Benefits of Long-Term Combination Therapy with Sildenafil Citrate and Beraprost Sodium in a Dog with Pulmonary Hypertension

doi:10.21203/rs.3.rs-5258608/v1

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Case Report

Benefits of Long-Term Combination Therapy with Sildenafil Citrate and Beraprost Sodium in a Dog with Pulmonary Hypertension

https://doi.org/10.21203/rs.3.rs-5258608/v1

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Background

Pulmonary hypertension, defined as sustained elevated pulmonary artery pressure, can lead to right-sided heart failure if untreated. While sildenafil citrate is a common treatment, recent findings suggest that its combination with beraprost sodium may enhance therapeutic efficacy in human medicine. This case report describes the successful management of canine pulmonary hypertension using combination therapy and suggests potential efficacy in veterinary medicine.

Case presentation

A 12-year-old, spayed female, Pekingese dog was referred to a veterinary medical teaching hospital owing to frequent episodes of syncope and exercise intolerance. On thoracic auscultation, a grade 4 heart murmur was detected on both sides of the chest, along with respiratory sinus arrhythmia. An electrocardiogram showed a right axis deviation, suggesting possible right ventricular hypertrophy. There were no abnormalities in heart size on thoracic radiographs. An increased contact area was observed between the sternum and the right heart in the lateral view owing to the enlarged right-sided heart. No significant pulmonary infiltration, tracheal collapse, or bronchial collapse was observed. Echocardiography revealed moderate tricuspid regurgitation and severe pulmonary hypertension. Based on clinical signs and diagnostic findings, the diagnosis was right-sided heart failure caused by brachycephalic obstructive airway syndrome (BOAS). The initial treatment plan included sildenafil citrate at 2mg/kg PO bid, pimobendan at 0.3mg/kg PO bid, enalapril at 0.5mg/kg PO bid, and furosemide at 1mg/kg PO bid. Despite taking medications for three months, the frequency of syncope episodes remained unchanged, and the pulmonary hypertension failed to improve. Therefore, beraprost sodium, a prostacyclin analog, was added to the treatment regimen. Thereafter, the dog’s clinical signs of syncope significantly improved, although the echocardiographic findings showed no change in tricuspid regurgitation and the severity of pulmonary hypertension (velocity 4.42m/s, pressure gradient 78.2mmHg). The dog maintained these improved clinical signs for 12 months, with a combination of sildenafil citrate at 3 mg/kg PO bid and beraprost sodium at 20 µg/kg PO bid.

Conclusions

This study showed that combining beraprost sodium with sildenafil significantly improved clinical symptoms in cases where sildenafil alone was ineffective, with no adverse effects observed over an extended treatment period.

beraprost sodium

dog

pulmonary hypertension

sildenafil citrate

Pulmonary hypertension is defined as the sustained elevation of blood pressure within the pulmonary vascular system [1]. In humans, it refers to a sustained condition where pulmonary artery pressure (PAP) exceeds 25 mmHg at rest, measured directly through right heart catheterization [2]. However, in veterinary medicine, owing to the invasive nature of catheterization and the associated anesthesia risks, echocardiography is often preferred for diagnosing pulmonary hypertension when the pressure exceeds 30 mmHg [3, 4]. If left untreated, pulmonary hypertension can progress to right-sided heart failure, leading to clinical symptoms such as syncope and exercise intolerance [5].

If pulmonary hypertension is diagnosed, appropriate medications should be administered to reduce PAP and prevent its progression to right-sided heart failure [6]. In veterinary medicine, sildenafil citrate is commonly used to treat pulmonary hypertension [6]. It inhibits the action of phosphodiesterase-5 (PDE5), an enzyme that breaks down cyclic guanosine monophosphate, leading to the relaxation of smooth muscles [7]. Numerous studies have reported that sildenafil citrate effectively lowers PAP and improves clinical symptoms in dogs with pulmonary hypertension [6, 7, 8].

Recent reports have shown that mutations in the PDE5A gene may affect the efficacy of sildenafil citrate as a treatment for pulmonary hypertension [9]. In human medicine, it has been reported that a combination of sildenafil citrate and beraprost sodium, which have different mechanisms of action, improved symptoms in patients with pulmonary hypertension [10]. Beraprost sodium, an analog of prostacyclin PGI2, promotes vasodilation, thereby reducing blood pressure [11]. In veterinary medicine, beraprost sodium has been reported to be effective in treating canine pulmonary hypertension and improving cardiac function [12, 13].

This report presents a unique case in which the combined administration of sildenafil and beraprost sodium resulted in significant clinical improvement, with no notable adverse effects observed despite the prolonged use of both medications for over a year.

A 12-year-old, spayed female, Pekingese dog weighing 5.21 kg was referred to a Veterinary Medical Teaching Hospital owing to frequent syncope and exercise intolerance. Medical history revealed that the dog experienced an average of two episodes of syncope per day, accompanied by exercise intolerance. There were no other notable clinical symptoms, such as coughing, nasal discharge, or dyspnea, and the dog was receiving heartworm prevention medication every month. Physical examination showed a blood pressure of 140 mmHg, and the dog was noted to be overweight, with a body conditions score of 6/9.

On thoracic auscultation, a grade 4 heart murmur was detected on both sides of the chest, along with respiratory sinus arrhythmia. The electrocardiogram showed a right axis deviation, suggesting possible right ventricular hypertrophy. Thoracic radiographs showed that accurate assessment was limited owing to the presence of pectus excavatum, but the intercostal space was 3.2, vertebral heart score was 9, and vertebral left atrial size was 2.1, all within normal ranges. In the lateral view, an increased contact area was observed between the sternum and the enlarged right-sided heart. No significant pulmonary infiltration, tracheal collapse, or bronchial collapse was observed (Figs. 1A and 1B). An echocardiographic study ruled out, congenital shunt, left-sided heart disease and heart worm disease (Fig. 2A). The echocardiogram showed no cardiac remodeling, with a low left atrium to aorta ratio of 1.07, a left ventricular internal dimension during diastole of 0.841, and no evidence of mitral valve disease (Fig. 2B and 2C). However, there was reduced systolic function, indicated by a low fractional shortening of 23.9% (reference range: 33%-46%; Fig. 2C). In addition, moderate tricuspid regurgitation was observed, filling approximately 50% of the right atrium during systole. The peak tricuspid regurgitation velocity measured 4.48 m/s, corresponding to a tricuspid pressure gradient of around 80.4 mmHg, classifying the case as severe pulmonary hypertension (Fig. 2D).

Blood tests revealed a normal platelet count of 385 K/µL (reference range: 148–484 K/µL), and coagulation factors (prothrombin time, activated partial thromboplastin time, D-dimer test) showed no remarkable findings. Based on the findings from thoracic radiography and blood tests, the possibility of pulmonary emboli, thrombi, or thromboemboli was excluded.

Based on clinical signs and diagnostic findings, the dog was diagnosed with right-sided heart failure with severe pulmonary hypertension induced by brachycephalic obstructive airway syndrome (BOAS). The treatment started with the administration of a selective PDE5 inhibitor (sildenafil citrate, 2 mg/kg PO bid; Palpal®, Hanmi, Pharmaceuticals) and heart failure medications, including pimobendan at 0.3 mg/kg PO bid (Vetmedin®, Boehringer Ingelheim), enalapril at 0.5 mg/kg PO bid (Enalapril maleate, CMG Pharmaceuticals), and furosemide at 1 mg/kg PO bid (Lasix®, Handok Pharmaceuticals). Despite taking medications for one month, there was no improvement in clinical symptoms; therefore, sildenafil citrate was increased to 3 mg/kg PO bid. However, over the following two months, the frequency of syncope episodes remained unchanged, and the severity of pulmonary hypertension did not improve. Consequently, beraprost sodium (Unibuerger®, Unimed Pharmaceuticals), a prostacyclin analog, was administered at 2 µg/kg PO bid and gradually increased to 20 µg/kg PO bid. After adding beraprost sodium, there was a significant improvement in the clinical signs of syncope, but echocardiographic findings showed no change in tricuspid regurgitation velocity (4.42m/s, pressure gradient 78.2mmHg) and severity of pulmonary hypertension (Fig. 3A).

In combination with sildenafil citrate at 3 mg/kg PO bid and beraprost sodium at 20 µg/kg PO bid, the dog has experienced no syncope episodes in the past two months, and echocardiographic findings show slight improvements in tricuspid regurgitation velocity (4.2 m/s, pressure gradient 70.6 mmHg) and severity of pulmonary hypertension (Fig. 3B). The dog had maintained improved clinical signs of syncope with no side effects for 12 months preceding the writing of this article (Fig. 4).

This study demonstrated the efficacy of beraprost sodium in treating canine pulmonary hypertension in cases where sildenafil citrate prescriptions failed to improve clinical symptoms. According to the ACVIM consensus classification, sildenafil citrate is effective in managing group 3 pulmonary hypertension, and its administration in dogs with this condition has been shown to improve clinical symptoms [5, 7]. However, recent reports have shown that the PDE5A mutation may affect the effectiveness of sildenafil citrate in treating pulmonary hypertension [9]. In such cases, other treatments such as ambrisentan or beraprost sodium have been used in dogs [12, 13, 14]. Beraprost sodium, a prostacyclin analog, induces vasodilation and reduces pulmonary blood pressure [11]. In veterinary medicine, beraprost sodium has been reported to effectively treat canine pulmonary hypertension and improve cardiac function without adverse effects. In contrast, its use in cats has been associated with side effects such as diarrhea, vomiting, sedation, increased heart rate, and decreased serum creatinine levels [12, 13, 15]. In the present study, beraprost sodium was administered in gradually increasing doses up to a maximum dose of 20 µg/kg PO bid for over a year, resulting in improved clinical symptoms without any side effects.

Pulmonary hypertension causes an overload on the right ventricle, which subsequently decreases cardiac output and can lead to episodes of syncope in affected patients [16]. A recent study reported that syncope was the most common complaint (16/25; 64%) in dogs with respiratory-associated pulmonary hypertension [17]. Treating the underlying respiratory disorder can help alleviate clinical symptoms and slow the progression of pulmonary hypertension [5]. In addition, weight loss in obese dogs can improve clinical signs by improving thoracic wall compliance and reducing extrathoracic and intra-abdominal adipose tissue, which can contribute to the condition [18]. Early surgical correction of upper airway obstruction components in dogs, especially those with BOAS, is essential to minimize the progression of clinical symptoms and prevent the potential development of pulmonary hypertension [19]. PDE5 inhibitors are recommended as a specific treatment for pulmonary hypertension for dogs classified in group 3 [6, 8, 17]. Pulmonary hypertension in dogs can be monitored by measuring PAP using echocardiography and assessing improvements in clinical symptoms [5]. However, it is important to note that improvements in echocardiographic indices do not always correlate with clinical symptom improvement in affected dogs [7]. Similarly in humans, the correlation between PAP and clinical signs is weak, and it is not advisable to rely solely on PAP as a variable for treatment evaluation [20]. Therefore, it is advised to prioritize clinical evaluations including exercise tolerance, syncope frequency, and functional assessments of cardiac health, when evaluating treatment response and marking decisions about treatment adjustments [21]. In the present study, dogs with group 3 pulmonary hypertension experienced frequent syncope as a primary symptom. After finding no therapeutic effect with sildenafil citrate alone, the addition of beraprost sodium resulted in a significant reduction in the frequency of syncope episodes.

The present report has one limitation. The frequency of syncopal episodes was assessed solely on caregiver interviews. While the exact numbers may not be precise, caregivers initially reported an average of two syncopal episodes per day before the addition of beraprost sodium. Following its introduction, caregivers noted a significant reduction in these episodes. Despite this limitation, the sharp decrease in the frequency of syncopal episodes before and after the administration of beraprost sodium is considered meaningful. Therefore, this report establishes the clinical effectiveness of a combination of beraprost sodium and sildenafil citrate in dogs with pulmonary hypertension.

In conclusion, sildenafil citrate is the primary treatment for pulmonary hypertension in veterinary medicine. However, this study showed that combining beraprost sodium with sildenafil significantly improved clinical symptoms in cases where sildenafil alone was ineffective, with no adverse effects observed over an extended treatment period.

PAP

Pulmonary artery pressure

PDE

Phosphodiesterase

BOAS

Brachycephalic obstructive airway syndrome

Ethics approval and consent to participate

Not applicable

Consent for publication

Written informed consent was obtained from the dog’s owner.

Availability of data and materials

All Data supporting our findings are included in this study.

Competing interests

The authors declare that they have no competing interests

Funding

This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Education (NRF-2023R1A2C1005348).

Authors' contributions

KH. J was the main contributor to the writing of the manuscript. KH. J, SB. C, SJ. O, JW. H, SY. K and HJ. K performed the study. KH. J, SB. C, and HJ. K analyzed the data and conducted clinical management of the case. HJ-K supervised the case management, edited the manuscript. All the authors have read and approved the final version of the manuscript.

Acknowledgement

The authors are grateful to the dog and the dog owner for participating in our report. Also, the authors would like to express their appreciation to the reviewers and editors for their insightful feedback.

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You are reading this latest preprint version

Benefits of Long-Term Combination Therapy with Sildenafil Citrate and Beraprost Sodium in a Dog with Pulmonary Hypertension

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Abstract

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Background

Case presentation

Discussion and conclusions

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