Mechanism Of Action
Sildenafil is an inhibitor of cGMP specific PDE-5 in the smooth muscle of the pulmonary vasculature, where PDE-5 is responsible for degradation of cGMP. Sildenafil, therefore, increases cGMP within pulmonary vascular smooth muscle cells resulting in relaxation. In patients with PAH, this can lead to vasodilation of the pulmonary vascular bed and, to a lesser degree, vasodilatation in the systemic circulation.
Studies in vitro have shown that sildenafil is selective for PDE5. Its effect is more potent on PDE5 than on other known phosphodiesterases (10-fold for PDE6, greater than 80-fold for PDE1, greater than 700-fold for PDE2, PDE3, PDE4, PDE7, PDE8, PDE9, PDE10, and PDE11). The approximately 4,000-fold selectivity for PDE-5 versus PDE3 is important because PDE3 is involved in control of cardiac contractility. Sildenafil is only about 10 times as potent for PDE5 compared to PDE6, an enzyme found in the retina and involved in the phototransduction pathway of the retina. This lower selectivity is thought to be the basis for abnormalities related to color vision observed with higher doses or plasma levels [see CLINICAL PHARMACOLOGY].
In addition to pulmonary vascular smooth muscle and the corpus cavernosum, PDE5 is also found in other tissues including vascular and visceral smooth muscle and in platelets. The inhibition of PDE5 in these tissues by sildenafil may be the basis for the enhanced platelet antiÂaggregatory activity of nitric oxide observed in vitro, and the mild peripheral arterial-venous dilatation in vivo.
Effects Of REVATIO On Hemodynamic Measures
Patients on all REVATIO doses achieved a statistically significant reduction in mean pulmonary arterial pressure (mPAP) compared to those on placebo in a study with no background vasodilators [see SUPER-1 in Clinical Studies]. Data on other hemodynamic measures for the REVATIO 20 mg three times a day and placebo dosing regimens is displayed in Table 2. The relationship between these effects and improvements in 6-minute walk distance is unknown.
Table 2: Changes from Baseline in Hemodynamic Parameters at Week 12 [mean (95% CI)] for the REVATIO 20 mg Three Times a Day and Placebo Group
(n = 65)*
|REVATIO 20 mg|
(n = 65)*
|mPAP (mmHg)||0.6 (-0.8, 2.0)||-2.1 (-4.3, 0.0)|
|PVR (dyn-s/cm5)||49 (-54, 153)||-122 (-217, -27)|
|SVR (dyn-s/cm5)||-78 (-197, 41)||-167 (-307, -26)|
|RAP (mmHg)||0.3 (-0.9, 1.5)||-0.8 (-1.9, 0.3)|
|CO (L/min)||-0.1 (-0.4, 0.2)||0.4 (0.1, 0.7)|
|HR (beats/min)||-1.3 (-4.1, 1.4)||-3.7 (-5.9, -1.4)|
|mPAP = mean pulmonary arterial pressure; PVR = pulmonary vascular resistance; SVR = systemic vascular resistance; RAP = right atrial pressure; CO = cardiac output; HR = heart rate.|
*The number of patients per treatment group varied slightly for each parameter due to missing assessments.
Patients on REVATIO medium and high dose groups achieved a dose related improvements in pulmonary vascular resistance index (PVRI) and mean pulmonary arterial pressure (mPAP) compared to those on placebo [see STARTS-1 in Clinical Studies]. Improvements were observed with cardiac index in all three REVATIO dose groups over placebo. Data on other hemodynamic measures for the REVATIO low, medium and high dose groups compared to placebo is displayed in Table 3.
Table 3: Placebo Corrected Changes in Hemodynamic Parameters by Dose Group
|Parameter [Estimate (95% CI)]||Low Dose||Medium Dose||High Dose|
|PVRI (%)||-2% (-20%, 20%)|
n = 37
|-18% (-32%, -2%)|
n = 51
|-27% (-39%, -14%)|
n = 68
|mPAP (mmHg)||1.6 (-4.5, 7.6)|
n = 39
|-3.5 (-8.9, 1.9)|
n = 55
|-7.3 (-12.4, -2.1)|
n = 71
|CI (%)||10% (-4%, 26%)|
n = 37
|4% (-7%, 18%)|
n = 51
|15% (3%, 29%)|
n = 69
|SVRI (%)||-9% (-22%, 7%)|
n = 37
|-5% (-17%, 10%)|
n = 50
|-16% (-26%, -4%)|
n = 68
|RAP (mmHg)||-0.17 (-1.91, 1.57)|
n = 39
|-0.19 (-1.73, 1.36)|
n = 55
|-1.14 (-2.61, 0.33)|
n = 71
|HR (%)||3% (-5%, 12%)|
n = 39
|2% (-5%, 9%)|
n = 55
|-2% (-9%, 5%)|
n = 71
|Abbreviations: CI = cardiac index; HR = heart rate; mPAP = mean pulmonary arterial pressure; PVRI = pulmonary vascular resistance index; RAP = right atrial pressure; SVRI = systemic vascular resistance index.|
Note: n = 52, 56, 55, 54, 56, and 56 placebo patients for PVRI, mPAP, CI, SVRI, RAP and HR, respectively.
Effects Of REVATIO On Blood Pressure
Single oral doses of sildenafil 100 mg administered to healthy volunteers produced decreases in supine blood pressure (mean maximum decrease in systolic/diastolic blood pressure of 8/5 mmHg). The decrease in blood pressure was most notable approximately 1-2 hours after dosing and was not different from placebo at 8 hours. Similar effects on blood pressure were noted with 25 mg, 50 mg, and 100 mg doses of sildenafil, therefore the effects are not related to dose or plasma levels within this dosage range. Larger effects were recorded among patients receiving concomitant nitrates [see CONTRAINDICATIONS].
Single oral doses of sildenafil up to 100 mg in healthy volunteers produced no clinically relevant effects on electrocardiogram (ECG). After chronic dosing of 80 mg three times a day to patients with PAH, no clinically relevant effects on ECG were reported.
After chronic dosing of 80 mg three times a day sildenafil to healthy volunteers, the largest mean change from baseline in supine systolic and supine diastolic blood pressures was a decrease of 9.0 mmHg and 8.4 mmHg, respectively.
After chronic dosing of 80 mg three times a day sildenafil to patients with systemic hypertension, the mean change from baseline in systolic and diastolic blood pressures was a decrease of 9.4 and 9.1 mmHg, respectively.
After chronic dosing of 80 mg three times a day sildenafil to patients with PAH, lesser reductions than above in systolic and diastolic blood pressures were observed (a decrease in both of 2 mmHg).
Effects Of REVATIO On Vision
At single oral doses of 100 mg and 200 mg, transient dose-related impairment of color discrimination (blue/green) was detected using the Farnsworth-Munsell 100-hue test, with peak effects near the time of peak plasma levels. This finding is consistent with the inhibition of PDE6, which is involved in phototransduction in the retina. An evaluation of visual function at doses up to 200 mg revealed no effects of REVATIO on visual acuity, intraocular pressure, or pupillometry.
Absorption And Distribution
REVATIO is rapidly absorbed after oral administration, with a mean absolute bioavailability of 41% (25 to 63%). Maximum observed plasma concentrations are reached within 30 to 120 minutes (median 60 minutes) of oral dosing in the fasted state. When REVATIO is taken with a high-fat meal, the rate of absorption is reduced, with a mean delay in Tmax of 60 minutes and a mean reduction in Cmax of 29%. The mean steady state volume of distribution (Vss) for sildenafil is 105 L, indicating distribution into the tissues. Sildenafil and its major circulating N-desmethyl metabolite are both approximately 96% bound to plasma proteins. Protein binding is independent of total drug concentrations.
Bioequivalence was established between the 20 mg tablet and the 10 mg/mL oral suspension when administered as a 20 mg single oral dose of sildenafil (as citrate).
Metabolism And Excretion
Sildenafil is cleared predominantly by the CYP3A (major route) and cytochrome P450 2C9 (CYP2C9, minor route) hepatic microsomal isoenzymes. The major circulating metabolite results from N-desmethylation of sildenafil, and is, itself, further metabolized. This metabolite has a phosphodiesterase selectivity profile similar to sildenafil and an in vitro potency for PDE-5 approximately 50% of the parent drug. In healthy volunteers, plasma concentrations of this metabolite are approximately 40% of those seen for sildenafil, so that the metabolite accounts for about 20% of sildenafilâ€™s pharmacologic effects. In patients with PAH, however, the ratio of the metabolite to sildenafil is higher. Both sildenafil and the active metabolite have terminal half-lives of about 4 hours.
After either oral or intravenous administration, sildenafil is excreted as metabolites predominantly in the feces (approximately 80% of the administered oral dose) and to a lesser extent in the urine (approximately 13% of the administered oral dose).
The pharmacokinetic profile of REVATIO has been characterized following intravenous administration. A 10 mg dose of REVATIO Injection is predicted to provide a pharmacological effect of sildenafil and its N-desmethyl metabolite equivalent to that of a 20 mg oral dose.
Age, gender, race, and renal and hepatic function were included as factors assessed in the population pharmacokinetic model to evaluate sildenafil pharmacokinetics in patients with PAH. The dataset available for the population pharmacokinetic evaluation contained a wide range of demographic data and laboratory parameters associated with hepatic and renal function. None of these factors had a significant impact on sildenafil pharmacokinetics in patients with PAH.
In patients with PAH, the average steady-state concentrations were 20 to 50% higher when compared to those of healthy volunteers. There was also a doubling of Cmin levels compared to healthy volunteers. Both findings suggest a lower clearance and/or a higher oral bioavailability of sildenafil in patients with PAH compared to healthy volunteers.
Body weight was shown to be a good predictor of drug exposure in children. Sildenafil plasma concentration half-life values were estimated to range from 2.9 to 4.4 hours for a range of 10 to 70 kg of body weight. Tmax was estimated at approximately 1 hour.
Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil, resulting in approximately 84% and 107% higher plasma concentrations of sildenafil and its active NÂdesmethyl metabolite, respectively, compared to those seen in healthy younger volunteers (18 to 45 years). Due to age-differences in plasma protein binding, the corresponding increase in the AUC of free (unbound) sildenafil and its active N-desmethyl metabolite were 45% and 57%, respectively.
In volunteers with mild (CLcr = 50-80 mL/min) and moderate (CLcr = 30-49 mL/min) renal impairment, the pharmacokinetics of a single oral dose of sildenafil (50 mg) was not altered. In volunteers with severe (CLcr less than 30 mL/min) renal impairment, sildenafil clearance was reduced, resulting in approximately doubling of AUC and Cmax compared to age-matched volunteers with no renal impairment. In addition, N-desmethyl metabolite AUC and Cmax values were significantly increased 200% and 79%, respectively, in patients with severe renal impairment compared to patients with normal renal function.
In volunteers with mild to moderate hepatic cirrhosis (Child-Pugh class A and B), sildenafil clearance was reduced, resulting in increases in AUC (84%) and Cmax (47%) compared to age-matched volunteers with no hepatic impairment. Patients with severe hepatic impairment (Child-Pugh class C) have not been studied.
Drug Interaction Studies
In vitro studies
Sildenafil metabolism is principally mediated by the CYP3A (major route) and CYP2C9 (minor route) cytochrome P450 isoforms. Therefore, inhibitors of these isoenzymes may reduce sildenafil clearance and inducers of these isoenzymes may increase sildenafil clearance.
Sildenafil is a weak inhibitor of the cytochrome P450 isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and 3A (IC50 greater than150 μM).
Sildenafil is not expected to affect the pharmacokinetics of compounds which are substrates of these CYP enzymes at clinically relevant concentrations.
In Vivo Studies
The effects of other drugs on sildenafil pharmacokinetics and the effects of sildenafil on the exposure to other drugs are shown in Figure 1 and Figure 2, respectively.
Figure 1: Effects of Other Drugs on Sildenafil Pharmacokinetics
Figure 2: Effects of Sildenafil on Other Drugs
CYP3A Inhibitors And Beta Blockers
Population pharmacokinetic analysis of data from patients in clinical trials indicated an approximately 30% reduction in sildenafil clearance when it was co-administered with mild/moderate CYP3A inhibitors and an approximately 34% reductions in sildenafil clearance when co-administered with beta-blockers. Sildenafil exposure at a dose of 80 mg three times a day without concomitant medication is shown to be 5-fold the exposure at a dose of 20 mg three times a day. This concentration range covers the same increased sildenafil exposure observed in specifically-designed drug interaction studies with CYP3A inhibitors (except for potent inhibitors such as ketoconazole, itraconazole, and ritonavir).
REVATIO Injection: Predictions based on a pharmacokinetic model suggest that drug-drug interactions with CYP3A inhibitors will be less than those observed after oral sildenafil administration.
CYP3A4 Inducers Including Bosentan
Concomitant administration of strong CYP3A inducers is expected to cause substantial decreases in plasma levels of sildenafil.
Population pharmacokinetic analysis of data from patients in clinical trials indicated approximately 3-fold the sildenafil clearance when it was co-administered with mild CYP3A inducers.
The mean reduction of sildenafil (80 mg three times a day) bioavailability when co-administered with epoprostenol was 28%, resulting in about 22% lower mean average steady state concentrations. Therefore, the slight decrease of sildenafil exposure in the presence of epoprostenol is not considered clinically relevant. The effect of sildenafil on epoprostenol pharmacokinetics is not known.
No significant interactions were shown with tolbutamide (250 mg) or warfarin (40 mg), both of which are metabolized by CYP2C9.
Sildenafil (50 mg) did not potentiate the hypotensive effect of alcohol in healthy volunteers with mean maximum blood alcohol levels of 0.08%.
SUPER-1 (NCT00644605) -REVATIO monotherapy [20 mg, 40 mg, and 80 mg three times a day]
A randomized, double-blind, placebo-controlled study of REVATIO (SUPER-1) was conducted in 277 patients with PAH (defined as a mean pulmonary artery pressure ≤25 mmHg at rest with a pulmonary capillary wedge pressure <15 mmHg). Patients were predominantly WHO Functional Classes II-III. Allowed background therapy included a combination of anticoagulants, digoxin, calcium channel blockers, diuretics, and oxygen. The use of prostacyclin analogues, endothelin receptor antagonists, and arginine supplementation were not permitted. Patients who had failed to respond to bosentan were also excluded. Patients with left ventricular ejection fraction less than 45% or left ventricular shortening fraction less than 0.2 also were not studied.
Patients were randomized to receive placebo (n = 70) or REVATIO 20 mg (n = 69), 40 mg (n = 67) or 80 mg (n = 71) three times a day for a period of 12 weeks. They had either primary pulmonary hypertension (PPH) (63%), PAH associated with CTD (30%), or PAH following surgical repair of left-to-right congenital heart lesions (7%). The study population consisted of 25% men and 75% women with a mean age of 49 years (range: 18 to 81 years) and baseline 6Âminute walk distance between 100 and 450 meters (mean 343).
The primary efficacy endpoint was the change from baseline at Week 12 (at least 4 hours after the last dose) in the 6-minute walk distance. Placebo-corrected mean increases in walk distance of 45-50 meters were observed with all doses of REVATIO. These increases were significantly different from placebo, but the REVATIO dose groups were not different from each other (see Figure 3), indicating no additional clinical benefit from doses higher than 20 mg three times a day. The improvement in walk distance was apparent after 4 weeks of treatment and was maintained at Week 8 and Week 12.
Figure 3: Change from Baseline in 6-Minute Walk Distance (meters) at Weeks 4, 8, and 12 in SUPER-1: Mean (95% Confidence Interval)
Figure 4 displays subgroup efficacy analyses in SUPER-1 for the change from baseline in 6ÂMinute Walk Distance at Week 12 including baseline walk distance, disease etiology, functional class, gender, age, and hemodynamic parameters.
Figure 4: Placebo-Corrected Change From Baseline in 6-Minute Walk Distance (meters) at Week 12 by Study Subpopulation in SUPER-1: Mean (95% Confidence Interval)
Key: PAH = pulmonary arterial hypertension; CTD = connective tissue disease; PH = pulmonary hypertension; PAP = pulmonary arterial pressure; PVRI = pulmonary vascular resistance index; TID = three times daily.
SUPER-2 (NCT00159887) Long-term Treatment Of PAH
In a long-term follow-up of patients who were treated with sildenafil (n=277), K-M estimates of survival at 1, 2, and 3 years were 94%, 88% , and 79%, respectively. These uncontrolled observations do not allow comparison with a group not given sildenafil and cannot be used to determine the long term-effect of sildenafil on mortality.
PACES-1 (NCT00159861) -REVATIO Co-administered With Epoprostenol
A randomized, double-blind, placebo-controlled study (PACES-1) was conducted in 267 patients with PAH who were taking stable doses of intravenous epoprostenol. Patients had to have a mean pulmonary artery pressure (mPAP) greater than or equal to 25 mmHg and a pulmonary capillary wedge pressure (PCWP) less than or equal to 15 mmHg at rest via right heart catheterization within 21 days before randomization, and a baseline 6-minute walk test distance greater than or equal to 100 meters and less than or equal to 450 meters (mean 349 meters). Patients were randomized to placebo or REVATIO (in a fixed titration starting from 20 mg to 40 mg and then 80 mg, three times a day) and all patients continued intravenous epoprostenol therapy.
At baseline patients had PPH (80%) or PAH secondary to CTD (20%); WHO Functional Class I (1%), II (26%), III (67%), or IV (6%); and the mean age was 48 years, 80% were female, and 79% were Caucasian.
There was a statistically significant greater increase from baseline in 6-minute walk distance at Week 16 (primary endpoint) for the REVATIO group compared with the placebo group. The mean change from baseline at Week 16 (last observation carried forward) was 30 meters for the REVATIO group compared with 4 meters for the placebo group giving an adjusted treatment difference of 26 meters (95% CI: 10.8, 41.2) (p = 0.0009).
Patients on REVATIO achieved a statistically significant reduction in mPAP compared to those on placebo. A mean placebo-corrected treatment effect of -3.9 mmHg was observed in favor of REVATIO (95% CI: -5.7, -2.1) (p = 0.00003).
Time to clinical worsening of PAH was defined as the time from randomization to the first occurrence of a clinical worsening event (death, lung transplantation, initiation of bosentan therapy, or clinical deterioration requiring a change in epoprostenol therapy). Table 4 displays the number of patients with clinical worsening events in PACES-1. Kaplan-Meier estimates and a stratified log-rank test demonstrated that placebo-treated patients were 3 times more likely to experience a clinical worsening event than REVATIO-treated patients and that REVATIO-treated patients experienced a significant delay in time to clinical worsening versus placebo-treated patients (p = 0.0074). Kaplan-Meier plot of time to clinical worsening is presented in Figure 5.
Table 4: Clinical Worsening Events in PACES-1
|Number of patients with clinical worsening first event||Placebo|
(N = 131)
(N = 134)
|First Event||All Events||First Event||AllEvents|
|Lung transplantation, n||1||1||0||0|
|Hospitalization due to PAH, n||9||11||8||8|
|Clinical deterioration resulting in:|
|Change of Epoprostenol Dose, n||9||16||0||2|
|Initiation of Bosentan, n||1||1||0||0|
|95% Confidence Interval||(0.12- 0.26)||(0.02 -0.10)|
Figure 5: Kaplan-Meier Plot of Time (in Days) to Clinical Worsening of PAH in PACES-1
Improvements in WHO Functional Class for PAH were also demonstrated in patients on REVATIO compared to placebo. More than twice as many REVATIO-treated patients (36%) as placebo-treated patients (14%) showed an improvement in at least one functional New York Heart Association (NYHA) class for PAH.
Study A1481243 (NCT00323297) -REVATIO Added To Bosentan Therapy â€“ Lack Of Effect On Exercise Capacity
A randomized, double-blind, placebo-controlled study was conducted in 103 patients with PAH who were on bosentan therapy for a minimum of 3 months. The PAH patients included those with primary PAH and PAH associated with CTD. Patients were randomized to placebo or sildenafil (20 mg three times a day) in combination with bosentan (62.5 to 125 mg twice a day). The primary efficacy endpoint was the change from baseline at Week 12 in 6-minute walk distance (6MWD). The results indicate that there is no significant difference in mean change from baseline on 6MWD observed between sildenafil 20 mg plus bosentan and bosentan alone.
STARTS-1 (NCT00159913) -Sildenafil In Treatment-Naive Children, Aged 1 To 17 Years, With Pulmonary Arterial Hypertension
A total of 234 patients with PAH aged 1 to 17 years were treated in a randomized, double-blind, multi-center, placebo-controlled parallel group, dose-ranging study. Patients (38% male and 62% female) had body weight ≥8 kg and had idiopathic pulmonary arterial hypertension (33%), or PAH associated with congenital heart disease (systemic-to-pulmonary shunt 37%, surgical repair 30%). In this trial, 27% of patients were <7 years old. Patients were WHO Functional Class I (32%), II (51%), III (15%), or IV (0.4%).
Patients were naÃ¯ve for specific PAH therapy and the use of prostacyclin, prostacyclin analogues and endothelin receptor antagonists were not permitted in the study, and neither were arginine supplementation, nitrates, alpha-blockers and potent CYP450 3A4 inhibitors.
The primary objective of the study was to assess the effect of REVATIO on percent change from baseline in PVO2, normalized to body weight, from baseline to week 16 as measured by the Cardiopulmonary Exercise Test (CPET) (patients who were developmentally able to perform the test, n = 115). Secondary endpoints included hemodynamic monitoring, symptom assessment, WHO Functional Class, change in background treatment, and quality of life measurements (n = 234).
Patients were allocated to one of three sildenafil treatment groups (low, medium, or high) or placebo. Actual doses administered were dependent on body weight (see Table 5).
Table 5: Treatment Allocation by Dose and Body Weight in Pediatric Study
|Body Weight (kg)||Placebo||Low Dose||Medium Dose||High Dose|
|>8 -20||18||na||10 mg||15||20 mg||35|
|>20 - 45||32||10 mg||31||20 mg||30||40 mg||31|
|>45||10||10 mg||11||40 mg||10||80 mg||11|
The proportion of patients receiving supportive medicinal products at baseline (anticoagulants, digoxin, calcium channel blockers, diuretics and/or oxygen) was similar in the combined sildenafil treatment group (48%) and the placebo treatment group (42%).
The primary endpoint was a percentage change in VO2peak from baseline to week 16 assessed by CPET. Mean baseline peak volume of oxygen consumed (VO2) values were similar across the sildenafil treatment groups (17 to 18 ml/kg/min), and slightly higher for the placebo treatment group (20 ml/kg/min). See Figure 6.
A total of 45% of patients were evaluable for CPET, which comprised those children ≤7 years old and developmentally able to perform the test. Children <7 years were evaluable only for the secondary endpoints.
Mean increases in VO2peak percentage change from baseline at Week 16, were observed with all 3 sildenafil doses (range of 6% to 13%, Figure 6), with little change with placebo (0.5%).
Figure 6: Percentage Change from Baseline in VO2Peak: Mean (95% Confidence Intervals)
The estimated difference between the combined sildenafil doses and placebo was 8% (95% CI: Â0.2 to 16). The results of the main analysis (combined dose groups versus placebo) were not statistically significant (p=0.056).
The estimated difference between the sildenafil medium dose group and placebo was 11±5% (95% CI: 2 to 21).
Impact On Hemodynamic Parameters
Dose related improvements were observed with PVRI and mPAP. Statistically significant PVRI reductions compared to placebo were seen with the sildenafil medium and high dose groups (18% [95% CI: -32% to -2%] and 27% [95% CI: -39% to -14%], respectively) but not the low dose group (2% (95% CI: -20%, 20%). The sildenafil medium and high dose groups displayed mPAP changes from baseline compared to placebo, of -3.5 mmHg (95% CI: -8.9, 1.9) and -7.3 mmHg (95% CI: -12.4, -2.1), respectively; while the low dose group showed little difference from placebo (difference of 1.6 mmHg [95% CI: -4.5, 7.6]). Improvements were observed with cardiac index with all three sildenafil groups over placebo, 10%, 4%, and 15% for the low, medium, and high dose groups, respectively [see CLINICAL PHARMACOLOGY].
STARTS-2 (NCT00159874) -Long-Term Survival With Oral Sildenafil Monotherapy In Treatment-NaÃ¯ve Pediatric Pulmonary Arterial Hypertension
Of the 234 pediatric patients treated in the short-term, placebo-controlled study, 220 patients entered the long-term extension study. Patients who had been in the placebo group in the short-term study were randomly reassigned to sildenafil treatment; patients weighing ≤20 kg entered the medium or high dose groups (1:2), while patients weighing >20 kg entered the low, medium, or high dose groups (1:1:1). Of the total 229 patients who received sildenafil, there were 55, 74, and 100 patients in the low, medium, and high dose groups, respectively. Across the short-term and long-term studies, the overall duration of treatment from start of double-blind for individual patients ranged from 3 to 3,129 days. By sildenafil treatment group, median duration of sildenafil treatment was 1,696 days (excluding the 5 patients who received placebo in double-blind and were not treated in the long-term extension study).
Peak VO2 was assessed 1 year after the start of the placebo-controlled study. Of sildenafil-treated patients developmentally able to perform the CPET 59/114 patients (52%) had not shown any deterioration in PVO2 from start of sildenafil. Similarly, 191 of 229 patients (83%) who had received sildenafil had either maintained or improved their WHO Functional Class at 1 year assessment.
Kaplan-Meier estimates of survival at 3 years in patients >20 kg in weight at baseline were 94%, 93%, and 85% in the low, medium, and high dose groups, respectively; for patients ≤20 kg in weight at baseline, the survival estimates were 94% and 93% for patients in the medium and high dose groups, respectively [see Use In Specific Populations Âand ADVERSE REACTIONS].
Study A1481324 (NCT02060487) -Study To Assess The Effects Of REVATIO On Mortality In Adults With PAH
A study to assess the effects of multiple doses of sildenafil on mortality in adults with PAH was conducted following the observation of a higher risk of mortality in pediatric patients taking a high dose of REVATIO TID, based on body weight, compared to those taking a lower dose of REVATIO in the long-term extension of the pediatric clinical trial.
The study was a randomized, double-blind, parallel-group study in 385 adults with PAH. Patients were randomly assigned 1:1:1 to one of three treatment groups (5, 20, and 80 mg TID). Most patients were PAH treatment naÃ¯ve (83%). For most patients the etiology of PAH was idiopathic (72%). The most common WHO Functional Class was Class III (58% of patients). Treatment groups were well balanced with respect to baseline demographics of strata history of PAH treatment and etiology of PAH, as well as the WHO Functional Class categories.
The primary objective of the study was to compare sildenafil 80 mg TID versus 5 mg TID for mortality, with success defined by ruling out twice the mortality at 80 mg.
The key secondary efficacy endpoint was time to first event of clinical worsening, defined as a composite endpoint of all-cause mortality, hospitalization for worsening PAH or disease progression. An additional secondary endpoint was 6MWD at Months 6 and 12.
At the time of a planned interim analysis (50% deaths) it was identified that the primary efficacy objective of this protocol was met and therefore the study was stopped. Based on the primary efficacy endpoint (mortality), the non-inferiority of sildenafil 80 mg TID arm versus 5 mg TID arm was met using a 2-sided significance level of 0.003 for the interim analysis. Primary comparison of the 80 mg TID group to the 5-mg TID group yielded the HR (99.7% CI) = 0.51 (0.22, 1.21); i.e., non-inferiority was established.
Table 6: Hazard Ratios for Overall Survival, Assessed in the Proportional Hazards Model â€“ Intent To Treat Population
N = 129
N = 128
|Sildenafil 80 mg|
N = 128
|Patient-years of follow-up||329.8||340.5||356.7|
|Number of deaths (%)||34 (26)||25 (20)||19 (15)|
|On treatment deathsa (%)||22 (17)||13 (10)||15 (12)|
|Off treatment deaths (%)||12 (9)||12 (9)||4 (3)|
|Hazard ratio relative to sildenafil 5mg|
|Hazard ratio estimateb||0.68||0.51|
|99.7% CI||0.31, 1.49||0.22, 1.21|
|Hazard ratio relative to sildenafil|
|20 mg Hazard ratio estimate||0.74|
|99.7% CI||0.30 1.84|
|a On treatment deaths: Any death within 7 days of last dose was regarded as “On treatment”, thus might include deaths occurred after discontinuation from study treatment|
b Hazard ratio estimates from the proportional Hazards model, stratified by actual previous PAH treatment and etiology of PAH.
Kaplan-Meier estimates of survival at 3 years were 66%, 79%, and 85% in the 5-, 20-, and 80Âmg TID dose groups, respectively
Sildenafil 80 mg was also superior to 5 mg for time to first event of clinical worsening with HR (99.7% CI) = 0.44 (0.22, 0.89).
Table 7: Hazard Ratios for Time to First Event of Clinical Worsening â€“ Intent To Treat Population
|Sildenafil 5 mg|
N = 129
|Sildenafil 20 mg|
N = 128
|Sildenafil 80 mg|
N = 128
|Patient-years of follow-up||249.6||276.4||306.5|
|Number of patients with clinical worsening||52||36||28|
|First Event of clinical worseninga n (%)|
|Disease progressionb||8 (6)||2 (2)||6 (5)|
|Hospitalization for PAHc||28 (22)||23 (18)||11 (9)|
|Deathd||16 (12)||11 (9)||11 (9)|
|Hazard ratio relative to sildenafil 5 mg|
|Hazard ratio estimatee||0.63||0.44|
|99.7% CI||0.33, 1.21||0.22, 0.89|
|Hazard ratio relative to sildenafil 20 mg|
|Hazard ratio estimatee||0.72|
|99.7% CI||0.34, 1.52|
|Note: Sildenafil 5 mg is not an approved dosage. Abbreviations: 6MWD = 6-minute walk distance; CI = confidence interval; PAH = pulmonary arterial hypertension.|
a Clinical worsening events were defined as reduction from baseline in the 6MWD test by at least 15% and worsening functional class from baseline, both confirmed by a second test/evaluation within 2 weeks.
b Count of cases of disease progression as the first event of clinical worsening.
c Count of non-elective hospital stays for worsening PAH as the first event of clinical worsening.
d Count of deaths as the first event of clinical worsening.
e Hazard ratio estimates from the proportional Hazards model, stratified by actual previous PAH treatment and etiology of PAH. P-value from the Wald test.
6MWD At Months 6 And 12
At baseline, the median of 6MWD for the intent-to-treat (ITT) population was 332 to 352 m. At Month 6, the median change from baseline was highest for sildenafil 80 mg TID with 28 m compared to 18 m and 19 m for sildenafil 5 mg TID and sildenafil 20 mg TID groups, respectively. The same was seen at Month 12, the median change from baseline for sildenafil 80 mg TID group was 33 m compared to 17 m for sildenafil 5 mg TID and 31 m in sildenafil 20 mg TID groups.
Overall, the safety data for sildenafil 20 mg TID and for the higher sildenafil 80 mg TID dose were consistent with the established safety profile of sildenafil in previous adult PAH studies [see ADVERSE REACTIONS].