Statins in the Treatment of Heart Failure: Failed Concept? · per lo Studio della Sopravvivenza ... [survival]) plot and time dependent covariate test • Kaplan Meier Survival curves

Statins in the Treatment of

Heart Failure: Failed Concept?

Tamara Horwich, MD, MS

Assistant Professor of Medicine

Division of Cardiology

March 16, 2012

Background: Heart Failure

and Statins

Heart Failure in the U.S.

Prevalence 5.7 million

Incidence 670,000 cases/ year

Lifetime Risk 1 out of 5

5-year outcomes 50% mortality

Est. Expenditures 2009 $37 billion

HF due to CAD ~ 50-75%

AHA Heart Disease and Stroke Statistics – 2009 update.

Lloyd-Jones DM et al. Circulation.

ACC/AHA Recommendations for

Symptomatic, Systolic Heart Failure

• Class I – Diuretics

– Salt restriction

– ACEI (or ARB)

– Beta-blocker

– Exercise

– Implantable Cardioverter Defibrillator

– Biventricular Pacemaker (if QRS>120ms)

– Aldosterone Antagonist

• Class IIA – Digoxin

– Hydralazine / Isosorbide Dinitrate

Hunt et al. J Am Coll Cardiol 2005;46:1116–43.

The Nation

13

30

5

44

18

57

31

72

17

18

Coronary Artery Disease (%)

Myocardial Infarction (%)

Hypertension (%)

Stroke of TIA (%)

Peripheral Vascular Disease (%)

n=105,388 from 10/2001 to 12/2003

CHD and Risk Equivalents in Hospitalized

HF Patients: ADHERE Registry

Current Smoker (%)

Chronic Renal Insufficiency (%)

Chronic Dialysis (%)

Diabetes (%)

Insulin Treated Diabetes (%)

ADHERE: 267 US Hospitals; 105,388 patients

Fonarow Rev Cardiovasc Med 2003;4:S21-30.

Use of Medications in Patients

Hospitalized with HF ADHERE

(N = 187,565) OPTIMIZE-HF (N = 48,612)

EVEREST (N = 4,133)

Admission Discharge Admission Discharge Admission Discharge

Diuretics 78 85 66 77 97 93

ACEI 44 54 40 53 74 74

ARB 14 15 12 12 12 13

Aldost Antagonist

6 9 7 12 56 58

β-blockers 56 64 53 64 67 75

Digoxin 31 32 23 27 47 47

Nitrates 2 2 22 24 16 10

CCB ? ? 21 20 8 9

Aspirin 41 49 40 46 ? ?

Warfarin 27 27 23 24 ? ?

Lipid

Lowering Agent

36 39 34

35

36 38

Adams KF Jr, et al. Am Heart J. 2005;149:209-216. Fonarow GC, et al. JAMA 2007;297:61-67.

Konstam, M. A. et al. JAMA 2007;297:1319-1331.

0

25

50

75

100

125

150

Gotto AM Jr, et al. Circulation. 1990;81:1721-1733. Castelli WP. Am J Med. 1984;76:4-12.

Relationship Between Cholesterol

and CHD Risk: Epidemiologic Trials 10-y

ear

CH

D d

eath

rate

(D

eath

s/10

00)

Serum cholesterol (mg/dL)

1% reduction in total cholesterol

is associated with a 2% decrease in

CHD risk

CH

D i

nd

icati

on

s p

er

1000

Each 1% increase in total cholesterol

level is associated with a 2%

increase in CHD risk

Serum cholesterol (mg/100 mL)

Framingham Study (n=5209) Multiple Risk Factor Intervention

Trial (MRFIT) (n=361,662)

204 205-234 235-264 265-294 295 150 200 250 300 0

50

40

30

20

10

0

10

20

30

40

50

60

70

80

90

total cohort

(n=1134)

Ischemic CMY

(n=542)

Non-ischemic

CMY (n=592)

Mo

rta

lity

, %

TC<129 129-160 161-189 190-223 TC>223

p=0.00001p=0.00001

p=0.00001

Horwich, Fonarow et al. J Card Fail 2002;8:216-224.

In Heart Failure, the Reverse is True.

Higher Cholesterol Levels are Associated

with Reduced Mortality

Even if TC and LDL are not Risk Factors

in Heart Failure - Potential Benefits of

Statins in Heart Failure

Impact of HMG CoA Reductase

Inhibitor Therapy on Risk of

Developing Heart Failure

Placebo Simvastatin0

2

4

6

8

10

12

Probability of CHF %

5 year risk

p = 0.015

24% risk reduction

Patients with coronary artery disease and cholesterol > 212 mg/dl

Kjekshus J of Cardiac Failure 1997;4:249-54

Observational Studies of

Statins in Heart Failure show

Marked Benefit

Horwich, MacLellan, and Fonarow . J Am Coll Cardiol; 2004;43:642–648.

0

20

40

60

80

100

0 3 6 9 12 15 18 21

Months

Su

rviv

al

(%)

Statin

No Statin

P < 0.001

0

20

40

60

80

100

0 3 6 9 12 15 18 21

Months

Su

rviv

al

(%)

Statin

No Statin

P < 0.001

Ischemic HF Non-ischemic HF

n = 551 advanced HF patients

51% of patients on statins (79% of CAD and 29% of non-CAD)

Observational Study: Statins in

Patients with Advanced, Chronic HF

Statin Better No Statin Better

1.0 0.5 0.1

TC ≤ 162 mg/dL

HR = 0.51 (0.33–0.80)

Adjusted HR = 0.52 (0.29–0.94)

TC > 162 mg/dL

HR = 0.46 (0.23–0.91)

Adjusted HR = 0.24 (0.09–0.60)

Statins Are Associated with Improved HF

Survival Independent of Total Cholesterol Level

Univariate

Adjusted*

2.0

Horwich and Fonarow. J Card Fail 2004; 10:S98.

Statin Therapy is Associated

with Lower Mortality In Severe

HF

PRAISE study analysis: 1153 patients with severe heart failure, 12% statin use

Mozaffarian Am J Cardiol 2004;93:1124-9.

Additional Observational Studies

of Statins in Heart Failure

Val-HeFT: 1602 of 3408 on statins, 2 year mortality

20.3% vs 17.9%, HR 0.81, P=0.029

CIBIS II: 226 of 2647 on statins, survival 98.3% in

statin/bisoprolol vs 87.2% in the no

statin/bisoprolol group

COMET: 21% of 3029 on statins, statin use adjusted

HR 0.75, P<0.001

ICONS Registry: 14% of 4888 pts discharge on

statin after HF hospitalizaiton, discharge statin HR

0.65 (95% CI 0.54-0.78) P<0.0001

Small Prospective Studies of

Statins in Heart Failure with

Surrogate Endpoints

Statins and Inflammation in Humans

with Non-Ischemic Heart Failure

Sola S et al. J Am Coll Cardiol 2006; 47:332-37

Baseline 12-month F/U

Placebo

N=54

Atorvastatin

N=54

Placebo

N=54

Atorvastatin

N=54

hsCRP 1.9+0.4 2.0+0.4 1.9+0.3 1.7+0.2*

IL-6 17.1+1.4 16.7+1.3 17.3+1 13.3+0.8*

TNF-a RII 33.4+4.2 33.3+3.2 34.5+3 24.3+2.3*

Statins and Cardiac Remodeling

in Humans

Node K et al. Circulation 2003

Simvastatin 3 months in

subjects with nonischemic HF

Effects of High-Dose HMG CoA

Reductase Inhibitor Therapy on

Ventricular Remodeling

Placebo

n=40

Rosuvastatin

n=46

P value

Reduction in LDL +3% -51% <0.001

LVEF (%) +5.3 +3.2 n.s.

LVEDD (mm) -1.7 +0.8 n.s.

LVESD (mm) -1.9 +0.1 n.s.

86 subjects with HF were randomized to Placebo or Rosuvastatin 40mg/day 6

months. No change seen in any biomarkers (BNP, ET-1, hsCRP, NE, TNF or IL-6)

Krum H et al., J Card Fail 2007 13:1-7

Time out: Composite Endpoints

• Measurable events that lie on a pathophysiologic spectrum; used to quantify overall treatment effect

• Frequently used in clinical trials (37%)

• Reduces sample size requirements, and thus cost of trial

• WARNING: “soft” but more frequent clinical endpoints (eg. Re-intervention, biomarker elevation) vs. “hard” but less frequent endpoints (eg. Death, disabling stroke) can drive the effect of therapy on the composite

Kaul and Diamond. JACC 2010; 55:415-27.


PAMI

Stent vs. angioplasty

Heterogeneity across

clinical endpoints

HOPE

Ramipril vs. placebo

No heterogeneity

Supports credibility

and validity of

compositie endpoint

TRITON TIMI 38

Prasugrel vs.

clopidogrel

Efficacy endpoints

combined with safety

endpoints masks

harmful effect

Recently published subgroup analysis

Cleland et al. JACC 2009; 54:1850-9.

CONCLUSIONS: Patients with heart failure

due to ischemic heart disease who have

NT-proBNP values <103 pmol/l (868 pg/ml)

may benefit from rosuvastatin.

Time out: Subgroup Analyses

• Problems

– Lack of pre-specification

– Testing of large number of subgroups without the use of statistical adjustment for interactions and multiple comparisons

• 20 subgroups : 0.64 chance of false positive

• False negatives can occur because of underpowering

– Should be considered exploratory and need to be confirmed


Potential Explanations for

CORONA Elderly HF patients are less likely to benefit from statin therapy

ACS events are an infrequent in cause of fatal events in HF and

therefore the wrong primary outcome was chosen

No incremental benefit when already treated with ACEI/ARB and

beta blockers

Dose was too low and higher doses of statin therapy needed

Not a class effect and other statins may provide benefit

Statins do not benefit patients with HF and the observational data

was confounded

Kjekshus J et al. N Engl J Med 2007;357.

The Gruppo Italiano

per lo Studio della Sopravvivenza

nell’Insufficienza

Cardiaca Heart Failure

(GISSI-HF) trial

GISSI-HF

Adapted from: Tavazzi et al. Eur J Heart Fail 2004;6:635–41.

GISSI-HF Investigators. Lancet 2008;doi:10.1016/S0140-6736(08)61240-4.

GISSI-HF

• GISSI-HF is a double-blind, placebo-controlled, randomized trial designed to assess the effects of n-3 polyunsaturated fatty acids (PUFAs) and rosuvastatin in symptomatic congestive heart failure patients.

• The primary objective was to investigate

whether the long-term administration of n-3

PUFA (1 g q.d.) and rosuvastatin (10 mg

q.d.) is more effective than the

corresponding placebo in the reduction of

two co-primary outcomes:

– all-cause mortality

– all-cause mortality or hospitalization for

cardiovascular (CV) reasons

GISSI-HF – Objectives

GISSI-HF Study Design

At each visit, the following assessments were performed: CV examination, vital signs,

12-lead electrocardiogram, compliance check, serious adverse events assessment and blood chemistry

NYHA=New York Heart Association; R1=randomization 1; R2=randomization 2; D=drug distribution

Rosuvastatin 10 mg q.d.

(n=2285)

Placebo

(n=2289)

Median follow-up 3.9 years

Visit:

Month: 1 0

1 2

3

3

D

6

4

D

12

5

D

18

6

D

24

7

D

30

8

D

36

9

D

R1, R2

Placebo

(n=3481)

n-3 PUFA 1 g q.d.

(n=3494)

R1 (n=6975)

R2 (n=4574)

Adapted from: Tavazzi et al. Eur J Heart Fail 2004;6: 635–41.

GISSI-HF Investigators. Lancet 2008;doi:10.1016/S01.40-6736(08)61240-4.

GISSI-HF – Study End Points Two Co-primary end points

– All-cause mortality*

– All-cause mortality or CV hospitalizations*

Secondary end points – CV mortality – CV mortality or hospitalization for any reason – Sudden cardiac death – Hospitalization for any reason – Hospitalization for CV reasons – Hospitalization for heart failure – Myocardial infarction (MI) – Stroke

*assessed as “to time to event”



GISSI-HF Power Analysis

• Power calculated on 1st co-primary

endpoint: time to death

• 90% power

• Expected mortality rate at 3 years in

placebo group of 25%

• Number of events needed to detect 15%

reduction by rosuvastatin n = 1252

Statistical Analysis

• “To estimate treatment effect, the main analysis was undertaken by fitting Cox proportional hazards models adjusted for the variables that were unbalanced between the randomized groups (P<0.1)” – Unconventional, but prespecified because prognostic variables

in this type of HF patients unknown

– Assumption of proportional hazard for the randomized treatments was appropriately checked by means of the log (-log[survival]) plot and time dependent covariate test

• Kaplan Meier Survival curves with log rank tests

• To explore effect modification of subjects receiving both treatments, Cox proportional hazards model with model for terms of PUFA, rosuvastatin, and their interaction

• The effects of the study drugs will be evaluated in the following predefined subgroups of patients: – Age (above vs. below median age; 70 years)

– Left ventricular (LV) function (LV ejection fraction [LVEF} >40% vs. <40%)

– Functional capacity (New York Heart Association [NYHA] class II vs. III-IV)

– Etiology (ischemic vs. non-ischemic)

– Diabetes (yes vs. no)

– Baseline total cholesterol levels (above vs. below median value; 4.97 mmol/L)

• The end point for all the subgroup analyses is the combined outcome measure of all-cause mortality or hospital admission for CV reasons.

Statistics – Subgroup Analysis



• Clinical evidence of heart failure of any etiology

– Classified as NYHA class II–IV

– Treated according to European Society of Cardiology

guidelines

• LVEF measured within three months of enrolment

• If EF is >40%, at least one hospital admission for

heart failure in the previous year is required

• Age 18 and over

GISSI-HF – Entry Criteria



• Known hypersensitivity to study treatment

• Presence of any non-cardiac disease (e.g. cancer) that is likely to significantly shorten life expectancy

• Treatment with any investigational agent within 1 month before randomization

• Acute coronary syndrome or revascularization procedure within 1 month prior to randomization

• Planned cardiac surgery expected to be performed within 3 months after randomization

• Significant liver disease

• Serum creatinine level >221 µmol/L

• Alanine and aspartate transaminase levels >1.5 times the upper limit of normal (ULN)

• Current creatine phosphokinase level above ULN

• Pregnant or lactating women or women of childbearing potential not protected from pregnancy by an accepted method of contraception

GISSI-HF – Exclusion Criteria



Patient Characteristics

Mean age (years) 68 68

>70 years (%) 43.9 44.2

Female sex (%) 23.8 21.4

Heart disease risk factors

Body mass index (kg/m2) 27.1 27.1

Systolic BP (mmHg) 127 127

Diastolic BP (mmHg) 77 77

Heart rate (BPM) 73 73

Current smoker (%) 14.1 14

History of hypertension (%) 55.1 53.5

NYHA class (%)

II 61.2 63.9

III 36.2 33.7

IV 2.6 2.4

EF(%) 33.4 33.1

EF>40% (%) 10.3 9.8

Rosuvastatin Placebo n=2285 n=2289

GISSI-HF – Baseline Characteristics

Adapted from GISSI-HF Investigators. Lancet 2008; doi:10.1016/S0140-6736(08)61240-4

Medical History

Hospitalization for HF in previous year (%) 52.0 49.4

Previous MI (%) 31.8 33.8

Previous stroke (%) 4.3 4.8

Diabetes mellitus (%) 27.4 25.0

CABG (%) 13.0 13.9

PCI (%) 8.1 8.4

ICD (%) 6.4 6.8

Pacemaker (%) 13.1 11.5

History of atrial fibrillation (%) 19.3 20.8

PVD (%) 8.1 7.0

COPD (%) 23.5 22.8

Neoplasia (%) 3.3 4.0

Rosuvastatin Placebo n=2285 n=2289

CABG–coronary artery bypass grafting; PCI–percutaneous coronary intervention; ICD–implantable cardioverter-defibrillator; PVD–peripheral vascular disease; COPD–chronic obstructive pulmonary disease; HF–heart failure


Adapted from GISSI-HF Investigators. Lancet 2008; doi:10.1016/S0140-6736(08)61240-4.

Heart Failure Cause/Etiology

Ischemic (%) 39.8 40.2

Dilatative (%) 34.7 34.2

Hypertensive (%) 17.9 18.1

Other causes (%) 3.1 2.8

Non-detectable/unknown (%) 4.5 4.7

Physical Examinations

Pulmonary râles (%) 28.3 26.8

Third heart sound (%) 25.2 24.1

Mitral insufficiency (%) 64.2 63.9

Aortic stenosis (%) 1.9 2.1

ECG Findings

*QRS>120 ms (%) 35.2 33.6

Atrial fibrillation (%) 18.8 19.8

Pathological Q waves (%) 16.8 19.2

LV hypertrophy (%) 21.5 19.6

Rosuvastatin Placebo

n=2285 n=2289



*Assessed with 2257 rosuvastatin patients and 2266 placebo patients

Medication

ACE inhibitors (%) 77.3 77.9

ARBs (%) 19.3 17.1

ACE inhibitors/ARBs (%) 94.1 92.9

Beta blockers (%) 62.7 62.0

Spironolactone (%) 39.0 41.3

Diuretics (%) 90.0 90.0

Digitalis (%) 40.0 40.0

Oral anticoagulants (%) 29.8 30.5

ASA (%) 44.6 45.6

Other antiplatelet agents (%) 7.8 8.2

Nitrates (%) 31.9 33.3

Calcium channel blockers (%) 10.1 10.1

Amiodarone (%) 20.3 18.4


n=2285 n=2289

ARB =angiotensin receptor blocker

GISSI-HF – Current Medications


First co-primary endpoint

(death from all causes) P

robabili

ty o

f D

eath

(all

causes)

Time Since Randomization (mo) 0 24 54

GISSI-HF Investigators. Lancet. 2008.

Second co-primary endpoint (death from

all causes or CV hospitalization) P

roba

bili

ty o

f A

ll-C

au

se D

ea

th o

r

Adm

issio

n f

or

CV

Reason

Time Since Randomization (mo) GISSI-HF Investigators. Lancet. 2008.

HR = hazard ratio; CI = confidence interval

*adjusted HR

Effect modification of rosuvastatin + fish oil excluded for both outcomes

0.90

0.94

P

value

[99% CI 0.91-

1.11]

[95.5% CI

0.90-1.12]

CI

1.01

1.00

HR*

1283 (56) 1305 (57) All-cause mortality or CV

hospitalizations

644 (28) 657 (29) All-cause mortality

Primary end points

Placebo

(n=2289)

n (%)

Rosuvastatin

(n=2285)

n (%)

(i) All-cause mortality and (ii) all-cause mortality or hospitalizations for CV reasons

GISSI-HF – Co-primary End Points


*adjusted HR

0.211 [0.89-1.70] 1.23 66 (2.9) 82 (3.6) Fatal/non-fatal stroke

0.516 [0.63-1.26] 0.89 70 (3.1) 61 (2.7) Fatal/non-fatal MI

0.626 [0.95-1.10] 1.02 1385 (60.5) 1417 (62.0) CV mortality or

hospitalization for any

reason

0.610 [0.87-1.09] 0.97 634 (27.7) 629 (27.5) Hospitalization for HF

0.371 [0.88-1.05] 0.96 1060 (46.3) 1033 (45.2) Hospitalization for CV

reason

0.776 [0.92-1.07] 0.99 1286 (56.2) 1278 (55.9) Patients hospitalized

0.257

0.550

P value

[0.92-1.36]

[0.85-1.09]

95% CI

1.12

0.96

HR*

196 (8.6) 220 (9.6) Sudden cardiac death

488 (21.3) 478 (20.9) CV mortality

Secondary end points

Placebo

(n=2289)

n (%)

Rosuvastatin

(n=2285)

n (%)

GISSI-HF - Secondary Endpoints


GISSI-HF – Cause of Death

179 (7.8) 156 (6.8) Non-CV mortality

488 (21.3) 478 (20.9) CV mortality

644 (28.1) 657 (28.8) Total mortality

23 (1.0)

75 (3.3)

81 (3.5)

29 (1.3)

38 (1.7)

198 (8.7)

203 (8.9)

10 (0.4)

Rosuvastatin (n=2285)

n (%)

26 (1.1) Not known

55 (2.4) Other non-CV reason

75 (3.3) Neoplasia

31 (1.4) Other CV reasons

29 (1.3) Stroke

182 (8.0) Presumed arrhythmic

231 (10.1) Worsening of heart failure

15 (0.7) Acute MI

Placebo (n=2289)

n (%)


Rosuvastatin

(n=2285)

Placebo

(n=2289)

Other CV

Stroke

Presumed arrhythmic

Worsening HF

Acute MI

GISSI-HF: Causes of CV Mortality

No. of CV

deaths= 488

No. of CV

deaths=478

10 15

203 231

29 31

38 29

198 182

Adapted from GISSI-HF Investigators. Lancet 2008;doi:10.1016/S01.40-6736(08)61240-4.

0

10

20

30

40

50

60

70

80

90

100

GISSI-HF – Predefined subgroup analysis

All cause mortality or hospitalizations for cardiovascular reasons

EF < 40% Age <70 yrs Age >70 yrs EF > 40% Ischaemic

HF

Non-ischaemic

HF

51.4%

55.8%

58.9%

63.0%

48.9%

56.9% 58.7%

52.1%

63.1% 63.6% 64.7%

51.4%

Placebo

Rosuvastatin

606/

1178

575/

1176

699/

1107

708/

1113

139/

236

132/

225

1166/

2049

1151/

2064

717/

1376

704/

1370

588/

909

579/

919

Patients

with e

vent (%

)

ns

ns ns

ns

ns

ns


GISSI-HF – Predefined Subgroup Analysis

All-cause mortality or hospitalizations for CV reasons

0

10

20

30

40

50

60

70

80

90

100

Patients

with e

vent (%

)

51.1%

63.8%

54.7%

58.6%

51.1%

63.5%

53.5% 53.9%

66.6% 64.8%

60.4%

53.2%

Placebo

Rosuvastatin

Diabetes NYHA II NYHA III-IV No diabetes TC

< 4.97 mmol/L

TC

> 4.97 mmol/L

714/

1398

747/

1462

591/

887

536/

827

908/

1660

919/

1718

397/

625

364/

571

609/

1131

595/

1118

685/

1135

676/

1153

ns ns

ns

ns ns

ns


LDL-C

Baseline; mmol/L (mg/dL) 3.16 (122) 3.13 (121)

One year; mmol/L (mg/dL) 2.15 (83) 3.37 (113)

Three years; mmol/L (mg/dL) 2.31 (89) 3.06 (118)


(n=2285) (n=2289)

GISSI-HF – Lipid Data


Exploratory analysis of treatment effect of how low LDL is lowered shows no

effect

1 0 Hepatocellular jaundice

1 4 Creatine phosphokinase increase

1 0 Lipid abnormality

7 7 Allergic reaction

0 1 Asthenia

44 34 GI disorders

0 1 Acute renal failure

0 2 Patients who permanently discontinued study

treatment due to serious ADR, n (%)

1

23

1

2

6

26

104 (4.6)

790 (34.6)

Rosuvastatin

(n=2285)

0 Acute dermatitis*

21 Muscle-related symptoms

0 Acute dermatitis*

0 Acute renal failure

4 Renal dysfunction

12 Liver dysfunction

91 (4.0)

Patients who permanently discontinued study

treatment due to ADR, n (%)

831 (36.3) Patients who permanently discontinued study

treatment, n (%)

Placebo

(n=2289)

GISSI-HF – Tolerability and Safety Data Permanent discontinuations and adverse drug reactions (ADR)


*Diagnosed as Stevens-Johnson syndrome by the investigator, not confirmed by an expert adjudicator

CK elevations

CK > 10 x ULN (n) 1 1

Serum creatinine

Doubling of serum creatinine, n (%) 65 (3%) 57 (2.6%)

Baseline, µmol/L (mg/dL)* 94.59 (1.07) 95.47 (1.08)

One year, µmol/L (mg/dL)* 96.36 (1.09) 97.24 (1.10)

Three years, µmol/L (mg/dL)* 97.24 (1.10) 97.24 (1.10)


(n=2285) (n=2289)

GISSI-HF – Tolerability and Safety Data

Laboratory safety data

*Median values


CK = creatine kinase

• GISSI-HF showed no difference between rosuvastatin 10 mg and placebo in the primary end points of death or CV hospitalization in patients with heart failure, with no specific indication for statin treatment, over and above optimized heart failure treatment.

• GISSI-HF supports the findings from CORONA by showing that adding a statin to optimized heart failure treatment does not significantly improve the prognosis for patients with heart failure because it cannot reverse or prevent the further deterioration of a failing heart.

• The investigators suggest that there are too few acute ischemic events (heart attacks and strokes) in heart failure patients for a statin to show a benefit.

• Rosuvastatin10 mg was well tolerated in nearly 2,300 patients during the course of the GISSI-HF study, with a safety profile similar to placebo.

GISSI-HF – Summary and Perspectives

Adapted from: GISSI-HF Investigators. Lancet 2008; doi:10.1016/S0140-6736(08)61240-4 .

Fonarow GC. Lancet 2008;doi:10.1016/S0140-6736(08)61241-6.

Kjekshus et al. N Engl J Med 2007;357:2248-61.

GISSI-HF • Limitations

– Statin class effect (unlikely), 1 dose tested, only

10% with EF>40%, 24% women, LDL 120 mg/dL

• Explanations

– Different HF phenotypes,

– benefit washed out by ACE/ARB and β-blocker (ie,

intensity of treatment)

– longer duration of treatment may be necessary

– “pleiotrophic” effects of statins not clinically relevant

– Any beneficial effects of statins in this population

are off-set by detrimental effect of lowering

cholesterol

In Heart Failure, the Reverse is True.

Higher Cholesterol Levels are Associated

with Reduced Mortality

1134 Advanced HF patients

Horwich. J of Card Failure 2002;8:216-224

0

10

20

30

40

50

60

70

80

90

100

<109

109-

128

129-

145

146-

160

161-

174

175-

189

190-

205

206-

223

224-

249

>250

Deciles of Total Cholesterol

De

ath

or

Urg

en

t T

ran

sp

lan

t, %

P=0.00001



HMG-CoA

Reductase

Acetyl-CoA

Dolichol,

Farnesylated

Protein (ie, Ras)

HMG-CoA Mevalonate

Geranylgeranyl-PP

Isopentenyl-PP

Geranyl-PP

Farnesyl-PP

Cholesterol

+ Isopentenyl-PP

Geranylgeranylated

Proteins (ie, Rho)

Squalene

Cholesterol-Independent Effects of Statins

Takemoto et al. Arterioscler Thromb Vasc Biol. 2001;21:1712-1719.

Documents

Statins in the Treatment of Heart Failure: Failed Concept? · per lo Studio della Sopravvivenza ... [survival]) plot and time dependent covariate test • Kaplan Meier Survival curves