Safety of Very Early Sheath Removal in Patients Treated With REG1 for Acute Coronary Syndromes: Insights From the RADAR Trial
Abstract: Background. RADAR compared REG1 (25%, 50%, 75%, 100% reversal) with unfractionated heparin (UFH) in 640 acute coronary syndrome (ACS) patients (479 REG1 patients, 161 UFH patients) undergoing an invasive management strategy. We sought to determine whether the REG1 anticoagulation system allows for safer early arterial sheath removal following cardiac catheterization. Methods. REG1 patients had arterial sheath removal immediately post catheterization. We measured arterial sheath management outcomes and vascular access complications in patients who had sheath removal without vascular closure device implantation; 461 patients were included (349 REG1 patients, 112 UFH patients). Results. The median (25th, 75th) time from end of catheterization to arterial sheath removal was shorter in REG1 arms regardless of reversal strategy (26 minutes [18, 46]) compared with UFH (210 minutes [102, 342]). There was no increase in median time from sheath removal to hemostasis (10 minutes [10, 20] and 10 minutes [10, 20]; P=.60); vascular access-site bleeding complications were numerically fewer with REG1 than UFH (6% vs 11%; odds ratio [OR], 0.57; 95% CI, 0.27-1.18; P=.14). There were no differences in time to ambulation or hospital length of stay between the groups. Conclusions. REG1 allows for very early arterial sheath removal following cardiac catheterization without increasing the time to hemostasis or vascular access-site bleeding complications. Further studies are needed to determine whether anticoagulation with REG1 will translate into shorter hospital lengths of stay and reduced costs in ACS patients.
J INVASIVE CARDIOL 2013;25(11):593-599
Key words: anticoagulation, aptamer, factor IX, bleeding, cardiac catheterization, REG1, pegnivacogin
Vascular-access complications after cardiac catheterization lead to substantial increases in cost and morbidity. Among patients undergoing percutaneous coronary intervention (PCI), a substantial proportion of bleeding events are hematomas that occur at the site of vascular access.1 Bleeding complications among patients with acute coronary syndrome (ACS) undergoing coronary angiography are associated with poor long-term outcomes and an increase in the risk of subsequent ischemic events and death.1-4 An analysis from the National Heart Lung and Blood Institute Dynamic Registry found that patients experiencing access-site hematomas requiring transfusion were approximately 9 times more likely to die in the hospital and 4.5 times more likely to die within 1 year, as compared with those not experiencing these access-site hematomas.2
Delays to arterial sheath removal following coronary angiography have been associated with an increased risk of bleeding at the site of arteriotomy.5 The use of vascular closure devices reduces time to sheath removal and ambulation following cardiac catheterization, but does not reduce vascular complications.6 Early arterial sheath removal immediately after the conclusion of the procedure may decrease the risk of bleeding, shorten the time to ambulation, decrease hospital lengths of stay, and even possibly allow for patients to be discharged on the same day.
The REG1 Anticoagulation System (Regado Biosciences) is a novel, aptamer-based, factor IXa inhibitor that is being developed for use in patients undergoing PCI and for the treatment of ACS. Aptamers are small oligonucleotides that can be developed to inhibit specific protein targets with high affinity and used as active drugs. Because aptamers are made of oligonucleotide sequences, they code for their own antidote that can be used to inhibit their function.
The REG1 Anticoagulation System is composed of the active aptamer drug, pegnivacogin, and an antidote, anivamersen. Pegnivacogin is a modified ribonucleic acid (RNA) made of 31 nucleotides. The antidote, anivamersen, is an RNA oligonucleotide that is 15 nucleotides in length. Anivamersen binds to pegnivacogin via traditional Watson-Crick base pairing to inhibit its function and reverse its anticoagulant effect (Figure 1). This mechanism allows for full or partial reversal of anticoagulation based on dosing of anivamersen that is titratable to clinical needs.7 Because of REG1’s controllable nature, it may allow for safer very-early arterial sheath removal following cardiac catheterization. The Randomized, Partially-Blinded, Multicenter, Active-Controlled, Dose-Ranging Study Assessing the Safety, Efficacy, and Pharmacodynamics of the REG1 Anticoagulation System in Patients with Acute Coronary Syndromes (RADAR) trial was designed to evaluate REG1 in ACS patients undergoing early transfemoral invasive management. Patients were randomized to REG1 with varying degrees of reversal (25%, 50%, 75%, or 100%) or unfractionated heparin (UFH) and received coronary angiography with PCI if indicated.8 Arterial sheath removal was to occur immediately following reversal in REG1 patients and per standard of care in heparin patients.
For the purposes of this study, we sought to evaluate differences in arterial sheath management, vascular access bleeding complications, and length of stay in patients treated with the REG1 system versus UFH among patients enrolled in the RADAR trial undergoing manual sheath removal. In particular, we assessed time from end of catheterization to sheath removal, time to hemostasis, vascular access-site bleeding complications, time to ambulation following sheath removal, and hospital lengths of stay.
Study design. The design and results of the RADAR trial have been published.8,9 Briefly, RADAR was a phase-2b, international, adaptive design, partially-blinded, dose-ranging clinical trial to assess the safety and efficacy of the REG1 anticoagulation system, compared with UFH, in patients with ACS undergoing an invasive management strategy. Eligibility criteria included 10 minutes of ischemic symptoms within 72 hours of enrollment associated with ST-segment changes, elevated cardiac biomarkers, or a previous history of coronary artery disease by angiography.8
Patients were randomized 3:1 to open-label REG1 or UFH. Glycoprotein IIb/IIIa inhibitor use was encouraged in patients assigned to UFH. Those randomized to REG1 received 1 mg/kg of open-label intravenous pegnivacogin prior to coronary angiography. They were then randomized in a 2:1:1:2 ratio to a blinded postprocedure dose of anivamersen of 0.075, 0.2, 0.4, or 1.0 mg/kg to achieve 25%, 50%, 75%, or 100% reversal, respectively.10,11
For patients randomized to UFH, guidance regarding heparin dosing was provided in the study protocol, but the final decisions on heparin dosing were left to the discretion of the operator. We recommended heparin dosing based on a weight-based algorithm adjusted for age, sex, and renal function. During the conduct of the PCI, heparin dosing was adjusted according to activated clotting time (ACT) monitoring. Operators were provided specific instructions to target an ACT goal of greater than 200 seconds and were given detailed instructions on redosing of heparin if ACT readings were below 200 seconds.
Detailed instructions were provided to operators regarding acceptable sheath sizes to be used for vascular access. Specifically, the planned use of sheath sizes >7 Fr was excluded from the study. RADAR did not provide any specific guidance on the use of bone landmarks (femoral head), micropuncture, ultrasound, etc. Physicians accessed the femoral artery according to their own local practices. Following the conclusion of the procedure, sheaths were removed 10 minutes after receiving anivamersen in those randomized to REG1. In UFH patients, sheaths were removed according to local standard of care.
After sheath removal, sites were instructed to hold manual pressure on the groin site for 10 minutes. If hemostasis was not achieved, manual pressure was held for another 10 minutes. If hemostasis was not achieved after 20 minutes of manual pressure in patients randomized to REG1, an additional open-label “rescue reversal” dose of 100% reversal anivamersen (1 mg/kg) could be administered to provide complete reversal of pegnivacogin. An ambulation challenge was recommended at 2 hours after sheath removal in REG1 patients and per local standard of care in UFH patients.
The primary endpoint of the trial was total bleeding at 30 days, which was the composite of major bleeding as defined in the Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial, plus hemarthrosis and any clinically overt bleeding not meeting the definition for ACUITY major bleeding. The ACUITY definition for major bleeding includes intracranial, intraocular, retroperitoneal bleeds, access-site hemorrhage requiring radiologic or surgical intervention, a 5-cm diameter hematoma at the puncture site, clinically overt blood loss resulting in a decrease in hemoglobin >3 g/dL, any decrease in hemoglobin >4 g/dL, re-operation for bleeding, and the use of blood products or transfusion.8,12 Secondary endpoints included major bleeding (ACUITY major bleeding plus hemarthrosis), and a composite ischemic endpoint that included death, non-fatal myocardial infarction, urgent target vessel revascularization, or recurrent ischemia in the target vessel distribution through 30 days. All bleeding and ischemic events were adjudicated by an independent clinical events committee blinded to study treatment using original source documents.
The RADAR trial employed an adaptive design, whereby the data safety monitoring board (DSMB) reviewed both the bleeding and ischemic events after enrollment of 100, 200, and 400 patients. Based on prespecified criteria, the DSMB could recommend cessation of enrollment either into lower reversal arms if an excess of bleeding was observed, or into higher reversal arms if an excess of ischemic events was noted. As a result, at the first interim analysis, the 25% reversal arm was closed to further enrollment as an excess of bleeding in that arm was observed.
All patients enrolled in the trial in the intention to treat population completed the predefined 48-hour follow-up and had discharge information available for the bleeding and ischemia endpoints. There were a total of 6 subjects in the REG1 group and 2 patients in the heparin group who were lost to follow-up at 30 days. The subjects were evenly distributed with 1 patient each in the 100% and 50% groups and 2 patients in the 75%, 25%, and heparin groups. If there was no information available on the patient at 30 days, the patients were removed from the denominator and not counted in the total for each REG1 group, REG1 total, or heparin patients. None of the patients with missing data at 30 days had met an endpoint at 48 hours or hospital discharge.
For the purposes of the current analysis, patients who had vascular closure devices implanted or had missing data regarding the use of a vascular closure device were excluded. Subjects in each of the REG1 arms were compared with each other and as a group to those in the UFH arm. The outcome measures for this study were time from end of cardiac catheterization to sheath removal, time from sheath removal to hemostasis, hospital length of stay, time to ambulation following cardiac catheterization, and arterial access-site bleeding complications. Major femoral vascular access-site bleeding complications were defined as a hematoma of at least 5 cm at the site of arteriotomy or a bleed requiring surgical or radiologic intervention for treatment. In addition, all vascular access-site bleeding, retroperitoneal bleeding, transfusions, and drops in hemoglobin >4 g/dL were recorded and compared among the arms.
To determine the impact of the high bleeding rate in the 25% reversal arm on the comparison of the combined REG1 arm to heparin, a group of combined REG1 patients excluding those in the 25% reversal arm was created. This served as a sensitivity analysis to determine the impact of REG1 versus heparin on the outcome measures.
Statistical analysis. Discrete variables are presented as frequencies with their respective percentages. Continuous variables are presented as means with standard deviations or medians with 25th and 75th percentiles. The Wilcoxon rank sum test was used to compare time to hemostasis among the combined REG1 groups versus heparin, and the likelihood ratio chi-square test was used to compare femoral artery bleeding complications among the same groups. All analyses were performed on an intention-to-treat basis. A 2-tailed P-level <.05 was considered statistically significant. Analyses were performed at the Duke Clinical Research Institute in Durham, North Carolina using SAS version 9.2 (SAS Institute, Inc), with full access to the trial database.
A total of 640 subjects (479 assigned to REG1 and 161 to UFH) were enrolled in the RADAR trial. Of these, vascular closure devices were used in 61 patients (12.7%) receiving REG1 and 27 patients (16.8%) receiving UFH and were excluded from this analysis. In addition, 69 patients (14.4%) in the REG1 arm and 22 patients (13.6%) in the UFH arm had missing data regarding the use of vascular closure devices and were also excluded from this analysis. Therefore, a total of 349 patients treated with REG1 and 112 patients treated with UFH were included in this analysis (Figure 2). Among the 349 patients in the REG1 arm, 21 were in the 25% reversal group, 86 were in the 50% reversal group, 92 were in the 75% reversal group, and 150 were in the 100% reversal group. Table 1 displays the baseline demographics for patients included in this analysis. In general, they represented a population of ACS patients similar to those enrolled in the ACUITY trial.12
Table 2 shows the treatment characteristic of patients enrolled in RADAR and included in this analysis. All patients in the UFH arm received heparin and 98.9% of patients in the REG1 arm received pegnivacogin. Among those who received REG1, 98.3% received the assigned anivamersen. Almost all patients received aspirin and approximately 90% received a thienopyridine, as directed by the protocol. Glycoprotein IIb/IIIa inhibitor use was higher in the UFH arm (15.2%) as compared with the REG1 arm (9.5%). Over 99% of patients in this study received coronary angiography. PCI was the management strategy chosen for 59.3% of patients in the REG1 arm and 67.9% of patients in the UFH arm. Medical management was chosen for less than one-third of subjects in both arms. The use of coronary artery bypass surgery as a revascularization strategy was chosen in 5.4% in the UFH arm and 9.2% in the REG1 arm.
Femoral Access-Site Management and Complications
As dictated by protocol, the time from the end of cardiac catheterization to arterial sheath removal differed greatly between those receiving REG1 as opposed to UFH. The median (25th, 75th) time to sheath removal ranged from 22 (16, 40) minutes to 30 (19, 51) minutes in the REG1 arms compared with 210 (102, 342) minutes in the UFH arm (Figure 3). The median time from sheath removal to hemostasis was 10 minutes in all groups, except for the 25% reversal group of REG1, where it was 20 minutes (25th, 75th was 10, 20 in all groups). Details regarding sheath sizes used for each of the enrollment groups are shown in Supplemental Table 1.
The rates of vascular access major bleeding complications through 30 days are shown in Figure 4. Access-site bleeding was highest in the 25% reversal group (19%) and significantly lower in all other REG1 reversal groups, ranging from 5%-8%. Combining the subjects randomized to REG1, either with or without those who received the 25% reversal dose of anivamersen, yielded an access-site bleeding rate of 6%. This rate was numerically lower than the 11% rate of access-site bleeding seen in those who received heparin (number needed to treat = 20). The odds ratio of the risk of major vascular access bleeding among those who received REG1 as compared with those who received UFH was 0.57 (95% confidence interval [CI], 0.27-1.18).
Other markers of vascular access bleeding. As shown in Table 3, the rates through hospital discharge of fatal bleeding, transfusions, retroperitoneal bleeding, hemodynamically significant bleeding, and drop in hemoglobin were low in all groups. Consistent with the overall results, the highest rates of hemodynamically significant bleeding and drop in hemoglobin were observed in the 25%
reversal arm, although the absolute numbers of events were small. There was only 1 fatal bleeding event and this occurred in the UFH arm.
Ambulation and hospital length of stay. The percentage of patients who were able to ambulate at 2 hours after sheath removal was similar in all groups, ranging from 41%-52%, except for the 25% reversal. Paradoxically, in the 25% reversal group, 18 of the 21 patients (90%) could ambulate at 2 hours. Hospitalization time did not significantly differ between the groups, with a mean length of stay ranging from 94 hours in the UFH group to 118 hours in the 50% reversal arm (Table 4).
In this study, we have demonstrated that patients anticoagulated with REG1 during cardiac catheterization with or without PCI had their arterial sheath removed more than 3 hours earlier, on average, than those anticoagulated with UFH. Despite very-early sheath removal, the time of manual pressure required to achieve hemostasis and the number of major vascular access bleeding complications did not increase. In fact, there were numerically fewer major access-site bleeding complications in those treated with REG1.
Because of its reversible properties, REG1 offers many potential advantages for use in the cardiac catheterization laboratory. REG1 provides a high level of anticoagulation, inhibiting nearly 100% of factor IXa’s activity, yet its anticoagulant effect can be titrated at the time of sheath removal or completely reversed should the clinical need arise. Thus, REG1 may concomitantly achieve reductions in both ischemic and bleeding complications that can occur during cardiac catheterization and PCI.
A recent analysis from the CathPCI National Cardiovascular Data Registry (NDCR) highlights the importance of vascular access-site bleeding complications and the impact the choice of antithrombotic regimen can have on this outcome.13 In this study, the authors demonstrate a temporal trend of reductions in overall bleeding complications associated with PCI from 2005 to 2009. However, this reduction was due solely to reductions in access-site bleeding largely driven by changes in antithrombotic therapy over that time. Therefore, it is reasonable to expect that REG1 has the possibility of further reducing access-site and overall bleeding rates associated with PCI.
In general, access-site bleeding complication rates observed in this study were higher than those seen in the ACUITY trial (0.8% with bivalirudin, 2.5% with UFH or bivalirudin plus glycoprotein IIb/IIIa inhibitors), which used the same definition (except for the addition of hemarthrosis in RADAR) and studied a similar population. However, it is important to note that the overall total bleeding rates were high in the RADAR trial, ranging from 30.4%–65.0%.9 The reasons for this are not fully understood, but likely stem from the vigilant manner in which bleeding events were assessed and recorded, as mandated by this phase-2 study protocol.
We also explored the possibility of early arterial sheath removal leading to quicker ambulation or hospital discharge. This study did not demonstrate reductions in time to either endpoint; however, this was an ACS study and hospital length of stay was more likely to have been dictated by the clinical care necessary for these patients than time to arterial sheath removal and ambulation. In an elective PCI population, however, REG1 may allow for earlier discharge as a result of the ability to remove the arterial sheath much sooner than is currently feasible. This remains to be demonstrated with the use of REG1, but there is mounting evidence that same-day hospital discharge after PCI is safe in carefully selected patients.14
Study limitations. This is a secondary data analysis and not powered to show statistically significant differences in femoral access bleeding rates. The dramatic differences in time to arterial sheath removal between the REG1 arms and UFH arm are largely due to what was mandated in the protocol and do not necessarily reflect what might be done in practice. The time to hemostasis was also largely driven by the study design, as sites were asked to hold pressure for 10 minutes, and if no hemostasis was achieved after that amount of time, to hold for an additional 10 minutes. Therefore, we were unable to detect subtle differences in time to hemostasis between the arms, as might have been the case had sites been asked to hold manual pressure until hemostasis was achieved without prespecifying an amount of time. However, this study does demonstrate that the arterial sheath can be removed very early after a catheterization procedure performed on full anticoagulation without significant increases in bleeding complications. In addition, we were able to demonstrate that with at least 50% reversal of REG1, there do not appear to be significant increases in time to hemostasis as compared with UFH.
The protocol also encouraged the use of glycoprotein IIb/IIIa inhibitors in the UFH arm, and their use was higher in this arm and may bias the bleeding results in favor of REG1. However, in those patients in the REG1 arm who also received glycoprotein IIb/IIIa inhibitors, early sheath removal may have also increased bleeding risk in the REG1 arms, whereas those receiving UFH + glycoprotein IIb/IIIa inhibitors may have had a more conservative sheath management strategy.
Finally, the results of this study only apply to those undergoing transfemoral access for cardiac catheterization and manual pressure for hemostasis. The patients receiving vascular closure devices were removed from this analysis to allow for a more direct comparison among patients at risk for delays to hemostasis between the two treatment groups. Furthermore, the use of transradial access allows for early sheath removal and reduced bleeding risk regardless of anticoagulant used. However, the use of transfemoral access remains common, especially in the United States, and for some procedures remains the only acceptable access site.
The REG1 Anticoagulation System possesses many possible advantages over currently available anticoagulants for use during cardiac catheterization. REG1 allows for a high level of anticoagulation that is controllable and fully reversible should the clinical need arise. This study demonstrates that REG1 allows for very-early arterial sheath removal following cardiac catheterization without increases in vascular access bleeding complications.
A large phase-3 study directly comparing REG1 to bivalirudin will test the hypothesis that REG1’s ability to provide a high level of anticoagulation during PCI, and to immediately titrate the anticoagulant effect based on clinical need, will lead to both reduced ischemic events and bleeding complications as compared to bivalirudin. Future studies of REG1 should prospectively evaluate the feasibility of very-early arterial sheath removal and its effect on vascular access complications, time to ambulation, hospital length of stay, and the downstream economic impact of this highly novel anticoagulant-reversal strategy.
- Kinnaird TD, Stabile E, Mintz GS, et al. Incidence, predictors, and prognostic implications of bleeding and blood transfusion following percutaneous coronary interventions. Am J Cardiol. 2003;92(8):930-935.
- Yatskar L, Selzer F, Feit F, et al. Access site hematoma requiring blood transfusion predicts mortality in patients undergoing percutaneous coronary intervention: data from the national heart, lung, and blood institute dynamic registry. Catheter Cardiovasc Interv. 2007;69(7):961-966.
- 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(9):1200-1206.
- Moscucci M, Fox KA, Cannon CP, et al. Predictors of major bleeding in acute coronary syndromes: the global registry of acute coronary events (GRACE). Eur Heart J. 2003;24(20):1815-1823.
- 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(1):73-83.
- Patel MR, Jneid H, Derdeyn CP, et al. Arteriotomy closure devices for cardiovascular procedures: a scientific statement from the American Heart Association. Circulation. 2010;122(18):1882-1893.
- Vavalle JP, Cohen MG. The REG1 anticoagulation system: a novel actively controlled factor IX inhibitor using RNA aptamer technology for treatment of acute coronary syndrome. Future Cardiol. 2012;8(3):371-382.
- Povsic TJ, Cohen MG, Mehran R, et al. A randomized, partially blinded, multicenter, active-controlled, dose-ranging study assessing the safety, efficacy, and pharmacodynamics of the REG1 anticoagulation system in patients with acute coronary syndromes: design and rationale of the RADAR phase IIb trial. Am Heart J. 2011;161(2):261-268.
- Povsic TJ, Vavalle JP, Aberle LH, et al. A phase 2, randomized, partially blinded, active-controlled study assessing the efficacy and safety of variable anticoagulation reversal using the REG1 system in patients with acute coronary syndromes: results of the RADAR trial. Eur Heart J. 2013;34(31):2481-2489 (Epub 2012 Aug 2).
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- Chan MY, Rusconi CP, Alexander JH, et al. A randomized, repeat-dose, pharmacodynamic and safety study of an antidote-controlled factor IXa inhibitor. J Thromb Haemost. 2008;6(5):789-796.
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- Subherwal S, Peterson ED, Dai D, et al. Temporal trends in and factors associated with bleeding complications among patients undergoing percutaneous coronary intervention: a report from the National Cardiovascular Data CathPCI registry. J Am Coll Cardiol. 2012;59(21):1861-1869.
- Rao SV, Kaltenbach LA, Weintraub WS, et al. Prevalence and outcomes of same-day discharge after elective percutaneous coronary intervention among older patients. JAMA. 2011;306(13):1461-1467.
From the 1Duke Clinical Research Institute, Duke University Medical Center, Durham,
North Carolina; 2Regado Biosciences, Basking Ridge, NJ; 3Mount Sinai School
of Medicine, New York, New York; 4Medical University of Lodz, Łódz, Poland; 5University
of Freiberg, Freiberg, Germany; 6Hamilton General Hospital, Hamilton, Ontario,
Canada; 7Institut de Cardiologie, Pitié-Salpétrière Hospital, Paris, France; 8Medisch
Centrum Alkmaar, Alkmaar, Netherlands; 9University of Miami Miller School
of Medicine, Miami, Florida.
Funding: The RADAR trial was supported by Regado Biosciences, Inc. This work was supported
internally by the Duke Clinical Research Institute (DCRI).
Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of
Potential Conflicts of Interest. Drs Povsic, Aberle, and Alexander are employees of DCRI,
which received research support from Regado; Dr Zelenkofske is a Regado employee; Dr
Alexander reports grant funds (Bristol Myers Squibb); consultant fees (Bristol Myers Squibb
and Pfizer). Dr Bode reports honoraria (AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi
Sankyo, and Sanofi Aventis). Dr Cornel is an Astra Zeneca board member. Dr Mehran is a
consultant (Abbott Vascular, AstraZeneca, Boston Scientific, Covidien, CSI, Behring, Janssen
(J+J), Maya Biotech, Merck, Sanofi-Aventis); board member (Covidien, Janssen (J+J), and
Sanofi-Aventis); and grants (The Medicines Co, BMS/Sanofi-Aventis, Lilly/Daiichi-Sankyo).
Dr Montalescot is a consultant (Bayer, BMS, Boehringer-Ingelheim, Duke Institute, Europa,
GSK, Iroko, Lead-Up, Novartis, Springer, TIMI group, WebMD, Wolters, AstraZeneca,
Biotronik, Eli Lilly, The Medicines Company, Medtronic, Menarini, Roche, Sanofi-Aventis,
Pfizer, and Accumetrics); grant funds (Abbott Vascular, AstraZeneca, Biotronik, Daiichi-Sankyo,
Eli-Lilly, Fédération Française de Cardiologie, Fondation de France, INSERM, Institut
de France, Medtronic, Nanospheres, Pfizer, Roche, Sanofi-Aventis, Stentys, Société Française
de Cardiologie, The Medicines Company, BMS, Menanini, and Accumetrics).
Manuscript submitted April 16, 2013, provisional acceptance given May 20, 2013,
final version accepted August 5, 2013.
Address for correspondence: John P. Vavalle, MD, Department of Medicine, Box
31356, Durham, NC 27710. Email: firstname.lastname@example.org