Search approach and appraisal of studies

Studies were found using Pubmed and Advance Google Scholar database web based search. The key terms used were: CRT, SE with dobutamine or exercise. When more than one study came from the same group, only the largest and most recent study was considered for inclusion.

Inclusion criteria

We considered for inclusion if they evaluated the use of LVCR and viability evaluated using pharmacological or exercise stress echocardiography in regard to response after CRT.

The inclusion criteria were:

1) human studies with participants of any age requiring CRT for any indication, according to guidelines criteria [4]: heart failure patients with NYHA class III and IV, depressed ejection fraction (EF < 35%) and QRS duration ≥120 ms;2) CRT and SE were performed on the same population of patients; 3) parameters of LVCR before and after CRT implantation were reported; 4) presence of at least 6 months of follow-up.

Exclusion criteria

Two blinded reviewers evaluated the records. Studies with only either LVCR or CRT data, case reports, case series, letters and editorials were excluded but relevant reviews were retrieved to identify additional studies. Full-text articles that did not meet inclusion criteria were excluded from final analysis.

Data abstraction

According to the Preferred Reporting Items for Systematic reviews and Meta-Analyses statement [7], from a Pubmed and Advance Google Scholar database web based search scan up to December 2016, we initially identified 5906 records, using the key terms CRT (cardiac resynchronization therapy) (5906 citations) AND SE (71 citations) AND dobutamine (19 citations) OR exercise echocardiography (7 citations). Of these records we removed the duplicate (1235 record) and the studies that did not perform SE (4600 records). Full-text articles assessed for eligibility were 71, screened to control whether the publications met the inclusion criteria. These inclusion criteria we identified 11 studies for analysis [8,9,10,11,12,13,14,15,16,17,18] (Fig. 1).

Fig. 1 Study selection process Full size image

The key data elements that were extracted from each study were categorized as study characteristics, patient characteristics, treatment characteristics, and clinical outcome. Specifically, the main characteristics considered for each study were: first author’s name, journal and year of publication, duration of follow-up, number of patients, type of intervention, type of stress and dosage of stressor (Tables 1 and 2).

Table 1 Clinical characteristics of the studies included in the analysis Full size table

Table 2 Rest and stress echocardiographic characteristics of the studies included in the analysis Full size table

For patients, the following variables were collected whenever available: sex; mean age; definition of significant disease; follow-up event; summary. In addition to these variables, estimates of sensitivity and specificity, and the absolute number of true-positive, false-negative, false-positive, and true-negative results were extracted per source study.

We did not contact authors to request additional information.

Various echocardiographic parameters were used to assess the LVCR identified eitheras a reduction in wall motion score index (WMSI, six studies) or an increase in ejection fraction (EF, five studies); in particular: decrease in WMSI >0.20 (three studies), >0.25 two studies) and >0.31 in one study; about EF: 1.5-fold increase (one study), >5 points (one study), >6.5% (one study), >7% (one study) and >20% (one study) (Table 2). Responders to CRT were identified on the basis of clinical (one study) or echocardiographic criteria (10 studies): clinical responders were defined as survivors who had a ≥ 1 grade improvement in NYHA class, and no new hospital admission for acute heart failure. Echocardiographic responders were defined as patients who showed decrease of LV end-systolic volume of at least 15% in 8 studies [9,10,11,12, 14, 16,17,18], decrease of LV end-systolic volume of at least 10% in 1 study [15] and improvement in LVEF of 5 points in 1 study [13].

Data analysis

The pooled weighted estimation of sensitivity, specificity and accuracy are reported in Table 3. Calculations of sensitivity, specificity and accuracy were performed according to standard definitions.

Table 3 Contractile reserve to SE (CR+) and responders to CRT (CRT+) of the studies included in the analysis Full size table

Meta-regression analysis with continuous and categorical parameters was conducted using the metafor package for R [19]. Estimates of the average effect and 95% confidence intervals (CIs) of different parameters on CRT response were calculated with a fixed [20] and random-effect model [21]. The heterogeneity was tested using the Cochran Q statistic (following the chi-squared distribution) and I-squared (I2) statistics Higgins [20], which describes the proportion of total variation explained by between-study variation instead of chance. Higher I2statistic values imply more heterogeneity between studies than would be expected by chance alone. When the test for heterogeneity was statistically significant the random-effect model was applied directly. The odds ratio was chosen as outcome measure. Individual odds ratio (ORs) were estimated as the cross-product of cell counts in the corresponding 2 × 2 table, with variance of natural logarithm (ln) of OR equal to the sum of the reciprocal cell counts.

We expressed continuous data as mean ± SD, and dichotomous variables as percentages. We considered statistically significant a p-value <0.05.

A graphical overview of the results was obtained by creating a forest plot [22] in which the observed effects were drawn proportional to the precision of the estimates (Fig. 2). Funnel plot was used for detecting heterogeneity (Fig. 3). The results are shown using a log scale for easier interpretation.

Fig. 2 Forest plots showing the benefits associated with presence of LVCR. They include the same eleven studies, but in the left panel a fixed-effect analysis was used and in the right panel a random-effect analysis. Individual studies (identified by first author and reference number) are shown on the left, and their corresponding odds ratios (and confidence intervals) on the right. The area of each square is proportional to the weight in the final result. The measure effect is plotted as a diamond, and its lateral margins indicate confidence intervals for this estimate. Rocchi G and Lancellotti P studies used exercise, all the others dobutamine as stressor Full size image