Abstract
To investigate the effect of ticagrelor combined with tirofiban versus clopidogrel combined with tirofiban on inflammation response and prognosis of patients with unstable angina pectoris (UA). The present prospective study included a total of 291 patients who were diagnosed as unstable UA from January 2018 to December 2019. All UA patients were divided into two groups: ticagrelor combined with tirofiban group (n = 159) and clopidogrel combined with tirofiban group (n = 132). Serum levels of C‐reactive protein (CRP), interleukin‐1β, interleukin‐6, tumor necrosis factor‐α, and matrix metalloproteinase‐9 were measured using commercially available enzyme‐linked immunosorbent assay kits. Kaplan–Meier (K‐M) curve was performed for analysis of cumulative incidences of major adverse cardiovascular events (MACEs). Both ticagrelor combined with tirofiban and clopidogrel combined with tirofiban significantly decreased the serum levels of inflammatory factors in UA patients. Compared to clopidogrel combined with the tirofiban group, ticagrelor combined with the tirofiban group had a lower platelet aggregation rate and improved cardiac function of UA patients. Besides, ticagrelor combined with tirofiban group had a better prognosis and the K‐M curve showed that UA patients treated by ticagrelor and tirofiban had lower incidences of MACEs in one‐year follow‐up. The treatment of ticagrelor combined with tirofiban significantly attenuated inflammation response and improved the prognosis of UA patients.
Keywords: clopidogrel, ticagrelor, tirofiban, unstable angina pectoris
1. INTRODUCTION
Acute coronary syndrome (ACS) is a common cardiovascular disease caused by coronary atherosclerotic stenosis or obstruction, including unstable angina pectoris (UA), ST‐segment elevation myocardial infarction (STEMI), and non‐ST segment elevation myocardial infarction (NSTEMI). 1 ACS leads to myocardial ischemia, hypoxia, or myocardial necrosis and seriously affects life and the prognosis of patients with high incidence and mortality rate. 2
As a kind of P2Y12 receptor antagonist, a variety of studies reveal ticagrelor significantly reduced the incidence of major cardiovascular events in ACS patients. 3 , 4 Julien et al. demonstrated that ticagrelor improved peripheral arterial function in ACS patients. 5 Clopidogrel is another kind of P2Y12 receptor antagonist widely used in clinical practice. It was reported that pretreatment with clopidogrel reduced the occurrence of death and thrombotic outcomes at the cost of minor bleeding for ACS patients. 6 The antiinflammatory effect of ticagrelor or clopidogrel was also reported in various researches on ACS. 7 , 8
Tirofiban is a kind of glycoprotein IIb/IIIa inhibitor (GPI) inhibitor. Tirofiban was reported to be established for the treatment of patients with non‐ST‐segment elevation ACS in clinic practice. 9 Another study found that tirofiban was a safe and tolerable therapy drug for ACS (UA/NSTEMI) patients referred to percutaneous coronary intervention (PCI). 10 In addition, numerous researches illustrated that tirofiban has an antiinflammatory effect on ACS patients. High bolus dose tirofiban (25 μg/kg) allows better inhibition of platelet aggregation and suppresses the inflammatory response after PCI on ACS patients with higher risk, such as diabetes mellitus. 11
Despite these researches, limited studies focused on the effect of dual antiplatelet therapy (DAPT) combined with tirofiban on the inflammatory response and prognosis of ACS patients. In the present study, we aimed to perform a prospective study to investigate the effect of ticagrelor combined with tirofiban or clopidogrel combined with tirofiban on inflammatory factors and the prognosis of UA patients. This study might bring more clinical evidence for DAPT combined with tirofiban in ACS patients.
2. METHOD
2.1. Patients and treatment
This prospective research included a total of 221 patients with UA admitted to our hospital from January 2018 to December 2019. All UA patients were consecutively enrolled during the study period. The diagnosis of UA referred to the recent guidelines. 12 , 13 The final diagnosis of UA was determined by a clinical advisory board based on electrocardiogram (ECG), coronary angiography, and myocardial perfusion imaging (MPI) as follows: 1) patients with UA accompanied by ischemic ECG changes; 2) patients without ECG records at the onset but had both significant coronary stenosis and perfusion defects on either resting or exercise MPI. Written informed consent was obtained from all patients. The present study was approved by the ethics committee of Tianyou Hospital Affiliated to Wuhan University of Science and Technology.
2.2. The inclusion and exclusion criteria
The inclusion criteria were as follows: (1) The patients diagnosed with UA without any prior history of angina/MI or prolonged chest pain (even at rest); (2) UA patients who received PCI; (3) a negative value of hs‐cardiac Troponin‐T(<0.014 ng/ml) even after 6 h of onset of symptoms; and (4) patients who agreed to participate in the study. All the included patients should meet all the four inclusion criteria. The exclusion criteria for all patients were as follows: (1) acute MI or history of angina, infective cardiomyopathy, cardiac neurosis, intercostal neuralgia, cerebral apoplexy, pulmonary infection, nephritis, renal failure, rheumatism, osteoarthritis, and similar inflammatory diseases; (2) Patients taken ticagrelor or clopidogrel before admission; (3) The platelet count<100 × 109/L, or ≥ 300 × 10 9 /L; and (4) patients with a history of neoplastic or autoimmune disease or any surgical procedure during the past 6 months.
3. TREATMENT
All UA patients were divided into two groups: ticagrelor combined with tirofiban group (n = 159) and clopidogrel combined with tirofiban group (n = 132). Patients in both groups received an initial oral aspirin LD of 300 mg, followed by a maintenance dose of 100 mg daily indefinitely. Intravenous tirofiban was administered to all patients at the rate of 0.4 U/(kg min) for 30 min before PCI, and then continuously administered at the rate of 0.1 U/(kg min) for 24 h. Ticagrelor combined with tirofiban group received ticagrelor with a 180 mg loading dose followed by 90 mg twice daily and clopidogrel combined with tirofiban group received clopidogrel with a 300 mg loading dose followed by 75 mg/day. The oral administration of ticagrelor or clopidogrel lasted for 1 year.
3.1. Enzyme‐linked immunosorbent assay
Measurement of Serum levels of C‐reactive protein (CRP), interleukin‐1β (IL‐1β), interleukin‐6 (IL‐6), tumor necrosis factor‐α (TNF‐α), and matrix metalloproteinase‐9 (MMP‐9) was performed by enzyme‐linked immunosorbent assay (ELISA) method. Briefly, peripheral venous blood samples from all participants were collected at admission and 7 days after the admission. The serum levels were then determined by using commercial ELISA kits: Human CRP ELISA Kit (CRP) (ab99995), Human IL‐1 beta ELISA Kit (ab214025), Human IL‐6 ELISA Kit(ab46027), Human TNF alpha ELISA Kit (ab100654), and Human MMP9 ELISA Kit (ab246539) (all purchased from Abcam, Cambridge, MA, USA).
3.2. Data collection
Clinical characteristics of all UA patients were collected, including age, sex, body mass index (BMI), complications, the left ventricular ejection fraction (LVEF), left ventricular end‐diastolic diameter (LVEDD), and laboratory indices of PLT, CRP, IL‐1β, IL‐6, TNF‐α and MMP‐9, TG, TC, LDL‐C, HDL‐C, and medications were measured and recorded. Major adverse cardiovascular events (MACE) were defined as cardiovascular death, angina recurrence, malignant arrhythmia, heart failure, or rehospitalization. Major adverse events and MACE were recorded. For incidences of MACEs analysis, all MACEs were recorded from the admission. The follow‐up lasted for 1 year from admission to death or the last follow‐up.
3.3. Statistical analysis
Continuous variables were expressed by mean ± SD when normally distributed, and median (range) if otherwise. A chi‐square test was used to compare the counting materials and rates. Comparison between two groups of continuous data was conducted using the Student t test. Comparison among three or more groups was performed by one‐way analysis of variance (ANOVA) followed by Tukey post hoc test. Kaplan–Meier (K‐M) curve was performed for the analysis of cumulative incidences of MACE in a one‐year follow‐up. A p value less than 0.05 was considered to be statistically significant. All calculations were made using SPSS 18.0.
4. RESULTS
4.1. Basic characteristics of all UA patients
The present study included a total of 313 patients and 22 cases were excluded for quitting or lost in the follow‐up or other reasons. And a total of 291 patients were finally enrolled in this study. The basic characteristics of all UA patients are shown in Tables 1, and no significant difference was found for the basic characteristics between the two groups.
TABLE 1.
Characteristics at baseline of UA patients
| Variables | Ticagrelor + tirofiban, n = 159 | Clopidogrel + tirofiban, n = 132 | p |
|---|---|---|---|
| Age, year | 68.32 ± 9.46 | 67.38 ± 9.32 | 0.395 |
| Male, n (%) | 97(61.01) | 86(65.15) | 0.466 |
| BMI, kg/m2 | 23.49 ± 2.75 | 23.63 ± 2.39 | 0.637 |
| Current smoker, n (%) | 75(47.17) | 66(50.00) | 0.631 |
| Hypertension, n (%) | 85(53.46) | 67(50.76) | 0.646 |
| Diabetes, n (%) | 46(28.93) | 37(28.03) | 0.866 |
| LVEF, (%) | 53.81 ± 4.77 | 54.61 ± 4.89 | 0.159 |
| PLT, × 109/L | 206.45 ± 55.11 | 204.30 ± 54.34 | 0.739 |
| TG, mmol/L | 1.54 ± 0.20 | 1.56 ± 0.21 | 0.426 |
| TC, mmol/L | 5.36 ± 0.94 | 5.50 ± 0.83 | 0.190 |
| LDL‐C, mmol/L | 3.57 ± 0.50 | 3.55 ± 0.53 | 0.709 |
| HDL‐C, mmol/L | 0.99 ± 0.06 | 1.00 ± 0.06 | 0.085 |
| Medications, n (%) | |||
| Aspirin | 159(100%) | 132(100%) | — |
| Statins | 63(39.62) | 65(49.24) | 0.100 |
| ACEI/ARB | 86(54.09) | 85(64.39) | 0.075 |
| β‐blocker | 85(53.46) | 83(62.88) | 0.105 |
| Diuretics | 8(5.03) | 5(3.79) | 0.609 |
| Calcium‐channel blocker | 43(27.04) | 46(34.85) | 0.150 |
Abbreviations: ACEI, angiotensin converting enzyme inhibitors; ARB, angiotensin II receptor blocker; HDL‐C, high density lipoprotein cholesterol; LDL‐C, low density lipoprotein cholesterol; LVEF, left ventricular ejection fraction; PLT, platelet; TC, total cholesterol; TG, triglyceride.
Note: p value was calculated between Ticagrelor + Tirofiban group and Clopidogrel + Tirofiban group.
TABLE 2.
The serum levels of inflammatory factors at the admission and 7 days after the admission
| Ticagrelor + tirofiban, n = 159 | Clopidogrel + tirofiban, n = 132 | |||||
|---|---|---|---|---|---|---|
| Variables | At admission | 7 days after the admission | At admission | 7 days after the admission | p 1 | p 2 |
| CRP, mg/L | 9.29 ± 3.76 | 3.55 ± 0.88 | 9.69 ± 3.91 | 5.03 ± 1.47 | 0.838 | 6.199e‐20 |
| IL‐1β, pg/ml | 3.76 ± 0.53 | 2.23 ± 0.33 | 3.67 ± 0.40 | 2.30 ± 0.41 | 0.132 | 0.117 |
| IL‐6, pg/ml | 9.67 ± 1.28 | 4.34 ± 1.14 | 9.81 ± 1.66 | 5.52 ± 1.14 | 0.441 | 1.267e‐16 |
| TNF‐α, ng/ml | 7.17 ± 2.29 | 3.50 ± 0.95 | 6.89 ± 2.32 | 4.23 ± 0.74 | 0.299 | 2.140e‐12 |
| MMP‐9, pg/ml | 61.34 ± 14.28 | 48.63 ± 11.94 | 64.60 ± 13.95 | 50.71 ± 13.30 | 0.051 | 0.167 |
Abbreviations: CRP, C‐reactive protein; IL‐1β, interleukin‐1β; IL‐6, interleukin‐6; MMP‐9, matrix metalloproteinase‐9.
Note: p 1 value was calculated between ticagrelor + tirofiban group and clopidogrel + tirofiban at admission; p 2 value was calculated between ticagrelor + tirofiban group and clopidogrel + tirofiban at 7 days after the admission;
4.2. Ticagrelor combined with tirofiban or clopidogrel combined with tirofiban significantly suppressed inflammatory response in UA patients
First, the serum levels of inflammatory factors were detected at the admission and 7 days after the admission. Compared to the admission, serum levels of CRP, IL‐1β, IL‐6, TNF‐α, and MMP‐9 obviously decreased in both groups 7 days after the admission (Table 2). Besides, we noticed that serum level of CRP, IL‐6, and TNF‐α in ticagrelor combined with the tirofiban group was significantly lower than clopidogrel combined with the tirofiban group. These findings suggested that the treatment of ticagrelor combined with tirofiban or clopidogrel combined with tirofiban could both attenuate the inflammatory response in UA patients. In addition, ticagrelor combined with tirofiban showed a better inhibition effect on serum levels of CRP, IL‐6, and TNF‐α.
4.3. Comparison of platelet aggregation rate and cardiac function between two groups
Subsequently, platelet aggregation rate (PAR) and cardiac function between the two groups were determined. Dynamic change of PAR was detected before PCI, 3 days after PCI, and 7 days after PCI (Table 3 ), the results showed that PAR in two groups decreased in a time‐dependent manner. Besides, PAR at 3 days after PCI and 7 days after PCI in ticagrelor combined with tirofiban group was remarkably lower than clopidogrel combined with tirofiban group. We also detected LVEF and LVEDD at admission and 30 days after PCI (Table 4). It was found that there was no difference for LVEF and LVEDD between the two groups at admission. LVEF was significantly higher in ticagrelor combined with tirofiban group than that of clopidogrel combined with tirofiban group at 30 days after PCI; however, LVEDD in ticagrelor combined with tirofiban group was notably lower than clopidogrel combined with tirofiban group. The above findings demonstrated that the treatment of ticagrelor combined with tirofiban could significantly inhibit PAR and improve cardiac function compared to clopidogrel combined with tirofiban.
TABLE 3.
Dynamic change of platelet aggregation rate in two groups
| Variables | At admission | 3rd day post‐PCI | 7th day post‐PCI |
|---|---|---|---|
| Ticagrelor + tirofiban, n = 159 | 125.86 ± 14.19 | 82.82 ± 10.09 | 49.67 ± 11.72 |
| Clopidogrel + tirofiban, n = 132 | 127.91 ± 14.58 | 98.42 ± 12.57 | 65.68 ± 8.85 |
| p | 0.226 | 7.078e‐25 | 1.297e‐31 |
Abbreviation: PCI, percutaneous coronary intervention.
Note: p value was calculated between Ticagrelor + Tirofiban group and Clopidogrel + Tirofiban at 3rd‐day post‐PCI and 7th‐day post‐PCI, respectively.
TABLE 4.
Cardiac function in two groups at the admission and 30th‐day post‐PCI
| LVEF (%) | LVEDD (mm) | |||||
|---|---|---|---|---|---|---|
| Variables | At admission | 30th day post‐PCI | LVEF change | At admission | 30th day post‐PCI | LVEDD change |
| Ticagrelor + tirofiban, n = 159 | 53.81 ± 4.77 | 62.56 ± 4.41 | 8.75 ± 6.27 | 55.48 ± 3.64 | 45.13 ± 2.95 | −10.35 ± 4.67 |
| Clopidogrel + tirofiban, n = 132 | 54.61 ± 4.89 | 57.69 ± 4.60 | 3.08 ± 6.98 | 55.03 ± 2.92 | 50.42 ± 2.97 | −4.60 ± 4.28 |
| p | 0.159 | 6.918e‐18 | 2.701e | 0.238 | 2.381e‐38 | 3.416e‐23 |
Abbreviations: LVEF, left ventricular ejection fraction; LVEDD, left ventricular end‐diastolic diameter; PCI, percutaneous coronary intervention.
Note: p value was calculated between ticagrelor + tirofiban group and clopidogrel + tirofiban group at the admission, 30th‐day post‐PCI, and the change of LVEF or LVEDD.
4.4. Ticagrelor combined with tirofiban significantly decreased incidences of MACEs and major adverse events in a one‐year follow‐up
Finally, we analyzed MACE events and major adverse events in two groups. As shown in Table 5, the incidence of cumulative MACEs and major adverse events in ticagrelor combined with tirofiban was markedly lower in patients treated with ticagrelor and tirofiban compared to patients treated with clopidogrel and tirofiban. K‐M curve also showed UA patients treated with ticagrelor and tirofiban had lower incidences of MACEs in one‐year follow‐up (Figure 1).
TABLE 5.
MACE events and major adverse events in one‐year follow‐up
| Variables | Ticagrelor + tirofiban, n = 159 | Clopidogrel + tirofiban, n = 132 | p |
|---|---|---|---|
| Cardiac death, n (%) | 1(0.63) | 2(1.52) | 0.456 |
| Malignant arrhythmia, n (%) | 1(0.6) | 0(0) | — |
| Angina recurrence, n (%) | 2(1.26) | 4(3.03) | 0.289 |
| Heart failure, n (%) | 1(0.6) | 3(2.27) | 0.231 |
| Rehospitalization, n (%) | 3(1.89) | 7(5.30) | 0.111 |
| Cumulative MACE, n (%) | 8(5.03) | 16(12.12) | 0.029 |
| Massive hemorrhage, n (%) | 0(0) | (0) | — |
| Slight bleeding, n (%) | 3(1.89) | 8(6.06) | 0.063 |
| Dyspnea, n (%) | 3(1.89) | 5(3.79) | 0.323 |
| Major adverse events, n (%) | 6(3.77) | 13(9.85) | 0.037 |
Abbreviation: MACE, major adverse cardiovascular events.
FIGURE 1.
Kaplan–Meier curves of cumulative survival free of MACEs. MACE, major adverse cardiovascular events
5. DISCUSSION
Tirofiban was reported to have an obvious effect on blocking thrombosis, inhibiting platelet aggregation, and suppressing inflammatory response in different studies. 14 , 15 , 16 However, limited studies illustrated the combined treatment of DAPT with tirofiban in clinic practice. In the present study, we demonstrated for the first time that ticagrelor combined with tirofiban significantly inhibited inflammatory response in UA patients, and these patients had a better prognosis compared to patients treated with clopidogrel and tirofiban.
As we know, DAPT, including a P2Y12 receptor inhibitor in combination with aspirin has been recommended by current guidelines, an effective therapy against ACS, which significantly reduced platelet reactivity and prevent ischemic events. 17 As reported, patients with non‐ST‐elevation ACS undergoing PCI received a loading dose of ticagrelor or prasugrel during the procedure provided optimal P2Y12‐ADP receptor blockade in 2 h and maximal inhibition within 4 h. 18 Fefer et al. illustrated clopidogrel dose‐related effect could be responsible for the reduced atherothrombotic complications in ACS patients undergoing PCI. 19 Furthermore, glycoprotein IIb/IIIa inhibitor combined with dual antiplatelet agent therapy is considered an initial therapy in ACS patients in clinical practice. A previous research stated that ticagrelor combined with tirofiban significantly increased thrombolysis in myocardial infarction 3 (TIMI3) blood flow and TIMI myocardial perfusion grade 3 (TMPG3) and shortened the hospitalization duration, meanwhile, the combined therapy decreased the incidence of reinfarction during hospitalization, postinfarction angina and severe arrhythmia in diabetic patients with acute myocardial infarction. 20 A meta‐analysis suggested that routine and early use of tirofiban before primary PCI may decrease the MACE in STEMI patients treated with aspirin and clopidogrel but did not remarkably increase major bleeding. 21 Therefore, a clinical trial is urgently needed to confirm these findings. In the present study, we found that ticagrelor combined with tirofiban significantly inhibited PAR and improved cardiac function compared to the therapy of clopidogrel with tirofiban. Besides, ticagrelor combined with tirofiban decreased incidences of MACEs and major adverse events in one‐year follow‐up. We for the first time compared the effect of ticagrelor combined with tirofiban and clopidogrel with tirofiban on UA patients receiving PCI.
The role of dual antiplatelet agent therapy and tirofiban in inflammatory response has been reported in ACS patients. Except for the effect on markedly lowering platelet reactivity to adenosine diphosphate, long‐term clopidogrel therapy was reported to be associated with an antiinflammatory effect in ACS patients. 22 As stated in the study of Oh et al., the 6‐month treatment of clopidogrel or ticagrelor obviously decreased carotid atherosclerotic plaque inflammation. 23 ZHANG et al. found that serum Hs‐CRP, IL‐6, and sICAM‐1 levels in patients treated with aspirin, clopidogrel, and tirofiban significantly decreased 24 h after the treatment and was notably lower than patients treated with aspirin and clopidogrel. 24 Our results also showed that both clopidogrel and ticagrelor combined with tirofiban suppress inflammation response in UA patients, but ticagrelor combined with tirofiban showed a better effect on decreasing serum level of CRP, IL‐6, and TNF‐α.
The present study also has some limitations. First, the sample size of the research is limited and we did not investigate inflammation response and prognosis of patients treated with clopidogrel or ticagrelor alone. Second, how the DAPT combined with tirofiban influences STEMI and NSTEMI patients needs to be revealed.
6. CONCLUSION
In conclusion, we conducted a prospective study to compare the effect of clopidogrel combined with tirofiban and ticagrelor combined with tirofiban on UA patients. The results demonstrated that dual antiplatelet agent therapy combined with tirofiban is effective for suppressing inflammation response but ticagrelor combined with tirofiban was superior to clopidogrel combined with tirofiban on attenuating inflammation response and improve prognosis. This study might provide a new research direction for UA.
CONFLICT OF INTEREST
The authors declare that they have no competing interests.
Deng L, Jia H‐Z, Li M‐C, Zhu W. Comparison of the effect of ticagrelor combined with tirofiban versus clopidogrel combined with tirofiban on inflammation response and prognosis of patients with unstable angina pectoris in long term follow‐up. Kaohsiung J Med Sci. 2021;37:1010–1015. 10.1002/kjm2.12421
Li Deng and Hai‐Zhen Jia contributed equally to this study.
Funding information Health commission of Hubei Province Scientific Research Project, Grant/Award Number: WJ2019H229
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