Does Teriparatide Improve Femoral Neck Fracture Healing: Results From A Randomized Placebo-controlled Trial.

BACKGROUND: There is a medical need for therapies that improve hip fracture healing. Teriparatide (Forteo(®)/ Forsteo(®), recombinant human parathyroid hormone) is a bone anabolic drug that is approved for treatment of osteoporosis and glucocorticoid-induced osteoporosis in men and postmenopausal women at high fracture risk. Preclinical and preliminary clinical data also suggest that teriparatide may enhance bone healing. QUESTIONS/PURPOSES: We wished to test the hypotheses that treatment with teriparatide versus placebo would improve femoral neck fracture healing after internal fixation as measured by (1) frequency of revision surgery, (2) radiographic fracture healing, and (3) other outcomes including pain control, gait speed, and safety. METHODS: We initiated two separate, but identically designed, clinical trials to meet FDA requirements to provide substantial evidence to support approval of a new indication. The two prospective, randomized double-blind, placebo-controlled Phase III studies were designed to evaluate the effect of subcutaneous teriparatide (20 µg/day) for 6 months versus placebo on fracture healing at 24 months. The trials were conducted concurrently with a planned enrollment of 1220 patients per trial. However, enrollment was stopped owing to very slow patient accrual, and an a priori decision was made to pool the results of those studies for statistical analyses before study completion; pooling was specified in both protocols. Randomization was stratified by fixation (sliding hip screw or multiple cancellous screws) and fracture type (displaced or nondisplaced). An independent Central Adjudication Committee reviewed revision surgical procedures and radiographs. A total of 159 patients were randomized in the two trials (81 placebo, 78 teriparatide). The combined program had very low power to detect the originally expected treatment effect but had approximately 80% power to detect a larger difference of 12% between treatment groups for risk of revision surgery. RESULTS: The proportion of patients undergoing revision surgery at 12 months was 14% (11 of 81) in the placebo group versus 17% (13 of 78) in the teriparatide group. Central Adjudication Committee review excluded two of these patients treated with placebo from the primary analysis. After exclusions, the proportion of patients who did not undergo revision surgery at 12 months (primary endpoint) was not different between the study and placebo groups, at 88% in the placebo group (90% CI, 0.79-0.93) versus 84% in the teriparatide group (90% CI, 0.75-0.90; p = 0.743). There also were no differences between groups in the proportion of patients achieving radiographic fracture healing at 12 months (75% [61 of 81] placebo versus 73% [57 of 78] teriparatide; odds ratio, 0.89; 90% CI, 0.46-1.72; p = 0.692) or in measures of pain control (such as pain during ambulation, 92% [55 of 62] placebo versus 91% [52 of 57] teriparatide; odds ratio, 0.91; 90% CI, 0.25-3.37; p = 0.681). The frequency of patients reporting adverse events was 49% [40 of 81] in the placebo group versus 45% [35 of 78] in the teriparatide group (p = 0.634) during the 6-month treatment period. CONCLUSIONS: The small sample size limited this study's power to detect potential differences, and the results are exploratory. With the patients available, teriparatide did not decrease the risk of revision surgery, improve radiographic signs of fracture healing, or decrease pain compared with the placebo. The adverse event data observed were consistent with the teriparatide safety profile. Functional and health outcome data from the studies may help improve our understanding of patients recovering from femoral neck fractures. Further large controlled studies are required to determine the effect of teriparatide on fracture healing. LEVEL OF EVIDENCE: Level II, prospective study.

Implementing Benefit-Risk Assessment for the Periodic Benefit-Risk Evaluation Report.

BACKGROUND: In 2012, the International Conference on Harmonisation (ICH) E2C (R1) guideline for periodic safety update reporting (PSUR) for medicines was revised. Several new concepts that expanded the scope of the report were added, including a new section focused on benefits and an additional section focused on integrated benefit-risk (B-R) assessment. These changes are reflected in the new title of the report, namely, the Periodic Benefit-Risk Evaluation Report (PBRER). Recently, structured frameworks have been developed by the pharmaceutical industry and regulatory agencies to facilitate B-R analysis for medicines. METHODS: This manuscript provides suggestions for incorporating the elements of a structured B-R assessment into the PBRER and also includes practical approaches for implementing the ICH guidelines for the B-R analysis section. RESULTS: The main components of a B-R assessment for the PBRER include decision context; key benefits and key risks; strengths, limitations, and uncertainties of the evidence; risk management; and the overall B-R conclusions. CONCLUSIONS: A structured, systematic approach to defining a medicine's B-R profile will help ensure compliance with this ICH objective for the PBRER.

Effects of teriparatide on bone mineral density and bone turnover markers in Japanese subjects with osteoporosis at high risk of fracture in a 24-month clinical study: 12-month, randomized, placebo-controlled, double-blind and 12-month open-label phases.

This multicenter study assessed the safety and efficacy of teriparatide 20 microg/day in Japanese men and women with osteoporosis at high risk of fracture during a 12-month, randomized, double-blind, placebo-controlled treatment period followed by second and third treatment periods (to 18 and 24 months, respectively,) in which all subjects received open-label teriparatide. Subjects (93% female; median age 70 years) were randomized 2:1 to teriparatide versus placebo (randomized at baseline, teriparatide n=137, placebo-teriparatide n=70; entering the second period, teriparatide n=119, placebo-teriparatide n=59; entering the third period, teriparatide n=102, placebo-teriparatide n=50). For subjects with measurements at 12 months, teriparatide significantly increased bone mineral density (BMD) at the lumbar spine L2-L4 (mean percent change+/-SD, teriparatide 10.04+/-5.23% versus placebo-teriparatide 0.19+/-4.33%), the femoral neck (teriparatide 2.01+/-4.63% versus placebo-teriparatide 0.44+/-3.97%), and the total hip (teriparatide 2.72+/-4.04% versus placebo-teriparatide -0.26+/-3.42%). In the placebo-teriparatide group at 24 months (12-month teriparatide dosing) BMD increased by 9.11+/-5.14% at the lumbar spine, 2.19+/-4.81% at the femoral neck and 2.46+/-3.54% at the total hip. In the teriparatide group at 18 and 24 months, BMD increased from baseline at the lumbar spine by 11.93+/-5.79% and 13.42+/-6.12%, respectively; at the femoral neck by 2.68+/-4.45% and 3.26+/-4.25%, respectively; and at the total hip by 3.02+/-3.79% and 3.67+/-3.98%, respectively. Serum procollagen I N-terminal pro-peptide (PINP) increased rapidly with teriparatide treatment (P<0.001 versus placebo at 1 month) and changed from baseline in the teriparatide and placebo-teriparatide groups at 12 months by a median of 78.95% and -17.23%, respectively, (P<0.001) and at 24 months by 49.24% and 76.12%, respectively. The incidence of treatment-emergent adverse events (TEAEs), serious TEAEs, and discontinuations due to TEAEs were comparable in the teriparatide and placebo-teriparatide groups. These data show that teriparatide 20 microg/day was well tolerated and stimulated bone formation in Japanese subjects with osteoporosis at high risk of fracture during 18 and 24 months of treatment.

Bone formation markers in patients with glucocorticoid-induced osteoporosis treated with teriparatide or alendronate.

Reduced osteoblast function is a primary defect in glucocorticoid-induced osteoporosis (GIO), and is reflected by decreased biochemical markers of bone formation, such as serum osteocalcin (OC) and procollagen type I N-terminal propeptide (PINP). This analysis compared the effects of teriparatide and alendronate on OC and PINP in patients with GIO. In a double-blind study, women (N=159) and men (N=38) with GIO were randomized to either teriparatide 20 mug/day by subcutaneous injection or to alendronate 10 mg/day orally. OC and PINP were measured in fasting-state serum samples obtained at baseline and at 1, 6, 18, and 36 months. Baseline bone formation markers were below the reference interval (low) in 33% of patients for OC and in 4% of patients for PINP. On teriparatide therapy, the median OC and PINP levels increased by 92% and 108%, respectively, and this resulted in only 12% and 1% of patients being low at 6 months. On alendronate therapy, the median OC and PINP levels decreased by 40% and 53%, respectively, and this resulted in 68% and 34% of patients being low at 6 months. We conclude that bone formation as determined by surrogate markers was increased in teriparatide-treated patients with GIO and decreased in alendronate-treated patients with GIO.

Correlations between biochemical markers of bone turnover and bone density responses in patients with glucocorticoid-induced osteoporosis treated with teriparatide or alendronate.

The purpose of this post hoc analysis was to determine whether baseline concentrations or early changes in serum bone turnover markers were correlated with changes in bone mineral density (BMD) at 18 months in patients with glucocorticoid-induced osteoporosis (GIO) treated with teriparatide (n=80; 20 mug/day) or alendronate (n=77; 10 mg/day). Bone markers included type I collagen N-terminal propeptide (PINP), type I collagen C-terminal propeptide (PICP), bone alkaline phosphatase (bone ALP), and cross-linked C-telopeptide of type I collagen (Sbeta-CTX). The relationship between baseline and early changes in markers and the 18-month changes in lumbar spine (LS) and femoral neck (FN) BMD was evaluated using Spearman correlation analysis. In the teriparatide group, increases in LS and FN BMD at 18 months were not significantly correlated with baseline marker concentrations (P>0.05) but were correlated with the increases in PINP at 1 and 6 months (P<0.05). In the alendronate group, the increase in FN BMD at 18 months was positively correlated with baseline marker concentrations (P<0.05) and negatively correlated with change in PINP and Sbeta-CTX at 1 and 6 months. In addition, in the alendronate group, the increase in LS BMD was negatively correlated with change in Sbeta-CTX at 1 month (P<0.05). Increases in BMD at the spine and hip were independent of baseline bone turnover in the teriparatide group, while increases in hip BMD were dependent on baseline bone turnover in the alendronate group. With both therapies, early changes in some bone turnover markers were correlated with 18-month gains in BMD in patients with GIO.

Baseline glucocorticoid dose and bone mineral density response with teriparatide or alendronate therapy in patients with glucocorticoid-induced osteoporosis.

OBJECTIVE: This post-hoc analysis studied the effect of baseline glucocorticoid dose on the 18-month bone mineral density (BMD) response to teriparatide 20 microg/day or alendronate 10 mg/day in 387 patients with glucocorticoid-induced osteoporosis (GIO) from a randomized, double-blind trial. METHODS: Lumbar spine (LS), femoral neck (FN), and total hip (TH) BMD were measured at baseline and 18 months. Mean baseline glucocorticoid dose was categorized as low (< or = 5 mg/day), medium (> 5 and < 15 mg/day), or high (> or = 15 mg/day). RESULTS: Baseline LS, FN, and TH BMD were similar between groups, and between glucocorticoid dose categories within each group. LS BMD increases at the low, medium, and high glucocorticoid doses were 8.1%, 6.6%, and 4.6%, respectively, with teriparatide, and 3.6%, 2.8%, and 2.3% with alendronate. Analyzed as a continuous variable, higher glucocorticoid doses had a negative, but non-significant, effect on the percentage increase in LS BMD in both groups. Glucocorticoid dose did not significantly affect FN or TH BMD increases in either group. Across the 3 glucocorticoid dose categories, the overall LS BMD increases were different for both treatments combined (p = 0.033), but the relative differences between the treatment groups were not different (interaction, p = 0.52). CONCLUSION: Teriparatide and alendronate increased LS and hip BMD across a range of baseline glucocorticoid doses. LS BMD increases with teriparatide were greater in the low-dose category than in the high-dose category. Overall LS BMD increases were significantly greater with teriparatide compared with alendronate, which may reflect the respective anabolic and antiresorptive mechanisms of action. Clinical Trial Registry Number: NCT00051558.

Effects of teriparatide versus alendronate for treating glucocorticoid-induced osteoporosis: thirty-six-month results of a randomized, double-blind, controlled trial.

OBJECTIVE: To compare the bone anabolic drug teriparatide (20 microg/day) with the antiresorptive drug alendronate (10 mg/day) for treating glucocorticoid-induced osteoporosis (OP). METHODS: This was a 36-month, randomized, double-blind, controlled trial in 428 subjects with OP (ages 22-89 years) who had received > or =5 mg/day of prednisone equivalent for > or =3 months preceding screening. Measures included changes in lumbar spine and hip bone mineral density (BMD), changes in bone biomarkers, fracture incidence, and safety. RESULTS: Increases in BMD from baseline were significantly greater in the teriparatide group than in the alendronate group, and at 36 months were 11.0% versus 5.3% for lumbar spine, 5.2% versus 2.7% for total hip, and 6.3% versus 3.4% for femoral neck (P < 0.001 for all). In the teriparatide group, median percent increases from baseline in N-terminal type I procollagen propeptide (PINP) and osteocalcin (OC) levels were significant from 1 to 36 months (P < 0.01), and increases in levels of C-terminal telopeptide of type I collagen (CTX) were significant from 1 to 6 months (P < 0.01). In the alendronate group, median percent decreases in PINP, OC, and CTX were significant by 6 months and remained below baseline through 36 months (P < 0.001). Fewer subjects had vertebral fractures in the teriparatide group than in the alendronate group (3 [1.7%] of 173 versus 13 [7.7%] of 169; P = 0.007), with most occurring during the first 18 months. There was no significant difference between groups in the incidence of nonvertebral fractures (16 [7.5%] of 214 subjects taking teriparatide versus 15 [7.0%] of 214 subjects taking alendronate; P = 0.843). More subjects in the teriparatide group (21%) versus the alendronate group (7%) had elevated predose serum calcium concentrations (P < 0.001). CONCLUSION: Our findings indicate that subjects with glucocorticoid-induced OP treated with teriparatide for 36 months had greater increases in BMD and fewer new vertebral fractures than subjects treated with alendronate.

Patient experience with a new teriparatide delivery device.

OBJECTIVE: To determine functionality and acceptability of a new teriparatide (Forteo, Eli Lilly and Company, Indianapolis, IN, USA) delivery device by patients with osteoporosis. RESEARCH DESIGN AND METHODS: This was an eight week, single-arm, multicenter, open-label clinical trial. Patients received teriparatide 20 microg/day by subcutaneous injection using a new delivery device. Men and postmenopausal women with osteoporosis at high risk for fracture were stratified to Current User (n = 92) or Not Current User (n = 107) groups. Current Users had used the original delivery device for > or =8 weeks, including uninterrupted use for four weeks before enrollment. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT00577863. MAIN OUTCOME MEASURES: The primary objective was to detect common complaints (> or =3% for all patients) regarding the functionality and acceptability of the new device. Complaints were categorized as functional (e.g., malfunction), nonfunctional (e.g., size), or user manual. Secondary objectives included questionnaire assessment of preference of the new versus original device, features of the new delivery device, and analysis of adverse events. RESULTS: A total of 31 patients (16%) reported 47 complaints (four functional, 27 nonfunctional, and 16 user manual). There were two common complaints: device size (4.0%) and lack of information on alcohol swabs (3.5%). Overall, patients agreed that the new device was easy to use (99.5%), easy to learn to use (99%), easy to attach a needle (97%), easy to hold while injecting (95%), and that it reduced their reluctance to take injections (90%). Most Current Users (92%) preferred the new delivery device over the original device. Adverse events reported by > or =2% of patients were upper respiratory infection (3.5%), urinary tract infection (2%), influenza (2%), and headache (2%). Limitations include the one-arm study design and the short (eight week) duration of the study. CONCLUSIONS: Patients found the new teriparatide delivery device easy to use and Current Users preferred the new delivery device over the original device.

Active comparator trial of teriparatide vs alendronate for treating glucocorticoid-induced osteoporosis: results from the Hispanic and non-Hispanic cohorts.

Glucocorticoid use is a leading cause of secondary osteoporosis. This post hoc analysis compared teriparatide vs alendronate on bone mineral density (BMD) in Hispanic and non-Hispanic patients with glucocorticoid-induced osteoporosis. The 18-mo results from all patients (N=428) in a double-blind trial of teriparatide (20 microg/d) and alendronate (10 mg/d) who had taken glucocorticoids for >or=3 mo were reported (Saag et al. N Engl J Med 2007). The present study analyzed results from the Hispanic (n=61) and non-Hispanic (n=367) cohorts. The BMD was measured by dual-energy X-ray absorptiometry (DXA). In the Hispanic cohort at 18 mo, there were significantly greater increases from baseline in the teriparatide vs alendronate group in lumbar spine BMD (9.8%+/-1.7% vs 4.2%+/-1.4%; p<0.001; mean+/-SE) and total hip BMD (5.9%+/-1.6% vs 1.3%+/-1.3%, p<0.001), with no significant difference between groups at the femoral neck (4.3%+/-2.2% vs 2.0%+/-1.8%, p=0.228). Within each treatment group, the BMD responses were not significantly different in the Hispanic vs non-Hispanic cohort. The number of patients reporting >or=1 adverse event was not significantly different between treatments in either cohort, with more patients reporting nausea in the teriparatide group. In summary, teriparatide was more efficacious than alendronate in increasing BMD in Hispanic and non-Hispanic patients with glucocorticoid-induced osteoporosis. Both treatments were generally well tolerated.

Comparison of speed of onset of platelet inhibition after loading doses of clopidogrel versus prasugrel in healthy volunteers and correlation with responder status.

Failure to achieve an adequate level of platelet inhibition during percutaneous coronary intervention is associated with an increased risk for periprocedural myocardial injury. This study was conducted to compare the initial rate of platelet inhibition after a loading dose (LD) of prasugrel or clopidogrel and determine the association between the initial rate of inhibition and pharmacodynamic responder status. Data were pooled from 3 studies in which healthy subjects received LDs of prasugrel (60 mg; n = 76) or clopidogrel (300 mg; n = 87). Maximum platelet aggregation (MPA; 20 mumol/L adenosine diphosphate) was measured by turbidimetric aggregometry (0.25 to 24 hours after dosing). A mechanistic model was used to estimate the initial rate of decrease in MPA per hour (fast onset: MPA decrease >20%/hour). Subjects were defined as pharmacodynamic poor responders if the absolute decrease in MPA from baseline was <15% at either 4 to 5 or 24 hours after dosing. The median initial rate of decrease in MPA was greater after prasugrel (203%/hour) than with clopidogrel (23%/hour) (p <0.001). Overall, 76 subjects (100%) receiving prasugrel had fast onset of platelet inhibition compared with 47 subjects (54%) receiving clopidogrel. The initial rate of decrease in MPA was highly correlated with responder status (p <0.001). After prasugrel, subjects had a lower median MPA compared with clopidogrel (p <0.001; from >0.25 to 24 hours after dosing), and intersubject variability in MPA response was less after prasugrel compared with clopidogrel (p <0.001; from >1 to 24 hours after dosing). In conclusion, platelet inhibition after a 60-mg LD of prasugrel was more rapid in onset, less variable, and greater in magnitude than with a 300-mg LD of clopidogrel. After a thienopyridine LD, the initial rate of platelet inhibition was predictive of pharmacodynamic responder status.

Effects of tadalafil on myocardial blood flow in patients with coronary artery disease.

OBJECTIVE: Erectile dysfunction and coronary artery disease share similar risk factors. Although phosphodiesterase-5 inhibitors used to treat erectile dysfunction do not adversely affect hemodynamic parameters in patients with coronary artery disease, their effects on myocardial blood flow are unknown. METHODS: In a randomized, double-blind, crossover study we examined the effects of tadalafil, 20 mg, compared with placebo on myocardial blood flow in patients with stable coronary artery disease (n=7, 52-73 years old). After tadalafil or placebo, myocardial blood flow was measured with positron emission tomography (nine-segment model) at rest, during maximal coronary hyperemia with adenosine, and during increased myocardial work with dobutamine. Abnormal flow was defined as myocardial blood flow <75% of maximum perfusion during adenosine plus placebo (46 normal/17 abnormal segments dentified). RESULTS: Compared with placebo, tadalafil had no significant effect on global myocardial blood flow at rest, during adenosine infusion, or during dobutamine infusion. Similarly, in normal and abnormal segments, tadalafil versus placebo had no significant effect on resting myocardial blood flow or on adenosine-induced increases in myocardial blood flow. In normal segments, myocardial blood flow with dobutamine plus tadalafil was greater than that with dobutamine plus placebo (1.79+/-0.56 versus 1.56+/-0.37 ml/g per min, P<0.01), and in abnormal segments, there was a trend for tadalafil compared with placebo to increase myocardial blood flow during dobutamine infusion (1.46+/-0.44 versus 1.36+/-0.36 ml/g per min, P=0.7). CONCLUSIONS: Tadalafil had no significant effect on global myocardial blood flow at rest, during adenosine infusion, or during dobutamine infusion. Compared with placebo, tadalafil significantly augmented myocardial blood flow during increased workload in normal regions, with a trend toward improving myocardial blood flow in poorly perfused regions.

Psychosocial outcomes and drug attributes affecting treatment choice in men receiving sildenafil citrate and tadalafil for the treatment of erectile dysfunction: results of a multicenter, randomized, open-label, crossover study.

INTRODUCTION: Although sildenafil citrate (sildenafil) and tadalafil are efficacious and well-tolerated treatments for erectile dysfunction (ED), preference studies have shown that patients may favor one medication over the other. AIM: To determine whether psychosocial outcomes differed when men with ED received tadalafil compared with sildenafil. MAIN OUTCOME MEASURES: Measures included a treatment preference question, Psychological and Interpersonal Relationship Scales (PAIRS), and Drug Attribute Questionnaire. METHODS: Randomized, open-label, crossover study. After a 4-week baseline, men with ED (N = 367; mean age = 54 years; naïve to type 5 phosphodiesterase inhibitor therapy) were randomized: tadalafil for 12 weeks then sildenafil for 12 weeks or vice versa (8-week dose optimization/4-week assessment phases). During dose optimization, patients started with 10 mg tadalafil, or 25 or 50 mg sildenafil and could titrate to their optimal dose (10 or 20 mg tadalafil; 25, 50, or 100 mg sildenafil). Medications were taken as needed. Patients completing both 12-week periods chose which medication to continue during an 8-week extension. RESULTS: Of 291 men completing both treatment periods, 71% (N = 206) chose tadalafil and 29% (N = 85) chose sildenafil (P < 0.001) for the 8-week extension. When taking tadalafil compared with sildenafil men had higher mean endpoint scores on PAIRS Sexual Self-Confidence (tadalafil = 2.91 vs. sildenafil = 2.75; P < 0.001) and Spontaneity (tadalafil = 3.32 vs. sildenafil = 3.17; P < 0.001) Domains and a lower mean endpoint score on Time Concerns Domain (tadalafil = 2.2 vs. sildenafil = 2.59; P < 0.001). The two most frequently chosen drug attributes to explain treatment preference were ability to get an erection long after taking the medication and firmness of erections. Tadalafil and sildenafil were well tolerated with 12 (3.3%) patients discontinuing for an adverse event. CONCLUSIONS: As measured with PAIRS, men with ED had higher sexual self-confidence and spontaneity and less time concerns related to sexual encounters when treated with tadalafil compared with sildenafil. These psychosocial outcomes may help explain why more men (71%) preferred tadalafil for the treatment of ED in this clinical trial.

Cardiovascular safety update of Tadalafil: retrospective analysis of data from placebo-controlled and open-label clinical trials of Tadalafil with as needed, three times-per-week or once-a-day dosing.

Because most men with erectile dysfunction have underlying vascular disease, it is important to update the cardiovascular safety profile of medications used in the treatment of erectile dysfunction. This retrospective analysis evaluated serious cardiovascular treatment-emergent adverse events (CVTEAEs) reported in 36 clinical trials of tadalafil, a phosphodiesterase-5 inhibitor used for the treatment of erectile dysfunction. A serious CVTEAE was defined as myocardial infarction, cardiovascular death, or cerebrovascular death. In the 36 trials, 12,487 men (mean age 55 years) with erectile dysfunction received tadalafil, with 5,771 patient-years (PYs) of exposure, and 2,047 men (mean age 56 years) received placebo, with 460 PYs of exposure. Tadalafil 2 to 50 mg was taken as needed, 3 times/week, or once a day. Co-morbidities at baseline included hypertension (31%), diabetes (21%), hyperlipidemia (17%), and coronary artery disease (5%). Across all trials, the incidence rate of serious CVTEAEs was 0.40/100 PYs in tadalafil-treated patients and 0.43/100 PYs in placebo-treated patients. In patients taking tadalafil as needed, 3 times/week, or once a day, the incidence rates of serious CVTEAEs ranged from 0.17 to 0.54/100 PYs across placebo-controlled and open-label trials. In conclusion, the incidence rates of serious CVTEAEs were comparable among men with erectile dysfunction taking tadalafil as needed, 3 times/week, or once a day, and these rates were also comparable with those in placebo-treated patients. In this clinical trial population of men with erectile dysfunction, tadalafil was not associated with an increased risk for serious cardiovascular adverse events.

An open-label, multicentre, randomized, crossover study comparing sildenafil citrate and tadalafil for treating erectile dysfunction in men naïve to phosphodiesterase 5 inhibitor therapy.

OBJECTIVES: To compare treatment preference, efficacy, and tolerability of sildenafil citrate (sildenafil) and tadalafil for treating erectile dysfunction (ED) in men naïve to phosphodiesterase 5 (PDE5) inhibitor therapy. PATIENTS AND METHODS: This was an open-label, crossover study of sildenafil and tadalafil (taken as needed). After a 4-week baseline assessment, 367 men with ED (mean age 54 years) were randomized to receive sildenafil for 12 weeks followed by tadalafil for 12 weeks or vice versa (8-week dose optimization and 4-week assessment phases). During dose optimization, patients started taking 25- or 50-mg sildenafil or 10-mg tadalafil and could titrate to find their optimum dose (25-, 50- or 100-mg sildenafil; 10- or 20-mg tadalafil). After completing both 12-week periods, patients chose which treatment to continue during an 8-week extension. Efficacy was measured with the International Index of Erectile Function (IIEF) and Sexual Encounter Profile (SEP) diary. RESULTS: Of the 291 men who completed both treatments, 85 (29%) chose sildenafil and 206 (71%) chose tadalafil (P < 0.001) for the 8-week extension. The IIEF erectile function domain scores were 14.2 at baseline, 23.9 at endpoint on sildenafil, and 24.3 at endpoint on tadalafil (P = 0.08, sildenafil vs tadalafil). The mean per patient percentage success scores for SEP2 (penetration) were: baseline (46%), sildenafil (post-baseline 82%) and tadalafil (post-baseline 85%; P = 0.06, sildenafil vs tadalafil), and for SEP3 (successful intercourse) were: baseline (19%), sildenafil (post-baseline 72%), and tadalafil (post-baseline 77%; P = 0.003, sildenafil vs tadalafil). The only treatment-emergent adverse events that were reported by >5% of men were headache and flushing. CONCLUSIONS: In men with ED who were naïve to PDE5 inhibitor therapy, sildenafil and tadalafil were both effective and well tolerated. After treatment with sildenafil and tadalafil, 29% of men chose sildenafil and 71% chose tadalafil for ED therapy during an 8-week extension.

The combined use of ibutilide as an active control with intensive electrocardiographic sampling and signal averaging as a sensitive method to assess the effects of tadalafil on the human QT interval.

OBJECTIVES: This study was designed to evaluate effects of tadalafil, a phosphodiesterase-5 inhibitor used for the treatment of erectile dysfunction (ED), on the QT interval. BACKGROUND: Cardiovascular disease is common in men with ED. Men with cardiovascular disease and ED may have decreased cardiac repolarization reserve. METHODS: Effects of tadalafil (100 mg by mouth), ibutilide (0.002 mg/kg intravenously), and placebo on the QT interval in healthy men were compared (placebo and tadalafil [n = 90], with a subset [n = 61] receiving all treatments; mean age 30 years, range 18 to 53 years). Electrocardiographic sampling was done for two days before treatment and on treatment days. The QT was corrected for RR interval with five correction methods, including an individual correction (QTcI). Plasma concentrations of tadalafil were measured to evaluate concentration-QT effect relationships. RESULTS: At the time corresponding to maximum plasma concentration of tadalafil, the mean difference in the change in QTcI between tadalafil and placebo was 2.8 ms; tadalafil was equivalent to placebo (a priori, upper limit of 90% confidence interval < 10 ms [actual = 4.4 ms]; post hoc, upper limit of 95% confidence interval < 5 ms [actual = 4.8]). The active control, ibutilide, significantly increased QTcI by 6.9 and 8.9 ms compared with tadalafil and placebo, respectively. Similar statistical results were obtained with four additional QT correction methods. No subject had a QTcI > or = 450 ms or an increase in QTcI > or = 30 ms with any treatment. CONCLUSIONS: Based on the a priori statistical test of equivalence, placebo and high-dose tadalafil produced equivalent effects on the QT interval. This study reliably discerned 5- to 10-ms changes in corrected QT in the ibutilide active control group.

Interaction between the phosphodiesterase 5 inhibitor, tadalafil and 2 alpha-blockers, doxazosin and tamsulosin in healthy normotensive men.

PURPOSE: Tadalafil, a phosphodiesterase type 5 inhibitor, is effective therapy for erectile dysfunction (ED). Men with ED have a high incidence of comorbid conditions including cardiovascular disease, diabetes mellitus and benign prostatic hyperplasia. Although phosphodiesterase type 5 inhibitors are safe when administered with most medications, sildenafil given with doxazosin and vardenafil given with terazosin evoke orthostatic hypotension in some patients. We examined the hemodynamic interactions of tadalafil with the alpha-blockers doxazosin and tamsulosin. MATERIALS AND METHODS: In separate double-blind, placebo controlled, randomized crossover studies (18 patients in each study) we evaluated the hemodynamic effects of doxazosin 8 mg with tadalafil 20 mg, and tamsulosin 0.4 mg with tadalafil 10 and 20 mg. Blood pressure (BP) and heart rate were recorded before dosing and for 24 hours after dosing. RESULTS: Tadalafil 20 mg augmented the hypotensive effect of doxazosin by producing a mean maximal decrease in standing systolic BP (SBP) that was significantly greater than placebo (a mean difference of 9.8 mm Hg). Analysis of BP outliers showed that the number of subjects with a standing SBP of less than 85 mm Hg was greater after doxazosin plus tadalafil (28%) versus doxazosin plus placebo (6%). In subjects on tamsulosin, tadalafil 10 and 20 mg produced mean maximal decreases in standing SBP that were similar to placebo (mean difference of 1.7 and 2.3 mm Hg, respectively). No subject taking tamsulosin had a decrease in standing SBP less than 85 mm Hg. CONCLUSIONS: Tadalafil augmented the hypotensive effects of doxazosin but had little hemodynamic interaction with tamsulosin. In patients taking tadalafil for ED, tamsulosin 0.4 mg may be given for the treatment of benign prostatic hyperplasia.

Update on clinical trials of tadalafil demonstrates no increased risk of cardiovascular adverse events.

INTRODUCTION: Cardiovascular disease and erectile dysfunction (ED) share similar risk factors and often occur concomitantly. Therefore, men with ED may be at increased risk for cardiovascular adverse events. AIM: The aim of this retrospective analysis was to evaluate the cardiovascular adverse events in clinical trials of tadalafil, an effective medication for the treatment of ED. METHODS: An integrated analysis of cardiovascular adverse events was performed on a database from 35 controlled clinical trials (placebo [N = 2,118] and tadalafil [N = 5,228]) and eight open-label trials of tadalafil (tadalafil [N = 6,939]). Some patients in controlled trials also received tadalafil in the open-label extension phase of four trials. Across all trials, the dose range of tadalafil was 2-25 mg, with the majority of patients receiving tadalafil 20 mg. This analysis represents an update of previous published results. RESULTS: In 35 controlled tadalafil clinical trials, the incidence of cardiovascular adverse events was low and comparable in tadalafil- and placebo-treated patients. The rate of myocardial infarction (MI) across all controlled and open-label studies was 0.33 per 100 patient-years in tadalafil-treated patients (N = 10,460, patient exposure = 5,088 patient-years). The MI rate in tadalafil-treated patients was comparable to that in placebo-treated patients (0.41 per 100 patient-years; N = 2,118; 489 patient-years), and to that in an age-standardized male population (0.6 per 100 patient-years). The cardiac mortality rate in tadalafil-treated patients across all studies (N = 10,460) was 0.12 per 100 patient-years which was not increased compared with the cardiac mortality rate of 0.26 per 100 patient-years reported in an age-standardized male population. CONCLUSIONS: In tadalafil clinical trials, the incidence of cardiovascular adverse events in patients receiving tadalafil was low and comparable to placebo. Tadalafil did not increase the rate of MI or cardiac mortality compared with reported rates from epidemiological studies. This favorable cardiovascular safety profile for tadalafil is important, because men with ED commonly have cardiovascular disease and may seek medical therapy for ED.