Challenges in Treating Cardiovascular Disease: Restricting Sodium and Managing Hyperkalemia

Clegg, Deborah J.; Cody, Michael J.; Palmer, Biff F.

doi:10.1016/j.mayocp.2017.04.006

Cited by 11 publications

(8 citation statements)

References 62 publications

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“…Calcium rather than sodium was chosen as the counterexchange ion in patiromer primarily because high sodium intake augments cardiorenal risk, either by leading to hypertension or by reducing the efficacy of RAASi [ 25 ]. In addition, treatment guidelines restrict sodium intake in patients with hypertension, CKD, and HF; the American Heart Association [ 26 ] currently recommends a dietary sodium intake of < 1.5 g per day for patients with these disorders, who are most at risk for hyperkalemia.…”

Section: Discussionmentioning

confidence: 99%

Safety and Tolerability of the Potassium Binder Patiromer From a Global Pharmacovigilance Database Collected Over 4 Years Compared with Data from the Clinical Trial Program

Rossignol

Lea

Chan

et al. 2021

Drugs - Real World Outcomes

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Introduction The availability of the sodium-free potassium binder patiromer opens new opportunities for hyperkalemia management. Objective Our objective was to compare data from a 4-year global pharmacovigilance database of adverse events (AEs) reported in patients prescribed patiromer in clinical practice compared with data obtained from the clinical trial program. Methods Postmarketing safety data regarding patiromer (Veltassa ® ; Vifor Pharma, Inc.), collected and recorded in the company's global pharmacovigilance database, were analyzed for the period from January 2016 through September 2019. These data were both solicited (i.e., via an organized data-collection method such as a patient-support program) and unsolicited (i.e., voluntarily reported by healthcare professionals, consumers, and competent authorities worldwide). The cumulative annualized mortality rate (events per 100 patient-years [PYs]) for the pharmacovigilance database analysis period were compared with the rate obtained in the longest patiromer clinical trial to date (up to 52 weeks of treatment). For individual AEs, reporting rates (% of events/100 PYs) for events collected in the global pharmacovigilance database were compared with the frequencies (% of patients with event/patients exposed) of events collected in the clinical trial program (N = 666). Results Over 4 years, the global pharmacovigilance database contained an estimated 45,000 PYs of exposure (17,823 individual case reports and 38,109 AEs), with most cases (95%) from the USA; > 85% of cases utilized 8.4 g/day. In total, 1214 deaths were reported, with a cumulative annualized mortality rate of 2.69/100 PYs (vs. 5.70 deaths/100 PYs in the 52-week clinical trial). Global pharmacovigilance reporting rates for the two most common AEs, constipation and diarrhea, were 6.90 and 3.48%, respectively. Respective frequencies were 7.2 and 4.8% in the clinical trial program. The pharmacovigilance reporting rate for AEs of decreased blood potassium was 0.45%; serum potassium < 3.5 mmol/L was reported in 4.7% of patients in the clinical trial program. For hypomagnesemia or decreased blood magnesium, reporting rates in the postmarketing setting were 0.02 and 0.16%, respectively, and they were observed in 5.3 and 0.8% of patients, respectively, in the clinical trial program. Conclusions Global pharmacovigilance data over 4 years confirmed that the tolerability and safety of patiromer in clinical practice is predictable and consistent with clinical trial data, with no evidence of any new safety signals to date.

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Section: Discussionmentioning

confidence: 99%

Safety and Tolerability of the Potassium Binder Patiromer From a Global Pharmacovigilance Database Collected Over 4 Years Compared with Data from the Clinical Trial Program

Rossignol

Lea

Chan

et al. 2021

Drugs - Real World Outcomes

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“…Of note, trials have shown reduced mortality rate by RAAS inhibition with higher dose only and whether the same outcome can be expected with lower dosage is uncertain (Rubinstein & Sanford, 2019). RAAS inhibitors may also be limited by hyperkalaemia, which can lead to detrimental arrhythmias (Clegg, Cody, & Palmer, 2017). Recently, a superior dual‐acting angiotensin receptor antagonists and neprilysin inhibitor, sacubitril–valsartan, was approved for use in heart failure with satisfactory renal tolerance (Damman et al, 2018).…”

Section: Diagnosis Prognosis and Treatment Of Cardiorenal Syndromementioning

confidence: 99%

Cardiorenal syndrome: Multi‐organ dysfunction involving the heart, kidney and vasculature

Savira

Magaye

Liew

et al. 2020

British J Pharmacology

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Cardiorenal syndrome (CRS) is a multi-organ disease, encompassing heart, kidney and vascular system dysfunction. CRS is a worldwide problem, with high morbidity, mortality, and inflicts a significant burden on the health care system. The pathophysiology is complex, involving interactions between neurohormones, inflammatory processes, oxidative stress and metabolic derangements. Therapies remain inadequate, mainly comprising symptomatic care with minimal prospect of full recovery. Challenges include limiting the contradictory effects of multi-organ targeted drug prescriptions and continuous monitoring of volume overload. Novel strategies such as multi-organ transplantation and innovative dialysis modalities have been considered but lack evidence in the CRS context. The adjunct use of pharmaceuticals targeting alternative pathways showing positive results in preclinical models also warrants further validation in the clinic. In recent years, studies have identified the involvement of gut dysbiosis, uraemic toxin accumulation, sphingolipid imbalance and other unconventional contributors, which has encouraged a shift in the paradigm of CRS therapy.

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“…7,12 An elevated serum bicarbonate concentration may, however, be associated with deleterious outcomes, and concern persists that administration of the sodium load that accompanies bicarbonate administration could increase blood pressure. 13…”

Section: Association With Cardiovascular Diseasementioning

confidence: 99%

Sodium bicarbonate to improve physical function in patients over 60 years with advanced chronic kidney disease: the BiCARB RCT

Witham

Band

Chong

et al. 2020

Health Technol Assess

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Background Advanced chronic kidney disease is common in older people and is frequently accompanied by metabolic acidosis. Oral sodium bicarbonate is used to treat this acidosis, but evidence is lacking on whether or not this provides a net gain in health or quality of life for older people. Objectives The objectives were to determine whether or not oral bicarbonate therapy improves physical function, quality of life, markers of renal function, bone turnover and vascular health compared with placebo in older people with chronic kidney disease and mild acidosis; to assess the safety of oral bicarbonate; and to establish whether or not oral bicarbonate therapy is cost-effective in this setting. Design A parallel-group, double-blind, placebo-controlled randomised trial. Setting The setting was nephrology and geriatric medicine outpatient departments in 27 UK hospitals. Participants Participants were adults aged ≥ 60 years with advanced chronic kidney disease (glomerular filtration rate category 4 or 5, not on dialysis) with a serum bicarbonate concentration of < 22 mmol/l. Interventions Eligible participants were randomised 1 : 1 to oral sodium bicarbonate or matching placebo. Dosing started at 500 mg three times daily, increasing to 1 g three times daily if the serum bicarbonate concentration was < 22 mmol/l at 3 months. Main outcome measures The primary outcome was the between-group difference in the Short Physical Performance Battery score at 12 months, adjusted for baseline. Other outcome measures included generic and disease-specific health-related quality of life, anthropometry, 6-minute walk speed, grip strength, renal function, markers of bone turnover, blood pressure and brain natriuretic peptide. All adverse events were recorded, including commencement of renal replacement therapy. For the health economic analysis, the incremental cost per quality-adjusted life-year was the main outcome. Results In total, 300 participants were randomised, 152 to bicarbonate and 148 to placebo. The mean age of participants was 74 years and 86 (29%) were female. Adherence to study medication was 73% in both groups. A total of 220 (73%) participants were assessed at the 12-month visit. No significant treatment effect was evident for the primary outcome of the between-group difference in the Short Physical Performance Battery score at 12 months (–0.4 points, 95% confidence interval –0.9 to 0.1 points; p = 0.15). No significant treatment benefit was seen for any of the secondary outcomes. Adverse events were more frequent in the bicarbonate arm (457 vs. 400). Time to commencement of renal replacement therapy was similar in both groups (hazard ratio 1.22, 95% confidence interval 0.74 to 2.02; p = 0.43). Health economic analysis showed higher costs and lower quality of life in the bicarbonate arm at 1 year, with additional costs of £564 (95% confidence interval £88 to £1154) and a quality-adjusted life-year difference of –0.05 (95% confidence interval –0.08 to –0.01); placebo dominated bicarbonate under all sensitivity analyses for incremental cost-effectiveness. Limitations The trial population was predominantly white and male, limiting generalisability. The increment in serum bicarbonate concentrations achieved was small and a benefit from larger doses of bicarbonate cannot be excluded. Conclusions Oral sodium bicarbonate did not improve a range of health measures in people aged ≥ 60 years with chronic kidney disease category 4 or 5 and mild acidosis, and is unlikely to be cost-effective for use in the NHS in this patient group. Once other current trials of bicarbonate therapy in chronic kidney disease are complete, an individual participant meta-analysis would be helpful to determine which subgroups, if any, are more likely to benefit and which treatment regimens are more beneficial. Trial registration Current Controlled Trials ISRCTN09486651 and EudraCT 2011-005271-16. The systematic review is registered as PROSPERO CRD42018112908. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 27. See the NIHR Journals Library website for further project information.

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Challenges in Treating Cardiovascular Disease: Restricting Sodium and Managing Hyperkalemia

Cited by 11 publications

References 62 publications

Safety and Tolerability of the Potassium Binder Patiromer From a Global Pharmacovigilance Database Collected Over 4 Years Compared with Data from the Clinical Trial Program

Safety and Tolerability of the Potassium Binder Patiromer From a Global Pharmacovigilance Database Collected Over 4 Years Compared with Data from the Clinical Trial Program

Cardiorenal syndrome: Multi‐organ dysfunction involving the heart, kidney and vasculature

Sodium bicarbonate to improve physical function in patients over 60 years with advanced chronic kidney disease: the BiCARB RCT

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