1 / 22

GISSI-HF

GISSI-HF. The G ruppo I taliano per lo S tudio della S opravvivenza nell’ I nsufficienza Cardiaca H eart F ailure (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.

masako
Download Presentation

GISSI-HF

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. GISSI-HF TheGruppoItaliano per lo StudiodellaSopravvivenzanell’Insufficienza CardiacaHeartFailure(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.

  2. 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

  3. 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

  4. GISSI-HF Study Design R1, R2 R1 (n=6975) n-3 PUFA 1 g q.d.(n=3494) Placebo (n=3481) R2 (n=4574) Placebo (n=2289) Rosuvastatin 10 mg q.d.(n=2285) Median follow-up 3.9 years Visit: 1 2 3 4 5 6 7 8 9 0 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 chemistryNYHA=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.

  5. 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 GISSI-HF – Study End Points *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.

  6. 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 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.

  7. 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.

  8. 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.

  9. 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/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 Adapted from GISSI-HF Investigators. Lancet 2008; doi:10.1016/S0140-6736(08)61240-4

  10. 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 7.0 COPD (%) 23.5 22.8 Neoplasia (%) 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.

  11. 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.

  12. GISSI-HF – Current Medications RosuvastatinPlacebo n=2285 n=2289 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 Adapted from GISSI-HF Investigators. Lancet 2008; doi:10.1016/S0140-6736(08)61240-4.

  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 0.90-1.12] 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 Adapted from GISSI-HF Investigators. Lancet 2008; doi:10.1016/S0140-6736(08)61240-4.

  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 [0.85-1.09] 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 hospitalizationfor 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.

  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) 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:10.1016/S0140-6736(08)61240-4.

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

  17. GISSI-HF – Predefined subgroup analysis All cause mortality or hospitalizations for cardiovascular reasons 100 90 Rosuvastatin Placebo 80 70 ns ns ns 64.7% ns 63.6% 63.1% 63.0% 60 ns 58.9% 58.7% ns 56.9% 55.8% 50 Patients with event (%) 52.1% 51.4% 51.4% 48.9% 40 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 0 Age <70 yrs Age >70 yrs Ischaemic HF Non-ischaemic HF EF < 40% EF > 40% Adapted from GISSI-HF Investigators. Lancet 2008; doi:10.1016/S0140-6736(08)61240-4.

  18. GISSI-HF – Predefined Subgroup Analysis All-cause mortality or hospitalizations for CV reasons 100 90 Rosuvastatin Placebo 80 ns 70 ns 66.6% ns 64.8% 63.8% 63.5% 60 ns ns 60.4% 58.6% ns 54.7% Patients with event (%) 53.9% 53.5% 53.2% 50 51.1% 51.1% 40 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 0 NYHA II NYHA III-IV TC< 4.97 mmol/L TC > 4.97 mmol/L Diabetes No diabetes Adapted from GISSI-HF Investigators. Lancet 2008; doi:10.1016/S0140-6736(08)61240-4.

  19. GISSI-HF – Lipid Data Rosuvastatin Placebo (n=2285) (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) Adapted from GISSI-HF Investigators. Lancet 2008; doi:10.1016/S0140-6736(08)61240-4.

  20. GISSI-HF – Tolerability and Safety DataPermanent 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 44 34 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.

  21. GISSI-HF – Tolerability and Safety DataLaboratory safety data Rosuvastatin Placebo (n=2285) (n=2289) • CK elevations • CK > 10 x ULN (n) 1 1 • Serum creatinine • Doublingof 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.

  22. 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.

More Related