YEAR IN CARDIOLOGY SERIES
The Year in Heart Failure
W.H. Wilson Tang, MD, FACC1,* and
Gary S. Francis, MD, FACC2
Department of Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland, Ohio.
Manuscript received September 29, 2005;
accepted October 4, 2005.
* Reprint requests and correspondence: Dr. W. H. Wilson Tang, Department of Cardiovascular Medicine, Cleveland Clinic Foundation, 9500 Euclid Avenue, F25, Cleveland, Ohio 44195. (Email: tangw{at}ccf.org).
Heart failure continues (HF) to be prevalent, costly, and difficult to treat despite much emerging data. This year’s major developments involve promising refinement of our ability to detect, monitor, and risk stratify patients with HF. Furthermore, results from several proof-of-concepts trials in HF therapeutics have been presented or published, which may lead to the clinical development of newer treatment strategies.
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New understanding of dilated cardiomyopathy (DCM)
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There have been important contributions in our understanding of the pathogenesis of DCM that are clinically applicable. Gene expression profiling may have demonstrable differences between ischemic versus non-ischemic cardiomyopathy (1). Recent evaluation of myocardial biopsy specimens reveal that over two-thirds of patients with idiopathic DCM have evidence of viral genome (2), and particularly parvovirus B19 (3). Furthermore, several mutations common to hypertrophic cardiomyopathy were found to be prevalent in familial DCM (such as troponin T and beta-myosin heavy chain) (4,5). Treatable asymptomatic DCM can be identified in as many as 4.6% of asymptomatic relatives of patients with cardiomyopathy (6). With this new understanding, effective genetic and screening strategies would be helpful to better distinguish the cardiomyopathic phenotype from what would otherwise be considered as "idiopathic."
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Objective quantification of clinical status in HF
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Natriuretic peptides.
The popularity of using B-type natriuretic peptide (BNP) or aminoterminal pro-BNP as an aid to the diagnosis of HF continues to increase in 2005. New evidence has also suggested that BNP may not be so tightly coupled to hemodynamic alterations as previously believed (7–9). Natriuretic peptides have also been utilized in new settings beyond the diagnosis of patients with acute dyspnea, including triage for pulmonary edema (10) and myocardial ischemia (11). In contrast, there has been further appreciation of possible confounders of plasma natriuretic peptide levels beyond established confounders (e.g., renal function, assay types, and demographics), including body mass index (lower levels with obesity) (8), hemoglobin (higher levels found in anemia) (12), and coronary ischemia (higher levels with ischemia) (11,13).
Natriuretic peptides will likely provide information beyond diagnosis and prognosis of HF (14). Perhaps the most exciting development was the announcement of the Systolic Heart Failure Treatment Supported by BNP (STARS-BNP) trial results at the American College of Cardiology (ACC) scientific session, where a BNP-guided strategy of HF management resulted in improved clinical end points (15). Several novel biomarkers have also emerged this past year to provide good prognostic values in patients with chronic HF, including cardiac troponins (16), high-sensitivity C-reactive protein (17), erythropoietin (18), urocortin-1 levels (19), and adiponectin (20) to name a few. Whether these biomarkers are concordant risk markers or genuine risk factors remains to be determined.
Hemodynamic assessment.
This year marked the announcement of several landmark clinical studies using hemodynamic assessment to guide clinical management of patients with acute and chronic HF. First, results from the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) have recently been published (21). In the ESCAPE trial, 433 subjects admitted with acute decompensated HF were randomized to receive either pulmonary artery catheter (PAC)-guided therapy or usual care. The patient population had rather advanced HF (mean left ventricular ejection fraction [LVEF] 19%, serum creatinine 1.5 mg/dl, 6-min walk  400 feet). At the end of six months, the primary end point of "total number of days patients are well" did not show any differences between the two groups (21). Overall mortality at six months was similar at 19%. This prospective, randomized controlled trial may have laid to rest concerns that use of PAC in patients with advanced HF is associated with increased death and hospitalization. At the same time, the ESCAPE study investigators also suggest that PAC should not be used routinely to guide therapy; the complication rate was 4%, and outcomes were not clearly improved due to PAC monitoring. Despite the neutrality of the primary end point, post-hoc analysis suggests that when compared with conventional management, PAC-guided therapy may lead to better preservation of renal function, more use of vasodilators and less use of thiazides, and prescription of significantly smaller doses of loop diuretics upon discharge (22). There is a growing recognition that use of large doses of diuretics used chronically for stable HF may be imprudent.
Meanwhile, new implantable devices to measure intracardiac hemodynamic variables are emerging, and the prototype device, Chronicle (Medtronic Inc., Minneapolis, Minnesota) was put to the test in the Chronicle Offers Management to Patients With Advanced Signs and Symptoms of Heart Failure (COMPASS-HF) study. Preliminary results of this six-month randomized, single-blind study were presented at the ACC Annual Scientific Sessions in 2005(23). This study demonstrated statistically significant reductions in all-cause mortality and mortality plus hospitalizations in the group randomized to optimal medical care guided by the Chronicle device (n = 134) versus optimal medical care alone (control, n = 140). The use of the ambulatory monitoring device in addition to optimal therapy was associated with a 22% reduction in overall HF-related events and decreased worsening HF by 33% compared with optimal therapy alone. Furthermore, in a subset of New York Heart Association (NYHA) functional class III patients, the use of the Chronicle reduced the rate of heart-failure-related events by 41%. However, widespread adoption of remote hemodynamic monitoring will need innovative strategies for data compression and effective integration into everyday clinical practice, without overburdening the busy health care providers.
Impedance is a measure for the manner and degree a component resists the flow of electrical current if a given voltage is applied, and can be applied to assess the degree of total body or pulmonary edema in the HF patient. There has been accruing evidence that measuring impedance may be a valuable tool for risk stratification of patients with HF. There have been over 500 publications in the literature regarding the use of impedance measurements in cardiology, but many of these studies relied on crude correlative statistics and observational studies. This has been complicated by the fact that there are many different proprietary algorithms to detect impedance, and several variables may affect the reliability of the results (such as body habitus and electrode positioning). The lack of a "gold standard" of cardiac decompensation also poses validation problems. Like BNP, the clinical significance and application of data derived from impedance measurements will likely need independent research beyond correlation with standard hemodynamic measures. Preliminary results of the 212-patient Prospective Evaluation of Cardiac Decompensation in Patients with Heart Failure by Impedance Cardiography Test (PREDICT) trial (24) illustrate for the first time the ability of three variables from the BioZ (CardioDynamics Inc., San Diego, California) impedance cardiography (thoracic fluid content index, velocity index, and left ventricular ejection time) to risk stratify outpatients with HF. However, like the Chronicle, much work is still needed to provide validation and guidance to effectively incorporate impedance cardiographic information into clinical practice.
A new concept has emerged after the approval of a device-based intrathoracic impedance measurement technique. This new device is capable of generating daily averages of intrathoracic impedance measurements from the right ventricular lead of the cardiac resynchronization system (InSync Sentry, Medtronic Inc.). Recent data demonstrate the promise of this technique for early detection and prediction of HF decompensation and progressive fluid retention using a derived index of intrathoracic fluid accumulation (25). With the broad adoption of device therapies for patients with HF, wider applications of device-based remote monitoring strategies will continue to evolve. It remains to be seen how such additional information will be used and whether it will be translated into better outcomes.
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Disease management in HF
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The traditional path of HF drug development has relied upon positive results from randomized controlled trials to deliver significant morbidity and mortality benefits. However, the incremental benefit of add-on drug therapy has been diminishing, and, therefore, several current strategies to improve HF outcomes have focused on improving delivery and organization of care. A large randomized controlled trial suggests that participation in a HF disease management program results in a significant long-term survival benefit, most notably in symptomatic systolic HF patients (26). Nurse-driven HF disease management intervention delivered uniformly across a diverse provider system of a well-treated patient population can still reduce hospitalization rates (27,28). However, disease management programs may not improve objective measures of functional capacity and may not reduce cost and health care utilization. In contrast, the addition of pre-discharge teaching session can result in improved clinical outcomes, increased self-care measure adherence, and reduced cost of care in patients with systolic HF (29).
Quality improvement initiatives were highlighted with the launching of the ACC/American Heart Association (AHA) Get-with-the-Guidelines initiative and the quality and clinical performance measures from the Joint Commission on Accreditation of Healthcare Organizations and ACC/AHA (30,31). When surveyed across hospitalized patients with decompensated HF, there is significant individual variability in conformity to quality-of-care indicators and clinical outcomes and a substantial gap in overall performance (32). Adherence of physicians to HF treatment guidelines has shown to be a strong predictor of fewer cardiovascular hospitalizations in actual practice in Europe (33).
Managing comorbidities continues to be a popular topic. Several outcomes research groups reported on the potential benefits of insulin sensitizers (thiazolidinediones and metformin) in elderly diabetic patients after HF hospitalizations (34) or acute myocardial infarction (35). Diuretic use and renal insufficiency remain the focus of several ongoing research studies in acute HF. Anemia has also been a widely discussed therapeutic target in HF, as baseline and changes in hemoglobin over 12 months have been shown to be inversely associated with subsequent risk of mortality and morbidity, independent of other important predictors (36,37). Cognitive impairment and depression have also become more widely recognized in the HF population (38,39).
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Refining pharmacologic therapy in HF
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New guidelines for HF therapy.
While the focus of HF therapy remains neurohormonal blockade and volume management, several exciting new paradigms in HF management have emerged during the past year. This year also witnessed the publication of new American guidelines for the management of chronic HF (40) and new European guidelines for both acute and chronic HF (41,42). The ACC/AHA guidelines have preserved and refined the concept of the four stages of HF presented in 2001, with stages A and B designated patients "at risk for HF" and stages C and D including patients with symptomatic HF. Stage A now includes obesity as a risk factor for the development of HF. Additional changes include recommendations for secondary prevention in stages A and B patients with atherosclerotic vascular disease, control of blood sugar in diabetic patients, and non-invasive evaluation of cardiac function in patients with a strong family history of cardiomyopathy or in those receiving cardiotoxic drugs. Follow-up visits should include assessment of activities of daily living, volume status and weight, use of cardiotoxic drugs and therapies, and potential causative factors. However, routine serial measurements of plasma natriuretic peptides still cannot be recommended at this time. Angiotensin II receptor blockers (ARBs) are now a reasonable alternative to angiotensin-converting enzyme (ACE) inhibitors as first-line agents for HF. Angiotensin II receptor blockers or ACE inhibitors are useful to prevent HF in selected stage A and B patients, and candesartan can improve outcomes in patients with impaired cardiac function who are intolerant of ACE inhibitors. Digitalis has been downgraded from the 2001 guidelines from a class I to a class IIa recommendation. Addition of an aldosterone receptor antagonist is reasonable in selected patients with moderate-to-severe symptoms of HF and reduced LVEF or in the post-infarction setting, and should be given to those who can expect to have renal function and serum electrolytes carefully monitored. The use of combination hydralazine and nitrates for stage C patients with impaired LVEF who are intolerant of ACE inhibitors and/or ARBs is now class IIb, as is the addition of an ARB to persistently symptomatic patients with reduced LVEF who are already being treated with conventional therapy. The recommendations for implantable cardioverter-defibrillators (ICDs) have been extensively expanded. Recommendations from the European guidelines for chronic HF are generally concordant in the overall approach, although there may be some differences in how the guidelines construct their final recommendations.
Neurohormonal antagonists in chronic HF.
Data continue to be robust with regard to the role of renin angiotensin aldosterone system blockade for reverse cardiac remodeling, particularly in the setting of post-infarction remodeling. Reverse remodeling continues to be an excellent surrogate marker for long-term outcomes. This is best demonstrated with the similar changes in myocardial geometry of the three treatment groups that paralleled their equivalent outcomes in the Valsartan in Acute Myocardial Infarction trial (VALIANT) (43). Furthermore, results of the Reversal of Ventricular Remodeling with Toprol XL (REVERT) study presented at the recent Heart Failure Society of America Annual Scientific Sessions also pointed to a dose-dependent improvement in left ventricular structure and performance with metoprolol succinate therapy even in the asymptomatic setting (44).
The sequence of initiation for neurohormonal antagonists has been re-examined (45). The traditional view of starting therapy with ACE inhibitor/ARB has been further challenged in the Third Cardiac Insufficiency Bisoprolol study (CIBIS-III) (46). This study randomized two strategies of drug initiation (enalapril first, then bisoprolol vs. the reverse order) in 1,010 elderly subjects with chronic HF (LVEF <40%, NYHA functional class II to III) and found non-inferiority between the two strategies on long-term mortality. Because polypharmacy continues to be a problem for patients with HF, such re-evaluation of treatment strategies is an attempt to individualize drug therapy.
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Achieving nitric oxide (NO) balance in HF
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Perhaps one of the most important new concepts in HF over the past year has been the recognition of the importance of nitric oxide (NO) in patients with acute and chronic HF. The role of NO in HF has been unclear over the past decade, and the pros and cons of oxidative stress and the relative contributions of NO/redox pathways have provided a dizzying array of hypotheses that continue to be debated in the basic science arena. However, results of several new clinical trials have established the need to move this debate to human studies.
NO donors.
The early termination and the publication of the African American Heart Failure Trial (A-HeFT) sparked a debate about the role of NO donor therapy and the concept of race as a surrogate for pharmacogenetic differentiation. Studying only symptomatic African American patients with chronic HF, the A-HeFT study demonstrated a 4% absolute reduction in mortality with add-on hydralazine-isosorbide dinitrate combination (BiDil, NitroMed Inc., Lexington, Massachusetts) (47), with accompanying modest antiremodeling effects. These results are astonishing, but it is important to note that the mortality curves of the two groups do not diverge until after the first six months of therapy (Fig. 1), even though the HF hospitalization curves diverge earlier on. There have been several assumptions that were made in this otherwise very well-designed study. First, the role of baseline blood pressure in this somewhat hypertensive population has been adjusted statistically, but the contribution of blood pressure lowering effects of BiDil is apparent. Also, the emphasis of these beneficial results has been attributed to the NO donor properties of isosorbide dinitrate. Certainly, this study has raised the discussion about the use of race to target therapeutic responses, but there is a paucity of mechanistic evidence in humans because NO is difficult to measure directly in patients with HF.
Meanwhile, other methods to enhance NO donor properties, such as nebivolol, also show benefit in patients with HF. Nebivolol is a novel beta-adrenergic blocking drug with NO-donating properties. The study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalisation in Seniors With Heart Failure (SENIORS) trial, randomizing nebivolol versus placebo in elderly patients with HF, also demonstrated a 12% relative risk reduction in all-cause mortality and a 14% relative reduction in mortality plus HF hospitalizations (48). While some critics may frown on the relatively less robust mortality benefits in comparison with other beta-blocker mortality trials, it is important to recognize that this is one of the few large-scale mortality trials that focuses on treating HF in the elderly population.
NO synthase inhibitors.
At the other end of the spectrum, overzealous production of NO under inflammatory and oxidative stress has recently been implicated in the development of hypotension seen in cardiogenic shock after acute coronary syndromes. Tilarginine acetate is a synthetically produced endogenous small molecule, NG-monomethyl-l-arginine monoacetate (L-NMMA), which inhibits the production of NO. Data from a phase II dose-ranging study with intravenous L-NMMA infusion were presented at the AHA meeting in November 2004 (49). The study found that tilarginine was well tolerated, and the survival findings were encouraging, particularly in those tolerating the highest doses of tilarginine. A phase III trial, Tilarginine Acetate for Injection in a Randomized International Study in Unstable Acute Myocardial Infarction Patients with Cardiogenic Shock (TRIUMPH), is now underway.
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Renal preservation in acute HF
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The Acute Decompensated Heart Failure National (ADHERE) registry.
The importance of renal function preservation in the treatment of acute decompensated heart failure (ADHF) have long been recognized, but has recently been catalyzed by several observations from a national acute HF registry. Fonarow et al. (32) utilized the ADHERE registry to estimate the mortality risk in patients hospitalized with acute decompensated HF. A total of 33,046 hospitalizations (derived cohort) were validated and analyzed. The best single predictor for mortality was high admission levels of blood urea nitrogen ( 43 mg/dl [15.35 mmol/l]), followed by low admission systolic blood pressure (<115 mm Hg) and high levels of serum creatinine (2.75 mg/dl [243.1 µmol/l]). These predictors emphasize the importance of preserving renal function in patients with acute decompensated HF. We can look forward to new strategies to better understand the important role of volume status and titration of diuretic therapy in the development of the grave cardio-renal syndrome.
Nesiritide and other vasodilators.
Two post-hoc analyses by Sackner-Bernstein et al. (50,51) have introduced the possibility that nesiritide may be associated with the development of renal dysfunction (50) and heightened mortality (51) (Table 1). A panel of experts was assembled under the leadership of Dr. Eugene Braunwald to further investigate and report on nesiritide use in the context of the Sackner-Bernstein observations. The panel made a number of important recommendations including: 1) use of nesiritide should be limited to patients who are hospitalized with acute decompensated HF; and 2) nesiritide should not be used for intermittent outpatient infusion, for scheduled repetitive use, to improve renal function, or to enhance diuresis (52). The use of nesiritide to treat outpatients with chronic HF should be restricted to an ongoing randomized trial, Follow Up Serial Infusions Of Natrecor (FUSION II). Questions about the use of nesiritide to treat chronic HF remain, but some clarification is expected from the FUSION II trial, which has enrolled about one-half of its target sample at the time of this writing.
Meanwhile, several new vasodilator/natriuretic peptides are under clinical development for possible use in the acute decompensated HF setting. The early termination of Value of Endothelin Receptor Inhibition with Tezosentan in Acute Heart Failure Studies (VERITAS) was a disappointment that contributes to a long line of unsuccessful attempts to demonstrate efficacy of endothelin receptor blockade in patients with HF (53). The role of endothelin receptor blockers in pulmonary and systemic hypertension is still under study. What is intriguing is that while the acute hemodynamic effects of tezosantan are undisputed, the clinical outcome measurements are unimpressive. The study makes the point that it is difficult to find adequate clinical end points for acute decompensated HF trials. Even the quantitative measurement of dyspnea remains problematic. The questions of how to measure clinical end points and exactly which clinical end points to measure in patients with acute decompensated HF remain elusive. This will certainly be challenging for several upcoming vasodilating natriuretic peptide drugs (such as carperitide and ularitide) and aquaretic agents/devices (such as tolvaptan and ultrafiltration).
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Continuing challenges to develop novel therapies in HF
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Inodilator therapy.
Over the past few years, a large clinical development program with the drug, enoximone, a phosphodiesterase inhibitor, yielded promising preliminary results during an era of concomitant cardioprotection with beta-blockers and ICDs. The phase II results of Oral Enoximone in Intravenous Inotrope-Dependent Subjects (EMOTE) demonstrated promise (54). However, the phase III Studies of Oral Enoximone Therapy in Advanced Heart Failure (ESSENTIAL) trials were recently presented in the 2005 European Society of Cardiology Congress and demonstrated a lack of statistically significant differences in all predefined end points (55). Time to all-cause mortality and time to first cardiovascular hospitalization were similar in the enoximone and placebo study groups (hazard ratios 0.97 and 0.98, respectively). Interestingly, both all-cause mortality and mortality or cardiovascular hospitalization rates were lower with enoximone in the last one-half of follow-up (beyond 16.4 months) (5.4% with enoximone vs. 8.8% with placebo, p = 0.045; and 12.5% with enoximone vs. 17.4% with placebo; p = 0.09). Furthermore, patients with LVEF <20% had greater improvement in 6-min walk test distance in the enoximone group (55). High hopes have also been placed on the results of the two phase III trials on another inodilator drug, levosimendan. Results of two prospective trials, Survival in Patients with Acute Heart Failure in Need of Intravenous Inotropic Support (SURVIVE) and Second Randomized Multicenter Evaluation of Intravenous Levosimendan Efficacy Versus Survival in the Short Term Treatment of Decompensated Heart Failure (REVIVE-II) (56) will be presented at the upcoming AHA Scientific Sessions.
Xanthine oxidase inhibition.
Another novel target that has been tested in patients with advanced HF involves inhibition of xanthine oxidase. Small observational trials had previously shown that allopurinol, a known inhibitor of xanthine oxidase, is associated with improvement in endothelial function and exercise capacity in patients with HF. Oxypurinol, an active derivative of allopurinol, has been developed as a potential oral therapy for patients with advanced HF. However, results of the phase II Oxypurinol Therapy for Congestive Heart Failure OPT-CHF (OPT-CHF) study (57) were somewhat disappointing, as the preliminary analysis suggested no added benefit. This follows in the footsteps of unsuccessful attempts to block specific anti-inflammatory pathways with anticytokine therapy in HF. All hopes are currently focused on two new strategies, a novel non-pharmacologic form of immune modulation therapy (Celacade, Vasogen Inc., Mississauga, Ontario, Canada) (58), and statin therapy (59)—both strategies are currently undergoing multicenter phase III mortality trials (Advanced Chronic Heart Failure Clinical Assessment of Immune Modulation Therapy [ADVANCED] and Controlled Rosuvastatin Multinational Study in Heart Failure [CORONA], respectively).
Surgical therapies for HF.
There were several controversial developments in the area of surgical therapies for HF this year. The CorCap Cardiac Support Device (CSD) is a proprietary mesh wrap that is implanted around the heart to attenuate cardiac remodeling. The 300-subject multicenter Assessment of a CSD in Patients With Heart Failure (ACORN) trial was announced in November 2004 at the AHA Scientific Sessions. In comparison with control patients, patients with CorCap CSD demonstrated sustained improvements in cardiac structure and function, significant improvements in quality of life, and a 50% relative reduction in need for additional cardiac procedures for worsening HF such as transplant or implants of ventricular assist or electrical stimulation devices (60). Although a U.S. Food and Drug Administration external advisory board found the data to be less than robust, there is still hope that this cardiac support device may find its way to the market.
While long-term experience with surgical ventricular restoration surgery for post-infarction ventricular dilatation appears to be favorable (61), the role of mitral valve repair in the case of patients with severe HF is being challenged. A large surgical series found no clearly demonstrable long-term mortality benefit conferred by mitral valve annuloplasty for significant mitral regurgitation with severe left ventricular dysfunction (62). Further studies are still necessary to better define the responder population.
Stem cell therapy remains an exciting area of research, with the use of a wide range of stem/progenitor cell types for the regeneration of the infarcted heart (including embryonic stem cells, hematopoietic stem and progenitor cells, mesenchymal stem and progenitor cells, as well as resident cardiac "stem" cells). Different strategies have also been developed to manipulate cardiomyocyte cell growth in vitro for its use in HF. The current status of this field involves many different types of regenerating cells. The delivery of these cells varies widely, and long-term experience for autologous skeletal myoblast and progenitor cell transplant in patients with ischemic cardiomyopathy has been reassuring (63–66).
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Role of device therapies for HF
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Cardiac resynchronization therapy (CRT).
Cardiac resynchronization therapy has received another round of acceptance with the presentation and publication of the large-scale mortality European trial, the Cardiac Resynchronization in Heart Failure (CARE-HF) study. This 813-patient, well-designed, randomized study is the first to show benefit with CRT with respect to survival, and the first to show benefit and continued improvement for a period of over two years in patients with LVEF  35% and QRS duration 120 ms (Fig. 2) (67). Remarkably, 255 patients randomized to the CRT arm had complete or near-complete resolution of their symptoms, 57 CRT patients had LVEF >40% at the 18-month follow-up. These data, in combination with the CRT arm of the Comparison of Medical Therapy, Pacing, and Defibrillation in Chronic Heart Failure (COMPANION) trial, clearly demonstrated the mortality benefits of CRT. Furthermore, CRT has been found to be cost effective in managing advanced HF patients (68), and reverse remodeling by CRT may directly lead to improved survival independent of symptomatic benefits (69). However, the criteria used in selecting patients for CRT continue to evolve with the broad availability of tissue synchronization echocardiography and better defined echocardiographic measurements of inter- and intraventricular delay. The ongoing Predictors of Response to Cardiac Resynchronization Therapy (PROSPECT) trial is designed to address optimal patient selection (70).
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Figure 2 Primary results of the Cardiac Resynchronization in Heart Failure trial (CARE-HF). Reproduced with permission (67).
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ICDs.
Primary prevention of sudden cardiac death in patients with HF has been the center of attention after the announcement of clinical indications for ICD therapy by the Centers for Medicare and Medicaid Services and the wide endorsement of the ACC/AHA guidelines (40). Beyond all traditional indications, all patients with prior myocardial infarction and LVEF 30% (Multicenter Automatic Defibrillator Implantation Trial-2 [MADIT-2] criteria), symptomatic (NYHA functional class II to III) patients with prior myocardial infarction and LVEF of 30% to 35%, or symptomatic (NYHA functional class II to III) patients with non-ischemic cardiomyopathy for over nine months with LVEF 35% (Sudden Cardiac Death in Heart Failure Trial [SCD-HeFT] criteria) may also qualify for ICD. Nevertheless, physicians should tailor their discussion with their patients about the risks and benefits of ICD therapy in the context of their expectations for their HF condition in order to best utilize this life-saving (and costly) therapy.
Rhythm control in atrial fibrillation.
New evidence favoring rhythm control with atrial fibrillation has emerged (71). While rate control may not be inferior to rhythm control, a subset of subjects in the Rate Control versus Electrical Cardioversion (RACE) study with mild-to-moderate HF demonstrated higher rates of cardiovascular death, HF hospitalization, and bleeding in the rate control compared to the rhythm control group (72). Catheter ablation techniques for rhythm control (such as pulmonary vein isolation) in this population are particularly promising (73,74), but the relative risks versus benefits remain to be determined.
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Summary and conclusions
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The rate of generation of new knowledge and expansion of therapeutic approaches to the diagnosis and treatment of acute and chronic HF continues to be dramatic. Recent updates of major clinical guidelines have facilitated the translation of clinical evidence into everyday practice. However, as more and more options become available for this patient population, resource allocation and cost-effectiveness become challenging issues. Device therapies will continue to evolve with newer and broader indications. However, there are still major knowledge gaps regarding the prediction of treatment response and disease progression. New concepts in HF therapeutics (such as NO homeostasis and renal preservation) will need rigorous testing, and traditional strategies should continue to be challenged.
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Footnotes
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1 Dr. Tang serves as a consultant for GlaxoSmithKline, Medtronic, Neurocrine, and Amylin, and is a member in the Speakers’ Bureau for Medtronic, GlaxoSmithKline, and Takeda. He receives research support from the American Heart Association. 
2 Dr. Francis serves on Scientific Advisory Boards for Pfizer, GlaxoSmithKline, Novartis, Merck, and Biosite, and receives research grant support from Pfizer. Dr. Francis also serves as a consultant to Otsuka, and has served on the Data Safety Monitoring Boards for Scios, Acorn, and Arginox for their phase III clinical trials.
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