A Pilot Study of Treatment of Adults With Sickle Cell Disease Associated Pulmonary Hypertension Based on Hemodynamic Stratification: Safety and Tolerability Study of Imatinib and Carvedilol

Sickle Cell Disease related pulmonary hypertension is a heterogeneous condition that results in a high mortality and for which no therapy has been documented to be beneficial. We propose to perform a safety and tolerability study of treatments based on right heart catheterization derived hemodynamic profiles associated with higher mortality in our cohort. These same hemodynamic profiles have previously been described and confirmed in other large cohorts as well. We propose treatment of sickle cell subjects with pulmonary arterial hypertension (PAH), defined hemodynamically by pulmonary arterial mean pressures (mPAP) of 25 mmHg or greater, with low estimated left ventricular filling pressures (low pulmonary capillary wedge pressures, or PCWP), and high pulmonary vascular resistance (PVR), with imatinib, a tyrosine kinase inhibitor that modifies the Platelet Derived Growth Factor (PDGF) pathway. PDGF is involved in Sickle Cell related PAH and there is now evidence that imatinib is effective in the treatment of idiopathic PAH. The hemodynamic profile of elevated mPAP with elevated left ventricular filling pressures is also associated with higher mortality rates, and we propose to treat this subgroup with carvedilol, a unique beta-adrenergic receptor antagonist that has been demonstrated to attenuate the adrenergic response and improve right and left heart function. The third subgroup with elevated mPAP is the hyperdynamic group, which by definition has low PVR and the absence of elevated left ventricular filling pressures. This group is also at higher risk but over a longer period of time and for less evident reasons. We will continue with aggressive sickle cell management in the hyperdynamic group according to the expertise offered by the Sickle Cell Group at the Clinical Center while systematically following them and intervening with optimal care. Those who do not quality for any of the three subgroups described above will go into a fourth subgroup and be followed for mortality and data sharing. Our primary endpoint is the safety and tolerability of these interventions and our secondary endpoints will be the clinical efficacy of these treatments.