Background: Vardenafil is a new phosphodiesterase-5 inhibitor that has shown some efficacy in the treatment of pulmonary arterial hypertension (PAH).
Objective: To examine the long-term effects of vardenafil in patients with PAH.
Methods: A multicentre, open-label study of 1-year’s duration was undertaken in 45 patients with PAH to determine the long-term safety and efficacy of vardenafil (5 mg once daily for the first 4 weeks, then 5 mg twice daily) and make a preliminary assessment of its monthly acquisition cost compared with other PAH-active treatments. The patients’ clinical features, exercise capacity, WHO functional class and haemodynamic variables were measured at baseline and at 3 and at least 9 months after initiating vardenafil treatment.
Results: At the 3 months and a mean (SD) of 14 (3) months (range 9–18) follow-up assessments, the 6 min walking distance was significantly increased from baseline by 70.7 (78.4) m (p<0.001) and 83.4 (91.8) m (p<0.001), respectively. Furthermore, long-term treatment with vardenafil for a mean duration of >1 year was also associated with improvements in haemodynamic parameters, WHO functional class and serum uric acid concentrations. Overall, vardenafil treatment was well tolerated. No patients were withdrawn owing to adverse events and none died during the course of the study.
Conclusion: Long-term treatment with vardenafil is well tolerated and has sustained beneficial effects on PAH, as measured by patients’ exercise capacity, WHO functional class and haemodynamic parameters.
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Pulmonary arterial hypertension (PAH) is a progressive disease characterised by an elevation of pulmonary artery pressure and pulmonary vascular resistance, ultimately leading to right ventricular failure and death. Currently, the efficacy of several drugs in PAH has been established. These treatments include prostanoids,1 2 3 endothelin receptor inhibitors,4 5 6 and phosphodiesterase-5 (PDE5) inhibitors.7 8 PDE5 is a phosphodiesterase isoenzyme that degrades cyclic guanosine monophosphate (cGMP) causing constriction of blood vessel walls.9 10 Sildenafil, a widely used PDE5 inhibitor, has gained recognition as a useful oral treatment option for PAH.7 8 11 12 Based on its favourable effects in patients with PAH, sildenafil was approved by the FDA and the EMEA in 2005 for the treatment of symptomatic PAH.
Recently, a new PDE5 inhibitor, vardenafil was approved for the treatment of erectile dysfunction. Vardenafil is significantly more potent than sildenafil in inhibiting PDE5 and may therefore have a more favourable clinical profile.13 Ghofrani et al14 reported that with short-term use in patients with PAH, vardenafil appeared to lack specificity for the pulmonary circulation despite inducing significant pulmonary vasorelaxation. Currently, the efficacy and safety of mid- to long-term vardenafil treatment in patients with PAH has only been examined in case reports,15 which had insufficient power and sample size. Consequently, it is still unclear whether vardenafil is an effective and well-tolerated treatment for PAH.
The aim of this study was to investigate whether vardenafil can safely improve the functional capacity and haemodynamic parameters of patients with PAH over the course of about 1 year. As PAH-active treatments such as bosentan and iloprost are quite expensive in China and patients are not reimbursed for such treatment, a secondary objective of the study was to compare the monthly acquisition cost of vardenafil with that of comparator drugs to make a preliminary assessment of whether it might prove a more affordable treatment option in China and other developing countries.
A long-term, open-label study was conducted at five pulmonary vascular or cardiovascular centres in China during October 2006 to January 2008. The study protocol was reviewed and approved by ethics committees at local centres, and written informed consent was obtained from all patients who were enrolled.
The study included patients with PAH who were admitted for diagnosis and treatment to the participating study centres. To make the patient population as homogeneous as possible, only those with idiopathic PAH (sporadic or familial), advanced pulmonary vasculopathy associated with connective tissue disease and congenital heart disease, or portopulmonary hypertension were included. Patients with chronic pulmonary obstruction, chronic pulmonary thromboembolism and pulmonary hypertension associated with left heart disease were excluded. A mean pulmonary artery pressure (mPAP) >30 mm Hg and pulmonary vascular resistance (PVR) >5 Wood units at rest in the presence of a normal pulmonary capillary wedge pressure (PCWP; <15 mm Hg) measured during cardiac catheterisation before the study were criteria for inclusion. Patients with WHO functional class II–IV were permitted to enter the study if their disease was stable. Patients were enrolled if they were able to walk a maximum of 550 m during a 6 min walk test, but we did not establish any lower limit for inclusion.
During the study, patients continued to receive conventional treatment (including diuretics, warfarin, digoxin or supplemental oxygen) if necessary. However, no vasodilators other than vardenafil were permitted at least 3 months before or during the study. In particular, prostacyclin analogues, bosentan and sildenafil were not given to any patient.
Patients who met the inclusion criteria were hospitalised in one of the study centres for pretreatment (baseline) evaluation, which consisted of history, physical examination, echocardiography, ECG, chest x-ray examination, nuclear ventilation-perfusion scan, chest computed tomography scan and a 6 min walk test. All patients underwent diagnostic cardiac catheterisation. Patients were given vardenafil 5 mg orally daily for 1 month after which the dosage was increased to 5 mg orally twice daily if no significant adverse events occurred. Subsequent evaluations included assessment of the WHO functional class and exercise capacity at 3 months and a complete re-evaluation at 9–18 months. All patients continued to receive vardenafil after the end of the study period.
WHO functional class and exercise capacity
The 6 min walk test was performed according to a standardised protocol at baseline and after 3 and at least 9 months of vardenafil treatment. Subjects were asked to walk and cover as much ground as possible in 6 min. The patients’ WHO functional class was also evaluated at baseline and at 3 months and at least 9 months.
To characterise the baseline haemodynamic profile and the haemodynamic response to oral vardenafil treatment, all patients underwent right heart catheterisation and were scheduled to repeat the procedure after 9 months. This was performed via the right internal jugular or left antebrachial veins using a 7F Swan-Ganz catheter (7F, 131HF7P; Edwards Lifesciences World Trade, USA). Measurement of systemic blood pressure and arterial blood gases was performed via an arterial line inserted into the radial artery. Cardiac output (CO; which was measured in triplicate by the thermodilution technique with ice-cold isotonic sodium chloride solution), cardiac index (calculated by dividing CO by body surface area), systemic blood pressure, mPAP, right atrial pressure and PCWP were also measured at baseline and after vardenafil treatment. Aerosolised iloprost or infused adenosine was administered as a screening agent to assess pulmonary vasoreactivity in all patients. As recommended in recent guidelines,16 17 18 19 a positive vasodilator response was defined as a fall of mPAP of at least 10 mm Hg to ⩽40 mm Hg, with an increased or unchanged CO. Only non-responders were selected as candidates to receive vardenafil treatment.
Standard clinical assessments for PAH recommended in several recent guidelines were performed in all patients, including blood gas analysis, measurement of pulmonary function, an ECG, echocardiography, chest x-ray examination and a ventilation–perfusion scan. All parameters were reassessed after 3 and at least 9 months of treatment with vardenafil.
Laboratory tests, including evaluation of hepatic and renal function and routine blood tests, were performed at baseline and every 3 months in all subjects who received vardenafil. To detect any adverse effects or changes in clinical status, patients underwent medical evaluations every 3 months.
Haemodynamic parameters were expressed as mean (SD) values. SPSS 13.0 software (SPSS Chicago, Illinois, USA) was used for statistical analysis. A paired t test was applied to compare differences in clinical characteristics and haemodynamic variables between baseline and the post-treatment assessments. A χ2 test was used to compare differences in WHO functional class distribution between baseline and the post-treatment assessments. Significance was set at p<0.05.
A total of 45 patients (36 women, nine men; mean (SD) age 32.5 (10.3) years) with PAH were evaluated and treatment started with vardenafil. Diagnoses were idiopathic PAH in 10 and secondary PAH in 35 patients (associated with connective tissue disease in 11, congenital heart disease in 23 and portopulmonary hypertension in one). Among the patients with congenital heart disease, three had defects repaired by interventional or surgical treatment and 20 had Eisenmenger syndrome (12 with ventricular septal defect, four with atrial septal defect and four with patent ductus arteriosus). At the beginning of the study, all participants were in WHO functional classes II through IV. None of the patients had been treated with other PAH-active drugs, including bosentan, prostanoids and sildenafil, in the previous 3 months. Vardenafil was given for a mean (SD) of 14 (3) months (range 9–18). Table 1 shows the baseline characteristics of the patient population enrolled in the study.
Changes in clinical characteristics during vardenafil treatment
During vardenafil treatment, the mean (SD) 6 min walking distance was increased by 70.7 (78.4) m at 3 months and 83.4 (91.8) m at 14 (3) months (fig 1). The improvement in 6 min walking distance was statistically significant between baseline and the 3 month assessment (p<0.001), but the increase between 3 and 14 (3) months did not reach statistical significance (p = 0.36). The serum uric acid (UA) concentration was significantly decreased after 1-year’s treatment with vardenafil treatment (p = 0.038). A slight decrease was also seen in right ventricular end-diastolic diameter by echocardiography after 14 (3) months, but the change from baseline did not reach statistical significance.
At the beginning of the study, 12% of patients were in WHO functional class IV, 64% in class III, 24% in class II and none in class I. After 3 months, there was a substantial improvement in WHO functional class (p<0.001) and a further improvement was seen at 14 (3) months (p<0.001 compared with baseline; p<0.05 compared with month 3). At the end of the study, 11% of patients were in WHO functional class I, 69% in class II, 18% in class III and 2% in class IV (fig 2).
Changes in cardiopulmonary haemodynamic and blood gas variables
Twenty patients underwent repeated right heart catheterisation and blood gas analysis after a mean follow-up time of 14 (3) months (range 10–18 months; table 2 and fig 3). In these patients there were significant decreases from the baseline value in mPAP (from 67.4 (16.1) to 59.7 (16.0) mm Hg; p = 0.001), in PVR (from 17.5 (9.7) to 11.4 (5.1) Wood units; p<0.001) and in heart rate (from 86.5 (11.3) to 80.8 (11.2) bpm; p = 0.009), along with significant increases in cardiac index (from 2.7 (1.0) to 3.3 (1.2) l/min/m2; p = 0.001) and in SvO2 (from 66.2 (15.0)% to 68.8 (14.0)%; p = 0.009). Additionally, the PVR/systemic vascular resistance (SVR) ratio was also significantly decreased after vardenafil treatment (from 0.76 (0.24) to 0.66 (0.22); p = 0.006). Although treatment with vardenafil had a slight beneficial effect on right atrial pressure and arterial oxygen saturation (table 2), these changes did not reach statistical significance.
Safety and tolerability
No patients died during the course of the study. Overall, vardenafil treatment was well tolerated. Although the majority of patients experienced an adverse event (table 3), most events were mild and transient. No patient discontinued treatment prematurely owing to adverse events. However, two patients were admitted to hospital because of progressive shortening of breath and deterioration in right heart function at 6 months and 11 months, respectively. Both patients were treated with additional PAH-active drugs (bosentan and iloprost, respectively).
This multicentre, open-label study has demonstrated that vardenafil may improve both exercise tolerance and pulmonary vascular haemodynamic parameters in patients with PAH. The 6 min walking distance increased during the first 3 months of vardenafil treatment and this improvement was maintained for more than 1 year. In addition, long-term treatment was not associated with any major adverse sequelae attributable to vardenafil.
Vardenafil has been reported to exhibit both more potent and more selective inhibition of PDE5 than sildenafil.20 Several previous studies have shown that short-term treatment with sildenafil significantly reduces mPAP and PVR.21 22 23 In a comparison of the short-term effects of three different PDE5 inhibitors on pulmonary and systemic haemodynamic parameters in patients with PAH, Ghofrani et al14 found that sildenafil and tadalafil caused a significant reduction in the PVR/SVR ratio, while vardenafil caused an almost equipotent reduction of PVR and SVR, suggesting that it lacks selectivity for the pulmonary circulation, even at high doses. Similar findings for the acute effects of oral vardenafil were also reported in another study by Aizawa et al.15 However, in the latter study, the PVR/SVR ratio was significantly decreased by 20.7% after vardenafil administration for 3 months. In our study, selectivity for the pulmonary vasculature was evident with long-term vardenafil administration, as reflected by a decrease in the PVR/SVR ratio of 13.2% after 14 (3) months of treatment. Therefore, the long-term effects of vardenafil may differ from its short-term effects, as has been observed with epoprostenol.24 25 26
In addition to pulmonary vasodilatation, other effects of PDE5 inhibition such as an anti-smooth muscle proliferative effect on pulmonary artery cells27 and a direct effect on the right ventricle to enhance contractility and CO28 may be involved in the long-term effect of vardenafil. Vardenafil may also influence bone marrow-derived endothelial progenitor cells, the migration of which into the peripheral circulation promotes endothelial repair and neovascularisation.29 Foresta et al have reported a significant increase in the number of circulating endothelial progenitor cells in humans after vardenafil administration,30 suggesting that this phenomenon may have a role in the drug’s long-term effects.
In the study of Ghofrani et al,14 sildenafil, but not vardenafil or tadalafil, improved arterial oxygenation after short-term administration. The authors attributed this difference to an additional effect of sildenafil in amplifying local cGMP-based vasoregulatory loops. As alveolar oxygenation is an important determinant of local nitric oxide (NO) production and cGMP levels, poorly ventilated areas of the lung would be expected to have lower NO and cGMP levels and therefore the local effect of PDE5 inhibition would be expected to be less than in well-ventilated lungs.31 Consequently, PDE5 inhibition may improve rather than disturb the ratio of perfusion to ventilation distribution. In this study, arterial oxygen saturation was slightly improved after oral vardenafil treatment had been given for 14 (3) months, but the change from baseline did not reach statistical significance. This long-term effect was similar to that reported in previous short-term studies.15 In comparison with sildenafil, vardenafil has different selectivities for PDE isoenzymes.32 Further studies are needed to examine the question of whether this different profile is related to differences in the pattern of PDE inhibition or to other, currently unknown mechanisms.
Pulmonary hypertension characterised by extensive remodelling of the pulmonary vasculature increases right ventricular after load. Subsequently, the balance of oxygen supply and consumption deteriorates owing to a decrease in CO. A feature of PAH and one that was evident in the patients we studied, is an elevated baseline serum UA concentration which (as a marker of impaired oxidative metabolism) is positively correlated with total pulmonary resistance and negatively correlated with CO and has been shown to be independently related to mortality.33 In this study, long-term treatment with vardenafil caused a significant reduction of both the serum UA concentration and mPAP. The decrease in mPAP may ameliorate the increased wall stress in the right ventricle and the impaired left ventricular diastolic function due to the enlarged right ventricle of these patients and improve the balance of oxygen supply and consumption owing to a significant increase of CO.
Oral vardenafil treatment proved to be well tolerated. No patient died during the course of our study and none was withdrawn owing to intolerable adverse effects. As with sildenafil,8 the most common adverse effects with vardenafil were flushing and headache. Most adverse events were transient and of mild severity and only two patients needed to be admitted to hospital during the study (at 6 months and 11 months, respectively) owing to clinical worsening of PAH. In both these patients, additional PAH-active drugs were given and a combination therapeutic regimen was established.
In China and in many other developing countries, expensive PAH-active drugs are not covered by government medical insurance. Although we did not conduct a full pharmacoeconomic analysis, a comparison of 2008 drug acquisition costs showed that vardenafil at a dose of 5 mg twice daily costs US$212 a month, which is considerably cheaper than bosentan 125 mg twice daily (US$4234 a month) and also cheaper than sildenafil 20 mg three times daily (US$255 a month). Thus, vardenafil could make PAH treatment more affordable to patients in many developing countries.
Our study has some limitations. First, it was a non-randomised, open-label study and confirmation of its findings in a randomised, controlled clinical trial is necessary to verify the efficacy and tolerability of vardenafil in patients with PAH. Second, it was not a dose-titrated study and only one dose was investigated. As the response to higher doses of vardenafil beyond 10 mg daily has not been investigated, the ideal maintenance dose is not yet known.
In conclusion, the results of this 1-year, open-label study indicate that long-term vardenafil treatment is well tolerated and significantly improves the haemodynamic parameters, WHO functional class and exercise capacity of patients with PAH. Oral vardenafil may therefore be beneficial as a selective pulmonary vasodilator to treat patients with this condition.
Funding This study was supported by Shanghai Pujiang Programme (08PJ14086) and China National 973 Project (2007CB512008).
Competing interests None.
Ethics approval Approval from the ethics committee of the PI institute, Shanghai Pulmonary Hospital, Tongji University.
Provenance and peer review Not commissioned; externally peer reviewed.