On-treatment CRP levels do not predict subsequent CV events
Evaluation of C-Reactive Protein Before and On-Treatment as a Predictor of Benefit of Atorvastatin
A Cohort Analysis From the Anglo-Scandinavian Cardiac Outcomes Trial Lipid-Lowering Arm
Sever, PS, Poulter NR, Chang, CL et al.
J Am Coll Cardiol. 2013;62(8):717-729. doi:10.1016/j.jacc.2013.02.098
BackgroundIncreasing efforts are focused on understanding the role of various molecular and cellular components that are activated during the inflammatory response and that may contribute to plaque rupture and the presentation of acute coronary syndromes . C-reactive protein (CRP) has been proposed as a clinical risk predictor for cardiovascular disease (CVD) [2-4], but its clinical utility is disputed .
It has been debated whether statin-associated CRP reduction is an independent predictor of CVD after consideration of concomitant LDL-c reduction [6,7]. The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) showed that CRP did not usefully improve the prediction of CV events in hypertensive patients selected on the basis of traditional risk factors. Moreover, CRP reduction associated with statin therapy alone did not predict CV outcome, nor in combination with LDL-c . However, data of few patients with on-treatment levels of CRP were available.
Therefore, this analysis extends the previous observations by including a full cohort analysis of all eligible white patients in ASCOT-LLA (lipid-lowering arm) from whom baseline and on-treatment CRP-values were available .
- Baseline CRP was positively associated with risk of a CV event and CHD, but not with the risk of stroke. HR for CV events was 1.21 (95%CI: 1.09-1.33, p=0.0003) per 1 SD increase in log-transformed CRP, after adjusting for classic risk factors.
- The effect of statins on preventing CVD was not affected by level of CRP.
- After 6 months of atorvastatin 10 mg treatment, median LDL-c was reduced by 38.7% (3.46 mmol/l to 2.12 mmol/l), as opposed to a 1.7% (from 3.46 mmol/l to 3.40 mmol/l) decrease after placebo. Median CRP showed a 25.8% reduction with atorvastatin (from 2.21 mg/l to 1.64 mg/l) as compared to placebo (from 2.25 mg/l to 2.24 mg/l).
- A 1 mmol/l LDL-c decrease over 6 months of treatment was associated with a reduced risk of CV events (HR: 0.83, 95%CI: 0.69-0.99, P=0.04) and CHD events (HR: 0.83, 95%CI: 0.67-1.02, P=0.07), irrespective of treatment group assignment.
A 10 mg/l CRP decrease showed no association with CV or CHD events (HR: 1.03, 95%CI: 0.90-1.18, P=0.69 and HR: 1.05, 95%CI: 0.92-1.20, P=0.48 respectively).
- People who achieved a CRP-level below the median at 6 months, irrespective of treatment group, did not have a significantly different risk of CV or CHD from those who did not. Subjects who achieved LDL-c below the median, did have a significant reduction in risk of CV events (HR:0.54, 95%CI: 0.34-0.85, P=0.008).
- There was no significant atorvastatin group difference for achieved CRP below versus above the median, while this was the case for achieving LDL-c below the median.
- In comparison to placebo, the lowest risk of CV events was seen in subjects receiving atorvastatin and who achieved LDL-c below the median, irrespective of on-treatment CRP levels.
ConclusionThis trial in hypertensive patients with modest CV risk shows that baseline CRP independently predicts subsequent CV events, while neither baseline nor achieved levels of CRP with atorvastatin 10 mg/day predicted the efficacy of the statin in preventing CV events. Thus, this study confirms earlier observations of ASCOT that lowering CRP yields no additional benefit; on-treatment CRP levels have virtually no predictive value.
Editorial comment Although ASCOT-LLA included more CV events than the previous ASCOT cohort, the number of cases with on-treatment CRP data was still limited. It remains possible that with greater statistical power, significant reductions in CVD events might be observed. Given known demographic variations in CRP-levels, the white, older and over >80% male composition of the ASCOT-LLA cohort makes it less generalisable to women, other ethnicities and younger patients.
The absolute statin benefit depends on absolute risk. CRP only modestly adds extra information to clinical metrics generally in use. Even if CRP is not a causal risk factor, it reflects underlying inflammatory processes that may be causal and modifiable by lifestyle improvements and pharmacotherapy.
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