Metoprolol In Acute Myocardial Infarction Research Articles

Five-Year Outcomes and Prognostic Value of Feature-Tracking Cardiovascular Magnetic Resonance in Patients Receiving Early Prereperfusion Metoprolol in Acute Myocardial Infarction

The aim of the present study was to investigate the long-term impact of early intravenous metoprolol in ST-segment elevation myocardial infarction (STEMI) patients in terms of left ventricular (LV) strain with feature-tracking cardiovascular magnetic resonance (CMR) and its association with prognosis. A total of 270 patients with first anterior STEMI enrolled in the randomized METOCARD-CNIC clinical trial, assigned to receive up to 15 mg intravenous metoprolol before primary percutaneous coronary intervention versus conventional STEMI therapy, were included. LV global circumferential (GCS) and longitudinal (GLS) strain were assessed with feature-tracking CMR at 1 week after STEMI in 215 patients. The occurrence of major adverse cardiac events (MACE) at 5-year follow-up was the primary end point. Among 270 patients enrolled, 17 of 139 patients assigned to metoprolol arm and 31 of 131 patients assigned to control arm experienced MACE (hazard ratio [HR] 0.500, 95% confidence interval [CI] 0.277 to 0.903; p = 0.022). Impaired LV GCS and GLS strain were significantly associated with increased occurrence of MACE (GCS: HR 1.208, 95% CI 1.076 to 1.356, p =0.001; GLS: HR 1.362, 95% CI 1.180 to 1.573, p < 0.001). On multivariable analysis, LV GLS provided incremental prognostic value over late gadolinium enhancement (LGE) and LV ejection fraction (LVEF) (LGE + LVEF chi-square = 12.865, LGE + LVEF + GLS chi-square = 18.459; p =0.012). Patients with GLS ≥-11.5% (above median value) who received early intravenous metoprolol were 64% less likely to experience MACE than their counterparts with same degree of GLS impairment (HR 0.356, 95% CI 0.129 to 0.979; p = 0.045). In conclusion, early intravenous metoprolol has a long-term beneficial prognostic effect, particularly in patients with severely impaired LV systolic function. LV GLS with feature-tracking CMR early after percutaneous coronary intervention offers incremental prognostic value over conventional CMR parameters in risk stratification of STEMI patients.

Diabetes and Not Lack of Treatment with Atenolol Predicts Decreased Survival after Noncardiac Surgery

Veterans Administration Medical Center; Anesthesia (129); San Francisco, California 94121;awallace@best.comIn Reply:-Thank you for allowing me to respond to Dr. Leung's comments about the two studies. [1,2]In February 1998, Dr. Leung wrote to Anesthesiology with six criticisms of Anesthesiology and New England Journal of Medicine articles. These criticisms included suggestions that it was inappropriate to withhold study drug from patients who might have a side effect, questions concerning the statistics in the New England Journal of Medicine article, requests for more postoperative hemodynamic data, questions about the withholding of beta blockade, interactions of diabetes and atenolol, and the lack of women in the study. I responded to all of these criticisms in writing, and those comments were published in Anesthesiology. [3]Dr. Leung was dissatisfied with the results of the letter to Anesthesiology and has sent a second letter to Anesthesiology with more criticisms, including:1. “Their study did not provide statistical support for such a claim.”2. “… this indicated that the effect of atenolol was not different from that of placebo, i.e., no influence of atenolol on survival.3. “[Greek small letter beta]-adrenergic blocking agents have reduced incidence of morbidity and mortality can not be supported by the current studies.”4. “… the recent popularized use of perioperative beta blockade is based on misinformation.”5. “Physicians caring for such patients should reevaluate the validity of recommending perioperative beta blockade for improved survival.”We strongly disagree with Dr. Leung and her misunderstanding of the results of the two manuscripts. [1,2]The primary end-point of the atenolol [2]study was the reduction of perioperative myocardial ischemia by atenolol. Perioperative administration of atenolol for 1 week to patients at high risk for coronary artery disease significantly reduced the incidence of postoperative myocardial ischemia (P = 0.029). Furthermore, a secondary finding was that reductions in perioperative myocardial ischemia were associate with reductions in the risk for death at 2 yr (P = 0.025). The primary end-point of the atenolol long-term study [4]was the effect of atenolol on 2-yr mortality. In patients who have or are at risk for coronary artery disease who must undergo noncardiac surgery, treatment with atenolol during hospitalization reduced mortality (P = 0.019) and the incidence of cardiovascular complications for as long as 2 yr after surgery (P = 0.008). These two studies provide clear and statistically significant evidence to support the claims that perioperative atenolol reduced incidence of morbidity and mortality and improves survival in patients at risk for cardiac morbidity.Dr. Leung does not understand the interpretation of univariable and multivariable models presented in Table 2of the Mangano et al. manuscript. [4]Once statistical significance is established, it is acceptable to do a secondary analysis of the data to look for other predictors of outcomes. We demonstrated clearly that atenolol reduced the risk of death. Diabetes mellitus and ischemia increased the risk of death. In the multivariable model we demonstrated that diabetes was statistically significant, but once patients with diabetes were excluded there was not sufficient power to demonstrate the effect of atenolol. Thirty-one percent of the patients in this trial had diabetes. If one exclude 31% of the patients in a trial, power is lost. That in no way brings the results into question; it simply implies that if one excludes 31% of the patients, one also loses power to see the effect. Furthermore, Dr. Leung is incorrect in stating that P = 0.06 (6% type I error) is not significantly when P = 0.05 (5% type I error) is suddenly significant. It is simply the difference between a 5% and 6% chance of a type I error. Perioperative administration of atenolol reduces the incidence of perioperative myocardial ischemia, postoperative mortality, and cardiovascular complications.Dr. Leung's statement that the use of perioperative beta blockade is based on misinformation is incorrect. It is important to understand statistics and study design before making such a statement. Physicians should clearly evaluate any therapy. Many trials of beta-blocker use demonstrate benefits in nonsurgical patients, including the ISIS-1 (International Study of Infact Survival), [5]the MIAMI (Metoprolol in Acute Myocardial Infarction), [6]the MAPHY (Metoprolol versus Thiazide Diuretics in Hypertension), [7]and the ASIST (Atenolol Silent Ischemia Study)[8]trials. We added to this abundant literature and have clearly demonstrated that perioperative beta blockade improves survival in surgical patients at risk for cardiac morbidity.Arthur Wallace, M.D., Ph.D.Veterans Administration Medical Center; Anesthesia (129); San Francisco, California 94121;awallace@best.com(Accepted for publication November 11, 1998.)

Effects of Beta Blockade on Sudden Cardiac Death During Acute Myocardial Infarction and the Postinfarction Period

About half of all deaths after myocardial infarction (MI) are sudden cardiac deaths. Most of these are thought to be due to ventricular fibrillation (VF). A number of interventions and many different antiarrhythmic agents have been investigated, but so far only β-blocker therapy has been found to produce significant reductions in the risk of sudden cardiac death after MI. Reductions in total mortality and sudden cardiac death were first reported in 1981 in 3 placebo-controlled studies, the Norwegian Timolol Study, the American Beta-Blocker Heart Attack Trial (BHAT), and the Göteborg Metoprolol Trial. A few years later, two very large trials, the Metoprolol in Acute Myocardial Infarction (MIAMI) study and the First International Study of Infarct Survival (ISIS-1), which included 6,000 and 16,000 patients, respectively, showed that β-blocker therapy could reduce mortality within the first 2 weeks after onset of MI. Data from 24 postinfarction studies with long-term follow-up show an average 20% mortality reduction over 2 years. Pooled results of 28 short-term, randomized, placebo-controlled trials in which β blockers were given intravenously shortly after onset of MI indicate an average 13% mortality reduction within 2 weeks. In the 16 studies in which the sudden cardiac death rate was reported, the beneficial effect of β blockade was even more marked: a 34% average reduction of risk. Not all studies with β blockers, however, have demonstrated a significant reduction in the incidence of sudden cardiac death. Such an effect has been clearly demonstrated only for the more lipophilic β blockers (timolol, metoprolol, and propranolol). Two of these lipophilic β blockers, metoprolol and propranolol, have also been shown to prevent VF after MI in clinical studies. Based on observations from animal experiments, it has been proposed that β blockers with a high degree of lipophilicity penetrate the brain and thereby maintain high vagal tone during stress. A combination of direct anti-ischemic effects due to β 1 blockade and preservation of vagal tone appears to prevent VF in these animal models. Further clinical studies are needed to explore this hypothesis.

Early treatment with intravenous metoprolol for suspected acute myocardial infarction: a Phase IV United States trial

Recent randomized clinical trials have shown that total mortality and cardiovascular mortality are reduced by the early intravenous administration of beta-blockers to patients suspected of suffering from acute myocardial infarction. These trials were conducted on patients meeting strict entry criteria. In order to assess this therapy when applied to a broader range of myocardial infarction patients, we performed a Phase IV study of metoprolol in acute myocardial infarction. The study was designed to test whether early (less than 8 hours from onset of chest pain) intervention by practicing physicians with open label intravenous metoprolol for cases of suspected acute myocardial infarction achieved mortality results similar to those obtained in large randomized clinical trials. We studied 3824 patients treated by 741 physicians representing a broad spectrum of clinical practice in the United States. Seventy-two percent of the patients entered into the study had confirmed myocardial infarction (39% anterior, 39% inferior, 22% other locations) and 85% of all individuals treated tolerated the full intravenous dose of 15 mg of metoprolol. The 15 day total mortality and cardiovascular mortality rates were 4.9% and 4.5%; 90 day mortality rates were 6.9 and 5.9%. Patients with anterior infarctions had a significantly greater cumulative mortality rate than patients with other types of infarctions. Marked bradycardia (heart rate less than 45 beats per minute) in the first 8 hours post treatment occurred in 4.7% cases and hypotension (systolic blood pressure less than 90 mm Hg) occurred in 9.8% of cases. When compared with the results of the Göteborg and MIAMI trials of metoprolol, it appears that there is no appreciable increase in mortality or morbidity when metoprolol is used in the community practice of acute coronary care.

Does acute-phase beta-blockade reduce mortality in acute myocardial infarction by limiting infarct size?

The mechanism by which early intervention with beta-blockers reduces mortality in acute myocardial infarction is unclear. Therefore the effects of intravenous, followed by oral, metoprolol on indices of infarct size were studied in a double-blind fashion with a median delay of 6.75 hours from onset of symptoms. In 129 patients peak enzyme release and QRS score on the electrocardiogram were assessed, while myocardial perfusion score on thallium-201 scintigraphy was studied in 45 patients. There was a close correlation between all the indices of infarct size. While the correlation coefficients did not appear to be influenced by metoprolol treatment, the slope of the regression was affected. Peak aspartate aminotransferase and lactic dehydrogenase were lower by 11 and 7%, respectively, in the metoprolol-treated group, but no reduction was noted in QRS score or in thallium-201 perfusion defect size in the actively treated group. Thus, it seems likely that early intervention with metoprolol in acute myocardial infarction reduces mortality, not by limiting infarct size, but by some other mechanism.

Hemodynamic effects of intravenous metoprolol in acute myocardial infarction: The role of anatomic subsets in predicting patient response

The acute effects of intravenous metoprolol were evaluated in 30 patients with myocardial infarction by means of serial hemodynamic and radionuclide measurements of left ventricular function. Within 1 hour of completion of the metoprolol dosing, 90% of the patients underwent cardiac catheterization to define anatomy and to assess patients for interventional therapy; the remainder had catheterization by 72 hours. All patients tolerated intravenous metoprolol without significant side effects. Patient responses to therapy were divided into two groups based on the angiographic findings. At catheterization, all group 1 patients had visible collaterals to or a patent vessel supplying the vascular distribution of the infarction. All group 2 patients had occluded coronary arteries without evidence of collaterals to the infarct zone. Group 1 (n = 13) improved both systolic and diastolic left ventricular function (mean ejection fraction [EF] = 46% to 55%, peak filling rate [PFR] = 2.1 to 3.2 Edv/sec), while group 2 (n = 17) patients were unchanged (EF = 43% to 42%, PFR = 2.0 to 1.9). Patient characteristics and time to treatment were similar in both groups, as were the hemodynamic effects of metoprolol. Heart rate decreased 20% in group 1 and 22% in group 2 and cardiac output fell 22% in group 1 and 32% in group 2. Acute improvement in ventricular function in these patients appears to be closely related to the coronary anatomy, and in those with flow to the infarct zone, intravenous metoprolol may be effective in preserving left ventricular function.

Metoprolol in acute myocardial infarction reduces ventricular arrhythmias both in the early stage and after the acute event

Fifty three of the 5778 patients included in the MIAMI (Metoprolol in Acute Myocardial Infarction) trial were investigated with long-term ECG recordings in order to evaluate the effect of acute beta-blockade on premature ventricular complexes in and after acute myocardial infarction. Twenty five patients were given placebo and 28 metoprolol in a double-blind randomized fashion for 15 days. After this period the patients were put on open beta-blockade without breaking individual study codes. The mean number of premature ventricular complexes during the inclusion day (day 0) was the same in the two groups. The median numbers were also similar in the two groups: 190 and 154 in the placebo and metoprolol groups, respectively. Metoprolol significantly reduced the median number of premature ventricular complexes in the randomized period. The median numbers on days 1, 2 and 15 were 146, 101, 84 in the placebo group and 73, 59 and 10 in the metoprolol group, respectively ( P < 0.05). Also during the further follow-up, when investigated 1, 3 and 6 months after the infarction, the median number of premature ventricular complexes was lower in the metoprolol group (74, 257, 142 in the placebo group and 7, 5 and 11 in the metoprolol group, P < 0.05). This indicates that metoprolol treatment in the acute phase of myocardial infarction reduces ventricular arrhythmias both in the early stage and also after the acute event.

Metoprolol in acute myocardial infarction. A pharmacokinetic and pharmacodynamic study.

A combined i.v. and oral dosage regimen of metoprolol early in acute myocardial infarction has been evaluated. Metoprolol 15 mg i.v. in three divided doses followed by 200 mg orally in divided doses was administered to 20 patients. The median delay from onset of pain to start of treatment was 7.5 h. Following the i.v. dose absorption of the first oral dose was prolonged in several patients, but the plasma metoprolol concentration rapidly stabilized at a mean of about 200 nmol/l. A significant correlation was found between the change in resting heart rate and the plasma concentration of metoprolol 15 min after the start of treatment. Blood pressure was not correlated with metoprolol concentration. Nine patients were restudied after 16-19 days of chronic therapy. The time to maximal plasma concentration of metoprolol on chronic treatment was reduced compared to that observed after the first oral dose. The median minimum plasma concentration during steady state averaged around 200 nmol/l and was comparable to the mean trough levels 24 and 48 h after the start of therapy. In the majority of patients, the dosage regimen rapidly produced and maintained plasma levels of metoprolol which should induce a significant degree of beta-blockade.

Hemodynamic effects of metoprolol in acute myocardial infarction: A randomized, placebo-controlled multicenter study

The central hemodynamic effects of metoprolol in acute myocardial infarction have been studied in a multicenter, double-blind, randomized trial. One hundred and ninety patients with acute myocardial infarction not previously on β blockers with heart rate >65 beats/min and blood pressure >105 mm Hg and without clinical signs of serious heart failure were included. After insertion of a pulmonary artery catheter, patients were randomized to metoprolol, 15 mg intravenously, and 50 mg 4 times a day orally (n = 95) or placebo (n = 95) with a mean delay of 7.2 hours. Hemodynamic measurements were made at baseline and repeatedly during 24 hours. Heart rate, systolic blood pressure and cardiac index were all immediately reduced by 10 to 20% in the metoprolol group and the difference compared with placebo was maintained throughout the 24 hours (p < 0.001). Pulmonary capillary wedge pressure (PCWP) in the metoprolol group increased from 13.7 ± 6.7 to a peak of 15.5 ± 5.5 mm Hg 30 minutes after injection. The difference compared with placebo was maintained for 8 hours (p < 0.01). This increase was seen only in the patient group with initial PCWP below the median of 13 mm Hg. In patients with initial PCWP above the median a continuous decrease was observed in both the placebo and metoprolol groups. Thus high initial PCWP was not associated with intolerance to metoprolol. Based on hemodynamic measurements tolerance to metoprolol was good.

Relationship between infarct size and incidence of severe ventricular arrhythmias in a double-blind trial with metoprolol in acute myocardial infarction

In 585 patients having an acute myocardial infarction for the first time the relationship was investigated between estimated infarct size and the incidence of ventricular fibrillation and treated ventricular tachycardia during hospitalization. The size of the infarct was estimated from analyses of heat stable lactate dehydrogenase (LD) (EC 1.1.1.27.) in serum collected every 12 hr for 48–108 hr. All patients participated in a double-blind comparison of the β 1-selective blocker metoprolol with placebo in suspected acute myocardial infarction. A correlation was observed between the enzymatically estimated infarct size and the incidence of ventricular fibrillation and treated ventricular tachycardia in patients on placebo ( P < 0.001), while this could not be demonstrated in patients on the beta-blocker ( P > 0.2). In placebo treated patients there was a correlation between the maximum heat stable LD activity and early ventricular fibrillation ( P = 0.034), late ventricular fibrillation ( P < 0.001), primary ventricular fibrillation ( P = 0.002) as well as secondary ventricular fibrillation ( P = 0.034). It is concluded that there seems to be a relatively strong correlation between the final size of the infarction and the occurrence of severe ventricular arrhythmias. Treatment with beta-blockade appeared to disturb this correlation.

Early intervention with a beta-blocking drug after acute myocardial infarction

Several controlled studies with long-term administration of beta blockers in postinfarction patients have demonstrated a reduction in cardiac events and mortality. During acute myocardial infarction (AMI), conventional treatment is directed mainly at such complications as pump failure and arrhythmias. Another approach attempts to influence the natural evolution of impending myocardial necrosis by interrupting the process in its reversible phase. In a double-blind trial with metoprolol in suspected or definite AMI, 1,395 patients were studied, 698 of whom received metoprolol and 697 placebo. The 3-month mortality was 36% lower in the metoprolol group (p = 0.024). A reduction in severe ventricular arrhythmias (ventricular fibrillation and tachycardia) was also seen. Chest pain was reduced and there was less need of analgesic drugs in the metoprolol group. Intervention within 12 hours resulted in a limitation of infarct size, a decreased need for furosemide and a shortened hospital stay. A significant reduction in mortality was maintained after 2 years of follow-up despite the same treatment in both groups between 3 and 24 months. Early institution of metoprolol in AMI has resulted in reduced mortality and morbidity.

Prophylactic antiarrhythmic therapy in acute myocardial infarction

Safe, effective prophylaxis of arrhythmias in acute myocardial infarction (AMI) is an important clinical goal. Despite rescue squads, out-of-hospital ventricular fibrillation (VF) has a poor prognosis. Even in-hospital VF has an important morbidity and mortality. Successful prophylactic therapy may also prevent infarct size enlargement associated with tachyarrhythmias. Several antiarrhythmic drugs have been investigated. In 3 studies, mortality was significantly reduced, but all of these have serious methodologic flaws and the validity of their conclusions is debatable. More reliance can be placed on 2 other studies which suggested that VF was significantly reduced by prophylactic therapy. However, in one of these studies, which used high-dose intravenous lidocaine, an unusually high incidence of VF was observed in the placebo-treated patients. The second study, reporting the use of metoprolol in AMI, was based on retrospective subset analysis. The reduction in VF was seen from the fourth day onwards and not during the acute phase of infarction. The favorable results with high-dose intravenous lidocaine are the basis for widespread use of prophylactic arrhythmia therapy in AMI. Uncontrolled observations provide some corroboration of the benefit. However, the claimed efficacy for lidocaine remains scientifically poorly substantiated and the safety of the high-dose regimen is controversial. Effective prophylaxis of arrhythmias in AMI could have important clinical benefit. However, the strategy would entail administration of a drug to many patients not at risk of arrhythmias (those without AMI) and to a number of patients in whom the complications of infarction are destined to develop.(ABSTRACT TRUNCATED AT 250 WORDS)

Hemodynamic effects of the cardioselective beta-blocking agent metoprolol in acute myocardial infarction. A 24-hour catheterization study.

Hemodynamic changes were studied in ten patients with uncomplicated transmural myocardial infection during 24 hours on beta-blockade. The cardioselective beta-adrenergic blocking drug metoprolol was injected (15 mg i.v.) within the first 24 hours after onset of chest pain and was followed by oral therapy (25-50 mg at 6-hour intervals). There was a decrease in heart rate, systolic BP, and cardiac output, which was most marked after the injection. The stroke volume and diastolic BP for the whole group of patients remained unchanged. The pulmonary artery end diastolic pressure did not change significantly after the injection but a continuous fall was obtained in three out of four patients with initially elevated values. The preejection period, measured from the ECG and carotid pressure curve, as initially short and was prolonged in all patients after administration of the beta-blocking drug. It is concluded that the cardioselective beta-blocking drug metoprolol may be used in selected patients in the acute phase of myocardial infarction without danger of hemodynamic deterioration during the first 24 hours of therapy. The selection of patients can be based on clinical criteria. In this study signs of left heart failure, hypotension, poor peripheral circulation, bradycardia, and AV block were regarded as contraindications.