Felodipine-metoprolol combination tablet: a valuable option to initiate antihypertensive therapy?

The aim of the present study was to assess the efficacy and tolerability of a calcium antagonist/beta-blocker fixed combination tablet used as first-line antihypertesnive therapy in comparison with an angiotensin converting enzyme inhibitor and placebo. Patients with uncomplicated essential hypertension (diastolic blood pressure between 95 and 110 mm Hg at the end of a 4-week run-in period) were randomly allocated to a double-blind, 12-week treatment with either a combination tablet of felodipine and metoprolol (Logimax), 5/50 mg daily (n = 321), enalapril, 10 mg daily (n = 321), or placebo (n = 304), with the possibility of doubling the dose after 4 or 8 weeks of treatment if needed (diastolic blood pressure remaining >90 mm Hg). The combined felodipine-metoprolol treatment controlled blood pressure (diastolic < or =90 mm Hg 24 h after dose) in 72% of patients after 12 weeks, as compared with 49% for enalapril and 30% for placebo. A dose adjustment was required in 38% of patients receiving the combination, in 63% of patients allocated to placebo, and 61% of enalapril-treated patients. The overall incidence of adverse events was 54.5% during felodipine-metoprolol treatment; the corresponding values for enalapril and placebo were 51.7% and 47.4%, respectively. Withdrawal of treatment due to adverse events occurred in 18 patients treated with the combination, in 10 patients on enalapril, and 12 patients on placebo. No significant change in patients' well-being was observed in either of the three study groups. These results show that a fixed combination tablet of felodipine and metoprolol allows to normalize blood pressure in a substantially larger fraction of patients than enalapril given alone. This improved efficacy is obtained without impairing the tolerability. The fixed-dose combination of felodipine and metoprolol, therefore, may become a valuable option to initiate antihypertensive treatment.

Relation of exercise capacity to left ventricular systolic function and diastolic filling in idiopathic or ischemic dilated cardiomyopathy.

Although exercise intolerance is a cardinal symptom of patients with dilated cardiomyopathy (DC) and heart failure, the factors that limit exercise capacity in these patients remain a matter of debate. To assess the contribution of left ventricular (LV) diastolic filling to the variable exercise capacity of patients with DC, we studied 47 patients (60 +/- 12 years) with DC in stable mild-to-moderate heart failure with a mean LV ejection fraction of 28%. Exercise capacity was measured as total body peak oxygen consumption (VO2) during symptom-limited bicycle (10 W/min) and treadmill (modified Bruce protocol) exercise. LV systolic function and diastolic filling were assessed at rest before each exercise by M-mode, Doppler echocardiography, and radionuclide ventriculography. As expected, treadmill exercise always yielded higher peak VO2 than bicycle exercise (21 +/- 6 vs 18 +/- 5 ml/kg/min, range 12 to 35 and 7 to 30 ml/kg/min, respectively, p <0.001). Both of these VO2 measurements were highly reproducible (R = 0.98). With univariate analysis, close correlations were found between peak VO2 (with either exercise modalities) and Doppler indexes of LV diastolic filling, as well as with the radionuclide LV ejection fraction. Stepwise multiple regression analysis identified 3 nonexercise variables as independent correlates of peak VO2, of which the most powerful was the E/A ratio (multiple r2 = 0.38, p <0.0001), followed by peak A velocity (r2 = 0.54, p <0.0001) and mitral regurgitation grade (r2 = 0.58, p = 0.024). In conclusion, our data indicate that in patients with DC, peak VO2 is better correlated to diastolic filling rather than systolic LV function.

Risk stratification in patients with dilated cardiomyopathy: contribution of Doppler-derived left ventricular filling.

Dilated cardiomyopathy (DCM) is a major cause of mortality among patients with heart failure. The aim of the present study was to investigate the independent contribution of Doppler-derived left ventricular (LV) filling to the prediction of survival in patients with DCM, of either ischemic or nonischemic origin, and to derive a simple risk stratification score based on easily available clinical and echocardiographic parameters. We followed 197 consecutive patients (159 men, mean age 60+/-13 years) with an echocardiographic diagnosis of DCM (LV end-diastolic dimension >60 mm, fractional shortening <25%) over an average period of 62+/-13 months. The presumed etiology of DCM was ischemic in 52% of the patients. During follow up, 69 patients died of cardiac causes and 41 required transplantation. At 5 years, overall cardiac event-free survival was 55% and freedom from death or heart transplantation was 43% (compared with 86% for the 5-year age- and sex-adjusted survival rate in our country). Kaplan-Meier survival curves generated for different thresholds of the peak E velocity and the E/A ratio indicated significant worsening of prognosis with increasing values of these parameters in both ischemic and nonischemic patients. Using Cox stepwise regression analyses, age (chi-square to remove 24.4; p <0.001), peak E velocity (chi-square to remove=18.9; p <0.001), LV ejection fraction (chi-square to remove 6.4; p <0.011), and systolic blood pressure (chi-square to remove 4.5; p=0.034) independently predicted cardiac deaths, whereas New York Heart Association (NYHA) functional class (chi-square to remove 48.5; p < 0.001), LV ejection fraction (chi-square to remove 19.1; p <0.001), E/A ratio (chi-square to remove 10.8; p <0.001), and systolic blood pressure (chi-square to remove 5.8; p <0.016) were independently associated with cardiac death or need for transplantation. Based on these parameters, a risk score was elaborated, which allowed appropriate classification of each individual patient into low- (5-year survival rate of 72%), intermediate- (46% survival rate), and high-risk groups (11% survival rate). In conclusion, our data show that among the noninvasive parameters commonly available in patients with either ischemic or nonischemic DCM, age, the NYHA functional class, the LV ejection fraction, the systolic blood pressure, the peak E velocity, and the E/A ratio provide relevant and independent information regarding the risk of cardiac death or the need for heart transplantation.

Pathophysiologic mechanisms underlying dobutamine- and exercise-induced wall motion abnormalities.

BACKGROUND: Dobutamine and exercise echocardiography are accepted as tests of comparable efficacy for the diagnosis of coronary artery disease. Although dobutamine has been classified as "exercise simulating," the mechanisms of ischemia with dobutamine and exercise have not been well studied. This study sought to compare the determinants of myocardial oxygen consumption. METHODS AND RESULTS: We studied 54 patients with coronary artery disease undergoing dobutamine and exercise stress. A subgroup of 13 patients with comparable degrees of wall motion abnormalities and ST-segment changes during both stresses were selected to compare the determinants of ischemia in comparable circumstances. Dobutamine was infused to a mean maximal dose of 32+/-8 microg/kg/min, and exercise was stopped at an average of 135+/-25 W. The mean regional wall motion score was not statistically different between the two protocols (p = 0.27). At the onset of wall motion abnormalities and peak stress, the heart rate increased significantly less during dobutamine than during exercise (106+/-23 vs 126+/-19 beats/min, p < 0.001). The same was true of systolic blood pressure (155+/-21 vs 205+/-24 mm Hg, p < 0.001) and the rate-pressure product (16.5+/-4.6 vs 25.9+/-5, p < 0.001). Cardiac volumes were similar during both tests. CONCLUSIONS: Ischemia occurs at a lower level of external cardiac work during dobutamine than during exercise stress. We suspect that additional mechanisms, such as the oxygen wasting effect of dobutamine, may be responsible for this observation.

Effects of spironolactone-altizide on left ventricular hypertrophy.

OBJECTIVE: To investigate the effects of the association spironolactone (25 mg)/altizide (15 mg) as monotherapy on left ventricular hypertrophy (LVH) in patients with mild to moderate hypertension. Additionally, to study the correlation between left ventricular mass (LVM) index and electrocardiographic (ECG) criteria for LVH. METHODS AND RESULTS: This was an open, prospective study of 6 months. Patients with mild to moderate essential hypertension were treated with spironolactone/altizide for two months and were included in the study if their blood pressure (BP) at the end of this first treatment period was normalised according to protocol criteria (systolic BP < 160 mm Hg and diastolic BP < 95 mm Hg). Patients then entered a second 4-month treatment period. LVM was determined by echocardiography performed at the beginning of treatment and after 6 months. LVH was defined as LVM > or = 100 g/m2 in women and LVM > or = 131 g/m2 in men. Echocardiograms were interpreted blindly by two echocardiography reading laboratories. Seventy-one patients with a normalised BP after two months of treatment, were enrolled in the study. Changes in LVM index were studied in 31/71 patients with LVH (25 women and 6 men, mean LVM index +/- (SD) 119.9 +/- 16.4 g/m2 in women and 147.8 +/- 10.9 g/m2 in men). Spironolactone/altizide significantly reduced LVM index by 10%, from 125.3 +/- 22.5 to 114.2 +/- 25.1 g/m2 (p < 0.005). Posterior and septal wall thickness decreased by 4% (p = 0.06) and 5% (p = 0.026), respectively. End-diastolic dimension was reduced by 3%, from 50.3 +/- 3.3 to 48.9 +/- 3.4 mm (p = 0.006). The posterior wall thickness to end-diastolic dimension ratio remained unchanged. Complete regression of LVH according to mass criteria occurred in 11 patients out of 31 (34.5%). The observed changes in ECG voltage criteria were in accordance with a decrease of LVM index. CONCLUSION: In this open study, the potassium-sparing diuretic spironolactone/altizide decreases LVM index in hypertensive patients, who were selected for follow-up because they had echocardiographic LVH and because their BP had normalised during an initial 2-month treatment period.

The pathophysiology of myocardial ischaemia.

In this review paper on the pathophysiology of myocardial ischaemia, the recent concepts of the ischaemic cascade, as well as the concepts of stunning and hibernating myocardium, are discussed. It is clear that painful ischaemia is the final phenomenon in the ischaemic cascade and that it is preceded by biochemical disturbances, diastolic and systolic dysfunction and electrocardiographic abnormalities. Silent ischaemia remains a difficult research field.

Permutation distribution estimation applied to the comparison of the profile of the activity of two antianginal drugs.

The comparison of the anti-ischemic activity of trimetazidine and propranolol was evaluated by multiple end points (clinical, exercise test, and ambulatory electrocardiogram [ECG] monitoring criteria) in 149 male patients with effort angina who received either trimetazidine 20 mg tid or propranolol 40 mg tid during a period of 3 months. The distribution of the standardized differences between the two treatments for each variable was obtained by a permutation method. The medians (estimation of the actual difference between the two treatments) and the 5, 25, 75 and 95% quantiles were represented on the same diagram for all end points. The pattern of the standardized distribution of the differences showed a similar activity of both drugs on symptoms and nitrates consumption, on exercise tolerance and increase in ischemic threshold at exercise, and on ischemia recorded at ambulatory ECG monitoring. Conversely, only propranolol decreased heart rate and rate pressure product at rest as well as at exercise, underlining the difference in the mode of action of the two drugs. This descriptive technique is an attractive method to evaluate the differences between drugs considering multiple criteria favouring the estimation of these differences together with their variability.

Improved identification of coronary artery disease in patients with left bundle branch block by use of dobutamine stress echocardiography and comparison with myocardial perfusion tomography.

This study compared the efficacy of dobutamine stress testing using 2-dimensional echocardiography and perfusion tomography for the noninvasive identification of coronary artery disease (CAD) in patients with left bundle branch block (LBBB). Twenty-four patients with permanent, complete LBBB (11 with previous myocardial infarction) were studied prospectively with dobutamine echocardiography and perfusion tomography. The presence of > 50% luminal diameter coronary stenosis was compared with the presence of dobutamine-induced fixed or reversible perfusion defects, and with resting or dobutamine-induced abnormalities of wall thickening. For each test, the left anterior coronary artery territory was compared with the circumflex and/or right coronary artery. Significant CAD was found in the left anterior descending coronary artery in 12 patients; all (100%) were identified by perfusion imaging, and 10 (83%, p = NS) by 2-dimensional stress echocardiography. In the 12 patients without left anterior descending CAD, scintigraphy was also positive in all (specificity: 0%), and echocardiography in only 1 (specificity: 92%, p < 0.01). The diagnostic accuracy was 50% and 87% (p < 0.05), respectively. This low specificity of perfusion tomography was improved by requiring an associated apical defect to indicate left anterior descending CAD and was corrected by restricting the diagnosis of coronary disease to those patients with partially reversible defects. In the circumflex and/or right coronary artery territory, sensitivity and specificity were similar using both techniques. We conclude that dobutamine-stress echocardiography is a specific and accurate test for the noninvasive identification of CAD, even in the left anterior descending artery territory of patients with LBBB.

Trimetazidine European Multicenter Study versus propranolol in stable angina pectoris: contribution of Holter electrocardiographic ambulatory monitoring.

The major objective of the Trimetazidine European Multicenter Study (TEMS) was to compare in a double-blind trial the anti-ischemic effects of trimetazidine (20 mg 3 times daily) with those of propranolol (40 mg 3 times daily). The inclusion criteria were based on an abnormal response to a multistage exercise test. After 3 months of treatment the improvements noted in all exercise testing data were similar in the trimetazidine and propranolol groups; similar data were obtained for the grades and severity of anginal attacks during daily life (from patient diaries). A 24-hour Holter monitoring was performed at entry and at the end of the study, but an abnormal Holter monitoring (1-mm ST-segment depression during at least 1 minute) was not an inclusion criterion. This explains why at entry only 50% of the patients in both groups had an abnormal Holter recording. After 3 months of treatment, there were no significant differences between the 2 groups, but we observed a trend toward a decrease in ambulatory ischemia in the trimetazidine group and a trend toward an increase in ambulatory ischemia in the propranolol group. These data in the propranolol group are in total disagreement with the available literature on beta blockers, which was due to a totally erratic behavior pattern in 2 patients in the propranolol group. When we excluded these 2 erratic cases from the propranolol group and extended our analysis to all available paired comparisons (day -14 to day 30 and day 0 to day 90), we were able to compare 44 and 60 observations, both off therapy and on either propranolol or trimetazidine, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Patient compliance and therapeutic coverage: comparison of amlodipine and slow release nifedipine in the treatment of hypertension. The Belgian Collaborative Study Group.

To study patient compliance in hypertensive outpatients amlodipine (5 mg once daily) and slow release nifedipine (20 mg twice daily) were compared in an open, crossover study in general practices. Four methods of assessment for patient compliance (pill count, taking compliance, days with correct dosing, timing compliance) were used in both study arms. For the latter three assessment a special device, the medication event monitoring system, was used to record the time and date of each opening and closure of the container. The compliance of the 320 hypertensive patients with once-daily amlodipine was markedly superior to twice-daily slow release nifedipine. Therapeutic coverage was also significantly better for amlodipine in the hypertensive patients. Amlodipine was better tolerated than nifedipine slow release. Patient compliance and therapeutic coverage with the calcium antagonist amlodipine given once daily was superior to slow release nifedipine b.d. in hypertensive outpatients recruited in general practice.

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.

How accurate is dobutamine stress electrocardiography for detection of coronary artery disease? Comparison with two-dimensional echocardiography and technetium-99m methoxyl isobutyl isonitrile (mibi) perfusion scintigraphy.

OBJECTIVES: This study was designed to establish the appropriate diagnostic criteria for positive dobutamine electrocardiographic (ECG) stress test results and to compare their accuracy with those of dobutamine two-dimensional echocardiography and perfusion scintigraphy. BACKGROUND: Conventional criteria for positive findings on ECG exercise testing may not be appropriate for use with dobutamine ECG stress testing. METHODS: One hundred twenty-nine consecutive patients with an interpretable ECG and without previous myocardial infarction were prospectively studied at the time of coronary arteriography. All completed a standard dobutamine protocol (5 to 40 micrograms/kg body weight per min in 3-min dose increments) without side effects. Significant coronary artery disease, defined as > 50% lumen diameter stenosis of a major epicardial coronary artery on coronary angiography, was present in 83 patients. Empiric receiver operating curves were generated for various ECG criteria derived from computer-averaged signals. RESULTS: The best ECG criterion, with a sensitivity of 42% and a specificity of 83%, was an ST segment shift, relative to baseline, of 0.5 mm 80 ms after the J point. The sensitivity of this criterion was greater than that of the conventional criterion of 1-mm ST segment depression 60 (23%) or 80 (18%) ms after the J point, was comparable to that of chest pain occurring during the test (44%, p = NS) but remained inferior to the sensitivities of technetium-99m methoxyl isobutyl isonitrile (mibi) perfusion (76%) or stress echocardiography (76%, p < 0.001, for both). The specificity of this criterion was not significantly different from that of technetium-99m mibi perfusion tomography (65%) or stress echocardiography (89%) but was superior to that of chest pain (59%, p < 0.025). CONCLUSIONS: We conclude that this new criterion for dobutamine electrocardiography is specific but that an imaging technique is still required to accurately predict coronary artery disease.

Patient compliance and therapeutic coverage: amlodipine versus nifedipine (slow-release) in the treatment of angina pectoris. Belgian Collaborative Group.

Patient compliance with therapy is often poor and overestimated by the treating physician; it is particularly important in cardiovascular diseases such as hypertension and angina pectoris. Compliance was studied in an open parallel study in out-patients with stable angina pectoris, given either amlodipine (5 mg, once daily) or slow-release nifedipine (20 mg, twice daily) for 12 weeks. Compliance was assessed using pill counting and using an electronic device, the medication event monitoring system, to record the time and date of each opening and closure of the pill container. There was no difference between the two groups in pill count or in 'taking compliance' (the percentage of prescribed doses taken as indicated by the monitoring system). Compliance was significantly better (P < 0.001) with amlodipine, however, for 'correct dosing' (the percentage of days on which the correct dose was taken) and for 'timing compliance' (the percentage of doses taken at the prescribed time interval after the last dose). 'Therapeutic coverage' (the estimated proportion of treatment time for which the drug was active) was also significantly better for amlodipine (P < 0.001). There was no difference in reported side-effects between the two therapies.

Patient compliance and therapeutic coverage: amlodipine versus nifedipine SR in the treatment of hypertension and angina: interim results. Steering Committee and Cardiologists and General Practitioners involved in the Belgium Multicentre Study on Patient Compliance.

An interim analysis of patient compliance is reported in 234 hypertension outpatients who were entered into a large-scale, open, crossover, comparative study between a new-generation calcium antagonist, amlodipine (5 mg, once daily), and nifedipine SR (20 mg, twice daily). An analysis was also performed on 84 outpatients with stable angina pectoris, who were included in an open, parallel study and received the same dosing regimen of either amlodipine or nifedipine SR as the patients in the hypertension arm of the study. In the hypertensive patients, there were significant differences in favor of amlodipine, using all four methods to assess patient compliance. In the angina patients, a significant difference between the groups in favor of amlodipine was only found using the "correct dosing" and the "timing compliance" methods. With the traditional pill-counting and also the "taking compliance" methods, there was no observed difference in compliance between the two groups. It was concluded that, in terms of patient compliance, once-daily amlodipine was markedly superior to twice-daily nifedipine in the crossover study involving the hypertension patients. Amlodipine was also better tolerated than nifedipine. In the angina arm of the study, patient compliance was again better with amlodipine than with nifedipine, but there was no difference observed in the levels of tolerance between the two therapies.

Comparative ability of dobutamine and exercise stress in inducing myocardial ischaemia in active patients.

OBJECTIVE: To compare the ability of dobutamine and exercise stress to induce myocardial ischaemia and perfusion heterogeneity under routine clinical circumstances. DESIGN: 86 active patients without previous myocardial infarction were studied by dobutamine and exercise stress protocols and coronary angiography. During both tests patients underwent electrocardiography, digitised echocardiography, and perfusion scintigraphy using Tc-99m methoxybutylisonitrile (MIBI) single photon emission computed tomography. MAIN OUTCOME MEASURE: Coronary disease defined as an ST segment depression of > or = 0.1 mV, a resting or stress induced perfusion defect, or a resting or stress induced wall motion abnormality on exercise and dobutamine stress testing. RESULTS: Dobutamine stress was submaximal in 51 patients because of ingestion of beta adrenoceptor blocking agents on the day of the test (n = 25) or failure to attain the peak dose owing to side effects (n = 28). Exercise was limited in 23 patients by non-cardiac symptoms. The peak heart rate with dobutamine was less than that attained with exercise (105 (25) v 132 (24) beats/min, P < 0.0001); the response to maximal dobutamine stress significantly exceeded that to submaximal stress. Peak blood pressure was greatest with exercise (206 (27) v 173 (25) mm Hg, P < 0.001), values at maximal and submaximal dobutamine stress being comparable. Electrocardiographic evidence of ischaemia was induced less frequently by dobutamine than exercise (32% v 77% of the 56 patients with significant coronary disease, P < 0.01), as was abnormal wall motion (54% v 88%, P < 0.001). Ischaemia was induced more readily with maximal stress of either type; thus the sensitivities of dobutamine and exercise echocardiography were comparable only in patients undergoing a maximal dobutamine testing (73% v 77%, NS). Perfusion heterogeneity was induced in 58% of patients with coronary disease at submaximal dobutamine stress, 73% at maximal dobutamine stress, and 73% at exercise stress (NS). Among 30 patients without coronary stenoses, normal function was obtained in 83% of echocardiography studies with dobutamine and in 80% with exercise (NS). Normal perfusion was identified in 70% of these patients at exercise MIBI, and 68% at dobutamine stress (NS). CONCLUSIONS: In a group of patients studied under normal clinical circumstances antianginal treatment and inability to complete the stress protocol are frequent and compromise the capacity of dobutamine stress to induce ischaemia. In contrast, the induction of perfusion heterogeneity is less susceptible to submaximal stress.

Trimetazidine: a new concept in the treatment of angina. Comparison with propranolol in patients with stable angina. Trimetazidine European Multicenter Study Group.

1. Trimetazidine has a direct anti-ischaemic effect on the myocardium without altering the rate x pressure product or coronary blood flow. 2. The effects of trimetazidine (20 mg three times daily) were compared with those of propranolol (40 mg three times daily) in a double-blind parallel group multicentre study in 149 men with stable angina. 3. Reproducibility of exercise performance was verified during a 3 week run-in placebo washout period. All patients had > 1 mm ST-depression on exercise test. 4. After 3 months, similar anti-anginal efficacy was observed between the trimetazidine (n = 71) and propranolol (n = 78) groups. No significant differences were observed between trimetazidine and propranolol as regards anginal attack rate per week (mean difference P-TMZ: 2; 95% CI: -4.4, 0.5) and exercise duration (mean difference P-TMZ: 0 s; 95% CI: -33, 34) or time to 1 mm ST segment depression (mean difference P-TMZ: 13 s; 95% CI: -24, 51). Heart rate and rate x pressure product at rest and at peak exercise remained unchanged in the trimetazidine group but significantly decreased with propranolol (P < 0.001 in all cases). With both drugs there was a trend to decreased ischaemic episodes in the 46% patients who experienced ambulatory ischaemia on Holter monitoring. Six patients stopped trimetazidine and 12 propranolol. Of these, five in each group were withdrawn because of deterioration in cardiovascular status. 5. The results suggest that trimetazidine and propranolol at the doses studied have similar efficacy in patients with stable angina pectoris.(ABSTRACT TRUNCATED AT 250 WORDS)

Amlodipine and the total ischemic burden: circadian anti-ischemia program in Europe (CAPE) trial-methodology, safety and toleration. The Steering Committee members and all of the investigators.

The Circadian Anti-Ischemic Program in Europe (CAPE) trial was a large, multinational trial, taking place in ten countries and involving over 100 investigators. It was a double-blind, parallel, randomized, placebo-controlled trial comparing once-daily amlodipine with placebo in chronic stable angina pectoris. It consisted of two phases, the first being a 2-week, single-blind, placebo run-in phase during which stable doses of anti-anginal drugs were maintained (65% of patients were receiving beta-blockers), and the second an 8-week active treatment phase in which patients received either amlodipine or placebo, 5 mg once daily, for the first 4 weeks, increasing to 10 mg once daily for the second 4 weeks. Patients were randomized in a ratio of 2 patients receiving amlodipine to each patient receiving placebo. Out of an initial 1,160 patients screened, 315 entered the study, with 250 having complete efficacy-evaluable data. Patients were included if they experienced > or = 4 ambulatory ECG ischemic episodes (> or = 1 mm ST-segment depression for > or = 1 min) and/or > or = 20 min total ischemia time over 48 h. Data were obtained on the total frequency of ST-segment depression events, the ischemia area (ST-segment depression integral), the ischemic time and peak ST-segment depression. Patient diary information on angina attack rate and nitroglycerin tablet consumption was also collected. Patients in both groups were compared for age, blood pressure, heart rate, duration of angina and baseline ischemia at entry. Amlodipine and placebo had similar safety profiles, with 17.3% of amlodipine patients recording adverse events, compared with 13.3% of placebo patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical features of an anti-anginal drug in angina pectoris.

Trimetazidine (TMZ) exerts anti-ischaemic effects without any associated central haemodynamic change, both at rest and with exercise. These findings suggest that TMZ has a direct cytoprotective effect, the efficacy of which has been confirmed by clinical studies in effort angina. TMZ as monotherapy when compared with placebo, in acute (60 mg) as well as in chronic (20 mg t.i.d.) administration, significantly improves exercise tolerance: total work, duration of exercise and time to 1 mm ST segment depression, without changing the rate-pressure product. Moreover, during chronic treatment TMZ decreases the rate of anginal attacks. In patients with coronary heart disease insufficiently controlled with nifedipine or a beta-blocker as monotherapy, the addition of TMZ (20 mg t.i.d.) significantly reduces the number of anginal attacks and improves exercise capacity. TMZ antianginal activity in monotherapy has also been compared in double-blind controlled studies with that of a calcium channel antagonist and a beta-blocker as reference drugs. TMZ is as efficient as nifedipine or propranolol on clinical variables as well as on ergometric criteria, but unlike these two reference drugs, which act through a haemodynamic mechanism, TMZ does not decrease rate-pressure product. Furthermore, in the study comparing TMZ with propranolol, TMZ was shown to decrease ischaemic episodes recorded by ECG ambulatory monitoring. These data show that TMZ belongs to the major antianginal agents available today. However, the absence of central haemodynamic effects suggests that the drug has a novel anti-ischaemic mechanism involving direct myocardial cytoprotection.

Optimal use of dobutamine stress for the detection and evaluation of coronary artery disease: combination with echocardiography or scintigraphy, or both?

OBJECTIVES: This study was conducted to examine the efficacy of dobutamine stress two-dimensional echocardiography and perfusion scintigraphy for the detection of coronary artery disease in routine practice, to establish the causes of erroneous results and to derive appropriate criteria for the selection of either or both tests. BACKGROUND: Dobutamine stress combined with echocardiography or perfusion scintigraphy may be used to detect coronary artery disease. Although both imaging approaches have demonstrated similar levels of accuracy, it is not known whether there may be particular indications for the use of one or the other technique or a rationale for their combination. METHODS: Two hundred seventeen patients without previous infarction were studied prospectively with dobutamine stress echocardiography and technetium-99m methoxy isobutyl nitrile (sestamibi) single-photon emission computed tomography at the time of diagnostic coronary angiography. The presence of coronary stenoses of > or = 50% diameter was compared with the presence of rest or stress-induced abnormalities of perfusion and regional function. The extent of these abnormalities was correlated with an equivalent score of extent of angiographic disease. RESULTS: Significant coronary artery disease was found in 142 patients; 102 (72%) were identified by dobutamine echocardiography and 108 (76%, p = NS) by perfusion imaging. In 75 patients without significant disease, the specificity of dobutamine echocardiography was 83% compared with 67% for scintigraphy (p = 0.05). Echocardiographic sensitivity was lower in patients unable to complete the test because of side effects (n = 64) than in the remainder (59% vs. 77%, p = 0.02); this influence was less apparent with scintigraphy (71% vs. 78%, p = NS). Selective use of scintigraphy in the 31 patients with a negative submaximal stress echocardiogram led to a sensitivity of 80% for this combination. Patients with left ventricular hypertrophy accounted for most of the difference in specificity between echocardiography and scintigraphy (94% vs. 59%, p = 0.02). Their respective accuracies were 76% and 73%. CONCLUSIONS: Dobutamine stress echocardiography and perfusion scintigraphy have equivalent accuracy. In patients with left ventricular hypertrophy, echocardiography appears to be the test of choice. Selective use of sestamibi scintigraphy in patients with a negative submaximal echocardiogram enhances the accuracy of stress echocardiography alone.