Medical Therapies for PVS
Medical therapies for children with pulmonary vein stenosis can be broken into 2 broad categories 1) therapies aimed at treating symptoms and 2) experimental therapies aimed at treating the underlying disease process. End stage PVS is associated with right heart failure and secondary pulmonary hypertension. Optimizing medical therapies is essential for patients undergoing high risk interventions, awaiting transplant and also for those opting for palliation. Aggressive diuresis is the main stay of therapy. Afterload reduction of the pulmonary bed is typically for acute crisis in the ICU following interventions, although some children will take pulmonary hypertensive therapies. Resistance to routine use of pulmonary afterload reduction is derived from the PVOD literature, whereby in the majority of patients, these medications results in pulmonary edema. While PVOD is restricted to the distal venules within the lung parenchyma and PVS tends to be more in larger order veins, the silent and insidious progression of PVS makes it difficult to predict who is able to safely tolerate pulmonary afterload reduction.
Experimental therapies are becoming more common as adjuncts to current interventions. Case reports document use of sirolimus and other adjuncts; however the impact of these interventions are limited by small numbers and heterogeneous disease presentation.
Currently, there are 3 registered clinical trials related to pulmonary vein stenosis. Two trials target myofibroblast hypercellularity using known chemotherapeutic agents. The evidence backing these trials is limited to histological characteristics of end stage human samples. The first trial is a pilot phase II trial that looks at the safety and efficacy of methotrexate and vinblastine (NCT00215046). This trial targets children with advanced congenital pulmonary vein stenosis. Initial results show that in 29 children, the side effect profile of the medical regimen complicated treatment protocols in many patients. Among the 23 patients who were evaluated for progression, 1 year survival was 38% in a high risk cohort (Rehman M et al, 2011). The second registered trial (NCT00891527) targets pulmonary vein obstructive disease using Imatinib, a tyrosine kinase inhibitor and Avastin, a chemotherapy agent. The results of the registered trial are pending. Results from the same institution employing a multimodal approach of catheter based interventions and Imatinib in children with pulmonary vein stenosis demonstrate that survival at 1 year is approximately 57% (Quinonez LG et al, 2015).
The third pilot trial addresses the safety of losartan in children with pulmonary vein stenosis. Data backing this trial is from a porcine pig model, where losartan administration showed a reduction in neointimal formation, potentially by blocking TGF-B mediated endothelial to mesenchymal transition (NCT02769130, Kato H et al, 2014; Zhu J et al, 2015). This study is currently enrolling patients and results anticipated in 2 years.
Experimental therapies are becoming more common as adjuncts to current interventions. Case reports document use of sirolimus and other adjuncts; however the impact of these interventions are limited by small numbers and heterogeneous disease presentation.
Currently, there are 3 registered clinical trials related to pulmonary vein stenosis. Two trials target myofibroblast hypercellularity using known chemotherapeutic agents. The evidence backing these trials is limited to histological characteristics of end stage human samples. The first trial is a pilot phase II trial that looks at the safety and efficacy of methotrexate and vinblastine (NCT00215046). This trial targets children with advanced congenital pulmonary vein stenosis. Initial results show that in 29 children, the side effect profile of the medical regimen complicated treatment protocols in many patients. Among the 23 patients who were evaluated for progression, 1 year survival was 38% in a high risk cohort (Rehman M et al, 2011). The second registered trial (NCT00891527) targets pulmonary vein obstructive disease using Imatinib, a tyrosine kinase inhibitor and Avastin, a chemotherapy agent. The results of the registered trial are pending. Results from the same institution employing a multimodal approach of catheter based interventions and Imatinib in children with pulmonary vein stenosis demonstrate that survival at 1 year is approximately 57% (Quinonez LG et al, 2015).
The third pilot trial addresses the safety of losartan in children with pulmonary vein stenosis. Data backing this trial is from a porcine pig model, where losartan administration showed a reduction in neointimal formation, potentially by blocking TGF-B mediated endothelial to mesenchymal transition (NCT02769130, Kato H et al, 2014; Zhu J et al, 2015). This study is currently enrolling patients and results anticipated in 2 years.