Method for providing information on predicting bleeding events in patients receiving dual antiplatelet therapy

Abstract

In the present invention, different P2Y12 reaction unit values are used as cut-offs for predicting low platelet reactivity and bleeding risk in patients receiving dual antiplatelet therapy with ticagrelor or clopidogrel, thereby enabling the prediction of bleeding risk, breathlessness risk, and the possibility of early cessation in patients receiving dual antiplatelet therapy.

Description

Method for providing information on predicting the occurrence of bleeding in patients receiving dual antiplatelet therapy

[0001] The present invention relates to a method for providing information on predicting the occurrence of bleeding in a patient receiving dual antiplatelet therapy.

[0002]

[0003] Although ticagrelor is more effective than clopidogrel in reducing atherothrombotic events in patients with acute coronary syndromes (ACS) (1), safety concerns related to bleeding episodes and dyspnea during ticagrelor treatment have emerged. Current data challenge the net clinical benefit of ticagrelor over clopidogrel in these patients. A recent large retrospective cohort analysis raised concerns about an increased risk of bleeding and dyspnea during ticagrelor treatment, which may lead to premature discontinuation of the drug. It has been pointed out that the benefits of ticagrelor observed in clinical trials may not be observed in clinical practice.

[0004] An individualized approach that weighs the efficacy and duration of antithrombotic strategies in patients with ACS requires a balanced approach that considers the risks of thrombosis and bleeding. Therefore, many clinical trials are evaluating the clinical benefits of de-escalation strategies, particularly for dual antiplatelet therapy (DAPT) that includes potent P2Y12 inhibitors. Clinical evidence is accumulating regarding short-term DAPT, including early aspirin discontinuation, a uniform dose reduction strategy of potent P2Y12 inhibitors, or switching from potent P2Y12 inhibitors to clopidogrel.

[0005] Standard-dose ticagrelor (90 mg twice daily) remains the antiplatelet therapy recommended by Western guidelines for high-risk ACS patients. The term "East Asian Paradox" describes the unique risk-benefit tradeoffs and pharmacokinetic profiles of antithrombotic therapy in East Asian patients. To understand the conflicting results regarding the clinical benefits of potent P2Y12 inhibitors versus clopidogrel and the significant reduction in bleeding following a de-escalation strategy in East Asians, studies assessing the association between potency / type of antiplatelet agent and adverse events, and their contribution to medication adherence and clinical outcome are needed.

[0006]

[0007] The present invention aims to provide information on the relationship between dual antiplatelet therapy and the occurrence of bleeding, dyspnea, and premature discontinuation in patients receiving dual antiplatelet therapy, and on the prediction thereof.

[0008]

[0009] 1. A method for providing information on predicting the occurrence of bleeding in patients receiving dual antiplatelet therapy, which provides information that if the P2Y12 reaction unit (PRU) measured in a patient receiving dual antiplatelet therapy and receiving ticagrelor is 20 or less, the patient is more likely to experience bleeding than a patient who is not receiving dual antiplatelet therapy.

[0010] 2. In the above 1, a method for providing information on the prediction of bleeding occurrence in a patient with acute coronary syndrome who has undergone percutaneous coronary intervention and is receiving dual antiplatelet therapy.

[0011] 3. A method for providing information on predicting the occurrence of bleeding in patients receiving dual antiplatelet therapy, which provides information that if the P2Y12 reaction unit (PRU) measured in a patient receiving dual antiplatelet therapy and receiving clopidogrel is 110 or less, the patient is more likely to experience bleeding than a patient who is not receiving dual antiplatelet therapy.

[0012] 4. In the above 1, a method for providing information on the prediction of bleeding occurrence in a patient with acute coronary syndrome who has undergone percutaneous coronary intervention and is receiving dual antiplatelet therapy.

[0013]

[0014] The present invention provides a cutoff for predicting low platelet reactivity and the possibility of bleeding in patients receiving dual antiplatelet therapy receiving ticagrelor or clopidogrel.

[0015] The method of the present invention can predict the possibility of bleeding, dyspnea, and early discontinuation in patients receiving dual antiplatelet therapy using the above cutoff.

[0016]

[0017] Figure 1 is a flow chart of the present invention. ACS stands for acute coronary syndrome, and PCI stands for percutaneous coronary intervention.

[0018] Figure 2 shows the rate of early discontinuation of initial DAPT therapy. CI, confidence interval; DAPT, dual antiplatelet therapy; HR, hazard ratio.

[0019] Figure 3 shows the association between bleeding episodes and platelet reactivity according to DAPT therapy. (A) Receiver Operating Characteristic (ROC) curve analysis: cutoffs for "low platelet reactivity" according to P2Y12 inhibitor type and (B) prevalence of "low platelet reactivity." AUC, area under the curve; CI, confidence interval; DAPT, dual antiplatelet therapy; OR, odds ratio; PRU, P2Y12 response unit; ROC, receiver operating characteristic.

[0020] Figure 4 shows premature discontinuation of DAPT due to early occurrence of adverse events: (A) four groups: presence of bleeding or dyspnea; and (B) two groups: presence of bleeding or dyspnea. DAPT, dual antiplatelet therapy; HR, hazard ratio.

[0021]

[0022] The present invention is described in detail below.

[0023]

[0024] The present invention relates to a method for providing information on predicting the occurrence of bleeding in a patient receiving dual antiplatelet therapy.

[0025] DAPT stands for "Dual Antiplatelet Therapy," and is a treatment method that prevents blood clots in patients with acute coronary syndrome to prevent restenosis, myocardial infarction, and stroke. It involves taking two types of antiplatelet drugs, typically aspirin and a P2Y12 inhibitor such as clopidogrel or ticagrelor.

[0026] Aspirin inhibits platelet aggregation and has been shown in several studies to reduce the incidence of major short- and long-term cardiovascular events, including myocardial infarction and death, in patients with unstable angina. P2Y12 inhibitors have the advantage of inhibiting platelets more rapidly and carrying a lower risk of side effects compared to other drugs.

[0027] The present invention provides a correlation between the therapy (type of P2Y12 inhibitor) and the occurrence of bleeding, adverse effects such as dyspnea, and early discontinuation in patients receiving such dual antiplatelet therapy, and a standard for predicting the occurrence of bleeding.

[0028] The present invention can provide information that if the P2Y12 reaction unit (PRU) measured in a patient receiving dual antiplatelet therapy and receiving ticagrelor is 20 or less, the patient is more likely to experience bleeding than a patient who is not.

[0029] P2Y12 reaction units can be obtained using a method known as VerifyNow analysis.

[0030] In patients receiving dual antiplatelet therapy, the P2Y12 reaction unit (PRU) value can be used as a cutoff to predict low platelet reactivity and bleeding episodes. For example, a PRU of 20 or less measured in a patient receiving ticagrelor on dual antiplatelet therapy may provide information that the patient has low platelet reactivity and thus a higher risk of bleeding compared to patients not receiving dual antiplatelet therapy. Otherwise, the patient may be receiving ticagrelor on dual antiplatelet therapy but have a PRU of >20.

[0031] In the present invention, patients receiving dual antiplatelet therapy may be patients with acute coronary syndrome who have undergone percutaneous coronary intervention.

[0032] Additionally, the method of the present invention can provide information that patients with a higher risk of developing the above-described bleeding are more likely to experience dyspnea and premature discontinuation of dual antiplatelet therapy than patients without such a risk.

[0033]

[0034] In addition, the present invention relates to a method for providing information on predicting the occurrence of bleeding in a patient receiving dual antiplatelet therapy, which provides information that if the P2Y12 reaction unit (PRU) measured in a patient receiving dual antiplatelet therapy and receiving clopidogrel is 110 or less, the patient is more likely to experience bleeding than a patient who is not receiving dual antiplatelet therapy.

[0035] A PRU of 110 or less in a patient receiving dual antiplatelet therapy (DAPT) and taking clopidogrel may indicate a lower platelet reactivity and a higher risk of bleeding compared to patients not receiving DAPT. A patient receiving clopidogrel but with a PRU of 20 or more may be on DAPT.

[0036] In the present invention, patients receiving dual antiplatelet therapy may be patients with acute coronary syndrome who have undergone percutaneous coronary intervention.

[0037] Additionally, the method of the present invention can provide information that patients with a higher risk of developing the above-described bleeding are more likely to experience dyspnea and premature discontinuation of dual antiplatelet therapy than patients without such a risk.

[0038]

[0039] The present invention will be described in more detail with reference to the following examples.

[0040]

[0041] Materials and Methods

[0042] study patients

[0043] The study population was derived from the G-NUH (Gyeongsang National University Hospital, NCT04650529) registry, a prospective two-center database (Jinju and Changwon Gyeongsang National University Hospitals) that enrolled patients with coronary artery disease (CAD) undergoing percutaneous coronary intervention (PCI). Using data collected between September 2014 and December 2018, we assessed the prevalence of adverse events (e.g., bleeding, dyspnea) and platelet function measured by the VerifyNow test at 1-month follow-up in patients with ACS receiving ticagrelor versus clopidogrel DAPT. Patients admitted for ACS with or without ST-segment elevation and symptom onset in the preceding 24 hours were eligible for enrollment. The diagnosis of ACS was defined by current guidelines. The initial cohort consisted of patients treated with PCI for whom the VerifyNow test was available at admission. Patients who were taking oral anticoagulants, missed platelet function tests or questionnaires at 1-month follow-up, or were not followed up within 12 months were excluded from this initial cohort (Figure 1).

[0044] Baseline demographic, angiographic, procedural characteristics, and clinical outcome data were collected prospectively. Patients were followed routinely at 1, 6, and 12 months after the index procedure and annually thereafter.

[0045] Additional information was collected through medical records or telephone contact, if necessary. The hospital's institutional review board approved the study protocol and waived the requirement for written informed consent for access to the institutional registry. This study was conducted in accordance with Good Clinical Practice Guidelines and the principles of the Declaration of Helsinki.

[0046]

[0047] Procedures and Surveys

[0048] Upon arrival at the emergency department, patients with suspected ACS were treated with standard-dose aspirin and a P2Y12 receptor inhibitor. Emergency PCI was performed with aspirin 300 mg and ticagrelor 180 mg or clopidogrel 600 mg, based on the attending physician's judgment. Enrolled patients underwent PCI promptly if they had significant coronary artery stenosis (visual estimate >50%) and were eligible for PCI. Unfractionated heparin was administered for anticoagulation according to label instructions (100 IU / kg). The use of glycoprotein IIb / IIIa inhibitors was permitted during the procedure at the discretion of the interventionalist in emergency cases. After PCI, patients received aspirin 100 mg once daily plus ticagrelor 90 mg twice daily or clopidogrel 75 mg once daily. All patients received guideline-recommended medications.

[0049] One month later, adherence to medication was assessed through a pre-outpatient interview, a water intake survey, and a dedicated questionnaire. For patients who visited the clinic earlier than scheduled, the questionnaire was obtained before the physician's appointment. The survey data were collected by the study coordinator. Bleeding episodes were determined using a questionnaire based on the Bleeding Academic Research Consortium (BARC) criteria.

[0050] Dyspnea was classified using the modified Medical Research Council (mMRC) scale (19) (Table 1). Classification of BARC bleeding type and mMRC dyspnea grade was performed by the primary investigators (MG Kang and YH Jeong).

[0051]

[0052]

[0053]

[0054] Platelet function test

[0055] Platelet function was assessed using the VerifyNow P2Y12 assay before PCI and at 1-month follow-up. Blood samples for platelet function tests (PFTs) were collected at admission in the catheterization laboratory immediately after arterial sheath placement before PCI. The interval between antiplatelet loading and sampling was 2–12 hours for non-ST-segment elevation ACS, whereas the post-loading sampling time was relatively short (1–2 hours) for ST-segment elevation ACS. During the follow-up period, blood sampling was performed 2–6 hours after the last dose of study drug from the antecubital vein. We recommended performing a follow-up PFT immediately after hospital arrival before changing the DAPT regimen if the P2Y12 inhibitor was to be changed within 1 month.

[0056] Blood samples for platelet function analysis using the VerifyNow assay (Accriva, San Diego, CA, USA) were collected in 3.2% sodium citrate Vacuette tubes (Greiner Bio-One Vacuette North America, Inc., Monroe, NC, USA). This assay is a whole-blood, point-of-care, turbidimetric-based optical detection assay designed to measure platelet aggregation in response to agents based on the ability of activated platelets to bind fibrinogen. The channel contains fibrinogen-coated polystyrene beads, 20 mM adenosine diphosphate, and 22 nM prostaglandin E1. The optical signal from this channel is reported as P2Y12 response units (PRU).

[0057]

[0058] Endpoints and Results

[0059] The primary endpoint was the incidence of BARC bleeding and mMRC dyspnea, reported by a dedicated questionnaire, during 1 month of ticagrelor or clopidogrel treatment. Secondary endpoints included: (1) determinants of bleeding and dyspnea during 1 month of treatment; and (2) predictors of DAPT nonadherence during 12 months of treatment.

[0060] During the 1-year clinical follow-up period, data on major adverse cardiovascular events (MACE), BARC bleeding, and DAPT adherence were collected at months 1, 3, 6, and 12. MACE was defined as a composite of cardiac death, myocardial infarction (MI), or revascularization.

[0061]

[0062] Statistical analysis

[0063] The Kolmogorov-Smirnov test was performed to analyze the normal distribution of continuous variables. Continuous variables were presented as mean ± standard deviation or median (interquartile range [IQR]), and categorical variables were reported as frequencies and percentages. The Student unpaired t-test was used for parametric continuous variables and the Mann-Whitney U test for nonparametric continuous variables. Comparisons between categorical variables were performed using the Pearson Chi-square test or Fisher exact test, as appropriate. Receiver operating characteristic (ROC) curve analysis was performed to determine the optimal cutoff point for continuous variables, which were then converted to dichotomous covariates. All demographic characteristics and laboratory measurements were evaluated using univariate analysis to predict determinants of bleeding, dyspnea, and early discontinuation of DAPT. Variables with a p-value <0.1 in the univariate analysis were entered into multivariable logistic regression to provide odds ratios (ORs) and 95% confidence intervals (CIs).

[0064] Cumulative adherence probabilities for DAPT and survival curves were constructed using the Kaplan-Meier method and compared using the log-rank test. A p-value < 0.05 was considered statistically significant, and statistical analysis was performed using SPSSv24.0 software (SPSS Inc., Chicago, IL, USA).

[0065]

[0066] result

[0067] Patient characteristics

[0068] A total of 944 ACS patients (270 ticagrelor DAPT vs. 674 clopidogrel DAPT) met the eligibility criteria (Table 2).

[0069]

[0070]

[0071]

[0072] Patients on DAPT (ticagrelor) were younger and had higher rates of dyslipidemia and smoking compared to those on DAPT (clopidogrel). Procedural characteristics and concomitant medications were similar between DAPT regimens.

[0073] After antiplatelet loading, patients on DAPT (ticagrelor) had lower platelet reactivity than those on DAPT (clopidogrel) (138 ± 107 vs. 212 ± 84 PRU; △74 PRU; p < 0.001). After 1 month of maintenance, ticagrelor treatment showed a significantly stronger antiplatelet effect than clopidogrel treatment (22 ± 28 vs. 181 ± 69 PRU; △159 PRU; p < 0.001).

[0074] During 12 months of follow-up, a total of 4 (1.5%) MACEs (2 cardiac deaths, 1 nonfatal MI, 1 revascularization procedure) occurred in patients treated with ticagrelor, whereas 20 (3.0%) MACEs (9 cardiac deaths, 8 nonfatal MI, 4 revascularization procedures) occurred in patients treated with clopidogrel (p = 0.254).

[0075]

[0076] Incidence of bleeding, dyspnea, and premature discontinuation of dual antiplatelet therapy

[0077] The prevalence of bleeding and dyspnea at 1 month, based on a dedicated questionnaire, was common regardless of DAPT regimen (Table 3).

[0078]

[0079]

[0080]

[0081] The majority of events were reported as 'BARC type 1 bleeding' (86.2% of all bleeding) and 'mMRC grade 1 dyspnea' (73.0% of all dyspnea), respectively.

[0082] During the 1-month follow-up period, bleeding episodes were observed more frequently in patients treated with ticagrelor (45.6% vs. 23.6%; OR, 2.71; 95% CI, 2.01–3.65; p < 0.001). In addition, the incidence of dyspnea was higher in patients receiving ticagrelor DAPT (26.3% vs. 13.6%; OR, 2.25; 95% CI, 1.59–3.20; p < 0.001). However, the prevalence of severe bleeding (BARC type 3 bleeding) and severe dyspnea (mMRC grade 3 dyspnea) did not differ between DAPT regimens (bleeding: 2.2% vs. 2.1%, p = 0.889 and dyspnea: 4.1% vs. 2.4%, p = 0.157, respectively).

[0083] Discontinuation or switch to a P2Y12 receptor inhibitor was frequently observed within 12 months of ticagrelor treatment (27.8% vs. 4.7%; adjusted OR, 8.84; 95% CI, 4.50 to 17.24; p < 0.001) (Figure 2 ). Most premature discontinuations of standard-dose ticagrelor occurred within 6 months (14.4% at 1 month and 21.9% at 6 months, respectively) (Table 3 ), of which switches to clopidogrel (12.2%) and reduced ticagrelor dose (60 mg) (7.4%) were primarily applied to maintain DAPT therapy.

[0084]

[0085] Determinants of adverse events and criteria for low platelet reactivity

[0086] First, we evaluated the association between bleeding episodes and P2Y12 inhibitor type. In multivariable analysis, ticagrelor DAPT was significantly associated with an increased risk of 1-month BARC bleeding compared with clopidogrel DAPT (adjusted OR, 2.69; 95% CI, 1.97–3.67; p < 0.001) (Table 4A). 'PRU ≤ 82' was identified as the optimal cutoff for 'low platelet reactivity (LPR)' (highest combined sensitivity and specificity) to predict BARC bleeding at 1-month follow-up (area under the curve [AUC], 0.659; 95% CI, 0.620–0.698; p < 0.001) (Fig. 3A).

[0087] In the next step, this LPR criterion was incorporated into the bleeding prediction model (Table 4B). A PRU ≤ 82 independently increased the bleeding rate by approximately 2.7-fold (95% CI, 1.73–4.17; p < 0.001), eliminating the effect of ticagrelor versus clopidogrel on bleeding incidence. Therefore, the increased risk of bleeding during ticagrelor versus clopidogrel treatment can be explained by its stronger antiplatelet effect.

[0088] We also evaluated the LPR cutoff between ticagrelor and clopidogrel (which have different binding properties to the platelet P2Y12 receptor). For clopidogrel, which has irreversible binding properties, 'PRU ≤ 110' was the optimal cutoff for predicting bleeding episodes (AUC, 0.648; 95% CI, 0.592-0.702; p < 0.001) (Figure 3A). For ticagrelor, which has reversible binding properties, the cutoff for LPR ('PRU ≤ 20') was lower than that for clopidogrel (AUC, 0.583; 95% CI, 0.526-0.639; p = 0.014). The proportion of patients meeting LPR criteria was significantly higher in ticagrelor-treated patients (68.1% vs. 16.5%; OR, 6.41; 95% CI, 4.70-8.74; p < 0.001) (Fig. 3B).

[0089] Regardless of the type of P2Y12 inhibitor, LPR criteria were significantly associated with bleeding risk (clopidogrel: OR, 2.51; 95% CI, 1.63-3.89; p < 0.001 and ticagrelor: OR, 1.89; 95% CI, 1.12-3.21; p = 0.012, respectively).

[0090] In multivariable analysis, the occurrence of mMRC dyspnea during 1 month of treatment was significantly associated with BARC bleeding episodes (OR, 2.94; 95% CI, 2.02–4.25; p < 0.001) and DAPT regimen (ticagrelor vs. clopidogrel: OR, 2.19; 95% CI, 1.49–3.20; p < 0.001) (Table 4C), supporting that the type of P2Y12 inhibitor may be associated with dyspnea.

[0091]

[0092]

[0093]

[0094] Determinants of early discontinuation of dual antiplatelet therapy

[0095] Compared with clopidogrel DAPT, ticagrelor DAPT significantly increased the risk of discontinuation or switching to a P2Y12 inhibitor (adjusted OR, 7.42; 95% CI, 4.76–11.55; p < 0.001) (Table 5A). We also evaluated the impact of the occurrence of bleeding and dyspnea within 1 month on premature discontinuation of DAPT. The early occurrence of bleeding and dyspnea appeared to have a synergistic effect on premature discontinuation of DAPT, regardless of the type of DAPT regimen (adjusted OR, 2.40; 95% CI, 1.23–4.54; p = 0.007) (Table 5B).

[0096]

[0097]

[0098]

[0099] The highest rates of premature DAPT discontinuation were observed in patients with both bleeding and dyspnea episodes (Figure 4A). Furthermore, early reporting of adverse events (bleeding or dyspnea within 1 month) was significantly associated with a higher risk of DAPT nonadherence (16.1% vs. 8.7%; HR, 1.89; 95% CI, 1.30–2.76; p = 0.001) (Figure 4B).

Claims

1. A method for providing information on predicting the occurrence of bleeding in patients receiving dual antiplatelet therapy, which provides information that if the P2Y12 reaction unit (PRU) measured in a patient receiving dual antiplatelet therapy and receiving ticagrelor is 20 or less, the patient is more likely to experience bleeding than a patient who is not receiving dual antiplatelet therapy.

2. A method for providing information on the prediction of bleeding occurrence in a patient receiving dual antiplatelet therapy, wherein the patient is an acute coronary syndrome patient who underwent percutaneous coronary intervention according to claim 1.

3. A method for providing information on predicting the occurrence of bleeding in patients receiving dual antiplatelet therapy, which provides information that if the P2Y12 reaction unit (PRU) measured in a patient receiving dual antiplatelet therapy and receiving clopidogrel is 110 or less, the patient is more likely to experience bleeding than patients who are not receiving dual antiplatelet therapy.

4. A method for providing information on the prediction of bleeding occurrence in a patient receiving dual antiplatelet therapy, wherein the patient is an acute coronary syndrome patient who underwent percutaneous coronary intervention according to claim 1.

Images