Equal predictive value of C-reactive protein and cholesterol levels

Ridker PM, Kastelein JJ, Genest J, Koenig W.
Eur Heart J. 2013 May;34(17):1258-61. doi: 10.1093/eurheartj/eht022- Current opinion

Background

Measuring biomarkers serves to predict risk, as well as to better target therapy and improve the patient’s life. Before a biomarker is used for cardiovascular (CV) risk prediction (either by a clinician or when writing guidelines) two questions should be answered affirmatively, namely whether there is clear evidence that the biomarker predicts future CV events independent of other risk markers, and whether clear evidence exists that those identified by the biomarkers benefit from a therapy they otherwise would not have received. For some imaging or plasma biomarkers this is not the case.
This ‘Current Opinion’ discusses that both C-reactive protein (CRP) and cholesterol can answer both questions affirmatively. Despite this, recent guidelines issued by the European Society of Cardiology on the prevention of heart disease strongly endorse cholesterol screening, but remain silent on CRP.

Evidence that cholesterol and C-reactive protein are equally strong independent predictors of risk

Inflammation is a central component of atherosclerosis. Large-scale prospective studies have already demonstrated that the predictive value of the inflammatory biomarker CRP is at least as large as that of cholesterol. This is important since about half of all people who suffer from heart attacks or strokes have average if not low cholesterol levels.
The Emerging Risk Factors Collaboration recently confirmed the observation that CRP and lipids are equal contributors to vascular risk, in a meta-analysis of 38 prospective studies that included 166596 individuals without prior disease. This meta-analysis yielded a multivariate adjusted hazard ratio associated with a 1 SD increase in CRP was 1.20, as compared to 1.17 for a comparable 1 SD increase in total cholesterol. Thus, CRP and lipids are virtually identical in their capacity to identify those at risk for future CV events and each factor adds equally to the other. Despite this, according to some, CRP does not merit inclusion in risk prediction guidelines.

Evidence that individuals identified by cholesterol or C-reactive protein screening benefit from a therapy they otherwise would not have received

This type of evidence is a crucial aspect of evidence-based medicine yet often overlooked in the process of guideline writing. In parallel to the pivotal WOSCOPS trial that laid the basis for the use of statins as primary prevention in individuals with elevated cholesterol, the JUPITER trial  answered this question for those who had elevated CRP-levels but who would otherwise not qualify for statin therapy. Among 17802 individuals with LDL-C levels below treatment thresholds, but with CRP>2 mg/L and therefore identified to be at increased CV risk, rosuvastatin reduced the incidence of major vascular events by 44% (P<0.0001) and all-cause mortality by 20% (P=0.02). Similar risk reductions were seen in women and non-Caucasian participants. Absolute risk increased with higher baseline CRP levels, as did risk reduction upon statin therapy.

What works and in whom?

A simple, easily applied, evidence-based alternative to guidelines for the use of statin therapy in the prevention of cardiovascular disease
Recent trials such as CORONA, AURORA and GISSI-HF taught that high risk patients who achieved large LDL-C reductions with statins, did not profit from significant clinical benefit. Therefore, the authors prefer that guidelines and clinical practice be based on the principle of ‘what works?’ and ‘in whom?’ rather than on epidemiological modelling and risk simulations.
Nowadays there is abundant safety data as well as data on the efficacy in different patient groups, and the benefits of statin are known to outweigh the risks. Thus there is no need for epidemiological extrapolation. Also costs have substantially been reduced because most statins are off patent. Therefore, on the basis of the abundant high-quality randomized trial data, the authors propose a simple evidence-based guideline for statin therapy:

1. Statin therapy should be used as an adjunct to diet, exercise and smoking cessation as secondary prevention in patients with a history of myocardial infarct, stroke or clinically apparent atherosclerosis (4S, HPS, CARE, LIPID).
2. Statin can be considered an adjunct to diet, exercise and smoking cessation as primary preventions for those aged 50 and over with either diabetes (CARDS), elevated LDL-C (WOSCOPS, MEGA), low HDL-C (AFCAPS) or elevated hsC-reactive protein (JUPITER). Physicians may decide to limit these patients groups to only those with an additional risk factor, or they may extend the criteria to patients with a genetic predisposition or a strong family history of premature coronary disease.
3. Physicians should seek to maximize the intensity of statin treatment and focus on compliance and long-term adherence (PROVE IT, TNT, IDEAL), based on the patient’s  tolerance.
4. The use of non-statin lipid-lowering agents as monotherapy or in combination with statin should be limited until there is evidence that such an approach further reduced CV event rates in specific patient groups (AIM-HIGH, ACCORD, HELD, THRIVE). Evidence exists that such approaches may be suboptimal.
5. A guideline based on trial evidence (to know what works) and on trial entry criteria (to know in whom) will result in broad clinical acceptance. New insights in prevention should be incorporated into guidelines as quickly as possible.

The American FDA provided a new labelling claim for statin therapy that included reductions in myocardial infarction and stroke among individuals with elevated CRP and at least one additional risk factor, based on the JUPITER data. The Canadian Cardiovascular Society guidelines for the prevention of CV disease endorsed the use of statins as CV prevention in patients with elevated CRP and a 10-year projected risk between 10 and 20%. Although European participants of JUPITER had at least as much benefit as those enrolled in the USA or Canada, the European Medicines Agency only provided, based on the same data, the indication for a small subset of trial participants defined by the agency on a post hoc basis that did not on its own have evidence for the benefit.

Despite highly consistent evidence favouring CRP, some continue to create controversy.
The authors write that their primary prevention patients with elevated CRP benefit from statin therapy just like primary prevention patients with elevated LDL-C. The authors say that it is inconsistent with evidence-based practice and disservice to patients to withhold potentially life-saving therapy, because of an unwillingness to address new data.

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