Safety and Effectiveness of the Orsiro Sirolimus Eluting Coronary Stent System in Subjects With Coronary Artery Lesions (BIOFLOW-V)

BIOTRONIK - A Prospective Randomized Multicenter Study to Assess the SaFety and Effectiveness of the Orsiro SiroLimus Eluting Coronary Stent System in the Treatment Of Subjects With up to Three De Novo or Restenotic Coronary Artery Lesions - V

The objective of this study is to assess the safety and efficacy of the Orsiro Sirolimus Eluting Coronary Stent System in the treatment of subjects with up to three native de novo or restenotic (standard PTCA only) coronary artery lesions compared to the Xience coronary stent system.

Study Overview

• Status: Completed
• Conditions: Myocardial Ischemia; Coronary Artery Disease; Angina Pectoris; Acute Coronary Syndrome; Ischemic Heart Disease; Atherosclerosis, Coronary
• Intervention / Treatment: Device: Orsiro DES; Device: Xience DES

Detailed Description

The BIOTRONIK BIOFLOW-V clinical trial is a prospective, multicenter, randomized, controlled trial combining data on the randomized subjects with data from two historical studies by employing a Bayesian approach.

Subjects with CAD that qualify for PCI with stenting will be screened per the protocol inclusion and exclusion criteria to achieve a total of up to 1,400 randomized subjects. Eligible subjects will be randomized in a 2:1 ratio, stratified by study center, to undergo percutaneous coronary revascularization with either the Orsiro Sirolimus Eluting Stent System (treatment group) or the Xience Everolimus Eluting Stent System (control group).

Subjects may receive treatment of up to three target lesions, one or two target lesions per target vessel, for a maximum of two target vessels. The target lesion(s) must be de novo or restenotic lesion(s) of ≤ 36 mm in length in native coronary artery(ies), with a reference vessel diameter of 2.25-4.0 mm. Treatment of restenotic lesions is allowed provided that the target lesion was previously treated with PTCA only. All treatment with study stents is to be performed during a single index procedure. Note: Concurrent treatment of non-target lesions during the index procedure is not allowed.

Randomized subjects will have clinical follow-up at 1 month, 6 months, 12 months and at 2, 3, 4 and 5 years following the index procedure.

To assess the non-inferiority of the Orsiro stent compared to the Xience stent, BIOFLOW-V randomized subjects will be combined with historical subjects from the BIOFLOW-II and BIOFLOW-IV randomized trials employing a Bayesian approach. Only subjects who meet all clinical and angiographic eligibility criteria of the BIOFLOW-V trial will be included in the analysis.

• Study Type: Interventional
• Enrollment (Actual): 1334
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Australia
  • Adelaide, Australia, SA 5011
• Belgium
  • Genk, Belgium, 3600
  • Leuven, Belgium, 3000
  • Roeselare, Belgium, 8800
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 4Z6
• Denmark
  • Aarhus, Denmark, 8200
• Germany
  • Bad Segeberg, Germany, 23795
  • Berlin, Germany, 10249
  • Berlin, Germany, 10967
  • Hamburg, Germany, 20246
  • Minden, Germany, 32429
  • Neuss, Germany, 41464
• Hungary
  • Budapest, Hungary, 1085
  • Pécs, Hungary, 7624
  • Szeged, Hungary, 6720
• Israel
  • Haifa, Israel, 31096
  • Jerusalem, Israel, 91120
  • Petach Tikva, Israel, 49101
  • Rehovot, Israel, 76100
  • Tel Aviv, Israel, 64239
• Korea, Republic of
  • Daegu, Korea, Republic of, 705-718
  • Gwangju, Korea, Republic of, 501-757
  • Seoul, Korea, Republic of, 137-701
  • Seoul, Korea, Republic of, 110-744
  • Seoul, Korea, Republic of, 135-720
• Netherlands
  • Breda, Netherlands, 4818 CK
  • Eindhoven, Netherlands, 5623 EJ
  • Nieuwegein, Netherlands, 3435 CM
• New Zealand
  • Auckland, New Zealand, 1142
• Spain
  • Barcelona, Spain, 08036
  • Barcelona, Spain, 08907
  • Madrid, Spain, 28222
  • Malaga, Spain, 29010
  • Sevilla, Spain, 41071
• Switzerland
  • Lausanne, Switzerland, 1011
  • Zurich, Switzerland, 8091
  • Zurich, Switzerland, 8063
• United States
  • Alabama
    • Fairhope, Alabama, United States, 36535
  • California
    • Concord, California, United States, 94520
    • La Mesa, California, United States, 91942
    • Laguna Hills, California, United States, 92653
    • Mission Viejo, California, United States, 92691
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
  • Florida
    • Clearwater, Florida, United States, 33756
    • Hollywood, Florida, United States, 33021
    • Orlando, Florida, United States, 32803
    • Tampa, Florida, United States, 33613
  • Georgia
    • Atlanta, Georgia, United States, 30309
  • Illinois
    • Urbana, Illinois, United States, 61801
  • Indiana
    • Fort Wayne, Indiana, United States, 46845
  • Maryland
    • Baltimore, Maryland, United States, 21218
  • Massachusetts
    • Boston, Massachusetts, United States, 02120
  • Michigan
    • Bay City, Michigan, United States, 48708
    • Detroit, Michigan, United States, 48236
    • Lansing, Michigan, United States, 48912
    • Pontiac, Michigan, United States, 48341
    • Rochester, Michigan, United States, 48307
    • Troy, Michigan, United States, 48085
    • Ypsilanti, Michigan, United States, 48197
  • Minnesota
    • Minneapolis, Minnesota, United States, 55407
  • Nebraska
    • Omaha, Nebraska, United States, 68124
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
    • Neptune, New Jersey, United States, 07753
    • Newark, New Jersey, United States, 07102
  • New York
    • New York, New York, United States, 10032
    • New York, New York, United States, 10021
    • New York, New York, United States, 10029
  • North Carolina
    • Asheville, North Carolina, United States, 28803
    • Greensboro, North Carolina, United States, 27401
  • North Dakota
    • Fargo, North Dakota, United States, 58102
  • Ohio
    • Cincinnati, Ohio, United States, 45219
    • Cleveland, Ohio, United States, 44111
    • Columbus, Ohio, United States, 43210
    • Elyria, Ohio, United States, 44035
    • Toledo, Ohio, United States, 43606
    • Toledo, Ohio, United States, 43608
  • Oregon
    • Portland, Oregon, United States, 97225
  • Pennsylvania
    • Butler, Pennsylvania, United States, 16001
    • Mechanicsburg, Pennsylvania, United States, 17050
    • Wynnewood, Pennsylvania, United States, 19096
    • York, Pennsylvania, United States, 17403
  • Rhode Island
    • Providence, Rhode Island, United States, 02906
  • South Carolina
    • Greenville, South Carolina, United States, 29605
    • Rock Hill, South Carolina, United States, 29732
  • Tennessee
    • Knoxville, Tennessee, United States, 37934
  • Texas
    • Dallas, Texas, United States, 75226
    • Houston, Texas, United States, 77030
    • McKinney, Texas, United States, 75069
    • Tyler, Texas, United States, 75701
  • Virginia
    • Charlottesville, Virginia, United States, 22908
    • Virginia Beach, Virginia, United States, 23454
  • West Virginia
    • Charleston, West Virginia, United States, 25304

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Subject is ≥18 years or the minimum age required for legal adult consent in the country of enrollment.
2. Subject is an acceptable candidate for PCI.
3. Subject is an acceptable candidate for CABG.
4. Subject has clinical evidence of ischemic heart disease, stable or unstable angina pectoris or documented silent ischemia.
5. Subject is eligible for dual anti-platelet therapy treatment with aspirin plus either, clopidogrel, prasugrel, ticagrelor or ticlopidine.
6. Subject has provided written informed consent.
7. Subject is willing to comply with study follow-up requirements.

Each target lesion/vessel must meet all of the following angiographic criteria for the subject to be eligible for the trial:

1. Subject has up to three target lesions in up to two separate target vessels (two target lesions in one vessel and one target lesion in a separate vessel).
2. Target lesion must be de novo or restenotic lesion in native coronary artery; restenotic lesion must have been treated with a standard PTCA only.
3. Target lesion must be in major coronary artery or branch (target vessel).
4. Target lesion must have angiographic evidence of ≥ 50% and < 100% stenosis (by operator visual estimate). If the target lesion is < 70% stenosed, clinical evidence of ischemia by positive functional study, CT, electrocardiography, FFR, or post infarct angina.
5. TIMI flow > 1.
6. Target lesion must be ≤ 36 mm in length by operator visual estimate.
7. Target vessel RVD of 2.25-4.0 mm by operator visual estimate.
8. Target lesion must be treatable with a maximum of two overlapping stents.

Exclusion Criteria:

1. Subject has clinical symptoms and/or electrocardiogram (ECG) changes consistent with acute ST elevation myocardial infarction (STEMI) within 72 hours prior to the index procedure. Hemodynamically stable non-STEMI (NSTEMI) subjects are eligible for study enrollment.
2. Subject is hemodynamically unstable.
3. Subject is pregnant and/or breastfeeding or intends to become pregnant during the duration of the study.
4. Subject has a known allergy to contrast medium that cannot be adequately pre-medicated, or any known allergy to thienopyridine, aspirin, both heparin and bivalirudin, L-605 cobalt-chromium (Co-Cr) alloy or one of its major elements (cobalt, chromium, tungsten and nickel), acrylic, fluoropolymers, silicon carbide, PLLA, sirolimus or everolimus.
5. Revascularization of any target vessel within 9 months prior to the index procedure or previous PCI of any non-target vessel within 30 days prior to the index procedure.
6. Planned treatment of a lesion not meeting angiographic inclusion and exclusion criteria during the index procedure or after the index procedure.
7. Planned surgery within 6 months of index procedure unless dual antiplatelet therapy can be maintained throughout the peri-surgical period.
8. History of a stroke or transient ischemic attack (TIA) within 6 months prior to the index procedure.
9. Subjects with active bleeding disorders, active coagulopathy, or any other reason, who are ineligible for DAPT.
10. Subject will refuse blood transfusions.
11. Subject has documented left ventricular ejection fraction (LVEF) < 30% within 90 days prior to the index procedure.
12. Subject is dialysis-dependent.
13. Subject has impaired renal function (i.e., blood creatinine > 2.5 mg/dL or 221 μmol/L determined within 7 days prior to the index procedure).
14. Subject has leukopenia (i.e. < 3,000 white blood cells/mm3), thrombocytopenia (i.e. < 100,000 platelets/mm3) or thrombocytosis (i.e. > 700,000 platelet/mm3).
15. Subject is receiving oral or intravenous immunosuppressive therapy (inhaled steroids are permitted), or has known life-limiting immunosuppressive or autoimmune disease (e.g., human immunodeficiency virus, systemic lupus erythematosus; diabetes mellitus is permitted).
16. Subject is receiving chronic anticoagulation (e.g. coumadin, dabigatran, apixaban, rivaroxaban or any other agent).
17. Subject has life expectancy of < 1 year.
18. Subject is participating in another investigational (medical device or drug) clinical study. Subjects may be concurrently enrolled in a post-market study, as long as the post-market study device, drug or protocol does not interfere with the investigational treatment or protocol of this study.
19. In the investigator's opinion, subject will not be able to comply with the follow-up requirements.

Subjects will be excluded from the trial if any of the target lesions/vessels meets any of the following angiographic criteria:

1. Target lesion is located within a saphenous vein graft or arterial graft.
2. Target lesion is a restenotic lesion that was previously treated with a bare metal or drug eluting stent (in-stent restenosis).

3. Target lesion has any of the following characteristics:

   1. Lesion location is within the left main coronary artery, or within 3 mm of the origin of the left anterior descending (LAD) or left circumflex (LCX).
   2. Involves a side branch of > 2.0 mm in diameter. Note: Lesions within 3 mm of the origin of the right coronary artery may be treated.
4. Target vessel/lesion is excessively tortuous/angulated or is severely calcified, that would prevent complete inflation of an angioplasty balloon. This assessment should be based on visual estimation.
5. Target vessel has angiographic evidence of thrombus.
6. Target lesion is totally occluded (100% stenosis).
7. Target vessel was treated with brachytherapy any time prior to the index procedure.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Orsiro sirolimus coronary stent system; Intervention with a Orsiro DES.	Device: Orsiro DES; Orsiro is a device/drug combination product composed of two components, a device (coronary stent system including a cobalt chromium stent platform), and a drug product (a formulation of sirolimus) contained in a bioabsorbable polymer coating.; Other Names: Orsiro sirolimus coronary stent system
Active Comparator: Xience everolimus coronary stent system; Intervention with a Xience DES.	Device: Xience DES; Other Names: Xience everolimus coronary stent system

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Target Lesion Failure (TLF) at 12 Months Post-Index Procedure by Bayesian Estimation	TLF is defined as all cardiac death, target vessel Q-wave or non-Q-wave myocardial infarction (MI), or clinically driven target lesion revascularization (TLR).	12-Months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Lesions With Device Success	Defined as attainment of < 30% residual stenosis of the target lesion using the assigned study stent only.	Hospital Discharge (6-24 hours post-index procedure)
Number of Lesions With Lesion Success	Defined as attainment of < 30% residual stenosis of the target lesion using any percutaneous method.	Hospital Discharge (6-24 hours post-index procedure)
Number of Participants With Procedure Success	Defined as attainment of < 30% residual stenosis of the target lesion using the assigned study stent only without occurrence of in-hospital major adverse cardiac events (MACE; composite of all-cause death, Q-wave or non-Q-wave MI, and any clinically-driven TLR).	Hospital Discharge (6-24 hours post-index procedure)
Number of Participants With Myocardial Infarction		Hospital Discharge (6-24 hours post-index procedure), 1, 6, 12 months, 2, 3, 4 and 5 years
Number of Participants With Myocardial Infarction or Cardiac Death		Hospital Discharge (6-24 hours post-index procedure), 1, 6, 12 months, 2, 3, 4 and 5 years
Number of Participants With MACE and Individual MACE Components	MACE events are defined as all-cause death, Q-wave or non-Q-wave MI, or any clinically-driven TLR. The number of participants with any MACE event is provided, as well as number of participants with each of the individual components.	Hospital Discharge (6-24 hours post-index procedure), 1, 6, 12 months, 2, 3, 4 and 5 years
Number of Participants With TLF and Individual TLF Components	TLF events are defined as cardiac death, target vessel Q-wave or non-Q-wave MI, or any clinically-driven TLR. The number of participants with any TLF event is provided, as well as number of participants with each of the individual components.	Hospital Discharge (6-24 hours post-index procedure), 1, 6, 12 months, 2, 3, 4 and 5 years
Number of Participants With Target Vessel Failure (TVF) and Individual TVF Components	TVF events are defined as cardiac death, target vessel Q-wave or non-Q-wave MI, or any clinically-driven TVR. The number of participants with any TVF event is provided, as well as number of participants with each of the individual components.	Hospital Discharge (6-24 hours post-index procedure), 1, 6, 12 months, 2, 3, 4 and 5 years
Number of Participants With Stent Thrombosis	Stent thrombosis according to the Academic Research Consortium criteria.	24 hours, 30 days, 1 year, and 5 years post-index procedure

Collaborators and Investigators

• Sponsor: Biotronik, Inc.
• Collaborators: Medstar Health Research Institute; Biotronik AG; Baim Institute for Clinical Research
• Investigators: Study Chair: Ron Waksman, MD, MedStar Washington Hospital Center; Principal Investigator: Jacques Koolen, MD, Catharina Ziekenhuis

Publications and helpful links

General Publications

• Toelg R, Slagboom T, Waltenberger J, Lefevre T, Saito S, Kandzari DE, Koolen J, Richardt G. Individual patient data analysis of the BIOFLOW study program comparing safety and efficacy of a bioresorbable polymer sirolimus eluting stent to a durable polymer everolimus eluting stent. Catheter Cardiovasc Interv. 2021 Nov 1;98(5):848-856. doi: 10.1002/ccd.29254. Epub 2020 Sep 5.
• Hemetsberger R, Abdelghani M, Toelg R, Garcia-Garcia HM, Farhan S, Mankerious N, Elbasha K, Allali A, Windecker S, Lefevre T, Saito S, Kandzari D, Waksman R, Richardt G. Complex vs. non-complex percutaneous coronary intervention with newer-generation drug-eluting stents: an analysis from the randomized BIOFLOW trials. Clin Res Cardiol. 2022 Jul;111(7):795-805. doi: 10.1007/s00392-022-01994-4. Epub 2022 Feb 25.
• Hemetsberger R, Abdelghani M, Toelg R, Mankerious N, Allali A, Garcia-Garcia HM, Windecker S, Lefevre T, Saito S, Slagboom T, Kandzari D, Koolen J, Waksman R, Richardt G. Impact of Coronary Calcification on Clinical Outcomes After Implantation of Newer-Generation Drug-Eluting Stents. J Am Heart Assoc. 2021 Jun 15;10(12):e019815. doi: 10.1161/JAHA.120.019815. Epub 2021 May 29.
• Dan K, Garcia-Garcia HM, Kolm P, Windecker S, Saito S, Kandzari DE, Waksman R. Comparison of Ultrathin, Bioresorbable-Polymer Sirolimus-Eluting Stents and Thin, Durable-Polymer Everolimus-Eluting Stents in Calcified or Small Vessel Lesions. Circ Cardiovasc Interv. 2020 Sep;13(9):e009189. doi: 10.1161/CIRCINTERVENTIONS.120.009189. Epub 2020 Sep 8.
• Doros G, Massaro JM, Kandzari DE, Waksman R, Koolen JJ, Cutlip DE, Mauri L. Rationale of a novel study design for the BIOFLOW V study, a prospective, randomized multicenter study to assess the safety and efficacy of the Orsiro sirolimus-eluting coronary stent system using a Bayesian approach. Am Heart J. 2017 Nov;193:35-45. doi: 10.1016/j.ahj.2017.08.001. Epub 2017 Aug 5.
• Kandzari DE, Mauri L, Koolen JJ, Massaro JM, Doros G, Garcia-Garcia HM, Bennett J, Roguin A, Gharib EG, Cutlip DE, Waksman R; BIOFLOW V Investigators. Ultrathin, bioresorbable polymer sirolimus-eluting stents versus thin, durable polymer everolimus-eluting stents in patients undergoing coronary revascularisation (BIOFLOW V): a randomised trial. Lancet. 2017 Oct 21;390(10105):1843-1852. doi: 10.1016/S0140-6736(17)32249-3. Epub 2017 Aug 26. Erratum In: Lancet. 2017 Oct 21;390(10105):1832.
• Kandzari DE, Koolen JJ, Doros G, Massaro JJ, Garcia-Garcia HM, Bennett J, Roguin A, Gharib EG, Cutlip DE, Waksman R; BIOFLOW V Investigators. Ultrathin Bioresorbable Polymer Sirolimus-Eluting Stents Versus Thin Durable Polymer Everolimus-Eluting Stents. J Am Coll Cardiol. 2018 Dec 25;72(25):3287-3297. doi: 10.1016/j.jacc.2018.09.019. Epub 2018 Sep 23.
• Roguin A, Kandzari DE, Marcusohn E, Koolen JJ, Doros G, Massaro JM, Garcia-Garcia HM, Bennett J, Gharib EG, Cutlip DE, Waksman R. Subgroup Analysis Comparing Ultrathin, Bioresorbable Polymer Sirolimus-Eluting Stents Versus Thin, Durable Polymer Everolimus-Eluting Stents in Acute Coronary Syndrome Patients. Circ Cardiovasc Interv. 2018 Oct;11(10):e007331. doi: 10.1161/CIRCINTERVENTIONS.118.007331.
• Kandzari DE, Koolen JJ, Doros G, Garcia-Garcia HM, Bennett J, Roguin A, Gharib EG, Cutlip DE, Waksman R; BIOFLOW V Investigators. Ultrathin Bioresorbable-Polymer Sirolimus-Eluting Stents Versus Thin Durable-Polymer Everolimus-Eluting Stents for Coronary Revascularization: 3-Year Outcomes From the Randomized BIOFLOW V Trial. JACC Cardiovasc Interv. 2020 Jun 8;13(11):1343-1353. doi: 10.1016/j.jcin.2020.02.019.
• Mattke S, Hanson M, Bentele M, Kandzari DE. Cost and Mortality Implications of Lower Event Rates After Implantation of an Ultrathin-Strut Coronary Stent Compared With a Thin-Strut Stent Over Four Years. Cardiovasc Revasc Med. 2020 Jul;21(7):835-842. doi: 10.1016/j.carrev.2019.12.018. Epub 2019 Dec 18.
• Mattke S, Hanson M, Dallmann AC, Bentele M. Health Economic Evaluation of an Ultrathin, Bioresorbable-Polymer Sirolimus-Eluting Coronary Stent Compared to a Thin, Durable-Polymer Everolimus-Eluting Stent. Cardiovasc Revasc Med. 2019 Sep;20(9):752-757. doi: 10.1016/j.carrev.2018.11.006. Epub 2018 Nov 20.

Study record dates

Study Major Dates

• Study Start: May 1, 2015
• Primary Completion (Actual): April 1, 2017
• Study Completion (Actual): March 1, 2021

Study Registration Dates

• First Submitted: March 2, 2015
• First Submitted That Met QC Criteria: March 10, 2015
• First Posted (Estimate): March 17, 2015

Study Record Updates

• Last Update Posted (Actual): August 3, 2022
• Last Update Submitted That Met QC Criteria: August 1, 2022
• Last Verified: August 1, 2022

More Information

Terms related to this study

• Keywords: Sirolimus; DES; Drug eluting coronary stents; Bioabsorbable polymer
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Pain; Neurologic Manifestations; Coronary Disease; Chest Pain; Heart Diseases; Coronary Artery Disease; Myocardial Ischemia; Ischemia; Atherosclerosis; Acute Coronary Syndrome; Angina Pectoris; Physiological Effects of Drugs; Anti-Infective Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Everolimus; Sirolimus
• Other Study ID Numbers: BIOFLOW-V

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided