16 May 2022: Review Articles
A Review of the Role of the Antiplatelet Drug Ticagrelor in the Management of Acute Coronary Syndrome, Acute Thrombotic Disease, and Other Diseases
Luyuan Tao1BCE, Shijia Ren1BC, Li Zhang1CD, Wenhua Liu2CDF, Yi Zhao1F, Changgong Chen1C, Xiang Mao1B, Zili Chen1FG, Xingjian Gu1A*DOI: 10.12659/MSM.935664
Med Sci Monit 2022; 28:e935664
Abstract
ABSTRACT: P2Y12 inhibitors, including aspirin, are key components of dual-antiplatelet therapy (DAPT), which is the optimal therapeutic strategy for preventing arterial thrombosis in patients with acute coronary syndromes (ACS) who underwent stent implantation. Ticagrelor is a cyclopentyl-triazole pyrimidine antiplatelet drug that was the first reversible oral P2Y12 receptor antagonist. Compared with clopidogrel, ticagrelor exerts a faster onset and offset of function by reversible and selective inhibition of platelet aggregation in ACS patients, including those with coronary artery blood revascularization. Despite improvement in stent materials, stent thrombosis (ST) due to high on-treatment platelet reactivity (HPR) to clopidogrel continues to occur. In addition to antiplatelet aggregation, ticagrelor displays pleiotropic cardioprotective effects, including improving coronary blood flow, reducing myocardial necrosis after an ischemic event, and anti-inflammatory effects. The benefits of ticagrelor over clopidogrel were consistent in the PLATO results, with lower incidence of the primary endpoint. Also, in 2020, the findings from the phase 3 THALES trial (NCT03354429) showed that aspirin combined with 90 mg of ticagrelor significantly reduced the rates of stroke and death compared with aspirin alone in patients with AIS or TIA. Here, we review recent research on the superiority of ticagrelor over clopidogrel, discuss the pharmacological mechanism, and present future perspectives. This review aims to present the roles of ticagrelor in the management of acute coronary syndrome, acute thrombotic disease, and other diseases.
Keywords: acute coronary syndrome, clopidogrel, Dual Anti-Platelet Therapy, ticagrelor, Aspirin, Humans, percutaneous coronary intervention, Platelet Aggregation Inhibitors, Purinergic P2Y Receptor Antagonists, Thrombosis
Background
Acute coronary syndrome (ACS), including ST-elevation myocardial infarction, non-ST-elevation myocardial infarction, and unstable angina pectoris, is a common cardiovascular disease with high sudden death rate and serious morbidity. Dual-antiplatelet treatment (DAPT) is the cornerstone of treatment for ACS patients, regardless of whether percutaneous coronary intervention (PCI) is administered. The atherosclerotic plaque rupture activates platelet aggregation, resulting in arterial thrombosis, a pathological basis for ACS [1]. While contributing to development of thrombosis, activated platelets further trigger the release of various inflammatory factors, promoting the progression of atherosclerosis.
Aspirin is the first antiplatelet drug that was developed to irreversibly block platelet-induced cyclooxygenase (Cox)-1 enzyme for inhibiting the formation of thromboxane-A2, an effective agonist of platelet aggregation and vasoconstrictor [2]. P2Y12 receptor antagonists are another commonly used class of antiplatelet agents, including thiophene pyridine (clopidogrel and prasugrel) and non-thiophene pyridine (ticagrelor). According to the guidelines, PCI is strongly recommended in high-risk ACS patients [3]. Notably, successful PCI will enhance these benefits as well as the treatment of DAPT [4]. The P2Y12 receptor antagonist could prevent stent thrombosis or restenosis by effectively inhibiting the superimposing of platelet-rich thrombus [5]. At present, aspirin combined with a P2Y12 receptor antagonist is a fundamental treatment for patients with ACS or coronary stent implantation [6]. Since 1997, clopidogrel has been recommended by the Food and Drug Administration as a standard P2Y12 receptor antagonist. However, clinical trials have demonstrated that approximately 25–50% of patients have poor response to clopidogrel, and high platelet residual activity can still be detected in patients receiving sufficient and regular medication [7–9]. In this case, a 2- to 6-fold increase in the risk of a variety of thrombotic events has been found in patients with poor response to clopidogrel as compared to those with normal response; this phenomenon is clinically referred to as high platelet reactivity in treatment (HRP) [10–12].
Recently, large-scale clinical trials have shown that the new P2Y12 receptor antagonists ticagrelor and prasugrel are more effective than clopidogrel in inhibiting platelet aggregation and are significantly better at reducing the incidence of ischemic events [13,14]. Ticagrelor, which was approved for use in the United States in 2011, is a non-thienopyridine, reversible inhibitor of adenosine diphosphate (ADP) receptors (P2Y 12) on platelets and is used to decrease the risk of recurrent coronary thromboses in patients who undergo interventions during an acute coronary syndrome. Ticagrelor is available in 90-mg tablets under the commercial name Brilinta. The usual maintenance dose is 90 mg twice daily in combination with daily low-dose aspirin (<100 mg). Meanwhile, studies such as the THALES trial (NCT03354429) [15], 2020 ESC Guidelines [16], Triton-TIMI 38 [17], TRILOGY-ACS Trials [17], ONSET/OFFSET [18], and PLATO [17,19] provided more evidence that ticagrelor and prasugrel are superior to clopidogrel. For patients with ACS, ticagrelor is currently recommended as a first-line antiplatelet agent [20–22]. However, 2 other large randomized controlled trials (RT) [23,24] and 2 observational trials (OBS) [25,26] found that compared with clopidogrel, ticagrelor did not significantly reduce the incidence of ischemic events. Furthermore, comprehensive meta-analyses have revealed that antagonistic effects of ticagrelor in some categories of patients, which involve many interference factors, may have some limitations, while there exist controversies regarding the safety and practical efficacy of this novel oral ADP receptor antagonist [27,28]. Based on the controversial data on the efficacy and safety of ticagrelor, the present article briefly reviews pharmacokinetics, pharmacodynamics, clinical indications, and adverse effects of P2Y12 antagonists, while presenting the latest evidence that ticagrelor is superior to clopidogrel. We also discuss various guidelines and reviews of clinical studies in which P2Y12 receptor antagonists were reasonably selected for ACS patients in dual-antiplatelet treatment. This review aims to present the roles of ticagrelor in the management of acute coronary syndrome, acute thrombotic disease, and other diseases.
Mechanisms
Ticagrelor, a cyclopentolate triazolopyridine, is thought to be a nucleoside analog with a structure similar to that of adenosine [2]. While being a new oral P2Y12 receptor antagonist with direct action and reversible binding, ticagrelor itself is an active drug with an average absolute bioavailability of 36%, which is not affected by cytochrome P450 (cytochrome P450, CYP) 2C19 genotype [29]. Compared with clopidogrel, ticagrelor displayed a faster onset of action after a loading dose with 30 min, inhibiting 88% of platelets at 2 h [2], with a half-life of 10.9–14.9 h [30]. Ticagrelor was absorbed rapidly with no effect by food, degrading to a major active metabolite. Ticagrelor and its active metabolite with high plasma protein binding rate have linear pharmacokinetics showing no clinically significant effect of body weight, sex, race, or smoking. Clopidogrel is a thiophene pyridine that irreversibly inhibits platelet adenosine diphosphate (ADP) receptors to prevent platelet aggregation induced by activated platelets-released ADP. Clopidogrel is a drug precursor that is metabolized by liver cytochrome p450 enzymes into active metabolites with irreversible binding to the p2Y12 receptor. The presence of very low plasma concentration of the original drug clopidogrel is attributed to its rapid metabolization in the liver, which leads to a peak concentration of blood levels of the drug in 1 h and a half-life of plasma clearance at 7–8 h. Compared with clopidogrel, ticagrelor exerts a faster and stronger inhibition of platelet aggregation, especially in cases of ACS and emergency PCI [31,32].
Improving Coronary Blood Flow
Use of a high level of adenosine in ticagrelor treatment was hypothesized to optimize preconditioning, possibly decreasing infarct size and preventing sudden cardiac death [33]. Furthermore, human and animal studies have shown that ticagrelor reduced the contraction of the great and small arteries induced by 2-Mes-ADP, probably improving coronary vasospasm. This observation demonstrated a unique property of ticagrelor, which has not been found in the case of prasugrel or clopidogrel [34,35]. In addition to inhibiting P2Y12, ticagrelor has other biological effects on increasing coronary blood flow. It has been shown that ticagrelor enhances adenosine-induced coronary flow in a canine model [36] and normal healthy volunteers based on transthoracic Doppler echocardiography compared with placebo [37], as well as in ACS patients as compared to prasugrel [38]. Meanwhile, due to inhibition on adenosine uptake via human erythrocytes [36], ACS patients receiving ticagrelor displayed a higher endogenous adenosine plasma level (APL) than those taking clopidogrel [39,40]. It was reported that adenosine could alleviate ischemia/reperfusion injury of the peri-infarct myocardium [41]. Ticagrelor could reduce ischemia-related arrhythmic events or salvage jeopardized tissue in ACS by augmenting APL. Patients with stable CAD treated with ticagrelor exhibited augmented global coronary flow induced by adenosine compared with those receiving clopidogrel [42]. In a ticagrelor group, these benefits were present in areas with impaired myocardial blood flow reserve, achieving equal effect to both medium and high doses of adenosine [42]. Compared with placebo, ticagrelor significantly increased adenosine-induced coronary blood flow velocity (CBFV) [37]. Ticagrelor also exerts many more functions, such as improving coronary blood flow after PCI with coronary artery chronic total occlusion (CTO) [43].
Reducing Myocardial Infarction Area
Ticagrelor can reduce myocardial infarct size, whereas clopidogrel cannot. Treatment with ticagrelor leads to activation of adenosine-receptor as well as downstream upregulation of cyclooxygenase-2 (COX2) and endothelial nitric oxide synthase, exerting an important myocardial-protective effect [44]. Adenosine is a key mediator of protection against myocardial ischemia-reperfusion injury, while forming a basis for the myocardial protection via various pharmacological and ischemic preconditioning [45,46]. Statins can activate the conversion of adenosine monophosphate into adenosine induced by ecto-5′ nucleotidase [47] and reduce infarct size (IS) via adenosine-receptor activation [45,46,48]. Moreover, the myocardial-protective effects of statins are dependent of the activation of cyclooxygenase-2 (COX2) [49–51]. As specific inhibitors of COX2, statins exhibit IS-limiting effects that can be abrogated by high-dose aspirin [50,52]. It was recently suggested that the potential interaction between high maintenance doses of aspirin and ticagrelor [53,54] may underlie the association between some of the myocardial benefits of ticagrelor and COX2 activity, which can be attenuated by higher doses of aspirin [55]. Patients with multivessel coronary disease undergoing PCI who received ticagrelor or prasugrel had smaller total infarct size and lower rate of microvascular obstruction (MVO) based on cardiac magnetic resonance (CMR) imaging than those receiving clopidogrel. These findings may give a reasonable explanation of clinical outcomes with the antiplatelet agents of third-generation agents compared to clopidogrel [56]. In another substudy, ticagrelor was associated with lower MVO incidence and smaller infarct size [56], and another randomized trial presented the same results [57].
Reducing High On-Treatment Platelet Reactivity
Although DAPT has achieved greater efficacy, especially in patients with stent implantation, a substantial proportion of patients receiving such therapy still experience recurrent ischemic events [58], which is attributed to the difference in pharmacodynamic response among clopidogrel-treated patients [59–61]. As a two-edged sword, the variability of pharmacodynamic response to P2Y12 receptor inhibitors has placed hyporesponsive patients at risk for thrombotic events, while creating a potential risk of bleeding in hyperresponsive patients [62]. Both Matetzky et al [59] and Bliden et al have reported a connection between low response to clopidogrel and HPR to adenosine diphosphate (ADP) in ischemic events. The relationship between HPR and thrombotic events following PCI has been well documented in several large studies. HPR related to short-term thrombotic events, such as acute and subacute stent thrombosis, has been detected in patients with stent implantation [59,63–69]. Multiple studies have demonstrated that ADP-stimulated platelet function provides significant prognostic information for patients who received clopidogrel treatment [70–74]. The PLATO substudy showed that for ACS treatment, ticagrelor displays greater activities in activation of antiplatelet in the first hours of therapy or during maintenance treatment than clopidogrel [32]. A prospective randomized study reported that, compared with clopidogrel, prasugrel and ticagrelor exert similar levels of P2Y12 inhibition and reduce HPR rates. The ONSET/OFFSET study [18] indicated that ticagrelor displays faster and greater platelet inhibition than clopidogrel. Several studies on Hispanic, Chinese, and Black patients found that during both the loading dose and maintenance dose, ticagrelor achieves a more rapid and greater antiplatelet effect in patients with ACS or stable coronary artery disease than does clopidogrel [75–78]. Ticagrelor exerts highly effective platelet inhibition and overcomes HPR in high-risk coronary patients who have HPR with clopidogrel treatment [79]. Compared with clopidogrel, ticagrelor causes more prompt and potent inhibition of platelets, as well as lower HPR rates in low-risk ACS patients undergoing PCI [80]. In a Chinese study of 102 patients with acute myocardial infarction [81], 48 patients with HPR were randomly assigned to either a ticagrelor group or a high-dose clopidogrel group for 24 h, and the ticagrelor group had lower platelet reactivity than the high-dose clopidogrel group. Two other studies [82,83] have shown that tailored DAPT can ameliorate the antiplatelet response in patients with HPR, possibly reducing thrombotic events and causing no increased risk of bleeding.
Reducing Ischemia-Reperfusion Injury and Improving Cardiac Function
Studies on animal models revealed that compared with clopidogrel, ticagrelor can better protect against myocardium reperfusion injury and improve myocardial remodeling. In the pig models [84], pigs underwent different treatments such as ticagrelor (180 mg; 90 mg/bid), clopidogrel (600 mg; 75 mg/qd), and placebo-control. Compared with the control group, the 2 P2Y12 antagonists reduced infarct size at day 3 after treatment, and there was a further 5% reduction in the ticagrelor group (P<0.05 vs clopidogrel). Notably, a reduction of edema (≈23%) associated with smaller scar size was evident in the ticagrelor group at day 42 after treatment. The ejection fraction (EF) of the left ventricular was increased in the ticagrelor group 3 days after MI, and high EF lasted up to day 42. There was extensive and severe abnormal wall motion in the control and clopidogrel groups, as well as reduced myocardial viability in the jeopardized myocardium due to lower myocardial AMPK and Akt/PKB activation with decreased aquaporin-4 levels, but these abnormalities were absent in the ticagrelor group. Similarly, another study [85] reported that ticagrelor reduced the infarct size in a dose-dependent manner by decreasing apoptosis and increasing myocardial levels of adenosine, endothelial NO synthase, phosphorylated Akt, and ERK 1/2, while clopidogrel had no such effects. In addition, ticagrelor improved EF 4 weeks after ischemia/reperfusion by attenuating fibrosis and decreasing the mRNA level of collagen-III, but clopidogrel did not. Moreover, ticagrelor decreased the levels of interleukin-1β, proinflammatory tumor necrosis factor-α, and interleukin-18, while increasing the levels of anti-inflammatory 15-epi-lipoxin-A4 [85], in agreement with other research [86]. To date, there has been no large randomized, double-blind, and multicenter research to investigate whether ticagrelor can improve myocardial remodeling after myocardial infarction. A trial [87] that is being conducted at 10 sites in Korea might provide a satisfactory answer.
Clinical Research
STEMI PATIENTS:
The PLATO study of a STEMI subgroup enrolled 8430 STEMI patients, including 4201 in the ticagrelor group and 4229 in the clopidogrel group; most of the patients underwent reperfusion therapy. The study showed that patients treated with ticagrelor had a lower risk of cardiovascular primary composite endpoints than those administered clopidogrel (9.3% vs 11.0%, P=0.02), consistent with the overall PLATO results [88]. The ATLANTIC study suggested that early pre-hospital administration of ticagrelor significantly reduced the risk of stent thrombosis of PCI compared with in-hospital administration [89]. Patients undergoing ambulance administration of ticagrelor had a lower probability of stent thrombosis after PCI than those receiving in-hospital administration of ticagrelor. Ticagrelor and prasugrel were associated with similar rates of stent thrombosis [90]. A recent trial from Canada (TOTAL) [91] recruited 9932 patients at hospital discharge, who were divided into clopidogrel, prasugrel, and ticagrelor groups. After adjustment, ticagrelor was associated with a lower risk of cardiovascular complications than clopidogrel. Three real-world studies on STEMI patients with PCI revealed that, compared with clopidogrel, ticagrelor improved 1-year survival [92], and was associated with lower adjusted 12-month mortality [93] and all-cause mortality rates [94].
PATIENTS WITH NON-ST ELEVATED ACUTE CORONARY SYNDROME:
Patients with non-ST elevated acute coronary syndrome include unstable angina pectoris and NSTEMI, both of which have similar pathogenesis and clinical manifestations, but with different severity [95]. For these patients, risk stratification should be carried out early, while relevant treatment strategies should be selected according to the degree of risk. Clinical application recommendations are as follows: (1) For patients with early invasive treatment of ischemic high-risk programs, ticagrelor is administered at a loading dose of 180 mg followed by a maintenance dose of 90 mg twice per day; (2) For patients with early conservative treatment, ticagrelor is recommended; and (3) Ticagrelor should be used in combination with aspirin for at least 12 months. The PLATO study enrolled 11 080 patients with non-ST elevated acute coronary syndrome. Among all the patients, 74%, 46%, and 5% underwent coronary angiography, PCI treatment, and coronary artery bypass grafting, respectively, within the first 10 days, while 5366 (48.4%) did not receive revascularization. Compared with clopidogrel, ticagrelor significantly decreased the rate of cardiovascular event complex endpoints and all-cause mortality, as well as rates of cardiovascular mortality and myocardial infarction. Ticagrelor and clopidogrel displayed the same benefits in reducing ischemic events and total mortality in patients with non-ST elevated acute coronary syndrome as those in the PLATO whole test, and these benefits occurred irrespective of whether revascularization was performed during the first 10 days [96].
ACS PATIENTS UNDERGOING CABG:
About 10% of patients in the PLATO study were randomly grouped to receive CABG treatment; among these patients, 1261 stopped the study drug for no more than 7 days before surgery. According to the study protocol, these patients should stop ticagrelor 1–3 days before surgery or clopidogrel 5 days before surgery. Compared with the clopidogrel group, the rates of cardiovascular death and all-cause death in the ticagrelor group were significantly lower, while the bleeding risk was similar. Ticagrelor reduces the risk of death after CABG, and this reduction may be associated with the effect of ticagrelor on decreasing death from cardiovascular disease, bleeding, and infection [97]. A study on CABG patients in China [98] found that the ticagrelor group exhibited a greater inhibition of platelet aggregation 2 h after the first drug administration than the clopidogrel group (34.2% vs 5.3%, P<.001). Moreover, the maximum mean inhibition rate of platelet aggregation within 2–24 h in the ticagrelor group remained higher than that in the clopidogrel group, but there was no associated increased risk of bleeding or major adverse cardiac events.
STABLE CORONARY HEART DISEASE:
Regarding non-revascularization patients, the PEGASUS-TIMI54 research project [99] enrolled patients with a history of myocardial infarction for more than 1 year as well as more than 1 of the following risk factors: older than 65 years of age, diabetes, renal insufficiency, multiple lesions, and over 2 myocardial infarctions. In the study, 90 mg/day and 60 mg/day groups of ticagrelor on aspirin displayed lower major therapeutic end-events (7.85% and 7.77%, respectively) than the placebo group (9.04%), and the risk of cardiovascular death was lower in the ticagrelor groups. Moreover, prolonged treatment with ticagrelor plus aspirin for 30 months decreased MACEs without increasing fatal bleeding in patients with MI. The ONSET/OFFSET study [18] has shown that greater IPA (platelet inhibition) occurred in patients treated with ticagrelor versus clopidogrel. The rate of patients who achieved >50% IPA and >70% IPA was higher in the ticagrelor group 2 h after receiving the loading dose.
Special Groups
PATIENTS WITH CHRONIC KIDNEY DISEASE (CKD):
Ticagrelor has a very low rate of metabolism and is excreted through the kidneys, while the recovery of ticagrelor and its active metabolites in the urine is less than 1% of the dose. There were no significant differences in pharmacodynamics, pharmacokinetics, and safety data between patients with severe renal failure (creatinine clearance <30%) versus those with normal renal function [100]. Compared with clopidogrel, ticagrelor remarkably reduced the risk of active endpoint events (17.3% vs 22%, P<0.05) and all-cause mortality (10.0% vs 14.0%, P<0.05) in the CKD subgroup [101]. Moreover, ticagrelor displayed a higher rate of platelet inhibition and faster inhibitory effect in dialysis patients and patients with impaired renal function compared to clopidogrel [102–104]. Recent studies have revealed that in comparison with clopidogrel, ticagrelor markedly reduced hospitalization and 1-year cardiovascular events without increasing the risk of bleeding in patients with acute myocardial infarction and end-stage renal failure [105].
PATIENTS WITH COMPLEX CORONARY ARTERY LESIONS:
The PLATO study included a total of 4646 patients with complex coronary lesions. Compared with clopidogrel, ticagrelor significantly reduced cardiovascular complex endpoints (14.9% vs 17.6% P<0.05) [106].
DIABETES:
Diabetes is a strong independent predictor of short-term and long-term recurrent ischemic events in patients with coronary heart disease [107,108]. Compared with patients without diabetes, the risk of cardiovascular death was 1.8 times higher in ACS patients with diabetes and 1.4 times higher in patients with MI [109]. Abnormal regulation of platelets in diabetic patients via multiple signaling pathways, including receptors and intracellular and downstream pathways, leads to increased platelet reactivity [110,111]. Although aspirin combined with clopidogrel improves the prognosis of ACS patients, patients with diabetes remain at high risk of adverse events during follow-up [112]. The PLATO study, involving 4662 diabetic patients, revealed that the absolute risk of endpoint events and all-cause mortality were both decreased in the ticagrelor group, but there was no increase in major bleeding [113]. The PLATO study on a prespecified subgroup of diabetic patients identified an additional benefit of ticagrelor treatment in reducing cardiovascular accident over a 12-month follow-up. Another study found that, compared with clopidogrel, ticagrelor significantly reduced the incidence of thrombus formation in CAD patients [114]. A Chinese group [115] investigated 200 ACS patients with diabetes and found better outcomes for angina and lower stent thrombosis and all-cause mortality one month after PCI in the ticagrelor group versus the clopidogrel group. Compared with clopidogrel, ticagrelor reduced platelet resistance [116] and vascular inflammatory response, while improving vascular endothelial function [117] and vascular blood flow [118] in patients with coronary heart disease and diabetes.
ELDERLY PATIENTS:
The risk of recurrent ischemic events and death is high in elderly ACS patients with catheter-based complications. The PLATO trial found relationships between the primary composite outcome and age, as well as major bleeding. The composite of cardiovascular death, stroke, myocardial infarction, cardiovascular death, definite stent thrombosis, and all-cause mortality was not significantly different between patients aged ≥75 and those <75 years of age and both groups showed the clinical benefit of ticagrelor over clopidogrel. No increase in PLATO-defined major bleeding was found with ticagrelor versus clopidogrel in patients aged ≥75 years. Ticagrelor treatment led to the common adverse events of dyspnea and ventricular pauses, which were not related to age. It has been demonstrated that the overall safety and significant clinical benefit of ticagrelor versus clopidogrel in ACS patients of the PLATO study were not dependent on age [119].
PATIENTS WITH THROMBOLYSIS:
Early fibrinolysis can provide timely and effective myocardial reperfusion [120–123] for STEMI patients who cannot receive timely treatment of primary PCI. If primary PCI treatment is delayed by 2 h or longer, fibrinolytic therapy causes similar mortality rates as PCI [124,125]. When primary PCI cannot be performed within 2 h after diagnosis of STEMI, medication is recommended, including immediate fibrinolytic therapy associated with rescue PCI [126,127]. It was reported that ticagrelor is better than clopidogrel in fibrinolytic treatment of STEMI patients undergoing early PCI [128]. Patients treated with ticagrelor undergoing PCI within 24 h in treatment of tenecteplase (TNK) who received ticagrelor after PCI had significantly lower PRU (platelet reactivity units) compared with clopidogrel. A good endpoint was observed in 87.8% of patients treated with ticagrelor and 57.6% of patients receiving the treatment of clopidogrel. Consistently, another study on STEMI patients undergoing fibrinolytic treatment and early PCI [129] provided evidence that patients receiving ticagrelor displayed a significantly higher rate of adequate platelet inhibition (platelet reactivity units PRU <208) on long-term follow-up than those treated with clopidogrel (clopidogrel, 82.6% vs ticagrelor, 100.0%; P=0.038). It has been shown that while post-fibrinolysis HPR is common in STEMI patients, lower HPR was observed in patients treated with ticagrelor versus high-dose clopidogrel [130]. There were no differences in major, fatal, and intracranial bleeding in ticagrelor and clopidogrel groups associated with a significantly lower frequency of cardiovascular events in the ticagrelor-treated group in a trial [131] of 3799 patients with STEMI undergoing fibrinolytic therapy.
ANTIPLATELET THERAPY UNDER THE GUIDANCE OF GENOTYPES:
Several studies have found that clopidogrel did not effectively inhibit platelet aggregation in some patients. This phenomenon is known as “clopidogrel low response”, which could be an important predictor of coronary ischemic events. Meanwhile, some patients were prone to significant bleeding reactions; this observation may be related to polymorphisms in the CYP2C19 gene. The ONSET/OFFSET and RESPOND genotype studies [132] first introduced genotypes such as cyp2c19 (*1,*2,*3,*4,*5,*6,*7,*8,*17), which were associated with clopidogrel low response and cardiovascular events. According to the manifestations of different CYP2C19 genotypes, polymorphisms in CYP2C19 including loss-of-function (LOF) and increased function alleles could be categorized into ultrafast, rapid, intermediate (IM), and poor metabolizers (PM) [133]. Approximately 18% to 45% and 2% to 15% of the clinical population were classified as clopidogrel IM and PM, respectively, both of which were associated with clopidogrel low reactivity [134]. The proportion of patients with IM (about 50%) and PM (about 13~23%) in an Asian population was much higher than that in European and American populations [134]. Cytochrome P4502C19 (CYP2C19) plays a key role in metabolic transformation of clopidogrel. The CYP2C19*17 gain-of-function allele reduced platelet reactivity by increasing the bioavailability of clopidogrel’s active metabolites. Loss-of-function alleles CYP2C19*2 and CYP2C19*3 decreased activity of the metabolites by affecting functional metabolites of the enzyme, leading to a high platelet response. Patients with CYP2C19*17 [29] and CYP4F2 T alleles [135] were at higher risk of bleeding. The PLATO study found that ticagrelor was superior to clopidogrel in reducing cardiovascular composite endpoints in all CYP2C19 genotypes. On the contrary, the incidence of 30d cardiovascular events in the clopidogrel treatment group was significantly higher among allelic carriers of CYP2C19 loss-of-function alleles, and the risk of bleeding was markedly higher in the clopidogrel treatment group. A study on Chinese patients [136] withor without CYP2C19 genotype measured ADP-induced platelet aggregation using thromboelastography (TEG) and found that TEGADP was significantly higher in non-carriers, while the level of TEGADP was similar between non-carriers and carriers in the ticagrelor group. A study of PCI in China reported a significantly lower risk of MACE in patients receiving genotype-guided therapy versus conventional therapy [137]. Finally, a study in the Netherlands with elective PCI reported that prasugrel displayed a lower risk of MACE in PM compared with clopidogrel [138]. A trial [139] of patients with stent implantation showed that carriers of loss-of-function alleles CYP2C19*2 or CYP2C19*3 receiving ticagrelor or prasugrel achieved more favorable results without increased bleeding outcome than the corresponding non-carriers treated with clopidogrel. In a study involving 1815 patients from 7 institutions, genetic testing of CYP2C19 was available for clinical use in PCI patients, and prasugrel or ticagrelor was recommended in IM/PM [140]. Compared with alternative therapies, clopidogrel treatment was associated with a significantly higher risk of MACE in IM/PM during 12-month follow-up.
Tolerability and Safety
BLEEDING:
In the PLATO study, no significant differences in major bleeding were found between ticagrelor and clopidogrel [141]. However, non-CABG (coronary artery bypass grafting)-related hemorrhages and non-surgical-related bleeding were more common in the ticagrelor group, especially after 30 days of treatment, compared with clopidogrel. Likewise, several studies have shown that the incidence of bleeding is higher in ticagrelor-treated patients compared with those treated with prasugrel, especially during long-term treatment [142, 143]. There has been no antidote for reversal of ticagrelor, which cannot be cleared by dialysis. In case of bleeding, appropriate supportive treatment with particular emphasis on local hemostasis is needed. Anti-fibrinolytic therapy (aminoacetic acid or carbamic acid) and/or recombinant factor VIIa may enhance hemostatic effects. Ticagrelor can be reused after the cause of the bleeding is determined and the bleeding is controlled [144–146].
DYSPNEA:
Dyspnea is a common adverse reaction of ticagrelor and may be associated with increased plasma adenosine concentration. The rates of mild-to-moderate dyspnea are dose-related, which is probably associated with the drug’s mechanism of activity [147]. Studies on healthy volunteers have demonstrated that intravenously injected adenosine can increase ventilation and heart rate, while inducing dyspnea [148,149]. Some clinical studies revealed that the percentage of patients with dyspnea after ticagrelor treatment was 10–15%, which was significantly higher than with other P2Y12 inhibitors. Notably, other trials found that nearly 40% of patients had this adverse reaction [23,150,151]. Although shortness of breath is often reported, lung function (pulmonary volume, spirometry, and pulse oximetry) of patients treated with either ticagrelor or clopidogrel was not affected [151,152]. Also, dyspnea was not related to patient age, and the efficacy and overall safety of ticagrelor were not associated with this adverse reaction [119,150]. In the PLATO study, the incidence of dyspnea in the ticagrelor group was 14.5%; among these cases, most were mild to moderate, while only 0.4% were severe. Dyspnea mostly occurred in the early stages (the median time: 23days in ticagrelor group and 43 days in the clopidogrel group, P<0.0001), and resolved without treatment in most cases. Approximately 0.9% of the patients decided to stop the treatment because of dyspnea [150].
HYPERURICEMIA:
In the PLATO study, a higher increase in serum uric acid levels in the first and twelfth months of treatment was found in the ticagrelor group compared with the clopidogrel group with no statistically significant difference between the 2 groups at 1 month after ceasing treatment [13]. Butler and Teng [153] conducted a randomized, cross-over, placebo-controlled study, and found that ticagrelor elevated hypoxanthine and xanthine levels in serum, resulting in increased levels of serum uric acids. Ticagrelor-associated hyperuricemia is usually mild and reversible, and it may be related to adenosine pathways. However, a single-center study found no difference in the baseline uric acid and creatinine levels between patients treated with clopidogrel versus ticagrelor for a period of 30–90 days [154]. Another trial [155] revealed that in patients treated with DAPT, uric acid level did not affect response of platelet reactivity to ticagrelor, clopidogrel, and aspirin.
ARRHYTHMIA:
Ticagrelor has been found to increase the incidence of bradyarrhythmias, including ventricular pauses detected by Holter [156]. A Holter substudy conducted continuous electrographic analysis on 2908 patients. In the first week, patients receiving ticagrelor had a higher frequency of ventricular pauses ≥3 s than those treated with clopidogrel. A month later, the pauses ≥3 s occurred less frequently overall, and the frequency was similar between the 2 groups of patients. Most were ventricular pauses, and the largest portion associated with ticagrelor were asymptomatic, sinoatrial nodal in origin (66%), and nocturnal. There were no differences in the occurrence of clinically reported bradycardic adverse events, such as syncope, cardiac arrest, and pacemaker placement between ticagrelor versus clopidogrel groups.
Conclusions
This review has presented the current status of regulatory approvals for the use of ticagrelor in the management of acute coronary syndrome, and acute thrombotic disease when combined with aspirin, and its superiority to clopidogrel. Further controlled clinical trials are needed to determine the role of ticagrelor in the management of other diseases.
References
1. Linden MD, Jackson DE, Platelets: Pleiotropic roles in atherogenesis and atherothrombosis: Int J Biochem Cell Biol, 2010; 42(11); 1762-66
2. Htun WW, Steinhubl SR, Ticagrelor: The first novel reversible P2Y(12) inhibitor: Expert Opin Pharmacother, 2013; 14(2); 237-45
3. Neumann FJ, Sousa-Uva M, Ahlsson A, 2018 ESC/EACTS guidelines on myocardial revascularization: Eur Heart J, 2019; 40(2); 87-165
4. Cowley MJ, Kuritzky L, Developments in antiplatelet therapy for acute coronary syndromes and considerations for long-term management: Curr Med Res Opin, 2009; 25(6); 1477-90
5. Grove EL, Wurtz M, Thomas MR, Kristensen SD, Antiplatelet therapy in acute coronary syndromes: Expert Opin Pharmacother, 2015; 16(14); 2133-47
6. Anderson JL, Adams CD, Antman EM, ACC/AHA 2007 guidelines for the management of patients with unstable angina/non ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non ST-Elevation Myocardial Infarction): developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons: Endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine: Circulation, 2007; 116(7); e148-304
7. Siller-Matula JM, Trenk D, Schror K, Response variability to P2Y12 receptor inhibitors: Expectations and reality: JACC Cardiovasc Interv, 2013; 6(11); 1111-28
8. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, Variability in individual responsiveness to clopidogrel: Clinical implications, management, and future perspectives: J Am Coll Cardiol, 2007; 49(14); 1505-16
9. Price MJ, Berger PB, Angiolillo DJ, Evaluation of individualized clopidogrel therapy after drug-eluting stent implantation in patients with high residual platelet reactivity: Design and rationale of the GRAVITAS trial: Am Heart J, 2009; 157(5); 818-24
10. Stone GW, Witzenbichler B, Weisz G, Platelet reactivity and clinical outcomes after coronary artery implantation of drug-eluting stents (ADAPT-DES) : A prospective multicentre registry study: Lancet, 2013; 382(9892); 614-23
11. Price MJ, Endemann S, Gollapudi RR, Prognostic significance of post-clopidogrel platelet reactivity assessed by a point-of-care assay on thrombotic events after drug-eluting stent implantation: Eur Heart J, 2008; 29(8); 992-1000
12. Wang ZJ, Zhou YJ, Liu YY, Impact of clopidogrel resistance on thrombotic events after percutaneous coronary intervention with drug-eluting stent: Thromb Res, 2009; 124(1); 46-51
13. Wallentin L, Becker RC, Budaj A, Ticagrelor versus clopidogrel in patients with acute coronary syndromes: N Engl J Med, 2009; 361(11); 1045-57
14. Wiviott SD, Braunwald E, McCabe CH, Prasugrel versus clopidogrel in patients with acute coronary syndromes: N Engl J Med, 2007; 357(20); 2001-15
15. Johnston SC, Amarenco P, Denison H, The acute stroke or transient ischemic attack treated with ticagrelor and aspirin for prevention of stroke and death (THALES) trial: Rationale and design: Int J Stroke, 2019; 14(7); 745-51
16. , Corrigendum to: 2020 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: The Task Force for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC): Eur Heart J, 2021; 42(23); 2298
17. Husted S, Boersma E, Case study: Ticagrelor in PLATO and prasugrel in TRITON-TIMI 38 and TRILOGY-ACS trials in patients with acute coronary syndromes: Am J Ther, 2016; 23(6); e1876-e89
18. Gurbel PA, Bliden KP, Butler K, Randomized double-blind assessment of the ONSET and OFFSET of the antiplatelet effects of ticagrelor versus clopidogrel in patients with stable coronary artery disease: The ONSET/OFFSET study: Circulation, 2009; 120(25); 2577-85
19. Cannon CP, Harrington RA, James S, Comparison of ticagrelor with clopidogrel in patients with a planned invasive strategy for acute coronary syndromes (PLATO) : A randomised double-blind study: Lancet, 2010; 375(9711); 283-93
20. Windecker S, Kolh P, Alfonso FAuthors/Task Force members, 2014 ESC/EACTS Guidelines on myocardial revascularization: The Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS)Developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI): Eur Heart J, 2014; 35(37); 2541-619
21. Roffi M, Patrono C, Collet JP, 2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: Task Force for the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-Segment Elevation of the European Society of Cardiology (ESC): Eur Heart J, 2016; 37(3); 267-315
22. Valgimigli M, Bueno H, Byrne RA, 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: The Task Force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS): Eur Heart J, 2018; 39(3); 213-60
23. Cannon CP, Husted S, Harrington RA, Safety, tolerability, and initial efficacy of AZD6140, the first reversible oral adenosine diphosphate receptor antagonist, compared with clopidogrel, in patients with non-ST-segment elevation acute coronary syndrome: Primary results of the DISPERSE-2 trial: J Am Coll Cardiol, 2007; 50(19); 1844-51
24. Goto S, Huang CH, Park SJ, Emanuelsson H, Kimura T, Ticagrelor vs. clopidogrel in Japanese, Korean and Taiwanese patients with acute coronary syndrome – randomized, double-blind, phase III PHILO study: Circ J, 2015; 79(11); 2452-60
25. Zocca P, van der Heijden LC, Kok MM, Clopidogrel or ticagrelor in acute coronary syndrome patients treated with newer-generation drug-eluting stents: CHANGE DAPT: EuroIntervention, 2017; 13(10); 1168-76
26. Park KH, Jeong MH, Ahn Y, Comparison of short-term clinical outcomes between ticagrelor versus clopidogrel in patients with acute myocardial infarction undergoing successful revascularization: from Korea Acute Myocardial Infarction Registry-National Institute of Health: Int J Cardiol, 2016; 215; 193-200
27. Guan W, Lu H, Yang K, Choosing between ticagrelor and clopidogrel following percutaneous coronary intervention: A systematic review and Meta-Analysis (2007–2017): Medicine, 2018; 97(43); e12978
28. Bonello L, Laine M, Lemesle G, Meta-analysis of potent P2Y12-ADP receptor antagonist therapy compared to clopidogrel therapy in acute coronary syndrome patients with chronic kidney disease: Thromb Haemost, 2018; 118(10); 1839-46
29. Wallentin L, James S, Storey RF, Effect of CYP2C19 and ABCB1 single nucleotide polymorphisms on outcomes of treatment with ticagrelor versus clopidogrel for acute coronary syndromes: A genetic substudy of the PLATO trial: Lancet, 2010; 376(9749); 1320-28
30. Franchi F, Angiolillo DJ, Novel antiplatelet agents in acute coronary syndrome: Nat Rev Cardiol, 2015; 12(1); 30-47
31. Bliden KP, Tantry US, Storey RF, The effect of ticagrelor versus clopidogrel on high on-treatment platelet reactivity: Combined analysis of the ONSET/OFFSET and RESPOND studies: Am Heart J, 2011; 162(1); 160-65
32. Storey RF, Angiolillo DJ, Patil SB, Inhibitory effects of ticagrelor compared with clopidogrel on platelet function in patients with acute coronary syndromes: The PLATO (PLATelet inhibition and patient Outcomes) PLATELET substudy: J Am Coll Cardiol, 2010; 56(18); 1456-62
33. Serebruany VL, Adenosine release: A potential explanation for the benefits of ticagrelor in the PLATelet inhibition and clinical outcomes trial?: Am Heart J, 2011; 161(1); 1-4
34. Hogberg C, Svensson H, Gustafsson R, The reversible oral P2Y12 antagonist AZD6140 inhibits ADP-induced contractions in murine and human vasculature: Int J Cardiol, 2010; 142(2); 187-92
35. Deeks ED, Ticagrelor: A review of its use in the management of acute coronary syndromes: Drugs, 2011; 71(7); 909-33
36. van Giezen JJ, Sidaway J, Glaves P, Ticagrelor inhibits adenosine uptake in vitro and enhances adenosine-mediated hyperemia responses in a canine model: J Cardiovasc Pharmacol Ther, 2012; 17(2); 164-72
37. Wittfeldt A, Emanuelsson H, Brandrup-Wognsen G, Ticagrelor enhances adenosine-induced coronary vasodilatory responses in humans: J Am Coll Cardiol, 2013; 61(7); 723-27
38. Alexopoulos D, Moulias A, Koutsogiannis N, Differential effect of ticagrelor versus prasugrel on coronary blood flow velocity in patients with non-ST-elevation acute coronary syndrome undergoing percutaneous coronary intervention: an exploratory study: Circ Cardiovasc Interv, 2013; 6(3); 277-83
39. Bonello L, Laine M, Kipson N, Ticagrelor increases adenosine plasma concentration in patients with an acute coronary syndrome: J Am Coll Cardiol, 2014; 63(9); 872-77
40. Fromonot J, Dignat-Georges F, Rossi P, Ticagrelor improves peripheral arterial function in acute coronary syndrome patients: Relationship with adenosine plasma level: J Am Coll Cardiol, 2016; 67(16); 1967-68
41. Gerczuk PZ, Kloner RA, An update on cardioprotection: A review of the latest adjunctive therapies to limit myocardial infarction size in clinical trials: J Am Coll Cardiol, 2012; 59(11); 969-78
42. Pelletier-Galarneau M, Hunter C, Ascah KJ, Randomized trial comparing the effects of ticagrelor versus clopidogrel on myocardial perfusion in patients with coronary artery disease: J Am Heart Assoc, 2017; 6(5); e005894
43. Brugaletta S, Gomez-Lara J, Caballero J, Ticagrelor versus clopidogrel for recovery of vascular function immediately after successful chronic coronary total occlusion recanalization: A randomized clinical trial: Am Heart J, 2018; 204; 205-9
44. Nanhwan MK, Ling S, Kodakandla M, Chronic treatment with ticagrelor limits myocardial infarct size: An adenosine and cyclooxygenase-2-dependent effect: Arterioscler Thromb Vasc Biol, 2014; 34(9); 2078-85
45. Kitakaze M, Minamino T, Node K, Adenosine and cardioprotection in the diseased heart: Jpn Circ J, 1999; 63(4); 231-43
46. Kloner RA, Current state of clinical translation of cardioprotective agents for acute myocardial infarction: Circ Res, 2013; 113(4); 451-63
47. Sanada S, Asanuma H, Minamino T, Optimal windows of statin use for immediate infarct limitation: 5′-nucleotidase as another downstream molecule of phosphatidylinositol 3-kinase: Circulation, 2004; 110(15); 2143-49
48. Cohen MV, Downey JM, Adenosine: Trigger and mediator of cardioprotection: Basic Res Cardiol, 2008; 103(3); 203-15
49. Atar S, Ye Y, Lin Y, Atorvastatin-induced cardioprotection is mediated by increasing inducible nitric oxide synthase and consequent S-nitrosylation of cyclooxygenase-2: Am J Physiol Heart Circ Physiol, 2006; 290(5); H1960-68
50. Birnbaum Y, Ye Y, Rosanio S, Prostaglandins mediate the cardioprotective effects of atorvastatin against ischemia-reperfusion injury: Cardiovasc Res, 2005; 65(2); 345-55
51. Ye Y, Martinez JD, Perez-Polo RJ, The role of eNOS, iNOS, and NF-kappaB in upregulation and activation of cyclooxygenase-2 and infarct size reduction by atorvastatin: Am J Physiol Heart Circ Physiol, 2008; 295(1); H343-51
52. Birnbaum Y, Lin Y, Ye Y, Aspirin before reperfusion blunts the infarct size limiting effect of atorvastatin: Am J Physiol Heart Circ Physiol, 2007; 292(6); H2891-97
53. Berger JS, Aspirin, clopidogrel, and ticagrelor in acute coronary syndromes: Am J Cardiol, 2013; 112(5); 737-45
54. Mahaffey KW, Wojdyla DM, Carroll K, Ticagrelor compared with clopidogrel by geographic region in the Platelet Inhibition and Patient Outcomes (PLATO) trial: Circulation, 2011; 124(5); 544-54
55. Eikelboom JW, Hirsh J, Spencer FA: Chest, 2012; 141(2 Suppl); e89S-e119S
56. Khan JN, Greenwood JP, Nazir SA, Infarct size following treatment with second-versus third-generation P2Y12 antagonists in patients with multivessel coronary disease at ST-segment elevation myocardial infarction in the CvLPRIT study: J Am Heart Assoc, 2016; 5(6); e003403
57. Kim EK, Park TK, Yang JH, Ticagrelor versus clopidogrel on myocardial infarct size in patients undergoing primary percutaneous coronary intervention: J Am Coll Cardiol, 2017; 69(16); 2098-99
58. Winter MP, Grove EL, De Caterina R, Advocating cardiovascular precision medicine with P2Y12 receptor inhibitors: Eur Heart J Cardiovasc Pharmacother, 2017; 3(4); 221-34
59. Matetzky S, Shenkman B, Guetta V, Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction: Circulation, 2004; 109(25); 3171-75
60. Gurbel PA, Bliden KP, Hiatt BL, O’Connor CM, Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity: Circulation, 2003; 107(23); 2908-13
61. Barragan P, Bouvier JL, Roquebert PO, Resistance to thienopyridines: clinical detection of coronary stent thrombosis by monitoring of vasodilator-stimulated phosphoprotein phosphorylation: Catheter Cardiovasc Interv, 2003; 59(3); 295-302
62. Tantry US, Bonello L, Aradi D, Consensus and update on the definition of on-treatment platelet reactivity to adenosine diphosphate associated with ischemia and bleeding: J Am Coll Cardiol, 2013; 62(24); 2261-73
63. Sibbing D, Braun S, Morath T, Platelet reactivity after clopidogrel treatment assessed with point-of-care analysis and early drug-eluting stent thrombosis: J Am Coll Cardiol, 2009; 53(10); 849-56
64. Geisler T, Zurn C, Simonenko R, Early but not late stent thrombosis is influenced by residual platelet aggregation in patients undergoing coronary interventions: Eur Heart J, 2010; 31(1); 59-66
65. Buonamici P, Marcucci R, Migliorini A, Impact of platelet reactivity after clopidogrel administration on drug-eluting stent thrombosis: J Am Coll Cardiol, 2007; 49(24); 2312-17
66. Migliorini A, Valenti R, Marcucci R, High residual platelet reactivity after clopidogrel loading and long-term clinical outcome after drug-eluting stenting for unprotected left main coronary disease: Circulation, 2009; 120(22); 2214-21
67. Gori AM, Marcucci R, Migliorini A, Incidence and clinical impact of dual nonresponsiveness to aspirin and clopidogrel in patients with drug-eluting stents: J Am Coll Cardiol, 2008; 52(9); 734-39
68. Cuisset T, Frere C, Quilici J, Predictive values of post-treatment adenosine diphosphate-induced aggregation and vasodilator-stimulated phosphoprotein index for stent thrombosis after acute coronary syndrome in clopidogrel-treated patients: Am J Cardiol, 2009; 104(8); 1078-82
69. Gurbel PA, Bliden KP, Samara W, Clopidogrel effect on platelet reactivity in patients with stent thrombosis: Results of the CREST Study: J Am Coll Cardiol, 2005; 46(10); 1827-32
70. Cuisset T, Frere C, Quilici J, High post-treatment platelet reactivity is associated with a high incidence of myonecrosis after stenting for non-ST elevation acute coronary syndromes: Thromb Haemost, 2007; 97(2); 282-87
71. Gurbel PA, Antonino MJ, Bliden KP, Platelet reactivity to adenosine diphosphate and long-term ischemic event occurrence following percutaneous coronary intervention: A potential antiplatelet therapeutic target: Platelets, 2008; 19(8); 595-604
72. Lev EI, Patel RT, Maresh KJ, Aspirin and clopidogrel drug response in patients undergoing percutaneous coronary intervention: The role of dual drug resistance: J Am Coll Cardiol, 2006; 47(1); 27-33
73. Gurbel PA, Bliden KP, Saucedo JF, Bivalirudin and clopidogrel with and without eptifibatide for elective stenting: Effects on platelet function, thrombelastographic indexes, and their relation to periprocedural infarction results of the CLEAR PLATELETS-2 (Clopidogrel with Eptifibatide to Arrest the Reactivity of Platelets) study: J Am Coll Cardiol, 2009; 53(8); 648-57
74. Komosa A, Siller-Matula JM, Lesiak M, Association between high on-treatment platelet reactivity and occurrence of cerebral ischemic events in patients undergoing percutaneous coronary intervention: Thromb Res, 2016; 138; 49-54
75. Price MJ, Clavijo L, Angiolillo DJ, A randomised trial of the pharmacodynamic and pharmacokinetic effects of ticagrelor compared with clopidogrel in Hispanic patients with stable coronary artery disease: J Thromb Thrombolysis, 2015; 39(1); 8-14
76. Forni Ogna V, Bassi I, Menetrey I, Comparative long-term effect of three anti-P2Y12 drugs after percutaneous angioplasty: An observational study based on electronic drug adherence monitoring: Front Pharmacol, 2017; 8; 738
77. Waksman R, Maya J, Angiolillo DJ, Ticagrelor versus clopidogrel in black patients with stable coronary artery disease: Prospective, randomized, open-label, multiple-dose, crossover pilot study: Circ Cardiovasc Interv, 2015; 8(7); e002232
78. Liu GZ, Zhang S, Sun DH, Half-dose ticagrelor versus high-dose clopidogrel in reducing platelet reactivity in acute coronary syndrome patients with high on-clopidogrel platelet reactivity (divide study): Eur J Clin Pharmacol, 2019; 75(8); 1059-68
79. Musallam A, Orvin K, Perl L, Effect of modifying antiplatelet treatment to ticagrelor in high-risk coronary patients with low response to clopidogrel (MATTIS): Can J Cardiol, 2016; 32(10); 1246e13-e19
80. Angiolillo DJ, Franchi F, Waksman R, Effects of ticagrelor versus clopidogrel in troponin-negative patients with low-risk ACS undergoing ad hoc PCI: J Am Coll Cardiol, 2016; 67(6); 603-13
81. Li P, Yang Y, Chen T, Ticagrelor overcomes high platelet reactivity in patients with acute myocardial infarction or coronary artery in-stent restenosis: A randomized controlled trial: Sci Rep, 2015; 5; 13789
82. Paarup Dridi N, Johansson PI, Lonborg JT, Tailored antiplatelet therapy to improve prognosis in patients exhibiting clopidogrel low-response prior to percutaneous coronary intervention for stable angina or non-ST elevation acute coronary syndrome: Platelets, 2015; 26(6); 521-29
83. Cecchi E, Marcucci R, Chiostri M, Dual antiplatelet therapy tailored on platelet function test after coronary stent implantation: A real-world experience: Intern Emerg Med, 2015; 10(7); 805-14
84. Vilahur G, Gutierrez M, Casani L, P2Y12 antagonists and cardiac repair post-myocardial infarction: Global and regional heart function analysis and molecular assessments in pigs: Cardiovasc Res, 2018; 114(14); 1860-70
85. Ye Y, Birnbaum GD, Perez-Polo JR, Ticagrelor protects the heart against reperfusion injury and improves remodeling after myocardial infarction: Arterioscler Thromb Vasc Biol, 2015; 35(8); 1805-14
86. Birnbaum Y, Tran D, Chen H, Ticagrelor improves remodeling, reduces apoptosis, inflammation and fibrosis and increases the number of progenitor stem cells after myocardial infarction in a rat model of ischemia reperfusion: Cell Physiol Biochem, 2019; 53(6); 961-81
87. Park Y, Choi SW, Oh JH, Rationale and design of the high platelet inhibition with ticagrelor to improve left ventricular remodeling in patients with ST-segment elevation myocardial infarction (HEALING-AMI) trial: Korean Circ J, 2019; 49(7); 586-99
88. Steg PG, James S, Harrington RA, Ticagrelor versus clopidogrel in patients with ST-elevation acute coronary syndromes intended for reperfusion with primary percutaneous coronary intervention: A Platelet Inhibition and Patient Outcomes (PLATO) trial subgroup analysis: Circulation, 2010; 122(21); 2131-41
89. Montone RA, Hoole SP, West NE, Prehospital ticagrelor in ST-segment elevation myocardial infarction: N Engl J Med, 2014; 371(24); 2338-39
90. Vos NS, Amoroso G, Vink MA, Prehospital prasugrel versus ticagrelor in real-world patients with ST-elevation myocardial infarction referred for primary PCI: Procedural and 30-day outcomes: J Invasive Cardiol, 2018; 30(12); 431-36
91. Welsh RC, Sidhu RS, Cairns JA, Outcomes among clopidogrel, prasugrel, and ticagrelor in ST-elevation myocardial infarction patients who underwent primary percutaneous coronary intervention from the TOTAL trial: Can J Cardiol, 2019; 35(10); 1377-85
92. Vercellino M, Sanchez FA, Boasi V, Ticagrelor versus clopidogrel in real-world patients with ST elevation myocardial infarction: 1-year results by propensity score analysis: BMC Cardiovasc Disord, 2017; 17(1); 97
93. Krishnamurthy A, Keeble C, Anderson M, Real-world comparison of clopidogrel, prasugrel and ticagrelor in patients undergoing primary percutaneous coronary intervention: Open Heart, 2019; 6(1); e000951
94. Hee L, Gibbs OJ, Assad JG, Real-world use of ticagrelor versus clopidogrel in percutaneous coronary intervention-treated ST-elevation myocardial infarction patients: A single-center registry study: J Saudi Heart Assoc, 2019; 31(4); 151-60
95. Amsterdam EA, Wenger NK, Brindis RG, 2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines: J Am Coll Cardiol, 2014; 64(24); e139-228
96. Lindholm D, Varenhorst C, Cannon CP, Ticagrelor vs. clopidogrel in patients with non-ST-elevation acute coronary syndrome with or without revascularization: results from the PLATO trial: Eur Heart J, 2014; 35(31); 2083-93
97. Varenhorst C, Alstrom U, Scirica BM, Factors contributing to the lower mortality with ticagrelor compared with clopidogrel in patients undergoing coronary artery bypass surgery: J Am Coll Cardiol, 2012; 60(17); 1623-30
98. Xu F, Feng W, Zhou Z, Antiplatelet effects of ticagrelor versus clopidogrel after coronary artery bypass graft surgery: A single-center randomized controlled trial: J Thorac Cardiovasc Surg, 2019; 158(2); 430-37e4
99. Bonaca MP, Braunwald E, Sabatine MS, Long-term use of ticagrelor in patients with prior myocardial infarction: N Engl J Med, 2015; 373(13); 1274-75
100. Uegami S, Ikawa K, Ohge H, Pharmacokinetics and pharmacodynamic target attainment of intravenous pazufloxacin in the bile of patients undergoing biliary pancreatic surgery: J Chemother, 2014; 26(5); 287-92
101. James S, Budaj A, Aylward P, Ticagrelor versus clopidogrel in acute coronary syndromes in relation to renal function: Results from the Platelet Inhibition and Patient Outcomes (PLATO) trial: Circulation, 2010; 122(11); 1056-67
102. Jeong KH, Cho JH, Woo JS, Platelet reactivity after receiving clopidogrel compared with ticagrelor in patients with kidney failure treated with hemodialysis: A randomized crossover study: Am J Kidney Dis, 2015; 65(6); 916-24
103. Barbieri L, Pergolini P, Verdoia M, Platelet reactivity in patients with impaired renal function receiving dual antiplatelet therapy with clopidogrel or ticagrelor: Vasc Pharmacol, 2016; 79; 11-15
104. Kim JS, Woo JS, Kim JB, The pharmacodynamics of low and standard doses of ticagrelor in patients with end stage renal disease on hemodialysis: Int J Cardiol, 2017; 238; 110-16
105. Lee CH, Tsai TH, Lin CJ, Efficacy and safety of ticagrelor compared with clopidogrel in patients with end-stage renal disease with acute myocardial infarction: Am J Cardiovasc Drugs, 2019; 19(3); 325-34
106. Kotsia A, Brilakis ES, Held C, Extent of coronary artery disease and outcomes after ticagrelor administration in patients with an acute coronary syndrome: Insights from the PLATelet inhibition and patient Outcomes (PLATO) trial: Am Heart J, 2014; 168(1); 68-75e2
107. Beckman JA, Paneni F, Cosentino F, Creager MA, Diabetes and vascular disease: Pathophysiology, clinical consequences, and medical therapy: Part II: Eur Heart J, 2013; 34(31); 2444-52
108. Haffner SM, Lehto S, Ronnemaa T, Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction: N Engl J Med, 1998; 339(4); 229-34
109. Malmberg K, Yusuf S, Gerstein HC, Impact of diabetes on long-term prognosis in patients with unstable angina and non-Q-wave myocardial infarction: Results of the OASIS (Organization to Assess Strategies for Ischemic Syndromes) Registry: Circulation, 2000; 102(9); 1014-19
110. Vinik AI, Erbas T, Park TS, Platelet dysfunction in type 2 diabetes: Diabetes Care, 2001; 24(8); 1476-85
111. Ferroni P, Basili S, Falco A, Davi G, Platelet activation in type 2 diabetes mellitus: J Thromb Haemost, 2004; 2(8); 1282-91
112. Patti G, Proscia C, Di Sciascio G, Antiplatelet therapy in patients with diabetes mellitus and acute coronary syndrome: Circ J, 2014; 78(1); 33-41
113. James S, Angiolillo DJ, Cornel JH, Ticagrelor vs. clopidogrel in patients with acute coronary syndromes and diabetes: A substudy from the PLATelet inhibition and patient Outcomes (PLATO) trial: Eur Heart J, 2010; 31(24); 3006-16
114. Zafar MU, Baber U, Smith DA, Antithrombotic potency of ticagrelor versus clopidogrel in type-2 diabetic patients with cardiovascular disease: Thromb Haemost, 2017; 117(10); 1981-88
115. Li DT, Li SB, Zheng JY, Analysis of ticagrelor’s cardio-protective effects on patients with ST-segment elevation acute coronary syndrome accompanied with diabetes: Open Med (Wars), 2019; 14; 234-40
116. Sweeny JM, Angiolillo DJ, Franchi F, Impact of diabetes mellitus on the pharmacodynamic effects of ticagrelor versus clopidogrel in troponin-negative acute coronary syndrome patients undergoing ad hoc percutaneous coronary intervention: J Am Heart Assoc, 2017; 6(4); e005650
117. He M, Li D, Zhang Y, Effects of different doses of ticagrelor on platelet aggregation and endothelial function in diabetic patients with stable coronary artery disease: Platelets, 2019; 30(6); 752-61
118. Mangiacapra F, Panaioli E, Colaiori I, Clopidogrel versus ticagrelor for antiplatelet maintenance in diabetic patients treated with percutaneous coronary intervention: Results of the CLOTILDIA study (clopidogrel high dose versus ticagrelor for antiplatelet maintenance in diabetic patients): Circulation, 2016; 134(11); 835-37
119. Husted S, James S, Becker RC, Ticagrelor versus clopidogrel in elderly patients with acute coronary syndromes: A substudy from the prospective randomized PLATelet inhibition and patient Outcomes (PLATO) trial: Circ Cardiovasc Quality Outcomes, 2012; 5(5); 680-88
120. Armstrong PW, Gershlick AH, Goldstein P, Fibrinolysis or primary PCI in ST-segment elevation myocardial infarction: N Engl J Med, 2013; 368(15); 1379-87
121. Boersma E, Maas AC, Deckers JW, Simoons ML, Early thrombolytic treatment in acute myocardial infarction: reappraisal of the golden hour: Lancet, 1996; 348(9030); 771-75
122. Roule V, Ardouin P, Blanchart K, Prehospital fibrinolysis versus primary percutaneous coronary intervention in ST-elevation myocardial infarction: A systematic review and meta-analysis of randomized controlled trials: Crit Care, 2016; 20(1); 359
123. Vora AN, Holmes DN, Rokos I, Fibrinolysis use among patients requiring interhospital transfer for ST-segment elevation myocardial infarction care: A report from the US National Cardiovascular Data Registry: JAMA Intern Med, 2015; 175(2); 207-15
124. Pinto DS, Frederick PD, Chakrabarti AK, Benefit of transferring ST-segment-elevation myocardial infarction patients for percutaneous coronary intervention compared with administration of onsite fibrinolytic declines as delays increase: Circulation, 2011; 124(23); 2512-21
125. Boersma EPrimary Coronary Angioplasty vs. Thrombolysis Group, Does time matter? A pooled analysis of randomized clinical trials comparing primary percutaneous coronary intervention and in-hospital fibrinolysis in acute myocardial infarction patients: Eur Heart J, 2006; 27(7); 779-88
126. O’Gara PT, Kushner FG, Ascheim DD, 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: Executive summary: A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: Circulation, 2013; 127(4); 529-55
127. Ibanez B, James S, Agewall S, 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC): Eur Heart J, 2018; 39(2); 119-77
128. Dehghani P, Lavoie A, Lavi S, Effects of ticagrelor versus clopidogrel on platelet function in fibrinolytic-treated STEMI patients undergoing early PCI: Am Heart J, 2017; 192; 105-12
129. Yang A, Pon Q, Lavoie A, Long-term pharmacodynamic effects of Ticagrelor versus Clopidogrel in fibrinolytic-treated STEMI patients undergoing early PCI: J Thromb Thrombolysis, 2018; 45(2); 225-33
130. Alexopoulos D, Perperis A, Koniari I, Ticagrelor versus high dose clopidogrel in ST-segment elevation myocardial infarction patients with high platelet reactivity post fibrinolysis: J Thromb Thrombolysis, 2015; 40(3); 261-67
131. Berwanger O, Nicolau JC, Carvalho AC, Ticagrelor vs clopidogrel after fibrinolytic therapy in patients with ST-elevation myocardial infarction: A randomized clinical trial: JAMA Cardiol, 2018; 3(5); 391-99
132. Tantry US, Bliden KP, Wei C, First analysis of the relation between CYP2C19 genotype and pharmacodynamics in patients treated with ticagrelor versus clopidogrel: the ONSET/OFFSET and RESPOND genotype studies: Circ Cardiovasc Genet, 2010; 3(6); 556-66
133. Caudle KE, Dunnenberger HM, Freimuth RR, Standardizing terms for clinical pharmacogenetic test results: Consensus terms from the Clinical Pharmacogenetics Implementation Consortium (CPIC): Genet Med, 2017; 19(2); 215-23
134. Scott SA, Sangkuhl K, Stein CM, Clinical pharmacogenetics implementation consortium guidelines for CYP2C19 genotype and clopidogrel therapy: 2013 update: Clin Pharmacol Ther, 2013; 94(3); 317-23
135. Tatarunas V, Kupstyte-Kristapone N, Norvilaite R, The impact of CYP2C19 and CYP4F2 variants and clinical factors on treatment outcomes during antiplatelet therapy: Pharmacogenomics, 2019; 20(7); 483-92
136. Xu JJ, Tang XF, Song YImpact of CYP2C19 genotypes on antiplatelet therapy among Chinese patients with acute myocardial infarction after percutaneous coronary intervention: Zhonghua Xin Xue Guan Bing Za Zhi, 2017; 45(2); 116-20 [in Chinese]
137. Shen DL, Wang B, Bai J, Clinical value of CYP2C19 genetic testing for guiding the antiplatelet therapy in a Chinese population: J Cardiovasc Pharmacol, 2016; 67(3); 232-36
138. Deiman BA, Tonino PA, Kouhestani K, Reduced number of cardiovascular events and increased cost-effectiveness by genotype-guided antiplatelet therapy in patients undergoing percutaneous coronary interventions in the Netherlands: Neth Heart J, 2016; 24(10); 589-99
139. Claassens DMF, Vos GJA, Bergmeijer TO: N Engl J Med, 2019; 381(17); 1621-31
140. Cavallari LH, Lee CR, Beitelshees AL, Multisite investigation of outcomes with implementation of CYP2C19 genotype-guided antiplatelet therapy after percutaneous coronary intervention: JACC Cardiovasc Interv, 2018; 11(2); 181-91
141. Becker RC, Bassand JP, Budaj A, Bleeding complications with the P2Y12 receptor antagonists clopidogrel and ticagrelor in the PLATelet inhibition and patient Outcomes (PLATO) trial: Eur Heart J, 2011; 32(23); 2933-44
142. Sakurai R, Burazor I, Bonneau HN, Kaneda H, Head-to-head comparison of prasugrel versus ticagrelor in patients undergoing percutaneous coronary intervention: A meta-analysis of randomized controlled trials: J Interv Cardiol, 2017; 30(5); 457-64
143. Deharo P, Bassez C, Bonnet G, Prasugrel versus ticagrelor in acute coronary syndrome: A randomized comparison: Int J Cardiol, 2013; 170(2); e21-22
144. Makris M, Van Veen JJBritish Committee for Standards in Haematology, Guideline on the management of bleeding in patients on antithrombotic agents: Br J Haematol, 2013; 160(1); 35-46
145. Steg PG, Huber K, Andreotti F, Bleeding in acute coronary syndromes and percutaneous coronary interventions: Position paper by the Working Group on Thrombosis of the European Society of Cardiology: Eur Heart J, 2011; 32(15); 1854-64
146. Levi M, Eerenberg E, Kamphuisen PW, Bleeding risk and reversal strategies for old and new anticoagulants and antiplatelet agents: J Thromb Haemost, 2011; 9(9); 1705-12
147. Husted S, van Giezen JJ, Ticagrelor: The first reversibly binding oral P2Y12 receptor antagonist: Cardiovasc Ther, 2009; 27(4); 259-74
148. Alexopoulos D, Xanthopoulou I, Gkizas V, Response to letter regarding article, “Randomized assessment of ticagrelor versus prasugrel antiplatelet effects in patients with ST-segment-elevation myocardial infarction”: Circ Cardiovasc Interv, 2013; 6(2); e29
149. Burki NK, Dale WJ, Lee LY, Intravenous adenosine and dyspnea in humans: J Appl Physiol, 2005; 98(1); 180-85
150. Storey RF, Becker RC, Harrington RA, Characterization of dyspnoea in PLATO study patients treated with ticagrelor or clopidogrel and its association with clinical outcomes: Eur Heart J, 2011; 32(23); 2945-53
151. Storey RF, Bliden KP, Patil SB, Incidence of dyspnea and assessment of cardiac and pulmonary function in patients with stable coronary artery disease receiving ticagrelor, clopidogrel, or placebo in the ONSET/OFFSET study: J Am Coll Cardiol, 2010; 56(3); 185-93
152. Storey RF, Becker RC, Harrington RA, Pulmonary function in patients with acute coronary syndrome treated with ticagrelor or clopidogrel (from the Platelet Inhibition and Patient Outcomes [PLATO] pulmonary function substudy): Am J Cardiol, 2011; 108(11); 1542-46
153. Butler K, Teng R, Evaluation and characterization of the effects of ticagrelor on serum and urinary uric acid in healthy volunteers: Clin Pharmacol Ther, 2012; 91(2); 264-71
154. Nardin M, Verdoia M, Pergolini P, Serum uric acid levels during dual antiplatelet therapy with ticagrelor or clopidogrel: Results from a single-centre study: Nutr Metab Cardiovasc Dis, 2016; 26(7); 567-74
155. Barbieri L, Verdoia M, Pergolini P, Uric acid and high-residual platelet reactivity in patients treated with clopidogrel or ticagrelor: Nutr Metab Cardiovasc Dis, 2016; 26(4); 352-58
156. Scirica BM, Cannon CP, Emanuelsson H, The incidence of bradyarrhythmias and clinical bradyarrhythmic events in patients with acute coronary syndromes treated with ticagrelor or clopidogrel in the PLATO (Platelet Inhibition and Patient Outcomes) trial: Results of the continuous electrocardiographic assessment substudy: J Am Coll Cardiol, 2011; 57(19); 1908-16
In Press
05 Mar 2024 : Clinical Research
Role of Critical Shoulder Angle in Degenerative Type Rotator Cuff Tears: A Turkish Cohort StudyMed Sci Monit In Press; DOI: 10.12659/MSM.943703
06 Mar 2024 : Clinical Research
Comparison of Outcomes between Single-Level and Double-Level Corpectomy in Thoracolumbar Reconstruction: A ...Med Sci Monit In Press; DOI: 10.12659/MSM.943797
21 Mar 2024 : Meta-Analysis
Economic Evaluation of COVID-19 Screening Tests and Surveillance Strategies in Low-Income, Middle-Income, a...Med Sci Monit In Press; DOI: 10.12659/MSM.943863
10 Apr 2024 : Clinical Research
Predicting Acute Cardiovascular Complications in COVID-19: Insights from a Specialized Cardiac Referral Dep...Med Sci Monit In Press; DOI: 10.12659/MSM.942612
Most Viewed Current Articles
17 Jan 2024 : Review article
Vaccination Guidelines for Pregnant Women: Addressing COVID-19 and the Omicron VariantDOI :10.12659/MSM.942799
Med Sci Monit 2024; 30:e942799
14 Dec 2022 : Clinical Research
Prevalence and Variability of Allergen-Specific Immunoglobulin E in Patients with Elevated Tryptase LevelsDOI :10.12659/MSM.937990
Med Sci Monit 2022; 28:e937990
16 May 2023 : Clinical Research
Electrophysiological Testing for an Auditory Processing Disorder and Reading Performance in 54 School Stude...DOI :10.12659/MSM.940387
Med Sci Monit 2023; 29:e940387
01 Jan 2022 : Editorial
Editorial: Current Status of Oral Antiviral Drug Treatments for SARS-CoV-2 Infection in Non-Hospitalized Pa...DOI :10.12659/MSM.935952
Med Sci Monit 2022; 28:e935952