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Acute myocardial infarction is still the most common cause of death in most western industrialised countries. Thrombolysis as well as primary angioplasty have been proven to be effective treatments for acute myocardial infarction, resulting in a significant reduction in mortality.1-6 Based on the findings of large randomised trials, the current guidelines of the American College of Cardiology and the American Heart Association7 therefore recommend the use of thrombolytic treatment in patients with acute myocardial infarction who present to the hospital within 12 hours of symptom onset, regardless of age and sex. For patients with contraindications to thrombolytic treatment or who are at increased risk of bleeding, primary angioplasty is recommended.
Despite these evident beneficial effects of early reperfusion treatment and the strong recommendations for its use, prospective observational studies have shown that only a minority of patients with acute myocardial infarction receive any reperfusion treatment.8 9 Rogers and colleagues9reported a reperfusion rate of 35.1% among 240 989 consecutive patients with acute myocardial infarction in the national registry of myocardial infarction in the USA; this is substantially lower than the 51–62% of patients with acute myocardial infarction who it is deemed should be eligible for thrombolysis.10 Consequently the hospital mortality was more than twice as high in the patient group without reperfusion as compared to that with reperfusion treatment (13.1% v 5.9%, p < 0.01). Using a decision analysis model, Fendrick and associates11showed that more than 10 000 deaths annually are attributable to the underutilisation of thrombolytic treatment for acute myocardial infarction in the USA.
Large German prospective observational registries of acute myocardial infarction documented higher reperfusion rates: the 60 minutes myocardial infarction project,12 involving 14 980 patients enrolled consecutively between 1992 and 1994, observed a reperfusion rate of 53%; and the myocardial infarction registry (MIR),13 with 14 598 patients enrolled consecutively between 1996 and 1998, showed a reperfusion rate of 46.1%. But there still remain patients eligible for thrombolysis who do not receive reperfusion treatment.
Reasons for underuse of reperfusion treatment
Barron and associates8 identified 84 663 of 272 651 (31%) consecutive patients with acute myocardial infarction as eligible for reperfusion treatment. Out of this subgroup of eligible patients 24% did not receive any reperfusion treatment; the hospital mortality was 14.8% versus 5.7% for patients who received reperfusion treatment. After adjusting for differences in demographic and clinical characteristics, significant determinants for not receiving reperfusion treatment were left bundle branch block (odds ratio (OR) 0.22), the lack of chest pain on admission (OR 0.22), age older than 75 years (OR 0.40), and female sex (OR 0.88).
Out of 21 092 consecutive patients with acute myocardial infarction enrolled in MIR and MITRA (maximal individual therapy of acute myocardial infarction registry) in Germany, 10 166 (48%) did not receive any reperfusion treatment; 6109 (29%) were not eligible for thrombolysis, while 4057 (19%) had no obvious contraindications (unwarranted non-reperfusion).14 The main reason for the failed eligibility for thrombolysis was a prehospital delay longer than 12 hours between the onset of symptoms and the hospital admission in 86% of these patients; only 14% had contraindications against thrombolysis.
The patients with unwarranted non-reperfusion were older (mean age 72v 64 years, p < 0.001), more often female (40% v 28%, p < 0.001), and had a higher incidence of diabetes (29% v 18%, p < 0.001) and hypertension (44% v 36%, p < 0.001). After correction for demographic and clinical differences, the determinants for not applying reperfusion treatment were a non-diagnostic ECG on admission, age older than 70 years, a prehospital delay longer than four hours but still within 12 hours, heart failure on admission, and previous resuscitation (fig 1). In addition, logistic parameters such as size and specialisation of the hospital and the time of admission (office hoursv non-office hours) seem to influence the decision for instituting reperfusion treatment for acute myocardial infarction. Hospitals with more than 500 beds and hospitals with cardiology departments were more likely to apply reperfusion treatment (OR 1.21, 95% confidence interval (CI) 1.03 to 1.41; OR 1.31, 95% CI 1.12 to 1.53, respectively). Patients presenting during non-office hours (after 5.00 pm and during weekends) were less likely to receive acute reperfusion treatment (OR 0.67, 95% CI 0.57 to 0.78). The consequences of the unwarranted non-reperfusion were an increased hospital mortality (OR 1.54, 95% CI 1.35 to 1.77) as well as an increased long term mortality (1.5 years, OR 2.40, 95% CI 1.74 to 3.31).
How to improve reperfusion treatment
SHORTENING OF PREHOSPITAL DELAY
The majority of patients with acute myocardial infarction, who do not receive reperfusion treatment, are not eligible for thrombolysis because of late arrival in the hospital. This prehospital delay could be shortened by mass media campaigns to educate the public about the symptoms of acute myocardial infarction, advising patients to call for medical help if they suffer from angina for more than 20 minutes.
NON-DIAGNOSTIC INITIAL ECG
In the case of an initial non-diagnostic ECG for acute myocardial infarction on admission in those patients with typical symptoms, short term controls are recommended, initially every 30 minutes, to decrease the number of missed diagnoses and to guarantee early reperfusion treatment.
INCREASE OF REPERFUSION FREQUENCY IN PATIENTS WITH PRE-HOSPITAL DELAYS OF 4–12 HOURS
Observational studies have shown that those patients who arrive at the hospital between 4–12 hours after symptom onset are less likely to receive reperfusion treatment. Although the evidence suggests that the benefit from thrombolysis in this time window is not as good as when administered in the first hours after symptom onset, there still is some benefit to be gained. However, those patients at greater risk from possible complications of reperfusion treatment, such as the elderly, diabetics, and hypertensives, are more likely to have treatment withheld during this time period. The registry data of consecutive patients provide important information on these patients as they are underrepresented in clinical trials. Zahn and colleagues15found a significantly decreased hospital mortality for patients with pre-hospital delays longer than six hours treated with angioplasty as compared to thrombolysis. Based on these data, angioplasty should be the reperfusion treatment of first choice, especially in patients with longer pre-hospital delays. If angioplasty is not available, the treating physician should be aware of the reduced—but still beneficial—effects of thrombolysis administered up to 12 hours after symptom onset, and consider thrombolytic treatment in this patient group. If there are contraindications to thrombolytic treatment, angioplasty should be considered even if the patient has to be transferred to another hospital.
AGE > 75 YEARS
The registries of consecutive patients with acute myocardial infarction identified age over 75 years as a major independent determinant for withholding thrombolytic treatment.8 14In a retrospective cohort study of thrombolytic treatment in 7864 patients with myocardial infarction who were older than 75 years, Thiemann and colleagues16 found that the use of thrombolytic agents was associated with a survival disadvantage and an adjusted hazard ratio of 1.38 (95% CI 1.12 to 1.71) in patients 76–86 years old. These new data differ from those from randomised trials of thrombolysis,1 which showed a non-significant trend toward an absolute benefit of thrombolysis in patients older than 75 years, and postulates for the first time that thrombolysis may even do more harm than good in these patients. These new results further weaken the evidence of benefit of thrombolysis for acute myocardial infarction in elderly patients. As these new results are derived from clinical practice data from one large prospective registry with consecutive patients, other registries should be analysed with respect to this specific and clinically important question. The analysis of data from the German registries MITRA and MIR shows that thrombolysis for acute myocardial infarction in patients older than 75 years was neither beneficial nor harmful to the overall subgroup of patients with respect to hospital mortality (OR 0.95, 95% CI 0.81 to 1.12), but showed a clear beneficial effect on long term outcome with a significant reduction of 18 months mortality for those patients discharged alive (OR 0.58, 95% CI 0.39 to 0.88).17
This raises the question of how to treat this patient subgroup. Hospital mortality in patients with acute myocardial infarction is increasing with age. If thrombolysis does not improve hospital mortality, how can we improve fatality rates in the elderly? The meta-analysis of randomised trials of primary angioplasty versus thrombolytic treatment by Weaver and colleagues18 showed that angioplasty has proven to result in a 34% risk reduction for death. The pooled outcome data of PAMI (primary angioplasty in myocardial infarction), ZWOLLE, and Mayo Clinic randomised trials of primary angioplasty versus thrombolytic treatment of acute myocardial infarction19 showed similar effects with a reduction in mortality which was greatest for patients older than 70 years. In addition, Weaver and colleagues18 showed that angioplasty resulted in a far greater safety profile with a reduction of intracerebral haemorrhage from 1.1% to 0.1% (p < 0.001). Therefore, if available, primary angioplasty nowadays clearly appears to be the preferable reperfusion treatment because of the lower complication rate. In patients older than 75 years for whom angioplasty is not available, based on the results of the randomised trials, thrombolysis should still be recommended after careful weighing of expected benefit versus possible complications—large infarction size versus high bleeding risk.
Although meta-analysis of randomised trials of primary angioplasty versus thrombolytic treatment18 19 should have put to rest the controversy over the relative efficacy of mechanical versus pharmacologic reperfusion treatment, and whether primary angioplasty is clearly superior to thrombolysis especially in subsets of patients, it indicates that patients with acute myocardial infarction should always be sent to specialised centres with the facilities and expertise to perform primary angioplasty. For large German cities such as Munich it is estimated that about 500 additional lives could be saved every year by adopting such a policy. This strategy ideally would require a close network of specialised centres and 24 hour services for primary angioplasty, which seems unrealistic in light of the increasing costs of the national health systems. As a compromise, at least high risk patients, such as those in cardiogenic shock, the elderly or patients with longer prehospital delays, should be brought to hospitals with the necessary facilities for undertaking primary angioplasty.
Despite the overwhelming data showing the beneficial effects of reperfusion treatment for patients with acute myocardial infarction, there still exists a clear underutilisation of such treatment in daily clinical practice. By improving adherence to the existing guidelines for the treatment of acute myocardial infarction, and also by increasing access to specialised centres, we might be able to decrease further hospital and long term mortality.