Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Large simple trials (LSTs) emerged in response to the need for large sample sizes to answer important clinical questions in which treatments have a moderate effect on clinical endpoints. Between 1991 and 1996 the National Heart, Lung, and Blood Institute and the Department of Veterans Affairs (VA) Cooperative Studies Program conducted an LST entitled "Digitalis Investigation Group (DIG): Trial to Evaluate the Effect of Digitalis on Mortality in Heart Failure." The VA Cooperative Studies Program Clinical Research Pharmacy Coordinating Center served as the DIG pharmacy coordinating center (PCC). As a direct result of involvement in the DIG trial, the PCC identified the need for an increased emphasis on computerization and automated support of clinical trials, especially LSTs.
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PMID:The role of the pharmacy coordinating center in the DIG trial. 1464 75

Before any clinical trial can begin to recruit patients, participating clinical centers must obtain approval from their institutional review board (IRB). When studies are federally funded, such as by the U.S. Department of Health and Human Services (DHHS), centers must also have or obtain a federal compliance agreement from the Office of Human Research Protections (formerly the Office for Protection from Research Risks [OPRR]). The Digitalis Investigation Group trial was a large, international, double-blind, DHHS-funded randomized trial on the effect of digoxin on mortality in heart failure. Due to the anticipated number of centers (>200), the study's data coordinating center (DCC) was requested to assume additional responsibilities that included: (1) acting as a liaison between the OPRR and all study centers; (2) reviewing and correcting all assurance statements before submission to the OPRR; (3) reviewing and approving all centers' informed consent forms; and (4) helping the many research-inexperienced centers to establish IRBs or to locate an IRB in their region that would accept IRB responsibility for them. Although a heavy burden was placed on the DCC, the IRB and OPRR approval process was probably shortened by many weeks at those centers not already possessing a federal compliance agreement. This enabled the study to be completed on schedule and within budget.
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PMID:The role of the data coordinating center in the IRB review and approval process: the DIG trial experience. 1464 77

The Digitalis Investigation Group (DIG) trial was a randomized, double-blind placebo-controlled trial whose primary objective was to determine whether digoxin had beneficial, harmful, or no effect on total mortality in patients with heart failure who were in sinus rhythm and whose ejection fraction was </=0.45. The study was designed as a large simple trial with a large number of centers (302) in the United States and Canada, many of which were inexperienced in research. To ensure that the results of the trial would be reported accurately without possible bias due to missing data, the study leadership decided that no outcome results would be reported until the vital status at the end of the study was known for at least 97% of the study participants. Planning for closeout of the study began a year prior to the common end date of December 31, 1995 and included plans for obtaining vital status on December 31, 1995. Participants were given postcards at their final study visit to be completed and mailed on or after January 1, 1996. Of 5602 postcards distributed, 5070 (90.5%) were completed and returned. A contract search agency was hired to locate the remaining participants. Of the total 7788 participants entered into the DIG trial, only 97 participants (1.2%) could not have their vital status as of December 31, 1995 determined. It is recommended that investigators having an outcome measure with a common end date include plans in their protocols for obtaining their measures and activate those plans as early as possible during the course of the study.
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PMID:Determination of vital status at the end of the DIG trial. 1466 78

Hypertension is not an isolated problem. Co-morbidities of smoking, obesity, diabetes and dyslipidemia are all associated with microvascular disease (MVD) with abnormal PET scan and endothelial dysfunction. MVD may contribute to left ventricular hypertrophy (LVH) via an imbalance between hyperplasia and apoptotic signals. Digitalis and other anti-hypertensive agents have anti-apoptotic action and MVD blunting effects, respectively. Heart failure progression must then be based on the preservation of myocyte integrity. Indeed, altered contractility appears to be a consequence of rather than the cause of myocyte deterioration. LV systolic dysfunction improvement is already a late strategy. Furthermore, the efficacy of anti-hypertension therapy may be limited in restoring LV diastolic function. Recognition of the role of apoptosis and MVD may initiate a paradigm shift in clinical practice.
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PMID:Microvascular disease relevance in the hypertension syndrome. 1472 54

Risk factors of cardiovascular disease, such as hypertension, diabetes, and myocardial infarction, if left untreated, will increase the risk of the development of chronic heart failure. Much is known about the pathophysiology and effective treatments of chronic heart failure from left ventricular systolic dysfunction; however, little clinical trial evidence exists concerning benefits of treating patients with chronic heart failure and preserved systolic function, also known as left ventricular diastolic dysfunction. Rather, an understanding of the pathophysiology and patient signs and symptoms has usually dictated choice of treatments. With the results of ongoing trials, as well as the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM)-Preserved and the Digitalis Investigation Group (DIG) trials, clinical evidence is accumulating to support effective treatments in patients with left ventricular diastolic dysfunction. The focus of this review is to discuss the risks of, identification of, and rationale for therapeutic choices being employed for treating left ventricular diastolic dysfunction and implications from studies that may support these choices.
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PMID:Left ventricular diastolic dysfunction: risks, identification, and treatment. 1501 55

Heart failure affects nearly 5 million people in the United States and is a major contributor to mortality, hospitalization, and medical costs. Approximately 40% of patients with heart failure have preserved left ventricular systolic function, thus exhibiting diastolic heart failure. More common in women and the elderly, this condition is associated with hypertension, coronary artery disease, and/or atrial fibrillation. With the exception of the Digitalis Investigation Group (DIG) and the Candesartin in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM)-Preserved trials, no completed large randomized clinical trial has addressed the management of such patients. Symptomatic treatment involves administration of diuretics and nitrates, but long-term management with angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, aldosterone antagonists, beta-blockers, and calcium channel blockers targets the underlying disorders. Recent studies found that diabetes mellitus produces functional, biochemical, and morphologic myocardial abnormalities independent of coronary atherosclerosis and hypertension. These abnormalities may result in impaired left ventricular diastolic function, contributing importantly to heart failure with normal systolic function. Although tight glycemic control decreases the risk of heart failure in patients with diabetes, the effects of different diabetic treatment regimens on heart failure with normal systolic function are unknown and remain subject to future investigation.
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PMID:New insights into diastolic heart failure: role of diabetes mellitus. 1501 64

Renal dysfunction is a common complication for patients with heart failure, but its association with clinical outcomes has not been fully characterized. We evaluated the association of glomerular filtration rate (GFR) with heart failure survival and the effect of digoxin on heart failure outcomes across GFR strata. A secondary analysis from the Digitalis Intervention Group trial was conducted of 6800 outpatients with systolic heart failure. Renal function was categorized as estimated GFR (expressed in ml/min per 1.73 m(2)). All-cause mortality (mean, 3 yr) was inversely proportional to GFR (GFR >60, 31% mortality; GFR 30 to 60, 46% mortality; GFR <30, 62% mortality; P < 0.001). Among patients with a GFR <50, lower GFR were associated with greater adjusted mortality risk (GFR <30: hazard ratio [HR], 2.06, 95% confidence interval [CI], 1.69 to 2.51; GFR 30 to 40: HR, 1.42, 95% CI, 1.22 to 1.67; GFR 40 to 50: HR, 1.22, 95% CI, 1.07 to 1.39; GFR 50 to 60: HR, 1.00, referent). In contrast, participants with GFR 60 to 70 had similar risk (HR, 1.00; 95% CI, 0.88 to 1.14) compared with GFR 50 to 60, and those with GFR >70 had a slightly lower mortality hazard (0.89; 95% CI, 0.78 to 1.00). Linear spline analyses confirmed that GFR = 50 was the appropriate risk threshold; above 50, GFR had no association with mortality, whereas below 50, mortality risk increased sharply with declining GFR (spline coefficient, P < 0.0001). Digoxin efficacy did not differ by level of GFR (P = 0.19 for interaction). Renal dysfunction is strongly associated with mortality in stable outpatients with heart failure, notably in patients with estimated GFR <50 ml/min per 1.73 m(2). The effect of digoxin did not differ by level of renal function.
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PMID:Renal function, digoxin therapy, and heart failure outcomes: evidence from the digoxin intervention group trial. 1528 5

Digitalis glycosides have played an important role in the treatment of patients with heart failure (HF) for more than two centuries. Despite the introduction of new therapeutic strategies in the treatment of HF, and controversies regarding the role of digitalis in HF in sinus rhythm and its effect on mortality, digoxin is one of the most commonly prescribed drugs in the community and in hospital settings, particularly in the elderly. The Italian Group of Pharmacosurveillance in the Elderly (GIFA) monitored 20,047 hospitalized patients in 1988, 1991 and 1993, and found that digoxin was the most frequently prescribed drug in the management of HF. Inappropriate prescriptions of digitalis, defined with standardized criteria, were uncommon, and the mean daily dosage was low. Compared to earlier studies the incidence rate of adverse drug reactions (ADRs) to digoxin, was also low. The reduction in ADRs incidence was probably due to a better understanding of digoxin pharmacokinetics and to a lower daily dosage in the elderly. Nevertheless, digoxin toxicity was significantly more frequent in patients aged >or= 80 years than in those aged < 65 and and 65-79 years. In a multidrug approach to the treatment of chronic HF, digoxin exerts clinical benefits also in patients with sinus rhythm, it is not costly, it is easy to administer, and toxic effects are not common.
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PMID:Digitalis in the treatment of heart failure in the elderly. The GIFA study results. 1537 50

For centuries, drugs that increase the power of contraction of the failing heart have been used for the treatment of congestive heart failure (dropsy). The cardiac effect is due to the content of cardiac glycosides. Squill or sea onion, Urginea (Scilla) maritima, a seashore plant, was known by the ancient Romans and Syrians and possibly also by the ancient Egyptians. Squills were used erratically, but some prescriptions indicate that they may have been used for the treatment of oedematous states. The toxic effect of strophanthus species was known from poisoned arrows used by the natives in Africa. Digitalis, derived form the foxglove plant, Digitalis purpurea, is mentioned in writings as early as 1250; a Welsh family, known as the Physicians of Myddvai, collected different herbs and digitalis was included in their prescriptions. However, the druge was used erratically until the 18th century, when William Withering, an English physician and botanist, published a monograph describing the clinical effects of an extract of the foxglove plant. Later, in 1785, the indication and the toxicity of digitalis were reported in his book, "An account of the Foxglove and some of its medical uses with practical remarks on dropsy, and other diseases". In Denmark, the leaves of Digitalis purpurea or Digitalis lanata were tested for cardiac glycoside activity. The standardized digitalis powder was used in tinctures, infusions, and tablets. The preparations were included in successive editions of the Danish pharmacopoeia, some of the tinctures already in 1828, i.e. before the standardization of the drug. Isolation of cardiac glycosides from digitalis, strophanthus and squill and determination of their chemical structures initiated biochemical and pharmacological studies. The scientific advances led to an understanding of cardiac muscle contractility and the Na,K pump as the cellular receptor for the inotropic action of digitalis. Examination of putative endogenous ligands to the receptor revealed some endogenous cardiac glycosides of similar or identical structures as those found in digitalis, strophanthus and squill. Increased concentrations of these glycosides are found in patients with heart failure. Further investigations are needed to determine whether the secretion of glycosides might be a physiologic response to a diminished cardiac output.
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PMID:[Cardiac glycosides: From ancient history through Withering's foxglove to endogeneous cardiac glycosides]. 1568 83

Patients with heart failure (HF) and preserved ejection fraction (HF-PEF) constitute up to 30% to 50% of patients with HF, and HF-PEF affects women more often than men. Not much is known about the role of gender in the clinical presentation, symptoms, or disease severity of HF-PEF or about the contribution of these differences to gender differences in morbidity and mortality in patients with HF-PEF. This study examined gender differences in clinical presentation, hospitalization, and mortality in patients with HF-PEF (ejection fraction > or = 50%) enrolled in the ancillary arm of the Digitalis Investigation Group trial. Time-to-event analysis was performed using Cox proportional-hazards modeling. The study cohort included 719 patients (378 men, 341 women). At baseline, compared with men, women were older and had greater clinical severity of HF, as evidenced by worse New York Heart Association functional class, more frequent symptoms and signs of HF, and more treatment with diuretics. Ischemia was identified as the primary cause of HF in 46% of women and 56% of men (p = 0.01). During a median follow-up of 39 months, crude mortality was similar in women and men (24.6% and 24.3%, p = 0.93), but more women were hospitalized for HF (26.7% vs 15.9%, p <0.001). After adjustment for baseline differences, female gender was an independent predictor of lower mortality (hazard ratio 0.59, 95% confidence interval 0.43 to 0.82), but HF hospitalization rates were similar between men and women (hazard ratio 1.09, 95% confidence interval 0.77 to 1.53). In conclusion, although the clinical manifestations of HF appear to be more severe in women with HF-PEF, after adjustment for baseline clinical differences, HF hospitalizations are not increased and survival expectancy is better for women compared with men.
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PMID:Comparison of morbidity in women versus men with heart failure and preserved ejection fraction. 1661 31


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