Sleep Breath DOI 10.1007/s11325-014-0940-x
Effect of continuous positive airway pressure on homocysteine levels in patients with obstructive sleep apnea: a meta-analysis Xiong Chen & Xun Niu & Ying Xiao & Jiaqi Dong & Rui Zhang & Meixia Lu & Weijia Kong
Received: 7 August 2013 / Revised: 15 November 2013 / Accepted: 13 January 2014 # Springer-Verlag Berlin Heidelberg 2014
Abstract Purpose Continuous positive airway pressure (CPAP) is an effective treatment for obstructive sleep apnea hypopnea syndrome (OSAHS), but previous studies assessing the effect of CPAP on homocysteine (HCY) in patients with OSAHS yielded conflicting results. In this study, we conducted a meta-analysis to determine whether CPAP therapy could reduce plasma HCY levels. Methods Searches of PUBMED, SCI, and Elsevier databases were completed. Studies of adult patients with OSAHS who reported HCY levels pre- and post-CPAP treatment were collected by two independent reviewers. RevMan (version 5.2) and STATA (version 12.0) were used to perform data synthesis. Results A total of 6 studies involving 206 participants were included. Meta-analysis showed that the total weighted mean difference (WMD) for HCY levels was −0.62 units (95 % confidence interval (CI) −1.21 to −0.04, P0.05), but it was significantly reduced after 3 months therapy (WMD, −1.22, 95 % CI −2.07 to −0.38,P5.4
(poor compliance group ) Silk Ryan  Jodan W [18 ] Robinson GV 
2007 2004 2004
49 12 52
CPAP CPAP CPAP
1.5M 5M 1M
4.6(1.3) >4 5.0(1.9)
SCT SCT RCT
2 2 1
H NR H
CPAP continuous positive airway pressure, M month, h hour, SCTself- control trials, RCT Randomized controlled trials, LOE level of evidence, H have, NR not reported
Sleep Breath Table 2 Patients’ characteristics of the trials included in the meta-analysis Author
Marta kumor A  (pure OSAHS group ) Marta kumor B  (OSAHS with IDH group ) Ftima crintra A  (1 month group ) Ftima crintra B  (6 month group ) Paschalis A  (good compliance group ) Paschalis B  (poor compliance group ) Silk Ryan  Jodan W [18 ]
Robinson GV 
SD standard deviation, HCY homocysteine, BMI body mass index, AHI apnea - hypopnea index, CPAP continuous positive airway pressure
hypothesize that, in gaining sample size, we will clarify the relationship between CPAP and HCY.
Inclusion/exclusion criteria of literature The studies were included if they satisfied the following criteria:
Methods Literature search We searched for English articles included in SCI, PUBMED, and Elsevier databases. Search terms included sleep apnea, continuous positive airway pressure, CPAP, and homocysteine. The computerized search was supplemented with a manual search of the bibliographies of all articles retrieved. Potentially relevant articles were assessed for inclusion against prespecified inclusion and exclusion criteria.
1. All subjects of the study were limited to adults with OSAHS diagnosed by polysomnography according to the data of apnea hypopnea index (AHI) ≥5 events/h. 2. The study must have both before and after CPAP HCY values reported. 3. CPAP had to be used for ≥1 month before and after repeat HCY. 4. The study provided sufficient data that allowed for a metaanalysis. A study was excluded if information available was not adequate for data extraction.
Fig. 2 Meta-analysis and forest plot of all studies included. Calculation based on fix effects model. Results are expressed as weighted mean difference (WMD) and 95 % confidence intervals (95 % CI)
Fig. 3 Subgroup analysis and forest plot based on treatment duration ≤3 months. Calculation was based on fix effects model. Results are expressed as weighted mean difference (WMD) and 95 % confidence intervals (95 % CI)
Besides, abstract, letters to the editor, and case report were excluded.
Results Search results
Statistical analysis Statistical calculations were performed by using Review manager 5.2 and STATA version 12.0. Weighted mean difference (WMD) and a 95 % confidence interval (CI) were employed to present the statistical result for continuous outcomes. Risk ratio (RR) and a 95 % confidence interval were used to present the statistical result for dichotomous outcomes. MantelHaenszel analysis method was utilized for dichotomous variables, and inverse variance method was used for continuous variables . The statistical significance was set at a P50), and AHI (≤50 and >50). Forest plot were synthesized. Potential publication bias was explored by funnel plot , the Begg test , and the test of Egger . We used trim and fill method to identify and correct for funnel plot asymmetry arising from publication bias .
The initial search was independently executed by two reviewers, and 50 articles were preliminarily selected. The 50 articles were then roughly screened by title and abstract on the basis of inclusion/exclusion criteria. Upon careful discussion between the two reviewers, eight articles were found to be related to this study. The eight articles then underwent second-stage review. One article  was excluded by the lack of before and after CPAP HCY data, and the other study  was eliminated because only an abstract was available. Finally, a total of six studies were included for the meta-analysis. The detailed steps of the literature search are shown in Fig. 1. Characteristics of include studies Six studies [14-19] comprising data from a total of 206 participants were included in this review. Three of those studies [14-16] were respectively provided two sets of data. One study  reported all results separately for OSAHS group and OSAHS with ischemic heart disease (IHD) group. Another study  listed all results separately for 1 month group and 6 month group. And the other study  reported all results separately for good compliance group and poor compliance group. The information of author, year of publication, exclusion criteria, sample size, follow-up time, daily duration, treatment, study design and the level of evidence of each study are included in Table 1. All the self-control trials included were defined as level 2 and randomized controlled trails as level 1, on the basis of study design . The information of mean age, BMI, AHI, and HCY of each study are shown in Table 2.
Fig. 4 Subgroup analysis and forest plot based on treatment duration >3 months. Calculation based on fix effects model. Results are expressed as weighted mean difference (WMD) and 95 % confidence intervals (95 % CI)
Fig. 5 Subgroup analysis and forest plot based on treatment body mass index (BMI) ≤30. Calculation based on fix effects model. Results are expressed as weighted mean difference (WMD) and 95 % confidence intervals (95 % CI)
Pooled analysis Our analysis showed that I2 =22 % (I2 0.1), indicating the studies were not heterogeneous. Therefore, the fix effects model were used to combine effect size. Meta-analysis revealed that the total WMD for the HCY levels was −0.62 units (95 % CI −1.21 to −0.04,P0.05) (Fig. 3). Treatment duration > 3 month: The total WMD in the studies with average follow-up time beyond 3 month is significant with a corresponding value of −1.22 (95 % CI −2.07~−0.38, P0.05 ) (Fig. 7). Average AHI >50: The total WMD in the studies with average AHI beyond 50 is significant with a corresponding value of −1.03(95 % CI −1.91 to −0.14, P0.05 ) (Fig. 5). Average BMI >30: The total WMD in the studies with average BMI beyond 30 is significant with a corresponding value of −1.19 (95 % CI −2.01 to −0.37, P30. Calculation based on fix effects model. Results are expressed as weighted mean difference (WMD) and 95 % confidence intervals (95 % CI)
Fig. 7 Subgroup analysis and forest plot based on treatment apnea hypopnea index (AHI) ≤50. Calculation based on fix effects model. Results are expressed as weighted mean difference (WMD) and 95 % confidence intervals (95 % CI)
significant decrease in HCY levels. Begg tests (P=0.754) and Egger tests (P=0.19) showed there were no evidence to support publication bias in our study. Moreover, I2 =22 % (I2 < 50 %) and P=0.22 (P>0.1), indicating that there existed no heterogeneity among the studies. Therefore, the six studies were comparable and homogeneous and the results of our study could represent the true relationship between CPAP therapy and plasma HCY levels. To further understand how long it will take to reduce HCY levels by CPAP treatment, we performed a subgroup analysis in terms of therapy duration. The results showed that HCY levels were decreased nonsignificantly in less than 3 months therapy, and it was significantly decreased after 3 months therapy, which were consistent with the studies [14, 16, 18]. Inconsistent with our results, the study  reported a significant reduction of HCY after 1 month CPAP therapy, and the study  reported nonsignificant reduction of HCY after 6 months CPAP therapy. Because of the complexity of factors affecting effectiveness of CPAP on HCY levels, we could not identify precise time period for CPAP treatment to reduce HCY levels in OSAHS patients in our meta-analysis. Nevertheless, on the basis of the limited data available, we believe that long-term CPAP treatment (more than 3 months) could lower HCY levels. In addition, subgroup analysis of studies with mean AHI >50 and BMI >30 yielded significant total weighted mean difference. It indicates that HCY levels in patients with AHI >50 or BMI >30 may respond better to CPAP therapy. The role of HCY levels in OSAHS is unclear, with some studies reporting higher levels only in OSAHS patients suffering from preexisting cardiovascular disease and other reports identifying HCY levels to be independently associated with OSAHS [7, 9, 10, 18, 30, 31]. However, CPAP is
considered to be the primary treatment for OSAHS , and as a noninvasive treatment of OSAHS, CPAP can significantly reduce cardiovascular morbidity and mortality [32, 33]. Meanwhile, Boushey et al. found that when the plasma HCY was increased by 5 μmol/l, the risk of coronary disease could be increased by 60 to 80 % and the incidence of cerebrovascular diseases was increased by 50 % . According to a study by John et al., hyperhomocysteine (HHCY) accounted for 10 % of the total risk of cardiovascular diseases, and it could prevent about 25 % of cardiovascular events if the level of HCY was reduced . Our meta-analysis suggested that CPAP treatment appears to significantly lower HCY levels by 0.62 μmol/l, and it might be beneficial to delay or prevent the occurrence of cardiovascular disease in patients with OSAHS. Despite these important findings, our study was also with limitations. First, the number and size of studies included in the analysis was relatively small and larger and more numerous studies would allow for more precise effect size estimation as well as more sophisticated moderator analysis. Second, in our meta-analysis, different studies utilized a variety of measurement techniques for HCY, ranging from enzyme immunoassay , fluorometric detection and isocratic elution [15, 18, 19], and fluorometric polarization immunoassay [16, 17]. However, the potential moderating effect of these different methods did not reach significance in a mixed effect model (P=0.834). In conclusion, the current meta-analysis demonstrated that HCY, as an independent risk factor for cardiovascular diseases, was present and significantly reduced by CPAP therapy in patients with OSAHS. Based on our results, the change in HCY levels could be considered as a potential predictor for
Fig. 8 Subgroup analysis and forest plot based on treatment apnea hypopnea index (AHI) >50. Calculation based on fix effects model. Results are expressed as weighted mean difference (WMD) and 95 % confidence intervals (95 % CI)
Sleep Breath Fig. 9 Funnel plot showed the possibility of a small publication bias. SE standard error, MD mean difference
CPAP therapy among OSAHS patients. However, the clinical significance of this finding as it relates to cardiovascular risk reduction in OSAHS patients requires further study. Acknowledgments This study was supported by the Natural Science Foundation of Hubei Province in China (NO: 2011CDC072). Conflict of interest None of the authors have any conflicts of interest to declare.
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