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Effects of the dual endothelin receptor antagonist bosentan in patients with pulmonary hypertension: a placebo-controlled study
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Abstracts
0.007 mm/month vs. 0.002 mm/month, p⫽0.29; II: 0.001 vs.0.001, p⫽0.95). 11 patients have been identified with moderate-severe (Grade 3-4) TCAD by IVUS and followed for a median of 24 months after diagnosis (range 9-60 months). 5 patients have been identified with severe TCAD by angiography. 1/11 IVUS patients, compared to 5/5 patients with severe TCAD by angiography developed inotropic-dependent heart failure or sudden death within 12 months of diagnosis (p⫽0.0002). 1/11 IVUS patients ultimately developed severe disease by angiography 4 years after severe (Grade 4) disease was diagnosed by IVUS. These findings indicate that IVUS detects a steady rate of increase in pediatric TCAD both early and late after transplantation, similar to findings in adult recipients. Severe pediatric TCAD defined by angiography is associated with imminent cardiac events, while moderate-severe pediatric TCAD defined by IVUS is not. Angiography may best identify pediatric patients with TCAD at highest risk for cardiac events and need for retransplantation. 329 INTERACTION OF VOLUME AND ERA ON SURVIVAL OF CHILDREN LISTED FOR CARDIAC TRANSPLANTATION I. Balfour1, D. Naftel2, J. Fricker3, B. Friedman1, E. Frazier4, R. Shaddy5, J. Kirklin2, W. Morrow4, Pediatric Heart Transplant Study Group6; 1Cardinal Glennon Children’s Hospital, St. Louis, MO; 2University of Alabama at Birmingham, Birmingham, AL; 3 Shands Hospital at the Univeristy of Florida, Gainesville, FL; 4 Arkansas Children’s Hospital, Little Rock, AR; 5Primary Children’s Medical Center, Salt Lake City, UT; 6Pediatric Heart Transplant Study Group (PHTS), USA Overall survival after pediatric heart transplantation (HTx) is good despite smaller numbers of patients at individual institutions. To determine the effect of center volume and era on survival after listing and HTx we examined actuarial survival among 14 centers who have participated continuously in the PHTS. Methods: 850 pediatric patients (0-18yrs) underwent HTx between January 1, 1993 and Dec 31, 1999. Survival before and after HTx were assessed using competing outcomes and actuarial analysis with multi-variable analysis in the hazard domain. Two eras were examined; Era 1 from 1993-94, Era 2 from 1995-99. Results: 193 patients died following HTx. 8 centers performed ⬎ 50 transplants (high volume) for a total of 676 HTx (range 50-138) and 6 centers performed ⬍ 50 transplants (low volume) for a total of 174 HTx (range 18-38). Overall actuarial survival after HTx was similar between high (Hvol) and low volume (Lvol) institutions with 80% survival at one year and 72% at 5 years. Survival after HTx for both Lvol (p⫽.001) and Hvol (p⫽.01) institutions improved significantly from Era 1 to Era 2. Survival after listing and HTx (including pre and post HTx mortality) also showed significant improvement over time in Lvol centers (p⫽.0002). In fact, by 7 years post listing there was no difference in actuarial survival post HTx (p⫽.5) or overall survival post listing and HTx (p⫽.8) between Lvol and Hvol groups. By multivariable analysis center volume was a significant risk factor for death after transplant in Era 1 (p⫽.03). Importantly, the interaction of center volume and year of transplant was a significant risk factor for death after HTx over the entire study period (p⫽.01). Inferences: Center experience and not center volume per se importantly affects outcome after listing and HTx in pediatric centers. Continuous participation in a multi-center transplant study group may have a favorable effect on outcomes after listing and HTx.
The Journal of Heart and Lung Transplantation February 2001 330 PAEDIATRIC HEART TRANSPLANTATION IN THE UNITED KINGDOM ⴚ A FIVE YEAR REVIEW OF PRACTICE AND RESULTS I. Saeed1, C.A. Rogers1, A.J. Murday, The UK Cardiothoracic Transplant Audit, The Royal College of Surgeons of England, London, United Kingdom Aim: To review the practice and results of paediatric heart transplantation in the UK. Subjects: All paediatric (£ 16 years) heart transplant recipients, transplanted in the UK between April 1995 and March 2000. Methods: Prospective multi-centre case-series. Patients were divided into three subgroups according to age: infants (⬍1 year), children (1-10 years), and teenagers (11-16 years). Survival curves were estimated using the Kaplan-Meier method. Results: One hundred and thirty-six transplants were performed. Median age at transplant was 7 years (IQ range 2-12). Only 7% of transplants were in infants. Indications for transplantation were: dilated cardiomyopathy (59%), congenital heart disease (24%), retransplant (3%), and miscellaneous (14%). Dilated cardiomyopathy was the major indication for transplantation within each age group; 91% of patients with congenital heart disease had one or more corrective procedures prior to transplant; 50% patients were in-patients at the time of transplant, with 42% requiring inotropic support and 12% ventilated. Median ischaemic time was 205 minutes. Median ITU and hospital stay (respectively) were: 7 and 27 days (infants), 3 and 23 days (children), and 3 and 24 days (teenagers). Overall 30 day, 1 year and 3 year patient survival was 88% (95% CI 82-93), 80% (95% CI 72-87), and 75% (95% CI 66-84). Three-year patient survival by age group was: 80% (95% CI 45-100, infants), 76% (95% CI 64-88, children), and 74% (95% CI 61-88, teenagers). Conclusion: Results are comparable to or better than those reported by other national/multi-institute studies. The proportionately small number of infant transplants reflects infant donor organ shortages, the poor results of infant transplantation in eras before the study period, and an established acceptance that corrective surgery (despite variable results) is the therapy of choice for these patients. Based on these data, we suggest that the option of heart transplantation should be considered more often when devising management strategies for infants with uncorrectable congenital heart disease. 331 EFFECTS OF THE DUAL ENDOTHELIN RECEPTOR ANTAGONIST BOSENTAN IN PATIENTS WITH PULMONARY HYPERTENSION: A PLACEBOCONTROLLED STUDY R. Channick1, D. B. Badesch2, V. F. Tapson3, G. Simonneau4, I. Robbins5, A. Frost6, S Roux7, M. Rainisio7, F. Bodin7, L. J. Rubin1, 1UCSD, San Diego, CA; 2University of Colorado, Denver, CO; 3Duke University, Durham, NC; 4Hospital Antoine Beclere, Clamert, France; 5Vanderbilt University, Nashville, TN; 6Baylor University, Houston, TX; 7Actelion, France Background: Endothelin-1 (ET-1) has been implicated as a key mediator in the pathogenesis of pulmonary arterial hypertension (PAH). The potential benefits of bosentan, an orally active dual ET-1 receptor antagonist was evaluated in patients with PAH.
The Journal of Heart and Lung Transplantation Volume 20, Number 2 Methods: Patients (pts; n⫽32),WHO functional class III/IV with PAH either primary or secondary to scleroderma received, in addition to background therapy, either placebo (PL) or bosentan (BOS) 62.5 mg bid for 4 weeks followed by 125 mg bid for 8 weeks. Change from baseline (BL) in exercise capacity (6 minute walk test) and invasive hemodynamic variables were assessed after 12 weeks. Results: PL and BOS treated pts did not differ in baseline characteristics. Compared to PL, at 12 weeks, BOS significantly increased six minute walk distance by 76 m [13, 139 m, 95% CI]
Abstracts
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and the cardiac index by 1.0 l/min/m2 [0.7, 1.4, 95% CI]. In addition, mean pulmonary artery pressure decreased (-2 vs.⫹5 mmHg, p⫽0.03) and pulmonary vascular resistance decreased (-230 vs. ⫹190 dynes/sec/cm-5) compared to placebo. Three PL pts dropped out due to worsening of their PAH (p⬍0.05). Tolerability/safety of bosentan was comparable to PL. Conclusion: Chronic treatment with bosentan markedly improves walk test and pulmonary hemodynamics in patients with PAH. Oral bosentan may become a major therapeutic option in pulmonary arterial hypertension.
Abstracts
0.007 mm/month vs. 0.002 mm/month, p⫽0.29; II: 0.001 vs.0.001, p⫽0.95). 11 patients have been identified with moderate-severe (Grade 3-4) TCAD by IVUS and followed for a median of 24 months after diagnosis (range 9-60 months). 5 patients have been identified with severe TCAD by angiography. 1/11 IVUS patients, compared to 5/5 patients with severe TCAD by angiography developed inotropic-dependent heart failure or sudden death within 12 months of diagnosis (p⫽0.0002). 1/11 IVUS patients ultimately developed severe disease by angiography 4 years after severe (Grade 4) disease was diagnosed by IVUS. These findings indicate that IVUS detects a steady rate of increase in pediatric TCAD both early and late after transplantation, similar to findings in adult recipients. Severe pediatric TCAD defined by angiography is associated with imminent cardiac events, while moderate-severe pediatric TCAD defined by IVUS is not. Angiography may best identify pediatric patients with TCAD at highest risk for cardiac events and need for retransplantation. 329 INTERACTION OF VOLUME AND ERA ON SURVIVAL OF CHILDREN LISTED FOR CARDIAC TRANSPLANTATION I. Balfour1, D. Naftel2, J. Fricker3, B. Friedman1, E. Frazier4, R. Shaddy5, J. Kirklin2, W. Morrow4, Pediatric Heart Transplant Study Group6; 1Cardinal Glennon Children’s Hospital, St. Louis, MO; 2University of Alabama at Birmingham, Birmingham, AL; 3 Shands Hospital at the Univeristy of Florida, Gainesville, FL; 4 Arkansas Children’s Hospital, Little Rock, AR; 5Primary Children’s Medical Center, Salt Lake City, UT; 6Pediatric Heart Transplant Study Group (PHTS), USA Overall survival after pediatric heart transplantation (HTx) is good despite smaller numbers of patients at individual institutions. To determine the effect of center volume and era on survival after listing and HTx we examined actuarial survival among 14 centers who have participated continuously in the PHTS. Methods: 850 pediatric patients (0-18yrs) underwent HTx between January 1, 1993 and Dec 31, 1999. Survival before and after HTx were assessed using competing outcomes and actuarial analysis with multi-variable analysis in the hazard domain. Two eras were examined; Era 1 from 1993-94, Era 2 from 1995-99. Results: 193 patients died following HTx. 8 centers performed ⬎ 50 transplants (high volume) for a total of 676 HTx (range 50-138) and 6 centers performed ⬍ 50 transplants (low volume) for a total of 174 HTx (range 18-38). Overall actuarial survival after HTx was similar between high (Hvol) and low volume (Lvol) institutions with 80% survival at one year and 72% at 5 years. Survival after HTx for both Lvol (p⫽.001) and Hvol (p⫽.01) institutions improved significantly from Era 1 to Era 2. Survival after listing and HTx (including pre and post HTx mortality) also showed significant improvement over time in Lvol centers (p⫽.0002). In fact, by 7 years post listing there was no difference in actuarial survival post HTx (p⫽.5) or overall survival post listing and HTx (p⫽.8) between Lvol and Hvol groups. By multivariable analysis center volume was a significant risk factor for death after transplant in Era 1 (p⫽.03). Importantly, the interaction of center volume and year of transplant was a significant risk factor for death after HTx over the entire study period (p⫽.01). Inferences: Center experience and not center volume per se importantly affects outcome after listing and HTx in pediatric centers. Continuous participation in a multi-center transplant study group may have a favorable effect on outcomes after listing and HTx.
The Journal of Heart and Lung Transplantation February 2001 330 PAEDIATRIC HEART TRANSPLANTATION IN THE UNITED KINGDOM ⴚ A FIVE YEAR REVIEW OF PRACTICE AND RESULTS I. Saeed1, C.A. Rogers1, A.J. Murday, The UK Cardiothoracic Transplant Audit, The Royal College of Surgeons of England, London, United Kingdom Aim: To review the practice and results of paediatric heart transplantation in the UK. Subjects: All paediatric (£ 16 years) heart transplant recipients, transplanted in the UK between April 1995 and March 2000. Methods: Prospective multi-centre case-series. Patients were divided into three subgroups according to age: infants (⬍1 year), children (1-10 years), and teenagers (11-16 years). Survival curves were estimated using the Kaplan-Meier method. Results: One hundred and thirty-six transplants were performed. Median age at transplant was 7 years (IQ range 2-12). Only 7% of transplants were in infants. Indications for transplantation were: dilated cardiomyopathy (59%), congenital heart disease (24%), retransplant (3%), and miscellaneous (14%). Dilated cardiomyopathy was the major indication for transplantation within each age group; 91% of patients with congenital heart disease had one or more corrective procedures prior to transplant; 50% patients were in-patients at the time of transplant, with 42% requiring inotropic support and 12% ventilated. Median ischaemic time was 205 minutes. Median ITU and hospital stay (respectively) were: 7 and 27 days (infants), 3 and 23 days (children), and 3 and 24 days (teenagers). Overall 30 day, 1 year and 3 year patient survival was 88% (95% CI 82-93), 80% (95% CI 72-87), and 75% (95% CI 66-84). Three-year patient survival by age group was: 80% (95% CI 45-100, infants), 76% (95% CI 64-88, children), and 74% (95% CI 61-88, teenagers). Conclusion: Results are comparable to or better than those reported by other national/multi-institute studies. The proportionately small number of infant transplants reflects infant donor organ shortages, the poor results of infant transplantation in eras before the study period, and an established acceptance that corrective surgery (despite variable results) is the therapy of choice for these patients. Based on these data, we suggest that the option of heart transplantation should be considered more often when devising management strategies for infants with uncorrectable congenital heart disease. 331 EFFECTS OF THE DUAL ENDOTHELIN RECEPTOR ANTAGONIST BOSENTAN IN PATIENTS WITH PULMONARY HYPERTENSION: A PLACEBOCONTROLLED STUDY R. Channick1, D. B. Badesch2, V. F. Tapson3, G. Simonneau4, I. Robbins5, A. Frost6, S Roux7, M. Rainisio7, F. Bodin7, L. J. Rubin1, 1UCSD, San Diego, CA; 2University of Colorado, Denver, CO; 3Duke University, Durham, NC; 4Hospital Antoine Beclere, Clamert, France; 5Vanderbilt University, Nashville, TN; 6Baylor University, Houston, TX; 7Actelion, France Background: Endothelin-1 (ET-1) has been implicated as a key mediator in the pathogenesis of pulmonary arterial hypertension (PAH). The potential benefits of bosentan, an orally active dual ET-1 receptor antagonist was evaluated in patients with PAH.
The Journal of Heart and Lung Transplantation Volume 20, Number 2 Methods: Patients (pts; n⫽32),WHO functional class III/IV with PAH either primary or secondary to scleroderma received, in addition to background therapy, either placebo (PL) or bosentan (BOS) 62.5 mg bid for 4 weeks followed by 125 mg bid for 8 weeks. Change from baseline (BL) in exercise capacity (6 minute walk test) and invasive hemodynamic variables were assessed after 12 weeks. Results: PL and BOS treated pts did not differ in baseline characteristics. Compared to PL, at 12 weeks, BOS significantly increased six minute walk distance by 76 m [13, 139 m, 95% CI]
Abstracts
263
and the cardiac index by 1.0 l/min/m2 [0.7, 1.4, 95% CI]. In addition, mean pulmonary artery pressure decreased (-2 vs.⫹5 mmHg, p⫽0.03) and pulmonary vascular resistance decreased (-230 vs. ⫹190 dynes/sec/cm-5) compared to placebo. Three PL pts dropped out due to worsening of their PAH (p⬍0.05). Tolerability/safety of bosentan was comparable to PL. Conclusion: Chronic treatment with bosentan markedly improves walk test and pulmonary hemodynamics in patients with PAH. Oral bosentan may become a major therapeutic option in pulmonary arterial hypertension.