XIENCE 90: A Safety Evaluation of 3-month DAPT After XIENCE Implantation for HBR Patients.

Study Overview
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Brief Summary
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XIENCE 90 study is a prospective, single arm, multi-center, open label trial to evaluate the safety of 3-month dual antiplatelet therapy (DAPT) in subjects at high risk of bleeding (HBR) undergoing percutaneous coronary intervention (PCI) with the approved XIENCE family of coronary drug-eluting stents. The XIENCE family stent systems include commercially approved XIENCE Xpedition Everolimus Eluting Coronary Stent System (EECSS), XIENCE Alpine EECSS, XIENCE PRO^X EECSS [rebrand of the XIENCE Xpedition Stent System and is only available outside of the United States (OUS)], XIENCE PRO^A EECSS (rebrand of the XIENCE Alpine Stent System and is only available OUS) and XIENCE Sierra EECSS of coronary drug-eluting stents.

Detailed Description
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A. Primary Objective: To show non-inferiority of the primary endpoint of all death or all MI (modified ARC) from 3 to 12 months following XIENCE implantation in HBR subjects treated with 3-month DAPT compared to a historical control after propensity score adjustment. B. Secondary Objective: To show superiority of the major secondary endpoint of major bleeding (Bleeding Academic Research Consortium [BARC] type 2-5) from 3 to 12 months following XIENCE implantation in HBR subjects treated with 3-month DAPT compared to a historical control after propensity score adjustment. To evaluate stent thrombosis (ARC definite/probable) from 3 to 12 months following XIENCE implantation in HBR subjects treated with 3-month DAPT against a performance goal (PG). All registered subjects will be followed at 3, 6 and 12 months post index procedure. The data collected from this study will be compared with the historical control of non-complex HBR subjects treated with standard DAPT duration of up to 12 months from the XIENCE V USA study, which is a US post-approval study to evaluate the safety of XIENCE V EECSS in all-comer population under real-world setting.

Official Title
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A Safety Evaluation of 3-month Dual Antiplatelet Therapy in Subjects at High Risk of Bleeding Undergoing Percutaneous Coronary Intervention With XIENCE.

Conditions
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Coronary Artery Lesions

Intervention / Treatment
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* Device: XIENCE
* Drug: DAPT


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject is considered at high risk for bleeding (HBR), defined as meeting one or more of the following criteria at the time of registration and in the opinion of the referring physician, the risk of major bleeding with > 3-month DAPT outweighs the benefit: ≥ 75 years of age. Clinical indication for chronic (at least 6 months) or lifelong anticoagulation therapy. History of major bleeding which required medical attention within 12 months of the index procedure. History of stroke (ischemic or hemorrhagic). Renal insufficiency (creatinine ≥ 2.0 mg/dl) or failure (dialysis dependent). Systemic conditions associated with an increased bleeding risk (e.g. hematological disorders, including a history of or current thrombocytopenia defined as a platelet count <100,000/mm^3, or any known coagulation disorder associated with increased bleeding risk). Anemia with hemoglobin < 11g/dl. Subject must be at least 18 years of age. Subject or a legally authorized representative must provide written informed consent as approved by the Institutional Review Board (IRB)/Ethics Committee (EC) of the respective clinical site prior to any study related procedure. Subject is willing to comply with all protocol requirements, including agreement to stop taking P2Y12 inhibitor at 3 months, if eligible per protocol. Subject must agree not to participate in any other clinical trial for a period of one year following the index procedure. Angiographic Inclusion Criteria Up to three target lesions with a maximum of two target lesions per epicardial vessel. Note: The definition of epicardial vessels means left anterior descending coronary artery (LAD), left circumflex coronary artery (LCX) and right coronary artery (RCA) and their branches. For example, the patient must not have >2 lesions requiring treatment within both the LAD and a diagonal branch in total. If there are two target lesions within the same epicardial vessel, the two target lesions must be at least 15 mm apart per visual estimation; otherwise this is considered as a single target lesion. Target lesion ≤ 32 mm in length by visual estimation. Target lesion must be located in a native coronary artery with visually estimated reference vessel diameter between 2.25 mm and 4.25 mm. Exclusive use of XIENCE family of stent systems during the index procedure. Target lesion has been treated successfully, which is defined as achievement of a final in-stent residual diameter stenosis of <20% with final TIMI-3 flow assessed by online quantitative angiography or visual estimation, with no residual dissection NHLBI grade ≥ type B, and no transient or sustained angiographic complications (e.g., distal embolization, side branch closure), no chest pain lasting > 5 minutes, and no ST segment elevation > 0.5 mm or depression lasting > 5 minutes. General Exclusion Criteria Subject with an indication for the index procedure of acute ST-segment elevation MI (STEMI). Subject has a known hypersensitivity or contraindication to aspirin, heparin/bivalirudin, P2Y12 inhibitors (clopidogrel/prasugrel/ticagrelor), everolimus, cobalt, chromium, nickel, tungsten, acrylic and fluoro polymers or contrast sensitivity that cannot be adequately pre-medicated. Subject with implantation of another drug-eluting stent (other than XIENCE) within 9 months prior to index procedure. Subject has a known left ventricular ejection fraction (LVEF) <30%. Subject judged by physician as inappropriate for discontinuation from P2Y12 inhibitor use at 3 months, due to another condition requiring chronic P2Y12 inhibitor use. Subject with planned surgery or procedure necessitating discontinuation of P2Y12 inhibitor within 3 months following index procedure. Subject with a current medical condition with a life expectancy of less than 12 months. Subject intends to participate in an investigational drug or device trial within 12 months following the index procedure. Pregnant or nursing subjects and those who plan pregnancy in the period up to 1 year following index procedure. Female subjects of child-bearing potential must have a negative pregnancy test done within 7 days prior to the index procedure per site standard test. Note: Female patients of childbearing potential should be instructed to use safe contraception (e.g., intrauterine devices, hormonal contraceptives: contraceptive pills, implants, transdermal patches, hormonal vaginal devices, injections with prolonged release.) It is accepted, in certain cases, to include subjects having a sterilised regular partner or subjects using a double barrier contraceptive method. However, this should be explicitly justified in special circumstances arising from the study design, product characteristics and/or study population Subject is part of a vulnerable population, defined as subject whose willingness to volunteer in a clinical investigation could be unduly influenced by the expectation, whether justified or not, of benefits associated with participation or of retaliatory response from senior members of a hierarchy in case of refusal to participate. Examples of populations which may contain vulnerable subjects include: individuals with lack of or loss of autonomy due to immaturity or through mental disability, persons in nursing homes, children, impoverished persons, subjects in emergency situations, ethnic minority groups, homeless persons, nomads, refugees, and those incapable of giving informed consent. Other vulnerable subjects include, for example, members of a group with a hierarchical structure such as university students, subordinate hospital and laboratory personnel, employees of the sponsor, members of the armed forces, and persons kept in detention. Subject is currently participating in another clinical trial that has not yet completed its primary endpoint. Angiographic Exclusion Criteria Target lesion is in a left main location. Target lesion is located within an arterial or saphenous vein graft. Target lesion is restenotic from a previous stent implantation. Target lesion is a total occluded lesion (TIMI flow 0). Target lesion contains thrombus as indicated in the angiographic images (per SYNTAX score thrombus definition). Target lesion is implanted with overlapping stents, whether planned or for bailout. Note: If there is more than one target lesion, all target lesions must satisfy the angiographic eligibility criteria. Non-target lesion (i.e., lesions that do not meet the angiographic criteria listed above) treatments are not allowed during the index procedure.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: XIENCE<br>Subjects will receive XIENCE family stents and if a subject was DAPT compliant and event free, then took 3 month DAPT, following with aspirin mono-therapy until 12 month | Device: XIENCE<br>* Subjects who received XIENCE family stent systems will be included.<br>Drug: DAPT<br>* 3-month clear subjects who receive 3-month DAPT without interruption of either aspirin and/or P2Y12 receptor inhibitor for > 7 consecutive days. Subject who are 3-month clear will discontinue P2Y12 inhibitor after 3-month visit, but continue taking aspirin through 12-month follow-up. Subjects who are not eligible for early P2Y12 inhibitor discontinuation will be treated per site standard of care.<br>* Other names: Dual antiplatelet therapy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Composite Rate of All Death or All Myocardial Infarction (MI)(Modified Academic Research Consortium [ARC]), by Propensity Score Quintiles | All death: All deaths are considered cardiac unless an unequivocal non-cardiac cause can be established. Specifically, any unexpected death even in patients with coexisting potentially fatal non-cardiac disease should be classified as cardiac. MI (Modified ARC): Patients present any of the following clinical or imaging evidence of ischemia: Clinical symptoms of ischemia; ECG changes indicative of new ischemia - new ST-T changes or new left bundle branch block, development of pathological Q waves; Imaging evidence of a new loss of viable myocardium or a new regional wall motion abnormality) AND confirmed with elevated cardiac biomarkers per ARC criteria: Periprocedural MI Spontaneous MI: CK-MB > URL or Troponin > URL with baseline value < UR The propensity score for each individual was calculated using a logistic regression model that included the study group as the outcome & the baseline demographic, clinical and procedural covariates as the predictors | From 3 to 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Major Bleeding Rate by Bleeding Academic Research Consortium (BARC) Type 2-5, by Propensity Score Quintiles | Type 2: Any overt, actionable sign of hemorrhage Type 3a: Overt bleeding plus Hb drop of 3 to < 5g/dL;Any transfusion with overt bleeding Type 3b: Overt bleeding plus Hb drop ≥ 5 g/dL;Cardiac tamponade;Bleeding requiring surgical intervention for control;Bleeding requiring IV vasoactive agents Type 3c: ICH; Subcategories confirmed by autopsy/imaging/lumbar puncture;Intraocular bleed compromising vision Type 4: CABG-related bleeding: Perioperative intracranial bleeding within 48h;Reoperation after closure of sternotomy for the purpose of controlling bleeding;Transfusion of ≥ 5 U whole blood or packed RBC within 48h;Chest tube output ≥ 2L within 24h Type 5: Fatal bleeding The propensity score for each individual was calculated using a logistic regression model that included the study group as the outcome & the baseline demographic, clinical and procedural covariates as the predictors. | From 3 to 12 months | 
| Number of Participants With Stent Thrombosis (ARC Definite/Probable) | Definite stent thrombosis: Definite stent thrombosis is considered to have occurred by either angiographic or pathologic confirmation. Probable stent thrombosis: Clinical definition of probable stent thrombosis is considered to have occurred after intracoronary stenting in the following cases: Any unexplained death within the first 30 days Irrespective of the time after the index procedure, any MI that is related to documented acute ischemia in the territory of the implanted stent without angiographic confirmation of stent thrombosis and in the absence of any other obvious cause | From 3 to 12 months | 
| Number of Participants With All Death, Cardiac Death, Vascular Death, Non-cardiovascular Death | All Death: All deaths are considered cardiac unless an unequivocal non-cardiac cause can be established. Specifically, any unexpected death even in patients with coexisting potentially fatal non-cardiac disease (e.g. cancer, infection) should be classified as cardiac. Cardiac death: Any death due to proximate cardiac cause (e.g. MI, low-output failure, fatal arrhythmia), unwitnessed death and death of unknown cause, all procedure related deaths including those related to concomitant treatment. Vascular death: Death due to non-coronary vascular causes such as cerebrovascular disease, pulmonary embolism, ruptured aortic aneurysm, dissecting aneurysm, or other vascular cause. Non-cardiovascular death: Any death not covered by the above definitions such as death caused by infection, malignancy, sepsis, pulmonary causes, accident, suicide or trauma. | From 3 to 12 months | 
| Number of Participants With All Myocardial Infarction (MI) and MI Attributed to Target Vessel (TV-MI, Modified ARC) | All Myocardial Infarction (Modified ARC): Patients present any of the following clinical or imaging evidence of ischemia: Clinical symptoms of ischemia; ECG changes indicative of new ischemia - new ST-T changes or new left bundle branch block (LBBB), development of pathological Q waves; Imaging evidence of a new loss of viable myocardium or a new regional wall motion abnormality) AND confirmed with elevated cardiac biomarkers per ARC criteria: Periprocedural MI: Within 48h after PCI: CK-MB >3 x URL or Troponin > 3 x URL with baseline value < URL Within 72h after CABG: CK-MB >5 x URL or Troponin > 5 x URL with baseline value < URL Spontaneous MI (> 48h following PCI, > 72h following CABG): CK-MB > URL or Troponin > URL with baseline value < URL TV-MI: All infarcts that cannot be clearly attributed to a vessel other than the target vessel will be considered related to the target vessel. | From 3 to 12 months | 
| Number of Participants With Composite of Cardiac Death or MI (Modified ARC) | Cardiac death: Any death due to proximate cardiac cause (e.g. MI, low-output failure, fatal arrhythmia), unwitnessed death and death of unknown cause, all procedure related deaths including those related to concomitant treatment. MI (Modified ARC): Patients present any of the following clinical or imaging evidence of ischemia: Clinical symptoms of ischemia; ECG changes indicative of new ischemia - new ST-T changes or new left bundle branch block (LBBB), development of pathological Q waves; Imaging evidence of a new loss of viable myocardium or a new regional wall motion abnormality) AND confirmed with elevated cardiac biomarkers per ARC criteria: Periprocedural MI: Within 48h after PCI: CK-MB >3 x URL or Troponin > 3 x URL with baseline value < URL Within 72h after CABG: CK-MB >5 x URL or Troponin > 5 x URL with baseline value < URL Spontaneous MI (> 48h following PCI, > 72h following CABG): CK-MB > URL or Troponin > URL with baseline value < URL | From 3 to 12 months | 
| Number of Participants With All Stroke, Ischemic Stroke and Hemorrhagic Stroke | An acute symptomatic episode of neurological dysfunction attributed to a vascular cause lasting more than 24 hours or lasting 24 hours or less with a brain imaging study or autopsy showing new infarction. Ischemic Stroke: An acute symptomatic episode of focal cerebral, spinal, or retinal dysfunction caused by an infarction of central nervous system tissue. Hemorrhagic Stroke: An acute symptomatic episode of focal or global cerebral or spinal dysfunction caused by a non-traumatic intraparenchymal, intraventricular, or subarachnoid hemorrhage. Undetermined Stroke: A stroke with insufficient information to allow categorization as ischemic or hemorrhagic. Pharmacologic, i.e., thrombolytic drug administration, or Non-pharmacologic, i.e., neurointerventional procedure (e.g., intracranial angioplasty) | From 3 to 12 months | 
| Number of Participants With Clinically-indicated Target Lesion Revascularization (CI-TLR) | Target Lesion Revascularization (TLR) is defined as any repeat percutaneous intervention of the target lesion or bypass surgery of the target vessel performed for restenosis or other complication of the target lesion. All TLR should be classified prospectively as clinically indicated [CI] or not clinically indicated by the investigator prior to repeat angiography. Clinically Indicated [CI] Revascularization: A revascularization is considered clinically indicated if angiography at follow-up shows a percent diameter stenosis ≥ 50% and if one of the following occurs: A positive history of recurrent angina pectoris, presumably related to the target vessel; Objective signs of ischemia at rest (ECG changes) or during exercise test (or equivalent), presumably related to the target vessel; Abnormal results of any invasive functional diagnostic test A TLR/TVR with a diameter stenosis ≥70% in the absence of the above mentioned ischemic signs or symptoms. | From 3 to 12 months | 
| Number of Participants With Clinically-indicated Target Vessel Revascularization (CI-TVR) | TVR is defined as any repeat percutaneous intervention or surgical bypass of any segment of the target vessel. The target vessel is defined as the entire major coronary vessel proximal and distal to the target lesion which includes upstream and downstream branches and the target lesion itself. A revascularization is considered clinically indicated if angiography at follow-up shows a percent diameter stenosis ≥ 50% and if one of the following occurs: A positive history of recurrent angina pectoris, presumably related to the target vessel; Objective signs of ischemia at rest (ECG changes) or during exercise test (or equivalent), presumably related to the target vessel; Abnormal results of any invasive functional diagnostic test (e.g., Doppler flow velocity reserve, fractional flow reserve); A TVR with a diameter stenosis ≥70% in the absence of the above mentioned ischemic signs or symptoms. | From 3 to 12 months | 
| Number of Participants With Target Lesion Failure (TLF, Composite of Cardiac Death, TV-MI and CI-TLR) | TLF is defined as a composite of all cardiac death, myocardial infarction attributed to target vessel or clinically-indicated TLR. | From 3 to 12 months | 
| Number of Participants With Target Vessel Failure (TVF, Composite of Cardiac Death, TV-MI and CI-TVR) | TVF is defined as a composite of cardiac death, MI attributed to target vessel, clinically-indicated TLR, or clinically-indicated TVR, non-TLR. | From 3 to 12 months | 
| Number of Participants With Major Bleeding Defined by the Bleeding Academic Research Consortium (BARC) Type 3-5 | Bleeding per Bleeding Academic Research Consortium (BARC) adjudicated definitions are as follows: Type 3a: Overt bleeding plus Hemoglobin(Hb) drop of 3 to < 5 g/dL; Any transfusion with overt bleeding Type 3b: Overt bleeding plus Hb drop ≥ 5 g/dL; Cardiac tamponade; Bleeding requiring surgical intervention for control; Bleeding requiring IV vasoactive agents Type 3c: Intracranial hemorrhage;Subcategories confirmed by autopsy or imaging or lumbar puncture; Intraocular bleed compromising vision Type 4: CABG-related bleeding: Perioperative intracranial bleeding within 48 h; Reoperation after closure of sternotomy for the purpose of controlling bleeding; Transfusion of ≥ 5 U whole blood or packed red blood cells within a 48-h period; Chest tube output ≥ 2L within a 24-h period Type 5: Fatal bleeding Type 5a: Probable fatal bleeding; no autopsy or imaging confirmation but clinically suspicious Type 5b: Definite fatal bleeding;overt bleeding or autopsy or imaging confirmation | From 3 to 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Coronary Artery Lesions, XIENCE, Dual Antiplatelet Therapy (DAPT), Reduced DAPT, Risk of bleeding, Drug-eluting stents