W.H. Wilson Tang, MD; Gary S. Francis, MD

Disclosures

J Am Coll Cardiol. 2010;55(7):688-696. 

In This Article

Management of HF

Guideline Updates

A broad range of clinical guidelines from major professional societies have emerged this year, but the new recommendations are more refinements than major overhauls. In both the European and American guideline updates, broader adoption of natriuretic peptide testing was recommended based on emerging supportive data, even though much emphasis has focused on diagnostic evaluation of patients in the acute setting. There have been some upgraded recommendations on the use of add-on vasodilator therapy based on the data from the A-HeFT (African American Heart Failure Trial), with new observational studies suggesting the potential incremental benefit of add-on hydralazine plus isosorbide dinitrate beyond African Americans.[54] Expansion of device therapy also has been incorporated, with simplification of inclusion criteria to left ventricular ejection fraction (LVEF) ≤35%. The emphasis of rhythm control in patients with HF and atrial fibrillation has been relaxed based on neutral data from the AF-CHF (Atrial Fibrillation in Congestive Heart Failure) trial.[55] Meanwhile, in the absence of positive data, recommendations regarding the treatment strategies for heart failure with preserved ejection fraction (HFpEF) have remained largely unchanged. Some refinements in diagnostic criteria regarding the evaluation of diastolic dysfunction have been proposed by the American Society of Echocardiography.[56] The American guidelines have added an expanded discussion on the appropriate management of hospitalized patients with HF, which consists largely of expert opinion with the emphasis on maintaining or initiating evidence-based pharmacologic therapies during acute exacerbations as tolerated.

Device Therapy for HF

Cardiac resynchronization therapy (CRT) continues to be an important treatment for patients with advanced HF. The major focus this year has been the exploration of potential expansion of the standard clinical indications. Two important studies have been reported this year. First, the 24-month follow-up of the European cohort of the REVERSE (Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction) trial has provided an important demonstration of reverse remodeling and clinical improvement using a composite response end point. The use of CRT provided a beneficial response in patients with an LVEF ≤40% and a QRS duration ≥120 ms but with only mild (New York Heart Association functional class I to II) symptoms.[57] The likelihood of left ventricular reverse remodeling was the highest in those with nonischemic etiology or with significant conduction or mechanical delay. The recently published MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy) demonstrated a 34% relative risk reduction in death or HF events and reverse remodeling with CRT plus defibrillator compared with defibrillator alone in 1,820 subjects with LVEF ≤30% and QRS duration ≥130 ms (Fig. 1). The benefits were largely driven by reduction in HF events, particularly in those with QRS duration ≥150 ms.[58] These landmark findings secure the role of CRT as a standard therapy for patients with significant conduction delays across the symptom spectrum of chronic systolic HF. However, unlike drug therapy, CRT is invasive and expensive; therefore, it may be subject to further scrutiny despite the demonstrated clinical benefits and corresponding reversal of left ventricular remodeling. There will likely be some debate in the months ahead (both in guideline revisions as well as reimbursement decisions) regarding the pros and cons of adopting the traditional rule of honoring the exact inclusion/exclusion criteria from the trial evidence, versus stronger endorsement for only those responder subgroups (i.e., those with wide QRS duration, predominantly ≥150 ms).

Figure 1.

Primary Results From the MADIT-CRT Trial
Effect of cardiac resynchronization therapy for mild heart failure on the probability of survival free of heart failure (top) and reverse remodeling (bottom). Reprinted, with permission, from Moss et al.[58] CRT = cardiac resynchronization therapy; ICD = implantable cardioverter-defibrillator; LVEDV = left ventricular end-diastolic volume; LVESV = left ventricular end-systolic volume.

One of the major limitations in device trials has been the assumption that once implanted, CRT will deliver an equivalent benefit regardless of settings or device functionalities. Optimization of CRT has been widely discussed and tested with sophisticated imaging techniques, but a stepwise review of several simple parameters (such as ensuring appropriate lead placement, maximizing percent biventricular pacing, detecting and treating underlying arrhythmia, optimizing atrioventricular delay, as well as providing appropriate HF disease management) may provide benefit in a subgroup of nonresponding CRT patients.[59] The ability of an imaging modality to select the appropriate candidates for CRT and predict response has been a notion without direct demonstration.[60]

Exercise Training in HF

Simple assessment of exercise endurance continues to be a useful prognostic tool in this population,[61] and the lack of improvement after a training program portends a poor prognosis.[62] However, the potential risks and benefits of high-intensity exercise training have been unclear. Subjects in the National Institutes of Health–sponsored HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) received either usual exercise recommendations or a structured program including 3 months of supervised exercise (40 min 5 times/week) and continued aerobic exercise at home thereafter. The primary results of HF-ACTION showed an overall neutral effect of an exercise training program on the combined end points of mortality and HF hospitalizations, but improved overall health status in 2,331 subjects with chronic systolic HF.[63,64] The investigators attempted to further analyze the data according to adherence to a recommended training regimen, and found a dose–response relationship between regular aerobic exercise and patient outcomes (with modest improvement in the primary end point of all-cause death or all-cause hospitalization, hazard ratio: 0.95, 95% confidence interval: 0.92 to 0.98, p = 0.003). The HF-ACTION study provides important safety reassurance for patients and for physicians in developing an exercise prescription. In addition, it provides much-needed justification for reimbursement of cardiac rehabilitation for this patient population and highlights the uphill battle to convince patients to adhere to this aggressive lifestyle modification.

New Insights in the Treatment of Myocarditis

After a decade of relatively disappointing results, diagnosis and management of myocarditis remains mostly empirical. After advances in the treatment of other viral-mediated diseases, the potential for reducing viral burden within the myocardium in those patients with so-called viral persistence is still considered a testable hypothesis. In the BICC (Beta-Interferon in Chronic Viral Cardiomyopathy) trial presented at the 2008 American Heart Association annual meeting, improved symptoms and reduced viral load (including adenovirus, enterovirus, and/or parvovirus) in endomyocardial biopsy samples of 143 patients was more likely to be associated with beta-interferon treatment than placebo. However, there were no differences or changes in cardiac structure or myocardial performance between groups, even though beta-interferon therapy appeared safe.[65] Because viral persistence has yet to be linked to an inferior prognosis,[66] the benefits of an antiviral therapeutic strategy remain in question, particularly with the need for invasive evaluation and the high cost of therapy.

Meanwhile, for those patients with no evidence of viral persistence, a new randomized study suggests that immunosuppression therapy may provide some benefit. In the TIMIC (Tailored Immunosuppression in Inflammatory Cardiomyopathy) trial, 85 subjects with chronic left ventricular systolic dysfunction and evidence of ongoing myocardial inflammation were randomized to receive azathioprine plus prednisone versus placebo. Additional immunosuppressive therapy was associated with a greater degree of reverse remodeling when compared with placebo in addition to at least 6 months of standard medical therapy.[67] These data are indirectly consistent with the positive mechanistic data on reduction of infarct size observed with cyclosporine infusion at the time of percutaneous coronary intervention during acute myocardial infarction,[68] illustrating the importance of ongoing immune activity in the progression of cardiac dysfunction.

Treating HFpEF

The highly anticipated I-PRESERVE (Irbesartan in Heart Failure with Preserved Ejection Fraction) trial randomized 4,128 patients age >60 years with symptomatic HFpEF (LVEF >45%) to receive irbesartan or placebo. This large and well-executed trial in patients already receiving extensive background therapy found no incremental benefit of irbesartan in the end points of mortality or HF hospitalizations[69] (Fig. 2). This was a disappointing outcome. The findings of I-PRESERVE have also reinforced our concept that HFpEF is distinctly different than systolic HF in ways that are not yet fully appreciated.

Figure 2.

Primary Results of the I-PRESERVE Trial
Primary outcome of death from any cause or hospitalization for pre-specified cardiovascular causes (worsening heart failure, myocardial infarction, stroke, atrial or ventricular arrhythmia, or myocardial infarction or stroke occurring during hospitalization for any cause). Reprinted, with permission, from Massie et al.[69]

Pulmonary and Systemic Vasodilators

Expanded indications for phosphodiesterase 5 inhibitors for moderately symptomatic patients with pulmonary hypertension have been supported by several studies showing improved functional capacity and reduced pulmonary vascular resistance. Meanwhile, the presence of preserved transpulmonary natriuretic peptide uptake coupled with diminished cyclic guanosine monophosphate release has been observed in patients with pulmonary hypertension associated with left heart diseases. These observations suggest a relative deficiency of downstream mediators of vasodilator response in patients with increased pulmonary vascular resistance. They also support the potential benefit of phosphodiesterase 5 inhibitors or newer soluble guanylate cyclase activators (cinaciguat or BAY 58-2667) in combination with nitric oxide donors.[70–72] Several ongoing clinical studies are exploring the potential therapeutic benefits of such agents.

With the persistent promise of endogenous vasodilator peptides as potential therapeutic agents, relaxin (a pregnancy hormone produced to inhibit uterine contraction that facilitates the softening and lengthening of the cervix and the pubic symphysis during childbirth) is being evaluated. In 234 subjects with normal to high blood pressure, intravenous relaxin resulted in rapid and sustained improvement in dyspnea and favorable trends toward improved rates of cardiovascular death and HF rehospitalization at 60 days (3% to 10% vs. 17%, p = 0.06), and lower cardiovascular death rates (0 to 6% vs. 14%, p = 0.04) within a mean follow-up of 4.5 months.[73] Further early-phase clinical trials on this and several other endogenous vasodilator compounds will soon be underway.

Renal-sparing Therapies

The search for renal protective agents persists, as worsening renal function continues to be a major comorbidity and impediment to effective treatment for acute decompensated HF. This year we witnessed the formal approval of the first oral drug that antagonizes the vasopressin system, tolvaptan. Its role in preserving renal function remains largely unclear, but tolvaptan does improve hyponatremia under some conditions. Tolvaptan appears to generate an aquaresis without significant hemodynamic effects.[74] Another promising candidate drug class, adenosine A1 receptor antagonists, has encountered major hurdles this year. Preliminary results of the PROTECT (Placebo-controlled Randomized Study of the Selective A1 Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized with Acute Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function Trial) on intravenous rolofylline were announced at the European Society of Cardiology meeting and indicated no significant differences in major outcomes between rolofylline and placebo using cardiac and renal end points, despite more symptomatic relief in 2,033 subjects hospitalized for HF.[75] In particular, rolofylline did not reduce the incidence of renal impairment compared with placebo (15% vs. 13.7%), yet showed a trend toward more strokes and seizures. This class of drugs faces major challenges in further development.

Pharmacological Inotropic Support

Pharmacologic support for end-stage (stage D) HF remains a challenge. Once a patient is deemed inotropic-dependent, the prognosis is poor and the choice of chronic inotropic drug infusions (dobutamine or milrinone) does not seem to affect long-term outcomes.[76] The search for a safe and effective vasoactive drug continues, and the final publication for the ESSENTIAL (Studies of Oral Enoximone Therapy in Advanced Heart Failure) trial highlights the challenges in studying a drug therapy for this patient population, as enoximone yielded a neutral outcome.[77] Meanwhile, another approach using a drug called istaroxime that inhibits sodium–potassium adenosine triphosphatase activity while stimulating the sarcoplasmic reticulum calcium adenosine triphosphatase isoform 2 has been examined in the HORIZON-HF (Hemodynamic, Echocardiographic, and Neurohormonal Effects of Istaroxime, a Novel Intravenous Inotropic and Lusitropic Agent: a Randomized Controlled Trial in Patients Hospitalized with Heart Failure).[78] The administration of intravenous istaroxime resulted in rapid hemodynamic improvement with a corresponding reduction in heart rate and improvement in echocardiographic indexes of diastolic function. However, like many prior vasoactive drugs, the road to approval is long and treacherous.

Surgical Management for Advanced HF

Hypothesis 2 of the STICH (Surgical Treatment for Ischemic Heart Failure) trial was published this year.[79] It showed a lack of benefit for surgical ventricular reconstruction (SVR) (or modified Dor procedure) in the setting of coronary artery bypass surgery for patients showing systolic HF (LVEF ≤35%) and anteroapical dysfunction. This occurred despite a greater reduction in indexed left ventricular systolic volume in the SVR group. Some proponents of SVR may still believe that there was a selection bias against enrollment of those who would benefit from the procedure, whereas others postulate that impaired diastolic distensibility caused by reducing the left ventricular volume may also contribute to the operation's lack of benefit. Nevertheless, these rather disappointing results provide justification for not routinely performing SVR at the time of coronary artery bypass surgery.

Novel Devices

Several devices tackling novel concepts of HF care have been tested in multicenter clinical trials. The MOMENTUM (Multicenter Trial of the Orqis Medical Cancion System for the Enhanced Treatment of Heart Failure Unresponsive to Medical Therapy) was published this year, and indicates relatively neutral findings using a novel continuous-flow augmentation device for severe acute HF.[80] Results of a multicenter study on the safety and efficacy of another novel implantable device that delivers nonexcitatory electrical signals during the refractory period to improve cardiac contractility (cardiac contractility modulation [CCM]) also were presented this year. The FIX-HF-5 (Evaluation of the Safety and Efficacy of the OPTIMIZER System With Active Fixation Leads in Subjects With Heart Failure Resulting From Systolic Dysfunction) study randomized 428 patients with advanced HF (LVEF ≤35% and narrow QRS) to either CCM or no CCM,[81] and found that CCM failed to improve the primary efficacy outcome of the anaerobic threshold.[82] However, the investigators observed in a less sick group (New York Heart Association functional class III, LVEF ≤25%, n = 185) that improvement in exercise parameters and quality-of-life scores with CCM was possible.[82] Although only hypothesis-generating, these findings are quite intriguing because they provide some indication that this treatment modality requires some reserve for contractile improvement. Regardless, exercise parameters are often difficult end points for clinical trials to achieve for various reasons that are not well understood.

Mechanical Assist Devices and Destination Therapy

The approval of the HeartMate II device (Thoratec Corporation, Pleasanton, California) as a new-generation nonpulsatile ventricular assist device (VAD) has paved the way to a much needed advancement in this arena. Long-term follow-up of patients with the HeartMate II has provided reassuring data regarding its long-term safety and reliability.[83] However, gastrointestinal and intracranial bleeding risks have been observed. The nonpulsatile nature of circulatory support has even been associated with acquired coagulopathies in some patients.[84] Smaller devices have also emerged, although they are still in early clinical developmental stages,[85,86] and pilot studies on less sick patients are in the planning phases. Questions regarding appropriate patient selection, cost effectiveness, perioperative management, and organization of care delivery for VADs will likely continue to pose important challenges and receive ongoing scrutiny.[87,88]

Disease Management

Increasing HF readmission rates have been the emerging focus of public reporting as a surrogate of quality of care and competency.[89] It is often the assumption that many of the readmissions are preventable, and a major initiative has been launched by the American College of Cardiology to reduce the readmissions rate by 20% in 2012 (the Hospital-to-Home campaign). In many cases, readmission rates are undeterred by advances in drug and device therapies. Prediction models for readmissions are uniformly inadequate because they do not necessarily address many environmental and social factors, and do not always precisely characterize disease severity or underlying comorbidities.[90] There is much debate over methodologies of how to define preventable readmissions and appropriateness of adjustments. Therefore, we still lack a mechanism to explore why readmissions occur in individual patients, which may be a prerequisite for improvement. Remote monitoring remains an attractive concept for disease management, but demands resources and logistics as well as proof of concept. Device-derived data such as intrathoracic impedance continue to shed light onto the clinical stability of individual patients,[91–93] and even on the setting of diastolic HF.[94] However, like any other diagnostic tool, studies to gauge efficacy are difficult to design, and interpretations of unexplained deviations of impedance signals remain a practical challenge.

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