Anticoagulation For Pulmonary Hypertension in Sickle Cell Disease

Pulmonary Hypertension Clinical Trial

Official title:

An Exploratory Study of Anticoagulation For Pulmonary Hypertension in Sickle Cell Disease

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01036802
• Other study ID #: 09-1596
• Secondary ID: R01HL094592-01A1
• Status: Terminated
• Phase: Phase 2
• First received: December 18, 2009
• Last updated: January 6, 2014
• Start date: December 2009
• Est. completion date: September 2012

Study information

• Verified date: January 2014
• Source: University of North Carolina, Chapel Hill
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal GovernmentUnited States: Food and Drug AdministrationUnited States: Institutional Review Board
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 3
• Est. completion date: September 2012
• Est. primary completion date: September 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 16 Years to 65 Years

Eligibility

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.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Anemia, Sickle Cell
• Hypertension
• Hypertension, Pulmonary
• Pulmonary Hypertension

Intervention

Drug:
• Warfarin
Patients on the active treatment arm will receive warfarin to achieve a target international normalized ratio of between 2 and 3

Locations

Country	Name	City	State
United States	University of North Carolina	Chapel Hill	North Carolina

Sponsors (2)

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

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Effect of Anticoagulation on Pulmonary Artery Systolic Pressure Was Obtained by Doppler Echocardiography	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.	Measurements were obtained at Screening, and at Months 3, 6, 9, and 12	No
Secondary	6-minute Walk Test	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.	Measurements were obtained at Screening, Months 3, 6, 9, and 12	No
Secondary	Thrombin Generation	We evaluated the effect of warfarin on a plasma measure of thrombin generation (thrombin-antithrombin complex)	Measurements were obtained at Screening, and at Months 3, 6, 9, and 12	No
Secondary	Platelet Activation	We evaluated the effect of anticoagulation with warfarin on platelet activation assessed by measuring plasma levels of soluble CD40 ligand	Measurements were obtained at Screening, Prior to Run-in, and at Months 3, 6, 9, and 12	No
Secondary	Endothelial Activation	We assessed the effect of warfarin on plasma measures of endothelial activation (soluble vascular cell adhesion molecule-1)	Measurements were obtained at Screening, and at Months 3, 6, 9, and 12	No
Secondary	All-cause Mortality	We assessed the effect of warfarin on mortality in the study subjects	Assessment was obtained until completion of study at 12 months	No
Secondary	Major and Minor Bleeding Complications	We evaluated the safety of warfarin by evaluating for major and minor bleeding complications in study subjects	Evaluations were obtained at Screening, and at Months 3, 6, 9, and 12	Yes