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Imaging and Case Report

J-Valve Transcatheter Treatment of Native Valve Aortic Regurgitation

Associated With a Left Ventricular Assist Device

Santiago Garcia, MD, Robert Dowling, MD, Eugene Chung, MD, Gregory F. Egnaczyk, MD,

TerriL.Stewart-Dehner,MD,GeoffreyA.Answini,MD,DebraPaige,RN,DeanJ.Kereiakes,MD

The Christ Hospital Heart and Vascular Institute and the Lindner Research Center, Cincinnati, Ohio

The use of left ventricular assist devices (LVAD) has expanded

rapidly for both destination therapy and as a bridge to transplant.

Aortic regurgitation (AR) can affect 15% to 52% of these patients after 1

year of LVAD support

2,3

and is often progressive.

The proposed mechanisms underlying LVAD-related AR include

leaﬂet deterioration, commissural fusion, aortic sinus dilatation, and

increased transvalvular gradients, all of which alter normal hemody-

namics and result in both risk of hospitalization and decreased survival.

Although treatment of LVAD-related AR with transcatheter heart valves

(THV) designed for aortic stenosis has been reported in small series, the

results have been poor owing to the lack of effective THV anchoring,

increased risk of ventricular embolization, and occurrence of residual

AR.

4,5

The J-Valve (J.C. Medical) is an investigational THV particularly

designed for the treatment of AR and consists of the following: (1) a

self-expanding, low proﬁle nitinol frame with bovine pericardial leaﬂets;

(2) a valve locating feature consisting of 3 nitinol anchor rings designed

to conform to the native aortic valve sinuses; and (3) sinus cutouts to

facilitate coronary access and physiologic sinus washout (Figure 1 ).

We report the ﬁrst-in-human compassionate use of J-Valve for the

treatment of severe, symptomatic AR in a 43-year-old man after

continuous-ﬂow LVAD (HeartMate III; Abbott Vascular) implantation

(Figure 1).

Methods and procedure

After recurrent New York Heart Association Functional Classiﬁcation

Class IV heart failure hospital admissions in the months preceding the

procedure, consideration by a multidisciplinary heart team, and exclusion

from the ALIGN-AR trial of the investigational JenaValve THV for treat-

ment of severe AR, the patient was offered compassionate use treatment

with J-Valve. The native valve comprised 3 leaﬂets and was noncalciﬁed

(Figure 1). The patient was approved for compassionate use treatmentby

The Christ HospitalInstitutional ReviewBoard andCenter for Devices and

Radiological Health before signing informed consent for the procedure.

The procedure was performed in a hybrid catheterization laboratory

under general anesthesia with transesophageal echocardiographic

guidance. A 20F DrySeal sheath catheter (Gore Medical) was inserted

through the right common femoral artery and a 31.0-mm J-Valve was

inserted over a Safari guide wire (Boston Scientiﬁc) placed at the left

ventricular apex. During deployment, the anchor rings were exposed in

the ascending aorta, and the J-Valve was advanced to the aortic valve

annuluswith the anchorrings placed at the base of each sinus of Valsalva.

Proper position was guided by transesophageal echocardiography and

contrast injection in each cusp. Once the anchor rings were in position,

the LVAD speed was reduced to 5200 rpm brieﬂy, while the J-Valve was

released without rapid pacing. After valve deployment, the LVAD speed

was immediately increased to 6800 rpm, and postprocedural angiog-

raphy revealed trace residualAR (Supplemental Video 1). The patienthad

rapid, symptomatic improvement and was discharged from hospital to

home next day.

Discussion

Catheter-based treatment of severe AR related to LVAD support in

patients with noncalciﬁed, native aortic valves is challenging and

fraught with the potential complications of THV migration, emboliza-

tion, the requirement for an immediate additional THV or surgical

conversion, and signiﬁcant residual perivalve regurgitation. The J-Valve

anchor rings co-apted the base of the noncalciﬁed native valve leaﬂets

within the sinus of Valsalva to effectively anchor and seal the THV as

observed in the presented case. THV devices that do not rely on cal-

cium for anchoring may provide an attractive alternative to redo surgery

for patients with severe AR related to LVAD.

Peer review statement

Deputy Editor Dean J. Kereiakes had no involvement in the peer

review of this article and has no access to information regarding its peer

Keywords: aortic regurgitation; left ventricular assist device; transcatheter aortic valve replacement.

* Corresponding author: djkereiakes@gmail.com (D.J. Kereiakes).

https://doi.org/10.1016/j.jscai.2023.101044

Received 8 May 2023; Accepted 11 May 2023

Available online 9 June 2023

the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Journal of the Society for Cardiovascular Angiography & Interventions 2 (2023) 101044

review. Full responsibility for the editorial process for this article was

delegated to Section Editor David G. Rizik.

Declaration of competing interest

The author(s) declared no potential conﬂicts of interest with respect

to the research, authorship, and/or publication of this article.

Funding sources

This research did not receive any speciﬁc grant from funding

agencies in the public, commercial, or not-for-proﬁt sectors.

Ethics statement

This compassionate use research adhered to all relevant ethical

guidelines.

Supplementary material

To access the supplementary material accompanying this article,

visit the online version of the Journal of the Society for Cardiovascular

Angiography & Interventions at 10.1016/j.jscai.2023.101044.

References

1. Kirklin JK, Naftel DC, Pagani FD, et al. Seventh INTERMACS annual report: 15,000

patients and counting. J Heart Lung Transplant. 2015;34(12):1495–1504.

2. Jorde UP, Uriel N, Nahumi N, et al. Prevalence, signiﬁcance, and management of

aortic insufﬁciency in continuous ﬂow left ventricular assist device recipients. Circ

Heart Fail. 2014;7(2):310–319.

3. Truby LK, Garan AR, Givens RC, et al. Aortic Insufﬁciency During Contemporary Left

Ventricular Assist Device Support: Analysis of the INTERMACS Registry. J Am Coll

Cardiol HF. 2018;6(11):951–960.

4. Yoon SH, Schmidt T, Bleiziffer S, et al. Transcatheter aortic valve replacement in pure

native aortic valve regurgitation. J Am Coll Cardiol. 2017;70(22):2752–2763.

5. Cowger J, Rao V, Massey T, et al. Comprehensive review and suggested strategies for

the detection and management of aortic insufﬁciency in patients with a continuous-

ﬂow left ventricular assist device. J Heart Lung Transplant. 2015;34(2):149–157.

Figure 1.

Transfemoral J-Valve system.(A) Diagram of the J-Valve system. Computed tomography of the aortic valve complex showing annular dimensions (B), sinuses of Valsalva (C), and

iliofemoral angiography (D). (E) Still echocardiographic frame showing severe aortic regurgitation.

2 S. Garcia et al. / Journal of the Society for Cardiovascular Angiography & Interventions 2 (2023) 101044

Данная книга находится в списке для перевода на русский язык сайта https://meduniver.com/

Editorial

Late Mortality and Paclitaxel-Coated Devices: Has the Controversy Finally

Come to an End?

Aishwarya Raja, MD

, Eric A. Secemsky, MD, MSc

Department of Medicine, Columbia University Medical Center, New York, New York;

Richard A. and Susan F. Smith Center for Outcomes Research in

Cardiology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts;

Division of Cardiology, Department of Medicine, Beth

Israel Deaconess Medical Center, Boston, Massachusetts

Advances in technology have led to the emergence of endovascular

therapy as a primary treatment option for patients with peripheral artery

disease (PAD),with the goal of improving quality of life and limb-related

outcomes.

1,2

Numerous randomized controlled trials (RCTs) and

meta-analyses have demonstrated higher patency and lower target

lesion failure rates associated with drug-coated devices,

3–6

establishing

these devices, particularly drug-coated balloons (DCBs) containing the

antiproliferative agent paclitaxel, as the ﬁrst-line treatment for patients

with symptomatic femoropopliteal PAD.

7–9

Despite the promising evidence supporting the use of drug-coated

devices in the periphery, the summary-level meta-analysis of Katsanos

et al

in 2018 generated major ripples in the vascular community. The

study found that paclitaxel-coated devices were associated with a

higher rate of mortality relative to non–paclitaxel-coated devices at 2

years and through 5 years after treatment. The authors also reported a

positive association between increasing paclitaxel doses and absolute

risk of mortality. These ﬁndings had widespread impact across the

regulatory and scientiﬁc sectors. The Food and Drug Administration

(FDA) convened a Medical Device Advisory Panel in June 2019 to

investigate the possibility of a late mortality signal.

internal trial data of paclitaxel-coated devices and arriving at similar

conclusions, they issued warnings about the possibility of increased

mortality associated with these devices despite not establishing a

causal relationship and recommended restricting use to high-risk pa-

tients only.

It also led to the halting of major clinical trials, such as the

Swedish Drug-elution Trial in Peripheral Arterial Disease (SWEDEPAD)

and Balloon versus Stenting in severe Ischemia of the Leg-3 (BASIL-3),

as well as an overall decrease in the use of drug-coated devices.

From a methodological standpoint, the study of Katsanos et al

was

found to have many limitations. This included the presence of hetero-

geneous patient populations across the pooled RCTs; a substantial loss

to follow-up, withdrawal, and patient cross-over; as well as the lack of an

established mechanism to explain the late mortality signal associated

with paclitaxel. To address these limitations and further explore the

association between paclitaxel and mortality risk in other populations,

several studies have since been published, including updated

meta-analyses, subanalyses of RCTs, and large observational cohort and

registry studies (Figure 1). For example, the Vascular InterVentional

Advances (VIVA) physicians group performed a meta-analysis using

patient-level data from 8 RCTs of paclitaxel-coated devices approved in

the United States. After including expanded follow-up information and

reducing missing data, the study showed a signiﬁcant but attenuated

risk of mortality associated with paclitaxel-coated devices up to 4

years.

14,15

Additionally, the meta-analysis of Dinh et al,

which

included additional trials and a larger sample size, showed no increased

risk of mortality associated with paclitaxel-coated devices up to 60

months of follow-up. Unplanned interim and subgroup analyses of the

SWEDEPAD

and Vascular Outcomes Study of ASA Along With

Rivaroxaban in Endovascular or Surgical Limb Revascularization

(VOYAGER PAD)

RCTs, respectively, also failed to demonstrate mor-

tality signals.

To complement these prospective studies, multiple real-world

observational studies using the Vascular Quality Initiative registry,

19,20

health insurance claims,

23,24

and Medicare claims

have also failed to

detect survival differences among patients treated with paclitaxel-coated

and uncoated devices. For instance, the Safety Assessment of Femo-

ropopliteal Endovascular Treatment with Paclitaxel-coated Devices

(SAFE-PAD) study (ClinicalTrials.gov identiﬁer NCT04496544), an

ongoing prespeciﬁed longitudinal safety assessment of paclitaxel-coated

devices among Medicare patients with a median follow-up exceeding 5

years, has thus far noted no evidence of long-term harm associated with

these devices.

26,27

With this context in mind, in this issue of JSCAI, the study of Lyden

et al

extends the assessment of mortality risk associated with

drug-coated devices using pooled individual-level data from the Stel-

larex DCB trials program. The aim of the study was to evaluate the

5-year all-cause mortality rate among patients treated with the Stellarex

DOI of original article: https://doi.org/10.1016/j.jscai.2023.100634.

Keywords: drug-coated balloon; paclitaxel; peripheral artery disease.

* Corresponding author: esecemsk@bidmc.harvard.edu (E.A. Secemsky).

https://doi.org/10.1016/j.jscai.2023.100981

Received 6 April 2023; Accepted 10 April 2023

the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Journal of the Society for Cardiovascular Angiography & Interventions 2 (2023) 100981

DCB compared with uncoated percutaneous transluminal angioplasty

(PTA), which is an extension of a prior meta-analysis of the ProspectIve,

Randomized, SingLe-Blind, U.S. MuLti-Center Study to EvalUate

TreatMent of Obstructive SupErﬁcial Femoral Artery or Popliteal Le-

sioNs With A Novel PacliTaxel-CoatEd Percutaneous Angioplasty

Balloon (ILLUMENATE) RCTs that showed no difference in all-cause

mortality between treatments through 4 years of follow-up.

An in-

dependent third party performed the patient-level meta-analysis that

involved pooling all prospective RCTs. Included patients had Rutherford

2-4 symptomatic femoropopliteal disease, and the primary outcome

was all-cause mortality.

Overall, the meta-analysis showed no difference in survival between

the Stellarex DCB and the PTA arms at 5 years. Importantly, there was

no difference in mortality when stratiﬁed by terciles of cumulative

paclitaxel dose received, further debunking a dose-mortality relation-

ship presented in the original Katsanos meta-analysis. Finally, when

examining predictors of death, neither paclitaxel dose nor overall

exposure was shown to be signiﬁcantly associated with future mortality.

Particular strengths of the study include its large sample size and

homogenous patient cohort. Importantly, the vital status compliance

was 93.8% across the RCTs, which allowed for a more complete

assessment of the endpoint (for context, pivotal trials had between 10%

and 30% missing vital status data at the time of the initial meta-analysis).

Limitations of the study include the inability to quantify the number of

patients exposed to paclitaxel in the PTA group due to inconsistently

reported repeat revascularization data; potential inaccuracies in calcu-

lating the paclitaxel dose due to unmeasured variables like lesion

characteristics and blood ﬂow; and the lack of generalizability of the

study’s ﬁndings to other paclitaxel-coated devices.

So where do we stand now? Since the original Katsanos meta-

analysis was published in December 2019, we have more than a

dozen independent analyses that have failed to associate paclitaxel

exposure and long-term survival. As loss to follow-up has been incre-

mentally addressed, signals of harm have attenuated to the point of

nonsigniﬁcance, suggesting there was something different about pa-

tients who had survival data available versus not when the initial meta-

analyses were performed. Drug-coated devices in clinical use have in

parallel rebounded in the United States, moving closer to precon-

troversy rates. Nonetheless, US regulators have maintained the current

position that there remains a possibility of harm related to these de-

vices. This has impacted use for some clinicians and institutions across

the country, whereas the largest inﬂuence of this stance may in fact be

with regulatory bodies outside the United States, who often look to the

United States for guidance. With the ILLUMENATE trials program of 589

total patients with 5 years of data (the original meta-analysis only had

863 patients at 4-5 years) clearly demonstrating no survival difference, it

is difﬁcult to label this speciﬁc device as harmful.

The upcoming year will be critical. We will see updated data from

pooled patient-leveldata acrossall device platforms as well as from other

studies including the ongoing Safety Assessment of Femoropopliteal

Endovascular treatment with Paclitaxel-coated Devices study. Will this be

enough to re-enter into conversations with the FDA about revising the

current letter to health care providers and label changes? As of now, it

remains unclear, yet the body of work that has been produced as a result

of this controversy towers over the original meta-analysis, with consistent

signals of safety.

Declaration of competing interest

Eric Secemsky reports research grants to Beth Israel Deaconess

Medical Center) from the National Institutes of Health/National Heart,

Lung, and Blood Institute (K23HL150290), Food & Drug Administration,

BD, Boston Scientiﬁc, Cook, CSI, Laminate Medical, Medtronic, and

Philips. Eric Secemsky is a consultant for or receives speaking fees from

Abbott, Bayer, BD, Boston Scientiﬁc, Cook, Cordis, CSI, Inari, InfraRedx,

Medtronic, Philips, Shockwave, and VentureMed. Aishwarya Raja re-

ported no ﬁnancial interests.

Funding sources

This research did not receive any speciﬁc grant from funding

agencies in the public, commercial, or not-for-proﬁt sectors.

References

1. de Donato G, Bosiers M, Setacci F, et al. 24-month data from the BRAVISSIMO: A

large-scale prospective registry on iliac stenting for TASC A and B and TASC C and

D lesions. Ann Vasc Surg. 2015;29(4):738–750.

2. Bradbury AW, Adam DJ, Bell J, et al. Bypass versus Angioplasty in Severe Ischaemia

of the Leg (BASIL) trial: an intention-to-treat analysis of amputation-free and overall

survival in patients randomized to a bypass surgery-ﬁrst or a balloon angioplasty-ﬁrst

revascularization strategy. J Vasc Surg. 2010;51(5 suppl):5S–17S.

3. Dake MD, Ansel GM, Jaff MR, et al. Durable clinical effectiveness with paclitaxel-

eluting stents in the femoropopliteal artery: 5-year results of the Zilver PTX

randomized trial. Circulation. 2016;133(15):1472–1483. discussion 1483.

4. Dake MD, Ansel GM, Jaff MR, et al. Paclitaxel-eluting stents show superiority to

balloon angioplasty and bare metal stents in femoropopliteal disease: twelve-

month Zilver PTX randomized study results. Circ Cardiovasc Interv. 2011;4(5):

495–504.

5. Tepe G, Laird J, Schneider P, et al. Drug-coated balloon versus standard

percutaneous transluminal angioplasty for the treatment of superﬁcial femoral and

popliteal peripheral artery disease: 12-month results from the IN.PACT SFA

randomized trial. Circulation. 2015;131(5):495–502.

Figure 1.

Summary of updated data since the publication of the original meta-analysis. Independent randomized and real-world evidence demonstrates no mortality signal with paclitaxel.

2 Editorial / Journal of the Society for Cardiovascular Angiography & Interventions 2 (2023) 100981

Данная книга находится в списке для перевода на русский язык сайта https://meduniver.com/

6. Tepe G, Schnorr B, Albrecht T, et al. Angioplasty of femoral-popliteal arteries with

drug-coated balloons: 5-year follow-up of the THUNDER trial. J Am Coll Cardiol

Intv. 2015;8(1 Pt A):102–108.

7. Ng VG, Mena C, Pietras C, Lansky AJ. Local delivery of paclitaxel in the treatment of

peripheral arterial disease. Eur J Clin Invest. 2015;45(3):333–345.

8. Feldman DN, Armstrong EJ, Aronow HD, et al. SCAI consensus guidelines for

device selection in femoral-popliteal arterial interventions. Catheter Cardiovasc

Interv. 2018;92(1):124–140.

9. Bailey SR, Beckman JA, Dao TD, et al. ACC/AHA/SCAI/SIR/SVM 2018 appropriate use

criteria for peripheral artery intervention: a report of the American College of

Cardiology Appropriate Use Criteria Task Force, American Heart Association,

Society for Cardiovascular Angiography and Interventions, Society of Interventional

Radiology,and Society for Vascular Medicine. JAmCollCardiol. 2019;73(2):214–237.

10. Katsanos K, Spiliopoulos S, Kitrou P, Krokidis M, Karnabatidis D. Risk of death

following application of paclitaxel-coated balloons and stents in the

femoropopliteal artery of the leg: a systematic review and meta-analysis of

randomized controlled trials. J Am Heart Assoc. 2018;7(24):e011245.

11. June 19-20, 2019: circulatory system devices panel of the Medical Devices Advisory

Committee meeting announcement. U.S. Food and Drug Administration. June 19-

20, 2019. Accessed April 1, 2023. https://www.fda.gov/advisory-committees/advis

ory-committee-calendar/june-19-20-2019-circulatory-system-devices-panel-medical

-devices-advisory-committee-meeting

12. FDA executive summary. U.S. Food and Drug Administration; 2019. Accessed

April 1, 2023. https://www.fda.gov/media/127698/download

13. McKeown LA. Two trials halted in wake of study linking paclitaxel-coated devices to

deaths in PAD. tctMD. December 17, 2018. Accessed April 1, 2023. https://www.

tctmd.com/news/two-trials-halted-wake-study-linking-pac litaxel-coated-devices-d

eaths-pad

14. Rocha-Singh KJ, et al. VIVA-NAMSA presentation. Presented at: Circulatory System

Devices Panel Meeting; June 19, 2019; Gaithersburg, MD.

15. Rocha-Singh KJ, Duval S, Jaff MR, et al. Mortality and paclitaxel-coated devices: an

individual patient data meta-analysis. Circulation. 2020;141(23):1859–1869.

16. Dinh K, Limmer AM, Chen AZL, et al. Mortality rates after paclitaxel-coated device use

in patients with occlusive femoropopliteal disease: an updated systematic review and

meta-analysis of randomized controlled trials. JEndovascTher. 2021;28(5):755–777.

17. Nordanstig J, James S, Andersson M, et al. Mortality with paclitaxel-coated devices

in peripheral artery disease. N Engl J Med. 2020;383(26):2538–2546.

18. Hess CN. VOYAGER PAD: long-term safety of drug-coated devices in peripheral

artery revascularization. tctMD. October 18, 2020. Accessed April 1, 2023. https:

//www.tctmd.com/slide/voyager-pad-long-term-safety-drug-coated-devices-periph

eral-artery-revascularization

19. Bertges DJ, Sedrakyan A, Sun T, et al. Mortality after paclitaxel coated balloon

angioplasty and stenting of superﬁcial femoral and popliteal artery in the Vascular

Quality Initiative. Circ Cardiovasc Interv. 2020;13(2):e008528.

20. Bertges DJ, Eldrup-Jorgensen J, Robbins S, et al. Vascular Quality Initiative

surveillance of femoropopliteal artery paclitaxel devices. J Am Coll Cardiol Intv

2021;14(23):2598–2609.

21. Se

cemsky EA, Barrette E, Bockstedt L, et al. Long-term safety of drug-coated

devices for peripheral revascularisation. EuroIntervention. 2021;17(7):

590–598.

22. Gutierrez JA, Rao SV, Jones WS, et al. Survival and causes of death among

veterans with lower extremity revascularization with paclitaxel-coated devices:

insights from the Veterans Health Administration. J Am Heart Assoc.2021;

10(4):e018149.

23. Freisinger E, Koeppe J, Gerss J, et al. Mortality after use of paclitaxel-based devices

in peripheral arteries: a real-world safety analysis. Eur Heart J. 2020;41(38):

3732–3739.

24. Behrendt CA, Sedrakyan A, Peters F, et al. Editor’s choice – long term survival after

femoropopliteal artery revascularisation with paclitaxel coated Devices: a

propensity score matched cohort Analysis. Eur J Vasc Endovasc Surg. 2020;59(4):

587–596.

25. Safety assessment of femoropopliteal endovascular treatment with paclitaxel-

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ials.gov/ct2/show/NCT04496544.

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femoropopliteal artery revascularization with drug-coated devices. JAMA Cardiol.

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27. Secemsky EA, Song Y, Schermerhorn M, Yeh RW. Update from the longitudinal

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Cardiovasc Interv. 2022;15(6):e012074.

28. Lyden SP, Brodmann M, Schroeder H, et al. Five-year independent patient-level

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Editorial / Journal of the Society for Cardiovascular Angiography & Interventions 2 (2023) 100981 3

Original Research

Longer-Term Outcomes Following Mechanical Thrombectomy for

Intermediate- and High-Risk Pulmonary Embolism: 6-Month FLASH

Registry Results

Sameer Khandhar, MD

, Wissam Jaber, MD

, Matthew C. Bunte, MD, MS

, Kenneth Cho,

MD, MBA

, Mitchell D. Weinberg, MD

, Bushra Mina, MD

, Brian Stegman, MD

Jeffrey Pollak, MD

, Akhil Khosla, MD

, Fakhir Elmasri, MD

, David Zlotnick, MD

Daniel Brancheau, DO

, Gerald Koenig, MD

, Mohannad Bisharat, MD

, Jun Li, MD

Catalin Toma, MD

, for the FLASH Investigators

Division of Cardiovascular Medicine, Penn Presbyterian Medical Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia,

Pennsylvania;

Emory University Hospital, Atlanta, Georgia;

Saint Luke’s Mid America Heart Institute, Kansas City, Missouri;

Department of Cardiology,

Northwell Health, Zucker School of Medicine at Hofstra/Northwell, Staten Island University Hospital, Staten Island, New York;

Department of Pulmonary

Critical Care Medicine, Lenox Hill Hospital, Northwell Health, Zucker School of Medicine at Hofstra/Northwell, New York, New York;

CentraCare Heart and

Vascular Center, St Cloud, Minnesota;

Department of Radiology and Biomedical Imaging, Yale University, New Haven, Connecticut;

Department of

Pulmonary, Critical Care and Sleep Medicine, Yale University, Yale New Haven Hospital, New Haven, Connecticut;

Division of Interventional Radiology,

Lakeland Regional Medical Center, Lakeland, Florida;

Division of Cardiovascular Medicine, University at Buffalo, Gates Vascular Institute, Buffalo General

Medical Center, Buffalo, New York;

Ascension Genesys Hospital, Grand Blanc, Michigan;

Division of Cardiovascular Medicine, Henry Ford Health System,

Wayne State University School of Medicine, Detroit, Michigan;

Memorial Hospital Jacksonville, Jacksonville, Florida;

Harrington Heart and Vascular

Institute, University Hospitals, Cleveland, Ohio;

Heart and Vascular Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania

ABSTRACT

Background: Mechanical thrombectomy provides rapid hemodynamic improvements after acute pulmonary embolism (PE), but long-term beneﬁts are

uncertain.

Methods: FlowTriever All-comer Registry for Patient Safety and Hemodynamics is a prospective, single-arm, multicenter registry of patients with acute PE

treated with the FlowTriever System (Inari Medical). Six-month outcomes including modiﬁed Medical Research Council dyspnea scores (MMRCD), right

ventricular (RV) function, 6-minute walk test distances, and PE quality-of-life scores (QoL) were assessed.

Results: In total, 799 patients were enrolled and 75% completed the study with a mean follow-up of 204  46 days. Demographic characteristics included

54.1% men, mean age of 61.2 years, 77.1% intermediate-high-risk PE, and 8.0% high-risk PE. All-cause mortality was 4.6% at study completion. The pro-

portion of patients with normal echocardiographic RV function increased from 15.1% at baseline to 95.1% at 6 months (P < .0001). MMRCD score improved

from 3.0 at baseline to 0.0 at 6 months (P < .0001). 6-minute walk test distances increased from 180 m at 48 hours to 398 m at 6 months (P < .001). Median PE

QoL total scores were 9.38 at 30 days and 4.85 at 6 months (P < .001). Prevalence of site-reported chronic thromboembolic pulmonary hypertension wa s

1.0% and chronic thromboembolic disease was 1.9%.

Conclusions: In this large diverse group of PE patients, 6-month all-cause mortality, chronic thromboembolic pulmonary hypertension, and chronic thrombo-

embolicdisease were lowfollowingthrombectomy with theFlowTriever system. Signiﬁcantimprovements in RV function, patient symptoms, exercise capacity, and

QoL were observed at 6 months, suggesting that rapid extraction of thrombus may prevent long-term sequelae in patients with PE.

Abbreviations: 6MWT, 6-minute walk test; AC, anticoagulation; CDT, catheter-directed thrombolysis; CTED, chronic thromboembolic disease; CTEPH, chronic thromboembolic

pulmonary hypertension; FLASH, FlowTriever All-comer Registry for Patient Safety and Hemodynamics; PE, pulmonary embolism; PEmb-QoL, Pulmonary Embolism Quality of Life;

PPEI, post-PE impairment; RPVO, residual pulmonary vascular obstruction.

Keywords: mechanical thrombectomy; long-term outcomes; percutaneous intervention; pulmonary embolism.

* Corresponding author: sameer.khandhar@pennmedicine.upenn.edu (S. Khandhar).

Current afﬁliation: Einstein Medical Center Montgomery, Dresher, Pennsylvania.

https://doi.org/10.1016/j.jscai.2023.101000

Received 29 March 2023; Received in revised form 12 April 2023; Accepted 18 April 2023

Available online 19 May 2023

CC BY license (http://creativecommons.org/licenses/by/4.0/).

Journal of the Society for Cardiovascular Angiography & Interventions 2 (2023) 101000

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Introduction

Pulmonary embolism (PE) remains a clinically challenging disease

that is associated with both short- and long-term morbidity and mor-

tality. Given the acuity of PE, studies evaluating interventional treat-

ments have focused on establishing short-term safety, improving short-

term right ventricular (RV) hemodynamics, preventing hemodynamic

decompensation, and reducing in-hospital death. However, survivors of

PE can have signiﬁcant limitations late after diagnosis, including

persistent dyspnea, impaired exercise capacity, and reduced quality of

life (QoL),

known as post-PE impairment (PPEI). This long-term func-

tional pulmonary impairment can impact up to 50% of PE survivors

and

encompasses a spectrum of diseases with increasing severity and

varying presentations ranging from post-PE syndrome or chronic

thromboembolic disease (CTED) to chronic thromboembolic pulmo-

nary hypertension (CTEPH).

CTED is characterized by persistent dys-

pnea in the absence of resting pulmonary hypertension and may be

associated with residual pulmonary vascular obstruction (RPVO).

CTEPH, the most severe form of PPEI, is manifested by persistent

dyspnea, RPVO, and resting pulmonary hypertension, all of which are

associated with a high rate of morbidity and mortality.

Both CTED and

CTEPH are associated with a signiﬁcant reduction in QoL and portend a

worse prognosis.

Over the past decade, catheter-based treatment options for acute

PE have evolved beyond traditional thrombolytic treatments to include

large-bore mechanical thrombectomy to disrupt and aspirate PE

thrombus. The FlowTriever System (Inari Medical) has demonstrated

favorable acute safety and effectiveness for treating PE, including

acutely reduced pulmonary artery pressure (PAP), improved RV func-

tion, and increased cardiac output during the index hospitalization.

4–9

However, the longer-term beneﬁts of large-bore mechanical throm-

bectomy are less certain.

The FlowTriever All-Comer Registry for Patient Safety and Hemo-

dynamics (FLASH) is a prospective, multicenter, single-arm study to

evaluate the acute and longer-term safety and effectiveness of the

FlowTriever System among a large and geographically diverse popu-

lation with acute PE. In-hospital and 30-day outcomes from the fully

enrolled US cohort of 800 patients have been published previously.

This report focuses on the longer-term outcomes, including late

all-cause mortality, RV remodeling, residual symptoms, functional sta-

tus, and PE-speciﬁc QoL through 6-month follow-up after treatment

with the FlowTriever System.

Methods

Study design

FLASH is an all-comer, prospective, multicenter registry (ClinicalT

rials.gov identiﬁer: NCT03761173) to evaluate real-world outcomes in

patients with PE treated with mechanical thrombectomy using the

FlowTriever System. The FlowTriever System is composed of 2 main

components: the Triever aspiration catheter used for controlled aspi-

ration of thromboemboli, and the FlowTriever catheter comprised of

self-expanding nitinol disks designed to engage the thrombus for

removal via aspiration.

Details of the FLASH registry study design have been previously

reported.

9,10

Inclusion criteria were limited to patients aged 18 years

old with acute intermediate- or high-risk PE per European Society of

Cardiology guidelines.

Exclusion criteria included patients unable to

be anticoagulated and life expectancy of <30 days. Investigators ob-

tained institutional review board approval at each site prior to enrolling

patients, and all patients provided written informed consent. Follow-up

assessments occurred at 48 hours, 30 days, and 6 months post-

thrombectomy. When patients were unable to attend an in-person

follow-up assessment because of COVID-19 or other restrictions,

every effort was made to perform a telehealth appointment to measure

those parameters suitable to this type of assessment. All safety events

and their relatedness to the study device and/or procedure were

adjudicated by a third-party independent medical monitor, including all

serious adverse events (SAEs) occurring throughout the study follow-up

period. SAEs were events meeting the deﬁnition of serious in

ISO14155,

which included any event that resulted in death, was

life-threatening, resulted in or prolonged hospitalization, resulted in

signiﬁcant disability/incapacity or permanent impairment of a bodily

function, or necessitated medical or surgical intervention.

Clinical outcomes assessed

Follow-up visits included echocardiography examinations to eval-

uate recovery of RV function, dyspnea symptom assessment, exercise

capacity evaluation via 6-minute walk tests (6MWT), QoL measure-

ments, and adverse event screening. Echocardiography examinations,

6MWT, and QoL measurements were required at 30 days and 6 months

but were optional at 48 hours. Evaluation for dyspnea symptoms and

adverse event assessments were required at every follow-up visit.

Echocardiographic examinations included evaluation of RV systolic

pressure, size, and function, and RV/left ventricular (RV/LV) ratio, which

were evaluated at the site level by physicians using the site’s standard

clinical practice. RV function was scored as either normal or mildly,

moderately, or severely reduced. Dyspnea assessment used the modi-

ﬁed Medical Research Council scale, a self-assessment from 0 (breath-

less only on strenuous exercise) to 4 (too breathless to leave house, or

breathless when dressing/undressing).

The 6MWTs

were performed

to assess exercise capability by recording the total distance walked in

meters during a 6-minute interval. The patient was also asked to score

their level of dyspnea and fatigue before and after the test using the

10-point Borg Scale.

Patient QoL was assessed using the Pulmonary Embolism Quality of

Life (PEmb-QoL) questionnaire.

The questionnaire is a validated,

disease-speciﬁc assessment that consists of 6 parts, or domains, to

assess different aspects of the patients’ lives. Results from each of the

individual domains were then incorporated into a total score for each

patient,

which was calculated from the mean of all nonmissing do-

mains. Higher scores indicate worse health and outcomes.

Prevalence of CTED and CTEPH at 6 months was also evaluated

based on site-reported assessments to determine any longer-term

disease sequelae. A diagnosis of CTED required evidence at follow-

up of persistent dyspnea but without pulmonary hypertension (mean

PAP <25 mm Hg). A diagnosis of CTEPH required evidence at follow-up

of persistent dyspnea, pulmonary hypertension (mean PAP 25 mm

Hg), and abnormal imaging, although the study protocol did not specify

imaging type.

Statistical analyses

Data are presented as either proportion (%), mean  SD, or median

(IQR). For variables where baseline measurements were available, Wil-

coxon signed-rank test and McNemar’s or McNemar-Bowker’s tests

were applied to test the changes from baseline for continuous and

categorical outcomes, respectively, using available paired values. For

variables where baseline measurements were not available, trend over

time analysis was performed using a generalized linear mixed effects

model assuming patient-speciﬁc random slope and intercept, using all

available data. The model was adjusted for the effect of age, body mass

index, and sex. Time was computed as the number of days between

procedure date and visit date. A 2-sided P value of .05 was used to

determine statistical signiﬁcance. Analyses were performed using SAS

2 S. Khandhar et al. / Journal of the Society for Cardiovascular Angiography & Interventions 2 (2023) 101000

9.4 (SAS Institute) and R version 4.1.2.

Kaplan-Meier assessment of

freedom from mortality was calculated using R version 4.1.2.

To address the potential effects of missingness on study ﬁndings, a

sensitivity analysis using mixed models for repeated measures was

performed assuming a missing-at-random model. Each outcome of

interest incorporated a random intercept of subjects and random slopes

of study follow-up visits in addition to relevant covariates. The mean

estimates and probability distributions derived from mixed models for

repeated measures for each follow-up timepoint had similar trends

compared with the actual means and proportion distributions reported

in this manuscript. These sensitivity analysis ﬁndings are therefore

consistent with the missing-at-random assumption.

Results

Baseline and procedural characteristics

The FLASH registry enrolled 800 patients treated with the Flow-

Triever System at 50 sites across the United States between December

2018 and December 2021. The analysis population was 799 patients

because 1 patient was deemed ineligible postenrollment for meeting

an exclusion criterion (RV/LV ratio of <0.9). A more extensive pre-

sentation of baseline and procedural characteristics of this cohort has

been previously published.

In brief, 8.0% of the patients had

high-risk (massive) PE, and 77.1% had intermediate–high-risk (sub-

massive) PE. Average age was 61.2  14.6 years, and 54.1% of pa-

tients were men. The mea n simpliﬁed Pulmonary Embolism Severity

Index was 1.6  1.1, and 32.1% had a relative or absolute contrain-

dication to thrombolytic drugs. Of the 799 patients in the analysis

population, 599 (75.0%) completed the study, and the mean follow-up

duration of these 599 patients was 204  46 days. Disposition of the

remaining patients who did not complete the study is provided in

Figure 1.

The immediate improvements in hemodynamics and vital signs,

including mean PAP, heart rate, and total pulmonary vascular resistance

following thrombectomy have been previously published.

Median

(IQR) thrombectomy time was 43 (29-62) minutes. Nineteen patients

(2.4%) received adjunctive treatment for PE (18 received

catheter-directed thrombolysis [CDT] and 1 received additional percu-

taneous mechanical thrombectomy).

Longer-term mortality, safety, and chronic disease outcomes

There were 2 deaths at 48 hours and 27 additional deaths during the

study follow-up, resulting in 4.6% all-cause mortality among the 628

patients with known mortality status at the end of the study (Table 1).

Freedom from mortality events determined by Kaplan-Meier analysis is

shown in Figure 2. Mortality events occurred at a steady, approximately

linear rate throughout the follow-up period, with all deaths occurring

prior to 150 days postthrombectomy except for an outlier at 291

days (not shown). A total of 103 SAEs were reported in 84 patients

(13.2%) during the study follow-up, 101 of which were adjudicated to

be unrelated to the FlowTriever System and the remaining 2 of which

were adjudicated to have an unknown relationship to the device. A

listing of all SAEs reported throughout the study is provided in

Supplemental Table S1. At the 6-month visit, evidence of CTED was

reported in 11 patients (1.9%), whereas evidence of CTEPH was

reported in 6 patients (1.0%).

Longer-term anticoagulant use

Among patients completing the 30-day follow-up visit, 89.9% were

treated with some form of anticoagulation (AC). This proportion

remained similar at the 6-month visit, where 91.2% were receiving AC

therapy. The proportions of patients on different types of AC at the 30-

day and 6-month follow-up visit are shown in Supplemental Table S2.At

the 6-month follow-up visit, 87.2% of patients on AC were being treated

with a new oral AC/direct oral AC, with a minority of patients on vitamin

K antagonists or other agents.

RV function outcomes

All prespeciﬁed echocardiographic parameters demonstrated

signiﬁcant improvement from baseline to 48 hours, with further im-

provements continuing out to 6 months (Figure 3). Mean RV/LV ratios

improved from 1.23  0.36 at baseline to 0.98  0.30, 0.78  0.16 and

0.80  0.28 at 48 hours, 30 days, and 6 months, respectively

(Figure 3A, P < .0001). Similarly, mean estimated RV systolic pressure

declined from 48.8  14.9 mm Hg at baseline t o 38.7  14.6, 30.0 

11.4, and 27.3  8.9mmHgat48hours,30days,and6months,

respectively (Figure 3B, P < .0001). The proportion of patients with RV

systolic pressure of 40 mm Hg improved from 28.5% at baseline to

93.5% at 6 months. The distribution of patients at each RV function

level changed signiﬁcantly over time (Figure 3C, P < .0001), with the

proportion of patients with normal function increasing from 15.1% at

baseline to 95.1% at 6 months. Similarly, RV size also improved

signiﬁcantly over the follow-up period (Figure 3D, P < .0001), with the

proportion of patients exhibiting norm al RV size increasing from 9.9%

at baseline to 88.2% at 6 months.

Dyspnea, QoL, and 6MWT outcomes

edian (IQR) dyspnea scores decreased from 3.0 (2.0-4.0) at

baseline to 1.0 (0.0-2.0) at 48 hours and 0.0 (0.0-1.0) at both 30

days and 6 months. The distribution of dyspnea scores changed

signiﬁcantly over time (Figure 4, P < .0001), with the proportion of

patients reporting absent or mild dyspnea (score of 0 or 1)

Figure 1.

Flow diagram of patient enrollment and follow-up.

Table 1. Six-month mortality, safety, and chronic disease outcomes.

Outcome n/N (%)

All-cause mortality through study exit

29/628 (4.6%)

Patients with SAEs through study exit

84/638 (13.2%)

Prevalence of CTEPH at 6-month visit 6/581 (1.0%)

Prevalence of CTED/post-PE Syndrome at 6-mo nth visit 11/591 (1.9%)

CTED, chronic thromboembolic disease; CTEPH, chronic thromboembolic pul-

monary hypertension; PE, pulmonary embolism; SAE, serious adverse event.

All deaths were adjudicated to be unrelated to the FlowTriever System. The

denominator shown represents all patients with known mortality status at the

end of the study.

Two SAEs were adjudicated to have unknown relationship

to the FlowTriever System. All other SAEs were unrelated.

S. Khandhar et al. / Journal of the Society for Cardiovascular Angiography & Interventions 2 (2023) 101000 3

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increasing from 21.9% at baseline to 67.4% at 48 hours, 83.1% at

30 days, and 90.1% a t 6 months. The median values for the 6MWT

distances walked at each timepoint are presented in Figure 5A.

The median di stance walked increased signiﬁcantly over time from

180.0 (90.0-315.2) m at 48 hours to 375.6)273.0-468.0) m at 30

days, and 398.1 (300.0-490.0) m at 6 months (P < .001). Median

dyspnea and fatigue scores were 0.0 immediately prior to the

6MWT at 48 hours, which were maintained out to 6 months

(Figure 5B, C). Median dyspnea and fatigue scores following the

6MWT were 2.0 at 48 hours, indicating patients had some difﬁculty

with exercise at this early assessment. Notably, the median post-

6MWT dyspnea scores were signiﬁcantly reduced to 1.0 at 30

days and 6 months (P < .001), whereas median post-6MWT fatigue

scores were reduced to 0.5 at 30 days and 6 months (P < .001).

Median (IQR) PEmb-QoL total scores were 9.38 (1.22-29.37) at the

30-day visit and 4.85 (0.67-17.18) at the 6-month visi t (Figure 6),

where lower scores indicated a higher QoL. These key longer-term

effectiveness outcomes are summarized in the Central Illustration.

Figure 2.

Kaplan-Meier analysis of freedom from mortality. Kaplan-Meier time-to-event analysis was performed to evaluate freedom from mortality over time. *One additional death occurred

at day 291.

Figure 3.

RV echocardiographic parameters at

baseline and 48 hours, 30 days, and 6

months postthrombectomy. (A) Right ven-

tricular (RV) to left ventricular (LV) ratio at

baseline and follow-up times (P < .0001 for

available paired assessments; Wilcoxon

signed-rank test). (B) RV systolic pressure at

baseline and follow-up times (P < .0001 for

available paired assessments; Wilcoxon

signed-rank test). (C) Distribution of patients’

RV function at baseline and follow-up times

(P < .0001 for available paired assessments;

McNemar-Bowker’s test). (D) Distribution of

RV size at baseline and follow-up times (P <

.0001 for available paired assessments;

McNemar-Bowker’s test). The sample sizes

below each posttreatment timepoint repre-

sent the number of patients who had paired

measurements with baseline values.

4 S. Khandhar et al. / Journal of the Society for Cardiovascular Angiography & Interventions 2 (2023) 101000

Discussion

The FLASH study is the largest prospective catheter-based

interventional study of PE to evaluate short- and now longer-term

outcomes among a geographically diverse and pragmatic popula-

tion of US patients. There is an established body of evidence from

FLASH as well as other single-center and multicenter studies

reporting the acute hemodynamic improvements and favorable

safety proﬁle of FlowTriever mechanical thrombectomy for treatment

of acute PE,

4–10

but data describing longer-term clinical outcomes

of this interventional treatm ent are limited by comparison. In addi-

tion to assessing acute beneﬁts, the FLASH study also followed

patients for 6 months postthrombectomy to provide lo nger-term

follow-up data, addressing an important gap in the clinical evi-

dence available for PE treatment with mechanical thrombectomy. In

this report, patients treated with mechanical thrombectomy had

improved echocardiographic parameters during 6-month fo llow-up.

Perhaps more importantly to patients, the patient-reported out-

comes including dyspnea score, QoL, and 6MWT distance all

improved quickly after treatment, and these improvements were

sustained throughout follow-up.

Echocardiographic measurements of RV parameters all showed

signiﬁcant improvements within 48 hours that continued out to 6

months following FlowTriever treatment, with 95.1% of patients

having normal RV function at 6 months. Patients also experienced

longer-term improvements in dyspnea, exercise capacity, and QoL

over the follow-up period, including improvement in the median

PEmb-QoL total score from 9.38 at 30 days to 4.85 at 6 months,

improvement in 6MWT distances from 180 m at 48 hours to 398 m

at 6 months, and signiﬁ cant reductions in both dyspnea and fatigue

scores immediately following the 6MWT over time. Interestin gly,

most of the echocardiographic and functional improvements were

achieved in the ﬁrst 30 days with sustained beneﬁt out to 6 months.

These results support the hypothesis that early thrombus removal

from pulmonary arteries reduces RV afterload, improves RV function,

and helps patients experience early symptom relief that is main-

tained out to at least 6 months.

Patients are often hindered by signiﬁcant and prolonged func-

tional limitations after their initial PE, and it can take substantial time

for patients to recover. Among patients treated with AC alone in the

ELOPE study, approximately 50% of patients experienced signiﬁcant

exercise limitations after their initial PE, with symptoms and func-

tional exercise capacity improving slowly over the ﬁrst year.

These

results are supported by the FOCUS study, whi ch found that almost

20% of patients met the diagnosis of PPEI over a 2-year follow-up,

and these patients had reduced QoL and higher all-cause mortality

compared with those without PPEI.

18,19

The FOCUS study also noted

a slow improvement of the PEmb-QoL scores over the course of th e 2

years after a PE, with PPEI patients recording PEmb-QoL scores of

59.5, 46.9, and 23.3 at 3, 12, and 24 months, respectively. Patients

without PPEI saw lower but also slowly improving scores of 20.7,

12.3, and 9.8 over the same time period.

18,19

Patients with PE

enrolled in the ELOPE study demonstrated a mean baseline

PEmb-QoL score of 45.2, with total reductions of 11.0, 20.8, 25.4,

and 32.1 points at 1, 3, 6, and 12 months, respectively.

1,20

The

6MWT results from the ELOPE study demonstrated a similar trajec-

tory of slow improvement in walk distances over the 1-year post-PE

follow-up, with total increases of 20.7, 30.1, and 40.0 m above the

1-month distance at 3, 6, and 12 months.

These data suggest that

PPEI is common and associated with poor functional outcomes and

decreased QoL and that some patients will never return to their

pre-PEbaselinefunctionalcapacitywhentreatedwithACalone.The

present study suggests that patients undergoing large-bore me-

chanical thrombectomy with the Fl owTriever System have signiﬁcant

improvements in their functional capacity by 30 days, considerably

earlier than those treated with conventional therapy. This rapid

attainment of near-normal values can potentially translate into lower

health care costs and a quicker return to normal daily activities for

patients treated with mechanical thrombectomy. It may also establish

the importance of intermediate follow-up timepoints, such as 30 days

in future PE studies in addition to the standard longer-term time-

points to differentiate those treatments that may offer a more

expedient response.

Long-term functional outcomes following catheter-based interven-

tion have not been well studied, and a limited volume of data exists. A

recent propensity-matched retrospective analysis matched patients

receiving catheter-directed therapies (96.8% of patients received CDT

and 3.2% received mechanical thrombectomy) to patients receiving

Figure 4.

Dyspnea score distribution at baseline, 48 hours, 30

days, and 6 months postthrombectomy. Dyspnea was

assessed at baseline and at follow-up visits at 48 hours, 30

days, and 6 months postthrombectomy using the modiﬁed

Medical Research Council assessment tool (higher score ¼

worse dyspnea). The proportion of patients with each score

(0-4) is presented, showing a signiﬁcant change in score

distribution (P < .0001 for available paired assessments;

McNemar-Bowker’s test). Mean  SD and median (IQR)

values for each timepoint are shown in the table below the

graph (P < .0001 for available paired assessments; Wilcoxon

signed-rank test). The sample sizes below each posttreat-

ment timepoint represent the number of patients who had

paired measurements with baseline values.

S. Khandhar et al. / Journal of the Society for Cardiovascular Angiography & Interventions 2 (2023) 101000 5

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