Monotherapy with amlodipine or atenolol versus their combination in stable angina pectoris.

BACKGROUND: The basic cause of angina pectoris is imbalance between the metabolic needs of the myocardium and the capacity of the coronary circulation to deliver sufficient oxygenated blood to satisfy these needs. HYPOTHESIS: The study was undertaken to evaluate whether the effect of combined amlodipine and atenolol therapy on patients with stable angina pectoris and with ST-depression during exercise testing and 48-h ambulatory electrocardiographic monitoring is superior to that of either agent given alone. METHODS: Patients with stable angina pectoris and ST depression during exercise and ambulatory monitoring were randomized to receive amlodipine (n = 116) or atenolol (n = 116), or both (n = 119). All patients were also treated with short- and long-acting nitrates. The design was a double-blind, randomized, triple-arm parallel group study with 10 weeks of administration of the test medication. RESULTS: In terms of time to onset of ST depression > 1 mm, time to onset of angina, total exercise time, maximum achieved workload, and peak intensity of angina, amlodipine and atenolol alone were as effective as their combination. During ambulatory monitoring, atenolol was more effective than amlodipine regarding total time and number of ST-depression episodes, and as effective as the combined drugs. CONCLUSION: For individual patients with stable angina pectoris, combination of a beta blocker with a calcium antagonist is not necessarily more effective than either drug given alone.

Effects of felodipine versus nifedipine on exercise tolerance in stable angina pectoris.

The effects of single doses of felodipine (5 and 10 mg) and nifedipine (10 and 20 mg) on chronic stable effort angina pectoris were assessed in a placebo-controlled, double-blind, crossover study of 24 patients receiving beta blockers and short-acting nitroglycerin. The effects were measured by repeated bicycle ergometer tests. The total work, and time until 1 mm of ST depression increased significantly by 9 to 31% after both active drugs at both dose levels in comparison with placebo. The differences were not significant between drugs or doses. At rest, blood pressure decreased (10 to 15%) and heart rate increased (5 to 10%) significantly after both active drugs. During exercise at the highest comparable work load, systolic blood pressure decreased significantly (23 to 26%), whereas heart rate was not affected after felodipine and nifedipine compared with placebo. The 2 drugs were well tolerated, and side effects were mild. Therefore, single doses of 5 and 10 mg of felodipine, and 10 and 20 mg of nifedipine have similar antianginal and anti-ischemic properties. However, felodipine has a longer duration of action, which may improve compliance.

Antianginal and anti-ischemic efficacy of nicorandil compared with nifedipine in patients with angina pectoris and coronary heart disease: a double-blind, randomized, multicenter study.

Patients with stable, effort-induced angina pectoris and a typical combination of anginal pain and ischemic ST depression in exercise tolerance tests were randomized to treatment for 8 weeks with nicorandil (a newly developed antianginal and anti-ischemic drug) or nifedipine. After 4 weeks, the dosage of nicorandil was increased from 10 mg b.i.d. to 20 mg b.i.d., but the recommended dosage of nifedipine, 20 mg b.i.d., was kept constant during the study period. Double-blind treatment was preceded by a 2-week prephase during which patients were treated with isosorbide dinitrate. During the study period, patients were asked to report the rate of anginal attacks and consumption of sublingual nitroglycerin. Measurements of blood pressure and heart rate at rest and during exercise always were performed 2 h after drug intake. Fifty-eight patients were randomized--29 to nicorandil and 29 to nifedipine. There were large individual variations in anginal attack rates, which makes group comparisons difficult, but in the nicorandil group, the anginal attack rate decreased significantly compared with baseline frequency. Systolic blood pressure at rest was reduced significantly only with the highest dose of nicorandil, but nifedipine had a significant effect on both systolic and diastolic blood pressures as well as on the heart rate. Both treatments significantly increased exercise duration, time to onset of angina pectoris, and time to 1-mm ST depression. In the nicorandil group, an improvement was noted with the 20-mg dose compared with the 10-mg dose, but no significant differences were noted between the nicorandil and nifedipine groups after either 4 or 8 weeks of treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

CHD in Sweden: mortality, incidence and risk factors over 20 years in Gothenburg.

Mortality from coronary heart disease (CHD) increased among Swedish men between 1968 and 1981, but after that, began to decline. CHD mortality in women decreased slightly, mostly among older women. From 1980, the incidence of non-fatal myocardial infarction (MI) started to decrease among men. Among middle-aged women, however, there was a significantly increased incidence. Mortality during the two years following hospital discharge decreased both in men and women between 1968 and 1985 in Gothenburg. Between one-sixth and one-fifth of major CHD events occur among patients with previous MI or angina pectoris. Serum cholesterol and smoking habits increased among middle-aged men from 1963 to 1973, but decreased thereafter. Blood pressure decreased, and the percentage of people on treatment increased. Blood pressure and serum cholesterol decreased among middle-aged women, but smoking and triglycerides increased. These different trends might explain an increasing CHD incidence among younger women but decreasing incidence and mortality among older women.

Abrupt withdrawal of isosorbide-5-mononitrate in Durules (Imdur) after long term treatment in patients with stable angina pectoris.

In a single-blind study of 6 weeks' duration, 32 patients with stable angina pectoris, who had been receiving controlled-release, Durules, isosorbide-5-mononitrate (Imdur) 60 to 180 mg daily for at least 1 year, were assessed after abrupt withdrawal of the nitrate. After 2 weeks of placebo treatment nitrate therapy was re-instituted, and the patients followed for another 2 weeks. The possibility of development of tolerance and rebound phenomena was also investigated. Three patients experienced severe anginal symptoms necessitating hospitalization when controlled-release isosorbide-5-mononitrate was withdrawn abruptly. Patients complained of more severe anginal symptoms during the placebo period, experienced more frequent anginal attacks and used more glyceryl trinitrate tablets than during active treatment. ST segment changes during exercise were more pronounced with placebo. After controlled-release isosorbide-5-mononitrate was re-introduced, these variables indicated significant improvement. On the other hand, no deterioration occurred in exercise performance during the placebo phase. Responsiveness to glyceryl trinitrate was maintained, as shown by comparisons of exercise tests performed after the long term treatment and during the placebo phase. Controlled-release isosorbide-5-mononitrate retains a beneficial effect in patients with angina pectoris during prolonged use, although some attenuation of the effect is seen. Abrupt withdrawal of the drug is not recommended because of the possibility of severe exacerbation of anginal symptoms, although no clearcut rebound phenomena were seen.

Physical inactivity as a risk factor for primary and secondary coronary events in Göteborg, Sweden.

Physical activity at work and during leisure time were studied by using a questionnaire in a random sample of 7495 middle-aged men from the Primary Prevention Study in Göteborg and in 1273 able-bodied male patients with a first myocardial infarction, registered in the Infarction Register in the same city over the period 1968-84. Data on coronary risk factors and socio-economic factors were recorded in the population sample as were data on risk factors and known somatic predictors for prognosis in the infarction group. An inverse and graded association was found between leisure time physical activity and mean diastolic blood pressure, total cholesterol, body mass index, tobacco smoking, socio-economic status and mental stress in the random sample. During the approximate 12-year follow-up, low physical activity during leisure time, but not at work, was associated with an increased risk of coronary deaths and non-fatal infarctions in univariate analysis. Inactive subjects had twice the incidence of total coronary events (9.4%) as physically active contemporaries (4.2%). After controlling for major coronary risk factors, occupational class, diabetes, family history of coronary heart disease and mental stress in a multivariate logistic regression analysis, the association between leisure time physical activity and total coronary events disappeared. Physical activity at work and during leisure time estimated for the 12-month period preceding the first infarction was not associated with long-term prognosis after infarction. Infarction patients assessed to be in need of additional rehabilitation due to somatic restrictions, work-related factors and emotional instability, resumed work later and had a higher mortality and non-fatal recurrence rate during follow-up than patients not considered to require additional rehabilitation. Physical inactivity was not a risk factor for primary and secondary coronary events in this study. The inverse direction of the association between leisure time physical activity and coronary risk factors suggests that increased physical activity alters the risk factor profile in a favourable direction.

Prognostic importance of somatic and psychosocial variables after a first myocardial infarction.

The prognostic importance of somatic and psychosocial variables after a first myocardial infarction was studied in 201 consecutive Gothenburg, Sweden men below 61 years of age who had survived a first myocardial infarction between December 1976 and December 1978. The maximum follow-up time was 100 months. The prognostic importance of somatic, social, and psychological variables was related to the endpoints of death, nonfatal reinfarction, and total events. During follow-up, 48 deaths and 37 nonfatal recurrences occurred. Four variables, none of them significantly correlated with each other, were related to risk of an endpoint. Being single increased risk of death (p less than 0.01) and risk of all events (p less than 0.001), whereas an index reflecting infarct size was correlated to risk of death (p less than 0.001). A prognostic index based upon data available at three months after the myocardial infarction (angina pectoris, hypertension, serum aspartate aminotransferase (S-ASAT) maximum, and smoking) was correlated to risk of nonfatal reinfarction (p less than 0.05). Use of sedatives was also related to risk of reinfarction (p less than 0.05) and to risk of total event (p less than 0.05). The probability of death, reinfarction, and total event was estimated within two and five years after the infarction for all combinations of the variables that were related to risk of an endpoint. It was thus demonstrated that the predictive power increased over time and that the somatic and psychosocial variables independently added information.

Anti-anginal efficacy of a controlled-release formulation of isosorbide-5-mononitrate once daily in angina patients on chronic beta-blockade.

The anti-anginal effect of a controlled-release (Durules) formulation of isosorbide-5-mononitrate (5-ISMN) 60 mg, Imdur, once daily was evaluated in a randomised double-blind, placebo-controlled, crossover study with a placebo run-in period. Each period lasted for 2 weeks. A total of 70 patients (58 men and 12 women) with stable exertional angina pectoris on beta-blockade, mean age 59 years (range 39-71), were included. Exercise testing was performed on a bicycle ergometer 3 hours after the dose at the end of each period. Anginal attacks and intake of sublingual nitroglycerin tablets were noted. Imdur in combination with a beta-blocker significantly increased the total exercise capacity, the time and total work until the onset of chest pain and at 1 mm ST-depression compared with beta-blockade alone. The attack rate and the nitroglycerin consumption were significantly decreased. Headache was the only significant side-effect. In conclusion, the addition of Imdur once daily to beta-blockade significantly increased the anti-anginal effect.

Mononitrates as monotherapy in the prophylactic treatment of angina pectoris.

This article reviews the results of double-blind comparative studies on the therapeutic use of isosorbide 5-mononitrate as monotherapy in the prophylaxis of angina pectoris. Isosorbide 5-mononitrate appears at least as effective as the same dosage of isosorbide dinitrate and is probably superior to the calcium antagonists. Recent data have shown that isosorbide 5-mononitrate in a controlled-release formulation given once daily has a significantly better antianginal effect than placebo without inducing the development of tolerance.

Abrupt withdrawal of isosorbide 5-mononitrate (Imdur) after long term treatment in stable angina pectoris. A preliminary report.

32 patients with stable angina pectoris who had been receiving a controlled-release formulation Durules of isosorbide 5-mononitrate (Imdur) 60 to 120 mg daily with concomitant beta-blocker therapy for at least 1 year were entered into a study to evaluate possible rebound phenomena from the abrupt withdrawal of isosorbide 5-mononitrate and to determine whether nitrate tolerance had developed. Isosorbide 5-mononitrate was abruptly withdrawn and substituted with placebo for 2 weeks, after which the active drug was reintroduced. No deterioration of exercise performance could be detected during withdrawal of therapy, but an increase was seen after reinstitution. No tolerance was found for systolic blood pressure and ST segment changes or for the number of anginal attacks and short-acting glyceryl trinitrate tablets consumed. Three patients had to be hospitalised because of a sudden deterioration of symptoms on withdrawal of isosorbide 5-mononitrate. It was concluded that isosorbide 5-mononitrate in Durules has a beneficial effect and that tolerance does not appear to be clinically relevant.

The effect of isosorbide-5-mononitrate (5-ISMN) Durules on exercise tolerance in patients with exertional angina pectoris. A placebo controlled study.

Twenty-four patients with stable exercise-induced angina pectoris entered a double-blind cross-over study. Isosorbide-5-mononitrate (5-ISMN) 60 mg in a controlled release formulation (Durules) given once daily was compared with identical placebo. The exercise tolerance was determined by bicycle ergometry before and 3 h after a single dose of 5-ISMN and following one week's treatment with 5-ISMN and placebo. Nineteen patients completed the study. Exercise tolerance until the onset of chest pain and until 1 mm ST segment depression increased significantly 3 h after dose. The same increase was seen both after a single dose and the same dose under steady-state conditions. No increase was seen with placebo. The heart rate and systolic blood pressure reactions in the standing position were less pronounced 3 h after dose in steady-state than after a single dose of 5-ISMN. Headache was the only bothersome side-effect reported. The study demonstrates that 60 mg 5-ISMN in a Durules formulation given once daily has a significant anti-anginal effect and that tolerance does not develop.

Long-term prognosis after myocardial infarction in men with diabetes.

Men (1306) who survived a first myocardial infarction (MI) were studied. The mean follow-up time was 6.5 yr, and at the end of the follow-up period survival status was known for all patients. By the time of the MI the prevalence of diabetes was 5.6%. Patients with and without diabetes were compared. There were no differences in the estimated primary or secondary risk. The cumulative survival rate 1, 2, and 5 yr after the MI was 82, 78, and 58% among the diabetic subjects compared with 94, 92, and 82% among the nondiabetic subjects (P less than 0.001). The difference remained even after allowance for age and estimated secondary risk in a multivariate regression analysis. There were no differences in mortality rates among patients with type I diabetes compared with type II diabetes, nor among patients treated with diet alone, sulfonylurea, or insulin, but the numbers were small. The cumulative rate of reinfarctions after 1, 2, and 5 yr was 18, 28, and 46% in diabetic subjects and 12, 17, and 27% in nondiabetic subjects (P = 0.004). A history of diabetes was an independent secondary risk factor among male survivors of a first MI with respect to deaths and reinfarctions.

Cessation of smoking after myocardial infarction in women. Effects on mortality and reinfarctions.

Among 262 women with a first myocardial infarction discharged alive from hospital in Göteborg, Sweden between 1968 and 1977, 161 (61%) were smokers at the time of infarction. Postinfarction smoking was established after three months. In relation to smoking status three months after the infarction, subsequent survival and reinfarction rate were calculated by comparing those who smoked before infarction and later stopped (52%) with those who continued to smoke after the infarction (48%). There were no differences in preinfarction characteristics between quitters and continuing smokers. Women who stopped smoking after the infarction had higher serum enzymes during the acute phase than those who continued to smoke. The cumulative five-year survival rate was 85% among those who stopped smoking compared to 73% among those who continued to smoke (p less than 0.05). No significant difference was found in the cumulative reinfarction rate between the two groups with different smoking habits.

Recurrent myocardial infarction. 1. Natural history of fatal and non-fatal events.

1306 men below 68 years of age who survived a first myocardial infarction (MI) during 1968-1977 were followed up between 2 and 12 years after discharge from hospital. The mean follow-up time was 6.5 years. The patients were unselected and paid regular visits to a Post-MI Clinic where treatment was standardized. The diagnosis of a non-fatal reinfarction was based on conventional clinical criteria, and the diagnosis of a fatal reinfarction on autopsy findings of a recent myocardial injury and/or a fresh coronary thrombus. The autopsy rate was high and the follow-up of endpoints was complete. The total cumulative rate of endpoint free patients was 64% at 5 years and 50% at 10 years follow-up. The total mortality rate was 19% at 5 years and 33% at 10 years follow-up. The total cumulative rate of a first reinfarction was 28% at 5 years and 37% at 10 years follow-up (80% non-fatal and 20% fatal). 63 patients suffered more than one reinfarction. The mortality rate was strongly associated with age. In contrast the rate of non-fatal reinfarctions was independent of age.

Recurrent myocardial infarction. 2. Possibilities of prediction.

1306 men less than 68 years of age who survived a first myocardial infarction (MI) during 1968-1977 were followed up between 2 and 12 years. The mean follow-up time was 6.5 years. The patients were unselected and paid regular visits to a Post-MI Clinic where treatment was standardized. The autopsy rate was high and the follow-up of endpoints was complete. The diagnosis of a non-fatal reinfarction was based on conventional clinical criteria, and the diagnosis of a fatal reinfarction on autopsy findings of a recent myocardial injury and/or a fresh coronary thrombus. The patients were randomly assigned to two halves. One was used only for derivation of the predictive models, and the other only for validation. Common clinical variables judged to be prognostically important were selected. Among variables available at discharge from hospital a history of hypertension, angina pectoris or diabetes before the MI and the maximal serum ASAT during the MI were independently related to reinfarctions during the follow-up. A predictive index was formed and validated. The rate of reinfarction among risk quartiles in the validation sample increased from 24 to 38% (P = 0.003). The aetiologic fraction (the percent of reinfarctions predicted by the index) was 24%. Among variables from the follow-up only cessation of smoking after the MI had independent predictive power. A new predictive index including this variable was formed and validated. The reinfarction rate in the risk quartiles increased from 15 to 39% (P less than 0.001). The aetiologic fraction was 44%. When only reinfarctions occurring before the median follow-up time of 21 months were considered, the aetiologic fraction was 62%.

Prognostic importance of cholesterol levels after myocardial infarction.

The aim of this study was to analyze the relationship between serum cholesterol level and all causes mortality in men who sustained a first myocardial infarction. The cholesterol distribution 3 months after the infarction was established. Ten annual cohorts (n = 1,204) were followed for a maximum period of 11 years. Secondary risk factors were comparable among the groups of the serum cholesterol distribution quintiles according to a multiple logistic prognostic function based on left heart failure, atrial fibrillation, breathlessness on infarction, maximum S-ASAT, relative heart size, and a history of hypertension. When all ages were analyzed together, the total mortality was higher in the upper cholesterol quintiles (P = 0.02). This association was confirmed when analyzed with Coxian adjustments for age, change in smoking habits after infarction, and the previously mentioned prognostic function. When broken down by age (less than or equal to 49, 50-59, greater than or equal to 60) and period of follow-up (3-24 and 25-84 months), the association between mortality and cholesterol quintiles was confined to patients under 50 years during the late follow-up period (P = 0.01), whereas there was no association for the other age groups.

Sex differences in preinfarction characteristics and longterm survival among patients with myocardial infarction.

The prevalence of primary risk factors, previous medical history, and physical activity were assessed among 262 women and 1259 men who suffered a first nonfatal myocardial infarction between 1968 and 1977 in Göteborg, Sweden. The probability of suffering a myocardial infarction based on the conventional factors cholesterol level, systolic blood pressure and smoking habits was estimated in both sexes by means of a multiple risk function. Comparisons between sexes were made with age alone and age and estimated primary risk as confounders. Survival rate and reinfarction rate were calculated for a 5-year period of follow-up. Women with infarctions had higher serum cholesterol levels (p less than 0.001) and higher blood pressure values (p less than 0.001) but were less often smokers than men (p less than 0.001). The female patients also reported chest pain and dyspnea on exertion, and low physical activity both at work and during leisure time significantly more often than men; these differences remained after controlling for estimated primary risk. An overrepresentation of hypertension and diabetes prior to myocardial infarction was found among women below 45 years of age compared with men. A high frequency of women in this age group was also on sick leave or disability pension at onset of myocardial infarction, suggesting that mainly women with several risk factors including socioeconomic factors suffer an infarction at this age. No similar and consistent differences were found between women and men of older ages. The cumulative 5-year survival rate was 80% in women and 81% in men. Below age 45 the survival rate was lower among women than men (p less than 0.01). No sex difference was found in the recurrence rate of nonfatal reinfarctions. This indicates that once women have suffered a myocardial infarction they are exposed to at least as high a risk as men.

Declining trend in mortality after myocardial infarction.

All patients under 60 years of age who were discharged from hospital after a first myocardial infarction between 1968 and 1977 in Göteborg were followed for a minimum of 24 months. The patients were unselected, and treatment was standardised. The patients were divided into five two yearly cohorts, and the prognostic comparability and mortality of these cohorts were assessed. There was a reduction in the two year mortality rate after discharge during the 10 year period. Small baseline differences between the cohorts were controlled by multivariate methods, and a subsequent analysis showed that there was a declining trend in mortality between 1968 and 1977. A higher tendency among smokers to give up smoking and a lower prevalence of angina pectoris could explain only part of the reduction in mortality. A small number of patients underwent a coronary bypass operation; the slight increase in the number of operations during the period cannot, however, account for the reduced mortality. Most of the patients in the later cohorts were treated with beta blockers, and this is the most likely explanation for the majority of the decline in mortality.