We performed a secondary analysis of the BETTER-HF trial (ClinicalTrials.gov identifier NCT02413151),9 a prospective, interventional, single-center randomized clinical trial of the effect of cardiac rehabilitation on clinical and echocardiographic response in patients with HF with reduced ejection fraction (HFrEF) treated by CRT. One hundred and twenty-one adult HFrEF patients referred for CRT were prospectively enrolled between April 2011 and February 2015. Patients underwent baseline assessment before CRT, including clinical parameters, laboratory tests, transthoracic echocardiogram and cardiopulmonary exercise test (CPET), and were reassessed at six months after CRT.

All patients provided written informed consent before any procedure. The study was approved by the institutional review board and ethics committee.

The BETTER-HF trial9 included consecutive patients referred for CRT with or without indication for defibrillator implantation.

The inclusion criteria were stable HF patients receiving optimal HF pharmacologic therapy for at least three months, age ≥18 years, LVEF <35%, QRS duration ≥120 ms, referral for CRT at Santa Marta Hospital according to European Society of Cardiology (ESC) recommendations,10–12 and stable condition for >1 month (no hospitalization for congestive HF, no change in medication, and no change in New York Heart Association [NYHA] functional class).

Exclusion criteria were residence far from the hospital making frequent hospital visits difficult or impossible; incapacitating orthopedic, neurologic or other conditions precluding exercise testing; refusal to participate in the study; inability to sign informed consent; previous treatment with an intravenous inotropic agent within the 30 days prior to implantation; or death or CRT device removal during the first six months.

Baseline and follow-up data up to November 2015 were obtained from hospital files, systematic follow-up phone calls, and the national health database, which holds information from national health care providers.

Patient assessment included NYHA functional class at baseline and six months after CRT implantation, the HeartQoL quality-of-life score,13 transthoracic echocardiography (LVEF, left ventricular end-systolic volume [LVESV], left ventricular end-diastolic volume [LVEDV] and stroke volume), CPET (peak oxygen consumption [peak VO2]), and blood samples (serum creatinine and B-type natriuretic peptide [BNP]) for a more objective quantification of the physiologic and clinical benefits of CRT.

Baseline demographic data (age and gender), HF etiology, risk factors (hypertension, hyperlipidemia, diabetes, smoking and obesity), medication and electrocardiogram were also recorded.

The primary endpoint was a composite of all-cause death, heart transplantation and hospitalization for HF (unplanned hospitalization for more than 24 hours caused by HF decompensation) during follow-up.

Taking into account the seventeen different primary response criteria identified by Fornwalt et al.6 in a review of the 26 publications with most citations addressing response to CRT, and adapting them to our routine assessment of CRT patients, we included in the analysis eleven different response criteria: four clinical, six echocardiographic, and one combined criterion, as listed in Table 1.

Data analysis was performed using IBM SPSS® version 20. Continuous data were expressed as mean ± standard deviation and compared using the non-parametric Wilcoxon rank test. Categorical data were displayed as frequencies and percentages, and compared using the chi-square test or Fisher's exact test as appropriate.

Response criteria that were potential predictors of survival free from major adverse cardiac events (MACE) were assessed by univariate Cox regression analysis. The results are expressed as hazard ratios (HR) with 95% confidence intervals (CI). The best predictive criteria (clinical and echocardiographic) were subsequently combined (a patient who had fulfilled both response criteria was classified as a responder) to determine whether the predictive value improved with each isolated criterion. The two-sided level of significance was set at p<0.05.

Agreement between the different response criteria was assessed using Cohen's kappa (κ), ranging from -1 (perfect disagreement) to +1 (perfect agreement), with 0 indicating that agreement is exactly that expected by chance.32 κ values ≥0.75 were considered as strong agreement, 0.4-0.75 as moderate agreement, and ≤0.4 as poor agreement.33

Of the 121 consecutive patients included in the BETTER-HF trial,9 six were excluded from this analysis (in two, the system was removed in the first six months due to infection, two died before the six-month reassessment, and two did not undergo the six-month exams).

A total of 115 patients with advanced HF were included (73.9% in NYHA class III-IV), mean age 68 years, 68% male. Ischemic HF was present in 37% of the patients and atrial fibrillation in 24%. Mean baseline QRS duration was 146 ms and mean LVEF was 27%. A CRT defibrillator (CRT-D) was implanted in 95 patients (82.6%) and a CRT pacemaker (CRT-P) in the remaining.

During a mean follow-up of 25±13 months, at least one MACE occurred in 29 patients (25%). Fifteen patients (13%) died (two from sudden cardiac death [SCD], 10 from congestive HF, and three from systemic infection), 25 were hospitalized for HF (21.7%), and one (0.8%) underwent heart transplantation. The incidence of SCD (two patients with CRT-D) was 1% per year. There were no significant differences between patients with and without MACE in most of the baseline characteristics analyzed, except for serum creatinine and BNP levels, both of which were higher in patients with MACE (serum creatinine 1.28±0.52 mg/dl vs. 1.04±0.39 mg/dl, p=0.007; BNP 734±683 pg/ml vs. 392±390 pg/ml, p=0.005).

The characteristics of the overall population at baseline and according to occurrence of MACE are presented in Table 2.

Patients without MACE during the follow-up period were more frequently responders by all the response criteria, achieving significantly higher response rates on the NYHA, LVEF and LVESV criteria (Table 3).

Of all the response criteria analyzed, only five were predictors of MACE. The strongest predictor was the combined clinical criterion including reduction of at least one NYHA class or >10% improvement in peak VO2 and being alive, with no hospitalization for HF in the first six months after CRT implantation (HR 0.21; 95% CI 0.10-0.46, p<0.001). The most strongly predictive isolated clinical response criterion was reduction of at least one NYHA class, which was associated with 61% lower risk for future MACE (HR 0.39; 95% CI 0.18-0.83, p=0.014). The best echocardiographic response criterion was a relative increase in LVEF of at least 15%, which was associated with 57% lower risk for future MACE (HR 0.43, 95% CI 0.20-0.90, p=0.024) (Table 4 and Figure 1).

Figure 1.

Survival curves of cumulative occurrence of major adverse cardiac events in responders or non-responders to cardiac resynchronization therapy according to the most strongly predictive response criteria. (A) Criterion of ↓NYHA ≥1; (B) criterion of ↓NYHA ≥1 or ↑peak VO2>10% and alive, no hospitalization for heart failure; (C) criterion of ↑LVEF ≥5% (absolute); (D) criterion of ↑LVEF ≥15%; (E) criterion of ↑LVEF ≥5% (absolute) and ↓NYHA ≥1 or ↑HeartQoL ≥0.5. ↑: higher: ↓: lower; CI: confidence interval; CRT: cardiac resynchronization therapy; HF: heart failure; HR: hazard ratio; LVEF: left ventricular ejection fraction; NYHA: New York Heart Association functional class; QoL: HeartQoL quality-of-life score.

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The combination of the best clinical and echocardiographic criteria (reduction of at least one NYHA class or >10% improvement in peak VO2 and being alive, with no hospitalization for HF in the first six months after CRT implantation, and increase in LVEF of at least 15%) was more strongly predictive than the echocardiographic criterion but not more so than the clinical criterion alone (HR 0.256, 95% CI 0.118-0.554, p=0.001). The combination of reduction of at least one NYHA class and increase in LVEF of at least 15% was more predictive of no MACE than either of the two criteria alone (HR 0.292, 95% CI 0.132-0.646, p=0.002).

Agreement between the different response criteria as a group (κ=0.24±0.25), and also between echocardiographic response criteria and clinical criteria (κ=0.19±0.21 and 0.25±0.36, respectively) was poor. Of the total of 55 pairs analyzed, the majority (78.2%) had poor agreement, and only three (5.5%) had κ values in the range of strong agreement. Excluding response criteria whose definition included multiple variables, and assessing the isolated clinical criteria, there was a moderate agreement between improvement in NYHA functional class and quality of life (κ=0.56), but poor agreement between these and increase in peak VO2 (κ=-0.16 and κ=-0.10, respectively). Between the six echocardiographic criteria, only three pairs achieved moderate agreement, higher LVEF/lower LVESV (κ=0.60) and lower LVEDV/higher LVESV (κ=0.51) (Figure 2).

Figure 2.

Agreement between response criteria was strong in only 7.6% of response criteria pairs. Cohen's κ values are color-coded according to the following ranges: dark gray=strong agreement (κ ≥0.75), light gray=moderate agreement (κ 0.4-0.75), none=poor agreement (κ ≤0.4). ↑: higher: ↓: lower; Comb: combined; HF: heart failure; LVEDV: left ventricular end-diastolic volume; LVEF: left ventricular ejection fraction; LVESV: left ventricular end-systolic volume; NYHA: New York Heart Association functional class; peak VO2: oxygen consumption at peak exercise; QoL: HeartQoL quality-of-life score.

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