Efficacy and Safety of L-Carnitine Treatment for Chronic Heart...

Review ArticleEfficacy and Safety of L-Carnitine Treatment for Chronic HeartFailure A Meta-Analysis of Randomized Controlled Trials

Xiaolong Song12 Huiyan Qu1 Zongguo Yang3 Jingfeng Rong1 Wan Cai1 and Hua Zhou1

1Department of Cardiology Shuguang Hospital Shanghai University of Traditional Chinese Medicine Shanghai 201203 China2Department of Cardiology Yancheng Traditional Chinese Medicine Hospital Affiliated to Nanjing University of Chinese MedicineYancheng 224001 China3Department of Traditional Chinese Medicine Shanghai Public Health Clinical Center Fudan University Shanghai 201508 China

Correspondence should be addressed to Hua Zhou zhouhuahm163com

Received 12 January 2017 Revised 19 March 2017 Accepted 22 March 2017 Published 13 April 2017

Academic Editor Hai-Feng Pan

Copyright copy 2017 Xiaolong Song et al This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Background Whether additional benefit can be achieved with the use of L-carnitine (L-C) in patients with chronic heart failure(CHF) remains controversialWe therefore performed ameta-analysis of randomized controlled trials (RCTs) to evaluate the effectsof L-C treatment in CHF patients Methods Pubmed Ovid Embase Web of Science and Cochrane Library databases ChineseNationalKnowledge Infrastructure (CNKI) databaseWanfang database Chinese Biomedical (CBM)database andChinese Scienceand Technology Periodicals database (VIP) until September 30 2016 were identified Studies that met the inclusion criteria weresystematically evaluated by two reviewers independently Results 17 RCTs with 1625 CHF patients were included in this analysisL-C treatment in CHF was associated with considerable improvement in overall efficacy (OR = 347 119875 lt 001) left ventricularejection fraction (LVEF) (WMD 414 119875 = 001) strike volume (SV) (WMD 821ml 119875 = 001) cardiac output (CO) (WMD088 Lmin119875 lt 001) and EA (WMD 023119875 lt 001) Moreover treatment with L-C also resulted in significant decrease in serumlevels of BNP (WMD minus12460 pgml 119875 = 001) serum levels of NT-proBNP (WMD minus51036 pgml 119875 lt 001) LVESD (WMDminus406mm 119875 lt 001) LVEDD (WMD minus479mm 119875 lt 001) and LVESV (WMD minus2016ml 95 CI minus3565 to minus467 119875 lt 001)However there were no significant differences in all-cause mortality 6-minute walk and adverse events between L-C and controlgroups Conclusions L-C treatment is effective for CHF patients in improving clinical symptoms and cardiac functions decreasingserum levels of BNP and NT-proBNP And it has a good tolerance

1 Introduction

Chronic heart failure (CHF) is a complex clinical syndromecharacterized by decreased myocardial contractility hemo-dynamic abnormality and neuroendocrine activation It is aglobal public health problem affecting estimated 26 millionworldwide [1] Currently the neurohormonal antagonists(ACE-inhibitors beta-blockers angiotensin receptor block-ers and mineralocorticoid receptor antagonists) are recom-mended for CHF as cornerstones [2 3] However it remainsa leading cause of morbidity and mortality throughout theworld

Recently there has been a growing appreciation of thecomplex metabolic processes underlying HF pathophysiol-ogy and symptoms [4] In fact the failing heart may be

defined as ldquoan engine out of fuelrdquo [5] L-carnitine is a vitamin-like and modified amino acid that plays an important role insupporting the bodyrsquos metabolic activities There is growingevidence that high concentrations of L-C provide beneficialeffects in various diseases such as coronary artery diseasecongestive heart failure peripheral vascular diseases type 2diabetes dyslipidemia and hypertension [6]

However the clinical guidelines about nutritional supple-ments in different countries are not consistent In Chineseguideline nutritional supplements (trimetazidine coenzymeQ10 and L-C) may be helpful to CHF [7] But as a treatmentof heart failure L-C has not been recommended in patientswith current or prior symptoms of heart failure with reducedejection fraction and heart failure with preserved ejectionfraction in the American guideline [3]The recommendation

HindawiBioMed Research InternationalVolume 2017 Article ID 6274854 11 pageshttpsdoiorg10115520176274854

2 BioMed Research International

of nutritional supplements has not been proposed in theEuropean guideline [2]

In addition two meta-analyses of RCTs has been per-formed to assess the therapeutic effects of L-C in the sec-ondary prevention of cardiovascular disease [8 9] but thereis no meta-analysis of RCTs in CHF Over the past fewdecades several small RCTs have been conducted to evaluatethe effects of L-C treatment in patients with CHF Thus weperformed ameta-analysis of RCTswith critical inclusion andexclusion criteria to evaluate the efficacy and tolerance of L-C

2 Materials and Methods

21 Search Strategy We searched Pubmed Ovid EmbaseWeb of Science and Cochrane Library databases ChineseNational Knowledge Infrastructure (CNKI) database Wan-fang database Chinese Biomedical (CBM) database Chi-nese Science and Technology Periodicals database (VIP)until September 30 2016 The following medical subjectheadings were used ldquoL-carnitinerdquo ldquocarnitinerdquo ldquolevocarni-tinerdquo ldquonovainrdquo ldquoL-cthernitinerdquo ldquoVitaminBTrdquo ldquoBicarnesinerdquoldquoheart failurerdquo ldquocardiac dysfunctionrdquo ldquocardiac insufficiencyrdquoldquocardiac inadequacyrdquo ldquocardiomyopathyrdquo and ldquoventriculardysfunctionrdquo Electronic searches were supplemented withmanual searches of reference lists of all retrieved reviewarticles primary studies and abstracts from meetings toidentify other studies not found in the electronic searchesLiterature was searched by two authors (X Song and Z Yang)independently The search was limited to human subjectswith no restriction for language

22 Study Selection Two authors independently selectedtrials and discussed with each other when inconsistencieswere found Articles that meet the following criteria wereincluded (1) study types randomized controlled trials (2)participants chronic heart failure patients (age ge 18 years)(3) interventions L-C with placebo routine or conventionaltreatment (4) outcome measures studies that used one ormore of the following measurements were eligible all-causemortality cardiovascular events NewYorkHeart Association(NYHA) classification overall efficacy exercise capacity (ie6-minute walk) changes in cardiac function parameters(ie left ventricular ejection fraction (LVEF) strike volume(SV) cardiac output (CO) EA left ventricular end-systolicdimension (LVESD) left ventricular end-diastolic dimen-sion (LVEDD) and left ventricular end-systolic volume(LVESV)) brain natriuretic peptide (BNP) N-terminal pro-brain natriuretic peptide (NT-proBNP) and adverse events(5) Full texts available Studies without randomized methodfrom CNKI CBM and VIP were excluded Studies thatincluded other nutritional supplements (ie trimetazidinecoenzyme Q10) were excluded Nonrandomized evaluationspharmacokinetic studies animallaboratory studies and gen-eral reviews were excluded and duplicated publicationsreporting the same groups of patients were also excluded(Figure S1 in Supplementary Material available online athttpsdoiorg10115520176274854)

23 Quality Assessment The methodological qualities ofthe included RCTs were assessed according to CochraneCollaborationrsquos tool described inHandbook version 510 [10]Two authors (X Song and Z Yang) assessed the qualityindependently and inconsistency was discussed with a thirdreview author (H Zhou) who acted as an arbiter

24 Data Extraction Two researchers read the full textsindependently and extracted the following contents publi-cation data (first authorrsquos name year of publication) studycharacteristic (study design sample size follow-up durationinclusion criteria and endpoints) patient characteristics(age gender NYHA classification cardiac histology andLVEF) treatment protocol (L-C dose) and outcome mea-sures (all-cause mortality overall efficacy NYHA classifica-tion 6-minute walk LVEF SV CO EA LVEDD LVESDLVESV BNP NT-proBNP and adverse events) Authors werecontacted by e-mail for additional information if data wereunavailable

25 Statistical Methods Data were processed in accordancewith the Cochrane Handbook [10] Intervention effects wereexpressed with odds ratios (ORs) and associated 95 confi-dence intervals (CIs) for dichotomous data By contrast theeffects were expressed with mean differences and 95 CIsfor continuous data Statistical heterogeneity was measuredusing 1198682 statistic and 1198682 statistic with significance set at 1198682greater than 50 [11]

The fixed-effects model was first used for meta-analysesThe random-effects model was used in the presence ofheterogeneity Description analysis was performed whenthe quantitative data could not be pooled Intention-to-treat (ITT) principle was used Review Manage (v51 theCochrane Collaboration) was used for data analysis

3 Results

31 Study and Patient Characteristics The flow of selectingstudies for the meta-analysis is shown in Figure S1 Brieflyamong the initial 2870 reports 468 articles were retrievedfor detailed evaluation and 17 RCTs [12ndash28] enrolling 1625participants that fulfilled the inclusion criteria were finallyanalyzed The study and patient characteristics are shown inTable 1 L-C dosage ranged from 15 to 6 gday and follow-upperiods from 7 days to 3 years

32 Methodological Quality Assessment All studies includedin this meta-analysis were randomized controlled trials Thequality assessment of the included RCTs is shown in Figure 1Four studies [12 13 21 26] did not report the method ofrandomization whereas the others reported a randomizationnumber sequence or adaptive minimization randomizationscheme There were three studies [13 17 26] using the blindmethod blind methods of all the other studies are unclearOne study [21] had high performance bias for the reason thatmore than 20 of patients were lost to follow-up Selectivereporting was found in three studies [13 21 26] becausethey did not present the ITT analysis data These studies had

BioMed Research International 3

Table1Ba

selin

echaracteristicso

fstudies

inclu

dedin

thismeta-analysis

Stud

yPatie

nt(L-C

con

trol)

Age

(mean

year)

(L-C

con

trol)

Male(119873)

(L-C

con

trol)

L-Cdo

se(gday)

Follo

w-up

duratio

nIschem

iccause()

NYH

Acla

ssLV

EF(m

ean

)

(L-C

con

trol)

Inclu

sioncriteria

Endp

oints

Gurlek2000

51(312

0)64

3662

2717

21m

onth

100

321332

378415

Ischem

iccardiomyopathy

LVEFred

cellsuperoxide

dism

utase

activ

ityadverse

events

Rizos2

000

80(4238)

5048

1920

2Th

reey

ears

0III-IV

2729

Dilatedcardiomyopathy

MortalityWeber

classificatio

nmaxim

altim

eofcardiop

ulmon

aryexercise

test

peak

VO2consum

ption

COadverse

events

Xi2006

60(3030)

6363

1816

314

days

42III-IV

3334

ChronicH

FEffi

cacy

ratedSV

COC

ILV

EFE

A

NYH

Acla

ssadverse

events

Chen

2009

62(313

1)685708

2022

310

days

35III-IV

3433

ChronicH

FEffi

cacy

ratedNYH

Acla

ssLVEF

LVES

DLVES

V

Lin2009

70(3535)

43ndash7842ndash76

1819

320

weeks

20III-IV

356367

Chronics

ystolic

HFLV

EFle40

Effi

cacy

ratedNYH

Acla

ssB

NPLV

EF

LVED

DLVES

Dadverse

events

Serati2010

60(2931)

5558

87

153mon

ths

NA

IINA

NYH

AIILVEFgt45

mild

diastolic

dysfu

nctio

nEcho

cardiographicp

aram

eters(ieE

AE1015840 EA)

Ding2012

136(6868)

7574

4140

214

days

NA

III-IV

3738

Chronicc

ongestive

HF

MortalityLV

EDDLVEFN

T-proB

NP

Cheng2013

120(6060)

579701

3436

315

days

31III-IV

3435

ChronicH

FEffi

cacy

ratedNYH

Acla

ssLVED

D

LVES

DLVES

VLV

EFN

T-proB

NPScr

Cysc

Pan2014

86(4343)

673689

2925

214

days

NA

NA

NA

ChronicH

FEffi

cacy

ratedNYH

Acla

ssB

NP

120573-end

orph

inadverse

events

Nish

imura

2015

72(3636)

643647

1414

11y

ear

NA

IV5253

Chronich

emod

ialysis

with

HFneedingho

spita

lization

Mortalityserum

carnitine

levelBN

PLV

EFE

ALVMIBM

IPP

Ding2015

69(3534)

642645

2523

314

days

100

IIndashIV

NA

ChronicH

Fstableisc

hemic

heartfailure

Efficacy

ratedNYH

Acla

ssN

T-proB

NP

Gao

2015

136(6868)

61ndash7562ndash76

4544

31y

ear

100

III-IV

35433610

ChronicH

Fstableisc

hemic

heartfailure

Mortalityeffi

cacy

ratedNYH

Aclass

NT-proB

NP6-minutew

alkLV

EFSV

COadverse

events

Ma2

015

72(3636)

55835602

2120

214

days

25III-IV

4412

4374

ChronicH

FCR

SEffi

cacy

ratedNYH

Acla

ss

LVEFSVCO

EA

ScrB

UNC

ysc

adversee

vents

Zhang2015

96(4848)

459472

3334

37days

583

III-IV

373362

CRSwith

outh

emod

ialysis

Efficacy

ratedNYH

Acla

ssLVEF

LVED

DLVES

DScrB

UNadverse

events

Jing2016

261(133128)

519524

8470

67days

NA

IIndashIV

4112

4039

ChronicH

FNYH

AII-IV

Efficacy

ratedNYH

Acla

ssLVEF

NT-proB

NP6-minutew

alkserum

carnitine

levels

adversee

vents

Wu2016

100(5050)

74227370

2628

215

days

NA

III-IV

353110

ChronicH

Fwith

Diabetes

Efficacy

ratedNYH

Acla

ssFPG

TC

LVEFC

OE

A

Zhang2016

94(4747)

563583

2729

315

days

NA

III-IV

NA

ChronicH

FEffi

cacy

ratedNYH

Acla

ssLVED

D

LVES

Dadverse

events

L-C

L-carnitineH

FheartfailureSV

strikevolumeCO

cardiac

outputC

IcardiacindexBN

Pbrainnatriuretic

peptideNT-proB

NP

N-te

rminalpro-brainnatriuretic

peptideLV

EFleft

ventric

leejectio

nfractio

nmitralE

peak

velocity

oftheearly

fillin

gwaveof

thetransm

itralflo

wm

itralAp

eakvelocity

oftheatria

lfilling

waveof

thetransm

itralflo

wE

Am

itralEALVED

Dleft

ventric

ular

end-diastolic

dimensio

nLV

ESDleft

ventric

ular

end-systo

licdimensio

nLV

ESV

leftventric

ular

end-systo

licvolumeLV

MILeftventric

ular

massindex

NYH

AN

ewYo

rkHeartAssociatio

nCR

Scardiorenalsyn

drom

eBM

IPP

I-120573-m

ethylio

doph

enylpentadecanoica

cidFP

Gfastin

gbloo

dglucoseTC

totalcholesterolScrserum

creatin

ineBU

Nblood

urea

nitro

gen

Cysccystatin

cNAn

otavailable


Random sequence generation (selection bias)

Allocation concealment (selection bias)

Blinding of participants and personnel (performance bias)

Blinding of outcome assessment (detection bias)

Incomplete outcome data (attrition bias)

Selective reporting (reporting bias)

Other bias

Low risk of biasUnclear risk of biasHigh risk of bias

25 50()

75 1000

(a) Risk of bias graph review authorsrsquo judgements about each risk of bias item presented as percentages acrossall included studies

Chen

g an

d Ta

ng 2

013

Chen

and

Ye 2

009

Din

g an

d H

u 20

12

Din

g an

d Fe

ng 2

015

Gao

201

5

Guumlr

lek

et al

200

0

Jing

et al

201

6

Lin

et al

200

9

Ma e

t al

2015

Nish

imur

a et a

l 20

15

Pan

2014

Rizo

s 200

0

Sera

ti et

al 2

010

Wu

2016

Xi et

al 2

006

Zhan

g 20

16

Zhan

g et

al 2

015







Other bias

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+++

++

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

++

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

minusminus minusminus

(b) Risk of bias summary review authorsrsquo judgements about each risk of bias item for each included study

Figure 1 Risk of bias assessment

high performance bias and detection biasThe other potentialbiases were unclear in these trials (Figure 2) Because most ofthe studies were conducted in China we cautiously drew theconclusion that publication bias might have been present inthe meta-analysis The differences of treatment period wouldinfluence the outcomes of chronic heart failure patients Eightstudies [14 18ndash20 22 24 27 28] had a treatment period of 2weeks and the follow-up period of other studies still rangedvariously In this conditionwe conducted a subgroup analysisin these studies with 2 -week treatment period (Figure S3)

33 All-Cause Mortality for Cardiac Causes Four studies [1318 21 23] reported all-cause mortality As shown in Figure 2no significant differences were found in heterogeneity in bothper-protocol (PP) and ITT analysis (1198682 = 6 119875 = 036and 1198682 = 7 119875 = 036 resp) The results of PP analysisshowed that all-cause mortality in the L-C group was notlower than control (OR = 048 95 CI 021 to 106 119875 =007 Figure 2(a)) ITT analysis also showed no differences inall-cause mortality between heart failure patients in both

groups (OR = 049 95 CI 022 to 108 119875 = 008Figure 2(b))

34 Functional Capacity The improvement in cardiac func-tion (decreasedNYHA class) was rated as overall efficacyTheendpoint was a decrease of at least one NYHA class withefficacy rated as effective (decrease of two classes decreaseof one class) or ineffective (no class change) The overallefficacy consisted of excellent and effective rate Twelvestudies [14ndash16 19 20 22ndash28] reported overall efficacy therewere no significant differences in heterogeneity (1198682 = 0119875 = 045) Meta-analysis indicated that patients who receivedL-C treatment had higher overall efficacy than those incontrol group (OR = 347 95 CI 249 to 482 119875 lt 001Figure 3(a)) Subgroup analysis of 2-week treatment periodalso demonstrated that overall efficacy of L-C treatmentwas higher than the control group (OR = 511 95 CI287 to 910 119875 lt 001 Figure S3) Considering significantheterogeneity between studies [23 26] when we compareddifference values about Δ6-minute walk meta-analysis with


L-Carnitine ControlEvents Total Events Total

3 68 4 6868 4 68

5 32 5 31Nishimura et al 2015 Rizos 2000 1

1

37 6 33

200Total (95 CI) 205 Total events 10 19

Odds ratio Odds ratioWeight

210216235339

074 [016 343]024 [003 219]096 [025 372]013 [001 110]

1000 048 [021 106]

Favours L-carnitine 01 10 1 100 001

Favours control

Study or subgroup

Ding and Hu 2012Gao 2015

M-H fixed 95 CIM-H fixed 95 CI

Heterogeneity 1205942 = 318 df = 3 (P = 036) I2 = 6

Test for overall effect Z = 182 (P = 007)

(a) PP analysis

3

51

1

Total events

68 4 6868 4 6836 5 3642 6 38

21021410 19

210216236338

074 [016 343]024 [003 219]100 [026 380]013 [001 114]

1000 049 [022 108]


Favours control

Nishimura et al 2015 Rizos 2000

Total (95 CI)



Odds ratio Odds ratioWeightStudy or subgroup M-H fixed 95 CIM-H fixed 95 CI



(b) ITT analysis

Figure 2 Forest plots for all-cause mortality

random-effect model revealed that there were no significantdifferences in improvement of exercise tolerance between thetwo treatments (WMD 4541m 95 CI minus1446 to 10529119875 = 014 Figure 3(b))

35 Serum Markers Heterogeneity was significant amongthe included studies [16 18ndash23 26] in which there werechanges in serum levels of BNP and NT-proBNP (1198682 = 97119875 lt 001 and 1198682 = 99 119875 lt 001 resp) Thus a random-effects model was applied we found that in serum levels ofBNP and NT-proBNP were significantly decreased in the L-C group compared with those in the control group (WMDminus12460 pgml 95 CI minus22049 to minus2871 119875 = 001 WMDminus51036 pgml 95 CI minus78542 to minus23530 119875 lt 001resp Figure 4) Subgroup analysis indicated that levels ofNT-proBNP were significantly decreased in the L-C group(WMD minus61244 pgml 95 CI minus82941 to minus39547 119875 lt 001Figure S3)

36 Left Ventricular Structure and Function Twelve stud-ies [12 14ndash16 18 19 21 23ndash27] provided data on LVEFconsidering that significant heterogeneity was found amongthe included studies (1198682 = 70 119875 lt 001) we used arandom-effect model and a profound improvement in LVEFwas observed in patients who received L-C therapy (WMD414 95 CI 234 to 593 119875 = 001 Figure 5(a)) As shownin Figures 5(b) and 5(c) no significant differences were foundin heterogeneity in both SV [14 23 24] andCO [14 23 24 27]analysis (1198682 = 0 119875 = 074 and 1198682 = 0 119875 = 065 resp)

SV and COwere significantly higher in patients who receivedL-C therapy than control group (WMD 821ml 95 CI641 to 1001 119875 = 001 WMD 088 Lmin 95 CI 076 to101 119875 lt 001 resp Figures 5(b) and 5(c)) Heterogeneitywas significant among the studies [14 17 21 24 27] whencomparing EA (1198682 = 82 119875 lt 001) Thus a random-effects model was used Our data revealed that EA wassignificantly higher for patients who received L-C treatment(WMD 023 95 CI 011 to 035 119875 lt 001 Figure 5(d)) Inaddition our results indicated that L-C was associated witha significant drop in LVESD [15 16 19 25 28] and LVEDD[16 18 19 25 28] for patients (WMD minus406mm 95 CIminus657 to minus155 119875 lt 001 WMD minus479mm 95 CI minus708 tominus249 119875 lt 001 resp Figures 6(a) and 6(b)) We also foundthat LVESV [15 19] was significantly decreased in responseto L-C therapy (WMD minus2016ml 95 CI minus3565 to minus467119875 lt 001 Figure 6(c)) According to subgroup analysis of2-week treatment period statistically significant associationwas found between LVEF SV CO EA LVESD and LVEDD(WMD 663 95CI 478 to 847119875 lt 001WMD 928ml95 CI 590 to 1267 119875 lt 001 WMD 090 Lmin 95 CI078 to 103 119875 lt 001 WMD 031 95 CI 016 to 046119875 lt 001 WMD minus650mm 95CI minus811 to minus489 119875 lt 001WMD minus324mm 95 CI minus593 to minus055 119875 lt 001 respFigure S3)

37 Major Adverse Events Six studies [12 14 16 24 25 28]reported that there were no adverse events related to L-CFour reports [13 20 23 26] contained data on specific adverse


30 31 29 31Chen and Ye 2009Cheng and Tang 2013 57 60 50 60

34 35 28 3465 68 57 68

Ding and Feng 2015Gao 2015Jing et al 2016 78 128 51 114

31 35 23 3533 36 27 3641 43 35 4349 50 36 5026 30 20 3045 47 38 47

Lin et al 2009 Ma et al 2015 Pan 2014Wu 2016Xi et al 2006 Zhang 2016 Zhang et al 2015 45 48 30 48

611 596534 424

23612061

511645539

207 [018 2407]380 [099 1458]729 [083 6415]418 [111 1573]193 [115 322]

404 [115 1416]367 [090 1490]469 [093 2353]

17 1906 [240 15160]653945

325 [089 1190]533 [108 2618]900 [244 3324]

1000 347 [249 482]



Total (95 CI)Total events


Test for overall effect Z = 740 (P lt 000001) Favours control 100 001 10 01 1

Favours L-carnitine

(a) Overall efficacy

L-Carnitine ControlMean SD Mean SD1391 376 68 632 429 68 501Gao 2015

Jing et al 2016 612 612 120 464 512 107 4997590 [6234 8946]1480 [017 2943]

188 175 1000

Mean differenceTotal Total

WeightStudy or subgroupIV random 95 CI

Mean differenceIV random 95 CI

Total (95 CI) 4541 [minus1446 10529]


Heterogeneity 1205912 = 181482 1205942 = 3605 df = 1 (P lt 000001) I2 = 97

Favours control minus100 minus50 100 50 0

Favours L-carnitine

(b) Δ 6-minute walk exercise

Figure 3 Forest plots for functional capacity

1276 227 35 3392 278 4193602 4403 27 3101 1688 26

35172Nishimura et al 2015

Pan 2014

Lin et al 2009

23704 6054 43 34585 5825 43 410

105 104 1000

L-Carnitine ControlMean SD Mean SD




Favours L-carnitine Favours control0 250 minus250minus500 500

Total (95 CI)Heterogeneity 1205912 = 567865 1205942 = 5968 df = 2 (P lt 000001) I2 = 97


minus12460 [minus22049 2871]

minus10881 [minus13392 minus8370]

5010 [minus12820 22840]


(a) BNP

6060Cheng and Tang 2013 10860 1540 10Ding and Hu 2012 21027 8837 68 29135 8329

24968 196

Ding and Feng 2015 79775 11403 35 122082 11236 34 247Gao 2015 4482 11702 68 6542 14014 68Jing et al 2016 18295 34932 128 22725 41313 114

24861

359 344 1000





Favours L-carnitineminus250minus500 0 250 500

Favours control




minus44300 [minus141323 52723]





(b) NT-proBNP

Figure 4 Forest plots for serum markers


45 10 31 11 3141 6250 21 60 38 19 60 4246 8 68 40 11 68 92

4826 532 68 4429 566 68 116

1200 [483 1917]600 [277 923]397 [212 582]

423 89 31 438 83 20 68441 83 128 449 86 114 111428 58 35 384 31 35 110

6288 716 36 5631 801 36 88537 95 27 519 6 26 7648 12 50 40 10 50 7545 9 30 41 10 30 68

Chen and Ye 2009Cheng and Tang 2013Ding and Hu 2012Gao 2015Guumlrlek et al 2000Jing et al 2016Lin et al 2009Ma et al 2015Nishimura et al 2015Wu 2016Xi et al 2006Zhang et al 2015 528 82 48 475 79 48 93

440 [222 658]657 [306 1008]

800 [367 1233]

530 [208 852]

612 586 1000 414 [234 593]





Favours L-carnitineminus10minus20 10 200

Favours control

Total (95 CI)

400 [minus081 881]

180 [minus246 606]

minus080 [minus294 134]minus150 [minus630 330]

400 [minus123 923]

Heterogeneity 1205912 = 635 1205942 = 3723 df = 11 (P = 00001) I2 = 70

Test for overall effect Z = 452 (P lt 000001)

(a) LVEF

6634 677 68 58567105 1364 36 6111

Gao 2015Ma et al 2015Xi et al 2006 56 8 30 47

134

5851301

8

68 717 778 [565 991]36 85 994 [378 1610]30 198 900 [495 1305]

134 1000 821 [641 1001]



WeightStudy or subgroupIV fixed 95 CI

Mean differenceIV fixed 95 CI

Favours controlminus50minus100 100500

Favours L-carnitine

Total (95 CI)Heterogeneity 1205942 = 061 df = 2 (P = 074) I2 = 0


(b) SV

Gao 2015Ma et al 2015Wu 2016Xi et al 2006

449 119 68 382 138 68 80533 035 441 022 36 819

5 13 42 11 50 6747 12

365030 4 14 30 34

067 [024 110]092 [078 106]080 [033 127]070 [004 136]

184 1000 088 [076 101]184






Favours control



(c) CO

104 012 36 082 013 36 26911 06 27 11 06 26 94

092 018 29 082 01 31 25914 04 50 097 023 50 218

Ma et al 2015Nishimura et al 2015Serati et al 2010Wu 2016Xi et al 2006 13 04 30 1 04 30 159

022 [016 028]

010 [003 017]043 [030 056]030 [010 050]

172 173 1000 023 [011 035]





Favours controlminus2minus4 2 40

Favours L-carnitine

Total (95 CI)Heterogeneity 1205912 = 001 1205942 = 2220 df = 4 (P = 00002) I2 = 82


000 [minus032 032]

(d) EA

Figure 5 Forest plots for left ventricular structure and function (I)


Chen and Ye 2009 4728 954 31 4435 797 31 149Cheng and Tang 2013 4238 814 60 4758 789 60 201Lin et al 2009 407 76 35 461 93 35 162Zhang 2016 333 34 47 404 59 47 234Zhang et al 2015 421 3 48 457 32 48 255

221 221 1000







Total (95 CI) minus406 [minus657 minus155]

minus360 [minus484 minus236]minus710 [minus905 minus515]minus540 [minus938 minus142]minus520 [minus807 minus233]293 [minus145 731]


Favours control

(a) LVESD

Cheng and Tang 2013 5818 786 60 6201 779 60 186Ding and Hu 2012 673 81 68 679 75 68 192Lin et al 2009 533 63 35 618 47 35 193Zhang 2016 483 58 47 534 48 47 209Zhang et al 2015 476 52 48 533 38 48 221

258 258 1000





Favours L-carnitine



Total (95 CI)

minus570 [minus752 minus388]minus510 [minus725 minus295]minus850 [minus1110 minus590]minus060 [minus322 202]minus383 [minus663 minus103]


minus50 0 50 100minus100

Favours control

(b) LVEDD


91

40295699

31 446554

91 1000





Favours L-carnitine






Favours control

(c) LVESV

Figure 6 Forest plots for left ventricular structure and function (II)

events Dry mouth and gastrointestinal problems were themajor adverse events and rash was reported by a study of Pan[20] in both L-C group (443) and control group (243) Noparticipants have withdrawn from the study for the reason ofadverse events Meta-analysis demonstrated no differences inadverse events between patients in both groups (54 versus58 OR = 092 95 CI 044 to 192 119875 = 083 Figure S2)The other seven trials did not report adverse events

4 Discussion

L H Opie indicated that ldquothe heart is more than a pumpIt is also an organ that needs energy from metabolism Ametabolic disease ischaemia should ideally be treated bymetabolic therapyrdquo [29] CHF is currently conceived as asystemic and multiorgan syndrome with metabolic failure asbasic mechanism In fact the failing heart may be definedas ldquoan engine out of fuelrdquo [5] L-C is a natural constituentof human cells and participates in fatty acid metabolismL-C plays an important role in lipid metabolism by actingas an obligatory cofactor for oxidation of fatty acids and

facilitating the transport of long-chain fatty acids (LCFAs)across the mitochondrial membrane to provide enoughadenosine triphosphate (ATP) for myocardial cells [30]

Although heart failure is not listed as one of indications inpackage insert of L-C clinical application of L-C has shownsignificant relief of heart failure which was confirmed in ourresearch

Recently DiNicolantonio et al (2013) [9] conducted ameta-analysis of L-C in the secondary prevention of cardio-vascular disease Compared with placebo L-C was associatedwith a 27 reduction in all-cause mortality a 65 reductionin ventricular arrhythmias and a 40 reduction in angina inpatients experiencing an acute myocardial infarction (AMI)However our study suggests that the additional use of L-Cfailed to reduce all-cause mortality in CHF patients

Chronic oral L-C supplementation has been shownto ameliorate factors associated with metabolic syndromeand cardiovascular disease such as arterial hypertensioncholesterol levels impaired glucose tolerance and insulinresistance L-C appears to be particularly suitable as a treat-ment for metabolic syndrome patients who are often obese


insulin resistant and hypertensive [31ndash33] One includedstudy [27] suggested that L-C can significantly amelioratetotal cholesterol blood sugar and cardiac function andimprove clinical symptoms of patients for heart failurepatients with diabetes mellitus

Our findings of this meta-analysis are that the beneficialeffects have been shown by the increase of overall efficacyLVEF strike volume cardiac output and EA by the decreaseof left ventricular end-diastolic diameter left ventricular end-systolic diameter and left ventricular end-systolic volumeand serum levels of BNP and NT-proBNP and with sat-isfactory safety Some reports [21 24 25] indicated thatclinical symptom cardiac function and renal function inCHF patients with renal insufficiency were more likely to beameliorated with L-C treatment

According to the ldquoenergy starvationrdquo hypothesis whichinduces that insufficient ATP supply underlies the contrac-tile dysfunction presenting in heart failure [34] it seemsreasonable that L-C improves energy metabolism in car-diomyocytes which may finally translate into mechanicalefficiency and contribute to the improvement of clinicalsymptoms and cardiac function Furthermore noteworthy isthat L-C exerts cardioprotective effects through alternativemechanisms such as oxidative stress [35] nitric oxide [36]arterial hypertension cardiac inflammation and fibrosis [37ndash39] and interstitial remodeling [40] as well as by improvingendothelial function [41]

It is noteworthy that based on existing conventionaltreatment L-C was used in treatment of energy metabolismdisorder It acted as a supplementation to preexisting treat-ment rather than a replacement Chronic heart failure is adisease that requiresmultitargeted andphase dependent ther-apeutic methods Our research showed that L-C representsa safe and effective adjuvant therapy which by increasinghigh energy phosphate for systolic and diastolic functionmay have a synergistic effect with other drugs

According to study relatively high degree of hetero-geneity was found regarding the following four indicesLVEF BNP NT-proBNP and 6-minute walking distanceThrough analyzing the included references we speculated thefollowing possible causes for the discrepancies (1) differentuses doses of L-C utilized in these studies (2) Different statesof illness and stages of therapies of patients included in thesestudies (3)Manufacturers and specifications of L-C being notclearly indicated in most of these studies

Some limitations of our meta-analysis need to beacknowledged Firstly themethodological quality of includedstudies was less than optimal so we were not able to excludethe potential risk of bias in these trials Secondly it is worthnoticing that only 1625 patients were involved in the 17 RCTswhich justifies the performance of more large-scale RCTs forevaluating the impact of L-C treatment on CHF patientsThirdly the follow-up duration in these studies varied widelyfrom 7 days to 3 years Owing to these limitations ourresults are insufficient to recommend the method as afirst-line treatment or to establish the quality of life andlong-term results Therefore further research is requiredto more accurately assess the results of L-C for treatingCHF

In conclusion our meta-analysis demonstrates that L-Ctreatment in CHF patients may improve clinical symptomsand cardiac function and decrease serum levels of BNP andNT-proBNP and has good tolerance

Abbreviations

L-C L-CarnitineCHF Chronic heart failureNYHA New York Heart AssociationBNP Brain natriuretic peptideNT-proBNP N-terminal pro-brain natriuretic peptideLVEF Left ventricle ejection fractionLVEDD Left ventricular end-diastolic dimensionLVESD Left ventricular end-systolic dimensionLVESV Left ventricular end-systolic volumemitral E Peak velocity of the early filling wave of

the transmitral flowmitral A Peak velocity of the atrial filling wave of

the transmitral flowEA Mitral EACI Confidence intervalWMD Weighted mean differences

Disclosure

The funders had no role in study design data collectionand analysis decision to publish or preparation of themanuscript

Conflicts of Interest

The authors declare that they have no competing interests

Acknowledgments

This work was partly supported by the National NaturalScience Foundation of China (Research Grants no 81673753and no 81373625 to H Zhou)

References

[1] A P Ambrosy G C Fonarow J Butler et al ldquoThe globalhealth and economic burden of hospitalizations for heart fail-ure lessons learned from hospitalized heart failure registriesrdquoJournal of the American College of Cardiology vol 63 no 12 pp1123ndash1133 2014

[2] J Spinar J Hradec L Spinarova and J Vıtovec ldquoSummaryof the 2016 ESC Guidelines on the diagnosis and treatment ofacute and chronic heart failure Prepared by the Czech Societyof Cardiologyrdquo Cor et Vasa vol 58 no 5 pp e530ndashe568 2016

[3] C W Yancy M Jessup B Bozkurt et al ldquo2013 ACCFAHAguideline for the management of heart failure executivesummary a report of the American college of cardiologyfoundationAmerican Heart Association task force on practiceguidelinesrdquo Circulation vol 128 no 16 pp 1810ndash1852 2013

[4] WDoehnerM Frenneaux and SDAnker ldquoMetabolic impair-ment in heart failure the myocardial and systemic perspectiverdquo


Journal of the American College of Cardiology vol 64 no 13 pp1388ndash1400 2014

[5] S Neubauer ldquoThe failing heartmdashan engine out of fuelrdquo NewEngland Journal of Medicine vol 356 no 11 pp 1140ndash1151 2007

[6] R Ferrari E Merli G Cicchitelli D Mele A Fucili and CCeconi ldquoTherapeutic effects of L-carnitine and propionyl-L-carnitine on cardiovascular diseases a reviewrdquo Annals of theNew York Academy of Sciences vol 1033 pp 79ndash91 2004

[7] Chinese Society of Cardiology of Chinese Medical AssociationldquoEditorial Board of Chinese Journal of Cardiology Guidelinesfor the diagnosis andmanagement of chronic heart failure 2014rdquoChinese Journal of Cardiology vol 42 no 2 pp 98ndash122 2014(Chinese)

[8] R Shang Z Sun and H Li ldquoEffective dosing of l-carnitine inthe secondary prevention of cardiovascular disease a systematicreview and meta-analysisrdquo BMC Cardiovascular Disorders vol14 pp 88ndash96 2014

[9] J J DiNicolantonio C J Lavie H Fares A R Menezes andJ H OrsquoKeefe ldquoL-carnitine in the secondary prevention ofcardiovascular disease systematic review and meta-analysisrdquoMayo Clinic Proceedings vol 88 no 6 pp 544ndash551 2013

[10] J P T Higgins and S Green Eds Cochrane Handbook forSystematic Reviews of Interventions Version 510 The CochraneCollaboration 2011 httphandbookcochraneorg

[11] J P T Higgins and S GThompson ldquoQuantifying heterogeneityin ameta-analysisrdquo Statistics inMedicine vol 21 no 11 pp 1539ndash1558 2002

[12] A Gurlek E Tutar E Akcil et al ldquoThe effects of L-carnitinetreatment on left ventricular function and erythrocyte superox-ide dismutase activity in patients with ischemic cardiomyopa-thyrdquo European Journal of Heart Failure vol 2 no 2 pp 189ndash1932000

[13] I Rizos ldquoThree-year survival of patients with heart failurecaused by dilated cardiomyopathy and L-carnitine administra-tionrdquo American Heart Journal vol 139 no 2 pp S120ndashS1232000

[14] H Xi W Liang J Wu and Z Tan ldquoClinical research ofL-carnitine treatment on chronic congestive heart failurerdquoPractical Journal of Cardiac Cerebral Pneumal and VascularDisease vol 14 no 9 pp 714ndash715 2006 (Chinese)

[15] L Chen and W Ye ldquoClinical research of L-carnitine treatmenton sixty-two patients with chronic congestive heart failurerdquoChina Foreign Medical Treatment vol 22 article 47 2009(Chinese)

[16] C Lin J Li J Tang and P Yang ldquoEffects of levocarnitine amongpatients with chronic heart failurerdquoZhejiang PracticalMedicinevol 14 no 2 pp 109ndash110 2009 (Chinese)

[17] A R Serati M R Motamedi S Emami P Varedi and M RMovahed ldquoL-carnitine treatment in patients with mild dias-tolic heart failure is associated with improvement in diastolicfunction and symptomsrdquoCardiology vol 116 no 3 pp 178ndash1822010

[18] C Ding and X Hu ldquoThe effectiveness of L-carnitine treatmenton senile congestive heart failurerdquo Chinese Journal of Gerontol-ogy vol 32 no 13 pp 2881ndash2882 2012 (Chinese)

[19] L Cheng and X-F Tang ldquoInfluence of levocarnitine on heartfunction and endocrine among patients with heart failurerdquoChinese Journal of Epidemiology vol 34 no 6 pp 630ndash6322013

[20] X Pan ldquoClinical research of L-carnitine for elderly patients withchronic congestive heart failurerdquo Zhongguo Ji Ceng Yi Yao vol21 no 23 pp 3550ndash3552 2014 (Chinese)

[21] M Nishimura T Tokoro T Takatani et al ldquoEffects ofintravenous L-carnitine on myocardial fatty acid imaging inhemodialysis patients responders or non-responders to L-carnitinerdquo SpringerPlus vol 4 pp 353ndash362 2015

[22] J Ding and Q Feng ldquoThe efficiency assessment of intravenousL-carnitine on elderly patients with heart failure of coronaryheart diseaserdquoChinese Journal of ConvalescentMedicine vol 24no 7 pp 728ndash729 2015 (Chinese)

[23] L Gao ldquoClinical efficiencies of levocarnitine in the treatmentof ischemic cardiomyopathy heart failure and its effect onmyocardial cell functionrdquo Journal of Bengbu Medical Collegevol 40 no 12 pp 1643ndash1645 2015 (Chinese)

[24] J Ma X Zhou and X Li ldquoThe influence of L-carnitine onpatientsrsquo cardiac function and renal function with resultingfrom chronic heart failurerdquo Chinese Journal of Gerontology vol35 no 20 pp 5761ndash5762 2015 (Chinese)

[25] W Zhang Z Dai J Zhou et al ldquoClinical research of L-carnitine treatment on patients of cardiorenal syndrome with-out hemodialysisrdquoChinese Journal of Clinical RationalDrugUsevol 8 no 8C pp 61ndash62 2015 (Chinese)

[26] Z-C Jing B-X Wu J-Q Peng et al ldquoEffect of intravenousl-carnitine in Chinese patients with chronic heart failurerdquoEuropeanHeart Journal Supplement vol 18 pp A27ndashA36 2016

[27] WWu ldquoThe clinical effects of intravenous L-carnitine in elderlypatients with heart failure of diabetesrdquo Xin Xue Guan Bing FangZhi Zhi Shi vol 6 pp 84ndash85 2016 (Chinese)

[28] K Zhang ldquoClinical effects and safety of intravenous L-carnitinetreatment on patients of chronic heart failurerdquo Guide of ChinaMedicine vol 14 no 4 pp 153ndash154 2016 (Chinese)

[29] L H Opie ldquoProof that glucose-insulin-potassium providesmetabolic protection of ischaemic myocardiumrdquo Lancet vol353 no 9155 pp 768ndash769 1999

[30] A P Wong A Niedzwiecki and M Rath ldquoMyocardial ener-getics and the role of micronutrients in heart failure a criticalreviewrdquo American Journal of Cardiovascular Disease vol 6 no3 pp 81ndash92 2016

[31] Z T Bloomgarden ldquoObesity hypertension and insulin resis-tancerdquo Diabetes Care vol 25 no 11 pp 2088ndash2097 2002

[32] R H Eckel K Alberti S M Grundy and P Z Zimmet ldquoThemetabolic syndromerdquoThe Lancet vol 375 no 9710 pp 181ndash1832010

[33] R A DeFronzo ldquoPathogenesis of type 2 diabetes mellitusrdquoMedical Clinics of North America vol 88 no 4 pp 787ndash8352004

[34] A M Katz ldquoIs the failing heart energy depletedrdquo CardiologyClinics vol 16 no 4 pp 633ndash644 1998

[35] J L Flanagan P A Simmons J Vehige M D Willcox andQ Garrett ldquoRole of carnitine in diseaserdquo Nutrition andMetabolism vol 7 article 30 2010

[36] A Koc T Ozkan A Z Karabay A Sunguroglu and F AktanldquoEffect of L-carnitine on the synthesis of nitric oxide in RAW264sdot7 murine macrophage cell linerdquo Cell Biochemistry andFunction vol 29 no 8 pp 679ndash685 2011

[37] A J Blanca M V Ruiz-Armenta S Zambrano et al ldquoInflam-matory and fibrotic processes are involved in the cardiotoxiceffect of sunitinib protective role of L-carnitinerdquo ToxicologyLetters vol 241 pp 9ndash18 2016

[38] S Zambrano A J Blanca M V Ruiz-Armenta et al ldquoL-carnitine protects against arterial hypertension-related cardiacfibrosis through modulation of PPAR-120574 expressionrdquo Biochemi-cal Pharmacology vol 85 no 7 pp 937ndash944 2013


[39] Y Omori T Ohtani Y Sakata et al ldquoL-Carnitine preventsthe development of ventricular fibrosis and heart failure withpreserved ejection fraction in hypertensive heart diseaserdquoJournal of Hypertension vol 30 no 9 pp 1834ndash1844 2012

[40] A Orlandi A Francesconi A Ferlosio et al ldquoPropionyl-L-carnitine prevents age-related myocardial remodeling in therabbitrdquo Journal of Cardiovascular Pharmacology vol 50 no 2pp 168ndash175 2007

[41] S G Dzugkoev I V Mozhaeva M A Otiev O I Margievaand F S Dzugkoeva ldquoEffect of L-carnitine afobazole and theircombination with L-arginine on biochemical and histologicalindices of endothelial dysfunctions in cobalt intoxication inratsrdquo Patologicheskaia fiziologiia i eksperimentalrsquonaia terapiiavol 59 no 2 pp 70ndash75 2015

Submit your manuscripts athttpswwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



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OphthalmologyJournal of


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Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


of nutritional supplements has not been proposed in theEuropean guideline [2]

In addition two meta-analyses of RCTs has been per-formed to assess the therapeutic effects of L-C in the sec-ondary prevention of cardiovascular disease [8 9] but thereis no meta-analysis of RCTs in CHF Over the past fewdecades several small RCTs have been conducted to evaluatethe effects of L-C treatment in patients with CHF Thus weperformed ameta-analysis of RCTswith critical inclusion andexclusion criteria to evaluate the efficacy and tolerance of L-C

2 Materials and Methods

21 Search Strategy We searched Pubmed Ovid EmbaseWeb of Science and Cochrane Library databases ChineseNational Knowledge Infrastructure (CNKI) database Wan-fang database Chinese Biomedical (CBM) database Chi-nese Science and Technology Periodicals database (VIP)until September 30 2016 The following medical subjectheadings were used ldquoL-carnitinerdquo ldquocarnitinerdquo ldquolevocarni-tinerdquo ldquonovainrdquo ldquoL-cthernitinerdquo ldquoVitaminBTrdquo ldquoBicarnesinerdquoldquoheart failurerdquo ldquocardiac dysfunctionrdquo ldquocardiac insufficiencyrdquoldquocardiac inadequacyrdquo ldquocardiomyopathyrdquo and ldquoventriculardysfunctionrdquo Electronic searches were supplemented withmanual searches of reference lists of all retrieved reviewarticles primary studies and abstracts from meetings toidentify other studies not found in the electronic searchesLiterature was searched by two authors (X Song and Z Yang)independently The search was limited to human subjectswith no restriction for language

22 Study Selection Two authors independently selectedtrials and discussed with each other when inconsistencieswere found Articles that meet the following criteria wereincluded (1) study types randomized controlled trials (2)participants chronic heart failure patients (age ge 18 years)(3) interventions L-C with placebo routine or conventionaltreatment (4) outcome measures studies that used one ormore of the following measurements were eligible all-causemortality cardiovascular events NewYorkHeart Association(NYHA) classification overall efficacy exercise capacity (ie6-minute walk) changes in cardiac function parameters(ie left ventricular ejection fraction (LVEF) strike volume(SV) cardiac output (CO) EA left ventricular end-systolicdimension (LVESD) left ventricular end-diastolic dimen-sion (LVEDD) and left ventricular end-systolic volume(LVESV)) brain natriuretic peptide (BNP) N-terminal pro-brain natriuretic peptide (NT-proBNP) and adverse events(5) Full texts available Studies without randomized methodfrom CNKI CBM and VIP were excluded Studies thatincluded other nutritional supplements (ie trimetazidinecoenzyme Q10) were excluded Nonrandomized evaluationspharmacokinetic studies animallaboratory studies and gen-eral reviews were excluded and duplicated publicationsreporting the same groups of patients were also excluded(Figure S1 in Supplementary Material available online athttpsdoiorg10115520176274854)

23 Quality Assessment The methodological qualities ofthe included RCTs were assessed according to CochraneCollaborationrsquos tool described inHandbook version 510 [10]Two authors (X Song and Z Yang) assessed the qualityindependently and inconsistency was discussed with a thirdreview author (H Zhou) who acted as an arbiter

24 Data Extraction Two researchers read the full textsindependently and extracted the following contents publi-cation data (first authorrsquos name year of publication) studycharacteristic (study design sample size follow-up durationinclusion criteria and endpoints) patient characteristics(age gender NYHA classification cardiac histology andLVEF) treatment protocol (L-C dose) and outcome mea-sures (all-cause mortality overall efficacy NYHA classifica-tion 6-minute walk LVEF SV CO EA LVEDD LVESDLVESV BNP NT-proBNP and adverse events) Authors werecontacted by e-mail for additional information if data wereunavailable

25 Statistical Methods Data were processed in accordancewith the Cochrane Handbook [10] Intervention effects wereexpressed with odds ratios (ORs) and associated 95 confi-dence intervals (CIs) for dichotomous data By contrast theeffects were expressed with mean differences and 95 CIsfor continuous data Statistical heterogeneity was measuredusing 1198682 statistic and 1198682 statistic with significance set at 1198682greater than 50 [11]

The fixed-effects model was first used for meta-analysesThe random-effects model was used in the presence ofheterogeneity Description analysis was performed whenthe quantitative data could not be pooled Intention-to-treat (ITT) principle was used Review Manage (v51 theCochrane Collaboration) was used for data analysis

3 Results

31 Study and Patient Characteristics The flow of selectingstudies for the meta-analysis is shown in Figure S1 Brieflyamong the initial 2870 reports 468 articles were retrievedfor detailed evaluation and 17 RCTs [12ndash28] enrolling 1625participants that fulfilled the inclusion criteria were finallyanalyzed The study and patient characteristics are shown inTable 1 L-C dosage ranged from 15 to 6 gday and follow-upperiods from 7 days to 3 years

32 Methodological Quality Assessment All studies includedin this meta-analysis were randomized controlled trials Thequality assessment of the included RCTs is shown in Figure 1Four studies [12 13 21 26] did not report the method ofrandomization whereas the others reported a randomizationnumber sequence or adaptive minimization randomizationscheme There were three studies [13 17 26] using the blindmethod blind methods of all the other studies are unclearOne study [21] had high performance bias for the reason thatmore than 20 of patients were lost to follow-up Selectivereporting was found in three studies [13 21 26] becausethey did not present the ITT analysis data These studies had


Table1Ba

selin

echaracteristicso

fstudies

inclu

dedin

thismeta-analysis

Stud

yPatie

nt(L-C

con

trol)

Age

(mean

year)

(L-C

con

trol)

Male(119873)

(L-C

con

trol)

L-Cdo

se(gday)

Follo

w-up

duratio

nIschem

iccause()

NYH

Acla

ssLV

EF(m

ean

)

(L-C

con

trol)

Inclu

sioncriteria

Endp

oints

Gurlek2000

51(312

0)64

3662

2717

21m

onth

100

321332

378415

Ischem

iccardiomyopathy

LVEFred

cellsuperoxide

dism

utase

activ

ityadverse

events

Rizos2

000

80(4238)

5048

1920

2Th

reey

ears

0III-IV

2729


MortalityWeber

classificatio

nmaxim

altim

eofcardiop

ulmon

aryexercise

test

peak

VO2consum

ption

COadverse

events

Xi2006

60(3030)

6363

1816

314

days

42III-IV

3334

ChronicH

FEffi

cacy

ratedSV

COC

ILV

EFE

A

NYH

Acla

ssadverse

events

Chen

2009

62(313

1)685708

2022

310

days

35III-IV

3433

ChronicH

FEffi

cacy

ratedNYH

Acla

ssLVEF

LVES

DLVES

V

Lin2009

70(3535)

43ndash7842ndash76

1819

320

weeks

20III-IV

356367

Chronics

ystolic

HFLV

EFle40

Effi

cacy

ratedNYH

Acla

ssB

NPLV

EF

LVED

DLVES

Dadverse

events

Serati2010

60(2931)

5558

87

153mon

ths

NA

IINA

NYH

AIILVEFgt45

mild

diastolic

dysfu

nctio

nEcho

cardiographicp

aram

eters(ieE

AE1015840 EA)

Ding2012

136(6868)

7574

4140

214

days

NA

III-IV

3738

Chronicc

ongestive

HF

MortalityLV

EDDLVEFN

T-proB

NP

Cheng2013

120(6060)

579701

3436

315

days

31III-IV

3435

ChronicH

FEffi

cacy

ratedNYH

Acla

ssLVED

D

LVES

DLVES

VLV

EFN

T-proB

NPScr

Cysc

Pan2014

86(4343)

673689

2925

214

days

NA

NA

NA

ChronicH

FEffi

cacy

ratedNYH

Acla

ssB

NP

120573-end

orph

inadverse

events

Nish

imura

2015

72(3636)

643647

1414

11y

ear

NA

IV5253

Chronich

emod

ialysis

with

HFneedingho

spita

lization

Mortalityserum

carnitine

levelBN

PLV

EFE

ALVMIBM

IPP

Ding2015

69(3534)

642645

2523

314

days

100

IIndashIV

NA

ChronicH

Fstableisc

hemic

heartfailure

Efficacy

ratedNYH

Acla

ssN

T-proB

NP

Gao

2015

136(6868)

61ndash7562ndash76

4544

31y

ear

100

III-IV

35433610

ChronicH

Fstableisc

hemic

heartfailure

Mortalityeffi

cacy

ratedNYH

Aclass

NT-proB

NP6-minutew

alkLV

EFSV

COadverse

events

Ma2

015

72(3636)

55835602

2120

214

days

25III-IV

4412

4374

ChronicH

FCR

SEffi

cacy

ratedNYH

Acla

ss

LVEFSVCO

EA

ScrB

UNC

ysc

adversee

vents

Zhang2015

96(4848)

459472

3334

37days

583

III-IV

373362

CRSwith

outh

emod

ialysis

Efficacy

ratedNYH

Acla

ssLVEF

LVED

DLVES

DScrB

UNadverse

events

Jing2016

261(133128)

519524

8470

67days

NA

IIndashIV

4112

4039

ChronicH

FNYH

AII-IV

Efficacy

ratedNYH

Acla

ssLVEF

NT-proB

NP6-minutew

alkserum

carnitine

levels

adversee

vents

Wu2016

100(5050)

74227370

2628

215

days

NA

III-IV

353110

ChronicH

Fwith

Diabetes

Efficacy

ratedNYH

Acla

ssFPG

TC

LVEFC

OE

A

Zhang2016

94(4747)

563583

2729

315

days

NA

III-IV

NA

ChronicH

FEffi

cacy

ratedNYH

Acla

ssLVED

D

LVES

Dadverse

events

L-C

L-carnitineH

FheartfailureSV

strikevolumeCO

cardiac

outputC

IcardiacindexBN

Pbrainnatriuretic

peptideNT-proB

NP

N-te


peptideLV

EFleft

ventric

leejectio

nfractio

nmitralE

peak

velocity

oftheearly

fillin

gwaveof

thetransm

itralflo

wm

itralAp

eakvelocity

oftheatria

lfilling

waveof

thetransm

itralflo

wE

Am

itralEALVED

Dleft

ventric

ular

end-diastolic

dimensio

nLV

ESDleft

ventric

ular

end-systo

licdimensio

nLV

ESV

leftventric

ular

end-systo

licvolumeLV

MILeftventric

ular

massindex

NYH

AN

ewYo

rkHeartAssociatio

nCR

Scardiorenalsyn

drom

eBM

IPP

I-120573-m

ethylio

doph

enylpentadecanoica

cidFP

Gfastin

gbloo

dglucoseTC


creatin

ineBU

Nblood

urea

nitro

gen

Cysccystatin

cNAn

otavailable








Other bias


25 50()

75 1000


Chen

g an

d Ta

ng 2

013

Chen

and

Ye 2

009

Din

g an

d H

u 20

12

Din

g an

d Fe

ng 2

015

Gao

201

5

Guumlr

lek

et al

200

0

Jing

et al

201

6

Lin

et al

200

9

Ma e

t al

2015

Nish

imur

a et a

l 20

15

Pan

2014

Rizo

s 200

0

Sera

ti et

al 2

010

Wu

2016

Xi et

al 2

006

Zhan

g 20

16

Zhan

g et

al 2

015







Other bias

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+++

++

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

++

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+










3 68 4 6868 4 68


1

37 6 33



210216235339

074 [016 343]024 [003 219]096 [025 372]013 [001 110]

1000 048 [021 106]


Favours control

Study or subgroup





(a) PP analysis

3

51

1

Total events

68 4 6868 4 6836 5 3642 6 38

21021410 19

210216236338

074 [016 343]024 [003 219]100 [026 380]013 [001 114]

1000 049 [022 108]


Favours control


Total (95 CI)






(b) ITT analysis









34 35 28 3465 68 57 68


31 35 23 3533 36 27 3641 43 35 4349 50 36 5026 30 20 3045 47 38 47


611 596534 424

23612061

511645539

207 [018 2407]380 [099 1458]729 [083 6415]418 [111 1573]193 [115 322]

404 [115 1416]367 [090 1490]469 [093 2353]

17 1906 [240 15160]653945

325 [089 1190]533 [108 2618]900 [244 3324]

1000 347 [249 482]






Favours L-carnitine



Jing et al 2016 612 612 120 464 512 107 4997590 [6234 8946]1480 [017 2943]

188 175 1000




Total (95 CI) 4541 [minus1446 10529]




Favours L-carnitine



1276 227 35 3392 278 4193602 4403 27 3101 1688 26


Pan 2014

Lin et al 2009

23704 6054 43 34585 5825 43 410

105 104 1000








minus12460 [minus22049 2871]


5010 [minus12820 22840]


(a) BNP


24968 196


24861

359 344 1000






Favours control




minus44300 [minus141323 52723]





(b) NT-proBNP



45 10 31 11 3141 6250 21 60 38 19 60 4246 8 68 40 11 68 92

4826 532 68 4429 566 68 116

1200 [483 1917]600 [277 923]397 [212 582]

423 89 31 438 83 20 68441 83 128 449 86 114 111428 58 35 384 31 35 110

6288 716 36 5631 801 36 88537 95 27 519 6 26 7648 12 50 40 10 50 7545 9 30 41 10 30 68


440 [222 658]657 [306 1008]

800 [367 1233]

530 [208 852]

612 586 1000 414 [234 593]






Favours control

Total (95 CI)

400 [minus081 881]

180 [minus246 606]


400 [minus123 923]



(a) LVEF

6634 677 68 58567105 1364 36 6111


134

5851301

8

68 717 778 [565 991]36 85 994 [378 1610]30 198 900 [495 1305]

134 1000 821 [641 1001]






Favours L-carnitine



(b) SV


449 119 68 382 138 68 80533 035 441 022 36 819

5 13 42 11 50 6747 12

365030 4 14 30 34

067 [024 110]092 [078 106]080 [033 127]070 [004 136]

184 1000 088 [076 101]184






Favours control



(c) CO

104 012 36 082 013 36 26911 06 27 11 06 26 94

092 018 29 082 01 31 25914 04 50 097 023 50 218


022 [016 028]

010 [003 017]043 [030 056]030 [010 050]

172 173 1000 023 [011 035]






Favours L-carnitine



000 [minus032 032]

(d) EA




221 221 1000










Favours control

(a) LVESD


258 258 1000





Favours L-carnitine



Total (95 CI)




Favours control

(b) LVEDD


91

40295699

31 446554

91 1000





Favours L-carnitine






Favours control

(c) LVESV



4 Discussion














Abbreviations




Disclosure




Acknowledgments


References


















































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Table1Ba

selin

echaracteristicso

fstudies

inclu

dedin

thismeta-analysis

Stud

yPatie

nt(L-C

con

trol)

Age

(mean

year)

(L-C

con

trol)

Male(119873)

(L-C

con

trol)

L-Cdo

se(gday)

Follo

w-up

duratio

nIschem

iccause()

NYH

Acla

ssLV

EF(m

ean

)

(L-C

con

trol)

Inclu

sioncriteria

Endp

oints

Gurlek2000

51(312

0)64

3662

2717

21m

onth

100

321332

378415

Ischem

iccardiomyopathy

LVEFred

cellsuperoxide

dism

utase

activ

ityadverse

events

Rizos2

000

80(4238)

5048

1920

2Th

reey

ears

0III-IV

2729


MortalityWeber

classificatio

nmaxim

altim

eofcardiop

ulmon

aryexercise

test

peak

VO2consum

ption

COadverse

events

Xi2006

60(3030)

6363

1816

314

days

42III-IV

3334

ChronicH

FEffi

cacy

ratedSV

COC

ILV

EFE

A

NYH

Acla

ssadverse

events

Chen

2009

62(313

1)685708

2022

310

days

35III-IV

3433

ChronicH

FEffi

cacy

ratedNYH

Acla

ssLVEF

LVES

DLVES

V

Lin2009

70(3535)

43ndash7842ndash76

1819

320

weeks

20III-IV

356367

Chronics

ystolic

HFLV

EFle40

Effi

cacy

ratedNYH

Acla

ssB

NPLV

EF

LVED

DLVES

Dadverse

events

Serati2010

60(2931)

5558

87

153mon

ths

NA

IINA

NYH

AIILVEFgt45

mild

diastolic

dysfu

nctio

nEcho

cardiographicp

aram

eters(ieE

AE1015840 EA)

Ding2012

136(6868)

7574

4140

214

days

NA

III-IV

3738

Chronicc

ongestive

HF

MortalityLV

EDDLVEFN

T-proB

NP

Cheng2013

120(6060)

579701

3436

315

days

31III-IV

3435

ChronicH

FEffi

cacy

ratedNYH

Acla

ssLVED

D

LVES

DLVES

VLV

EFN

T-proB

NPScr

Cysc

Pan2014

86(4343)

673689

2925

214

days

NA

NA

NA

ChronicH

FEffi

cacy

ratedNYH

Acla

ssB

NP

120573-end

orph

inadverse

events

Nish

imura

2015

72(3636)

643647

1414

11y

ear

NA

IV5253

Chronich

emod

ialysis

with

HFneedingho

spita

lization

Mortalityserum

carnitine

levelBN

PLV

EFE

ALVMIBM

IPP

Ding2015

69(3534)

642645

2523

314

days

100

IIndashIV

NA

ChronicH

Fstableisc

hemic

heartfailure

Efficacy

ratedNYH

Acla

ssN

T-proB

NP

Gao

2015

136(6868)

61ndash7562ndash76

4544

31y

ear

100

III-IV

35433610

ChronicH

Fstableisc

hemic

heartfailure

Mortalityeffi

cacy

ratedNYH

Aclass

NT-proB

NP6-minutew

alkLV

EFSV

COadverse

events

Ma2

015

72(3636)

55835602

2120

214

days

25III-IV

4412

4374

ChronicH

FCR

SEffi

cacy

ratedNYH

Acla

ss

LVEFSVCO

EA

ScrB

UNC

ysc

adversee

vents

Zhang2015

96(4848)

459472

3334

37days

583

III-IV

373362

CRSwith

outh

emod

ialysis

Efficacy

ratedNYH

Acla

ssLVEF

LVED

DLVES

DScrB

UNadverse

events

Jing2016

261(133128)

519524

8470

67days

NA

IIndashIV

4112

4039

ChronicH

FNYH

AII-IV

Efficacy

ratedNYH

Acla

ssLVEF

NT-proB

NP6-minutew

alkserum

carnitine

levels

adversee

vents

Wu2016

100(5050)

74227370

2628

215

days

NA

III-IV

353110

ChronicH

Fwith

Diabetes

Efficacy

ratedNYH

Acla

ssFPG

TC

LVEFC

OE

A

Zhang2016

94(4747)

563583

2729

315

days

NA

III-IV

NA

ChronicH

FEffi

cacy

ratedNYH

Acla

ssLVED

D

LVES

Dadverse

events

L-C

L-carnitineH

FheartfailureSV

strikevolumeCO

cardiac

outputC

IcardiacindexBN

Pbrainnatriuretic

peptideNT-proB

NP

N-te


peptideLV

EFleft

ventric

leejectio

nfractio

nmitralE

peak

velocity

oftheearly

fillin

gwaveof

thetransm

itralflo

wm

itralAp

eakvelocity

oftheatria

lfilling

waveof

thetransm

itralflo

wE

Am

itralEALVED

Dleft

ventric

ular

end-diastolic

dimensio

nLV

ESDleft

ventric

ular

end-systo

licdimensio

nLV

ESV

leftventric

ular

end-systo

licvolumeLV

MILeftventric

ular

massindex

NYH

AN

ewYo

rkHeartAssociatio

nCR

Scardiorenalsyn

drom

eBM

IPP

I-120573-m

ethylio

doph

enylpentadecanoica

cidFP

Gfastin

gbloo

dglucoseTC


creatin

ineBU

Nblood

urea

nitro

gen

Cysccystatin

cNAn

otavailable








Other bias


25 50()

75 1000


Chen

g an

d Ta

ng 2

013

Chen

and

Ye 2

009

Din

g an

d H

u 20

12

Din

g an

d Fe

ng 2

015

Gao

201

5

Guumlr

lek

et al

200

0

Jing

et al

201

6

Lin

et al

200

9

Ma e

t al

2015

Nish

imur

a et a

l 20

15

Pan

2014

Rizo

s 200

0

Sera

ti et

al 2

010

Wu

2016

Xi et

al 2

006

Zhan

g 20

16

Zhan

g et

al 2

015







Other bias

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+++

++

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

++

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+










3 68 4 6868 4 68


1

37 6 33



210216235339

074 [016 343]024 [003 219]096 [025 372]013 [001 110]

1000 048 [021 106]


Favours control

Study or subgroup





(a) PP analysis

3

51

1

Total events

68 4 6868 4 6836 5 3642 6 38

21021410 19

210216236338

074 [016 343]024 [003 219]100 [026 380]013 [001 114]

1000 049 [022 108]


Favours control


Total (95 CI)






(b) ITT analysis









34 35 28 3465 68 57 68


31 35 23 3533 36 27 3641 43 35 4349 50 36 5026 30 20 3045 47 38 47


611 596534 424

23612061

511645539

207 [018 2407]380 [099 1458]729 [083 6415]418 [111 1573]193 [115 322]

404 [115 1416]367 [090 1490]469 [093 2353]

17 1906 [240 15160]653945

325 [089 1190]533 [108 2618]900 [244 3324]

1000 347 [249 482]






Favours L-carnitine



Jing et al 2016 612 612 120 464 512 107 4997590 [6234 8946]1480 [017 2943]

188 175 1000




Total (95 CI) 4541 [minus1446 10529]




Favours L-carnitine



1276 227 35 3392 278 4193602 4403 27 3101 1688 26


Pan 2014

Lin et al 2009

23704 6054 43 34585 5825 43 410

105 104 1000








minus12460 [minus22049 2871]


5010 [minus12820 22840]


(a) BNP


24968 196


24861

359 344 1000






Favours control




minus44300 [minus141323 52723]





(b) NT-proBNP



45 10 31 11 3141 6250 21 60 38 19 60 4246 8 68 40 11 68 92

4826 532 68 4429 566 68 116

1200 [483 1917]600 [277 923]397 [212 582]

423 89 31 438 83 20 68441 83 128 449 86 114 111428 58 35 384 31 35 110

6288 716 36 5631 801 36 88537 95 27 519 6 26 7648 12 50 40 10 50 7545 9 30 41 10 30 68


440 [222 658]657 [306 1008]

800 [367 1233]

530 [208 852]

612 586 1000 414 [234 593]






Favours control

Total (95 CI)

400 [minus081 881]

180 [minus246 606]


400 [minus123 923]



(a) LVEF

6634 677 68 58567105 1364 36 6111


134

5851301

8

68 717 778 [565 991]36 85 994 [378 1610]30 198 900 [495 1305]

134 1000 821 [641 1001]






Favours L-carnitine



(b) SV


449 119 68 382 138 68 80533 035 441 022 36 819

5 13 42 11 50 6747 12

365030 4 14 30 34

067 [024 110]092 [078 106]080 [033 127]070 [004 136]

184 1000 088 [076 101]184






Favours control



(c) CO

104 012 36 082 013 36 26911 06 27 11 06 26 94

092 018 29 082 01 31 25914 04 50 097 023 50 218


022 [016 028]

010 [003 017]043 [030 056]030 [010 050]

172 173 1000 023 [011 035]






Favours L-carnitine



000 [minus032 032]

(d) EA




221 221 1000










Favours control

(a) LVESD


258 258 1000





Favours L-carnitine



Total (95 CI)




Favours control

(b) LVEDD


91

40295699

31 446554

91 1000





Favours L-carnitine






Favours control

(c) LVESV



4 Discussion














Abbreviations




Disclosure




Acknowledgments


References


















































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of























Other bias


25 50()

75 1000


Chen

g an

d Ta

ng 2

013

Chen

and

Ye 2

009

Din

g an

d H

u 20

12

Din

g an

d Fe

ng 2

015

Gao

201

5

Guumlr

lek

et al

200

0

Jing

et al

201

6

Lin

et al

200

9

Ma e

t al

2015

Nish

imur

a et a

l 20

15

Pan

2014

Rizo

s 200

0

Sera

ti et

al 2

010

Wu

2016

Xi et

al 2

006

Zhan

g 20

16

Zhan

g et

al 2

015







Other bias

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+++

++

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

++

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+










3 68 4 6868 4 68


1

37 6 33



210216235339

074 [016 343]024 [003 219]096 [025 372]013 [001 110]

1000 048 [021 106]


Favours control

Study or subgroup





(a) PP analysis

3

51

1

Total events

68 4 6868 4 6836 5 3642 6 38

21021410 19

210216236338

074 [016 343]024 [003 219]100 [026 380]013 [001 114]

1000 049 [022 108]


Favours control


Total (95 CI)






(b) ITT analysis









34 35 28 3465 68 57 68


31 35 23 3533 36 27 3641 43 35 4349 50 36 5026 30 20 3045 47 38 47


611 596534 424

23612061

511645539

207 [018 2407]380 [099 1458]729 [083 6415]418 [111 1573]193 [115 322]

404 [115 1416]367 [090 1490]469 [093 2353]

17 1906 [240 15160]653945

325 [089 1190]533 [108 2618]900 [244 3324]

1000 347 [249 482]






Favours L-carnitine



Jing et al 2016 612 612 120 464 512 107 4997590 [6234 8946]1480 [017 2943]

188 175 1000




Total (95 CI) 4541 [minus1446 10529]




Favours L-carnitine



1276 227 35 3392 278 4193602 4403 27 3101 1688 26


Pan 2014

Lin et al 2009

23704 6054 43 34585 5825 43 410

105 104 1000








minus12460 [minus22049 2871]


5010 [minus12820 22840]


(a) BNP


24968 196


24861

359 344 1000






Favours control




minus44300 [minus141323 52723]





(b) NT-proBNP



45 10 31 11 3141 6250 21 60 38 19 60 4246 8 68 40 11 68 92

4826 532 68 4429 566 68 116

1200 [483 1917]600 [277 923]397 [212 582]

423 89 31 438 83 20 68441 83 128 449 86 114 111428 58 35 384 31 35 110

6288 716 36 5631 801 36 88537 95 27 519 6 26 7648 12 50 40 10 50 7545 9 30 41 10 30 68


440 [222 658]657 [306 1008]

800 [367 1233]

530 [208 852]

612 586 1000 414 [234 593]






Favours control

Total (95 CI)

400 [minus081 881]

180 [minus246 606]


400 [minus123 923]



(a) LVEF

6634 677 68 58567105 1364 36 6111


134

5851301

8

68 717 778 [565 991]36 85 994 [378 1610]30 198 900 [495 1305]

134 1000 821 [641 1001]






Favours L-carnitine



(b) SV


449 119 68 382 138 68 80533 035 441 022 36 819

5 13 42 11 50 6747 12

365030 4 14 30 34

067 [024 110]092 [078 106]080 [033 127]070 [004 136]

184 1000 088 [076 101]184






Favours control



(c) CO

104 012 36 082 013 36 26911 06 27 11 06 26 94

092 018 29 082 01 31 25914 04 50 097 023 50 218


022 [016 028]

010 [003 017]043 [030 056]030 [010 050]

172 173 1000 023 [011 035]






Favours L-carnitine



000 [minus032 032]

(d) EA




221 221 1000










Favours control

(a) LVESD


258 258 1000





Favours L-carnitine



Total (95 CI)




Favours control

(b) LVEDD


91

40295699

31 446554

91 1000





Favours L-carnitine






Favours control

(c) LVESV



4 Discussion














Abbreviations




Disclosure




Acknowledgments


References


















































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


















3 68 4 6868 4 68


1

37 6 33



210216235339

074 [016 343]024 [003 219]096 [025 372]013 [001 110]

1000 048 [021 106]


Favours control

Study or subgroup





(a) PP analysis

3

51

1

Total events

68 4 6868 4 6836 5 3642 6 38

21021410 19

210216236338

074 [016 343]024 [003 219]100 [026 380]013 [001 114]

1000 049 [022 108]


Favours control


Total (95 CI)






(b) ITT analysis









34 35 28 3465 68 57 68


31 35 23 3533 36 27 3641 43 35 4349 50 36 5026 30 20 3045 47 38 47


611 596534 424

23612061

511645539

207 [018 2407]380 [099 1458]729 [083 6415]418 [111 1573]193 [115 322]

404 [115 1416]367 [090 1490]469 [093 2353]

17 1906 [240 15160]653945

325 [089 1190]533 [108 2618]900 [244 3324]

1000 347 [249 482]






Favours L-carnitine



Jing et al 2016 612 612 120 464 512 107 4997590 [6234 8946]1480 [017 2943]

188 175 1000




Total (95 CI) 4541 [minus1446 10529]




Favours L-carnitine



1276 227 35 3392 278 4193602 4403 27 3101 1688 26


Pan 2014

Lin et al 2009

23704 6054 43 34585 5825 43 410

105 104 1000








minus12460 [minus22049 2871]


5010 [minus12820 22840]


(a) BNP


24968 196


24861

359 344 1000






Favours control




minus44300 [minus141323 52723]





(b) NT-proBNP



45 10 31 11 3141 6250 21 60 38 19 60 4246 8 68 40 11 68 92

4826 532 68 4429 566 68 116

1200 [483 1917]600 [277 923]397 [212 582]

423 89 31 438 83 20 68441 83 128 449 86 114 111428 58 35 384 31 35 110

6288 716 36 5631 801 36 88537 95 27 519 6 26 7648 12 50 40 10 50 7545 9 30 41 10 30 68


440 [222 658]657 [306 1008]

800 [367 1233]

530 [208 852]

612 586 1000 414 [234 593]






Favours control

Total (95 CI)

400 [minus081 881]

180 [minus246 606]


400 [minus123 923]



(a) LVEF

6634 677 68 58567105 1364 36 6111


134

5851301

8

68 717 778 [565 991]36 85 994 [378 1610]30 198 900 [495 1305]

134 1000 821 [641 1001]






Favours L-carnitine



(b) SV


449 119 68 382 138 68 80533 035 441 022 36 819

5 13 42 11 50 6747 12

365030 4 14 30 34

067 [024 110]092 [078 106]080 [033 127]070 [004 136]

184 1000 088 [076 101]184






Favours control



(c) CO

104 012 36 082 013 36 26911 06 27 11 06 26 94

092 018 29 082 01 31 25914 04 50 097 023 50 218


022 [016 028]

010 [003 017]043 [030 056]030 [010 050]

172 173 1000 023 [011 035]






Favours L-carnitine



000 [minus032 032]

(d) EA




221 221 1000










Favours control

(a) LVESD


258 258 1000





Favours L-carnitine



Total (95 CI)




Favours control

(b) LVEDD


91

40295699

31 446554

91 1000





Favours L-carnitine






Favours control

(c) LVESV



4 Discussion














Abbreviations




Disclosure




Acknowledgments


References


















































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


















34 35 28 3465 68 57 68


31 35 23 3533 36 27 3641 43 35 4349 50 36 5026 30 20 3045 47 38 47


611 596534 424

23612061

511645539

207 [018 2407]380 [099 1458]729 [083 6415]418 [111 1573]193 [115 322]

404 [115 1416]367 [090 1490]469 [093 2353]

17 1906 [240 15160]653945

325 [089 1190]533 [108 2618]900 [244 3324]

1000 347 [249 482]






Favours L-carnitine



Jing et al 2016 612 612 120 464 512 107 4997590 [6234 8946]1480 [017 2943]

188 175 1000




Total (95 CI) 4541 [minus1446 10529]




Favours L-carnitine



1276 227 35 3392 278 4193602 4403 27 3101 1688 26


Pan 2014

Lin et al 2009

23704 6054 43 34585 5825 43 410

105 104 1000








minus12460 [minus22049 2871]


5010 [minus12820 22840]


(a) BNP


24968 196


24861

359 344 1000






Favours control




minus44300 [minus141323 52723]





(b) NT-proBNP



45 10 31 11 3141 6250 21 60 38 19 60 4246 8 68 40 11 68 92

4826 532 68 4429 566 68 116

1200 [483 1917]600 [277 923]397 [212 582]

423 89 31 438 83 20 68441 83 128 449 86 114 111428 58 35 384 31 35 110

6288 716 36 5631 801 36 88537 95 27 519 6 26 7648 12 50 40 10 50 7545 9 30 41 10 30 68


440 [222 658]657 [306 1008]

800 [367 1233]

530 [208 852]

612 586 1000 414 [234 593]






Favours control

Total (95 CI)

400 [minus081 881]

180 [minus246 606]


400 [minus123 923]



(a) LVEF

6634 677 68 58567105 1364 36 6111


134

5851301

8

68 717 778 [565 991]36 85 994 [378 1610]30 198 900 [495 1305]

134 1000 821 [641 1001]






Favours L-carnitine



(b) SV


449 119 68 382 138 68 80533 035 441 022 36 819

5 13 42 11 50 6747 12

365030 4 14 30 34

067 [024 110]092 [078 106]080 [033 127]070 [004 136]

184 1000 088 [076 101]184






Favours control



(c) CO

104 012 36 082 013 36 26911 06 27 11 06 26 94

092 018 29 082 01 31 25914 04 50 097 023 50 218


022 [016 028]

010 [003 017]043 [030 056]030 [010 050]

172 173 1000 023 [011 035]






Favours L-carnitine



000 [minus032 032]

(d) EA




221 221 1000










Favours control

(a) LVESD


258 258 1000





Favours L-carnitine



Total (95 CI)




Favours control

(b) LVEDD


91

40295699

31 446554

91 1000





Favours L-carnitine






Favours control

(c) LVESV



4 Discussion














Abbreviations




Disclosure




Acknowledgments


References


















































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















45 10 31 11 3141 6250 21 60 38 19 60 4246 8 68 40 11 68 92

4826 532 68 4429 566 68 116

1200 [483 1917]600 [277 923]397 [212 582]

423 89 31 438 83 20 68441 83 128 449 86 114 111428 58 35 384 31 35 110

6288 716 36 5631 801 36 88537 95 27 519 6 26 7648 12 50 40 10 50 7545 9 30 41 10 30 68


440 [222 658]657 [306 1008]

800 [367 1233]

530 [208 852]

612 586 1000 414 [234 593]






Favours control

Total (95 CI)

400 [minus081 881]

180 [minus246 606]


400 [minus123 923]



(a) LVEF

6634 677 68 58567105 1364 36 6111


134

5851301

8

68 717 778 [565 991]36 85 994 [378 1610]30 198 900 [495 1305]

134 1000 821 [641 1001]






Favours L-carnitine



(b) SV


449 119 68 382 138 68 80533 035 441 022 36 819

5 13 42 11 50 6747 12

365030 4 14 30 34

067 [024 110]092 [078 106]080 [033 127]070 [004 136]

184 1000 088 [076 101]184






Favours control



(c) CO

104 012 36 082 013 36 26911 06 27 11 06 26 94

092 018 29 082 01 31 25914 04 50 097 023 50 218


022 [016 028]

010 [003 017]043 [030 056]030 [010 050]

172 173 1000 023 [011 035]






Favours L-carnitine



000 [minus032 032]

(d) EA




221 221 1000










Favours control

(a) LVESD


258 258 1000





Favours L-carnitine



Total (95 CI)




Favours control

(b) LVEDD


91

40295699

31 446554

91 1000





Favours L-carnitine






Favours control

(c) LVESV



4 Discussion














Abbreviations




Disclosure




Acknowledgments


References


















































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


















221 221 1000










Favours control

(a) LVESD


258 258 1000





Favours L-carnitine



Total (95 CI)




Favours control

(b) LVEDD


91

40295699

31 446554

91 1000





Favours L-carnitine






Favours control

(c) LVESV



4 Discussion














Abbreviations




Disclosure




Acknowledgments


References


















































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
























Abbreviations




Disclosure




Acknowledgments


References


















































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





























































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















Efficacy and Safety of L-Carnitine Treatment for Chronic Heart...

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