ORIGINAL ARTICLE Effects of Statin Therapy on Inflammatory Markers in Chronic Heart Failure: A Meta-analysis of Randomized Controlled Trials Lei Zhang, a, * Shuning Zhang, a, * Hong Jiang, a, * Aijun Sun, a Yunkai Wang, a Yunzeng Zou, a,b Junbo Ge, a,b and Haozhu Chen a,b a Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Shanghai Medical College of Fudan University, Shanghai, China b Institutes of Biomedical Sciences, Fudan University, Shanghai, China Received for publication May 25, 2010; accepted August 23, 2010 (ARCMED-D-10-00255). Background and Aims. Inflammation is thought to be important in mediating the progres- sion of chronic heart failure (CHF). Whether beneficial effects on inflammation can be achieved by statins in patients with CHF remains uncertain. This meta-analysis was con- ducted to determine the role of statin therapy in inflammation markers in CHF patients. Methods. Pubmed, MEDLINE, EMBASE, and EBM Reviews databases were searched for randomized controlled trials comparing statin treatment with non-statin treatment in CHF patients. Two reviews independently assessed studies and extracted data. Stan- dardized mean differences (SMD) were calculated using random effects models. Results. Ten studies with 6052 patients were included. Pooled analysis showed that statin therapy was associated with significant decrease in high-sensitivity C-reactive protein (SMD 5 0.74, 95% CI 1.16 to 0.32; p 5 0.0005) and soluble vascular cell adhesion molecule-1 (SMD 5 0.49, 95% CI 0.91 to 0.08; p 5 0.02). However, the beneficial effects of statin were not shown regarding interleukin-6 (SMD 5 0.85, 95% CI 2.09 to 0.38; p 5 0.18) and tumor necrosis factor-a (SMD 5 0.13, 95% CI 0.50 to 0.25; p 5 0.51). Sources of heterogeneity were not found by meta-regression analyses, whereas subgroup analyses showed that difference in age, etiology, baseline left ventricular ejection fraction, type of statins and follow-up duration might influence the effects of statins. Conclusions. Statin may partially suppress inflammatory markers in patients with CHF; moreover, this beneficial effect may be associated with different types of statins, treat- ment intervals and characteristics of patients. Ó 2010 IMSS. Published by Elsevier Inc. Key Words: Statins, Chronic heart failure, Inflammatory marker, Meta-analysis. Introduction Chronic heart failure (CHF) is associated with intensified oxidative stress, activated inflammation, and unbalanced neurohormones (1e3). Inflammatory cytokines, which are produced by activated macrophages, vascular wall cells, and cardiac myocytes, are elevated in CHF (4e7). Meanwhile, studies have revealed that hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) possess a number of additional properties beyond their lipid-lowering effect, e.g., anti- inflammation (8,9). In view of these facts, statins were consid- ered to be a promising candidate for the treatment of CHF, and many clinical trials have been conducted to determine the effects of statin treatment on inflammatory markers in patients with CHF. However, the results were conflicting. In order to provide a more robust estimate of the potential benefits of statin therapy, we performed a meta-analysis of randomized controlled trials to evaluate the impact of statin treatment on serum markers of inflammation in CHF patients. * These authors contributed equally to this work. Address reprint requests to: Junbo Ge, MD, FACC, FESC, FSCAI, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Shanghai Medical College of Fudan University, 180 Fenglin Road, Shanghai 200032, China; Phone: þ86-21-64041990 ext. 2745; FAX: þ86-21-64223006; E-mail: [email protected]0188-4409/$ - see front matter. Copyright Ó 2010 IMSS. Published by Elsevier Inc. doi: 10.1016/j.arcmed.2010.08.009 Archives of Medical Research 41 (2010) 464e471
Transcript
Archives of Medical Research 41 (2010) 464e471
ORIGINAL ARTICLE
Effects of Statin Therapy on Inflammatory Markers in Chronic Heart Failure:A Meta-analysis of Randomized Controlled Trials
Lei Zhang,a,* Shuning Zhang,a,* Hong Jiang,a,* Aijun Sun,a Yunkai Wang,a Yunzeng Zou,a,b
Junbo Ge,a,b and Haozhu Chena,b
aShanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Shanghai Medical College of Fudan University, Shanghai, ChinabInstitutes of Biomedical Sciences, Fudan University, Shanghai, China
Received for publication May 25, 2010; accepted August 23, 2010 (ARCMED-D-10-00255).
*These authors con
Address reprint r
Shanghai Institute o
Shanghai Medical C
Shanghai 200032, C
þ86-21-64223006; E
0188-4409/$ - see frodoi: 10.1016/j.arcm
Background and Aims. Inflammation is thought to be important in mediating the progres-sion of chronic heart failure (CHF). Whether beneficial effects on inflammation can beachieved by statins in patients with CHF remains uncertain. This meta-analysis was con-ducted to determine the role of statin therapy in inflammation markers in CHF patients.
Methods. Pubmed, MEDLINE, EMBASE, and EBM Reviews databases were searchedfor randomized controlled trials comparing statin treatment with non-statin treatmentin CHF patients. Two reviews independently assessed studies and extracted data. Stan-dardized mean differences (SMD) were calculated using random effects models.
Results. Ten studies with 6052 patients were included. Pooled analysis showed that statintherapy was associated with significant decrease in high-sensitivity C-reactive protein(SMD 5 �0.74, 95% CI �1.16 to �0.32; p 5 0.0005) and soluble vascular cell adhesionmolecule-1 (SMD 5 �0.49, 95% CI �0.91 to �0.08; p 5 0.02). However, the beneficialeffects of statin were not shown regarding interleukin-6 (SMD 5 �0.85, 95% CI �2.09to 0.38; p 5 0.18) and tumor necrosis factor-a (SMD 5 �0.13, 95% CI �0.50 to 0.25;p5 0.51). Sources of heterogeneity were not found by meta-regression analyses, whereassubgroup analyses showed that difference in age, etiology, baseline left ventricularejection fraction, type of statins and follow-up duration might influence the effects ofstatins.
Conclusions. Statin may partially suppress inflammatory markers in patients with CHF;moreover, this beneficial effect may be associated with different types of statins, treat-ment intervals and characteristics of patients. � 2010 IMSS. Published by Elsevier Inc.
Chronic heart failure (CHF) is associated with intensifiedoxidative stress, activated inflammation, and unbalancedneurohormones (1e3). Inflammatory cytokines, which areproduced by activated macrophages, vascular wall cells, and
nt matter. Copyright � 2010 IMSS. Published by Elseviered.2010.08.009
cardiac myocytes, are elevated in CHF (4e7). Meanwhile,studies have revealed that hydroxymethylglutaryl coenzymeA reductase inhibitors (statins) possess a number of additionalproperties beyond their lipid-lowering effect, e.g., anti-inflammation (8,9). In view of these facts, statins were consid-ered to be a promising candidate for the treatment of CHF, andmany clinical trials have been conducted to determine theeffects of statin treatment on inflammatorymarkers in patientswith CHF. However, the results were conflicting. In order toprovide a more robust estimate of the potential benefits ofstatin therapy, we performed a meta-analysis of randomizedcontrolled trials to evaluate the impact of statin treatment onserum markers of inflammation in CHF patients.
465Statin for Inflammation Markers in Chronic Heart Failure
Materials and Methods
Search Strategy and Selection Criteria
We performed a literature search in Pubmed, MEDLINE,EMBASE, and EBM Reviews databases until July 2009.Search terms were statin, heart, cardiac, dysfunction,insufficiency, inadequacy, and failure without restrictionsof language and publication form (including meetingabstracts). The reference lists of studies that met our inclu-sion criteria were also searched for potentially relevanttitles.
Studies were included in our analysis if they met thefollowing criteria: (1) the design was a prospective,randomized controlled trial (regardless of sample size);(2) patients with established CHF, regardless of the etiologyand severity of the disease, were assigned to statin treat-ment (regardless of the type and dose of statins) or control(non-statin treatment or placebo) in addition to concurrenttherapy; and (3) they reported data on high-sensitivityC-reactive protein (hsCRP), interleukin-6 (IL-6), tumornecrosis factor-a (TNF-a), and soluble vascular cell adhe-sion molecule (sVCAM-1).
Data Extraction and Quality Assessment
Two investigators (L.Z., S.Z.) independently reviewed allpotentially eligible studies using predefined eligibilitycriteria and collected data from the included trial; disagree-ments were resolved by consensus. We extracted details onstudy characteristics, patient characteristics, interventionstrategies, follow-up duration, and levels of inflammatorymarkers including hsCRP, IL-6, TNF-a and sVCAM-1.
Quality assessments were evaluated with Jadad qualityscale, and a numerical score between 0 and 5 was assignedas a measure of study design (10).
Data Synthesis and Analysis
All end points were based on the change from baseline tofollow-up, and pooled effects were presented as standard-ized mean differences (SMD) with 95% confidence inter-vals (CI) using random effect models because variousmeasurement units were applied in the included studies.Statistical heterogeneity was measured using the I2 statistic(I2 O50% was considered representative of significantstatistical inconsistency). Meta-regression and subgroupanalyses were conducted to explore heterogeneity. Sensi-tivity analyses (including exclusion of one study at a time)were performed to determine the stability of pooled results.Furthermore, on the basis of the data on hsCRP, publicationbias was tested using the Begg adjusted-rank correlationtest (11) and Egger regression asymmetry test (12); p valueswere two-tailed and statistical significance was set at 0.05.All analyses were performed with STATA software 8.0(StataCorp, College Station, TX).
Results
Selected Studies and Characteristics
The flow of selection of studies for inclusion in the meta-analysis is shown in Figure 1. Of the initial 4205 hits, 10randomized controlled trials (RCTs) with a total of 6052patients satisfying the inclusion criteria were identifiedand analyzed (13e22). A summary of baseline characteris-tics of the included trials is shown in Table 1. The level ofevidence for each trial was graded from 1e5 according toJadad quality score. Additionally, there existed a widerange of follow-up duration (from 1e46.8 months) amongthe studies, whereas one of the studies had enrolled rela-tively younger patients (mean age 5 38 years) (21), ascompared with the average of 71 years of all includedstudies. Moreover, no significant differences were observedbetween groups assigned statins and placebo in backgroundCHF therapies, including angiotensin-converting enzymeinhibitor (ACEI) (or angiotensin receptor blocker) andbeta-blocker therapy.
Effects of Statin Treatment on hsCRP, IL-6, TNF-aand sVCAM-1
The overall pooled results with random-effects analysisshowed that additional statin therapy was significantly supe-rior to standard medical therapy with respect to hsCRP(SMD 5 �0.74, 95% CI �1.16 to �0.32; p 5 0.0005, I2 593.9%) (Figure 2). Moreover, statin therapy was similarlyfound to have benefits concerning sVCAM-1 (SMD 5�0.49, 95% CI �0.91 to �0.08; p 5 0.02, I2 5 0.0%)(Figure 3). In addition, statin therapy also tended to be associ-ated, albeit nonsignificantly, with reduction of IL-6 (SMD5�0.85, 95% CI �2.09 to 0.38; p 5 0.18, I2 5 95.4%)(Figure 4A) and TNF-a (SMD 5 �0.13, 95% CI �0.50 to0.25; p 5 0.51, I2 5 35.4%) (Figure 4B), as compared withcontrol. The above findings suggest that statin may partiallydownregulate inflammatory markers in patients with CHF.
Meta-regression and Subgroup Analyses
In view of the fact that statistical heterogeneity existedacross the enrolled studies, a number of exploratory meta-regression analyses were performed to appraise the impactof different covariates on the change of hsCRP level asso-ciated with statin therapy. However, we did not find a statis-tically significant association between the benefits of statintherapy and year of publication ( p 5 0.65), age of patients( p 5 0.55), sex of patients ( p 5 0.76), etiology of CHF( p 5 0.44), baseline left ventricular ejection fraction(LVEF) ( p 5 0.67) and follow-up duration ( p 5 0.96). Withrespect to other endpoints (IL-6, TNF-a and sVCAM-1),meta-regression were not performed because of inadequatepower due to the low number of studies. Subsequently,subgroup analyses were separately performed with regard
Figure 1. Search flow diagram for studies included in the meta-analysis.
466 Zhang et al./ Archives of Medical Research 41 (2010) 464e471
to the effects of statin treatment on hsCRP, IL-6 and TNF-a(Table 2). The results showed that the difference in age,etiology, baseline LVEF, type of statin and follow-up dura-tion might influence the effects of statin on hsCRP. Specif-ically, patients with age $60 y, ischemic etiology, baseline
Table 1. Characteristics of 10 clinical trials included in the meta-analysis
Laufs et al. (17) 2004 15 51 NA IIeIIISola et al. (18) 2006 108 54 62 IIeIV
Tousoulis et al. (19) 2005 26 69 100 IIIeIV
Tousoulis et al. (20) 2005 38 67 NA IIeIV
Wojnicz et al. (21) 2006 74 38 81 IIeIIIYamada et al. (22) 2007 38 64 79 IeIII
NYHA, New York Heart Association; LVEF, left ventricular ejection fraction; N
LVEF $30% and follow-up $12 months seemed to bemore likely to get benefits from statin treatment. Mean-while, atorvastatin was superior to other types of statins.Moreover, results also showed that longer interval ($12months) of statin treatment on younger CHF patients
Etiology
schemic, %)
LVEF
(mean, %) Statin (type, dose)
Follow-up
(month)
Jadad
score
0 25 Atorvastatin 80 mg/day 3 4
100 31 Rosuvastatin 10 mg/day 32.8 4
40 33 Rosuvastatin 10 mg/day 46.8 5
12 29 Rosuvastatin 10e40 mg/day 6 2
0 42 Cerivastatin 0.4 mg/day 5 3
0 33 Atorvastatin 20 mg/day 12 3
100 26 Atorvastatin 10 mg/day 1 2
66 NA Atorvastatin 10 mg/day 1 1
0 28 Atorvastatin 40 mg/day 6 3
53 34 Atorvastatin 10 mg/day 31 5
A, not available.
Figure 2. Comparison of changes in hsCRP for patients with CHF randomized to statin treatment or non-statin treatment. The effect size of each study is
proportional to the statistical weight. The diamond indicates the overall summary estimate for the analysis; the width of the diamond represents the 95% CI.
hsCRP, high sensitivity C-reactive protein; SMD, standardized mean differences; CI, confidence intervals. (A color figure can be found in the online version
of this article.)
467Statin for Inflammation Markers in Chronic Heart Failure
(!60 years) with non-ischemic etiology were moreinclined to yield beneficial effects concerning the downre-gulation of IL-6.
Sensitivity Analyses and Publication Bias
Sensitivity analyses excludingone study at a timeconfirmed indirection and magnitude of statistical significance concerningthe results of hsCRP, IL-6 and TNF-a. Nevertheless, we foundthat the beneficial effect of statins on sVCAM-1 turned to bevague when either one of the two studies (19,20) conductedby Tousoulis et al. was omitted (SMD 5 �0.42, 95% CI�1.02 to 0.18; p 5 0.17 or SMD 5 �0.35, 95% CI �0.90to 0.19; p 5 0.21). Assessment of publication bias usingEgger’s and Begg’s tests showed that no potential publication
Figure 3. Comparison of changes in sVCAM-1 for patients with CHF randomized
proportional to the statistical weight. The diamond indicates the overall summary
sVCAM-1, soluble vascular cell adhesion molecule; SMD, standardized mean diff
version of this article.)
bias existed among the included trials (Egger’s test: p5 0.86;Begg’s test: p5 0.46) (Figure 5A and 5B).
Discussion
We performed this meta-analysis of 10 RCTs to evaluatethe effects of additional statin therapy on inflammatorymarkers in patients with CHF. The results revealed that sta-tin treatment significantly decreased the levels of hsCRPand sVCAM-1 as compared with controls; however, itfailed to show a marked reduction in IL-6 and TNF-a.
A number of studies have revealed that heart failuremay, in part, be an inflammatory disease (23,24), whereasvarious adhesion molecules and cytokines such as IL-6
to statin treatment or non-statin treatment. The effect size of each study is
estimate for the analysis; the width of the diamond represents the 95% CI.
erences; CI, confidence intervals. (A color figure can be found in the online
Figure 4. Comparison of changes in IL-6 (A) and TNF-a (B) for patients with CHF randomized to statin treatment or non-statin treatment. The effect size of
each study is proportional to the statistical weight. The diamond indicates the overall summary estimate for the analysis; the width of the diamond represents
the 95% CI. IL-6, interleukin-6; TNF-a, tumor necrosis factor-a; SMD, standardized mean differences; CI, confidence intervals. *Study published in The
European Journal of Heart Failure. #Study published in the journal of Atherosclerosis. (A color figure can be found in the online version of this article.)
468 Zhang et al./ Archives of Medical Research 41 (2010) 464e471
and TNF-a may contribute to endothelial dysfunction,cardiac myocyte apoptosis, structural deterioration and leftventricular dysfunction (7,25,26). Moreover, the inflamma-tory marker that presently seems most suitable to assessinflammation is hsCRP, which is an independent predictorof prognosis in CHF and can provide additional prognosticinformation for the risk stratification and treatment inpatients with CHF (27,28).
Besides the well-established lipid-lowering property(29), multiple studies have additionally disclosed manyother pleiotropic effects of statins including decreasingoxidative stress, facilitating nitric oxide (NO) synthesis,improving endothelial function, and reducing markers ofinflammation (9,30e32), which may be related with theability of statins to inhibit isoprenylation and the activation
of members of the Rho family, blocking pro-inflammatorytransduction pathways (33). This meta-analysis confirmedthe effects of statin on hsCRP and sVCAM-1, suggestinga potential role of statin in blunting the inflammatoryresponse associated with CHF and modifying the outcomeof these patients. Consistent with our hypotheses, a recentmeta-analysis (34) showed that statins could not onlyincrease LVEF but also decrease hospitalization for wors-ening heart failure. Furthermore, all-cause mortality couldas well be reduced but only if atorvastatin was utilized.
Considering the significant heterogeneity that existed inthis pooled analysis, we performed a variety of meta-regression analyses to explore potential sources; however,no evidence was found regarding year of publication, age,sex, etiology, baseline LVEF and follow-up duration. Despite
Figure 5. Egger’s test (linear regression, p 5 0.86) (A) and Begg’s funnel
plot ( p 5 0.46) (B) for hs-CRP, suggesting no publication bias existing in
the pooled analysis.
469Statin for Inflammation Markers in Chronic Heart Failure
this, it is worth noticing that the characteristics of 10 includedtrials were not quite the same. Thus, we subsequently per-formed subgroup analyses to better understand the associationin different subgroups. The results indicated that older CHFpatients ($60 years) with ischemic etiology and higher base-line LVEF ($30%) seemed to be more likely to get benefitsfrom statin therapy in regard to the downregulation of hsCRP,whereas long interval ($12 months) of atorvastatin treatmentwas superior to relatively shorter interval (!12 months) oftreatment with other types of statins, which is partially consis-tent with the results of the former study (34). Previous studieshave verified the drug-specific effects of statins (35,36),whereas atorvastatin may reduce hsCRP-induced inflamma-tory response via inhibiting nuclear factor-kB pathway (37).Moreover, it may be more effective for statins to exert theiranti-inflammatory effects in ischemic heart disease (IHD),considering that inflammatory markers (e.g., hsCRP) arehighly elevated in IHD (38,39). Therefore, the aforementionedfactors should be taken into account when evaluating theeffects of statins on hsCRP in CHF patients. In addition,although the pooled analyses failed to show significant bene-fits of statin therapy on IL-6, subgroup analyses suggested thatlonger interval ($12 months) of statin treatment on youngerCHF patients (!60 years) with nonischemic etiology mayyield better outcomes. However, we should note that only
470 Zhang et al./ Archives of Medical Research 41 (2010) 464e471
one study (18) was included in the subgroup analyses (age!60 years, non-ischemic etiology and follow-up duration$12months) that showed beneficial effects of statin treatmenton IL-6, suggesting more studies are needed to verify thisbenefit.
Unexpectedly, this meta-analysis failed to demonstratea beneficial role of statins in downregulation of TNF-a,which may be explained by two reasons. One possibilityregarding lack of benefit may relate to the backgroundCHF therapies. Patients have been actively treated and mostwere on ACEI (or angiotensin receptor blocker) and beta-blocker therapy, which have already been confirmed tosuppress inflammatory cytokines such as TNF-a (40,41).Thus, it would be extremely difficult to demonstrate anincremental beneficial clinical effect of novel agents addi-tional to these background medications. The other possi-bility may be the low number of included studies (fiveRCTs) with small size of population (180 patients), whichmay not have sufficient power to disclose all potentialbenefits.
Sensitivity analyses excluding one study at a time wereperformed to determine the stability of overall pooled anal-yses, whereas equivocal results were only observed withrespect to sVCAM-1, which from our point of view, maybe accounted for by the small number of included studies(three RCTs) in the overall analysis. Finally, there existedno publication bias based on the data of hsCRP, indicatingthat it would not influence the results in favor of statin treat-ment in CHF patients.
Limitations of meta-analysis are well known. Drawbackspertinent to the present study include lack of raw and uniformdata from included studies, differences in characteristicsamong included studies, encompassing age, etiology, type ofstatin, follow-upduration, etc.Moreover, significant heteroge-neity was observed among studies, suggesting the pooledresults should be viewed with caution.
In conclusion, current cumulative evidence suggests thatstatin therapy may confer benefits not only in decreasinghsCRP but also in reducing sVCAM-1. Additionally, morelarge-scale RCTs may be needed in the future for mining allpotential benefits of statins in patients with CHF.
AcknowledgmentsThis study was supported by the Key Projects in the NationalScience & Technology Pillar Program in the Eleventh Five-yearPlan Period (Grant No. 2006BAI 01A04), National NaturalScience Foundation of China (Grant No. 30871073) and ShanghaiInternational Cooperation Project (Grant No. 09540703500).
Disclosures
There are no financial or other competing interests thatmight pose a conflict of interest.
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