Illustrating the Impact of a Time-Varying Covariate With an Extended Kaplan-Meier Estimator

Snapinn, Steven; Jiang, Qi; Iglewicz, Boris

doi:10.1198/000313005x70371

Cited by 202 publications

(213 citation statements)

References 19 publications

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“…However, over time, SBP or HR as risk markers may vary and can place patients into different risk groups. Time varying statistical analyses have been used to analyze outcomes by Kaplan-Meier analyses for the shift of patients from one to another risk group, 31 an approach which was used to study the effects of SBP on clinical outcomes in the ONTARGET trial. 32 Herein, we have used multiple readings of HR and SBP for a given patient and averaged values when the number of visits exceeded 2 and determined mean SBP and mean HR over 10.7±2.2 visits.…”

Section: Discussionmentioning

confidence: 99%

Systolic Blood Pressure Variation and Mean Heart Rate Is Associated With Cognitive Dysfunction in Patients With High Cardiovascular Risk

et al. 2015

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Abstract— Elevated systolic blood pressure (SBP) correlates to cognitive decline and incident dementia. The effects of heart rate (HR), visit to visit HR variation, and visit to visit SBP variation are less well established. Patients without preexisting cognitive dysfunction (N=24 593) were evaluated according to mean SBP, SBP visit to visit variation (coefficient of variation [standard deviation/mean×100%], CV), mean HR, and visit to visit HR variation (HR-CV) in the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial and the Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease. Cognitive function was assessed with mini mental state examination. Cognitive dysfunction (fall in mini mental state examination ≤24 points), important cognitive decline (drop of ≥5 points), and cognitive deterioration (drop of >1 point per year or decline to < 24 points) were assessed. SBP and HR were measured over 10.7±2.2 (mean±SD) visits. Mean SBP, mean HR, and SBP-CV were associated with cognitive decline, dysfunction, and deterioration (all P <0.01, unadjusted). After adjustment, only SBP-CV ( P =0.0030) and mean HR ( P =0.0008) remained predictors for cognitive dysfunction (odds ratios [95% confidence intervals], 1.32 [1.10–1.58] for 5th versus 1st quintile of SBP-CV and 1.40 [1.18–1.66] for 5th versus 1st quintile of mean HR). Similar effects were observed for cognitive decline and deterioration. SBP-CV and mean HR showed additive effects. In conclusion, SBP-CV and mean HR are independent predictors of cognitive decline and cognitive dysfunction in patients at high CV risk. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT 00153101.

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Section: Discussionmentioning

confidence: 99%

Systolic Blood Pressure Variation and Mean Heart Rate Is Associated With Cognitive Dysfunction in Patients With High Cardiovascular Risk

et al. 2015

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“…These factors are adjusted for in multivariable Cox proportional hazards models to estimate HRs and 95% CIs for the baseline and time-varying covariates (18). Extended Kaplan-Meier curves were used to illustrate the effect of time-varying covariates from proportional hazards models (19). The curves describe the survival experience of patients according to their repeated measurements of these biomarkers during the entire study (the values used for the timevarying covariate in the proportional hazards model collapsed into categories according to the median).…”

Section: Methodsmentioning

confidence: 99%

Increase in Cholesterol Predicts Survival Advantage in Renal Cell Carcinoma Patients Treated with Temsirolimus

Lee

Marschner

Simes

et al. 2012

Clinical Cancer Research

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Purpose: Temsirolimus is an effective treatment for renal cell carcinoma. It is associated with increases in serum cholesterol, triglyceride, and glucose. We investigated whether changes of these biomarkers could predict its efficacy.Experimental Design: We examined serial measurements of cholesterol, triglycerides, and glucose from patients randomized to IFN or temsirolimus in the Global Advanced Renal Cell Carcinoma Trial. Using time-dependent proportional hazards models, we quantified the association between changes in these biomarkers from baseline with overall survival (OS) and progression-free survival (PFS). We also assess the extent to which changes of these biomarkers predict the effects of temsirolimus on survival.Results: Temsirolimus was associated with larger mean increases in cholesterol (1.02 mmol/L; P < 0.0001), triglycerides (0.32 mmol/L; P ¼ 0.0008), and glucose (1.28 mmol/L; P < 0.0001) compared with IFN and improved survival rate (OS: HR ¼ 0.76, P ¼ 0.02; PFS: HR ¼ 0.70, P ¼ 0.001). Cholesterol increase during study was associated with longer survival (OS: HR ¼ 0.77 per mmol/L, P < 0.0001; PFS: HR ¼ 0.81 per mmol/L; P < 0.0001). Temsirolimus effect on cholesterol predicted its effect on survival with no additional survival advantage observed after adjusting for cholesterol change during study (OS: HR ¼ 1.14, P ¼ 0.37; PFS: HR ¼ 0.88, P ¼ 0.35). Temsirolimus effect on triglycerides or glucose did not predict its effect on survival, with survival advantage in favor of temsirolimus still observed after adjusting for these factors (P ¼ 0.003 and P ¼ 0.002).Conclusion: Cholesterol increase is a potential predictor for temsirolimus efficacy. Longer survival in patients treated with temsirolimus was observed in those with larger increases in cholesterol. Prospectively designed biomarker studies of temsirolimus or other mTOR inhibitors are recommended.

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“…To illustrate the results of time-varying covariate analyses, new-onset AF rate over time was plotted as a function of changing in-treatment SBP group using a univariate modified Kaplan-Meier method, implemented in SAS Release 8.2 on the WIN_PRO platform. 33 Additional multivariable Cox analyses were performed in which hazard ratios for new-onset AF were calculated for 5-mm Hg decrements of in-treatment SBP, in which for each cutoff value AF risk was compared between patients with SBP at that level or lower and patients with SBP greater than that level. Adjusted hazard ratios were plotted versus in-treatment SBP.…”

Section: 28mentioning

confidence: 99%

Effect of Lower On-Treatment Systolic Blood Pressure on the Risk of Atrial Fibrillation in Hypertensive Patients

et al. 2015

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A trial fibrillation (AF) is a common arrhythmia 1,2 that is increasing in prevalence. 2 The incidence of AF increases with age 1 and is increased in patients with heart failure, left ventricular hypertrophy (LVH), coronary heart disease, and hypertension. [3][4][5][6][7][8][9][10][11][12][13][14] The higher risk of death, [3][4][5] sudden cardiac death, 6 heart failure, 5 and stroke 3,7,8 in patients with AF and the substantial risks associated with antithrombotic therapies aimed at decreasing the risk of embolic sequelae 15 make prevention of the development of new AF a major clinical and epidemiological goal.Hypertension is the most important risk factor for new AF, estimated to account for between 14% and 22% of the population-attributable risk 9,11 ; AF risk is also related to the severity of hypertension. 8,13,14 Some, [16][17][18] but not all, studies 13 suggest that reductions in blood pressure (BP) can reduce the risk of developing new AF. Recent work found that even upper normal levels of systolic BP (SBP) were associated with an increased long-term risk of AF,19 suggesting that more aggressive BP control may further decrease AF risk. More intensive antihypertensive treatment aimed at greater reduction of BP or a lower achieved pressure to further reduce cardiovascular risk has produced mixed outcomes 16,[20][21][22][23][24] and remains controversial. 25,26 However, there are only limited data on whether achievement of a lower SBP during treatment of hypertension is associated with a decreased risk of AF. 14,16 Therefore, the purpose of this study was to examine whether lower achieved SBP (≤130 mm Hg) is associated with a lower incidence of AF compared with typical SBP control (131-141 mm Hg) and less-adequate control (SBP ≥142 mm Hg) in hypertensive patients with ECG LVH, independent of treatment modality, baseline risk factors, in-treatment diastolic BP, and the previously demonstrated predictive value of in-treatment heart rate and regression of ECG LVH by Cornell product criteria for new AF in this population. 27,28Abstract-There is a well-established association between hypertension and atrial fibrillation (AF); indeed, even upper normal systolic blood pressures (SBP) are long-term predictors of incident AF. These findings suggest that more aggressive BP control may reduce the risk of new AF. However, whether lower achieved SBP is associated with a lower incidence of AF remains unclear. The risk of new-onset AF was examined in relation to last in-treatment SBP before AF diagnosis or last in-study measurement in the absence of new AF in 8831 hypertensive patients with ECG left ventricular hypertrophy with no history of AF, in sinus rhythm on their baseline ECG, randomly assigned to losartan-or atenololbased treatment. Patients with in-treatment SBP ≤130 mm Hg (lowest quintile at last measurement) and SBP between 131 and 141 mm Hg were compared with patients with in-treatment SBP ≥142 mm Hg (median SBP at last measurement). During follow-up of 4.6±1.1 years, new-onset AF was diagnosed in 701 patie...

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Illustrating the Impact of a Time-Varying Covariate With an Extended Kaplan-Meier Estimator

Cited by 202 publications

References 19 publications

Systolic Blood Pressure Variation and Mean Heart Rate Is Associated With Cognitive Dysfunction in Patients With High Cardiovascular Risk

Systolic Blood Pressure Variation and Mean Heart Rate Is Associated With Cognitive Dysfunction in Patients With High Cardiovascular Risk

Increase in Cholesterol Predicts Survival Advantage in Renal Cell Carcinoma Patients Treated with Temsirolimus

Effect of Lower On-Treatment Systolic Blood Pressure on the Risk of Atrial Fibrillation in Hypertensive Patients

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