Studies Of Left Ventricular Dysfunction Trial Research Articles

Recent Trends in the Incidence, Treatment, and Prognosis of Patients With Heart Failure and Atrial Fibrillation (the Worcester Heart Failure Study)

Atrial fibrillation (AF) and heart failure (HF) are common cardiovascular diseases and the co-occurrence of AF and HF has been associated with reduced survival. Data are needed on the potentially changing trends in the characteristics, treatment, and prognosis of patients with acute decompensated HF (ADHF) and AF. The study population consisted of 9,748 patients hospitalized with ADHF at 11 hospitals in the Worcester, Massachusetts, metropolitan area during 4 study years (1995, 2000, 2002, and 2004). Of the 9,748 patients admitted with ADHF, 3,868 (39.7%) had a history of AF and 449 (4.6%) developed new-onset AF during hospitalization. The rates of new-onset AF remained stable (4.9% in 1995; 5.0% in 2004), but the proportion of patients with pre-existing AF (34.5% in 1995; 41.6% in 2004) increased over time. New-onset and pre-existing AF were associated with older age, but pre-existing AF was more closely linked to a greater co-morbid disease burden. The use of HF therapies did not differ greatly by AF status. Despite this, new-onset AF was associated with a longer length of stay (7.5 vs 6.1 days) and greater in-hospital death rates (11.4% vs 6.6%). In contrast, pre-existing AF was associated with lower rates of postdischarge survival compared to patients with no AF (p <0.05 for all). The mortality rates improved significantly over time in patients with AF. In conclusion, AF was common among patients with ADHF, and the proportion of ADHF patients with co-occurring AF increased during the study period. Despite improving trends in survival, patients with ADHF and AF are at increased risk of in-hospital and postdischarge mortality.

Thromboembolism and Antithrombotic Therapy in Patients With Heart Failure in Sinus Rhythm

Heart failure (HF) represents a major and growing public health problem because of its prevalence, incidence, morbidity, mortality, and economic costs. The prevalence of HF is 2% to 3% of the general population.1 Five million Americans are affected, with >550 000 cases diagnosed each year.2 The mortality rate from severe HF remains >60% within 5 years of diagnosis, and 50% of hospitalized patients with HF require readmission within 6 months of discharge. In the US estimated costs amount to > $35 billion per year.3 Although several therapies (eg, β-blockers, angiotensin-converting enzyme [ACE] inhibitors, and cardiac resynchronization therapy) have been proven effective in improving HF outcomes, many unanswered questions about optimal treatment remain. One area of ongoing uncertainty is the appropriate role for antithrombotic therapy in patients with HF. Observational data suggest that patients with HF have an increased venous thromboembolism (VTE) risk (deep venous thromboembolism [DVT], pulmonary embolism [PE], peripheral arterial thromboembolism, and stroke).4 These epidemiological findings are supported by multiple mechanisms that can contribute to a hypercoagulable state in patients with HF. Despite this increased risk of VTE, the role of antithrombotic therapy remains unclear. In this article, we provide an overview of epidemiology, pathophysiology, clinical trial data, and therapeutic recommendations for prevention of thromboembolism in HF. We searched PubMed for articles published between 1958 and 2010 using the following search terms: epidemiology of heart failure , thromboembolism and heart failure , thrombogenesis and heart failure , anticoagulation in heart failure , antiplatelet agent and heart failure , aspirin and heart failure , bleeding risk and anticoagulation , and aspirin and angiotensin-converting enzyme inhibitors . We also studied abstracts from national and international cardiovascular meetings to identify unpublished studies using the key words anticoagulation and dilated cardiomyopathy . Data from published observational studies and secondary …

Epidemiologic analysis of racial/ethnic disparities: A rejoinder to Frank and Exner

Epidemiologic analysis of racial/ethnic disparities: A rejoinder to Frank and Exner

Temporal variations in hematocrit values in patients with left ventricular dysfunction: Relationship with cause-specific mortality and morbidity and optimal monitoring – further insights from SOLVD

Anemia is associated with an increased risk of death in heart failure (HF) patients. Currently, the relationship between temporal variations in hematocrit and specific causes of mortality and morbidity, as well as the most appropriate way to monitor changes in hematocrit, is unknown. To evaluate the prognostic value of changes in hematocrit during follow-up on specific causes of mortality and morbidity in the Studies Of Left Ventricular Dysfunction (SOLVD). A retrospective analysis of the SOLVD trials was conducted. Changes in hematocrit were evaluated in two ways: hematocrit as an absolute value at baseline and at each visit, and relative hematocrit variations compared with baseline. Low absolute hematocrit values during follow-up were associated with cardiovascular (CV), non-CV and HF mortality, HF and non-CV hospitalizations, and cardiac ischemic events (P<0.05 for all end points). Decreases in hematocrit during follow-up compared with baseline were associated with HF hospitalizations (P<0.05) and non-CV death in patients receiving placebo (P=0.01 for interaction). Hematocrit values during follow-up provide independent prognostic information in patients with HF for both CV and non-CV events. Absolute values of hematocrit are more closely related with outcomes and are therefore more clinically relevant to monitor than relative variations.

Section 14: Managing Patients With Hypertension and Heart Failure

Section 14: Managing Patients With Hypertension and Heart Failure

The Effect of Gender on Outcome in Digitalis-Treated Heart Failure Patients

Background The use of digitalis is recommended for the treatment of heart failure to reduce hospitalization. Recent data suggest that digitalis treatment may adversely affect survival in women but not in men. We studied patients with left ventricular dysfunction enrolled in the Studies of Left Ventricular Dysfunction (SOLVD) to determine whether there was a gender-based survival difference in patients treated with digitalis. Methods and Results Symptomatic (n = 2569) and asymptomatic (n = 4228) patients with left ventricular ejection fraction ≤0.35 were studied. Digitalis use was assessed at baseline and baseline demographic variables were catalogued and compared. A multivariate analysis, incorporating known covariates of risk for adverse cardiovascular events, was used to examine the association of digitalis with all-cause mortality, cardiovascular death, death from heart failure, and arrhythmic death, with, or without, worsening heart failure in women compared with men. Analysis for an interaction between digitalis and gender on mortality was also performed. No interaction between gender and digitalis treatment on survival was found, and there was no significant difference in the hazard ratios for men and women on digitalis either with respect to all-cause mortality, cardiovascular mortality, heart failure mortality, or arrhythmic death with worsening heart failure. When mortality for arrhythmic death without worsening heart failure was adjusted for the probability of being treated with digitalis (propensity analysis), women fared better than men. Conclusion Data from the SOLVD trials suggest that digitalis treatment of heart failure does not result in a difference in survival between men and women. Because a randomized trial to definitively answer the question is unlikely, and perhaps inappropriate, examination of other heart failure populations for a gender-digitalis interaction is indicated.

Most hospitalized older persons do not meet the enrollment criteria for clinical trials in heart failure

Background Although it is widely accepted that clinical trials in heart failure may not apply to older populations, the magnitude of the discrepancy between trial populations and patients seen in community-based practice are not known. Our objective was to determine the proportion of older persons meeting enrollment criteria of randomized controlled trials of agents that prolong life in heart failure. Methods We conducted a cross-sectional study of Medicare beneficiaries >64 years old with the principal diagnosis of heart failure who were discharged from acute care hospitals in the United States between April 1998 and March 1999. Enrollment criteria of the Studies of Left Ventricular Dysfunction (SOLVD), Metroprolol CR/LX Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF), and Randomized Aldactone Evaluation Study (RALES) trials were applied to the population, and the proportions meeting the criteria were determined by subgroups of age and sex. Results Of the 20,388 patients studied, 18%, 13%, and 25% met the enrollment criteria of the SOLVD, MERIT-HF, and RALES trials, respectively. Although trial eligibility was less than a third for any sex or age group, significantly fewer women than men met trial criteria (13% vs 23% for SOLVD, 11% vs 17% for MERIT-HF, and 21% vs 32% for RALES, P <.0001 for all). The oldest patients were also less likely to fulfill enrollment criteria. The proportion of all patients not included because of preserved left ventricular systolic function was twice as large as the proportion meeting the inclusion criteria for any trial. Conclusions A minority of hospitalized older persons with heart failure fit the profile of populations of clinical trials. There is an urgent need for research in heart failure for typical heart failure patients, including the very old, women, and patients with preserved left ventricular systolic function.

Revascularization Versus Implantable Cardioverter-Defibrillators to Prevent Sudden Death in Patients With Severe Left Ventricular Dysfunction

Sudden death remains a dreaded consequence of coronary artery disease, and efforts to predict its incidence and to prevent its occurrence remain a major concern. A number of the challenges in management are highlighted in the article by Veenhuyzen et al1 in the present issue of Circulation . In their study, mortality and modes of death were assessed in 5410 patients with ischemic left ventricular function who were enrolled in the Studies of Left Ventricular Dysfunction (SOLVD) study.2 There were 1870 patients who had had prior coronary artery bypass grafting (CABG) and 3540 who had not had prior CABG. The SOLVD trial database is a good source for these data, both because it is large and because the cause of death (ie, whether cardiac and whether sudden or not) was established. See p 1489 The key findings of Veenhuyzen et al1 are that CABG was associated with a 25% reduction in the risk of death (from 24.3% to 18.4%) and a 46% reduction in the risk of sudden death (from 7.5% to 4.1%). These findings are independent of ejection fraction, severity of heart failure symptoms, age, and other clinical variables. In a stratified analysis by severity of left ventricular dysfunction, there was some evidence for interaction, but similar results were noted overall. Prior CABG was not associated with an alteration in the risk of death from progressive heart failure. The results were applied to a group of patients with left ventricular dysfunction from the Coronary Artery Surgery Study Registry who had not undergone surgery, offering a predicted annual rate of death of 8.2% and sudden death …

Vascular protective effects of angiotensin converting enzyme inhibitors and their relation to clinical events.

Endothelial cells are a rich source of a variety of vasoactive substances, which either cause vasodilation or vasoconstriction. Important endothelium-derived vasodilators are prostacyclin, bradykinin, nitric oxide and endothelium-derived hyperpolarizing factor. In particular, nitric oxide inhibits cellular growth and migration. In concert with prostacyclin. nitric oxide exerts potent anti-atherogenic and thromboresistant properties by preventing platelet aggregation and cell adhesion. Endothelium-derived contracting factors include the 21 amino acid peptide endothelin (ET). vasoconstrictor prostanoids such as thromboxane A2 and prostaglandin H2, as well as free radicals and components of the renin angiotensin system. In hypertension, elevated blood pressure transmits into cardiovascular disease by causing endothelial dysfunction. Hence, modem therapeutic strategies in human hypertension focus on preserving or restoring endothelial integrity. Angiotensin converting enzyme (ACE) inhibitors are a primary candidate for that concept as they inhibit the circulating and local renin angiotensin system. Angiotensin converting enzyme is an endothelial enzyme which converts angiotensin-I (A-I) into angiotensin-II (A-II). This effect of the ACE inhibitor prevents direct effects of angiotensin-II such as vasoconstriction and proliferation in the vessel wall but also prevents activation of the ET system and of plasminogen activator inhibitor. Furthermore, inhibition of ACE prolongs the half-life of bradykinin and stabilizes bradykinin receptors linked to the formation of nitric oxide and prostacyclin. In isolated arteries ACE inhibitors prevent the contractions induced by angiotensin II and enhance relaxation induced by bradykinin. Chronic treatment of experimental hypertension with ACE inhibitors normalizes endothelium-dependent relaxation to acetylcholine and other agonists. In addition, the dilator effects of exogenous nitric oxide donors are enhanced, at least in certain models of hypertension. In humans with essential hypertension ACE inhibitors augment endothelium-dependent relaxation to bradykinin, while those to acetylcholine remain unaffected, at least in the time frame of the published studies, i.e. 3-6 months. In patients with coronary artery disease, however, paradoxical vasoconstriction to acetylcholine is markedly reduced after 6 months of ACE inhibition. After myocardial infarction ACE inhibitors reduce the development of overt heart failure, the occurrence of reinfarction and cardiovascular death in hypertensive patients. These effects have also been demonstrated in a subgroup analysis of the SOLVD (Studies of Left Ventricular Dysfunction) trial. Thus, in summary, ACE inhibitors are an important class of drugs providing cardiovascular protection in patients with increased cardiovascular risk.

Echocardiographic predictors of clinical outcome in patients with left ventricular dysfunction enrolled in the SOLVD registry and trials: significance of left ventricular hypertrophy

OBJECTIVESTo assess the relation of left ventricular (LV) and left atrial (LA) dimensions, ejection fraction (EF) and LV mass to subsequent clinical outcome of patients with LV dysfunction enrolled in the Studies of Left Ventricular Dysfunction (SOLVD) Registry and Trials.BACKGROUNDData are lacking on the relation of LV mass to prognosis in patients with LV dysfunction and on the interaction of LV mass with other measurements of LV size and function as they relate to clinical outcome.METHODSA cohort of 1,172 patients enrolled in the SOLVD Trials (n = 577) and Registry (n = 595) had baseline echocardiographic measurements and follow-up for 1 year.RESULTSAfter adjusting for age, New York Heart Association (NYHA) functional class, Trial vs. Registry and ischemic etiology, a 1-SD difference in EF was inversely associated with an increased risk of death (risk ratio, 1.62; p = 0.0008) and cardiovascular (CV) hospitalization (risk ratio, 1.59; p = 0.0001). Consequently, the other echo parameters were adjusted for EF in addition to age, NYHA functional class, Trial vs. Registry and ischemic etiology. A 1-SD difference in LV mass was associated with increased risk of death (risk ratio of 1.3, p = 0.012) and CV hospitalization (risk ratio of 1.17, p = 0.018). Similar results were observed with the LA dimension (mortality risk ratio, 1.32; p < 0.02; CV hospitalizations risk ratio, 1.18; p < 0.04). Likewise, LV mass ≥298 g and LA dimension ≥4.17 cm were associated with increased risk of death and CV hospitalization. An end-systolic dimension >5.0 cm was associated with increased mortality only. A protective effect of EF was noted in patients with LV mass ≥298 g (those in the group with EF >35% had lower mortality) but not in the group with LV mass <298 g.CONCLUSIONSIn patients with LV dysfunction enrolled in the SOLVD Registry and Trials, increasing levels of hypertrophy are associated with adverse events. A protective effect of EF was noted in patients with LV mass ≥298 g (those in the group with EF >35% fared better) but not in the group with LV mass <298 g. These data support the development and use of drugs that can inhibit hypertrophy or alter its characteristics.

Diabetes mellitus, a predictor of morbidity and mortality in the studies of left ventricular dysfunction (SOLVD) trials and registry

Diabetes is an independent predictor of morbidity and mortality in patients with symptomatic heart failure, patients with asymptomatic left ventricular dysfunction (defined as an ejection fraction of 35% or less), and in a broader registry population with less stringent entry criteria. Although the SOLVD Trials made a major clinical contribution by proving the value of enalapril, diabetes remains a significant predictor of outcome even after adjusting for treatment with enalapril.

Proinflammatory cytokine levels in patients with depressed left ventricular ejection fraction: A report from the studies of left ventricular dysfunction (SOLVD)

This study sought to assess proinflammatory cytokine levels in patients in the studies of left ventricular dysfunction trial (SOLVD) in relation to both their New York Heart Association functional classification and their neurohormonal status before randomization. Elevated levels of tumor necrosis factor-alpha have been identified in 30% to 40% of patients with heart failure. However, it is unclear which subsets of patients with heart failure elaborate tumor necrosis factor-alpha. It is also unclear what the mechanism for the increased expression of proinflammatory cytokines is. Tumor necrosis factor-alpha and interleukin-6 levels were analyzed by enzymes-linked immunoassay using randomly selected plasma samples from patients in functional classes I to III who were enrolled in neurohormonal substudies of the SOLVD trial; age-matched healthy subjects served as the control group. Plasma levels of tumor necrosis factor-alpha (p < 0.001) were elevated in patients in functional classes I to III ([mean +/- SD] 1.95 +/- 0.54, 2.63 +/- 0.48, 6.4 +/- 1.9 pg/ml, respectively) compared with age-matched control subjects (0.75 +/- 0.05 pg/ml) and were progressively elevated in relation to decreasing functional status of the patient. Plasma levels of interleukin-6 (p < 0.001) were elevated in patients in functional classes I to III (3.3 +/- 0.55, 6.2 +/- 1.1, 5.22 +/- 0.9 pg/ml, respectively) compared with age-matched control subjects (1.8 +/- 0.5 pg/ml and were progressively elevated in relation to decreasing functional status of the patient. Cox proportional-hazards analysis showed that there was a trend toward significance between plasma tumor necrosis factor-alpha (p < 0.07) and survival, whereas there was no significant relation for plasma interleukin-6 (p < 0.72). Except for atrial natriuretic factor, which correlated weakly (r = 0.23, p = 0.04) with circulating tumor necrosis factor-alpha levels, there was no significance correlation between neurohormonal and proinflammatory cytokine levels. Circulating levels of proinflammatory cytokines increase in patients as their functional heart failure classification deteriorates. Moreover, activation of the neurohumoral axis is unlikely to completely explain the elaboration of proinflammatory cytokines in heart failure.

Reduction of ischemic events with angiotensin-converting enzyme inhibitors: lessons and controversy emerging from recent clinical trials.

Angiotensin-converting enzyme (ACE) inhibitor therapy has been associated with a substantial (> or = 20%) reduction in the risk of major ischemic events in two recent clinical trials with long-term follow-up: Studies of Left Ventricular Dysfunction (SOLVD) and the Survival and Ventricular Enlargement (SAVE) study. Participants in these studies included patients with a low ejection fraction (< or = 0.35 in SOLVD and < or = 0.40 in SAVE), generally without symptoms of congestive heart failure. Approximately 80% of patients enrolled in SOLVD and all participants in SAVE had histories of ischemic heart disease or acute myocardial infarction (SAVE). In both SOLVD and SAVE the risk of experiencing a major ischemic event such as myocardial infarction was reduced significantly following prolonged ACE inhibitor therapy. In the SOLVD trial, this effect was evident across a range of patient subgroups, including varying concomitant drug therapies. In both studies, several months elapsed before this benefit became apparent, suggesting an effect on underlying ischemic pathophysiology. A third trial of ACE inhibitor therapy postinfarction, the Acute Infarction Ramipril Efficacy (AIRE) Study, demonstrated a 27% reduction in all cause mortality but no effect on myocardial infarction after a 15-month mean follow-up. No effect of ACE inhibition on risk of survival or reinfarction was reported in the Cooperative New Scandinavian Enalapril Survival Study (CONSENSUS-II), which began the drug within 24 hours of infarction and terminated follow-up at 6 months, a time not likely to demonstrate infarction reduction benefit based on the SOLVD and SAVE observations. Neither AIRE nor CONSENSUS-II had objectively determined left ventricular dysfunction as an entry criterion, as did SOLVD and SAVE, but AIRE mandated "clinical" congestive heart failure prior to randomization. More recently, preliminary results from the third Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI-3), the Fourth International Study of Infarct Survival (ISIS-4), and the Chinese Captopril Trial suggested that angiotensin-converting enzyme (ACE) inhibitor mortality benefits post-myocardial infarction would be detected in these megatrials as early as 35 days after the event.(ABSTRACT TRUNCATED AT 400 WORDS)

Angiotensin-converting enzyme inhibitors in heart failure: new strategies justified by recent clinical trials

New information suggests that heart failure treatment strategies should change. Indeed, angiotensin-converting enzyme (ACE) inhibitors now should be considered first-line therapy in some instances. It is important, therefore, to review results of recently completed mortality end-point trials of ACE inhibitors in patients with congestive heart failure and asymptomatic left ventricular dysfunction. In the Treatment Trial of Studies of Left Ventricular Dysfunction (SOLVD), addition of enalapril to baseline therapy significantly improved prognosis in patients with mild to moderate heart failure. These results extend the findings of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS), and indicate that ACE inhibition is beneficial to patients with all grades of overt congestive heart failure. In the Prevention Trial of SOLVD, and the Survival and Ventricular Enlargement Study (SAVE), therapy with enalapril or captopril improved prognosis among patients with, generally, asymptomatic left ventricular dysfunction. In particular, the risk of development of overt heart failure was reduced. Importantly, a marked anti-ischaemic effect of ACE inhibition was identified in both the SOLVD and SAVE trials. Clinical data amassed in nearly 9000 patients identify a substantial role for ACE inhibition in patients with all grades of symptomatic heart failure as well as in those with asymptomatic left ventricular dysfunction (such as often follows a myocardial infarction). Data support early intervention with ACE inhibitor therapy alone in asymptomatic cardiac failure and triple combination therapy (ACE inhibitor, diuretic, digoxin) in patients with symptomatic congestive heart failure.

Heart failure, ventricular remodelling and the renin-angiotensin system: insights from recently completed clinical trials.

Increased insight has been gained into the pathophysiology of heart failure, which is now recognized as a milieu created by specific diseases that cause myocardial dysfunction resulting in haemodynamic abnormalities. Subsequent compensatory circulatory and hormonal changes cause substantive metabolic derangement, and it is the haemodynamic and metabolic abnormalities that produce the congestive and low cardiac output symptoms and physical findings associated with heart failure. One of the earliest abnormalities noted in the failing heart is activation of the renin-angiotensin-neurohormonal axis. This is associated with both dilation and hypertrophy of the left ventricle. This remodelling may be regulated, at least in part, by myocardial tissue angiotensin-converting enzyme systems. Clinical drug trials in patients with heart failure have demonstrated that certain agents reduce mortality and interdict detrimental hormonal activity and remodelling. The Veterans Administration's (VHEFT-I and II) and Scandinavian (CONSENSUS-I) heart failure trials, as well as Studies of Left Ventricular Dysfunction (SOLVD) and the post myocardial infarction captopril trial (SAVE--Survival and Ventricular Enlargement) indicate that vasodilators and, in particular, angiotensin-converting enzyme inhibitors, decrease heart failure mortality. Furthermore, diminution in morbidity measured as a reduction in hospitalization for congestive heart failure or myocardial infarction was a dramatic beneficial effect noted even in relatively asymptomatic patients with left ventricular dysfunction. Importantly, in the SOLVD and SAVE trials, the diminution in major ischaemic events observed in the treatment groups were noted whether drug was started one week (SAVE) or one year (SOLVD) post infarct.(ABSTRACT TRUNCATED AT 250 WORDS)

Studies of left ventricular dysfunction (SOLVD) registry: Rationale, design, methods and description of baseline characteristics

The Studies of Left Ventricular Dysfunction (SOLVD) comprises 2 double-blind, randomized clinical trials to test improved survival by an angiotensin-converting enzyme inhibitor in patients with left ventricular dysfunction, with or without congestive heart failure. Patients entering the trials may be a highly selected subset of the population of such patients; those with the worst and best prognosis are likely to be excluded. To obtain the clinical history of a broader group, a registry of 6,273 patients included a relatively unselected cohort of patients with heart failure or left ventricular dysfunction, or both, from SOLVD hospitals. Registry data were obtained from hospital records. Because data collection from medical records may lead to incomplete data and more investigations in “sicker” patients, 898 randomly chosen subjects from different disease strata were seen in clinic where neurohumoral measures, echocardiograms, x-rays and electrocardiograms were obtained, and a 6-minute walking test was performed. The design and methodologic features, and the baseline characteristics of the participants in this 2-tiered registry are described, and its use in complementing the results and interpretation of the SOLVD trials is discussed.