Pharmacological Treatment

Preview

Summary

Pharmacological Treatment

The major aims of treating patients with HF are to relieve symptoms, prevent hospitalisation, and to improve functional capacity, quality of life and survival.⁶ Drugs that fulfil these aims frequently also ameliorate LV remodeling and lower circulating natriuretic peptides. The cornerstones of medical treatment are diuretics, ACE-inhibitors or AT1-receptor blockers (ARB), β-adrenergic receptor antagonists (β-blockers) and mineralocorticoid antagonists (MRA; see Figure 1). Furthermore, in some patients with sinus rhythm in whom HR reduction is insufficient despite β-blockade, the use of ivabradine is justified, and digitalis glycosides may be useful to improve morbidity and to control HR in patients with AF. In the following paragraphs, we give an overview on the use of these drugs, their mechanisms of action, and in particular, the clinical evidence supporting their use.

Diuretics
Although the effects of diuretics on morbidity and mortality were never tested in patients with HF, they are absolutely essential for decongestion and thus, improvement of symptoms. Loop diuretics are more effective in inducing diuresis compared with thiazides and can be used intravenously during acute decompensation or orally during stable phases of disease to maintain euvolaemia (patient´s ‘dry weight’). The most commonly used diuretics are furosemide and torasemide, whose doses can be (self-) adjusted depending on signs of fluid retention (monitored by body weight).⁶ Since ACE-inhibitors/AT1-antagonists and MRAs, and in particular the combination of these, can elevate serum potassium, loop diuretics or thiazides are better suited than potassium-sparing diuretics in patients with HF.⁶

Angiotensin-converting Enzyme Inhibitors
The two major trials that established the use of ACE-inhibitors in the treatment of HF are the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS)¹⁴ and the Studies of Left Ventricular Dysfunction (SOLVD)¹⁵ trials. In CONSENSUS, enalapril was tested against placebo in 253 patients with HF in New York Heart Association (NYHA) functional class IV on a stable background therapy consisting of vasodilators and diuretics for a follow-up period of 188 days. Enalapril improved survival by 31 % and also symptoms, but had no effect on sudden cardiac death.¹⁴ The fact that enalapril improved prognosis in patients with or without concomitant use of other vasodilators indicated that the beneficial effect of enalapril was the result of reducing Ang II levels (which may ameliorate LV remodeling) rather than of pure haemodynamic improvement (reduction of afterload).¹⁴ Since CONSENSUS was performed in severely ill patients (NYHA IV),¹⁴ in the SOLVD study enalapril was compared with placebo in 2,569 patients with less severe HF (NYHA functional class II-III) and left ventricular ejection fraction (LVEF) ≤35 %, on a background therapy consisting of spironolactone and digitalis.¹⁵ Enalapril reduced total mortality by 16 %, aggravation of HF by 22 % and death or hospitalisation for HF by 26 %, respectively.¹⁵ Again, no benefit on sudden cardiac death was achieved.¹⁵ It is important to up-titrate ACE-inhibitors to the maximal tolerable dose, since a trial with lisinopril (Assessment of Treatment with Lisinopril and Survival [ATLAS]) indicated a benefit of high-dose over low-dose lisinopril in NYHA functional class II-III HF patients.¹⁶ Further support for the use of ACE-inhibitors in HF comes from a metaanalysis¹⁷ and three larger trials in patients with HF, LV dysfunction or both after myocardial infarction (Survival and Ventricular Enlargement trial [SAVE], Acute Infarction Ramipril Efficacy [AIRE] and Trandolapril in Cardiac Evaluation [TRACE]).¹⁸ Finally, ACE-inhibitors are the only drugs with a proven benefit in asymptomatic patients with HF based on a 20 % relative risk reduction (RRR) in the SOLVD Prevention trial.¹⁹ ACE-inhibitors should only be used in patients with sufficient renal function (i.e. creatinine ≤2.5 mg/dl or estimated glomerular filtration rate [eGFR] ≥30 mL/min/1.73 m₂ and normal potassium levels).⁶

Beta-blockers
A landmark study about the use of β-blockers in patients with HF was published by Waagstein et al.²⁰ in 1975, who reported improved symptoms and LV function in seven patients with dilated cardiomyopathy in response to β-blockers. At that time, β-blockers were strictly contraindicated in patients with HF since it was assumed that the relief of sympathetic activation would deprive the heart of a critical stimulus to maintain contractility. In fact, acute administration of β-blockers in patients with HF can lead to a transient deterioration of C.O.,²¹ while a more long-term treatment typically increases LVEF²¹ and reverses remodeling of the LV (decreasing LV chamber size).²² On a cellular level, improvements of cardiac function by β-blockers are associated with a restoration of cardiomyocyte calcium handling proteins and contractile filaments.²³ After promising (but not yet significant) results with the second-generation β-blockers, metoprolol tartrate and bisoprolol in the Metoprolol in Dilated (MDC)²⁴ and Cardiac Insufficiency Bisoprolol Study (CIBIS) trials²⁵ in the early 1990s, a study programme with the third-generation β-blocker carvedilol was terminated early due to a 65 % reduction in overall mortality by carvedilol versus placebo.²⁶ In subsequent years, larger and better designed randomised clinical trials confirmed the benefits of β-blockade with metoprolol succinate (Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure [MERIT-HF]),²⁷ bisoprolol (CIBIS II)²⁸ and carvedilol (Carvedilol Prospective Randomized Cumulative Survival [COPERNICUS]).²⁹ Importantly, the benefits of β-blockers (~34 % RRR of all-cause mortality by metoprolol succinate,²⁷ bisoprolol²⁸ and carvedilol,²⁹ respectively) were generated on the background of ACE-inhibitor therapy (>90 % of patients) and were overall comparable among the three mentioned agents. Although one trial reported superiority of carvedilol over metoprolol (Carvedilol or Metoprolol European Trial [COMET]³⁰), it has to be taken into account that this trial³⁰ was conducted with short-acting metoprolol tartrate, while the successful MERIT-HF trial²⁷ was conducted with long-acting metoprolol succinate. Further support for the benefit of β-blockers comes from the Study of Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors With Heart Failure (SENIORS) trial,³¹ in which the third-generation β-blocker nebivolol was tested versus placebo in elderly (≥70 years) patients with HF, of whom 36 % had a LVEF of >35 %. Nebivolol reduced the combined endpoint of death or cardiovascular mortality, but did not reduce mortality.³¹ Bucindolol, another third-generation β-blocker with partial agonist activity³² did not reduce mortality in the Beta-Blocker Evaluation in Survival Trial (BEST).³³

Taken together, the 2012 ESC Guidelines on the treatment of HF recommend the use of bisoprolol, carvedilol, metoprolol succinate or nebivolol in patients with HF (Class I, Level A recommendation). It is important to start on a low dose (to prevent initial deterioration of HF) and up-titrate the drug to the maximally tolerated dose, ideally aiming at a HR between 60 and 70 beats per minute (bpm). During decompensation of a patient with HF, continuation of the β-blocker is safe, although a dose reduction may be required.³⁴