration from symptom onset to diagnosis of PE greater than 2 weeks is an independent risk factor for CTEPH [13]. The best cut-off value for the time from symptom onset to treatment was shorter in our study, which may be related to the patients enrolled in our study having acute pulmonary embolism (time from the onset of symptoms to the diagnosis of PE within 30 days). Delayed anticoagulation and thrombolytic therapy can lead to thrombofibrosis and promote the release of inflammatory factors, leading to the occurrence of CTEPH[25]. Early diagnosis of acute PE can reduce the incidence of CTEPH. LACHANT D et al. [26] reported that pulmonary artery systolic blood pressure at baseline was associated with the development of CTEPH. An estimated baseline pulmonary artery systolic blood pressure > 50 mmHg was associated with the persistence of pulmonary hypertension and RV dysfunction[27]. We also concluded that the TRPV at baseline was a risk factor for suspected CTEPH in haemodynamically stable pulmonary embolism patients. The optimal cut-off value was 3.4 m/s, the sensitivity was 78.8%, and the specificity was 66.3%. A previous study showed that an RV/LV > 1 was a risk factor for CTEPH [17], which was not confirmed in our study. Our study concluded that an sPESI score ≥ 1 at baseline was an independent risk factor for suspected CTEPH. When the sPESI score was ≥ 1, the sensitivity was 75.8%, and the specificity was 63.9%. At present, studies on the application of the sPESI for predicting the long-term prognosis of pulmonary embolism, especially for patients with CTEPH, are rare. VALERIO L et al.[7] reported that patients with pulmonary embolism and an sPESI score ≥ 1 are more likely to develop post pulmonary embolism syndrome. In our study, when combined with the time from symptom to treatment, the TRPV, and sPESI scores were used to predict suspected CTEPH at 3–6 months in patients with haemodynamically stable pulmonary embolism, and the AUC was 0.905, indicating high predictive value.
Our study has several limitations. First, our study was a retrospective single-centre cohort study. The potential CTEPH population was screened through symptoms, echocardiography and CTPA during follow-up, but only 4 patients were confirmed to have CTEPH by right cardiac catheterization; not all patients were confirmed to have CTEPH by right cardiac catheterization and the true occurrence of CTEPH was unknown. However, we recommend echocardiography inspection for pulmonary embolism patients with right heart dysfunction indicated by imaging after 3 months of anticoagulation therapy to reduce missed diagnoses in CTEPH patients. Second, although we tried to exclude patients who had underlying RV dysfunction preceding acute hospitalization, we cannot rule out the possibility that some patients had underlying undiagnosed pulmonary hypertension or right heart disease. Therefore, prospective studies with large sample sizes are needed to verify our conclusions.