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Results
Baseline Characteristics
In total, 488 subjects with an event and 3,797 with no event during follow-up in the ASCOT-LLA and ASCOT-BPLA were included in the analyses of predictive values of baseline CRP (Figure 1). The mean age of the subjects was 64.3 ± 8.1 years, and 85.6% were male. A comparison of the baseline characteristics between those in whom an event developed and those in whom one did not demonstrated that those in whom an event developed had a generally worse clinical profile (Table 1).
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Figure 1.
ASCOT C-Reactive Protein Cohort Trial Profile
ASCOT = Anglo-Scandinavian Cardiac Outcomes Trial; BPLA = blood pressure–lowering arm; CRP = C-reactive protein; LLA = Lipid-Lowering Arm; UK = United Kingdom.
Figure drawn by Craig Skaggs.
Baseline CRP was positively correlated with total cholesterol, LDL-C, triglyceride level, and BMI but negatively with HDL-C in both groups (Online Table 1.)
Baseline CRP and Risk of Subsequent CV Events
The risk of the development of a CV event and CHD alone increased with baseline CRP (Table 2). Baseline CRP was not, however, significantly associated with the risk of stroke alone, although there were trends toward a positive association. The HR for CV events was 1.21 (95% CI: 1.09 to 1.33; p = 0.0003) per 1 SD increased in loge-transformed CRP, after adjusting for classic risk factors and randomization. Similar results were noted in the analyses by tertiles of CRP (Table 2, Figure 2). Similar results were observed in a sensitivity analysis of subjects who were not assigned to receive atorvastatin (Online Table 2).
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Figure 2.
Baseline CRP and Cumulative Probability of CVD Events
Cumulative probability of cardiovascular disease (CVD) events according to the concentration of C-reactive protein (CRP) at baseline. CHD = coronary heart disease.
Figure drawn by Craig Skaggs.
Statin Efficacy Effect by Baseline CRP
There was no evidence of an interaction between baseline LDL-C or CRP and treatment effect (statin-/placebo- or atenolol-/amlodipine-based treatment) on CV events or CHD or stroke; specifically, the statin effect in preventing CVD did not differ significantly according to the tertiles of baseline CRP (p > 0.60) (Online Table 3).
Achieved CRP and LDL-C at 6 Months and Risk of CV Event
After 6 months of atorvastatin treatment, the median LDL-C was reduced by 38.7% (3.46 mmol/l [IQR: 2.96 to 3.95 mmol/l] to 2.12 mmol/l [IQR: 1.74 to 2.56 mmol/l]), whereas in the placebo group, the median decreased by 1.7% (from 3.46 mmol/l [IQR: 2.99 to 3.96 mmol/l] to 3.40 mmol/l [IQR: 2.86 to 3.92 mmol/l]; comparing change, p < 0.0001). The concomitant changes for CRP were a 25.8% reduction with atorvastatin (from 2.21 mg/l [IQR: 1.12 to 4.63 mg/l) to 1.64 mg/l (IQR: 0.82 to 3.43 mg/l) compared with 0.4% in the placebo group (from 2.25 mg/l [IQR: 1.09 to 4.4 mg/l] to 2.24 mg/l [IQR: 1.13 to 4.48 mg/l]; p = 0.02). The Spearman correlation between the percentage of change in CRP and the percentage of change in LDL-C was modest (r = 0.12, p < 0.0001).
Changes in LDL-C or CRP from baseline to 6 months were normally distributed. Irrespective of treatment group assignment in the ASCOT-LLA cohort, a 1-mmol/l decrease in LDL-C between baseline and 6 months of in-trial treatment was associated with a 17% (HR: 0.83; 95% CI: 0.69 to 0.99; p = 0.04) and a 17% (HR: 0.83; 95% CI: 0.67 to 1.02; p = 0.07) risk reduction in CV and CHD events, respectively, after adjustment for baseline levels, age, and sex. These estimated effects were essentially unchanged after multiple adjustments for other risk factors, but were no longer significant (HR: 0.86; 95% CI: 0.66 to 1.12 and HR: 0.87; 95% CI: 0.63 to 1.19, respectively). In contrast, the effect of a 10-mg/l decrease in CRP showed no evidence of an association with CV or CHD events (HR: 1.03; 95% CI: 0.90 to 1.18; p = 0.69 for CV and HR: 1.05; 95% CI: 0.92 to 1.20; p = 0.48 for CHD). Those who did not achieve CRP below the median value at 6 months in either the placebo (median, 2.24 mg/l) or atorvastatin (median, 1.64 mg/l) group did not have a significantly altered risk of CV or CHD events compared with those who did (Table 3).
Similar analyses were repeated using a separate imputed dataset. In this dataset, the multivariable analyses (model 4) showed that the HRs for CV were similar to those reported in the complete case analysis of Table 3 (Online Table 1).
After adjusting for risk factors (including baseline CRP and LDL-C), subjects allocated to atorvastatin had a nonsignificant 19% to 22% reduced risk of CV events regardless of whether they achieved a CRP less than the median of 1.64 mg/l (Figure 3, Table 4). In contrast, those who achieved LDL-C below the median had a significant 46% reduction in the risk of CV events (HR: 0.54; 95% CI: 0.34 to 0.85; p = 0.008) in the multivariable-adjusted analysis. In the atorvastatin group, those who achieved LDL-C below the median had a 42% reduced risk compared with those who did not (HR 0.58; 95% CI: 0.34 to 0.97; p = 0.04) (model 2 in Table 4). Similar results were also noted in the CHD analyses (Figure 3, Table 4). Post hoc analyses of on-treatment non-HDL showed similar significant results (data not shown).
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Figure 3.
Hazard Ratios for CVD and CHD Events
Multiple adjusted hazard ratios for CVD and CHD events according to achieved level of CRP or LDL cholesterol (LDL-c) at 6 months. CI = confidence interval; HR = hazard ratio; other abbreviations as in Figure 2.
On-treatment CRP and LDL-C analyses were repeated using a dataset including imputed data for missing data. A significant treatment effect for CHD (39% risk reduction) was observed in those who achieved CRP below the median. However, in contrast to findings for achieved LDL-C, there was, once again, no significant atorvastatin group difference for achieved CRP below, versus above, the median (HR: 0.75; 95% CI: 0.43 to 1.32; p = 0.32). Overall, the effect estimates of on-treatment CRP and LDL-C on CV and CHD events were similar to those reported in the complete case analyses (Table 5).
Compared with placebo, the lowest risk of CV events was noted in subjects allocated to atorvastatin who achieved LDL-C below the median level (<2.1 mmol/l) irrespective of on-treatment CRP levels (Figure 4, Table 6). A significantly lower risk of CHD was noted in subjects taking atorvastatin who achieved low LDL-C but had a high level of on-treatment CRP (Figure 5, Table 6). However, this result was based on 6 subjects with an event. Sensitivity analyses using imputed data showed similar results (Figure 6).
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Figure 4.
Hazard Ratios for CV Events
Hazard ratios for cardiovascular (CV) events according to achieved LDL cholesterol and CRP after 6 months of atorvastatin treatment. Abbreviations as in Figures Figure 1 through 3 Figure drawn by Craig Skaggs.
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Figure 5.
Hazard Ratios for CHD Events
Multiple adjusted hazard ratios for CHD events according to achieved LDL cholesterol and CRP after 6 months of atorvastatin. Abbreviations as in Figure 2 and 3.
Figure drawn by Craig Skaggs.
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Figure 6.
Hazard Ratios for CVD and CHD Events (Using Imputed Data)
Multiple adjusted hazard ratios for CVD and CHD events according to achieved level of LDL cholesterol and CRP at 6 months using imputed data. Abbreviations as in Figure 2 and 3. Figure drawn by Craig Skaggs.
We conducted additional analyses using alternative cutoffs such as CRP more than and less than 2 mg/l and either LDL-C more than and less than 2.59 mmol/l (100 mg/dl) or non-HDL-C more than and less than 3.37 mmol/l (130 mg/dl). In neither of these analyses was there an additional benefit to be gained by lowering CRP to <2 mg/l (data not shown).
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