INTRODUCTION
Lipid-lowering therapy with statins is essential in the management of acute coronary syndrome (ACS). Clinical trials have demonstrated the benefits of early statin initiation following an ACS event. For instance, the pravastatin or atorvastatin evaluation and infection therapy (PROVE-IT) study found that administering statins within 10 days of an ACS event significantly reduced major adverse cardiovascular events (MACE) compared to placebo. Similarly, the myocardial ischemia reduction with aggressive cholesterol lowering (MIRACLE) study showed that initiating statin therapy within 24 to 96 hours of ACS also led to a reduction in MACE [1,2]. Based on these findings, current guidelines recommend starting high-intensity statin therapy as early as possible after hospital admission [3].
Early revascularization with percutaneous coronary intervention (PCI) is an important treatment strategy for patients with ACS. The role of statins in the context of PCI has been widely studied, particularly the effects of high-dose statin pretreatment compared to conventional dosing. The atorvastatin for reduction of myocardial damage during angioplasty-acute coronary syndrome (ARMYDA-ACS) trial demonstrated that pretreatment with 120 mg of atorvastatin 12 hours before PCI significantly reduced the risk of 30-day MACE by 88%, including a reduction in periprocedural myocardial infarction [4]. Similarly, Yun et al. [5] reported that administering 40 mg of rosuvastatin approximately 16 hours before PCI resulted in a 53% reduction in the risk of periprocedural myocardial infarction and a 63% reduction in 30-day MACE compared to no statin pretreatment. Subsequent meta-analyses of seven randomized controlled trials confirmed that high-dose statin pretreatment (80-120 mg of atorvastatin or 30-40 mg of rosuvastatin) significantly reduced the incidence of periprocedural myocardial infarction and MACE [6]. However, the effects of different statin doses or types have been less thoroughly investigated. In particular, no studies have specifically examined pretreatment with rosuvastatin 20 mg. We conducted a single-center, retrospective study to evaluate the impact of a single 20 mg dose of rosuvastatin given prior to PCI on outcomes in patients with ACS, specifically assessing its effectiveness in reducing periprocedural myocardial injury and MACE compared to no statin pretreatment.
METHODS
1. Study population
We analyzed a single-center registry of patients with non-ST segment elevation ACS who underwent PCI between July 2013 and December 2020. Figure 1 presents a flowchart of the patient selection process. During the study period, 2,571 consecutive patients were enrolled and followed to document patient characteristics, PCI-related data, and laboratory results at baseline, as well as at 6, 24, and 48 hours after PCI. Clinical outcomes were also assessed at 30 days and 2 years. Patients were excluded if they had been on chronic statin therapy for more than 1 month, had received a statin loading dose other than rosuvastatin, had received statin pretreatment more than 24 hours before PCI, or lacked laboratory or clinical data. The final study population included 1,701 patients, comprising 1,421 who received 20 mg of rosuvastatin pretreatment and 280 who received no statin pretreatment prior to PCI. PCI was performed according to current clinical practice at the discretion of the treating physician, using second-generation drug-eluting stents. All patients received a loading dose of 300 mg aspirin and either 300 mg clopidogrel or 180 mg ticagrelor before the procedure. Following PCI, all patients were prescribed 100 mg/day aspirin, 75 mg/day clopidogrel or 180 mg/day ticagrelor, and 10 mg rosuvastatin. Creatine kinase MB fraction (CK-MB) and troponin T levels were measured at admission and at 6, 24, and 48 hours after PCI. High-sensitivity C-reactive protein (CRP) was measured at admission, 24 hours, 48 hours, and 1 month following PCI. The study protocol for processing anonymized patient data was approved by the Institutional Review Board (IRB) of Wonkwang University Hospital (2024-06-009). The IRB waived the requirement for informed consent due to the retrospective, observational nature of the study and the absence of patient-identifying information.
2. Endpoint
The primary endpoint was periprocedural myocardial injury, defined as an absolute increase in cardiac troponin from baseline to more than 70 times the upper reference limit, in accordance with the Academic Research Consortium-2 consensus definition [7]. Additional definitions evaluated included an increase in cardiac troponin to more than five times the upper reference limit, as defined by the Fourth Universal Definition of Myocardial Infarction, and a 35-fold elevation based on expert consensus from the Society for Cardiovascular Angiography and Interventions and the Academic Research Consortium-2 [7-9]. At our institution, the reference value of troponin T was <0.14 ng/mL.
The secondary endpoint was MACE, defined as a composite of all-cause death, myocardial infarction, stroke, and any revascularization -both target and non-target vessel-occurring during the 30-day follow-up period. Only cases of spontaneous myocardial infarction during the clinical follow-up were included.
3. Statistical analysis
All analyses were conducted using SAS version 9.4 (SAS Institute, Cary, NC, USA). Continuous data were presented as means with standard deviations and compared using independent t-tests, both before and after matching. Categorical variables were expressed as counts (percentages) and compared using the chi-square test or Fisher’s exact test, as appropriate. At each follow-up time point, values of cardiac biomarkers and inflammatory markers were compared using generalized estimation equations. Cumulative incidences of MACE were calculated using Kaplan-Meier estimates and compared with the log-rank test. A Cox proportional hazards model was used to compare MACE outcomes, with results reported as hazard ratios and corresponding 95% confidence intervals, adjusted for age, sex, hypertension, diabetes, and diagnosis.
The propensity score was calculated based on the likelihood of receiving statin pretreatment. Since risk factors and diagnoses differed between the two groups, variables included in the propensity score model were selected to balance baseline characteristics. These variables included age, sex, history of hypertension and diabetes, diagnosis, body mass index, baseline estimated glomerular filtration rate, and low-density lipoprotein cholesterol. Propensity score matching was performed using a 1:4 nearest neighbor algorithm without replacement, with a caliper of 0.5 and random selection in the case of ties. Primary and secondary outcomes were compared between patients who received rosuvastatin 20 mg pretreatment and those who received no statin pretreatment, following propensity score matching. A two-sided P-value of less than 0.05 was considered statistically significant.
RESULTS
Rosuvastatin 20mg pretreatment was administered a median of 10 hours before PCI (interquartile range, 2-16 hours) prior to PCI. Patients who received rosuvastatin pretreatment had a significantly higher prevalence of hypertension, diabetes mellitus, and myocardial infarction, as well as a higher estimated glomerular filtration rate, compared to those who did not receive statin pretreatment. After propensity score matching, 1,070 patients in the rosuvastatin pretreatment group and 279 patients in the no-statin group were identified. A love plot illustrating baseline characteristics before and after propensity score matching is shown in Figure 2. Following matching, there were no significant differences between the two groups in baseline risk factors, diagnosis, laboratory findings, or angiographic and procedural characteristics (Table 1). The incidence of periprocedural complications, including slow or no reflow, side branch occlusion, distal embolization, and vessel perforation or rupture, was similar between the groups (5.2% vs. 3.6%, P=0.255).
Periprocedural myocardial injury, defined as a troponin elevation >70 times the upper reference limit, was observed in 3.7% of patients who received rosuvastatin pretreatment and in 3.6% of those without statin pretreatment (P=0.946) (Fig. 3). The incidence of myocardial injury based on alternative definitions was also similar between the two groups. Serial changes in cardiac biomarkers, including both CK-MB and troponin T, did not differ significantly between the groups (Fig. 4). Cumulative troponin T release, reflecting the extent of myonecrosis, was 2.16±5.53 ng/mL in the rosuvastatin group and 2.16±5.50 ng/mL in the no-statin group (P=0.996). Changes in inflammatory markers, including white blood cell count and high-sensitivity CRP, were also not statistically different between the two groups (Fig. 4).
DISCUSSION
In this study, we demonstrated that a single, 20 mg of rosuvastatin pretreatment before PCI did not reduce periprocedural myocardial injury and was not associated with improved clinical outcomes. Furthermore, rosuvastatin 20 mg pretreatment did not suppress the inflammatory response after the procedure, as indicated by similar postprocedural CRP elevations compared with no statin pretreatment.
PCI is the most common and reliable revascularization strategy for patients with ACS. However, it can trigger an inflammatory response associated with vascular injury, leading to myocardial injury as reflected by elevated cardiac biomarkers [10-12]. Furthermore, the extent of inflammation and periprocedural myocardial injury has been shown to correlate with increased cardiovascular risk [10,13,14]. Statins have demonstrated anti-inflammatory effects, antithrombotic properties, and the ability to stabilize atherosclerotic plaques, potentially offering benefits during PCI [15-17]. Numerous studies have explored whether statin pretreatment can prevent periprocedural myocardial injury and improve clinical outcomes. In a 2011 meta-analysis of individual patient data from 13 randomized studies, Patti et al. [18] reported that among 3,341 patients undergoing PCI, high-dose statin therapy administered before the procedure significantly reduced the incidence of periprocedural myocardial infarction and 30-day post-PCI MACE. However, evidence specifically focusing on patients with ACS was limited.
Both atorvastatin and rosuvastatin have been studied for the prevention of periprocedural myocardial infarction in patients with ACS. Patti et al. [4] and Yu et al. [19] reported that atorvastatin pretreatment with 80 mg administered 12 hours before PCI and 40 mg given 2 hours prior significantly reduced the incidence of periprocedural myocardial infarction and improved 30-day MACE outcomes. However, Jang et al. [20] found that even with a similar pretreatment regimen to those used in the studies by Patti et al. 4 and Yu et al. [19], atorvastatin pretreatment did not confer additional benefit compared with standard post-PCI atorvastatin therapy at 40 mg/day. These discrepancies are likely attributable to differences in the incidence of myocardial infarction, the use of periprocedural medications such as antiplatelet agents or beta-blockers, postprocedural statin doses, and varying definitions of periprocedural myocardial infarction across studies. Studies involving rosuvastatin have shown more consistent results compared to those using atorvastatin. Yun et al. [5,21] reported that pretreatment with 40 mg of rosuvastatin administered 7-25 hours before PCI reduced postprocedural elevations in troponin and CRP, leading to improved clinical outcomes at both 30 days and 1 year compared to no statin pretreatment. Gao et al. [22] demonstrated that rosuvastatin pretreatment with 20 mg administered 12 hours and 10 mg given 2 hours before PCI significantly reduced periprocedural myocardial injury and cytokine release and improved clinical outcomes. Similarly, Luo et al. [23] reported comparable benefits using a regimen of 20 mg rosuvastatin given 12 hours and again 2 hours prior to PCI, compared to no statin pretreatment. These findings suggest that pretreatment with 30 to 40 mg of rosuvastatin may be effective in preventing periprocedural myocardial injury and suppressing the associated inflammatory response.
In this study, we evaluated the effect of pretreatment with 20 mg of rosuvastatin, a lower dose compared to those used in previous studies. Rosuvastatin 20 mg has been established as effective for the primary prevention of coronary artery disease. The justification for the use of statins in prevention: an intervention trial evaluating rosuvastatin (JUPITER) demonstrated that 20 mg of rosuvastatin significantly reduced CRP levels and lowered the incidence of MACE in healthy individuals with elevated CRP levels [24] Following the JUPITER trial, rosuvastatin 20 mg became widely used for secondary prevention in patients with coronary artery disease and for primary prevention in the Republic of Korea. However, in our study, rosuvastatin 20 mg did not reduce postprocedural troponin or CRP levels compared to no statin pretreatment. As a result, the incidence of periprocedural myocardial injury and MACE was similar between the two groups. A key difference between our study and previous ones lies in the definition of periprocedural myocardial injury. We defined it as an increase of more than 70 times the upper reference limit [7], which led to a lower observed incidence of myocardial injury in both the statin pretreatment and no pretreatment groups compared to other studies. Nonetheless, even when using alternative definitions, the incidence of myocardial injury remained similar between the two groups. We evaluated potential confounding variables such as diabetes, chronic kidney disease, and ACS diagnostic category, and found no significant differences in primary or secondary endpoints between the groups. A single 20 mg dose of rosuvastatin may be insufficient to suppress postprocedural inflammatory responses and prevent periprocedural myocardial injury in patients with ACS.
This study has several limitations. First, it was retrospective in design and had a relatively small sample size. However, a total of 1,349 patients were analyzed after propensity score matching, which is substantial compared to many prospective studies. Second, despite propensity score matching, it was not possible to eliminate all sources of bias. Third, the study period was relatively long. In earlier years, rosuvastatin 20 mg was considered a high-dose statin, and maintenance therapy with rosuvastatin 10 mg was regarded as appropriate. However, current clinical practice often involves higher and more potent statin therapy. Therefore, the findings of this study should be interpreted in the context of evolving statin dosing, suggesting that a 20 mg dose of rosuvastatin may no longer be sufficient for patients with ACS. Fourth, other rosuvastatin doses were not evaluated; future studies should investigate varying doses to assess potential dose-dependent effects. Finally, caution should be exercised when generalizing these results to non-Korean populations.
In conclusion, pretreatment with a 20 mg dose of rosuvastatin administered 10 hours before PCI did not reduce periprocedural myocardial injury or MACE in patients with ACS. Further research is needed to evaluate the effects of different doses and types of statins.
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