Circulatory power and ventilatory power over time under goal‐oriented sequential combination therapy for pulmonary arterial hypertension (original) (raw)
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Life Sciences, 2014
The 6-min walking distance is often used for assessing the exercise capacity under the treatment with an endothelin receptor antagonist (ERA) in patients with chronic thromboembolic pulmonary hypertension (CTEPH). The cardiopulmonary exercise testing (CPX) was reported to be more useful for the patients with pulmonary arterial hypertension (PAH), however, few reports exist in patients with inoperable CTEPH. The aim of this study was to investigate the effects of an oral dual ERA, bosentan, on exercise capacity using CPX in patients with PAH and inoperable CTEPH. Main methods: This study included all patients diagnosed with 17 PAH and 12 CTEPH in the World Health Organization functional classes II-IV who started treatment with bosentan therapy. They underwent CPX, which was performed before bosentan therapy and at 3 to 6 months of the treatment. Key findings: In PAH patients, peak VO 2 significantly increased after the bosentan treatment (p = 0.009). On the other hand, in CTEPH patients, there were no significant differences in the peak VO 2. However, the peak PETCO 2 was significantly increased from 23.9 ± 5.2 mm Hg at baseline to 29.3 ± 10.7 mm Hg after the bosentan treatment (p = 0.040). In addition, peak heart rate during exercise tended to decrease after the bosentan therapy (p = 0.089). Significance: Bosentan therapy improved peak PETCO 2 but not peak VO 2 in patients with inoperable CTEPH. These findings demonstrated that CPX is useful for assessing the exercise capacity of patients with PAH and inoperable CTEPH under the treatment with an ERA.
Anadolu Kardiyoloji Dergisi/The Anatolian Journal of Cardiology, 2010
Comparative effects of losartan and nifedipine therapy on exercise capacity, Doppler echocardiographic parameters and endothelin levels in patients with secondary pulmonary hypertension Sekonder pulmoner hipertansiyonu bulunan hastalarda losartan ve nifedipin tedavisinin egzersiz kapasitesi, Doppler ekokardiyografi parametreleri ve endotelin düzeylerine etki açısından karşılaştırılması 43 ABS TRACT Objective: Pulmonary hypertension (PHT) is associated with high mortality and morbidity. Interest has increased in the use of drugs that, because of their neurohumoral inhibitory effects, inhibit the renin angiotensin system. In this study, we sought to examine whether losartan therapy is non-inferior to nifedipine in the treatment of secondary PHT. Methods: This prospective randomized study consisted of 63 patients (mean age, 63.7±9.1 years) with PHT who underwent Doppler echocardiographic examination. A baseline 6-minute walk test (6MWT) and cardiopulmonary exercise test (CPET) were performed, and the endothelin-1 level of each patient was measured. Patients were assigned to two groups receiving treatment with nifedipine (n=30) and losartan (n=33). After 2 months of treatment, those measurements were repeated. The groups were compared with regard to effectiveness for the studied parameters using 2*2 factorial ANOVA design for repeated measurements. Results: When posttreatment values were compared with baseline values in both groups, the following statistically significant changes were noted: the mean values of both mean and systolic pulmonary artery pressures (PAPs) were reduced (p<0.05) on Doppler echocardiography; exercise duration, work rate, and end-tidal carbon dioxide pressure (PETCO 2) were higher (p<0.05 for all); and the minute ventilation (VE) and ventilatory equivalents for carbon dioxide (VE/VCO 2) were lower (p<0.05 for both) according to the results of a CPET. No statistically significant change was noted in the mean levels of serum endothelin-1. With regard to the results cited above, no statistically significant difference was detected between the losartan and nifedipine groups (p > 0.05). Conclusion: The findings of this study indicate that losartan is non-inferior to nifedipine for reducing PAP and improving exercise capacity. However, the short-term use of losartan or nifedipine had no statistically significant effect on endothelin-1 levels in patients with secondary PHT.
Exercise physiological responses to drug treatments in chronic thromboembolic pulmonary hypertension
Journal of Applied Physiology, 2016
We tested the hypothesis that patients with chronic thromboembolic pulmonary hypertension (CTEPH) that was deemed to be inoperable were more likely to respond to drugs for treating pulmonary arterial hypertension (PAH) by using cardiopulmonary exercise (CPX) testing than those with CTEPH that was deemed to be operable. We analyzed CPX testing data of all patients with CTEPH who were treated with PAH drugs and had undergone CPX testing before and after treatment at a single pulmonary hypertension center between February 2009 and March 2013. Suitability for pulmonary endarterectomy (PEA) was decided by experts in PEA who were associated with a treatment center. The group with inoperable CTEPH included 16 patients, the operable group included 26 patients. There were no differences in demographics and baseline hemodynamic data between the groups. Unlike patients in the operable group, after drug treatment patients with inoperable CTEPH had a significantly higher peak V̇o2 ( P < 0.001...
BMC pulmonary medicine, 2015
Recent vasodilating drugs have improved prognosis of Pulmonary arterial hypertension (PAH). Some reports describe the merits of combination therapies for PAH, and this study evaluated the efficacy and safety of phosphodiesterase type 5 inhibitors (PDE5i) combination therapy, using sildenafil and tadalafil, for multi-drug-resistant PAH. We retrospectively analyzed 7 consecutive refractory patients with PAH administered either sildenafil 60 mg or tadalafil 40 mg as well as both ERA and prostanoid as combination therapies. All were started on the dual PDE5i (sildenafil and tadalafil at maximum dose). Treatment was generally well tolerated without severe adverse events. On completion of the study, the seven patients received right heart catheterization and the 6-minute walk test (6WMT) 9.6 ± 1.4 months after initiation of the dual PDE5i therapy, showing significant improvements in hemodynamic parameters and exercise tolerance. Mean pulmonary arterial pressure and pulmonary vascular resi...
Journal of Translational Medicine, 2014
Background: Patients with pulmonary arterial hypertension (PAH) are treated with vasodilators, including endothelin receptor antagonists (ERAs), phosphodiesterase-5 (PDE-5) inhibitors, soluble guanylyl cyclase activators, and prostacyclin. Despite recent advances in pharmacotherapy for individuals with PAH, morbidity and mortality rates in this patient population remain unacceptably high. Here, we tested the hypothesis that combination therapy with two PAH drugs that target distinct biochemical pathways will provide superior efficacy relative to monotherapy in the rat SU5416 plus hypoxia (SU-Hx) model of severe angioproliferative PAH, which closely mimics the human condition. Methods: Male Sprague Dawley rats were injected with a single dose of SU5416, which is a VEGF receptor antagonist, and exposed to hypobaric hypoxia for three weeks. Rats were subsequently housed at Denver altitude and treated daily with the PDE-5 inhibitor, tadalafil (TAD), the type A endothelin receptor (ET A) antagonist, ambrisentan (AMB), or a combination of TAD and AMB for four additional weeks. Results: Monotherapy with TAD or AMB led to modest reductions in pulmonary arterial pressure (PAP) and right ventricular (RV) hypertrophy. In contrast, echocardiography and invasive hemodynamic measurements revealed that combined TAD/AMB nearly completely reversed pulmonary hemodynamic impairment, RV hypertrophy, and RV functional deficit in SU-Hx rats. Efficacy of TAD/AMB was associated with dramatic reductions in pulmonary vascular remodeling, including suppression of endothelial cell plexiform lesions, which are common in human PAH. Conclusions: Combined therapy with two vasodilators that are approved for the treatment of human PAH provides unprecedented efficacy in the rat SU-Hx preclinical model of severe, angioproliferative PAH.
Risk Reduction and Hemodynamics with Initial Combination Therapy in Pulmonary Arterial Hypertension
American Journal of Respiratory and Critical Care Medicine, 2021
Rationale: An initial oral combination of drugs is being recommended in pulmonary arterial hypertension (PAH), but the effects of this approach on risk reduction and pulmonary vascular resistance (PVR) are not known. Objectives: To test the hypothesis that a low-risk status would be determined by the reduction of PVR in patients with PAH treated upfront with a combination of oral drugs. Methods: The study enrolled 181 treatment-naive patients with PAH (81% idiopathic) with a follow-up right heart catheterization at 6 months (interquartile range, 144-363 d) after the initial combination of endothelin receptor antagonist 1 phosphodiesterase-5 inhibitor drugs and clinical evaluation and risk assessments by European guidelines and Registry to Evaluate Early and Long-Term PAH Disease Management scores. Measurements and Main Results: Initial combination therapy improved functional class and 6-minute-walk distance and decreased PVR by an average of 35% (median, 40%). One-third of the patients had a decrease in PVR ,25%. This poor hemodynamic response was independently predicted by age, male sex, pulmonary artery pressure and cardiac index, and at echocardiography, a right/left ventricular surface area ratio of greater than 1 associated with low tricuspid annular plane systolic excursion of less than 18 mm. A low-risk status at 6 months was achieved or maintained in only 34.8% (Registry to Evaluate Early and Long-Term PAH Disease Management score) to 43.1% (European score) of the patients. Adding criteria of poor hemodynamic response improved prediction of a low-risk status. Conclusions: A majority of patients with PAH still insufficiently improved after 6 months of initial combinations of oral drugs is identifiable at initial evaluation by hemodynamic response criteria added to risk scores.
New Insights in the Treatment Strategy for Pulmonary Arterial Hypertension
Cardiovascular Drugs and Therapy, 2006
Recent advances in our understanding of the pathophysiological and molecular mechanisms involved in pulmonary arterial hypertension have led to the development of novel and rational pharmacological therapies. In addition to conventional therapy (i.e., supplemental oxygen and calcium channel blockers), prostacyclin or endothelin receptor antagonists have been recommended as a first-line therapy for pulmonary arterial hypertension. However, these treatments have potential limitations with regard to their long-term efficacy and improvement in survival. Furthermore, intravenous prostacyclin (epoprostenol) therapy, which is recommended by most experts for patients with New York Heart Association (NYHA) functional class IV, is complicated, uncomfortable for patients, and expensive because of the cumbersome administration system. Considering these circumstances, it is necessary to develop additional novel therapeutic approaches that target the various components of this multifactorial disease. In this short review, we present an overview of the current treatment options for pulmonary arterial hypertension and describe a case report with primary pulmonary hypertension. A male patient with NYHA functional class IV and showing no response to calcium channel blockers and prostacyclin exhibited significantly improved exercise tolerance and hemodynamics and long-term survival for more than 2.5 years after receiving an oral combination therapy of a phosphodiesterase type 5 inhibitor (sildenafil), phosphodiesterase type 3 inhibitor (pimobendan), and nicorandil. We also discuss the background and plausible potential mechanisms involved in this case, as well as future perspectives in the treatment of pulmonary arterial hypertension.
Haemodynamics, exercise capacity and clinical events in pulmonary arterial hypertension
European Respiratory Journal, 2012
The purpose of this study was to clarify whether changes in cardiopulmonary haemodynamics induced by pharmacological therapy correlate with exercise capacity and clinical events in patients with pulmonary arterial hypertension. 16 randomised trials including 2353 patients, followed up for 16.4¡10.6 weeks, measuring cardiopulmonary haemodynamics by right heart catheterisation and reporting clinical events were included. Meta-analysis and meta-regression analysis were performed to assess the effects of treatments on clinical events and the relationship between haemodynamic changes (pulmonary artery pressure, pulmonary vascular resistance, cardiac index and right atrial pressure) and clinical events. Treatments significantly reduced all-cause death (OR 0.5, 95% CI 0.3-0.7; p,0.01), hospitalisation for pulmonary arterial hypertension (OR 0.4, 95% CI 0.2-0.7; p,0.01), initiation of rescue therapy (OR 0.3, 95% CI 0.2-0.6; p,0.01) and the composite outcome (OR 0.3, 95% CI 0.3-0.5; p,0.01). No relationship was found between changes of haemodynamic parameters and clinical events, whereas changes of cardiac index and pulmonary vascular resistance significantly correlated with changes in the 6-min walking distance (r50.64, p50.03; r5-0.55, p50.04, respectively). In patients with pulmonary arterial hypertension, improvements of cardiopulmonary haemodynamics observed in randomised clinical trials correlate with exercise capacity changes but do not predict clinical events in a short-term follow-up. @ERSpublications In PAH, cardiopulmonary haemodynamic improvements correlate with exercise capacity changes but not with clinical events http://ow.ly/lzTdC This article has supplementary material available from www.erj.ersjournals.com