Editorials
Tolvaptan, Is It a Trump to Worsening Renal Function?
2017 Volume 81 Issue 5 Pages 642-644
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2017 Volume 81 Issue 5 Pages 642-644
Renal dysfunction is very frequently associated with heart failure (HF). In addition to baseline renal dysfunction, WRF, which occurs in 30–50% of hospitalized patients with HF is recognized as a more thorny problem in the management of HF. The most important factor leading to WRF is venous congestion caused by volume overload.1 However, many other factors, including hypertension, diabetes mellitus, underlying renal dysfunction etc., are also related to the occurrence of WRF2–5 (Table 1). Dosage of diuretics converted to furosemide is also one of them. Rapid depletion of intravascular volume by intravenous furosemide induces reflective sympathetic nerve activity and subsequent enhancement of the renin-angiotensin system6 and decrease in the glomerular filtration rate (GFR).7 Through such mechanisms, high-dose diuretic therapy may induce WRF and even worsen survival in a dose-dependent manner.8–10 Thus, we must recognize that releasing renal congestion by loop diuretics is a “two-edged sword”. Although loop diuretics are positioned as class I treatment in the guidelines for alleviating symptoms related to congestion with chronic HF, that is because there have been no better drugs than loop diuretics for achieving this purpose.
| History of chronic kidney disease2 |
| Creatinine >1.5 mg/dL (132.6 umol/L)4 |
| Elevated creatinine level at admission3 |
| LVEF2 |
| NYHA class on admission2 |
| History of heart failure3,4 |
| Old age5 |
| Diabetes3–5 |
| Hypertension3–5 |
| Acute coronary syndromes5 |
| History of diabetes mellitus4 |
| Furosemide daily dose2,3 |
| Calcium-channel blocker use3 |
LVEF, left ventricular ejection fraction; WRF, worsening renal function.
Article p 740
Debut and Achievement of TolvaptanIn December, 2010, tolvaptan was approved in Japan for the treatment of body fluid excess not responding to loop diuretics, although it is yet to be approved for HF in the USA and EU countries because randomized trials conducted in these countries failed to demonstrate mortality benefit11 or symptom relief.12,13 Although hypernatremia as a specific adverse event of this drug drew attention soon after marketing, its usefulness in the treatment of volume overloaded HF seems to be established in Japan in contrast to the negative evaluation in other countries. As the experience of the clinical use of this drug, tolvaptan is getting used more often in the acute phase of decompensated HF, although initially it began use as an add-on drug to loop diuretics in chronic HF. The appearance of this drug shone the spotlight on diuretics, which are one on of the oldest drug classes for HF therapy and much clinical research on tolvaptan has been conducted in Japan. Some of these studies investigated the effect of tolvaptan on renal function in comparison with conventional furosemide therapy.14–17 In this issue of the Journal, Tamaki et al present their results of focusing on reducing the risk of WRF in patients with ADHF and HF with preserved ejection fraction (HFpEF).18
As every cardiologist knows, currently there is no all-in-one therapy that can improve the prognosis of HFpEF. The treatment strategy of HFpEF is confused and a new treatment strategy is being sought. In Japan, tolvaptan has been actively used in HFpEF patients as well as HF patients with reduced EF (HFrEF) since its marketing. In the phase III study in Japan, QUEST, average EF was nearly 50%, indicating that many patients recruited in this study had preserved EF.19 In the PMS study, which analyzed the data from more than 1,000 patients with HF, mean EF was 47%.20 Therefore it is realistic and practical to focus on the effect of tolvaptan in HFpEF patients. The most representative manifestation of ADHF caused by HFpEF is acute cardiogenic pulmonary edema. In these patients, systemic volume overload is not usually marked and the dominant pathophysiology is characterized by a fluid shift from the blood vessel to the pulmonary interstitial space. In such circumstances, stereotypical administration of furosemide induces rapid and excessive depletion of intravascular volume, and it can be well imagined that subsequently impairment of renal function caused by decreased renal blood flow occurs. Takei et al reported that the estimated plasma volume reduction during hospitalization is a predictor of WRF in patients with HFpEF but not in HFrEF.21 If so, tolvaptan, which efficiently shifts volume from the interstitial space to the vasculature, may be more suitable. However, as the lowering effect of tolvaptan on pulmonary wedge pressure is only modest,22 concomitant use of a vasodilator and/or noninvasive positive pressure ventilation are also practically necessary to alleviate symptoms of pulmonary congestion. Moreover, the characteristics of volume overload may not be clearly distinguished between HFpEF and HFrEF, and WRF occurs equally in either type of HF. In Forman’s report based on data from more than 1,000 patients with HF, there was no statistical difference in LVEF or the prevalence of HFpEF between patients with and without WRF. Thus each patient’s volume status should be evaluated and an appropriate treatment strategy for volume control should be chosen regardless of LVEF.
Comparison of Clinical Studies on the Effect of Tolvaptan on WRFThe aforementioned studies investigating the effects of tolvaptan on renal function in patients with acute HF are summarized in Table 2. Most of these studies claimed favorable effects of tolvaptan on WRF. Among them, LVEF is generally preserved except in Shirakabe’s report, indicating that the majority of the patients treated with tolvaptan were HFpEF. The preventive effect of tolvaptan on WRF was not significant only in Matsue et al’s report, in which doses of furosemide and tolvaptan were relatively higher compared with the other reports.16 The incidence of WRF is probably determined by the doses of both furosemide and tolvaptan and the optimal dose of tolvaptan for prevention of WRF is likely to be 7.5 mg/day. A meta-analysis of these studies may give us more useful and reliable information on the effect of tolvaptan on renal function.
| Tolvaptan dose (mg/24 h) |
Furosemide dose (mg/24 h) | Incidence of WRF | LVEF | ||||
|---|---|---|---|---|---|---|---|
| Tolvaptan | Control | Tolvaptan | Control | P value | |||
| Shirakabe et al* (2014)14 | 7.5 | 17.7 | 40 | 2.7 | 21.6 | 0.028 | 35 |
| Kimura et al (2016)15 | 8.37 | 20 | 38.46 | 26.9 | 57.7 | 0.025 | 47.54–56.73 |
| Matsue et al (2016)16 | 15 | 40 | 60 | 24.1 | 27.8 | NS | 45.4–46.8 |
| Jujo et al (2016)17 | 7.5 | 23 | 33 | 6.7 | 33 | <0.01 | LVD 33.5%** |
| Tamaki et al (2017)18 | 13.9 | 8.2 | 59.5 | 12 | 42 | 0.0236 | 59.7–60.7 |
*Worsening AKI instead of WRF. **Proportion of LV systolic dysfunction (EF <40%); average EF not indicated. AKI, acute kidney injury; LVD, left ventricular dysfunction. Other abbreviations as in Table 1.
However, we should be cautious about excessive expectations of tolvaptan. When witnessing a beneficial effect of tolvaptan on renal function, one might get the impression that tolvaptan has a direct renoprotective effect. However, so far not enough data support the renoprotective effect of tovaptan in the clinical setting, although a few animal experiments suggested this effect of tolvaptan.23,24 Further deployment of basic and clinical research on this topic is necessary.
The long-term benefit of alleviating WRF by tolvaptan in acute phase HF may also need to be investigated. Although it is known that WRF is a determinant of prognosis in patients with HF,2,3 whether any intervention to prevent WRF can improve prognosis or not is not fully proven yet. Tamaki et al followed up patients for only 48 h and so the long-term effect of early intervention with tolvaptan is yet to be elucidated.
The cost-effectiveness of tolvaptan, which is much more expensive than furosemide, should also be considered. In the AVCMA trial, Suzuki et al reported that adverse events were fewer and average cost was lower in the tolvaptan arm than in thecarperitide arm in patients with acute HF.25 The overall cost-benefit of adding tolvaptan to furosemide in order to prevent WRF must also be evaluated.
