Abstract
Background The xanthine oxidase (XO) system is a significant source of vascular oxidative stress, which is believed to impair endothelial function, an important contributor to atherosclerotic disease. We tested whether febuxostat, a potent XO inhibitor, improves coronary endothelial function (CEF) in patients with stable coronary artery disease (CAD) in a single-center, randomized, placebo-controlled, double-blind crossover trial. Methods CEF was measured using noninvasive magnetic resonance imaging (MRI) assessment of changes in 30 patients with stable CAD and baseline impaired CEF. Patients received either febuxostat or placebo for 6 weeks and then were crossed over to the alternative for an additional 6 weeks. MRI-detected changes in coronary flow and in coronary cross-sectional area from rest to isometric handgrip exercise, a known endothelial-dependent stressor, were measured at the end of each 6 week period. Results Mean serum urate levels were lower at the end of the 6-week febuxostat period (2.9 ± 0.8 mg/dL) than at the end of the 6-week placebo period (5.9 ± 0.04, P <.001). However, there were no significant differences in any of the CEF parameters measured at the end of the febuxostat and placebo periods. Conclusions In summary, although XO inhibition with febuxostat was well tolerated and lowered serum urate, it did not improve the primary end point of the study, CEF measured using MRI after 6 weeks of treatment. In conclusion, these findings suggest that short-term inhibition of XO does not significantly improve impaired CEF in patients with stable CAD.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 85-93 |
| Number of pages | 9 |
| Journal | American heart journal |
| Volume | 197 |
| DOIs | |
| State | Published - Mar 2018 |
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine
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In: American heart journal, Vol. 197, 03.2018, p. 85-93.
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TY - JOUR
T1 - The influence of febuxostat on coronary artery endothelial dysfunction in patients with coronary artery disease
T2 - A phase 4 randomized, placebo-controlled, double-blind, crossover trial
AU - Hays, Allison G.
AU - Iantorno, Micaela
AU - Schär, Michael
AU - Lai, Shenghan
AU - Czarny, Matthew
AU - Breton, Elayne
AU - Palmer, Robert N.
AU - Whelton, Andrew
AU - Weiss, Robert G.
AU - Gerstenblith, Gary
N1 - Funding Information: This was a phase 4, single-center, randomized, placebo-controlled, double-blind, crossover study conducted at Johns Hopkins Hospital. Subjects with known coronary artery disease (coronary stenosis ≥ 50% on prior clinically indicated coronary x-ray angiogram) underwent baseline testing of coronary endothelial function. Screening consisted of laboratory tests, electrocardiogram (ECGs), a modified Bruce protocol treadmill exercise tolerance test (ETT), and MRI assessment of CEF. At baseline, following 6 weeks of either placebo or febuxostat, and then following 6 weeks of the alternate study arm, the following procedures were performed: MRI CEF studies, an exercise treadmill test, an assessment of symptomatic angina using the Seattle Angina Questionnaire, and a blood draw for measurement of high-sensitivity C-reactive protein (hsCRP), interleukin (IL)-6, and sUA levels. The investigators were blinded to the study drug assignment. Subjects were instructed to fast overnight prior to the MRI testing, and there were no dietary or fluid restrictions. The protocol was approved by the Institutional Review Board at The Johns Hopkins University School of Medicine and complies with the Declaration of Helsinki. All participants provided written informed consent. Enrollment began October 2013, and the trial ended April 2015. Additional information can be found at www.clinical trials.gov ( NCT01763996 , IND: 58,229). The study was supported by a grant from the Takeda Pharmaceutical International, Inc . The authors are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the paper, and its final contents. Those with abnormal CEF, defined as an increase of <10 mL/min coronary blood flow from rest to IHE in 1 of the 3 major coronary arteries, underwent assessment of symptomatic angina and ETT. After completing all screening procedures, subjects were randomly assigned, 1 to 1, to 1 of the following 2 crossover sequences: Image 1 Sequence Regimen 1 6 weeks of febuxostat 80 mg qd followed by 6 weeks of placebo qd 2 6 weeks of placebo qd followed by 6 weeks of febuxostat 80 mg qd A schematic of the study design is presented in . The half-life of febuxostat 80 mg is 5-8 hours, and the MRI was performed 6 weeks following crossover from febuxostat to placebo in those randomized to the first sequence, allowing adequate febuxostat washout time. Figure 1 Two weeks after initiation of the study drug, repeat laboratory studies, including urate levels, were obtained. Subjects were selected based on entry criteria of (1) sUA ≥4.0 mg/dL; (2) a history of coronary artery disease, defined as coronary artery stenosis ≥50% on prior imaging study or history of myocardial infarction; and (3) a change in coronary blood flow, from rest to IHE, of 1 SD from the reference range values. The change in coronary blood flow with IHE criterion was chosen so as to ensure that all had an impaired response at baseline days prior to screening. Subjects with an MRI procedure within the prior 30 days indicating that they met the MRI entry criteria for this study could, if their anti-ischemic regimen had not changed, undergo the other screening procedures and, if they met those, could be enrolled. sUA determinations were blinded after entry. 11 so as to better identify whether there was any improvement associated with febuxostat. Subjects who were currently receiving anti-ischemic regimens were on stable therapy for at least 30 Exclusion criteria: The exclusion criteria were as follows: 1. Received any investigational compound within 30 days prior to screening. 2. Received allopurinol or febuxostat in a previous clinical study or as a therapeutic agent within 6 months prior to randomization. 3. Gout or secondary hyperuricemia, for example, due to a myeloproliferative disorder or organ transplant. 4. History of xanthinuria. 5. Known contraindication to MRI scanning. 6. An immediate family member of or in a dependent relationship with a study site employee who was involved in the conduct of the study. 7. History of hypersensitivity or allergies to febuxostat or nitroglycerin. 8. Hemoglobin <10 g/L at screening. 9. History or clinical manifestations of a significant medical condition that might affect the ability to complete the study. 10. Acute coronary syndrome or coronary revascularization within the prior 2 months. 11. Receiving any anti-inflammatory agent other than aspirin 81 mg/d. 12. In addition, any of the following during screening: a. New York Heart Association class III or IV heart failure. b. Wolff-Parkinson-White syndrome. c. Implanted pacemaker or cardioverter defibrillator. d. Arrhythmias which might impact MRI gating (eg, atrial fibrillation/flutter) A commercial human 3-T MRI scanner (Achieva, Philips, Best, the Netherlands) with a 32-element cardiac coil for signal reception was used with multitransmit radiofrequency. MRI was performed in the morning after an overnight fast and prior to administration of any prescribed vasoactive medications. Images were taken perpendicular to a proximal or midlinear segment of the coronary artery best identified on survey scans, as previously described. minutes of continuous IHE as previously described. 13,24 The coronary segment evaluated was located in an angiographically smooth native coronary segment over approximately 2 cm with no significant luminal stenosis (defined as <30% stenosis), and distant from significant stenosis and branch vessels. Only 1 segment with the best image quality throughout all 3 MRI examinations was included in analysis. For coronary endothelial function imaging, alternating anatomical and velocity-encoded images were collected at baseline and during approximately 4½ 11,13 Each subject performed sustained IHE using an MRI-compatible handgrip dynamometer (Stoelting, Wood Dale, IL) at 30% of their maximum grip strength 25 while under direct supervision by a research nurse to ensure patient compliance. Heart rate and blood pressure were measured throughout using a noninvasive and MRI-compatible ECG and blood pressure monitor (Invivo, Precess, Orlando, FL). Detailed MRI parameters have been previously published. 11,13 Images were analyzed blinded to study-drug assignment for coronary cross-sectional area (CSA) using a semiautomated software tool (Cine version 3.15.17, General Electric, Milwaukee, WI) as previously reported. 12 For flow measurements, images were analyzed using semiautomated commercial software (FLOW Version 3.0, Medis, Leiden, the Netherlands). Peak diastolic coronary flow velocity (CFV) was used for the velocity measurement to avoid adverse effects of motion blurring and because through-plane coronary motion is minimized during diastole. Coronary artery blood flow (CBF, in mL/min) was calculated using the adapted equation (to convert units to mL/min) as coronary artery CSA × coronary artery peak diastolic velocity × 0.3. 26 All data for the study were collected at Johns Hopkins Hospital. Our prior studies using this methodology demonstrate no significant intra- or interobserver variability. 11 The intent-to-treat approach was used. Baseline characteristics were described using mean and SD or medians and ranges for continuous variables and proportions for discrete variables. The primary efficacy end point was the change in coronary flow from rest to IHE at the end of the febuxostat or placebo administration periods. There were no changes to trial outcomes after the study commenced. Comparisons were made between the groups using an analysis of variance model which included sequence, period, and treatment as fixed factors and subjects within sequence as a random factor. Unless otherwise specified, all statistical tests and confidence intervals were 2-sided and conducted at the .05 significance level; all summary data are presented as mean ± SD unless otherwise indicated. If data were nonnormally distributed, median and interquartile range (IQR) were reported. The secondary efficacy end points were change in coronary artery CSA and CFV with IHE. In a subset of patients, we assessed the change in coronary artery area, velocity, and flow following the administration of sublingual nitroglycerin to evaluate whether the endothelial-independent responses differed between the febuxostat and placebo periods. The secondary efficacy end points also included time to onset of angina during ETT, time to onset of ≥1-mm ST-segment depression during ETT, and maximum ST-segment depression during ETT. These changes were analyzed similarly to that of the primary efficacy variable as described above. The percentage of subjects stopping ETT because of angina is summarized by study group, and the groups are compared using Fisher exact test. Overall, safety and tolerability were assessed by evaluating the incidence of treatment-emergent adverse events, laboratory tests, vital signs, and other safety variables. Treatment-emergent adverse events were defined as any adverse events—regardless of relationship to study drug—that occurred on or after the first double-blind dose date and up to 30 days after the last dose date of the double-blind study drug. Adverse events were summarized based on the study drug being received at the time of the event. Treatment-emergent adverse events were summarized using the full analysis set. Laboratory test variables and vital signs were summarized by study drug and visit using descriptive statistics. The sample size was based on the primary outcome, which was the change in diastolic coronary blood flow from rest to isometric handgrip when the subjects were receiving febuxostat and when subjects were receiving placebo. We estimated that there would be at least a 26-mL/min increase in the rest to exercise mean diastolic coronary blood flow when subjects were receiving febuxostat, as compared with placebo, and that the within-subject SD around the mean rest to exercise value would be 30 mL/min. 11 There was an 80% probability (power) of detecting this change, at a 2-sided P value of .05, when 23 subjects were studied. We therefore enrolled 30 subjects with the conservative assumption of a 20% “dropout” rate in this 12-week study. Publisher Copyright: © 2017 Elsevier Inc.
PY - 2018/3
Y1 - 2018/3
N2 - Background The xanthine oxidase (XO) system is a significant source of vascular oxidative stress, which is believed to impair endothelial function, an important contributor to atherosclerotic disease. We tested whether febuxostat, a potent XO inhibitor, improves coronary endothelial function (CEF) in patients with stable coronary artery disease (CAD) in a single-center, randomized, placebo-controlled, double-blind crossover trial. Methods CEF was measured using noninvasive magnetic resonance imaging (MRI) assessment of changes in 30 patients with stable CAD and baseline impaired CEF. Patients received either febuxostat or placebo for 6 weeks and then were crossed over to the alternative for an additional 6 weeks. MRI-detected changes in coronary flow and in coronary cross-sectional area from rest to isometric handgrip exercise, a known endothelial-dependent stressor, were measured at the end of each 6 week period. Results Mean serum urate levels were lower at the end of the 6-week febuxostat period (2.9 ± 0.8 mg/dL) than at the end of the 6-week placebo period (5.9 ± 0.04, P <.001). However, there were no significant differences in any of the CEF parameters measured at the end of the febuxostat and placebo periods. Conclusions In summary, although XO inhibition with febuxostat was well tolerated and lowered serum urate, it did not improve the primary end point of the study, CEF measured using MRI after 6 weeks of treatment. In conclusion, these findings suggest that short-term inhibition of XO does not significantly improve impaired CEF in patients with stable CAD.
AB - Background The xanthine oxidase (XO) system is a significant source of vascular oxidative stress, which is believed to impair endothelial function, an important contributor to atherosclerotic disease. We tested whether febuxostat, a potent XO inhibitor, improves coronary endothelial function (CEF) in patients with stable coronary artery disease (CAD) in a single-center, randomized, placebo-controlled, double-blind crossover trial. Methods CEF was measured using noninvasive magnetic resonance imaging (MRI) assessment of changes in 30 patients with stable CAD and baseline impaired CEF. Patients received either febuxostat or placebo for 6 weeks and then were crossed over to the alternative for an additional 6 weeks. MRI-detected changes in coronary flow and in coronary cross-sectional area from rest to isometric handgrip exercise, a known endothelial-dependent stressor, were measured at the end of each 6 week period. Results Mean serum urate levels were lower at the end of the 6-week febuxostat period (2.9 ± 0.8 mg/dL) than at the end of the 6-week placebo period (5.9 ± 0.04, P <.001). However, there were no significant differences in any of the CEF parameters measured at the end of the febuxostat and placebo periods. Conclusions In summary, although XO inhibition with febuxostat was well tolerated and lowered serum urate, it did not improve the primary end point of the study, CEF measured using MRI after 6 weeks of treatment. In conclusion, these findings suggest that short-term inhibition of XO does not significantly improve impaired CEF in patients with stable CAD.
UR - http://www.scopus.com/inward/record.url?scp=85039995233&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85039995233&partnerID=8YFLogxK
U2 - 10.1016/j.ahj.2017.11.006
DO - 10.1016/j.ahj.2017.11.006
M3 - Article
C2 - 29447788
AN - SCOPUS:85039995233
SN - 0002-8703
VL - 197
SP - 85
EP - 93
JO - American Heart Journal
JF - American Heart Journal
ER -