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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, placebo-controlled,
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)
R1, R2
Visit:
Month:
1
0
D
Placebo
(n=2289)
Median follow-up 3.9 years
2
1
3
3
4
6
5
12
6
18
7
24
8
30
9
36
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:10.1016/S01.40-6736(08)61240-4.
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
*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 – 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;
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
n=2285
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% (%)
Placebo
n=2289
68
43.9
23.8
68
44.2
21.4
27.1
127
77
73
14.1
27.1
127
77
73
14
55.1
53.5
61.2
36.2
2.6
33.4
10.3
Adapted from GISSI-HF Investigators. Lancet 2008; doi:10.1016/S0140-6736(08)61240-4
63.9
33.7
2.4
33.1
9.8
GISSI-HF – Baseline Characteristics
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 (%)
Rosuvastatin
n=2285
Placebo
n=2289
52.0
31.8
4.3
27.4
13.0
8.1
6.4
13.1
19.3
8.1
23.5
3.3
49.4
33.8
4.8
25.0
13.9
8.4
6.8
11.5
20.8
7.0
22.8
4.0
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.
GISSI-HF – Baseline Characteristics
Rosuvastatin
n=2285
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 (%)
Placebo
n=2289
39.8
34.7
17.9
3.1
4.5
40.2
34.2
18.1
2.8
4.7
28.3
25.2
64.2
1.9
26.8
24.1
63.9
2.1
35.2
18.8
16.8
21.5
33.6
19.8
19.2
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
Rosuvastatin
n=2285
Medication
ACE inhibitors (%)
ARBs (%)
ACE inhibitors/ARBs (%)
Beta blockers (%)
Spironolactone (%)
Diuretics (%)
Digitalis (%)
Oral anticoagulants (%)
ASA (%)
Other antiplatelet agents (%)
Nitrates (%)
Calcium channel blockers (%)
Amiodarone (%)
77.3
19.3
94.1
62.7
39.0
90.0
40.0
29.8
44.6
7.8
31.9
10.1
20.3
ARB =angiotensin receptor blocker
Adapted from GISSI-HF Investigators. Lancet 2008; doi:10.1016/S0140-6736(08)61240-4.
Placebo
n=2289
77.9
17.1
92.9
62.0
41.3
90.0
40.0
30.5
45.6
8.2
33.3
10.1
18.4
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 0.911.11]
0.90
HR = hazard ratio; CI = confidence interval
*adjusted HR
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
Rosuvastatin
(n=2285)
n (%)
Placebo
(n=2289)
n (%)
Total mortality
657 (28.8)
644 (28.1)
CV mortality
478 (20.9)
488 (21.3)
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)
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)
Acute MI
Non-CV mortality
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
38
31
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:10.1016/S01.40-6736(08)61240-4.
GISSI-HF – Predefined subgroup analysis
All cause mortality or hospitalizations for cardiovascular reasons
Patients with event (%)
100
90
Rosuvastatin
80
Placebo
70
60
50
ns
ns
63.1%
ns
63.6%
ns
ns
56.9%
58.9%
64.7%
63.0%
ns
58.7%
55.8%
51.4%
52.1%
51.4%
717/
1376
704/
1370
48.9%
40
30
20
10
0
606/
1178
575/
1176
Age <70 yrs
699/
1107
708/
1113
Age >70 yrs
1166/
2049
1151/
2064
EF < 40%
139/
236
132/
225
EF > 40%
588/
909
579/
919
Ischaemic
HF
Adapted from GISSI-HF Investigators. Lancet 2008; doi:10.1016/S0140-6736(08)61240-4.
Non-ischaemic
HF
GISSI-HF – Predefined Subgroup Analysis
All-cause mortality or hospitalizations for CV reasons
Patients with event (%)
100
90
Rosuvastatin
80
Placebo
ns
70
66.6%
60
50
ns
64.8%
63.5%
63.8%
ns
ns
54.7%
51.1%
51.1%
714/
1398
747/
1462
ns
60.4%
ns
58.6%
53.5%
53.9%
53.2%
609/
1131
595/
1118
40
30
20
10
0
NYHA II
591/
887
536/
827
NYHA III-IV
397/
625
364/
571
Diabetes
908/
1660
919/
1718
No diabetes
Adapted from GISSI-HF Investigators. Lancet 2008; doi:10.1016/S0140-6736(08)61240-4.
685/
1135
676/
1153
TC
< 4.97 mmol/L
TC
> 4.97 mmol/L
GISSI-HF – Lipid Data
Rosuvastatin
(n=2285)
LDL-C
Baseline; mmol/L (mg/dL)
One year; mmol/L (mg/dL)
Three years; mmol/L (mg/dL)
3.16 (122)
2.15 (83)
2.31 (89)
Adapted from GISSI-HF Investigators. Lancet 2008; doi:10.1016/S0140-6736(08)61240-4.
Placebo
(n=2289)
3.13 (121)
3.37 (113)
3.06 (118)
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
0
Allergic reaction
7
7
Liver dysfunction
26
12
Lipid abnormality
0
1
Creatine phosphokinase increase
4
1
Renal dysfunction
6
4
Acute renal failure
2
0
Hepatocellular jaundice
0
1
Acute dermatitis*
1
0
Muscle-related symptoms
23
21
Patients who permanently discontinued study
treatment due to serious ADR, n (%)
2
0
Acute renal failure
1
0
Acute dermatitis*
1
0
*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.
GISSI-HF – Tolerability and Safety Data
Laboratory safety data
Rosuvastatin
(n=2285)
CK elevations
CK > 10 x ULN (n)
Serum creatinine
Doubling of serum creatinine, n (%)
Baseline, µmol/L (mg/dL)*
One year, µmol/L (mg/dL)*
Three years, µmol/L (mg/dL)*
1
65 (3%)
94.59 (1.07)
96.36 (1.09)
97.24 (1.10)
*Median values
CK = creatine kinase
Adapted from GISSI-HF Investigators. Lancet 2008; doi:10.1016/S0140-6736(08)61240-4.
Placebo
(n=2289)
1
57 (2.6%)
95.47 (1.08)
97.24 (1.10)
97.24 (1.10)
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.