| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Guest Access | Sign In via User Name/Password
|
|
|
|||||||
Guest Access | Sign In via User Name/Password |
|||||||||
London, ON, Canada
Dr. Mehta is Associate Professor of Medicine, Vascular Biology Group, Lawson Health Research Institute, London Health Sciences Centre, University of Western Ontario. Dr. Mehta has received consulting and speaking fees (Glaxo-Burroughs-Wellcome, Actelion Pharmaceuticals), and clinical investigator fees (Actelion, Pfizer, Encysive) from firms that own, market, and distribute pharmaceutical agents for PAH.
Correspondence to: Sanjay Mehta, MD, FCCP, Division of Respirology, London Health Sciences Center, Victoria South St Campus, 375 South St, London, ON, Canada, N6A 4G5; e-mail: sanjay.mehta{at}lhsc.on.ca
Pulmonary arterial hypertension (PAH) is a clinical hemodynamic syndrome characterized by elevation of pulmonary artery pressure (PAP) and pulmonary vascular resistance in the absence of left-sided heart disease, lung disease, or pulmonary thromboembolic disease.1 2 PAH can be idiopathic (primary pulmonary hypertension [PPH]) or familial, and can arise in association with connective tissue diseases (CTDs), infection with the HIV, portal hypertension, and congenital heart disease (CHD).
Patients with PAH have dyspnea, a progressive limitation of exertion tolerance, and an impairment of right ventricular (RV) function, frequently culminating in RV failure and death within 2 to 3 years. Until recently, there were few therapeutic options for patients with PAH. However, ongoing basic and clinical research has led to tremendous advances in our understanding of the pathobiology of PAH. Moreover, an increasing number of novel therapeutic agents that target these pathobiological features are being studied in randomized clinical trials (RCTs).
Over the past few years, many new therapeutic choices have been added to the menu for clinical use in patients with PAH. But how does one choose between them? What are the relative benefits and risks of each? Which patients with PAH are likely to benefit? What are the costs? The decision to initiate therapy in a patient with PAH depends on objective assessment of the severity of PAH, characterization of pulmonary circulation hemodynamics, and knowledge of some basic concepts of PAH pathobiology.
The pathobiology of PAH is complex.3 Until recently, PAH was presumed due mainly to pulmonary vasoconstriction. Thus, early therapies consisted largely of vasodilators. It has become clear that pulmonary vascular remodeling, eg, proliferation of endothelial and smooth-muscle cells, inflammation, matrix alterations, and thrombosis, is often more important than vasoconstriction in PAH. Progress in our understanding of the pathobiology of PAH has been paralleled by an evolution in our therapeutic choices.
In some patients, PAH arises largely because of pulmonary vasoconstriction. These patients can be identified by assessing acute vasoreactivity to agents such as IV prostacyclin or inhaled nitric oxide. Twenty to 25% of patients with PPH typically demonstrate acute vasodilator responsiveness,4 5 6 although Sitbon et al7 have recently suggested that vasodilator responsiveness may be less frequent.
In patients with PAH and acute vasodilator responses, initial therapy with oral vasodilators is indicated. Only calcium-channel blockers (CCBs) have demonstrated long-term benefit. In a landmark study, Rich et al4 administered high-dose CCBs to 17 patients with PPH and acute vasodilator responses, and demonstrated improved 5-year survival (> 90%) vs an untreated cohort of nonvasodilator responders and a historical cohort. Based on the dramatic survival benefit in this nonrandomized cohort trial, and a wealth of clinical experience with these agents, high-dose CCBs are accepted as first-line effective, oral therapy in PAH. However, CCBs have never been assessed in an RCT, and a meta-analysis8 proved difficult because of a lack of published data. Moreover, many patients with PAH simply cannot tolerate high-dose CCB therapy, eg, 540 to 960 mg/d of diltiazem or 20 to 30 mg/d of amlodipine, because of side effects of hypotension and edema. Indeed, perhaps half of patients with PAH and acute vasodilator responsiveness demonstrate long-term hemodynamic and clinical responses to CCB.7
In the vast majority of patients with PAH, acute administration of a vasodilator does not result in a significant fall in PAP.1 4 5 6 Thus, addressing pulmonary vasoconstriction alone is not an effective, long-term therapeutic strategy. Pulmonary vascular wall remodeling is largely responsible for the vasodilator-unresponsive component of PAH. There is an increasing number of therapeutic agents for PAH that may target pulmonary vascular remodeling and other pathobiological features of PAH. For example, microvascular thrombosis is recognized in pathologic specimens in more than half of patients with PPH,9 and is consistent with evidence of enhanced coagulation and impaired fibrinolysis in blood studies.10 11 A retrospective review12 and a nonrandomized, prospective cohort study4 have both demonstrated a survival benefit of systemic anticoagulation in PPH. Although never studied in an RCT, systemic anticoagulation is recommended for the majority of patients with PAH, in the absence of a clear contraindication based on assessment of individual bleeding risk. Although low-level (international normalized ratio [INR], 1.5 to 2.0) anticoagulation has been suggested as being safer and equally effective as full anticoagulation (INR, 2.0 to 3.0), this issue has not been studied.
Several novel therapeutic agents have been rigorously evaluated in the first-ever RCTs performed in PAH.13 14 15 16 17 18 19 Three agents, IV prostacyclin, subcutaneous treprostinil (prostacyclin analog), and oral bosentan (dual endothelin A/B-receptor antagonist), have been approved for clinical use in many parts of the world. To make an informed choice from this rich menu of novel therapeutic choices for our patients with PAH, we need to consider the details and limitations of the trials, as well as the relative risks and benefits of these agents (Table 1 ).
|
Prostacyclin, treprostinil, and bosentan all resulted in improvements in one or more clinically relevant end points. Functional capacity (6MWT) improved to varying degrees with all three agents. Improved functional capacity was generally associated with improvements in WHO functional class, as well as hemodynamic benefit, as characterized principally by an increase in cardiac index (CI), but also by small reductions in PAP. Several studies have also reported improvements in dyspnea scores and objective measures of quality of life.
Are these novel therapies for PAH associated with improvements in RV function and long-term prognosis? IV prostacyclin therapy improved RV function after 12 weeks, evidenced by a decrease in RV size, reduced RV systolic pressure (surrogate for systolic PAP), and less abnormal septal motion echocardiographically.20 Similar cardiac benefits have been observed in bosentan-treated patients with PAH.21 In addition, IV prostacyclin delays, sometimes indefinitely, the need for lung transplantation.22 Similarly, bosentan therapy has been associated with a stabilization of PAH over 12 to 16 weeks, as reflected by reduced rates of clinical worsening (eg, requirement for hospitalization, transplantation, or additional therapies such as IV prostacyclin).15 16
Given the short duration of these trials (Table 1) , survival has generally not been addressed. Barst et al13 did show that IV prostacyclin was associated with a significant survival benefit, with no mortality at 12 weeks vs 20% in the control group. Two groups23 24 have recently reported long-term survival during IV prostacyclin therapy. In 162 WHO class III/IV patients with PPH treated with IV prostacyclin for a mean of 3 years, McLaughlin et al23 showed improved survival of 88%, 76%, and 63% at 1, 2, and 3 years, respectively, vs predicted survival of 59%, 46%, and 35% based on hemodynamic severity, using an equation derived from the National Institutes of Health database.25 26 Sitbon et al24 reported nearly identical survival of 85%, 70%, and 63% at 1, 2, and 3 years, respectively, in 178 IV prostacyclin-treated patients with PPH.
A survival benefit of IV prostacyclin has thus far only been demonstrated in patients with PPH, not in other PAH patients, such as CTD PAH.14 27 28 Preliminary data also suggest a possible long-term survival benefit of oral bosentan therapy.29 In patients with PPH initially enrolled in the two RCTs (Table 1) and continued on open-label bosentan, intention-to-treat survival at 1, 2, and 3 years was 96%, 89%, and 86%, respectively (vs 69%, 57%, and 48% predicted). However, an independent survival effect of bosentan needs to be confirmed, as 15% of patients failed annually, requiring addition of other therapies, eg, IV prostacyclin or subcutaneous treprostinil.
What are the adverse effects of these novel treatment options? Prostacyclin and its derivatives (eg, treprostinil) are associated with frequent side effects, such as diarrhea and systemic vasodilation-related flushing, headaches, jaw pain, and hypotension.13 18 As well, there are important complications of the delivery systems, including risks of line sepsis and rebound PAH from accidental interruption of IV prostacyclin, and skin rash/pain in > 80% of treprostinil-treated patients. The major adverse effect of bosentan is 10 to 15% incidence of liver injury, reflected by elevated levels of aspartate transaminase/alanine transaminase, usually spontaneously reversible.15 16
What about the relative costs of these novel therapies? The article by Highland et al in the current issue of CHEST (see page 2087) uses decision analysis to model benefit vs cost for prostacyclin, bosentan, and treprostinil. Based on the relative benefit in 6MWT, the authors suggest that bosentan is more cost-effective and has a greater impact on quality of life than either epoprostenol or treprostinil. As the authors recognize, such an analysis is limited by the number of assumptions required, the availability of published data, and the lack of consideration of side effects.
There are many other novel therapeutic agents for PAH under development and in RCTs. These include prostacyclin analogues delivered orally (beraprost) or via inhalation (iloprost), new endothelin-receptor antagonists (sitaxsentan), and phosphodiesterase inhibitors (sildenafil). Moreover, combination therapy with two or more agents targeting different pathobiological pathways is already being studied, and is likely to be a more common clinical approach in the future. As well, current and future trials will need to assess a greater spectrum of clinically relevant end points, including not only functional capacity and hemodynamics, but also quality of life. Although the menu of therapeutic choices for patients with PAH has already become more interesting over the past few years, continued basic biological research and well-designed RCTs will ensure that patients and their physicians have a greater number of even more effective, therapeutic choices on the menu.
References
This article has been cited by other articles:
|
|
 |
|
  S Mehta and G J Shoemaker Improving survival in idiopathic pulmonary arterial hypertension: revisiting the "kingdom of the near-dead" Thorax, December 1, 2005; 60(12): 981 - 983. [Full Text] [PDF]
|
|
|
|
 |
|
 J. Shen, B. He, and B. Wang Effects of Lipo-Prostaglandin E1 on Pulmonary Hemodynamics and Clinical Outcomes in Patients With Pulmonary Arterial Hypertension Chest, August 1, 2005; 128(2): 714 - 719. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. M. Lowson Alternatives to nitric oxide Br. Med. Bull., November 5, 2004; 70(1): 119 - 131. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Confalonieri, V. Antonaglia, U. Lucangelo, A. Gullo, M. Humbert, and G. Simonneau Sildenafil in Pulmonary Arterial Hypertension Am. J. Respir. Crit. Care Med., June 1, 2004; 169(11): 1256 - 1257. [Full Text]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
