The Effects Of Intravenous Rho-Kinase Inhibition Fasudil With Different Dosages And Combination With Sildenafil On Patients With Severe Pulmonary Arterial Hypertension

Part Ⅰ The acute effects of intravenous Rho-kinase inhibition fasudil on patients with severe pulmonary arterial hypertensionObjectiveThe optimal dose of fasudil is still controversial in severe pulmonary arterial hypertension(PAH).This study aimed to compare acute hemodynamic changes after different doses of fasudil in 104 consecutive adult patients with severe PAH,as well as the evaluation of right ventricular function with echocardiography(Echo).MethodsThis is a prospective randomized controlled trial.104 patients who were admitted to Xuzhou Center Hospital from June 2014 to May 2017 for PAH with the procedure of right cardiac catheterization(RHC)and met the inclusion criteria were continuously enrolled.There were 30 males and 74 females included.These patients were randomly divided into fasudil 30 or 60 mg.The hemodynamic parameters were measured at baseline and after 30 minutes of fasudil through RHC.Blood gas results were obtained from the pulmonary artery,right ventricle,right atrium,superior and inferior vena cava,and femoral artery.Pulmonary vascular resistance(PVR)and systemic arterial resistance(SVR)were calculated.The results of Echo and laboratory test were also collected.Resμlts:1.No significant difference had been found before and after intravenous fasudil between the 60 mg group and the 30 mg group in the left atrial diameter(LAd)、left ventricμlar end diastolic diameter、Right ventricμlar end diastolic diameter、Left ventricμlar ejection fraction(P>0.05).2.Compared with the 30-mg group,the changes in inferior vena cava collapsibility index(IVCCI)、the peak rate of tricuspid regurgitation velocity(TRV)、Tei index of right ventricμlar、tricuspid annular plane systolic excursion(TAPSE)systolic pulmonary artery pressure(sPAP)were more pronounced in the 60 mg group(P<0.05).3.The changes in systolic pulmonary artery pressure(sPAP)(-13.1%vs-9.3%,P<0.05),diastolic PAP(dPAP)(-17.6%vs-14.5%,P<0.05),mean PAP(mPAP)(-12.4%vs-8.5%,P<0.05),and PVR(-35.8%vs-22.2%,P<0.05)were more in the 60-mg group than in the 30 mg group.4.The level of endothelin-1(ET-1),nitric oxide(NO)and hypoxia inducible factor-1(HIF-1α)in the two groups were not statistically significant difference at admission(P>0.05).The changes of the three indicators were all more pronounced in the 60-mg group than in the 30-mg group(P<0.05).5.All patients had no obvious adverse reactions related to peripheral blood pressure reduce after intravenous fasudil.Conclusions:1.Fasudil could improve the hemodynamics of patients with severe PAH following single bolus doses,especially with the 60 mg dose.2.Fasudil could improve the right heart function of patients with severe PAH following single bolus doses,especially with the 60 mg dose.3.As a Rho/ROCK inhibitor,fasudil could reduce the level of blood ET-1.HIF-1α as well as increase the level of blood NO,which could play roles of being effective.4、There were no serious adverse reactions related to peripheral blood pressure decreased after intravenous fasudil.The Rho kinase inhibitor fasudil is a promising new class of drugs for the therapy in severe PAH,as well as the improvement of right heart function.Part Ⅱ Combination therapy with different dosage intravenous fasudil and sildenafil in patients with severe pulmonary arterial hypertensionObjectiveData on the effect of combination therapy with different dosage intravenous fasudil and sildenafil on in-hospital and long-term outcomes in patients with severe pulmonary arterial hypertension are scarce.This study aimed to compare clinical benefits after combination therapy with different doses of fasudil in 117 consecutive adult patients with severe PAH.MethodsThis is a prospective randomized controlled trial.117 patients who were admitted to Xuzhou Center Hospital from June 2014 to May 2017 for PAH with the procedure of right cardiac catheterization(RHC)and met the inclusion criteria were continuously enrolled.There were 41 males and 76 females included.We randomly assigned,in a 1:1:1 ratio,participants with World Health Organization functional class(WHO-FC)Ⅱ or Ⅲ symptoms of pulmonary arterial hypertension who had not previously received treatment to receive combination therapy with 30 mg of intravenous fasudil plus 25 mg of sildenafil,60 mg of intravenous fasudil plus 25 mg of sildenafil,25 mg of sildenafil monotherapy,all fasudil administered once daily and sildenafil administered three daily.We observed the changes of 6 minutes walking distance(6MWD)、WHO-FC、brain natriuretic peptide(BNP)at baseline and after(10±1)days administering the drugs.The hemodynamic parameters and right heart function were measured through Echo.Adverse and serious adverse events were also recorded.Patients were seen at months 1,3,and 6.At each visit,clinical assessments and blood tests were performed.Results:1.No significant difference had been found in the sPAP、dPAP、mPAP、PVR、cardiac index(CI)and saturation of mixed venous blood oxygen(SVO2)after RHC in each groups.2.Compared with sildenafil monotherapy,combination therapy of different dosages fasudil both improved 6MWD significantly(P<0.05),especially the 60 mg group.There were higher percentage of patients with a satisfactory WHO-FC in combination therapy groups than in monotherapy group(P<0.05),especially in the 60 mg group.3.Both of the combination therapy groups had greater reductions from baseline in BNP levels than did the monotherapy group,especially in 60 mg group(mean change,-42.49%vs.-26.03%,P<0.05;-34.40%vs.-26.03%,P<0.05;-42.49%vs.-34.40%.P<0.05)4.Compared with sildenafil monotherapy,there was only significant increase of the changes in inferior vena cava collapsibility index、tricuspid annμlar plane systolic excursion and significant reduction of the the peak rate of tricuspid regurgitation velocity(TRV)、Tei index of right ventricular、and systolic pulmonary artery pressure(sPAP)in 60 mg group(P<0.05),while no significant difference in 30 mg group(P>0.05).5.There was no death case in-hospital in three groups;the deterioration case of right heart function are 1,2,1 respectively.All patients had no obvious adverse reactions related to intravenous fasudil.6.At 1 st month,the benefits from the combination therapy still exist,but it’s disappeared at 3rd month and 6th month.Conclusions:1.Combination Therapy with fasudil and sildenafil could improve 6MWD,percentage of patients with a satisfactory WHO-FC and reduce the BNP level more significantly than sildenafil monotherapy,especially with the 60 mg dose.2.Combination therapy with Fasudil and Sildenafil could improve the right heart function of patients with severe PAH following single bolus doses,especially with the 60 mg dose.3.Compared with sildenafil monotherapy,there was only significant increase of the changes in IVCCI、TAPSE and significant reduction of TRV,sPAP,Tei indexv in 60 mg group,while no significant difference in 30 mg group.4.The benefits from the combination therapy still exist after 1st month,but they disappeared after 3rd month and 6th month.Combination therapy of 60 mg fasudil and sildenafil is safe and effective to severe pulmonary arterial hypertension.