Abstract
Aims
This multicentre, randomized, controlled, double‐blind, parallel‐group Phase III study was conducted to confirm the non‐inferiority of OPC‐61815 (tolvaptan sodium phosphate) intravenous injections to oral tolvaptan tablets in patients with congestive heart failure and volume overload despite receiving diuretics other than vasopressin antagonists.
Methods and results
Congestive heart failure patients with volume overload despite receiving diuretics other than vasopressin antagonists were randomly assigned (1:1) to receive OPC‐61815 (16‐mg injection; n = 149) or oral tolvaptan (15‐mg tablet; n = 145) once daily for 5 days. Most patients were male; the mean age and weight were 74.7 years and 62.1 kg, respectively; other demographic and clinical characteristics were similar between groups. In this study, the primary endpoint was the change in body weight from baseline to the day after the last dose. Secondary endpoints included improvement from baseline in congestive findings and New York Heart Association classification. The change in body weight was −1.67 kg [95% confidence interval (CI): −1.93, −1.41] and −1.36 kg (95% CI: −1.62, −1.10) in the OPC‐61815 group and tolvaptan group, respectively; the difference in the least squares mean between the groups was −0.31 kg (95% CI: −0.68, 0.06). Given the upper CI did not exceed the pre‐specified limit of 0.48, this confirmed the non‐inferiority of injectable OPC‐61815 to oral tolvaptan. Daily urine volume and daily fluid intake increased, and daily fluid balance was negative throughout the treatment period; changes were similar for both groups. All evaluated congestive symptoms and New York Heart Association classifications showed improvement and safety findings were similar between the groups. The incidence of hyperkalaemia was higher in the OPC‐61815 group, and the incidence of thirst and dry mouth was higher in the tolvaptan group. Most treatment‐emergent adverse events were mild to moderate; one serious treatment‐emergent adverse event of hyperkalaemia in the OPC‐61815 group was considered treatment related.
Conclusions
OPC‐61815 (16‐mg injection) was confirmed as non‐inferior to oral tolvaptan (15‐mg tablet) in patients with congestive heart failure and inadequate response to diuretics; no new safety concerns were observed.
Keywords: Arginine vasopressin V2 receptor antagonist, Congestive heart failure, Intravenous, Non‐inferiority study, OPC‐61815, Tolvaptan
Introduction
Intravenous (i.v.) loop diuretics are a cornerstone of acute heart failure (HF) treatment, 1 , 2 , 3 with Japanese registry studies reporting that approximately 70–80% of patients who were hospitalized for HF in Japan had fluid retention and 76–84% of hospitalized patients were treated with a diuretic. 4 , 5 Accurate assessment of early treatment interventions is critical for the management of disease; after starting therapy for acute HF, continued follow‐up assessments should be appropriately timed. 6 , 7 Furthermore, it is recommended that the diagnosis and treatment of congestive symptoms are managed at the same time. 8 A previous study demonstrated that early treatment with a loop diuretic was associated with better in‐hospital clinical outcomes and lower mortality. 9
Loop diuretics block sodium re‐absorption, which increases sodium excretion and urine output and induces natriuresis; however, in some patients, loop diuretics alone are not enough to improve congestion. Furthermore, treatment with loop diuretics promotes neurohormonal activation and worsening renal function. In contrast, aquaretic drugs antagonize the V2 receptor to directly promote free water excretion; treatment has little effect on neurohormonal activation and renal function. 10 , 11 , 12
Tolvaptan, an oral aquaretic, acts as an arginine vasopressin V2 receptor antagonist, 13 and in clinical trials and real‐world studies, tolvaptan treatment reduces body weight and improves congestive symptoms in patients. 14 , 15 In the EVEREST study, tolvaptan did not contribute to an improvement in the long‐term prognosis of patients who were hospitalized for HF, although it did improve several signs and symptoms of HF. 16 The observed improvement in congestive symptoms in patients with acute cardiac insufficiency is clinically significant. Tolvaptan was first approved in Japan in 2010 for the treatment of volume overload in patients with HF who did not achieve an adequate response on diuretics; approvals in other Asian countries for the same indication then followed. 14 , 17 The ESC and AHA guidelines, meanwhile, suggest that tolvaptan be considered in patients with HF and hyponatraemia and symptoms and signs of congestion. 8 , 18 Oral tolvaptan is increasingly used in combination with i.v. loop diuretics for the treatment of congestion in the acute phase of HF in Japan, 19 , 20 , 21 and Japanese guidelines recommend tolvaptan as second‐line therapy following an inadequate response to loop diuretics in acute HF. 2 However, it was considered necessary to develop i.v. diuretics because the treatment of congestion in acute HF requires a rapid onset of effect and the ability to administer treatment to patients with difficulty in oral intake. Furthermore, as tolvaptan has low water solubility, it is not suitable for development as an injectable drug. 22
OPC‐61815 (tolvaptan sodium phosphate), a prodrug of tolvaptan with improved water solubility, has been developed for i.v. use. 22 As with oral tolvaptan, i.v. OPC‐61815 is expected to be effective for the treatment of volume overload in HF and was evaluated over 5 days in a dose‐determining Phase II trial in patients with congestive HF. 22 The Phase II study determined that drug exposures for a single i.v. administration of 16‐mg OPC‐61815 and a single 15‐mg oral tablet of tolvaptan were similar. Patients had increased urine volume, decreased body weight, and improved lower limb oedema on Day 6 of the treatment period.
Because OPC‐61815 is a water diuretic that can be administered i.v., the primary expected use is for the treatment of congestion in acute HF, where there is a greater need for i.v. diuretics. However, it was first necessary to verify the efficacy of OPC‐61815 in patients who are able to take tolvaptan orally. We conducted a multicentre, randomized, controlled, double‐blind, parallel‐group Phase III trial in Japan to confirm the non‐inferiority of the OPC‐61815 injection formulation (16 mg once daily) to oral tolvaptan tablets (15 mg once daily) in patients with congestive HF who had volume overload despite treatment with diuretics (other than vasopressin antagonists) [OPC‐61815 tolvaptan sodium phosphate intravenous administration for heart failure (OPTION‐HF)]. The non‐inferiority study design was chosen so as to develop an indication that is similar to the active comparator, tolvaptan, which has shown superiority over placebo in cardiac oedema in Japan.
Methods
Patients
Male or female patients were potentially eligible for study inclusion if they were aged 20–85 years, had congestive HF, were taking oral diuretics [loop diuretics (equivalent to ≥40 mg oral furosemide if using loop diuretics alone), combination of loop diuretic and thiazide diuretic, or combination of loop diuretic and aldosterone antagonist or potassium‐sparing diuretic agent], and were inpatients. Additional inclusion criteria were presence of lower limb oedema, jugular distention, or pulmonary congestion due to volume overload; received diuretics with no dose or regimen change during the run‐in period; and had no more than a 1.0 kg change in body weight over the 2 days (of the run‐in period) immediately prior to receiving the study drug. Major exclusion criteria were acute HF that required emergency treatment, mainly non‐cardiogenic congestive symptoms, acute myocardial infarction within the 30 days prior to the screening visit, definitive diagnosis of active myocarditis or amyloid cardiomyopathy, difficulty with fluid intake, current symptoms or a history of hepatic impairment, systolic blood pressure <90 mmHg, serum creatinine >3 mg/dL, or serum sodium <125 or >147 mEq/L. A serum sodium level <125 mEq/L was a criterion for exclusion because in Japan it is recommended that tolvaptan is reduced to 7.5 mg/day in HF patients due to the possibility of inducing a serum electrolyte imbalance and causing hypernatraemia. All patients provided written informed consent prior to participation.
Study design and treatments
This was a multicentre, randomized, controlled, double‐blind, parallel‐group Phase III study to assess the non‐inferiority of OPC‐61815 (16‐mg injection once daily) vs. tolvaptan (15‐mg tablet once daily) in patients with congestive HF who had volume overload despite prior treatment with diuretics (other than vasopressin antagonists). The dosage and regimen of diuretics used before the start of the run‐in period were maintained throughout the treatment period. Patients were randomly assigned (1:1) to receive either OPC‐61815 16‐mg injection or tolvaptan 15‐mg tablet using an interactive web response system provided by an external vendor (BELLSYSTEM24, Inc., Tokyo, Japan).
Figure 1 A shows the detailed trial design. Patients were hospitalized from the day before the start of the run‐in period (Day −4) to the end of the treatment period (Day 6). The 3 days before the start of study drug administration comprised the run‐in period, during which the use of diuretics, change in body weight, and congestive symptoms were assessed. Only patients who met the inclusion criteria for the run‐in period entered the treatment period. During the treatment period, the study drug was administered once daily for 5 days; patients received either OPC‐61815 injection plus placebo tablet or placebo injection plus tolvaptan tablet. Patients were instructed to ingest the oral tablet with water, after which the injection was administered by the investigator (infusion time: 1 h ± 5 min). The placebo and investigational agents were indistinguishable from each other. Blinding was maintained using a double‐dummy method. There was a completion assessment on Day 6 and a follow‐up assessment between Days 12 and 15.
Figure 1.
(A) Study design and (B) patient disposition. R, randomization.
The study was conducted in accordance with the Declaration of Helsinki, the International Conference on Harmonization guidelines for Good Clinical Practice, 23 and applicable local laws and regulations. The protocol was approved by the institutional review board at each study site. The study was registered at www.clinicaltrials.gov (NCT03772041) and www.clinicaltrials.jp (JapicCTI‐173676).
Study endpoints
The primary endpoint was the change in body weight from baseline to the time of the final administration of study drug (considered to be the day after the final dosing), which was used as a measure to reflect the aquaretic effects of OPC‐61815 and tolvaptan on the general state of volume overload. Patients were permitted to drink water at any time and urinate upon waking and prior to weighing with a calibrated weighing scale before breakfast. Secondary endpoints included improvement rates from baseline to the time of the final administration of study drug in congestive symptoms (lower limb oedema and jugular venous pressure) and New York Heart Association (NYHA) classification. Pharmacodynamic parameters, including daily urine volume, daily fluid intake, daily fluid balance (daily urine volume − daily fluid intake), change in serum sodium and potassium, and biomarkers [plasma concentrations of plasma arginine vasopressin (AVP) and brain natriuretic peptide (BNP), and plasma renin activity] were assessed at baseline and Day 6. Adverse events (AEs), clinical laboratory tests, physical examinations, vital signs, and 12‐lead electrocardiograms were monitored for safety. AEs were coded using the Medical Dictionary for Regulatory Activities (Version 23.0) system organ class and preferred term classifications.
Statistical methods
Based on the upper limit of the 95% confidence intervals (CI) for the least squares (LS) mean of the difference in body weight for tolvaptan (15 mg) and placebo [−0.99 (95% CI: −1.57, −0.42) and −0.96 (95% CI: −1.37, −0.55), respectively] in a Phase III clinical trial (unpublished data; Otsuka Pharmaceutical), the expected (at 95% probability) minimum difference in body weight decrease (maximum difference in body weight) between the tolvaptan 15‐mg tablet group and the placebo group was considered to be in the range of 0.42–0.55. The non‐inferiority margin for the present trial was therefore set at 0.48, which corresponds to half of the treatment difference of 0.96 between the tolvaptan 15‐mg tablet group and the placebo group in the tolvaptan Phase III trial. The detection power was set at 90%, and the significance level at 5%. We set the mean [standard deviation (SD)] change in body weight from baseline at the time of final administration at −1.30 (1.25) for both the tolvaptan 15‐mg tablet group and the OPC‐61815 16‐mg injection group, based on the value obtained with the tolvaptan 15‐mg tablet for body weight up until the morning after Day 5 of treatment in the tolvaptan Phase III trial. Therefore, the number of patients required for this trial was determined to be 288 (144 patients per group).
The full analysis set included all patients who received at least one dose of study drug and had evaluable post‐treatment body weight data. The safety analysis set included all patients who received at least one dose of study drug. The pharmacodynamic analysis set included all patients who received at least one dose of study drug and had evaluable post‐treatment pharmacodynamic data.
An analysis of covariance model with treatment as a fixed effect and baseline body weight as a covariate was used to calculate the LS mean difference and its two‐sided 95% CI between the two study treatments for change in weight (non‐inferiority was confirmed when the upper limit of the CI did not exceed 0.48), jugular venous pressure, and hepatomegaly. Improvement rate and resolution rate at the time of final study drug administration were calculated for lower limb oedema and pulmonary congestion; improvement rate was calculated for NYHA class. Continuous and categorical data were summarized using descriptive statistics.
Sub‐group analysis of the primary endpoint was performed according to sex, age, NYHA classification, ischaemic heart disease, use of loop diuretic, dosage of loop diuretic, category of diuretic, and baseline daily urine volume, creatinine, AVP concentration, and albumin. All statistical analyses were conducted using SAS software Version 9.4M5 (SAS Institute, Inc., Cary, NC, USA).
Results
Patients
This trial was conducted at 72 sites in Japan between January 2019 and July 2020. Of the 362 patients screened, 294 received the study drug; of those, 149 were randomly assigned to the OPC‐61815 group and 145 to the tolvaptan group (Figure 1 B ). In the OPC‐61815 group, 135/149 (90.6%) patients completed the trial, and 14 (9.4%) discontinued, most commonly due to AEs [8/149 (5.4%)]. In the tolvaptan group, 135/145 (93.1%) patients completed the trial and 10 (6.9%) discontinued, most commonly due to AEs and physician decision [3/145 (2.1%) each]. AEs leading to discontinuation included aspartate aminotransferase/alanine aminotransferase increased to >3× the upper limit of normal or higher, serum or plasma sodium increased by ≥12 mEq/L within 24 h after the start of study drug administration, and serum or plasma sodium increased to ≥155 mEq/L.
Patient characteristics at baseline are shown in Table 1 . Patients were predominantly male (210/294, 71.4%), had a mean age of 74.7 years, and had a mean weight of 62.1 kg. Demographic and clinical characteristics were generally similar between the two treatment groups.
Table 1.
Baseline demographic and clinical characteristics (all randomly assigned patients)
| OPC‐61815 | Tolvaptan | Total | |
|---|---|---|---|
| n = 149 | n = 145 | N = 294 | |
| Male | 112 (75.2) | 98 (67.6) | 210 (71.4) |
| Age, years, mean (min–max) | 74.0 (40–85) | 75.4 (47–85) | 74.7 (40–85) |
| Age, >80 years | 58 (38.9) | 50 (34.5) | 108 (36.7) |
| Weight, kg, mean (SD) | 63.3 (14.6) | 61.0 (13.3) | 62.1 (14.0) |
| Primary disease | |||
| Ischaemia | 36 (24.2) | 51 (35.2) | 87 (29.6) |
| Cardiomyopathy | 23 (15.5) | 15 (10.3) | 38 (12.9) |
| Valvular disease | 40 (26.8) | 39 (26.9) | 79 (26.9) |
| Hypertensive heart disease | 51 (24.3) | 47 (32.4) | 98 (33.3) |
| Arrhythmia | 58 (38.9) | 51 (35.2) | 109 (37.1) |
| NYHA class | |||
| I | 13 (8.7) | 23 (15.9) | 36 (12.2) |
| II | 101 (67.8) | 95 (65.5) | 196 (66.7) |
| II | 34 (22.8) | 26 (17.9) | 60 (20.4) |
| IV | 1 (0.7) | 1 (0.7) | 2 (0.7) |
| Co‐morbidities | |||
| Hypertension | 109 (73.2) | 112 (77.2) | 221 (75.2) |
| Angina pectoris | 26 (17.4) | 29 (20.0) | 55 (18.7) |
| Diabetes mellitus | 61 (40.9) | 63 (43.4) | 124 (42.2) |
| Renal impairment | 79 (53.0) | 72 (49.7) | 151 (51.4) |
| Arrhythmia | 124 (83.2) | 119 (82.1) | 243 (82.7) |
| Renal function a , mean (SD) | |||
| Creatinine (mg/dL) | 1.30 (0.50) | 1.33 (0.53) | ‐ |
| Blood urea nitrogen (mg/dL) | 27.53 (13.10) | 27.82 (12.37) | ‐ |
| Brain natriuretic peptide b (pg/mL) | 290.42 (412.70) | 327.38 (369.47) | ‐ |
| Use of loop diuretic | |||
| Monotherapy | 48 (32.2) | 59 (40.7) | 107 (36.4) |
| Combined with other diuretic | 1001 (67.8) | 86 (59.3) | 187 (63.6) |
| Dose of loop diuretic | |||
| <40 mg/day | 68 (45.6) | 46 (31.7) | 114 (38.8) |
| 40–<80 mg/day | 67 (45.0) | 89 (61.4) | 156 (53.1) |
| ≥80 mg/day | 14 (9.4) | 10 (6.9) | 24 (8.2) |
| Lower limb oedema | |||
| None | 27 (18.1) | 34 (23.4) | 61 (20.7) |
| Mild | 97 (65.1) | 84 (57.9) | 181 (61.6) |
| Moderate | 19 (12.8) | 19 (13.1) | 38 (12.9) |
| Severe | 6 (4.0) | 8 (5.5) | 14 (4.8) |
| Pulmonary congestion | |||
| None | 26 (17.4) | 24 (16.6) | 50 (17.0) |
| Mild | 97 (65.1) | 98 (67.6) | 195 (66.3) |
| Moderate | 25 (16.8) | 23 (15.9) | 48 (16.3) |
| Severe | 1 (0.7) | 0 (0.0) | 1 (0.3) |
| Jugular venous distention | |||
| Yes | 52 (34.9) | 59 (40.7) | 111 (37.8) |
| No | 96 (64.4) | 86 (59.3) | 182 (61.9) |
| Not done | 1 (0.7) | 0 (0.0) | 1 (0.3) |
| Hepatomegaly | |||
| Yes | 12 (8.1) | 10 (6.9) | 22 (7.5) |
| No | 137 (91.9) | 135 (93.1) | 272 (92.5) |
NYHA, New York Heart Association; SD, standard deviation.
Data are n (%) unless stated otherwise.
Safety analysis set (n = 149, n = 145).
Pharmacodynamic analysis set (n = 148, n = 145).
Efficacy
The primary endpoint, the difference in the LS mean (95% CI) body weight between the OPC‐61815 and tolvaptan groups, was −0.31 kg (−0.68, 0.06) (Figure 2 A ). The upper limit of the 95% CI was below the pre‐defined non‐inferiority margin of 0.48, thus confirming the non‐inferiority of OPC‐61815 16‐mg injection to the tolvaptan 15‐mg tablet. Mean change in body weight over time is shown in Figure 2 B .
Figure 2.
Change in body weight as (A) LS mean (95% CI) change from baseline to the time of final study drug administration and (B) mean (standard deviation) change from baseline over time. CI, confidence interval; LS, least squares. aThe non‐inferiority of OPC‐61815 16‐mg injection to tolvaptan 15‐mg oral tablet was confirmed, as the upper limit of the CI did not exceed the pre‐set non‐inferiority margin of 0.48.
Daily urine volume (Figure 3 A ) and fluid intake (Figure 3 B ) increased from baseline throughout the treatment period in both groups, with the greatest increases observed on Day 2 (first day after study drug administration was initiated). Changes from baseline in daily urine volume and daily fluid intake were similar for both treatment groups throughout the treatment period. Changes from baseline for daily fluid balance showed negative values for both groups throughout the treatment period and were similar between groups (Figure 3 C ). All congestive symptoms evaluated showed improvement from baseline at the time of final study drug administration in both treatment groups. Lower limb oedema improvement rates were 68.9 and 75.7%, respectively, in the OPC‐61815 and tolvaptan groups and 56.1 and 64.7%, respectively, for pulmonary congestion.
Figure 3.
Change in (A) daily urine volume, (B) daily fluid intake, and (C) daily fluid balance over time.
The improvement rates in NYHA classification (patients who improved by ≥1 grade from baseline to the time of final study drug administration) were 44.9 and 42.5% in the OPC‐61815 and tolvaptan groups, respectively. The difference in improvement (95% CI) between the two groups was 2.4% (−10.2, 14.6). The LS mean change (95% CI) from baseline in jugular venous pressure in patients with baseline values was −2.89 cmH2O (−3.45, −2.33) for the OPC‐61815 group and −3.15 cmH2O (−3.68, −2.62) for the tolvaptan group; for hepatomegaly, the respective values were −0.93 cm (−1.44, −0.43) and −0.88 cm (−1.43, −0.33) (Table S1 ).
The pre‐specified sub‐group analysis revealed no differences in the LS mean changes from baseline in body weight at the time of final study drug administration between the treatment groups for sex, age, NYHA classification, ischaemic heart disease, concomitant diuretics, daily urine volume ≥1500 mL, and creatinine, plasma AVP concentration, and albumin at baseline (Table S2 ). Sub‐groups with a weight loss of >1 kg compared with the tolvaptan group included age <65 years, NYHA Classes III–IV, and albumin <3 g/dL. Serum sodium concentrations increased on Day 2 vs. baseline in both groups and remained generally constant throughout the treatment period, with a similar degree of change in both groups (Figure 4 A ). Serum potassium concentrations were relatively unchanged throughout the treatment period (Figure 4 B ). There were no clinically meaningful changes in haemodynamics or renal function from baseline through follow‐up (Figures S1 A to S1 D ). Changes in each biomarker (plasma AVP, BNP, and renin activity) on Day 6 compared with baseline were similar in both groups. For both the OPC‐61815 and tolvaptan groups, plasma AVP concentrations increased (Figure S1 E ) and plasma BNP concentrations decreased slightly (Figure S1 F ) from baseline. No notable changes from baseline were seen in plasma renin activity on Day 6 in either group (Figure S1 G ). Urine osmolality decreased from baseline throughout the treatment period for both groups; the degree of change was similar (Table S3 ). Levels of daily sodium excretion (urine) demonstrated minimal change throughout the treatment period, with a slight increase from Day 2 through Day 4 and a slight decrease on Day 6 in both groups (Table S3 ).
Figure 4.
Serum electrolyte changes over time for (A) sodium (B) potassium.
Safety
Safety data are shown in Table 2 . The overall incidences of AEs (OPC‐61815 vs. tolvaptan: 63.1% vs. 66.9%), treatment‐emergent AEs (TEAEs; 55.7% vs. 58.6%), and treatment‐related TEAEs (30.2% vs. 30.3%) were similar between the two treatment groups. Constipation, thirst, dry mouth, dehydration, and hyperkalaemia were reported as TEAEs in ≥5% of patients in either treatment group. The incidence of dehydration and hyperkalaemia was higher in the OPC‐61815 group (vs. tolvaptan), and the incidence of thirst and dry mouth was higher in the tolvaptan group (vs. OPC‐61815). Most TEAEs were mild to moderate in severity. The incidence of serious TEAEs was similar in both groups [OPC‐61815, 6/149 (4.0%); tolvaptan, 5/145 (3.4%)]; only one serious TEAE (hyperkalaemia, OPC‐61815 group) was considered related to the study treatment. Sodium‐related AEs included blood sodium increased in 2/149 patients (1.3%) in the OPC‐61815 group, hypernatraemia in 4/149 patients (2.7%) in the OPC‐61815 group, and 3/145 patients (2.1%) in the tolvaptan group and rapid correction of hyponatraemia in 1/149 patients (0.7%) in the OPC‐61815 group. The incidence of TEAEs leading to treatment discontinuation was higher in the OPC‐61815 vs. tolvaptan group [8/149 (5.4%) vs. 3/145 (2.1%), respectively] (Table S4 ). There were no deaths reported during the trial.
Table 2.
Adverse events (safety analysis set)
|
OPC‐61815 n = 149 |
Tolvaptan n = 145 |
|
|---|---|---|
| Patients with AEs | 94 (63.1) | 97 (66.9) |
| AEs, number of events | 201 | 177 |
| Patients with TEAEs | 83 (55.7) | 85 (58.6) |
| TEAEs, number of events | 163 | 139 |
| Patients with treatment‐related TEAEs | 45 (30.2) | 44 (30.3) |
| Serious TEAEs | 6 (4.0) | 5 (3.4) |
| Patients with treatment‐related serious TEAEs | 1 (0.7) | 0 (0.0) |
| Deaths | 0 (0.0) | 0 (0.0) |
| Discontinuations due to an AE | 8 (5.4) | 3 (2.1) |
| Discontinuations due to a treatment‐related AE | 5 (3.4) | 3 (2.1) |
| TEAEs occurring in ≥5% of patients | ||
| Constipation | 9 (6.0) | 9 (6.2) |
| Dehydration | 15 (10.1) | 6 (4.1) |
| Dry mouth | 4 (2.7) | 8 (5.5) |
| Hyperkalaemia | 9 (6.0) | 3 (2.1) |
| Thirst | 13 (8.7) | 16 (11.0) |
| Serious TEAEs | ||
| Atrial fibrillation | 1 (0.7) | 0 (0.0) |
| Cardiac failure | 1 (0.7) | 0 (0.0) |
| Cardiac failure acute | 1 (0.7) | 0 (0.0) |
| Coronary artery stenosis | 0 (0.0) | 1 (0.7) |
| Gastric antral vascular ectasia | 1 (0.7) | 0 (0.0) |
| General infarction | 0 (0.0) | 1 (0.7) |
| Hyperkalaemia a | 1 (0.7) | 0 (0.0) |
| Sepsis | 1 (0.7) | 0 (0.0) |
| Sinus node dysfunction | 0 (0.0) | 1 (0.7) |
| Urinary tract infection | 0 (0.0) | 1 (0.7) |
| Ventricular tachycardia | 0 (0.0) | 1 (0.7) |
| Na‐related adverse events | ||
| Blood sodium increase | 2 (1.3) | 0 (0.0) |
| Hypernatraemia | 4 (2.7) | 3 (2.1) |
| Rapid correction of hyponatraemia | 1 (0.7) | 0 (0.0) |
AE, adverse event; TEAE, treatment‐emergent adverse event.
Data are n (%) unless stated otherwise.
Serious hyperkalaemia was judged by an investigator and solely based on serum potassium levels.
Discussion
This study demonstrated that when using body weight change over 5 days as a primary outcome measure, daily treatment with OPC‐61815 16‐mg injection was non‐inferior to tolvaptan 15‐mg oral tablet in patients with congestive HF and an inadequate response to diuretics other than vasopressin antagonists. The mean change (SD) in body weight from baseline to the time of final tolvaptan administration (5 days) was −1.32 (1.36) kg, which is comparable with that reported in the Phase III QUEST trial of tolvaptan that confirmed its superiority over placebo [15‐mg tablet, 7 days, −1.54 (1.61) kg]. 14 The QUEST trial is the only study that has verified diuretic superiority over placebo in a randomized controlled trial, which suggests that 15‐mg tolvaptan is an appropriate active control for OPC‐61815. Notably, patients in the present study had no restrictions regarding drinking; therefore, the effect of weight loss was confirmed in patients who were drinking normally.
In this study, a maximum increase in urine output was observed on Day 2 (first day after study drug administration was initiated), and urine output was increased throughout the treatment period for both study drugs. Fluid balance was negative throughout the treatment period although water intake increased; similar results were obtained regardless of treatment. Urine sodium concentration did not change in any meaningful way. Urine osmolality was reduced from baseline throughout the study for both treatment groups, thus confirming the aquaretic effect of both OPC‐61815 and tolvaptan. The incidence of AEs and TEAEs was similar between the groups, and most TEAEs were mild or moderate; no safety concerns were observed.
In general, decreased renal function and hypoalbuminaemia can affect a patient's response to diuretics. 24 In this study, sub‐group analysis found that weight loss was not affected by creatinine levels in patients treated with OPC‐61815, with similar outcomes between patients with <2 and ≥2 mg/mL creatinine. This was in line with the trend reported in the phase III QUEST study of tolvaptan vs. placebo in HF patients with volume overload despite treatment with diuretics. 14 However, both studies are somewhat in contrast to a study by Kida et al., which reported a trend towards greater urine output and weight loss in HF patients with Stage 3b chronic kidney disease compared with Stage 4 or 5 chronic kidney disease. 25 This discrepancy is expected to be resolved following the collection of real‐world data in future analyses.
Although more pronounced in the OPC‐61815 group, patients in both treatment groups with an albumin value of <3 g/dL tended to have greater weight loss. This outcome is consistent with that reported in two small studies of tolvaptan in patients with congestive HF with and without hypoalbuminaemia. 26 , 27
The incidence of serious TEAEs was similar in both groups (OPC‐61815, 4.0%; tolvaptan, 3.4%). Only one serious TEAE (hyperkalaemia; OPC‐61815 group) was considered treatment related by study investigators. Of note, TEAEs with higher incidences in the OPC‐61815 treatment group (vs. tolvaptan) included dehydration, sodium‐related TEAEs (hypernatraemia and rapid correction of hyponatraemia), and hyperkalaemia. The higher incidence of sodium‐related TEAEs, dehydration, and hyperkalaemia may be attributed to the direct injection of OPC‐61815 into the bloodstream, which results in a shorter time to onset of effect. In addition, 4/9 patients with hyperkalaemia also had concomitant renal dysfunction. Notably, thirst (8.4%) and hypernatraemia (4.4%) were the most commonly reported adverse drug reactions in the real‐world SMILE study. 15 The present study reported comparable incidences, with 8.7% and 11.0% of patients who received OPC‐61815 and tolvaptan, respectively, reporting thirst and a respective 2.7% and 2.1% experiencing hypernatraemia.
The results from a combined analysis of data from the double‐blind Phase II comparative study of OPC‐61815 22 and the current Phase III non‐inferiority confirmatory trial, both of which used tolvaptan as a control, showed no significant difference in the incidence of hypernatraemia‐related AEs between the treatment groups (OPC‐61815 16 mg vs. tolvaptan 15 mg). Given that OPC‐61815 is a new i.v. diuretic and is not exactly the same as oral tolvaptan, it is necessary to adequately monitor serum electrolytes as well as monitor for the common side effect of dry mouth.
As OPC‐61815 is being developed for the same target indication as tolvaptan, which is to treat ‘fluid retention in heart failure with inadequate response to other diuretics such as loop diuretics’, the inclusion/exclusion criteria, criteria for moving to the treatment period, prohibited concomitant medications, and restriction of medication use for the present study were set to be similar to those used in the pivotal Phase III study of tolvaptan in Japan (HF patients with volume overload despite treatment with diuretics) to ensure a similar background for data analysis. 14 Congestion‐related symptoms are often the first presentations of acute cardiac insufficiency, and early improvement in congestion is time sensitive and prognostically important. 6 , 8 However, oral medications take longer to take effect relative to i.v. medications owing to the nature of their formulation. Additionally, oral medications can be difficult to administer when patients are under non‐invasive positive pressure ventilation to relive dyspnoea or have a reduced level of consciousness due to impaired oxygenation. As such, there is a clinical need for i.v. drugs to provide immediate decongestion. To further confirm the tolerability of OPC‐61815, a separate Phase III trial has been conducted in patients with cardiac oedema (including acute HF) who are currently being administered i.v. diuretics and in whom oral medications are difficult to administer. 28 This study verified the non‐inferiority of OPC‐61815 to oral tolvaptan. Because oral tolvaptan has been shown to improve congestion in Western studies such as the EVEREST study, 29 the non‐inferiority of OPC‐61815 indicates that it may be effective not only in Japan but also in the rest of the world. However, we still believe further data is required on i.v. diuretic use in patients with acute heart failure in the future.
Limitations
A key limitation was the lack of a placebo comparator group; however, because tolvaptan is considered the standard of care in this patient population, it was deemed inappropriate to compare OPC‐61815 with placebo, and, thus, a non‐inferiority trial was conducted. In general practice, OPC‐61815 is expected to be used primarily for acute HF requiring i.v. diuretic treatment. However, in our study, patients with acute HF who required emergency treatment were excluded, and concomitant use of i.v. diuretics was prohibited. Therefore, the current results cannot be extrapolated to the use of OPC‐61815 in patients with acute HF. Furthermore, patients with low serum sodium levels (<125 mEq/L) were excluded, which limits the generalizability of these results to real‐world settings where HF patients are often complicated by hyponatraemia. In addition, a detailed (hourly) timing of urine volume increase was not conducted in this study, and this information remains to be clarified. Finally, this was a non‐inferiority study and was designed with the primary endpoint of weight change after treatment with i.v. OPC‐61815 or oral tolvaptan; it was not designed to detect significant differences in the occurrence of AEs between the two drugs. As such, careful monitoring during use in clinical practice is recommended.
Conclusions
The non‐inferiority of OPC‐61815 16‐mg injection to tolvaptan 15‐mg oral tablet was confirmed using change in body weight as the primary outcome measure, and no new safety concerns were observed. The i.v. route of administration of OPC‐61815 makes this a viable alternative for decompensated HF patients with overload despite receiving diuretics. Overall, better strategies to improve congestion are required, and we believe that the novel diuretic OPC‐61815 is a clinically meaningful addition to the treatment options available for symptoms of congestion.
Conflict of interest
N.S. reports consultation fees from Otsuka Pharmaceutical Co., Ltd., Terumo Corporation, Novartis, Bristol Myers Squibb, and Bayer and lecture fees from Otsuka Pharmaceutical Co., Ltd., Ono Pharmaceutical, Terumo Corporation, Novartis, Bristol Myers Squibb, and Bayer. S.U., Y.K., and S.K. are employed by Otsuka Pharmaceutical Co., Ltd.
Funding
This work was supported by Otsuka Pharmaceutical Co. Ltd.
Supporting information
Table S1. Improvements in congestive findings.
Table S2. Subgroup analysis for change from baseline in body weight at the time of final study drug administration.
Table S3. Urine osmolality and urinary sodium excretion.
Table S4. Adverse events leading to withdrawal.
Table S5. Participating sites and investigators.
Figure S1. Change in (A) blood pressure, (B) pulse rate, (C) creatinine, (D) blood urea nitrogen, (E) plasma AVP, (F) plasma BNP, (G) plasma renin activity. For panel A, filled symbols indicate systolic blood pressure and open symbols indicate diastolic blood pressure. AVP, arginine vasopressin; BNP, brain natriuretic peptide.
Acknowledgements
The authors wish to express their gratitude to the institutions and personnel that participated in this study (Table S5 ). The authors would also like to thank Sarah Bubeck, PhD, of Edanz (www.edanz.com) for providing medical writing support, which was funded by Otsuka Pharmaceutical Co. Ltd., in accordance with Good Publication Practice (GPP3) guidelines (http://www.ismpp.org/gpp3).
Sato, N. , Uno, S. , Kurita, Y. , Kim, S. , and the OPTION‐HF Investigators (2022) Efficacy and safety of intravenous OPC‐61815 compared with oral tolvaptan in patients with congestive heart failure. ESC Heart Failure, 9: 3275–3286. 10.1002/ehf2.14021.
References
- 1. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, Falk V, Gonzalez‐Juanatey JR, Harjola VP, Jankowska EA, Jessup M, Linde C, Nihoyannopoulos P, Parissis JT, Pieske B, Riley JP, Rosano GM, Ruilope LM, Ruschitzka F, Rutten FH, van der Meer P, Authors/Task Force Members, Document Reviewers . 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: The task force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the heart failure association (HFA) of the ESC. Eur J Heart Fail. 2016; 18: 891–975. [DOI] [PubMed] [Google Scholar]
- 2. Tsutsui H, Isobe M, Ito H, Ito H, Okumura K, Ono M, Kitakaze M, Kinugawa K, Kihara Y, Goto Y, Komuro I, Saiki Y, Saito Y, Sakata Y, Sato N, Sawa Y, Shiose A, Shimizu W, Shimokawa H, Seino Y, Node K, Higo T, Hirayama A, Makaya M, Masuyama T, Murohara T, Momomura SI, Yano M, Yamazaki K, Yamamoto K, Yoshikawa T, Yoshimura M, Akiyama M, Anzai T, Ishihara S, Inomata T, Imamura T, Iwasaki YK, Ohtani T, Onishi K, Kasai T, Kato M, Kawai M, Kinugasa Y, Kinugawa S, Kuratani T, Kobayashi S, Sakata Y, Tanaka A, Toda K, Noda T, Nochioka K, Hatano M, Hidaka T, Fujino T, Makita S, Yamaguchi O, Ikeda U, Kimura T, Kohsaka S, Kosuge M, Yamagishi M, Yamashina A, Japanese Circulation Society and the Japanese Heart Failure Society Joint Working Group . JCS 2017/JHFS 2017 guideline on diagnosis and treatment of acute and chronic heart failure – Digest version. Circ J. 2019; 83: 2084–2184. [DOI] [PubMed] [Google Scholar]
- 3. Palazzuoli A, Ruocco G, Pellegrini M, Beltrami M, Del Castillo G, Nuti R. Loop diuretics strategies in acute heart failure: From clinical trials to practical application. Curr Drug Targets. 2015; 16: 1246–1253. [DOI] [PubMed] [Google Scholar]
- 4. Sato N, Kajimoto K, Keida T, Mizuno M, Minami Y, Yumino D, Asai K, Murai K, Muanakata R, Aokage T, Sakata Y, Mizuno K, Takano T, TEND Investigators . Clinical features and outcome in hospitalized heart failure in Japan (from the ATTEND registry). Circ J. 2013; 77: 944–951. [DOI] [PubMed] [Google Scholar]
- 5. Yaku H, Ozasa N, Morimoto T, Inuzuka Y, Tamaki Y, Yamamoto E, Yoshikawa Y, Kitai T, Taniguchi R, Iguchi M, Kato M, Takahashi M, Jinnai T, Ikeda T, Nagao K, Kawai T, Komasa A, Nishikawa R, Kawase Y, Morinaga T, Su K, Kawato M, Sasaki K, Toyofuku M, Furukawa Y, Nakagawa Y, Ando K, Kadota K, Shizuta S, Ono K, Sato Y, Kuwahara K, Kato T, Kimura T, on behalf of the KCHF Study Investigators . Demographics, management, and in‐hospital outcome of hospitalized acute heart failure syndrome patients in contemporary real clinical practice in Japan ― observations from the prospective, multicenter Kyoto congestive heart failure (KCHF) registry. Circ J. 2018; 82: 2811–2819. [DOI] [PubMed] [Google Scholar]
- 6. Shiraishi Y, Kawana M, Nakata J, Sato N, Fukuda K, Kohsaka S. Time‐sensitive approach in the management of acute heart failure. ESC Heart Fail. 2021; 8: 204–221. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. Mullens W, Damman K, Harjola VP, Mebazaa A, Brunner‐La Rocca HP, Martens P, Testani JM, Tang WHW, Orso F, Rossignol P, Metra M, Filippatos G, Seferovic PM, Ruschitzka F, Coats AJ. The use of diuretics in heart failure with congestion – A position statement from the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail. 2019; 21: 137–155. [DOI] [PubMed] [Google Scholar]
- 8. McDonagh TA, Metra M, Adam M, Gardner RS, Baumbach A, Böhm M, Burri H, Butler J, Čelutkienė J, Chioncel O, Cleland JGF, Coats AJS, Crespo‐Leiro MG, Farmakis D, Gilard M, Heymans S, Hoes AW, Jaarsma T, Jankowska EA, Lainscak M, Lam CSP, Lyon AR, McMurray JJV, Mebazaa A, Mindham R, Muneretto C, Piepoli MF, Price S, Rosano GMC, Ruschitzka F, Skibelund AK, ESC ScientificDocument Group . 2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: Developed by the task force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2021; 42: 3599–3726. [DOI] [PubMed] [Google Scholar]
- 9. Matsue Y, Damman K, Voors AA, Kagiyama N, Yamaguchi T, Kuroda S, Okumura T, Kida K, Mizuno A, Oishi S, Inuzuka Y, Akiyama E, Matsukawa R, Kato K, Suzuki S, Naruke T, Yoshioka K, Miyoshi T, Baba Y, Yamamoto M, Murai K, Mizutani K, Yoshida K, Kitai T. Time‐to‐furosemide treatment and mortality in patients hospitalized with acute heart failure. J Am Coll Cardiol. 2017; 69: 3042–3051. [DOI] [PubMed] [Google Scholar]
- 10. Boorsma EM, Ter Maaten JM, Damman K, Dinh W, Gustafsson F, Goldsmith S, Burkhoff D, Zannad F, Udelson JE, Voors AA. Congestion in heart failure: A contemporary look at physiology, diagnosis and treatment. Nat Rev Cardiol. 2020; 17: 641–655. [DOI] [PubMed] [Google Scholar]
- 11. Jujo K, Saito K, Ishida I, Furuki Y, Kim A, Suzuki Y, Sekiguchi H, Yamaguchi J, Ogawa H, Hagiwara N. Randomized pilot trial comparing tolvaptan with furosemide on renal and neurohumoral effects in acute heart failure. ESC Heart Fail. 2016; 3: 177–188. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. Tamaki S, Yamada T, Morita T, Furukawa Y, Kawasaki M, Kikuchi A, Kawai T, Seo M, Abe M, Nakamura J, Yamamoto K, Kayama K, Kawahira M, Tanabe K, Ueda K, Kimura T, Sakamoto D, Tamura Y, Fujita T, Fukunami M. Impact of adjunctive tolvaptan on sympathetic activity in acute heart failure with preserved ejection fraction. ESC Heart Fail. 2020; 7: 933–937. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. Yamamura Y, Nakamura S, Itoh S, Hirano T, Onogawa T, Yamashita T, Yamada Y, Tsujimae K, Aoyama M, Kotosai K, Ogawa H, Yamashita H, Kondo K, Tominaga M, Tsujimoto G, Mori T. OPC‐41061, a highly potent human vasopressin V2‐receptor antagonist: Pharmacological profile and aquaretic effect by single and multiple oral dosing in rats. J Pharmacol Exp Ther. 1998; 287: 860–867. [PubMed] [Google Scholar]
- 14. Matsuzaki M, Hori M, Izumi T, Fukunami M, Tolvaptan Investigators . Efficacy and safety of tolvaptan in heart failure patients with volume overload despite the standard treatment with conventional diuretics: A phase III, randomized, double‐blind, placebo‐controlled study (QUEST study). Cardiovasc Drugs Ther. 2011; 25: S33–S45. [DOI] [PubMed] [Google Scholar]
- 15. Kinugawa K, Sato N, Inomata T, Yasuda M, Shimakawa T, Fukuta Y. Real‐world effectiveness and tolerability of tolvaptan in patients with heart failure – Final results of the Samsca post‐marketing surveillance in heart failure (SMILE) study. Circ J. 2019; 83: 1520–1527. [DOI] [PubMed] [Google Scholar]
- 16. Konstam MA, Gheorghiade M, Burnett JC Jr, Grinfeld L, Maggioni AP, Swedberg K, Udelson JE, Zannad F, Cook T, Ouyang J, Zimmer C, Orlandi C, on behalf of Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) Investigators . Effects of oral tolvaptan in patients hospitalized for worsening heart failure: The EVEREST outcome trial. JAMA. 2007; 297: 1319–1331. [DOI] [PubMed] [Google Scholar]
- 17. Tolvaptan (SAMSCA) tablets, orally disintegrating tablets, and granules [Japanese package insert]. Otsuka Pharmaceutical Co., Ltd., Tokyo, Japan; Second edition, April 2021. https://www.info.pmda.go.jp/go/pack/2139011D1022_1_09/ (26 May 2021).
- 18. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Drazner MH, Fonarow GC, Geraci SA, Horwich T, Januzzi JL, Johnson MR, Kasper EK, Levy WC, Masoudi FA, McBride PE, McMurray JJV, Mitchell JE, Peterson PN, Riegel B, Sam F, Stevenson LW, Wilson Tang WH, Tsai EJ, Wilkoff BL, on behalf of the American College of Cardiology Foundation and American Heart Association Task Force on Practice Guidelines . 2013 ACCF/AHA guideline for the management of heart failure: A report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines. J Am Coll Cardiol; 2013: e147–e239. [DOI] [PubMed] [Google Scholar]
- 19. Tanaka TD, Sawano M, Ramani R, Friedman M, Kohsaka S. Acute heart failure management in the USA and Japan: Overview of practice patterns and review of evidence. ESC Heart Fail. 2018; 5: 931–947. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. Kuragaichi T, Sato Y. Temporal trends of a vasopressin V2 receptor antagonist in heart failure using a nationwide database in Japan. ESC Heart Fail. 2021; 8: 527–538. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21. Ellison DH, Felker GM. Diuretic treatment in heart failure. N Engl J Med. 2017; 377: 1964–1975. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22. Sato N, Uno S, Yamasaki Y, Hirano T, Seongryul K, on behalf of the OPC‐61815 investigators . Pharmacokinetics, pharmacodynamics and efficacy of OPC‐61815, prodrug of tolvaptan for intravenous administration, in patients with congestive heart failure ― A phase II, multicenter, double‐blind, randomized, active‐controlled trial. Circ J. 2021. [DOI] [PubMed] [Google Scholar]
- 23. ICH harmonised guideline integrated addendum to ICH E6(R1): Guideline for good clinical practice ICH E6(R2) ICH consensus guideline. Good Clinical Practice Network; updated December 2016. https://ichgcp.net/ (26 May 2021).
- 24. Gupta R, Testani J, Collins S. Diuretic resistance in heart failure. Curr Heart Fail Rep. 2019; 16: 57–66. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25. Kida K, Shibagaki Y, Tominaga N, Matsumoto N, Akashi YJ, Miyake F, Kimura K. Efficacy of tolvaptan added to furosemide in heart failure patients with advanced kidney dysfunction: A pharmacokinetic and pharmacodynamic study. Clin Pharmacokinet. 2015; 54: 273–284. [DOI] [PubMed] [Google Scholar]
- 26. Masuda T, Ohara K, Nagayama I, Matsuoka R, Murakami T, Nakagawa S, Oka K, Asakura M, Igarashi Y, Fukaya Y, Miyazawa Y, Maeshima A, Akimoto T, Saito O, Nagata D. Impact of serum albumin levels on the body fluid response to tolvaptan in chronic kidney disease patients. Int Urol Nephrol. 2019; 51: 1623–1629. [DOI] [PubMed] [Google Scholar]
- 27. Okabe T, Yakushiji T, Igawa W, Ono M, Kido T, Ebara S, Yamashita K, Yamamoto MH, Saito S, Hoshimoto K, Amemiya K, Isomura N, Araki H, Ochiai M. The efficacy of tolvaptan in congestive heart failure patients with and without hypoalbuminemia: A pilot study. Cardiovasc Ther. 2015; 33: 275–281. [DOI] [PubMed] [Google Scholar]
- 28. Kinugawa K, Nakata E, Hirano T, Kim S. Tolerability of the intravenously administered tolvaptan prodrug, OPC‐61815, in patients with congestive heart failure who have difficulty with, or are incapable of, oral intake (TRITON‐HF). Circ J. 2022. Published online ahead of print 10th March 2022. [DOI] [PubMed] [Google Scholar]
- 29. Konstam MA, Gheorghiade M, Burnett JC, Grinfeld L, Maggioni AP, Swedberg K, Udelson JE, Zannad F, Cook T, Ouyang J, Zimmer C, Orlandi C, et al. Effects of oral tolvaptan in patients hospitalized for worsening heart failure: The EVEREST outcome trial. JAMA. 2007; 297: 1319–1331. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Table S1. Improvements in congestive findings.
Table S2. Subgroup analysis for change from baseline in body weight at the time of final study drug administration.
Table S3. Urine osmolality and urinary sodium excretion.
Table S4. Adverse events leading to withdrawal.
Table S5. Participating sites and investigators.
Figure S1. Change in (A) blood pressure, (B) pulse rate, (C) creatinine, (D) blood urea nitrogen, (E) plasma AVP, (F) plasma BNP, (G) plasma renin activity. For panel A, filled symbols indicate systolic blood pressure and open symbols indicate diastolic blood pressure. AVP, arginine vasopressin; BNP, brain natriuretic peptide.