EDITORIAL

Use of C-reactive protein to prevent atherosclerosis: between Jupiter and Mars

Marcio H. Miname^I; Raul D. SantosII, ^*

^IMédico, Pós-Graduando da Disciplina de Cardiologia da Faculdade de Medicina da Universidade de São Paulo - FMUSP, São Paulo, SP

^IIProfessor Livre Docente da Faculdade de Medicina da Universidade de São Paulo - FMUSP; Diretor da Unidade Clínica de Lípides Instituto do Coração -InCor - Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo - USP, São Paulo, SP

There is no doubt about the fact that lowering cholesterol levels using statins decreases the mortality and morbidity rates caused by cardiovascular diseases in individuals who do not present with a previous manifestation of atherosclerosis.^1,2 However, the real benefit and cost-effectiveness ratio of these treatments will depend on the absolute risk of cardiovascular outcomes. The current guidelines recommend that the calculation of the cardiovascular risk in 10 years should be based on age, total cholesterol levels, HDL-cholesterol, blood pressure, and smoking to guide the beginning and intensity of the treatment with statins in primary prevention patients.³ Nevertheless, there is evidence that many patients who could have a clinical event in the future are not treated because they are considered to be at low cardiovascular risk.⁴ It is the so-called "detection gap," which affects mainly younger individuals and women. Several tools have been used to improve the stratification of patients' cardiovascular risk, from research on subclinical atherosclerosis with imaging studies⁵ to the use of laboratory biomarkers such as high sensitivity C-reactive protein (CRP),⁶ among others.

CRP is an acute-phase plasma protein mainly produced by hepatocytes. It is a member of the pentraxin family.⁶ There is much evidence of its role in the atherogenesis, such as: increased expression of VCAM, ICAM-1, E-selectin, MCP-1, increased smooth muscle cell migration, in vivo endothelial dysfunction, among others.⁶ Several clinical trials have demonstrated its role as a marker of cardiovascular risk. The following are the most important ones: Physicians Health Study (PHS), Women's Health Study (WHS), Honolulu Heart Study, Nurses Health Study, MONICA (Monitoring Trends and Determinants in Cardiovascular Disease), and Cardiovascular Health Study.⁷ Based on such evidence, CRP was included in the 4th Brazilian Guideline of Atherosclerosis Prevention as a risk aggravator, that is, high CRP levels could cause an increase in the cardiovascular risk and change the treatment goals.³ Ridker et al. suggested the inclusion of CRP in a clinical score (Reynolds Risk Score) in order to improve the stratification of cardiovascular risk.⁸ However, recent studies using new statistical methods to test the presence or absence of the additional utility of biomarkers compared the traditional risk factors have not confirmed the usefulness of CRP as a risk marker.^9,10 Currently, it is well known that the definition of the traditional measures of association, such as odds ratios or hazard ratios, are not enough to assess the real predictive value of a biomarker with regard to the complete set of risk factors for atherosclerosis.¹¹ Lloyd-Jones et al.⁹ analyzed the value added by the CRP to the traditional risk factors in large clinical trials using c-statistics and areas under receiver-operating characteristic curves (AUCs) for models with traditional risk factors before and after adding CRP: WHS 0.81 vs. 0.81; Rotterdam Study 0.746 vs. 0.748; MONICA 0.735 vs. 0.750; Reykjavik Cohort 0.645 vs. 0.65; Framingham Offspring Study 0.74 vs. 0.74; Framingham Heart Study 0.80 vs. 0.80; Cardiovascular Health Study 0.73 vs. 0.72. These authors concluded that the determination of CRP does not change the AUC, that is, it does not improve risk discrimination compared to the traditional risk factors and, therefore, there is not consistent evidence to recommend its use in the routine clinical practice.⁹ More recently, a Sweden cohort study, involving 5,067 participants without cardiovascular disease, assessed the role of six biomarkers, among which was CRP, in the prediction of cardiovascular risk.¹⁰ During a median follow-up of 12.8 years, there were 418 cardiovascular and 230 coronary events. CRP did not increase the discriminant power of the traditional risk factors when it was analyzed alone for cardiovascular events (increase in c-statistics of 0.003; p = 0.14) and it showed a slight increase when analyzed in combination with N-BNP (brain natriuretic peptide, increase in c-statistics of 0.007; p = 0.04).¹⁰ The study also concluded that the biomarkers could be able to produce a slight increase in the reclassification of intermediate-risk individuals; however, this would be the case mainly when reclassifying to a lower risk level,¹⁰ which would not change the clinical practice, since the treatment of the present risk factors would not be interrupted. The studies by Lloyd-Jones et al. and Melanger et al.^9,10 raised questions about the biomarkers and initiated a great debate within the context of preventive cardiology over the use (or not) of CRP to assess cardiovascular risk.

Several studies have demonstrated that statins, in addition to lowering LDL-cholesterol (LDL-C), can also reduce CRP levels, which would be a sign of an anti-inflammatory effect of this class of drugs. The natural question that results from that is: what is the clinical consequence of that? The PROVE-IT TIMI-22 study assessed the effects of an intensive regimen (atorvastatin 80 mg/day) vs. a moderate regimen (pravastatin 40 mg/day) to lower the cholesterol levels of acute coronary syndrome patients. In addition to demonstrating the benefit of the intensive regimen in terms of a more significant reduction of cardiovascular events (RR = -16%, number needed to treat = 25), the study also showed that the patients who achieved the dual goal of LDL-C < 70 mg/dL and CRP < 2 mg/L comprised the subgroup that had the highest decrease in the number of events, even when compared to the individuals who achieved only one of the goals.¹² The A to Z study demonstrated a similar finding in patients with acute coronary syndrome using intensive and conservative simvastatin strategies.¹³ The REVERSAL study, which measured the progression of atherosclerosis using intravascular ultrasonography in intensive and moderate treatments of cholesterol reduction, demonstrated that the individuals who remained below the median for LDL-C and CRP had a slower rate of progression of atherosclerosis.¹⁴ Thus, new hypotheses regarding the dual goal attainment started to be proposed: reduction of cholesterol and reduction of the inflammatory process. The JUPITER study (Justification for the Use of Statins in Primary Prevention: an International Trial Evaluating Rosuvastatin) was designed with the purpose of testing the hypothesis that patients with normal LDL-C (< 130 mg/dL) and elevated CRP (> 2 mg/L) might benefit from statin treatment (rosuvastatin 20 mg/day).¹⁵

The JUPITER study included primary prevention patients, 50-year-old or older men, 60-year-old or older women, all of them with LDL-C lower than 130 mg/dL (median 108 mg/dL) and CRP higher than 2 mg/L (median 4.25 mg/L).¹⁵ The primary end point included myocardial infarction, stroke, arterial revascularization, hospitalization for unstable angina, or death for cardiovascular causes. The study included 17,802 patients, who were randomly assigned to rosuvastatin 20 mg/day or placebo. The trial was stopped after a median follow-up of 1.9 years (maximum, 5.0). Rosuvastatin lowered LDL-C levels by 50% and CRP by 37%. The rates of primary end point were 0.77 and 1.35 per 100 person/year of follow-up, respectively for rosuvastatin and placebo (the hazard ration for rosuvastatin was 0.56; 96%CI 0.46-0.69, p < 0.00001). There was also a decrease in the rate of death from any cause in favor of rosuvastatin (hazard ratio 0.80; 95%CI 0.67-0.97; p = 0.02).¹⁵

A prospective analysis of the JUPITER study also revealed that there was a higher decrease in the vascular events in patients who achieved LDL-C < 70 mg/dL and CRP < 2 mg/L compared to individuals who achieved one or none of these goals.¹⁶ The results of the PROVE-IT and JUPITER studies triggered another great debate: should CRP levels be monitored to assess the effectiveness of the treatment in the same way as the cholesterol levels? Should a dual goal, LDL-C and CRP, be set to improve prevention? In addition to being used for risk assessment, should CRP also be used to monitor the treatment? This issue has been the reason for strong debates in cardiology. Even though we strongly believe in the inflammatory theory of atherosclerosis, in our opinion, having a dual-goal treatment incorporated into the guidelines is a very distant reality. Since statins, in addition to lowering CRP levels, also reduce cholesterol, (and as a matter of fact, these drugs were created and approved with that purpose), it is difficult, even using complex statistical methods, to separate the isolated effects of reduced cholesterol and CRP levels on the clinical outcomes.¹⁶ Therefore, it is not possible to demonstrate the isolated benefit of improving the inflammation caused by these drugs. To solve this problem, there is need of further studies assessing drugs that reduce only the inflammatory process without affecting the lipids, and we are very far from achieving that.

According to our point of view, the immediate consequence of the JUPITER study will be to change the goals of LDL-C levels for patients at moderate risk (risk > 10% in 10 years) for at least < 100 mg/dL or < 70 mg/dL. However, even though it is a multicentric trial of great impact, the JUPITER study also raises some questions that remain unanswered. The lack of inclusion of patients with CRP < 2 mg/L challenges the fact that CRP itself really indicates a group of individuals that would benefit from the use of statins. If the authors of the JUPITER study really wish to test CRP as a tool to indicate the use of statins, they should include a group with CRP < 2.0 mg/L, randomized or not for statins. We should keep in mind that a reduction of 53 mg/dL in the LDL-C, such as the one found in the JUPITER study, could reduce cardiovascular risk, regardless of the baseline values of LDL-C, in more than 25% according to the meta-analysis of the Cholesterol Treatment Trialists' (CTT).¹ Half of the patients involved in the JUPITER study (n = 8,895) were not at low risk and, therefore, had a Framingham score higher than 10%, that is, they represent a population in which the benefit of using statin would be expected even with median LDL-C of 108 mg/dL.¹⁵ The duration of follow-up of the JUPITER study was short (median = 1.9 years), which makes it impossible to draw conclusions regarding a longer use of statins in this population. However, there is an important aspect that diminishes the relevance of this limitation, the longer the cholesterol levels are reduced using statins the stronger the impact of the benefits reached.¹

Another issue is related to the impact of the JUPITER study in terms of public health. Should all patients who meet the inclusion criteria of the JUPITER study be treated with statin? What is the cost-benefit ratio? How many individuals in Brazil would fit this profile? We cannot answer that, but an estimate from the USA calculated that 6.5 million of U.S. individuals would be potential candidates for treatment with statin after the JUPITER study.¹⁷ We should consider that risk factors such as obesity and smoking also increase CRP and these patients should always be stimulated to change their lifestyle. We still believe that the treatment of patients should be conducted according to the current guidelines, mainly based on the cardiovascular risk, keeping in mind that the higher the risk the higher the benefit of the treatment with statins. Individuals at higher risk should obviously be treated with a more intensive regimen regarding LDL-C, and the JUPITER study corroborates the data from previous studies.^1,2 Finally, according to our point of view, the use of CRP in the clinical practice will certainly depend on better designed clinical trials; however, to date, its use seems to depend on the caprices of the Gods of Olympus: it depends on the good will of Jupiter, the father of all gods and, due to all the debate going on, it depends on his son Mars, the god of war.

References

• 1. Cholesterol Treatment Trialists´(CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90.056 participants in 14 randomised trials of statins. Lancet. 2005;366:1267-78.
• 2. Brugts JJ, Yetgin T, Hoeks SE, Gotto AM, Shepherd J, Westendorp RGJ, et al The benefits of statins in people without established cardiovascular disease but with cardiovascular risk factors: meta-analysis of randomised controlled trials. BMJ. 2009;338:b2376.
• 3. Sposito AC, Caramelli B, Fonseca FA, Bertolami MC, Afiune Neto A, Souza AD, et al. IV Brazilian Guideline for Dyslipidemia and Atherosclerosis prevention: Department of Atherosclerosis of Brazilian Society of Cardiology. Arq Bras Cardiol. 2007;88(Suppl 1):2-19.
• 4. Akosah KO, Schaper A, Cogbill C, Schoenfeld P. Preventing myocardial infarction in the ypung adult in the first place: how do the national cholesterol education panel III guidelines perform? J Am Coll Cardiol. 2003;41:1475-9.
• 5. Santos RD, Nasir K. Insights into atherosclerosis from invasive and non-invasive imaging studies: should we treat subclinical atherosclerosis? Atherosclerosis. 2008;205(2):349-56.
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• 7. 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.
• 8. Ridker PM, Buring JE, Rifai N, Cook NR. Development and validation of improved algorithms for the assessment of global cardiovascular risk in women: the Reynolds Risk Score. JAMA. 2007;297:611-9.
• 9. Lloyd-Jones DM, Liu K, Tian L, Greenland P. Narrative review: assessment of C-reactive protein in risk prediction for cardiovascular disease. Ann Intern Med. 2006;145:35-42.
• 10. Melander O, Newton-Cheh C, Almgren P, Hedblad B, Berglund G, Engström G, et al. Novel and conventional biomarkers for prediction of incident cardiovascular events in the community. JAMA. 2009;302:49-57.
• 11. Pepe MS, Janes H, Longton G, Leisering W, Newcomb P. Limitations of the odds ratio in gauging the performance of a diagnostic, prognostic or screening marker. Am J Epidemiol. 2004;159:882-90.
• 12. Ridker PM, Morrow DA, Rose LM, Rifai N, Cannon CP, Braunwald E. Relative efficacy of atorvastatin 80mg and pravastatin 40mg in achieving the dual goals of low-density lipoprotein cholesterol <70mg/dL and C-reactive protein <2mg/L. J Am Coll Cardiol. 2005;45:1644-8.
• 13. DA Morrow, de Lemos JA, Sabatine MS, Wiviott SD, Blazing MA, Shui A, et al. Clinical relevance of C-reactive protein during follow-up of patients with acute coronary syndromes in the Aggrastat-to-Zocor Trial. Circulation. 2006;114:281-8.
• 14. Nissen SE, Tuzcu EM, Schoenhagen P, Crowe T, Sasiela WJ, Tsai J, et al. Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease. N Engl J Med. 2005;352:29-38.
• 15. Ridker PM, Danielson E, Fonseca FAH, Genest J, Gotto AM, Kastelein JJP, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359:2195-207.
• 16. Ridker PM, Danielson E, Fonseca FAH, Genest J, Gotto AM, Kastelein JJP, et al. Reduction in C-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin: a prospective study of the JUPITER trial. Lancet. 2009;373:1175-82.
• 17. Michos ED, Blumenthal RS. Prevalence of low low-density lipoprotein cholesterol with elevated high sensitivity C-reactive protein in the U.S. Implications of the JUPITER (Justification for the use of statins in primary prevention: an intervetion trial evaluating rosuvastatin) Study. J Am Coll Cardiol. 2009;53:931-5.

Publication Dates

• Publication in this collection
  17 Nov 2009
• Date of issue
  2009