GISSI-3: Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarcto Miocardico
Purpose
To determine whether the ACE inhibitor lisinopril, transdermal glyceryl nitrate or a combination of both improve survival and ventricular function after acute MI
Reference
Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarcto Miocardico. GISSI-3: effects of lisinopril and transdermal glyceryl trinitrate singly and together on 6-week mortality and ventricular function after acute myocardial infarction. Lancet 1994;343:1115–22.
GISSI-3: Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarcto Miocardico - TRIAL DESIGN -
Design: Multicenter, randomized, open, controlled
Patients: 18,895 patients within 24h of onset of acute MI
Follow up and primary endpoint: Primary endpoint: all-cause mortality. Six weeks follow up
Treatment: Patients randomized to one of four groups:
Lisinopril 5 mg initially, increased over 48 h to 10 mg daily
Glyceryl nitrate 5 μg/min IV initially, increasing by 5–20 μg/min every 5 min for first 30 min or until systolic BP fell by >10%; infusion replaced after 24h by patch providing 10 mg/day
Lisinopril and glyceryl nitrate, as above
No trial therapy
GISSI-3: Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarcto Miocardico - RESULTS -
With lisinopril, mortality was significantly reduced compared with control (odds ratio 0.88, 95% CI 0.79–0.99, 2P=0.03), as was combined endpoint of mortality and severe ventricular dysfunction (odds ratio 0.90, 95% CI 0.84–0.98, 2P=0.009)
With nitrate, no significant reduction in these endpoints compared with control
With combination nitrate and lisinopril, significant reduction in both endpoints compared with control (for mortality: odds ratio 0.83, 95% CI 0.70–0.97, 2P=0.021), with some evidence of additive effect
Despite significant excess persistent hypotension and renal dysfunction with lisinopril, these did not result in increased mortality or severe renal failure
GISSI-3: Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarcto Miocardico - RESULTS continued-
Time after acute MI (days)
Cumulative
survival
(%)
0
14
28
42
92
96
94
98
100
Survival at 6 weeks
GISSI. Lancet1994; 343:1115–22.
0
14
28
42
92
96
94
98
100
Control
Lisinopril
Control
Nitrate
P (log-rank) = 0.27
P (log-rank) = 0.03
GISSI-3: Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarcto Miocardico - RESULTS continued-
2P
*
No of deaths (%)
Combined endpoint events
(%)
Deaths
Clinical heart failure
Ejection fraction <35%
0.88 (0.79
–
0.99)
0.90 (0.84
–
0.98)
0.03
0.009
6-week mortality and combined endpoints in lisinopril
and control groups
Controls
(n=9460)
Lisinopril
(n=9435)
GISSI. Lancet1994; 343:1115–22.
673 (7.1)
1609 (17.0)
673 (7.1)
354 (3.7)
530 (5.3)
597 (6.3)
1473 (15.6)
597 (6.3)
366 (3.9)
451 (4.8)
*
Two-tailed P value for difference between groups
Odds ratio
(95% CI)
GISSI-3: Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarcto Miocardico - RESULTS continued-
2P
*
No of deaths (%)
Combined endpoint events
(%)
Deaths
Clinical heart failure
Ejection fraction <35%
0.94 (0.84
–
1.05)
0.94 (0.87
–
1.02)
0.28
0.12
6-week mortality and combined endpoints in nitrate
and control groups
Controls
(n=9442)
Nitrate
(n=9453)
GISSI. Lancet1994; 343:1115–22.
617 (6.5)
1502 (15.9)
617 (6.5)
357 (3.8)
483 (5.1)
653 (6.9)
1580 (16.7)
653 (6.9)
363 (3.8)
498 (5.3)
*
Two-tailed P value for difference between groups
Odds ratio
(95% CI)
GISSI-3: Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarcto Miocardico - SUMMARY -
In patients with acute MI up to 24 hours previously, lisinopril reduced:
Mortality, and combined endpoint of mortality and severe ventricular dysfunction
Combined endpoint in women and patients >70 years old
Nitrate conferred no benefit except when combined with lisinopril