Cholesterol-lowering therapy in women and elderly patients with myocardial infarction or angina pectoris: findings from the Scandinavian Simvastatin Survival Study (4S)

BACKGROUND: The Scandinavian Simvastatin Survival Study (4S) demonstrated pronounced reductions in mortality and major coronary events in a cohort of patients with established coronary heart disease (CHD). The present study provides a detailed, post hoc assessment of the efficacy and safety of simvastatin therapy in the following subgroups of 4S patients: those > or = 65 years of age, those < 65 years of age, women, and men. METHODS AND RESULTS: The 4S cohort of 4444 CHD patients included 827 women and 1021 patients > or = 65 years of age. Total cholesterol at baseline was 5.5 to 8.0 mmol/L with triglycerides < or = 2.5 mmol/L. Patients were randomized to therapy with simvastatin 20 to 40 mg daily or placebo for a median follow-up period of 5.4 years. End points consisted of all-cause and CHD mortality, major coronary events (primarily CHD death and nonfatal myocardial infarction), other acute CHD and atherosclerotic events, hospitalizations for CHD and cardiovascular events, and coronary revascularization procedures. Mean changes in serum lipids were similar in the different subgroups. In patients > or = 65 years of age in the simvastatin group, relative risks (95% confidence intervals) for clinical events were as follows: all-cause mortality, 0.66 (0.48 to 0.90); CHD mortality, 0.57 (0.39 to 0.83); major coronary events, 0.66 (0.52 to 0.84); any atherosclerosis-related event, 0.67 (0.56 to 0.81); and revascularization procedures, 0.59 (0.41 to 0.84). In women, the corresponding figures were 1.16 (0.68 to 1.99); 0.86 (0.42 to 1.74), 0.66 (0.48 to 0.91), 0.71 (0.56 to 0.91), and 0.51 (0.30 to 0.86), respectively. CONCLUSIONS: Cholesterol lowering with simvastatin produced similar reductions in relative risk for major coronary events in women compared with men and in elderly (> or = 65 years of age) compared with younger patients. There were too few female deaths to assess the effects on mortality in women. Because mortality rates increased substantially with age, the absolute risk reduction for both all-cause and CHD mortality in simvastatin-treated subjects was approximately twice as great in the older patients.     

Access to coronary catheterisation: fair shares for all?

OBJECTIVE: To determine the effects of patient's sex and area's material deprivation on utilisation rates of coronary catheterisation and angiography in the investigation of ischaemic heart disease. DESIGN: Retrospective analysis of routinely collected hospital statistics. SETTING: Acute hospitals throughout Northern Ireland. SUBJECTS: 24,179 episodes of patients discharged from hospital with a primary diagnosis of ischaemic heart disease and 1270 episodes relating to patients with an underlying diagnosis of ischaemic heart disease who had either coronary catheterisation or angiography. MAIN OUTCOME MEASURES: Age standardised admission rates for heart disease and age standardised utilisation rates for catheterisation or angiography, or both, for 566 electoral wards ranked by Townsend "deprivation" scores. RESULTS: Catheterisation-angiography rates in men were over fivefold those of women, ranging from 85.5/100,000 v 16/100,000 in patients from "well off" areas to 123/100,000 v 22/100,000 for patients from deprived areas. After admission rates for heart disease were controlled for, the overall rate ratio for women was 0.48 (95% confidence interval 0.38 to 0.60). After differential admission rates for heart disease and other potential clinical confounders were controlled for, the investigation rates of patients from the least and most "deprived" areas were not significantly different (rate ratio 1.04 (0.87 to 1.25)). CONCLUSION: Although investigation rates were significantly lower in women than in men, further clinical data would be required before labelling this underutilisation as evidence of bias. There was no significant difference in invasive investigation rates for heart disease in areas of varying deprivation or affluence.     

Changes in population cholesterol levels and coronary heart disease deaths in seven countries

BACKGROUND: Are trends in coronary heart disease deaths based on risk factor changes? OBJECTIVE: To study the relationship between trends in coronary deaths and changes in blood cholesterol in the Seven Countries Study. MATERIAL AND METHODS: Sixteen cohorts of men aged 40-59 years from seven countries (U.S.A., Finland, the Netherlands, Italy, Croatia (former Yugoslavia), Serbia (former Yugoslavia), Greece, Japan) were units for the analyses of serum cholesterol measured at entry and after 5 and 10 years, and for mortality over 25 years. RESULTS: In the populations, the ecological relationship of mean serum cholesterol at entry to late coronary heart disease death rates during the 10- to 25-year follow-up was weak, with an R-square of 0.31. Cholesterol measurements made at year 10, and an indicator of cholesterol change during the first 10 years, increased the association (R-square, 0.49). A negative and significant interaction was shown between baseline population cholesterol levels and their 10-year change. As an indicator of acceleration in mortality, cholesterol change over 10 years was also positively correlated (partial R-square 0.44) with the ratio of 25-year to 5-year deaths. CONCLUSIONS: In the Seven Countries Study, late coronary heart disease death rates are largely "explained' by changes in blood cholesterol levels during the early phases of the study, mainly due to increases in lower cholesterol levels among some cohorts.     

Lipoprotein changes and reduction in the incidence of major coronary heart disease events in the Scandinavian Simvastatin Survival Study (4S)

BACKGROUND: The Scandinavian Simvastatin Survival Study (4S) randomized 4444 patients with coronary heart disease (CHD) and serum cholesterol 5.5 to 8.0 mmol/L (213 to 310 mg/dL) with triglycerides < or =2.5 mmol/L (220 mg/dL) to simvastatin 20 to 40 mg or placebo once daily. Over the median follow-up period of 5.4 years, one or more major coronary events (MCEs) occurred in 622 (28%) of the 2223 patients in the placebo group and 431 (19%) of the 2221 patients in the simvastatin group (34% risk reduction, P<.00001). Simvastatin produced substantial changes in several lipoprotein components, which we have attempted to relate to the beneficial effects observed. METHODS AND RESULTS: The Cox proportional hazards model was used to assess the relationship between lipid values (baseline, year 1, and percent change from baseline at year 1) and MCEs. The reduction in MCEs within the simvastatin group was highly correlated with on-treatment levels and changes from baseline in total and LDL cholesterol, apolipoprotein B, and less so with HDL cholesterol, but there was no clear relationship with triglycerides. We estimate that each additional 1% reduction in LDL cholesterol reduces MCE risk by 1.7% (95% CI, 1.0% to 2.4%; P<.00001). CONCLUSIONS: These analyses suggest that the beneficial effect of simvastatin in individual patients in 4S was determined mainly by the magnitude of the change in LDL cholesterol, and they are consistent with current guidelines that emphasize aggressive reduction of this lipid in CHD patients.     

Acute ischaemic lesions in death due to ischaemic heart disease. An autopsy study of 333 cases of out-of-hospital death

The frequency of acute coronary artery thrombus and myocardial infarction in subjects dying suddenly or unexpectedly from ischaemic heart disease (IHD) is still unclear, with previous autopsy studies reporting an incidence between 4% and 100%. In this study of 333 randomly selected out-of-hospital deaths, detailed autopsy showed IHD as the sole cause of death in 206 (62%). One hundred and seventeen acute coronary thrombi were present in 96 cases whilst four had an established acute infarct without an identifiable coronary thrombus. Thus 100 (48.5%) IHD deaths had evidence of an acute ischaemic lesion. Acute lesions were equally prevalent among males and females, but the incidence declined with increasing age and they were less frequent among those with a prior clinical history of heart disease. One hundred and forty-seven IHD deaths were witnessed. The proportion of cases with an acute ischaemic lesion increased with the duration of pre-morbid symptoms. Of those with an acute lesion, only 17% died without symptoms compared to 63% of those without an acute lesion. All cases with symptoms lasting more than 3.5 h had an acute lesion. Overall, almost half out-of-hospital IHD deaths in this study were related to an acute ischaemic lesion. Differences in the detail of the pathological examination and examination of differing sub-groups of the out-of-hospital death population probably account for the differing results of previous studies.     

Increased socioeconomic differences in mortality in eight Spanish provinces

In Spain, the study of socioeconomic differences in mortality has been limited by the fact that death certificates often do not include complete information on occupation. In this study, we chose those geographic areas with the highest quality information on occupation of the deceased in order to study socioeconomic differences in mortality from various causes of death. We used information from the death certificates of males who died between 30 and 64 years of age in eight Spanish provinces to compare mortality from the leading causes of death in professionals and managers (group I) and in manual laborers (group II) in 1980-82 and 1988-90. In each period the standardized mortality ratios (SMRs) were higher in group II, except for ischaemic heart disease during the first period, and cancer of the colon and rectum in both, although in the latter case the differences were not statistically significant. The ratio between the SMR from all causes in group II and group I was 1.27 in 1980-82, and 1.72 in 1988-90; for cancer of the colon and rectum the ratio went from 0.98 to 0.84, and for ischaemic heart disease, from 0.80 to 1.31. Except for cancer of the colon and rectum, which resulted in higher mortality in occupational group I, the excess mortality in occupational group II increased between the first and second period. The relation between socioeconomic level and mortality for ischaemic heart disease was reversed, a phenomenon similar to that which took place in the 1960s and 1970s in the developed countries.(ABSTRACT TRUNCATED AT 250 WORDS)     

Age-period-cohort effects on ischaemic heart disease mortality in Sweden from 1969 to 1993, and forecasts up to 2003

AIMS: Mortality from ischaemic heart disease has been decreasing in most industrialized countries since the 1960s. The aim of this study was to analyse ischaemic heart disease mortality during 1969-1993 in Sweden, and to predict mortality trends until 2003. METHODS AND RESULTS: Age-period cohort models were used to analyse ischaemic heart disease mortality in Sweden between 1969 and 1993, and to predict age-specific death rates and total number of deaths for the periods 1994-1998 and 1999-2003. Mortality rates in the age group 25-89 years decreased from 719 to 487 per 100,000 for men, and from 402 to 215 per 100,000 for women over the study period (average annual decrease of 1.5% for men and 2.2% for women). The decline started earlier for women than for men. The ratio of age-adjusted mortality between men and women increased steadily over the study period. Predictions based on the full age-period cohort model for the period 1999-2003 gave mortality rates of 346 and 155 per 100,000 for men and women, respectively. Despite the ageing of the population, the total numbers of ischaemic heart disease deaths in Sweden are predicted to decline by approximately 25% in both men and women from 1989-93 to 1999-2003. CONCLUSION: A major decline in ischaemic heart disease mortality has been observed in the last 15 years in Sweden. Both factors, cohort and calendar period, contain information which helps explain the decline in ischaemic heart disease mortality trends in Sweden. Predictions indicate that the decline of both age-specific and total mortality is to continue.     

Survival and incidence of myocardial infarction in men with ambulatory ECG-detected frequent and complex ventricular arrhythmias. 10 year follow-up of the 'Men born 1914' study in Malm?, Sweden

AIM: To assess to what extent do frequent or complex ventricular arrhythmias, detected during 24 h ambulatory electrocardiographic recording (ECG), influence prognosis with regard to survival and incidence of ischaemic heart disease. METHODS AND RESULTS: The study subjects were the 456 randomly selected men born in 1914, the population-based cohort study of 1982-83, in Malm?, Sweden. The main outcome measures were total mortality and incidence of cardiac event (myocardial infarction and death from ischaemic heart disease). Frequent or complex ventricular arrhythmias (Lown classes 2-5) were detected in 49% of the men with (n = 77), and in 35% of those without, a history of myocardial infarction or angina pectoris at baseline, P = 0.019. Independent of clinically evident coronary artery disease at baseline, and after adjustment for traditional atherosclerotic risk factors and use of digitalis or beta-blocker therapy, frequent or complex ventricular arrhythmias were associated with an increased mortality from ischaemic heart disease (relative risk (RR), 2.1; 95% confidence interval (CI), 1.2-3.9) and an increased cardiac event rate (RR, 1.6; 95% CI, 1.0-2.5)). Men free from both ischaemic-type ST depression and frequent or complex ventricular arrhythmias (used as the control group) had the lowest ischaemic heart disease death rate, 5.9 per 1000 person-years. The combination of ST depression and frequent or complex ventricular arrhythmias was associated with an ischaemic heart disease death rate of 20.9 per 1000 person-years. The cardiac event rate in these two groups was 15.6 and 76.1 per 1000 person-years, respectively (adjusted RR, 2.3; CI, 1.1-4.6). CONCLUSIONS: In elderly men without a history of myocardial infarction and angina pectoris, frequent or complex ventricular arrhythmias during ambulatory ECG recording is associated with an increased incidence of myocardial infarction and mortality. Men who, during ambulatory ECG recording, also demonstrate ST-segment depression have an even less favourable prognosis.     

Variations between countries in invasive cardiac procedures and outcomes in patients with suspected unstable angina or myocardial infarction without initial ST elevation. OASIS (Organisation to Assess Strategies for Ischaemic Syndromes) Registry Investigators

BACKGROUND: There are wide variations between countries in the use of invasive cardiac catheterisation and revascularisation procedures for patients with acute ischaemic syndromes. We studied the relation between rates of such procedures and rates of cardiovascular death, myocardial infarction, stroke, refractory angina, and major bleeding in a prospective, registry-based study in six countries with widely varying intervention rates. METHODS: 7987 consecutive patients presenting with unstable angina or suspected myocardial infarction without ST-segment elevation were recruited prospectively from 95 hospitals in six countries and followed up for 6 months. FINDINGS: The rates of all procedures were highest in patients in Brazil and the USA, intermediate in Canada and Australia, and lowest in Hungary and Poland. There were no significant differences in rates of cardiovascular death or myocardial infarction among these countries (4.7% overall [range 3.7-5.6] at 7 days; 11% overall [9-12] at 6 months). For the countries with the highest rates of invasive procedures (59%) versus the rest (21%) there was no difference in rate of cardiovascular death or myocardial infarction (adjusted odds ratio 0.88 at 7 days and 1.0 at 6 months). Rates of stroke were higher in Brazil and the USA than in the countries with lower intervention rates (adjusted odds ratio at 7 days 3.0, p=0.012; at 6 months 1.8, p=0.004) but rates of refractory angina at 7 days (0.7, p<0.001) and readmission for unstable angina at 6 months were lower (0.70, 0.63; both p<0.001). Comparison of results for hospitals without cardiac-catheterisation facilities and for those with such facilities gave adjusted odds ratios for cardiovascular death, myocardial infarction, or stroke at 6 months of 0.83 (10.6% vs 12.5%, p=0.05) and for refractory angina of 1.25 (19.3% vs 16.1%, p=0.09). INTERPRETATION: Higher rates of invasive and revascularisation procedures were associated with lower rates of refractory angina or readmission for unstable angina, no apparent reduction in cardiovascular death or myocardial infarction, but with higher rates of stroke. Randomised trials should assess the relative impact of conservative and more aggressive approaches to invasive cardiac procedures and revascularisations in patients with unstable angina.     

Super Profile analysis of socioeconomic variations in coronary investigation and revascularisation rates

OBJECTIVES: To investigate socioeconomic variations in the utilisation of tertiary cardiology services. DESIGN: Cross sectional ecological study, using the Super Profile classification of enumeration districts, and ischaemic heart disease standardised mortality ratios as a proxy for needs. SETTING: The former Yorkshire Regional Health Authority area in England and its seven constituent district health authority areas. SUBJECTS: Patients with a primary diagnosis of ischaemic heart disease aged > or = 25 years who underwent investigation by angiography, or treatment by coronary artery bypass grafting (CABG) or percutaneous transluminal coronary angioplasty (PTCA), as a primary procedure between April 1992 and March 1994 in an NHS hospital. MAIN RESULTS: There is an overall increasing trend in investigation and revascularisation rates from the affluent to the deprived in the region suggesting equity. However, the gradient is slight compared with the corresponding mortality gradient. Age specific analysis shows a more appropriate trend in rates for the under 65s, but a downward trend from affluence to deprivation for the elderly. Much of the regional trend is caused by very high rates in one geographically small but densely populated district that has two tertiary cardiology centres. In other districts, with higher heart disease mortality but much lower procedure rates, there is a decreasing trend from the affluent to the deprived suggesting considerable inequity. CONCLUSIONS: This study confirms wide socioeconomic variations in coronary investigation and revascularisation within the former Yorkshire Region, suggesting that in some districts need is not being met and that service utilisation is inequitable. Such inequities are over and above those that result from proximity to tertiary cardiology centres.     

Cardiac rehabilitation: structure, effectiveness and the future

Despite advances in the investigation and treatment of angina and myocardial infarction, and increased knowledge of the factors associated with the development and progression of ischaemic heart disease, it remains the leading cause of death and morbidity in the majority of industrialized countries. Cardiac rehabilitation provides a means of modifying lifestyle and other risk factors in patients presenting with established, symptomatic coronary artery disease, thereby reducing the risk of further cardiac events. It has also been proven to be cost-efficient.     

Effects of amlodipine on transient myocardial ischaemia in patients with a severe coronary condition treated with a beta-blocker. Amlor-Holter Study Investigators

The purpose of this trial was to study the additional anti-ischaemic effects of amlodipine in coronary patients with ambulant ischaemia despite beta-blocker therapy. Beta-blockers are the most effective drug therapy for reducing the frequency and duration of ambulatory ischaemic episodes. However, the therapeutic advantage of combined calcium antagonist-beta-blocker treatment remains questionable. Three hundred and thirteen patients with documented coronary artery disease, a positive exercise test within 6 months before entry and background beta-blocker therapy, were screened. Inclusion criteria (> or = 4 episodes of transient ST segment depression of > or = 1.0 mm and/or > or = 20 min of ischaemia) were demonstrated in a 48 h ECG during the placebo run-in period in 84 (25%) of the patients. Eighty-nine percent of the ischaemic episodes were silent. The eligible patients were then randomized in a 2-week, double-blind, parallel group study comparing placebo to amlodipine 10 mg daily added to the beta-blocker. The anti-ischaemic efficacy of the combination therapy was assessed by 48 h ECG monitoring and exercise tests. Compared to placebo, amlodipine did not significantly reduce either the frequency (3.7 +/- 4.3 vs 4 +/- 4.8 episodes in the amlodipine group) or the duration of ambulatory ischaemia (mean duration: 43.9 +/- 57.1 vs 39.6 +/- 65.7 min, total duration 3.1 +/- 6.7 vs 2.8 +/- 6.1 h). Exercise-induced ST segment depression tended to decrease with amlodipine (58% vs 73% in the placebo group) and the ischaemia-free workload capacity was increased (+1.7 stage vs 0.7 stage in the placebo group, P = 0.08). These results suggest that 2 weeks treatment with amlodipine may not provide any additional anti-ischaemic benefit in patients with ambulant ischaemia resistant to a beta-blocker therapy.     

Comparison of sudden and nonsudden coronary deaths in the United States

BACKGROUND: The present study was designed to compare risk factor prevalences in coronary heart disease deaths in persons dying within 1 hour of onset of cardiovascular symptoms (sudden coronary death), those dying without such sudden symptoms (nonsudden coronary death), and those with unknown duration of symptoms before death (other coronary death). METHODS AND RESULTS: Data from the 1986 National Mortality Followback Survey and the US Bureau of the Census were examined to assess death rates for sudden, nonsudden, and other coronary deaths. Multivariate logistic regression methods were used to calculate the odds ratio (OR), compared with nonsudden and other coronary deaths, for sudden coronary death associated with socioeconomic status variables, the person's location at death, and coronary heart disease risk factors. Mortality rates for all coronary deaths increased with age, were higher for men than women, and increased with decreasing years of schooling. The rate of sudden coronary death was highest for Hispanics. In 1986, an estimated 251,000 sudden coronary deaths (95% CI = 238,000 to 263,000) occurred in the United States. Sudden coronary deaths were less likely than nonsudden coronary deaths to occur at home (OR = 0.5, 95% CI = 0.4 to 0.6), but individuals who died of sudden coronary death were more likely to have been current cigarette smokers (OR = 1.3, 95% CI = 1.0 to 1.8). No other modifiable risk factors for coronary heart disease distinguished sudden coronary deaths from nonsudden coronary deaths. CONCLUSIONS: Contrary to the commonly held view, coronary deaths in the home are more likely to be nonsudden than sudden. Cigarette smoking more likely results in sudden than nonsudden coronary death, perhaps because of nicotine-induced ventricular arrhythmias.     

Importance of trends in the interpretation of an overall odds ratio in the meta-analysis of clinical trials

OBJECTIVE: To investigate the predictive value of fasting insulin concentrations for subsequent fatal or non-fatal ischaemic heart disease at five year follow up and to examine the associations between insulin and other indicators of risk. DESIGN: A prospective population study among 2512 men aged 45 to 59 at recruitment. SETTING: A whole population sample of men resident in Caerphilly, South Wales. MEASUREMENTS: At recruitment fasting blood samples were taken for measurement of plasma lipids and serum insulin. Men were re-examined at a five year follow up and ischaemic heart disease events during this period were assessed from hospital notes, death certificates, and electrocardiograms. MAIN RESULTS: Diabetic men and those men with a fasting blood glucose of > or = 8 mmol/l were excluded from all analyses. In a univariate analysis the incidence of ischaemic heart disease increased with increasing concentration of fasting insulin, such that for men in the top 20% of the insulin distribution the odds of developing ischaemic heart disease were 1.87 relative to men in the bottom 20%. On multivariate analysis this relation disappeared on adjusting for plasma triglycerides, body mass index, and evidence of ischaemic heart disease at recruitment. CONCLUSION: In this population in South Wales there was no evidence that the fasting insulin concentration is an independent risk factor for ischaemic heart disease. The univariate association between insulin and incident disease was almost entirely explained by the association of both with triglycerides and body mass index.     

Ecological study of reasons for sharp decline in mortality from ischaemic heart disease in Poland since 1991

OBJECTIVE: To investigate the reasons for the decline in deaths attributed to ischaemic heart disease in Poland since 1991 after two decades of rising rates. DESIGN: Recent changes in mortality were measured as percentage deviations in 1994 from rates predicted by extrapolation of sex and age specific death rates for 1980-91 for diseases of the circulatory system and selected other categories. Available data on national and household food availability, alcohol consumption, cigarette smoking, socioeconomic indices, and medical services over time were reviewed. MAIN OUTCOME MEASURES: Age specific and age standardised rates of death attributed to ischaemic heart disease and related causes. RESULTS: The change in trend in mortality attributed to diseases of the circulatory system was similar in men and women and most marked (> 20%) in early middle age. For ages 45 to 64 the decrease was greatest for deaths attributed to ischaemic heart disease and atherosclerosis (around 25%) and less for stroke (< 10%). For most of the potentially explanatory variables considered, there were no corresponding changes in trend. However, between 1986-90 and 1994 there was a marked switch from animal fats (estimated availability down 23%) to vegetable fats (up 48%) and increased imports of fruit. CONCLUSION: Reporting biases are unlikely to have exaggerated the true fall in ischaemic heart disease; neither is it likely to be mainly due to changes in smoking, drinking, stress, or medical care. Changes in type of dietary fat and increased supplies of fresh fruit and vegetables seem to be the best candidates.     

Renal insufficiency after heart transplantation: a case-control study

BACKGROUND: In Rotterdam 304 heart transplants have been performed since 1984. End-stage renal failure, necessitating renal replacement therapy, has developed in 24 patients (8%) after an interval of 25-121 months (median 79 months). After starting renal replacement therapy one-year survival was only 60%. Overall survival after heart transplantation, however, was favourable: 5 and 10 year survival rates of 79% and 50% respectively. METHODS: A case-control study was performed to identify possible risk factors in cases who went on to develop end-stage renal failure compared to controls. RESULTS: We found that renal failure was not limited to elderly patients with ischaemic heart disease, but also occurred in young patients having dilated cardiomyopathy. A significant rise in the serum creatinine was found in cases compared to controls as early as 3 months after transplantation. Cyclosporin dose and trough levels were not different between cases and controls. Neither were there differences in the use of calcium-antagonists or other antihypertensive drugs, allopurinol or diuretics. Rejection incidence was also similar between the two groups. CONCLUSIONS: Renal failure after heart transplantation is a long term complication of cyclosporin use that is not limited to elderly patients with ischaemic heart disease. Cyclosporin dose and trough levels in the cases were not different from patients maintaining stable good renal function, indicating that cyclosporin nephrotoxicity is the result of an individually determined susceptibility to cyclosporin. Suggestions for future strategies to prevent renal failure are given.     

Expression of collagenase and stromelysin in skin fibroblasts from recessive dystrophic epidermolysis bullosa

OBJECTIVE: To compare the effects of felodipine and placebo in patients with New York Heart Association functional class II or III and stable congestive heart failure despite treatment with an angiotensin converting enzyme inhibitor, diuretic, or digoxin, or any combination of these three drugs. PATIENTS AND DESIGN: 252 patients were randomised in a double blind, parallel group study after a 2-4 week placebo run-in to oral treatment with either felodipine extended release formulation or placebo 2.5-10 mg twice daily given in addition to existing background medication for a further 12 weeks. METHODS: Patients aged 18-75 years of either sex with chronic congestive heart failure due to ischaemic heart disease, hypertensive heart disease, or dilated cardiomyopathy with or without secondary mitral insufficiency that was stable during the preceding two months were included in the study. Treadmill exercise tests according to the modified Naughton protocol were performed at baseline, and after six, 11, and 12 weeks of treatment. Signs and symptoms of heart failure were assessed at every visit. Physical examination was performed and left ventricular ejection fraction measured at baseline and after 12 weeks. RESULTS: Mean (SD) baseline exercise test times increased from 434 (162) s and 480 (157) s for felodipine and placebo groups respectively to 541 (217) s and 591 (218) s at 12 weeks or the last visit. The change in exercise from baseline to last visit was 107 (141) s for patients given felodipine and 112 (128) s for those given placebo (P > 0.20). There was also no difference between treatments with respect to the other efficacy variables. There were few deaths in the study (felodipine n = 3, placebo n = 2). More patients who received felodipine were withdrawn from treatment (n = 29) than those who received placebo (n = 17). The most common adverse events of the 54 and 28 cited as reasons for withdrawal in the felodipine and placebo groups respectively were increased need for non-study heart failure treatment (n = 10; 8%)--that is, starting new medication or changes in the dosage of existing treatment for patients given felodipine, and nausea (n = 4; 3%) for those given placebo. Patients withdrawn from the study due to increased need for non-study heart failure treatment rapidly stabilised and recovered. CONCLUSION: Felodipine has not been shown to be of benefit in patients with mild to moderate heart failure.     

Intravenous diltiazem in acute myocardial infarction. Diltiazem as adjunctive therapy to activase (DATA) trial

OBJECTIVES: This study was defined as a pilot investigation of the usefulness and safety of intravenous diltiazem as adjunctive therapy to tissue plasminogen activator in acute myocardial infarction, followed by oral therapy for 4 weeks. BACKGROUND: Experimental studies have documented that calcium antagonists protect the myocardial cell against the damage caused by coronary artery occlusion and reperfusion, yet no benefits have been conclusively demonstrated in acute myocardial infarction (AMI) in humans. METHODS: In this pilot study, 59 patients with an AMI treated with tissue-type plasminogen activator (t-PA) were randomized, double blinded, to intravenous diltiazem or placebo for 48 h, followed by oral therapy for 4 weeks. The primary objective was to detect an effect on indices of regional left ventricular function and perfusion. Patients were also closely monitored for clinical events, coronary artery patency and indices of infarct size and of left ventricular function. RESULTS: Creatine kinase elevation, Q wave score, global and regional left ventricular function and coronary artery patency at 48 h were not significantly different between the diltiazem and placebo groups. A greater improvement observed in regional perfusion and function with diltiazem was likely explained by initial larger defects. Diltiazem, compared to placebo, reduced the rate of death, reinfarction or recurrent ischemia at 35 days from 41% to 13% (p=0.027) and prevented the need for an urgent intervention. The rate of death or myocardial infarction was reduced by 65% (p=0.15). These benefits could not be explained by differences in baseline characteristics such as age, site and extent of infarction, time of inclusion or concomitant therapy. Heart rate and blood pressure were reduced throughout the study with active diltiazem treatment. Side effects of diltiazem were bradycardia and hypotension that required transient or permanent discontinuation of the study drug in 27% of patients, vs. 17% of patients with placebo. CONCLUSIONS: A protective effect for clinical events related to early postinfarction ischemia and reinfarction was suggested in this study, with diltiazem administered intravenously with t-PA followed by oral therapy for 1 month, with no effect on coronary artery patency and left ventricular function and perfusion.     

Early experience with dobutamine stress testing and cardiac cine-tomographic imaging in the elderly: antianginal effects of nifedipine-GITS

OBJECTIVE: To determine the effects of nifedipine-GITS (GITS = gastrointestinal transport system) on angina and cardiovascular responses to stress-dobutamine infusion, we used ultrafast cine-computed tomography (CT) to assess regional wall motion, myocardial perfusion, and indices of ventricular filling and emptying. DESIGN: Randomized, double-blind placebo-controlled efficacy study after an open-label dose titration phase. SETTING: University of California, San Francisco. PATIENTS: Elderly patients (> 60 years; n = 9:8 male, 1 female) with coronary artery disease by history and diagnostic treadmill or coronary angiography. INTERVENTION: After a 3-week open-label dose-titration phase, eight subjects were randomized to receive either placebo or nifedipine-GITS at the highest tolerated dose for 2 weeks, followed by a crossover to the alternate therapy for 2 weeks. One declined because of singulus in the open-label period. MAIN OUTCOME MEASURES: Symptomatic angina relief (frequency and nitroglycerin consumption), dobutamine stress responses (time to ischemia during dobutamine infusions, cardiac output, cardiac ejection fraction, ventricular segmental wall motion, and perfusion as measured by ultrafast cine-CT), and reported adverse effects. RESULTS: When compared with placebo, nifedipine-GITS administration was associated with less frequent angina and nitroglycerin consumption (NS) and significantly decreased systolic blood pressure. Nifedipine-GITS administration also increased resting supine heart rates. Dobutamine infusions increased heart rate, cardiac output, cardiac ejection fraction, and stroke volume and induced angina symptoms. Neither double product at angina nor systolic indices of cardiac function in response to dobutamine differed between nifedipine-GITS and placebo, although heart rate responses were greater during nifedipine. A trend toward increased peak filling rates was seen during dobutamine stress in the nifedipine-administration period. In most subjects (6/8), perfusion and regional wall motion abnormalities were not visualized on regional wall motion abnormalities were not visualized on either rest or stress cine-CT studies. Edema without congestive heart failure occurred frequently during nifedipine-GITS administration. CONCLUSIONS: These data suggest that (1) dobutamine stress can be used to induce cardiac ischemia in elderly patients with coronary artery disease, (2) nifedipine-GITS provides symptomatic angina relief in elderly patients, (3) peripheral edema is frequent in elderly patients on nifedipine-GITS, and (4) ultrafast computed cine-tomography testing can be used to assess ventricular performance, but current methodology may not detect perfusion or wall motion abnormalities during angina.     

Randomised placebo controlled trial of effect on mood of lowering cholesterol concentration. Oxford Cholesterol Study Group

OBJECTIVE: To evaluate the effects on mood of a substantial and prolonged reduction in total cholesterol concentration. DESIGN: Randomised placebo controlled comparison of patients who had been allocated to receive simvastatin 20 mg or 40 mg daily versus those allocated matching placebo in a ratio of 2:1. Follow up at an average of 152 weeks after randomisation. SUBJECTS: Men and women aged between 40 and 75 years at entry with blood total cholesterol of 3.5 mmol/l or greater, who were considered to be at higher than average risk of coronary heart disease based on medical history. MAIN OUTCOME MEASURES: The shortened profile of mood states questionnaire, reported use of psychotropic medication, and symptoms possibly related to mood. RESULTS: Simvastatin reduced total cholesterol by 1.9 mmol/l (26.7%) at the time of follow up. Among all 621 patients randomised to simvastatin (414 patients) or placebo (207 patients) there were no significant differences in the use of psychotropic medication or in reports of symptoms possibly related to mood. Of these patients, 491 (334 simvastatin, 157 placebo) completed the mood questionnaire, and there were no significant differences between the treatment groups in total or subscale scores, even when patients with low baseline cholesterol concentrations or elderly subjects were considered separately. CONCLUSION: These results do not support the hypothesis that treatment to lower cholesterol concentration causes mood disturbance.