1. GISSI-HF
The Gruppo Italiano per lo Studio della Sopravvivenza nell’Insufficienza Cardiaca Heart Failure (GISSI-HF) trial
References Tavazzi L, Tognoni G, Franzosi MG et al. Rationale and design of the GISSI heart failure trial: a large trial to assess the effects of n-3 polyunsaturated fatty acids and rosuvastatin in symptomatic congestive heart failure. Eur J Heart Fail (5):635–641 GISSI-HF Investigators. Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet 2008; doi: /S (08)
Adapted from: Tavazzi et al. Eur J Heart Fail 2004;6:635–41. GISSI-HF Investigators. Lancet 2008;doi: /S (08)

2. 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.
Results from observational studies and post-hoc analyses suggest that statins may have beneficial effects in heart failure. We saw however in the CORONA trial that in elderly (mean age 73) patients with advanced heart failure, the addition of a statin to optimized heart failure therapy did not provide an incremental benefit and was not able to prevent the deterioration of a failing heart muscle; there was an 8% reduction in the combined primary endpoint of cardiovascular death or nonfatal myocardial infarction or nonfatal stroke (p=0.12) which was primarily driven by the reduction of atherosclerotic events, ie stroke and myocardial infarctions (post hoc analysis p=0.05).
With regard to n-3 PUFA, the GISSI-Prevenzione trial showed that 3-year treatment with low-dose n-3 PUFA was associated with a significant total mortality reduction of 21% in patients who survived a recent MI (starting treatment within 3 months from symptom onset). A post-hoc analysis of the causes of death showed that among all cardiac causes, the most affected by n-3 PUFA was sudden cardiac death. Other experimental, epidemiological, as well as small size human studies are consistent with these findings and support the hypothesis that n-3 PUFA can exert antiarrhythmic or antifibrillatory effects. This can be relevant for heart failure patients because nearly half of the deaths of patients with symptomatic heart failure are classified as sudden cardiac deaths. A post-hoc analysis of the GISSI-Prevenzione trial showed that, in nearly 2000 post-infarction patients with LV dysfunction/failure enrolled in the trial, the effects of n-3 PUFA on all-cause and sudden mortality were similar to those observed in the total population of the trial. Therefore, the hypothesis that n-3 PUFA can improve the outcome of patients with heart failure of any aetiology and any level of left ventricular function merits formal testing.
References:
GISSI-HF Investigators. Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet 2008; doi: /S (08)
Kjekshus J et al. Rosuvastatin in Older Patients with Systolic Heart Failure. N Eng J Med 2007; 357 (22):
GISSI-Prevenzione Investigators. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamine E afeter myocardial infarction: results of the GISSI-Prevenzione trial. Lancet 1999; 354:

3. 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
The primary objectives were to investigate whether the long-term administration of n-3 PUFA (1 g daily) and rosuvastatin (10 mg daily) 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 reasons
References Tavazzi L, Tognoni G, Franzosi MG et al. Rationale and design of the GISSI heart failure trial: a large trial to assess the effects of n-3 polyunsaturated fatty acids and rosuvastatin in symptomatic congestive heart failure. Eur J Heart Fail (5):635–641 GISSI-HF Investigators. Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet 2008; doi: /S (08)

4. Rosuvastatin 10 mg q.d. (n=2285)
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
GISSI-HF trial design
GISSI-HF was a double-blind, placebo-controlled, randomized trial designed to assess the effects of n-3 polyunsaturated fatty acids (PUFAs) and rosuvastatin in patients who had-
clinical evidence of heart failure of any aetiology:-
classified as NYHA class II–IV
treated according to European Society of Cardiology Guidelines
left ventricular ejection fraction measured within 3 months of enrollment
if their ejection fraction was >40%, they had to have had at least one hospital admission for heart failure in the previous year
aged 18 and above; no age limit
Note; of the 6975 patients eligible for R1, 2401 patients were not included in the R2 (rosuvastatin) arm of the study;1576 required statin therapy, 395 were contraindicated to statins and 430 were not suitable in the opinion of the investigator.
References Tavazzi L, Tognoni G, Franzosi MG et al. Rationale and design of the GISSI heart failure trial: a large trial to assess the effects of n-3 polyunsaturated fatty acids and rosuvastatin in symptomatic congestive heart failure. Eur J Heart Fail (5):635–641 GISSI-HF Investigators. Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet 2008; doi: /S (08)
Visit: 1 2 3 4 5 6 7 8 9 1 3 6 12 18 24 30 36
Month: D D D D D 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
Adapted from: Tavazzi et al. Eur J Heart Fail 2004;6: 635–41. GISSI-HF Investigators. Lancet 2008;doi: /S (08)

5. GISSI-HF – Study End Points
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
PRIMARY ENDPOINTS
Two co-primary endpoints for both R1 and R2 were:-
All-cause mortality (time to death)
All-cause mortality (time to death) or hospitalisation for CV reasons
All primary analyses were performed for the ITT population.
Classification of causes of hospitalization
CV cause of hospitalization [Myocardial infarction (MI), angina, worsening heart failure, arrhythmia, revascularization procedures, other cardiac cause, stroke, transient ischemic attack, other vascular cause]
Non CV cause of hospitalization [Neoplasia - gastrointestinal, pulmonary, mammary, prostate, brain, skin, genital-urinary, other neoplasia; Myopathy; Renal failure; Liver dysfunction; other non CV cause of hospitalization; Unknown cause of hospitalization
SECONDARY ENDPOINTS
Hospitalization means admission to a hospital involving an overnight stay or resulting in death. Day-care admissions are not included in the secondary end-point.
References
GISSI-HF stats analysis plan
Tavazzi L, Tognoni G, Franzosi MG et al. Rationale and design of the GISSI heart failure trial: a large trial to assess the effects of n-3 polyunsaturated fatty acids and rosuvastatin in symptomatic congestive heart failure. Eur J Heart Fail (5):635–641 GISSI-HF Investigators. Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet 2008; doi: /S (08)
*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: /S (08)

6. GISSI-HF – 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)
Aetiology (ischemic vs. non-ischemic)
Diabetes (yes vs. no)
Baseline total cholesterol levels (above vs. below median value; 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.
Sub-group analyses
For both randomisations (R1 and R2), subgroup analyses will be performed as specified in the protocol. The objective of these subgroup analyses was to show the consistency of treatment effects across a variety of patient groups.
The primary end-point for all the subgroup analyses was the combined outcome measure of all-cause mortality or hospital admission for CV reasons.
By using the combined outcome measure of all-cause mortality or hospital admission for CV reasons, the effects of the study drugs will be evaluated in the following predefined subgroups of patients:-
age (above/below the median value, which was 70 years);
left ventricular function (LVEF% >40% vs <40%);
aetiology (ischemic vs non-ischemic);
functional capacity (NYHA class II vs III-IV);
diabetes (yes vs no);
baseline total cholesterol levels (above/below the median value; which was 4.97 mmol/L; 192mg/dL)
References Tavazzi L, Tognoni G, Franzosi MG et al. Rationale and design of the GISSI heart failure trial: a large trial to assess the effects of n-3 polyunsaturated fatty acids and rosuvastatin in symptomatic congestive heart failure. Eur J Heart Fail (5):635–641 GISSI-HF Investigators. Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet 2008; doi: /S (08)
Adapted from: Tavazzi et al. Eur J Heart Fail 2004;6: 635–41. GISSI-HF Investigators. Lancet 2008;doi: /S (08)

7. 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
GISSI-HF trial design
Patients with clinical evidence of heart failure of any aetiology:-
classified as NYHA class II–IV
treated according to European Society of Cardiology Guidelines
left ventricular ejection fraction measured within 3 months of enrollment
if their ejection fraction was >40%, they had to have had at least one hospital admission for heart failure in the previous year
aged 18 and above; no age limit
References Tavazzi L, Tognoni G, Franzosi MG et al. Rationale and design of the GISSI heart failure trial: a large trial to assess the effects of n-3 polyunsaturated fatty acids and rosuvastatin in symptomatic congestive heart failure. Eur J Heart Fail (5):635–641 GISSI-HF Investigators. Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet 2008; doi: /S (08)
Adapted from: Tavazzi et al. Eur J Heart Fail 2004;6: 635–41. GISSI-HF Investigators. Lancet 2008;doi: /S (08)

8. 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
EXCLUSION CRITERIA
- acute coronary syndrome or revascularization procedure within 1 month of randomisation;
- planned cardiac surgery, expected to be performed within 3 months of randomisation;
- known hypersensitivity to study treatments;
- significant liver disease;
- serum creatinine concentration > 221 micromol/L
- current ALT, AST level >1.5 times the upper normal limit;
- current CPK above the upper normal limit
- pregnant or lactating women or women of childbearing potential who are not protected from pregnancy by an accepted method of contraception;
- any condition that in the opinion of the investigator would jeopardize the evaluation of efficacy or safety or be associated with poor adherence to the protocol;
- 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;
- patients already on treatment with n-3 PUFA or statin for whom the prescription is confirmed.
References Tavazzi L, Tognoni G, Franzosi MG et al. Rationale and design of the GISSI heart failure trial: a large trial to assess the effects of n-3 polyunsaturated fatty acids and rosuvastatin in symptomatic congestive heart failure. Eur J Heart Fail (5):635–641 GISSI-HF Investigators. Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet 2008; doi: /S (08)
Adapted from: Tavazzi et al. Eur J Heart Fail 2004;6: 635–41. GISSI-HF Investigators. Lancet 2008;doi: /S (08)

9. GISSI-HF – Baseline Characteristics
Rosuvastatin Placebo n= n=2289
Patient Characteristics
Mean age (years)
>70 years (%)
Female sex (%)
Heart disease risk factors
Body mass index (kg/m2)
Systolic BP (mmHg)
Diastolic BP (mmHg)
Heart rate (BPM)
Current smoker (%)
History of hypertension (%)
NYHA class (%) II
III IV
EF(%)
EF>40% (%)
Patients in each group were similar at entry. Patients in GISSI-HF had a mean age of 68, over 40% were over the age of 70. They had predominantly NYHA class II (approx 60%) and III (approx 35%) heart failure and mean ejection fraction of 33%1
[For comparison, patients in CORONA had a mean age was 73 years, approximately 40% of patients were over the age of 75. They had predominantly NYHA class II (approx 37%) and III (approx 61%) heart failure with an impaired left ventricular function (mean ejection fraction of 31%)] 2
References GISSI-HF Investigators. Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet 2008; doi: /S (08)
Kjekshus J et al. Rosuvastatin in Older Patients with Systolic Heart Failure. N Eng J Med 2007; 357 (22):
Adapted from GISSI-HF Investigators. Lancet 2008; doi: /S (08) 9

10. GISSI-HF – Baseline Characteristics
Rosuvastatin Placebo n= n=2289
Medical History
Hospitalization for HF in previous year (%)
Previous MI (%)
Previous stroke (%)
Diabetes mellitus (%)
CABG (%)
PCI (%)
ICD (%)
Pacemaker (%)
History of atrial fibrillation (%)
PVD (%)
COPD (%)
Neoplasia (%)
GISSI-HF patients had a lower incidence of previous MI and stroke than patients in CORONA
References GISSI-HF Investigators. Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet 2008; doi: /S (08)
Kjekshus J et al. Rosuvastatin in Older Patients with Systolic Heart Failure. N Eng J Med 2007; 357 (22):
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: /S (08) 10

11. GISSI-HF – Baseline Characteristics
Rosuvastatin Placebo n= n=2289
Heart Failure Cause/Etiology
Ischemic (%)
Dilatative (%)
Hypertensive (%)
Other causes (%)
Non-detectable/unknown (%)
Physical Examinations
Pulmonary râles (%)
Third heart sound (%)
Mitral insufficiency (%)
Aortic stenosis (%)
ECG Findings
*QRS>120 ms (%)
Atrial fibrillation (%)
Pathological Q waves (%)
LV hypertrophy (%)
In contrast to CORONA, in which all patients had ischaemic heart failure, only 40% of patients in GISSI-HF had heart failure of ischaemic origin.
References GISSI-HF Investigators. Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet 2008; doi: /S (08)
Kjekshus J et al. Rosuvastatin in Older Patients with Systolic Heart Failure. N Eng J Med 2007; 357 (22):
*Assessed with 2257 rosuvastatin patients and 2266 placebo patients
Adapted from GISSI-HF Investigators. Lancet 2008; doi: /S (08) 11

12. GISSI-HF – Current Medications
Rosuvastatin Placebo n= n=2289
Medication
ACE inhibitors (%)
ARBs (%)
ACE inhibitors/ARBs (%)
Beta blockers (%)
Spironolactone (%)
Diuretics (%)
Digitalis (%)
Oral anticoagulants (%)
ASA (%)
Other antiplatelet agents (%)
Nitrates (%) Calcium channel blockers (%)
Amiodarone (%)
Patients in GISSI-HF were being well treated for heart failure with 90% on diuretics, 93% on an ACE inhibitor or an Angiotensin Receptor Blocker, 62% on beta-blockers therapy and 40% on spironolactone (aldosterone antagonist).
[Similar to CORONA, with almost 90% on diuretics, 90% on an ACEi or an ARB, 75% on a beta-blocker and 39% on an aldosterone antagonist]
References GISSI-HF Investigators. Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet 2008; doi: /S (08)
Kjekshus J et al. Rosuvastatin in Older Patients with Systolic Heart Failure. N Eng J Med 2007; 357 (22):
ARB =angiotensin receptor blocker
Adapted from GISSI-HF Investigators. Lancet 2008; doi: /S (08) 12

13. 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 ]
0.94
All-cause mortality or CV hospitalizations
1305 (57)
1283 (56)
1.01
[99% CI ]
0.90
Results: The was no difference between rosuvastatin and placebo for either of the co-primary endpoints.
All-cause mortality - there were 657 deaths in the rosuvastatin group (29%) and in 644 deaths in placebo group (28%) - HR 1.00; 95.5% CI, 0.90 to 1.12; p= 0.94;
All-cause mortality or CV hospitalisations - There were 1305 deaths/CV hospitalisations in the rosuvastatin group (57.1%) and 644 in the placebo group (56.1%) - HR 1.01; 99% CI, 0.91 to 1.11; p= 0.90.
[In the per-protocol analysis of the 2874 patients who were fully compliant ie those who had taken treatment for at least 80% of the time of observation, the rate of all-cause death was 29% (429/1461) with rosuvastatin and 27% (377/1413) with placebo (adjusted HR 1·12, 95·5%, CI 0·97-1·29; p=0·16)]
Reference GISSI-HF Investigators. Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet 2008; doi: /S (08)
HR = hazard ratio; CI = confidence interval
*adjusted HR
Adapted from GISSI-HF Investigators. Lancet 2008; doi: /S (08) 13

14. 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
[ ]
0.550
Sudden cardiac death
220 (9.6)
196 (8.6)
1.12
[ ]
0.257
Patients hospitalized
1278 (55.9)
1286 (56.2)
0.99
[ ]
0.776
Hospitalization for CV reason
1033 (45.2)
1060 (46.3)
0.96
[ ]
0.371
Hospitalization for HF
629 (27.5)
634 (27.7)
0.97
[ ]
0.610
CV mortality or hospitalization for any reason
1417 (62.0)
1385 (60.5)
1.02
[ ]
0.626
Results: The was no difference between rosuvastatin and placebo for any of the secondary endpoints.
Reference GISSI-HF Investigators. Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet 2008; doi: /S (08)
Fatal/non-fatal MI
61 (2.7)
70 (3.1)
0.89
[ ]
0.516
Fatal/non-fatal stroke
82 (3.6)
66 (2.9)
1.23
[ ]
0.211
*adjusted HR
Adapted from GISSI-HF Investigators. Lancet 2008; doi: /S (08) 14

15. GISSI-HF – Cause of Death
Rosuvastatin
(n=2285)
n (%)
Placebo
(n=2289)
n (%)
Total mortality
657 (28.8)
644 (28.1)
CV mortality
478 (20.9)
488 (21.3)
Acute MI
10 (0.4)
15 (0.7)
Worsening of heart failure
203 (8.9)
231 (10.1)
Presumed arrhythmic
198 (8.7)
182 (8.0)
Stroke
38 (1.7)
29 (1.3)
Other CV reasons
29 (1.3)
31 (1.4)
Results: Looking at the causes of cardiovascular death in the GISSI-HF trial, of note was the low number of fatal MI and strokes (92/966 CV deaths) in this population compared with the number of deaths caused by worsening heart failure or presumed arrhythmic (814/966 CV deaths). This suggests that the mode of death in this population of patients is unlikely to be related to acute coronary ischemia which is where benefit with statins has been demonstrated.
Reference GISSI-HF Investigators. Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet 2008; doi: /S (08)
Kjekshus J et al. Rosuvastatin in Older Patients with Systolic Heart Failure. N Eng J Med 2007; 357 (22):
Non-CV mortality
156 (6.8)
179 (7.8)
Neoplasia
81 (3.5)
75 (3.3)
Other non-CV reason
75 (3.3)
55 (2.4)
Not known
23 (1.0)
26 (1.1)
Adapted from GISSI-HF Investigators. Lancet 2008; doi: /S (08) 15

16. GISSI-HF: Causes of CV Mortality
No. of CV
deaths=478
No. of CV deaths= 488 29 31 38 29
Other CV
198
182
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: /S (08)

17. All cause mortality or hospitalizations for cardiovascular reasons
GISSI-HF – Predefined subgroup analysis
All cause mortality or hospitalizations for cardiovascular reasons
100 90
Rosuvastatin
Placebo 80 70 ns ns ns 60
63.1%
63.6% ns
64.7%
63.0% ns
58.9%
58.7% ns
56.9%
55.8%
Patients with event (%) 50
51.4%
52.1%
51.4%
48.9% 40
Results: The risk of all-cause mortality or CV hospitalisation was not affected by rosuvastatin in any of the pre-defined subgroups (shown here, age, ejection fraction and HF aetiology).
Reference GISSI-HF Investigators. Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet 2008; doi: /S (08) 30 20 10
606/ 1178
575/ 1176
699/ 1107
708/ 1113
1166/ 2049
1151/ 2064
139/ 236
132/ 225
588/ 909
579/ 919
717/ 1376
704/ 1370
Age <70 yrs
Age >70 yrs
EF < 40%
EF > 40%
Ischaemic HF
Non-ischaemic HF
Adapted from GISSI-HF Investigators. Lancet 2008; doi: /S (08)

18. All-cause mortality or hospitalizations for CV reasons
GISSI-HF – Predefined Subgroup Analysis
All-cause mortality or hospitalizations for CV reasons
100 90
Rosuvastatin
Placebo 80 ns 70 ns
66.6%
64.8% ns 60
63.5%
63.8% ns ns
60.4% ns
58.6%
Patients with event (%)
54.7% 50
53.5%
53.9%
53.2%
51.1%
51.1% 40
Results: The risk of all-cause mortality or CV hospitalisation was not affected by rosuvastatin in any of the pre-defined subgroups (shown here, NYHA class, diabetes and total cholesterol).
Reference GISSI-HF Investigators. Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet 2008; doi: /S (08) 30 20 10
714/ 1398
747/ 1462
591/ 887
536/ 827
397/ 625
364/ 571
908/ 1660
919/ 1718
685/ 1135
676/ 1153
609/ 1131
595/ 1118
NYHA II
NYHA III-IV
Diabetes
No diabetes
TC < 4.97 mmol/L
TC > 4.97 mmol/L
Adapted from GISSI-HF Investigators. Lancet 2008; doi: /S (08)

19. GISSI-HF – Lipid Data Rosuvastatin Placebo (n=2285) (n=2289) LDL-C
Baseline; mmol/L (mg/dL) (122) (121)
One year; mmol/L (mg/dL) (83) (113)
Three years; mmol/L (mg/dL) (89) (118)
Reference GISSI-HF Investigators. Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet 2008; doi: /S (08)
Adapted from GISSI-HF Investigators. Lancet 2008; doi: /S (08)

20. GISSI-HF – Tolerability and Safety Data Permanent discontinuations and adverse drug reactions (ADR)
Rosuvastatin
(n=2285)
Placebo
(n=2289)
Patients who permanently discontinued study treatment, n (%)
790 (34.6)
831 (36.3)
Patients who permanently discontinued study treatment due to ADR, n (%)
104 (4.6)
91 (4.0)
GI disorders 34 44
Asthenia 1
Allergic reaction 7 7
Liver dysfunction 26 12
Lipid abnormality 1
Creatine phosphokinase increase 4 1
Renal dysfunction 6 4
Acute renal failure
Tolerability and safety: Rosuvastatin was generally well tolerated. The number of patients who discontinued study drug was similar for rosuvastatin and placebo.
Reference GISSI-HF Investigators. Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet 2008; doi: /S (08)
Fonarow GC. Statins and n-3 fatty acid supplementation in heart failure. Lancet 2008; doi: /S (08) 2
Hepatocellular jaundice 1
Acute dermatitis* 1
Muscle-related symptoms 23 21
Patients who permanently discontinued study treatment due to serious ADR, n (%) 2
Acute renal failure 1
Acute dermatitis* 1
*Diagnosed as Stevens-Johnson syndrome by the investigator, not confirmed by an expert adjudicator
Adapted from GISSI-HF Investigators. Lancet 2008; doi: /S (08) 20

21. GISSI-HF – Tolerability and Safety Data Laboratory safety data
Rosuvastatin Placebo (n=2285) (n=2289)
CK elevations
CK > 10 x ULN (n)
Serum creatinine
Doubling of serum creatinine, n (%) (3%) (2.6%)
Baseline, µmol/L (mg/dL)* (1.07) (1.08)
One year, µmol/L (mg/dL)* (1.09) (1.10)
Three years, µmol/L (mg/dL)* (1.10) (1.10)
Tolerability and safety:
There was no significant difference in the number of patients with elevations in creatine kinase (CK) between the rosuvastatin and placebo groups (1 patient in each group reported CK > 10x ULN)
There were no cases of rhabdomyolysis in either the rosuvastatin or placebo groups
Rosuvastatin was well-tolerated:-
the change in serum creatinine from baseline to 1 year and 3 years was similar with rosuvastatin (n= 2285, from 94.59μmol/L to 96.36μmol/L and 97.24μmol/L respectively) and placebo (n= 2289, from 95.47μmol/L to 97.24μmol/L and 97.24μmol respectively).
a low number of patients experienced a doubling of serum creatinine level with both rosuvastatin and placebo (p=ns)
Reference GISSI-HF Investigators. Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet 2008; doi: /S (08)
Fonarow GC. Statins and n-3 fatty acid supplementation in heart failure. Lancet 2008; doi: /S (08)
*Median values
CK = creatine kinase
Adapted from GISSI-HF Investigators. Lancet 2008; doi: /S (08)

22. 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.
Reference GISSI-HF Investigators. Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet 2008; doi: /S (08)
Kjekshus J et al. Rosuvastatin in Older Patients with Systolic Heart Failure. N Eng J Med 2007; 357 (22):
Fonarow GC. Statins and n-3 fatty acid supplementation in heart failure. Lancet 2008; doi: /S (08)
Adapted from: GISSI-HF Investigators. Lancet 2008; doi: /S (08)
Fonarow GC. Lancet 2008;doi: /S (08)
Kjekshus et al. N Engl J Med 2007;357: