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

• ClinicalTrials.gov Identifier: NCT02389946
• Recruitment Status: Completed
• First Posted: March 17, 2015
• Results First Posted: August 1, 2019
• Last Update Posted: August 3, 2022
• Sponsor: Biotronik, Inc.
• Collaborators: Biotronik AG; Baim Institute for Clinical Research; Medstar Health Research Institute
• Information provided by (Responsible Party): Biotronik, Inc.

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Coronary Artery Disease; Atherosclerosis, Coronary; Myocardial Ischemia; Ischemic Heart Disease; Acute Coronary Syndrome; Angina Pectoris	Device: Orsiro DES; Device: Xience DES	Not Applicable

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 1334 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: May 2015
• Actual Primary Completion Date: April 2017
• Actual Study Completion Date: March 2021

Arms and Interventions

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 Name: Orsiro sirolimus coronary stent system
Active Comparator: Xience everolimus coronary stent system; Intervention with a Xience DES.	Device: Xience DES; Other Name: Xience everolimus coronary stent system

Outcome Measures

Primary Outcome Measures :

1. Percentage of Participants With Target Lesion Failure (TLF) at 12 Months Post-Index Procedure by Bayesian Estimation [ Time Frame: 12-Months ]
   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).

Secondary Outcome Measures :

1. Number of Lesions With Device Success [ Time Frame: Hospital Discharge (6-24 hours post-index procedure) ]
   Defined as attainment of < 30% residual stenosis of the target lesion using the assigned study stent only.
2. Number of Lesions With Lesion Success [ Time Frame: Hospital Discharge (6-24 hours post-index procedure) ]
   Defined as attainment of < 30% residual stenosis of the target lesion using any percutaneous method.
3. Number of Participants With Procedure Success [ Time Frame: Hospital Discharge (6-24 hours post-index procedure) ]
   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).
4. Number of Participants With Myocardial Infarction [ Time Frame: Hospital Discharge (6-24 hours post-index procedure), 1, 6, 12 months, 2, 3, 4 and 5 years ]
5. Number of Participants With Myocardial Infarction or Cardiac Death [ Time Frame: Hospital Discharge (6-24 hours post-index procedure), 1, 6, 12 months, 2, 3, 4 and 5 years ]
6. Number of Participants With MACE and Individual MACE Components [ Time Frame: Hospital Discharge (6-24 hours post-index procedure), 1, 6, 12 months, 2, 3, 4 and 5 years ]
   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.
7. Number of Participants With TLF and Individual TLF Components [ Time Frame: Hospital Discharge (6-24 hours post-index procedure), 1, 6, 12 months, 2, 3, 4 and 5 years ]
   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.
8. Number of Participants With Target Vessel Failure (TVF) and Individual TVF Components [ Time Frame: Hospital Discharge (6-24 hours post-index procedure), 1, 6, 12 months, 2, 3, 4 and 5 years ]
   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.
9. Number of Participants With Stent Thrombosis [ Time Frame: 24 hours, 30 days, 1 year, and 5 years post-index procedure ]
   Stent thrombosis according to the Academic Research Consortium criteria.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Locations

United States, Alabama

Fairhope, Alabama, United States, 36535

United States, California

Concord, California, United States, 94520

La Mesa, California, United States, 91942

Laguna Hills, California, United States, 92653

Mission Viejo, California, United States, 92691

United States, District of Columbia

Washington, District of Columbia, United States, 20010

United States, Florida

Clearwater, Florida, United States, 33756

Hollywood, Florida, United States, 33021

Orlando, Florida, United States, 32803

Tampa, Florida, United States, 33613

United States, Georgia

Atlanta, Georgia, United States, 30309

United States, Illinois

Urbana, Illinois, United States, 61801

United States, Indiana

Fort Wayne, Indiana, United States, 46845

United States, Maryland

Baltimore, Maryland, United States, 21218

United States, Massachusetts

Boston, Massachusetts, United States, 02120

United States, 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

United States, Minnesota

Minneapolis, Minnesota, United States, 55407

United States, Nebraska

Omaha, Nebraska, United States, 68124

United States, New Jersey

Hackensack, New Jersey, United States, 07601

Neptune, New Jersey, United States, 07753

Newark, New Jersey, United States, 07102

United States, New York

New York, New York, United States, 10021

New York, New York, United States, 10029

New York, New York, United States, 10032

United States, North Carolina

Asheville, North Carolina, United States, 28803

Greensboro, North Carolina, United States, 27401

United States, North Dakota

Fargo, North Dakota, United States, 58102

United States, 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

United States, Oregon

Portland, Oregon, United States, 97225

United States, Pennsylvania

Butler, Pennsylvania, United States, 16001

Mechanicsburg, Pennsylvania, United States, 17050

Wynnewood, Pennsylvania, United States, 19096

York, Pennsylvania, United States, 17403

United States, Rhode Island

Providence, Rhode Island, United States, 02906

United States, South Carolina

Greenville, South Carolina, United States, 29605

Rock Hill, South Carolina, United States, 29732

United States, Tennessee

Knoxville, Tennessee, United States, 37934

United States, Texas

Dallas, Texas, United States, 75226

Houston, Texas, United States, 77030

McKinney, Texas, United States, 75069

Tyler, Texas, United States, 75701

United States, Virginia

Charlottesville, Virginia, United States, 22908

Virginia Beach, Virginia, United States, 23454

United States, West Virginia

Charleston, West Virginia, United States, 25304

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, 110-744

Seoul, Korea, Republic of, 135-720

Seoul, Korea, Republic of, 137-701

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, 8063

Zurich, Switzerland, 8091

Sponsors and Collaborators

Biotronik, Inc.

Biotronik AG

Baim Institute for Clinical Research

Medstar Health Research Institute

Investigators

• Study Chair: Ron Waksman, MD; Medstar Washington Hospital Center
• Principal Investigator: David Kandzari, MD; Piedmont Heart Institute
• Principal Investigator: Jacques Koolen, MD; Catharina Ziekenhuis

  Study Documents (Full-Text)

Documents provided by Biotronik, Inc.:

Study Protocol  [PDF] February 11, 2016

Statistical Analysis Plan  [PDF] September 14, 2017

More Information

Publications of Results:

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.

Other Publications:

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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

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.

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.

• Responsible Party: Biotronik, Inc.
• ClinicalTrials.gov Identifier: NCT02389946
• Other Study ID Numbers: BIOFLOW-V
• First Posted: March 17, 2015
• Results First Posted: August 1, 2019
• Last Update Posted: August 3, 2022
• Last Verified: August 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

Keywords provided by Biotronik, Inc.:

Drug eluting coronary stents; Sirolimus; Bioabsorbable polymer; DES

Additional relevant MeSH terms:

Coronary Artery Disease; Myocardial Ischemia; Heart Diseases; Acute Coronary Syndrome; Atherosclerosis; Angina Pectoris; Ischemia; Coronary Disease; Cardiovascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Vascular Diseases; Pathologic Processes; Chest Pain; Pain; Neurologic Manifestations; Sirolimus; Everolimus; MTOR Inhibitors; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Antineoplastic Agents; Anti-Bacterial Agents; Anti-Infective Agents; Antibiotics, Antineoplastic; Antifungal Agents