Effects of atorvastatin and ticagrelor combination therapy on renal function and the levels of suppression of tumorigenicity 2 and interleukin-33 in patients with ST-segment elevation myocardial infarction.

OBJECTIVE: We evaluated the effects of atorvastatin and ticagrelor combination therapy on renal function and the levels of suppression of tumorigenicity 2 (ST2) and interleukin 33 (IL-33) in patients with ST-segment elevation myocardial infarction (STEMI).
METHODS: Eighty-four STEMI patients who underwent emergency percutaneous coronary intervention at our hospital from January 2015 to March 2018 were retrospectively analyzed and divided into a control group (n = 44) and an observation group (n = 40). The control group was treated with atorvastatin as routine STEMI treatment, whereas the observation group was concurrently administered ticagrelor.
RESULTS: After treatment, significantly better outcomes were observed in the control group than in the observation group in terms of clinical indices, including chest pain relief, enzyme levels, duration of reperfusion-associated arrhythmia, and depression of the ST segment. Both groups exhibited improvements in cardiac ultrasound indices, whereas the observation group showed lower left ventricular end-diastolic and end-systolic diameters and higher left ventricular ejection fractions than the control group.
CONCLUSIONS: Atorvastatin and ticagrelor combination therapy is clinically effective and safe for STEMI patients as it reduces the degree of myocardial infarction, protects the heart and renal functions, improves inflammation, and reduces adverse cardiac event incidences.

Introduction

ST-segment elevation myocardial infarction (STEMI) refers to a clinical condition in which the epicardial artery is completely and continuously blocked because of myocardial ischemia and blood flow truncation in the collateral branch of the coronary artery. Continuous artery blockage may result in an insufficient or even interrupted blood supply to various organs and lead to ischemic necrosis of cardiomyocytes.[1,2] Recently, this condition has become increasingly prevalent among the elderly population and patients with atherosclerosis. It is a significant life-threatening health condition with high disability and fatality rates.[3,4] In the early stage, reperfusion therapy is the main approach to treat stenosis and blockage of the coronary artery lumen via percutaneous coronary intervention (PCI).[5,6] The effectively curative and life-saving benefits of this therapy, as well as its ability to improve the quality of life of patients, have been demonstrated in several clinical cases. Given the advantages of PCI that include treating the infarcted coronary artery, recovering myocardial perfusion, and reducing mortality, it is always the preferred treatment for patients with coronary disease. Thus, drug therapies that help avoid surgery and subsequent surgical wounds have been suggested as an alternative for STEMI treatment.[7]

Statins control the progression of heart failure that results from lipid metabolism disorders and regulate the endocrine secretion of response factors for heart function. Atorvastatin, a member of this family, protects endothelial cells.[8,9] Ticagrelor selectively inhibits the binding of adenosine diphosphate to its receptor, thereby bypassing liver metabolism in vivo and plays a significant role in inhibiting platelet aggregation and preventing thrombus formation.[10] Studies suggest that STEMI-associated myocardial damage may arise from complicated conditions or atheromatous plaque ruptures, leading to microvascular obstruction and even transient vascular occlusion or spasm. Patients with myocardial infarction may also experience acute renal failure due to improper control and treatment of the disease, and these cases account for a large proportion of hospital-acquired kidney injury patients.[11] A previous study[12] reported that as a significant factor inducing atherosclerosis, inflammation is closely associated with STEMI, but the levels of inflammatory markers vary during the development and progression of STEMI. Therefore, the present study aimed to investigate the effect of atorvastatin and ticagrelor combination therapy on STEMI patients by evaluating their renal function and inflammation indices.

Materials and methods

Patient characteristics

Eighty-four patients with STEMI who underwent emergency PCI at our hospital from January 2015 to March 2018 were included in this retrospective analysis and divided into the control group (n = 44) and the observation group (n = 40). Patients in the control group were treated with atorvastatin as routine STEMI treatment, whereas those in the observation group concurrently received ticagrelor. All patients and their family members signed an informed consent form and agreed to participate in the study. The study was approved by the Ethics Committee of The Second Affiliated Hospital of Nanjing Medical University.

Inclusion and exclusion criteria

Inclusion criteria were as follows: patients who had been diagnosed with STEMI based on the Guidelines for the Management of Acute Myocardial Infarction in Patients Presenting with ST-segment Elevation written by the European Society of Cardiology and demonstrated to comply with the STEMI diagnosis standards in Clinical Cardiology Diagnostic Imaging and treatment indications in the Guidelines and Consensus for the Prevention and Treatment of Cardiovascular Diseases.[13,14] Patients were excluded if they had received relevant treatments before this study; been suffering from concomitant organic lesions in the brain, concomitant coagulation function diseases or immunity diseases, or mental/cognitive impairment; or were lactating.

Reagents and materials

Ticagrelor was obtained from AstraZeneca Pharmaceutical Co., Ltd. (Cambridge, UK) with the approval no. H20171079, and atorvastatin calcium tablets were obtained from Pfizer Pharmaceuticals Limited (New York, NY, USA) with the approval no. H20051408. A Carotid doppler ultrasound (CDU) was obtained from Qisheng (Shanghai) Medical Device Co., Ltd. with the approval no. GXZJ20153541809, a 12-lead electrocardiogram (ECG) machine (model ECG-1350) was obtained from Jinan Shengrui Biotechnology Co., Ltd., and an automatic biochemical analyzer was obtained from Shandong Biobase Technological Instrument Co., Ltd. An enzyme-linked immunosorbent assay (ELISA) kit was obtained from Shanghai Jingkang Bioengineering Co., Ltd., and an enzyme-labeling instrument was obtained from Shanghai Yongchuang Bioengineering Co., Ltd.

Treatments

Patients in the observation group were orally administered ticagrelor at an initial dose of 180 mg and subsequent doses of 90 mg two times per day for 2 months according to routine symptomatic and thrombolytic therapies for myocardial ischemia. Patients in the control group were additionally given 80 mg of atorvastatin calcium tablets orally before thrombolytic therapy, followed by subsequent oral doses of 20 mg/day for 2 months. Atorvastatin was used in the later stage as a long-term treatment for patients with myocardial infarction.

Detection of indices

Under inactive conditions, patients laid down in a left lateral position to undergo transthoracic echocardiography via CDU to measure left ventricular end-diastolic and end-systolic diameters (LVESD and LVEDD, respectively) and left ventricular ejection fraction (LVEF). Before treatment, a routine 12-lead ECG fluctuation curve was obtained for all patients using a 12-lead ECG machine, and the results were evaluated and analyzed using the Selvester QRS scoring system (a 54 criterion/32-score system, with each score representing 3% of the left ventricular area) to determine the myocardial infarct size.[15] The renal function indices in both groups, including serum creatinine (Scr), cystatin C (Cys-C), and β2 macroglobulin (β2-MG) levels, were determined using an automatic biochemical analyzer. With the patients in a fasting state, 5 mL of blood were drawn from the peripheral vein and centrifuged at 3920 ×g for 5 minutes to obtain the serum, which was stored at −80°C and analyzed using an ELISA kit to determine the levels of suppression of tumorigenicity 2 (ST2) and interleukin 33 (IL-33). Standards at gradient concentrations were prepared according to the manufacturers’ instructions. The optical density (OD) was measured at a 490-nm wavelength using an enzyme-labeling instrument, and IL-33 and ST2 levels in the samples were calculated based on the standard curve. The examinations were performed after 2 months.

Observation indices

The two groups were observed, and changes in clinical indices, cardiac ultrasound indices (LVESD, LVEDD, and LVEF), myocardial infarct size, renal function, ST2 and IL-33 levels, clinical effects, adverse cardiovascular events, and other adverse reactions were compared before and after treatment. Clinical effects were graded as markedly effective if there was a complete improvement in angina pectoris symptoms and a rapid recovery of ECG changes and serum myocardial markers to normal levels; effective if the onset times or duration of angina pectoris were significantly reduced, ST segment on ECG dropped after treatment but failed to recover to the normal level, flat T wave transformed into a vertical shape, and myocardial marker levels recovered after a long period; and ineffective if the symptoms were not improved, ECG showed no changes, or no significant recovery was observed in myocardial marker levels.[16]

Statistical analysis

Statistical analyses were performed using IBM SPSS Statistics for Windows, Version 19.0 (IBM Corp., Armonk, NY, USA) for experimental data. Nominal data were tested using the chi-square test, and numerical data were expressed as means ± standard deviations. Comparison studies were conducted using a t-test between the two groups and paired t-test for pre- and post-comparisons within a group. Graphpad Prism 8 (Graphpad Software, San Diego, CA, USA) was used for drawing plots. For all statistical comparisons, significance was set at p < 0.05.

Results

The study participants consisted of 52 men and 32 women (mean age, 65.36 ± 9.47 years) and included cases of concomitant hypertension (n = 55), concomitant diabetes (n = 36), anterior myocardial infarction (n = 28), inferior wall myocardial infarction (n = 34), inferior and posterior wall myocardial infarction (n = 13), and other diseases (n = 9). The two groups showed no significant differences in terms of gender, age, and the presence of hypertension and diabetes (Table 1).

Table 1.

Patient characteristics.

Group	Control Group (n = 44)	Observation Group (n = 40)	χ2/t	P
Gender, n (%)			0.011	0.915
Male	27 (61.36)	25 (62.50)
Female	17 (38.64)	15 (37.50)
Age (year)	65.19 ± 9.53	65.52 ± 9.38	0.160	0.874
BMI (kg/m2)	23.11 ± 1.12	23.31 ± 1.17	0.800	0.426
Hypertension, n (%)			0.008	0.930
Yes	29 (65.91)	26 (65.00)
No	15 (34.09)	14 (35.00)
Diabetes, n (%)			0.004	0.950
Yes	19 (43.18)	17 (42.50)
No	25 (56.82)	23 (57.50)
Smoking, n (%)			0.043	0.836
Yes	13 (29.55)	11 (27.50)
No	31 (70.45)	29 (72.50)
Infarction site, n (%)			0.259	0.968
Anterior	15 (34.09)	13 (32.50)
Inferior wall	18 (40.91)	16 (40.00)
Inferior wall and posterior	7 (15.91)	6 (15.00)
Other	4 (9.09)	5 (12.50)
Killip classification of heart function, n (%)			0.290	0.962
Class I	19 (43.18)	17 (42.50)
Class II	13 (29.55)	11 (27.50)
Class III	9 (20.45)	8 (20.00)
Class IV	3 (6.82)	4 (10.00)
Degree of stenosis (%)	79.45 ± 9.54	79.63 ± 9.72	0.086	0.932
Thrombus location (n)			0.021	0.885
Proximal blood vessel	27 (61.36)	24 (60.00)
Distal vessel	17 (38.64)	16 (40.00)
Myocardial ischemic necrosis (n)			0.081	0.776
Yes	25 (56.82)	22 (55.00)
No	19 (43.18)	18 (45.00)

The degree of vascular diameter stenosis was measured by the quantitative analysis of coronary angiography.

BMI, body mass index.

Changes in clinical indices

After treatment, significantly better outcomes were observed in the control group than in the observation group in terms of chest pain relief, enzyme levels, duration of reperfusion-associated arrhythmia, and depression of the ST segment (p < 0.05; Table 2).

Table 2.

Changes in clinical indices.

Group	Control Group (n = 44)	Observation Group (n = 40)	t	P
Duration of chest pain relief (h)	1.47 ± 0.93	1.05 ± 0.84	2.164	0.033
Occurrence of enzyme peak (h)	13.63 ± 2.67	10.16 ± 2.15	6.519	<0.001
Duration of reperfusion-associated arrhythmia (h)	1.59 ± 0.35	1.21 ± 0.27	5.531	<0.001
Depression of ST segment (mV)	1.34 ± 0.46	1.02 ± 0.39	3.421	0.001

Cardiac ultrasound indices

There were no significant between-group differences in LVESD, LVEDD, and LVEF before treatment; however, significantly lower LVESD and LVEDD and higher LVEF were observed after treatment in the observation group than in the control group (p < 0.05, Figure 1).

Figure 1.

Cardiac ultrasound indices before and after treatment in STEMI patients. The control group (n = 44) and observation group (n = 40) were given oral atorvastatin (80 mg before thrombolytic therapy and subsequent doses of 20 mg/day for 2 months) or a combination of atorvastatin and ticagrelor (initial dose of 180 mg and subsequent doses of 90 mg two times per day for 2 months), respectively. (A) Both groups demonstrated a decrease in LVESD, which was significant in the observation group. (B) Both groups demonstrated a decrease in LVEDD, which was significant in the observation group. (C) Both groups demonstrated an increase in LVEF, which was significant in the observation group. The results are presented as the mean ± standard deviation, and * represents p < 0.05.

ST-segment elevation myocardial infarction, STEMI; LVESD, left ventricular end-diastolic diameter; LVEDD, left ventricular end-systolic diameter; LVEF, left ventricular ejection fraction.

Myocardial infarct size

There were no significant between-group differences in myocardial infarct size before treatment. The infarct size markedly decreased after treatment in both groups, with the observation group exhibiting a significant decrease (p < 0.05; Figure 2).

Figure 2.

Myocardial infarct size before and after treatment in ST-segment elevation myocardial infarction (STEMI) patients. The control group (n = 44) and observation group (n = 40) were given oral atorvastatin (80 mg before thrombolytic therapy and subsequent doses of 20 mg/day for 2 months) or a combination of atorvastatin and ticagrelor (initial dose of 180 mg and subsequent doses of 90 mg two times per day for 2 months), respectively. Treatment resulted in a reduction in myocardial infarct size, which was significant in the observation group. The results are presented as the mean ± standard deviation. *represents p < 0.05 for pre- and post-comparisons in the same group before and after treatment and the comparisons between the two groups after treatment.

Renal function

There were no significant between-group differences in Scr, Cys-C, and β2-MG levels before treatment. These levels markedly decreased after treatment, with the observation group exhibiting a significant decrease (p < 0.05; Figure 3).

Figure 3.

Renal function before and after treatment in STEMI patients. The control group (n = 44) and observation group (n = 40) were given oral atorvastatin (80 mg before thrombolytic therapy and subsequent doses of 20 mg/day for 2 months) or a combination of atorvastatin and ticagrelor (initial dose of 180 mg and subsequent doses of 90 mg two times per day for 2 months), respectively. (A) Both groups demonstrated a decrease in Scr levels, which was significant in the observation group. (B) Both groups demonstrated a decrease in Cys-C levels, which was significant in the observation group. (C) Both groups demonstrated a decrease in β2-MG levels, which was significant in the observation group. The results are presented as the mean ± standard deviation, and * represents p < 0.05

ST-segment elevation myocardial infarction, STEMI; Scr, serum creatinine; Cys-C, cystatin C; β2-MG, β2 macroglobulin

ST2 and IL-33 levels

There were no significant between-group differences in ST2 and IL-33 levels before treatment. These levels markedly decreased after treatment, with the observation group exhibiting a significant decrease (p < 0.05; Figure 4).

Figure 4.

ST2 and IL-33 levels before and after treatment in STEMI patients. The control group (n = 44) and observation group (n = 40) were given oral atorvastatin (80 mg before thrombolytic therapy and subsequent doses of 20 mg/day for 2 months) or a combination of atorvastatin and ticagrelor (initial dose of 180 mg and subsequent doses of 90 mg two times per day for 2 months), respectively. (A) Both groups demonstrated a decrease in ST2 levels, which was significant in the observation group. (B) Both groups demonstrated a decrease in IL-33 levels, which was significant in the observation group. The results are presented as the mean ± standard deviation, and * represents p < 0.05.

ST-segment elevation myocardial infarction, STEMI; ST2, suppression of tumorigenicity 2; IL-33, interleukin-33.

Clinical effects

The total effective rate in the control group was significantly lower than that in the observation group after treatment (p < 0.05; Table 3).

Table 3.

Clinical effects [n (%)].

Group	Control Group (n = 44)	Observation Group (n = 40)	χ2	P
Markedly effective	19 (43.18)	27 (67.50)	–	–
Effective	17 (38.64)	11 (27.50)	–	–
Ineffective	9 (20.45)	2 (50.00)	–	–
Total effective rate	35 (79.55)	38 (95.00)	4.397	0.036

Adverse cardiovascular events and adverse reactions

After treatment, the control group exhibited a significantly higher total incidence of adverse cardiovascular events than the observation group (p < 0.05); however, no significant between-group differences were observed in the total incidence of adverse reactions (Tables 4 and 5).

Table 4.

Adverse cardiovascular event incidences [n (%)].

Group	Control Group (n = 44)	Observation Group (n = 40)	χ2	P
Postinfarction angina pectoris	3 (6.82)	1 (2.50)	–	–
Congestive heart failure	4 (9.09)	1 (2.50)	–	–
Recurrent myocardial infarction	3 (6.82)	1 (2.50)	–	–
Cardiac death	1 (2.27)	0	–	–
Total incidence of adverse cardiovascular events	11 (25.00)	3 (7.50)	4.620	0.032

Table 5.

Total incidence of adverse reactions [n (%)].

Group	Control Group (n = 44)	Observation Group (n = 40)	χ2	P
Nausea	2 (4.55)	2 (5.00)	–	–
Vomiting	1 (2.27)	1 (2.50)	–	–
Abdominal discomfort	1 (2.27)	0	–	–
Total incidence of adverse reactions	4 (9.09)	3 (7.50)	0.069	0.792

Discussion

STEMI progresses rapidly and may lead to the development of coronary artery disease.[17] STEMI has a poor prognosis; however, when the condition is detected early, further deterioration may be effectively prevented using thrombolytic therapy to recover blood oxygen reperfusion. Thrombolytic drugs vary in efficacy and safety.[18] Atorvastatin regulates metabolism and cholesterol levels in the liver and helps recover vascular endothelial functions by selectively inhibiting the biosynthesis of cholesterol and 3-hydroxy-3-methylglutaryl coenzyme A, increasing lipoprotein receptor levels, reducing the surface density of liver cells, and decreasing lipoprotein and cholesterol levels in the body.[19] In addition to suppressing platelet aggregation, ticagrelor can significantly reduce the incidence of postoperative hemorrhage.[20] Previous studies have reported that together with classical stress response cytokines, IL-33 regulates cellular activity and contributes to immune response regulation.[21] IL-33 transduces signals to ST2L via ST2 to induce the expression of Th2-associated cytokines, thus enhancing the inflammatory response.[22] Both drugs are useful in patients with STEMI, but the clinical efficacy of their combination is seldom reported. Studies on STEMI have shown that in the advanced stage, the status of renal function and inflammatory parameters affect the prognosis. Therefore, the present study explored the effect of a combination of atorvastatin and ticagrelor on renal function and the levels of ST2 and IL-33 in patients with STEMI to elucidate the most effective therapeutic option.

Changes in clinical indices and efficacy were observed in the two groups. After treatment, the observation group showed significantly lower clinical indices and a higher total effective rate than the control group, indicating that using a combination of the two drugs improves the effects on heart function recovery and pain relief compared with atorvastatin alone. To explore the factors contributing to the enhanced drug efficacy, cardiac ultrasound indices were first analyzed. The results showed that these were improved after treatment, with significant improvements observed in the observation group, indicating that the combination promotes cardiac vascular endothelial protection and cardiac ejection efficiency. The results of a previous study[23] suggested that atorvastatin calcium tablets could effectively protect vascular endothelial function, inhibit atherosclerosis and intravascular plaque formation, and maintain cardiac systole and pumping function. Additionally, one study[24] showed that ticagrelor could rapidly prevent platelet aggregation, which is the main cause of vascular endothelial and cardiomyocyte injury, and contribute to the recovery of cardiac vessels and cardiomyocytes. The myocardial infarct size in both groups was markedly reduced, with a significant reduction observed in the observation group, indicating that the combination of the two drugs results in a higher recovery efficiency and enhanced cardiac reperfusion than atorvastatin alone. A previous report[25] proposed that ticagrelor accelerated the recovery of coronary blood flow, reduced the release of oxygen free radicals and injury due to oxidative stress, and contributed to the recovery of antioxidant function in the body. This further explains why the combination of the two drugs can enhance the efficacy of reperfusion and prevent myocardial infarction by protecting the cardiac ejection ability and reducing myocardial cell oxidation. Furthermore, Scr, Cys-C, and β2-MG levels were decreased after treatment, with a significant reduction observed in the observation group. A previous study suggested[26] that patients treated with ticagrelor exhibited improvements in hemodynamics and cerebral blood volume, which was beneficial for the steady flow of blood in the kidneys, reduction of ischemic renal injury, and improvement of glomerular filtration rate and sodium excretion because of the diuretic function of this drug. In the present study, inflammatory parameters were also analyzed in the two groups. After treatment, ST2 and IL-33 levels were reduced in both groups, with a significant reduction observed in the observation group, demonstrating that the combination of the two drugs can more effectively reduce inflammation. Furthermore, a previous study[27] reported that ticagrelor promoted myocardial cell repair and restored cardiac function via its inflammatory resistance and myocardial protection functions. For adverse reactions, the control group exhibited a higher total incidence of adverse cardiovascular events after treatment; however, no significant difference was noted in the total incidence of adverse reactions. These results indicate that the combination of the two drugs did not increase adverse effects but rather alleviated the severity of cardiovascular diseases, which was suggested to be correlated with the effect of the two drugs as a combination treatment on improving heart and renal functions and reducing inflammation.

In conclusion, atorvastatin and ticagrelor combination therapy demonstrated a good safety profile by recovering heart and renal functions, reducing inflammation, and stabilizing the condition of patients with STEMI. However, the present study had limitations. Specifically, minimal information was obtained regarding the effect of myocardial infarction severity on renal function and other factors that cause changes in renal function. In addition, the exclusion criteria were insufficient and not clear enough when selecting study subjects. These questions should be prioritized and answered in future studies.