Effect of Ambrisentan on Exercise Capacity in Adult Patients After the Fontan Procedure




The Fontan operation is a common end point for children born with a single functional ventricle. Fontan patients typically experience physiological deterioration leading to transplant or death in their third or fourth decades of life. This deterioration is partially attributable to progressive increases in pulmonary vascular resistance (PVR) and as such endothelin receptor antagonists, which are known to decrease pulmonary vascular resistance, have been proposed as potentially beneficial in this population. We conducted a single-center, randomized, double-blind, placebo-controlled, crossover study of 12 weeks of ambrisentan therapy (10 mg per day) versus placebo to test the hypothesis that endothelin receptor antagonism will improve cardiopulmonary exercise test parameters and 36-item short form (SF-36) assessed quality of life in adult Fontan patients. Twenty-eight patients entered the trial, 19 patients completed the protocol. Ambrisentan therapy improved peak oxygen consumption by 1.7 ml/kg/min in patients who achieved a respiratory exchange ratio of >0.95 (p = 0.05) and decreased the slope of the ventilatory equivalent ratio for oxygen (−2.8, p = 0.019) in all completers. It did not change SF-36 physical function score compared with placebo (p = 0.28). Ambrisentan therapy resulted in a decrease in (−1.4 g/dl, p <0.001) with no change in liver or renal function. Therapy was generally well tolerated, with no greater rate of side effects than placebo. In conclusion, ambrisentan is well tolerated and improves exercise capacity in adult Fontan patients.


As is the case in other congenital heart lesions, patients born with a single functional ventricle have benefitted significantly from developments in medical and surgical care over the past 5 decades. Although Fontan palliations performed for such patients have improved prognosis, they leave patients with a fundamentally disordered physiology predisposed to failure. Compromised cardiac output in combination with elevated central venous pressures and loss of pulsatile pulmonary blood flow lead to activation of adverse neurohormonal pathways. Among the pathways upregulated in Fontan patients, the endothelin (ET) pathway is of particular interest. ET levels are known to be elevated in single ventricle patients, both pre-and post-Fontan. Furthermore, Fontan patients demonstrate high levels of ET receptor expression in the pulmonary vasculature, and common polymorphisms of the ET receptor correlate with prognosis in Fontan palliated patients. In the present study, we report the results of a randomized, blinded, placebo-controlled, crossover study investigating the efficacy of the ET receptor antagonist ambrisentan in improving exercise performance in Fontan patients.


Methods


We conducted a single-center randomized, double-blind, placebo-controlled crossover trial of ambrisentan versus placebo. Patients received oral placebo or 5 mg of ambrisentan (1 tablet) daily for 3 weeks, which if tolerated was increased to 10 mg (2 tablets) daily for 9 weeks, for a total of 12 weeks of therapy. The study was approved by the Institutional Review Board at Washington University School of Medicine, was in accordance with the Declaration of Helsinki, and the International Conference on Harmonization Good Clinical Practice guidelines.


All participants were recruited from a clinical database maintained at Washington University School of Medicine. Patients were required to be aged >18 years and to have had a Fontan type of palliation with single ventricle physiology, be clinically stable, have had no recent surgery and no surgery planned at the time of enrollment. A complete list of inclusion and exclusion criteria are available in Supplementary Material .


The primary efficacy end points were individual changes in maximal and peak oxygen consumption and the 36-item short form (SF-36) assessed quality of life (a widely used health related quality of life metric ) at the end of each of the 2 treatment periods compared with baseline. Maximal oxygen consumption was defined as the oxygen consumption at a respiratory exchange ratio (RER) of >0.95, whereas peak oxygen consumption was defined as the highest oxygen consumption achieved regardless of RER.


Secondary efficacy end points were individual changes in ventilatory threshold (VT) the slope of the ventilatory equivalent ratio for carbon dioxide (Ve/VCO2), slope of the ventilatory equivalent ratio for oxygen (Ve/VO2), oxygen uptake efficiency slope (OUES), changes in baseline oxygen saturation and changes in chronotropic response to exercise (chronotrophic response defined as peak heart rate achieved–baseline heart rate at rest just before cardiopulmonary exercise test [CPET]). OUES was calculated by plotting oxygen consumption in ml/min on the y-axis and minute ventilation (Ve) in L/min on the semilog-transformed x-axis. The slope of the line derived in this manner is the OUES.


Safety and tolerability end points included adverse event rates, and individual changes in aspartate amino transferase (AST), alanine amino transferase (ALT), creatinine clearance (CrCl), hemoglobin (Hgb) and comprehensive venous stasis classification system (CEAP) score at the end of each study period compared with baseline.


A research pharmacist responsible for drug dispensation randomized participants at the time of their first study visit to receive either placebo or ambrisentan during the first study period. No other research member was aware of the randomization scheme. Placebo tablets were identical in appearance to ambrisentan tablets. All patients had 3 study visits: baseline, after the first 12-week study period, and finally, after the second 12-weeks study period. At each of these visits, participants performed a CPET, SF-36, assessment of interval history, vital signs, and CEAP evaluation of lower extremity venous insufficiency. Patients underwent complete blood count at the time of visits 1 and 2, and 1 month after the first and the second visits. In addition, patients underwent comprehensive metabolic panel assessment monthly during each of the 2 study periods. All women additionally underwent urine pregnancy testing monthly during both study periods. At the conclusion of the first 12-week study period, there was a 2-week washout period before initiation of drug to begin the second study period.


VO 2 peak, VT, Ve/VCO 2 , Ve/VO 2 , and OUES were determined during graded treadmill exercise. Patients first performed a 2- to 3-minute warm-up to establish an initial individualized walking speed. Individualized protocols were selected in the present study as the goal was to achieve a maximal RER in each individual, based on the opinion of the exercise physiologist that individualization would be more likely to achieve this goal. After a brief rest, patients resumed exercise while respiratory gas exchange was measured using a metabolic cart (Parvo Medics TrueOne 2400, Parvo Medics, Sandy, Utah). The electrocardiogram was monitored continuously and blood pressure was measured periodically, whereas the speed and/or grade of the treadmill were incrementally increased every 1 to 2 minutes until volitional fatigue. For a given patient, the protocol established during visit 1 was used during visits 2 and 3. Respiratory gas exchange was calculated at 30 seconds intervals, with VO2 peak defined as the highest 1 minute average. VT was determined using the V-slope method, with Ve/VCO2 and Ve/VO2 calculated through regression analysis using all sub-VT data points. OUES was calculated as described by Baba et al.


The research coordinator called participants monthly during the study period to screen for both adverse events and to monitor patient compliance. In addition, all patients were asked to maintain a drug compliance diary, and pills were counted at each study visit. The data safety monitoring board met monthly to review safety data for the entire duration of the study.


Sample size was calculated based on the data of Giardini et al. Specifically, a mean cardiac index at rest for placebo of 2.9 with standard deviation (s.d.) = 0.8 was assumed, whereas during treatment, a mean cardiac index at rest was assumed to be 3.7 with s.d. = 1.0. Cardiac index was used to power the present study given the direct correlation between this and VO2 max. The study design incorporated repeated measures on the same subject and correlation between periods was assumed to be modest at 0.30. The study was powered on testing the difference between treatment and placebo at alpha = 0.05. Under these assumptions, a sample size of 21 was calculated to result in a power of 90%. Given the overall illness of the study population, we had a goal enrollment of 30 patients to allow for dropouts.


Patient characteristics and study end points for each individual patient who completed the study are presented. All CPET variables were computed by a single exercise physiologist blinded to randomization, not directly affiliated with the conduct of the study. CEAP score was assessed by the research coordinator.


Mean outcome and 95% CIs by treatment and period were obtained from model results. Adverse events were additionally analyzed using McNemar’s test which assumes no carryover and period effects hold. A more detailed description of analysis can be found in Supplementary Materials .


All analysis conducted in SAS, version 9.4 (SAS Institute Inc., Cary, North Carolina).




Results


Fifty-nine patients were screened for enrollment in the trial by review of records at Washington University Center for Adults with Congenital Heart Disease, of whom 36 were found to meet enrollment criteria and were approached for study participation. Of them, 28 patients enrolled in the study, and 19 patients completed the study ( Figure 1 ). There were no differences in demographics or cardiac morphology between participants and the 8 patients who declined participation.




Figure 1


Flowchart showing enrollment, dropouts, and progression through crossover design to study completion. Reasons for dropout: ♦ changed mind and unreachable respectively; ∗ withdrawal for rash and changed mind respectively; † withdrawal because of acute kidney injury and mild rash, respectively; § patient relocated and was no longer able to make follow-up visits; ‡ withdrawal because of edema/weight gain and chest pain and changed mind, respectively. QOL; quality of life.


Of 19 patients (67.9%) who completed the trial, all were included in final analysis, and all demographic data are presented in Table 1 . There was poor compliance with pill diaries as well as with return of unused study drug during both placebo and ambrisentan treatment periods precluding accurate assessment of patient medication compliance.



Table 1

Demographic data for each subject














































































































































































































































































































































































Demographics
Subject Group Gender Age ACEI B Block Digoxin Diuretic Ventricular
Morphology 		Fontan Type Age at Fontan Fenest-
ration 		AV Valve Grade EF% Arrhy-
thmia 		PPM PLE
1 P/A MALE 35 ARB YES NO NO LEFT ATRIOPULMONARY 2 NO NO >50% NO NO NO
2 A/P FEMALE 22 NO NO NO NO LEFT LATERAL TUNNEL 3 YES MILD >50% NO NO NO
3 P/A MALE 21 YES NO NO NO LEFT EXTRACARDIAC Unknown YES NO 40-49% NO NO NO
4 A/P MALE 23 YES NO NO NO LEFT EXTRACARDIAC 3 NO MILD 30-39% YES YES NO
5 A/P FEMALE 34 ARB YES YES YES RIGHT ATRIOPULMONARY 13 NO MODERATE 30-39% YES YES NO
6 A/P MALE 22 NO NO NO NO BILATERAL LATERAL TUNNEL 1.5 NO MILD >50% YES YES NO
7 P/A FEMALE 20 YES NO NO YES RIGHT LATERAL TUNNEL 4 NO NO >50% NO NO YES
8 A/P FEMALE 28 NO YES NO NO BILATERAL EXTRACARDIAC 3 NO MILD >50% NO NO NO
9 A/P MALE 21 YES NO NO YES RIGHT EXTRACARDIAC 8 NO MILD 30-39% YES NO NO
10 A/P FEMALE 33 YES YES YES YES RIGHT ATRIOPULMONARY 6 NO MILD 40-49% YES YES NO
11 P/A MALE 30 NO YES NO YES LEFT ATRIOPULMONARY 3 NO NO >50% YES NO NO
12 A/P FEMALE 21 NO NO NO NO LEFT EXTRACARDIAC 3 YES NO 40-49% NO YES NO
13 P/A MALE 27 YES NO NO NO LEFT EXTRACARDIAC Unknown NO MILD >50% YES YES NO
14 P/A MALE 21 YES NO NO NO RIGHT LATERAL TUNNEL 9 NO SEVERE >50% NO NO NO
15 P/A MALE 24 YES NO NO NO LEFT LATERAL TUNNEL 3 NO NO 30-39% NO NO NO
16 P/A MALE 18 YES NO NO NO RIGHT EXTRACARDIAC 3 YES MILD 30-39% NO NO NO
17 A/P MALE 31 ARB NO NO YES LEFT LATERAL TUNNEL 4 YES NO >50% YES YES NO
18 P/A MALE 21 NO YES NO NO LEFT LATERAL TUNNEL 2 YES MILD >50% YES NO NO
19 A/P MALE 21 YES YES NO NO LEFT LATERAL TUNNEL 19 YES NO 40-49% YES YES NO

A/P = ambrisentan during the first study period, placebo during the second; ACEI = angiotensin-converting enzyme inhibitor; ARB = antiogensin II receptor blocker; AV = atrioventricular; B block = beta blocker; EF = ejection fraction; PPM = permanent pacemaker; P/A = placebo during the first study period; PLE = protein losing enteropathy.


Four patients failed to achieve an RER >0.95 in at least one of the 3 CPET tests. Among the remaining 15 patients, there was an increase in VO2 max of 1.7 ml/kg/min with ambrisentan therapy (95% CI 0.0 to 3.4, p = 0.05; Figure 2 ). Including all patients, there was a nonsignificant trend toward improvement in peak VO2 during treatment with ambrisentan (1.16 ml/kg/min, 95% CI −0.24 to 2.56, p = 0.10 and 0.10 L/min higher 95% CI −0.007 to 0.214, p = 0.07; Figure 3 ). There was no change in SF-36 assessed quality of life related to physical function seen with ambrisentan (p = 0.28). There was a nonsignificant trend toward a period effect in VO2 max (p = 0.06), and SF-36 (p = 0.13) and a significant period effect in peak VO2 (p = 0.019).




Figure 2


VO2 max values at baseline compared with ambrisentan or placebo. Filled circles connected by dashed lines indicate individual patients. Open diamonds with solid black lines indicate averages.



Figure 3


Graphical representation of mean difference in the change between baseline and placebo or ambrisentan with 95% CI. p Values are indicated. ∗ Indicates a statistically significant treatment effect. § OUES values multiplied by 10 to better fit axis.


There was a trend toward an improvement in Ve/VCO2 slope (mean decrease = −2.6, 95% CI −5.6 to 0.5, p = 0.09), and OUES (mean improvement = 0.1, 95% CI 0.0 to 0.2, p = 0.08) and a significant improvement in Ve/VO2 slope (mean decrease −2.8, 95% CI −5.0 to −0.5, p = 0.019) favoring ambrisentan ( Figure 2 ). There were no changes in baseline oxygen saturation, VT, or in chronotropic response to exercise. All end point data are in Table 2 .



Table 2

End point data for each subject






































































































































































































































































































































































































































































































































































































































































































































Endpoints
Subject Baseline Placebo Ambrisentan
Change inHR OxygenSaturation PeakExerciseB/P VO2(L/min) VO2(ml/kg/min) VT RER VE/VO2Slope VE/VCO2Slope OUES SF-36Physicalfunctioningscoreaverage Changein HR OxygenSaturation PeakExerciseB/P VO2(L/min) VO2(ml/kg/min) VT RER VE/VO2Slope VE/VCO2Slope OUES SF-36Physicalfunctioningscoreaverage Change in HR OxygenSaturation PeakExerciseB/P VO2(L/min) VO2(ml/kg/min) VT RER VE/VO2Slope VE/VCO2Slope OUES SF-36Physicalfunctioningscoreaverage
1 92 88 140/62 2.04 31.05 1.69 1.24 24.65 27.39 2.33 95.0 93 89 148/80 1.91 29.52 1.06 1.25 22.15 26.05 2.22 95.0 89 92 118/72 2.13 32.77 1.87 1.21 24.43 25.83 2.40 95.0
2 97 86 144/86 1.04 19.12 0.72 1.06 18.66 26.80 1.31 70.0 96 90 312/78 1.15 21.34 0.74 1.07 20.68 25.80 1.36 75.0 104 96 144/82 1.22 22.68 0.71 1 17.47 27.47 1.47 75.0
3 10 82 164/80 1.71 17.48 0.88 0.98 6.20 21.17 2.45 75.0 5 82 136/78 1.55 15.74 1.14 0.96 14.37 27.65 2.18 70.0 4 79 130/66 1.52 15.18 1.05 1 19.83 28.71 2.07 70.0
4 58 98 190/98 1.73 23.76 1.14 0.96 22.36 28.52 2.11 70.0 81 94 178/86 1.99 27.52 1.20 1.04 25.36 34.83 2.84 60.0 56 94 166/94 1.90 26.24 1.05 1.03 18.30 29.66 2.55 55.0
5 50 81 108/60 0.98 13.19 0.84 0.87 31.15 37.61 1.74 50.0 67 76 136/70 0.92 12.23 0.71 1.07 24.24 33.05 1.03 50.0 67 81 110/62 0.94 12.88 0.69 1.05 26.11 34.88 1.06 50.0
6 89 93 152/82 1.82 23.64 0.89 1.06 9.06 15.94 2.04 70.0 77 95 150/70 1.66 22.77 0.84 1.02 21.05 33.47 1.94 80.0 73 92 142/78 1.73 22.79 0.80 1.07 16.70 26.28 2.02 85.0
7 66 90 176/70 1.23 20.74 0.78 1.05 16.09 22.13 1.96 90.0 74 92 148/60 1.12 18.92 0.82 0.95 26.12 32.32 1.68 80.0 69 95 174/50 1.22 19.74 0.86 0.96 21.85 29.78 2.24 85.0
8 101 96 180/78 1.66 29.23 0.91 0.95 18.70 28.75 2.20 95.0 108 99 138/70 1.76 31.48 0.86 1.05 15.10 24.31 2.16 100.0 94 97 140/72 1.66 29.80 0.76 1.05 9.13 19.68 2.27 100.0
9 18 94 132/78 0.71 12.52 NP 0.89 NP NP 1.05 60.0 38 86 132/62 0.79 14.29 0.48 0.95 10.69 24.52 0.88 30.0 36 88 136/76 0.88 15.88 NP 0.9 NP NP 0.97 35.0
10 38 93 110/54 1.06 15.99 0.72 1.04 21.86 35.13 1.40 72.2 32 96 100/60 1.08 16.59 0.67 1.07 26.92 37.65 1.36 80.0 20 88 110/54 0.92 13.94 0.73 1.05 20.71 27.76 1.28 65.0
11 64 92 162/88 2.60 18.08 1.60 1.16 18.02 27.91 2.69 70.0 70 92 160/100 2.46 17.18 1.60 1.08 27.59 40.21 2.74 75.0 53 92 162/90 2.36 16.39 1.53 1.16 23.98 30.23 2.67 65.0
12 69 90 140/82 1.08 17.65 0.68 1.01 26.58 40.40 1.55 45.0 65 87 134/88 0.99 15.66 0.66 0.88 21.72 34.41 1.71 75.0 58 91 126/76 0.60 9.23 0.47 0.84 20.24 43.03 1.11 65.0
13 22 93 146/68 1.12 15.20 0.72 0.95 24.00 32.81 1.70 40.0 12 96 150/50 1.06 13.87 0.69 1.05 18.99 26.33 1.40 35.0 41 94 150/70 1.52 19.49 1.10 1.1 25.83 31.42 1.82 90.0
14 41 93 132/68 1.11 18.47 0.83 1.08 31.31 36.00 1.23 80.0 61 95 150/90 1.16 19.08 0.79 1.30 32.37 36.29 1.11 65.0 55 95 152/78 1.56 25.28 1.10 1.17 24.25 25.06 1.50 82.5
15 80 94 190/78 1.76 25.66 1.10 1.02 15.98 25.42 2.33 95.0 92 92 98/70 1.92 27.91 1.00 1.06 19.89 30.19 2.03 95.0 86 94 194/48 2.44 35.21 1.13 1.14 15.39 21.38 2.52 100.0
16 81 94 132/70 1.66 29.64 0.93 1.31 24.28 33.15 1.75 100.0 74 92 140/90 1.44 25.85 1.09 1.21 22.20 24.47 1.72 95.0 89 95 122/62 1.70 30.41 1.08 1.22 17.55 26.07 1.79 95.0
17 55 79 144/70 2.29 17.67 1.56 1.12 29.76 33.77 2.70 65.0 65 78 102/60 2.18 20.84 1.29 1.15 28.17 30.31 2.61 80.0 67 78 132/58 2.68 22.87 1.42 1.07 21.30 26.43 3.00 80.0
18 21 91 120/70 0.86 12.23 NP 0.86 NP NP 1.33 50.0 16 92 104/68 0.97 14.08 NP 0.85 NP NP 1.81 50.0 11 92 130/70 0.94 13.54 NP 0.95 NP NP 1.86 55.0
19 67 95 118/74 1.72 20.28 1.30 1.14 18.71 21.55 2.13 75.0 97 93 124/70 1.55 18.50 1.31 1.2 32.43 30.65 1.89 85.0 86 95 110/60 1.61 19.42 1.25 1.26 28.17 31.02 2.00 90.0

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Nov 26, 2016 | Posted by in CARDIOLOGY | Comments Off on Effect of Ambrisentan on Exercise Capacity in Adult Patients After the Fontan Procedure

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