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European Journal of Heart Failure 2003 5(1):5-8; doi:10.1016/S1388-9842(02)00159-9
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© 2002 European Society of Cardiology

The pharmacological management of heart failure: too many treatments?

Dirk J. van Veldhuisena,*,1 and Wiek H. van Gilsta,b

a Department of Cardiology, Thoraxcenter, University Hospital Groningen P.O. Box 30.001, 9700 RB Groningen, The Netherlands
b Institute for Clinical Pharmacology, University of Groningen Groningen, The Netherlands

* Corresponding author. Tel.: +31-50-3612355; fax: +31-50-3614391 E-mail address: d.j.van.veldhuisen{at}thorax.azg.nl

Chronic heart failure (CHF) has become one of the largest medical and epidemiological problems of the Western world, carrying a high morbidity and mortality. Traditional treatment of CHF consisted of digoxin and diuretics, but this changed at the beginning of the 1980s, when the hemodynamic concept of increased pre-load and after-load in CHF led to the use of vasodilators. These drugs were soon found to be of benefit, and in the first V-HeFT study [1] vasodilators were shown to reduce mortality in this syndrome. This was soon followed in 1987 by CONSENSUS [2] in which the angiotensin converting enzyme (ACE) inhibitor enalapril was shown to have a much more pronounced effect on mortality. In the years that followed ACE inhibitors were found to be beneficial in all patients with symptomatic CHF, and even in those with asymptomatic left ventricular dysfunction. As a consequence, ACE inhibitors, generally in combination with diuretics, became a cornerstone in the treatment of CHF. However, despite the use of these drugs many patients remained symptomatic and prognosis remained poor. For this reason, a large number of new drugs were developed and tested as add-on treatment, which included phosphodiesterase inhibitors (milrinone, enoximone, and the related ‘calcium-sensitizing’ agents such as pimobendan), calcium antagonists (felodipine, amlodipine), dopamine agonists (ibopamine), and other vasodilators (flosequinan, prostacyclin). However, while most of these compounds had shown promising short-term results and improved exercise tolerance, none of them was found useful in long-term trials which examined mortality [3].

The first ‘new’ class of drugs which was found to be an exception to these disappointing findings was the beta-blockers. These agents had traditionally been considered contraindicated in CHF because of their negative inotropic properties. However, already in the early 1970s this concept had been successfully challenged in Scandinavia [4] and in 1996 results of the much larger US Carvedilol study [5] showed that this drug could further reduce mortality when added to a regimen of ACE inhibitors and diuretics, with or without digoxin. These promising results were soon followed by other large mortality trials with other, more selective beta-1 blockers, such as bisoprolol (CIBIS-II) and metoprolol (MERIT-HF). Although these trials together provided overwhelming evidence that beta-blockade was useful in CHF, some doubts remained about the safety of these agents, particularly in advanced CHF. Recent data in this patient group, (COPERNICUS), however, have shown that beta-blockers, when given carefully, are safe and at least as effective in advanced CHF as in mild CHF, with a survival benefit of >30%, when given on top of ACE inhibitors [6].

The next class of drugs to be tested on a large scale was the angiotensin II receptor blockers (ARBs). Long ago it had become clear that by inhibiting the ACE, the production of angiotensin II was not completely blocked, and that alternative pathways were also operative. It thus seemed reasonable to assume that by directly blocking the angiotensin II receptor, at least the same benefit could be expected as by inhibiting the ACE. Initial small-scale studies indeed showed promising findings, but the first adequately powered survival trial which compared the ARB losartan and the ACE inhibitor captopril (ELITE-II) could not show superiority of the ARB and in fact showed a trend for a more favorable effect of the ACE inhibitor [7]. More recently presented data of the Valsartan Heart Failure Trial (Val-HeFT) [8] have further clarified the place of ARBs in CHF. In the study, valsartan was given on top of maximal medication in 5010 patients with CHF. The ARB did not have an effect on mortality, but a significant (13%) reduction in the combined endpoint of mortality and morbidity was found, which included a 28% reduction in re-hospitalizations for CHF. The most pronounced effects, however, were found in patients not taking ACE inhibitors, in patients taking both ACE inhibitors and beta-blockers the addition of valsartan seemed to have a deleterious effect on outcome. It is impossible to draw definite conclusions at this time, since the full data have not been published and results of the third large trial of ARBs in CHF (CHARM) [9] must also be awaited.

Another option to prevent (escaped) activation of the renin angiotensin aldosterone system after ACE inhibition is aldosterone receptor blockade. The only large study available so far examining this issue is the RALES study, in which spironolactone reduced both mortality and morbidity by approximately 30% in patients with advanced CHF and volume overload [10]. However, only a small proportion of patients in the study were taking beta-blockers, and spironolactone may cause a considerable number of side-effects, which may be overcome with more selective receptor blockade. A large study in patients with CHF after myocardial infarction (EPHESUS) with the drug eplerenone [11], is currently underway.

Several other classes of drugs are currently being tested in patients with CHF, of which endothelin antagonists, cytokine antagonists, and neutral endopeptidase (NEP) (or vasopeptidase) inhibitors are probably the most widely studied, but there are many other potentially interesting new treatment options. Despite early positive reports, larger trials in most if not all of these compounds were to some extent overshadowed by less favorable long-term data.

Endothelin antagonists (both selective and non-selective) were initially found to cause favorable hemodynamic effects, but in a larger study in 370 patients with CHF (REACH-1) [12], bosentan was found to cause increases in liver enzymes (despite some clinical efficacy). Since there was a suggestion, that this untoward effect was related to the higher doses of the drug (500 mg b.i.d.), a follow-up study with a lower dose (125 mg b.i.d.) was conducted (ENABLE). It was recently reported, however, that at this lower dose the drug did not have any beneficial clinical effect compared to placebo [13].

Vasopeptidase (or NEP) inhibitors are another novel class of drugs, and in one earlier medium-sized head-to-head comparative study (IMPRESS), the vasopeptidase inhibitor omapatrilat was slightly more effective in terms of clinical endpoints than the ACE inhibitor lisinopril [14]. However, earlier data had suggested that this agent was possibly associated with an increased incidence of angio-oedema [15]. Recently, somewhat disappointing data were also reported about this drug. In a much larger direct comparative study in CHF (OVERTURE), which was powered to examine mortality, omapatrilat was found not to be superior to enalapril in 6000 patients with CHF [13], which makes its potential value over ACE inhibitors unsure.

Cytokine antagonists, particularly the TNF{alpha}-blocker etanercept, initially appeared to be another promising approach and several small studies confirmed this enthusiasm [16]. However, recently the large trial program in CHF with this compound, which included two studies (RENAISSANCE in the USA, and RECOVER in Europe), was terminated because of futility, after recommendation of the data safety monitoring board [17,18], which was certainly a surprising but also a very disappointing result.


   1. Where are we now in the treatment of CHF?
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There can be no question that the combination of ACE inhibitors and beta-blockers has become the backbone in the treatment of CHF. Diuretics obviously also have an important place (although a favorable effect on mortality has never been demonstrated). This holds particularly for patients with fluid overload, but it may be argued that in patients who are not fluid overloaded the use of diuretics should be reduced when possible and sometimes stopped. The place of digoxin has diminished since the DIG study only showed some effect on hospitalizations for CHF, but no effect on mortality [19]. Also, since part of its beneficial effect is probably due to neurohormonal inhibition, this may be taken over by beta-blockade and ACE inhibition. ARBs appear to be an attractive alternative in patients who do not tolerate ACE inhibitors (and beta-blockers), and the Val-HeFT data seem to support this concept [8]. Spironolactone must be considered for patients with more advanced CHF, particularly in those with fluid overload. For other classes of drugs, there is currently no place in general, apart from some exceptions such as the use of anti-coagulants in patients with atrial fibrillation.

Despite the combination of ACE inhibitors (or ARBs, when ACE inhibitors are not tolerated), beta-blockers, with or without diuretics, and possibly digoxin, morbidity and mortality remain high and the search to develop new drugs that improve outcome in CHF continues. There are several problems, however, in the development and use of new, additional drugs in CHF. First, such development programs are costly and the outcome at the end (i.e. use of the drug in CHF) is far from certain, which means that only large pharmaceutical companies can embark on such enterprises. Second, negative interactions with other drugs already used by the patient are an increasing concern, and have led to discontinuation of development programs of drugs, for example mibefradil [20]. Third, with the increasing use of other effective drugs (particularly ACE inhibitors and beta-blockers) prognosis in CHF has improved [21], and the potential benefit of a new drug (e.g. regarding its effect on mortality) on top of this regimen becomes smaller, which means that the trials must be of increasingly large size. Fourth, rules and regulations from both the sponsor and regulatory authorities are becoming stricter, which means more difficult patient inclusion, but also and more importantly, a study population that is very selected (particularly younger patients and more males), thereby being less representative for the general CHF population.

Another issue is that in the last 15–20 years drug development has focused on (further blockade) of neurohormonal activation, since this appeared to be a very effective approach, and the success of ACE inhibitors, beta-blockers and spironolactone support this concept. However, some degree of neurohormonal activation may be necessary in the condition of CHF, and complete or excessive blockade may well prove counterproductive, as was discussed in several recent editorials [22,23]. The question is then, obviously, how we can further substantially improve the prognosis of CHF patients?


   2. How to further optimize treatment in CHF? Drugs vs. devices
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Given the situation discussed above, one should consider other strategies in CHF, instead of adding more drugs to the current regimen.

One option may be to tailor the therapy based on the patient's individual characteristics, which may relate to clinical aspects (‘phenotype’), but also to genotype. For example, a patient with a high heart rate may be a relatively better candidate for beta-blockade (or amiodarone) [24] than one with a slow heart rate. Similarly, DNA polymorphisms may be used to select which patients are more likely to respond to certain therapies [25,26].

A second option is to replace one drug with another, instead of adding more drugs to an existing regimen. Given the fact, that drugs already taken have some proven value, this would mean that trials must be designed in which new treatments are compared to older, established therapy in a head-to-head fashion. This approach may be dangerous for a new drug, as was shown in the ELITE-II [7] and OVERTURE trials. Still, such direct comparative trials are probably important since they may affect the order in which drugs are being used (and added) in CHF, and thus change the paradigm, when the results are positive. Initiation of beta-blockade before ACE inhibition is ‘on board’ is one example of this, and there are currently a few trials examining this issue, including the CARMEN Study [27].

A third option in the further optimization of CHF treatment is the non-pharmacological approach. In the last 10–20 years, many surgical modalities have been suggested in CHF, mainly in patients with end-stage disease, but of all these options, only heart transplantation has really proved successful [28]. Much more benefit may be derived from two relatively new techniques. The first is the (prophylactic) use of the implantable cardiac defibrillator (ICD). A number of studies have now clearly shown that ICD implantation may save lives in several patient categories, including those with CHF [29]. The discussion, however, obviously concerns the cost-effectiveness of this approach [30], in particular since not all studies are positive [31,36]. The other step forward in the non-pharmacological treatment of CHF is cardiac resynchronisation with biventricular pacing (also referred to as multisite pacing). Recent data indicate that this technique improves exercise tolerance and quality of life in CHF [32], in selected patients with intraventricular conduction delay. However, the technique is somewhat complex and may be technically difficult; whether it also improves mortality in CHF is the subject of two larger, ongoing studies: CARE-HF and COMPANION [33].

A fourth option is the use of (nurse-led) CHF disease management programs, in which patients get advice and counseling on how to cope with their illness [34]. This approach appears to be effective and may particularly reduce the number of readmissions for CHF [35]. It is not yet clear how much and how long such interventions should last, and this is the subject of current trials.


   3. Conclusions
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CHF remains a large medical problem, with a high morbidity and mortality. Large-scale studies in recent years, which tested new pharmacologic treatments, have not substantially improved outcome in this disorder. Indeed, although many new, theoretically interesting compounds were tested, most of them have not been of use in CHF. This may partly be related to the fact that too many old drugs were already taken by the patient, as discussed above. Therefore, we may have the paradoxical situation of too many ‘old’ and too many ‘new’ pharmacologic treatments in CHF.

As a result we must seriously consider other approaches. This can be done by individualizing (or titrating) treatment, by changing the order of drug treatment instead of the conventional ‘step-up’ approach, by non-pharmacological therapy, i.e., the use of devices, or by nurse-led CHF programs. In the next few years many data will become available which will determine the value of these approaches.


   Notes
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1 Established Investigator of the Netherlands Heart Foundation (Grant D97.017). Back


   References
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