Clinical effects of adding tolvaptan to intravenous furosemide in patients with congestive heart failure

Mahoto Kato; Kazuto Tohyama; Toshiyuki Ohya; Atsushi Hirayama

doi:10.4103/rcm.rcm_29_17

ORIGINAL ARTICLE

Year : 2017 | Volume : 6 | Issue : 4 | Page : 14-19

Clinical effects of adding tolvaptan to intravenous furosemide in patients with congestive heart failure

Mahoto Kato, Kazuto Tohyama, Toshiyuki Ohya, Atsushi Hirayama
Department of Medicine, Division of Cardiology, Nihon University School of Medicine, Tokyo, Japan

Date of Web Publication

22-Jan-2018

Correspondence Address:
Dr. Mahoto Kato
30-1 Ohyaguchi-Kamicho, Itabashi, Tokyo 173-8610
Japan

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/rcm.rcm_29_17

Abstract

Background: Tolvaptan, a vasopressin V2 receptor antagonist, is a strong diuretic with a new mechanism of action and has good adaptation to patients with congestive heart failure. Knowledge on the proper use of furosemide, an existing therapeutic drug, is not yet sufficient. Objectives: Clinical differences when 7.5 mg of tolvaptan was added to the usual furosemide therapy were examined. Materials and Methods: Patients who required hospitalization for congestive heart failure were randomly assigned to a group treated for 7 days with furosemide alone (FRO group) and a group treated with furosemide plus tolvaptan (TLV group) for 7 days and examined for symptoms. Physical examinations were performed every day, and blood testing, including N-terminal pro-brain natriuretic peptide (NT-proBNP) level, plasma renin activity (PRA), plasma aldosterone concentration (PAC), and noradrenaline (NAD) level, was performed on days 1, 3, and 7. Results: FRO and TLV groups consisted of 51 (age, 66.4 ± 11.8 years, 62% of males) and 47 patients (67.9 ± 14.5 years, 64% of males), respectively. During the study, the TLV group had higher urine volume and decreased blood pressure due to the suppressed diuretic effect. The two groups showed significant differences in the degree of improvement of the jugular venous pressure (FRO vs. TLV groups: 6.3 ± 1.6 vs. 7.6 ± 2.5 cmH₂O, P < 0.001, on day 3) and other physical findings. Although no significant differences in NT-proBNP and NAD levels were found, there were significant differences in PRA (19.8 ± 12.9 vs. 11.8 ± 8.0 ng/[mL . h], P < 0.001, on day 3) and PAC (FRO vs. TLV groups: 180.4 ± 148.4 vs. 124.7 ± 95.5 ng/mL, P < 0.01 on day 3 and 79.4 ± 73.9 vs. 56.8 ± 38.2 ng/mL, P < 0.05 on day 7). Conclusion: Adding 7.5 mg of tolvaptan to existing treatments with furosemide resulted in differences in clinical findings and neurohormonal factors, even though the degree of improvement in congestive heart failure was the same.

Keywords: Acute decompensated heart failure, Physical findings, Renin-angiotensin-aldosterone system, Tolvaptan, worsening renal function

How to cite this article:
Kato M, Tohyama K, Ohya T, Hirayama A. Clinical effects of adding tolvaptan to intravenous furosemide in patients with congestive heart failure. Res Cardiovasc Med 2017;6:14-9

How to cite this URL:
Kato M, Tohyama K, Ohya T, Hirayama A. Clinical effects of adding tolvaptan to intravenous furosemide in patients with congestive heart failure. Res Cardiovasc Med [serial online] 2017 [cited 2023 Mar 27];6:14-9. Available from: https://www.rcvmonline.com/text.asp?2017/6/4/14/223783

Introduction

In the aged society, the number of patients with congestive heart failure continues to increase. Although the diagnosis of congestive heart failure ^[1] has remained almost unchanged for 50 years, the treatments that remove congestion have evolved.^[2],[3] Furosemide was the main remedy for removing excess fluid from patients with heart failure, but recently, tolvaptan a vasopressin V2 receptor antagonist is an aquaretic that acts on renal tubules in the kidneys and brings a water diuretic effect ^[4],[5] has been considered to be another effective treatment strategy. Numerous reports have described its clinical effects in patients with heart failure,^{[6],[7],[8],[9],[10],[11]} especially patients who could not expect clinical effects with furosemide.^[9],[10] The clinical problem of furosemide is that it adversely affects renal function, inducing a diuretic response in which both sodium and moisture are excreted, causing intravascular dehydration.^{[12],[13],[14]} In that respect, the mechanism of action of tolvaptan causes excretion of water only from the tubule of the kidney, increased sodium concentration in blood vessels, and increased osmotic pressure. Thus, it is presumed that intravascular dehydration hardly occurs due to the excess interstitial fluid.^[9] In other words, patients treated with tolvaptan should show a liquid distribution in the body that is different from that in patients treated with furosemide. However, still few reports have evaluated the precise differences in physical findings caused by these two drugs.^[15] The prognosis of patients with chronic heart failure has been reported to be improved by the inhibitory effect of myocardial remodeling by renin-angiotensin-aldosterone system (RAAS) inhibitors.^{[16],[17],[18]} Even in the acute phase, inhibition of RAAS seems meaningful, but a previous study reported that intravenous administration of furosemide in the acute treatment of patients with acute heart failure activates RAAS.^{[19],[20],[21]} On the other hand, tolvaptan has been reported to suppress the enhancement of RAAS in acute treatment.^[22] However, still few reports directly compared the effects of both drugs on neurohormonal factors.^[5],[15]

Now that clinicians have become accustomed to the clinical use of tolvaptan, the findings on how to use it in combination with other drugs are still not enough. In this study, we hypothesized that the treatment with tolvaptan can reduce the effects on neurohormonal factors including RAAS in patients with acute heart failure.

Objective

We compared the clinical and neurohormonal effects of existing furosemide therapies and a new furosemide therapy with tolvaptan in patients with congestive heart failure with fluid overload.

Materials and Methods

Participants

Consecutive patients who needed hospitalization for worsening of heart failure with excessive fluid retention in our hospital from April 1, 2014, to March 31, 2016, were recruited. Congestive heart failure was diagnosed in accordance with the Framingham criteria.^[1] We included male or female patients aged ≥20 years who needed diuretic therapy and agreed to participate in the clinical trials at admission. We excluded patients with coexisting acute coronary syndrome, acute cerebral infarction or bleeding, severe infection disease, chronic kidney disease (an estimated glomerular filtration rate of <30 ml/min/1.73 m ²), anemia (hemoglobin <10.0 g/ml), hypernatremia (a serum sodium concentration of >146 mEq/L), and active collagen disease that required steroid therapy; patients who needed noninvasive positive pressure ventilation or intubation for respiratory support and any surgical treatments during hospitalization, and those judged by the attending physician as difficult to continue examination.

Protocol

After hospitalization, oxygen was administered to all patients to keep SpO₂ at ≥ 94%. isosorbide dinitrate (ISDN), whose diuretic effect as a vasodilator has not been reported yet, was administered at a dose adjusted by the attending physician to keep the systolic blood pressure (sBP) between 100 and 140 mmHg when patients had an orthopnea. The use of vasodilator other than ISDN was not permitted during the study. After confirming one or more evidence of fluid overload condition, jugular venous pressure (JVP) after adjustment of sBP, hepatojugular reflux, edema on lower extremities, and pleural effusion on chest radiography, 40 mg of furosemide was administered intravenously. Patients whose 24-h urine volume was <1500 mL after intravenous administration of 40 mg of furosemide were randomly assigned to the furosemide group and furosemide plus tolvaptan group one to one by simple randomization which were conducted by research coordinators in our institute not involved in medical treatment. The patients assigned to the furosemide group received the existing treatment with furosemide alone and patients assigned to the furosemide plus tolvaptan group were treated with furosemide with 7.5 mg of tolvaptan for 7 days (from days 1 to 7). During the study, the attending physician increases or decreased the furosemide dose as appropriate according to the patient's condition. Patients treated with any inotropic agent or carperitide, recombinant human natriuretic peptide, and any diuretic except intravenous furosemide for the duration of the study were excluded from the study and patients who had sBP <100 mmHg, patients with symptoms or signs of fluid overload disappeared, patients with serum sodium of 146 mEq/L or more, or patients judged to be difficult to continue trial by the attending physician during this study were discontinued.

This investigation conformed to the ethical guidelines of the 1975 Helsinki Declaration. The institutional scientific and ethical committees approved the protocol, and each patient provided written informed consent to participate in the study.

Symptoms and physical examinations

On each hospital day, two or more attending physicians assessed patient symptoms in the morning by using the visual analog scale (VAS; 0: none to 10: worst symptom); JVP, measured as the height from the sternal horn (cm); lower limb edema evaluated in 5 grades (0: no edema, 1: slight, 2: mild, 3: moderate, and 4: severe); and rales in 4 grades (0: no rales, 1: only bases, 2: bases to 50% way up, 3: bases to > 50% way up).

Statistical analysis

Continuous variables were represented as mean ± standard deviation, numerous variables were represented as medians and 25–75 percentiles, and numbers were represented as number (%) in tables. The means of the continuous variables between the two groups on the same date were compared by conducting a Student's t-test, and the numerous variables and numbers were compared by using the Mann–Whitney U-test. All statistical analyses were performed with SAS version 9.2 (SAS Institute Inc, Cary, NC, USA), and values of P < 0.05 were considered as statistically significant.

Results

Study population

During the study, 572 patients fulfilled the inclusion criteria. When 40 mg of furosemide was administered intravenously, 184 patients had <1500 mL of urine volume daily and 117 were randomly assigned to either the furosemide group or the tolvaptan plus furosemide group, and were given intravenous furosemide or furosemide plus 7.5 mg of tolvaptan, respectively, at 9:00 am the next day. During the treatment course, seven patients in the furosemide group, including 4 patients with resolved excess body fluid and three patients with a sBP of <100 mmHg, and 12 patients in the furosemide plus tolvaptan group, including 9 patients with resolved excess body fluid, one patient with a sBP of <100 mmHg, and two patients with a serum sodium level of >146 mEq/L withdrew from the study. Fifty-one patients in the furosemide group and 47 patients in the furosemide plus tolvaptan group completed the protocol [Figure 1]. No statistically significant differences were found between the two groups at randomization [Table 1].

Figure 1: A diagram of participants flow. BP: Blood pressure

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Table 1: Patients' characteristics

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Dehydration effects

The daily urine volume was significantly higher in the tolvaptan group [Figure 2]. Although no significant difference in the change in body weight (BW) was found between the two groups, a tendency to decrease more in the furosemide plus tolvaptan group was observed [Figure 2]. For diuretic effect, the furosemide plus tolvaptan group was proved to be superior to the furosemide group despite adjustment of the furosemide dose by the attending physician. Trends in sBP during the study tended to be dominantly lower in the furosemide group; that is, sBP did not decrease in the furosemide plus tolvaptan group despite greater urine volume [Figure 3].

Figure 2: Changes in daily urine volume (mL/day) and body weight (kg). ◼ : Only furosemide, ♦: Add tolvaptan. ^§P < 0.01, versus the furosemide group

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Figure 3: Changes in systolic blood pressure (mmHg). ♦: Only furosemide, ♦: Add tolvaptan. ^§P < 0.01, versus the furosemide group

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Symptom and physical examinations

No significant differences in the symptoms in the VAS scale were found between the two groups [Figure 4]a. Improvement in JVP was predominantly faster in the furosemide group. However, no significant difference was found between the two groups [Figure 4]b. Finally, although improvement in the grade of rales was observed early in the furosemide plus tolvaptan group, the difference between the two groups disappeared [Figure 4]c. Regarding lower limb edema, dominant improvement was observed over time in the furosemide plus tolvaptan group [Figure 4]d.

Figure 4: (a) Changes in symptom assessed by using the visual analog scale. (b) Change in jugular vein pressure (cmH2O). §P<0.01, versus the furosemide group. (c) Change in the degree of rales. Rales was assessed in 4 grades (0: no rales, 1: only bases, 2: bases to 50%, 3: bases to > 50%). §P<0.01, versus the furosemide group. (d) Changes in leg edema. Leg edema was assessed in 5 grades (0: no edema, 1: slight, 2: mild, 3: moderate, 4: severe). §P<0.01, versus the furosemide group. (◼ : Only furosemide group, ♦: Add tolvaptan group)

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N-terminal pro-brain natriuretic peptide level and neurohormonal activity

During the study, intensive treatment improved the N-terminal pro-brain natriuretic peptide level in both groups without significant difference. Regarding neurohormonal factors, although no significant differences in noradrenaline, an indicator of sympathetic activity, and plasma renin activity (PRA) and plasma aldosterone concentration (PAC), indicators of RAAS activity, were found, PRA gained a dominant difference on day 3 [Figure 5]a and PAC on days 3 and 7 [Figure 5]b.

Figure 5: (a) Plasma renin activity (ng/mL/h). ^§P < 0.01, versus the furosemide group. (b) Plasma aldosterone concentration (ng/mL). ^§P < 0.01, versus the furosemide group

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Total amount of furosemide

During the study, since the furosemide dose was adjusted by the attending physician, in the comparison of the total furosemide dose administered during the study, the total amount was predominantly higher in the furosemide group [Figure 6].

Figure 6: The total furosemide dose (mg) administered during the study

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Discussion

As well-known, tolvaptan is superior to furosemide in its effect of discharging only free water from the body through its unique mechanism.^[4],[6] In the present study, we compared clinical effects between the usual treatment with intravenous furosemide and treatment with intravenous furosemide plus 7.5 mg of tolvaptan in patients with congestive heart failure who needed diuretics. The patients' background characteristics are shown in [Table 1].

Dehydration effect

Comparing changes in BW between the two groups, we found no significant difference; that is, the total amount of water removed did not significantly differ between the two groups. However, sBP was significantly higher in the furosemide plus tolvaptan group throughout the study period [Figure 2]. This is because tolvaptan induces discharge of only free water outside the body, the sodium concentration in the blood vessel increases semi-statically, and the blood osmotic pressure increases, whereby free water moves from the interstitium into the blood vessel, which means that blood pressure is maintained by holding fluid in the blood vessel. On the other hand, as furosemide discharges water together with sodium outside the body, the osmotic pressure in the blood vessel is not changed. If the diuretic effect is too strong, it causes intravascular dehydration, which is well-known to cause not only decreased blood pressure but also worsening renal function (WRF), which together disrupts kidney function. In fact, the frequency of WRF has been reported to decrease by treatment with tolvaptan added to the usual treatment.^{[23],[24],[25]}

Although the total dose of furosemide was small in the adding tolvaptan group, contrary to expectation, the difference was only 70 mg [Figure 6]. One of the reasons was that patients targeted in this study had relatively good response to furosemide and as a result the dose that had to be administered was small amount. Recruited patients who were more resistant to furosemide, there is a high possibility that the effect of reduction in furosemide by adding tolvaptan is remarkably recognized.

Symptoms and physical examination

No significant differences in the changes over time of symptoms of congestive heart failure assessed by using the VAS score were found between the two groups. JVP was significantly alleviated in the furosemide group. The grade of rales improved faster in the furosemide plus tolvaptan group, and leg edema finally significantly improved in the furosemide plus tolvaptan group. As we mentioned earlier, the change in BW between the two groups was equivalent, which indicates that the total amount of water removed from the body was the same between the two groups. This difference in physical examination findings can be explained by the difference in the location of water. In the furosemide group, water with sodium in the blood vessel was discharged outside, but in addition, the body fluid in the furosemide plus tolvaptan group was accompanied by recovery of the fluid from the interstitium into the blood vessel. Therefore, fluid present in the pleural effusion and interstitium of the lower extremity is more quickly alleviated, and rales and leg edema are improved.

Suppressing neurohormonal factors

In the present study, we showed the RAAS inhibitory effect by additionally administering tolvaptan to furosemide [Figure 5]a and [Figure 5]b. As well-known, treatment that suppresses neurohormonal factors such as beta-blockers and RAAS inhibitors have been shown to improve prognosis in patients with chronic heart failure. Vasopressin, which tolvaptan antagonizes, is one of the neurohormonal factors and is closely related to RAAS.^[26] Therefore, tolvaptan therapy was expected to improve the prognosis of patients with heart failure. However, currently, its effect is denied by some clinical trials.^{[7],[23],[24]} Moreover, the RAAS inhibitory effect of tolvaptan in the present study is presumed to be a result of the suppression of the activation of RAAS by excess intravascular dehydration due to relative overdose of furosemide rather than direct action by tolvaptan.

Limitations of our study that may have influenced the applicability of our results are as follows: first, although this trial is randomly assigned, there is a possibility of being biased because treatment is not blinded. Second, patients recruited in this study were relatively mild, and patients with markedly impaired cardiac function or renal function were not entered. Third, the effect of tolvaptan on long-term prognosis, including its method of use and selection of target patients, is a future subject.

Conclusion

We demonstrated that adding tolvaptan to the traditional furosemide treatment improved physical findings and inhibited RAAS via the prevention of intravascular dehydration, and reduced the total amount of furosemide.

Implication for health policy makers/practice/research/medical education

By adding 7.5 mg of tolvaptan to intravenous administration of furosemide, it is possible to obtain water removal effect from interstitium, which makes it possible to stabilize hemodynamics and reduce the frequency of WRF on patients with congestive heart failure.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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