Safety of Clopidogrel vs. Ticagrelor in Dual Antiplatelet Therapy Regimens for High-Bleeding Risk Acute Coronary Syndrome Patients: A Comprehensive Meta-analysis of Adverse Outcomes.

INTRODUCTION: Patients of acute coronary syndrome (ACS) at a high-bleeding risk (HBR) often require dual antiplatelet therapy (DAPT) to reduce the risk of recurrent cardiovascular events. Clopidogrel and ticagrelor are the most commonly used antiplatelet agents in DAPT regimens. However, the safety profiles of these drugs in ACS patients at HBR remain a subject of ongoing debate. AIM: To investigate any difference between the safety of clopidogrel and ticagrelor used as a part of DAPT regimen in ACS patients at HBR. METHODS: A systematic search on PubMed, Cochrane Library, and Google Scholar was conducted to identify experimental and observational studies published up to the knowledge cutoff date in September 2023. Studies comparing the safety of clopidogrel and ticagrelor in ACS patients at HBR were included for analysis. The primary outcomes assessed were major bleeding events, stroke, and myocardial infarction (MI), while secondary outcomes included all-cause mortality, major adverse cardiac and cerebrovascular events (MACCE), and net adverse clinical and cerebral events (NACCE). RESULTS: We included a total of 8 observational studies in our meta-analysis. The pooled analysis revealed a statistically significant increase in the risk of MI (pooled RR = 1.43; 95% CI 1.12-1.83; P = 0.005) in the patients using clopidogrel. There were no statistically significant differences in major bleeding events (pooled RR = 0.94; 95% CI 0.82-1.09; P = 0.44), stroke (pooled RR = 1.36; 95% CI 0.86-2.14; P = 0.18), all-cause mortality (pooled RR = 1.17; 95% CI 0.97-1.41; P = 0.10), MACCE (pooled RR = 1.07; 95% CI 0.76-1.50; P = 0.69) and NACCE (pooled RR = 0.95; 95% CI 0.66-1.37; P = 0.78) between the two groups. Subgroup analyses based on region were performed. CONCLUSION: Both drugs are generally safe for treating ACS patients with HBR at baseline, although a higher risk of MI was observed with the use of clopidogrel. Nevertheless, drug choice should factor in regional variations, patient-specific characteristics, cost, accessibility, and potential drug interactions.

The efficacy and safety of aspirin-ticagrelor vs. aspirin-clopidogrel in ischemic stroke patients with cerebral artery stenting.

OBJECTIVE: First, the efficacy and safety of aspirin-ticagrelor after cerebral artery stenting in ischemic stroke patients is controversial. Second, there is a gap in the research on guiding two antiplatelet therapy (DAPT) after stenting based on the CYP2C19 genotype. METHODS: This retrospective study included patients who underwent cerebral artery stenting at the First Affiliated Hospital of Chongqing Medical University from January 2019 to February 2023. We divided them into the aspirin-clopidogrel group and aspirin-ticagrelor group and carefully collected baseline information laboratory data and imaging results from the patients. The efficacy outcomes were 30 days recurrent stroke, 90 days recurrent stroke, and 180 days recurrent stroke, and the safety outcome was intracranial hemorrhage. T-tests or Fisher's tests were performed for study outcomes in both groups of patients. OUTCOME: A total of 372 patients were included. For efficacy outcomes, aspirin-ticagrelor was associated with a reduced risk of 180 days recurrent stroke, in patients with CYP2C19 LOF allele (OR = 0.426, CI = 0.184-0.986, P = 0.042) and CYP2C19 intermediate metabolic genotype (OR = 0.237, CI = 0.026-1.034, P = 0.044), compared with aspirin-clopidogrel. There was no significant difference in the rate of intracranial hemorrhage (ICH) between patients with aspirin-clopidogrel and aspirin-ticagrelor, regardless of overall (OR = 1.221, CI = 0.115-7.245, P = 0.683), CYP2C19 LOF allele carriers (OR = 1.226, CI = 0.411-3.658, P = 0.715), or CYP2C19 intermediate metabolizer (OR = 1.221, CI = 0.115-7.245, P = 0.683). No significant differences were found between the two DAPTs on other efficacy and safety outcomes. CONCLUSION: A cohort study found that aspirin-ticagrelor was significantly superior to aspirin-clopidogrel in reducing 180 days recurrent stroke in CYP2C19 LOF allele carriers and CYP2C19 intermediate metabolizers. There was no significant difference between aspirin-ticagrelor and aspirin-clopidogrel in the risk of intracranial hemorrhage in terms of ICH rates.

Ticagrelor Induced Cheyne-Stokes Respiration and Asystolic Ventricular Standstill: A Case Report.

Ticagrelor is a potent, direct-acting, and reversible P2Y12­adenosine diphosphate receptor blocker. It has a rapid onset of action and an intense and consistent platelet reactivity inhibition that has been demonstrated to be superior to clopidogrel in decreasing major adverse events in acute coronary syndrome (ACS). Although ticagrelor is well tolerated in ACS patients, it has side effects, such as dyspnea and bradyarrhythmia, as reported in the Platelet Inhibition and Patient Outcomes (PLATO) study. Furthermore, it was reported that ticagrelor's bradyarrhythmic potential was transient and not clinically significant beyond the acute initiation phase. Nor was there a difference in rates of syncope or need for pacemaker insertion during 30 days of follow-up. Here we report a case of ticagrelor associated with Cheyne-Stokes respiration and asystolic ventricular standstill in a patient with ACS who required resuscitation and insertion of a temporary pacemaker.

Comparison of ticagrelor and clopidogrel in anemic patients with acute coronary syndrome: efficacy and safety outcomes over one year.

OBJECTIVE: This retrospective study aimed to investigate the potential impact of ticagrelor and clopidogrel treatment on cardiovascular outcomes in patients with anemia and acute coronary syndrome (ACS) and to provide insights into the optimal therapeutic approach for this vulnerable patient population. METHODS: A retrospective research design was employed, involving patients diagnosed with ST-segment elevation myocardial infarction (STEMI) or non-ST-segment elevation myocardial infarction (NSTEMI) between 2014 and 2021. Inclusion criteria required a hemoglobin level below 12 mg/dL and a minimum 12-month P2Y12 inhibitor treatment. Comprehensive clinical, biochemical, and echocardiographic data were collected from the hospital's electronic repository. The primary efficacy endpoint was major adverse cardiovascular events (MACE), encompassing total mortality, cardiovascular mortality, reinfarction, ischemic stroke, and hemorrhagic stroke. Major hemorrhage was the primary safety endpoint. Secondary outcomes included total mortality, cardiovascular mortality, reinfarction, ischemic stroke, and hemorrhagic stroke, individually. RESULTS: Patients treated with ticagrelor (n = 118) and clopidogrel (n = 538) were compared. No significant difference was observed in major adverse cardiovascular events (MACE) and major bleeding between ticagrelor and clopidogrel treatment groups (MACE: clopidogrel 10.0% vs. ticagrelor 11.0%, p = 0.75; major bleeding: clopidogrel 2.8%, ticagrelor 2.5%, p = 0.88). Patients with hemoglobin levels ≤ 8 mg/dL demonstrated significantly higher MACE and major bleeding rates in the ticagrelor group (p = 0.008 and p = 0.002, respectively). Among patients aged ≥ 75 years, ticagrelor treatment was associated with a higher risk of major bleeding (p = 0.04). CONCLUSIONS: Ticagrelor and clopidogrel exhibited comparable efficacy and safety outcomes in anemic ACS patients over a one-year period. Although ticagrelor demonstrated superiority in reducing ischemic events, it is crucial to recognize the limitations of retrospective studies in informing clinical practice. This study offers valuable insights into tailoring antiplatelet therapy for anemic ACS patients and provides guidance for personalized treatment strategies, acknowledging the hypothesis-generating nature of retrospective analyses.

Ticagrelor vs Clopidogrel for Complex Percutaneous Coronary Intervention in Chronic Coronary Syndrome.

BACKGROUND: Whether ticagrelor in chronic coronary syndrome patients undergoing complex percutaneous coronary intervention (PCI) can prevent cardiovascular events is unknown. OBJECTIVES: The authors sought to evaluate outcomes of complex PCI and the efficacy of ticagrelor vs clopidogrel in stable patients randomized in the ALPHEUS (Assessment of Loading with the P2Y12 inhibitor ticagrelor or clopidogrel to Halt ischemic Events in patients Undergoing elective coronary Stenting) trial. METHODS: All PCI procedures were blindly reviewed and classified as complex if they had at least 1 of the following criteria: stent length >60 mm, 2-stent bifurcation, left main, bypass graft, chronic total occlusion, use of atherectomy or guiding catheter extensions, multiwire technique, multiple stents. The primary endpoint was a composite of type 4a or b myocardial infarction (MI) and major myocardial injury during the 48 hours after PCI. We compared the event rates according to the presence or not of complex PCI criteria and evaluated the interaction with ticagrelor or clopidogrel. RESULTS: Among the 1,866 patients randomized, 910 PCI (48.3%) were classified as complex PCI. The primary endpoint was more frequent in complex PCI (45.6% vs 26.6%; P < 0.001) driven by higher rates of type 4 MI and angiographic complications (12.2% vs 4.8 %; P < 0.001 and 19.3% vs 8.6%; P < 0.05, respectively). The composite of death, MI, and stroke at 48 hours (12.7% vs 5.1 %; P < 0.05) and at 30 days (13.4% vs 5.3%; P < 0.05) was more frequent in complex PCI. No interaction was found between PCI complexity and the randomized treatment for the primary endpoint (Pinteraction = 0.47) nor the secondary endpoints. CONCLUSIONS: In chronic coronary syndrome, patients undergoing a complex PCI have higher rates of periprocedural and cardiovascular events that are not reduced by ticagrelor as compared with clopidogrel.

Effect of ticagrelor versus clopidogrel after implantation of drug-eluting stents guided by either intravascular ultrasound or angiography in patients with acute coronary syndrome-propensity score matching analysis.

BACKGROUND: The effect of different dual antiplatelet therapies on thrombotic events on the background of intravascular ultrasound (IVUS) guidance is unclear. We investigated whether ticagrelor can provide any additional benefit to clopidogrel in reducing thrombotic events in acute coronary syndrome (ACS) treated with drug- eluting stent (DES), when guided by IVUS or not. METHODS: A total of 5,666 ACS patients who underwent DES implantation and who were discharged on dual antiplatelet therapy were enrolled and grouped according to the use of IVUS or not. Each group was subdivided into two subgroups according to the type of P2Y12 inhibitor used after discharge. Propensity score matching (PSM) was used between the IVUS and no-IVUS groups. Covariate adjustment of Cox proportional hazards model was used between the ticagrelor and clopidogrel groups. Thrombotic event at 12 months was compared in groups separately. RESULTS: After PSM, 12-month follow-up data were available for 1,174 patients. Major adverse cardiac events (MACE) were less frequent in the IVUS-guided group (2.2% vs. 4.3%, P = 0.081) with a trend toward statistical significance. Comparison of antiplatelet regimens revealed significantly fewer major adverse cardiac and cerebrovascular events (MACCE) with ticagrelor in the entire PSM cohort and angiography-guided subgroup (2.9% vs. 5.7%, P = 0.035; 3.1% vs. 6.4%, P = 0.020, respectively). Among patients in the IVUS-guided group the outcome was comparable (2.5% vs. 4.4%, P = 0.312). Ticagrelor was associated with increasing bleeding incidence in the entire PSM cohort (1.3% vs. 3.3%, P = 0.030), mainly due to Bleeding Academic Research Consortium type 2 bleeding (0.7% vs. 2.6%, P = 0.010). The results were consistent after covariate adjustment of Cox proportional hazards model. CONCLUSION: The comparison of ischemic benefit between ticagrelor and clopidogrel was similar in patients receiving IVUS guidance during stent implantation, probably due to the precise implantation of IVUS. Multicenter, randomized studies should be performed to validate this conclusion.

Central Sleep Apnea in Patients With Coronary Heart Disease Taking P2Y12 Inhibitors.

ABSTRACT: Central sleep apnea (CSA) is common in patients with heart failure. Recent studies link ticagrelor use with CSA. We aimed to evaluate CSA prevalence in patients with coronary heart disease (CHD) and whether ticagrelor use is associated with CSA. We reviewed consecutive patients with CHD who underwent a polysomnography (PSG) test over a 5-year period from 3 sleep centers. We sampled patients who were on ticagrelor or clopidogrel during a PSG test at a 1:4 ticagrelor:clopidogrel ratio. Patients with an active opioid prescription during PSG test were excluded. Age, left ventricle (LV) dysfunction, and P2Y12 inhibitor use were included in a multivariate logistic regression. A total of 135 patients were included with 26 on ticagrelor and 109 on clopidogrel (age 64.1 ± 11.4, 32% male). High CSA burden (12%) and strict CSA (4.4%) were more common in patients on ticagrelor than in those on clopidogrel (27% vs. 8.3% and 10.0% vs. 1.8%). Ticagrelor use (vs. clopidogrel) was associated with high CSA burden (OR 3.53, 95% CI 1.04-12.9, P = 0.039) and trended toward significance for strict CSA (OR 6.32, 95% CI 1.03-51.4, P = 0.052) when adjusting for age and LV dysfunction. In an additional analysis also adjusting for history of atrial fibrillation, ticagrelor use and strict CSA became significantly associated (OR 10.0, 95% CI 1.32-117, P = 0.035). CSA was uncommon in patients with CHD undergoing sleep studies. Ticagrelor use (vs. clopidogrel) was associated with high CSA burden and trended toward significance for strict CSA.

The Effect of Platelet Activity, ABCB1 Genetic Polymorphism, and Renal Function on the Development of Ticagrelor-Related Dyspnea in Patients with Acute Coronary Syndrome.

Purpose: The aim of this study was to determine the effect of ABCB1 genetic polymorphism and renal function on the occurrence of ticagrelor-related dyspnea. Patients and Methods: A total of 299 patients with acute with type 1, 2, or 3 myocardial infarction (with and without ST-segment elevation), who underwent coronary angiography and PTCA with stent implantation and were treated with antiplatelet drugs (ticagrelor and aspirin), were enrolled in this prospective study. For all enrolled patient's platelet aggregation (induction with high-sensitivity adenosine diphosphate, ADP HS) testing was performed using a MULTIPLATE® analyzer. Venous blood was also collected for genotyping. Results: Patients experiencing ticagrelor-related dyspnea had lower ADP HS value (ADP HS ≤ 19.5 U; OR = 2.254; P = 0.009), higher creatinine concentration (>90 µmol/l; OR = 3.414; P = 0.019), and lower GFR value (<60 mL/min/1.73 m2; OR = 2.211; P = 0.035). ABCB1 T allele was associated with ticagrelor-related dyspnea (OR = 2.550; P = 0.04). Conclusion: Ticagrelor-related dyspnea was found to be related to low platelet aggregation, increased plasma creatinine concentration, decreased GFR, and ABCB1 T allele. Carriers of the ABCB1 T allele had a higher plasma creatinine concentration that could be associated with an inhibitory effect of ticagrelor on P-glycoprotein function.

Impact of Preloading Strategy With Ticagrelor on Periprocedural Myocardial Injury in Patients With Non-ST Elevation Myocardial Infarction Undergoing Early Invasive Strategy.

ABSTRACT: Pretreatment with an oral P2Y12 receptor blocker (before coronary angiography) versus treatment in the catheterization laboratory has been a matter of debate in patients presenting with non-ST segment elevation myocardial infarction (NSTEMI). The primary aim of this study was to assess the impact of an immediate preloading strategy with ticagrelor on periprocedural myocardial injury in patients with NSTEMI treated with an early invasive strategy. NSTEMI patients who underwent coronary angiography and subsequent percutaneous coronary intervention (PCI) within 24 hours after hospital admission were divided into 2 groups: the first group (pretreatment group) included patients who received ticagrelor pretreatment as soon as possible after admission and the second group (no pretreatment group) included patients who received a loading dose of ticagrelor after coronary angiography. The pretreatment group included 232 patients, and the no pretreatment group included 87 patients. Male patients represented the majority of the patients. The 2 groups were similar in baseline characteristics, except for a greater incidence of hypertension ( P = 0.014) and higher hemoglobin levels ( P = 0.01) in the pretreatment group in comparison with the no pretreatment group. Patients in the ticagrelor pretreatment group had less myocardial injury until coronary angiography based on troponin measurements collected at 12 hours after admission ( P = 0.025). Patients in the ticagrelor pretreatment group also had fewer periprocedural myocardial injuries based on troponin measurements taken between 12 and 24 hours after the PCI ( P = 0.026 and P = 0.022, respectively). Our findings suggested that ticagrelor pretreatment reduces periprocedural myocardial injury in NSTEMI patients who underwent PCI within 24 hours after admission.

Ticagrelor was associated with lower fracture risk than clopidogrel in the dual anti-platelet regimen among patients with acute coronary syndrome treated with percutaneous coronary intervention.

PURPOSE: Patients with coronary artery disease have increased fracture risks. P2Y12 inhibitors may impact fracture risks. We compared the fracture risks associated with ticagrelor and clopidogrel in dual anti-platelet therapy (DAPT). METHODS: We identified all adults who underwent first-ever percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS) between 2010 and 2017 from a territory-wide PCI registry in Hong Kong. Following 1:1 propensity-score matching for baseline characteristics, patients were followed up till event occurrence, death, or 30 June 2022. Outcomes of interest were major osteoporotic fractures (MOF) identified by validated ICD-9-CM codes. Cox proportional hazards regression was used to compute the hazard ratio (HR) for MOF associated with ticagrelor versus clopidogrel use. RESULTS: 3018 ticagrelor users and 3018 clopidogrel users were identified after propensity-score matching (mean age: 61.4 years; 84.1% men). Upon median follow-up of 6.5 years, 59 ticagrelor users and 119 clopidogrel users sustained MOF (annualized fracture risks: 0.34% and 0.56%, respectively). Ticagrelor use was associated with lower risks of MOF (HR 0.60, 95%CI 0.44-0.83; p = 0.002). Consistent HRs were observed for fractures over vertebrae, hip and upper limbs. Subgroup analyses showed no interaction according to age, sex, presence of diabetes, presence of chronic kidney disease and prior fracture history. CONCLUSION: Among adults who underwent first-ever PCI for ACS, ticagrelor use in the DAPT was associated with a lower risk of MOF compared with clopidogrel. Our results support the use of ticagrelor in the DAPT from the perspective of bone health.

Preferred monotherapy after short-term dual antiplatelet therapy: Systematic review and network meta-analysis of randomized trials.

BACKGROUND: Randomized controlled trials (RCTs) have demonstrated the efficacy and safety of P2Y12 inhibitor monotherapy following short-term dual antiplatelet therapy (DAPT) in patients undergoing percutaneous coronary intervention (PCI). However, no studies have compared P2Y12 inhibitor and aspirin monotherapy following short-term DAPT. We aimed to compare available strategies for DAPT duration and post-DAPT antiplatelet monotherapy following PCI. METHODS: Seven DAPT strategies [ticagrelor or clopidogrel following 1-month DAPT, ticagrelor following 3-month DAPT, aspirin following 3-6 months of DAPT (reference strategy), aspirin or P2Y12 inhibitor following 6-18-months of DAPT, and DAPT for ≥18 months] were compared using a network meta-analysis. The primary efficacy outcome was defined as a composite of all-cause death, myocardial infarction, and stroke. The primary bleeding outcome was trial-defined major or minor bleeding. RESULTS: Our analysis identified 25 eligible RCTs, including 89,371 patients who underwent PCI. Overall, none of the strategies negatively affected the primary efficacy outcomes. For primary bleeding outcomes, ticagrelor following 3-month DAPT was associated with a reduced risk of primary bleeding outcomes (HR 0.73; 95 % CI 0.57-0.95). Clopidogrel following 1-month DAPT was also associated with a reduced risk of primary bleeding outcomes (HR 0.54; 95 % CI 0.34-0.85), however, the strategy was associated with an increased risk of myocardial infarction or stent thrombosis. Similar trends were observed among patients with acute coronary syndrome and high bleeding risk. CONCLUSIONS: Compared with aspirin monotherapy following short-term DAPT, ticagrelor following 3-month DAPT was associated with a reduced risk of primary bleeding outcomes without increasing any ischemic outcomes.

Ticagrelor Steady-State Trough Concentration in Chinese Patients Undergoing Percutaneous Coronary Intervention.

BACKGROUND AND OBJECTIVE: Platelets play a pivotal role in thrombotic events associated with acute coronary syndrome (ACS), making oral antiplatelet therapy a cornerstone in antithrombotic strategies. The dosing regimen for the oral antiplatelet drug ticagrelor warrants evaluation to ensure its appropriateness in clinical practice. Therefore, this study aimed to investigate the real-world clinical application of ticagrelor by determining the optimal therapeutic concentration of ticagrelor in Chinese patients undergoing percutaneous coronary intervention (PCI). METHODS: We enrolled a cohort of 912 patients who underwent PCI with drug-eluting stent implantation for the treatment of ACS. We measured steady-state plasma drug concentrations using high-performance liquid chromatography-tandem mass spectrometry. The therapeutic drug concentration range at steady state was established on the basis of clinical pharmacodynamic indices, with verification of reliability through concentration-effect analysis and receiver operating characteristic curve assessment. RESULTS: Analysis of plasma samples from the 912 patients revealed significant variations in the steady-state trough concentration of ticagrelor associated with factors such as gender, age, hypertension, and hyperlipidemia. On the basis of this analysis, the optimal therapeutic range for steady-state trough concentration was determined to be 240.65-335.83 ng/mL. Furthermore, the upper limit values for steady-state concentration were established at 439.97 ng/mL for male patients and 347.06 ng/mL for female patients. CONCLUSIONS: This study provides robust and reliable insights into the optimal therapeutic steady-state trough concentrations of ticagrelor in Chinese patients with post-percutaneous coronary intervention. These findings have significant implications for guiding the rational use of antiplatelet drugs and facilitating precise drug administration in Chinese patients undergoing percutaneous coronary intervention.