Paclitaxel-Coated Balloon vs Uncoated Balloon for Coronary In-Stent Restenosis: The AGENT IDE Randomized Clinical Trial

Robert W Yeh; Richard Shlofmitz; Jeffrey Moses; William Bachinsky; Suhail Dohad; Steven Rudick; Robert Stoler; Brian K Jefferson; William Nicholson; John Altman; Cinthia Bateman; Amar Krishnaswamy; J Aaron Grantham; Frank J Zidar; Steven P Marso; Jennifer A Tremmel; Cindy Grines; Mustafa I Ahmed; Azeem Latib; Behnam Tehrani; J Dawn Abbott; Wayne Batchelor; Paul Underwood; Dominic J Allocco; Ajay J Kirtane

doi:10.1001/jama.2024.1361

. 2024 Mar 9;331(12):1015–1024. doi: 10.1001/jama.2024.1361

Paclitaxel-Coated Balloon vs Uncoated Balloon for Coronary In-Stent Restenosis

The AGENT IDE Randomized Clinical Trial

Robert W Yeh ^1,^✉, Richard Shlofmitz ², Jeffrey Moses ³, William Bachinsky ⁴, Suhail Dohad ⁵, Steven Rudick ⁶, Robert Stoler ⁷, Brian K Jefferson ⁸, William Nicholson ⁹, John Altman ¹⁰, Cinthia Bateman ¹¹, Amar Krishnaswamy ¹², J Aaron Grantham ¹³, Frank J Zidar ¹⁴, Steven P Marso ¹⁵, Jennifer A Tremmel ¹⁶, Cindy Grines ¹⁷, Mustafa I Ahmed ¹⁸, Azeem Latib ¹⁹, Behnam Tehrani ²⁰, J Dawn Abbott ²¹, Wayne Batchelor ²⁰, Paul Underwood ²², Dominic J Allocco ²², Ajay J Kirtane ³, for the AGENT IDE Investigators

¹Beth Israel Deaconess Medical Center, Boston, Massachusetts

²St Francis Hospital, Roslyn, New York

³Columbia University Irving Medical Center/NewYork-Presbyterian Hospital and the Cardiovascular Research Foundation, New York

⁴University of Pittsburgh Medical Center, Harrisburg, Pennsylvania

⁵Cedars Sinai Medical Center, Los Angeles, California

⁶Lindner Center for Research and Education at Christ Hospital, Cincinnati, Ohio

⁷Baylor Scott & White Heart and Vascular Hospital, Dallas, Texas

⁸HCA Tristar Centennial Medical Center, Nashville, Tennessee

⁹Emory University Hospital, Atlanta, Georgia

¹⁰St Anthony Hospital, Denver, Colorado

¹¹South Denver Cardiology, Littleton, Colorado

¹²Cleveland Clinic Foundation, Cleveland, Ohio

¹³St Luke’s Hospital of Kansas City, Kansas City, Missouri

¹⁴Austin Heart, Austin, Texas

¹⁵Overland Park Regional Medical Center, Overland Park, Kansas

¹⁶Stanford University Medical Center, Stanford, California

¹⁷Northside Hospital Cardiovascular Institute, Atlanta, Georgia

¹⁸University of Alabama at Birmingham

¹⁹Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York

²⁰The Inova Schar Heart and Vascular Institute, Falls Church, Virginia

²¹Lifespan Cardiovascular Institute, Rhode Island Hospital, Providence

²²Boston Scientific Corp, Marlborough, Massachusetts

Group Information: The AGENT IDE Investigators appear in Supplement 3.

Accepted for Publication: January 30, 2024.

Published Online: March 9, 2024. doi:10.1001/jama.2024.1361

^✉

Corresponding Author: Robert W. Yeh, MD, MSc, Richard and Susan Smith Center for Outcomes Research, Beth Israel Deaconess Medical Center, 375 Longwood Ave, Fourth Floor, Boston, MA 02215 (ryeh@bidmc.harvard.edu).

Author Contributions: Drs Yeh and Kirtane had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Yeh, Bachinsky, Dohad, Stoler, Tremmel, Latib, Underwood, Allocco, Kirtane.

Acquisition, analysis, or interpretation of data: Shlofmitz, Moses, Bachinsky, Dohad, Rudick, Stoler, Jefferson, Nicholson, Altman, Bateman, Krishnaswamy, Grantham, Zidar, Marso, Tremmel, Grines, Ahmed, Latib, Tehrani, Abbott, Batchelor, Underwood, Allocco, Kirtane.

Drafting of the manuscript: Yeh, Bachinsky, Dohad, Stoler, Zidar, Underwood, Kirtane.

Critical review of the manuscript for important intellectual content: All authors.

Statistical analysis: Bachinsky.

Administrative, technical, or material support: Dohad, Stoler, Altman, Ahmed, Tehrani, Underwood.

Supervision: Yeh, Shlofmitz, Stoler, Ahmed, Latib, Underwood, Allocco.

Other–editing: Grines.

Other–trial steering committee and patient enrollment: Abbott.

Other–medical monitor: Underwood.

Conflict of Interest Disclosures: Dr Yeh reported receiving personal fees and grants from Boston Scientific during the conduct of the study; as well as grants and personal fees from Boston Scientific, Abbott Vascular, and Medtronic and personal fees from the US Food and Drug Administration, Elixir Medical, Shockwave Medical, and Infraredx outside the submitted work. Dr Shlofmitz reported receiving personal fees from Shockwave Medical outside the submitted work. Dr Moses reported receiving nonfinancial support from Orchestra BioMed outside the submitted work. Dr Bachinsky reported serving on the advisory board and his institution receiving funds from Abbott Vascular, Bard, Metavention, Medtronic, and Boston Scientific during the conduct of the study and his institution receiving funds from Abbott Vascular, Bard, Metavention, Medtronic, and Boston Scientific outside the submitted work. Dr Dohad reported receiving personal fees from Boston Scientific during the conduct of the study; and personal fees from Abbott Vascular and Penumbra outside the submitted work. Dr Stoler reported receiving personal fees from Boston Scientific, Medtronic, and Biotronik during the conduct of the study and personal fees from Edwards Lifesciences outside the submitted work. Dr Jefferson reported receiving personal fees from Boston Scientific during the conduct of the study; and personal fees from Shockwave Medical and Medtronic outside the submitted work. Dr Bateman reported receiving personal fees from Boston Scientific and Shockwave Medical during the conduct of the study and personal fees from Boston Scientific and Shockwave Medical outside the submitted work. Dr Grantham reported receiving personal fees from Boston Scientific, Teleflex, Shockwave Medical, Asahi Intecc, and Medtronic and grants from Boston Scientific, Asahi Intecc, and Abiomed outside the submitted work. Dr Zidar reported receiving personal fees from Abbott Vascular and Medtronic outside the submitted work. Dr Tremmel reported receiving research support from Boston Scientific during the conduct of the study; and personal fees from Abbott Vascular, Shockwave Medical, Avinger, and Boston Scientific outside the submitted work. Dr Ahmed reported serving on the advisory board for Medtronic and Boston Scientific. Dr Latib reported receiving personal fees from Medtronic, Abbott, Boston Scientific, Philips, and ANT and serving as a study principal investigator for Concept Medical outside the submitted work. Dr Abbott reported receiving grants from Boston Scientific during the conduct of the study; and grants from MED Alliance and Shockwave Medical and personal fees from Penumbra, Medtronic, Abbott, and the RECORD Trial outside the submitted work. Dr Batchelor reported receiving grants from Boston Scientific (independent investigator-initiated research grant) outside the submitted work and serving as a consultant for Boston Scientific, Edwards Lifesciences, Abbott, and Medtronic. Dr Underwood reported being an employee of Boston Scientific Corp. Dr Allocco reported being a full-time employee and stockholder of Boston Scientific Corp. Dr Kirtane reported receiving grants from Boston Scientific consisting of institutional funding to Columbia University and/or Cardiovascular Research Foundation. In addition to research grants, institutional funding includes fees paid to Columbia University and/or Cardiovascular Research Foundation for consulting and/or speaking engagements in which Dr Kirtane controlled the content. Dr Kirtane reported receiving travel expenses/meals from Boston Scientific during the conduct of the study; and institutional funding to Columbia University and/or Cardiovascular Research Foundation from Medtronic, Boston Scientific, Abbott Vascular, Amgen, CathWorks, CSI, Philips, ReCor Medical, Neurotronic, Biotronik, Chiesi, Bolt Medical, Magenta Medical, Canon, SoniVie, and Shockwave Medical. Additionally, Dr Kirtane reported receiving travel expenses and meals from Amgen, Medtronic, Biotronik, Boston Scientific, Abbott Vascular, CathWorks, Concept Medical, Edwards, CSI, Novartis, Philips, Abiomed, ReCor Medical, Chiesi, Zoll, Shockwave Medical, and Regeneron. No other disclosures were reported.

Funding/Support: This study was supported by Boston Scientific Corp. Quantitative coronary angiography was conducted by Baim Institute for Clinical Research Inc, an independent angiographic core laboratory.

Role of the Funder/Sponsor: Boston Scientific was involved in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Statistical analyses and data validation were performed by an independent contract research organization.

Group Information: The list of AGENT IDE Investigators appears in Supplement 3.

Meeting Presentation: This paper was presented at the CRT24 Meeting of Cardiovascular Research Technologies; March 9, 2024; Washington, DC.

Data Sharing Statement: See Supplement 4.

Additional Contributions: We thank Pooja Bhatt, PhD, and Shannon Song, MSc (both of Boston Scientific Corp), for assistance in manuscript preparation and statistical analysis, respectively.

^✉

Corresponding author.

PMCID: PMC10924708 PMID: 38460161

Key Points

Question

Is treatment with a coronary paclitaxel-coated balloon superior to an uncoated balloon for 1-year target lesion failure in patients undergoing percutaneous coronary intervention for in-stent restenosis?

Findings

In a multicenter randomized trial of 600 patients designed to support US regulatory approval, target lesion failure was significantly lower in the paclitaxel-coated balloon group (17.9%) compared with the uncoated balloon group (28.6%) (P = .003). Ischemia-driven target lesion revascularization and target vessel myocardial infarction were also lower after treatment with a paclitaxel-coated balloon.

Meaning

Treatment with a paclitaxel-coated balloon offers an effective treatment strategy for the management of coronary in-stent restenosis.

Abstract

Importance

Drug-coated balloons offer a potentially beneficial treatment strategy for the management of coronary in-stent restenosis. However, none have been previously evaluated or approved for use in coronary circulation in the United States.

Objective

To evaluate whether a paclitaxel-coated balloon is superior to an uncoated balloon in patients with in-stent restenosis undergoing percutaneous coronary intervention.

Design, Setting, and Participants

AGENT IDE, a multicenter randomized clinical trial, enrolled 600 patients with in-stent restenosis (lesion length <26 mm and reference vessel diameter >2.0 mm to ≤4.0 mm) at 40 centers across the United States between May 2021 and August 2022. One-year clinical follow-up was completed on October 2, 2023.

Interventions

Participants were randomized in a 2:1 allocation to undergo treatment with a paclitaxel-coated (n = 406) or an uncoated (n = 194) balloon.

Main Outcomes and Measures

The primary end point of 1-year target lesion failure—defined as the composite of ischemia-driven target lesion revascularization, target vessel–related myocardial infarction, or cardiac death—was tested for superiority.

Results

Among 600 randomized patients (mean age, 68 years; 157 females [26.2%]; 42 Black [7%], 35 Hispanic [6%] individuals), 574 (95.7%) completed 1-year follow-up. The primary end point at 1 year occurred in 17.9% in the paclitaxel-coated balloon group vs 28.6% in the uncoated balloon group, meeting the criteria for superiority (hazard ratio [HR], 0.59 [95% CI, 0.42-0.84]; 2-sided P = .003). Target lesion revascularization (13.0% vs 24.7%; HR, 0.50 [95% CI, 0.34-0.74]; P = .001) and target vessel–related myocardial infarction (5.8% vs 11.1%; HR, 0.51 [95% CI, 0.28-0.92]; P = .02) occurred less frequently among patients treated with paclitaxel-coated balloon. The rate of cardiac death was 2.9% vs 1.6% (HR, 1.75 [95% CI, 0.49-6.28]; P = .38) in the coated vs uncoated balloon groups, respectively.

Conclusions and Relevance

Among patients undergoing coronary angioplasty for in-stent restenosis, a paclitaxel-coated balloon was superior to an uncoated balloon with respect to the composite end point of target lesion failure. Paclitaxel-coated balloons are an effective treatment option for patients with coronary in-stent restenosis.

Trial Registration

ClinicalTrials.gov Identifier: NCT04647253

This clinical trial compares a paclitaxel-coated balloon vs an uncoated balloon in patients with in-stent restenosis undergoing percutaneous coronary intervention.

Introduction

Millions of individuals undergo percutaneous coronary intervention worldwide each year, with most receiving treatment with 1 or more drug-eluting stents.^1,2 Despite improvements in drug-eluting stent technology that have led to a decreased risk of in-stent restenosis, neointimal hyperplasia and neoatherosclerosis³ still occur within drug-eluting stents, leading to the recurrence of chronic and acute coronary syndromes and necessitating further revascularization procedures when symptoms recur. The incidence of in-stent restenosis is encountered frequently in the United States, occurring in approximately 5% to 10% of patients undergoing percutaneous coronary intervention with drug-eluting stents in the first year.⁴

Current treatment of coronary in-stent restenosis in the United States commonly involves angioplasty followed by the placement of additional drug-eluting stents, which have been demonstrated to be superior to balloon angioplasty and vascular brachytherapy in reducing subsequent restenosis.^5,6,7,8,9 Drug-coated balloons, designed to administer antiproliferative agents to coronary lesions without the use of a metallic stent, were developed as an alternative treatment for coronary artery disease, and specifically for in-stent restenosis, where the introduction of additional layers of stent that further reduce lumen area may be undesirable. While drug-coated balloons currently have a class IA recommendation for the treatment of coronary restenosis in European guidelines,¹⁰ prior randomized trials evaluating their use have had small sample sizes,^{5,11,12,13,14} and none have been conducted in the United States. Consequently, no drug-coated balloons are currently approved in the United States for use in coronary arteries.

The AGENT IDE trial is a multicenter randomized trial conducted to evaluate the treatment of coronary in-stent restenosis by coronary angioplasty using a paclitaxel-coated balloon vs an uncoated balloon.

Methods

Study Design and Oversight

The AGENT IDE (A Clinical Trial to Assess the Agent Paclitaxel Coated PTCA Balloon Catheter for the Treatment of Subjects With In-Stent Restenosis) trial is a multicenter, single-blind, randomized controlled, superiority trial comparing angioplasty with the AGENT paclitaxel-coated balloon (Boston Scientific Corp) vs an uncoated balloon in patients with coronary in-stent restenosis.¹⁵ The trial was designed and conducted in consultation with the Food and Drug Administration to support a premarket application for the AGENT drug-coated balloon in the United States and was sponsored and funded by Boston Scientific Corp. The protocol (available in Supplement 1) was approved by the institutional review boards for each site. The trial was performed in accordance with the principles of the Declaration of Helsinki, and the study design adhered to the CONSORT 2010 Statement for randomized clinical trials. An independent steering committee and data and safety monitoring committee oversaw trial progress; an independent clinical events committee adjudicated key clinical outcomes.

Patient Selection

Patients were eligible for enrollment if they had in-stent restenosis with visually estimated reference vessel diameter greater than 2.0 mm to up to 4.0 mm and length less than 26 mm, and had target lesion stenosis of less than 100% but greater than 50% (in symptomatic patients) or greater than 70% (in asymptomatic patients). Key exclusion criteria included recent ST-elevation or Q-wave myocardial infarction, unprotected left main disease, saphenous vein or arterial graft disease, left ventricular ejection fraction less than 25%, or thrombus in the target vessel. All patients provided signed written informed consent. Additional inclusion and exclusion criteria are provided in eTables 3 and 4 in Supplement 2. Race and ethnicity were evaluated to assess the generalizability of the enrolled study population to real-world practice, and were collected using self-reporting or self-identification based on fixed categories.

Randomization and Treatment

Patients who satisfied the study selection criteria and underwent successful predilation of the target lesion were randomized in a 2:1 ratio to receive either the paclitaxel-coated balloon or an uncoated balloon (Figure 1). Successful predilation was defined as dilation with a balloon catheter of appropriate length and diameter, or pretreatment with directional or rotational coronary atherectomy, laser, or cutting/scoring balloon with no greater than 50% residual stenosis and no dissection greater than National Heart, Lung, and Blood Institute type C. Randomization was stratified by center and whether the target lesion had a single layer vs multiple stent layers of prior stents. Only 1 target lesion was eligible for randomization for each patient. A single nontarget lesion in a nontarget vessel could undergo percutaneous coronary intervention as determined by the operator prior to randomization. Patients, core laboratory personnel, and the clinical events committee remained blinded to the assigned treatment. Operators were not blinded to treatment due to the different packaging of the paclitaxel-coated vs uncoated balloons. The biostatistician remained blinded until analysis of the primary end point.

Figure 1. — ^aPatients assessed for eligibility were those with suspected in-stent restenosis who provide informed consent to participate in the trial.

^bPatients did not meet additional angiographic criteria listed in eTables 3 and 4 in Supplement 2.

^cNo additional information available.

Dual antiplatelet therapy with aspirin and a P2Y12 inhibitor was prescribed for at least 1 month post procedure regardless of the randomized assignment. Antiplatelet monotherapy was continued thereafter for the duration of the study.

Clinical Follow-Up and Outcomes

Clinical follow-up was performed in hospital at 30 days, 6 months, and 12 months and will continue through 5 years. The primary end point was the rate of 12-month target lesion failure, defined as the composite occurrence of ischemia-driven target lesion revascularization, target vessel–related myocardial infarction, or cardiac death. Periprocedural myocardial infarction occurring within 48 hours of the index procedure was adjudicated by the Society for Cardiovascular Angiography and Interventions definition,¹⁶ and spontaneous myocardial infarction occurring 48 hours after the index procedure was adjudicated according to the fourth universal definition of myocardial infarction.¹⁷ Additional prespecified end points were individual components of the primary end point, all-cause death, target vessel revascularization, target vessel failure (defined as the composite of ischemia-driven target vessel revascularization), myocardial infarction related to the target vessel or cardiac death, and stent thrombosis (as defined by the Academic Research Consortium).¹⁸ Periprocedural end points included the rates of technical and procedural success. Health status was measured using the EuroQol-5 Dimension Questionnaire scores.¹⁹ The definitions of all outcome measures are provided in the study protocol (Supplement 1).

Statistical Analysis

This study used an adaptive group sequential design²⁰ with an initial planned enrollment of 480 patients and 1 formal interim analysis on the 1-year data after randomization of the first 90% of patients, with the expectation that the first 40% of randomized patients would have 1-year follow-up at that time (details provided in Supplement 1). With a sample size of 480 patients, the study had 85% power to demonstrate superiority (1-sided P < .025) of the paclitaxel-coated balloon over the uncoated balloon, assuming respective event rates of 10.6% and 21.2%, with an expected attrition rate of 3%.¹⁵ Given uncertainty in the accuracy of these estimated event rates, the interim analysis was prespecified to be performed by the data and safety monitoring committee for potential sample size re-estimation of up to 600 patients.¹⁵ Due to rapid enrollment in the trial, no patients had completed 1-year follow-up at the time of the planned interim analysis, and therefore the data and safety monitoring committee recommended to continue enrollment to the maximum of 600 patients. The trial enrolled 600 patients at 40 centers in the United States between May 2021 and August 2022; 1-year clinical follow-up was completed on October 2, 2023. However, to determine final sample size for the primary end point analysis, the Food and Drug Administration proposed that the data and safety monitoring committee perform an interim analysis on the first 40% of patients (n = 192) with 1-year data when those data were available using the prespecified adaptive design strategy. Based on this analysis conducted on April 18, 2023, the data and safety monitoring committee recommended conducting the primary end point analysis on the first 480 patients, consistent with the original adaptive design strategy for the trial. These analyses can be found in eTable 7 in Supplement 2). The results for the full 600-patient cohort are presented within this article.

The primary analysis was performed in the intention-to-treat population irrespective of whether the assigned treatment was received. Continuous variables are presented as means (SDs) and differences between groups tested with the t test. Discrete variables are reported as percentages and counts, and differences between groups were assessed by the χ² or Fisher exact test, as appropriate. A z test with unpooled variance for the difference of 2 proportions was used to test the primary end point hypothesis of superiority of paclitaxel-coated balloon over the uncoated balloon. Differences in the rates of the primary end point and additional prespecified outcomes are reported using survival methodology as cumulative incidence rates and associated hazard ratios (HRs) with 95% CIs. Prespecified subgroup analyses of the primary outcome were analyzed using Cox regression models that included subgroup by treatment group interaction terms. All statistical analyses were performed using SAS version 9.4 or later (SAS Institute Inc).

Results

Patients and Enrollment

A total of 600 patients were randomly assigned to treatment with the paclitaxel-coated balloon (406 patients) vs uncoated balloon (194 patients). After randomization, 16 patients were lost to follow-up, 9 withdrew consent for participation, and 1 was excluded due to investigator discretion (Figure 1). The 1-year primary analysis included data from 600 randomized patients (Figure 1). Baseline characteristics were well balanced between the groups (Table 1). The mean age of patients was 68 years, and 26.2% patients were female. The patients had high rates of coronary risk factors including a 50.7% prevalence of diabetes. Coronary artery disease was extensive, with 78.9% having a history of multivessel coronary artery disease and 30.1% with a history of coronary artery bypass grafting. The index clinical presentation was non–ST-elevation acute coronary syndrome in 37.0% of patients.

Table 1. Baseline Clinical and Lesion Characteristics of the Patients^a.

Clinical characteristic	Paclitaxel-coated balloon (n = 406)	Uncoated balloon (n = 194)
Age, mean (SD), y	68.4 (9.8)	67.9 (9.7)
Sex
Male	302 (74.4)	141 (72.7)
Female	104 (25.6)	53 (27.3)
Race and ethnicity^b
American Indian or Alaska Native	0	1 (0.5)
Asian	9 (2.2)	6 (3.1)
Black, of African heritage	32 (7.9)	10 (5.2)
Hispanic or Latino	26 (6.4)	9 (4.6)
Native Hawaiian or Other Pacific Islander	1 (0.2)	1 (0.5)
White	304 (74.9)	148 (76.3)
Not disclosed	23 (5.7)	18 (9.3)
Other^c	16 (3.9)	3 (1.5)
Body mass index, mean (SD) [No.]^d	30.0 (5.5) [396]	30.1 (5.9) [191]
Currently smokes	42/406 (10.3)	19/194 (9.8)
Medical history
Hypertension	383/405 (94.6)	186/194 (95.9)
Hyperlipidemia	382/404 (94.6)	184/194 (94.8)
Multivessel coronary artery disease	317/400 (79.3)	149/190 (78.4)
Current diabetes	206/404 (51.0)	97/194 (50.0)
Myocardial infarction	198/398 (49.7)	95/190 (50.0)
Coronary artery bypass graft surgery	124/403 (30.8)	55/192 (28.6)
Insulin-treated diabetes	93/404 (23.0)	49/194 (25.3)
Congestive heart failure	92/401 (22.9)	41/192 (21.4)
Left main coronary artery disease	89/394 (22.6)	39/188 (20.7)
Peripheral vascular disease	78/401 (19.5)	31/192 (16.1)
Kidney disease	74/402 (18.4)	32/193 (16.6)
Transient ischemic attack or cerebrovascular accident	57/402 (14.2)	19/194 (9.8)
Indication for procedure
Stable angina	225 (55.4)	100 (51.5)
Non–ST-elevation acute coronary syndrome	149 (36.7)	73 (37.6)
Silent ischemia	7 (1.7)	5 (2.6)
Other indication^e	25 (6.2)	16 (8.2)
Lesion characteristics^f
Stent layer in target lesion^g
Single	230 (56.7)	112 (57.7)
Multiple	176 (43.3)	82 (42.3)
Target lesion vessel
Right coronary artery	156 (38.4)	69 (35.6)
Left anterior descending artery	141 (34.7)	69 (35.6)
Left circumflex artery	98 (24.1)	47 (24.2)
Left main coronary artery	11 (2.7)	9 (4.6)
Lesion length, mean (SD), mm [No.]	12.8 (6.3) [404]	11.8 (6.6) [188]
Reference vessel diameter, mean (SD), mm [No.]	2.7 (0.5) [405]	2.7 (0.5) [192]
In-lesion minimum lumen diameter, mean (SD), mm [No.]	1.0 (0.4) [405]	0.9 (0.4) [191]
In-lesion diameter stenosis, mean (SD), % [No.]	65.0 (12.1) [405]	66.4 (12.8) [191]
Mehran in-stent restenosis pattern^h
1A (Articulation)	0/403	0/189
1B (Margin)	4/403 (1.0)	2/189 (1.1)
1C (Focal)	148/403 (36.7)	84/189 (44.4)
1D (Multifocal)	3/403 (0.7)	2/189 (1.1)
2 (Diffuse intrastent)	230/403 (57.1)	89/189 (47.1)
3 (Diffuse proliferative)	16/403 (4.0)	9/189 (4.8)
4 (Total occlusion)	2/403 (0.5)	3/189 (1.6)
Thrombolysis In Myocardial Infarction grade flow
0 (Complete occlusion)	8/405 (2.0)	6/192 (3.1)
1 (Some flow)	2/405 (0.5)	3/192 (1.6)
2 (Partial flow)	21/405 (5.2)	8/192 (4.2)
3 (Normal flow)	374/405 (92.3)	175/192 (91.1)

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^{^a}

All entries are No. (%) or No./total (%) [when N differs from column No. due to missing values], unless otherwise noted.

^{^b}

Data on race and ethnicity were collected in a combined format using self-reporting or self-identification. A patient may be identified in multiple ethnicity and race categories. The category terms were those used during data collection.

^{^c}

No additional information provided as determined by the site.

^{^d}

Body mass index is the weight in kilograms divided by height in meters squared.

^{^e}

Indicated for procedure due to cardiac conditions other than stable angina, non–ST-elevation acute coronary syndrome, or silent ischemia.

^{^f}

Baseline lesion characteristics were quantified by the angiographic core laboratory.

^{^g}

Site-reported values.

^{^h}

Mehran in-stent restenosis pattern proposed by Mehran et al.²¹

Baseline lesion characteristics were relatively similar between the 2 groups (Table 1). Multiple-layer in-stent restenosis was present in 43.0% of patients. Angiographic core laboratory–reported mean reference vessel diameter was similar in both groups (2.7 mm), and mean lesion length was 12.8 mm and 11.8 mm in the paclitaxel-coated balloon and uncoated balloon groups, respectively. Prior to randomization, lesions were treated with a combination of conventional angioplasty techniques (eTable 5 in Supplement 2); intravascular imaging use was performed in 73.8% of patients and well-balanced between groups. Clinical procedural success (based on site assessment including estimated diameter stenosis <30%) was 92.1% in the paclitaxel-coated balloon group and 88.7% in the uncoated balloon group (P = .17). The rates of technical success were also similar (paclitaxel-coated balloon group: 93.4%, uncoated balloon group: 89.7%; P = .12). Three patients in the paclitaxel-coated balloon group and 1 patient in the uncoated balloon group received bailout stents. Most patients continued dual antiplatelet therapy through 12 months (eTable 6 in Supplement 2). Specifically, the respective treatment rates with dual antiplatelet therapy to 6 and 12 months were 85.7% and 79.6% for the paclitaxel-coated balloon group and 83.2% and 77.8% for the uncoated balloon group, with no significant differences between groups.

Primary End Point and Components

Kaplan-Meier estimates of the primary composite end point and individual components in the full trial population are shown in Figure 2. At 1 year, the incidence of the primary end point of target lesion failure occurred in 17.9% of patients in the paclitaxel-coated balloon group and 28.6% patients in the uncoated balloon group (HR, 0.59 [95% CI, 0.42-0.84]; 2-sided P = .003 for superiority). Results were similar after adjustment for stratification variables using Cox regression (eTable 8 in Supplement 2) as well as after considering the competing risk of noncardiac death (eTable 9 in Supplement 2). Target lesion revascularization occurred less frequently in the paclitaxel-coated balloon group (13.0% vs 24.7%; HR, 0.50 [95% CI, 0.34-0.74]; P = .001), as did myocardial infarction related to the target vessel (5.8% vs 11.1%; HR, 0.51 [95% CI, 0.28-0.92]; P = .02). There was no difference in the incidence of cardiac death between the groups (paclitaxel-coated balloon, 2.9% vs uncoated balloon, 1.6%; HR, 1.75 [95% CI, 0.49-6.28]; P = .38).

Additional Outcomes and Subgroup Analyses

There were no occurrences of definite or probable stent thrombosis at 1 year in the paclitaxel-coated balloon group, while 6 patients in the uncoated balloon group experienced definite or probable stent thrombosis (Table 2). Quality-of-life outcomes were similar between the 2 groups through 1 year of follow-up (eTable 10 in Supplement 2).

Table 2. Prespecified Clinical Outcomes Through 1 Year.

Clinical outcomes^a	No. %		Difference (95% CI), %	HR (95% CI)	Log-rank P value
Clinical outcomes^a	Paclitaxel-coated balloon (n = 406)	Uncoated balloon (n = 194)	Difference (95% CI), %	HR (95% CI)	Log-rank P value
Primary outcome
Target lesion failure^b	71 (17.9)	54 (28.6)	−10.7 (−18.2 to −3.2)	0.59 (0.42 to 0.84)	.003
Additional prespecified outcomes
Target lesion revascularization^c
Overall	51 (13.0)	46 (24.7)	−11.6 (−18.7 to −4.5)	0.50 (0.34 to 0.74)	.001
PCI	39 (10.0)	43 (22.8)	−12.9 (−19.6 to −6.1)	0.41 (0.26 to 0.63)	<.001
CABG	13 (3.3)	8 (4.5)	−1.2 (−4.8 to 2.4)	0.77 (0.32 to 1.86)	.56
Target vessel revascularization^c
Overall	56 (14.3)	49 (26.2)	−11.8 (−19.1 to −4.6)	0.51 (0.35 to 0.75)	.001
PCI	44 (11.3)	46 (24.4)	−13.1 (−20.0 to −6.2)	0.43 (0.28 to 0.64)	<.001
CABG	14 (3.6)	8 (4.5)	−0.9 (−4.5 to 2.7)	0.83 (0.35 to 1.98)	.68
Target vessel revascularization not in target lesion^c^,^d
Overall	20 (5.1)	13 (6.9)	−1.8 (−6.0 to 2.4)	0.72 (0.36 to 1.46)	.36
PCI	17 (4.3)	11 (5.8)	−1.5 (−5.3 to 2.4)	0.73 (0.34 to 1.55)	.41
CABG	4 (1.0)	3 (1.6)	−0.6 (−2.6 to 1.5)	0.64 (0.14 to 2.85)	.55
Target vessel failure^e	73 (18.4)	57 (30.1)	−11.7 (−19.3 to −4.1)	0.57 (0.40 to 0.81)	.001
Myocardial infarction	29 (7.5)	23 (12.1)	−4.7 (−10.0 to 0.7)	0.58 (0.34 to 1.01)	.05
Related to target vessel	23 (5.8)	21 (11.1)	−5.3 (−10.3 to −0.2)	0.51 (0.28 to 0.92)	.02
Q-wave myocardial infarction	1 (0.3)	1 (0.5)	−0.3 (−1.4 to 0.9)	0.48 (0.03 to 7.64)	.59
Related to target vessel	0	1 (0.5)	−0.5 (−1.5 to 0.5)	NA	.15
Non–Q-wave myocardial infarction	28 (7.2)	22 (11.6)	−4.4 (−9.7 to 0.9)	0.59 (0.34 to 1.03)	.06
Related to target vessel	23 (5.8)	20 (10.6)	−4.8 (−9.7 to 0.2)	0.54 (0.30 to 0.98)	.04
Related to target vessel-unknown^f	11 (2.8)	4 (2.2)	0.7 (−2.0 to 3.3)	1.32 (0.42 to 4.16)	.63
Not related to target vessel	5 (1.4)	2 (1.1)	0.4 (−1.5 to 2.3)	1.19 (0.23 to 6.12)	.84
All death^g	16 (4.1)	7 (3.7)	0.4 (−3.0 to 3.7)	1.09 (0.45 to 2.65)	.85
Cardiac	11 (2.9)	3 (1.6)	1.3 (−1.2 to 3.7)	1.75 (0.49 to 6.28)	.38
Noncardiac	5 (1.3)	4 (2.2)	−0.9 (−3.3 to 1.5)	0.60 (0.16 to 2.22)	.43
Stent thrombosis^g	1 (0.4)	7 (3.7)	−3.3 (−6.1 to −0.5)	0.07 (0.01 to 0.55)	.001
Definite or probable	0	6 (3.2)	−3.2 (−5.7 to −0.7)	NA	<.001
Definite	0	6 (3.2)	−3.2 (−5.7 to −0.7)	NA	<.001
Probable	0	0	0.0 (0.0 to 0.0)	NA	Undefined
Possible	1 (0.4)	1 (0.5)	−0.2 (−1.4 to 1.1)	0.48 (0.03 to 7.63)	.59

Open in a new tab

Abbreviations: CABG, coronary artery bypass graft surgery; HR, hazard ratio; NA, not available; PCI, percutaneous coronary intervention.

^{^a}

Rates of outcomes with their associated HRs and 95% CIs were calculated using survival methodology.

^{^b}

Defined as any ischemia-driven revascularization of the target lesion, myocardial infarction (Q-wave and non–Q-wave) related to the target vessel, or cardiac death. If it could not be determined with certainty whether the myocardial infarction was related to the target vessel, it was considered a target lesion failure.

^{^c}

The numbers may not equal the overall totals because patients could have multiple events.

^{^d}

Refers to lesions more than 5 mm from the stent borders, but within the same major coronary vessel.

^{^e}

Defined as any ischemia-driven revascularization of the target vessel, myocardial infarction (Q-wave and non–Q-wave) related to the target vessel, or cardiac death. If it could not be determined with certainty whether the myocardial infarction was related to the target vessel by the clinical events committee, it is considered a target vessel failure.

^{^f}

All unknown non–Q-wave myocardial infarction counted as related to target vessel.

^{^g}

As defined by the Academic Research Consortium.¹⁸

The results of the primary end point analyses in the prespecified subgroups are shown in Figure 3. The results were largely consistent across prespecified subgroups: the relative risk of target lesion failure was lower in patients treated with a paclitaxel-coated balloon than an uncoated balloon. Among patients with multiple stent layers, the rate of target lesion failure was 23.8% in the paclitaxel-coated balloon group and 40.0% in the uncoated balloon group (HR, 0.55 [95% CI, 0.34-0.87]; P = .009). Among patients with diabetes, the rates of target lesion failure were 21.6% in the paclitaxel-coated balloon group vs 29.2% in the uncoated balloon group (HR, 0.71 [95% CI, 0.43-1.17]; P = .18).

Discussion

This trial is the largest randomized clinical trial to date examining the efficacy and safety of a drug-coated balloon in patients with coronary in-stent restenosis, and the first trial of coronary drug-coated balloons to be conducted in the United States. Patients treated with a paclitaxel-coated balloon had a lower rate of target lesion failure, largely driven by a lower rate of ischemia-driven revascularization and target vessel myocardial infarction, compared with patients treated with an uncoated balloon.

Drug-coated balloons have emerged internationally as an alternative treatment option that may provide the benefits of localized drug delivery to reduce neointimal growth, while avoiding the placement of additional stent layers within existing stents. These devices have been approved internationally for use, principally on the basis of smaller randomized trials.^11,12,13,14 Paclitaxel-coated balloons were previously shown to reduce restenosis compared with balloon angioplasty among 52 patients randomized at 5 centers in Germany.¹¹ Additionally, the ISAR-DESIRE 3 trial that was conducted at 3 German sites demonstrated significantly reduced occurrence of repeat revascularization through 10 years of follow-up in patients treated with a paclitaxel-coated balloon (n = 137 patients) compared with an uncoated balloon (n = 134 patients).²²

Despite these promising international data, drug-coated balloons have not been previously evaluated or approved for use in the United States for various reasons, including the challenge and cost of conducting adequately powered randomized trials needed to support regulatory approval as well as significant improvements in drug-eluting stent technology. The introduction of drug-eluting stents represented an important breakthrough in device technology to limit the occurrence of in-stent restenosis, which previously occurred in 20% to 40% of patients treated with bare metal stents.²³ However, there has been growing recognition that despite these advances in stent technology, patients with coronary in-stent restenosis continue to comprise approximately 10% of individuals undergoing percutaneous coronary intervention each year and have poor long-term outcomes.^4,24 Due to the growing sentiment that drug-coated balloons could address an unmet clinical need among patients with coronary artery disease in the United States, the AGENT drug-coated balloon was designated as a Breakthrough Device by the Food and Drug Administration.

The AGENT drug-coated balloon catheter consists of a semicompliant balloon coated with a low-dose formation of paclitaxel and the excipient acetyl tri-n-butyl citrate that allows paclitaxel to be transferred to the vessel wall and dwell for an average of 90 days. The current trial randomized patients to treatment with either the paclitaxel-coated balloon or an uncoated balloon after successful angioplasty, with less than 50% residual stenosis and no significant coronary artery dissection. However, angioplasty without local administration of antiproliferative therapy can lead to localized neointimal hyperplasia that can result in coronary restenosis. In this trial, treatment with the paclitaxel-coated balloon lowered the rate of target lesion failure compared with an uncoated balloon, providing further evidence supporting the beneficial effects of localized drug delivery after angioplasty. In addition to a reduction in ischemia-driven target lesion revascularization, the rate of target vessel myocardial infarction at 1 year was 5.8% in the paclitaxel-coated balloon group compared with 11.1% in the uncoated balloon group, and no cases of definite or probable stent thrombosis occurred among the paclitaxel-coated balloon group compared with 6 cases (3.2%) within the uncoated balloon group. These data—in conjunction with the presentation with non–ST-elevation acute coronary syndrome in one-third of the enrolled cohort—support prior observations demonstrating that in-stent restenosis is not necessarily a benign or slowly progressive process.^4,25

More than 40% of the patients in this trial had multiple prior stents at the site of the target lesion, representing a patient group at very high risk for recurrent restenosis.²⁶ Rates of 1-year target lesion failure were nearly 2-fold greater in these patients compared with those who had previously had only a single layer of stent in the target lesion. Nevertheless, treatment with the paclitaxel-coated balloon in this high-risk group had a consistent relative risk reduction and numerically greater absolute risk reduction in events. A drug-coated balloon may be particularly useful in this setting, where additional stenting would result in 3 or more layers of stent that may further reduce lumen area and limit future therapeutic options by further constraining the vessel wall.

Limitations

This trial had several limitations. First, although patients and event adjudicators were not aware of the assigned treatment, operators were not blinded due to the different appearance of the paclitaxel-coated vs uncoated balloons. In addition, the study was conducted at high-volume sites and rates of intravascular ultrasound were higher than in conventional practice in the United States. Whether findings might differ at less-experienced centers and those with less-frequent intravascular imaging use is unknown. Second, a strategy of treatment with a drug-coated balloon is predicated on achievement of a successful conventional angioplasty without dissection or flow limitation (ie, a result that can be durable without the scaffolding provided by a stent). Third, an alternative design might have assessed noninferiority of the paclitaxel-coated balloon against a drug-eluting stent. A superiority assessment was conducted against an uncoated balloon because many patients, particularly those with multiple layers of stent as were enrolled in this trial, are treated with conventional angioplasty. There was a strong preference to include such patients in this trial because they represent a population with potentially the greatest need for new treatment options. This study does not answer the question of whether treatment with a drug-eluting stent or a drug-coated balloon might be the optimal approach for patients with in-stent restenosis. Fourth, the study was not powered to examine differences in treatment effect in potentially important subgroups and low-frequency events (ie, stent thrombosis).

Conclusions

Supplement 1.

Trial Protocol

jama-e241361-s001.pdf^{(3.6MB, pdf)}

Supplement 2.

eTable 1. AGENT IDE Investigators, Study Support, and Enrollment by Site Name

eTable 2. AGENT IDE Committees

eTable 3. Agent IDE Study Inclusion Criteria

eTable 4. Agent IDE Study Exclusion Criteria

eTable 5. Procedural and Postprocedural Outcomes

eTable 6. Antiplatelet Medication Usage Through 1-Year

eTable 7. One-Year Primary End Point Results in the Analysis Cohort

eTable 8. Stratified Primary End Point Results

eTable 9. Competing Risk Analysis for the Primary Endpoint

eTable 10. EQ-5D Scores Through 1-Year

eReferences

jama-e241361-s002.pdf^{(447KB, pdf)}

Supplement 3.

Nonauthor Collaborators. AGENT IDE Investigators

jama-e241361-s003.pdf^{(110.7KB, pdf)}

Supplement 4.

Data Sharing Statement

jama-e241361-s004.pdf^{(12.3KB, pdf)}

References

1.Inohara T, Kohsaka S, Spertus JA, et al. Comparative trends in percutaneous coronary intervention in Japan and the United States, 2013 to 2017. J Am Coll Cardiol. 2020;76(11):1328-1340. doi: 10.1016/j.jacc.2020.07.037 [DOI] [PubMed] [Google Scholar]
2.Timmis A, Townsend N, Gale CP, et al. ; European Society of Cardiology . European Society of Cardiology: cardiovascular disease statistics 2019. Eur Heart J. 2020;41(1):12-85. doi: 10.1093/eurheartj/ehz859 [DOI] [PubMed] [Google Scholar]
3.Jinnouchi H, Kuramitsu S, Shinozaki T, et al. Difference of tissue characteristics between early and late restenosis after second-generation drug-eluting stents implantation: an optical coherence tomography study. Circ J. 2017;81(4):450-457. doi: 10.1253/circj.CJ-16-1069 [DOI] [PubMed] [Google Scholar]
4.Moussa ID, Mohananey D, Saucedo J, et al. Trends and outcomes of restenosis after coronary stent implantation in the United States. J Am Coll Cardiol. 2020;76(13):1521-1531. doi: 10.1016/j.jacc.2020.08.002 [DOI] [PubMed] [Google Scholar]
5.Byrne RA, Neumann FJ, Mehilli J, et al. ; ISAR-DESIRE 3 investigators . Paclitaxel-eluting balloons, paclitaxel-eluting stents, and balloon angioplasty in patients with restenosis after implantation of a drug-eluting stent (ISAR-DESIRE 3): a randomised, open-label trial. Lancet. 2013;381(9865):461-467. doi: 10.1016/S0140-6736(12)61964-3 [DOI] [PubMed] [Google Scholar]
6.Kufner S, Cassese S, Valeskini M, et al. ; ISAR-DESIRE 3 Investigators . Long-term efficacy and safety of paclitaxel-eluting balloon for the treatment of drug-eluting stent restenosis: 3-year results of a randomized controlled trial. JACC Cardiovasc Interv. 2015;8(7):877-884. doi: 10.1016/j.jcin.2015.01.031 [DOI] [PubMed] [Google Scholar]
7.Kastrati A, Mehilli J, von Beckerath N, et al. ; ISAR-DESIRE Study Investigators . Sirolimus-eluting stent or paclitaxel-eluting stent vs balloon angioplasty for prevention of recurrences in patients with coronary in-stent restenosis: a randomized controlled trial. JAMA. 2005;293(2):165-171. doi: 10.1001/jama.293.2.165 [DOI] [PubMed] [Google Scholar]
8.Holmes DR Jr, Teirstein P, Satler L, et al. ; SISR Investigators . Sirolimus-eluting stents vs vascular brachytherapy for in-stent restenosis within bare-metal stents: the SISR randomized trial. JAMA. 2006;295(11):1264-1273. doi: 10.1001/jama.295.11.1264 [DOI] [PubMed] [Google Scholar]
9.Stone GW, Ellis SG, O’Shaughnessy CD, et al. ; TAXUS V ISR Investigators . Paclitaxel-eluting stents vs vascular brachytherapy for in-stent restenosis within bare-metal stents: the TAXUS V ISR randomized trial. JAMA. 2006;295(11):1253-1263. doi: 10.1001/jama.295.11.1253 [DOI] [PubMed] [Google Scholar]
10.Neumann FJ, Sousa-Uva M, Ahlsson A, et al. ; ESC Scientific Document Group . 2018 ESC/EACTS guidelines on myocardial revascularization. Eur Heart J. 2019;40(2):87-165. doi: 10.1093/eurheartj/ehy394 [DOI] [PubMed] [Google Scholar]
11.Scheller B, Hehrlein C, Bocksch W, et al. Treatment of coronary in-stent restenosis with a paclitaxel-coated balloon catheter. N Engl J Med. 2006;355(20):2113-2124. doi: 10.1056/NEJMoa061254 [DOI] [PubMed] [Google Scholar]
12.Hamm CW, Dörr O, Woehrle J, et al. A multicentre, randomised controlled clinical study of drug-coated balloons for the treatment of coronary in-stent restenosis. EuroIntervention. 2020;16(4):e328-e334. doi: 10.4244/EIJ-D-19-00051 [DOI] [PubMed] [Google Scholar]
13.Scheller B, Clever YP, Kelsch B, et al. Long-term follow-up after treatment of coronary in-stent restenosis with a paclitaxel-coated balloon catheter. JACC Cardiovasc Interv. 2012;5(3):323-330. doi: 10.1016/j.jcin.2012.01.008 [DOI] [PubMed] [Google Scholar]
14.Rittger H, Waliszewski M, Brachmann J, et al. Long-term outcomes after treatment with a paclitaxel-coated balloon versus balloon angioplasty: insights from the PEPCAD-DES Study (Treatment of Drug-eluting Stent [DES] In-Stent Restenosis With SeQuent Please Paclitaxel-Coated Percutaneous Transluminal Coronary Angioplasty [PTCA] Catheter). JACC Cardiovasc Interv. 2015;8(13):1695-1700. doi: 10.1016/j.jcin.2015.07.023 [DOI] [PubMed] [Google Scholar]
15.Yeh RW, Bachinsky W, Stoler R, et al. Rationale and design of a randomized study comparing the agent drug coated balloon to plain old balloon angioplasty in patients with in-stent restenosis. Am Heart J. 2021;241:101-107. doi: 10.1016/j.ahj.2021.07.008 [DOI] [PubMed] [Google Scholar]
16.Moussa ID, Klein LW, Shah B, et al. Consideration of a new definition of clinically relevant myocardial infarction after coronary revascularization: an expert consensus document from the Society for Cardiovascular Angiography and Interventions (SCAI). J Am Coll Cardiol. 2013;62(17):1563-1570. doi: 10.1016/j.jacc.2013.08.720 [DOI] [PMC free article] [PubMed] [Google Scholar]
17.Thygesen K, Alpert JS, Jaffe AS, et al. ; Executive Group on behalf of the Joint European Society of Cardiology (ESC)/American College of Cardiology (ACC)/American Heart Association (AHA)/World Heart Federation (WHF) Task Force for the Universal Definition of Myocardial Infarction . Fourth universal definition of myocardial infarction (2018). J Am Coll Cardiol. 2018;72(18):2231-2264. doi: 10.1016/j.jacc.2018.08.1038 [DOI] [PubMed] [Google Scholar]
18.Cutlip DE, Windecker S, Mehran R, et al. ; Academic Research Consortium . Clinical end points in coronary stent trials: a case for standardized definitions. Circulation. 2007;115(17):2344-2351. doi: 10.1161/CIRCULATIONAHA.106.685313 [DOI] [PubMed] [Google Scholar]
19.Herdman M, Gudex C, Lloyd A, et al. Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L). Qual Life Res. 2011;20(10):1727-1736. doi: 10.1007/s11136-011-9903-x [DOI] [PMC free article] [PubMed] [Google Scholar]
20.Mehta CR, Pocock SJ. Adaptive increase in sample size when interim results are promising: a practical guide with examples. Stat Med. 2011;30(28):3267-3284. doi: 10.1002/sim.4102 [DOI] [PubMed] [Google Scholar]
21.Mehran R, Dangas G, Abizaid AS, et al. Angiographic patterns of in-stent restenosis: classification and implications for long-term outcome. Circulation. 1999;100(18):1872-1878. doi: 10.1161/01.CIR.100.18.1872 [DOI] [PubMed] [Google Scholar]
22.Giacoppo D, Alvarez-Covarrubias HA, Koch T, et al. Coronary artery restenosis treatment with plain balloon, drug-coated balloon, or drug-eluting stent: 10-year outcomes of the ISAR-DESIRE 3 trial. Eur Heart J. 2023;44(15):1343-1357. doi: 10.1093/eurheartj/ehad026 [DOI] [PubMed] [Google Scholar]
23.Kastrati A, Mehilli J, Pache J, et al. Analysis of 14 trials comparing sirolimus-eluting stents with bare-metal stents. N Engl J Med. 2007;356(10):1030-1039. doi: 10.1056/NEJMoa067484 [DOI] [PubMed] [Google Scholar]
24.Tamez H, Secemsky EA, Valsdottir LR, et al. Long-term outcomes of percutaneous coronary intervention for in-stent restenosis among Medicare beneficiaries. EuroIntervention. 2021;17(5):e380-e387. doi: 10.4244/EIJ-D-19-01031 [DOI] [PMC free article] [PubMed] [Google Scholar]
25.Magalhaes MA, Minha S, Chen F, et al. Clinical presentation and outcomes of coronary in-stent restenosis across 3-stent generations. Circ Cardiovasc Interv. 2014;7(6):768-776. doi: 10.1161/CIRCINTERVENTIONS.114.001341 [DOI] [PubMed] [Google Scholar]
26.Yabushita H, Kawamoto H, Fujino Y, et al. Clinical outcomes of drug-eluting balloon for in-stent restenosis based on the number of metallic layers. Circ Cardiovasc Interv. 2018;11(8):e005935. doi: 10.1161/CIRCINTERVENTIONS.117.005935 [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplement 1.

Trial Protocol

jama-e241361-s001.pdf^{(3.6MB, pdf)}

Supplement 2.

eTable 1. AGENT IDE Investigators, Study Support, and Enrollment by Site Name

eTable 2. AGENT IDE Committees

eTable 3. Agent IDE Study Inclusion Criteria

eTable 4. Agent IDE Study Exclusion Criteria

eTable 5. Procedural and Postprocedural Outcomes

eTable 6. Antiplatelet Medication Usage Through 1-Year

eTable 7. One-Year Primary End Point Results in the Analysis Cohort

eTable 8. Stratified Primary End Point Results

eTable 9. Competing Risk Analysis for the Primary Endpoint

eTable 10. EQ-5D Scores Through 1-Year

eReferences

jama-e241361-s002.pdf^{(447KB, pdf)}

Supplement 3.

Nonauthor Collaborators. AGENT IDE Investigators

jama-e241361-s003.pdf^{(110.7KB, pdf)}

Supplement 4.

Data Sharing Statement

jama-e241361-s004.pdf^{(12.3KB, pdf)}

[joi240016r1] 1.Inohara T, Kohsaka S, Spertus JA, et al. Comparative trends in percutaneous coronary intervention in Japan and the United States, 2013 to 2017. J Am Coll Cardiol. 2020;76(11):1328-1340. doi: 10.1016/j.jacc.2020.07.037 [DOI] [PubMed] [Google Scholar]

[joi240016r2] 2.Timmis A, Townsend N, Gale CP, et al. ; European Society of Cardiology . European Society of Cardiology: cardiovascular disease statistics 2019. Eur Heart J. 2020;41(1):12-85. doi: 10.1093/eurheartj/ehz859 [DOI] [PubMed] [Google Scholar]

[joi240016r3] 3.Jinnouchi H, Kuramitsu S, Shinozaki T, et al. Difference of tissue characteristics between early and late restenosis after second-generation drug-eluting stents implantation: an optical coherence tomography study. Circ J. 2017;81(4):450-457. doi: 10.1253/circj.CJ-16-1069 [DOI] [PubMed] [Google Scholar]

[joi240016r4] 4.Moussa ID, Mohananey D, Saucedo J, et al. Trends and outcomes of restenosis after coronary stent implantation in the United States. J Am Coll Cardiol. 2020;76(13):1521-1531. doi: 10.1016/j.jacc.2020.08.002 [DOI] [PubMed] [Google Scholar]

[joi240016r5] 5.Byrne RA, Neumann FJ, Mehilli J, et al. ; ISAR-DESIRE 3 investigators . Paclitaxel-eluting balloons, paclitaxel-eluting stents, and balloon angioplasty in patients with restenosis after implantation of a drug-eluting stent (ISAR-DESIRE 3): a randomised, open-label trial. Lancet. 2013;381(9865):461-467. doi: 10.1016/S0140-6736(12)61964-3 [DOI] [PubMed] [Google Scholar]

[joi240016r6] 6.Kufner S, Cassese S, Valeskini M, et al. ; ISAR-DESIRE 3 Investigators . Long-term efficacy and safety of paclitaxel-eluting balloon for the treatment of drug-eluting stent restenosis: 3-year results of a randomized controlled trial. JACC Cardiovasc Interv. 2015;8(7):877-884. doi: 10.1016/j.jcin.2015.01.031 [DOI] [PubMed] [Google Scholar]

[joi240016r7] 7.Kastrati A, Mehilli J, von Beckerath N, et al. ; ISAR-DESIRE Study Investigators . Sirolimus-eluting stent or paclitaxel-eluting stent vs balloon angioplasty for prevention of recurrences in patients with coronary in-stent restenosis: a randomized controlled trial. JAMA. 2005;293(2):165-171. doi: 10.1001/jama.293.2.165 [DOI] [PubMed] [Google Scholar]

[joi240016r8] 8.Holmes DR Jr, Teirstein P, Satler L, et al. ; SISR Investigators . Sirolimus-eluting stents vs vascular brachytherapy for in-stent restenosis within bare-metal stents: the SISR randomized trial. JAMA. 2006;295(11):1264-1273. doi: 10.1001/jama.295.11.1264 [DOI] [PubMed] [Google Scholar]

[joi240016r9] 9.Stone GW, Ellis SG, O’Shaughnessy CD, et al. ; TAXUS V ISR Investigators . Paclitaxel-eluting stents vs vascular brachytherapy for in-stent restenosis within bare-metal stents: the TAXUS V ISR randomized trial. JAMA. 2006;295(11):1253-1263. doi: 10.1001/jama.295.11.1253 [DOI] [PubMed] [Google Scholar]

[joi240016r10] 10.Neumann FJ, Sousa-Uva M, Ahlsson A, et al. ; ESC Scientific Document Group . 2018 ESC/EACTS guidelines on myocardial revascularization. Eur Heart J. 2019;40(2):87-165. doi: 10.1093/eurheartj/ehy394 [DOI] [PubMed] [Google Scholar]

[joi240016r11] 11.Scheller B, Hehrlein C, Bocksch W, et al. Treatment of coronary in-stent restenosis with a paclitaxel-coated balloon catheter. N Engl J Med. 2006;355(20):2113-2124. doi: 10.1056/NEJMoa061254 [DOI] [PubMed] [Google Scholar]

[joi240016r12] 12.Hamm CW, Dörr O, Woehrle J, et al. A multicentre, randomised controlled clinical study of drug-coated balloons for the treatment of coronary in-stent restenosis. EuroIntervention. 2020;16(4):e328-e334. doi: 10.4244/EIJ-D-19-00051 [DOI] [PubMed] [Google Scholar]

[joi240016r13] 13.Scheller B, Clever YP, Kelsch B, et al. Long-term follow-up after treatment of coronary in-stent restenosis with a paclitaxel-coated balloon catheter. JACC Cardiovasc Interv. 2012;5(3):323-330. doi: 10.1016/j.jcin.2012.01.008 [DOI] [PubMed] [Google Scholar]

[joi240016r14] 14.Rittger H, Waliszewski M, Brachmann J, et al. Long-term outcomes after treatment with a paclitaxel-coated balloon versus balloon angioplasty: insights from the PEPCAD-DES Study (Treatment of Drug-eluting Stent [DES] In-Stent Restenosis With SeQuent Please Paclitaxel-Coated Percutaneous Transluminal Coronary Angioplasty [PTCA] Catheter). JACC Cardiovasc Interv. 2015;8(13):1695-1700. doi: 10.1016/j.jcin.2015.07.023 [DOI] [PubMed] [Google Scholar]

[joi240016r15] 15.Yeh RW, Bachinsky W, Stoler R, et al. Rationale and design of a randomized study comparing the agent drug coated balloon to plain old balloon angioplasty in patients with in-stent restenosis. Am Heart J. 2021;241:101-107. doi: 10.1016/j.ahj.2021.07.008 [DOI] [PubMed] [Google Scholar]

[joi240016r16] 16.Moussa ID, Klein LW, Shah B, et al. Consideration of a new definition of clinically relevant myocardial infarction after coronary revascularization: an expert consensus document from the Society for Cardiovascular Angiography and Interventions (SCAI). J Am Coll Cardiol. 2013;62(17):1563-1570. doi: 10.1016/j.jacc.2013.08.720 [DOI] [PMC free article] [PubMed] [Google Scholar]

[joi240016r17] 17.Thygesen K, Alpert JS, Jaffe AS, et al. ; Executive Group on behalf of the Joint European Society of Cardiology (ESC)/American College of Cardiology (ACC)/American Heart Association (AHA)/World Heart Federation (WHF) Task Force for the Universal Definition of Myocardial Infarction . Fourth universal definition of myocardial infarction (2018). J Am Coll Cardiol. 2018;72(18):2231-2264. doi: 10.1016/j.jacc.2018.08.1038 [DOI] [PubMed] [Google Scholar]

[joi240016r18] 18.Cutlip DE, Windecker S, Mehran R, et al. ; Academic Research Consortium . Clinical end points in coronary stent trials: a case for standardized definitions. Circulation. 2007;115(17):2344-2351. doi: 10.1161/CIRCULATIONAHA.106.685313 [DOI] [PubMed] [Google Scholar]

[joi240016r19] 19.Herdman M, Gudex C, Lloyd A, et al. Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L). Qual Life Res. 2011;20(10):1727-1736. doi: 10.1007/s11136-011-9903-x [DOI] [PMC free article] [PubMed] [Google Scholar]

[joi240016r20] 20.Mehta CR, Pocock SJ. Adaptive increase in sample size when interim results are promising: a practical guide with examples. Stat Med. 2011;30(28):3267-3284. doi: 10.1002/sim.4102 [DOI] [PubMed] [Google Scholar]

[joi240016r21] 21.Mehran R, Dangas G, Abizaid AS, et al. Angiographic patterns of in-stent restenosis: classification and implications for long-term outcome. Circulation. 1999;100(18):1872-1878. doi: 10.1161/01.CIR.100.18.1872 [DOI] [PubMed] [Google Scholar]

[joi240016r22] 22.Giacoppo D, Alvarez-Covarrubias HA, Koch T, et al. Coronary artery restenosis treatment with plain balloon, drug-coated balloon, or drug-eluting stent: 10-year outcomes of the ISAR-DESIRE 3 trial. Eur Heart J. 2023;44(15):1343-1357. doi: 10.1093/eurheartj/ehad026 [DOI] [PubMed] [Google Scholar]

[joi240016r23] 23.Kastrati A, Mehilli J, Pache J, et al. Analysis of 14 trials comparing sirolimus-eluting stents with bare-metal stents. N Engl J Med. 2007;356(10):1030-1039. doi: 10.1056/NEJMoa067484 [DOI] [PubMed] [Google Scholar]

[joi240016r24] 24.Tamez H, Secemsky EA, Valsdottir LR, et al. Long-term outcomes of percutaneous coronary intervention for in-stent restenosis among Medicare beneficiaries. EuroIntervention. 2021;17(5):e380-e387. doi: 10.4244/EIJ-D-19-01031 [DOI] [PMC free article] [PubMed] [Google Scholar]

[joi240016r25] 25.Magalhaes MA, Minha S, Chen F, et al. Clinical presentation and outcomes of coronary in-stent restenosis across 3-stent generations. Circ Cardiovasc Interv. 2014;7(6):768-776. doi: 10.1161/CIRCINTERVENTIONS.114.001341 [DOI] [PubMed] [Google Scholar]

[joi240016r26] 26.Yabushita H, Kawamoto H, Fujino Y, et al. Clinical outcomes of drug-eluting balloon for in-stent restenosis based on the number of metallic layers. Circ Cardiovasc Interv. 2018;11(8):e005935. doi: 10.1161/CIRCINTERVENTIONS.117.005935 [DOI] [PubMed] [Google Scholar]

PERMALINK

Paclitaxel-Coated Balloon vs Uncoated Balloon for Coronary In-Stent Restenosis

Robert W Yeh, MD, MSc

Richard Shlofmitz, MD

Jeffrey Moses, MD

William Bachinsky, MD

Suhail Dohad, MD

Steven Rudick, MD

Robert Stoler, MD

Brian K Jefferson, MD

William Nicholson, MD

John Altman, MD

Cinthia Bateman, MD

Amar Krishnaswamy, MD

J Aaron Grantham, MD

Frank J Zidar, MD

Steven P Marso, MD

Jennifer A Tremmel, MD, MS

Cindy Grines, MD

Mustafa I Ahmed, MD

Azeem Latib, MD

Behnam Tehrani, MD

J Dawn Abbott, MD

Wayne Batchelor, MD

Paul Underwood, MD

Dominic J Allocco, MD

Ajay J Kirtane, MD, SM

Key Points

Question

Findings

Meaning

Abstract

Importance

Objective

Design, Setting, and Participants

Interventions

Main Outcomes and Measures

Results

Conclusions and Relevance

Trial Registration

Introduction

Methods

Study Design and Oversight

Patient Selection

Randomization and Treatment

Figure 1. Enrollment, Randomization, and Follow-Up in the AGENT IDE Trial.

Clinical Follow-Up and Outcomes

Statistical Analysis

Results

Patients and Enrollment

Table 1. Baseline Clinical and Lesion Characteristics of the Patientsa.

Primary End Point and Components

Figure 2. One-Year Time-to-Event Curves for the Primary End Point and Individual Components.

Additional Outcomes and Subgroup Analyses

Table 2. Prespecified Clinical Outcomes Through 1 Year.

Figure 3. Prespecified Subgroup Analyses of the Primary Outcome at 1 Year.

Discussion

Limitations

Conclusions

References

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

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Cited by other articles

Links to NCBI Databases

Table 1. Baseline Clinical and Lesion Characteristics of the Patients^a.