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Communications to the Editor |

Sitaxsentan in Pulmonary Arterial Hypertension FREE TO VIEW

Sotiria C. Apostolopoulou; Spyridon Rammos
Author and Funding Information

Affiliations: Onassis Cardiac Surgery Center Athens, Greece,  New York Presbyterian Hospital New York, NY

Correspondence to: Sotiria C. Apostolopoulou, MD, Department of Pediatric Cardiology, Onassis Cardiac Surgery Center, 356 Syngrou Ave, Athens, GR 176 74, Greece; e-mail: riapos@hol.gr



Chest. 2003;123(5):1772-1773. doi:10.1378/chest.123.5.1772
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Published online

To the Editor:

We read with interest the article in CHEST by Barst et al (June 2002)1 concerning endothelin antagonism with sitaxsentan in patients with pulmonary arterial hypertension (PAH). In contrast with previous studies with epoprostenol2 as well as bosentan3 showing improved cardiac index in patients with PAH, the authors report significant decrease in pulmonary artery pressure and resistance without improved cardiac index. The hypothesis that sitaxsentan may have a unique mode of action in patients with PAH may not be the only explanation for this observation. An almost 30% decrease in pulmonary artery resistance accompanied with a less pronounced but almost 20% decrease in pulmonary artery pressure with stable pulmonary capillary wedge pressure, as reported in this study, should be connected with increased systemic cardiac index in patients without possibility of shunting between the pulmonary and systemic circulation. According to the text though, this study population included 10 patients with congenital systemic to pulmonary shunts, while at least two of these patients had possibly unrestrictive shunts at ventricular level. Patients with PAH due to congenital mixing between systemic and pulmonary circulation have relatively preserved systemic cardiac index at the expense of significant cyanosis. In these patients, a decrease in pulmonary vascular resistance leading to increased pulmonary cardiac index may result in decreased systemic cardiac index, albeit decreased right-to-left shunt and improved cyanosis. The results presented in Figure 4 showing individuals with significant increases as well as decreases in systemic cardiac index with sitaxsentan would be consistent with this explanation, especially if some of the patients with relatively normal but falling systemic cardiac indexes belong to the group with systemic to pulmonary mixing. Presentation of detailed hemodynamic data and analysis according to the presence or not of mixing in this population may help in explaining the absence of systemic cardiac index improvement. A detailed analysis of the hemodynamic effect of endothelin antagonism in patients with PAH with data analysis according to the etiology of PAH may help in elucidating the pathophysiology and mechanisms involved in this patient population.

References

Barst, RJ, Rich, S, Widlitz, A, et al (2002) Clinical efficacy of sitaxsentan, an endothelin-A receptor antagonist, in patients with pulmonary arterial hypertension.Chest121,1860-1868. [PubMed] [CrossRef]
 
Barst, RJ, Rubin, LJ, McGoon, MD, et al Survival in primary pulmonary hypertension with long-term continuous intravenous prostacyclin.Ann Intern Med1994;121,409-415. [PubMed]
 
Channick, RN, Simonneau, G, Sitbon, O, et al Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study.Lancet2001;358,1119-1123. [PubMed]
 
To the Editor:

It is a pleasure to see how carefully Drs. Apostolopoulou and Rammos read our article. Unfortunately, due to space issues in CHEST as well as virtually all other peer-reviewed journals, we were unable to elaborate on the hemodynamic changes observed with this pilot open-label, uncontrolled sitaxsentan trial in patients with pulmonary arterial hypertension.

Although several patients did have systemic-to-pulmonary communications, as well as right-to-left shunting resulting in systemic arterial oxygen desaturation prior to receiving sitaxsentan therapy, when sitaxsentan was administered over a long period, systemic arterial oxygen saturation either increased or remained unchanged, ie, no patients had worsening of their right-to-left shunting and all patients maintained a normal resting cardiac index. In the several patients in whom cardiac index decreased after 12 weeks of therapy with sitaxsentan, despite the decrease that occurred in these patients, particularly those with a high resting cardiac index (which was partly due to right-to-left intracardiac shunting), cardiac index remained within a normal resting range for all patients at 12 weeks and, as expected, increased in those patients in whom the baseline cardiac index was low. Therefore, when oxygen delivery was calculated, despite a variable response in cardiac index as displayed in Figure 4, oxygen delivery did improve consistent with the patient’s clinical improvement

Of course, with systemic-to-pulmonary communications, the determination of pulmonary vs systemic blood flow depends upon several factors in addition to pulmonary vascular resistance vs systemic vascular resistance: obligatory shunting, effects of streaming, as well as right and left heart filling pressures and respiratory effects on intrathoracic pressures. We anticipate that ongoing clinical investigation, including patients with unrepaired or residual systemic-to-pulmonary communications, will further enlighten our understanding of the mechanisms of action of endothelin receptor antagonists


Figures

Tables

References

Barst, RJ, Rich, S, Widlitz, A, et al (2002) Clinical efficacy of sitaxsentan, an endothelin-A receptor antagonist, in patients with pulmonary arterial hypertension.Chest121,1860-1868. [PubMed] [CrossRef]
 
Barst, RJ, Rubin, LJ, McGoon, MD, et al Survival in primary pulmonary hypertension with long-term continuous intravenous prostacyclin.Ann Intern Med1994;121,409-415. [PubMed]
 
Channick, RN, Simonneau, G, Sitbon, O, et al Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study.Lancet2001;358,1119-1123. [PubMed]
 
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