The DEFINE-FLOW Study: Combined CFR and FFR Lesion Assessment

August 6th, Highlight Session of TCTAP & AP VALVES 2020 VIRTUAL

On August 6th, at the Highlight Session of TCTAP & AP VALVES 2020 VIRTUAL, Nils Johnson, MD (McGovern Medical School at UTHealth, Texas, USA) introduced ¡°DEFINE-FLOW¡¯ study with great expectation. As a result of several pivotal randomized controlled trials, fractional flow reserve (FFR) started to play a dominant role in physiologic assessment on an epicardial level. Although coronary flow reserve (CFR) can interrogate the entire coronary circulation on both epicardial and microcirculatory levels, it should be measured invasively using either Doppler flow velocity or thermodilution techniques. Considering the binary abnormal values of FFR ¡Â 0.8 and CFR < 2.0, FFR and CFR disagree in 30%-40% of cases. Prior literature regarding prognosis and revascularization necessity for these frequent discordant cases has been limited by the selection bias of treatment as well as its being retrospective and single-center design. As a result, uncertainty persists when faced with FFR and CFR discordance.

To resolve this clinical uncertainty, Nils P. Johnson and his colleagues designed a nonrandomized nonblinded study named DEFINE-FLOW (Distal Evaluation of Functional performance with Intravascular sensors to assess the Narrowing Effect - combined pressure and Doppler FLOW velocity measurements).
They hypothesized that lesions with an intact CFR ¡Ã 2.0 but reduced FFR ¡Â 0.8 will have a 2-year outcome with medical treatment similar to lesions with FFR > 0.80 and CFR ¡Ã 2.0, as based on previously conducted studies with a 10-year follow-up. PCI will only be performed immediately after intermediate lesion assessment when both binary FFR and CFR are abnormal; all other lesions will be deferred from revascularization to study their ¡°natural history¡± (Figure 2). The primary endpoint is the 24-month rate of major adverse cardiac events (MACE) defined as a composite of all-cause death, myocardial infarction (MI), unplanned or urgent revascularization, and elective revascularization. Specifically, the MACE rates will be compared in each discordant group (low FFR but intact CFR, intact FFR but low CFR) against lesions with intact FFR and CFR.

They have completed enrollment of 455 subjects and started the follow-up on the clinical events. Details of study design and baseline characteristics of the fully enrolled cohort were published in American Heart Journal this April (Am Heart J 2020;222:139-46) and the results are expecting to be announced on this upcoming TCT 2020. DEFINE-FLOW will be able to show whether a simultaneous assessment of CFR offers independent prognostic and clinical values once FFR is known.
William Fearon, MD (Stanford University School of Medicine, California, USA), a panelist, asked a question about the blindness of the operators/physicians and the adequate power calculations - small number of participants - of the DEFINE-FLOW study.
Dr. Johnson replied, ¡°In order to adopt good Doppler signals, it is not practically possible for us to blind operators. Therefore, the operators are not blinded to the result, in fact, the CFR value have to be unblinded to have a uniform approach to treating lesions that had lower FFR values.¡±, ¡°To the second point, you¡¯re right. The study is going to be hypothesis generating for what to do with that group both FFR positive but CFR intact lesions. I think it's a steppingstone along that way to the definitive trial.¡±

¡°Plaques at those lesions with low FFR and high CFR are exposed to very high wall shear stress, that is associated with a vulnerable plaque formation. If you are going to plan a randomized trial for the patients with low FFR and high CFR, you may need a very long-term follow-up to integrate the influence of those wall shear stress.¡± Bon-Kwon Koo, MD (Seoul National University Hospital, Seoul, South Korea) commented.

CHECK THE SESSION

Editor: Mineok Chang, MD (Seoul National University Hospital, Korea)