Accepted Manuscript

Radiation Exposure and Vascular Access in Acute Coronary Syndromes: TheRADMatrix Trial

Alessandro Sciahbasi, MD, PhD, Enrico Frigoli, MD, Alessandro Sarandrea, Eng,Martina Rothenbühler, M. Sc., Paolo Calabrò, MD, PhD, Alessandro Lupi, MD,Francesco Tomassini, MD, Bernardo Cortese, MD, Stefano Rigattieri, MD, PhD,Enrico Cerrato, MD, Dennis Zavalloni, MD, Antonio Zingarelli, MD, Paolo Calabria,MD, Paolo Rubartelli, MD, Gennaro Sardella, MD, Matteo Tebaldi, MD, StephanWindecker, MD, Peter Jüni, MD, Dik Heg, PhD, Marco Valgimigli, MD, PhD

PII: S0735-1097(17)36042-4

DOI: 10.1016/j.jacc.2017.03.018

Reference: JAC 23519

To appear in: Journal of the American College of Cardiology

Received Date: 16 February 2017

Revised Date: 8 March 2017

Accepted Date: 10 March 2017

Please cite this article as: Sciahbasi A, Frigoli E, Sarandrea A, Rothenbühler M, Calabrò P, Lupi A,Tomassini F, Cortese B, Rigattieri S, Cerrato E, Zavalloni D, Zingarelli A, Calabria P, Rubartelli P,Sardella G, Tebaldi M, Windecker S, Jüni P, Heg D, Valgimigli M, Radiation Exposure and VascularAccess in Acute Coronary Syndromes: The RADMatrix Trial, Journal of the American College ofCardiology (2017), doi: 10.1016/j.jacc.2017.03.018.

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Radiation Exposure and Vascular Access in Acute Coronary Syndromes:

The RADMatrix Trial

1Alessandro Sciahbasi, MD, PhD,

2Enrico Frigoli, MD,

3Alessandro Sarandrea, Eng,

4Martina Rothenbühler, M. Sc.,

5Paolo Calabrò, MD, PhD,

6Alessandro Lupi MD,

7Francesco Tomassini, MD,

8Bernardo Cortese, MD,

1Stefano Rigattieri, MD, PhD,

7Enrico Cerrato, MD,

9Dennis Zavalloni, MD,

10Antonio Zingarelli, MD,

11Paolo

Calabria, MD, 12

Paolo Rubartelli, MD, 13

Gennaro Sardella, MD, 14

Matteo Tebaldi,

MD,15

Stephan Windecker, MD,4Peter Jüni, MD,

4Dik Heg, PhD,

15Marco Valgimigli,

MD, PhD.

1Interventional Cardiology, Sandro Pertini Hospital, ASL RM2, Rome – Italy,

2Eustrategy Association, Forlì – Italy,

3HSE Management, Rome – Italy,

4CTU Bern,

and Institute of Social and Preventive Medicine – University of Bern – Switzerland, 5Department of Cardio-Thoracic Sciences, Second University of Naples – Italy,

6Cardiology, ASL VCO, Domodossola – Italy,

7Department of Cardiology, Infermi

Hospital, Rivoli – Italy, 8Interventional Cardiology, Fatebenefratelli Hospital, Milan –

Italy, 9Humanitas Research Hospital, IRCCS, Rozzano – Italy,

10Interventional

Cardiology Unit, IRCCS AOU San Martino, IST, Genova – Italy, 11

Cardiology Unit,

Misericordia Hospital, Grosseto – Italy, 12

Villa Scassi Hospital, Genova – Italy, 13

Departmentof Cardiovascular Sciences, Policlinico Umberto I, Rome – Italy, 14

Cardiology Unit, AziendaOspedalieraUniversitaria di Ferrara – Italy, 15

Swiss

Cardiovascular Center, Bern University Hospital – Switzerland

The MATRIX program is conducted with support from The Medicines Company and

Terumo.

Running title: Radiation exposure and PCI

Address for correspondence:

Dr. Marco Valgimigli

Swiss Cardiovascular Center Bern

Bern University Hospital

3010 Bern, Switzerland

Telephone: +41 31 632 96 53

Fax: +41 31 632 47 71

Email: marco.valgimigli@insel.ch

Conflicts of Interest

Dr. Rigattieri reports personal fees from Astra Zeneca, outside the submitted work;

Dr. Cortese reports personal fees from The Medicines Company, during the conduct

of the study; personal fees from Astra Zeneca, grants and personal fees from Abbott

Vascular, grants, personal fees and non-financial support from AB Medica, grants and

non-financial support from Innova HTS, grants and non-financial support from

Kardia, grants and non-financial support from Stentys, grants from Hexacath, grants

from Amgen, outside the submitted work; Dr. Windecker reports personal fees from

ASTRA ZENECA, grants from Biotronik, grants and personal fees from Boston

Scientific, personal fees from Daiichi Sankyo, grants from Edwards life sciences,

grants from Medtronic, outside the submitted work; Dr.Jüni reports other from

Abbott Vascular, other from Biosensors, other from Medtronic, other from Johnson &

Johnson, other from Ablynx, other from Amgen, other from AstraZeneca, other from

Boehringer-Ingelheim, other from Eisai, other from Eli Lilly, other from Exelixis,

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other from Geron, other from Gilead Sciences, other from Nestlé, other from

Novartis, other from Novo Nordisc, other from Padma, other from Roche, other from

Schering-Plough, other from St. Jude Medical, other from Swiss Cardio Technologies,

outside the submitted work; and Unpaid steering committee or statistical executive

committee member of trials funded by Abbott Vascular, Biosensors, Medtronic and

Johnson & Johnson. Dr. Valgimigli reports grants from Terumo, grants from The

Medicines Company, during the conduct of the study; grants and personal fees from

Astra Zeneca, personal fees from Terumo, personal fees from Bayer, personal fees

from Biosensors, outside the submitted work.

The other authors report nothing to disclose.

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Abstract

Background: It remains unclear whether radial increases the risk of operator or

patient radiation exposure when performed by expert operators

Objectives: To determine whether radial access increases radiation exposure

Methods: We randomly assigned 8404 patients, with or without ST-segment

elevation acute coronary syndrome, to radial or femoral access for coronary

angiography and percutaneous intervention, and collected fluoroscopy time and dose

area product (DAP). In the radiation sub-study (RAD-MATRIX), we anticipated that

13 or more operators, each wearing a thorax (primary endpoint), wrist and head

(secondary endpoints) lithium fluoride thermo luminescent dosimeter and

randomizing at least 13 patients per access site were needed to establish non-

inferiority of radial versus femoral access.

Results: Among eighteen operators, performing 777 procedures in 767 patients, the

non-inferiority primary endpoint was not achieved (p-value for non-

inferiority=0.843). Operator equivalent dose at the thorax was significantly higher

with radial than femoral access (77 µSv [IQR:40-112] vs. 41 µSv [IQR:23-59],

p=0.02). After normalization of operator radiation dose by fluoroscopy time or DAP,

the difference remained significant. Radiation dose at wrist or head did not differ

between radial and femoral access. Thorax operator dose did not differ in the right

radial (84 µSv [IQR:47-146]) compared to the left radial access (52 µSv [IQR:33-92];

p=0.15) In the overall MATRIX population, fluoroscopy time (10 min; IQR:6-16 vs.

9 min IQR:5-15; p<0.0001] and DAP—available in 7570 procedures and 6902

patients—(65 Gy*cm2 [IQR:29-120] vs. 59 Gy*cm

2 [26-110]; p=0.0001) were higher

with radial as compared to femoral access.

Conclusions: Radial, as compared with femoral access is associated with greater

operator and patient radiation exposure when performed by expert operators in current

practice. Radial operators and institutions should be sensitized towards radiation risks

and adopt adjunctive radio-protective measures.

Key Words: Radiation dose –Radial access –Femoral access –Acute coronary

syndromes –PCI

Abbreviations

ACS: acute coronary syndrome

DAP: dose area product

MATRIX: Minimizing Adverse Haemorrhagic Events by TRansradial Access Site

and Systemic Implementation of angioX

PCI: percutaneous coronary intervention

STEMI: ST-segment elevationmyocardial infarction

Condensed abstract

Operator radiation exposure during percutaneous coronary procedures for acute

coronary syndromes was evaluated in 18 operators participating in the MATRIX trial.

Operator equivalent dose was measured after randomization for vascular access

(radial vs femoral). The radial approach was associated with a significant higher

operator radiation dose compared to femoral access. In term of patient exposure,

fluoroscopy time and dose area product were significantly higher with radial as

compared to femoral access. Radial operators should pay special attention to radio-

protective measures in order to minimize the effects of radiation to patients, staff and

themselves.

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Introduction

The use of radial, instead of femoral, access for coronary angiography and percutaneous

coronary intervention (PCI) has been associated to lower risk of bleeding, vascular complications

and greater survival in patients with acute coronary syndrome undergoing invasive

management(1,2). European clinical practice guidelines endorse the use of radial access in

patients with non-ST elevation acute coronary syndromes undergoing invasive management with

a class I recommendation over femoral access (3), and the uptake of radial access is increasing

worldwide (4).

However, prior studies have raised concerns over the increased risk of radiation exposure

for both patients and operators with radial instead of femoral access (5). Only a minority of

randomized controlled studies evaluated radiation doses (5), especially in ACS patients( 6) and

none used dedicated dosimeters to assess operator exposure. As part of the MATRIX

(Minimizing Adverse Haemorrhagic Events by TRansradial Access Site and Systemic

Implementation of angioX) programme (NCT01433627), (7) we collected fluoroscopy time and

dose area product and equipped radial operators consenting to participate with dedicated

dosimeters during study conduct to assess operator radiation dose with radial or femoral access.

Methods

Study design and population

The design of the MATRIX trial and of the radiation (RAD-MATRIX) substudy has been

previously reported (7,8). Briefly, all patients with an ACS with or without ST-segment elevation

myocardial infarction were randomized to radial or femoral access (see web extra material). Only

expert radial operators were involved in the RAD-MATRIX substudy.

Study protocol and randomization

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Before the coronary angiography all patients were centrally randomized (1:1) to radial or

femoral access for diagnostic angiography and percutaneous coronary intervention if clinically

indicated. The randomization sequence was computer generated and modified using

minimisation on intended new or ongoing use of ticagrelor or prasugrel, presence or absence of

STEMI, troponin positivity and anticipated use of immediate PCI in non-STEMI patients.

Operators participating in the radiation sub-study were to follow central randomization in regards

to radial or femoral access for the primary endpoint comparison (operator radiation exposure at

thorax), and for the patient radiation exposure comparison. A further randomization was

performed in patients centrally allocated to radial access based on the patient identification (ID)

number with odd ID numbers assigned to right radial and even ID numbers to left radial access.

These patient IDs were automatically generated by the centralized web-based randomization and

data capture system, so were not under control of the study personnel. This allowed a fairly

balanced proportion of right radial access versus left radial access, used to assess whether the use

of left radial as compared to right radial is associated to lower radiation burden (secondary

endpoint).

Procedures

Access site management during and after the diagnostic or therapeutic procedure was left

to the discretion of the treating physician and closure devices were allowed as per local practice.

Standard operator radioprotection was ensured using a lead apron, a thyroid lead collar, lower

body X-ray curtain fixed on the angiographic table and an upper mobile leaded glass suspended

from the ceiling. Staged procedures were allowed, with no restriction with respect to timing,

during which the protocol mandated that the access site remained as originally allocated.

Radiation Measurement

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Radiation measures collected were fluoroscopy time (expressed in minutes) and the DAP

(expressed in Gy*cm2). The DAP is the product of the absorbed dose to air and the cross-

sectional area of the X-ray field for all segments of an interventional radiology procedure. This

parameter was measured using specially designed ionization chambers mounted at the collimator

system and calculated by the software present in each angiographic system. DAP provides a

good estimation of the total radiation energy delivered to a patient during a procedure and is

correlated with the long-term stochastic risk of cancer (9).

The operator radiation exposure was measured for each participating operator with three

dedicated lithium fluoride thermo-luminescent dosimeters with a range of linearity from 1 µGy

to 10 Gy, separate for femoral, left radial and right radial randomized access site. They were to

be worn during each procedure by the participating operator on the left wrist, at mid thorax level,

in the breast pocket outside the lead apron and at head level (in the middle front to measure the

eye dose) (Fig S1- S2). The dosimeters used different detectors according to their location

(superficial for the wrist, 3 mm depth for the eye and 10 mm depth for the thorax). Each

dosimeter was distributed to operators in a sealed envelope and was labelled with operator’s

code, access site (femoral, right or left radial) and body destination (eye, thorax or wrist – 3

locations time 3 access sites equals 9 dosimeters per operator). No protocol violation was

declared by participating operators regarding type and position of dosimeters throughout study

execution. All dosimeters were collected for central reading at TECNORAD co. (Verona, Italy)

and represent cumulative exposure during all procedures performed by the operator, separate for

femoral, left radial, and right radial randomized access site. After central reading and correction

for the radiation weighting factor (for X rays this factor is 1) the results were expressed as

Equivalent doses in microSievert. The Equivalent dose at thorax was also converted in operator

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effective dose dividing it by a factor 33 according with an apron thickness 0.5 mm lead

equivalent with a tube voltage under the table (10). Patient effective dose has been calculated

using a conversion factor of 0.20 mSv/Gy*cm2, as previously shown (11).

Statistical analysis

The primary non-inferiority hypothesis was that radial access was not associated to higher

operator radiation dose as compared to femoral access(8). Since dosimeters measure the

cumulative procedural radiation dose for each operator, the sample size was calculated for the

number of operators (i.e. dosimeters) needed rather than for the number of procedures or

patients. Using previous information(12), it was estimated that at least 13 operator dosimeters

were needed in order to prove non-inferiority with anabsolute non-inferiority margin of 25 µSv,

one-sided alpha level of 0.05 and 80%power. An arbitrary minimum of 13 procedures per

operator and per main access site was mandated to minimize the risks of imbalances due to

variation in the complexity of the diagnostic or therapeutic procedures within each operator. The

non-inferiority test for the primary outcome was performed using a one-sided unpaired t-test to

estimate the upper bound of the confidence interval of the difference in thorax radiation dosage

comparing radial versus femoral on the operator level. Differently, superiority testing for the

primary end-point was performed using two-sided Wilcoxon rank-sum unpaired test. A further

secondary analysis using a paired Wilcoxon rank-sum test was also performed. Details on the

statistical analysis are available in the web extra material.

Endpoints

The primary end-point of the study was the cumulative operator radiation dose at the

thorax. Secondary end-points included operator radiation dose at left wrist or at head level,

patient procedural radiation dose assessed with DAP values as well as total fluoroscopy time.

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Role of the funding source

The MATRIX program was designed by the last author and approved by the institutional

review board at each participating center. The RAD MATRIX substudy(8) was pre-specified in

the main study protocol and approved by all participating centers as amended number 5 to the

original study protocol. MATRIX was sponsored by the Italian Society of Invasive Cardiology

(GISE), a nonprofit organization, and received grant support from The Medicines Company and

TERUMO (see Online Appendix). The sponsor and funders had no role in study design, data

collection, data monitoring, analysis, interpretation, or writing of the report. Sponsor and

companies had no role in study design, data collection, data monitoring, analysis, interpretation,

or writing of the report. AS, MR, DH and MV had unrestricted access to all the data of the trial.

AS and MV had final responsibility for the decision to submit for publication.

Results

Between October 2011 and November 2014, 8404 patients in 78 centers in Italy, the

Netherlands, Spain, and Sweden were randomly allocated to radial (4197 patients) or femoral

access (4207 patients). DAP was collected for 6902 patients and a total of 7570 procedures

(Online Figure 3). A total of 767 patients undergoing 777 procedures were included in the

operator radiation sub-study (RAD MATRIX) performed by 18 operators (Online Figure 3).

Four operators refused to further randomize radial patients to left or right radial access (due to

the unwillingness to sustain a prolonged uncomfortable position during left radial access in three

operators, and in one due to perceived lack of clinical equipoise between left and right radial

access) and were excluded from this sub-analysis. As a result, 252 radial procedures were

performed in 250 patients by 14 operators, which were allocated to left radial (131 procedures in

130 patients) or right radial access site (121 procedures in 120 patients) (Online Figure 3)

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Procedural Characteristics

Clinical characteristics between radial and femoral groups were similar (Online Table 1).

Percutaneous coronary intervention was attempted in more than 80% of the patients in each

group (Table 1). Patients allocated to the radial group more frequently received the non-

randomly allocated access than patients in the femoral group (7% vs. 5%: p=0.0002). In the RAD

MATRIX subsample, cross over rates were balanced in the two access groups (Table 1).

Patient Radiation Exposure

Median fluoroscopy time was higher in the radial (10.2 min; IQR: 6-16) compared to

femoral group (9.1 min; IQR: 5.1-15, p<0.0001, Table 1). Median DAP values were also higher

in the radial (64.7 Gy*cm2; IQR: 28.6-120.3) compared to the femoral group (59.1 Gy*cm2

;IQR: 25.9-109.5, p=0.0001, Table 1). Mean difference of DAP values between radial and

femoral access stratified for pre-specified subgroups is shown in Online Figure 4. The results

were consistent according to the angiographic system employed (Online Table 3). Fluoroscopy

time and DAP values were consistently correlated in the radial (R=0.56) as well as in the femoral

group (R=0.56) (Online Figure 5).

Operator Radiation Exposure

Radial or Femoral Access

The primary non-inferiority hypothesis was not reached (mean difference 34.34 µSv with

an upper 95% confidence limit of 49.57); p-value for non-inferiority= 0.843); median operator

dose per procedure at the thorax level was higher in the radial compared to femoral access group

(77 µSv; IQR: 39.9-112 vs. 41 µSv IQR: 23.4-58.5, respectively, p-value for superiority= 0.019,

Central Illustration and Table 2). A paired analysis yielded identical results. After

normalization of the operator dose either for fluoroscopy times or DAP, the difference between

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radial and femoral access remained significant (Table 2). Procedural operator doses at left wrist

and head levels did not differ, although both were numerically higher with radial access (Central

Illustration and Table 2). The higher radiation dose with radial as compared to femoral access

was consistent across individual operators (Online Figure 5).

Left or Right Radial Access

The baseline and procedural features, including DAP and fluoroscopy time, were similar

between left and right radial access groups (Online Table 2). Median procedural operator dose at

the thorax did not differ in the right radial (84 µSv) compared to the left radial access (52 µSv;

p=0.15; Table 3 and Figure 1). Compared to femoral access, radiation dose did not differ

compared to the left radial access, whereas was significantly higher in the right radial access

(Online Tables 4 and 5). The radiation doses at wrist and head did not differ in the right radial

compared to the left radial access group (Table 3 and Figure 1).

Discussion

Our study is to date the largest study evaluating the radiation exposure in patients and

operators during percutaneous coronary interventions with radial or femoral access. Our main

finding is that in the setting of ACS with or without ST-segment elevation, operator and patient

radiation exposure is higher with radial compared to femoral access. The average increase in

radiation exposure for patients undergoing radial instead of femoral access was relatively small,

in the range of 10%. However, the radial, compared to femoral access, was associated to an

almost two-fold increase in operator radiation exposure at the thorax level. Our results confirm

previous observations (13) that DAP is a weak predictor of operator exposure.

In a recent meta-analysis, the difference in patient radiation exposure with radial as

compared to femoral access was shown to narrow over time, suggesting that this difference may

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not be present in current practice with experienced radial operators (5). Our findings support the

notion that this difference persists in contemporary practice with experienced operators and it

may be much greater than previously anticipated especially for complex multivessel intervention,

such in non-ST segment elevation MI patients or those with diabetes mellitus.

There are multiple potential explanations for the higher patient and operator radiation

exposure associated with radial access. Procedures undertaken via radial access are technically

more demanding for operators, especially in case of tortuosity of the subclavian-aortic axis,

which can be observed in up to 30% of patients. More intense catheter manipulation is therefore

required to overcome the vascular tortuosity and engage the coronary ostia; while the success

rate in expert hands is similar to femoral access these maneuvers increase the fluoroscopy time

and consequently the radiation dose to patients and operators. Our study confirms previous

findings that fluoroscopy time and DAP are correlated and that both are significantly higher in

the radial group (5,6).

Other aspects should be considered regarding operator radiation exposure between radial

and femoral access. Operator position with respect to X-ray tube and patient can affect radiation

exposure by a factor of 40 during percutaneous procedures (14). At variance with operators’

position during femoral access, which is well standardized, operators’ position during radial

access can substantially vary across centers or even within operators of the same center. In many

instances, in order to better manipulate the catheter at insertion site in the radial artery, operators

are closer to the X-ray tube and are less shielded by the leaded glass mobile panel. Also, the

upper ceiling leaded glass is frequently positioned closer to the patient during radial instead of

femoral access, in order to have direct access to the arterial sheath. Unfortunately, this translates

into a less effective shielding capability from scatter radiation to the operator.

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We did not observe a clear difference in terms of operator radiation dose between right

and left radial. Several studies have compared operator radiation dose between radial left or right

with inconsistent results (15-19); some showed less operator radiation dose with left instead of

right radial but others reported similar radiation dose or higher operator dose with left radial.

Various operator positions with respect to X-ray tube and inconsistent locations of mobile

shielding devices across operators during right or left radial access may account for such

heterogeneous observations.

The absolute increase in DAP values for patients receiving radial instead of femoral

access was 5.6 Gy*cm2. This difference is small and when expressed in terms of patient effective

dose is around 1.12mSv. Considering an additional lifetime cancer risk of 2.5%/Sv (1:40000)

between age 40 and 60 years (20), radial access would be associated with an increased lifetime

cancer risk of 1:35714 (0.0028%). One could consider this an acceptable risk considering that

radial instead of femoral access may avoid 6 deaths for every 1000 patients treated (1).

At variance from patients, interventional cardiologists perform thousands of procedures

during their lifetime, with the potential for a cumulative effect. Operator exposure was almost

twice higher with radial than femoral. Most of the operator body is covered with dedicated

shields, such as lead apron and thyroid collar but some operator body regions, such as the head

or arms, remain unprotected and directly exposed to radiation. Since a direct correlation between

the dose and the risk of cancer even for very low dose of radiation exposure has been suggested

(11) and taking also the deterministic risk of radiation into account (i.e. the cumulative risk of

cataract) (21) our findings should raise caution within the medical community; the incremental

operator effective dose for a single procedure undertaken with radial instead of femoral access is

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in the range of 1.1 µSv, corresponding to an additive 330 µSv every 300 procedures. This is

similar to an additive radiation exposure of 17 chest X rays.

Some studies suggested significant reductions in operator radiation doses using

adjunctive protective drapes placed on patients (22-24) during radial access. Adjunctive personal

protections as non-lead protective caps that reduce the head radiation doses should be also

considered (25).

Some limitations of our study should be considered. The use of thermoluminescent

dosimeters allows only a cumulative analysis of the operator radiation dose. Hence, further

analyses of the radiation dose in regards to the complexity of each single procedure performed

was not possible, e.g. to target improvements in procedures to reduce radiation exposure. The use

of electronic dosimeters that show radiation dose at the end of each procedure would have

allowed a better understanding, which factors might ameliorate, or even negate, the differences

in radiation exposure observed between radial and femoral access. However, thermoluminescent

dosimeters allowed operators to remain blinded to study results. As per study protocol, we did

not standardize patient preparation and set-up for radial access but asked each operator to follow

his or her routine practice. The inclusion of 18 experienced operators from different centers

likely provided a representative sample of current practice with radial access, but cannot be

translated to less experienced operators or operators with limited training in the radial access site.

The consistency of higher operator radiation exposure across participating operators with radial

instead of femoral access suggests that the greater radiation dose is a common issue in current

practice. The null finding of right versus left right radial comparison in terms of operator

exposure may reflect a power issue and requires further investigation.

Conclusions

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In conclusion, our study shows that radial access is associated with higher operator and

patient radiation exposure compared to femoral access. Radial operators and institutions should

be sensitized towards radiation risks and adopt adjunctive radio-protective measures.

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15. Kado H, Patel AM, Suryadevara S et al. Operator radiation exposure and physical

discomfort during a right versus left radial approach for coronary interventions: a randomized

evaluation. JACC CardiovascInterv2014;7:810-6.

16. Sciahbasi A, Romagnoli E, Trani C et al. Operator radiation exposure during

percutaneous coronary procedures through the left or right radial approach: the TALENT

dosimetricsubstudy. CircCardiovascInterv2011;4:226-31.

17. Kallinikou Z, Puricel SG, Ryckx N et al. Radiation Exposure of the Operator During

Coronary Interventions (from the RADIO Study). Am J Cardiol2016;118:188-94.

18. Dominici M, Diletti R, Milici C et al. Operator exposure to x-ray in left and right radial

access during percutaneous coronary procedures: OPERA randomised study. Heart 2013;99:480-

4.

19. Pancholy SB, Joshi P, Shah S, Rao SV, Bertrand OF, Patel TM. Effect of Vascular

Access Site Choice on Radiation Exposure During Coronary Angiography: The REVERE Trial

(Randomized Evaluation of Vascular Entry Site and Radiation Exposure). JACC

CardiovascInterv 2015;8:1189-96.

20. 1990 Recommendations of the International Commission on Radiological Protection.

Ann ICRP 1991;21:1-201.

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21. Authors on behalf of I, Stewart FA, Akleyev AV et al. ICRP publication 118: ICRP

statement on tissue reactions and early and late effects of radiation in normal tissues and organs--

threshold doses for tissue reactions in a radiation protection context. Ann ICRP 2012;41:1-322.

22. Musallam A, Volis I, Dadaev S et al. A randomized study comparing the use of a pelvic

lead shield during trans-radial interventions: Threefold decrease in radiation to the operator but

double exposure to the patient. Catheter CardiovascInterv 2015;85:1164-70.

23. Lange HW, von Boetticher H. Reduction of operator radiation dose by a pelvic lead

shield during cardiac catheterization by radial access: comparison with femoral access. JACC

CardiovascInterv2012;5:445-9.

24. Sciahbasi A, Rigattieri S, Sarandrea A, et al. Radiation dose absorbed by operators during

transradial percutaneous coronary procedures comparing different protective drapes: the

RADIATION study. EuroIntervention. 2017 Jan 3;12(13). pii: EIJ-D-16-00288. doi:

10.4244/EIJ-D-16-00288.

25. Alazzoni A, Gordon CL, Syed J et al. Randomized Controlled Trial of Radiation

Protection With a Patient Lead Shield and a Novel, Non lead Surgical Cap for Operators

Performing Coronary Angiography or Intervention. Circ Cardiovasc Interv 2015;8:e002384.

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Figure Legends

Central Illustration: Operator radiation exposure for radial and femoral access. Red boxes:

patients randomized to the femoral group. Grey boxes: patients randomized to the radial group.

Figure 1: Operator radiation exposure for left and right radial access. Dark grey boxes:

patients randomized to the radial right group. Light grey boxes: patients randomized to the radial

left group.

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Table 1. Procedural characteristics of the full MATRIX population and the RAD-MATRIX subsample MATRIX RAD-MATRIX

Radial Femoral P Radial Femoral P Operators

141

155

18

18

Patients 3448 3454 373 393 Procedures 3773 3797 379 398 PCI attempted 3073 (81%) 3094 (82%) 0.971 320 (84%) 324 (81%) 0.284 Number of diagnostic catheters

1.0 ± 0.6 1.0 ± 0.6 0.04 1.0 ± 0.6 1.0 ± 0.6 0.664

Number of guiding catheters 1.6 ± 0.8 1.6 ± 0.7 <0.0001 1.5 ± 0.6 1.6 ± 0.6 0.034 Cross over 273 (7%) 197 (5%) 0.0002 11 (3%) 14 (4%) 0.764 Contrast dose (ml) 163 ± 82 164 ± 86 0.833 170 ± 86 162 ± 81 0.471 Fluoroscopy time (min) 10.2 (6-16) 9.1 (5.1-15) <0.0001 10 (6-16) 8 (5-14) 0.0004 DAP (Gy*cm2) 64.7 (28.6-120.3) 59.1 (25.9-109.5) 0.0001 74.1 (33.7-130) 67.5 (24.5-114.6) 0.751 Patient Effective dose (mSv) 12.9 (5.7-24.1) 11.8 (5.2-21.9) <0.0001 14.8 (6.7-26) 13.5 (4.9-22.9) 0.238 PCI Completed 3072 (81%) 3093 (82%) 0.971 320 (84%) 324 (81%) 0.284 Treated artery Left main 149 (5%) 122 (4%) 0.082 17 (5%) 21 (7%) 0.878 LAD 1541 (50%) 1534 (50%) 0.656 161 (50%) 154 (48%) 0.463 Left circumflex 876 (29%) 861 (28%) 0.554 87 (27%) 87 (27%) 0.908 Right coronary 1029 (34%) 1029 (33%) 0.850 110 (34%) 112 (35%) 0.868 Number of stents 1.5 ± 0.9 1.5 ± 0.9 0.070 1.6 ± 0.9 1.4± 0.9 0.030 Total stent length (mm) 68 ± 44 67 ± 43 0.276 75 ± 46 68 ± 43 0.131 Thromboaspiration 798 (26%) 827 (27%) 0.498 96 (30%) 88 (27%) 0.681 Results expressed as means± standard deviation, median with interquartile range, or absolute number with percentage in brackets. 652 patients underwent two procedures and eight patients underwent three procedures during index hospitalization The p-values are estimated accounting for clusters at patient level in the MATRIX population and for clusters both at patient and operator level in the RAD-MATRIX subsample. DAP, dose area product; LAD, left anterior descending; PCI, percutaneous coronary intervention

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Table 2. Operator radiation exposure for radial and femoral access

Radial access

Femoral access

Difference between expected and actual sum of ranks for femoral access

P

Operators

18

18

Procedures 379 398 Median number of procedures 19.5 (9-23) 16 (10-36) 6 0.849 Thorax dose per procedure (µSv) 77.3 (39.9-112) 40.6 (23.4-58.5) 74 0.019 Wrist dose per procedure (µSv) 117 (68.3-197.8) 74.6 (44.2-115.3) 48.5 0.125 Eye dose per procedure (µSv) 33.9 (14.2-44.8) 20.6 (9.6-32.7) 46 0.146 Operator Effective dose (µSv) 2.3 (1.2-3.4) 1.2 (0.7-1.8) 74 0.019 Dose normalized by FT(µSv/min) Thorax dose 5.6 (4-9.8) 3.6 (3-4.9) 69 0.029 Wrist dose 8.8 (6.6-13.7) 5.3 (4.6-9.3) 41 0.195 Eye dose 2.4 (1.5-3.4) 1.7 (1-2.2) 37 0.242 Dose normalized by DAP (µSv/Gy*cm²) Thorax dose 0.8 (0.6-1.1) 0.5 (0.3-0.6) 77 0.015 Wrist dose 1.2 (0.9-2.3) 0.9 (0.6-1.3) 48 0.129 Eye dose 0.3 (0.2-0.5) 0.3 (0.1-0.4) 39 0.217

Results expressed as median with interquartile range The p-values refer to superiority and come from two-sided unpaired Wilcoxon rank-sum test. DAP, dose area product; FT, fluoroscopy time

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Table 3. Operator radiation exposure for left and right radial access

Left radial access

Right radial access

Difference between expected and actual sum of ranks for right radial access

P

Operators

14

14

Procedures 131 121 Median number of procedures 6.5 (4-10) 9 (2-14) -14 0.519 Thorax dose per procedure (µSv) 51.7 (33.2-91.9) 84.2 (47.1-146.1) -31 0.154 Wrist dose per procedure (µSv) 86.5 (52.6-139.8) 152.6 (89.4-214.6) -35 0.108 Eye dose per procedure (µSv) 14.8 (11-34.8) 38.6 (21.1-50) -38.5 0.077 Operator Effective Dose (µSv) 1.6 (1-2.8) 2.6 (1.4-4.4) -31.0 0.016 Dose normalized by FT (µSv/minute) Thorax dose 4.1 (2.5-7.3) 7.1 (4-10.8) -36.5 0.093 Wrist dose 8.8 (4.6-11) 11.5 (6.4-15.4) -30 0.168 Eye dose 1.3 (0.6-2.9) 2.6 (1.3-3.9) -32 0.141 Dose normalized by DAP (µSv/Gy*cm²) Thorax dose 0.6 (0.4-0.8) 0.7 (0.5-1.1) -27 0.215 Wrist dose 1.0 (0.6-1.2) 1.2 (0.9-2.3) -25.5 0.241 Eye dose 0.2 (0.1-0.5) 0.3 (0.2-0.5) -17 0.435

Results expressed as median with interquartile range The p-values come from two-sided unpaired Wilcoxon rank-sum test. DAP, dose area product; FT, fluoroscopy time

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Radiation Exposure and Vascular Access in in Acute Coronary Syndromes: A

Randomised Multicentre Trial

Sciahbasi,et al.

TABLE OF CONTENTS

MATRIX Program Organization: list of investigators

Funding

MATRIX Program Inclusion and Exclusion Criteria

Additional Details on Statistical Analyses

Table S1. Clinical and procedural characteristics of the MATRIX population and the

RAD-MATRIX subsample

Table S2. Clinical and procedural characteristics of RAD-MATRIX subsample for

right or left radial access

Table S3. Radiation dose according to angiographic sytems

Table S4. Radiation exposure comparing left radial vs femoral

Table S5. Radiation exposure comparing right radial vs femoral

Figure S1 Operator Dosimeters

Figure S2 Detailed Dosimeters description

Figure S3. Patient and Operator Flow Chart

Figure S4. Stratified analysis for dose area product (DAP)

Figure S5. Correlation between dose area product and fluoroscopy time

Figure S6. Detailed operator radiation doses

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MATRIX Program Organization: list of investigators Study Sponsors: Italian Society of Invasive Cardiology (GISE) and EUSTRATEGY (co-sponsor). Study Director: Maria Salomone, M.D., Ph.D., (Clinical Research Director), T.F.S., Italy. Data Monitoring: T.F.S., Italy andthe Netherlands; F.L.S.-Research Support, Spain; Gothia Forum, Sweden. Data Management : EUSTRATEGY, Enrico Frigoli, M.D. (Project Leader), Italy; Pierpaolo Occhilupo; Veronica Lodolini; Monia Monti, B.Sc.; Maria Grazia Mazzone, Italy; Erika Delos, M.D.;Maria Teresa Caruso; Maggie Testa; Nestor Ciociano; Maurizio Lazzero; Davide Gazzotti; Lorenzo Cagliari; Leila Shahmohammadi; Martina Caiazza; Vittorio Virga; Elena Guerra, M.D.; Eva Michalska; Sara Castellini; Vincenzo Serino; Gabriella Visconti, M.D.; Gianluca Pendenza, M.D.; Monica Portolan; Marco Anzini, M.D.; Elisa Silvetti; Tiziana Coco; Francesco Costa, M.D.; Sara Ariotti, M.D.; Linda Valli; Marianna Adamo, M.D.; Marcello Marino, M.D. Clinical Event Committee: Pascal Vranckx, M.D., Ph.D. (Chair), Belgium; Sergio Leonardi, M.D., M.H.S. (Co-Chair), Italy; Pierluigi Tricoci, M.D., Ph.D., USA. Statistical Committee: Peter Jüni, M.D. (Chair), Martina Rothenbühler (trial statistician), Dik Heg, Switzerland Participating countries: Italy, Netherlands, Spain, and Sweden. Executive Committee: Marco Valgimigli, M.D., Ph.D., (Principal Investigator [PI] and Chair), Erasmus Medical Center, Rotterdam, Netherlands; Andrea Gagnor, M.D., Ospedale degli Infermi, Rivoli (TO), Italy; Paolo Calabrò, M.D., Ph.D., Ospedale dei Colli, Napoli, Italy; Paolo Rubartelli, M.D., Ospedale Villa Scassi, Genova, Italy; Stefano Garducci, M.D., A.O. Ospedale Civile di Vimercate (MB), Italy; Giuseppe Andò, M.D., A.O. Universitaria G. Martino, Messina, Italy; Andrea Santarelli, M.D., Ospedali degli Infermi, Rimini, Italy; Mario Galli, M.D., Azienda Ospedaliera Sant'Anna, Como, Italy; Roberto Garbo, San Giovanni Bosco Hospital, Torino, Italy; Ezio Bramucci, M.D., Policlinico San Matteo, Pavia, Italy; Salvatore Ierna, M.D., Ospedale Sirai - Carbonia (CI), Italy; Carlo Briguori, M.D., Clinica Mediterranea, Napoli, Italy; Bernardo Cortese, M.D., Ospedale Fate bene Fratelli, Milano, Italy; Ugo Limbruno, M.D., Ospedale della Misericordia, Grosseto, Italy; Roberto Violini, M.D., A.O. San Camillo-Forlanini, Roma, Italy; Patrizia Presbitero, M.D., IRCCS Humanitas, Rozzano (MI), Italy; Nicoletta de Cesare, M.D., Policlinico San Marco, Zingonia (BG), Italy; Paolo Sganzerla, M.D., A.O. Treviglio (BG),Italy; Arturo Ausiello, M.D., Casa di Cura Villa Verde, Taranto, Italy; Paolo Tosi, M.D., Ospedale Mater Salutis di Legnago (VR), Italy; Gennaro Sardella, M.D., Ph.D., Policlinico Umberto I, Roma, Italy; Manel Sabate’, M.D., Ph.D. and Salvatore Brugaletta, M.D., Ph.D., University Hospital Clinic, Barcelona, Spain. Steering Committee: Giovanni Saccone, M.D., A.O. Giovanni Paolo II, Sciacca (AG), Italy; Pietro Vandoni, M.D., A.O. Ospedale di Desio (MB), Italy; Antonio

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Zingarelli, M.D., A.O. Universitaria San Martino, Genova, Italy; Armando Liso, M.D., Città di Lecce Hospital (GVM), Lecce, Italy; Stefano Rigattieri, M.D., A.O. Sandro Pertini, Roma, Italy; Emilio Di Lorenzo, M.D., A.O. G. Moscati, Avellino, Italy; Carlo Vigna, M.D., IRCCS Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo (FG), Italy; Cataldo Palmieri, M.D., Ospedale Pasquinucci, Massa, Italy; Camillo Falcone, M.D., Ospedale Sacra Famiglia, Erba (CO), Italy; Raffaele De Caterina, M.D., Ph.D., Marcello Caputo, M.D., Ospedale Clinicizzato SS. Annunziata Chieti, Italy; Giovanni Esposito, M.D., Ph.D., Policlinico Federico II, Napoli, Italy; Alessandro Lupi, M.D., A.O.U Maggiore della Carità, Novara, Italy; Pietro Mazzarotto, M.D., Ospedale di Lodi, Italy; Fernando Varbella, M.D., Ospedale degli Infermi, Rivoli (TO), Italy; Tiziana Zaro, M.D., A.O. Ospedale Civile di Vimercate (MB), Italy; Marco Nazzaro, M.D., A.O. San Camillo-Forlanini, Roma, Italy; Sunil V. Rao, M.D., Duke Clinical Research Institute, Durham, NC, USA, Arnoud WJ van‘t Hof, M.D., Isala Klinieken, Zwolle, Netherlands; Elmir Omerovic, M.D., Ph.D., Sahlgrenska University Hospital, Sweden. National Coordinating Investigators Paolo Calabrò, M.D., Ph.D., Ospedale dei Colli, Napoli, Italy Arnoud W J van‘t Hof, M.D., Isala Klinieken, Zwolle, Netherlands Manel Sabate’, M.D., Ph.D. and Salvatore Brugaletta, M.D., Ph.D., University Hospital Clinic, Barcelona, Spain Elmir Omerovic, M.D., Ph.D., Sahlgrenska University Hospital, Sweden Investigators and Clinical Sites: Gianluca Campo (PI), Marco Valgimigli (PI until October 20, 2013), Azienda Ospedaliero-Universitaria di Ferrara, Ferrara, Italy; Lucia Uguccioni (PI), A.O. Ospedali Riuniti, Marche Nord, Pesaro, Italy; Corrado Tamburino (PI), A.O. Universitaria Ferrarotto, Catania, Italy; Patrizia Presbitero (PI), Dennis Zavalloni-Parenti, IRCCS Humanitas, Rozzano (MI), Italy; Fabio Ferrari, (PI), A.O. Universitaria San Luigi Gonzaga di Orbassano (TO), Italy; Roberto Ceravolo (PI), Azienda Ospedaliera Pugliese Ciaccio, Catanzaro, Italy; Andrea Santarelli (PI), Ospedali degli Infermi, Rimini, Italy; Fabio Tarantino (PI), Ospedale G. B. Morgagni, Forlì, Italy; Paolo Calabrò (PI), Ospedale dei Colli, Napoli, Italy; Giampaolo Pasquetto (PI), P.O. di Este (PD), Italy; Giovanni Esposito (PI), Policlinico Federico II, Napoli, Italy; Salvatore Ierna (PI), Ospedale Sirai - Carbonia (CI), Italy; Gavino Casu (PI), Stefano Mameli, Maria Letizia Stochino, Ospedale San Francesco, Nuoro, Italy; Nicoletta de Cesare (PI), Policlinico San Marco, Zingonia (BG), Italy; Pietro Mazzarotto, (PI), Ospedale di Lodi, Italy; Alberto Cremonesi (PI), Villa Maria Cecilia Hospital, Cotignola (RA), Italy; Francesco Saia (PI), Policlinico S. Orsola, Bologna, Italy; Giovanni Saccone (PI), Fabio abate, A.O. Giovanni Paolo II, Sciacca (AG), Italy; Ugo Limbruno (PI), Andrea Picchi, Ospedale della Misericordia, Grosseto, Italy; Roberto Violini (PI), Marco Nazzaro, A.O. San Camillo-Forlanini, Roma, Italy; Roberto Garbo (PI), Salvatore Colangelo, Giacomo Boccuzzi, San Giovanni Bosco Hospital, Torino, Italy; Paolo Tosi (PI), Ospedale Mater Salutis di Legnago (VR), Italy; Vincenzo Guiducci (PI), A.O. Santa Maria Nuova, Reggio Emilia, Italy; Carlo Vigna (PI), IRCCS Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo (FG), Italy; Antonio Zingarelli (PI), A.O. Universitaria San Martino, Genova, Italy; Andrea Gagnor (PI), Ferdinando Varbella, Ospedale degli Infermi, Rivoli (TO), Italy; Stefano Garducci (PI), Tiziana Zaro, A.O. Ospedale Civile di Vimercate (MB), Italy; Simone Tresoldi (PI), Pietro Vandoni (PI until June 17, 2014), A.O. Ospedale di Desio (MB), Italy; Marco Contarini (PI), Ospedale Umberto I, Siracusa, Italy;

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Armando Liso (PI), Città di Lecce Hospital (GVM), Lecce, Italy; Antonio Dellavalle (PI), Ospedali Riuniti ASL 17, Savigliano (CN), Italy; Salvatore Curello (PI), A.O. Spedali Civili, Brescia, Italy; Fabio Mangiacapra (PI) Campus Biomedico, Roma, Italy; Paolo Rubartelli (PI), Ospedale Villa Scassi, Genova, Italy; Rosario Evola (PI), P.O. San Vincenzo, Taormina (ME), Italy; Giuseppe Andò (PI), A.O. Universitaria G. Martino, Messina, Italy; Cataldo Palmieri (PI), Ospedale Pasquinucci, Massa, Italy; Camillo Falcone (PI), Ospedale Sacra Famiglia, Erba (CO), Italy; Francesco Liistro (PI), Ospedale San Donato, Arezzo, Italy; Manuela Creaco (PI), Ospedale Gravina, Caltagirone (CT), Italy; Antonio Colombo (PI), Alaide Chieffo, Ospedale San Raffaele IRCCS, Milano, Italy; Andrea Perkan (PI), A.O.U. Ospedali Riuniti di Trieste, Italy; Stefano De Servi, Ospedale Civile di Legnano, Italy; Dionigi Fischetti (PI), Ospedale Vito Fazzi , Lecce, Italy; Stefano Rigattieri (PI), Alessandro Sciahbasi, A.O. Sandro Pertini, Roma, Italy; Edoardo Pucci (PI), Ospedale Santa Maria Goretti, Latina, Italy; Enrico Romagnoli (PI), Policlinico Casilino, Roma, Italy; Claudio Moretti (PI), A.O.U. San Giovanni Battista, Torino, Italy; Luciano Moretti (PI), A.O. C. G. Mazzoni, Ascoli Piceno, Italy; Raffaele De Caterina (PI), Marcello Caputo (PI), Marco Zimmarino, Ospedale Clinicizzato SS. Annunziata Chieti, Italy;Paolo Sganzerla (PI), A.O. Treviglio (BG), Italy; Maurizio Ferrario (PI), Ezio Bramucci (PI until June 17, 2014), Policlinico San Matteo, Pavia, Italy; Emilio Di Lorenzo (PI), A.O. G. Moscati, Avellino, Italy; Carlo Briguori, M.D., Clinica Mediterranea, Napoli, Italy; Maurizio Turturo (PI), Ospedale Di Venere, Bari, Italy; Roberto Bonmassari (PI), Ospedale Santa Chiara, Trento, Italy; Carlo Penzo (PI), Ospedale Civile di Mirano (VE), Italy; Bruno Loi (PI), A.O. Brotzu, Cagliari, Italy; Ciro Mauro (PI), AORN Cardarelli, Napoli, Italy; Arturo Ausiello, M.D., Casa di Cura Villa Verde, Taranto, Italy; Anna Sonia Petronio (PI), A.O. Universitaria Cisanello, Pisa, Italy; Gabriele Gabrielli (PI), Ospedali Riuniti Di Ancona, Italy; Gennaro Sardella, M.D., Ph.D., Policlinico Umberto I, Roma, Italy; Antonio Micari (PI), Villa Maria Eleonora Hospital, Palermo, Italy; Flavia Belloni (PI), Ospedale Santo Spirito in Saxia, Roma, Italy; Alessandro Lupi (PI), A.O.U. Maggiore della Carità, Novara, Italy; Francesco Amico (PI), Ospedale Sant’Elia, Caltanissetta, Italy; Marco Comeglio (PI), Ospedale del Ceppo, Pistoia, Italy; Claudio Fresco (PI), A.O.U. S. Maria della Misericordia, Udine, Italy; Arnoud WJ van‘t Hof, (PI), Isala Klinieken, Zwolle, Netherlands; Nicolas Van Mieghem (PI), Roberto Diletti, Evelyn Regar, Thoraxcenter, Erasus Medical Center, Rotterdam, Netherlands; Elmir Omerovic (PI) Sahlgrenska University Hospital, Sweden; Salvatore Brugaletta (PI), Manel Sabaté, University Hospital Clinic, Barcelona, Spain; Joan Antoni Gómez Hospital (PI), Hospital de Bellvitge, Barcelona, Spain; José Francisco Díaz Fernández (PI) Hospital Juan Ramón Jiménez, Huelva, Spain; Vicente Mainar (PI) Hospital General Universitario de Alicante, Alicante, Spain; Jose Maria de la Torre Hernandez (PI), Hospital Marques de Valdecilla, Santander, Spain.

Funding The study sponsor, Italian Society of Invasive Cardiology (GISE), a nonprofit organization, received grant support for the conduct of the MATRIX program from The Medicines Company and TERUMO. Other than supplying financial support and bivalirudin, the funding companies were not involved with the study processes, including site selection and management, and data collection and analysis. No agreements exist regarding confidentiality of the data among the funding companies, the sponsor, and the investigators.

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MATRIX Program Inclusion and Exclusion Criteria Inclusion Criteria Inclusion criteria for non –ST-segment elevation acute coronary syndrome ALL THREE MUST BE PRESENT FOR ELIGIBILITY History consistent with new, or worsening ischemia, occurring at rest or with minimal

activity Enrolment within 7 days of the most recent symptoms Planned coronary angiography with indication to PCI AT LEAST TWO OF THE FOLLOWING CRITERIA Aged 60 years or older Troponin T or I or creatine kinase MB above the upper limit of normal Electrocardiographic changes compatible with ischemia, i.e. ST depression of 1 mm or greater in two contiguous leads, T-wave inversion more than 3 mm, or any dynamic ST shifts Inclusion criteria for ST -segment elevation myocardial infarction BOTH CRITERIA MUST BE PRESENT FOR ELIGIBILITY Chest pain for more than 20 minutes with an electrocardiographic ST-segment elevation 1 mm or greater in two or more contiguous leads, or with a new left bundle-branch block or with ST-segment depression of 1 mm or greater in two or more of leads V1–3 with a positive terminal T wave Admission either within 12 hours of symptom onset or between 12 and 24 hours after onset with evidence of continuing ischemia or previous fibrinolytic treatment. Exclusion Criteria ANY OF THE FOLLOWING: Patients who cannot give informed consent or have a life expectancy of less than 30 days Allergy or intolerance to bivalirudin or unfractionated heparin Treatment with low-molecular-weight heparin within the past 6 hours Treatment with any glycoprotein inhibitor in the previous 3 days Absolute contraindications or allergy, that cannot be premedicated, to iodinated contrast or to any of the study medications, including both aspirin and clopidogrel Contraindications to angiography, including but not limited to severe peripheral vascular disease If it is known, a creatinine clearance less than 30 ml per minute or dialysis dependent Previous enrolment in this study PCI in the previous 30 days

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Additional Details on Statistical Analyses All analyses were performed according to the intention-to-treat principle. Differences

between randomization groups at patient level in the full MATRIX sample (for patient

radiation exposure) were assessed using Student’s t-test and χ2 or Fisher’s exact

test. In the RAD MATRIX subsample (for operator radiation exposure), differences

due to the randomized access site were estimated using mixed models accounting

for patients nested at the operator level. P-values for differences in the procedural

characteristics were estimated with mixed models accounting for procedures nested

at patient level in case of the full MATRIX sample and at patient and operator level in

case of the RAD MATRIX subsample. Medians at operator level (Table 2 and 3 in

the manuscript) in the RAD MATRIX subsample are compared using the Wilcoxon

rank sum unpaired test. The correlation between fluoroscopy time and DAP was

assessed using Pearson’s correlation coefficient. The non-inferiority test for the

primary outcome has been performed using a one-sided unpaired test with alpha of

5%. All hypotheses were two sided and p-value<0·05 was deemed statistically

significant. All analyses were performed using STATA release 14·1 and R 3·3·0.

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Table S1. Clinical and procedural characteristics o f the MATRIX population and the RAD-MATRIX subsample

MATRIX

RAD-MATRIX

Radial

Femoral

P

Radial

Femoral

P

Patients (n)

3448

3454

373

393

Procedures (n) 3773 3797 379 398 Male Sex 2548 (74%) 2503 (73%) 0.180 288 (77%) 277 (71%) 0.035 Age (years) 66 ± 12 66 ± 12 0.239 66 ± 12 66 ± 12 0 .944 Height (cm) 169 ± 98 169 ± 8 0.457 170 ± 9 169 ± 8 0.162 Weight (Kg) 77 ± 14 77 ± 14 0.410 77 ± 14 77 ± 14 0 .782 Body mass index 27 ± 4 27 ± 4 0.825 27 ± 4 27 ± 4 0 .228 Smoking habitus* 1884 (55%) 1915 (55%) 0.503 223 (60%) 223 (57%) 0.274 Hypertension 2202 (64%) 2244 (65%) 0.338 239 (64%) 256 (65%) 0.760 Diabetes 802 (23%) 785 (23%) 0.599 90 (24%) 101 (26%) 0.616 Dyslipidemia 1529 (44%) 1615 (47%) 0.044 147 (40)

% 181 (46%) 0.063

PVD 293 (9%) 316 (9%) 0.340 42 (11%) 41 (10%) 0.964 Previous MI 485 (14%) 528 (15%) 0.152 56 (15%) 66 (17%) 0.494 Previous PCI 523 (15%) 492 (14%) 0.751 52 (14%) 64 (16%) 0.351 LV ejection fraction (%) 51 ± 10 51 ± 10 0.101 51 ± 10 51 ± 9 0.516 Diagnosis at admission STEMI 1620 (47%) 1624 (47%) 0.977 178 (48%) 176 (45%) 0.558 NSTEACS 1828 (53%) 1830 (53%) 0.977 195 (52%) 217 (55%) 0.558 SAP (mmHg) 139 ± 26 140 ± 26 0.157 144 ± 28 143 ± 2 7 0.612 Heart rate (min-1) 76 ± 17 76 ± 17 0.459 78 ± 20 76 ± 16 0.114 Staged Procedure 571 (17%) 585 (17%) 0.675 77 (21%) 74 (19%) 0.619

Results expressed as mean ± standard deviation or absolute number and percent in bracket. 652 patients underwent two procedures and eight patients underwent three procedures during index hospitalization *Previous or current. LV denotes left ventricular; MI, myocardial infarction; NSTEACS, non ST-elevation acute coronary syndromes; PCI, percutaneous coronary intervention; PVD, peripheral vascular disease; SAP, systolic arterial pressure; STEMI, ST-elevation acute myocardial infarction.

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Table S2. Clinical and procedural characteristics o f RAD-MATRIX subsample for right or left radial access Left

radial access Right

radial access P

Operators 14 13 Patients 130 120 Procedures 131 121 Clinical characteristics Male Sex 107 (82%) 88 (73%) 0.089 Age (years) 67 ± 12 67 ± 12 0.864 Height (cm) 170 ± 9 169 ± 9 0.226 Weight (Kg) 77 ± 15 76 ± 13 0.446 Body mass index 27 ± 4 27 ± 4 0.943 Smoking habitus¶ 75 (58%) 76 (63%) 0.439 Hypertension 85 (65%) 79 (66%) 0.941 Diabetes 30 (23%) 28 (23%) 0.961 Dyslipidemia 57 (44%) 45 (38%) 0.308 PVD 12 (9%) 16 (13%) 0.297 Previous MI 26 (20%) 18 (15%) 0.301 Previous PCI 25 (19%) 13 (11%) 0.063 LV ejection fraction (%) 51 ± 9 51 ± 11 0.938 Diagnosis at admission STEMI 63 (49%) 49 (41%) 0.271 NSTEACS 67 (51%) 71 (59%) 0.271 SAP (mmHg) 147 ± 27 142 ± 29 0.147 Heart rate (min-1) 78 ± 20 78 ± 21 0.958 Staged Procedure 29 (22%) 20 (17%) 0.278 Procedural characteristics PCI attempted 112 (86%) 101 (84%) 0.682 Diagnostic catheters 1.1 ± 0.6 1.0 ± 0.8 0.307§ Guiding catheters 1.5 ± 0.6 1.6 ± 0.7 0.182 Cross over 3 (2%) 3 (3%) 0.701 Contrast dose (ml) 171 ± 86 179 ± 94 0.476 Fluoroscopy time (min)* 10 (5-16) 11 (7-16) 0.210 DAP (Gy*cm2)* 78.5 (40.5-142.8) 76.1 (34.1-130.7) 0.3951 PCI Completed 112 (86%) 101 (84%) 0.682 Treated artery Left main 3 (3%) 7 (7%) 0.156§ LAD 46 (41%) 54 (54%) 0.071 Left circumflex 31 (28%) 33 (33%) 0.411 Right coronary 47 (42%) 28 (28%) 0.031 Number of stents 1.6 ± 1 1.5 ± 0.9 0.675 Total stent length 75 ± 45 69 ± 44 0.394 Thromboaspiration 38 (34%) 28 (28%) 0.507

Results expressed as mean ± standard deviation or absolute number and percent in brackets. The p-values for clinical characteristics are estimated accounting for clusters at operator level, whereas the p-values of the procedural characteristics are estimated accounting for both operator and patient level. Two patients underwent two procedures. Four operators were excluded due two lack of left versus right randomization. One operator was randomized only to left radial access. DAP, dose area product; LAD, left anterior descending; LV, Left ventricular; MI, myocardial infarction; NSTEACS, non ST-elevation acute coronary syndromes; PCI, percutaneous coronary intervention; PVD, peripheral vascular disease; SAP, systolic arterial pressure; STEMI, ST-elevation acute myocardial infarction. *Median with interquartile range ¶Previous or current §p-value estimated accounting for cluster effect at operator level only.

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Table S3. Breakdown of angiographic systems accordi ng to vascular access Angiographic System Full Matrix population Rad Matrix sub-sample Procedures (N) Radial

3773 Femoral

3797 p Radial

379 Femoral

398 p

Siemens Artis 794 (21) 848 (22.3) 21 (5.5) 21 (5.3) Philips Integris 245 (6.5) 252 (6.6) 0 0 Philips Allura 1547 (41) 1525 (40.2) 174 (45.9) 182 (45.7) General ElectricsInnova 1021 (27.1) 1053 (27.7) 142 (37.5) 161 (40.5) Toshiba Infinix 166 (4.4) 119 (3.1) 42 (11.1) 34 (8.5) DAP (Gy*cm2) Siemens Artis 38.2 (15.7-88) 34.2 (14.1-78) 0.071 98.2 (63.8-190.1) 81.1 (37.9-130.5) 0.117 Philips Integris 79 (42.9-142.5) 68 (39.5-121.5) 0.097 No procedures No procedures Philips Allura 65.4 (30.2-125.4) 58 (25.3-107.5) 0.001 45 (22.2-100.9) 36.3 (12.6-88.6) 0.469 General Electrics Innova 80 (42.7-125.4) 74.3 (39.2-129) 0.278 97.5 (63.9-145.6) 89.7 (56.9-136.2) 0.517 Toshiba Infinix 50.7 (26.7-110.1) 62.9 (44-108.9) 0.152 70.7 (44.2-120.7) 67 (52.4-108.9) 0.840 Fluoroscopy time (min) Siemens Artis 9.1 (5.4-16) 9 (5-15) 0.017 7 (5-14) 8 (5-11) 0.495 Philips Integris 11 (6.9-16.2) 9.4 (6-14.9) 0.022 No procedures No procedures Philips Allura 10 (6-16.1) 8.4 (5-14.4) <0.001 10 (5-16) 6 (4-12) 0.003 General Electrics Innova 11.6 (7.1-16) 10.4 (6.5-16) 0.414 12 (7-17) 10 (7-16) 0.111 Toshiba Infinix 8 (4-14) 8 (5-13) 0.828 8.5 (5-13) 7 (4-10) 0.289

DAP: Dose area Product

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Table S4. Operator radiation exposure for left radi al and femoral access

Left Radial

access

Femoral access

Difference between

expected and actual sum of ranks for femoral access

P

Operators

14

14

Procedures 131 239 Median number of procedures 6.5 (4-10) 13 (9-17) -61.5 0.005 Thorax dose per procedure (µSv) 51.7 (33.2-91.9) 38.1 (23.4-77.6) 21 0.335 Wrist dose per procedure (µSv) 86.5 (52.6-139.8) 109.2 (44.2-128.7) 2 0.927 Eye dose per procedure (µSv) 14.8 (11-34.8) 18.8 (9.6-28.3) -1.0 0.713 Effective Dose (µSv) 1.6 (1.0-2.8) 1.2 (0.7-2.4) 21.0 0.335 Dose normalized by FT Thorax dose 4.1 (2.5-7.3) 3.4 (2.6-4.8) 14 0.520 Wrist dose 8.8 (4.6-11) 6.9 (4.0-11.9) -1.0 0.963 Eye dose 1.3 (0.6-2.9) 1.7 (0.8-2.2) -8.0 0.242 Dose normalized by DAP Thorax dose 0.6 (0.4-0.8) 0.5 (0.3-0.6) 29 0.182 Wrist dose 1.0 (0.6-1.2) 0.9 (0.6-1.3) 8.5 0.696 Eye dose 0.2 (0.1-0.5) 0.2 (0.1-0.4) 3.5 0.872

Results expressed as median with interquartile range DAP: Dose Area Product; FT: Fluoroscopy time

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Table S5. Operator radiation exposure for right rad ial and femoral access

Right Radial

access

Femoral access

Difference between

expected and actual sum of ranks for femoral access

P

Operators

14

14

Procedures 121 239 Median number of procedures 9 (2-14) 13 (9-17) -37 0.089 Thorax dose per procedure (µSv) 84.2 (47.1-146.1) 38.1 (23.4-77.6) 48 0.027 Wrist dose per procedure (µSv) 152.6 (89.4-214.6) 109.2 (44.2-128.7) 32 0.141 Eye dose per procedure (µSv) 38.6 (21.1-50) 18.8 (9.6-28.3) 31 0.154 Effective Dose (µSv) 2.6 (1.4-4.4) 1.2 (0.7-2.4) 48 0.027 Dose normalized by FT Thorax dose 7.1 (4-10.8) 3.4 (2.6-4.8) 51.5 0.018 Wrist dose 11.5 (6.4-15.4) 6.9 (4.0-11.9) 24 0.270 Eye dose 2.6 (1.3-3.9) 1.7 (0.8-2.2) 30 0.168 Dose normalized by DAP Thorax dose 0.7 (0.5-1.1) 0.5 (0.3-0.6) 50.5 0.020 Wrist dose 1.2 (0.9-2.3) 0.9 (0.6-1.3) 26.5 0.223 Eye dose 0.3 (0.2-0.5) 0.2 (0.1-0.4) 27 0.214

Results expressed as median with interquartile range DAP: Dose Area Product; FT: Fluoroscopy time

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Figure S1 Operator Dosimeters

Panel A provides an overview of the 9 dosimeters, supplied to participating operators in the RAD-MATRIX. They were supplied in three separate envelopes containing each a set of three dosimeters (envelopes labelled “femoral access site”, “left radial access site”, “right radial access site”). Panel B shows how an operator participating into the RAD MATRIX wearing a set of 3 dosimeters (one placed at the thorax, one at the head and one at the left wrist). The locations of the dosimeters were the same for the three randomized access sites compared (femoral, right radial, left radial).

Panel A:

Panel B:

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Figure S2. Detailed Dosimeters description

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Figure S3. Patient and Operator Flow Chart In the left panel, patients with their procedures analyzed in the MATRIX trial, for the patient radiation exposure (DAP). In the right panel, operators with their patients and procedures analyzed for the operator radiation exposure sub-study (RAD-MATRIX). DAP denotes dose area product.

* Thirteen operators received at least once a left radial and at least once a right radial randomization, one operator received two times left radial randomization and zero times right radial randomization, so effective sample size is n=14 operators left radial access and n=13 operators right radial access

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Figure S4. Stratified analysis for dose area produc t (DAP) Mean difference of DAP values between radial and femoral access according to specified subgroups

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Figure S5. Correlation between dose area product an d fluoroscopy time. Red circles: patients randomized to the femoral group. Grey circles: patients randomized to the radial group.

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Figure S6. Detailed operator radiation doses.

Each line represents an operator with red and grey bar showing cumulative radiation

exposure in micro Sievert with femoral or radial access, respectively.