Sildenafil for Pulmonary Arterial Hypertension: Exciting, But Protection Required

Abstract

Pulmonary arterial hypertension (PAH) is a serious, often fatal condition. The clinical hallmarks are progressive breathlessness, exertion limitation, and frequently an inexorable decline to right ventricular (RV) failure and death. Since its initial description > 100 years ago, PAH has remained a difficult and frustrating condition to diagnose and manage for patients and physicians alike. However, based on bedside clinical observation, clinical trials, and basic biological research, we are in a time of great enthusiasm and optimism on both scientific and therapeutic fronts.PAH is defined by a persistent elevation in pulmonary artery (PA) pressure, which is due, in part, to pulmonary vasoconstriction. Disturbances in key vascular mediator pathways have been recognized as contributing to the increase in PA tone. These abnormalities include relative deficiencies of vasodilators such as nitric oxide (NO) and prostacyclin,1Giaid A Saleh D Reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension.N Engl J Med. 1995; 333: 214-221Crossref PubMed Scopus (1215) Google Scholar2Kaneko FT Arroliga AC Dweik RA et al.Biochemical reaction products of nitric oxide as quantitative markers of primary pulmonary hypertension.Am J Respir Crit Care Med. 1998; 158: 917-923Crossref PubMed Scopus (185) Google Scholar3Cella G Bellotto F Tona F et al.Plasma markers of endothelial dysfunction in pulmonary hypertension.Chest. 2001; 120: 1226-1230Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar4Christman BW McPherson CD Newman JH et al.An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary hypertension.N Engl J Med. 1992; 327: 70-75Crossref PubMed Scopus (1046) Google Scholar as well as exaggerated production of vasoconstrictors such as endothelin, thromboxanes, and serotonin.5Stewart DJ Levy RD Cernacek P et al.Increased plasma endothelin-1 in pulmonary hypertension: marker or mediator of disease?.Ann Intern Med. 1991; 114: 464-469Crossref PubMed Scopus (894) Google Scholar6Herve P Launay JM Scrobohaci ML et al.Increased plasma serotonin in primary pulmonary hypertension.Am J Med. 1995; 99: 249-254Abstract Full Text PDF PubMed Scopus (469) Google ScholarGiven the putative role of pulmonary vasoconstriction in PAH, vasodilators were a natural initial therapeutic choice. Over the past 40 years, a large number of agents from different classes, including adrenergic agonists (eg, isoproterenol) and antagonists (eg, phentolamine), arterial vasodilators (eg, hydralazine), nitrates (eg, nitroglycerin), angiotensin-converting enzyme inhibitors, calcium-channel blockers (CCBs), and prostaglandins have been administered to patients with PAH. Many were initially hailed as “effective,” “life-saving” “breakthroughs” based on the strength of case reports and uncontrolled case series. However, most have been consigned to the dustbin of failed PAH therapies because of lack of long-term symptomatic, functional, or survival benefit. In addition, long-term administration of several of these vasodilators has been associated with significant adverse effects, including worsening RV function and increased mortality.The adverse effects and lack of long-term benefit of most vasodilators is due to the nature of their hemodynamic effects. The action of most vasodilators is not specific to the pulmonary circulation, and thus there is usually concomitant systemic vasodilation, hypotension, and resulting side effects of headache, nausea, dizziness, and syncope. By virtue of this systemic vasodilatory effect, the majority of vasodilators increase cardiac output, resulting in a decline in calculated pulmonary vascular resistance (PVR), but often in the absence of a significant reduction in PA pressure. Unfortunately, this hemodynamic pattern does not reduce RV load but may actually be associated with a greater impairment of RV function.7Sniderman AD Fitchett DH Vasodilators and pulmonary arterial hypertension: the paradox of therapeutic success and clinical failure.Int J Cardiol. 1988; 20: 173-181Abstract Full Text PDF PubMed Scopus (46) Google Scholar8Galie N Ussia G Passarelli P et al.Role of pharmacologic tests in the treatment of primary pulmonary hypertension.Am J Cardiol. 1995; 75: 55A-62AAbstract Full Text PDF PubMed Scopus (121) Google Scholar Moreover, systemic hypotension in the face of elevated RV chamber pressure may impair right coronary artery perfusion and contribute to ischemic RV dysfunction. Consequently, investigators and clinicians have long sought the “ideal” vasodilator that would be pulmonary vascular specific and that would significantly reduce PA pressure rather than just increase cardiac output.Although no such “ideal” vasodilator exists, NO comes closer than any other agent. NO is a potent, endogenous, endothelium-derived vasodilator that directly relaxes vascular smooth muscle through stimulation of soluble guanylate cyclase and increased intracellular cyclic guanosine 3′-5′ monophosphate (cGMP). PAH is associated with a defect in endothelial NO production and thus, NO-dependent PA vasodilation.9Cremona G Higenbortam TW Bower EA et al.Hemodynamic effects of basal and stimulated release of endogenous nitric oxide in isolated human lungs.Circulation. 1999; 100: 1316-1321Crossref Scopus (19) Google Scholar For example, levels of NO in exhaled gas are reduced at rest and during exercise in patients with PAH.10Kharitonov SA Cailes JB Black CM et al.Decreased nitric oxide in the exhaled air of patients with systemic sclerosis with pulmonary hypertension.Thorax. 1997; 52: 1051-1055Crossref PubMed Scopus (132) Google Scholar11Riley MS Porszasz J Miranda J et al.Exhaled nitric oxide during exercise in primary pulmonary hypertension and pulmonary fibrosis.Chest. 1997; 111: 44-50Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar Plasma levels of nitrites/nitrates, metabolites of NO, are also reduced in PAH.2Kaneko FT Arroliga AC Dweik RA et al.Biochemical reaction products of nitric oxide as quantitative markers of primary pulmonary hypertension.Am J Respir Crit Care Med. 1998; 158: 917-923Crossref PubMed Scopus (185) Google Scholar3Cella G Bellotto F Tona F et al.Plasma markers of endothelial dysfunction in pulmonary hypertension.Chest. 2001; 120: 1226-1230Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar Can we therapeutically reverse this relative deficiency of NO? This has been pursued through administration of exogenous L-arginine, the substrate for endogenous NO synthesis, administration of NO-releasing agents (eg, NONOates), and administration of NO itself.12Mehta S Stewart DJ Langleben D et al.Short-term pulmonary vasodilation with L-arginine in pulmonary hypertension.Circulation. 1995; 92: 1539-1545Crossref PubMed Scopus (162) Google Scholar13Hampl V Tristanifirouzi M Hutsell TC et al.Nebulized nitric oxide/nucleophile adduct reduces chronic pulmonary hypertension.Cardiovasc Res. 1996; 31: 55-62Crossref PubMed Scopus (54) Google Scholar14Pepke-Zaba J Higenbottam TW Dinh-Xuan AT et al.Inhaled nitric oxide as a cause of selective pulmonary vasodilatation in pulmonary hypertension.Lancet. 1991; 338: 1173-1174Abstract PubMed Scopus (949) Google Scholar15Hasuda T Satoh T Shimouchi A et al.Improvement in exercise capacity with nitric oxide inhalation in patients with precapillary pulmonary hypertension.Circulation. 2000; 101: 2066-2070Crossref PubMed Scopus (44) Google Scholar Given its gaseous nature under ambient conditions, NO can be administered to patients via inhalation. Following diffusion from alveolar gas into the pulmonary circulation, NO is rapidly inactivated through oxidative metabolism by hemoglobin to soluble nitrate, thus minimizing the systemic vascular effects of inhaled NO. Indeed, inhaled NO has demonstrated acute and chronic pulmonary-specific vasodilatory effects.14Pepke-Zaba J Higenbottam TW Dinh-Xuan AT et al.Inhaled nitric oxide as a cause of selective pulmonary vasodilatation in pulmonary hypertension.Lancet. 1991; 338: 1173-1174Abstract PubMed Scopus (949) Google Scholar15Hasuda T Satoh T Shimouchi A et al.Improvement in exercise capacity with nitric oxide inhalation in patients with precapillary pulmonary hypertension.Circulation. 2000; 101: 2066-2070Crossref PubMed Scopus (44) Google Scholar Thus, inhaled NO has become a very useful agent for acute vasodilator testing in PAH, and continuous inhaled NO therapy is currently approved for newborns with persistent PAH.16Roberts Jr, JD Fineman JR Morin III, FC et al.Inhaled nitric oxide and persistent pulmonary hypertension of the newborn: The Inhaled Nitric Oxide Study Group.N Engl J Med. 1997; 336: 605-610Crossref PubMed Scopus (660) Google ScholarAn alternative experimental strategy for increasing the activity of endogenous NO in PAH has been to enhance NO-dependent, cGMP-mediated PA vasodilation by inhibition of the breakdown of cGMP by type 5 phosphodiesterase (PDE5). Several PDE5 inhibitors have been studied including dipyridamole17Ziegler JW Ivy DD Fox JJ et al.Dipyridamole potentiates pulmonary vasodilation induced by acetylcholine and nitric oxide in the ovine fetus.Am J Respir Crit Care Med. 1998; 157: 1104-1110Crossref PubMed Scopus (42) Google Scholar and most recently sildenafil. Sildenafil is a more potent acute pulmonary vasodilator than inhaled NO, but sildenafil is not pulmonary vascular specific.18Jackson G Benjamin N Jackson N et al.Effects of sildenafil citrate on human hemodynamics.Am J Cardiol. 1999; 83: 13C-20CAbstract Full Text Full Text PDF PubMed Scopus (354) Google Scholar19Michelakis E Tymchak W Lien D et al.Oral sildenafil is an effective and specific pulmonary vasodilator in patients with pulmonary arterial hypertension: comparison with inhaled nitric oxide.Circulation. 2002; 105: 2398-2403Crossref PubMed Scopus (508) Google Scholar When administered in combination with inhaled NO, sildenafil augments and prolongs the effects of inhaled NO.19Michelakis E Tymchak W Lien D et al.Oral sildenafil is an effective and specific pulmonary vasodilator in patients with pulmonary arterial hypertension: comparison with inhaled nitric oxide.Circulation. 2002; 105: 2398-2403Crossref PubMed Scopus (508) Google Scholar20Lepore J Maroo A Pereira N et al.Effect of sildenafil on the acute pulmonary vasodilator response to inhaled nitric oxide in adults with primary pulmonary hypertension.Am J Cardiol. 2002; 90: 677-680Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar Sildenafil also prevents rebound pulmonary vasoconstriction on withdrawal of inhaled NO.20Lepore J Maroo A Pereira N et al.Effect of sildenafil on the acute pulmonary vasodilator response to inhaled nitric oxide in adults with primary pulmonary hypertension.Am J Cardiol. 2002; 90: 677-680Abstract Full Text Full Text PDF PubMed Scopus (140) Google ScholarThere are few data on long-term sildenafil treatment in PAH apart from isolated case reports.21Prasad S Wilkinson J Gatzoulis MA Sildenafil in primary pulmonary hypertension [letter].N Engl J Med. 2000; 343: 1342Crossref PubMed Scopus (306) Google Scholar22Sayin T Zenci M Sildenafil in primary pulmonary hypertension: is there a subset of patients who respond favourably?.Can J Cardiol. 2002; 18: 676-678PubMed Google Scholar In the current issue of CHEST (see page 1293), Stiebellehner et al report the effects of chronic oral sildenafil in three patients with severe PAH (two patients with primary PAH, and one patient with persistent PAH following surgical closure of an atrial septal defect) already being treated with stable doses of continuous IV prostacyclin. The addition of 75 to 200 mg/d of sildenafil in divided doses over 5 months was associated with reduced dyspnea, improved 6-min walk distance by 35 to 105 m, and reduced mean PA pressure by 14 to 41%. Dose-limiting adverse effects consisted of headache and nausea, likely due to systemic vasodilation and mild hypotension.This uncontrolled trial contributes to a building sense of excitement that sildenafil may be an effective treatment in PAH, especially as sildenafil targets an endogenous deficiency of NO production or activity, a recognized pathobiological pathway in PAH. The safety of sildenafil has already largely been established, at least for standard doses (50 to 100 mg) administered intermittently for erectile dysfunction. However, sildenafil therapy in PAH will require continuous exposure to possibly larger doses, suggesting that adverse effects due to systemic hypotension may be more troublesome, especially given that the vasodilatory effects of sildenafil are not pulmonary vascular specific. Since so many vasodilators have not lived up to their initial promise, we should protect our patients (and ourselves) and refrain from empirically administering sildenafil for PAH at present. A rigorous, blinded, placebo-controlled, randomized clinical trial (RCT) is required to confirm efficacy and establish safety of long-term sildenafil for PAH.The above-mentioned limitations of vasodilator therapy in PAH have raised suspicion that addressing pulmonary vasoconstriction alone is not likely to be an effective, long-term therapeutic strategy in most patients with PAH. The pathophysiology of PAH is also characterized by vascular wall inflammation and matrix alterations, growth and proliferation of endothelial and vascular smooth-muscle cells, as well as microvascular thrombosis.23Mehta S McCormack DG Pathophysiology of pulmonary vascular disease.in: Spina D Drugs for the treatment of respiratory diseases. Cambridge University Press, Cambridge, UK2002: 453-472Google Scholar These changes are collectively referred to as vascular remodeling, and are likely responsible for the vasodilator-unresponsive component of increased PA pressure and PVR. More recently, therapeutic agents for PAH have addressed the importance of pulmonary vascular remodeling. For example, pathophysiologic features of PAH that are targeted by currently available pharmaceutical agents include microvascular thrombotic arteriopathy (by systemic anticoagulants), increased vascular smooth-muscle calcium levels (by CCBs), reduced endogenous endothelial-derived prostacyclin production (by prostacyclin analogues), and increased circulating and tissue endothelin levels (by endothelin receptor antagonists).5Stewart DJ Levy RD Cernacek P et al.Increased plasma endothelin-1 in pulmonary hypertension: marker or mediator of disease?.Ann Intern Med. 1991; 114: 464-469Crossref PubMed Scopus (894) Google Scholar24Pietra GG Edwards WD Kay JM et al.Histopathology of primary pulmonary hypertension: a qualitative and quantitative study of pulmonary blood vessels from 58 patients in the National Heart, Lung, and Blood Institute, Primary Pulmonary Hypertension Registry.Circulation. 1989; 80: 1198-1206Crossref PubMed Scopus (401) Google Scholar25Rich S Kaufmann E Levy PS The effect of high doses of calcium-channel blockers on survival in primary pulmonary hypertension.N Engl J Med. 1992; 327: 76-81Crossref PubMed Scopus (1386) Google Scholar26Barst RJ Rubin LJ Long WA et al.A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension: The Primary Pulmonary Hypertension Study Group.N Engl J Med. 1996; 334: 296-302Crossref PubMed Scopus (0) Google Scholar27Giaid A Yanagisawa M Langleben D et al.Expression of endothelin-1 in the lungs of patients with pulmonary hypertension.N Engl J Med. 1993; 328: 1732-1739Crossref PubMed Scopus (1652) Google ScholarIt is reassuring in this age of evidence-based medicine that many of these novel therapeutic agents have been rigorously evaluated in the first-ever RCTs to be performed in PAH, all of which have been published over the past 6 years. A nonplacebo-controlled RCT showed that continuous IV prostacyclin was an important, if complicated, and adverse effect-prone means of improving survival in severely ill patients with PAH.26Barst RJ Rubin LJ Long WA et al.A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension: The Primary Pulmonary Hypertension Study Group.N Engl J Med. 1996; 334: 296-302Crossref PubMed Scopus (0) Google Scholar More recently, placebo-controlled RCTs of an oral endothelin receptor antagonist (bosentan), and of prostacyclin analogues in aerosolized (iloprost), subcutaneous (treprostinil), and oral (beraprost) forms have been reported.28Channick 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.Lancet. 2001; 358: 1119-1123Abstract Full Text Full Text PDF PubMed Scopus (1401) Google Scholar29Rubin LJ Badesch DB Barst RJ et al.Bosentan therapy for pulmonary arterial hypertension.N Engl J Med. 2002; 346: 896-903Crossref PubMed Scopus (2437) Google Scholar30Olschewski H Simonneau G Galie N et al.Inhaled iloprost for severe pulmonary hypertension.N Engl J Med. 2002; 347: 322-329Crossref PubMed Scopus (1498) Google Scholar31Simonneau G Barst RJ Galie N et al.Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertension: a double-blind, randomized, placebo-controlled trial.Am J Respir Crit Care Med. 2002; 165: 800-804Crossref PubMed Scopus (1221) Google Scholar32Galie N Humbert M Vachiery JL et al.Effects of beraprost sodium, an oral prostacyclin analogue, in patients with pul-monary arterial hypertension: a randomized, double-blind, placebo-controlled trial.J Am Coll Cardiol. 2002; 39: 1496-1502Abstract Full Text Full Text PDF PubMed Scopus (603) Google Scholar These trials have contributed to the wealth of therapeutic options currently available for patients with PAH.The trial by Stiebellehner et al is also important as it reflects the future of PAH therapy—concomitant treatment with two or more agents addressing different pathobiological pathways. Although the formal concept of combination therapy is relatively new in PAH treatment, it is noteworthy that all of the recent RCTs of IV prostacyclin, inhaled iloprost, oral beraprost, and oral bosentan enrolled many patients on stable, concomitant therapy for PAH, including CCBs in 22 to 69% and systemic anticoagulation in up to 73%. More formal combination therapy trials are currently being planned or carried out. These include combinations of bosentan and prostacyclin, as well as the addition of sildenafil to ongoing IV prostacyclin therapy.This is an exciting time for patients with PAH and their physicians. Careful clinical observations and uncontrolled trials, such as the study by Stiebellehner et al, continue to be important in suggesting new therapeutic avenues. However, it is on the strong foundation of basic biological research and well-designed RCTs that we will continue to improve the functional capacity, quality of life, and survival of patients with PAH, and that we may eventually find a cure for PAH. Pulmonary arterial hypertension (PAH) is a serious, often fatal condition. The clinical hallmarks are progressive breathlessness, exertion limitation, and frequently an inexorable decline to right ventricular (RV) failure and death. Since its initial description > 100 years ago, PAH has remained a difficult and frustrating condition to diagnose and manage for patients and physicians alike. However, based on bedside clinical observation, clinical trials, and basic biological research, we are in a time of great enthusiasm and optimism on both scientific and therapeutic fronts. PAH is defined by a persistent elevation in pulmonary artery (PA) pressure, which is due, in part, to pulmonary vasoconstriction. Disturbances in key vascular mediator pathways have been recognized as contributing to the increase in PA tone. These abnormalities include relative deficiencies of vasodilators such as nitric oxide (NO) and prostacyclin,1Giaid A Saleh D Reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension.N Engl J Med. 1995; 333: 214-221Crossref PubMed Scopus (1215) Google Scholar2Kaneko FT Arroliga AC Dweik RA et al.Biochemical reaction products of nitric oxide as quantitative markers of primary pulmonary hypertension.Am J Respir Crit Care Med. 1998; 158: 917-923Crossref PubMed Scopus (185) Google Scholar3Cella G Bellotto F Tona F et al.Plasma markers of endothelial dysfunction in pulmonary hypertension.Chest. 2001; 120: 1226-1230Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar4Christman BW McPherson CD Newman JH et al.An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary hypertension.N Engl J Med. 1992; 327: 70-75Crossref PubMed Scopus (1046) Google Scholar as well as exaggerated production of vasoconstrictors such as endothelin, thromboxanes, and serotonin.5Stewart DJ Levy RD Cernacek P et al.Increased plasma endothelin-1 in pulmonary hypertension: marker or mediator of disease?.Ann Intern Med. 1991; 114: 464-469Crossref PubMed Scopus (894) Google Scholar6Herve P Launay JM Scrobohaci ML et al.Increased plasma serotonin in primary pulmonary hypertension.Am J Med. 1995; 99: 249-254Abstract Full Text PDF PubMed Scopus (469) Google Scholar Given the putative role of pulmonary vasoconstriction in PAH, vasodilators were a natural initial therapeutic choice. Over the past 40 years, a large number of agents from different classes, including adrenergic agonists (eg, isoproterenol) and antagonists (eg, phentolamine), arterial vasodilators (eg, hydralazine), nitrates (eg, nitroglycerin), angiotensin-converting enzyme inhibitors, calcium-channel blockers (CCBs), and prostaglandins have been administered to patients with PAH. Many were initially hailed as “effective,” “life-saving” “breakthroughs” based on the strength of case reports and uncontrolled case series. However, most have been consigned to the dustbin of failed PAH therapies because of lack of long-term symptomatic, functional, or survival benefit. In addition, long-term administration of several of these vasodilators has been associated with significant adverse effects, including worsening RV function and increased mortality. The adverse effects and lack of long-term benefit of most vasodilators is due to the nature of their hemodynamic effects. The action of most vasodilators is not specific to the pulmonary circulation, and thus there is usually concomitant systemic vasodilation, hypotension, and resulting side effects of headache, nausea, dizziness, and syncope. By virtue of this systemic vasodilatory effect, the majority of vasodilators increase cardiac output, resulting in a decline in calculated pulmonary vascular resistance (PVR), but often in the absence of a significant reduction in PA pressure. Unfortunately, this hemodynamic pattern does not reduce RV load but may actually be associated with a greater impairment of RV function.7Sniderman AD Fitchett DH Vasodilators and pulmonary arterial hypertension: the paradox of therapeutic success and clinical failure.Int J Cardiol. 1988; 20: 173-181Abstract Full Text PDF PubMed Scopus (46) Google Scholar8Galie N Ussia G Passarelli P et al.Role of pharmacologic tests in the treatment of primary pulmonary hypertension.Am J Cardiol. 1995; 75: 55A-62AAbstract Full Text PDF PubMed Scopus (121) Google Scholar Moreover, systemic hypotension in the face of elevated RV chamber pressure may impair right coronary artery perfusion and contribute to ischemic RV dysfunction. Consequently, investigators and clinicians have long sought the “ideal” vasodilator that would be pulmonary vascular specific and that would significantly reduce PA pressure rather than just increase cardiac output. Although no such “ideal” vasodilator exists, NO comes closer than any other agent. NO is a potent, endogenous, endothelium-derived vasodilator that directly relaxes vascular smooth muscle through stimulation of soluble guanylate cyclase and increased intracellular cyclic guanosine 3′-5′ monophosphate (cGMP). PAH is associated with a defect in endothelial NO production and thus, NO-dependent PA vasodilation.9Cremona G Higenbortam TW Bower EA et al.Hemodynamic effects of basal and stimulated release of endogenous nitric oxide in isolated human lungs.Circulation. 1999; 100: 1316-1321Crossref Scopus (19) Google Scholar For example, levels of NO in exhaled gas are reduced at rest and during exercise in patients with PAH.10Kharitonov SA Cailes JB Black CM et al.Decreased nitric oxide in the exhaled air of patients with systemic sclerosis with pulmonary hypertension.Thorax. 1997; 52: 1051-1055Crossref PubMed Scopus (132) Google Scholar11Riley MS Porszasz J Miranda J et al.Exhaled nitric oxide during exercise in primary pulmonary hypertension and pulmonary fibrosis.Chest. 1997; 111: 44-50Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar Plasma levels of nitrites/nitrates, metabolites of NO, are also reduced in PAH.2Kaneko FT Arroliga AC Dweik RA et al.Biochemical reaction products of nitric oxide as quantitative markers of primary pulmonary hypertension.Am J Respir Crit Care Med. 1998; 158: 917-923Crossref PubMed Scopus (185) Google Scholar3Cella G Bellotto F Tona F et al.Plasma markers of endothelial dysfunction in pulmonary hypertension.Chest. 2001; 120: 1226-1230Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar Can we therapeutically reverse this relative deficiency of NO? This has been pursued through administration of exogenous L-arginine, the substrate for endogenous NO synthesis, administration of NO-releasing agents (eg, NONOates), and administration of NO itself.12Mehta S Stewart DJ Langleben D et al.Short-term pulmonary vasodilation with L-arginine in pulmonary hypertension.Circulation. 1995; 92: 1539-1545Crossref PubMed Scopus (162) Google Scholar13Hampl V Tristanifirouzi M Hutsell TC et al.Nebulized nitric oxide/nucleophile adduct reduces chronic pulmonary hypertension.Cardiovasc Res. 1996; 31: 55-62Crossref PubMed Scopus (54) Google Scholar14Pepke-Zaba J Higenbottam TW Dinh-Xuan AT et al.Inhaled nitric oxide as a cause of selective pulmonary vasodilatation in pulmonary hypertension.Lancet. 1991; 338: 1173-1174Abstract PubMed Scopus (949) Google Scholar15Hasuda T Satoh T Shimouchi A et al.Improvement in exercise capacity with nitric oxide inhalation in patients with precapillary pulmonary hypertension.Circulation. 2000; 101: 2066-2070Crossref PubMed Scopus (44) Google Scholar Given its gaseous nature under ambient conditions, NO can be administered to patients via inhalation. Following diffusion from alveolar gas into the pulmonary circulation, NO is rapidly inactivated through oxidative metabolism by hemoglobin to soluble nitrate, thus minimizing the systemic vascular effects of inhaled NO. Indeed, inhaled NO has demonstrated acute and chronic pulmonary-specific vasodilatory effects.14Pepke-Zaba J Higenbottam TW Dinh-Xuan AT et al.Inhaled nitric oxide as a cause of selective pulmonary vasodilatation in pulmonary hypertension.Lancet. 1991; 338: 1173-1174Abstract PubMed Scopus (949) Google Scholar15Hasuda T Satoh T Shimouchi A et al.Improvement in exercise capacity with nitric oxide inhalation in patients with precapillary pulmonary hypertension.Circulation. 2000; 101: 2066-2070Crossref PubMed Scopus (44) Google Scholar Thus, inhaled NO has become a very useful agent for acute vasodilator testing in PAH, and continuous inhaled NO therapy is currently approved for newborns with persistent PAH.16Roberts Jr, JD Fineman JR Morin III, FC et al.Inhaled nitric oxide and persistent pulmonary hypertension of the newborn: The Inhaled Nitric Oxide Study Group.N Engl J Med. 1997; 336: 605-610Crossref PubMed Scopus (660) Google Scholar An alternative experimental strategy for increasing the activity of endogenous NO in PAH has been to enhance NO-dependent, cGMP-mediated PA vasodilation by inhibition of the breakdown of cGMP by type 5 phosphodiesterase (PDE5). Several PDE5 inhibitors have been studied including dipyridamole17Ziegler JW Ivy DD Fox JJ et al.Dipyridamole potentiates pulmonary vasodilation induced by acetylcholine and nitric oxide in the ovine fetus.Am J Respir Crit Care Med. 1998; 157: 1104-1110Crossref PubMed Scopus (42) Google Scholar and most recently sildenafil. Sildenafil is a more potent acute pulmonary vasodilator than inhaled NO, but sildenafil is not pulmonary vascular specific.18Jackson G Benjamin N Jackson N et al.Effects of sildenafil citrate on human hemodynamics.Am J Cardiol. 1999; 83: 13C-20CAbstract Full Text Full Text PDF PubMed Scopus (354) Google Scholar19Michelakis E Tymchak W Lien D et al.Oral sildenafil is an effective and specific pulmonary vasodilator in patients with pulmonary arterial hypertension: comparison with inhaled nitric oxide.Circulation. 2002; 105: 2398-2403Crossref PubMed Scopus (508) Google Scholar When administered in combination with inhaled NO, sildenafil augments and prolongs the effects of inhaled NO.19Michelakis E Tymchak W Lien D et al.Oral sildenafil is an effective and specific pulmonary vasodilator in patients with pulmonary arterial hypertension: comparison with inhaled nitric oxide.Circulation. 2002; 105: 2398-2403Crossref PubMed Scopus (508) Google Scholar20Lepore J Maroo A Pereira N et al.Effect of sildenafil on the acute pulmonary vasodilator response to inhaled nitric oxide in adults with primary pulmonary hypertension.Am J Cardiol. 2002; 90: 677-680Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar Sildenafil also prevents rebound pulmonary vasoconstriction on withdrawal of inhaled NO.20Lepore J Maroo A Pereira N et al.Effect of sildenafil on the acute pulmonary vasodilator response to inhaled nitric oxide in adults with primary pulmonary hypertension.Am J Cardiol. 2002; 90: 677-680Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar There are few data on long-term sildenafil treatment in PAH apart from isolated case reports.21Prasad S Wilkinson J Gatzoulis MA Sildenafil in primary pulmonary hypertension [letter].N Engl J Med. 2000; 343: 1342Crossref PubMed Scopus (306) Google Scholar22Sayin T Zenci M Sildenafil in primary pulmonary hypertension: is there a subset of patients who respond favourably?.Can J Cardiol. 2002; 18: 676-678PubMed Google Scholar In the current issue of CHEST (see page 1293), Stiebellehner et al report the effects of chronic oral sildenafil in three patients with severe PAH (two patients with primary PAH, and one patient with persistent PAH following surgical closure of an atrial septal defect) already being treated with stable doses of continuous IV prostacyclin. The addition of 75 to 200 mg/d of sildenafil in divided doses over 5 months was associated with reduced dyspnea, improved 6-min walk distance by 35 to 105 m, and reduced mean PA pressure by 14 to 41%. Dose-limiting adverse effects consisted of headache and nausea, likely due to systemic vasodilation and mild hypotension. This uncontrolled trial contributes to a building sense of excitement that sildenafil may be an effective treatment in PAH, especially as sildenafil targets an endogenous deficiency of NO production or activity, a recognized pathobiological pathway in PAH. The safety of sildenafil has already largely been established, at least for standard doses (50 to 100 mg) administered intermittently for erectile dysfunction. However, sildenafil therapy in PAH will require continuous exposure to possibly larger doses, suggesting that adverse effects due to systemic hypotension may be more troublesome, especially given that the vasodilatory effects of sildenafil are not pulmonary vascular specific. Since so many vasodilators have not lived up to their initial promise, we should protect our patients (and ourselves) and refrain from empirically administering sildenafil for PAH at present. A rigorous, blinded, placebo-controlled, randomized clinical trial (RCT) is required to confirm efficacy and establish safety of long-term sildenafil for PAH. The above-mentioned limitations of vasodilator therapy in PAH have raised suspicion that addressing pulmonary vasoconstriction alone is not likely to be an effective, long-term therapeutic strategy in most patients with PAH. The pathophysiology of PAH is also characterized by vascular wall inflammation and matrix alterations, growth and proliferation of endothelial and vascular smooth-muscle cells, as well as microvascular thrombosis.23Mehta S McCormack DG Pathophysiology of pulmonary vascular disease.in: Spina D Drugs for the treatment of respiratory diseases. Cambridge University Press, Cambridge, UK2002: 453-472Google Scholar These changes are collectively referred to as vascular remodeling, and are likely responsible for the vasodilator-unresponsive component of increased PA pressure and PVR. More recently, therapeutic agents for PAH have addressed the importance of pulmonary vascular remodeling. For example, pathophysiologic features of PAH that are targeted by currently available pharmaceutical agents include microvascular thrombotic arteriopathy (by systemic anticoagulants), increased vascular smooth-muscle calcium levels (by CCBs), reduced endogenous endothelial-derived prostacyclin production (by prostacyclin analogues), and increased circulating and tissue endothelin levels (by endothelin receptor antagonists).5Stewart DJ Levy RD Cernacek P et al.Increased plasma endothelin-1 in pulmonary hypertension: marker or mediator of disease?.Ann Intern Med. 1991; 114: 464-469Crossref PubMed Scopus (894) Google Scholar24Pietra GG Edwards WD Kay JM et al.Histopathology of primary pulmonary hypertension: a qualitative and quantitative study of pulmonary blood vessels from 58 patients in the National Heart, Lung, and Blood Institute, Primary Pulmonary Hypertension Registry.Circulation. 1989; 80: 1198-1206Crossref PubMed Scopus (401) Google Scholar25Rich S Kaufmann E Levy PS The effect of high doses of calcium-channel blockers on survival in primary pulmonary hypertension.N Engl J Med. 1992; 327: 76-81Crossref PubMed Scopus (1386) Google Scholar26Barst RJ Rubin LJ Long WA et al.A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension: The Primary Pulmonary Hypertension Study Group.N Engl J Med. 1996; 334: 296-302Crossref PubMed Scopus (0) Google Scholar27Giaid A Yanagisawa M Langleben D et al.Expression of endothelin-1 in the lungs of patients with pulmonary hypertension.N Engl J Med. 1993; 328: 1732-1739Crossref PubMed Scopus (1652) Google Scholar It is reassuring in this age of evidence-based medicine that many of these novel therapeutic agents have been rigorously evaluated in the first-ever RCTs to be performed in PAH, all of which have been published over the past 6 years. A nonplacebo-controlled RCT showed that continuous IV prostacyclin was an important, if complicated, and adverse effect-prone means of improving survival in severely ill patients with PAH.26Barst RJ Rubin LJ Long WA et al.A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension: The Primary Pulmonary Hypertension Study Group.N Engl J Med. 1996; 334: 296-302Crossref PubMed Scopus (0) Google Scholar More recently, placebo-controlled RCTs of an oral endothelin receptor antagonist (bosentan), and of prostacyclin analogues in aerosolized (iloprost), subcutaneous (treprostinil), and oral (beraprost) forms have been reported.28Channick 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.Lancet. 2001; 358: 1119-1123Abstract Full Text Full Text PDF PubMed Scopus (1401) Google Scholar29Rubin LJ Badesch DB Barst RJ et al.Bosentan therapy for pulmonary arterial hypertension.N Engl J Med. 2002; 346: 896-903Crossref PubMed Scopus (2437) Google Scholar30Olschewski H Simonneau G Galie N et al.Inhaled iloprost for severe pulmonary hypertension.N Engl J Med. 2002; 347: 322-329Crossref PubMed Scopus (1498) Google Scholar31Simonneau G Barst RJ Galie N et al.Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertension: a double-blind, randomized, placebo-controlled trial.Am J Respir Crit Care Med. 2002; 165: 800-804Crossref PubMed Scopus (1221) Google Scholar32Galie N Humbert M Vachiery JL et al.Effects of beraprost sodium, an oral prostacyclin analogue, in patients with pul-monary arterial hypertension: a randomized, double-blind, placebo-controlled trial.J Am Coll Cardiol. 2002; 39: 1496-1502Abstract Full Text Full Text PDF PubMed Scopus (603) Google Scholar These trials have contributed to the wealth of therapeutic options currently available for patients with PAH. The trial by Stiebellehner et al is also important as it reflects the future of PAH therapy—concomitant treatment with two or more agents addressing different pathobiological pathways. Although the formal concept of combination therapy is relatively new in PAH treatment, it is noteworthy that all of the recent RCTs of IV prostacyclin, inhaled iloprost, oral beraprost, and oral bosentan enrolled many patients on stable, concomitant therapy for PAH, including CCBs in 22 to 69% and systemic anticoagulation in up to 73%. More formal combination therapy trials are currently being planned or carried out. These include combinations of bosentan and prostacyclin, as well as the addition of sildenafil to ongoing IV prostacyclin therapy. This is an exciting time for patients with PAH and their physicians. Careful clinical observations and uncontrolled trials, such as the study by Stiebellehner et al, continue to be important in suggesting new therapeutic avenues. However, it is on the strong foundation of basic biological research and well-designed RCTs that we will continue to improve the functional capacity, quality of life, and survival of patients with PAH, and that we may eventually find a cure for PAH.