Renal, Cardiovascular, and Safety Outcomes of Canagliflozin by Baseline Kidney Function: A Secondary Analysis of the CREDENCE Randomized Trial

BackgroundCanagliflozin reduced renal and cardiovascular events in people with type 2 diabetes in the CREDENCE trial. We assessed efficacy and safety of canagliflozin by initial estimated glomerular filtration rate (eGFR).MethodsCREDENCE randomly assigned 4401 participants with an eGFR of 30 to <90 ml/min per 1.73 m2 and substantial albuminuria to canagliflozin 100 mg or placebo. We used Cox proportional hazards regression to analyze effects on renal and cardiovascular efficacy and safety outcomes within screening eGFR subgroups (30 to <45, 45 to <60, and 60 to <90 ml/min per 1.73 m2) and linear mixed effects models to analyze the effects on eGFR slope.ResultsAt screening, 1313 (30%), 1279 (29%), and 1809 (41%) participants had an eGFR of 30 to <45, 45 to <60, and 60 to <90 ml/min per 1.73 m2, respectively. The relative benefits of canagliflozin for renal and cardiovascular outcomes appeared consistent among eGFR subgroups (all P interaction >0.11). Subgroups with lower eGFRs, who were at greater risk, exhibited larger absolute benefits for renal outcomes. Canagliflozin’s lack of effect on serious adverse events, amputations, and fractures appeared consistent among eGFR subgroups. In all subgroups, canagliflozin use led to an acute eGFR drop followed by relative stabilization of eGFR loss. Among those with an eGFR of 30 to <45 ml/min per 1.73 m2, canagliflozin led to an initial drop of 2.03 ml/min per 1.73 m2. Thereafter, decline in eGFR was slower in the canagliflozin versus placebo group (–1.72 versus –4.33 ml/min per 1.73 m2; between-group difference 2.61 ml/min per 1.73 m2).ConclusionsCanagliflozin safely reduced the risk of renal and cardiovascular events, with consistent results across eGFR subgroups, including the subgroup initiating treatment with an eGFR of 30 to <45 ml/min per 1.73 m2. Absolute benefits for renal outcomes were greatest in subgroups with lower eGFR.Clinical Trial registry name and registration numberEvaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy (CREDENCE), NCT02065791.

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Added value of cardiovascular calcifications for prediction of recurrent cardiovascular events and cardiovascular interventions in patients with established cardiovascular disease

The International Journal of Cardiovascular Imaging ◽

10.1007/s10554-021-02164-9 ◽

2021 ◽

Author(s):

Cilie C. van ’t Klooster ◽

◽

Yolanda van der Graaf ◽

Hendrik M. Nathoe ◽

Michiel L. Bots ◽

...

Keyword(s):

Cardiovascular Disease ◽

Heart Valve ◽

Cardiovascular Events ◽

Proportional Hazards ◽

Cox Proportional Hazards ◽

Added Value ◽

Cvd Risk ◽

Major Cardiovascular Events ◽

Cox Proportional Hazards Models ◽

Cardiovascular Interventions

AbstractThe purpose is to investigate the added prognostic value of coronary artery calcium (CAC), thoracic aortic calcium (TAC), and heart valve calcium scores for prediction of a combined endpoint of recurrent major cardiovascular events and cardiovascular interventions (MACE +) in patients with established cardiovascular disease (CVD). In total, 567 patients with established CVD enrolled in a substudy of the UCC-SMART cohort, entailing cardiovascular CT imaging and calcium scoring, were studied. Five Cox proportional hazards models for prediction of 4-year risk of MACE + were developed; traditional CVD risk predictors only (model I), with addition of CAC (model II), TAC (model III), heart valve calcium (model IV), and all calcium scores (model V). Bootstrapping was performed to account for optimism. During a median follow-up of 3.43 years (IQR 2.28–4.74) 77 events occurred (MACE+). Calibration of predicted versus observed 4-year risk for model I without calcium scores was good, and the c-statistic was 0.65 (95%CI 0.59–0.72). Calibration for models II–V was similar to model I, and c-statistics were 0.67, 0.65, 0.65, and 0.68 for model II, III, IV, and V, respectively. NRIs showed improvement in risk classification by model II (NRI 15.24% (95%CI 0.59–29.39)) and model V (NRI 20.00% (95%CI 5.59–34.92)), but no improvement for models III and IV. In patients with established CVD, addition of the CAC score improved performance of a risk prediction model with classical risk factors for the prediction of the combined endpoint MACE+ . Addition of the TAC or heart valve score did not improve risk predictions.

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Association Between Change in Accelerometer-Measured and Self-Reported Physical Activity and Cardiovascular Disease in the Look AHEAD Trial

10.2337/figshare.17157926 ◽

2022 ◽

Author(s):

John M. Jakicic ◽

Robert I. Berkowitz ◽

Paula Bolin ◽

George A. Bray ◽

Jeanne M. Clark ◽

...

Keyword(s):

Physical Activity ◽

Type 2 Diabetes ◽

Cardiovascular Disease ◽

Proportional Hazards ◽

Secondary Analysis ◽

Cox Proportional Hazards ◽

Self Report ◽

Look Ahead ◽

The Look

OBJECTIVE: To conduct post-hoc secondary analysis examining the association between change in physical activity (PA), measured with self-report and accelerometry, from baseline to 1 and 4 years and cardiovascular disease (CVD) outcomes in the Look AHEAD Trial. RESEARCH DESIGN AND METHODS: Participants were adults with overweight/obesity and type 2 diabetes with PA data at baseline and year 1 or 4 (n = 1,978). Participants were randomized to diabetes support and education or intensive lifestyle intervention. Measures included accelerometry-measured moderate-to-vigorous PA (MVPA), self-reported PA, and composite (morbidity and mortality) CVD outcomes. RESULTS: In pooled analyses of all participants, using Cox proportional hazards models, each 100 MET-min/wk increase in accelerometry-measured MVPA from baseline to 4 years was associated with decreased risk of the subsequent primary composite outcome of CVD. Results were consistent for changes in total MVPA [HR=0.97 (95% CI: 0.95, 0.99)] and MVPA accumulated in >10-minute bouts [HR=0.95 (95% CI: 0.91, 0.98)], with a similar pattern for secondary CVD outcomes. Change in accelerometry-measured MVPA at 1 year and self-reported change in PA at 1 and 4 years were not associated with CVD outcomes. CONCLUSIONS: Increased accelerometry-measured MVPA from baseline to year 4 is associated with decreased risk of CVD outcomes. This suggests the need for long-term engagement in MVPA to reduce the risk of CVD in adults with overweight/obesity and type 2 diabetes.

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Effect of Blood Pressure on Cardiovascular Outcomes: A 15-Year Prospective Cohort Study

10.21203/rs.3.rs-904375/v1 ◽

2021 ◽

Author(s):

Qi Yu ◽

Qing-Dong Jin

Keyword(s):

Blood Pressure ◽

Proportional Hazards ◽

Positive Association ◽

Cubic Spline ◽

Cox Proportional Hazards ◽

Cardiovascular Outcomes ◽

Composite Outcome ◽

Nutrition Survey ◽

Cox Models ◽

Diabetes Status

Abstract Objective The association between blood pressure(BP) and cardiovascular outcomes has not been well investigated by large prospective studies on Chinese. We aim to analyze the association of BP with cardiovascular outcomes in Chinese population. Method We included a total of 4,569 adults aged 40–90 years from the China Health and Nutrition Survey (CHNS) cohort. Cox proportional hazards regression models were used to estimate hazard ratios and 95% CIs. Restricted cubic spline analyses were used to explore linear and nonlinear relationships of BP with cardiovascular outcomes. Result With a mean follow-up of 12.1 years, a total of 4,569 individuals were enrolled in our study, of whom 403 developed cardiovascular outcomes. Multivariable adjusted Cox models showed a strong positive association between BP and cardiovascular outcomes. SBP was significantly associated with composite outcome(HR per 10 mmHg 1.23[1.16–1.29]), myocardial infarction(MI)(HR per 10 mmHg 1.17[1.07–1.27]), and stroke(HR per 10 mmHg 1.29[1.21–1.38]). DBP was significantly associated with composite outcome(HR per 10 mmHg 1.32[1.20–1.44]), MI(HR per 10 mmHg 1.26[1.10–1.44]), and stroke(HR per 10 mmHg 1.39[1.25–1.55]). Restricted cubic spline analyses showed linear relationships of either SBP or DBP with composite outcome, MI and stroke. Conclusion Either SBP or DBP is independently and linearly related to the risk of cardiovascular outcomes. These associations are steeper for stroke than for MI, and vary widely by age, use of antihypertensive treatment, and diabetes status.

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Treatment of Sleep Disturbance May Reduce the Risk of Future Probable Alzheimer’s Disease

Journal of Aging and Health ◽

10.1177/0898264318795567 ◽

2018 ◽

Vol 31 (2) ◽

pp. 322-342 ◽

Cited By ~ 3

Author(s):

Shanna L. Burke ◽

Tianyan Hu ◽

Christine E. Spadola ◽

Aaron Burgess ◽

Tan Li ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Sleep Disturbance ◽

Proportional Hazards ◽

Secondary Analysis ◽

Cox Proportional Hazards ◽

Data Set ◽

Proportional Hazards Regression ◽

Increased Risk ◽

Research Questions

Objective: This study explored two research questions: (a) Does sleep medication neutralize or provide a protective effect against the hazard of Alzheimer’s disease (AD)? (b) Do apolipoprotein (APOE) e4 carriers reporting a sleep disturbance experience an increased risk of AD? Method: This study is a secondary analysis of the National Alzheimer’s Coordinating Center’s Uniform Data Set ( n = 6,782) using Cox proportional hazards regression. Results: Sleep disturbance was significantly associated with eventual AD development. Among the subset of participants taking general sleep medications, no relationship between sleep disturbance and eventual AD was observed. Among individuals not taking sleep medications, the increased hazard between the two variables remained. Among APOE e4 carriers, sleep disturbance and AD were significant, except among those taking zolpidem. Discussion: Our findings support the emerging link between sleep disturbance and AD. Our findings also suggest a continued need to elucidate the mechanisms that offer protective factors against AD development.

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Serum FGF21 Is Associated with Future Cardiovascular Events in Patients with Coronary Artery Disease

Cardiology ◽

10.1159/000486127 ◽

2018 ◽

Vol 139 (4) ◽

pp. 212-218 ◽

Cited By ~ 9

Author(s):

Yun Shen ◽

Xueli Zhang ◽

Yiting Xu ◽

Qin Xiong ◽

Zhigang Lu ◽

...

Keyword(s):

Coronary Artery Disease ◽

Regression Analysis ◽

Coronary Artery ◽

Cardiovascular Events ◽

Proportional Hazards ◽

Cox Proportional Hazards ◽

Cox Proportional Hazards Regression ◽

Proportional Hazards Regression ◽

Kaplan Meier ◽

Artery Disease

Objectives: To investigate whether serum fibroblast growth factor 21 (FGF21) levels can be used to predict the future development of major adverse cardiovascular events (MACEs). Methods: This study included 253 patients who received subsequent follow-up, and complete data were collected for 234 patients. Independent predictors of MACEs were identified by using the Cox proportional-hazards regression analysis. The prognostic value of FGF21 levels for MACEs was evaluated by Kaplan-Meier survival analysis. Results: Of 229 patients finally enrolled in the analysis, 27/60 without coronary artery disease (CAD) at baseline experienced a MACE, and 132/169 patients with CAD at baseline experienced a MACE. Among patients with CAD at baseline, serum FGF21 levels were significantly higher in patients with MACEs (p < 0.05) than in patients without MACEs. Kaplan-Meier survival analysis showed patients with a higher serum FGF21 had a significantly lower event-free survival (p = 0.001) than those with a lower level. Further Cox proportional-hazards regression analysis, including the traditional risk factors for cardiovascular disease, showed that serum FGF21 was an independent predictor of MACE occurrence. Conclusions: In patients with CAD at baseline, an elevated serum FGF21 level was associated with the development of a MACE in the future.

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Non-alcoholic fatty liver disease and incident major adverse cardiovascular events: results from a nationwide histology cohort

Gut ◽

10.1136/gutjnl-2021-325724 ◽

2021 ◽

pp. gutjnl-2021-325724

Author(s):

Tracey G Simon ◽

Bjorn Roelstraete ◽

Hannes Hagström ◽

Johan Sundström ◽

Jonas F Ludvigsson

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

Fatty Liver Disease ◽

Cardiovascular Events ◽

Proportional Hazards ◽

Cox Proportional Hazards ◽

Major Adverse Cardiovascular Events ◽

Alcoholic Fatty Liver ◽

Alcoholic Fatty Liver Disease ◽

Population Controls

ObjectiveSome data suggest a positive association between non-alcoholic fatty liver disease (NAFLD) and incident major adverse cardiovascular events (MACEs). However, data are lacking from large cohorts with liver histology, which remains the gold standard for staging NAFLD severity.DesignThis population-based cohort included all Swedish adults with histologically confirmed NAFLD and without cardiovascular disease (CVD) at baseline (1966–2016, n=10 422). NAFLD was defined from prospectively recorded histopathology and categorised as simple steatosis, non-fibrotic steatohepatitis, non-cirrhotic fibrosis and cirrhosis. Patients with NAFLD were matched to ≤5 population controls without NAFLD or CVD, by age, sex, calendar year and county (n=46 517). Using Cox proportional hazards modelling, we calculated multivariable adjusted HRs (aHRs) and 95% CIs for MACE outcomes (ie, ischaemic heart disease (IHD), stroke, congestive heart failure (CHF) or cardiovascular (CV) mortality).ResultsOver a median of 13.6 years, incident MACE was confirmed in 2850 patients with NAFLD and 10 648 controls. Patients with NAFLD had higher incidence of MACE than controls (24.3 vs 16.0/1000 person-years (PY); difference=8.3/1000 PY; aHR 1.63, 95% CI 1.56 to 1.70), including higher rates of IHD (difference=4.2/1000 PY; aHR 1.64, 95% CI 1.54 to 1.75), CHF (difference=3.3/1000 PY; aHR 1.75, 95% CI 1.63 to 1.87), stroke (difference=2.4/1000 PY; aHR 1.58, 95% CI 1.46 to 1.71) and CV mortality (difference=1.2/1000 PY; aHR 1.37, 95% CI 1.27 to 1.48). Rates of incident MACE increased progressively with worsening NAFLD severity (ptrend=0.02), with the highest incidence observed with cirrhosis (difference vs controls=27.2/1000 PY; aHR 2.15, 95% CI 1.77 to 2.61).ConclusionCompared with matched population controls, patients with biopsy-proven NAFLD had significantly higher incidence of MACE, including IHD, stroke, CHF and CV mortality. Excess risk was evident across all stages of NAFLD and increased with worsening disease severity.

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Abstract WP218: Increased Systolic Blood Pressure Variability Among Diabetic Patients is Associated With Higher Risk of Incident Stroke: A Secondary Analysis of ACCORDION

Stroke ◽

10.1161/str.51.suppl_1.wp218 ◽

2020 ◽

Vol 51 (Suppl_1) ◽

Author(s):

Adam H de Havenon ◽

Ka-Ho Wong ◽

Eva Mistry ◽

Mohammad Anadani ◽

Shadi Yaghi ◽

...

Keyword(s):

Blood Pressure ◽

Blood Pressure Variability ◽

Proportional Hazards ◽

Secondary Analysis ◽

Cox Proportional Hazards ◽

Diabetic Patients ◽

Adjusted Risk ◽

Cox Proportional Hazards Models ◽

Increased Risk

Background: Increased blood pressure variability (BPV) has been associated with stroke risk, but never specifically in patients with diabetes. Methods: This is a secondary analysis of the Action to Control Cardiovascular Risk in Diabetes Follow-On Study (ACCORDION), the long term follow-up extension of ACCORD. Visit-to-visit BPV was analyzed using all BP readings during the first 36 months. The primary outcome was incident ischemic or hemorrhagic stroke after 36 months. Differences in mean BPV was tested with Student’s t-test. We fit Cox proportional hazards models to estimate the adjusted risk of stroke across lowest vs. highest quintile of BPV and report hazard ratios along with 95% confidence intervals (CI). Results: Our analysis included 9,241 patients, with a mean (SD) age of 62.7 (6.6) years and 61.7% were male. Mean (SD) follow-up was 5.7 (2.4) years and number of BP readings per patient was 12.0 (4.3). Systolic, but not diastolic, BPV was higher in patients who developed stroke (Table 1). The highest quintile of SBP SD was associated with increased risk of incident stroke, independent of mean blood pressure or other potential confounders. (Table 2, Figure 1). There was no interaction between SBP SD and treatment arm assignment, although the interaction for glucose approached significance (Table 2). Conclusion: Higher systolic BPV was associated with incident stroke in a large cohort of diabetic patients. Future trials of stroke prevention may benefit from interventions targeting BPV reduction.

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Abstract T MP48: Androgen Suppression in Patients with Prostate Cancer Increases Incidence of Combined Cardiovascular Outcomes

Stroke ◽

10.1161/str.46.suppl_1.tmp48 ◽

2015 ◽

Vol 46 (suppl_1) ◽

Author(s):

Zuber S Ali ◽

Danielle M Greere ◽

Robyn L Shearer ◽

Syed Ali Gardezi ◽

Arshad Jahangir

Keyword(s):

Prostate Cancer ◽

Proportional Hazards ◽

Age Groups ◽

The Elderly ◽

Cox Proportional Hazards ◽

Cardiovascular Outcomes ◽

Elevated Risk ◽

Disease Stage ◽

Cox Proportional Hazards Models ◽

Androgen Suppression

Introduction: Androgen suppression therapy for prostate cancer is controversial due to adverse fatal and non-fatal cardiovascular outcomes reported in some studies. However, effects of androgen suppression on stroke have not been fully assessed in the elderly. Methods: Patients diagnosed with prostate cancer during 2007-2013 in a large community-based healthcare system were identified from the Cancer Registry, electronic records, and billing codes. Those who underwent androgen suppression therapy with Gonadotropin-releasing hormone agonist (GnRH) were propensity-matched to patients treated without androgen suppression therapy by age at cancer diagnosis, race/ethnicity, disease stage and outcome, body mass index and use of surgery, radiation, and chemotherapy. Tests of independence and Cox proportional hazards models were used to examine effects of hormone therapy on acute myocardial infarction (AMI), stroke, and mortality outcomes. Models also adjusted for patient comorbidities. Results: A total of 1282 patients and 641 matched-pairs were identified, with mean diagnosis age of 69 yr and follow-up period of 3.05 yr. Effects of androgen suppression therapy on AMI (P=0.051) and stroke (P=0.062) were of marginal to non-significance, but adjusted-odds of death and combined AMI, stroke, and death were 1.61 times (P=0.002; odds ratio [OR] 95% CI: 1.19-2.18) and 1.70 times (P<0.001; OR 95% CI: 1.26-2.28) greater, respectively, for men with than without androgen suppression. An interaction of androgen suppression and age-group (<65 yr, 65-74 yr, >74 yr) was discovered for combined outcomes, suggesting increased probability of AMI, stroke, and/or death with age (8.6-20.0%; P=0.003) for patients without androgen suppression but elevated risk of outcomes across all age groups (18.3-22.4%; P=0.546) for men treated with androgen suppression therapy. Conclusion: Endogenous androgen suppression presents elevated risk of combined cardiovascular and death outcomes, especially for men <65 yr.

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Out-of-sequence DTP and measles vaccinations and child mortality in Guinea-Bissau: a reanalysis

BMJ Open ◽

10.1136/bmjopen-2018-024893 ◽

2019 ◽

Vol 9 (9) ◽

pp. e024893 ◽

Cited By ~ 1

Author(s):

Sanne M Thysen ◽

Amabelia Rodrigues ◽

Peter Aaby ◽

Ane B Fisker

Keyword(s):

Mortality Rate ◽

Child Mortality ◽

Proportional Hazards ◽

Child Survival ◽

Secondary Analysis ◽

Oral Polio Vaccine ◽

Vaccination Schedule ◽

Cox Proportional Hazards ◽

Vaccination Status ◽

Guinea Bissau

ObjectivesTo assess whether the sequence of diphtheria-tetanus-pertussis vaccine (DTP) and measles vaccine (MV) was associated with child survival in a dataset previously used to assess non-specific effects of vaccines with no consideration of vaccination sequence.DesignProspective cohort study analysed using the landmark approach.SettingBandim Health Project’s Health and Demographic Surveillance System covering 100 village clusters in rural Guinea-Bissau. The recommended vaccination schedule was BCG and oral polio vaccine (OPV) at birth, DTP and OPV at 6, 10 and 14 weeks, MV at 9 months and booster DTP and OPV at 18 months of age.ParticipantsChildren aged 9–17 months (main analysis) and 18–35 months (secondary analysis: age of booster DTP) with vaccination status assessed between April 1991 and April 1996.MethodsSurvival during the 6 months after assessing vaccination status was compared by vaccination sequence in Cox-proportional hazards models with age as underlying time. Analyses were stratified by sex and village cluster.Main outcome measureMortality rate ratio (MRR) for out-of-sequence vaccinations compared with in-sequence vaccinations.ResultsAmong children aged 9–17 months, 60% of observations (3574/5937) were from children who had received both MV and DTP. Among these, 1590 observations were classified as in-sequence vaccinations (last DTP before MV), and 1984 observations were out-of-sequence vaccinations (1491: MV with DTP and 493: MV before DTP). Out-of-sequence vaccinations were associated with higher mortality than in-sequence vaccinations (MRR 2.10, 95% CI 1.07 to 4.11); the MRR was 2.30 (95% CI 1.15 to 4.58) for MV with DTP and 1.45 (95% CI 0.50 to 4.22) for DTP after MV. Associations were similar for boys and girls (p=0.77). Between 18 and 35 months the mortality rate increased among children vaccinated in-sequence and the differential effect of out-of-sequence vaccinations disappeared.ConclusionOut-of-sequence vaccinations may increase child mortality. Hence, sequence of vaccinations should be considered when planning vaccination programmes or introducing new vaccines into the current vaccination schedule.

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Bi-directional association between epilepsy and dementia

Neurology ◽

10.1212/wnl.0000000000011077 ◽

2020 ◽

Vol 95 (24) ◽

pp. e3241-e3247 ◽

Cited By ~ 1

Author(s):

Maria Stefanidou ◽

Alexa S. Beiser ◽

Jayandra Jung Himali ◽

Teng J. Peng ◽

Orrin Devinsky ◽

...

Keyword(s):

Proportional Hazards ◽

Secondary Analysis ◽

Cox Proportional Hazards ◽

Dementia Risk ◽

Incident Dementia ◽

Heart Study ◽

Allele Status ◽

Ε4 Allele ◽

Nested Case Control

ObjectiveTo assess the risk of incident epilepsy among participants with prevalent dementia and the risk of incident dementia among participants with prevalent epilepsy in the Framingham Heart Study (FHS).MethodsWe analyzed prospectively collected data in the Original and Offspring FHS cohorts. To determine the risk of developing epilepsy among participants with dementia and the risk of developing dementia among participants with epilepsy, we used separate, nested, case–control designs and matched each case to 3 age-, sex- and FHS cohort–matched controls. We used Cox proportional hazards regression analysis, adjusting for sex and age. In secondary analysis, we investigated the role of education level and APOE ε4 allele status in modifying the association between epilepsy and dementia.ResultsA total of 4,906 participants had information on epilepsy and dementia and dementia follow-up after age 65. Among 660 participants with dementia and 1,980 dementia-free controls, there were 58 incident epilepsy cases during follow-up. Analysis comparing epilepsy risk among dementia cases vs controls yielded a hazard ratio (HR) of 1.82 (95% confidence interval 1.05–3.16, p = 0.034). Among 43 participants with epilepsy and 129 epilepsy-free controls, there were 51 incident dementia cases. Analysis comparing dementia risk among epilepsy cases vs controls yielded a HR of 1.99 (1.11–3.57, p = 0.021). In this group, among participants with any post–high school education, prevalent epilepsy was associated with a nearly 5-fold risk for developing dementia (HR 4.67 [1.82–12.01], p = 0.001) compared to controls of the same educational attainment.ConclusionsThere is a bi-directional association between epilepsy and dementia. with either condition carrying a nearly 2-fold risk of developing the other when compared to controls.

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