Statins in the Treatment of Heart Failure: Failed Concept?

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 Incidence 5.7 million 670,000 cases/ year Lifetime Risk 1 out of 5 5-year outcomes Est. Expenditures 2009 50% mortality $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.

CHD and Risk Equivalents in Hospitalized HF Patients: ADHERE Registry n=105,388 from 10/2001 to 12/2003 Coronary Artery Disease (%) Myocardial Infarction (%) Hypertension (%) Stroke of TIA (%) Peripheral Vascular Disease (%) Current Smoker (%) Chronic Renal Insufficiency (%) Chronic Dialysis (%) Diabetes (%) Insulin Treated Diabetes (%) The Nation 57 31 72 17 18 13 30 5 44 18 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 6 9 7 12 56 58 Antagonist 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.

10-year CHD death rate (Deaths/1000) CHD indications per 1000 Relationship Between Cholesterol and CHD Risk: Epidemiologic Trials Multiple Risk Factor Intervention Trial (MRFIT) (n=361,662) 50 40 150 125 Framingham Study (n=5209) 30 20 100 75 50 10 25 0 150 200 250 300 0 204 205-234 235-264 265-294 295 Serum cholesterol (mg/dl) 1% reduction in total cholesterol is associated with a 2% decrease in CHD risk Serum cholesterol (mg/100 ml) Each 1% increase in total cholesterol level is associated with a 2% increase in CHD risk Gotto AM Jr, et al. Circulation. 1990;81:1721-1733. Castelli WP. Am J Med. 1984;76:4-12.

In Heart Failure, the Reverse is True. Higher Cholesterol Levels are Associated with Reduced Mortality Mortality, % TC<129 129-160 161-189 190-223 TC>223 90 80 70 p=0.00001 p=0.00001 p=0.00001 60 50 40 30 20 10 0 total cohort (n=1134) Ischemic CMY (n=542) Non-ischemic CMY (n=592) Horwich, Fonarow et al. J Card Fail 2002;8:216-224.

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 Probability of CHF % 12 10 8 6 4 2 0 Placebo p = 0.015 24% risk reduction Sim vastatin 5 year risk 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

Survival (%) Survival (%) Observational Study: Statins in Patients with Advanced, Chronic HF Ischemic HF Non-ischemic HF 100 80 Statin 100 80 Statin 60 40 20 P < 0.001 No Statin 0 0 3 6 9 12 15 18 21 60 40 20 P < 0.001 No Statin 0 0 3 6 9 12 15 18 21 Months Months n = 551 advanced HF patients 51% of patients on statins (79% of CAD and 29% of non-cad) Horwich, MacLellan, and Fonarow. J Am Coll Cardiol; 2004;43:642 648.

Horwich and Fonarow. J Card Fail 2004; 10:S98. Statins Are Associated with Improved HF Survival Independent of Total Cholesterol Level Univariate Adjusted* 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) 0.1 0.5 1.0 2.0 Statin Better No Statin Better

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 Baseline 12-month F/U Placebo Atorvastatin Placebo Atorvastatin N=54 N=54 N=54 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* Sola S et al. J Am Coll Cardiol 2006; 47:332-37

Statins and Cardiac Remodeling in Humans Simvastatin 3 months in subjects with nonischemic HF Node K et al. Circulation 2003

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

Recently published subgroup analysis 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. Cleland et al. JACC 2009; 54:1850-9.

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

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.

GISSI-HF The Gruppo Italiano per lo Studio della Sopravvivenza nell Insufficienza Cardiaca Heart Failure (GISSI-HF) trial 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, placebocontrolled, randomized trial designed to assess the effects of n-3 polyunsaturated fatty acids (PUFAs) and rosuvastatin in symptomatic congestive heart failure patients.

GISSI-HF Objectives 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 Study Design R1 (n=6975) n-3 PUFA 1 g q.d. (n=3494) Placebo (n=3481) R2 (n=4574) Rosuvastatin 10 mg q.d. (n=2285) Placebo (n=2289) R1, R2 Median follow-up 3.9 years Visit: 1 2 3 4 5 6 7 8 9 Month: 0 1 3 6 12 18 24 30 36 D D 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 D D D D D 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 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 Power Analysis Power calculated on 1 st 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

Statistics Subgroup Analysis 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. 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 Entry Criteria 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 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 Exclusion 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 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 Baseline Characteristics Rosuvastatin Placebo n=2285 n=2289 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/m 2 ) 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 Adapted from GISSI-HF Investigators. Lancet 2008; doi:10.1016/s0140-6736(08)61240-4

GISSI-HF Baseline Characteristics Rosuvastatin Placebo n=2285 n=2289 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 CABG coronary artery bypass grafting; PCI percutaneous coronary intervention; ICD implantable cardioverter-defibrillator; PVD COPD peripheral vascular (%) disease; COPD chronic obstructive pulmonary disease; HF heart 23.5 failure 22.8 Neoplasia (%) 3.3 Adapted from GISSI-HF Investigators. Lancet 2008; doi:10.1016/s0140-6736(08)61240-4. 7.0

GISSI-HF Baseline Characteristics Rosuvastatin Placebo n=2285 n=2289 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 *Assessed with 2257 rosuvastatin patients and 2266 placebo patients Adapted from GISSI-HF Investigators. Lancet 2008; doi:10.1016/s0140-6736(08)61240-4.

GISSI-HF Current Medications Medication Rosuvastatin Placebo n=2285 n=2289 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 ARB =angiotensin receptor blocker Adapted from GISSI-HF Investigators. Lancet 2008; doi:10.1016/s0140-6736(08)61240-4.

Probability of Death (all causes) First co-primary endpoint (death from all causes) Time Since Randomization (mo) 0 24 54 GISSI-HF Investigators. Lancet. 2008.

Probability of All-Cause Death or Admission for CV Reason Second co-primary endpoint (death from all causes or CV hospitalization) GISSI-HF Investigators. Lancet. 2008. Time Since Randomization (mo)

GISSI-HF Co-primary End Points (i) All-cause mortality and (ii) all-cause mortality or hospitalizations for CV reasons Rosuvastatin (n=2285) n (%) Placebo (n=2289) n (%) HR* CI P value Primary end points All-cause mortality 657 (29) 644 (28) 1.00 [95.5% CI 0.90-1.12] 0.94 All-cause mortality or CV hospitalizations 1305 (57) 1283 (56) 1.01 [99% CI 0.91-1.11] 0.90 HR = hazard ratio; CI = confidence interval *adjusted HR Effect modification of rosuvastatin + fish oil excluded for both outcomes Adapted from GISSI-HF Investigators. Lancet 2008; doi:10.1016/s0140-6736(08)61240-4.

GISSI-HF - Secondary Endpoints Rosuvastatin (n=2285) n (%) Placebo (n=2289) n (%) HR* 95% CI P value Secondary end points CV mortality 478 (20.9) 488 (21.3) 0.96 [0.85-1.09] 0.550 Sudden cardiac death 220 (9.6) 196 (8.6) 1.12 [0.92-1.36] 0.257 Patients hospitalized 1278 (55.9) 1286 (56.2) 0.99 [0.92-1.07] 0.776 Hospitalization for CV reason 1033 (45.2) 1060 (46.3) 0.96 [0.88-1.05] 0.371 Hospitalization for HF 629 (27.5) 634 (27.7) 0.97 [0.87-1.09] 0.610 CV mortality or hospitalization for any reason 1417 (62.0) 1385 (60.5) 1.02 [0.95-1.10] 0.626 Fatal/non-fatal MI 61 (2.7) 70 (3.1) 0.89 [0.63-1.26] 0.516 Fatal/non-fatal stroke 82 (3.6) 66 (2.9) 1.23 [0.89-1.70] 0.211 *adjusted HR Adapted from GISSI-HF Investigators. Lancet 2008; doi:10.1016/s0140-6736(08)61240-4.

GISSI-HF Cause of Death Total mortality CV mortality Acute MI Worsening of heart failure Presumed arrhythmic Stroke Other CV reasons Non-CV mortality Neoplasia Other non-cv reason Not known Rosuvastatin (n=2285) n (%) 657 (28.8) 478 (20.9) 10 (0.4) 203 (8.9) 198 (8.7) 38 (1.7) 29 (1.3) 156 (6.8) 81 (3.5) 75 (3.3) 23 (1.0) Placebo (n=2289) n (%) 644 (28.1) 488 (21.3) 15 (0.7) 231 (10.1) 182 (8.0) 29 (1.3) 31 (1.4) 179 (7.8) 75 (3.3) 55 (2.4) 26 (1.1) Adapted from GISSI-HF Investigators. Lancet 2008; doi:10.1016/s0140-6736(08)61240-4.

GISSI-HF: Causes of CV Mortality No. of CV deaths=478 No. of CV deaths= 488 29 31 38 29 198 182 Other CV Stroke Presumed arrhythmic Worsening HF Acute MI 203 231 10 15 Rosuvastatin (n=2285) Placebo (n=2289) Adapted from GISSI-HF Investigators. Lancet 2008;doi:10.1016/S01.40-6736(08)61240-4.

Patients with event (%) GISSI-HF Predefined subgroup analysis All cause mortality or hospitalizations for cardiovascular reasons 100 90 80 Rosuvastatin Placebo 70 60 50 51.4% ns 48.9% ns ns 63.1% 63.6% 64.7% ns 58.9% 58.7% 56.9% 55.8% ns 63.0% 52.1% ns 51.4% 40 30 20 10 0 606/ 1178 575/ 1176 699/ 1107 708/ 1113 1166/ 2049 Age <70 yrs Age >70 yrs EF < 40% EF > 40% Ischaemic HF 1151/ 2064 139/ 236 132/ 225 588/ 909 579/ 919 717/ 1376 704/ 1370 Non-ischaemic HF Adapted from GISSI-HF Investigators. Lancet 2008; doi:10.1016/s0140-6736(08)61240-4.

Patients with event (%) GISSI-HF Predefined Subgroup Analysis All-cause mortality or hospitalizations for CV reasons 100 90 Rosuvastatin 80 Placebo 70 60 50 51.1% ns 51.1% 66.6% ns 64.8% 63.5% ns 63.8% ns ns 60.4% 58.6% 54.7% 53.5% 53.9% ns 53.2% 40 30 20 10 0 714/ 1398 747/ 1462 591/ 887 536/ 827 397/ 625 NYHA II NYHA III-IV Diabetes No diabetes TC < 4.97 mmol/l 364/ 571 908/ 1660 919/ 1718 685/ 1135 676/ 1153 609/ 1131 595/ 1118 TC > 4.97 mmol/l Adapted from GISSI-HF Investigators. Lancet 2008; doi:10.1016/s0140-6736(08)61240-4.

GISSI-HF Lipid Data Rosuvastatin (n=2285) Placebo (n=2289) 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) Exploratory analysis of treatment effect of how low LDL is lowered shows no effect Adapted from GISSI-HF Investigators. Lancet 2008; doi:10.1016/s0140-6736(08)61240-4.

GISSI-HF Tolerability and Safety Data Permanent discontinuations and adverse drug reactions (ADR) Patients who permanently discontinued study treatment, n (%) Patients who permanently discontinued study treatment due to ADR, n (%) GI disorders Asthenia Allergic reaction Liver dysfunction Lipid abnormality Creatine phosphokinase increase Renal dysfunction Acute renal failure Hepatocellular jaundice Acute dermatitis* Muscle-related symptoms Patients who permanently discontinued study treatment due to serious ADR, n (%) Acute renal failure Acute dermatitis* Rosuvastatin (n=2285) 790 (34.6) 104 (4.6) *Diagnosed as Stevens-Johnson syndrome by the investigator, not confirmed by an expert adjudicator Adapted from GISSI-HF Investigators. Lancet 2008; doi:10.1016/s0140-6736(08)61240-4. 34 1 7 26 0 4 6 2 0 1 23 2 1 1 Placebo (n=2289) 831 (36.3) 91 (4.0) 44 0 7 12 1 1 4 0 1 0 21 0 0 0

GISSI-HF Tolerability and Safety Data Laboratory safety data Rosuvastatin (n=2285) Placebo (n=2289) 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) *Median values CK = creatine kinase Adapted from GISSI-HF Investigators. Lancet 2008; doi:10.1016/s0140-6736(08)61240-4.

GISSI-HF Summary and Perspectives 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. 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.

Limitations GISSI-HF 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

Death or Urgent Transplant, % In Heart Failure, the Reverse is True. Higher Cholesterol Levels are Associated with Reduced Mortality 100 90 80 70 60 50 40 30 20 10 0 <109 109-128 129-145 146-160 161-174 175-189 P=0.00001 190-205 206-223 Deciles of Total Cholesterol 1134 Advanced HF patients Horwich. J of Card Failure 2002;8:216-224 224-249 >250

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

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

Cholesterol-Independent Effects of Statins Acetyl-CoA HMG-CoA HMG-CoA Reductase Mevalonate Isopentenyl-PP Geranyl-PP Dolichol, Farnesylated Protein (ie, Ras) Farnesyl-PP + Isopentenyl-PP Squalene Geranylgeranyl-PP Cholesterol Takemoto et al. Arterioscler Thromb Vasc Biol. 2001;21:1712-1719. Geranylgeranylated Proteins (ie, Rho)