Combined Pressure and Flow Measurements to Guide Treatment of Coronary Stenoses (DEFINE-FLOW)

• ClinicalTrials.gov Identifier: NCT02328820
• Recruitment Status: Active, not recruiting
• First Posted: December 31, 2014
• Last Update Posted: January 17, 2019
• Sponsor: The University of Texas Health Science Center, Houston
• Collaborators: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA); Volcano Corporation
• Information provided by (Responsible Party): Nils Johnson, The University of Texas Health Science Center, Houston

Tracking Information

• First Submitted Date: December 18, 2014
• First Posted Date: December 31, 2014
• Last Update Posted Date: January 17, 2019
• Actual Study Start Date: October 2014
• Estimated Primary Completion Date: November 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 23, 2014)

Major adverse cardiac events [ Time Frame: 24 months ]

All-cause death, non-fatal myocardial infarction, urgent and elective revascularization

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: December 23, 2014)

Angina (Canadian Cardiovascular Society (CCS) anginal class (or freedom from angina) [ Time Frame: 24 months ]

Canadian Cardiovascular Society (CCS) anginal class (or freedom from angina)

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Combined Pressure and Flow Measurements to Guide Treatment of Coronary Stenoses
• Official Title: DEFINE-FLOW (Distal Evaluation of Functional Performance With Intravascular Sensors to Assess the Narrowing Effect - Combined Pressure and Doppler FLOW Velocity Measurements)
• Brief Summary: This study evaluates the prognostic value and therapeutic potential of combined pressure and flow measurements when evaluating a coronary artery stenosis. Lesions with intact coronary flow reserve (CFR) despite a reduced fractional flow reserve (FFR) will receive optimal medical therapy. Only lesions with a simultaneous reduction in both CFR and FFR will be treated with percutaneous coronary intervention (PCI).
• Detailed Description: Pressure and flow represent the two physiologic variables that can be measured directly inside a coronary artery. Already pressure measurements have proven their clinical value in the form of fractional flow reserve (FFR). However, myocardial function can remain intact with sufficient flow, even at a low perfusion pressure. Therefore, combined pressure and flow measurements provide a more complete description of physiologic stenosis severity as a guide to medical treatment versus revascularization. Based on existing work relating the most common flow measurement, coronary flow reserve (CFR), to FFR and linking both variables with subsequent prognosis, we hypothesize that lesions with an intact CFR>=2.0 can be reasonably treated with medical therapy despite a reduced FFR<=0.8.
• Study Type: Interventional
• Study Phase: Not Applicable
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Diagnostic
• Condition: Coronary Artery Disease

Intervention

• Other: Percutaneous coronary intervention (PCI)
  For lesions with both FFR<=0.8 and CFR<2.0
• Other: Optimal medical therapy (OMT)
  For lesions with FFR>0.8 or CFR>=2.0 or both

Study Arms

All patients

All lesions undergo simultaneous assessment with a combined pressure and flow sensor

Interventions:

• Other: Percutaneous coronary intervention (PCI)
• Other: Optimal medical therapy (OMT)

Publications *

• Johnson NP, Kirkeeide RL, Gould KL. Is discordance of coronary flow reserve and fractional flow reserve due to methodology or clinically relevant coronary pathophysiology? JACC Cardiovasc Imaging. 2012 Feb;5(2):193-202. doi: 10.1016/j.jcmg.2011.09.020.
• van de Hoef TP, van Lavieren MA, Damman P, Delewi R, Piek MA, Chamuleau SA, Voskuil M, Henriques JP, Koch KT, de Winter RJ, Spaan JA, Siebes M, Tijssen JG, Meuwissen M, Piek JJ. Physiological basis and long-term clinical outcome of discordance between fractional flow reserve and coronary flow velocity reserve in coronary stenoses of intermediate severity. Circ Cardiovasc Interv. 2014 Jun;7(3):301-11. doi: 10.1161/CIRCINTERVENTIONS.113.001049. Epub 2014 Apr 29.
• Stegehuis VE, Wijntjens GWM, van de Hoef TP, Casadonte L, Kirkeeide RL, Siebes M, Spaan JAE, Gould KL, Johnson NP, Piek JJ. Distal Evaluation of Functional performance with Intravascular sensors to assess the Narrowing Effect-combined pressure and Doppler FLOW velocity measurements (DEFINE-FLOW) trial: Rationale and trial design. Am Heart J. 2020 Apr;222:139-146. doi: 10.1016/j.ahj.2019.08.018. Epub 2019 Sep 1.
• Gould KL, Johnson NP, Roby AE, Nguyen T, Kirkeeide R, Haynie M, Lai D, Zhu H, Patel MB, Smalling R, Arain S, Balan P, Nguyen T, Estrera A, Sdringola S, Madjid M, Nascimbene A, Loyalka P, Kar B, Gregoric I, Safi H, McPherson D. Regional, Artery-Specific Thresholds of Quantitative Myocardial Perfusion by PET Associated with Reduced Myocardial Infarction and Death After Revascularization in Stable Coronary Artery Disease. J Nucl Med. 2019 Mar;60(3):410-417. doi: 10.2967/jnumed.118.211953. Epub 2018 Aug 16.
• Matsumura M, Johnson NP, Fearon WF, Mintz GS, Stone GW, Oldroyd KG, De Bruyne B, Pijls NHJ, Maehara A, Jeremias A. Accuracy of Fractional Flow Reserve Measurements in Clinical Practice: Observations From a Core Laboratory Analysis. JACC Cardiovasc Interv. 2017 Jul 24;10(14):1392-1401. doi: 10.1016/j.jcin.2017.03.031.
• Johnson NP, Gould KL, Di Carli MF, Taqueti VR. Invasive FFR and Noninvasive CFR in the Evaluation of Ischemia: What Is the Future? J Am Coll Cardiol. 2016 Jun 14;67(23):2772-2788. doi: 10.1016/j.jacc.2016.03.584. Review.
• Gould KL, Johnson NP. Coronary Blood Flow After Acute MI: Alternative Truths. JACC Cardiovasc Interv. 2016 Mar 28;9(6):614-7. doi: 10.1016/j.jcin.2016.02.009.
• Gould KL. Intense Exercise and Native Collateral Function in Stable Moderate Coronary Artery Disease: Incidental, Causal, or Clinically Important? Circulation. 2016 Apr 12;133(15):1431-4. doi: 10.1161/CIRCULATIONAHA.116.022037. Epub 2016 Mar 15.
• Gould KL, Johnson NP. Myocardial Bridges: Lessons in Clinical Coronary Pathophysiology. JACC Cardiovasc Imaging. 2015 Jun;8(6):705-9. doi: 10.1016/j.jcmg.2015.02.013.
• Gould KL, Johnson NP, Kaul S, Kirkeeide RL, Mintz GS, Rentrop KP, Sdringola S, Virmani R, Narula J. Patient selection for elective revascularization to reduce myocardial infarction and mortality: new lessons from randomized trials, coronary physiology, and statistics. Circ Cardiovasc Imaging. 2015 May;8(5). pii: e003099. doi: 10.1161/CIRCIMAGING.114.003099. Review.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: January 15, 2019): 455
• Original Estimated Enrollment (submitted: December 23, 2014): 500
• Estimated Study Completion Date: November 2019
• Estimated Primary Completion Date: November 2019 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Age ≥ 18 years.
• Eligible for PCI based on local practice standards during the current procedure (PCI cannot be staged).

• At least one epicardial stenosis of ≥50% diameter (by visual or quantitative assessment) and meeting the following criteria as determined by the operator based on either a prior or the current diagnostic angiogram:

  • <100% diameter (not a chronic, total occlusion);
  • in a native coronary artery (including side branches but excludes bypass grafts);
  • of ≥2.5mm reference diameter (near the level of the stenosis);
  • and supplies sufficiently viable myocardium (exclude regions of known, prior, transmural myocardial infarction).
• Ability to understand and the willingness to sign a written informed consent.

Exclusion Criteria:

• Anatomic exclusions:

  • Prior CABG.
  • Preferred treatment strategy for revascularization would be CABG based on local practice standards.
  • Left main coronary artery disease requiring revascularization.
  • Extremely tortuous or calcified coronary arteries precluding intracoronary physiologic measurements. Operators may also exclude subtotal or similar high-grade lesions, which in their judgment may be threatened by ComboWire placement.
  • Known severe LV hypertrophy (septal wall thickness at echocardiography of >13 mm).

• Clinical exclusions:

  • Inability to receive intravenous adenosine (for example, severe reactive airway disease, marked hypotension, or high-grade AV block without pacemaker).
  • Recent (within 3 weeks prior to cardiac catheterization) ST-segment elevation myocardial infarction (STEMI) in any arterial distribution (not specifically target lesion).
  • Culprit lesions (based on clinical judgment of the operator) for either STEMI or non-STEMI cannot be included.
  • Severe cardiomyopathy (LV ejection fraction <30%).
  • Planned need for cardiac surgery (for example, valve surgery, treatment of aortic aneurysm, or septal myomectomy).

• General exclusions:

  • A life expectancy of less than 2 years.
  • Inability to sign an informed consent, due to any mental condition that renders the subject unable to understand the nature, scope, and possible consequences of the trial or due to mental retardation or language barrier.
  • Potential for non-compliance towards the requirements for follow-up visits.
  • Participation or planned participation in another cardiovascular clinical trial before completing the 24 month follow-up.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Denmark, Italy, Japan, Netherlands, Spain, United Kingdom

Administrative Information

• NCT Number: NCT02328820
• Other Study ID Numbers: HSC-MS-14-0442; NL48375.018.14 ( Other Identifier: Academic Medical Center (AMC), University of Amsterdam )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Nils Johnson, The University of Texas Health Science Center, Houston
• Study Sponsor: The University of Texas Health Science Center, Houston

Collaborators

• Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Volcano Corporation

Investigators

• Principal Investigator: Nils Johnson, MD; University of Texas Medical School at Houston
• Study Director: Jan J Piek, MD, PhD; Academic Medical Center (AMC), Amsterdam

• PRS Account: The University of Texas Health Science Center, Houston
• Verification Date: January 2019