Rationale and design of ACTIVE: the atrial fibrillation clopidogrel trial with irbesartan for prevention of vascular events.

BACKGROUND: Atrial fibrillation (AF) is the most frequently occurring cardiac arrhythmia with often serious clinical consequences. Many patients have contraindications to anticoagulation, and it is often underused in clinical practice. The addition of clopidogrel to aspirin (ASA) has been shown to reduce vascular events in a number of high-risk populations. Irbesartan is an angiotensin receptor-blocking agent that reduces blood pressure and has other vascular protective effects. METHODS AND RESULTS: ACTIVE W is a noninferiority trial of clopidogrel plus ASA versus oral anticoagulation in patients with AF and at least 1 risk factor for stroke. ACTIVE A is a double-blind, placebo-controlled trial of clopidogrel in patients with AF and with at least 1 risk factor for stroke who receive ASA because they have a contraindication for oral anticoagulation or because they are unwilling to take an oral anticoagulant. ACTIVE I is a partial factorial, double-blind, placebo-controlled trial of irbesartan in patients participating in ACTIVE A or ACTIVE W. The primary outcomes of these studies are composites of vascular events. A total of 14000 patients will be enrolled in these trials. CONCLUSIONS: ACTIVE is the largest trial yet conducted in AF. Its results will lead to a new understanding of the role of combined antiplatelet therapy and the role of blood pressure lowering with an angiotensin II receptor blocker in patients with AF.

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.

Blockade of angiotensin II type 1 receptors: effect on carotid and radial artery structure and function in hypertensive humans.

Converting-enzyme inhibition reduces cardiovascular hypertrophy in hypertensive subjects. Whether the blockade of angiotensin II type 1 (AT(1)) receptors reduces arterial hypertrophy has never been investigated. In a double-blind study versus placebo in subjects with essential hypertension, the effect of the AT(1) blocker irbesartan (150 mg/day for 8 weeks) on blood pressure, wall thickness, diameter and stiffness of the common carotid and radial arteries was studied, using echotracking techniques of high resolution. With irbesartan, mean blood pressure decreased significantly and proportionally to the baseline levels of active renin, and angiotensin I and II. There was a significant decrease in radial artery wall thickness. The percent change from baseline (+/- SEM) was -10.51 +/- 3.42 versus 6.18 +/- 4.77. There was no significant change in diameter or distensibility. This effect was correlated neither to blood pressure changes nor to hormonal baseline levels of the renin-angiotensin system. Carotid wall thickness and diameter were unchanged. Thus a 2-month treatment with an AT(1) antagonist significantly reduced radial but not carotid artery wall thickness. Blood pressure reduction could be explained on the basis of circulating renin-angiotensin activity. On the contrary, radial artery wall thickness reduction was independent of the baseline circulating renin-angiotensin activity and was not correlated with the effects of AT(1) blockade on blood pressure, thus implying the involvement of local hemodynamic and/or cellular mechanisms.

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.

Identification of post acute myocardial infarction patients with potential benefit from prophylactic treatment with amiodarone. A substudy of EMIAT (the European Myocardial Infarct Amiodarone Trial).

AIMS: To perform a retrospective analysis of subgroups of patients enrolled into the European Myocardial Infarct Amiodarone Trial (EMIAT) in order to identify patients who might benefit from prophylactic amiodarone treatment and patients in whom amiodarone might be harmful. METHODS: Baseline characteristics of the 1486 patients enrolled in EMIAT were used to investigate the all-cause mortality effect of amiodarone (intention-to-treat) in patients with a left ventricular ejection fraction 30-40% and < 30%, in patients with and without arrhythmia signs on Holter recordings, in patients with high and low baseline resting heart rate, in patients on and off beta-blocker treatment, and in a combination of these groups. RESULTS: A univariate analysis suggested that all-cause mortality is reduced on amiodarone in patients with an ejection fraction < 30%, with arrhythmia on the initial Holter, on beta-blocker treatment, and with an increased initial heart rate. A trend towards an increase of all-cause mortality was noted in patients with an ejection fraction 30-40%, without arrhythmia on Holter, off beta-blockers, and with a low baseline heart rate. A multivariate analysis suggested that the univariate observations are mutually additive. CONCLUSIONS: The study might serve as a basis for future prospective trials where amiodarone could be tested in patients with a recent myocardial infarction, having a reduced left ventricular ejection fraction, a high initial heart rate, and taking beta-blockers.

Randomised trial of effect of amiodarone on mortality in patients with left-ventricular dysfunction after recent myocardial infarction: EMIAT. European Myocardial Infarct Amiodarone Trial Investigators.

BACKGROUND: Ventricular arrhythmias are a major cause of death after myocardial infarction, especially in patients with poor left-ventricular function. Previous attempts to identify and suppress arrhythmias with various antiarrhythmic drugs failed to reduce or actually increase mortality. Amiodarone is a powerful antiarrhythmic drug with several potentially beneficial actions, and has shown benefit in several small-scale studies. We postulated that this drug might reduce mortality in patients at high risk of death after myocardial infarction because of impaired ventricular function, irrespective of whether they had ventricular arrhythmias. METHODS: The European Myocardial Infarct Amiodarone Trial (EMIAT) was a randomised double-blind placebo-controlled trial to assess whether amiodarone reduced all-cause mortality (primary endpoint) and cardiac mortality and arrhythmic death (secondary endpoints) in survivors of myocardial infarction with a left-ventricular ejection fraction (LVEF) of 40% or less. Intention-to-treat and on-treatment analyses were done. FINDINGS: EMIAT enrolled 1486 patients (743 in the amiodarone group, 743 in the placebo group). Median follow-up was 21 months. All-cause mortality (103 deaths in the amiodarone group, 102 in the placebo group) and cardiac mortality did not differ between the two groups. However, in the amiodarone group, there was a 35% risk reduction (95% CI 0-58, p = 0.05) in arrhythmic deaths. INTERPRETATION: Our findings do not support the systematic prophylactic use of amiodarone in all patients with depressed left-ventricular function after myocardial infarction. However, the lack of proarrhythmia and the reduction in arrhythmic death support the use of amiodarone in patients for whom antiarrhythmic therapy is indicated.

The European Myocardial Infarct Amiodarone Trial (EMIAT). EMIAT Investigators.

The objective of the European Myocardial Infarct Amiodarone Trial (EMIAT) is to assess the efficacy of amiodarone on mortality of patients with depressed left ventricular (LV) function following myocardial infarction (MI). The rationale for the trial is as follows: patients with poor LV function after acute MI have a high sudden cardiac death (SCD) mortality; amiodarone is a successful prophylactic therapy against SCD in patients with ventricular arrhythmias; a number of small studies (Canadian Amiodarone Myocardial Infarction Arrhythmia Trial [CAMIAT] pilot study, Basel Antiarrhythmic Study & Infarct Survival [BASIS], and the Polish Amiodarone Trial [PAT]) of prophylactic amiodarone post AMI have shown a beneficial response attributable to amiodarone. Patients are enrolled between 5 and 21 days after acute MI if LV ejection fraction (assessed by multiple-gated image acquisition nuclear angiography) is < or = 40%. The study group is stratified according to ejection fraction (stratum 1, 31-40%; stratum 2, < 31%). Amiodarone or placebo treatment (blind, randomized) is initiated prior to the discharge of the patient from the hospital and each patient is followed up for the duration of the study, at least 1 year. Recruitment began on November 30, 1990, and will continue for 4 years; > 700 patients are enrolled from > 60 centers (13 countries). The total study mortality (10% at 500 days) and the differential mortality of both strata are as anticipated. Side effects have been infrequent and very few patients have been withdrawn from the study. Trial conclusion is forecast for October 1995.

Dose-effect study of intranasal administration of growth hormone-releasing hormone-44-NH2 in healthy subjects.

Intranasal (in) administration of GH-releasing hormone-40- (GHRH-40) has been demonstrated to be efficient in stimulating GH secretion at doses equal to or higher than 30 micrograms/kg in man. We performed a dose-response study with GHRH-44-NH2 (GHRH) given by nasal spray and closely monitored local tolerance. Twelve normal young men were given 5 GNRH doses (125, 250, 500, 750, and 1000 micrograms) and placebo in random order according to a latin square design. Mild symptoms of local intolerance, subjective, objective, or both, were noted in the first 20 min after spray in 30 of 72 tests, and a significant difference (P = 0.003) was obtained in their frequency between the group placebo plus the lowest dose and the group of the other doses. The areas under the GH curves were significantly different between the subjects and the doses (by analysis of variance, P = 0.001 and P = 0.025, respectively). Multiple comparison tests showed a significant difference between the 3 highest doses and the placebo (P = 0.005, P = 0.05, and P = 0.02, respectively) and a significant difference between the highest dose and the 2 lowest doses (P = 0.005). By weighted linear regression between GH areas under the curve and GHRH doses the dose-response relationship was established as: y = 1.226x + 457. The magnitude of the GH peaks induced by in GHRH was significantly lower than that induced by iv GHRH. We conclude that in the normal young men tested, who were high responders to GHRH (as demonstrated by iv test), a 500-micrograms dose is sufficient to elicit GH secretion. Local tolerance, although imperfect, appears satisfactory to permit a clinical trial in children.

A placebo-controlled trial of intranasal growth hormone-releasing hormone [GHRH(1-44)-NH2] administration in normal young adults.

Growth hormone-releasing hormone, GHRH(1-44), was administered intranasally to 16 healthy young adult male volunteers in a placebo-controlled study using a dose of 1,000 micrograms dissolved in two different solvent vehicles: water alone and water with the surface tension-lowering agent Tween 80 (0.12%). The growth hormone (GH)-releasing effects of intranasal GHRH as well as that of the vehicle were established and compared to the effects of 80 micrograms intravenous GHRH. Plasma GH response was assessed by frequent blood sampling over an 180-min period, using both peak response and area under the curve (AUC). The results show that the GH-release effects of intranasal GHRH are comparable whichever vehicle is used, and are similar, with the dose of 1,000 micrograms, to the response obtained following the administration of 80 micrograms intravenous GHRH. Peak GH responses to GHRH (means +/- SEM) were 25.6 +/- 4.2 ng/ml (1,000 micrograms GHRH with water), 32.9 +/- 9.1 ng/ml (1,000 micrograms with water plus Tween 80) and 36.3 +/- 7.8 ng/ml (80 micrograms i.v. administration) (not significant). There was no significant GH response to placebo. Mean peak GH responses occurred after approximately 30 min in all three active treatments (29.2 +/- 2.7, 33.9 +/- 3.2 and 30.9 +/- 3.9 min, respectively). The AUC values (ng.min.ml-1) were not statistically different: 1,914.4 +/- 386.7 (water), 2,176.2 +/- 599.9 (water plus Tween 80) and 2,419.2 +/- 506.9 (i.v.) (not significant). Intranasal GHRH administration was well tolerated in all subjects. Occasional local reactions consisted of a prickly sensation in the nostrils or sneezing irrespective of the vehicle used.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of repetitive administration of growth hormone-releasing hormone on growth hormone secretion, insulin-like growth factor I, and bone metabolism in postmenopausal women.

This study sought to determine whether GH response to synthetic GHRH was impaired in 13 postmenopausal (55-71 years) as compared with that in 8 eugonadal women and whether IGF-I and bone metabolism were consequently depressed. Thereafter, the effects of daily iv injections of 80-micrograms GHRH-44 for 8 days were studied in the same postmenopausal group. In addition to significantly higher basal IGF-I and osteocalcin levels (P less than 0.005) in eugonadal as compared with the postmenopausal women, the administration of one GHRH-44 injection resulted in significantly higher 120-min postinjection GH maximum peak and cumulative responses in the former group as well (P less than 0.005). Highly significant correlations were observed between 17 beta-estradiol plasma levels and either GH maximum peak or cumulative responses to GHRH-44 when both groups were pooled together, but not when considered independently. In postmenopausal women, a correlation was found between both age and duration of menopause and GH responses. Repeated GHRH-44 injections in postmenopausal women induced a significant increase in GH response (P less than 0.001) as well as in IGF-I levels from day 4 to 8. No phospho-calcium parameters were modified except for a significant rise in osteocalcin from day 2 to 8. These data indicate an age-related loss of sensitivity of somatotrope cells to GHRH-44 in postmenopausal women, partly corrected by repeated daily GHRH-44 injections. As a consequence of the GHRH-induced increase in GH secretion, IGF-I was also enhanced and may be responsible for a stimulatory effect on bone formation, as shown by the osteocalcin increase, uncoupled from bone resorption.