11 Baigent C, Collins R, Appleby P, Parish S, Sleight P, Peto R, for the ... Julian DG, Pocock SJ, Wellwood M, Waters J, for the AIMS Study. Group. Intravenous ...
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References 1 Maroo A. The early history and development of thrombolysis in acute myocardial infarction. J Thromb Haemost 2004; 2: 1867–70. 2 European Working Party. Streptokinase in recent myocardial infarction: a controlled multicentre trial. European working party. Br Med J. 1971; 3: 375–31. 3 Dioguardi N, Lotto A, Levi GF, Rota M, Proto C, Mannucci PM, Rossi P, Lomanto B, Mattei G, Fiorelli G, Agostoni A. Controlled trial
of streptokinase and heparin in acute myocardial infarction. Lancet 1971; 2: 891–5. 4 Bett JH, Castaldi PA, Hale GS, Isbister JP, McLean KH, O’Sullivan EF, Biggs JC, Chesterman CN, Hirsh J, McDonald IG, Morgan JJ, Rosenbaum M. Australian multicentre trial of streptokinase in acute myocardial infarction. Lancet 1973; 1: 57–60. 5 Gruppo Italiano per lo Studio della Streptochinasi nell’Infarto Miocardio (GISSI). Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Lancet 1986; 1: 397–402.
M . G . F R A N Z O S I and S . G A R A T T I N I Istituto di Ricerche Farmacologiche ‘Mario Negri’, Milan, Italy
To cite this article: Franzosi MG, Garattini S. Thrombolytic therapy in acute myocardial infarction. J Thromb Haemost 2005; 3: 2807–8.
20 years of GISSI The 20th birthday of GISSI (Gruppo Italiano per lo Studio della Streptochinasi nell’Infarto) has been recently celebrated by the cardiological community worldwide [1–4]. The GISSI-1 study was the first prospective megatrial (commonly defined as a trial enrolling more than 10 000 patients) that demonstrated convincingly that thrombolytic therapy reduced mortality rates in acute myocardial infarction. The trial, conducted between February 1984 and June 1985 in 11 712 patient, showed a statistically significant 18% relative reduction of overall in-hospital mortality rate in patients treated with streptokinase within 12 h from the onset of symptoms. The extent of the benefit was time-dependent, with the relative reductions of in-hospital mortality rates of 47% and 23% in patients treated within 1 and 3 h from the onset of symptoms, respectively [5]. Also, the first report came from the GISSI-1 documenting that the advantage was sustained for at least 1 year [6]. The publication of the study results in early 1986 has been widely recognized as the opening of the thrombolytic era [7]. Thrombolytic trials have since become plentiful, with the most comprehensive review provided by the Fibrinolytic Therapy TrialistsÕ (FTT) Collaborative Group [8]. The key message of the GISSI-1 results could not have had a better confirmation, both with respect to the time to treatment and to its implications on the time dependence of survival advantage. The demonstration that large trials not only were necessary but could actually be performed constitutes the most important contribution of the GISSI organization. Its basis can be summarized in three main issues: (i) the collaboration between two not-for-profit Institution, the Mario Negri Pharmacological Research Institute, a non-profit Foundation and the Italian National Association of Hospital Cardiologists (ANMCO); (ii) the involvement of almost all of the coronary care units in the Correspondence: Silvio Garattini, Istituto di Ricerche Farmacologiche ÔMario NegriÕ, Via Eritrea 62, Milan, Italy. Tel.: +39 02 390141; fax: +39 02 3546277; e-mail: garattini@ marionegri.it Ó 2005 International Society on Thrombosis and Haemostasis
nation; and (iii) an emphasis on clinically important outcomes that would impact care and consequent efforts to enhance cardiovascular clinical practice through collaborative clinical research in Italy. An additional advantage of the GISSI-1 trial with its large number of participating physicians has been the rapid transfer of research results to the clinical beds. The nature of the GISSI organization allowed a further step in the knowledge of the benefits of thrombolytic therapy: the follow-up at 10 years [9]. The vital status of all the patients originally randomized in GISSI-1 was sought through the census offices of their towns of residence. Surprisingly, the results showed that the difference in survival produced by the in-hospital streptokinase treatment was still significant at the 10-year follow-up. A short infusion of a simple and inexpensive treatment reduced the risk of death over the ensuing 10 years from 469 per 1000 patients treated to 450 per 1000. These figures result in a net benefit of 19 lives saved per 1000 patients treated over that time. In patients who presented for medical attention within 1 h of the onset of symptoms, this benefit is dramatically magnified with 80 lives saved per 1000 patients treated supporting the concept of a Ôfirst golden hourÕ in myocardial infarction [10]. Combined with the 10-year follow-up from ISIS-2 [11], these data gave an impressive picture of how a simple intervention could improve an important clinical outcome and how the short-term advantage is sustained over a period in which profound changes have occurred in post-MI interventions. GISSI-1 raised a debate on some critical issues that are still open [12]. They concern the mechanism of sustained benefit, including salvage of ischemic myocardium, prevention of left ventricular remodeling and improvement of electrical stability, and the reasons why the survival curves were still parallel at 10 year and not continued to widen. A late (after 1 year) extra benefit could be expected as a result of the salvage of ischemic myocardium produced by the thrombolytic treatment. Indeed, a slight divergence was observed only in the survival curves of patients randomized within the first hour and discharged alive, further supporting the hypothesis that the Ôgolden hourÕ
2808 Forum
reperfusion correlates with a survival benefit that may increase in the long run. The plausibility and reasons for a lack of an extra late benefit has long been debated. Better survival rates after hospital discharge in patients successfully treated with thrombolytic therapy could be related to a restoration of an early and sustained coronary patency with infarct size reduction and subsequent attenuation of ventricular dilation, whereas worse survival rates may be related to an excess of rethrombosis and reinfarction. The Ôreperfusion paradoxÕ has been invoked to explain the lack of an extra late benefit: a higher-risk population would remain alive in the streptokinase-treated patients compared with those treated with standard care [13,14]. Looking at the subpopulation of patients, long-term survival data are strictly symmetrical with those observed at hospital discharge: in the elderly and in patients with ST-segment depression at admission, the treatment effect went in the wrong direction, confirming previous results in the ST-segment depression group and raising an interesting issue for the elderly. In patients with non-anterior myocardial infarction, the benefit was relatively small. Beyond the original contribution of the results, the 10-year follow-up of the GISSI-1 should be considered per se an important event in the evolution of the clinical trials methodology. It deserves a reflection. For most of the evidence-based interventions used in modern medicine, we do not know how long the benefit is sustained. The duration of the follow-up period in clinical trials is usually planned in order to document reliably a benefit of a treatment. With few exceptions [11,15], extension of the follow-up in order to observe the evolution of the benefit in a randomized population exposed to the real world is a rare event. The GISSI organization allowed to do it. References 1 Braunwald E. Happy birthday, GISSI! Am Heart J 2004; 148: 187. 2 Sleight P. We could all learn from the Italian cardiologists. Am Heart J 2004; 148: 188–9. 3 Armstrong PW, Kaul P, on behalf of the VIGOUR group. Charting the course of clinical research: from an inspired past to a promising future. Am Heart J 2004; 148: 190–2.
4 Yusuf S. Transforming the scientific, health care, and socio-political culture of an entire country through clinical research: the story of GISSI. Am Heart J 2004; 148: 193–5. 5 Gruppo Italiano per lo Studio della Streptochinasi nell’Infarto Miocardio (GISSI). Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Lancet 1986; 1: 397–402. 6 Gruppo Italiano per lo Studio della Streptochinasi nell’Infarto Miocardio (GISSI). Long-term effects of intravenous thrombolysis in acute myocardial infarction: final report of the GISSI study. Lancet 1987; 2: 871–4. 7 Maroo A, Topol EJ. The early history and development of thrombolysis in acute myocardial infarction. J Thromb Haemost 2004; 2: 1867– 70. 8 Fibrinolytic Therapy TrialistsÕ (FTT) Collaborative Group. Indications for fibrinolytic therapy in suspected acute myocardial infarction: collaborative overview of early mortality and major morbidity results from all randomised trials of more than 1000 patients. Lancet 1994; 343: 311–22. 9 Franzosi MG, Santoro E, De Vita C, Geraci E, Lotto A, Maggioni AP, Mauri F, Rovelli F, Santoro L, Tavazzi L, Tognoni G, on behalf of the GISSI Investigators. Ten-year follow-up of the first megatrial testing thrombolytic therapy in patients with acute myocardial infarction: results of the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto-1 Study. Circulation 1998; 98: 2659–65. 10 Boersma E, Maas ACP, Deckers JW, Simoons ML. Early thrombolytic treatment in acute myocardial infarction: reappraisal of the golden hour. Lancet 1996; 348: 771–5. 11 Baigent C, Collins R, Appleby P, Parish S, Sleight P, Peto R, for the ISIS Collaborative Group. ISIS-2: 10 year survival among patients with suspected acute myocardial infarction in randomised comparison of intravenous streptokinase, oral aspirin, both, or neither. BMJ 1998; 316: 1337–43. 12 Califf RM. Ten years of benefit from a one-hour intervention. Circulation 1998; 98: 2649–51. 13 Van de Werf F. Thrombolysis for acute myocardial infarction: why is there no extra benefit after hospital discharge? Circulation 1995; 91: 2862–4. 14 The Reperfusion Therapy Consensus Group. Selection of reperfusion therapy for individual patients with evolving myocardial infarction. Eur Heart J. 1997; 18: 1371–81. 15 Hillis WS, Chamberlain DA, de Bono DP, Fox KAA, Murray RG, Julian DG, Pocock SJ, Wellwood M, Waters J, for the AIMS Study Group. Intravenous anistreplase in acute myocardial infarction: continued reduction in mortality up to 5 years: long-term results of the AIMS study. Eur Heart J. 1992; 13: 305 Abstract.
Ó 2005 International Society on Thrombosis and Haemostasis
