Sarcopenia predicts adverse outcomes in an elderly population with coronary artery disease: a systematic review and meta-analysis

Background The development of sarcopenia is attributed to normal aging and factors like type 2 diabetes, obesity, inactivity, reduced testosterone levels, and malnutrition, which are factors of poor prognosis in patients with coronary artery disease (CAD). This study aimed to perform a meta-analysis to assess whether preoperative sarcopenia can be used to predict the outcomes after cardiac surgery in elderly patients with CAD. Methods PubMed, Embase, the Cochrane library, and Web of Science were searched for available papers published up to December 2020. The primary outcome was major adverse cardiovascular outcomes (MACE). The secondary outcomes were mortality and heart failure (HF)-related hospitalization. The random-effects model was used. Hazard ratios (HRs) with 95% confidence intervals (95%CIs) were estimated. Results Ten studies were included, with 3707 patients followed for 6 months to 4.5 ± 2.3 years. The sarcopenia population had a higher rate of MACE compared to the non-sarcopenia population (HR = 2.27, 95%CI: 1.58–3.27, P < 0.001; I2 = 60.0%, Pheterogeneity = 0.02). The association between sarcopenia and MACE was significant when using the psoas muscle area index (PMI) to define sarcopenia (HR = 2.86, 95%CI: 1.84–4.46, P < 0.001; I2 = 0%, Pheterogeneity = 0.604). Sarcopenia was not associated with higher late mortality (HR = 2.15, 95%CI: 0.89–5.22, P = 0.090; I2 = 91.0%, Pheterogeneity < 0.001), all-cause mortality (HR = 1.35, 95%CI: 0.14–12.84, P = 0.792; I2 = 90.5%, Pheterogeneity = 0.001), and death, HF-related hospitalization (HR = 1.37, 95%CI: 0.59–3.16, P = 0.459; I2 = 62.0%, Pheterogeneity = 0.105). The sensitivity analysis revealed no outlying study in the analysis of the association between sarcopenia and MACE after coronary intervention. Conclusion Sarcopenia is associated with poor MACE outcomes in patients with CAD. The results could help determine subpopulations of patients needing special monitoring after CAD surgery. The present study included several kinds of participants; although non-heterogeneity was found, interpretation should be cautious. Supplementary Information The online version contains supplementary material available at 10.1186/s12877-021-02438-w.


Background
Sarcopenia is a progressive, generalized skeletal muscle disorder characterized by low muscle strength, low muscle quantity or quality, and low physical performance [1,2]. The prevalence of sarcopenia is estimated at 5-13% in patients of > 60 years of age and 11-50% in patients of > 80 years of age [3,4]. Multiple definitions and criteria of sarcopenia are available, using different cutoff points and leading to a lack of standardization and poor application of these definitions in clinical practice [1,2]. Still, the diagnosis of sarcopenia, using any definition of sarcopenia, is relatively straightforward since it requires the measurement of a combination of muscle mass, muscle strength, and physical performance, and since all definitions use at least two of these parameters [1,2]. The disease burden from sarcopenia arises from the fact that it is a relatively common condition associated with short-term and long-term adverse effects. Sarcopenia is associated with higher risks of falls and fractures [5] and is a major risk factor for loss of independence in the elderly [6]. The muscular degeneration observed in sarcopenia might ultimately impair daily life activities and adversely affect major surgery outcomes in terms of complications, morbidity, and mortality [7][8][9][10][11][12].
To date, several studies have examined sarcopenia as a prognostic factor in patients with CAD [35][36][37]. Still, the available studies about the impact of sarcopenia on CAD outcomes yield conflicting results [35][36][37][38][39][40][41][42][43][44], with studies suggesting a poorer prognosis of CAD in patients with sarcopenia, while other studies suggest no association or associations no longer significant after adjustment for traditional risk factors of poor prognosis. Hence, the exact contributions of sarcopenia to CADrelated health and outcomes are unknown.
We hypothesized that sarcopenia negatively affects the outcomes of elderly patients with CAD who undergo cardiac surgery. Therefore, this meta-analysis aimed to assess whether preoperative sarcopenia can be used to predict the outcomes after cardiac surgery in elderly patients with CAD. The results could help determine subpopulations of patients needing special monitoring after surgery.

Literature search
This systematic review and meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [45]. The relevant articles were identified based on the PICO principle [46], followed by screening using the eligibility criteria. PubMed, Embase, the Cochrane library, and Web of Science were searched for available papers published up to December 2020 using the MeSH terms of 'Coronary artery disease', 'Coronary heart disease', and 'Sarcopenia', as well as relevant key words.

Definition of MACE
The definition of MACE could vary among studies, but MACE is generally defined as a composite endpoint including nonfatal stroke, nonfatal myocardial infarction, cardiovascular and cerebrovascular death, revascularization, and heart failure in this study [47,48].

Data extraction
The data were extracted by two investigators according to a pre-specified protocol. The study characteristics (authors, year of publication, country, study design, sex, sample size, sarcopenia index, cutoff value to define sarcopenia, and follow-up duration) and outcomes (MACE, mortality, and heart failure (HF)-related hospitalization) were extracted. If a study reported hazard ratios (HRs), the adjusted HRs with 95% confidence intervals (CIs) were extracted; otherwise, the crude HRs with 95%CIs were obtained.

Quality of the evidence
Ten studies were included. The level of evidence of all articles was assessed independently by two authors according to the Newcastle-Ottawa Scale (NOS) criteria for quality assessment of cohort studies [49]. Discrepancies in the assessment were resolved through discussion until a consensus was reached. The details were summarized in Supplementary Table S1.

Statistical analysis
HRs and corresponding 95%CIs were used to summarize the results. Statistical heterogeneity among studies was calculated using Cochran's Q-test and the I 2 index. An I 2 > 50% and Q-test P < 0.10 indicated high heterogeneity. The random-effects model was used to avoid possible heterogeneity among studies.
The possible publication bias was not assessed by funnel plots and Egger's test because the number of studies with MACE as the primary outcome was less than 10, in which case the funnel plots and Egger's test could yield misleading results [50,51]. A sensitivity analysis was performed by sequentially excluding each study in turn. If the 95%CI of each analysis still included the HR of the initial whole analysis, the results revealed that no single study was outlying and driving the results by itself. All analyses were

Results
Selection of the studies Figure 1 and Supplementary Table S1 present the study selection process. The initial search yielded 483 records, and 427 records were screened after removing the duplicates. After excluding 250 records, 177 full text articles or abstracts were assessed for eligibility, and 167 were excluded (study aim/design, n = 94; population, n = 32; outcomes, n = 7; exposure, n = 31; and animal study, n = 3).
Ten studies were included [35, 38-44, 52, 53], with a total of 3707 patients who were followed for 6 months to 4.5 ± 2.3 years (Supplementary Table S2). Nine studies were from Asia [35, 39-44, 52, 53] and one from the United States of America [38]. Supplementary Table S2 shows that the definition of sarcopenia varied among the studies.

Sensitivity analysis
The sensitivity analysis suggested that there was no outlying study in the analysis of the association between sarcopenia and MACE after coronary intervention (Fig. 6).

Discussion
The available studies about the impact of sarcopenia on the outcomes of CAD yield conflicting results. Hence, this meta-analysis aimed to assess whether preoperative sarcopenia can be used to predict the outcomes after cardiac surgery in elderly patients with CAD. The results showed that sarcopenia is associated with poor MACE outcomes in patients with CAD. These findings highlight the importance of performing a routine physical assessment for risk stratification and sarcopenia in CAD patients. In this context, sarcopenia is a functional status to be detected early in clinical practice, and the importance of PMI is indispensable for identifying simple methods. This is important since a recent meta-analysis showed that sarcopenia could be observed in 31.4% of patients with CAD [54]. Sarcopenia has also been associated with hypertension in older adults [55], with type 2 diabetes [26,56,57], and obesity [58,59]. Hypertension, diabetes, and obesity are also risk factors for the occurrence of CAD [27,[60][61][62] but are also well-known factors for adverse outcomes in patients with CAD [62][63][64][65]. In addition, other factors associated with the development of sarcopenia are also risk factors for poor outcomes after surgery. Indeed, low testosterone levels are associated with increased mortality after CAD and after surgery for CAD [66,67]. Malnutrition is a factor of poor prognosis in hospitalized patients [68,69]. Low levels of growth factors are also related to poor outcomes after CAD and surgery [70,71]. Still, this study showed that only the MACEs after coronary intervention for CAD were affected by sarcopenia, while mortality was not associated. Previous metaanalyses showed that sarcopenia is a risk factor for mortality in the general elderly population [72][73][74] and a factor of poor prognosis in cancer patients [75,76]. No previous meta-analysis examined specifically the impact of sarcopenia on MACEs and mortality after coronary intervention. Still, a previous meta-analysis showed that handgrip strength was associated with CAD in the community [77], but a prospective study showed no such association [78]. Still, an association with an increased risk of MACE, even in the absence of increased mortality, signifies a higher disease burden and lower quality of life for the patients [79,80] and higher healthcare costs for the patients, their family, and society [81].
This meta-analysis revealed wide differences among studies (and even within a single country) regarding the definition of sarcopenia, and these definitions affected the association of sarcopenia with the primary outcome (MACEs). Liu et al. [72] also showed that the method for determining sarcopenia, dual X-ray absorptiometry vs. bioelectrical impedance analysis in their case, affected their results of the association between sarcopenia and all-cause mortality. A recent meta-analysis highlighted the need for the proper diagnosis of sarcopenia and that properly diagnosed sarcopenia was associated with the outcomes after major gastrointestinal surgery [82]. The conclusions of this meta-analysis must be considered along with its limitations. Indeed, metaanalyses inherit all the included studies' limitations, and some caveats should be considered while interpreting the findings. Because of non-randomized registry data's intrinsic limitations, the differences in baseline characteristics between groups can affect the outcome. To minimize such biases, two studies [40,43] performed propensity score-matched analyses, and others used a multivariable logistic regression model. Second, the included sample of 3707 patients was relatively large. Finally, studies that used other and PMI to define sarcopenia demonstrated that the sarcopenia population has a higher MACE rate compared with the non-sarcopenia population. Still, studies performed using SMI/height squared index did not observe the statistical difference between the two groups. Nevertheless, the sensitivity analysis demonstrated no outlying study. Future studies should look to reconcile these definitions of sarcopenia. A major limitation is that suitable cutoff values for sarcopenia potentially differ among races, sexes, and age groups. In addition, there are many different cutoff values used for the definition of sarcopenia in the literature. Thus, it is difficult to obtain a universal definition of sarcopenia. The cutoff value for sarcopenia was defined as the lowest quartile in most studies [38,40,42,44]. In contrast, some of the other studies performed a receiver operating characteristic (ROC) curve analysis to obtain the optimal cutoff value to define sarcopenia [43,52]. Because of heterogeneity, a sensitivity analysis was performed and demonstrated no outlying study. In addition, the present study included several kinds of participants such as CAD, NSTEMI/STMI, HF, off-pump CABG, and heart valve surgery. Although non-heterogeneity was found, interpretation should be cautious.

Conclusion
In conclusion, sarcopenia is associated with poor MACE outcomes in patients with CAD. Still, the definitions of sarcopenia were different among the included studies. Future studies should look to standardize the definition of sarcopenia to achieve better estimations of the associations of sarcopenia with adverse outcomes. Although non-heterogeneity was found, interpretation should be cautious because various types of patients were included.   Availability of data and materials All data generated or analyzed during this study are included in this published article and its supplementary information files.

Declarations
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