Simon G Williams
The Cardiothoracic Centre
Academic Unit of Molecular Vascular Medicine
University of Leeds
Leeds General Infirmary
Drs Williams and Tan have participated in a number of clinical trials and lectures sponsored by various pharmaceutical companies, including AstraZeneca and Novartis.
With medical advances producing more effective treatments, more patients survive cardiovascular diseases, leading to an increased incidence and prevalence of chronic heart failure (CHF), which is now becoming a global problem.(1,2) Mortality rate reduction means that more people survive longer, although the fact that the extra longevity gained may actually be spent in debility and ill-health is a major concern. Improving quality of life, in addition to extending longevity, is increasingly becoming an important objective of therapy,(3) especially since the majority of CHF patients are elderly.(4)
Current recommendations for CHF therapy include pharmacological regimens consisting of diuretics, digoxin, angiotensin-converting enzyme (ACE) inhibitors, angiotensin-II (Ang-II) receptor blockers (ARBs) and beta-blockers (see Resource).(5) With an increasing number of agents available for use, it is vital that clinicians and pharmacists know how to select the various drugs to maximise the benefits for individual patients, through understanding the pathophysiology of CHF and the pharmacological properties of drugs. For example, how do ACE inhibitors, ARBs and beta-blockers produce prognostic benefits, in contrast to the symptomatic benefits gained from diuretic and digoxin therapy? As cardiac functional reserve diminishes, a number of compensatory mechanisms come into play, such as activation of the sympathetic and renin–angiotensin (RAS) systems. This normal physiological response initially helps maintain circulatory function, but eventually becomes pathological, leading to progressive myocardial damage(6–8) and, further, to structural and functional deterioration characteristic of adverse ventricular remodelling.(9) The deleterious effects of persistently elevated Ang-II levels also include vasoconstriction, increased aldosterone secretion and sodium reabsorption.
ARBs suppress the RAS by a mechanism different from that of ACE inhibitors, by selectively binding the Ang-II type 1 (AT(1)) receptor, thereby blocking the harmful effects of Ang-II, rather than its production, and avoiding the ACE inhibitor-induced accumulation of bradykinin, which is claimed to be responsible for troublesome coughs.(10) A primary objective of therapy with ARBs is to prevent further losses of cardiac myocytes, by ameliorating progressive ventricular dysfunction through decrease of the accelerated attrition of cardiomyocytes secondary to the cardiotoxic effects of catecholamines and Ang-II.(6,11,12) The net effect of slowing down cardiomyocyte attrition rate is the prolonged preservation of cardiac functional reserve, upon which depend the patient’s exercise capability, quality of life and ability to cope better with the usual stresses in life. (9,13,14)
The Val-HeFT trial
Val-HeFT (Valsartan Heart Failure) was a randomised, double-blind, placebo-controlled trial to evaluate the long-term effects of the addition of valsartan to standard therapy on morbidity and mortality in 5,010 CHF patients with clinically stable symptomatic CHF over an average follow-up of 23 months.(15) The study group received placebo or valsartan titrated to 160mg twice daily, in addition to their background therapies (93% of patients were taking ACE inhibitors). The investigators deemed the dose of ACE inhibitors prescribed to be optimal.
Although all-cause mortality was similar in the valsartan and placebo groups (19.7% and 19.4%, respectively), the incidence of combined mortality and morbidity (defined as cardiac arrest with resuscitation, hospital admission for CHF, or administration of intravenous inotropic or vasodilator drugs for more than four hours without hospital admission) was 13.2% lower with valsartan than with placebo (relative risk, 0.87; 97.5% CI, 0.77–0.97; p=0.009). The major effect observed on this combined endpoint was a 27.5% reduction in the incidence of hospitalisations for CHF (p<0.001). The most striking benefits of valsartan were seen in patients who were not receiving an ACE inhibitor at baseline (n=366).(16) In these patients, both the primary endpoints of all-cause mortality and combined mortality/morbidity were significantly reduced with valsartan. This provided the basis for the FDA approval of valsartan for the indication of CHF in patients intolerant to ACE inhibitors. Valsartan is currently the only ARB approved for the treatment of CHF in the USA.
Another unique feature of the Val-HeFT study concerns the effects of treatment on symptoms and quality of life. Because of the subjective nature of symptoms, wide variability and lack of an instrument with enough resolution, it is usually very difficult to obtain statistically significant results in clinical trials. As most patients with CHF are elderly, improving quality of life is of paramount importance. In Val-HeFT, significantly more patients receiving valsartan improved their New York Heart Association (NYHA) functional class compared with placebo (23.1% vs 20.7%, p<0.001), and fewer patients in the valsartan group experienced a worsening in their NYHA class compared with the placebo group (10.1% vs 12.8%, p<0.001). CHF signs and symptoms such as dyspnoea, fatigue, oedema and rales were also significantly improved by valsartan compared with placebo.(17) Quality of life, measured using the MLWHF (Minnesota Living With Heart Failure) questionnaire, worsened significantly in the placebo patients compared with the valsartan patients (p=0.005).(18) However, there is currently a lack of evidence to show that ARBs improve exercise capacity. This may be difficult to demonstrate, due to trial design and dosing regimens.(19,20)
Valsartan was well tolerated, as may be expected considering the established superior safety and tolerability profile of ARBs in comparison with other antihypertensive drug classes.(21,22) The target dose for valsartan treatment in Val-HeFT was 320mg/day, which was achieved in 84% of patients receiving valsartan (mean dose 254mg). The most common adverse events leading to treatment discontinuation in the valsartan group were dizziness (1.6%), hypotension (1.3%) and renal impairment (1.1%).
The findings from the recently published ARB trials in HF patients, the CHARM (Candersatan in Heart Failure – Assessment of Mortality and Morbidity)(23) and VALIANT (Valsartan in Acute Myocardial Infarction) trials, reinforced the findings from the Val-HeFT study, showing that treatment with ARBs confers important prognostic benefits in patients with CHF and postmyocardial infarction left ventricular (post-MI LV) dysfunction.(24)
However, of all major clinical randomised controlled trials showing benefits of ACEIs, ARBs, beta-blockers and aldosterone blockers in CHF patients, Val-HeFT remains the only one to have demonstrated statistically significant symptomatic benefits.
CHF is reaching epidemic proportions, and there is a pressing need for more widespread use of treatments that not only improve quality of life but also prevent disease progression and improve prognosis, in particular RAS-modulating agents, which are currently underprescribed.(25) The Val-HeFT and CHARM trials have established that ARBs added to patients’ usual therapy are effective in reducing morbidity and slowing the progression of CHF. The emergence of ARBs as approved therapy for CHF patients is a major new development in treatment options for the management of this chronic and debilitating condition. Despite the fact that ACE inhibitors are first-line therapy for CHF, substantial numbers of patients are not taking them. Reports indicate that 24–66% of CHF patients are not receiving ACE inhibitors.(25,26) The findings of Val-HeFT, CHARM and VALIANT show that ARBs are a well-tolerated and effective class of drugs across patient groups for the management of CHF and post-MI LV systolic dysfunction, and can be used safely as an alternative or in addition to ACE inhibitors.
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