Inflammation plays a pivotal role in the pathogenesis of

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1 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 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 3 upper 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. (Circulation. 2003;107: ) Key Words: angioplasty coronary disease inflammation statins stents 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), and those who undergo percutaneous coronary interventions (PCIs) 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, statins have been related to early benefits among patients with ACS or those undergoing PCI, a state of vascular injury and inflammation 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 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 prospec- Received October 9, 2002; revision received December 31, 2002; accepted January 16, 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 achan@ochsner.org 2003 American Heart Association, Inc. Circulation is available at DOI: /01.CIR E9 1750

2 Chan et al Inflammation and Statin Therapy in PCI 1751 TABLE 1. Baseline Clinical Characteristics Characteristics Statin Pretreatment (n 615) No Statin Pretreatment (n 937) P Demographics Age, y Female, % Body mass index, kg/m Risk factors Current smoker Diabetes mellitus Hypercholesterolemia Hypertension Comorbidity Prior MI Prior coronary bypass surgery Heart failure Renal insufficiency Peripheral vascular disease Prior stroke Medications Aspirin Thienopyridine Blocker ACE inhibitor Calcium channel blocker Diuretic Antiarrhythmic agent Procedural factors Recent MI Unstable angina LVEF 35% Type B 2 /C lesion* Vein graft intervention Multivessel PCI Stent use Rotational atherectomy GP IIb/IIIa inhibitor use Restenotic lesion Procedural success All data are expressed in percent except for those in demographics. LVEF indicates left ventricular ejection fraction. *Lesion classification as per modified ACC/AHA criteria. Procedural success was defined by 50% residual diameter stenosis after angioplasty or 20% stenosis after stenting for all intervened lesions. tively 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, -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 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 -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. 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. 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.

3 1752 Circulation April 8, 2003 TABLE 2. Clinical Characteristics by Baseline CRP Levels Preprocedural CRP Quartile (Range, mg/dl) Characteristics 1st ( 0.13) 2nd (0.14 to 0.41) 3rd (0.42 to 1.10) 4th ( 1.11) P Age, y* Female* Body mass index, kg/m 2 * Smoking* Diabetes mellitus* Insulin-requiring* Non insulin-requiring Hypertension Total cholesterol, mg/dl LDL cholesterol, mg/dl HDL cholesterol, mg/dl Triglyceride, mg/dl Aspirin Thienopyridine Statin Blocker* ACE inhibitor* Calcium-channel blocker Diuretic* Antiarrhythmic agent* Heart failure* Prior MI Prior coronary bypass surgery Renal insufficiency* Peripheral vascular disease Prior stroke* Recent MI* Unstable angina* LVEF 35%* No. of diseased coronary arteries Multivessel PCI Type B 2 /C lesion SVG intervention Restenotic lesions Rotational atherectomy Stents Glycoprotein IIb/IIIa inhibitor Procedural success All numbers are percentages unless otherwise specified. LVEF indicates left ventricular ejection fraction. *Factors that were correlated with elevated baseline hscrp levels. Values of the 353 patients who underwent PCI in the first 2 months of each half-year period. 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 -blocker use, unstable angina, and thienopyridine therapy. The goodness of fit of the propensity model was 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

4 Chan et al Inflammation and Statin Therapy in PCI 1753 Figure 1. Relationship of preprocedural inflammatory state, statin therapy, and periprocedural MI events. 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 B 2 /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). 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 com- 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.

5 1754 Circulation April 8, 2003 TABLE 3. Independent Predictors for 1-Year Composite End Points of Death or MI After PCI Characteristics Hazard Ratio 95% Confidence Interval P Without statin therapy CRP quartile to Prior MI to Acute coronary syndrome to LVEF 35% to Heart failure to Age 75 years to Renal insufficiency to Type B 2 /C lesion to Bypass graft PCI to With statin therapy LVEF 35% to LVEF indicates left ventricular ejection fraction. posite 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 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 PCI 37 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 al 20 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 compared with predominantly late benefit in patients with stable CAD 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

6 Chan et al Inflammation and Statin Therapy in PCI 1755 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. References 1. Buffon A, Biasucci LM, Liuzzo G, et al. Widespread coronary inflammation in unstable angina. N Engl J Med. 2002;347: Bhatt DL, Topol EJ. 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