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Klein GL. Is calcium a link between inflammatory bone resorption and heart disease? eLife 2022; 11:83841. [PMID: 36580074 PMCID: PMC9799968 DOI: 10.7554/elife.83841] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Accepted: 12/08/2022] [Indexed: 12/30/2022] Open
Abstract
Several epidemiologic studies associate bone-resorbing chronic inflammatory conditions with increased risk of atherosclerotic heart disease. These include post-menopausal osteoporosis, spinal cord injury, rheumatoid arthritis, and osteoarthritis. Additional studies have noted that the use of anti-resorptive agents following hip fracture, during rheumatoid arthritis, and prior to intensive care management have resulted in reduced overall mortality and mortality from cardiovascular disorders. The careful study of burn patients has allowed us to detect that children and adolescents have a mechanism that protects them from the entry of calcium into the circulation following inflammatory bone resorption. That is, they respond to pro-inflammatory cytokines by up-regulating the parathyroid calcium-sensing receptor (CaSR) with consequent development of hypocalcemic hypoparathyroidism and hypercalciuria. As extracellular calcium appears to exacerbate and/or prolong the inflammatory response, this responsiveness of the CaSR to inflammatory cytokines may be the factor that reduces cardiovascular morbidity and mortality. In adults with chronic inflammatory conditions, the ability of the CaSR to respond to pro-inflammatory cytokines is lost, suggesting that the calcium that enters the circulation following inflammatory bone resorption may persist in the circulation, entering the small coronary blood vessels and favoring the formation of coronary artery calcification, inflammation, and consequent cardiovascular disease.
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Affiliation(s)
- Gordon L Klein
- Department of Orthopaedic Surgery and Rehabilitation, The University of Texas Medical Branch at GalvestonGalvestonUnited States
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2
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Prevention of vascular calcification by the endogenous chromogranin A-derived mediator that inhibits osteogenic transdifferentiation. Basic Res Cardiol 2021; 116:57. [PMID: 34647168 PMCID: PMC8514386 DOI: 10.1007/s00395-021-00899-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 09/15/2021] [Accepted: 10/01/2021] [Indexed: 11/26/2022]
Abstract
The adrenal glands participate in cardiovascular (CV) physiology and the pathophysiology of CV diseases through their effects on sodium and water metabolism, vascular tone and cardiac function. In the present study, we identified a new adrenal compound controlling mesenchymal cell differentiation that regulates osteoblastic differentiation in the context of vascular calcification. This peptide was named the “calcification blocking factor” (CBF) due to its protective effect against vascular calcification and is released from chromogranin A via enzymatic cleavage by calpain 1 and kallikrein. CBF reduced the calcium content of cells and thoracic aortic rings under calcifying culture conditions, as well as in aortas from animals treated with vitamin D and nicotine (VDN animals). Furthermore, CBF prevented vascular smooth muscle cell (VSMC) transdifferentiation into osteoblast-like cells within the vascular wall via the sodium-dependent phosphate transporter PIT-1 and by inhibition of NF-κB activation and the subsequent BMP2/p-SMAD pathway. Pulse pressure, a marker of arterial stiffness, was significantly decreased in VDN animals treated with CBF. In line with our preclinical data, CBF concentration is significantly reduced in diseases characterized by increased calcification, as shown in patients with chronic kidney disease. In preparation for clinical translation, the active site of the native 19-AS long native CBF was identified as EGQEEEED. In conclusion, we have identified the new peptide CBF, which is secreted from the adrenal glands and might prevent vascular calcification by inhibition of osteogenic transdifferentiation. The anti-calcific effects of CBF and short active site may therefore promote the development of new tools for the prevention and/or treatment of vascular calcification.
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Schwantes-An TH, Vatta M, Abreu M, Wetherill L, Edenberg HJ, Foroud TM, Chertow GM, Moe SM. The Contribution of Known Familial Cardiovascular Disease Genes to Sudden Cardiac Death in Patients Undergoing Hemodialysis. Cardiorenal Med 2021; 11:174-183. [PMID: 34433165 PMCID: PMC8393692 DOI: 10.1159/000517123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Accepted: 05/03/2021] [Indexed: 11/19/2022] Open
Abstract
INTRODUCTION Patients with chronic kidney disease experience high rates of cardiovascular mortality and morbidity. When kidney disease progresses to the need for dialysis, sudden cardiac death (SCD) accounts for 25-35% of all cardiovascular deaths. The objective was to determine if rare genetic variants known to be associated with cardiovascular death in the general population are associated with SCD in patients undergoing hemodialysis. METHODS We performed a case-control study comparing 126 (37 African American [AfAn] and 89 European ancestry [EA]) SCD subjects and 107 controls (34 AfAn and 73 EA), matched for age, sex, self-reported race, dialysis duration (<2, 2-5 and >5 years), and the presence or absence of diabetes mellitus. To target the coding regions of genes previously reported to be associated with 15 inherited cardiac conditions (ICCs), we used the TruSight Cardio Kit (Illumina, San Diego, CA, USA) to capture the genetic regions of interest. In all, the kit targets 572-kb regions that include the protein-coding regions and 40-bp 5' and 3' end-flanking regions of 174 genes associated with the 15 ICCs. Using the sequence data, burden tests were conducted to identify genes with an increased number of variants among SCD cases compared to matched controls. RESULTS Eleven genes were associated with SCD, but after correction for multiple testing, none of the 174 genes were identified as having more variants in the SCD cases than the matched controls, including previously identified genes. Secondary burden tests grouping variants based on diseases and gene function did not produce statistically significant associations. DISCUSSION/CONCLUSIONS We found no associations between genes known to be associated with ICCs and SCD in our sample of patients undergoing hemodialysis. This suggests that genetic causes are unlikely to be a major pathogenic factor in SCD in hemodialysis patients, although our sample size limits definitive conclusions.
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Affiliation(s)
- Tae-Hwi Schwantes-An
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, IN, USA
| | - Matteo Vatta
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, IN, USA
| | - Marco Abreu
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, IN, USA
| | - Leah Wetherill
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, IN, USA
| | - Howard J. Edenberg
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, IN, USA
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, IN, USA
| | - Tatiana M. Foroud
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, IN, USA
| | - Glenn M. Chertow
- Stanford University Department of Medicine, Division of Nephrology, Stanford, CA, USA
| | - Sharon M. Moe
- Department of Medicine, Division of Nephrology and Hypertension, Indianapolis, IN, USA
- Department of Medicine, Roudebush Veterans Administration Medical Center, Indianapolis, IN, USA
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Singh AK, Blackorby A, Cizman B, Carroll K, Cobitz AR, Davies R, Jha V, Johansen KL, Lopes RD, Kler L, Macdougall IC, McMurray J, Meadowcroft AM, Obrador GT, Perkovic V, Solomon S, Wanner C, Waikar SS, Wheeler DC, Wiecek A. Study design and baseline characteristics of patients on dialysis in the ASCEND-D trial. Nephrol Dial Transplant 2021; 37:960-972. [PMID: 33744933 PMCID: PMC9035347 DOI: 10.1093/ndt/gfab065] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Indexed: 01/15/2023] Open
Abstract
Background The Anemia Studies in chronic kidney disease (CKD): Erythropoiesis via a Novel prolyl hydroxylase inhibitor Daprodustat-Dialysis (ASCEND-D) trial will test the hypothesis that daprodustat is noninferior to comparator epoetin alfa or darbepoetin alfa for two co-primary endpoints: hemoglobin (Hb) efficacy and cardiovascular (CV) safety. Methods We report the trial design, key demographic, clinical and laboratory findings, and baseline therapies of 2964 patients randomized in the open-label (sponsor-blinded) active-controlled, parallel-group, randomized ASCEND-D clinical trial. We also compare baseline characteristics of ASCEND-D patients with patients who are on dialysis (CKD G5D) enrolled in other large CV outcome trials (CVOTs) and in the most relevant registries. Results The median age of patients was 58 years, 43% were female; 67% were White and 16% were Black. The median Hb at baseline was 10.4 g/dL. Among randomized patients, 89% were receiving hemodialysis and 11% peritoneal dialysis. Among key comorbidities, 42% reported a history of diabetes mellitus and 45% a history of CV disease. Median blood pressure was 134/74 mmHg. The median weekly dose of epoetin was 5751 units. Intravenous and oral iron uses were noted in 64 and 11% of patients, respectively. Baseline demographics were similar to patients with CKD G5D enrolled in other CVOTs and renal patient registries. Conclusions ASCEND-D will evaluate the efficacy and safety of daprodustat compared with epoetin alfa or darbepoetin alfa in the treatment of patients with anemia with CKD G5D. This trial is registered with ClinicalTrials.gov: NCT02879305. EudraCT Number: 2016-000541-31; Sponsor Protocol Number: 200807.
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Affiliation(s)
- Ajay K Singh
- Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | | | | | | | | | | | - Vivekanand Jha
- George Institute for Global Health, New Delhi, India.,Faculty of Medicine, Imperial College, London, UK.,Manipal Academy of Higher Education, Manipal, India
| | | | - Renato D Lopes
- Duke Clinical Research Institute, Duke Health, Durham, NC, USA
| | - Lata Kler
- GlaxoSmithKline, Collegeville, PA, USA
| | | | | | | | | | | | - Scott Solomon
- Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | | | - Sushrut S Waikar
- Boston University School of Medicine and Boston Medical Center, Boston, MA, USA
| | - David C Wheeler
- Department of Renal Medicine, University College London, London, UK
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Block GA, Chertow GM, Cooper K, Xing S, Fouqueray B, Halperin M, Danese MD. Fibroblast growth factor 23 as a risk factor for cardiovascular events and mortality in patients in the EVOLVE trial. Hemodial Int 2020; 25:78-85. [PMID: 33016505 DOI: 10.1111/hdi.12887] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Revised: 09/17/2020] [Accepted: 09/18/2020] [Indexed: 01/10/2023]
Abstract
INTRODUCTION High mortality rates in patients with chronic kidney disease-mineral and bone disorder (CKD-MBD) receiving maintenance hemodialysis are largely due to cardiovascular (CV) events. METHODS We evaluated associations between MBD parameters, fibroblast growth factor 23 (FGF23) concentrations, and clinically adjudicated CV events from the Evaluation of Cinacalcet Hydrochloride Therapy to Lower Cardiovascular Events (EVOLVE) trial. Patients enrolled in EVOLVE, who had not experienced any study endpoints between randomization and week 20 with evaluable baseline and week 20 values for key laboratory parameters (parathyroid hormone, calcium, phosphate, and FGF23), were assessed. We used adjusted Cox proportional hazards regression models to estimate relative risk of outcomes (primary composite, all-cause mortality, and CV events) based on FGF23 and MBD parameters. Laboratory values were modeled with linear terms and using natural cubic splines with two degrees of freedom. FINDINGS For the primary endpoint, patients assessed (N = 2309) were followed up over a mean duration of 3.1 years, during which 1037 CV events (497 deaths, 540 nonfatal events) occurred. Adjusted models showed an association between FGF23 and the risk of CV events. Hazard ratio per log unit of FGF23 at week 20 was 1.09 [95% CI: 1.03-1.16], and the hazard ratio per log unit change in FGF23 from week 0 to week 20 was 1.09 [95% CI: 1.00-1.17]. DISCUSSION Our data highlight FGF23 as an independent CV risk factor and potential biomarker and therapeutic target for patients with CKD-MBD receiving maintenance hemodialysis.
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Affiliation(s)
| | - Glenn M Chertow
- Stanford University School of Medicine, Palo Alto, California, USA
| | | | - Shan Xing
- Amgen Inc., Thousand Oaks, California, USA
| | | | - Marc Halperin
- Outcomes Insights, Inc., Agoura Hills, California, USA
| | - Mark D Danese
- Outcomes Insights, Inc., Agoura Hills, California, USA
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6
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Nigwekar SU. Cardiovascular Calcifications Among Patients With Uremia: Answers to Hard Questions. Adv Chronic Kidney Dis 2019; 26:407-408. [PMID: 31831118 DOI: 10.1053/j.ackd.2019.11.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Accepted: 11/07/2019] [Indexed: 11/11/2022]
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7
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Moe SM, Long J, Schwantes-An THL, Decker BS, Wetherill L, Edenberg HJ, Xuei X, Vatta M, Foroud TM, Chertow GM. Angiotensin-related genetic determinants of cardiovascular disease in patients undergoing hemodialysis. Nephrol Dial Transplant 2019; 34:1924-1931. [PMID: 29982608 PMCID: PMC6826165 DOI: 10.1093/ndt/gfy191] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2017] [Accepted: 05/15/2018] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND Cardiovascular mortality in patients receiving dialysis remains unacceptably high, with unexplained ancestry differences suggesting a genetic component. METHODS We analyzed DNA samples from 37% of subjects enrolled in the EValuation Of Cinacalcet Hydrochloride (HCl) Therapy to Lower CardioVascular Events (EVOLVE) trial, a randomized trial conducted in patients receiving hemodialysis with secondary hyperparathyroidism, comparing cinacalcet to placebo on a background of usual care. DNA was analyzed for single-nucleotide polymorphisms (SNPs) in the genes encoding the angiotensin-converting enzyme receptor type I (AGTR1) and angiotensin-converting enzyme (ACE). Survival analyses were conducted separately in European Ancestry (EA) and African Ancestry (AfAn) due to known differences in cardiovascular events, minor alleles for the same variant and the frequency of minor alleles. Our primary determination was a meta-analysis across both races. RESULTS Meta-analysis showed significant associations between rs5186 in AGTR1 and increased rates by 25-34% for the primary endpoint (composite of death or nonfatal myocardial infarction, hospitalization for unstable angina, heart failure or peripheral vascular event), all-cause mortality, cardiovascular mortality and heart failure; all P < 0.001. Three correlated SNPs in ACE were associated with lower rates of sudden cardiac death (SCD) in EA samples. One ACE SNP, rs4318, only found in the AfAn samples, was associated with a lower rate of SCD in the AfAn samples. CONCLUSIONS The C allele in rs5186 in AGTR1 was associated with higher rates of death and major cardiovascular events in a meta-analysis of EA and AfAn patients with end-stage kidney disease. SNPs in ACE were associated with SCD.
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Affiliation(s)
- Sharon M Moe
- Division of Nephrology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
- Department of Medicine, Roudebush Veterans Administration Medical Center, Indianapolis, IN, USA
| | - Jin Long
- Division of Nephrology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Tae-Hwi Linus Schwantes-An
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Brian S Decker
- Division of Nephrology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Leah Wetherill
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Howard J Edenberg
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Xiaoling Xuei
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Matteo Vatta
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Tatiana M Foroud
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Glenn M Chertow
- Division of Nephrology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
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Issa H, Hénaut L, Abdallah JB, Boudot C, Lenglet G, Avondo C, Ibrik A, Caus T, Brazier M, Mentaverri R, Zibara K, Kamel S. Activation of the calcium-sensing receptor in human valvular interstitial cells promotes calcification. J Mol Cell Cardiol 2019; 129:2-12. [DOI: 10.1016/j.yjmcc.2019.01.021] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2018] [Revised: 12/17/2018] [Accepted: 01/24/2019] [Indexed: 01/10/2023]
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Solbu MD, Mjøen G, Mark PB, Holdaas H, Fellström B, Schmieder RE, Zannad F, Herrington WG, Jardine AG. Predictors of atherosclerotic events in patients on haemodialysis: post hoc analyses from the AURORA study. Nephrol Dial Transplant 2018; 33:102-112. [PMID: 27798199 DOI: 10.1093/ndt/gfw360] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2016] [Accepted: 09/06/2016] [Indexed: 12/24/2022] Open
Abstract
Background Patients on haemodialysis (HD) are at high risk for cardiovascular events, but heart failure and sudden death are more common than atherosclerotic events. The A Study to Evaluate the Use of Rosuvastatinin in Subjects on Regular Hemodialysis: An Assessment of Survival and Cardiovascular Events (AURORA) trial was designed to assess the effect of rosuvastatin on myocardial infarction and death from any cardiac cause in 2773 HD patients. We studied predictors of the atherosclerotic cardiovascular events in AURORA. Methods We readjudicated all deaths and presumed myocardial infarctions according to the criteria used in the Study of Heart and Renal Protection (SHARP); these were specifically developed to separate atherosclerotic from non-atherosclerotic cardiovascular events. The readjudicated atherosclerotic end point included the first event of the following: non-fatal myocardial infarction, fatal coronary heart disease, non-fatal and fatal non-haemorrhagic stroke, coronary revascularization procedures and death from ischaemic limb disease. Stepwise Cox regression analysis was used to identify the predictors of such events. Results During a mean follow-up of 3.2 years, 506 patients experienced the new composite atherosclerotic outcome. Age, male sex, prevalent diabetes, prior cardiovascular disease, weekly dialysis duration, baseline albumin [hazard ratio (HR) 0.96; 95% confidence interval (CI) 0.94-0.99 per g/L increase], high-sensitivity C-reactive protein (HR 1.13; 95% CI 1.04-1.22 per mg/L increase) and oxidized low-density lipoprotein (LDL) cholesterol (HR 1.09; 95% CI 1.03-1.17 per 10 U/L increase) were selected as significant predictors in the model. Neither LDL cholesterol nor allocation to placebo/rosuvastatin therapy predicted the outcome. Conclusions Even with the use of strict criteria for end point definition, non-traditional risk factors, but not lipid disturbances, predicted atherosclerotic events in HD patients.
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Affiliation(s)
- Marit D Solbu
- University of Glasgow, Institute of Cardiovascular and Medical Sciences, Glasgow, UK.,Section of Nephrology, Division of Internal Medicine, University Hospital of North Norway, Tromsø, Norway.,Metabolic and Renal Research Group, UiT The Arctic University of Norway, Tromsø, Norway
| | - Geir Mjøen
- Department of Nephrology Ullevål, Oslo University Hospital, Oslo, Norway
| | - Patrick B Mark
- University of Glasgow, Institute of Cardiovascular and Medical Sciences, Glasgow, UK.,Queen Elizabeth University Hospital Glasgow, The Renal and Transplant Unit, Glasgow, UK
| | - Hallvard Holdaas
- Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway
| | - Bengt Fellström
- Division of Nephrology, Department of Internal Medicine, Uppsala University Hospital, Uppsala, Sweden
| | - Roland E Schmieder
- Department of Nephrology and Hypertension, University Hospital, Erlangen-Nürnberg, Germany
| | - Faiez Zannad
- Inserm, Clinical Investigation Centre 1433, Université de Lorraine and CHU, Nancy, France
| | | | - Alan G Jardine
- University of Glasgow, Institute of Cardiovascular and Medical Sciences, Glasgow, UK.,Queen Elizabeth University Hospital Glasgow, The Renal and Transplant Unit, Glasgow, UK
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Lai CF, Chen YT, Gu J, Nerbonne JM, Lin CH, Yang KC. Circulating long noncoding RNA DKFZP434I0714 predicts adverse cardiovascular outcomes in patients with end-stage renal disease. Int J Cardiol 2018; 277:212-219. [PMID: 30097337 DOI: 10.1016/j.ijcard.2018.08.013] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2017] [Revised: 06/25/2018] [Accepted: 08/04/2018] [Indexed: 12/11/2022]
Abstract
BACKGROUND Cardiovascular (CV) diseases are major causes of mortality in uremic patients. Conventional risk factors fail to identify uremic patients with increased propensity for adverse CV outcomes. We aimed to test the hypothesis that circulating long noncoding RNAs (lncRNAs) could be a prognostic marker to predict adverse CV outcomes in uremic patients. METHODS AND RESULTS Plasma lncRNAs were profiled in patients with end-stage renal disease (ESRD, n = 28) or chronic kidney disease (CKD, n = 8) and in healthy (n = 12) subjects by RNA sequencing. A total of 179 lncRNAs were significantly dysregulated with ESRD; the expression signature of plasma lncRNAs distinguished ESRD from both CKD and control samples. Analysis on a microarray dataset obtained from renal biopsy samples of patients with advanced kidney disease (GSE66494) revealed that a significant proportion of plasma lncRNAs (30.7%) and mRNAs (49.5%) dysregulated with uremia were similarly dysregulated in diseased kidneys, suggesting that plasma RNA profiles mirror the transcriptomal changes in diseased kidney tissues. Further analyses identified eight plasma lncRNAs as potential predictors of adverse CV outcomes in uremic patients. Validation study in an independent cohort of ESRD patients (n = 111) confirmed that elevated plasma lncRNA DKFZP434I0714 is a significant independent predictor of adverse CV outcomes in uremic patients. Additional experiments demonstrated the functional involvement of DKFZP434I0714 in the pathogenesis of endothelial dysfunction. CONCLUSIONS In summary, plasma lncRNA expression signature reflects the disease states of uremia. Elevated plasma levels of lncRNA DKFZP434I0714 in uremic patients portend a worse CV outcome and warrant closer monitoring and more aggressive management.
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Affiliation(s)
- Chun-Fu Lai
- Division of Nephrology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Yen-Ting Chen
- Graduate Institute of Pharmacology, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Jian Gu
- Thermo Fisher Scientific, Austin, TX, USA
| | - Jeanne M Nerbonne
- Department of Developmental Biology and Center for Cardiovascular Research, Washington University School of Medicine, St Louis, MO, USA
| | - Chin-Hsien Lin
- Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan.
| | - Kai-Chien Yang
- Graduate Institute of Pharmacology, National Taiwan University College of Medicine, Taipei, Taiwan; Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
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11
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Incidence, predictors and therapeutic consequences of hypocalcemia in patients treated with cinacalcet in the EVOLVE trial. Kidney Int 2018. [DOI: 10.1016/j.kint.2017.12.014] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
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12
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Dey V, Farrah TE, Traynor JP, Spalding EM, Robertson SE, Geddes CC. Symptomatic fracture risk in the renal replacement therapy population. Nephrol Dial Transplant 2018; 32:1211-1216. [PMID: 27257273 DOI: 10.1093/ndt/gfw222] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2015] [Accepted: 04/27/2016] [Indexed: 11/13/2022] Open
Abstract
Background Bone fractures are an important cause of morbidity and mortality in patients on renal replacement therapy (RRT). The aim of this multicentre observational study was to quantify the incidence of radiologically proven bone fracture by anatomical site in prevalent RRT groups and study its relationship to potential risk factors. Methods We performed a retrospective analysis of electronic records of all 2096 adults prevalent on RRT in the West of Scotland on 7 July 2010 across all hospitals (except one where inception was 1 August 2011) to identify all subsequent radiologically proven fractures during a median 3-year follow-up. Results There were 340 fractures, with an incidence of 62.8 per 1000 patient-years. The incidences were 37.6, 99.2 and 57.6 per 1000 patient-years in the transplant, haemodialysis (HD) and peritoneal dialysis (PD) groups, respectively (P < 0.05). In the multivariable model, age and HD (relative to transplant or PD) were independently associated with increased risk of fractures, while primary glomerular disease, increasing serum albumin and taking alfacalcidol or lanthanum were associated with decreased risk. In a multivariable model of only HD patients, age was independently associated with an increased risk of fractures, while glomerular disease, high serum albumin and being on alfacalcidol and lanthanum were associated with decreased risk. In a multivariable model in transplant patients, there were no significant independent predictors of fracture. Conclusions The risk of symptomatic bone fracture is high in RRT patients and is ∼2.5 times higher in HD than in renal transplant patients, with the increased risk being independent of baseline factors. Fracture risk increases with age and lower serum albumin and is reduced if the primary renal diagnosis is glomerular disease. The possible protective role of alfacalcidol and lanthanum in HD patients deserves further exploration.
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Affiliation(s)
- Vishal Dey
- Renal Unit, University Hospital Crosshouse, Kilmarnock, UK
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13
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Dzingarski D, Mladenovska K. Pharmacotherapy in chronic kidney disease hyperphosphatemia – effects on vascular calcification and bone health. MAKEDONSKO FARMACEVTSKI BILTEN 2017. [DOI: 10.33320/maced.pharm.bull.2017.63.01.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Hyperphosphatemia (HP) in patients with chronic kidney disease (CKD) leads to complications such as renal osteodistrophy, cardiovascular calcification and hemodynamic abnormalities, all of them having a serious impact on the survival rate and quality of life. Also, HP is a key pathogenic factor in the development of secondary hyperparathyroidism (SHPT) in CKD. Having in regard the significance of controlling serum phosphorus levels (Pi), in this paper, the needs and obstacles to successful pharmacological management of HP in CKD are presented, with an overview of major classes of phosphate binders (PBs) and other drugs affecting Pi level, such as active vitamin D sterols and calcimimetics (CMs). In addition, their effects on progression of cardiovascular calcification and bone health are elaborated. In this regard, a PubMed search was carried out to capture all abstracts and articles relevant to the topic of CKD, HP and mineral metabolism, bone disorders and vascular/valvular calcification (VC), published from January 2007 to August 2017. The search was limited to English language, with the search terms including drug name AND hyperphosphatemia or cardiovascular calcification or bone disorder. Comparative studies, clinical studies/trials and meta-analyses related to different classes/representatives of PBs, vitamin D analogues and CMs were reviewed and research data related to their efficacy and safety compared.
Keywords: chronic kidney disease, hyperphosphatemia, phosphate binders, active vitamin D sterols, calcimimetics, bone disorders, cardiovascular calcification
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Affiliation(s)
- Dimce Dzingarski
- Faculty of Pharmacy, University “Ss Cyril and Methodius”, Mother Theresa St. 47, 1000 Skopje, Republic of Macedonia
| | - Kristina Mladenovska
- Faculty of Pharmacy, University “Ss Cyril and Methodius”, Mother Theresa St. 47, 1000 Skopje, Republic of Macedonia
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Diaz-Tocados JM, Peralta-Ramirez A, Rodríguez-Ortiz ME, Raya AI, Lopez I, Pineda C, Herencia C, Montes de Oca A, Vergara N, Steppan S, Pendon-Ruiz de Mier MV, Buendía P, Carmona A, Carracedo J, Alcalá-Díaz JF, Frazao J, Martínez-Moreno JM, Canalejo A, Felsenfeld A, Rodriguez M, Aguilera-Tejero E, Almadén Y, Muñoz-Castañeda JR. Dietary magnesium supplementation prevents and reverses vascular and soft tissue calcifications in uremic rats. Kidney Int 2017; 92:1084-1099. [DOI: 10.1016/j.kint.2017.04.011] [Citation(s) in RCA: 59] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2016] [Revised: 03/21/2017] [Accepted: 04/06/2017] [Indexed: 01/14/2023]
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Moe SM, Wetherill L, Decker BS, Lai D, Abdalla S, Long J, Vatta M, Foroud TM, Chertow GM. Calcium-Sensing Receptor Genotype and Response to Cinacalcet in Patients Undergoing Hemodialysis. Clin J Am Soc Nephrol 2017; 12:1128-1138. [PMID: 28630081 PMCID: PMC5498355 DOI: 10.2215/cjn.11141016] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2016] [Accepted: 03/23/2017] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND OBJECTIVES We tested the hypothesis that single nucleotide polymorphisms (SNPs) in the calcium-sensing receptor (CASR) alter the response to the calcimimetic cinacalcet. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We analyzed DNA samples in the Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) trial, a randomized trial comparing cinacalcet to placebo on a background of usual care. Of the 3883 patients randomized, 1919 (49%) consented to DNA collection, and samples from 1852 participants were genotyped for 18 CASR polymorphisms. The European ancestry (EA; n=1067) and African ancestry (AfAn; n=405) groups were assessed separately. SNPs in CASR were tested for their association with biochemical measures of mineral metabolism at baseline, percent change from baseline to 20 weeks, and risk of clinical fracture as dependent variables. RESULTS There were modest associations of CASR SNPs with increased baseline serum parathyroid hormone and bone alkaline phosphatase primarily with the minor allele in the EA group (all P≤0.03), but not in the AfAn sample. In contrast, there was a modest association of decreased baseline serum calcium and FGF23 with CASR SNPs (P=0.04) primarily with the minor allele in the AfAn but not in the EA sample. The minor allele of two SNPs was associated with decreased percent reduction in parathyroid hormone from baseline to 20 weeks in the EA population (P<0.04) and this was not altered with cinacalcet. In both EA and AfAn, the same SNP (rs9740) was associated with decreased calcium with cinacalcet treatment (EA and AfAn P≤0.03). Three SNPs in high linkage disequilibrium were associated with a higher risk of clinical fracture that was attenuated by cinacalcet treatment in the EA sample (P<0.04). CONCLUSIONS These modest associations, if validated, may provide explanations for differences in CKD-mineral bone disorder observed in EA and AfAn populations, and for differential biochemical responses to calcimimetics.
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Affiliation(s)
- Sharon M. Moe
- Division of Nephrology, Department of Medicine and
- Department of Medicine, Roudebush Veterans Administration Medical Center, Indianapolis, Indiana; and
| | - Leah Wetherill
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana
| | | | - Dongbing Lai
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana
| | - Safa Abdalla
- Division of Nephrology, Department of Medicine, Stanford School of Medicine, Stanford, California
| | - Jin Long
- Division of Nephrology, Department of Medicine, Stanford School of Medicine, Stanford, California
| | - Matteo Vatta
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana
| | - Tatiana M. Foroud
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana
| | - Glenn M. Chertow
- Division of Nephrology, Department of Medicine, Stanford School of Medicine, Stanford, California
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Portillo MR, Rodríguez-Ortiz ME. Secondary Hyperparthyroidism: Pathogenesis, Diagnosis, Preventive and Therapeutic Strategies. Rev Endocr Metab Disord 2017; 18:79-95. [PMID: 28378123 DOI: 10.1007/s11154-017-9421-4] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Uremic secondary hyperparathyroidism is a multifactorial and complex disease often present in advanced stages of chronic kidney disease. The accumulation of phosphate, the increased FGF23 levels, the reduction in active vitamin D production, and the tendency to hypocalcemia are persistent stimuli for the development and progression of parathyroid hyperplasia with increased secretion of PTH. Parathyroid proliferation may become nodular mainly in cases of advanced hyperparathyroidism. The alterations in the regulation of mineral metabolism, the development of bone disease and extraosseous calcifications are essential components of chronic kidney disease-mineral and bone disorder and have been associated with negative outcomes. The management of hyperparathyroidism includes the correction of vitamin D deficiency and control of serum phosphorus and PTH without inducing hypercalcemia. An update of the leading therapeutic tools available for the prevention and clinical management of secondary hyperparathyroidism, its diagnosis, and the main mechanisms and factors involved in the pathogenesis of the disease will be described in this review.
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Affiliation(s)
- Mariano Rodríguez Portillo
- Nephrology Service, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Reina Sofía University Hospital/University of Córdoba, Avda. Menéndez Pidal, S/N, 14004, Córdoba, Spain.
- REDinREN, Madrid, Spain.
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Pasch A, Block GA, Bachtler M, Smith ER, Jahnen-Dechent W, Arampatzis S, Chertow GM, Parfrey P, Ma X, Floege J. Blood Calcification Propensity, Cardiovascular Events, and Survival in Patients Receiving Hemodialysis in the EVOLVE Trial. Clin J Am Soc Nephrol 2017; 12:315-322. [PMID: 27940458 PMCID: PMC5293330 DOI: 10.2215/cjn.04720416] [Citation(s) in RCA: 108] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2016] [Accepted: 10/11/2016] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND OBJECTIVES Patients receiving hemodialysis are at risk of cardiovascular events. A novel blood test (T50 test) determines the individual calcification propensity of blood. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS T50 was determined in 2785 baseline serum samples of patients receiving hemodialysis enrolled in the Evaluation of Cinacalcet Therapy to Lower Cardiovascular Events (EVOLVE) trial and the T50 results were related to patient outcomes. RESULTS Serum albumin, bicarbonate, HDL cholesterol, and creatinine were the main factors positively/directly and phosphate was the main factor negatively/inversely associated with T50. The primary composite end point (all-cause mortality, myocardial infarction [MI], hospitalization for unstable angina, heart failure, or peripheral vascular event [PVE]) was reached in 1350 patients after a median follow-up time of 619 days. After adjustments for confounding, a lower T50 was independently associated with a higher risk of the primary composite end point as a continuous measure (hazard ratio [HR] per 1 SD lower T50, 1.15; 95% confidence interval [95% CI], 1.08 to 1.22; P<0.001). Furthermore, lower T50 was associated with a higher risk in all-cause mortality (HR per 1 SD lower T50, 1.10; 95% CI, 1.02 to 1.17; P=0.001), MI (HR per 1 SD lower T50, 1.38; 95% CI, 1.19 to 1.60; P<0.001), and PVE (HR per 1 SD lower T50, 1.22; 95% CI, 1.05 to 1.42; P=0.01). T50 improved risk prediction (integrated discrimination improvement and net reclassification improvement, P<0.001 and P=0.001) of the primary composite end point. CONCLUSIONS Blood calcification propensity was independently associated with the primary composite end point, all-cause mortality, MI, and PVE in the EVOLVE study and improved risk prediction. Prospective trials should clarify whether T50-guided therapies improve outcomes.
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Affiliation(s)
| | | | | | - Edward R. Smith
- The Royal Melbourne Hospital, Victoria, Melbourne, Australia
| | | | | | | | - Patrick Parfrey
- Health Sciences Center, St. John’s, Newfoundland, Canada; and
| | | | - Juergen Floege
- Rheinisch-Westfaelische Technische Hochschule University of Aachen, Aachen, Germany
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18
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Ribeiro C, Penido MGMG, Guimarães MMM, Tavares MDS, Souza BDN, Leite AF, de Deus LMC, Machado LJDC. Parathyroid ultrasonography and bone metabolic profile of patients on dialysis with hyperparathyroidism. World J Nephrol 2016; 5:437-447. [PMID: 27648407 PMCID: PMC5011250 DOI: 10.5527/wjn.v5.i5.437] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2016] [Revised: 04/12/2016] [Accepted: 06/29/2016] [Indexed: 02/07/2023] Open
Abstract
AIM To evaluate the parathyroid ultrasonography and define parameters that can predict poor response to treatment in patients with secondary hyperparathyroidism due to renal failure.
METHODS This cohort study evaluated 85 patients with chronic kidney disease stage V with parathyroid hormone levels above 800 pg/mL. All patients underwent ultrasonography of the parathyroids and the following parameters were analyzed: Demographic characteristics (etiology of chronic kidney disease, gender, age, dialysis vintage, vascular access, use of vitamin D), laboratory (calcium, phosphorus, parathyroid hormone, alkaline phosphatase, bone alkaline phosphatase), and the occurrence of bone changes, cardiovascular events and death. The χ2 test were used to compare proportions or the Fisher exact test for small sample frequencies. Student t-test was used to detect differences between the two groups regarding continuous variables.
RESULTS Fifty-three patients (66.4%) had parathyroid nodules with higher levels of parathyroid hormone, calcium and phosphorus. Sixteen patients underwent parathyroidectomy and had higher levels of phosphorus and calcium × phosphorus product (P = 0.03 and P = 0.006, respectively). They also had lower mortality (32% vs 68%, P = 0.01) and lower incidence of cardiovascular or cerebrovascular events (27% vs 73%, P = 0.02). Calcium × phosphorus product above 55 mg2/dL2 [RR 1.48 (1.06, 2.08), P = 0.03], presence of vascular calcification [1.33 (1.01, 1.76), P = 0.015] and previous occurrence of vascular events [RR 2.25 (1.27, 3.98), P < 0.001] were risk factors for mortality in this population. There was no association between the occurrence of nodules and mortality.
CONCLUSION The identification of nodules at ultrasonography strengthens the indication for parathyroidectomy in patients with secondary hyperparathyroidism due to renal failure.
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Chen L, Wang K, Yu S, Lai L, Zhang X, Yuan J, Duan W. Long-term mortality after parathyroidectomy among chronic kidney disease patients with secondary hyperparathyroidism: a systematic review and meta-analysis. Ren Fail 2016; 38:1050-8. [PMID: 27198474 DOI: 10.1080/0886022x.2016.1184924] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Parathyroidectomy (PTx) and medical treatments are both recommended for reducing serum intact parathyroid hormone (iPTH) and curing secondary hyperparathyroidism (sHPT) in patients with chronic kidney disease (CKD), but their therapeutic effects on long-term mortality are not well-known. Thus, we aim to assess such therapeutic effect of PTx. Electronic literatures published on Pubmed, Embase, and Cochrane Central Register of Controlled Trials in any language until 27 November 2015 were systematically searched. All literatures that compared outcomes (survival rate or mortality rate) between PTx-treated and medically-treated CKD patients with sHPT were included. Finally, 13 cohort studies involving 22053 patients were included. Data were extracted from all included literatures in a standard form. The outcomes of all-cause and cardiovascular mortalities were assessed using DerSimonian and Laird's random effects model. We find PTx-treated versus medically-treated patients had a 28% reduction in all-cause mortality and a 37% reduction in cardiovascular mortality. Thus, PTx versus medical treatments might reduce the risks of all-cause and cardiovascular mortalities in CKD patients with sHPT. Further studies with prospective and large-sample clinical trials are needed to find out the real effect of PTx and to assess whether mortality rates differ among patterns of PTx.
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Affiliation(s)
- Lin Chen
- a Department of Endocrinology, Yantai Hospital of Traditional Chinese Medicine , Shandong University of Traditional Chinese Medicine , Yantai , Shandong , PR China
| | - Kongbo Wang
- b Department of Interventional Vascular Surgery, Yantai Hospital of Traditional Chinese Medicine , Shandong University of Traditional Chinese Medicine , Yantai , Shandong , PR China
| | - Shanlan Yu
- c Endoscopy Room, Yantai Hospital of Traditional Chinese Medicine , Shandong University of Traditional Chinese Medicine , Yantai , Shandong , PR China
| | - Liping Lai
- d Department of Cardiology , People's Hospital of Shouguang , Weifang , Shandong , PR China
| | - Xiaoping Zhang
- e Department of the PLA , Jinan Military Region Air Force Aftermath Work Office of out-Patient, ENT , Jinan , Shandong , PR China
| | - Jingjing Yuan
- f Department of Endocrinology , The People's Liberation Army 107th Hospital , Yantai , Shandong , PR China
| | - Weifeng Duan
- g Department of Periphery Vascular Surgery, Yantai Hospital of Traditional Chinese Medicine , Shandong University of Traditional Chinese Medicine , Yantai , Shandong , PR China
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20
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The win ratio approach to analyzing composite outcomes: An application to the EVOLVE trial. Contemp Clin Trials 2016; 48:119-24. [DOI: 10.1016/j.cct.2016.04.001] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2015] [Revised: 03/17/2016] [Accepted: 04/05/2016] [Indexed: 10/22/2022]
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Pun PH, Abdalla S, Block GA, Chertow GM, Correa-Rotter R, Dehmel B, Drüeke TB, Floege J, Goodman WG, Herzog CA, London GM, Mahaffey KW, Moe SM, Parfrey PS, Wheeler DC, Middleton JP. Cinacalcet, dialysate calcium concentration, and cardiovascular events in the EVOLVE trial. Hemodial Int 2015; 20:421-31. [PMID: 26564024 DOI: 10.1111/hdi.12382] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Among patients receiving hemodialysis, abnormalities in calcium regulation have been linked to an increased risk of cardiovascular events. Cinacalcet lowers serum calcium concentrations through its effect on parathyroid hormone secretion and has been hypothesized to reduce the risk of cardiovascular events. In observational cohort studies, prescriptions of low dialysate calcium concentration and larger observed serum-dialysate calcium gradients have been associated with higher risks of in-dialysis facility or peri-dialytic sudden cardiac arrest. We performed this study to examine the risks associated with dialysate calcium and serum-dialysate gradients among participants in the Evaluation of Cinacalcet Hydrochloride Therapy to Lower Cardiovascular Events (EVOLVE) trial. In EVOLVE, 3883 hemodialysis patients were randomized 1:1 to cinacalcet or placebo. Dialysate calcium was administered at the discretion of treating physicians. We examined whether baseline dialysate calcium concentration or the serum-dialysate calcium gradient modified the effect of cinacalcet on the following adjudicated endpoints: (1) primary composite endpoint (death or first non-fatal myocardial infarction, hospitalization for unstable angina, heart failure, or peripheral vascular event); (2) cardiovascular death; and (3) sudden death. In EVOLVE, use of higher dialysate calcium concentrations was more prevalent in Europe and Latin America compared with North America. There was a significant fall in serum calcium concentration in the cinacalcet group; dialysate calcium concentrations were changed infrequently in both groups. There was no association between baseline dialysate calcium concentration or serum-dialysate calcium gradient and the endpoints examined. Neither the baseline dialysate calcium nor the serum-dialysate calcium gradient significantly modified the effects of cinacalcet on the outcomes examined. The effects of cinacalcet on cardiovascular death and major cardiovascular events are not altered by the dialysate calcium prescription and serum-dialysate calcium gradient.
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Affiliation(s)
- Patrick H Pun
- Department of Medicine, Duke University, Durham, North Carolina, USA
| | - Safa Abdalla
- Department of Medicine, Stanford University School of Medicine, Palo Alto, California, USA
| | | | - Glenn M Chertow
- Department of Medicine, Stanford University School of Medicine, Palo Alto, California, USA
| | - Ricardo Correa-Rotter
- Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, District Federal, Mexico
| | | | - Tilman B Drüeke
- Inserm Unit 1088, UFR Médecine/Pharmacie, Université de Picardie, Amiens, France
| | - Jürgen Floege
- Department of Nephrology, Universitätsklinikum der RWTH Aachen, Aachen, Germany
| | | | | | - Gerard M London
- Hôpital Manhès, Paris, France.,Indiana University School of Medicine and Roudebush Veterans Administration Medical Center, Indianapolis, Indiana, USA
| | - Kenneth W Mahaffey
- Department of Medicine, Stanford University School of Medicine, Palo Alto, California, USA
| | - Sharon M Moe
- Hôpital Manhès, Paris, France.,Indiana University School of Medicine and Roudebush Veterans Administration Medical Center, Indianapolis, Indiana, USA
| | | | | | - John P Middleton
- Department of Medicine, Duke University, Durham, North Carolina, USA
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Moe SM, Chertow GM, Parfrey PS, Kubo Y, Block GA, Correa-Rotter R, Drüeke TB, Herzog CA, London GM, Mahaffey KW, Wheeler DC, Stolina M, Dehmel B, Goodman WG, Floege J. Cinacalcet, Fibroblast Growth Factor-23, and Cardiovascular Disease in Hemodialysis: The Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) Trial. Circulation 2015; 132:27-39. [PMID: 26059012 DOI: 10.1161/circulationaha.114.013876] [Citation(s) in RCA: 222] [Impact Index Per Article: 22.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2014] [Accepted: 04/22/2015] [Indexed: 11/16/2022]
Abstract
BACKGROUND Patients with kidney disease have disordered bone and mineral metabolism, including elevated serum concentrations of fibroblast growth factor-23 (FGF23). These elevated concentrations are associated with cardiovascular and all-cause mortality. The objective was to determine the effects of the calcimimetic cinacalcet (versus placebo) on reducing serum FGF23 and whether changes in FGF23 are associated with death and cardiovascular events. METHODS AND RESULTS This was a secondary analysis of a randomized clinical trial comparing cinacalcet to placebo in addition to conventional therapy (phosphate binders/vitamin D) in patients receiving hemodialysis with secondary hyperparathyroidism (intact parathyroid hormone ≥300 pg/mL). The primary study end point was time to death or a first nonfatal cardiovascular event (myocardial infarction, hospitalization for angina, heart failure, or a peripheral vascular event). This analysis included 2985 patients (77% of randomized) with serum samples at baseline and 2602 patients (67%) with samples at both baseline and week 20. The results demonstrated that a significantly larger proportion of patients randomized to cinacalcet had ≥30% (68% versus 28%) reductions in FGF23. Among patients randomized to cinacalcet, a ≥30% reduction in FGF23 between baseline and week 20 was associated with a nominally significant reduction in the primary composite end point (relative hazard, 0.82; 95% confidence interval, 0.69-0.98), cardiovascular mortality (relative hazard, 0.66; 95% confidence interval, 0.50-0.87), sudden cardiac death (relative hazard, 0.57; 95% confidence interval, 0.37-0.86), and heart failure (relative hazard, 0.69; 95% confidence interval, 0.48-0.99). CONCLUSIONS Treatment with cinacalcet significantly lowers serum FGF23. Treatment-induced reductions in serum FGF23 are associated with lower rates of cardiovascular death and major cardiovascular events. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00345839.
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Affiliation(s)
- Sharon M Moe
- From Indiana University School of Medicine and Roudebush Veterans Administration Medical Center, Indianapolis (S.M.M.); Stanford University School of Medicine, Palo Alto, CA (G.M.C., K.W.M.); Health Sciences Center, St. John's, NL, Canada (P.S.P.); Amgen Inc, Thousand Oaks, CA (Y.K., M.S., B.D., W.G.G.); Denver Nephrology, CO (G.A.B.); Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico (R.C.-R.); Inserm Unit 1088, UFR Médecine/Pharmacie, Université de Picardie, Amiens, France (T.B.D.); University of Minnesota, Minneapolis (C.A.H.); Hôpital Manhès, Paris, France (G.M.L.); University College London, London, UK (D.C.W.); and Universitätsklinikum der RWTH Aachen, Germany (J.F.).
| | - Glenn M Chertow
- From Indiana University School of Medicine and Roudebush Veterans Administration Medical Center, Indianapolis (S.M.M.); Stanford University School of Medicine, Palo Alto, CA (G.M.C., K.W.M.); Health Sciences Center, St. John's, NL, Canada (P.S.P.); Amgen Inc, Thousand Oaks, CA (Y.K., M.S., B.D., W.G.G.); Denver Nephrology, CO (G.A.B.); Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico (R.C.-R.); Inserm Unit 1088, UFR Médecine/Pharmacie, Université de Picardie, Amiens, France (T.B.D.); University of Minnesota, Minneapolis (C.A.H.); Hôpital Manhès, Paris, France (G.M.L.); University College London, London, UK (D.C.W.); and Universitätsklinikum der RWTH Aachen, Germany (J.F.)
| | - Patrick S Parfrey
- From Indiana University School of Medicine and Roudebush Veterans Administration Medical Center, Indianapolis (S.M.M.); Stanford University School of Medicine, Palo Alto, CA (G.M.C., K.W.M.); Health Sciences Center, St. John's, NL, Canada (P.S.P.); Amgen Inc, Thousand Oaks, CA (Y.K., M.S., B.D., W.G.G.); Denver Nephrology, CO (G.A.B.); Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico (R.C.-R.); Inserm Unit 1088, UFR Médecine/Pharmacie, Université de Picardie, Amiens, France (T.B.D.); University of Minnesota, Minneapolis (C.A.H.); Hôpital Manhès, Paris, France (G.M.L.); University College London, London, UK (D.C.W.); and Universitätsklinikum der RWTH Aachen, Germany (J.F.)
| | - Yumi Kubo
- From Indiana University School of Medicine and Roudebush Veterans Administration Medical Center, Indianapolis (S.M.M.); Stanford University School of Medicine, Palo Alto, CA (G.M.C., K.W.M.); Health Sciences Center, St. John's, NL, Canada (P.S.P.); Amgen Inc, Thousand Oaks, CA (Y.K., M.S., B.D., W.G.G.); Denver Nephrology, CO (G.A.B.); Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico (R.C.-R.); Inserm Unit 1088, UFR Médecine/Pharmacie, Université de Picardie, Amiens, France (T.B.D.); University of Minnesota, Minneapolis (C.A.H.); Hôpital Manhès, Paris, France (G.M.L.); University College London, London, UK (D.C.W.); and Universitätsklinikum der RWTH Aachen, Germany (J.F.)
| | - Geoffrey A Block
- From Indiana University School of Medicine and Roudebush Veterans Administration Medical Center, Indianapolis (S.M.M.); Stanford University School of Medicine, Palo Alto, CA (G.M.C., K.W.M.); Health Sciences Center, St. John's, NL, Canada (P.S.P.); Amgen Inc, Thousand Oaks, CA (Y.K., M.S., B.D., W.G.G.); Denver Nephrology, CO (G.A.B.); Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico (R.C.-R.); Inserm Unit 1088, UFR Médecine/Pharmacie, Université de Picardie, Amiens, France (T.B.D.); University of Minnesota, Minneapolis (C.A.H.); Hôpital Manhès, Paris, France (G.M.L.); University College London, London, UK (D.C.W.); and Universitätsklinikum der RWTH Aachen, Germany (J.F.)
| | - Ricardo Correa-Rotter
- From Indiana University School of Medicine and Roudebush Veterans Administration Medical Center, Indianapolis (S.M.M.); Stanford University School of Medicine, Palo Alto, CA (G.M.C., K.W.M.); Health Sciences Center, St. John's, NL, Canada (P.S.P.); Amgen Inc, Thousand Oaks, CA (Y.K., M.S., B.D., W.G.G.); Denver Nephrology, CO (G.A.B.); Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico (R.C.-R.); Inserm Unit 1088, UFR Médecine/Pharmacie, Université de Picardie, Amiens, France (T.B.D.); University of Minnesota, Minneapolis (C.A.H.); Hôpital Manhès, Paris, France (G.M.L.); University College London, London, UK (D.C.W.); and Universitätsklinikum der RWTH Aachen, Germany (J.F.)
| | - Tilman B Drüeke
- From Indiana University School of Medicine and Roudebush Veterans Administration Medical Center, Indianapolis (S.M.M.); Stanford University School of Medicine, Palo Alto, CA (G.M.C., K.W.M.); Health Sciences Center, St. John's, NL, Canada (P.S.P.); Amgen Inc, Thousand Oaks, CA (Y.K., M.S., B.D., W.G.G.); Denver Nephrology, CO (G.A.B.); Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico (R.C.-R.); Inserm Unit 1088, UFR Médecine/Pharmacie, Université de Picardie, Amiens, France (T.B.D.); University of Minnesota, Minneapolis (C.A.H.); Hôpital Manhès, Paris, France (G.M.L.); University College London, London, UK (D.C.W.); and Universitätsklinikum der RWTH Aachen, Germany (J.F.)
| | - Charles A Herzog
- From Indiana University School of Medicine and Roudebush Veterans Administration Medical Center, Indianapolis (S.M.M.); Stanford University School of Medicine, Palo Alto, CA (G.M.C., K.W.M.); Health Sciences Center, St. John's, NL, Canada (P.S.P.); Amgen Inc, Thousand Oaks, CA (Y.K., M.S., B.D., W.G.G.); Denver Nephrology, CO (G.A.B.); Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico (R.C.-R.); Inserm Unit 1088, UFR Médecine/Pharmacie, Université de Picardie, Amiens, France (T.B.D.); University of Minnesota, Minneapolis (C.A.H.); Hôpital Manhès, Paris, France (G.M.L.); University College London, London, UK (D.C.W.); and Universitätsklinikum der RWTH Aachen, Germany (J.F.)
| | - Gerard M London
- From Indiana University School of Medicine and Roudebush Veterans Administration Medical Center, Indianapolis (S.M.M.); Stanford University School of Medicine, Palo Alto, CA (G.M.C., K.W.M.); Health Sciences Center, St. John's, NL, Canada (P.S.P.); Amgen Inc, Thousand Oaks, CA (Y.K., M.S., B.D., W.G.G.); Denver Nephrology, CO (G.A.B.); Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico (R.C.-R.); Inserm Unit 1088, UFR Médecine/Pharmacie, Université de Picardie, Amiens, France (T.B.D.); University of Minnesota, Minneapolis (C.A.H.); Hôpital Manhès, Paris, France (G.M.L.); University College London, London, UK (D.C.W.); and Universitätsklinikum der RWTH Aachen, Germany (J.F.)
| | - Kenneth W Mahaffey
- From Indiana University School of Medicine and Roudebush Veterans Administration Medical Center, Indianapolis (S.M.M.); Stanford University School of Medicine, Palo Alto, CA (G.M.C., K.W.M.); Health Sciences Center, St. John's, NL, Canada (P.S.P.); Amgen Inc, Thousand Oaks, CA (Y.K., M.S., B.D., W.G.G.); Denver Nephrology, CO (G.A.B.); Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico (R.C.-R.); Inserm Unit 1088, UFR Médecine/Pharmacie, Université de Picardie, Amiens, France (T.B.D.); University of Minnesota, Minneapolis (C.A.H.); Hôpital Manhès, Paris, France (G.M.L.); University College London, London, UK (D.C.W.); and Universitätsklinikum der RWTH Aachen, Germany (J.F.)
| | - David C Wheeler
- From Indiana University School of Medicine and Roudebush Veterans Administration Medical Center, Indianapolis (S.M.M.); Stanford University School of Medicine, Palo Alto, CA (G.M.C., K.W.M.); Health Sciences Center, St. John's, NL, Canada (P.S.P.); Amgen Inc, Thousand Oaks, CA (Y.K., M.S., B.D., W.G.G.); Denver Nephrology, CO (G.A.B.); Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico (R.C.-R.); Inserm Unit 1088, UFR Médecine/Pharmacie, Université de Picardie, Amiens, France (T.B.D.); University of Minnesota, Minneapolis (C.A.H.); Hôpital Manhès, Paris, France (G.M.L.); University College London, London, UK (D.C.W.); and Universitätsklinikum der RWTH Aachen, Germany (J.F.)
| | - Maria Stolina
- From Indiana University School of Medicine and Roudebush Veterans Administration Medical Center, Indianapolis (S.M.M.); Stanford University School of Medicine, Palo Alto, CA (G.M.C., K.W.M.); Health Sciences Center, St. John's, NL, Canada (P.S.P.); Amgen Inc, Thousand Oaks, CA (Y.K., M.S., B.D., W.G.G.); Denver Nephrology, CO (G.A.B.); Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico (R.C.-R.); Inserm Unit 1088, UFR Médecine/Pharmacie, Université de Picardie, Amiens, France (T.B.D.); University of Minnesota, Minneapolis (C.A.H.); Hôpital Manhès, Paris, France (G.M.L.); University College London, London, UK (D.C.W.); and Universitätsklinikum der RWTH Aachen, Germany (J.F.)
| | - Bastian Dehmel
- From Indiana University School of Medicine and Roudebush Veterans Administration Medical Center, Indianapolis (S.M.M.); Stanford University School of Medicine, Palo Alto, CA (G.M.C., K.W.M.); Health Sciences Center, St. John's, NL, Canada (P.S.P.); Amgen Inc, Thousand Oaks, CA (Y.K., M.S., B.D., W.G.G.); Denver Nephrology, CO (G.A.B.); Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico (R.C.-R.); Inserm Unit 1088, UFR Médecine/Pharmacie, Université de Picardie, Amiens, France (T.B.D.); University of Minnesota, Minneapolis (C.A.H.); Hôpital Manhès, Paris, France (G.M.L.); University College London, London, UK (D.C.W.); and Universitätsklinikum der RWTH Aachen, Germany (J.F.)
| | - William G Goodman
- From Indiana University School of Medicine and Roudebush Veterans Administration Medical Center, Indianapolis (S.M.M.); Stanford University School of Medicine, Palo Alto, CA (G.M.C., K.W.M.); Health Sciences Center, St. John's, NL, Canada (P.S.P.); Amgen Inc, Thousand Oaks, CA (Y.K., M.S., B.D., W.G.G.); Denver Nephrology, CO (G.A.B.); Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico (R.C.-R.); Inserm Unit 1088, UFR Médecine/Pharmacie, Université de Picardie, Amiens, France (T.B.D.); University of Minnesota, Minneapolis (C.A.H.); Hôpital Manhès, Paris, France (G.M.L.); University College London, London, UK (D.C.W.); and Universitätsklinikum der RWTH Aachen, Germany (J.F.)
| | - Jürgen Floege
- From Indiana University School of Medicine and Roudebush Veterans Administration Medical Center, Indianapolis (S.M.M.); Stanford University School of Medicine, Palo Alto, CA (G.M.C., K.W.M.); Health Sciences Center, St. John's, NL, Canada (P.S.P.); Amgen Inc, Thousand Oaks, CA (Y.K., M.S., B.D., W.G.G.); Denver Nephrology, CO (G.A.B.); Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico (R.C.-R.); Inserm Unit 1088, UFR Médecine/Pharmacie, Université de Picardie, Amiens, France (T.B.D.); University of Minnesota, Minneapolis (C.A.H.); Hôpital Manhès, Paris, France (G.M.L.); University College London, London, UK (D.C.W.); and Universitätsklinikum der RWTH Aachen, Germany (J.F.)
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23
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Moe SM, Abdalla S, Chertow GM, Parfrey PS, Block GA, Correa-Rotter R, Floege J, Herzog CA, London GM, Mahaffey KW, Wheeler DC, Dehmel B, Goodman WG, Drüeke TB. Effects of Cinacalcet on Fracture Events in Patients Receiving Hemodialysis: The EVOLVE Trial. J Am Soc Nephrol 2015; 26:1466-75. [PMID: 25505257 PMCID: PMC4446874 DOI: 10.1681/asn.2014040414] [Citation(s) in RCA: 136] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2014] [Accepted: 09/07/2014] [Indexed: 11/03/2022] Open
Abstract
Fractures are frequent in patients receiving hemodialysis. We tested the hypothesis that cinacalcet would reduce the rate of clinical fractures in patients receiving hemodialysis using data from the Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events trial, a placebo-controlled trial that randomized 3883 hemodialysis patients with secondary hyperparathyroidism to receive cinacalcet or placebo for ≤64 months. This study was a prespecified secondary analysis of the trial whose primary end point was all-cause mortality and non-fatal cardiovascular events, and one of the secondary end points was first clinical fracture event. Clinical fractures were observed in 255 of 1935 (13.2%) patients randomized to placebo and 238 of 1948 (12.2%) patients randomized to cinacalcet. In an unadjusted intention-to-treat analysis, the relative hazard for fracture (cinacalcet versus placebo) was 0.89 (95% confidence interval [95% CI], 0.75 to 1.07). After adjustment for baseline characteristics and multiple fractures, the relative hazard was 0.83 (95% CI, 0.72 to 0.98). Using a prespecified lag-censoring analysis (a measure of actual drug exposure), the relative hazard for fracture was 0.72 (95% CI, 0.58 to 0.90). When participants were censored at the time of cointerventions (parathyroidectomy, transplant, or provision of commercial cinacalcet), the relative hazard was 0.71 (95% CI, 0.58 to 0.87). Fracture rates were higher in older compared with younger patients and the effect of cinacalcet appeared more pronounced in older patients. In conclusion, using an unadjusted intention-to-treat analysis, cinacalcet did not reduce the rate of clinical fracture. However, when accounting for differences in baseline characteristics, multiple fractures, and/or events prompting discontinuation of study drug, cinacalcet reduced the rate of clinical fracture by 16%-29%.
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Affiliation(s)
- Sharon M Moe
- Indiana University School of Medicine and Roudebush Veterans Administration Medical Center, Indianapolis, Indiana;
| | - Safa Abdalla
- Stanford University School of Medicine, Palo Alto, California
| | - Glenn M Chertow
- Stanford University School of Medicine, Palo Alto, California
| | | | | | - Ricardo Correa-Rotter
- Salvador Zubirán National Institute of Medical Sciences and Nutrition, Mexico City, Mexico
| | | | | | | | | | | | | | | | - Tilman B Drüeke
- French Institute of Health and Medical Research (INSERM) Unit 1088, Faculty of Medicine/Pharmacy, University of Picardie, Amiens, France
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24
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Gillespie IA, Floege J, Gioni I, Drüeke TB, de Francisco AL, Anker SD, Kubo Y, Wheeler DC, Froissart M. Propensity score matching and persistence correction to reduce bias in comparative effectiveness: the effect of cinacalcet use on all-cause mortality. Pharmacoepidemiol Drug Saf 2015; 24:738-47. [PMID: 26011775 PMCID: PMC5033013 DOI: 10.1002/pds.3789] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2014] [Revised: 03/25/2015] [Accepted: 03/30/2015] [Indexed: 12/25/2022]
Abstract
Purpose The generalisability of randomised controlled trials (RCTs) may be limited by restrictive entry criteria or by their experimental nature. Observational research can provide complementary findings but is prone to bias. Employing propensity score matching, to reduce such bias, we compared the real‐life effect of cinacalcet use on all‐cause mortality (ACM) with findings from the Evaluation of Cinacalcet Therapy to Lower Cardiovascular Events (EVOLVE) RCT in chronic haemodialysis patients. Methods Incident adult haemodialysis patients receiving cinacalcet, recruited in a prospective observational cohort from 2007–2009 (AROii; n = 10,488), were matched to non‐exposed patients regardless of future exposure status. The effect of treatment crossover was investigated with inverse probability of censoring weighted and lag‐censored analyses. EVOLVE ACM data were analysed largely as described for the primary composite endpoint. Results AROii patients receiving cinacalcet (n = 532) were matched to 1790 non‐exposed patients. The treatment effect of cinacalcet on ACM in the main AROii analysis (hazard ratio 1.03 [95% confidence interval (CI) 0.78–1.35]) was closer to the null than for the Intention to Treat (ITT) analysis of EVOLVE (0.94 [95%CI 0.85–1.04]). Adjusting for non‐persistence by 0‐ and 6‐month lag‐censoring and by inverse probability of censoring weight, the hazard ratios in AROii (0.76 [95%CI 0.51–1.15], 0.84 [95%CI 0.60–1.18] and 0.79 [95%CI 0.56–1.11], respectively) were comparable with those of EVOLVE (0.82 [95%CI 0.67–1.01], 0.83 [95%CI 0.73–0.96] and 0.87 [95%CI 0.71–1.06], respectively). Conclusions Correcting for treatment crossover, we observed results in the ‘real‐life’ setting of the AROii observational cohort that closely mirrored the results of the EVOLVE RCT. Persistence‐corrected analyses revealed a trend towards reduced ACM in haemodialysis patients receiving cinacalcet therapy. © 2015 The Authors. Pharmacoepidemiology and Drug Safety Published by John Wiley & Sons Ltd.
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Affiliation(s)
| | - Jürgen Floege
- Division of Nephrology, Medizinische Klinik II, RWTH University Hospital Aachen, Aachen, Germany
| | | | - Tilman B Drüeke
- Inserm Unit 1088, UFR de Médecine et de Pharmacie, Université de Picardie, Amiens, France
| | - Angel L de Francisco
- Servicio de Nefrología, Hospital Universitario Valdecilla, Universidad de Cantabria, Santander, Spain
| | - Stefan D Anker
- Department of Innovative Clinical Trials, University Medical Centre Göttingen, Göttingen, Germany
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25
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Floege J, Kubo Y, Floege A, Chertow GM, Parfrey PS. The Effect of Cinacalcet on Calcific Uremic Arteriolopathy Events in Patients Receiving Hemodialysis: The EVOLVE Trial. Clin J Am Soc Nephrol 2015; 10:800-7. [PMID: 25887067 DOI: 10.2215/cjn.10221014] [Citation(s) in RCA: 86] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2014] [Accepted: 12/07/2014] [Indexed: 12/16/2022]
Abstract
BACKGROUND AND OBJECTIVES Uncontrolled secondary hyperparathyroidism (sHPT) in patients with ESRD is a risk factor for calcific uremic arteriolopathy (CUA; calciphylaxis). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Adverse event reports collected during the Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events trial were used to determine the frequency of CUA in patients receiving hemodialysis who had moderate to severe sHPT, as well as the effects of cinacalcet versus placebo. CUA events were collected while patients were receiving the study drug. RESULTS Among the 3861 trial patients who received at least one dose of the study drug, 18 patients randomly assigned to placebo and six assigned to cinacalcet developed CUA (unadjusted relative hazard, 0.31; 95% confidence interval [95% CI], 0.13 to 0.79; P=0.014). Corresponding cumulative event rates (95% CI) at year 4 were 0.011% (0.006% to 0.018%) and 0.005% (0.002% to 0.010%). By multivariable analysis, other factors associated with CUA included female sex, higher body mass index, higher diastolic BP, and history of dyslipidemia or parathyroidectomy. Median (10%, 90% percentile) plasma parathyroid hormone concentrations proximal to the report of CUA were 796 (225, 2093) pg/ml and 410 (71, 4957) pg/ml in patients randomly assigned to placebo and cinacalcet, respectively. Active use of vitamin K antagonists was recorded in 11 of 24 patients with CUA, nine randomly assigned to placebo, and two to cinacalcet, in contrast to 5%-7% at any one time point in patients in whom CUA was not reported. CONCLUSION Cinacalcet appeared to reduce the incidence of CUA in hemodialysis recipients who have moderate to severe sHPT.
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Affiliation(s)
- Jürgen Floege
- Division of Nephrology, RWTH University of Aachen, Aachen, Germany;
| | - Yumi Kubo
- Amgen Inc., Thousand Oaks, California
| | - Anna Floege
- Division of Nephrology, RWTH University of Aachen, Aachen, Germany
| | - Glenn M Chertow
- Division of Nephrology, Department of Medicine, Stanford University School of Medicine, Palo Alto, California; and
| | - Patrick S Parfrey
- Department of Medicine, Memorial University, St. John's, Newfoundland, Canada
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26
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Kubo Y, Sterling LR, Parfrey PS, Gill K, Mahaffey KW, Gioni I, Trotman ML, Dehmel B, Chertow GM. Assessing the treatment effect in a randomized controlled trial with extensive non-adherence: the EVOLVE trial. Pharm Stat 2015; 14:242-51. [PMID: 25851955 DOI: 10.1002/pst.1680] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2014] [Revised: 01/15/2015] [Accepted: 03/06/2015] [Indexed: 11/06/2022]
Abstract
Intention-to-treat (ITT) analysis is widely used to establish efficacy in randomized clinical trials. However, in a long-term outcomes study where non-adherence to study drug is substantial, the on-treatment effect of the study drug may be underestimated using the ITT analysis. The analyses presented herein are from the EVOLVE trial, a double-blind, placebo-controlled, event-driven cardiovascular outcomes study conducted to assess whether a treatment regimen including cinacalcet compared with placebo in addition to other conventional therapies reduces the risk of mortality and major cardiovascular events in patients receiving hemodialysis with secondary hyperparathyroidism. Pre-specified sensitivity analyses were performed to assess the impact of non-adherence on the estimated effect of cinacalcet. These analyses included lag-censoring, inverse probability of censoring weights (IPCW), rank preserving structural failure time model (RPSFTM) and iterative parameter estimation (IPE). The relative hazard (cinacalcet versus placebo) of mortality and major cardiovascular events was 0.93 (95% confidence interval 0.85, 1.02) using the ITT analysis; 0.85 (0.76, 0.95) using lag-censoring analysis; 0.81 (0.70, 0.92) using IPCW; 0.85 (0.66, 1.04) using RPSFTM and 0.85 (0.75, 0.96) using IPE. These analyses, while not providing definitive evidence, suggest that the intervention may have an effect while subjects are receiving treatment. The ITT method remains the established method to evaluate efficacy of a new treatment; however, additional analyses should be considered to assess the on-treatment effect when substantial non-adherence to study drug is expected or observed.
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Parfrey PS, Drüeke TB, Block GA, Correa-Rotter R, Floege J, Herzog CA, London GM, Mahaffey KW, Moe SM, Wheeler DC, Kubo Y, Dehmel B, Goodman WG, Chertow GM. The Effects of Cinacalcet in Older and Younger Patients on Hemodialysis: The Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) Trial. Clin J Am Soc Nephrol 2015; 10:791-9. [PMID: 25710802 DOI: 10.2215/cjn.07730814] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2014] [Accepted: 01/20/2015] [Indexed: 11/23/2022]
Abstract
BACKGROUND AND OBJECTIVES The calcimimetic cinacalcet reduced the risk of death or cardiovascular (CV) events in older, but not younger, patients with moderate to severe secondary hyperparathyroidism (HPT) who were receiving hemodialysis. To determine whether the lower risk in younger patients might be due to lower baseline CV risk and more frequent use of cointerventions that reduce parathyroid hormone (kidney transplantation, parathyroidectomy, and commercial cinacalcet use), this study examined the effects of cinacalcet in older (≥65 years, n=1005) and younger (<65 years, n=2878) patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) was a global, multicenter, randomized placebo-controlled trial in 3883 prevalent patients on hemodialysis, whose outcomes included death, major CV events, and development of severe unremitting HPT. The age subgroup analysis was prespecified. RESULTS Older patients had higher baseline prevalence of diabetes mellitus and CV comorbidity. Annualized rates of kidney transplantation and parathyroidectomy were >3-fold higher in younger relative to older patients and were more frequent in patients randomized to placebo. In older patients, the adjusted relative hazard (95% confidence interval) for the primary composite (CV) end point (cinacalcet versus placebo) was 0.70 (0.60 to 0.81); in younger patients, the relative hazard was 0.97 (0.86 to 1.09). Corresponding adjusted relative hazards for mortality were 0.68 (0.51 to 0.81) and 0.99 (0.86 to 1.13). Reduction in the risk of severe unremitting HPT was similar in both groups. CONCLUSIONS In the EVOLVE trial, cinacalcet decreased the risk of death and of major CV events in older, but not younger, patients with moderate to severe HPT who were receiving hemodialysis. Effect modification by age may be partly explained by differences in underlying CV risk and differential application of cointerventions that reduce parathyroid hormone.
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Affiliation(s)
- Patrick S Parfrey
- Department of Medicine, Health Sciences Center, St. John's, Newfoundland, Canada;
| | - Tilman B Drüeke
- French Institute of Health and Medical Research Unit 1088, Faculty of Medicine and Pharmacy, University of Picardie, Amiens, France
| | | | - Ricardo Correa-Rotter
- Department of Nephrology and Mineral Metabolism, Salvador Zubirán National Institute of Health Sciences and Nutrition, Mexico City, Mexico
| | - Jürgen Floege
- Department of Nephrology, RWTH Aachen University Hospital, Aachen, Germany
| | - Charles A Herzog
- Department of Internal Medicine, University of Minnesota, Minneapolis, Minnesota
| | | | - Kenneth W Mahaffey
- Department of Medicine, Stanford University School of Medicine, Palo Alto, California
| | - Sharon M Moe
- Department of Medicine, Indiana University School of Medicine and Roudebush Veterans Administration Medical Center, Indianapolis, Indiana
| | - David C Wheeler
- Centre for Nephrology, University College London, United Kingdom; and
| | - Yumi Kubo
- Amgen Inc, Thousand Oaks, California
| | | | | | - Glenn M Chertow
- Department of Medicine, Stanford University School of Medicine, Palo Alto, California
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28
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Ballinger AE, Palmer SC, Nistor I, Craig JC, Strippoli GFM. Calcimimetics for secondary hyperparathyroidism in chronic kidney disease patients. Cochrane Database Syst Rev 2014; 2014:CD006254. [PMID: 25490118 PMCID: PMC10614033 DOI: 10.1002/14651858.cd006254.pub2] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
BACKGROUND Calcimimetic agents lower abnormal serum parathyroid hormone (PTH) levels in people who have chronic kidney disease (CKD), but the benefits and harms on patient-level outcomes are uncertain. Since this review was first published in 2006 showing that evidence for calcimimetics was largely restricted to biochemical outcomes, additional studies have been conducted. This is an update of a review first published in 2006. OBJECTIVES To evaluate the benefits and harms of cinacalcet on patient-level outcomes in adults with CKD. SEARCH METHODS MEDLINE, EMBASE, CENTRAL and conference proceedings were searched for randomised controlled trials (RCTs) evaluating any calcimimetic against placebo or another agent in adults with CKD (persistent albuminuria > 30 mg/g with or without reduced glomerular filtration rate (GFR) (below 60 mL/min/1.73 m²)). We updated searches to 7 February 2013 including the Cochrane Renal Group's Specialised Register to complete this update. SELECTION CRITERIA We included all RCTs of a calcimimetic administered to patients with CKD for the treatment of elevated serum PTH levels. DATA COLLECTION AND ANALYSIS Data were extracted on all relevant patient-centred and surrogate outcomes. We summarised treatment estimates using random effects and expressed treatment effects as a risk ratio (RR) or mean difference (MD) with 95% confidence intervals (CI). MAIN RESULTS Eighteen studies (7446 participants) compared cinacalcet in addition to standard therapy with no treatment or placebo plus standard therapy. In adults with GFR category G5 (GFR below 15 mL/min/1.73 m²) treated with dialysis, routine cinacalcet treatment had little or no effect on all-cause mortality (RR 0.97, 95% CI 0.89 to 1.05), imprecise effects on cardiovascular mortality (RR 0.67, 95% CI 0.16 to 2.87), and prevented surgical parathyroidectomy (RR 0.49, 95% CI 0.40 to 0.59) and hypercalcaemia (RR 0.23, 95% CI 0.05 to 0.97), but increased hypocalcaemia (RR 6.98, 95% CI 5.10 to 9.53), nausea (RR 2.02, 95% CI 1.45 to 2.81) and vomiting (RR 1.97, 95% CI 95% CI 1.73 to 2.24). Cinacalcet decreased serum PTH (MD -281.39 pg/mL, 95% CI -325.84 to -234.94) and calcium (MD -0.87 mg/dL, 95% CI -0.96 to -0.77) levels, but had little or no effect on serum phosphorous levels (MD -0.23 mg/dL, 95% CI -0.58 to 0.12).Data were sparse for adults with GFR categories G3a to G4 (GFR 15 to 60 mL/min/1.73 m²) and kidney transplant recipients.Overall, based on GRADE criteria, evidence for cinacalcet in adults with GFR category G5 treated with dialysis (mortality, parathyroidectomy, hypocalcaemia, and nausea) is of high or moderate quality. High quality evidence suggests "further research is very unlikely to change our confidence in the estimate of treatment effect" and moderate quality evidence is "further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate". Information for adults with less severe CKD GFR category G3a to G4 is of low or very low quality. This means that further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate AUTHORS' CONCLUSIONS Routine cinacalcet therapy reduced the need for parathyroidectomy in adults treated with dialysis and elevated PTH levels but does not improve all-cause or cardiovascular mortality. Cinacalcet increases risks of nausea, vomiting and hypocalcaemia, suggesting harms may outweigh benefits in this population.
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Affiliation(s)
- Angela E Ballinger
- University of Otago ChristchurchDepartment of Medicine2 Riccarton AveChristchurchNew Zealand8041
| | - Suetonia C Palmer
- University of Otago ChristchurchDepartment of Medicine2 Riccarton AveChristchurchNew Zealand8041
| | - Ionut Nistor
- "Gr. T. Popa" University of Medicine and PharmacyNephrology DepartmentBdul Carol I, No 50IasiIasiRomania700503
- Ghent University HospitalEuropean Renal Best Practice Methods Support TeamGhentBelgium
| | - Jonathan C Craig
- The University of SydneySydney School of Public HealthEdward Ford Building A27SydneyNSWAustralia2006
- The Children's Hospital at WestmeadCochrane Renal Group, Centre for Kidney ResearchWestmeadNSWAustralia2145
| | - Giovanni FM Strippoli
- The University of SydneySydney School of Public HealthEdward Ford Building A27SydneyNSWAustralia2006
- The Children's Hospital at WestmeadCochrane Renal Group, Centre for Kidney ResearchWestmeadNSWAustralia2145
- University of BariDepartment of Emergency and Organ TransplantationBariItaly70100
- Mario Negri Sud ConsortiumDepartment of Clinical Pharmacology and EpidemiologySanta Maria ImbaroItaly
- DiaverumMedical‐Scientific OfficeLundSweden
- Amedeo Avogadro University of Eastern PiedmontDivision of Nephrology and Transplantation, Department of Translational MedicineNovaraItaly28100
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29
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Wheeler DC, London GM, Parfrey PS, Block GA, Correa-Rotter R, Dehmel B, Drüeke TB, Floege J, Kubo Y, Mahaffey KW, Goodman WG, Moe SM, Trotman ML, Abdalla S, Chertow GM, Herzog CA. Effects of cinacalcet on atherosclerotic and nonatherosclerotic cardiovascular events in patients receiving hemodialysis: the EValuation Of Cinacalcet HCl Therapy to Lower CardioVascular Events (EVOLVE) trial. J Am Heart Assoc 2014; 3:e001363. [PMID: 25404192 PMCID: PMC4338730 DOI: 10.1161/jaha.114.001363] [Citation(s) in RCA: 87] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Background Premature cardiovascular disease limits the duration and quality of life on long‐term hemodialysis. The objective of this study was to define the frequency of fatal and nonfatal cardiovascular events attributable to atherosclerotic and nonatherosclerotic mechanisms, risk factors for these events, and the effects of cinacalcet, using adjudicated data collected during the EValuation of Cinacalcet HCl Therapy to Lower CardioVascular Events (EVOLVE) Trial. Methods and Results EVOLVE was a randomized, double‐blind, placebo‐controlled clinical trial that randomized 3883 hemodialysis patients with moderate to severe secondary hyperparathyroidism to cinacalcet or matched placebo for up to 64 months. For this post hoc analysis, the outcome measure was fatal and nonfatal cardiovascular events reflecting atherosclerotic and nonatherosclerotic cardiovascular diseases. During the trial, 1518 patients experienced an adjudicated cardiovascular event, including 958 attributable to nonatherosclerotic disease. Of 1421 deaths during the trial, 768 (54%) were due to cardiovascular disease. Sudden death was the most frequent fatal cardiovascular event, accounting for 24.5% of overall mortality. Combining fatal and nonfatal cardiovascular events, randomization to cinacalcet reduced the rates of sudden death and heart failure. Patients randomized to cinacalcet experienced fewer nonatherosclerotic cardiovascular events (adjusted relative hazard 0.84, 95% CI 0.74 to 0.96), while the effect of cinacalcet on atherosclerotic events did not reach statistical significance. Conclusions Accepting the limitations of post hoc analysis, any benefits of cinacalcet on cardiovascular disease in the context of hemodialysis may result from attenuation of nonatherosclerotic processes. Clinical Trials Registration Unique identifier: NCT00345839. URL: ClinicalTrials.gov.
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Affiliation(s)
| | | | | | | | - Ricardo Correa-Rotter
- Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico (R.C.R.)
| | - Bastian Dehmel
- Amgen, Inc, Thousand Oaks, CA (B.D., Y.K., W.G.G., M.L.T.)
| | - Tilman B Drüeke
- Inserm Unit 1088, UFR Médecine/Pharmacie, Université de Picardie, Amiens, France (T.B.D.)
| | - Jürgen Floege
- Universitätsklinikum der RWTH Aachen, Aachen, Germany (F.)
| | - Yumi Kubo
- Amgen, Inc, Thousand Oaks, CA (B.D., Y.K., W.G.G., M.L.T.)
| | - Kenneth W Mahaffey
- Stanford University School of Medicine, Palo Alto, CA (K.W.M., S.A., G.M.C.)
| | | | - Sharon M Moe
- Indiana University School of Medicine, Roudebush Veterans Administration Medical Center, Indianapolis, IN (S.M.M.)
| | | | - Safa Abdalla
- Stanford University School of Medicine, Palo Alto, CA (K.W.M., S.A., G.M.C.)
| | - Glenn M Chertow
- Stanford University School of Medicine, Palo Alto, CA (K.W.M., S.A., G.M.C.)
| | - Charles A Herzog
- Hennepin County Medical Center, University of Minnesota, Minneapolis, MN (C.A.H.)
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Goldsmith D, Covic A. The EVOLVE study is negative, so what does this 'bitter pill' of disappointment mean now for renal patients? Int J Clin Pract 2014; 68:286-9. [PMID: 24588948 DOI: 10.1111/ijcp.12261] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
The extremely high morbidity and mortality experienced by subjects with chronic kidney disease (CKD) has often been described and reviewed, but this familiarity should not breed indifference to the huge burden of premature cardiovascular disease – something which becomes more obvious, but increasingly challenging to treat, as GFR declines, or proteinuria increases. The health outcomes for a middle-aged person entering renal replacement therapy are as bad as those seen with a major solid organ malignancy; while there has been modest progress in improving outcomes over the last two decades, the diagnosis of significant or progressive CKD should and thus still does continue to cast a shadow over patients, carers and healthcare professionals alike.
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Affiliation(s)
- D Goldsmith
- Nephrology, Guy's Hospital, King's Health Partners, London, UK
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Parfrey PS, Chertow GM, Block GA, Correa-Rotter R, Drüeke TB, Floege J, Herzog CA, London GM, Mahaffey KW, Moe SM, Wheeler DC, Dehmel B, Trotman ML, Modafferi DM, Goodman WG. The clinical course of treated hyperparathyroidism among patients receiving hemodialysis and the effect of cinacalcet: the EVOLVE trial. J Clin Endocrinol Metab 2013; 98:4834-44. [PMID: 24108314 DOI: 10.1210/jc.2013-2975] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
CONTEXT The clinical course of secondary hyperparathyroidism (sHPT) in patients on hemodialysis is not well described, and the effect of the calcimimetic cinacalcet on disease progression is uncertain. OBJECTIVE Our objective was to describe 1) the clinical course of sHPT in patients treated with phosphate binders and/or vitamin D sterols and 2) the impact of cinacalcet on the occurrence of severe unremitting HPT, defined by the persistence of markedly elevated PTH concentrations together with hypercalcemia or parathyroidectomy (PTX). DESIGN AND SETTING This was a randomized, double-blind, placebo-controlled, global, multicenter clinical trial. PATIENTS Of 5755 patients screened with moderate to severe sHPT, 3883 patients on hemodialysis were included in the trial. MAIN OUTCOME MEASURES Outcomes included PTX; severe, unremitting HPT; and use of commercial cinacalcet (a protocol violation). INTERVENTION Intervention was cinacalcet (30-180 mg daily) or placebo for up to 64 months. RESULTS In the 1935 patients randomized to placebo, 278 patients (14%) underwent PTX (median PTH 1872 pg/mL within the previous 12 weeks from surgery). Age, sex, geographic region, co-morbidity, calcium-containing phosphate binder use, and baseline serum calcium, phosphorus, and PTH concentrations were associated with PTX. Commercial cinacalcet was started in 443 (23%) patients (median PTH 1108 pg/mL before treatment began). Severe unremitting HPT developed in 470 patients (24%). In a multivariable Cox model, the relative hazard (comparing patients randomized to cinacalcet versus placebo) of severe unremitting HPT was 0.31 (95% confidence interval = 0.26-0.37). The relative hazard differed little when adjusted by baseline clinical characteristics. CONCLUSIONS Severe unremitting HPT develops frequently in patients on hemodialysis despite conventional therapy, and cinacalcet substantially reduces its occurrence.
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Affiliation(s)
- Patrick S Parfrey
- MD, Health Sciences Center, Memorial University, St John's, Newfoundland, Canada A1B 3V6.
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Moe SM, Thadhani R. What have we learned about chronic kidney disease-mineral bone disorder from the EVOLVE and PRIMO trials? Curr Opin Nephrol Hypertens 2013; 22:651-5. [PMID: 24100218 PMCID: PMC3983668 DOI: 10.1097/mnh.0b013e328365b3a3] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
PURPOSE OF REVIEW The treatment of chronic kidney disease-mineral bone disorder (CKD-MBD) has traditionally focused on improvement in biochemical parameters of the disease. However, studies evaluating hard clinical end points or surrogate end points are limited. RECENT FINDINGS Two randomized controlled trials have recently been published. In the EVOLVE study (Evaluation of Cinacalcet Hydrochloride Therapy to Lower Cardiovascular Events), cinacalcet was compared with placebo in 3883 haemodialysis patients with secondary hyperparathyroidism. The primary end point (death, myocardial infarction, unstable angina, heart failure or peripheral vascular disease) in an unadjusted intention-to-treat analysis was not significant [hazard ratio 0.93; 95% confidence interval (CI) 0.85-1.02, P=0.11]. However, the pre-specified secondary end points of an adjusted intention-to-treat analysis (hazard ratio 0.88; 95% CI 0.79-0.97, P=0.008) were significant. In the PRIMO (Paricalcitol Capsule Benefits in Renal Failure Induced Cardiac Morbidity) trial, 227 patients with CKD stage 3-4 and left ventricular hypertrophy by echocardiography were randomized to paricalcitol or placebo. The primary end point of change in left ventricular mass index by MRI after 12 months was not different between the two groups, but the prespecified end point of cardiovascular-related hospitalizations was reduced in the paricalcitol-treated group (P=0.04). SUMMARY The results of these two randomized controlled trials have negative primary end points but significant secondary end points and thus require physicians to individualize therapies for the treatment of secondary hyperparathyroidism.
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Affiliation(s)
- Sharon M Moe
- aIndiana University School of Medicine and Roudebush Veterans Administration Medical Center, Indianapolis, Indiana bMassachusettes General Hospital, Harvard Medical School, Boston, Massachusetts, USA
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Drüeke TB, Olgaard K. Report on 2012 ISN Nexus Symposium: ‘Bone and the Kidney’. Kidney Int 2013; 83:557-62. [DOI: 10.1038/ki.2012.453] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
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Abstract
Parathyroid hormone (PTH) is a uremic toxin with multiple systemic effects including bone disorders (renal osteodystrophy), myopathy, neurologic abnormalities, anemia, pruritus, and cardiomyopathy. Hyperparathyroidism is common in CKD and results in significant morbidity and mortality if left untreated. Clinical practice guidelines from the Kidney Disease Improving Global Outcomes initiative broadened the optimal PTH range to >2 and <9 times the upper limit of normal for the assay measured. Furthermore, the guidelines recommend following trends in PTH to determine the appropriate therapy. These guidelines overcome issues with the assay variability and help clinicians make judgments when treating individual patients. They also require frequent measurement in order to determine trends and implement appropriate treatments.
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Affiliation(s)
- Stuart M Sprague
- Division of Nephrology and Hypertension, NorthShore University HealthSystem, Evanston, IL 60201, USA.
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Chertow GM, Block GA, Correa-Rotter R, Drüeke TB, Floege J, Goodman WG, Herzog CA, Kubo Y, London GM, Mahaffey KW, Mix TCH, Moe SM, Trotman ML, Wheeler DC, Parfrey PS. Effect of cinacalcet on cardiovascular disease in patients undergoing dialysis. N Engl J Med 2012; 367:2482-94. [PMID: 23121374 DOI: 10.1056/nejmoa1205624] [Citation(s) in RCA: 615] [Impact Index Per Article: 47.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Disorders of mineral metabolism, including secondary hyperparathyroidism, are thought to contribute to extraskeletal (including vascular) calcification among patients with chronic kidney disease. It has been hypothesized that treatment with the calcimimetic agent cinacalcet might reduce the risk of death or nonfatal cardiovascular events in such patients. METHODS In this clinical trial, we randomly assigned 3883 patients with moderate-to-severe secondary hyperparathyroidism (median level of intact parathyroid hormone, 693 pg per milliliter [10th to 90th percentile, 363 to 1694]) who were undergoing hemodialysis to receive either cinacalcet or placebo. All patients were eligible to receive conventional therapy, including phosphate binders, vitamin D sterols, or both. The patients were followed for up to 64 months. The primary composite end point was the time until death, myocardial infarction, hospitalization for unstable angina, heart failure, or a peripheral vascular event. The primary analysis was performed on the basis of the intention-to-treat principle. RESULTS The median duration of study-drug exposure was 21.2 months in the cinacalcet group, versus 17.5 months in the placebo group. The primary composite end point was reached in 938 of 1948 patients (48.2%) in the cinacalcet group and 952 of 1935 patients (49.2%) in the placebo group (relative hazard in the cinacalcet group vs. the placebo group, 0.93; 95% confidence interval, 0.85 to 1.02; P=0.11). Hypocalcemia and gastrointestinal adverse events were significantly more frequent in patients receiving cinacalcet. CONCLUSIONS In an unadjusted intention-to-treat analysis, cinacalcet did not significantly reduce the risk of death or major cardiovascular events in patients with moderate-to-severe secondary hyperparathyroidism who were undergoing dialysis. (Funded by Amgen; EVOLVE ClinicalTrials.gov number, NCT00345839.).
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