J Waldenström

EFFECT ON MORTALITY OF METOPROLOL IN ACUTE MYOCARDIAL INFARCTION: A Double-blind Randomised Trial

The effect of metoprolol on mortality was compared with that of placebo in a double blind randomised trial in patients with definite or suspected acute myocardial infarction. Treatment with metoprolol or placebo started as soon as possible after the patients arrival in hospital and was continued for 90 days. Metoprolol was given as a 15 mg intravenous dose followed by oral administration of 100 mg twice daily. 1395 patients (697 on placebo and 698 on metoprolol) were included in the trial. Definite acute myocardial infarction developed in 809 and probable infarction in 162. Patients were allocated to various risk groups and within each group patients were randomly assigned to treatment with metoprolol or placebo. There were 62 deaths in the placebo group (8.9%) and 40 deaths in the metoprolol group (5.7%), a reduction of 36% (p less than 0.03). Mortality rates are given according to the treatment group to which the patients were initially randomly allocated.

Effect of metoprolol on indirect signs of the size and severity of acute myocardial infarction

In a double-blind randomized trial, 1,395 patients with suspected acute myocardial infarction (MI) were investigated to evaluate the possibility of limiting indirect signs of the size and severity of acute MI with the beta 1-selective adrenoceptor antagonist metoprolol. Metoprolol (15 mg) was given intravenously and followed by oral administration for 3 months (200 mg daily). Placebo was given in the same way. The size of the MI was estimated by heat-stable lactate dehydrogenase (LD[EC 1.1.1.27]) analyses and precordial electrocardiographic mapping. Lower maximal enzyme activities compared with placebo were seen in the metoprolol group (11.1 +/- 0.5 mukat X liter-1) when the patient was treated within 12 hours of the onset of pain (13.3 +/- 0.6 mukat X liter-1; n = 936; p = 0.009). When treatment was started later than 12 hours, no difference was found between the 2 groups. Enzyme analyses were performed in all but 20 patients (n = 1,375). Precordial mapping with 24 chest electrodes was performed in patients with anterior wall MI. The final total R-wave amplitude was higher and the final total Q-wave amplitude lower in the metoprolol group than in the placebo group. Patients treated with metoprolol less than or equal to 12 hours also showed a decreased need for furosemide, a shortened hospital stay, and a significantly reduced 1-year mortality compared with the placebo group, whereas no difference was observed among patients treated later on. After 3 months, however, there was a similar reduction in mortality among patients in whom therapy was started less than or equal to 12 hours and greater than 12 hours after the onset of pain. The results support the hypothesis that intravenous metoprolol followed by oral treatment early in the course of suspected myocardial infarction can limit infarct size and improve long-term prognosis.

Five-year mortality rate in relation to enzyme-estimated infarct size in acute myocardial infarction

In 727 patients with acute myocardial infarction, different enzyme variables reflecting infarct size were related to the 5-year mortality rate. The maximum activity of serum heat-stable lactate dehydrogenase (LD), analyzed every 12 hours for 48 to 108 hours, was significantly associated with the 5-year mortality rate when patients with a first myocardial infarction were evaluated (p less than 0.001), and similarly (p less than 0.001) when patients with a previous myocardial infarction were included in the analyses. Very similar results were found when the maximum activity of aspartate aminotransferase (ASAT) analyzed once daily for 3 days was related to the mortality rate over 5 years, whereas the maximum activity of creatine kinase (CK) and CK subunit B analyzed every 6 hours for 48 hours in a subset of patients did not predict the outcome to the same extent. The results from LD and ASAT analyses clearly indicated that the association between infarct size and 5-year mortality rate was caused by the much higher mortality rate in patients with larger infarcts during the first year after onset of infarction, whereas after the first year, incidence of death appeared to be independent of the original infarct size. Thus we conclude that although a highly significant relationship between infarct size and overall 5-year survival was found, the mortality rate seemed to be higher in patients with larger infarcts, particularly during the first year after infarction.

Relationship between electrocardiographically and enzymatically estimated size in anterior myocardial infarction

In 179 patients with anterior myocardial infarction the electrocardiographically estimated infarct size was related to serum enzyme activity. A precordial map containing 24 precordial positions and the peak activity of heat stable dehydrogenase (LD; EC 1.1.1.27) were used. A positive correlation was found between the area at risk (initial sum of ST-elevation) and the peak LD activity (r = 0.48 - 0.55; p less than 0.001). When the final Q-and R-wave amplitude were related to peak enzyme activity a better correlation was observed (r = 0.56 - 0.68; p less than 0.001). The sum of R-waves (sigma R) and the sum of Q-waves (sigma Q) in the 24 precordial leads were related to sigma R and sigma Q in five precordial standard leads. A good correlation was found between the two ECG methods (r = 0.75 - 0.83; p less than 0.001), indicating that an increased number of precordial leads gives information regarding the extent of infarction similar to that obtained with the routinely used standard leads. It is concluded that in the individual patient, serum enzyme activity and the final Q-and R-wave changes can give different information about infarct size. If, however, these two independent methods are used in a large number of patients in intervention studies they will probably give similar information about relative influence of the intervention on the mean infarct size.

Infarct Size Limitation after Early Intervention with Metoprolol in the MIAMI Trial

One of the secondary objectives of the MIAMI Trial which evaluated the role of the beta-1-selective blocker metoprolol in suspected acute myocardial infarction was to further assess whether early intervention with beta-blockade can limit infarct size. A total of 5,778 patients from 104 worldwide centres were randomized into the trial. Various enzymes such as aspartate aminotransferase (ASAT), creatine kinase (CK), CK MB, CK B, lactate dehydrogenase (LD) and LD isoenzyme I were analysed. All enzymes were used according to the clinical routine of the respective hospital, except ASAT which was analysed once daily for 3 days in the majority of cases and LD I which was analysed every 12 h for 72 h in a subsample. A consistent observation was the lower serum enzyme activity among patients receiving metoprolol and randomized early after onset of symptoms, whereas no difference between metoprolol and placebo was observed in patients treated later in the course. The results of the MIAMI Trial support previous observations that early institution of metoprolol therapy limits infarct size, as indicated by the maximum serum enzyme activity.

Relationship between Serum Enzyme Activity in Acute Myocardial Infarction and Morbidity during a 2-Year Follow-Up

In 585 patients with a first myocardial infarction the enzymatically estimated infarct size was related to the clinical course during a 2-year follow-up. Infarct size was estimated from maximum heat-stable lactate dehydrogenase activity. A higher maximum serum activity was associated with a higher mortality rate, more treatment with diuretics, digitalis and antiarrhythmics and a lower frequency of return to work. Patients with smaller infarcts according to maximum serum activity, however, had a higher incidence of angina pectoris and a higher reinfarction rate. We conclude that although there is a strong association between serum enzyme activity and mortality during a 2-year follow-up, the relation with morbidity appears to be more complex.

The diagnostic value of different enzymes and standard ECG in acute myocardial infarction

Serum (S) enzyme activity of aspartate aminotransferase (ASAT, E.C. 2.6.1.1.), heat stable lactate dehydrogenase (LD, E.C. 1.1.1.27.), creatine kinase (CK, E.C. 2.7.3.2.) and CK-B subunit and the respective standard electrocardiograms (ECG) were compared in 463 patients with suspected acute myocardial infarction (MI) in order to evaluate sensitivity and specificity. Serum ASAT was analysed daily for 3 days, S-heat stable LD every 12 h for 48-108 h, S-CK and S-CK-B every 6 h for 48 h and ECG once daily for 3 days. All four enzymes had a high sensitivity, varying from 99% for LD to 97% for CK-B. The highest specificity was observed for CK-B and CK (98%) as compared with heat stable LD (91%) and ASAT (74%). Standard ECG showed a high specificity (96%) and a low sensitivity (80%).

Myocardial Protective Effect of Maintained Beta-Blockade in Aorto-Coronary Bypass Surgery

Twenty-nine patients were randomly allocated to two groups before undergoing aorto-coronary bypass surgery. In one group the beta-blocking medication was withdrawn three days preoperatively, and in the other group it was maintained. The patients in the latter group were additionally given 100 mg metoprolol per os two hours before surgery. The degree of myocardial injury, as judged from cumulated activity of S-CK B, was less when the beta-blockade was maintained.

Electrocardiographic changes and their relation to serum enzyme activity after heart surgery

In 80 patients who underwent heart surgery the incidence of electrocardiographic (ECG) changes after the operation was analysed. A precordial grid containing 24 leads and leads II, III and aVF was used. Electrocardiographic measurements were taken the day before the operation and again 5 days after the operation. New Q-waves were observed in 2 patients (2.5%) in the 24 precordial leads, in 2 patients in leads II, III and aVF, and in one patient in both precordial leads and leads II, III and aVF. New T-wave inversions were observed in 20 patients (25%) in the 24 precordial leads, in 5 patients (6%) in leads II, III and aVF, and in 3 patients in both precordial leads and leads II, III and aVF. A similar serum enzyme activity was observed both in patients developing Q-waves as well as T-wave inversions compared with cases in whom ECG changes did not appear.