Stephen P. Glasser

Effect of pravastatin on cardiovascular events in older patients with myocardial infarction and cholesterol levels in the average range. Results of the Cholesterol and Recurrent Events (CARE) trial.

Three fourths of deaths from myocardial infarction occur in patients older than 65 years of age, making cardiovascular disease the leading cause of death in older persons [1, 2]. Older patients, despite their high risk for cardiovascular death, are less likely to receive cardioprotective medications or interventions [3-15] or to be enrolled in clinical trials that test potentially beneficial treatments [3]. Although much information is available on serum cholesterol as a predictor of coronary artery disease in younger patients, as well as on the benefits of reduction of serum cholesterol levels, the role of cholesterol in coronary artery disease in older patients is less clear. Elevated cholesterol levels do not strongly predict coronary events in older patients [16-23]; thus, the need for cholesterol screening and treatment in older persons has generated much divergent opinion [22-31]. Recent analysis of a cohort of older persons (mean age, 80 years) strongly suggested that concomitant disease or debilitation was associated with low blood cholesterol levels and was responsible for the reduced ability of serum cholesterol levels to predict the incidence of coronary events. After adjustment for low serum iron and albumin levels and exclusion of events in the first year of follow-up, serum cholesterol levels became a significant predictor of coronary death [32]. Without this adjustment, no such association was seen [32]. Almost all trials of cholesterol treatment have excluded patients who were 65 years of age or older. The National Cholesterol Education Panel guidelines [33] therefore extrapolated findings from the treatment of younger patients in their recommendations for treating older patients, noting the considerable potential for absolute risk reduction given the high incidence of cardiovascular events in older patients. More recently, researchers observed that simvastatin treatment of hypercholesterolemic patients with coronary artery disease reduced recurrent major coronary events in the subset of patients who were 65 to 70 years of age at study entry [34]. However, information is needed on the effect of lipid treatment in older patients who have had myocardial infarction and have average cholesterol levels; most patients who have had myocardial infarction have cholesterol values in the average, not elevated, range [35-37]. The Cholesterol and Recurrent Events (CARE) trial [38] investigated whether reducing average cholesterol levels by using pravastatin in patients who have had myocardial infarction would prevent recurrent cardiac events. It showed that in patients with average cholesterol levels, pravastatin therapy reduced the risk for coronary death or recurrent myocardial infarction by 24% (P = 0.003), reduced the risk for fatal and nonfatal myocardial infarction by 25% (P = 0.006), reduced the risk for coronary artery bypass grafting and angioplasty by 27% (P < 0.001), and reduced the risk for stroke by 31% (P = 0.03) [38]. It also reported that patients who were older than the median age of 59 years had a reduced rate of coronary death, nonfatal myocardial infarction, coronary artery bypass grafting, or percutaneous transluminal coronary angioplasty. Of the 4159 patients in the CARE trial, 1283 (31%) were 65 to 75 years of age at baseline; these patients are eligible for retirement health care (Medicare) benefits in the United States. We report on the effect of pravastatin on individual cardiovascular events in these older patients, including myocardial infarction, coronary artery bypass grafting, angioplasty, and stroke, as well as on overall hospitalization for cardiovascular disease. Methods Study Design and Patients The design and results of the CARE trial have been described in detail elsewhere [38, 39]. The study was a randomized, double-blind, placebo-controlled trial with a planned average follow-up of 5 years. Patients were recruited from 80 participating centers in the United States and Canada. Institutional review board approval was obtained for investigation of human participants. Patients were eligible if they had had an acute myocardial infarction 3 to 20 months before randomization; were 21 to 75 years of age; and had plasma total cholesterol levels less than 6.2 mmol/L (240 mg/dL), low-density lipoprotein (LDL) cholesterol levels of 3.0 to 4.5 mmol/L (115 to 174 mg/dL), and fasting triglyceride levels less than 4.0 mmol/L (350 mg/dL). The diagnosis of myocardial infarction was confirmed by the MI Confirmation Core Laboratory, which evaluated reports of changes in serum creatine kinase levels, electrocardiographic evidence, and clinical symptoms [38, 39]. Plasma lipids were measured at least 2 months after discharge from hospitalization for the index myocardial infarction. Women were required to be postmenopausal or surgically sterile. All participants received dietary counseling according to the National Cholesterol Education Program Step 1 guidelines. After the screening visits were completed, eligible patients returned for a randomization visit, during which they were assigned to receive either pravastatin (40 mg/d) or identically appearing placebo by means of a telephone call from a clinical center to the Data Coordinating Center. The patient was the unit of randomization, randomization was stratified within each clinical center, and the allocation schedule was generated by computer. The code for treatment assignment was maintained only at the Data Coordinating Center. The primary trial outcome was fatal coronary artery disease or confirmed nonfatal myocardial infarction. For the primary analysis of the treatment effects in subgroups, we used an expanded end point (death from coronary artery disease, nonfatal myocardial infarction, angioplasty, or coronary artery bypass grafting), called major coronary events. Statistical Analysis All analyses were done on an intention-to-treat basis. P values (all of which were two-sided) less than 0.05 were deemed statistically significant. Baseline characteristics in the two treatment groups were determined by using the standard z-test for continuous variables and chi-square tests for categorical variables [40]. All hypothesis testing and risk reductions (with their CIs) were assessed by using the Cox proportional-hazards model. Kaplan-Meier survival curves for the control and pravastatin groups were calculated [41]. The relative risk reduction was calculated as 1 the hazard ratio. The upper and lower bounds of the 95% CIs for the relative risk reductions were applied to the rates in the placebo group to compute the CI for absolute risk reduction, and these bounds were inverted to provide the CIs for the number of patients needed to treat to prevent an event. To determine whether imbalances in risk factors at baseline could have affected the estimates of risk reduction attributable to therapy, we performed subsidiary multivariate analyses that included the following covariates: age, sex, baseline lipid levels, smoking, diabetes, hypertension, and left ventricular ejection fraction. Potential clinical center effects were assessed by including 79 indicator variables to denote the 80 clinical centers in the Cox proportional-hazards analysis. We used SAS software, version 6.12 (SAS Institute, Cary, North Carolina), to execute all analyses. Role of the Study Sponsor The CARE trial was an investigator-initiated study proposed to and funded by Bristol-Myers Squibb. The data were collected and analyzed by and are now maintained at the Coordinating Center, University of Texas School of Public Health. The sponsor is entitled to comment on manuscripts before submission. The authors may consider these comments, but the rights to publication reside contractually with the investigators. The sponsor, a member of the Executive Committee of the trial, was contractually required to fund the study until its conclusion. The sponsor maintained information on adverse events and other trial data, as required by federal regulations. Results Screening and Exclusion before Randomization From a total of 11 207 patients identified from records in hospitals and ambulatory practices for possible inclusion in the CARE trial, 3244 (29%) were at least 65 years of age (hereafter referred to as older patients). Of these 3244 older patients, 1139 (35%) qualified for the trial. An additional 144 patients reached the age of 65 years between their screening date and randomization; thus, 1283 older patients were randomly assigned in the CARE trial. A similar percentage of the patients younger than 65 years of age (hereafter referred to as younger patients)-39% (3020 patients)-qualified for the trial. Older patients were less likely than younger patients to be ineligible because of elevated total cholesterol, LDL cholesterol, or triglyceride levels (8% and 12%, respectively). However, older patients were more likely than younger patients to be ineligible because criteria for myocardial infarction were not met (61% and 53%, respectively) (P < 0.05 for all comparisons). Baseline Characteristics The median follow-up was 5 years (25th and 75th percentiles, 4.3 and 5.4 years). The mean age of the older patients was 69 years at randomization (25th and 75th percentiles, 66 and 73 years) and 74 years at the end of the trial. Baseline coronary risk factors significantly differed between the two age groups (Table 1). Older patients more frequently were female (18% compared with 12% of younger patients), had hypertension (48% compared with 40%), and had diabetes (19% compared with 12%). In addition, they were more likely to have had a second previous myocardial infarction (21% compared with 15%) and less frequently were current smokers (12% compared with 24%), had ever smoked (70% compared with 81%), or had a family history of coronary artery disease (33% compared with 44%) (P < 0.05 for all comparisons). Table 1. Baseline Characteristics of Patients Younger Than 65 Years of Age and Those 65

Age-related abnormalities in arterial compliance identified by pressure pulse contour analysis : Aging and arterial compliance

The objective of this study was to evaluate age-related changes in pulsatile arterial function. Aging alters arterial pulsatile function and produces consistent changes in the pressure pulse contour. A reduced systemic arterial compliance that can be derived from analysis of the pulse contour is regarded as the best clinical index of impaired pulsatile arterial function and may mark the presence of early vascular damage. We analyzed intra-arterial brachial artery waveforms in 115 healthy normotensive volunteers (83 men, 32 women) and radial artery waveforms obtained with the use of a calibrated tonometer device in 212 healthy volunteers (147 women, 65 men). A computer-based assessment of the diastolic pressure decay and a modified Windkessel model of the circulation were used to quantify changes in arterial waveform morphology in terms of large artery or capacitive compliance, oscillatory or reflective compliance in the small arteries, inertance, and systemic vascular resistance. Large artery compliance and oscillatory compliance correlated negatively with age for both invasive and noninvasive groups (r=-0.50 and r=-0.55; r=-0.37 and r=-0.66; P<0.001 for all). The slopes of the regression lines for the decline in oscillatory compliance with age were significantly steeper than those recorded for large artery compliance estimates. The change in blood pressure with age independently contributed to the decrease in large artery compliance but not oscillatory compliance in both groups. Consistent age-related changes were found in the pressure pulse contour by analysis of waveforms obtained invasively or noninvasively from the upper limb. The change in the oscillatory or reflective compliance estimate was independent of blood pressure change and may represent a better marker than large artery or capacitive compliance of the degenerative aging process in altering pulsatile arterial function.

Effect of pravastatin on cardiovascular events in women after myocardial infarction: the Cholesterol and Recurrent Events (CARE) trial

OBJECTIVES We sought to determine the effect of pravastatin on recurrent cardiovascular events in women with average cholesterol levels after myocardial infarction (MI). BACKGROUND Little information is available on the effectiveness of lipid lowering in secondary prevention of coronary heart disease (CHD) in women; in particular, those with CHD and average cholesterol levels. METHODS In the Cholesterol and Recurrent Events (CARE) trial, 576 postmenopausal women, between 3 and 20 months after MI, with a total cholesterol level <240 mg/dl and a low density lipoprotein cholesterol level 115 to 174 mg/dl, were randomized to receive pravastatin 40 mg/day or matching placebo for a median follow-up period of 5 years. The main outcome measures were combined coronary events (coronary death, nonfatal MI, percutaneous transluminal coronary angioplasty [PTCA] or coronary artery bypass graft surgery [CABG]), the primary trial end point (coronary death or nonfatal MI) and stroke. RESULTS Women treated with pravastatin had a risk reduction of 43% for the primary end point (p = 0.035), 46% for combined coronary events (p = 0.001), 48% for PTCA (p = 0.025), 40% for CABG (p = 0.14) and 56% for stroke (p = 0.07). The 3,583 men in the CARE trial also showed a reduction in risk, but the magnitude tended to be less. Pravastatin improved plasma lipids similarly in men and women. There were no differences in risk of coronary events in the placebo group between men and women. Minor differences between men and women were present in baseline characteristics and treatment for MI, in general, conferring a higher risk status and a lower incidence of CABG in the women. CONCLUSIONS Pravastatin led to significant early reduction of a wide range of cardiovascular events in post-MI women with average cholesterol levels.

Metabolic Syndrome and Growth Hormone Deficiency in Adult Survivors of Childhood Acute Lymphoblastic Leukemia

The purpose of the study was to determine the prevalence of metabolic syndrome, growth hormone deficiency, and cardiovascular risk factors among adult survivors of childhood acute lymphoblastic leukemia (ALL) treated with or without cranial irradiation.

Reduced small artery but not large artery elasticity is an independent risk marker for cardiovascular events

BACKGROUND Atherosclerosis begins in the arterial wall, with endothelial dysfunction accompanied by functional and structural changes that influence arterial stiffness. Pulse contour analysis provides an assessment of compliance or elasticity of the large conduit arteries (C(1)) and small microcirculatory arteries (C(2)). In this study, the predictive value of reduced elasticity of these arteries was evaluated by follow-up of subjects who underwent pulse contour analysis at the University of Minnesota. METHODS Questionnaires were sent to 870 subjects who had radial artery pulse wave analysis performed between 1993 and 1999 using a noninvasive sensor, parameter estimating algorithm and modified Windkessel model of the circulation. Responses from 419 subjects >19 years of age reported on any cardiovascular events including death, myocardial infarction, stroke, transient ischemic attacks, angina, or coronary or peripheral vascular interventional procedures. RESULTS Of the subjects, 168 (41%) reported one or more cardiovascular events. Events were more common in those with elevated blood pressure, elevated cholesterol, diabetes, and family history of events. Age, reduced C(1), and reduced C(2) were univariate predictors of events. After adjusting for age, a 2-unit decrease in C(2) remained a significant predictor (odds ratio 1.50, P <.001), whereas C(1) was no longer predictive. CONCLUSION Reduced small artery elasticity, which is a measure of endothelial dysfunction, is significantly associated with cardiovascular events independent of age.

Intermittent transdermal nitroglycerin therapy in the treatment of chronic stable angina.

The effectiveness of an intermittent regimen of transdermal nitroglycerin in chronic stable angina was evaluated in 206 patients using serial treadmill testing. After a placebo stabilization phase, patients were randomized to 4 weeks of double-blind treatment with transdermal nitroglycerin, 10 or 20 cm2 (equivalent to 5 or 10 mg/24 h) (Group A); transdermal nitroglycerin, 30 or 40 cm2 (equivalent to 15 or 20 mg/24 h) (Group B), or placebo. Patches were applied at 8:00 AM and removed at 8:00 PM each day throughout the study. Treadmill testing was performed 0, 4, 8 and 12 h after patch application at baseline (day 0) and on days 1, 15 and 29. After short-term application of the transdermal patches, treadmill walking time was greater for patients in both Group A and Group B than for the placebo group at all time points tested; differences from placebo were statistically significant at 12 h for Group A and at 4, 8 and 12 h for Group B. After 2 and 4 weeks of long-term therapy, treadmill walking time was again greater for Group B than for the placebo group at all postapplication time points; differences from placebo reached statistical significance at 4 h (2 weeks) and 8 h (2 and 4 weeks). The improvement in the treadmill walking time seen over the short-term in Group A was largely lost after 4 weeks of long-term therapy. Potentially important differences in the patient characteristics of the two active treatment groups, particularly the greater use of a beta-adrenergic blocker among patients in Group A, may have contributed to these observed differences in treatment effect. An unexpected finding was the ability of the placebo group to exercise longer than either active treatment group just before patch application during long-term therapy; nonetheless, absolute responsiveness to transdermal nitroglycerin after patch application remained virtually unchanged in both active treatment groups during the 4 week treatment period. Intermittent transdermal nitroglycerin therapy was well tolerated in the vast majority of patients; nine patients experienced an increase in nonexertional angina during the patch-off periods but completed the study uneventfully.

Subsets of ambulatory myocardial ischemia based on heart rate activity. Circadian distribution and response to anti-ischemic medication. The Angina and Silent Ischemia Study Group (ASIS)

BACKGROUND Identification of whether episodes of ambulatory ischemia are caused by increases in myocardial oxygen demand or to episodic coronary vasoconstriction in patients with stable coronary disease may be important to guide selection of optimal anti-ischemic therapy and to gain insight into mechanisms responsible for adverse cardiac events. METHODS AND RESULTS Mean minute heart rate activity during ambulatory ECG (AECG) monitoring was determined for 50 patients treated with propranolol, diltiazem, nifedipine, or placebo in a randomized, double-blind, crossover trial. Periods of heart rate increases of various magnitudes and durations and starting at various baseline heart rates on each therapy were identified throughout each 48-hour AECG recording, and the proportion of these periods associated with an ischemic episode was determined. The circadian variation of ischemic episodes categorized by the presence or absence of an increase in heart rate was analyzed. Eighty-one percent of ischemic episodes were preceded by an increase in heart rate > or = 5 beats per minute. The likelihood of developing ischemia associated with a heart rate increase was proportional to the magnitude and duration of the heart rate increase and the baseline heart rate before the increases in heart rate: likelihood ranged from 4% when the heart rate increased 5-9 beats per minute and lasted < 10 minutes to 60% when the heart rate increased > or = 20 beats per minute and lasted > or = 40 minutes. The likelihoods of developing ischemia based on changes in the heart rate variables were similar for each of the therapies. Propranolol therapy significantly reduced the magnitude and duration of heart rate increase and the baseline heart rate compared with therapy with placebo, diltiazem, or nifedipine (P < .001). Ischemic episodes associated with a heart rate increase displayed a daytime peak, whereas ischemia occurring without a heart rate increase occurred evenly throughout the day. Propranolol reduced the proportion of heart rate-related ischemic episodes and increased the proportion of non-heart rate-related episodes compared with placebo (P < .02), and nifedipine exerted the opposite effect (P = .005). Multivariate analysis indicated that the probability of developing ischemia was strongly associated with heart rate variables and was unaffected by time of day. CONCLUSIONS Most episodes of ambulatory ischemia are associated with a preceding period of increased heart rate. The likelihood of developing ischemia is predicted by heart rate variables and unaffected by time of day. Anti-ischemic efficacy is generally a result of the medications efficacy in reducing heart rate variables. A minority of ischemic episodes are not associated with preceding periods of increased heart rate, may be caused by episodic coronary vasoconstriction, and are more effectively reduced by nifedipine than propranolol.

Association of Race and Sex With Risk of Incident Acute Coronary Heart Disease Events

CONTEXT It is unknown whether long-standing disparities in incidence of coronary heart disease (CHD) among US blacks and whites persist. OBJECTIVE To examine incident CHD by black and white race and by sex. DESIGN, SETTING, AND PARTICIPANTS Prospective cohort study of 24,443 participants without CHD at baseline from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort, who resided in the continental United States and were enrolled between 2003 and 2007 with follow-up through December 31, 2009. MAIN OUTCOME MEASURE Expert-adjudicated total (fatal and nonfatal) CHD, fatal CHD, and nonfatal CHD (definite or probable myocardial infarction [MI]; very small non-ST-elevation MI [NSTEMI] had peak troponin level <0.5 μg/L). RESULTS Over a mean (SD) of 4.2 (1.5) years of follow-up, 659 incident CHD events occurred (153 in black men, 138 in black women, 254 in white men, and 114 in white women). Among men, the age-standardized incidence rate per 1000 person-years for total CHD was 9.0 (95% CI, 7.5-10.8) for blacks vs 8.1 (95% CI, 6.9-9.4) for whites; fatal CHD: 4.0 (95% CI, 2.9-5.3) vs 1.9 (95% CI, 1.4-2.6), respectively; and nonfatal CHD: 4.9 (95% CI, 3.8-6.2) vs 6.2 (95% CI, 5.2-7.4). Among women, the age-standardized incidence rate per 1000 person-years for total CHD was 5.0 (95% CI, 4.2-6.1) for blacks vs 3.4 (95% CI, 2.8-4.2) for whites; fatal CHD: 2.0 (95% CI, 1.5-2.7) vs 1.0 (95% CI, 0.7-1.5), respectively; and nonfatal CHD: 2.8 (95% CI, 2.2-3.7) vs 2.2 (95% CI, 1.7-2.9). Age- and region-adjusted hazard ratios for fatal CHD among blacks vs whites was near 2.0 for both men and women and became statistically nonsignificant after multivariable adjustment. The multivariable-adjusted hazard ratio for incident nonfatal CHD for blacks vs whites was 0.68 (95% CI, 0.51-0.91) for men and 0.81 (95% CI, 0.58-1.15) for women. Of the 444 nonfatal CHD events, 139 participants (31.3%) had very small NSTEMIs. CONCLUSIONS The higher risk of fatal CHD among blacks compared with whites was associated with cardiovascular disease risk factor burden. These relationships may differ by sex.

Comparison of propranolol, diltiazem, and nifedipine in the treatment of ambulatory ischemia in patients with stable angina. Differential effects on ambulatory ischemia, exercise performance, and anginal symptoms. The ASIS Study Group.

Episodes of transient myocardial ischemia during ambulatory activities are common in patients with stable coronary artery disease and who are often asymptomatic. Selection of therapy for episodes of asymptomatic ischemia is limited by a lack of direct comparative studies. To determine the most effective monotherapy for patients with stable angina and a high frequency of asymptomatic ischemic episodes, propranolol-LA (mean daily dose, 293 mg), diltiazem-SR (mean daily dose, 350 mg), nifedipine (mean daily dose, 79 mg) were each compared with placebo, each for 2 weeks, in a randomized, double-blinded, crossover trial. Entry criteria were a positive exercise treadmill test during placebo therapy characterized by 1.0 mm or more ST segment depression and angina pectoris, and six or more episodes of transient ST segment depression of 1.0 mm or more on a 48-hour ambulatory electrocardiogram. One hundred ninety-four patients were screened, 63 were eligible and received randomized therapy, of which 56 patients completed at least two of the four treatment periods and were included in an intent-to-treat analysis. Fifty patients completed all four treatment phases and were included in the protocol-completed analysis. Anti-ischemia efficacy was assessed by 48-hour ambulatory electrocardiographic monitoring, exercise treadmill tests, and anginal diaries. Ninety-four percent of all episodes of ambulatory ischemia were asymptomatic. Compared with placebo, only propranolol was associated with a marked reduction in all manifestations of asymptomatic ischemia during ambulatory electrocardiographic monitoring (2.3 versus 1.0 episodes/24 hr; mean duration of ischemia per 24 hours, 43.6 versus 5.7 minutes; both p less than 0.0001). Diltiazems reduction of the frequency of episodes compared with placebo (2.3 versus 1.9 episodes/24 hr) was associated with a trend (p = 0.08) in the protocol-completed analysis and with a significant reduction in the intent-to-treat analysis (p = 0.03). Nifedipine had no significant effect on any measured variable of ambulatory ischemia. The dosages of medication used may have been excessive for some patients, and a more beneficial effect may have been evident at a lower dose. In contrast to the marked effects of the active agents on ambulatory asymptomatic ischemia, the effects on exercise performance and angina pectoris were slight. The active agents modestly improved treadmill exercise duration time until 1 mm ST segment depression (3%), and only propranolol and diltiazem had significant effects. Only diltiazem significantly prolonged the total exercise time. Anginal frequency was significantly decreased by both propranolol and diltiazem.(ABSTRACT TRUNCATED AT 400 WORDS)

The effect of vardenafil, a potent and highly selective phosphodiesterase-5 inhibitor for the treatment of erectile dysfunction, on the cardiovascular response to exercise in patients with coronary artery disease☆

OBJECTIVES The effect of vardenafil, a potent and highly selective phosphodiesterase-5 (PDE5) inhibitor, on symptom-limited exercise time, time to first awareness of angina, and time to ischemic threshold (ST-segment depression > or =1 mm from baseline) during exercise tolerance testing (ETT) was examined in patients with stable coronary artery disease (CAD). BACKGROUND Erectile dysfunction (ED) is common among men with CAD. PDE5 inhibition is increasingly the preferred treatment option for ED. However, the effect of PDE5 inhibition on exercise-induced ischemia in CAD patients has received limited prospective evaluation. METHODS In this double-blind, crossover, single-dose multicenter study, 41 men with reproducible stable exertional angina due to ischemic CAD received vardenafil 10 mg or placebo, followed by ETT (5 to 10 metabolic equivalents [METS], Bruce protocol) 1 h postdose. Sublingual nitrate use was prohibited for > or =24 h pre- and postexercise study days. End points included symptom-limited treadmill exercise time, time to first awareness of angina, time to ischemic threshold, and safety. RESULTS Relative to placebo, vardenafil 10 mg did not alter exercise treadmill time (427 +/- 105 s vs. 433 +/- 109 s, p = 0.39), or time to first awareness of angina (292 +/- 110 s vs. 291 +/- 123 s, p = 0.59), but significantly prolonged time to ischemic threshold (334 +/- 108 s vs. 381 +/- 108, p = 0.0004). At peak exercise, vardenafil 10 mg did not alter blood pressure, heart rate, or rate-pressure product relative to placebo. The most common adverse events (facial flushing and headache) were of mild or moderate intensity, and short-lived. CONCLUSIONS Vardenafil 10 mg did not impair the ability of patients with stable CAD to exercise at levels equivalent or greater than that attained during sexual intercourse (average of 2.5 to 3.3 METS).