January 28th, 2011

Does CRP Level Modify the Benefit of Statins? Paul Ridker Reacts to New Data

CardioExchange welcomes Paul M. Ridker, a leading researcher on the value of C-reactive protein (CRP) concentration as a prognostic marker of cardiovascular risk, to respond to the latest data on CRP and statin therapy from the Heart Protection Study (HPS).

The New HPS Findings on CRP: The HPS investigators sought to determine whether statin therapy might be especially beneficial to patients with high CRP concentrations. They took the more than 20,000 HPS participants who had been randomized to receive simvastatin (40 mg/day) or placebo for a mean of 5 years and stratified them into 6 groups according to baseline CRP level, ranging from <1.25 mg/L to ≥8 mg/L.

The incidence of major vascular events — coronary death, MI, stroke, or revascularization — was significantly lower among simvastatin recipients than among placebo recipients (19.8% vs. 25.2%). The investigators found no evidence that incidence of that endpoint or its components varied according to baseline CRP concentration. Nor did relative risk reduction vary across four subgroups that were defined by high or low baseline levels of LDL cholesterol and CRP. Even patients with low baseline levels of both LDL-c and CRP benefited significantly from simvastatin.

Dr. Ridker’s Response:

First, although the HPS investigators report that baseline CRP does not modify the vascular benefits of statin therapy, it is important to remember that baseline LDL-c also did not modify the benefit of statin therapy in their study.

Second, the data presented clearly show that CRP levels track directly with absolute risk in the HPS. For example, within the placebo group, the baseline CRP level corresponded with the incidence of vascular events: 19% incidence among patients with low CRP, climbing to 31% among those with high CRP. Thus, although these data are not discussed at all in the article, they nonetheless confirm the ability of CRP to predict high risk.

Third, the HPS investigators elected not to address the core hypothesis that on-treatment levels of CRP correlate with the risk reduction attributable to statins, as has been shown in many prior statin trials. The authors make the claim that such an analysis should not be done, as it would be nonrandomized. Yet they go on to conclude that the benefits of statin therapy accrue solely to on-treatment LDL, an analysis that suffers equally from the same nonrandomized limitations.

Fourth, the well-conducted HPS was performed almost entirely among patients with a prior history of MI, stroke, peripheral artery disease, or diabetes. Therefore, the HPS cannot be interpreted as a primary-prevention trial. Primary prevention is the setting in which (1) CRP measurement has been shown to provide as much incremental information on vascular risk as does total or HDL cholesterol and (2) CRP testing is recommended to identify patient groups who benefit from statin therapy but otherwise would not qualify for treatment on the basis of LDL-c levels.

In the end, the only way to test the inflammatory hypothesis of atheroscerlosis is to directly randomize patients to targeted anti-inflammatory therapies. My research team and I hope to launch two such trials this year.

2 Responses to “Does CRP Level Modify the Benefit of Statins? Paul Ridker Reacts to New Data”

  1. Most analysys of the protective effects of statins agree that the relative reduction of vascular risk by statins is similar regardless of baseline clinical conditions and, remarkably, also lipid levels. Therefore the absolute benefit of statins relates essentially to the basal absolute risk of patients.
    Big studies also suggest that increased CRP is a marker of increased vascular risk, although mendelian randomization studies do not support a causal role for CRP in the development of atherosclerosis or its complications. Interventional studies addressed directly to reduce CRP or its presumed mechamism of vascular injury must be conducted to further clarify this issue.
    Whetner CRP plays a casual role or is a mere epiphenomenon reflecting someway ongoing inflammation, it might be useful as a marker of increased vascular risk.
    For any risk marker to be useful, it should provide clear additional prognostic information on top of classical risk factors (such as those included in the Framingham equations). CRP correlates with many of such risk factors, so it is not suprising that it seems to provide additional information when some of these factors are poorly included in risk equations (such as using dychotomous variables for obesity or smoking).
    Last but not least, a significant improvement of risk estimation in the population level may be of little interest for the individual patient. The high degree of intraindividual variation (thus reclassifying individual patients into different groups of risk according to different measurements of CRP) makes this parameter a poor choice to guide desirably predictable therapeutic algorythms

    Competing interests pertaining specifically to this post, comment, or both:
    I do not have conflicts of interest pertaining to this subject

  2. How many markers are needed to stratify those who are either at intermediate to high risk of vascular events? Along with hsCRP, ApoB, ApoB/ApoA-1 ratio,Flow mediated vasodilatation, Carotid intimal medial thickness(CMT),Coronary calcium score by EBCT and may more are proposed to stratified risks. Recently Genome wide association (GWA) studies,which includes identification of high risk SNPs,by using micro-array technologies etc & etc!
    Is there any end of of all these technological break-through(?),all these hype, come to an end? Is it not simply history & physical examinations,including family history of premature CHD/CVD,Gender,Systolic BP,Total Cholesterol,HDL cholesterol; which in summation Framingham risk score(FRS) + ATP-3 data are sufficient?
    How many studies have showed that those above mentioned High-Tech dependent markers consistently superior to predict absolute CHD/CVD events & mortality? And have changed clinical decision by categorizing consistently intermediate to high risk category to change meaningful management decision of the Clinicians caring for those patients?
    AHA predicted that in USA cost of caring patients with cardiovascular diseases will increased dramatically in next 2-decades. How much cost our Patients & how much confusion our Physician afford to tolerate in near future?