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Novel Risk Factors for Progression of Diabetic and Nondiabetic CKD: Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study.
Anderson, AH, Xie, D, Wang, X, Baudier, RL, Orlandi, P, Appel, LJ, Dember, LM, He, J, Kusek, JW, Lash, JP, et al
American journal of kidney diseases : the official journal of the National Kidney Foundation. 2021;(1):56-73.e1
Abstract
RATIONALE & OBJECTIVE Identification of novel risk factors for chronic kidney disease (CKD) progression may inform mechanistic investigations and improve identification of high-risk subgroups. The current study aimed to characterize CKD progression across levels of numerous risk factors and identify independent risk factors for CKD progression among those with and without diabetes. STUDY DESIGN The Chronic Renal Insufficiency Cohort (CRIC) Study is a prospective cohort study of adults with CKD conducted at 7 US clinical centers. SETTING & PARTICIPANTS Participants (N=3,379) had up to 12.3 years of follow-up; 47% had diabetes. PREDICTORS 30 risk factors for CKD progression across sociodemographic, behavioral, clinical, and biochemical domains at baseline. OUTCOMES Study outcomes were estimated glomerular filtration rate (eGFR) slope and the composite of halving of eGFR or initiation of kidney replacement therapy. ANALYTICAL APPROACH Stepwise selection of independent risk factors was performed stratified by diabetes status using linear mixed-effects and Cox proportional hazards models. RESULTS Among those without and with diabetes, respectively, mean eGFR slope was-1.4±3.3 and-2.7±4.7mL/min/1.73m2 per year. Among participants with diabetes, multivariable-adjusted hazard of the composite outcome was approximately 2-fold or greater with higher levels of the inflammatory chemokine CXCL12, the cardiac marker N-terminal pro-B-type natriuretic peptide (NT-proBNP), and the kidney injury marker urinary neutrophil gelatinase-associated lipocalin (NGAL). Among those without diabetes, low serum bicarbonate and higher high-sensitivity troponin T, NT-proBNP, and urinary NGAL levels were all significantly associated with a 1.5-fold or greater rate of the composite outcome. LIMITATIONS The observational study design precludes causal inference. CONCLUSIONS Strong associations for cardiac markers, plasma CXCL12, and urinary NGAL are comparable to that of systolic blood pressure≥140mm Hg, a well-established risk factor for CKD progression. This warrants further investigation into the potential mechanisms that these markers indicate and opportunities to use them to improve risk stratification.
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Study of cardiovascular disease prediction model based on random forest in eastern China.
Yang, L, Wu, H, Jin, X, Zheng, P, Hu, S, Xu, X, Yu, W, Yan, J
Scientific reports. 2020;(1):5245
Abstract
Cardiovascular disease (CVD) is the leading cause of death worldwide and a major public health concern. CVD prediction is one of the most effective measures for CVD control. In this study, 29930 subjects with high-risk of CVD were selected from 101056 people in 2014, regular follow-up was conducted using electronic health record system. Logistic regression analysis showed that nearly 30 indicators were related to CVD, including male, old age, family income, smoking, drinking, obesity, excessive waist circumference, abnormal cholesterol, abnormal low-density lipoprotein, abnormal fasting blood glucose and else. Several methods were used to build prediction model including multivariate regression model, classification and regression tree (CART), Naïve Bayes, Bagged trees, Ada Boost and Random Forest. We used the multivariate regression model as a benchmark for performance evaluation (Area under the curve, AUC = 0.7143). The results showed that the Random Forest was superior to other methods with an AUC of 0.787 and achieved a significant improvement over the benchmark. We provided a CVD prediction model for 3-year risk assessment of CVD. It was based on a large population with high risk of CVD in eastern China using Random Forest algorithm, which would provide reference for the work of CVD prediction and treatment in China.
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A Body Mass Index-Based Cross-Classification Approach for the Assessment of Prognostic Factors in Chronic Kidney Disease Progression.
Kataoka, H, Ono, K, Mochizuki, T, Hanafusa, N, Imai, E, Hishida, A, Nitta, K
Kidney & blood pressure research. 2019;(3):362-383
Abstract
BACKGROUND/AIMS: Cross-classification analyses are rarely reported. We investigated the prognostic factors for chronic kidney disease (CKD) progression using a body mass index (BMI)-based cross-classification approach. METHODS Patients' renal outcome (≥50% decline in the estimated glomerular filtration rate or end-stage renal disease) in each subcohort was examined. RESULTS The number of prognostic factors identified in the multivariate Cox analysis was smaller in the "BMI ≥25, female" and CKD stage 3 subcohorts than in other subcohorts. Prognostic factors identified in the "BMI ≥25, CKD stage 3" subcohort only comprised albuminuria and male sex, and those in the "BMI ≥25, female" subcohort only comprised albuminuria, hyperphosphatemia, and anemia. Albuminuria, kidney impairment, male sex, hyperphosphatemia, anemia, and increased pulse pressure × heart rate product (PP × HR; pulsatile stress) were stable renal prognostic factors in almost all subcohorts. On the other hand, the prognostic value of increased BMI, younger age, hypoalbuminemia, increased intact parathyroid hormone, and decreased estimated 24-h urinary potassium excretion (e24hUK) differed according to subcohort. BMI was positively associated with CKD progression in the "BMI ≥25, age ≥65 years" and "BMI ≥25, CKD stages 4-5" subcohorts, whereas it was negatively associated with CKD progression in the "BMI <25, diabetes mellitus" subcohort. PP × HR was independently associated with CKD progression in the "BMI <25, CKD stage 3" subcohort, which had relatively few identified renal prognostic factors. Decreased e24hUK was a renal prognostic factor for CKD progression in the "BMI <25, CKD stages 4-5" subcohort, while no significant factors were observed in the "BMI ≥25, CKD stages 4-5" subcohort. CONCLUSION A BMI-based cross-classification approach, which provides more comprehensive findings than that in previous approaches, is expected to be an effective method for evaluating renal prognostic factors in patients with CKD who are affected by multiple risk factors.
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Validation of a genetic risk score for atrial fibrillation: A prospective multicenter cohort study.
Muse, ED, Wineinger, NE, Spencer, EG, Peters, M, Henderson, R, Zhang, Y, Barrett, PM, Rivera, SP, Wohlgemuth, JG, Devlin, JJ, et al
PLoS medicine. 2018;(3):e1002525
Abstract
BACKGROUND Atrial fibrillation (AF) is the most commonly encountered arrhythmia and is associated with an elevated risk of stroke. Improving the identification of patients with the highest risk for AF to enable appropriate surveillance and treatment, if necessary, is critical to reducing AF-associated morbidity and mortality. Multiple common single nucleotide polymorphisms (SNPs) are unequivocally associated with the lifetime risk of AF. In the current study we aimed to prospectively validate an AF genetic risk score (GRS) in previously undiagnosed patients at risk for AF. METHODS AND FINDINGS Individuals 40 years of age or older with 1 clinical risk factor for AF, presenting with symptoms of AF, or with a first diagnosis of AF, were enrolled for genetic testing and ambulatory cardiac rhythm monitoring with an adhesive patch monitor or a long-term Holter monitor (mean wear time 10 days 21 hours and 13 days 18 hours, respectively). An AF event was the first diagnosis of AF by ECG, patch monitor, or long-term Holter monitor. The AF GRS was determined for each participant based on the weighted contribution of 12 genetic risk loci. Of 904 participants, 85 manifested AF. Their mean age was 66.2 (SD 11.8) years; 38% of participants were male. Participants in the highest quintile of AF GRS were more likely (odds ratio 3.11; 95% CI 1.27-7.58; p = 0.01) to have had an AF event than participants in the lowest quintile after adjusting for age, sex, smoking status, BMI, hypertension, diabetes mellitus, heart failure, and prior myocardial infarction. Study limitations included an ethnically homogenous population, a restricted rhythm monitoring period, and the evolving discovery of SNPs associated with AF. CONCLUSIONS Prospective assessment of a GRS for AF identified participants with elevated risk of AF beyond established clinical criteria. Accordingly, a GRS for AF could be incorporated into overall risk assessment to better identify patients at the highest risk of developing AF, although further testing in larger populations is needed to confirm these findings. TRIAL REGISTRATION ClinicalTrials.gov NCT01970969.
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Prospective evaluation of integrated device diagnostics for heart failure management: results of the TRIAGE-HF study.
Virani, SA, Sharma, V, McCann, M, Koehler, J, Tsang, B, Zieroth, S
ESC heart failure. 2018;(5):809-817
Abstract
AIMS: The primary aim of the TRIAGE-HF trial was to correlate cardiac implantable electronic device-generated heart failure risk status (HFRS) with signs, symptoms, and patient behaviours classically associated with worsening heart failure (HF). METHODS AND RESULTS TRIAGE-HF enrolled 100 subjects with systolic HF implanted with a Medtronic high-performance device and followed up at three Canadian HF centres. Study follow-up was up to 8 months. The HFRS assigned each subject's overall risk of HF hospitalization in the next 30 days and also highlighted abnormal device parameters contributing to a patient's risk status at the time of remote data transmission. Subjects with a high HFRS were contacted by telephone to assess symptoms, and compliance with prescribed therapies, nutrition, and exercise. Clinician-assessed risk and HFRS-calculated risk were correlated at both study baseline and exit. Twenty-four high HFRS occurrences were observed among 100 subjects. Device parameters associated with increased risk of HF hospitalization included OptiVol index (n = 20), followed by low patient activity (n = 18) and elevated night heart rate (n = 12). High HFRS was associated with symptoms of worsening HF in 63% of cases (n = 15) increasing to 83% of cases (n = 20) when non-compliance with pharmacological therapies and lifestyle was considered. CONCLUSIONS TRIAGE-HF is the first study to provide prospective data on the distribution of abnormal device parameters contributing to high HFRS. High HFRS has good predictive accuracy for patient-reported signs, symptoms, and behaviours associated with worsening HF status. As such, HFRS may be a useful tool for ambulatory HF monitoring to improve both patient-centred and health system level outcomes.
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Unfavourable risk factor control after coronary events in routine clinical practice.
Sverre, E, Peersen, K, Husebye, E, Gjertsen, E, Gullestad, L, Moum, T, Otterstad, JE, Dammen, T, Munkhaugen, J
BMC cardiovascular disorders. 2017;(1):40
Abstract
BACKGROUND Risk factor control after a coronary event in a recent European multi-centre study was inadequate. Patient selection from academic centres and low participation rate, however, may underscore failing risk factor control in routine clinical practice. Improved understanding of the patient factors that influence risk factor control is needed to improve secondary preventive strategies. The objective of the present paper was to determine control of the major risk factors in a coronary population from routine clinical practice, and how risk factor control was influenced by the study factors age, gender, number of coronary events, and time since the index event. METHODS A cross-sectional study determined risk factor control and its association with study factors in 1127 patients (83% participated) aged 18-80 years with acute myocardial infarction and/or revascularization identified from medical records. Study data were collected from a self-report questionnaire, clinical examination, and blood samples after 2-36 months (median 16) follow-up. RESULTS Twenty-one percent were current smokers at follow-up. Of those smoking at the index event 56% continued smoking. Obesity was found in 34%, and 60% were physically inactive. Although 93% were taking blood-pressure lowering agents and statins, 46% were still hypertensive and 57% had LDL cholesterol >1.8 mmol/L at follow-up. Suboptimal control of diabetes was found in 59%. The patients failed on average to control three of the six major risk factors, and patients with >1 coronary events (p < 0.001) showed the poorest overall control. A linear increase in smoking (p < 0.01) and obesity (p < 0.05) with increasing time since the event was observed. CONCLUSIONS The majority of coronary patients in a representative Norwegian population did not achieve risk factor control, and the poorest overall control was found in patients with several coronary events. New strategies for secondary prevention are clearly needed to improve risk factor control. Even modest advances will provide major health benefits. TRIAL REGISTRATION Registered at ClinicalTrials.gov (ID NCT02309255 ).
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Excess mortality and guideline-indicated care following non-ST-elevation myocardial infarction.
Dondo, TB, Hall, M, Timmis, AD, Gilthorpe, MS, Alabas, OA, Batin, PD, Deanfield, JE, Hemingway, H, Gale, CP
European heart journal. Acute cardiovascular care. 2017;(5):412-420
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Abstract
BACKGROUND Adherence to guideline-indicated care for the treatment of non-ST-elevation myocardial infarction (NSTEMI) is associated with improved outcomes. We investigated the extent and consequences of non-adherence to guideline-indicated care across a national health system. METHODS A cohort study ( ClinicalTrials.gov identifier: NCT02436187) was conducted using data from the Myocardial Ischaemia National Audit Project ( n = 389,057 NSTEMI, n = 247 hospitals, England and Wales, 2003-2013). Accelerated failure time models were used to quantify the impact of non-adherence on survival according to dates of guideline publication. RESULTS Over a period of 1,079,044 person-years (median 2.2 years of follow-up), 113,586 (29.2%) NSTEMI patients died. Of those eligible to receive care, 337,881 (86.9%) did not receive one or more guideline-indicated intervention; the most frequently missed were dietary advice ( n = 254,869, 68.1%), smoking cessation advice ( n = 245,357, 87.9%), P2Y12 inhibitors ( n = 192,906, 66.3%) and coronary angiography ( n = 161,853, 43.4%). Missed interventions with the strongest impact on reduced survival were coronary angiography (time ratio: 0.18, 95% confidence interval (CI): 0.17-0.18), cardiac rehabilitation (time ratio: 0.49, 95% CI: 0.48-0.50), smoking cessation advice (time ratio: 0.53, 95% CI: 0.51-0.57) and statins (time ratio: 0.56, 95% CI: 0.55-0.58). If all eligible patients in the study had received optimal care at the time of guideline publication, then 32,765 (28.9%) deaths (95% CI: 30,531-33,509) may have been prevented. CONCLUSION The majority of patients hospitalised with NSTEMI missed at least one guideline-indicated intervention for which they were eligible. This was significantly associated with excess mortality. Greater attention to the provision of guideline-indicated care for the management of NSTEMI will reduce premature cardiovascular deaths.
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A Phase 3 Study of Evolocumab (AMG 145) in Statin-Treated Japanese Patients at High Cardiovascular Risk.
Kiyosue, A, Honarpour, N, Kurtz, C, Xue, A, Wasserman, SM, Hirayama, A
The American journal of cardiology. 2016;(1):40-7
Abstract
Evolocumab (AMG 145), a fully human monoclonal antibody against PCSK9, significantly reduced low-density lipoprotein cholesterol (LDL-C) levels in phase 2 and 3 studies. This phase 3 study evaluated the efficacy and safety of evolocumab plus atorvastatin in Japanese patients with hyperlipidemia or mixed dyslipidemia and high cardiovascular risk. Patients were randomized to atorvastatin 5 or 20 mg/day for 4 weeks. Subsequently, patients underwent second randomization to evolocumab 140 mg biweekly (Q2W) or 420 mg monthly (QM) or placebo Q2W or QM. Coprimary end points were % change from baseline in LDL-C at week 12 and mean of weeks 10 and 12. Secondary end points included change and % change in other lipids and proportion of patients reaching LDL-C <70 mg/dl. Adverse events and laboratory values were recorded. Four hundred four patients were randomized to study drug. At baseline, the mean (SD) age was 61 (10) years (placebo) and 62 (11) years (evolocumab); 39% and 40% were women; 14% and 12% had cerebrovascular or peripheral arterial disease; and 51% and 47% had diabetes. At entry, mean (SD) calculated LDL-C was 128 (23) mg/dL; after stabilization on atorvastatin 5 and 20 mg/day, baseline LDL-C levels were 118 (35) and 94 (24) mg/dL, respectively. Mean LDL-C reductions at week 12 for evolocumab versus placebo ranged from 67% to 76%. No imbalances were observed in adverse events between treatment groups. Efficacy and safety for Q2W or QM evolocumab dosing were similar. In conclusion, in high-risk Japanese patients receiving stable statin therapy, evolocumab markedly reduced LDL-C and was well tolerated.
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Value of CACS compared with ETT and myocardial perfusion imaging for predicting long-term cardiac outcome in asymptomatic and symptomatic patients at low risk for coronary disease: clinical implications in a multimodality imaging world.
Chang, SM, Nabi, F, Xu, J, Pratt, CM, Mahmarian, AC, Frias, ME, Mahmarian, JJ
JACC. Cardiovascular imaging. 2015;(2):134-44
Abstract
OBJECTIVES This prospective, observational study in 988 asymptomatic or symptomatic low-risk patients without prior coronary artery disease was conducted to define the relative value of coronary artery calcium score (CACS), exercise treadmill testing (ETT), and stress myocardial perfusion single-photon emission computed tomography (SPECT) variables in predicting long-term risk stratification. BACKGROUND CACS, ETT, and stress myocardial perfusion SPECT results predict patients' outcome. There are currently no data comparing their relative value in long-term risk stratification. METHODS Patients were stratified by Framingham risk score (FRS), with a median follow-up of 6.9 years. Cardiac events were defined as a composite of cardiac death, nonfatal myocardial infarction, and the need for coronary revascularization. Most patients (87%) were considered appropriate candidates for functional testing as defined by current appropriate use criteria. RESULTS The long-term cardiac event rate was 11.2% (1.6% per year). Multivariate risk predictors in all patients and in the appropriate use cohort were abnormal SPECT (hazard ratio [HR]: 1.83 and 1.99), ETT ischemia (HR: 1.70 and 1.76), decreasing exercise capacity (HR: 1.11 and 1.17), decreasing Duke treadmill score (HR: 1.07 for both), and CACS severity (HR: 1.29 for both), respectively. Throughout the 10-year follow-up, CACS improved risk prediction, with event rates ranging from 0.6% per year (CACS ≤10) to 3.7% per year (CACS >400) (p < 0.0001). CACS also improved risk prediction in all patients, in the appropriate use cohort and among those with low-risk ETT and SPECT results (all, p < 0.001). Area under the receiver-operating characteristic curve was increased when CACS variables (from 0.63 to 0.70; p = 0.01) but not ETT variables (from 0.63 to 0.65) were added to FRS. Moreover, net reclassification improvement was significantly increased when CACS was added to FRS + functional variables in all patients and in the appropriate use cohort (both, p < 0.0001). CONCLUSIONS CACS significantly improved long-term risk stratification beyond FRS, ETT, and SPECT results across the spectrum of clinical risk and importantly even among those who are currently considered appropriate candidates for functional testing or have low-risk functional test results. Our findings support CACS as a first-line test over ETT or SPECT for accurately assessing long-term risk in such patients.
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Functional Impairments Mediate Association Between Clinical Fracture Risk and Type 2 Diabetes Mellitus in Older Women.
Lee, RH, Pieper, CF, Colón-Emeric, C
Journal of the American Geriatrics Society. 2015;(8):1546-51
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Abstract
OBJECTIVES To examine the effect of functional impairments in older women with diabetes mellitus (DM) on incident clinical fractures. DESIGN Secondary analysis of two large prospective cohort studies. SETTING North Carolina Established Populations for Epidemiologic Studies of the Elderly (EPESE) and Women's Health Initiative (WHI) clinical trials. PARTICIPANTS EPESE included 2,704 community-dwelling women aged 65 and older; WHI clinical trials included 68,125 postmenopausal women. MEASUREMENTS Women with DM at baseline were compared with women without in successive Cox proportional hazards models. Functional limitations were determined according to self-reported difficulties with activities of daily living (ADLs) and physical activities. RESULTS The risk of any clinical fracture during the study period was greater in women with DM, after controlling for age, race and ethnicity, and body mass index, in the EPESE (hazard ratio (HR) = 1.36, 95% confidence interval (CI) = 1.08-1.72) and WHI (HR = 1.29, 95% CI = 1.19-1.39) cohorts. After inclusion of functional limitations, the greater risk of fracture associated with DM decreased in the EPESE (HR = 1.25, 95% CI = 0.98-1.59) and WHI (HR = 1.21, 95% CI = 1.12-1.31) cohorts. In participants with DM, difficulties with moderate physical activities, such as bending or stooping, walking several blocks, and heavy housework, were significantly associated with incident fracture (P < .05). CONCLUSION Older women with DM are at greater risk of clinical fractures than those without, independent of bone mineral density. Greater functional impairment in moderate physical activities mediates this greater fracture risk in part, although there remains an unexplained residual DM-associated risk for fracture.