Management and outcomes in chronic thromboembolic pulmonary hypertension: From expert centers to a nationwide perspective

doi:10.1016/j.ijcard.2015.11.039

International Journal of Cardiology

Volume 203, 15 January 2016, Pages 938-944

https://doi.org/10.1016/j.ijcard.2015.11.039 Get rights and content

Abstract

Background

The Spanish “Registry of Pulmonary Arterial Hypertension” (REHAP), started in 2007, includes chronic thromboembolic hypertension (CTEPH) patients. Based on data provided by this registry and retrospective data from patients diagnosed during 2006 (≤ 12 months since the registry was created), clinical management and long-term outcomes of CTEPH patients are analyzed nationwide for the first time in a scenario of a decentralized organization model of CTEPH management.

Methods and results

A total of 391 patients (median [Q1:Q3] age 63.7 [48.0;73.3] years, 58% females) with CTEPH included during the period January 1, 2006–December 31, 2013 in the REHAP registry were analyzed. Rate of pulmonary endarterectomy (PEA) was 31.2%, and highly asymmetric among centers: rate was 47.9% at two centers designated as CTEPH expert centers, while it was 4.6% in other centers. Among patients not undergoing PEA, 82% were treated with therapies licensed for pulmonary arterial hypertension (PAH). Five-year survival rate was 86.3% for PEA patients, and 64.9% for non-PEA patients. Among non-PEA patients, presenting proximal lesions (42% of non-referred patients) was associated with a 3-fold increase in mortality. PEA patients achieved significantly better hemodynamic and clinical outcomes at one-year follow-up compared to non-PEA patients. Patients not being referred for PEA assessment were older and had a worse functional capacity. Older age was the most deterrent factor for non-operability.

Conclusion

Despite the increase in diagnosis and expertise in PEA-specialized centers, an important percentage of patients do not benefit of PEA in a decentralized organization model of CTEPH management.

Introduction

Chronic pulmonary thromboembolic hypertension (CTEPH) is one of the leading causes of severe pulmonary hypertension (PH) and as such, it is associated with significant morbidity and mortality [1], [2]. Even though recognition of CTEPH has recently increased [3], epidemiological data are scarce [3], [4] and there is an urgent need to identify patients.

Pulmonary endarterectomy (PEA) is the treatment of choice for CTEPH patients given its potential to cure the disease [5], with restoration of hemodynamics to normal or nearly normal and improvement in clinical symptoms in most patients [3], [6], [7]. PEA is performed in highly specialized centers, and outcomes are associated with growing expertise in the technique, optimal patient selection, and better perioperative management [3], [8]. Until the launch in 2015 of riociguat – currently the only treatment licensed for CTEPH – which has demonstrated to significantly improve exercise capacity and PVR in CTEPH patients deemed inoperable or those with residual PH after PEA [9], [10], patients were treated with medical therapies proven to be effective in pulmonary arterial hypertension (PAH) [5].

Current knowledge on the outcomes associated with the management of CTEPH arises precisely from these PEA-specialized centers [3], [11]. However, this information is far from capturing outcomes of CTEPH patients at a nationwide perspective since country-specific management issues, and specifically how referral for PEA assessment is undertaken (i.e. mandatory and centralized in reference centers vs. optional and based on a decentralized decision-making model), may greatly influence outcomes at this level. These kinds of analyses, which are fundamental to outline policies for CTEPH management, are scarce and only available from countries where a centralized model is followed [3], [12].

A national observational registry of pulmonary arterial hypertension (REHAP) has been running in Spain since 2007 providing valuable information about CTEPH epidemiology and survival [4]. This registry is one of the largest currently in place in Europe. One of its objectives was to evaluate the clinical management of CTEPH patients and long-term outcomes under a nationwide perspective, according to the management organization model established. This model is characterized for being decentralized, with management of patients (i.e. diagnosis and treatment, some of them including PEA) taking place at so-designated PH-specialized centers and at general hospitals. In centers not performing PEA, decision regarding referral for PEA assessment is left to doctor's judgment. Two of the PH-specialized centers bring together most CTEPH patients and are designated as expert centers.

The REHAP offers therefore a unique opportunity to analyze from a nationwide perspective how patients are treated and long-term outcomes according to treatment in a decentralized model of CTEPH management. This is also especially interesting since only a few long-term evidence of outcomes in CTEPH patients receiving PAH-specific therapies is currently available [3]. Other data of interest such as how patient selection for PEA assessment is undertaken when left to doctor's judgment is also provided.

Section snippets

Study subjects

Analyzed CTEPH patients were included in the REHAP registry from January 1, 2006 to December 31, 2013. Patients diagnosed during 2006 (≤ 12 months since the registry was created) were included retrospectively, and prospectively thereafter. Centers reporting data to the registry included 31 PH-specialized centers and general hospitals, which covered 15 of the 17 administrative regions of Spain. Two of these centers managing more than 50 CTEPH patients (those belonging to the health administrative

Study population

A total of 391 CTEPH patients meeting the inclusion criteria had been included in the registry by December 2013, and constituted the study population. Patients presented a median age (Q1;Q3) of 63.7 (48.0;73.3), were women in 58% of cases and had a severe clinical and hemodynamic condition (Table 1).

Treatment at diagnosis

Among all patients, 122 (31.2%) underwent PEA during this period (hereafter PEA patients). Of these, 115 PEAs (94% of all PEAs) took place among the 240 patients (47.9%) managed at the two expert

Discussion

Our study, based on data provided by the REHAP registry, provides novel useful information regarding diagnosis and outcomes associated to CTEPH patient management from a nationwide perspective vs. PEA-specialized enter in a specific scenario of decentralized decision-making model of referral for PEA assessment. Analysis of the data has revealed the existence of an important gap between operability rate at PEA-specialized centers and that of the country, when considered as a whole. This implies

Conclusions

The low rate of PEA reported in our national registry, and thus the important percentage of patients whom do not benefit from this potentially curative option, highlights that despite efforts made in CTEPH patient management such as increasing awareness and expertise in PEA at specialized centers, such efforts do not seem to translate into generalized benefits for patients when a decentralized model of decision making with respect to referral for PEA assessment is followed. Organizational

Acknowledgments

We express our gratitude to Bayer Schering Pharma for supporting this Registry with an unrestricted educational grant. We gratefully acknowledge all investigators who form part of the REHAP Registry. We also thank the Registry Coordinating Center, S & H Medical Science Service, for their quality control, logistic and administrative support. We also thank Beatriz Viejo, PhD for her assistance in the writing of the manuscript and editorial support.

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Epoprostenol requires continuous infusion and may lead to catheter-related complications. Evidence regarding the comparison between peripherally inserted central catheters (PICC) or tunneled central catheters in Pulmonary Hypertension (PH) is scarce. We sought to study the incidence of mechanical and infectious complications associated with PICC and Hickman catheters in patients with PH under epoprostenol treatment.
This is a single-center retrospective study of patients with PH who received continuous treatment with intravenous epoprostenol for at least 24 h between January 2010 and July 2020. Mechanical and infectious complications were analyzed according to the catheter type: PICC and Hickman. The incidence of catheter-related complications was calculated per 1000 exposure-days of risk.
175 catheters were implanted in 109 patients, of which 100 (57.1%) were Hickman and 75 (42.9%) were PICC. After a median follow-up of 334 [130–798] days, there were no differences in the rates of local (0.22 vs 0.21; p = 0.904) or blood-stream infections (0.13 vs 0.21; p = 0.405). Mechanical complications were more frequent in the PICC group (0.98 vs 0.23 p=<0.001), including venous thrombosis (0.16 vs 0.00 p = 0.003) and catheter occlusion (0.66 vs 0.04 p=<0.001). These complications were associated with a greater need for hospitalization (1.48 vs 0.50; p=<0.001), without differences in mortality during follow-up (0.33 vs 0.21; p = 0.288).
In patients with PH treated with intravenous epoprostenol, both Hickman and PICC catheters were associated with high rate of complications. Although there were no differences in the frequency of infectious-related complications, PICC was associated with a higher frequency of catheter occlusion and deep venous thrombosis.
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The diagnosis of chronic thromboembolic pulmonary hypertension (CTEPH) is complex, and the modality of treatment is surgery and targeted medication. Patients with CTEPH could have a poor prognosis if their diagnosis or treatment is delayed. The incidence of CTEPH and its clinical features are largely unknown in Taiwan, even among other Asian populations. In this study, we aimed to investigate the geodemographics of CTEPH in Taiwan and describe the practical management and treatment outcomes in patients with CTEPH.
This study retrospectively enrolled patients in the Taiwan cohort – Registry of CTEPH. The study was conducted over 2 years inclusive of follow-up. The enrolment criteria depended on the current global guideline.
From January 2018 to March 2020, 107 CTEPH patients enrolled in the Taiwan registry. All patients received right heart catheterisation examinations. The overall median age was 61.4 ± 16.5 years, and the cohort was dominated by female patients (75/107). Risk factors included pulmonary embolism (81.3%), deep vein thrombosis (22.4%), and previous major surgery (20.6%). Twenty-one (19.6%) patients underwent pulmonary endarterectomy operation alone, and 38 (35.5%) patients underwent balloon pulmonary angioplasty alone.
To our knowledge, this is the first national cohort study that demonstrated the raw CTEPH incidence in Taiwan. It also showed the CTEPH incidence between male and female patients in the Asian population was different from the Caucasian population.
Chronic thromboembolic pulmonary hypertension in Spain: a decade of change
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El tratamiento de la hipertensión pulmonar tromboembólica crónica (HTPTEC) ha evolucionado en la última década. Sin embargo, apenas se dispone de información sobre el impacto de estos logros en la población general a escala nacional. Este estudio se diseñó para describir las características de los pacientes con HTPTEC en España en la última década.
Se recogieron prospectivamente datos epidemiológicos, clínicos y pronósticos de los pacientes con HTPTEC consecutivos incluidos en el registro español REHAP desde el 1 de enero de 2007 al 31 de diciembre de 2018. Se evaluaron las diferencias entre diferentes periodos de tiempo, estableciendo 2013 como fecha de referencia para el análisis. Se calculó la puntuación de propensión para la intervención mediante un modelo multivariable de regresión logística.
Se incluyó a 1.019 pacientes; se remitió a 659 (64,4%) a un centro nacional de referencia en HTPTEC. Del total, se seleccionó a 350 (34,3%) para cirugía y a 97 (9,6%) para tratamiento percutáneo. Entre los pacientes diagnosticados entre 2007 y 2012 hubo más frecuencia de muerte que entre los diagnosticados de 2013 en adelante (HR = 1,83; IC95%, 1,07-3,15; p = 0,027). En el grupo de pacientes ajustado por el modelo de puntuación de propensión, las resistencias vasculares pulmonares basales y la distancia recorrida en el test de 6 min de marcha también fueron determinantes del pronóstico (respectivamente, HR = 1,24; IC95%, 1,15-1,33; p = 0,011, y HR = 0,93; IC95%, 0,90-0,97; p = 0,001). Las tasas de supervivencia de los pacientes que se sometieron a un procedimiento intervencionista (trombendarterectomía pulmonar o angioplastia con balón de arterias pulmonares) resultaron llamativamente altas.
Durante la última década, el diagnóstico y el pronóstico de la HTPTEC han mejorado de manera considerable. La gravedad de la enfermedad al diagnóstico determinó el perfil de riesgo. Los pacientes a los que se realizaron trombendarterectomía pulmonar o angioplastia con balón de arterias pulmonares tuvieron mejores resultados.
Chronic thromboembolic pulmonary hypertension (CTEPH) treatment has evolved in the last decade. However, there is scarce information on the long-term impact of this progress in a real-life population at a national level. This study was designed to analyze the characteristics of CTEPH patients in Spain over the last decade.
We prospectively collected epidemiological, clinical, and prognostic data from CTEPH patients consecutively included in the Spanish REHAP registry from January 1, 2007, to December 31, 2018. We evaluated differences over time, establishing 2013 as the reference date for analysis. Propensity scores for interventional treatment were calculated using a multivariable logistic regression model.
A total of 1019 patients were included; 659 (64.4%) were evaluated at a national CTEPH center. Overall, 350 patients (34.3%) were selected for surgery and 97 (9.6%) for percutaneous treatment. Patients diagnosed between 2007 and 2012 died more frequently than those diagnosed from 2013 onward (HR, 1.83; 95%CI, 1.07-3.15; P = .027). Within the subgroup of patients adjusted by propensity score, baseline pulmonary vascular resistance and the 6-minute walk test distance also determined the outcome (HR, 1.24; 95%CI, 1.15-1.33; P = .011; and HR, 0.93; 95%CI, 0.90-0.97; P = .001, respectively). High survival rates were found in patients who underwent an invasive procedure (pulmonary endarterectomy or balloon pulmonary angioplasty).
CTEPH diagnosis and prognosis have consistently improved in the last decade. Baseline disease severity determines the risk profile. Patients who undergo pulmonary endarterectomy or balloon pulmonary angioplasty have better outcomes.
Riociguat treatment in patients with chronic thromboembolic pulmonary hypertension: Final safety data from the EXPERT registry
2021, Respiratory Medicine
The soluble guanylate cyclase stimulator riociguat is approved for the treatment of adult patients with pulmonary arterial hypertension (PAH) and inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH) following Phase 3 randomized trials. The EXPosurE Registry RiociguaT in patients with pulmonary hypertension (EXPERT) study was designed to monitor the long-term safety of riociguat in clinical practice.
EXPERT was an international, multicenter, prospective, uncontrolled, non-interventional cohort study of patients treated with riociguat. Patients were followed for at least 1 year and up to 4 years from enrollment or until 30 days after stopping riociguat treatment. Primary safety outcomes were adverse events (AEs) and serious adverse events (SAEs) coded using Medical Dictionary for Regulatory Activities preferred terms and System Organ Classes version 21.0, collected during routine clinic visits and collated via case report forms.
In total, 956 patients with CTEPH were included in the analysis. The most common AEs in these patients were peripheral edema/edema (11.7%), dizziness (7.5%), right ventricular (RV)/cardiac failure (7.7%), and pneumonia (5.0%). The most common SAEs were RV/cardiac failure (7.4%), pneumonia (4.1%), dyspnea (3.6%), and syncope (2.5%). Exposure-adjusted rates of hemoptysis/pulmonary hemorrhage and hypotension were low and comparable to those in the long-term extension study of riociguat (Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase–Stimulator Trial [CHEST-2]).
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Citation Excerpt :
More recently, a French study found survival rates of 86% at 1 year and 55% at 3 years [6]. Another study [7], focusing on patients with chronic thromboembolic PH (CTEPH), reported a survival rate of 86% after pulmonary endarterectomy at 5 years. As far as we know, with the exception of three studies [8–10], none has compared prognosis between the five forms of PH.
Pulmonary hypertension (PH) is a heterogeneous, severe and progressive disease with an impact on quality of life and life-expectancy despite specific therapies.
(i) to compare prognosis significance of each PH subgroup in a cohort from a referral center, (ii) to identify phenotypically distinct high-risk PH patient using machine learning.
Patients with PH were included from 2002 to 2019 and routinely followed-up. We collected clinical, laboratory, imaging and hemodynamic variables. Four-year survival rate of each subgroups was then compared. Next, phenotypic domains were imputed with 5 eigenvectors for missing values and filtered if the Pearson correlation coefficient was > 0.6. Thereafter, agglomerative hierarchical clustering was used for grouping phenotypic variables and patients: a heat map was generated and participants were separated using Penalized Model-Based Clustering. P < 0.05 was considered significant.
328 patients were prospectively included (mean age 63 ± 18 yo, 46% male). PH secondary to left heart disease (PH-LHD) and lung disease (PH-LD) had a significantly increased mortality compared to pulmonary arterial hypertension (PAH) patients: HR = 2.43, 95%CI = (1.24–4.73) and 2.95, 95%CI = (1.43–6.07) respectively. 25 phenotypic domains were pinpointed and 3 phenogroups identified. Phenogroup 3 had a significantly increased mortality (log-rank P = 0.046) compared to the others and was remarkable for predominant pulmonary disease in older male, accumulating cardiovascular risk factors, and simultaneous three major comorbidities: coronary artery disease, chronic kidney disease and interstitial lung disease.
PH-LHD and PH-LD has 2-fold and 3-fold increase in mortality, respectively compared with PAH. PH patients with simultaneous kidney-cardiac-pulmonary comorbidities were identified as having high-risk of mortality. Specific targeted therapy in this phenogroup should be prospectively evaluated.
L’hypertension pulmonaire (HTP) est une pathologie hétérogène, sévère et chronique avec un impact sur la qualité et l’espérance de vie malgré l’arrivée de plusieurs thérapeutiques spécifiques.
Comparer le pronostic des 5 formes d’HTP entre elles à partir d’une cohorte d’un centre de compétence, et identifier, à l’aide du machine learning, un phénotype de patient au pronostic péjoratif.
Les patients porteurs d’une HTP ont été inclus de 2002 à 2019 et régulièrement suivis. Leurs données cliniques, biologiques, d’imagerie et hémodynamiques ont été collectées. La mortalité à 4 ans de chacun des groupes a ensuite été comparée. Les variables phénotypiques avec des données manquantes ont été imputées et filtrées si le coefficient de corrélation de Pearson était > 0,6. Par la suite, la fonction « agglomerative hierarchical clustering » a été utilisée pour grouper les variables phénotypiques choisies ainsi que les patients et une heat map a été générée. La cohorte a été ensuite séparée en phénogroupes. Un p < 0,05 était considéré comme significatif.
Au total, 328 patients ont été prospectivement inclus (âge moyen de 63 ± 18 ans, 46 % d’hommes). L’HTP secondaire aux pathologies cardiaques gauches (groupe 2) et celle secondaire aux pathologies pulmonaires (groupe 3) avaient une surmortalité comparée à celle des patients porteur d’une hypertension artérielle pulmonaire (HTAP) : HR = 2,43, IC95 % = (1,24–4,73) et 2,95, IC95 % = (1,43–6,07) respectivement. Vingt-cinq variables phénotypiques ont été choisies et 3 phénogroupes identifiés. Comparé aux 2 autres, le 3^e phénogroupe avait une surmortalité (log rank p = 0,046) et se différenciait par la prédominance d’hommes âgés, accumulant plusieurs facteurs de risques cardiovasculaires, et simultanément 3 comorbidités : insuffisance rénale chronique, insuffisance coronarienne et pneumopathie interstitielle diffuse.
L’HTP secondaire aux pathologies cardiaques gauches et celle secondaire aux pathologies pulmonaires ont une mortalité respectivement multipliée par 2 et 3 comparé aux patients avec une HTAP. La présence simultanée de comorbidités cardiaque, rénale et pulmonaires est associés à un sur-risque de mortalité chez les patients porteurs d’une HTP.
Does combination therapy work in chronic thromboembolic pulmonary hypertension?
2020, IJC Heart and Vasculature
The current experience with combination therapy in chronic thromboembolic pulmonary hypertension (CTEPH) is limited. We present the first survival results up to 5 years for dual combination therapy versus monotherapy in CTEPH.
All consecutive, non-operated CTEPH or residual PH after pulmonary endarterectomy patients treated with PH-specific medical therapy between January 2002 and November 2019 were included. We report and compare survival between monotherapy and (upfront or sequential) dual combination therapy until five years after medication initiation.
In total, 183 patients (mean age 65 ± 14 years, 60% female, 66% WHO FC III/IV, 86% non-operated) were included, of which 83 patients received monotherapy and 100 patients received dual combination therapy. At baseline, patients receiving combination therapy had a higher NT-proBNP (p = 0.02) mean pulmonary artery pressure (p = 0.0001) and pulmonary vascular resistance (p = 0.02), while cardiac index was lower (p = 0.03). Total follow-up duration was 3.3 ± 1.8 years, during which 31 (17%) patients died. Estimated 1-, 3- and 5-year survival for monotherapy were 99%, 92% and 79%, respectively. For combination therapy percentages were 98%, 89% and 70%, respectively. Survival did not significantly differ between both groups (p = 0.22).
Survival up to 5 years for patients treated with combination therapy, regardless of the combination strategy, was similar as patients with monotherapy, despite worse clinical and haemodynamic baseline characteristics.

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¹: These two authors contributed equally to this work.

²: REHAP: Registro Español de Hipertensión Arterial Pulmonar (Spanish Registry of Pulmonary Arterial Hypertension). A full list of REHAP investigators is given in the Appendix.

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Management and outcomes in chronic thromboembolic pulmonary hypertension: From expert centers to a nationwide perspective

Abstract

Background

Methods and results

Conclusion

Introduction

Section snippets

Study subjects

Study population

Treatment at diagnosis

Discussion

Conclusions

Acknowledgments

J. Thorac. Cardiovasc. Surg.

Int. J. Cardiol.

J. Am. Coll. Cardiol.

J. Thorac. Cardiovasc. Surg.

Arch. Bronconeumol.

Arch. Bronconeumol.

J. Am. Coll. Cardiol.

J. Am. Coll. Cardiol.

Chest

J. Am. Coll. Cardiol.

Int. J. Cardiol.

Chronic thromboembolic pulmonary hypertension (CTEPH)

Heart

Chronic thromboembolic pulmonary hypertension

Circulation