David J. Frid

Effect of Amlodipine on Morbidity and Mortality in Severe Chronic Heart Failure

BACKGROUND Previous studies have shown that calcium-channel blockers increase morbidity and mortality in patients with chronic heart failure. We studied the effect of a new calcium-channel blocker, amlodipine, in patients with severe chronic heart failure. METHODS We randomly assigned 1153 patients with severe chronic heart failure and ejection fractions of less than 30 percent to double-blind treatment with either placebo (582 patients) or amlodipine (571 patients) for 6 to 33 months, while their usual therapy was continued. The randomization was stratified on the basis of whether patients had ischemic or nonischemic causes of heart failure. The primary end point of the study was death from any cause and hospitalization for major cardiovascular events. RESULTS Primary end points were reached in 42 percent of the placebo group and 39 percent of the amlodipine group, representing a 9 percent reduction in the combined risk of fatal and nonfatal events with amlodipine (95 percent confidence interval, 24 percent reduction to 10 percent increase; P=0.31). A total of 38 percent of the patients in the placebo group died, as compared with 33 percent of those in the amlodipine group, representing a 16 percent reduction in the risk of death with amlodipine (95 percent confidence interval, 31 percent reduction to 2 percent increase; P=0.07). Among patients with ischemic heart disease, there was no difference between the amlodipine and placebo groups in the occurrence of either end point. In contrast, among patients with nonischemic cardiomyopathy, amlodipine reduced the combined risk of fatal and nonfatal events by 31 percent (P=0.04) and decreased the risk of death by 46 percent (P<0.001). CONCLUSIONS Amlodipine did not increase cardiovascular morbidity or mortality in patients with severe heart failure. The possibility that amlodipine prolongs survival in patients with nonischemic dilated cardiomyopathy requires further study.

Restenosis after coronary angioplasty: An overview☆

Despite substantial basic and clinical efforts to address the problem of restenosis after percutaneous coronary intervention, effective preventive therapies have not yet been developed. Nevertheless, the accumulated information has provided much insight into the process of restenosis in addition to allowing standards to be developed for adequate clinical trials. The pathophysiology of restenosis increasingly appears to be distinct from that of primary atherosclerosis. Restenosis involves elastic recoil, incorporation of thrombus into the lesion and fibrocellular proliferation in varying degrees in different patients. Lack of an animal model that satisfactorily mimics restenosis is a major impediment to further understanding of the process. Clinical studies are hampered by difficulties in finding a single unifying definition of restenosis and by variable methods of reporting follow-up. Reporting of clinical outcomes of all patients in angiographic substudies would allow a more satisfactory interpretation of the results of clinical trials. Current noninvasive test results are not accurate enough to substitute for angiographic and clinical outcome data in intervention trials. In the majority of observational studies, only diabetes and unstable angina have emerged as consistently associated with restenosis; whereas most of the standard risk factors for atherosclerosis have a less consistent relation. Disappointingly, the new atherectomy and laser technologies have not affected restenosis rates. The one possible exception is coronary stenting, as a result of the larger luminal diameter achieved by the placement of the stent. In conclusion, although substantial continued effort is necessary to explore the basic aspects of cellular proliferation and mechanical alteration of atherosclerotic vessels, attention to the principles of clinical trials and observation are required to detect the impact of risk factors and interventions on the multifactorial problem of restenosis. Adequate sample sizes, collection of clinical and angiographic outcomes and factorial study designs hold promise for unraveling this important limitation of percutaneous intervention.

Psychological predictors of adherence and outcomes among patients in cardiac rehabilitation.

PURPOSE The purpose of this study was to evaluate the effects of optimism, depression, and neuroticism on adherence and outcomes among patients in cardiac rehabilitation (CR). METHODS Participants included 46 patients (34 men) with coronary heart disease (CHD) who completed measures of psychological functioning (optimism, depression, neuroticism), physical functioning (exercise stress test, body mass index, symptom reports), and CHD knowledge during the first week (baseline) and last week of a 12-week CR program. RESULTS Baseline depression scores accounted for 9.5% of the variance associated with change in aerobic capacity (maximum oxygen consumption), when controlling for relevant demographic variables and program attendance. However, optimism and neuroticism were not predictive of CR outcomes. Results also indicated that program dropouts were significantly younger and reported more psychological distress at baseline than did participants who completed the program. CONCLUSION Depression appears to have a significant influence on adherence and improvement among patients in CR, but optimism and neuroticism were not significant predictors of change.

Mental Stress–Induced Ischemia in the Laboratory and Ambulatory Ischemia During Daily Life Association and Hemodynamic Features

BACKGROUND The purpose of this study was to determine the correspondence of mental stress-induced ischemia in the laboratory with ambulatory ischemia and to assess the relationship between hemodynamic responses to mental stress and the occurrence of ischemia. Although exercise testing is usually used to elicit myocardial ischemia, ischemia during daily life usually occurs at relatively low heart rates and in the absence of strenuous physical exercise. Mental stress has been shown to trigger ischemic events in the laboratory at lower heart rates but at blood pressures comparable to exercise. We therefore compared the extent to which mental stress and exercise testing identify patients who develop ischemia out of hospital. METHODS AND RESULTS One hundred thirty-two patients with documented coronary disease and recent evidence of exercise-induced myocardial ischemia underwent 48-hour ambulatory monitoring and radionuclide ventriculography during exercise and mental stress testing. Patients who displayed mental stress-induced ischemia in the laboratory were more likely to exhibit ischemia during daily life (P < .021). Furthermore, patients who exhibited ischemia during ambulatory monitoring displayed larger diastolic blood pressure (P < .006), heart rate (P < .039), and rate-pressure product responses (P < .018) during mental stress. CONCLUSIONS Among patients with prior positive exercise stress tests, mental stress-induced ischemia, defined by new wall motion abnormalities, predicts daily ischemia independent of exercise-induced ischemia. Exaggerated hemodynamic responses during mental stress testing also identify individuals who are more likely to exhibit myocardial ischemia during daily life and mental stress.

Gender differences in quality of life among cardiac patients.

Objective Prior studies of quality of life among cardiac patients have examined mostly men. This study evaluated gender differences in quality of life and examined the degree to which social support was associated with quality of life. Methods A sample of 536 patients (35% women) was recruited during a 14-month period from the inpatient cardiology service of a University-based hospital. Participants completed assessments at baseline and at 3-month intervals over the subsequent 12 months, for a total of 5 assessments. Measures at each assessment included quality of life [Mental Component Score (MCS) and Physical Component Score (PCS) from the Medical Outcomes Study—Short Form 36] and social support [Interpersonal Support Evaluation List—Short Form]. Results A total of 410 patients completed the baseline assessment and at least one follow-up, and were included in the data analyses. Linear mixed effects modeling of the MCS score revealed a significant effect of gender (p = .028) and time (p < .001), as well as a significant interaction of gender by social support (p = .009). Modeling of the PCS revealed a significant effect of gender (p = .010) and time (p < .001). Conclusions Women with cardiac disease indicated significantly lower quality of life than men with cardiac disease over the course of a 12-month longitudinal follow-up. Social support, especially a sense of belonging or companionship, was significantly associated with emotional quality of life (MCS) among women. Strategies to increase social support may be important for health and well-being of women with cardiac disease.

Effect of amlodipine on mode of death among patients with advanced heart failure in the praise trial

Investigations of calcium antagonists in patients with advanced heart failure have raised concern over an increased risk of worsening heart failure and heart failure deaths. We assessed the effect of amlodipine on cause-specific mortality in such patients enrolled in a randomized, double-blind, placebo-controlled trial. In total, 1,153 patients in New York Heart Association class IIIb or IV heart failure were randomized to receive amlodipine or placebo, along with angiotensin-converting enzyme inhibitors, diuretics, and digitalis. Over a median 14.5 months of follow-up, 413 patients died. Cardiovascular deaths accounted for 89% of fatalities, 50% of which were sudden deaths and 45% of which were due to pump failure, with fewer attributed to myocardial infarction (3.3%) or other cardiovascular causes (1.6%). Amlodipine treatment resulted in a greater relative reduction in sudden deaths (21%) than in pump failure deaths (6.6%) overall. When patients were classified by etiology of heart failure (ischemic or nonischemic), cause-specific mortality did not differ significantly between treatment groups in the ischemic stratum. In the nonischemic stratum, however, sudden deaths and pump failure deaths were reduced by 38% and 45%, respectively, with amlodipine. Thus, when added to digitalis, diuretics, and angiotensin-converting enzyme inhibitors in patients with advanced heart failure, amlodipine appears to have no effect on cause-specific mortality in ischemic cardiomyopathy, but both pump failure and sudden deaths appear to be decreased in nonischemic heart failure patients treated with amlodipine.

Circadian rhythm and sudden death in heart failure: results from Prospective Randomized Amlodipine Survival Trial.

OBJECTIVE The purpose of this study was to address the timing of sudden death in advanced heart failure patients. BACKGROUND Sudden death is a catastrophic event in cardiovascular disease. It has a circadian pattern prominent in the early AM, which has been thought to be due to a surge of sympathetic stimulation. We postulated that the distribution of events in advanced heart failure, with chronic sympathetic activation, would be more uniform implicating other potential mechanisms. METHODS We analyzed data from Prospective Randomized Amlodipine Survival Trial (PRAISE). Sudden deaths were analyzed by time of death in 4-h and 1-h blocks for uniformity of distribution in the entire cohort, and in the prespecified ischemic and nonischemic stratum. Further analyses were undertaken in the treatment groups of amlodipine and placebo, and among those receiving background therapy of aspirin and warfarin. RESULTS Sudden deaths in the overall cohort showed a nonuniform distribution with a PM peak but not an AM peak. The ischemic stratum also showed a PM peak, but sudden deaths within the nonischemic stratum were uniformly distributed. Neither amlodipine treatment nor aspirin or warfarin use altered the distribution. CONCLUSIONS Sudden death in advanced heart failure did not show an AM peak, suggesting that circadian sympathetic activation did not strongly influence these events. The PM peak noted is likely complex in origin and was not affected by antiischemic or antithrombotic medications.

Short-term effects of exercise and music on cognitive performance among participants in a cardiac rehabilitation program.

OBJECTIVE Exercise has been associated with improved cognitive performance among patients with coronary artery disease. Music listening has been associated with enhanced cognitive functioning among healthy adults. This study evaluated the combined influence of exercise and music listening on cognitive performance among patients in cardiac rehabilitation (CR). DESIGN AND SETTING Using a within-subjects repeated measures design, this study was conducted in an outpatient University-based CR facility. SAMPLE Thirty-three men and women (mean age = 62.6 +/- 10.5 years) participated in this study. METHODS Participants completed 1 exercise session accompanied by music and a second exercise session without music. Order of conditions was assigned randomly. Before and after each exercise session, participants completed a brief assessment of depression and anxiety, and a cognitive test of verbal fluency. RESULTS The music condition was associated with significant improvements in verbal fluency, but the no-music control condition was not associated with cognitive change. CONCLUSION The study provides preliminary evidence of the combined benefit of exercise and music listening for cognitive performance among patients in CR.

Relation of cardiovascular responses to mental stress and cardiac vagal activity in coronary artery disease

Forty-six patients with documented coronary artery disease were studied to examine the relation of cardiovascular reactivity to mental stress and cardiac vagal activity. Cardiac vagal activity was measured by means of frequency-domain analysis of heart rate variability with 48-hour out-of-hospital Holter monitoring. The amplitude of the high-frequency component (0.16 to 0.40 Hz) of heart rate variability is considered to be an index of cardiac vagal activity. Cardiovascular reactivity was measured in the laboratory during a 3-minute public speaking task. Results revealed that (1) the amplitude of the high-frequency component was significantly higher during sleep (24.6 +/- 11.3 ms) than during waking (18.2 +/- 8.0 ms) (p = 0.002); (2) compared to subjects with low diastolic blood pressure reactivity, those who displayed high diastolic blood pressure reactivity exhibited a significantly lower amplitude of the high-frequency component (19.2 +/- 6.9 vs 23.4 +/- 9.6 ms, p = 0.03). These results indicate that decreased cardiac vagal activity may contribute to the exaggerated diastolic blood pressure reactivity to mental stress in patients with coronary artery disease.

Initial functional and economic status of patients with multivessel coronary artery disease randomized in the Bypass angioplasty revascularization investigation (BARI)

Randomized trials of coronary angioplasty and bypass surgery have hypothesized that these procedures will have equivalent long-term rates of death and myocardial infarction. Functional status, quality of life, employment, and healthcare cost will therefore be critical measures of the efficacy of these alternative revascularization procedures. Patients at 7 sites in the Bypass Angioplasty Revascularization Investigation (BARI) were enrolled in an ancillary Study of Economics and Quality of Life (SEQOL). Physical function was assessed by the Duke Activity Status Index and emotional status by the Mental Health Inventory. Employment patterns and health care utilization were also measured at study entry and at 3-month intervals in follow-up. The 934 patients enrolled in SEQOL were similar to the 895 remaining BARI randomized patients. Most patients (63%) aged < or = 64 years were working, and almost all working patients (96%) intended to return to work. Patients aged > or = 65 years had lower household incomes but better health insurance coverage. Overall health ratings were significantly correlated with both physical and emotional status (p < 0.001). Patients enrolled in SEQOL are representative of the overall BARI population. Data collected in SEQOL will provide a detailed picture of the physical, emotional, and economic well-being after coronary angioplasty and bypass surgery.