Statins in heart failure: do we need another trial?

Figures & data

Table 1 Hypothesis, mechanism, and effects of statins in heart failure

Hypothesis	Mechanisms	Effects
Endotoxin–lipoprotein hypothesis	Inhibition of HMG-CoA reductase resulting in reduced circulating plasma cholesterol and triglyceride-rich lipoproteins	• Lowered cholesterol reduces provision of metabolic reserves and protection in increased resting energy consumption in HF^Citation98
		• Low cholesterol is associated with poorer HF outcomes^Citation94
		• Cholesterol and triglyceride-rich lipoproteins bind and detoxify endotoxin entering into the blood via GIT^Citation95
		• Endotoxin mediates HF progression via activation and release of proinflammatory cytokines
		• Statin enhances circulating endotoxin levels and further elevates proinflammatory cytokines to worsen HF^Citation17
Ubiquinone hypothesis	Inhibition of ubiquinone synthesis downstream of the mevalonate pathway	• Ubiquinone is key to mitochondrial respiration in cells
		• Statin decreases ATP production in the myocardium
		• Statins inhibit the antioxidant function of ubiquinone and reduce cellular protection from free radical injury
		• Statins adversely affect ventricular function and exercise tolerance in HF^Citation96
		• Statins inhibit ubiquinone synthesis to cause statin-induced myalgias and myopathy^Citation96
Selenoprotein hypothesis	Inhibition of selenoprotein synthesis by blockade of HMG-CoA reductase in the mevalonate pathway	• Selenoproteins are critical in skeletal and cardiac muscle metabolism
		• Statins decrease selenoprotein production to cause skeletal and cardiac muscle myopathy^Citation99

Abbreviations: ATP, adenosine triphosphate; GIT, gastrointestinal tract; HF, heart failure; HMG-CoA, hydroxyl methyl glutaryl-coenzyme A.

Table 2 Retrospective analyses of statin trials in various cardiovascular conditions

Study	Sample	Population	HF in population	Intervention	Duration (years)	Outcomes in HF subgroup	Findings
4S^Citation4	4444	CAD/↑CHL	412	Simvastatin	5.4	Mortality	↓
CARE^Citation10	4159	MI/↑CHL	706	Pravastatin	5.0	Death from CAD, EF > 40% versus EF < 40%	↓
LIPID^Citation6	9014	MI/unstable angina	None at baseline	Pravastatin	6.1	Death	↓
MIRACL^Citation11	3086	Unstable angina	253	Atorvastatin	0.3	HF onset/rehospitalization	↔
PROSPER^Citation60	5814	PVD	NYHA class III-IV HF excluded	Pravastatin	3.2	HF hospitalization	↔
GREACE^Citation100	1600	CAD	118	Atorvastatin	3.0	Death, MI, unstable angina	↓
A-Z^Citation12	4497	ACS	221	Simvastatin	2.0	New HF onset	↓
GRACE^Citation103	19537	ACS	N/A	Atorvastatin	3.5	HF during hospitalization	↓
ALLIANCE^Citation13	2442	CAD	162	Atorvastatin	4.3	Hospitalization	↔
IDEAL^Citation101	8888	Acute MI	537	Atorvastatin	4.8	Risk of hospitalization	↔
HPS^Citation82	20536	DM, VD	HF excluded	Simvastatin	5.0	Hospitalization or death	↓
TNT^Citation102	10001	Stable CAD	781	Atorvastatin	4.9	Hospitalization	↓

Notes: ↔, no effect; ↓, decrease; ↑, increase.

Abbreviations: ACS, acute coronary syndrome; CAD, coronary artery disease; CHL, cholesterol; DM, diabetes mellitus; EF, ejection fraction; MI, myocardial infarction; PVD, peripheral vascular disease; VD, vascular disease; HF, heart failure.

Table 3 Major non-randomized studies evaluating effect of statins in heart failure outcomes

Study	Sample	Statin	Follow-up (months)	Outcome	Findings
Hognestad et al^Citation110	5301	Any	25	Mortality	Improved mortality
Joynt et al^Citation107	96	Any	12	C-reactive protein	No effect
Ezekowitz et al^Citation14	6427	Any	12	Mortality	Improved mortality
Ray et al^Citation111	28828	Any	96	Mortality	Improved mortality
Sola et al^Citation112	446	Any	24	Mortality/hospitalization	Improved outcomes
Go et al^Citation108	24598	Any	29	Mortality/hospitalization	Improved outcomes
Foody et al^Citation109	54960	Any	36	Mortality	Improved mortality
Senthil et al^Citation113	10510	Any	31	Mortality	Improved mortality
Maison et al^Citation114	281	Any	96	Mortality	Improved mortality
Paloma et al^Citation115	960	Any	109	Mortality	Improved mortality

Table 4 Randomized controlled trials of statins in heart failure

Study	Sample	Intervention	Duration (months)	Outcome	Findings
GISSI-HF^Citation15	4574	Rosuvastatin 10 mg	46	Mortality/CV admission	↔
CORONA^Citation16	5011	Rosuvastatin 10 mg	32	Mortality/CV admission	↔ mortality, ↓ CV admission
Vrtovec et al^Citation116	110	Atorvastatin 10 mg	12	Sudden cardiac death	↓
Wojnicz et al^Citation117	74	Atorvastatin 40 mg	6	LVEF and NYHA class	↑ LVEF; ↓ NYHA class
Xie et al^Citation118	119	Atorvastatin 10/20 mg	12	LVEF, QTc, and QTcd	↑ LVEF; ↓ QTc and ↓ QTcd
Yamada et al^Citation120	38	Atorvastatin 10 mg	31	LVEF and BNP	↑ LVEF; ↓ BNP
Krum et al^Citation61	95	Rosuvastatin 10–40 mg	6	LVEF	↔ LVEF
Sola et al^Citation119	108	Atorvastatin 20 mg	12	LVEF, markers	↑ LVEF; ↓ markers
Hamaad et al^Citation122	23	Atorvastatin 40 mg	3	HRV	↔ HRV
Node et al^Citation121	51	Simvastatin 5–10 mg	3	LVEF, NYHA, markers, and BNP	↑ LVEF; ↓ BNP, and ↓ markers
Erbs et al^Citation126	42	Rosuvastatin 40 mg	3	LVEF, FMD, CPCs, VEGF, and oxLDL	↑ LVEF, ↑ CPCs, ↑ FMD, ↑ VEGF and ↓ oxLDL
Bleske et al^Citation123	15	Atorvastatin 80 mg	3	LVEF, markers, BNP, and HRV	↔
Tsutamoto et al^Citation127	63	Atorvastatin 5/R2.5 mg	6	LVEF, markers, and BNP	↑ A, R ↔
Andreou et al^Citation128	60	Rosuvastatin 10 mg	1	MPO	MPO ↓
Tousoulis et al^Citation125	60	Rosuvastatin 10 mg	1	CPCs, FMD, and oxLDL	↑ CPCs, ↑ FMD, ↓ oxLDL ↓
Bielecka et al^Citation129	68	Atorvastin 10–40 mg	6	6MWT, NYHA, and markers	↑ 6MWT, ↓ markers, ↓ NYHA
Tousoulis et al^Citation130	38	Atorvastatin 20 mg	1	Blood flow, markers	↑ Blood flow, ↓ markers
Horwich et al^Citation131	26	Atorvastatin 10 mg	3	MSNA, LVEF, BNP, and QoL	↔

Notes: ↔, No effect; ↑, increase; ↓, Decrease.

Abbreviations: 6MWT, six minute walk test; A, atorvastatin; BNP, brain natriuretic peptide; CPCs, circulating progenitor cells; CV, cardiovascular; FMD, flow-mediated dilation; HRV, heart rate variability; LVEF, left ventricular ejection fraction; markers, inflammatory biomarkers; MPO, myeloperoxidase; MSNA, muscle sympathetic nerve activity; NYHA, New York Heart Association; oxLDL, oxidized low-density lipoprotein; QoL, quality of life; QTc, corrected QT interval; QTcd, corrected QT interval dispersion; R, rosuvastatin; S, simvastatin; VEGF, vascular endothelial growth factor.

Figure 1 Statins influence the pathophysiological mechanisms in heart failure (indicated by A).

PoehlmanETScheffersJGottliebSSFisherMLVaitekeviciusPIncreased resting metabolic rate in patients with congestive heart failureAnn Intern Med1994121118608627772113

 PubMed Web of Science ®Google Scholar

RauchhausMClarkALDoehnerWThe relationship between cholesterol and survival in patients with chronic heart failureJ Am Coll Cardiol200342111933194014662255

 PubMed Web of Science ®Google Scholar

TreasureCBKleinJLWeintraubWSBeneficial effects of cholesterol-lowering therapy on the coronary endothelium in patients with coronary artery diseaseN Engl J Med199533284814877830728

 PubMed Web of Science ®Google Scholar

RauchhausMCoatsAJAnkerSDThe endotoxin-lipoprotein hypothesisLancet2000356923393093311036910

 PubMed Web of Science ®Google Scholar

MortensenSALethAAgnerERohdeMDose-related decrease of serum coenzyme Q10 during treatment with HMG-CoA reductase inhibitorsMol Aspects Med199718SupplS137S1449266515

 PubMedGoogle Scholar

RundekTNainiASaccoRCoatesKDiMauroSAtorvastatin decreases the coenzyme Q10 level in the blood of patients at risk for cardiovascular disease and strokeArch Neurol200461688989215210526

 PubMedGoogle Scholar

Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S)Lancet19943448934138313897968073

 PubMed Web of Science ®Google Scholar

SacksFMPfefferMAMoyeLAThe effect of pravastatin on coronary events after myocardial myocardial infarction in patients with average cholesterol levels.Cholesterol and Recurrent Events trial investigatorsN Engl J Med199633514100110098801446

 PubMed Web of Science ®Google Scholar

Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study GroupN Engl J Med199833919134913579841303

 PubMed Web of Science ®Google Scholar

SchwartzGGOlssonAGEzekowitzMDMyocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Study InvestigatorsEffects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomised controlled trialJAMA2001285131711171811277825

 PubMed Web of Science ®Google Scholar

ShepherdJBlauwGJMurphyMBPROSPER study groupPROspective Study of Pravastatin in the Elderly at Risk. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trialLancet200236093461623163012457784

 PubMed Web of Science ®Google Scholar

AthyrosVGMikhailidisDPPapageorgiouAAEffect of atorvastatin on high density lipoprotein cholesterol and its relationship with coronary events: a subgroup analysis of the GREek Atorvastatin and Coronary-heart-disease Evaluation (GREACE) StudyCurrent medical research and opinion5200420562763715171226

 PubMed Web of Science ®Google Scholar

de LemosJABlazingMAWiviottSDInvestigatorsEarly intensive versus a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trialJAMA2004292111307131615337732

 PubMed Web of Science ®Google Scholar

KubotaTMiyagishimaMAlvarezRJExpression of proinflammatory cytokines in the failing human heart: comparison of recent-onset and end-stage congestive heart failureJ Heart Lung Transplant200019981982411008069

 PubMed Web of Science ®Google Scholar

KorenMJHunninghakeDBALLIANCE InvestigatorsClinical outcomes in managed care patients with coronary heart diseas treated agressively in lipid-lowering disease management clinics: the alliance studyJ Am Coll Cardiol20044491772177915519006

 PubMed Web of Science ®Google Scholar

PedersenTRFaergemanOKasteleinJJIncremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) Study GroupHigh – dose atorvastatin vrs usual – dose simvastatin for secondary prevention after myocardial infarction: IDEAL study: a randomized-controlled trialJAMA2005294192437244516287954

 PubMed Web of Science ®Google Scholar

Heart Protection Study Collaborative GroupMRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20536 high-risk individuals: a randomised placebo-controlled trialLancet2002360932672212114036

 PubMed Web of Science ®Google Scholar

KhushKKWatersDDBittnerVEffect of high-dose atorvastatin on hospitalization for heart failure: subgroup analysis of the Treat to New Targets (TNT) studyCirculation2007115557658317261662

 PubMed Web of Science ®Google Scholar

HognestadADicksteinKMyhreESnapinnSKjekshusJOPTIMAAL InvestigatorsEffect of combined statin and beta-blocker treatment on one-year morbidity and mortality after acute myocardial infarction associated with heart failureAm J Cardiol200493560360614996587

 PubMed Web of Science ®Google Scholar

JoyntKEGattisWAHasselbladVEffect of angiotensin-converting enzyme inhibitors, beta blockers, statins, and aspirin on C-reactive protein levels in outpatients with heart failureAm J Cardiol200493678378515019895

 PubMed Web of Science ®Google Scholar

EzekowitzJMcAlisterFAHumphriesKHAPPROACH InvestigatorsThe association among renal insufficiency, pharmacotherapy, and outcomes in 6,427 patients with heart failure and coronary artery diseaseJ Am Coll Cardiol20044481587159215489090

 PubMed Web of Science ®Google Scholar

RayJGGongYSykoraKTuJVStatin use and survival outcomes in elderly patients with heart failureArch Intern Med20051651626715642876

 PubMedGoogle Scholar

SolaSMirMQSRajagopalanSHelmyTTandonNKhanBVStatin therapy is associated with improved cardiovascular outcomes and levels of inflammatory markers in patients with heart failureJ Card Fail200511860761216230264

 PubMed Web of Science ®Google Scholar

GoASLeeWYYangJLoJCGurwitzJHStatin therapy and risks for death and hospitalization in chronic heart failureJAMA2006296172105211117077375

 PubMed Web of Science ®Google Scholar

FoodyJMShahRGalushaDMasoudiFAHavranekEPKrumholzHMStatin and mortality among elderly patients hospitalized with heart failureCirculation200611381086109216490817

 PubMed Web of Science ®Google Scholar

ThambidoraiSKDeshmukhARWaltersRWImpact of statin use on heart failure mortalityInt J Cardiol2011147343844320971517

 PubMed Web of Science ®Google Scholar

MaisonPDesamericqGHemeryFRelationship between recommended chronic heart failure treatments and mortality over 8 years in real-world conditions: a pharmacoepidemiological studyEur J Clin Pharmacol201369490190822993100

 PubMed Web of Science ®Google Scholar

GastelurrutiaPLupónJde AntonioMStatins in heart failure: the paradox between large randomized clinical trials and real lifeMayo Clin Proc201287655556022677075

 PubMed Web of Science ®Google Scholar

KjekshusJApetreiEBarriosVCORONA GroupRosuvastatin in older patients with systolic heart failureN Engl J Med2007357222248226117984166

 PubMed Web of Science ®Google Scholar

TavazziLMaggioniAPMarchioliRGissi-HF InvestigatorsEffect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trialLancet200837296451231123918757089

 PubMed Web of Science ®Google Scholar

VrtovecBOkrajsekRGolicnikAAtorvastatin therapy may reduce the incidence of sudden cardiac death in patients with advanced chronic heart failureJ Card Fail200814214014418325461

 PubMed Web of Science ®Google Scholar

WojniczRWilczekKNowalany-KozielskaEUsefulness of atorvastatin in patients with heart failure due to inflammatory dilated cardiomyopathy and elevated cholesterol levelsAm J Cardiol200697689990416516598

 PubMed Web of Science ®Google Scholar

XieRQCuiWLiuFYangCPeiWNLuJCStatin therapy shortens QTc, QTcd, and improves cardiac function in patients with chronic heart failureInt J Cardiol2010140225525719042044

 PubMed Web of Science ®Google Scholar

YamadaTNodeKMineTLong-term effect of atorvastatin on neurohumoral activation and cardiac function in patients with chronic heart failure: A prospective randomized controlled studyAm Heart J200715361055. e11055. e817540209

 PubMed Web of Science ®Google Scholar

KrumHAshtonEReidCDouble-Blind, randomized, placebo-controlled study of high-dose hmg coa reductase inhibitor therapy on ventricular remodeling, pro-inflammatory cytokines and neurohormonal parameters in patients with chronic systolic heart failureJ Card Fail20071311717338996

 PubMed Web of Science ®Google Scholar

SolaSMirMQLerakisSTandonNKhanBVAtorvastatin improves left ventricular systolic function and serum markers of inflammation in nonischemic heart failureJ Am Coll Cardiol200647233233716412856

 PubMed Web of Science ®Google Scholar

HamaadASosinMLipGYMacFadyenRJShort-term adjuvant atorvastatin improves frequency domain indices of heart rate variability in stable systolic heart failureCardiovasc Drugs Ther200519318318716142595

 PubMed Web of Science ®Google Scholar

NodeKFujitaMKitakazeMHoriMLiaoJKShort-term statin therapy improves cardiac function and symptoms in patients with idiopathic dilated cardiomyopathyCirculation2003108783984312885745

 PubMed Web of Science ®Google Scholar

ErbsSBeckEBLinkeAHigh-dose rosuvastatin in chronic heart failure promotes vasculogenesis, corrects endothelial function, and improves cardiac remodeling – results from a randomized, double-blind, and placebo-controlled studyInt J Cardiol20111461566320236716

 PubMed Web of Science ®Google Scholar

BleskeBENicklasJMBardRLNeutral effect on markers of heart failure, inflammation, endothelial activation and function, and vagal tone after high-dose HMG-CoA reductase inhibition in non-diabetic patients with non-ischemic cardiomyopathy and average low-density lipoprotein levelJ Am Coll Cardiol200647233834116412857

 PubMed Web of Science ®Google Scholar

TsutamotoTSakaiHIbeKEffect of atorvastatin vs rosuvastatin on cardiac sympathetic nerve activity in non-diabetic patients with dilated cardiomyopathyCirc J20117592160216621737951

 PubMed Web of Science ®Google Scholar

AndreouITousoulisDMiliouAEffects of rosuvastatin on myeloperoxidase levels in patients with chronic heart failure: a randomized placebo-controlled studyAtherosclerosis2010210119419819962701

 PubMed Web of Science ®Google Scholar

TousoulisDAndreouITentolourisCComparative effects of rosuvastatin and allopurinol on circulating levels of matrix metalloproteinases and tissue inhibitors of metalloproteinases in patients with chronic heart failureInt J Cardiol2010145343844319539384

 PubMed Web of Science ®Google Scholar

Bielecka-DabrowaAGochJHMikhailidisDPRyszJMaciejewskiMBanachMThe influence of atorvastatin on parameters of inflammation and function of the left ventricle in patients with dilated cardiomyopathyMed Sci Monit20091512MS12MS2319946241

 PubMed Web of Science ®Google Scholar

TousoulisDAntoniadesCBosinakouEEffects of atorvastatin on reactive hyperemia and inflammatory process in patients with congestive heart failureAtherosclerosis2005178235936315694946

 PubMed Web of Science ®Google Scholar

HorwichTBMiddlekauffHRMaclellanWRFonarowGCStatins do not significantly affect muscle sympathetic nerve activity in humans with nonischemic heart failure: a double-blind placebo-controlled trialJ Card Fail2011171187988622041323

 PubMed Web of Science ®Google Scholar