Chinese Medical Journal 2012;125(13):2250-2254
Effect of high-dose rosuvastatin loading before percutaneous coronary intervention in female patients with non-ST-segment elevation acute coronary syndrome

GAO Yuan,  JIA Zhi-mei,  SUN Yu-jiao,  ZHANG Zhi-hong,  REN Li-na ,  QI Guo-xian

GAO Yuan (Department of Cardiology, First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, China)

JIA Zhi-mei (Department of Cardiology, First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, China)

SUN Yu-jiao (Department of Cardiology, First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, China)

ZHANG Zhi-hong (Department of Cardiology, First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, China)

REN Li-na (Department of Cardiology, First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, China)

QI Guo-xian (Department of Cardiology, First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, China)

Correspondence to:QI Guo-xian,Department of Cardiology, First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, China (Tel: 86-24-83282226. Fax:86-24- 83282226. E-mail:qigx2002@medmail.com.cn)
Keywords
rosuvastatin; acute coronary syndrome; angioplasty; female; inflammation
Abstract
Background  Early loading statin therapy before percutaneous coronary intervention (PCI) is associated with reduced mortality and periprocedural myocardial injury. The aim of this study was to study the effect of rosuvastatin loading therapy before PCI in female patients with non-ST-segment elevation acute coronary syndrome (NSTEACS).
Methods  Consecutive 117 female patients with NSTEACS were randomly assigned to either the group of rosuvastatin loading before PCI (20 mg 12 hours before angioplasty procedure, with a further 10 mg dose 2 hours before procedure, the loading dose group, n=59) or the no rosuvastatin treatment group before PCI (control group, n=58). Periprocedural myocardial injury, periprocedural changes of high sensitivity C-reactive protein (hs-CRP), interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-a in serum and the incidence of major adverse cardiac events (MACE) 3 months and 6 months later were assessed.
Results  The incidence of periprocedural myocardial injury was higher in control group than loading dose group (CKMB: 10.17% vs. 25.86% , P=0.027; Troponin I: 11.86% vs. 29.31%, P=0.019). MACE occurred in 1.69% of patients in loading dose group and 12.07% of those in control group 3 months after procedure (P=0.026), 3.39% vs. 17.24% at 6 months (P=0.014). The levels of hs-CRP, IL-1, IL-6, and TNF-a in serum were not significantly different between the two groups before PCI, but after PCI they were significantly higher in control group.
Conclusions  High-dose rosuvastatin loading before PCI significantly reduced periprocedural myocardial injury and periprocedural inflammation cytokines release and improved 3-month and 6-month clinical outcomes in female patients with NSTEACS who underwent PCI.
Mortality and morbidity due to coronary heart disease (CHD) in women has increased rapidly. Women with acute coronary syndrome (ACS) have higher risk characteristics at presentation and higher risk at hospitals.1 In recent years, more and more studies focus on women with ACS.
 
Early and aggressive statin therapy in patients with ACS can decrease periprocedural myocardial injury during percutaneous coronary intervention (PCI). And it is associated with the reduction of adverse cardiovascular events.2,3 The ARMYDA-ACS trial, which included 21.1% of women participants showed that pretreatment with atorvastatin (80 mg 12 hours before PCI, with a further 40 mg pre-procedure dose) was associated with a 70% reduction in the incidence of periprocedural myocardial infarction and an 88% reduction in 1 month major adverse cardiac events (MACE).4 The beneficial pleiotropic lipid independent effects, especially the anti-inflammatory effect, of statins are well documented both in vitro and in vivo.5,6
 
However, there were only a few reports on the effect of rosuvastatin loading therapy in female patients with non-ST-segment elevation acute coronary syndrome (NSTEACS). We designed a prospective randomized study in female NSTEACS patients to investigate whether a loading dose rosuvastatin therapy before angioplasty procedure, has beneficial effects on periprocedural myocardial injury and the incidence of MACE. We also investigated high sensitivity C-reactive protein (hs-CRP), interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-a in serum.
 
METHODS
 
Study population and study design
From December 2009 to May 2010 we randomly recruited 167 consecutive female patients with NSTEACS who underwent diagnostic coronary angiography at Department of Cardiology of the First Affiliated Hospital of China Medical University. The study was approved by the ethical committee of the hospital. Inclusion criteria were the presence of a NSTEACS (unstable angina or non-ST-segment elevation acute myocardial infarction) sent to early (<48 hours) coronary angiography. Exclusion criteria were: ST-segment elevation acute myocardial infarction; NSTEACS with high risk features warranting emergency coronary angiography; any increase in liver enzymes; left ventricular ejection fraction <40%; renal failure with creatinine >221 mmol/L; history of liver or muscle disease; previous or current treatment with statins; seriously ill (such as cancer) and life expectancy <1 year. Forty-four patients were excluded: 12 because of previous or current treatment with statins, 7 because of NSTEACS requiring emergency invasive approach, 7 because of serial three branch coronary leisions (treated medically or with bypass surgery), 10 because of low ejection fraction, 5 because of contraindications to statin treatment (liver or muscle disease), 2 because of renal failure, and 1 because of lung cancer. The enrolled 123 patients were randomly divided into two groups: 62 patients randomized to receive loading dose rosuvastatin (loading dose group, 20 mg loading dose given a mean of 12 hours before coronary angiography, with a further 10 mg dose 2 hours before procedure) and 61 patients were given placebo before procedure (control group). All enrolled patients underwent PCI via radial artery puncture. They were given aspirin 300 mg and clopidogrel 300 mg loading dose at least 4 hours before procedure. After procedure aspirin 100 mg/d, clopidogrel 75 mg/d and rosuvastatin 10 mg/d were administered for at least 1 year. Angiographic success of PCI was defined as: thrombolysis in myocardial infarction (TIMI) 3 flow with residual stenosis below 20%.
 
Blood samples were collected before and 24 hours after PCI to measure CKMB, troponin I, hs-CRP, IL-1, IL-6, and TNF-a levels. For evaluation of IL-1, IL-6, and TNF-a, blood samples were drawn between 8 o’clock and 9 o’clock after an overnight fast. The blood samples were vortexed and centrifuged immediately at 4°C for 20 minutes at 1000 r/min and plasma samples were stored at -80°C until assayed. IL-1, IL-6, and TNF-a levels were measured with commercial enzyme linked immunosorbent assay (ELISA) kits (Wuhan EIAab Science, China). Total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-c) levels were evaluated before PCI and 7 days after PCI.
 
End points
The primary end points were 3-month and 6-month incidence of MACE: cardiac death, myocardial infarction (MI), target vessel revascularization (included bypass surgery or repeat PCI of the target vessel). MI was defined as post-procedural increase as troponin I or CKMB greater than 3 times the ninety-ninth percentile of upper limits of normal (ULN) in patients with normal baseline levels and as a subsequent elevation >2 times in troponin I or CKMB in patients with raised baseline levels.7
 
The secondary end point was any post-procedural increase of troponin I or CKMB above ULN or subsequent elevation <2 times in CKMB or troponin I in patients with raised baseline levels.
 
Statistical analysis
Continuous data were expressed as mean ± standard deviation (SD). And t test was used for comparing the two groups. Categorical data expressed as n and percent were analyzed by  c2 tests. A P value of less than 0.05 was considered statistically significant. All data analyses were performed using SPSS 14.0 for Windows (SPSS Inc. USA).
 
RESULTS
 
Patients
An increase of over 3 times the upper normal limit of liver enzymes (alanine amino transferases) was observed in two patients in loading dose group and one patient in control group after the procedure. Then rosuvastatin was discontinued and the three patients were excluded. There were no significant differences in the most relevant clinical characteristics between the two groups (Table 1), but loading dose group has more diuretics prescription (27.12% vs. 10.34%, P=0.020, Table 1). The angiographic and procedural characteristics were similar between the two groups (Table 2), but there were more right coronary lesions in the control group (55.17% vs. 35.59%, P=0.033). There was no patient with significant side branch closure during PCI. There was one patient in loading dose group and two patients in control group with TIMI flow grade  £2 after PCI and the three patients were excluded.
 

view in a new window
Table 1. Main clinical characteristics
 

view in a new window
Table 2. Procedural characteristics
 
Primary end point
The primary end points were evaluated 3 months and 6 months later (Table 3). No patient in either group died during the 6 months follow-up. The incidence of MACE 3 months after PCI was 1.69% in loading dose group and 12.07% in control group (P=0.026). Among the components of the primary end point at 3 months there were MI (0 vs. 6.90% P=0.040) and target vessel revascularization (1.69% vs. 5.17%, P=0.599). The composite primary end points 6 months after procedure occurred in 3.39% of patients in the loading dose group and in 17.24% of those in the control group (P=0.014), including MI (1.69% vs. 8.62%, P=0.089), and target vessel revascularization (1.69% vs. 8.62%, P=0.089).
 

view in a new window
Table 3. Incidence of primary end points after 3 months and 6 months ((n (%))
 
Secondary end point
There was no difference in the proportions of patients with levels of myocardial markers above the upper limit of the normal range before PCI in loading dose group and control group (CKMB 5.08% vs. 8.62%, P=0.449 and troponin I 10.17% vs.13.79% P=0.546). It showed statistically significant differences in the proportion of patients with post-PCI myocardial markers levels elevation between two groups. There were six patients with CKMB elevation after PCI in loading dose group and 15 patients in control group. There were seven patients with troponin I elevation after PCI in loading dose group and 17 patients in control group. Compared to control group, loading dose group was significantly lower (CKMB: 10.17% vs. 25.86% P=0.027, troponin I: 11.86% vs. 29.31%, P=0.019, Figure 1).
 

view in a new window
Figure 1. Postprocedural cardiac marker elevations. The secondary end point: incidence of post-procedural increase of CKMB and troponin I.
 
Changes of hs-CRP, IL-1, IL-6, TNF-a, TC, and LDL-c
The levels of hs-CRP, IL-1, IL-6, and TNF-a were not significantly different in the two groups before PCI. The post-PCI levels of hs-CRP, IL-1, IL-6, and TNF-a in the two groups were significantly higher than their respective pre-PCI levels; they were significantly higher in control group than loading dose group. TC and LDL-c levels were more reduced in loading dose group than control group (Table 4). The pre-PCI and post-PCI changes of hs-CRP, IL-1, IL-6, and TNF-a in loading dose group were significantly lower than in control group (Table 5).
 

view in a new window
Table 4. Values of hs-CRP, IL-1, IL-6, TNF-α, LDL-c, TC pre-PCI, and post-PCI (mean±SD)
 

view in a new window
Table 5. Values of LDL-c and TC pre-PCI and post-PCI (mean±SD)
 
DISCUSSION
 
It is very important that a series of cytokines take part in inflammatory reactions in ACS pathophysiology.8 In patients with ACS, an increased inflammatory cell density is observed in plaque, and consequently greater local and systemic production of inflammatory markers and cytokines are detected. CRP is an acute-phase reactant that serves as a marker of vascular inflammation9 as well as it plays a direct role in the inflammatory process.10,11 Pro-inflammatory cytokine IL-6 stimulates the production of CRP, and CRP also stimulates monocyte release of inflammatory cytokines such as IL-1, IL-6, and TNF-a. Myocardial damage during PCI is associated with inflammatory response, and the degree of inflammation has been shown to correlate with cardiovascular risk.12 Bonz et al13 found that the increase in serum concentrations of IL-6 and CRP was associated with the post-procedural troponin T elevation.
 
Myocardial biomarker release after PCI is common, occurring in 10%-40% of cases.14 PCI-related myocardial damage includes several mechanisms: slow or no reflow, distal microembolization, transient vessel closure from dissection or spasm, and side branch occlusion due to plaque shifting. It does not result in obvious clinical symptoms, any change in electrocardiogram, or impairment in cardiac functions; instead, such damage may seem “silent”, only appearing as an increase in myocardial biomarker levels. However, the elevation of CKMB and troponin I levels following PCI were associated with higher long-term mortality. Despite successful procedure and optimal management directed toward complications, the rate of periprocedural MI remains high. Anti-atherosclerotic and anti- inflammatory therapies may provide an additional benefit.
 
Statins have anti-atherosclerotic and anti-inflammatory effect. They alter pathways involved in cytokine production and adhesion molecule expression. Statins reduce the formation of isoprenoids, which are responsible for the activation of nuclear transcription factors involved in proinflammatory mechanisms, mediated by Rho and Ras. They enhance PI3K and the Akt pathways, resulting in eNOS3 and the following signal transduction cascade activation.15 Statins greatly impacted the treatment of coronary heart disease with obvious benefit in primary and secondary prevention. It has been found that statins initiation within 24 hours in acute myocardial infarction patients is associated with a significantly lower occurrence of early complications, a reduced infarct size, and better survival.16 MIRACL17 and PROVE-IT18 have confirmed that early treatment of ACS patients with high dose of statins can reduce the incidence of MACE. ARMYDA-ACS trial4 first showed that high dose statin loading therapy before PCI can be beneficial to ACS patients. The results of the trial indicated that 80 mg atorvastatin loading at 12 hours before PCI and further 40 mg 2 hours before PCI made a 70% reduction of post-procedural biomarker elevation and an 88% reduction of 1 month MACE. We performed a similar randomized study,19 using different loading dose atorvastatin before PCI, resulting in a reduction in the risk of periprocedural myocardial infarction (MI) and a reduction in the risk of 30 days MACE compared to no atorvastatin pretreatment. Moreover, recently, Yun et al20 reported that 40 mg dose of rosuvastatin approximately 16 hours prior to PCI reduced periprocedural myocardial injury and 1 month MACE in patients with NSTEACS, which included 38.7% female patients. In our current study, we prescribed 20 mg rosuvastatin 12 hours before PCI, with a further 10 mg rosuvastatin dose 2 hours before the procedure for the patients. The results showed that short term rosuvastatin loading dose treatment before PCI in female NSTEACS patients can reduce the incidence of periprocedural myocardial damage and reduce the incidence of 3-month and 6-month MACE. It has beneficial periprocedural protective effect. Furthermore, this trail showed loading dose treatment of rosuvastatin made periprocedural increase of hs-CRP, IL-1, IL-6, and TNF-a levels from baseline lower, and made TC, LDL-c rapidly decline in short term. This demonstrated that the cardial periprocedural protection and improvement of clinical outcomes were associated with the anti-inflammatory effect of loading dose rosuvastatin. In the results, we also found that MI incidence was higher in control group 3 months after the procedure (0 vs. 6.90%, P=0.040), but there was no significantly statistical difference 6 months after the procedure between the two groups (1.69% vs. 8.62%, P =0.089). We propose that it was mainly because the anti-inflammatory effect of loading dose rosuvastatin may play a key role in the early period after the procedure. In the published studies,4,20 it has been found that loading dose of statins therapy before PCI reduced MI incidence in the early 30 days.
 
The benefits of statins in cardiovascular diseases can be explained not only by its cholesterol lowering effect, but also by its pleiotropic effects.21 They modify endothelial function, inflammatory responses, plaque stability, and thrombus formation. Statins have been consistently reported to reduce oxidative stress, cytokines, and adhesion molecules in inflammatory reaction. These anti-inflammatory effects may provide additional vascular protection and myocardial protection.
 
In conclusion, high dose of rosuvastatin loading therapy in female NSTEACS patients before PCI may reduce periprocedural myocardial damage and MACE resulting from the inhibition of inflammation. This result emphasizes the need for loading dose statin therapy before PCI. The study still has limitation. It was not blinded, and the sample size was small. Furthermore, the optimal loading dose of rosuvastatin and the time or frequency of onset before PCI were not identified. Larger-scale controlled, randomized trials are needed.
 
REFERENCES
 
1.  Blomkalns AL, Chen AY, Hochman JS, Peterson ED, Trynosky K, Diercks DB, et al. For the CRUSADE Investigators: Gender disparities in the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes: large-scale observations from the CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the American College of Cardiology/American Heart Association Guidelines) National Quality Improvement Initiative. J Am Coll Cardiol 2005; 45: 832-837.
2.  Schwartz GG, Olsson AG, Ezekowitz MD, Ganz P, Oliver MF, Waters D, et al. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA 2001; 285: 1711-1718.
3.  Ray KK, Cannon CP, McCabe CH, Cairns R, Tonkin AM, Sacks FM, et al. Early and late benefits of high-dose atorvastatin in patients with acute coronary syndromes: results from the PROVE IT-TIMI 22 trial. J Am Coll Cardiol 2005; 46: 1405-1410.
4.  Patti G, Pasceri V, Colonna G, Miglionico M, Fischetti D, Sardella G,  et al. Atorvastatin pretreatment improves outcomes in patients with acute coronary syndromes undergoing early percutaneous coronary intervention: results of the ARMYDA-ACS randomized trial. J Am Coll Cardiol 2007; 49: 1272-1278.
5.  Yun KH, Shin IS, Park EM. Effect of additional statin therapy on endothelial function and prognosis in patients with vasospastic angina. Korean Circ J 2008; 38: 638-643.
6.  Nishino M, Hoshida S, Kato H, Egami Y, Shutta R, Yamaguchi H, et al. Preprocedural statin administration can reduce thrombotic reaction after stent implantation. Circ J 2008; 72: 232-237.
7.  Thygesen K, Alpert JS, White HD. On behalf of the joint ESC/ACCF/AHA/WHF task force for the redefinition of myocardial infarction. Universal definition of myocardial infarction. J Am Coll Cardiol 2007; 50: 2173-2195.
8.  Libby P, Theroux P. Pathophysiology of coronary artery disease. Circulation 2005; 111: 3481-3488. 
9.  Hansson GK. Immune mechanisms in atherosclerosis. Arterioscler Thromb Vasc Biol 2001; 21: 1876-1890.
10.  Rus HG, Vlaicu R, Niculescu F. Interleukin-6 and interleukin-8 protein and gene expression in human arterial atherosclerotic wall. Atherosclerosis 1996; 127: 263-271.
11.  Buffon A, Biasucci LM, Liuzzo G, D’Onofrio G, Crea F, Maseri A. Widespread coronary inflammation in unstable angina. N Engl J Med 2002; 347: 5-12.
12.  Balbay Y, Tikiz H, Baptiste RJ, Ayaz S, Sasmaz H, Korkmaz S. Circulating IL-1 beta, IL-6, TNF alpha and soluble ICAM-1 in patients witch chronic stable angina and myocardial infarction. Angiology 2001; 52: 109-114.
13.  Bonz AW, Lengenfelder B, Jacobs M, Strotmann J, Held S, Ertl G, et al. Cytokine response after percutaneous coronary intervention in stable angina: effect of selective glycoprotein IIb/IIIa receptor antagonism. Am Heart J 2003; 145: 693-699.
14.  Abdelmeguid AE, Topol EJ, Whitlow PL, Sapp SK, Ellis SG. Significance of mild transient release of creatine-kinase MB fraction after percutaneous coronary interventions. Circulation 1996; 94: 1528-1536.
15.  Morikawa S, Takabe W, Mataki C, Kanke T, Itoh T, Wada Y, et al. The effect of statins on mRNA levels of genes related to inflammation, coagulation, and vascular constriction in HUVEC. Human umbilical vein endothelial cells. J Atheroscler Thromb 2002; 9: 178-183.
16.  Stenestrand U, Wallentin L. Early statin treatment following acutemyocardial infarction and 1-year survival. JAMA 2001; 285: 430-436.
17.  Schwartz GG, Olsson AG, Ezekowitz MD, Ganz P, Oliver MF, Waters D, et al. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACLE study. A randomized conrolled trial. JAMA 2001; 285: 1711-1718.
18.  Cannon CP, Braunwald E, McCabe CH, Rader DJ, Rouleau JL, Belder R, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Eng J Med 2004; 350: 1495-1504.
19.  Sun Y, Qi G, Gao Y, Zhang H, Pang X, Zhao W, et al. Effect of different loading doses of atorvastatin on percutaneous coronary intervention for acute coronary syndromes. Can J Cardiol 2010; 26: 481-485.
20.  Yun KH, Jeong MH, Oh SK, Rhee SJ, Park EM, Lee EM, et al. The beneficial effect of high loading dose of rosuvastatin before percutaneous coronary intervention in patients with acute coronary syndrome. Int J Cardiol 2009; 137: 246-251.
21.  Sposito AC, Chapman MJ. Statin therapy in acute coronary syndromes. Mechanistic insight into clinical benefit. Arterioscler Thromb Vasc Biol 2002; 22: 1524-1534.