J A C C : C L I N I C A L E L E C T R O P H Y S I O L O G Y V O L . 6 , N O . 1 , 2 0 2 0

P U B L I S H E D B Y E L S E V I E R O N B E H A L F O F T H E AM E R I C A N C O L L E G E O F

C A R D I O L O G Y F O U N D A T I O N . T H I S I S A N O P E N A C C E S S A R T I C L E U N D E R T H E

C C B Y - N C - N D L I C E N S E ( h t t p : / / c r e a t i v e c o mm o n s . o r g / l i c e n s e s / b y - n c - n d / 4 . 0 / ) .

VASCULAR CLOSURE

Venous Vascular Closure System VersusManual Compression Following MultipleAccess Electrophysiology ProceduresThe AMBULATE Trial

Andrea Natale, MD,a,b,c,d Sanghamitra Mohanty, MD, MS,a,b P.Y. Liu, PHD,e Suneet Mittal, MD,f Amin Al-Ahmad, MD,a

David B. De Lurgio, MD,g Rodney Horton, MD,a William Spear, MD,h Shane Bailey, MD,a Jared Bunch, MD,i

Dan Musat, MD,f Padraig O’Neill, MD,j Steven Compton, MD,k Mintu P. Turakhia, MD, MAS,l,m for the AMBULATETrial Investigators

ABSTRACT

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OBJECTIVES This study compared the efficacy and safety of the VASCADE MVP Venous Vascular Closure System

(VVCS) device (Cardiva Medical, Santa Clara, California) to manual compression (MC) for closing multiple access sites

after catheter-based electrophysiology procedures.

BACKGROUND The VASCADE MVP VVCS is designed to provide earlier ambulatory hemostasis than MC after catheter-

based procedures.

METHODS The AMBULATE (A Randomized, Multi-center Trial to Compare Cardiva Mid-Bore [VASCADE MVP] VVCS to

Manual Compression in Closure of Multiple Femoral Venous Access Sites in 6 - 12 Fr Sheath Sizes) trial was a multicenter,

randomized trial of device closure versus MC in patients who underwent ablation. Outcomes included time to ambulation

(TTA), total post-procedure time (TPPT), time to discharge eligibility (TTDe), time to hemostasis (TTH), 30-day major and

minor complications, pain medication usage, and patient-reported outcomes.

RESULTS A total of 204 patients at 13 sites were randomized to the device arm (n ¼ 100; 369 access sites) or the

MC arm (n ¼ 104; 382 access sites). Baseline characteristics were similar between groups. Mean TTA, TPPT, TTDe, and

TTH were substantially lower in the device arm (respective decreases of 54%, 54%, 52%, and 55%; all p < 0.0001).

Opioid use was reduced by 58% (p ¼ 0.001). There were no major access site complications. Incidence of minor com-

plications was 1.0% for the device arm and 2.4% for the MC arm (p ¼ 0.45). Patient satisfaction scores with duration of

and comfort during bedrest were 63% and 36% higher in device group (both p < 0.0001). Satisfaction with bedrest pain

was 25% higher (p ¼ 0.001) for the device overall, and 40% higher (p ¼ 0.002) for patients with a previous ablation.

CONCLUSIONS Use of the closure device for multiple access ablation procedures resulted in significant reductions

in TTA, TPPT, TTH, TTDe, and opioid use, with increased patient satisfaction and no increase in complications.

(A Randomized, Multi-center Trial to Compare Cardiva Mid-Bore VVCS to Manual Compression in Closure of Multiple

Femoral Venous Access Sites in 6 - 12 Fr Sheath Sizes [AMBULATE]; NCT03193021). (J Am Coll Cardiol EP 2020;6:111–24)

Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the

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

N 2405-500X https://doi.org/10.1016/j.jacep.2019.08.013

m the aTexas Cardiac Arrhythmia Institute, St. David’s Medical Center, Austin, Texas; bDell Medical School, University of

xas, Austin, Texas; cCase Western Reserve University, Cleveland, Ohio; dInterventional Electrophysiology, Scripps Clinic, San

go, California; eFred Hutchinson Cancer Research Center, Seattle, Washington; fValley Health System and the Snyder Center

Comprehensive Atrial Fibrillation, Ridgewood, New Jersey; gEmory Healthcare, Atlanta, Georgia; hAdvocate Christ Medical

nter, Oak Lawn, Illinois; iIntermountain Medical Center, Salt Lake City, Utah; jMercy Medical Group, Sacramento, California;

laska Heart and Vascular Institute, Anchorage, Alaska; lStanford University, Stanford, California; and the mVA Palo Alto Health

re System, Palo Alto, California. This study was sponsored by Cardiva Medical, Inc. Dr. Natale has been a consultant for

ABBR EV I A T I ON S

AND ACRONYMS

ANCOVA = analysis of

covariance

MC = manual compression

TPPT = total post-procedure

time

TTA = time to ambulation

TTCe = time to closure

eligibility

TTD = time to discharge

TTDe = time to discharge

eligibility

TTH = time to hemostasis

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112

T he volume of catheter ablation pro-cedures for the treatment of atrialfibrillation and other arrhythmias

continues to rise year after year, both in theUnited States and worldwide (1). Specifically,for atrial fibrillation, innovation and refine-ment in ablation tools, techniques, and strate-gies have led to greater efficacy, shorterprocedure times, and a decline in complica-tion rates (2). Despite these proceduraladvances, certain critical aspects of post-procedural management have remained rela-tively unchanged. For example, manualcompression (MC) followed by post-procedure bedrest—often up to 8 h when mul-

tiple access sites are present—remains the standard ofcare for post-procedural closure of venous access sites.Prolonged bedrest may itself be associated with otherinterventions, including use or persistence of an in-dwelling bladder catheter and longer length of stay (3).

SEE PAGE 125

Device-based vascular closure has dramaticallyshortened bedrest and post-procedure care afterdiagnostic and interventional arterial procedures (4).It has facilitated early ambulation, which itself hasbeen associated with favorable clinical and economicoutcomes in a variety of medical procedures, greaterpatient satisfaction, same-day discharge, and lowerrisk of complications (5,6).

Closure of venous access sites with specializeddevices could have similar potential to shorten bed-rest and facilitate early ambulation and dischargeafter catheter-based procedures. The VASCADE MVP(Cardiva Medical, Santa Clara, California) VenousVascular Closure System (VVCS) is a novel, investi-gational, single-use vascular closure device designedto achieve hemostasis at mid-bore femoral venousaccess sites (Online Figure 1). The device establisheshemostasis by delivering a resorbable, extravascularcollagen plug into the tissue tract, created by a

ebster, Boston Scientific, Medtronic, Biotronik, Abbott, and Bay

ronic, and Attricure. Dr. Spear has received fees from Cardiva Med

e Webster, Janssen Pharmaceuticals, Bristol-Myers Squibb, and

n Scientific and Boehringer Ingelheim. Dr. O’Neill is a member

ants from Medtronic and St. Jude Medical. Dr. Turakhia has recei

recision Health Economics, Cardiva Medical, and iRhythm Tech

holds equity interest/stocks options (no-public) in AliveCor, Ziplin

AstraZeneca Pharmaceuticals, Janssen Pharmaceuticals, Medtr

All other authors have reported that they have no relationships

s attest they are in compliance with human studies committees

nd Food and Drug Administration guidelines, including patient

CC: Clinical Electrophysiology author instructions page.

received March 13, 2019; revised manuscript received August 20

procedural introducer sheath. The closure device isdesigned for use with up to 12-F inner diametersheaths, including the Flexcath Steerable Sheath(Medtronic, Minneapolis, Minnesota), for use withthe Artic Front CyroAblation Balloon (Medtronic), andthe WATCHMAN left atrial appendage occlusion de-vice (Boston Scientific, Natick, Massachusetts). Thedevice is based on the design of the VASCADE VCS(Cardiva Medical), which is currently approved forarterial and venous closure after 5-F to 7-F proced-ures. The results of the randomized controlled U.S.pivotal RESPECT (A Prospective, Randomized, PivotalTrial of a Novel Extravascular Collagen-Based ClosureDevice Compared to Manual Compression in Diag-nostic and Interventional Patients) trial (n ¼ 420)demonstrated that the VASCADE VCS was safe andeffective in sealing femoral arterial access sites afterendovascular procedures performed through 6-F or 7-F introducer sheaths, with no major vascular com-plications, fewer minor vascular complications, andshorter time to hemostasis, ambulation, anddischarge eligibility compared with MC (7,8).

We evaluated the efficacy and safety of the inves-tigational venous closure device compared with thatof MC, for closing multiple access sites after catheter-based electrophysiology procedures. In addition toclinical outcomes, we also conducted several analysesthat evaluated patient satisfaction with recovery andpatterns of pain medication use.

METHODS

STUDY DESIGN. The AMBULATE (A Randomized,Multi-center Trial to Compare Cardiva Mid-Bore VVCStoManual Compression in Closure of Multiple FemoralVenous Access Sites in 6 - 12 Fr Sheath Sizes) trial was arandomized, controlled, open-label investigationaldevice exemption clinical trial conducted at multipleU.S. sites (NCT03193021). The aim was to demonstratethe efficacy and safety of the closure device comparedwith that of MC. The trial was conducted in

lis Medical. Dr. DeLurgio has been a consultant for

ical; and has been a member of the Speakers Bureau

Stereotaxis. Dr. Bunch has received research grants

of the Speakers Bureau for Pfizer; and has received

ved compensation for services from Akebia, St. Jude

nologies; has received Speakers Bureau fees from

eMedical, and iBeat, Inc.; and has received research

onic, Inc., Veterans Administration, and Boehringer

relevant to the contents of this paper to disclose.

and animal welfare regulations of the authors’ in-

consent where appropriate. For more information,

, 2019, accepted August 22, 2019.

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compliance with Food and Drug Administration andInternational Council for Harmonisation (ICH) regu-lations for Good Clinical Practice. The protocol andinformed consent forms were approved by the insti-tutional review board at each site.

Adults 18 years or older who underwent elective,nonemergent, catheter-based procedures via thecommon femoral vein(s) using a 6-F to 12-F innerdiameter introducer sheath, a minimum of 3 andmaximum of 4 femoral venous access sites, and amaximum of 2 access sites per leg were enrolled.Exclusion criteria included active systemic or cuta-neous infection or inflammation in the vicinity of thegroin; any pre-existing immunodeficiency disorder;long-term use of high-dose systemic steroids; historyof bleeding diathesis, coagulopathy, hypercoagula-bility, or thromboembolic events; plateletcount <100,000 cells/mm3; or severe comorbiditieswith life expectancy <12 months in the opinion of thesite investigator.

After providing informed consent, patients under-went the appropriate ablation procedure. During theablation procedure, patients could be furtherexcluded from the study before randomization if anyof the following occurred: attempted femoral arterialaccess or inadvertent arterial puncture; proceduralcomplications that interfered with routine recovery,ambulation, or discharge times; difficulty with needlepuncture or insertion of the introducer sheath;incorrect sheath placement; intraprocedural bleedingor thrombotic complications; final sheath size <6-F or>12-F inner diameter; or tissue tract <2.5 cm deep.

The follow-up period consisted of in-hospital as-sessments through 30 days after patient discharge.

SAMPLE SIZE AND POWER. Sample size calculationsassumed a normal distribution for time to ambula-tion (TTA) according to Food and Drug Administra-tion requirements for a more conservative treatmentof outlier data. Based on the results of the RESPECTstudy (7), mean TTA for MC was estimated at 7.2 h.The same mean for Cardiva Mid-Bore VVCS wasestimated at 5 h including an outlier and at 4.3 hexcluding the outlier. With an estimated joint SD of5.4 h, the power for reaching a statistically signifi-cant difference at a 2-sided p < 0.05 level, with atotal sample size of 204 patients (102 per group), was0.83 including the outlier in the calculation; thesame power was 0.97 excluding the outlier. Althoughthe primary TTA analysis used an analysis ofcovariance (ANCOVA) model that accounted for therandomization stratification factor (number of accesssites: 3 vs. 4), the distribution of access sites andtheir impact on TTA was unknown at the planning

stage. Therefore, the sample size estimation wasbased on a simple 2-arm comparison as a reasonableapproximation.

RANDOMIZATION PROCEDURE. At the end of thecatheter-based procedure, and with the proceduralsheaths still in place, patients who met allpre-operative and intraoperative study criteria wererandomly assigned in a 1:1 scheme to vascular closurewith the closure device or MC. Variable block ran-domizations were performed separately, that is,stratified, by number of venotomy sites (3 vs. 4) ateach investigational site.

ENDPOINTS AND DEFINITIONS. The primary efficacyendpoint was time to ambulation, defined as theelapsed time between removal of the final closuredevice or removal of final sheath and when the pa-tient stood and walked 20 ft without evidence ofvenous re-bleeding from the femoral access site. Theprimary safety endpoint was the incidence of majorcomplications related to venous access site closureoccurring within 30 � 7 days after the procedure, bylimb. A schema defining all primary and secondaryoutcomes is shown in Figure 1.

Secondary efficacy endpoints were total post-procedure time (TPPT; elapsed time betweenremoval of the last procedural device for the indexprocedure and when the patient was able to success-fully ambulate); time to hemostasis (TTH; elapsed timebetween removal of the closure device or the sheathand first observed and confirmed venous hemostasis,for each access site); time to discharge eligibility(TTDe) (elapsed time between removal of the finalclosure device orfinal sheath andwhen the patientwaseligible for hospital discharge based solely on theassessment of the access site, as determined by themedical team); time to discharge (TTD; elapsed timebetween removal of the final closure device or finalsheath and when the patient was discharged from theinstitution); and time to closure eligibility (TTCe;elapsed time between removal of the last proceduraldevice for the index procedure and removal of the firstclosure device or first sheath).

The secondary safety endpoint was incidence ofminor complications within 30 days after the pro-cedure. According to a pre-specified substudy, asubgroup of 25 patients from each treatment groupunderwent an ultrasound examination of the bilateralaccess sites to further evaluate safety. The ultrasoundwas performed at the 30-day office visit.

Other endpoints were patient experience withduration of, comfort during, and pain associated withbedrest, and use of analgesic and antianxietymedication.

FIGURE 1 Study Design Flowchart

Last Procedural Device Pulled from Pa�ent

1st Procedural Sheath Pulled

Last access site hemostasis

Ambula�on

Time to Closure Eligibility(TTCE)

~10 Minutes

Time to Hemostasis(TTH x 3-4)

~5 Minutes (ea)

Time to Ambula�on(TTA)

~2-2.5 Hours

Total Post Procedure Time (TPPT) = 2.5-3 Hours

DischargeAssessment

Time to Discharge Eligibility (TTDE)

Discharge

Time to Discharge (TTD)

Study design flowchart showing evaluation time points for efficacy measures.

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STUDY PROCEDURES. Patients randomized to inter-vention underwent attempted closure of all femoralvenous sites using the previously described closuredevice. Deployment of the VASCADE MVP closuredevice was carried out after completion of eachcatheterization procedure through the 6-F to 12-Finner diameter introducer sheath(s) placed duringthe catheter ablation procedure. First, the introducersheaths were exchanged for short sheaths of equiva-lent diameter at each access site. The closure devicecatheter was inserted through the short sheath andthen the distal tip of the closure device catheter wasdeployed to open and expand a low-profile, 23-Fpolyurethane covered nickel-titanium disc withinthe lumen of the femoral vein (Online Figure 1). Theintroducer sheath was removed over the closure de-vice catheter, and the low-profile disc was placedagainst the inner wall, located the vessel wall,temporarily sealed the venotomy, and positioned thedevice for collagen-patch deployment within the tis-sue tract immediately adjacent and extravascular tothe venotomy site. Placement was verified using im-aging before release of the collagen plug, and oncethe plug was deployed, the disc collapsed and thedevice removed. The total deployment proceduretook approximately 1 min per access site. Gentle MCwas applied for up to 5 min. Hemostasis time wasrecorded and reconfirmed 5 min later, and at 15-min

intervals for the next hour. Intraprocedural devicefailures were converted to MC. Protocol guidelinesrecommended bedrest for 2 to 2.5 h, then ambulationif stable, with groin checks immediately and 15 minafter ambulation.

In case of repeat procedures, the same femoral veincould be accessed after 30 days of the previous pro-cedure using the VASCADE MVP device for venousclosure.

For the MC arm, sheaths were exchanged or left inplace according to institutional protocol. After finalsheath removal, sustained compression was appliedaccording to local practice of the institution, oper-ating physician, and care team. Hemostasis time wasrecorded and re-confirmed 5 min following sheathpull and at 15-min intervals for the next hour. Proto-col guidelines advised investigators to follow insti-tutional guidelines for standard of care forambulation, with groin checks immediately and15 min after ambulation. Periprocedural anti-coagulation management (choice or drug and dose,interruption, resumption) and protamine reversalwere not pre-specified in the protocol and were doneat the discretion of the operator and in accordancewith operator or institutional usual care or practice.PATIENT-REPORTED OUTCOMES. All participantscompleted a 3-part patient experience survey (OnlineFigure 2) after successful ambulation and discharge

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eligibility determination, but before discharge. Thesurvey was developed according to guidance from theFood and Drug Administration (9) and previousstudies of pain and discomfort after other types ofinterventional cardiology procedures (10–19). Ques-tions were designed to characterize patients’ level ofsatisfaction with their current experience and theirhypothetical preferences for duration, discomfort, andpain associated with supine bedrest post-procedure.Patients who underwent a repeat ablation procedurewere asked to compare the current episode with pastexperience. Answers were scored on an anchored rat-ing scale of 0 (very dissatisfied) to 10 (very satisfied).

PAIN MEDICATION USE. Analgesic or antianxietymedication for pain management during bedrest wasprescribed according to local institutional protocolsand recorded. When patients received multiplemedications, use was categorized according to thestrongest and/or most potent therapeutic class pre-scribed (i.e., analgesic/antipyretics less than nonste-roidal anti-inflammatory drugs less than opioids).

ADJUDICATION OF ENDPOINTS. An independentcombination of the Clinical Events Committee andData Safety Monitoring Board (referred to as the DataSafety Monitoring Committee) was responsible forsystematic review and adjudication of all reportedmajor and minor access site closure�related endpointcomplications. All other events reported to bepotentially device- or procedure-related by theinvestigator were reviewed by the chairman of theData Safety Monitoring Committee to determinewhether it met criteria for adjudication. To enhanceobjectivity and reduce the potential for bias, the DataSafety Monitoring Committee members were inde-pendent of the sponsor as well as the investigationalsites and/or investigators. Members consisted of atleast 3 independent physicians with experience incatheter-based procedures and a statistician. Themethodology for performing these responsibilitieswas developed and outlined in a pre-specified adju-dication charter. Operational provisions were estab-lished to minimize potential bias.

STATISTICAL ANALYSIS. Basel ine character i s t i cs .Patient demographics, baseline characteristics,medical history, periprocedural anticoagulantregimen, experience, and use of pain medicationwere summarized descriptively by randomizedtreatment arm.Efficacy analys i s . Efficacy analysis was conductedaccording to the intent-to-treat principle. The intent-to-treat population consisted of all randomized pa-tients. The null hypothesis for the primary endpointTTA was that mean TTADevice ¼ mean TTAMC.

The primary TTA analysis was an ANCOVA withtreatment as the independent variable of interest, aswell as randomization stratification factor and num-ber of access sites as the only covariates. In addition,Student’s t-test and Wilcoxon’s rank-sum test werealso performed for unadjusted TTA comparison be-tween the closure device and MC. A 2-sidedp value <0.05 in favor of the device was consideredstatistically significant for demonstration of the su-periority of the closure device efficacy over MC.

To limit the study-wide type I error rate to 0.05(2-sided), a gated hierarchical testing approach waspre-specified, with endpoints ordered to reflect theirclinical relevance. If TTA results were positive, sec-ondary endpoints were analyzed in the order of TPPT,TTH, TTDe, and TTD between the 2 study arms; testingwould stop whenever a p value >0.05 was encoun-tered. For analysis, TPPT, TTDe, and TTD werecompared between treatments using the same ana-lyses as described for the TTA analysis. Because therewere multiple access sites per patient (and per limb inmany cases), TTH was analyzed by the bootstrapmethod with the patient as the re-sampling unit. Anoninferiority comparison was conducted, with anoninferiority margin of 5 min for the closure devicecompared with MC.

Summary statistics for additional efficacy end-points of time to closure eligibility, procedure suc-cess, and proportion of device success by access site(closure device only) were presented without hy-pothesis testing.

Safety analys i s . Safety analyses were carried out atthe limb level. The primary safety endpoint was thecombined limb incidence rate of major complicationsrelated to access site closure, with a noninferioritymargin of an absolute 5% for the closure device. Toaccount for potential correlation between the 2 limbsof the same patient, bootstrap analysis was per-formed with the patient as the re-sampling unit. Alllimbs that received any portion of the closure devicetreatment were analyzed as a closure device limb.Otherwise, all limbs that were randomized to the MCcontrol treatment were analyzed as MC limbs.

For secondary safety measures, the combined andindividual incidence rates for minor access siteclosure complications were reported by limb, bytreatment received, without noninferiority testing.Other reported adverse events were analyzed bytreatment group, regardless of relationship to accesssite closure. All index procedures and assessmentswere completed for all patients.

The study database was locked in April 2018. Dataanalyses were carried out using the SAS version 9.4

FIGURE 2 Study Design Flowchart Showing Final Disposition of Patients

Reasons for intraoperative screen failures: femoral arterial access during procedure (n ¼ 11); complications during the index procedure that

were expected to interfere with study procedures (n¼ 9; physician orders that conflicted with study procedures (n¼ 7); and venous access sites

did not meet intraoperative screening requirements (n ¼ 31). Four patients were excluded for >1 reason. ITT ¼ intent to treat.

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(SAS Institute Inc., Cary, North Carolina), R statisticalEnvironment (R Foundation for StatisticalComputing, Vienna, Austria), and Microsoft Excel(Microsoft, Redmond, Washington).

RESULTS

PATIENT CHARACTERISTICS. Between September2017 and March 2018, 258 patients across 28 operatorsand 13 sites consented to enroll into the randomizedtrial (Figure 2, Central Illustration). Of those, 204consecutive patients met pre-operative and intra-operative selection criteria and were randomized toreceive the closure device (n ¼ 100; 369 access sites)or MC (n ¼ 104; 382 access sites). Of those, 87 of 100

(87%) patients who received the closure device and 91of 104 (88%) patients who underwent MC completeda follow-up office visit per protocol. The remainingpatients received the 30-day follow-up by phoneand/or received follow-up outside of the protocolspecified window. One patient in each arm was lost tofollow-up.

Demographics and baseline clinical characteristicswere similar between groups (Table 1). Afterrandomization, there were 369 access sites in theclosure device intent-to-treat group. Ultrasoundguidance, either alone or in combination with othertechniques, was used for access in 65% of closuredevice and 74% of MC access sites. Actual attempts todeploy the closure device occurred in 363 access sites,

TABLE 1 Patient Baseline Demographics and Clinical Characteristics

ClosureDevice

(n ¼ 100)

ManualCompression(n ¼ 104) p Value*

Age, yrs 61.5 � 11.6 63.4 � 11.1 0.24

Body mass index, kg/m2 29.0 � 4.6 29.3 � 5.2 0.69

Male 67 (67) 64 (62) 0.47

Ethnicity

Hispanic or Latino 3 (3) 6 (6) 0.50

Not Hispanic or Latino 97 (97) 95 (91)

Unknown 0 (0) 3 (3)

Race

White 86 (86) 93 (89) 0.52

Black or African American 6 (6) 4 (4)

American Indian or Alaska Native 3 (3) 0 (0)

Asian 2 (2) 1 (1)

Other 3 (3) 6 (6)

Comorbidities

Hypercholesterolemia 57 (57) 58 (56) 0.88

Hypertension 58 (58) 69 (66) 0.25

Current or ex-smoker 42 (42) 42 (40) 0.89

Diabetes mellitus 14 (14) 18 (17) 0.57

Diabetes treatments

Insulin 5 (5) 3 (3) 0.49

Diet 5 (5) 5 (5) 1.00

Oral hypoglycemics 11 (11) 15 (14) 0.53

Lower right limb neuropathy 1 (1) 2 (2) 1.00

Lower left limb neuropathy 1 (1) 2 (2) 1.00

Other relevant medical history 16 (16) 16 (15) 1.00

No. of access sites

3 sticks 31 (31) 34 (33)

4 sticks 69 (69) 70 (67) 0.88

Procedure type

AF 64 (64) 68 (65)

AF þ AFL 14 (14) 19 (18)

AFL 6 (6) 7 (7)

SVT 14 (14) 8 (8)

VT 2 (2) 2 (2) 0.58

Energy source

RF 77 (77) 79 (76)

Cryo 20 (20) 23 (22)

Both (RF þ Cryo) 3 (3) 2 (2) 0.83

Pre-procedural anticoagulation

Aspirin 29 (29) 21 (20) 0.19

Warfarin 5 (5) 3 (3) 0.49

Clopidogrel 0 (0) 2 (2) 0.50

Ticagrelor 1 (1) 0 (0) 0.49

Rivaroxaban 29 (29) 25 (24) 0.43

Dabigatran 3 (3) 4 (4) 1.00

Apixaban 37 (37) 46 (44) 0.32

Low molecular weight heparin 1 (1) 2 (1) 1.00

Any of the above 84 (84) 88 (85) 1.00

None 16 (16) 16 (15) 1.00

Values are mean � SD or n (%). *Age and body mass index, Student’s t-test; all other characteristics, Fisher exacttest.

AF ¼ atrial fibrillation; AFL ¼ atrial flutter; RF ¼ radiofrequency; SVT ¼ supraventricular tachycardia;VT ¼ ventricular tachycardia.

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and 351 were successfully deployed (97% devicesuccess in the as-treated population). Proceduresuccess was 98% for the device group and 99% for theMC group. Six closure device access sites across 3patients were converted to MC and were reported asprotocol deviations. In 1 of those patients (4 accesssites), the intraluminal positioning disc pulledthrough during the procedure in the first access site.The operator deviated from the protocol and con-verted the remaining 3 sites (including 2 on thecontralateral limb) to MC. Thus, according to theintent-to-treat protocol, the patient was included inthe closure device group for efficacy analyses. How-ever, each limb was considered separately for thesafety analysis on an as-treated basis. Protamine wasused in 78 of the 100 (78%) patients randomized tothe device (78 of 85 patients; 92% as-treated withheparin) and in 86 of 104 (83%) patients randomizedto MC (86 of 94 patients; 91% as-treated withheparin).

PRIMARY OUTCOME. Compared with MC, use of theclosure device to achieve venous access site closureafter catheterization resulted in an approximately3.3-h (54%) decrease (2.8 � 1.3 h vs. 6.1 � 1.6 h;ANCOVA p < 0.0001) in the primary efficacy outcome,overall mean TTA per patient (Table 2, Figure 3A).

SECONDARY OUTCOMES. The first secondaryoutcome was TPPT (Table 2, Figures 2 and 3B). Therewas a 3.7-h (54%) decrease (3.1 � 1.3 h vs. 6.8 � 1.7 h;ANCOVA p < 0.0001) in TPPT when the closure devicewas compared with MC.

According to the pre-specified hierarchical testingorder, TTH was evaluated next by bootstrap analysis,at the level of individual access site (Table 3,Figure 3C). There was a mean decrease of 7.6 min (6.1� 3.7 min vs. 13.7 � 6.5 min; 95% confidenceinterval: �8.8 to �6.3) in the closure versus MCgroups. The result met pre-specified significancethresholds for noninferiority and superiority. Thetime course of hemostasis in Figure 3E shows that90% of access sites closed with the closure devicereached hemostasis within 7 min, whereas it tookbetween 20 and 25 min for 90% of access sites toreach hemostasis in the MC group.

Consistent with other measures, there was a 3.4-h(52%) decrease in TTDe (3.1 � 1.3 h vs 6.5 � 1.9 h;ANCOVA p < 0.0001) (Table 2, Figure 3D). There wasno statistically significant difference in overall TTDbetween the 2 groups (21.8 � 13.4 h vs. 21.8 � 9.5 h)(Table 2, Figure 3E). Most cases involved an overnightstay with next-day discharge.

TABLE 2 Per-Patient Efficacy Outcomes

Closure Device Manual Compression

p Value*Total

(N ¼ 100)3 Access Sites

(n ¼ 31)4 Access Sites

(n ¼ 69)Total

(N ¼ 104)3 Access Sites

(n ¼ 34)4 Access Sites

(n ¼ 70)

TTA, h†

Mean � SD 2.8 � 1.3 2.5 � 0.8 2.9 � 1.5 6.1 � 1.6 5.9 � 1.2 6.2 � 1.7 <0.0001

Median (min–max) 2.2 (2.0–11.5) 2.2 (2.0–5.6) 2.3 (2.0–11.5) 6.1 (3.4–15.7) 5.3 (4.2–9.1) 6.2 (3.4–15.7) <0.0001

TPPT, h†

Mean � SD 3.1 � 1.3 2.7 � 0.8 3.3 � 1.5 6.8 � 1.7 6.4 � 1.3 6.9 � 1.9 <0.0001

Median (min–max) 2.6 (2.2–11.8) 2.4 (2.2–5.9) 2.7 (2.2–11.8) 6.4 (4.2–15.9) 6.2 (4.5–9.8) 6.6 (4.2–15.9) <0.0001

TTDe, h†

Mean � SD 3.1 � 1.3 2.7 � 0.8 3.2 � 1.5 6.5 � 1.9 6.2 � 1.3 6.6 � 2.2 <0.0001

Median (min–max) 2.5 (2.3–11.7) 2.5 (2.3–5.9) 2.6 (2.3–11.7) 6.3 (4.3–21.3) 5.7 (4.6–9.4) 6.5 (4.3–21.3) <0.0001

TTD, h

Mean � SD 21.8 � 13.4 20.5 � 10.8 22.3 � 14.5 21.8 � 9.5 22.7 � 10.6 21.4 � 9.0 0.98

Median (min–max) 22.3 (2.3–96.1) 22.9 (2.3–48.2) 22.3 (3.5–96.1) 22.1 (5.7–72.9) 22.8 (5.7–71.5) 21.6 (5.8–72.9) 0.85

TTCe, min

Mean � SD 10.5 � 6.0 9.0 � 4.1 11.1 � 6.6 37.6 � 33.2 32.2 � 27.6 40.3 � 35.5 <0.0001

Median (min–max) 10.1 (1.7–47.5) 9.8 (1.7–17.5) 10.2 (2.0–47.5) 25.2 (1.8–132.3) 21.1 (2.0–108.9) 27.8 (1.8–132.3) <0.0001

*The p values for time to ambulation (TTA), total post-procedure time (TPPT), time to discharge eligibility (TTDe), and time to discharge (TTD) from 2-sided t-test for means, and 2-sided Wilcoxon rank-sumtest associated with medians, unadjusted for stratification factor. For time to closure eligibility (TTCe), nominal p values presented for descriptive purposes only. †The primary analysis of covariance p valuesfor TTA, TPPT, and TTDe were <0.0001.

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Finally, TTCe was evaluated (Table 2, Figure 3F).Mean TTCe times were 27 min (72%) shorter for theclosure device compared with MC (10.5 � 6.0 min vs.37.6 � 33.2 min; nominal p < 0.0001). Formal hy-pothesis testing was not pre-specified for thisendpoint in the protocol; therefore, nominal p valuesare presented in Table 2 for descriptive purposes only.

Variability in TTCe among study operators wasobserved in the MC groups. It was mainly driven bythe location of the sheath pull as per the preferenceof the operators. The mean time to sheath removal inthe MC group varied widely based on whether thesheath was removed in the laboratory (n ¼ 39) or atrecovery (n ¼ 65) (14.76 � 17.1 min vs. 51.33 �33.04 min, respectively).

SAFETY OUTCOMES. At 30 days post-procedure,there were zero access site closure�related majorcomplications in either group. As a result, the plan-ned bootstrap analysis could not be performed.Instead, Newcombe’s Wilson score 95% confidenceintervals were constructed both by limb and by pa-tient to estimate confidence intervals accounting forpotential limb correlation in both independent andcompletely correlated scenarios, respectively (7). Theresulting 2-sided 95% confidence intervals for theVVCS-MC differences were �1.9% to 1.8% and �3.6%to 3.7%, respectively. In other words, an absolute 5%or higher VVCS closure device major complicationincidence was ruled out (i.e., rejected with a 2-sidedp < 0.05 in either case), and the noninferiority crite-rion was met.

There were 2 minor complications related tovenous access site closure in the device treatmentgroup and 5 in the MC group (Table 4). In the ultra-sound substudy, minor complications per limb were0.0% in the closure device group and 2.0% in the MCgroup.

Adverse events (any) not related to the accessclosure sites were reported in 19 (19.0%) of thepatients who received the closure device and in 17(16.3%) of the patients who underwent MC(p ¼ 0.71). Serious adverse events not related to theaccess closure sites were reported in 8 (8%) of thedevice group patients and 2 (2%) of patients whounderwent MC (p ¼ 0.06). There were no deaths ineither group. A full listing of the adverse events isavailable in Online Table 1, and serious adverseevents not related to access site closure are listed inOnline Table 2.

Six sites elected to participate in the ultrasoundsubstudy. A total of 25 patients from each treatmentgroup were enrolled. Because 1 patient in the MCgroup declined to return for the ultrasound, 98 ex-aminations were performed in 49 participants. Theultrasound substudy identified no clinically signifi-cant safety issues in either treatment group.

PATIENT-REPORTED EXPERIENCE. Patient surveyresponses indicated that patients in both groupsexhibited a strong preference for the shorter dura-tion of supine bedrest associated with the closuredevice group compared with the MC group(Table 5). Patients in the MC group expressed

FIGURE 3 Primary and Secondary Efficacy Outcomes

The graphs depict the time course for VVCS Closure Device and MC primary and secondary efficacy endpoints. Time to ambulation (A), total post-procedure

time (B), time to hemostasis (C), time to discharge eligibility (D), time to discharge (E), and time to closure eligibility (F). MC ¼ manual compression.

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CENTRAL ILLUSTRATION Results From the Multicenter, Randomized AMBULATE Trial for VenousVascular Closure Following Multi-Access Electrophysiology Procedures

Primary SafetyOutcomes, per limb

Secondary SafetyOutcomes, per limb

Pain Medication UsageDuring Bedrest

Major access site closure-related complication

Minor access site closure-related complication

Any pain medication

0(0.00%) 0(0.00%)

2(1.00%)

Primary Outcome

Hour

s

Time to ambulationp < 0.0001

Total post proceduretime

p < 0.0001

Time to homeostasis, by access sitep < 0.0001

Time to dischargeeligibility

p < 0.00010

0

5

10

15

20

25

30

35

VVCS MC VVCS

VVCS MC

MC VVCS MC

4

2

6

8

10

Min

utes

Secondary outcomes

5(2.40%) 0.45

_

_

24(24%)15(15%)76(76%)

51(49%) 0.000337(36%) 0.00153(51%)

Opioid narcoticNo pain medication

VVCSDevice

258 patients were screenedof which 204 meeting thepre- and intra-proceduralcriteria were enrolled

• Randomized 1:1

Closure Device(VVCS)

100 patients

Manual Compression(MC)

• 13 U.S. sites• 28 enrolling physicians

104 patients

The AMBULATE Trial

p-valueManual

Compression(MC)

VVCS DeviceVASCADE MVP by Cardiva Medical Inc.®

Data are presented as n (%)p-values from one-sided t-test for means, and one-sided Wilcoxon

Safety and Pain Medication Usage Outcomes

Insert VASCADE MVPin procedural sheathand deploy disc

A

C D

B

Remove sheath andplace disc againstvessel wall

Retract sleeve andexpose collagenagainst vessel wall

Collapse disc, removedevice. Collagen left intissue tract at venotomy

Natale, A. et al. J Am Coll Cardiol EP. 2020;6(1):111–24.

MC ¼ manual compression; VVCS ¼ Cardiva VASCADE MVP Closure Device.

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TABLE 3 TTH, per Access Site*

Outcome

Closure Device Access Sites Manual Compression Access Sites

Total(N ¼ 369)

3 Access Sites(n ¼ 93)

4 Access Sites(n ¼ 276)

Total(N ¼ 382)

3 Access Sites(n ¼ 102)

4 Access Sites(n ¼ 280)

TTH, min

Mean � SD 6.1 � 3.7 5.4 � 2.0 6.3 � 4.1 13.7 � 6.5 11.4 � 6.4 14.5 � 6.4

Median (min–max) 5.1 (0.4–33.3) 5.1 (1.3–23.3) 5.1 (0.4–33.3) 11.7 (0.6–37.1) 10.0 (2.9–32.7) 12.5 (0.6–37.1)

*p < 0.0001 for means and medians; 1-sided p value from bootstrap analysis.

TTH ¼ time to hemostasis.

TABLE 4 Access Site Closure–Related Minor Complications at 30 Days and Other Adverse

Events (Limb Level)*

Closure Device(n ¼ 199)

Manual Compression(n ¼ 209) p Value

Any access site closure–related minorcomplication

2 (1.0) 5 (2.4) 0.45

Access site–related hematoma >6 cmdocumented by ultrasound

0 (0.0) 2 (1.0) 0.50

Localized access site infection confirmedand treated with intramuscular or oralantibiotics

1 (0.5) 1 (0.5) 1.00

Arteriovenous fistula not requiringtreatment

0 (0.0) 1 (0.5) 1.00

Pseudoaneurysm requiring thrombin/fibrinadhesive injection or ultrasound-guidedcompression

1 (0.5) 0 (0.0) 0.49

Transient access site–related nerve injury 0 (0.0) 1 (0.5) 1.00

Any access site closure–related adverseevent, excluding major or minor accesssite closure–related complications

15 (7.5) 12 (5.7) 0.55

Access site venous re-bleeding after initialhemostasis confirmed for 5 min

12 (6.0) 6 (2.9) 0.15

Access site hematoma <6 cm 2 (1.0) 5 (2.4) 0.45

Pain at the access site 2 (1.0) 1 (0.5) 0.62

Superficial arterial bleed 1 (0.5) 0 (0.0) 0.49

Access site oozing 1 (0.5) 0 (0.0) 0.49

Right leg edema 0 (0.0) 1 (0.5) 1.00

Values are n (%). *p ¼ 0.45 by 2-sided Fisher exact test, both by limb and by patient (any access site closure�related minor complication). Data were analyzed at the level of events per limb. Due to an intraproceduralprotocol deviation, the limbs in 1 patient were considered separately for the safety analysis, resulting in an oddnumber of limbs for each group. See text for details.

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greater dissatisfaction with the duration of bedrestand level of pain than their counterparts in theclosure device group. Mean satisfaction scores forthe length of time spent on supine bedrest were63% higher in the closure device group comparedwith the MC group, and satisfaction scoresregarding discomfort from supine bedrest were 36%higher (p < 0.0001 for both comparisons). Patientsin the closure device group also indicated 25% lesspain during supine bedrest compared with patientsin the MC group (p ¼ 0.001).

When the 2 groups were queried separately abouthow they would feel if the duration of their bedrestwas altered, patients in the closure device groupindicated that their satisfaction would havedecreased dramatically if they had experienced 2 to 3additional hours of supine bedrest (Table 5).Conversely, patients who underwent MC believedthat they would have preferred spending 2 to 3 fewerhours lying on their backs and would have experi-enced less discomfort and pain.

A total of 30 patients in the closure device group(30%) and 41 patients in the MC group (39%) reportedthat they had previously undergone previous cardiacablation (Table 5). In the MC group, patients who hadprevious ablation rated their current experience asapproximately equal or slightly better than previous(i.e., no significant change in satisfaction with theduration, discomfort, and pain from supine bedrest).However, in the closure device group, patients withprevious ablation reported markedly higher levels ofsatisfaction with the duration, discomfort, and painfrom supine bedrest compared with their previousexperience.PAIN MEDICATION USE. An evaluation of post-procedural use of pain medication showed lower useof pain medications in the closure device group (24%vs. 49%; p ¼ 0.0003) (Online Table 3). When catego-rized according to the most potent drug class pre-scribed per patient, 36% of patients who underwentMC were treated with narcotic drugs compared with15% of patients in the closure device group (58%relative decrease; p ¼ 0.001).

DISCUSSION

The AMBULATE multicenter randomized trial evalu-ated the safety and efficacy of the investigationalvascular closure device, VASCADE MVP, in electro-physiological procedures using venous access.Closure with the VASCADE MVP device had greaterefficacy and safety compared with MC, including forthe primary efficacy endpoint of TTA. Secondary ef-ficacy endpoints were also improved in the closuredevice arm, including TPPT, TTH, and TTDe. TTD wasthe only outcome that was comparable between the 2groups, although there were no instructions in thestudy protocol directing study sites to attemptearlier-than-standard discharge times after standard

TABLE 5 Patient-Reported Outcomes After Bed Rest*

Satisfaction Measure

Closure Device(n ¼ 100)

Manual Compression(n ¼ 104)

p Value†n Mean Rating n Mean Rating

Level 1: all patients

Duration, current episode 100 8.3 � 2.4 102 5.1 � 3.4 <0.0001

Discomfort, current episode 100 7.2 � 3.1 102 5.3 � 3.1 <0.0001

Pain, current episode 100 7.5 � 3.2 102 6.0 � 3.4 0.001

Level 2: patients randomized to VVCS

Duration, if 2–3 h longer 98 2.6 � 3.1 d d d

Discomfort, if 2–3 h longer 98 2.7 � 2.9 d d d

Pain, if 2–3 h longer 98 3.2 � 3.4 d d d

Level 2: patients randomized to MC

Duration, if 2–3 h shorter d d 102 9.1 � 1.7 d

Discomfort, if 2–3 h shorter d d 101 8.4 � 2.2 d

Pain, if 2–3 h shorter d d 100 8.2 � 2.5 d

Level 3: patients with a previous cardiac ablation procedure

Duration, compared with previous experience 30 7.9 � 2.3 39 5.6 � 3.0 0.001

Discomfort, compared with previous experience 30 7.5 � 2.1 39 5.4 � 2.8 0.001

Pain, compared with previous experience 30 7.7 � 2.8 38 5.5 � 2.9 0.002

Values are mean � SD. *Patient-reported satisfaction ratings were scored on a scale of 0 (most unfavorable) to 10 (most favorable). “N” indicates the number of patients ineach study population and “n” indicates the number of patient responses to each question. †Two-sided t-test.

MC ¼ manual compression; VVCS ¼ Cardiva VASCADE MVP venous vascular closure system.

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TTDe. There were no major access site complicationsreported in either group.

Cardiac catheter ablation procedures using eitherradiofrequency energy or cryogenic sources requiremultisite venous access (20,21). Absolute bedrest withminimal limb movement for a certain period isnecessary to achieve effective MC hemostasis (22).MC protocols commonly require at least 10 min ofsustained compression at the access site followed by6 to 8 h of supine bedrest. Prolonged immobilizationcan lead to higher usage of indwelling bladder cath-eters and can also cause discomfort, back pain, andfatigue. In a randomized trial of patients who had acardiac catheterization, intermittent position chang-ing and earlier ambulation and undertaking of self-care activities were shown to be associated with anincrease in satisfaction and comfort, and a decrease inthe fatigue level (16). Early ambulation is also knownto reduce the hospital staff use, thereby increasingthe workflow efficiency (23). Furthermore, extendedimmobility is reported to be associated with high riskof venous thromboembolism, including deep veinthrombosis and pulmonary embolism (24). Moreover,although no formal analysis was undertaken in thisstudy, selected patients were eligible to be dischargedon the same day after being mobile without any painor access site complications.

In our study population, the total post-proceduretime was significantly lower in the closure devicegroup. Removal of the femoral sheath and achievinghemostasis in a short time thereafter, along with early

mobility, were reported to improve patient satisfac-tion, reduce groin complications, as well as post-procedural bedrest, hospital stay, and subsequenthealth care cost (25,26).

Operators worldwide aim for safe venous accessand uncomplicated and adequate hemostasis (26).Achieving hemostasis may be more challenging whenprocedures are performed under uninterrupted anti-coagulation. However, despite the large number ofcases performed under continuous anticoagulation inour study, 90% of access sites closed with the devicereached initial hemostasis within 7 min, whereas ittook between 20 and 25 min for the same outcome inthe MC group. Earlier randomized trials of arterialclosure reported similar results (7,27).

An alternative approach, temporary subcutaneousFigure-of-eight suture to maintain hemostasisafter the venous sheath removal was described inpublished reports (20,28,29). In the single-centerretrospective study conducted by Issa et al. (28), thetime to hemostasis was reported to be significantlyshorter in the Figure-of-eight cohort compared withthe MC group. However, other published trials alsoreported longer immobilization after the removal ofthe Figure-of-eight sutures (20,29). Lakshmanadosset al. (29) reported the post-procedure bedrest time tobe at least 6 h (29), and in the study by Aytemir et al.(20), the time to mobilization was similar in theFigure-of-eight group and the MC cohort. We foundno published prospective trial data of a Figure-of-eight suture to define bedrest times, workflow, or

PERSPECTIVES

COMPETENCY IN MEDICAL KNOWLEDGE: MC followed by

prolonged bedrest is the standard of care for post-procedural

closure of venous access sites in patients undergoing catheter-

based procedures. However, this approach may often lead to pa-

tient discomfort, pain, prolonged immobility, additional inter-

ventions, and delayed discharge. The findings of this randomized

trial demonstrated that the strategy of venous vascular closure

and short bedrest is efficacious, comparedwith usual care, across a

number of primary and secondary patient-centered outcomes.

TRANSLATIONAL OUTLOOK: This was the first randomized

trial to compare the safety andefficacyof an investigational venous

access site closure device with standard MC in achieving hemo-

stasis atmultiple sites following catheter-based electrophysiology

procedures (e.g., atrial fibrillation ablation). We also evaluated

patient satisfaction with recovery and prevalence of pain medica-

tion usage in both groups. Our findings demonstrated the superi-

ority of the vascular closure device in attaining effective

hemostasis at a shorter time and therebyproviding the patients the

ability to ambulate and the satisfaction and freedom to perform

simple self-care tasks. These results indicated that a strategy of

vascular closure with shortened bedrest can improve a variety of

outcomes that are important to patients, improve workflow,

potentially minimize interventions, such as pain medications or

indwelling bladder catheters, and facilitate earlier discharge.

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safety. In the experience of some of the authors, theFigure-of-eight suturing technique is associated withpain at the groin site and some risk of bleeding,particularly with inadvertent vascular injury fromdeeply placed sutures. Still, the cost of the venousclosure device may be a consideration, particularly if>1 is needed. An economic analysis factoring in costdifferences in outcomes based on the AMBULATEtrial is planned.

TTD was comparable between the groups. Theovernight stay might reflect long-standing institu-tional practice. We were cautiously optimistic thatshortened TTA might, in turn, facilitate shorter TTD,including obviating the need for an overnight stay insome cases.

The use of pain medications of all kinds was lowerin the device group compared with patients treatedwith standard of care. This suggested that, as in othersurgical fields, interventions and protocols thatfacilitated early ambulation after surgical proceduresmight help reduce the risk of pain medication oropioid requirements and the associated risks. In arecently published retrospective analysis of ablation,femoral venous closure using the 5-F to 7-F VASCADEVCS device was associated with higher comfort andsatisfaction level and lower catheter-related urinarycomplications compared with MC (30). In that study,patients who had previous experience with the post-ablation recovery procedure expressed a notable in-crease in satisfaction with the shorter duration ofbedrest and for the associated decrease in pain anddiscomfort.STUDY LIMITATIONS. First The complication rateswere low, which could be due to the narrow patientinclusion criteria and stringent pre-screening as partof a controlled randomized trial, as well as high use ofultrasound-guided access. However, in a retrospec-tive study, no access site hematoma, infection, orother complications were reported in real-world pa-tients (31). Second, the protocol to assess the eligi-bility for ambulation was not standardized in the MCgroup. Rather, it was pre-specified that the siteswould follow their standard of care with the rationalethat the goal was to compare the device against usualoperator or institutional care or practice. Third, thiswas an unblinded study, and all care providers evendownstream of the intervention (e.g., nurses) knewthe treatment assignment because it informed clinicalcare. Fourth, our patient-reported outcome ques-tionnaire was not validated or applied in previousstudies. The survey included questions to comparethe current experience of patients with a hypotheticalexperience. In the absence of any validated measures,the questionnaire was developed by a global health

outcome research firm with 3 levels of questions;level 2 questions were hypothetical in nature tounderstand patient preferences regarding pain anddiscomfort. Finally, post-anesthesia assessment datawere not collected, and that could have affectedTTA.

CONCLUSIONS

When used for closure of multiple, 6-F to 12-F venousaccess sites after cardiac catheter ablation, the VAS-CADE MVP closure device shortened TTA and otherclinical measures of the post-procedure recoverycourse, increased patient satisfaction, and decreasedthe use of opioid narcotics, with no increase in com-plications compared with MC.

ACKNOWLEDGMENT The authors thank JeanneMcAdara, PhD, for professional medical writingassistance which was funded by the sponsor.

ADDRESS FOR CORRESPONDENCE: Dr. Mintu Tur-akhia, VA Palo Alto Health Care System, 3801 MirandaAvenue, 111C, Palo Alto California 94304. E-mail:mintu@stanford.edu.

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KEY WORDS ambulation, atrial fibrillation,catheter ablation, femoral access,hemostasis venous access, venous closure

APPENDIX For a complete list of theAMBULATE trial investigators as well as sup-plemental tables and figures, please see theonline version of this paper.