THE LANCET Articles Early thrombolytic treatment in acute myocardial infarction reappraisal of the golden hour Eric Boersma Arthur C P Maas Jaap W Deckers Maarten L Simoons Summary Background There is conclusive evidence from clinical trials that reduction of mortality by fibrinolytic therapy in acute myocardial infarction is related to the time elapsing betw een onset of symptoms and commencement of treatment However the exact pattern of this relation continues to be debated This paper discusses whether or not appreciable additional gain can be achieved with very early treatment Methods The relation between treatment delay and shortterm mortality up to 35 days was evaluated using tabulated data from all randomised trials of at least 100 patients n 22 50 246 patients that compared fibrinolytic therapy with placebo or control reported between 1983 and 1993 Findings Benefit of fibrinolytic therapy was 65 SD 14 37 9 26 6 and 29 5 lives saved per 1000 treated patients in the 0 1 1 2 2 3 and 3 6 h intervals respectively Proportional mortality reduction was significantly higher in patients treated within 2 h compared to those treated later 44 95 CI 32 53 vs 20 15 25 p 0 001 The relation between treatment delay and mortality reduction per 1000 treated patients was expressed significantly better by a non linear 19 4 0 6x 29 3x 1 than a linear 34 7 1 6x regression equation p 0 03 Interpretation The beneficial effect of fibrinolytic therapy is substantially higher in patients presenting within 2 h after symptom onset compared to those presenting later Lancet 1996 348 771 75 Erasmus University Rotterdam Netherlands E Boersma MSc A C P Maas MD Prof J W Deckers MD Prof M L Simoons PhD Correspondence to Prof M L Simoons Thoraxcenter Bd 434 Erasmus University and University Hospital Rotterdam Dijkzigt Dr Molewaterplein 40 3015 GD Rotterdam Netherlands Vol 348 September 21 1996 Introduction The reduction in mortality that can be achieved with reperfusion therapy in patients with evolving myocardial infarction depends on the time elapsing between onset of symptoms and initiation of treatment or more specifically on the duration of coronary occlusion before reperfusion 1 Although earlier reperfusion yields a better clinical outcome the relation between treatment delay and mortality reduction is controversial A key question is whether or not a substantial additional reduction of the mortality risk can be achieved with very early treatment ie within 2 3 h after onset of symptoms The concept of a first golden hour 2 is supported both by experimental studies and randomised trials comparing pre hospital with in hospital therapy 2 3 By contrast the Fibrinolytic Therapy Trialists FTT Collaborative Group in a pooled dataset of randomised trials of more than 1000 patients 4 reported only a gradual decrease of benefit with longer delay We present an alternative analysis of data from previous trials Experimental studies The duration of coronary occlusion and the extent of collateral circulation are the main determinants of infarct size in pigs dogs cats and other animals 5 7 In animals with a coronary collateral circulation similar to that of humans an occlusion persisting for 15 30 min generally does not lead to significant myocardial damage 6 7 Thus necrosis can be prevented provided reperfusion is achieved within this period 8 A small area of necrosis usually occurs with reperfusion after 45 min occlusion while the midendocardial and subendocardial zones are still viable 6 Longer durations of coronary occlusion result in progressive growth of the infarction and reduction of the amount of salvageable myocardium At 90 min the extent of cell death involves 40 50 of the area at risk less than half of the jeopardised myocardium remains viable at that time 3 6 6 h after the onset of continuous ischaemia the area at risk is fully infarcted such that myocardial salvage will be minimal In humans the thrombotic event frequently consists of multiple cycles of temporary occlusion and reperfusion The degree of chest pain if present varies among patients so that it is often difficult to determine the exact duration of the coronary occlusion Nevertheless data indicate that evolution of enzymatically detectable infarct size over time in humans shows a pattern similar to that in animals 9 Pre hospital versus in hospital thrombolysis Various clinical trials have shown that early restoration of coronary patency improves survival 10 13 Later recanalisation may also be beneficial particularly in patients with sufficient collateral flow and in those with stuttering infarction Randomised trials comparing pre771 Absolute mortality per 1 000 treated patients THE LANCET McNeill14 n 57 Schofer15 n 78 Barbash16 n 87 Castaigne17 n 100 McAleer18 n 145 GREAT 19 n 311 MITI 20 n 360 EMIP 21 n 5469 150 100 50 0 0 1 2 3 4 5 Treatment delay h Figure 1 Mortality at 35 days in randomised studies comparing prehospital circles with inhospital squares thrombolytic therapy All trials ex cept that of Castaigne showed trend favouring prehospital thrombolysis Regression line bold weighted by number of patients included in mortality result was mainly determined by EMIP study hospital with in hospital therapy14 21 have shown a substantial beneficial effect of very early thrombolytic therapy Although these studies were too small to show statistical significance such significance was reached in pooled analyses of the data 2 22 The largest EMIP trial with 5469 randomised patients reported 15 SD 8 additional patients alive at 30 days per 1000 patients as a result of 1 h earlier treatment 21 Figure 1 shows the weighted regression line of all eight randomised studies 14 21 In these studies the average delay from symptom onset to initiation of therapy was 2 1 h in the prehospital patients and 3 1 h in the inhospital patients 1 h earlier treatment within 3 h from symptom onset is associated with a benefit of 21 6 lives per 1000 treated p 0 002 FTT analysis The Fibrinolytic Therapy Trialists Collaborative Group presented a systematic analysis of the pooled data from all unconfounded trials of fibrinolytic therapy versus control or placebo that randomised at least 1000 patients with suspected myocardial infarction 4 Nine trials were included with 58 600 patients among whom 6177 deaths 10 5 were reported within 35 days The effect of treatment on mortality and morbidity was studied in various patient categories One of the FTT subanalyses described the benefits
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