EXPEDITED PUBLICATION
Novel Approaches for Preventing or Limiting Events (Naples) II TrialImpact of a Single High Loading Dose of Atorvastatin on Periprocedural Myocardial Infarction
Carlo Briguori, MD, PhD*, ,*,
Gabriella Visconti, MD*,
Amelia Focaccio, MD*,
Bruno Golia, MD*,
Alaide Chieffo, MD,
Alfredo Castelli, MD,
Marco Mussardo, MD,
Matteo Montorfano, MD,
Bruno Ricciardelli, MD* and
Antonio Colombo, MD
* Laboratory of Interventional Cardiology and Department of Cardiology, Clinica Mediterranea, Naples, Italy
Laboratory of Interventional Cardiology, "Vita e Salute" University School of Medicine, San Raffaele Scientific Institute, Milan, Italy. Dr. Colombo is a minor shareholder of Cappella Inc
Manuscript received May 18, 2009;
revised manuscript received June 25, 2009,
accepted July 1, 2009.
* Reprint requests and correspondence: Dr. Carlo Briguori, Interventional Cardiology, Clinica Mediterranea, Via Orazio, 2, I-80121, Naples, Italy (Email: carlobriguori{at}clinicamediterranea.it).
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Abstract
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Objectives: Atorvastatin administered at least 7 days before the percutaneous coronary intervention (PCI) reduces the rate of periprocedural myocardial infarction (MI). It is unknown whether a single, high (80 mg) loading dose of atorvastatin may reduce the rate of periprocedural MI.
Background: Periprocedural MI is a prognostically important complication of PCI.
Methods: Six hundred and sixty-eight statin-naive patients the day before the elective PCI were randomly assigned to atorvastatin 80 mg (atorvastatin group; n = 338) or no statin treatment (control group; n = 330). Creatine kinase myocardial isoenzyme (CK-MB) (upper limit of normal [ULN] 3.5 ng/ml) and cardiac troponin I (ULN 0.10 ng/ml) were assessed before and 6 and 12 h after the intervention. Periprocedural MI was defined as a CK-MB elevation >3x ULN alone or associated with chest pain or ST-segment or T-wave abnormalities.
Results: The incidence of a periprocedural MI was 9.5% in the atorvastatin group and 15.8% in the control group (odds ratio: 0.56; 95% confidence interval: 0.35 to 0.89; p = 0.014). Median CK-MB peak after PCI was 2.10 ng/ml (interquartile range 1.00 to 12.50 ng/ml) in the atorvastatin group and 3.20 ng/ml (interquartile range 1.37 to 16.07 ng/ml) in the control group (p = 0.014). The incidence of cardiac troponin I elevation >3x ULN was 26.6% in the atorvastatin group and 39.1% in the control group (odds ratio: 0.56; 95% confidence interval: 0.40 to 0.78; p < 0.001).
Conclusions: A single, high (80 mg) loading (within 24 h) dose of atorvastatin reduces the incidence of periprocedural MI in elective PCI.
Key Words: statin • angioplasty • stent • complication • myocardial infarction
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Abbreviations and Acronyms
| | CI = confidence interval | | CK-MB = creatine kinase-myocardial isoenzyme | | CRP = C-reactive protein | | cTnI = cardiac troponin I | | MI = myocardial infarction | | OR = odds ratio | | PCI = percutaneous coronary intervention | | ULN = upper limit of normal |
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An increase in cardiac biomarkers has been shown to occur in 5% to 30% of patients after otherwise successful percutaneous coronary interventions (PCIs) (1). This elevation of cardiac enzymes is indicative of cell death and, according to the new criteria, should be labeled as a myocardial infarction (MI) (1,2). At present, a creatine kinase-myocardial isoenzyme (CK-MB) elevation >3x normal has been recommended as a cutoff for periprocedural MI after PCI (1–3). It has been demonstrated that the risk of subsequent cardiac events (death or MI) is related to the extent of cardiac troponin or CK-MB increase (4,5).
Different strategies have been proposed and tested to prevent periprocedural MI (6–8). Compelling data suggest that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) may reduce the rate of periprocedural MI (9–12). The available data suggest that statin administration should be started at least 3 to 7 days before the procedure (9,10). This implies the need to postpone PCI in all statin-naive patients. Due to the fact that this beneficial effect of statins seems to be because of their "pleiotropic" effect, independent from cholesterol reduction (13–15), we hypothesized that a high (80 mg) loading dose of atorvastatin administered within 24 h before the procedure may be effective in reducing the rate of periprocedural MI. Therefore, we conducted a 2-center, prospective randomized study to assess whether a single, high (80 mg) loading (within 24 h) dose of atorvastatin is effective in preventing elevation of biomarkers of MI after elective coronary stent implantation.
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Methods
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Patient population.
From January 2005 to December 2008, 668 naive (i.e., not taking statin) patients scheduled for: 1) elective coronary angiography due to symptomatic coronary artery disease; or 2) PCI in de novo lesions in native coronary arteries were considered eligible for the study. The day before the procedure, all eligible patients were randomly assigned to atorvastatin treatment (atorvastatin group) or to no atorvastatin treatment (control group). Randomization was performed by a 1:1 ratio using computer-generated random numbers. To ensure that an almost equal number of patients received 1 of the 2 treatments, a randomization block of 4 was used (Plan Procedure of SAS, version 8.2, SAS Inc., Cary, North Carolina). The local ethics committee approved the study, and all patients gave written informed consent.
PCI 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 MI, need for bypass surgery or repeat PCI, or death). All patients received daily aspirin long-life (100 mg/day) and clopidogrel 300 mg the previous day followed by daily administration of 75 mg for at least 30 days after PCI in case of bare-metal stent implant or at least 6 months in case of drug-eluting stent implant. Patients randomized in the atorvastatin group started statin treatment (loading dose atorvastatin 80 mg) within 24 h before stent deployment. All patients received a 70-IU/kg intravenous bolus of unfractionated heparin. Additional heparin boluses were given to maintain activated clotting time >250 s. The activated clotting time was measured on the ACT PLUS Automated Coagulation Timer System (Medtronic Vascular Inc., Santa Rosa, California) 5 min after heparin administration.
Glycoprotein IIb/IIIa inhibitors were administered according to operator preference. The occurrence of angiographic complications during PCI was recorded. Angiographic complications included minor/major side branch compromise or occlusions, abrupt intraprocedural vessel closure, major arterial dissection, thrombus formation, transient and/or prolonged slow-no reflow, distal embolization, or coronary perforation.
Post-procedure management and follow-up.
Aspirin (325 mg/day) and clopidogrel (75 mg daily for 30 days) were prescribed to all patients. All patients were discharged on statins (atorvastatin 20 mg/day). CK-MB (mass concentration) and cardiac troponin I (cTnI) were assessed before, 6 and 12 h after PCI using a radioimmunoassay analyzer (Stratus CS-STAT Fluorometric Analyzer, Dade Behring Marburg GmbH, Marburg, Germany). Additional samples were obtained if the patient developed signs or symptoms of myocardial ischemia. CK-MB mass and cTnI upper limit of normal levels (ULN) were  3.5 ng/ml (range 0.6 to 3.5 ng/ml) and 0.10 ng/ml (range 0.00 to 0.10 ng/ml), respectively. Abnormal baseline CK-MB and/or cTnI levels were exclusion criteria for enrollment into the study. Plasma C-reactive protein (CRP) levels were assessed the day before the PCI by the RapiTex CRP (Dade Behring Marburg GmbH). This was a semiquantitative test. It is based upon the immunochemical reaction between CRP and antibodies to CRP bound to latex particles. Elevated CRP concentration (>6 mg/l) leads to visible agglutination of the latex particles.
Study end point.
The primary end point of the study was the rate of periprocedural MI, defined as a CK-MB elevation >3x ULN alone or associated with chest pain or ST-segment or T-wave abnormalities (new definition of MI), in the 2 study groups. The secondary end points were: 1) the rate of cTnI elevation >3x ULN; and 2) the composite of all the in-hospital events, including death, MI, and repeated revascularization.
Statistical analysis.
The sample size was selected to demonstrate a reduction in the primary end point from 15% in the control group to 8% in the atorvastatin group (9,10). Using a chi-square test for 2 x 2 tables and a 2-sided alpha of 0.05, 650 randomized patients afforded the study 80% power. Continuous variables are presented as mean ± 1 SD or as median and interquartile ranges, as appropriate. Differences between groups in normally and non-normally distributed variables were assessed using the unpaired Student t test and the Mann-Whitney U test, respectively. Categorical variables were analyzed by chi-square test. In order to test whether CRP at baseline may impact the effectiveness of atorvastatin treatment on periprocedural MI, we used an analysis of covariance (ANCOVA) model after transforming CK-MB levels into a natural logarithm (to overcome the problem of the non-normal distribution), putting the peak log-CK-MB as the dependent variable, treatment strategy (as defined by protocol randomization) as a fixed factor, baseline log-CK-MB as a covariate, and CRP levels as a random factor. Furthermore, we tested the interaction between atorvastatin therapy and the usage of glycoprotein IIb/IIIa inhibitors by the Cochran's Q test. All probability values were 2-tailed and a value of p < 0.05 was considered significant. Data were analyzed with SPSS for Windows version 13.0 (SPSS Inc., Chicago, Illinois).
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Results
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Clinical characteristics.
Between January 2005 and December 2008, 1,385 patients not taking statin (statin naive) and scheduled for elective coronary angiography or angioplasty in our institutions were recruited for this study and randomized into the 2 groups of treatment. Approximately one-half of these patients were eventually excluded due to lack of satisfaction of final inclusion criteria (i.e., PCI and stent implantation in a de novo lesion in a native coronary artery) (Fig. 1). Therefore, 668 patients were included in the final analysis: 338 in the atorvastatin group and 330 in the control group (Fig. 1). There were no significant differences in the most relevant clinical characteristics in the 2 groups (Table 1). Total cholesterol and low-density cholesterol levels at the time of the procedure were similar in the 2 groups (Table 2). At the time of the PCI, the rate of high levels of CRP was similar in the 2 groups (25.4% in the atorvastatin group versus 29.4% in the control group; p = 0.31). There were no instances of a significant increase in serum liver enzymes (alanine aminotransferase and aspartate aminotransferase levels >3x ULN) and/or myopathy in the atorvastatin group.
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Figure 1 Flow Chart of the Study
Diagram showing the flow of participants through each stage of the trial. CABG = coronary artery bypass grafting; ISR = in-stent restenosis; PCI = percutaneous coronary intervention.
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Angiographic and procedural characteristics.
Direct stenting was performed in 28.5% of cases in the atorvastatin group and in 30.3% in the control group (p = 0.51). Directional or rotational atherectomy was performed in 1.5% of the subjects in the atorvastatin group and in 2.1% of the subjects in the control group (p = 0.54). All the other angiographic and procedural characteristics were similar in the 2 groups (Table 3). Glycoprotein IIb/IIIa inhibitors were administered in 43 of 338 patients (12.7%) in the atorvastatin group and in 46 of 330 patients (13.6%) in the control group (p = 0.65). Angiographic complications during the procedure occurred in 16 patients (4.7%) in the atorvastatin group and in 22 patients (6.6%) in the control group (p = 0.61; odds ratio [OR]: 086; 95% confidence interval [CI]: 0.48 to 1.52) (Table 4).
Cardiac markers increase.
The incidence of a CK-MB elevation >3x ULN was 9.5% (32 of 338) in the atorvastatin group and 15.8% (52 of 330) in the control group (OR: 0.56; 95% CI: 0.35 to 0.89; p = 0.014) (Fig. 2A). The incidence of cTnI elevation >3x ULN was 26.6% (90 of 338) in the atorvastatin group and 39.1% (129 of 330) in the control group (OR: 0.56; 95% CI: 0.40 to 0.78; p < 0.001) (Fig. 3A). Additional data on the changes in cardiac enzymes after PCI in the 2 groups are reported in Table 5. A post hoc analysis suggests that the cardioprotective effect of atorvastatin was more pronounced in the subgroup of patients with high CRP levels at baseline (Figs. 2 and 3B). Indeed, there was a significant interaction between treatment strategy and CRP levels at baseline (F = 8.12, p = 0.004 by the ANCOVA model). On the contrary, no evidence of statistical interaction between atorvastatin therapy and usage of glycoprotein IIb/IIIa inhibitors was found at analytical testing (p = 0.62).
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Figure 2 CK-MB Increase in the 2 Treatment Groups
(A) Incidence of creatine kinase myocardial isoenzyme (CK-MB) increase >3x the upper limit of normal (ULN) in the atorvastatin group and in the control group. (B) Incidence of CK-MB increase >3x ULN in the subgroup of patients with normal and high C-reactive protein (CRP) in both the atorvastatin group and in the control group. CI = confidence interval; OR = odds ratio.
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Figure 3 Troponin I Increase in the 2 Treatment Groups
(A) Incidence of troponin I (TnI) increase >3x ULN in the atorvastatin group and in the control group. (B) Incidence of TnI increase >3x ULN in the subgroup of patients with normal and high CRP in both the atorvastatin group and in the control group. Abbreviations as in Figure 2.
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In-hospital major adverse cardiac events.
Acute stent thrombosis occurred in 2 cases in the atorvastatin group (0.58%) and in 1 case in the control group (0.30%) (p = 0.57). In-hospital death occurred in 1 case in the atorvastatin group, due to coronary perforation complicated by cardiac tamponade and Q-wave MI. No case of urgent in-hospital repeated revascularization was observed. The composite end point of all in-hospital events (death, MI, and repeated revascularization) occurred in 34 of 338 patients (10%) in the atorvastatin group versus 52 of 330 (15.7%) in the control group (p = 0.029; OR: 0.63; 95% CI: 0.39 to 0.95).
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Discussion
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This randomized study demonstrated that a single high (80 mg) loading dose of atorvastatin administered within 24 h before stenting is effective in reducing the rate of periprocedural MI. This result confirms previous observations demonstrating that statins prevent MI after coronary stent implantation. However, in the previous studies, statin administration was started at least 3 to 7 days before the procedure (9,10). The effectiveness of a single high (80 mg) loading dose of atorvastatin administered within 24 h before stenting extends our knowledge of the cardioprotective effect of statin, overturning the need to postpone PCI in all statin-naive patients undergoing an elective coronary procedures. Although the majority of patients undergoing an elective coronary procedure are on statin therapy, the proportion of statin-naive patients is not trivial. In our experience, during the recruitment time period of the present trial, statin-naive patients undergoing elective coronary procedures encompassed approximately 10% of the global population. This proportion was significantly higher (31%) in the recently presented ARMYDA-RECAPTURE (Atorvastatin for Reduction of Myocardial Damage during Angioplasty) trial (16).
The present study was not designed to clarify the potential mechanism(s) of the cardioprotective effect of the statins. Previous studies suggest the benefits of statins in reducing the rate of periprocedural MI should be mostly related to their nonlipid-related mechanisms (so-called "pleiotropic effects"). The pleiotropic effects encompass several mechanisms that modify inflammation responses, endothelial function, plaque stability, and thrombus formation (13–15,17–21). Notably, both the anti-inflammatory and the endothelial effects may occur immediately after a single dose of statin. Ostadal et al. (22), indeed, demonstrated that a single dose of cerivastatin at the time of admission of patients with unstable angina or non–ST-segment elevation MI positively influences the inflammatory parameters of CRP and interleukin-6 at 24 h. Romano et al. (23) observed that a 24-h treatment with lovastatin and simvastatin induces inhibition of monocyte chemotactic protein-1 synthesis in mononuclear and endothelial cells in vitro. The reduction of interleukin-6 mRNA and protein was described after 6 to 24 h of incubation of endothelial cells with pravastatin, simvastatin, and fluvastatin in vitro (24). Our observation that the beneficial effect seems to be much more prevalent in the subgroup of patients with baseline high CRP supports the concept that the anti-inflammatory properties have an important role. However, the immediate positive effect on endothelial function may represent a further mechanism. Statins indeed have beneficial effects on endothelial function by a rapid increase in nitric oxide bioavailability; this effect has been observed as early as 3 h after statin administration (25). Nitric oxide has been shown to act as a physiological inhibitor of leukocyte-endothelial cell interaction by suppressing up-regulation of several endothelial cell adhesion molecules, including P-selectin, vascular cell adhesion molecule-1, and intercellular adhesion molecule-1 (26). Statins attenuated neutrophil-endothelium interaction in the coronary microvasculature (27,28). Furthermore, a brief (10-min) exposure of the normo-cholesterolemic adult heart to atorvastatin, after a period of injurious ischemia, recruits the phosphatidyl inositol 3-kinase pathway, leading to cardioprotection (29).
Study limitations.
The study was not blinded. We can only speculate on the possible cardioprotective mechanisms of a single, high loading dose of atorvastatin. Indeed, we did not assess CRP at 24 to 48 h after atorvastatin administration, nor did we dose other inflammatory markers, such as interleukin-6 and monocyte chemotactic protein-1. Furthermore, we did not assess endothelial function either before or after atorvastatin administration. The use of IIb/IIIa inhibitors and beta-blockers was not randomized: this may have influenced our results. However, we did not find any interaction between atorvastatin administration and use of IIb/IIIa inhibitors. Finally, although not statistically different, the proportion of high-risk patients (i.e., chronic kidney disease) and the rate of angiographic complications was numerically higher in the control group.
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Conclusion
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This randomized study supports the cardioprotective effect of a single high (80 mg) loading dose of atorvastatin administered within 24 h before stent implantation.
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References
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Abstract
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