ArticlesEarly thrombolytic treatment in acute myocardial infarction: reappraisal of the golden hour
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 patients4, reported only a gradual decrease of benefit with longer delay. We present an alternative analysis of data from previous trials.
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, 6, 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 mid-endocardial 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
Various clinical trials have shown that early restoration of coronary patency improves survival.10, 11, 12, 13 Later recanalisation may also be beneficial, particularly in patients with sufficient collateral flow and in those with stuttering infarction. Randomised trials comparing prehospital with in-hospital therapy14, 15, 16, 17, 18, 19, 20, 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, 15, 16, 17, 18, 19, 20, 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).
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 of fibrinolytic therapy in five subgroups according to the delay from symptom onset to randomisation (0-1, ⩾1–3, ⩾3–6, ⩾6–12 and ⩾12–24 h). Mortality reduction was highest among patients presenting in hospital within 1 h: the absolute benefit was 35 (11) additional patients alive per 1000 treated. In patients presenting ⩾1–3 and ⩾3–6 h the benefits were 25 (5) and 19 (5) additional alive patients per 1000 treated, respectively.
In patients with ST elevation or bundle branch block (n=45 000, 77% of the population) the absolute effects of fibrinolytic therapy were slightly larger. Benefits per 1000 treated patients were 39 (12), 30 (5), 27 (6), 21 (7), and 7 (7) in the respective subgroups. The relation between these benefits and the average delay from symptom onset (0·98, 2·50, 4·79, 9·11, and 17·48 h, respectively) was described as a straight regression line. Every additional hour of treatment delay from onset of symptoms was associated with a reduction in benefit by approximately 1·6 (0·6) lives per 1000 patients.
The FTT investigators concluded from these data a gradually increasing benefit with earlier treatment, without significant additional treatment effect at 0-1 h. According to this analysis little would be gained by extra efforts to achieve very early, prehospital, therapy.
Since the FTT analysis is at variance with the experimental data, and with the larger benefit found in direct, randomised comparison of prehospital with in-hospital therapy, an alternative presentation of the trial data seems appropriate. Furthermore, estimations of benefit for early treatment in the FTT analysis may have been influenced by the chosen framework for analysis.
The inclusion-threshold of 1000 patients for each of the nine studies included in the FTT analysis is rather arbitrary. There is no good reason to exclude smaller trials. Although the number of patients in the smaller studies may not be sufficient to prove the effect of thrombolytic therapy, these studies may nevertheless assist a more powerful estimation of treatment effects in subgroups of patients in a pooled dataset; more so, because several smaller studies excluded from the FTT analysis included a significant proportion of patients who were treated very early.
The statistical analysis was based on subdivision of patients according to delay from symptom onset with only two benefit estimations in the first 3 h (at average delay times of 0-98 and 2-50 h, respectively). In this way, part of a potential large effect in the first 2 h may be obscured by a relatively small effect in the third hour. A more differentiated subdivision seems more appropriate to study the effect of very early therapy.23 Furthermore, non-linear models might be developed and tested in addition to the linear FTT model.
Section snippets
Methods
For the reasons given, we studied the delay/benefit relation in a modified dataset, covering all randomised trials of fibrinolytic therapy versus placebo or control which included at least 100 patients. These trials were reported between 1983 and 1993 and indexed in the MEDLINE information system.24 There are 22 such trials12, 13, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44 The indication for fibrinolytic therapy in two of the trials may not have been
Results
The 22 trials included a total of 50 246 patients, of whom 5762 (11%) were randomised within 2 h of symptom onset and another 10 435 (21%) between 2 and 3 h. Fibrinolytic therapy appeared to be beneficial up to at least 12 h (figure 2). The absolute reduction in mortality was greatest among patients who presented within 1 h of symptom onset (average delay 0·75 h). Benefit in this group was estimated at 65 (SD 14; 95% CI 38, 93) lives saved per 1000 treated patients, which is higher than the FTT
Discussion
In animals with a coronary circulation similar to that of humans, the amount of myocardial tissue that is salvageable directly depends on the duration of coronary occlusion. This dependency is non-linear. Very early reperfusion of the occluded coronary artery (within 30 min) may lead to full recovery of ischaemic tissue and thus prevent necrosis. In experimental models most of the irreversible damage to the myocardium occurs between 1 and 2 h, after the occlusion, and little or no salvage can
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