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 . 1 1 , N O . 1 , 2 0 1 8

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Impact of Sex on Comparative Outcomesof Radial Versus Femoral Access inPatients With Acute Coronary SyndromesUndergoing Invasive ManagementData From the Randomized MATRIX-Access Trial

Giuseppe Gargiulo, MD,a,b Sara Ariotti, MD,a Pascal Vranckx, MD, PHD,c,d Sergio Leonardi, MD,e Enrico Frigoli, MD,a

Nestor Ciociano, PHARMD,f Carlo Tumscitz, MD,g Francesco Tomassini, MD,h Paolo Calabrò, MD,i

Stefano Garducci, MD,j Gabriele Crimi, MD,e,k Giuseppe Andò, MD, PHD,l Maurizio Ferrario, MD,e

Ugo Limbruno, MD,m Bernardo Cortese, MD,n,o Paolo Sganzerla, MD,p Alessandro Lupi, MD,q Filippo Russo, MD,r

Roberto Garbo, MD,s Arturo Ausiello, MD,t Dennis Zavalloni, MD,u Gennaro Sardella, MD,v

Giovanni Esposito, MD, PHD,b Andrea Santarelli, MD,w Simone Tresoldi, MD,x Marco Stefano Nazzaro, MD, PHD,y

Antonio Zingarelli, MD,z Anna Sonia Petronio, MD,aa Stephan Windecker, MD,a Bruno R. da Costa, PHD,a,bb

Marco Valgimigli, MD, PHDa

ABSTRACT

OBJECTIVES This study sought to assess whether transradial access (TRA) compared with transfemoral access (TFA)

is associated with consistent outcomes in male and female patients with acute coronary syndrome undergoing

invasive management.

BACKGROUND There are limited and contrasting data about sex disparities for the safety and efficacy of TRA versus

TFA for coronary intervention.

METHODS In the MATRIX (Minimizing Adverse Haemorrhagic Events by TRansradial Access Site and Systemic

Implementation of angioX) program, 8,404 patients were randomized to TRA or TFA. The 30-day coprimary outcomes

were major adverse cardiovascular and cerebrovascular events (MACCE), defined as death, myocardial infarction, or

stroke, and net adverse clinical events (NACE), defined as MACCE or major bleeding.

RESULTS Among 8,404 patients, 2,232 (26.6%) were women and 6,172 (73.4%) were men. MACCE and NACE were

not significantly different between men and women after adjustment, but women had higher risk of access site

bleeding (male vs. female rate ratio [RR]: 0.64; p ¼ 0.0016), severe bleeding (RR: 0.17; p ¼ 0.0012), and transfusion

(RR: 0.56; p ¼ 0.0089). When comparing radial versus femoral, there was no significant interaction for MACCE and NACE

stratified by sex (pint ¼ 0.15 and 0.18, respectively), although for both coprimary endpoints the benefit with TRA was

relatively greater in women (RR: 0.73; p ¼ 0.019; and RR: 0.73; p ¼ 0.012, respectively). Similarly, there was no

significant interaction between male and female patients for the individual endpoints of all-cause death (pint ¼ 0.79),

myocardial infarction (pint ¼ 0.25), stroke (pint ¼ 0.18), and Bleeding Academic Research Consortium type 3 or 5

(pint ¼ 0.45).

CONCLUSIONS Women showed a higher risk of severe bleeding and access site complications, and radial access

was an effective method to reduce these complications as well as composite ischemic and ischemic or bleeding

endpoints. (J Am Coll Cardiol Intv 2018;11:36–50) © 2018 by the American College of Cardiology Foundation.

AB BR E V I A T I O N S

AND ACRONYM S

ACS = acute coronary

syndrome(s)

BARC = Bleeding Academic

Research Consortium

CABG = coronary artery bypass

grafting

MACCE = major adverse

cardiovascular and

cerebrovascular event(s)

MI = myocardial infarction

NACE = net adverse clinical

event(s)

NSTE-ACS = non–ST-segment

elevation acute coronary

syndrome(s)

PCI = 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 . 1 1 , N O . 1 , 2 0 1 8 Gargiulo et al.J A N U A R Y 8 , 2 0 1 8 : 3 6 – 5 0 MATRIX-Access Trial and Sex

37

T he advent of combined antithrombotic thera-pies and early invasive management hasreduced the ischemic burden but increased

bleeding risk in patients with acute coronary syn-drome (ACS) (1–3). The use of radial instead of femoralaccess mitigates bleeding while preserving ischemicrisks, thereby providing consistent mortality benefitacross trials (4).

Female patients have increased periproceduralbleeding risk as compared with men (1,5). However,female patients have smaller radial arteries that aremore prone to spasm as well as shorter aortic rootsthan men, which adds to the operative difficulty andmay undermine the efficacy of radial access in thispopulation. Previous studies have shown contrastingevidence about potential sex disparities for the safetyand efficacy of transradial access (TRA) versus trans-femoral access (TFA) (6,7).

SEE PAGE 51RR = rate ratio

TFA = transfemoral access

TRA = transradial access

We sought to investigate the comparative efficacy

and safety outcomes across sex of radial versus femoralaccess in ACS patients participating in the MATRIX-Access (Minimizing Adverse Haemorrhagic Events byTRansradial Access Site and Systemic Implementationof angioX) trial.

From the aDepartment of Cardiology, Bern University Hospital, Bern, Switzer

Federico II University of Naples, Naples, Italy; cDepartment of Cardiology an

Ziekenhuis, Hasselt, Belgium; dFaculty of Medicine and Life Sciences, Has

Dipartimento CardioToracoVascolare, Fondazione IRCCS Policlinico San Ma

Italy; gCardiology Unit, Azienda Ospedaliero Universitaria di Ferrara, Cona, It

Torino 3, Turin, Italy; iDivision of Cardiology, Department of Cardiothoracic

Naples, Italy; jStruttura complessa di Cardiologia ASST di Vimercate, Desio, I

Scassi, Genoa, Italy; lAzienda Ospedaliera Universitaria Policlinico “GaetanmUO Cardiologia, Azienda USL Toscana Sudest, Grosseto, Italy; nASST Fateb

Gabriele Monasterio, Pisa, Italy; pASST Bergamo Ovest, Ospedale di Trevigli

pital “Maggiore della Carità,” Novara, Italy; rCardiovascular Interventional U

Italy; sInterventional Cardiology Unit, Ospedale San Giovanni Bosco, TuruHumanitas Research Hospital, IRCCS, Rozzano, Italy; vDepartment of Cardi

and Geriatric Sciences, Policlinico Umberto I, “Sapienza” University of Rome

Hospital, Rimini, Italy; xCardiology Unit, A.O. Ospedale di Desio, Desio, Ital

lanini, Rome, Italy; zInterventional Cardiology Unit, IRCCS AOU San M

Cardiothoracic and Vascular Department, University of Pisa, Pisa, Italy; an

University of Bern, Bern, Switzerland. The trial was sponsored by the Socie

zation),which receivedgrant support fromTheMedicinesCompanyandTerum

funding. Dr. Gargiulo has received research grant support from the Cardiopa

diologia supported byMSD Italia-Merck Sharp and Dohme Corporation. Dr. Vr

and Bayer Healthcare. Dr. Leonardi has received personal fees from The M

submittedwork; and grant support fromAstraZeneca outside the submittedw

Terumo and Volcano-Phillips; and personal fees from Abbott, Bayer Healthcar

Dr. Cortese has received research grants from AB Medica, Abbott, St. Jude M

AstraZeneca, Daiichi-Sankyo and Eli-Lilly, Stentys, all outside the submitted w

Scientific, and Abbott. Dr Windecker has received research grants to the instit

Valgimigli has received research grant support from The Medicines Compan

Terumo, St. JudeVascular, andAbbottVascular. Dr. Soniahas served as a consu

Windecker has received institutional research grants from Abbott, Boston Sc

andSt. JudeMedical.All other authorshave reported that theyhaveno relation

Manuscript received July 17, 2017; revised manuscript received September 1

METHODS

STUDY DESIGN. The MATRIX-Access was arandomized, multicenter, superiority trialcomparing radial with femoral access in pa-tients with ACS with or without ST-segmentelevation undergoing coronary angiographyand percutaneous coronary intervention(PCI), if indicated (4,8). This was the first of 3trials of the MATRIX program (Clinical-Trials.gov; NCT01433627) and was performedin all patients with an ACS consenting toparticipate in the program. The institutionalreview board at each participating centerapproved the trial, and all patients gavewritten informed consent to participate.

STUDY PATIENTS. Patients were eligible ifthey had an ACS with or without ST-segmentelevation, were scheduled to undergo aninvasive approach, and the interventionalcardiologist was willing to proceed with

either radial or femoral access with expertise forboth, including at least 75 coronary interventionsperformed and at least 50% of interventions in ACSvia the radial route during the previous year. Patients

land; bDepartment of Advanced Biomedical Sciences,

d Critical Care Medicine, Hartcentrum Hasselt, Jessa

selt University, Hasselt, Belgium; eUOC Cardiologia,

tteo, Pavia, Italy; fEUSTRATEGY Association, Forlì,

aly; hCardiology Unit, Ospedali Riuniti di Rivoli, ASL

Sciences, University of Campania “Luigi Vanvitelli,”

taly; kDepartment of Cardiology, ASL3 Ospedale Villa

o Martino,” University of Messina, Messina, Italy;

enefratelli-Sacco, Milan, Italy; oFondazione Toscana

o, Bergamo, Italy; qCardiology Unit, University Hos-

nit, Cardiology Department, S.Anna Hospital, Como,

in, Italy; tCasa di Cura Villa Verde, Taranto, Italy;

ovascular, Respiratory, Nephrologic, Anesthesiologic

, Rome, Italy; wCardiovascular Department, Infermi

y; yInterventional Cardiology Unit, San Camillo-For-

artino, Genoa, Italy; aaCatheterisation Laboratory,

d the bbInstitute of Primary Health Care (BIHAM),

tà Italiana di Cardiologia Inasiva (a nonprofit organi-

o. This substudydidnot receive anydirect or indirect

th PhD program and from the Società Italiana di Car-

anckx has received personal fees fromDaiichi-Sankyo

edicines Company, AstraZeneca, Chiesi, outside the

ork. Dr. Andò has received nonfinancial support from

e Pharmaceuticals, AstraZeneca, and Daiichi-Sankyo.

edical, and Stentys; and personal fees from Abbott,

ork. Dr. Petronio is consultant for Medtronic, Boston

ution from Bracco, Boston Scientific, and Terumo. Dr.

y, Terumo, and AstraZeneca; and personal fees from

ltant forMedtronic, Boston Scientific, andAbbott. Dr.

ientific, Biotronik, Medtronic, Edwards Lifesciences,

ships relevant to the contentsof thispaper todisclose.

2, 2017, accepted September 14, 2017.

TABLE 1 Baseline Characteristics According to Access Site and Sex

Male Patients Female PatientsMale

Patients(n ¼ 6,172)

FemalePatients

(n ¼ 2,232) p ValueRadial

(n ¼ 3,126)Femoral

(n ¼ 3,046) p ValueRadial

(n ¼ 1,071)Femoral

(n ¼ 1,161) p Value

Age, yrs 63.8 � 11.6 64.2 � 11.6 0.18 70.7 � 11.2 70.2 � 11.1 0.36 64.0 � 11.6 70.4 � 11.1 <0.0001

Age $75 yrs 623 (19.9) 636 (20.9) 0.35 445 (41.5) 466 (40.1) 0.50 1,259 (20.4) 911 (40.8) <0.0001

STEMI 1,552 (49.6) 1,541 (50.6) 0.46 449 (41.9) 468 (40.3) 0.44 3,093 (50.1) 917 (41.1) <0.0001

NSTE-ACS 1,574 (50.4) 1,505 (49.4) 0.46 622 (58.1) 693 (59.7) 0.44 3,079 (49.9) 1,315 (58.9) <0.0001

Weight, kg 80.7 � 13.1 80.0 � 12.3 0.020 67.8 � 12.7 69.4 � 13.7 0.0042 80.3 � 12.8 68.6 � 13.2 <0.0001

Body mass index, kg/m2 27.3 � 3.9 27.1 � 3.8 0.0083 26.4 � 4.7 27.0 � 5.1 0.0083 27.2 � 3.8 26.7 � 4.9 <0.0001

Diabetes mellitus 687 (22.0) 656 (21.5) 0.018 272 (25.4) 288 (24.8) 0.75 1,343 (21.8) 560 (25.1) 0.0001

Insulin dependent 135 (4.3) 171 (5.6) 0.75 74 (6.9) 86 (7.4) 0.75 306 (5.0) 160 (7.2) 0.0001

Current smoker 1,218 (39.0) 1,141 (37.5) 0.36 241 (22.5) 287 (24.7) 0.42 2,359 (38.2) 528 (23.7) <0.0001

Hypercholesterolemia 1,292 (41.3) 1,340 (44.0) 0.035 507 (47.3) 552 (47.5) 0.92 2,632 (42.6) 1,059 (47.4) 0.0001

Hypertension 1,839 (58.8) 1,830 (60.1) 0.86 786 (73.4) 856 (73.7) 0.86 3,669 (59.4) 1,642 (73.6) <0.0001

Family history of CAD 861 (27.5) 861 (28.3) 0.53 285 (26.6) 286 (24.6) 0.28 1,722 (27.9) 571 (25.6) 0.035

Previous MI 473 (15.1) 486 (16.0) 0.37 112 (10.5) 132 (11.4) 0.49 959 (15.5) 244 (10.9) <0.0001

Previous PCI 501 (16.0) 474 (15.6) 0.62 109 (10.2) 111 (9.6) 0.63 975 (15.8) 220 (9.9) <0.0001

Radial access 94 (3.0) 63 (2.1) 0.019 25 (2.3) 21 (1.8) 0.38 157 (2.5) 46 (2.1) 0.20

Femoral access 225 (7.2) 234 (7.7) 0.47 51 (4.8) 52 (4.5) 0.75 459 (7.4) 103 (4.6) <0.0001

Both radial and femoral access 29 (0.9) 32 (1.1) 0.63 7 (0.7) 3 (0.3) 0.16 61 (1.0) 10 (0.4) 0.017

Access site unknown 153 (4.9) 145 (4.8) 0.81 26 (2.4) 35 (3.0) 0.40 298 (4.8) 61 (2.7) <0.0001

Previous CABG 92 (2.9) 124 (4.1) 0.016 19 (1.8) 22 (1.9) 0.83 216 (3.5) 41 (1.8) 0.0001

Previous TIA or stroke 135 (4.3) 147 (4.8) 0.34 60 (5.6) 83 (7.1) 0.14 282 (4.6) 143 (6.4) 0.0007

Peripheral vascular disease 249 (8.0) 272 (8.9) 0.17 92 (8.6) 100 (8.6) 0.98 521 (8.4) 192 (8.6) 0.82

COPD 182 (5.8) 201 (6.6) 0.21 68 (6.3) 82 (7.1) 0.50 383 (6.2) 150 (6.7) 0.39

History of renal failure 36 (1.2) 36 (1.2) 0.91 10 (0.9) 23 (2.0) 0.041 72 (1.2) 33 (1.5) 0.26

Dialysis 3 (0.1) 3 (0.1) 1.00 1 (0.1) 1 (0.1) 1.00 6 (0.1) 2 (0.1) 0.92

Continued on the next page

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MATRIX-Access Trial and Sex J A N U A R Y 8 , 2 0 1 8 : 3 6 – 5 0

38

presenting with non–ST-segment elevation ACS(NSTE-ACS) were eligible if they had a historyconsistent with new or worsening ischemia, occur-ring at rest or with minimal activity within 7 daysbefore randomization, and fulfilled at least 2 high-risk criteria (4,8). Patients with ST-segment eleva-tion myocardial infarction were eligible if theypresented within 12 h of the onset of symptoms orbetween 12 and 24 h after symptom onset if there wasevidence of continued ischemia or previous fibrino-lytic treatment and if they had ST-segment elevationof at least 1 mm in 2 or more contiguous leads, newleft bundle branch block, or true posterior MI. Themain inclusion and exclusion criteria were previouslyreported (4,8).

STUDY PROTOCOL AND RANDOMIZATION. Beforethe start of angiography, patients were randomlyassigned 1:1 to radial or femoral access for diagnosticangiography and PCI, if indicated, using a web-based system to ensure adequate concealment of

allocation. The randomization sequence was com-puter generated, blocked, and stratified by site,intended new or ongoing use of ticagrelor orprasugrel, type of ACS (ST-segment elevationmyocardial infarction or troponin-positive ortroponin-negative NSTE-ACS), and anticipated useof immediate PCI. Access site management duringand after the diagnostic or therapeutic procedurewas left to the discretion of the treating physician,and closure devices were allowed as per local prac-tice. The use of anticoagulant agents outside theprotocol of the MATRIX program was not allowed.Bivalirudin administration was consistent with theapproved product labeling, whereas unfractionatedheparin was dosed at 70 to 100 U/kg in patients notreceiving glycoprotein IIb or IIIa inhibitors and at50 to 70 U/kg in patients receiving glycoprotein IIbor IIIa inhibitors. Use of all other antithromboticmedications, including oral antiplatelet agentsand nonantithrombotic medications, such as beta-blockers, angiotensin-converting enzyme inhibitors,

TABLE 1 Continued

Male Patients Female PatientsMale

Patients(n ¼ 6,172)

FemalePatients

(n ¼ 2,232) p ValueRadial

(n ¼ 3,126)Femoral

(n ¼ 3,046) p ValueRadial

(n ¼ 1,071)Femoral

(n ¼ 1,161) p Value

Clinical presentation

Cardiac arrest 59 (1.9) 66 (2.2) 0.44 26 (2.4) 17 (1.5) 0.098 125 (2.0) 43 (1.9) 0.78

Killip class

I 2,845 (91.0) 2,781 (91.3) 0.69 951 (88.8) 1,019 (87.8) 0.45 5,626 (91.2) 1,970 (88.3) 0.0001

II 193 (6.2) 197 (6.5) 0.64 75 (7.0) 104 (9.0) 0.089 390 (6.3) 179 (8.0) 0.0061

III 56 (1.8) 49 (1.6) 0.58 32 (3.0) 30 (2.6) 0.56 105 (1.7) 62 (2.8) 0.0018

IV 32 (1.0) 19 (0.6) 0.083 13 (1.2) 8 (0.7) 0.27 51 (0.8) 21 (0.9) 0.61

Previous lytic therapy 73 (2.3) 83 (2.7) 0.33 21 (2.0) 21 (1.8) 0.88 156 (2.5) 42 (1.9) 0.085

Systolic arterial pressure, mm Hg 138.3 � 25.1 138.1 � 25.4 0.80 139.1 � 26.8 140.7 � 26.3 0.16 138.2 � 25.2 139.9 � 26.6 0.0081

Heart rate, beats/min 75.8 � 16.3 75.3 � 16.4 0.27 77.9 � 17.1 77.9 � 17.7 0.97 75.5 � 16.4 77.9 � 17.4 <0.0001

Left ventricular ejection fraction, % 51.1 � 9.5 51.0 � 9.6 0.48 51.7 � 9.8 50.6 � 10.2 0.0093 51.0 � 9.5 51.1 � 10.0 0.81

eGFR 86.2 � 24.9 85.8 � 24.5 0.54 78.4 � 26.2 76.9 � 27.0 0.19 86.0 � 24.7 77.6 � 26.6 <0.0001

<60 ml/min/1.73 m2 433 (13.9) 399 (13.2) 0.39 267 (25.2) 316 (27.5) 0.23 832 (13.6) 583 (26.4) <0.0001

<30 ml/min/1.73 m2 20 (0.6) 19 (0.6) 0.94 15 (1.4) 30 (2.6) 0.047 39 (0.6) 45 (2.0) <0.0001

Medications before the cath lab

Aspirin 2,960 (94.7) 2,884 (94.7) 0.99 996 (93.0) 1,070 (92.2) 0.45 5,844 (94.7) 2,066 (92.6) 0.0003

Clopidogrel 1,445 (46.2) 1,386 (45.5) 0.57 570 (53.2) 611 (52.6) 0.78 2,831 (45.9) 1,181 (52.9) <0.0001

Prasugrel 411 (13.1) 402 (13.2) 0.95 74 (6.9) 66 (5.7) 0.23 813 (13.2) 140 (6.3) <0.0001

Ticagrelor 754 (24.1) 758 (24.9) 0.48 224 (20.9) 271 (23.3) 0.17 1,512 (24.5) 495 (22.2) 0.028

Enoxaparin 476 (15.2) 488 (16.0) 0.39 211 (19.7) 254 (21.9) 0.21 964 (15.6) 465 (20.8) <0.0001

Fondaparinux 309 (9.9) 332 (10.9) 0.19 119 (11.1) 136 (11.7) 0.65 641 (10.4) 255 (11.4) 0.17

ACE inhibitor 915 (29.3) 899 (29.5) 0.83 338 (31.6) 402 (34.6) 0.12 1,814 (29.4) 740 (33.2) 0.0009

Angiotensin II receptor blocker 290 (9.3) 290 (9.5) 0.74 160 (14.9) 172 (14.8) 0.93 580 (9.4) 332 (14.9) <0.0001

Statins 1,356 (43.4) 1,303 (42.8) 0.63 456 (42.6) 560 (48.2) 0.0073 2,659 (43.1) 1,016 (45.5) 0.047

Beta-blocker 1,216 (38.9) 1,206 (39.6) 0.58 478 (44.6) 569 (49.0) 0.038 2,422 (39.2) 1,047 (46.9) <0.0001

Warfarin 44 (1.4) 39 (1.3) 0.66 28 (2.6) 25 (2.2) 0.47 83 (1.3) 53 (2.4) 0.0010

PPI 1,552 (49.6) 1,546 (50.8) 0.38 606 (56.6) 646 (55.6) 0.65 3,098 (50.2) 1,252 (56.1) <0.0001

Previous unfractionated heparin 991 (31.7) 961 (31.5) 0.90 248 (23.2) 276 (23.8) 0.73 1,952 (31.6) 524 (23.5) <0.0001

Bivalirudin 4 (0.1) 2 (0.1) 0.69 0 (0.0) 0 (0.0) 1.00 6 (0.1) 0 (0.0) 0.35

Values are mean � SD or n (%).

ACE ¼ angiotensin-converting enzyme; CABG ¼ coronary artery bypass graft; CAD ¼ coronary artery disease; COPD ¼ chronic obstructive pulmonary disease; eGFR ¼ estimated glomerular filtration rate;MI ¼ myocardial infarction; NSTE-ACS ¼ non–ST-segment elevation acute coronary syndrome; PCI ¼ percutaneous coronary intervention; PPI ¼ proton pump inhibitor; STEMI ¼ ST-segment elevationmyocardial infarction; TIA ¼ transient ischemic attack.

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 . 1 1 , N O . 1 , 2 0 1 8 Gargiulo et al.J A N U A R Y 8 , 2 0 1 8 : 3 6 – 5 0 MATRIX-Access Trial and Sex

39

and other antihypertensive agents, were allowed asper guidelines (9).

STUDY OUTCOMES. Two coprimary 30-day compos-ite outcomes were pre-specified: major adverse car-diovascular and cerebrovascular events (MACCE),defined as the composite of all-cause mortality, MI, orstroke; and net adverse clinical events (NACE),defined as the composite of MACCE or noncoronaryartery bypass grafting–related major bleeding(Bleeding Academic Research Consortium [BARC]type 3 or 5) (10). Secondary outcomes includedeach component of the composite outcomes,

cardiovascular mortality, and stent thrombosis.Bleeding was also assessed and adjudicated on thebasis of the Thrombolysis In Myocardial Infarctionand GUSTO (Global Utilization of Streptokinase andTissue Plasminogen Activator for Occluded CoronaryArteries) scales (11,12). Stent thrombosis was definedas the definite or probable occurrence of a stent-related thrombotic event according to the AcademicResearch Consortium classification (13). All outcomeswere pre-specified (4,8). An independent clinicalevents committee blinded to treatment allocationadjudicated all suspected outcome events byreviewing relevant medical records after site

TABLE 2 Procedural Characteristics According to Access Site and Sex

Male Patients Female PatientsMale

Patients(n ¼ 6,172)

FemalePatients

(n ¼ 2,232) p ValueRadial

(n ¼ 3,126)Femoral

(n ¼ 3,046) p ValueRadial

(n ¼ 1,071)Femoral

(n ¼ 1,161) p Value

No PCI attempted after coronary angiography 490 (15.7) 501 (16.4) 0.41 337 (31.5) 342 (29.5) 0.30 991 (16.1) 679 (30.4) <0.0001

CABG 130 (4.2) 122 (4.0) 0.76 25 (2.3) 33 (2.8) 0.45 252 (4.1) 58 (2.6) 0.0016

Patient with significant lesion and medicaltreatment

246 (7.9) 243 (8.0) 0.87 244 (22.8) 256 (22.0) 0.68 489 (7.9) 500 (22.4) <0.0001

Patient without significant lesion 114 (3.6) 136 (4.5) 0.10 68 (6.3) 53 (4.6) 0.063 250 (4.1) 121 (5.4) 0.0073

PCI attempted 2,634 (84.3) 2,542 (83.5) 0.39 734 (68.5) 816 (70.3) 0.37 5,176 (83.9) 1,550 (69.4) <0.0001

PCI completed 2,634 (84.3) 2,542 (83.5) 0.39 733 (68.4) 815 (70.2) 0.37 5,176 (83.9) 1,548 (69.4) <0.0001

Crossover 162 (5.2) 72 (2.4) <0.0001 81 (7.6) 24 (2.1) <0.0001 234 (3.8) 105 (4.7) 0.037

Medications in the cath lab

Aspirin 161 (5.2) 193 (6.3) 0.045 61 (5.7) 66 (5.7) 0.99 354 (5.7) 127 (5.7) 0.90

Clopidogrel 200 (6.4) 180 (5.9) 0.42 69 (6.4) 74 (6.4) 0.95 380 (6.2) 143 (6.4) 0.66

Prasugrel 281 (9.0) 246 (8.1) 0.20 54 (5.0) 45 (3.9) 0.18 527 (8.5) 99 (4.4) <0.0001

Ticagrelor 283 (9.1) 297 (9.8) 0.35 98 (9.2) 98 (8.4) 0.55 580 (9.4) 196 (8.8) 0.38

Glycoprotein IIb/IIIa inhibitor 473 (15.1) 423 (13.9) 0.17 100 (9.3) 99 (8.5) 0.50 896 (14.5) 199 (8.9) <0.0001

Planned GPI 354 (11.3) 307 (10.1) 0.11 65 (6.1) 65 (5.6) 0.64 661 (10.7) 130 (5.8) <0.0001

Bailout GPI 119 (3.8) 116 (3.8) 1.00 35 (3.3) 34 (2.9) 0.64 235 (3.8) 69 (3.1) 0.12

Unfractionated heparin 1,568 (50.2) 1,415 (46.5) 0.0036 464 (43.3) 449 (38.7) 0.026 2983 (48.3) 913 (40.9) <0.0001

Unfractionated heparin, U/kg 73.6 � 30.1 73.7 � 28.8 0.92 81.9 � 31.8 79.2 � 27.3 0.20 73.7 � 29.5 80.5 � 29.6 <0.0001

Subtherapeutic regimen (<50 U/kg) 356 (11.4) 258 (8.5) 0.00013 106 (9.9) 75 (6.5) 0.0030 614 (9.9) 181 (8.1) 0.015

Therapeutic regimen ($50 U/kg) 1,212 (38.8) 1,157 (38.0) 0.52 358 (33.4) 374 (32.2) 0.54 2,369 (38.4) 732 (32.8) <0.0001

Bivalirudin 1,332 (42.6) 1,300 (42.7) 0.96 387 (36.1) 437 (37.6) 0.46 2,632 (42.6) 824 (36.9) <0.0001

Prolonged infusion post-PCI 672 (21.5) 647 (21.2) 0.81 197 (18.4) 224 (19.3) 0.59 1,319 (21.4) 421 (18.9) 0.012

Average duration of post-PCI bivalirudininfusion

360.0 � 204.5 372.2 � 269.9 0.35 370.5 � 293.9 403.7 � 286.3 0.24 366.0 � 238.8 388.2 � 290.0 0.13

Full bivalirudin regimen post-PCI 241 (7.7) 225 (7.4) 0.63 82 (7.7) 78 (6.7) 0.39 466 (7.6) 160 (7.2) 0.57

Average duration of full bivalirudinregimen

249.3 � 64.8 272.3 � 292.1 0.23 288.1 � 267.7 270.7 � 153.7 0.62 260.4 � 208.3 279.6 � 219.1 0.32

Low bivalirudin regimen post-PCI 431 (13.8) 422 (13.9) 0.94 115 (10.7) 146 (12.6) 0.18 853 (13.8) 261 (11.7) 0.011

Average duration of low bivalirudinregimen

421.9 � 228.5 425.5 � 241.3 0.82 429.2 � 298.8 474.8 � 314.5 0.24 423.7 � 234.8 454.7 � 307.9 0.094

Intra-aortic balloon pump 51 (1.6) 68 (2.2) 0.086 33 (3.1) 34 (2.9) 0.83 119 (1.9) 67 (3.0) 0.0037

PCI completed (n ¼ 2,634) (n ¼ 2,542) (n ¼ 733) (n ¼ 815) (n ¼ 5,176) (n ¼ 1,548)

TIMI flow grade 3 in all treated lesions 2,501 (95.0) 2,421 (95.2) 0.63 695 (94.8) 773 (94.8) 0.98 4,922 (95.1) 1,468 (94.8) 0.67

Coronary stenosis <30% in all treated lesions 2,524 (95.8) 2,423 (95.3) 0.38 695 (94.8) 780 (95.7) 0.41 4,947 (95.6) 1,475 (95.3) 0.64

Procedural success in all treated lesions 2,446 (92.9) 2,361 (92.9) 0.98 677 (92.4) 756 (92.8) 0.76 4,807 (92.9) 1,433 (92.6) 0.69

Duration of procedure, min 51.8 � 29.1 50.0 � 28.3 0.017 45.6 � 26.9 45.6 � 27.7 1.00 50.9 � 28.7 45.6 � 27.3 <0.0001

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monitoring by Trial Form Support (Lund, Sweden) inItaly and the Netherlands, FLS-Research Support(Barcelona, Spain) in Spain, and Gothia Forum (VästraGötaland) in Sweden.

STATISTICAL ANALYSIS. Statistical analyses wereperformed by an academic statistical group led by 1 ofthe authors (B.R.d.C.), who had access to the fulldeidentified data set.

The trial was powered for superiority on the 2coprimary composite outcomes at 30 days expecting a

rate reduction of 30%, corresponding to rate ratio(RR) of 0.70.

All analyses were performed per intention-to-treatprinciple, including all patients in the analysis basedon the allocated access. Events up to 30 days post-randomization were considered. We analyzed pri-mary and secondary outcomes separately for maleand female patients as time to first event using theMantel-Cox method, accompanied by log-ranktests to calculate corresponding 2-sided p values.We did not perform any adjustments for multiple

TABLE 2 Continued

Male Patients Female PatientsMale

Patients(n ¼ 6,172)

FemalePatients

(n ¼ 2,232) p ValueRadial

(n ¼ 3,126)Femoral

(n ¼ 3,046) p ValueRadial

(n ¼ 1,071)Femoral

(n ¼ 1,161) p Value

Fluoroscopic time, min 11.0 (6.7–17.1) 9.7 (5.5–15.2) 0.88 9.2 (5.0–15.0) 8.1 (4.2–14.4) 0.43 10.2 (6.0–16.2) 9.0 (4.5–14.6) 0.27

Treated vessel(s) per patient

Left main coronary artery 107 (4.1) 88 (3.5) 0.26 45 (6.1) 31 (3.8) 0.033 195 (3.8) 76 (4.9) 0.039

Left anterior descending artery 1,318 (50.1) 1,248 (49.2) 0.51 367 (50.1) 402 (49.3) 0.75 2,566 (49.6) 769 (49.7) 0.93

Left circumflex artery 707 (26.9) 709 (27.9) 0.39 197 (26.9) 200 (24.5) 0.29 1,416 (27.4) 397 (25.7) 0.18

Right coronary artery 872 (33.1) 833 (32.8) 0.81 244 (33.3) 289 (35.5) 0.38 1,705 (33.0) 533 (34.5) 0.28

Bypass graft 18 (0.7) 33 (1.3) 0.025 2 (0.3) 3 (0.4) 0.74 51 (1.0) 5 (0.3) 0.015

At least 2 vessels treated 344 (13.1) 339 (13.4) 0.76 107 (14.6) 101 (12.4) 0.20 683 (13.2) 208 (13.4) 0.80

Lesions treated per patient 1.0 (1.0–1.0) 1.0 (1.0–1.0) 0.92 1.0 (1.0–1.0) 1.0 (1.0–1.0) 0.71 1.0 (1.0–1.0) 1.0 (1.0–1.0) 0.52

1 2,068 (78.5) 1,993 (78.5) 576 (78.7) 657 (80.6) 4,061 (78.5) 1,233 (79.7)

2 454 (17.2) 448 (17.6) 132 (18.0) 133 (16.3) 902 (17.4) 265 (17.1)

3 or more 111 (4.2) 98 (3.9) 24 (3.3) 25 (3.1) 209 (4.0) 49 (3.2)

At least 1 complex lesion 1,393 (52.9) 1,306 (51.4) 0.29 375 (51.2) 398 (48.8) 0.35 2,699 (52.2) 773 (49.9) 0.13

Median number of stents per patient 1.0 (1.0–2.0) 1.0 (1.0–2.0) 0.13 1.0 (1.0–2.0) 1.0 (1.0–2.0) 0.62 1.0 (1.0–2.0) 1.0 (1.0–2.0) 0.49

Overall stent length per patient, mm 71.3 � 44.9 70.5 � 44.5 0.54 66.6 � 39.7 66.9 � 42.7 0.88 70.9 � 44.7 66.8 � 41.3 0.0018

Lesions

Number of lesions with PCI (n ¼ 3,332) (n ¼ 3,205) (n ¼ 919) (n ¼ 1,000) (n ¼ 6,537) (n ¼ 1,919)

Lesions stented 3,052 (91.6) 2,892 (90.2) 0.070 826 (89.9) 909 (90.9) 0.57 5,944 (90.9) 1,735 (90.4) 0.51

At least 1 drug-eluting stent 2,251 (67.6) 2,150 (67.1) 0.51 565 (61.5) 647 (64.7) 0.068 4,401 (67.3) 1,212 (63.2) 0.0011

At least 1 bare-metal stent 801 (24.0) 742 (23.2) 0.77 261 (28.4) 262 (26.2) 0.093 1,543 (23.6) 523 (27.3) 0.0016

Lesions not stented 280 (8.4) 313 (9.8) 0.070 93 (10.1) 91 (9.1) 0.57 593 (9.1) 184 (9.6) 0.51

TIMI flow grade pre-procedure

0 or 1 1,289 (38.7) 1,254 (39.2) 0.80 342 (37.2) 371 (37.1) 0.79 2,543 (38.9) 713 (37.2) 0.070

2 428 (12.9) 417 (13.0) 0.86 103 (11.2) 113 (11.3) 0.95 845 (12.9) 216 (11.3) 0.070

3 1,613 (48.4) 1,532 (47.8) 0.90 474 (51.6) 516 (51.6) 0.81 3,145 (48.1) 990 (51.6) 0.0042

TIMI flow grade post-procedure

0 or 1 58 (1.7) 53 (1.7) 0.81 19 (2.1) 20 (2.0) 0.94 111 (1.7) 39 (2.0) 0.66

2 82 (2.5) 74 (2.3) 0.75 23 (2.5) 27 (2.7) 0.80 156 (2.4) 50 (2.6) 0.53

3 3,190 (95.8) 3,076 (96.0) 0.65 877 (95.4) 953 (95.3) 0.31 6,266 (95.9) 1,830 (95.4) 0.50

Coronary stenosis <30% 3,215 (96.5) 3,080 (96.2) 0.41 870 (94.7) 959 (95.9) 0.36 6,295 (96.4) 1,829 (95.3) 0.21

Procedural success 3,129 (93.9) 3,012 (94.0) 0.91 852 (92.7) 935 (93.5) 0.55 6,141 (93.9) 1,787 (93.1) 0.24

Number of lesions stented (n ¼ 3,052) (n ¼ 2,892) (n ¼ 826) (n ¼ 909) (n ¼ 5,944) (n ¼ 1,735)

Total stent length per lesion, mm 26.2 � 14.5 26.0 � 14.0 0.49 25.1 � 14.5 25.9 � 14.6 0.34 26.1 � 14.3 25.5 � 14.5 0.16

Average stent diameter per lesion, mm 3.1 � 0.5 3.1 � 0.5 0.74 3.0 � 0.4 2.9 � 0.4 0.33 3.1 � 0.5 3.0 � 0.4 <0.0001

At least 1 direct stenting 697 (22.8) 641 (22.2) 0.68 166 (20.1) 195 (21.5) 0.30 1,338 (22.5) 361 (20.8) 0.14

Post-dilatation 1,382 (45.3) 1,304 (45.1) 0.92 344 (41.6) 418 (46.0) 0.13 2,686 (45.2) 762 (43.9) 0.28

Values are mean � SD, n (%), or median (range).

GPI ¼ glycoprotein IIb/IIIa inhibitor; PCI ¼ percutaneous coronary intervention; TIMI ¼ Thrombolysis In Myocardial Infarction.

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comparisons but set the alpha error at 2.5% to cor-rect for the 2 coprimary outcomes. We analyzedsecondary outcomes with a 2-sided alpha value setat 5% to allow conventional interpretation of results.Survival curves were constructed using Kaplan-Meier estimates. We performed stratified analysesaccording to the pre-specified subgroup of random-ization to heparin or bivalirudin, and estimated

possible interaction terms across ordered groupsseparately for the male and female study pop-ulations. We also analyzed clinical outcomes in theoverall population irrespective of randomized accessto compare male and female patients, but due to thesignificant differences in baseline and proceduralcharacteristics, multivariable adjustment was per-formed including the following variables: age, type

TABLE 3 Clinical Outcomes at 30 Days in Male and Female Patients

MalePatients

(n ¼ 6,172)

FemalePatients

(n ¼ 2,232)

Rate Ratio(95% CI)

(Unadjusted)Unadjustedp Value

Rate Ratio(95% CI)(Adjusted)

Adjustedp Value

Death, MI, stroke 560 (9.1) 238 (10.7) 0.84 (0.72–0.98) 0.030 1.04 (0.88–1.22) 0.67

Death, MI, stroke, BARC type 3 or 5 624 (10.2) 272 (12.2) 0.82 (0.70–0.95) 0.0071 1.02 (0.88–1.20) 0.76

Death, MI, stroke, BARC type 3 or 5, TVR, ST 636 (10.4) 274 (12.3) 0.83 (0.71–0.96) 0.011 1.03 (0.88–1.20) 0.74

Death 91 (1.5) 66 (3.0) 0.49 (0.36–0.68) <0.0001 0.80 (0.56–1.16) 0.24

Death cardiovascular 88 (1.4) 61 (2.7) 0.52 (0.37–0.72) 0.0001 0.82 (0.56–1.19) 0.30

MI 460 (7.5) 169 (7.6) 0.98 (0.81–1.17) 0.80 1.11 (0.92–1.34) 0.29

Stroke 20 (0.3) 12 (0.5) 0.60 (0.29–1.22) 0.15 0.75 (0.33–1.71) 0.49

TIA 6 (0.1) 12 (0.5) 0.18 (0.07–0.48) 0.0001 0.31 (0.10–0.91) 0.033

TVR 65 (1.1) 24 (1.1) 0.97 (0.61–1.55) 0.90 0.88 (0.53–1.47) 0.63

ST definite 45 (0.7) 12 (0.5) 1.35 (0.71–2.55) 0.36 1.32 (0.67–2.59) 0.43

Acute 26 (0.4) 7 (0.3) 1.34 (0.58–3.08) 0.50 1.15 (0.48–2.78) 0.75

Subacute 20 (0.3) 5 (0.2) 1.43 (0.54–3.81) 0.47 1.65 (0.58–4.71) 0.35

ST definite/probable 63 (1.0) 17 (0.8) 1.33 (0.78–2.27) 0.30 1.45 (0.81–2.57) 0.21

Acute 30 (0.5) 8 (0.4) 1.35 (0.62–2.95) 0.45 1.24 (0.54–2.85) 0.61

Subacute 35 (0.6) 9 (0.4) 1.39 (0.67–2.89) 0.38 1.82 (0.83–4.02) 0.14

Bleeding 654 (10.7) 302 (13.7) 0.76 (0.66–0.88) 0.0002 0.87 (0.75–1.01) 0.067

BARC type 1 327 (5.3) 147 (6.8) 0.79 (0.65–0.96) 0.020 0.84 (0.68–1.04) 0.11

BARC type 2 238 (3.9) 104 (4.7) 0.82 (0.65–1.03) 0.090 0.92 (0.71–1.18) 0.51

BARC type 3 93 (1.6) 45 (2.0) 0.74 (0.52–1.05) 0.094 1.06 (0.72–1.56) 0.77

BARC type 3a 47 (0.8) 26 (1.2) 0.65 (0.40–1.04) 0.072 1.03 (0.61–1.75) 0.91

BARC type 3b 42 (0.7) 18 (0.8) 0.84 (0.48–1.45) 0.52 1.11 (0.61–2.03) 0.73

BARC type 3c 5 (0.1) 1 (0.0) 1.79 (0.21–15.36) 0.59 1.55 (0.14–16.68) 0.72

BARC type 4 10 (0.2) 2 (0.1) 1.79 (0.39–8.17) 0.45 2.12 (0.43–10.48) 0.36

BARC type 5 6 (0.1) 15 (0.7) 0.14 (0.06–0.37) <0.0001 0.17 (0.06–0.50) 0.0012

BARC type 5a 3 (0.0) 12 (0.5) 0.09 (0.03–0.32) <0.0001 0.13 (0.03–0.51) 0.0036

BARC type 5b 3 (0.0) 3 (0.1) 0.36 (0.07–1.78) 0.19 0.25 (0.04–1.63) 0.15

BARC type 3 or 5 99 (1.6) 60 (2.7) 0.59 (0.43–0.81) 0.0011 0.84 (0.59–1.19) 0.32

BARC type 3 or 5 access site 33 (0.6) 26 (1.2) 0.45 (0.27–0.76) 0.0020 0.65 (0.37–1.16) 0.14

BARC type 3 or 5 non–access site 66 (1.1) 34 (1.5) 0.70 (0.46–1.05) 0.084 0.97 (0.62–1.53) 0.90

BARC type 2, 3, or 5 335 (5.5) 161 (7.3) 0.74 (0.61–0.90) 0.0019 0.90 (0.73–1.10) 0.29

BARC type 2, 3, or 5 access site 165 (2.7) 101 (4.6) 0.58 (0.45–0.74) <0.0001 0.64 (0.49–0.85) 0.0016

BARC type 2, 3, or 5 non–access site 176 (2.9) 60 (2.7) 1.06 (0.79–1.42) 0.71 1.39 (1.01–1.90) 0.042

TIMI major 38 (0.6) 25 (1.1) 0.54 (0.33–0.90) 0.017 0.68 (0.39–1.20) 0.18

TIMI minor 32 (0.6) 24 (1.1) 0.48 (0.28–0.81) 0.0050 0.75 (0.42–1.36) 0.35

TIMI major/minor 70 (1.2) 49 (2.2) 0.51 (0.35–0.74) 0.0002 0.71 (0.47–1.07) 0.10

GUSTO severe 32 (0.5) 18 (0.8) 0.64 (0.36–1.14) 0.12 0.91 (0.48–1.72) 0.77

GUSTO moderate 31 (0.5) 24 (1.1) 0.46 (0.27–0.79) 0.0036 0.65 (0.36–1.17) 0.15

GUSTO mild 591 (9.7) 264 (12.1) 0.79 (0.68–0.92) 0.0020 0.88 (0.75–1.03) 0.11

GUSTO moderate/severe 63 (1.0) 42 (1.9) 0.54 (0.36–0.79) 0.0015 0.74 (0.48–1.14) 0.18

Composite of surgical access site repair andblood transfusion

61 (1.0) 53 (2.4) 0.41 (0.28–0.59) <0.0001 0.56 (0.37–0.84) 0.0056

Surgical access site repair 11 (0.2) 8 (0.4) 0.49 (0.20–1.22) 0.12 0.49 (0.18–1.32) 0.16

Blood transfusion 55 (0.9) 49 (2.2) 0.40 (0.27–0.59) <0.0001 0.56 (0.37–0.87) 0.0089

Values are n (%), unless otherwise indicated.

BARC ¼ Bleeding Academic Research Consortium; CI ¼ confidence interval; GUSTO ¼ Global Utilization of Streptokinase and Tissue Plasminogen Activator for OccludedCoronary Arteries; ST ¼ stent thrombosis; TVR ¼ other abbreviations as in Tables 1 and 2.

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of ACS, body mass index, diabetes, smoking,hypercholesterolemia, hypertension, previous MI,previous CABG, previous stroke or transientischemic attack, Killip class, renal function,

crossover, glycoprotein IIb or IIIa, and intra-aorticballoon pump. All analyses were performed usingthe statistical package Stata 13.1 (StataCorp, CollegeStation, Texas).

FIGURE 1 Main Outcomes of Radial Versus Femoral Access in Male and Female

Patients

Radial and femoral access were compared on the basis of sex subgroups, with rate ratios

and 95% confidence intervals (CIs), for the coprimary endpoints and their components

(death, myocardial infarction [MI], stroke, Bleeding Academic Research Consortium

[BARC] type 3 or 5).

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RESULTS

PATIENTS. The MATRIX-Access trial enrolled 8,404patients with ACS from 78 centers in Italy, theNetherlands, Spain, and Sweden between October2011 and November 2014. Of these patients, 6,172(73.4%) were men, of whom 3,126 (37.2%) were allo-cated to radial and 3,046 (36.2%) to femoral access;and 2,232 (26.6%) were women, of whom 1,071 (12.8%)were assigned to radial and 1,161 (13.8%) to femoralaccess.

Baseline and procedural characteristics werelargely imbalanced between sexes (Tables 1 and 2).Compared with men, women were older; had lowerbody weight and body mass index; presented morefrequently with NSTE-ACS and advanced Killip class;and had a higher prevalence of diabetes, hypercho-lesterolemia, hypertension, renal dysfunction, andprior cerebrovascular events. However, women lessfrequently were smokers or had prior MI, PCI, orCABG. Crossover rates, use of intra-aortic balloonpump, left main treatment, and bare-metal stent im-plantation occurred more often in women, whileattempted PCI, use of glycoprotein IIb/IIIa inhibitors,and bypass graft treatment were less frequent inwomen and stent diameter and length were lower(Table 1). Before arrival in the catheterization labo-ratory, female patients received aspirin and newP2Y12 inhibitors less frequently as compared withmen (Table 1).

On the contrary, female and male subgroups allo-cated to radial versus femoral access were generallywell matched in terms of demographics, medicalhistory, clinical presentation, and procedural aspects(Tables 1 and 2). Medications at discharge are shownin Online Table 1. Crossover rate from radial tofemoral was numerically higher in women ascompared with men (Table 2), however interactiontesting did not confirm heterogeneity across sexes(interaction p ¼ 0.051).

CLINICAL OUTCOMES OF MALE VERSUS FEMALE

PATIENTS. MACCE and NACE were significantlylower in men compared with women at unadjustedanalysis but they no longer differed after adjustmentfor the multiple imbalances identified across patients’characteristics (Table 3). Similarly, after adjustment,neither of the single components of both coprimaryendpoints differed significantly in male comparedwith female patients (Table 3). There was however atrend toward higher risk of BARC type 3 or 5 accesssite bleeding and a 36% increase of BARC type 2, 3, or

5 access site bleeding rates in women compared withmen after adjustment (Table 3). The need for trans-fusion and the composite of surgical access site repairand blood transfusion were also increased afteradjustment in female compared with male patients(Table 3).

CLINICAL OUTCOMES OF RADIAL VERSUS FEMORAL

ACCESS ACCORDING TO SEX. Overall crossoverrates were higher in women as compared with men(4.7% vs. 3.8%; p ¼ 0.037), however this differencedisappeared after adjustment (p ¼ 0.42).

No significant interaction was noted between ac-cess site and sex with respect to both coprimaryendpoints of 30-day MACCE and NACE (interactionp ¼ 0.15 and 0.18, respectively) (Figures 1 and 2,Table 4). MACCE and NACE were significantlyreduced with radial as compared with femoral in fe-male patients (MACCE: 9.1% vs. 12.2%; RR: 0.73; 95%confidence interval [CI]: 0.56 to 0.95; p ¼ 0.019;NACE: 10.4% vs. 13.9%; RR: 0.73; 95% CI: 0.56 to 0.93;

FIGURE 2 Coprimary Composite Outcomes at 30 Days in Male and Female Patients

(A, B) Cumulative incidence of the coprimary outcome of major adverse cardiac or ce-

rebrovascular events and net adverse clinical events, respectively. Blue indicates radial

access (transradial access [TRA]), red indicates femoral access (transfemoral access

[TFA]), continuous line indicates male patient, dashed line indicates female patient.

Abbreviations as in Figure 1.

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p ¼ 0.012) (Figure 1, Table 4) and trended in favor ofradial, albeit nonsignificantly in men (MACCE: 8.7%vs. 9.5%; RR: 0.92; 95% CI: 0.77 to 1.09; p ¼ 0.31;NACE: 9.6% vs. 10.8%; RR: 0.89; 95% CI: 0.76 to 1.05;p ¼ 0.16) (Figure 1, Table 4). Radial access wasconsistently (interaction p ¼ 0.79) associated to lowerall-cause fatalities in both sex groups (women: 2.4%vs. 3.5%; RR: 0.70; 95% CI: 0.43 to 1.15; men: 1.3% vs.1.7%; RR: 0.76; 95% CI: 0.50 to 1.15) (Figure 3, Table 4).At further analysis, no signal of interaction was noted

between access site and sex for stroke (interactionp ¼ 0.18), myocardial infarction (interaction p ¼ 0.25)and for other secondary endpoints includingcardiovascular mortality (interaction p ¼ 0.92), stentthrombosis (interaction p ¼ 0.18), target vesselrevascularization (interaction p ¼ 0.18), or the com-posite of access site surgery or blood transfusion(interaction p ¼ 0.18) (Figure 3, Table 4).

The key safety endpoint of BARC type 3 or 5bleeding was similarly reduced (interactionp ¼ 0.45) in the radial groups across sex, even ifformal statistical significance was achieved in fe-male (2.0% vs. 3.4%; RR: 0.58; 95% CI: 0.34 to0.98; p ¼ 0.040) but not in male patients (1.4% vs.1.9%; RR: 0.74; 95% CI: 0.50 to 1.11; p ¼ 0.14)(Table 4). Access site BARC type 3 or 5 bleedingwas consistently (interaction p ¼ 0.45) reduced inboth female and male patients whereas non–accesssite BARC type 3 or 5 bleeding did not differ withradial in both sexes (Table 4). Results remainedconsistent across any BARC, TIMI, or GUSTObleeding scales.

ADDITIONAL ANALYSES. Figures 4 and 5 show theconsistency of randomized treatment effect (radialvs. femoral) on MACCE, NACE, all-cause death andBARC bleeds in female and male patients stratified byrandomly allocated antithrombin type (bivalirudin orunfractionated heparin).

DISCUSSION

We assessed the role of sex disparities on clinicaloutcomes in largely unselected ACS patients recruitedin the MATRIX-Access trial and undergoing invasivemanagement via either radial or femoral access. Themain findings are the following.

First, male and female patients differed consid-erably for multiple baseline characteristics, proce-dural features, and choice of medications. Althoughunadjusted analyses apparently yielded greater riskof main efficacy and safety endpoints in femalepatients as compared with men, they no longerdiffered after adjustment. Only access sitebleeding, but not overall bleeding, along withtransfusion rates alone or in combination withsurgical repair for the instrumented access site,remained higher in female as compared with malepatients.

Second, there was no clear signal of heterogeneityacross sex with respect to any of the investigated

TABLE 4 Clinical Outcomes at 30 Days in Radial Versus Femoral Access According to Sex

Male Patients Female Patients

p ForInteraction

Radial(n ¼ 3,126)

Femoral(n ¼ 3,046)

Rate Ratio(95% CI) p Value

Radial(n ¼ 1,071)

Femoral(n ¼ 1,161)

Rate Ratio(95%CI)

pValue

Death, MI, stroke 272 (8.7) 288 (9.5) 0.92 (0.77–1.09) 0.31 97 (9.1) 141 (12.2) 0.73 (0.56–0.95) 0.019 0.15

Death, MI, stroke, BARC type 3 or 5 299 (9.6) 325 (10.8) 0.89 (0.76–1.05) 0.16 111 (10.4) 161 (13.9) 0.73 (0.56–0.93) 0.012 0.18

Death, MI, stroke, BARC type 3 or 5, TVR, ST 307 (9.9) 329 (10.9) 0.90 (0.77–1.06) 0.21 112 (10.5) 162 (14.0) 0.73 (0.57–0.93) 0.012 0.15

Death 40 (1.3) 51 (1.7) 0.76 (0.50–1.15) 0.20 26 (2.4) 40 (3.5) 0.70 (0.43–1.15) 0.15 0.79

Death cardiovascular 39 (1.2) 49 (1.6) 0.77 (0.51–1.18) 0.23 25 (2.3) 36 (3.1) 0.75 (0.45–1.25) 0.26 0.92

MI 228 (7.4) 232 (7.7) 0.95 (0.79–1.15) 0.62 71 (6.7) 98 (8.5) 0.77 (0.56–1.05) 0.10 0.25

Stroke 12 (0.4) 8 (0.3) 1.46 (0.60–3.57) 0.41 4 (0.4) 8 (0.7) 0.54 (0.16–1.78) 0.30 0.18

TIA 2 (0.1) 4 (0.1) 0.49 (0.09–2.65) 0.39 3 (0.3) 9 (0.8) 0.36 (0.10–1.32) 0.11 0.78

TVR 39 (1.3) 26 (0.9) 1.46 (0.89–2.40) 0.13 10 (0.9) 14 (1.2) 0.77 (0.34–1.73) 0.52 0.18

ST definite 26 (0.8) 19 (0.6) 1.33 (0.74–2.41) 0.34 4 (0.4) 8 (0.7) 0.54 (0.16–1.78) 0.30 0.18

Acute 18 (0.6) 8 (0.3) 2.19 (0.95–5.06) 0.058 3 (0.3) 4 (0.3) 0.81 (0.18–3.61) 0.78 0.24

Subacute 9 (0.3) 11 (0.4) 0.79 (0.33–1.92) 0.61 1 (0.1) 4 (0.4) 0.27 (0.03–2.40) 0.21 0.35

ST definite/probable 35 (1.1) 28 (1.0) 1.22 (0.74–2.00) 0.44 7 (0.7) 10 (0.9) 0.75 (0.29–1.98) 0.56 0.38

Acute 20 (0.6) 10 (0.3) 1.95 (0.91–4.17) 0.080 4 (0.4) 4 (0.3) 1.08 (0.27–4.31) 0.92 0.46

Subacute 17 (0.5) 18 (0.6) 0.92 (0.47–1.78) 0.80 3 (0.3) 6 (0.5) 0.54 (0.13–2.15) 0.37 0.49

Bleeding 236 (7.6) 418 (13.9) 0.53 (0.45–0.62) <0.0001 114 (10.7) 188 (16.5) 0.63 (0.50–0.80) 0.0001 0.23

BARC type 1 113 (3.6) 214 (7.1) 0.50 (0.40–0.63) <0.0001 55 (5.2) 92 (8.2) 0.63 (0.45–0.89) 0.0073 0.27

BARC type 2 85 (2.7) 153 (5.1) 0.53 (0.41–0.70) <0.0001 42 (4.0) 62 (5.4) 0.72 (0.49–1.08) 0.11 0.21

BARC type 3 37 (1.2) 56 (1.9) 0.64 (0.42–0.97) 0.034 17 (1.6) 28 (2.5) 0.65 (0.35–1.19) 0.16 0.97

BARC type 3a 18 (0.6) 29 (1.0) 0.60 (0.33–1.08) 0.087 11 (1.0) 15 (1.3) 0.79 (0.36–1.72) 0.55 0.59

BARC type 3b 17 (0.5) 25 (0.8) 0.66 (0.36–1.22) 0.18 6 (0.6) 12 (1.1) 0.54 (0.20–1.43) 0.21 0.72

BARC type 3c 2 (0.1) 3 (0.1) 0.65 (0.11–3.88) 0.63 0 (0.0) 1 (0.1) 0.36 (0.01–8.83) 1.00 0.46

BARC type 4 5 (0.2) 5 (0.2) 0.97 (0.28–3.36) 0.96 1 (0.1) 1 (0.1) 1.08 (0.07–17.16) 0.96 0.95

BARC type 5 6 (0.2) 0 (0.0) 12.67 (0.71–224.81) 0.031 4 (0.4) 11 (1.0) 0.39 (0.12–1.23) 0.095 0.0033

BARC type 5a 3 (0.1) 0 (0.0) 6.82 (0.35–131.98) 0.25 3 (0.3) 9 (0.8) 0.36 (0.10–1.32) 0.11 0.022

BARC type 5b 3 (0.1) 0 (0.0) 6.82 (0.35–131.98) 0.25 1 (0.1) 2 (0.2) 0.54 (0.05–5.95) 0.61 0.094

BARC type 3 or 5 43 (1.4) 56 (1.9) 0.74 (0.50–1.11) 0.14 21 (2.0) 39 (3.4) 0.58 (0.34–0.98) 0.040 0.45

BARC type 3 or 5 access site 8 (0.3) 25 (0.9) 0.31 (0.14–0.69) 0.0023 8 (0.8) 18 (1.6) 0.48 (0.21–1.10) 0.075 0.47

BARC type 3 or 5 non–access site 35 (1.2) 31 (1.0) 1.10 (0.68–1.78) 0.71 13 (1.2) 21 (1.8) 0.66 (0.33–1.33) 0.24 0.24

BARC type 2, 3, or 5 127 (4.1) 208 (6.9) 0.58 (0.47–0.73) <0.0001 62 (5.8) 99 (8.6) 0.66 (0.48–0.92) 0.012 0.51

BARC type 2, 3, or 5 access site 36 (1.2) 129 (4.3) 0.27 (0.18–0.39) <0.0001 33 (3.1) 68 (5.9) 0.51 (0.34–0.78) 0.0016 0.021

BARC type 2, 3, or 5 non–access site 92 (3.0) 84 (2.8) 1.06 (0.79–1.43) 0.68 29 (2.7) 31 (2.7) 1.01 (0.61–1.67) 0.98 0.85

TIMI major 19 (0.6) 19 (0.6) 0.97 (0.51–1.84) 0.93 7 (0.7) 18 (1.6) 0.42 (0.17–1.00) 0.043 0.12

TIMI minor 15 (0.5) 17 (0.6) 0.86 (0.43–1.72) 0.66 9 (0.8) 15 (1.3) 0.64 (0.28–1.48) 0.29 0.61

TIMI major/minor 34 (1.1) 36 (1.2) 0.92 (0.57–1.47) 0.72 16 (1.5) 33 (2.9) 0.52 (0.28–0.94) 0.029 0.14

GUSTO severe 17 (0.5) 15 (0.5) 1.10 (0.55–2.21) 0.79 6 (0.6) 12 (1.0) 0.54 (0.20–1.43) 0.21 0.24

GUSTO moderate 14 (0.5) 17 (0.6) 0.80 (0.39–1.62) 0.53 9 (0.9) 15 (1.3) 0.64 (0.28–1.47) 0.29 0.69

GUSTO mild 206 (6.6) 385 (12.8) 0.50 (0.42–0.60) <0.0001 100 (9.4) 164 (14.5) 0.64 (0.49–0.82) 0.0005 0.13

GUSTO moderate/severe 31 (1.0) 32 (1.1) 0.94 (0.57–1.54) 0.81 15 (1.4) 27 (2.4) 0.59 (0.32–1.12) 0.10 0.26

Composite of surgical access site repair andblood transfusion

26 (0.9) 35 (1.2) 0.72 (0.43–1.20) 0.20 15 (1.4) 38 (3.3) 0.42 (0.23–0.77) 0.0035 0.18

Surgical access site repair 2 (0.1) 9 (0.3) 0.22 (0.05–1.00) 0.031 2 (0.2) 6 (0.5) 0.36 (0.07–1.78) 0.19 0.65

Blood transfusion 25 (0.9) 30 (1.0) 0.81 (0.48–1.38) 0.43 15 (1.4) 34 (3.0) 0.47 (0.26–0.87) 0.013 0.19

Values are n (%), unless otherwise indicated.

Abbreviations as in Tables 1 to 3.

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outcome measures, including the 2 coprimary com-posite endpoints or each of the individual compo-nents. Women but not men showed a significantreduction of both coprimary endpoints (fulfilling thepre-specified level of significance at an alpha error

of 2.5%) with radial access, indicating that the well-known sex-specific procedural challenges of trans-radial coronary catheterization and intervention donot mitigate the expected benefits in femalepatients.

FIGURE 3 Components of Coprimary Composite Outcomes at 30 Days in Male and Female Patients

Panels show the cumulative incidence of the coprimary outcome of (A) all-cause death, (B) myocardial infarction, (C) stroke, and (D) BARC type 3 or 5 bleeding.

Blue indicates radial access (TRA), red indicates femoral access (TFA), continuous line indicates male patient, dashed line indicates female patient. Abbreviations as

in Figures 1 and 2.

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Advances in PCI procedures and optimization ofconcomitant antithrombotic agents have improvedoutcomes of patients with ACS by reducing ischemicevents, but at the cost of greater bleeding risk. Thelatter remains a matter of concerns especially forpatients at increased procedural hemorrhagic risksuch as female patients. Although the spontaneous(i.e., out of hospital) bleeding risk appears not todiffer among sexes (14–17), female patients havebeen consistently shown to suffer the greatest fromaccess site hemorrhagic complications as comparedwith male counterparts (1,5) Access site bleedsrepresent a large part of periprocedural bleeding andTRA has emerged as the most appealing and cost-saving treatment strategy to mitigate those

complications. However, sex-specific proceduralchallenges of transradial coronary catheterizationand intervention, possibly leading to a delayed orless effective percutaneous treatment especially inACS female patients, remain a matter of concern.Previous studies have reported that female sex is anindependent predictor of failure of transradial PCI(18) and an independent predictor of radial spasm(19), limiting the success of the transradialprocedure.

The MATRIX-Access trial is the largest (n ¼ 8,404)randomized trial to compare radial and femoral ac-cess, including unselected patients at high baselineand procedural risk. Our current findings are inagreement with those of previous observational

FIGURE 4 Main Outcomes of Radial Versus Femoral Access Stratified by Antithrombin Type in Female Patients

Radial and femoral access were compared on the basis of the randomly assigned antithrombin type (bivalirudin or unfractionated heparin

[UFH]), with rate ratios and 95% CIs, for the coprimary endpoints, death, and BARC type 3 or 5. Abbreviations as in Figure 1.

FIGURE 5 Main Outcomes of Radial Versus Femoral Access Stratified by Antithrombin Type in Male Patients

Radial and femoral access were compared on the basis of the randomly assigned antithrombin type (bivalirudin or unfractionated heparin),

with rate ratios and 95% CIs, for the coprimary endpoints, death, and BARC type 3 or 5. Abbreviations as in Figure 1.

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studies (20,21), and those reported in the RIVAL(Radial Vs femorAL access for coronary intervention)trial. A pre-specified subgroup analysis of RIVALcompared outcomes in women (n ¼ 1,861) and men(n ¼ 5,160) who were randomized to radial versusfemoral access and showed that women undergoingcoronary angiography and PCI had a higher risk ofvascular access site complications compared withmen, but radial access was an effective method toreduce these complications (7). In the RIVAL trial thetype of antithrombotic medications during coronaryintervention was not protocol-mandated. As a result,the majority of patients were treated with heparinrather than bivalirudin (approximately 2.6%).Therefore, it was not possible to exclude that usingbivalirudin would have reduced the benefits ofradial access especially in female patients (22). In theMATRIX-Access trial, heparin and bivalirudin wererandomly and evenly assigned to patients at thetime of coronary intervention. No signal of hetero-geneity was noted for type of anticoagulant agentand access site for both men and women across thecoprimary endpoints, mortality, or the key safetybleeding endpoint. This novel and unique observa-tion that the benefits of radial access remainconsistent in both sexes irrespective of the choice ofparenteral anticoagulation during PCI has notableimplications for current practice. Against the wide-spread belief that radial access and use of bivalir-udin represent competing treatment strategies tominimize bleeding risks, our findings support theircomplementary role to mitigate both access site andnon–access site bleeding risks, both in male and fe-male patients.

The SAFE-PCI for Women (Study of Access Site forEnhancement of PCI for Women) trial was unique forselecting exquisitely women to undergo radial orfemoral access (6). The trial was stopped prematurelydue to lower than expected event rate and no signif-icant difference was found in the primary efficacyendpoint (BARC 2, 3, or 5 bleeding or vascular com-plications requiring intervention) between TRA andTFA in patients undergoing PCI (n ¼ 691; primaryendpoint cohort). However, in a secondary analysisalso including female patients who underwent car-diac catheterization (n ¼ 1,787), radial access signifi-cantly reduced bleeding and vascular complications(6). Hence, the apparent lack of benefit of radialover femoral access in this study likely reflects

limited study power more than lack of treatment ef-fect in women.

We observed that women randomized to TRAmore frequently needed crossovers to TFA comparedwith men (7.6% vs. 5.2%). This likely reflects greaterchallenges in women to obtain vascular access whenattempting TRA, likely because of smaller and moreprone to spasm radial arteries. Yet, the duration ofthe procedure was overall shorter in women ascompared with men, and in the former group TRAdid not require longer procedural or fluoroscopictime as compared with TFA. This observation sug-gests that female patients who are intervened uponvia the radial access do not pose specific furthertechnical challenges once vascular access has beenestablished.

Overall, present findings contribute to support theconcept that radial access should be preferred overthe femoral access, adding to the current knowledgefirm evidence that this approach is applicable to bothmale and female patients, and that probably it is evenmore beneficial in women who are characterized byincreased risk of bleeding and access site relatedcomplications. Therefore, efforts should be done toincrease the adoption of radial access, but at the sametime improving the operators’ training, which isfundamental to reach the most appropriate skills,particularly in women where radial access might bemore challenging due to anatomical reasons.

STUDY LIMITATIONS. Although a sex subgroupanalysis was pre-specified, the MATRIX-Access trialwas not powered to explore differences betweensexes, and randomization was not stratified by sex. Assuch, the current analyses may be subject to type IIerror. As expected in an exploratory analysis of effectmodification, an ad hoc power analysis indicates a30% power for the analysis of our primary outcome.Female study population was smaller compared withthe male group, as observed in most trials investi-gating patients with CAD. Yet, the benefits of TRAover TFA were consistent across sexes and if anythingseemed to be slightly more pronounced amongwomen. We did not adjust for multiple comparisons,increasing the risk of type I error. Radial artery oc-clusion was not systematically looked for in thecontext of the MATRIX study. Results apply to thecontext of this trial in which most centers partici-pating were highly experienced in the radial

PERSPECTIVES

WHAT IS KNOWN? There are limited and contrasting data

about sex disparities for the safety and efficacy of TRA versus

TFA for coronary intervention.

WHAT IS NEW? The MATRIX-Access trial results showing su-

periority of TRA versus TFA were consistent across sexes. Women

experienced a higher risk of severe bleeding and access site

complications, and radial access was an effective method to

reduce these complications, as well as composite ischemic and

ischemic or bleeding endpoints.

WHAT IS NEXT? Radial access should become the default ac-

cess for patients with ACS undergoing invasive management,

irrespective of sex.

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technique; therefore, similar outcomes may notapply in centers performing lower volumes of radialaccess.

CONCLUSIONS

This sex-specific analysis of the largest trial comparingradial versus femoral access in ACS patients invasivelymanaged suggests that women experienced a higherrisk of severe bleeding and access site complications,and radial access was an effective method to reducethese complications, as well as composite ischemicand ischemic or bleeding endpoints.

ADDRESS FOR CORRESPONDENCE: Dr. MarcoValgimigli, Bern University Hospital, Freiburgstrasse 4,CH-3010, Bern, Switzerland. E-mail: marco.valgimigli@insel.ch.

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KEY WORDS acute coronary syndrome(s),female, femoral access, male, MATRIX,radial access

APPENDIX For a supplemental table, pleasesee the online version of this paper.