The Gruppo Italiano per lo Studio della Sopravvivenza nell’Insufficienza Cardiaca Heart Failure (GISSI-HF) trial GISSI-HF Adapted from: Tavazzi et al

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 chemistryNYHA=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: 10

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 PointsCo-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”


• 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.

GISSI-HF – 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 CharacteristicsMean age (years) 68 68 >70 years (%) 43.9 44.2Female sex (%) 23.8 21.4Heart disease risk factorsBody mass index (kg/m2) 27.1 27.1Systolic BP (mmHg) 127 127Diastolic BP (mmHg) 77 77Heart rate (BPM) 73 73Current smoker (%) 14.1 14History of hypertension (%) 55.1 53.5NYHA class (%)

II 61.2 63.9III 36.2 33.7IV 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 HistoryHospitalization for HF in previous year (%) 52.0 49.4Previous MI (%) 31.8 33.8Previous stroke (%) 4.3 4.8Diabetes mellitus (%) 27.4 25.0CABG (%) 13.0 13.9PCI (%) 8.1 8.4ICD (%) 6.4 6.8Pacemaker (%) 13.1 11.5History of atrial fibrillation (%) 19.3 20.8 PVD (%) 8.1 7.0COPD (%) 23.5 22.8Neoplasia (%) 3.3 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.

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

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 33.3Calcium channel blockers (%) 10.1 10.1

Amiodarone (%) 20.3 18.4


ARB =angiotensin receptor blocker

GISSI-HF – Current Medications


HR = hazard ratio; CI = confidence interval *adjusted HR

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]1.2366 (2.9)82 (3.6)Fatal/non-fatal stroke

0.516[0.63-1.26]0.8970 (3.1)61 (2.7)Fatal/non-fatal MI

0.626[0.95-1.10]1.021385 (60.5)1417 (62.0)CV mortality or hospitalization for any reason

0.610[0.87-1.09]0.97634 (27.7)629 (27.5)Hospitalization for HF

0.371[0.88-1.05]0.961060 (46.3)1033 (45.2)Hospitalization for CV reason

0.776[0.92-1.07]0.991286 (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 (%)


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)


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 (%)



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

Pat

ient

s w

ith e

vent

(%

)

ns

nsns

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

Pat

ient

s w

ith 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

DiabetesNYHA 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

nsns

ns

nsns

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)

Rosuvastatin Placebo (n=2285) (n=2289)

GISSI-HF – Lipid Data


10 Hepatocellular jaundice

14 Creatine phosphokinase increase

10 Lipid abnormality

77 Allergic reaction

01 Asthenia

4434 GI disorders

01Acute renal failure

02Patients who permanently discontinued study treatment due to serious ADR, n (%)

1

23

1

2

6

26

104 (4.6)

790 (34.6)


0Acute 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

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


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.

Documents

The Gruppo Italiano per lo Studio della Sopravvivenza nell’Insufficienza Cardiaca Heart Failure (GISSI-HF) trial GISSI-HF Adapted from: Tavazzi et al