Effect of Extended-Release Niacin on Carotid Intima Media Thickness, Reactive Hyperemia, and Endothelial Progenitor Cell Mobilization: Insights From the Atherosclerosis Lesion Progression Intervention Using Niacin Extended Release in Saphenous Vein Gra

Abstract: Background. Thirty-eight patients with intermediate (30%-60% diameter stenosis) saphenous vein graft lesions were randomized to extended-release niacin (ER-niacin) or placebo for 12 months. We sought to evaluate the impact of ER-niacin on carotid intima media thickness (CIMT), endothelial function, and endothelial progenitor cell (EPC) mobilization. Methods. Carotid B-mode ultrasound was used to image the common and internal carotid arteries, at baseline and at 12 months after enrollment. Reactive hyperemia peripheral arterial tonometry, as assessed with EndoPAT 2000 (Itamar Medical, Inc) and EPC mobilization assessed with flow cytometry, were measured at enrollment, and at 1 and 12 months. Results. The baseline clinical characteristics were similar in the two study groups. High-density lipoprotein cholesterol levels tended to increase more in the ER-niacin group (5.9 ± 8.7 mg/dL vs 1.4 ± 7.1 mg/dL; P=.14). Between baseline and 12 months, right common carotid artery (0.96 ± 0.44 mm vs 0.70 ± 0.24 mm; P=.04), and left common carotid artery (0.80 ± 0.30 mm vs 0.70 ± 0.20 mm; P=.08) CIMT tended to decrease in the ER-niacin group, compared with no change in the placebo group. The change in logarithmic reactive hyperemia index between 1 month and 12 months was similar in patients receiving ER-niacin vs placebo (0.003 ± 0.12 vs -0.058 ± 0.12; P=.39), whereas EPC mobilization increased in the ER-niacin group and decreased in the placebo group (8.65 ± 28.41 vs -5.87 ± 30.23 EPC colony forming units/mL of peripheral blood; P=.02). Conclusions. ER-niacin did not have a significant impact on CIMT or endothelial function, but increased EPC mobilization.

J INVASIVE CARDIOL 2015;27(12):555-560

Key words: atherosclerosis, niacin, carotid artery disease, cardiac surgery, saphenous vein graft

_______________________________________

The Atherosclerosis Lesion Progression Intervention using Niacin Extended Release in Saphenous Vein Grafts (ALPINE-SVG) study (NCT01221402) was a phase-II, single-center, double-blind trial that randomized prior coronary artery bypass graft (CABG) patients with an intermediate saphenous vein graft (SVG) lesion on clinically indicated coronary angiography, and high-density lipoprotein cholesterol (HDL-C) <60 mg/dL to extended-release niacin (ER-niacin) at a dose of 1500-2000 mg daily or matching placebo (containing 50 mg of niacin, which can cause flushing but has no lipid-lowering effect) for 12 months. The primary objective was to compare the progression of SVG atherosclerosis between the two study groups, as assessed by intravascular ultrasonography. 

Enrollment in ALPINE-SVG was stopped early after publication of the Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes (AIM-HIGH) trial^1,2 and the Heart Protection Study 2 — Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) trial^3-5 results, which demonstrated no benefit with niacin when added to statin therapy and increased risk for side effects. Among the 38 patients enrolled in ALPINE-SVG, administration of ER-niacin did not have a significant impact on intermediate SVG lesion atherosclerosis; however, the study was underpowered due to early termination of enrollment. 

The present manuscript reports the impact of ER-niacin on carotid intima media thickness (CIMT), endothelial function, and endothelial progenitor cell (EPC) mobilization. 

Methods

Patients. Three secondary endpoints of ALPINE-SVG were: (1) change in CIMT between baseline and 12 months; (2) change in natural logarithmic scaled reactive hyperemia index (L_RHI) between baseline, 1 and 12 months; and (3) change in EPC-colony forming units/mL (CFU/mL) of peripheral blood between baseline and follow-up measurements.

Inclusion criteria for the ALPINE-SVG trial included: (1) age ≥18 years; (2) willing and able to give informed consent; (3) clinically indicated coronary and SVG angiography; (4) intermediate SVG lesion (defined as 30%-60% angiographic diameter stenosis) without previous percutaneous intervention, amenable to examination with intravascular ultrasound; and (5) no thrombus or ulceration on intravascular imaging. Exclusion criteria included: (1) known allergy to niacin; (2) history of statin-induced myopathy; (3) positive pregnancy test or breastfeeding; (4) coexisting conditions limiting life expectancy to <12 months or that could affect a patient’s compliance with the protocol; (5) uncontrolled fasting triglyceride levels (≥500 mg/dL); (6) fasting low-density lipoprotein cholesterol (LDL-C) >200 mg/dL; (7) fasting HDL-C >60 mg/dL; (8) poorly controlled diabetes; (9) current active liver disease or hepatic dysfunction; (10) aspartate transaminase (AST) or alanine transaminase (ALT) >2x the upper limit of normal; (11) uncontrolled hypothyroidism; (12) unexplained creatine kinase elevations (>3x upper limit of normal); (13) recent history of acute gout; (14) serum creatinine >2.5 mg/dL; (15) human immunodeficiency virus infection; (16) use of high-dose, antioxidant vitamins; (17) severe peripheral arterial disease limiting vascular access; (18) referral for cardiac catheterization by a physician who was an investigator; (19) New York Heart Association class-III or class-IV heart failure or left ventricular ejection fraction <25%; (20) uncontrolled hypertension, defined as either a resting diastolic blood pressure of ≥100 mm Hg or a resting systolic blood pressure of ≥200 mm Hg; (21) history of allergic reaction to iodine-based contrast agents;  and (22) significant medical or psychological condition that, in the opinion of the investigator, could compromise the patient’s safety or successful participation in the study.

Study protocol. Study subjects received a statin in order to achieve a goal LDL-C of <70 mg/dL. In order to establish that ER-niacin was well tolerated, they also underwent a 4-week run-in period, during which they received ER-niacin once daily in the evening, titrated by 500 mg daily at weekly intervals, beginning with 500 mg once daily in the evening to a maximum of 2000 mg daily. Subjects received either ER-niacin at a dose of 1500-2000 mg daily (according to the dose tolerated during the run-in period) or placebo, which contained 50 mg of crystalline niacin to cause flushing.

Reactive hyperemia peripheral arterial tonometry (RH-PAT). The EndoPAT 2000 device (Itamar Medical, Inc) was used to obtain peripheral arterial tonometry signals. Finger probes were placed on the middle finger of each subject’s hand. Pulsatile volume changes were sensed by pressure transducers and recorded by the EndoPAT 2000 device. A decrease in arterial blood volume causes a subsequent decrease in pulsatile arterial column changes, reflected as a decrease in the measured PAT signal, and vice versa. Blood pressure and heart rate were measured using an automated blood pressure monitor. 

Endothelial function was measured via the RH-PAT index. The RH protocol consists of a 5-minute baseline measurement, after which a blood pressure cuff on the test arm was inflated to 60 mm Hg above baseline systolic blood pressure or at least 200 mm Hg for 5 minutes. Occlusion of pulsatile arterial flow was confirmed by the reduction of the PAT tracing to zero. After 5 minutes, the cuff was deflated, and the PAT tracing was recorded for an additional 6 minutes. The ratio of the PAT signal after cuff release compared with baseline was calculated through a computer algorithm and reflected the reactive hyperemia index (RHI). The natural logarithmic scaled RHI (L_RHI) was calculated from the same ratio between the digital pulse volume during RH and at baseline. 

Biomarker and EPC measurements. EPC mobilization was assessed by colony forming units (EPC-CFU)/mL of peripheral blood. EPC measurements were performed at the time of baseline angiography, and at 1 month and 12 months. Peripheral mononuclear cells (PMNCs) were isolated from the blood using Ficoll density gradient centrifugation within 4 hours of blood collection. All measurements were blinded to study group allocation. The PMNCs were seeded on collagen-treated tissue culture plates. A 5-day CFU-Hill assay (Stem Cell Technologies, Inc) was followed to quantify and compare the EPC colonies.⁶ Comparison was made with baseline EPC-CFU/mL levels. 

Carotid intima-media thickness. The intima-media of the right and left common and internal carotid arteries was visualized using B-mode ultrasound at baseline and at 12-month follow-up. The mean CIMT of the far wall of each arterial segment was measured using Cardiovascular Suite version 2.8 software (Quipu); all measurements were performed in triplicate for each arterial segment and averaged. The common carotid artery segment was defined as 30-40 mm proximal to bulb widening and the internal carotid artery segment was defined as 10-20 mm distal to the tip of the flow divider. Ideal measurements for common carotid and internal carotid segments included a box area with a 20 mm and 10 mm length, respectively. 

Statistical analyses. Continuous parameters were presented as mean ± standard deviation and compared using the t-test or Wilcoxon sum-rank test, as appropriate. Nominal parameters were presented as percentages and compared using chi-square or Fisher’s exact test, as appropriate. Analyses were performed with JMP version 11 (SAS Institute) and SPSS 17.0 (SPSS, Inc). A P-value <.05 was considered statistically significant.

Results

Study population.  Between February 2011 and December 2012, a total of 38 patients were enrolled in the study; 19 patients were randomized to ER-niacin and 19 patients were randomized to placebo. The baseline characteristics of the two study groups were similar (Table 1). All patients tolerated the study medication well. Between baseline and follow-up, HDL-C levels significantly increased in the ER-niacin group (38.6 ± 7.5 mg/dL vs 44.1 ± 8.6 mg/dL; P=.03), but not in the placebo group (36.8 ± 8.4 mg/dL vs 39.2 ± 6.3 mg/dL; P=.45). 

Three of the 19 ER-niacin patients required repeat revascularization on a native artery prior to the 12-month follow-up. Among placebo-treated patients, 1 suffered a stroke and 1 had a myocardial infarction, followed by revascularization of a non-study vessel.

Carotid intima media thickness. Of the 38 patients, a total of 28 (11 in the ER-niacin group and 17 in the placebo group) completed baseline and 12-month CIMT imaging. Between baseline and 12 months, right common carotid artery (0.96 ± 0.44 mm vs 0.70 ± 0.24 mm; P=.04), and left common carotid artery CIMT tended to decrease in the ER-niacin group (0.80 ± 0.30 mm vs 0.70 ± 0.20 mm; P=.08), whereas no significant change was observed in the placebo group (Figure 1). No significant change was observed in the right and left internal carotid artery intima media thickness (Table 2). 

Reactive hyperemia peripheral arterial tonometry and EPC measurements. We found no difference in L_RHI between 1 month and 12 month follow-up between the ER-niacin and placebo groups (LogDifference of 0.003 ± 0.12 vs -0.058 ± 0.12; P=.39) (Table 3, Figure 3). EPC-CFU/mL of peripheral blood increased in the ER-niacin group and decreased in the placebo group (8.65 ± 28.41 vs -15.87 ± 30.23; P=.02 for the between-group difference) (Table 3, Figure 2).  

Discussion

The main finding of our study is that administration of ER-niacin did not result in CIMT reduction or improvement in endothelial function, but it increased EPC mobilization. However, the study was underpowered due to early termination of enrollment.

When the ALPINE-SVG study was started, niacin was considered to be a promising therapeutic agent in further reducing atherosclerosis progression and clinical events among patients with atherosclerosis. Multiple studies showed that niacin, alone or in combination with statins or other lipid therapies, favorably impacted lipid levels, atherosclerosis progression, and incidence of adverse cardiac events in high-risk patients.^7-9 However, support for using niacin rapidly declined after publication of the results of the AIM-HIGH and HPS2-THRIVE trials. In AIM-HIGH,  even though niacin increased HDL-C levels, it did not reduce the incidence of cardiovascular events and was associated with a larger number of strokes.^1,2 In the HSP2-THRIVE trial, the combination of niacin and laropiprant not only did not reduce the incidence of cardiovascular events, but was also associated with higher risk of adverse events (such as poor diabetes control, new onset of diabetes, gastrointestinal, musculoskeletal, skin, infectious, and bleeding serious adverse effects).^3-5

The findings of our study are consistent with the above trials. Although we observed potentially beneficial changes in surrogate endpoints (increase in HDL-C and in EPC mobilization), we found no significant difference in CIMT. This is in contrast to prior studies that have reported beneficial effects of niacin on CIMT. The Arterial Biology for the Investigation of Treatment Effects of Reducing Cholesterol (ARBITER) 2 and 3 trials assessed 1 g/day of ER-niacin in addition to baseline statin therapy (mean LDL-C was 89 mg/dL) in patients with low HDL-C (<45 mg/dL) and known coronary heart disease on common carotid intima media thickness over 12 months.^10,11 CIMT increased significantly in the placebo group over 12 months and was unchanged in the niacin group. After 2 years, ARBITER 3 patients continued on niacin demonstrated CIMT regression.¹¹ The Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6-HLD and LCL Treatment Strategies in Atherosclerosis (ARBITER-6 HALTS) study compared ER-niacin (goal dose, 2 g/day) and ezetimibe (10 mg/day), added to stable statin monotherapy, on CIMT progression over 14 months. The trial was stopped early due to a prespecified, blinded interim analysis showing superior efficacy in the ER-niacin arm based on the change in mean CIMT between groups and a reduction in cardiovascular events in ER-niacin patients (n = 97) vs ezetimibe patients (n = 111) (1% vs 5%, respectively; P=.04) among those who had completed the entire 14 months of treatment.¹² The results demonstrated a correlation between regression of CIMT and increased drug exposure to niacin vs a paradoxical increase in CIMT when exposure to ezetimibe was increased.¹³ Similarly, magnetic resonance imaging of the carotids has shown a decrease in atherosclerosis when ER-niacin was added to aggressive statin therapy.¹⁴ The lack of effect of ER-niacin on CIMT in our study could be due to lack of effect or due to the small sample size with the resulting low power to detect a difference. Moreover, the study population was different; prior CABG patients are known to have multiple comorbidities and worse clinical outcomes as compared with non-prior CABG patients.^15-17

A recent meta-analysis of seven randomized-controlled trials demonstrated that niacin administration significantly improved endothelial function, as measured by endothelium-dependent flow-mediated dilation (FMD);¹⁸ however, this effect was only observed among patients with low HDL-C.¹⁹ Additionally, Shearer et al recruited 60 metabolic syndrome subjects in a randomized, double-blind, 16-week trial that underwent dual-placebo, P-OM3 (4 g/day), ER-niacin (2 g/day), or combination therapy. The study showed that neither ER-niacin, P-OM3, nor a combination had any significant effect on endothelial function as measured by RHI (-0.04, 0.08, and 0.14 units, respectively).²⁰ Our results are similar to the latter findings, as we did not see any significant change in L_RHI when patients were treated with niacin vs placebo (Table 3). Studies have shown that niacin can act independent of its action on lipid regulation and potentially contains its own anti-atherosclerotic properties,^21,22 creating doubts about whether an increase in HDL-C is needed for efficacy when niacin is administered to halt atherosclerotic progression.   

 A therapeutic role of EPCs for vascular repair has been reported.^23-25 Sorrentino et al demonstrated that ER-niacin improved endothelial repair by EPCs through restoration of HDL function in diabetic patients²⁶ and animal studies demonstrated similar effects independent of plasma lipid levels.²⁷ Recently, several studies examined the correlation between EPCs, severity of endothelial dysfunction, and clinical outcomes. A substudy of the Reinfusion of Enriched Progenitor cells And Infarct Remodeling in Acute Myocardial Infarction (REPAIR-AMI) trial demonstrated that progenitor cells could restore microvascular function of infarct-related arteries after bone-marrow stem-cell transfusion.²⁸ In a study of 107 patients, Lupatelli et al demonstrated that flow-mediated endothelial dysfunction increased with decreasing levels of HDL-C.²⁹ Noor et al postulated that circulating EPC levels might increase in response to increased HDL levels due to increase in survival period and prevention of apoptosis. HDL was shown to inhibit caspase-3 activity, thus providing this protection,³⁰ while its activity in increasing endothelial nitric oxide synthase expression in EPCs through binding to scavenger receptor-BI increased progenitor cell mobilization from bone marrow.^31,32 Similar to those studies, a positive correlation between niacin therapy and EPC-CFU increase was observed in ALPINE-SVG (Table 3). 

There are several potential explanations for the lack of benefit of ER-niacin in our study group. Our study was underpowered due to early termination of enrollment; hence, a potential beneficial effect could not be excluded. The duration of study intervention (12 months) may not have been long enough for detecting beneficial CIMT, EPC, or L_RHI changes. Moreover, raising HDL may not be an important target for preventing atherosclerosis progression in a background of intensive statin therapy and low LDL-C levels. 

Conclusion

Our study did not demonstrate a beneficial effect of ER-niacin on CIMT progression and endothelial function, although it was associated with increased EPC mobilization.  

References

1.    AIM-HIGH Investigators. The role of niacin in raising high-density lipoprotein cholesterol to reduce cardiovascular events in patients with atherosclerotic cardiovascular disease and optimally treated low-density lipoprotein cholesterol: baseline characteristics of study participants. The Atherothrombosis Intervention in Metabolic syndrome with low HDL/high triglycerides: impact on Global Health outcomes (AIM-HIGH) trial. Am Heart J. 2011;161:538-543.

2.    Boden WE, Probstfield JL, Anderson T, et al; AIM-HIGH Investigators. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011;365:2255-2267.

3.    Haynes R, Jiang L, Hopewell JC, et al. HPS2-THRIVE randomized placebo-controlled trial in 25,673 high-risk patients of ER niacin/laropiprant: trial design, pre-specified muscle and liver outcomes, and reasons for stopping study treatment. Eur Heart J. 2013;34:1279-1291.

4.    Masana L, Cabre A, Plana N. HPS2-THRIVE results: bad for niacin/laropiprant, good for ezetimibe? Atherosclerosis. 2013;229:449-450.

5.    Landray MJ, Haynes R, Hopewell JC, et al; HPS2-THRIVE Collaborative Group. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med. 2014;371:203-212.

6.     Banerjee S, Brilakis E, Zhang S, et al. Endothelial progenitor cell mobilization after percutaneous coronary intervention. Atherosclerosis. 2006;189:70-75. 

7.    Villines TC, Kim AS, Gore RS, et al. Niacin: the evidence, clinical use, and future directions. Curr Atheroscler Rep. 2012;14:49-59.

8.     Clofibrate and niacin in coronary heart disease. JAMA. 1975;231:360-381.

9.     Canner PL, Berge KG, Wenger NK, et al. Fifteen year mortality in coronary drug project patients: long-term benefit with niacin. J Am Coll Cardiol. 1986;8:1245-1255.

10.     Taylor AJ, Sullenberger LE, Lee HJ, et al. Arterial biology for the investigation of the treatment effects of reducing cholesterol (ARBITER) 2: a double-blind, placebo-controlled study of extended-release niacin on atherosclerosis progression in secondary prevention patients treated with statins. Circulation. 2004;110:3512-3517.

11.    Taylor AJ, Lee HJ, Sullenberger LE. The effect of 24 months of combination statin and extended-release niacin on carotid intima media thickness: ARBITER 3. Curr Med Res Opin. 2006;22:2243-2250.

12.     Taylor AJ, Villines TC, Stanek EJ, et al. Extended-release niacin or ezetimibe and carotid intima-media thickness. N Engl J Med. 2009;361:2113-2122.

13.     Villines TC, Stanek EJ, Devine PJ, et al. The ARBITER 6-HALTS trial (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6-HDL and LDL Treatment Strategies in Atherosclerosis): final results and the impact of medication adherence, dose, and treatment duration. J Am Coll Cardiol. 2010;55:2721-2726.

14.    Lee JMS, Robson MD, Yu L-M, et al. Effects of high-dose modified-release nicotinic acid on atherosclerosis and vascular function: a randomized, placebo-controlled, magnetic resonance imaging study. J Am Coll Cardiol. 2009;54:1787-1794.

15.    Boatman DM, Saeed B, Varghese I, et al. Prior coronary artery bypass graft surgery patients undergoing diagnostic coronary angiography have multiple uncontrolled coronary artery disease risk factors and high risk for cardiovascular events. Heart Vessels. 2009;24:241-246.

16.    Brilakis ES, de Lemos JA, Cannon CP, et al. Outcomes of patients with acute coronary syndrome and previous coronary artery bypass grafting (from the Pravastatin or Atorvastatin Evaluation and Infection Therapy [PROVE IT-TIMI 22] and the Aggrastat to Zocor [A to Z] trials). Am J Cardiol 2008;102:552-558.

17.    Brilakis ES, Held C, Meier B, et al. Effect of ticagrelor on the outcomes of patients with prior coronary artery bypass graft surgery: insights from the PLATelet inhibition and patient outcomes (PLATO) trial. Am Heart J. 2013;166:474-480.    

18.    Sahebkar A. Effect of niacin on endothelial function: a systematic review and meta-analysis of randomized controlled trials. Vasc Med. 2014;18:54-66.

19.    Warnholtz A, Wild P, Ostad MA, et al. Effects of oral niacin on endothelial dysfunction in patients with coronary artery disease: results of the randomized, double-blind, placebo-controlled INEF study. Atherosclerosis. 2009;204:216-221.

20.     Shearer GC, Pottala JV, Hansen SN, Brandenburg V, Harris WS. Effects of prescription niacin and omega-3 fatty acids on lipids and vascular function in metabolic syndrome: a randomized controlled trial. J Lipid Res. 2012;53:2429-2435.

21.    Ganji SH, Qin S, Zhang L, Kamanna VS, Kashyap ML. Niacin inhibits vascular oxidative stress, redox-sensitive genes, and monocyte adhesion to human aortic endothelial cells. Atherosclerosis 2009; 202(1):68-75.

22.    Hughes-Large JM, Pang DKT, Robson DL, Chan P, Toma J, Borradaile NM. Niacin receptor activation improves human microvascular endothelial cell angiogenic function during lipotoxicity. Atherosclerosis. 2014;237:696-704.

23.    Pesce M, Orlandi A, Iachininoto MG, et al. Myoendothelial differentiation of human umbilical cord blood-derived stem cells in ischemic limb tissues. Circ Res. 2003;93:51-62.

24.    Ott I, Keller U, Knoedler M, et al. Endothelial-like cells expanded from CD34þ blood cells improve left ventricular function after experimental myocardial infarction. FASEB J. 2005;19:992-994.

25.    Asahara T, Kawamoto A, Masuda H. Concise review: circulating endothelial progenitor cells for vascular medicine. Stem Cells. 2011;29:1650-1615.

26.     Sorrentino SA, Besler C, Rohrer L, et al. Endothelial-vasoprotective effects of high-density lipoprotein are impaired in patients with type 2 diabetes mellitus but are improved after extended-release niacin therapy. Circulation. 2010;121:110-122.

27.    Huang P, Lin C, Wang C, et al. Niacin improves ischemia-induced neovascularization in diabetic mice by enhancement of endothelial progenitor cell functions independent of changes in plasma lipids. Angiogenesis. 2012;15:377-389.

28.     Erbs S, Linke A, Schachinger V, et al. Restoration of microvascular function in the infarct-related artery by intracoronary transplantation of bone marrow progenitor cells in patients with acute myocardial infarction: the Doppler substudy of the reinfusion of enriched progenitor cells and infarct remodeling in acute myocardial infarction (REPAIR-AMI) trial. Circulation. 2007;116:366-374.

29.     Lupattelli G, Marchesi S, Roscini AR, et al. Direct association between high-density lipoprotein cholesterol and endothelial function in hyperlipidemia. Am J Cardiol. 2002;90:648-650.

30.    Noor R, Shuaib U, Wang CX, et al. High-density lipoprotein cholesterol regulates endothelial progenitor cells by increasing eNOS and preventing apoptosis. Atherosclerosis. 2007;192:92-99.

31.    Aicher A, Heeschen C, Mildner-Rihm C, et al. Essential role of endothelial nitric oxide synthase for mobilization of stem and progenitor cells. Nat Med. 2003;9:1370-1376.

32.    Iwakura A, Luedemann C, Shastry S, et al. Estrogen-mediated, endothelial nitric oxide synthase-dependent mobilization of bone marrow-derived endothelial progenitor cells contributes to re-endothelialization after arterial injury. Circulation. 2003;108:3115-3121.

______________________________________________

From the VA North Texas Healthcare System, Dallas, Texas, and University of Texas Southwestern Medical Center, Dallas, Texas.

Clinical Trial Registration: NCT01221402.

Funding: Research reported in this publication was supported by the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health under award number R01HL102442-01A1. Part of the study medication was provided by Abbott Vascular.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. A. Guerra and A. Sosa report grants from National Heart, Lung, and Blood Institute at the National Institutes of Health (5R25HL096367 Training Grant). B. Rangan reports research funds from Spectranetics Corporation and Infraredx. Dr McGuire reports personal fees from Merck, Sanofi Aventis, Regeneron, and AstraZeneca. Dr Banerjee report research grants from Gilead and the Medicines Company; consultant/speaker honoraria from Covidien and Medtronic; ownership in MDCARE Global (spouse); intellectual property in HygeiaTel. Dr Brilakis reports consulting honoraria/speaker fees from St. Jude Medical, Terumo, Asahi Intecc, Abbott Vascular, Somahlution, Elsevier, and Boston Scientific; research grants from InfraRedx and Boston Scientific; spouse is an employee of Medtronic. The remaining authors report no conflicts of interest regarding the content herein.

Manuscript submitted April 9, 2015, provisional acceptance given June 1, 2015, final version accepted June 23, 2015.

Address for correspondence: Emmanouil S. Brilakis, MD, PhD, Dallas VA Medical Center (111A), 4500 South Lancaster Road, Dallas, TX 75216. Email: esbrilakis@gmail.co