Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico acuto-2 - GISSI-2

Description:

Alteplase vs. streptokinase for mortality in acute myocardial infarction.

Hypothesis:

The pharmacologically more promising profile of alteplase translates into a clinically relevant advantage (higher efficacy, lower hemorrhagic risk) when compared directly with SK.

An anticoagulant prophylactic regimen with subcutaneous heparin adds to the effect of aspirin by lowering the incidence of early postinfarction ischemic events.

Study Design

Study Design:

Patients Screened: not given
Patients Enrolled: 20,891
NYHA Class: not given
Mean Follow Up: not given
Mean Patient Age: not given
Female: not given
Mean Ejection Fraction: not given

Patient Populations:

Chest pain accompanied by ST segment elevation of 1mm or more in any limb lead of the ECG or 2 mm (or more) in any precordial lead or both.
Admission to a CCU within six hours from the onset of symptoms.
No clear contraindication to fibrinolytic treatments or to heparin.

Primary Endpoints:

Combined endpoint of mortality and extensive left ventricular damage

Drug/Procedures Used:

50% of patients randomly allocated to receive SK (1.5 million U in 100 mL physiological saline infused over 30 to 60 minutes); 50% of patients received tPA (100 mg infused IV over 3 hours: 10 mg as an initial bolus, 50 mg in the first hour, 20 mg in the second and third hours)
50% of patients randomly allocated to receive 12,500 U of subcutaneous heparin bid, beginning 12 hours after the beginning of the tPA or SK infusion and to be continued until hospital discharge

Concomitant Medications:

At time of discharge, 77% were taking aspirin (300 to 325 mg per day); 25% beta-adrenergic blocking agents (atenolol 5 to 10 mg by slow IV injection as soon as evolving MI was diagnosed); 33% calcium channel antagonists

Principal Findings:

SK and tPA showed no specific differences in their effect on the combined endpoint of death and left ventricular damage (tPA: 23.1%; SK: 22.5%; relative risk: 0.99; confidence interval: 0.91-1.08). Rates of major in-hospital cardiac complications were also similar. The overall incidence of stroke was low (slightly more than 1%). More strokes were reported with tPA, though the frequency of confirmed hemorrhagic stroke was similar for tPA and SK. Allergic reactions and hypotension occurred more frequently with SK. More strokes were also reported in the elderly with both agents.

Heparin showed no specific effect on reinfarction, probably caused by the aspirin that was also being concomitantly administered. Patients treated with SK plus subcutaneous heparin had a statistically significant better survival rate. However, SK and heparin were both independently associated with a higher incidence of major bleeds, the highest frequency being observed in patients treated with both SK and heparin. (Nevertheless, major bleeds were not responsible for excess deaths.) Minor bleeding complications were more frequently seen with tPA. Subcutaneous heparin had no effect on the incidence of stroke and reinfarction.

Mortality rates after six months were similar for patients randomized to tPA or SK, and for patients randomized to heparin or no heparin. Reinfarction and cardiovascular accidents were similar in all treatment groups. A surprising finding was that women appeared to have a higher mortality risk from acute MI in the longer follow-up at six months.

Primary VF, irrespective of its timing, was an independent predictor of in-hospital mortality. Postdischarge to 6-month prognosis was unaffected by the occurrence of either early or late primary VF.

Interpretation:

Predictors of poor prognosis for long-term survival include advanced age, previous MI, and severity of the acute presentation of the MI (high Killip scale). The female population should be a priority target for intervention. The delay between onset of symptoms and thrombolysis should be minimized (<3 hours). The combined treatment of thrombolysis, aspirin and heparin may be appropriate for all acute MI patients who do not have specific contraindications. Although no difference was detected between streptokinase and t-PA in GISSI-2, the dosing of concomitant heparin may have been suboptimal. The GUSTO trial revealed that t-PA had better efficacy than SK with optimal heparin dosing.

References:

1. Lancet 1990;336:71-5. Final results (in-hospital mortality)
2. Eur Heart J 1992;13:1692-7. Six-month survival.
3. J Am Coll Cardiol 1994;24:608-61. Predictors of nonfatal MI
4. Eur Heart J 1997;18:835-45. Psychological factors
5. Am J Cardiol 1998;82:265-71. Prognosis of VF

Clinical Topics: Anticoagulation Management, Dyslipidemia, Lipid Metabolism

Keywords: Thrombolytic Therapy, Myocardial Infarction, Stroke, Hospital Mortality, Hypotension, Heparin, Electrocardiography, Streptokinase, Chest Pain, Survival Rate, Hypersensitivity, Tissue Plasminogen Activator


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