Original Contribution

Effect of Extended-Release Niacin on Saphenous Vein Graft Atherosclerosis: Insights from the Atherosclerosis Lesion Progression Intervention Using Niacin Extended Release in Saphenous Vein Grafts (ALPINE-SVG) Pilot Trial

Anna P. Kotsia, MD1;  Bavana V. Rangan, BDS, MPH1;  Georgios Christopoulos, MD1;  Ameka Coleman, BS1;  Michele Roesle, RN, BSN1;  Daisha Cipher, PhD2;  James A. de Lemos, MD1;  Darren K. McGuire, MD, MHSc1;  Milton Packer, MD1;  Subhash Banerjee, MD1;  Emmanouil S. Brilakis, MD, PhD1

Anna P. Kotsia, MD1;  Bavana V. Rangan, BDS, MPH1;  Georgios Christopoulos, MD1;  Ameka Coleman, BS1;  Michele Roesle, RN, BSN1;  Daisha Cipher, PhD2;  James A. de Lemos, MD1;  Darren K. McGuire, MD, MHSc1;  Milton Packer, MD1;  Subhash Banerjee, MD1;  Emmanouil S. Brilakis, MD, PhD1

Abstract: Background. Intermediate saphenous vein graft (SVG) lesions have high rates of progression. The purpose of this study was to examine the impact of extended-release niacin (ER-niacin) vs placebo on intermediate SVG lesions. Methods. Patients with intermediate (30%-60% diameter stenosis) SVG lesions were randomized to ER-niacin vs placebo for 12 months. Quantitative coronary angiography (QCA), intravascular ultrasonography (IVUS), and optical coherence tomography (OCT) were performed at baseline and at 12 months. The primary endpoint was change in percent atheroma volume (∆PAV). Enrollment was planned for 138 patients for 90% power to detect ≥2.5% difference in the primary endpoint of ∆PAV, but stopped early after publication of two negative outcome trials of ER-niacin, with enrolled patients completing the 12-month trial protocol. Results. Thirty-eight patients were randomized to niacin (n = 19) or placebo (n = 19), yielding power of 47% to detect the primary planned treatment effect of 2.5 ± 4.0% difference in ∆PAV. Between baseline and 12-month follow-up, no significant difference was found between study groups in ∆PAV (-1.31 ± 6.05% vs 1.05 ± 17.8%; P=.60). By OCT, the ER-niacin vs placebo group had less plaque rupture within the intermediate SVG lesion (0.0% vs 36.0%; P=.01). Conclusion. Administration of ER-niacin did not significantly impact intermediate SVG disease, with the notable limitation of compromised statistical power due to early termination of enrollment.

J INVASIVE CARDIOL 2015;27(10):E204-E210

Key words: saphenous vein grafts, atherosclerosis, niacin, intravascular imaging


Aortocoronary saphenous vein bypass graft (SVG) failure is common and is associated with high morbidity and mortality.1-4 Treatment of occluded or severely stenosed SVGs is challenging, making prevention important.5 Intermediate SVG lesions are common, have high rates of progression to severe lesions or occlusion, and are associated with a high incidence of adverse clinical outcomes.6-11

Although intensive statin therapy can improve clinical outcomes of prior coronary artery bypass graft (CABG) surgery patients, 12-14 they have little effect on low high-density lipoprotein cholesterol (HDL-C) levels that are associated with and may contribute to SVG atherosclerosis progression and clinical events.15 Niacin raises HDL-C and reduces low-density lipoprotein cholesterol (LDL-C), triglycerides, and lipoprotein (a) (Lpa(a)),16-18 effects that individually and in aggregate have the potential to retard progression of and stabilize atherosclerotic lesions. However, the role of niacin for preventing progression of SVG atherosclerosis remains unknown. The aim of the present study was to investigate the impact of extended-release niacin (ER-niacin) compared with placebo on intermediate SVG lesion progression, when used on a background of intensive statin therapy.


The Atherosclerosis Lesion Progression Intervention using Niacin Extended Release in Saphenous Vein Grafts (ALPINE-SVG) study was a phase II, single-center, double-blind trial that randomized prior CABG patients with an intermediate SVG lesion detected by clinically-indicated coronary angiography, and HDL-C <60 mg/dL to ER-niacin at a dose of 1500-2000 mg daily or matching placebo (containing 50 mg of niacin that can cause flushing but has no lipid-lowering effect) for 12 months. The primary objective of this study was to compare the progression of SVG atherosclerosis between the two study groups. The research project was approved by the Dallas VA Medical Center institutional review board.

Inclusion criteria were: (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 a lesion with 30%-60% angiographic diameter stenosis) without previous percutaneous intervention, amenable to examination with IVUS; and (5) no thrombus or ulceration on intravascular imaging. The exclusion criteria were: (1) known allergy or prior intolerance to niacin; (2) history of statin-induced myopathy; (3) positive pregnancy test or breast feeding; (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 LDL-C >200 mg/dL; (7) fasting HDL-C >60 mg/dL; (8) diabetes with HbA1c >10%; (9) active liver disease or hepatic dysfunction; (10) AST or ALT > 2x the upper limit of normal; (11) uncontrolled hypothyroidism; (12) unexplained creatine phosphokinase 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 (NYHA) class III or IV heart failure or left ventricular ejection fraction (LVEF) <25%; (20) resting systolic blood pressure ≥200 mm Hg or resting diastolic blood pressure ≥100 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.

Patients who fulfilled the study eligibility criteria and provided informed written consent underwent a 4-week run-in period during which they received ER-niacin once daily in the evening, titrated by 500 mg/day at weekly intervals, beginning with 500 mg once daily in the evening to a maximum of 2000 mg daily in order to establish that ER-niacin was well tolerated. They also received a statin with dose adjusted to achieve a goal LDL-C of <70 mg/dL. Patients who tolerated niacin were randomized to receive 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.

Coronary angiography, intravascular ultrasonography (IVUS), and optical coherence tomography (OCT) of the intermediate SVG lesion were performed at enrollment and after 12 months in each patient; liver function tests, fasting lipid profiles, and creatine phosphokinase (CPK) values were also collected at baseline and follow-up. 

Enrollment in the ALPINE-SVG study was stopped early after publication of the Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes (AIM-HIGH) trial19 and the Heart Protection Study 2 – Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) trial20 results, which showed no benefit on the incidence of major adverse cardiovascular events when ER-niacin/laropiprant was added to statin therapy and increased risk for clinical and metabolic side effects, thereby compromising equipoise of the present research question. All patients entering the trial prior to early termination of enrollment completed the trial.

Intracoronary and intragraft nitroglycerin was administered before angiography. The projection that best showed the intermediate bypass graft lesion both at baseline and at follow-up was used. All QCA measurements were performed using a computer-based algorithm (CAAS II; Pie Medical). The minimal luminal diameter (MLD), reference lumen diameter, and percent diameter stenosis were measured using the catheter as a scaling factor. Angiographic SVG failure was defined as a minimum luminal diameter decrease of >0.6 mm.14 All analyses were performed blinded to treatment assignment.

Following intracoronary administration of 0.2 mg nitroglycerin, IVUS imaging was performed using a motorized transducer pullback system (0.5-1.0 mm/s) and a commercial scanner. Quantitative IVUS analyses were performed according to criteria of the American College of Cardiology Clinical Expert Consensus document on IVUS.21 The baseline and 12-month IVUS data were analyzed blinded to treatment assignment and to sequence of recording. The ostium of the SVG was used as the beginning point to ensure analysis of the same intermediate SVG lesion segment between baseline and 12-month IVUS assessment. Every 30th image was analyzed, representing cross-sections spaced 0.5 mm apart. Manual planimetry using Echoplaque 4 software (Indec, Inc) was performed to trace the leading edges of the lumen and external elastic membrane (EEM) and calculate the corresponding areas. The percent atheroma volume (PAV) was calculated as Σ ([EEMCSA – lumenCSA]/EEMCSA x 100), where EEMCSA was the cross-sectional area of the external elastic membrane and lumenCSA was the cross-sectional area of the lumen. The change in percent atheroma volume (ΔPAV) of the target intermediate SVG lesion was computed as: (PAV at 12 months – PAV at baseline). Total atheroma volume (TAV) in each target SVG segment was calculated as Σ (EEMCSA – lumenCSA).22,23 The change in total atheroma volume (ΔTAV) of the target SVG segment was computed as: (TAV at month 12 – TAV at baseline)/(TAV at baseline) x 100. The normalized total atheroma volume (nTAV), the average area of atheroma per cross-section, was calculated as: Average atheroma area = (EEMCSA – lumenCSA)/n, where n was the number of cross-sections in the pullback. The change in nTAV (ΔnTAV) of the target SVG segment was calculated as: (nTAV at month 12 – nTAV at baseline). The interobserver and intraobserver measurement correlation was excellent (Pearson’s r was 0.93 and 0.96, respectively).

OCT was performed with the C7 Dragonfly Intravascular Imaging Catheter (St. Jude, Inc) during intragraft administration of contrast. OCT qualitative analysis was performed using LightLab Imaging Software version D.0.2 (St. Jude, Inc). The baseline and 12-month OCT images were analyzed blinded to treatment assignment and to the sequence of recording. For each target lesion, fibrocalcific plaque was defined as plaque containing fibrous tissue and calcium; necrotic core as signal-poor, diffusely-bordered lesion within an atherosclerotic plaque; fibroatheroma as a delineated fibrous cap and a necrotic core. Fibrous-cap thickness was defined as the minimum distance from the coronary artery lumen to the inner border of the necrotic core. The thinnest fibrous-cap thickness measurement obtained from three imaging locations was used.24 Microchannels were defined as no-signal tubuloluminal structures without a connection to the vessel lumen recognized on ≥3 consecutive cross-sectional OCT images.25 Plaque rupture was defined as fibrous cap discontinuity and cavity formation within the plaque.26 Intracoronary thrombus was defined as a mass protruding into the vessel lumen and causing signal attenuation.

The study’s primary endpoint was ΔPAV of the target intermediate SVG lesion as determined by IVUS, while the secondary endpoints were: (1) ΔTAV; (2) ΔnTAV; (3) SVG target lesion total occlusion at 12-month follow-up angiography; and (4) change in fibrous cap thickness, plaque rupture, and other qualitative plaque characteristics, as determined by OCT.

Continuous parameters are presented as mean ± standard deviation or median with interquartile ranges, 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). A P-value of .05 was considered to be significant.

The study was designed to detect ≥2.5 ± 4.0% change in ΔPAV with ER-niacin vs placebo at 90% power with 2-sided alpha of 0.05, yielding a sample size of 55 patients per arm that was increased to 69 patients per arm to allow 20% dropout. Given the early termination of enrollment, with 38 patients completing the trial, the power based on the original assumptions was reduced to 47%; 38 patients (19 in each group) yields 90% power to detect ΔPAV of ≥4%.


Between February 2011 and December 2012, a total of 38 patients were enrolled: 19 were randomized to ER-niacin and 19 to placebo. Baseline characteristics were well balanced between the two study groups (Table 1). 

Patients tolerated the study medication well, with 89% receiving niacin and 95% receiving placebo being compliant to the study drug administration (P=.54), defined as at least 10-month adherence to the randomized assignment.  Twelve-month angiographic follow-up was performed in all but 2 patients (both from the ER-niacin group) who refused to return. Three of the 19 ER-niacin patients required repeat revascularization on a native artery prior to the 12-month follow-up exam. Among placebo-treated patients, 1 suffered a stroke and 1 had a myocardial infarction, followed by revascularization of a non-study vessel. All study SVGs were patent at 12-month angiographic follow-up in both groups. 

Selected laboratory measurements at baseline and follow-up are presented in Table 2. Values were well balanced at baseline, except for triglycerides, which were significantly higher in the ER-niacin group. In intragroup comparisons between baseline and follow-up, no significant changes were detected in the placebo group. HDL-C 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).

Among the 36 patients who had both baseline and follow-up cardiac catheterization, 3 IVUS pullbacks could not be analyzed because of suboptimal image quality. There was no difference in quantitative measurements between the two study groups (Table 3). The primary study endpoint, ΔPAV, was not statistically different between the ER-niacin and placebo-treated patients (-1.31 ± 6.05% vs 1.05 ± 17.8%; P=.60). ΔTAV (-2.52 ± 25.89% vs -4.97 ± 20.16%; P=.76), and ΔnTAV (-0.059 ± 0.158 vs -0.031 ± 0.147; P=.61) were also not statistically different between the two groups. On quantitative coronary angiography, there were no differences in baseline or follow-up measurements between the randomized trial groups (Table 4).

OCT evaluation revealed no statistical differences in baseline or follow-up SVG lesion characteristics between the ER-niacin and placebo groups (Table 5), except for plaque rupture detected at the 12-month protocol evaluation, observed in 3 patients in the placebo group vs none in the ER-niacin group (P=.01).


The ALPINE-SVG study did not demonstrate any significant effect of ER-niacin on progression of atherosclerosis in intermediate SVG lesions, observations to be interpreted in the context of termination of enrollment that notably compromised the planned statistical power.

Intermediate SVG lesions: (1) are common; (2) have high rates of progression to severe lesions or occlusion; and (3) are associated with a high incidence of adverse clinical outcomes.6-11 Lipid lowering with statins,14,27,28 gemfibrozil,29  and colestipol and niacin30-32 demonstrated reduction in the angiographic progression of SVG disease, along with reduction in clinical events,14,27 but no medical therapy study has focused specifically on intermediate SVG lesions.

At the time of study initiation, plausibility remained that niacin might favorably affect atherosclerosis progression and reduce clinical atherosclerotic vascular disease risk. Niacin administered with lovastatin had slowed atherosclerosis progression in the HDL Atherosclerosis Treatment Study (HATS) trial.33 Niacin in combination with colestipol also slowed atherosclerosis progression and lowered cardiovascular events among men with high levels of apolipoprotein B in the Familiar Atherosclerosis Treatment Study (FATS) trial.34 The combination of niacin and colestipol also reduced the progression of SVG atherosclerosis and the incidence of cardiovascular events in the Cholesterol Lowering Atherosclerosis Study (CLAS) trial.31,32 

The publication of the results of the AIM-HIGH and HPS2-THRIVE trials, which occurred during ALPINE-SVG trial enrollment, extinguished the optimism of potential clinical benefits of niacin.  AIM-HIGH randomized 3414 patients with cardiovascular disease and dyslipidemia receiving intensive statin therapy (LDL-C <80 mg/dL) to niacin or placebo.19 The study was stopped early for futility, as niacin provided no evident clinical benefit compared with placebo and numerically higher stroke events were observed in the niacin arm, even though niacin treatment increased HDL-C levels and lowered triglyceride and LDL-C levels. The trial randomized >25,000 patients at increased risk of cardiovascular events to niacin with laropiprant vs placebo on a background of statin therapy with or without ezetimibe.20 Approximately one-fourth of patients discontinued the study drug because of intolerance; moreover, during 4 years of follow-up, niacin/laropiprant did not reduce cardiovascular events and was associated with higher risk of adverse events (serious disturbances in diabetes control; new diabetes diagnoses; gastrointestinal, musculoskeletal, skin, infection, and bleeding serious adverse effects).

There are several potential explanations for the lack of benefit of ER-niacin in our study. First, the study power was markedly compromised due to early termination of enrollment; therefore, a potential beneficial effect cannot be definitively excluded. Second, HDL-C increase may not be an important target for preventing atherosclerosis progression on a background of intensive statin therapy and low LDL-C levels (67.0 ± 31.1 mg/dL in the ER-niacin and 71.2 ± 25.0 mg/dL in the placebo group). It remains possible that ER-niacin could be effective in patients who are statin intolerant or to patients with familial hypercholesterolemia and high LDL-C levels high despite statin therapy.35 Third, SVG atherosclerosis is different from native coronary atherosclerosis, as it often consists of friable and thrombotic lesions and may respond poorly to HDL-C raising therapies. For example, SVGs have thicker walls as compared with native coronary arteries: mean percent atheroma volume was 56.1 ± 8.8% in ALPINE-SVG vs 39.6 ± 8.5% in A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden (ASTEROID)22 and 39.5 ± 10.8% and 38.4 ± 11.3%, respectively, in the pravastatin and atorvastatin arms of the Reversal of Atherosclerosis With Aggressive Lipid Lowering Therapy  (REVERSAL) trial.36 Fourth, the duration of study intervention (12 months) may not have been long enough to induce beneficial SVG changes. Lastly, ER-niacin may not significantly affect atherosclerosis and the incidence of clinical events, as suggested by AIM-HIGH and HPS2-THRIVE.

ALPINE-SVG is the first study to apply longitudinal OCT imaging in SVG lesions. OCT studies in native coronary arteries demonstrated that statin therapy can cause plaque stabilization with increase in fibrous-cap thickness in patients with an acute coronary syndrome37 or stable angina.38 OCT of SVGs in our study demonstrated frequent circumferential fibrous neointima, thin-cap fibroatheroma, plaque rupture, and adherent thrombus.39,40 Our study confirmed that SVG intermediate lesions have circumferential fibrous neointima and consist mainly of fibroatheromatic and fibrocalcific tissue.41 Fibrous cap thickness, microchannels, thrombus, and extent of necrotic core were similar in ER-niacin and placebo-treated patients. Although the frequency of plaque rupture at follow-up was significantly lower in patients who received ER-niacin (0% vs 36%; P=.01), this is likely the play of chance given the small number of events, the lack of correction for multiple statistical comparisons, and inconsistency with other coronary imaging endpoints.

Study limitations. Our study has a number of important limitations. As described above, enrollment was stopped early, limiting the power of the study. It was performed at a single center and the duration of study-drug treatment was limited to 12 months; longer administration of the study medication could increase the likelihood of observing a beneficial effect. 


In summary, ALPINE-SVG did not demonstrate benefit with ER-niacin in preventing intermediate SVG lesion progression when added to intensive statin therapy, noting the compromise of statistical power given early termination of enrollment.


1.    Alexander JH, Hafley G, Harrington RA, et al. Efficacy and safety of edifoligide, an E2F transcription factor decoy, for prevention of vein graft failure following coronary artery bypass graft surgery: PREVENT IV: a randomized controlled trial. JAMA. 2005;294:2446-2454.

2.    Shroyer AL, Grover FL, Hattler B, et al. On-pump versus off-pump coronary-artery bypass surgery. N Engl J Med. 2009;361:1827-1837.

3.    Goldman S, Zadina K, Moritz T, et al. Long-term patency of saphenous vein and left internal mammary artery grafts after coronary artery bypass surgery: results from a Department of Veterans Affairs Cooperative Study. J Am Coll Cardiol. 2004;44:2149-2156.

4.    Fitzgibbon GM, Kafka HP, Leach AJ, Keon WJ, Hooper GD, Burton JR. Coronary bypass graft fate and patient outcome: angiographic follow-up of 5,065 grafts related to survival and reoperation in 1,388 patients during 25 years. J Am Coll Cardiol. 1996;28:616-626.

5.    Lichtenwalter C, de Lemos JA, Roesle M, et al. Clinical presentation and angiographic characteristics of saphenous vein graft failure after stenting: insights from the SOS (stenting of saphenous vein grafts) trial. JACC Cardiovasc Interv. 2009;2:855-860.

6.    Ellis SG, Brener SJ, DeLuca S, et al. Late myocardial ischemic events after saphenous vein graft intervention — importance of initially “nonsignificant” vein graft lesions. Am J Cardiol. 1997;79:1460-1464.

7.    Knatterud GL, White C, Geller NL, et al. Angiographic changes in saphenous vein grafts are predictors of clinical outcomes. Am Heart J. 2003;145:262-269.

8.    Rodes-Cabau J, Facta A, Larose E, et al. Predictors of aorto-saphenous vein bypass narrowing late after coronary artery bypass grafting. Am J Cardiol. 2007;100:640-645.

9.    Rodes-Cabau J, Bertrand OF, Larose E, et al. Comparison of plaque sealing with paclitaxel-eluting stents versus medical therapy for the treatment of moderate nonsignificant saphenous vein graft lesions. The Moderate VEin Graft LEsion Stenting With the Taxus Stent and Intravascular Ultrasound (VELETI) pilot trial. Circulation. 2009;120:1978-1986.

10.    Rodes-Cabau J, Bertrand OF, Larose E, et al. Five-year follow-up of the plaque sealing with paclitaxel-eluting stents vs medical therapy for the treatment of intermediate nonobstructive saphenous vein graft lesions (VELETI) trial. Can J Cardiol. 2014;30:138-145.

11.    Abdel-Karim AR, Da Silva M, Lichtenwalter C, et al. Prevalence and outcomes of intermediate saphenous vein graft lesions: findings from the stenting of saphenous vein grafts randomized-controlled trial. Int J Cardiol. 2013;168:2468-2473.

12.    Motwani JG, Topol EJ. Aortocoronary saphenous vein graft disease: pathogenesis, predisposition, and prevention. Circulation. 1998;97:916-931.

13.    Okrainec K, Platt R, Pilote L, Eisenberg MJ. Cardiac medical therapy in patients after undergoing coronary artery bypass graft surgery: a review of randomized controlled trials. J Am Coll Cardiol. 2005;45:177-184.

14.    The effect of aggressive lowering of low-density lipoprotein cholesterol levels and low-dose anticoagulation on obstructive changes in saphenous-vein coronary-artery bypass grafts. The Post Coronary Artery Bypass Graft Trial Investigators. N Engl J Med. 1997;336:153-162.

15.    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.

16.    Carlson LA. Nicotinic acid: the broad-spectrum lipid drug. A 50th anniversary review. J Intern Med. 2005;258:94-114.

17.    Capuzzi DM, Morgan JM, Weiss RJ, Chitra RR, Hutchinson HG, Cressman MD. Beneficial effects of rosuvastatin alone and in combination with extended-release niacin in patients with a combined hyperlipidemia and low high-density lipoprotein cholesterol levels. Am J Cardiol. 2003;91:1304-1310.

18.    Maccubbin D, Bays HE, Olsson AG, et al. Lipid-modifying efficacy and tolerability of extended-release niacin/laropiprant in patients with primary hypercholesterolaemia or mixed dyslipidaemia. Int J Clin Pract. 2008;62:1959-1970.

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

20.    Group HTC, Landray MJ, Haynes R, et al. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med. 2014;371:203-212.

21.    Mintz GS, Nissen SE, Anderson WD, et al. American College of Cardiology clinical expert consensus document on standards for acquisition, measurement and reporting of intravascular ultrasound studies (IVUS): a report of the American College of Cardiology task force on clinical expert consensus documents developed in collaboration with the European Society of Cardiology endorsed by the Society of Cardiac Angiography and Interventions. J Am Coll Cardiol. 2001;37:1478-1492.

22.    Nissen SE, Nicholls SJ, Sipahi I, et al. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA. 2006;295:1556-1565.

23.    Nissen SE, Tuzcu EM, Schoenhagen P, et al. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA. 2004;291:1071-1080.

24.    Jang IK, Tearney GJ, MacNeill B, et al. In vivo characterization of coronary atherosclerotic plaque by use of optical coherence tomography. Circulation. 2005;111:1551-1555.

25.    Kitabata H, Tanaka A, Kubo T, et al. Relation of microchannel structure identified by optical coherence tomography to plaque vulnerability in patients with coronary artery disease. Am J Cardiol. 2010;105:1673-1678.

26.    Kubo T, Imanishi T, Takarada S, et al. Assessment of culprit lesion morphology in acute myocardial infarction: ability of optical coherence tomography compared with intravascular ultrasound and coronary angioscopy. J Am Coll Cardiol. 2007;50:933-939.

27.    Knatterud GL, Rosenberg Y, Campeau L, et al. Long-term effects on clinical outcomes of aggressive lowering of low-density lipoprotein cholesterol levels and low-dose anticoagulation in the post coronary artery bypass graft trial. Post CABG Investigators. Circulation. 2000;102:157-165.

28.    Makuuchi H, Furuse A, Endo M, et al. Effect of pravastatin on progression of coronary atherosclerosis in patients after coronary artery bypass surgery. Circ J. 2005;69:636-643.

29.    Frick MH, Syvanne M, Nieminen MS, et al. Prevention of the angiographic progression of coronary and vein-graft atherosclerosis by gemfibrozil after coronary bypass surgery in men with low levels of HDL cholesterol. Lopid Coronary Angiography Trial (LOCAT) study group. Circulation. 1997;96:2137-2143.

30.    Blankenhorn DH, Johnson RL, Nessim SA, Azen SP, Sanmarco ME, Selzer RH. The cholesterol lowering atherosclerosis study (CLAS): design, methods, and baseline results. Control Clin Trials. 1987;8:356-387.

31.    Cashin-Hemphill L, Mack WJ, Pogoda JM, Sanmarco ME, Azen SP, Blankenhorn DH. Beneficial effects of colestipol-niacin on coronary atherosclerosis. A 4-year follow-up. JAMA. 1990;264:3013-3017.

32.    Azen SP, Mack WJ, Cashin-Hemphill L, et al. Progression of coronary artery disease predicts clinical coronary events. Long-term follow-up from the cholesterol lowering atherosclerosis study. Circulation. 1996;93:34-41.

33.    Brown BG, Zhao XQ, Chait A, et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med. 2001;345:1583-1592.

34.    Brown G, Albers JJ, Fisher LD, et al. Regression of coronary artery disease as a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein B. N Engl J Med. 1990;323:1289-1298.

35.    Nasser Figueiredo V, Vendrame F, Colontoni BA, et al. Short-term effects of extended-release niacin with and without the addition of laropiprant on endothelial function in individuals with low HDL-C: a randomized, controlled crossover trial. Clin Ther. 2014;36:961-966.

36.    Schoenhagen P, Tuzcu EM, Apperson-Hansen C, et al. Determinants of arterial wall remodeling during lipid-lowering therapy: serial intravascular ultrasound observations from the reversal of atherosclerosis with aggressive lipid lowering therapy (REVERSAL) trial. Circulation. 2006;113:2826-2834.

37.    Takarada S, Imanishi T, Kubo T, et al. Effect of statin therapy on coronary fibrous-cap thickness in patients with acute coronary syndrome: assessment by optical coherence tomography study. Atherosclerosis. 2009;202:491-497.

38.    Hattori K, Ozaki Y, Ismail TF, et al. Impact of statin therapy on plaque characteristics as assessed by serial OCT, grayscale and integrated backscatter-IVUS. JACC Cardiovasc Imaging. 2012;5:169-177.

39.    Adlam D, Antoniades C, Lee R, et al. OCT characteristics of saphenous vein graft atherosclerosis. JACC Cardiovasc Imaging. 2011;4:807-809.

40.    Davlouros P, Damelou A, Karantalis V, et al. Evaluation of culprit saphenous vein graft lesions with optical coherence tomography in patients with acute coronary syndromes. JACC Cardiovasc Interv. 2011;4:683-693.

41.    Wood FO, Badhey N, Garcia B, et al. Analysis of saphenous vein graft lesion composition using near-infrared spectroscopy and intravascular ultrasonography with virtual histology. Atherosclerosis. 2010;212:528-533.


From the 1VA North Texas Healthcare System and University of Texas Southwestern Medical Center, Dallas, Texas; and 2College of Health Innovation, University of Texas at Arlington, Arlington, Texas.

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. Part of the study medication was provided by Abbott.

Clinical Trial Registration: NCT01221402.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Rangan reports grant funds from Spectranetics and InfraRedX. Dr McGuire reports consultant fees/honoraria from  Merck, Sharp and Dohme Corporation, Lilly USA, Takeda Pharmaceuticals North America, AstraZeneca, Sanofi Aventis, and Regeneron. Dr Banerjee reports 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/speaker honoraria from Abbott Vascular, Asahi Intecc, Boston Scientific, Elsevier, Somahlution, St Jude Medical, and Terumo; research support from Boston Scientific and InfraRedx; spouse is employee of Medtronic. The remaining authors report no conflicts of interest regarding the content herein.

Manuscript submitted April 6, 2015 and accepted May 12, 2015.

Address for correspondence: Emmanouil S. Brilakis, MD, PhD, VA North Texas Health Care System, The University of Texas Southwestern Medical Center at Dallas, Division of Cardiology (111A), 4500 S. Lancaster Rd, Dallas, TX 75216. Email: esbrilakis@gmail.com