Journal of Cardiovascular Pharmacology and Therapeutics http://cpt.sagepub.com/
Conversion From Sildenafil to Tadalafil: Results From the Sildenafil to Tadalafil in Pulmonary Arterial Hypertension (SITAR) Study Robert P. Frantz, Louise Durst, Charles D. Burger, Ronald J. Oudiz, Robert C. Bourge, Veronica Franco, Aaron B. Waxman, Susanne McDevitt and Susan Walker J CARDIOVASC PHARMACOL THER published online 17 April 2014 DOI: 10.1177/1074248414528066 The online version of this article can be found at: http://cpt.sagepub.com/content/early/2014/04/16/1074248414528066
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Article
Conversion From Sildenafil to Tadalafil: Results From the Sildenafil to Tadalafil in Pulmonary Arterial Hypertension (SITAR) Study
Journal of Cardiovascular Pharmacology and Therapeutics 1-8 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/1074248414528066 cpt.sagepub.com
Robert P. Frantz, MD1, Louise Durst, RN2, Charles D. Burger, MD3, Ronald J. Oudiz, MD4, Robert C. Bourge, MD5, Veronica Franco, MD6, Aaron B. Waxman, MD, PhD7, Susanne McDevitt, RN, MSN, ACNP8, and Susan Walker, MS8
Abstract Purpose: Among phosphodiesterase type 5 inhibitors, tadalafil offers clinicians a once-daily alternative to 3 times daily sildenafil for the treatment of pulmonary arterial hypertension (PAH). This study assessed the safety and patient satisfaction with conversion from sildenafil to tadalafil. Methods: In this multicenter, prospective, 6-month study, patients with PAH were instructed to take their last dose of sildenafil in the evening and initiate tadalafil 40 mg/d the next morning. Patients completed the Treatment Satisfaction Questionnaire for Medication at baseline and 30, 90, and 180 days after transition to assess PAH symptoms and patient satisfaction. Safety was assessed on the basis of recorded adverse events (AEs). Results: Of the 35 patients who met the study criteria, 56% were receiving 2 PAH therapies. At the time of transition, the sildenafil dose ranged from 40 to 300 mg/d, with 20% of the patients on >20 mg of sildenafil 3 times daily. Transition to tadalafil was generally well tolerated, and the incidence of common AEs, except for myalgia, appeared to decrease over time on tadalafil therapy. Five (14%) patients switched back to sildenafil. A greater percentage of patients were satisfied than were dissatisfied after conversion to tadalafil (55% vs 19% at 90 days), while 26% felt about the same degree of satisfaction. Conversion to tadalafil resulted in significant improvement in patient ratings of therapy convenience. Conclusions: Transition of patients from sildenafil to tadalafil was usually well tolerated, with improved convenience and may enhance treatment satisfaction. Keywords sildenafil, tadalafil, switch, pulmonary arterial hypertension, patient satisfaction
Introduction Pulmonary arterial hypertension (PAH) is a rare, progressive disease characterized by increasing pulmonary arterial pressure and pulmonary vascular resistance, ultimately leading to right ventricular (RV) failure and death.1,2 Greater disease awareness and improved diagnostics, coupled with a marked increase in the number of PAH-targeted therapies recently, have advanced management of patients with PAH. Widely used PAH therapies target 1 or more of the 3 main pathways in disease pathogenesis: prostacyclin, endothelin receptor antagonists (ERAs), and phosphodiesterase type 5 inhibitors (PDE-5Is). The PDE-5I class of PAH treatment blocks phosphodiesterase type 5-dependent inactivation of cyclic guanosine monophosphate, increasing nitric oxide-mediated pulmonary arterial vasodilation.3-5 Sildenafil was the first PDE-5I approved for treatment of PAH on the basis of the results of the Sildenafil Use in
1
Division of Cardiovascular Diseases, College of Medicine, Mayo Clinic, Rochester, MN, USA 2 Mayo Clinic, Rochester, MN, USA 3 Division of Pulmonary Medicine, Mayo Clinic, Jacksonville, FL, USA 4 Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA 5 Cardiovascular Medicine, University of Alabama at Birmingham, Birmingham, AL, USA 6 Cardiovascular Medicine, Ohio State University Medical Center, Columbus, OH, USA 7 Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, MA, USA 8 United Therapeutics Corporation, Research Triangle Park, NC, USA Manuscript submitted: July 26, 2013; accepted: February 20, 2014. Corresponding Author: Robert P. Frantz, 200 First Street SW, Mayo Clinic, Gonda 5, Rochester, MN 55905, USA. Email: [email protected]
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Pulmonary Arterial Hypertension (SUPER-1) study that randomized treatment-naive patients with PAH to sildenafil 20, 40, or 80 mg 3 times daily or placebo.5 Although the US Food and Drug Administration (FDA) approved sildenafil 20 mg 3 times daily for the treatment of PAH6 on the basis of the finding that there were no significant differences in 6-minute walk distance (6MWD) between the 20-, 40-, or 80-mg dosing groups, a greater hemodynamic effect was seen with the 80-mg 3 times daily dose, raising the possibility that the maximum approved dose was not the most hemodynamically effective dose for at least some patient subsets.5 In the open-label extension, patients receiving sildenafil 80 mg 3 times daily appeared to experience sustained benefit to the extent that this can be assessed in an open-label setting. However, there are no data regarding durability of treatment when patients are maintained on a 20-mg 3 times daily dose. Additionally, when sildenafil is used in combination with an ERA, bosentan, there are decreased plasma levels of sildenafil, providing more rationale for the use of higher doses of sildenafil.7 Thus, the optimal dosing regimen for sildenafil is controversial and has resulted in confusion among some clinicians who have been treating patients with sildenafil doses substantially above the FDArecommended dose. Treating patients above the FDArecommended dose can create challenges such as added cost and insurance coverage restrictions. Furthermore, dosing with a 3 times daily medication may lead to increased pill burden and lack of adherence in patients with PAH. Tadalafil is a once-daily PDE-5I approved for the treatment of patients with World Health Organization (WHO) group 1 PAH at a dose of 40 mg daily.8 Tadalafil’s longer half-life of 17.5 hours in healthy individuals and 35 hours in patients with PAH,9 compared with that of sildenafil at 4 to 5 hours,10 allows for once-daily dosing. In a large, multicenter, placebo-controlled pivotal study (PHIRST-1), patients were randomized to placebo or 2.5 mg, 10 mg, 20 mg, or 40 mg of tadalafil daily for 16 weeks.11 Approximately half of the patients were on bosentan at the time of study entry and half were treatment naive. A dose-dependent improvement in 6MWD was observed, with the highest dose studied (40 mg daily) having the greatest effect on 6MWD and clinical worsening. Tadalafil 40 mg also improved time to clinical worsening and health-related quality of life. In a hemodynamic substudy, there was a statistically significant improvement in hemodynamics in the tadalafil 40-mg group versus placebo. Treatment with tadalafil may offer several benefits over sildenafil therapy.12 Tadalafil therapy with once-daily dosing and a low pill burden (2 pills per day) may offer convenience and improved adherence to treatment. Sildenafil therapy with doses of 80 mg 3 times daily may result in a substantial pill burden (12-15 pills per day), which can also increase nonadherence. Sildenafil doses >20 mg 3 times daily may not be fully covered by insurance and, therefore, patient out-of-pocket and overall health care system costs may be reduced with tadalafil therapy. Additionally, there are long-term data for treatment durability at the FDA-approved dose for tadalafil.13 It is anticipated that because of these benefits, many patients and clinicians may
choose transition from sildenafil to tadalafil therapy. However, there is little reported clinical experience in converting patients from sildenafil to tadalafil. In this prospective multicenter open-label study, safety and patient satisfaction with conversion from sildenafil to tadalafil were assessed.
Methods Study Design This was a multicenter, prospective, open-label, 6-month study of patients with PAH who were transitioned from sildenafil to tadalafil treatment at home (in the outpatient setting). Adult males and females with WHO group 1 PAH, who were treated with sildenafil at a dose of 20 mg 3 times daily or greater for at least 30 days, and for whom a clinical decision to transition to tadalafil had been made, were included in this study. Patients were excluded from the study if they had any other disease associated with PAH that was non-WHO group 1; advanced liver or kidney disease; acute decompensation of underlying illness or hospitalization for PAH within 4 weeks before enrollment; a history of hypersensitivity reaction or adverse effect related to tadalafil use; participated in an investigational drug or device clinical study within 4 weeks of enrollment; or concomitant use of nitrates or potent CYP3A inhibitors. No limitations were set as to the number and types of non-PDE-5I background therapies that patients could be on, including ERAs and inhaled and parenteral prostanoid therapies. Informed consent was obtained from all participants. The study was approved by the institutional review boards and was registered with ClinicalTrials.gov (NCT01043627).
Method of Transition After baseline data collection, patients were instructed to take the last dose of sildenafil in the evening and then initiate tadalafil (usually 40 mg) the next morning. The tadalafil dose was reduced (eg, 20 mg) if there were any adverse events (AEs) attributable to tadalafil therapy.
Clinical Assessments Patients were evaluated at baseline and at 30 days, 3 months, and 6 months after transition to tadalafil. Treatment tolerability, patient preferences, and symptoms were measured by having patients complete the Treatment Satisfaction Questionnaire for Medication (TSQM)14 at baseline and at 30 days, 3 months, and 6 months after conversion to tadalafil. Patients reported satisfaction with treatment in this survey as ‘‘much less satisfied,’’ ‘‘less satisfied,’’ ‘‘about same,’’ ‘‘more satisfied,’’ or ‘‘much more satisfied.’’ Patients were also asked to rate their PAH symptoms as ‘‘much worse,’’ ‘‘somewhat worse,’’ ‘‘about same,’’ ‘‘somewhat better,’’ or ‘‘much better.’’ Aside from the serial questionnaires, no protocol-mandated tests were performed. The treating clinician provided information regarding why the patient was transitioning from sildenafil to tadalafil. Clinical assessments were recorded as available
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according to each center’s routine clinical practice. Demographic parameters, disease characteristics, use of concomitant medications, and any echocardiographic and 6-minute walk data that had been clinically obtained within 3 months of study enrollment and without change in PAH medication were collected at baseline. As available, serial parameters from 3 and 6 months following conversion were also abstracted from the charts and entered into the case report forms. Safety was assessed on the basis of recorded AEs, vital signs, and clinically available laboratory measures.
Statistical Analysis Data for all variables collected in this study were summarized using descriptive statistics. Continuous variables (6MWD and echocardiography parameters) were summarized using mean and standard deviation. Categorical variables (WHO functional class, response to TSQM, and AEs) were summarized using the number and percentage of patients in each category.
Results Baseline Characteristics A total of 35 patients who were prospectively enrolled at 6 centers from April 2010 to February 2011 and met the study entry criteria were switched from sildenafil to tadalafil. Demographic and baseline disease characteristics of the patients converted from sildenafil to tadalafil are shown in Table 1. The majority of patients were female with idiopathic PAH (IPAH)/heritable PAH and were in WHO functional classes II and III. About 21% of patients in the study were receiving calcium channel blocker therapy. Most (54%) patients were receiving 2 or more PAH therapies, and 17% of patients were on 3 PAH therapies. About 26% of the patients were receiving inhaled or parenteral prostacyclin therapy. The mean 6MWD was 394 + 102 m at baseline.
Patient Disposition and Transition Dosing Considerations All patients were switched from sildenafil to tadalafil per the specified dosing regimen. Mean duration of sildenafil treatment was 124 + 100 weeks (range 10-385 weeks). At the time of transition, 20% of the patients were on >20 mg 3 times daily of sildenafil, with 1 patient receiving as high as 100 mg 3 times daily of sildenafil. Clinicians cited that the majority of patients were converted from sildenafil to tadalafil for convenience and cost reasons (Table 2). Of the 35 patients transitioned from sildenafil to tadalafil, 5 (14%) transitioned back to sildenafil. Four patients required the addition of a parenteral prostanoid within the 6-month period after transitioning to tadalafil.
Tolerability of Conversion from Sildenafil to Tadalafil Transition from sildenafil to tadalafil was generally well tolerated, with headache, myalgia, dizziness, diarrhea, flushing, and nausea reported as common AEs (Figure 1). Most AEs were
Table 1. Patient Demographics and Characteristics. Parameter
Patients (N ¼ 35)
Age, y, mean (range) Male:female, n PAH etiology, n (%) Idiopathic or heritable CTD Other Missing Echo parameters, mean + SD RVSP, mm Hg TAPSE, cm CO, L/min WHO functional class, n I:II:III PAH/Background medications, n (%) PDE-5I monotherapy PDE-5I þ ERA PDE-5I þ ERA þ inhaled prostanoid PDE-5I þ ERA þ parenteral prostanoid PDE-5I þ parenteral prostanoid Sildenafil dose at transition, n (%) 20 mg tid >20 mg tid Duration of sildenafil, mean + SD, week 6MWD before transition, mean + SD, m BNP, median (range), pg/mL NT-proBNP, median (range), pg/mL
56 (20-84) 9:26 22 (63) 4 (11) 8 (23) 1 (3) 77 + 20a 1.9 + 5.7b 4.5 + 3.0c 1:14:18d 16 (46) 10 (29) 1 (3) 5 (14) 3 (9) 28 (80) 7 (20) 124 + 104e 394 + 101f 170 (12-6129)g 349 (21-7765)h
Abbreviations: BNP, B-type natriuretic peptide; CO, cardiac output; CTD, connective tissue disease; echo, echocardiography; ERA, endothelin receptor antagonist; 6MWD, 6-minute walk distance; NT-proBNP, N-terminal proBNP; PAH, pulmonary arterial hypertension; PDE-5I, phosphodiesterase type 5 inhibitor; RVSP, right ventricular systolic pressure; SD, standard deviation; TAPSE, tricuspid annual plane systolic excursion; tid, 3 times daily; WHO, World Health Organization. a n ¼ 31. b n ¼ 23. c n ¼ 24. d n ¼ 33. e n ¼ 30. f n ¼ 32. g n ¼ 17. h n ¼ 15.
Table 2. Reasons for Conversion to Tadalafil.a Reason Convenience Cost Sildenafil dose >20 mg tid Other
Patients n (%) 14 (40) 15 (43) 5 (14) 15 (43)
Abbreviation: tid, 3 times daily. a Patients could have been converted for multiple reasons.
mild to moderate. Before conversion to tadalafil, common AEs with sildenafil therapy included diarrhea, flushing, dizziness, myalgia, and headache. We did not observe any substantial differences in the AE profile, but headache early following conversion may have been more common while diarrhea and flushing seemed to be less prominent. The most common
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30
SIL baseline (n = 35) TAD 30 days (n = 35) TAD 90 days (n = 35) TAD 180 days (n = 35)
Percent of Patients
26
20
20 17 14
14
14 11 10
9
17
17
9
14 11
11
11
9 6 6
9 6
6
6 3
3 0 Headache
Myalgia
Dizziness
Diarrhea
Flushing
Nausea
Figure 1. Common adverse events associated with PDE-5I therapy before conversion to tadalafil and by time on tadalafil. PDE-5I indicates phosphodiesterase type 5 inhibitor; SIL, sildenafil; TAD, tadalafil.
severe AEs associated with the conversion to tadalafil included headache, nasal congestion, pain in extremity, myalgia, and dizziness, which were more common in the initial 30 days after conversion. Details of failed transitions Patient 1. A 59-year-old female with IPAH on therapy with amlodipine and sildenafil 20 mg 3 times daily, with blood pressure (BP) 96/50 prior to transition. Prior history notable for severe chronic fatigue. She noted myalgias and worsening fatigue after transition. Tadalafil dose reduction to 20 mg improved but did not resolve the aggravation of these symptoms so she was converted back to sildenafil. Patient 2. A 52-year-old female with IPAH on therapy with bosentan and sildenafil 20 mg 3 times daily. Light sensitivity after the transition that resolved after several days and worsening gastroesophageal reflux that improved with omeprazole were noted. She also described myalgias, nasal stuffiness, and constipation. The possibility of reducing the dose of tadalafil was discussed, but she elected to transition back to sildenafil 2 weeks after starting the tadalafil. Patient 3. A 74-year-old female with IPAH, on therapy with 80 ng/kg/min intravenous (iv) treprostinil and sildenafil 20 mg 3 times daily. She had an estimated glomerular filtration rate of 31 mL/min. Following transition, she experienced symptomatic lightheadedness and worsening dyspnea. She remained functional class III before and after the transition so converted back to sildenafil. Potentially, 20 mg of tadalafil would have been a more optimal starting dose in such a setting. Down titrating the tadalafil rather than switching back to sildenafil could have been considered. Patient 4. For this patient, a reason for the transition back to sildenafil was not provided.
Patient 5. A 42-year-old female with IPAH on therapy with bosentan and sildenafil 20 mg 3 times daily. Following transition, she noted significant lower extremity aching unresponsive to ibuprofen and mild pedal edema. Two months after transition, she was converted back to sildenafil. There was not an attempt to reduce her tadalafil dose. Symptoms of PAH and satisfaction with therapy. Among patients who answered the questionnaire at each time point, there appeared to be a greater percentage of patients who reported the same or improved general PAH symptoms over time (Figure 2). Within 30 days after conversion to tadalafil, 88% of patients reported the same or improved general PAH symptoms (n ¼ 32). After 90 (n ¼ 31) and 180 days (n ¼ 26) of having transitioned to tadalafil, 87% and 85% of patients reported the same or improved PAH symptoms, respectively. In addition, 48% and 38% of patients reported improvement in PAH symptoms after 90 and 180 days of having transitioned to tadalafil, respectively. There was a greater percentage of patients who were satisfied (more satisfied and much more satisfied) than were dissatisfied (less satisfied and much less satisfied) after conversion to tadalafil (30 days, 47% vs 16%; 90 days, 55% vs 19%; 180 days, 50% vs 8%; Figure 3). Two patients reported ‘‘much less satisfied’’ in the 90-day survey only following conversion to tadalafil. Although global satisfaction score following transition to tadalafil did not significantly improve versus baseline (mean improvement of 0.3 after 180 days; P ¼ .7309), TSQM scores showed a significant improvement in convenience (mean improvement of 15.9 after 180 days; P ¼ .0312).
Summary of Clinically Available Serial Testing Given the small number of patients who had serial 6MWD available, we can only say that for most of them there was no
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70
TAD 30 days (n = 32)
Percent of Patients
TAD 90 days (n = 31)
59
60
TAD 180 days (n = 26)
50
46 39
40 30
22 20 12 10
10 0
0
3
26
23
23
15
15 6
0
Much worse
Somewhat worse
About same
Somewhat better
Much better
Figure 2. Patient assessment of pulmonary arterial hypertension symptoms after conversion from sildenafil to tadalafil, by time on tadalafil. TAD indicates tadalafil.
50
TAD 30 days (n = 32) TAD 90 days (n = 31) TAD 180 days (n = 26)
42 38
Percent of Patients
40
38
29
30
31 26
26
20
19
16 13
10
0
0
9
8
6 0
Much less satisfied
Less satisfied
About same
More satisfied
Much more satisfied
Figure 3. Patient assessment of satisfaction with pulmonary arterial hypertension treatment after conversion from sildenafil to tadalafil, by time on tadalafil. TAD indicates tadalafil.
conspicuous pattern of change in walk distance after transitioning to tadalafil therapy (Figure 4). The change in mean 6MWD (+standard error) from baseline was 11.0 (9.0) m, 10.8 (33.7) m, and 17.3 (25.6) m after 30 days (n ¼ 7), 90 days (n ¼ 13), and 180 days (n ¼ 14) of having transitioned from sildenafil to tadalafil therapy, respectively. No particular trends in the mean RV systolic pressure (RVSP) were observed (4.4 mm Hg and 4.3 mm Hg after 90 days (n ¼ 11) and 180 days (n ¼ 11), respectively, compared with baseline, after transitioning to tadalafil. There was no significant change in tricuspid annual plane systolic excursion (0.34 and 0.36 cm after 90 days (n ¼ 8) and 180 days (n ¼ 8), respectively, after having transitioned to tadalafil,
and the very small number of patients with serial data precludes meaningful conclusions. Detailed review of the 2 patients with major drop in 6MWD Patient 1. Transient drop in walk that was felt not to be representative of clinical compensation. A 67-year-old female with diet drug-related PAH in the context of obesity, type 2 diabetes mellitus, obstructive sleep apnea controlled with CPAP, and need for supplemental oxygen of 3 L/min during activity. She was receiving 100 mg 3 times daily of sildenafil as monotherapy for her PAH and was switched to tadalafil 40 mg daily when her insurance carrier refused to continue payment for
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A
B n=7
700
n = 14
700
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600
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700
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Baseline
Day 30
300
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n = 13
Baseline
Month 3
Baseline
Month 6
Figure 4. Change in 6MWD from baseline for patients with serial data available. A, Baseline to day 30. B, Baseline to month 3. C, Baseline to month 6. Mean 6MWD is plotted as dotted lines. 6MWD indicates 6-minute walk distance.
sildenafil. She had previously been intolerant of inhaled iloprost and oral treprostinil and had not had clinical benefit from bosentan. One month prior to the switch, she was WHO functional class III, with 6-minute walk of 372 m on 3L oxygen with drop in systemic saturation from 95% to 82%. Her N-terminal pro-B-type natriuretic peptide (NT-proBNP) level was 264 pg/mL. The RVSP by implanted Chronicle hemodynamic monitor was 95 mm Hg, with RVEDP of 7 mm Hg. Echocardiography showed moderate RV enlargement, moderate tricuspid regurgitation, and tricuspid annular plane systolic excursion of 19 mm, with estimated cardiac index of 3.0 L/min/ m2. Four months following conversion to tadalafil, she felt clinically unchanged and remained functional class III. Her walk distance of only 114 m was performed the day after she had a very busy day entertaining guests and had arisen at 3 AM in order to attend the clinic. She felt exhausted and stopped walking after only 1 minute 46 seconds and felt the walk was not representative of her overall clinical status. N-terminal pro B-type natriuretic peptide was 485 pg/mL, and interrogation of her implantable hemodynamic monitor showed no change in her hemodynamics compared to prior to switching to tadalafil. Echocardiography-estimated cardiac index was preserved at 2.7 L/min/m2. Her therapy was not changed. Ten months following conversion, she remained functional class III on tadalafil without additional therapy, with 6-minute walk of 337 m and NT-proBNP of 592 pg/mL. At most recent follow-up, 3 years following the switch, she remains functional class III on
tadalafil monotherapy, with stable echo parameters, a 6minute walk of 313 m, and NT-proBNP of 557 pg/mL. Patient 2. Stable walk at 3 months, but reduction in walk at 6 months. This patient was on triple therapy with sildenafil 30 mg 3 times daily, bosentan 125 mg twice daily, and iv epoprostenol 115 ng/kg/min with 6-minute walk of 390 m prior to conversion to tadalafil. At 3-month follow-up after conversion, her 6MWD was preserved at 395 m with preserved B-type natriuretic peptide (BNP) level of 144 pg/mL. However, at the 6-month follow-up, she had developed pulmonary infiltrates, was more hypoxic, and her walk had deteriorated to 126 m, with BNP 587 pg/mL. She was diagnosed with anti-PR3 vasculitis that responded to rituximab. Two months later, her walk had improved to 239 m with BNP 485 pg/mL. She was subsequently converted to treprostinil in an effort to deal with worsening thrombocytopenia. She stayed on tadalafil throughout her course, and 2½ years later required lung transplantation. It was not felt that the deterioration in walk distance at 6 months was related to the prior conversion to tadalafil.
Discussion In this prospective study, most patients were successfully converted from sildenafil to tadalafil in the outpatient setting while maintaining PAH therapeutic class efficacy and improving treatment satisfaction. Factors of convenience and cost were
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commonly cited as reasons for transition to tadalafil. Improved treatment satisfaction with tadalafil appeared to relate primarily to the improved sense of convenience reported by patients. The patients in this study were stable on sildenafil before transition to tadalafil with many of the patients on combination therapies, including 37% on 2 PAH therapies and 17% on 3 PAH therapies. Furthermore, patients taking >20 mg 3 times daily of sildenafil were successfully transitioned to tadalafil 40 mg once daily. Transition to tadalafil from sildenafil was generally well tolerated. Most patients who transitioned to tadalafil remained on tadalafil throughout the 6 months of our study, but some patients switched back to sildenafil due to more problematic side effects or, in 1 patient, increased dyspnea. The incidence of common AEs appeared to decrease over time on tadalafil therapy, with the exception of myalgia. Although there was a higher incidence of headache (28%) within the first 30 days of transition in this study, the incidence decreased over time (14% by 6 months). Headache and myalgia were also 2 of the most commonly reported AEs in the 16-week PHIRST-1 trial.11 Similar to this study, the incidence of headache decreased rapidly after 1 week of tadalafil therapy in the PHIRST-1 trial and remained infrequent through the openlabel PHIRST-2 trial (68 weeks).15 These results suggest that the incidence of AEs such as headache may be initially higher when patients are transitioned to tadalafil but these tend to diminish in frequency upon continued treatment.
Practical Lessons Regarding the Transition Process 1. For patients with mild to moderate renal insufficiency, a starting dose of 20 mg daily is recommended, with potential to increase to 40 mg daily if tolerated. For patients with severe renal insufficiency, tadalafil should be avoided. 2. A dose of tadalafil of 40 mg daily appears to have a more maximally phosphodiesterase-5 inhibiting effect than 20 mg 3 times daily of sildenafil. Accordingly for patients who have been on 20 mg of sildenafil 3 times daily with particularly low blood pressure, for example, less than 100 mg Hg prior to transition, a starting dose of 20 mg daily should be considered. 3. For patients already on parenteral prostanoids who have been on 20 mg of sildenafil 3 times daily, starting with tadalafil 20 mg daily may be advisable to assess tolerability, with subsequent dose increase if tolerated. It should be noted that, unlike sildenafil, there are no randomized clinical trial data regarding the addition of tadalafil to parenteral prostanoids so information regarding this combination is quite limited.
Possible Explanation for Improved Treatment Satisfaction With Tadalafil Compared to Sildenafil The greater proportion of patients reporting improved treatment satisfaction with tadalafil therapy in this study may in part
be because of the reduced pill burden and frequency of dosing. Although not specifically examined in this study, reducing the pill burden from an often high number of pills per day on a 3 times daily schedule for sildenafil to 2 pills taken once daily for tadalafil may improve patient adherence. Pill fatigue and lack of compliance have been well described in the HIV population along with improvements in outcomes related to simplifying of therapy regimen,16,17 A similar finding may occur in PAH as well, and thus, decreasing pill burden may have a positive impact. In a recent analysis of pharmacy claims (specialty pharmacy services and retail) from Medco Health Solutions, Inc, conducted between 2008 and 2010, the overall adherence to tadalafil was 61%, compared with 44% for sildenafil (P < .0001).18 Limitations of this study include the open-label nature of the study and the small sample size. Awareness of the transition may create bias, generating a perceived improvement from the transition. Echocardiography and 6MWD tests were not protocol mandated and thus were only available for some of the patients during follow-up. Because of the small sample size and lack of protocol-mandated testing, the study was not powered to rigorously assess clinical outcomes; therefore, in this regard it is exploratory in nature. Finally, although treatment with tadalafil is expected to result in improved compliance with therapy, this study did not specifically assess medication adherence. Despite these limitations, this multicenter prospective study provides important information on how to transition patients from sildenafil to tadalafil. Sildenafil and tadalafil appear to have similar efficacy and safety profiles in patients with PAH (functional classes II or III).5,11 In this context, other potential attributes may rise in relative importance. Indeed, tadalafil may have characteristics that make it a useful alternative to sildenafil, including convenience and pill burden, potential for fewer drug–drug interactions in combination with ERAs, and clear dosing in which the FDA-approved dose is the most effective dose with data for treatment durability.7,19,20 Because of these benefits and its relatively low cost, tadalafil may be a useful alternative in patients with PAH. Consistent with the results from this study, a recent small study reported that transitioning patients from sildenafil to tadalafil was safe and generally well tolerated.21 In conclusion, converting directly from sildenafil to tadalafil was generally well tolerated without any obvious safety issues. There was a greater percentage of patients who were satisfied than were dissatisfied after conversion to tadalafil. Declaration of Conflicting Interests The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Support for this study was provided by United Therapeutics Corporation. Editorial assistance was provided under the direction of the authors by MedThink Communications with support from United Therapeutics Corporation. United Therapeutics Corporation provided support for data collection, data management, and statistical analysis. SM and SW are employees of United Therapeutics Corporation and as authors were involved in data interpretation and had the right to approve or disapprove publication of the finished manuscript. RF has served on advisory boards
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for United Therapeutics, without personal financial gain, aside from coverage of travel expenses, in keeping with the Mayo Clinic’s conflict of interest policy for clinical investigators. He has received research funding for unrelated research projects and educational grants from United Therapeutics, without personal financial gain. LD serves on a steering committee for Medtronic, without personal financial gain, aside from coverage of travel expenses, in keeping with the Mayo Clinic’s conflict of interest policy for study staff. CB has received research funding from Actelion Pharmaceuticals, Gilead Sciences, and United Therapeutics, without personal financial gain. RO has received consulting and/or steering committee honoraria from Actelion Pharmaceuticals, Bayer, Gilead Sciences, Lung Rx, Medtronic, Novartis Pharmaceuticals, Pfizer, and United Therapeutics. RO has received grant support for clinical trials from Actelion Pharmaceuticals, Bayer, Gilead Sciences, Lung Rx, Pfizer, and United Therapeutics. He has also received speaker fees from Gilead Sciences and United Therapeutics. RB has received research support from Pfizer, United Therapeutics, Gilead Sciences, Actelion Pharmaceuticals, Novartis Pharmaceuticals, Medtronic, GeNO, and Bayer. He serves as a consultant for United Therapeutics, Gilead Sciences, Actelion Pharmaceuticals, Novartis Pharmaceuticals, and Medtronic. He also has received compensation for participation in speakers bureaus for Gilead Sciences and United Therapeutics. VF has served on advisory boards for Gilead Sciences and Bayer and has received compensation for participation in Gilead Sciences’ speakers bureau. AW is a consultant for United Therapeutics, Gilead Sciences, Pfizer, and Medtronic. He has also received research support from United Therapeutics, Gilead Sciences, Pfizer, and Medtronic, without personal financial gain. SM and SW are employees of United Therapeutics.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
References 1. McLaughlin VV, Archer SL, Badesch DB, et al. ACCF/AHA 2009 Expert consensus document on pulmonary hypertension: a report of the American college of cardiology foundation task force on expert consensus documents and the American heart association: developed in collaboration with the American college of chest physicians, American thoracic society, Inc., and the pulmonary hypertension association. Circulation. 2009;119(16):2250-2294. 2. Farber HW, Loscalzo J. Pulmonary arterial hypertension. N Engl J Med. 2004;351(16):1655-1665. 3. Michelakis E, Tymchak W, Lien D, Webster L, Hashimoto K, Archer S. Oral Sildenafil is an effective and specific pulmonary vasodilator in patients with pulmonary arterial hypertension: comparison with inhaled nitric oxide. Circulation. 2002; 105(20):2398-2403. 4. Tantini B, Manes A, Fiumana E, et al. Antiproliferative effect of sildenafil on human pulmonary artery smooth muscle cells. Basic Res Cardiol. 2005;100(2):131-138. 5. Galie` N, Ghofrani HA, Torbicki A, et al. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med. 2005;353(20): 2148-2157.
6. Revatio [package insert]. New York, NY: Pfizer Inc., 2010. 7. Burgess G, Hoogkamer H, Collings L, Dingemanse J. Mutual pharmacokinetic interactions between steady-state bosentan and sildenafil. Eur J Clin Pharmacol. 2008;64(1):43-50. 8. Adcirca [package insert]. Indianapolis, IN: Eli Lilly and Company, 2011. 9. Forgue ST, Patterson BE, Bedding AW, et al. Tadalafil pharmacokinetics in healthy subjects. Br J Clin Pharmacol. 2006;61(3):280-288. 10. Wright PJ. Comparison of phosphodiesterase type 5 (PDE5) inhibitors. Int J Clin Pract. 2006;60(8):967-975. 11. Galie` N, Brundage BH, Ghofrani HA, et al. Tadalafil therapy for pulmonary arterial hypertension. Circulation. 2009;119(22): 2894-2903. 12. Levin YD, White RJ. Novel therapeutic approaches in pulmonary arterial hypertension: focus on tadalafil. Drugs Today (Barc). 2011;47(2):145-156. 13. Oudiz RJ, Beardsworth A, Chan MLS, Barst RJ. Blinded, longterm safety and efficacy of tadalafil in treatment for pulmonary arterial hypertension. Am J Respir Crit Care Med. 2009;179: A1042. 14. Atkinson M, Sinha A, Hass S, et al. Validation of a general measure of treatment satisfaction, the treatment satisfaction questionnaire for medication (TSQM), using a national panel study of chronic disease. Health Qual Life Outcomes. 2004;2:1-13. 15. Berman Rosenzweig E, Arneson C, Golden G. Relationship between dosing and common adverse events with tadalafil in patients with pulmonary arterial hypertension. CHEST J. 2010; 138(4):352A-352A. 16. O’Connor JL, Gardner EM, Mannheimer SB, et al. Factors associated with adherence amongst 5295 people receiving antiretroviral therapy as part of an international trial. J Infect Dis. 2013; 208(1):40-49. 17. Cohen CJ, Meyers JL, Davis KL. Association between daily antiretroviral pill burden and treatment adherence, hospitalisation risk, and other healthcare utilisation and costs in a US medicaid population with HIV. BMJ Open. 2013;3(8). pii: e003028. 18. Waxman A, Chen SY, Boulanger L, Golden G. Adherence to phosphodiesterase type 5 inhibitors for the treatment of pulmonary arterial hypertension - a real-world analysis. CHEST J. 2011;140(4):736A-736A. 19. Spence R, Harrison B, Mandagere A, Dufton C. No clinically relevant pharmacokinetic interactions between ambrisentan and tadalafil. CHEST J. 2008;134(4):p161002. 20. Wrishko RE, Dingemanse J, Yu A, Darstein C, Phillips DL, Mitchell MI. Pharmacokinetic interaction between tadalafil and bosentan in healthy male subjects. J Clin Pharmacol. 2008; 48(5):610-618. 21. Shlobin O, Whitney Brown A, Weir N, Ahmad S, Lemma M, Nathan S. Transition of PH patients from sildenafil to tadalafil: feasibility and practical considerations. Lung. 2012;190(5): 573-578.
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Conversion From Sildenafil to Tadalafil: Results From the Sildenafil to Tadalafil in Pulmonary Arterial Hypertension (SITAR) Study Robert P. Frantz, Louise Durst, Charles D. Burger, Ronald J. Oudiz, Robert C. Bourge, Veronica Franco, Aaron B. Waxman, Susanne McDevitt and Susan Walker J CARDIOVASC PHARMACOL THER published online 17 April 2014 DOI: 10.1177/1074248414528066 The online version of this article can be found at: http://cpt.sagepub.com/content/early/2014/04/16/1074248414528066
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Article
Conversion From Sildenafil to Tadalafil: Results From the Sildenafil to Tadalafil in Pulmonary Arterial Hypertension (SITAR) Study
Journal of Cardiovascular Pharmacology and Therapeutics 1-8 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/1074248414528066 cpt.sagepub.com
Robert P. Frantz, MD1, Louise Durst, RN2, Charles D. Burger, MD3, Ronald J. Oudiz, MD4, Robert C. Bourge, MD5, Veronica Franco, MD6, Aaron B. Waxman, MD, PhD7, Susanne McDevitt, RN, MSN, ACNP8, and Susan Walker, MS8
Abstract Purpose: Among phosphodiesterase type 5 inhibitors, tadalafil offers clinicians a once-daily alternative to 3 times daily sildenafil for the treatment of pulmonary arterial hypertension (PAH). This study assessed the safety and patient satisfaction with conversion from sildenafil to tadalafil. Methods: In this multicenter, prospective, 6-month study, patients with PAH were instructed to take their last dose of sildenafil in the evening and initiate tadalafil 40 mg/d the next morning. Patients completed the Treatment Satisfaction Questionnaire for Medication at baseline and 30, 90, and 180 days after transition to assess PAH symptoms and patient satisfaction. Safety was assessed on the basis of recorded adverse events (AEs). Results: Of the 35 patients who met the study criteria, 56% were receiving 2 PAH therapies. At the time of transition, the sildenafil dose ranged from 40 to 300 mg/d, with 20% of the patients on >20 mg of sildenafil 3 times daily. Transition to tadalafil was generally well tolerated, and the incidence of common AEs, except for myalgia, appeared to decrease over time on tadalafil therapy. Five (14%) patients switched back to sildenafil. A greater percentage of patients were satisfied than were dissatisfied after conversion to tadalafil (55% vs 19% at 90 days), while 26% felt about the same degree of satisfaction. Conversion to tadalafil resulted in significant improvement in patient ratings of therapy convenience. Conclusions: Transition of patients from sildenafil to tadalafil was usually well tolerated, with improved convenience and may enhance treatment satisfaction. Keywords sildenafil, tadalafil, switch, pulmonary arterial hypertension, patient satisfaction
Introduction Pulmonary arterial hypertension (PAH) is a rare, progressive disease characterized by increasing pulmonary arterial pressure and pulmonary vascular resistance, ultimately leading to right ventricular (RV) failure and death.1,2 Greater disease awareness and improved diagnostics, coupled with a marked increase in the number of PAH-targeted therapies recently, have advanced management of patients with PAH. Widely used PAH therapies target 1 or more of the 3 main pathways in disease pathogenesis: prostacyclin, endothelin receptor antagonists (ERAs), and phosphodiesterase type 5 inhibitors (PDE-5Is). The PDE-5I class of PAH treatment blocks phosphodiesterase type 5-dependent inactivation of cyclic guanosine monophosphate, increasing nitric oxide-mediated pulmonary arterial vasodilation.3-5 Sildenafil was the first PDE-5I approved for treatment of PAH on the basis of the results of the Sildenafil Use in
1
Division of Cardiovascular Diseases, College of Medicine, Mayo Clinic, Rochester, MN, USA 2 Mayo Clinic, Rochester, MN, USA 3 Division of Pulmonary Medicine, Mayo Clinic, Jacksonville, FL, USA 4 Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA 5 Cardiovascular Medicine, University of Alabama at Birmingham, Birmingham, AL, USA 6 Cardiovascular Medicine, Ohio State University Medical Center, Columbus, OH, USA 7 Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, MA, USA 8 United Therapeutics Corporation, Research Triangle Park, NC, USA Manuscript submitted: July 26, 2013; accepted: February 20, 2014. Corresponding Author: Robert P. Frantz, 200 First Street SW, Mayo Clinic, Gonda 5, Rochester, MN 55905, USA. Email: [email protected]
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Pulmonary Arterial Hypertension (SUPER-1) study that randomized treatment-naive patients with PAH to sildenafil 20, 40, or 80 mg 3 times daily or placebo.5 Although the US Food and Drug Administration (FDA) approved sildenafil 20 mg 3 times daily for the treatment of PAH6 on the basis of the finding that there were no significant differences in 6-minute walk distance (6MWD) between the 20-, 40-, or 80-mg dosing groups, a greater hemodynamic effect was seen with the 80-mg 3 times daily dose, raising the possibility that the maximum approved dose was not the most hemodynamically effective dose for at least some patient subsets.5 In the open-label extension, patients receiving sildenafil 80 mg 3 times daily appeared to experience sustained benefit to the extent that this can be assessed in an open-label setting. However, there are no data regarding durability of treatment when patients are maintained on a 20-mg 3 times daily dose. Additionally, when sildenafil is used in combination with an ERA, bosentan, there are decreased plasma levels of sildenafil, providing more rationale for the use of higher doses of sildenafil.7 Thus, the optimal dosing regimen for sildenafil is controversial and has resulted in confusion among some clinicians who have been treating patients with sildenafil doses substantially above the FDArecommended dose. Treating patients above the FDArecommended dose can create challenges such as added cost and insurance coverage restrictions. Furthermore, dosing with a 3 times daily medication may lead to increased pill burden and lack of adherence in patients with PAH. Tadalafil is a once-daily PDE-5I approved for the treatment of patients with World Health Organization (WHO) group 1 PAH at a dose of 40 mg daily.8 Tadalafil’s longer half-life of 17.5 hours in healthy individuals and 35 hours in patients with PAH,9 compared with that of sildenafil at 4 to 5 hours,10 allows for once-daily dosing. In a large, multicenter, placebo-controlled pivotal study (PHIRST-1), patients were randomized to placebo or 2.5 mg, 10 mg, 20 mg, or 40 mg of tadalafil daily for 16 weeks.11 Approximately half of the patients were on bosentan at the time of study entry and half were treatment naive. A dose-dependent improvement in 6MWD was observed, with the highest dose studied (40 mg daily) having the greatest effect on 6MWD and clinical worsening. Tadalafil 40 mg also improved time to clinical worsening and health-related quality of life. In a hemodynamic substudy, there was a statistically significant improvement in hemodynamics in the tadalafil 40-mg group versus placebo. Treatment with tadalafil may offer several benefits over sildenafil therapy.12 Tadalafil therapy with once-daily dosing and a low pill burden (2 pills per day) may offer convenience and improved adherence to treatment. Sildenafil therapy with doses of 80 mg 3 times daily may result in a substantial pill burden (12-15 pills per day), which can also increase nonadherence. Sildenafil doses >20 mg 3 times daily may not be fully covered by insurance and, therefore, patient out-of-pocket and overall health care system costs may be reduced with tadalafil therapy. Additionally, there are long-term data for treatment durability at the FDA-approved dose for tadalafil.13 It is anticipated that because of these benefits, many patients and clinicians may
choose transition from sildenafil to tadalafil therapy. However, there is little reported clinical experience in converting patients from sildenafil to tadalafil. In this prospective multicenter open-label study, safety and patient satisfaction with conversion from sildenafil to tadalafil were assessed.
Methods Study Design This was a multicenter, prospective, open-label, 6-month study of patients with PAH who were transitioned from sildenafil to tadalafil treatment at home (in the outpatient setting). Adult males and females with WHO group 1 PAH, who were treated with sildenafil at a dose of 20 mg 3 times daily or greater for at least 30 days, and for whom a clinical decision to transition to tadalafil had been made, were included in this study. Patients were excluded from the study if they had any other disease associated with PAH that was non-WHO group 1; advanced liver or kidney disease; acute decompensation of underlying illness or hospitalization for PAH within 4 weeks before enrollment; a history of hypersensitivity reaction or adverse effect related to tadalafil use; participated in an investigational drug or device clinical study within 4 weeks of enrollment; or concomitant use of nitrates or potent CYP3A inhibitors. No limitations were set as to the number and types of non-PDE-5I background therapies that patients could be on, including ERAs and inhaled and parenteral prostanoid therapies. Informed consent was obtained from all participants. The study was approved by the institutional review boards and was registered with ClinicalTrials.gov (NCT01043627).
Method of Transition After baseline data collection, patients were instructed to take the last dose of sildenafil in the evening and then initiate tadalafil (usually 40 mg) the next morning. The tadalafil dose was reduced (eg, 20 mg) if there were any adverse events (AEs) attributable to tadalafil therapy.
Clinical Assessments Patients were evaluated at baseline and at 30 days, 3 months, and 6 months after transition to tadalafil. Treatment tolerability, patient preferences, and symptoms were measured by having patients complete the Treatment Satisfaction Questionnaire for Medication (TSQM)14 at baseline and at 30 days, 3 months, and 6 months after conversion to tadalafil. Patients reported satisfaction with treatment in this survey as ‘‘much less satisfied,’’ ‘‘less satisfied,’’ ‘‘about same,’’ ‘‘more satisfied,’’ or ‘‘much more satisfied.’’ Patients were also asked to rate their PAH symptoms as ‘‘much worse,’’ ‘‘somewhat worse,’’ ‘‘about same,’’ ‘‘somewhat better,’’ or ‘‘much better.’’ Aside from the serial questionnaires, no protocol-mandated tests were performed. The treating clinician provided information regarding why the patient was transitioning from sildenafil to tadalafil. Clinical assessments were recorded as available
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according to each center’s routine clinical practice. Demographic parameters, disease characteristics, use of concomitant medications, and any echocardiographic and 6-minute walk data that had been clinically obtained within 3 months of study enrollment and without change in PAH medication were collected at baseline. As available, serial parameters from 3 and 6 months following conversion were also abstracted from the charts and entered into the case report forms. Safety was assessed on the basis of recorded AEs, vital signs, and clinically available laboratory measures.
Statistical Analysis Data for all variables collected in this study were summarized using descriptive statistics. Continuous variables (6MWD and echocardiography parameters) were summarized using mean and standard deviation. Categorical variables (WHO functional class, response to TSQM, and AEs) were summarized using the number and percentage of patients in each category.
Results Baseline Characteristics A total of 35 patients who were prospectively enrolled at 6 centers from April 2010 to February 2011 and met the study entry criteria were switched from sildenafil to tadalafil. Demographic and baseline disease characteristics of the patients converted from sildenafil to tadalafil are shown in Table 1. The majority of patients were female with idiopathic PAH (IPAH)/heritable PAH and were in WHO functional classes II and III. About 21% of patients in the study were receiving calcium channel blocker therapy. Most (54%) patients were receiving 2 or more PAH therapies, and 17% of patients were on 3 PAH therapies. About 26% of the patients were receiving inhaled or parenteral prostacyclin therapy. The mean 6MWD was 394 + 102 m at baseline.
Patient Disposition and Transition Dosing Considerations All patients were switched from sildenafil to tadalafil per the specified dosing regimen. Mean duration of sildenafil treatment was 124 + 100 weeks (range 10-385 weeks). At the time of transition, 20% of the patients were on >20 mg 3 times daily of sildenafil, with 1 patient receiving as high as 100 mg 3 times daily of sildenafil. Clinicians cited that the majority of patients were converted from sildenafil to tadalafil for convenience and cost reasons (Table 2). Of the 35 patients transitioned from sildenafil to tadalafil, 5 (14%) transitioned back to sildenafil. Four patients required the addition of a parenteral prostanoid within the 6-month period after transitioning to tadalafil.
Tolerability of Conversion from Sildenafil to Tadalafil Transition from sildenafil to tadalafil was generally well tolerated, with headache, myalgia, dizziness, diarrhea, flushing, and nausea reported as common AEs (Figure 1). Most AEs were
Table 1. Patient Demographics and Characteristics. Parameter
Patients (N ¼ 35)
Age, y, mean (range) Male:female, n PAH etiology, n (%) Idiopathic or heritable CTD Other Missing Echo parameters, mean + SD RVSP, mm Hg TAPSE, cm CO, L/min WHO functional class, n I:II:III PAH/Background medications, n (%) PDE-5I monotherapy PDE-5I þ ERA PDE-5I þ ERA þ inhaled prostanoid PDE-5I þ ERA þ parenteral prostanoid PDE-5I þ parenteral prostanoid Sildenafil dose at transition, n (%) 20 mg tid >20 mg tid Duration of sildenafil, mean + SD, week 6MWD before transition, mean + SD, m BNP, median (range), pg/mL NT-proBNP, median (range), pg/mL
56 (20-84) 9:26 22 (63) 4 (11) 8 (23) 1 (3) 77 + 20a 1.9 + 5.7b 4.5 + 3.0c 1:14:18d 16 (46) 10 (29) 1 (3) 5 (14) 3 (9) 28 (80) 7 (20) 124 + 104e 394 + 101f 170 (12-6129)g 349 (21-7765)h
Abbreviations: BNP, B-type natriuretic peptide; CO, cardiac output; CTD, connective tissue disease; echo, echocardiography; ERA, endothelin receptor antagonist; 6MWD, 6-minute walk distance; NT-proBNP, N-terminal proBNP; PAH, pulmonary arterial hypertension; PDE-5I, phosphodiesterase type 5 inhibitor; RVSP, right ventricular systolic pressure; SD, standard deviation; TAPSE, tricuspid annual plane systolic excursion; tid, 3 times daily; WHO, World Health Organization. a n ¼ 31. b n ¼ 23. c n ¼ 24. d n ¼ 33. e n ¼ 30. f n ¼ 32. g n ¼ 17. h n ¼ 15.
Table 2. Reasons for Conversion to Tadalafil.a Reason Convenience Cost Sildenafil dose >20 mg tid Other
Patients n (%) 14 (40) 15 (43) 5 (14) 15 (43)
Abbreviation: tid, 3 times daily. a Patients could have been converted for multiple reasons.
mild to moderate. Before conversion to tadalafil, common AEs with sildenafil therapy included diarrhea, flushing, dizziness, myalgia, and headache. We did not observe any substantial differences in the AE profile, but headache early following conversion may have been more common while diarrhea and flushing seemed to be less prominent. The most common
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30
SIL baseline (n = 35) TAD 30 days (n = 35) TAD 90 days (n = 35) TAD 180 days (n = 35)
Percent of Patients
26
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20 17 14
14
14 11 10
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9 6 6
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3 0 Headache
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Figure 1. Common adverse events associated with PDE-5I therapy before conversion to tadalafil and by time on tadalafil. PDE-5I indicates phosphodiesterase type 5 inhibitor; SIL, sildenafil; TAD, tadalafil.
severe AEs associated with the conversion to tadalafil included headache, nasal congestion, pain in extremity, myalgia, and dizziness, which were more common in the initial 30 days after conversion. Details of failed transitions Patient 1. A 59-year-old female with IPAH on therapy with amlodipine and sildenafil 20 mg 3 times daily, with blood pressure (BP) 96/50 prior to transition. Prior history notable for severe chronic fatigue. She noted myalgias and worsening fatigue after transition. Tadalafil dose reduction to 20 mg improved but did not resolve the aggravation of these symptoms so she was converted back to sildenafil. Patient 2. A 52-year-old female with IPAH on therapy with bosentan and sildenafil 20 mg 3 times daily. Light sensitivity after the transition that resolved after several days and worsening gastroesophageal reflux that improved with omeprazole were noted. She also described myalgias, nasal stuffiness, and constipation. The possibility of reducing the dose of tadalafil was discussed, but she elected to transition back to sildenafil 2 weeks after starting the tadalafil. Patient 3. A 74-year-old female with IPAH, on therapy with 80 ng/kg/min intravenous (iv) treprostinil and sildenafil 20 mg 3 times daily. She had an estimated glomerular filtration rate of 31 mL/min. Following transition, she experienced symptomatic lightheadedness and worsening dyspnea. She remained functional class III before and after the transition so converted back to sildenafil. Potentially, 20 mg of tadalafil would have been a more optimal starting dose in such a setting. Down titrating the tadalafil rather than switching back to sildenafil could have been considered. Patient 4. For this patient, a reason for the transition back to sildenafil was not provided.
Patient 5. A 42-year-old female with IPAH on therapy with bosentan and sildenafil 20 mg 3 times daily. Following transition, she noted significant lower extremity aching unresponsive to ibuprofen and mild pedal edema. Two months after transition, she was converted back to sildenafil. There was not an attempt to reduce her tadalafil dose. Symptoms of PAH and satisfaction with therapy. Among patients who answered the questionnaire at each time point, there appeared to be a greater percentage of patients who reported the same or improved general PAH symptoms over time (Figure 2). Within 30 days after conversion to tadalafil, 88% of patients reported the same or improved general PAH symptoms (n ¼ 32). After 90 (n ¼ 31) and 180 days (n ¼ 26) of having transitioned to tadalafil, 87% and 85% of patients reported the same or improved PAH symptoms, respectively. In addition, 48% and 38% of patients reported improvement in PAH symptoms after 90 and 180 days of having transitioned to tadalafil, respectively. There was a greater percentage of patients who were satisfied (more satisfied and much more satisfied) than were dissatisfied (less satisfied and much less satisfied) after conversion to tadalafil (30 days, 47% vs 16%; 90 days, 55% vs 19%; 180 days, 50% vs 8%; Figure 3). Two patients reported ‘‘much less satisfied’’ in the 90-day survey only following conversion to tadalafil. Although global satisfaction score following transition to tadalafil did not significantly improve versus baseline (mean improvement of 0.3 after 180 days; P ¼ .7309), TSQM scores showed a significant improvement in convenience (mean improvement of 15.9 after 180 days; P ¼ .0312).
Summary of Clinically Available Serial Testing Given the small number of patients who had serial 6MWD available, we can only say that for most of them there was no
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70
TAD 30 days (n = 32)
Percent of Patients
TAD 90 days (n = 31)
59
60
TAD 180 days (n = 26)
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46 39
40 30
22 20 12 10
10 0
0
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15 6
0
Much worse
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Figure 2. Patient assessment of pulmonary arterial hypertension symptoms after conversion from sildenafil to tadalafil, by time on tadalafil. TAD indicates tadalafil.
50
TAD 30 days (n = 32) TAD 90 days (n = 31) TAD 180 days (n = 26)
42 38
Percent of Patients
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31 26
26
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16 13
10
0
0
9
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6 0
Much less satisfied
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Figure 3. Patient assessment of satisfaction with pulmonary arterial hypertension treatment after conversion from sildenafil to tadalafil, by time on tadalafil. TAD indicates tadalafil.
conspicuous pattern of change in walk distance after transitioning to tadalafil therapy (Figure 4). The change in mean 6MWD (+standard error) from baseline was 11.0 (9.0) m, 10.8 (33.7) m, and 17.3 (25.6) m after 30 days (n ¼ 7), 90 days (n ¼ 13), and 180 days (n ¼ 14) of having transitioned from sildenafil to tadalafil therapy, respectively. No particular trends in the mean RV systolic pressure (RVSP) were observed (4.4 mm Hg and 4.3 mm Hg after 90 days (n ¼ 11) and 180 days (n ¼ 11), respectively, compared with baseline, after transitioning to tadalafil. There was no significant change in tricuspid annual plane systolic excursion (0.34 and 0.36 cm after 90 days (n ¼ 8) and 180 days (n ¼ 8), respectively, after having transitioned to tadalafil,
and the very small number of patients with serial data precludes meaningful conclusions. Detailed review of the 2 patients with major drop in 6MWD Patient 1. Transient drop in walk that was felt not to be representative of clinical compensation. A 67-year-old female with diet drug-related PAH in the context of obesity, type 2 diabetes mellitus, obstructive sleep apnea controlled with CPAP, and need for supplemental oxygen of 3 L/min during activity. She was receiving 100 mg 3 times daily of sildenafil as monotherapy for her PAH and was switched to tadalafil 40 mg daily when her insurance carrier refused to continue payment for
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A
B n=7
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Figure 4. Change in 6MWD from baseline for patients with serial data available. A, Baseline to day 30. B, Baseline to month 3. C, Baseline to month 6. Mean 6MWD is plotted as dotted lines. 6MWD indicates 6-minute walk distance.
sildenafil. She had previously been intolerant of inhaled iloprost and oral treprostinil and had not had clinical benefit from bosentan. One month prior to the switch, she was WHO functional class III, with 6-minute walk of 372 m on 3L oxygen with drop in systemic saturation from 95% to 82%. Her N-terminal pro-B-type natriuretic peptide (NT-proBNP) level was 264 pg/mL. The RVSP by implanted Chronicle hemodynamic monitor was 95 mm Hg, with RVEDP of 7 mm Hg. Echocardiography showed moderate RV enlargement, moderate tricuspid regurgitation, and tricuspid annular plane systolic excursion of 19 mm, with estimated cardiac index of 3.0 L/min/ m2. Four months following conversion to tadalafil, she felt clinically unchanged and remained functional class III. Her walk distance of only 114 m was performed the day after she had a very busy day entertaining guests and had arisen at 3 AM in order to attend the clinic. She felt exhausted and stopped walking after only 1 minute 46 seconds and felt the walk was not representative of her overall clinical status. N-terminal pro B-type natriuretic peptide was 485 pg/mL, and interrogation of her implantable hemodynamic monitor showed no change in her hemodynamics compared to prior to switching to tadalafil. Echocardiography-estimated cardiac index was preserved at 2.7 L/min/m2. Her therapy was not changed. Ten months following conversion, she remained functional class III on tadalafil without additional therapy, with 6-minute walk of 337 m and NT-proBNP of 592 pg/mL. At most recent follow-up, 3 years following the switch, she remains functional class III on
tadalafil monotherapy, with stable echo parameters, a 6minute walk of 313 m, and NT-proBNP of 557 pg/mL. Patient 2. Stable walk at 3 months, but reduction in walk at 6 months. This patient was on triple therapy with sildenafil 30 mg 3 times daily, bosentan 125 mg twice daily, and iv epoprostenol 115 ng/kg/min with 6-minute walk of 390 m prior to conversion to tadalafil. At 3-month follow-up after conversion, her 6MWD was preserved at 395 m with preserved B-type natriuretic peptide (BNP) level of 144 pg/mL. However, at the 6-month follow-up, she had developed pulmonary infiltrates, was more hypoxic, and her walk had deteriorated to 126 m, with BNP 587 pg/mL. She was diagnosed with anti-PR3 vasculitis that responded to rituximab. Two months later, her walk had improved to 239 m with BNP 485 pg/mL. She was subsequently converted to treprostinil in an effort to deal with worsening thrombocytopenia. She stayed on tadalafil throughout her course, and 2½ years later required lung transplantation. It was not felt that the deterioration in walk distance at 6 months was related to the prior conversion to tadalafil.
Discussion In this prospective study, most patients were successfully converted from sildenafil to tadalafil in the outpatient setting while maintaining PAH therapeutic class efficacy and improving treatment satisfaction. Factors of convenience and cost were
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commonly cited as reasons for transition to tadalafil. Improved treatment satisfaction with tadalafil appeared to relate primarily to the improved sense of convenience reported by patients. The patients in this study were stable on sildenafil before transition to tadalafil with many of the patients on combination therapies, including 37% on 2 PAH therapies and 17% on 3 PAH therapies. Furthermore, patients taking >20 mg 3 times daily of sildenafil were successfully transitioned to tadalafil 40 mg once daily. Transition to tadalafil from sildenafil was generally well tolerated. Most patients who transitioned to tadalafil remained on tadalafil throughout the 6 months of our study, but some patients switched back to sildenafil due to more problematic side effects or, in 1 patient, increased dyspnea. The incidence of common AEs appeared to decrease over time on tadalafil therapy, with the exception of myalgia. Although there was a higher incidence of headache (28%) within the first 30 days of transition in this study, the incidence decreased over time (14% by 6 months). Headache and myalgia were also 2 of the most commonly reported AEs in the 16-week PHIRST-1 trial.11 Similar to this study, the incidence of headache decreased rapidly after 1 week of tadalafil therapy in the PHIRST-1 trial and remained infrequent through the openlabel PHIRST-2 trial (68 weeks).15 These results suggest that the incidence of AEs such as headache may be initially higher when patients are transitioned to tadalafil but these tend to diminish in frequency upon continued treatment.
Practical Lessons Regarding the Transition Process 1. For patients with mild to moderate renal insufficiency, a starting dose of 20 mg daily is recommended, with potential to increase to 40 mg daily if tolerated. For patients with severe renal insufficiency, tadalafil should be avoided. 2. A dose of tadalafil of 40 mg daily appears to have a more maximally phosphodiesterase-5 inhibiting effect than 20 mg 3 times daily of sildenafil. Accordingly for patients who have been on 20 mg of sildenafil 3 times daily with particularly low blood pressure, for example, less than 100 mg Hg prior to transition, a starting dose of 20 mg daily should be considered. 3. For patients already on parenteral prostanoids who have been on 20 mg of sildenafil 3 times daily, starting with tadalafil 20 mg daily may be advisable to assess tolerability, with subsequent dose increase if tolerated. It should be noted that, unlike sildenafil, there are no randomized clinical trial data regarding the addition of tadalafil to parenteral prostanoids so information regarding this combination is quite limited.
Possible Explanation for Improved Treatment Satisfaction With Tadalafil Compared to Sildenafil The greater proportion of patients reporting improved treatment satisfaction with tadalafil therapy in this study may in part
be because of the reduced pill burden and frequency of dosing. Although not specifically examined in this study, reducing the pill burden from an often high number of pills per day on a 3 times daily schedule for sildenafil to 2 pills taken once daily for tadalafil may improve patient adherence. Pill fatigue and lack of compliance have been well described in the HIV population along with improvements in outcomes related to simplifying of therapy regimen,16,17 A similar finding may occur in PAH as well, and thus, decreasing pill burden may have a positive impact. In a recent analysis of pharmacy claims (specialty pharmacy services and retail) from Medco Health Solutions, Inc, conducted between 2008 and 2010, the overall adherence to tadalafil was 61%, compared with 44% for sildenafil (P < .0001).18 Limitations of this study include the open-label nature of the study and the small sample size. Awareness of the transition may create bias, generating a perceived improvement from the transition. Echocardiography and 6MWD tests were not protocol mandated and thus were only available for some of the patients during follow-up. Because of the small sample size and lack of protocol-mandated testing, the study was not powered to rigorously assess clinical outcomes; therefore, in this regard it is exploratory in nature. Finally, although treatment with tadalafil is expected to result in improved compliance with therapy, this study did not specifically assess medication adherence. Despite these limitations, this multicenter prospective study provides important information on how to transition patients from sildenafil to tadalafil. Sildenafil and tadalafil appear to have similar efficacy and safety profiles in patients with PAH (functional classes II or III).5,11 In this context, other potential attributes may rise in relative importance. Indeed, tadalafil may have characteristics that make it a useful alternative to sildenafil, including convenience and pill burden, potential for fewer drug–drug interactions in combination with ERAs, and clear dosing in which the FDA-approved dose is the most effective dose with data for treatment durability.7,19,20 Because of these benefits and its relatively low cost, tadalafil may be a useful alternative in patients with PAH. Consistent with the results from this study, a recent small study reported that transitioning patients from sildenafil to tadalafil was safe and generally well tolerated.21 In conclusion, converting directly from sildenafil to tadalafil was generally well tolerated without any obvious safety issues. There was a greater percentage of patients who were satisfied than were dissatisfied after conversion to tadalafil. Declaration of Conflicting Interests The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Support for this study was provided by United Therapeutics Corporation. Editorial assistance was provided under the direction of the authors by MedThink Communications with support from United Therapeutics Corporation. United Therapeutics Corporation provided support for data collection, data management, and statistical analysis. SM and SW are employees of United Therapeutics Corporation and as authors were involved in data interpretation and had the right to approve or disapprove publication of the finished manuscript. RF has served on advisory boards
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Journal of Cardiovascular Pharmacology and Therapeutics
for United Therapeutics, without personal financial gain, aside from coverage of travel expenses, in keeping with the Mayo Clinic’s conflict of interest policy for clinical investigators. He has received research funding for unrelated research projects and educational grants from United Therapeutics, without personal financial gain. LD serves on a steering committee for Medtronic, without personal financial gain, aside from coverage of travel expenses, in keeping with the Mayo Clinic’s conflict of interest policy for study staff. CB has received research funding from Actelion Pharmaceuticals, Gilead Sciences, and United Therapeutics, without personal financial gain. RO has received consulting and/or steering committee honoraria from Actelion Pharmaceuticals, Bayer, Gilead Sciences, Lung Rx, Medtronic, Novartis Pharmaceuticals, Pfizer, and United Therapeutics. RO has received grant support for clinical trials from Actelion Pharmaceuticals, Bayer, Gilead Sciences, Lung Rx, Pfizer, and United Therapeutics. He has also received speaker fees from Gilead Sciences and United Therapeutics. RB has received research support from Pfizer, United Therapeutics, Gilead Sciences, Actelion Pharmaceuticals, Novartis Pharmaceuticals, Medtronic, GeNO, and Bayer. He serves as a consultant for United Therapeutics, Gilead Sciences, Actelion Pharmaceuticals, Novartis Pharmaceuticals, and Medtronic. He also has received compensation for participation in speakers bureaus for Gilead Sciences and United Therapeutics. VF has served on advisory boards for Gilead Sciences and Bayer and has received compensation for participation in Gilead Sciences’ speakers bureau. AW is a consultant for United Therapeutics, Gilead Sciences, Pfizer, and Medtronic. He has also received research support from United Therapeutics, Gilead Sciences, Pfizer, and Medtronic, without personal financial gain. SM and SW are employees of United Therapeutics.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
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