Carmine Dario Vizza

Effects of beraprost sodium, an oral prostacyclin analogue, in patients with pulmonary arterial hypertension: a randomized, double-blind, placebo-controlled trial ☆

OBJECTIVES The purpose of this study was to assess the efficacy and safety of beraprost sodium, an orally active prostacyclin analogue, in New York Heart Association (NYHA) functional class II and III patients with pulmonary arterial hypertension (PAH). BACKGROUND Pulmonary arterial hypertension is a life-threatening disease for which continuous intravenous infusion of prostacyclin has been proven effective. However, this treatment is associated with serious complications arising from the complex delivery system. METHODS In this double-blind, placebo-controlled study, 130 patients with PAH were randomized to the maximal tolerated dose of beraprost (median dose 80 microg four times a day) or to placebo for 12 weeks. The primary end point was the change in exercise capacity assessed by the 6-min walk test. Secondary end points included changes in Borg dyspnea index, cardiopulmonary hemodynamics and NYHA functional class. RESULTS Patients treated with beraprost improved exercise capacity and symptoms. The difference between treatment groups in the mean change of 6-min walking distance at week 12 was 25.1 m (95% confidence interval [CI]: 1.8 to 48.3, p = 0.036). The difference in the mean change of Borg dyspnea index was -0.94 (95% CI: -1.63 to -0.24, p = 0.009). In the sub-group of patients with primary pulmonary hypertension, the difference in the mean change of 6-min walking distance was 46.1 m (95% CI: 3.0 to 89.3, p = 0.035). Cardiopulmonary hemodynamics and NYHA functional class had no statistically significant changes. Drug-related adverse events were common in the titration phase and decreased in the maintenance period. CONCLUSIONS Beraprost improves exercise capacity and symptoms in NYHA functional class II and III patients with PAH and, in particular, in those with primary pulmonary hypertension.

Chronic Inhibition of cGMP Phosphodiesterase 5A Improves Diabetic Cardiomyopathy A Randomized, Controlled Clinical Trial Using Magnetic Resonance Imaging With Myocardial Tagging

Background— cGMP phosphodiesterase type 5 protein is upregulated in myocardial hypertrophy. However, it has never been ascertained whether phosphodiesterase type 5 inhibition exerts an antiremodeling effect in nonischemic heart disease in humans. We explored the cardioreparative properties of a selective phosphodiesterase type 5 inhibitor, sildenafil, in a model of diabetic cardiomyopathy. Methods and Results— Fifty-nine diabetic men (60.3±7.4 years) with cardiac magnetic resonance imaging consistent with nonischemic, nonfailing diabetic cardiomyopathy (reduced circumferential strain [&sgr;], −12.6±3.1; increased left ventricular [LV] torsion [&thgr;], 18.4±4.6°; and increased ratio of LV mass to volume, 2.1±0.5 g/mL) were randomized to receive sildenafil or placebo (100 mg/d). At baseline, the metabolic indices were correlated with torsion, strain, N-terminal pro–B-type natriuretic peptide, vascular endothelial growth factor, monocyte chemotactic protein-1, and blood pressure. After 3 months, sildenafil produced a significant improvement compared with placebo in LV torsion (&Dgr;&thgr;: sildenafil, −3.89±3.11° versus placebo, 2.13±2.35°; P<0.001) and strain (&Dgr;&sgr;: sildenafil, −3.30±1.86 versus placebo, 1.22±1.84; P<0.001). Sildenafil-induced improvement of LV contraction was accompanied by consistent changes in chamber geometry and performance, with a 6.5±11 improvement in mass-to-volume ratio over placebo (P=0.021). Monocyte chemotactic protein-1 and transforming growth factor-&bgr; were the only markers affected by active treatment (&Dgr;monocyte chemotactic protein-1: −75.30±159.28 pg/mL, P=0.032; &Dgr;transforming growth factor-&bgr;: 5.26±9.67 ng/mL, P=0.009). No changes were found in endothelial function, afterload, or metabolism. Conclusions— The early features of diabetic cardiomyopathy are LV concentric hypertrophy associated with altered myocardial contraction dynamics. Chronic phosphodiesterase type 5 inhibition, at this stage, has an antiremodeling effect, resulting in improved cardiac kinetics and circulating markers. This effect is independent of any other vasodilatory or endothelial effects and is apparently exerted through a direct intramyocardial action. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00692237.

Long term effects of bosentan treatment in adult patients with pulmonary arterial hypertension related to congenital heart disease (Eisenmenger physiology) : safety, tolerability, clinical, and haemodynamic effect

Background: Oral bosentan is an established treatment for pulmonary arterial hypertension (PAH). Objective: To evaluate safety, tolerability, and clinical and haemodynamic effects of bosentan in patients with PAH related to congenital heart disease (CHD). Patients: 22 patients with CHD related PAH (8 men, 14 women, mean (SD) age 38 (10) years) were treated with oral bosentan (62.5 mg×2/day for the first 4 weeks and then 125 mg×2/day). Main outcome measures: Clinical status, liver enzymes, World Health Organisation (WHO) functional class, resting oxygen saturations and 6-min walk test (6MWT) were assessed at baseline and at 1, 3, 6, and 12 months. Haemodynamic evaluation with cardiac catheterisation was performed at baseline and at 12 month follow-up. Results: 12 patients had ventricular septal defect, 5 atrioventricular canal, 4 single ventricle, and 1 atrial septal defect. All patients tolerated bosentan well. No major side effects were seen. After a year of treatment, an improvement was seen in WHO functional class (2.5 (0.7) v 3.1 (0.7); p<0.05), oxygen saturation at rest (87 (6%) v 81 (9); p<0.001), heart rate at rest (81 (10) v 87 (14) bpm; p<0.05), distance travelled in the 6MWT (394 (73) v 320 (108) m; p<0.001), oxygen saturation at the end of the 6MWT (71 (14) v 63 (17%); p<0.05), Borg index (5.3 (1.8) v 6.5 (1.3); p<0.001), pulmonary vascular resistances index (14 (9) v 22 (12) WU m2; p<0.001), systemic vascular resistances index (23 (11) v 27 (10) WU.m2; p<0.01), pulmonary vascular resistances index/systemic vascular resistances index (0.6 (0.5) v 0.9 (0.6); p<0.05); pulmonary (4.0 (1.3) v 2.8 (0.9) l/min/m2; p<0.001) and systemic cardiac output (4.2 (1.4) v 3.4 (1.1) l/min/m2; p<0.05). Conclusions: Bosentan was safe and well tolerated in adults with CHD related PAH during 12 months of treatment. Clinical status, exercise tolerance, and pulmonary haemodynamics improved considerably.

Changes in Right Ventricular Function Measured by Cardiac Magnetic Resonance Imaging in Patients Receiving Pulmonary Arterial Hypertension–Targeted Therapy The EURO-MR Study

Background—Most measures that predict survival in pulmonary hypertension (PH) relate directly to, or correlate with, right ventricular (RV) function. Direct assessment of RV function using noninvasive techniques such as cardiac MRI may therefore be an appropriate way of determining response to therapy and monitoring disease progression in PH. Methods and Results—In this pan-European study, 91 patients with PH (mean pulmonary arterial pressure 46±15 mm Hg) underwent clinical and cardiac MRI assessments at baseline and after 12 months of disease-targeted therapy (predominantly endothelin receptor antagonists [47.3%] or phosphodiesterase type-5 inhibitors [25.3%]). At month 12, functional class had improved in 21 patients, was unchanged in 63 patients, and had deteriorated in 7 patients. Significant improvements were achieved in RV and left ventricular ejection fraction (P<0.001 and P=0.0007, respectively), RV stroke volume index (P<0.0001), and left ventricular end-diastolic volume index (P=0.0015). Increases in 6-minute walk distance were significant (P<0.0001) and correlated with change in RV ejection fraction and left ventricular end-diastolic volume, although correlation coefficients were low (r=0.28, P=0.01 and r=0.26, P=0.02, respectively). Conclusions—On-treatment changes in cardiac MRI–derived variables from left and right sides of the heart reflected changes in functional class and survival in patients with PH. Direct measurement of RV function using cardiac MRI can fully assess potential benefits of treatment in PH.

Outcomes of noncardiac, nonobstetric surgery in patients with PAH: an international prospective survey

We conducted an international, prospective, 3-year questionnaire-based survey among 11 pulmonary hypertension centres to assemble data from patients with pulmonary arterial hypertension (PAH) undergoing noncardiac and nonobstetric surgery. Data were collected between July 2007 and June 2010 from 114 patients with PAH (70% female, mean age 57 years) who underwent major surgery. At the time of surgery, 43% were in functional class III/IV. 82% of the interventions were performed under general anaesthesia and 18% under spinal anaesthesia. Major complications occurred in seven (6.1%) of the patients, of whom four died, resulting in an overall perioperative mortality rate of 3.5%. The mortality rate was 15% (two out of 13) in emergency procedures, compared with 2% (two out of 101) in nonemergency procedures (p=0.01). Risk factors for major complications were an elevated right atrial pressure (OR 1.1, 95% CI 1.0–1.3; p=0.01), a 6-min walking distance <399 m at the last preoperative assessment (OR 2.2, 95% CI 1.1–3.7; p=0.04), the perioperative use of vasopressors (OR 1.5, 95% CI 1.2–2.7; p=0.03) and the need for emergency surgery (OR 2.4, 95% CI 1.4–3.6; p=0.01). Major surgery in patients with PAH continues to be a high-risk procedure, particularly when emergency interventions are needed.

Long term treatment of pulmonary arterial hypertension with beraprost, an oral prostacyclin analogue

OBJECTIVE To evaluate the effects of one years treatment with beraprost, an orally active prostacyclin analogue, in patients with severe pulmonary hypertension. PATIENTS 13 patients with severe pulmonary hypertension. This was primary in nine, thromboembolic in three, and caused by Eisenmenger syndrome in one. METHODS All patients underwent right heart catheterisation. Mean (SD) right atrial pressure was 5 (3) mm Hg, mean pulmonary artery pressure was 48 (12) mm Hg, cardiac index was 2.6 (0.8) l/min/m2, and mixed venous oxygen saturation was 68 (7)%. Beraprost was started at the dose of 20 μg three to four times a day (1 μg/kg/day), increasing after one month to 40 μg three to four times a day (2 μg/kg/day), with further increases of 20 μg three to four times a day in case of clinical deterioration. MAIN OUTCOME MEASURES New York Heart Association (NYHA) functional class, exercise capacity measured by distance walked in six minutes, and systolic pulmonary pressure (by echocardiography) were evaluated at baseline, after one months treatment, and then every three months for a year. RESULTS After the first month of treatment, NYHA class decreased from 3.4 (0.7) to 2.9 (0.7) (p < 0.05), the six minute walking distance increased from 213 (64) to 276 (101) m (p < 0.05), and systolic pulmonary artery pressure decreased from 93 (15) to 85 (18) mm Hg (NS). One patient died after 40 days from refractory right heart failure, and another was lost for follow up at six months. The 11 remaining patients had persistent improvements in functional class and exercise capacity and a significant decrease in systolic pulmonary artery pressure in the period from 1–12 months. Side effects were minor. CONCLUSIONS Oral administration of beraprost may result in long lasting clinical and haemodynamic improvements in patients with severe pulmonary hypertension.

Acute Hemodynamic Effects of Single-Dose Sildenafil When Added to Established Bosentan Therapy in Patients With Pulmonary Arterial Hypertension: Results of the COMPASS-1 Study

This study investigated the acute pharmacodynamic effects of sildenafil in patients with pulmonary arterial hypertension (PAH) and concomitant bosentan treatment, in view of a mutual pharmacokinetic interaction between the 2 drugs. This prospective, open‐label, noncomparative, multicenter, phase II study enrolled 45 patients (≥18 years) with stable PAH (idiopathic, familial, or related to corrected congenital systemic‐to‐pulmonary shunts, drugs, or toxins) and on bosentan treatment for at least 3 months. Patients underwent right heart catheterization to evaluate the acute hemodynamic effects of (a) inhaled nitric oxide (iNO) and (b) a single oral dose of sildenafil (25 mg). Mean pulmonary vascular resistance (PVR) decreased from baseline following iNO (−15%; 95% confidence limits: −21%, −8%; P = .0001). A statistically significant decrease from baseline in mean PVR was also observed 60 minutes following sildenafil administration (−15%; 95% confidence limits: −21%, −10%; P < .0001). The reduction in PVR following sildenafil was comparable to that resulting from iNO. There were no unexpected safety findings. The pharmacodynamic effect suggests that addition of sildenafil to bosentan treatment can elicit additional hemodynamic benefits. These data represent a rationale for long‐term combination studies with the 2 compounds.

Treatment of pulmonary hypertension in patients undergoing cardiac surgery with cardiopulmonary bypass: A randomized, prospective, double-blind study

Objective Pulmonary hypertension can already be present in patients undergoing cardiac surgery or can be exacerbated by cardiopulmonary bypass. Postoperative treatment is still a challenge for physicians. The aim of this study was to evaluate the effects of inhaled prostacyclin (iPGI2) and nitric oxide (iNO) compared with those of intravenous vasodilators. Methods This prospective, randomized, double-blind study included 58 patients affected by severe mitral valve stenosis and pulmonary hypertension with high pulmonary vascular resistance (> 250 dynes·s·cm−5) and a mean pulmonary artery pressure > 25 mmHg. All patients were monitored by central venous, radial arterial and Swan–Ganz catheters. Data were recorded at six different time points, before induction of anaesthesia, during and after surgery. Prostacyclin and nitric oxide were administered by inhalation 5 min before weaning from cardiopulmonary bypass and continued in the intensive care unit. Right ventricular function was evaluated by transoesophageal echocardiography. Results Hospital mortality was 3.4%. After drug administration, the mean pulmonary artery pressure and pulmonary vascular resistance were significantly decreased in the iNO and iPGI2 groups with respect to the baseline values (P < 0.05) and such a decrease was maintained throughout the study; this was not observed in the control group. In the iNO and iPGI2 groups we demonstrated a significant increase in cardiac indices and right ventricular ejection fraction after drug administration with respect to baseline. Furthermore, patients in the inhaled drug groups were weaned easily from cardiopulmonary bypass (P = 0.04) and had a shorter intubation time (P = 0.03) and intensive care unit stay (P = 0.02) than the control group. Conclusions Our data suggest that both iNO and iPGI2 are effective in the treatment of pulmonary hypertension. iPGI2 has a number of advantages over iNO, including its easy administration and lower cost. Intravenous vasodilator treatment, on the other hand, is effective in terms of mortality but has a higher morbidity rate.

Pulmonary hemodynamics contribute to indicate priority for lung transplantation in patients with cystic fibrosis

OBJECTIVE Lung transplantation is a viable option for patients with cystic fibrosis. The current strategy of selection, based on spirometry and deterioration of quality of life, results in a high mortality on the waiting list. We reviewed the case histories of patients with cystic fibrosis accepted for lung transplantation to ascertain whether pulmonary hemodynamics could contribute to predict life expectancy. METHODS Forty-five patients with cystic fibrosis were accepted: 11 died on the waiting list (group I), 24 underwent transplantation (group II), and 10 are still waiting (group III). During evaluation we recorded spirometry, oxygen requirement, ratio of arterial oxygen tension to inspired oxygen fraction (PaO (2)/FIO (2)), arterial carbon dioxide tension (PaCO (2)), 6-minute walk test results, right ventricular ejection fraction, echocardiography, and pulmonary hemodynamics. We compared data from group I, II, and III patients. A comparison was also made within group II between the data collected at the time of evaluation and at the time of transplantation to quantify the deterioration during the waiting time. RESULTS The waiting time, spirometry, 6-minute walk test results, and right ventricular ejection fraction did not differ among the three groups. A statistically significant difference was found for PaO (2)/FIO (2), PaCO (2), mean pulmonary artery pressure, cardiac index, pulmonary arterial wedge pressure, and intrapulmonary shunt between groups I and II. Groups I and III showed statistically significant differences for mean pulmonary artery pressure, PaO (2)/FIO (2), and systemic vascular resistance indexed. No differences were observed between groups II and III. The comparison within group II showed a significant deterioration of pulmonary hemodynamics during the waiting time. CONCLUSIONS Pulmonary hemodynamics are worst in patients dying on the waiting list and deteriorate significantly during the waiting time. They may thus contribute to establish priority for lung transplantation in patients with cystic fibrosis.

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.