Effect of Rosuvastatin Therapy on Troponin I Release FollowingPercutaneous Coronary Intervention in Nonemergency Patients

(from the TIP 3 Study)

Josef Veselka, MD, PhDa,*, Petr Hájek, MDa, Pavol Toma�sov, MDa, David Tesa�r, MD, PhDa,Hana Br�uhová, MDb, Martin Mat�ejovi�c, MD, PhDb, Marian Branny, MDc, Martin Studen�can, MD, PhDd,

and David Zemánek, MD, PhDa

Several randomized studies have suggested that pretreatment with statins may reduce a

aDepartment osity, University Hoof Medicine, CharHospital in PilsenPodlesi Hospital, TEast Slovakia InsManuscript receivaccepted October

This study waCzech Republic)(00064203).

See page 450*Correspondin

4920.E-mail addres

0002-9149/13/$ -http://dx.doi.org/1

periprocedural biomarker release in patients who underwent percutaneous coronary inter-vention (PCI); however, results remain controversial. The purpose of this study was toinvestigate the effect of a 1-day rosuvastatin therapy on troponin I release in patients whounderwent nonemergency PCI. A total of 445 patients with angina pectoris were randomlyassigned to therapy with rosuvastatin (20mg 12 hours before coronary angiographyD 20mgimmediately before PCI; rosuvastatin group, 220 patients) or PCI without statin therapy(control group, 225 patients). In patients taking statins (73%), rosuvastatin was added to theirlong-term statin therapy. Theprimary endpointwas the incidence ofTnImicroleak defined asTnI elevation >1.53 upper limit of normal, and the secondary end point was the incidence ofpost-PCI TnI elevation >33 upper limit of normal. The incidence of primary and secondaryend point in the rosuvastatin versus control groupwas 13.6% versus 12% (p[ 0.61) and 8.2%versus 7.1% (p [ 0.67), respectively. Patients with C-reactive protein ‡2.0 mg/L had adecreased release of post-PCI TnI in the rosuvastatin group (0.032 [0.010 to 0.143] mg/L vs0.056 [0.018 to 0.241]mg/L; p[ 0.04). In conclusion, 1-day rosuvastatin therapy (20mg twicea day) did not influence post-PCI TnI release in patients with angina. However, these resultssuggest that, in patients with an advanced inflammatory status, rosuvastatin loading therapymight have a cardioprotective effect. � 2014 Elsevier Inc. All rights reserved. (Am JCardiol2014;113:446e451)

The high postinterventional troponin I (TnI) release isconsidered to represent the myocardial injury or periproce-dural myocardial infarction (PMI), which is a relativelycommon complication of percutaneous coronary interven-tion (PCI), mostly with a silent clinical course.1 Althoughthe impact of PMI on long-term clinical prognosis is still ondebate, several studies have demonstrated a relation betweenthe incidence and extent of PMI and long-term mortality.2,3

Recently, it has been suggested that even minor post-procedural elevation of TnI is associated with a subsequentincrease in cardiovascular risk.3 Therefore, we presume thatprevention of myocardial injury would improve the long-term PCI outcome. Results from several randomized trials

f Cardiology, Second Medical School, Charles Univer-spital Motol, Prague, Czech Republic; bFirst Departmentles University in Prague, Medical School and Teaching, Pilsen, Czech Republic; cDepartment of Cardiology,rinec, Czech Republic; and dDepartment of Cardiology,titute for Cardiovascular Diseases, Kosice, Slovakia.ed July 21, 2013; revised manuscript received and5, 2013.s supported by the project (Ministry of Health, Prague,for conceptual development of research organization

for disclosure information.g author: Tel: (þ42) 022-443-4900; fax: (þ42) 022-443-

s: josef.veselka@fnmotol.cz (J. Veselka).

see front matter � 2014 Elsevier Inc. All rights reserved.0.1016/j.amjcard.2013.10.026

have demonstrated that both statin-naive patients and pa-tients on long-term statin therapy assigned to pretreatmentwith a high dose of atorvastatin or rosuvastatin were asso-ciated with a reduced occurrence of myocardial injury orPMI, resulting in better short-term outcomes.4e15 However,according to further studies, the effect of statins on theincidence of biomarker release remains controversial.16e20

The purpose of this study was to investigate the effect of a1-day rosuvastatin therapy on TnI release in nonemergencypatients admitted for coronary angiography (CAG) andsubsequently treated by PCI.

Methods

The TIP 3 study (rosuvasTatin pretreatment Influencesthe risk of Percutaneous coronary intervention) was amulticenter, international, and randomized study performedin 4 cardiovascular centers in 2 countries between May 2010and June 2012.

A total of 1,752 patients with stable and TnI-negativecoronary artery disease underwent CAG; 445 patients with ade novo lesion >50% indicated for PCI were enrolled andrandomized (ratio 1:1) to loading therapy with rosuvastatin(20 mg 12 hours before PCI þ 20 mg immediately beforePCI; rosuvastatin group; 220 patients) or PCI withoutloading statin therapy (control group; 225 patients). Patientswere randomized independently of their lipid levels, level ofC-reactive protein (CRP), and presence or absence of long-

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Table 1Baseline patient characteristics

Variable Rosuvastatin Group(n ¼ 220)

Control Group(n ¼ 225)

pValue

Age (yrs) (range) 67 � 9 (38e87) 68 � 10 (33e88) 0.33Men 71% 63% 0.08Body mass index,

median (IQR)(kg/m2)

28 (26e32) 29 (27e33) 0.01

Angina pectoris,Canadian Societyof Cardiologyclass

1.7 � 1.1 1.5 � 1.2 0.25

Dyspnea, NYHAclass

1.6 � 0.9 1.7 � 1.1 0.38

Previous myocardialinfarction

32% 34% 0.66

Previous coronarybypass

13% 12% 0.48

Previouspercutaneouscoronaryintervention

27% 29% 0.85

Previous stroke 6.4% 6.2% 0.85Atrial fibrillation 11% 8% 0.29Current smoker 18% 19% 0.80Hypertension 84% 88% 0.18CRP (mg/L), median

(IQR)1.7 (0.7e4.5) 2 (0.9e6) 0.27

Serum creatinine(mmol/L), median(IQR)

84 (71e97) 80 (69e97) 0.14

Total cholesterol>5 mmol/L(>193 mg/dl)

29% 32% 0.55

Total plasmacholesterol(mmol/L; mg/dl)

4.8 � 3.3;186 � 128

4.6 � 1.2;178 � 46

0.78

LDL cholesterol(mmol/L; mg/dl)

2.6 � 0.9;101 � 35

2.7 � 1.0;104 � 39

0.99

HDL cholesterol(mmol/L; mg/dl)

1.1 � 0.3;43 � 12

1.1 � 0.4;43 � 16

0.95

Hypertriglyceridemia>2 mmol/L(>177 mg/dl)

27% 32% 0.22

Plasma triglyceride(mmol/L; mg/dl)

1.8 � 1.5;159 � 133

1.8 � 1.2;159 � 106

0.60

Diabetes mellitus 36% 38% 0.61

IQR ¼ interquartile range; LDL ¼ low-density lipoprotein; NYHA ¼New York Heart Association.

Table 2Preprocedural medical therapy

Variable Rosuvastatin Group(n ¼ 220) (%)

Control Group(n ¼ 225) (%)

pValue

b blockers 62 70 0.06Calcium antagonists 28 31 0.43Angiotensin-converting

enzyme inhibitors49 60 0.03

Angiotensin II receptorblockers

19 19 0.66

Coronary Artery Disease/Rosuvastatin Before PCI 447

term statin therapy. In patients taking statins, rosuvastatinwas added to their long-term statin therapy. Blood samplesfor TnI measurements (Architect, Abbott, Illinois) weretaken immediately before PCI, 6 to 12 hours, and 16 to24 hours thereafter. Additional samples of biomarkers wereobtained if the patient developed elevated post-PCI TnIlevel. The high-sensitivity CRP level (WACO Pure Chem-ical Industries, Osaka, Japan) was measured at admission,which was 1 day before CAG examination. According tobaseline CRP levels taken before loading rosuvastatintherapy, patients were divided into 2 groups (�2 mg/L or<2 mg/L) to assess the influence of rosuvastatin loading

therapy on post-PCI TnI release in relation with a minorCRP elevation. Similarly, patients were divided into 3groups according to long-term statin therapy to assess itsinfluence on the incidence of post-PCI TnI microleak. Thefirst group comprised patients without statin therapy, thesecond group comprised patients with long-term low-dosestatin therapy (atorvastatin 10 mg, atorvastatin 20 mg, flu-vastatin 20 mg, lovastatin 20 mg, rosuvastatin 10 mg,simvastatin 10 mg, simvastatin 20 mg, and simvastatin40 mg), and the third group comprised patients with long-term high-dose statin therapy (atorvastatin 40 mg, atorvas-tatin 80 mg, rosuvastatin 20 mg, and rosuvastatin 40 mg).

All study protocols were approved by the local ethicscommittee, and all patients provided written informedconsent. The study was registered at ClinicalTrials.gov(ClinicalTrials.gov; identifier: NCT01378715).

Coronary intervention was performed immediately afterCAG. All patients received 100 mg of aspirin and 300 mg ofclopidogrel 1 day before PCI. After PCI, aspirin (100 mg/d),clopidogrel (75 mg/d), and statins were prescribed to all thepatients.

The primary end point was the peak TnI concentration�1.5 times the upper limit of normal (ULN; “TnI micro-leak”)3 up to 24 hours after PCI. The secondary end pointwas the TnI concentration �3 times the ULN. Because thelast definition of myocardial infarction was published aftertermination of our study in 2012,1 we also evaluated theincidence of post-PCI TnI level �5 times the ULN, which isa new definition of periprocedural myocardial infarction(PMI). Angiographic success of PCI was defined as residualdiameter stenosis <20%, determined by a visual estimationand Thrombolysis in Myocardial Infarction flow grade 3.

The sample size (220 vs 220 patients) was based onprevious studies3,4,15 to demonstrate a reduction in the pri-mary end point from 33% in the control group to 20% in therosuvastatin group (2-sided chi-square test, a ¼ 0.05,power ¼ 0.87). Continuous variables are expressed asmean � SD or medians with interquartile range; discretevariables are expressed as counts and percentages. The datawere tested for normal distribution using the Kolmogorov-Smirnov test. Differences between groups were tested usingthe chi-square test, Fisher’s exact test, or Mann-WhitneyU test as appropriate. Odds ratios and 95% confidence in-tervals assessing the risk of the primary end point accordingto potential confounding variables were assessed by logisticregression. The following parameters were evaluated, first ina univariate model: rosuvastatin (re) loading therapy, long-term therapy with b blockers, long-term therapy with statins,

Table 3Long-term statin treatment

Variable RosuvastatinGroup (n ¼ 220) (%)

Control Group(n ¼ 225) (%)

pValue

Atorvastatin 10 mg 8.2 5.8 0.32Atorvastatin 20 mg 32.3 35.1 0.53Atorvastatin 40 mg 8.6 10.2 0.57Atorvastatin 80 mg 4.1 6.7 0.23Fluvastatin 20 mg 1.8 0.9 0.40Lovastatin 20 mg 0.5 0.4 0.99Rosuvastatin 10 mg 0.5 2.7 0.06Rosuvastatin 20 mg 3.2 5.3 0.26Rosuvastatin 40 mg 0.5 0.4 0.99Simvastatin 10 mg 2.7 0.4 0.05Simvastatin 20 mg 5.5 6.7 0.59Simvastatin 40 mg 3.2 0.4 0.03Without statins 28.6 24.9 0.37

Table 4Peri-procedural intervention and angiographic characteristics of studypopulation

Variable RosuvastatinGroup (n ¼ 220)

Control Group(n ¼ 225)

pValue

Coronary artery narrowed inLeft anterior descending 39% 40% 0.82Right 29% 33% 0.37Left circumflex 27% 25% 0.61Saphenous vein graft 5% 3% 0.19Left main 3% 3% 0.73

Percutaneous coronaryintervention on morevessels

4% 4% 0.67

1 45% 43% 0.682 29% 27% 0.643 26% 30% 0.36

Type of coronary lesionA 11% 12% 0.82B1 21% 16% 0.27B2 41% 38% 0.63C 28% 34% 0.20

In-stent restenosis 9% 7% 0.34Total occlusion 12% 12% 0.93Preinterventional stenosis (%) 87 � 10 90 � 10 0.99Postinterventional stenosis (%) 6 � 20 5 � 18 0.69Intracoronary thrombosis 2% 7% 0.54Number of treated narrowings 1.2 � 0.4 1.2 � 0.4 0.94Stents per patient (n) 1.1 1.2 0.59Direct stenting 49% 50% 0.74Mean length of stents (mm) 20 � 13 20 � 14 0.90Angiographic success 96% 96% 0.67Complete revascularization 63% 60% 0.62Fluoroscopic time (min),

median (IQR)6.4 (4e10) 7.2 (5e11) 0.02

Inflation time (s), median (IQR) 20 (10e60) 31 (10e48) 0.60Transient vessel closure 2% 3% 0.79Major dissection 3% 5% 0.33Q-wave myocardial infarction

within 24 h (n)0 0 1.0

IQR ¼ interquartile range.

Figure 1. Median of TnI in both groups. Max ¼ maximum.

448 The American Journal of Cardiology (www.ajconline.org)

multivessel disease, complex lesion (type B2/C vs A/B1),level of total cholesterol and high-density lipoprotein (HDL)cholesterol, symptomatic peripheral atherosclerotic disease,diabetes mellitus, anginal pain at rest, radial approach,gender, and age of the patients. Variables with a p value<0.15 were then entered into a multivariate analysis, whichwas performed using a logistic regression to identify pre-dictors of the primary end point. A p value <0.05 wasconsidered statistically significant. The statistical softwareprograms Stata, release 9.2 (Stata Corp. LP, College Station,Texas), and GraphPad PRISM, version 4 (GrafPad SoftwareInc., La Jolla, California), were used for all analyses.

Results

A total of 445 patients with coronary artery disease wererandomized and underwent PCI. Clinical and proceduralvariables were comparable between both groups of patients(Table 1). Long-term pharmacotherapy of the study popu-lation is summarized in Tables 2 and 3.

Angiographic and procedural characteristics were similarin both groups of patients (Table 4). Troponin I values inboth groups are summarized in Figure 1. The baselinevalues were 0.01 (0.01 to 0.02) mg/L versus 0.01 (0.01 to0.02) mg/L (p ¼ 0.83). There were no differences in theincidence of primary or secondary end points betweengroups (Table 5).

Multivariate analysis was performed to identify the pre-dictors of TnI microleak release. In this model, only pre-treatment with b blockers was identified as the independentpredictor of the primary end point (Table 6).

A total of 218 patients (49%) and 70 patients (16%) hadbaseline CRP �2 mg/L and CRP >6 mg/L, respectively.Patients with CRP �2 mg/L compared with patients withCRP <2 mg/L were different with regard to male gender(62% vs 73%; p ¼ 0.01), body mass index (29.4 vs 28.4;p ¼ 0.01), and HDL cholesterol level (1.07 vs 1.14; p ¼0.03). From 218 patients with CRP �2 mg/L, 102 patients(47%) were included in the rosuvastatin group and 116(53%) in the control group. Baseline characteristics weresimilar in these 2 groups, with the exception of serumcreatinine levels, which were higher in the rosuvastatin

group (87.5 [74 to 104] mmol/L vs 81.5 [68 to 100] mmol/L; p ¼ 0.05), and male gender, which was more common inthe rosuvastatin group (69% vs 55%; p ¼ 0.04). There wasno difference in the incidence of the primary end point in

Figure 3. Median of TnI in patients with CRP <2 mg/L.

Table 5The incidence of postprocedural high TnI release

Variable Rosuvastatin Group (n ¼ 220) (%) Control Group (n ¼ 225) (%) p Value OR (95% CI)

Post-PCI TnI 1e1.49� ULN 16.4 17.7 0.72 0.91 (0.56e1.50)Post-PCI TnI �1.5� ULN 13.6 12 0.61 0.86 (0.50e1.50)Post-PCI TnI �3� ULN 8.2 7.1 0.67 0.86 (0.43e1.73)Post-PCI TnI �5� ULN 7.3 3.6 0.08 0.47 (0.20e1.12)

CI ¼ confidence interval; OR ¼ odds ratio.

Table 6Multivariate analysis showing predictors of the primary end point

Variable OR (95% CI) p Value

Rosuvastatin pretreatment 1.19 (0.67e2.11) 0.54b blockers pretreatment 0.52 (0.29e0.92) 0.03CRP 1.03 (1e1.06) 0.07

CI ¼ confidence interval; OR ¼ odds ratio.

Figure 2. Median of TnI in patients with CRP �2 mg/L.

Coronary Artery Disease/Rosuvastatin Before PCI 449

both groups (12% in the rosuvastatin group vs 14% in thecontrol group; p ¼ 0.66). However, patients with CRP�2.0 mg/L had a decreased release of post-PCI TnI in therosuvastatin group (0.032 [0.010 to 0.143] mg/L vs 0.056[0.018 to 0.241] mg/L; p ¼ 0.04; Figure 2). This differencewas not present in patients with baseline CRP <2 mg/L(Figure 3).

The patient population was divided into 3 groups ac-cording to long-term statin therapy. A total of 119 patients

(27%) had no statin therapy before randomization, 225 pa-tients (51%) had low-dose statin therapy, and 101 patients(23%) were on high-dose statins. There were no significantdifferences in the incidence of post-PCI TnI microleakamong these 3 groups (13% vs 15% vs 9%; p ¼ 0.28). Therewere also no significant differences in the incidence of post-PCI TnI microleak in these groups with regard to 1-dayrosuvastatin therapy.

Discussion

This is the only international, multicenter, randomizedstudy to date evaluating the effect of a 1-day therapy withrosuvastatin in nonemergency, all-comer patients who un-derwent PCI for angina pectoris. The results of this studysuggest that (1) the (re)loading of rosuvastatin (40 mg)preceding PCI was not associated with a lower incidence ofhigh TnI release and (2) in patients with an advanced in-flammatory status rosuvastatin therapy might have a car-dioprotective effect.

Although the present findings do not accord with mostprevious studies, they are consistent with the TIP 1 studydemonstrating the absence of both short- and long-termeffects of atorvastatin therapy before PCI in low-risk statin-naive patients.17,18 Similarly, a recent study published byGordin et al19 demonstrated that no difference in incidenceof TnI increases �3 times ULN in patients on long-termstatin therapy versus those not on long-term statin therapytreated by PCI. Additionally, the TIP 2 study demonstratedno beneficial effect of 7-day atorvastatin pretreatment on theincidence of PMI after PCI in patients receiving long-termstatin therapy.20 The discrepant findings of pre-PCI statintherapy can be explained by examining the randomizedstudies; they suggest that the incidence of myocardial injurymight be slightly reduced if high-dose statins are adminis-tered to high-risk, statin-naive patients upstream to PCI.14

However, the reduction in absolute risk of PMI ormyocardial injury in low-risk populations is likely lowerthan previously believed. In the Atorvastatin for Reductionof Myocardial Damage during Angioplasty Recapture(ARMYDA-RECAPTURE) trial,6 patients who were onlong-term statin therapy were treated, or untreated, with ahigh dose of atorvastatin (80 mg 12 hours before PCI and40 mg 2 hours before PCI). Although the study reached thecomposite primary end point (30-day incidence of cardiacdeath, myocardial infarction, or unplanned revasculariza-tion), there were no significant differences in the incidenceof PMI (p ¼ 0.06). Moreover, the high-dose atorvastatintherapy did not influence the incidence of the major adversecardiac events within 30 days in patients with stable angina

450 The American Journal of Cardiology (www.ajconline.org)

(p ¼ 0.98). However, in the Atorvastatin for Reduction ofMyocardial Damage during Angioplasty in Acute CoronarySyndromes (ARMYDA-ACS) trial that enrolled high-riskpatients with acute coronary syndromes, the atorvastatinpretreatment led to a threefold reduction of the incidence ofPMI.5 Thus, results of these studies also support the hy-pothesis that the high-dose pre-PCI statin therapy influencesthe incidence of myocardial injury only in patients with ahigh procedural risk. Therefore, we feel that is still debat-able, whether current data justify possible postponement ofPCI because of statin pretreatment in all-comer populationof mostly stable patients with coronary artery disease.

CRP is a general marker of systemic inflammation and isassociated with increased cardiovascular risk. In the lastdecade, researchers began to use a CRP level of �2 mg/L asthe threshold for defining higher cardiovascular risk.21,22

With the use of this threshold, 52% of the adult populationin the United States22 and 49% of this study populationwould be considered at slightly higher cardiovascular risk.With regard to CRP level, this study population is compa-rable with a civilian, noninstitutionalized population of theUnited States. Results of the present study suggest that pre-PCI rosuvastatin (re)loading might be beneficial in patientswith CRP level �2 mg/L. Although higher levels of CRPwere associated with other potential risk factors (higherbody mass index, lower HDL cholesterol, and femalegender), multivariable analysis performed in this studysuggests a strong trend toward an independent role of CRPin the pathophysiology of post-PCI TnI microleak (p ¼0.065). In contrast, although the patients with CRP�2.0 mg/L had a decreased release of post-PCI TnI in therosuvastatin group (p ¼ 0.04), this difference was nottranslated in the significantly lower incidence of post-PCITnI microleak. Furthermore, we have to bear in mind thatinterpretation of subgroup analyses is highly problematic.23

Thus, these findings seem to be consistent with previoustrials and further specify the level of CRP with a potentialrisk. Our results could have implications for future trialsspecifically designed to address the role of statin pretreat-ment in patients with different CRP levels. Moreover, allfuture studies evaluating the relations between pre-PCIstatin therapy and the incidence of PMI should also assessbaseline CRP levels. Additionally, higher doses of rosu-vastatin should be tested in the future because present doseswere probably not sufficiently high to scavange the gener-ated oxygen-free radicals during PCI.24

The limitations of this study should be considered wheninterpreting the results. First, although this study is the thirdlargest randomized study dealing with pre-PCI statin ther-apy, we have to bear in mind that the small size of therandomized cohort (similarly to other studies in this field)and relatively low expected incidence of end points mightbe associated with statistical type II error. Second, clinicalrelevance of rosuvastatin pretreatment must be studied in along-term trial with clinical end points.

Acknowledgment: The authors are grateful to Eva Hans-venclová and Marek Malý, PhD, for their assistance withstatistical analysis.

Disclosures

The authors have no conflicts of interest to disclose.

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