Tenapanor as Therapy for Hyperphosphatemia in Maintenance Dialysis Patients: Results from the OPTIMIZE Study.

BACKGROUND: OPTIMIZE was a randomized, open-label study evaluating different tenapanor initiation methods. OPTIMIZE evaluated tenapanor alone and in combination with phosphate binders (PBs) to achieve target serum phosphate (P) ≤5.5 mg/dL. METHODS: Patients with inadequately controlled P receiving maintenance dialysis from 42 US locations who were taking PBs with baseline P >5.5 mg/dL and ≤10.0 mg/dL, or were PB-naive with baseline P >4.5 mg/dL and ≤10.0 mg/dL, were included in OPTIMIZE. Participants taking PBs at baseline were randomized to switch from PBs to tenapanor (Straight Switch; n = 151) or reduce PB dosage by ≥50% and add tenapanor (Binder Reduction; n = 152); PB-naive patients started tenapanor alone (Binder-Naive; n = 30). Participants received tenapanor 30 mg twice a day for 10 weeks (part A), followed by an elective, 16-week open-label extension (part B). Outcomes included changes from baseline in P, intact fibroblast growth factor 23 (iFGF23), parathyroid hormone (PTH), serum calcium, and medication burden; patient-reported outcomes; and safety. RESULTS: By part A endpoint, 34.4% (Straight Switch), 38.2% (Binder Reduction), and 63.3% (Binder-Naive) of patients achieved P ≤5.5 mg/dL. Mean P reduction and median pill burden reduction from baseline to part A endpoint were 0.91± 1.7 mg/dL and 4 pills/day for the Straight Switch and 0.99± 1.8 mg/dL and 1 pill/day for the Binder Reduction group. The mean P reduction for Binder-Naive patients was 0.87± 1.5 mg/dL. Among Straight Switch and Binder Reduction patients who completed patient experience questionnaires, 205 of 243 (84.4%) reported an improved phosphate-management routine. Diarrhea was the most common adverse event (133 of 333 [39.9%]). CONCLUSIONS: Tenapanor as monotherapy or in combination with PBs effectively lowered P toward the target range in patients who were PB naïve or who were not at goal despite PB use. FUNDING: Ardelyx, Inc. TRIAL REGISTRATION: NCT04549597.

An open-label, single-arm study evaluating the immunogenicity and safety of the hepatitis B vaccine HepB-CpG (HEPLISAV-B®) in adults receiving hemodialysis.

BACKGROUND: Hemodialysis patients are at increased risk of hepatitis B virus (HBV) infection and are poorly responsive to HBV vaccines. Current vaccine recommendations for hemodialysis patients utilize more than twice the amount of hepatitis B surface antigen (HBsAg) used for healthy adults and achieve lower immune responses. METHODS: An open-label, single-arm, multicenter trial was conducted among adults 18 years of age and older who were initiating or undergoing hemodialysis who had not previously received hepatitis B vaccine. Participants received four doses of HepB-CpG (HEPLISAV-B®) (20 mcg rHBsAg + 3000 mcg CpG 1018, a Toll-like receptor 9 agonist) administered at 0, 4, 8, and 16 weeks. Participants are being followed for 68 weeks. This paper reports the final immunogenicity analysis of the primary endpoint at study week 20 and an interim safety analysis. RESULTS: We enrolled 119 participants receiving hemodialysis who were followed for a median of 47.4 weeks. Of the 119 participants, 75 were in the per-protocol population. At week 20, the seroprotection rate (% with antibodies to hepatitis B surface antigen [anti-HBs] ≥ 10 mIU/mL) was 89.3% and the percentage of participants with anti-HBs ≥ 100 mIU/mL was 81.3%. The anti-HBs geometric mean concentration was 1061.8 mIU/mL. HepB-CpG was well tolerated with no observed safety concerns. CONCLUSION: In patients receiving hemodialysis, HepB-CpG given as four doses was well tolerated and induced very high anti-HBs concentrations and seroprotection in a very high proportion of recipients.

Safety and Efficacy of Tenapanor for Long-term Serum Phosphate Control in Maintenance Dialysis: A 52-Week Randomized Phase 3 Trial (PHREEDOM).

Background: Treating hyperphosphatemia is a tenet of dialysis care. This trial assessed the safety and efficacy of tenapanor for the management of hyperphosphatemia. Methods: In this 52-week phase 3 study (NCT03427125), participants receiving maintenance dialysis with both hyperphosphatemia (serum phosphate 6.0-10.0 mg/dl) and a 1.5 mg/dl increase after phosphate binder washout were randomized (3:1) to tenapanor 30 mg twice daily for 26 weeks (randomized treatment period) or sevelamer carbonate (52-week safety control). Participants completing 26 weeks of treatment with tenapanor were rerandomized (1:1) to tenapanor or placebo for 12 weeks (randomized withdrawal period), and were eligible to enter the 14-week safety extension period. With input from the US Food and Drug Administration, the primary efficacy end point was the difference in the change in serum phosphate from the end of the randomized treatment period to the end of the randomized withdrawal period, among participants who achieved ≥1.2 mg/dl decrease in serum phosphate during the randomized treatment period (efficacy analysis set). Efficacy was also evaluated in the intention-to-treat (ITT) analysis set. Results: Of 564 eligible participants randomized to receive tenapanor (n=423) or sevelamer carbonate (n=141) during the randomized treatment period, 255 (60%) in the tenapanor group subsequently were rerandomized to tenapanor (n=128) or placebo (n=127) during the randomized withdrawal period. In the efficacy analysis set (n=131), the difference in estimated mean change in serum phosphate level between tenapanor and placebo from the beginning to the end of the randomized withdrawal period was -1.4 mg/dl (P<0.0001); in the ITT analysis set (n=243), the estimated mean difference was -0.7 mg/dl (P=0.002). Loosened stools were the most frequently reported adverse event (53% during the randomized treatment period). Serious adverse events were reported more frequently for participants treated with sevelamer carbonate (16%-23% across the three study periods) compared with tenapanor (11%-17%). Conclusions: Tenapanor reduced serum phosphate concentrations and maintained control of serum phosphate in participants receiving maintenance dialysis, with an acceptable safety and tolerability profile.

Intradialytic acid-base changes and organic anion production during high versus low bicarbonate hemodialysis.

The use of high dialysate bicarbonate for hemodialysis in end-stage renal disease is associated with increased mortality, but potential physiological mediators are poorly understood. Alkalinization due to high dialysate bicarbonate may stimulate organic acid generation, which could lead to poor outcomes. Using measurements of ß-hydroxybutyrate (BHB) and lactate, we quantified organic anion (OA) balance in two single-arm studies comparing high and low bicarbonate prescriptions. In study 1 (n = 10), patients became alkalemic using 37 meq/L dialysate bicarbonate; in contrast, with the use of 27 meq/L dialysate, net bicarbonate loss occurred and blood bicarbonate decreased. Total OA losses were not higher with 37 meq/L dialysate bicarbonate (50.9 vs. 49.1 meq using 27 meq/L, P = 0.66); serum BHB increased in both treatments similarly (P = 0.27); and blood lactate was only slightly higher with the use of 37 meq/L dialysate (P = 0.048), differing by 0.2 meq/L at the end of hemodialysis. In study 2 (n = 7), patients achieved steady state on two bicarbonate prescriptions: they were significantly more acidemic when dialyzed against a 30 meq/L bicarbonate dialysate compared with 35 meq/L and, as in study 1, became alkalemic when dialyzed against the higher bicarbonate dialysate. OA losses were similar to those in study 1 and again did not differ between treatments (38.9 vs. 43.5 meq, P = 0.42). Finally, free fatty acid levels increased throughout hemodialysis and correlated with the change in serum BHB (r = 0.81, P < 0.001), implicating upregulation of lipolysis as the mechanism for increased ketone production. In conclusion, lowering dialysate bicarbonate does not meaningfully reduce organic acid generation during hemodialysis or modify organic anion losses into dialysate.

Quantifying the effect of age on short-term and long-term case fatality in 14,000 patients with incident cases of cardiovascular disease.

BACKGROUND: Age is a major determinant of case fatality following acute cardiovascular disease (CVD) events. Its impact, however, varies by time after the event, sex and diagnostic category. We were able to quantify these effects with good precision in a large cohort of patients. DESIGN: A national cohort of 14,227 CVD patients representing all the recorded first-CVD events in people aged 35-84 years in New Zealand in 1995 were examined, using electronic linkage of routine health data. METHODS: Case fatality by age was assessed in three phases: prehospital deaths, fatality after hospitalization up to 28 days and from 28 days up to 5 years after the event. It was assessed in these phases by sex and by the diagnostic categories: acute myocardial infarction (AMI), stroke and other coronary heart diseases. RESULTS: Case fatality in the prehospital phase showed substantial age differences. In particular, a strong positive monotonic age gradient was observed for AMI, but a U-shaped age-case-fatality gradient for stroke. From admission to 28 days, AMI case fatality demonstrated the strongest age gradient. In contrast, there was minimal age effect on 28-day stroke mortality, and case fatality for other coronary heart diseases was low. From 28 days to 5 years, there was a substantial positive monotonic age by case-fatality gradient for all diagnoses. CONCLUSION: Age has a large impact on case fatality following cardiovascular events, although the effect varies significantly by time elapsed after the event, diagnostic category and sex. As the lifetime benefits of many cardiovascular interventions depend on preintervention risk and case fatality, the role of age needs careful attention while making treatment decisions.

The effect of a change in epoetin alfa reimbursement policy on anemia outcomes in hemodialysis patients.

In 1997, the Health Care Financing Administration Hematocrit Measurement Audit (HMA) program initiated use of a 3-month rolling average hematocrit (Hct) level for reimbursement of epoetin claims in hemodialysis patients, with denial of payment when this value exceeded 36.5%. This study evaluated the impact of the HMA program on anemia-related outcomes in hemodialysis patients. An observational, retrospective study of 987 hemodialysis patients from 11 dialysis centers in the United States was performed, collecting data between October 1996 and December 1997. Centers were selected from a pool of nearly all facilities in the United States, which during May 1997 satisfied one of two criteria: greater than 75% of patients at the facility had mean Hct level of > or =33% (Group A) or fewer than 50% of patients at the facility had mean Hct level of > or =33% (Group B). Each facility maintained its own anemia management practices without specific anemia management interventions as part of this study. Hct level, hemoglobin (Hb) level, and epoetin dose were analyzed to compare the pre-HMA period (October 1996 to May 1997) to the HMA period (June to December 1997) and/or for each of the five quarters of the study period. The primary study endpoint was the percentage of patients with Hct levels of > or =33% during each study quarter. The mean Hct level at baseline was 34% in Group A and 33.4% in Group B (p = 0.01). Hct levels, which were increasing before implementation of the HMA program, decreased during the HMA period (p < 0.001 and p = 0.013 in Groups A and B, respectively). The percentage of patients in Groups A and B with mean quarterly Hct levels of > or =33% decreased during the last quarter of the HMA implementation period compared to the quarter immediately preceding the start of the HMA program (p < 0.001 for both comparisons). Changes in Hb levels were similar to those seen in Hct levels. The mean epoetin dose administered decreased from 13,090 U/week at the start of the study to 11,884 U/week immediately before the HMA program took effect (p < 0.05). The HMA program adversely affected anemia treatment outcomes, regardless of whether dialysis units before HMA implementation had <50% of patients with a Hct level of > or =33% or had >75% of patients with a Hct level of > or =33%. The decline in mean weekly dose of epoetin was likely a result of withholding doses out of concern among providers about risk of reimbursement denial.

Did the invisible hand rock the cradle? An investigation of children's hospitalisations in New Zealand.

OBJECTIVES: To test the hypothesis that the overall growth in children's hospitalisations since the instigation of New Zealand's economic and social reforms in 1984 reflects an increase in morbidity caused by socio-economic factors such as poverty, unemployment, household overcrowding and the cost of primary care. METHODS: All publicly funded hospitalisations amongst children aged 1-14 years, for the years 1988/89 to 2002/03, were categorised as either avoidable or unavoidable based on primary discharge diagnosis. Trends in avoidable and unavoidable hospitalisation rates over time and for various demographic and socio-economic groups were analysed. RESULTS: Growth in avoidable and unavoidable hospitalisations amongst children was similar over the period, with unavoidable hospitalisations growing slightly faster. Growth in avoidable hospitalisations was greatest for children who live in the least deprived areas and lowest for children who live in the most deprived areas. Making primary care substantially free for children aged less than six years did not appear to slow the growth in avoidable hospitalisations. CONCLUSIONS: Trends in avoidable and unavoidable hospitalisations over time are not consistent with the hypothesis being tested. The available evidence does not support a link between morbidity attributable to socio-economic factors and growth in children's hospitalisations. Given the lack of other evidence for deterioration in overall child health, the available evidence does not support a link between economic and social reforms in New Zealand and a decline in children's health status.

Hemoglobin variability in epoetin-treated hemodialysis patients.

BACKGROUND: Understanding the clinical variability of hemoglobin measurements in epoetin-treated hemodialysis patients is important, particularly when this therapy is aimed at maintaining patient hemoglobin levels within a narrow range, such as the 11 to 12 g/dL range recommended in National Kidney Foundation Kidney Dialysis Outcomes Quality Initiative (NKF-K/DOQI) guidelines. This study examines hemoglobin variability under conditions of standard clinical practice in epoetin-treated hemodialysis patients. METHODS: We studied 987 hemodialysis patients participating in an observational retrospective study that evaluated anemia management practices from October 1, 1996 to December 31, 1997 at 11 United States dialysis centers that were randomly selected from a pool of nearly all United States dialysis facilities. Each participating facility maintained its own anemia management protocols without specific anemia management recommendations or interventions made as part of this study. Hemoglobin variability was determined by calculating the 1-month and 2- to 6-month rolling average hemoglobin for each patient. The range of mean hemoglobin values that included the middle 50% (25th to 75th percentile), 80% (10th to 90th percentile), and 90% (5th to 95th percentile) of values were determined. The hemoglobin ranges that included 1 standard deviation (SD) (67%) of the study values and 2 SD (95%) of the study values for each time period were calculated. RESULTS: The mean hemoglobin was between 10.9 and 11.2 g/dL throughout the study. The hemoglobin range encompassing 50%, 80%, and 90% of values from a single month was 1.7, 3.3, and 4.4 g/dL, respectively. A progressive narrowing in the range of hemoglobin values encompassed by each percentile grouping (i.e., hemoglobin variability) was observed as longer rolling intervals were averaged. The hemoglobin range within the 25th to 75th percentile was 1.7 g/dL using single-month hemoglobin values and 1.1 g/dL using a 6-month rolling average. The range of hemoglobin values that encompassed 90% of patients was 4.4 g/dL using single-month values, 3.7 g/dL using 3-month rolling averages, and 3.2 g/dL using 6-month rolling averages. Fewer than 50% of patients had hemoglobin values within the 1.0 g/dL NKF-K/DOQI recommended range, even when a 6-month rolling average was applied. When hemoglobin values were measured for 1 month, 1 SD was 1.4 g/dL; for the 3-month rolling average, 1 SD was 1.1 g/dL; and for the 4-, 5-, and 6-month rolling averages, 1 SD was 1.0 g/dL. Greater hemoglobin variability correlated with higher mean corpuscular hemoglobin (P = 0.003) and serum ferritin (P = 0.047), and inversely correlated with age (P = 0.006) and serum albumin (P = 0.0001). CONCLUSION: Substantial variability occurs in hemoglobin values in epoetin-treated hemodialysis patients. The NKF-K/DOQI recommended hemoglobin range appears to be too narrow in clinical practice. Expanding the target range and use of rolling average hemoglobin intervals of 3 to 6 months as a clinical and quality assurance measure avoids clinical variability inherent with the use of isolated hemoglobin values or single-month hemoglobin averages.

Exercise for the dialyzed: aerobic and strength training during hemodialysis.

OBJECTIVE: To investigate the safety and feasibility of aerobic and strength training during hemodialysis for end-stage renal disease patients and to evaluate its impact on their cardiac fitness, muscle strength, and functional status. DESIGN: A total of 22 patients undergoing hemodialysis for end-stage renal disease had assessment of their cardiac fitness with stress tests and walk tests, assessment of their muscle strength by one repetition maximum of knee extension, and assessment of their functional status by Medical Outcomes Study Short Form-36 before and after exercise training. Training, consisting of cycle ergometer exercise and strengthening of the knee extensors two to three times a week for 3 mo, was done during dialysis. RESULTS: Eighteen of 22 patients completed 3 mo of training and four dropped out due to knee pain or medical complications unrelated to exercise. No patient developed major complications from the program. After training, there was a significant improvement in the mental and physical components of the Short Form-36 and one repetition maximum of knee extension. Among 14 of 18 patients who agreed and completed a follow-up fitness testing, five showed improvement on the stress tests and eight on the walk tests. CONCLUSIONS: A well designed exercise program during hemodialysis can be performed safely with proper supervision and patient education, improving muscle strength, mental and physical function, and possibly cardiac fitness.

Sodium ferric gluconate complex in hemodialysis patients: adverse reactions compared to placebo and iron dextran.

BACKGROUND: Parenteral iron is often required by hemodialysis patients to maintain adequate iron stores. Until recently, the only available form of intravenous iron was iron dextran, which is associated with significant adverse reactions, including anaphylaxis and death. Sodium ferric gluconate complex (SFGC) was recently approved for use in the U.S. under FDA's priority drug review. This Phase IV study was designed to evaluate the safety of a single dose of intravenous SFGC as compared to placebo and a historical iron dextran control. METHODS: This multicenter, crossover, randomized, double blind, placebo-controlled prospective comparative study was performed in hemodialysis patients requiring at least 125 mg of elemental iron. The historical control was obtained from a meta-analysis of four publications examining outcomes in patients exposed to iron dextran. SFGC naïve patients were administered SFGC without a test dose, undiluted, at a rate of 125 mg over 10 minutes, and compared to placebo comprising bacteriostatic saline. RESULTS: A total of 2534 patients were enrolled. The incidence of drug intolerance (an adverse event precluding re-exposure) was significantly less [0.44%, confidence interval (CI) 0.21 to 0.71%] after SFGC as compared to the iron dextran control (2.47%, CI 1.87 to 3.07%, P < 0.0001), but higher than after placebo (0.1%, P = 0.02). There was no difference found between SFGC and placebo in serious adverse events. A single life-threatening event occurred after SFGC (0.04%, CI 0.00 to 0.22%), which was significantly less than following iron dextran (0.61%, CI 0.36 to 0.86%), P = 0.0001. CONCLUSION: SFGC is well tolerated when given by intravenous push without a test dose. SFGC has a significantly lower incidence of drug intolerance and life-threatening events as compared to previous studies using iron dextran. The routine use of iron dextran in hemodialysis patients should be discontinued.