Faculty Bibliography

BACKGROUND: Combined inhibition of the angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP) may produce greater benefits in heart failure than ACE inhibition alone. METHODS AND RESULTS: We randomly assigned 5770 patients with New York Heart Association class II to IV heart failure to double-blind treatment with either the ACE inhibitor enalapril (10 mg BID, n=2884) or to the ACE-NEP inhibitor omapatrilat (40 mg once daily, n=2886) for a mean of 14.5 months. The primary end point-the combined risk of death or hospitalization for heart failure requiring intravenous treatment--was used prospectively to test both a superiority and noninferiority hypothesis (based on the effect of enalapril in the Studies of Left Ventricular Dysfunction [SOLVD] Treatment Trial). A primary end point was achieved in 973 patients in the enalapril group and in 914 patients in the omapatrilat group (hazard ratio 0.94; 95% CI: 0.86 to 1.03, P=0.187)--a result that fulfilled prespecified criteria for noninferiority but not for superiority. The omapatrilat group also had a 9% lower risk of cardiovascular death or hospitalization (P=0.024) and a 6% lower risk of death (P=0.339). Post hoc analysis of the primary end point with the definition used in the SOLVD Treatment Trial (which included all hospitalizations for heart failure) showed an 11% lower risk in patients treated with omapatrilat (nominal P=0.012). CONCLUSION: Omapatrilat reduces the risk of death and hospitalization in chronic heart failure but was not more effective than ACE inhibition alone in reducing the risk of a primary clinical event. Between-group differences in favor of omapatrilat observed in secondary and post hoc analyses warrant further study

The INternational VErapamil SR/trandolapril STudy (INVEST) is the first long-term, large-scale clinical trial being conducted primarily using Web-based technology. The Web is a powerful tool for enhancing clinical trial management because of its ability to centralize all study information and coordinate multiple trial processes in real time at lower cost. The result is improved efficiency, accuracy, and safety in clinical trials conduct. In Web-based clinical trials, sites are able to focus primarily on medicine and science, rather than on trial administration. Site training, study documentation, subject recruitment, randomization, medication dispensing, and management procedures are simplified by using Web-based software to enhance processes. This paper summarizes the advantages achieved for INVEST investigators, sponsor representatives, monitors, and subjects resulting from the centralization and coordination of multiple tasks through Web-based technology

CONTEXT: Plasma levels of the inflammatory biomarker C-reactive protein (CRP) predict cardiovascular risk, and retrospective studies suggest that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) may lower CRP in a manner largely independent of low-density lipoprotein cholesterol (LDL-C). However, prospective trial data directly evaluating this anti-inflammatory effect of statins are not available. OBJECTIVE: To test the hypothesis that pravastatin has anti-inflammatory effects as evidenced by CRP reduction. DESIGN, SETTING, AND PARTICIPANTS: Community-based, prospective, randomized, double-blind trial including 1702 men and women with no prior history of cardiovascular disease (primary prevention cohort) and open-label study including 1182 patients with known cardiovascular disease (secondary prevention cohort) who provided at least baseline and 12-week blood samples. The study was conducted in US office-based practices from February to December 2000. INTERVENTIONS: Participants in the double-blind primary prevention trial were randomly assigned to receive 40 mg/d of pravastatin (n = 865) or placebo (n = 837) for 24 weeks. Participants in the secondary prevention cohort received 40 mg/d of open-label pravastatin for 24 weeks. MAIN OUTCOME MEASURE: Change in CRP levels from baseline to 24 weeks. RESULTS: In the primary prevention trial, compared with placebo, pravastatin reduced median CRP levels by 16.9% (P<.001) at 24 weeks, reflecting a decrease of 0.02 mg/dL in the pravastatin group while no change in CRP levels was observed in the placebo group. This effect was seen as early as 12 weeks (median reduction in CRP with pravastatin, 14.7%; P<.001) and was present among all prespecified subgroups according to sex, age, smoking status, body mass index, baseline lipid levels, presence of diabetes, and use of aspirin or hormone replacement therapy. No significant association was observed between baseline CRP and baseline LDL-C levels, end-of-study CRP and end-of-study LDL-C levels, or change in CRP and change in LDL-C levels over time. In linear regression analyses, the only significant predictors of change in CRP on a log scale were randomized pravastatin allocation and baseline CRP levels (P<.001 for both). Similar reductions in CRP levels were observed at 12 weeks (-14.3%) and 24 weeks (-13.1%) in the secondary prevention cohort treated with pravastatin (P<.005 for both). CONCLUSIONS: In this prospective trial, pravastatin reduced CRP levels at both 12 and 24 weeks in a largely LDL-C-independent manner. These data provide evidence that statins may have anti-inflammatory effects in addition to lipid-lowering effects

BACKGROUND: Randomized, controlled trials demonstrate that HMG CoA reductase inhibition reduces coronary event rates in both primary and secondary prevention. In addition to reducing cholesterol levels, laboratory evidence suggests that statins also have anti-inflammatory activity, a property that may be critical for maintaining plaque stability. Recently, the inflammatory marker high-sensitivity C-reactive protein (hs-CRP) has been shown to predict vascular risk in individuals with and without hyperlipidemia. Furthermore, in the Cholesterol and Recurrent Events (CARE) trial, the relative efficacy of pravastatin in reducing events was greatest among those with elevated levels of hs-CRP. However, the time course and magnitude of this effect in both primary and secondary prevention is controversial. METHODS: PRavastatin Inflammation CRP Evaluation (PRINCE) is an investigator-initiated, multicenter, community-based trial that will evaluate the effects of pravastatin on hs-CRP in up to 1182 individuals with coronary artery disease and up to 1702 individuals without coronary artery disease. Lipid profiles and hs-CRP levels will be obtained at baseline, 12 weeks, and 24 weeks in all study participants. Patients with known coronary artery disease will receive 40 mg/d pravastatin, whereas those without coronary artery disease will be randomly assigned to receive placebo or 40 mg/d pravastatin. CONCLUSIONS: The potential clinical impact of the PRINCE trial is substantial because nearly 50% of myocardial infarctions in the United States occur in persons with normal cholesterol levels, and inflammatory markers such as hs-CRP may provide a means to detect such individuals at high risk who do not currently qualify for statin therapy. The PRINCE trial will determine the time course of effect of this statin on hs-CRP and whether any observed effect on hs-CRP is independent of pravastatin-induced changes in low-density lipoprotein cholesterol

OBJECTIVE: To determine the relative efficacy and safety of cerivastatin and pravastatin in patients with type II hypercholesterolemia. PATIENTS AND METHODS: In this prospective, double-blind, parallel-group study, hypercholesterolemic patients were randomized to treatment with cerivastatin, 0.3 mg (n=250) or 0.4 mg (n=258), or pravastatin, 20 mg (n=266) or 40 mg (n=256), for 8 weeks. RESULTS: Cerivastatin, 0.3 mg, was significantly more effective than pravastatin, 20 mg, in reducing low-density lipoprotein (LDL) cholesterol from baseline (-29.6% vs -26.8%; P=.008). Cerivastatin, 0.4 mg, was significantly more effective than pravastatin, 40 mg, in reducing LDL cholesterol (-34.2% vs -30.3%; P<.001). A larger proportion of cerivastatin-treated patients had greater than 40% reductions in LDL cholesterol than those receiving pravastatin (11.1% vs 6.0%). The percentage of patients who achieved the National Cholesterol Education Program (NCEP) target was 71.3% with cerivastatin, 0.3 mg, compared with 67.5% with pravastatin, 20 mg, and 74.0% with cerivastatin, 0.4 mg, compared with 71.1% with pravastatin, 40 mg (no significant difference). Cerivastatin, 0.3 mg, reduced total cholesterol to a greater extent than did pravastatin, 20 mg (P<.03). Both agents reduced triglycerides and increased high-density lipoprotein cholesterol to a similar degree (no significant differences). Cerivastatin and pravastatin were well tolerated. CONCLUSIONS: Cerivastatin, 0.3 mg and 0.4 mg, showed greater efficacy than pravastatin, 20 mg and 40 mg, respectively, in lowering LDL cholesterol. Cerivastatin is safe and effective for patients with hypercholesterolemia who require aggressive LDL cholesterol lowering to achieve NCEP-recommended targets

OBJECTIVES: Our objective was to test fractal dimension (D), a measure of clustering of ventricular premature complexes (VPCs), on entry Holter recording as a predictor of future arrhythmic death and other-cause mortality in postinfarction patients in the Cardiac Arrhythmic Suppression Trial (CAST). BACKGROUND: Nonlinear dynamic methods of signal processing are being applied in medicine to provide new insights into apparently 'chaotic' biologic events, including cardiac arrhythmias. One such application is the derivation of a fractal D to describe the clustering of VPCs in time. METHODS: Baseline Holter recordings were analyzed in blinded manner for 484 patients: 237 died or had a resuscitated cardiac arrest during follow-up, and 247 matched patients had no events. Fractal D, measured in four ways, was assessed as a predictor using Cox regression. RESULTS: One measure of D (high resolution D) was a significant univariate (relative hazard ratio 0.79 per SD change, p = 0.011) and multivariate (hazard ratio 0.75, p = 0.046) predictor of arrhythmic death but not other death (univariate p = 0.95, relative hazard 0.95, p = 0.66). Fractal D was greater (VPCs less clustered) in those patients free of arrhythmic events. On subgroup analysis, the predictive value of D resided in the randomized patient group (i.e., those who showed VPC suppression during initial antiarrhythmic drug titration and were randomized to blinded therapy with active drug or placebo) (multivariate hazard ratio 0.57, p = 0.001). CONCLUSIONS: A high resolution fractal D was predictive of arrhythmic (but not nonarrhythmic) death in a large postinfarction cohort. Further study of this new signal processing approach to ambulatory electrocardiographic recording will be of interest

Heart disease is the leading cause of death among women in the United States. The prognosis for heart disease is worse for women than for men. Also, although women are less likely than men to initially present with a myocardial infarction (MI), they are more likely to die following an MI. A number of factors have been identified that partially account for the gender difference in post-MI morbidity and mortality. However, limited data are available on the sex differences in clinical, psychosocial, and demographic factors that may combine to explain the poorer prognosis for women following an acute MI. The Cardiac Arrhythmia Suppression Trials collected detailed demographic, clinical, and psychosocial data on 2,043 men and 448 women following acute MIs. Analyses indicate that women had a worse clinical, socioeconomic, and psychosocial profile than did men. In addition, significant differences in psychosocial profiles persisted after controlling for demographic and clinical data, suggesting that women presenting with MIs have a cluster of complex factors that put them at high risk for morbidity and mortality following an MI. Future longitudinal studies that include adequate numbers of women as well as reliable assessments of both clinical and psychological variables are needed to better understand the factors that influence the poor prognosis for women with coronary heart disease

The onset of acute myocardial infarction (AMI) has been shown to occur in a reproducible pattern with a peak in mid-morning and a secondary peak in late afternoon and early evening. More detailed information on the timing of this catastrophic event may provide important pathophysiologic information. Using the database from the Holter Registry of the Cardiac Arrhythmia Suppression Trial (CAST) (n = 22,516), the day of the week, the month, and season of the onset of AMI was obtained and correlated with demographic characteristics. The pattern of the day of onset for the entire population was significantly nonuniform (p <0.0001) with a Monday peak and a weekend nadir. This pattern was observed in most of the examined subgroups. Analysis of seasonal data revealed nonuniform distribution (p <0.001) with a peak in winter and autumn. We conclude that AMI is not a random event but occurs in definite patterns related to the day of the week and the season of the year. These patterns were observed in a wide variety of patient subgroups and appear related to climate, occupation, and other factors

The relation between the circadian occurrence of ventricular premature depolarizations (VPD) and sudden arrhythmic death was examined in a subset of patients entered into the Cardiac Arrhythmia Suppression Trial (CAST). Ambulatory electrocardiographic recordings with hourly measurement of VPD frequency were available in 357 patients. Forty percent of the patients (142 of 357) demonstrated circadian variation in VPD frequency between 6:00 A.M. and 9:59 A.M. that was significantly higher (p < 0.05) than what could randomly be expected from an overall 24-hour average for that patient. The only baseline characteristics in patients with circadian VPDs were age (p < 0.04), history of cardiac arrest (p < 0.01), presence of higher frequency of VPDs (p < 0.002), more frequent episodes of ventricular tachycardia (p < 0.04), and more frequent episodes of slow runs (p < 0.04). There was no difference in mortality in patients with or without circadian VPD variation; drug treatment did not effect mortality. These data indicate that the presence of circadian VPDs is not a predictor of sudden arrhythmic death in patients with a high frequency of VPDs