C-reactive protein, bezafibrate, and recurrent coronary events in patients with chronic coronary heart disease

C-reactive protein, bezafibrate, and recurrent coronary events in patients with chronic coronary heart disease Moti Haim, MD, a Michal Benderly, PhD, b David Tanne, MD, c Zipora Matas, PhD, d Valentina Boyko, MsC, b Enrique Z. Fisman, MD, e Alexander Tenenbaum, MD, PhD, e Reuven Zimmlichman, MD, d Alexander Battler, MD, a Uri Goldbourt, PhD, b and Solomon Behar, MD b Petach-Tiqva, Tel-Hashomer; and Holon, Israel

Background Elevated C-reactive protein (CRP) levels are related to increased coronary risk in healthy subjects and in patients with acute coronary syndromes. The aims of the present study were to assess the following: (1) the association between CRP and subsequent coronary risk in patients with chronic coronary heart disease (CHD), (2) the effect of long-term bezafibrate treatment on CRP levels, and (3) to evaluate the consequences of change in CRP level over time on subsequent risk. Methods Patients with chronic CHD (n = 3122) were recruited to a secondary prevention study that assessed the efficacy of bezafibrate versus placebo. C-reactive protein was measured in plasma samples collected at prerandomization and after 2 years of follow-up. Mean follow-up time was 6.2 years. Primary end point was fatal and nonfatal myocardial infarction and sudden cardiac death. Results Increased baseline CRP levels were associated with increased risk (hazard ratios [HRs] per unit of log-transformed CRP level change) of myocardial infarction (HR 1.17, 95% CI 1.03-1.33), the primary end point (HR 1.19, 95% CI 1.061.34), total death (HR 1.19, 95% CI 1.02-1.40) and cardiac death (HR 1.28, 95% CI 1.04-1.59). After 2 years, CRP levels increased by 3.0% (from a mean level of 3.44 mg/L) in the bezafibrate group and by 3.7% (from 3.49 mg/L) in the placebo group. C-reactive protein levels after 2 years were associated with increased subsequent cardiovascular risk. Conclusions Baseline CRP and 2-year CRP levels were associated with subsequent risk of myocardial infarction and death in patients with chronic CHD. Bezafibrate did not reduce CRP levels as compared with placebo. (Am Heart J 2007;154:1095-101.) Elevated C-reactive protein (CRP) levels are related to increased risk of myocardial infarction (MI), stroke, and peripheral arterial disease in persons with no history of coronary heart disease (CHD)1-4 and with increased risk of recurrent coronary events and mortality in patients with acute coronary syndromes. 5-10 Based on these observations, a class IIa recommendation was recently made to measure CRP in patients with CHD for risk stratification.11 Studies using CRP in patients with chronic heart disease are relatively few and found an association between elevated CRP and subsequent coronary events and mortality. 12-14 However, these studies were small, 13,14 of

From the aCardiology Department, Rabin Medical Center, Petach-Tiqva, Israel, bNeufeld Cardiac Research Institute, Sheba Medical Center, Tel-Hashomer, Israel, cNeurology Department, Stroke Unit, Sheba Medical Center, Tel-Hashomer, Israel, dBiohemistry Laboratory, Wolsfon Medical Center, Holon, Israel, and eCardiac Rehabilitation Institute, Sheba Medical Center, Tel-Hashomer, Israel. All authors affiliated with Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. This study was funded by the Israeli Society for Prevention of Heart Attacks. Submitted November 16, 2006; accepted July 23, 2007. Reprint requests: Moti Haim, MD, Cardiology Department, Rabin Medical Center, Jabotinsky St. Petach-Tiqva, Israel. E-mail: [email protected] 0002-8703/$ - see front matter © 2007, Mosby, Inc. All rights reserved. doi:10.1016/j.ahj.2007.07.026

relatively short follow-up,14 and with few cardiac events. 13,14 Our hypothesis in conducting this study was that CRP will be an independent predictor of risk in patients with stable CHD as shown in patients with no CHD. Reducing of CRP level by statins is beneficial in patients with CHD. 15,16 Bezafibrate was shown to reduce CHD events in patients with elevated triglycerides, and this was related to reduction in triglyceride levels. 20 In addition, bezafibrate was shown to reduce levels of fibrinogen, a known acute-phase inflammatory reactant associated with cardiovascular events. 20 The effect of long-term treatment with bezafibrate on CRP levels was not assessed in a large-scale population of CHD patients, whereas small studies showed conflicting results. 17-19 The aims of the present study were the following: (1) to assess the association between CRP levels and subsequent risk of coronary events in a large cohort of patients with chronic CHD, (2) to assess the effect of bezafibrate on CRP, and (3) to evaluate the consequences of change in CRP level on subsequent risk of coronary events.

Methods Study subjects The study included patients with stable CHD (n = 3122) who were recruited to a secondary prevention randomized placebo-controlled trial that compared the effect of bezafibrate

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Laboratory methods Blood samples, which were drawn in the participating medical centers after 12 hours of fasting (to determine levels of cholesterol, high-density lipoprotein cholesterol (HDL-C), triglycerides, and plasma fibrinogen), were transferred in cooled containers to a central laboratory. Laboratory measurements were performed using standard automated procedures with commercially available kits (Roche Diagnostics, Basel, Switzerland). For the purpose of the present study, we measured CRP concentration in samples of citrated plasma stored at −70°C. These samples were taken from each study participant before randomization to bezafibrate or placebo (baseline) and at the 2-year follow-up visit. The validity of using plasma citrate compared with serum was obtained by analysis of samples of 30 randomly selected individuals. C-reactive protein levels in plasma citrate were 68% of the serum levels. Two thousand nine hundred eighty (95%) baseline plasma samples were available for CRP laboratory analysis and 2760 (of 2999 patients, 92%) from the 2-year follow-up visit. Four patients with CRP levels above or below the kit detection range in repeated measurements were excluded from the present analysis: CRP values N15 mg/L (2 patients from the 2-year followup visit) or CRP values b0.01 mg/L (2 patients, 1 at baseline visit and 1 at follow-up visit). Thus, the final number of available baseline plasma samples was 2979 (1486 allocated to placebo, 1493 to bezafibrate) and 2762 (1369 placebo, 1393 bezafibrate) from the 2-year follow-up visit. Plasma samples from both visits were available for 1306 patients allocated to placebo and 1326 patients allocated to bezafibrate. After thawing plasma samples, high-sensitive C-reactive protein levels were measured in plasma citrate on

Table I. Baseline characteristics of patients with chronic CHD according to baseline CRP level CRP tertiles (mg/L) 2.3 mg/L 2.3-5.4 mg/L 5.4 mg/L (n = 982) (n = 1013) (n = 984)

CRP* mg/L (95% CI)

1.26 (1.22-1.30) Age, mean ± SD (y) 60 ± 7 Men (%) 920 (94) Previous MI (%) 764 (78) Diabetes mellitus (%) 68 (7) Hypertension (%) 303 (31) Previous stroke (%) 3 (0.3) Angina pectoris (%) 536 (55) PAD (%) 27 (3) Current smoking (%) 62 (6) Previous smoking (%) 574 (58) Family history 95 (10) of CHD (%) BMI, mean ± SD 26 ± 3 (kg/m2) SBP (mm Hg) 131 ± 17 DBP (mm Hg) 80 ± 9 Cholesterol 5.49 ± 0.44 (mmol/L) HDL-C (mmol/L) 0.91 ± 0.14 LDL-C (mmol/L) 38.6 ± 0.41 TG (mmol/L) 1.47 (1.44-1.50) Fibrinogen 8.8 ± 1.5 (μmol/L) Glucose 5.5 ± 0.83 (mmol/L)

V

V

retard 400 mg once daily versus placebo in the prevention of fatal and nonfatal MI and sudden cardiac death—the BIP study. 20 This study was approved by the institutional review committee in each participating center, and the study subjects gave informed consent to participate in it. 20 Patients were defined as having stable CHD based on 1 of the following: (1) documented MI 6 months to 5 years before randomization to the study; (2) symptomatic stable angina pectoris and a positive exercise test, evidence of myocardial ischemia by myocardial perfusion scan, or N60% stenosis of 1 of the major coronary arteries demonstrated by coronary angiography; or (3) documented coronary revascularization—percutaneous or surgical. Patients were allowed to take prescribed medications for cardiac and other conditions except for lipid-lowering drugs. The combined primary end point of the study was fatal MI, nonfatal MI, or sudden cardiac death (occurring within 24 hours of onset of symptoms). Death from any cause was monitored and recorded. Myocardial infarction was defined according to the previous World Health Organization criteria of presence of 2 of the following 3 criteria: elevated creatine kinase level, ischemic symptoms, and/or ischemic electrocardiographic changes compatible with ST- or non–ST-elevation MI. An independent critical event committee, whose members were blinded to the treatment assignment, reviewed primary end points and causes of mortality. Routine visits to the clinics were scheduled bimonthly for study medication distribution and every 4 months for clinical evaluation. The mean length of follow-up was 6.2 years (range 4.7-7.6 years).

P

3.55 (3.50-3.60) 60 ± 7 932 (92) 776 (77) 109 (11) 329 (32) 11 (1.1) 562 (55) 37 (4) 112 (11) 596 (59) 96 (10)

10.10 (9.77-10.45) 60 ± 7 871 (88) 785 (80) 120 (12) 331 (34) 21 (2.1) 608 (62) 39 (4) 178 (18) 576 (58) 84 (8)

.30 b.01 .20 b.01 .40 b.01 b.01 .30 b.01 .99 .01

27 ± 3

27 ± 3

b.01

134 ± 18 81 ± 9 5.49 ± 0.46

135 ± 18 b.01 81 ± 9 .03 5.51 ± 0.44 .50

0.89 ± 0.14 38.6 ± 0.44 1.56 (1.53-1.60) 9.7 ± 1.7

0.87 ± 0.14 38.6 ± 0.41 1.60 (1.56-1.62) 11.7 ± 2.3

5.6 ± 0.99

b.01 .95 b.01 b.01

5.6 ± 0.99 b.01

Geometric mean (95% CI). PAD, Peripheral arterial disease; SBP, systolic blood pressure; DBP, diastolic blood pressure; LDL-C, low-density lipoprotein cholesterol; TG, triglyceride.

IMMULITE 2000 analyzer from Diagnostics Products Corporation with solid-phase chemiluminescent immunometric assay.

Statistical analysis Data were analyzed with the SAS software (SAS, Cary, NC). Patients were divided into 3 tertiles equal in size based on their baseline CRP level. Baseline characteristics and the rate of the various outcomes were compared between these tertiles. The χ2 test and t test (for normally distributed variables) were used to determine the statistical significance of differences between proportions and means, respectively. To account for the skewed distribution of CRP and triglycerides, geometric means are presented with 95% CI. For the assessment of differences after 2 years between the bezafibrate and placebo groups, an analysis of covariance with terms for treatment and baseline values was used based on log-transformed data. Percentage of changes from baseline to 2 years were presented as geometric mean and interquartile range and compared using Wilcoxon rank sum test. Multivariable analysis was performed using the Cox proportional hazard model adjusting for age, sex, history of MI, smoking status at entry, body mass index (BMI), hypertension, baseline HDL-C, diabetes, history of stroke,

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Table II. Rate (per 1000 person-years) and adjusted HRs of coronary events and cardiac and all-cause death according to baseline CRP tertiles at baseline (HRs are compared with first-tertile reference group) All patients (n = 2979)

Myocardial infarction CRP (mg/L) b2.3 2.3-5.4 N5.4 Combined end point CRP (mg/L) b2.3 2.3-5.4 N5.4 Cardiac death CRP (mg/L) b2.3 2.3-5.4 N5.4 Total death CRP (mg/L) b2.3 2.3-5.4 N5.4

Placebo (n = 1486)

Bezafibrate (n = 1493)

Rate

Adjusted* HR (95% CI)

Rate

Adjusted* HR (95% CI)

Rate

Adjusted* HR (95% CI)

16.1 20.8 25.5

1 1.16 (0.85-1.59) 1.43 (1.05-1.93)

15.9 24.3 26.7

1 1.31 (0.86-2.00) 1.52 (1.01-2.30)

16.2 17.3 24.3

1 1.00 (0.63-1.59) 1.31 (0.84-2.06)

20.0 25.5 31.3

1 1.17 (0.88-1.56) 1.42 (1.07-1.88)

18.9 29.3 33.3

1 1.45 (0.96-2.18) 1.63 (1.09-2.44)

21.1 21.8 29.2

1 0.94 (0.62-1.42) 1.21 (0.81-1.82)

4.5 5.4 7.7

1 1.04 (0.62-1.75) 1.27 (0.77-2.11)

5.5 9.4 14.0

1 1.92 (0.78-4.72) 1.95 (0.79-4.82)

9.3 8.9 12.4

1 0.73 (0.37-1.42) 1.03 (0.55-1.92)

12.6 17.1 22.4

1 1.20 (0.82-1.76) 1.33 (0.91-1.94)

9.7 17.1 23.8

1 1.77 (0.95-3.31) 2.16 (1.18-3.98)

15.3 17.1 20.8

1 0.93 (0.57-1.54) 0.92 (0.55-1.52)

*Adjusted for age, sex, history of MI, smoking status at entry, BMI, hypertension, diabetes, HDL-C, stroke, angina pectoris, and study arm (model for all patients).

angina pectoris, and, where appropriate, allocation to bezafibrate versus placebo. C-reactive protein as a continuous variable was log-transformed to account for its skewed distribution. Estimates of hazard ratio (HR) and 95% CI are presented. We tested the linearity assumption for CRP as a continuous variable by fitting the models with added quadratic term (P for quadratic term = .17).

Results Baseline characteristics and CRP Patients with elevated baseline CRP levels included a higher proportion of women and patients with diabetes mellitus, previous stroke, and history of angina pectoris. In addition, they had higher BMI and systolic and diastolic blood pressure. Total and low-density lipoprotein cholesterol levels were not related to CRP level, but fasting triglycerides, fasting glucose, and fibrinogen levels were directly and high-density lipoprotein inversely related to CRP level (Table I). C-reactive protein and subsequent coronary events There was a direct and significant association between baseline CRP level and the incidence rate and relative risks of MI and of the combined primary end point in the placebo group and in the entire cohort (Table II). The increase in risk associated with higher CRP levels was attenuated and nonsignificant among patients allocated to bezafibrate (Table II). Table III lists other variables

Table III. Independent predictors of primary end point HR (95% CI) CRP highest tertile Age Male Smoking BMI Previous MI Angina pectoris

1.42 1.18 1.59 1.57 1.08 1.26 1.22

(1.07-1.88) (0.99-1.40) (1.00-2.52) (1.16-2.12) (1.01-1.15) (0.95-1.68) (0.97-1.53)

found to be independent predictors of the combined primary end point (Table III). In the entire cohort, each 1 natural log unit increase in the concentration of baseline CRP was associated with greater risk of MI (adjusted HR 1.17, 95% CI 1.03-1.33) and of the combined end point (adjusted HR 1.19, 95% CI 1.06-1.34). Corresponding elevations in baseline CRP in the placebo group (adjusted HR 1.17, 95% CI 1.00-1.37) and in the bezafibrate group (adjusted HR 1.21, 95% CI 1.01-1.45) were associated with increased risk of the combined primary end point.

C-reactive protein and subsequent death In the placebo group, the risk of total death was N2 times greater in the top tertile of baseline CRP as compared with patients in the lowest tertile, whereas the risk of cardiac death was also higher but did not reach statistical significance (Table II).

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Table IV. C-reactive protein levels in placebo and bezafibrate groups at baseline and follow-up

Figure 1

Follow-up CRP (mg/L) _2 >

Baseline CRP (mg/L) Placebo All b2 ≥2 Bezafibrate All b2 ≥2

366 (28) 937 (72)

370 213 (58) 110 (12)

370 153 (42) 827 (88)

370 (28) 957 (72)

365 228 (62) 137 (14)

962 142 (38) 820 (86)

V

2

All

The multivariate adjusted risk of cardiac death for each 1 natural log unit increase in baseline CRP levels was 1.28 (95% CI 1.04-1.59) in the entire cohort and 1.44 (95% CI 1.04-1.99) in the placebo groups. Corresponding values for total death were 1.19 (95% CI 1.02-1.40) in the entire BIP cohort and 1.38 (95% CI 1.11-1.73) in the placebo group. Patients on bezafibrate in the lowest CRP tertile had relatively high cardiac and total mortality rates as compared with those with higher CRP levels, and there was no increase in the risk with elevated CRP concentration when assessed in categories (Table II) or as a continuous variable.

Effect of bezafibrate on CRP Mean CRP levels increased after 2 years from 3.49 to 3.62 mg/L in the placebo group (mean change 0.13 mg/L) and from 3.44 to 3.55 mg/L in bezafibrate-treated patients (mean change 0.11 mg/L). The percentage of change in CRP levels was 3.7% in the placebo group and 3.0% in the bezafibrate group. There was no significant difference in the magnitude of change in CRP level between the placebo and bezafibrate groups. The effect of bezafibrate was not significant, and there was no interaction between bezafibrate and CRP levels. The proportions of patients with baseline CRP levels b2 mg/L (28%) or N2 mg/L (72%) were similar in the bezafibrate and placebo groups (Table IV). Approximately 60% of those with baseline CRP levels b2 mg/L remained within these levels after 2 years of follow-up in the placebo and bezafibrate groups (Table IV). In a large proportion (approximately 40%) of patients with baseline CRP level b2 mg/L, CRP levels increased after 2 years to N2 mg/L (Table IV). Most patients (bezafibrate group 86%, placebo group 88%) with baseline CRP values N2 mg/L remained in this category after 2 years and to a similar proportion in the bezafibrate and placebo groups (Table IV). We also computed the percentage of change in CRP level from baseline for each patient as 100% (follow-up level minus baseline level)/baseline level. Over the

Rate (per 1000 person-years) of MI, the combined primary end point (PEP), and death according to CRP level after 2 years.

2 years of follow-up, 50% of the patients had no change in CRP level or very moderate decrease (b1%); the rest had elevation ranging between a fraction of a percent to 43%. This was similar in the bezafibrate and placebo groups.

C-reactive levels after 2 years and consequent risk The incidence of subsequent coronary events and death was related to CRP levels at 2 years (Figure 1). The risk of MI was 1.10 (95% CI 0.76-1.60) in the second tertile of CRP and 1.52 (95% CI 1.07-2.15) in the third. Corresponding risks of the combined primary end point were 1.13 (95% CI 0.81-1.56) and 1.49 (95% CI 1.09-2.04), and the risks of death were 1.49 (95% CI 1.03-2.17) and 1.84 (95% CI 1.28-2.65). C-reactive levels after 2 years of follow-up were associated with MI (HR 1.18, 95% CI 1.04-1.35, for each unit of natural log increase), the combined primary end point (HR 1.20, 95% CI 1.07-1.36), cardiac death (HR 1.32, 95% CI 1.06-1.65), and total death (HR 1.28, 95% CI 1.09-1.50). The rate of the combined primary end point of patients who increased their CRP levels from baseline to 2 years (11.9%) was not significantly different as compared with patients with increase in their CRP levels (12.8%). There was no specific difference in the incidence of each end point as well (death and/or MI).

Discussion The main findings of the present study are the following. First, elevated baseline levels of CRP were associated with increased long-term risk of recurrent

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coronary events and death. Second, increases in CRP levels during the first 2 years of the study were associated with increased risk of subsequent events. Third, bezafibrate did not affect plasma CRP levels after 2 years of therapy.

C-reactive protein and subsequent risk of coronary events As previously described in healthy persons,2,21 and in patients with acute coronary syndromes,5,8,22-24 elevated baseline CRP levels in the present study were associated with increased risk of recurrent MI and death over a long-term period of 6.2 years. Most previous studies that reported the association between CRP and cardiac risk in patients with CHD included exclusively or mainly patients with acute coronary syndromes. 5,6,8-10,12-15,22,24-29 Only a limited number of studies included or assessed specifically patients with stable CHD, and these were mostly small or with a short follow-up.12-14,30 Bickel et al, 6 in a study that included patients with acute as well as chronic CHD, found higher levels of CRP in patients who subsequently died of cardiac causes. Patients in the top quartile of CRP level had an almost double risk of cardiac death, a risk estimate that is similar to that in our placebo group. In another study, among patients with stable angina (N = 599), elevated CRP levels were associated with 5-fold higher risk of death but not with the risk of subsequent MI. 12 Haverkate et al 13 reported that among patients with stable angina pectoris, CRP level at the top quintile was associated with almost 2 times greater risk of sudden death and MI as compared with patients with low CRP levels. Similar findings were reported by Arroyo-Espliguero et al. 14 In the present study, we demonstrate not only the association between CRP and the combined end point of death and MI over a long term follow-up time but also with MI alone, a finding that was not reported previously in patients with chronic CHD. Patients with low baseline CRP levels allocated to bezafibrate had excess mortality, but this was not statistically significant (relative risk 1.58, 95% CI 0.972.63). We have no reasonable explanation for this. This observation could be either a spurious finding or a true adverse event that could identify patients who might be harmed by bezafibrate. Any interpretation of this unexpected finding should be made with caution, and no definite conclusions can be drawn at this point. Further studies are necessary to clarify this issue. The significance of change in CRP levels over time and association with subsequent risk has been rarely reported so far. Ridker et al 15 reported that in patients with acute coronary syndromes treated by statins, those whom, at follow-up, reached CRP levels b2 mg/L had lower risk of recurrent coronary events as compared with counterparts who attained CRP levels N2 mg/L. The

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degree of CRP reduction by statin therapy correlated with the degree of coronary atheroma regression in the REVERSAL study. 16 In the present study, patients who increased their CRP levels during the first 2 years of study were at increased risk for recurrent coronary events and mortality. Furthermore, those who had high levels (N2 mg/L) of CRP after 2 years were at increased risk for subsequent adverse events as compared with those who reached levels b2 mg/L. These findings support observations made with statins 15,16 and are in line with the theory that CRP reduction is beneficial for secondary prevention.

Effect of bezafibrate on CRP level The increase in CRP level was 3% during a 2-year follow-up in the placebo arm, a rate which concurs with findings by Haverkate et al 13 in patients with stable angina pectoris. Patients on bezafibrate and placebo had a similar increase in their CRP level. A recent study reported increased variability of CRP levels in patients with stable CHD. 31 In the present study, we found increased variability in CRP levels among patients with baseline CRP b2 mg/L: 40% of patients were found to have levels N2 mg/L after 2 years. Thus, patients who were initially categorized to be at low risk were later categorized to a higher risk group after 2 years. In contrast, among patients with baseline CRP levels N2 mg/L, plasma levels were stable, and almost 90% remained in a high-risk category after 2 years of follow-up, supporting previous observations. 32 Of note, the proportions of patients who showed increase or decrease from their baseline CRP level during 2 years were similar in the bezafibrate and placebo groups, thus establishing the lack of any significant effect of bezafibrate on CRP in the present cohort. This lack of effect of bezafibrate on CRP after 2 years of treatment despite its significant effects on triglycerides, HDL-C, and fibrinogen 20 was unexpected and rather intriguing. This may partially explain the overall null effect of bezafibrate in the BIP study. There are few data on the effect of different fibrates on CRP levels. Clofibrate reduced CRP levels by 37%, 33 and bezafibrate insignificantly reduced CRP levels in one study 17 and did not reduce CRP in another study in CHD patients. 18 In a small study of 18 patients with severe hypertriglyceridemia, bezafibrate reduced CRP levels significantly after 6 weeks of treatment. 19 Fenofibrate reduced CRP level by 30% to 42%. 34-36 Gemfibrozil reduced CRP levels by 33% in a study of 31 patients with the metabolic syndrome. 37 Some fibrates have no significant effect on basal CRP expression, but strongly reduce the interleukin 1 induction of CRP. In contrast, interleukin 6–induced CRP expression is essentially not reduced in the presence of ciprofibrate. 38 A similar mechanism could be responsible for the lack of CRP decrease in this study.

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Our study has some limitations worth noting. C-reactive protein levels as well as prognosis may be affected by other factors as well; some of them, such as left ventricular ejection fraction as well other modifiers that were included in our analyses, were not available to us. We did not assess CRP levels at the end of the study, thus possibly missing potential very long effects of bezafibrate on CRP. Statins were not used in the study, so we could not assess their effect on CRP or outcome. We did not evaluate in this study the other inflammatory markers known to be associated with cardiovascular events because we wanted to focus on CRP, which has the most robust body of evidence in the literature. However, despite these limitations, our study was conducted in a large cohort; it was a placebo-controlled, randomized, and had a long follow-up time. Thus, we were able to assess both temporal trends and changes in CRP levels (placebo group) as well as the effects of bezafibrate on CRP and prognosis. In conclusion, in the present large cohort of patients with stable CHD, baseline CRP levels were strongly related to long-term risk of MI and death. Increase in CRP level over time was associated with increased risk of subsequent coronary events and death. Bezafibrate did not reduce CRP levels after 2 years of treatment.

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