This Article Free upon publication Abstract Full Text (PDF) All Versions of this Article: 107/13/1750    most recent 01.CIR.0000060541.18923.E9v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Chan, A. W. Articles by Ellis, S. G. Search for Related Content PubMed PubMed Citation Articles by Chan, A. W. Articles by Ellis, S. G. Related Collections Lipids Secondary prevention Catheter-based coronary interventions: stents

(Circulation. 2003;107:1750.)
© 2003 American Heart Association, Inc.

Clinical Investigation and Reports

Relation of Inflammation and Benefit of Statins After Percutaneous Coronary Interventions

Albert W. Chan, MD, MSc; Deepak L. Bhatt, MD; Derek P. Chew, MBBS, MPH; Joel Reginelli, MD; Jakob P. Schneider, RN; Eric J. Topol, MD; Stephen G. Ellis, MD

From the Department of Cardiology, Ochsner Clinic Foundation, New Orleans, La (A.W.C.); Department of Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland, Ohio (D.L.B., J.R., J.P.S., E.J.T., S.G.E.); and Division of Cardiology, Flinders Medical Center, Australia (D.P.C.).

Correspondence to Albert W. Chan, MD, Associate Director, Catheterization Laboratory, Department of Cardiology, Ochsner Clinic Foundation, 1514 Jefferson Highway, New Orleans, LA 70121. E-mail achan{at}ochsner.org

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Background— Beyond lipid lowering, statins are known to possess antiinflammatory and antithrombotic properties. Recent studies suggested an association between statins and early reduction in death or myocardial infarction (MI) after percutaneous coronary interventions (PCIs). We sought to examine the interrelationship between inflammation, statin use, and PCI outcomes.

Methods and Results— In the year 2000, 1552 consecutive United States residents underwent elective or urgent PCI at the Cleveland Clinic and were prospectively followed for 1 year. Preprocedural serum high-sensitivity C-reactive protein (hsCRP) levels were routinely measured. Patients who had statins initiated before the procedure (39.6%) had a lower median hsCRP level (0.40 versus 0.50 mg/dL, P=0.012) independent of the baseline cholesterol levels and had less frequent periprocedural MI (defined by CKMB 3xupper limit of normal, 5.7% versus 8.1%, P=0.038). At 1 year, statin pretreatment was predictive of survival predominantly among patients within the highest hsCRP quartile (mortality rate with statin pretreatment versus no pretreatment when hsCRP 1.11 mg/dL, 5.7% versus 14.8%, P=0.009). Using multivariate analysis, preprocedural hsCRP level remained an independent predictor for 1-year death or MI only in patients without statin therapy (hazard ratio, 1.32/quartile; P=0.001). After adjusting for the propensity of receiving statins, statin pretreatment was an independent predictor for 1-year survival within the highest hsCRP quartile (hazard ratio, 0.44; P=0.039).

Conclusions— Statin therapy before PCI is associated with a marked reduction in mortality among patients with high hsCRP levels. A hsCRP-guided strategy may improve targeting of statin therapy and clinical outcome among patients undergoing PCI.

Key Words: angioplasty • coronary disease • inflammation • statins • stents

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
Inflammation plays a pivotal role in the pathogenesis of coronary atherosclerosis and acute coronary events.^1–4 High-sensitivity C-reactive protein (hsCRP) has been incontrovertibly shown to predict major adverse cardiac events among the healthy population,^5–9 patients with stable coronary artery disease (CAD) or acute coronary syndrome (ACS),^10–14 and those who undergo percutaneous coronary interventions (PCIs).^15–17 Hydroxymethylglutaryl-coenzyme A reductase inhibitors, or statins, have been consistently shown to affect inflammation.^{10,11,18–23} Besides their role in the primary and secondary prevention that has been unequivocally established in 7 clinical trials,^24–30 statins have been related to early benefits among patients with ACS or those undergoing PCI, a state of vascular injury and inflammation.^31–35 In contrast to a reduction in primary end points that was observed only after 2 years of administration of statins in patients without vascular injury, an early mortality benefit was observed in these studies when statins were initiated at the time of the index events. In the present study, we sought to examine the interrelationship of inflammation, statin therapy, and its clinical benefit during PCI.

	Methods

Top Abstract Introduction Methods Results Discussion References

 
Patient Selection and Data Collection
Between January and December 2000, we prospectively followed up all United States residents who underwent elective or urgent PCI at Cleveland Clinic. Baseline characteristics, medication use, procedural details, and results were prospectively recorded by trained personnel into a registry. Measurement of serum hsCRP levels was routinely performed immediately before each intervention. Interventional procedures were performed as per conventional standards. Postprocedural creatine kinase was routinely measured at 6 to 8 hours after PCI, the morning after PCI, and in event of occurrence of symptoms suggestive of ischemia. Periprocedural myocardial infarction (MI) was defined by a rise in CKMB isoform by 3 times the upper limit of normal or development of new Q-waves associated with CKMB elevation consistent with myocardial necrosis. Major adverse cardiac events, which included death, MI, or the need for revascularization (PCI or coronary bypass surgery), were prospectively recorded during the index hospitalization, at 30 days, and at 1 year by research coordinators through hospital record review or through telephone contact with patients, their family, primary physicians, and the United States Social Security Administration Death Master File. Patients who had acute MI (within 24 hours of procedures) or cardiogenic shock were excluded from the analysis. The use of the interventional registry and subsequent data analysis were approved by the institutional review board.

Statistical Analysis
The primary objective was to compare patients with statin pretreatment with those without pretreatment, stratified by the preprocedural hsCRP levels. Patients were categorized into quartiles of hsCRP levels. Categorical data were expressed as percentages and were analyzed by means of ² tests. Continuous variables were presented as mean±SD and were analyzed by Student’s t test or Wilcoxon rank-sum tests, depending on normalcy of the data distribution. Kaplan-Meier method was used to estimate the time to event, and log-rank tests were used to compare time-dependent end points between groups pretreated with statins and not pretreated with statins.

To examine the relationship between baseline hsCRP and statin pretreatment, Cox proportional hazards modeling, including the propensity of prescribing statin therapy before PCI, was performed.³⁶ The following 22 baseline clinical characteristics were entered into a multivariate logistic regression model to define the propensity score: age, gender, presentation acuity, body mass index, left ventricular ejection fraction, presence of heart failure, cigarette smoking, history of MI, diabetes, hypertension, hypercholesterolemia, coronary bypass surgery, renal insufficiency, stroke, peripheral vascular disease, and concomitant medication use (aspirin, thienopyridine, angiotensin-converting enzyme [ACE] inhibitor, ß-blocker, calcium-channel blocker, diuretic, or antiarrhythmics). The population was then divided into quintiles by propensity score. Within each quintile, statin-pretreated patients were compared with nonpretreated patients with respect to their clinical characteristics. The propensity score was then entered into the Cox proportional hazards model as a continuous variable, along with other potential confounders, to examine the adjusted effects of statin pretreatment in correlating with PCI outcomes. An interaction term for statin use and hsCRP levels was also introduced into the multivariate model to examine its significance. All probability values were 2-tailed, and P<0.05 was considered significant in all analyses.

	Results

Top Abstract Introduction Methods Results Discussion References

 
Baseline Characteristics
A total of 1552 PCI patients fulfilled the criteria for the present analysis. Of these, 615 patients (39.6%) received statin therapy before index procedures. Baseline characteristics are listed in Table 1. Of note, patients pretreated with statins tended to be younger and were more likely to be treated with ACE inhibitors but less likely to receive ß-blockers. In addition, they were more likely to have a history of coronary bypass surgery and to undergo multivessel or vein graft revascularizations during index procedures.

View this table: [in this window] [in a new window]   TABLE 1. Baseline Clinical Characteristics

Numerous clinical characteristics were correlated with an increase in baseline hsCRP levels, and these are depicted in Table 2. Of note, there were no apparent correlations between hsCRP levels and the serum concentrations of total cholesterol, LDL cholesterol, HDL cholesterol, or triglycerides.

View this table: [in this window] [in a new window]   TABLE 2. Clinical Characteristics by Baseline CRP Levels

Periprocedural Period
Compared with the patients without statin pretreatment, patients taking statins before the procedures had a lower preprocedural hsCRP (median, 0.40 versus 0.50 mg/dL; P=0.012). Procedural success rates were similar between statin-pretreated and nonpretreated patients. However, there was a trend of increased periprocedural MI events with increase in preprocedural hsCRP levels (Figure 1). Furthermore, statin pretreatment was associated with a lower periprocedural MI event rate in the overall study population (5.7% versus 8.1%, P=0.038) and also among patients within each hsCRP quartile.

View larger version (25K): [in this window] [in a new window]   Figure 1. Relationship of preprocedural inflammatory state, statin therapy, and periprocedural MI events.

In a propensity model, the following factors were independent predictors for statin pretreatment (in descending order): hyperlipidemia, history of coronary bypass surgery, recent MI, age <75 years, ACE inhibitor use, absence of ß-blocker use, unstable angina, and thienopyridine therapy. The goodness of fit of the propensity model was 0.71. Using multivariate regression analysis to adjust for the characteristics that were significant correlates with periprocedural MI in the univariate analysis, including the hsCRP quartiles and the propensity score, statin pretreatment remained the sole independent predictor for lower incidence of periprocedural MI (odds ratio [OR], 0.58; P=0.014). Other independent predictors for periprocedural MI included bypass graft intervention (OR, 2.95; P<0.001), type B₂/C lesion (OR, 2.39; P<0.001), acute coronary syndrome (OR, 1.98; P=0.004), and multivessel PCI (OR, 1.75; P=0.015).

Periprocedural MI was associated with an increase in mortality rate (5.0% versus 13.1%; hazard ratio [HR], 2.62; P=0.001), recurrent MI (1.7% to 3.7%, HR, 2.18; P=0.120), repeat revascularization (16.6% versus 23.4%, HR, 1.41; P=0.073), and composite end point of death, MI, or revascularization (21.8% versus 34.6%; HR, 1.59; P=0.002) within the first year after PCI.

Interaction Between Inflammation and Statin Therapy
The interaction between statin pretreatment and hsCRP quartiles remained a significant factor (P=0.003) in correlating with 1-year death or MI when it was added to the Cox proportional hazards model that contained statin pretreatment and hsCRP quartiles as covariates. Subsequent analyses were therefore performed by stratification according to hsCRP quartiles and statin pretreatment.

HSCRP as a Predictor for 1-Year Outcomes After PCI
Baseline hsCRP level was predictive of adverse clinical outcomes at 1 year predominantly among patients who did not receive statin therapy (Figure 2). After adjusting for smoking, gender, renal function, diabetic status, left ventricular systolic function, heart failure, acuity of presentation, history of stroke or peripheral vascular disease, and lesion score, baseline hsCRP remained an independent predictor for 1-year composite end point of death or MI among patients not pretreated with statins (Table 3). Within this group, hsCRP was also a strong independent predictor for 1-year mortality (HR, 1.85/quartile; 95% CI, 1.40 to 2.45; P<0.001).

View larger version (19K): [in this window] [in a new window]   Figure 2. Major adverse cardiac events within the first year of PCI stratified by statin pretreatment before index procedure and preprocedural CRP (in quartiles). A, death; B, nonfatal MI; C, composite of death or MI; and D, coronary revascularization.

View this table: [in this window] [in a new window]   TABLE 3. Independent Predictors for 1-Year Composite End Points of Death or MI After PCI

Among patients receiving statin therapy, the absolute and relative risks were much attenuated, except for mortality, in which patients above the median hsCRP seemed to have a higher risk relative to those below the median (HR, 3.69; P=0.009) (Figure 2A). On multivariate analysis, hsCRP was marginally predictive of mortality when patients were pretreated with statins (HR, 1.56/quartile; 95% CI, 1.02 to 2.40; P=0.041). No significant association existed between composite end point of death or MI with hsCRP in this group of patients (HR, 1.18/quartile; 95% CI, 0.94 to 1.48; P=0.166).

Relation of Inflammatory Status and Clinical Benefits of Statin Therapy in PCI
Within the first year after PCI, statin therapy was associated with favorable effects on mortality (3.4% versus 6.9%, P=0.003) and MI (6.3% versus 9.8%, P=0.016) but not on revascularization (17.2% versus 17.0%, P=NS). These benefits were found among patients with elevated hsCRP levels (Figure 2). In particular, statin therapy was associated with lowering of death or MI rates of the highest hsCRP quartile to a level similar to those of the 3rd quartile (Figures 2A through 2C). Statins also seemed to be associated with a trend of lower 1-year revascularization rate within the 4th hsCRP quartile (Figure 2d). With respect to the composite end point of death, MI, or revascularization at 1 year, statin therapy was associated with a 40% reduction among patients within the highest hsCRP quartile (23.3% versus 38.6%, P=0.003), but such an association was not present at the lower hsCRP levels (1st quartile, 23.6% versus 21.6%; 2nd quartile, 25.3% versus 24.4%; 3rd quartile, 26.6% versus 31.0%; all P=NS).

Using the Cox proportional hazards modeling to adjust for the propensity score, left ventricular systolic function, and age, statin pretreatment remained an independent predictor for mortality at 1 year after PCI in the population within the highest hsCRP quartile (HR, 0.44; P=0.039, where hsCRP 1.11 mg/dL), but not when hsCRP <75th percentile.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
Within a large interventional registry, statin pretreatment was associated with lower hsCRP and was an independent predictor for fewer periprocedural and 1-year adverse events, including mortality. These benefits occurred predominantly among patients with high hsCRP levels. In addition, we confirm the predictive value of hsCRP for 1-year major adverse cardiac events after PCI. However, hsCRP as a prognostic indicator was relevant only among patients who did not receive statin therapy, and these correlations were much attenuated in the presence of statin therapy.

This study corroborates and extends the results of several other studies. Statins have been previously noted to have a specific effect on lowering hsCRP levels, independent of the effects on cholesterol or other inflammatory markers^18,22 ; however, a direct correlation with clinical outcome was not available in these studies. On the other hand, statin pretreatment was correlated with reduced myocardial necrosis in high-risk patients undergoing PCI³⁷ and with smaller infarct size during the onset of ACS,³⁸ the conditions associated with heightened inflammation. Using data from a primary prevention trial, Ridker et al²⁰ demonstrated a marked benefit of lovastatin among patients with high hsCRP but low cholesterol levels. In another study involving patients with a history of MI, the correlation of hsCRP and recurrent coronary events was present among patients not assigned to pravastatin treatment, and this association was attenuated in the presence of statins.¹¹ Likewise, in a relatively small PCI study, statin therapy attenuated the predictive value of hsCRP for composite of death, MI, and revascularization at 6 months after coronary stenting.¹⁷ In contrast to these studies, our study for the first time links the relationship of statin pretreatment, lowering of inflammation, and improvement of each individual clinical end point (death, MI, and revascularization) in PCI setting. This was present in the context of concomitant use of glycoprotein IIb/IIIa inhibitors, which are presently used in >70% of PCI patients in the United States and shown to reduce periprocedural thrombotic events.

The interrelationship of inflammation and statin benefit deserves particular attention. CRP reduces nitric oxide production by endothelial cells and increases endothelial expression of adhesion molecules.^39,40 It plays a crucial role in chemotaxis of monocytes and foam cell formation in atherosclerotic plaques.^41,42 Besides, CRP promotes tissue factor release and potentiates the effect of killer T cells on endothelial cells.^43,44 In addition to its direct role in plaque formation, CRP also enhances vasoreactivity of unstable plaques.^39,45,46 Indeed, higher CRP concentrations were found within ruptured plaques in patients who died from cardiac cause compared with those in patients with stable coronary disease or patients who died from noncardiac causes.⁴⁷ Clinical efficacy of the antiinflammatory effect of statins has been demonstrated consistently within randomized clinical trials and registry settings.^{10,11,19,20,22,23} Possibly through these antiinflammatory mechanisms, our study shows that statins reduce the risk of thrombotic events, independent of lipid lowering. Furthermore, because ACS and PCI are conditions more likely than stable CAD to be associated with elevated CRP levels, the link between statin benefit and high CRP levels observed in our study may explain the reports of early statin benefit among ACS and PCI patients^31–35 compared with predominantly late benefit in patients with stable CAD.^24–29

The effect of statins may extend beyond the culprit lesions intervened on during the index procedures. Using invasive approaches, there is emerging evidence for the presence of widespread inflammation and multifocal ulcerative plaques in patients with ACS.^1,48 Hence, systemic therapy with statins not only has antiinflammatory and antithrombotic effects on the target lesions but may also have positive impact throughout the coronary and noncoronary circulation.

The implication of the present findings should be considered within the context of recently published clinical trials. The Heart Protection Study and Lescol Intervention Prevention Study have concluded that statins should be administered based on high-risk clinical profile, irrespective of baseline cholesterol levels.^30,31 This would imply that all patients in the present analysis should be given statin therapy. Although neither hsCRP levels nor economic analysis are available from the two studies, our findings may provide evidence of subgroup populations who may derive even greater therapeutic benefits with this class of drugs and hence improve targeting of drug therapy. Our study additionally supports the finding that for patients with elevated hsCRP, delaying nonemergent PCI for tailoring statin therapy may result in clinical benefit. Such a hsCRP-guided strategy before PCI, however, remains to be tested.²

Limitations
Inherent to any observational studies, the assignment of statin therapy was nonrandomized. Despite the use of contemporary statistical methods to adjust for statin pretreatment, unmeasured confounders may affect the decision of statin therapy and long-term outcomes. Moreover, both the duration of statin pretreatment and the compliance of medical therapy were variable. However, given that the onset of antiinflammatory effect of statins could occur as early as 2 weeks,¹⁸ the observed effects of statin therapy would underestimate the true pleiotropic effects that would occur with adequate therapeutic dosing. Furthermore, many non-statin–pretreated patients would be started on a statin after PCI (96.5% of the statin-pretreated and 88.3% of the non–statin-pretreated PCI patients were discharged with a statin in the year 2002 in Cleveland Clinic), and any crossover between the comparison groups would only reduce the effect estimate toward null.

Conclusions
The benefit of statin therapy during the periprocedural period and long-term follow-up is dependent on the baseline inflammatory status, suggesting benefits with statin therapy mediated by the attenuation of the hazard effects of inflammation. Measurement of hsCRP levels may improve targeting of statin therapy, and perhaps dosing, beyond lipid level measurement in the secondary prevention among high-risk patients or those undergoing revascularization procedures.

Received October 9, 2002; revision received December 31, 2002; accepted January 16, 2003.

	References

Top Abstract Introduction Methods Results Discussion References

 
1. Buffon A, Biasucci LM, Liuzzo G, et al. Widespread coronary inflammation in unstable angina. N Engl J Med. 2002; 347: 5–12.[Abstract/Free Full Text]

2. Bhatt DL, Topol EJ. Need to test the arterial inflammation hypothesis. Circulation. 2002; 106: 136–140.[Free Full Text]

3. Yeh ET, Anderson HV, Pasceri V, et al. C-reactive protein: linking inflammation to cardiovascular complications. Circulation. 2001; 104: 974–975.[Free Full Text]

4. Ross R. Atherosclerosis: an inflammatory disease. N Engl J Med. 1999; 340: 115–126.[Free Full Text]

5. Ridker PM, Rifai N, Rose L, et al. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med. 2002; 347: 1557–1565.[Abstract/Free Full Text]

6. Albert CM, Ma J, Rifai N, et al. Prospective study of C-reactive protein, homocysteine, and plasma lipid levels as predictors of sudden cardiac death. Circulation. 2002; 105: 2595–2599.[Abstract/Free Full Text]

7. Ridker PM, Hennekens CH, Buring JE, et al. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med. 2000; 342: 836–843.[Abstract/Free Full Text]

8. Ridker PM, Glynn RJ, Hennekens CH. C-reactive protein adds to the predictive value of total and HDL cholesterol in determining risk of first myocardial infarction. Circulation. 1998; 97: 2007–2011.[Abstract/Free Full Text]

9. Ridker PM, Cushman M, Stampfer MJ, et al. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med. 1997; 336: 973–979.[Abstract/Free Full Text]

10. Ridker PM, Rifai N, Pfeffer MA, et al. Long-term effects of pravastatin on plasma concentration of C-reactive protein: the Cholesterol and Recurrent Events (CARE) Investigators. Circulation. 1999; 100: 230–235.[Abstract/Free Full Text]

11. Ridker PM, Rifai N, Pfeffer MA, et al. Inflammation, pravastatin, and the risk of coronary events after myocardial infarction in patients with average cholesterol levels: Cholesterol and Recurrent Events (CARE) Investigators. Circulation. 1998; 98: 839–844.[Abstract/Free Full Text]

12. Haverkate F, Thompson SG, Pyke SD, et al. Production of C-reactive protein and risk of coronary events in stable and unstable angina. European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group. Lancet. 1997; 349: 462–466.[CrossRef][Medline] [Order article via Infotrieve]

13. Lindahl B, Toss H, Siegbahn A, et al. Markers of myocardial damage and inflammation in relation to long-term mortality in unstable coronary artery disease: FRISC Study Group. Fragmin during Instability in Coronary Artery Disease. N Engl J Med. 2000; 343: 1139–1147.[Abstract/Free Full Text]

14. Toss H, Lindahl B, Siegbahn A, et al. Prognostic influence of increased fibrinogen and C-reactive protein levels in unstable coronary artery disease: FRISC Study Group. Fragmin during Instability in Coronary Artery Disease. Circulation. 1997; 96: 4204–4210.[Abstract/Free Full Text]

15. Buffon A, Liuzzo G, Biasucci LM, et al. Preprocedural serum levels of C-reactive protein predict early complications and late restenosis after coronary angioplasty. J Am Coll Cardiol. 1999; 34: 1512–1521.[Abstract/Free Full Text]

16. Chew DP, Bhatt DL, Robbins MA, et al. Incremental prognostic value of elevated baseline C-reactive protein among established markers of risk in percutaneous coronary intervention. Circulation. 2001; 104: 992–997.[Abstract/Free Full Text]

17. Walter DH, Fichtlscherer S, Sellwig M, et al. Preprocedural C-reactive protein levels and cardiovascular events after coronary stent implantation. J Am Coll Cardiol. 2001; 37: 839–846.[Abstract/Free Full Text]

18. Plenge JK, Hernandez TL, Weil KM, et al. Simvastatin lowers C-reactive protein within 14 days: an effect independent of LDL cholesterol reduction. Circulation. 2002; 106: 1447–1452.[Abstract/Free Full Text]

19. Ridker PM, Rifai N, Lowenthal SP. Rapid reduction in C-reactive protein with cerivastatin among 785 patients with primary hypercholesterolemia. Circulation. 2001; 103: 1191–1193.[Abstract/Free Full Text]

20. Ridker PM, Rifai N, Clearfield M, et al. 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: 1959–1965.[Abstract/Free Full Text]

21. Jialal I, Stein D, Balis D, et al. Effect of hydroxymethyl glutaryl coenzyme A reductase inhibitor therapy on high sensitive C-reactive protein levels. Circulation. 2001; 103: 1933–1935.[Abstract/Free Full Text]

22. Albert MA, Danielson E, Rifai N, et al. 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.[Abstract/Free Full Text]

23. Horne BD, Muhlestein JB, Carlquist JF, et al. Statin therapy, lipid levels, C-reactive protein and the survival of patients with angiographically severe coronary artery disease. J Am Coll Cardiol. 2000; 36: 1774–1780.[Abstract/Free Full Text]

24. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994; 344: 1383–1389.[CrossRef][Medline] [Order article via Infotrieve]

25. Shepherd J, Cobbe SM, Ford I, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia: West of Scotland Coronary Prevention Study Group. N Engl J Med. 1995; 333: 1301–1307.[Abstract/Free Full Text]

26. Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels: Cholesterol and Recurrent Events Trial investigators. N Engl J Med. 1996; 335: 1001–1009.[Abstract/Free Full Text]

27. The effect of aggressive lowering of low-density lipoprotein cholesterol levels and low-dose anticoagulation on obstructive changes in saphenous-vein coronary-artery bypass grafts: the Post Coronary Artery Bypass Graft Trial Investigators. N Engl J Med. 1997; 336: 153–162.[Abstract/Free Full Text]

28. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels: the Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. N Engl J Med. 1998; 339: 1349–1357.[Abstract/Free Full Text]

29. Downs JR, Clearfield M, Weis S, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA. 1998; 279: 1615–1622.[Abstract/Free Full Text]

30. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 6 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002; 2053:360: 7–22.

31. Serruys PW, De Feyter P, Macaya C, et al. Fluvastatin for prevention of cardiac events following successful first percutaneous coronary intervention: a randomized controlled trial. JAMA. 2002; 287: 3215–3222.[Abstract/Free Full Text]

32. Aronow HD, Topol EJ, Roe MT, et al. Effect of lipid-lowering therapy on early mortality after acute coronary syndromes: an observational study. Lancet. 2001; 357: 1063–1068.[CrossRef][Medline] [Order article via Infotrieve]

33. Stenestrand U, Wallentin L. Early statin treatment following acute myocardial infarction and 1-year survival. JAMA. 2001; 285: 430–436.[Abstract/Free Full Text]

34. Schwartz GG, Olsson AG, Ezekowitz MD, et al. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA. 2001; 285: 1711–1718.[Abstract/Free Full Text]

35. Chan AW, Bhatt DL, Chew DP, et al. Early and sustained survival benefit associated with statin therapy at the time of percutaneous coronary intervention. Circulation. 2002; 105: 691–696.[Abstract/Free Full Text]

36. Rubin DB. Estimating causal effects from large data sets using propensity scores. Ann Intern Med. 1997; 127: 757–763.[Abstract/Free Full Text]

37. Aronow HD, Quinn MJ, Gurm HS, et al. Myocardial necrosis is halved in patients undergoing elective percutaneous coronary intervention who are pretreated with lipid-lowering therapy. J Am Coll Cardiol. 2002; 39: 32A.Abstract.

38. Aronow HD, McRae T, Quinn MJ, et al. Patients on lipid-lowering therapy at the time of myocardial infarction have smaller infarcts: further evidence to suggest a salutary effect in acute coronary syndrome. J Am Coll Cardiol. 2002; 39: 318A.Abstract.

39. Verma S, Wang CH, Li SH, et al. A self-fulfilling prophecy: C-reactive protein attenuates nitric oxide production and inhibits angiogenesis. Circulation. 2002; 106: 913–919.[Abstract/Free Full Text]

40. Pasceri V, Willerson JT, Yeh ET. Direct proinflammatory effect of C-reactive protein on human endothelial cells. Circulation. 2000; 102: 2165–2168.[Abstract/Free Full Text]

41. Torzewski M, Rist C, Mortensen RF, et al. C-reactive protein in the arterial intima: role of C-reactive protein receptor-dependent monocyte recruitment in atherogenesis. Arterioscler Thromb Vasc Biol. 2000; 20: 2094–2099.[Abstract/Free Full Text]

42. Zwaka TP, Hombach V, Torzewski J. C-reactive protein-mediated low density lipoprotein uptake by macrophages: implications for atherosclerosis. Circulation. 2001; 103: 1194–1197.[Abstract/Free Full Text]

43. Nakajima T, Schulte S, Warrington KJ, et al. T-cell-mediated lysis of endothelial cells in acute coronary syndromes. Circulation. 2002; 105: 570–575.[Abstract/Free Full Text]

44. Penn MS, Topol EJ. Tissue factor, the emerging link between inflammation, thrombosis, and vascular remodeling. Circ Res. 2001; 89: 1–2.[Free Full Text]

45. Fichtlscherer S, Rosenberger G, Walter DH, et al. Elevated C-reactive protein levels and impaired endothelial vasoreactivity in patients with coronary artery disease. Circulation. 2000; 102: 1000–1006.[Abstract/Free Full Text]

46. Tomai F, Crea F, Gaspardone A, et al. Unstable angina and elevated c-reactive protein levels predict enhanced vasoreactivity of the culprit lesion. Circulation. 2001; 104: 1471–1476.[Abstract/Free Full Text]

47. Katritsis D, Korovesis S, Giazitzoglou E, et al. C-Reactive protein concentrations and angiographic characteristics of coronary lesions. Clin Chem. 2001; 47: 882–886.[Abstract/Free Full Text]

48. Rioufol G, Finet G, Ginon I, et al. Multiple atherosclerotic plaque rupture in acute coronary syndrome: a three-vessel intravascular ultrasound study. Circulation. 2002; 106: 804–808.[Abstract/Free Full Text]

This article has been cited by other articles:

				G. Heusch, P. Kleinbongard, D. Bose, B. Levkau, M. Haude, R. Schulz, and R. Erbel Coronary Microembolization: From Bedside to Bench and Back to Bedside Circulation, November 3, 2009; 120(18): 1822 - 1836. [Abstract] [Full Text] [PDF]

				G. Montalescot, H. Drexler, R. Gallo, T. Pearson, M. Thoenes, and D. L. Bhatt Effect of irbesartan and enalapril in non-ST elevation acute coronary syndrome: results of the randomized, double-blind ARCHIPELAGO study Eur. Heart J., November 2, 2009; 30(22): 2733 - 2741. [Abstract] [Full Text] [PDF]

				Y. S. Choi, J. K. Shim, S. W. Hong, D. H. Kim, J. C. Kim, and Y. L. Kwak Risk factors of atrial fibrillation following off-pump coronary artery bypass graft surgery: predictive value of C-reactive protein and transfusion requirement Eur. J. Cardiothorac. Surg., November 1, 2009; 36(5): 838 - 843. [Abstract] [Full Text] [PDF]

				H. Hara, M. Nakamura, I. Yokouchi, K. Kimura, N. Nemoto, S. Ito, T. Ono, H. Itaya, M. Shiba, M. Wada, et al. Aggressive statin therapy in multicenter and effectiveness for the reduction of intra-myocardial damage caused by non-ST elevation acute coronary syndrome: AMERICA study Therapeutic Advances in Cardiovascular Disease, October 1, 2009; 3(5): 357 - 365. [Abstract] [PDF]

				S. G. Ellis and S. Anwaruddin Recapturing the Magic: Revisiting the Pleiotropic Effects of Statins in Percutaneous Coronary Revascularization J. Am. Coll. Cardiol., August 4, 2009; 54(6): 566 - 568. [Full Text] [PDF]

				R. Jaumdally, C. Varma, R. J. Macfadyen, and G. Y.H. Lip Coronary sinus blood sampling: an insight into local cardiac pathophysiology and treatment? Eur. Heart J., April 2, 2007; 28(8): 929 - 940. [Abstract] [Full Text] [PDF]

				C. D. Collard, S. C. Body, S. K. Shernan, S. Wang, D. T. Mangano, and Multicenter Study of Perioperative Ischemia (MCSPI Preoperative statin therapy is associated with reduced cardiac mortality after coronary artery bypass graft surgery. J. Thorac. Cardiovasc. Surg., August 1, 2006; 132(2): 392 - 400. [Abstract] [Full Text] [PDF]

				H. -K. Yip, C. -H. Lu, C. -H. Yang, H. -W. Chang, W. -C. Hung, C. -I. Cheng, S. -M. Chen, and C. -J. Wu Levels and value of platelet activity in patients with severe internal carotid artery stenosis Neurology, March 28, 2006; 66(6): 804 - 808. [Abstract] [Full Text] [PDF]

				K. Iwakura, H. Ito, S. Kawano, A. Okamura, T. Kurotobi, M. Date, K. Inoue, and K. Fujii Chronic pre-treatment of statins is associated with the reduction of the no-reflow phenomenon in the patients with reperfused acute myocardial infarction Eur. Heart J., March 1, 2006; 27(5): 534 - 539. [Abstract] [Full Text] [PDF]

				D. A. Pascual, J. M. Arribas, P. L. Tornel, F. Marin, C. Oliver, M. Ahumada, J. Gomez-Plana, P. Martinez, R. Arcas, and M. Valdes Preoperative Statin Therapy and Troponin T Predict Early Complications of Coronary Artery Surgery Ann. Thorac. Surg., January 1, 2006; 81(1): 78 - 83. [Abstract] [Full Text] [PDF]

				K. Hindler, C. S. Cleeland, E. Rivera, and C. D. Collard The Role of Statins in Cancer Therapy. Oncologist, January 1, 2006; 11(3): 306 - 315. [Abstract] [Full Text] [PDF]

				J. Herrmann Peri-procedural myocardial injury: 2005 update Eur. Heart J., December 1, 2005; 26(23): 2493 - 2519. [Abstract] [Full Text] [PDF]

				B. Jaschke, C. Michaelis, S. Milz, M. Vogeser, T. Mund, L. Hengst, A. Kastrati, A. Schomig, and R. Wessely Local statin therapy differentially interferes with smooth muscle and endothelial cell proliferation and reduces neointima on a drug-eluting stent platform Cardiovasc Res, December 1, 2005; 68(3): 483 - 492. [Abstract] [Full Text] [PDF]

				Part 5: Acute Coronary Syndromes Circulation, November 29, 2005; 112(22_suppl): III-55 - III-72. [Full Text] [PDF]

				S. Susen, K. Sautiere, F. Mouquet, F. Cuilleret, A. Chmait, E. P. McFadden, B. Hennache, F. Richard, P. de Groote, J.-M. Lablanche, et al. Serum hepatocyte growth factor levels predict long-term clinical outcome after percutaneous coronary revascularization Eur. Heart J., November 2, 2005; 26(22): 2387 - 2395. [Abstract] [Full Text] [PDF]

				S. De Servi, M. Mariani, G. Mariani, and A. Mazzone C-Reactive Protein Increase in Unstable Coronary Disease: Cause or Effect? J. Am. Coll. Cardiol., October 18, 2005; 46(8): 1496 - 1502. [Abstract] [Full Text] [PDF]

				S.-J. Park Inflammatory Biomarkers for Prediction of Outcomes After Unprotected Left Main Coronary Intervention Circulation, October 11, 2005; 112(15): 2226 - 2227. [Full Text] [PDF]

				R. F. Bonvini, T. Hendiri, and E. Camenzind Inflammatory response post-myocardial infarction and reperfusion: a new therapeutic target? Eur. Heart J. Suppl., October 1, 2005; 7(suppl_I): I27 - I36. [Abstract] [Full Text] [PDF]

				D. L. Bhatt and E. J. Topol Periprocedural Cardiac Enzyme Elevation Predicts Adverse Outcomes Circulation, August 9, 2005; 112(6): 906 - 922. [Full Text] [PDF]

				G. C. Fonarow, C. W. Yancy, J. T. Heywood, and for the ADHERE Scientific Advisory Committee, Stud Adherence to Heart Failure Quality-of-Care Indicators in US Hospitals: Analysis of the ADHERE Registry Arch Intern Med, July 11, 2005; 165(13): 1469 - 1477. [Abstract] [Full Text] [PDF]

				S. Steiner, W. S. Speidl, J. Pleiner, D. Seidinger, G. Zorn, C. Kaun, J. Wojta, K. Huber, E. Minar, M. Wolzt, et al. Simvastatin Blunts Endotoxin-Induced Tissue Factor In Vivo Circulation, April 12, 2005; 111(14): 1841 - 1846. [Abstract] [Full Text] [PDF]

				C. Briguori, A. Colombo, F. Airoldi, A. Violante, A. Focaccio, P. Balestrieri, P. Paolo Elia, B. Golia, S. Lepore, G. Riviezzo, et al. Statin administration before percutaneous coronary intervention: impact on periprocedural myocardial infarction Eur. Heart J., October 2, 2004; 25(20): 1822 - 1828. [Abstract] [Full Text] [PDF]

				K. Toutouzas, A. Colombo, and C. Stefanadis Inflammation and restenosis after percutaneous coronary interventions Eur. Heart J., October 1, 2004; 25(19): 1679 - 1687. [Abstract] [Full Text] [PDF]

				W. Pan, T. Pintar, J. Anton, V.-V. Lee, W. K. Vaughn, and C. D. Collard Statins Are Associated With a Reduced Incidence of Perioperative Mortality After Coronary Artery Bypass Graft Surgery Circulation, September 14, 2004; 110(11_suppl_1): II-45 - II-49. [Abstract] [Full Text] [PDF]

				T.-S. Lee, C.-C. Chang, Y. Zhu, and J. Y.-J. Shyy Simvastatin Induces Heme Oxygenase-1: A Novel Mechanism of Vessel Protection Circulation, September 7, 2004; 110(10): 1296 - 1302. [Abstract] [Full Text] [PDF]

				D. A. Morrow Preprocedural C-Reactive Protein for Risk Prediction Before Percutaneous Coronary Intervention (PCI): A US Perspective Clin. Chem., September 1, 2004; 50(9): 1489 - 1491. [Full Text] [PDF]

				S. Z.H. Rittersma, R. J. de Winter, K. T. Koch, C. E. Schotborgh, M. Bax, G. S. Heyde, J. P. van Straalen, K. J. Mulder, J. G.P. Tijssen, G. T. Sanders, et al. Preprocedural C-Reactive Protein Is Not Associated with Angiographic Restenosis or Target Lesion Revascularization after Coronary Artery Stent Placement Clin. Chem., September 1, 2004; 50(9): 1589 - 1596. [Abstract] [Full Text] [PDF]

				V. Pasceri, G. Patti, A. Nusca, C. Pristipino, G. Richichi, G. Di Sciascio, and on behalf of the ARMYDA Investigators Randomized Trial of Atorvastatin for Reduction of Myocardial Damage During Coronary Intervention: Results From the ARMYDA (Atorvastatin for Reduction of MYocardial Damage during Angioplasty) Study Circulation, August 10, 2004; 110(6): 674 - 678. [Abstract] [Full Text] [PDF]

				M. Schillinger, M. Exner, W. Mlekusch, J. Amighi, S. Sabeti, M. Muellner, H. Rumpold, O. Wagner, and E. Minar Statin therapy improves cardiovascular outcome of patients with peripheral artery disease Eur. Heart J., May 1, 2004; 25(9): 742 - 748. [Abstract] [Full Text] [PDF]

				J. M Backes, P. A Howard, and P. M Moriarty Role of C-Reactive Protein in Cardiovascular Disease Ann. Pharmacother., January 1, 2004; 38(1): 110 - 118. [Abstract] [Full Text] [PDF]

				P. M Ridker and on behalf of the JUPITER Study Group 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, November 11, 2003; 108(19): 2292 - 2297. [Full Text] [PDF]

				D. J. Kereiakes Adjunctive Pharmacotherapy before Percutaneous Coronary Intervention in Non-ST-Elevation Acute Coronary Syndromes: The Role of Modulating Inflammation Circulation, October 21, 2003; 108(90161): III-22 - 27. [Abstract] [Full Text] [PDF]

				B. K. Nallamothu and E. R. Bates Periprocedural myocardial infarction and mortality: Causality versus association J. Am. Coll. Cardiol., October 15, 2003; 42(8): 1412 - 1414. [Full Text] [PDF]

				J. J. Piek and R. J. de Winter Type II secretory phospholipase A2: The emerging role of biochemical markers of plaque inflammation Eur. Heart J., October 2, 2003; 24(20): 1804 - 1806. [Full Text] [PDF]

				Pre-PCI CRP Levels and Statin Use Journal Watch Cardiology, July 11, 2003; 2003(711): 3 - 3. [Full Text]

This Article Free upon publication Abstract Full Text (PDF) All Versions of this Article: 107/13/1750    most recent 01.CIR.0000060541.18923.E9v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Chan, A. W. Articles by Ellis, S. G. Search for Related Content PubMed PubMed Citation Articles by Chan, A. W. Articles by Ellis, S. G. Related Collections Lipids Secondary prevention Catheter-based coronary interventions: stents