Search results
We initially identified 365 potentially relevant articles. Eighty-five papers were of interest and were retrieved for full-text review. Sixty-six articles were excluded for reasons of reviews (n=26), incorrect comparisons (n=18), no clinical outcomes (n=14) and animal study (n=8). The remaining 14 RCTs and 5 prospective cohort studies were finally included in the analysis (Figure 1).
Study characteristics
A total of 14 published RCTs [26,27,29-31,34-37,39,41-42] and 5 cohort studies [28,32,33,38,40] comprising a total of 1172 patients with SCAD or RA were included. The total number of patients in each study was in the range of 23–150, and the median duration of follow-up was 6.0 months (range 3–72 months). The participants’ ages were in the range of 65.3±5.7 years. Most patients were men (mean, 75.3%) and nearly half of the patients (41.5%) had diabetes mellitus. The baseline left ventricular ejection fraction (LVEF) was 42.1%±7.3%. The mean CCS angina class and NYHA class were 2.2±0.7 and 2.1±0.5, respectively. There were three comparisons in two studies [26,31]. Based on the CSWT treatment scope for each ischemic target region, patients in the one study [32] were divided into the regular CSWT group (9 spots of each ischemic target region, performed 9 times within 3 months), expanding scope CSWT group (25 spots of each ischemic target region, performed 9 times within 3 months), and the control group. Moreover, patients in one study [26] were separated into a regular CSWT group (performed 9 times within 3 months), a short-term CSWT group (performed 9 times within 1 month), and a control group according to the CSWT treatment duration. A short-term CSWT treatment procedure (9 times within 1 month) was also used in another study [33]. All studies were with a NOS score of 6 and more and considered as “high quality” (Table 1).
Primary endpoint
MACE
Four RCTs [26,29-31] and three cohort studies[32,33,40] provided data about MACE. Of the 388 patients in the CSWT group, MACE occurred in 60 patients (15.5%). In the control group, MACE occurred in 84 patients out of a total of 189 (44.4%). Compared with the control group, CSWT significantly lowered the risk of MACE (RR, 0.39; 95% CI, 0.29–0.53; P<0.001; I2=0.0%) (Figure 2), and there was low level of heterogeneity (I2=0.0%). The funnel plot did not show marked asymmetry in Begg’s test (P=0.67) and Egger’s test (P=0.82). Sensitivity analysis was performed by removing each of the trials one at a time, which did not detect any influence on the risk of MACE.
Secondary endpoints
Rehospitalization
Four RCTs [26,29-31] and two cohort studies [32,40] reported the occurrence of rehospitalization. There were 306 patients in the CSWT group, 52 of whom were rehospitalized (17.0%). Of the 167 patients in the control group, 78 were rehospitalized (46.7%). Overall, CSWT treatment was associated with a significantly decreased rate of rehospitalization (RR, 0.37; 95% CI, 0.27–0.51; P<0.001; I2=0.0%) compared with the control group (Figure 3). In addition, there was a low level of heterogeneity (I2=0.0%), and the funnel plot did not show marked asymmetry in Begg’s test (P=0.71) and Egger’s test (P=0.76).
Coronary artery revascularization
The rate of coronary artery revascularization during the follow-up period was presented in two RCTs [26,29] and one cohort study [40]. There were one (0.5%) and three cases (3.9%) of coronary artery revascularization in the CSWT (n=187) and control (n=77) groups, respectively. Overall, the rate of revascularization was not significantly different between the CSWT and control groups (RR, 0.31; 95% CI, 0.07–1.44; P=0.136; I2=0.0%). Moreover, there was a low level of heterogeneity (I2=0.0%), and the funnel plot did not show marked asymmetry in Begg’s test (P=0.74) and Egger’s test (P=0.83).
Mortality
The risk of mortality was reported in four RCTs [26,29-31] and one cohort study [33]. Seven out of 203 patients (3.4%) in the CSWT group and 3 out of 117 (2.6%) in the control group died. Overall, CSWT treatment was associated with a risk of mortality similar to that in the control group (RR, 0.93; 95% CI, 0.32–2.65; P=0.887; I2=0.0%). There was a low level of heterogeneity (I2=0.0%), and the funnel plot did not show marked asymmetry in Begg’s test (P=0.73) and Egger’s test (P=0.69).
Sensitivity analysis
To determine the influence of individual trials on the overall pooled results of MACE and rehospitalization, we performed the sensitivity analysis by removing each of the trials one at a time, which did not detect any influence on the overall result of MACE or rehospitalization (P>0.05).
Meta-regression analyses
In meta-regression, no significant correlations were observed between the RR for MACE and study type (t=0.34, p=0.74), age (t=0.08, p=0.94), gender (t=1.05, p=0.31), LVEF (t=0.24, p=0.83), HP (t=-0.02, p=0.97), DM (t=-0.17, p=0.87), CCS (t=-0.24, p=0.82), NYHA (t=-0.37, p=0.73) and follow-up duration (t=0.95, p=0.37).
Additionally, study type (t=0.15, p=0.89), age (t=0.15, p=0.89), gender (t=0.11, p=0.92), LVEF (t=0.10, p=0.93), HP (t=0.08, p=0.94), DM (t=-0.18, p=0.86), CCS (t=-0.04, p=0.97), NYHA (t=0.05, p=0.96) and follow-up duration (t=-0.12, p=0.91) were not significantly associated with the pooled RR for rehospitalization.
Subgroup analysis
In sub-group analysis, the pooled RR in studies enrolling patients with higher CCS (≥2.4) (RR, 0.36; 95% CI, 0.26–0.50; P<0.001) was significantly lower than that in studies enrolling patients with lower CCS (<2.4) (RR, 0.58; 95% CI, 0.29–1.16; P<0.001) (Figure 4). And the between-study variance was both relatively lower in the two subgroups (I2 = 0 vs. I2 = 0). However, there was no significant difference in pooled RR for MACE and rehospitalization in other subgroups (Table 2).
Trial sequential analysis
The TSA analysis showed that, assuming a 20% difference between CSWT and control groups in the risk of MACE or rehospitalization, the RIS required 935, 1383 participants, respectively. Figure 5 shows that the cumulative Z curve crossed trial sequential boundaries, indicating statistically significant differences in the risk of MACE or rehospitalization between CSWT and control groups. (Figure 5).