Chronic thromboembolic pulmonary hypertension.
Experience of a reference center in Argentina
MARÍA LUJÁN TALAVERA, MARIANO CAMPORROTONDO, ADRIANA ACOSTA, PABLO SPALETRA,
ANDRÉS ROMERA, ALEJANDRO MERETTA, AGUSTINA SCIANCALEPORE, MARIANO LÓPEZ,
MARÍA ESTER ARIS CANCELA, MIRTA DIEZ.
Instituto Cardiovascular de Buenos Aires (ICBA)
(1428) CABA, Argentina E-mail
Recibido 17-ENE-18 – ACEPTADO despues de revisión el 28-FEBRERO-2018.
There are no conflicts of interest to disclose.
Methods: Of a total of 44 patients diagnosed with pulmonary hypertension (HP), 15 patients with chronic thromboembolic pulmonary hypertension were detected (January 2010 to June 2016). Two patients were lost in the follow-up, so the total analyzed were: 13; 12 were considered candidates for endarterectomy and 1 patient was proposed to undergo angioplasty due to high surgical risk. Results: Regarding surgical patients (12), one died because of massive hemoptysis pending surgery and another refused the procedure. As a conclusion, 10 endarterectomies were performed. At the time of diagnosis, most of the population were in functional class III/IV (77%, 10 pts) and more than half (54%, 7 pts) had clinical signs of right heart failure. Surgical results: length of hospital stay was 13 (IQR 25-75: 8-19) days. As complications, reperfusion edema and right ventricular failure were recorded in 20% (2 pts), one of the patients died 72 hours after surgery (pulmonary vascular resistance (PVR) 1357 dynes.sec.cm-5). Median pre-operatory pulmonary vascular resistance was 572 (IQR 25-75: 375-1149) dynes.sec.cm-5 and the mPAP of 51 (IQR 25-75: 31-61) mmHg. After surgery, a reduction of mPAP was observed: 22 (IQR 25-75: 20-37) mmHg, (p = 0.005). Conclusions: At 12 months, 100% of patients had FC I / II; 2 patients (20%) developed residual pulmonary HTN because of distal vasculopathy, both of them are under treatment with riociguat. The patient undergoing angioplasty had improvement of dyspnea (FC II with reduced pulmonary pressure (mPAP 36 mmHg); she is on riociguat.
Chronic thromboembolic pulmonary hypertension (CTEPH) is a pathology that occurs as a consequence of thrombotic obstruction of pulmonary arteries by unsolved thrombosis. After acute pulmonary embolism, progression to CTEPH ranges between 0.8% to 8.8% according to the published series [1,2,3,4,5]. This was linked to the heterogeneity of the population included and the selection criteria of the additional methods for the research of the disease in follow-up.
One of the possible pathophysiological explanations that attempt to explain the progression into a chronic form, is the lack of pulmonary thrombi resolution in patients with an acute embolic event, that may have even been overlooked. This could be due to genetic and environmental factors preventing the proper lysis of the thrombus .
In its evolution, the disease generates functional class impairment with progressive dyspnea and a poor quality of life; but in its more advanced stages, right ventricular failure may occur, representing the most significant factor of a poor prognosis.
The disease is in group 4 of the current classification of pulmonary hypertension (PH) and is considered, after pulmonary hypertension associated to left heart disease (group 2), the second most frequent cause of pulmonary hypertension .
Pulmonary endarterectomy surgery is the treatment of choice because it is curative. The pharmacological treatments available currently, unlike surgery, do not solve the pathology and should be saved for nonsurgical patients (due to high risk and/or by distal disease) or with residual hypertension after surgery. Pulmonary angioplasty arose like a therapeutic alternative in patients that are not surgical candidates, in the period of full expansion [8,9].
The aim of this study was to describe the population of patients with chronic thromboembolic pulmonary hypertension, the ascribed treatment and its evolution in a reference center.
MATERIAL AND METHODS
There were 44 patients analyzed, with diagnosis of pulmonary hypertension consecutively included since January 2010 to June 2016, 15 patients were detected with chronic thromboembolic pulmonary hypertension (CTEPH). There were 2 losses in the follow-up, so the total analyzed was 13 patients.
Each patient was discussed in the pulmonary hypertension work group, constituted by 3 cardiologists, 1 pneumonologist, 2 hematologists, 3 imaging specialists, 1 hemodynamics specialist, 1 cardiovascular surgeon, and a nurse trained in PH. The therapeutic choice in each case was taken jointly taking into account the anatomy, co-morbidities and the will of the patient.
All the patients included were studied according to the international and national guidelines of pulmonary hypertension. Diagnostic screening was made by perfusion ventilation scintigraphy, which should have at least 1 segment with ventilation-perfusion mismatch. The presence of perfusion defects generated the pulmonary anatomy test by tomography angiography and pulmonary angiography; the confirmation by angiography was made by the observation of webs, arterial stenosis or total interruptions of pulmonary vessels. Moreover, the presence of pulmonary hypertension with right cardiac catheterization was documented: all patients had a mean pulmonary artery pressure (MPAP) ≥25 mmHg, measured in rest and a pulmonary capillary wedge pressure (PCWP) <15 mmHg. The date of diagnosis was established on the day of right cardiac catheterization.
Before establishing the definitive diagnosis of CTEPH, patients received anticoagulation for at least 90 days, with the demonstration of being properly anticoagulated during this time period.
The epidemiological and clinical characteristics were analyzed; also tests made on the population, time of diagnosis, treatment prescribed and follow-up over time.
For statistical analysis, the Statistics software, version 7, was used. The results were expressed as medians with first and third interquartile intervals (IQI 25.75) or as means and percentages as it corresponded. For the comparison of populations, Wilcoxon was used for continuous variables or Chi squared for the categorical ones. A p value <0.05 was established as significant.
Analysis of the general population.
There were 13 patients analyzed, with diagnosis of CTEPH. From them, 12 were considered candidates to endarterectomy and in 1 patient, treatment with angioplasty was chosen due to co-morbidities and a high surgical risk (84 years and positive frailty test). From the 12 patients candidates to surgery, one died while waiting for surgery by massive hemoptysis and another one refused the intervention; as a total 10 endarterectomies were carried out. All received treatment with anticoagulation.
Mean follow-up was 15 months (IQI 25-75: 10-20). Within the basal characteristics (Table 1) 69% (9 pts) of the population were females, the mean age was 40 years (IQI 25-75: 32-66) and the time of evolution since the onset of symptoms until diagnosis was 10 months (IQI 25-75: 10-57) in spite of most having a clear history of a previous thromboembolic event (pulmonary embolism or deep venous thrombosis: 85% and 39%, respectively); risk factors were detected linked to thromboembolism in 23% (3 pts): a case of essential thrombocytosis, another of polycythemia vera, and another of antiphospholipid syndrome. At the time of diagnosis, most of the population was in an advanced functional class (FC) (77%, 10 pts) and more than half (54%, 7 pts) had clinical signs of right heart failure. The basal hemodynamic characteristics are summarized in Table 2.
Table 1. Basal characteristics of the population
Dyspnea FC III / IV
Clinical right failure
Admissions due to right HF
In relation to the additional methods, in ECG 100% of patients were in sinus rhythm, and 92% (12 pts) had signs of right chambers enlargement. Color Doppler echo showed some degree of right ventricular function impairment in 54% of the population (7 pts) and in just one case there was presence of pericardial effusion. Of all cases analyzed, the 6-minute walk test was carried out in those who were in a condition to do it (61%, 8 pts), the median of walked meters was 435 m (IQI 25-75: 327-513), 100% of patients presented desaturation in stress; the rest of the population (5 pts) could not perform the study as they were in FC IV with severe hypoxemia. As previously mentioned, all patients underwent V/Q scintigraphy as screening method, which was pathological in 100% of the population and the diagnosis was subsequently confirmed by tomography angiography and pulmonary angiography (Figures 1 and 2).
Analysis of patients who underwent surgery or angioplasty.
From the total population (13 pts), pulmonary endarterectomy surgery was chosen in 12; one of them rejected the intervention, and another one died while waiting to be operated due to massive hemoptysis. There was a single female patient who was ruled out for surgery due to the high risk (because of co-morbidities); she was indicated pulmonary angioplasty. In total, 10 surgeries were conducted, 8 patients corresponding to group 3 of Jamieson’s classification, 1 to group 2, and another one to group 4 .
Pulmonary endarterectomy surgery was carried out (Figure 3) according to the protocol of the Institute. The time of extracorporeal circulation was 252 minutes (IQI 25-75: 218-262) and the time of circulatory arrest, 40 minutes (IQI 25-75: 38-46). Hospital stay was 13 days (IQI 25-75: 8-19), with a median of days in respiratory assistance of 4 days (IQI 25-75: 1-5). In terms of complications, the following were recorded: reperfusion edema and right ventricular failure in 20% (2 pts) of the population; one of the patients died 72 h after the surgery (PVR 1357 dynes.s.cm-5) (Table 3). Basally, pulmonary vascular resistances in the operated patients was 572 dynes.s.cm-5 (IQI 25-75: 375-1149) and MPAP of 1 mmHg (IQI 25-75: 31-61). After surgery, MPAP reduced significantly: 22 mmHg (IQI 25-75: 20-37) (p=0.005).
Table 3. In-hospital evolution
Time of extracorporeal circulation
Time of circulatory arrest
Days of respiratory assistance
In the 12-month follow-up, 100% of patients was in FC I/II and the 6-minute walk test improved by 90 meters (IQI 25-75: 50-140); those patients that could not walk in the preoperative period walked 310 meters (IQI 25-75: 391-420). There were 2 cases that developed residual PH confirmed by catheterization due to peripheral vasculopathy (pulmonary angiography with no evidence of recurrence of embolism); both are under treatment with riociguat.
In relation to the patient who underwent angioplasty, she presented a significant dyspnea, receiving treatment with riociguat and with control cardiac catheterization at 6 months after her last session of angioplasty, with a mean pulmonary pressure of 36 mmHg.
This registry represents the cases of a center having a team trained on PH and with an active program of pulmonary endarterectomy. This group meets the requirements detailed in both national and international PH guidelines .
All patients were evaluated according to the standards recommended by guidelines on clinical practice. Each patient has been analyzed in the group and decisions were agreed by all its members.
The age reported in these cases (median 40 years) was much lower than that reported in European, US and Japanese registries (age median 63, 52 and 67 years, respectively); in our series the female gender was predominant (69%); this also differs from the US and European registries (50% for both) but is similar to the Japanese one (72%). The history of thrombophilia was observed in almost a fourth of the population, a value somewhat lower than that in US and European registries (30% for both) and somewhat higher than in the Japanese registry (12%) [12,13,14].
In the delay in the cases in which diagnosis was made at 12 months, the common denominator both in our series and in international registries, was an advanced functional class at the time of diagnosis in spite of most patients analyzed having a history of thromboembolism. Another datum linked to the delay in diagnosis was that half of the population presented clinical right heart failure signs, which represents a factor of advanced disease and marked a poor outcome in these patients.
From the point of view of hemodynamics, the MPAP and PVR were comparable to the populations published in the mentioned registries. On the contrary, in the functional assessment, the meters walked in the population presented here were more than in the Japanese and European registries (435 versus 330 and 329 meters, respectively); although it is difficult to draw conclusions on this variable, because in our series individuals in FC IV and with severe hypoxia were excluded.
Although pulmonary endarterectomy is the treatment of choice because it is curative , the eligibility of patients depends on the intervening team and fundamentally, on the experience of the surgeon in charge. In the presented series, only 1 patient was rejected due to high co-morbidities; the rest were presented with the possibility of surgery. The in-hospital evolution of the patients who underwent surgery was satisfactory; only 1 death was recorded in a patient with parameters of advanced disease (PVR >1000 dynes.s.com-5). In follow-up, the rate of residual PH was similar to that reported in the bibliography . These patients with residual PH are receiving treatment with riociguat, as it is the only pharmacological treatment that has shown benefits in this population of patients, and therefore is the recommended drug in guidelines .
Angioplasty is a treatment saved for nonsurgical cases that are in an expansion stage. The patient excluded from surgery received pulmonary angioplasty and riociguat as an additional treatment without complications. In the follow-up, the patient reduced MPAP (though it did not normalize it) and kept a proper functional class .
The limitations of this registry are multiple: first, the number of patients included is low; the results do not reflect in any way the reality of Argentina where there are only 3 active centers, including ours, performing pulmonary endarterectomy. Undoubtedly, more cases of pulmonary angioplasty are required to obtain results that could be compared with the data published in literature.
The multidisciplinary team work and the experience of a reference center in pulmonary endarterectomy, the gold standard of treatments for patients with chronic thromboembolic pulmonary hypertension, represent a chance to change the evolution of a progressive and devastating disease if not treated .
Among the characteristics of the population presented in this series, the youngest age median, with a female predominance, stands out.
The surgical results (endarterectomy) of a reference center of the country are comparable to those published in literature, an achievement of a multidisciplinary team work.
The clinical evolution of the intervened patients was satisfactory, with a rate of residual pulmonary hypertension similar to that reported in other series, with a good response to treatment with riociguat (soluble guanylate cyclase stimulator).
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