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

Abstract 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

Thrombolysis in high-risk patients with acute pulmonary embolism: underuse of a life-saving treatment in the real-world setting

This editorial refers to ‘Trends in thrombolytic treatment and outcomes of acute pulmonary embolism in Germany’, by K. Keller et al., doi:10.1093/eurheartj/ehz236

704-3 Relation of Neurohormonal Activation to Functional Class in Patients with Primary or Precapillary Secondary Pulmonary Hypertension

Intense neurohormonal activation has been demonstrated in patients with primary or precapillary secondary pulmonary hypertension (PH) but the relation of neurohormons to functional impairment is not well known. Plasma levels of atrial natriuretic peptide (ANP), aldosterone (ALD), renin activity (PRA), epinephrine (PE), norepinephrine (PNE) and endothelin (ET) were assessed from the antecubital vein in 12 patients with primary PH, 7 patients with precapillary secondary PH (2 connective tissue disease, 2 chronic thromboembolic, 3 closed atrial septal defect) and 10 control subjects. Twelve patients were in NYHA functional class II (PH-II) and 7 in class III/IV (PH-III/IV). Mean PA pressure (PAP), cardiac index (CI), pulmonary vascular resistance (PVR) and right atrial pressure were assessed by heart catheterization:PAPCIPVRRAP(mmHg)(l/minlm2)(RU)(mmHg)PH-II53 ± 132.4 ± 0.412 ± 33 ± 2PH-III/IV61 ± 92.0 ± 0518 ± 611 ±5P0.170.070.0090.0001Neurohormons plasma levels in control subjects (C), PH-II and PH-III/IV patients were as follows:ANPALDPRAPEPNEET(pg/ml)(pg/ml)(ng/ml/h)(pg/ml)(pg/ml)(pg/ml)C58 ± 18110 ± 650.7 ± 0.433 ± 19220 ± 1011.7 ± 0.3PH-II167 ± 96*144 ± 10215 ± 2.0298 ± 263*420 ± 294*3.6 ± 1.4*PH-III/IV276 ± 153*†209 ± 2703.2 ± 3.9*462 ± 524*820 ± 693*†8.4 ± 3.9*°*p < 0.05 vs C° p < 0.001 vs PH-II †P < 0.09 vs PH-IIConclusionsNeurohormonal activation in primary or precapillary secondary PH is detectable also in patients without overt clinical and hemodynamic signs of right heart failure (PH-II). Neurohormonal activation seems to be progressive and is more severe in functional class III/IV patients. ET shows the best statistically significant relation with functional impairment

Correlation between aortic root dimension and coronary ectasia

BACKGROUND: Aortic aneurysms are associated with coronary artery ectasia (CAE). However, the relation between the extent of CAE and the severity of aortic dilatation is not understood. This study was undertaken to investigate the relationship between angiographic extension of CAE and aortic dimension. PATIENTS AND METHODS: We retrospectively include 135 patients with angiographic diagnosis of CAE defined as dilatation of coronary segment more than 1.5 times than an adjacent healthy one. Study population was divided in four groups according to the maximum diameter of ascending aorta beyond sinus of Valsalva obtained in the parasternal long-axis view (group 1: <40 mm; group 2: 40-45 mm; group 3: 45-55 mm; group 4: >55 mm or previous surgery because of aortic aneurysm/dissection). The relationship between aortic dimension and the extension of CAE was investigated by means of multivariable linear regression, including variables selected at univariable analysis (P < 0.1). The total estimated ectatic area (EEA total) was used as dependent variable. RESULTS: Baseline characteristics of study groups were well balanced. Patients in group 4 were more likely to have both higher neutrophil count and neutrophil to lymphocyte ratio. On univariable analysis ascending aorta diameter [Coef. = 0.075; 95% confidence interval (CI) 0.052-0.103, P < 0.01] and c-reactive protein (CRP) values [Coef. = 0.033, 95% CI 0.003-0.174, P = 0.04] showed a linear association with total EEA. After adjustment for CRP values only the ascending aorta diameter was still associated with the extent of CAE (95% CI 0.025-0.063, P < 0.01). CONCLUSION: In patients with diagnosis of CAE, a strong linear association between aortic dimension and coronary ectasia extent exists

Use of β-Blockers in Pulmonary Hypertension

International audienceContrasting with the major attention that left heart failure has received, right heart failure remains understudied both at the preclinical and clinical levels. However, right ventricle failure is a major predictor of outcomes in patients with precapillary pulmonary hypertension because of pulmonary arterial hypertension, and in patients with postcapillary pulmonary hypertension because of left heart disease. In pulmonary hypertension, the status of the right ventricle is one of the most important predictors of both morbidity and mortality. Paradoxically, there are currently no approved therapies targeting the right ventricle in pulmonary hypertension. By analogy with the key role of β-blockers in the management of left heart failure, some authors have proposed to use these agents to support the right ventricle function in pulmonary hypertension. In this review, we summarize the current knowledge on the use of β-blockers in pulmonary hypertension