madman
Super Moderator
Efficacy and safety of avanafil as compared with sildenafil in the treatment of erectile dysfunction: A randomized, double-blind, multicenter clinical trial (2022)
Manish Kumar, Amey D Pathade, S VijayaBhaskara Gupta, Sanjay Goyal, Debadarshi Rath, Manish Thakre, Jayesh Sanmukhani, and Ravindra Mittal
Objective: To compare the efficacy and safety of avanafil as compared with sildenafil in the management of patients with erectile dysfunction.
Methods: It was a prospective, randomized, double-blind, two-arm, active-controlled, parallel, multicenter, non-inferiority clinical study carried out in patients with erectile dysfunction for at least 3 months and International Index of Erectile Function – Erectile Function domain score of <26 at enrolment.
Results: A total of 220 patients were randomized to receive either avanafil tablets 100 mg or sildenafil tablets 50 mg in a 1:1 ratio. After 4 weeks of treatment, 40.0% of patients in the avanafil group and 45.6% of patients in the sildenafil group required dose escalation to a high dose (avanafil 200 mg/sildenafil 100 mg). The difference in the mean change of International Index of Erectile Function – Erectile Function score from baseline in the two groups increased from week 4 (1.1, 95% confidence interval 0.2 to 2.5) to week 8 (1.4, 95% confidence interval 0.1–2.7) and week 12 (2.1, 95% confidence interval 0.8–3.5), showing non-inferiority at week 4, and superiority at week 8 and week 12. Avanafil showed a faster onset of action as shown by a significantly better response to modified Sexual Encounter Profile 1 in the avanafil group (84.8%) as compared with that in the sildenafil group (28.2%; P < 0.001). Both avanafil and sildenafil were well tolerated by all the patients in the study; the most common adverse event reported during the study was a headache in both groups.
Conclusion: Avanafil is superior to sildenafil in improving the International Index of Erectile Function – Erectile Function domain score at the end of 12 weeks of treatment with the added advantage of faster onset of action.
Introduction
ED is defined as the inability to attain or maintain an erection sufficient for satisfactory sexual performance. Worldwide, more than 150 million men are reported to be affected by ED, with an estimated incidence rate of 26 new cases per 1000 men annually. With the expected rise in the aging population, the demand for therapies for the treatment of ED will continue to increase.1 The causes of ED are often multifactorial, and consist of a mix of organic and psychogenic factors.2 Various medical and interventional therapies are available for management of ED, such as PDE5 inhibitors, vacuum erection devices, penile self-injection regimens (with vasoactive drugs such as alprostadil), and penile prostheses; however, because of the ease of use, good efficacy, and favorable adverse effect profiles, PDE5 inhibitors have been recognized as the first-line of therapy.3
Various PDE5 inhibitors, such as sildenafil, tadalafil, udenafil, and vardenafil, have shown efficacy rates as high as 80% in ED patients, associated with comorbidities, such as diabetes, hypertension, cardiovascular disease, neurological disorders (such as spinal cord injury, multiple sclerosis), renal insufficiency and a history of urological pelvic surgery. The efficacy of these available PDE5 inhibitors has been acceptable with both on-demand and chronic use; however, they are often associated with adverse events, such as headache, flushing, dyspepsia, visual disturbances, back pain, tachycardia, and nasal congestion, attributed to non-selective inhibition of other PDE isoenzymes in the body.1,3–5 Also, there are still a number of patients who fail to respond clinically to PDE5 treatment due to lack of efficacy or intolerable adverse effects, or a combination of the two. Up to 70% of men who seek care for their ED discontinue treatment within 2–3 years of follow-up.1,6 Hence, physicians continue to seek out novel and alternative formulations to maximize efficacy and minimize adverse effects
Avanafil (4-[(3-chloro-4-methoxybenzyl)amino]-2-[2-(hydroxymethyl)-1-pyrrolidinyl]-N-(2-pyrimidinylmethyl)-5-pyrimidinecarboxamide), a second-generation selective PDE5 inhibitor, has a rapid onset of action (as early as 15 min), a Tmax of 30–45 min and a terminal half-life of 3–5 h. The recommended starting dose of avanafil is 100 mg taken as early as approximately 15 min before sexual activity, on an as-needed basis, and based on efficacy and/or tolerability, the dose can be increased to 200 mg taken as early as approximately 15 min before sexual activity, or decreased to 50 mg taken approximately 30 min before sexual activity.7 Avanafil has already been approved in the USA since 2012, in the European Union since 2013 and various other countries, such as South Korea, Australia, New Zealand, Russia, Jordan, UAE, Turkey, and Saudi Arabia, based on the favorable efficacy and safety profile of the product as confirmed in a number of double-blind, placebo-controlled, randomized clinical trials, carried out both in the general population and in “difficult” to treat patient subgroups, such as those with diabetes mellitus or those who have undergone nerve-sparing radical prostatectomy.8–12
Even after many years of approval and successful use in the management of ED, only limited data are available on the comparative evaluation of the efficacy and safety of avanafil with other PDE5 inhibitors. To date, only a single study has been published comparing the efficacy and safety of avanafil to sildenafil, which is too difficult to treat a subset of patients; that is, patients undergoing rehabilitation therapy after robot-assisted unilateral nerve-sparing prostatectomy.13 The current study was planned to compare the efficacy and safety of avanafil to sildenafil in the management of Indian patients with ED.
Study procedures and drugs
Patients satisfying the eligibility criteria were randomized in a 1:1 ratio to receive either the test (avanafil) or reference (sildenafil) drugs, in a double-blind fashion. Avanafil 100 mg tablets were similar to sildenafil 50 mg tablets, whereas avanafil tablets 200 mg were similar to sildenafil 100 mg tablets. Patients were followed up for a total duration of 12 weeks, with scheduled visits at 4-week intervals during the present study. Patients were asked to take the study drugs (test – avanafil tablets 100 mg/200 mg or reference – sildenafil tablets 50 mg/100 mg) before the initiation of sexual activity. All patients were given a low dose of the medication; that is, avanafil tablets 100 mg/sildenafil tablets 50 mg to begin with. After 4 weeks of treatment, if the dose was required to be increased, the patients were given avanafil tablets 200 mg/sildenafil tablets 100 mg. Patients were allowed to take only one dose of study medication in a day (calendar day) and were asked to take at least four doses of the medication (and attempt intercourse) on four separate occasions during each 4-week follow-up period.
Discussion
This study presents the results of the randomized, double-blind study comparing the efficacy and safety of avanafil with sildenafil in the treatment of ED in Indian patients. Although the study was designed to show non-inferiority of avanafil as compared with sildenafil, the study showed statistical superiority of avanafil over sildenafil in almost all the efficacy variables, including the IIEF-EF domain scores and modified SEP 1, SEP 2, and SEP 3 patient diary questions at the end of 12 weeks of treatment
Since their introduction, PDE5 inhibitors have been considered as the first-line of treatment for ED irrespective of the cause of the disease. Although effective, the first-generation PDE5 inhibitors are associated with few concerns; for example, reduced efficacy due to improper time of dosing (related to delayed onset of action) and side effects due to off-target action of the drugs (inhibition of other PDE isoenzymes).16
Avanafil addresses both these problems with its favorable pharmacokinetic and pharmacodynamic profile.
PDE5 inhibitors have often been used as an on-demand therapy, and patients tend to use the drug just before sexual intercourse; however, the currently available PDE5 inhibitors have a late onset of action (30–60 min for sildenafil and 15– 45 min for tadalafil), often leading to reduced therapeutic efficacy. Avanafil has a distinct advantage in terms of its onset of action, which starts well within 15 min of drug intake.17 This effect was also seen in the present study, as the patients reported the start of drug activity (i.e. some erection) within 15 min of drug intake in >84% doses of avanafil, as compared with just 28% doses of sildenafil consumed during the study. This earlier onset of action with avanafil is linked to the better pharmacokinetic profile of the drug; the Tmax of avanafil is 30–45 min, as compared with 60 min for sildenafil and vardenafil, and 120 min for tadalafil.17 A separate randomized, double-blind placebo-controlled study has been carried out to specifically evaluate the therapeutic effect of avanafil 15 min after dosing in men with mild-to-severe ED. The study showed significantly greater percentages of successful intercourse attempts (SEP 3) within approximately 15 min after dosing with avanafil 100 mg (mean 25.9%) and 200 mg (mean 29.1%), as compared with placebo (mean 14.9%). This significant difference in the proportion of successful intercourse attempts (SEP 3) was noted as early as 10 min in the 200 mg group and 12 min in the 100 mg group, as compared with a placebo.18 In another randomized double-blind placebo-controlled study, the proportions of successful intercourse by time interval from dose to attempt was evaluated, and it was found that avanafil has a similar success rate irrespective of the time interval from dose to attempt; that is, whether the attempt is made within 15 min of drug intake or even after 6 h of drug intake.9 Based on the rapid onset of action, avanafil is recommended to be taken 15 min before the desired sexual activity on an as-needed basis,7 whereas sildenafil is recommended to be taken approximately 1 h before the desired sexual activity.19
Avanafil is also advantageous in terms of side effects due to its high selectivity for PDE5. Preclinical studies have reported that avanafil strongly inhibited PDE5 (half maximal inhibitory concentration, 5.2 nmol/L) in a competitive manner. In an in vitro receptor-binding study comparing the inhibitory effects of avanafil on 11 PDE isozymes with those of sildenafil, vardenafil, and tadalafil, avanafil potently inhibited PDE5 activity without significant inhibition of other PDE isozymes. In contrast, sildenafil, vardenafil, and tadalafil produced inhibitory activity for other PDE isozymes (PDE1, PDE6, and PDE11). Avanafil has higher selectivity against PDE6 (120-fold) than sildenafil (16-fold) and vardenafil (21- fold); against PDE1 (>10 000-fold), as compared with sildenafil (380-fold) and vardenafil (1000-fold); and against PDE11 (>19 000), as compared with tadalafil (25 fold). As avanafil has relatively little cross-reactivity with other PDE isoenzymes, especially PDE1, PDE6, and PDE11, which are causes of various side-effects (PDE1 isozyme affects vascular smooth muscle contraction and its inhibition leads to vasodilation and symptomatic hypotension, headache, and flushing; PDE6 is involved in phototransduction in the retina, and its inhibition leads to the inability to discriminate between blue and green [blue/green] and transient cyanopsia; whereas inhibition of PDE11 leads to increased incidence of back pain and myalgia), it is expected to confer improved tolerability in long-term clinical use, as compared with the other PDE5 inhibitors.20 In fact, on comparing the safety profile of various PDE5 inhibitors from published literature, it was found that avanafil 200 mg has the lowest rate of common adverse events in terms of headache (9.3% vs sildenafil 100 mg 12.8% vs tadalafil 20 mg 14.5% and vs vardenafil 20 mg 16%), flushing (3.7% vs sildenafil 100 mg 10.4% vs tadalafil 20 mg 4.1% and vardenafil 20 mg 12%), abnormal vision (none vs sildenafil 100 mg 1.9% and vardenafil 20 mg <2%) and back pain/myalgia (<2% vs tadalafil 6.5%/5.7%).17
The results of the present prospective, randomized, double-blind, two-arm, active-controlled, parallel, multicenter, noninferiority clinical trial show that avanafil is superior to sildenafil in improving the IIEF-EF domain score at the end of 12 weeks of treatment. Avanafil was also found to be non-inferior/superior to sildenafil in other efficacy parameters, including the percentage of attempts with successful vaginal penetration and successful intercourse, and improvement in the IIEF scores in the other domains. Also, avanafil was found to be superior to sildenafil in the percentage of doses that led to an erection in <15 min, further establishing its faster onset of action, as compared with sildenafil.
Manish Kumar, Amey D Pathade, S VijayaBhaskara Gupta, Sanjay Goyal, Debadarshi Rath, Manish Thakre, Jayesh Sanmukhani, and Ravindra Mittal
Objective: To compare the efficacy and safety of avanafil as compared with sildenafil in the management of patients with erectile dysfunction.
Methods: It was a prospective, randomized, double-blind, two-arm, active-controlled, parallel, multicenter, non-inferiority clinical study carried out in patients with erectile dysfunction for at least 3 months and International Index of Erectile Function – Erectile Function domain score of <26 at enrolment.
Results: A total of 220 patients were randomized to receive either avanafil tablets 100 mg or sildenafil tablets 50 mg in a 1:1 ratio. After 4 weeks of treatment, 40.0% of patients in the avanafil group and 45.6% of patients in the sildenafil group required dose escalation to a high dose (avanafil 200 mg/sildenafil 100 mg). The difference in the mean change of International Index of Erectile Function – Erectile Function score from baseline in the two groups increased from week 4 (1.1, 95% confidence interval 0.2 to 2.5) to week 8 (1.4, 95% confidence interval 0.1–2.7) and week 12 (2.1, 95% confidence interval 0.8–3.5), showing non-inferiority at week 4, and superiority at week 8 and week 12. Avanafil showed a faster onset of action as shown by a significantly better response to modified Sexual Encounter Profile 1 in the avanafil group (84.8%) as compared with that in the sildenafil group (28.2%; P < 0.001). Both avanafil and sildenafil were well tolerated by all the patients in the study; the most common adverse event reported during the study was a headache in both groups.
Conclusion: Avanafil is superior to sildenafil in improving the International Index of Erectile Function – Erectile Function domain score at the end of 12 weeks of treatment with the added advantage of faster onset of action.
Introduction
ED is defined as the inability to attain or maintain an erection sufficient for satisfactory sexual performance. Worldwide, more than 150 million men are reported to be affected by ED, with an estimated incidence rate of 26 new cases per 1000 men annually. With the expected rise in the aging population, the demand for therapies for the treatment of ED will continue to increase.1 The causes of ED are often multifactorial, and consist of a mix of organic and psychogenic factors.2 Various medical and interventional therapies are available for management of ED, such as PDE5 inhibitors, vacuum erection devices, penile self-injection regimens (with vasoactive drugs such as alprostadil), and penile prostheses; however, because of the ease of use, good efficacy, and favorable adverse effect profiles, PDE5 inhibitors have been recognized as the first-line of therapy.3
Various PDE5 inhibitors, such as sildenafil, tadalafil, udenafil, and vardenafil, have shown efficacy rates as high as 80% in ED patients, associated with comorbidities, such as diabetes, hypertension, cardiovascular disease, neurological disorders (such as spinal cord injury, multiple sclerosis), renal insufficiency and a history of urological pelvic surgery. The efficacy of these available PDE5 inhibitors has been acceptable with both on-demand and chronic use; however, they are often associated with adverse events, such as headache, flushing, dyspepsia, visual disturbances, back pain, tachycardia, and nasal congestion, attributed to non-selective inhibition of other PDE isoenzymes in the body.1,3–5 Also, there are still a number of patients who fail to respond clinically to PDE5 treatment due to lack of efficacy or intolerable adverse effects, or a combination of the two. Up to 70% of men who seek care for their ED discontinue treatment within 2–3 years of follow-up.1,6 Hence, physicians continue to seek out novel and alternative formulations to maximize efficacy and minimize adverse effects
Avanafil (4-[(3-chloro-4-methoxybenzyl)amino]-2-[2-(hydroxymethyl)-1-pyrrolidinyl]-N-(2-pyrimidinylmethyl)-5-pyrimidinecarboxamide), a second-generation selective PDE5 inhibitor, has a rapid onset of action (as early as 15 min), a Tmax of 30–45 min and a terminal half-life of 3–5 h. The recommended starting dose of avanafil is 100 mg taken as early as approximately 15 min before sexual activity, on an as-needed basis, and based on efficacy and/or tolerability, the dose can be increased to 200 mg taken as early as approximately 15 min before sexual activity, or decreased to 50 mg taken approximately 30 min before sexual activity.7 Avanafil has already been approved in the USA since 2012, in the European Union since 2013 and various other countries, such as South Korea, Australia, New Zealand, Russia, Jordan, UAE, Turkey, and Saudi Arabia, based on the favorable efficacy and safety profile of the product as confirmed in a number of double-blind, placebo-controlled, randomized clinical trials, carried out both in the general population and in “difficult” to treat patient subgroups, such as those with diabetes mellitus or those who have undergone nerve-sparing radical prostatectomy.8–12
Even after many years of approval and successful use in the management of ED, only limited data are available on the comparative evaluation of the efficacy and safety of avanafil with other PDE5 inhibitors. To date, only a single study has been published comparing the efficacy and safety of avanafil to sildenafil, which is too difficult to treat a subset of patients; that is, patients undergoing rehabilitation therapy after robot-assisted unilateral nerve-sparing prostatectomy.13 The current study was planned to compare the efficacy and safety of avanafil to sildenafil in the management of Indian patients with ED.
Study procedures and drugs
Patients satisfying the eligibility criteria were randomized in a 1:1 ratio to receive either the test (avanafil) or reference (sildenafil) drugs, in a double-blind fashion. Avanafil 100 mg tablets were similar to sildenafil 50 mg tablets, whereas avanafil tablets 200 mg were similar to sildenafil 100 mg tablets. Patients were followed up for a total duration of 12 weeks, with scheduled visits at 4-week intervals during the present study. Patients were asked to take the study drugs (test – avanafil tablets 100 mg/200 mg or reference – sildenafil tablets 50 mg/100 mg) before the initiation of sexual activity. All patients were given a low dose of the medication; that is, avanafil tablets 100 mg/sildenafil tablets 50 mg to begin with. After 4 weeks of treatment, if the dose was required to be increased, the patients were given avanafil tablets 200 mg/sildenafil tablets 100 mg. Patients were allowed to take only one dose of study medication in a day (calendar day) and were asked to take at least four doses of the medication (and attempt intercourse) on four separate occasions during each 4-week follow-up period.
Discussion
This study presents the results of the randomized, double-blind study comparing the efficacy and safety of avanafil with sildenafil in the treatment of ED in Indian patients. Although the study was designed to show non-inferiority of avanafil as compared with sildenafil, the study showed statistical superiority of avanafil over sildenafil in almost all the efficacy variables, including the IIEF-EF domain scores and modified SEP 1, SEP 2, and SEP 3 patient diary questions at the end of 12 weeks of treatment
Since their introduction, PDE5 inhibitors have been considered as the first-line of treatment for ED irrespective of the cause of the disease. Although effective, the first-generation PDE5 inhibitors are associated with few concerns; for example, reduced efficacy due to improper time of dosing (related to delayed onset of action) and side effects due to off-target action of the drugs (inhibition of other PDE isoenzymes).16
Avanafil addresses both these problems with its favorable pharmacokinetic and pharmacodynamic profile.
PDE5 inhibitors have often been used as an on-demand therapy, and patients tend to use the drug just before sexual intercourse; however, the currently available PDE5 inhibitors have a late onset of action (30–60 min for sildenafil and 15– 45 min for tadalafil), often leading to reduced therapeutic efficacy. Avanafil has a distinct advantage in terms of its onset of action, which starts well within 15 min of drug intake.17 This effect was also seen in the present study, as the patients reported the start of drug activity (i.e. some erection) within 15 min of drug intake in >84% doses of avanafil, as compared with just 28% doses of sildenafil consumed during the study. This earlier onset of action with avanafil is linked to the better pharmacokinetic profile of the drug; the Tmax of avanafil is 30–45 min, as compared with 60 min for sildenafil and vardenafil, and 120 min for tadalafil.17 A separate randomized, double-blind placebo-controlled study has been carried out to specifically evaluate the therapeutic effect of avanafil 15 min after dosing in men with mild-to-severe ED. The study showed significantly greater percentages of successful intercourse attempts (SEP 3) within approximately 15 min after dosing with avanafil 100 mg (mean 25.9%) and 200 mg (mean 29.1%), as compared with placebo (mean 14.9%). This significant difference in the proportion of successful intercourse attempts (SEP 3) was noted as early as 10 min in the 200 mg group and 12 min in the 100 mg group, as compared with a placebo.18 In another randomized double-blind placebo-controlled study, the proportions of successful intercourse by time interval from dose to attempt was evaluated, and it was found that avanafil has a similar success rate irrespective of the time interval from dose to attempt; that is, whether the attempt is made within 15 min of drug intake or even after 6 h of drug intake.9 Based on the rapid onset of action, avanafil is recommended to be taken 15 min before the desired sexual activity on an as-needed basis,7 whereas sildenafil is recommended to be taken approximately 1 h before the desired sexual activity.19
Avanafil is also advantageous in terms of side effects due to its high selectivity for PDE5. Preclinical studies have reported that avanafil strongly inhibited PDE5 (half maximal inhibitory concentration, 5.2 nmol/L) in a competitive manner. In an in vitro receptor-binding study comparing the inhibitory effects of avanafil on 11 PDE isozymes with those of sildenafil, vardenafil, and tadalafil, avanafil potently inhibited PDE5 activity without significant inhibition of other PDE isozymes. In contrast, sildenafil, vardenafil, and tadalafil produced inhibitory activity for other PDE isozymes (PDE1, PDE6, and PDE11). Avanafil has higher selectivity against PDE6 (120-fold) than sildenafil (16-fold) and vardenafil (21- fold); against PDE1 (>10 000-fold), as compared with sildenafil (380-fold) and vardenafil (1000-fold); and against PDE11 (>19 000), as compared with tadalafil (25 fold). As avanafil has relatively little cross-reactivity with other PDE isoenzymes, especially PDE1, PDE6, and PDE11, which are causes of various side-effects (PDE1 isozyme affects vascular smooth muscle contraction and its inhibition leads to vasodilation and symptomatic hypotension, headache, and flushing; PDE6 is involved in phototransduction in the retina, and its inhibition leads to the inability to discriminate between blue and green [blue/green] and transient cyanopsia; whereas inhibition of PDE11 leads to increased incidence of back pain and myalgia), it is expected to confer improved tolerability in long-term clinical use, as compared with the other PDE5 inhibitors.20 In fact, on comparing the safety profile of various PDE5 inhibitors from published literature, it was found that avanafil 200 mg has the lowest rate of common adverse events in terms of headache (9.3% vs sildenafil 100 mg 12.8% vs tadalafil 20 mg 14.5% and vs vardenafil 20 mg 16%), flushing (3.7% vs sildenafil 100 mg 10.4% vs tadalafil 20 mg 4.1% and vardenafil 20 mg 12%), abnormal vision (none vs sildenafil 100 mg 1.9% and vardenafil 20 mg <2%) and back pain/myalgia (<2% vs tadalafil 6.5%/5.7%).17
The results of the present prospective, randomized, double-blind, two-arm, active-controlled, parallel, multicenter, noninferiority clinical trial show that avanafil is superior to sildenafil in improving the IIEF-EF domain score at the end of 12 weeks of treatment. Avanafil was also found to be non-inferior/superior to sildenafil in other efficacy parameters, including the percentage of attempts with successful vaginal penetration and successful intercourse, and improvement in the IIEF scores in the other domains. Also, avanafil was found to be superior to sildenafil in the percentage of doses that led to an erection in <15 min, further establishing its faster onset of action, as compared with sildenafil.
