Statin administration before percutaneous coronary intervention: impact on periprocedural myocardial infarction
Carlo Briguoria,b,*,
Antonio Colombob,
Flavio Airoldib,
Anna Violantea,
Amelia Focaccioa,
Pasquale Balestrieria,
Pietro Paolo Eliaa,
Bruno Goliaa,
Stefano Leporea,
Guido Riviezzoa,
Pierfranco Scarpatoa,
Mariateresa Libreraa,
Erminio Bonizzonic and
Bruno Ricciardellia
a Laboratory of Interventional Cardiology and Department of Cardiology, Clinica Mediterranea, Via Orazio 2, I-80121 Naples, Italy
b Laboratory of Interventional Cardiology, "Vita e Salute" University School of Medicine, San Raffaele Hospital, Milan, Italy
c Institute of Medical Statistics and Biometry, University of Milan, Milan, Italy
Received March 11, 2004;
revised May 6, 2004;
accepted July 15, 2004
* Corresponding author. Tel.: +39 81 7259 764; fax: +39 81 7259 724 (E-mail: briguori.carlo{at}hsr.it).
 |
Abstract
|
---|
AIMS: Peri-procedural non-Q-wave myocardial infarction is a frequent and prognostically important complication of percutaneous coronary intervention (PCI). It has been postulated that statins may reduce the rate of myocardial injury after PCI.
METHODS AND RESULTS: Four hundred and fifty-one patients scheduled for elective PCI and not on statins were randomly assigned to either no treatment or to statin treatment. Statin administration was started at least 3 days before the procedure.Incidence of peri-procedural myocardial injury was assessed by analysis of creatinine kinase myocardial isoenzyme (CK-MB: upper limit of normal [ULN] 3.5 ng/ml) and cardiac troponin I (cTn I, ULN 0.10 ng/ml) before, 6 and 12 h after the intervention. A large non-Q-wave myocardial infarction was defined as a CK-MB elevation >5 times ULN alone or associated with chest pain or ST segment or T wave abnormalities.
Median CK-MB peak after PCI was 1.70 (interquartile ranges 1.103.70) ng/ml in the Statin group and 2.20 (1.305.60) ng/ml in the Control group (p=0.015). Median peak of cTnI after PCI was 0.13 (0.050.45) ng/ml in the Statin group and 0.21 (0.060.85) ng/ml in the Control group (p=0.033). The incidence of a large non-Q-wave myocardial infarction was 8.0% in the Statin group and 15.6% in the Control group (p=0.012: OR=0.47; 95% CI=0.260.86). The incidence of cTnI elevation >5 times ULN was 23.5% in the Statin group and 32% in the Control group (p=0.043: OR=0.65; 95% CI=0.420.98). By logistic regression analysis, the independent predictors of CK-MB elevation >5 times ULN after PCI were intra-procedural angiographic complications (OR=9.36; 95% CI=3.0628.64; p<0.001), statin pre-treatment (OR=0.33; 95% CI=0.130.86; p=0.023) and age >65 years (OR=2.58; 95% CI=1.096.11; p=0.031).
CONCLUSIONS: Pre-procedural statin therapy reduces the incidence of large non-Q-wave myocardial infarction after PCI.
 |
Introduction
|
---|
An increase of cardiac biomarkers has been shown to occur in 530% after otherwise successful percutaneous coronary interventions (PCI).13 This elevation of cardiac enzymes is indicative of cell death and, according to the new criteria, should be labelled as a myocardial infarction.4 It has been demonstrated that the risk of subsequent cardiac events (death or myocardial infarction) is related to the extent of cardiac troponin or creatinine kinase MB isoform (CK-MB) increase.3,513 Patients with CK-MB elevation >5 times normal had higher late mortality and more unfavourable event-free survival than those patients with a normal or lower CK-MB rise after PCI.68,12
Different strategies have been proposed and tested to prevent peri-procedural myocardial infarction.1417 Some clinical and experimental data suggest that 3-hydroxy-3-methylglutaryl co-enzyme A (HMG-CoA) reductase inhibitors (statins) may exert anti-thrombotic effects, independent of cholesterol reduction, by affecting the vessel wall as well platelet function.18,19 Hermann et al.20 reported an observational study suggesting that pre-procedural statin therapy was associated with a lower risk of CK-MB elevation after stent implantation.
Therefore, we designed a prospective randomized study to assess whether pre-procedural statin administration is effective in preventing elevation of biomarkers of myocardial injury after elective coronary stent implantation.
 |
Methods
|
---|
Patient population
From September 2002 to September 2003, patients not taking statins but scheduled for elective PCI in de novo lesions in native coronary arteries were randomly assigned to statin treatment (Statin group) or to no statin treatment (Control group). Randomization was performed by a 1:1 ratio using computer-generated random numbers. The local ethics committee approved the study, and all patients gave written informed consent.
Percutaneous coronary intervention procedure
Stents were implanted according to current clinical practice. Angiographic success was defined as a final angiographic residual stenosis of <20% by visual estimation. Procedural success was considered in cases of angiographic success and absence of any in-hospital major complication (acute myocardial infarction, need for bypass surgery or repeat PCI, or death). All patients received aspirin 325 mg and ticlopidine (250 mg bid) or clopidogrel (75 mg daily) starting ⩾3 days before stent deployment. Patients randomized in the Statin group started statin treatment ⩾3 days before stent deployment. The type and the dosage of the statin used was left to the physician discretion. All patients received 70 IU/kg intravenous bolus of unfractionated heparin. Additional heparin boluses were given to maintain activated clotting time >300 s. Glycoprotein IIb/IIIa inhibitors were administered according to operator preference. Angiographic measurements were performed with an automated computer-based system (QCA-CMS version 3.0, MEDIS, Leiden, The Netherlands).21 The occurrence of angiographic complications during PCI was recorded. Angiographic complications included: minor/major side branch compromise or occlusions; abrupt intra-procedural vessel closure; major or minor arterial dissection; thrombus formation; transient and/or prolonged slow-no reflow; distal embolisation.
Post-procedural management and follow-up
Aspirin (325 mg/day), and ticlopidine (250 mg bid for 30 days) or clopidogrel (75 mg daily for 30 days) were prescribed to all patients. All patients had a statin prescription after procedure. CK-MB (mass concentration) and cardiac troponin I (cTnI) were assessed before, 6 and 12 h after PCI using a radioimmunoassay analyser (Stratus CS STAT Fluorometric Analyzer; Dade Behring Marburg GmbH, Marburg,Germany). Additional samples were obtained if the patient developed signs or symptoms of myocardial ischaemia. CK-MB mass upper limit of normal levels (ULN) was ⩽3.5 (range 0.63.5) ng/ml. cTnI ULN was ⩽0.10 (range 0.000.10) ng/ml. Abnormal baseline CK-MB and/or cTnI levels was an exclusion criteria for enrolment into the study. Plasma C-reactive protein (CRP) levels were assessed the day before the PCI by the RapiTex CRP (Dade Behring Marburg GmbH, Marburg,Germany). This is a semi-quantitative test. It is based upon immunochemical reaction between CRP and antibodies to CRP bound to latex particles. Elevated CRP concentration (>6 mg/l) lead to visible agglutination of the latex particles.
Study endpoint
The endpoint for the study was the rate of a large non-Q-wave myocardial infarction, defined as a CK-MB elevation >5 times ULN alone or associated with chest pain or ST segment or T wave abnormalities,6,7,12,13 in the two study groups.
Statistical analysis
The sample size was selected to demonstrate a reduction in the primary endpoint from a 12% in the Control group6,7 to 6% in the Statin group. Using a
2 test for 2x2 tables and a two-sided α of 0.05, 390 randomized patients afforded the study 80% power. Recruitment of approximately 450 patients was thus planned to accommodate incomplete data ascertainment or follow-up. Continuous variables are presented as means±1 standard deviation and, respectively, or as median and interquartile ranges, as appropriate. Differences between groups in normally and non-normally distributed variables were assessed using the unpaired Student's t test and the MannWhitney U test, respectively. Categorical variables were analysed by the
2 test. A multivariable logistic regression model was constructed to identify independent predictors for CK-MB elevation >5 times ULN after the PCI. The following variables, selected according to the literature data69,14,17,20,23 and the study hypothesis, were inserted into the logistic regression analysis: statin pre-treatment, intra-procedural angiographic complications, glycoprotein IIb/IIIa inhibitors administration, age, unstable angina, complex lesion, multi-vessel stenting, high CRP level and β-blockers. The HosmerLemeshow goodness of fit index was used for assessing overall model fit. All probability values were two-tailed and p<0.05 was considered significant. Data were analysed with SPSS for Windows, release 10.0 (SPSS Inc., Chicago, IL).
 |
Results
|
---|
Clinical characteristics
Four hundred and fifty-one patients were enrolled into the study: 226 in the Statin group and 225 in the Control group. Statin treatment was started 17±8 (range 331) days prior to the index procedure. The majority (84%) of patients had a statin treatment ⩾2 weeks before PCI. The type and the dosage of the statin used was as follows: (1) atorvastatin 29% of cases (mean dose=22±9 mg/day); (2) pravastatin, 29% of cases (mean dose=32±10 mg/day); (3) simvastatin, 39% of cases (mean dose=24±9 mg/day); and (4) fluvastatin, 3% of cases (80 mg/day). There was no significant difference in the most relevant clinical characteristics in the two groups (Table 1). Total cholesterol and low-density cholesterol levels at the time of the procedure were significantly lower in the Statin group than the Control group (Table 2). At the time of the PCI, high levels of CRP occurred more frequently in the Control group that in the Statin group (27% vs. 13.8%, p=0.007). There were no instances of significant increase in serum liver enzymes (alanine aminotransferase and aspartate aminotransferase levels >3 times ULN) and/or myopathy in the Statin group.
Angiographic and procedural characteristics
Direct stenting was performed in 89% of cases in the Statin group and in 85% in the Control group (p=0.56). In no cases were atherectomy (either directional or rotational) performed. All the other angiographic and procedural characteristics were similar in the two groups (Table 3). Glycoprotein IIb/IIIa inhibitors were electively administered in the 46% of patients in the Statin group and 54% of patients in the Control group (p=0.09). Elective glycoprotein IIb/IIIa inhibitors administration was more frequent in the case of complex, rather than non-complex, lesions (70% vs. 40%; p<0.001). Rescue glycoprotein IIb/IIIa inhibitor administration occurred in 9 patients with angiographic complications (six patients in the Statin group and three in the Control group; p=0.50) (see Table 3).
Angiographic success was reached in 99.6% of cases in both groups. Angiographic complications during the procedure occurred in 20 patients (9%) in the Statin group and 11 patients (5.0%) in the Control group (p=0.13%, see Table 4).
In-hospital MACE
Acute stent thrombosis occurred in two cases, one in each group. No case of death, Q-wave myocardial infarction and/or cardiac bypass surgery occurred.
Predictors of cardiac markers increase
Median peak of CK-MB was 2.20 (1.305.60) ng/ml in the Control group and 1.70 (1.103.70) ng/ml in the Statin group (p=0.015). CK-MB elevation >3 times ULN occurred in 31 (13.7%) patients in the Statin group and 37 (16.4%) in the Control group (p=0.41). CK-MB elevation >5 times ULN occurred in 18 (8%) patients in the Statin group and 35 (15.6%) in the Control group (p=0.012: OR=0.47; 95% CI=0.260.86; Fig. 1(a)). Length of statin therapy was not statistically different in patients with and without cardiac enzymes elevation (16±5 days in patients with CK-MB elevation >5 times ULN vs. 17±6 days in patients without CK-MB elevation >5 times ULN; p=0.62). Rate of CK-MB elevation >5 times ULN, according to the type of statin used, was as follows: (1) atorvastatin 6% of cases; (2) pravastatin 6.2% of cases; (3) simvastatin 10% of cases; and (4) fluvastatin 0% of cases (p=0.53). Median peak of cTnI was 0.21 (0.060.85) ng/ml in the Control group and 0.13 (0.050.45) ng/ml in the Statin group (p=0.039). Post-procedural elevations of cTnI >0.10 ng/ml (ULN) occurred in 59% of patients in the Statin groups and 63% in the Control group (p=0.32). cTnI elevation >5 times ULN occurred in 53 (23.5%) patients in the Statin group and in 72 (32%) in the Control group (p=0.043; OR=0.65; 95% CI 0.420.98; Fig. 1(b)).

View larger version (10K):
[in this window]
[in a new window]
|
Fig. 1 (a) Incidence of CK-MB increase >5 times upper limit of normal (ULN) in the Statin and Control groups. (b) Incidence of cTnI increase >5 times ULN in the Statin and Control groups.
|
|
The influence of clinical, angiographic, and procedural variables on CK-MB elevation >5 times ULN after stenting was evaluated with a multivariable logistic regression analysis. The HosmerLemeshow goodness of fit index was 0.40. As reported in Table 5, the independent predictors of CK-MB elevation >5 times ULN after PCI were angiographic complications (OR=9.36; 95% CI=3.0628.64; p<0.001), statin pre-treatment (OR=0.33; 95% CI=0.130.86; p=0.023) and age >65 years (OR=2.58; 95% CI=1.096.11; p=0.031).
 |
Discussion
|
---|
This randomized study confirms the cardioprotective effects of statin pre-treatment in patients undergoing elective stent implantation.20,22,23 The incidence of large periprocedural non-Q-wave myocardial infarction (i.e., CK-MB elevation >5 times ULN) was significantly lower in patients pre-treated with statins. It has been demonstrated that periprocedural myocardial injury is associated with a worse long-term clinical outcome.13,513 As in experimental studies, statin pre-treatment resulted in a substantial reduction in the extent rather than in the overall incidence of peri-procedural myocardial infarction. Hermann et al.,20 recently reported a non-randomized, observational study supporting the cardioprotective effect of statins in PCI. Relative to control patients, the incidence of CK-MB elevation >3 times ULN was more than 90% lower in statin-treated patients. In our randomized study, the incidence of CK-MB elevation >5 times ULN was approximately 50% lower in the statin treated-patients. Additionally, also the CK-MB peak after stenting was significantly lower in the Statin group than in the Control group.
The results of the present study support what was previously reported by Chan et al.,22,23 who demonstrated in two observational, non-randomized studies, that statin therapy is an independent predictor of survival benefit after PCI. The benefits of statins in cardiovascular diseases can be explained not only by their lipid-lowering potential but also by non-lipid-related mechanisms (so-called "pleiotropic effects"). The pleiotropic effects encompass non-lipid mechanisms that modify endothelial function, inflammation responses, plaque stability and thrombus formation.18,19
Inflammation status
Chan et al.23 reported that statin pre-treatment is an independent predictor of survival after PCI predominantly among patients with a high CRP level. We found that the positive effect of statin pre-treatment on cardiac enzymes elevation after stent implantation was independent of the pre-procedural CRP level. In our study, we address the prevention of large non-Q-wave myocardial infarction, while in the study by Chan et al., new de novo events are likely to be prevented. This suggests that the protective effect is probably different and that the antiinflammatory effect of statins may have a minor role in their cardioprotective activity during stent implantation.
Plaque stabilization
Statin therapy induces important changes in the plaque composition reducing inflammatory activity and favouring a reduction in the relative content of cholesterol esters that are important factors influencing plaque stability.18,19 Lowering blood low-density lipoprotein cholesterol (LDL-C) levels may facilitate plaque stability either through a reduction in size24 or by an alteration of the physiochemical properties of lipid cores.25
Platelet aggregation and thrombus formation
Following plaque disruption statins influence thrombosis through variable inhibitory actions on platelet deposition and aggregation, coagulation factors, rheology and fibrinolysis.18,19 Statins reduce platelet aggregation and thromboxane production.2628 Statins may reduce platelet aggregation by changing the cholesterol content of platelet membrane thus altering membrane fluidity.2931 Experimental and clinical studies have indicated a relationship between hyperlipidaemic status and high blood thrombogenicity.18 Statins diminish pro-coagulant activity observed at different stages of the coagulation cascade including tissue factor activity, conversion of prothrombin to thrombin and thrombin activity.18,19 Statins stimulate fibrinolysis by altering the levels and activities of tissue-plasminogen activator and plasminogen activator inhibitor-1.32
Role of other independent predictors of CK-MB increase
Angiographic complications occurring during the procedure16 and age22,23 are independent predictors of non-Q-wave periprocedural myocardial infarction. According to Ellis et al.,33 we did not find any independent effect of glycoprotein IIb/IIIa inhibitors administration and β-blockers therapy on CK-MB elevation >5 times ULN. The apparent deleterious effect of glycoprotein IIb/IIIa inhibitor administration observed in the present study may be explained by the fact that these drugs were used at the discretion of the operator and in general more frequently when treating complex, rather than non-complex, lesions and as a rescue strategy in case of angiographic complications.
Study limitations
The study was not blinded. Since the non-lipid properties of statins differ despite comparable LDL-cholesterol lowering the net clinical efficacy of these agents requires validation by randomized clinical trials. Furthermore, optimal statin dose and time of onset before stent implantation were not identified. Use of glycoprotein IIb/IIIa inhibitors and β-blockers was not randomized: this may have influenced our negative results. Multivariable analysis with multiple testing could have inflated the risk of type I error.
 |
Conclusions
|
---|
This randomized study supports the effectiveness of statin pre-treatment on limiting the rate of peri-procedural myocardial injury following stent implantation.
 |
References
|
---|
- Califf RM, Abdelmeguid AE, Kunitz RE, et al. Myonecrosis after revascularization procedures J Am Coll Cardiol 1998;31:241-251.[Medline]
- Klein LW, Kramer BL, Howard E, et al. Incidence and clinical significance of transient creatine kinase elevations and the diagnosis of non-Q wave myocadial infarction associated with coronary angioplasty J Am Coll Cardiol 1991;17:321-326.
- Abdelemeguid AE, Topol EJ, Whitlow PL, et al. Significance of mild transient release of creatine kinase-MB fraction after percutaneous coronary interventions Circulation 1996;94:1528-1536.[Abstract/Free Full Text]
- The Joint European Society of Cardiology/American College of Cardiology Committee. Myocardial infarction redefined A consensus document of the Joint European Society of Cardiology/American College of Cardiology Committee for the Redefinition of Myocardial infarction. J Am Coll Cardiol 2000;36:95969.
- Kong TQ, Davidson CJ, Meyers SN, et al. Prognostic implications of creatinine kinase elevation following elective coronary artery interventions JAMA 1997;277:461-466.[Abstract]
- Stone GW, Mehran R, Dangas G, et al. Differential impact on survival of electrocardiographic Q-wave versus enzymatic myocardial infarction after percutaneous intervention. A device-specific analysis of 7147 patients Circulation 2001;104:642-647.[Abstract/Free Full Text]
- Saucedo JF, Mehran R, Dangas G, et al. Long-term clinical events following creatine kinase-myocardial band isoenzyme elevation after successful coronary stenting J Am Coll Cardiol 2000;35:1134-1141.[CrossRef][Medline]
- Kini A, Marmur JD, Kini S, et al. Creatine kinase-MB elevation after coronary intervention correlates with diffuse atherosclerosis, and low-to-medium level elevation has a benign clinical course J Am Coll Cardiol 1999;34:663-671.[CrossRef][Medline]
- Ellis SG, Chew D, Chan A, et al. Death following creatine kinase-MB elevation after coronary intervention. Identification of an early risk period: importance of creatine kinase-MB level, completeness of revascularization, ventricular function, and probable benefit of statin therapy Circulation 2002;106:1205-1210.[Abstract/Free Full Text]
- Ricciardi MJ, Davidson CJ, Gubernikoff G, et al. Troponin I elevation and cardiac events after percutaneous coronary intervention Am Heart J 2003;145:522-528.[CrossRef][Medline]
- Herrmann J, von Birgelen C, Haude M, et al. Prognostic implication of cardiac troponin T increase following stent implantation Heart 2002;87:549-553.[Abstract/Free Full Text]
- Kugelmass AD, Cohen CJ, Moscucci M, et al. Elevation of creatine kinase myocardial isoform following otherwise successful direction coronary atherectomy and stenting Am J Cardiol 1994;74:748-754.[Medline]
- Topol EJ, Leya F, Pinkerton CA, et al. A comparison of direction atherectomy with coronary angioplasty in patients with coronary disease N Engl J Med 1993;329:221-227.[Abstract/Free Full Text]
- Blankenship JC, Tasissa G, O'Shea C, et al. Effect of glycoprotein IIb/IIIa receptor inhibition on angiographic complications during percutaneous coronary intervention in the ESPRIT trial J Am Coll Cardiol 2001;38:653-658.[CrossRef][Medline]
- EPISTENT Investigators. Randomized controlled trial to assess safety of coronary stenting with use of abciximab. Lancet 1998;352:8590.
- Steinhubl SR, Lauer MS, Mukherjer DP, et al. The duration of pretreatment with ticlopidine prior to stenting is associated with the risk of procedure-related non-Q-wave myocardial infarction J Am Coll Cardiol 1998;32:1366-1370.[CrossRef][Medline]
- Sharma SK, Kini A, Marmur JD, et al. Cardioprotective effect of prior β-blocker therapy in reducing creatine kinase-MB elevation after coronary intervention: benefit is extended to improvement in intermediate-term survival Circulation 2000;102:166-172.[Abstract/Free Full Text]
- Sposito AC, Chapman J. Statin therapy in acute coronary syndromes. Mechanisms insight into clinical benefit Arterioscler Thromb Vasc Biol 2002;22:1524-1534.[Abstract/Free Full Text]
- Rosenson RS, Tangney CC. Antiatherothrombotic properties of statins. Implications for cardiovascular event reduction JAMA 1998;279:1643-1650.[Abstract/Free Full Text]
- Hermann J, Leramn A, Baumgart D, et al. Preprocedural statin medication reduces the extent of periprocerural non-Q wave myocardial infarction Circulation 2002;106:2180-2183.[Abstract/Free Full Text]
- Reiber JHC, Serruys PW. Progress in quantitative coronary arteriographyDordrecht: Kluwer; 1994.
- 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]
- Chan AW, Bhatt DL, Chew DP, et al. Relation of inflammation and benefit of statins after percutaneous coronary interventions Circulation 2003;107:1750-1756.[Abstract/Free Full Text]
- Shiomi M, Ito, Tsukada T, et al. Reduction of serum cholesterol levels alters lesional composition of atherosclerotic plaques: effect of pravastatin sodium on atherosclerosis in mature WHHL rabbits Atherioscler Thromb Vasc Biol 1995;15:1938-1944.[Abstract/Free Full Text]
- Williams JK, Sukhora GK, Herrington DM, et al. Pravastatin has cholesterol lowering independent effects on the artery wall of atherosclerosis monkeys J Am Coll Cardiol 1998;31:684-691.[CrossRef][Medline]
- Notarbartolo A, Davi G, Averna M, et al. Inhibition of tromboxane biosynthesis and platelet function by simvastatin in type IIa hypercholesterolemia Arterioscler Thromb Vasc Biol 1995;15:247-251.[Abstract/Free Full Text]
- Le Quan Sang KH, Levenson J, Megnien JL, et al. Platelet cytosolic Ca2+ and membrane dynamics in patients with primary hypercholesterolemia: effect of pravastatin Arterioscler Thromb Vasc Biol 1995;15:759-764.[Abstract/Free Full Text]
- Dangas G, Smith DA, Hung AH, et al. Pravastatin: an antithrombotic effect independent of the cholesterol-lowering effect Thromb Haemost 2000;83:688-692.[Medline]
- Carvalho AC, Colman RW, Less RS. Platelet function in hyperlipoproteinemia N Engl J Med 1974;290:434-438.[Medline]
- Badimon JJ, Badimon L, Turitto VT, et al. Platelet deposition at high shear rates is enhanced by high plasma cholesterol levels: in vivo study in the rabbit model Arterioscler Thromb Vasc Biol 1991;11:395-402.[Abstract]
- Osamah H, Mira R, Sorina S, et al. Reduced platelet aggregation after fluvastatin therapy is associated with altered platelet lipid composition and drug binding to the platelets Br J Clin Plarmacol 1997;44:77-84.[CrossRef]
- Bourcier T, Libby P. HMG-CoA reductase inhibitors reduce plasminogen activator inhibitor-1 expression by human vascular smooth muscle and endothelial cells Arterioscler Thromb Vasc Biol 2000;20:556-562.[Abstract/Free Full Text]
- Ellis SG, Brener SJ, Lincoff M, et al. β-Blockers before percutaneous coronary intervention do not attenuate post-procedural creatine-kinase isoenzyme rise Circulation 2001;104:2685-2688.[Abstract/Free Full Text]