INTRODUCTION

The prevalence of heart failure (HF) is estimated between 1-3% in the adult population and increases to more than 10% and 30% in those over 70 and 85 years of age, respectively. (1) In recent years, advances in medical treatment have substantially improved the prognosis of these patients. (2,3) However, when optimal medical treatment is insufficient and the patient continues to deteriorate, cardiac resynchronization therapy (CRT) emerges as an effective alternative to improve quality of life, increase left ventricular ejection fraction (LVEF) and reduce mortality in patients who meet the criteria for its indication. (4,5).

The response to CRT depends on multiple factors including adequate patient selection, underlying heart disease, gender, electrode implantation in the appropriate vein of the coronary sinus, A-V and V-V interval programming, and maintenance of a biventricular pacing rate close to 100%, among others. Despite all this, there is a percentage of these patients who do not respond to CRT, which would imply worse long-term clinical outcomes.

OBJECTIVES

The aim of this study was to assess differences in echocardiographic parameters of reverse remodeling and event rates [hospitalization for heart failure (HHF), all-cause mortality (ACM), heart transplantation (HTX) and appropriate therapies (AT, including antitachycardia pacing and appropriate shocks)] between responder vs. non-responder patients to CRT at 2-year follow-up.

METHODS

A retrospective analysis was carried out of prospectively collected data from a single-center cohort of 418 patients with HF in whom CRT devices were implanted between March 2003 and December 2020. Among them, 75 patients were excluded from the analysis due to lack of complete follow-up data. Based on clinical and echocardiographic parameters, patients were classified into responders (those who reduced at least one NYHA functional class, or increased LVEF by 5% in absolute values) and non-responders (those who did not meet these criteria). A 2-year follow-up was performed, in which echocardiographic parameters of reverse remodeling were evaluated: LV diastolic diameter (LVDD), LV systolic diameter (LVSD) and LVEF, and the incidence of significant events: HHF, ACM, HTX and AT.

Statistical analysis

Continuous variables are presented as mean and standard deviation, and were compared with the t test. Categorical variables are expressed as frequencies and percentages, and were compared with the chi-square test or Fisher´s exact test, as appropriate. A 2-tailed p value <0.05 was considered statistically significant.

RESULTS

Among the 343 patients evaluated, 58 (17 %) were non-responders and 285 (83 %) were responders. Baseline population characteristics are shown in Table 1. Mean age at implantation was 64 years, and the percentage of women in the non-responder group was higher. Sixty-eight percent of responders had non-ischemic etiology, while in the non-responder group this occurred in 50%. There were no significant differences between groups in terms of cardiovascular risk factors, nor in the baseline echocardiogram. Most patients were in NYHA functional class I or II. There were differences in the baseline electrocardiogram (ECG): in the non-responder group only 31% had complete left bundle branch block (LBBB), vs. 66% of responders. Baseline QRS duration was shorter in the non-responder group.

At 6 and 12 months there were no significant differences in ventricular diameters, but there were, logically, significant differences in LVEF (p=0.0001), since an increase in LVEF was one of the criteria for defining response to treatment. At 24 months, there were differences in the group of responders, with significantly lower LVDD (p=0.004) and LVSD (p=0.003), and higher LVEF (p<0.001) (Figure 1).

Figure 1

Echocardiographic evolution in responders and non-responders.

LVDD: left ventricular diastolic diameter; LVSD: left ventricular systolic diameter; LVEF: left ventricular ejection fraction.

At the end of the 2-year follow-up, 82% of non-responders had had HHF compared with 13.6% of responders (p<0.001). Six non-responder patients (10.3%) died during follow-up (all were cardiovascular deaths, 5 due to HF and 1to sudden death). Among responders, 12 (4.2%) died, 8 from cardiovascular causes (7 from HF and 1 from electrical storm) and 4 from non-cardiovascular causes. This implies a difference at the limit of statistical significance (p= 0.056). Heart transplantation was performed in 10.3% of non-responders vs. 2.10% of responders (p=0.001). The incidence of appropriate therapies was 17.2% in non-responders vs. 5.6% in responders (p=0.002). (Figure 2).

Figure 2

Incidence of events in responders and non-responders.

HHF: hospitalization for heart failure; ACM: All cause mortality; AT: appropriate therapies; HTX: heart transplantation.

DISCUSSION

Cardiac resynchronization therapy is an effective treatment for HF refractory to medical therapy, in a subgroup of patients who meet criteria for its indication. This was demonstrated in large randomized studies, including the MIRACLE, COMPANION, CARE HF, REVERSE, MADIT CRT and RAFT trials, on which current clinical practice guideline recommendations are based (6,7,8,9,10,11). However, not all patients respond to CRT. According to the study analyzed, this percentage varies between 20% and 40%, which depends, in part, on the definition of response to treatment used. Although there is currently no consensus on the definition of CRT response parameters, the most commonly used are clinical parameters (functional class and quality of life), echocardiographic parameters of reverse remodeling, and rates of clinical events, such as HHF and mortality. According to the author, these are used alone or in combination to define response. For years, attempts have been made to detect the factors related to this lack of response: the first ones identified were QRS width, LBBB and functional class, on which the indication criteria are currently based. In 2009 Mullens et al. studied 75 patients with persistent HF symptoms and lack of LV reverse remodeling 6 months after implantation. Most patients had identifiable reasons for suboptimal response: inadequate device configuration (47%), suboptimal medical therapy (32%), arrhythmias causing low percentage of CRT (32%), inadequate LV catheter position (21%), and lack of baseline dyssynchrony (9%). (12) Gender is also a factor to be taken into account; a meta-analysis showed that women had lower total mortality and higher reverse remodeling compared with men. (13) Another fundamental factor is etiology. In 2005 Gasparini et al. showed that patients with non-ischemic cardiomyopathy had greater increase in LVEF and improvement in functional class. (14) This was confirmed by subsequent studies. (15) There are now indications that some genetic variables might also be related, although much remains to be studied. (16)

In our study, to our knowledge the largest and longest follow-up study in Argentina, we used combined parameters of functional class improvement and reverse remodeling to define response. The percentage of non-responders was 17%, and the long-term evolution of these patients was worse, with a significantly higher rate of HHF, HTX, ACM and AT compared with responders. Although our work had a low rate of non-responders compared with the literature, the adverse clinical outcomes in this population encourages us to continue working in order to identify factors related with suboptimal response to CRT, to perform early interventions and try to improve their long-term prognosis.

CONCLUSION

In our population, responder patients had significantly better echocardiographic parameters of reverse remodeling. This may explain the significantly lower rate of HHF, ACM, HTX, and AT compared with non-responders.