Evaluate The Clinical Effectiveness, Safety And Tolerability Of Sildenafil Used In Doses ≥20mg TID For The Treatment Of Pulmonary Arterial Hypertension

• Sponsor: Pfizer's Upjohn has merged with Mylan to form Viatris Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01365585
• Collaborator: (none)
• Enrollment: 227
• Locations: 2
• Duration (Months): 3
• Patients Per Site: 113.5
• Patients Per Site Per Month: 37.6

Study Details

Study Description

Brief Summary

The objective of this observational study is to gain clinical insight on the actual use of sildenafil citrate (Revatio™) for the treatment of pulmonary arterial hypertension (PAH). The primary objective is to assess effectiveness and safety of sildenafil at doses ≥20mg three times daily for the treatment of PAH.

Condition or Disease	Intervention/Treatment	Phase
Pulmonary Arterial Hypertension	Drug: sildenafil citrate

Detailed Description

The study design proposed is a retrospective chart review going back five years (01 April 2006 estimate) from the time of study initiation (31 March 2011 estimate). Within this five-year period, study index will occur the first time an adult patient begins sildenafil for the treatment of PAH for a period of at least three months. The patient has to be taking sildenafil at doses ≥ 20mg tid for the treatment of PAH.

Study Design

• Study Type: Observational
• Actual Enrollment: 227 participants
• Observational Model: Cohort
• Time Perspective: Retrospective
• Official Title: Evaluate The Clinical Effectiveness, Safety And Tolerability Of Sildenafil Used In Doses ≥20mg TID For The Treatment Of Pulmonary Arterial Hypertension
• Study Start Date: Jul 1, 2011
• Actual Primary Completion Date: Oct 1, 2011
• Actual Study Completion Date: Oct 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Sildenafil ≥20mg three times daily Subjects receiving sildenafil ≥20mg three times daily for the treatment of PAH	Drug: sildenafil citrate; Sildenafil citrate, 20mg oral tablets, taken at least three times daily

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in 6-Minute Walk Distance (6MWD) at Year 1 [Baseline, Year 1]

   6MWD was the distance that a participant could walk in 6 minutes. Participants were asked to perform the test at a pace that was comfortable to them, with as many breaks as they needed.

2. Change From Baseline in 6-Minute Walk Distance (6MWD) at Year 2 [Baseline, Year 2]

   6MWD was the distance that a participant could walk in 6 minutes. Participants were asked to perform the test at a pace that was comfortable to them, with as many breaks as they needed.

3. Change From Baseline in 6-Minute Walk Distance (6MWD) at Year 3 [Baseline, Year 3]

   6MWD was the distance that a participant could walk in 6 minutes. Participants were asked to perform the test at a pace that was comfortable to them, with as many breaks as they needed.

4. Change From Baseline in 6-Minute Walk Distance (6MWD) at Year 4 [Baseline, Year 4]

   6MWD was the distance that a participant could walk in 6 minutes. Participants were asked to perform the test at a pace that was comfortable to them, with as many breaks as they needed.

Secondary Outcome Measures

1. Change From Baseline in New York Heart Association, World Health Organization (NYHA/WHO) Functional Class in Participants With Pulmonary Arterial Hypertension (PAH) at Year 1, 2, 3 and 4 [Baseline, Year 1, 2, 3, 4]

   NYHA/WHO functional classification for PAH range from Class I (no limitation in physical activity, no dyspnea with normal activity) to Class IV (can not perform a physical activity without any symptoms, dyspnea at rest). Improvement=reduction in functional class, deterioration = increase in functional class, no change = no change in functional class. Number of participants in each functional class was reported.

2. Change From Baseline in Right Atrial Pressure (RAP) at Year 1, 2, 3 and 4 [Baseline, Year 1, 2, 3, 4]

   RAP was measured using a pressure transducer positioned at the mid-axillary line with the participant in the supine position.

3. Change From Baseline in Mean Pulmonary Arterial Pressure (mPAP) at Rest at Year 1, 2, 3 and 4 [Baseline, Year 1, 2, 3, 4]

   mPAP was measured using a pressure transducer positioned at the mid-axillary line with the participant in the supine position.

4. Change From Baseline in Pulmonary Vascular Resistance (PVR) at Year 1, 2, 3 and 4 [Baseline, Year 1, 2, 3, 4]

   PVR: calculated by subtracting PCWP from mPAP and dividing by cardiac output in pulmonary circulation (COpulm).

5. Change From Baseline in Cardiac Index (CI) at Year 1, 2, 3 and 4 [Baseline, Year 1, 2, 3, 4]

   CI: calculated as COsys divided by BSA.

6. Change From Baseline in Pulmonary Capillary Wedge Pressure (PCWP) at Year 1, 2, 3 and 4 [Baseline, Year 1, 2, 3, 4]

   PCWP was measured by pulmonary artery catheterization and provided an indirect measure of left atrial pressure.

7. Change From Baseline in Borg Dyspnea Index at Year 1, 2, 3 and 4 [Baseline, Year 1, 2, 3, 4]

   Borg dyspnea scale: 10-point scale where following scores stands for severity of dyspnea: 0=no breathlessness at all;0.5=very very slight (just noticeable); 1=very slight; 2=slight breathlessness; 3=moderate; 4=some what severe; 5=severe; 7=very severe breathlessness; 9=very very severe (almost maximum) and 10=maximum.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients must be at least 18 years of age at study index;

• Patients must have a diagnosis of PAH. PAH is conventionally defined as a mean pulmonary arterial pressure (PAP) of > 25 mmHg and a pulmonary capillary wedge pressure (PCWP) ≤ 15 mmHg and a pulmonary vascular resistance (PVR) ≥ 240 dynes/s/cm-5 at right heart catheterization;

• Patients must have initiated sildenafil for the treatment of their PAH; at dose ≥ 20 mg tid within 5 years prior to study initiation

Exclusion Criteria:

• Patient has known contraindications to sildenafil at study index;

• Patient participated in an investigational study of sildenafil treatment for PAH during the period beginning 6 months prior to study index

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Medizinische Hochschule Hannover	Hannover		Germany	30625
2	Mater Misericordiae Hospital	Dublin		Ireland	7

Sponsors and Collaborators

• Pfizer's Upjohn has merged with Mylan to form Viatris Inc.

Investigators

• Study Director: Pfizer CT.gov Call Center, Pfizer

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Pfizer's Upjohn has merged with Mylan to form Viatris Inc.
• ClinicalTrials.gov Identifier: NCT01365585
• Other Study ID Numbers: A1481297
• First Posted: Jun 3, 2011
• Last Update Posted: Feb 1, 2021
• Last Verified: Jan 1, 2021

• Keywords provided by Pfizer's Upjohn has merged with Mylan to form Viatris Inc.: Pulmonary arterial hypertension; sildenafil citrate; Revatio
• Additional relevant MeSH terms: Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension; Hypertension; Sildenafil Citrate

Study Results

Participant Flow

Arm/Group Title	Sildenafil
Arm/Group Description	Participants who received sildenafil greater than or equal to 20 milligram (mg) three times daily as per Summary of Product Characteristics (SmPC) for the treatment of pulmonary arterial hypertension (PAH) for a period of at least 3 months, were observed retrospectively for 5 years.
Period Title: Overall Study
STARTED	227
COMPLETED	227
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Sildenafil
Arm/Group Description	Participants who received sildenafil greater than or equal to 20 milligram (mg) three times daily as per Summary of Product Characteristics (SmPC) for the treatment of pulmonary arterial hypertension (PAH) for a period of at least 3 months, were observed retrospectively for 5 years.
Overall Participants	227
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	60.5 (14.37)
Sex/Gender, Customized (participants) [Number]
Female	145 63.9%
Male	81 35.7%
Six-Minute Walk Distance (6MWD) (meter) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [meter]	331.7 (117.42)
New York Heart Association, World Health Organization (NYHA/WHO) Functional Class (participants) [Number]
Class I	1 0.4%
Class II	39 17.2%
Class III	163 71.8%
Class IV	13 5.7%
Right Atrial Pressure (RAP) (millimeters of mercury (mmHg)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [millimeters of mercury (mmHg)]	6.6 (4.85)
Mean Pulmonary Arterial Pressure (mPAP) at rest (mmHg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmHg]	44.8 (12.37)
Pulmonary Vascular Resistance (PVR) (dynes*second/centimeter^5) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [dynes*second/centimeter^5]	612.8 (250.54)
Cardiac Index (CI) ((Liter/minute)/square meter([L/min]/m^2)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [(Liter/minute)/square meter([L/min]/m^2)]	2.5 (1.51)
Pulmonary Capillary Wedge Pressure (PCWP) (mmHg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmHg]	7.6 (3.84)
Borg Dyspnea Index (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	3.7 (1.91)

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in 6-Minute Walk Distance (6MWD) at Year 1
Description	6MWD was the distance that a participant could walk in 6 minutes. Participants were asked to perform the test at a pace that was comfortable to them, with as many breaks as they needed.
Time Frame	Baseline, Year 1

Outcome Measure Data

Analysis Population Description

Analysis population included all participants who satisfied the eligibility criteria for the study. Here, 'N' (number of participants analyzed) included those participants who were evaluable for this measure.

Arm/Group Title	Sildenafil
Arm/Group Description	Participants who received sildenafil greater than or equal to 20 milligram (mg) three times daily as per Summary of Product Characteristics (SmPC) for the treatment of pulmonary arterial hypertension (PAH) for a period of at least 3 months, were observed retrospectively for 5 years.
Measure Participants	132
Mean (Standard Deviation) [meter]	29.4 (81.38)

2. Primary Outcome

Title	Change From Baseline in 6-Minute Walk Distance (6MWD) at Year 2
Description	6MWD was the distance that a participant could walk in 6 minutes. Participants were asked to perform the test at a pace that was comfortable to them, with as many breaks as they needed.
Time Frame	Baseline, Year 2

Outcome Measure Data

Analysis Population Description

Analysis population included all participants who satisfied the eligibility criteria for the study. Here, 'N' (number of participants analyzed) included those participants who were evaluable for this measure.

Arm/Group Title	Sildenafil
Arm/Group Description	Participants who received sildenafil greater than or equal to 20 milligram (mg) three times daily as per Summary of Product Characteristics (SmPC) for the treatment of pulmonary arterial hypertension (PAH) for a period of at least 3 months, were observed retrospectively for 5 years.
Measure Participants	74
Mean (Standard Deviation) [meter]	20.8 (83.82)

3. Primary Outcome

Title	Change From Baseline in 6-Minute Walk Distance (6MWD) at Year 3
Description	6MWD was the distance that a participant could walk in 6 minutes. Participants were asked to perform the test at a pace that was comfortable to them, with as many breaks as they needed.
Time Frame	Baseline, Year 3

Outcome Measure Data

Analysis Population Description

Analysis population included all participants who satisfied the eligibility criteria for the study. Here, 'N' (number of participants analyzed) included those participants who were evaluable for this measure.

Arm/Group Title	Sildenafil
Arm/Group Description	Participants who received sildenafil greater than or equal to 20 milligram (mg) three times daily as per Summary of Product Characteristics (SmPC) for the treatment of pulmonary arterial hypertension (PAH) for a period of at least 3 months, were observed retrospectively for 5 years.
Measure Participants	31
Mean (Standard Deviation) [meter]	8.7 (73.82)

4. Primary Outcome

Title	Change From Baseline in 6-Minute Walk Distance (6MWD) at Year 4
Description	6MWD was the distance that a participant could walk in 6 minutes. Participants were asked to perform the test at a pace that was comfortable to them, with as many breaks as they needed.
Time Frame	Baseline, Year 4

Outcome Measure Data

Analysis Population Description

Analysis population included all participants who satisfied the eligibility criteria for the study. Here, 'N' (number of participants analyzed) included those participants who were evaluable for this measure.

Arm/Group Title	Sildenafil
Arm/Group Description	Participants who received sildenafil greater than or equal to 20 milligram (mg) three times daily as per Summary of Product Characteristics (SmPC) for the treatment of pulmonary arterial hypertension (PAH) for a period of at least 3 months, were observed retrospectively for 5 years.
Measure Participants	9
Mean (Standard Deviation) [meter]	-50.2 (86.24)

5. Secondary Outcome

Title	Change From Baseline in New York Heart Association, World Health Organization (NYHA/WHO) Functional Class in Participants With Pulmonary Arterial Hypertension (PAH) at Year 1, 2, 3 and 4
Description	NYHA/WHO functional classification for PAH range from Class I (no limitation in physical activity, no dyspnea with normal activity) to Class IV (can not perform a physical activity without any symptoms, dyspnea at rest). Improvement=reduction in functional class, deterioration = increase in functional class, no change = no change in functional class. Number of participants in each functional class was reported.
Time Frame	Baseline, Year 1, 2, 3, 4

Outcome Measure Data

Analysis Population Description

Analysis population included all participants who satisfied the eligibility criteria for the study. Here, 'N' (number of participants analyzed) included those participants who were evaluable for this measure. Here, 'n' included those participants who were evaluable for this measure at specified time points.

Arm/Group Title	Sildenafil
Arm/Group Description	Participants who received sildenafil greater than or equal to 20 milligram (mg) three times daily as per Summary of Product Characteristics (SmPC) for the treatment of pulmonary arterial hypertension (PAH) for a period of at least 3 months, were observed retrospectively for 5 years.
Measure Participants	214
Year 1: Improved >1 class (n=214)	3 1.3%
Year 1: Improved 1 class (n=214)	36 15.9%
Year 1: No change (n=214)	140 61.7%
Year 1: Worsened 1 class (n=214)	12 5.3%
Year 1: Worsened >1 class (n=214)	5 2.2%
Year 2: Improved >1 class (n=156)	1 0.4%
Year 2: Improved 1 class (n=156)	27 11.9%
Year 2: No change (n=156)	100 44.1%
Year 2: Worsened 1 class (n=156)	7 3.1%
Year 2: Worsened >1 class (n=156)	4 1.8%
Year 3: Improved >1 class (n=88)	1 0.4%
Year 3: Improved 1 class (n=88)	12 5.3%
Year 3: No change (n=88)	57 25.1%
Year 3: Worsened 1 class (n=88)	7 3.1%
Year 3: Worsened >1 class (n=88)	0 0%
Year 4: Improved >1 class (n=45)	0 0%
Year 4: Improved 1 class (n=45)	6 2.6%
Year 4: No change (n=45)	27 11.9%
Year 4: Worsened 1 class (n=45)	2 0.9%
Year 4: Worsened >1 class (n=45)	0 0%

6. Secondary Outcome

Title	Change From Baseline in Right Atrial Pressure (RAP) at Year 1, 2, 3 and 4
Description	RAP was measured using a pressure transducer positioned at the mid-axillary line with the participant in the supine position.
Time Frame	Baseline, Year 1, 2, 3, 4

Outcome Measure Data

Analysis Population Description

Data was not summarized because results were available for very few participants and were insufficient for analysis.

Arm/Group Title	Sildenafil
Arm/Group Description	Participants who received sildenafil greater than or equal to 20 milligram (mg) three times daily as per Summary of Product Characteristics (SmPC) for the treatment of pulmonary arterial hypertension (PAH) for a period of at least 3 months, were observed retrospectively for 5 years.
Measure Participants	0

7. Secondary Outcome

Title	Change From Baseline in Mean Pulmonary Arterial Pressure (mPAP) at Rest at Year 1, 2, 3 and 4
Description	mPAP was measured using a pressure transducer positioned at the mid-axillary line with the participant in the supine position.
Time Frame	Baseline, Year 1, 2, 3, 4

Outcome Measure Data

Analysis Population Description

Data was not summarized because results were available for very few participants and were insufficient for analysis.

Arm/Group Title	Sildenafil
Arm/Group Description	Participants who received sildenafil greater than or equal to 20 milligram (mg) three times daily as per Summary of Product Characteristics (SmPC) for the treatment of pulmonary arterial hypertension (PAH) for a period of at least 3 months, were observed retrospectively for 5 years.
Measure Participants	0

8. Secondary Outcome

Title	Change From Baseline in Pulmonary Vascular Resistance (PVR) at Year 1, 2, 3 and 4
Description	PVR: calculated by subtracting PCWP from mPAP and dividing by cardiac output in pulmonary circulation (COpulm).
Time Frame	Baseline, Year 1, 2, 3, 4

Outcome Measure Data

Analysis Population Description

Data was not summarized because results were available for very few participants and were insufficient for analysis.

Arm/Group Title	Sildenafil
Arm/Group Description	Participants who received sildenafil greater than or equal to 20 milligram (mg) three times daily as per Summary of Product Characteristics (SmPC) for the treatment of pulmonary arterial hypertension (PAH) for a period of at least 3 months, were observed retrospectively for 5 years.
Measure Participants	0

9. Secondary Outcome

Title	Change From Baseline in Cardiac Index (CI) at Year 1, 2, 3 and 4
Description	CI: calculated as COsys divided by BSA.
Time Frame	Baseline, Year 1, 2, 3, 4

Outcome Measure Data

Analysis Population Description

Data was not summarized because results were available for very few participants and were insufficient for analysis.

Arm/Group Title	Sildenafil
Arm/Group Description	Participants who received sildenafil greater than or equal to 20 milligram (mg) three times daily as per Summary of Product Characteristics (SmPC) for the treatment of pulmonary arterial hypertension (PAH) for a period of at least 3 months, were observed retrospectively for 5 years.
Measure Participants	0

10. Secondary Outcome

Title	Change From Baseline in Pulmonary Capillary Wedge Pressure (PCWP) at Year 1, 2, 3 and 4
Description	PCWP was measured by pulmonary artery catheterization and provided an indirect measure of left atrial pressure.
Time Frame	Baseline, Year 1, 2, 3, 4

Outcome Measure Data

Analysis Population Description

Data was not summarized because results were available for very few participants and were insufficient for analysis.

Arm/Group Title	Sildenafil
Arm/Group Description	Participants who received sildenafil greater than or equal to 20 milligram (mg) three times daily as per Summary of Product Characteristics (SmPC) for the treatment of pulmonary arterial hypertension (PAH) for a period of at least 3 months, were observed retrospectively for 5 years.
Measure Participants	0

11. Secondary Outcome

Title	Change From Baseline in Borg Dyspnea Index at Year 1, 2, 3 and 4
Description	Borg dyspnea scale: 10-point scale where following scores stands for severity of dyspnea: 0=no breathlessness at all;0.5=very very slight (just noticeable); 1=very slight; 2=slight breathlessness; 3=moderate; 4=some what severe; 5=severe; 7=very severe breathlessness; 9=very very severe (almost maximum) and 10=maximum.
Time Frame	Baseline, Year 1, 2, 3, 4

Outcome Measure Data

Analysis Population Description

Analysis population included all participants who satisfied the eligibility criteria for the study. Here, 'N' (number of participants analyzed) included those participants who were evaluable for this measure. 'n' included those participants who were evaluable for this measure at specified time points.

Arm/Group Title	Sildenafil
Arm/Group Description	Participants who received sildenafil greater than or equal to 20 milligram (mg) three times daily as per Summary of Product Characteristics (SmPC) for the treatment of pulmonary arterial hypertension (PAH) for a period of at least 3 months, were observed retrospectively for 5 years.
Measure Participants	118
Change at Year 1 (n=118)	-0.4 (1.88)
Change at Year 2 (n=65)	0.0 (2.01)
Change at Year 3 (n=27)	0.3 (1.82)
Change at Year 4 (n=8)	0.4 (1.92)

Adverse Events

Adverse Event Reporting Description	Only those adverse events that were determined to be related to sildenafil by the investigator were reported in this observational retrospective study.
Arm/Group Title	Sildenafil
Arm/Group Description	Participants who received sildenafil greater than or equal to 20 milligram (mg) three times daily as per Summary of Product Characteristics (SmPC) for the treatment of pulmonary arterial hypertension (PAH) for a period of at least 3 months, were observed retrospectively for 5 years.
All Cause Mortality
	Sildenafil
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Sildenafil
	Affected / at Risk (%)	# Events
Total	0/227 (0%)
Other (Not Including Serious) Adverse Events
	Sildenafil
	Affected / at Risk (%)	# Events
Total	11/227 (4.8%)
General disorders
Ankle oedema, facial flushing	1/227 (0.4%)
Back pain or dizziness or eyesight	1/227 (0.4%)
Cough	1/227 (0.4%)
Dizziness	1/227 (0.4%)
Gastro-intestinal symptoms	1/227 (0.4%)
Head fuzzy/mild headache/mild flushing/mild nasal congestion	1/227 (0.4%)
Headache, diarrhoea and anxiety	1/227 (0.4%)
Mild headache/increased heart rate	1/227 (0.4%)
Nasal stuffiness/headache	1/227 (0.4%)
Nose bleeds	1/227 (0.4%)
Rash/itch (severe)	1/227 (0.4%)
Red face/peripheral oedema	1/227 (0.4%)
Vague upper abdominal discomfort by suspected pancreatic cancer	1/227 (0.4%)
Worsening of PAH	1/227 (0.4%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.