Fractional Flow Reserve in Critical Limb Ischemia Patients

The golden standard imaging modality for Percutaneous Transluminal Angioplasty
(PTA) is Digital Subtraction Angiography (DSA) using an iodine contrast agent.
This imaging modality can visualize the diameter of the vessel where the
contrast agent is injected, thus enabling the surgeon to estimate the size of
the stenosis in the vessel wall. This technique however has its shortcomings.
Firstly, it does not give a clear indication whether the stenosis is
significant with regard to the blood flow and demand post-stenosis. Secondly,
it does not give sufficient information regarding the microvascularization of
the tissue that is supplied by the affected blood vessel. This information
could change intraoperative decision-making. It might influence the decision
whether a diseased blood vessel should be treated and how this will be
executed.

Fractional Flow Reserve (FFR) is a technique commonly applied within the field
of Cardiology. FFR is an invasive index of the functional severity of a
stenosis determined from changes in intra-arterial pressure during a
catheterization procedure. FFR expresses maximum achievable blood flow to the
surrounding tissue supplied by a stenotic artery measured during the maximum
state of hyperemia, as a fraction of normal maximum flow. FFR is the ratio
measured in a hyperemic state of distal intraluminal pressure (Pd), measured
post-stenosis, to proximal intraluminal pressure, measured pre-stenosis (Pp).
Hyperemia is induced by intracoronary or intravenous injection of papaverine.
FFR has been proven to be useful in guiding Percutaneous Coronary Intervention
(PCI) by accurately determining the clinical significance of a stenosis
expressed in the blood flow and demand post-stenosis. This has resulted in a
reduction of overtreatment in stenotic segments that are angiographically
significant, yet do not appear to be hemodynamically significant after
measuring the FFR. Furthermore, FFR could predict the success of PTA in terms
of symptom reduction by determining which stenoses are hemodynamically
insignificant and which tissues have low flow demand because of damage to the
microvasculature.

Due to the fact that DSA does not sufficiently depict the significance of a
stenosis, as proven within the field of Cardiology, we will investigate the
possible role of FFR in peripheral arterial disease. The clinical relevance and
possible value of FFR within the peripheral vascular system has not been
thoroughly investigated thus far. There have been a limited amount of studies
regarding the application of FFR in the peripheral vascular system. These
studies suggest that using FFR in the peripheral arteries can assist in
determining whether a stenosis is significant. FFR provides information on the
quality of microvasculature in the tissue supplied by the artery of interest,
which in interventional Cardiology is used to predict the long-term outcome
after PCI. In the long term, we aim to determine whether FFR can be used in a
similar role in peripheral vascular surgery. Thus, further studies are
necessary to evaluate the clinical relevance and possibilities of FFR within
the field of Vascular Surgery. This study will be one of the first steps, using
FFR in a small population of patients undergoing PTA to provide proof of its
safety and feasibility, i.e. its ability to measure the clinical significance
of a stenosis, in below the knee arteries. This study will focus on below the
knee (BTK) arteries, as these are most comparable of all peripheral vessels
compared to the coronary arteries.

This proof-of-concept study aims to prove the safety and feasibility of FFR in
BTK lesions. Safety is defined here as conducting the FFR measurement without
complications caused by the FFR measurement. Feasibility is defined here as
successfully completing the FFR measurement during PTA.

This study will be a proof-of-principle study. It will be a one-armed trial
where patients are their own control, thus the measurements as described do not
need a control group to provide the information required to achieve the stated
objectives. The study will be conducted between January 1, 2023, and January 1,
2025, in the Zuyderland MC. 20 patients who undergo PTA guided by conventional
DSA. After locating the stenosis in the target vessel, FFR measurements will be
conducted. The FFR measurements will be analyzed after the PTA is concluded.
Patients will undergo the regular follow-up for PTA and will be followed for 6
weeks post-procedure. This is adequate to detect adverse events caused by the
procedure or measurements. As this is one of the first prospective studies
using FFR in BTK arteries, this study is necessary as a step-up to larger
trials.

The potential risks regarding FFR measurement are mainly caused by the
injection of intravascular papaverine. Papaverine is a vasodilator and has an
effect on the smooth muscles and a minor effect on the arterioles. It also acts
as a spasmolytic agent. Contra-indications for the use of papaverine are a
complete AV-nodal heart block and patients whose cardiac conduction is
depressed, because of increased risk of transient ectopic rhythms of
ventricular origin (premature beats or paroxysmal tachycardia).
The following side effects have been reported: general discomfort, nausea,
abdominal discomfort, anorexia, constipation or diarrhea, skin rash, malaise,
vertigo, headache, intensive flushing of the face, perspiration, increase in
the depth of respiration, increase in heart rate, a slight rise in blood
pressure, and excessive sedation. Hepatitis, probably related to an immune
mechanism, has been reported infrequently. Rarely, this has progressed to
cirrhosis. These side effects are mild an easily manageable.