To continue or Not to To continue or Not to Continue statin therapy in Continue statin therapy in

patients with diagnosed patients with diagnosed CHF?CHF?

Erin WoodardErin Woodard

Mercer UniversityMercer University

October 2011October 2011

Chronic Heart Failure (CHF)Chronic Heart Failure (CHF) Complex clinical syndrome resulting from any structural or Complex clinical syndrome resulting from any structural or

functional cardiac disorder that impairs ability of ventricle to functional cardiac disorder that impairs ability of ventricle to fill with or eject bloodfill with or eject blood

Pericardium, Pericardium, myocardiummyocardium, endocardium, endocardium

Systolic dysfunctionSystolic dysfunction EF < 40%EF < 40% Impaired LV contractilityImpaired LV contractility Dilated LVDilated LV

Diastolic dysfunctionDiastolic dysfunction Normal EFNormal EF Impaired LV fillingImpaired LV filling Contractility preservedContractility preserved

In most patients, abnormalities of systolic and diastolic In most patients, abnormalities of systolic and diastolic dysfunction coexist, regardless of EF.  dysfunction coexist, regardless of EF. 

CHF OverviewCHF Overview Clinical PresentationClinical Presentation

DyspneaDyspnea FatigueFatigue Lead to limiting exercise tolerance & excess fluid retention Lead to limiting exercise tolerance & excess fluid retention

pulmonary congestion and peripheral edemapulmonary congestion and peripheral edema EpidemiologyEpidemiology

CADCAD HTNHTN Dilated cardiomyopathyDilated cardiomyopathy

There is no single diagnostic test for HF because it is largely a There is no single diagnostic test for HF because it is largely a clinical diagnosis that is based on a careful history and clinical diagnosis that is based on a careful history and physical examination. physical examination.

CHF Overview Cont. CHF Overview Cont.

Symptomatic disorderSymptomatic disorder NYHA Functional assessmentNYHA Functional assessment

Progressive disorderProgressive disorder

NYHA ClassificationNYHA Classification Class I (Class I (asymptomaticasymptomatic): Patients with no limitation of ): Patients with no limitation of

activities due to their HF; they suffer no symptoms from activities due to their HF; they suffer no symptoms from ordinary activities. ordinary activities.

Class II (mild): Class II (mild): Slight limitation of physical activity. Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in Comfortable at rest, but ordinary physical activity results in fatigue, palpitation, or dyspnea.fatigue, palpitation, or dyspnea.

Class III (moderate): Patients with marked limitation of Class III (moderate): Patients with marked limitation of activity due to their HF; they are comfortable only at rest. activity due to their HF; they are comfortable only at rest.

Class IV (severe): Patients who have to be at complete rest, Class IV (severe): Patients who have to be at complete rest, confined to bed or chair due to their HF; any physical activity confined to bed or chair due to their HF; any physical activity brings on discomfort and symptoms occur at rest.brings on discomfort and symptoms occur at rest.

CHF TreatmentCHF Treatment

Jessup M et al. N Engl J Med 2003;348:2007-18.

Statins – Friend vs FoeStatins – Friend vs Foe Known benefit and part of first-line Known benefit and part of first-line

treatment for patients with CADtreatment for patients with CAD

HMG-coA reductase inhibitorsHMG-coA reductase inhibitors Increase presentation of LDL receptorsIncrease presentation of LDL receptors

Total CholesterolTotal Cholesterol DesirableDesirable

<200 mg/dL <200 mg/dL

Borderline highBorderline high200 – 239 mg/dL200 – 239 mg/dL

HighHigh>>240 mg/dL240 mg/dL

Treat CAD and prevent events Treat CAD and prevent events decrease new onset HFdecrease new onset HF

Lipoprotein – Endotoxin HypothesisLipoprotein – Endotoxin Hypothesis

Hypothesize optimum lipoprotein concentration Hypothesize optimum lipoprotein concentration Serum lipoproteins to modulate the inflammatory immune Serum lipoproteins to modulate the inflammatory immune

functionfunction CHF patients have increased serum cytokine CHF patients have increased serum cytokine increased increased

endotoxinsendotoxins Circulating cholesterol – and triglyceride rick lipoproteins are Circulating cholesterol – and triglyceride rick lipoproteins are

natural nonspecific buffers of endotoxinsnatural nonspecific buffers of endotoxins Bind and detox bacterial LPSBind and detox bacterial LPS

Patients with CHF, a non-lipid-lowering statin (with Patients with CHF, a non-lipid-lowering statin (with immunomodulatory and anti-inflammatory actions) could be immunomodulatory and anti-inflammatory actions) could be as effective or even more beneficial than a lipid-lowering as effective or even more beneficial than a lipid-lowering statinstatin

Patients with CAD should be treated differently from patients Patients with CAD should be treated differently from patients with ischemic CHFwith ischemic CHF

Ubiquinone hypothesisUbiquinone hypothesis

Inhibition of mevalonate synthesis Inhibition of mevalonate synthesis decreases ubiquinonedecreases ubiquinone

Ubiquinone most abundant in heartUbiquinone most abundant in heart Essential component of mitochondrial Essential component of mitochondrial

respiratory chain respiratory chain ATP ATP Deleterious effects on cardiac musclesDeleterious effects on cardiac muscles CHF patients found to have depleted CHF patients found to have depleted

ubiquinone levelsubiquinone levels Addition of CoQ helpful?Addition of CoQ helpful?

Selenoprotein hypothesisSelenoprotein hypothesis

Reduction of mevalonate Reduction of mevalonate reduction of reduction of isopentenyl-pyrophosphateisopentenyl-pyrophosphate

Interfere with enzyme isopentenylation of Sec-Interfere with enzyme isopentenylation of Sec-tRNA preventing maturationtRNA preventing maturation

Literature SupportLiterature Support19981998 Vrederoe et al. Skin test anergy in advanced heart failure Vrederoe et al. Skin test anergy in advanced heart failure

secondary to either ischemic or idiopathic dilated secondary to either ischemic or idiopathic dilated cardiomyopathycardiomyopathy

Observational Observational

20002000 Rauchhaus et al. Inflammatory cytokines and the possible Rauchhaus et al. Inflammatory cytokines and the possible immunological role for lipoproteins in CHFimmunological role for lipoproteins in CHF

ObservationalObservational

Small sampleSmall sample

20022002 Horwich et al. Low serum total cholesterol is associated with Horwich et al. Low serum total cholesterol is associated with marked increase in mortality in advanced heart failuremarked increase in mortality in advanced heart failure

ObservationalObservational

Large sampleLarge sample

20032003 Rauchhaus et al. Relationship between cholesterol and survival in Rauchhaus et al. Relationship between cholesterol and survival in patients with chronic heart failurepatients with chronic heart failure

Cohort Cohort

20062006 Review:Review: Statins in the treatment of chronic heart failure: Statins in the treatment of chronic heart failure: Biological and clinical considerationsBiological and clinical considerations

20072007 CORONACORONA Randomized, double-Randomized, double-blind placebo controlledblind placebo controlled

20082008 GISSI-HFGISSI-HF Randomized, double-Randomized, double-blind placebo controlledblind placebo controlled

Vredevoe DL et al. Skin test anergy in advanced Vredevoe DL et al. Skin test anergy in advanced heart failure secondary to either ischemic or heart failure secondary to either ischemic or

idiopathic dilated cardiomyopathy. Am J Cardiol idiopathic dilated cardiomyopathy. Am J Cardiol 1998:82:323-8.1998:82:323-8.

Vrederoe - 1998Vrederoe - 1998

Skin test anergy in advanced HF secondary to Skin test anergy in advanced HF secondary to either ischemic or idopathic dilated either ischemic or idopathic dilated cardiomyopathycardiomyopathy

222 patients enrolled followed for 1 year222 patients enrolled followed for 1 year Skin testing in NYHA functional class III,IV Skin testing in NYHA functional class III,IV

and assess mortalityand assess mortality Primary endpointsPrimary endpoints

Skin test anergySkin test anergy MortalityMortality

Vrederoe - 1998Vrederoe - 1998 ResultsResults

Skin test anergy occurred in 45% of HF patientsSkin test anergy occurred in 45% of HF patients More with NYHA class IVMore with NYHA class IV HF patients significantly less reactive for 3 antigensHF patients significantly less reactive for 3 antigens

MortalityMortality Increased with lack of ACEi, dec CO, dec lipidsIncreased with lack of ACEi, dec CO, dec lipids

Significant differences in lipid values for TC, Significant differences in lipid values for TC, LDL, and TG (all lower in anergy)LDL, and TG (all lower in anergy) Lower levels of lipids were predictors of higher mortalityLower levels of lipids were predictors of higher mortality Idiopathic: no significanceIdiopathic: no significance Ischemic: decreased lipids and increased mortalityIschemic: decreased lipids and increased mortality

Only 1 year follow – up Only 1 year follow – up

Rauchhaus M, Koloczek V et al. Rauchhaus M, Koloczek V et al. Inflammatory Inflammatory cytokines and the possible immunological role for cytokines and the possible immunological role for

lipoproteins in chronic heart failure. Int J lipoproteins in chronic heart failure. Int J Cardiology 2000; 76:125-33Cardiology 2000; 76:125-33

Rauchhaus - 2000Rauchhaus - 2000

Goal: Observe fasting cholesterol, LDL, HDL, & TG Goal: Observe fasting cholesterol, LDL, HDL, & TG in patient with CHF in relation to concentrations of in patient with CHF in relation to concentrations of tumor necrosis factor-alpha (TNFa), soluble TNF tumor necrosis factor-alpha (TNFa), soluble TNF receptor-1 and -2 and a ratio potentially indicating receptor-1 and -2 and a ratio potentially indicating recent endotoxin bioactivity (sCD14/TC)recent endotoxin bioactivity (sCD14/TC)

58 CHF patients and 19 controls 58 CHF patients and 19 controls

Hypothesis – lipoprotein bind endotoxin as natural Hypothesis – lipoprotein bind endotoxin as natural bufferbuffer

Rauchhaus - 2000Rauchhaus - 2000

ResultsResults sTNF-R1 and sCD14 were higher in CHF patients sTNF-R1 and sCD14 were higher in CHF patients

than controls where as TNFalpha and sTNF-R2 than controls where as TNFalpha and sTNF-R2 were not. were not.

Increase cholesterol Increase cholesterol decreased TNFalpha decreased TNFalpha TC <200 TC <200 poor outcome poor outcome

Limited small sample size, short term F/ULimited small sample size, short term F/U

Horwich TB et al. Low serum total Horwich TB et al. Low serum total cholesterol is associated with marked cholesterol is associated with marked

increase in mortality in advanced heart increase in mortality in advanced heart failure. J Card Failure 2002; 8:216-24failure. J Card Failure 2002; 8:216-24

Horwich - 2002Horwich - 2002

1134 patients with advanced HF regardless of 1134 patients with advanced HF regardless of etiology (NYHA class III, IV)etiology (NYHA class III, IV)

PurposePurpose Describe correlation between cholesterol and baseline Describe correlation between cholesterol and baseline

patient characteristics important in prognosispatient characteristics important in prognosis Investigate relationship between lipids, lipoproteins, and Investigate relationship between lipids, lipoproteins, and

HF mortalityHF mortality Excluded patients LVEF <40%Excluded patients LVEF <40% Primary endpointPrimary endpoint

Death or urgent heart transplantDeath or urgent heart transplant

Horwich - 2002Horwich - 2002

ResultsResults Patients divided into quintiles based on baseline lipidsPatients divided into quintiles based on baseline lipids 1 and 5 year survival rates (death or urgent heart 1 and 5 year survival rates (death or urgent heart

transplant)transplant) Lowest death/urgent heart transplant at TC 190-205Lowest death/urgent heart transplant at TC 190-205

Decreased TC Decreased TC worse outcomes HF worse outcomes HF More severe symptoms CHFMore severe symptoms CHF

Increased LDL, HDL, TG Increased LDL, HDL, TG longer survival longer survival < 25% with TC <129 survived >5yr< 25% with TC <129 survived >5yr > 50% with TC>190 survived >5yr> 50% with TC>190 survived >5yr

Confirmed findings of small sample trialConfirmed findings of small sample trial

Total Total CholesterolCholesterol

<129<129

(n= 222)(n= 222)

129-160129-160

(n= 225)(n= 225)

161-189161-189

(n=227)(n=227)

190-223190-223

(n=232)(n=232)

>223>223

(n=228)(n=228)

1 year1 year

Death/UTDeath/UT

MortalityMortality

9898

46.5%46.5%

6262

29.6%29.6%

7373

36%36%

4545

21.4%21.4%

5151

25.9%25.9%

2 year2 year

Death/UTDeath/UT

MortalityMortality

114114

56.3%56.3%

7777

38.6%38.6%

9191

47.8%47.8%

6363

32.8%32.8%

6060

31.8%31.8%

5 year5 year

Death/UTDeath/UT

MortalityMortality

137137

76.2%76.2%

108108

64.9%64.9%

103103

62.8%62.8%

7777

48.4%48.4%

7272

44.8%44.8%

1yr1yr SurvivorsSurvivors

(n=805)(n=805)

NonsurvivorsNonsurvivors

(n=329)(n=329)

TCTC 185185 165165

LDLLDL 120120 106106

TGTG 155155 124124

Similar lipid lowering therapy•14% in each group•Drug unspecified

Mortality based on Quintile of total cholesterol

Horwich TB et al. Low serum total cholesterol is associated with marked increase in mortality in advanced heart failure. J Card Failure 2002; 8:216-24

Rauchhaus et al. Relationship between Rauchhaus et al. Relationship between cholesterol and survival in patients cholesterol and survival in patients with chronic heart failure. JACC with chronic heart failure. JACC

2003; 42: 112003; 42: 11

Rauchhaus - 2003Rauchhaus - 2003

Report on 2 cohort studiesReport on 2 cohort studies 114 patients with CHF recruited to metabolic study 114 patients with CHF recruited to metabolic study

and followed for minimum 12 months (derivation and followed for minimum 12 months (derivation study)study)

303 unselected patients with CHF (validation 303 unselected patients with CHF (validation study)study)

PurposePurpose Relationship between endogenous lipoproteins and Relationship between endogenous lipoproteins and

survival was exploredsurvival was explored

Rauchhaus - 2003Rauchhaus - 2003

ResultsResults ““reciever operator curve analysis” showed reciever operator curve analysis” showed

201mg/dL 201mg/dL Decreased serum cholesterol = increased sTNF Decreased serum cholesterol = increased sTNF

receptor-1 levelsreceptor-1 levels

Theoretical HarmTheoretical Harm Lower total cholesterol (<190mg/dl) indicative of Lower total cholesterol (<190mg/dl) indicative of

poor prognosis for CHF patients in NYHA class III poor prognosis for CHF patients in NYHA class III and IVand IV

CAD lead to CHFCAD lead to CHF Statin is proven outcomes to treat CAD and prevent Statin is proven outcomes to treat CAD and prevent

coronary event coronary event Statin has been shown to prevent new onset CHFStatin has been shown to prevent new onset CHF Statin decreasing levels of TC lead to poor prognosis?Statin decreasing levels of TC lead to poor prognosis? Statin used after diagnosis NYHA class III, IV?Statin used after diagnosis NYHA class III, IV? Studies and evaluation needed to describe risk/benefit Studies and evaluation needed to describe risk/benefit

in pharmacologically induced low TC (statin) vs in pharmacologically induced low TC (statin) vs naturally low TCnaturally low TC

Kjeckshus, J. et al. Rosuvastatin in Older Kjeckshus, J. et al. Rosuvastatin in Older Patients with Systolic Heart Failure. New Patients with Systolic Heart Failure. New

Engl J Med 2007; 357:2248-61.Engl J Med 2007; 357:2248-61.

““CORONA”CORONA”Controlled Rosuvastatin Multinational Trial in Controlled Rosuvastatin Multinational Trial in

Heart FailureHeart Failure

*supported by AstraZeneca**supported by AstraZeneca*

CORONA - 2007CORONA - 2007 Large randomized placebo controlled studyLarge randomized placebo controlled study

Total of 5011 patients, >60yoTotal of 5011 patients, >60yo NYHA class II,III, or IV ischemic, systolic heart failureNYHA class II,III, or IV ischemic, systolic heart failure EF of no more than 40%EF of no more than 40% Investigator thought no need for cholesterol-lowering drugInvestigator thought no need for cholesterol-lowering drug

Hypothesized beneficial effects of rosuvastatin would outweigh Hypothesized beneficial effects of rosuvastatin would outweigh any theoretical hazardsany theoretical hazards improve survival, reduce morbidity, increase well-being improve survival, reduce morbidity, increase well-being

Study drug: Study drug: 10mg of rosuvastatin vs placebo, 35 month follow up10mg of rosuvastatin vs placebo, 35 month follow up

Primary OutcomePrimary Outcome Death from composite of cardiovascular causes, nonfatal MI, nonfatal Death from composite of cardiovascular causes, nonfatal MI, nonfatal

strokestroke

CORONA - 2007CORONA - 2007

Results:Results:

Baseline TC 5.35mmol/LBaseline TC 5.35mmol/L Baseline LDL 3.54mmol/L (137) Baseline LDL 3.54mmol/L (137) 1.96mmol/L (76) at 3 months 1.96mmol/L (76) at 3 months Baseline HDL 1.24mmol/L (48) Baseline HDL 1.24mmol/L (48) 1.29mmol/L (50) at 3 months 1.29mmol/L (50) at 3 months Baseline TG 2.01mmol/L (178) Baseline TG 2.01mmol/L (178) 1.56mmol/L (138) at 3 months 1.56mmol/L (138) at 3 months Baseline hsCRP 3.1mg/L Baseline hsCRP 3.1mg/L 2.1mg/L 2.1mg/L

ConclusionConclusion No significant reduction in primary outcome of deaths from any causeNo significant reduction in primary outcome of deaths from any cause Significantly fewer hospitalizations of any type in rosuvastatin group than Significantly fewer hospitalizations of any type in rosuvastatin group than

placebo group (for cardiovascular causes and heart failure)placebo group (for cardiovascular causes and heart failure)

Primary OutcomePrimary Outcome YY NN

RosuvastatinRosuvastatin

(n = 2514)(n = 2514)

692692 18221822

PlaceboPlacebo

(n=2497)(n=2497)

732732 17651765

NNT = 55

GISSI-HF Investigators. Effect of GISSI-HF Investigators. Effect of rosuvastatin in patietns with chronic heart rosuvastatin in patietns with chronic heart

failure: a randomised, double-blind, failure: a randomised, double-blind, placebo-controlled trial. The Lancet; 372: placebo-controlled trial. The Lancet; 372:

1231- 1239.1231- 1239.

““GISSI/HF”GISSI/HF”Gruppo Italiano per lo Studio della Gruppo Italiano per lo Studio della

Sopravvivenza nell’Infarto miocardico trialSopravvivenza nell’Infarto miocardico trial

*Funded by Societa Prodotti Antibiotici (SPA;Italy), Pfizer, *Funded by Societa Prodotti Antibiotici (SPA;Italy), Pfizer, Sigma Tau, and AstraZenecaSigma Tau, and AstraZeneca

GISSI/HF – 2008 GISSI/HF – 2008

Randomized, double-blind placebo controlled trial Randomized, double-blind placebo controlled trial Italy. Italy.

CHF class II-IV irrespective of LVEFCHF class II-IV irrespective of LVEF Intervention: rosuvastatin 10mg vs placeboIntervention: rosuvastatin 10mg vs placebo Followed for 3 – 9 yearFollowed for 3 – 9 year Primary endpointPrimary endpoint

Time to deathTime to death Time to death + time to admission to hospital for Time to death + time to admission to hospital for

cardiovascular reasonscardiovascular reasons Intent- to-treat Intent- to-treat

GISSI/HF – 2008GISSI/HF – 2008

ResultsResults

ConclusionConclusion Rosuvastatin 10mg daily did not affect clinical outcoems Rosuvastatin 10mg daily did not affect clinical outcoems

in patients with chronic heart failure of any cause, in in patients with chronic heart failure of any cause, in whom drug was safewhom drug was safe

Death Death Death or hospitalDeath or hospital

RR 657 (29%)657 (29%) 1305 (57%)1305 (57%)

PP 644 (28%)644 (28%) 1283 (56%)1283 (56%)

P=0.943P=0.943 P=0.903P=0.903

Low TC a Cause or Consequence?Low TC a Cause or Consequence?

Association between Total Cholesterol (TC) and Association between Total Cholesterol (TC) and all-cause mortality all-cause mortality Positive at 40 yoPositive at 40 yo Negligible at 50 – 70 yoNegligible at 50 – 70 yo Negative at age 80 +Negative at age 80 +

Incidence/prevalence of CHF increasing steeply Incidence/prevalence of CHF increasing steeply with agewith age

CHF patient untreated with statin naturally have CHF patient untreated with statin naturally have cholesterol levels decrease? cholesterol levels decrease?

Discussion PointsDiscussion Points

Most individuals on statin d/t CAD treatmentMost individuals on statin d/t CAD treatment Take them off? Take them off? Titrate down? Decrease aggressive tx?Titrate down? Decrease aggressive tx?

Those individuals not already on a statin with Those individuals not already on a statin with prior needprior need Start statin?Start statin? Goal of increasing TC?Goal of increasing TC?

Leave it alone? Benefit vs. risk?Leave it alone? Benefit vs. risk?

Other ReferencesOther References

Hunt SA, Abraham WT, Chin MH, et al. 2009 focused Hunt SA, Abraham WT, Chin MH, et al. 2009 focused update incorporated into the ACC/AHA 2005 update incorporated into the ACC/AHA 2005 guidelines for the diagnosis and management of guidelines for the diagnosis and management of chronic heart failure in the adult. JACC chronic heart failure in the adult. JACC 2009;53(15):e1-90.2009;53(15):e1-90.