Influential Articles in Pulmonary Hypertension, 2006
Influential Articles in Pulmonary Hypertension, 2006
A number of important articles were published in 2006 on various aspects of pulmonary hypertension (PH). Here is a review of a few that made original contributions worth noting for the practicing clinician, either from a unique clinical or research perspective.
Tapson VF, Gomberg-Maitland M, McLaughlin VV, et al
Chest. 2006;129:683-688
This article reports the results of a prospective, open-label, multicenter, 12-week study of intravenous (IV) treprostinil (TRE) as therapy for pulmonary arterial hypertension (PAH). Sixteen patients with World Health Organization (WHO) group classification as idiopathic pulmonary arterial hypertension (IPAH) in whom IV prostanoid therapy was believed to be indicated were included. Fourteen of the patients were WHO functional class III, and the remaining two were class IV. The mean pulmonary artery pressure of the group at baseline was 58 ± 15 mm Hg; their right atrial pressures were 12 ± 5 mm Hg; and their cardiac index was 1.7 ± 0.4 L/minute/m. Patients were hospitalized for initiation of therapy, and the mean dose of IV TRE at discharge was 5 ng/kg/minute. At the end of the 12-week period, the mean dose was 41 ± 14 ng/kg/minute in the 14 patients who completed the study. Their Six-Minute Walk Test distance (6MWD) increased by 82 m from 319 m at baseline to 400 m at 12 weeks. Six of the 14 patients improved by at least 1 WHO functional class, and none of the remaining 8 had deterioration in their WHO functional class. There was a 9% improvement in their mean pulmonary artery pressures, a 29% increase in the cardiac index, and a 33% reduction in pulmonary vascular resistance. Although this was an open-label study of a small number of patients, it does provide a basis and rationale for the use of IV TRE in patients for whom an IV prostanoid is indicated.
Abstract
Barst RJ, Galie N, Naeije R, et al
Eur Respir J. 2006;28:1195-1203
This study assessed the long-term benefits of chronic subcutaneous (SQ) TRE in a group of 860 patients who received this as initial therapy. This study included 496 patients who had previously been enrolled in 3 placebo-controlled studies of SQ TRE and who were subsequently continued on open-label drug. The remaining patients were started on open-label TRE de novo. Specifically the study group included patients with IPAH (48%), Eisenmenger's physiology (21%), and diffuse systemic sclerosis (8%). Of the 860 patients, 506 (59%) discontinued the drug prematurely for various reasons, including 136 who died, 11 who were transplanted, and 117 who had clinical deterioration. Concomitant or alternative PAH medications included conversion to alternative prostacyclin analogs in 98 patients; add-on therapy with bosentan occurred in 105 (12%) patients and with sildenafil in 25 patients (3%). The survival rates at 1, 2, 3, and 4 years were 87%, 78%, 71%, and 68%, respectively. Survival was similar for those patients who were continued on TRE monotherapy only. The most pertinent drug-specific/delivery-specific side effects were infusion site pain and site reaction, which were reported by 92% and 81% of the patients, respectively. The infusion site pain necessitated the discontinuation of therapy in up to a quarter of patients. It does nonetheless appear that SQ TRE is a reasonable alternative as first-line therapy in cases in which it is deemed necessary for a parenteral prostanoid agent.
Abstract
Barst RJ, Langleben D, Badesch D, et al
J Am Coll Cardiol. 2006;47:2049-2056
Sitaxsentan is an endothelin A receptor blocker that was studied in a prospective, randomized fashion in 245 patients with PAH (WHO class II, III, or IV). Patients consisted of 59% with IPAH, 30% with connective tissue disease, and 11% with congenital heart disease. Patients were randomized to receive placebo (n = 62), sitaxsentan at 50 mg daily (n = 62), sitaxsentan at 100 mg daily (n = 61), or open-label bosentan at the standard dose of 125 mg twice daily (n = 60). At 18 weeks, the change from baseline in the 6MWD was -6.5 m in the placebo group, +17.8 m in the 50-mg sitaxsentan group, +24.9 m in the sitaxsentan 100-mg group, and +23 m in the bosentan group. In terms of functional class, 13% of the sitaxsentan 100-mg group improved vs 10% of the placebo arm, whereas 13% of the placebo arm had worsened functional status vs 2% of the sitaxsentan 100-mg group (13% worsened in the sitaxsentan 50-mg group and 9% in the bosentan group). Liver abnormalities were reported in 5% of the placebo group, 5% in the sitaxsentan 50-mg group, 3% in the sitaxsentan 100-mg group, and 11% in the bosentan group. It therefore appears that sitaxsentan is an effective agent for the treatment of PAH with an optimal dose of 100 mg daily. There was no significant difference between sitaxsentan and bosentan, nor was the study powered to detect such a difference.
Abstract
Handa T, Nagai S, Miki S, et al
Chest. 2006;129:1246-1252
PH commonly complicates the course of patients with stage IV sarcoidosis. The study authors sought to characterize the prevalence of PH in a prospective observational study of 246 consecutive Japanese sarcoidosis patients evaluated at a specialized sarcoidosis clinic. Estimates of systolic pulmonary artery pressure (sPAP) were obtained with transthoracic echocardiography. Estimated sPAP was obtainable in 86% of the patients. Some 5.7% (n = 12) of the patients were classified as having PH that was based on an estimated sPAP ≥ 40 mm Hg. Male gender, advanced radiographic stage, and decrease of oxygen saturation (SaO2) were all associated with PH. Among 165 patients who had echocardiograms and contemporaneous pulmonary function studies, there was a significant association between a reduce forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), total lung capacity (TLC), and PH. Of interest, there did not appear to be a correlation between the diffusing capacity of the lung for carbon monoxide (DLCO) and PH. On the basis of the pulmonary function test (PFT) profiles of the patient group, it does appear that this study included mostly patients with milder disease. The study authors devoted some attention to the pitfalls of echo sPAP estimates and provided a disclaimer that echocardiography should not supplant right heart catheterization measurements in the appropriate clinical setting.
Abstract
Lang I, Gomez-Sanchez M, Kneussl M, et al
Chest. 2006;129:1636-1643
One hundred twenty-two patients were included in this study from 3 European centers. Of these patients, 99 had PAH and 23 had PH secondary to chronic thromboembolic disease (CTED). The mean pulmonary artery pressure (mPAP) of the cohort was 60.3 mm Hg with 6.6% of the patients being in New York Heart Association (NYHA) class II, 66.4% in class III, and 27% in class IV. Patients were followed for a mean of 26.2 months (range, 3-57 months). The mean 6MWD increased from a baseline of 305 ± 111 m to 444 ± 29 m at 49-54 months (P < .0001). The mean dose of treprostinil was 26.2 ng/kg/minute at 1 year, 31.9 ng/kg/minute at 2 years, and 39.8 ng/kg/minute at 3 years. Treatment was discontinued in 13 (10.6%) of the patients, with 6 of these (4.9%) discontinuations for intractable site pain. This was the most commonly reported side effect occurring in 82% of the patients. The study authors reported site changes every 5-28 days, with patients changing less than once per week having less pain. During the study, 48 patients had treatment failure (death n = 31, transplantation n = 5, clinical worsening n = 20, atrial septostomy n = 7, and/or therapy with bosentan or sildenafil n = 22). Survival rates of the group were 88.6%, 70.6%, and 65.6% at 1, 3, and 4 years, respectively. This study underscores the clinical efficacy and sustained effects of subcutaneous treprostinil and confirms this as a reasonable alternative to continuous intravenous epoprostenol.
Abstract
Tashkin DP, Elashoff R, Clements PJ, et al
N Engl J Med. 2006;354:2655-2666
The Scleroderma Lung Study was a 13-center, double-blind study assessing the role of cyclophosphamide therapy in patients with either limited or diffuse systemic sclerosis. Inclusion criteria included evidence on computed tomographic (CT) scan or bronchoalveolar lavage fluid of active alveolitis, an FVC of 45% to 85% predicted, and grade 2 exertional dyspnea. Exclusion criteria included a DLCO < 30% predicted, evidence of PAH requiring therapy, prior therapy with cyclophosphamide, and a prednisone dose of > 10 mg/day. The target dose for cyclophosphamide in the treatment arm was 2 mg/kg/day. One hundred fifty-eight patients were randomized over a 40-month period. Three patients in the cyclophosphamide arm vs 5 in the placebo arm had treatment failure as defined by a decrement in the FVC of > 15%. A total of 54 patients in the cyclophosphamide group (68.4%) and 55 in the placebo group (69.6%) completed 12 months of therapy. The mean absolute difference in the FVC at 12 months between the 2 groups was 2.53% favoring cyclophosphamide (P < .03). In the majority of patients, the change was < 5%, which is within range of the natural variability of the test. The combined endpoint of time to death plus the FVC at 12 months also favored the treatment group (P = .04). There was no difference in the DLCO between the 2 groups. Adverse events were more common in the cyclophosphamide group. Although a significant difference was attained in this study, the modest response to cyclophosphamide should be placed in the context of the significant drug toxicity for any scleroderma patient in whom this therapy is being considered.
Abstract
Hughes RJ, Jais X, Bonderman D, et al
Eur Respir J. 2006;28:138-143
There have been anecdotal reports of successful medical therapy of patients with CTED. Long-term follow-up (1 year) of the use of bosentan in such patients was the subject of this retrospective review from 3 European specialist centers. Forty-seven patients with inoperable CTED qualified for the analysis. Eight of these patients had previously undergone pulmonary endarterectomy (PEA) (17%). The baseline 6MWD of the group was 312 ± 17 m. By 4 months, the 6MWD had increased by 49 ± 8.4 m, and at 1 year the 6MWD was 52 ± 10 m compared with baseline. By 1 year, 2 patients had died; 2 had commenced on alternative therapies for their disease; and 3 had their bosentan dose increased to 250 mg twice daily. The improvement in the 6MWD was most significant in those patients who had previously undergone PEA compared with those who had not (102 m vs 0 m). The 1-year survival rate was 96%, with 43 patients remaining on bosentan monotherapy. In conclusion, bosentan was well tolerated and can result in sustained improvement in function and exercise capacity in patients with CTED, and may also improve survival. All such patients should first be assessed as potential surgical candidates, and all should receive long-term anticoagulation.
Abstract
Galie N, Beghetti M, Gatzoulis MA, et al
Circulation. 2006;114:48-54
This study reported the results of the "BREATH-5" study, which was designed to investigate the effects of bosentan in patients with Eisenmenger's syndrome. This multicenter, prospective, 16-week study included 54 patients who were randomized to receive bosentan or placebo in a 2:1 fashion. The study authors sought to establish that gas exchange was not worsened by looking at the change in SaO2 from baseline to week 16 on room air at rest. A second primary endpoint was the change in the pulmonary vascular resistance index at the 2 time periods. The placebo-corrected effect on the SaO2 was 1.0, demonstrating noninferiority and therefore meeting the primary endpoint of the study. The pulmonary vascular resistance index increased in the placebo arm by 5.4% vs a decrease in the bosentan arm of 9.3%. The 6MWD decreased in the placebo arm by 9.7 m and increased in the bosentan group by 43.3 m. Some 35% of the bosentan patients improved to WHO class II vs 13% of the placebo patients. One patient in each group deteriorated to class IV and the rest remained in WHO class III. An open-label extension included 11 patients who had previously been in the placebo arm and 26 of the treated patients. There was an increase in the 6MWD in the former group of 33.2 m and maintenance of the salutary effect in the latter group (6MWD +6.7 m) at 24 weeks. This trial demonstrated that bosentan improves hemodynamics and exercise capacity without compromising oxygenation in patients with Eisenmenger's syndrome.
Abstract
Becattini C, Agnelli G, Pesavento R, et al
Chest. 2006;130:172-175
How many patients with acute pulmonary emboli (PE) are at risk of developing CTED? It has been variously estimated that this figure is between 0.1% and 3.8%. This study sought to establish the incidence of CTED by prospectively studying 259 consecutive patients diagnosed with acute PE. To qualify for inclusion, all patients had their PE's objectively confirmed and required anticoagulation therapy for a period of 3-12 months. Patients with known persistent risk factors for thromboembolism were excluded. PE was "unprovoked" in 135 of the patients and was associated with a temporary risk factor in the remaining 124. The average follow-up period was 46 months, during which time 21 patients died (8.1%) and 31 (12%) had recurrence of a thromboembolic event, with a second PE in half of these. CTED was documented in only 2 cases for an incidence of 0.8%. Both cases occurred within 2 years of the initial PE event. Both patients did not have risk factors for PE, and therefore the incidence in patients without temporary risk factors translated to 1.5% (2 of 135). This low incidence of CTED may be related to the low severity of the initial PE event and the effects of appropriate anticoagulation thereafter. This study also demonstrated that CTED may occur relatively early after a single episode of acute PE.
References
Abstract
Reichenberger F, Voswinckel R, Steveling E, et al
Eur Respir J. 2006;28:563-567
This retrospective review reported the results of the use of sildenafil in 14 cases of portopulmonary hypertension. Of these cases, 6 were already on active PAH therapy with inhaled prostanoids, and the sildenafil was employed as "add-on" therapy. The other 7 patients were treatment-naive. In terms of symptoms, 14 of the patients were NYHA class III and the remaining 4 were class IV. The baseline mean 6MWD of the group was 307 ± 109 m. The mean hemodynamic measurements of the group included mPAP of 55 mm Hg, cardiac index of 2.2 L/minute/m, and a pulmonary vascular resistance of 1130 dyne/second/cm. The dose of sildenafil employed was 50 mg 3 times y daily. Two patients died within 3 months of therapy. For the remaining 12 patients, the 6MWD improved from a mean of 312 m to 397 m at 3 months and 407 m at 1 year. For the remaining patients their mPAP decreased to 46 mm Hg and the cardiac index improved to 2.8 L/minute/m at 1 year. Although there are inherent problems with this study in terms of the number of patients and its retrospective design, it does provide some proof as to the efficacy and safety of sildenafil in patients with portopulmonary hypertension.
Abstract
McLaughlin VV, Oudiz RJ, Frost A, et al
Am J Respir Crit Care Med. 2006;174:1257-1263
In this randomized, multicenter, double-blind, 12-week study (STEP), the investigators sought to assess the efficacy and tolerability of bosentan with inhaled iloprost. Sixty-seven patients on bosentan monotherapy for at least 4 months were randomized to either inhaled iloprost (n = 34) or placebo (n = 33) administered 6-9 times per day. Outcome measures included the difference in the change in the 6MWD at 12 weeks, change in NYHA class, and time to clinical worsening. The mean number of inhalations was 5.6 in the treatment group. At 12 weeks, the postinhalation mean increase in the 6MWD was 30 m in the iloprost group vs 4 m in the placebo arm (placebo-adjusted difference of 26 m, P = .051). The NYHA class association improved in 34% of the iloprost group vs 6% of the placebo arm (P = .002). The time to clinical worsening was also prolonged in the iloprost group (P = .0219) with none of the treatment arm meeting the predefined criteria vs 5 of 33 (15%) patients in the placebo arm. The combination was generally very well tolerated, with most of the reported side effects being typical for a prostanoid (headache, flushing, and jaw pain). It does therefore appear that in the short term, inhaled iloprost as add-on therapy to bosentan has a beneficial effect in modulating the course of patients with PAH.
Abstract
A number of important articles were published in 2006 on various aspects of pulmonary hypertension (PH). Here is a review of a few that made original contributions worth noting for the practicing clinician, either from a unique clinical or research perspective.
Tapson VF, Gomberg-Maitland M, McLaughlin VV, et al
Chest. 2006;129:683-688
This article reports the results of a prospective, open-label, multicenter, 12-week study of intravenous (IV) treprostinil (TRE) as therapy for pulmonary arterial hypertension (PAH). Sixteen patients with World Health Organization (WHO) group classification as idiopathic pulmonary arterial hypertension (IPAH) in whom IV prostanoid therapy was believed to be indicated were included. Fourteen of the patients were WHO functional class III, and the remaining two were class IV. The mean pulmonary artery pressure of the group at baseline was 58 ± 15 mm Hg; their right atrial pressures were 12 ± 5 mm Hg; and their cardiac index was 1.7 ± 0.4 L/minute/m. Patients were hospitalized for initiation of therapy, and the mean dose of IV TRE at discharge was 5 ng/kg/minute. At the end of the 12-week period, the mean dose was 41 ± 14 ng/kg/minute in the 14 patients who completed the study. Their Six-Minute Walk Test distance (6MWD) increased by 82 m from 319 m at baseline to 400 m at 12 weeks. Six of the 14 patients improved by at least 1 WHO functional class, and none of the remaining 8 had deterioration in their WHO functional class. There was a 9% improvement in their mean pulmonary artery pressures, a 29% increase in the cardiac index, and a 33% reduction in pulmonary vascular resistance. Although this was an open-label study of a small number of patients, it does provide a basis and rationale for the use of IV TRE in patients for whom an IV prostanoid is indicated.
Abstract
Barst RJ, Galie N, Naeije R, et al
Eur Respir J. 2006;28:1195-1203
This study assessed the long-term benefits of chronic subcutaneous (SQ) TRE in a group of 860 patients who received this as initial therapy. This study included 496 patients who had previously been enrolled in 3 placebo-controlled studies of SQ TRE and who were subsequently continued on open-label drug. The remaining patients were started on open-label TRE de novo. Specifically the study group included patients with IPAH (48%), Eisenmenger's physiology (21%), and diffuse systemic sclerosis (8%). Of the 860 patients, 506 (59%) discontinued the drug prematurely for various reasons, including 136 who died, 11 who were transplanted, and 117 who had clinical deterioration. Concomitant or alternative PAH medications included conversion to alternative prostacyclin analogs in 98 patients; add-on therapy with bosentan occurred in 105 (12%) patients and with sildenafil in 25 patients (3%). The survival rates at 1, 2, 3, and 4 years were 87%, 78%, 71%, and 68%, respectively. Survival was similar for those patients who were continued on TRE monotherapy only. The most pertinent drug-specific/delivery-specific side effects were infusion site pain and site reaction, which were reported by 92% and 81% of the patients, respectively. The infusion site pain necessitated the discontinuation of therapy in up to a quarter of patients. It does nonetheless appear that SQ TRE is a reasonable alternative as first-line therapy in cases in which it is deemed necessary for a parenteral prostanoid agent.
Abstract
Barst RJ, Langleben D, Badesch D, et al
J Am Coll Cardiol. 2006;47:2049-2056
Sitaxsentan is an endothelin A receptor blocker that was studied in a prospective, randomized fashion in 245 patients with PAH (WHO class II, III, or IV). Patients consisted of 59% with IPAH, 30% with connective tissue disease, and 11% with congenital heart disease. Patients were randomized to receive placebo (n = 62), sitaxsentan at 50 mg daily (n = 62), sitaxsentan at 100 mg daily (n = 61), or open-label bosentan at the standard dose of 125 mg twice daily (n = 60). At 18 weeks, the change from baseline in the 6MWD was -6.5 m in the placebo group, +17.8 m in the 50-mg sitaxsentan group, +24.9 m in the sitaxsentan 100-mg group, and +23 m in the bosentan group. In terms of functional class, 13% of the sitaxsentan 100-mg group improved vs 10% of the placebo arm, whereas 13% of the placebo arm had worsened functional status vs 2% of the sitaxsentan 100-mg group (13% worsened in the sitaxsentan 50-mg group and 9% in the bosentan group). Liver abnormalities were reported in 5% of the placebo group, 5% in the sitaxsentan 50-mg group, 3% in the sitaxsentan 100-mg group, and 11% in the bosentan group. It therefore appears that sitaxsentan is an effective agent for the treatment of PAH with an optimal dose of 100 mg daily. There was no significant difference between sitaxsentan and bosentan, nor was the study powered to detect such a difference.
Abstract
Handa T, Nagai S, Miki S, et al
Chest. 2006;129:1246-1252
PH commonly complicates the course of patients with stage IV sarcoidosis. The study authors sought to characterize the prevalence of PH in a prospective observational study of 246 consecutive Japanese sarcoidosis patients evaluated at a specialized sarcoidosis clinic. Estimates of systolic pulmonary artery pressure (sPAP) were obtained with transthoracic echocardiography. Estimated sPAP was obtainable in 86% of the patients. Some 5.7% (n = 12) of the patients were classified as having PH that was based on an estimated sPAP ≥ 40 mm Hg. Male gender, advanced radiographic stage, and decrease of oxygen saturation (SaO2) were all associated with PH. Among 165 patients who had echocardiograms and contemporaneous pulmonary function studies, there was a significant association between a reduce forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), total lung capacity (TLC), and PH. Of interest, there did not appear to be a correlation between the diffusing capacity of the lung for carbon monoxide (DLCO) and PH. On the basis of the pulmonary function test (PFT) profiles of the patient group, it does appear that this study included mostly patients with milder disease. The study authors devoted some attention to the pitfalls of echo sPAP estimates and provided a disclaimer that echocardiography should not supplant right heart catheterization measurements in the appropriate clinical setting.
Abstract
Lang I, Gomez-Sanchez M, Kneussl M, et al
Chest. 2006;129:1636-1643
One hundred twenty-two patients were included in this study from 3 European centers. Of these patients, 99 had PAH and 23 had PH secondary to chronic thromboembolic disease (CTED). The mean pulmonary artery pressure (mPAP) of the cohort was 60.3 mm Hg with 6.6% of the patients being in New York Heart Association (NYHA) class II, 66.4% in class III, and 27% in class IV. Patients were followed for a mean of 26.2 months (range, 3-57 months). The mean 6MWD increased from a baseline of 305 ± 111 m to 444 ± 29 m at 49-54 months (P < .0001). The mean dose of treprostinil was 26.2 ng/kg/minute at 1 year, 31.9 ng/kg/minute at 2 years, and 39.8 ng/kg/minute at 3 years. Treatment was discontinued in 13 (10.6%) of the patients, with 6 of these (4.9%) discontinuations for intractable site pain. This was the most commonly reported side effect occurring in 82% of the patients. The study authors reported site changes every 5-28 days, with patients changing less than once per week having less pain. During the study, 48 patients had treatment failure (death n = 31, transplantation n = 5, clinical worsening n = 20, atrial septostomy n = 7, and/or therapy with bosentan or sildenafil n = 22). Survival rates of the group were 88.6%, 70.6%, and 65.6% at 1, 3, and 4 years, respectively. This study underscores the clinical efficacy and sustained effects of subcutaneous treprostinil and confirms this as a reasonable alternative to continuous intravenous epoprostenol.
Abstract
Tashkin DP, Elashoff R, Clements PJ, et al
N Engl J Med. 2006;354:2655-2666
The Scleroderma Lung Study was a 13-center, double-blind study assessing the role of cyclophosphamide therapy in patients with either limited or diffuse systemic sclerosis. Inclusion criteria included evidence on computed tomographic (CT) scan or bronchoalveolar lavage fluid of active alveolitis, an FVC of 45% to 85% predicted, and grade 2 exertional dyspnea. Exclusion criteria included a DLCO < 30% predicted, evidence of PAH requiring therapy, prior therapy with cyclophosphamide, and a prednisone dose of > 10 mg/day. The target dose for cyclophosphamide in the treatment arm was 2 mg/kg/day. One hundred fifty-eight patients were randomized over a 40-month period. Three patients in the cyclophosphamide arm vs 5 in the placebo arm had treatment failure as defined by a decrement in the FVC of > 15%. A total of 54 patients in the cyclophosphamide group (68.4%) and 55 in the placebo group (69.6%) completed 12 months of therapy. The mean absolute difference in the FVC at 12 months between the 2 groups was 2.53% favoring cyclophosphamide (P < .03). In the majority of patients, the change was < 5%, which is within range of the natural variability of the test. The combined endpoint of time to death plus the FVC at 12 months also favored the treatment group (P = .04). There was no difference in the DLCO between the 2 groups. Adverse events were more common in the cyclophosphamide group. Although a significant difference was attained in this study, the modest response to cyclophosphamide should be placed in the context of the significant drug toxicity for any scleroderma patient in whom this therapy is being considered.
Abstract
Hughes RJ, Jais X, Bonderman D, et al
Eur Respir J. 2006;28:138-143
There have been anecdotal reports of successful medical therapy of patients with CTED. Long-term follow-up (1 year) of the use of bosentan in such patients was the subject of this retrospective review from 3 European specialist centers. Forty-seven patients with inoperable CTED qualified for the analysis. Eight of these patients had previously undergone pulmonary endarterectomy (PEA) (17%). The baseline 6MWD of the group was 312 ± 17 m. By 4 months, the 6MWD had increased by 49 ± 8.4 m, and at 1 year the 6MWD was 52 ± 10 m compared with baseline. By 1 year, 2 patients had died; 2 had commenced on alternative therapies for their disease; and 3 had their bosentan dose increased to 250 mg twice daily. The improvement in the 6MWD was most significant in those patients who had previously undergone PEA compared with those who had not (102 m vs 0 m). The 1-year survival rate was 96%, with 43 patients remaining on bosentan monotherapy. In conclusion, bosentan was well tolerated and can result in sustained improvement in function and exercise capacity in patients with CTED, and may also improve survival. All such patients should first be assessed as potential surgical candidates, and all should receive long-term anticoagulation.
Abstract
Galie N, Beghetti M, Gatzoulis MA, et al
Circulation. 2006;114:48-54
This study reported the results of the "BREATH-5" study, which was designed to investigate the effects of bosentan in patients with Eisenmenger's syndrome. This multicenter, prospective, 16-week study included 54 patients who were randomized to receive bosentan or placebo in a 2:1 fashion. The study authors sought to establish that gas exchange was not worsened by looking at the change in SaO2 from baseline to week 16 on room air at rest. A second primary endpoint was the change in the pulmonary vascular resistance index at the 2 time periods. The placebo-corrected effect on the SaO2 was 1.0, demonstrating noninferiority and therefore meeting the primary endpoint of the study. The pulmonary vascular resistance index increased in the placebo arm by 5.4% vs a decrease in the bosentan arm of 9.3%. The 6MWD decreased in the placebo arm by 9.7 m and increased in the bosentan group by 43.3 m. Some 35% of the bosentan patients improved to WHO class II vs 13% of the placebo patients. One patient in each group deteriorated to class IV and the rest remained in WHO class III. An open-label extension included 11 patients who had previously been in the placebo arm and 26 of the treated patients. There was an increase in the 6MWD in the former group of 33.2 m and maintenance of the salutary effect in the latter group (6MWD +6.7 m) at 24 weeks. This trial demonstrated that bosentan improves hemodynamics and exercise capacity without compromising oxygenation in patients with Eisenmenger's syndrome.
Abstract
Becattini C, Agnelli G, Pesavento R, et al
Chest. 2006;130:172-175
How many patients with acute pulmonary emboli (PE) are at risk of developing CTED? It has been variously estimated that this figure is between 0.1% and 3.8%. This study sought to establish the incidence of CTED by prospectively studying 259 consecutive patients diagnosed with acute PE. To qualify for inclusion, all patients had their PE's objectively confirmed and required anticoagulation therapy for a period of 3-12 months. Patients with known persistent risk factors for thromboembolism were excluded. PE was "unprovoked" in 135 of the patients and was associated with a temporary risk factor in the remaining 124. The average follow-up period was 46 months, during which time 21 patients died (8.1%) and 31 (12%) had recurrence of a thromboembolic event, with a second PE in half of these. CTED was documented in only 2 cases for an incidence of 0.8%. Both cases occurred within 2 years of the initial PE event. Both patients did not have risk factors for PE, and therefore the incidence in patients without temporary risk factors translated to 1.5% (2 of 135). This low incidence of CTED may be related to the low severity of the initial PE event and the effects of appropriate anticoagulation thereafter. This study also demonstrated that CTED may occur relatively early after a single episode of acute PE.
References
Fedullo KM, Auger WR, Fedullo FP, et al. Chronic major-vessel pulmonary hypertension. Circulation. 1990;81:1735-1743.
Pengo V, Lensing AWA, Prins MH, et al. Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism. N Engl J Med. 2004;350:2257-2264.
Abstract
Reichenberger F, Voswinckel R, Steveling E, et al
Eur Respir J. 2006;28:563-567
This retrospective review reported the results of the use of sildenafil in 14 cases of portopulmonary hypertension. Of these cases, 6 were already on active PAH therapy with inhaled prostanoids, and the sildenafil was employed as "add-on" therapy. The other 7 patients were treatment-naive. In terms of symptoms, 14 of the patients were NYHA class III and the remaining 4 were class IV. The baseline mean 6MWD of the group was 307 ± 109 m. The mean hemodynamic measurements of the group included mPAP of 55 mm Hg, cardiac index of 2.2 L/minute/m, and a pulmonary vascular resistance of 1130 dyne/second/cm. The dose of sildenafil employed was 50 mg 3 times y daily. Two patients died within 3 months of therapy. For the remaining 12 patients, the 6MWD improved from a mean of 312 m to 397 m at 3 months and 407 m at 1 year. For the remaining patients their mPAP decreased to 46 mm Hg and the cardiac index improved to 2.8 L/minute/m at 1 year. Although there are inherent problems with this study in terms of the number of patients and its retrospective design, it does provide some proof as to the efficacy and safety of sildenafil in patients with portopulmonary hypertension.
Abstract
McLaughlin VV, Oudiz RJ, Frost A, et al
Am J Respir Crit Care Med. 2006;174:1257-1263
In this randomized, multicenter, double-blind, 12-week study (STEP), the investigators sought to assess the efficacy and tolerability of bosentan with inhaled iloprost. Sixty-seven patients on bosentan monotherapy for at least 4 months were randomized to either inhaled iloprost (n = 34) or placebo (n = 33) administered 6-9 times per day. Outcome measures included the difference in the change in the 6MWD at 12 weeks, change in NYHA class, and time to clinical worsening. The mean number of inhalations was 5.6 in the treatment group. At 12 weeks, the postinhalation mean increase in the 6MWD was 30 m in the iloprost group vs 4 m in the placebo arm (placebo-adjusted difference of 26 m, P = .051). The NYHA class association improved in 34% of the iloprost group vs 6% of the placebo arm (P = .002). The time to clinical worsening was also prolonged in the iloprost group (P = .0219) with none of the treatment arm meeting the predefined criteria vs 5 of 33 (15%) patients in the placebo arm. The combination was generally very well tolerated, with most of the reported side effects being typical for a prostanoid (headache, flushing, and jaw pain). It does therefore appear that in the short term, inhaled iloprost as add-on therapy to bosentan has a beneficial effect in modulating the course of patients with PAH.
Abstract
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