statins in the treatment of heart failure: failed concept? · per lo studio della sopravvivenza ......
TRANSCRIPT
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Statins in the Treatment of
Heart Failure: Failed Concept?
Tamara Horwich, MD, MS
Assistant Professor of Medicine
Division of Cardiology
March 16, 2012
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Background: Heart Failure
and Statins
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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.
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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.
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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.
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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.
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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
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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
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Even if TC and LDL are not Risk Factors
in Heart Failure - Potential Benefits of
Statins in Heart Failure
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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
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Observational Studies of
Statins in Heart Failure show
Marked Benefit
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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
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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.
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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.
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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
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Small Prospective Studies of
Statins in Heart Failure with
Surrogate Endpoints
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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*
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Statins and Cardiac Remodeling
in Humans
Node K et al. Circulation 2003
Simvastatin 3 months in
subjects with nonischemic HF
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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
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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.
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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
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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.
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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.
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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.
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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.
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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.
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• 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
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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.
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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.
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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
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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
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• 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
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.
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• 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
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.
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• 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
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.
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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
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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
GISSI-HF – Baseline Characteristics
Adapted from GISSI-HF Investigators. Lancet 2008; doi:10.1016/S0140-6736(08)61240-4.
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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
GISSI-HF – Baseline Characteristics
Adapted from GISSI-HF Investigators. Lancet 2008; doi:10.1016/S0140-6736(08)61240-4.
*Assessed with 2257 rosuvastatin patients and 2266 placebo patients
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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
Rosuvastatin Placebo
n=2285 n=2289
ARB =angiotensin receptor blocker
GISSI-HF – Current Medications
Adapted from GISSI-HF Investigators. Lancet 2008; doi:10.1016/S0140-6736(08)61240-4.
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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.
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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.
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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
Adapted from GISSI-HF Investigators. Lancet 2008; doi:10.1016/S0140-6736(08)61240-4.
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*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
Adapted from GISSI-HF Investigators. Lancet 2008; doi:10.1016/S0140-6736(08)61240-4.
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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 (%)
Adapted from GISSI-HF Investigators. Lancet 2008; doi:10.1016/S0140-6736(08)61240-4.
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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.
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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
Adapted from GISSI-HF Investigators. Lancet 2008; doi:10.1016/S0140-6736(08)61240-4.
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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
Adapted from GISSI-HF Investigators. Lancet 2008; doi:10.1016/S0140-6736(08)61240-4.
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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)
Rosuvastatin Placebo
(n=2285) (n=2289)
GISSI-HF – Lipid Data
Adapted from GISSI-HF Investigators. Lancet 2008; doi:10.1016/S0140-6736(08)61240-4.
Exploratory analysis of treatment effect of how low LDL is lowered shows no
effect
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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)
Adapted from GISSI-HF Investigators. Lancet 2008; doi:10.1016/S0140-6736(08)61240-4.
*Diagnosed as Stevens-Johnson syndrome by the investigator, not confirmed by an expert adjudicator
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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)
Rosuvastatin Placebo
(n=2285) (n=2289)
GISSI-HF – Tolerability and Safety Data
Laboratory safety data
*Median values
Adapted from GISSI-HF Investigators. Lancet 2008; doi:10.1016/S0140-6736(08)61240-4.
CK = creatine kinase
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• 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.
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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
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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
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Kaul and Diamond. JACC 2010; 55:415-27.
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Kaul and Diamond. JACC 2010; 55:415-27.
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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.