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Etiology

C-reactive protein was associated with an increased risk for MI and ischemic stroke

ACP J Club. 1997 Nov-Dec;127:81. doi:10.7326/ACPJC-1997-127-3-081


Source Citation

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 Apr 3;336:973-9.


Abstract

Objective

To determine whether inflammation increases the risk for a first thrombotic event in men and whether aspirin reduces this risk.

Design

Nested case-control study of participants in the Physicians' Health Study.

Setting

United States.

Participants

22 071 male physicians were enrolled in a randomized controlled trial of aspirin and β-carotene as primary prevention for cardiovascular disease and cancer. 543 men who reported a first myocardial infarction (MI), stroke, or venous thrombosis were matched with 543 men who had not had a thrombotic event. Matching was done for age, smoking status, and time since random assignment.

Assessment of risk factors

Blood samples collected at baseline were used to measure C-reactive protein (CRP) levels (a marker for systemic inflammation) by ELISA testing. Men were classified into quartiles of CRP levels (≤ 0.55, 0.56 to 1.14, 1.15 to 2.1, and ≥ 2.11 mg/L), with the lowest level as reference (relative risk [RR] of 1.0). Other risk factors assessed were treatment assignment; body mass index; diabetes; history of hypertension; parental history of coronary artery disease; and lipid, tissue plasminogen activator antigen, fibrinogen, D-dimer, and homocysteine levels.

Main outcome measures

First thrombotic events (MI, stroke, and venous thrombosis) were confirmed by blinded assessment of hospital records, autopsy reports, and death certificates.

Main results

Men in the highest 3 quartiles of CRP had an increased risk for MI (RR 1.7 for the second level, 95% CI 1.1 to 2.9, P = 0.03; RR 2.6 for the third level, CI 1.6 to 4.3, P < 0.001; and RR 2.9 for the highest level, CI 1.8 to 4.6, P < 0.001). For men who did not smoke, only the highest 2 levels of CRP were associated with an increased risk for MI (RR 2.5, CI 1.5 to 4.1, P < 0.001; and RR 2.8, CI 1.7 to 4.7, P < 0.001). Men in the highest 2 levels also had an increased risk for ischemic stroke (RR 1.9, CI 1.1 to 3.2, P = 0.02; and RR 1.9, CI 1.1 to 3.3, P = 0.02). CRP levels were not associated with venous thrombosis. The risk for MI showed similar patterns after adjustment for other risk factors. Aspirin reduced the risk for MI in all quartiles of CRP (P = 0.048 for the trend) with risk reduction increasing by increasing quartiles.

Conclusion

In men, increased levels of C-reactive protein were associated with an increased risk for myocardial infarction and ischemic stroke but not venous thrombosis.

Source of funding: National Institutes of Health.

For article reprint: Dr. P.M. Ridker, Division of Preventive Medicine and Cardiovascular Disease, Brigham and Women's Hospital, 900 Commonwealth Avenue East, Boston, MA 02215-1204, USA. FAX 617-732-7134.


Commentary

One of the underlying problems in prevention of cardiovascular disease is the very low specificity with which we are able to detect persons at risk. It is important to sharpen the methods for identifying those persons. The study by Ridker and colleagues enhances this ability and suggests 2 important possibilities: CRP is a risk factor for future MI and stroke in low-risk persons, and treatment with anti-inflammatory agents might prevent future cardiovascular disease. The first possibility was previously suggested by Kuller and colleagues (1), who used a nested case-control design to show an association between CRP and coronary heart disease mortality (mostly sudden deaths) in high-risk persons. They did not show an association with nonfatal MI. The second possibility, a preventive role for anti-inflammatory agents, is suggested by the authors on the basis of the observed effect of aspirin on risk for MI across CRP quartiles. This effect is consistent with the hypothesis of the infectious origin of coronary artery disease. On the other hand, as the authors also suggest, the link between aspirin and CRP may be related to increased activity of tissue factor with increased levels of CRP, which may enhance clotting and thrombosis (2).

The implications of this study are promising, but we still need further evidence from prospective studies specifically designed to test the inflammatory hypothesis using several determinations of CRP over time or, preferably, more specific inflammatory markers. A role for anti-inflammatory agents in reducing the incidence of cardiovascular diseases is supported by the randomized controlled trial of aspirin on which the current report is based (3).

Carlos Brotons, MD
Gaieta Permanyer, MDUniversity Hospital Vall d'HebronBarcelona, Spain


References

1. Kuller LH, Tracy RP, Shaten J, Meilahn EN for the MRFIT Research Group. Relation of the C-reactive protein and coronary heart disease in the MRFIT nested case-control study. Am J Epidemiol. 1996;144:537-47.

2. Cermak J, Key NS, Bach RR, Jacobs HS, Vercellotti GM. C-reactive protein induces human peripheral blood monocytes to synthesize tissue factor. Blood. 1993;82:513-20.

3. Steering Committee of the Physicians' Health Study Research Group. Final report on the aspirin component of the ongoing Physicians' Health Study. N Engl J Med. 1996; 334:1145-9.