The Use of Pressure Indices,Such as Fractional Flow Reserve,in Peripheral Arterial Disease-A Review of Current Literature and Potential Prospects

Abstract

Purpose

To assess the evidence in the current literature, identify the knowledge gaps and propose future standards for the use of pressure indices in peripheral arterial disease (PAD).

Methods

A search of all medical databases was performed to identify studies performed between 01/01/2000 and 31/12/2024, looking at the use of FFR or IFR in the management of PAD. The Newcastle-Ottawa scale was used to assess the quality of the papers. A comparison of the studies was performed using various parameters including; study design, cohort demographics, aim, lesions treated, hyperaemic agent used/pressure indices utilised, FFR endpoint and clinical outcomes.

Results

136 studies were found in initial search. Only studies investigating FFR were identified, none looked at IFR. Following the application of the exclusion criteria, 8 relevant studies with a total of 247 patients were included in the final analyses. No randomised controlled or prospective trials were found. Significant heterogeneity was observed in the methodology and data collection among the included papers. Despite this, the analysis demonstrated initial evidence showing the potential of pressure measurements to revolutionise diagnostic, intra-procedural and prognostic decisions in PAD, akin to the data that already exists in coronary artery disease.

Conclusions

Further standardised research of FFR is needed in peripheral vascular disease to improve objective understanding of physiological parameters pre and post-treatment. To this end, a standardisation tool has been proposed to homogenise and aid future research in drawing more robust conclusions for the use of pressure indices in PAD.

Introduction

Endovascular therapy (EVT) is currently the first-line procedural treatment option for the majority of patients with peripheral vascular disease (PVD). In recent years, while interventional techniques and devices have been developing rapidly, the clinical decision making and patient selection are essentially unchanged. ¹

The main parameters integral to diagnosis, patient selection and the prediction of procedural outcomes remain clinical history and imaging investigations; such as duplex ultrasound, computed tomography angiography (CTA), magnetic resonance angiography (MRA), interventional angiography and ankle-pressure index (ABI). However, none of these methods is effective or practical at making an objective assessment of the lesion’s hemodynamic status, pre and post-intervention. Although the decision to intervene should consider the patient’s perceived symptoms as well as the actual impact on quality of life, the technical aspects of the procedures still depend on diagnostic methods that provide information limited to anatomical features, without offering insights into the significance of physiological functions.

Hence, there is a need for robust and accurate guiding measures to assess atherosclerotic lesions, in particular the equivocal ones properly, and to objectively optimise intervention techniques and treatment outcomes. ¹

In the management of coronary artery disease, cardiologists routinely use indices derived from invasive intra-arterial pressure measurements to guide decision-making intraoperatively, including whether and how to treat.^2,3 These indices are called the fractional flow reserve (FFR) and the instantaneous wave-free ratio (IFR). FFR is defined as the ratio between mean post-stenosis coronary arterial and aortic blood pressures under vasodilator-induced hyperaemic conditions. ² In the last few decades, it has been used as the gold standard for assessing the functional severity of coronary artery lesions. ⁴

On the other hand, IFR is defined as the ratio between the mean values of post stenosis coronary arterial and aortic blood pressure during the diastolic wave-free period under non-hyperaemic resting conditions. ⁵ IFR can be measured without the need for vasodilator administration, and has emerged as an alternative index of stenosis severity.^2,6,7

The key value of these pressure-derived indices are in determining whether a lesion is haemodynamically significant and measuring the change following the intervention. These indices can also be performed during the procedure, unlike CTA and ABI, and acted on immediately which makes them a helpful adjunct to angiography and intravascular ultrasound. This would also allow an objective assessment to be made, helping to provide standardised care.

While these methods have been widely researched within in the context of coronary disease, there has been little data related to peripheral vascular disease. Pressure-derived indices may be able to objectively assess the effectiveness of treatments and better guide interventional radiologists and vascular surgeons in treating and managing their PVD patients.

Methods

This study was split into 2 sections: a literature review, followed by an analysis of the relevant studies. The literature search followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses.^8,9

The aim of this review is:

(1) To establish the current knowledge of FFR or IFR during peripheral endovascular revascularisation.

(2) To identify any study that combined physiological measurements with other imaging guidance such as IVUS, angiography (2D or 3D) perfusion or any other perfusion measurement tool to assess clinical outcomes.

(3) To identify the gaps in knowledge when compared to established practice in coronary arteries and recommend further steps in future research.

For the review design, it was decided to include any paper that looked at the use of FFR or IFR in the management of peripheral arterial disease. The ideal comparison was any modality that was not a pressure measurement, and the outcome was to identify if there was a benefit of using FFR and IFR over all other modalities. All medical databases, including PUBMED, EMBASE, COCHRANE and OVID were searched from 01/01/2000 until 31/12/2023. Another updated search was also conducted to cover the period from September 2023 to 31/12/2024. The search criteria focused on gathering papers looking at FFR or IFR in the management of peripheral vascular disease and were restricted to English manuscripts and only those including human participants in their research.

Papers that did not refer to peripheral vessels, i.e coronary arteries were excluded. Papers with single case reports, letters to the editor and commentaries were also excluded.

The search string was edited for each database to meet their requirements and is seen in Figure 1, the refined of the strategy was based on the vast literature on coronary arteries.

Figure 1.

Search Strategy

Two researchers (KK, AAR) then independently reviewed all the acquired papers, strictly filtering by applying our inclusion and exclusion criteria. A third member of the team (MS) then went through both sets of data to identify any discrepancies and resolve any differences of opinion. Each relevant paper was then analysed and data was extracted through pre-determined outcome variable seen in Figure 2.

Figure 2.

Data Collection Points

Subsequently, the Newcastle-Ottawa scale (NOS) was used to assess the quality of the papers. The NOS, recommended by the Cochrane Collaboration, contains 8 items, categorized into 3 dimensions: selection, comparability, and outcome or exposure for cohort studies or non-randomised case–control studies. Studies are graded one point each for all items except comparability which has the potential to score up to 2 points, with the maximum possible score being 9. Studies are rated from 0-9, with those studies rating 0-2 (poor quality), 3-5 (fair quality), 6-9 (good/high quality). ¹⁰

At this point, it was evident there was very little literature available for effective meta-analysis, and the studies lacked effective standardisation to compare results from their participant cohorts to measured parameters statistically. Instead, a narrative review of their results and findings was performed.

Results

There were 137 studies found in the aforementioned databases following the application of our search criteria. However, once we filtered their titles and abstracts, with the inclusion and exclusion criteria/removed duplications, only 12 studies remained. A further 4 studies were then removed following an extensive full article review, as were conference abstracts or review papers.^11-19 Updated search until December 2024 found one more paper of 45 patients ¹⁹ . This left a total of 9 relevant studies as seen in Figure 3. All 9 studies were prospective single centre trials.

Figure 3.

PRISMA Flow Diagram for Screening

Within these 9 studies, there were 292 patients. There was no overall trend within these studies for demographics, but importantly all of them investigated FFR measurements and none looked at IFR. Different studies included participants with a stenosis at different anatomical locations, with 4 studies assessing superficial femoral artery lesions, 3 studies assessing iliofemoral lesions and one on below-knee lesions.

Table 1 compares standardised parameters in each relevant study. It depicts the follow-up period of each study, design, aim, patient cohort, methods, hyperaemic agent (as all studies used FFR), the comparator, FFR endpoint and outcomes.

Table 1.

Comparison of the Relevant Studies

Study	Time period	Design	Aim	Number of patients	Methods	Hyperaemic agent	Comparator	FFR endpoint	Clinical outcome
Kobayashi N et al- ability of fractional flow reserve to predict restenosis after superficial	July 2013-June 2014	Prospective, single-centre nonrandomised study	Evaluating the clinical efficacy of post stenting on FFR	48 included (total 51 SFA lesions)	Performed angioplasty+/− stenting of the SFA via a contra lateral cross over approach	30 mg of papaverine was selectively injected from the ostium of the common iliac artery	FFR measurement following EVT	The best post stenting mean FFR cutoff value for predicting restenosis was 0.92	Post stenting mean FFR is useful for predicting restenosis in SFA disease. A FFR 0.92 provides a statistically significant cut-off for predicting re-stenosis
Femoral artery stenting				Originally 121 patients with SFA lesions were enrolled	Standardised use of drugs and equipment
					All patients had DAPT for 1 month and standardised follow up for 12 months
Ikeoka K et al- pathophysiological significance of velocity-based	NA	Prospective, single-centre nonrandomised study	To investigate the infra-inguinal arterial physiological response through a hyperaemic condition and the pathophysiological significance of microvascular resistance in peripheral arterial disease	16 (10m, 6f) patients for mid/distal SFA lesions	Performed angioplasty+/− stenting via a contra lateral cross over approach	30 mg of papaverine was selectively injected from the ostium of the common iliac artery	FFR measurement pre and post EVT	NA	Endovascular therapy improved FFR and can be utilised in assessing EVT.
Microvascular resistance at maximal hyperemia in peripheral artery disease	Paper published 2018				Standardised use of drugs and equipment
Hioki H et al- diagnostic value of peripheral fractional flow reserve in isolated iliac artery stenosis: a Comparison with the post-exercise ankle-brachial index	December 2012 to November 2013	Prospective, single-centre nonrandomised study	To examine patients with aortoiliac lesions and the relationship between the post-exercise ABI and FFR.	16 patients all male (17 total lesions)	All patient had failed medical management and were to undergo EVT.	Hyperaemia was then induced by administering papaverine hydrochloride in the ipsilateral common iliac artery. Different doses were adminstered, hyperemia was induced with 20	Comparing ABPI and FFR when assessing lesions	NA	There is a significant linear correlation between post-exercise ABI and FFR in aortoiliac lesions. The
				All patients had aortoiliac lesions	Compared the ABPI pre-procedure with the FFR pre-procedure	mg, 25 mg or 30 mg to induce maximal hyperaemia			FFR was more accurate than a peak-to-peak pressure gradient in assessing the physiological significance of a stenosis
Lotfi AS et al- use of fraction flow reserve to predict changes over time in management of superficial	December 2007 to April 2009	Prospective, single-centre nonrandomised study	Establish the feasibility of obtaining FFR in the peripheral vascular circulation. Assess its association with duplex ultrasound and its predictor of future re-stenosis	20 patients. (12 male and 8 female)	Performed FFR measurements	Adenosine 1 mg/kg bolus (IA) via the sheath was given intraarterial into the SFA	FFR measurement pre and post EVT compared to conventional duplex US imaging	NA	FFR predicted duplex US changes and is a feasible method to assess for re-stenosis
Femoral artery				All had SFA lesions					A value of <0.95 was a strong predictor of re-stenosis
Ruzsa Z et al- fractional flow reserve in below the knee arteries with critical limb ischemia and validation against gold-standard morphologic, functional measures and long term clinical outcomes	NA	Prospective, single-centre nonrandomised study	Assess the correlation of FFR and non-ivasive duplex US following treatment of below the knee lesions	39 patients with below the knee occlusions	FFR measurement pre and post EVT.	200 μg of adenosine or 40 mg of papaverine was used	FFR against quantitative angiography, doppler and duplex ultrasound	NA	FFR did not show correlation with duplex US.
	Not specified				Compared changes with conventional measures
Kobayashi N et al-measuring procedure and maximal hyperemia in the assessment of fractional flow reserve for superficial femoral artery disease	February 2013-September 2014	Prospective, single-centre nonrandomised study	Determining the optimal method and papaverine dose for measuring FFR and	45 patients with 48 SFA lesions	Attempted to assess the optimum techniques for performing FFR.	Incremental administration of papaverine (20 mg, 30 mg and 40 mg) was performed	Papaverine doses for measuring FFR	NA	The contralateral femoral crossover approach is useful for measuring FFR. The maximal hyperamia is induced with 30 mg of papaverine
Murata N et al- validation of pressure gradient and peripheral fractional flow reserve measured by a pressure wire for diagnosis of iliofemoral artery disease with intermediate stenosis	April 2012-August 2012	Prospective, single-centre nonrandomised study	Determining the haemodynamic significance of FFR in peripheral arterial stenosis	22 patients with iliofemoral stenosis	Comparing how well FFR correlates with non-invasive investigations	250 μg of isosorbide dinitrate (ISDN) was injected via the guiding system to induce a hyperemic state	FFR against non-invasive duplex US imaging	NA	FFR is reliable for prediction of hemodynamic significance in iliofemoral intermediate stenosis. The optimal value of FFR for hemodynamic significance was 0.85
Albayati MA et al- intra-arterial fractional flow reserve measurements provide an objective assessment of the functional significance of peripheral arterial stenoses	NA	Prospective, single-centre nonrandomised study	To investigate the use of FFR in the peripheral vasculature in patients with limb ischaemia	41 patients (32 male) with 61 stenoses (iliac 32; femoral 29)	Measuring FFR during PTA	Hyperaemia was induced using 100 mg/kg adenosine administered as an intra-arterial bolus distal to the index lesion	Resting ABPI (rABPI) and exercise ABPI (eABPI), DUS, CT angiography, and assessment of calf oxygenation by blood oxygenation level dependent (BOLD) cardiovascular magnetic resonance (CMR)	NA	Fractional flow reserve can objectively measure functional significance of stenosis. It proposed a post-PTA FFR index of >0.74 predicted successful revascularisation
	Not specified
Iwasaki et al	April 2022-aug 2023	Prospective, single centre, observational	To assess relation between peripheral FFR and patency one year after DCB in FP	45	FFR was assessed post DCB angioplasty under hyperaemic conditions and restenosis was assessed at one year with Doppler US, 12 months follow up	30 mg papaverine	Using peripheral FFR post angioplasty using microcatheter	Residual stenosis of <50%with no flow limitation	Rates of freedom from restenosis at one year were significantly higher in the pFFR >0.92 group compared with the pFFR≤0.92 group
Impact of post-procedural peripheral FFR after DCB angioplasty in FP lesions								On an angiography scan

All 9 studies investigated the relation between FFR and clinical outcomes, however a range of different outcomes was used meaning their results are not directly comparable. The outcomes studied for each investigation are summarised in Table 1. All included studies focused on examining the physiology of stenosis and immediate benefits following the intervention. Only 1/8 studies ¹¹ looked at long term outcomes, using the FFR data to help predict re-stenosis after 12 months. The other 8/9 focused on intra and early post-procedural use of FFR. Interestingly, all the papers identified a benefit to utilising FFR in the management of peripheral vascular disease.

The majority of the papers (6/9) utilised the same hyperaemic agent, papaverine, when measuring FFR. Two papers used adenosine and one paper isosorbide dinitrate. There was also variation in the manner FFR was utilised. Some papers (5/9) focused on the change in values following intervention, others compared FFR to another measure of stenosis severity to determine how effective it is as an assessment (3/9), and 1/9 looked at the optimal technique to measure FFR in the peripheral system.

As a result of the lack of standardisation within the studies and their outcomes, it was necessary to assess the quality of reporting and validity of the studies before commenting on their results. The NOS checklist was used to assess the quality of reporting and validity of the studies and the results are shown in Table 2. The majority of papers (6/9) were judged fair with the remaining (5/9) good. All 9 studies, however, fared poorly in the comparability category, and most (8/9) did not follow up their cohorts with no longitudinal justification of their findings. ²⁰

Table 2.

Table for NOS Score

Study name	Selection score	Comparability score	Outcome score	NOS total score
Kobayashi N et al- ability of fractional flow reserve to predict restenosis after superficial				6
Femoral artery stenting
Ikeoka K et al- pathophysiological significance of velocity-based				5
Microvascular resistance at maximal hyperemia in peripheral artery disease
Hioki H et al- diagnostic value of peripheral fractional flow reserve in isolated iliac artery stenosis: a Comparison with the post-exercise ankle-brachial index				4
Lotfi AS et al- use of fraction flow reserve to predict changes over time in management of superficial femoral artery				5
Ruzsa Z et al- fractional flow reserve in below the knee arteries with critical limb ischemia and validation against gold-standard morphologic, functional measures and long term clinical outcomes				7
Kobayashi N et al-measuring procedure and maximal hyperemia in the assessment of fractional flow reserve for superficial femoral artery disease				4
Murata N et al- validation of pressure gradient and peripheral fractional flow reserve measured by a pressure wire for diagnosis of iliofemoral artery disease wit intermediate stenosis				5
Albayati MA et al- intra-arterial fractional flow reserve measurements provide an objective assessment of the functional significance of peripheral arterial stenoses				7
Iwasaki Y,et al impact of post-procedural peripheral fractional flow reserve after drug-coated balloon angioplasty in femoropopliteal lesions				7

Discussion

The use of pressure-derived indices is well researched in the setting of coronary artery disease, with research demonstrating that FFR guided revascularisation has a 43% reduction in 1 year mortality in cardiac patients, against intervention without FFR. ²¹ This degree of uptake has not yet occurred in peripheral vascular disease despite the substantial improvements in outcomes seen in interventional cardiology.

This systematic search of the literature found 9 studies investigating the use of FFR in this setting. There were no randomised controlled trials or large prospective single or multicentre series. The 8 studies used different methodologies which precluded direct comparison of their results. However, the available work has demonstrated the potential benefits of FFR in the management of peripheral vascular disease through a range of outcomes. These studies have also suggested FFR values in their cohorts that can be used as a cut-off to assess treatment success and the probability of re-stenosis.

There was only one longitudinal study with a 12 month follow up of 48 patients and a total of 51 lesions. ¹¹ This study indicated that following intervention, the patients that had re-stenosis generally had lower FFR values. The authors proposed that an FFR value of <0.92 post-stenting as an indicator of predicting re-stenosis. This highlights that FFR measurements could probably assess the need for intervention and provide an indication of how effective the treatment has been and risk stratify patients for the likelihood of re-stenosis.

All the studies had no complications from performing FFR measurements, suggesting that this was a safe addition to any already ongoing EVT and that giving a vasodilator, in FFR, does not have any morbidity or mortality. Furthermore, 7 of the 9 studies provided evidence that FFR was capable of identifying lesions and that it improved following treatment as seen in Table 1. Interestingly, 3 of the studies included a small number of patients with multiple lesions and their treatment did not appear to be standardised within each paper and the relevance was not considered.

Four studies suggested FFR cut-off values to predict re-stenosis in the cohorts they examined giving values of 0.92, ¹¹ , 0.95 ¹² and 0.85. ¹³ It must be noted that the first 2 studies^11,12 had cohorts of patients with SFA lesions whereas the latter study looked at iliofemoral stenosis. ¹³ This may be one of the confounding factors causing the discrepancy. The patient demographic, cohort size, lesion location, number of lesions, co-morbidities may just be a few factors which could influence FFR value cut-offs for predicting re-stenosis and treatment outcomes. Further research is essential to understand how peripheral vessel pressure gradients respond to these factors and to create standardised figures to assess patients post-treatment. Given the heterogeneity in methodology, equipment used, and endpoints among the included studies, this narrative review refrains from recommending a specific FFR threshold value. However, there is a clear trend across nearly all work in this field, indicating that FFR is likely to play a role in maximising both technical and probably clinical outcomes of PVD interventions.

A recent study of 41 patients with isolated iliac or superficial femoral arteries ¹⁴ concluded that FFR can be an objective measure to assess the functional significance of peripheral artery stenosis and proposed that it could be used to influence management decisions for patients at a more personalised level. It was also the only study to isolate patients whose symptoms persisted post treatment and proposed an FFR cut-off of >0.74 for successful revascularisation. The study had only 10 cases whose symptoms persisted, and so further data is needed to confirm this finding. The discrepancy between this suggested cut-off and previous estimates suggests that the relevant FFR level to determine whether revascularisation is appropriate and whether revascularisation has been successful may be different. The latest published single centre series of 45 patients examined the role of peripheral FFR post drug coated angioplasty ²¹ . The researchers also concluded that an FFR threshold of <0.92 could be a good predictor of restenosis at one year.

The oldest study by Lotfi et al, ¹² compared FFR to conventional vascular imaging investigations, duplex ultrasound imaging, in 20 patient with SFA lesions. The study showed that FFR results could be used to predict the changes seen on duplex ultrasound. The doppler-derived peak systolic velocity, which is a known to predict the likelihood of restenosis, directly correlated with FFR. However, this authors suggested that further investigations were required to confidently draw any conclusions given the small sample size and non-randomised design.

The findings from the NOS checklist assessment reaffirmed the poor comparability of the studies and the inconsistencies of the factors examined, highlighting the lack of standard scientific expectation when assessing FFR in peripheral vascular disease. Therefore, future research should adopt a strict framework and design. It should take into account the complexities of PAD and some fundamental differences from coronary disease.

All papers included in this systematic review acknowledged the lack of statistical power. Across all 9 papers the total patient number was 292. This is a relatively small number and given all the limitations that have been discussed, and the variability of the chosen cut-off value for FFR within each study, it is clear that large, well designed studies are required to determine how FFR can be used in practice.

To address the gaps in knowledge, the following frameworks are suggested to guide future research in the field.

1. FFR predictive values should be compared against gold standard methods of diagnosing ischaemia and ideally combined with tissue perfusion assessment. Investigators should include, besides anatomical criteria, the assessment of FFR before and after intervention.

2. Prognostic importance of FFR in terms of limb salvage, tissue perfusion and stenosis recurrence rate should be evaluated in properly powered cohorts with longitudinal follow up of at least 24 to 48 months. These outcomes can be determined in patients without revascularisation or post revascularisation.

3. FFR measurements should account for the number, anatomical locations of lesions, the proximity of tandem lesions and should ideally address the role of inflow stenoses.

4. The practicality and cost effectiveness of implementing physiological studies should be compared to a control group using current practice.

Upon review of the manuscripts, the observed lack of standardisation is presumably attributable to the absence of comprehensive data regarding the utilisation of hyperaemic agents, pressure measurement techniques, and general procedural methods. Each centre has implemented its respective local protocols and preferences. The adoption of the aforementioned framework, in conjunction with multi-centre collaboration and a standardised study protocol, will be essential for conducting more rigorous future research.

The key finding in this review is that there is evidence that pressure indices have the potential to refine diagnostic, intra-procedural and prognostic decisions in peripheral vascular disease. They can give an indication of the haemodynamic burden of a stenosis, demonstrate an objective change pre and post intervention and may also allow interventional radiologists to estimate the likelihood of restenosis. At the very least this will provide invaluable information for when and how aggressively treatment should be offered. This is akin to the data that already exists with respect to coronary artery disease. ² Similar to most radical changes in routine practice, the barriers to implementing radical changes in intervention practice are expected to be challenging. These hurdles should be addressed through collaboration with industry to smooth out workflow in angiosuite as well as designing pragmatic trials that allow timely recruitment and investigator engagement. The interventional community must be persuaded to use the physiology tools by creating the appropriate evidence and ensuring that no significant cost burden is incurred.

Conclusion

The FFR can potentially identify lesions which need intervention and those that do not, determine how effective an intervention has been and help risk stratify how the follow-up and monitoring plan should be structured. However, current data are limited, and considerably more research is needed before FFR can be used for peripheral vascular disease in routine clinical practice. Further work should consider the FFR and its correlation with other measures of ischaemia and with clinical outcomes and the impact of incorporating FFR into clinical decision making and should perform these studies in appropriately powered clinical studies.