INTRODUCTION

Dual antiplatelet therapy (DAPT) remains a standard approach to mitigating postoperative thrombotic event risk in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI). Indeed, the combination of ticagrelor and aspirin (TIC + ASP) was confirmed to significantly lower ischemic event incidence following PCI in ACS patients relative to clopidogrel monotherapy in the PLATO trials.1 However, enhanced antiplatelet therapy can also contribute to an elevated bleeding risk, particularly among individuals facing a high risk of gastrointestinal (GI) bleeding, including patients with erosive gastritis, ulcers, or GI tumors. Selecting the most appropriate antiplatelet regimens to balance the risk between bleeding and thrombosis/embolism is critical to ensuring optimal patient outcomes. Although the STOPDAPT-2 trial2 offers some therapeutic guidance for the monotherapeutic application of P2Y12 receptor inhibitors, clopidogrel resistance rates have previously been estimated to range from 4% to 44%,3 and in one recent analysis, clopidogrel monotherapy was found to be associated with an elevated risk of cardiovascular events as compared with ticagrelor monotherapy (TIC) among individuals facing a high risk of post-PCI bleeding.4 As the 30-day-postoperative period is the time for the greatest risk of in-stent thrombosis (ST) following PCI,5 many studies use a 1- to 3-month DAPT treatment period,4,6,7 and reports applying ticagrelor as monotherapy have been limited. This study was thus designed to examine the relative safety and efficacy of TIC in ACS patients facing a high risk of post-PCI GI bleeding.

METHODS Study Participants

This was a retrospective study enrolling eligible patients with ACS and a high risk of post-PCI GI bleeding from the Affiliated Hospital of the Jiangnan University from August 2016 to December 2019.

Inclusion Criteria

For this study, ACS (ST-elevation myocardial infarction [MI], non–ST-elevation MI, unstable angina pectoris) was diagnosed as per the 2019 China ACS Emergency Rapid Care Guidelines.8 Only patients ≥18 years of age undergoing PCI using new-generation drug-eluting or drug-coated stents (DESs) were enrolled. Elevated bleeding risk was defined based on the presence of peptic ulcers, erosive gastritis with bleeding, GI tumors, or related conditions that have been diagnosed through endoscopy and/or pathological assessment.

Exclusion Criteria

Patients were excluded if they exhibited any history of intracranial bleeding, major adverse ischemic or bleeding events within 1 month of being diagnosed with ACS, exhibited contraindications for aspirin use, were diagnosed with severe anemia and thrombocytopenia (platelet count <100,000/mm3), were affected by uncontrolled severe hypertension (systolic blood pressure >180 mm Hg and/or diastolic blood pressure >110 mm Hg), or had a history of kidney or liver failure. The Ethics Committee of the Affiliated Hospital of the Jiangnan University approved this study, with all patients and their family members having provided written informed consent.

Treatment and Follow-up

Two groups of patients were established for this study, including a control group in which patients were treated with TIC + ASP (n = 141) and a study group in which patients were administered TIC (n = 128). Aspirin was administered to patients once per day in the form of an enteric-coated tablet (100 mg/dose), whereas ticagrelor was administered twice per day (90 mg/dose). Enteric-coated lansoprazole tablets (30 mg/dose) were administered once per day to reduce the risk of GI bleeding in these high-risk patients. Demographic characteristics and clinical history were taken from all patients enrolled in this study, and levels of hemoglobin, platelet count, creatinine clearance, and low-density lipoprotein cholesterol were analyzed. Patients underwent in-person or telephone-based follow-up after 1, 3, 6, and 12 months.

End point Analyses

The primary end points for this study included the incidence of target vessel revascularization, ST, ischemic stroke (IS), and MI (defined as per the third universal definition9), and revascularization and ST were classified based on the Academic Research Consortium criteria.10 Bleeding Academic Research Consortium (BARC) type 2, 3, or 5 bleeding was also a primary study end point.11

Statistical Analysis

Statistical analyses were performed with SPSS 23.0. Data are reported as means ± SD and were compared with t-tests. Categorical variables are given as percentages and were compared with χ2 tests. Time series data for bleeding incidence were plotted as cumulative incidence curves. P < 0.05 was the threshold for significance.

RESULTS Baseline Characteristics

No significant differences in age, gender, weight, routine clinical tests, comorbidities, smoking history, or site of hemodynamic reconstruction were observed between the 2 patient groups at baseline. There were also no differences in the proportions of diseases associated with high GI bleeding risk in these 2 groups (Table 1).

TABLE 1. - Baseline Characteristics Characteristic Ticagrelor Monotherapy (N = 128) Ticagrelor plus Aspirin (N = 141) P Men (%) 85 (66.4) 92 (65.3) 0.842 Women (%) 43 (33.6) 49 (34.7) Age (y; m ± SD) 64.9 ± 8.2 65.3 ± 7.9 0.651 Weight (kg) 69.7 ± 6.9 68.0 ± 8.0 0.069 Hemoglobin (G/L; m ± SD) 124.4 ± 16.4 121.7 ± 19.4 0.212 Platelet (G/L; m ± SD) 252.8 ± 57.0 245.6 ± 69.3 0.353 LDL (mmol/L; m ± SD) 3.0 ± 0.9 3.2 ± 0.8 0.078 Ccr (mL/min; m ± SD) 70.4 ± 16.6 72.5 ± 18.7 0.337 Hypertension (%)  Yes 72 (56.2) 92 (65.2) 0.131  No 56 (43.8) 49 (34.8) Dyslipidemia (%)  Yes 57 (44.5) 51 (36.2) 0.162  No 71 (55.5) 90 (63.8) Smoker (%)  Yes 47 (36.7) 48 (34.0) 0.646  No 81 (63.3) 93 (66.0) Heart failure (%)  Yes 31 (24.2) 34 (24.1) 0.984  No 97 (75.8) 107 (75.9) Previous PCI (%)  Yes 19 (14.8) 19 (13.5) 0.748  No 109 (85.2) 122 (86.5) Prior stroke (%)  Yes 25 (19.5) 32 (22.7) 0.526  No 103 (80.5) 109 (77.3) Diabetes (%)  Yes 47 (36.7) 59 (41.8) 0.390  No 81 (63.3) 82 (58.2) Severe calcification (%)  Yes 54 (42.2) 61 (43.3) 0.859  No 74 (57.8) 80 (56.7) Multivessel coronary artery disease (%)  Yes 85 (66.4) 101 (71.6) 0.354  No 43 (33.6) 40 (28.4) Bifurcation coronary lesions  Yes 63 (49.2) 60 (42.6) 0.273  No 65 (50.8) 81 (57.4) Bleeding erosive gastritis or PU (%)  Yes 91 (71.1) 100 (70.9) 0.975  No 37 (28.9) 41 (29.1) GI cancer (%)  Yes 37 (28.9) 42 (29.8) 0.874  No 91 (71.1) 99 (70.2)

Ccr, creatinine clearance rate; LDL, low-density lipoprotein.

Ischemic and Bleeding Event Incidence

Over the 12-month follow-up period, ischemic events in this study cohort included 4 cases of ST, 4 cases of acute MI, 3 cases of IS, 4 cases of unplanned revascularization, and 7 instances of all-cause mortality. Of the included patients, 8 (6.3%) in the TIC group and 14 (9.9%) in the combination treatment group reached the primary ischemic end point within 1 year with no significant difference between these groups (Table 2; P > 0.05). Bleeding events were most frequently observed in the skin mucosa, affecting 6 patients (4.7%) in the TIC group and 10 patients (7.1%) in the TIC + ASP group. The second most common bleeding events were instanced of GI bleeding, which affected 1 patient (0.8%) in the TIC group and 11 patients (7.8%) in the TIC + ASP group, with additional cases of hematuria in 3 patients (2.3%) in the TIC group and 8 patients (5.7%) in the TIC + ASP group, as well as gum bleeding in 1 patient (0.8%) in the TIC group and 4 (2.8%) in the TIC + ASP group. The combination treatment group exhibited 2 cases of fundus hemorrhage and 3 cases of cerebral hemorrhage. Fatal bleeding events included 2 cases of cerebral bleeding and 4 of GI bleeding (Figure 1). Rates of BARC type 2, 3, or 5 bleeding and BARC type 3 or 5 bleeding differed significantly between these 2 groups (Table 2; P < 0.05).

TABLE 2. - Outcomes Between 1 and 12 Months after PCI Ticagrelor Monotherapy （N = 128） Ticagrelor plus (N = 141) P Ischemic end points  ST (%)   Yes 2 (1.6) 2 (1.4) 1.000   No 126 (98.4) 139 (98.6)  MI (%)   Yes 2 (1.6) 2 (1.4) 1.000   No 126 (98.4) 139 (98.6)  IS (%)   Yes 2 (1.6) 1(0.7) 0.606   No 126 (98.4) 140 (99.3)  Target-vessel revascularization (%)   Yes 1 (0.8) 3 (2.1) 0.624   No 127 (99.2) 138 (97.9)  Death from any cause (%)   Yes 1 (0.8) 6 (4.3) 0.123   No 127 (99.2) 135 (95.7) Bleeding end points  BARC type 2, 3, or 5 (%)   Yes 11 (8.6) 38 (27.0) <0.001*   No 117 (91.4) 107 (73.0)  BARC type 3 or 5 (%)   Yes 1 (0.8) 10 (7.1) 0.009*   No 127 (99.2) 131 (92.9)

*Statistical significance, p-value <0.05.

FIGURE 1.:

Bleeding site distribution.

Twelve-Month Cumulative Bleeding Event Incidence

Cumulative bleeding event incidence was compared between these 2 groups at 1, 3, 6, and 12 months of follow-up. This analysis revealed a significantly lower cumulative incidence of these bleeding events in the TIC group relative to the combination treatment group (P < 0.05; Figure 2).

FIGURE 2.:

Cumulative incidence of bleeding.

DISCUSSION

In this study, the relative safety and efficacy of TIC following PCI was assessed in ACS patients facing an elevated GI bleeding risk. Over a 12-month follow-up duration, patients in the TIC group experienced significant clinical benefit primarily attributable to the lower rates of bleeding complications without any significant change in ischemic event incidence.

Under current guidelines, it is recommended that ACS patients undergo combined treatment with both aspirin and a potent P2Y12 receptor antagonist such as ticagrelor for at least 12 months, including those patients previously using clopidogrel who should discontinue its use in favor of ticagrelor.12 Ticagrelor is a cyclopentyltriazolopyrimidine, and it is thus unaffected by the hepatic enzyme cytochrome P450 (CYP) 2C19 genotype in contrast to clopidogrel. It can facilitate rapid and robust inhibition of platelet activity without any metabolic activation, thereby decreasing the incidence of cardiomyocyte or vascular endothelial cell damage while also acting directly on platelet receptors to more effectively inhibit platelet accumulation. Such treatment is associated with a significantly lower risk of mortality and enhanced absolute cardiovascular benefit, particularly among patients with complex coronary lesions with high ischemia risk.13

The TRACER study14 demonstrated that both recurrent ischemic events and bleeding events resulted in time-dependent increases in morbidity and mortality among ACS patients undergoing antiplatelet therapy, underscoring the prognostic importance of bleeding events in this patient population. Accordingly, experts have proposed a step-down therapy approach in which drugs are changed (ticagrelor to clopidogrel), doses are adjusted, and the duration of dual treatment is shortened. However, the levels and activity of clopidogrel-derived active metabolites vary substantially among patients with some exhibiting low levels of responsibility or clopidogrel resistance.15–17 In-stent thrombosis has been determined to primarily occur within the 1-month period following PCI, and the ADAPT-DES study18 was able to attribute ∼60% of these thrombotic events to clopidogrel resistance. This study only enrolled ACS patients that underwent treatment following PCI, and clopidogrel was not used for the treatment of any of these individuals to reduced ischemic risk.

A large meta-analysis19 demonstrated that a <6-month DAPT course was safe and efficacious in ACS following PCI as compared with the standard 12-month course, leading to an increasing focus on balancing ischemic and bleeding risks by reducing the DAPT treatment period. As the risk of in-stent thrombosis is highest within 1 month after PCI among ACS patients, most large studies have employed combination antiplatelet therapy for this period. However, the risk of bleeding is directly proportional to the intensity of antithrombotic therapy,20 which would explain why the incidence of bleeding was higher in ACS patients at 30 days after PCI.21–23 The GLOBAL LEADERS trial24 was the first study to investigate this strategy clinically. The trial assessed 15,968 patients undergoing PCI involving treatment with TIC + ASP for 1 month followed by a 23-month TIC regimen. This was found to be associated with a nonsignificant 14% lower incidence of BARC type 3 or 5 bleeding at 1 year compared with TIC + ASP. The GLOBAL-LEADERS trial was followed by a subgroup analysis of 7487 patients with ACS, which is of particular interest as the discontinuation of aspirin was found to significantly reduce the risk of major bleeding events by 48% and numerically reduced the risk of Q-wave MI or death (P = 0.07).25 The TWILIGHT study7 employed similar experimental approaches, obtaining similar results while overcoming certain deficiencies of the GLOBAL LEADERS study. This trial showed that there was a significant 44% reduction in the primary end point of BARC 2–5 bleeding, favoring TIC and with no difference in MACE observed between the groups. The TICO trial also confirmed the benefit of TIC in patients with ACS, observing that the risk of the composite end point of ischemic, thrombotic, and bleeding events was significantly reduced by 37% with TIC26; the results remained consistent in the ACS patient subgroup characterized by a higher bleeding risk. In this study, the high incidence (27%) of bleeding episodes in the TIC + ASP group compared with the earlier results may be attributed to the use of a patient cohort with high risk of GI bleeding. However, our data were similar, finding that TIC was associated with a significantly lower risk of BARC type 2, 3, or 5 bleeding than TIC + ASP without ischemic damage and that the bleeding-related benefits of TIC extended to more severe BARC type 3 or 5 bleeds. At 12 months, the cumulative incidence of bleeding was increased in the TIC + ASP group, suggesting that the prognostic significance of major bleeding is similar to or greater than that of major ischemic events, whereas minor bleeding can lead to abrupt discontinuation of antiplatelet therapy, which may result in a higher incidence of ischemic events.27 The TEMPLATE study28 provides potential explanations for the mechanism underlying these discrepancies in adverse events observed in the above trials of TIC versus TIC + ASP. The similar antithrombotic effects observed between the groups may reflect comparable inhibition of the platelet thrombin-activation pathway29,30; however, the lower incidence of bleeding in the TIC group may be attributable to partial preservation of the platelet glycoprotein VI (collagen)–mediated activation pathways in the TIC group. This suggests that P2Y12 inhibitors provide sufficient thrombotic protection, which might lessen the need for aspirin.

In real-world settings, GI bleeds account for ∼77.2% of spontaneous bleeding events following PCI in discharged patients. With the exception of skin mucosal bleeding events, which can be managed in some cases without the need for intervention, this study observed similar results based on analyses of the highest percentage of GI bleeding events in both groups. These high rates have led to increasing research focus on risk factors linked to GI bleeding. Several analyses examined the relationship between acute lower GI bleeding and drug selection, demonstrating that these bleeding events were generally associated with low-dose aspirin.31 Injury to the gastric mucosa is a common side effect of aspirin treatment, which is commonly applied as a component of the antiplatelet regimen administered to ACS patients. The risk of injury to the digestive tract is significantly higher for individuals with a history of digestive tract diseases, as with a 13-fold higher risk of peptic ulcer bleeding.32 Although ACS guidelines suggest that these patients should also be administered proton pump inhibitor therapy, this alone cannot sufficiently control the risk of bleeding events, and sustained aspirin treatment will contribute to substantially higher GI bleeding risk. Among GI cancer patients and patients with ulcers treated in our hospital, many are also affected by ACS and some are unable to tolerate aspirin during the perioperative period. There is thus an urgent need to determine how these patients can most effectively benefit from antiplatelet therapy.

A major strength of this study is that it included a 12-month follow-up interval to assess the relative safety and efficacy of TIC relative to conventional DAPT following PCI among ACS patients facing a high GI bleeding risk. The overall results strongly suggest that the bleeding risk was significantly lower for patients in the TIC group without any loss of ischemic benefit relative to the combination treatment group. The reduced risk of bleeding may increase the net benefit for these patients without the need for a trade-off in efficacy. Such monotherapeutic treatment may thus represent an appropriate antiplatelet strategy that can address treatment bottlenecks facing these at-risk ACS patients, particularly those unable to tolerate aspirin.

However, as a single-center retrospective study, these results are subject to some limitations. For one, some data were missing when collecting these historical patient data, and the limited sample size may constrain the overall reliability of these analyses. Future large-scale, multicenter, prospective, randomized, controlled studies will thus be vital to provide a stronger evidence base in support of the safety and efficacy of routine TIC application in the clinic.

REFERENCES 1. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361:1045–1057. 2. Watanabe H, Domei T, Morimoto T, et al. Effect of 1 month dual antiplatelet therapy followedby clopidogrel versus 12-month dual antiplatelet therapy on cardiovascular and bleeding events in patients receiving PCI: the STOPDAPT-2 Randomized Clinical Trial. JAMA. 2019;321:2414–2427. 3. Snoep JD, Hovens MM, Eikenboom JC, et al. Clopidogrel nonresponsiveness in patients undergoing percutaneous coronary intervention with stenting: a systematic review and meta-analysis. Am Heart J. 2007;154:221–231. 4. Ming CY, Hua YZ, Jun ZL, et al. Clinical observation of monotherapy with antiplatelet in patients with high risk of bleeding after PCI. J Pract Med. 2021;37:379–384. 5. Han YL. De-escalation of anti-platelet therapy in patients with acute coronary syndromes undergoing percutaneous coronary intervention: a narrative review. Chin Med J (Engl). 2019;132:197–210. 6. Kim BK, Hong SJ, Cho YH, et al. Effect of ticagrelor monotherapy versus ticagrelor with aspirin on major bleeding and cardiovascular events in patients with acute coronary syndrome: the TICO randomized clinical trial. JAMA. 2020;323:2407–2416. 7. Mehran R, Baber U, Sharma SK, et al. Ticagrelor with or without aspirin in high-risk patients after PCI. Nengl J Med. 2019;381:2032–2042. 8. Chao ZX, Zhong YX, Ying CF, et al. Guidelines for emergency rapid diagnosis and treatment of acute coronary syndromes. J Clin Emerg Med. 2019;20:253–262. 9. Thygesen K, Alpert JS, Jaffe AS, et al. Third universal definition of myocardial infarction. Nat Rev Cardiol. 2012;9:620–633. 10. Cutlip DE, Windecker S, Mehran R, et al. Clinical end points in coronary stent trials: a case for standardized definitions. Circulation. 2007;115:2344–2351. 11. Mehran R, Rao SV, Bhatt DL, et al. Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the bleeding academic research consortium. Circulation. 2011;123:2736–2747. 12. Valgimigli M, Bueno H, Byrne RA, et al.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 (KSC) and of the European association for cardio-thoracic surgery (EACTS). Eur Heart J. 2018;39:213–260. 13. Kotsia A, Brilakis ES, Held C, et al. 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;168:68–75.e2. 14. Vranckx P, White HD, Huang Z, et al. Validation of BARC bleeding criteria in patients with acute coronary syndromes: the TRACER trial. J Am Coll Cardiol. 2016;67:2135–2144. 15. Qing TZ, Gao GF. Progress in the study of polymorphic CYP2C19 carrying gene and clopidogrel resistance. Chin J Circ. 2017;32:101–103. 16. Gurbel PA, Bliden KP, Butler K, et al. 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;120:2577–2585. 17. Siller-Matula JM, Trenk D, Schrör K, et al. Response variability to P2Y12 receptor inhibitors: expectations and reality. JACC Cardiovasc Interv. 2013;6:1111–1128. 18. Stone GW, Witzenbichler B, Weisz G, et al. Platelet reactivity and clinical outcomes after coronary artery implantation of drug-eluting stents (ADAPT-DES): a prospective multicentre registry study. Lancet. 2013;382:614–623. 19. Yin SH, Xu P, Wang B, et al. Duration of dual antiplatelet therapy after percutaneous coronary intervention with drug-eluting stent: systematic review and network meta-analysis. BMJ. 2019;365:12222. 20. Valgimigli M, Costa F, Lokhnygina Y, et al. Trade-off of myocardial infarction vs. bleeding types on mortality after acute coronary syndrome: lessons from the Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) randomized trial. Eur Heart J. 2017;38:804–810. 21. Manzano-Fernandez S, Sanchez-Martinez M, Flores-Blanco PJ, et al. Comparison of the global registry of acute coronary events risk score versus the can rapid risk stratification of unstable angina patients suppress adverse outcomes with early implementation of the ACC/AHA guidelines risk score to predict in hospital mortality and major bleeding in acute coronary syndromes. Am J Cardiol. 2016;117:1047–1054. 22. Brener SJ, Kirtane AJ, Stuckey TD, et al. The impact of timing of ischemic and hemorrhagic events on mortality after percutaneous coronary intervention: the ADAPT-DES study. JACC: Cardiovasc Interv. 2016;9:1450–1457. 23. Kazi DS, Leong TK, Chang TI, et al. Association of spontaneous bleeding and myocardial infarction with long-term mortality after percutaneous coronary intervention. J Am Coll Cardiol. 2015;65:1411–1420. 24. Vranckx P, Valgimigli M, Jüni P, et al. Ticagrelor plus aspirin for 1 month, followed by ticagrelor monotherapy for 23 months versus aspirin plus clopidogrel or ticagrelor for 12 months, followed by aspirin monotherapy for 12 months after implantation of a drug-eluting stent: a multicentre, open-label, randomised superiority trial. Lancet. 2018;392:940–949. 25. Tomaniak M, Chichareon P, Onuma Y, et al. Benefit and risks of aspirin inaddition to Ticagrelor in acute coronary syndromes. JAMA Cardiol. 2019;4:1092–1101. 26. Cho JY, Lee SY, Yun KH, et al. Factors related to major bleeding after ticagrelor therapy: results from the TICO trial. J Am Heart Assoc. 2021;10:e019630. 27. Buccheri S, Capodanno D, James S, et al. Bleeding after antiplatelet therapy for the treatment of acute coronary syndromes: a review of the evidence and evolving paradigms. Expert Opin Drug Saf. 2019;18:1171–1189. 28. Johnson TW, Baos S, Collett L, et al. Pharmacodynamic comparison of ticagrelor monotherapy versus ticagrelor and aspirin in patients after percutaneous coronary intervention: the TEMPLATE(Ticagrelor Monotherapy and Platelet Reactivity) randomized controlled trial. J Am Heart Assoc. 2020;9:e016495. 29. Angiolillo DJ, Capodanno D, Goto S. Platelet thrombin receptor antagonism and atherothrombosis. Eur Heart J. 2010;31:17–28. 30. Reininger AJ, Bernlochner I, Penz SM, et al. A 2-step mechanism of arterial thrombus formation induced by human atherosclerotic plaques. J Am Coll Cardiol. 2010;55:1147–1158. 31. Hreinsson JP, Palsdóttir S, Bjornsson ES. The association of drugs with severity and specific causes of acute lower gastrointestinal bleeding: a prospective study. J Clin Gastroenterol. 2016;50:408–413. 32. Zheng W, Zhang YJ, Liu R, et al. Prediction of gastrointestinal bleeding events in patients with acute coronary syndrome undergoing percutaneous coronary intervention: an observational cohort study (STROBE compliant). Medicine (Baltimore). 2020;99:e21312.