Extended Mortality Benefit of Early Postinfarction Reperfusion
To the Editor:
Ross et al1 (April 28, 1998) report that in the GUSTO-1 angiographic substudy, successful reperfusion produced mortality benefits that were amplified beyond the first 30 days. This extended mortality benefit has been reported previously in the Grampian Region Early Anistreplase Trial (GREAT).2 In this randomized, double-blind, controlled clinical trial, 311 patients with suspected acute myocardial infarction either received anistreplase prehospital at 105 minutes (median) after symptom onset or in hospital at 240 minutes. At 30 days, there was a trend in favor of prehospital thrombolysis (≈6 lives saved per 100), but this did not reach statistical significance (log rank=3.4, P<0.10). Between 30 days and 2 years, however, there was a significant additional survival benefit of ≈10 lives per 100 (log rank=6.3, P<0.025).
An “open artery” is the common pathway for several different mechanisms of benefit, with significant myocardial salvage and recovery of function only within the first 2 hours.3 By 4 to 6 hours, myocardial necrosis is irreversible, but reperfusion of the infarct-related artery is still beneficial because it confers electrical stability on the infarct and minimizes infarct expansion. Myocardial salvage would be expected to give extended benefit, whereas the other mechanisms would not.
GUSTO-1 had a short median time to treatment of 2.8 hours,4 so many patients would have benefited from myocardial salvage. The extended mortality benefit described by Ross et al1 is more closely related to left ventricular ejection fraction than to TIMI 3 flow, suggesting that it results from myocardial salvage rather than patency of the infarct-related artery itself. In GREAT, 64% of patients in the prehospital group were treated within 2 hours compared with <1% in the hospital group. The extended mortality benefit in this trial is also likely to be a consequence of myocardial salvage.
In ISIS-2, in which there was no significant additional mortality benefit from streptokinase (or aspirin) after 35 days,5 only 15% of patients were randomized within 2 hours, the median time of randomization was 5 hours, and there was an additional delay between randomization and treatment. GUSTO-I and GREAT therefore differ from ISIS-2 not only in their use of thrombolytic agents that have higher and therefore faster patency rates than streptokinase, but also in having a much higher proportion of patients treated within 2 hours. The extended benefit demonstrated in both these trials is very likely to be due to myocardial salvage, which would not have been the mechanism of benefit for most patients in ISIS-2 nor, indeed, in other hospital trials in which randomization was >4 hours after onset.
- Copyright © 1998 by American Heart Association
Ross AM, Coyne KS, Moreyra E, Reiner JS, Greenhouse SW, Walker PL, Simoons ML, Draoui YC, Califf RM, Topol EJ, Van de Werf F, Lundergan CF, for the GUSTO-I Angiographic Investigators. Extended mortality benefit of early postinfarction reperfusion. Circulation. 1998;97:1549–1556.
Weaver WD. Time to thrombolytic treatment: factors affecting delay and their influence on outcome. J Am Coll Cardiol. 1995;25(suppl):3S–9S.
Baigent C, Collins R, Appleby P, Parish S, Sleight P, Peto R, on behalf of the ISIS-2 (Second International Study of Infarct Survival) 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;316:1337–1343.
We agree with Dr Rawles that myocardial salvage and consequent preservation of ventricular function is likely the dominant mechanism underlying the long-term augmented survival benefits we reported. However, we wish to point out that when evaluated by multivariate analysis that tested both time to treatment and convalescent left ventricular function, the achievement of early TIMI grade 3 flow in the infarct-related artery was shown to be an independent predictor of increasing survival benefit between 30 days and 2 years after infarction.R1
Ross AM, Coyne, KS, Moreyra E, Reiner JS, Greenhouse SW, Simoons ML, Draoui YC, Califf RM, Topol EJ, Van de Werf F, Lundergan CF, for the GUSTO-I Angiographic Investigators. Extended mortality benefit of early postinfarction reperfusion. Circulation. 1998;97:1549–1556.