Effect of cardiac shock wave therapy for rehospitalization in patients with severe coronary artery disease: a meta-analysis and trial sequential analysis

Abstract

Objective We have previously demonstrated that cardiac shock wave therapy (CSWT) effectively improves myocardial ischemia in patients with severe coronary artery disease. In this study, we further addressed the efficacy and safety of CSWT in patients with severe coronary artery disease (SCAD) or refractory angina (RA).

Methods We undertook a meta-analysis of randomized clinical trials (RCTs) and prospective cohort studies identified in systematic searches of MEDLINE, EMBASE, the Cochrane Database, and Chinese SinoMed Database. Primary endpoint was the rate of major adverse cardiac events (MACE, the composite outcome of mortality, coronary artery revascularization, and rehospitalization). Required information size (RIS) was calculated with trial sequential analysis (TSA).

Results A total of 14 RCTs and 5 prospective cohort studies involving 1172 patients with a mean follow-up of 10.6 months (range 3–72) months were included. Overall, CSWT significantly decreased the rate of MACE compared with the control group (RR, 0.39; 95%CI, 0.29–0.53), which was mainly attributed to markedly lower risk of rehospitalization in the CSWT group (RR, 0.37; 95% CI, 0.27–0.51). Subgroup analysis showed that the pooled RR in studies enrolling patients with higher CCS (≥2.4) (RR, 0.36; 95% CI, 0.26–0.50) was significantly lower than that in studies enrolling patients with lower CCS (<2.4) (RR, 0.58; 95% CI, 0.29–1.16). TSA showed that The RIS for MACE was 935, and the accrued information size was 577.

Conclusions CSWT could decrease the rate of rehospitalization and MACE among patients with SCAD or RA.

Introduction

As a consequence of severe coronary artery disease (SCAD), refractory angina (RA) is a disabling and prevalent condition, characterized by cardiac pain and refractory to conventional therapies including long-acting nitrates, β-receptor blockers, calcium-channel blockers, and traditional revascularization (percutaneous coronary intervention and coronary artery bypass surgery) [1, 2]. The mortality rate during follow-up of these patients is 3.9% at 1 year and 28.4% at 9 years [3]. Although RA does not adversely affect the risk of mortality compared with stable, chronic CAD, it is associated with recurrent and sustained cardiac pain, poor health status, psychological distress, and activity restriction [4]. Therefore, these individuals suffer severely impaired quality of life and increased rate of rehospitalization for cardiovascular reasons. Therapeutic strategies are thus directed primarily at improving patients’ quality of life and decreasing cardiovascular rehospitalization by relieving symptoms of angina pectoris. Although numerous innovative pharmacological (metabolic modulation and angiogenesis) and nonpharmacological (coronary sinus reducer, spinal cord stimulation, stem cell therapy, and enhanced external counterpulsation) therapeutic options have been studied recently, none have demonstrated clear clinical efficacy [5–9].

Extracorporeal cardiac shock wave therapy (CSWT) is a cutting-edge technology developed in the world for more than 20 years[10–13]. It passed the European CE certification in 2004, and has been tested in Germany, Japan, Switzerland, Italy and other countries for its effectiveness and safety. In 2006, the CSWT instrument was approved for clinical use in China. Shanghai, Yunnan, Beijing and other medical centers have introduced this technology and have experienced more than ten years of exploration and research, and we have carried out different studies on cell biology, animal models, and clinical practice, and have accumulated many clinical experience[14].

Recently, experts from the Cardiovascular Physician Branch of the Chinese Medical Doctor Association and the Cardiac Rehabilitation Management Professional Committee of the Chinese Hospital Association summarized a number of domestic and foreign studies, combined with the clinical experience of various domestic centers, and published Chinese expert consensus on extracorporeal cardiac shock wave therapy of coronary heart disease (2022 version)[15]. The current research results suggest that CSWT can effectively treat refractory angina pectoris, significantly improve the clinical symptoms and quality of life of patients, improve the exercise tolerance of patients with heart failure, and provide a new treatment option for patients with advanced coronary heart disease [16–18]. However, previous evidence is limited to mainly small-sized, single-arm, low- to moderate-quality, single-center studies with mixed results. Furthermore, the effect of CSWT on hard endpoints, such as mortality, myocardial infarction, and rehospitalization has not been evaluated before[18, 19]. As the evidence gathered has recently increased, we have performed a meta-analysis and trial sequential analysis (TSA) to evaluate the effect of CSWT treatment on major adverse cardiac events (MACE) in patients with SCAD or RA.

Methods

Data sources and search strategies

We searched MEDLINE (source, PubMed from 2005 to July 2021), EMBASE (2005 to July 2021), the Cochrane Controlled Clinical Trials Register Database (to July 2021), the ClinicalTrials.gov website (to July 2021), and the Chinese SinoMed Database (to July 2021) using the terms “cardiac shock wave therapy,” “adverse cardiac event,” “rehospitalization,” “mortality,” “severe coronary artery disease,” “refractory angina,” and “randomized trial.” Manual reference checking of the bibliographies of all relevant articles was performed. No restrictions were applied. The review was registered in https://inplasy.com/ (INPLASY202210103).

Study selection

We first conducted an initial screening of titles and abstracts; the second evaluation was based on full-text review. Trials were considered eligible if they met these criteria: (1) patients included were diagnosed as SCAD or RA; (2) the study was a randomized controlled trial (RCT) or a prospective cohort study; (3) intervention consisted of CSWT; (4) the primary outcome of interest was rate of MACE. Exclusion criteria were (1) non-RCTs or prospective cohort study, and (2) duplicated data.

Trials are considered eligible if they meet these criteria: (1) patients included are diagnosed as refractory angina or ischemic heart failure; (2) the study is a randomized controlled trial (RCT) or a prospective cohort study; (3) intervention consisted of CSWT; (4) patients in the control group are treated with optimal medical therapy, (5)the primary outcome of interest is rate of MACE. Exclusion criteria were (1) patients with acute myocardial infarction, (2) repeated CSWT, (3) with coronary artery revascularization, (4) without primary outcome, (5) retrospective study, and (6)duplicated data.

Data extraction

Two reviewers (L.P. and J.N.) extracted data concerning patients’ characteristics, the duration and frequency of CSWT treatment, study quality, change of cardiac function, clinical symptoms, exercise capacity, quality of life, and clinical outcomes using a standard data-collection form. Disagreements were resolved by discussion.

Primary outcome was the rate of MACE (the composite outcome of mortality, coronary artery revascularization, and rehospitalization). Secondary outcomes were the rates of mortality, coronary artery revascularization and rehospitalization. Moreover, changes of Canadian Cardiovascular Society (CCS) angina class, New York Heart Association (NYHA) class, walk distance in 6 min were also extracted and evaluated.

Quality assessment

The Preferred Reporting Items for Systemic Reviews and Meta-Analyses (PRISMA) statement [20] was followed. Additionally, using the Newcastle-Ottawa scale (NOS), two reviewers (L.P. and B.L.) evaluated the methodological quality[21]. NOS scale varies from 0 to 9 stars using eight criteria that cover three components: patient selection, study groups comparability, and outcomes assessment. Studies with a NOS score of 6 and more were considered as “high quality”, while those with a score less than 6 as “low quality”. 

Data synthesis and analysis

Results were analyzed quantitatively with STATA 14.0 software (Stata Corp, College Station, TX, USA) using the fixed- and random-effects (DerSimonian and Laird random-effects) models [22]. We calculated the pooled relative risk (RR) for dichotomous outcomes and the standard mean difference (SMD) for continuous data with 95% confidence interval (CI).

Heterogeneity was examined by the I² statistic and the chi-squared test. A value of I²>50% was considered a substantial level of heterogeneity [23]. For outcomes with significant heterogeneity (I²>50%), the random-effects models are reported in the text and figures; for all others, the fixed-effects models are reported. Once heterogeneity was noted, between-study sources of heterogeneity were investigated using subgroup analysis by stratifying original estimates according to study characteristics. Publication bias was assessed quantitatively using the Begg’s adjusted rank correlation test and the Egger’s regression asymmetry test (P≤0.10 for both) [24]. Sensitivity analyses were conducted to determine the influence of individual trials on the overall pooled results. Univariate meta-regression analysis was used to identify possible contributors to between-study variance. In particular, we investigated associations between the RR for MACE, rehospitalization and clinically plausible factors, including age, gender, left ventricular ejection fraction (LVEF), diabetes, hypertension, CCS, NYHA, study type and follow-up duration. All analyses were performed according to the intention-to-treat principle. Statistical significance was set at 0.05.

Subgroup Analysis

Based on the mean level of baseline clinical factors (age, gender, LVEF, diabetes, hypertension, CCS, NYHA, follow-up duration) and study type, the patients’ age was classified into “<67.7 years” and “≥67.7 years”; male was classified into “<74.6%” and “≥74.6%”; LVEF was classified into “<46.7%” and “≥46.7%”; HP was categorized as “<71.1%” and “≥71.1%”; DM was categorized as “<42.6%” and “≥42.6%”; CCS was reported as “<2.4” and “≥2.4”; NYHA was reported as “<2.2” and “≥2.2”. In addition, study type was divided into “RCT” and “cohort study”; follow-up duration was divided into “<6.9 months” and “≥6.9 months”.  

Trial Sequential Analysis

In the meta-analyses, trial sequential analysis (TSA) was used to reduce the risk of reaching a false-positive or false-negative conclusion [25]. When the cumulative Z-curve crossed the trial sequential monitoring boundary or entered the futility area, a sufficient level of evidence for the anticipated intervention effect was reached, and no further trials were needed. If the Z-curve did not cross any of the boundaries and the required information size (RIS) had not been reached, evidence to reach a conclusion was insufficient, and more trials were needed to confirm the results. For this TSA for MACE and rehospitalization, we estimated the RIS based on an RR reduction of 20%. The type I error (α) = 0.05 (two-sided) and power (1 – β) = 0.80. The control event proportions were 45% for MACE and 35% for rehospitalization, which were calculated from the comparator group. The TSA was conducted using TSA Version 0.9.5.10 Beta (www.ctu.dk/tsa).

Results

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). 

Discussion

Our study confirms that CSWT significantly reduced the rate of rehospitalization (RR, 0.37; 95% CI, 0.27–0.51) and MACE (RR, 0.39; 95% CI, 0.29–0.53) in patients with SCAD or RA. Subgroup analysis showed that the pooled RR in studies enrolling patients with higher CCS (≥ 2.4) (RR, 0.36; 95% CI, 0.26–0.50) was significantly lower than that in studies enrolling patients with lower CCS (< 2.4) (RR, 0.58; 95% CI, 0.29–1.16). TSA showed that The RIS for MACE was 935, and the accrued information size was 577. One could conclude that CSWT can offer beneficial effects to patients with SCAD or RA.

CSWT can potentially reduce the rate of rehospitalization in patients with SCAD or RA. The treatment of SCAD or RA is challenging, as patients with SCAD or RA experience angina even with minimal activity or at rest [43]. Therefore, these individuals suffer a severely increased rate of rehospitalization for frequent angina, although the risk of mortality is similar to that for stable CAD [4]. CSWT has been reported to potentially promote coronary angiogenesis in ischemic myocardium [11], inhibit ischemia/hypoxia-induced H9c2 myoblast cell apoptosis [14], promote cardiomyocyte autophagy during hypoxia [15], improve myocardial blood flow [12], reduce angina symptoms [13], and increase cardiac function [44]. Hence, CSWT may potentially decrease the rate of rehospitalization as a consequence of angina symptoms. In a clinical study of CSWT for 45 RA patients, Yang et al. found that CSWT markedly decreased the rate of rehospitalization for myocardial ischemic symptoms at 6-month follow-up in comparison with a control group (20.0% versus 55.0%, P < 0.05) [29]. In another study conducted in China with 12 months of follow-up, old myocardial infarction patients in the control group were associated with a significantly higher rate of rehospitalization because of CAD when compared with patients in the regular CSWT group (56.0% vs 21.8%) or those in the expanding scope CSWT group (56.0% vs 16.7%) [34]. Consistent with previous studies, this meta-analysis confirms the clinical benefit of CSWT with respect to rehospitalization for frequent angina. However, two studies demonstrated that CSWT, whether with a regular (performed 9 times within 3 months) or short-term (performed 9 times within 1 month) pattern [26, 31], was unable to decrease the risk of rehospitalization within 8–12 months of follow-up. All included studies are limited to single-center, mostly uncontrolled and underpowered trials, and no study evaluated the long-term effect of CSWT for RA. Therefore, more studies are needed to confirm the potential clinical benefit of CSWT.

CSWT produces a prominent anti-ischemic effect for patients with SCAD or RA. Several studies have confirmed that CSWT was associated with significantly improved myocardial perfusion, cardiac function, exercise tolerance, myocardial ischemia symptoms, and quality of life in patients with SCAD over short-term [26, 31, 32, 36–42] and long-term [33] follow-up. In a multicenter trial involving 50 RA patients from four institutes in Japan [45], Kikuchi et al. demonstrated that CSWT markedly improved the angina symptoms and 6-min walking distance. However, the percent myocardial ischemia assessed by drug-induced stress myocardial perfusion imaging tended to be improved only in the treated segments (P = 0.06), and no change was noted in the whole left ventricle [45]. As previous studies are limited to single-center, mostly uncontrolled and underpowered trials, most publications on CSWT provide only low- to moderate-quality results on the clinical benefits of CSWT. Recently in a prospective, randomized, triple-blind, sham-procedure-controlled study, 72 RA patients were randomized at a 1:1 ratio to an optimal medical therapy plus CSWT group (n = 37) and an optimal medical therapy with sham-procedure group (n = 35), whereby at 6-month follow-up CSWT exerted a neutral effect on quality of life and level of angina. Moreover, exercise duration in the modified Bruch treadmill test was not significantly improved with CSWT (P > 0.05) [37], which was consistent with the findings of a study by Leibowitz et al. [46]. The less pronounced effect of CSWT might be attributed to the different protocol used. In contrast to previous studies that applied CSWT only to ischemic segments, this study provided CSWT sequentially to all segments of the left ventricle. In addition, placebo may have a significant ameliorating effect on subjective outcome assessments such as angina [38], SAQ score, and exercise capacity, and the PACIFIC trial found that 28% of improvement in the CCS angina class was due to investigator bias [47]. Thus, as both investigators and patients tend to be biased toward an improvement over time because of placebo, a modest CSWT effect in this study [37] might be masked by a prominent placebo effect. Furthermore, exercise duration is insufficiently sensitive and specific for ischemic assessment, which could be better evaluated by stress echocardiography of single-photon emission computed tomography to estimate the anti-ischemic effect of CSWT.

Recently, one updated meta-analyses of CSWT in patients with CAD [18, 48] has been published. Compared with this analyses, our study has provided several new findings. First, all studies included in our analysis are RCTs or prospective cohort studies, whereas single-arm and retrospective studies are also included in the two previous meta-analyses [18, 48], which could increase the risk of bias. Furthermore, the effects of CSWT on MACE were rarely reported in recent meta-analyses. Our study indicates that CSWT could significantly decrease the risk of rehospitalization in patients with SCAD or RA, although more studies are needed to confirm these findings.

Study Limitations

The present study has a few limitations. First, our analysis is based on study-level data, and as such shares the flaws of original studies. Second, all studies included are single-center, uncontrolled, and underpowered trials, which could increase the risk of bias and lower the methodological quality. Third, our analysis enrolled patients with different CSWT protocols, which might be associated with different anti-ischemic effects. Fourth, the sample size is inadequate to exclude small differences in outcome between the two groups. TSA showed that The RIS for MACE and rehospitalization were 935, 1383, and the accrued information size were 577, 473, respectively. Fifth, the median follow-up was limited to 6.9 months. The benefit of CSWT on adverse cardiac events is expected to accrue with time, and only long-term follow-up is able to definitively address this issue. Therefore, our meta-analysis represents just a possible indication, and future studies will require larger numbers of patients, careful matching of key clinical and technical variables, and a longer follow-up to definitively quantify the potential anti-ischemic effects of CSWT.

Conclusions

Our meta-analysis indicates that CSWT could effectively decrease the rate of rehospitalization and MACE in patients with SCAD or RA. However, TSA shows that the RIS for MACE is 935, and the accrued information size is 577, and more high-quality RCTs are needed to evaluate the long-term clinical benefit of CSWT.

Declarations

Ethics approval and consent to participate

This is a meta-analysis and no ethics approval and consent to participate is needed.

Consent for publication

All authors are consent for publication.

Availability of data and materials

All data and materials will be available from the corresponding author by request. 

Competing interests

There were no competing interests.

Funding

This work was supported by grants from the Capital Health Project (Z131100004013032) and the Beijing Hospital Clinical Research 121 Project (121-2016004). 

Authors' contributions

Peng Li wrote the main manuscript text. Peng Li, Na Jia, Bing Liu analyzed the data. Qing He designed this work.

Acknowledgements

We thank Hugh McGonigle, from Liwen Bianji, Edanz Group China (www.liwenbianji.cn/ac), for editing the English text of a draft of the manuscript.

Conflict of interest

There were no conflict of interests.

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