Clinical trial NCT04397211: Angiography-Derived FFR And IVUS for Clinical Outcomes in Patients With Coronary Artery Disease
Official title: Comparison of Angiography-derived Fractional FLow Reserve- And IntraVascular Ultrasound-guided Intervention Strategy for Clinical OUtcomes in Patients With CoRonary Artery Disease
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: NA
Conditions: Coronary Artery Disease
Keywords: Angiography-derived fractional flow reserve
Intravascular ultrasound
Percutaneous coronary intervention
Fractional flow reserve
Lead sponsor: Second Affiliated Hospital, School of Medicine, Zhejiang University
Sponsor class: OTHER
Collaborators: name: Seoul National University Hospital
name: Affiliated Hangzhou First People's Hospital
name: Wuhan University
name: Peking University Third Hospital
name: The Affiliated Hospital of Hangzhou Normal University
name: RenJi Hospital
name: Second Hospital of Shanxi Medical University
name: First Affiliated Hospital of Wenzhou Medical University
name: Second Affiliated Hospital of Wenzhou Medical University
name: Changxing People's Hospital
name: The Affiliated Hospital of Medical College, Ningbo University
name: Jinhua Central Hospital
name: Shandong University of Traditional Chinese Medicine
name: Dongyang People's Hospital
name: The First Affiliated Hospital of Nanchang University
name: Jining First People's Hospital
name: Second Affiliated Hospital of Shantou University Medical College
name: Ulsan University Hospital
name: Huizhou Municipal Central Hospital
name: Zhejiang Greentown Cardiovascular Hospital
name: The Fourth People's Hospital of Jinan
name: First Affiliated Hospital of Kunming Medical University
First posted: 2020-05-21
Enrollment: 1872
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Parallel Assignment
Primary purpose: TREATMENT

Brief summary: Comparison of Angiography-derived Fractional FLow Reserve And IntraVascular Ultrasound-guided Intervention Strategy for Clinical OUtcomes in Patients with CoRonary Artery Disease

Detailed description: 1. The primary hypothesis is that angiography-derived FFR-guided strategy for PCI with a drug-eluting stent (DES) will show non-inferiority in rates of patients-oriented composite outcomes (POCO) at 12 months after randomization, compared with IVUS-guided strategy for PCI with a DES in patients with coronary artery disease.
2. Study population and sample size calculation： Sample size calculation based on the event rates of previous trials, investigators predicted the rates of POCO at 12 months after PCI will be 7% in the Angiography-derived FFR-guided arm, and 8% in the IVUS-guided arm

   * Primary endpoint: patient-oriented composite outcome (a composite of all-cause death, MI, any revascularization) at 12 months after PCI
   * Design: non-inferiority, delta = 2.5%
   * Sampling ratio: angiography-derived FFR-guided strategy: IVUS-guided strategy = 1:1
   * Type I error (α): One-sided 2.5%
   * Accrual time: 3 years
   * Total time: 4 years (accrual 3 years + follow-up 1 years)
   * Assumption: POCO 7.0% vs. 8.0% in angiography-derived FFR or IVUS-guided strategy, respectively
   * Statistical power (1- β): 80%
   * Primary statistical method: Kaplan-Meier survival analysis with log-rank test
   * Estimated attrition rate: total 5%
   * Stratification in Randomization: Presence of diabetes mellitus (35% of patients in each group) Based on the above assumption, we would need total 1,872 patients (936 patients in each group) with consideration of an attrition rate.
3. Research Materials and Indication for Revascularization： For the angiography-derived FFR-guided strategy arm, criteria for revascularization: angiography-derived FFR ≤ 0.80. For the IVUS-guided strategy arm, the criterion for revascularization is MLA ≤ 3mm2 or \[3mm2 \< MLA ≤ 4mm2 and plaque burden \> 70%\].

Eligibility criteria: Inclusion Criteria:

* ① Subject must be ≥ 18 years. ② Subject is able to verbally confirm understandings of risks, benefits and treatment alternatives of receiving invasive physiologic or imaging evaluation and PCI with a drug-eluting stent (DES) and he/she or his/her legally authorized representative provides written informed consent prior to any study related procedure. ③ Patients suspected with ischemic heart disease. ④ Patients with ≥ 50% stenosis by angiography-based visual estimation eligible for stent implantation. ⑤ Target vessel size ≥ 2.5mm in visual estimation. ⑥ Target vessels are limited to major epicardial coronary arteries (left anterior descending artery\[LAD\], left circumflex artery \[LCX\], right coronary artery \[RCA\])

Exclusion Criteria:

* ① The patient has a known hypersensitivity or contraindication to any of the following medications: Heparin, Aspirin, Clopidogrel, Prasugrel, Ticagrelor, Contrast media (Patients with documented sensitivity to contrast media which can be effectively premedicated with steroids and diphenhydramine \[e.g. rash\] may be enrolled.) ② Patients with active pathologic bleeding. ③ Gastrointestinal or genitourinary major bleeding within the prior 3 months. ④ History of bleeding. diathesis, known coagulopathy (including heparin-induced thrombocytopenia). ⑤Non-cardiac co-morbid conditions with life expectancy \< 1 year. ⑥ Target vessel total occlusion. ⑦ Target lesion located in coronary arterial bypass graft. ⑧ Left main coronary artery stenosis ≥ 50%. ⑨ Not eligible for angiography-derived FFR (ostial RCA ≥ 50% stenosis, myocardial bridging, severe tortuosity, severe overlap, poor image quality)

Primary outcomes:
measure: Patient-oriented composite outcome
timeFrame: 12 months
Secondary outcomes:
measure: Patient-oriented composite outcome (POCO)
timeFrame: 24, 60 months
measure: Target vessel failure
timeFrame: 12, 24 and 60 months
measure: Cost-effectiveness analysis
timeFrame: 12, 24 and 60 months
measure: All-cause and cardiac death
timeFrame: 12, 24 and 60 months
measure: Any nonfatal MI without peri-procedural MI
timeFrame: 12, 24 and 60 months
measure: Any nonfatal MI with peri-procedural MI
timeFrame: 12, 24 and 60 months
measure: Any target vessel/lesion revascularization
timeFrame: 12, 24 and 60 months
measure: Any non-target vessel/lesion revascularization
timeFrame: 12, 24 and 60 months
measure: Any revascularization (ischemia-driven or all)
timeFrame: 12, 24 and 60 months
measure: Stent thrombosis (definite/probable/possible)
timeFrame: 12, 24 and 60 months
measure: Stroke (ischemic and hemorrhagic)
timeFrame: 12, 24 and 60 months
measure: Acute success of procedure and rate of PCI optimization
timeFrame: At discharge (1 week after index procedure)
Other outcomes:
Locations:
city: Hangzhou
country: China
facility: Second Affiliated Hospital, School of Medicine, Zhejiang University, China
state: Zhejiang
city: Beijing
country: China
facility: Peking University Third Hospital
city: Guangdong
country: China
facility: Second Affiliated Hospital of Shantou University Medical College
city: Hangzhou
country: China
facility: Affiliated Hangzhou First People's Hospital
city: Hangzhou
country: China
facility: The Affiliated Hospital of Hangzhou Normal University
city: Hangzhou
country: China
facility: Zhejiang Greentown Cardiovascular Hospital
city: Huzhou
country: China
facility: Changxing People's Hospital
city: Huzhou
country: China
facility: Huzhou Central Hospital
city: Jinan
country: China
facility: The Fourth People's Hospital of Jinan
city: Jinhua
country: China
facility: Dongyang People's Hospital
city: Jinhua
country: China
facility: Jinhua Central Hospital
city: Kunming
country: China
facility: First Affiliated Hospital of Kunming Medical University
city: Nanchang
country: China
facility: The First Affiliated Hospital of Nanchang University
city: Ningbo
country: China
facility: The Affiliated Hospital of Medical College, Ningbo University
city: Shandong
country: China
facility: Shandong Jining No.1 People's Hospital
city: Shandong
country: China
facility: Shandong University of Traditional Chinese Medicine
city: Shanghai
country: China
facility: Renji Hospital Shanghai Jiaotong University School of Medicine
city: Taiyuan
country: China
facility: Second hospital of Shanxi Medical University
city: Wenzhou
country: China
facility: The first affiliated hospital of Wenzhou Medical University
city: Wenzhou
country: China
facility: The second affiliated hospital of Wenzhou Medical University
city: Wuhan
country: China
facility: Zhongnan Hospital of Wuhan University
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital,
city: Ulsan
country: Korea, Republic of
facility: Ulsan University Hospital
Study officials:
affiliation: Second Affiliated Hospital, School of Medicine, Zhejiang University
name: Jian'an Wang, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Seoul National University Hospital
name: Bon-Kwon Koo, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Levine GN, Bates ER, Blankenship JC, Bailey SR, Bittl JA, Cercek B, Chambers CE, Ellis SG, Guyton RA, Hollenberg SM, Khot UN, Lange RA, Mauri L, Mehran R, Moussa ID, Mukherjee D, Nallamothu BK, Ting HH; American College of Cardiology Foundation; American Heart Association Task Force on Practice Guidelines; Society for Cardiovascular Angiography and Interventions. 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention. A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. J Am Coll Cardiol. 2011 Dec 6;58(24):e44-122. doi: 10.1016/j.jacc.2011.08.007. Epub 2011 Nov 7. No abstract available.
citation: De Bruyne B, Fearon WF, Pijls NH, Barbato E, Tonino P, Piroth Z, Jagic N, Mobius-Winckler S, Rioufol G, Witt N, Kala P, MacCarthy P, Engstrom T, Oldroyd K, Mavromatis K, Manoharan G, Verlee P, Frobert O, Curzen N, Johnson JB, Limacher A, Nuesch E, Juni P; FAME 2 Trial Investigators. Fractional flow reserve-guided PCI for stable coronary artery disease. N Engl J Med. 2014 Sep 25;371(13):1208-17. doi: 10.1056/NEJMoa1408758. Epub 2014 Sep 1.
citation: Melikian N, De Bondt P, Tonino P, De Winter O, Wyffels E, Bartunek J, Heyndrickx GR, Fearon WF, Pijls NH, Wijns W, De Bruyne B. Fractional flow reserve and myocardial perfusion imaging in patients with angiographic multivessel coronary artery disease. JACC Cardiovasc Interv. 2010 Mar;3(3):307-14. doi: 10.1016/j.jcin.2009.12.010.
citation: Pijls NH, van Schaardenburgh P, Manoharan G, Boersma E, Bech JW, van't Veer M, Bar F, Hoorntje J, Koolen J, Wijns W, de Bruyne B. Percutaneous coronary intervention of functionally nonsignificant stenosis: 5-year follow-up of the DEFER Study. J Am Coll Cardiol. 2007 May 29;49(21):2105-11. doi: 10.1016/j.jacc.2007.01.087. Epub 2007 May 17.
citation: Westra J, Tu S, Campo G, Qiao S, Matsuo H, Qu X, Koltowski L, Chang Y, Liu T, Yang J, Andersen BK, Eftekhari A, Christiansen EH, Escaned J, Wijns W, Xu B, Holm NR. Diagnostic performance of quantitative flow ratio in prospectively enrolled patients: An individual patient-data meta-analysis. Catheter Cardiovasc Interv. 2019 Nov 1;94(5):693-701. doi: 10.1002/ccd.28283. Epub 2019 Apr 9.
citation: Fearon WF, Achenbach S, Engstrom T, Assali A, Shlofmitz R, Jeremias A, Fournier S, Kirtane AJ, Kornowski R, Greenberg G, Jubeh R, Kolansky DM, McAndrew T, Dressler O, Maehara A, Matsumura M, Leon MB, De Bruyne B; FAST-FFR Study Investigators. Accuracy of Fractional Flow Reserve Derived From Coronary Angiography. Circulation. 2019 Jan 22;139(4):477-484. doi: 10.1161/CIRCULATIONAHA.118.037350.
citation: Westra J, Tu S, Winther S, Nissen L, Vestergaard MB, Andersen BK, Holck EN, Fox Maule C, Johansen JK, Andreasen LN, Simonsen JK, Zhang Y, Kristensen SD, Maeng M, Kaltoft A, Terkelsen CJ, Krusell LR, Jakobsen L, Reiber JHC, Lassen JF, Bottcher M, Botker HE, Christiansen EH, Holm NR. Evaluation of Coronary Artery Stenosis by Quantitative Flow Ratio During Invasive Coronary Angiography: The WIFI II Study (Wire-Free Functional Imaging II). Circ Cardiovasc Imaging. 2018 Mar;11(3):e007107. doi: 10.1161/CIRCIMAGING.117.007107.
citation: Westra J, Andersen BK, Campo G, Matsuo H, Koltowski L, Eftekhari A, Liu T, Di Serafino L, Di Girolamo D, Escaned J, Nef H, Naber C, Barbierato M, Tu S, Neghabat O, Madsen M, Tebaldi M, Tanigaki T, Kochman J, Somi S, Esposito G, Mercone G, Mejia-Renteria H, Ronco F, Botker HE, Wijns W, Christiansen EH, Holm NR. Diagnostic Performance of In-Procedure Angiography-Derived Quantitative Flow Reserve Compared to Pressure-Derived Fractional Flow Reserve: The FAVOR II Europe-Japan Study. J Am Heart Assoc. 2018 Jul 6;7(14):e009603. doi: 10.1161/JAHA.118.009603.
citation: Collet C, Onuma Y, Sonck J, Asano T, Vandeloo B, Kornowski R, Tu S, Westra J, Holm NR, Xu B, de Winter RJ, Tijssen JG, Miyazaki Y, Katagiri Y, Tenekecioglu E, Modolo R, Chichareon P, Cosyns B, Schoors D, Roosens B, Lochy S, Argacha JF, van Rosendael A, Bax J, Reiber JHC, Escaned J, De Bruyne B, Wijns W, Serruys PW. Diagnostic performance of angiography-derived fractional flow reserve: a systematic review and Bayesian meta-analysis. Eur Heart J. 2018 Sep 14;39(35):3314-3321. doi: 10.1093/eurheartj/ehy445.
citation: Xu B, Tu S, Qiao S, Qu X, Chen Y, Yang J, Guo L, Sun Z, Li Z, Tian F, Fang W, Chen J, Li W, Guan C, Holm NR, Wijns W, Hu S. Diagnostic Accuracy of Angiography-Based Quantitative Flow Ratio Measurements for Online Assessment of Coronary Stenosis. J Am Coll Cardiol. 2017 Dec 26;70(25):3077-3087. doi: 10.1016/j.jacc.2017.10.035. Epub 2017 Oct 31.
citation: Tu S, Westra J, Yang J, von Birgelen C, Ferrara A, Pellicano M, Nef H, Tebaldi M, Murasato Y, Lansky A, Barbato E, van der Heijden LC, Reiber JHC, Holm NR, Wijns W; FAVOR Pilot Trial Study Group. Diagnostic Accuracy of Fast Computational Approaches to Derive Fractional Flow Reserve From Diagnostic Coronary Angiography: The International Multicenter FAVOR Pilot Study. JACC Cardiovasc Interv. 2016 Oct 10;9(19):2024-2035. doi: 10.1016/j.jcin.2016.07.013.
citation: Fujii K, Carlier SG, Mintz GS, Yang YM, Moussa I, Weisz G, Dangas G, Mehran R, Lansky AJ, Kreps EM, Collins M, Stone GW, Moses JW, Leon MB. Stent underexpansion and residual reference segment stenosis are related to stent thrombosis after sirolimus-eluting stent implantation: an intravascular ultrasound study. J Am Coll Cardiol. 2005 Apr 5;45(7):995-8. doi: 10.1016/j.jacc.2004.12.066.
citation: Ahn JM, Kang SJ, Yoon SH, Park HW, Kang SM, Lee JY, Lee SW, Kim YH, Lee CW, Park SW, Mintz GS, Park SJ. Meta-analysis of outcomes after intravascular ultrasound-guided versus angiography-guided drug-eluting stent implantation in 26,503 patients enrolled in three randomized trials and 14 observational studies. Am J Cardiol. 2014 Apr 15;113(8):1338-47. doi: 10.1016/j.amjcard.2013.12.043. Epub 2014 Jan 31.
citation: Nam CW, Yoon HJ, Cho YK, Park HS, Kim H, Hur SH, Kim YN, Chung IS, Koo BK, Tahk SJ, Fearon WF, Kim KB. Outcomes of percutaneous coronary intervention in intermediate coronary artery disease: fractional flow reserve-guided versus intravascular ultrasound-guided. JACC Cardiovasc Interv. 2010 Aug;3(8):812-7. doi: 10.1016/j.jcin.2010.04.016.
citation: Davies JE, Sen S, Dehbi HM, Al-Lamee R, Petraco R, Nijjer SS, Bhindi R, Lehman SJ, Walters D, Sapontis J, Janssens L, Vrints CJ, Khashaba A, Laine M, Van Belle E, Krackhardt F, Bojara W, Going O, Harle T, Indolfi C, Niccoli G, Ribichini F, Tanaka N, Yokoi H, Takashima H, Kikuta Y, Erglis A, Vinhas H, Canas Silva P, Baptista SB, Alghamdi A, Hellig F, Koo BK, Nam CW, Shin ES, Doh JH, Brugaletta S, Alegria-Barrero E, Meuwissen M, Piek JJ, van Royen N, Sezer M, Di Mario C, Gerber RT, Malik IS, Sharp ASP, Talwar S, Tang K, Samady H, Altman J, Seto AH, Singh J, Jeremias A, Matsuo H, Kharbanda RK, Patel MR, Serruys P, Escaned J. Use of the Instantaneous Wave-free Ratio or Fractional Flow Reserve in PCI. N Engl J Med. 2017 May 11;376(19):1824-1834. doi: 10.1056/NEJMoa1700445. Epub 2017 Mar 18.
citation: Zhang J, Gao X, Kan J, Ge Z, Han L, Lu S, Tian N, Lin S, Lu Q, Wu X, Li Q, Liu Z, Chen Y, Qian X, Wang J, Chai D, Chen C, Li X, Gogas BD, Pan T, Shan S, Ye F, Chen SL. Intravascular Ultrasound Versus Angiography-Guided Drug-Eluting Stent Implantation: The ULTIMATE Trial. J Am Coll Cardiol. 2018 Dec 18;72(24):3126-3137. doi: 10.1016/j.jacc.2018.09.013. Epub 2018 Sep 24.
citation: Park KW, Kang SH, Yang HM, Lee HY, Kang HJ, Cho YS, Youn TJ, Koo BK, Chae IH, Kim HS. Impact of intravascular ultrasound guidance in routine percutaneous coronary intervention for conventional lesions: data from the EXCELLENT trial. Int J Cardiol. 2013 Aug 10;167(3):721-6. doi: 10.1016/j.ijcard.2012.03.059. Epub 2012 Apr 4.
citation: Kang J, Koo BK, Hu X, Lee JM, Hahn JY, Yang HM, Shin ES, Nam CW, Doh JH, Lee BK, Ahn C, Wang J, Tahk SJ. Comparison of Fractional FLow Reserve And Intravascular ultrasound-guided Intervention Strategy for Clinical OUtcomes in Patients with InteRmediate Stenosis (FLAVOUR): Rationale and design of a randomized clinical trial. Am Heart J. 2018 May;199:7-12. doi: 10.1016/j.ahj.2017.11.001. Epub 2017 Nov 6.
citation: Garcia-Garcia HM, McFadden EP, Farb A, Mehran R, Stone GW, Spertus J, Onuma Y, Morel MA, van Es GA, Zuckerman B, Fearon WF, Taggart D, Kappetein AP, Krucoff MW, Vranckx P, Windecker S, Cutlip D, Serruys PW; Academic Research Consortium. Standardized End Point Definitions for Coronary Intervention Trials: The Academic Research Consortium-2 Consensus Document. Circulation. 2018 Jun 12;137(24):2635-2650. doi: 10.1161/CIRCULATIONAHA.117.029289.
citation: ISCHEMIA Trial Research Group; Maron DJ, Hochman JS, O'Brien SM, Reynolds HR, Boden WE, Stone GW, Bangalore S, Spertus JA, Mark DB, Alexander KP, Shaw L, Berger JS, Ferguson TB Jr, Williams DO, Harrington RA, Rosenberg Y. International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) trial: Rationale and design. Am Heart J. 2018 Jul;201:124-135. doi: 10.1016/j.ahj.2018.04.011. Epub 2018 Apr 21.
citation: Maron DJ, Hochman JS, Reynolds HR, Bangalore S, O'Brien SM, Boden WE, Chaitman BR, Senior R, Lopez-Sendon J, Alexander KP, Lopes RD, Shaw LJ, Berger JS, Newman JD, Sidhu MS, Goodman SG, Ruzyllo W, Gosselin G, Maggioni AP, White HD, Bhargava B, Min JK, Mancini GBJ, Berman DS, Picard MH, Kwong RY, Ali ZA, Mark DB, Spertus JA, Krishnan MN, Elghamaz A, Moorthy N, Hueb WA, Demkow M, Mavromatis K, Bockeria O, Peteiro J, Miller TD, Szwed H, Doerr R, Keltai M, Selvanayagam JB, Steg PG, Held C, Kohsaka S, Mavromichalis S, Kirby R, Jeffries NO, Harrell FE Jr, Rockhold FW, Broderick S, Ferguson TB Jr, Williams DO, Harrington RA, Stone GW, Rosenberg Y; ISCHEMIA Research Group. Initial Invasive or Conservative Strategy for Stable Coronary Disease. N Engl J Med. 2020 Apr 9;382(15):1395-1407. doi: 10.1056/NEJMoa1915922. Epub 2020 Mar 30.