Preliminary study of the application of aniracetam in adult patients with Fontan circulation

Article from ~Chinese Cardiovascular Disease Research

Authors and Unit(s): Cardiac Surgery Catheterization Unit, Wuhan Asian Heart Hospital, Wuhan, Hubei, China (Xiao Ke Shang, Rong Lu, Shu Na Xiao, Gang Cheng Zhang, Chang Yu Qin, Chang Dong Zhang); ICU, Wuhan First Hospital, Wuhan, China (Mei Liu); Cardiology Catheterization Unit, Department of Cardiology, Hanzhong Railway Hospital, Hanzhong City, Shaanxi Province, China (Haitao Yin)

Fund project: National 12th Five-Year Plan Science and Technology Support Project (No. 2011BAI11B15)

The Fontan approach improves oxygen saturation, life expectancy and quality of life by introducing vena cava flow into the pulmonary circulation [1,2]. Numerous clinical studies have found that while Fontan-like procedures can provide these benefits to patients, exercise tolerance is significantly reduced in adult patients with Fontan circulation [3]. Several prospective studies using targeted therapeutic agents for pulmonary hypertension to reduce pulmonary artery pressure and total pulmonary resistance have shown some results [4,5]. Anrisentan, a classical drug for the treatment of severe pulmonary hypertension, is a selective endothelin receptor antagonist, approved for the treatment of severe arterial hypertension (PAH) disease and is recognized to improve hemodynamic indices and clinical symptoms in patients [6]. It also has a lower hepatotoxicity compared to bosentan [7], which is very beneficial in patients with Fontan circulation, where patients with high body venous pressure are present and are likely to have hepatic dysfunction. The main purpose of this pilot study was to investigate the safety of 6 months of treatment with aniracetam in adult patients with Fontan circulation.

1 Data and Methods

1.1 Study data Patients aged 18 years or older who underwent Fontan surgery at the Wuhan Asian Heart Hospital from January 2010 to June 2014 were selected. All enrollees had to meet the following criteria: New York cardiac function class I or II, and consent to participate in the 6-month study and all follow-up visits. Exclusion criteria: non-sinus rhythm, presence of hepatic and renal dysfunction, women preparing to become pregnant, and patients on or preparing to use other targeted drugs for pulmonary hypertension in the last 1 month. The study was approved by the Ethics Committee of the Wuhan Asian Heart Hospital, and all patients signed an informed consent form.

1.2 Trial design The study design was a prospective single-center open study for a total of 6 months. Venous hemoglobin (Hb), platelet count (PLT), alanine aminotransferase (ALT), creatinine (Cr), and transcutaneous oxygen saturation at rest were checked in all patients before the start of the trial. Patients received oral aniracetam 5 mg once/d at the start of the trial. the above tests were repeated on days 15, 30, 60, 120 and 180 at the start of the trial. Patients' 6 min walking distance (6MWT), Borg dyspnea index and New York Heart Association (NYHA) assessment were recorded at baseline and at month 6, and left ventricular ejection fraction was assessed by transthoracic cardiac echocardiography. Adverse events were monitored throughout the study.

Observations included primary and other observations. The primary observables were clinical adverse events, defined as serious changes in liver or renal function, or patients with significant abnormalities in other hematologic parameters that necessitated discontinuation of the drug, and hemodynamic deterioration that prevented continuation of the trial. Other observables included patient 6MWT, Borg dyspnea index and assessment of cardiac function in New York, and transthoracic cardiac echocardiography to assess changes in left ventricular ejection fraction.

1.3 Statistical methods SPSS 16.0 statistical software was used for data analysis. The measurement data were expressed as ±s with non-parametric test; the count data were expressed as rate, and the χ2 test was used for before and after control. p<0.05 was considered as a statistically significant difference.

2 Results

2.1 Screening Enrollment Forty-seven patients with Fontan circulation were screened at the Wuhan Asian Cardiology Hospital Preconditioning Center; only 12 patients met the enrollment criteria and 8 patients agreed to participate in this study. Two patients withdrew from the study at month 2 (both requested to withdraw for personal reasons unrelated to the trial); one patient withdrew from the study at month 3 (the patient had taken sildenafil once during the study). A total of 5 patients completed the 6-month study, and their baseline characteristics are shown in Table 1. 6 patients applied aniracetam 10 mg once/d during the study until the end of the study, with no dose adjustment and no provision for next drug therapy for enrolled patients.

2.2 Safety of Anrisentan Five study subjects completed the study. All patients showed no significant abnormalities in liver or kidney function, no significant decrease in hemoglobin or platelet count, and no significant decrease in oxygen saturation. One patient had a small pleural effusion detected during ultrasound examination during the study, which did not change significantly after increasing the diuretic dose, and the small amount of pleural effusion persisted until the end of the study in this patient and was not considered to be related to aniracetam. No patient presented with definite or specific symptoms. See Table 2.

2.3 Other results After 6 months of treatment with aniracetam, no statistical difference was seen in 5 patients6 MWD compared to the baseline data (P=0.69). borg dyspnea index 1.60±1.14, reduced from 2.60±1.82 in the baseline data (P=0.06). nyha classification 91.40±0.55, reduced from 1.80±0.45 in the baseline data (P=0.06) lower (P=0.06). No statistical difference was seen when comparing left ventricular ejection fraction values P=0.41. Comparing liver function (ALT), kidney function (Cr), whole blood cell Hb and PLT before and after treatment, no statistical difference was seen (P>0.05). However, in transcutaneous oxygen saturation test (SpO2), the baseline information was (94.2±2.59)% and after treatment was (98.00±2.12)%, and the difference was statistically significant when comparing the two (P=0.04).

3 Discussion

The number of patients undergoing Fontan surgery is increasing, and more and more studies are focusing on this particular circulatory modality. In addition to adequate ventricular preload and adequate cardiac output, a low pulmonary vascular resistance (PVR) is essential to maintain a good Fontan circulation. If PVR is increased postoperatively, complications such as low cardiac output and reduced exercise tolerance may occur [8]. Therefore controlling PVR in Fontan circulation is particularly important. This study is the first prospective study using selective endothelin receptor antagonists to control PVR in patients undergoing Fontan circulation in adults.

Table 1 Baseline information of 5 patients [±s, number of cases and percentage (%)

Note: ELT: extracardiac tunnel; LT: intraatrial tunnel; ECC: extraatrial conduit; 6MWT: 6-minute walking distance; ALT: alanine aminotransferase; Cr: creatinine; NYHA: New York Classification of Heart Function; SpO2: transcutaneous oxygen saturation; Hb: hemoglobin; PLT: platelet count

Table 2 Comparison with baseline information after 6 months of treatment (±s)

Preliminary study of the application of aniracetam in adult patients with Fontan circulation

Note: 6MWT: 6-minute walking distance; ALT: alanine aminotransferase; Cr: creatinine; NYHA: New York Classification of Heart Function; SpO2: transcutaneous oxygen saturation; Hb: hemoglobin; PLT: platelet count

Gewillig et al [8] concluded that elevated pulmonary vascular resistance may play a crucial role in the significant reduction of cardiac output in patients with Fontan circulation, and also high PVR may be associated with Fontan circulatory failure [9].The cause of progressively higher PVR in Fontan patients is not very precise and may be due to nonpulsatile blood flow in the pulmonary arteries, vascular abnormal expression of active substances of systole such as overexpression of endothelin-1 [10]. Qin Changyu et al [11] observed eight patients after Fontan surgery and found that ET-1 showed a dominant effect in patients after Fontan surgery extracorporeal circulation and may play an important role in the mechanism of vasoconstriction after Fontan surgery, while AM is involved in the protective mechanism after Fontan surgery.In 2009 Ovaert et al [12] studied the effect of bosentan on Fontan circulation The efficacy of bosentan in patients was included in a total of 10 patients with a mean time interval of 7.84 years from Fontan surgery to study entry.The participants received 4 weeks of half-dose bosentan treatment followed by a change to full maintenance for 12 weeks.Study metrics included oxygen saturation at rest and during exercise, blood biochemical tests, and patient's conscious symptoms, and evaluated 6 MWT at baseline, during the study, and 16 weeks after treatment.Results Oxygen saturation and exercise capacity were found to be significantly improved in five patients, and the use of bosentan was tentatively considered safe. 2012 Bowater et al [5] studied the safety and cardiac function status of 18 post-Fontan patients on endothelin receptor antagonists, with six patients eventually completing the study, three of whom had transient adverse events, mainly including mild leg edema , nausea, palpitations, and progressively worse dyspnea, but the investigators concluded that there was no correlation with bosentan treatment and no significant adverse events occurred, especially no abnormal liver function was found. The results of the study showed a statistically significant difference in the improvement of ventricular systolic function as observed by New York cardiac function classification and cardiac ultrasound in patients after 6 months of bosentan application. However, there were no changes in 6 MWT and respiratory function measurements. There is also a study [13] on the effect of bosentan in improving pulmonary vascular resistance and pressure in patients with functional single ventricle. The results of the study showed that mean pulmonary artery pressure, mean pulmonary vascular resistance index, and mean pulmonary vascular resistance/body circulation resistance were significantly reduced with bosentan, and all patients had significant clinical improvement and underwent successful second-stage Fontan surgery.

All of these studies mentioned above showed the safety and efficacy of the endothelin receptor antagonist bosentan before and after single-ventricle correction with ventricular double inlet, but all of them coincidentally mentioned the concern about the complication of bosentan liver function impairment, although the results of the studies did not show clear liver function abnormalities, but these studies were characterized by small study sample size, short study time, and small dose of bosentan administration. The strength of the evidence provided is not sufficient. In addition, the special circulation of the Fontan procedure makes it possible for patients to have complications of low cardiac output and hepatic stasis, and the use of bosentan in this setting may further increase the risk of hepatotoxicity. Therefore, it may be safer to use a selective endothelin receptor antagonist with a lower risk of hepatotoxicity, while still being able to exert endothelin receptor antagonism to suppress the increase in pulmonary vascular resistance. The main purpose of this study was to understand the safety of aniracetam in treating Fontan patients because it does not inhibit the bile salt output pump [14] and thus has a low incidence of abnormal liver function. We believe that aniracetam may benefit patients more.

After 6 months of application of aniracetam, the five patients who completed this study showed no significant abnormalities in liver function, nor in renal function or blood biochemistry. No other clinically significant adverse events associated with the use of aniracetam occurred during the study treatment period. Previous studies [12] reported that the most common adverse effects of long-term use of aniracetam were peripheral edema, headache, upper respiratory tract infection, and dizziness, and the incidence of liver function abnormalities at 1 and 2 years was only 1.8% and 3.9%. There was not a single case of similar complications in this study, and the results confirm that the safety profile of aniracetam is no worse than that of patients with Fontan circulation currently on bosentan. In addition, both Borg dyspnea score and NYHA FC showed a trend of improvement compared to the baseline data, although no statistical difference was seen between them, but both P values were close to 0.05, which may be related to the small sample size of the enrolled group, and it is believed that with the expansion of the sample size there may be a statistical difference between them. No statistical difference was seen in the change in left ventricular ejection fraction values, which was related to the conditions of screening for enrollment. The patients enrolled in this study were adults with cardiac function class I or II, and the baseline information on the left ventricular ejection fraction values themselves were in the normal range, and no significant changes in the left ventricular ejection fraction were found in the study at 6 months. The only change in this study was in the transcutaneous oxygen saturation measurements, which increased to varying degrees in all patients at 6 months after dosing, and all patients reached saturation in oxygen saturation, with 2 patients even reaching 100% SpO2, similar to some studies of bosentan in post-Fontan patients, showing the partial effectiveness of aniracetam.

The main limitation of this study was the relatively small number of patients enrolled. Compared to the current studies of selective endothelin receptor antagonists in Fontan patients, it is difficult to avoid the shortcomings of this study, including the small number of study subjects, short observation time, single-center provision, and non-randomized double-blind, thus providing a limited level of evidence. However, this trial is the first prospective study of a non-selective endothelial receptor antagonist, and we hope that the safety data obtained from the current study will provide assurance for future clinical trials.

Although limited by the small sample size, the results from our study are still encouraging. The application of aniracetam to this small sample of patients with Fontan circulation had a good safety and tolerability profile. Although no firm conclusions were drawn regarding the efficacy, especially without a placebo group for comparison, we at least observed that the application of aniracetam improved the hemodynamic trend and oxygen saturation of patients without serious adverse effects. We believe that a double-blind, randomized, placebo comparative study in Fontan patients is warranted. Our data support the view that the postoperative application of aniracetam in Fontan patients requires further study.

4 References

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[2] Liu Xiaobing, Chen Zaimei, Cen Jianzheng, et al. Modified Fontan procedure for direct connection between pulmonary artery and inferior vena cava. Chinese Journal of Thoracic and Cardiovascular Surgery, 2014, 30: 65-67.

[3]Diller GP,Giardini A,Dimopoulos K,et al.Predictors of morbidity and mortality in contemporary Fontan patients:results from a multicenter study including cardiopulmonary exercise testing in 321 patients.Eur Heart J,2010,31:3073-3083。

[4] Shang SK, Li YP, Liu M, et al. Effect of endothelin receptor antagonists on the medium and long-term prognosis of patients after Fontan surgery. Chinese Journal of Cardiovascular Diseases, 2013, 41: 1025-1028.

[5]Bowater SE,Weaver RA,Thorne SA,et al.The safety and effects of bosentan in patients with a Fontan circulation.Congenit Heart Dis,2012,7:243-249。

[6] Wen L, Jiang X, An P, et al. Long-term efficacy of anrisentan monotherapy in patients with pulmonary arterial hypertension. Chinese Journal of Cardiovascular Diseases, 2014, 42: 469-473.

[7]Oudiz RJ,Galiè N,Olschewski H,et al.Long-term ambrisentan therapy for the treatment of pulmonary arterial hypertension.J Am Coll Cardiol,2009,54:1971-1981。

[8]GewilligM,Brown SC,EyskensB,etal.TheFontan circulation:who controls cardiac output? Interact Cardiovasc Thorac Surg,2010,10:428-433。

[9]MitchellMB,CampbellDN,IvyD,etal.Evidenceof pulmonary vascular disease after heart transplantation for Fontan circulation failure.J Thorac Cardiovasc Surg,2004,128:693-702。

[10]Ishida H,Kogaki S,Ichimori H,et al.Overexpression of endothelin-1 and endothelin receptors in the pulmonary arteries of failed Fontan patients.Int J Cardiol,2012,159:34-39。

[11] Qin Changyu, Deng Xiaoxian, Shang Xiao Ke, et al. Alterations of plasma endothelin-1 and adrenomedullin after Fontan surgery. Chinese Cardiovascular Disease Research, 2015, 13: 75-78.

[12]Ovaert C,Thijs D,Dewolf D,et al.Het effect van bosentan bij patiënten met een falende Fontancirculatie.Cardiol Young,2009,19:331-339.

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[14]Fattinger K,Funk C,Pantze M,et al.The endothelin antagonist bosentan inhibits the canalicular bile salt export pump:a potential mechanism for hepatic adverse reactions.Clin Pharmacol Ther,2001,69:223-231.

Een vooronderzoek bij volwassen patiënten met Fontan-circulatie die Ambrisentan tabletten slikken

Shang Xiaoke, Lu Rong, Liu Mei, Yin Haitao, Xiao Shuna, Zhang Gangcheng, Qin Changyu, Zhang Changdong

[Abstract] Doelstelling Het onderzoeken van de veiligheid van de selectieve endotheline receptor antagonist aniracetam bij volwassen patiënten met een Fontan circulatie en het beoordelen van het effect op de hemodynamica van de patiënt. Methoden Zevenenveertig patiënten van 18 jaar of ouder die van januari 2010 tot juni 2014 een Fontan-operatie ondergingen in het Aziatische hartziekenhuis in Wuhan, werden geselecteerd voor een prospectieve open studie in één centrum met een totale duur van 6 maanden. Bij alle patiënten werden voor het begin van de proef het complete bloedbeeld, de leverfunctie, de nierfunctie en de transcutane zuurstofsaturatie in rust gecontroleerd; na het begin van de proef kregen de patiënten eenmaal daags 5 mg aniracetam oraal toegediend. Deze tests werden herhaald op dagen 15, 30, 60, 120 en 180 van de proef. De 6 min wandelafstand van de patiënten en de Borg dyspneu index en de beoordeling van de hartfunctie in New York werden geregistreerd op de basislijn en op maand 6, en de linker ventriculaire ejectiefractie werd beoordeeld met transthoracale cardiale echocardiografie. Ongewenste voorvallen werden gedurende het onderzoek gevolgd. De waarnemingen waren primaire en bijkomende waarnemingen, met inbegrip van klinische ongewenste voorvallen en hemodynamische beoordelingen. Resultaten In totaal hebben 5 patiënten de studie van 6 maanden voltooid en alle patiënten hebben geen bijwerkingen ondervonden. De transcutane zuurstofverzadiging was significant hoger dan voorheen, met een statistisch significant verschil (p=0,04), terwijl er geen statistisch significante verschillen werden gezien in enig ander opzicht. Conclusies De toepassing van aniracetam werd goed verdragen bij volwassen patiënten met een Fontan-circulatie gedurende een periode van 6 maanden. De veiligheid en verdraagbaarheid van aniracetam bij een grotere groep patiënten blijven echter onbekend en grotere studies zijn nodig.

[Sleutelwoorden] Fontan circulatie; selectieve endotheline receptor antagonisten; aniracetam; pulmonale arteriële druk; totale pulmonaire weerstand

Een vooronderzoek bij volwassen patiënten met Fontan-circulatie die Ambrisentan tabletten slikken

SHANG Xiao-ke*,LU Rong,LIU Mei,et al.*Cardiac Surgical Interventional Cath Lab Wuhan Asia Heart Hospital(Ninth Cath Lab),Wuhan 430022,China

【Abstract】 Doel Het primaire doel van deze studie was het bestuderen van de Fontan circulatie van volwassen patiënten met selectieve endotheline receptor antagonist "Ambrisentan tabletten", gevolgd door het beoordelen van hun invloed op de hemodynamica van de patiënt. Methoden Patiënten die ouder waren dan 18 jaar ondergingen een Fontan operatie in het Wuhan Asia Heart Hospital, de studieopzet was een prospectieve single-center open-label studie van in totaal zes maanden, alle patiënten voor het begin van de test om het complete bloedbeeld, de leverfunctie en nierfunctie, de transcutane zuurstofsaturatie in rust te controleren.Wanneer de test begon, moest de patiënt 5 mg Ambrisentan tabletten oraal innemen, eenmaal per dag. Deze controles in de vijftiende dagen na het begin van de test, 30 dagen, 60 dagen, 120 dagen en 180 dagen moeten herhaald worden. De 6 minuten wandelafstand en de Borg dyspnea index en de New York Heart Association functionele beoordeling, transthoracale echocardiografie om de ventriculaire ejectiefractie te beoordelen op de basislijn en de zesde maand, het monitoren van ongewenste voorvallen gedurende de studie.Observatie-indexen met inbegrip van de belangrijkste observatie-indexen en andere indexen, met inbegrip van klinische ongewenste voorvallen en hemodynamische evaluatie.Resultaten Een totaal van 5 patiënten voltooide 6 maanden van de studie, alle patiënten zonder ongewenste voorvallen. De transcutane zuurstofsaturatie vertoonde een duidelijke stijging ten opzichte van de vorige, het verschil was statistisch significant (P=0,04), er waren geen statistisch significante verschillen in andere aspecten. Conclusie Binnen zes maanden hadden volwassen patiënten met Fontan circulatie die Ambrisentan tabletten innamen een betere verdraagbaarheid.Maar in een grotere groep patiënten zijn de veiligheid en verdraagbaarheid van Ambrisentan tabletten nog steeds onbekend, er is behoefte aan grotere studies.

Kernwoorden. Fontan circulatie; Selectieve endotheline receptor antagonist; Ambrisentan tabletten;Pulmonale arteriële druk;Totale pulmonale weerstand

Fundamenteel project: Nationaal Ondersteuningsproject voor wetenschap en technologie in het kader van het 12e vijfjarenplan (nr. 2011BAI11B15)

Auteurs: Cardiac Surgery Catheterization Unit, Wuhan Asian Heart Hospital, Wuhan, Hubei, 430022, China (Shang Xiao Ke, Lu Rong, Xiao Shuna, Zhang Gangcheng, Qin Changyu, Zhang Changdong); ICU, Wuhan First Hospital, Wuhan, China (Liu Mei); Cardiology Catheterization Unit, Department of Cardiology, Railway Hospital, Hanzhong City, Shaanxi Province, China (Yin Haitao)

doi: 10. 3969/j. issn. 1672-5301. 2015. 04. 004

CICS R654.2

Artikelnummer: 1672-5301 (2015) 04-0303-05

(datum van ontvangst: 2015-01-16)