Cardiovascular mortality and cardiovascular event rates in patients with inflammatory rheumatic diseases in the CARdiovascular in rheuMAtology (CARMA) prospective study—results at 5 years of follow-up

Abstract

Introduction

Patients with chronic inflammatory rheumatic diseases (CIRD) such as RA, AS and PsA are at increased risk of developing fatal and non-fatal cardiovascular (CV) events (CVE) [1–3].

A multifactorial effect of chronic inflammation along with traditional CV risk factors (CVRFs) and a genetic component lead to endothelial dysfunction, subclinical atherosclerosis and subsequently to CVE in patients with RA [4–7].

In SpA, there is an increased CV mortality only partially explained by the presence of classic CVRFs, representing also an accelerated atherogenesis process [2, 8]. In patients with PsA, a greater increase in cardiovascular disease (CVD) was also observed, which seems to be associated with chronic inflammation and, at least partially, with a metabolic syndrome commonly linked to the disease itself, which includes hypertension, hypertriglyceridaemia, hyperglycaemia, insulin resistance and abdominal obesity [8, 9]. In this regard, an additive effect of CVRF on the development of atherosclerotic disease has been observed in CIRD [10].

Since most studies addressing CVD in patients with CIRD had been retrospective, in 2009 we set up a prospective 10-year follow-up cohort study, the CARdiovascular in rheuMAtology (CARMA) project, to identify the CVD risk profile in patients with CIRD after 10 years of follow-up. In the present study we aimed to determine the CV mortality and the incidence of the first CVE in the CARMA cohort after 5 years of follow-up.

Methods

Study design

As previously described, the CARMA project is a 10-year prospective follow-up study of two cohorts of patients. The first one includes patients with RA, AS and PsA followed up at outpatient rheumatology clinics from 67 Spanish public hospitals; the second includes a series of subjects with non-inflammatory diseases (control subjects) followed at the same clinics, and during the same period of time. The present study analyses the results of the 5-year visit corresponding to half of the study period.

Study population

The CARMA project started in July 2010 including 2910 subjects over 18 years of age, of whom 774 fulfilled the 1987 ACR classification criteria for RA [11], 738 were classified as having AS according to the modified New York criteria [12] and 721 as PsA based on the criteria proposed by Moll and Wright [13]. Patient recruitment was carried out between July 2010 and January 2012. The group of controls without inflammatory diseases included 677 individuals. Their selection was made at the same rheumatology clinics where patients with RA, AS and PsA were collected, and during the same period of recruitment. Full information on the selection of subjects has been previously described [14]. The study was performed following the principles outlined in the Helsinki Declaration, and a written informed consent was obtained from all subjects before their inclusion into the project. The study protocol was approved by the Ethics Committee for Clinical Research of Lugo, Galicia, Spain (protocol number: 2009/077).

Follow-up

The follow-up was considered successful if the patient fulfilled the 5-year follow-up visit, had suffered his/her first CVE within the 5 years follow-up period or had died as a consequence of a CVE. In the case of patients who were lost to follow-up, vital status after 5 years of inclusion was recovered from the mortality register of the Spanish National Statistics Institute.

Variables and operative definitions

To determine CV mortality, fatal CVE were assessed. CVE were considered as the following events: ischaemic heart disease (IHD), cerebrovascular accident, peripheral arterial disease and heart failure (HF). Secondary variables included were (i) sociodemographic variables (age and sex); (ii) traditional (classic) CVRFs (hypertension, dyslipidaemia, obesity, smoking and diabetes); (iii) parameters of inflammation and disease activity; (iv) comorbidities and laboratory parameters; and (v) potential confounding factors (disease severity, duration of disease and therapies administered). Operative definitions of all of the variables analysed can be found in the supplementary material of the article published by Castañeda et al. [14].

Statistical analysis

Descriptive analyses were performed for the demographic and clinical variables. Numerical variables were assessed using the Student’s t-test or the Mann–Whitney U test. Qualitative variables were assessed by χ², Yates correction or Fisher exact tests in 2 × 2 tables. A descriptive analysis of losses to follow-up was carried out. To determine the estimated risk of the CV mortality for each group at 5 years of follow-up, we used the Systematic COronary Risk Evaluation (SCORE) function for predicting 10-year CV mortality recommended by The Third Joint European Task Force on cardiovascular prevention [15]. Poisson models were used to estimate the incidence rates of the first CVE (IHD, cerebrovascular accident, peripheral arterial disease, HF and mortality from any of these causes) per 1000 person-years along with 95% CI for each group of conditions. Weibull proportional hazard model was used to calculate hazard ratio (HR) and 95% CI of the risk factors, in which first CVE from the entry in the study up to 5 years of follow-up was the dependent variable. The selection of independent variables in the multivariate model was based on clinical and statistical criteria, including those with P <0.20 in the bivariate analysis. All analyses were done using the SPSS 22.0 program (IBM SPSS Statistics for Windows, IBM Corp., Armonk, NY, USA). Statistical significance was assumed at P <0.05.

Results

Overall, a total of 2910 patients were recruited. The main basal demographic and clinical characteristics of the patients included in this study have been previously reported [14]. From them, 2382 patients (81.9% of the total) (669 RA, 610 AS, 597 PsA and 506 controls) completed the 5 year-follow-up visits. After excluding those with CVE prior to inclusion in the study, the remaining total number of patients was 2171.

The main characteristics of the patients are showed in Table 1. The control group included the higher number of individuals who were lost during the follow-up (25%). Losses to follow-up in patients with CIRD were 17.5% in PsA, 17.3% in AS and 13.5% among those with RA. The main sociodemographic features and clinical characteristics of the patients lost compared with those that were not lost to follow-up are shown in supplementary Table S1, available at Rheumatology online.

Global and cardiovascular mortality

From the 2910 patients recruited at the beginning of the study, 15 subjects died due to CVE and 60 due to other complications unrelated to CV morbidity at 5 years of follow-up. Overall, the mortality of the whole cohort included in the study at 5 years was 2.5% (75 cases).

Of the 15 patients who died from CVE, 11 belonged to the CIRD group and 5 of them had not presented any CVE before study entry. CV deaths observed in the CIRD cohort were lower than that predicted by SCORE risk charts at 5 years (Fig. 1). Thirty patients died due to cancer and 16 due to infections. The remaining patients died from other causes.

Fig. 1

Cardiovascular mortality stratified by groups at 5 years of follow-up

Excluded are those patients with cardiovascular disease prior to the inclusion in the study (baseline). *Estimated cardiovascular deaths according to the SCORE function for predicting 10-year cardiovascular mortality SCORE recommended by the Third Joint European Task Force on Cardiovascular Prevention [15]. SCORE: Systematic COronary Risk Evaluation.

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Incidence rates of the first CVE at 5 years

In our study, 86 patients had experienced a first CVE at 5 years follow-up. Thirty-five of them were due to IHD, 30 cerebrovascular accident, 13 peripheral arterial disease and 8 HF episodes. Data stratified by group are shown in Table 2.

At 5 years from the inclusion, the group with the highest incidence rate of a first CVE [7.39 cases per 1000 person-years (95% CI 4.63, 11.18)] was PsA, followed by patients with RA [6.39 cases per 1000 person-years (95% CI 3.90, 9.86)] and finally those with AS [6.0 cases per 1000 patients (95% CI 3.56, 9.49)]. The CVE incidence rate in patients without CIRD was 5.08 cases per 1000 person-years (95% CI 2.68, 8.61).

Factors associated with developing the first CVE at 5 years of follow-up

Table 3 shows the main characteristics of the patients who developed a first CVE during the 5 years of follow-up, after excluding those with CVE prior to inclusion in the study. Regarding the multivariable model, the highest risk of developing a first CVE was found in those patients with AS (HR 4.60; 95% CI 1.32, 15.99; P =0.02), older age (HR 1.09; 95% CI 1.05, 1.13; P <0.001), hypertension (HR 2.64; 95% CI 1.32, 5.25; P =0.01) and longer duration of the disease (HR 1.07; 95% CI 1.03, 1.12; P <0.01). In contrast, female gender was a protective factor for developing CVEs (HR 0.45; 95% CI 0.21, 0.99; P =0.047) (Table 4).

Discussion

Cardiovascular mortality in our cohort was low. In this sense, it was lower than initially expected. Furthermore, patients with AS were found to be at increased risk of developing a CVE after 5 years of follow-up when compared with controls without CIRD, after adjusting for classic CVRFs and specific features of the inflammatory disease.

We were very surprised by the low number of fatal CVEs in our cohort. A possible explanation could be the protective effect of biologic therapy, by favourably influencing insulin sensitivity, lipid profile and metabolic changes mediated by inflammatory cytokines, all of which are involved in the development of accelerated atherogenesis in this population [16]. In line with this, >40% of the CIRD patients from our study were under biologic treatment at the recruitment time [14]. In keeping with that, in the meta-analysis by De La Forest Divonne et al. [17], which included 43 biological registers and 27 publications on the safety of anti-TNF in RA, mortality [relative risk (RR) 0.60; 95% CI 0.38, 0.94] and CVD (RR 0.62; 95% CI 0.44, 0.88) decreased significantly. It is worth noting that in our study the SCORE function overestimated the 5-year CV mortality in both patients and controls. We consider that this could be due to a good control of lifestyles and CVRFs in both cohorts of patients followed up regularly at rheumatology out-patient clinics, both with CIRD and without CIRD. In addition, there were no significant geographic differences that could explain the difference in fatal CV risk using the same SCORE function throughout Spain (algorithm for low-risk countries according to international recommendations of the European Society of Cardiology).

Regarding the development of the first CVE, the results found in the present study were in line with those obtained in our cohort at 2.5 years of follow-up [18]. These results were explained by a greater proportion of men in the AS group (3:1), a longer duration of the disease and because almost 50% of these patients were under biologic therapy [14], which might indicate, indirectly, a history of higher chronic inflammatory burden. Moreover, patients with AS were more commonly smokers and used more NSAIDs at the beginning of the study than patients with RA or PsA [14].

Our results differ from those published by Schieir et al. [1], where patients with AS showed an increased incidence of myocardial infarction but without reaching statistical significance (RR 1.24; 95% CI 0.93, 1.65). However, the meta-analysed study by Schieir had methodological differences from ours, mainly due to the retrospective design, as well as based on the characteristics of the selected subjects and the follow-up [1, 19].

Regarding RA patients of our study, contrary to what might be expected, we have not found an increased risk of CVE compared with controls. In the meta-analysis by Schieir et al. [1], an increased incidence of myocardial infarction was found (RR 1.52; 95% CI 1.37, 1.69), but the methodological characteristics of that study also differed from ours: of the 14 included studies, 10 were retrospective with a highly variable follow-up period from 4 to 46 years. In the Danish population-based study by Khalid et al. [20], RA constituted a risk factor for developing HF (HR 1.30; 95% CI 1.17, 1.45). In this study, the baseline level of inflammatory activity of the patients was unknown, as was the percentage of subjects taking biologic drugs, issues that prevented us from performing comparisons with our cohort.

Since the EULAR recommendations for CVD risk management in patients with RA have been actively discussed over recent years in our Rheumatology Society [21, 22], it is possible that the impact of these recommendations, along with further recommendations proposed by members of our Rheumatology Society [21, 23–25], including an active search of patients with RA at high risk of CVD using non-invasive tools [26–28], might have accounted for a positive influence on the favourable results found in our prospective cohort. In this regard, the percentage of current smokers among CARMA cohort RA patients decreased from 24.32% at the time of recruitment to 19.38% at 5 years of follow-up (data not published).

In our study, we also did not find a higher risk of CVE in PsA patients when compared with controls. These results are in agreement with those by Egeberg et al. [29]. In contrast, in the meta-analysis by Schieir et al. [1], patients with PsA showed a higher risk of developing myocardial infarction (RR 1.36; 95% CI 1.12, 1.66), although these results should be interpreted with caution since they came from a single retrospective study.

Apart from the classic CVRFs for the development of CVE, other variables such as the duration of the disease seem to influence the development of accelerated atherogenesis in CIRD patients [2, 30, 31]. In this regard, the magnitude and chronicity of the inflammatory burden correlated directly with the presence of subclinical atherosclerosis in patients with RA [32]. In keeping with that, in our study, a longer duration of the disease was independently associated with an increased risk of developing CVE at 5 years.

An aspect worth highlighting, regarding the incidence of the first CVD in the follow-up of the CARMA project patients, was that no differences were found between the different types of CIRD. Similarly, Lauper et al. [33] also found no differences between RA, AS and PsA, suggesting that it is inflammation itself that increases the risk of developing CVE and not the type of pathology.

The main limitation of our study was the number of losses in the control group without CIRD. However, our study has several strengths. First, the prospective design of a large cohort of subjects with CIRD undergoing scheduled follow-up visits (every 2.5 years) to standardize the data collection and minimize losses. In addition. Also, the results were adjusted for classic CVRFs and specific disease factors associated to the development of CVD, in contrast to other studies where the results were shown raw or only adjusted for sociodemographic variables such as age and sex.

Finally, our study has a low risk of underestimating the incidence of CV mortality, since the number of losses and causes of death during follow-up was collected from the Spanish mortality registry of the National Statistics Institute, minimizing this possible bias.

In conclusion, CV mortality in patients with CIRD from the CARMA prospective cohort was lower than expected. Patients with AS followed up at rheumatology outpatient clinics showed a higher risk of developing a first CVE after 5 years compared with individuals without CIRD. Close monitoring of CVRFs and tight control of the disease appears to be crucial to reduce of CV complications in patients with CIRD.

The members of the CARdiovascular in rheuMAtology (CARMA) Project Collaborative Group are listed in the Acknowledgements.

Acknowledgements

CARMA Project Collaborative Group: the members of the CARdiovascular in rheuMAtology Project Collaborative Group include Eugenia González de Rabago, Elena Alonso Blanco Morales, J. Carlos Fernández Lopez, Natividad Oreiro Villar, Antonio Atanes Sandoval, Francisco J. Blanco García (Complejo Hospitalario A Coruña, Xubias de Arriba, A Coruña); Cayetano Alegre De Miquel, María J. González Fernández, Ramón Huguet Codina, Beatriz Yoldi, Mercedes Ramentol (Instituto Dexeus, Barcelona); Gabriela Ávila, Sara Marsal Barril (Hospital Universitari Vall d’Hebron, Barcelona); Martina Steiner, Santiago Muñoz (Hospital Infanta Sofía, Madrid); Fernando Gamero, José García Torón (Hospital S. Pedro de Alcántara, Cáceres); Pilar Espino, Inmaculada Ros, Mónica Ibáñez, Claudia Murillo (Hospital Son Llatzer, Palma de Mallorca); Ramon Sanmartí, Horacio Berman, Sonia Cabrera, Virginia Ruiz, Raúl Castellanos-Moreira, Sebastián C. Rodríguez-García (Hospital Clinic i Provincial, Barcelona); Sergio Ros Expósito (Hospital de Viladecans, Barcelona); Sergio Rodriguez Montero (Hospital Universitario de Valme, Sevilla); Benjamín Fernandez, Oscar Fontseré Patón, Lydia Abasolo (Hospital Clínico Univ. San Carlos, Madrid); Dolores Fábregas Canales (Hospital de Barbastro, Huesca); Joan M. Nolla (Hospital Univ. de Bellvitge, Barcelona); Rosario García de Vicuña, Isidoro González-Álvaro, Esther Patiño, Jesús A. García Vadillo (Hospital Univ. La Princesa, Madrid); Antonio Fernández Nebro, Sara Manrique Arija, Inmaculada Ureña, María V. Irigoyen, Virginia Coret Cagigal (Hospital Regional Universitario Carlos Haya, Málaga); Daniel Pielfort Garrido, Angel M. García Aparicio, Rebeca Belmonte Gómez, Pastora Granados Bautista, Azucena Hernández Sanz (Hospital Virgen de la Salud, Toledo); Eugenio Giménez Úbeda, Jesús Marzo García, Chesús Beltrán Audera, Marta Medrano, Ángela Pecondón (Hospital Univ. Miguel Servet, Zaragoza); Celia Erausquin-Arruabarrena, Soledad Ojeda, Juan Carlos Quevedo, Félix Francisco, Carlos Rodríguez Lozano (Hospital Dr Negrín, Las Palmas de Gran Canaria); Julia Martinez Barrio, Delia Gerona, Carlos González Fernández, Indalecio Monteagudo (Hospital Gregorio Marañón, Madrid); Ana Turrión, María D. Sánchez González, Olga Martinez Gonzalez, Javier del Pino Montes (Hospital Univ. de Salamanca); Alfonso Corrales, Enriqueta Peiró (Hospital Univ. Marqués de Valdecilla, Santander); José C. Rosas, Jose M. Senabre (Hospital de la Marina Baixa, Alicante); Silvia Martinez Pardo (Hospital Mutua Terrassa, Barcelona); Isabel Rotés, Estefanía Moreno, Alba Erra, Dolors Grado (Hospital de San Rafael, Barcelona); Ana Ruibal Escribano (Hospital Santiago Apostol, Vitoria), Amalia Rueda (Hospital General. Universitario, Valencia); Isabel Rodríguez (Instituto Poal, Barcelona); Emilio Giner Serret (Hospital General de Teruel Obispo Polanco, Teruel); Enrique Raya, Pilar Morales, Ana Nieto, Inmaculada Jiménez, Cesar Magro (Hospital Clínico Univ. San Cecilio, Granada); Ginés Sánchez Nievas, Enrique Júdez Navarro, Manuela Sianes Fernández, María A. García Morales, Isabel Labiano Bastero, Gloria García Consuegra (Hospital General de Albacete); Manel Riera Soler (Hospital Dos de Maig, Barcelona); Jordi Fiter (Hospital Universitario Son Dureta; Palma de Mallorca); Manel Pujol, Elena Riera Alonso, Georgina Salvador (Hospital Mutua Terrassa, Terrassa); Beatriz Gonzalez, Alberto Cantabrana (Hospital Ntra Sra de Candelaria, Santa Cruz de Tenerife); Sagrario Bustabad Reyes, Esmeralda Delgado (Hospital Univ. de Canarias, La Laguna, Tenerife); Julia Martinez Alejandro Muñoz, Luis M. Jiménez (Hospital Univ. de Valme, Sevilla); Javier Rivera Redondo, Teresa González Hernández (Instituto Provincial de Rehabilitación, Madrid); José M. Moreno, Carla Lannuzzelli Barroso (Hospital Obispo Polanco, Teruel); Laura Cebrián Méndez (Hospital Infanta Leonor, Madrid); Teresa Navío (Hospital Universitario Infanta Leonor, Madrid); Elisabet Berzosa Sola, Teresa Pedraz Penalva (Hospital General de Elda, Alicante); Encarnación Pagán, Pablo Mesa del Castillo (Hospital Los Arcos, Murcia); Ana Cruz (Hospital Severo Ochoa, Madrid); María Galindo, Julio Sánchez, Javier García González (Hospital Univ. 12 de Octubre, Madrid); Eduardo Collantes, Desireé Ruiz, Pilar Font (Hospital Univ. Reina Sofía, Córdoba); Antonio López Meseguer (Hospital Gutiérrez Ortega, Valdepeñas, Ciudad Real); Manuel J. Moreno, María J. Moreno Martínez, María D. Beteta Fernández, Luis F. Linares (Hospital Virgen de la Arrixaca, Murcia); Mercedes Morcillo, María L. González Gómez (Hospital del Escorial, Madrid); Natalia A. Rivera, Olaia Fernández Berrizbeitia, María L. García Vivar (Hospital de Basurto, Bilbao); Yolanda M. León (Hospital Dos de Maig, Barcelona); Joan Maymó, Miriam Amirall, Silvia Iniesta Escolano, Silvia Sánchez Serrano, María P. Lis Bona (Hospital del Mar, Barcelona); Julia Fernández Melón, Luis Espadaler (Hospital Universitario Son Espases, Palma de Mallorca); Olga Maiz, Joaquín Belzunegui (Hospital de Donostia, Donosti); César Díaz (Hospital de la Santa Creu i Sant Pau, Barcelona); Ramón Valls (Hospital de Palamós, Gerona); Iván Castellví, María Bonet, Estefania Moreno Ruzafa (Hospital Comarcal de L’Alt Penedés, Vilafranca del Penedés, Barcelona); Elena Aurrecoechea (Hospital Sierrallana, Torrelavega); Trinidad Pérez Sandoval (Complejo Asistencial de León); Eva Revuelta Evrard (Hospital General de Ciudad Real); Javier R. Godo, María C. Fernández Espartero (Hospital General de Móstoles, Madrid); Francisco J. Navarro Blasco, José A. González (Hospital General Universitario de Elche, Alicante); José A. Miranda-Filloy (Hospital Xeral Calde, Lugo).

Funding: This project has been supported by an unrestricted grant from Abbvie, Spain. However, the design, analysis, interpretation of results and preparation of the manuscript have been done independently of Abbvie. M.A.G.-G.’s research has been supported by grants from ‘Fondo de Investigación Sanitaria’ (grants PI06/0024, PS09/00748, PI12/00060 and PI15/00525) from ‘Instituto de Salud Carlos III’ (ISCIII, Health Ministry, Spain) and by RETICS Programs RD12/0009 and RD16/0012 (RIER) from ‘Instituto de Salud Carlos III’ (ISCIII, Health Ministry, Spain).

Disclosure statement: All authors declare no conflicts of interest.

Data availability statement

Data are available upon reasonable request by any qualified researchers who engage in rigorous, independent scientific research, and will be provided following review and approval of a research proposal and Statistical Analysis Plan (SAP) and execution of a Data Sharing Agreement (DSA). All data relevant to the study are included in the article.

Supplementary data

Supplementary data are available at Rheumatology online.

References