GISSI3: Gruppo Italiano per lo Studio della Sopravvivenza nellInfarcto Miocardico

1
GISSI-3 Gruppo Italiano per lo Studio della
Sopravvivenza nellInfarcto 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 nellInfarcto 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 1994343111522.

2
GISSI-3 Gruppo Italiano per lo Studio della
Sopravvivenza nellInfarcto 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 520 µg/min every 5 min for first
  30 min or until systolic BP fell by gt10
  infusion replaced after 24h by patch providing 10
  mg/day
• Lisinopril and glyceryl nitrate, as above
• No trial therapy

3
GISSI-3 Gruppo Italiano per lo Studio della
Sopravvivenza nellInfarcto Miocardico - RESULTS
-

• With lisinopril, mortality was significantly
  reduced compared with control (odds ratio 0.88,
  95 CI 0.790.99, 2P0.03), as was combined
  endpoint of mortality and severe ventricular
  dysfunction (odds ratio 0.90, 95 CI 0.840.98,
  2P0.009)
• 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 0.700.97, 2P0.021), 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

4
GISSI-3 Gruppo Italiano per lo Studio della
Sopravvivenza nellInfarcto Miocardico - RESULTS
continued-
Survival at 6 weeks
Cumulative
100
100
survival
Control
Control
()
Lisinopril
Nitrate
98
98
96
96
94
94
P (log-rank) 0.27
P (log-rank) 0.03
92
92
0
14
28
42
0
14
28
42
Time after acute MI (days)
GISSI. Lancet1994 343111522.
5
GISSI-3 Gruppo Italiano per lo Studio della
Sopravvivenza nellInfarcto Miocardico - RESULTS
continued-
6-week mortality and combined endpoints in
lisinopril
and control groups
Odds ratio
Controls
Lisinopril
2P

(n9460)
(n9435)
(95 CI)
No of deaths ()
0.88 (0.79

0.99)
0.03
673 (7.1)
597 (6.3)
Combined endpoint events
0.90 (0.84

0.98)
0.009
1609 (17.0)
1473 (15.6)
()


Deaths
673 (7.1)
597 (6.3)
Clinical heart failure
354 (3.7)
366 (3.9)
Ejection fraction lt35
530 (5.3)
451 (4.8)
GISSI. Lancet1994 343111522.

Two-tailed P value for difference between groups
6
GISSI-3 Gruppo Italiano per lo Studio della
Sopravvivenza nellInfarcto Miocardico - RESULTS
continued-
6-week mortality and combined endpoints in nitrate
and control groups
Controls
Nitrate
Odds ratio
2P

(n9442)
(n9453)
(95 CI)
No of deaths ()
0.94 (0.84

1.05)
0.28
617 (6.5)
653 (6.9)
Combined endpoint events
0.94 (0.87

1.02)
0.12
1502 (15.9)
1580 (16.7)
()


Deaths
617 (6.5)
653 (6.9)
Clinical heart failure
357 (3.8)
363 (3.8)
Ejection fraction lt35
483 (5.1)
498 (5.3)
GISSI. Lancet1994 343111522.


Two-tailed P value for difference between groups
7
GISSI-3 Gruppo Italiano per lo Studio della
Sopravvivenza nellInfarcto 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 gt70 years
  old
• Nitrate conferred no benefit except when
  combined with lisinopril