Bruno Magnani

The Effect of the Angiotensin-Converting–Enzyme Inhibitor Zofenopril on Mortality and Morbidity after Anterior Myocardial Infarction

Background Left ventricular dilatation and neuroendocrine activation are common after acute anterior myocardial infarction. Long-term treatment with an angiotensin-converting–enzyme (ACE) inhibitor may improve outcome by attenuating these processes. We investigated whether the ACE inhibitor zofenopril, administered for six weeks after anterior myocardial infarction, could improve both short-term and long-term outcome. Methods A total of 1556 patients were enrolled within 24 hours after the onset of symptoms of acute anterior myocardial infarction, and they were randomly assigned in a double-blind fashion to receive either placebo (784 patients) or zofenopril (772 patients) for six weeks. At this time we assessed the incidence of death or severe congestive heart failure. The patients were reexamined after one year to assess survival. Results The incidence of death or severe congestive heart failure at six weeks was significantly reduced in the zofenopril group (55 patients, 7.1 percent), as compared with t...

Calcium Antagonist Lacidipine Slows Down Progression of Asymptomatic Carotid Atherosclerosis Principal Results of the European Lacidipine Study on Atherosclerosis (ELSA), a Randomized, Double-Blind, Long-Term Trial

Background—Most cardiovascular events associated with hypertension are complications of atherosclerosis. Some antihypertensive agents influence experimental models of atherosclerosis through mechanisms independent of blood pressure lowering. Methods and Results—The European Lacidipine Study on Atherosclerosis (ELSA) was a randomized, double-blind trial in 2334 patients with hypertension that compared the effects of a 4-year treatment based on either lacidipine or atenolol on an index of carotid atherosclerosis, the mean of the maximum intima-media thicknesses (IMT) in far walls of common carotids and bifurcations (CBMmax). This index has been shown by epidemiological studies to be predictive of cardiovascular events. A significant (P <0.0001) effect of lacidipine was found compared with atenolol, with a treatment difference in 4-year CBMmax progression of −0.0227 mm (intention-to-treat population) and −0.0281 mm (completers). The yearly IMT progression rate was 0.0145 mm/y in atenolol-treated and 0.0087 mm/y in lacidipine-treated patients (completers, 40% reduction;P =0.0073). Patients with plaque progression were significantly less common, and patients with plaque regression were significantly more common in the lacidipine group. Clinic blood pressure reductions were identical with both treatments, but 24-hour ambulatory systolic/diastolic blood pressure changes were greater with atenolol (−10/−9 mm Hg) than with lacidipine (−7/−5 mm Hg). No significant difference between treatments was found in any cardiovascular events, although the relative risk for stroke, major cardiovascular events, and mortality showed a trend favoring lacidipine. Conclusion—The greater efficacy of lacidipine on carotid IMT progression and number of plaques per patient, despite a smaller ambulatory blood pressure reduction, indicates an antiatherosclerotic action of lacidipine independent of its antihypertensive action.

The Verapamil in Hypertension and Atherosclerosis Study (VHAS): results of long-term randomized treatment with either verapamil or chlorthalidone on carotid intima-media thickness.

Background It is unclear whether the carotid intima–media thickness can be influenced by antihypertensive treatment and whether some antihypertensive agents, such as calcium antagonists, may have a greater effect on this parameter than others, such as diuretics. The present paper reports the principal results of the ultrasound substudy of the randomized, prospective, controlled, Verapamil in Hypertension and Atherosclerosis Study (VHAS). Design and methods In 498 hypertensive patients in eight Italian centres, randomized to either verapamil (240 mg once a day) or chlorthalidone (25 mg once a day), a B-mode ultrasound scan was performed according to a standardized procedure at baseline and after 3, 12, 24, 36 and 48 months of treatment. The maximum intima–media thicknesses of the far walls of common, bifurcation and internal carotid arteries were measured bilaterally, and the following indices calculated: the mean thickness at the six measured sites, the mean thickness at the common and bifurcation sites and the single maximum thickness. The primary endpoint for treatment efficacy was the slope of the change over 4 years (rate of change, mm/year), corrected by using the initial mean over the six sites (baseline + 3 months) as a covariate (mm/year per mm). The patients were also classified into three strata according to their baseline single maximum thickness: those with normal carotid arteries (single maximum (1 mm), those with thickened carotid arteries (single maximum >1 and ≤ 1.5 mm and those with carotid plaques (single maximum >1.5 mm). Results Among the 456 patients with satisfactory baseline ultrasound readings, 33% were classified with normal carotid arteries, 27% with thickened carotid arteries and 40% with plaques. In the intention-to-treat population (377 patients with ultrasound measurements taken on at least three different occasions over a period of at least 2 years), the rate of change in the mean thickness at the six sites measured was rather small (0.015 mm/year), but significantly (P < 0.05) smaller in patients with plaques (0.003 mm/year) than in patients with thickened or with normal carotids (0.023 and 0.025 mm/year, respectively). When related to initial values, the rate of change in the mean thickness at the six sites had a negative slope (−0.059 mm/year per mm, P < 0.01). Although rates of change in the carotid intima–media thickness in unstratified patients were not different in those treated with verapamil or with chlorthalidone, when changes in the mean thickness of six sites were related to the initial value, the slope of this relationship was significantly different in the two treatment groups (verapamil −0.082 versus chlorthalidone −0.037 mm/year per mm, P < 0.02). The blood pressure-lowering effect of the two randomized treatments was similar. Taking fatal and nonfatal, major and minor cardiovascular events together, there were 19 events in the verapamil group and 35 in the chlorthalidone group, with a significantly (P < 0.01) greater incidence in patients with plaques, and among patients with plaques in those who were randomized to chlorthalidone (P < 0.05). Conclusions In accord with evidence from animal models of atherosclerosis, the calcium antagonist verapamil was more effective than the diuretic chlorthalidone in promoting regression of thicker carotid lesions. Changes in the carotid intima–media thickness were small in both groups, and the differences between the changes under the two treatments were consequently small, but the observation that these small differences in carotid wall changes were paralleled by differences in the incidence of cardiovascular events (better intima–media thickness regression with verapamil paralleled by a lower cardiovascular event rate) suggests that even small effects on carotid plaques may have clinical and prognostic relevance.

Effectiveness of loading oral flecainide for converting recent-onset atrial fibrillation to sinus rhythm in patients without organic heart disease or with only systemic hypertension

Sixty-two patients with recent-onset (less than or equal to 1 week) atrial fibrillation (New York Heart Association functional class 1 and 2) were randomized in a single-blind study to 1 of the following treatment groups: (1) flecainide (300 mg) as a single oral loading dose; or (2) amiodarone (5 mg/kg) as an intravenous bolus, followed by 1.8 g/day; or (3) placebo for the first 8 hours. Twenty-four-hour Holter recording was performed, and conversion to sinus rhythm at 3, 8, 12 and 24 hours was considered as the criterion of efficacy. Conversion to sinus rhythm was achieved within 8 hours (placebo-controlled period) in 20 of 22 patients (91%) treated with flecainide, 7 of 19 (37%) treated with amiodarone (p less than 0.001 vs flecainide), and 10 of 21 (48%) treated with placebo (p less than 0.01 vs flecainide). Resumption of sinus rhythm within 24 hours occurred in 21 of 22 patients (95%) with flecainide and in 17 of 19 (89%) with amiodarone (p = not significant). Mean conversion times were shorter for flecainide (190 +/- 147 minutes) than for amiodarone (705 +/- 418; p less than 0.001). No major side effects occurred. At Holter monitoring, a pause of 9.3 seconds was observed in 1 asymptomatic patient treated with flecainide. Phases of atrial flutter with a ventricular rate less than or equal to 150 beats/min were detected before sinus conversion in 1 patient receiving placebo and in 2 receiving flecainide.(ABSTRACT TRUNCATED AT 250 WORDS)

Dynamic Electrophysiological Behavior of Human Atria During Paroxysmal Atrial Fibrillation

BACKGROUND The aims of our study were to investigate the meaning of local atrial activation and its behavior during paroxysmal atrial fibrillation and to study the effect of overdrive pacing on local atrial activity. METHODS AND RESULTS Twenty-five patients with lone paroxysmal atrial fibrillation underwent electrophysiological study. Functional and effective atrial refractoriness was determined. Mean and fifth percentile values of 100 consecutive atrial fibrillation intervals (FF) were evaluated at three atrial sites either at arrhythmia onset or at self-termination (or at minute 5). A high-voltage burst pacing was performed after 6 minutes of stable atrial fibrillation in 10 patients. Mean FF intervals were evaluated 5 seconds before and after atrial pacing. Forty-nine atrial fibrillation episodes were induced: 39 self-terminating within 5 minutes and 10 long-lasting. A significant correlation was found between mean FF and atrial functional refractory period (r = .73, P < .001) and between fifth percentile FF and atrial effective refractory period (r = .57, P < .005). Atrial fibrillation self-termination was associated with significant mean FF prolongation, whereas long-lasting fibrillation behaved the opposite. In 10 patients, burst pacing resulted in significant shortening of the mean FF at the stimulation site; no changes were observed in the two distant recording sites. CONCLUSIONS The analysis of the FF intervals demonstrates a strict correlation with atrial functional refractoriness. The self-termination of atrial fibrillation is related to a prolongation of the functional refractoriness (mean FF), whereas a shortening of both functional and effective refractoriness (fifth percentile) is associated with atrial fibrillation persistence. The provoked shortening of the mean FF at the stimulation site is consistent with the presence of a gap of excitability during atrial fibrillation in the human atria.

Oral Propafenone To Convert Recent-Onset Atrial Fibrillation in Patients with and without Underlying Heart Disease: A Randomized, Controlled Trial

The optimal way to convert recent-onset atrial fibrillation to sinus rhythm is a subject of much debate. The effectiveness of intravenous propafenone has been shown [1-3], but the full antiarrhythmic effect of this regimen depends not only on the parent compound but on its 5-hydroxylated metabolite [4, 5]. This dependence provides a strong rationale for the use of oral loading regimens [3]. Results of previous controlled studies have shown that oral loading of propafenone is highly effective in converting recent-onset atrial fibrillation to sinus rhythm [6, 7]. Safety is a major concern with antiarrhythmic therapy. One of the primary proarrhythmic risks of propafenone and flecainide is the transformation of atrial fibrillation to flutter with 1:1 atrioventricular conduction and hemodynamic impairment [8-10]. We sought to determine whether the effectiveness and safety of propafenone differ in patients who have structural heart disease and patients who do not. Methods From June 1990 to June 1994, consecutive patients with recent-onset atrial fibrillation ( 7 days) who presented to one of three centers were considered for enrollment. Onset of arrhythmia was documented by electrocardiography or by an abrupt onset of palpitations with subsequent evidence of atrial fibrillation on electrocardiography. Patients were excluded for any of the following reasons: age greater than 80 years, heart failure greater than NYHA (New York Heart Association) class II, mean ventricular rate during atrial fibrillation less than 70 beats/min, recent myocardial infarction (within <6 months), unstable angina pectoris, previous or current electrocardiographic evidence ventricular preexcitation or complete bundle-branch block, previous electrocardiographic evidence of second- or third-degree atrioventricular block or bifascicular block, the sick sinus syndrome, hypokalemia (potassium level <3.5 mEq/L), renal or hepatic failure with severe hypoxia (Pao 2 < 55 mm Hg), severe metabolic disturbances, or known thyroid dysfunction. Patients who were receiving long-term digoxin therapy or antiarrhythmic drugs or had received such treatments within 8 hours before study entry were also excluded. Patients who had atrial fibrillation that lasted 72 hours or longer were enrolled only if they were receiving long-term warfarin therapy for anticoagulation. Patients provided informed consent. Eligible patients had a 24-hour Holter monitor applied; after 1 to 2 hours of observation to assess the stability of atrial fibrillation, they were randomly assigned by center in a single-blind manner to receive propafenone (300 mg in two tablets as a single oral dose) or placebo. All patients received intravenous saline throughout the study period. The electrocardiogram was monitored by telemetry, blood pressure was measured every 2 hours, and 12-lead electrocardiography was done every hour for the first 4 hours and then every 2 hours for the next 4 hours. When patients converted to sinus rhythm, 12-lead electrocardiography was done immediately. Conversion was defined as a stable sinus rhythm that lasted for at least 1 hour. Eight hours after the study drug was administered, physicians could continue treatment with the study drug or switch to a different therapeutic option. Holter monitor tapes were analyzed by two blinded observers using computer scanning systems (Marquette 8000, Milwaukee, Wisconsin, and Del Mar Avionics, Irvine, California) to determine the time of conversion to sinus rhythm and whether an abnormal rhythm was present. Within 24 hours after enrollment, echocardiography was done for each patient and left atrial diameter was measured in the left parasternal long-axis view. On the basis of clinical history and the results of physical examination, echocardiography, and chest radiography, patients were classified as having structural heart disease (defined as the presence of cardiac abnormalities other than atrial fibrillation), hypertension without structural heart disease (defined as previously recognized systemic hypertension according to the criteria of the World Health Organization), or neither. Continuous outcomes and baseline characteristics of the patients were compared by using the chi-square statistic and t-test as appropriate. The rates of conversion to sinus rhythm were assessed at 3 and 8 hours. Odds ratios and corresponding CIs were calculated according to the methods of Gardner and Altman [11]. We did logistic regression analysis to describe how the interaction of treatment with the presence or absence of heart disease and hypertension affected the probability of conversion to sinus rhythm. Analyses were done using SPS software, version 6.1.3 (SPS, Inc., Chicago, Illinois). Results Patients During the study period, 407 patients presented to the three centers and were screened for eligibility. Two hundred forty-three patients were eligible, and 240 gave consent. A total of 164 patients were excluded for one or more of the following reasons: age greater than 80 years (n = 10), heart failure greater than NYHA class II (n = 33), recent myocardial infarction (n = 20), bundle-branch block (n = 24), the sick sinus syndrome (n = 6), severe hypoxia (n = 13), thyroid dysfunction (n = 12), and previous antiarrhythmic treatment (n = 63). Two hundred forty patients were randomly assigned to receive propafenone (n = 119) or placebo (n = 121). The two groups were similar with regard to age, sex, cause of atrial fibrillation, NYHA class, left atrial dimension (measured by echocardiography), structural heart disease, and hypertension (Table 1). The duration of atrial fibrillation before randomization ranged from 2.5 to 120 hours and did not differ significantly between the treatment groups. Table 1. Patient Characteristics Conversion to Sinus Rhythm and Presence of Heart Disease The probability of conversion to sinus rhythm was greater after propafenone than after placebo at 3 and 8 hours (P < 0.001) (Figure 1). Corresponding odds ratios were 3.8 (95% CI, 2.1 to 6.8) at 3 hours and 5.4 (CI, 3.0 to 9.4) at 8 hours. Figure 1. Conversion to sinus rhythm within 8 hours in patients receiving propafenone or placebo. At 8 hours, the probability of conversion to sinus rhythm was significantly higher in the propafenone group than in the placebo group for patients who had heart disease (odds ratio, 21.7 [CI, 5.9 to 80.1]; P < 0.001), patients who had hypertension (odds ratio, 6.4 [CI, 2.3 to 17.6]; P < 0.001), and patients who did not have structural heart disease (odds ratio, 2.8 [CI, 1.2 to 6.7]; P = 0.02). Conversion rates at 8 hours for patients receiving propafenone were similar among the three heart disease subgroups, but conversion rates for patients receiving placebo differed significantly (56% for patients without structural heart disease, 27% for patients with hypertension, and 17% patients with structural heart disease [P = 0.009 by logistic regression model]). At 3 hours, the probability of conversion to sinus rhythm was higher in the propafenone group than in the placebo group for patients who did not have heart disease (48% for propafenone compared with 26% for placebo; odds ratio, 2.6 [CI, 1.2 to 6.0]; P = 0.02), patients who had hypertension (41% for propafenone compared with 16% for placebo; odds ratio, 3.5 [CI, 1.2 to 10.5]; P = 0.02), and patients who had structural heart disease (47% for propafenone compared with 7% for placebo; odds ratio, 12.3 [CI, 2.5 to 60.5]; P < 0.001). By logistic regression analysis, no significant correlation between heart disease and treatment was seen at 3 hours (P = 0.2). Mean time SD for conversion to sinus rhythm within 8 hours was 181 118 minutes for propafenone and 181 112 minutes for placebo (P > 0.2). Adverse Effects Sustained atrial flutter or tachycardia (lasting 1 min) occurred in eight patients (7%) receiving propafenone and seven patients (6%) receiving placebo (P > 0.2), regardless of heart disease status. Among these patients, atrioventricular conduction was 2:1 in two patients receiving propafenone (heart rate, 115 to 140 beats/min) and three patients receiving placebo (heart rate, 120 to 150 beats/min), 3:1 in six patients receiving propafenone (heart rate, 60 to 95 beats/min) and three patients receiving placebo (heart rate, 60 to 100 beats/min), and 1:1 in one patient receiving placebo (heart rate, 240 beats/min). This patient developed atrial flutter and collapsed. Pauses in ventricular rate lasting longer than 2 seconds were seen in one patient (1%) receiving propafenone and three patients (2%) receiving placebo (P > 0.2). Among patients receiving propafenone, nine (8%) had the following adverse effects: QRS complexes of the electrocardiogram greater than 120 ms (n = 3), hypotension (n = 2), slight hypotension and bradycardia at conversion (n = 3), and phases of junctional rhythm after conversion (n = 1). No ventricular proarrhythmic effects occurred. Discussion Oral loading of propafenone was effective for conversion to sinus rhythm in our study, as it has been in smaller studies [3, 6, 7, 12, 13]. The recent findings of Wijffels and colleagues [14] in a model of chronic atrial fibrillation in animals indicate that electrophysiologic remodeling occurs within a few hours of persistent atrial fibrillation and results primarily from changes in atrial refractoriness that enhance the persistence of atrial fibrillation. This observation provides a strong rationale for prompt conversion to sinus rhythm. Therefore, oral loading of propafenone (which has an effectiveness similar to that of intravenous propafenone [3]) offers many advantages over such regimens as oral quinidine and intravenous amiodarone, which require titration of dose or a longer period of time to achieve an effect [6, 13, 15]. In controlled trials, propafenone was shown to be more effective and to take effect more quickly than amiodarone [13] or digoxin plus quinidine [6]. Intravenous amiodarone was no more effective than placebo and

Evidence of a Partial Escape of Renin‐Angiotensin‐Aldosterone Blockade in Patients with Acute Myocardial Infarction Treated with Ace Inhibitors

Angiotensin‐Converting enzyme (ACE) inhibitors have been designed to block the renin‐angiotensin system and can represent an effective therapeutic approach in those settings where such a system is active, such as myocardial infarction. In a randomized placebo‐controlled study, 10 patients with acute myocardial infarction allocated to treatment with increasing doses of zofenopril calcium and 10 patients allocated to placebo were studied in hospital, within 24 hours from symptoms, during 11 sampling periods to assess the time course of ACE inhibition and renin‐angiotensin‐aldosterone blockade. Zofenopril administration was followed by a dose‐dependent inhibition of in vitro ACE activity (7.5 mg, 65%; 15 mg, 89%; 30 mg, 94.5%) and a progressive increase in plasma active renin. Conversely, plasma aldosterone decreased during the first 3 days of treatment and then returned toward baseline values, as did blood pressure, despite a persistent inhibition of ACE. The present data suggest the existence of an interesting dissociation between the time‐course of ACE inhibition and that of blockade of the renin‐angiotensin system in patients with acute myocardial infarction. This discrepancy could arise from the combination of an only partial in vivo ACE inhibition and the compensatory increase in plasma renin that occurs during treatment with ACE inhibitors. A better understanding of this relationship would seem to be useful in addressing the correct use of ACE inhibitors in patients with acute myocardial injury.

A controlled study on oral propafenone versus digoxin plus quinidine in converting recent onset atrial fibrillation to sinus rhythm

UNLABELLED Eighty-seven patients with recent onset atrial fibrillation (< or = 8 days) without clinical signs of heart failure were randomly allocated to one of the following treatments: (i) oral propafenone (600 mg as a loading dose followed after 8 h by 300 mg t.i.d.); (ii) intravenous digoxin as acute scheme (up to 1.125 mg/24 h) followed after 6 h by hydroquinidine chlorhydrate (total dose, 1350 mg); or (iii) placebo. The patients were submitted to Holter monitoring for 48 h. RESULTS propafenone achieved higher successful conversion rates at 6, 12 and 24 h compared either with placebo (62% vs. 17%, 83% vs. 34%; 86% vs. 55%; P < 0.01, respectively) or with digoxin at 6 h (62% vs. 38%; P < 0.05) and digoxin plus quinidine at 12 h (83% vs. 48%; P < 0.05). At 48 h, a placebo conversion rate of 76% was observed with consequent lack of any significant difference with the active treatments. Mean conversion times within 48 h were 267 +/- 238 min for propafenone, 648 +/- 631 min for digoxin plus quinidine (P < 0.01 vs. propafenone) and 893 +/- 622 min for placebo (P < 0.001 vs. propafenone). Propafenone and digoxin plasma levels were within the therapeutic range. Asymptomatic phases of atrial flutter with > or = 2:1 atrio-ventricular conduction ratio were observed during Holter monitoring, before conversion to sinus rhythm, in four patients treated with propafenone, in one patient taking digoxin plus quinidine and in four patients with placebo.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical results of the verapamil in hypertension and atherosclerosis study

Objective The Verapamil in Hypertension and Atherosclerosis Study (VHAS) is a prospective randomized study the objective of which was to compare the long-term effects of verapamil and chlorthalidone on the blood pressure, clinical safety, and the progression/regression of carotid wall lesions in members of a large population of hypertensive patients. Design After a 3-week placebo run-in period, 1414 hypertensive patients [692 men and 722 women, aged 53.2 ± 7 years, blood pressure 168.9 ± 10.5/ 102.2 ± 5.0 mmHg (means ± SD)] were assigned randomly to be administered either 240 mg sustained- release verapamil (n = 707) or 25 mg chlorthalidone (n = 707) once a day for 2 years. The study design was double blind for the first 6 months and open thereafter. 25–50 mg/day captopril were added to the treatment of non-responding patients; subsequently, patients not responding to combined therapy were switched to any therapy chosen by the treating doctors (free therapy). The blood pressure of the sitting subject, heart rate, and a standard clinical safety profile (electrocardiogram, laboratory tests, adverse events, cardiovascular events, and deaths) were assessed regularly throughout the study. Results After 2 years the systolic and diastolic blood pressures were reduced significantly in members of both treatment groups (by 16.3/16.6% with verapamil and by 16.9/16.2% with chlorthalidone, both by analysis of variance, P < 0.0001). The patients for whom we added captopril treatment constituted 22.6% of the verapamil and 26.2% of the chlorthalidone group; while 11.6 and 12.2% of patients in these groups, respectively, were administered free therapy. Normalization of the diastolic blood pressure (to ≤ 90 mmHg or to ≤ 95 mmHg with a ≥ 10% decrease) was achieved for 69.3% of the verapamil and 66.9% of the chlorthalidone group. A decrease in heart rate (by 5.8%) occurred in members of the verapamil group only. A decrease in total serum cholesterol (from 223.6 to 216.9 mg/dl, P < 0.01) and in the total cholesterol : high-density lipoprotein cholesterol ratio (from 4.9 to 4.5, P < 0.01) was noted for the verapamil group only, whereas significantly greater rates of hyperuricemia (plasma urate > 7.0 mg/dl; 10.8 versus 3.9%) and hypokalemia (serum K < 3.5 mmol/l; 24.6 versus 4.4%) were observed for the chlorthalidone group (P < 0.01, versus verapamil for both). Adverse events were reported by 32.5% of patients treated with verapamil and by 33.4% of those treated with chlorthalidone. The most frequent adverse events were constipation in members of the verapamil group (13.7%) and asthenia in members of the chlorthalidone group (8.5%). In total 315 dropped out (153 from the verapamil and 162 from the chlorthalidone group). The occurrence of cardiovascular events was similar for both treatments (42 events for verapamil and 43 for chlorthalidone, NS). Conclusion Similar antihypertensive efficacies, tolerabilities and cardiovascular event rates were observed with verapamil and with chlorthalidone. However, treatment with chlorthalidone was associated with significantly higher incidences of hyperuricemia and hypokalemia than was treatment with verapamil.

Amlodipine reduces transient myocardial ischemia in patients with coronary artery disease: Double-blind circadian anti-ischemia program in Europe (CAPE trial)

OBJECTIVES This study was carried out to determine the effect of the once-daily calcium channel blocking agent amlodipine (half-life 35 to 50 h) on the circadian pattern of myocardial ischemia in patients with chronic stable angina. BACKGROUND Myocardial ischemia during normal daily life, both symptomatic and asymptomatic, has been associated with increased risk of cardiovascular morbidity and mortality, and the circadian pattern parallels that for myocardial infarction and sudden death. METHODS The Circadian Anti-Ischemia Program in Europe (CAPE) was a large, 10-week international (63 sites), double-blind, parallel study. After a 2-week, single-blind placebo phase, during which stable doses of antianginal treatment were maintained (beta-adrenergic blocking agents in 65% of patients), patients with chronic stable angina with at least three attacks of angina per week, with at least four ischemic episodes or > or = 20 min of ST segment depression in 48 h of Holter monitoring, were randomized to receive treatment with either 5 mg/day of amlodipine or placebo (2:1 randomization). The dose was increased to 10 mg/day after 4 weeks. During week 7 of treatment, 48-h ambulatory ECG monitoring was repeated. RESULTS Three hundred fifteen of 1,160 patients screened were eligible, and 250 had complete evaluable data. Compared with placebo, amlodipine significantly reduced both the frequency of ST segment depression episodes (60% for amlodipine vs. 44% for placebo, p = 0.025) and total integrated ST ischemic area (62% mm-min vs. 50% mm-min, p = 0.042). Amlodipine reduced ischemia over the 24 h with the intrinsic circadian pattern maintained. In addition, diary data showed a significant reduction in angina (70% for amlodipine vs. 44% for placebo, p = 0.0001) and in nitroglycerin consumption (67% vs. 22%, respectively, p = 0.0006). Amlodipine and placebo demonstrated similar safety profiles (adverse events 17.3% for amlodipine and 13.3% for placebo; discontinuation rates due to adverse events were 2% vs. 4.4%, respectively). CONCLUSIONS Once-daily amlodipine, when added to background treatment, significantly reduced both symptomatic and asymptomatic ischemic events over 24 h in patients with chronic stable angina.