[Oral combination therapy for the treatment of patients with pulmonary arterial hypertension: what evidence from long-term studies?] / La terapia di combinazione orale nel trattamento dei pazienti con ipertensione arteriosa polmonare: quali evidenze dagli studi a lungo termine?

The introduction of specific drugs for the treatment of pulmonary arterial hypertension over the last 20 years has led to an improvement of clinical and hemodynamic conditions and prognosis of affected patients. The use of combination therapy has made it possible to act simultaneously on several biological pathways involved in the etiopathogenesis of the disease. However, although the diagnosis and management have radically changed in recent years, the disease remains progressive and often fatal. The purpose of this paper is to review and discuss the results of the main clinical trials and the future perspectives of combination strategies for the treatment of pulmonary arterial hypertension.

Long-term safety and efficacy of imatinib in pulmonary arterial hypertension.

BACKGROUND: Imatinib is an oral inhibitor of several protein kinases implicated in the pathophysiology of pulmonary hypertension. Treatment with imatinib resulted in improved hemodynamics and exercise capacity in a controlled trial (Imatinib [QTI571] in Pulmonary Arterial Hypertension, a Randomized Efficacy Study [IMPRES]), among pulmonary arterial hypertension (PAH) patients inadequately responsive to 2 to 3 PAH-specific therapies. METHODS: The long-term (up to 204 weeks) safety and efficacy of imatinib in this open-label extension study were reviewed until early study termination on April 16, 2014. Of 202 IMPRES-enrolled patients, 66 imatinib and 78 placebo recipients entered the extension. RESULTS: Overall, 93.8% (135 of 144) of patients discontinued the extension study; administrative issues (i.e., sponsor termination; 32.6%) and adverse events (31.3%) were the primary reasons for discontinuation. Nine patients completed the extension study before it was terminated. Serious and unexpected adverse events were frequent. These included 6 subdural hematomas in the extension study and 17 deaths during or within 30 days of study end. Although the patients who tolerated imatinib and remained in the extension for a longer duration did experience an improvement in functional class and walk distance, most discontinued the drug and the study. CONCLUSIONS: Severe adverse events, significant side effects, and a high discontinuation rate limit the utility of imatinib in the treatment of PAH. These risks outweigh any possible improvements in hemodynamics and walk distance seen in those patients able to remain on drug. The off-label use of this compound in PAH is discouraged.

Right ventricular remodeling in idiopathic pulmonary arterial hypertension: adaptive versus maladaptive morphology.

BACKGROUND: Although increased pulmonary pressure is caused by changes in the pulmonary vasculature, prognosis in idiopathic pulmonary arterial hypertension (IPAH) is strongly associated with right ventricular (RV) function. The aim of this study was to describe the best RV adaptive remodeling pattern to increased afterload in IPAH. METHODS: In 60 consecutive patients with IPAH, RV morphologic and functional features were evaluated by echocardiography and cardiac magnetic resonance imaging. To address the question of the best RV adaptation pattern, we divided the study population into two groups by the median value of RV mass/volume ratio (0.46) because this parameter allows the distinction between RV eccentric (≤0.46) and concentric hypertrophy (>0.46). The two groups were compared for RV remodeling and systolic function parameters, World Health Organization class, pulmonary hemodynamics, and 6-minute walk test. RESULTS: Despite similar pulmonary vascular resistance, mean pulmonary pressure, and compliance, patients with eccentric hypertrophy had advanced World Health Organization class and worse 6-minute walk test, hemodynamics, RV remodeling, and systolic function parameters compared with patients with concentric hypertrophy. The group with concentric hypertrophy had higher RV to pulmonary arterial coupling compared with the group with eccentric hypertrophy (1.24 ± 0.26 vs 0.83 ± 0.33, p = 0.0001), indicating higher RV efficiency. A significant correlation was found between pulmonary vascular resistance and RV to pulmonary arterial coupling (r = -0.55, r(2) = 0.31, p = 0.0001), with patients with RV mass/volume ratio > 0.46 at the higher part of the scatterplot, confirming more adequate RV function. CONCLUSIONS: Concentric hypertrophy might represent a more favorable RV adaptive remodeling pattern to increased afterload in IPAH because it is associated with more suitable systolic function and mechanical efficiency.

Right ventricular dyssynchrony in idiopathic pulmonary arterial hypertension: determinants and impact on pump function.

BACKGROUND: Right ventricular (RV) dyssynchrony has been described in pulmonary arterial hypertension (PAH), but no evidence is available on its morphologic determinants and its effect on systolic function. The aim of this study was to evaluate the morphologic determinants of RV dyssynchrony by echocardiographic and cardiac magnetic resonance imaging and its effect on systolic function. METHODS: In 60 consecutive idiopathic PAH (IPAH) patients with narrow QRS, RV dyssynchrony was evaluated by 2D speckle-tracking echocardiography, calculating the standard deviation of the times to peak systolic strain for the four mid-basal RV segments (RV-SD4). Patients were grouped by the median value of RV-SD4 (19 milliseconds) and compared for RV remodeling and systolic function parameters, WHO class, pulmonary hemodynamics and 6-minute walk test (6MWT). RESULTS: Despite similar pulmonary vascular resistance and mean pulmonary arterial pressure, patients with RV-SD4 at >19 milliseconds had advanced WHO class and worse 6MWT, RV hemodynamics, RV remodeling and systolic function parameters compared with patients at ≤19 milliseconds. The morphologic determinants of RV dyssynchrony resulted RV end-diastolic area, LV diastolic eccentricity index and RV mass volume ratio (r = 0.69, r(2) = 0.47, p < 0.0001). Finally, we found a significant inverse correlation between RV mid-basal segments post-systolic shortening time and cardiac index (r = -0.64, r(2) = 0.41, p = 0.001), accounting for the significant correlation between RV-SD4 and cardiac index (r = 0.57, r(2) = 0.32, p = 0.003). CONCLUSIONS: In IPAH with narrow QRS, RV dyssynchrony is associated with RV dilation and eccentric hypertrophy pattern, suggesting a role of segmental wall stress heterogeneity as the major determinant of mechanical delay. Post-systolic shortening, as inefficient contraction, contributes to pump dysfunction.