Sumario Vol.43 - Nº 3 Julio-Septiembre 2014 Imprimir sólo la columna central

First Pulmonary Hypertension Collaborative Registry in Argentina

Diego Echazarreta
(1), Eduardo Perna (1), María Lorena Coronel (1),
Mirta Diez
(2), Adrián Lescano (2), Nicolás Atamañuk (2),
Juan Antonio Mazzei
(3), Jorge Caneva (3), Juan Osses (3), Alejandro Nitsche (4)Alejandra Babini (4), Gustavo Casado (4), Dora Haag (5-2), Mariana Cazalas (5-2), Carolina Stepffer (5-2) e Investigadores del RECOPILAR.
1. Federación Argentina de Cardiología (FAC), 2. Sociedad Argentina de Cardiología (SAC), 3. Asociación Argentina de Medicina Respiratoria (AAMR), 4. Sociedad Argentina de Reumatología (SAR), 5. Sociedad Argentina de Pediatría (SAP).


Sección de Insuficiencia Cardiaca e Hipertensión Pulmonar. Servicio de Cardiologia.
Hospital San Juan de Dios. (1900) La Plata, Buenos Aires. Argentina.
E-mail

 
Recibido 04-JUL-2014 – ACEPTADO 25-JULIO-2014.
The authors declare not having conflicts of interest
 
Rev Fed Arg Cardiol. 2014; 43(3): 146-149
ABSTRACT

In the past 25 years, progress in the treatment of pulmonary hypertension (PH) has allowed a better recognition of its epidemiology and clinical evolution through various national and international registries. The data provided by the Argentine registry Hinpulsar that included 422 subjects, showed that treatment of PH in our country takes place in centers with different complexity, using multiple strategies and underusing diagnostic methods deemed necessary by the different guidelines, especially right heart catheterization. Therefore, and according to the need for epidemiological data that reflect the reality of this disease in our country, it is essential to integrate different scientific institutions involved in evaluation and treatment of this condition to realize a collaborative registry. Thus, this is not only an epidemiological, but a therapeutic tool for patients newly diagnosed with HP in Argentina.
Key words: Pulmonary hypertension. Heart failure. Registry.

 

INTRODUCTION
Pulmonary hypertension (PH) is a rare disease, that may have different causes and that entails different treatments. Pulmonary hypertension has a prevalence estimated in 15/1,000,000 inhabitants and an incidence of 2.4/million inhabitants per year. In the last 25 years, the advancement in the treatment of this disease allowed a better recognition of its epidemiology and clinical evolution through different national and international registries [1]. Recently, the REVEAL Registry has provided new data on the evolution of the disease and it allowed us to develop a useful tool to stratify risk [2].

However, we should take into account that the chance of making an extrapolation of these epidemiological inferences is limited by the regional and geographical differences. For instance, the high prevalence of pulmonary hypertension associated to schistosomiasis in Brazil or the impact of altitude in Mexico. In spite of having individual registries in some Latin American countries, the data in Argentina are scant. According to international figures, there should be between 600-2000 patients with PH, with 90-300 new cases per year.

The data presented recently from the Argentine registry Hinpulsar [3,4] that included 422 individuals, showed a distribution between groups 1 through 5 of pulmonary hypertension of 29.4%, 52.8%, 10%, 6.4% and 1.4%, respectively. The treatment was clearly different from Group 1 in comparison to the other groups. In individuals with PH, the evaluation included; electrocardiogram (90%), chest X-rays (82%), 6-minute walk test (65%), V/Q scintigraphy (33%), pulmonary functional tests (61%), CT angiography (4%), angiography (10%), and cardiopulmonary stress test (7%). Right heart catheterization was carried out in 65%, and included pulmonary vasoreactivity tests in half of them. The specific therapy is used in 80% of patients: 77% sildenafil, 11% iloprost, 12% bosentan, 5% ambrisentan and 5% treprostinil.

In spite of a high prescription of specific drugs for the treatment of PH, they were indicated over the course of the disease. On the other hand, the combined therapy was prescribed in a similar proportion in patients with mild and severe symptoms, which suggests a poor adherence to the treatment guidelines [5]. As a limitation, the inclusion criteria for the study were the presence of systolic pulmonary pressure ≥40 mmHg measured by Doppler echo or mean pulmonary pressure ≥25 mmHg in right heart catheterization. The results showed that the treatment of PH in our country was made in many centers, using different strategies, with diagnostic methods considered necessary by the different guidelines being underused. In this sense, it is interesting to highlight in our country, the recent publication by the Fundación Favaloro [6] on a series of 125 patients with follow-up during 39 months where prognostic markers are observed, that are easy to obtain in a population with PH in group I.

The acquired experience through this registry should be continued with an intervention addressed to optimize the diagnostic strategies, using a common algorithm considering the extensive bibliography published during recent years on this pathology [7-10].

 

HYPOTHESIS
The execution of this national PH registry through inter-institutional collaboration, will allow obtaining a wider and more appropriate epidemiological profile of pulmonary hypertension in our country.

 

OBJECTIVES

  • To evaluate the clinical characteristics, diagnostic strategies, risk stratification and therapeutic management of the patients with diagnosed pulmonary hypertension by right catheterization in Argentina.
  • To characterize the different groups of PH according to the following specific Registries that make this collaborative study:
    • Incident cases (prospective registry)
      • Pulmonary hypertension
        • Associated to collagen diseases.
      • Pulmonary hypertension associated to left ventricular heart disease.
      • Pulmonary hypertension associated to pulmonary diseases and hypoxemia
      • Pulmonary hypertension in Pediatrics
      • Pulmonary hypertension in groups 4 and 5
  • Prevalent cases (retrospective registry).
  • To improve the identification and routine evaluation of patients with pulmonary hypertension in groups 1 through 5, by the systematic use of diagnostic algorithms, including right catheterization.
  • To improve the differential diagnosis between group 1 of pulmonary hypertension and the rest of the mentioned groups.
  • To promote the systematic use of diagnostic tools: pulmonary functional test, V/Q scintigraphy, right heart catheterization, 6-minute walk test, CT angiography, biomarkers to arrive to an accurate diagnosis in each subset, and to optimize risk stratification.
  • To compare the therapeutic strategies in the prevalent and incident cases.
  • To evaluate the annual survival of patients with pulmonary hypertension.
  • To allow the comparison with other regional and international registries with similar features.

 

How would the proposal have an impact on the clinical practice of pulmonary hypertension?
Pulmonary hypertension affects people in all social strata, which entails in many cases, difficulties in the access to the high-complexity centers.

The spread of the care of these patients in centers with less complexity favors the access to a high-cost care, especially in the population with less economic resources, but with the risk of receiving inappropriate evaluation strategies.

The knowledge of a greater number of epidemiological variables of the disease will allow us to know with more accuracy the difficulties that exist nowadays in our country to obtain a proper diagnosis, etiopathogenic classification, and risk stratification and therapeutic strategies according to the recommendations by daily practice guidelines, mainly in countries with a particular health-care structure, where the care fragmentation of the system is the predominant characteristic and therefore, the epidemiological survey of a pathology constitutes a true epidemiological challenge [11,12].

 

METHODS
Collaborative inter-institutional (FAC, SAC, AAMR, SAR, SAP), multi-center, prospective, observational registry that will include patients with diagnosis of PH (including the 5 groups), classified in two cohorts:
- Prevalent cases: Defined by those diagnosed between July 1, 2009, and June 30, 2014.
- Incident cases: Defined by those diagnosed between July 1, 2014, and July 1, 2015 (6 months between the onset of the symptoms and the performance of right catheterization).
- Inclusion criteria.

  • >3 months of age.
  • ≥25 mmHg of mean pulmonary artery pressure evaluated by right catheterization made in a scenario of clinical stability.
  • Clinical stability requires the absence of hospitalization or IV treatment over the last month.
  • In patients younger than 16 years, the performance of right catheterization (RHC) will be subject to the decision of the pediatrician attending the patient with the following criteria.
  • Diagnostic catheterization will not be made in congenital heart diseases with right-to-left shunt.
  • Diagnostic catheterization will be made in:
  • PH without shunt.
  • PH in corrected congenital heart diseases.
  • PH in congenital heart diseases with left-to-right or bidirectional shunt.

- Exclusion criteria

  • The presence of a pathology different from PH that would limit life expectancy <1 year.

A Coordinating Scientific Committee (CSC) of the Registry will be created with representatives of every participating Scientific institution, namely:
FAC: Drs. Diego Echazarreta, Eduardo Perna, María Lorena Coronel
SAC: Drs. Mirta Diez, Adrián Lescano, Nicolás Atamañuk
AAMR: Drs. Juan Antonio Mazzei, Jorge Cáneva, Juan Osses
SAR: Drs. Alejandro Nitsche, Alejandra Babini, Gustavo Casado
SAP/SAC: Drs. Dora Haag, Mariana Cazalas, Carolina Stepffer.

Computer support will be applied, provided by the Centro de Teleinformática Médica of the Federación Argentina de Cardiología (CETIFAC), dependent on the Facultad de Ingeniería/Bioingeniería/CONICET, of the Universidad Nacional de Entre Ríos (UNER), that will have a website with username and password for every investigator that would make up the registry. They will only have access to the data entered by the investigator involved, and the coordinator(s) that will be appointed for it.

It is purposefully clarified that the registry will not receive an exclusive sponsorship by any company, industry or particular party, remaining under the responsibility of the CSC and CETIFAC to safeguard the privacy of the entered data.

- Statistical analysis
The categorical variables will be expressed as percentages and will be compared with the Pearson’s chi-squared test. The continuous variables will be presented as mean and standard deviation, and will be compared to the student’s t-test or Mann-Whitney U test. The variables of the factors associated to mortality and the hospitalizations will be evaluated in an univariate and multivariate analysis by the Cox proportional model. Kaplan-Meier survival curves will be constituted. A value of p <0.05 in all the analyses will be considered statistically significant. All the statistical analyses will be made with the SPSS program 18.0 (SPSS Inc., Chicago, Ill).

- Data control group
Its role is to guarantee the quality of the data entered in the registry. They will monitor the data from the different participating centers and will analyze whether they meet the inclusion/exclusion criteria and the submission of data in a timely manner. They will also make audit visits to the participating centers with the aim of training and controlling the data upload or entering. They will be in direct contact with the single data center to evaluate the data entered by the different centers. Finally, they will provide their expert opinion on the design of the registry in terms of new topics to explore. Within the structure of the data control group, there will be a representative for every Scientific Society participating in the registry. The representative will be responsible of performing the functions indicated previously.

  • Dr. María Lorena Coronel (FAC); Dr. Nicolás Atamañuk (SAC); Dr. Jorge Cáneva (AAMR); Dr. Alejandro Nitsche (SAR); Dr. Mariana Cazalas (SAP/SAC).

- Publication policy
The physicians participating in RECOPILAR that wish to carry out an investigation project using the variables included in the registry, will send the protocol to the CSC. Every project will be analyzed considering the scientific aspect of it. The statistical advisor will be consulted on the feasibility of the project. The CSC will request from the Data Center to release to the main investigator of the project, the data required to perform the project.

Once the project is finished, the main investigator will send it to the CSC for review/approval. To be the main investigator and be able to pose a work hypothesis, his/her center should cover a minimum of included patients. The investigator should add the participating physicians that included most patients to the project of investigation. The investigator that made the investigation project will be considered the author, and the rest of the authors will be assigned according to the number of patients added and their interest in the project.

- Single data center (Centro de Teleinformática Médica de FAC: CETIFAC)
It is the area that will handle the database, will perform the maintenance of the registry, and will control the data upload from the different centers. It will not provide information to the personal requests of the participating physicians unless within the framework of an investigation project with the support of the publication group and the CSC. The single data center will report on the advancement to the CSC.

- Data monitoring
It will be responsible to control the quality of the data entered, making a follow-up of each center participating in the registry and of the participating investigators.

- Policy of rights and publication
RECOPILAR is a multi-center project. The physicians participating in the registry are owners of the data of their own site or center. The consolidated data, indicated as anonymous, are property of the CSC constituted by the representatives from the 5 Scientific Societies that constitute it.

- Data capture and security
An advanced system of electronic data capture through the Internet will be employed. Access to the database will be restricted to the authorized users, who will identify themselves with a single identification key (code) of user ID and password. An https.// connection will be used for a safe transfer of the data. The data will be encoded during the transfer on the Internet, and will be stored in a database protected against unauthorized access.

- Confidentiality of the data of the patient
The privacy of the patients in the registry will be guaranteed since the names or initials of the patients will not be stored in the database. The patients will be identified by a single patient key. (When introducing the identification data of the patient, the system sends them to a closed box and generates the single key of the patient). Every center will only have access to the data of those patients under their direct care.

- Quality control of the data
The use of the advanced electronic data capture system will allow checking the quality of the data when introducing them and will verify missing data and incomplete information. All the management of the data and the analysis will occur in a validated computerized environment. The data of the registry will not be verified or confronted with the source documents.

- Independent Committee on Ethics (ICE)
The RECOPILAR Registry has been approved on August 6, 2014, by the Committee on Bioethics of the Hospital Especializado Materno Infantil “Victorio Tetamanti” and the Hospital Interzonal General de Agudos “Dr. Oscar Alende” of Mar del Plata, Province of Buenos Aires.
Depending on the local regulations and policies of the Institution of the participating physician, he/she may have to submit the protocol recording, a letter of authorization by the patient and another with relevant information to the ICE. In such a case, the approval by the ICE should be obtained before introducing the data into the database. The information/approval of the ICE should be documented in a letter addressed to the participating physician, clearly identifying the name of the registry, the reviewed documents, and the date of approval.

- Authorization of the patient
A proper authorization (consent) will be obtained from each patient if the institutional policies or the national or state privacy regulations related to medical information so require it. This should be done before introducing the data into RECOPILAR. To do this, two different types of documents were prepared: adults older than 16 years, and pediatric patients or younger than that age.

- Withdrawal of the patient
The participation of the patient is voluntary. At any time, the patient may withdraw their consent to participate, and this should not affect his/her medical care or treatment.

- Withdrawal of an investigator or Center
The regulation considers the voluntary withdrawal or not of an investigator or of a center. The patients included by them into the registry will remain in it.

 

REFERENCES

  1. Perna ER, Diez F; Perrone SV, et al. Diseño del Registro HINPULSAR: HIpertensióN PULmonar y aSociaciones en la ARgentina. Insuf Card 2010; 5 (3): 126-31.
  2. Coronel ML, Perna E, Echazarreta D, et al. Treatment of pulmonary arterial hypertension according with functional class in the Argentinean HINPULSAR Registry. Eur J Heart Fail 2012; 11 (S1): S55.
  3. Perna ER, Coronel ML, Echazarreta D, et al. Pulmonary hypertension and associations in Argentina: results of Hinpulsar Registry. 2013,. 5th World Symposium on Pulmonary Hypertension 2013: Page 41. Nice, France.
  4. Echazarreta D, Coronel ML, Bonafede R. Different profile and management but some overlapping in the treatment of patients with arterial and venous pulmonary hypertension. Insights from Hinpulsar Registry. 5th World Symposium on Pulmonary Hypertension 2013, Page 60. Nice, France.
  5. Talavera ML, Caneva JO, Favaloro LE, et al. Hipertensión arterial pulmonar: Registro de un centro de referencia en la Argentina. Rev Am Med Resp 2014; 14 (2): 144-52.
  6. Dweik RA, Rounds S, Erzurum SC, et al. An official American Thoracic Society Statement: pulmonary hypertension phenotypes. Am J Respir Crit Care Med 2014; 189 (3): 345-55.
  7. Guazzi M, Vitelli A, Labate V, et al. Treatment for pulmonary hypertension of left heart disease. Curr Treat Options Cardiovasc Med 2012; 14 (4): 319-27.
  8. Grunig E. Treatment of pulmonary arterial hypertension in connective tissue disease. Drugs 2012. 72 (8): 1039-56.
  9. Guidelines for the diagnosis and treatment of pulmonary hypertension. Rev Port Cardiol 2012; 31 (1): 71-115
  10. // Eur Heart J 2009; 30: 2493-2537
  11. Beachem J, Litton K. Take a deep breath: understanding pulmonary arterial hypertension. Crit Care Nurs Q 2014; 37 (2): 188-98.
  12. Mair KM, Joahansen AK, Wright AF, et al. Pulmonary arterial hypertension: basis of sex differences in incidence and treatment response. Br J Pharmacol 2014. 171 (3): 567-79.

 

Publication: September 2014



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