Cinacalcet hydrochloride treatment significantly improves all-cause and cardiovascular survival in a large cohort of hemodialysis patients
2010; Elsevier BV; Volume: 78; Issue: 6 Linguagem: Inglês
10.1038/ki.2010.167
ISSN1523-1755
AutoresGeoffrey A. Block, David Zaun, Gerard Smits, Martha S. Persky, Stephanie Brillhart, Kimberly Nieman, Jiannong Liu, Wendy L. St. Peter,
Tópico(s)Dialysis and Renal Disease Management
ResumoSecondary hyperparathyroidism (SHPT) affects a significant number of hemodialysis patients, and metabolic disturbances associated with it may contribute to their high mortality rate. As patients with lower serum calcium, phosphorus, and parathyroid hormone are reported to have improved survival, we tested whether prescription of the calcimimetic cinacalcet to hemodialysis patients with SHPT improved their survival. We prospectively collected data on hemodialysis patients from a large provider beginning in 2004, a time coincident with the commercial availability of cinacalcet hydrochloride. This information was merged with data in the United States Renal Data System to determine all-cause and cardiovascular mortality. Patients included in the study received intravenous (i.v.) vitamin D therapy (a surrogate for the diagnosis of SHPT). Of 19,186 patients, 5976 received cinacalcet and all were followed from November 2004 for up to 26 months. Unadjusted and adjusted time-dependent Cox proportional hazards modeling found that all-cause and cardiovascular mortality rates were significantly lower for those treated with cinacalcet than for those without calcimimetic. Hence, this observational study found a significant survival benefit associated with cinacalcet prescription in patients receiving i.v. vitamin D. Definitive proof, however, of a survival advantage awaits the performance of randomized clinical trials. Secondary hyperparathyroidism (SHPT) affects a significant number of hemodialysis patients, and metabolic disturbances associated with it may contribute to their high mortality rate. As patients with lower serum calcium, phosphorus, and parathyroid hormone are reported to have improved survival, we tested whether prescription of the calcimimetic cinacalcet to hemodialysis patients with SHPT improved their survival. We prospectively collected data on hemodialysis patients from a large provider beginning in 2004, a time coincident with the commercial availability of cinacalcet hydrochloride. This information was merged with data in the United States Renal Data System to determine all-cause and cardiovascular mortality. Patients included in the study received intravenous (i.v.) vitamin D therapy (a surrogate for the diagnosis of SHPT). Of 19,186 patients, 5976 received cinacalcet and all were followed from November 2004 for up to 26 months. Unadjusted and adjusted time-dependent Cox proportional hazards modeling found that all-cause and cardiovascular mortality rates were significantly lower for those treated with cinacalcet than for those without calcimimetic. Hence, this observational study found a significant survival benefit associated with cinacalcet prescription in patients receiving i.v. vitamin D. Definitive proof, however, of a survival advantage awaits the performance of randomized clinical trials. Despite recent modest improvements in adjusted mortality rates among hemodialysis patients, mortality rates remain above 225 per 1000 patient-years, nearly six times the rates in the general age-matched population.1.U.S. Renal Data System USRDS 2008 Annual Data Report: Atlas of Chronic Kidney Disease & End-Stage Renal Disease in the United States. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland2008Google Scholar Overall 5-year survival of hemodialysis patients remains only 31% and the mortality rate for patients on dialysis for longer than 5 years is above 250 per 1000 patient-years.1.U.S. Renal Data System USRDS 2008 Annual Data Report: Atlas of Chronic Kidney Disease & End-Stage Renal Disease in the United States. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland2008Google Scholar In the last decade, considerable emphasis has been placed on the role of abnormalities in mineral metabolism (elevated levels of calcium, phosphorus, and parathyroid hormone (PTH)) in this high rate of mortality.2.Block G.A. Klassen P.S. Lazarus J.M. et al.Mineral metabolism, mortality, and morbidity in maintenance hemodialysis.J Am Soc Nephrol. 2004; 15: 2208-2218Crossref PubMed Scopus (2080) Google Scholar Secondary hyperparathyroidism (SHPT) is present in a substantial percentage of hemodialysis patients and prevalence increases with increasing dialysis duration. For much of the past two decades, the primary SHPT treatments have been phosphate binders to control serum phosphorus, and intravenous (i.v.) vitamin D to suppress PTH. As i.v. vitamin D commonly increases serum calcium and phosphorus, efforts to control PTH often resulted in elevated serum calcium and phosphorus values. Elevations in serum calcium, phosphorus, and PTH have all been associated with increased morbidity and mortality in observational studies.3.Block G.A. Hulbert-Shearon T.E. Levin N.W. et al.Association of serum phosphorus and calcium x phosphate product with mortality risk in chronic hemodialysis patients: a national study.Am J Kidney Dis. 1998; 31: 607-617Abstract Full Text Full Text PDF PubMed Scopus (2013) Google Scholar, 4.Kalantar-Zadeh K. Kuwae N. Regidor D.L. et al.Survival predictability of time-varying indicators of bone disease in maintenance hemodialysis patients.Kidney Int. 2006; 70: 771-780Abstract Full Text Full Text PDF PubMed Scopus (750) Google Scholar, 5.Tentori F. Blayney M.J. Albert J.M. et al.Mortality risk for dialysis patients with different levels of serum calcium, phosphorus, and PTH: the dialysis outcomes and practice patterns study (DOPPS).Am J Kidney Dis. 2008; 52: 519-530Abstract Full Text Full Text PDF PubMed Scopus (739) Google Scholar, 6.Covic A. Kothawala P. Bernal M. et al.Systematic review of the evidence underlying the association between mineral metabolism disturbances and risk of all-cause mortality, cardiovascular mortality and cardiovascular events in chronic kidney disease.Nephrol Dial Transplant. 2009; 24: 1506-1523Crossref PubMed Scopus (171) Google Scholar Observational data suggest that optimal outcomes are associated with serum calcium values in the low-normal range of 7.5–9.5 mg/dl and serum phosphorus values in the range of 3–5 mg/dl.5.Tentori F. Blayney M.J. Albert J.M. et al.Mortality risk for dialysis patients with different levels of serum calcium, phosphorus, and PTH: the dialysis outcomes and practice patterns study (DOPPS).Am J Kidney Dis. 2008; 52: 519-530Abstract Full Text Full Text PDF PubMed Scopus (739) Google Scholar Serum PTH levels associated with optimal outcomes are less well defined and vary by specific study; however, it is difficult to show an independent effect of PTH on outcomes until PTH values are above 600 pg/ml.6.Covic A. Kothawala P. Bernal M. et al.Systematic review of the evidence underlying the association between mineral metabolism disturbances and risk of all-cause mortality, cardiovascular mortality and cardiovascular events in chronic kidney disease.Nephrol Dial Transplant. 2009; 24: 1506-1523Crossref PubMed Scopus (171) Google Scholar The strength of observational data has led to many national and international patient care guidelines that recommend control of serum calcium, phosphorus, and PTH within specific ranges. The most well recognized of these sets of guidelines is the US-based National Kidney Foundation Kidney Disease Outcomes Quality Initiative (KDOQI). The KDOQI guideline for bone and mineral disease recommends target calcium of 8.4–9.5 mg/dl, target phosphorus of 3.5–5.5 mg/dl, and target PTH of 150–300 pg/ml.7.National Kidney Foundation K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease.Am J Kidney Dis. 2003; 42: S1-S201Crossref PubMed Scopus (648) Google Scholar Calcimimetics increase the sensitivity of the calcium-sensing receptor to extracellular calcium and represent an alternative therapy for SHPT. The first calcimimetic, cinacalcet hydrochloride (Sensipar; Amgen, Thousand Oaks, CA, USA), was approved for clinical use in April 2004 and became commercially available in May 2004. Pivotal clinical trials were conducted in patients with persistent SHPT despite use of a standard therapy (phosphate binders and vitamin D). These trials consistently showed that adding cinacalcet reduced PTH, calcium, and phosphorus levels.8.Block G.A. Martin K.J. de Francisco A.L. et al.Cinacalcet for secondary hyperparathyroidism in patients receiving hemodialysis.N Engl J Med. 2004; 350: 1516-1525Crossref PubMed Scopus (898) Google Scholar Extension studies and post-hoc analyses suggested that adding cinacalcet produced long-term favorable effects on these biomarkers and that patients given cinacalcet were more likely to reach target values than patients given standard therapy.9.Moe S.M. Chertow G.M. Coburn J.W. et al.Achieving NKF-K/DOQI bone metabolism and disease treatment goals with cinacalcet HCl.Kidney Int. 2005; 67: 760-771Abstract Full Text Full Text PDF PubMed Scopus (281) Google Scholar, 10.Moe S.M. Cunningham J. Bommer J. et al.Long-term treatment of secondary hyperparathyroidism with the calcimimetic cinacalcet HCl.Nephrol Dial Transplant. 2005; 20: 2186-2193Crossref PubMed Scopus (126) Google Scholar Compelled by the observations that patients with lower serum values of calcium, phosphorus, and PTH had improved survival, we prospectively tested the hypothesis that prescribing cinacalcet to a large hemodialysis population with SHPT would be associated with improved survival. The final study population consisted of 5976 patients with cinacalcet prescriptions and 13,210 without. Detailed descriptions of patient characteristics at baseline and at first cinacalcet prescription are shown in Tables 1 and 2. Patients with cinacalcet prescriptions were younger with longer dialysis duration, more likely to be African American, and less likely to have diabetes. In the baseline period, a higher percentage of patients with cinacalcet prescriptions had 0 hospital days and a lower percentage had >5 hospital days. Consistent with these demographic differences suggesting that patients with cinacalcet prescriptions were generally healthier, baseline cardiovascular comorbidity was also lower. Cardiovascular medication use was generally similar between patients with and without cinacalcet prescriptions; however, cinacalcet patients were less likely to receive prescriptions for calcium-containing phosphate binders and more likely to receive prescriptions for sevelamer. Baseline serum calcium, phosphorus, and PTH values were higher for cinacalcet than for non-cinacalcet patients. In particular, proportions of cinacalcet patients with severe hyperparathyroidism (PTH >600 pg/ml), hypercalcemia (calcium >10.2 mg/dl), and hyperphosphatemia (phosphorus >8.0 mg/dl) in the baseline period were higher than proportions of non-cinacalcet patients.Table 1Patient demographic and health information at baseline (1 November 2004) and at first cinacalcet useCinacalcet patientsaDemographic information defined on 1 November 2004; baseline hospital days determined from 1 May to 31 October 2004.All patients,aDemographic information defined on 1 November 2004; baseline hospital days determined from 1 May to 31 October 2004. 1 November1 NovemberAt first cinacalcet usebCharacteristics collected immediately before first cinacalcet prescription or, for hospital days, in the 6 months before first cinacalcet prescription.Non-cinacalcet patients,aDemographic information defined on 1 November 2004; baseline hospital days determined from 1 May to 31 October 2004. 1 NovemberCharacteristicsnPercentnPercentnPercentnPercentMean age (year)62.958.359.265.0Age groups, %19,1865976597613,210 0–44241812.6111918.7103017.212999.8 45–64697636.4260243.5257843.1437433.1 65–74510826.6140523.5142423.8370328.0 ≥75468424.485014.294415.8383429.0Mean dialysis duration (year)3.84.45.33.5Dialysis duration, %19,1795975597613,204 5 years478625.0191732.1255342.7286921.7Mean body mass index (kg/m2)18,86126.9586127.7586627.612,82026.5Body mass index, % 0-<18.59064.92163.72153.76905.4 ≥18.5 to <25.0756940.5216837.0221037.7540142.1 ≥25.0 to <30.0543929.1171229.2172329.4372729.1 ≥30.0 to <35.0272214.693516.091015.5178714.0 ≥35.0 to 5513226.8133822.4126421.2379428.7a Demographic information defined on 1 November 2004; baseline hospital days determined from 1 May to 31 October 2004.b Characteristics collected immediately before first cinacalcet prescription or, for hospital days, in the 6 months before first cinacalcet prescription. Open table in a new tab Table 2Comorbid conditions, medication use, and laboratory values at baseline (1 November 2004) and at first cinacalcet useCinacalcet patientsaBaseline comorbidity determined 1 May to 31 October 2004; at least one record of medication prescription in the medication class required in the 3 baseline months (August–October 2004) to be counted as medication exposure; baseline laboratory data determined 1 August to 31 October 2004, using values closest to 31 October 2004.All patients,aBaseline comorbidity determined 1 May to 31 October 2004; at least one record of medication prescription in the medication class required in the 3 baseline months (August–October 2004) to be counted as medication exposure; baseline laboratory data determined 1 August to 31 October 2004, using values closest to 31 October 2004. 1 November1 NovemberAt first cinacalcet usebBaseline comorbidity determined in the 6 months before first cinacalcet prescription; at least one record of medication prescription in the medication class required in the 3 months before first cinacalcet prescription to be counted as a medication exposure; baseline laboratory data determined in the 3 months before first cinacalcet prescription.Non-cinacalcet patients,aBaseline comorbidity determined 1 May to 31 October 2004; at least one record of medication prescription in the medication class required in the 3 baseline months (August–October 2004) to be counted as medication exposure; baseline laboratory data determined 1 August to 31 October 2004, using values closest to 31 October 2004. 1 NovemberCharacteristicsnPercentnPercentnPercentnPercentDiabetes11,67260.8324154.2328455.0843163.8CVD CHF888646.3242740.6248341.5645948.9 ASHD686635.8171628.7180730.2515039.0 PVD685935.8178329.8189231.7507638.4 CVA/TIA328417.179613.381313.6248818.8 Dysrhythmia473024.7109318.3123420.6363727.5 Other CVDcIncludes ill-defined complication of heart disease, tachycardia, palpitations, murmurs, acute pericarditis, acute and subacute endocarditis, other diseases of pericardium, and other diseases of the endocardium.587930.6159426.7160726.9428532.4Cancer15798.24247.14207.011558.7COPD311816.379513.387314.6232317.6Beta blockersdAcebutolol, atenolol, betaxolol, bisoprolol, carteolol, carvedilol, esmolol, labetalol, metoprolol, nadolol, penbutolol, pindolol, propranolol, and timolol.10,44254.4337056.4360160.3707253.5Calcium channel blockerseDihydropyridine-based: amlodipine, bepridil, felodipine, isradipine, nicardipine, nifedipine, and nisoldipine; non-dihydropyridine-based: diltiazem and verapamil. Dihydropyridine901247.0299750.2302350.6601545.5 Nondihydropyridine15548.15198.75128.610357.8StatinsfAtorvastatin, cerivastatin, fluvastatin, lovastatin, pravastatin, and simvastatin.603631.5177429.7190031.8426232.3ACEIs/ARBsgACEIs: benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, and trandolapril; ARBs: candesartan, eprosartan, irbesartan, losartan, telmisartan, and valsartan.11,03057.5359060.1362860.7744056.3Phosphate binders Calcium-based998052.0285047.7251142.0713054.0 Lanthanum—0.0—0.093915.700.0 Sevelamer10,13452.8400467.0444474.4613046.4Albumin, g/dl, mean (s.d.)18,9853.9 (0.4)59353.9 (0.4)59043.9 (0.4)13,0503.8 (0.4)Albumin, % <3.6380720.183014.094216.0297722.8 ≥3.6 to <4.0681535.9206034.7207435.1475536.4 ≥4.0836344.1304551.3288848.9531840.8Corrected calcium, mg/dl, mean (s.d.)18,9189.6 (0.7)59239.8 (0.7)58959.7 (0.7)12,9959.5 (0.7)Corrected calcium, % 10.2313416.6149825.3145624.7163612.6Phosphorus, mg/dl, mean (s.d.)18,9905.4 (1.6)59365.7 (1.6)59066.1 (1.7)13,0545.2 (1.5)Phosphorus, % <3.514677.72654.52033.412029.2 ≥3.5 to <5.0659534.7171428.9138623.5488137.4 ≥5.0 to <6.0511827.0168328.4151425.6343526.3 ≥6.0 to <7.0307316.2113619.1123320.9193714.8 ≥7.0 to <8.015278.062310.579713.59046.9 ≥8.012106.45158.777313.16955.3Intact PTH, pg/ml, median (IQR)18,830251.9 (225.0)5902323.1 (317.3)5890548.1 (465.5)12,928230.8 (186.5)Intact PTH, % 300≤600524827.9200534.0240840.9324325.1 >600204210.8115719.6258043.88856.8Hemoglobin, g/dl, mean (s.d.)18,95912.4 (1.4)592912.4 (1.3)589912.4 (1.3)13,03012.3 (1.4)Hemoglobin, % 12 to ≤13539831.3195433.0191932.5398430.6 >13561229.6180730.5170728.9380529.2Bicarbonate, mEq/l, mean (s.d.)18,92521.2 (4.0)592221.0 (3.9)589423.2 (3.7)13,00321.3 (4.0)Bicarbonate, % 302181.2641.11692.91541.2Kt/V UKM, mean (s.d.)18,8321.7 (0.3)59081.6 (0.3)58821.6 (0.3)12,9241.7 (0.3)Kt/V UKM, % 1.415,53682.5487982.6485482.510,65782.5URR, mean (s.d.)18,93673.9 (6.7)592473.8 (6.6)588974.0 (6.6)13,01274.0 (6.8)URR, % <6514167.54347.33946.79827.5 ≥6517,52092.5549092.7549593.312,03092.5Abbreviations: ACEI, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; ASHD, atherosclerotic heart disease; CHF, congestive heart failure; COPD, chronic obstructive pulmonary disease; CVA, cerebrovascular accident; CVD, cardiovascular disease; IQR, inter-quartile range; Kt/V, dialysis adequacy; PTH, parathyroid hormone; PVD, peripheral vascular disease; s.d., standard deviation; TIA, transient ischemic attack; UKM, urea kinetic modeling; URR, urea reduction ratio.a Baseline comorbidity determined 1 May to 31 October 2004; at least one record of medication prescription in the medication class required in the 3 baseline months (August–October 2004) to be counted as medication exposure; baseline laboratory data determined 1 August to 31 October 2004, using values closest to 31 October 2004.b Baseline comorbidity determined in the 6 months before first cinacalcet prescription; at least one record of medication prescription in the medication class required in the 3 months before first cinacalcet prescription to be counted as a medication exposure; baseline laboratory data determined in the 3 months before first cinacalcet prescription.c Includes ill-defined complication of heart disease, tachycardia, palpitations, murmurs, acute pericarditis, acute and subacute endocarditis, other diseases of pericardium, and other diseases of the endocardium.d Acebutolol, atenolol, betaxolol, bisoprolol, carteolol, carvedilol, esmolol, labetalol, metoprolol, nadolol, penbutolol, pindolol, propranolol, and timolol.e Dihydropyridine-based: amlodipine, bepridil, felodipine, isradipine, nicardipine, nifedipine, and nisoldipine; non-dihydropyridine-based: diltiazem and verapamil.f Atorvastatin, cerivastatin, fluvastatin, lovastatin, pravastatin, and simvastatin.g ACEIs: benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, and trandolapril; ARBs: candesartan, eprosartan, irbesartan, losartan, telmisartan, and valsartan. Open table in a new tab Abbreviations: ACEI, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; ASHD, atherosclerotic heart disease; CHF, congestive heart failure; COPD, chronic obstructive pulmonary disease; CVA, cerebrovascular accident; CVD, cardiovascular disease; IQR, inter-quartile range; Kt/V, dialysis adequacy; PTH, parathyroid hormone; PVD, peripheral vascular disease; s.d., standard deviation; TIA, transient ischemic attack; UKM, urea kinetic modeling; URR, urea reduction ratio. The unadjusted all-cause mortality rate for patients with cinacalcet prescriptions was significantly lower than for non-cinacalcet patients (17.6 vs 23.0 deaths per 100 patient-years, respectively, hazard ratio (HR) 0.73, 95% confidence interval (CI) 0.68–0.78, P<0.001; Table 3). Fully adjusted models showed an almost identical HR of 0.74 (95% CI 0.67–0.83), suggesting that demographic characteristics favoring cinacalcet patients were balanced by laboratory characteristics favoring non-cinacalcet patients (Table 4). Unadjusted cardiovascular mortality rates were 8.1 deaths per 100 patient-years for cinacalcet patients and 10.0 for non-cinacalcet patients. Models adjusted for all variables showed an HR of 0.76 (95% CI 0.66–0.86, P<0.001) for cardiovascular mortality (Table 5).Table 3Unadjusted all-cause and cardiovascular mortalityVariableCinacalcet patientsNon-cinacalcet patientsPn597619,174All-cause mortality Follow-up Mean, patient-years1.11.3 Minimum–maximum, years0.0–2.20.0–2.2 Total deaths, n (%)1148 (19.2)5882 (30.7) Mortality incidence rate, per 100 patient-years (95% CI)17.6 (16.58–18.61)23.0 (22.38–23.55) Raw hazard ratioaTime-dependent Cox-proportional hazard regression model. (95% CI)0.73 (0.68–0.78)<0.0001 Time to event, monthsbLog-rank test.<0.0001 1-year survival (s.e.)0.85 (0.01)0.80 (0.00) 2-year survival (s.e.)0.70 (0.01)0.63 (0.00)Cardiovascular mortality Follow-up Mean, patient-years1.11.3 Minimum–maximum, years0.0–2.20.0–2.2 Cardiovascular deaths, n (%)525 (8.8)2571 (13.4) Cardiovascular mortality incidence rate, per 100 patient-years (95% CI)8.1 (7.36–8.73)10.0 (9.65–10.43) Raw hazard ratioaTime-dependent Cox-proportional hazard regression model. (95% CI)0.78 (0.71–0.86)<0.0001 Time to event, monthsbLog-rank test.<0.0001 1-year survival (s.e.)0.92 (0.00)0.91 (0.00) 2-year survival (s.e.)0.85 (0.01)0.82 (0.00)Abbreviations: CI, confidence interval; s.e., standard error.a Time-dependent Cox-proportional hazard regression model.b Log-rank test. Open table in a new tab Table 4Adjusted hazard ratios for all-cause mortalityaTime-dependent Cox proportional hazards regression model, adjusted for demographic characteristics, comorbidity, hospital days, vascular access, and laboratory information.ParameterParameter estimates.e.Hazard ratio (95% CI)PTreatment (referent: non-cinacalcet patients)-0.2980.0540.74 (0.67–0.83)<0.0001Age, year (referent: 18–44) 45–640.5080.1061.66 (1.35–2.04)<0.0001 65–740.8470.1192.33 (1.85–2.95)<0.0001 ≥751.1470.1213.15 (2.48–3.99)<0.0001Sex (referent: men)-0.0730.0400.93 (0.86–1.01)0.0669Race (referent: white) African American-0.3650.0480.69 (0.63–0.76)<0.0001 Other-0.2860.0490.75 (0.68–0.83)<0.0001Dialysis duration, year (referent: 1–3) 50.2140.0741.24 (1.07–1.43)0.0036BMI, kg/m 2 (referent: ≥18–<25) <18.50.3660.0741.44 (1.25–1.67)<0.0001 ≥25 to <30-0.2820.0430.75 (0.69–0.82)<0.0001 ≥30 to <35-0.4160.0540.66 (0.59–0.73)<0.0001 ≥35 to <40-0.6040.0810.55 (0.47–0.64)<0.0001 ≥40-0.4610.0910.63 (0.53–0.75) 50.1260.0561.14 (1.02–1.27)0.0242Diabetes (referent: no)0.1870.0581.21 (1.08–1.35)0.0013Congestive heart failure (referent: no)0.2500.0421.28 (1.18–1.39)<0.0001Atherosclerotic heart disease (referent: no)0.0040.0451.00 (0.92–1.10)0.932Peripheral vascular disease (referent: no)0.0930.0401.10 (1.01–1.19)0.0206CVA/TIA (referent: no)0.1420.0461.15 (1.05–1.26)0.002Dysrhythmia (referent: no)0.1690.0441.18 (1.09–1.29)0.0001Other CVDbIncludes ill-defined complication of heart disease, tachycardia, palpitations, murmurs, acute pericarditis, acute and subacute endocarditis, other disease of pericardium, and other diseases of the endocardium. (referent: no)0.0980.0431.10 (1.01–1.20)0.0245Cancer (referent: no)0.1630.0681.18 (1.03–1.34)0.016GI bleeding (referent: no)0.0860.0701.09 (0.95–1.25)0.2223COPD (referent: no)0.1730.0471.19 (1.08, 1.30)0.0002Liver disease (referent: no)0.0800.1161.08 (0.86, 1.36)0.4892Albumin, g/dl (referent: ≥4.0) <3.61.0140.0342.76 (2.58–2.95)<0.0001 ≥3.6 to <4.00.3730.0301.45 (1.37–1.54)<0.0001Corrected calcium, mg/dl (referent: ≥9.0–≤10.2) 10.20.1270.0461.14 (1.04–1.24)0.0059Phosphorus, mg/dl (referent: ≥3.5–<5.0) <3.50.0600.1161.06 (0.85–1.33)0.6028 ≥5.0 to <6.00.0650.0431.07 (0.98–1.16)0.1279 ≥6.0 to <7.00.1410.0501.15 (1.04–1.27)0.0048 ≥7.0 to <8.00.2070.0691.23 (1.07–1.41)0.0028 ≥8.00.3650.0731.44 (1.25–1.66) 150–≤300) 300 to ≤6000.0250.0441.03 (0.94–1.12)0.5748 >6000.1710.0631.19 (1.05–1.34)0.0065Bicarbonate, mEq/l (referent: ≥22–≤30) 300.2960.0721.34 (1.17–1.55)<0.0001Hemoglobin, g/dl (referent: ≥10–≤12) 12 to ≤13-0.1070.0270.90 (0.85–0.95) 13-0.0790.0290.92 (0.87–0.98)0.0065Kt/V UKM per treatment (referent: ≥1.2–≤1.4) 1.4-0.2310.0390.79 (0.74–0.86)<0.0001TSAT, % (referent: ≥20–<50) <200.1640.0471.18 (1.07–1.29)0.0005 ≥50-0.0350.0410.97 (0.89–1.05)0.3941Ferritin, ng/ml (referent: ≥200–<500) <200-0.0670.0860.94 (0.79–1.11)0.4303 ≥500 to <8000.0190.0301.02 (0.96–1.08)0.5205 ≥800 to <10000.0060.0391.01 (0.93–1.09)0.8847 ≥10000.1800.0381.20 (1.11–1.29)<0.0001WBC, mm3 (referent: ≥1000–≤10,000) <10003.1050.70522.31 (5.60–88.83) 10,0000.2980.0471.35 (1.23–1.48)<0.0001Vascular access (referent: fistula) Catheter0.3650.0431.44 (1.32–1.57)<0.0001 Graft0.1880.0321.21 (1.13–1.29)<0.0001 Other0.9320.6482.54 (0.71–9.04)0.1503Abbreviations: BMI, body mass index; CI, confidence interval; COPD, chronic obstructive pulmonary disease; CVA, cerebrovascular accident; CVD, cardiovascular disease; GI, gastrointestinal; PTH, parathyroid hormone; s.e., standard error; TIA, transient ischemic attack; TSAT, transferrin saturation; UKM, urea kinetic modeling; WBC, white blood cell count.a Time-dependent Cox proportional hazards regression model, adjusted for demographic characteristics, comorbidity, hospital days, vascular access, and laboratory information.b Includes ill-defined complication of heart disease, tachycardia, palpitations, murmurs, acute pericarditis, acute and subacute endocarditis, other disease of pericardium, and other diseases of the endocardium. Open table in a new tab Table 5Adjusted hazard ratios for cardiovascular mortalityaTime-dependent Cox proportional hazards regression model, adjusted for demographic characteristics, comorbidity, hospital days, vascular access, and laboratory information.ParameterParameter estimates.e.Hazard ratio (95% CI)PTreatment (referent: non-cinacalcet patients)–0.2810.06920.76 (0.66–0.86)<0.0001Age, year (referent: 18–44) 45–640.5200.1191.68 (1.33–2.12)<0.0001 65–740.8410.1252.32 (1.81–2.96)<0.0001 ≥751.0850.1272.96 (2.31–3.80)<0.0001Sex (referent: men)–0.0840.0470.92 (0.84–1.01)0.0777Race (referent: white) African American–0.2960.0570.74 (0.67–0.83)<0.0001 Other–0.1960.0600.82 (0.73–0.92)0.0010Dialysis duration, year (referent: 1–3) 50.2240.0701.25 (1.09–1.43)0.0013BMI, kg/m2 (referent: ≥18–<25) <18.50.4830.0881.62 (1.36–1.93)<0.0001 ≥25 to <30–0.2460.0530.78 (0.70–0.87)<0.0001 ≥30 to <35–0.3890.0710.68 (0.59–0.78)<0.0001 ≥35 to <40–0.6620.1080.52 (0.42–0.64)<0.0001 ≥40–0.6230.1300.54 (0.42–0.69) 50.1210.0621.13 (1.00–1.28)0.0510Diabetes (referent: no)0.1440.0691.15 (1.01–1.32)0.0372Congestive heart failure (referent: no)0.3180.0511.37 (1.24–1.52)<0.0001Atherosclerotic heart disease (referent: no)0.0880.0521.09 (0.99–1.21)0.0923Peripheral vascular disease (referent: no)0.1570.0481.17 (1.06–1.29)0.0012CVA/TIA (referent: no)0.1050.0551.11 (1.00–1.24)0.0583Dysrhythmia (referent: no)0.2570.0521.29 (1.17–1.43)<0.0001Other CVDbIncludes ill-defined complication of heart disease, tachycardia, palpitations, murmurs, acute pericarditis, acute and subacute endocarditis, other disease of pericardium, and other diseases of the endocardium. (referent: no)0.0820.0521.09 (0.98–1.20)0.1194Cancer (referent: no)–0.0550.0810.95 (0.81–1.11)0.4995GI bleeding (referent: no)0.0580.0811.06 (0.91–1.24)0.4692COPD (referent: no)0.1680.0561.18 (1.06–1.32)0.0027Liver disease (referent: no)–0.0500.1220.95 (0.75–1.21)0.6806Albumin, g/dl (referent: ≥4.0) <3.60.8500.0492.34 (2.13–2.58)<0.0001 ≥3.6 to <4.00.3400.0431.4
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