Clinical trial NCT02966002
Conditions: Fontan Procedure
Sponsor: University of Michigan
Start date: 2016-04-01; Completion date: 2017-05-25
Enrollment: 9 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Patients who have undergone the Fontan procedure (a congenital heart surgery) may develop complications many years after their operation. Studies have shown that some of these patients develop an ongoing inflammatory state, which may be the cause of these late complications. Aspirin is a common over the counter anti-inflammatory medication used for many other chronic diseases. This study may help determine if aspirin therapy can limit the inflammation seen in Fontan patients and prevent these late complications.

Detailed description:

Arms: arm 1: 650 mg. Twice a day for 8 weeks
Interventions: intervention 1: Aspirin
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_SAP_000.pdf: 
 
Aspirin as a Novel Anti-Inflammatory Modality in the Fontan Patients 
NCT02966002 
 
November 23, 2015 
 
 


Background: 
Over the past 40 years, one of the most important advances in the field of congenital heart disease has 
been the development of a long-term palliation strategy for individuals with single ventricle.  Pioneers 
such as Fontan [1], Kreutzer[2]], de Leval  [3], Bove [4], as well as many others, have contributed to 
creating an effective surgical palliation for individuals with single ventricle physiology  by using a unique 
surgical reconstruction strategy of directing systemic venous blood flow  to the pulmonary circulation in 
the absence of the pulsatile force of the sub-pulmonary ventricle.  As a result of this surgical strategy, 
newborns with single ventricle congenital heart disease that were felt to have a near uniformly lethal 
type of heart disease 45 years ago, now have over a 70% chance of surviving 15-25 years after surgery. 
[5-8] 
However, as these individuals have grown into adolescence and adulthood, it is now clear that there are 
significant long-term limitations with this strategy. Arrhythmias, valvular insufficiency and ventricular 
dysfunction are common. [9, 10] In addition there is growing evidence for a multitude of end-organ 
dysfunction, including poor somatic growth and development, increased risk of thromboembolism, 
peripheral venous insufficiency, and diabetes, protein losing enteropathy, plastic bronchitis and hepatic 
cirrhosis. [11-17]  
Many have suggested that the combined effect of low cardiac output and increased central venous 
pressure are the cause of most late-complications associated with the Fontan operation. [15, 18]  
However, even though all Fontan patients have elevated central venous pressures and low to low 
normal cardiac output, these variables are not predictive of either when or which Fontan patient will 
develop a specific late complication.[19] For example, no all individuals with protein losing enteropathy 
have high central venous pressure and low cardiac outputs. [20, 21] We speculate that an alternate 
hypothesis for the cause of late-complications associated with the Fontan operation is that the chronic 
increase in central venous pressure produces generalized lymphedema, especially in the abdomen, that 
leads to chronic inflammation and resultant damage to many of the abdominal organs. Olszewski 
[22]has reported that the level of cytokines are elevated in lymphedema lymph. Olszewski  also 
speculated that the high levels of cytokines are attributed to their local production by infiltrating 
immune cells. He reported that the lymph levels of cytokines, exceeded serum concentration by factors 
of 10 or more, and clearly point to an intensive inflammatory process in the tissues affected by the 
lymphedema [23].  Ostrow et al reported elevated inflammatory  markers, increased TNF-alpha, CRP and 
C-reactive protein,  in Fontan patients  with protein-losing enteropathy [24]. Furthermore, Rychik 
reported that on endoscopic evaluation his group has found subtle evidence for inflammation/colitis in a 
number of individuals with protein-losing enteropathy following the Fontan operation [15].  Racz et al  
reported that the plastic bronchitis airway casts from children with Fontan physiology are composed of 
fibrin and are cellular and inflammatory in nature, providing evidence that their formation cannot be 
explained simply by lymph leak into the airways [25]. Consequences of cellular necrosis including 
extracellular histones and the apparent low number of T cells indicate that a derangement in 
inflammation resolution likely contributes to cast formation. There have been few reports of abnormal 
inflammatory markers in Fontan patients who are doing well.  Zyblewski et al  reported that after the 
Fontan operation, the plasma HDL-cholesterol levels were significantly reduced [26]. Since HDL-


cholesterol has been identified as an important anti-inflammatory mediator [27], Zyblewski et al have 
speculated that the low levels of HDL-cholesterol observed in their study raises the possibility that 
single-ventricle patients may be in a chronic inflammatory state. We have also [28] demonstrated an 
abnormal lipid profile in Fontan patients. We reported that Fontan patients have decreased total 
cholesterol, LDL-cholesterol and HDL-cholesterol, while triglycerides remain normal. In a recent study 
we have demonstrated that the decrease in cholesterol is related to a decrease in biosynthesis that may 
be mediated by inflammation ( our Fontan patients had significantly higher CRP’s compared to our 
control subjects).(unpublished data) A similar lipid profile has previously been reported in individuals 
with rheumatoid arthritis. Amezaga-Urruela et al [29] reported a continuous decline in total cholesterol 
and LDL-cholesterol has been demonstrated during the 5 years prior to the development of rheumatoid 
arthritis and an increase in the total cholesterol/HDL-cholesterol ratio was also observed. Increasing CRP 
has been negatively associated with total cholesterol and HDL-cholesterol.[30] Furthermore, in 
rheumatoid arthritis,  as inflammations decreases with therapy, lipid levels rise. [31, 32] Based on the 
similar lipid profile in Fontan patients with rheumatoid arthritis patients, we hypothesis that abnormal 
lipids in Fontan patients are an early marker of chronic inflammation. 
HDL-cholesterol levels may also relate to the pathogenesis of protein losing enteropathy. In the protein 
losing enteropathy patients in our study,[28]they had markedly low HDL-cholesterol and higher 
triglyceride levels. One determinate of HDL-cholesterol levels is lipoprotein lipase activity. [33] Blades et 
al [34]have reported that high hepatic triglyceride lipase and low lipoprotein lipase activity are both 
important contributors to low HDL-cholesterol levels in both normotriglyceride and hypertriglyceride 
subjects.  In rheumatoid arthritis these is an inverse relation between lipoprotein lipase activity and 
inflammatory state. [35] Bode et al {Bode, 2005 #496} has demonstrated that loss of heparin sulfate 
proteoglycans from the basolateral surface of intestinal epithelial cells plays a central role in the 
pathogenesis of experimental meddles of protein losing enteropathy. Lipoprotein lipase is secreted by 
many tissues of the body, particularly metabolically active adipose tissue in the abdomen. It is 
transferred to the luminal surface of endothelial cells, where it is bound as homodimers to heparin 
sulfate proteoglycans and can be released by administration of heparin.{Lewis, 2005 #468} Therefore, if 
HDL-cholesterol levels are low in Fontan patients due to a decrease in lipoprotein lipases activity, based 
on Bode’s report {Bode, 2005 #496} there may be a direct relationship between HDL-cholesterol level 
and protein losing enteropathy. 
Abnormal lipoprotein lipase activity has also been speculated to relate to abnormal adipose tissue fatty 
acid trafficking and maybe part of the pathophysiological basis for ectopic fat deposition in the abdomen 
and heart. [36] We have recently demonstrated that Fontan patients have abnormally increased 
amounts of epicardial fat content when compared to age and body mass index adjusted group of 
patients with repaired tetralogy of Fallot. (Unpublished data) 
Based on this review of the literature and our preliminary studies, we hypothesis that the abnormal lipid 
values in Fontan patient reflect the presence of chronic inflammation. Aspirin is a well-known agent that 
has been used to treat chronic inflammations associated with a number of diseases including Kawasaki’s 
disease, rheumatoid arthritis and acute rheumatic fever. It has known to be well tolerated by both 
adults and children. Aspirin exerts some of its anti-inflammatory action by inhibiting the activity of IκB 


kinases-β (IKKs-β). We and others have demonstrated that aspirin can prevent or correct the insulin 
resistance associated with obesity.[37, 38] Pharmacologic modulation of arachidonic acid 
metabolites, such as aspirin, can positively modify lipid metabolism, increase HDL cholesterol. [39-
41] Therefore in an attempt to test our hypothesis that the abnormal lipid values in Fontan patient 
reflect the presence of chronic inflammation, we plan to determine if the anti-inflammatory agent , 
aspirin, will normalize the lipid abnormalities in Fontan patients. 
Protocol: 
Patient Population:  We plan to study 20 young adult subjects who have had Fontan repair of single 
ventricle. All subjects will be over 18 years of age and in good health. Individuals will be excluded if they 
have had active protein losing enteropathy within the past three years, have congestive heart failure, 
active arrhythmias, or on Coumadin.  Any individual with a bleeding disorder or known esophageal 
varicies will also be excluded. Subjects who known to have more than 10 drinks per week will be 
excluded. Females who are pregnant and /or planning become pregnant will be excluded.  
Protocol: After informed consent is obtained. Subjects will have fasting blood drawn for measurement 
of lipids, total cholesterol, HDL-Cholesterol, LDL-cholesterol and triglycerides, a complete metabolic 
panel, GGT, Complete blood count and differential, plasma insulin, inflammatory markers including 
sedimentation rate, high sensitivity C-reactive protein and haptoglobin. Individuals will also be asked to 
fill out the Short-Form 36 Quality of Life Survery.  Individuals will be told to stop their current 81 mg/day 
of aspirin, and then be started on 650 mg (two 325 mg tablets ) of aspirin 2 times a day. All aspirin will 
be provided by use. After two weeks of aspirin therapy all individuals will have a blood salicylate level 
taken 6 hours after their morning aspirin dose. Goal aspirin levels will be 15-20 mg/dl. If the level is less 
than 10 or greater than 20 mg/dl the aspirin dose will be adjusted.  All individuals will be instructed into 
the early symptoms of aspirin toxicity include nausea, vomiting, tinnitus, and hyperventilation. If they 
should experience any of these symptoms they will be instructed to immediately call us.  In addition, if 
the individuals have any excess bleeding, blood in their stool or abdominal pain they will be told to 
immediately call. After 8 weeks of aspirin therapy the individual will be asked to return for repeat fasting 
blood test including a salicylate level and repeat the Short-Form 36 Quality of Life Survey.  In addition to 
measuring salicylate levels, drug compliance will be monitored by pill count. All individuals will be 
provided with more aspirin pills than necessary for the study. They will be asked to return all the unused 
aspirin pills and the number or remaining pills will be counted. 
Statistical analysis:   
This is a pilot study to determine the safety and feasibility of a larger randomized trial. This study will 
form the basis for a statistically valid sample size for this planned larger trial. 
Our primary outcome variable will be a change in total cholesterol and HDL-Cholesterol. It is our 
hypothesis that aspirin therapy will result in an increase of either total cholesterol and/or HDL-
cholesterol. 


Secondary outcomes: We would expect that aspirin therapy would improve the inflammatory markers 
(decrease high sensitivity CRP, decrease neutrophil to lymphocyte ratio, decrease sedimentation rate 
and decrease haptoglobin level).  We also expect that aspirin will decrease plasma insulin levels and 
reduce the calculated HOMA-IR value [(Fasting glucose*Fasting  insulin)/405; where glucose is in mg/dl 
and insulin is in mU/l].  We also hope that aspirin therapy might improve perception of quality of life and 
possibly improve liver function tests. 
 
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