Trial Design

Design and rationale of the RadIal Vs. femorAL access for coronary intervention (RIVAL) trial: A randomized comparison of radial versus femoral access for coronary angiography or intervention in patients with acute coronary syndromes
Sanjit S. Jolly, MD, MSc, a,l Kari Niemel, MD, PhD, b,l Denis Xavier, MD, c,l Petr Widimsky, MD, d,l Andrzej Budaj, MD, PhD, e,l Vicent Valentin, MD, f,l Basil S. Lewis, MD, g,l Alvaro Avezum, MD, PhD, h,l Philippe Gabriel Steg, MD, i,l Sunil V. Rao, MD, j,l John Cairns, MD, k,l Susan Chrolavicius, BScN, a,l Salim Yusuf, MBBS, D.Phil, a,l and Shamir R. Mehta, MD, MSc a,l Ontario and Vancouver, Canada; Tampere, Finland; Bangalore, India; Prague, Czech Republic; Warsaw, Poland; Valencia, Spain; Haifa, Israel; Sao Paulo, Brazil; Paris, France; and Durham, NC

Background Major bleeding in acute coronary syndromes (ACS) is associated with an increased risk of subsequent mortality and recurrent ischemic events. Observational data and small randomized trials suggest that radial instead of femoral access for coronary angiography/intervention results in fewer bleeding complications, with preserved and possibly improved efficacy. Radial access versus femoral access has yet to be formally evaluated in a randomized trial adequately powered for the comparison of clinically important outcomes. Objectives The aim of this study is to evaluate the efficacy and safety of radial versus femoral access for coronary angiography/intervention in patients with ACS managed with an invasive strategy. Design This was a multicenter international randomized trial with blinded assessment of outcomes. 7021 patients with ACS (with or without ST elevation) have been randomized to either radial or femoral access for coronary angiography/ intervention. The primary outcome is the composite of death, myocardial infarction, stroke, or noncoronary artery bypass graft-related major bleeding up to day 30. The key secondary outcomes are (1) death, myocardial infarction, or stroke up to day 30 and (2) noncoronary artery bypass graft-related major bleeding up to day 30. Percutaneous coronary intervention (PCI) success rates will also be compared between the two access sites. Conclusions The RIVAL trial will help define the optimal access site for coronary angiography/intervention in patients with ACS. (Am Heart J 2011;161:254-260.e4.)

From the aMcMaster University and the Population Health Research Institute, Hamilton Health Sciences, Hamilton, Ontario, Canada, bTampere University Hospital, Tampere, Finland, cSt John's Medical College and Research Institute, Bangalore, India, dCharles University, Hospital Kralovske Vinohrady, Prague, Czech Republic, ePostgraduate Medical School, Department of Cardiology, Grochowski Hospital, Warsaw, Poland, fHospital Universitari Dr Peset, Valencia, Spain, gLady Davis Carmel Medical Center, Haifa, Israel, h Dante Pazzanese Institute of Cardiology, Sao Paulo, Brazil, iINSERM U-698. Recherche Clinique en Athrothrombose. Universit Paris 7 and Assistance PubliqueHpitaux de Paris, Paris, France, jDuke Clinical Research Institute, Duke University, Durham, North Carolina, and kUniversity of British Columbia, Vancouver, Canada. l On behalf of the RIVAL steering committee. See online Appendix B for complete listing. Reg. number NCT01014273. Marc Cohen, MD, served as guest editor for this article. Submitted October 20, 2010; accepted November 23, 2010. Reprint requests: Sanjit S. Jolly, MD, MSc, Rm C3-118, DBCVSRI Building, Hamilton General Hospital, 237 Barton St. East, Hamilton, Ontario, Canada L8L 2X2. E-mail: jollyss@mcmaster.ca 0002-8703/$ - see front matter 2011, Mosby, Inc. All rights reserved. doi:10.1016/j.ahj.2010.11.021

Among patients with acute coronary syndromes (ACS) (ie, ST elevation myocardial infarction [MI] [STEMI], non ST-segment elevation MI [NSTEMI], or unstable angina), 2% to 5% experience major bleeding,1-3 a substantial proportion of which originates from the vascular access site.4 In multiple observational studies (in both ACS and percutaneous coronary intervention [PCI]), major bleeding has been independently associated with a 2- to 10-fold increased risk of death.4-7 Vascular access for coronary angiography/intervention via the radial artery, a superficial and readily compressible site, could result in a lower risk of bleeding than that associated with access via the femoral artery site. Observational studies have suggested that radial access may be independently associated with a 50% to 60% reduction in the odds of major bleeding compared to

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femoral access.8,9 A meta-analysis of 18 small randomized trials (n = 4,458 patients, 61 major bleeding events) showed that radial access was associated with a 73% reduction in major bleeding compared to femoral access (0.5% vs 2.3%, respectively, odds ratio [OR] 0.27, 95% CI 0.16-0.45, P b .001).10 Currently, radial access accounts for only 6% to 12% of procedures worldwide.9,11-14 Due to technical challenges related to radial artery diameter, subclavian tortuosity, and reduced guide catheter support, there are perceptions that the radial approach may be associated with a greater PCI procedural failure rate. In addition, the inability to use large bore hemodynamic support devices such as intra-aortic balloon pumps via the radial artery may lead to concerns among operators that they may not be able to respond adequately to emergencies that arise during the procedure. On the other hand, femoral access has a long history of use, allows for larger diameter catheters for complex procedures, and, during emergency situations, has the advantage of ease of access to the femoral vein for transvenous pacing and of the availability of the femoral artery route for the insertion of an intraaortic balloon pump. Femoral access allows superior guide support and therefore may be associated with greater rates of PCI success. Although femoral artery vascular closure devices allow earlier sheath removal, they have not been shown to reduce major bleeding in randomized trials.15 There is an emerging hypothesis that major bleeding may cause recurrent ischemic events because of (1) activation of the coagulation cascade, (2) adverse effects of blood transfusion, (3) cessation of antithrombotic and antiplatelet therapies or reversal of their effects, and (4) decreased ischemic threshold due to anemia or hypovolemia. Observational studies have demonstrated an association between major bleeding and subsequent ischemic events, but causality remains uncertain.4-6,16 Several randomized trials (OASIS 5, HORIZONS) have demonstrated that a reduction in early bleeding events using safer antithrombotic therapies is strongly associated with a reduction in longer-term mortality, MI, and stroke; this relationship is likely to be causal.2,17 Whether procedural methods to reduce bleeding such as radial access could reduce ischemic events and death is an unanswered question; such a relationship would help support the causal relationship between major bleeding and mortality. Although observational studies have suggested that radial access is associated with a lower risk of mortality than femoral access, potential selection bias necessitates a cautious interpretation of the findings.8,11 The meta-analysis of small randomized trials performed by our group found that radial access was associated with a trend toward less death, MI, or stroke compared to femoral access (OR 0.71, 95% CI 0.49-1.01, P = .058).10

The results from observational studies and meta-analyses of small randomized trials require confirmation in a large adequately powered randomized trial. Accordingly, we designed RIVAL, a multicenter randomized trial to compare the 2 procedures among 7,000 patients with ACS.

The RIVAL study

Primary objective Among patients with ACS (with or without ST-segment elevation), to determine whether radial access is superior to femoral access for the composite of death, MI, stroke or noncoronary artery bypass graft (CABG)-related major bleeding up to 30 days.

Design
RIVAL is a multinational, multicenter, randomized, parallel group study comparing radial versus femoral access for coronary angiography/intervention among patients with nonST-segment elevation ACS (NSTEACS) or STEMI (Figure 1). The trial began as an investigator initiated randomized substudy of the CURRENT-OASIS 718 trial, which compared 2 regimens of clopidogrel (double dose vs standard dose) and 2 regimens of aspirin (high vs low dose) among patients with NSTE-ACS or STEMI.19,20 The main CURRENT-OASIS 7 study was completed in July 2009,19 and the RIVAL study has continued as a stand-alone study.

Eligibility criteria
Patients with NSTE-ACS or STEMI who are to be managed with an invasive approach are eligible i) if the interventional cardiologist is willing to proceed with either a radial or femoral approach; ii) if an operator is available, with the requisite expertise for both the radial (50 such procedures in the past year) and the femoral approach; and iii) if the patient has a normal Allen test (ie, confirmation of collateral flow to the hand) (Table I).

Expertise We mandated that each operator in the RIVAL study had performed 50 radial procedures within the previous year. An alternative approach would have been to use expertise-based randomization. The advantage of this approach is that the procedure is performed by experts who are completely familiar with the technique. However, there are also disadvantages to expertise-based randomization. First, linking the randomly allocated treatment to specific operators may introduce confounding, and this could threaten the very essence of randomization (which endeavors to balance known and unknown variables). For example, radial experts may have intrinsically better catheterization skills and use lower heparin doses, which may lead to a

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Figure 1

RIVAL study design: a randomized trial of radial versus femoral access in patient with NSTE-ACS and STEMI.

difference in outcomes not because of the randomized treatment. Second, expertise-based randomization may limit the external validity of the trial because only a select few, highly specialized individuals would be eligible to participate. Finally, in our meta-analysis,10 the benefits of radial compared to femoral access were seen in both trials of radial experts (operators' preferred route was radial) and nonradial experts. The cut point of a requirement of 50 procedures in the previous year is based on published data on the learning curve of previously exclusive femoral operators to proficiently use radial access with high success rates and within an acceptable procedure time.21,22 Specifically, in a study of 4 experienced femoral operators during their first 415 radial procedures, the learning curve plateaued at 50 radial procedures per operator in procedural success, fluoroscopy, and procedural time, and these results have been replicated in other studies of the radial learning curve in experienced femoral operators.21,22 In a recent randomized trial of 1,024 patients, experienced femoral operators who had performed 50 radial procedures demonstrated high radial procedural success rates of 96.5% (3.5% crossover to femoral).23 Annual operator volume for both radial and femoral diagnostic and PCI procedures is being recorded on the

case report forms. Based on interim data from the first 6,925 patients randomized, the procedural volumes of the operators in the RIVAL trial were high (median 300 PCI/y, first quartile (Q1) 186 and third quartile (Q3) 400 PCI/y), and they had experience with both procedures (median proportion annual PCI radial 40%, Q1 25% and Q3 70%).

Randomization
Patients are randomized in equal proportions to the 2 groups using a 24-hour computer central automated voice response system located at the coordinating center in Hamilton, Canada.

Interventions
1. Radial access to perform coronary angiography and PCI (if clinically indicated); or 2. Femoral access to perform coronary angiography and PCI (if clinically indicated). The use of an arterial vascular closure device is allowed at the discretion of the treating physician.

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Table I. Eligibility criteria

Inclusion criteria ACS patients Patients with UA or NSTEMI

Ischemic symptoms suspected to represent a nonST-segment elevation ACS (UA or NSTEMI) were defined as clinical history consistent with new onset or a worsening pattern of characteristic ischemic chest pain occurring at rest or with minimal exertion (lasting longer than 10 min) and at least one of the following: (1) ECG changes compatible with new ischemia (ST depression of at least 1 mm or transient ST elevation or ST elevation of 1 mm or T wave inversion N3 mm in at least 2 contiguous leads); (2) patients N60 y with normal ECG are eligible provided that there is a high degree of certainty that presenting symptoms are because of myocardial ischemia. Such patients must have documented evidence of previous CAD with at least one of the following: (a) prior MI requiring hospitalization, (b) prior revascularization procedure (N3 m ago), (c) cardiac catheterization showing significant CAD, (d) positive exercise test, and (e) other objective evidence of atherosclerotic vascular disease; or (3) already elevated cardiac biomarkers (CK-MB or troponin T or I) above the upper limit of normal. Patients with STEMI (1) Presenting with signs or symptoms of acute MI lasting 20 min and (2) definite ECG changes compatible with STEMIpersistent ST elevation (2 mm in 2 contiguous precordial leads or N1 mm in 2 limb leads) or new left bundle-branch block or Q wave in 2 contiguous leads. Intent to perform same-sitting coronary angiography and PCI during index hospitalization Written informed consent Suitable candidate for either radial or femoral artery PCI, including (a) palpable radial artery with documented normal Allen test, (b) previous experience of the operator with 50 cases within the past year of radial artery access for coronary angiography/intervention, and (c) acceptance by operator to use whichever route is assigned by randomization Exclusion Criteria Age b18 y Active bleeding or significant increased risk of bleeding (severe hepatic insufficiency, current peptic ulceration, proliferative diabetic retinopathy) Uncontrolled hypertension Cardiogenic shock Prior CABG surgery with use of N1 internal mammary artery Documented severe peripheral vascular disease precluding a femoral approach Previously entered in the study Investigational treatment (drug or device) within the previous 30 d Medical, geographic, or social factors making study participation impractical or inability to provide written informed consent and to understand the full meaning of the informed consent
UA, Unstable angina; CAD, coronary artery disease.

Procedures
Patients are screened before undergoing coronary angiography with the permission of the treating interventional cardiologist and then randomized after informed consent. In patients undergoing PCI, troponin, creatine kinase (CK), and CK-MB must be drawn immediately pre PCI and at 2, 6, and 12 hours post PCI. For patients requiring CABG, blood must be drawn for CK and CK-MB immediately pre CABG and at 6 and 12 hours post CABG. All patients must have electrocardiogram (ECG) pre CABG, immediately post CABG, and at the time of discharge.

Other outcomes
1. Death within 30 days; 2. Components of primary outcome at 48 hours and at 30 days; 3. PCI procedural success; 4. Major vascular access site complications at 48 hours and 30 days after the procedure (major vascular access site complications include pseudoaneurysms requiring ultrasound compression, thrombin injection, or surgical repair; and large hematomas requiring prolonged hospitalization, arteriovenous fistulae, limb ischemia, or damage to adjacent nerve). Study outcome definitions are listed in Table II. Mortality is the first and most important other outcome and has the potential to confirm the link between mortality and major bleeding.

Outcomes
Primary outcome The primary efficacy outcome is the occurrence of death, MI, stroke or nonCABG-related major bleeding within 30 days. Key secondary outcomes The 2 key secondary outcomes are:
1. Death, MI, or stroke within 30 days; and 2. NonCABG-related major bleeding within 30 days.

Central events adjudication

A committee of clinicians blinded to treatment allocation will adjudicate all primary efficacy outcomes and bleeding events.

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Table II. Outcome definitions

First occurrence until day 30 of any component of death, MI, stroke, nonCABG-related major bleeding Term NonCABG-related major bleeding Definition Defined as bleeding that is (a) fatal, (b) results in transfusion of 2 U of red blood cells or equivalent whole blood, (c) causes significant hypotension with the need for inotropes or surgical intervention (a requirement for surgical access-site repair will constitute major bleeding only if there has been significant hypotension or transfusion of 2 U), (d) causes significantly disabling sequellae, or (e) is intracranial and symptomatic or intraocular and leads to significant visual loss. The primary outcome uses all-cause mortality. All deaths will be subclassified as cardiovascular and noncardiovascular. All deaths with a clear cardiovascular cause or unknown will be classified as cardiovascular (including complications of procedures and bleeding). Only deaths because of documented noncardiovascular cause (eg, cancer) will be classified as noncardiovascular. The diagnosis of new MI will depend on the timing of the event after randomization (ie, within the first 24 h of randomization, between 24 h and 7 d after randomization, and N7 d after randomization), the presence or absence of an associated MI at baseline, and whether the suspected event occurred after a revascularization procedure. No associated MI at baseline In patients with no associated baseline MI, either one of the 2 following criteria satisfies the diagnosis for an acute MI: (1) typical rise and fall of biochemical markers of myocardial necrosis including troponin, CK-MB, CK to N2 ULN (or if markers are already elevated, N50% of the lowest recovery enzyme level from the index infarction) with at least one of the following: (a) ischemic symptoms, (b) development of pathologic Q waves on the ECG, and (c) ECG changes indicative of ischemia (ST-segment elevation or depression); or (2) pathologic findings of an acute MI. MI within 24 h of randomization In UA/NSTEMI patients with an associated MI at baseline or in STEMI patients, a new MI within 24 h of randomization is defined as (1) new ischemic symptoms N20 min and (2) new or recurrent ST-segment elevation or depression N1 mm in 2 contiguous leads, not due to changes from evolution of the index MI or STEMI patients. MI between 24 h and 7 d In UA/NSTEMI patients with an associated MI at baseline or in STEMI patients, of randomization a new MI between 24 h and 7 d is defined as (a) new ischemic symptoms N20 min and (b) elevation or reelevation of CK-MB (or total CK if CK-MB is not available) 2 the upper limit of normal or N50% above the previous valley level and N2 the upper limit of normal in patients with already elevated enzymes or new or recurrent ST-segment elevation or depression N1 mm or new significant Q waves in 2 contiguous leads discrete from the baseline MI. MI occurring after 7 d or hospital In all patients, the definition of new MI occurring after hospital discharge or discharges, whichever comes first after 7 d, whichever comes first, will be either one of the 2 following criteria satisfies the diagnosis for an acute, evolving, or recent MI: typical rise and fall of biochemical markers of myocardial necrosis (including troponin, CK-MB, and CK) to N2 ULN (or if markers are already elevated, N50% of the lowest recovery enzyme level from the index infarction and N2 ULN) with at least one of the following: (a) ischemic symptoms, (b) development of pathologic Q waves on the ECG, and (c) ECG changes indicative of ischemia (ST-segment elevation or depression); or pathologic findings of an acute MI. MI post PCI For patients with MI within 24 h after PCI, a new MI is defined by (1) CK-MB (or total CK if CK-MB is unavailable) 3 the upper limit of normal or increased by 50% from the preprocedural valley level and 3 ULN in patients with already elevated enzymes or (2) new ST-segment elevation or development of new or significant Q waves in 2 contiguous leads (discrete from the baseline MI in STEMI patients). MI post CABG For patients with MI within 24 h after CABG, a new MI is defined by CK-MB (or total CK, if CK-MB is unavailable) (1) 5 the upper limit of normal or increased by 50% from the preprocedural valley level and 5 ULN in patients with already elevated enzymes and development of new pathologic Q waves in 2 contiguous leads or (2) CK-MB value 10 ULN without new pathologic Q waves. In all cases of new MI, troponin T or I may be used for the diagnosis of new MI in the absence of CK-MB at the discretion of the event adjudication committee, taking into consideration all available clinical and laboratory evidence. In addition, the event adjudication committee may request further details of the revascularization procedure such as the PCI or CABG written report or supplementary narratives to assist in ascertainment of new post PCI or CABG MI.

Death

MI

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Table II (continued)
First occurrence until day 30 of any component of death, MI, stroke, nonCABG-related major bleeding Term Stroke Definition Any stroke is defined as the presence of a new focal neurologic deficit thought to be vascular in origin, with signs or symptoms lasting N24 h. It is strongly recommended (but not required) that an imaging procedure such as a CT or MRI be performed. Failure: no success at dilating attempted lesion(s) and/or failure to cross/dilate/not attempted. Partial success: one of 2 attempted lesions was successfully dilated and procedure performed but N50% residual or TIMI flow b3 or failure. Full success: lesion(s) attempted was successfully dilated with b50% residual or TIMI 3 flow.

PCI success

Steering committee: S. Jolly (coprincipal investigator), S.R. Mehta (coprincipal investigator), A. Avezum, A. Budaj, J. Cairns, S. Chrolavicius (project manager), R. Diaz, V. Dzavik, M.G. Franzosi, C. Granger, C. Joyner (events adjudication committee chair), M. Keltai, F. Lanas, B. Lewis, K. Niemela, S. Rao, P.G. Steg, V. Valentin, P. Widimsky, D. Xavier, and S. Yusuf (steering committee chair). Data monitoring committee: P. Sleight (chair), J.L. Anderson, D.L. DeMets, J. Hirsh, D.R. Holmes, Jr, and D.E. Johnstone. Project office staff: S. Chrolavicius (project manager), R. Afzal (statistician), L. Blake, W. Chen, S. Di Diodato, C. Cramp (research coordinator), C. Horsman (research coordinator), B. Jedrzejowski (research coordinator), M. Lawrence (event adjudication coordinator), A. Lehmann, A. Robinson (research coordinator), R. Manojlovic, L. Mastrangelo, E. Pasadyn, T. Sovereign, L. Wasala, L. Xu (statistician). If available, troponin may be used instead of CK-MB post PCI if no associated MI at baseline. CT, computed tomography; MRI, magnetic resonance imaging. TIMI, thrombolysis in myocardial infarction; ULN, upper limit of normal.

Statistical considerations
The originally estimated sample size was 4,000 patients, which was chosen to provide 80% power for the detection of a relative risk reduction of 25% for a 10% rate of the primary outcome with a 2-sided .05. However, it was evident by July 2009 that the aggregate event rate was much lower than originally estimated, and a revised estimate of 6% for the primary outcome at 30 days in the femoral access group led to the calculation of a revised sample size of approximately 7,000 patients to provide 80% power to detect a relative risk reduction of 25%, with 2-sided .05. In September 2010, before the end of enrollment and before blinding, the steering committee clarified that the major bleeding component of the primary outcome refers to non-CABG major bleeding. This was because CABG-related major bleeding is unlikely to be modified by vascular access site. The protocol clarification was issued to all sites. Coronary artery bypass graftrelated major bleeding will be reported as a tertiary outcome. For the primary analysis, the relative efficacy of radial access versus femoral access will be assessed on the primary outcome by a comparison of the survival curves (estimated using the Kaplan-Meier method) for the 2 treatments using the log-rank statistic (primary test of treatment effect). Treatment effect, expressed as the hazard ratio (radial access vs femoral access) and corresponding 95% CIs, will be estimated from a Cox proportional hazards model. Statistical significance will be assessed using a 2-sided .05. There will be no adjustment for multiple comparisons of key secondary outcomes because there are only 2, and each contains components of the primary outcome. An analysis of subgroups by tertiles of both center and operators' radial procedural volume will be performed as well.

Limitations
The first potential limitation of the RIVAL trial is the exclusion of higher risk patients. For example, operators may have been unwilling to randomize morbidly obese patients because of a lack of clinical equipoise in this population. A second potential limitation is that very high-proportion radial operators (N90%) may not have commonly participated in the trial potentially because of a lack clinical equipoise between the 2 procedures among these operators. However, on the other hand, very high-proportion radial operators could have higher femoral complications rates; accordingly, we designed a pragmatic trial engaging operators with expertise in both procedures. Finally, the optimal minimum annual number of radial procedures to define expertise is unknown; accordingly, there is a potential limitation in the chosen cut point of 50 radial procedures annually. However, in practice, the RIVAL trial was successful in engaging highvolume operators who had significantly exceeded these minimum requirements for radial volume and who had extensive experience with both procedures.

Study status
Enrollment was completed on November 3, 2010, with 7,021 patients randomized with the expectation that 30-day data are likely to be available by the spring or summer of 2011. The recruitment by country and site is shown in an online Appendix.

Summary
The RIVAL trial will be the first large randomized trial comparing radial versus femoral access for coronary angiography/intervention among patients with ACS that

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is adequately powered to determine effects on major efficacy and safety outcomes.

Disclosures
Funding for the RIVAL trial was provided by SanofiAventis, Population Health Research Institute, and the Canadian Network and Center for Trials Internationally (CANNeCTIN), which is funded by the Canadian Institutes of Health Research.

References
1. Stone GW, McLaurin BT, Cox DA, et al. Bivalirudin for patients with acute coronary syndromes. N Engl J Med 2006;355:2203-16. 2. Yusuf S, Mehta SR, Chrolavicius S, et al. Comparison of fondaparinux and enoxaparin in acute coronary syndromes. N Engl J Med 2006; 354:1464-76. 3. Fox KA, Goodman SG, Klein W, et al. Management of acute coronary syndromes. Variations in practice and outcome; findings from the Global Registry of Acute Coronary Events (GRACE). Eur Heart J 2002;23:1177-89. 4. Budaj A, Eikelboom JW, Mehta SR, et al. Improving clinical outcomes by reducing bleeding in patients with nonST-elevation acute coronary syndromes. Eur Heart J 2008. 5. Rao SV, O'Grady K, Pieper KS, et al. Impact of bleeding severity on clinical outcomes among patients with acute coronary syndromes. Am J Cardiol 2005;96:1200-6. 6. Eikelboom JW, Mehta SR, Anand SS, et al. Adverse impact of bleeding on prognosis in patients with acute coronary syndromes. Circulation 2006;114:774-82. 7. Ndrepepa G, Berger PB, Mehilli J, et al. Periprocedural bleeding and 1-year outcome after percutaneous coronary interventions: appropriateness of including bleeding as a component of a quadruple end point. J Am Coll Cardiol 2008;51:690-7. 8. Chase AJ, Fretz EB, Warburton WP, et al. The association of arterial access site at angioplasty with transfusion and mortality: the M.O.R.T. A.L study: (Mortality benefit of Reduced Transfusion After PCI via the Arm or Leg). Heart 2008. 9. Rao SV, Ou FS, Wang TY, et al. Trends in the prevalence and outcomes of radial and femoral approaches to percutaneous coronary intervention: a report from the National Cardiovascular Data Registry. JACC Cardiovasc Interv 2008;1:379-86. 10. Jolly SS, Amlani S, Hamon M, et al. Radial versus femoral access for coronary angiography or intervention and the impact on major bleeding and ischemic events: a systematic review and meta-analysis of randomized trials. Am Heart J 2009;157:132-40.

11. Montalescot G, Ongen Z, Guindy R, et al. Predictors of outcome in patients undergoing PCI. Results of the RIVIERA study. Int J Cardiol 2007. 12. Cantor WJ, Mahaffey KW, Huang Z, et al. Bleeding complications in patients with acute coronary syndrome undergoing early invasive management can be reduced with radial access, smaller sheath sizes, and timely sheath removal. Catheter Cardiovasc Interv 2007;69: 73-83. 13. Hamon M, Steg G, Faxon D, et al. Major bleeding in patients with acute coronary syndrome undergoing early invasive management can be reduced by fondaparinux, even in the context of trans-radial coronary intervention: insights from OASIS-5 trial. Circulation 2006; 114(Suppl II):552. 14. Hamon M, Rasmussen LH, Manoukian SV, et al. Choice of arterial access site and outcomes in patients with acute coronary syndromes managed with an early invasive strategy: the ACUITY trial. EuroIntervention 2009;5:115-20. 15. Biancari F, D'Andrea V, Di Marco C, et al. Meta-analysis of randomized trials on the efficacy of vascular closure devices after diagnostic angiography and angioplasty. Am Heart J 2010;159: 518-31. 16. Manoukian SV, Feit F, Mehran R, et al. Impact of major bleeding on 30-day mortality and clinical outcomes in patients with acute coronary syndromes: an analysis from the ACUITY trial. J Am Coll Cardiol 2007;49:1362-8. 17. Stone GW, Witzenbichler B, Guagliumi G, et al. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med 2008;358: 2218-30. 18. Mehta SR, Bassand JP, Chrolavicius S, et al. Design and rationale of CURRENT-OASIS 7: a randomized, 2 2 factorial trial evaluating optimal dosing strategies for clopidogrel and aspirin in patients with ST and nonST-elevation acute coronary syndromes managed with an early invasive strategy. Am Heart J 2008;156:1080-8.e1. 19. Mehta SR, Bassand JP, Chrolavicius S, et al. Dose comparisons of clopidogrel and aspirin in acute coronary syndromes. N Engl J Med 2010;363:930-42. 20. Mehta SR, Tanguay JF, Eikelboom JW, et al. Double-dose versus standard-dose clopidogrel and high-dose versus low-dose aspirin in individuals undergoing percutaneous coronary intervention for acute coronary syndromes (CURRENT-OASIS 7): a randomised factorial trial. Lancet 2010;376:1233-43. 21. Spaulding C, Lefevre T, Funck F, et al. Left radial approach for coronary angiography: results of a prospective study. Cathet Cardiovasc Diagn 1996;39:365-70. 22. Hildick-Smith DJ, Lowe MD, Walsh JT, et al. Coronary angiography from the radial arteryexperience, complications and limitations. Int J Cardiol 1998;64:231-9. 23. Brueck M, Bandorski D, Kramer W, et al. A randomized comparison of transradial versus transfemoral approach for coronary angiography and angioplasty. JACC Cardiovasc Interv 2009;2:1047-54.

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Appendix A
Table I. Recruitment by country
Country No. of patients randomized 94 55 43 183 551 1475 146 208 1 187 1124 187 94 31 902 9 Country No. of patients randomized 239 129 11 80 1 17 9 583 12 1 5 20 432 50 20 122

BELGIUM (43 patients) 936 Dr P-E Massart, Clinique et Maternite SainteElisabeth de Namur (21) 937 Prof Vincent Dangoisse, Cliniques Universitaires de Mont-Godinne (7) 938 Dr Marc Vincent, Clinique gnrale Saint-Jean (15) BRAZIL (183 patients) 315 Dr Jos Armando Mangione, Hospital Beneficincia Portuguesa de So Paulo (8) 320 Dr Sandra Andrade, Mendona Hilgemberg Incor-hemocardio (9) 326 Dr Maria Sanali Moura de Oliveira Paiva, Natal Hospital Center (10) 328 Dr Gilmar Reis, Hospital So Francisco de Assis (17) 331 Dr Jos Francisco Kerr Saraiva, HMCP PucCampinas Hospital e Maternidade Celso Pierro (5) 332 Dr Ari Timerman, Instituto Dante Pazzanese de Cardiologia (48) 333 Dr Rogrio Tadeu Tumelero, Hospital So Vicente de Paulo (38) 334 Dr Wladimir Faustino Saporito, Hospital Estadual Mario Covas (8) 336 Dr Roberto Vieira Botelho, Instituto do Coracao do Triangulo Mineir (40) BULGARIA (551 patients) 431 Dr Alexander Doganov, National Heart Hospital (23) 432 Prof Julia Jorgova-Makedonska, St Ekaterina University Hospital (21) 435 Dr Atanas Penev, UMHAT-Sveta Marina (3) 433 Dr Georgi Mazhdrakov, UMHAT St Anna (52) 436 Dr Ivan Manoukov, Clinic of Invasive Cardiology, University Hospital Sveti Georgi (452) CANADA (1,475 patients) 001 Dr Sanjit Jolly/Dr Shamir Mehta, Hamilton General Hospital (696) 002 Dr Michael Rokoss, Henderson Hospital (31) 003 Dr Omid Salehian, McMaster University Medical Centre (29) 004 Dr Gilbert Gosselin, Montreal Heart Institute (1) 005 Dr Jeffrey Pang/Dr Cam Joyner, Sunnybrook Health Sciences Centre (30) 006 Dr Sven Pallie, Niagara Health System (NHS) St Catharines General Hospital Site (58) 007 Dr Anthony Fung, Vancouver General Hospital (150) 009 Dr Yun Kai Chan, NHSGreater Niagara General Site (12) 013 Dr Farrukh Hussain, St Boniface General Hospital (10) 014 Dr C. Van Kieu, CSSSRY C.H. Honore Mercier (1) 018 Dr Asim Cheema, St Michael's Hospital (138)

Argentina Australia Belgium Brazil Bulgaria Canada Chile China Croatia Czech Republic Finland France Germany Hungary India Ireland

Israel Italy Latvia Lithuania Malaysia Mexico New Zealand Poland Romania Russia Singapore Slovakia Spain Sweden United Kingdom United States

Appendix B: RIVAL program list of principal investigators and recruitment by site

ARGENTINA (94 patients) 252 Dr Eduardo Conrado Conci, Instituto Modelo De Cardiologia Priv. S.R.L. (3) 260 Dr L. L. Lobo Marquez, Instituto de Cardiologia de TucumanSRL (1) 265 Dr Guillermo Covelli, Clinica Privada del Prado (16) 266 Dr Miguel Angel Hominal, Sanatorio Medico de Diagnostico y Tratamiento (13) 271 Dr Gerardo Zapata, Instituto Cardiovascular de Rosario (5) 272 Dr J. C. Pomposiello, Hospital Privadomde Comunidad (12) 277 Dr Simon Salzberg, Hospital Juan A. Fernandez (15) 278 Dr Alejandro Sanchez, Policlinico Modelo Cipolletti (14) 280 Dr Daniel Santos, Instituto Cardiologico Especializado SRL (1) 282 Dr Daniel Piskorz, Sanatorio Britanico de Rosario (2) 284 Dr Mario Berli, Hospital Provinicial Dr Jose Maria Cull (5) 286 Dr Claudo Rodolfo Majul, Hospital Britanico de Buenos Aires (7) AUSTRALIA (55 patients) 233 Dr Matthew Worthley, Royal Adelaide Hospital (54) 240 Prof Peter Thompson, Sir Charles Gairdner Hospital (1)

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019 Dr G. Calvin, MacCallum Memorial University Eastern Health Sciences Center (7) 020 Dr Frank Nigro, Intermountain Research Consultants (2) 026 Dr Patrick Beliveau, CHUQHotel Dieu de Quebec (49) 030 Dr Denis-Carl Phaneuf, Hospital Pierre-Le Gardeur (3) 031 Dr Jean-Pierre Dery, Hpital Laval (7) 033 Dr Vlad Dzavik, University Health Network (22) 035 Dr Salima Shariff, Surrey Memorial Hospital (27) 039 Dr Joseph Berlingieri, Joseph Berlingieri and William Nisker (JBN) Medical Diagnostic Services (19) 062 Dr Warren Cantor, York PCI Group Inc (53) 063 Dr Robert Boone, Providence Health Care, St Paul's (42) 064 Dr Francois Charbonneau, University of Calgary (88) CHILE (146 patients) 353 Dr R. Lamich Betancourt, Hospital Barros Luco (70) 354 Dr C.P.P. Jofre, Hospital Dr Herman Henriquez Aravena (52) 355 Dr E.E.G. Flores, Hospital Clinico Regional Valdivia (23) 360 Dr Misael Lopetegui, Hospital Clnico San Borja Arriarn (1) CHINA (208 patients) 906 Dr Shuyang Zhang, Peking Union Medical College Hospital (10) 912 Dr Yaling Han, The General Hospital of Shenyang Military C (11) 914 Dr Meng Wei, Shanghai No. 6 People Hospital (22) 915 Dr Daowen Wang, Tongji Hospital of Huazhong University (9) 917 Dr Jianan Wang, Second Affiliated Hospital Zhejiang University (22) 919 Dr Jiyan Chen, GuangDong Provincial People's Hospital (60) 924 Prof Tianchang Li, Beijing Tongren Hospital (1) 927 Dr Biao Xu, The Affiliated Drum Tower Hospital (31) 928 Dr Genshan Ma, Zhong Da Hospital (42) CROATIA (1 patient) 457 Dr Mijo Bergovec, Klinicka bolnica Dubrava (1) CZECH REPUBLIC (187 patients) 404 Assoc Prof Dr Pavel Cervinka, Masaryk Hospital (54) 405 MUDr Zdenek Coufal, Regional Hospital T. Bati a.s. Zln (14) 410 Dr Petr Kala, Fakultn nemocnice Brno ( 10) 412 Prof Ales Linhart, General Faculty Hospital (3)

413 Dr Roman Ondrejcak, KKN a.s., Nemocnice Karlovy Vary, kardiologick odd (29) 421 Prof Jan Vojacek, Fakultni nemocnice Hradec Kralove (6) 422 Dr Richard Rokyta, I. Intern klinika, Fakultn (27) 430 Dr Michal Rezek, University Hospital St Anna (44) FINLAND (1,124 patients) 636 Oyl Saila Vikman, Heart Center, Tampere University Hospital (232) 637 Prof Juhani Airaksinen, Turku University Hospital (30) 640 Oyl Antti Ylitalo, Satakunta Central Hospital (5) 641 Oyl Matti Niemela, Oulu University Hospital (857) FRANCE (187 patients) 583 Dr Emile Ferrari, CHU de NiceHpital Pasteur (160) 585 Dr Gilles Grollier, CHU de caenHpital Cte de Nacre (6) 595 Prof Gabriel Steg, Hpital Bichat Claude Bernard (21) GERMANY (94 patients) 508 Dr Dietrich Andresen, Vivantes Klinikum am Urban (8) 510 Dr Florin Laubenthal, Elisabeth-Krankenhaus Essen (1) 522 Dr Juergen vom Dahl, Kliniken Maria Hilf GmbH (62) 525 Dr Christoph Nienaber, Universitaet Rostock (7) 532 Dr Stefan Hoffmann, Vivantes Klinikum im Friedrichshain (16) HUNGARY (31 patients) 485 Dr Peter Polgr Josa Andras Teaching Hospital (1) 487 Dr Bla Nagybaczoni Bajcsy Zsilinszky Hospital (30) INDIA (902 patients) 851 Dr Kumar Rajendra Premchand, Krishna Institute of Medical Sciences (240) 852 Dr M. Bhaskar Rao, CARE Hospital (71) 854 Dr Keyur Parikh, S.A.L. Hospital & Medical Institute (161) 862 Dr Nakul Sinha, Sanjay Gandhi PGIMS (299) 863 Dr Hemang Baxi, The Heart Care Clinic (38) 872 Dr Brian Pinto, Holy Family Hospital (76) 874 Dr Sudhir R. Naik, Apollo Hospitals (2) 881 Dr Pradeep Kumar Shetty, Narayana Hrudayalaya (15) IRELAND (9 patients) 391 Dr Peter Crean, St James's Hospital (9) ISRAEL (239 patients) 971 Dr Yoav Turgeman, Haemek Medical Centre (17)

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972 Prof Basil S. Lewis, Lady Davis Carmel Medical Centre (114) 980 Dr Joel Arbel, Meir Medical Center (3) 981 Dr Alon Marmor, Heart Institute (62) 983 Dr Majdi Halabi, Division of Invasive Cardiology (43) ITALY (129) 756 Dr Marco Rossi, Istituto Clinico Humanitas (1) 766 Prof Giancarlo Piovaccari, Ospedale Infermi U.O. Cardiologia (56) 767 Dott Salvatore Pirelli, Div. Di Cardiologia, Azienda Istituti Ospitalieri Cremona (43) 771 Dr Giuseppe Steffenino, Azienda Ospeddliera Santa Croce e Carle (3) 773 Dr Roberto Zanini, Azienda Ospedaliera Carlo Poma (12) 775 Dr Ugo Limbruno, Ospedale della Misericordia (14) LATVIA (11 patients) 396 Dr Andrejs Erglis, Pauls Stradins Clinical University Hospital (11) LITHUANIA (80 patients) 992 Dr Ramunas Unikas, Kaunas Medical University Hospital (80) MALAYSIA (1 patient) 801 Dr Chong Wei Peng, University Malaya Medical Centre (1) MEXICO (17 patients) 363 Dr Jose Luis Arenas Leon, Hospital Angeles Centro Medico Del Potos (5) 370 Dr M.S.L.Velasco, Star Medica Morelia (12) NEW ZEALAND (9 patients) 067 Dr Gerard Devlin, Waikato Hospital (6) 068 Dr Scott Harding, Wellington Hospital (3) POLAND (583 patients) 617 Prof Andrzej Budaj, Szpital Grochowski (134) 618 Dr Piotr Achremczyk, Radomski Szpital Specjalistyczny (7) 619 Dr Pawel Miekus, Szpital Miejski im. J. Brudzinskiego (6) 621 Dr Barbara Kusnierz, Wojewdzki Szpital Specjalistyczny nr 4 (19) 623 Dr Bozena Wrzosek, Wojewdzki Szpital Specjalistyczny (181) 624 Dr Jerzy Kopaczewski, Szpital Wojewodzki (16) 628 Dr Jan Wodniecki, Szpital Specjalistyczny w Zabrzu (3) 628 Dr Damian Kawecki, Szpital Specjalistyczny w Zabrzu (26)

631 Dr Maciej Dalkowski, Regionalny Osrodek Kardiologii, Miedziowe Centrum Zdrowia S.A. (171) 647 Prof Lech Polonski, III, Katedra i Oddzial Kliniczny Kardiologii SUM (14) 648 Prof Zbigniew Kalarus, Slaskie Center for Heart Disease (6) ROMANIA (12 patients) 442 Prof Radu Capalneanu, Institutul Inimii N. Stancioiu (12) RUSSIA (1 patient) 813 Prof Svetlana Berns, Municipal Healthcare Institution (1) SINGAPORE (5 patients) 791 Prof Tian Hai Koh, National Heart Centre (5) SLOVAKIA (20 patients) 452 Dr Roman Margozcy, Stredoslovensky ustav srdcovych a cievnych chorob (10) 454 Dr Peter Kurray, Kardiocentrum Nitra sro (10) SPAIN (432 patients) 701 Dr Vicent Valentin, Hospital Universitario Dr Peset (128) 702 Dr Nicolas Vazquez, Hospital Universitario Juan Canalejo (13) 706 Dr Juan Angel Ferrer, Hospital General Vall D'Hebron (25) 707 Dr Manel Sabate, Hospital De La Santa Creu i De Sant Pau (4) 713 Dr Inaki Lekuona, Hospital De Galdakao-Usansolo (51) 721 Dr Francisco Bosa, Hospital Universitario de Canarias (116) 722 Dr Jose Moreu, Hospital Virgen de la Salud (1) 724 Dr Andrs Iiguez, Hospital Meixoeiro (24) 725 Dr Francisco Macaya, Hospital Clnico San Carlos (29) 730 Dr Juan Sanchis, Hospital Clinico de Valencia (4) 732 Dr Ramn Lpez Palop, Hospital Universitario San Juan de Alicante (35) 738 Dr Ramiro Trillo, Hospital Clinico de Santiago (2) SWEDEN (50 patients) 652 Dr Aida Hot-Bjelak, Capio St Goran's Hospital (15) 653 Dr Loghman Henareh, Karolinska University Hospital (5) 654 Prof Goran Olivecrona, Lund University Hospital (30) UNITED KINGDOM (20 patients) 941 Dr Andreas Baumbach, Bristol Royal Infirmary (15)

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944 Prof Adam de Belder, Royal Sussex County Hospital (2) 948 Dr Iqbal Malik, St Mary's Hospital (1) 950 Dr Mike Pitt, Heart of England NHS Foundation Trust (2) USA (122 patients) 75 Dr Mehrdad Saririan, Maricopa Integrated Health System (1)

104 Dr Ramesh Mazhari, GWU Medical Faculty Associates (7) 105 Dr Steven L. Goldberg, University of Washington (1) 172 Dr Narendra Singh, Northside Cardiology (32) 178 Dr Joseph Chambers, Endovascular Research (1) 183 Dr Stephen Thew, Heart Clinics Northwest (62) 186 Dr M. Kevin Ariani, Northridge Hospital Medical Center (1) 192 Dr Joana Magno, The Queen's Medical Center (4)