Effect of extended-release niacin on cardiovascular events and kidney function in chronic kidney disease: a post hoc analysis of the AIM-HIGH trial

• DOI: 10.1038/ki.2014.383
• Publication Date: 2015-02-04T16:36:17Z
• Authors: Roberto S. Kalil; Jeffrey H. Wang; Ian H. de Boer; Roy O. Mathew; Joachim H. Ix; Arif Asif; Xuefeng Shi; William E. Boden
• Keywords: Niacin; Post-hoc analysis

Chronic kidney disease (CKD) in patients is strongly associated with cardiovascular morbidity and mortality, prevalent abnormal lipid metabolism. The AIM-HIGH trial examined the benefits of adding extended-release niacin (ERN) to simvastatin established coronary heart disease. Here we conducted a post hoc analysis examining whether participants derived or renal when stratified by function. Of 3414 participants, 505 had stage 3 CKD at baseline. Among subset, demographics (CVD) risk factors were well balanced ERN placebo arms. Compared placebo, receiving significant decrease triglycerides median 59.0 mg/dl, high-density lipoprotein cholesterol significantly increased mean 11.3 mg/dl over follow-up years. CVD events similar between both However, all-cause mortality was higher group (hazard ratio 1.73). Mean change eGFR among ERN-treated not different study Thus, CKD, addition for secondary prevention improved triglyceride lipoprotein-cholesterol concentrations but did improve outcomes function, mortality. Coronary leading cause chronic (CKD). Individuals are greater major adverse cardiac than general population.1Go A.S. Chertow G.M. Fan D. et al.Chronic risks death, hospitalization.N Engl J Med. 2004; 351: 1296-1305Crossref PubMed Scopus (9021) Google Scholar Despite this, traditional factor reduction strategies that reduce event population, such as low-density (LDL-C) lowering, confer less benefit patients.2Cholesterol Treatment Trialists’ (CTT) CollaborationEfficacy safety more intensive lowering LDL cholesterol: meta-analysis data from 170,000 26 randomized trials.Lancet. 2010; 376 (168): 1670Abstract Full Text PDF (4550) In Study Heart Renal Protection, although treatment plus ezetimibe subjects led 17% composite outcome compared it mortality.3Biagent C. Landray M.J. Reith al.The effects (Study Protection): placebo-controlled trial.Lancet. 2011; 377: 2181-2192Abstract (1892) Low levels (HDL-C) high (TG) CKD.4Vaziri N.D. Dyslipidemia failure: nature, mechanisms, potential consequences.Am Physiol. 2006; 290: F262-f272Crossref (392) Niacin raises HDL-C lowers TG levels. known raising translates into patients. Prior studies suggest lipid-lowering therapy may also prevent progression CKD.5Shepherd J. Kastelein Bittner V. al.Effect atorvastatin on function artery disease: Treating New Targets (TN) study.Clin Am Soc Nephrol. 2007; 2: 1131-1139Crossref (278) Although animal protect against GFR loss,6Cho K. Kim H. Rodriguez-Iturbe B. al.Niac ameliorates oxidative stress, inflammation, proteinuria, hypertension rats failure.Am Physiol 2009; 297: F106-F113Crossref (88) our knowledge, effect longitudinal humans has been studied previously. Atherothrombosis Intervention Metabolic Syndrome HDL/High TGs: Impact Global Health Outcomes (AIM-HIGH) tested hypothesis ERN, added statin therapy, reduced stable preselected low baseline elevated TGs placebo. Ezetimibe could be either arm, needed, achieve maintain an on-treatment LDL-C 40 80 mg/dl. primary findings show incremental clinical versus optimal despite improvement profile.7AIM-HIGH InvestigatorsThe role atherosclerotic optimally treated characteristics participants. syndrome HDL/high triglycerides: impact trial.Am 161: 538-543Abstract (109) present investigation enrolled trial. Because population represents subset risk, hypothesized would these subjects. Secondary objectives evaluate tolerability CKD. Baseline characteristics: 3413 non-missing estimated glomerular filtration rate (eGFR) trial, 85.2% male, 3.4% African Americans, 4.1% Hispanic ethnicity. Five hundred five (14.8%) these, 50.3±7.7 ml/min per 1.73 m2. all, 496 (98.2%) within range 30–59 m2, 9 (1.8%) eGFR<30 Approximately 80% 4% Hispanics. without those older likely female, prevalence diabetes hypertension, use tobacco. Systolic blood pressures pulse slightly (Table 1).Table 1Baseline StatusCKD (N=505)No (N=2908)P-valueAge (years), (s.d.)70.7 (7.3)62.5 (8.4)<0.001Gender (male), N (%)408 (80.8)2501 (86.0)0.002Race—African American, (%)20 (4.0)97 (3.3)0.476Ethnicity—Hispanic, (%)19 (3.8)121 (4.2)0.676Current smoker, (%)58 (11.6)564 (19.5)<0.001Coronary disease, (%)452 (89.5)2694 (92.6)0.015Diabetes, (%)207 (41.0)951 (32.7)<0.001Hypertension, (%)401 (79.4)2037 (70.0)<0.001Diastolic BP (mm Hg), (s.d.)71.4 (10.2)74.9 (9.6)<0.001Systolic (s.d.)130.5 (17.4)127.9 (16.1)<0.001Pulse pressure (s.d.)59.1 (16.4)53.0 (13.4)<0.001Use ACE-Is ARBs, (%)391 (77.4)2137 (73.5)0.062Abbreviations: AIM-HIGH, Triglycerides: Outcomes; BP, pressure; Open table new tab Abbreviations: (n=254) (n=251), demographic variables, medical conditions, CAD Lipid profiles 2).Table 2Baseline features randomization CKDPlacebo (N=251)Niacin (N=254)P-valueAge (s.d.)70.8 (7.4)70.6 (7.2)0.764Gender (%)200 (79.7)208 (81.9)0.529Race—African (%)10 (4.0)10 (3.9)0.978Ethnicity—Hispanic, (%)6 (2.4)13 (5.1)0.107Current (%)33 (13.3)25 (10.0)0.244Body mass index (kg/m2), (s.d.)30.4 (5.8)30.9 (5.4)0.390Coronary (%)231 (92.0)221 (87.0)0.066Diabetes, (%)102 (40.6)105 (41.3)0.873Metabolic syndrome, (%)206 (83.1)214 (84.3)0.719Hypertension, (%)194 (77.3)207 (81.5)0.243LDL cholesterol, (s.d.)74.3 (21.2)73.8 (21.9)0.794HDL (s.d.)34.5 (6.2)34.9 (6.1)0.462Triglycerides, (Q1,Q3)160 (133 ,231)175 (132, 222)0.839Diastolic (s.d.)70.9 (10.5)71.9 (9.8)0.290Systolic (s.d.)130.1 (16.9)130.9 (17.9)0.602Pulse (s.d.)59.2 (16.7)59.0 (16.2)0.920Use (%)191 (76.1)200 (78.7)0.453Abbreviations: disease; HDL, lipoprotein; LDL, Q1,Q3, interquartile range. Participants non-CKD groups achieved increases decreases arm relative group, concentration 34.5 34.9 groups, respectively. At years, 39.2 (8.2) 45.9 (12.6) respectively (placebo vs. P<0.0001). (interquartile range) 160.0 (133.0, 231.0 mg/dl) 175.0 (132.0, 222.0 group. 153.0 (111.0, 192.0 113.0 (80.0, 156.0 (P<0.0001). 47.0 (P=0.031), after years 3).Table 3Lipid status treatment: actual values valuesLipid ParameterTimeCKDaCKD: Year 1-N=454; 3-N=233.(N=505)No CKDbNo CKD: 1-N=2660; 3-N=1505.(N=2908)Placebo (N=254)Placebo (N=1444)Niacin (N=1464)Total (mg/dl), (s.d.)Baseline146.6 (26.0)146.1 (26.3)144.9 (26.7)145.3 (28.5)Year 1144.0 (25.1)137.0 (25.0)143.4 (25.6)138.2 (27.3)Change baseline-3.1 (27.3)-8.9 (31.0)-1.2 (31.1)-7.0 (32.6)Year 3140.7 (25.9)137.7 (32.1)141.6 (23.4)136.7 (27.6)Change baseline-8.6 (32.4)-10.6 (36.8)-4.7 (28.9)-10.0 (33.8)LDL (s.d.)Baseline74.3 (21.9)73.9 (22.9)74.3 (23.7)Year 170.4 (18.1)65.4 (20.0)70.4 (19.0)66.6 (19.9)Change baseline-4.8 (21.8)-8.4 (25.6)-3.5 (24.8)-7.9 (26.2)Year 367.9 (21.3)66.2 (24.1)68.4 (19.0)65.0 (21.5)Change baseline-8.8 (26.8)-9.2 (31.2)-6.6 (24.0)-10.6 (27.8)HDL (s.d.)Baseline34.5 (6.1)35.0 (5.5)34.5 (5.6)Year 138.5 (8.4)45.5 (12.2)38.4 (7.5)43.3 (10.6)Change baseline3.9 (5.9)10.8 (10.1)3.4 (5.5)8.8 (8.2)Year 339.2 (8.2)45.9 (12.6)39.1 (7.6)43.8 (11.1)Change baseline4.7 (6.3)11.3 (11.3)4.2 (5.7)9.5 (9.0)Lipoprotein (a) (nmol/l), (Q1, Q3)Baseline33.3 (15.3, 105.7)34.8 112.8)32.3 (12.8, 122.4)36.1 (13.4, 127.6)Year 132.8 (14.8, 112.14)24.6 (8.2, 90.0)30.1 (9.7, 124.9)27.5 (8.4, 110.7)Change baseline-0.7 (-9.4, 5.8)-5.6 (-19.4, 0.0)-1.3 3.8)-6.0 (-20.2, 0.1)Triglyceride Q3)Baseline160.0 231.0)175.0 222.0)163.0 (131.0, 215.0)166.0 (130.5, 218.0)Year 1153.5 (119.0, 213.5)112.0 (79.0, 164.0)155.0 (118.0, 207.0)122.5 (88.0, 172.0)Change baseline-10.5 (-37.5, 28.5)-55.0 (-93.0, -9.0)-8.0 (-45.0, 30.0)-43.0 (-80.0, -5.0)Year 3153.0 192.0)113.0 156.0)152.0 (115.0, 206.0)121.0 (85.0, 174.0)Change baseline-20.0 (-60.0, 22.0)-59.0 (-111.0, -16.0)-14.0 (-53.0, 29.0)-47.0 (-90.0, -6.0)Abbreviations: range.a 3-N=233.b No 3-N=1505. There no end points 60 (23.6%) (23.93%) reached point (ERN hazard 1.02, 95% confidence interval 0.71, 1.45). All-cause 39 deaths (15.4%) 23 (8.9%) ratio=1.73, 1.03, 2.89, P=0.038). there difference assigned 19 CV (7.5%) 12 (4.8%) ratio=1.62, 0.78, 3.33). We observe interaction models with/without stratification (data shown). Most noncardiovascular due cancer 4).Table 4Cardiovascular end-point ratios statusClinical eventCKDNo (N=254)Niacin Placebo HRaHazard based model (95% CI)Placebo (N=1464)Niacin HR CI)Exposure (patient-year)74873744444477Primary pointbPrimary defined first occurrence CHD nonfatal MI, ischemic stroke, hospitalization acute symptom-driven cerebral revascularization.60 (23.9%)60 (23.6%)1.02 (0.71–1.45)214 (14.9%)222 (15.2%)1.03 (0.85–1.24)Secondary First “high risk” syndrome40 (15.9%)41 (16.1%)1.05 (0.68–1.63)118 (8.2%)130 (8.9%)1.10 (0.85–1.41) stroke35 (13.9%)39 (15.4%)1.15 (0.73–1.82)103 (7.1%)117 (8.0%)1.13 (0.87–1.47) Cardiovascular mortality12 (4.8%)19 (7.5%)1.62 (0.78–3.33)26 (1.8%)26 (1.8%)0.99 (0.57–1.70)Overall mortality23 (9.2%)39 (15.4%)1.73 (1.03–2.89)*P=0.038.59 (4.1%)57 (3.9%)0.96 (0.67–1.38) Cardiac12 (4.8%)16 (6.3%)1.35 (0.64–2.86)22 (1.5%)22 (1.5%)0.99 (0.55–1.79) Vascular, noncardiac0 (0.0%)3 (1.2%)NA4 (0.3%)4 (0.3%)0.99 (0.25–3.97) Noncardiovascular11 (4.4%)18 (7.1%)1.67 (0.79–3.53)32 (2.2%)29 (2.0%)0.90 (0.54–1.49)Cardiovascular death MI30 (12.0%)34 (13.4%)1.16 (0.71–1.90)91 (6.3%)95 (6.5%)1.03 (0.78–1.38)Abbreviations: CHD, niacin; eGFR, rate; HR, ratio; myocardial infarction; NA, applicable.a Hazard group.b Primary revascularization.* P=0.038. applicable. When entire sample evaluated together regardless status, 2.8% (14.0%) (n=872) 1.2% (n=866) (P=0.03). statistically (P-interaction=0.004) percent year 3. Data separately shown Table 5. 3.3% (24.2%) whereas 1.8% (22.3%) result reach statistical significance (P=0.10). Conversely, 3.8% (13.6%) experienced only 1.1% (13.5%) (Figure 1). This finding (P=0.0001). incident cases observed during study.Table 5Effect eGFRTimeCKDNo (N=254)P-valuePlacebo (N=1464)P-valueBaseline (s.d.)50.5 (7.6)50.0 (7.7)84.9 (12.6)84.4 (12.9)Year 1, N19119310931106Change (s.d.)2.0 (10.3)2.6 (10.1)0.5-1.4 (9.1)0.3 (8.7)<0.0001Percent % (s.d.)4.6 (21.8)5.4 (21.3)-1.4 (11.3)0.6 (11.4)Year 3, N123110749756Change (s.d.)1.5 (11.6)-0.9 (11.3)0.1-3.3 (10.9)-1.1 (10.7)0.0001Percent (s.d.)3.3 (24.2)-1.8 (22.3)-3.8 (13.6)-1.1 (13.5)Abbreviations: niacin. Within discontinuation (32.7 22.7%, P=0.01). rates flushing, glucose, gastrointestinal symptoms arm. Specifically symptomatic flushing/itching, accounted nearly 30% reason drug 14% 6).Table 6Reasons assignmentCKDNo CKDPlaceboNiacinP-valuePlaceboNiacinP-valueN25125414441464Discontinued (%)57 (22.7%)83 (32.7%)0.012284 (19.7%)353 (24.2%)0.004Primary Flushing, itching8 (14.0%)25 (30.1%)35 (12.3%)79 (22.4%) Liver test abnormality0 (0.0%)1 (1.2%)5 (1.8%)4 (1.1%) Patient request22 (36.8%)24 (28.9%)115 (40.5%)102 (29.0%) Nonstudy physician request8 (14.0%)9 (10.8%)27 (9.5%)40 (11.3%) Other discontinue16 (28.1%)13 (15.7%)79 (27.8%)83 (23.5%) Increased glucose2 (3.5%)5 (6.0%)12 (4.2%)24 (6.8%) Gastrointestinal symptoms1 (1.8%)5 (6.0%)11 (3.9%)21 (5.9%)Abbreviation: Abbreviation: this important, high-risk respect events. As expected, much indicating very residual subgroup. It important note most because cancer, association observed. clear why results do demonstrate several possibilities: (1) prevention. 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