Abstract
Rationale: Although the phosphodiesterase type 5 inhibitors sildenafil and tadalafil have demonstrated efficacy in patients with pulmonary arterial hypertension (PAH), monotherapy with these agents has not been conclusively shown to reduce clinical worsening events.
Objectives: To evaluate the safety and efficacy of the phosphodiesterase type 5 inhibitor vardenafil in Chinese patients with PAH.
Methods: In a randomized, double-blind, placebo-controlled study, 66 patients with PAH were randomized 2:1 to vardenafil (5 mg once daily for 4 wk then 5 mg twice daily; n = 44) or placebo (n = 22) for 12 weeks. Patients completing this phase were then treated with open-label vardenafil (5 mg twice daily) for a further 12 weeks.
Measurements and Main Results: At Week 12, the mean placebo-corrected 6-minute walking distance was increased with vardenafil (69 m; P < 0.001), and this improvement was maintained for at least 24 weeks. Vardenafil also increased the mean placebo-corrected cardiac index (0.39 L·min−1·m−2; P = 0.005) and decreased mean pulmonary arterial pressure and pulmonary vascular resistance (−5.3 mm Hg, P = 0.047; −4.7 Wood U, P = 0.003; respectively) at Week 12. Four patients in the placebo group (20%) and one in the vardenafil group (2.3%) had clinical worsening events (hazard ratio 0.105; 95% confidence interval, 0.012–0.938; P = 0.044). Vardenafil was associated with only mild and transient adverse events.
Conclusions: Vardenafil is effective and well tolerated in patients with PAH at a dose of 5 mg twice daily.
Although the phosphodiesterase type 5 inhibitors sildenafil and tadalafil have demonstrated efficacy in patients with pulmonary arterial hypertension, monotherapy with these agents has not been conclusively shown to reduce clinical worsening events.
The favorable effects of vardenafil monotherapy on symptoms, exercise capacity, hemodynamics, and clinical outcome (improvements in Borg dyspnea index and World Health Organization functional class, fewer clinical worsening events) in treatment-naive patients with pulmonary arterial hypertension and the relatively low cost of this medication suggest its usefulness as a first-line treatment in developing countries.
There is no cure for PAH; however, the currently approved treatment options (i.e., prostanoids, endothelin receptor antagonists, and phosphodiesterase type 5 inhibitors) improve symptoms, exercise capacity, and clinical outcome. These treatment options, however, are limited either by parenteral or inhaled delivery systems, the need for laboratory monitoring, frequent dosing schedules or dosing uncertainties, and elevated costs (6).
PAH is associated with impaired release of nitric oxide (7), caused at least in part by reduced expression of nitric oxide synthase in the vascular endothelium of pulmonary arteries (8). Downstream activation of soluble guanylate cyclase is thus reduced with less cellular synthesis of cyclic guanosine monophosphate. Phosphodiesterase type 5 inactivates cyclic guanosine monophosphate in the pulmonary vasculature and seems to be up-regulated in pulmonary hypertension (9, 10). Inhibition of phosphodiesterase type 5 increases cyclic guanosine monophosphate levels, which may mediate the antiproliferative (11) and vasodilating (12) effects of endogenous nitric oxide. Controlled trials of sildenafil and tadalafil in the treatment of patients with PAH have shown improvements in exercise capacity, hemodynamic parameters, and clinical outcome (13–16). However, sildenafil reduced the incidence of clinical worsening events only when added to epoprostenol and with a dose fourfold higher than the currently approved dose (17). In addition, tadalafil improved the time to clinical worsening in a study in which more than 50% of the patients were already being treated with the endothelin receptor antagonist bosentan (16). Therefore, it is not yet clear if monotherapy with phosphodiesterase type 5 inhibitors at approved dosages is able to improve clinical outcomes in patients with PAH. The relevance of this observation is highlighted by the frequent initiation of treatment of these patients with phosphodiesterase type 5 inhibitor monotherapy for cost reasons (18).
Vardenafil is a phosphodiesterase type 5 inhibitor that was approved for the treatment of erectile dysfunction in 2005. Pharmacodynamic studies of this agent have shown it to be more potent than sildenafil and tadalafil in inhibiting phosphodiesterase type 5 (19, 20). Preliminary favorable effects with vardenafil treatment in patients with PAH have been reported in small open-label series and case reports (21, 22).
This report describes the results of a randomized, double-blind, placebo-controlled, multicenter study (Efficacy and Safety of Vardenafil in the Treatment of Pulmonary Arterial Hypertension) that was designed to determine the effects of 12 weeks of oral vardenafil monotherapy, 5 mg twice daily, on exercise capacity, cardiopulmonary hemodynamics, and clinical outcome in a cohort of patients with PAH. Some of the results of the study have been previously reported in the form of an abstract (23).
Patients eligible for this study were males or females between 12 and 65 years of age who were in World Health Organization (WHO) functional classes II and III PAH despite the use of conventional therapies, including oral anticoagulants, digoxin, diuretics, or supplemental oxygen. The patients were screened at nine centers in China and were enrolled in the trial between September 2008 and May 2009; the 24-week follow-up period was completed before November 2009. No PAH-specific treatments (prostanoids, endothelin receptor antagonists, or phosphodiesterase type 5 inhibitors) were allowed for at least 3 months before enrollment.
The etiologies of PAH included idiopathic PAH; PAH associated with connective tissue diseases (systemic lupus erythematosus, scleroderma, or mixed connective tissue disease); and repaired congenital systemic-to-pulmonary shunts (≥3 yr after percutaneous or surgical defect closure). A baseline 6-minute walking distance (6MWD) between 150 and 550 m, a resting mean pulmonary artery pressure greater than or equal to 25 mm Hg and pulmonary capillary wedge pressure less than or equal to 15 mm Hg, and pulmonary vascular resistance greater than 4 Wood Units measured by right heart catheterization at enrollment were required for inclusion. Patients who were acute responders to a vasoreactivity test were excluded.
The study was conducted according to the provisions of the Declaration of Helsinki, and adhered to local guidelines for good clinical practice. Local ethics review committees approved the protocol, and written informed consent was obtained from all patients.
The study was a double-blind, randomized, placebo-controlled trial performed at nine centers in mainland China. Enrolled patients were randomly assigned 2:1 to 5-mg vardenafil once daily for the first 4 weeks increasing to the target dosage of 5 mg twice daily (n = 44) unless severe drug-related adverse events developed (e.g., severe headache, muscle pain, or visual disturbances), or to matching doses of placebo (n = 22). Randomization was computer-generated using the DMS System, with a block size of 6. The 2:1 randomization ratio (vardenafil: placebo) was the same for each center. The primary efficacy endpoint was the 6MWD and it was assessed at the end of the 12-week randomized treatment period. Secondary measures of efficacy included cardiopulmonary hemodynamics (mean right atrial pressure, cardiac index, mean pulmonary artery pressure, and pulmonary vascular resistance) measured by right heart catheterization; the Borg dyspnea index; WHO functional class (at baseline and Week 12); and occurrence of clinical worsening events defined as death (all causes) or hospitalization for PAH progression.
All patients who completed the randomized trial, irrespective of their treatment arm, were given the opportunity to enter into a 12-week, open-label extension trial with vardenafil, 5 mg twice daily. Blinding of their treatment arm during the randomized phase was preserved during the open-label study. During the extension trial, efficacy was further assessed by the 6MWD, WHO functional class, and the Borg dyspnea index. The safety profile of vardenafil was evaluated by the occurrence of adverse events and blood test (hematologic and biochemical) results.
A sample size of 66 patients was calculated to be required to detect a mean difference of 60 m with a standard deviation of 60 m in the 6MWD from baseline to Week 12, with 90% power and at a one-sided level of 0.05 by Student t test. To minimize bias, missing data at the Week 12 assessment were derived from predefined replacement rules. Discontinuation of the study because of clinical worsening was analyzed by assessment of patients at the time of premature withdrawal. If no assessment was recorded (including dead patients), these patients were assigned the worst rank value: 0 m for the 6MWD; a score of 10 for the Borg dyspnea index; and class IV for WHO functional class. However, patients who did not undergo right heart catheterization at the 12-week assessment were excluded from hemodynamic evaluation.
The significance of the differences from baseline to Week 12 between the treatment groups for the 6MWD, Borg dyspnea index, and cardiopulmonary hemodynamic measurements was assessed by the two-sample Student t test. Confirmatory analysis was performed with Wilcoxon rank-sum test. Changes from baseline to Week 12 and Week 24 in the WHO functional class were analyzed with Fisher exact test. The time from randomization to clinical worsening was analyzed by the log-rank test, and Kaplan-Meier estimates of the proportions of patients with clinical worsening were determined. The treatment effect was reported as the hazard ratio of the vardenafil versus the placebo group and tested with the Cox proportional-hazard model. All P values less than 0.05 were considered as significant; 95% confidence intervals were calculated for differences within and between the treatment groups.
All statistical analyses were performed with SPSS software (version 15.0; IBM, Chicago, IL).
A total of 70 patients with PAH were screened, and 66 (55 females and 11 males; age range, 12–59 yr) were randomized (Figure 1). Four of the screened patients were not randomized: two because of severely impaired lung function tests, one because of chronic thromboembolic pulmonary hypertension, and one because of severe anemia. Two patients randomized to placebo were lost to follow-up without any follow-up data being recorded. Four patients in the placebo group and one patient in the vardenafil group withdrew because of clinical worsening. Thus, 59 patients completed the randomized phase.
The baseline characteristics of the patient population enrolled in the study are shown in Table 1. The two randomized treatment groups were well matched with respect to baseline patient characteristics. The predominant etiology was idiopathic PAH in both groups. At the beginning of the study, all participants were in WHO functional classes II and III and were clinically stable. Nearly two-thirds of patients (41 [64%] of 64) were receiving at least one of the conventional background therapies (digoxin, warfarin, diuretics, or supplemental oxygen).
Characteristics | Placebo (n = 20) | Vardenafil (n = 44) |
|---|---|---|
| Demographic variables | ||
| Sex | ||
| Men, n (%) | 3 (15) | 8 (18) |
| Women, n (%) | 17 (85) | 36 (82) |
| Age, mean (SD) yr | 29 (8) | 32 (12) |
| BSA, mean (SD) m2 | 1.6 (0.2) | 1.6 (0.2) |
| Etiologies of PAH | ||
| Idiopathic, n (%) | 14 (70) | 25 (57) |
| Connective tissue disease, n (%) | 4 (20) | 15 (34) |
| Repaired right-to-left shunting, n (%) | 2 (10) | 4 (9) |
| WHO functional class | ||
| II, n (%) | 9 (45) | 21 (48) |
| III, n (%) | 11 (55) | 23 (52) |
| 6-Minute walking distance, mean (SD) m | 388 (83) | 395 (80) |
| Borg dyspnea index, mean (SD) | 2.6 (0.9) | 2.6 (1.3) |
| Conventional therapies | 13 (65) | 28 (64) |
| Hemodynamic variables | ||
| Heart rate, mean (SD) bpm | 82 (13) | 81 (10) |
| Blood pressure, mean (SD) mm Hg | 86 (11) | 85 (11) |
| Right atrial pressure, mean (SD) mm Hg | 8.9 (4.2) | 9 (5.3) |
| Pulmonary arterial pressure, mean (SD) mm Hg | 64 (16) | 60 (16) |
| Pulmonary capillary wedge pressure, mean (SD) mm Hg | 9.3 (2.5) | 8.9 (2.6) |
| Cardiac index, mean (SD) L·min−1·m−2 | 2.5 (0.6) | 2.2 (0.7) |
| Pulmonary vascular resistance, mean (SD) Wood U | 15 (8) | 16 (9) |
| Systemic vascular resistance, mean (SD) Wood U | 21 (8) | 23 (7) |
| SvO2,% | 60 (7) | 62 (11) |
| SaO2,% | 94 (3) | 95 (3) |
The median 6MWD was increased by 59 m in patients treated with vardenafil, whereas the distance was decreased by 10 m in those treated with placebo; the mean placebo-corrected treatment effect of vardenafil was 69 m (95% confidence interval [CI], 41–98 m; P < 0.001). The placebo-adjusted change in 6MWD in patients in WHO functional class II was 32 m (95% CI, 6–59 m; P = 0.017) compared with 83 m (95% CI, 64–102 m; P < 0.001) in patients in WHO functional class III. In the extension phase, the improvement in the vardenafil group was maintained at Week 24 (69 m increase from baseline; P < 0.001), and a significant increase in 6MWD was observed in the ex-placebo group at Week 24 after receiving vardenafil therapy at a dose of 5 mg twice daily (49 m increased from baseline, P < 0.001; 59 m increased from Week 12, P < 0.001) (Figure 2).
Figure 2. Changes in 6-minute walking distance (6MWD) from baseline to Week 24. Patients who did not complete the Week 12 or Week 24 assessments had their last observed value carried forward. In the randomized phase, the placebo-corrected treatment effect of vardenafil was 69 m (vardenafil, n = 44; placebo, n = 20; P < 0.001) at Week 12 and this improvement was maintained at Week 24. The improvement in patients switched from placebo to vardenafil therapy was 49 m (vardenafil, n = 43; placebo, n = 16; P < 0.001). Bars = standard errors; points = means.
[More] [Minimize]Treatment with vardenafil significantly improved cardiopulmonary hemodynamics at Week 12 compared with placebo (Table 2). Mean pulmonary arterial pressure was significantly reduced from baseline in patients treated with vardenafil, but was unchanged in those treated with placebo. Mean pulmonary vascular resistance decreased in the vardenafil group, and increased in the placebo group. Additionally, treatment with vardenafil increased the mean cardiac index in contrast to a decrease observed in the placebo group. There was also a greater increase in mixed venous oxygen saturation in the vardenafil group, but the difference versus placebo did not achieve statistical significance.
Change from Baseline | Difference Between Treatments | |||||
|---|---|---|---|---|---|---|
| Variables | Placebo (n = 16) | Vardenafil (n = 43) | Difference (95% CI) | P Value | ||
| Heart rate, mean (SE) bpm | −0.3 (3.3) | −4.3 (1.4) | −4 (−11.4 to 3.4) | 0.272 | ||
| Blood pressure, mean (SE) mm Hg | −3.8 (1.9) | −1.1 (1.6) | 2.6 (−2.8 to 8.3) | 0.359 | ||
| Mean right atrial pressure, mean (SE) mm Hg | 0.8 (0.9) | −1.2 (0.6) | −2 (−4.3 to 0.3) | 0.085 | ||
| Pulmonary capillary wedge pressure, mean (SE) mm Hg | −0.1 (0.5) | 0 (0.5) | 0.1 (−1.5 to 1.7) | 0.923 | ||
| Mean pulmonary arterial pressure, mean (SE) mm Hg | 0.6 (1.5) | −4.8 (1.6) | −5.3 (−10.6 to −0.1) | 0.047 | ||
| Cardiac index, mean (SE) L·min−1·m−2 | −0.2 (0.1) | 0.2 (0.1) | 0.4 (0.1 to 0.7) | 0.005 | ||
| Pulmonary vascular resistance, mean (SE) Wood U | 1.4 (1) | −3.3 (0.9) | −4.7 (−7.8 to −1.7) | 0.003 | ||
| Systemic vascular resistance, mean (SE) Wood U | 0.4 (1.2) | −2.8 (1.1) | −3.1 (−7 to 0.7) | 0.107 | ||
| SvO2, mean (SE) % | 0.3 (1.3) | 2.1 (0.9) | 1.8 (−1.5 to 5.2) | 0.277 | ||
The improvements in cardiopulmonary hemodynamics seen with vardenafil were not associated with a change in the mean systemic arterial blood pressure. Two patients in the placebo group died during the 12-week randomized phase and were excluded from the hemodynamic assessment.
After 12 weeks of treatment with vardenafil, 10 (22.7%) of 44 patients improved at least one WHO functional class, 32 (72.8%) remained stable, and two (4.5%) deteriorated to class III and IV (P = 0.032). In contrast, among the patients who received placebo, only 1 (5%) of 20 patients improved from class III to class II, 15 (75%) remained stable, two (10%) deteriorated from class II to class III, and two deteriorated from class III to class IV (the two patients who died were classified as class IV) (P = 0.585) (Figure 3).
Figure 3. Changes in World Health Organization functional class from baseline to Week 12 and Week 24 in the vardenafil and placebo groups. Patients who did not complete the Week 12 or Week 24 assessments because of aggressive right ventricular failure (two in the placebo group during the randomized phase and none in vardenafil group) had their last observed value carried forward. Patients who died during the study (two in the placebo group during the randomized phase and one in the vardenafil group during the extension phase) had a worst WHO functional class (class IV).
[More] [Minimize]During the extension phase, improvements of the WHO functional class were maintained in the ex-vardenafil group when vardenafil therapy was continued. In the ex-placebo group, improvements were seen at Week 24 (Figure 3).
The mean Borg dyspnea index was improved at Week 12 (−0.4; 95% CI, −0.9 to −0.0; P = 0.046) in patients treated with vardenafil, whereas a deterioration was observed in those treated with placebo (1.8; 95% CI, 0.6–2.9; P = 0.004). In the extension phase, the improvement of the Borg dyspnea index in the ex-vardenafil group was maintained (0.2; 95% CI, −0.3–0.7; P = 0.427) and a significant improvement was observed in the ex-placebo group (−1.1; 95% CI, −2 to −0·2; P = 0.017) (Figure 4).
Figure 4. Changes in the Borg dyspnea scale in the vardenafil and placebo groups in the randomized phase and the extension phase. Patients who did not complete the Week 12 or Week 24 assessments because of aggressive right ventricular failure (two in the placebo group during the randomized phase and none in the vardenafil group) had their last observed value carried forward. Patients who died during the study (two in the placebo group during the randomized phase and one in the vardenafil group during the extension phase) had a worst score (10). Bars = standard errors; columns = means.
[More] [Minimize]During the course of the randomized phase of the study (≤12 wk), five patients had clinical worsening events, four in the placebo group (20%) and one in the vardenafil group (2.3%) (hazard ratio 0.105; 95% CI, 0.012–0.938; P = 0.044) (Table 3, Figure 5). One patient died suddenly at Day 7, and one died because of refractory right heart failure at Day 48 in the placebo group. Two other patients receiving placebo experienced clinical worsening (at Days 28 and 34, respectively); both were hospitalized and then treated with inhaled iloprost and intravenous dopamine. One clinical worsening event (pneumonia and right heart failure on Day 44) was reported in a patient receiving vardenafil. Oral bosentan and intravenous dopamine were initiated during hospitalization in this patient.
Placebo (n = 20) | Vardenafil (n = 44) | |
|---|---|---|
| Clinical worsening, n (%)* | 4 (20) | 1 (2.3) |
| Death | 2 (10) | 0 (0) |
| Hospitalization for worsening PAH | 2 (10) | 1 (2.3) |
| Adverse events, n (%)* | 6 (30) | 25 (57) |
| Headache | 2 (10) | 8 (18.2) |
| Flushing | 2 (10) | 20 (45) |
| Diarrhea | 1 (5) | 0 (0) |
| Myalgia | 0 (0) | 1 (2.3) |
| Muscle pain | 1 (5) | 1 (2.3) |
| Nasal congestion | 0 (0) | 2 (5) |
| Vision disturbance | 1 (5) | 0 (0) |
| Dizziness | 1 (5) | 3 (6.8) |
| Chest pain | 1 (5) | 0 (0) |
| Insomnia | 0 (0) | 1 (2.3) |
| Respiratory infection | 1 (5) | 1 (2.3) |
Figure 5. Kaplan–Meier estimates of the proportions of patients with clinical worsening events at Week 12 in the vardenafil and placebo groups.
[More] [Minimize]Adverse events with vardenafil were generally mild and transient. The most frequent adverse events were headache or flushing (Table 3), which subsided within 2 weeks in nearly half of the patients. No patient discontinued vardenafil because of intolerable adverse events. No hypotension or clinically significant changes in hematologic or biochemical parameters were seen in either group.
The current study is the first randomized, placebo-controlled trial to evaluate the efficacy and safety of the phosphodiesterase type 5 inhibitor vardenafil in patients with PAH. The results show that oral vardenafil (5 mg twice daily) improves exercise capacity (Figure 2), symptoms (Figures 2 and 4), hemodynamics (Table 2), and clinical outcome. This is also the first study in which monotherapy with a phosphodiesterase type 5 inhibitor in treatment-naive patients with PAH was able to significantly reduce the occurrence of clinical worsening events, although the numbers of such events was small.
The placebo-corrected increase in 6MWD in the group of patients treated with vardenafil was 69 m, and these data are consistent with those observed in other pivotal studies, ranging from 16–59 m, with approved PAH medications used as monotherapy (24, 25). The extension study suggests that the favorable effect of vardenafil treatment on exercise capacity is durable for at least 24 weeks. In addition, the patients previously treated with placebo improved their exercise capacity when treated with vardenafil in the extension study (Figure 2).
The favorable effects on WHO functional class, the Borg dyspnea score, and hemodynamics achieved with vardenafil in this study are also comparable with those achieved with other approved PAH medications used as monotherapy (24, 25). However, an improvement in clinical outcome has not been shown invariably in randomized, controlled studies with PAH medications used either as monotherapy or in combination (26). With other phosphodiesterase type 5 inhibitors approved for PAH, sildenafil decreased clinical worsening events only when added to epoprostenol and with a dose fourfold higher than the currently approved dose (17), but not when used in monotherapy at different doses (14). In addition, tadalafil improved the time to clinical worsening in a study in which more than 50% of the patients were already being treated with the endothelin receptor antagonist bosentan (16). In the present study, four patients (20%) in the placebo group had clinical worsening events (two deaths and two hospitalizations) compared with only one hospitalization (2.3%) in the vardenafil group (Table 3, Figure 5). Therefore, vardenafil used as monotherapy in patients with PAH is the only phosphodiesterase type 5 inhibitor with a demonstrated effect on clinical outcome.
The reasons for these differing observations among phosphodiesterase type 5 inhibitors are not clear and may include a difference in the definitions used for clinical worsening, differences in the patient populations studied, differences in clinical histories in the countries in which the studies were performed, or differences in the effects of the three drugs on this specific parameter. Prevention of clinical deterioration is regarded as clinically important supportive evidence for the efficacy of PAH medications and has been used as a primary endpoint in ongoing PAH clinical trials (25). The definition of clinical worsening used in the current study was conservative (all-cause death and hospitalization because of PAH progression) and is less subjective compared with the definitions used in other trials, which also include “progression of PAH that does not require hospital stay” (26). Vardenafil is considered to be a more potent phosphodiesterase type 5 inhibitor than sildenafil and tadalafil, possibly because of its different chemical structure, which allows a slower dissociation rate from phosphodiesterase type 5 (20). Because the sample size of the present trial was rather small and clinical worsening was not the primary endpoint, the favorable effects on this parameter need to be confirmed by additional studies.
The adverse effects of vardenafil reported in this trial (Table 3) were mild in severity and transient, and were similar to those observed with other phosphodiesterase type 5 inhibitors (17, 18).
Limitations of the current study include the small sample size and the lack of assessment of different doses of vardenafil. The small sample size was related to the limited number of centers experienced in the management of pulmonary vascular diseases according to current guidelines (6) in mainland China. Interestingly, this is the third randomized, controlled study of phosphodiesterase type 5 inhibitors performed in patients with PAH enrolled exclusively in developing countries (13, 15) among the 26 trials currently published in this patient population (25). The three studies tested only phosphodiesterase type 5 inhibitors that are available in these geographic areas, and are less expensive compared with endothelin receptor antagonists and prostanoids, the other two classes of drugs approved for patients with PAH. The only other randomized, controlled trial of PAH treatments to be conducted exclusively in a developing country was the TRUST study of the intravenous prostacyclin analog treprostinil (27).
We evaluated the clinical efficacy of only a relatively low dose of vardenafil to assess a realistic economic treatment regimen to manage patients with PAH in China. In terms of the generalizability and external validity of our findings, a recent study has shown that polymorphisms of CYP3A4 and CYP3A5 can influence the pharmacokinetics of phosphodiesterase type 5 inhibitors, especially vardenafil (28). Genetic variants between the Chinese population and western people (29) may therefore contribute to some of the differences seen in this study compared with previous studies. Consequently, the generalizability and external validity of the study's findings need to be confirmed in other races and populations.
In conclusion, the favorable effects of vardenafil therapy on symptoms, exercise capacity, hemodynamics, and clinical outcome in treatment-naive patients with PAH and the relatively low cost of this medication suggest its usefulness as a first-line treatment in developing countries.
Acknowledgment: The authors acknowledge the collaboration and commitment of all the local investigators and their staff. Their gratitude also goes to Dr. L. J. Rubin for help with the study design and manuscript editing, and to Dr. Jue Li for his great contribution to the statistics of this study.
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