Abstract
A multicentre, randomised, open trial with a 2 x 2 factorial design was conducted to compare the benefits and risks of two thrombolytic agents, streptokinase (SK, 1·5 MU infused intravenously over 30-60 min) and alteplase (tPA, 100 mg infused intravenously over 3 h) in patients with acute myocardial infarction admitted to coronary care units within 6 h from onset of symptoms. The patients were also randomised to receive heparin (12 500 U subcutaneously twice daily until discharge from hospital, starting 12 h after beginning the tPA or SK infusion) or usual therapy. All patients without specific contraindications were given atenolol (5-10 mg iv) and aspirin (300-325 mg a day). The end-point of the study was the combined estimate of death plus severe left ventricular damage. 12 490 patients were randomised to four treatment groups (SK alone, SK plus heparin, tPA alone, tPA plus heparin). No specific differences between the two thrombolytic agents were detected as regards the combined end-point (tPA 23·1%; SK 22·5%; relative risk 1·04, 95% Cl 0·95-1·13), nor after the addition of heparin to the aspirin treatment (hep 22·7%, no hep 22·9%; RR 0·99, 95% Cl 0·91-1·08). The outcome of patients allocated to the four treatment groups was similar with respect to baseline risk factors such as age, Killip class, hours from onset of symptoms, and site and type of infarct. The rates of major in-hospital cardiac complications (reinfarction, post-infarction angina) were also similar. The incidence of major bleeds was significantly higher in SK and heparin treated patients (respectively, tPA 0·5%, SK 1·0%, RR 0·57, 95% Cl 0·38-0·85; hep 1·0%, no hep 0·6%, RR 1·64, 95% Cl 1·09-2·45), whereas the overall incidence of stroke was similar in all groups. SK and tPA appear equally effective and safe for use in routine conditions of care, in all infarct patients who have no contraindications, with or without post-thrombolytic heparin treatment. The 8·8% hospital mortality of the study population (compared with approximately 13% in the control cohort of the GISSI-1 trial) indicates the beneficial impact of the proven acute treatments for AMI.
| Original language | English |
|---|---|
| Pages (from-to) | 65-71 |
| Number of pages | 7 |
| Journal | The Lancet |
| Volume | 336 |
| Issue number | 8707 |
| DOIs | |
| Publication status | Published - Jul 14 1990 |
Bibliographical note
Funding Information:available when the trial was planned"21-23 and the results published during its implementation and analysis9,10 24,25 were entirely compatible with what the trial eventually showed. Even the major rationale for using tPA rather than SK-its higher recanalisation rate at 90 min (but not at 24 h21}-was seen on closer scrutiny as weak evidence. The differences in 90 min patency rates were not as striking in patients treated early as in those treated later 26 One objection that has been raised about GISSI-2 concerns the heparin regimen-namely, that the expression of the full thrombolytic potential of tPA necessitates concomitant iv heparin,21 rather than twice-daily subcutaneous treatment beginning after 12 h. Data supporting such claims, however, derive from small series, where results regarding patency rates are clearly conflicting; one factor in this may be the various time intervals set for coronary angiography after thrombolysis.27-29 Open coronary arteries are obviously better than closed ones, but too many pieces of the puzzle are lacking to say when, how rapidly, for how long, or how completely the infarct related artery should be open to reduce mortality or prevent ventricular dysfunction. The GISSI-2 results, at the very least, raise doubts about a widely held view, and illustrate that one role of trials is to propose additional mechanisms by which drugs may produce benefit.3O The comparative safety profile of tPA documented in GISSI-2 should, however, be reassessed, if iv heparin is considered an essential adjunctive therapy on the basis of the data reported in smaller series.27 The adoption of a combined end-point appears to have been satisfactory from a methodological point of view, since it bridges two usually separate lines of evaluation of acute treatments in evolving myocardial infarction.12 It may also be seen as a contribution to planning of future trials and overall strategies for intervention. While the data are compatible with the optimistic point of view declared above with respect to mortality, they also reliably document the burden of chronic or long-term consequences of AMI. Patients who survive the acute phase of an infarction complicated by severe left ventricular dysfunction are the next important target of preventive pharmacological measures to be tested in adequately sized trials. GISSI-2 was sponsored by Associazione Nazionale Medici Cardiologi Ospedalieri (ANMCO) and by Istituto di Ricerche Farmacologiche Mario Negri. The study was supported through a main grant from Boehringer Ingelheim Italy SpA. Financial support was received from ICI-Pharma Italy and Italfarmaco SpA. The Italian National Council of Research provided a complementary grant. Boehringer Ingelheim Italy SpA supplied alteplase, Pierrel SpA Italy and Kabi Sweden supplied streptokinase, and ICI Pharma Italy provided parenteral atenolol. GISSI-2 Steering committee G. A. Feruglio, A. Lotto, F. Rovelli, P. Solinas, L. Tavazzi, G. Tognoni. Coordination and data momtoring C. De Vita, M. G. Franzosi, A. P. Maggiom, F. Mauri, A. Volpi.
Funding
available when the trial was planned"21-23 and the results published during its implementation and analysis9,10 24,25 were entirely compatible with what the trial eventually showed. Even the major rationale for using tPA rather than SK-its higher recanalisation rate at 90 min (but not at 24 h21}-was seen on closer scrutiny as weak evidence. The differences in 90 min patency rates were not as striking in patients treated early as in those treated later 26 One objection that has been raised about GISSI-2 concerns the heparin regimen-namely, that the expression of the full thrombolytic potential of tPA necessitates concomitant iv heparin,21 rather than twice-daily subcutaneous treatment beginning after 12 h. Data supporting such claims, however, derive from small series, where results regarding patency rates are clearly conflicting; one factor in this may be the various time intervals set for coronary angiography after thrombolysis.27-29 Open coronary arteries are obviously better than closed ones, but too many pieces of the puzzle are lacking to say when, how rapidly, for how long, or how completely the infarct related artery should be open to reduce mortality or prevent ventricular dysfunction. The GISSI-2 results, at the very least, raise doubts about a widely held view, and illustrate that one role of trials is to propose additional mechanisms by which drugs may produce benefit.3O The comparative safety profile of tPA documented in GISSI-2 should, however, be reassessed, if iv heparin is considered an essential adjunctive therapy on the basis of the data reported in smaller series.27 The adoption of a combined end-point appears to have been satisfactory from a methodological point of view, since it bridges two usually separate lines of evaluation of acute treatments in evolving myocardial infarction.12 It may also be seen as a contribution to planning of future trials and overall strategies for intervention. While the data are compatible with the optimistic point of view declared above with respect to mortality, they also reliably document the burden of chronic or long-term consequences of AMI. Patients who survive the acute phase of an infarction complicated by severe left ventricular dysfunction are the next important target of preventive pharmacological measures to be tested in adequately sized trials. GISSI-2 was sponsored by Associazione Nazionale Medici Cardiologi Ospedalieri (ANMCO) and by Istituto di Ricerche Farmacologiche Mario Negri. The study was supported through a main grant from Boehringer Ingelheim Italy SpA. Financial support was received from ICI-Pharma Italy and Italfarmaco SpA. The Italian National Council of Research provided a complementary grant. Boehringer Ingelheim Italy SpA supplied alteplase, Pierrel SpA Italy and Kabi Sweden supplied streptokinase, and ICI Pharma Italy provided parenteral atenolol. GISSI-2 Steering committee G. A. Feruglio, A. Lotto, F. Rovelli, P. Solinas, L. Tavazzi, G. Tognoni. Coordination and data momtoring C. De Vita, M. G. Franzosi, A. P. Maggiom, F. Mauri, A. Volpi.
| Funders | Funder number |
|---|---|
| ANMCO | |
| Associazione Nazionale Medici Cardiologi Ospedalieri | |
| Boehringer Ingelheim Italy SpA | |
| Istituto di Ricerche Farmacologiche Mario Negri - IRCCS | |
| Consiglio Nazionale delle Ricerche |
ASJC Scopus Subject Areas
- General Medicine