Amiodarone interaction with beta-blockers: analysis of the merged EMIAT (European Myocardial Infarct Amiodarone Trial) and CAMIAT (Canadian Amiodarone Myocardial Infarction Trial) databases. The EMIAT and CAMIAT Investigators.

BACKGROUND: Investigations with in vitro and animal models suggest an interaction between amiodarone and beta-blockers. The objective of this work was to explore if an interaction with beta-blocker treatment plays a role in the decrease of cardiac arrhythmic deaths with amiodarone in patients recovered from an acute myocardial infarction. METHODS AND RESULTS: A pooled database from 2 similar randomized clinical trials, the European Amiodarone Myocardial Infarction Trial (EMIAT) and the Canadian Amiodarone Myocardial Infarction Trial (CAMIAT), was used. Four groups of post-myocardial infarction patients were defined: beta-blockers and amiodarone used, beta-blockers used alone, amiodarone used alone, and neither used. All analyses were done on an intention-to-treat basis. Unadjusted and adjusted relative risks for all-cause mortality, cardiac death, arrhythmic cardiac death, nonarrhythmic cardiac death, arrhythmic death, or resuscitated cardiac arrest were lower for patients receiving beta-blockers and amiodarone than for those without beta-blockers, with or without amiodarone. The interaction was statistically significant for cardiac death and arrhythmic death or resuscitated cardiac arrest (P=0.05 and 0.03, respectively). Findings were consistent across subgroups. CONCLUSIONS: These findings are based on a post hoc analysis. However, they confirm prior results from in vitro and animal experiments suggesting an interaction between beta-blockers and amiodarone. In practice, not only is the adjunct of amiodarone to beta-blockers not hazardous, but beta-blocker therapy should be continued if possible in patients in whom amiodarone is indicated.

Depressed heart rate variability identifies postinfarction patients who might benefit from prophylactic treatment with amiodarone: a substudy of EMIAT (The European Myocardial Infarct Amiodarone Trial).

OBJECTIVES: This substudy tested a prospective hypothesis that European Myocardial Infarct Amiodarone Trial (EMIAT) patients with depressed heart rate variability (HRV) benefit from amiodarone treatment. BACKGROUND: The EMIAT randomized 1,486 survivors of acute myocardial infarction (MI) aged < or =75 years with left ventricular ejection fraction (LVEF) < or =40% to amiodarone or placebo. Despite a reduction of arrhythmic mortality on amiodarone, all-cause mortality was not changed. METHODS: Heart rate variability was assessed from prerandomization 24-h Holter tapes in 1,216 patients (606 on amiodarone). Two definitions of depressed HRV were used: standard deviation of normal to normal intervals (SDNN) < or =50 ms and HRV index < or =20 units. The survival of patients with depressed HRV was compared in the placebo and amiodarone arms. A retrospective analysis investigated the prospective dichotomy limits. All tests were repeated in five subpopulations: patients with first MI, patients on beta-adrenergic blocking agents, patients with LVEF < or =30%, patients with Holter arrhythmia and patients with baseline heart rate > or =75 beats/min. RESULTS: Centralized Holter processing produced artificially high SDNN but accurate HRV index values. Heart rate variability index was < or =20 U in 363 (29.9%) patients (183 on amiodarone) with all-cause mortality 22.8% on placebo and 17.5% on amiodarone (23.2% reduction, p = 0.24) and cardiac arrhythmic mortality 12.8% on placebo and 4.4% on amiodarone (66% reduction, p = 0.0054). Among patients with prospectively defined depressed HRV, the largest reduction of all-cause mortality was in patients with first MI (placebo 17.9%, amiodarone 10.3%, 42.5% reduction, p = 0.079) and in patients with heart rate < or =75 beats/min (placebo 29.0%, amiodarone 19.3%, 33.7% reduction, p = 0.075). Among patients with first MI and depressed HRV, amiodarone treatment was an independent predictor of survival in a multivariate Cox analysis. The retrospective analysis found a larger reduction of mortality on amiodarone in 313 (25.7%) patients with HRV index < or =19 U: 23.9% on placebo and 17.1% on amiodarone (28.4% reduction, p = 0.15). This was more expressed in patients with first MI: 49.4% mortality reduction on amiodarone (p = 0.046), on beta-blockers: 69.0% reduction (p = 0.047) and with heart rate > or =75 beats/min: 37.9% reduction (p = 0.054). CONCLUSION: Measurement of HRV in a large set of centrally processed Holter recordings is feasible with robust methods of assessment. Patients with LVEF < or =40% and depressed HRV benefit from prophylactic antiarrhythmic treatment with amiodarone. However, this finding needs confirmation in an independent data set before clinical practice is changed.

Methods for the control of diabetes after acute myocardial infarction.

Blood glucose control in patients with diabetes after myocardial infarction is often poor, and this may contribute to increased mortality in the diabetic patient. A retrospective review of the records of 71 diabetic patients admitted with suspected myocardial infarction, and managed using a variety of methods, showed that adequate control (mean blood glucose less than 234 mg/dl; 13 mmol/L) was achieved in only 60%. Continuation of oral hypoglycemic agents and the use of irregular intermittent insulin in response to hyperglycemia were particularly associated with poor control. In a prospective study 68 consecutive patients were managed using regular subcutaneous insulin injections three times daily or a glucose-insulin-potassium intravenous infusion (in those with cardiogenic shock, severe hyperglycemia, or unable to eat). Control was adequate in 87% (P less than 0.001 versus retrospective group) and mean blood glucose concentration on days 1 and 2 were significantly lower than in the retrospective group (167 versus 232; 165 versus 236 mg/dl; both P less than 0.001). Simple protocols using three-times-daily subcutaneous insulin or glucose-insulin-potassium infusion provide a practical method for achieving good glycemic control in the diabetic patient with suspected acute myocardial infarction.

Increased survival after APSAC: 30-day and 12-month mortality data from the APSAC Intervention Mortality Study.

Preliminary analysis of mortality data from the anisoylated plasminogen streptokinase activator complex (APSAC) Intervention Mortality Study (AIMS) showed a 47% reduction in 30-day mortality (with a 95% confidence interval of 21 to 65%) for patients treated with APSAC within 6 hours of onset of acute myocardial infarction. After follow-up of 1,004 patients for 30 days after randomization in the double-blind, placebo-controlled, clinical trial, researchers found that 61 patients (12.2%) in the placebo group had died compared with 32 patients (6.4%) in the APSAC group (p = 0.0016). Incomplete follow-up of these patients for 1 year provided an estimated mortality of 19.4% in the placebo group and 10.8% in the APSAC group (log-rank test for survival to year p = 0.0006). Benefit was seen irrespective of age, site of infarction and time from onset of symptoms up to 6 hours.

Prevention of tolerance to nitroglycerin patches by overnight removal.

This investigation assesses the extent of tolerance development with nitroglycerin patches and whether tolerance might be prevented by overnight patch removal. On commencing therapy, active patches significantly prolonged exercise time (3.5 hours after patch application) in comparison with placebo, with an accompanying reduction in ST-segment depression at maximal common workload. Patients then received continuous or 12-hour-daily intermittent patch therapy, in a double-blind fashion, for 7 days. Exercise testing was repeated before and after active patch application, on the eighth day of each treatment phase. During continuous therapy, beneficial effects on exercise time and ST depression were abolished. By contrast, during intermittent therapy, prolongation of exercise time and reduction in ST-segment depression still occurred, on testing 3.5 hours after active patch application. These results confirm previous studies showing a high degree of tolerance during continuous therapy with nitroglycerin patches and suggest that tolerance can be prevented by 12-hour-daily intermittent therapy.

Anisoylated plasminogen streptokinase activator complex versus placebo. A preliminary multicentre study of safety and early mortality in acute myocardial infarction.

90 patients were enrolled into this preliminary multicentre study of the efficacy and safety of 30 units intravenous anisoylated plasminogen streptokinase activator complex (APSAC) compared with placebo in patients with acute myocardial infarction. 45 patients received APSAC and 45 placebo; the groups were similar for age, weight and site of infarction. There were significantly more women treated with APSAC (p less than 0.02). The mean time to treatment was 3.3 hours after symptoms of myocardial infarction for APSAC and 3 hours for placebo. The 30-day mortality was 7 patients in the placebo group and 1 in the APSAC group (p = 0.058). Adverse events were generally minor and were of similar overall frequency in both groups. There were more haemorrhagic events with APSAC, from which all patients recovered, and more cardiovascular events with placebo including 2 deaths from cardiogenic shock. APSAC showed a trend towards a reduction in 30-day mortality. Experience from this study has led to the initiation of the APSAC in myocardial infarction multicentre mortality study (AIMS).

A clinical and electrocardiographic method of assessing the severity of aortic stenosis.

A formula was devised by Wagner et al. (1977) for calculating gradients across stenotic aortic valves by using clinical and electrocardiographic criteria for patients aged two to 21 years. A modification of this formula was used in a preliminary survey to assess gradients across stenotic aortic values in eight older patients; the findings were similar to those obtained from cardiac catheterization. This formula was subsequently used for assessing the gradient across stenotic aortic valves in a further 14 patients; a high positive correlation coefficient (r = 0.75; p less than 0.01) with findings at cardiac catheterization was obtained in 13 patients in whom both sets of figures were available. This formula should be useful in conjunction with other clinical and laboratory findings, in the non-invasive evaluation of the severity of aortic stenosis.

Time as a factor in thrombolytic therapy.

Animal studies first demonstrated the importance of early reperfusion in limiting the size of eventual infarction. This has been confirmed by human studies in which the early patency of the infarct-related artery is correlated with prognosis. Large randomised clinical trials suggested a graded effect, with a particularly great benefit if therapy was administered during the first hour after the onset of symptoms, and a progressive diminution in the effect thereafter, up to 12 h, and perhaps beyond. These studies did not, however, randomise patients to earlier or later treatment so the comparisons of different time intervals were not entirely valid. Five mortality trials have now randomised patients to early or later treatment and have demonstrated a significant benefit if more than 1 h is gained thereby. These trials were individually not large enough to establish the degree of gain from earlier treatment, but pooling their results suggests that gaining about 1 h will reduce mortality by about 17%.

The APSAC interventional mortality study (AIMS) trial: mortality data.

The anistreplase (anisoylated plasminogen streptokinase activator complex or APSAC) intervention mortality study was designed as a double-blind, placebo-controlled study to test the effectiveness of anistreplase, 30 U administered intravenously within the first 6 hours of acute myocardial infarction. The primary endpoint of the study was mortality of all causes at 30 days and 1 year. Within 30 days, there were 77 deaths with placebo (17.8%) and 40 deaths (6.5%) with anistreplase, an odds reduction of 50.5% (p = 0.0006). By the end of one year, there had been a total of 113 deaths (17.8%) with placebo and 69 deaths (11.1%) with anistreplase, an odds reduction of 42.7% (p = 0.0007).

Guidelines for the early management of patients with myocardial infarction. British Heart Foundation Working Group.

In light of recent publications relating to resuscitation and pre-hospital treatment of patients suffering acute myocardial infarction of British Heart Foundation convened a working group to prepare guidelines outlining the responsibilities of general practitioners, ambulance services, and admitting hospitals. The guidelines emphasise the importance of the rapid provision of basic and advanced life support; adequate analgesia; accurate diagnosis; and, when indicted, thrombolytic treatment. The working group developed a standard whereby patients with acute myocardial infarction should receive thrombolysis, when appropriate, within 90 minutes of alerting the medical or ambulance service--the call to needle time. Depending on local circumstances, achieving this standard may involve direct admissions to coronary care units, "fast track" assessments in emergency departments, or pre-hospital thrombolytic treatment started by properly equipped and trained general practitioners.

A comparison of aspirin and anticoagulation following thrombolysis for myocardial infarction (the AFTER study): a multicentre unblinded randomised clinical trial.

OBJECTIVE: To compare aspirin with anticoagulation with regard to risk of cardiac death and reinfarction in patients who received anistreplase thrombolysis for myocardial infarction. DESIGN: A multicentre unblinded randomised clinical trial. SETTING: 38 hospitals in six countries. SUBJECTS: 1036 patients who had been treated with anistreplase for myocardial infarction were randomly assigned to either aspirin (150 mg daily) or anticoagulation (intravenous heparin followed by warfarin or other oral anticoagulant). The trial was stopped earlier than originally intended because of the slowing rate of recruitment. MAIN OUTCOME MEASURE: Cardiac death or recurrent myocardial infarction at 30 days. RESULTS: After 30 days cardiac death or reinfarction, occurred in 11.0% (57/517) of the patients treated with anticoagulation and 11.2% (58/519) of the patients treated with aspirin (odds ratio 1.02, 95% confidence interval 0.69 to 1.50, P = 0.92). Corresponding findings at three months were 13.2% (68/517) and 12.1% (63/519) (0.91, 0.63 to 1.32, P = 0.67). Patients receiving anticoagulation were more likely than patients receiving aspirin to have had severe bleeding or a stroke by three months (3.9% v 1.7% (0.44, 0.20 to 0.97, P = 0.04)). CONCLUSION: No evidence of a difference in the incidence of cardiac events was found between the two treatment groups, though the trial is too small to claim treatment equivalence confidently. A higher incidence of severe bleeding events and strokes was detected in the group receiving anticoagulation, suggesting that aspirin may be the drug of choice for most patients in this context.