Management of High Bleeding Risk Patients Post Bioresorbable Polymer Coated Stent Implantation With an Abbreviated Versus Prolonged DAPT Regimen

Overview

The study compares two lengths of medication therapy (a shortened versus a prolonged dual antiplatelet therapy) in order to prevent thrombus (blood cloth) formation after the successfully treatment for coronary heart disease with a drug covered stent (metallic tube).

This comparison will be done in patients who, compared to the average patient, are more likely to suffer from complications on antiplatelet therapy (bleeding). Both durations are within the current medical recommendations. The aim of this study is to help improve further standard antiplatelet duration guidelines.

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: November 2020

Detailed Description

The study objective is to determine in a high bleeding risk patient population undergoing PCI under standardized treatment (within current guidelines and instructions for use and including the bioresorbable polymer coated Ultimaster sirolimus-eluting stent), whether abbreviated DAPT is non-inferior to prolonged DAPT regimen in terms of NACE within 12 months, whether abbreviated DAPT is non-inferior to prolonged DAPT regimen in terms of MACCE within 12 months and whether abbreviated DAPT is superior to prolonged DAPT regimen in terms of MCB within 12 months.

There are two treatment strategies:

- abbreviated dual anti-platelet therapy: dual antiplatelet therapy is discontinued and a single antiplatelet agent is continued until at least 11 months post randomization (i.e. 12 months post stent implantation). In patients on oral anticoagulants, dual antiplatelet therapy is discontinued and either Aspirin or Clopidogrel is continued until 5 months post randomization (i.e. 6 months post stent implantation). Oral anticoagulation is continued until at least 11 months post randomization (i.e. 12 months post stent implantation) OR

- prolonged dual anti-platelet therapy: aspirin is continued for at least 11 months post randomization (i.e. 12 months post stent implantation), the P2Y12 inhibitor being taken at the time of randomization is continued for at least 5 months and up to 11 months post randomization (i.e. 12 months post stent implantation). In patients on oral anticoagulants, aspirin and Clopidogrel are continued for at least 2 months post randomization (i.e. 3 months post stent implantation) and up to 11 months post randomization (i.e. 12 months after stent implantation). Therefore either aspirin or Clopidogrel is continued up to 11 months post randomization (i.e. 12 months post stent implantation)

The study design is an investigator-initiated, randomized, multi-center, clinical trial to be conducted in approximately 100 interventional cardiology centers in across the globe excluding USA. The study includes 2 x 2150 patients (i.e. 4300 patients) Randomization will occur at one month after the PCI procedure. The expected duration of participation for each patient is 14 months.

Interventions

  • Drug: Aspirin
    • Dosing per current guidelines and local practice
  • Drug: P2Y12 inhibitor
    • Dosing per current guidelines and local practice

Arms, Groups and Cohorts

  • Other: Abbreviated antiplatelet regimen
    • Dual antiplatelet therapy is discontinued immediately after randomization (i.e. 1 month post stent implantation), and a single antiplatelet agent is continued until at least 11 months post randomization (i.e. 12 months post stent implantation). In patients on oral anticoagulants, dual antiplatelet therapy is discontinued immediately after randomization (i.e. 1 month post stent implantation), and either Aspirin or Clopidogrel is continued until 5 months post randomization (i.e. 6 months post stent implantation). Oral anticoagulation is continued until at least 11 months post randomization (i.e. 12 months post stent implantation)
  • Other: Prolonged antiplatelet regimen
    • Aspirin is continued for at least 11 months post randomization (i.e. 12 months post stent implantation), the P2Y12 inhibitor being taken at the time of randomization is continued for at least 5 months and up to 11 months post randomization (i.e. 12 months post stent implantation). In patients on oral anticoagulants, aspirin and Clopidogrel are continued for at least 2 months post randomization (i.e. 3 months post stent implantation) and up to 11 months post randomization (i.e. 12 months after stent implantation). Either aspirin or Clopidogrel is continued up to 11 months post randomization (i.e. 12 months post stent implantation)

Clinical Trial Outcome Measures

Primary Measures

  • Net adverse clinical endpoints (NACE) defined as a composite of all-cause death, myocardial infarction, stroke and bleeding events defined as BARC 3 or 5
    • Time Frame: 11 months
  • Major adverse cardiac and cerebral events (MACCE) defined as a composite of all-cause death, myocardial infarction and stroke
    • Time Frame: 11 months
  • Major or clinically relevant non-major bleeding (MCB) defined as a composite of type 2, 3 and 5 BARC bleeding events
    • Time Frame: 11 months

Secondary Measures

  • All cause death
    • Time Frame: 14 months
  • Death from cardiovascular causes
    • Time Frame: 14 months
  • Myocardial infarction
    • Time Frame: 14 months
  • Stroke
    • Time Frame: 14 months
  • Bleeding events
    • Time Frame: 14 months
  • Definite or probable stent thrombosis
    • Time Frame: 14 months
  • Any target vessel revascularization
    • Time Frame: 14 months
  • Urgent target vessel revascularization
    • Time Frame: 14 months
  • Urgent non-target vessel revascularization
    • Time Frame: 14 months
  • Clinically indicated non-target vessel revascularization
    • Time Frame: 14 months
  • Transfusion rates both in patients with and/or without clinically detected over bleeding
    • Time Frame: 14 months

Participating in This Clinical Trial

Inclusion Criteria

After index PCI, patients aged 18 years or more are eligible for inclusion into the study if the following criteria are met.

1. At least one among the HBR criteria (as defined below) is met.

2. All lesions are successfully treated with Ultimaster stent in the context of routine clinical care, i.e. post-procedural angiographic diameter stenosis <20% by visual estimation

3. Free from any flow-limiting angiographic complications (i.e. significant untreated dissection or major side-branch occlusion), which require prolonged DAPT duration based on operator's opinion.

4. All stages of PCI are complete (if any) and no further PCI is planned.

At randomization visit (one month after index PCI), the following criteria must be met:

1. Fulfilment of at least one HBR criterion (as defined below), or on the basis of post-PCI actionable (i.e. requiring medical attention) non-access site related bleeding episode

2. Uneventful 30-day clinical course, i.e. free from spontaneous MI, symptomatic restenosis, stent thrombosis, stroke and any revascularization (coronary and non-coronary) requiring prolonged DAPT

3. If not on OAC,

1. Patient is on a DAPT regimen of aspirin and a P2Y12 inhibitor

2. Patient with one type of P2Y12 inhibitor for at least 7 days (i.e. no switching between oral P2Y12 inhibitors has occurred in the previous 7 days)

4. If on OAC

1. Patient is on the same type of OAC (e.g. Vitamin K antagonist or NOAC) for at least 7 days

2. Patient is on clopidogrel for at least 7 days

Definition of HBR

Post-PCI patients are at HBR if at least one of the following criteria applies:

  • Clinical indication for treatment with oral anticoagulants (OAC) for at least 12 months
  • Recent (<12 months) non-access site bleeding episode(s), which required medical attention (i.e. actionable bleeding).
  • Previous bleeding episode(s) which required hospitalization if the underlying cause has not been definitively treated (i.e. surgical removal of the bleeding source)
  • Age equal or greater than 75 years
  • Systemic conditions associated with an increased bleeding risk (e.g. haematological disorders, including a history of or current thrombocytopaenia defined as a platelet count <100,000/mm3 (<100 x 109/L), or any known coagulation disorder associated with increased bleeding risk.
  • Documented anaemia defined as repeated haemoglobin levels <11 g/dl or transfusion within 4 weeks before randomization.
  • Need for chronic treatment with steroids or non-steroidal anti-inflammatory drugs
  • Diagnosed malignancy (other than skin) considered at high bleeding risk including gastro-intestinal, genito-urethral/renal and pulmonary.
  • Stroke at any time or TIA in the previous 6 months
  • PRECISE DAPT score of 25 or greater

Exclusion Criteria

1. Treated with stents other than Ultimaster stent within 6 months prior to index procedure

2. Treated for in-stent restenosis or stent thrombosis at index PCI or within 6 months before

3. Treated with a bioresorbable scaffold at any time prior to index procedure

4. Cannot provide written informed consent

5. Under judicial protection, tutorship or curatorship

6. Unable to understand and follow study-related instructions or unable to comply with study protocol

7. Active bleeding requiring medical attention (BARC≥2) on randomization visit

8. Life expectancy less than one year

9. Known hypersensitivity or allergy for aspirin, clopidogrel, ticagrelor, prasugrel, cobalt chromium or sirolimus

10. Any planned and anticipated PCI

11. Participation in another trial

12. Pregnant or breast feeding women

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • ECRI bv
  • Collaborator
    • Cardialysis B.V.
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • M. Valgimigli, Prof., Principal Investigator, Inselspital Universitätsspital Bern, Switzerland
    • P. Smits, Dr., Principal Investigator, Maasstad Ziekenhuis Rotterdam, The Netherlands
    • R Van Amsterdam, Study Director, ECRI bv

References

Authors/Task Force members, Windecker S, Kolh P, Alfonso F, Collet JP, Cremer J, Falk V, Filippatos G, Hamm C, Head SJ, Jüni P, Kappetein AP, Kastrati A, Knuuti J, Landmesser U, Laufer G, Neumann FJ, Richter DJ, Schauerte P, Sousa Uva M, Stefanini GG, Taggart DP, Torracca L, Valgimigli M, Wijns W, Witkowski A. 2014 ESC/EACTS Guidelines on myocardial revascularization: The Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS)Developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J. 2014 Oct 1;35(37):2541-619. doi: 10.1093/eurheartj/ehu278. Epub 2014 Aug 29.

Roffi M, Patrono C, Collet JP, Mueller C, Valgimigli M, Andreotti F, Bax JJ, Borger MA, Brotons C, Chew DP, Gencer B, Hasenfuss G, Kjeldsen K, Lancellotti P, Landmesser U, Mehilli J, Mukherjee D, Storey RF, Windecker S; ESC Scientific Document Group . 2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: Task Force for the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-Segment Elevation of the European Society of Cardiology (ESC). Eur Heart J. 2016 Jan 14;37(3):267-315. doi: 10.1093/eurheartj/ehv320. Epub 2015 Aug 29.

Levine GN, Bates ER, Bittl JA, Brindis RG, Fihn SD, Fleisher LA, Granger CB, Lange RA, Mack MJ, Mauri L, Mehran R, Mukherjee D, Newby LK, O'Gara PT, Sabatine MS, Smith PK, Smith SC, Jr. 2016 ACC/AHA Guideline Focused Update on Duration of Dual Antiplatelet Therapy in Patients With Coronary Artery Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines: An Update of the 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention, 2011 ACCF/AHA Guideline for Coronary Artery Bypass Graft Surgery, 2012 ACC/AHA/ACP/AATS/PCNA/SCAI/STS Guideline for the Diagnosis and Management of Patients With Stable Ischemic Heart Disease, 2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction, 2014 AHA/ACC Guideline for the Management of Patients With Non-ST-Elevation Acute Coronary Syndromes, and 2014 ACC/AHA Guideline on Perioperative Cardiovascular Evaluation and Management of Patients Undergoing Noncardiac Surgery. Circulation 2016

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