RESEARCH ARTICLE
Lung and heart-lung transplantation in pulmonary arterial hypertension Manuel Lo´pez-Meseguer1,2,3, Carlos A. Quezada4, Maria A. Ramon1,2,3, Marı´a La´zaro5, Laura Dos6, Antonio Lara7, Raquel Lo´pez8, Isabel Blanco3,9,10, Pilar Escribano4, Antonio Roman1,2,3*, on behalf of the REHAP Investigators¶
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1 Department of Pneumology, Hospital Universitari Vall d’Hebron, Barcelona, Spain, 2 Departament de Medicina, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain, 3 Biomedical Research Networking Center on Respiratory Diseases (CIBERES), Madrid, Spain, 4 Pulmonary Hypertension Unit. Cardiology Department, Hospital Universitario doce de Octubre. Madrid, Spain, 5 Department of Cardiology. Hospital Virgen de la Salud, Toledo, Spain, 6 Department of Cardiology. Unidad de C.C. Adolescente y Adulto Vall d’Hebron-Sant Pau. Barcelona, Spain, 7 Department of Cardiology. Hospital Universitario de Canarias. Santa Cruz de Tenerife, Spain, 8 Department of Pneumonology. Hospital Universitario La Fe, Valencia, Spain, 9 Department of Pulmonary Medicine, Hospital Clı´nic-IDIBAPS, University of Barcelona. Barcelona, Spain, 10 University of Barcelona. Barcelona, Spain ¶ REHAP: Registro Español de Hipertensio´n Arterial Pulmonar (Spanish Registry of Pulmonary Arterial Hypertension). The complete membership of the author group can be found in the Acknowledgments. *
[email protected].
OPEN ACCESS Citation: Lo´pez-Meseguer M, Quezada CA, Ramon MA, La´zaro M, Dos L, Lara A, et al. (2017) Lung and heart-lung transplantation in pulmonary arterial hypertension. PLoS ONE 12(11): e0187811. https://doi.org/10.1371/journal.pone.0187811 Editor: Vinicio A. de Jesus Perez, Stanford University, UNITED STATES
Abstract Background Real use of lung (LT) and heart-lung (HLT) transplantation in pulmonary arterial hypertension (PAH) is unknown. The objectives were to describe the indication of these procedures on PAH treatment in a national cohort of PAH patients, and to analyze the potential improvement of its indication in severe patients.
Received: May 30, 2017 Accepted: October 26, 2017 Published: November 21, 2017 Copyright: © 2017 Lo´pez-Meseguer et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: There are legal restrictions on sharing the data from this study because the data belong to a national registry, REHAP. Only REHAP investigators are allowed to use the information from the registry for research purposes, and they are only given the specific information for the topic they are investigating, after the REHAP scientific committee gives formal consent. To become a researcher of REHAP you must belong to any of the National Societies of medical specialties related to PAH (respiratory, cardiology, internal medicine National Societies) and sign the confidentiality agreement. To apply for
Methods Eligibility for LT/HLT was assessed for each deceased patient. Incident patients from REHAP diagnosed between January 2007 and March 2015 and considered eligible for LT/ HLT were grouped as follows: those who finally underwent transplantation (LTP) and those who died (D-Non-LT).
Findings Of 1391 patients included in REHAP, 36 (3%) were LTP and 375 (27%) died. Among those who died, 36 (3%) were D-Non-LT. LTP and D-Non-LT were equal in terms of age, gender, and clinical status. Ten percent of those who died were functional class I-II. Patients functional class IV were less likely to undergo LT (8.3% LTP vs. 30.6% D-Non-LT, p = 0.017). Patients with idiopathic and drug/toxin-associated PAH were more likely to undergo LT (44.4% LTP vs. 16.7% D-Non-LT, p = 0.011).
Conclusions The present results show that the use of LT/HLT could double for this indication. Relevant mortality in early functional class reflects the difficulties in establishing the risk of death in PAH.
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data access please contact REHAP Coordinators (
[email protected]). Funding: This work was supported by Bayer HealthCare. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. There was no additional external funding received for this study. Competing interests: Bayer HealthCare provided funding for this study. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials.
Introduction Pulmonary arterial hypertension (PAH) is a severe and life-threatening condition with high mortality [1–3]. Double lung and heart-lung transplantation must be considered in all patients with severe PAH who have an inadequate response to optimal specific drug therapy [4,5], even though LT is used infrequently in PAH, with only about 100 procedures performed yearly worldwide [6]. In patients with PAH, limited availability of organs leads to higher waiting list mortality. It has been quantified at 19% per year since the implementation of the lung allocation score, a mortality that is significantly higher than for the rest of the diseases with indication for lung transplantation (LT)/heart lung transplantation (HLT) [7,8] for which early referral strategies were developed in order to minimize the effect of the limitations imposed by organ availability [6,9]. Although bridging with extracorporeal support systems can potentially minimize mortality on the waiting list, elective LT continues to be the optimal strategy and, when possible, must be the first choice for transplant candidates [6,10]. We hypothesized that the impact of LT on the global mortality of PAH is limited. The objectives of this study were to evaluate the impact of LT/HLT on the treatment of PAH in a national cohort of incident PAH patients recruited over a long period and to analyse the potential increase in the use of this procedure in severe patients.
Methods REHAP The characteristics of the Spanish Registry of Pulmonary Arterial Hypertension (REHAP), which provides the most valuable epidemiological data for PAH in Spain, have been described elsewhere [3]. Briefly, REHAP is a voluntary registry comprising 52 Spanish hospitals that is designed to prospectively collect exhaustive information on the demographics, management, and outcome of patients newly and previously diagnosed with PAH and chronic thromboembolic pulmonary arterial hypertension (CTEPH). REHAP was launched in January 2007, and all patients diagnosed from that date were prospectively recruited and classed as incident patients.
Design and population In the present study, we retrospectively analysed all incident PAH patients who died or underwent LT between January 2007 and March 2015. Non-operable CTEPH patients were included in the analysis. Patients with human immunodeficiency virus (HIV) infection and portopulmonary hypertension were excluded, as they were not candidates for LT. Data from REHAP were contrasted with data from the Spanish National Transplant Organization. Death and LT were considered the final outcomes of PAH. Eligibility for LT was assessed in patients who died and patients who underwent LT. For the purposes of this study, the results obtained after a maximum of 3–4 months before the event were used to establish the patient’s clinical situation near LT or death. Almost all of the absolute and relative contraindications for LT are shown in Fig 1. Patients with obvious contraindications for LT and those who died from non–PAH-related causes were considered not eligible for LT. The remaining 72 patients were considered potentially eligible for LT and were grouped as follows: patients who underwent LT (LTP); patients who died but were potentially eligible for LT (D-Non-LT). D-Non-LT were considered eligible for LT if they were New York Heart Association (NYHA) functional class III or IV, as recorded in the REHAP 3 to 4 months before death, and died from a PAHrelated cause. Patients who died from a cause not related to PAH, those NYHA class I or II, and obese patients (BMI >35 kg/m2) were considered not eligible for LT [10]. Patients with
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pulmonary veno-occlusive disease (PVOD) were considered eligible for LT regardless of their functional class. Information about other comorbidities that could have influenced eligibility was not available. All patients signed the informed consent at the moment of inclusion in the REHAP Registry giving permission for research purposes. The National Registry successfully passed quality controls and specific Ethic Committee and IRB approval.
Statistical analysis Qualitative data are expressed as frequencies and percentages. Normally distributed quantitative data are expressed as mean±standard deviation (SD); non-normally distributed data are expressed as median and interquartile range (IQR). The demographic and clinical characteristics of LTP and D-Non-LT were compared using an unpaired t test, Mann Whitney test, chisquare test, or Fisher exact test, as appropriate. Time from diagnosis to transplantation or death was assessed in both groups using Kaplan-Meier curves and the log-rank test. The analysis was conducted using Stata 12.1 (StataCorp, College Station, Texas, USA). A p value
