Lipoprotein-associated phospholipase A(2) and future risk of subclinical disease and cardiovascular events in individuals with type 2 diabetes: the Cardiovascular Health Study.

AIMS/HYPOTHESIS: Type 2 diabetes is an established risk factor for cardiovascular disease (CVD). This increased risk may be due in part to the increased levels of inflammatory factors associated with diabetes. Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is a risk marker for CVD and has pro-inflammatory effects in atherosclerotic plaques. We therefore sought to determine whether Lp-PLA(2) levels partially explain the greater prevalence of subclinical CVD and greater incidence of CVD outcomes associated with type 2 diabetes in the Cardiovascular Health Study. METHODS: We conducted a cross-sectional and prospective study of 4,062 men and women without previous CVD from the Cardiovascular Health Study (1989 to 2007). Lp-PLA(2) mass and activity were measured in baseline plasma. Subclinical disease was determined at baseline and incident CVD was ascertained annually. We used logistic regression for cross-sectional analyses and Cox proportional hazards models for incident analyses. RESULTS: At baseline, Lp-PLA(2) mass did not differ significantly by type 2 diabetes status; however, Lp-PLA(2) activity was significantly higher among type 2 diabetic individuals. Baseline subclinical disease was significantly associated with baseline diabetes and this association was similar in models unadjusted or adjusted for Lp-PLA(2) (OR 1.68 [95% CI 1.31-2.15] vs OR 1.67 [95% CI 1.30-2.13]). Baseline type 2 diabetes was also significantly associated with incident CVD events, including fatal CHD, fatal myocardial infarction (MI) and non-fatal MI in multivariable analyses. There were no differences in these estimates after further adjustment for Lp-PLA(2) activity. CONCLUSIONS/INTERPRETATION: In this older cohort, differences in Lp-PLA(2) activity did not explain any of the excess risk for subclinical disease or CVD outcomes related to diabetes.

Comparison of the design differences between the Ginkgo Evaluation of Memory study and the GuidAge study.

The epidemic of late life dementia, prominence of use of alternative medications and supplements, and initiation of efforts to determine how to prevent dementia have led to efforts to conduct studies aimed at prevention of dementia. The GEM (Ginkgo Evaluation of Memory) and GuidAge studies are ongoing randomized double-blind, placebo-controlled trials of Ginkgo biloba, administered in a dose of 120 mg twice per day as EGb761, to test whether Ginkgo biloba is effective in the prevention of dementia (and especially Alzheimer's disease) in normal elderly or those early cognitive impairment. Both GEM and GuidAge will also add substantial knowledge to the growing need for expertise in designing and implementing clinical trials to test the efficacy of putative disease-modifying agents for the dementias. While there are many similarities between GEM and Guidage, there are also significant differences. We present here the first comparative design and baseline data fromGEM and Guidage, two of the largest dementia primary prevention trials to date.

Effects of lovastatin and warfarin on early carotid atherosclerosis: sex-specific analyses. Asymptomatic Carotid Artery Progression Study (ACAPS) Research Group.

BACKGROUND: Few clinical trials have documented the efficacy of preventive treatment in asymptomatic women. METHODS AND RESULTS: Lovastatin and minidose warfarin were evaluated in a factorially designed, placebo-controlled, randomized trial. The primary outcome was 3-year change in the mean maximum intimal-medial thickness of the carotid arteries as measured by B-mode ultrasonography. Participants (n=919) were randomized to 1 of 4 treatment groups: lovastatin alone, warfarin alone, lovastatin+warfarin combination, or a double-placebo group. Eligible participants were asymptomatic for cardiovascular disease, with evidence of early carotid atherosclerosis and moderately elevated LDL cholesterol level. Almost half (n=445) of the participants were women. To avoid confounding, 117 women taking estrogen were excluded from analysis. Both sexes experienced reductions in disease progression with lovastatin; there was no evidence of an overall sex x treatment interaction (P=0.72). When estimates of the sex-specific results were examined post hoc, women experienced disease regression to the greatest extent with the lovastatin + warfarin combination (P=0.02), although the women on lovastatin alone also had a reduction in progression (P=0.09). Men experienced the greatest reduction with lovastatin alone (P=0.02), although there is a suggestion that warfarin may also reduce progression to some extent. CONCLUSIONS: Lovastatin is beneficial in reducing disease progression in women and men. Warfarin has no effect in women, although it may reduce progression in men. In men, warfarin does not add to the benefit of lovastatin and has no advantage over lovastatin alone.

Treatment of isolated systolic hypertension is most effective in older patients with high-risk profile.

BACKGROUND: Although present guidelines suggest that treatment of hypertension is more effective in patients with multiple risk factors and higher risk of cardiovascular events, this hypothesis was never verified in older patients with systolic hypertension. METHODS AND RESULTS: Using data from the Systolic Hypertension in the Elderly Program, we calculated the global cardiovascular risk score according to the American Heart Association Multiple Risk Factor Assessment Equation in 4,189 participants free of cardiovascular disease (CVD) and in 264 participants with CVD at baseline. In the placebo group, rates of cardiovascular events over 4.5 years were progressively higher according to higher quartiles of CVD risk. The protection conferred by treatment was similar across quartiles of risk. However, the numbers needed to treat (NNTs) to prevent one cardiovascular event were progressively smaller according to higher cardiovascular risk quartiles. In participants with baseline CVD, the NNTs to prevent one cardiovascular event were similar to those estimated for CVD-free participants in the highest-risk quartile. CONCLUSIONS: Treatment of systolic hypertension is most effective in older patients who, because of additional risk factors or prevalent CVD, are at higher risk of developing a cardiovascular event. These patients are prime candidates for antihypertensive treatment.

Effect of pravastatin on coronary disease events in subgroups defined by coronary risk factors: the Prospective Pravastatin Pooling Project.

BACKGROUND: Previous trials have had insufficient numbers of coronary events to address definitively the effect of lipid-modifying therapy on coronary heart disease in subgroups of patients with varying baseline characteristics. METHODS AND RESULTS: The data from 3 large randomized trials with pravastatin 40 mg were pooled and analyzed with the use of a prospectively defined protocol. Included were 19 768 patients, 102 559 person-years of follow-up, 2194 primary end points (coronary death or nonfatal myocardial infarction), and 3717 expanded end points (primary end point, CABG, or PTCA). Pravastatin significantly reduced relative risk in younger (<65 years) and older (>/=65 years) patients, men and women, smokers and nonsmokers, and patients with or without diabetes or hypertension. The relative effect was smaller, but absolute risk reduction was similar in patients with hypertension compared with those without hypertension. Relative risk reduction was significant in predefined categories of baseline lipid concentrations. Tests for interaction were not significant between relative risk reduction and baseline total cholesterol (5% to 95% range 177 to 297 mg/dL, 4.6 to 7.7 mmol/L), HDL cholesterol (27 to 58 mg/dL, 0.7 to 1.5 mmol/L), and triglyceride (74 to 302 mg/dL, 0.8 to 3.4 mmol/L) concentrations, analyzed as continuous variables. However, for LDL cholesterol, the probability values for interaction were 0.068 for the prespecified primary end point and 0.019 for the expanded end point. Relative risk reduction was similar throughout most of the baseline LDL cholesterol range (125 to 212 mg/dL, 3.2 to 5.5 mmol/L) with the possible exception of the lowest quintile of CARE/LIPID (<125 mg/dL) (relative risk reduction 5%, 95% CI 19% to -12%). CONCLUSIONS: Pravastatin treatment is effective in reducing coronary heart disease events in patients with high or low risk factor status and across a wide range of pretreatment lipid concentrations.

Effect of amlodipine on the progression of atherosclerosis and the occurrence of clinical events. PREVENT Investigators.

BACKGROUND: The results of angiographic studies have suggested that calcium channel-blocking agents may prevent new coronary lesion formation, the progression of minimal lesions, or both. METHODS AND RESULTS: The Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial (PREVENT) was a multicenter, randomized, placebo-controlled, double-masked clinical trial designed to test whether amlodipine would slow the progression of early coronary atherosclerosis in 825 patients with angiographically documented coronary artery disease. The primary outcome was the average 36-month angiographic change in mean minimal diameters of segments with a baseline diameter stenosis of 30%. A secondary hypothesis was whether amlodipine would reduce the rate of atherosclerosis in the carotid arteries as assessed with B-mode ultrasonography, which measured intimal-medial thicknesses (IMT). The rates of clinical events were also monitored. The placebo and amlodipine groups had nearly identical average 36-month reductions in the minimal diameter: 0.084 versus 0.095 mm, respectively (P:=0.38). In contrast, amlodipine had a significant effect in slowing the 36-month progression of carotid artery atherosclerosis: the placebo group experienced a 0.033-mm increase in IMT, whereas there was a 0. 0126-mm decrease in the amlodipine group (P:=0.007). There was no treatment difference in the rates of all-cause mortality or major cardiovascular events, although amlodipine use was associated with fewer cases of unstable angina and coronary revascularization. CONCLUSIONS: Amlodipine has no demonstrable effect on angiographic progression of coronary atherosclerosis or the risk of major cardiovascular events but is associated with fewer hospitalizations for unstable angina and revascularization.

Depressive symptoms and risks of coronary heart disease and mortality in elderly Americans. Cardiovascular Health Study Collaborative Research Group.

BACKGROUND: Several epidemiological studies have associated depressive symptoms with cardiovascular disease. We investigated whether depressive symptoms constituted a risk for coronary heart disease (CHD) and total mortality among an apparently healthy elderly cohort. METHODS AND RESULTS: In a prospective cohort of 5888 elderly Americans (>/=65 years) who were enrolled in the Cardiovascular Health Study, 4493 participants who were free of cardiovascular disease at baseline provided annual information on their depressive status, which was assessed using the Depression Scale of the Center for Epidemiological Studies. These 4493 subjects were followed for 6 years for the development of CHD and mortality. The cumulative mean depression score was assessed for each participant up to the time of event (maximum 6-year follow-up). Using time-dependent, proportional-hazards models, the unadjusted hazard ratio associated with every 5-unit increase in mean depression score for the development of CHD was 1.15 (P:=0.006); the ratio for all-cause mortality was 1.29 (P:<0.0001). In multivariate analyses adjusted for age, race, sex, education, diabetes, hypertension, cigarette smoking, total cholesterol, triglyceride level, congestive heart failure, and physical inactivity, the hazard ratio for CHD was 1.15 (P:=0.006) and that for all-cause mortality was 1.16 (P:=0.006). Among participants with the highest cumulative mean depression scores, the risk of CHD increased by 40% and risk of death by 60% compared with those who had the lowest mean scores. CONCLUSIONS: Among elderly Americans, depressive symptoms constitute an independent risk factor for the development of CHD and total mortality.

Are all angiotensin-converting enzyme inhibitors interchangeable?

In the treatment of most medical conditions, there are many choices. A critical question for practicing clinicians is: "Are all drugs within a class interchangeable?" In the past decade, the market has seen a proliferation of drugs within popular drug classes. The original drugs within a class typically have better scientific documentation than the newer ones, which are often referred to as "me-too" drugs. Due to a lesser financial investment, the latter may be available at a lower cost. Good reasons exist for grouping drugs, however, there is no accepted definition of the term "class effect." Although members of a drug class share main actions, they may have clinically important differences in terms of efficacy and safety. There are many such examples in the literature. This article reviews the class effect concept as it applies to the angiotensin-converting enzyme (ACE) inhibitors. Only half of the 10 ACE inhibitors available in the U.S. have been shown to improve survival and reduce morbidity in patients with heart failure or myocardial infarction. It is unknown whether the other five have the same safety and efficacy profiles or what their optimal doses are. Thus, we do not know whether all ACE inhibitors are fully interchangeable. The practice of medicine ought to be based on solid scientific evidence, not on assumptions or extrapolations. For our patients, such practice is a legitimate expectation. Therefore, it seems prudent to recommend that patients requiring ACE inhibitor therapy be prescribed one that has been proven effective and safe.

Prognostic significance of ventricular ectopic activity in survivors of acute myocardial infarction.

Twenty-four hour ambulatory electrocardiography was performed on 3,290 survivors of acute myocardial infarction participating in the Beta-Blocker Heart Attack Trial (BHAT). History of myocardial infarction before the qualifying event, congestive heart failure and age were independently associated with the frequency and complexity of ventricular premature beats. Of the 1,640 patients randomized to placebo therapy, 163 died (76 suffered sudden death) during a 25 month average follow-up period. Ventricular ectopic activity was an independent predictor of total mortality after taking into consideration 16 other prognostic factors describing past history, risk factors, physical examination and laboratory investigations. Seven categoric definitions of ventricular ectopic activity predicted mortality, with similar odds ratios ranging from 2.27 to 2.69. A reciprocal relation of the sensitivity and specificity of each definition in predicting mortality was observed. Three clinical criteria (ST depression, cardiomegaly and prior infarction) allowed stratification of patients into four subsets with respective mortality rates of 35.5% (three criteria present), 19.0% (two criteria), 11.5% (one criterion) and 4.7% (none). Presence of ventricular ectopic activity (greater than or equal to 10 ventricular premature beats/h or pairs, ventricular tachycardia or multiform complexes) was associated with higher mortality rates in all four risk strata. The relative risk was higher (3.86) in the lowest risk stratum (mortality 2.4% without and 9.1% with ventricular ectopic activity). Thus, in survivors of acute myocardial infarction, ventricular ectopic activity was more pronounced in patients with prior myocardial infarction and congestive heart failure. It predicted mortality independently of other factors. Although mortality ratios were similar for all seven arrhythmia definitions, a reciprocal relation between sensitivity and specificity of the definitions in predicting mortality existed; ventricular ectopic activity was associated with increased mortality in all risk strata, but with a higher risk ratio in the numerically larger, low risk subset.

Effect of propranolol in patients with myocardial infarction and ventricular arrhythmia.

The Beta-Blocker Heart Attack Trial was a placebo-controlled, randomized, double-blind clinical trial of the long-term administration of propranolol hydrochloride to patients who had had at least one myocardial infarction. Among 3,837 patients followed up for an average of 25 months, 3,290 (85.7%) had 24 hour ambulatory electrocardiograms performed at the baseline examination. Four classifications of arrhythmia were examined. One of these, the presence of complex ventricular arrhythmias (at least 10 ventricular premature beats/h, or at least one pair or run of ventricular premature beats or multiform ventricular premature beats) was the subgroup of major interest. Regardless of the classification, the presence of arrhythmia identifies a group of patients with a higher risk of total mortality, coronary heart disease mortality, sudden cardiac death and instantaneous cardiac death. The a priori subgroup hypothesis that sudden death would be preferentially reduced by propranolol in patients with complex ventricular arrhythmias was not supported. The relative benefit of propranolol in reducing sudden death for this subgroup was 28 versus 16% for the subgroup without ventricular arrhythmia (relative risk of 0.72 versus 0.84, a nonsignificant relative difference of 14%). There were similar findings for two of the three other classifications of arrhythmia and for the other response variables. Although propranolol does not appear to be of special relative benefit in patients with ventricular arrhythmia, the presence of the arrhythmia does identify a high-risk group. The mechanism by which propranolol reduces mortality is still unclear, but is probably not solely an antiarrhythmic one.

Renal insufficiency and cardiovascular events in postmenopausal women with coronary heart disease.

OBJECTIVES: This study sought to determine the independent association of renal insufficiency with cardiovascular risk among women with known coronary heart disease (CHD). BACKGROUND: Although patients with end-stage renal disease and proteinuria are at high risk for cardiovascular events, little is known about the cardiovascular risk associated with moderate renal insufficiency. METHODS: The Heart and Estrogen/progestin Replacement Study (HERS) was a clinical trial among 2,763 women with coronary disease who were randomized to conjugated estrogen plus progestins or identical placebo and followed for a mean of 4.1 years. Women were categorized as having normal renal function (creatinine < 1.2 mg/dl; n = 2,012), mild renal insufficiency (1.2 mg/dl to 1.4 mg/dl; n = 567) and moderate renal insufficiency (>1.4 mg/dl; n = 182). We examined the independent association of renal function with incident cardiovascular events including CHD death, nonfatal myocardial infarction, hospitalization for unstable angina, stroke and transient ischemic attacks. RESULTS: Compared with women with normal renal function, those with mild and moderate renal insufficiency were older, more likely to be black, have a history of hypertension and diabetes and have higher serum levels of triglycerides and lipoprotein(a). After multivariate adjustment, both mild (relative hazards [RH] = 1.24; 95% confidence interval [CI]: 1.0 to 1.5) and moderate renal insufficiency (RH = 1.57; 95% CI: 1.2 to 2.1) were independently associated with increased risk for cardiovascular events compared with women with normal renal function. CONCLUSIONS: Renal insufficiency is an independent risk factor for cardiovascular events in postmenopausal women with known coronary artery disease. Renal function may add helpful information to CHD risk stratification.

Cardiac arrhythmias on 24-h ambulatory electrocardiography in older women and men: the Cardiovascular Health Study.

OBJECTIVES: This study describes the prevalence and correlates of cardiac arrhythmias in older persons. BACKGROUND: Cardiac arrhythmias are frequent in selected samples of elderly persons, but their prevalence and association with cardiovascular disease and its risk factors have not been examined in a large population-based sample. METHODS: In 1,372 participants in the Cardiovascular Health Study, a population-based study of cardiovascular disease risk factors, 24-h ambulatory electrocardiography was performed. RESULTS: Serious arrhythmias, such as sustained ventricular tachycardia and complete atrioventricular block, were uncommon, but brief episodes of ventricular tachycardia (> or = 3 consecutive ventricular depolarizations) were detected in 4.3% of women and 10.3% of men. Ventricular arrhythmias as a group (excluding ectopic beats < 15/h) were more common in men than in women but were not significantly associated with age. The same patterns were true for bradycardia/conduction blocks. Supraventricular arrhythmias as a group (excluding ectopic beats < 15/h), in contrast, did not differ by gender but were strongly associated with increased age. Multivariate analyses showed associations with arrhythmias to differ by gender, with only one association (increased age and supraventricular arrhythmias) present in both women and men. Ventricular arrhythmias, particularly in men, were associated with a higher prevalence of cardiovascular disease and its risk factors and with subclinical disease, as measured by increased left ventricular mass and impaired left ventricular function. CONCLUSIONS: Arrhythmias are common in the elderly, and their association with cardiovascular disease differs by gender. Although risk related to arrhythmias can only be determined by prospective study, such studies should have adequate power to examine potential gender differences in associations.

Prognostic value of exercise electrocardiogram in men at high risk of future coronary heart disease: Multiple Risk Factor Intervention Trial experience.

The prognostic value of the exercise electrocardiogram was examined in the 6,438 usual care men of the Multiple Risk Factor Intervention Trial in relation to fatal and nonfatal coronary heart disease events, rest electrocardiographic abnormalities and coronary heart disease risk factors. An abnormal response to exercise, defined as an ST depression integral of 16 microV-s or more, was observed in 12.2% of the men. There was a nearly fourfold increase in 7 year coronary mortality among men with an abnormal response to exercise compared with men with a normal ST segment in exercise (risk ratio 3.8, 95% confidence limits 2.5 to 5.5). The risk ratio for coronary death, adjusted for age, diastolic blood pressure, serum cholesterol and smoking status at baseline was 3.5, and the corresponding adjusted risk ratio for death from all causes was 1.6. A similar trend toward excess coronary events was seen for angina pectoris (risk ratio of 1.6). The trend was not significant for nonfatal myocardial infarction. Multivariate analyses indicated that the ST depression integral was a strong independent predictor of future coronary death (p less than 0.001). Men with an abnormal electrocardiogram at rest (mainly high amplitude R waves) and with an abnormal ST response to exercise had an over sixfold relative risk for coronary death compared with men with an abnormal electrocardiogram at rest and a normal ST response to exercise. These results suggest that exercise testing may be indicated for improved risk assessment and the assessment of the significance of minor rest electrocardiographic abnormalities in middle-aged men with elevated levels of coronary heart disease risk factors.

Digoxin Immune Fab therapy in the management of digitalis intoxication: safety and efficacy results of an observational surveillance study.

An observational surveillance study was conducted to monitor the safety and effectiveness of treatment with Digoxin Immune Fab (Ovine) (Digibind) in patients with digitalis intoxication. Before April 1986, a relatively limited number of patients received treatment with digoxin-specific Fab fragments through a multicenter clinical trial. Beginning with commercial availability in July 1986, this study sought additional, voluntarily reported clinical data pertaining to treatment through a 3 week follow-up. The study included 717 adults who received Digoxin Immune Fab (Ovine). Most patients were greater than or equal to 70 years old and developed toxicity during maintenance dosing with digoxin. Fifty percent of patients were reported to have a complete response to treatment, 24% a partial response and 12% no response. The response for 14% of patients was not reported or reported as uncertain. Six patients (0.8%, 95% confidence interval 0.3% to 1.8%) had an allergic reaction to digoxin-specific antibody fragments. Three of the six had a history of allergy to antibiotic drugs. Twenty patients (2.8%, 95% confidence interval 1.7% to 4.3%) developed recrudescent toxicity. Risk of recrudescent toxicity increased sixfold when less than 50% of the estimated dose of antibody was administered. A total of 215 patients experienced posttreatment adverse events. The events for 163 patients (76%) were judged to result from manifestations of underlying disease and thus considered unrelated to Fab treatment. Digoxin-specific antibody fragments were generally well tolerated and clinically effective in patients judged by treating physicians to have potentially life-threatening digitalis intoxication.

Sex bias and underutilization of lipid-lowering therapy in patients with coronary artery disease at academic medical centers in the United States and Canada. Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial (PREVENT) Investigators.

BACKGROUND: The efficacy of lipid-lowering therapy (LLT) has been well established for patients with preexisting coronary artery disease (CAD). However, limited information is available assessing the extent to which these medications are prescribed in academic medical centers. METHODS: The use of LLT for patients with CAD was prospectively evaluated in 825 men and women who were recruited from 16 academic medical centers in the United States and Canada to participate in the Prospective Evaluation of the Vascular Events of Norvasc Trial (PREVENT). The assessment of LLT use during the 3-year trial was evaluated in patients receiving amlodipine therapy and placebo; levels of low-density lipoprotein cholesterol (LDL-C) were used to assess the impact of LLT. RESULTS: Despite a baseline prevalence of LLT in 42% of men (38% in 1994), half of the patients had high levels of LDL-C (>3.36 mmol [>130 mg/dL]). During the subsequent 3 years, the prevalence of elevated LDL-C levels dropped in men (29%) but remained stagnant in women (48%). These changes were associated with increased LLT in men (55%) but not in women (35%) (P = .04). In 1994, the LDL-C target goal (<2.59 mmol/L [<100 mg/dL]) was attained in 17% of men and 6% of women (P = .006). At study completion in 1997, the LDL-C target goal was achieved in 31% of men and only 12% of women (P = .001). CONCLUSIONS: This study highlights the relatively low treatment rates of hyperlipidemia among patients with CAD overall and women in particular who were participating in a clinical trial at academic medical centers in the United States and Canada. Because LLT has been proven to reduce future cardiovascular events, these results suggest that more intensive efforts should be promoted in order to maximize CAD reduction.

Reductase inhibitor monotherapy and stroke prevention.

BACKGROUND: Epidemiologic evidence and meta-analyses of data from early clinical trials suggest that lowering the levels of cholesterol does not reduce the events of stroke. These analyses have not included more recent clinical trials using reductase inhibitors. OBJECTIVE: To conduct a meta-analysis of the effect of reducing cholesterol levels on stroke in all reported clinical trials of primary (n = 4) and secondary (n = 8) prevention of coronary heart disease that used reductase inhibitor monotherapy and provided information on incident stroke. RESULTS: Analysis of combined data from primary and secondary prevention trials showed a highly statistically significant reduction of stroke associated with the use of reductase inhibitor monotherapy (27% reduction in stroke; P = .001). Analysis of secondary prevention trials alone disclosed a similar statistically significant effect (32% reduction in stroke; P = .001). A smaller nonsignificant reduction in stroke was noted in the primary prevention trials (15% reduction in stroke; P = .48). CONCLUSIONS: Reductase inhibitors now in use for lowering cholesterol levels are more potent and have fewer side effects than the cholesterol-lowering agents previously available. They appear to reduce stroke, most notably in patients with prevalent coronary artery disease, which may be partly due to the effects of lowering the levels of cholesterol on the progression and plaque stability of extracranial carotid atherosclerosis or the marked reduction of incident coronary heart disease associated with treatment.

Lack of age-related differences in the clinical presentation of digoxin toxicity.

BACKGROUND: Digoxin toxicity occurs most commonly among the elderly. While the clinical syndrome of digoxin toxicity is well understood, how toxic manifestations change with age is not known. METHODS: We performed secondary analysis of data from a postmarketing surveillance study of patients with life-threatening digoxin toxicity treated with digoxin antibody therapy. Patients receiving long-term maintenance digoxin therapy and aged 55 years or older were divided into four age groups: 55 to 64, 65 to 74, 75 to 84, and 85 years and older (n = 45, 167, 183, and 83, respectively) and compared with regard to presenting manifestations, digoxin dosing, serum potassium and digoxin levels, and renal function. RESULTS: The prevalence of high-degree atrioventricular block showed an increasing but nonsignificant trend with age (40%, 40%, 42%, and 47%, respectively). Age-related trends in high-degree atrioventricular block were stronger among men than women and even stronger among men with underlying cardiac ischemia. The proportion of subjects with nausea/vomiting as a toxic manifestation did not consistently change with age (42%, 48%, 48%, and 46%, respectively). There were no age-related differences in degree of renal impairment or maintenance dose, but maintenance dose decreased with increasing renal impairment. CONCLUSIONS: Among patients with life-threatening digoxin toxicity, there is no age-related difference in clinical presentation.

Trends in pharmacologic management of hypertension in the United States.

BACKGROUND: Two new classes of antihypertensive agents were introduced in the 1980s, but their effectiveness in preventing heart disease and stroke has not been demonstrated. Lack of evidence of their efficacy might reasonably be expected to discourage their widespread use in management of hypertension. METHODS: Use of various classes of antihypertensive agents was estimated from published drug use information in an effort to estimate trends in antihypertensive drug use and evaluate the impact of these trends on costs of antihypertensive therapy in the United States. RESULTS: Proportionate use of the five major antihypertensive drug classes shifted markedly between 1982 and 1993. Diuretics accounted for 56% of all hypertensive drug mentions in 1982 but only 27% in 1993, a relative decline of 52%. Use of beta-blockers and central agents also declined during this period. Proportionate use of calcium antagonists showed the greatest gains, increasing from 0.3% to 27%, while the use of angiotensin-converting enzyme inhibitors increased from 0.8% to 24%. Given the higher costs of the newer agents, and assuming an estimated total cost of antihypertensive medications in 1992 of $7 billion, approximately $3.1 billion would have been saved had 1982 prescribing practices remained in effect in 1992. CONCLUSIONS: Use of calcium antagonists and angiotensin-converting enzyme inhibitors in hypertension has increased dramatically in the past 10 years. Without convincing evidence of the advantages of these agents, it is difficult to explain the continued decline in the use of less expensive agents, such as diuretics and beta-blockers, which are the only antihypertensive agents proved to reduce stroke and coronary disease in hypertensive patients.

Risk of recurrent coronary events in relation to use and recent initiation of postmenopausal hormone therapy.

BACKGROUND: The finding from the Heart and Estrogen/Progestin Replacement Study (HERS) of increased coronary risk restricted to the first year after starting postmenopausal hormone therapy raises new questions about the role of hormone therapy in women with coronary heart disease. We assessed the risk of recurrent myocardial infarction or coronary heart disease death associated with the use and recent initiation of hormone therapy in women who survived a first myocardial infarction. METHODS: The setting for this population-based inception cohort study was Group Health Cooperative, a health maintenance organization. We studied 981 postmenopausal women who survived to hospital discharge after their first myocardial infarction between July 1, 1986, and December 31, 1996. We obtained information on hormone use from the Group Health Cooperative computerized pharmacy database and identified recurrent coronary events by medical record review. RESULTS: During median follow-up of 3.5 years, there were 186 recurrent coronary events. There was no difference in the risk of recurrent coronary events between current users of hormone therapy and other women (adjusted relative hazard [RH], 0.96; 95% confidence interval [CI], 0.62-1.50). Relative to the risk in women not currently using hormones, there was a suggestion of increased risk during the first 60 days after starting hormone therapy (RH, 2.16; 95% CI, 0.94-4.95) and reduced risk with current hormone use for longer than 1 year (RH, 0.76; 95% CI, 0.42-1.36). CONCLUSION: These results are consistent with the findings from the HERS, suggesting a transitory increase in coronary risk after starting hormone therapy in women with established coronary heart disease and a decreased risk thereafter.

Temporal trends in the use of anticoagulants among older adults with atrial fibrillation.

BACKGROUND: Several recent randomized clinical trials have demonstrated that warfarin sodium treatment, and to a lesser extent aspirin, reduces risk of stroke and death compared with placebo in persons with atrial fibrillation. Insufficient documentation exists on the extent to which the use of these therapies following trial publications has continued to increase in the elderly with atrial fibrillation. METHODS: We used data from the Cardiovascular Health Study, a study of 5888 community-dwelling adults aged 65 years or older, to determine the prevalence of warfarin and aspirin use in persons with electrocardiogram-identified atrial fibrillation. Electrocardiogram examinations were conducted at baseline from 1989 through 1990, and at 6 subsequent annual examinations through 1995-1996. Medication data were collected by inventory methods at each examination. Temporal change in use of anticoagulants was analyzed by comparing percentage use in 1990 to use in each year through 1996. RESULTS: The use of warfarin increased 4-fold from 13% in 1990 to 50% in 1996 among participants with prevalent atrial fibrillation (P<.001). Daily use of aspirin did not increase over time. Participants younger than 80 years were 4 times more likely to use warfarin in 1996 (P<.001) than those 80 years and older. Use of aspirin did not vary significantly with age. CONCLUSIONS: Warfarin use in community-dwelling elderly persons with electrocardiogram-documented atrial fibrillation increased steadily following the first publication of its treatment benefit, reaching 50% by 1996. In contrast, use of aspirin was unchanged during this same period. Continued efforts to promote appropriate anticoagulation therapy to physicians and their patients may still be needed.