Instantaneous Wave-Free Ratio Measurement During Intracranial Submaximal Angioplasty: Case Series and 2-Dimensional Operative Video

Abstract

BACKGROUND

Instantaneous wave-free ratios (iFRs) are functional measures of arterial stenosis that have become essential to interventional cardiology procedures. Their use for intracranial submaximal angioplasty (angioplasty with an undersized balloon) has not been studied extensively.

OBJECTIVE

To describe the feasibility and technique of iFR measurement for stenosis assessment during intracranial angioplasty.

METHODS

We present a series of consecutive patients treated between January 1, 2017 and June 30, 2018 with submaximal intracranial angioplasty in whom pre- and postprocedure iFR measurements were obtained with a Verrata-Volcano pressure wire (Philips, Amsterdam, The Netherlands). We collected patient data on age, sex, comorbid conditions, presenting complaints, modified Rankin scale (mRS) score at admission, neurological findings, procedure duration, fluoroscopy time, intraprocedural complications, length of hospital stay, and mRS score at last clinical follow-up (favorable outcome, 0-2). Angiographic stenosis severity and iFR values were recorded before and after angioplasty.

RESULTS

A total of 12 patients underwent iFR-guided angioplasty during the study period. The median patient age was 69.5 yr (range 48-81 yr). All patients had symptomatic intracranial arterial stenosis (3-basilar, 2-vertebral, 6-middle cerebral, 1-internal carotid). Preangioplasty stenosis ranged from 55% to 90%. The median postangioplasty reduction in stenosis was 17% (range 9%-30%). Preangioplasty values ranged from 0.30 to 0.40 (n = 4). Postangioplasty values ranged from 0.6 to 0.9 (n = 5). iFR values improved considerably in all patients. No procedure-related complications occurred. The median follow-up was 8.9 mo (range 3-25 mo). Follow-up outcomes were favorable in 10 patients.

CONCLUSION

iFR measurement before and after intracranial angioplasty is feasible. It may be used to assess the adequacy of intracranial angioplasty.

ABBREVIATIONS

BA

basilar artery

F

French

FAME

Fractional Flow Reserve versus Angiography for Multivessel Evaluation

FDA

(US) Food and Drug Administration

FFR

fractional flow reserve

ICA

internal carotid artery

ICAD

intracranial atherosclerotic disease

iFR

instantaneous wave-free ratio

iPa

instantaneous aortic pressure

iPd

instantaneous distal pressure

MCA

middle cerebral artery

mRS

modified Rankin scale

SAMMPRIS

Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis

SPSS

Statistical Package for the Social Sciences

TIA

transient ischemic attack

VA

vertebral artery

VISSIT

Vitesse Intracranial Stent Study for Ischemic Therapy

WASID

Warfarin-Aspirin Symptomatic Intracranial Disease

Intracranial atherosclerotic disease (ICAD) is the leading cause of intracranial arterial stenosis, which results in transient ischemic attacks (TIAs) and strokes.¹ The investigators of the Vitesse Intracranial Stent Study for Ischemic Therapy (VISSIT) and the Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) trial reported an annual recurrent stroke risk as high as 12% for critically stenotic (>70%-99%) lesions.^2,3 Treatment of stenotic lesions has been conventionally guided by the calculated percentage of stenosis seen on an angiogram.⁴ However, the angiographic images may not disclose the exact degree of stenosis, especially when the stenosis is eccentric.

Current paradigms for the treatment of stenotic lesions include dual antiplatelet therapy and submaximal angioplasty (angioplasty performed with a balloon measured to 50%-70% of the healthy parent vessel diameter).^4,5 Patients with <70% stenosis had a lower risk of recurrent stroke in the Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) trial,⁴ but it is important to note that patients with 50% to 69% stenosis had a 40% risk of recurrent stroke.

Studies have shown that the percentage of the stenosis is not the only factor that needs to be considered when treating ICAD.^3,6,7 Collateral anatomy, plaque characteristics, and hemodynamic physiology also play an important role in medical and interventional decision making.^6,7 Fractional flow reserve (FFR) is defined as the maximal inducible increase in blood flow through a stenosed area relative to a nonstenotic area.⁸ The measurement of FFR pre- and postangioplasty has become a gold standard for percutaneous coronary intervention.⁹ FFR values are considered alongside angiographic findings to support the process of decision making on the extent of angioplasty.¹⁰ The measurement of FFR across a stenotic lesion requires the induction of hyperemia by administering adenosine, which can increase intracranial pressure or cause hemorrhage in chronically underperfused brain tissue. Instantaneous wave-free ratio (iFR) is an alternative to measuring flow reserve that does not require the induction of hyperemia. In 2013, the US Food and Drug Administration (FDA) approved the Verrata-Volcano pressure wire (Phillips, Amsterdam, The Netherlands) to measure iFR. According to a multicenter randomized controlled trial, iFR was found to be noninferior to FFR in determining the flow limitation caused by stenosis with comparable major cardiac adverse effects observed over 12 mo of follow-up.^11,12

To our knowledge, this is the first study of the use of iFR during the treatment of intracranial stenosis. We describe the feasibility and technique of iFR measurement and the associated early and mid-term clinical and angiographic outcomes.

METHODS

Patients and Data Collection

After receiving institutional review board approval, we retrospectively collected data for a consecutive case series of patients who underwent submaximal angioplasty for intracranial arterial stenosis with iFR measurement at our academic center between January 1, 2017 and June 30, 2018. The need for the use of iFR was determined by the senior author-neurointerventionist. Patients with pre- and postangioplasty iFR data, irrespective of age, sex, and location of ICAD, were included in this study. We recorded the following patient data: age, sex, comorbid conditions, presenting complaints, modified Rankin scale (mRS) score on admission, neurological findings, procedure duration, fluoroscopy time, intraprocedural complications, length of hospital stay, and mRS score at last clinical follow-up (favorable functional outcome, 0-2). Patient information was coded and anonymized.

Data Analysis

Data were analyzed using the Statistical Package for the Social Sciences (SPSS), version 24 (IBM, Armonk New York). Numerical data were presented as medians and ranges. Categorical data were presented as percentage and proportions. Pre- and postintervention iFR values were compared using a paired sample t test.

Technique for iFR During Angioplasty

All patients had procedures performed under conscious sedation as is standard practice at our institute. A 6-French (F) sheath was placed in the common femoral artery, and a guide catheter was advanced to a position in the internal carotid artery (ICA) necessary to support a microcatheter system.

A pressure transducer was attached to the 6F guide catheter and calibrated to the patient's systolic and diastolic blood pressures in the aorta. After ensuring that the guide catheter was not against the vessel wall, the pressure at the guide catheter's tip (the instantaneous aortic pressure [iPa]) was measured with the transducer. The guide catheter was then maintained at the same position in the ICA, while a 0.014 inch Verrata pressure wire (Philips, Amsterdam, The Netherlands) was advanced to its tip.

Contrast material was injected to generate a roadmap to allow the interventionist to safely cross the stenotic lesion with the pressure wire, and the sensor on the wire was kept nearly 2 to 3 cm past the lesion. The instantaneous distal pressure (iPd) was measured with the pressure wire sensor. The pressure wire was guided with an Excelsior SL-10 microcatheter (Stryker, Kalamazoo, Michigan). The iFR was calculated as the ratio of Pd to Pa (ie, Pd/Pa), and the translesional pressure gradient of Pa to Pd (ie, Pa/Pd) was measured. The measurements were repeated after the angioplasty. The guide catheter was kept in the same position during each blood pressure recording and iFR calculation, and care was taken to ensure that there was no wedging of the guide catheter against the vessel wall. For posterior circulation lesions, the guide catheter was kept at the V2-3 junction before the turn at the C1 vertebra. The rest of the procedure was the same. For lesions near bifurcations, such as the ICA terminus, the interventionist selected the less tortuous and larger caliber vessel for placement of the pressure wire to yield the most conservative pressure readings. To eliminate false readings with high velocities in the poststenotic segment, the sensor was advanced 2 to 3 cm past the lesion. The pressure wire was used to guide the angioplasty procedure by repeat inflation of the angioplasty balloon until an iFR result between 0.8 and 1 was achieved.

The technique for submaximal angioplasty using iFR is demonstrated in the video, Supplemental Digital Content. The patient provided informed consent for the procedure and video recording. Institutional board review was deemed unnecessary.

All angioplasty procedures were performed with small, noncompliant, over-the-wire, balloons, such as a Gateway (Boston Scientific, Marlborough, Massachusetts) or Sprinter (Medtronic, Dublin, Ireland). Measurements of balloon size were taken to allow for submaximal angioplasty where the maximal diameter of the inflated balloon was no more than 80% of the parent vessel diameter. Balloons were inflated 1 atm every 30 s and deflated at 1 atm every 15 s. The balloon was kept inflated at maximal diameter for 1 min before deflation was started. The balloon was repeatedly inflated until the desired iFR results had been achieved. After angioplasty was complete and the balloon was deflated, the pressure wire was advanced distal to the lesion again to measure the post-treatment iFR and translesional pressure gradient.

RESULTS

A total of 12 patients underwent iFR-guided angioplasty during the study period. The median age of the patients was 69.5 yr (range 48-81 yr). Six of these patients were men. Eight patients had a history of stroke and 4 had a history of TIAs. Three patients had basilar artery (BA) angioplasties for BA stenosis and 2 had vertebral artery (VA) angioplasties for VA stenosis. Six patients underwent angioplasty of M1 segment middle cerebral artery (MCA) stenosis and 1 patient had an ICA angioplasty for supraclinoid segment stenosis. Demographics and baseline clinical characteristics of each patient are presented in Table 1. The angiographic stenosis severity ranged from 55% to 90%. The median improvement in stenosis severity was 17% (range 9%-30%) immediately after submaximal angioplasty. The percentage of increase in the diameter of the vessels postintervention ranged from 9% to 30%. Considerable improvement in iFR values was seen in all patients. Preangioplasty values ranged from 0.30 to 0.40 (n = 4). Postangioplasty values ranged from 0.6 to 0.9 (n = 5).

TABLE 1.

Demographics and Baseline Clinical Characteristics

Case no.	Sex, age (yr)	Comorbid conditions	Previous stroke or TIA	Presenting symptoms	mRS on Adm	Stenosed blood vessel	Stenosis severity (%)
1	M, 69	HTN	No	Dysarthria facial droop, RUE weakness	4	BA	70
2	F, 69	DM, IHD	Yes	Diplopia, headache (previous stroke)	0	L MCA	55
3	F, 56	HTN, DM, CKD	No	Dizziness, diplopia, gait instability	4	L VA	85
4	M, 60	HTN, DM	Yes	R-sided weakness	3	L VA	84
5	F, 81	HTN	No	Weakness, pain near R eye, nausea, vomiting, facial numbness, facial droop	4	BA	80
6	M, 48	HTN	No	Aphasia	1	L MCA	75
7	M, 70	HTN, IHD	Yes	R-sided weakness, drift, facial droop, dysarthria (previous stroke)	0	L MCA	80
8	M, 73	HTN, DM	Yes	LUE weakness, dizziness	2	R MCA	84
9	F, 80	HTN	Yes	L hand weakness, L LE weakness	4	R MCA	76
10	F, 83	HTN, DM, IHD	Yes	Pressure-like discomfort in retrosternal area (previous stroke)	2	L MCA	84
11	F, 78	HTN, DM, IHD, CKD	Yes	Facial droop	5	L ICA	76
12	M, 64	HTN, IHD	Yes	Facial droop, dysarthria, focal weakness	2	BA	90

Adm, admission; BA, basilar artery; CKD, chronic kidney disease; DM, diabetes mellitus; F, female; HTN, hypertension; ICA, internal carotid artery; IHD, ischemic heart disease; L, left; LUE, left-upper extremity; LE, lower extremity; M, male; MCA, middle cerebral artery; M1, first segment of MCA; mRS, modified Rankin scale; no., number; R, right; RUE, right-upper extremity; TIA, transient ischemic attack; VA, vertebral artery.

No procedure-related complications were reported. The median procedure time was 68 (44-189 min). The median fluoroscopy time was 32.3 (29-97 min). There were no in-hospital deaths. The median length of hospital stay was 3 d (interquartile range 2-8 d). The median follow-up was 8.9 mo (range 3-25 mo). Outcomes were favorable in 10 patients. Two patients developed stroke in a territory not related to the treated artery and had mRS scores of 3 (case 10) and 5 (case 11; same score as preprocedure). No patient developed recurrent stroke. Three patients had worsening of stenosis on follow-up angiography (cases 1, 4, 12). However, none of these patients were symptomatic. Therefore, no patient required retreatment. Procedure- and outcome-related details are provided in Table 2. Figures 1A-1F and 2A-2D demonstrate 2 cases where iFR was used to treat stenoses of the MCA (case 6) and BA (case 12).

TABLE 2.

Procedure-Related and Follow-up Details

Case no.	Duration of procedure (min)	Immediate reduction in stenosis (%)	Improvement in iFR	Last follow-up (months postangioplasty)	mRS score on adm	mRS score at last follow-up
1	189	12	Yes	3	4	1
2	69	9	Yes	14	0	0
3	73	9	Yes	15	4	1
4	44	25	Yes	3	3	2
5	57	28	Yes	18	4	2
6	55	14	Yes	8	1	1
7	53	15	Yes	3	0	1
8	71	22	Yes	3	2	0
9	105	30	Yes	25	4	0
10	65	20	Yes	3	2	3
11	93	11	Yes	13	5	5
12	67	20	Yes	9	2	2

adm, admission; iFR, instantaneous wave-free ratio; mRS, modified Rankin scale; no., number.

FIGURE 1.

Case 6. A, Pretreatment anteroposterior (AP) projection showing severe left M1 stenosis (arrow). B, Position of the pressure wire in the distal MCA before angioplasty (arrow). C, Preoperative recording of iFR. D, Post-treatment AP projection showing significant improvement in the degree of stenosis. E, Post-treatment iFR recording of the procedure. Pretreatment iFR of 0.31 changed to 0.52. This indicates a considerable increase in blood flow through the area of stenosis after angioplasty, despite a lack of dramatic improvement in the anatomical degree of stenosis. Based on this considerable improvement in iFR, the procedure was stopped. F, Final run of the showing post angioplasty reduction of stenosis (arrow). HR indicates heart rate; FFR, fractional flow reserve; iPa, instantaneous aortic pressure; iPd, instantaneous distal pressure; Pa, proximal (aortic) pressure; and Pd, distal (intracoronary) pressure.

FIGURE 2.

Case 12. A, Pretreatment anteroposterior (AP) projection, vertebral artery injection, showing severe (90%) stenosis of the basilar artery near its origin (arrow). B, Position of the pressure wire in the left posterior cerebral artery for preangioplasty measurement of iFR (arrow). C, Position of the pressure wire for the iFR measurement after angioplasty (arrow). D, Post-treatment AP projection, vertebral artery injection, showing improvement in the severity of the angiographic stenosis (arrow) by 20%. The iFR changed from 0.30 to 0.60. Given the considerable increase in the iFR, the procedure was stopped.

DISCUSSION

The advantage of functional measures of stenosis severity such as FFR and iFR has been clearly established in the cardiac literature, in which these measures have led to decreased rates of postangioplasty restenosis and myocardial infarction.^9,13 The use of iFR during intracranial angioplasties in the cases in our series was feasible, safe, and without procedure-related complications. Although the 0.014 inch Verrata-Volcano pressure wire that we used was primarily designed for cardiac procedures, the ability to navigate catheters to distal locations, along with microcatheter support, allows for the use of this wire over short vessel segments. iPd and iPa can be measured with the wire for accurate comparison and assessment of translesional pressure gradients.

A study by Miao et al¹⁴ also reported on the feasibility of fractional flow assessment to guide intracranial angioplasty using similar pressure wire devices. Navigating a 0.014-inch wire across stenotic lesions—even in perforator-rich regions—did not increase the procedural risk or result in adverse outcomes related to measurement and planning in our study or the study conducted by Miao et al.¹⁴ On the basis of the postangioplasty angiographic results, both studies demonstrated a correlation of improvement in fractional flow with a decrease in luminal stenosis. Recognition of this correlation is important in order to understand how iFR can impact decision making.

Once a significant improvement in iFR (physiological flow) was achieved, we did not pursue the anatomic degree of stenosis. None of the patients included in the study had recurrent stroke in the territory of the treated artery over the length of the follow-up. This shows how iFR measurement can help in guiding the angioplasty procedure.

Alexander et al¹⁵ demonstrated that lesion characteristics had a significant relationship with outcomes after stenting for symptomatic ICAD. Understanding the relationships between perfusion analysis, functional measures of stenosis, and the stability of lesions may play a significant role in deciding whether to intervene in such circumstances. In their univariate analysis, Alexander et al¹⁵ suggested that patients with hypoperfusion had a limited risk of stroke, especially those with 60% to 99% stenosis.

Collaterals have an important role in maintaining cerebral perfusion. Liebeskind et al⁷ demonstrated that in intracranial vessels with 70% to 99% stenosis, extensive collaterals diminished the risk of subsequent territorial stroke, whereas with 50% to 69% stenosis, collaterals were associated with a higher likelihood of subsequent stroke. With more data, a correlation may be found between the functional degree of stenosis measured with iFR and angiographic measurements of stenosis, as was done with the help of the Fractional Flow Reserve versus Angiography for Multivessel Evaluation (FAME) study in the cardiac literature.¹³

Along with these factors, consideration must be given to changes occurring in the application of angioplasty for ICAD. After VISSIT and SAMMPRIS, stenting for lesions has not become commonplace because of the high-risk profile. With newer stent technology and a better understanding of the benefits of submaximal angioplasty, the risk-benefit analysis for patients and providers has shifted.¹⁶

Limitations

The sample size was small and the study design was a case series, yet the findings strongly support the feasibility and safety of iFR. To establish thresholds for iFR values that correlate with good clinical outcomes, more data are required.

From a technical aspect, the 0.014in Verrata-Volcano pressure wire is primarily designed for cardiac procedures. Although the wire is stiffer and less navigable than most cranial microwires, it is navigable in large vessels but requires some experience when navigating perforator-rich regions.

CONCLUSION

Reports in the literature have indicated the efficacy of iFR in determining when to intervene in cardiac atherosclerotic disease. Although the cerebral vasculature responds differently because of the ability for autoregulation, understanding when intracranial angioplasty may be beneficial to limit the risks for certain populations is important. This study, although comprised of a small cohort, shows the feasibility and technique iFR and the ease with which it can be done, even under conscious sedation. Understanding the potential and interaction between angiographic stenosis and iFR may help guide endovascular vs medical management.

Disclosures

Dr Davis has a research grant from the National Center for Advancing Translational Sciences of the National Institutes of Health under award number KL2TR001413 to the University at Buffalo; he is a consultant for Medtronic; receives honoraria from Neurotrauma Science, LLC; is a shareholder/has ownership interests in Cerebrotech, RIST Neurovascular. Dr Levy is a shareholder/has ownership interests in NeXtGen Biologics, RAPID Medical, Claret Medical, Cognition Medical, Imperative Care (formerly the Stroke Project), Rebound Therapeutics, StimMed, Three Rivers Medical; is the National Principal Investigator/on the Steering Committees for Medtronic (merged with Covidien Neurovascular) SWIFT Prime and SWIFT Direct Trials; receives honoraria from Medtronic (training and lectures); is a consultant for Claret Medical, GLG Consulting, Guidepoint Global, Imperative Care, Medtronic, Rebound, StimMed; serves on the advisory board for Stryker (AIS Clinical Advisory Board), NeXtGen Biologics, MEDX, Cognition Medical, Endostream Medical; is Site Principal Investigator for the CONFIDENCE study (MicroVention), and STRATIS Study—Sub I (Medtronic). Dr Siddiqui has financial interest/is investor/has stock options/ownership in Amnis Therapeutics, Apama Medical, Blink TBI Inc., Buffalo Technology Partners Inc., Cardinal Consultants, Cerebrotech Medical Systems, Inc. Cognition Medical, Endostream Medical Ltd, Imperative Care, International Medical Distribution Partners, Neurovascular Diagnostics Inc., Q’Apel Medical Inc, Rebound Therapeutics Corp., Rist Neurovascular Inc., Serenity Medical Inc., Silk Road Medical, StimMed, Synchron, Three Rivers Medical Inc., Viseon Spine Inc; is a consultant/on the advisory board for Amnis Therapeutics, Boston Scientific, Canon Medical Systems USA Inc., Cerebrotech Medical Systems Inc., Cerenovus, Corindus Inc., Endostream Medical Ltd, Guidepoint Global Consulting, Imperative Care, Integra LifeSciences Corp., Medtronic, MicroVention, Northwest University–DSMB Chair for HEAT Trial, Penumbra, Q’Apel Medical Inc., Rapid Medical, Rebound Therapeutics Corp., Serenity Medical Inc., Silk Road Medical, StimMed, Stryker, Three Rivers Medical, Inc., VasSol, W.L. Gore & Associates; is Principal investigator/on the steering committee of the following trials: Cerenovus NAPA and ARISE II, Medtronic SWIFT PRIME and SWIFT DIRECT, MicroVention FRED & CONFIDENCE, MUSC POSITIVE, and Penumbra 3D Separator, COMPASS, and INVEST. The other authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article.

Notes

Portions of this work were presented in poster format the American Association of Neurological Surgeons Annual Meeting, San Diego, California, April 13-17, 2019.

Supplemental Digital Content. Video. Two-dimensional video demonstrates the technique of submaximal angioplasty in an 83-year-old man with symptomatic left middle cerebral artery stenosis. © University at Buffalo Neurosurgery, 2019. With permission.