Oral sildenafil improves primary pulmonary hypertension refractory to epoprostenol.

BACKGROUND: Epoprostenol (prostaglandin I(2)) has become recognized as a therapeutic breakthrough that can improve hemodynamics and survival in patients with primary pulmonary hypertension (PPH). However, a significant number of patients have PPH that is refractory to epoprostenol, and lung transplantation has been the only remaining treatment option. METHODS AND RESULTS: The study subjects included 20 consecutive patients with PPH (mean pulmonary arterial pressure: 65+/-15 mmHg) who had received epoprostenol for more than 12 months. The patients were divided into 2 groups; responders and non-responders. In the non-responders, New York Heart Association (NYHA) functional class did not improve and mean right atrial pressure (mRA) increased to 8 mmHg or more, and additional sildenafil, a phosphodiesterase-5 inhibitor, was started. Six patients were included in the non-responders, whose mRA was 9+/-5 mmHg before and significantly increased to 13+/-3 mmHg after epoprostenol administration (p < 0.05). One patient died and the other 5 patients received oral sildenafil. The mRA of 12+/-4 mmHg (value before sildenafil) improved to 8+/-5 mmHg after sildenafil administration. Three patients were classified in the NYHA functional class 4 and improved to class 3, and 2 patients were in class 3 and remained in the same class after the addition of sildenafil. CONCLUSIONS: In patients with severe PPH refractory to epoprostenol treatment, additional oral sildenafil can improve pulmonary hemodynamics and symptoms. The combination therapy of epoprostenol and sildenafil is a new medical treatment to attempt before progressing to lung transplantation for patients with PPH refractory to epoprostenol.     

Marked improvement with sildenafil in a patient with primary pulmonary hypertension unresponsive to epoprostenol

We report a 48-year-old woman with right heart failure due to primary pulmonary hypertension. Continuous infusion of epoprostenol (prostaglandin I2) for 1.5 years failed to control her condition, but she was later successfully treated with additional sildenafil for a few months. Her mean pulmonary artery pressure was originally 57 mmHg, increased to 62 mmHg with epoprostenol, and decreased to 45 mmHg with sildenafil. Additional sildenafil may be an effective and life-saving agent in patients with primary pulmonary hypertension who show a poor response to epoprostenol, which is considered to be very powerful medical treatment for the disease.     

Outcome in 91 consecutive patients with pulmonary arterial hypertension receiving epoprostenol

Epoprostenol has markedly improved the treatment of pulmonary arterial hypertension, although predictors of outcome with epoprostenol are not well characterized. From June 1995 through August 2001, 91 patients with pulmonary arterial hypertension were treated with epoprostenol at our institution. We analyzed the effects of long-term epoprostenol treatment to determine features associated with outcome. Predictors of worse outcome included older age of disease onset (hazard ratio 3.2, 95% confidence interval 1.32-7.76 for patients above the median age of 44 years), World Health Organization functional Class IV, either at baseline or follow-up, (3.07, 1.42-6.62 compared with functional Class I, II, and III), and scleroderma spectrum of disease (2.32, 1.08-4.99). There were no baseline or follow-up hemodynamic factors predictive of outcome. Our results indicate that treatment with epoprostenol improves survival in patients with Primary Pulmonary Hypertension compared with that predicted by the National Institutes of Health Primary Pulmonary Hypertension Registry's survival equation and that their survival is significantly better than that of patients with scleroderma spectrum of disease (p = 0.001). Older patients treated with epoprostenol have significantly shorter survival, regardless of etiology.     

Acute and chronic effects of sildenafil in patients with pulmonary arterial hypertension

Sildenafil and inhaled nitric oxide (iNO) relax smooth muscle by inhibiting the degradation and stimulating the production of cyclic guanosine monophosphate, respectively. We compared the acute pulmonary vasodilator effects of sildenafil, iNO, and epoprostenol and asked whether the combination of iNO with sildenafil had additive pulmonary vasodilator effects. We assessed the effects of extended use of sildenafil in a small cohort of patients. Twenty patients with pulmonary arterial hypertension underwent an acute vasodilator trial with sildenafil (all patients), iNO and iNO plus sildenafil (11), and epoprostenol (19). We also provided sildenafil to patients who were ineligible for, or had clinical deterioration on epoprostenol, treprostinil, or bosentan. Mean+/-se pulmonary artery pressure dropped by 13+/-3%, 19+/-4%, 14+/-3%, and 26+/-4% with epoprostenol, iNO, sildenafil, and iNO+sildenafil, respectively. Cardiac index increased with epoprostenol and sildenafil. A correlation was found between the effects of iNO and epoprostenol. Nine out of ten patients who were started on long-term sildenafil treatment alone or in combination with other vasodilators had symptomatic improvement. Three died of right heart failure. In conclusion, sildenafil is a potent acute pulmonary vasodilator, an effect that is potentiated by combination with iNO. Long-term therapy of pulmonary hypertension with sildenafil alone or in combination with other agents appears to be safe and well tolerated.     

Long-term treatment with oral sildenafil in addition to continuous IV epoprostenol in patients with pulmonary arterial hypertension

OBJECTIVES: To evaluate the effect of long-term oral therapy with sildenafil in patients with pulmonary arterial hypertension receiving long-term IV epoprostenol. DESIGN: Open, uncontrolled trial. SETTING: University hospital. PATIENTS: Two patients with primary pulmonary hypertension and one patient with pulmonary arterial hypertension after surgical closure of an atrial septal defect. All patients were receiving continuous epoprostenol for 1.7 to 7.1 years; two patients also received inhaled iloprost for 1.8 years and 3.8 years, respectively. INTERVENTIONS: Addition of oral sildenafil, up to 200 mg/d, divided in four to six single doses, and hemodynamic measurements and the 6-min walking distance (6MWD) before and after 5 months of treatment with sildenafil. RESULTS: One patient was treated with sildenafil, 200 mg/d; two patients received 75 mg/d due to nausea and headache. Long-term treatment with sildenafil in the three patients reduced mean pulmonary artery pressure by 14%, 41%, and 22%, respectively; in two patients, pulmonary vascular resistance was decreased by 52% and 55%. The 6MWD increased by 34%, 6%, and 29%, respectively. No significant systemic hypotension or decrease of arterial oxygen saturation was seen. CONCLUSION: Sildenafil therapy may be of benefit in patients with pulmonary arterial hypertension receiving long-term infusion of epoprostenol.     

Treatment with epoprostenol reverts nitric oxide non-responsiveness in patients with primary pulmonary hypertension

OBJECTIVE—To assess whether long term treatment with epoprostenol might restore primary non-responsiveness to nitric oxide (NO) in patients with primary pulmonary hypertension.
METHODS—Seven patients with primary pulmonary hypertension receiving intravenous epoprostenol continuously because of failure of NO to influence pulmonary haemodynamics during initial testing were followed over a period of 13-29 months. Afterwards, acute vascular reactivity towards NO was tested again during right heart catheterisation.
RESULTS—Administration of NO after continuous epoprostenol treatment for a mean period of 18 months improved arterial oxygen saturation (p < 0.01) and cardiac index (p < 0.05), and decreased mean pulmonary artery pressure (p < 0.01) and total pulmonary vascular resistance (p < 0.01) in patients previously unresponsive to NO.
CONCLUSIONS—Long term treatment with epoprostenol reverts initial refractoriness to NO in patients with primary pulmonary hypertension. Thus the addition of NO to epoprostenol treatment might cause further improvement in the course of the disease.


Keywords: primary pulmonary hypertension; epoprostenol; vascular reactivity     

Hemodynamic effects of epoprostenol in patients with systemic sclerosis and pulmonary hypertension

STUDY OBJECTIVES: To determine the cause of pulmonary hypertension (PH) in systemic sclerosis (SSc) patients since PH can occur because of pulmonary arteriopathy, pulmonary parenchymal destruction, and left ventricular cardiac dysfunction. DESIGN AND SETTING: Consecutive case series in a university hospital. PATIENTS: Nine SSc patients with PH (mean pulmonary artery pressure, 41 mm Hg), with (n = 6) or without (n = 3) concomitant interstitial lung disease (ILD). METHODS: Acute infusion of epoprostenol was begun at 2 ng/kg/min and was titrated upward at a rate of 2 ng/kg/min every 30 min until symptomatic complications developed or pulmonary artery vascular resistance (PVR) was reduced by 50%. RESULTS: Eight of nine patients demonstrated a reduction of > or = 20% in PVR, suggesting that vasoreactivity is common despite the presence of significant ILD. A single patient had no response to infusion with unchanged hemodynamics and oxygenation. One patient developed hypoxemia as cardiac output increased, suggesting a worsening of ventilation/perfusion matching or the presence of an anatomic shunt. Acute pulmonary edema developed in one patient at an infusion rate of 6 ng/kg/min. The results of cardiac catheterization suggested that pulmonary edema was caused by SSc heart disease. CONCLUSION: SSc patients with ILD have diverse and sometimes multiple causes of PH that can be determined by short-term epoprostenol infusion. Beneficial effects can be obtained from epoprostenol despite extensive ILD.     

Acute hemodynamic effects of nicorandil in patients with primary pulmonary arterial hypertension

BACKGROUND: Pulmonary arterial hypertension is managed with vasodilators, and till date no specific drug has been identified with sufficient degree of success. Potassium channels have been implicated in the pathogenesis of primary pulmonary arterial hypertension. We undertook this study to assess the acute effect of oral nicorandil in patients of pulmonary arterial hypertension. METHODS AND RESULTS: We studied acute hemodymanic response of 40 mg oral nicorandil in 10 patients with primary pulmonary arterial hypertension aged between 15 and 39 years (mean age 27.2 +/- 6.7 years). Responders (Group I) were defined as those with > or =20% reduction of pulmonary vascular resistance index and no change or increase in cardiac index; and non-responders (Group II) were those with < 20% reduction of pulmonary vascular resistance index. There were 7 responders (pulmonary vascular resistance index decreased from 22.8 +/- 9.3 to 17.9 +/- 6.5 Wood units) and 2 non-responders (pulmonary vascular resistance index decreased from 26 +/- 3.5 to 25 +/- 1.0 Wood units). The maximum reduction in pulmonary vascular resistance index from baseline was 29.77 +/- 6.53% (23.7-40.5%) in responders and 7.3 +/- 4.2% (4.3-10.3%) in non-responders. The study was halted prematurely in one patient who developed hypotension, requiring intravenous inotropes. CONCLUSIONS: Our results suggest that nicorandil significantly decreases pulmonary artery pressure in primary pulmonary arterial hypertension acutely and can be cautiously tried for the therapeutic use in primary pulmonary arterial hypertension. Further studies are warranted.     

Treatment of primary pulmonary hypertension with oral sildenafil

Sildenafil, a selective phosphodiesterase-5 inhibitor, was administered orally to a 14-year-old girl with primary pulmonary hypertension (PPH) at a dose of 0.5 mg/kg/4 h on a daily basis, increased to doses of 1 and 2 mg/kg at monthly intervals. Following therapy, oxygen saturation increased and exercise capacity improved significantly, but with no change in pulmonary haemodynamics. No side-effects were noted. Sildenafil may be beneficial in children with PPH, but the mechanism of benefit is unclear.     

Acute effects of nebulised epoprostenol in pulmonary hypertension due to systemic sclerosis.

Pulmonary hypertension often has a lethal outcome in systemic sclerosis and the treatment is challenging. Epoprostenol is a potent pulmonary vasodilator and its efficacy has been demonstrated when delivered by the intravenous and aerosolized routes. We report the haemodynamic and functional benefits of epoprostenol administered by inhalation to a spontaneously breathing patient with partially reversible pulmonary hypertension due to systemic sclerosis. Aerosolized epoprostenol, equivalent to the maximum tolerated intravenous dose (31.2 micrograms), produced a 58% fall in pulmonary vascular resistance, increased the cardiac output by 42% and improved functional performance by one MET (3.5 ml kg-1 min-1 of oxygen uptake) without any significant side-effects. Selective distribution of epoprostenol by the inhaled route may offer a new strategy for treatment of pulmonary hypertension.     

Effects and problems of continuous infusion of epoprostenol for patients with primary pulmonary hypertension

OBJECTIVE: We examined the usefulness and the problems of epoprostenol (Epo) therapy in adult Japanese with primary pulmonary hypertension (PPH). SUBJECTS AND METHODS: In eleven cases with PPH, both acute and chronic effects, and clinical effects of Epo were assessed. RESULTS: In the acute challenge test (n = 6), Epo reduced both systemic and pulmonary vascular resistance and increased the cardiac output, but did not change the ratio of pulmonary to systemic vascular resistance, while the systemic and pulmonary blood pressure also did not change. In the chronic study (n = 9), Epo decreased the pulmonary blood pressure without changes in systemic blood pressure, and increased the cardiac output. Both systemic and pulmonary vascular resistance decreased with a decrease in the ratio of the pulmonary to systemic vascular resistance. The level of brain natriuretic peptide and atrial natriuretic peptide, NYHA functional class and 6-minute walking distance were improved by Epo therapy. In spite of Epo therapy, two patients did not improve and died. Another patient improved in terms of symptoms but then died suddenly from massive lung bleeding. Two patients who improved physically could not be discharged because of psychiatric problems. One patient underwent lung transplantation. Five out-patients have been continuing Epo therapy. CONCLUSION: We demonstrated that the chronic effect of Epo treatment is sufficient even at the dose used in our hospital. However, it was shown that there was resistance to this therapy in some of the cases and that we should pay attention to the severe adverse effects of Epo.     

A study of clinical efficacy of sildenafil in patients with primary pulmonary hypertension

BACKGROUND: Primary pulmonary hypertension is a disorder with limited treatment options and poor outcome. Sildenafil, a pulmonary vasodilator, is likely to be beneficial in primary pulmonary hypertension. We studied the clinical efficacy of sildenafil in patients with primary pulmonary hypertension. METHODS AND RESULTS: A registry of patients with primary pulmonary hypertension has been maintained in our hospital since January 1999. Of a total of 60 patients. 29 (M:16, F:13) consented to try sildenafiL. New York Heart Association functional class, six-minute walk test and Doppler echocardiographic evaluation of pulmonary artery pressure was done before and after treatment with sildenafil. Sildenafil was initiated at a dose of 25 mg thrice a day and increased up to 100 mg thrice a day as tolerated. There was a significant improvement in the functional class. The six-minute walked distance increased from 297.07+/-130.69 m at baseline to 427.68+/-85.35 m after 3 months of sildenafil therapy (p<0.0003). The mean of the pulmonary artery systolic pressure before starting sildenaffil was 109.26+/-24.15 mmHg (mean+/-SD) and it decreased to 95.15+/-24.64 mmHg (p<0.008). While 19 of the 31 historical controls in whom sildenafil was not given died during follow-up (11-44 months), only 1 of the 29 patients given sildenafil died (in an accident) during follow-up (5-20 months). CONCLUSIONS: Sildenafil, a pulmonary vasodilator, has a beneficial effect in patients with primary pulmonary hypertension in improving the functional class, six-minute walked distance and in decreasing the pulmonary artery pressures.     

Identical twins with primary pulmonary hypertension: beraprost vs epoprostenol

BACKGROUND: The course of 12-year-old, homozygotic twins with primary pulmonary hypertension (PPH) treated with different vasoactive agents, beraprost vs epoprostenol, is described. METHODS: Clinical, exercise, and hemodynamic assessments were made at baseline, and at 9 months and 24 months of treatment. FINDINGS: Twin A had a rapid improvement with epoprostenol. In contrast, twin B, initially treated with beraprost, had progressive worsening with subsequent improvement on epoprostenol. INTERPRETATION: Epoprostenol was efficacious for identical twins with PPH. A 9-month delay in initiating epoprostenol for twin B did not appear to have irreversible short-term detrimental effects.     

Pregnancy and primary pulmonary hypertension : successful outcome with epoprostenol therapy

Primary pulmonary hypertension (PPH) associated with pregnancy carries a high maternal mortality rate. Short-term epoprostenol infusion has been demonstrated to improve the hemodynamic profile in patients with PPH. We report a successful maternal-fetal outcome with epoprostenol therapy during pregnancy, cesarean section, and postpartum in a patient with PPH. Epoprostenol therapy did not produce any physical or developmental abnormalities in the fetus. A favorable maternal-fetal outcome may occur with a multidisciplinary approach.     

Acute pulmonary hypertensive crisis in a patient with primary pulmonary hypertension treated by both epoprostenol (prostacyclin) and nitroprusside

A 19-year-old girl was diagnosed as having primary pulmonary hypertension that was confirmed by right heart catheterization. Acute right heart failure was associated with syncope. Stabilization, while not achieved with intravenous epoprostenol (Prostacyclin) alone, was achieved with intravenous prostacyclin and nitroprusside.     

Treatment of primary pulmonary hypertension intravenous epoprostenol (prostacyclin)

Ten patients with severe primary pulmonary hypertension and pronounced disability who were unresponsive to oral vasodilators were treated with intravenous epoprostenol (prostacyclin). All had been referred for heart and lung transplantation. Short term administration of epoprostenol (mean dose 5.5 ng/kg/min) increased the mean cardiac index from 1.8 to 2.2 1/min/m2, improved pulmonary artery oxygen saturation from 48% to 57%, and increased calculated tissue oxygen delivery from 10 to 11.8 ml/kg/min. The mean pulmonary vascular resistance fell by 18% while mean systemic artery pressure fell by 32%. Pulmonary artery pressure rose in only two patients. Continued intravenous infusion of epoprostenol for 1-25 months was associated with subjective and clinical improvement. Exercise tolerance improved as measured by an increase in the maximum rate of oxygen consumption during progressive exercise testing. In those six patients who were able to exercise before treatment it rose from a mean of 7 to 15 ml/kg/min. Those who had been unable to exercise before treatment achieved comparable rates of oxygen consumption after treatment. Two patients died on treatment, three have undergone heart-lung transplantation, and in five the treatment is continuing. Complications included episodes of septicaemia and ascites. In this uncontrolled study of patients with severe pulmonary hypertension epoprostenol seemed to offer a means of optimally dosing the patients with a vasodilator to reduce pulmonary vascular resistance and thus increasing cardiac output and oxygen tissue delivery. There was no evidence to suggest that this treatment influenced the progress of the disease.