As life expectancy increases, the proportion of elderly

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1 Clinical Studies Effectiveness and Adverse Events of Tolvaptan in Octogenarians With Heart Failure Interim Analyses of Samsca Post-Marketing Surveillance In Heart failure (SMILE Study) Koichiro Kinugawa, 1 MD, Takayuki Inomata, 2 MD, Naoki Sato, 3 MD, Moriyoshi Yasuda, 4 PhD, Toshiyuki Shimakawa, 4 BSc, Kosuke Bando, 4 BSc, and Kazuki Mizuguchi, 4 BSc Summary The vasopressin receptor 2 (V2) receptor antagonist tolvaptan is an aquaretic agent that has been found to improve symptoms in patients with congestive heart failure. In this study (SMILE study), we administered tolvaptan to patients aged 80 years with heart failure accompanied by congestive symptoms and compared its effectiveness and safety profiles in this group with those in patients < 80 years (U-80). The results showed that the effectiveness of tolvaptan in the aged patients was similar to that in U-80 patients. In the safety profile, the incidence rate of thirst was lower in the aged patients than that in U-80 patients (9.6% versus 11.6%, P = ). Furthermore, the incidence of hypernatremia, defined as 150 meq/l in aged patients, was comparable with that in U-80 patients (2.9% versus 3.6%, respectively, P = ). Based on these findings, tolvaptan has similar effectiveness and safety profiles in aged patients compared with U-80 patients. In addition, we found that a higher starting dose of tolvaptan was markedly associated with the occurrence of hypernatremia exclusively in the aged population; therefore, we recommend that tolvaptan should be started at lower doses in aged patients. (Int Heart J 2015; 56: ) Key words: Aquauretic, Decongestion, Diuretic, Hypernatremia As life expectancy increases, the proportion of elderly people with congestive heart failure has been increasing. According to an epidemiologic study, the average age of patients first diagnosed with heart failure between 1950 and 1969 was 62.7 years, whereas between 1990 and 1999, an average age of 80.0 years was reported. 1) Elderly patients with heart failure have a poorer prognosis than younger patients because of increased comorbidities and deterioration in organ functions. 2,3) The age threshold for inclusion of study individuals has varied among studies. For example, studies using age thresholds of 75 years 4,5) and 80 years 6) have been reported. Because of the shift in population dynamics toward older ages in recent years, we considered it better to set the threshold at 80 years in this study. Editorial p.135 The vasopressin receptor 2 (V2) receptor antagonist tolvaptan is indicated for the treatment of patients with clinically significant hypervolemic and euvolemic hyponatremia, including patients with heart failure and the syndrome of inappropriate antidiuretic hormone in the United States. However, in Japan, the indication is volume overload in heart failure patients when adequate response is not obtained with other diuretics. 7) The efficacy of tolvaptan in promoting aquaresis and its safety profile have been demonstrated in clinical studies. 8-14) In addition, the results of a post marketing survey have confirmed its aquaretic effect and its benefit on congestive symptoms. 15) However, the efficacy and safety of tolvaptan in the elderly have not been reported in detail. Therefore, in this article, we describe the effectiveness of tolvaptan and adverse events in the elderly, using an age threshold of 80 years. Methods Study type: In the present report, we used the interim results (as of May18, 2014) of an ongoing, prospective, multicenter, noninterventional surveillance study, initiated in 2011 and involving 3,000 patients. The study has been conducted in compliance with Good Post-Marketing Study Practice, an ordinance issued by the Ministry of Health, Labor and Welfare, for the implementation of post-marketing surveillance of new drugs approved in Japan. Patients: We included patients for whom tolvaptan was indi- From the 1 Department of Therapeutic Strategy for Heart Failure, Graduate School of Medicine, The University of Tokyo, 2 Department of Cardiovascular Medicine, Kitasato University School of Medicine, Tokyo, 3 Department of Internal Medicine and Cardiology, Nippon Medical School Musashi-Kosugi Hospital, Kawasaki, and 4 Otsuka Pharmaceutical Co., Ltd, Tokyo, Japan. Address for correspondence: Koichiro Kinugawa, MD, Department of Therapeutic Strategy for Heart Failure, Graduate School of Medicine, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo , Japan. kinugawa-tky@umin.ac.jp Received for publication October 14, Revised and accepted October 27, Released in advance online on J-STAGE February 23, All rights reserved by the International Heart Journal Association. 137

2 138 KINUGAWA, ET AL Int Heart J March 2015 cated, such as those with heart failure and those who also were refractory to loop diuretics. Patients were excluded if they had anuria, disturbances of consciousness, difficulties with water intake, hypernatremia, or if they were pregnant. The standard observation period was 2 weeks; however, treatment could be continued beyond 2 weeks according to the attending physician s clinical judgment. Variables analyzed: We analyzed demographic data before tolvaptan treatment, body weight, cumulative 24-hour urine volume, congestive symptoms (lower-limb edema, dyspnea, pulmonary congestion, jugular venous distention, and hepatomegaly), and adverse drug events. Statistical analysis: Variations in body weight and urine output per body weight were calculated as mean changes from the baseline before study drug administration. Patients with baseline values and at least 1 postbaseline value were included in the analyses. The proportion of patients with congestive symptoms was assessed daily, and the mean values were calculated day-by-day. All events identified as adverse events were aggregated, regardless of their causal relationship with tolvaptan therapy. The terminology of adverse events was summarized according to the Medical Dictionary for Regulatory Activities (MedDRA) version All data are presented as means ± standard deviations (SDs) or in proportions (%). Because of the properties of each data set, Fisher s exact probability method, the χ 2 test, and Student s t test were used to compare patient backgrounds. All statistical analyses were performed using SAS version 9.3. Results A total of 2584 patients were enrolled, and case report forms were collected from 1905 patients. Fourteen patients who did not meet the enrollment criteria were excluded, and safety profile analyses were conducted for the remaining 1891 patients. Furthermore, we excluded data from 8 patients for whom the use of tolvaptan was off-label so effectiveness analyses were conducted using data from the remaining 1883 patients. In this study, the aged group was defined as being 80 years. Table I shows a comparison of patient characteristics for the aged group and U-80 groups. The aged group had a lower proportion of male patients (45% versus 67%) and had a lower body weight (53 kg versus 62 kg). Moreover, the aged group had a lower 24-hour urine volume before tolvaptan administration compared with the U-80 group (1241 ml versus 1476 ml, P < ). Other Table I. Baseline Characteristics of the Study Population All patients U-80 Aged P n Age 77 ± ± ± 5 < *** Gender, male (%) < *** Weight, (kg) 58 ± ± ± 12 < *** Urine volume 24 hours (ml) 1366 ± ± ± 718 < *** LVEF, (%) 47 ± ± ± 16 < *** NYHA class I/II, (%) NYHA class III/IV, (%) Medications Loop furosemide eq. (mg) 66 ± ± ± 51 < *** Angiotensin-converting enzyme inhibitor, (%) Angiotensin II receptor blocker, (%) *** Beta-blocker, (%) < *** Thiazide diuretics, (%) < *** Aldosterone antagonist, (%) ** Carperitide, (%) Laboratory value Protein total, (g/dl) 6.3 ± ± ± ** Serum albumin, (g/dl) 3.2 ± ± ± *** BUN, (mg/dl) 34.6 ± ± ± * Creatinine, (mg/dl) 1.6 ± ± ± egfr, (ml/minute/1.73 m 2 ) 42.7 ± ± ± 24.5 < *** Serum Na, (meq/l) ± ± ± Serum K, (meq/l) 4.1 ± ± ± AST, (IU/L) 40.0 ± ± ± ALT, (IU/L) 31.8 ± ± ± Bilirubin total, (mg/dl) 1.1 ± ± ± *** SBP, (mmhg) ± ± ± ** DBP, (mmhg) 65.3 ± ± ± Congestive symptoms Lower limb edema, (%) * Pulmonary congestion, (%) * Dyspnea, (%) Jugular venous distention, (%) Hepatomegaly, (%) ** * P < 0.05, ** P < 0.01, *** P <

3 Vol 56 No 2 TOLVAPTAN IN OCTOGENARIANS WITH HEART FAILURE 139 characteristics of the aged group were higher EF (51% versus 43%), lower total protein (6.2 g/dl versus 6.4 g/dl), lower albumin (3.1 g/dl versus 3.3 g/dl), higher blood urea nitrogen (35.9 mg/dl versus 33.3 mg/dl), lower egfr (39.1 ml/ minute/1.73 m 2 versus 46.1 ml/minute/1.73 m 2 ), lower bilirubin (1.0 mg/dl versus 1.2 mg/dl), and higher systolic blood pressure (119.7 mmhg versus mmhg). For concomitant medications, the aged group was administered a lower dose of loop diuretics (58 mg/day versus 74 mg/day), and lower proportions of angiotensin-receptor blockers (13% versus 19%), beta-blockers (32% versus 46%), thiazide diuretics (5% versus 11%), and aldosterone antagonists (5% versus 9%). Effectiveness: The mean changes in body weight and urine volume, and mean daily water intake over 14 days are displayed in Figure 1. We found that changes in body weight in the aged group were similar to those in the U-80 group, and both showed a trend of continuous decreases over the 14-day period. Increases in urine volume showed a peak on day 2 in both groups, but the increases were lower in the aged group (564 ml versus 809 ml, P = ). The aged group had lower water intake than the U-80 group on day 1 through day 14. As shown in Table I, differences were observed at the beginning of the tolvaptan treatment; the aged group had a higher proportion of patients with lower limb edema (84.6% versus A 80.2%, P = ) and pulmonary congestion (85.8% versus 81.7%, P = ); however, it also included a lower proportion of patients with hepatomegaly (29.3% versus 37.8%, P = ). The time-dependent proportion of patients who had congestive symptoms is shown in Figure 2. In both the aged and U-80 groups, the proportion of patients with congestive symptoms decreased in a similar way. On day 14, we found no differences between the 2 groups in terms of lower-limb edema, pulmonary congestion, or dyspnea (P = , P = , and P = , respectively). The aged group included a lower proportion of patients with jugular venous distention on day 14 (P = ). Safety profile: Table II shows the list of adverse events (at least 0.3% incidence rate) reported by investigators. The incidence rate of adverse events was 24.3% (460/1891) in total, including 25.6% (250/977) in the U-80 group and 23.0% (210/914, P = 0.198) in the aged group. The most frequently reported adverse event was thirst (9.6%), occurring in 11.6% of patients in the U-80 group and in 7.4% of patients in the aged group; this difference was statistically significant (P = 0.002). Cumulative incidences of thirst and hypernatremia: Figure 3A shows the cumulative incidence of thirst, following administration of tolvaptan. The total number of incidences of thirst was lower in the aged group than in the U-80 group throughout the 14-day period. Figure 3B shows the cumulative incidence of B C Figure 1. Mean changes in body weight (A), 24-hour urine volume (B), and mean daily water intake (C) after tolvaptan treatment in the aged and U-80 groups.

4 140 A KINUGAWA, ET AL B Int Heart J March 2015 C D E Figure 2. Mean changes in the proportions of patients with congestive symptoms over 14 days. A: lower-limb edema, B: pulmonary congestion, C: dyspnea, D: jugular venous distention, and E: hepatomegaly. hypernatremia, defined as any increase in the sodium level to 150 meq/l. The total number of incidences was comparable between aged and U-80 patients. Comparison of data after 2 years of monitoring: We divided all the patients into 2 groups according to the dates on which data were reported. One group (group 1) consisted of 1057 patients whose data were reported by May 18, 2013, and the other (group 2) was composed of 834 patients whose data were obtained from May 19, 2013 to May 18, In comparison with group 1, the rate of hypernatremia in the aged group was significantly decreased in group 2 (P = ), but the values were similar in the U-80 group (P = ). There was a higher incidence of hypernatremia in the aged group (group 1, P = ); however, this effect was not observed in the recent data (group 2, P = ) (Table IIIA). Regarding the starting dose of tolvaptan, the doses significantly decreased both in the aged and U-80 groups during the recent data-collection period (P < and P = , respective-

5 Vol 56 No 2 TOLVAPTAN IN OCTOGENARIANS WITH HEART FAILURE 141 Table II. Adverse Events With a Frequency of at Least 0.3%, by Decreasing Frequency, as Reported by Investigators All patients U-80 Aged P n All incidence 460 (24.3%) 250 (25.6%) 210 (23.0%) Thirst 181 (9.6%) 113 (11.6%) 68 (7.4%) ** Hypernatremia 79 (4.2%) 37 (3.8%) 42 (4.6%) Heart failure 30 (1.6%) 11 (1.1%) 19 (2.1%) BUN increased 24 (1.3%) 10 (1.0%) 14 (1.5%) Renal dysfunction 23 (1.2%) 9 (0.9%) 14 (1.5%) Dehydration 15 (0.8%) 6 (0.6%) 9 (1.0%) Hyperuricemia 15 (0.8%) 9 (0.9%) 6 (0.7%) Hyperkalemia 14 (0.7%) 9 (0.9%) 5 (0.6%) Creatinine increased 13 (0.7%) 7 (0.7%) 6 (0.7%) Liver dysfunction 10 (0.5%) 4 (0.4%) 6 (0.7%) Pneumonia 10 (0.5%) 5 (0.5%) 5 (0.6%) Ventricular tachycardia 9 (0.5%) 7 (0.7%) 2 (0.2%) Anemia 9 (0.5%) 4 (0.4%) 5 (0.6%) Serum sodium increased 8 (0.4%) 5 (0.5%) 3 (0.3%) Uric acid increased 8 (0.4%) 7 (0.7%) 1 (0.1%) Atrial fibrillation 8 (0.4%) 4 (0.4%) 4 (0.4%) Fever 6 (0.3%) 3 (0.3%) 3 (0.3%) Constipation 6 (0.3%) 2 (0.2%) 4 (0.4%) Blood pressure decreased 6 (0.3%) 2 (0.2%) 4 (0.4%) WBC increased 6 (0.3%) 5 (0.5%) 1 (0.1%) Rapid increase in serum sodium 6 (0.3%) 3 (0.3%) 3 (0.3%) ** P < A B Figure 3. Cumulative incidence cases for thirst (A) and increases in serum sodium to 150 meq/l and (B) after initiation of tolvaptan treatment. Table III. Comparison of the Incidence of Hypernatremia Defined as 150 meq/l (A) and the Starting Dose of Tolvaptan (B) Between Data Reported by 18 May 2013 (Group 1, n = 1057) and Data From May 19, 2013 to May 18, 2014 (Group 2, n = 834) in the Aged Group Versus the U-80 Group Total Group 1 Group 2 P A. Aged 3.61% 4.81% 2.17% P = U % 2.69% 3.10% P = Aged versus U-80 P = P = P = B. Aged P < U P = Aged versus U-80 P = P = ly). The trend was more robust in the aged group, and as a result the starting dose of the aged group was significantly lower than the U-80 group during the recent period (P = ) (Table IIIB). The usage of concomitant medications was the same between groups 1 and 2, except for thiazide diuretics. The proportion of patients administered thiazide was lower in group 2 than in group 1 (5.6% versus 10.0%, P = ). Incidence rates of hypernatremia by subgroup: Table IV

6 142 KINUGAWA, ET AL Int Heart J March 2015 Table IV. Comparison of the Incidence Rate of Hypernatremia Between the Aged and U-80 Groups and Low-Dose Versus the High-Dose Group Treated With Tolvaptan Starting dose Aged U-80 P 7.5 mg (low) 1.78% 2.44% P = > 7.5 mg, and 15 mg (high) 8.75% 3.73% P = Low versus high P < P = Table V. Incidence Rates of Hypernatremia Defined as 150 meq/l or More in Aged and U-80 Patients Stratified by Normal Serum Na Level (135mEq/L <) and Hyponatremia (< 135 meq/l) Before the Initiation of Tolvaptan, and High (7.5 mg <) and Low (< 7.5 mg) Starting Dose Aged U-80 Normal Hyponatremia P Normal Hyponatremia P High dose 7.5 mg < 11.24% 3.45% P = % 2.56% P = Low dose 7.5 mg 2.16% 1.05% P = % 1.44% P = Low versus high P < P = P = P = shows a comparison of the incidence rates of hypernatremia in the aged group and U-80 groups stratified by the starting dose of tolvaptan. If patients were prescribed a starting dose 7.5 mg, the incidence rate of hypernatremia was similar in both the aged and U-80 groups. However, when tolvaptan was initiated at a dose of > 7.5 mg, the aged group had a significantly higher incidence rate of hypernatremia (8.75% versus 3.73%, P = ). Notably, the incidence of hypernatremia did not depend on the initial dose of tolvaptan in the U-80 group (P = ). On the other hand, in the aged group, a higher starting dose was associated with a significantly increased incidence of hypernatremia (P < ). Table V shows the incidence rates of hypernatremia in the aged group and the U-80 group, for groups where the serum sodium level before tolvaptan was initiated was normal (135 meq/l or more) and hyponatremia (less than 135 meq/l), and also divided into groups where the starting dose of tolvaptan was high (more than 7.5 mg) and low (7.5 mg or less). Among aged patients with a normal serum sodium level, the incidence of hypernatremia was significantly higher in patients with a high starting dose than in those with a low starting dose. However, in the U-80 group, no significant difference was found. Discussion In this study, we investigated the effectiveness and safety profile of tolvaptan, applying a threshold of 80 years of age as the definition of elderly patients. We found no major differences between patients aged 80 years and patients < 80 years with respect to the effectiveness of tolvaptan. Few clinical trials have involved the participation of patients aged 80 years, and therefore data regarding drug efficacy and safety in this particular cohort remain to be obtained. In fact, in the EVEREST trial, a large-scale clinical trial of tolvaptan, the mean age of the subjects was 66 years. 8) In a phase 3 clinical trial conducted in Japan (the QUEST study), the mean age of the patients was 71 years. 9) The mean age in this study was 77 years, and we consider that this may be in line with patient demographics in Japan. Pharmacokinetics (PK) and pharmacodynamics (PD) are generally different in elderly people because of declining hepatic and renal functions. Details of PK/PD of tolvaptan in elderly people 80 years are not available. In this study, we investigated the aquaresis-inducing effect of tolvaptan, the concomitant improvement in congestive symptoms, and the drug s safety profile, as shown by the incidence of adverse events in patients 80 years. We clearly found that urine output increased in a similar time-dependent manner, both in aged and U-80 patients. However, in the aged group, the maximum changes of urine volume on day 2, following initiation of tolvaptan therapy, were less than those in the U-80 group. On the other hand, body weight decreased equally in spite of the smaller urine output in the aged group. The discrepancy may be attributable to the fact that aged patients had lower water intake, probably due to less sensitivity to thirst. Decreases in body weight should be the primary indicator of the clinical efficacy of tolvaptan, as was the case in the QUEST study, 9) and in this regard, we can state that the effectiveness was the same in the two groups. Data for adverse events showed that the overall incidence rates were similar in the aged group and in the U-80 group. Thirst was the most frequently reported adverse event, but the incidence rate was lower in the aged group than in the U-80 group. This may be due to the fact that people aged 80 years become less sensitive to thirst. 16) A concern is that if a patient experiences little thirst, he or she may not ingest sufficient fluids even after aquaresis treatment, which can lead to hypernatremia. However, despite the fact that aged people experience less thirst, we found no increase in the incidence rate of hypernatremia in aged patients. In fact, we found a decreasing trend in the incidence rate of hypernatremia in aged patients during the last year of observation compared with the data from the previous year of observation. The most likely reason for this is the influence of the starting dose of tolvaptan. Our analyses found that in cases of hypernatremia reported during the last year of observation, there was a significant decrease in the starting dose of tolvaptan. In addition, the data for the incidence rate of hypernatremia stratified by age and starting dose showed that the incidence rate of hypernatremia was significantly higher only in the group with a combination of aged patients and higher daily

7 Vol 56 No 2 TOLVAPTAN IN OCTOGENARIANS WITH HEART FAILURE 143 dose. This indicates that, in older patients, starting tolvaptan at a low dose of no more than 7.5 mg contributes to the prevention of hypernatremia. In addition, when data were stratified by serum sodium level before the initiation of tolvaptan, it became clear that in the aged group, patients with a serum sodium level of 135 meq/l or more before the initiation of tolvaptan and a starting dose of more than 7.5 mg were highrisk patients. Therefore, we recommend that tolvaptan is administered to aged patients at a low dose. In particular, treatment of patients who are 80 years or over and have a high serum sodium level should be started at a low dose. In addition, electrolyte levels should be frequently monitored if titration to a higher dose becomes necessary for these patients. Conclusion: We conclude that tolvaptan is effective and can be safely administered to aged as well as U-80 patients. However, a lower starting dose should be considered to prevent hypernatremia in aged patients. Acknowledgments We would like to express our gratitude to the physicians across Japan who participated in this research. We also thank CMIC-PMS Co, Ltd. and ACRONET Corporation for their support with the statistical analyses. A grant was received from Otsuka Pharmaceutical Co., Ltd. Disclosures Conflict of interest: Koichiro Kinugawa, Takayuki Inomata, and Naoki Sato are consultants for Otsuka Pharmaceutical Co., Ltd. Koichiro Kinugawa, Naoki Sato, and Takayuki Inomata have received honoraria from Otsuka Pharmaceutical Co., Ltd. for lectures. References 1. Levy D, Kenchaiah S, Larson MG, et al. Long-term trends in the incidence of and survival with heart failure. N Engl J Med 2002; 347: Pocock SJ, Wang D, Pfeffer MA, et al. Predictors of mortality and morbidity in patients with chronic heart failure. Eur Heart J 2006; 27: Abraham WT, Fonarow GC, Albert NM, et al. Predictors of inhospital mortality in patients hospitalized for heart failure: insights from the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF). J Am Coll Cardiol 2008; 52: Barsheshet A, Shotan A, Cohen E, et al. Predictors of long-term (4-year) mortality in elderly and young patients with acute heart failure. Eur J Heart Fail 2010; 12: Hülsmann M, Berger R, Mörtl D, Pacher R. Influence of age and in-patient care on prescription rate and long-term outcome in chronic heart failure: a data-based substudy of the EuroHeart Failure Survey. Eur J Heart Fail 2005; 7: Komajda M, Hanon O, Hochadel M, et al. Contemporary management of octogenarians hospitalized for heart failure in Europe: Euro Heart Failure Survey II. Eur Heart J 2009; 30: Kinugawa K, Imamura T, Komuro I. Experience of a vasopressin receptor antagonist, tolvaptan, under the unique indication in Japanese heart failure patients. Clin Pharmacol Ther 2013; 94: Gheorghiade M, Konstam MA, Burnett JC Jr, et al. Short-term clinical effects of tolvaptan, an oral vasopressin antagonist, in patients hospitalized for heart failure : the EVEREST Clinical Status Trials. JAMA 2007; 297: 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, placebocontrolled study (QUEST study). Cardiovasc Drug Ther 2011; 25: S Konstam MA, Gheorghiade M, Burnett JC, et al. Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST Outcome Trial. JAMA 2007; 297: Imamura T, Kinugawa K, Minatsuki S, et al. Urine sodium excretion after tolvaptan administration is dependent upon baseline serum sodium levels: a possible explanation for the improvement of hyponatremia with scarce chance of hypernatremia by a vasopressin receptor antagonist. Int Heart J 2014; 55: Imamura T, Kinugawa K, Minatsuki S, et al. Tolvaptan can improve clinical course in responders. Int Heart J 2013; 54: Imamura T, Kinugawa K, Kato N, et al. A case with recovery of response to tolvaptan associated with remission of acute kidney injury and increased urine osmolality. Int Heart J 2013; 54: Imamura T, Kinugawa K, Kato N, et al. Successful conversion from thiazide to tolvaptan in a patient with stage d heart failure and chronic kidney disease before heart transplantation. Int Heart J 2013; 54: Kinugawa K, Sato N, Inomata T, Shimakawa T, Iwatake N, Mizuguchi K. Efficacy and safety of tolvaptan in heart failure patients with volume overload. Circ J 2014; 78: Stachenfeld NS, DiPietro L, Nadel ER, Mack GW. Mechanism of attenuated thirst in aging: role of central volume receptors. Am J Physiol 1997; 272: R