Novel Therapeutic Strategies for Heart Failure

Many new options are becoming available very quickly, but because not all treatments will be beneficial for all patients, the challenge will be in selecting the appropriate approach for each patient.

By Mandeep R. Mehra, MD, and Patricia A. Uber, PharmD

Dr. Mehra is vice chairman of the Ochsner Heart and Vascular Institute and chief of the Ochsner Cardiomyopathy and Heart Transplantation Center in New Orleans, Louisiana. Dr. Uber is advanced clinical cardiovascular specialist in the Ochsner Cardiomyopathy and Heart Transplant Center.

Current strategies for treatment of systolic heart failure are shifting rapidly toward a multidimensional approach that focuses on the neurohormonal component of the disorder, rather than on the renin-angiotensin-aldosterone system and sympathetic activation. In this review, we discuss the most recent advances in this approach and on the practical aspects of adrenergic blockade. We also present the latest trial information and ongoing investigations in this expanding clinical arena.

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Evolution in the Treatment of Heart Failure

In the last decade, our focus in the treatment of systolic heart failure has moved progressively from addressing the cardiorenal causes of the disorder (with diuretic therapy), the hemodynamic causes (inotropic therapy), and the cardioperipheral causes (vasodilator therapy) to understanding its neurohormonal aspects. Whereas those earlier strategies all fulfilled the basic clinical needs of symptomatic relief and restoration of cardiac function, only the neurohormonal approach has provided an effective combination of symptom relief and survival benefit.

The treatment of heart failure in the last decade has been advanced significantly by several developments, among them the understanding that the disorder is both clinically overt and covert (that is, symptomatic and asymptomatic); the focus on preventing progression of the disease and addressing the neurohormonal causes to reduce morbidity and mortality among patients with heart failure; and the dependence on angiotensin-converting enzyme (ACE) inhibitors and beta-blockers as the mainstays of therapy.

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Adrenergic Blockade

Once considered contraindicated in the treatment of heart failure accompanied by systolic dysfunction, beta-blockade is now recognized as mandated therapy in the treatment of the disorder. The gradual acceptance of this seemingly counterintuitive strategy stems from the recognition of the importance of the adrenergic system in determining disease progression and patient survival and of the limitations of targeting the solitary renin-angiotensin system.

Today, of course, the medical literature overwhelmingly supports the use of beta-blockers, but the therapy does have its caveats and limitations. An overt decompensated state, for example, absolutely precludes the use of beta-blockade. The presence of severe heart failure is also a contraindication, because supporting evidence is lacking and a proper application strategy has not been devised. Beta-blockers must also be given in small amounts initially and the dose titrated gradually, and patients must be closely monitored for signs of decompensation during administration of the drugs.

Unlike ACE inhibitors, which are uniform in the effects they produce, beta-blockers as a class do not appear to be as consistent in the effects they generate. The  adrenergic blockers most validated for use in treating heart failure include carvedilol, metoprolol XL, and bisoprolol. Other beta-blockers are not as well supported by trial data, and their titration requirements and effects cannot be reasonably predicted from the data for drugs that have been studied more thoroughly.

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Recent Advances

Studies of newer agents that target the causes of heart failure at the neurohormonal level and beyond are showing encouraging results. Such drugs include the angiotensin-receptor blocker losartan, the aldosterone antagonist spironolactone, the beta-blocker bucindolol, and the vasopeptidase inhibitor omapatrilat. Recent trial data from some important studies of these drugs have shaped our current clinical treatment strategies (see table, below).

Angiotensin-receptor blocker therapy. Two recent trials, the Evaluation of Losartan in the Elderly (ELITE) study and its sequel, ELITE II, compared the angiotensin-receptor blocker losartan with the ACE inhibitor captopril in older patients who had symptomatic heart failure. The first ELITE study, reported in 1997, investigated the effects of those agents on renal function and found no difference between them when they were administered during a period of 48 weeks. Among the patients who received losartan, however, the investigators did observe a 46% (P <0.05) reduction in mortality associated with all causes and a 64% reduction in sudden death, although these results were based on only a small number (49) of deaths (Pitt et al., 1997; for complete reference to this and all other studies mentioned, see table, below). In addition, mortality was prespecified as an endpoint only after patient recruitment was complete and was not considered of primary or secondary interest.

In ELITE II, a multicenter, double-blind, randomized, parallel-group study, the authors sought to establish whether losartan was superior to captopril in reducing the risk of death from all causes (Pitt et al., 2000). Sudden death and resuscitated cardiac arrest were secondary outcomes. Also observed were the combined outcome of death and hospitalization from all causes and drug safety and tolerability. The study was designed with 90% power to detect a 25% difference in mortality associated with all causes and was event driven (expecting 510 deaths over 1.5 years).

During a median follow-up period of 1.5 years, the mortality rate among the groups who received losartan and captopril did not differ significantly. Nor did the rate of sudden death and resuscitated cardiac arrest, as a combined outcome, differ significantly between the two groups. The same was also true for the combined rate of death and hospitalization associated with all causes, although trends in all of those outcomes were consistently in favor of captopril. However, as in ELITE, losartan was significantly better tolerated than captopril: 14.5% of patients taking captopril discontinued their therapy, compared with only 9.4% of those receiving losartan (P <0.001).

The ELITE-II study has only partially clarified the role of angiotensin-receptor blocker therapy in the treatment of heart failure. For the moment, the current recommendation to administer the drugs only when a patient cannot tolerate ACE inhibitor therapy should still be followed, although conclusive support for that recommendation has yet to be established.

Adrenergic-receptor binder therapy. More recently, results of the Valsartan in Heart Failure Trial (Val-HeFT), which were reported by Cohn at the 2000 meeting of the American Heart Association, indicated that the addition of the adrenergic-receptor binder valsartan to usual therapy did not affect mortality associated with all causes. However, that combination did reduce by 13.3% the combined incidence of death and illness associated with all causes, particularly hospitalization for congestive heart failure. The benefit was particularly evident in the 7% of patients who were not receiving ACE inhibitor therapy. Subgroup analysis revealed, however, that in 35% of the patients who were receiving both valsartan and beta-blocker therapy, the combined incidence of death and illness associated with all causes increased by 10%. Further analysis revealed that this unfavorable trend was limited exclusively to patients undergoing both ACE inhibitor and beta-blocker therapy.

The issue of combining adrenergic-receptor binder therapy with ACE inhibitor and beta-blocker therapy will probably not be resolved until results from the next major trial are reported. Currently addressing that issue is the Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM) study, which is examining the effects of candesartan on three populations with heart failure: one group with reduced left ventricular function who are intolerant of ACE inhibitors; another similar group who are already receiving ACE inhibitor therapy; and one group who have preserved left ventricular function and will not be receiving ACE inhibitor therapy. Begun in early 1999, the trial is expected to end in 2003.

Aldosterone antagonist therapy. Aldosterone is important in the pathophysiology of heart failure because it promotes magnesium wasting, arrhythmia, and myocardial fibrosis. In the double-blind Randomized Aldactone Evaluation Study, 1663 patients with severe heart failure and a left ventricular ejection fraction (EF) of no more than 35% underwent ACE inhibitor, loop diuretic, and, in most cases, digoxin therapy. Of that group, 822 patients were randomly assigned to receive 25 mg daily of the aldosterone antagonist spironolactone and 841 were assigned to receive placebo.

The trial was discontinued early, after a mean follow-up period of 24 months, because an interim analysis determined that spironolactone was effective in reducing the risk of death from all causes (Pitt et al., 1999). The authors reported 386 deaths among the placebo group (46%) and 284 among the spironolactone group (35%; relative risk of death, 0.70; 95% confidence interval, 0.60 to 0.82; P <0.001).

The 30% reduction in the risk of death among patients in the spironolactone group was attributed to a lower risk of both death from progressive heart failure and sudden death from cardiac causes. The frequency of hospitalization for worsening heart failure was 35% lower among the spironolactone group than among the placebo group (relative risk of hospitalization, 0.65; 95% confidence interval, 0.54 to 0.77; P <0.001). In addition, symptoms of heart failure among patients who received spironolactone had resolved significantly, as assessed on the basis of the New York Heart Association (NYHA) functional class (P <0.001). Gynecomastia or breast pain was noted in 10% of men who received spironolactone, compared with 1% of men in the placebo group (P <0.001). The incidence of serious hyperkalemia was minimal in both groups.

Spironolactone therapy should be considered for moderately to severely ill patients who have had heart failure. Careful follow-up evaluation is necessary when hyperkalemia is present, particularly in patients with diabetic renal disease and underlying renal dysfunction. Currently, spironolactone therapy is not recommended for patients with mild heart failure.

Beta-blocker therapy. The double-blind, placebo-controlled Beta-blocker Evaluation Survival Trial (BEST) investigated the addition of the beta-blocker bucindolol to standard medical therapy to determine whether the combination could reduce mortality associated with all causes among patients with severe (NYHA class III/IV) heart failure and left ventricular systolic dysfunction (the BEST Steering Committee, 1995). Patients were assigned randomly to treatment according to the presence or absence of chronic heart disease, left ventricular EF, gender, and race. Twenty-three percent (23%) of the patients were African Americans, 22% were women, and 92% had NYHA class III heart failure and 8% had class IV heart failure. For patients assigned to receive bucindolol, 92% were receiving some quantity of bucindolol by the end of titration and 77% were receiving it by the end of the study.

During a period of six to eight weeks, bucindolol dosage was titrated upward from 3 mg to 50 mg twice daily in patients weighing less than 75 kg and from 100 mg in patients weighing more than 75 kg. Mortality among the bucindolol group was 10% lower than that of the placebo group (Z value = 1.60, P = 0.109 unadjusted; total events, 856). Although this result appeared to favor bucindolol, it did not reach statistical significance. Bucindolol reduced cardiovascular deaths by 12.5%, a statistically significant reduction that seemed to apply equally to the numbers of sudden deaths and deaths caused by pump failure or myocardial infarction.

Subgroup analysis yielded mixed results. After undergoing bucindolol therapy, patients with NYHA Class III heart failure or left ventricular EF greater than 20% survived longer than those taking placebo. In contrast, patients with NYHA Class IV heart failure or EF less than 20% did not appear to benefit from the drug. Similar results were noted among patients with or without coronary disease. The non-African-American subgroup enjoyed a statistically significant survival benefit. By contrast, the mortality rate among the African-American subgroup was 17% greater, which was not significantly different from that of the placebo group on subgroup analysis, suggesting a lack of benefit and a possible harmful effect.

The results of BEST raise a number of questions. Had the study enrolled a predominantly white population that had NYHA II/III heart failure, as did the Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (1999) and the Cardiac Insufficiency Bisoprolol Study (1999), it probably would have shown a much greater reduction in mortality associated with all causes. The question of racial difference in the response to beta-blocker therapy is important. Any explanation will have to consider the issues of inconsistent compliance with therapy, withdrawal from the study in response to adverse events, intrinsic absence of response, and the play of chance.

The results of BEST also call into question the wisdom of treating very advanced heart failure with beta-blocker therapy. Fortunately, one recent large study, the Carvedilol Prospective Randomized Cumulative Survival Trial (COPERNICUS), was stopped prematurely after a highly significant reduction in mortality was noted among patients with severe heart failure who received carvedilol. (Details of this investigation are currently unavailable, however.) Probably the most important question that the findings of BEST have raised is whether there are real differences in efficacy among the class of beta-blocking agents in the treatment of heart failure. It is unlikely that a metaanalysis comparing metoprolol, bisoprolol, carvedilol, and bucindolol will show significantly inconsistent effects among that group of agents.

Vasopeptidase inhibition therapy. Omapatrilat is a vasopeptidase inhibitor, a class of agents designed to inhibit both ACE and neutral endopeptidase in the treatment of hypertension and heart failure. Vasopeptidase inhibitors may be expected not only to reduce the production of angiotensin II but also to inhibit the degradation of bradykinin and natriuretic peptides. Thus, these agents may not only produce all the benefits of ACE inhibitors but may also increase natriuresis, reduce vascular tone, and affect tissues directly, including inhibiting vascular smooth muscle proliferation. However, they may also increase plasma concentrations of endothelin, a potentially adverse effect-endothelin is also a substrate for neutral endopeptidase. Omapatrilat is a particularly potent ACE inhibitor, and its power must be taken into account when assessing its effects.

In the Inhibition of Metalloproteinase by BMS186716 in a Randomised Exercise and Symptoms Study (IMPRESS), 573 patients with NYHA class II to IV heart failure were randomly assigned to receive omapatrilat 40 mg/day (289 patients) or lisinopril 20 mg/day (284 patients) (Rouleau et al., 2000). The mean left ventricular EF was 28%, and 63% of the patients had NYHA class II heart failure. All patients were receiving ACE inhibitor therapy before undergoing randomized selection, and 30% were receiving beta-blocker therapy. The follow-up period lasted 24 weeks.

Exercise capacity increased equally in both the omapatrilat and lisinopril groups. As all patients were already receiving ACE inhibitor therapy at enrollment this finding probably reflects a placebo effect. The NYHA classification tended to improve more among patients receiving omapatrilat, although the effect was significant only on subset analysis of patients with NYHA class III/IV heart failure. Sixteen patients receiving omapatrilat and 29 given lisinopril died or had worsening heart failure as defined above (risk ratio 0.52; P <0.04). Fewer patients in the omapatrilat group than in the lisinopril group had such adverse outcomes as marked worsening of renal function.

Although omapatrilat is the first in a class of promising new agents for the treatment of heart failure, definitive studies are still necessary. Currently underway is the Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events (OVERTURE) study, which will compare omapatrilat therapy with ACE inhibitor therapy in 4400 patients with heart failure.

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Latest Research

As mentioned earlier, the COPERNICUS trial, which investigated the effects of carvedilol in the treatment of severe heart failure, recently was discontinued because a highly significant reduction in mortality was noted among patients who received the drug. Again, no details have yet been released, as data analyses are not complete, but the United States Carvedilol Heart Failure Study Group had published in 1997 the results of a smaller trial that also alluded to a benefit in patients with severe heart failure (Cohn et al., 1997).

According to Packer, who presented the results of the second Prospective Randomized Amlodipine Survival Evaluation Study Group (PRAISE II) trial at the 2000 annual meeting of the American College of Cardiology, the calcium blocker amlodipine failed to deliver any benefit to patients who had nonischemic heart failure. In that study of 1652 patients, the mortality rate did not differ between patients who received the drug (278 deaths) and those who received placebo (262 deaths). As a result, the initial enthusiasm for amlodipine that was generated in the 1996 initial PRAISE trial was not substantiated (Packer et al., 1996).

Recent studies of other therapeutic strategies have yielded more promising results. Findings of phase I trials of vasopressin antagonists known as vaptans have suggested that these drugs may reverse the impaired urinary diluting capacity seen in chronic heart failure, increase sodium free water excretion, correct dilutional hyponatremia, decrease urinary aquaporin-2 excretion, promote peripheral vasodilatation, and improve cardiac output (Martin et al., 1999). Vasopressin release is mediated by either osmotic or nonosmotic (hemodynamic) triggers, both of which are involved in determining vasopressin modulation in heart failure. Vasopressin acts by mediation of V1 and V2 receptors. Currently in clinical development are WAY-VPA-985, a selective V2 antagonist, and YM087, a dual V1 and V2 antagonist.

Also showing promise are endothelin antagonist agents. Like angiotensin II, endothelin is a powerful vasoconstrictor neurohormone that is elevated in patients with heart failure. Endothelin levels correlate with disease severity and prognosis and are a viable therapeutic target. Several endothelin antagonists are in development. Bosentan was removed from active investigation, however, because it tends to produce hepatotoxic effects. Enrasentan is currently the subject of intense clinical scrutiny and appears promising for treatment of chronic heart failure.

In a preliminary investigation of etanercept, an anticytokine drug that functionally inactivates tumor necrosis factor alpha binding sites, Deswal and colleagues noted improvements in ventricular remodeling in patients with heart failure who received the drug (Deswal et al., 1999). After three months, they observed a reduction in left ventricular end diastolic volumes with small enhancements in EF. Such remodeling changes occurred concurrently with improvements in quality of life and clinical scores. These preliminary findings are currently being investigated in a large-scale trial dubbed RENNAISSANCE (Randomized Etanercept North American Strategy to Study Antagonism of Cytokines).

Clinical and experimental data from studies of growth factor therapy in animals and patients with end-stage heart failure caused by dilated cardiomyopathy or ischemic heart disease suggest a beneficial role of human recombinant growth hormone and insulinlike growth factor I (Osteziel et al., 1998; Genth-Zotz et al., 1999). Based on the results of human studies in patients with dilated cardiomyopathy, double-blind and placebo-controlled studies have shown increases in myocardial mass and a significant reduction of left ventricular wall stress, as demonstrated by magnetic resonance imaging. More recent short-term placebo-controlled studies, however, have yielded disappointing results with little clinical benefit (Sacca, 1999).

Thyroid hormone supplementation has been shown to produce inotropic, lusitropic, and vasodilator effects in patients with acute heart failure. Studies in ambulatory chronic heart failure have shown an improvement in cardiac function and resolution of symptoms after such therapy, but the long-term effects of this approach are currently unknown.

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