Anticoagulation For Pulmonary Hypertension in Sickle Cell Disease
This study has been terminated.
(Difficulty in accruing subjects)
First Posted: December 21, 2009
Last Update Posted: May 9, 2016
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National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
University of North Carolina, Chapel Hill
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.
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
||An Exploratory Study of Anticoagulation For Pulmonary Hypertension in Sickle Cell Disease
Primary Outcome Measures:
Secondary Outcome Measures:
- 6-minute Walk Test [ Time Frame: 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.
- Thrombin Generation [ Time Frame: 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)
- Platelet Activation [ Time Frame: 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
- Endothelial Activation [ Time Frame: 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)
- All-cause Mortality [ Time Frame: Assessment was obtained until completion of study at 12 months ]
We assessed the effect of warfarin on mortality in the study subjects
- Major and Minor Bleeding Complications [ Time Frame: 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
| Study Start Date:
| Study Completion Date:
| Primary Completion Date:
||September 2012 (Final data collection date for primary outcome measure)
Active Comparator: Warfarin
Patients on the active treatment arm will be anticoagulated using the vitamin K antagonist, warfarin
Patients on the active treatment arm will receive warfarin to achieve a target international normalized ratio of between 2 and 3
Other Name: Coumadin
Placebo Comparator: Placebo
matching active products
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.