Editorial Slides VP Watch –July 3, 2002 - Volume 2, Issue 26

A Call for “CRP-Lowering” or “CRP-Guided” Trial?

Atherosclerosis is an inflammatory disease. 1

Previous studies showed that markers of inflammation, in particular CRP, could be used to predict the clinical outcome of CAD patients.

Ridker et al. showed that high sensitive-CRP is a strong independent predictor of future coronary events in apparently healthy subjects.7

CRP; Marker of Inflammation

Ridker showed that the effect of aspirin in preventing first MI was greatest between men with the highest base-line CRP. 5

Ikonomidis et al. in another study showed that higher-dose aspirin (300 g/d) reduced macrophage colony stimulating factor, IL-6, and CRP after 6 weeks. 13

Aspirin and CRP

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Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 1997;336:973-979.

High Sensitive-CRP, Aspirin, and Risks of Future MI: Physicians' Health Study

CRP Quartile

Pravastatin Inflammation CRP Evaluation (PRINCE) was an investigator-initiated, multicenter, community-based trial that evaluates the effects of pravastatin on hs-CRP in individuals with and without CAD. 8

Ridker and colleagues in PRINCE trial showed that pravastatin reduced CRP at both 12 and 24 weeks in a largely LDL-independent manner (anti-inflammatory effects of statins). 9

Statins and CRP

Yeh, Willerson, and colleagues showed that CRP induces adhesion molecule expression in human endothelial cells. 10

These findings support the hypothesis that CRP may play a direct role in promoting the inflammatory component of atherosclerosis and present a potential target for the treatment of atherosclerosis.

Verma and coworkers showed that mixed endothelin (A/B) receptor antagonist and IL-6 inhibitor reduce atherogenic and inflammatory effect of CRP. 11

CRP Induces Inflammation

Potential roles of CRP on pathogenesis of atherosclerosis:

Inducing foam cell formation Inducing monocyte accumulation in arterial wallEnhancing thrombosisActivating complement system Increasing ICAM-1, VCAM-1, and E-selectin

expression on endothelial cells Inducing endothelial cells destruction by CD4+T cellsFacilitate LDL uptake by macrophages Inducing endothelin (A/B) receptor

Pathologic Effects of CRP on Atherosclerosis

Having CRP known as a risk factor predicting outcome as well as prognosis of cardiovascular event, it is appropriate to consider therapeutic approaches to reduce CRP as a primary end-point or as a guide for interventional therapies.

Ridker called for “CRP lowering trial”; a prospective, placebo controlled trial of statin therapy among individuals without overt hyperlipidemia. 14

CRP and Cardiovascular Events Outcome

As reported in VP Watch of this week, Topol and Bhatt called for a “CRP-guided clinical trial” to tailor therapy to patients with established CAD.15

Such a prospective study of patients with established cardiovascular disease and elevated baseline CRP in which incremental pharmacotherapy would be guided by reassessments of the CRP marker could allow formulation of a rational therapeutic strategy instead of an approach of "polypharmacy" for every patient . 15

• They discussed that if CRP remains elevated, the next medication in their algorithm would be prescribed. If an added agent had no effect on CRP, then it would be discontinued. 15

• In addition to evaluating the effect of such a strategy on clinical events, they suggested to follow the relationship between gene polymorphism of inflammatory markers and specific drug interactions. 15

Call for Anti-Inflammatory Clinical Trial

Deepak L. Bhatt and Eric J. Topol Need to Test the Arterial Inflammation Hypothesis ; Circulation 2002 106: 136 - 140

Potential trial design for utilization of CRP to allocate medical therapy

• There are no specific therapies have been suggested to specifically reduce high sensitive CRP.

• Statins reduce CRP as well as LDL. However their delayed effect leave a lot to be desired.

• Alpha-tocopherol significantly reduces CRP in diabetics and non-diabetics, and minimizes

other acute phase response and inflammatory damage in atherosclerosis. 16

Conclusion

An increasing need for launching a clinical trial on acute coronary patients to:1- tailor interventional therapies guided by inflammatory marker (CRP guided trial)2- reduce inflammatory risk factors (CRP

lowering trial)

An inflammation-directed trial would provide the opportunity for clinicians to ask if drug combinations really enhance patient’s care.

Questions:

• Which one of the following trials is more needed:

–CRP guided trial –CRP lowering trial

1) Ross R. Atherosclerosis: an inflammatory disease. N Engl J Med. 1999; 340: 115–126. (link)2) de Beer FC, Hind CR, Fox KM, et al. Measurement of serum C-reactive protein concentration in myocardial ischaemia and infarction. Br

Heart J. 1982; 47: 239–243 (link)3) Vorchheimer DA, Fuster V. Inflammatory markers in coronary artery disease: let prevention douse the flames. JAMA. 2001; 286: 2154–21564) Kervinen H, Palosuo T, Manninen V, et al. Joint effects of C-reactive protein and other risk factors on acute coronary events. Am Heart J.

2001; 141: 580–585 (link)5) (link)6) Bermudez EA, Ridker PM. C-reactive protein, statins, and the primary prevention of atherosclerotic cardiovascular disease. Prev Cardiol.

2002 Winter;5(1):42-6.(link)7) Rifai N, Ridker PM. ; High-sensitivity C-reactive protein: a novel and promising marker of coronary heart disease.; Clin Chem. 2001

Mar;47(3):403-11. (link)8) Albert MA, Staggers J, Chew P, Ridker PM; PRINCE Investigators.; The pravastatin inflammation CRP evaluation (PRINCE): rationale and

design.; Am Heart J. 2001 Jun;141(6):893-8. (link)9) Albert MA, Danielson E, Rifai N, Ridker PM; PRINCE Investigators.; Effect of statin therapy on C-reactive protein levels: the pravastatin

inflammation/CRP evaluation (PRINCE): a randomized trial and cohort study. JAMA. 2001 Jul 4;286(1):64-70. (link)10) Pasceri V, Willerson JT, Yeh ET. Direct proinflammatory effect of C-reactive protein on human endothelial cells. Circulation. 2000 Oct

31;102(18):2165-8. (link)11) Verma S, Li SH, Badiwala MV, Weisel RD, Fedak PW, Li RK, Dhillon B, Mickle DA.; Endothelin antagonism and interleukin-6 inhibition

attenuate the proatherogenic effects of C-reactive protein. Circulation. 2002 Apr 23;105(16):1890-6. (link)12) Feldman M, Jialal I, Devaraj S, Cryer B.; Effects of low-dose aspirin on serum C-reactive protein and thromboxane B2 concentrations: a

placebo-controlled study using a highly sensitive C-reactive protein assay.; J Am Coll Cardiol. 2001 Jun 15;37(8):2036-41. (link)13) Ikonomidis I, Andreotti F, et al. Increased proinflammatory cytokines in patients with chronic stable angina and their reduction by aspirin.

Circulation. 1999 Aug 24;100(8):793-8 (link)14) Ridker PM.; Should statin therapy be considered for patients with elevated C-reactive protein? The need for a definitive clinical trial.

Eur Heart J. 2001 Dec;22(23):2135-7. . (link)15) Deepak L. Bhatt and Eric J. Topol Need to Test the Arterial Inflammation Hypothesis ; Circulation 2002 106: 136 - 140 (link)16) Patrick L, Uzick M.; Cardiovascular disease: C-reactive protein and the inflammatory disease paradigm: HMG-CoA reductase inhibitors,

alpha-tocopherol, red yeast rice, and olive oil polyphenols. A review of the literature. Altern Med Rev. 2001 Jun;6(3):248-71. (link)

References