AHA: Ascot trial

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AHA: Ascot trial

  1. 1. Evaluation of C-reactive protein, prior to and on-treatment, as a predictor of benefit from atorvastatin: Observations from ASCOT Peter S. Sever*, Neil R Poulter, Choon L Chang, Aroon Hingorani, Simon McG Thom, Alun D Hughes, Paul Welsh, Naveed Sattar, on behalf of the ASCOT Investigators *Imperial College London .
  2. 2. ASCOT CRP Analysis Background • Lowering C-reactive protein (CRP) by statins has been shown to independently predict cardiovascular (CV) outcomes • The ASCOT database was used to explore the relationship between circulating CRP prior to, and on- treatment, with statins and their association with CV events
  3. 3. ASCOT Study Design 19342 hypertensive patients randomized to antihypertensive treatment ASCOT-BPLA stopped after 5.5 yrs Atenolol ± Amlodipine ± bendrofluazide perindopril 10305 patients eligible and randomized in lipid-lowering arm ASCOT-LLA TC ≤ 6.5 mmol/L (250 mg/dL) stopped after 3.3 yrs Atorvastatin 10 mg Placebo Investigator-led, multinational randomised controlled trial conducted in hypertensive patients, 40 -79 yrs, with no prior history of CHD, but with 3 additional cardiovascular risk factors (male sex, > 55 yrs, smoking etc )
  4. 4. Nested Case-control Trial Profile ASCOT – Subjects in the UK & Ireland On-treatment Analysis Population 14 cases & 37 controls (ASCOT-LLA) (n = 9098) were excluded because •LDL-C: 156 cases & 498 controls event occurred before •CRP: 166 cases & 522 controls blood samples were •LDL-C & CRP: 155 cases & 488 obtained. White European controls (n = 8217) 66 cases & 252 controls did not have both baseline and on- treatment CRP & LDL-C 6549 subjects met entry or with missing values in 235 cases & 777 controls criteria as potential covariates participating in ASCOT-LLA cases/controls 485 cases matched with 1367 Baseline CRP Analysis 490 cases & 5750 controls controls (ASCOT-BPLA case- Population (ASCOT-BPLA) with valid lab data control population) 452 cases & 1269 controls No controls available 33 cases & 98 controls with for 5 cases missing values in covariates
  5. 5. Study Subjects & Blood Samples • 485 cases (355 CHD & 130 stroke) matched with 1367 controls • Up to 3 controls from the same risk-set were matched to each case by age±1 year, sex and study entry time±90 days. • Fasting serum HDL-C, triglycerides and total cholesterol • Routinely measured at study visits • CRP at baseline and 6 months • Measured at the same time using stored serum samples • By a high sensitivity method (Dade-Behring, the lower limit of sensitivity was 0.1 mg/L)
  6. 6. Statistical Methods • t-test or Χ2 test for baseline characteristics comparison between cases and controls • Odd ratio obtained from a conditional logistic regression model for the association between CRP and the risk of CV events (CHD or stroke) • Loge CRP (baseline) as a continuous variable • Categorizing CRP into tertiles with the lowest as reference • Conditional logistic regression model • Model 1: unadjusted • Model 2 (Framingham CV risk factors + randomised treatment ) • Model 3 (extended CV risk factors): as in Model 2 plus • Body mass index (BMI) ,Loge transformed fasting glucose, Family history of coronary heart disease (FHCHD) ,Creatinine and Educational attainment
  7. 7. Baseline Characteristics Cases Controls Variable P value (n = 485) (n = 1367) Male (%) 409 (84.3) 1159 (84.8) 0.81 Age, years 64.80 (7.83) 64.65 (7.66) 0.71 Current Smokers (%) 127 (26.2) 297 (21.7) 0.04 Diabetes (%) 150 (30.9) 356 (26.0) 0.038 SBP, mmHg 164.61 (17.81) 161.70 (17.48) 0.002 DBP, mmHg 92.95 (10.37) 92.13 (9.83) 0.12 Total cholesterol, mmol/L 5.99 (1.07) 5.92 (1.07) 0.21 LDL- C, mmol/L 3.92 (0.97) 3.79 (0.96) 0.02 HDL-C, mmol/L 1.26 (0.33) 1.30 (0.34) 0.02 Loge triglyceride, mmol/L 0.52 (0.46) 0.50 (0.49) 0.44 Loge CRP, mg/L 1.13 (0.98) 0.95 (0.98) 0.0006 Loge glucose, mmol/L 1.82 (0.31) 1.78 (0.28) 0.03 Creatinine, mmol/L 102.34 (19.31) 99.23 (16.57) 0.0008 Amlodipine (%) 227 (46.8) 694 (50.8) 0.13 Atorvastatin* (%) 101 (43.0) 407(52.4) 0.01 Values are mean (SD) or n (%) Missing: LDL-C:121, triglycerides: 79, fasting glucose: 84, CRP: 4, creatinine: 45 *235 cases and 777 controls participated in ASCOT-LLA
  8. 8. Baseline CRP and Risk of CV Events (CHD or Stroke) Cases Control P value Trend Per 1 SD increase in loge CRP 452 1269 0.0004 Tertile 1 CRP: <1.74 mg/L 131 448 0.005 Model 1 Tertile 2 CRP: 1.74-4.09 mg/L 153 417 0.08 Unadjusted Tertile 3 CRP: >4.09 mg/L 168 404 0.005 Per 1 SD increase in loge CRP 452 1269 0.009 Tertile 1 CRP: <1.74 mg/L 131 448 0.057 Model 2* Tertile 2 CRP: 1.74-4.09 mg/L 153 417 0.29 Tertile 3 CRP: >4.09 mg/L 168 404 0.06 Per 1 SD increase in loge CRP 452 1269 0.006 Tertile 1 CRP: <1.74 mg/L 131 448 0.05 Model 3 Tertile 2 CRP: 1.74-4.09 mg/L 153 417 0.14 Adjusted as for in Model 2 plus BMI, loge-glucose, Tertile 3 CRP: >4.09 mg/L 168 404 0.05 family history of CHD, creatinine and educational attainment 0.5 1.0 1.5 2.0 Odd ratio (95% CI) *Model 2: Adjusted for current smoking status, diabetes mellitus, randomized BP treatment (atenolol/amlodipine), randomized atorvastatin/placebo/not in LLA, left ventricular hypertrophy, baseline SBP, total cholesterol and HDL-C
  9. 9. Predictive Ability of Baseline CRP in CVD Prediction Beyond Classical Risk Factors - 1 Modified Framingham Model Full Model (Model 2) (Model 3) Performance Measure Without CRP With CRP Without CRP With CRP Discrimination 0.592 0.600 0.620 0.627 Area under ROC (95% CI) (0.562, 0.621) (0.571, 0.630) (0.591, 0.650) (0.598, 0.656) P-value 0.20 0.18 Conditional Regression AIC 1127.41 1121.25 1117.42 1111.76 BIC 1176.00 1175.24 1203.81 1203.55 LR chi-square (df) 35.55 (9) 43.71 (10) 59.53 (16) 67.20 (17) Calibration Hosmer-Lemeshow, χ² ,deciles 5.94 10.88 2.83 2.97 P-value 0.65 0.21 0.94 0.94 AIC, Akaike’s information criterion; BIC, Bayes information criterion; ROC, receiver operator curve Framingham model: Adjusted for age, sex, smoking status, diabetic mellitus, baseline SBP, total cholesterol, HDL-C, randomized BP treatment, randomized statin/placebo/not in LLA and LVH Full model: as for reduced model plus loge glucose, family history of CHD, educational attainment, creatinine and BMI
  10. 10. Predictive Ability of Baseline CRP in CVD Prediction Beyond Classical Risk Factors - 2 • Net Reclassification Improvement (NRI) for model including CRP over model without CRP • In Model 2, NRI=2.1% (p=0.32) • In Model 3, NRI=3.0% (p=0.17) • Estimation of Integrated Discrimination Improvement (IDI) • When CRP was included • In Model 2, IDI increased 0.38% (P=0.015) • In Model 3, the increase in IDI was 0.49% (P=0.013) • It suggests that the addition of CRP to the model with established risk factors very modestly improved the discriminatory property of the model for the prediction of risk
  11. 11. Effect of Atorvastatin by Tertile of Baseline CRP Odd Ratios (95% CI) by Tertile of Baseline CRP Low Middle High Interaction* CVD 0.60 0.77 0.94 P=0.54 (0.33, 1.10) (0.41, 1.46) (0.51, 1.78) Adjusted for current smoking status, diabetes mellitus, randomized BP treatment (atenolol/amlodipine), randomized atorvastatin/placebo/not in ASCOT-LLA. Left ventricular hypertrophy, baseline SBP, total cholesterol, HDL-C, BMI, loge-glucose, family history of CHD, creatinine and educational attainment and baseline LDL-C. * Interaction between statin treatment and tertile baseline CRP
  12. 12. Effects of Atorvastatin on LDL-C and CRP 5 6 Baseline On-treatment (6 month) 4 40.3% reduction Median LDL-C (mmol/L) 4 Median CRP (mg/L) 3 27.4% reduction 2 2 1 0 0 Placebo Atorvastatin Placebo Atorvastatin • On-treatment change in CRP was independent of baseline classical risk factors, baseline CRP and change in LDL-C (P=0.02) • In ASCOT-LLA, in those assigned atorvastatin, age-adjusted Spearman’s correlation between percentage change in CRP and percentage change in LDL-C was modest (r=0.19 P=0.0006)
  13. 13. Baseline Profiles by 6 Month Median LDL-C and CRP On-treatment On-treatment On-treatment On-treatment Variable LDL-C ≥2.1mmol/L LDL-C <2.1mmol/L CRP ≥1.83mg/L CRP <1.83mg/L (n = 190) (n = 178) (n = 195) (n = 193) Male (%) 169 (88.9) 162 (91.0) 171 (87.7) 175 (90.7) Age (Years) 64.15 (7.60) 65.70 (6.88)* 64.69 (7.67) 65.44 (6.86) Current Smokers (%) 48 (25.3) 31 (17.4) 53 (27.2) 31 (16.1)** Alcohol (%): 37 (19.5) 38 (21.3) 45 (23.1) 35 (18.1) Never <=14/21 units/week 114 (60.0) 109 (61.2) 109 (55.9) 125 (64.8) >14/21 units/week 39 (20.5) 31 (17.4) 41 (21.0) 33 (17.1) SBP (mmHg) 162.45 (17.55) 162.47 (18.48) 161.59 (16.95) 163.63 (19.04) BMI (Kg/m2) 29.16 (4.17) 28.56 (4.53) 91.70 (9.17) 92.47 (9.52)*** Total Cholesterol (mmol/L) 5.87 (0.62) 5.15 (0.70)*** 29.76 (4.43) 27.95 (4.07) LDL-C (mmol/L) 3.87 (0.59) 3.14 (0.61)*** 5.53 (0.71) 5.51 (0.75) HDL-C (mmol/L) 1.25 (0.29) 1.27 (0.37) 3.53 (0.66) 3.50 (0.71)* Loge Triglyceride (mmol/L) 0.44 (0.42) 0.37 (0.50) 1.23 (0.30) 1.30 (0.36)* Loge CRP (mg/L) 0.99 (1.00) 0.94 (1.02) 0.46 (0.44) 0.35 (0.47)*** Loge glucose (mmol/L) 1.74 (0.26) 1.78 (0.27) 1.77 (0.31) 1.78 (0.25) Creatinine (mmol/L) 100.16 (15.98) 102.03 (18.41) 1.41 (0.91) 0.49 (0.89) Diabetes (%) 41 (21.6) 50 (28.1) 101.29 (19.43) 99.99 (14.62)* Family history CHD (%) 30 (15.8) 19 (10.7) 61 (31.3) 41 (21.2)** Amlodipine (%) 83 (43.7) 90 (50.6) 87 (44.6) 61 (31.6) Values are mean (SD) or n (%) * p<0.05; ** p<0.01; *** p<0.0001 Missing: fasting glucose: 25; creatinine: 13; triglyceride: 22; CRP: 1 Excluded events occurred before blood sampling: LDL-c≥2.1 mmol/L: 29; LDL-c <2.1 mmol/l: 38
  14. 14. On-treatment LDL-C (6 Month in Trial) and Risk of CV Events (CHD or Stroke) Cases Control P value Placebo 89 232 Atorvastatin LDL-C ≥2.1 mmol/L 44 126 0.87 Model 1 Unadjusted LDL-C <2.1 mmol/L 23 140 0.001 LDL-C <2.1 vs. ≥2.1 mmol/L 0.002 Placebo 89 232 Atorvastatin LDL-C ≥2.1 mmol/L 44 126 0.71 Model 2 LDL-C <2.1 mmol/L 23 140 0.003 Adjusted for baseline LDL-C and LDL-C <2.1 vs. ≥2.1 mmol/L 0.003 loge baseline CRP Placebo 89 232 Atorvastatin LDL-C ≥2.1 mmol/L 44 126 0.68 Model 3* LDL-C <2.1 mmol/L 23 140 0.003 LDL-C <2.1 vs. ≥2.1 mmol/L 0.004 0.0 0.5 1.0 1.5 2.0 Odd ratio (95% CI) *Model 3: Current smoking status, diabetes mellitus, randomized BP treatment (atenolol/amlodipine), left ventricular hypertrophy, baseline SBP, HDL-C, BMI, loge-glucose, family history of CHD, creatinine, educational attainment, baseline LDL-C or total cholesterol and loge baseline CRP
  15. 15. On-treatment CRP (6 Month in Trial) and Risk of CV Events (CHD or Stroke) Cases Control P value Placebo 93 245 Atorvastatin CRP ≥1.83 mg/L 41 137 0.47 Model 1 Unadjusted CRP <1.83 mg/L 32 140 0.03 CRP <1.83 vs. ≥1.83 mg/L 0.17 Placebo 93 245 Atorvastatin CRP ≥1.83 mg/L 41 137 0.39 Model 2 CRP <1.83 mg/L 32 140 0.14 Adjusted for baseline LDL-C and CRP <1.83 vs. ≥1.83 mg/L 0.56 loge baseline CRP Placebo 93 245 Atorvastatin CRP ≥1.83 mg/L 41 137 0.38 Model 3* CRP <1.83 mg/L 32 140 0.15 CRP <1.83 vs. ≥1.83 mg/L 0.60 0.0 0.5 1.0 1.5 2.0 Odd ratio (95% CI) *Model 3: Current smoking status, diabetes mellitus, randomized BP treatment (atenolol/amlodipine), left ventricular hypertrophy, baseline SBP, HDL-C, BMI, loge-glucose, family history of CHD, creatinine, educational attainment, baseline LDL-C or total cholesterol and loge baseline CRP
  16. 16. Risk of CV Events (CHD or Stroke) by On- treatment (6 Month in Trial) LDL-C and CRP* Cases Control P value Placebo 88 230 LDL-C ≥2.1 & CRP ≥1.83 27 65 0.40 LDL-C ≥2.1 & CRP <1.83 17 55 0.98 ASCOT Medians LDL-C <2.1 & CRP ≥1.83 11 62 0.02 LDL-C <2.1 & CRP <1.83 12 76 0.05 Placebo 88 230 LDL-C ≥1.8 & CRP ≥2 30 81 0.85 LDL-C ≥1.8 & CRP <2 27 94 0.80 JUPITER Cut-offs LDL-C <1.8 & CRP ≥2 3 36 0.01 LDL-C <1.8 & CRP <2 7 47 0.06 Placebo 88 230 LDL-C ≥1.8 & CRP ≥1 46 126 0.75 LDL-C ≥1.8 & CRP <1 11 49 0.48 JUPITER Cut-offs LDL-C <1.8 & CRP ≥1 5 53 0.003 LDL-C <1.8 & CRP <1 5 30 0.23 *LDL-C in mmol/L and CRP in mg/L 0.0 0.5 1.0 1.5 2.0 2.5 Odd ratio (95% CI) Adjusted for current smoking status, diabetes mellitus, randomised BP treatment (atenolol/amlodipine), , left ventricular hypertrophy, baseline SBP, total cholesterol, HDL-cholesterol, BMI, loge-glucose, family history of CHD, creatinine, educational attainment, and baseline LDL or total cholesterol and loge baseline CRP
  17. 17. Summary • Baseline LDL-C and loge transformed CRP were correlated and predicted CV events respectively • Inclusion of baseline CRP into a modified Framingham risk model in the whole cohort very modestly improved risk prediction • Baseline CRP was not an indicator of the magnitude of the effect of atorvastatin on CV outcome of those assigned atorvastatin • At 6 months, atorvastatin reduced median LDL-C by 40.3% and median CRP by 27.4% • In those randomized to atorvastatin • Lower on-treatment LDL-C at 6 months was associated with a highly significant reduction in subsequent CV events • By contrast, lower CRP at 6 months was not associated with CV events • Consequently, addition of on-treatment CRP to on-treatment LDL-C did not improve prediction of statin efficacy
  18. 18. Conclusion • In ASCOT-LLA, neither baseline nor on-treatment CRP provide useful information about the efficacy of statin treatment to reduce CV events beyond LDL-C reduction • The results do not support current proposals to measure CRP in the clinical setting either to assign statins to individuals on the basis of an elevated CRP alone, or to monitor CRP levels as an indicator of the efficacy of statin treatment
  19. 19. Back up
  20. 20. Baseline CRP and Risk of CHD Only Cases Control P value Trend Per 1 SD increase in loge CRP 331 939 0.0003 Tertile 1 CRP: <1.74 mg/L 87 330 0.01 Model 1 Tertile 2 CRP: 1.74-4.09 mg/L 119 310 0.024 Unadjusted Tertile 3 CRP: >4.09 mg/L 125 299 0.01 Per 1 SD increase in loge CRP 331 939 0.009 Tertile 1 CRP: <1.74 mg/L 87 330 0.16 Model 2* Tertile 2 CRP: 1.74-4.09 mg/L 119 310 0.13 Tertile 3 CRP: >4.09 mg/L 125 299 0.15 Per 1 SD increase in loge CRP 331 939 0.005 Tertile 1 CRP: <1.74 mg/L 87 330 0.10 Model 3 Tertile 2 CRP: 1.74-4.09 mg/L 119 310 0.09 Adjusted as for in Model 2 plus BMI, Tertile 3 CRP: >4.09 mg/L 125 299 0.09 loge-glucose, family history of CHD, creatinine and educational 0.5 1.0 1.5 2.0 2.5 attainment Odd ratio (95% CI) *Model 2: Adjusted for current smoking status, diabetes mellitus, randomized BP treatment (atenolol/amlodipine), randomized atorvastatin/placebo/not in LLA, left ventricular hypertrophy, baseline SBP, total cholesterol and HDL-C
  21. 21. Baseline CRP and Risk of Stroke Only Cases Control P value Trend Per 1 SD increase in loge CRP 121 330 0.44 Tertile 1 CRP: <1.74 mg/L 44 118 0.22 Model 1 Unadjusted Tertile 2 CRP: 1.74-4.09 mg/L 34 107 0.70 Tertile 3 CRP: >4.09 mg/L 43 105 0.20 Per 1 SD increase in loge CRP 121 330 0.50 Tertile 1 CRP: <1.74 mg/L 44 118 0.24 Model 2* Tertile 2 CRP: 1.74-4.09 mg/L 34 107 0.63 Tertile 3 CRP: >4.09 mg/L 43 105 0.25 Per 1 SD increase in loge CRP 121 330 0.64 Tertile 1 CRP: <1.74 mg/L 44 118 0.32 Model 3 Adjusted as for in Tertile 2 CRP: 1.74-4.09 mg/L 34 107 0.91 Model 2 plus BMI, Tertile 3 CRP: >4.09 mg/L 43 105 0.32 loge-glucose, family history of CHD, creatinine and educational 0.5 1.0 1.5 2.0 2.5 attainment Odd ratio (95% CI) *Model 2: Adjusted for current smoking status, diabetes mellitus, randomized BP treatment (atenolol/amlodipine), randomized atorvastatin/placebo/not in LLA, left ventricular hypertrophy, baseline SBP, total cholesterol and HDL-C
  22. 22. Predictive Ability of Baseline CRP in CVD Prediction Beyond Classical Risk Factors - 1 Modified Framingham Model Full Model (Model 2) (Model 3) Performance Measure Without CRP With CRP Without CRP With CRP Discrimination 0.592 0.600 0.620 0.627 Area under ROC (95% CI) (0.562, 0.621) (0.571, 0.630) (0.591, 0.650) (0.598, 0.656) P-value 0.20 0.18 Conditional Regression AIC 1127.41 1121.25 1117.42 1111.76 BIC 1176.00 1175.24 1203.81 1203.55 LR chi-square (df) 35.55 (9) 43.71 (10) 59.53 (16) 67.20 (17) Calibration Hosmer-Lemeshow, χ² ,deciles 5.94 10.88 2.83 2.97 P-value 0.65 0.21 0.94 0.94 AIC, Akaike’s information criterion; BIC, Bayes information criterion; ROC, receiver operator curve Framingham model: Adjusted for age, sex, smoking status, diabetic mellitus, baseline SBP, total cholesterol, HDL-C, randomized BP treatment, randomized statin/placebo/not in LLA and LVH Full model: as for reduced model plus loge glucose, family history of CHD, educational attainment, creatinine and BMI
  23. 23. Study Population • 485 cases (355 CHD & 130 stroke) matched with 1367 controls • Controls were selected from the UK & Ireland ASCOT study population who were alive at the time the case was diagnosed and free from CV disease in the study period. • Up to 3 controls from the same risk-set were matched to each case by age±1 year, sex and study entry time±90 days.
  24. 24. Laboratory Methods • Fasting serum HDL-C, triglycerides and total cholesterol • Routinely measured at study visits • CRP at baseline and 6 months • Measured at the same time using stored serum samples • By a high sensitivity method (Dade-Behring, the lower limit of sensitivity was 0.1 mg/L) • At Glasgow Royal Infirmary (CPA accredited) • On an Abbott Architect • By technicians blinded to the case-control status of the samples
  25. 25. Statistical Methods -1 • t-test or Χ2 test for baseline characteristics comparison between cases and controls • Age-adjusted partial correlation coefficients for the correlation between loge CRP (baseline) and baseline clinical characteristics • Odd ratio obtained from a conditional logistic regression model for the association between CRP and the risk of CV events (CHD or stroke) • Loge CRP (baseline) as a continuous variable • Categorizing CRP into tertiles with the lowest as reference
  26. 26. Statistical Methods - 2 Conditional logistic regression model • Model 1: unadjusted • Model 2 (modified Framingham CV risk factors): adjusted for • Current smoking status • Diabetes mellitus • Left ventricular hypertrophy • Baseline systolic blood pressure (SBP) • Total cholesterol and HDL • Randomized atorvastatin/placebo/not in ASCOT-LLA • Randomized atenolol/amlodipine • Model 3 (extended CV risk factors): adjusted for Model 2 plus • Body mass index (BMI) • Loge transformed fasting glucose • Family history of coronary heart disease (FHCHD) • Creatinine • Educational attainment
  27. 27. Baseline Characteristics – 2 Cases Controls Variable P value (n=485) (n=1367) Alcohol (%) Never 124 (25.6) 298 (21.8) ≤14/21 units/week 270 (55.7) 803 (58.7) >14/21 units/week 91 (18.8) 266 (19.5) 0.23 Family history CHD (%) 85 (17.5) 233 (17.0) 0.81 BMI, kg/m2 28.71 (4.05) 29.00 (4.50) 0.21 Heart Rate, bpm 69.65 (12.91) 70.35 (11.85) 0.28 Completed Education (%) Age: ≤12 182 (37.5) 452 (33.1) Age: ≤15 233 (48.0) 632 (46.2) Age: ≤18 46 (9.5) 154 (11.3) Age: 19+ 24 (4.9) 129 (9.4) 0.007 Values are mean (SD) or n (%)
  28. 28. Predictive Ability of Baseline CRP in CVD Prediction Beyond Classical Risk Factors – 1 Modified Framingham Model Full Model (Model 2) (Model 3) Performance Measure Without CRP With CRP Without CRP With CRP Discrimination 0.592 0.600 0.620 0.627 Area under ROC (95% CI) (0.562, 0.621) (0.571, 0.630) (0.591, 0.650) (0.598, 0.656) P-value 0.20 0.18 Conditional Regression AIC 1127.41 1121.25 1117.42 1111.76 BIC 1176.00 1175.24 1203.81 1203.55 LR chi-square (df) 35.55 (9) 43.71 (10) 59.53 (16) 67.20 (17) Calibration Hosmer-Lemeshow, χ² ,deciles 5.94 10.88 2.83 2.97 P-value 0.65 0.21 0.94 0.94 AIC, Akaike’s information criterion; BIC, Bayes information criterion; ROC, receiver operator curve Framingham model: Adjusted for age, sex, smoking status, diabetic mellitus, baseline SBP, total cholesterol, HDL-C, randomized BP treatment, randomized statin/placebo/not in LLA and LVH Full model: as for reduced model plus loge glucose, family history of CHD, educational attainment, creatinine and BMI
  29. 29. Predictive Ability of Baseline CRP in CVD Prediction Beyond Classical Risk Factors – 2 With CRP Reclassification Without CRP Number of Subjects Improvement % Framingham Covariate Model (Model 2) 10-<20% 20-<30% 30-<40% 40-<50% 50% Cases 10-<20% 38 12 0 0 0 20-<30% 13 203 29 0 0 3.32 30-<40% 0 24 109 11 0 40-<50% 0 0 2 9 2 Controls 10-<20% 213 50 0 0 0 20-<30% 67 555 69 0 0 1.18 30-<40% 0 47 229 12 0 40-<50% 0 0 2 23 0 50% 0 0 0 0 1 Net Reclassification Improvement, % 2.14 P=0.32 Framingham covariate model: Adjusted for age, sex, smoking status, diabetic mellitus, baseline SBP, total cholesterol, HDL-C, randomized BP treatment, randomized statin/placebo/not in LLA and LVH
  30. 30. Predictive Ability of Baseline CRP in CVD Prediction Beyond Classical Risk Factors – 3 With CRP Reclassification Without CRP Number of Subjects Improvement % Full Model (Model 3) 10-<20% 20-<30% 30-<40% 40-<50% 50% Cases 10-<20% 52 6 0 0 0 20-<30% 14 166 28 0 0 1.77 30-<40% 0 18 109 12 1 40-<50% 0 0 10 25 4 50-60% 0 0 0 1 5 Controls 10-<20% 282 46 0 0 0 20-<30% 62 473 41 0 0 -1.21 30-<40% 0 54 217 18 0 40-<50% 0 0 10 29 7 50%+ 0 0 0 1 5 Net Reclassification Improvement, % 2.98 P=0.17 Full model: as for Framingham covariate model plus loge glucose, family history CHD, educational attainment, creatinine and BMI
  31. 31. Predictive Ability of Baseline CRP in CVD Prediction Beyond Classical Risk Factors – 4 • Estimation of Integrated Discrimination Improvement (IDI) • When CRP was included • In Model 2, IDI increased 0.38% (P=0.015) • In Model 3, the increase in IDI was 0.49% (P=0.013) • It suggests that the addition of CRP to the model with established risk factors very modestly improved the discriminatory property of the model for the prediction of risk
  32. 32. Baseline Profiles by 6 Month Median LDL-C On-treatment On-treatment Variable LDL-C ≥2.1mmol/L LDL-C <2.1mmol/L P value (n = 190) (n = 178) Male (%) 169 (88.9) 162 (91.0) 0.5 Age (Years) 64.15 (7.60) 65.70 (6.88) 0.04 Current Smokers (%) 48 (25.3) 31 (17.4) 0.07 Alcohol (%): Never 37 (19.5) 38 (21.3) <=14/21 units/week 114 (60.0) 109 (61.2) >14/21 units/week 39 (20.5) 31 (17.4) 0.72 SBP (mmHg) 162.45 (17.55) 162.47 (18.48) 0.99 BMI (Kg/m2) 29.16 (4.17) 28.56 (4.53) 0.19 Total Cholesterol (mmol/L) 5.87 (0.62) 5.15 (0.70) <0.0001 LDL-C (mmol/L) 3.87 (0.59) 3.14 (0.61) <0.0001 HDL-C (mmol/L) 1.25 (0.29) 1.27 (0.37) 0.41 Loge Triglyceride (mmol/L) 0.44 (0.42) 0.37 (0.50) 0.14 Loge CRP (mg/L) 0.99 (1.00) 0.94 (1.02) 0.61 Loge glucose (mmol/L) 1.74 (0.26) 1.78 (0.27) 0.21 Creatinine (mmol/L) 100.16 (15.98) 102.03 (18.41) 0.31 Diabetes (%) 41 (21.6) 50 (28.1) 0.15 Family history CHD (%) 30 (15.8) 19 (10.7) 0.15 Amlodipine (%) 83 (43.7) 90 (50.6) 0.19 Values are mean (SD) or n (%) Missing: fasting glucose: 25; creatinine: 13; triglyceride: 22; CRP: 1 Excluded events occurred before blood sampling: LDL-c≥2.1 mmol/L: 29; LDL-c <2.1 mmol/l: 38
  33. 33. Baseline Profiles by 6 Month Median CRP On-treatment On-treatment Variable CRP ≥1.83mg/L CRP <1.83mg/L P value (n = 195) (n = 193) Male (%) 171 (87.7) 175 (90.7) 0.34 Age (Years) 64.69 (7.67) 65.44 (6.86) 0.31 Current Smokers (%) 53 (27.2) 31 (16.1) 0.008 Alcohol (%): Never 45 (23.1) 35 (18.1) <=14/21 units/week 109 (55.9) 125 (64.8) >14/21 units/week 41 (21.0) 33 (17.1) 0.20 SBP (mmHg) 161.59 (16.95) 163.63 (19.04) 0.27 DBP (mmHg) 91.70 (9.17) 92.47 (9.52) 0.42 BMI (Kg/m2) 29.76 (4.43) 27.95 (4.07) <0.0001 Total Cholesterol (mmol/L) 5.53 (0.71) 5.51 (0.75) 0.83 LDL-C (mmol/L) 3.53 (0.66) 3.50 (0.71) 0.69 HDL-C (mmol/L) 1.23 (0.30) 1.30 (0.36) 0.04 Loge Triglyceride (mmol/L) 0.46 (0.44) 0.35 (0.47) 0.03 Loge glucose (mmol/L) 1.77 (0.31) 1.78 (0.25) 0.73 Loge CRP (mg/L) 1.41 (0.91) 0.49 (0.89) <0.0001 Creatinine (mmol/L) 101.29 (19.43) 99.99 (14.62) 0.47 Diabetes (%) 61 (31.3) 41 (21.2) 0.02 Family history CHD (%) 87 (44.6) 61 (31.6) 0.008 Amlodipine (%) 31 (15.9) 23 (11.9) 0.26 Values are mean (SD) or n (%) Missing: fasting glucose: 24; creatinine: 12; LDL-C: 27; triglyceride: 22
  34. 34. Statistical Methods - 3 • To examine the predictive power of loge CRP on CV events • Unconditional logistic regression models with adjustment for age and sex on Framingham-based (Model 2) with and without loge CRP • The fully adjusted model (Model 3) with and without loge CRP • To assess global fit of Models 2 and 3, and the improvement after the addition of loge CRP • Akaike’s information criterion (AIC) • Bayes information criterion (BIC) • Likelihood-ratio tests • To measure the discrimination of the model • Area under the Receiver Operator Characteristic (ROC) curve • Model 2 ± loge CRP • Model 3 ± loge CRP • Net reclassification Improvement (NRI) • Integrated Discrimination Improvement (IDI) • To assess model calibration • Hosmer-Lemeshow goodness-of-fit test
  35. 35. Statistical Methods - 4 • To determine the impact of statin on CV events by on-treatment LDL-C and CRP • The cases and controls on atorvastatin were divided into 2 groups based on • LDL-C below or above the ASCOT median LDL-C at 6-month (1.83 mmol/L) OR • CRP below or above the ASCOT median CRP at 6-month (2.1 mg/L) • Model 3 (multiple conditional logistic regression model ) was used to estimate odd ratios for CV events in these groups compared with the placebo group • To investigate the effect of on-treatment CRP across the categories of on-treatment LDL-C and total cholesterol values • The cases and controls on atorvastatin were divided into 4 groups based on • LDL-C below or above 1.83 mmol/L and CRP below or above 2.1 mg/L OR • Cut-off values used in the JUPITER trial (LDL-C =1.8 mmol/L, CRP= 1 and 2 mg/L) • Model 3 was used to estimate odd ratios for CV events in these groups compared with the placebo group

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