*Corresponding author: Woo-Jin Song Signature Animal Medical Center, Seoul 06026, Korea Introduction
Pulmonary hypertension (PH) is the abnormally increased pressure within the pulmonary vasculature caused by increased pulmonary blood flow, increased pulmonary vascular resistance, increased pulmonary venous pressure, or a combination thereof [1]. In human medicine, PH is defined as a mean pulmonary arterial pressure of > 20 mmHg at rest, which is directly assessed by right heart catheterization (RHC) [2]. However, in veterinary medicine, as RHC is not routinely performed, echocardiographic evaluation is considered for patients with PH-related clinical symptoms to assess the probability of PH [1]. In humans, PH is classified into 5 groups according to the underlying diseases: pulmonary arterial hypertension (group 1), left heart disease (group 2), lung diseases and/or hypoxia (group 3), pulmonary arterial obstruction such as chronic thromboembolism (group 4), and unclear and/or multifactorial mechanisms (group 5). In veterinary medicine, these categories are expanded to include parasitic causes as a separate fifth group, with unclear or multifactorial conditions designated as group 6 to avoid overlap [1].
According to this veterinary classification, PH was diagnosed based on clinical findings and echocardiography. Dogs presenting with syncope, tachypnea, exercise intolerance, or cyanotic/pale mucous membranes underwent Doppler assessment of peak tricuspid regurgitation velocity (TRV) and evaluation of right heart enlargement to support the diagnosis of PH [1].
Treatment of PH includes management of the underlying disease and adjunctive pharmacotherapy [1,2]. Phosphodiesterase type 5 (PDE5) inhibitors are recommended as first-line therapy in human guidelines, with demonstrated efficacy and tolerability [1]. PDE5 inhibitors act by regulating the intracellular concentration of cyclic guanosine monophosphate (cGMP), which is involved in the nitric oxide pathway and plays a key role in smooth muscle cell relaxation [3,4]. When intracellular cGMP levels increase, cGMP binds to PDE5, and the cGMP concentration is lowered. This interferes with this action by competitively binding to PDE5 inhibitors, which are structurally similar to cGMP, at the binding site of cGMP on PDE5 [3,4].
The 2 PDE5 inhibitor drugs currently used in dogs are sildenafil and tadalafil [1]. Of these, sildenafil is usually selected as the first-line PDE5 inhibitor to treat PH and has been studied extensively, whereas tadalafil has been newly introduced, with a limited number of studies [1]. This study aimed to evaluate the clinical efficacy and tolerability of tadalafil for the management of PH in dogs, and to clarify whether tadalafil can serve as a viable alternative to sildenafil by providing comparable or superior therapeutic outcomes when underlying diseases are appropriately managed. We hypothesized that tadalafil, with its longer dosing interval and potential for improved compliance, would demonstrate effective control of clinical symptoms associated with PH in dogs.
Materials and Methods
Animals, inclusion, and exclusion criteria
The electronic medical records (EMRs) of the Veterinary Medical Teaching Hospital of Jeju National University were searched using the keyword, “tadalafil”. Records from January 2021 to July 2023 were evaluated and data on patients with a history of tadalafil use collected. The patient inclusion criteria were client-owned dogs diagnosed with PH and a history of tadalafil therapy. Dogs treated with tadalafil within 4 weeks or with insufficient chart information for PH diagnosis or suspicion were excluded.
PH diagnosis
The diagnostic criteria for PH were based on the American College of Veterinary Internal Medicine (ACVIM) consensus statement for canine PH [1]. Dogs showing clinical signs related to PH received an echocardiographic evaluation of the right parasternal and left apical views to estimate peak TRV (m/s) and anatomic signs of PH were considered and then evaluated for the echocardiographic probability of PH, which was performed by veterinarians under the guidance of a specialist, who is a diplomate of the Korean College of Veterinary Internal Medicine.
Dogs with PH were then classified into the following 6 groups depending on the underlying diseases that caused PH: group 1, pulmonary arterial hypertension; group 2, left heart disease; group 3, respiratory disease, hypoxia, or both; group 4, pulmonary thromboembolism; group 5, parasitic disease (i.e., heartworm infection); and group 6, multifactorial or unclear mechanisms.
Tadalafil administration and monitoring
For dogs with a history of tadalafil use for PH management, the initial dose of tadalafil was 1 mg/kg q24h (every 24 hours, Gugu-tablet; Hanmi Pharmaceutical Co.). Evaluation of the adverse effects and clinical efficacy of tadalafil administration was based on patient history and physical examination.
Results
A total of 16 dogs were diagnosed with PH and had a history of tadalafil administration were identified on the keyword search and enrolled. Among them, 5 dogs were excluded for the following reasons: dosing period of tadalafil within 4 weeks (n = 4) and insufficient chart information to support a diagnosis of PH (n = 1) (Fig. 1). As a result, 11 dogs were included in the study with signalment features described in Table 1. The patients had a mean age of 11.2 years (7.0-15.1 years), mean body weight of 6.0 kg (2.2-25.2 kg), and sex distribution consisting of 5 castrated males and 6 spayed females. Except for an Alaskan malamute, 10 dogs were small breeds, including Maltese, Shih-tzu, Pomeranian, Toy poodle, and Pug. Eleven dogs had underlying diseases such as atrioventricular block (n = 2), chronic kidney disease (n = 4), cognitive dysfunction syndrome (n = 2), chronic pancreatitis (n = 1), pyoderma (n = 1), urethral calculi (n = 1), perineal hernia (n = 1), proteinuria (n = 1), gallbladder mucocele (n = 2), and keratoconjunctivitis sicca (n = 1) (Table 1).
The clinical symptoms related to PH are presented in Table 2. The dogs were classified into 4 PH groups based on their underlying diseases: group 2 (n = 2), group 3 (n = 5), group 4 (n = 1), and group 6 (n = 3). Both left heart disease and respiratory disease were common contributors to PH in this cohort. No dogs were in group 1 or group 5.
Regarding tadalafil administration, 10 dogs were converted from sildenafil, with one patient receiving tadalafil as the first choice due to the side effects associated with sildenafil. The patients were switched to tadalafil because sildenafil provided no improvement in clinical signs (n = 7), for convenience, to increase administration intervals (n = 2), or for unknown reasons (n = 1). Among the 10 dogs, only one dog with sildenafil side effects had a washout period of sildenafil.
The initial dosage of tadalafil was 1 mg/kg q24h in 11 dogs, and 7 dogs received dosage control or discontinuation of the drug due to insufficient efficacy or adverse events. The final mean dosage was 1.18 mg/kg q24h, ranging from 1 mg/kg q48h to 1.5 mg/kg q24h. The mean administration period was 274 days (range, 28-685 days). For 2 dogs whose final administration period was difficult to confirm due to the loss to follow-up information, the administration period was calculated until the last visit date.
Clinical remission was assessed based on owner-reported improvement corroborated by veterinary physical examination. Complete remission was defined as the absence of all PH-related clinical signs (syncope, respiratory distress, exercise intolerance, tachypnea) for ≥4 weeks, with normal mucous membrane color and no respiratory effort at rest. Partial remission was defined as a ≥ 50% reduction in symptom frequency and severity, permitting occasional mild signs but reflecting a significant improvement in quality of life. Remission status was evaluated at each follow-up visit, with the final classification assigned at the end of the monitoring period. Adverse effects of tadalafil were observed in only one dog, which exhibited nausea that persisted for approximately 2 to 3 weeks despite dose reduction.
According to the history of clinical signs, 7 dogs achieved remission (partial to complete), whereas 4 dogs showed no improvement, indicating a promising remission rate in this limited sample. Importantly, 8 of the 11 dogs (72.7%) were receiving concurrent medications for underlying causes of PH at the time tadalafil therapy was initiated—specifically, sildenafil (n = 4), pimobendan (n = 5), furosemide (n = 4), enalapril (n = 1), spironolactone (n = 1), theophylline (n = 2), and prednisolone (n = 1). None of the dogs received sildenafil and tadalafil concurrently; in all cases, sildenafil was discontinued before starting tadalafil. Because these agents can independently improve hemodynamics or respiratory signs, their concomitant use may have contributed to the observed clinical responses, and thus the true magnitude of tadalafil’s benefit should be interpreted within this multidrug treatment context.
Discussion
In human medicine, the PDE5 inhibitors sildenafil, tadalafil and vardenafil have been studied as PH therapeutic drugs [5]. Among them, vardenafil has been used more recently and its clinical efficacy and safety have been demonstrated [6,7]. Sildenafil and tadalafil are mainly used to treat PH in humans and are mentioned in the European Society of Cardiology/European Respiratory Society guidelines (ESC/ERS) [2]. The rate of mention and frequency of use of sildenafil were overwhelmingly higher than those of tadalafil, which may be due to differences in the timing of drug development.
Sildenafil, developed by Pfizer (USA) in 1986, was approved by the Food and Drug Administration (FDA) as a treatment for erectile dysfunction under the product name Viagra in 1998, and by the FDA in 2005 as a treatment for pulmonary arterial hypertension under the product name Revatio. Tadalafil, developed by Eli Lilly and Company (USA) in 2003, has been applied as a PH treatment since 2009, when was licensed by the FDA as a treatment for pulmonary arterial hypertension under the product name Adcirca in 2009. Therefore, owing to this difference in development time, sildenafil has been studied more extensively and is more commonly used [8-10]. In the ACVIM consensus, sildenafil has been well studied and is commonly used to treat canine PH. However, tadalafil is a relatively recent drug with advantages as an alternative to sildenafil [1].
In humans, several studies have been conducted on the clinical tolerance and efficacy of switching from sildenafil to tadalafil in patients [11-17]. In one study, the reasons for converting sildenafil to tadalafil included the convenience of increasing the administration interval, insufficient efficacy of sildenafil, adverse effects of sildenafil, and cost problems [12]. Among these reasons, the most attractive is the convenience of longer dosing intervals than sildenafil, which is supported by the longer half-life of tadalafil compared to sildenafil [18]. The reasons for conversion in our retrospective study were similar to those reported in previous studies.
In humans, the ESC/ERS guidelines for PH recommend that risk assessment be conducted using the World Health Organization functioning class, 6-minutes walking test, and blood concentration of brain natriuretic peptide (BNP) or pro-BNP as prognostic factors when evaluating the prognosis of patients with PH [1]. In veterinary medicine, PH prognosis is evaluated mainly by monitoring clinical symptoms, whereas monitoring echocardiographic parameters is not essential as they may not be consistent with changes in clinical symptoms. However, unlike in human medicine, there is a paucity of studies evaluating pro-BNP as objective prognostic biomarkers in dogs with PH, and further research is needed to clarify their clinical utility in veterinary practice.
A previous pilot study compared the clinical efficacy of tadalafil and sildenafil in canine PH, where 11/21 dogs were administered tadalafil at a dose of 2 mg/kg q24h [19]. As a result, there was a significant improvement in the quality of life, while hemodynamic parameters showed no significant improvement [19]. There was also no significant difference in efficacy between sildenafil and tadalafil, and adverse effects were observed in 5 dogs [20]. Compared to this previous study, there were differences with our study, including an initial dosage of 1 mg/kg q24h, a monitoring period of at least 4 weeks, and a lower frequency of side effects. The lower incidence of adverse effects in our study may be due to the administration of a lower dose of tadalafil.
Four dogs (#1, 5, 6, and 11) did not show clinical remission, which may have been to an underlying disease that was not sufficiently managed, or another underlying disease that may have caused the symptoms to occur concurrently. In dog 1, there was insufficient remission due to myxomatous mitral valve degeneration with atrioventricular block, which seems to be another cause of syncope. In dog 5, due to its breed-specific nature, it is assumed that the narrow brachycephalic airway itself continuously causes hypoxia, inhibiting the adequate management of symptoms. Dog 6 was suspected to have laryngopharyngeal disease as the cause of non-remission of clinical symptoms, but the owner did not agree to intensive examination for diagnosis. Finally, dog 11 had pulmonary thromboembolism as an underlying disease of PH and was nonresponsive to thromboprophylactic agents.
Limitations of this study include (1) the relatively small sample size and heterogeneity of cases, as underlying causes of PH varied among individuals; (2) the absence of a control group (e.g., sildenafil‐treated cohort) to support causal conclusions; (3) the potential confounding effect of concurrent medications for underlying cardiac or respiratory conditions; and (4) variability in tadalafil dosing protocols (once‐daily versus every‐other‐day administration), which may have influenced drug exposure and clinical outcomes, similar to findings in human PH studies demonstrating dose‐related efficacy and tolerability differences. In addition, because standardized quantitative assessment tools and serial measurements of imaging and blood biomarkers (including NT‑proBNP) were not consistently available in this retrospective dataset, treatment response was primarily evaluated based on clinical symptom changes, limiting objective assessment of tadalafil efficacy and adverse effects.
As mentioned, ACVIM consensus suggests that PH prognosis should be evaluated mainly by monitoring clinical symptoms, and it is also said that Function EvaluaTion of Cardiac Health (FETCH) scoring could be beneficial [1,20]. The previous pilot study used FETCH scoring so that they could quantify the clinical efficacy [19]. In our study, however, there were insufficient medical records to use FETCH scoring or create our own scoring criteria. Therefore, studies on consistent therapeutic applications and the quantitative evaluation of clinical efficacy using a larger population and various dosages of the drug are needed.
In conclusion, this study showed that in PH dogs, mainly small breeds, if the underlying disease is properly managed, tadalafil administration with 1 mg/kg q 24h might be well-tolerated, effective, and more convenient than sildenafil with longer interval.
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