Author + information
- Received November 4, 2009
- Accepted November 13, 2009
- Published online March 1, 2010.
- Jung-Sun Kim, MD, PhD⁎,
- Jaedeok Kim, MD⁎,
- Donghoon Choi, MD, PhD⁎,⁎ (, )
- Chan Joo Lee, MD⁎,
- Sang Hak Lee, MD, PhD⁎,
- Young-Guk Ko, MD⁎,
- Myeong-Ki Hong, MD, PhD⁎,
- Byoung-Keuk Kim, MD, PhD†,
- Seong Jin Oh, MD†,
- Dong Woon Jeon, MD†,
- Joo-Young Yang, MD, PhD†,
- Jung Rae Cho, MD‡,
- Nam-Ho Lee, MD, PhD‡,
- Yun-Hyeong Cho, MD§,
- Deok-Kyu Cho, MD§ and
- Yangsoo Jang, MD, PhD⁎
- ↵⁎Reprint requests and correspondence
: Dr. Donghoon Choi, Division of Cardiology, Yonsei Cardiovascular Center, Yonsei University College of Medicine, Seongsan-ro, Seodaemun-gu, 120-752 Seoul, South Korea
Objectives This study sought to determine the efficacy of high-dose atorvastatin in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI).
Background Previous randomized trials have demonstrated that statin pre-treatment reduced major adverse cardiac events (MACEs) in patients with stable angina pectoris and acute coronary syndrome. However, no randomized studies have been carried out with STEMI patients in a primary PCI setting.
Methods A total 171 patients with STEMI were randomized to 80-mg atorvastatin (n = 86) or 10-mg atorvastatin (n = 85) arms for pre-treatment before PCI. All patients were prescribed clopidogrel (600 mg) before PCI. After PCI, both groups were treated with atorvastatin (10 mg). The primary end point was 30-day incidence of MACE including death, nonfatal MI, and target vessel revascularization. Secondary end points included corrected thrombolysis in myocardial infarction frame count, myocardial blush grade, and ST-segment resolution at 90 min after PCI.
Results MACE occurred in 5 (5.8%) and 9 (10.6%) patients in the 80-mg and 10-mg atorvastatin pre-treatment arms, respectively (p = 0.26). Corrected thrombolysis in myocardial infarction frame count was lower in the 80-mg atorvastatin arm (26.9 ± 12.3 vs. 34.1 ± 19.0, p = 0.01). Myocardial blush grade and ST-segment resolution were also higher in the 80-mg atorvastatin arm (2.2 ± 0.8 vs. 1.9 ± 0.8, p = 0.02 and 61.8 ± 26.2 vs. 50.6 ± 25.8%, p = 0.01).
Conclusions High-dose atorvastatin pre-treatment before PCI did not show a significant reduction of MACEs compared with low-dose atorvastatin but did show improved immediate coronary flow after primary PCI. High-dose atorvastatin may produce an optimal result for STEMI patients undergoing PCI by improving microvascular myocardial perfusion. (Efficacy of High-Dose AtorvaSTATIN Loading Before Primary Percutaneous Coronary Intervention in ST-Elevation Myocardial Infarction [STATIN STEMI]; NCT00808717).
Periprocedural myocardial injury during percutaneous coronary intervention (PCI) is associated with future adverse cardiac events (1,2). Previous clinical studies have shown that statin pre-treatment before PCI may improve clinical outcomes by reducing periprocedural myocardial infarctions in patients with stable angina pectoris or acute coronary syndrome (ACS) (3–5). Furthermore, a recent study demonstrated that reloading with high-dose statin produced an additional reduction of cardiovascular events after PCI, even in patients on chronic statin therapy (6).
However, little data exists to support statin pre-treatment before primary PCI in patients with ST-segment elevation myocardial infarction (STEMI). Several observational studies on patients with STEMI have suggested that previous statin use may improve coronary blood flow, based on Thrombolysis In Myocardial Infarction (TIMI) frame count after PCI, and is associated with reduced short-term (30-day) mortality (7,8). However, the beneficial effects of chronic statin pre-treatment has limitation in its applicability due to the unexpected nature of the onset of acute STEMI, whereas the acute effects of high-dose statin (i.e., improvement of clinical outcomes as well as coronary perfusion) may be more clinically relevant in the emergent setting in STEMI. Therefore, we conducted a prospective randomized trial to determine the efficacy of high-dose statin immediately before primary PCI in patients with STEMI.
The STATIN STEMI (Efficacy of High-Dose AtorvaSTATIN Loading Before Primary Percutaneous Coronary Intervention in ST-Elevation Myocardial Infarction) trial is a multicenter, randomized, prospective clinical trial conducted at 4 Korean institutions: Severance Hospital, Yonsei University of Seoul; National Health Insurance Corporation (NHIC) Ilsan Hospital of Koyang; Kangnam Sacred Heart Hospital of Seoul; and Myongji Hospital of Goyang (Fig. 1). Inclusion criteria were the presence of symptoms (<12 h) and ST-segment elevation of at least 0.1 mV in 2 contiguous leads of electrocardiogram (ECG) or new onset left bundle branch block and patient age 18 to 80 years. Exclusion criteria were previous (within 3 months) or current treatment with statins; known allergy to heparin, aspirin, clopidogrel, or abciximab; active severe bleeding; pregnancy; history of major surgery or trauma; significant gastrointestinal or genitourinary bleeding (<6 weeks); history of cerebrovascular attack (within 2 years) or cerebrovascular attack with a significant residual neurological deficit; and cardiogenic shock with mechanical ventilation. The study protocol was approved by the Institutional Review Board of Yonsei University College of Medicine, and written consent was obtained from all patients.
A total of 408 STEMI patients were admitted between March 2007 and December 2008 (Severance Hospital, n = 167; NHIC Ilsan Hospital, n = 92; Kangnam Sacred Heart Hospital, n = 89; and Myongji Hospital, n = 60). Of the 408 patients, 159 patients were excluded due to previous (within 3 months) or current treatment with statins, 10 patients died in the emergency room (ER), 20 patients had cardiogenic shock upon ER admission, 30 patients were older than 80 years, and 10 patients refused to participate in the study. Eligible patients (n = 179) were randomized to receive 80 or 10 mg of atorvastatin in the ER. Patients were assigned in a 1:1 ratio with a computer-generated randomization sequence; randomization blocks were created and distributed to the 4 centers. After coronary angiography, an additional 8 patients (4 patients in each randomization arm) who did not receive angioplasty were excluded from the study (6 patients were treated medically because of vasospasm and 2 patients received bypass surgery). The remaining 171 patients (80-mg atorvastatin arm, n = 86; 10-mg atorvastatin arm, n = 85) were enrolled in the study.
Study protocol and procedure
Physicians performing the procedure and the follow-up assessments were blinded to the randomization assignment. The patients were pre-treated at the ER before primary PCI with chewable aspirin (200 mg) and clopidogrel (600-mg loading dose). Before intervention, patients received weight-adjusted intravenous heparin with a target-activated clotting time of >300 s in the absence of glycoprotein IIb/IIIa inhibitor therapy and 200 to 300 s with glycoprotein IIb/IIIa. Glycoprotein IIb/IIIa inhibitors were used during the procedure at the operator's discretion. All PCIs were performed using standard technique (4). Procedural success was defined as reduced coronary artery stenosis to <30% residual narrowing and TIMI flow grade 3. After PCI, aspirin (100 mg/day) was continued indefinitely, and clopidogrel (75 mg/day) was administered for at least 6 months. After intervention, all patients were treated with the usual maintenance dose of atorvastatin (10 mg/day in Korea), irrespective of the initial randomization assignment.
Angiographic and electrocardiographic analysis
Pre- and post-PCI angiograms were reviewed in the angiographic core laboratory (Cardiovascular Research Center, Seoul, Korea). The TIMI flow grade before and after PCI, corrected TIMI frame count (cTFC), and myocardial blush grade (MBG) were analyzed by 2 experienced observers who were blinded to group randomization as described previously (9–11). The ECGs before and 90 min after primary PCI were transferred to core laboratory for analysis, which was performed by 2 experienced physicians who were blinded to group randomization. Resolution of ST-segment resolution (STR) was calculated as the sum of ST-segment elevation on initial ECG minus the sum of ST-segment elevation on the ECG at 90 min after PCI, divided by the sum of ST-segment elevation on initial ECG, and was expressed as a percentage (12). The complete early STR was defined as ≥70% STR.
Cardiac enzyme assay
In all patients, blood samples were collected as possible before and at 8, 12, 24, 48, and 72 h after PCI to determine creatine kinase-myocardial band (CK-MB) isoenzyme elevation; further measurements were performed in cases of post-procedural symptoms suggestive of myocardial ischemia. Normal limits of CK-MB and troponin T were defined as ≤5 ng/ml and <0.1 μg/l, respectively. The high sensitivity C-reactive protein was evaluated at 24 h after primary PCI.
The primary end point of the STATIN STEMI study was the occurrence of major adverse cardiac events (MACEs): death, nonfatal MI (including periprocedural MI), and target vessel revascularization within 30 days after PCI. Reinfarction within 24 h of primary PCI was defined as a re-elevation of CK-MB by at least 33% or 100% from the preceding nadir (which was ≥2 or <2 times normal, respectively) and reaching at least >3 times the normal value, in association with ischemic symptoms. After 24 h, reinfarction was defined as new pathological Q waves or re-elevation of CK-MB to >3 times the normal value (24 h to discharge) or >2 times the normal value (after hospital discharge) (13). Target vessel revascularization included unexpected and ischemia-driven bypass surgery or repeat PCI of the target vessels. Secondary end points of the study were: cTFC, MBG, and STR at 90 min after PCI.
A 9-month clinical follow-up was performed for all patients to evaluate MACEs (death, nonfatal MI, and target vessel revascularization). Incidence of stent thrombosis was also assessed according to Academic Research Consortium criteria (14).
Sample size calculation and statistical analysis
Calculation of sample size was based on a 2-sample and 2-sided test. We assumed the incidence of MACEs (death, nonfatal MI including periprocedural MI, and target vessel revascularization) might be similar between patients with ACS and patients with STEMI. Therefore, we calculated a sample size by analogy with the ARMYDA-ACS (Atorvastatin for Reduction of MYocardial Damage During Angioplasty—Acute Coronary Syndromes) study. The difference of MACE-free survival between treatment arms at 1 month was 14.0%, which was also seen in the ARMYDA-ACS study; MACE-free survival in the ARMYDA-ACS study was 95.0% for high-dose (80-mg) atorvastatin arm versus 81.0% for conventional dose (10-mg) arm. Using a 2-sided alpha level of 0.05 and statistical power of 80%, we estimated the need for 78 patients in high-dose atorvastatin arm and 78 patients in control arm, or a total of 170 patients after estimating 10% lost to follow-up.
Continuous variables were expressed as mean ± SD. Comparisons of categorical variables were made using the chi-square test and Fisher exact test, as indicated. Student t test was used to compare continuous variables for normally distributed values; otherwise the Mann-Whitney U test was used. Event-free survival analysis was analyzed by the Kaplan-Meier method with log-rank test group comparison. Interobserver and intraobserver variability in cTFC, MBG, and STR values were assessed with 20 randomly selected cases evaluated by 2 independent readers and by the same reader at 2 separate time points. Measurement variations were calculated using a linear mixed model that accounts for correlations between measurements obtained from the same patient. All analyses were performed using the Statistical Analysis System software (SAS version 9.1.3, SAS Institute, Cary, North Carolina). A p value <0.05 was considered statistically significant.
Baseline demographic and clinical characteristics are displayed in Table 1. Mean age was 60.3 ± 11.4 years and 77.2% of the patients were men. Demographic characteristics did not differ significantly between the 2 groups. Mean left ventricular ejection fraction was 47% in all patients and did not differ between the 2 groups. The pain-to-balloon time and door-to-balloon time were also not different between the 2 groups (231 ± 167 min vs. 241 ± 158 min, p = 0.56 and 76 ± 44 min vs. 77 ± 39 min, p = 0.40, respectively).
Angiographic and periprocedural findings
Angiographic findings and procedures are displayed in Tables 2 and 3.⇓⇓ TIMI flow grade 0 before PCI was observed in 86 patients (50.6%; 80-mg atorvastatin, n = 41 (48.2%); 10-mg atorvastatin, n = 45 (52.9%); p = 0.66) and intracoronary thrombi was observed in 113 patients (66.1%; 80-mg atorvastatin, n = 56 (65.1%); 10-mg atorvastatin, n = 57 (67.1%); p = 0.87). The periprocedural use of glycoprotein IIb/IIIa inhibitor and intra-aortic balloon pump occurred in 25 cases (14.6%) and 37 patients (21.8%), respectively, with little difference between the 2 groups. The proportion of patients taking medications after PCI was also similar between the 2 groups. Procedural success was obtained in 156 patients (91.2%); 23 patients (80-mg atorvastatin, n = 8; 10-mg atorvastatin, n = 15) showed no-reflow phenomenon after stent implantation and 15 patients (80-mg atorvastatin, n = 3; 10-mg atorvastatin, n = 2) fell short of recovering TIMI flow grade 3 after infusion of glycoprotein IIb/IIIa inhibitor, nitrate, and nicorandil. Among 171 patients, 169 patients (98.8%) were treated with stents; drug-eluting stents were used in 152 cases (88.9%). Mean number of stents per patient was 1.3; mean stent diameter and lengths were 3.1 ± 0.4 and 31.0 ± 11.6 mm, respectively, which were not significantly different between the 2 groups.
Primary end point
The primary end point was evaluated 30 days after primary PCI (Table 4). The composite primary end point of death, MI including periprocedural MI, and target vessel revascularization occurred in 5 patients (5.8%) in the 80-mg atorvastatin arm and 9 patients (10.6%) in the 10-mg atorvastatin arm (p = 0.26); no significant difference was found between groups in overall or individual cardiac events. Four patients died within 30 days after PCI and all 3 cardiovascular event-related deaths occurred in the 10-mg atorvastatin arm. Periprocedural MI occurred in 8 patients (80-mg atorvastatin, n = 3 (3.5%); 10-mg atorvastatin, n = 5 (5.9%); p = 0.50).
Secondary end points
The secondary end points are displayed in Table 3. We found that cTFC was lower in the 80-mg atorvastatin arm (26.9 ± 12.3 vs. 34.1 ± 19.0, p = 0.01), and MBG and STR at 90 min after primary PCI were higher in the 80-mg atorvastatin arm (MBG: 2.2 ± 0.8 vs. 1.9 ± 0.8, p = 0.02; STR: 61.8 ± 26.2 vs. 50.6 ± 25, p = 0.01). In addition, complete STR (≥70% STR at 90 min) was also higher in the 80-mg atorvastatin arm (34 patients [39.5%] vs. 19 patients [23.8%]; p = 0.03).
Interobserver and intraobserver coefficients of variation assessed in 20 randomly chosen cases were 0.89 (95% confidence interval [CI]: 0.74 to 0.96) and 0.86 (95% CI: 0.68 to 0.95) for cTFC, 0.84 (95% CI: 0.63 to 0.94) and 0.80 (95% CI: 0.71 to 0.96) for MBG, and 0.98 (95% CI: 0.94 to 0.99) and 0.95 (95% CI: 0.89 to 0.98) for STR, respectively.
Peak CK-MB level did not differ between groups (239 ± 162 vs. 239 ± 227; p = 0.99). As for the high sensitivity C-reactive protein level at 24 h, which was somewhat lower in the 80-mg atorvastatin arm (4.1 ± 8.0 vs. 7.5 ± 22.8; p = 0.10).
Kaplan-Meier survival curve analysis demonstrated no significant difference in MACE-free survival at 9 months between the 2 groups (Fig. 2). Definite stent thrombosis was observed in 1 patient in the 10-mg atorvastatin arm at 5 days after primary PCI and successfully treated with balloon angioplasty.
The STATIN-STEMI study is the first randomized trial to evaluate the efficacy of high-dose atorvastatin loading (80 mg) before primary PCI in STEMI. Occurrence of cardiac events was not significantly different between the 10-mg and 80-mg atorvastatin pre-treatment at the 1-month and 9-month clinical follow-up assessments. However, our study suggested that high-dose atorvastatin loading before PCI may improve microvascular coronary perfusion as determined by CTFC, MBG, and STR after PCI.
The benefit of statins in primary and secondary prevention for coronary artery disease is well established (15–17). Retrospective studies identified favorable effects of statin use before PCI as increased survival during early and intermediate follow-up periods as well as a reduction in periprocedural MI (5,18,19). Several prospective trials have been conducted to validate these findings of statin pre-treatment in PCI settings. For instance, the ARMYDA trial demonstrated an 81% risk reduction for periprocedural MI after PCI with 7-day atorvastatin pre-treatment in patients with stable angina pectoris (1). In the ARMYDA-ACS trial, short-term atorvastatin pre-treatment reduced the incidence of cardiac events in patients with ACS undergoing early PCI (4).
The benefits of statin pre-treatment before PCI have been supported with previous studies for patients with stable angina pectoris and ACS (unstable angina and non-STEMI); however, only a few retrospective studies have evaluated statin pre-treatment in STEMI. Celik et al. (7) demonstrated that previous statin use in patients with STEMI may improve coronary blood flow after PCI, possibly via beneficial effects on microvascular function. Lev et al. (8) recently reported that previous chronic statin treatment before primary PCI reduced the 30-day short-term mortality (1.5% vs. 3.8%) and was an independent predictor of 30-day mortality (odds ratio: 0.4; 95% CI: 0.13 to 0.96) after controlling for other clinical and angiographic factors (8). However, this study was a nonrandomized study and assessed the effects of chronic statin therapy. As for acute STEMI patients, application of chronic statin treatment in real-world clinical practice before the occurrence of event is impossible as the clinical nature of STEMI is an acute, unexpected event; therefore, we evaluated the efficacy of acute high-dose statin for cardiac events and coronary perfusion after primary PCI.
The STATIN-STEMI trial (3) showed no significant reduction of MACE at either 1-month or 9-month follow-up, but the effects of high-dose atorvastatin pre-treatment in this study could not be determined because the incidence of clinical events was lower in both patient groups than our original estimates, and thus sample size was insufficient. In contrast to the ARMYDA or ARMYDA-ACS trials, periprocedural MI was not frequently reported in the present study. There may be several reasons for this result: additional myocardial necrosis after PCI may have been relatively smaller than the preceding, initial myocardial necrosis, and post-procedural MI is difficult to distinguish from original MI in progress. Interesting, we found that cTFC was significantly lower and MBG was higher in the 80-mg atorvastatin arm; STR at 90 min and the frequency of complete STR were also higher in the 80-mg atorvastatin arm.
Although these beneficial effects on myocardial perfusion of acute high-dose statin treatment cannot be completely explained, this early protective effect of atorvastatin is unlikely to be the result of cholesterol lowering. Instead, statins exert pleiotropic effects that may be initiated before the lipid-lowering effects (20–22). Previous studies have provided evidence for beneficial effects of acute atorvastatin treatment that may be related to lipid-independent pleiotropic effects such as improvement of endothelial function, dilation of coronary microvessels (20,21), and anti-inflammatory and antithrombotic actions (22).
Recent clinical trials have reported supportive findings for the single high (80-mg) loading dose of atorvastatin (23). The Naples (Novel Approaches for Preventing or Limiting Events) II trial demonstrated that single high-dose (80-mg) atorvastatin within 24 h before PCI could improve the clinical outcomes. In addition, single high-dose statin loading may be more effective in STEMI than in other clinical situations because STEMI is characterized by extremely high inflammation. The Naples II and ARMYDA-RECAPTURE trials reported that high-dose statin was more effective in patients with ACS and high baseline values on the high sensitivity C-reactive protein (6,23). Furthermore, high-dose atorvastatin has been reported to exert stronger anti-inflammatory and platelet inhibitory effects than low-dose atorvastatin by reducing platelet activity and inflammatory chemokines (24). In the present study, the level of high sensitivity C-reactive protein was somewhat lower in the 80-mg atorvastatin group, consistent with results of the ARMYDA-ACS study, and may serve as evidence for anti-inflammatory effects of the acute high-dose statin used in our study.
Regarding whether sufficient time had passed for atorvastatin to show pleiotropic effects, door-to-balloon time was approximately 90 min in majority of the cases. A previous study by Hinoi et al. (21) demonstrated that atorvastatin improved blood flow within 1 h after administration, although the study population exhibited no significant coronary stenosis. Another study showed that a brief (10-min) exposure to atorvastatin could attenuate ischemia/reperfusion injury when administered at the onset of reperfusion (25). These studies may partially explain the mechanism for the beneficial effects of acute atorvastatin treatment. In addition, the high dose and short action time of atorvastatin may be another important reason for the results of our study. An 80-mg dose of atorvastatin is not a typical dose for the Korean population, who in most cases require dosages that are 2 times lower than those typical for Western populations. Thus, caution should be used in applying the results of this study to other populations.
First, the number of participants in this study was not sufficient to evaluate the effects of high-dose atorvastatin on MACE because the MACE rate was much lower than anticipated in the low-dose arm. Therefore, a large population study with sufficient statistical power is needed to confirm our findings. However, we were able to identify beneficial effects on myocardial perfusion using cTFC, MBG, and STR measurements. Second, serial measurements of cardiac enzymes were not available for all patients; only 70% of cases could be evaluated completely in this study. Because the peak CK-MB value was missing for some patients, we were unable to calculate the enzymatic infarct size using CK-MB. Finally, although immediate high-dose statin loading before PCI showed beneficial effects on myocardial perfusion, future studies are required to identify the mechanism behind these effects.
Our trial shows that a high-dose atorvastatin pre-treatment before PCI did not show a significant reduction of MACEs, but was associated with improved myocardial perfusion in patients with STEMI. Larger additional randomized studies with more than 1,200 STEMI patients are needed to confirm these clinical benefits of high-dose statin loading in patients who undergo primary PCI.
This study was supported in part by a grant from the Korea Health 21 R&D Project, the Ministry of Health and Welfare and Republic of Korea (0412-CR02-0704-0001), and grants from the Korea Healthcare Technology R&D Project, Ministry for Health, Welfare and Family Affairs, Republic of Korea (No. A085012, A000385, and A085136), and Cardiovascular Research Center, Seoul, Korea. The first 2 authors contributed equally to this study.
- Abbreviations and Acronyms
- acute coronary syndrome
- creatine kinase-myocardial band
- corrected thrombolysis in myocardial infarction frame count
- emergency room
- major adverse cardiac event
- myocardial blush grade
- percutaneous coronary intervention
- ST-segment elevation myocardial infarction
- ST-segment resolution
- Thrombolysis In Myocardial Infarction
- Received November 4, 2009.
- Accepted November 13, 2009.
- American College of Cardiology Foundation
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