Vasopressin Receptor Antagonists: Title and subTitle BreakWill the "Vaptans" Fulfill Their Promise?

Heart failure with decompensated systemic congestion is a common reason for cardiovascular hospitalization among patients older than 65 years.¹ Even though renin-angiotensin-aldosterone blockers and β-adrenergic blockers are highly effective therapies and remain the cornerstones of chronic treatment for heart failure, many patients with acute congestive decompensation have hyponatremia and hypervolemia that is poorly responsive to conventional loop diuretics. In recent clinical trials, use of drugs designed to block cytokines,^{2 - 3} endothelin receptors,⁴ and neutral endopeptidases^{5 - 6} was often limited to patients with compensated heart failure, and the results were disappointing. New data are now emerging, however, and have rekindled interest in blocking neurohormonal systems, leading to restored circulatory homeostasis and improved organ function.

The antidiuretic hormone arginine vasopressin (AVP) is a powerful vasoconstrictor⁷ that modulates free water transport in the kidney⁸ and has an important role in the normal regulation of cardiovascular physiology.⁹ It was therefore of great interest when, more than 20 years ago, several groups were able to demonstrate that plasma AVP levels are markedly increased in some patients with heart failure.^{10 - 11} Nevertheless, several factors must be considered in assessing a candidate neurohormone as a possible "pathogen" in heart failure, including (1) a strong pathophysiologic rationale; (2) consistency of elevated circulating levels that change with disease progression; and (3) the association of long-term suppression of the neurohormone with improved clinical outcomes.¹² The potential clinical value of AVP antagonism was suggested by partial demonstration of the first 2 criteria nearly 2 decades ago.^{13 - 14} The third criterion is only now beginning to be fulfilled by means of clinical trials of vasopressin antagonists (or "vaptans"), such as the study by Gheorghiade and colleagues¹⁵ in this issue of THE JOURNAL.

The story of AVP antagonists in heart failure is an old one, and it is useful to keep in mind some of the missing parts of the "vaptans" story. Although AVP was discovered more than 50 years ago, reasons that levels increase in patients with heart failure are still not well understood. Some believe that nonosmotic forces are important.¹⁶ At least 2 distinctive subtypes of vasopressor receptors exist: V_1A receptors, responsible for vasoconstriction and mitogenesis in the vascular smooth muscles; and V₂ receptors, which reduce free water excretion and modify urea and sodium reabsorption in the kidney. The latter is likely the main site of action for the vaptans' aquaretic effects (ie, the ability of these agents to promote excretion of free water). A third receptor, the V_1B (or V₃) receptor, may play a role in regulating the hypothalamic-pituitary-adrenal axis and is unlikely to have a significant role in heart failure.

It is clear that increasing concentrations of plasma AVP within the physiologically relevant range can cause vasoconstriction in patients with advanced heart failure.¹⁷ Therefore, a theoretical concern is that a selective AVP V₂ receptor antagonist (such as tolvaptan) could increase interaction of AVP with the unblocked V_1A receptors, leading to vasoconstriction, increased afterload stress, and worsening ventricular function.^{16 ,18} Unopposed activation of the V_1A receptor also could lead to coronary vasoconstriction and a vagally mediated myocardial depressant effect. In contrast, dual V_1A and V₂ receptor antagonists (such as conivaptan) ameliorate the unopposed V_1A receptor effects of AVP and lower pulmonary artery wedge pressures,¹⁹ but the clinical relevance of this remains to be verified in clinical trials.

Tolvaptan is an oral, nonpeptide vasopressin V₂ receptor antagonist that is administered once per day. As Gheorghiade et al¹⁵ report, the ACTIV in CHF study shows that initiating tolvaptan shortly after admission for decompensated heart failure leads to a reduction in volume without changing heart rate, blood pressure, serum potassium levels, or renal function.^{15 ,18} Edema was reduced by tolvaptan, whereas hyponatremia appeared to improve. However, some of the reduction in edema in the recent study¹⁵ was likely related to the concomitant use of loop diuretics.

Rather than being classified as a traditional diuretic, tolvaptan is more precisely characterized as an aquaretic. Both diuretics and aquaretics would be expected to be useful in patients with decompensated heart failure, but vaptans might have additional benefits for patients with significant edema and hyponatremia. The finding that there was no worsening of heart failure with tolvaptan over 60 days compared with placebo implies that selectively blocking the V₂ receptors may not cause harm in the short term.¹⁵ However, long-term follow-up studies are needed to determine if theoretical concerns are problematic in patients with heart failure and if the efficacy of dual V_1A and V₂ receptor antagonists may have some advantage vs that of selective V₂ receptor antagonists.

Tolvaptan is one of a new class of drugs and addresses important problems in acute heart failure, eg, hyponatremia, water retention, and renal dysfunction. The study by Gheorghiade et al¹⁵ also raises important regulatory issues. The question arises as to what should be measured to demonstrate efficacy in clinical trials of such new therapy for the treatment of acute or decompensated heart failure. Payers such as the Center for Medicare and Medicaid Services (CMS) and insurance carriers have a stake in this question, as new agents are likely to be expensive. Some demonstration of physiologic improvement, such as weight loss and correction of hyponatremia, is necessary but should be coupled to some index of improvement in clinical outcome. Heart failure researchers are still struggling to identify a measure of improved clinical outcome in the setting of acute heart failure that is objective, quantitative, reproducible, relevant, and reliable. Physicians can recognize when acutely ill patients with heart failure improve clinically, but the likely multiple subjective and objective variables that are assessed at the bedside and synthesized to reach these judgments have not been well understood. "Favorable clinical outcomes" must be defined in a quantitative manner in order to develop new drugs for patients with decompensated congestive heart failure.

On balance, ACTIV in CHF is an important clinical trial in the development of new drugs for treatment of acute decompensated congestive heart failure and possibly for treatment of chronic heart failure. The phase 3 Efficacy of Vasopressin Antagonism in Heart Failure (EVEREST) trial²⁰ will determine the long-term efficacy of tolvaptan. More trials with AVP antagonists are likely coming, and developments with these agents bear careful scrutiny.