What drug treatments for heart failure are in the pipeline?

Blockade of activated neurohumoral vasoconstrictor systems

he benefits of blocking activated neuro-hormonal vasoconstrictor systems in heart failure are well recognized. They are confirmed by the success of treatment strategies involving blockade of the renin-angiotensin-aldosterone system (RAAS) (specifically with angiotensin-converting enzyme [ACE] inhibitors, angiotensin II receptor antagonists, and aldosterone antagonists) and the sympathetic nervous system (specifically with |3-blockers).

Targeted drug therapy

There is a growing interest in targeting therapy to biological mechanisms and genetic makeup. Differential ethnic or racial responses to therapy may reflect either or both of these factors. There are suggestions that African Americans respond less well to ACE inhibition and better to combination therapy with hydralazine and isosorbide dinitrate. There is conflicting evidence about racial or ethnic background and response to (3-blocker therapy. The African-American Heart Failure Trial (A-HeFT) will compare clinical status and ventricular function between black men and women with New York Heart Association (NYHA) class III and IV heart failure randomized to placebo or hydralazine and isosorbide dinitrate.

Tailored drug therapy

Murdoch et al showed that a vasodilator approach tailored to the plasma brain-type natriuretic peptide (BNP) level is well tolerated and safe in heart failure and achieves deeper RAAS inhibition than apparently optimal ACE-inhibitor therapy. The most promising feature of this approach is the chronic reduction in plasma BNP levels and heart rate obtained by aggressive vasodilator therapy. Similarly, Troughton et al showed that drug treatment guided by the plasma N-terminal BNP (N-BNP) level decreased the total number of cardiovascular events compared with clinically guided treatment using the same range of therapies. Cardiovascular death, admissions, and new episodes of decompensated heart failure were all lower in the N-BNP-guided group. These reductions were achieved with increased dosages of ACE inhibitors and loop diuretics, and the use of spironolactone. In the clinically guided group, the ACE-inhibitor dosage was similar to that achieved in the Cooperative North Scandinavian ENalapril Survival Study (CONSENSUS) and Studies Of Left Ventricular Dysfunction (SOLVD), while the mortality rate was similar to that in the latter.

Other neurohumoral therapies Endotheliti antagonists

Plasma levels of endothelin-1 (ET-1) are elevated in heart failure, to a degree that correlates with disease severity, and are a powerful predictor of mortality. Yet, clinical studies with ET antagonists have given negative results. The recent ENdothelin Antagonist Bosentan for Lowering cardiac Events in heart failure (ENABLE) trial suggests that blocking the ETg receptor, which mediates prostaglandin-induced vasodilatation, may be much more deleterious than predicted. Hopefully, it will lead to future studies of selective and nonselective agents to be conducted with much lower doses.

Endothelin-converting enzyme inhibition

ET-converting enzyme (ECE) inhibition is another potential means of blocking the actions of ET-1. Early clinical studies have already been undertaken with drugs that inhibit both ECE and neutral endopeptidase (NEP).

Cytokine antagonists

Heart failure is associated with the activation of several key proinflammatory cytokines that may contribute to disease progression. Best characterized is tumor necrosis factor-a (TNF-a), elevated plasma levels of which are found in heart failure in association with an increase in inducible nitric oxide synthase (iNOS) in the myocardium. This may directly and indirectly impair ventricular function. TNF-a also has pro-oxidant and apoptotic properties and is a potent stimulator of ET production. There is some evidence that anticytokine interventions improve ventricular function and clinical status in heart failure. However, two parallel trials of the anti-TNF agent etanercept in heart failure, Randomized Etan-ercept North American Strategy to Study ANtago-nism of CytokinE (RENAISSANCE) and Research into Etanercept: Cytokine antagOnism in VEntricu-laR function (RECOVER), were recently discontinued due to lack of effect on morbidity and mortality.

Drugs augmenting plasma natriuretic peptide concentrations

Infusions of atrial natriuretic peptide (ANP) and BNP have positive hemodynamic, neurohumoral, and renal effects in heart failure. Since both are metabolized by NEP, their plasma concentrations increase in response to oral NEP inhibitors. However, the results with NEP inhibitors have been disappointing. For this reason the drugs in active development combine inhibition of NEP with that of other enzymes (ACE, ECE).

Multienzyme inhibitors

Combined NEP/ACE inhibitors simultaneously enhance a beneficial neurohumoral system while suppressing a harmful one. However, in the Oma-patrilat Versus Enalapril Randomized Trial of Utility in Reducing Events (OVERTURE), there was no significant difference in mortality between the two groups. The trial achieved only one of its primary end points (equivalence), suggesting that treatments were similar. Further drugs have thus been developed with multiple neurohumoral actions, including dual-enzyme NEP/ECE inhibitors and tripleenzyme NEP/ACE/ECE inhibitors.

Arginine vasopressin antagonists

Arginine vasopressin (AVP) is a potent vasoconstrictor and antidiuretic. It acts via Vj receptors, found on blood vessels and myocardium, and the V2 receptors which mediate its effects on fluid resorption in the renal tubule. Selective Vj and V2 and mixed Vl/V2 receptor antagonists are in the early phase of clinical development. Single doses of a Vj receptor antagonist have shown favorable hemodynamic effects, while V2 receptor antagonists induce diuresis and improve hyponatremia.

Adenosine antagonists

Selective adenosine At receptor blockade may induce diuresis and natriuresis in heart failure without reducing the glomerular filtration rate. This approach could be useful in the growing population of heart failure patients with azotemia.

Other antiadrenergic therapies

Nolomirole is an aminotetraline derivative that lowers plasma catecholamine levels. It is being evaluated in a heart failure outcome study.

Inotropic therapy

Early experience with oral inotropics was unfavorable, with increased mortality on (3-agonists (xa-moterol) and phosphodiesterase (PDE) inhibitors (milrinone, enoximone, vesnarinone and flose-quinan), possibly due to their proarrhythmic properties. There is renewed interest in PDE inhibitors at lower doses, and in combination with (3-blockers: PDE inhibition facilitates the introduction of (3-blockade, while (3-blockade protects against the proarrhythmic effect of PDE inhibition. New phase 3 morbidity/mortality trials with enoximone are under way. The calcium sensitizer levosimendan is also being evaluated in acute heart failure.

Targeting other key systems involved in the pathophysiological responses to myocardial injury

Further understanding of other key systems involved in the pathophysiological responses to myocardial injury has led to promising new avenues for pharmacological intervention.

Left ventricular remodeling

The multifactorial cascade resulting in left ventricular remodeling incorporates changes that are hemodynamic, genetic, energetic, and neurohumoral. All contribute to heart failure progression, while together offering multiple targets for therapeutic intervention. In the recent Carvedilol ACE inhibitor Remodeling Mild CHF EvaluatioN (CARMEN) trial, the combination of carvedilol and enalapril significantly lowered left ventricular end-systolic volume index (LVESVI) at 18 months (6 mL/m2) vs baseline and enalapril alone (1 mL/m2, P<0.002). Carvedilol alone had intermediate effects that were not significantly superior to enalapril alone nor inferior to the combination. Matrix metalloproteinase inhibition End-stage heart failure is associated with increased collagenase activity and reduced expression of tissue matrix metalloproteinase (MMP) inhibitors. Experimental MMP inhibition decreases ventricular dilatation but theoretical concerns remain over its use in patients. Acute ischemic episodes Acute ischemic episodes increase the risk of death and hospitalization in heart failure. Part of the benefit from ACE inhibitors and (3-blockers consists of a decrease in coronary events. Antiplatelet therapy and statins can also be expected to reduce coronary events. Hibernating myocardium Hibernating myocardium is viable muscle that is unable to contract due to a severely restricted blood flow. Restoration of coronary flow restores normal contractility, whereas continued hibernation may ultimately lead to cell death. The Carvedilol Hibernation Reversible ISchemia Trial: MArker of Success (CHRISTMAS) showed that over 50% of patients (hibernators) had evidence of myocardial hibernation affecting two or more segments and that almost 80% had a substantial volume of myocardium affected by either hibernation or ischemia. The left ventricular ejection fraction (LVEF) response to carvedilol tended to be greater in hibernators than in nonhibernators. However, those with a large volume of hibernating myocardium showed a much greater improvement in LVEF (+11% for four or more segments vs +1% for one segment; PcO.OOl). The study suggests that carvedilol, by virtue of its 13-blocker and/or antioxidant properties, may be an effective treatment for hibernating myocardium. Atrial fibrillation In principle, pharmacological maintenance of sinus rhythm should decrease the risk of hospitalization for exacerbated heart failure associated with atrial fibrillation. Sudden death is common in heart failure. Yet, antiarrhythmic drug therapy has had, at best, a neutral effect on mortality. It is hoped that implantable cardioverter defibrillators will improve prognosis. Correction of anemia There has been much recent interest in the finding that many patients with heart failure are anemic. Correction with iron supplementation and erythropoietin may improve symptoms and morbidity. Large-scale clinical trials are being considered. Renal dysfunction and depression Renal dysfunction and depression are common in heart failure and predict a poor prognosis. Corrective therapy may improve outcome. Heart failure with a preserved left ventricular ejection fraction Left ventricular systolic function appears preserved in a substantial minority of patients with the clinical heart failure syndrome. Because many such patients have underlying atherosclerosis, hypertension, diabetes, left ventricular hypertrophy, and atrial fibrillation, they should benefit from treatment with RAAS and sympathetic nervous system inhibitors. Ongoing trials to test this hypothesis include Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity (CHARM), Irbesartan in Heart Failure with Preserved Systolic Function (I-PRE-SERVE), Perindopril for Elderly People with Chronic Heart Failure (PEP-CHF), and the Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors (SENIORS). Coletta AP, Louis AA, Clark AL, Nitikin N, Cleland JG. Clinical trials update from the European Society of Cardiology: CARMEN, EARTH, OPT1MAAL, ACE, TEN-HMS, MAGIC, SOLVD-X and PATH-CHF II. Eur J Heart Fail. 2002;4:661-666. Coletta A, Thackray S, Nikitin N, Cleland JG. Clinical trials update: highlights of the scientific sessions of The American College of Cardiology 2002: UFE, DANAMI 2, MADIT-2, MIRAClf-ICD, OVERTURE, OCTAVE, ENABLE 1 & 2, CHRISTMAS, AFFIRM, RACE, WIZARD, AZACS, REMATCH, BNP trial and HARDBALL Eur J Heart Fail. 2002;4:381 -388. Krum H. New and emerging pharmacologic strategies in the management of chronic heart failure. Clin Cardiol. 2000;23:724-730. McMurray J, Pfeffer MA. New therapeutic options in congestive heart failure: Part II. Circulation. 2002;105:2223-2228. McMurray J, Pfeffer AAA. New therapeutic options in congestive heart failure: Parti. Circulation. 2002;105:2099-2106. Murdoch DR, McDonagh TA, Byrne J, et al. Titration of vasodilator therapy in chronic heart failure according to plasma brain natriuretic peptide concentration: randomized comparison of the hemodynamic and neuroendocrine effects of tailored versus empirical therapy. Am Heart J. 1999,138:1126-1132. Troughton RW, Frampton CM, Yandle TG, Espiner EA, Nkholls MG, Richards AM. Treatment of heart failure guided by plasma aminoterminal brain natriuretic peptide (N-BNP) concentrations. Lancet. 2000;335:1126-1130. Keywords management; new and emerging drug treatment; pathophysiology; neurohumoral activation; endothelin; cytokine; natriuretic peptide; multienzyme inhibitor; inotropic therapy [gallery ids=""]

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