In the light of recent scientific data, statins are considered not only as a means to lower cholesterol and treat dyslipidemia, but also as therapeutic agents with multi-vector effects, such as supporting the NO-synthetic function of the endothelium, stabilizing atherosclerotic plaques, countering oxidative stress and vascular inflammation. The results of two recently published studies have demonstrated the properties of atorvastatin to inhibit systemic inflammatory response, improve microcirculation parameters and prevent reperfusion injury of the myocardium in patients with acute coronary syndrome (ACS).
Preliminary intake of high doses of atorvastatin prevents microvascular dysfunction after stenting of the coronary arteries
Percutaneous coronary interventions (PCI) with the establishment of drug-eluting stents and appropriate drug support (antiaggregants, statins) have become the standard of management of patients with ACS. However, PCI involves a risk of perioperative damage to the myocardium, which is associated with worse outcomes. Previous studies have shown that even briefly taking statins before PCI can reduce the incidence of perioperative myocardial infarction-MI (G.Patti et al., 2007; C.Briguori et al., 2009; Y. Jang et al., 2014). The mechanism of this effect remains not fully understood. Moreover, the results of some studies have raised doubts that high doses of statins do prevent myocardial damage in PCI and improve clinical outcomes (J. Veselka et al., 2011; D. Zemanek et al., 2013).
In the autumn of 2016, the results of the Korean-American study RESIST-ACS were published, in which the effect of the loading dose of atorvastatin before PCI was studied, namely the effect on inflammation and perioperative myocardial damage by serial measurements of the index of microcirculatory resistance (IMR) level of cardiac enzymes and C-reactive protein (CRP) in patients with ACS without ST-segment elevation.
IMR is an invasive physiological indicator that reflects the condition of the microcirculatory bed of the myocardium (W.Fearon et al., 2003). IMR can be accurately measured under the conditions of a catheter laboratory, it is not affected by other hemodynamic parameters, such as coronary flow reserve (CFR). Recent studies have confirmed that IMR has high predictive value for the detection of coronary microcirculation disorders (W.F. Fearon et al., 2013).
Material and methods. RESIST-ACS is a multicenter, randomized, prospective study performed on the basis of four university clinics. It included adult patients who had coronary angiography (CAG) within 48 hours with suspected non-ST ACS (unstable angina or acute myocardial infarction without ST elevation). 205 patients were screened and randomized into two groups: 1) to receive atorvastatin at a loading dose of 80 mg 12-24 h before CAG, then 40 mg 2 hours before the procedure; 2) for the administration of atorvastatin at a dose of 10 mg for 12-24 h before CAG.
After the CAG, 128 patients were excluded for various reasons: 82 had no severe stenoses, 3 had left coronary artery (LCA), 11 had LCA branches or distal segments, 10 had total occlusion, 12 had a three-vessel lesion, 3 failed to draw a catheter to measure the pressure, 7 had a lesion of a CA with severe calcification or thrombosis. Thus, a homogeneous group of 77 patients was formed, immediately after the diagnostic CAG, PCI was performed.
According to the protocol, patients received 300 mg of acetylsalicylic acid before PCI, a loading dose of clopidogrel 600 mg at least 3 hours before the procedure and intravenous heparinization. Inhibitors of glycoprotein IIb / IIIa were used during PCI by the doctor’s decision. Blood samples were taken before PCI, 6 and 12 hours for CRP, myocardial fraction of creatine phosphokinase (CKF) and total CPK. After PCI, a maintenance dose of atorvastatin was prescribed by the decision of the attending physician.
PCI was performed by standard technique. The fractional flow reserve (FFR) was measured before and after the procedure; CFR, IMR and wedge pressure (Pw) were measured after PCI. The IMR was evaluated as the primary endpoint after the procedure. All other parameters of the coronary blood flow and biomarkers served as secondary endpoints. The disturbance of coronary microcirculation was defined as IMR ≥25.
Results. High-dose groups (39 patients) and low-dose (38 patients) atorvastatin therapy were well balanced in terms of age and gender composition, comorbid diseases and risk factors, current therapy and other baseline characteristics. They were also comparable in angiographic features of the coronary bed, localization of plaques, and the size of the stents implanted with PCI. Stents with a drug coating were used in all cases. All PCIs were completed successfully and without procedural complications in both groups. Side effects of therapy with atorvastatin, such as increased activity of hepatic enzymes or myopathy, were not observed.
After PCI, all patients successfully measured invasive physiological parameters – FFR, CFR, IMR and Pw. Post-procedural IMR, the primary endpoint of the study, was significantly lower in the high-dose therapy group of atorvastatin than in the low-dose group (14.1 ± 5.0 versus 19.2 ± 9.3 units, p = 0.003). The incidence of microcirculatory disorders was also lower in the group of high-dose therapy (2.6 vs. 23.7%, p = 0.007).
The post-procedural values of FFR, CFR and Pw were without significant differences between the groups.
The baseline levels of the total fraction of CK, CK-MB and CRP in patients of both groups were also comparable. After PCI, the levels of CK-MB and CRP significantly decreased in the group of high-dose therapy with atorvastatin. Comparison of biomarkers before and after the procedure showed that in the low-dose therapy group, the fraction of CK-MB and the content of CRP increased significantly, while this dose was not observed after taking high doses of atorvastatin.
Multivariate regression analysis showed that the preliminary administration of high doses of atorvastatin was the only independent predictor of the absence of post-procedural microcirculatory disorders (odds ratio 0.089, 95% confidence interval 0.009-0.843, p = 0.035).
Discussion and conclusions. RESIST-ACS results confirm that the short-term administration of high doses of atorvastatin before PCI in the ACS prevents periprocedural myocardial damage, as determined by IMR and biomarkers. Because the decrease in IMR was accompanied by a decrease in the level of CRP, this effect of atorvastatin is probably due to its ability to suppress the systemic inflammatory response.
With previous studies, it is consistent that the assessment of the state of microcirculation by IMR in the performance of PCI is useful for determining the outcomes of ACS. A low post-procedural IMR in the high-dose therapy group of atorvastatin was associated with low plasma activity of CK-MB, which reflects less damage to the myocardium.
Despite the significant difference in post-procedural IMR between groups, the CFR and Pw values did not differ. This can be explained by the fact that the coronary reserve depends on a number of other parameters of hemodynamics, and the jam pressure is less sensitive to changes in microcirculation than IMR.
Previous studies have shown that a systemic inflammatory response accompanied by an increase in CRP activity in PCI may increase the likelihood of further complications and damage to the myocardium (K.Ahmed et al., 2012; G.Patti et al., 2013). In the present study, post-procedural levels of CRP in the group of high-dose therapy were significantly lower than in the low-dose group, indicating support for the anti-inflammatory effect of atorvastatin.
Summing up, it should be noted that therapy with atorvastatin in a loading dose of 80 mg for 12-24 hours, then 40 mg 2 hours before the PCI is performed, prevents microvascular dysfunction and secondary myocardial damage.
Effect of high and low doses of atorvastatin on the level of highly sensitive CRP in patients with ACS
The systemic inflammatory process is now recognized as one of the most important links in the pathogenesis of atherosclerosis and coronary heart disease (IHD), and laboratory markers of the acute phase of inflammation, such as CRP, correlate with the risk of developing cardiovascular diseases and complications. Traditional qualitative analysis on CRP, reflecting its concentration in the “+” symbols, does not always detect this mediator of inflammation in the blood plasma, therefore, quantitative analysis of highly sensitive CRP (HCVB) is more often used today. Epidemiological studies have confirmed that hCPD is an independent and reliable marker of the risk of developing coronary events and peripheral arterial diseases (D.F. Geffken et al., 2001; M.T. Goodarzi et al., 2007). The property of statins to reduce the plasma activity of hsRSB can make a difference in the treatment of patients with ACS. The aim of the study of Iranian authors was to compare the dynamics of hsCRP in patients with ACS who were taking different doses of atorvastatin.
The study included 180 patients with middle-aged ACS of 59 years (69.4% of men) who were randomly divided into two groups for taking atorvastatin at a dose of 20 or 40 mg in addition to standard treatment. The level of hsCRP was determined at the time of admission and after 3 months. In 40 patients, MI with ST segment elevation was diagnosed, in 8 patients not with Q-MI, and in 132 with unstable angina. The composition of the groups was balanced by age, sex, prevalence of arterial hypertension (41.1%), diabetes mellitus, dyslipidemia, as well as the history of coronary heart disease.
After 3 months in the low-dose group, improvement in clinical status was observed in 81 patients (90%), repeated ACS in 8 patients, and 1 patient died. In the high-dose group, 85 patients (94.4%) improved and 5 had coronary events. Differences in these outcomes did not reach statistical certainty. But in patients who took 40 mg of atorvastatin, the level of hsCRP significantly decreased by 40% in 3 months, and in the 20 mg group only by 13.3% (the differences are significant, p = 0.001). The lowering of the low density lipoprotein cholesterol level as a result of taking 40 mg of atorvastatin was also more significant than in the low dose group: by 23 and 10%, respectively (p = 0.001).
The authors concluded that atorvastatin 40 mg / day in patients with ACS, along with a decrease in the content of atherogenic cholesterol in the blood, significantly reduces the level of hsRS, reflecting the acute phase of the inflammatory reaction. This did not affect the clinical outcomes in the groups of high-dose and low-dose therapy with atorvastatin, which, apparently, is due to the insufficient statistical power of the study. Thus, the clinical significance of the property of atorvastatin to suppress the systemic inflammatory response in ACS is to be studied in future studies.