The Síncrone study was an observational prospective multicenter registry conducted in 16 Portuguese centers. It was sponsored by the Portuguese Institute of Cardiac Rhythm (IPRC) and its steering committee included members of the IPRC and of the Working Groups on Echocardiography and Heart Failure of the Portuguese Society of Cardiology.

Centers invited to participate in the registry were those with appropriate capacity, facilities and human resources in the three relevant aspects of cardiology: HF (clinical assessment of patients, optimization of pharmacological therapy and referral), echocardiography (identification of patients with LVEF <35% and assessment of dyssynchrony-related parameters), and arrhythmology (assessment of arrhythmic risk and indication for device implantation) (Supplementary Table 1).

In centers that agreed to participate, the study protocol was submitted to the local ethics committee and the administrative board of the appropriate hospital, and patient recruitment began only after it was accepted by both these bodies.

All patients provided written informed consent for participation in the study and for the use of the data collected for research purposes.

The study included patients of both sexes aged 18 years or over with a diagnosis of HF, LVEF <35% and indication for ICD and/or CRT. The data were entered by the investigators at each center in an electronic database housed at the IPRC and accessible via the internet. Five time points for patient assessment were defined: before device implantation, at hospital discharge, and at three, six and 12±1 months after implantation, for a total of one year. Follow-up was conducted according to the practice of each center.

At each assessment, demographic, clinical, laboratory, therapeutic, radiological, echocardiographic, arrhythmic and electrophysiological data were to be provided. The echocardiographic parameters to be assessed were those recommended in the joint guidelines of the American Society of Echocardiography and the European Association of Echocardiography,10 and included criteria of atrioventricular, interventricular and intraventricular dyssynchrony (Supplementary Table 1).

In the initial study design patients were to be recruited for one year from the time of the first inclusion in each center. Difficulties in some centers in recruiting patients led to this period being extended and the steering committee eventually decided that the study would end when a total of 500 patients had been enrolled.

The primary combined endpoint of the Síncrone study was all-cause mortality and rehospitalization up to one year following device implantation.

Secondary endpoints were mortality and hospitalization due to HF. The study also aimed to determine patients’ clinical, electrophysiological and echocardiographic characteristics, to identify predictors of response to CRT, to analyze in-hospital and outpatient complications and their predictors, and to assess clinical practice in Portugal regarding implantation of ICDs and CRT devices.

Continuous variables were expressed as mean ± standard deviation and were compared using the Student's t test or the non-parametric Mann-Whitney test. Normality of distribution was assessed using the Kolmogorov-Smirnov test.

Categorical variables were expressed as number and percentage and were compared using the chi-square test and/or Fisher's exact test.

Logistic regression models were used to estimate odds ratios of predictors of clinical outcomes with 95% confidence intervals. The variables with p<0.01 on univariate analysis used to assess dyssynchrony as a predictor of clinical improvement in multivariate analysis were diabetes, intraventricular dyssynchrony and QRS duration.

A p value <0.05 was considered statistically significant. The statistical analysis was performed using IBM SPSS version 22.0.

Table 1 shows the baseline characteristics of the study population. Mean age was 65±12 years and 77% were male. The most frequent causes of HF were ischemic (47%) and idiopathic dilated cardiomyopathy (28%). Patients were under maximally tolerated optimal pharmacological therapy, with 76% taking angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs), 77% taking beta-blockers and 34% taking aldosterone antagonists.

Around 14% of the population had been hospitalized at least once in the previous year and 22% had a documented episode of ventricular tachycardia/ventricular fibrillation. In these cases the device was implanted for secondary prevention of sudden cardiac death.

Of the patients who underwent the initial assessment, half (n=243) received an ICD and the other half a CRT-D (n=208) or a CRT-P (n=35). Compared to those with CRT devices, those with ICDs were younger and more often male, and had fewer comorbidities such as diabetes or chronic kidney disease, and most (85%) were in New York Heart Association (NYHA) class I or II, while most (91%) with CRT devices were in NYHA class II or III.

Mean left ventricular ejection fraction (LVEF) was 28.7±8.5%, and right ventricular systolic function was preserved in most cases. Patients with CRT devices had greater ventricular volumes and lower LVEF (Table 2).

In patients with CRT devices, the mean QRS interval was 160±21 ms; in 73% QRS was ≥150 ms, 89% had complete LBBB, and 24% (n=58) had atrial fibrillation (Supplementary Table 2 and Supplementary Figures 1 and 2).

Overall one-year mortality, the study's primary outcome, was 3.6% (15 patients), and all-cause rehospitalization was 11% (46 patients) (Table 3). Cardiovascular mortality was 1.9% and the main cause for rehospitalization at one year was HF (4.5%), followed by procedure-related complications (2.6%) and arrhythmias (1.4%). Patients with CRT devices presented higher cardiovascular mortality (3.4% vs. 0.5%, p=0.028) and more were rehospitalized (17% vs. 5.6%, p<0.001) than those with ICDs. There was a trend toward higher overall mortality in patients with ischemic etiology (5.4% vs. 1.9%, p=0.05) (Table 3).

Independent predictors of the primary combined endpoint of all-cause mortality and cardiovascular rehospitalization were at least one hospitalization in the previous year (relative risk [RR] 5.20; 95% confidence interval [CI] 95% CI, 1.99-13.6; p=0.001) and higher body mass index (BMI) (RR 1.14; 95% CI, 1.02-1.26; p=0.02) (Figure 2).

Figure 2.

Predictors of overall mortality or cardiovascular rehospitalization. BMI: body mass index; CI: confidence interval; CKD: chronic kidney disease; CRT: cardiac resynchronization therapy device; LVEF: left ventricular ejection fraction; RR: relative risk.

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Implantation-related in-hospital complications were uncommon (4.1%; n=17), occurring mainly in patients with CRT devices (n=16). The most frequent were coronary sinus dissection (n=8), significant bleeding (n=5) and lead dislodgement (n=3). At one-year follow-up, device-related complications had been recorded in 8.6%, including problems with lead placement or function (n=17), phrenic nerve stimulation, (n=7), and pocket infection (n=4). Predictors of these complications were the use of CRT devices (RR 3.35; 95% CI, 1.26-8.90; p=0.02) and female gender (RR 3.35; 95% CI, 1.42-7.93; p=0.01).

Of patients with defibrillators (ICD or CRT-D), 71 received shocks (18.1%), most of them appropriate (77%).

Patients with CRT devices experienced significant reductions in QRS duration (160±21 ms baseline vs. 141±24 ms at follow-up, p<0.001) as well as improvement in NYHA functional class in 62% (Figure 3). There were no significant differences in the proportions of patients who presented improvement in NYHA class according to QRS duration (QRS ≥150 ms: 69% vs. QRS 130-149 ms: 67%, p=0.85) (Supplementary Table 3).

Figure 3.

Changes in NYHA functional class in patients undergoing cardiac resynchronization therapy. CRT: cardiac resynchronization therapy; NYHA: New York Heart Association.

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In patients with complete baseline echocardiographic assessment (n=82), the only predictor of improvement in NYHA functional class was the presence of intraventricular dyssynchrony (RR 5.23; 95% CI, 1.13-24.3; p=0.035) (Supplementary Figures 1 and 2 and Supplementary Table 3).

The Síncrone study has several limitations, the chief of which is that it was merely observational and did not require alterations to the participating centers’ clinical practice, which may not have been uniform, and this may have affected the final results.

The asymmetrical distribution of subjects included by the different centers, although reflecting the situation in Portugal, in which a few centers dominate, may have biased the results. The recruitment period was extended beyond that originally stipulated and 67 patients were lost to follow-up, which constitutes a limitation. However, there can be no doubt that the results obtained reflect high-quality clinical practice that incorporated current advances in HF treatment.

It should be borne in mind that participation in the registry was voluntary and that participating centers received no remuneration. The centers’ commitment to the study was repeatedly demonstrated and the professionalism of their approach was unrelated to their size.

When analyzed as a whole, the study's findings show the importance of establishing a systematic approach to the treatment of patients with HF and left ventricular dysfunction, as has been reported in other multicenter studies.

The small number of patients who underwent complete baseline echocardiographic studies, together with the simplicity and subjectivity of the measured outcome, are also limitations of the study.