| BackgroundChronic thromboembolic pulmonary hypertension(CTEPH)is considered to be a rare long-term complication of pulmonary embolism with a poor prognosis if left untreated.Although recent studies have reported much improved survival rates,the evidence from studies with more than 10-year follow-up is rare.ObjectivesTo investigate the clinical characteristics,long-term survival,and anticoagulation outcomes of CTEPH patients from China.MethodsWe conducted a retrospective cohort study,including patients with definite diagnosis of CTEPH from Jan 2006 to Dec 2021.Data on clinical characteristics and therapies were collected.Congenital thrombophilia was diagnosed through tests for congenital anticoagulants activity(including protein C,protein S,and antithrombin III),factor V Leiden and prothrombin G20210A mutations.Patients diagnosed before Jan 1,2015 were classified in the traditional therapy era,and after Jan 1,2015 were classified in the modern therapy era.All patients were followed-up till Jan 31,2022.The primary outcome was all-cause mortality.The secondary outcomes included incidences of recurrent venous thromboembolism(VTE)and clinically relevant bleeding.ResultsA total of 559 patients with CTEPH were enrolled,with a nearly equal gender distribution(48.8%were female).The mean ages of symptoms onset and diagnosis were respectively 51±15 and 55 ± 15 years,yielding a median diagnostic delay of 25(12-61)months.A documented history of VTE and recurrent VTE were confirmed in 402(71.9%)and 40(7.2%)patients,and 30(7.6%)patients were combined with antiphospholipid syndrome.At diagnosis,more than half(64.0%)were in WHO functional class Ⅲ-Ⅳ.Mean pulmonary arterial pressure was 49 ± 12 mm Hg,and pulmonary vascular resistance was 9.5 ± 4.6 Wood U.In terms of treatment,all patients received anticoagulation therapy,of whom 518(92.7%)received medications approved for pulmonary arterial hypertension,112(20.0%)received pulmonary endarterectomy and 215(38.5%)received refined balloon pulmonary angioplasty therapy.Thirty-seven(9.3%)patients were combined with congenital thrombophilia,including 13 with protein C deficiency(3.3%),20 with protein S deficiency(5.0%),and 4 with antithrombin Ⅲ deficiency(1.0%).No patients with factor V Leiden or prothrombin G20210A mutations were identified.Genotype for patients with thrombophilia revealed that 10(76.9%)protein C deficiency patients were PROC mutation carriers,4(20.0%)protein S deficiency were PROS1 mutation carriers,and 2(50.0%)anti thrombin Ⅲ deficiency were SERPINC1 mutation cariers.Patients with thrombophilia presented with fewer female(OR[95%CI],0.32[0.15-0.70],p=0.004),more history of VTE(OR[95%CI],5.60[1.32-23.75],p=0.020)and more proximal lesions in pulmonary arteries(OR[95%CI],4.07[1.90-8.70],p<0.001),The median follow-up time was 6.2(3.5-8.9)years,and 112(22.1%)patients died.The most common cause of death was right heart failure(75.0%).The 1-,3-,5-and 10-year survival rates were 96.0%,88.4%,81.2%and 62.5%,respectively.The modern therapy era(HR[95%CI],0.36[0.22-0.58],p<0.001),age of diagnosis(HR[95%CI],1.02[1.01-1.04],p=0.011),WHO functional class Ⅲ-Ⅳ(HR[95%CI],2.58[1.46-4.53],p=0.001)and mixed venous oxygen saturation(HR[95%CI],0.96[0.94-0.98],p<0.001)were associated with all-cause mortality in patients with CTEPH.Thirty(5.9%)patients occurred 32 cases of recurrent VTE,with an incidence of 1.26/100 person-year.A history of VTE(HR[95%CI],3.18[1.07-9.48],p=0.038)and interruption of anticoagulation therapy(HR[95%CI],7.02[3.33-14.80],p<0.001)were significantly associated with an increased risk of recurrent VTE.Sixty-six(13.0%)patients occurred 97 cases of clinically relevant bleeding,with an incidence of 3.82/100 person-year.Cancer(HR[95%CI],4.82[1.43-16.24],p=0.011),anemia(HR[95%CI],3.65[1.59-8.34],p=0.002)and glucocorticoid use(HR[95%CI],3.27[1.55-6.87],p=0.002)were significantly associated with an increased risk of clinically relevant bleeding.ConclusionsPatients with CTEPH had an equal gender distribution,with severely compromised cardiac function and hemodynamic parameters at diagnosis.9.3%of them were combined with congenital thrombophilia and presented with unique clinical characteristics.The 10-year survival rate of patients with CTEPH was 62.5%,and the survival rate was significantly improved in the modern therapy era.Also,age of diagnosis,WHO functional class and mixed venous oxygen saturation were associated with all-cause mortality in patients with CTEPH.Under anticoagulation therapy,the incidence of recurrent VTE and clinically relevant bleeding was 1.26/100 person-year and 3.82/100 person-year in CTEPH patients.A history of VTE and interruption of anticoagulation therapy were significantly associated with an increased risk of recurrent VTE;cancer,anemia and glucocorticoid use were significantly associated with an increased risk of clinically relevant bleeding.BackgroundRefined balloon pulmonary angioplasty(BPA)has been reported to be a therapeutic option for patients with inoperable chronic thromboembolic pulmonary hypertension(CTEPH).However,there is limited evidence about the effects of refined BPA on all-cause mortality of patients with inoperable CTEPH.Moreover,whether this technique can be applied to patients with residual pulmonary hypertension after pulmonary endarterectomy(PEA)and severe patients before PEA is unclear.ObjectivesThe primary objective was to investigate the effect of refined BPA on the all-cause mortality of patients with inoperable CTEPH.The secondary objective was to reveal the effects of refined BPA on hemodynamic and functional parameters of patients with residual pulmonary hypertension after PEA and severe patients before PEA.MethodsWe conducted a prospective cohort study.The primary analysis consecutively enrolled inoperable CTEPH patients that completed BPA procedure(the BPA group)from Jan 2016 to Dec 2021.Patients who refused BPA procedure(the medical therapy group)and who received PEA procedure(the PEA group)at the same period were also enrolled as concurrent control groups.The primary outcome was all-cause mortality.The secondary outcomes included changes from baseline to re-evaluation in pulmonary vascular resistance,mean pulmonary arterial pressure and 6-minute walking distance.The safety outcomes included BPA procedure-related complications.The secondary analysis consecutively enrolled CTEPH patients with residual pulmonary hypertension after PEA and those severe patients receiving BPA bridging therapy before PEA.The efficacy outcomes included changes in pulmonary vascular resistance,mean pulmonary arterial pressure and 6-minute walking distance.ResultsA total of 110 patients in the BPA group,45 in the medical therapy group and 88 in the PEA group were enrolled in the primary analysis.Compared with the medical therapy group,the BPA group had more female patients(60.0%vs.40.0%,p=0.023).Other baseline characteristics and medical therapies were similar between the two groups.In the BPA group,with a median follow-up time of 3.7(3.0-5.8)years,4 patients died,and the 5-year survival rate was 97.2%.In the medical therapy group,with a median follow-up time of 4.4(2.4-5.4)years,10 patients died,and the 5-year survival rate was 74.5%(Log-rank p<0.001 vs.the BPA group).The Cox regression model showed that refined BPA was associated with a significantly reduced hazard of all-cause mortality in inoperable CTEPH patients(HR[95%CI],0.08[0.02-0.29],p<0.001).There was no difference in hazards of all-cause mortality between the BPA group and the PEA group(HR[95%CI],0.86[0.19-3.88],p=0.844).In terms of secondary outcomes,the adjusted least-squares mean difference between the BPA group and the medical therapy group was-4.7 Wood U(95%CI:-5.6,-3.9,p<0.001)in pulmonary vascular resistance,-19 mm Hg(95%CI:-21,-16,p<0.001)in mean pulmonary arterial hypertension,and 0.1(95%CI:0.01,0.2,p=0.038)in Log-6-minute walking distance.Fifty-four patients(51.9%)in the BPA group came off medications approved for pulmonary arterial hypertension due to the improved hemodynamic and functional parameters.Two(1.8%)patients occurred peri-procedural deaths.The prevalence of BPA procedure-related complications was 18.0%,and the most common complication was lung injury(8.6%).However,most complications were self-limited and severe complications requiring noninvasive positive pressure ventilation only occurred in 3 of the total 521 sessions(0.6%).Nine patients with residual pulmonary hypertension after PEA who completed BPA procedure were enrolled in the secondary analysis.Refined BPA further significantly decreased the mean pulmonary arterial pressure(31 ± 10 vs.45±10 mm Hg,p=0.005),pulmonary vascular resistance(4.1± 2.7 vs.7.6± 4.8 Wood U,p=0.016),and increased the 6-minute walking distance(468[438-504]vs.447[375-457]meters,p=0.027).However,1 patient did not response to both PEA and BPA procedures due to the severe peripheral pulmonary artery remodeling,and died of refractory right heart failure and hypoxemia.Another 7 patients with severe CTEPH who received BPA bridging therapy before PEA were also enrolled in the secondary analysis.Refined BPA significantly decreased the mean pulmonary arterial pressure(45±12 vs.60±11 mm Hg,p<0.001),pulmonary vascular resistance(7.9 ± 3.8 vs.13.3±3.9 Wood U,p<0.001)and increased the 6-minute walking distance(380[340-483]vs.354[203-438]meters,p=0.047).ConclusionsRefined BPA was associated with a significant decrease in all-cause mortality of inoperable CTEPH patients with acceptable safety profiles.There was no difference in the survival rates between the BPA group and the PEA group.Refined BPA could significantly improve the hemodynamic and functional parameters of patients with residual pulmonary hypertension after PEA.However,it is still challenging for those with severe small pulmonary artery remodeling.BPA bridging therapy before PEA could significantly improve the hemodynamic and functional parameters of severe patients with CTEPH,and might act as a promising therapeutic option,but needed to be confirmed in the further studies. |
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