radial versus femoral access for coronary interventions ... · the use of radial access, as an...

J A C C : C A R D I O V A S C U L A R I N T E R V E N T I O N S V O L . 9 , N O . 1 4 , 2 0 1 6

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CORONARY

Radial Versus Femoral Access for CoronaryInterventions Across the Entire Spectrumof Patients With Coronary Artery DiseaseA Meta-Analysis of Randomized Trials

Giuseppe Ferrante, MD, PHD,a Sunil V. Rao, MD,b Peter Jüni, MD,c Bruno R. Da Costa, MSC, PHD,d

Bernhard Reimers, MD,a Gianluigi Condorelli, MD, PHD,a,e Angelo Anzuini, MD,f Sanjit S. Jolly, MD, MSC,g

Olivier F. Bertrand, MD, PHD,h Mitchell W. Krucoff, MD,b Stephan Windecker, MD,i Marco Valgimigli, MD, PHDi

ABSTRACT

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OBJECTIVES The aim of this study was to provide a quantitative appraisal of the effects on clinical outcomes of radial

access for coronary interventions in patients with coronary artery disease (CAD).

BACKGROUND Randomized trials investigating radial versus femoral access for percutaneous coronary interventions

have provided conflicting evidence. No comprehensive quantitative appraisal of the risks and benefits of each approach is

available across the whole spectrum of patients with stable or unstable CAD.

METHODS The PubMed, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov databases were

searched for randomized trials comparing radial versus femoral access for coronary interventions. Data were pooled by

meta-analysis using a fixed-effects or a random-effects model, as appropriate. Pre-specified subgroup analyses according

to clinical presentation, in terms of stable CAD, non–ST-segment elevation acute coronary syndromes, or ST-segment

elevation myocardial infarction were performed.

RESULTS Twenty-four studies enrolling 22,843 participants were included. Compared with femoral access, radial access

was associated with a significantly lower risk for all-cause mortality (odds ratio [OR]: 0.71; 95% confidence interval [CI]:

0.59 to 0.87; p ¼ 0.001, number needed to treat to benefit [NNTB] ¼ 160), major adverse cardiovascular events

(OR: 0.84; 95% CI: 0.75 to 0.94; p ¼ 0.002; NNTB ¼ 99), major bleeding (OR: 0.53; 95% CI: 0.42 to 0.65; p < 0.001;

NNTB ¼ 103), and major vascular complications (OR: 0.23; 95% CI: 0.16 to 0.35; p < 0.001; NNTB ¼ 117). The rates of

myocardial infarction or stroke were similar in the 2 groups. Effects of radial access were consistent across the whole

spectrum of patients with CAD for all appraised endpoints.

CONCLUSIONS Compared with femoral access, radial access reduces mortality and MACE and improves safety,

with reductions in major bleeding and vascular complications across the whole spectrum of patients with CAD.

(J Am Coll Cardiol Intv 2016;9:1419–34) © 2016 by the American College of Cardiology Foundation.

m the aDepartment of Cardiovascular Medicine, Humanitas Research Hospital, Humanitas Clinical and Research Center,

zzano, Italy; bDuke Clinical Research Institute, Durham, North Carolina; cApplied Health Research Centre The HUB, Li Ka Shing

owledge Institute, St. Michael’s Hospital, Department of Medicine, University of Toronto, Toronto, Ontario, Canada; dInstitute

Primary Health Care, University of Bern, Bern, Switzerland; eHumanitas University, Rozzano, Italy; fDepartment of Interven-

nal Cardiology, Humanitas Mater Domini, Castellanza, Italy; gMcMaster University and Population Health Research Institute,

milton Health Sciences, Hamilton, Ontario, Canada; hInterventional Cardiology, Quebec Heart-Lung Institute, Quebec City,

ebec, Canada; and the iDepartment of Cardiology, Swiss Cardiovascular Center Bern, Bern University Hospital, Bern,

itzerland. Dr. Jüni has received research grants to the institution from AstraZeneca, Biotronik, Biosensors International, Eli Lilly,

http://ClinicalTrials.gov

http://crossmark.crossref.org/dialog/?doi=10.1016/j.jcin.2016.04.014&domain=pdf

http://dx.doi.org/10.1016/j.jcin.2016.04.014

ABBR EV I A T I ON S

AND ACRONYMS

ACS = acute coronary

syndrome(s)

CI = confidence interval

MACE = major adverse

cardiovascular event(s)

NACE = net adverse clinical

event(s)

NSTE = non–ST-segment

elevation

NNTB = number of patients

needed to treat for an

additional beneficial outcome

OR = odds ratio

PCI = percutaneous coronary

intervention

STEMI = ST-segment elevation

myocardial infarction

and The M

Biosensors

Medicines

contents of

Manuscript

Ferrante et al. J A C C : C A R D I O V A S C U L A R I N T E R V E N T I O N S V O L . 9 , N O . 1 4 , 2 0 1 6

Radial Versus Femoral Access for Coronary Interventions J U L Y 2 5 , 2 0 1 6 : 1 4 1 9 – 3 4

1420

I n patients with stable or unstable clin-ical presentation undergoing coronaryangiography followed by percutaneous

coronary intervention (PCI), a substantialproportion of major bleeding occurs at thevascular access site (1,2). Bleeding is associ-ated with poor clinical outcomes at short-and long-term follow-up (3,4).

The use of radial access, as an alternativeto femoral access, for coronary interventionsreduces access-site bleeding because of theeasily compressible and superficial anatomyof this artery and improves patient comfort,with early mobility after procedures (5).However, radial access may have a longerlearning curve to develop technical skills,thus requiring higher procedure volumes toachieve and maintain proficiency (5). Inaddition, large multicenter studies investi-

gating the value of the radial compared with thefemoral approach have focused on patients withacute coronary syndromes (ACS) and have come todifferent conclusions with regard to ischemic,bleeding, and combined outcomes. Nevertheless, theadoption of radial access has undergone a rapid in-crease (6). This may be driven partly by evidence fromearlier trials showing that radial access may reducebleeding and has the potential to improve clinicaloutcomes (7,8). In the modern era, the superiority ofradial access over femoral access may be attenuatedbecause of smaller arterial sheaths and targetedanticoagulant agents that reduce bleeding risk.

SEE PAGE 1435

The aim of this study was to provide a comprehen-sive and quantitative assessment of evidence fromearly on as well as contemporary randomized trialsappraising the effects of radial access compared withfemoral access for coronary interventions in patientsacross the whole spectrum of ischemic heart disease.

METHODS

DATA SOURCES AND SEARCH STRATEGY. A meta-analysis of randomized trials was performed accord-ing to the Preferred Reporting Items for SystematicReviews and Meta-Analyses 2009 guidelines (9). Two

edicines Company; and serves as an unpaid member of the steerin

International, St. Jude Medical, and The Medicines Company. Dr.

Company and Terumo for the MATRIX trial. All other authors hav

this paper to disclose.

received March 14, 2016; accepted April 11, 2016.

reviewers (G.F., M.V.) independently identified therelevant studies by an electronic search of the MED-LINE, Embase, Cochrane Central Register ofControlled Trials, and ClinicalTrials.gov databases(from inception to January 2016). The followingsearch terms and key words were used: “radial,”“transradial,” “femoral,” “transfemoral,” and “ran-domized controlled trial.” No language, publicationdate, or publication status restrictions were imposed.Conference proceedings (from 2010 throughDecember 2015) of the American Heart Association,the American College of Cardiology, TranscatheterCardiovascular Therapeutics, and the European So-ciety of Cardiology were also searched through elec-tronic or hand searching. All suitable unpublishedcompleted registered studies were considered forinclusion. We checked the reference lists of identifiedreports, recent editorials, and related reviews.

STUDY SELECTION. Two reviewers (G.F., M.V.) inde-pendently assessed trial eligibility on the basis of titles,abstracts, full-text reports, and further informationfrom investigators as needed.

Discrepancies in study selection were resolved byconsensus.

Eligible trials had to satisfy the followingpre-specified criteria: 1) randomized design thatcompared radial versus femoral access for coronaryintervention; and 2) inclusion of patients undergoingcoronary angiography followed by PCI in at least 50%of cases. In contrast, studies were excluded if theyassessed the comparison of radial versus femoralaccess in patients undergoing coronary diagnosticprocedures only and/or PCI, following coronaryangiography, was performed in <50% cases.

DATA EXTRACTION AND QUALITY ASSESSMENT. Tworeviewers (G.F., M.V.) independently extracted data(baseline characteristics, definition of outcomes,numbers of events) using a standardized dataabstraction form. For 1 study (10), additional infor-mation regarding data on clinical events was providedon request by the principal investigator (S.V.R.).

Two reviewers (G.F., M.V.) independently and sys-tematically assessed the studies’ methodologicalquality using the Risk of Bias Assessment Tool from theCochrane handbook for randomized trials, thusfollowing the approach that identifies selection,

g groups of trials funded by AstraZeneca, Biotronik,

Valgimigli has received institutional grants from The

e reported they have no relationships relevant to the

http://ClinicalTrials.gov

FIGURE 1 Flow Diagram of the Search for Studies Included in the Meta-Analysis

According to the Preferred Reporting Items for Systematic Reviews and

Meta-Analyses Statement

PCI ¼ percutaneous coronary intervention.

J A C C : C A R D I O V A S C U L A R I N T E R V E N T I O N S V O L . 9 , N O . 1 4 , 2 0 1 6 Ferrante et al.J U L Y 2 5 , 2 0 1 6 : 1 4 1 9 – 3 4 Radial Versus Femoral Access for Coronary Interventions

1421

performance, attrition, detection, reporting bias, andother sources of bias for each study and classifies eachof these as low, unclear, or high by analyzing thefollowing 7 domains: random sequence generation,allocation concealment, blinding of participants and ofoutcome assessment, incomplete outcome data, se-lective outcome reporting, and “other issues” (11). Arisk for bias summary reporting each risk-for-bias itemfor each included study was reported (11). Disagree-ments were resolved by consensus of the 2 reviewers.

DATA SYNTHESIS AND DATA ANALYSIS. Outcome measures.There were 2 primary endpoints: all-cause mortalityand major bleeding. Secondary efficacy and safetyoutcomes were myocardial infarction, stroke, thecomposite of major adverse cardiovascular events(MACE), and major vascular complications. The com-posite of net adverse clinical events (NACE) (i.e., MACEand major bleeding) was also assessed, although thisendpoint was available only in a subgroup of studiesenrolling patients with non–ST-segment elevation(NSTE) ACS or ST-segment elevation myocardialinfarction (STEMI). Endpoints were attributed ac-cording to definition and timing used in each study.The definition of MACE consisted of the composite ofdeath, stroke, and myocardial infarction in moststudies. Major bleeding was defined according tothe scales used in each study (12,13). Major vascularcomplications were adjudicated according to thestudy definition or as hematoma >5 cm or pseudoa-neurysm if not reported in each study.

STATISTICAL ANALYSIS. The odds ratios (ORs) with95% confidence intervals (CIs) for the endpoints werecalculated from the available data. Trial-specific ORswere combined with the Mantel-Haenszel fixed-ef-fects model or with the DerSimonian and Lairdrandom-effects model if heterogeneity was statisti-cally significant or I2 >25% (14).

The number of patients needed to treat for anadditional beneficial outcome (NNTB) and the num-ber needed to treat for an additional harmful outcomewere calculated from weighted estimates of pooledORs from the random-effects meta-analytic model,using the macro “metannt,” as: 1/(projected controlgroup event rate � projected treatment group eventrate). The corresponding 95% CI was calculated byusing the 95% CI of the effect size applied to thecontrol group event rate.

We also calculated trial-specific absolute risk dif-ferences with 95% CIs for each endpoint, which werecombined using a fixed-effects or a random-effectsmodel, as appropriate, and reported the number ofevents avoided or caused per 1,000 patients treatedwith the 95% CI.

The presence of heterogeneity among studies wasevaluated with the Cochran Q chi-square test, withp # 0.10 considered to indicate statistical signifi-cance, estimating the between-studies variancetau-square, and using the I2 test to evaluate incon-sistency (15). The I2 statistic is derived from the Qstatistic ([Q � df/Q] � 100) and describes the per-centage of total variation across studies that is due toheterogeneity; values of 25%, 50%, and 75% corre-spond to low, moderate, and high heterogeneity,respectively (15).

The presence of publication bias was investigatedby using the Harbord test and by visual estimationwith the use of contour-enhanced funnel plots (16,17).

TABLE 1 Main Clinical, Angiographic, and Procedural Characteristics of the Included Studies

Study/FirstAuthor (Ref. #) Year

First Author(Ref. #) TRA, n TFA, n

ClinicalSyndrome

Mean Age, yrs

Follow-Up Multicenter Primary Endpoint Primary Statistical ResultTRA TFA

ACCESS 1997 Kiemeneij et al. (24) 300 300 Stable, ACS 61 62 30 days No 1. Access site–relatedendpoint

2. PTCA-related endpoints*

1. p < 0.001(radial better)

2. p ¼ NS

BRAFE 1997 Benit et al. (23) 50 55 Stable, ACS 57.7 58.2 30 days Yes Entry site complicationsand post-stenthospitalization time

p ¼ NS

FARMI 2007 Brasselet et al. (31) 57 57 STEMI 58 60 In-hospital No Peripheral arterialcomplications

p ¼ 0.014 (radial better)

Gan et al. (37) 2009 90 105 STEMI 53.6 52.3 In-hospital Yes NA NA

Hou et al. (38) 2010 100 100 STEMI 64.9 66.2 30 days No NA NA

Li et al. (32) 2007 184 186 STEMI 56.5 55.4 In-hospital No NA NA

Mann et al. (22) 1996 76 76 Stable NA NA In-hospital No NA NA

Mann et al. (28) 1998 68 77 STEMI, NSTEACS

63 62 In-hospital No NA NA

MATRIX 2015 Valgimigli et al. (20) 4,197 4,207 STEMI, NSTEACS

65.6 65.9 30 days Yes 1. Composite of all-causemortality, myocardialinfarction, or stroke

2. Composite of majorbleeding not relatedto CABG or MACE

1. p < 0.03 (radial better)2. p < 0.009

(radial better)

OCEAN RACE 2014 Kołtowski et al. (42) 52 51 STEMI 61 62.8 In-hospital No Composite of major andminor bleeding

p ¼ 0.238

OCTOPLUS 2004 Louvard et al. (25) 192 185 Stable, NSTEACS, STEMI

82.6 83 In-hospital Yes Composite vascularendpoint comprising$1 of the following†

p ¼ 0.029 (radial better)

OUTCLAS 2005 Slagboom et al. (26) 322 322 Stable 60 60 30 days No Not defined —

RADIAL-AMI 2005 Cantor et al. (30) 25 25 STEMI 52 58 30 days Yes 1. Reperfusion time2. Major bleeding,

access sitecomplications

1. p ¼ 0.04(femoral better)

2. p ¼ NS

RADIAMI 2009 Chodór et al. (35) 50 50 STEMI 59.9 59.1 In-hospital No Not defined —

RADIAMI II 2011 Chodór et al. (36) 49 59 STEMI 62.1 57.6 In-hospital No Not defined —

RIFLE-STEACS 2012 Romagnoli et al. (40) 500 501 STEMI 65 65 30 days Yes NACE p ¼ 0.003 (radial better)

RIVAL 2011 Jolly et al. (21) 3,507 3,514 STEMI, NSTE ACS 62 62 30 days Yes Death, myocardialinfarction, stroke,or non-CABG-related major bleeding

p ¼ 0.50

SAFE-PCI 2015 Rao et al. (10) 299 340 Stable, NSTE ACS 63.3 63.9 30 days Yes 1. Bleeding or vascularcomplicationsrequiring intervention

2. Access-site crossover

1. p ¼ 0.122. p < 0.01

(femoral better)

Santas et al. (27) 2009 670 335 Stable, STEMI 66 66 In-hospital No Percentage of procedurescompleted using theassigned approach

p < 0.0001(femoral better)

STEMI RADIAL 2012 Bernat et al. (41) 348 359 STEMI 62.7 61.5 30 days Yes Major bleeding andvascular access-sitecomplications

p ¼ 0.0001(radial better)

Continued on the next page

Ferranteet

al.JACC:CARDIO

VASCULAR

INTERVENTIO

NS

VOL.9,NO.14

,2016

Radial

Versus

Femoral

Access

forCoronary

InterventionsJULY

25,2016:1

419–34

1422

TABLE

1Co

ntinue

d

Stud

y/First

Aut

hor(R

ef.#

)Yea

rFirstAut

hor

(Ref.#

)TR

A,n

TFA,n

Clinical

Synd

rome

Mea

nAge

,yrs

Follow

-Up

Multice

nter

Prim

aryEn

dpoint

Prim

aryStatistica

lRes

ult

TRA

TFA

TEMPU

RA

2003

Saitoet

al.(29)

7772

STEM

I66

67

In-hospital

No

Major

adve

rsecardiac

even

tsp¼

0.44

Vazqu

ez-

Rod

rigue

zet

al.(33)

2010

217

222

STEM

INA

NA

30da

ysNo

NA

NA

Wan

get

al.(39)

2012

60

59ST

EMI

59.8

60.2

In-hospital

No

Not

define

d—

Yanet

al.(34)

2008

5746

STEM

I70

.371.4

30da

ysNo

Not

define

d—

*Necessity

topu

ncture

aseco

ndaccess

site

becauseof

anyproc

edural

failu

re.†

Vascu

larco

mplications

requ

iring

surgical

interven

tion

,blood

tran

sfusion,

aredu

ctionin

hemog

lobinby

$3g/dl

orhe

matoc

ritby

10%,a

cute

arm

orlegisch

emia,forea

rmco

mpa

rtmen

tsynd

rome,

orothe

rva

scular

complications

resultingin

delaye

ddischa

rgefrom

theho

spital.

ACS

¼acuteco

rona

rysynd

rome;

CABG¼

corona

ryartery

bypa

ssgrafting

;FARM

I¼Five

Fren

chArterialA

ccessWithReo

proin

Myo

cardialInfarction;

MACE

¼major

adve

rsecardiova

scular

even

t(s);M

ATR

IX¼

Minim

izingAdv

erse

Hae

morrhag

icEv

ents

byTran

srad

ial

AccessSite

andSy

stem

icIm

plem

entation

ofAng

iox;

NA¼

notav

ailable;

NACE

¼ne

tad

verseclinical

even

t(s);N

STE¼

non–

ST-seg

men

telev

ation;

OCE

ANRACE

¼access

forpe

rcutan

eous

corona

ryinterven

tion

inST

EMI:radial

vs.fem

oral-prosp

ective

;OUTC

LAS¼

Outpa

tien

tCo

rona

ryLo

w-Profile

Ang

ioplasty

Stud

y;PT

CA¼

percutan

eous

tran

slum

inal

corona

ryan

giop

lasty;

RADIAMI¼

Rad

ialV

ersusFe

moral

App

roachforPe

rcutan

eous

Corona

ryInterven

tion

sin

Patien

tsWithAcu

teMyo

cardialInfarction;

RIFLE

-STE

ACS

¼Rad

ial

VersusFe

moral

Ran

domized

Inve

stigationin

ST-Eleva

tion

Acu

teCo

rona

rySy

ndrome;

RIVAL¼

Rad

ialvs

Femoral

AccessforCo

rona

ryInterven

tion

;SA

FE-PCI

¼Stud

yof

AccessSite

forEn

hanc

emen

tof

PCIforWom

en;ST

EMI¼

ST-seg

men

telev

ationmyo

cardial

infarction

;ST

EMIR

ADIAL¼

STElev

ationMyo

cardialInfarction

trea

tedby

RADIALor

femoral

approa

ch;TE

MPU

RA¼

Test

forMyo

cardialInfarction

byProspe

ctiveUnicenter

Ran

domizationforAccessSites;

TFA¼

tran

sfem

oral

access;TR

A¼

tran

srad

ialaccess.


1423

The interpretation and meaning of contour-enhancedfunnel plots have been reported elsewhere (17).Briefly, contour-enhanced funnel plots make itpossible to determine whether the presence of anyobserved asymmetry could be related to publicationbias or to factors other than publication bias, on thebasis of which areas within the graph studies thatseem to be “missing” (to eliminate the asymmetry)would be plotted (17).

As sensitivity analysis, we used a Bayesian methoddeveloped for random-effects meta-analysis on thelog OR scale, reporting OR with 95% credible in-tervals. We implemented this model in a fully prob-abilistic (Bayesian) approach, which will provideposterior probability distributions given the modeland the data but requires that prior distributions bedefined for all parameters in the statistical model. Forthe control groups of each study, we set vague priorson the log of the odds of the event risk using normaldistributions centered at zero with variance of 1,000.We conducted the analyses using weakly informa-tive prior distributions with a half-normal distribu-tion with a mean of 0.5 and a 95% confidenceinterval from 0.02 to 1.4 for tau. We also calculatedthe minimum Bayes factor using the formula re-ported by Goodman (18), where the z score wasderived using the Bayesian estimates of the popu-lation effect “d” and its standard error, and reportedthe strength of evidence of treatment effect onthe basis of the minimum Bayes factor as “weak,”“moderate,” “moderate to strong,” or “strong to verystrong.”Subgroup ana lys i s . The impact of radial access onclinical outcomes was assessed across pre-specifiedsubgroups defined by the type of clinical syn-drome (i.e., stable coronary artery disease, NSTEACS, and STEMI). With respect to the endpoints ofmyocardial infarction and stroke, 2 patient sub-groups only were considered (i.e., stable coronaryartery disease and ACS), with no distinction be-tween NSTE ACS and STEMI, because of the lack ofseparate data.

Furthermore, the effect of radial PCI expertise onclinical outcomes was assessed in a pre-specifiedsubgroup analysis including those studies reportingseparate outcome data according to high or low radialPCI volume or percentage of radial PCIs performed,according to the definition used in each study. Aninteraction test was used to assess the statistical sig-nificance of the difference between summary esti-mates of 2 subgroups as previously recommended,with no adjustment for multiple 2-by-2 comparisons(19). All analyses were conducted according to theintention-to-treat principle.

TABLE 2 Pooled Analysis of Studies Comparing Radial Versus Femoral Access

Endpoint

Number of Events/Number of Patients,

Absolute Event Rate (%)

OR 95% CI p Value Risk Difference (95% CI)Radial Femoral

All-cause death 176/11,359 (1.55) 247/11,114 (2.22) 0.71 0.59 to 0.87 0.001 �0.005 (�0.009 to �0.000)

Major bleeding 123/11,467 (1.07) 233/11,222 (2.07) 0.53 0.42 to 0.65 <0.001 �0.01 (�0.013 to �0.007)

MACE 624/11,207 (5.56) 730/10,948 (6.67) 0.84 0.75 to 0.94 0.002 �0.008 (�0.015 to �0.001)

MI 431/10,240 (4.21) 466/10,292 (4.52) 0.92 0.80 to 1.05 0.22 �0.003 (�0.009 to 0.002)

Stroke 45/9,527 (0.47) 43/9,595 (0.45) 1.05 0.70 to 1.59 0.80 0.0 (�0.002 to 0.002)

Major vascularcomplications

27/11,152 (0.24) 123/10,897 (1.12) 0.23 0.16 to 0.35 <0.001 �0.009 (�0.011 to �0.007)

NACE 626/8,756 (7.1) 776/8,809 (8.8) 0.75 0.61 to 0.91 0.004 �0.022 (�0.039 to �0.006)

CI ¼ confidence interval; MI ¼ myocardial infarction; OR ¼ odds ratio; other abbreviations as in Table 1.



1424

The statistical level of significance was 2-tailedp < 0.05. Stata version 11.2 (StataCorp LP, CollegeStation, Texas), Review Manager version 5.1 (Copen-hagen, Denmark: Cochrane Collaboration), and Win-BUGS version 1.4.3 were used for statistical analyses.

FIGURE 2 Pooled Analysis of Studies Comparing Radial Access Vers

Forest plot reporting trial-specific and summary odds ratios (ORs) with

main analysis and across subgroups. ACS ¼ acute coronary syndrome; N

myocardial infarction. Trial acronyms as in Table 1.

RESULTS

SEARCH RESULTS. Figure 1 displays the PreferredReporting Items for Systematic Reviews and Meta-Analyses flow diagram for study search and selection.

us Femoral Access

95% confidence intervals (CIs) for the endpoint of all-cause death in

STE ¼ non–ST-segment elevation; STEMI ¼ ST-segment elevation


1425

Of the 855 citations screened, a total of 39 random-ized controlled trials were identified. Of these,15 studies were excluded because of a lack of sourcedata in 1 case, enrollment of patients undergoingonly diagnostic coronary angiography (n ¼ 8), or low(<50%) rates of PCI following diagnostic coronaryangiography (n ¼ 6). Therefore, a total of 24 random-ized trials including 22,843 patients with CAD under-going coronary angiography followed by PCI wereselected and included in this meta-analysis (10,20–42).

STUDY CHARACTERISTICS AND BIAS ASSESSMENT.

The main trial and patient characteristics of theincluded studies are reported in Table 1.

In 3 studies (SAFE-PCI [Study of Access Site forEnhancement of PCI for Women] [10], MATRIX[Minimizing Adverse Haemorrhagic Events by Trans-radial Access Site and Systemic Implementation ofAngiox] [20], and RIVAL [Radial vs Femoral Accessfor Coronary Intervention] [21]), data regarding the



cardiovascular events (MACE) in main analysis and across subgroups. AC

STEMI ¼ ST-segment elevation myocardial infarction. Trial acronyms as

endpoints of all-cause death, MACE, and majorbleeding, according to the type of clinical syndrome(i.e., stable coronary artery disease vs. NSTE ACSor NSTE ACS vs. STEMI), could be extracted fromseparate publication (43) or from databases pro-vided by the corresponding investigator (10). A totalof 7 studies enrolled mainly patients with stablecoronary artery disease undergoing elective PCI andwere allocated to the subgroup of patients withstable coronary artery disease at sensitivity analysesstratified on the basis of clinical presentation(10,22–27). Three studies included patients withNSTE ACS (10,20,43), 14 studies included patientswith STEMI (20,29–43). One study included a mixedpopulation of patients with NSTE ACS and thosewith STEMI (28), and was allocated in the subgroupof patients with STEMI at subgroup analyses ofclinical presentation.

Online Figure 1 summarizes systematic biasassessment of the included studies.

us Femoral Access

95% confidence intervals (CIs) for the endpoint of major adverse

S ¼ acute coronary syndrome; NSTE ¼ non–ST-segment elevation;

in Table 1.




1426

Overall, there was a high prevalence of high risk forbias for most domains across most studies, that is, allstudies enrolling patients with stable coronary arterydisease and several studies of patients with with ACS.A low risk for bias was observed in 5 studies(10,20,21,40,41).

HETEROGENEITY. In the main analysis, no detectableheterogeneity for each endpoint, as assessed by the Qchi-square test, was found, and I2 was equal to 0(Online Table 1).

In the subgroup of patients in stable condition, I2

was >25% for the endpoint of MACE (Online Table 2).In the subgroup of patients with NSTE ACS, signifi-cant heterogeneity was found for the endpoints of all-cause death, MACE, and NACE, (Online Table 2).Therefore, trial-specific ORs were combined using therandom-effects method for these endpoints, whilethe fixed-effects model was used for the remainingendpoints.


Forest plot reporting trial-specific and summary odds ratios (ORs) with 95

in main analysis and across subgroups. ACS ¼ acute coronary syndrome


PUBLICATION BIAS AND ASYMMETRY. No evidencefor publication bias was detected by the Harbord testfor all endpoints, except for major bleeding (OnlineTable 3). Contour-enhanced funnel plots for all end-points are reported in Online Figures 2 to 8. Evidencefor asymmetry was found for the endpoints of majorbleeding, major vascular complications, and NACE(Online Figures 3, 7, and 8). Smaller asymmetry wasalso noted for all-cause death (Online Figure 2). Vi-sual assessment of these plots indicated that theobserved asymmetry for major bleeding, majorvascular complications, and NACE was likely to bedue to both publication bias on the basis of statisticalsignificance and other factors. Potential factors couldbe the heterogeneity in the definitions of majorbleeding and major vascular complications acrossstudies, as well as the incomplete reporting of theNACE endpoint in several studies enrolling patientswith STEMI.

us Femoral Access

% confidence intervals (CIs) for the endpoint of myocardial infarction

; NSTE ¼ non–ST-segment elevation; STEMI ¼ ST-segment elevation










1427

OUTCOMES. In the overall population, radial access,compared with femoral access, was associated with alower risk for all-cause mortality (OR: 0.71; 95% CI:0.59 to 0.87; p ¼ 0.001; NNTB ¼ 160) and MACE (OR:0.84; 95% CI: 0.75 to 0.94; p ¼ 0.002; NNTB ¼ 99)(Table 2, Figures 2 and 3, Online Table 4). Rates ofmyocardial infarction and stroke did not differ be-tween the 2 groups (Table 2, Figures 4 and 5). Theradial approach was also associated with fewer majorbleeding events (OR: 0.53; 95% CI: 0.42 to 0.65;p < 0.001; NNTB ¼ 103) and major vascular compli-cations (OR: 0.23; 95% CI: 0.16 to 0.35; p < 0.001;NNTB ¼ 117) (Table 2, Figures 6 and 7, Online Table 4,Central Illustration).

Among patients with ACS, radial access, comparedwith femoral access, was associated with fewer NACE(OR: 0.75; 95% CI: 0.61 to 0. 91; p ¼ 0.004; NNTB ¼ 48)(Table 2, Online Figure 9, Online Table 4).

Similar results with respect to the comparisonof radial versus femoral access on clinical out-comes were obtained by random-effects Bayesian



analysis and across subgroups. ACS ¼ acute coronary syndrome; NSTE ¼ n

infarction. Trial acronyms as in Table 1.

meta-analysis (Table 3). The strength of evidence forthese findings varied depending on endpoints, beingstrong to very strong for major bleeding and majorvascular complications, moderate to strong for all-cause death, and moderate for MACE and NACE.

SUBGROUP ANALYSES. Table 4 reports the results ofsubgroup analyses according to the clinical syn-drome. The effect of the radial approach on allappraised clinical endpoints was consistent across thesubgroups of stable coronary artery disease, NSTEACS, and STEMI (Figures 2 to 7, Table 4). However, aquantitative interaction indicating greater benefit ofradial access on major bleeding among patientswith stable coronary syndrome than with NSTE ACS(p for interaction ¼ 0.01) or STEMI (p for interaction ¼0.06) was observed (Figure 6, Table 3). Trends towardhigher benefit of radial access on NACE were noted inpatients with STEMI compared with NSTE ACS (p forinteraction ¼ 0.06) (Online Figure 9, Table 4).

In a pre-specified subgroup pooled analysis of theRIVAL and MATRIX studies (20,21), radial access,

us Femoral Access

95% confidence intervals (CIs) for the endpoint of stroke in main

on–ST-segment elevation; STEMI ¼ ST-segment elevation myocardial






FIGURE 6 Pooled Analysis of Studies Comparing Radial Access Versus Femoral Access

Forest plot reporting trial-specific and summary odds ratios (ORs) with 95% confidence intervals (CIs) for the endpoint of major bleeding in

main analysis and across subgroups. ACS ¼ acute coronary syndrome; NSTE ¼ non–ST-segment elevation; STEMI ¼ ST-segment elevation




1428

compared with femoral access, was associated withbetter clinical outcomes among centers with highradial expertise, but not among centers with lowradial expertise (Table 5).

DISCUSSION

The main findings of this meta-analysis including22,843 patients across the whole spectrum of patientswith CAD undergoing coronary angiography followedby PCI, if indicated, are as follows: 1) the use of radialcompared with femoral access is associated with asignificant 29% relative risk reduction in all-causemortality and a 16% relative risk reduction inMACE; 2) the use of radial access is associated with alower risk for major bleeding and major vascularcomplications that is reduced by 47% and 77%,respectively; and 3) the rates of myocardial infarction

and stroke after transradial intervention are compa-rable with those of femoral access.

Bayesian analysis confirmed these findings,showing that the level of evidence for a beneficialeffect of radial access was strong to very strong forthe endpoint of major bleeding and major vascularcomplications, moderate to strong for all-causedeath, and moderate for MACE.

Pre-specified subgroup analyses found that thebeneficial effects of radial access on clinical outcomesare largely consistent across stable or unstable pre-sentation as well as type of ACS. Importantly, thebenefits of radial approach were realized at centersthat had high levels of radial expertise, which likelyperformed transradial procedures routinely.

These findings support the use of radial access asthe default approach for coronary angiography fol-lowed by PCI in the whole spectrum of patients with

FIGURE 7 Pooled Analysis of Studies Comparing Radial Access Versus Femoral Access

Forest plot reporting trial-specific and summary odds ratios (ORs) with 95% confidence intervals (CIs) for the endpoint of major vascular

complications in main analysis and across subgroups. ACS ¼ acute coronary syndrome; NSTE ¼ non–ST-segment elevation; STEMI ¼ ST-

segment elevation myocardial infarction. Trial acronyms as in Table 1.


1429

CAD undergoing invasive management and stronglysupport a change in the “femoral first” paradigm to a“radial first” approach.

The potential benefits of the radial approachcompared with femoral access have been suggestedby multiple individual studies and meta-analysesover the course of the past 20 years. However, theradial approach has also been challenged as being themore technically demanding procedure and as suchrequires longer procedure time, greater radiation(44), and a steep learning curve (45,46). Ball et al. (45)reported an inverse relationship between PCI failureand operator volume for transradial proceduresshowing that a case volume of at least 50 PCIs isrequired to achieve proficiency similar to that of op-erators performing >300 cases. A large nationallyrepresentative study in the United States suggestedthat the learning curve may be even shorter withprocedural metrics plateauing at 30 to 50 cases (47).

This meta-analysis provides evidence supportingthe implementation and development of suchtraining programs for radial access across differentsettings. Indeed, at the starting level of training (i.e.,among patients with stable coronary syndromes, thismeta-analysis shows that radial access, comparedwith femoral access, improves safety by significantlyreducing major bleeding and major vascular compli-cations). Of note, the magnitude of these reductions(i.e., 76% and 85% risk reductions, respectively) isnumerically sounder than that observed in the overallpopulation or among patients with ACS. Furthermore,no evidence for interaction between this patientsubgroup and radial access with respect to the end-points of mortality or MACE was observed, thusindicating a consistent beneficial effect of radialaccess in this subgroup. Therefore, these advantagesshould be considered valid reasons to promote pro-ficiency of interventional cardiologists in the radial

CENTRAL ILLUSTRATION Forest Plot Reporting Summary Odds Ratios With 95% ConfidenceIntervals for All Adverse Events, Based on Pooled Analyses of Studies Comparing Radial VersusFemoral Access, in the Main Analysis

Ferrante, G. et al. J Am Coll Cardiol Intv. 2016;9(14):1419–34.

CI ¼ confidence interval; MACE ¼ major adverse cardiovascular event(s); OR ¼ odds ratio.

TABLE 3 Pooled Ana

Random-Effects Baye

Endpoint

All-cause death 0.

Major bleeding 0

MACE 0

MI 0

Stroke 1.

Major vascularcomplications

0.

NACE 0

CrI ¼ credible interval; oth



1430

approach as soon as possible during the learningcurve.

Importantly, this meta-analysis provides thelargest body of evidence on randomized comparisonsbetween radial and femoral access in the subgroup ofpatients with NSTE ACS. A pooled analysis of 3 ran-domized studies enrolling only patients with NSTEACS, RIVAL (21), MATRIX (20), and SAFE-PCI (10),was performed with data provided by the trial in-vestigators (10). Before this analysis was done, dataon patients with NSTE ACS was available from thelarge-scale RIVAL trial only (21). This trial enrolled

lysis of Studies Comparing Radial Versus Femoral Access:

sian Meta-Analysis

OR (95% CrI) Tau-SquareMinimum

Bayes Factor Strength of Evidence

68 (0.49–0.90) 0.33 0.037 Moderate to strong

.45 (0.28–0.62) 0.39 0.0003 Strong to very strong

.83 (0.68–0.96) 0.17 0.085 Moderate

.93 (0.76–1.14) 0.11 0.767 Weak

02 (0.54–1.68) 0.32 0.998 Weak

20 (0.12–0.31) 0.31 5.6 � 10�10 Strong to very strong

.76 (0.54–0.96) 0.27 0.125 Moderate

er abbreviations as in Tables 1 and 2.

nearly 7,000 patients with NSTE ACS or STEMI andreported a lack of significant differences in mortalityor MACE rates between patients randomized to radialor femoral access in the entire study population.However, a significant interaction between the clin-ical syndrome (i.e., STEMI vs. NSTE ACS) and therandomized treatment on ischemic endpoints wasreported, with radial access being associated withsignificant reductions in mortality and MACE amongpatients with STEMI, whereas no such benefit wasobserved in patients with NSTE ACS (43). In therecently published large-scale MATRIX trial (20),which enrolled >8,000 patients with NSTE ACS orSTEMI, radial access was associated with a significant28% relative risk reduction in all-cause mortality anda 15% relative risk reduction for MACE, although thiseffect did not meet the pre-specified alpha level of2.5%. In the SAFE-PCI trial (10)—the first U.S.-based,multicenter, prospective, randomized trial, enrolling1,787 female patients with stable coronary syndromesor ACS—radial access was associated with a significant68% risk reduction in the primary endpoint ofbleeding and vascular complications. Yet focusing onpatients who underwent PCI after index coronaryangiography, no formal advantage was noted forradial over femoral access. This may be explained bythe limited sample size, as a signal for interaction was

TABLE 4 Subgroup Analysis of Studies Comparing Radial Versus Femoral Access Across Different Clinical Syndromes

Stable NSTE ACS STEMI p Value for Interaction

(n ¼ 3,096) p Value (n ¼ 9,876) p Value (n ¼ 9,871) p Value STEMI vs. Stable STEMI vs. NSTE ACS NSTE ACS vs. Stable

All-cause death 0.78 (0.29–2.14) 0.63 0.79 (0.27–2.34) 0.67 0.66 (0.52–0.83) 0.001 0.76 0.76 0.97

Major bleeding 0.24 (0.11–0.52) <0.001 0.71 (0.48–1.04) 0.08 0.51 (0.52–0.83) <0.001 0.06 0.15 0.01

MACE 0.72 (0.43–1.19) 0.20 0.95 (0.66–1.38) 0.79 0.80 (0.67–0.96) 0.015 0.68 0.39 0.35

ACS p Value for Interaction

MI 1.04 (0.69–1.55) 0.85 0.90 (0.78–1.04) 0.17 0.51

Stroke 0.32 (0.01–7.89) 0.49 1.08 (0.71–1.63) 0.72 0.48

Major vascular 0.15 (0.06–0.37) <0.001 0.26 (0.17–0.41) <0.001 0.29

NSTE ACSp Value for interaction(NSTE ACS vs. STEMI)

NACE NA 0.91 (0.70–1.17) 0.46 0.64 (0.48–0.84) 0.001 0.06

Abbreviations as in Tables 1 and 2.

TABLE 5 Subgroup Analysis of Radial Versus Femoral Access Across High- and

Low-Volume Centers

Endpoint High Volume p Value Low Volume p Valuep Value forInteraction

All-cause death 0.49 (0.31–0.77) 0.002 1.07 (0.67–1.71) 0.78 0.018

Major bleeding 0.53 (0.33–0.87) 0.013 0.92 (0.58–1.45) 0.71 0.10

MACE 0.61 (0.49–0.76) <0.001 0.98 (0.77–1.25) 0.89 0.003

NACE 0.60 (0.49–0.74) <0.001 0.96 (0.77–1.20) 0.74 0.0008

Abbreviations as in Tables 1 and 2.


1431

noted between patients undergoing PCI and thoseundergoing diagnostic catheterization only.

This pooled analysis, comprising 9,876 patientswith NSTE ACS, shows that radial access improvessafety and efficacy, with reductions in majorbleeding, mortality, and MACE, consistent with theresults observed in the main analysis. Furthermore, asignificant reduction of the NACE endpoint wasobserved favoring radial access.

Nevertheless, most studies included in this meta-analysis enrolled patients with STEMI. In the STEMI-RADIAL (ST Elevation Myocardial Infarction Treatedby Radial or Femoral Approach) trial (41), no mortalityor MACE reduction with radial access was observedamong 707 patients with STEMI undergoing primaryPCI, while significant reductions in major bleedingand severe access site complications were reported.By contrast, in the RIFLE-STEACS (Radial VersusFemoral Randomized Investigation in ST-ElevationAcute Coronary Syndrome) study (40), whichenrolled 1,001 patients with STEMI, radial access wasassociated with a significant reduction in mortality,MACE, and bleeding. In the subgroup of patients withSTEMI in the RIVAL study, radial access was associ-ated with significant reduction in mortality andMACE, but not in major bleeding (43).

Several studies have reported a strong associationbetween post-procedural bleeding and vascularcomplications and subsequent mortality (3,48–50).Blood transfusions have also been associated withincreased mortality in patients undergoing PCI (48) orwith ACS (51). Furthermore, bleeding has been linkedto increased risk for ischemic events (49,50). Hem-orrhagic and ischemic PCI-related risks are higher inpatients with STEMI (52). The finding of a significantrisk reduction in all-cause mortality and major

bleeding in this meta-analysis, in particular amongpatients with STEMI, reinforces the potential causalthe link between bleeding and mortality. Plausibleexplanations for the beneficial effects of radial accesson mortality reduction are therefore the reductionin major vascular complications, major bleeding,and avoidance of subsequent blood transfusions. Inaddition, the effect of antithrombotic therapies suchas higher dose of heparin and proportion of patientson glycoprotein IIb/IIIa inhibitors and a lower useof bivalirudin used in previous STEMI trials mighthave contributed to enhance the bleeding-sparingeffect of radial access compared with femoral ac-cess (53). However, no evidence for possible treat-ment heterogeneity was previously observed withrespect to mortality or MACE regarding the useof bivalirudin or unfractionated heparin with orwithout glycoprotein inhibitors in the large MATRIXtrial.

In contrast, in the RIVAL study, an interaction be-tween treatment effect and radial PCI volume wasobserved, indicating that radial access could bebeneficial compared with femoral access at high-volume centers for radial procedures (54). In the

PERSPECTIVES

WHAT IS KNOWN? Compared with femoral

access, radial access reduces access-site bleeding

and allows early patient mobilization. Bleeding

is associated with worse short- and long-term

clinical outcomes, in particular among patients

with ACS.

WHAT IS NEW? In patients across the whole

spectrum of coronary heart disease, radial access

improves clinical outcomes compared with femoral

access, as it reduces all-cause mortality and

MACE. Radial access also improves safety, with

reductions in major bleeding and major vascular

complications.

WHAT IS NEXT? The mechanisms by which radial

access is associated with reduced all-cause mortality

compared with femoral access, specifically whether

this involves a reduction in the risk for major bleeding,

require additional studies.



1432

MATRIX study the proportion of PCI undertakentransradially emerged as a potential effect modifierfor both coprimary endpoints of MACE and NACE andfor overall mortality (20). Our pre-specified subgrouppooled analysis of these 2 trials shows that radialaccess improves clinical outcomes at centers withhigh radial PCI volumes. These findings suggest theimportance of developing training programs toimprove the efficacy of radial access in coronaryinterventions.

A well-conducted single randomized trial has theadvantage of including a more homogeneous patientpopulation and assessing well-defined hypotheses,but it may suffer from type II error in detecting sig-nificant differences between treatment arms, leadingto inconclusive findings, whereas a large meta-analysis with robust statistical methods could pro-vide sufficient evidence that may help clinical deci-sion making in areas of uncertainty.

STUDY LIMITATIONS. Our study had important limi-tations. With respect to the endpoint of NACE, whichwas assessed in the subgroup of studies enrollingpatients with ACS, the detection of significant het-erogeneity and bias may reduce the strength of thisanalysis. The presence of significant heterogeneityfor the endpoints of all-cause death and of MACE inthe subgroup of patients with NSTE ACS is anotherlimitation. In general, despite lack of statisticallysignificant heterogeneity, studies differed with re-gard to the enrolled patient population, trial design,primary endpoints, endpoint definition, and length offollow-up. Bleeding complications were classifiedaccording to different scales across studies. Despitethe lack of statistically significant publication bias asassessed by the Harbord test, contour-enhancedfunnel plots showed the presence of some asymme-try, partially related to publication bias, for someendpoints. Furthermore, systematic assessment ofbias found the existence of high risk for bias for moststudies, in particular those enrolling patients withstable ischemic syndromes, which had smaller samplesize and were published earlier.

Although this meta-analysis provides evidencesupporting the superiority of radial approach,compared with the femoral approach, differences inabsolute event rates between groups were small forseveral endpoints, leading to a number needed totreat to benefit or harm greater than 100.

Finally, caution is needed when dealing withinteraction tests for the assessment of differencesbetween subgroups. Indeed, interaction tests may beaffected by type II error, so we cannot definitivelyrule out the existence of smaller than anticipated

differences in treatment effect among subgroups.However, these tests may also carry the risk for type Ierror when performing multiple 2-by-2 comparisonsbetween subgroups.

CONCLUSIONS

This meta-analysis of randomized studies providescomprehensive findings about the clinical effectsof radial compared with femoral access amongpatients undergoing coronary interventions. Therewas strong to very strong evidence that radial access,compared with femoral access, improves safety, withreductions in major bleeding and major vascularcomplications; moderate to strong evidence thatradial access is associated with reduction in all-causedeath; and moderate evidence that radial access re-duces MACE. These findings support the use of radialaccess as the default approach for patients undergo-ing coronary interventions.

REPRINT REQUESTS AND CORRESPONDENCE: Dr.Giuseppe Ferrante, Humanitas Clinical and ResearchCenter, Department of Cardiovascular Medicine,Humanitas Research Hospital, Via Manzoni, 56, 20089Rozzano,Milan, Italy. E-mail: [email protected]. ORDr. Marco Valgimigli, Department of Cardiology, SwissCardiovascular Center Bern, Freiburgstrasse 4, 3010 Bern,Switzerland. E-mail: [email protected].

mailto:[email protected]

mailto:[email protected]


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KEY WORDS bleeding, femoral access,percutaneous coronary intervention,radial access, vascular complications

APPENDIX For supplemental tables andfigures, please see the online version of thisarticle.













































































radial versus femoral access for coronary interventions ... · the use of radial access, as an...

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