NHLBI Workshop on C-Reactive Protein: Basic and Clinical Research Needs
July 10-11, 2006

Data on hsCRP from Clinical Trials
Paul M. Ridker

Prospective cohort studies consistently show hsCRP levels to be independently associated with increased risk of future vascular events and recent data from Cook et al demonstrate in prediction models including age, blood pressure, and smoking status, that (a) hsCRP improves prediction at least as much as do lipid measures, and (b) that hsCRP evaluation leads to a large proportion of patients being re-classified to higher or lower risk categories when estimated 10-year risk is otherwise between 5 and 10 or between 10 and 20 percent (1). Since it is not necessary for a marker of risk be in the causal pathway of disease for it to be clinically useful for risk stratification, it would appear that hsCRP is effective for this purpose, particularly for those above a 5 percent risk threshold. Nonetheless, it is of pathophysiologic interest to know if CRP is or is not in the causal pathway of disease, particularly if strategies to lower CRP are being considered for clinical practice.

To date, little data exist one way or the other evaluating the hypothesis that CRP reduction per se lowers vascular risk. However, a consistent series of studies has found concordant evidence that interventions already known to lower vascular risk such as diet, weight loss, smoking cessation, and lipid reduction do in fact lower hsCRP levels, while interventions such as HRT that increase vascular risk increase hsCRP. With regard to clinical trial data, this has best been evaluated in studies of statin therapy where published data indicate that (a) all statins lower hsCRP in a manner largely independent of LDL reduction; (b) that patients with elevated levels of hsCRP have better outcomes when treated with statin therapy compared to those with lower hsCRP levels, even when matched for baseline LDL or for LDL reduction; and (c) that in acute coronary syndromes or stable-post infarction patients, the level of hsCRP achieved after initiation of statin therapy is as important for determining outcome as the level of LDL cholesterol reduction achieved, even after adjusting for all covariates typically associated with risk (2-5). Further, in primary prevention, analyses of the AFCAPS/TexCAPS trial suggest that those with below median levels of LDL but above median levels of hsCRP benefit from statin therapy (6). This hypothesis - that statin therapy may be effective among those with low levels of LDL cholesterol but elevated levels of hsCRP – is being prospectively tested in the large-scale, hard-endpoint JUPITER trial which is being conducted in 20 countries and has enrolled over 11,000 patients (7). With regard to non-statin trials, the recently completed Val-MARC trial of patients with stage 2 hypertension has found that angiotensin receptor blockers (ARBs) also reduce hsCRP levels (8) and on this basis, discussions are underway to design endpoint studies of hypertension prevention and thrombosis prevention using hsCRP to define high risk patient groups. Similarly, multiple clinical trials of agents used for weight reduction (rimonabant), and diabetes control (metformin, insulin, TZDs) are in progress or have reported reductions in hsCRP levels.

While the above trials will evaluate hsCRP as a method to identify and target high-risk populations and will provide further pathopysiologic insight on drug mechanism, each of the above mentioned agents has multiple alternative primary effects. Thus, to formally address whether CRP reduction per se lowers risk, trials of direct CRP inhibition will be needed, particularly for agents that do not have alternative known beneficial effects. Preliminary data on several approaches to direct CRP inhibition have been presented and include anti-sense technologies targeting CRP translation (ISIS), extra-corporeal immunomodulation (Vasogen), and specific small-molecule CRP inhibitors (Pentraxin Therapeutics). The latter of these, based upon 1,6-bis(phosphocholine)-hexane as developed by Pepys et al, has recently shown some efficacy in inhibiting the increase in infarct size produced by human CRP injection in planned rat infarction models (9). Whether any of these approaches - or those targeting alternative components of the inflammatory response including cytokines, chemokines or adhesion molecules – will ultimately prove to have clinical efficacy for vascular disease prevention and/or treatment will require carefully designed clinical trials.

References

  1. Cook NR, Buring JE, Ridker PM. The effect of including C-reactive protein in cardiovascular risk prediction models for women. Ann Int Med 2006;145:21-29.
  2. Ridker PM. Rifai N, Pfeffer MA, Sacks FM, Moye LA, Goldman S, Flaker GC, Braunwald E. for the Cholesterol and Recurrent Events (CARE) Investigators. Circulation 1998;98:839-844. [CARE]
  3. Albert MA, Danielson E, Rifai N, Ridker PM. Effect of statin therapy on C-reactive protein levels: the Pravastatin Inflammation/CRP Evaluation (PRINCE): a randomized trial and cohort study. JAMA 2001;286:64-70 [PRINCE]
  4. Ridker PM, Cannon CP, Morrow D, Rifai N, Rose LM, McCabe CH, Pfeffer MA, Braunwald EB. C-reactive protein levels and outcomes after statin therapy. N Engl J Med 2005;352:20-28. [PROVE IT – TIMI 22]
  5. Nissen SE, Tuzcu EM, Schoenhagen P, Crowe T, Sasiela W, Tsai J, Orazem J, Magorien RD, O’Shaughnessy C, Ganz P. Statin therapy, LDL-C, C-reactive protein, and coronary artery disease. N Engl J Med 2005;352:29-38. [REVERSAL]
  6. Ridker PM, Rifai N, Clearfiled M, Downs JR, Weis SE, Miles JS, Gotto AM Jr. Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary events. N Engl J Med 2001;344:1959-65. [AFCAPS/TexCAPS]
  7. Ridker PM. Rosuvastatin in the primary prevention of cardiovascular disease among patients with low levels of low-density lipoprotein cholesterol and elevated high-sensitivity C-reactive protein: rationale and design of the JUPITER trial. Circulation 2003;108:2292-7 [JUPITER Protocol]
  8. Ridker PM, Danielson E, Rifai, N Glynn RJ, for the Val-MARC Investigators. Valsartan, blood pressure reduction, and C-reactive protein. Primary report of the Val-MARC trial. Hypertension 2006;48:1-7. [Val-MARC]
  9. Pepys MB, Hirschfield GM, Tennent GA, Galimore JR, Kahan MC, Bellotti V, Hawins PN, Myers RM, Smith MD, Polara A, Cobb AJA, Ley SV, Aquilina JA, Robinson CV, Sharif I, Gray GA, Sabin CA, Jenvey MC, Kolstoe SE, Thompson E, Wood SP. Targeting C-reactive protein for the treatment of cardiovascular disease. Nature 2006;440:1217-21 [Potential avenue for direct CRP inhibition]
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