EDITORIAL
Pulmonary arterial hypertension associated with congenital heart disease: the efficacy of
drug treatment in symptomatic patients
I.R. Henkens, H.W. Vliegen
Pulmonary arterial hypertension (PAH) results from progressive obliteration ofthe afferent pulmonary vasculature, typified by progressive right heart failure. The disease is characterised by vasculopathy of the small pulmonary arteries including intimal fibrosis, media hypertrophy, and plexiform lesions, which may be associated with in situ thrombosis. Historically, these lesions constituted the essential difference between PAH and pulmonary hypertension due to other causes. The renewed 2003 World Health Organisation Venetian convention classification of pulmonary hypertension now incorporates the intrinsic pathological differences into a clinical classification.I PAH has since become a clinical diagnosis based on stepwise elimination of other possible causes of pulmonary hypertension. Idiopathic PAH is extremely rare with an estimated incidence of 2 to 32 per million per year. Within 'risk groups' such as patients with congenital heart disease, however, incidence is much higher (up to 50% of patients with a ventricular septal defect).2 PAH associated with congenital heart disease is thought to result from a large systemic-to-pulmonary shunt. Prolonged increased shear stress due to disproportionate pulmonary flow induces obliterative changes in the afferent pulmonary vasculature. The rate of disease progression is dependent on presence and degree of concomitant pressure overload (e.g. ventricular septal defect, persistent ductus arteriosus or artificial systemic-to-pulmonary shunt). In general, if defects are not corrected, concomitant pressure overload will lead to symptoms early in life, whereas volume overload alone may be well tolerated for several I.R. Henkens H.W. Vilegen Department of Cardiology, Leiden University Medical Centre, Leiden, the Netherlands
Correspondence to: H.W. Vliegen Department of Cardiology, Leiden University Medical Centre, PO Box 9600, 2300 RC Leiden, the Netherlands E-mail: [email protected]
(C
Netherlands Heart Journal, Volume 14, Number 6, June 2006
decades. Presence of symptoms always means that pulmonary vascular resistance is pathologically elevated. Surgical correction is often no longer feasible in symptomatic patients since the increased right ventricular workload is associated with increased risk for perioperative right heart failure and death. A right-to-left shunt present at rest and worsening on exertion is pathognomonic for supra-systemic pulmonary vascular resistance and is called an Eisenmenger complex. Although exercise tolerance is severely impaired in Eisenmenger patients due to shunting-related low oxygen uptake, survival is far better than in patients with other forms of PAH.3 PAH attenuating drug therapy in Eisenmenger patients has drawn much interest in recent years as a means for postponing or avoiding (heart-)lung transplantation. The evident role of endothelin-1 in PAH has boosted research regarding the effects of endothelin receptor antagonists.4 Although retrospective reports of 'compassionate use' of these drugs showed promising results, a randomised controlled trial was lacking until recently.5 The Bosentan Randomised Trial of Endothelin Antagonist Therapy-5 (BREATHE-5) is the first prospective, randomised, placebo-controlled trial evaluating the effect of the dual endothelin-l receptor antagonist bosentan in Eisenmenger patients. The results of the trial were first presented at the 2005 Chest Convention in Montreal, Canada. The rationale behind this study was the implication ofelevated endothelin- 1 levels in PAH, the effectiveness of bosentan in patients with the idiopathic form of PAH, and the necessity for safety evaluation of bosentan in Eisenmenger patients. The bosentan safety profile is well known through its extensive worldwide use in idiopathic PAH patients. However, it was feared for a long time that the intrinsic blood pressure lowering effect might worsen the right-to-left shunt, and thereby decrease exercise tolerance. BREATHE-5 randomised patients >12 years of age in a 2:1 ratio to bosentan or placebo. Inclusion requirements were stable disease for at least three months, a baseline six-minute walk distance between 150 and 450 m, and clinical status concurrent with functional 207
EDITORIAL
New York Heart Association (NYHA) class III. Exclusion criteria were complex congenital heart disease, a left ventricular ejection fraction 3x upper limit of normal). Patients underwent right and left heart catheterisation at baseline and after 16 weeks. Oxygen samples were taken, and blood pressures in both systemic and pulmonary circulation were measured. Cardiac output was calculated by means ofthe Fick method. Pulmonary and systemic vascular resistances were calculated by dividing transpulmonary and tanssystemic gradients by pulmonary and systemic flow, respectively, and were subsequently indexed for body surface area. Initially, patients received 62.5 mg bosentan or placebo twice a day, which was increased to 125 mg twice a day after four weeks. The latter dose was then taken for another 12 weeks. Primary endpoints for the study were mean change from baseline at week 16 in systemic pulse oximetry at rest on room air and mean change in pulmonaryvascular resistance index (PVRI). At 16 weeks, systemic pulse oximetry had not changed significantly from baseline andwas not different between placebo- or bosentan-treated patients (84.0±1.6% vs. 83.9±0.9%, respectively). On average Eisenmenger patients receiving placebo (baseline PVRI 2870±1209 dynes*sec*cm-5) experienced a rise in PVRI, whereas those receiving bosentan (baseline PVRI 3425±1410 dynes*sec*cm-5) experienced a decrease in PVRI, resulting in a significant treatment effect between groups of -472 dynes*sec*cm-5 (p
Pulmonary arterial hypertension associated with congenital heart disease: the efficacy of
drug treatment in symptomatic patients
I.R. Henkens, H.W. Vliegen
Pulmonary arterial hypertension (PAH) results from progressive obliteration ofthe afferent pulmonary vasculature, typified by progressive right heart failure. The disease is characterised by vasculopathy of the small pulmonary arteries including intimal fibrosis, media hypertrophy, and plexiform lesions, which may be associated with in situ thrombosis. Historically, these lesions constituted the essential difference between PAH and pulmonary hypertension due to other causes. The renewed 2003 World Health Organisation Venetian convention classification of pulmonary hypertension now incorporates the intrinsic pathological differences into a clinical classification.I PAH has since become a clinical diagnosis based on stepwise elimination of other possible causes of pulmonary hypertension. Idiopathic PAH is extremely rare with an estimated incidence of 2 to 32 per million per year. Within 'risk groups' such as patients with congenital heart disease, however, incidence is much higher (up to 50% of patients with a ventricular septal defect).2 PAH associated with congenital heart disease is thought to result from a large systemic-to-pulmonary shunt. Prolonged increased shear stress due to disproportionate pulmonary flow induces obliterative changes in the afferent pulmonary vasculature. The rate of disease progression is dependent on presence and degree of concomitant pressure overload (e.g. ventricular septal defect, persistent ductus arteriosus or artificial systemic-to-pulmonary shunt). In general, if defects are not corrected, concomitant pressure overload will lead to symptoms early in life, whereas volume overload alone may be well tolerated for several I.R. Henkens H.W. Vilegen Department of Cardiology, Leiden University Medical Centre, Leiden, the Netherlands
Correspondence to: H.W. Vliegen Department of Cardiology, Leiden University Medical Centre, PO Box 9600, 2300 RC Leiden, the Netherlands E-mail: [email protected]
(C
Netherlands Heart Journal, Volume 14, Number 6, June 2006
decades. Presence of symptoms always means that pulmonary vascular resistance is pathologically elevated. Surgical correction is often no longer feasible in symptomatic patients since the increased right ventricular workload is associated with increased risk for perioperative right heart failure and death. A right-to-left shunt present at rest and worsening on exertion is pathognomonic for supra-systemic pulmonary vascular resistance and is called an Eisenmenger complex. Although exercise tolerance is severely impaired in Eisenmenger patients due to shunting-related low oxygen uptake, survival is far better than in patients with other forms of PAH.3 PAH attenuating drug therapy in Eisenmenger patients has drawn much interest in recent years as a means for postponing or avoiding (heart-)lung transplantation. The evident role of endothelin-1 in PAH has boosted research regarding the effects of endothelin receptor antagonists.4 Although retrospective reports of 'compassionate use' of these drugs showed promising results, a randomised controlled trial was lacking until recently.5 The Bosentan Randomised Trial of Endothelin Antagonist Therapy-5 (BREATHE-5) is the first prospective, randomised, placebo-controlled trial evaluating the effect of the dual endothelin-l receptor antagonist bosentan in Eisenmenger patients. The results of the trial were first presented at the 2005 Chest Convention in Montreal, Canada. The rationale behind this study was the implication ofelevated endothelin- 1 levels in PAH, the effectiveness of bosentan in patients with the idiopathic form of PAH, and the necessity for safety evaluation of bosentan in Eisenmenger patients. The bosentan safety profile is well known through its extensive worldwide use in idiopathic PAH patients. However, it was feared for a long time that the intrinsic blood pressure lowering effect might worsen the right-to-left shunt, and thereby decrease exercise tolerance. BREATHE-5 randomised patients >12 years of age in a 2:1 ratio to bosentan or placebo. Inclusion requirements were stable disease for at least three months, a baseline six-minute walk distance between 150 and 450 m, and clinical status concurrent with functional 207
EDITORIAL
New York Heart Association (NYHA) class III. Exclusion criteria were complex congenital heart disease, a left ventricular ejection fraction 3x upper limit of normal). Patients underwent right and left heart catheterisation at baseline and after 16 weeks. Oxygen samples were taken, and blood pressures in both systemic and pulmonary circulation were measured. Cardiac output was calculated by means ofthe Fick method. Pulmonary and systemic vascular resistances were calculated by dividing transpulmonary and tanssystemic gradients by pulmonary and systemic flow, respectively, and were subsequently indexed for body surface area. Initially, patients received 62.5 mg bosentan or placebo twice a day, which was increased to 125 mg twice a day after four weeks. The latter dose was then taken for another 12 weeks. Primary endpoints for the study were mean change from baseline at week 16 in systemic pulse oximetry at rest on room air and mean change in pulmonaryvascular resistance index (PVRI). At 16 weeks, systemic pulse oximetry had not changed significantly from baseline andwas not different between placebo- or bosentan-treated patients (84.0±1.6% vs. 83.9±0.9%, respectively). On average Eisenmenger patients receiving placebo (baseline PVRI 2870±1209 dynes*sec*cm-5) experienced a rise in PVRI, whereas those receiving bosentan (baseline PVRI 3425±1410 dynes*sec*cm-5) experienced a decrease in PVRI, resulting in a significant treatment effect between groups of -472 dynes*sec*cm-5 (p
