SHAPE Society

1. Editorial Slides
VP Watch –July 3, 2002 - Volume 2, Issue 26
A Call for
“CRP-Lowering” or “CRP-Guided” Trial?

2.  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

3.  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

4. 1.16
1
2.071.37
2.591.39
4.161.8
0.00
1.00
2.00
3.00
4.00
5.00
1 2 3 4
Placebo
Aspirin
RelativeriskofMI
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

5.  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

6.  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

7.  Potential roles of CRP on pathogenesis of
atherosclerosis:
Inducing foam cell formation
Inducing monocyte accumulation in arterial wall
Enhancing thrombosis
Activating complement system
Increasing ICAM-1, VCAM-1, and E-selectin
expression on endothelial cells
Inducing endothelial cells destruction by CD4+
T cells
Facilitate LDL uptake by macrophages
Inducing endothelin (A/B) receptor
Pathologic Effects of CRP on Atherosclerosis

8.  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

9.  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

10. • 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

11. 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

12. • 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

13. 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.

14. Questions:
• Which one of the following trials is
more needed:
–CRP guided trial
–CRP lowering trial

15. 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: 2154–2156
4) 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