Prof. Ali Oto,
Dr. Ismail Can
In Heart Failure (HF), despite survival improvement thanks to angiotensin converting enzyme (ACE) inhibitors and b-blockers, certain classes of drugs, first-generation calcium channel blockers, non-glycoside oral inotropic agents, class-I antiarrhythmics, direct vasodilators, cytokine and endothelin antagonists, have been proved to be harmful and are thus forbidden in the treatment of patients with heart failure.
Based on the data from published trials, ACE inhibitors are recommended as the first-line therapy not only for symptomatic HF, but also for the asymptomatic left ventricular dysfunction. b-blockers should be routinely prescribed to all patients with asymptomatic left ventricular dysfunction and stable HF caused by left ventricular dysfunction, unless they have a contraindication. Aldosterone antagonists, should be used in patients with recent or current NYHA class IV symptoms, despite the use of ACE inhibitors, b-blockers, digoxin and diuretics.
Heart failure is a complex clinical syndrome resulting from various structural or functional cardiac disorders impairing the ability of the ventricles to fill with or eject blood. Its incidence and prevalance have increased significantly. The medical treatment of this syndrome has evolved in the last 40 years from the use of diuretics to the use of inotropics and vasodilators. During this time, some trials which were very exciting when they started lead in fact to greater morbidity and mortality rates for the patients with heart failure.
Calcium channel blockers, excluding amlodipine and felodipine resulted in worsening symptoms and increased mortality due to negative inotropic effects and reflex neurohormonal activation (1).
Although oral inotropic agents improve hemodynamics and relieve symptoms on a short term basis, long term therapy has not shown any significant clinical benefit and resulted in increased mortality. Only digoxin, which has weak inotropic properties, has been shown to have a neutral effect on mortality. Among the non-glycoside inotropic agents; b1-adrenergic agonist xamoterol, phosphodiesterase inhibitor enoximone and milrinone, dopaminergic agents and ibopamine all resulted in increased mortality in patients with heart failure. Vesraninone, a phosphodiesterase inhibitor and potassium antagonist has been evaluated in two trials; in the Vesraninone Study Group (VSG) trial and in the larger Vesraninone Trial (VEST). Both trials resulted in increased mortality. Intravenous inotropes -either intermittent or continuous- also resulted in increased mortality. Given the lack of convincing evidence of clinical benefit and the abundant evidence of increased mortality, ESC guidelines do not recommend intermittent or continuous use of inotropes except for the purpose of palliation (2).
Since decreased systolic performance in heart failure leads to neurohormonal activation resulting in increased systemic vascular resistance, vasodilators were thought to be capable of improving hemodynamics and thereby preventing progression of heart failure and improving survival. However, two drugs, - flosequinan and epoprostenol respectively – having direct vasodilating properties, were evaluated in the Prospective Randomized Flosequinan Longevity Evaluation (PROFILE) trial and in the Flolan International Randomized Survival (FIRST) trial, but both trials were terminated early due to a higher mortality in patients with heart failure (2).
Furthermore, empiric antiarrhythmic therapy for patients with heart failure has proven no benefit either and has in fact been associated with increased proarrhythmic complications. After the increased mortality in the Cardiac Arrhythmia Suppression Trial (CAST) and in the CAST II, Class I trials, antiarrhythmics are contraindicated in the treatment of patients with heart failure as well (3).
Some of the investigational therapies have also resulted in increased mortality in patients with heart failure. Among these is therapy involving the tumor necrosis factor and endothelin antagonists. Though patients with heart failure have elevated levels of TNF and endothelin which correlate with the severity of disease, antagonists against TNF (etanercept) and endothelin (enrasertan) did not prove to be beneficial.
Thus, heart failure is a complex clinical syndrome with certain pharmacologic therapies that are not found to improve symptoms and long term survival. Possibly, the negative effect common to all may be the presence of and/or iatrogenic augmentation of the unopposed detrimental compensatory mechanisms activated during heart failure. So, it is fundamental to incorporate the absolute blockade of these compensatory pathways by ACE inhibitors, b-blockers, and aldosterone antagonists in the treatment strategy of the patients with HF to improve overall survival.
The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.
1. Klein L, O’Connor CM, Gattis WA, et al. Pharmacologic therapy for patients with chronic heart failure and reduced systolic function: Review of trials and practical considerations. Am J Cardiol 2003;91:18F-40F. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12729848&dopt=Abstract
2. Goldtsein RE, Boccuzzi SJ, Cruess D, et al. Diltiazem increases late-onset congestive heart failure in postinfarction patients with early reduction in ejection fraction: the Adverse Experience Committee, Multicenter Diltiazem Postinfarction Research Group, Circulation 1991;83:52-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1984898&dopt=Abstract
3. Echt DS, Liebson PR, Mitchell B, et al and the CAST investigators. Mortality and morbidity in patients receiving encainide, flecainide, or placebo: the Cardiac Arrhythmia Supression Trial. N Engl J Med 1991;324:781-788. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1900101&dopt=Abstract
Dr I. Can, Dr A. Oto Ankara, Turkey Member of the ESC Working Group on Heart Failure.
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