Anticoagulation For Pulmonary Hypertension in Sickle Cell Disease

• Sponsor: University of North Carolina, Chapel Hill (Other)
• Overall Status: Terminated
• CT.gov ID: NCT01036802
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI) (NIH)
• Enrollment: 3
• Location: 1
• Arms: 2
• Duration (Months): 33
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

Sickle cell disease (SCD) is often referred to as a hypercoagulable state. However, the contribution of coagulation activation to the pathogenesis of SCD remains uncertain. Pulmonary hypertension (PHT) is a common complication associated with significant morbidity and mortality. Autopsy studies of SCD patients with PHT show evidence of in situ thrombosis involving pulmonary vessels, similar to findings in non-sickle cell patients with PHT. Anticoagulation has been reported to be of benefit in non-sickle cell patients with PHT. With the evidence of increased coagulation activation in SCD, PHT represents a clinical endpoint that may be used to evaluate the contribution of coagulation activation to the pathophysiology of SCD. The investigators hypothesize that increased thrombin generation, as well as platelet activation are central to the pathophysiology of SCD and contribute to the occurrence of several SCD-related complications, including PHT. As a consequence, treatment modalities that down-regulate thrombin generation would be expected to delay the progression of PHT and result in improved survival in patients with SCD.

Condition or Disease	Intervention/Treatment	Phase
Pulmonary Hypertension	Drug: Warfarin; Drug: Placebo	Phase 2

Detailed Description

As a result of the presence of large vessel thrombotic complications, as well as the biochemical evidence of ongoing coagulation activation, sickle cell disease (SCD) is often referred to as a hypercoagulable state. However, the contribution of coagulation activation to the pathogenesis of SCD remains uncertain. While the majority of clinical studies using anticoagulants have shown no convincing benefit in the prevention or treatment of acute pain episodes, most of these studies were small and poorly controlled. Furthermore, because the acute pain episode appears to result from the occlusion of postcapillary venules by the interaction of red blood cells and other cellular elements with the vascular endothelium and subendothelial matrix proteins, it may not be the ideal clinical endpoint for assessing the effect of anticoagulation in SCD patients. Pulmonary hypertension (PHT), a common complication associated with significant morbidity and mortality, and with histopathologic findings of in situ thrombosis involving pulmonary vessels, represents a clinical endpoint that is likely due, at least in part, to increased thrombin generation, and may therefore be used to evaluate the contribution of coagulation activation to the pathophysiology of SCD. Twenty patients with sickle cell anemia (HbSS) or sickle beta zero thalassemia (Sickle beta zero thalassemia) and mild PHT who meet the eligibility requirements will be enrolled, 10 patients to receive anticoagulation with warfarin and 10 to receive placebo rfor 12 months of treatment.

Study Design

• Study Type: Interventional
• Actual Enrollment: 3 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: An Exploratory Study of Anticoagulation For Pulmonary Hypertension in Sickle Cell Disease
• Study Start Date: Dec 1, 2009
• Actual Primary Completion Date: Sep 1, 2012
• Actual Study Completion Date: Sep 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Warfarin Patients on the active treatment arm will be anticoagulated using the vitamin K antagonist, warfarin	Drug: Warfarin; Patients on the active treatment arm will receive warfarin to achieve a target international normalized ratio of between 2 and 3; Other Names: Coumadin
Placebo Comparator: Placebo matching active products	Drug: Placebo

Outcome Measures

Primary Outcome Measures

1. Effect of Anticoagulation on Pulmonary Artery Systolic Pressure Was Obtained by Doppler Echocardiography [Measurements were obtained at Screening, and at Months 3, 6, 9, and 12]

   We determined the effect of anticoagulation with warfarin on estimated pulmonary artery systolic pressure obtained by Doppler echocardiography. The presented data are average values for the study subjects in the treatment group. When data was missing, the previous value was carried forward.

Secondary Outcome Measures

1. 6-minute Walk Test [Measurements were obtained at Screening, Months 3, 6, 9, and 12]

   We evaluated the distance walked over 6 minutes. The presented data are average values for the study subjects in the treatment group. When data was missing, the previous value was carried forward.

2. Thrombin Generation [Measurements were obtained at Screening, and at Months 3, 6, 9, and 12]

   We evaluated the effect of warfarin on a plasma measure of thrombin generation (thrombin-antithrombin complex)

3. Platelet Activation [Measurements were obtained at Screening, Prior to Run-in, and at Months 3, 6, 9, and 12]

   We evaluated the effect of anticoagulation with warfarin on platelet activation assessed by measuring plasma levels of soluble CD40 ligand

4. Endothelial Activation [Measurements were obtained at Screening, and at Months 3, 6, 9, and 12]

   We assessed the effect of warfarin on plasma measures of endothelial activation (soluble vascular cell adhesion molecule-1)

5. All-cause Mortality [Assessment was obtained until completion of study at 12 months]

   We assessed the effect of warfarin on mortality in the study subjects

6. Major and Minor Bleeding Complications [Evaluations were obtained at Screening, and at Months 3, 6, 9, and 12]

   We evaluated the safety of warfarin by evaluating for major and minor bleeding complications in study subjects

Eligibility Criteria

Criteria

• Ages Eligible for Study: 16 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• At least 16 years of age

• Have a confirmed diagnosis of sickle cell anemia (HbSS) or sickle cell beta zero thalassemia

• Have evidence of persistent elevation of pulmonary artery systolic pressure on Doppler echocardiography (TR jet velocity of 2.5 to 2.9 m/s [or estimated pulmonary artery systolic pressure above the upper limit of reference adjusted ranges and up to 45 mm Hg]), but no evidence of moderate or severe diastolic dysfunction on tissue Doppler echocardiography. Mild PHT must be confirmed on repeat evaluation, at least 3 months later

• Have a serum creatinine =/< 1.5 mg/dl

• Have serum transaminase values (ALT) < 2 times upper limits of normal

• Have serum albumin =/> 3.2 g/dl

• Have a platelet count =/< 150,000 cu/mm

• Have normal baseline coagulation profile (PT/PTT)

• Patients on treatment with hydroxyurea should be on a stable dose for at least 6 months. Doses of hydroxyurea may only be adjusted during the course of the study for safety reasons.

• Be able to understand the requirements of the study and be willing to give informed consent.

• Women of childbearing age must be practicing (and will continue to practice for the course of the study) an adequate method of contraception.

Exclusion Criteria:

• Have a baseline hemoglobin < 6.0 gm/dl

• Have congenital heart disease, valvular heart disease, and other identified cause of pulmonary hypertension (including pulmonary fibrosis) unrelated to SCD

• Have an elevated pulmonary capillary wedge pressure, as evidenced by E/Em > 15 by pulsed wave and tissue Doppler imaging

• Have no measurable tricuspid regurgitant velocity on echocardiography

• Have a history of major gastrointestinal bleeding or a bleeding diathesis

• Have sickle cell complications such as recent vaso-occlusive crisis or acute chest syndrome, 4-weeks prior to commencing the study

• Have a history of clinically overt stroke(s) or seizures

• Have a brain magnetic resonance imaging/magnetic resonance angiography scan with evidence of Moya Moya within the preceding year

• Are pregnant or breastfeeding

• Are on chronic anticoagulant therapy

• Have a history of metastatic cancer

• Are chronically on therapy with aspirin or non-steroidal anti-inflammatory agents

• Are on a chronic transfusion program or have received a blood transfusion in the prior 8 weeks

• Have a positive urine toxicology screen for cocaine and amphetamines

• Have a history of alcohol abuse

• Are currently receiving treatment with epoprostenol (or similar prostacyclin analog), sildenafil (or similar phosphodiesterase 5 inhibitor), bosentan or arginine

• Have ingested any investigational drugs within the past 4 weeks.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of North Carolina	Chapel Hill	North Carolina	United States	27599

Sponsors and Collaborators

• University of North Carolina, Chapel Hill
• National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: Kenneth I Ataga, MD, University of North Carolina, Chapel Hill

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: University of North Carolina, Chapel Hill
• ClinicalTrials.gov Identifier: NCT01036802
• Other Study ID Numbers: 09-1596; R01HL094592-01A1
• First Posted: Dec 21, 2009
• Last Update Posted: May 9, 2016
• Last Verified: Jan 1, 2014

• Keywords provided by University of North Carolina, Chapel Hill: sickle cell disease; pulmonary hypertension; coagulation activation; platelet activation; endothelial activation
• Additional relevant MeSH terms: Hypertension, Pulmonary; Hypertension; Anemia, Sickle Cell; Warfarin

Study Results

Participant Flow

Recruitment Details	Patients were randomized 1:1 to receive anticoagulation with warfarin or placebo after evaluation in the clinical and translational research center. Enrollment began in January 2010 and ended in September 2012 due to poor patient accrual.
Pre-assignment Detail	Following patient identification, an open-label run-in period was begun to ensure patient doses of warfarin could be titrated to a stable level that achieved an international normalized ratio between 2.0 and 3.0 without exceeding a dose of 15 mg per day and to exclude patients with a level of compliance less than 80% (based on pill counts).

Arm/Group Title	Warfarin	Placebo
Arm/Group Description	Patients on the active treatment arm will be anticoagulated using the vitamin K antagonist, warfarin	Patients were randomized to placebo
Period Title: Overall Study
STARTED	2	1
COMPLETED	2	1
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Warfarin	Placebo	Total
Arm/Group Description	Patients on the active treatment arm will be anticoagulated using the vitamin K antagonist, warfarin	Patients were randomized to placebo	Total of all reporting groups
Overall Participants	2	1	3
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	2 100%	1 100%	3 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	29.5 (12.02)	53	37.3 (16.01)
Sex: Female, Male (Count of Participants)
Female	2 100%	1 100%	3 100%
Male	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	2 100%	1 100%	3 100%

Outcome Measures

1. Primary Outcome

Title	Effect of Anticoagulation on Pulmonary Artery Systolic Pressure Was Obtained by Doppler Echocardiography
Description	We determined the effect of anticoagulation with warfarin on estimated pulmonary artery systolic pressure obtained by Doppler echocardiography. The presented data are average values for the study subjects in the treatment group. When data was missing, the previous value was carried forward.
Time Frame	Measurements were obtained at Screening, and at Months 3, 6, 9, and 12

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Warfarin	Placebo
Arm/Group Description	Patients on the active treatment arm will be anticoagulated using the vitamin K antagonist, warfarin	Patients were randomized to placebo
Measure Participants	2	1
Screening (n=2,1)	41.3 (0)	43.6 (0)
Month 3 (n=1,1)	39.2	39.2
Month 6 (n=2,1)	41.3	43.6
Month 9 (n=1,1)	46	37
Month 12 (n=1,1)	46	37

2. Secondary Outcome

Title	6-minute Walk Test
Description	We evaluated the distance walked over 6 minutes. The presented data are average values for the study subjects in the treatment group. When data was missing, the previous value was carried forward.
Time Frame	Measurements were obtained at Screening, Months 3, 6, 9, and 12

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Warfarin	Placebo
Arm/Group Description	Patients on the active treatment arm will be anticoagulated using the vitamin K antagonist, warfarin	Patients were on placebo
Measure Participants	2	1
Screen (n=1,1)	1381 (0)	1135 (0)
Month 3 (n=1,1)	1275	1135
Month 6 (n=1,1)	1275	1075
Month 9 (n=1,1)	1275	1075
Month 12 (n=1,1)	1275	1075

3. Secondary Outcome

Title	Thrombin Generation
Description	We evaluated the effect of warfarin on a plasma measure of thrombin generation (thrombin-antithrombin complex)
Time Frame	Measurements were obtained at Screening, and at Months 3, 6, 9, and 12

Outcome Measure Data

Analysis Population Description

No analysis was performed due to the early termination of the study and the very small number of participating subjects.

Arm/Group Title	Warfarin	Placebo
Arm/Group Description	Patients on the active treatment arm will be anticoagulated using the vitamin K antagonist, warfarin	Patients were randomized to placebo
Measure Participants	0	0

4. Secondary Outcome

Title	Platelet Activation
Description	We evaluated the effect of anticoagulation with warfarin on platelet activation assessed by measuring plasma levels of soluble CD40 ligand
Time Frame	Measurements were obtained at Screening, Prior to Run-in, and at Months 3, 6, 9, and 12

Outcome Measure Data

Analysis Population Description

No analysis was performed due to the early termination of the study and the very small number of participating subjects.

Arm/Group Title	Warfarin	Placebo
Arm/Group Description	Patients on the active treatment arm will be anticoagulated using the vitamin K antagonist, warfarin	Patients were randomized to placebo
Measure Participants	0	0

5. Secondary Outcome

Title	Endothelial Activation
Description	We assessed the effect of warfarin on plasma measures of endothelial activation (soluble vascular cell adhesion molecule-1)
Time Frame	Measurements were obtained at Screening, and at Months 3, 6, 9, and 12

Outcome Measure Data

Analysis Population Description

As the number of subjects studied were very few, requiring discontinuation of the study, evaluation of endothelial activation was not performed.

Arm/Group Title	Warfarin	Placebo
Arm/Group Description	Patients on the active treatment arm will be anticoagulated using the vitamin K antagonist, warfarin	Patients were randomized to placebo
Measure Participants	0	0

6. Secondary Outcome

Title	All-cause Mortality
Description	We assessed the effect of warfarin on mortality in the study subjects
Time Frame	Assessment was obtained until completion of study at 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Warfarin	Placebo
Arm/Group Description	Patients on the active treatment arm will be anticoagulated using the vitamin K antagonist, warfarin	Patients were randomized to placebo
Measure Participants	2	1
Number [participants]	0 0%	0 0%

7. Secondary Outcome

Title	Major and Minor Bleeding Complications
Description	We evaluated the safety of warfarin by evaluating for major and minor bleeding complications in study subjects
Time Frame	Evaluations were obtained at Screening, and at Months 3, 6, 9, and 12

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Warfarin	Placebo
Arm/Group Description	Patients on the active treatment arm will be anticoagulated using the vitamin K antagonist, warfarin	Patients were randomized to placebo
Measure Participants	2	1
Screen	0 0%	0 0%
Month 3	0 0%	0 0%
Month 6	0 0%	0 0%
Month 9	0 0%	0 0%
Month 12	0 0%	0 0%

Adverse Events

Time Frame	2 years
Arm/Group Title	Warfarin		Placebo
Arm/Group Description	Patients on the active treatment arm will be anticoagulated using the vitamin K antagonist, warfarin		Patients were randomized to placebo
All Cause Mortality
	Warfarin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Warfarin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/2 (50%)		0/1 (0%)
Blood and lymphatic system disorders
Delayed hemolytic transfusion reaction	1/2 (50%)	1	0/1 (0%)	0
Other (Not Including Serious) Adverse Events
	Warfarin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/2 (0%)		0/1 (0%)

Limitations/Caveats

This study was terminated early due to difficulty in accruing subjects.

More Information

Certain Agreements

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

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.