YEAR IN CARDIOLOGY SERIES
The Year in Heart Failure
W.H. Wilson Tang, MD, FACC* and
Gary S. Francis, MD, FACC
Department of Cardiovascular Medicine, the Cleveland Clinic, Cleveland, Ohio.
* Reprint requests and correspondence: Dr. W. H. Wilson Tang, Department of Cardiovascular Medicine, Cleveland Clinic, 9500 Euclid Avenue, Desk F25, Cleveland, Ohio 44195. (Email: tangw{at}ccf.org).
Although it has been customary to highlight the results of pivotal clinical trials in this review, the year 2006 is best characterized as a year of consensus building in heart failure. Guidelines from several major cardiology societies worldwide have been revised, updated, and compared, and large registries have provided further observational insights into contemporary issues for the care for patients with heart failure. Challenges in drug development continue, and a noticeable shift has occurred toward better understanding of acute heart failure syndromes (AHFS), especially regarding the preservation of renal function. We summarize herein our view of a number of important publications and pivotal presentations from international meetings within this past year in the area of heart failure.
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Consensus guidelines in clinical management of heart failure
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Clinical management guidelines from several major cardiology societies around the world have been published in the past year (1–4). The latest addition is the comprehensive guidelines from the Heart Failure Society of America (HFSA) that address the full range of evaluation, care, and management of patients with heart failure (1). Included in this publication is a discussion of topics such as diastolic heart failure, myocarditis, and AHFS, for which we still lack robust data with respect to optimal treatment and management. The HFSA Guideline Committee plans to periodically update this document on their website. Fundamentally, all guidelines endorse evidence-based administration of neurohormonal antagonists, but there are some semantic differences in the approach to device-based therapies such as implantable cardioverter-defibrillators and cardiac resynchronization therapy (CRT). These differences are likely related to the regional variations of health care finances and delivery systems. We also have learned that there is significant individual variability in conformity to quality-of-care indicators and clinical outcomes throughout the U.S. (5). Two important publications from the American College of Cardiology and American Heart Association (ACC/AHA) describe key definitions (6) and clinical performance measures (7). Their goal is to provide a uniform standard of key components needed to compare hospital practices.
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Patients at risk to develop heart failure (Stages A and B)
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Genetic determinants of cardiomyopathies.
Several intriguing discoveries regarding the genetics of heart failure have emerged this year. New genetic mutations found in dilated cardiomyopathy have become the staple of several research laboratories during the past few years, and new discoveries have been made using kindred-based genome-wide linkage analyses (8,9). Recently, a contemporary classification scheme for cardiomyopathies has been proposed in an effort to recognize the rapid evolution of molecular genetics in this area (10). However, the future of targeted heart failure genomics will likely depend on the availability of tissue samples for genetic, transcriptomic, and proteomic analyses. A small-but-important study by Lowes et al. (11) reported on a series of patients who had undergone sequential endomyocardial biopsy evaluation and genetic microarray evaluation before and after medical therapy. The authors found that serial gene expression profiling was feasible in the intact human heart. In addition, intact failing remodeled human hearts demonstrated an activated state of gene expression, which decreased with clinical improvement.
Several new observations in polymorphism research also have brought us one step closer to the reality of pharmacogenetics in heart failure. The focus has shifted from identification of patients who have a poorer prognosis or may develop a particular phenotype to better understanding why different individuals respond differently to the same drug. In an elegant post-hoc study by Liggett et al.(12), varying polymorphisms within the ß1-adrenergic receptor were postulated to explain the differential responses to bucindolol in the large randomized, controlled BEST (Beta-blocker Evaluation of Survival Trial). Interestingly, in the BEST study, African American patients faired worse than Caucasian patients, whereas Caucasian patients demonstrated a survival benefit from bucindolol. It is possible that these differences in response are related to a polymorphism in the ß1-adrenergic receptor. The observations suggest that bucindolol may yet be an excellent choice of beta-blocker therapy in Caucasian subjects who lack the specific polymorphism in the ß1-receptor; a clinical trial to test this hypothesis is needed. Another recent report by McNamara et al. (13) observed that the TT genotype of the –344C allele, known to be linked to higher expression of aldosterone synthase, was associated with poorer event-free survival in African Americans in the A-HeFT (African American Heart Failure Trial) (13). This genotype, which was found predominantly in African Americans and has been previously linked to low-renin hypertension, also was associated with improvement in functional status after fixed-dose hydralazine-isosorbide dinitrate therapy (13).
Cardiotoxicity of cancer chemotherapy.
With the expansion of new drug regimens for treating cancers, there are growing concerns regarding cardiac complications. The "chemotherapy" population has not always been fully recognized by the oncology and cardiology communities to be at risk for heart failure. Traditionally, cardiotoxicity of anthracyclines and radiation therapy have been minimized by reducing dose, and no formal cardiac surveillance has been advocated in the absence of symptoms. However, heart failure leading to cardiac mortality can occur years to decades after radiation (14), and some relatively new drugs such as trastuzumab have been reported to be associated with cardiac dysfunction and incident heart failure (15–19). Fortunately, in some cases, neurohormonal antagonists can reverse trastuzumab-induced cardiac dysfunction (19). Recent concerns also have emerged regarding patients experiencing heart failure after treatment with imatinib mesylate, another "miracle-drug" in cancer chemotherapy and one of the first tyrosine kinase inhibitors to be used to treat chronic myelogenous leukemia and other malignancies (20,21). Histologic studies have demonstrated mitochondrial abnormalities and accumulation of membrane whorls in both vacuoles and the sarcoplasmic reticulum in the hearts of patients treated with imatinib who experience heart failure. With more tyrosine kinase inhibitors being developed as antineoplastic agents, vigilant cardiac surveillance of patients will be necessary for immediate as well as late cardiotoxic consequences. The timing and extent of cardiac evaluation, however, have not been not established.
Screening strategies for asymptomatic patients.
With widespread adoption of the AHA/ACC heart failure staging scheme, there is a greater need to detect cardiac dysfunction at its earliest, minimally-symptomatic stage (Stage B) (2). Natriuretic peptides have been considered the best candidate for population screening for cardiac dysfunction. However, significant limitations of the use of natriuretic peptides for population screening include biological and assay variability, as well as the relatively low specificity of diagnostic cutoffs that are associated with acceptable negative predictive values. Overall, B-type natriuretic peptide (BNP) and its amino-terminal fragment, NT-proBNP, are equivalent in accuracy when screening for cardiac dysfunction; NT-proBNP may be superior to BNP in detecting left ventricular ejection fraction  40% in men (22). Furthermore, both BNP and NT-proBNP are independent predictors of long-term mortality in otherwise-asymptomatic populations, even after adjusting for various clinical and echocardiographic variables (23). Screening large populations of patients at risk for heart failure is a rational strategy, but its cost-effectiveness can be challenged. Studies have moved beyond using a single biomarker for population screening. Ng et al. (24) have reported excellent accuracies and potential cost-savings using a combination of natriuretic peptides and inflammatory biomarkers like myeloperoxidase and C-reactive protein in a large community-based British population compared with single-marker or echocardiographic approaches. However, this combined strategy remains to be tested prospectively, particularly in populations with higher prevalence of cardiac dysfunction in which the yield of a biomarker-based screening strategy may be higher. Even if electrocardiography and natriuretic peptide screening are adequate in determining the probability of the presence of left ventricular systolic dysfunction, the challenge is to adequately screen for other structural abnormalities such as valvular disease or left ventricular hypertrophy that may ultimately lead to progression of cardiac dysfunction (25). Although screening asymptomatic patients at risk, detecting surrogate markers, and initiating early treatment to prevent heart failure appears to be an obvious strategy, there are several challenges that remain: very large sample sizes are needed to demonstrate benefits of early treatment, the most cost-effectiveness manner of screening patients is still unsettled, and the cost of screening is not uniformly covered by insurance or other payers.
Preventive therapy in heart failure.
Beyond the challenges of screening, the treatment of asymptomatic patients who are at risk of developing heart failure has some basis in clinical trials. Based on SOLVD (Studies of Left Ventricular Dysfunction), angiotensin-converting enzyme inhibitors have long been considered the drug of choice in patients with asymptomatic or minimally symptomatic left ventricular dysfunction. Recently, an interesting post-hoc analysis highlighted the potential benefits of losartan in reducing hospitalization for heart failure when compared with either placebo or to atenolol in patients without a history of heart failure (26). Although many of the cardiac risk factors for developing heart failure found in this study are well recognized (such as left ventricular hypertrophy, diabetes, previous myocardial infarction, increasing age, atrial fibrillation, and body mass index), others, such as urinary albumin/creatinine ratio (measure of microvascular integrity) and the presence of peripheral vascular disease (extension of vasculopathy), also appear to be predictive of subsequent development of heart failure.
The two most surprising observations regarding use of older drugs to prevent heart failure pertained to diuretics and statin therapy. In a post-hoc analysis of ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial), the relative risk of developing heart failure was lower with the use of chlorthalidone than with lisinopril or amlodipine during the first year, but this advantage appeared to diminish over time (27). Furthermore, patients with elevated plasma BNP levels who were treated with statin therapy had an associated reduction in heart failure hospitalization (28). Furthermore, a meta-analysis of four trials (27,546 patients) demonstrated a 27% reduction in the odds of hospitalization for heart failure in patients treated with intensive statin therapy (28). These findings may be explained, in part, by a reduction in recurrent myocardial ischemia, but there is a possibility that statins may have some as of yet undefined role in benefiting patients with heart failure.
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Chronic heart failure (Stages C and D)
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Serial monitoring of biomarkers.
This year marked the consolidation of additional evidence in the use of biomarker-guided therapy to manage heart failure. A natriuretic peptide-guided approach assumes a close association between reductions in plasma levels of natriuretic peptides and improvement in clinical outcomes. This relationship has been supported by two publications this year. In the setting of acute coronary syndrome, Morrow et al. (29) demonstrated that normalization of plasma BNP levels over a period of months may reflect low clinical risk of subsequent development of heart failure, whereas persistent or incident high plasma BNP levels are associated with a higher long-term event rate. In patients with chronic heart failure, Latini et al. (30) showed similar data with reduction in sequential BNP values being associated with improved clinical outcomes in the Val-HeFT (Valsartan in Heart Failure Trial). Although short-term changes in plasma BNP levels have not been closely associated with changes in blood volumes or invasive hemodynamics (31), longer term changes in plasma BNP levels do track with sequential intracardiac pressures measured by implanted hemodynamic devices (32). Several ongoing investigations will hopefully shed more light on the potential benefits and challenges of this targeted approach (33,34). In contrast to the natriuretic peptides, sequential troponin levels have not been shown to help guide therapy despite the fact that small increases in plasma troponin levels have prognostic importance in patients with advanced heart failure (35). This may change with the emergence of a commercially available ultra-sensitive troponin assay.
Natriuretic peptide assays are now widely used to facilitate the clinical diagnosis of heart failure and several different assays are available. Although they have different absolute values, BNP and NT-proBNP assays display near-identical test performance for detection of cardiac dysfunction and for prediction of long-term events (36). Several interesting observations have emerged regarding measurements of natriuretic peptides. In an elegant study performed at the Mayo Clinic, patients with severe heart failure were noted to have circulating natriuretic peptides moieties detected by standard clinical immunoassays that were higher than the biologically active BNP-32 peptide identified by mass spectroscopy (37). Recognizing the limitations of existing clinical immunoassasys that detect both the fragment of the cleaved prohormone as well as the intact prohormone itself, several new immunoassays have become available to detect the mid-regions of the prohormone (38,39). The concept of a "wet BNP," measured by alternative forms of natriuretic peptides or their ratios, has been raised as a potential diagnostic strategy. We still have a lot to learn about the regulation of synthesis, storage, and release of these natriuretic hormones from the heart and the regulation of their degradation once they are released into the circulation.
Neurohormonal antagonists in heart failure.
As the pathophysiologic role of aldosterone in human heart failure becomes more established (40), the appropriate use and clinical monitoring of aldosterone receptor antagonists in patients with heart failure remains a popular topic. The incidence of hyperkalemia and renal insufficiency in some cases may outweigh the potential benefits of this drug class (41,42). In particular, elderly patients (many of whom have reduced creatinine clearance and use multiple drugs) may be especially prone to adverse effects from this class of drugs. Therefore, their renal function and serum potassium levels should be carefully monitored during therapy (43). As the use of aldosterone antagonists expands into treatment of patients with less severe heart failure, guidelines regarding monitoring may be helpful. An intriguing retrospective analysis of a cohort of patients with mild-to-moderate chronic heart failure demonstrated a favorable trend of improved mortality when adding on spironolactone (44). The launching of a large multicenter study this year, the European EMPHASIS (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure) trial, hopefully will close the knowledge gap regarding the use of aldosterone receptor blockers in less severely ill patients.
The role of the cardiac mast cell in the pathophysiology of heart failure has also received some attention, with the publication of an important observation linking cardiac mast cells to myocardial renin production (45), as well as a prospective validation study using histamine H1 receptor antagonists to induce reverse remodeling in patients with dilated cardiomyopathy (46). With the ongoing clinical development program for oral renin inhibitors, such as aliskiren for hypertension, it is likely that cardiac renin will become important target of therapy. The results of the ongoing proof-of-concept Phase II study, ALOFT (Aliskiren in Heart Failure Trial), are eagerly awaited.
Several studies regarding the role of neurohormonal antagonists for reducing the incidence of atrial fibrillation have emerged this year. The incidence of atrial fibrillation can be reduced by treatment with angiotensin-converting enzyme inhibitors and with angiotensin receptor blockers in patients with mild-to-moderate heart failure (47–49). The onset of atrial fibrillation is less likely to be influenced by cardiac resynchronization therapy in advanced heart failure (50). Although heart rate control is still an acceptable option for managing atrial fibrillation and mild-to-moderate heart failure, there is an emerging belief that establishing normal sinus rhythm is the preferred strategy since the presence of atrial fibrillation portends worse prognosis (51–53).
Prediction models of prognosis in heart failure.
New models that use multiple variables to predict prognosis in patients with heart failure have emerged. Levy et al. (54) used commonly derived clinical variables from several large clinical trial databases and produced an interactive prediction model that allows clinicians to determine the differential impact of various interventions on outcomes in patients with heart failure. Many risk factors were also identified in the CHARM (Candesartan in Heart Failure Assessment of Reduction in Morbidity and Mortality) prognostic models (55). A limitation of such prediction models is the availability and reliability of the collected data. Nevertheless, many of the important predictors, such as advanced age, left ventricular ejection fraction, diabetes mellitus, and renal insufficiency, are well represented in these models.
Although metabolic stress testing has been one of the gold standards for prognostic evaluation for heart failure (and for the purpose of decision making for transplant candidacy), recent data have caused researchers to questioned the equivalency of prognostic value derived from peak exercise oxygen consumption (peak VO
2) between men and women (56). Women in this retrospective study had better 1-year survival rates than men for any given VO
2 level. Although clinicians base transplant candidacy on more than a single variable, it is important to take gender into account in the interpretation of peak VO
2 values.
Disease management in heart failure.
One of the most important and intriguing reports published this year was unrelated to new drugs, devices, surgical techniques, or basic science discoveries. Granger et al. (57) demonstrated that the morbidity and mortality benefits in the CHARM study were apparent for both candesartan and placebo groups if the participants adhered to taking >80% of their prescribed pills, even after adjustments for predictive factors for nonadherence (57). Nurse-management strategies using simple, low-technology communication again demonstrated improved outcomes (58,59), emphasizing the importance of team management in the care of these complex patients.
Several interesting epidemiological and observational reports have challenged traditional recommendations for patients with heart failure. One report described an association between modest alcohol consumption and reduced heart failure incidence in the elderly population (60). This was also found in the post-hoc analysis of the LIFE (Losartan Intervention for Endpoint Reduction) trial, where an inverse relationship between incident heart failure hospitalizations and alcohol use was found (26). Recent data also challenge the recommendation for alcohol abstinence in patients with mild-to-moderate heart failure (61). Only heavy drinking seems to portend a higher risk for heart failure hospitalizations (62). Another unexpected observation was paradoxical worsening of all-cause mortality despite tighter glycemic control in diabetic patients with advanced heart failure (63). These isolated observations have not been confirmed in larger cohorts or prospective studies and may be due to unrecognized confounding factors. Nevertheless, they do provoke interest, and prompt a rethinking of the "evidence" behind the many recommendations we routinely make to our patents with heart failure. We now know that our advice to our patients varies widely, especially with respect to non-pharmacologic issues (64).
Challenges to the inflammation hypothesis.
Results of several preliminary studies have generated skepticism regarding the strategy for targeting specific inflammatory pathways as a therapy for heart failure. The results of the 2,414-patient ACCLAIM (Advanced Chronic Heart Failure Clinical Assessment of Immune Modulation Therapy) trial will be presented at the World Congress in Cardiology as well as the HFSA Annual Scientific Meeting, but an early press release from the company has announced neutral results of the overall study. Challenges regarding further development of this treatment strategy will likely be raised.
Perhaps we need to better target specific "inflammatory" phenotypes of heart failure. Publications regarding inflammatory biomarkers in acute and chronic heart failure, such as C-reactive protein (65,66), myeloperoxidase (67), and even serum copper levels (68) continue to appear in the literature. Several interesting new inflammatory biomarkers also have emerged. One of these is adiponectin, an adipocyte-derived cytokine that has been shown to have anti-inflammatory properties. Serum adiponectin levels have been observed to be reduced in patients with coronary artery disease and diabetes mellitus, but high levels paradoxically confer a poor prognosis in patients with advanced heart failure (69,70). The true test for a useful "inflammatory biomarker" remains the ability to identify such a marker in an at-risk population and then reduce clinical events in this group with specific immunomodulatory strategies. To date, this has not been possible.
The promise of statin therapy.
One of the more promising therapeutic strategies related to the inflammation hypothesis has been the use of statins in patients with established heart failure. This year marked the publication of several more observational studies and post-hoc analyses in the area of statin therapy for heart failure (71,72). Two multicenter, prospective, double-blind, randomized trials indicate favorable effects with atorvastatin (20 to 40 mg/day) in subjects with nonischemic dilated cardiomyopathy over standard therapy (73,74). Both studies demonstrate evidence of reverse remodeling with atorvastatin therapy. Sola et al. (75) also showed further reduction of cytokine levels and clinical outcomes with atorvastatin (even at low doses). However, conflicting results also appeared in the literature with the publication of a mechanistic study where high-dose (80 mg/day for 12 weeks with crossover) atorvastatin failed to demonstrate significant improvement in biomarkers of inflammation, heart failure, endothelial function, and vagal tone when compared with that in the placebo group (76). Preliminary results of one of the most anticipated studies on this area have been presented at the recent ACC Scientific Sessions: the UNIVERSE (Rosuvastatin Impact on Ventricular Remodeling Cytokines and Neurohormones) study. This study tested the hypothesis that rosuvastatin therapy can reverse left ventricular remodeling as measured by magnetic resonance imaging. Compared to placebo, rosuvastatin was associated with significant reduction of low-density lipoprotein cholesterol, but no effects on left ventricular dimension, left ventricular ejection fraction, or neurohormones were observed (77). These disappointing data have dampened the initial enthusiasm regarding the role of statins in as primary therapy in treating heart failure. We shall see whether upcoming mortality trials demonstrate morbidity and mortality benefits with statin therapy.
Anemia as therapeutic target in heart failure.
Anemia has been recognized as a potential therapeutic target, after several reports illustrated the independent prognostic value of anemia from a wide range of clinical registries in patients with heart failure with either impaired and preserved systolic function (78–81). In older patients, anemia also can be an independent predictor of hospital readmission, but its relationship to increased mortality can also be largely explained by the severity of comorbid conditions such as renal insufficiency (82). Although the underlying cause for anemia in heart failure may be multifactorial, reduced sensitivity to erythropoietin receptors, the presence of a hematopoiesis inhibitor, and/or a defective iron supply for erythropoiesis are possible explanations (83,84). Some have challenged the prognostic importance of anemia in advanced heart failure when considered with other well-established prognostic factors (85). Recent combined results from Phase II trials showed treatment with darbepoetin alpha was associated with favorable trends toward an improvement in quality of life, better exercise capacity, and a suggestion of mortality benefit (86). A large international study, RED-HF (Reduction of Events with Darbepoetin in Heart Failure), has been launched this year to establish the safety and efficacy of darbepoetin in patients with heart failure.
New developments in diastolic heart failure.
There has been an increasing dialogue in the literature on the pathophysiologic concepts of diastolic heart failure, and careful examination of left ventricular myocardial structure and function has demonstrated significant differences in cardiomyocyte abnormalities between the two phenotypes (87). Disappointingly, drugs that had been postulated to have beneficial roles in this population, such as nebivolol (88) and digoxin (89), recently have been shown to have neutral long-term effects.
Two new reports in the New England Journal of Medicine highlighted the contemporary epidemiology of diastolic heart failure. In the Canadian study, patients with diastolic heart failure presented with significantly more pulmonary edema and pleural effusion and were more likely to be older, female, hypertensive, and have atrial fibrillation and chronic obstructive pulmonary disease. The unadjusted death rate at one year was 22.2%, compared with 25.5% for patients with systolic heart failure. However, after adjustments, they had equivalent, if not higher, mortality rates (90). In contrast, the long-term follow-up of the Mayo Clinic series demonstrates that the prevalence of diastolic heart failure has increased from 38% to 54%, which was attributed to increased hospital admission rates in this cohort (which held steady for those with systolic heart failure). In parallel to the lack of evidence-based guidelines for therapy, patients with diastolic heart failure have demonstrated stable death rates, whereas mortality decreased for patients with systolic heart failure (91). Although new trials looking at the role of aldosterone receptor antagonists and endothelin receptor antagonists are being launched, it will be years before we have evidence-based therapeutic strategies for this condition. Perhaps, the most positive data available pertains to candesartan, but this arm of the CHARM study was underpowered and failed to demonstrate a robust survival benefit (92).
Levosimendan for inotropic support in AHFS.
Although levosimendan has been approved for use in several countries, recent trial data presented at last year’s AHA Annual Scientific Sessions have sparked intense debate over its clinical development in the U.S. In the American REVIVE-II (Randomized Multicenter Evaluation of Intravenous Levosimendan Efficacy versus Placebo in the Short Term Treatment of Decompensated Heart Failure) trial, a total of 600 patients (left ventricular ejection fraction <35%) refractory to diuretics and vasodilators within 48 h of hospital admission were randomized to receive levosimendan or placebo. Patients who rated themselves as moderately or markedly improved at 6 h, 24 h, and 5 days were considered to be "improved," provided that they met no criteria for worsening (death, patient self-reported moderate or severe deterioration at any time point, or worsening symptoms at any time or persistent severe symptoms after 24 h requiring rescue therapy). This complex primary composite end point was more favorably affected by levosimendan (93), but only 6% more patients were deemed "improved." In contrast, levosimendan was associated with increasing trends for hypotension (50% vs. 36%), atrial fibrillation (8% vs. 2%), and even 90-day mortality (45 vs. 35 deaths) compared with the placebo group (93). The parallel European SURVIVE (Survival of Patients with Acute Heart Failure in Need of Intravenous Inotropic Support) trial examined 1,327 patients admitted for AHFS and requiring inotropic support, randomized to either dobutamine or levosimendan infusions. As in REVIVE-II, plasma BNP levels were significantly reduced in the levosimendan arm compared to the dobutamine arm. Compared to the dobutamine group, mortality in the levosimendan group up to 6 months was not reduced (93). These two trials highlight the major challenges in studying the safety and efficacy of a short-term drug infusion in patients with AHFS where surrogate markers may be affected differently than outcome benefits.
Meanwhile, the recent early termination of TRIUMPH (Tilarginine Acetate for Injection in a Randomized International Study in Unstable Acute Myocardial Infarction Patients with Cardiogenic Shock) halted the clinical development of tilarginine acetate injections for cardiogenic shock. Many of the clinical trials in AHFS will likely falter because we are still facing the difficult task of defining appropriate end points in a highly complex patient population.
Salt and water removal in volume overloaded states: vaptans and ultrafiltration.
The increasing emphasis of congestion as a target of therapy for AHFS represents a slow-but-steady migration of treatment philosophy toward devices and drugs that specifically target salt and water removal. Vasopressin receptor antagonists have emerged as a novel class of drugs ("aquaretics") that remove water by increasing aquaporin-2 activity at the collecting ducts. Preliminary data from a dose-ranging study on conivaptan demonstrated significant improvement in hyponatremia in patients with or without decompensated heart failure (94). Lixivaptan, another V2-specific vasopressin receptor antagonist, had similar aquaretic effects to tolvaptan (95). The large pivotal study for tolvaptan, EVEREST (The Efficacy of Vasopressin antagonism in Heart Failure Outcome Study with Tolvaptan) (96) will be announced later this year, and if results are favorable in reducing clinical events, this drug class will have a very important role in managing congestion.
Ultrafiltration (or "aquaphoresis" as it is now described as) has generated some attention this year with a number of publications from small-scale studies (97,98), plus the announcement of the results of the UNLOAD (Ultrafiltration versus IV Diuretics for Patients Hospitalized for Acute Decompensated Congestive Heart Failure) trial at the ACC Scientific Sessions (77,94). In the UNLOAD trial, treatment with ultrafiltration for mechanical salt and water removal resulted in a 53% reduction in the total number of hospitalizations (18% vs. 32%, p = 0.002), a 64% decrease in total number of rehospitalizations days (123 vs. 330 days, p = 0.022), and a 53% decrease in emergency room and unscheduled office visits (21% vs. 44%, p = 0.009) during the first 90 days after treatment compared with standard intravenous diuretics. Importantly, ultrafiltration treatment was associated with 44% more weight loss (5.0 vs. 3.1 kg, p = 0.001), and 30% more fluid loss (4.6 vs. 3.3 l, p = 0.001) than medical therapy as early as 48 h after initiation, without significant overall differences in renal function. Although these results are promising, broad clinical adoption may continue to be hindered by the cost and invasiveness of the technology.
Renal preservation and the promise of adenosine receptor antagonists.
The challenge of preserving renal function in patients with chronic and acute heart failure remains a critical obstacle. One of the newer developments in this area is the recognition that renal perfusion and glomerular filtration rates (GFRs) are important both prognostically and therapeutically. Post-hoc analyses from CHARM and other trials have suggested that both serum creatinine and estimated GFR are important prognostic indicators for long-term outcomes (99,100). Although poor renal function predicts a poor prognosis, patients with moderate renal insufficiency may derive the most benefit from drugs blocking the renin-angoitensin-aldosterone system. Plasma cystatin C has provided valuable information regarding early renal insufficiency (and even "preclinical" renal disease), and independently predicts long-term prognosis (101). Meanwhile, chronic diuretic use continues to be challenged, as post-hoc analyses of the DIG (Digitalis Investigation Group) trial indicated diuretic therapy may be a potentially harmful intervention (102,103).
The benefits of a new drug class known as adenosine receptor antagonists have been clarified and confirmed this year. Results from a series of Phase II studies with KW-3902 were presented in both European and American heart failure meetings this year. In a combined analysis of two studies involving 186 subjects, the adenosine A1 receptor antagonist, KW-3902, showed a dose-dependent increase in urine volume and a reduction in loop diuretic need in fluid-overloaded patients with AHFS (86). Meanwhile, there was a remarkable 30% improvement in GFR as well as renal plasma flow with KW-3902 compared with placebo in the setting of diminishing responses to loop diuretics during AHFS. Two adenosine receptor antagonists are currently undergoing clinical development.
Long-term follow-up for cardiac resynchronization therapy.
As broad use of CRT devices continues, data regarding sustained mortality benefits of CRT became available this year with the publication of the extension of the CARE-HF (Cardiac Resynchronization in Heart Failure) study. Cardiac resynchronization therapy demonstrates continued mortality benefit by reducing both pump failure and sudden cardiac death even in the absence of an implantable cardioverter-defibrillator (104). This has been observed in parallel with the echocardiographic evidence of long-term reverse remodeling, especially in patients with non-ischemic cardiomyopathy (105). There is also sustained hemodynamic improvement (106). However, diastolic dysfunction remains an important predictor of poor prognosis despite improvement in systolic performance after CRTs (107). Studies on symptomatic (New York Heart Association functional class III to IV) patients with narrow QRS complex have begun.
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Conclusions
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The heart failure world is ripe with new drugs and devices, and this review only summarizes some of the data that have emerged this year. Diligent mechanistic research and guideline consensus, in the absence of any blockbuster large mega-trials, have been featured in the past year. Major debates are emerging regarding how to best determine proper end points in clinical trials, particularly in acute heart failure. What seems more urgent, however, is how to better understand the modifiable factors in the heart failure phenotype. Now that we are becoming better at identifying patients who are at risk of developing heart failure, our ability to control these risk factors to prevent the onset of heart failure will likely be the greatest benefit to society.
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Footnotes
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Dr. Tang serves as a consultant for Medtronic Inc., Boston-Scientific Inc., Neurocrine Biosciences, Otsuka Pharmaceuticals, CV Therapeutics Inc., Amylin Pharmaceuticals, and NovaCardia Inc.; he is a member in the Speakers’ Bureau for Takeda Pharmaceuticals. Dr. Tang also receives research support from the American Heart Association, CV Therapeutics, GlaxoSmithKline Pharmaceuticals, and Abbott Diagnostics Inc. Dr. Francis serves on Scientific Advisory Boards for Pfizer Inc., GlaxoSmithKline Pharmaceuticals, Boehringer-Ingelheim GmbH, Neurocrine Biosciences, and Novartis Pharmaceuticals; he has received research grant support from Pfizer Inc. Dr. Francis also serves as a consultant to Otsuka, and has served on the Data Safety Monitoring Boards for Scios Inc. and Arginox Inc. for their Phase III clinical trials.
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