Chronic heart failure is common, disabling and deadly. It affects approximately five million people in the US and accounts for over one million hospitalizations annually. Despite continued improvements in heart failure therapy, mortality over five years is approximately 50%.This article summarizes significant recent developments in pharmacologic and device therapy for heart failure.
Angiotensin Receptor Blockers in the Context of Other Medical Therapies
Angiotensin-converting enzyme (ACE) inhibitors are the standard of care for patients with chronic heart failure due to ventricular systolic dysfunction, based on a large body of clinical trial evidence. Angiotensin receptor blockers (ARBs) offer an alternative method of blocking the effects of angiotensin II and have several theoretical advantages over ACE inhibitors. Whereas ACE inhibitors decrease the effects of angiotensin II by (incompletely) blocking its production, ARBs antagonize the angiotensin II receptor directly, theoretically providing a more complete blockade of angiotensin II effects. ARBs may also be better tolerated than ACE inhibitors, with lower incidence of troublesome side effects such as chronic cough. Several recent landmark trials have evaluated the efficacy of ARBs in patients with heart failure, either alone or in combination with ACE inhibitors.
The Valsartan in Heart Failure Trial (VAL-HeFT) evaluated the addition of the ARB valsartan 160mg twice a day to standard therapy (including ACE inhibitors in >90% of patients) in 5,010 patients with New York Heart Association (NYHA) class II-IV heart failure. While there was no reduction of all-cause mortality, valsartan did reduce the co-primary end-point of mortality and cardiovascular morbidity by 13% (p=0.009). Subgroup analysis of VAL-HeFT raised the possibility of an adverse effect when valsartan was combined with beta-blockers and ACE inhibitors, although this finding has not been confirmed by subsequent studies and seems likely to be due to chance alone.
The Candesartan in Heart failure Assessment of Reduction in Mortality and Morbidity (CHARM) program evaluated the role of the ARB candesartan in a variety of populations with chronic heart failure. The CHARM program was made up of three constituent trials evaluating candesartan in patients intolerant of ACE inhibitors (CHARM-alternative), patients who were already taking ACE inhibitors (CHARM-added), and with heart failure in the setting of preserved systolic function (CHARM-preserved).
Among patients who were intolerant to ACE inhibitors, candesartan reduced the primary end-point of cardiovascular death or heart failure hospitalization by 23% (p=0.0004). This finding had also been observed in a small subgroup of patients not on an ACE-inhibitor in the VAL-HeFT study. When candesartan was added to patients already taking optimized-dose ACE inhibitor, there was a statistically significant 15% decrease in the primary end-point.
Importantly, the CHARM program was the first large study to evaluate any therapy in the important population of patients with heart failure and preserved systolic function, in which candesartan treatment showed no improvement in mortality but a small decrease in heart failure hospitalizations. Taken together, the results of CHARM and VAL-HeFT suggest that ARBs are well tolerated and indicated as first-line therapy in heart failure patients who are intolerant of ACE inhibitors. In patients already taking ACE inhibitors, these agents appear to reduce heart failure hospitalizations and improve quality of life, and candesartan reduces cardiovascular mortality. ARBs, like ACE inhibitors, cause increased incidence of hyperkalemia, renal insufficiency, and hypotension, and therefore these parameters need to be monitored. The favorable effects of candesartan in patients with heart failure and preserved systolic function were modest, and studies of other ARBs and of spironolactone for heart failure with preserved systolic function are on-going.
Thus, patients with chronic heart failure and reduced left ventricular ejection fraction have improved survival with ACE inhibitors (or ARBs if intolerant) and with beta-blockers, and patients who remain symptomatic derive additional morbidity and morality benefit from spironolactone (if severely symptomatic) or ARBs.
Nitrates and Hyrdalazine
When used chronically in combination, nitrates and hyrdalazine provide balanced venous and arterial vasodilatation with hemodynamic effects similar to that of ACE inhibitors or ARBs. The original Veterans Administration Cooperative Vasodilator Heart Failure Trial (V-HeFT I), published in 1986, was the first large trial to demonstrate improved survival with pharmacologic intervention in patients with chronic heart failure, demonstrating a modest improvement in survival with the combination of nitrates and hydralazine compared with placebo.
Enthusiasm for this combination waned after the follow-up study VHeFT-II demonstrated more favorable survival with the ACE inhibitor enalapril compared with nitrates/hydralazine. Importantly, however, a subsequent analysis of the combined V-HeFT experience raised the hypothesis that the combination of isosorbide dinitrate and hydralazine might be particularly efficacious in African-American patients compared with Caucasians. Subsequent data from basic investigation provided a foundation of biologic plausibility for these findings, demonstrating that African-American patients had lower bioavailability of nitric oxide, which might be ameliorated by the nitrates-hydralazine combination.
These observations led to the African-American Heart Failure Trial (AHeFT).This study was stopped early by the Data Safety Monitoring Board due to a significant (43%) reduction in mortality in African-American patients with advanced systolic heart failure treated with a fixed-dose combination of isosorbide and hydralazine. Notably, this benefit was seen despite the fact that the study population was treated with contemporary pharmacotherapy, with high use of ACE inhibitors (69%), beta-blockers (74%), and ARBs (17%). While there is uncertainty as to the degree of survival benefit, given that there were only 86 total deaths, the p-value was not highly significant at 0.02, and trials stopped early may overestimate treatment effects, other components of the composite end-point (first hospitalization for heart failure and quality of life) were also significantly reduced with the combination of nitrates and hydralazine. This benefit is particularly impressive given the concern of many investigators that a ceiling of benefit may have been reached with current drug therapy. The benefits in AHeFT were at the cost of a significant excess of headache (48% for nitrates and hydralazine versus 19% for placebo, p<0.001) and dizziness (29% for nitrates and hydralazine versus 12% for placebo, p<0.001).
This trial was provocative in raising the issue of 'race-basedÔÇÖ medicine. While there was enthusiasm over a treatment being discovered that is of special benefit to a high-risk minority population, this was balanced by discomfort over using skin color to make treatment decisions as a crude measure for the genetic and environmental factors that are the more direct determinants of who may respond to certain treatments. More common and less functional variants of the nitric oxide synthase 3 gene in African-Americans provides a hypothesis for the AHeFT findings.
Genetic variants of the beta adrenergic receptor likewise appear to relate to prognosis in heart failure and acute coronary syndromes, and may prove helpful in selecting patients for beta-blocker treatment. These findings have provided optimism that there is fertile ground for pharmacogenetics in drug development in heart failure.
From a drug marketing standpoint, it remains to be seen the extent to which clinicians will embrace a proprietary combination pill when both components (isosorbide dinitrate and hydralazine) are widely available in much cheaper generic formulations.
Anemia and Heart Failure
Anemia is increasingly recognized as a common comorbid condition and a poor prognostic sign in patients with chronic heart failure. Multiple potential mechanisms for this link have been proposed, including inflammation, malnutrition, and renal dysfunction, among others. This observation has led to significant interest in anemia as a potential target for heart failure therapy. Several preliminary studies have demonstrated promising results using recombinant human erythropoietin in the treatment of patients with heart failure and concomitant anemia. Although these preliminary data are promising, the overall balance of risks and benefits from treating anemia remains unknown. More definitive studies focusing on exercise tolerance and mortality are currently being planned or are underway.
Implantable devices, such as implantable cardiac defibrillators (ICDs) and bi-ventricular pacemakers, are becoming an increasingly integral component of heart failure care. Recent data have supported a significant expansion of the use of ICDs for both the primary and secondary prevention of sudden cardiac death in patients with heart failure or left ventricular (LV) dysfunction. Most recently, the landmark Sudden Cardiac Death Heart Failure Trial (SCD-HFT), which evaluated the efficacy of ICD therapy in patients with ejection fraction (EF) Ôëñ35% and symptomatic heart failure, demonstrated a significant survival advantage (23% decrease in mortality risk) for ICD treatment compared with optimal medical therapy. These data have expanded the indications for ICD treatment to many patients with symptomatic heart failure (NYHA class II-III) and systolic dysfunction, regardless of heart failure etiology.
In addition to the expanding use of ICDs, cardiac resynchronization therapy (CRT) using bi-ventricular pacemakers has also moved into the mainstream of cardiac care. The recent Cardiac Resynchronization Heart Failure (CARE-HF) trial was the first study to conclusively demonstrate a mortality benefit from CRT in patients with evidence of cardiac dyssynchrony, with a 46% reduction in mortality with CRT compared with medical therapy alone. These results extend the findings of the previous Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) and Multicenter InSync Randomized Clinical Evaluation (MIRACLE) studies, and provide a body of evidence that strongly support the efficacy of CRT with or without an ICD in patients with heart failure and evidence of ventricular dyssynchrony. In spite of data supporting cost-effectiveness for ICDs, the rapid expansion of indications for ICDs and CRT has created difficulty for regulatory agencies and policy makers who are required to reconcile the demonstrated survival benefit of these therapies with their substantial costs. In light of these conflicts, significant on-going research seeks to further refine strategies for risk stratification to enable better patient selection for these expensive and invasive therapies.
In addition to developments in specific treatments for heart failure, paradigms for applying these treatments continue to evolve. Medication adherence has been shown to be one of the most powerful predictors of patient outcome. As with other chronic diseases, such as diabetes mellitus and asthma, significant research efforts have been focused on studying disease management strategies. Such strategies focus on careful longitudinal management, frequently involving intensive involvement by nurse clinicians, in order to decrease heart failure hospitalizations. Although studies evaluating such approaches have been highly variable, the totality of data suggests that such interventions do decrease hospitalization and may result in decreased costs of heart failure care. Continued improvements in device technology may provide increasing ability to monitor physiologic parameters in ambulatory heart failure patients using data derived from implanted devices.
Several important recent studies have also evaluated strategies for optimally applying proven pharmacotherapy. The IMPACT-HF study, for example, evaluated the optimal strategy for initiation of beta-blockers (during acute hospitalization or during outpatient follow-up). This study found that initiation during hospitalization was associated with a significantly greater proportion of patients achieving evidence-based targets for beta-blocker therapy.
The first significant trial evaluating the order of initiation for ACE inhibitors and beta-blocker therapy (CIBIS-3) has recently been presented, showing no difference between a strategy of beginning initial treatment with beta-blockers (bisoprolol) or ACE inhibitor enalapril. Given the inherent difficulties of compliance with increasingly complex medical regimens for heart failure, more studies addressing strategies of applying these treatments seem likely in the future.
As noted in this article, mortality and morbidity from chronic heart failure remain high despite the notable improvements in management. Several important trends will increasingly influence the future of heart failure care over the next decade.
First, the continued expansion of indications for implantable devices, whether for sudden cardiac death prevention (ICDs) or cardiac resynchronization therapy (bi-ventricular pacemakers), seems likely to continue. In addition to therapies delivered by these devices, their increasing deployment in the heart failure population will create new opportunities for continuous physiologic monitoring of ambulatory heart failure patients.
Secondly, the development of readily available tools for applying genomic and proteomic information to individual patients will increasingly allow for personalized selection of heart failure therapy. The AHeFT study, which targeted a specific population (African-Americans) based on an understanding of the mechanism of drug effects, is among the first example of such a targeted approach. In the future, it seems likely that identification of specific genetic features or levels of circulating biomarkers will be employed in selecting the therapy most likely to be beneficial (and least likely to cause harm) for an individual patient. Such approaches will both maximize the benefit of currently available therapies and identify new targets for future therapeutic development.