Discussion
In this prospective cohort of patients with heart failure and classic indication for CRT, with a high number of individuals with Chagas cardiomyopathy, upgraded therapy was independently associated with worsened 1-year survival after CRT implantation. Besides that, CC was also associated with worse prognosis in follow-up.
Patients submitted to the upgraded CRT implantation had similar clinical, echocardiographic and demographic characteristics when compared to the population of De novo CRT, only differing with a higher prevalence of Chagas cardiomyopathy. We observed a high prevalence of patients with advanced HF, with a mean LVEF below 25% and most patients classified as NYHA III-IV. There was no loss of follow-up and use of evidence-based medical therapies was higher than most previous CRT-trials. 7-8 Furthermore, the indication for CRT was consistent with guideline-based recommendations, with almost all patients presenting with LBBB (induced or spontaneous) and QRS> 150ms. Unlike previous studies comparing De novo CRT vs upgraded, we found no difference regarding the prevalence of atrial fibrillation or QRS duration between both groups. 5,9
In general, CRT was effective in improving systolic performance with a significant increase in LVEF. This left ventricular reverse remodeling occurred consistently in both groups, and it is in accordance with a recently published meta-analysis that demonstrated similar rates of improvement in LVEF in patients undergoing upgraded and de novo -CRT. 10
We observed a high overall mortality in 1-year follow-up of 30.1%, mainly in the upgraded-CRT group. In univariate analysis, Chagas disease and upgraded-CRT were directly associated with overall mortality in 1-year. The principal find of our study was that in the multivariate model, upgraded therapy was the only variable associated with the primary outcome. This result, and the excessive mortality-rate in the upgraded group, is consistent with the study of Vamos M et al, that followed 552 CRT implantations, including 177 upgrade procedures, and found a 1.65-fold increased mortality.5 Similarly, the cohort of Beca B et al, found a long-term mortality rate 2.86-fold increased.11 On the other hand, this data differs from previously mentioned meta-analysis, and the European CRT survey, that demonstrated that CRT upgrade is associated with similar risk for all-cause mortality compared to De novo resynchronization therapy.9
Some factors may justify these findings, firstly, it has been suggested that CRT upgrade procedures are associated with increased peri-procedural complications. In fact, all in-hospital deaths of our study occurred in the upgraded-CRT group and was directly related to the procedure. However, our sample size was not sufficient to test this hypothesis. Data comparing the rates of complications following CRT upgrade versus de novo CRT are limited and inconsistent. In a large European CRT Survey of 11088 patients, and 2396 (23.2%) upgrade procedures, overall peri-procedural complication rates were similar between upgraded-CRT and De novo CRT.12 In contrast, Cheung JW et al, using the United States National database, identified a significantly higher rate of complications in CRT upgrade patients compared to de novo CRT patients with a two-fold increased risk of in-hospital mortality.6
Another hypothesis is that patients in the upgrade group had more advanced heart disease and more comorbidities. In our series, upgraded patients had a trend to be older, with slightly lower left ventricular ejection fraction and higher prevalence of NYHA III and IV, despite the lack of statistical significance when they were compered to De novo CRT group. Perhaps, the indication for biventricular pacing was too late in this group and was associated to a worse prognosis.
Finally, the presence of Chagas cardiomyopathy may interfere in patient survival. CC has more severe heart dysfunction and worse clinical management, mainly due to its etiopathogenesis and worse ventricular remodelling, with a higher incidence of death from advanced heart failure and arrhythmic causes.13-14 Particularly in patients undergoing CRT, it has been consistently demonstrated that Chagas cardiomyopathy has a worse prognosis when compared to other dilated cardiomyopathies. Martinelli et al showed that Chagas disease had a two-fold higher risk of death in one-year compared to the others dilated cardiomyopathy.15 Simirlaly, Passos, et al also demonstrated a worse prognosis in combined events in patients with Chagas cardiomyopathy after CRT.16
It is important to emphasize that, since intrinsic LBBB in Chagas heart disease is uncommon, and it is considered an arrhythmogenic cardiomyopathy characterized by a wide variety of abnormalities of the conduction, it is expected a higher incidence of upgraded-CRT implantation in this patients. In fact, in the cohort presented by Martinelli et al, there was a 73.9% incidence of induced-LBBB in Chagas’ disease patients undergoing CRT.15 In our study, 72.7% of patients undergoing upgraded-CRT implantation had Chagas cardiomyopathy.
This is the first study that analysis the impact of the upgraded-CRT on mortality in a population where Chagas disease is a prevalent cause of cardiomyopathy. In fact, it is known by previous publications that CC was directly associated with an increase in short-term mortality after CRT implantation. However, after multivariate analysis adjusted for potential confounders in our analysis, it is suggested that this worse prognosis may be due to the higher incidence of upgraded-CRT. Studies with larger cohorts of patients with Chagas cardiomyopathy are necessary to confirm this hypothesis. Until then, considering the current scientific evidence, patients with HF secondary to Chagas disease and previous ventricular pacing, must have the indication for the upgrade procedure evaluated with great caution.
This study has some limitations. We emphasize the unicentric design of the study, which may impact in its external validity. Additionally, it is a non-randomized study that generates hypothesis and is exposed to confounding bias. Finally, the limited sample size makes the study vulnerable to type 1 error.