33 SchneiderUCSF 4-19 DCB 4-19 … · University of California, San Francisco DCB-what is the appropriate role in the management of fem-pop disease in 2019? DISCLOSURE Peter A. Schneider

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Peter A. Schneider, MDDivision of Vascular and Endovascular SurgeryUniversity of California, San Francisco

DCB-what is the appropriate role in the management of fem-pop disease in 2019?

DISCLOSUREPeter A. Schneider

Enter patients in studies sponsored by: Gore, Cordis, Medtronic, Silk Road, Bard, NIH, Limflow

Consultant: Silk Road, Surmodics, Profusa

Scientific Advisory Board: Abbott, Medtronic, Boston Scientific, CSI

Chief Medical Officer: Intact Vascular, Cagent

National co-PI: Roadster 2, Scaffold, Confidence, IN.PACT

I believe that drug delivery has beena major step forward for patients with SFA disease


SFA Disease 2013

SFA LesionCFA diseasePop-trifur disEndo failureReally bad runoff

OpenSurgeryOr hybrid

TASC C TASC D

Primary stentor stent-graft(Esp. if occlusion)

Standard PTAAtherectomy(Focal, no-stent zone)

Selectivestent

TASC A/B

Bypass, Stentor stent-graft

Limb salvage Claudication

Bypass in good Surgical candidates

Femoral-popliteal Disease: PTA and Stents PTAStent

Lesion length (cm)

12-m

onth

Prim

ary

Pate

ncy

RCT Data: PTA vs StentRCTsResilientFACT4EVERDurabilityAstronViennaVienna-3

PTA

Stents

TASC A/B


• Timing of SFA restenosis is longer compared to coronary stenting, which predominantly occurs within 6 months.

• Factors for restenosis in the SFA include the number of runoff vessels, severity of lower limb ischemia, and length of diseased segments.

Iida, O. et al. Cath and Cardiov Intv. 2011; 78:611–617.Kimura T, et al. N Engl J Med 1996;334:561–567.

ProbabilityofRestenosiswithBareMetalStentsRestenosis after SFA stenting peaks at 12 months

We would like to make the “peak” flatter andpush it out to a longer time frame.

Jonas et al, Cathet Cardiovasc Interv, 2007

Drug Eluting Coronary Stents in the US

Adoption of DES

Reduction in TLR


7

DCB concept works! 5 DCBs showing a biologic effect

Paccocath PTX 3 µg/mm2

+ Ultravist

Lutonix PTX 2 µg/mm2

+ Polysorbate & Sorbitol

In.Pact PTX 3.5 µg/mm2

+ Urea

Passeo 18 Lux

PTX 3.0 µg/mm2

+ BTHC

Advance PTX

PTX 3.0 µg/mm2

NO Excipient

Stellarex PTX 2.0 µg/mm2

PEG

1. Tepe G, Zeller T, Albrecht T, Heller S, Schwarzwälder U, Beregi JP, Claussen CD, Oldenburg A, Scheller B, Speck U. Local delivery of paclitaxel to inhibit restenosis during angioplasty of the leg. N Engl J Med. 2008 Feb 14;358(7):689-99 2. Werk M, Langner S, Reinkensmeier B, Boettcher HF, Tepe G, Dietz U, Hosten N, Hamm B, Speck U, Ricke J. Inhibition of restenosis in femoropopliteal arteries: paclitaxel-coated versus uncoated balloon: femoral paclitaxel randomized pilot trial.

Circulation. 2008 Sep 23;118(13):1358-65 3. Scheinert D, Duda S, Zeller T, Krankenberg H, Ricke J, Bosiers M, Tepe G, Naisbitt S, Rosenfield K. The LEVANT I (Lutonix paclitaxel-coated balloon for the prevention of femoropopliteal restenosis) trial for femoropopliteal revascularization: first-in-

human randomized trial of low-dose drug-coated balloon versus uncoated balloon angioplasty. JACC Cardiovasc Interv. 2014 Jan;7(1):10-9 4. Scheinert D, Schulte KL, Zeller T, Lammer J, Tepe G. Paclitaxel-Releasing Balloon in Femoropopliteal Lesions Using a BTHC Excipient: Twelve-Month Results From the BIOLUX P-I Randomized Trial. J Endovasc Ther. 2015 Feb;22(1):14-21 5. Werk M, Albrecht T, Meyer DR, Ahmed MN, Behne A, Dietz U, Eschenbach G, Hartmann H, Lange C, Schnorr B, Stiepani H, Zoccai GB, Hänninen EL. Paclitaxel-coated balloons reduce restenosis after femoro-popliteal angioplasty: evidence from the

randomized PACIFIER trial. Circ Cardiovasc Interv. 2012 Dec;5(6):831-40 6. D.Scheinert – LINC 2013 oral presentation 7. Schroeder H, Meyer DR, Lux B, Ruecker F, Martorana M, Duda S. Two-year results of a low-dose drug-coated balloon for revascularization of the femoropopliteal artery: Outcomes from the ILLUMENATE first-in-human study. Catheter Cardiovasc

Interv. 2015 Feb 23

SFA: Late Lumen Loss6 Different Paclitaxel DCB Preparations

Angiogram at 6 months: substantially less loss of lumen size

SUSTAINED DRUG, SUSTAINED BENEFIT. IMPORTANCE OF DRUG “RESERVOIRS”

PACLITAXEL RESERVOIR



Note: Study on file with Medtronic, represents 28-days post drug delivery.

Solid-phase paclitaxel embeds in vessel wall, creating “reservoirs” of drug that are sustained over time.

IN.PACT SFA

Primary'Patency''Kaplan/Meier'

Free from

Primary Patency

Event (%)

100 90 80 70 60 50 40 30 20 10 0

0 1 2 3 4 5 6 7 8 9 10 11 12 13 Months from Randomization Date

PTA

DCB

Survival %

Time Lutonix D C B Standard PTA P-value

365 days 73.5% 56.8% 0.001

Proportions-based difference was 65.2% for DCB vs. 52.6% for standard PTA � 12.6% difference

Tepe et al. Circ 2015;131:495

Rosenfield et al. NEJM 2015;373:145

Levant

50.4%@ day 410

73.7%@ day 410DCB 82.3% @ day 365

PTA 70.9% @ day 365

Lyden, TCT 2016

Illumenate

12 Month PatencyRCTs of DCB vs PTA


PTAStentStent-graft

DESDCB

Lesion length (cm)

12-m

onth

Prim

ary

Pate

ncy

RCT Data: DCB/DESRCTsDCB RCTsLevant 2IN.PACTIllumenateDES RCTZilver PTXImperial

Stent-graftRCTsViperVibrantViastar

Drug Coated Balloons and Drug-Eluting StentsFemoral-popliteal Disease

IN.PACT SFA Trial Primary Patency at 3 Years

2

24.4%

Schneider et al. Circ: Cardiovasc Interv 2018;11:e005891


Vessel Preparation§ Lumen gain§ Plaque modification, change vessel compliance§ Minimize arterial wall defects§ Prepare for drug delivery§ Prepare for definitive therapy

§ Results of may help determine which definitive therapy is appropriate

Technologies that Benefit§ Drug-coated balloon§ Woven nitinol stent§ Bioabsorbable vasc scaffold§ Stent graft/covered stent§ Self expanding nitinol stent- Including DES

Tools for Vessel Prep§ PTA§ Modifications of

angioplasty§ Atherectomy§ Lithoplasty

by similarly favorable results on ankle-brachial index,Rutherford class, and quality-of-life measures.

There is still uncertainty regarding the mostappropriate treatment strategy for TASC types C andD femoropopliteal artery disease. Despite its estab-lished limitations, PTA with or without stenting iswidely used at many centers. Self-expandablebare-metal stents have recently been shown to bebeneficial in comparison with standard PTA (10–12),especially when new-generation devices are used

(13–15) for relatively simple lesions. However, theinherent benefits of such permanent prosthesesover PTA alone have not convinced all operators touse them in a routine fashion, especially for longlesions for which placement of full metal jackets isnot considered the standard of care. Restenosisfollowing stenting in long superficial femoral arterylesions has been reported to occur at a frequencyof up to 50% (16–18). The pattern of restenosis infull metal jackets is diffuse in-stent restenosis or

FIGURE 1 Survival Free From Target Lesion Revascularization and Restenosis >50% (Primary Patency) at 12 Months

(A) Overall per protocol (PP) population. (B) Occlusive versus stenotic lesions.

Micari et al. J A C C : C A R D I O V A S C U L A R I N T E R V E N T I O N S V O L . 9 , N O . 9 , 2 0 1 6

Results of PCBs in Long SFA Lesions M A Y 9 , 2 0 1 6 : 9 5 0 – 6

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Primary Patency-DCB for Long Lesions

Micari et al. JACC Cardiovasc Interv 2016;9;950

Lesions >15cmMean lesion length 25cm49.5% occlusionsPrimary patency at 1 year=83.2%

CLI patients, and 1 amputation was pre-determinedbefore treatment. In the CLI group only, the ampu-tation rate was 5.3% at 1 year and 7.9% at 2 years.

The mean ABI improved from 0.56 ! 0.22 to 0.88 !0.16 (1 year) and to 0.80 ! 0.24 (2 years).

Patency rates were indeterminable for 56 of 288(19.4%) treated limbs at 1 year and 75 of 288 (26.0%)treated limbs at 2 years due to loss from follow-up.Similarly, TLR was indeterminable for 43 of 288(14.9%) treated limbs at 1 year and 55 of 288 (19.1%)treated limbs at 2 years.

Kaplan-Meier estimates of primary patency were79.2 ! 2.6% at 1 year and 53.7 ! 3.4% at 2 years for theentire cohort. When stratified according to anatomiclocation, lesions in the SFA-only had a patency rate of84.2 ! 2.9% and 57.1 ! 4.1% at 1 and 2 years, in the PA79.2 ! 8.3% and 58.4 ! 11.0%, and SFA lesionsextending into the PA 65.9 ! 6.2% and 42.5 ! 6.8%,respectively (SFA vs. PA: p ¼ NS; SFA vs. SFA þ PA:p ¼ 0.002). In those patients with repeated angiog-raphy and restenosis (n ¼ 115), the length of reste-nosis was significantly shorter than the baselinelesion length (14.4 ! 12.3 cm compared with 24.0 !10.2 cm; p < 0.0005).

Freedom from TLR was 85.4 ! 2.1% for the entirecohort at 1 year and 68.6 ! 3.0% at 2 years. Kaplan-Meier curves of primary patency and TLR rates areshown in Figures 2 and 3. All patients undergoingreintervention exhibited clinical symptoms, and TLRswere considered clinically driven.

Primary patency and TLR rates at 1 and 2 years ac-cording to clinical and lesion characteristics are givenin Table 3. Significant differences of survival curves forprimary patency were found in several subgroups,including male versus female, diabetic versus nondi-abetic, smokers versus nonsmokers, lesions withheavy calcification versus non/mild/moderate calcifi-cation, lesion location (SFA only vs. poplitealinvolvement), and ISR versus in-stent reocclusion. Denovo and nonstented restenosis showed a trend to-ward better patency versus ISR (Figure 4).

Significant differences of survival curves for TLRwere found in male versus female and de novo/nonstented restenosis versus ISR lesions.

To identify independent predictors of restenosisafter 2 years, stepwise logistic regression was per-formed including all factors associated with signifi-cant differences in patency rates and factors that arethought to be associated with a higher restenosis rate(female sex, lesion length $24 cm, ISR, involvementof the PA, severe calcification, TASC C and D lesions,percutaneous transluminal angioplasty without prioratherectomy/thrombectomy, residual stenosis $30%,diabetes mellitus, smoking, obesity, and chronic

renal insufficiency) (Table 3). Male sex was associatedwith a >50% risk reduction for restenosis after2 years (Figure 5). Furthermore, the presence of se-vere calcification and obesity were independent

FIGURE 2 Patency Rates of the Whole Cohort

FIGURE 3 TLR Rates of the Whole Cohort

TLR ¼ target lesion revascularization.

J A C C : C A R D I O V A S C U L A R I N T E R V E N T I O N S V O L . 9 , N O . 7 , 2 0 1 6 Schmidt et al.A P R I L 1 1 , 2 0 1 6 : 7 1 5 – 2 4 Drug-Coated Balloons for Complex Femoral Lesions

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Schmidt et al. JACC Cardiovasc Interv 2016;9;715

Lesions >15cmMean lesion length 24cm65.3% occlusionsPrimary patency:

1 year= 79.2%2 years=53.7%

Mean length 26cm

Provisional StentLL 15-25 cm:LL > 25 cm:

40.4% (63/156)33.3% (33/99)52.6% (30/57)

Schneider CX 4/16

shows the overlap in propensity scores for the5 strata demonstrating the success of theprocedure in matching subjects. There wereno differences in patient age, male gender,cardiovascular risk factors, or concomitantdiseases, such as renal insufficiency or Ruth-erford classification (Table 1). The only signif-icant difference between both cohorts waslesion involvement at the middle and distalpopliteal artery segments in the DCB cohort,which was an exclusion criterion for the DEScohort. There were no significant differencesin the degree of calcification or the percentageof subintimal recanalization procedures.

Procedure Outcomes

In the DCB cohort, 100 (76.3%) of the 131lesions were predilated, and provisional stentplacement was performed in 24 (18.3%)lesions for refractory stenosis (5, 3.8%), flow-limiting dissection (13, 9.9%), and otherreasons (6, 4.6%). There was no procedure-related mortality in either cohort. The binaryrestenosis rates were 23.9% (26/109) and30.4% (24/79, p¼0.319) in the DCB and DEScohorts, respectively; the clinically driven TLRrates were 15.6% (17/109) vs. 19.0% (15/79,p¼0.543), respectively.

Estimates for freedom from clinically drivenTLR (Fig. 2A) and event-free survival (Fig. 2B)were not different between the study cohorts.Stratification of TLR and event-free survival toDCB only, DCB with provisional stenting, andDES (Fig. 3) showed a trend toward betteroutcome for the DCB plus provisional stentcohort; however, the differences were notstatistically significant. No differences werefound in major adverse events at 1 year (Table3).

ABI at baseline was similar in both cohorts,and there was a significant increase in bothstudy cohorts without significant between-group differences at every follow-up (Table 2).It is worth noting that while most of the DESpatients were part of clinical trials and conse-quently subject to systematic follow-up at 1year, most of those from the DCB patientswere part of standard clinical practice. Thus,the DCB patients were more likely to have a12-month examination if PAD symptoms werepresent regardless of whether they were

related to the target lesion. Data from theDCB arm are therefore more sparse and likelyrepresentative of the worst portion of the fullDCB cohort.

DISCUSSION

Currently in the literature there are manyadvances in endovascular management ofTASC II type C/D femoropopliteal lesions, butstill, no published study has demonstrated thesuperiority of endovascular techniques oversurgical management. Thus, endovascular in-

Figure 2 ^ (A) Freedom from clinically driventarget lesion revascularization (TLR) (p¼0.632) and(B) event-free survival for the drug-coated balloon(DCB) vs. drug-eluting stent (DES) cohorts(p¼0.769).

J ENDOVASC THER DCB VS. DES IN FEMOROPOPLITEAL LESIONS 3632014;21:359–368 Zeller et al.

Zeller et al. J Endovasc Ther 2014;21;359

Mean lesion length 19cm53% occlusionsPrimary patency at 1 year:

DCB= 76.1%DES= 69.6%

Zilver PTX

IN. PACT

Schmidt et al. JACC Cardiovasc Interv 2016;9;715


PTAStentStent-graft

DESDCBAtherectomy

Lesion length (cm)

12-m

onth

Prim

ary

Pate

ncy

RegistriesIN.PACT GlobalLeipzigBad KrozingenItalyDefinitive LESuperb

Woven nitinol

DCB/DES for Longer Lesions

Drug Coated Balloons and Drug Eluting StentsFemoral-popliteal Disease

Total IN.PACT All-Subjects: Long Lesion SubgroupFreedom From CD-TLR through 12 months

DCB for Long Lesions

TASC D20-30 cm >30 cm

Lesion Length 25.24±2.96 34.75±4.17

Occluded Lesion 70.0% (142/203) 76.9% (70/91)

Provisional Stent 37.1% (75/202) 50.5% (46/91)

Schneider LINC 2019


DCB paradigm vs DES paradigm

DCB§ Dependent upon vessel prep§ No geographic miss§ How much scaffolding?§ Long lesions and occlusions§ Total paclitaxel dose

DES§ Stent entire lesion§ More severe morphologies§ Stent across healthier

segments§ In-stent restenosis

SFA Disease 2019

SFA LesionCFA diseasePop-trifur disEndo failureReally bad runoff

OpenSurgeryor hybrid

TASC C/D/D+++

Aggressive vessel prepDCB with focaldissection repair

TASC A/B

Good resultDCB with focaldissection repairas needed

Bad resultDES


Mortality Rates From Trials of SFA Therapy

All-Cause Death at 2 Years

Laird J, et al. J Am Coll Cardiol 2015: 66; 2329-38IN.PACT Japan Presented by Iida, O. LINC 2018, Leipzig GermanyIN.PACT Global Micari A, et al. J Am Coll Cardiol –Cardiovasc Interv 2018: 11; 945-53LEVANT 1 Scheinert D, et al. J Am Coll Cardiol - Cardiovasc Interv 2014: 7; 10-19LEVANT 2 Lutonix IFUILLUMENATE US Presented by Mathews S, NCVH 2018, New Orleans, USAILLUMENATE EU Presented by Schroder H, CIRSE 2017, Copenhagen, DenmarkACOART-I Presented by Guo W, LINC 2017, Leipzig, GermanyCONSEQUENT Albrecht T, et al. Cardiovasc Intervent Radiol 2018: 41; 1008-14

ZILVER PTX Dake M, et al. J Am Coll Cardiol 2013: 61; 2417-27Majestic Muller-Hulsbeck S, et al. Cardiovasc Interv Radiol 2017:40;1832-1838SMART SES and BMS Duda et al. J Endovasc Ther 2006: 14; 701-710Complete SE SFA Data on file. Medtronic, Inc.Durability II Rocha-Singh K, et al. Cather Cardiovasc Interv 2015 : 86; 164-170ETAP BMS Rastan A, et al. J Endovasc Ther 2015: 22; 22-27RESILIENT BMS LifeStent IFU. Revised 2/04-16.Dashed Line: Caro J, Migliaccio-Walle K, Ishak KJ and Proskorovsky I. BMC Cardiovasc Disord. 2005;5:14.

Risk of Death Following Application of Paclitaxel-Coated Balloons andStents in the Femoropopliteal Artery of the Leg: A Systematic Reviewand Meta-Analysis of Randomized Controlled TrialsKonstantinos Katsanos, MD, PhD, MSc, EBIR; Stavros Spiliopoulos, MD, PhD; Panagiotis Kitrou, MD, PhD; Miltiadis Krokidis, MD, PhD;Dimitrios Karnabatidis, MD, PhD

Background-—Several randomized controlled trials (RCTs) have already shown that paclitaxel-coated balloons andstents significantly reduce the rates of vessel restenosis and target lesion revascularization after lower extremityinterventions.

Methods and Results-—A systematic review and meta-analysis of RCTs investigating paclitaxel-coated devices in the femoral and/or popliteal arteries was performed. The primary safety measure was all-cause patient death. Risk ratios and risk differences werepooled with a random effects model. In all, 28 RCTs with 4663 patients (89% intermittent claudication) were analyzed. All-causepatient death at 1 year (28 RCTs with 4432 cases) was similar between paclitaxel-coated devices and control arms (2.3% versus2.3% crude risk of death; risk ratio, 1.08; 95% CI, 0.72–1.61). All-cause death at 2 years (12 RCTs with 2316 cases) wassignificantly increased in the case of paclitaxel versus control (7.2% versus 3.8% crude risk of death; risk ratio, 1.68; 95% CI, 1.15–2.47; —number-needed-to-harm, 29 patients [95% CI, 19–59]). All-cause death up to 5 years (3 RCTs with 863 cases) increasedfurther in the case of paclitaxel (14.7% versus 8.1% crude risk of death; risk ratio, 1.93; 95% CI, 1.27–2.93; —number-needed-to-harm, 14 patients [95% CI, 9–32]). Meta-regression showed a significant relationship between exposure to paclitaxel (dose-timeproduct) and absolute risk of death (0.4!0.1% excess risk of death per paclitaxel mg-year; P<0.001). Trial sequential analysisexcluded false-positive findings with 99% certainty (2-sided a, 1.0%).

Conclusions-—There is increased risk of death following application of paclitaxel-coated balloons and stents in the femoropoplitealartery of the lower limbs. Further investigations are urgently warranted.

Clinical Trial Registration-—URL: www.crd.york.ac.uk/PROSPERO. Unique identifier: CRD42018099447. ( J Am Heart Assoc.2018;7:e011245. DOI: 10.1161/JAHA.118.011245.)

Key Words: balloon angioplasty • paclitaxel • paclitaxel-coated balloon • paclitaxel-eluting stent

T o date, percutaneous transluminal angioplasty andstenting have developed to the mainstream treatment

of symptomatic peripheral arterial disease with constantlyincreasing numbers of procedures worldwide.1,2 The femor-opopliteal artery is the most common site of involvement inatherosclerosis of the lower limb and is typically characterizedby multilevel steno-occlusive disease, often complex calcifiedmorphology, and aggressive postangioplasty neointimal

hyperplasia associated with high rates of early vesselrestenosis and failure.3 Drug-eluting stents (DESs) and drug-coated balloons (DCBs) have been extensively investigated asa potential solution to inhibit vessel restenosis and improveclinical outcomes after endovascular revascularization of thefemoropopliteal artery.4

Following testing in numerous randomized controlled trials(RCTs) and various commercial coating formulations,

From the Patras University Hospital, Rion, Greece (K.K., P.K., D.K.); Attikon University Hospital, Athens, Greece (S.S.); Cambridge University Hospitals NHS FoundationTrust, Cambridge, UK (M.K.).

Accompanying Tables S1 through S4 and Figures S1 through S3 are available at https://www.ahajournals.org/doi/suppl/10.1161/JAHA.118.011245

Correspondence to: Konstantinos Katsanos, MD, PhD, MSc, EBIR, Department of Interventional Radiology, Patras University Hospital, Rion 26504, Greece. E-mail:[email protected]

Received October 20, 2018; accepted November 7, 2018.

ª 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley. This is an open access article under the terms of the Creative CommonsAttribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial, and no modifications or adaptations are made.

DOI: 10.1161/JAHA.118.011245 Journal of the American Heart Association 1

SYSTEMATIC REVIEW AND META-ANALYSIS

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JAHA 2018;7:e011245

risk of death) versus 27 deaths out of 334 cases in the control(8.1% crude risk of death) with a pooled risk ratio of 1.93 (95%CI, 1.27–2.93). Absolute risk difference was 7.2% (95% CI,3.1–11.3%) and NNH was 14 patients (95% CI, 9–32). Therewas no statistically significant heterogeneity between studies(P=0.92; Figure 3).

Sensitivity and Subgroup AnalysesThere was no visual asymmetry of the respective funnelplots to suggest publication bias at 1 year (Horbold-Eggertest, 0.27; P=0.66), 2 years (Horbold-Egger test, 0.47;P=0.55), or 4 to 5 years of follow-up (Horbold-Egger test,!0.43; P=0.11; Figure S3). We opted to report summaryestimates from a frequentist random effects model toaccount for conceptual and study design differences amongdifferent RCTs. The randomized studies included here tested

numerous designs of paclitaxel-coated devices with variabledrug dosages and different drug excipients in slightlydifferent patient populations. Hence, a different, but similartreatment effect was assumed as the basis for the randomeffects modeling.58 In addition, different methods of anal-yses (with or without continuity correction and Bayesianmethods) were employed to interrogate potential bias anduncertainty arising from meta-analysis of low event rates asrecommended elsewhere.59 Bayesian methods generallyincreased the size of treatment effect (Table S4). Thepooled point estimates remained consistent across sensi-tivity and subgroup analyses with some variation in themagnitude of effect size. There were also differences in theestimated long-term risk of death when examining differentpaclitaxel doses, although those results are underpowered,with variable follow-up periods, and informed by few studiesin each case (Table 2).

Figure 2. Random effects forest plot of all-cause death at 2 years. Pooled point estimate was expressed as risk ratio (RR).

Figure 3. Random effects forest plot of all-cause death at 4 to 5 years. Pooled point estimate was expressed as risk ratio (RR).

DOI: 10.1161/JAHA.118.011245 Journal of the American Heart Association 7

Deaths After Paclitaxel Interventions in the Leg Katsanos et al

SYST

EMATIC

REVIE

WAND

META-A

NALYSIS

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Coincidental, statistical aberration, real danger sign?

What is the mechanism?


Drug-eluting DevicesSome unique characteristics of these trials.

§ Powered for short-term patency, not long-term mortality.§ Small control groups (some RCTs 2:1).§ Expected attrition due to age and co-morbid factors.§ Missing data, censored patients not accounted.§ Assumptions about drug kinetics and doses.§ Not clear if valid to include DCB and DES in same analysis.§ Chance results (lowest mortality ever in RCT PTA group).§ No way to know who got paclitaxel (15% annual TLR rate).§ Ascertainment bias in assessment of mortality.

Clinic Visit Compliance After Treatment

PTA patients had more frequent follow-up

Schneider et al. JACC 2019


Dual Antiplatelet Therapy After Treatment

PTA patients more likely to continuedual antiplatelet therapy

Schneider et al. JACC 2019

Figure 1. Long-term Survival Following Femoropopliteal Artery Revascularization With Drug-Coated DevicesCompared With Non–Drug-Coated Devices

DES vs BMSC

40

30

20

10

0

Prob

abili

ty o

f Dea

th, %

0 60 120 180 240 300 360 420 480 540 600

Days From Procedure

DCB vs PTAB

No. at riskDCBPTA

27095796

24775203

23444893

22524663

21654496

18953993

14703254

10982563

7881858

4581111

132375

40

30

20

10

0

40

30

20

10

0

Prob

abili

ty o

f Dea

th, %

0 60 120 180 240 300 360 420 480 540 600

Days From Procedure

Log-rank P = .06

Drug vs nondrugA

No. at riskDrugNondrug

598910 571

55009517

51898955

49668560

47858237

42297321

33635935

25524610

18173337

10462016

298670

Prob

abili

ty o

f Dea

th, %

0 60 120 180 240 300 360 420 480 540 600

Days From Procedure

Log-rank P = .007

NondrugDrug

PTADCB

BMSDES

No. at riskDESBMS

25534775

23434314

22014062

20943897

20243741

17973328

14502681

11062047

7851479

453905

124295

Log-rank P = .56

Displayed are the cumulativeincidence curves for all-causemortality after femoropopliteal arteryrevascularization, stratified bytreatment with drug-coated devices(drug) vs non–drug-coated devices(nondrug) (A), drug-coated balloons(DCB) vs uncoated balloons (PTA)(B), and drug-eluting stents (DES)vs bare metal stents (BMS) (C).

Association of Survival With Femoropopliteal Artery Revascularization With Drug-Coated Devices Original Investigation Research

jamacardiology.com (Reprinted) JAMA Cardiology Published online February 12, 2019 E5

© 2019 American Medical Association. All rights reserved.

Downloaded from jamanetwork.com by Vanderbilt University user on 02/12/2019

16,560 patientsadmitted for FP revasc

Secemsky et al. JAMA Cardiol 2019; published online 2/12/19

DISCUSSION

Paclitaxel is a commonly-used cytotoxic agent origi-nally used in an intravenous application as achemotherapeutic to treat malignancies. The dosesfor administration range from a dose per body surfacearea of 135 to 175 mg/m2 in 3- or 24-h infusions. Thisresults in total dosage of the drug as a range of 236 to

306 mg for a 65-inch, 150-pound adult, or a range of302 to 392 mg for a 72-inch, 225-pound adult (14). Thenumber and schedule of these infusions varydepending on the malignancy and the patientresponse. The mean level of paclitaxel received bypatients from the DCB in this study by tercile wasapproximately 5.0 mg in the lower, 10.0 mg in themiddle, and 20.0 mg in the upper tercile.

print&

web4C=F

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CENTRAL ILLUSTRATION Kaplan-Meier Freedom From All-Cause Death by Paclitaxel Dose inAll DCB Patients

95%

90%

85%

100%

80%

10%

0%0 4836

Time After Index Procedure (Months)

Free

dom

from

All-

Caus

e De

ath

2412 60

Number at risk

696 90485526634 49526 62373407468 29614 8440501558 3

Adjusted p-value* = 0.731*p-value was from frailty model with study as random effect and IPTW adjusted

88.2%

85.8%

84.2%

DCB Lower Tercile DCB Mid Tercile DCB Upper Tercile

Paclitaxel Dose

DCB Lower Tercile

DCB Mid Tercile

DCB Upper Tercile

Distribution of Paclitaxel Dose in Each Paclitaxel Tercile in DCBN

696

526

614

Mean µg

5019.0

10007.5

19978.2

Std µg

1508.6

1757.7

6122.1

Median µg

4752.0

9504.0

18654.0

Q1, Q3 µg

3653, 6924

8448, 11618

15399, 22705

Range µg

1850, 6951

6989, 13822

13902, 61949

Schneider, P.A. et al. J Am Coll Cardiol. 2019;-(-):-–-.

Kaplan-Meier estimates of survival are stratified by nominal paclitaxel dosage terciles with all patient-level DCB data available through5 years. DCB ¼ drug-coated balloon; IPTW ¼ inverse probability of treatment weighting.

Schneider et al. J A C C V O L . - , N O . - , 2 0 1 9

Drug-Coated Balloon: Mortality Not Correlated to Paclitaxel - , 2 0 1 9 :- –-

8

FLA 5.5.0 DTD ! JAC25877_proof ! 2 April 2019 ! 3:56 am ! ce

1837 DCB patients

No difference in mortality


Patient-Level Meta-Analysis Key Differences from JAHA Meta-analysis

JAHA

24

Drug Coated Balloons-2019Conclusion

§ On the ground- Patients must be informed, Paclitaxel as secondary treatment, Trials?

Physicians and institutions decide with FDA guidance§ 30,000 foot view- DCB a major advance more restenosis, Future of paclitaxel? Patient-

level meta-analysis, Time frame at least 1 year, May not be resolved, Thousands of patients will receive less efficacious treatment.

§ 50,000 foot view- Likely to wipe out dozens of vascular start ups, R&D funding?,

vascular clinical trial research in limbo, class action in PAD space?, stimulate search for other anti-restenotic compounds?

Documents

33 SchneiderUCSF 4-19 DCB 4-19 … · University of California, San Francisco DCB-what is the appropriate role in the management of fem-pop disease in 2019? DISCLOSURE Peter A. Schneider