YEAR IN CARDIOLOGY SERIES
The year in heart failure
John J.V. McMurray, MD* and
Marc A. Pfeffer, MD, PhD
,*
* Department of Cardiology, Western Infirmary, Glasgow, Scotland, United Kingdom
Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts
Manuscript received September 8, 2004;
accepted September 17, 2004.
* Reprint requests and correspondence: Dr. Marc A. Pfeffer, Brigham and Women's Hospital, Medicine, 75 Francis Street, Boston, Massachusetts 02115
(Email: mpfeffer{at}rics.bwh.harvard.edu).
Heart failure (HF) remains a dynamic field. Treatment continues to be refined and improved and, at last, there is evidence that the increased survival demonstrated in randomized clinical trial cohorts has been translated to the unselected general population. Beyond angiotensin-converting enzyme (ACE) inhibitors and beta-blockers, two more classes of drug, the angiotensin receptor blockers and aldosterone antagonists, were unequivocally demonstrated to have a survival benefit during 2003. This year also establishes a new era in device therapies, which also improve outcomes in patients with HF.
 |
Improving clinical outcomes in HF
|
|---|
In a population-based study, Blackledge et al. (1) reported improving 30-day and 1-year survival after a first admission to hospital with HF in the English county of Leicestershire over the period 1993 to 2001. Postdischarge cardiovascular mortality fell by over 50%. Also of note, hospital admission rates increased from 1993 to 1998 but plateaued thereafter. These encouraging findings with respect to survival, first admissions, and readmissions mirror prior observations from Scotland, the Netherlands, the U.S. (Framingham, Massachusetts, and Northeast Ohio), and, more recently, Sweden and Canada (Ontario) (2–7). These consistent trends (Figs. 1 and 2) have been interpreted to reflect the population impact of the incremental survival and other benefits of ACE inhibitors, spironolactone, and beta-blockers. Indeed, the improvements in outcomes noted in these observational studies temporally correlate with the widespread uptake of ACE inhibitors and, to a lesser extent, spironolactone; it is only in the most recent studies that beta-blockers could have begun to have had an effect. It will be of interest to see if these findings can be replicated in additional countries and whether the trends identified continue as the full effect of beta-blockade becomes apparent.
View larger version (25K):
[in this window]
[in a new window]
|
Figure 1 Evidence of improving survival from heart failure in the general population. (a) Hazard ratio and 95% confidence intervals for all-cause mortality in patients having a first admission for heart failure, according to year of admission (adjusted for age, gender, comorbidity, and social deprivation). Hazard ratio for first year of study (1993/1994) set at 1. (b) Odds ratios and 95% confidence intervals for all-cause mortality ( 30 days after a first heart failure admission), according to year of admission (adjusted for age, gender, comorbidity, and social deprivation). Odds ratio for first year of period of study (1986) set at 1. (c) Standardized 30-day and 1-year case fatality rates (%) for women with a first admission to hospital for heart failure (similar trends noted in men). (d) Age-adjusted survival after the onset of heart failure in men. Values were adjusted for age (<55, 55 to 64, 65 to 74, 75 to 84, and 85 years). Estimates are shown for men who were 65 to 74 years of age. Similar trends were observed in women. Figure adapted from references 1, 2, 4, and 5.
|
|
|
HF with preserved left ventricular systolic function
|
|---|
An encouraging development that accelerated in 2003 was the shift to a broader focus of HF incorporating the substantial proportion of patients with signs and symptoms occurring in the absence of any major reduction in left ventricular systolic function (8–13). The pathophysiology and even terminology related to this latter, heterogeneous type of HF, however, remains controversial. Most of the recently reported epidemiologic and hospital cohort studies made no attempt to assess diastolic function, instead describing these patients as having HF with preserved systolic function (PSF). Zile (14) has argued that detailed evaluation would confirm diastolic dysfunction in most of these patients, though, to date, this has only been verified in small numbers of highly selected individuals. Some paradoxes also remain; HF-PSF is much more frequent in women than men, yet two population-based epidemiologic studies published in 2003 found that indexes of diastolic dysfunction were more common in men than women. Indeed, diastolic dysfunction was also remarkably common in older individuals generally, even in the absence of clinical HF (12,13). Redfield et al. (12) found that, of those age 75 years or older, 53% had mild, 15% moderate, and 3.4% severe diastolic dysfunction. Is the finding of diastolic dysfunction in a breathless elderly patient, therefore, a very specific finding? Others have drawn attention to vascular rather than myocardial differences between these two types of HF (15). The nonspecific nature of the signs and symptoms of HF and the complexity of performing and interpreting measures of diastolic function emphasize the great need for a simple and agreed upon diagnostic test for HF-PSF. Without a quantitative, reproducible, and clinically applicable measure of diastolic function, left ventricular ejection fraction will continue to serve as the distinguishing feature. B-type natriuretic peptides (BNP) provide additional underpinning for the clinical diagnosis of HF. The Breathing Not Properly study was one of the first to address this important question (16). Using a "gold standard" of a clinical diagnosis made by two independent cardiologists unaware of BNP levels, Maisel et al. (15) tested how BNP performed. Unfortunately, there was a significant overlap in BNP concentrations between patients with non-cardiac breathlessness and those with HF-PSF, especially women. Clearly, more studies of this type are needed, perhaps using a different "gold standard" or natriuretic peptide (e.g., N-terminal pro-BNP).
Whatever the underlying pathophysiology and optimal diagnostic approach, evidence continues to accumulate that HF-PSF is a common and important syndrome. Smith et al. (10) have added to the growing array of studies showing that, while HF-PSF is associated with a lower mortality than HF with reduced systolic function, it still leads to a comparable degree of functional limitation and morbidity as measured by admission to hospital. Fortunately, there has also been a drive to conduct major prospective randomized outcome studies to evaluate new treatments in this type of HF. The first of these to report was Candesartan in Heart Failure: Assessment of Reduction in Mortality and morbidity (CHARM)-Preserved, one of the three component trials of the CHARM program (see the following text) (17). In this study, candesartan was compared with placebo in 3,023 patients with HF and a left ventricular ejection fraction higher than 0.40. During a median of 37 months, candesartan treatment did not lead to a statistically significant reduction in the primary end point of cardiovascular death or hospital admission for HF (22% vs. 24%, hazard ratio 0.89, p = 0.118). Compared with placebo, however, candesartan did reduce the proportion of patients requiring admission to hospital for HF by 18% (p = 0.017) and the total number of admissions for HF by 29% (p = 0.014). This trial did demonstrate that the annual mortality rate of 5.4 %, although less than the patients with reduced left ventricular ejection fraction (11.2%), was higher than the general population, and that recurrent hospitalization for cardiovascular reasons was common.
|
Randomized trials of therapeutic interventions in chronic HF with reduced systolic function
|
|---|
Pharmacologic.
Angiotensin receptor blockers
The CHARM program confirmed and extended the findings of the Evaluation of Losartan in the Elderly (ELITE)-2 and Valsartan Heart Failure Trial (Val-HeFT) in patients with HF and reduced systolic function (18–20). In 2,028 patients previously intolerant of an ACE inhibitor, compared with placebo during 34 months of follow-up, candesartan reduced the primary end point of cardiovascular death or hospital admission for HF from 40% to 33% (hazard ratio 0.77, p = 0.0004) in CHARM-Alternative (18). In CHARM-Added, 2,548 patients all treated with an ACE inhibitor (and, in 55% of cases a beta-blocker as well), candesartan reduced the incidence of the same end point from 42% to 36% (hazard ratio 0.85, p = 0.011) during 41 months of follow-up (19). This finding is consistent with recent evidence of incremental and favorable remodeling effects with "triple therapy" (21). In both these low ejection fraction trials, candesartan reduced all-cause mortality from 31% to 28% (hazard ratio 0.88, p = 0.018). The benefits of candesartan were consistent across a wide range of subgroups and irrespective of background therapy, including ACE inhibitor, beta-blocker, and spironolactone, whether used individually or in any combination (20). Candesartan was also effective when added to either high- or lower-dose ACE inhibitor treatment.
Beta-blockers
The greatest advance in the treatment of HF since the introduction of ACE inhibitors was the demonstration in three landmark prospective, randomized, placebo-controlled trials of an approximately 33% relative reduction in all-cause mortality (and similarly impressive reductions in hospital admissions) with the addition of a beta-blocker. Of note, these benefits were identified early, and all three trials were terminated prematurely, after about one year's follow-up. The effective agents used were bisoprolol (in Cardiac Insufficiency Bisoprolol Study [CIBIS]-2), carvedilol (in the Effect of Carvedilol on Survival in Severe Chronic Heart Failure [COPERNICUS] trial), and a slow-release formulation of metoprolol (succinate) in Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF); each had an almost identical size of treatment effect (22–24). Of note, in the Beta Blocker Evaluation of Survival Trial (BEST), another beta-blocker, bucindolol, was not clearly shown to have these benefits (25). The results of Carvedilol Or Metoprolol European Trial (COMET), a rare type of randomized trial comparing two active treatments within the same drug class, were reported in 2003; COMET compared carvedilol to a short-acting formulation of metoprolol (tartrate), different from that used in MERIT-HF (which used metoprolol succinate) (26). This large (n = 3,029), long-term (mean follow-up 58 months) trial demonstrated that carvedilol led to a 17% relative risk reduction in all-cause mortality from 40% to 34% (p = 0.0017) compared with short-acting metoprolol tartrate. The interpretation of this remarkable difference between two beta-blockers has been controversial. Some have interpreted the COMET as demonstrating the advantages of the different molecular actions of carvedilol, namely nonselective (beta-1 and -2) adrenoceptor blockade, alpha-adrenoceptor blockade, and perhaps other effects, over metoprolol (which is a relatively beta-1 adrenoceptor antagonist). Others have criticized the COMET on the basis of comparing different intensities of beta-1 adrenoceptor antagonism, as a consequence of the unproven formulation of metoprolol used (the only sizable prior study with metoprolol tartrate, the Metoprolol in Dilated Cardiomyopathy [MDC] trial, used two or three times daily dosing and achieved a mean dose of metoprolol tartrate of 108 mg compared with 85 mg in the COMET). Other evidence suggests that 50-mg metoprolol tartrate prescribed twice daily does not give equivalent beta-blockade to metoprolol succinate 200 mg taken once daily, as the reduction in heart rate in the metoprolol group in the COMET was slightly less than in the MERIT-HF. One definite conclusion from the COMET, however, is that short-acting metoprolol tartrate, used only twice daily, is an inferior treatment to carvedilol in chronic heart failure (CHF).
Devices.
Cardiac resynchronization therapy (CRT).
Another intervention that may revolutionize the treatment of CHF is atriobiventricular pacing (27–30). It is estimated that about a quarter of patients with CHF have increased QRS duration (>120 ms). This is a marker of dyssynchrony of right and left ventricular activation, which causes inefficient pump function. Atriobiventricular pacing recoordinates ventricular contraction. In 2003, follow-up reports from the first controlled trials of this new therapy confirmed improvements in symptoms, quality of life, and functional capacity, and showed additional mechanistic benefits such as reduced left ventricular remodeling, reduced mitral regurgitation, and increased heart rate variability (27–29). An interesting meta-analysis suggested that CRT also reduces hospital admissions for HF and death from progressive pump failure but perhaps not all-cause mortality (30). The recently reported Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) trial supports this conclusion and also shows that CRT reduces the clinically important composite outcome of death or hospital admission for any reason by 19% (p = 0.014) although the benefits were not as great as in patients having both CRT and an implantable cardioverter-defibrillator (ICD) (31). The results of the second major outcome study of CRT in CHF, Cardiac Resynchronization in Heart Failure (CARE-HF) study, are due in 2005 and eagerly awaited (32). A number of other issues remain to be resolved with CRT. There is concern that a broadened QRS may not offer the best means of identifying patients with ventricular dyssynchrony. Consensus has yet to be reached on whether CRT therapy alone or a combined CRT-ICD device should be implanted (or in whom these different therapeutic modalities are indicated). The recent COMPANION trial and Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) argue powerfully for wider use of ICD therapy in CHF (31).
Ineffective treatments in CHF
The history of clinical trials in CHF is littered with failures as well as successes. Two examples of the former were published in 2003. The adverse Mortality Effect of Central Sympathetic Inhibition with Sustained-Release Moxonidine in Patients with Heart Failure (MOXCON) trial showed that not all anti-adrenergic therapies are beneficial in CHF (as also shown by V-HeFT 1 with the alpha-adrenoceptor prazosin) and once again raised the vexed issue of dose selection (33). The anti-TNF Therapy Against Congestive Heart Failure (ATTACH) trial showed that one type of anticytokine therapy does not improve outcome in CHF, and the recent publication of the results of Randomized Etanercept Worldwide Evaluation (RENEWAL) trial revealed a similar finding with a different inhibitor (34,35). These studies serve to emphasize two points. First, our understanding of sophisticated, inter-related, biologic systems is limited, and it cannot be assumed that activation of such a system in CHF is necessarily disadvantageous. Second, it is also clear that effects of inhibitors of these systems, especially when complex molecular therapies are used, are not easy to predict. The recent experience with endothelin receptor antagonists and dual neutral endopeptidase-ACE inhibitors serves to reinforce all of these issues about dose and biologic complexity.
|
HF after acute myocardial infarction
|
|---|
Clinical evidence of acute HF, even if transient, early after acute myocardial infarction identifies a patient at high risk of short- and longer-term adverse cardiovascular outcomes. The same is true for left ventricular systolic dysfunction without acute HF and, especially, if both of these problems are present. The recent findings of international registries have clearly illustrated this risk in contemporary cohorts of patients with acute coronary syndromes where pulmonary congestion was associated with up to a four-fold excess of death (36,37). The key role of early, sustained ACE inhibition in improving prognosis in these patients remains undisputed (38). The importance of concomitant beta-blockade was recently reinforced by the Carvedilol Post-Infarct Survival Controlled Evaluation (CAPRICORN) (39). Recently, two further therapeutic questions were answered. One was whether an angiotensin receptor blocker would be as, or more, effective than a proven dose of a proven ACE inhibitor and whether combination ACE inhibitor-angiotensin receptor blocker treatment would be better than ACE inhibitor monotherapy, as in CHF (see the preceding text) (40). The second question was whether the addition an aldosterone blocker to an ACE inhibitor and beta-blocker would further improve outcome in these patients (41).
The Valsartan in Acute Myocardial Infarction Trial (VALIANT) showed that the angiotensin receptor blocker valsartan used in a dose of up to 160 mg twice a day (as in Val-HeFT) was as effective in reducing risk of death and other major cardiovascular outcomes as the proven dose of captopril (50 mg three times a day) used in the Survival and Ventricular Enlargement (SAVE) study (and, subsequently, in ELITE-2 and Optimal Therapy in Myocardial Infarction with the Angiotensin II Antagonist Losartan [OPTIMAAL]) (40). Valsartan 80 mg twice a day, added to this dose of captopril, did not, however, lead to any further reduction in risk of the primary or secondary end points in the VALIANT (though the combination did lead to more intolerance). The possible explanations for this difference between the effects of combination ACE inhibitor-angiotensin receptor blocker therapy in CHF and acute myocardial infarction are discussed elsewhere (41,42).
In the Eplerenone Post-AMI Heart Failure Efficacy and Survival Study (EPHESUS), of patients with acute myocardial infarction with both acute HF and reduced left ventricular ejection fraction, the addition of the aldosterone blocker eplerenone led to a 15% relative risk reduction in all-cause mortality and a reduction in hospital admission for HF. These benefits were achieved despite high baseline use of ACE inhibitors and beta-blockers, demonstrating the incremental advance for these patients at especially high risk after acute myocardial infarction (39). The prior observation, in the Randomized Aldactone Evaluation Study (RALES), that spironolactone, added to an ACE inhibitor, improves survival in severe HF reinforces the findings of EPHESUS (43).
|
Acute decompensated HF
|
|---|
There has been a recent explosion of interest in what has become known as "acute decompensated HF," a term probably describing a mixture of syndromes including acute de novo HF and acute on-chronic HF (44). The clinical community is still struggling with how best to evaluate treatments in this type of HF (45,46). Since many are designed to be given intravenously for only a short period, it is difficult to know whether long-term outcomes can be improved. Several drugs including the endothelin receptor antagonist tezosentan (47) and the arginine vasopressin antagonist tolvaptan (48) have been shown to have favorable hemodynamic, neurohumoral renal, and other actions in acute HF. However, to date, none of these therapies has been shown to improve short-term survival or other clinical outcomes in patients presenting with acute HF. Large-scale outcome trials with these agents are now underway, adding to completed studies with "inodilators" and nesiritide (49,50).
|
The importance of comorbidity in HF
|
|---|
Heart failure is most commonly caused by coronary heart disease, hypertension, or both. Consequently, many patients have other complications of atherosclerosis and hypertension. Often these elderly individuals have related comorbidity, such as diabetes (51,52) and other conditions sharing a common etiology (e.g., smoking-related chronic pulmonary disease). Some comorbidities are complications of HF or the combination of HF, its underlying etiology, and advanced age (e.g., renal impairment) (53,54), stroke, atrial (55,56) and ventricular arrhythmias. The causes of others have yet to be fully elucidated (e.g., anemia, obstructive sleep apnea, and cachexia) (57). The importance of certain comorbidities as independent predictors of poor outcome has been highlighted in 2003. This recognition has also led to the view that these might themselves be therapeutic targets. The clearest example of this is anemia (58–61). Four recent studies found that low hemoglobin or hematocrit is a powerful prognostic factor in HF (58–61). In a small, single-blind, randomized, controlled trial, Mancini et al. (62) showed that correcting anemia with erythropoietin resulted in clinical improvement and an increase in exercise capacity. At least one prospective outcome trial using erythropoietic therapy is now planned. Another notable development, related to comorbidity, was recognition of the problems thiazolidinediones can cause, related to fluid retention, when given to treat diabetes in patients with HF (63).
Two studies published in 2003 add to prior evidence that continuous positive airway pressure improves ventricular function and well-being and reduces neurohumoral activity in patients with obstructive sleep apnea (64,65). At least one large trial is now testing the effect of continuous positive airway pressure on mortality and morbidity in HF.
|
Organizing and improving the delivery of care
|
|---|
Based on the results of randomized controlled trials, the treatment of patients with HF continues to improve and has been summarized in a number of authoritative, evidence-based guidelines. The challenge of developing these treatments, however, is matched by the challenge of ensuring these are widely adopted into clinical practice (66). In 2003, it was again shown that organized, nurse-led, multidisciplinary care aids this goal (67), though whether all patients gain from this intervention remains uncertain (68). New technology, such as home-telemonitoring, may also have a role to play in improving chronic disease management (69,70).
Determined efforts to implement guidelines can improve treatment locally and nationally, as illustrated in the Italian Health Service (71,72).
|
Summary and conclusions
|
|---|
Highlighting some of the important aspects of the recent progress in the diagnosis and management of patients with HF serves to underscore both the globalization of the problem in our aging populations and the collaborative effort needed in order to develop new treatments for it. The benefits observed in randomized controlled trials, at last, seem to have been realized in nontrial populations. The persistently high mortality and morbidity in HF, however, provide a continuing impetus to find additional pharmacologic and device treatments that will improve the quality and duration of life beyond what is currently available. The bar is set high though, with expectations raised by the success of optimal conventional therapy, success that may be increasingly difficult to exceed. However, the rate of generation of new knowledge is dramatic, greatly expanding the range of potential therapeutic approaches, and offering a realistic promise of continued meaningful progress in this important field.
View larger version (25K):
[in this window]
[in a new window]
|
Figure 2 Recent trends in hospital admissions for heart failure demonstrating recent plateau or decline. (a) Age-adjusted discharge rate for heart failure in men and women. (b) Gender-specific trends in hospitalizations (principal diagnosis) for heart failure in men. Squares = total episodes; triangles = number of individuals; circles = first-ever hospitalization. Similar trends were observed in women. (c) Gender- and age-specific trends in first-ever heart failure hospitalization rates (principal diagnosis) in individuals 40 years. (d) Age-adjusted annual incidence of first-ever hospitalization for heart failure (principal diagnosis).
|
|
|
Footnotes
|
|---|
Drs. Pfeffer and McMurray have served as consultants for or have received honoraria from Astra Zeneca, Bristol-Myers Squibb, Merck, Novartis, and Takeda. Dr. McMurray has received honoraria/consulted for Pfizer. Dr. Pfeffer is named as a co-inventor on a patent awarded to the Brigham and Women's Hospital regarding the use of inhibitors of the renin-angiotensin system in selected survivors of myocardial infarction; there is a licensing agreement between Novartis Pharmaceuticals and the Brigham and Women's Hospital that is not linked to sales.
|
References
|
|---|
- Blackledge HM, Tomlinson J, Squire IB. Prognosis for patients newly admitted to hospital with heart failure: survival trends in 12,220 index admissions in Leicestershire 1993–2001 Heart 2003;89:615-620.[Abstract/Free Full Text]
- MacIntyre K, Capewell S, Stewart S, et al. Evidence of improving prognosis in heart failure: trends in case fatality in 66,547 patients hospitalized between 1986 and 1995 Circulation 2000;102:1126-1131.[Abstract/Free Full Text]
- Mosterd A, Reitsma JB, Grobbee DE. Angiotensin converting enzyme inhibition and hospitalisation rates for heart failure in the Netherlands, 1980 to 1999: the end of an epidemic? Heart 2002;87:75-76.[Free Full Text]
- Levy D, Kenchaiah S, Larson MG, et al. Long-term trends in the incidence of and survival with heart failure N Engl J Med 2002;347:1397-1402.[Abstract/Free Full Text]
- Schaufelberger M, Swedberg K, Koster M, Rosen M, Rosengren A. Decreasing one-year mortality and hospitalization rates for heart failure in Sweden; data from the Swedish Hospital discharge registry 1988 to 2000 Eur Heart J 2004;25:300-307.[Abstract/Free Full Text]
- Lee DS, Mamdani MM, Austin PC, et al. Trends in heart failure outcomes and pharmacotherapy: 1992 to 2000 Am J Med 2004;116:581-589.[CrossRef][Medline]
- Baker DW, Einstadter D, Thomas C, Cebul RD. Mortality trends for 23,505 Medicare patients hospitalized with heart failure in Northeast Ohio, 1991 to 1997 Am Heart J 2003;146:258-264.[CrossRef][Medline]
- Masoudi FA, Havranek EP, Smith G, et al. Gender, age, and heart failure with preserved left ventricular systolic function J Am Coll Cardiol 2003;41:217-223.[Abstract/Free Full Text]
- Varadarajan P, Pai RG. Prognosis of congestive heart failure in patients with normal versus reduced ejection fractions: results from a cohort of 2,258 hospitalized patients J Cardiac Failure 2003;9:107-112.[CrossRef][Medline]
- Smith GL, Masoudi FA, Vaccarino V, Radford MJ, Krumholz HM. Outcomes in heart failure patients with preserved ejection fraction: mortality, readmission, and functional decline J Am Coll Cardiol 2003;41:1510-1518.[Abstract/Free Full Text]
- Gustafsson F, Torp-Pedersen C, Brendorp B, Seibaek M, Burchardt H, Kober L, DIAMOND Study Group Long-term survival in patients hospitalized with congestive heart failure: relation to preserved and reduced left ventricular systolic function Eur Heart J 2003;24:863-870.[Abstract/Free Full Text]
- Redfield MM, Jacobsen SJ, Burnett Jr JC, Mahoney DW, Bailey KR, Rodeheffer RJ. Burden of systolic and diastolic ventricular dysfunction in the community: appreciating the scope of the heart failure epidemic JAMA 2003;289:194-202.[Abstract/Free Full Text]
- Fischer M, Baessler A, Hense HW, et al. Prevalence of left ventricular diastolic dysfunction in the community: results from a Doppler echocardiographic-based survey of a population sample Eur Heart J 2003;24:320-328.[Abstract/Free Full Text]
- Zile MR. Heart failure with preserved ejection fraction: is this diastolic heart failure? J Am Coll Cardiol 2003;41:1519-1522.[Free Full Text]
- Burkhoff D, Maurer MS, Packer M. Heart failure with a normal ejection fraction: is it really a disorder of diastolic function? Circulation 2003;107:656-658.[Free Full Text]
- Maisel AS, McCord J, Nowak RM, et al. Breathing Not Properly Multinational Study Investigators. Bedside B-type natriuretic peptide in the emergency diagnosis of heart failure with reduced or preserved ejection fraction Results from the Breathing Not Properly Multinational StudyJ Am Coll Cardiol 2003;41:2010-2017.[Medline]
- Yusuf S, Pfeffer MA, Swedberg K, et al. CHARM Investigators and CommitteesEffects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved trial. Lancet 2003;362:777-781.[CrossRef][Medline]
- Granger CB, McMurray JJ, Yusuf S, et al. CHARM Investigators and CommitteesEffects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial. Lancet 2003;362:772-776.[CrossRef][Medline]
- McMurray JJ, Ostergren J, Swedberg K, et al. CHARM Investigators and CommitteesEffects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial. Lancet 2003;362:767-771.[CrossRef][Medline]
- Pfeffer MA, Swedberg K, Granger CB, et al. CHARM Investigators and CommitteesEffects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme. Lancet 2003;362:759-766.[CrossRef][Medline]
- McKelvie RS, Rouleau JL, White M, et al. Comparative impact of enalapril, candesartan or metoprolol alone or in combination on ventricular remodeling in patients with congestive heart failure Eur Heart J 2003;24:1727-1734.[Abstract/Free Full Text]
- The Cardiac Insufficiency Bisoprolol Study II Investigators The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial Lancet 1999;353:9-13.[CrossRef][Medline]
- Packer M, Coats AJ, Fowler MB, et al. Carvedilol Prospective Randomized Cumulative Survival Study GroupEffect of carvedilol on survival in severe chronic heart failure. N Engl J Med 2001;344:1651-1658.[Abstract/Free Full Text]
- Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF) Study Investigators Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF) Lancet 1999;353:2001-2007.[CrossRef][Medline]
- Beta-Blocker Evaluation of Survival Trial Investigators A trial of the beta-blocker bucindolol in patients with advanced chronic heart failure N Engl J Med 2001;344:1659-1667.[Abstract/Free Full Text]
- Poole-Wilson PA, Swedberg K, Cleland JG, et al. Carvedilol Or Metoprolol European Trial InvestigatorsComparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol Or Metoprolol European Trial (COMET): randomised controlled trial. Lancet 2003;362:7-13.[CrossRef][Medline]
- Linde C, Braunschweig F, Gadler F, Bailleul C, Daubert JC. Long-term improvements in quality of life by biventricular pacing in patients with chronic heart failure: results from the Multisite Stimulation in Cardiomyopathy study (MUSTIC) Am J Cardiol 2003;91:1090-1095.[CrossRef][Medline]
- St John Sutton MG, Plappert T, Abraham WT, et al. Multicenter InSync Randomized Clinical Evaluation (MIRACLE) Study GroupEffect of cardiac resynchronization therapy on left ventricular size and function in chronic heart failure. Circulation 2003;107:1985-1990.[Abstract/Free Full Text]
- Varma C, Sharma S, Firoozi S, McKenna WJ, Daubert JC, Multisite Stimulation in Cardiomyopathy (MUSTIC) Study Group Atriobiventricular pacing improves exercise capacity in patients with heart failure and intraventricular conduction delay J Am Coll Cardiol 2003;41:582-588.[Abstract/Free Full Text]
- Bradley DJ, Bradley EA, Baughman KL, et al. Cardiac resynchronization and death from progressive heart failure: a meta-analysis of randomized controlled trials JAMA 2003;289:730-740.[Abstract/Free Full Text]
- Bristow MR, Saxon LA, Boehmer J, et al. Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) InvestigatorsCardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med 2004;350:2140-2150.[Abstract/Free Full Text]
- Cleland JG, Daubert JC, Erdmann E, et al. CARE-HF Study Steering Committee and InvestigatorsThe CARE-HF study (CArdiac REsynchronisation in Heart Failure study): rationale, design and end-points. Eur J Heart Fail 2001;3:481-489.[CrossRef][Medline]
- Cohn JN, Pfeffer MA, Rouleau J, et al. MOXCON InvestigatorsAdverse mortality effect of central sympathetic inhibition with sustained-release moxonidine in patients with heart failure (MOXCON). Eur J Heart Failure 2003;5:659-667.[CrossRef][Medline]
- Chung ES, Packer M, Lo KH, Fasanmade AA, Willerson JT, Anti-TNF Therapy Against Congestive Heart Failure Investigators Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor-alpha, in patients with moderate-to-severe heart failure: results of the anti-TNF Therapy Against Congestive Heart Failure (ATTACH) trial Circulation 2003;107:3133-3140.[Abstract/Free Full Text]
- Mann DL, McMurray JJ, Packer M, et al. Targeted anticytokine therapy in patients with chronic heart failure: results of the Randomized Etanercept Worldwide Evaluation (RENEWAL) Circulation 2004;109:1594-1602.[Abstract/Free Full Text]
- Velazquez EJ, Pfeffer MA. Acute heart failure complicating acute coronary syndromes: deadly intersection Circulation 2004;109:440-442.[Free Full Text]
- Steg PG, Dabbous OH, Feldman LJ, et al. Global Registry of Acute Coronary Events InvestigatorsDeterminants and prognostic impact of heart failure complicating acute coronary syndromes: observations from the Global Registry of Acute Coronary Events (GRACE). Circulation 2004;109:494-499.[Abstract/Free Full Text]
- Antman EM, Anbe DT, Armstrong PW, et al. American College of Cardiology/American Heart Association Task Force on Practice Guidelines/Canadian Cardiovascular SocietyACC/AHA guidelines for the management of patients with ST elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1999 Guidelines for the Management of Patients with Acute Myocardial Infarction). J Am Coll Cardiol 2004;44:e1-211.[CrossRef][Medline]
- Dargie HJ. Effect of carvedilol on outcome after myocardial infarction in patients with left-ventricular dysfunction: the CAPRICORN randomised trial Lancet 2001;357:1385-1390.[CrossRef][Medline]
- Pfeffer MA, McMurray JJ, Velazquez EJ, et al. Valsartan in Acute Myocardial Infarction Trial InvestigatorsValsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med 2003;349:1893-1906.[Abstract/Free Full Text]
- Swedberg K, McMurray JJV. Angiotensin receptor blockers and heart failure: still CHARMing after VALIANT? Eur Heart J 2004;25:357-358.[Free Full Text]
- McMurray JJV, Pfeffer MA, Swedberg K, Dzau VJ. Which inhibitor of the renin-angiotensin system should be used in chronic heart failure and acute myocardial infarction? Circulation 2004;110:3281–8..
- Pitt B, Remme W, Zannad F, et al. Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study InvestigatorsEplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 2003;348:1309-1321.[Abstract/Free Full Text]
- Schiff GD, Fung S, Speroff T, McNutt RA. Decompensated heart failure: symptoms, patterns of onset, and contributing factors Am J Med 2003;114:625-630.[CrossRef][Medline]
- O'Connor CM, Gattis WA, Teerlink JR, Adams Jr KF, Gheorghiade M. Design considerations and proposed template for clinical trials in hospitalised patients with decompensated chronic heart failure Am Heart J 2003;145:S47-50.[CrossRef][Medline]
- Teerlink JR. Dyspnea as an end point in clinical trials of therapies for acute decompensated heart failure Am Heart J 2003;145:S26-33.[CrossRef][Medline]
- Torre-Amione G, Young JB, Colucci WS, et al. Hemodynamic and clinical effects of tezosentan, an intravenous dual endothelin receptor antagonist, in patients hospitalized for acute decompensated heart failure J Am Coll Cardiol 2003;42:140-147.[Abstract/Free Full Text]
- Gheorghiade M, Niazi I, Ouyang J, et al. Tolvaptan InvestigatorsVasopressin V2-receptor blockade with tolvaptan in patients with chronic heart failure: results from a double-blind, randomized trial. Circulation 2003;107:2690-2696.[Abstract/Free Full Text]
- Felker GM, Benza RL, Chandler AB, et al. OPTIME-CHF InvestigatorsHeart failure etiology and response to milrinone in decompensated heart failure: results from the OPTIME-CHF study. J Am Coll Cardiol 2003;41:997-1003.[Abstract/Free Full Text]
- Kivikko M, Lehtonen L, Colucci WS. Sustained hemodynamic effects of intravenous levosimendan Circulation 2003;107:81-86.[Abstract/Free Full Text]
- Tenenbaum A, Motro M, Fisman EZ, et al. Functional class in patients with heart failure is associated with the development of diabetes Am J Med 2003;114:271-275.[CrossRef][Medline]
- Vermes E, Ducharme A, Bourassa MG, Lessard M, White M, Tardif JC. Enalapril reduces the incidence of diabetes in patients with chronic heart failure: insight from the Studies Of Left Ventricular Dysfunction (SOLVD) Circulation 2003;107:1291-1296.[Abstract/Free Full Text]
- Smith GL, Vaccarino V, Kosiborod M, et al. Worsening renal function: what is a clinically meaningful change in creatinine during hospitalization with heart failure? J Cardiac Failure 2003;9:13-25.[CrossRef][Medline]
- Kittleson M, Hurwitz S, Shah MR, et al. Development of circulatory-renal limitations to angiotensin-converting enzyme inhibitors identifies patients with severe heart failure and early mortality J Am Coll Cardiol 2003;41:2029-2035.[Abstract/Free Full Text]
- Wang TJ, Larson MG, Levy D, et al. Temporal relations of atrial fibrillation and congestive heart failure and their joint influence on mortality: the Framingham Heart study Circulation 2003;107:2920-2925.[Abstract/Free Full Text]
- Vermes E, Tardif JC, Bourassa MG, et al. Enalapril decreases the incidence of atrial fibrillation in patients with left ventricular dysfunction: insight from the Studies Of Left Ventricular Dysfunction (SOLVD) trials Circulation 2003;107:2926-2931.[Abstract/Free Full Text]
- Anker SD, Negassa A, Coats AJ, et al. Prognostic importance of weight loss in chronic heart failure and the effect of treatment with angiotensin-converting-enzyme inhibitors: an observational study Lancet 2003;361:1077-1083.[CrossRef][Medline]
- Kosiborod M, Smith GL, Radford MJ, Foody JM, Krumholz HM. The prognostic importance of anemia in patients with heart failure Am J Med 2003;114:112-119.[CrossRef][Medline]
- Felker GM, Gattis WA, Leimberger JD, et al. Usefulness of anemia as a predictor of death and rehospitalization in patients with decompensated heart failure Am J Cardiol 2003;92:625-628.[CrossRef][Medline]
- Ezekowitz JA, McAlister FA, Armstrong PW. Anemia is common in heart failure and is associated with poor outcomes: insights from a cohort of 12,065 patients with new-onset heart failure Circulation 2003;107:223-225.[Abstract/Free Full Text]
- Mozaffarian D, Nye R, Levy WC. Anemia predicts mortality in severe heart failure: the Prospective Randomised Amlodipine Survival Evaluation (PRAISE) J Am Coll Cardiol 2003;41:1933-1939.[Abstract/Free Full Text]
- Mancini DM, Katz SD, Lang CC, LaManca J, Hudaihed A, Androne AS. Effect of erythropoietin on exercise capacity in patients with moderate to severe chronic heart failure Circulation 2003;107:294-299.[Abstract/Free Full Text]
- Nesto RW, Bell D, Bonow RO, et al. American Heart Association; American Diabetes Association. Thiazolidinedione use, fluid retention, and congestive heart failure: a consensus statement from the American Heart Association and American Diabetes AssociationOctober 7, 2003. Circulation 2003;108:2941-2948.[Free Full Text]
- Mansfield DR, Gollogly NC, Kaye DM, Richardson M, Bergin P, Naughton MT. Controlled trial of continuous positive airway pressure in obstructive sleep apnea and heart failure Am J Respir Crit Care Med 2003;169:361-366.[Medline]
- Mansfield DR, Gollogly NC, Kaye DM, Richardson M, Bergin P, Naughton MT. Controlled trial of continuous positive airway pressure in obstructive sleep apnea and heart failure Am J Respir Crit Care Med 2004;169:361-366.[Abstract/Free Full Text]
- Komajda M, Follath F, Swedberg K, et al. Study Group on Diagnosis of the Working Group on Heart Failure of the European Society of Cardiology. The EuroHeart Failure Survey programme—a survey on the quality of care among patients with heart failure in EuropePart 2: treatment. Eur Heart J 2003;24:464-474.[Abstract/Free Full Text]
- Stromberg A, Martensson J, Fridlund B, Levin LA, Karlsson JE, Dahlstrom U. Nurse-led heart failure clinics improve survival and self-care behaviour in patients with heart failure: results from a prospective, randomised trial Eur Heart J 2003;24:1014-1023.[Abstract/Free Full Text]
- Laramee AS, Levinsky SK, Sargent J, Ross R, Callas P. Case management in a heterogeneous congestive heart failure population: a randomized controlled trial Arch Intern Med 2003;163:809-817.[Abstract/Free Full Text]
- Jerant AF, Azari R, Martinez C, Nesbitt TS. A randomized trial of telenursing to reduce hospitalization for heart failure: patient-centered outcomes and nursing indicators Home Health Care Serv Q 2003;22:1-20.[Medline]
- Benatar D, Bondmass M, Ghitelman J, Avitall B. Outcomes of chronic heart failure Arch Intern Med 2003;163:347-352.[Abstract/Free Full Text]
- Ansari M, Shlipak MG, Heidenreich PA, et al. Improving guideline adherence: a randomized trial evaluating strategies to increase beta-blocker use in heart failure Circulation 2003;107:2799-2804.[Abstract/Free Full Text]
- Maggioni AP, Sinagra G, Opasich C, et al. Beta Blockers in Patients with Congestive Heart Failure: Guided Use in Clinical Practice InvestigatorsTreatment of chronic heart failure with beta-adrenergic blockade beyond controlled clinical trials: the BRING-UP experience. Heart 2003;89:299-305.[Abstract/Free Full Text]
This article has been cited by other articles:
|
|
|
|
 
Y. Michowitz, E. Goldstein, D. Wexler, D. Sheps, G. Keren, and J. George
Circulating endothelial progenitor cells and clinical outcome in patients with congestive heart failure
Heart,
September 1, 2007;
93(9):
1046 - 1050.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Bursi, S. A. Weston, M. M. Redfield, S. J. Jacobsen, S. Pakhomov, V. T. Nkomo, R. A. Meverden, and V. L. Roger
Systolic and diastolic heart failure in the community.
JAMA,
November 8, 2006;
296(18):
2209 - 2216.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. A Poole-Wilson, A. R. Lyon, and A. M. Jacques
A commentary on clinical trials in chronic heart failure.
Seminars in Cardiothoracic and Vascular Anesthesia,
September 1, 2006;
10(3):
242 - 245.
[Abstract]
[PDF]
|
|
|
|
|
|
|
J. J.V. McMurray, F. L. Andersson, S. Stewart, K. Svensson, A. C. Solal, R. Dietz, J. Vanhaecke, D. J. van Veldhuisen, J. Ostergren, C. B. Granger, et al.
Resource utilization and costs in the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) programme.
Eur. Heart J.,
June 1, 2006;
27(12):
1447 - 1458.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. C. Daubert, C. Leclercq, and P. Mabo
There Is Plenty of Room for Cardiac Resynchronization Therapy Devices Without Back-Up Defibrillators in the Electrical Treatment of Heart Failure
J. Am. Coll. Cardiol.,
December 20, 2005;
46(12):
2204 - 2207.
[Abstract]
[Full Text]
[PDF]
|
|
|
Top
Improving clinical outcomes in...
HF with preserved left...