On-treatment CRP levels do not predict subsequent CV eventsLiterature - Sever, PS, Poulter NR, Chang, CL et al. - J Am Coll Cardiol. 2013;62(8):717-729
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.
1.Shah PK. Inflammation and plaque vulnerability. Cardiovasc Drugs Ther 2009;23:31–40.
2.Ridker PM. C-reactive protein and the prediction of cardiovascular events among those at intermediate risk: moving an inflammatory hypothesis toward consensus. J Am Coll Cardiol 2007;49:2129–38.
3. Deveraj S, Singh U, Jialal I. The evolving role of C-reactive protein in atherothrombosis. Clin Chem 2009;55:229–38.
4. The Emerging Risk Factors Collaboration. C-reactive protein, fibrinogen, and cardiovascular disease prediction. N Engl J Med 2012;367: 1310–20.
5. Després J-P. CRP: star trekking the galaxy of risk markers. Lancet 2011;377:441–2.
6. Braunwald E. Creating controversy where none exists: the important role of C-reactive protein in the CARE, AFCAPS/TexCAPS, PROVE-IT, REVERSAL, A to Z, JUPITER, HEART PROTECTION, and ASCOT trials. Eur Heart J 2012;33:430–2.
7. Sever PS, Poulter NR, Chang CL, et al. Evaluation of C-reactive protein prior to and on-treatment as a predictor of benefit from atorvastatin: observations from the Anglo-Scandinavian Cardiac Outcomes
Trial. Eur Heart J 2012;33:486–94.
8. Sever PS, Dahlöf B, Poulter NR, et al., for the ASCOT Investigators. Rationale, design, methods and baseline demography of participants of the Anglo-Scandinavian Cardiac Outcomes Trial. ASCOT investigators.
J Hypertens 2001;6:1139–47.
9. Blumenthal RS, Ndumele CE, Martin SS et al. ASK NOT What CRP Can Do for You. J Am Coll Cardiol. 2013;62(8):730 doi:10.1016/j.jacc.2013.01.106