Effects of n-3 PUFA in 6975 patients with chronic heart failure. The GISSI-HF trial
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Transcript of Effects of n-3 PUFA in 6975 patients with chronic heart failure. The GISSI-HF trial
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Effects of n-3 PUFA in 6975 patients with chronic heart failure.
The GISSI-HF trial
Luigi Tavazzi
on behalf of the GISSI-HF Investigators
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• N-3 polyunsaturated fatty acids hypothesis
• Rosuvastatin hypothesis
in chronic HF patients
GISSI-HF trial
Two nested studies to test:
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• Experimental studies extensively documented in cellular and animal models the favourable effects of n-3 PUFA on:• inflammatory processes (including reduction of endothelial
activation and cytokine production)• platelet aggregation, • blood pressure and heart rate• ventricular function• autonomic tone• Arrhythmogenesis
n-3 PUFA rationale
• Epidemiological studies showed that fish consumption can be associated with a lower rate of cardiac death
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Effect of n-3 PUFA treatment inGISSI-Prevenzione (11.323 post-MI pts)
0%0%
-15%-15%
DeathDeathNon-fatal AMINon-fatal AMI
Non-fatal strokeNon-fatal stroke
p<0.02p<0.02
-20%-20%
CV DeathCV DeathNon-fatal AMINon-fatal AMI
Non-fatal strokeNon-fatal stroke
p<0.008p<0.008
-21%-21%
OverallOverallmortalitymortality
p<0.02p<0.02-30%-30%
CV deathCV death
p<0.02p<0.02
-44%-44%
SuddenSuddendeathdeath
p<0.01p<0.01
-4%-4%
Non-fatalNon-fataleventsevents
n.s.n.s.
-50%-50%
-45%-45%
-40%-40%
-35%-35%
-30%-30%
-25%-25%
-20%-20%
-15%-15%
-10%-10%
-5%-5%
% risk reduction% risk reduction(GISSI-Prevenzione Investigators, Lancet 1999; 354:447)
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• n-3 PUFA could improve morbidity and mortality of patients with symptomatic HF of any etiology and any level of LVEF
n-3 PUFA hypothesis
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Inclusion criteria
• Patients 18 years old with chronic symptomatic heart failure (ESC Guidelines) of any etiology and with any LVEF
Exclusion criteria
• Indication, contraindication or known hypersensivity to the n-3 PUFA
• Severe comorbidities unlikely to be compatible with a long follow-up or requiring surgery
• Acute coronary syndrome or cardiac procedure within the preceding 1 month.
GISSI-HF
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n. 3494 patientsn-3 PUFA 1g daily
n. 3481 patientsPlacebo
n. 2285 patientsRosuvastatin 10 mg daily
n. 2289 patientsPlacebo
4574patients
(eligible for rosuvastatin randomization)
n. 2401 patients not eligible for rosuvastatin: 1576 treated with statin 395 contraindications to statins 430 Investigator decision
6975patients
GISSI-HF design
3.9-years median follow-up(6 patients have been lost to follow-up)
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Patients’ characteristics6975 pts enrolled in 357 centres in Italy
n-3 PUFA(n. 3494)
Placebo(n. 3481)
Age (years), mean±SD 67±11 67±11
Females, n. (%) 777 (22) 739 (21)
BMI (kg/m2), mean±SD 27±5 27±5
SBP (mmHg), mean±SD 126±18 126±18
Heart rate (bpm), mean±SD 72±13 73±14BMI=body mass index; SBP=systolic blood pressure
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Heart failure characteristicsn-3 PUFA(n. 3494)
Placebo(n. 3481)
Etiology, n. (%)
Ischemic
Dilatative
Hypertensive
Other
Non detectable/Unknown
1717 (49)
1053 (30)
493 (14)
107 (3)
124 (4)
1750 (50)
972 (28)
543 (16)
89 (3)
127 (4)
NYHA class, n. (%)
II
III-IV
2226 (64)
1268 (36)
2199 (63)
1282 (37)
LVEF (%), mean±SD 33.0±8.5 33.2±8.5
LVEF >40%, n. (%) 333 (9.5) 320 (9.2)LVEF=left ventricular ejection fraction
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Medical historyn-3 PUFA(n. 3494)
Placebo(n. 3481)
History of hypertension (%) 54 55
Diabetes mellitus (%) 28 28
Hospitalisation for HF in the
previous year (%)* 50 47
Previous AMI (%) 42 42
Previous stroke (%) 5 5
History of atrial fibrillation (%) 19 18
Peripheral vascular disease (%) 8 9
COPD (%) 21 23 *p 0.05
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Concomitant medical treatmentn-3 PUFA(n. 3494)
Placebo(n. 3481)
ACE-inhibitors/ARBs (%) 93 93
Beta-blockers (%) 65 65
Spironolactone (%) 39 40
Diuretics (%) 89 90
Digitalis (%) 37 37
Oral anticoagulants (%) 29 28
Aspirin (%) 48 48
Nitrates (%) 35 35
Calcium-channel blockers (%) 10 10
Amiodarone (%) 19 20
Statin (open) (%) 22 23ARBs=angiotensin receptor blockers;
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RESULTS
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• All cause death
• All-cause death or hospitalization for CV reasons
Primary end-points
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Time to all-cause death
n-3 PUFA: 955/3494 (27.3%)Placebo: 1014/3481 (29.1%)Absolute RR = 1.8%
NNT = 56
unadjusted HR (95.5% CI) 0.93 (0.85 – 1.02), p value 0.124
adjusted HR (95.5% CI)* 0.91 (0.83 – 0.99), p value 0.041
*Cox proportional hazards model, adjusting for: hospitalisation for HF in the previous year, prior pacemaker, aortic stenosis (p<0.1).
n-3 PUFA
Placebo
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Time to all-cause death or hospitalisation for CV reasons
unadjusted HR (99% CI) 0.94 (0.87 – 1.02), p value 0.059adjusted HR (99% CI)* 0·92 (0.85 – 0.99), p value 0.009
n-3 PUFA
Placebo
*Cox proportional hazards model, adjusting for: hospitalisation for HF in the previous year, prior pacemaker, aortic stenosis (p<0.1).
n-3 PUFA: 1981/3494 (56.7%)Placebo: 2053/3481 (59.0%)Absolute RR = 2.3%NNT = 44
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n-3 PUFA(n. 3494)
%
Placebo(n. 3481)
%
Adjusted
HR 95%CI*p
value
Patients who died of a CV cause 20.4 22.0 0.90 0.81-0.99 0.045
Patients who had a SCD 8.8 9.3 0.93 0.79-1.08 0.333
Patients hospitalized 56.8 58.3 0.94 0.88-1.00 0.049
Patients hospitalized for a CV
reason
46.8 48.5 0.93 0.87-0.99 0.026
Patients hospitalized for HF 28.0 28.6 0.94 0.86-1.02 0.147
Patients who died of a CV cause
or hospitalized for any reason61.7 63.3 0.94 0.89-0.99 0.043
* Cox proportional hazards model adjusting for: hospitalisation for HF in the previous year, prior pacemaker, and aortic stenosis (p<0.1).
Predefined Secondary Outcomes
CV=cardiovascular; SCD=sudden cardiac death; HF=heart failure
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* Cox proportional hazards model adjusting for: hospitalisation for HF in the previous year, prior pacemaker, and aortic stenosis (p<0.1).
Predefined Secondary OutcomesVascular events
n-3 PUFA(n. 3494)
%
Placebo(n. 3481)
%
Adjusted
HR 95%CI* p
Patients with fatal and not fatal MI 3.1 3.7 0.82 0.63-1.06 0.12
Patients with fatal and not fatal stroke
Ischemic
Hemorrhagic
Not known
3.5
2.8
0.4
0.3
3.0
2.3
0.3
0.4
1.16 0.89-1.51 0.27
MI=myocardial infarction
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Effects of n-3 PUFA on arrhythmic events
n-3 PUFA(n. 3494)
%
Placebo(n. 3481)
%
HR 95%CI p
Presumed arrhythmic deaths 7.8 8.7 0.88 0.75-1.04 0.14
Patients hospitalized for ventricular arrhythmias
2.8 3.8 0.72 0.55-0.93 0.01
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Total cholesterol# ≤188 mg/dL
Diabetes
No diabetes
NYHA III-IV
NYHA II
Ischemic etiology
Not ischemic etiology
LVEF ≤40%
LVEF >40%
Age <69 years (median)
Age ≥69 years (median)
Total cholesterol# >188 mg/dL
0.96
0.92
0.94
1.02
0.95
0.94
0.93
0.96
0.89
0.96
0.91
0.96
Predefined Subgroup analysis
N-3 PUFAbetter
Placebobetter
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Permanent treatment discontinuations
n-3 PUFA(n. 3494)
Placebo(n. 3481)
p
Patients permanently discontinuing
study treatment, n. (%)1004 (28.7) 1029 (29.6) 0.45
Adverse drug reaction 102 104
Patients’ decision 478 500
Doctor decision 299 298
Other 125 127
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Time to all-cause death
unadjusted HR (95.5% CI)0.88 (0.79–0.98), p 0.019adjusted HR (95.5% CI)*0.86 (0.77–0.95), p0.004
Time to Combined Endpoint = time to death or CV hospitalization,
whichever comes first
unadjusted HR (99% CI)0.93 (0.84–1.03) p 0.064adjusted HR (99% CI)*0.92 (0.84–1.02) p 0.036
Per protocol analysis (4,994 patients)
*Cox proportional hazards model, adjusted for: hospitalization for HF in the previous year, aortic stenosis, prior revascularization and history of paroxistical AF (p<0.1)
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0 182 364 546 728 910 1092 1274 1456 1638 0 182 364 546 728 910 1092 1274 1456 1638
Placebo725/2482 (29.2%)
n-3 PUFA658/2512 (26.2%)
n-3 PUFA1339/2512 (53.3%)
Placebo1396/2482 (56.2%)
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Adverse drug reactions
n-3 PUFA(n. 3494)
Placebo(n. 3481)
p
Patients permanently discontinuing
study treatment due to ADR, n. (%)102 (2.9) 104 (3.0) 0.87
Gastro-intestinal disorder 96 92
Allergic reaction 3 9
Liver dysfunction 1 1
Lipid abnormality - 1
Hepatocellular jaundice - 1
Subdural hematoma 1 -
Muscle-related symptoms 1 -
ADR=adverse drug reaction
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• Long-term administration of 1g/day n-3 PUFA was
effective in reducing both all-cause mortality and
hospitalisations for CV reasons in the large
population of patients with HF included in the
pragmatic GISSI-HF trial , in a context of usual care.
GISSI-HF Conclusions
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• The benefit was moderate, smaller than expected
(RRR 7%-9% vs assumed 15%) but it was: - obtained on top of recommended therapies
- consistent across all predefined subgroups
- supported by per-protocol analysis (RRR 12%-14%)
• No adverse events were noted
• In chronic heart failure patients the n-3 PUFA treatment is moderately effective, safe, simple (once daily) and cheap.
GISSI-HF Conclusions
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The GISSI-HF trial was planned, conducted and analyzed by the GISSI group which has full ownership
of the data.
SPA, Pfizer, Sigma Tau and AstraZeneca concurred to fund the study.
Acknowledgements
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GISSI is endorsed by • Associazione Nazionale Medici Cardiologi Ospedalieri
(ANMCO), Firenze, Italy; • Ist.Ricerche Farmacologiche Mario Negri, Milan, Italy; • Consorzio Mario Negri Sud, Santa Maria Imbaro, Italy.
Acknowledgements
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Steering CommitteeL Tavazzi (Chairman), G Tognoni (Co-Chairman), MG Franzosi, R Latini, AP Maggioni, R Marchioli, GL Nicolosi, M Porcu Data and Safety Monitoring BoardS Yusuf (Chairman), F Camerini, JN. Cohn, A Decarli, B Pitt, PA. Poole-Wilson, Peter Sleight, Clinical Endpoint CommitteeE Geraci (Chairman), M Scherillo (Co-Chairman), G Fabbri (Coordinator), B Bartolomei (Secretary), D Bertoli, F Cobelli, CFresco, A Ledda, G Levantesi, C Opasich, F Rusconi, G Sinagra, F Turazza, A Volpi
Committees
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Clinical MonitoringM Ceseri (coordinator), G Alongi, A Atzori, F Bambi, D Bastarolo, F Bianchini, I Cangioli, V Canu, C Caporusso, G Cenni, L Cintelli, M Cocchio, A Confente, E Fenicia, G Friso, M Gianfriddo, G Grilli, B Lazzaro, G Lonardo, A Luise, R Nota, M Orlando, R Petrolo, C Pierattini, V Pierota, A Provenzani, V Quartuccio, A Ragno, CSerio, A Spolaor, A Tafi, E Tellaroli
Database Management and StatisticsD Lucci, S Barlera, M Gorini, L Gonzini, V Milani, G Orsini
Regulatory, Administrative and SecretariatE Bianchini, S Cabiddu, I Cangioli, L Cipressa, ML Cipressa, G Di Bitetto, B Ferri, L Galbiati, A Lorimer, C Pera, P Priami, A Vasamì
Coordinating Centers
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Ventricular Remodeling: Echo:S Ghio, E Ghizzardi
Biohumoral:R Latini, S Masson
Genetic: M GFranzosi, L Crociati
Arrhythmic/Autonomic :MT La Rovere
Exercise Capacity:U Corrà
Quality of Life and Depression: P Di Giulio
Implantable Cardiac Defibrillator:A Finzi
GISSI-HF Subprojects