Predictors for Tolvaptan Treatment and Future Perspectives

Abstract

H eart failure is a major cause of morbidity and mortality worldwide which poses a great burden not only on the patient but also society owing to its expensive health-care related costs.1) During the past 2 decades, the medication strategies for heart failure have progressed significantly like β-blockers, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and aldosterone blockers. Although these drugs have somewhat improved the prognosis of heart failure patients, there still remain many patients who suffer from congestive symptoms due to heart failure in spite of high dose diuretics. Tolvaptan (TLV), a unique drug with characteristics of aquaresis via its vasopressin type 2 (V2) receptor blockade,2) is a new drug which was manufactured originally in Japan for heart failure patients. TLV is a promising drug due to its low stimulation of the renin-angiotensin-aldosterone system (RAAS), and prevention of worsening renal function (WRF) and electrolyte balance abnormalities like hyponatremia and hypokalemia.3) Recently, many novel perspectives about the response to and TLV long-term effects of TLV in heart failure have been reported. [4][5][6] Among them, Kadota, et al reported new insights into predictors of a response to TLV by using the arginine-vasopressin (AVP)/plasma aldosterone concentration (PAC) ratio.7) This study was prospectively performed among 26 patients with decompensated heart failure who were treated with 15 mg of TLV. They investigated the effects of TLV on the RAAS and predictors for the response to TLV treatment by using multiple laboratory factors such as plasma renin activity, aldosterone concentration, AVP, and urine osmolality.TLV increased urine volume and decreased weight without WRF and caused no significant changes in the plasma renin activity or aldosterone concentration. The AVP/PAC ratio before TLV administration was positively correlated with urine volume and they reported the usefulness of the AVP/PAC ratio for predicting the TLV response. Although their study contains some limitations, it provokes important perspectives about prediction of the response to TLV and future challenges in the application of this promising drug. Article p.461Arginine-vasopressin (AVP) is synthesized in the supraoptic and paraventricular nuclei of the hypothalamus and released depending on hyperosmolarity or effective circulation volume loss. Non-osmotic stimulation of AVP is observed, especially among heart failure patients. It was reported that the severity of HF positively correlates with plasma AVP concentration 8) and higher AVP is related to a worse outcome. TLV inhibits AVP connection to V2 receptors in the renal collecting ducts and reduces water re-absorption via aquaporin-2 as a consequence. This aquaresis mechanism has many advantages compared to conventional loop diuretics. Loop diuretics are known for their activation of RAAS and decrease the glomerular filtration ratio and activation of the sympathetic nervous system by reducing the effective circulation volume via s...

New Insights Into Tolvaptan Treatment and the Renin-Angiotensin-Aldosterone System

“…The ratio of AVP/PAC may reflect the activation of AQP-2 in the collecting duct. 13) Kadota, et al 9) suggested that tolvaptan may be more effective in patients with AVP-dominant HF compared to those with RAASdominant HF.…”