Review
`
`For reprint orders, please contact reprints@future-drugs.com
`
`Medical therapeutics for
`pulmonary arterial hypertension:
`from basic science and clinical trial
`design to evidence-based medicine
`Roxana Sulica and Michael Poon†
`Pulmonary arterial hypertension is a severe disease with poor prognosis, caused by
`obliteration of the pulmonary vasculature as a result of pulmonary-vascular remodeling,
`active vasoconstriction and in situ thrombosis. Left untreated, pulmonary arterial
`hypertension results in right-ventricular failure and death. There has been dramatic
`progress in the treatment of pulmonary arterial hypertension during recent years. A
`remarkable number of randomized-controlled trials with agents known to target specific
`abnormalities present in pulmonary arterial hypertension have been completed. Most
`commonly, therapeutic efficacy was judged by the ability of the drug under study to
`improve exercise capacity and to decrease the rate of severe complications. Completed
`clinical trials have mainly evaluated patients with relatively advanced disease. Despite
`these advances, responses to therapy in pulmonary arterial hypertension are not uniformly
`favorable and frequently incomplete. In addition, the methods of delivery and the adverse
`effect profile of the currently available pulmonary arterial hypertension-specific drugs
`create further management difficulties. Based on newly identified pathobiologic
`abnormalities in the pulmonary vasculature, future studies are likely to focus on the
`discovery of new therapeutic targets. Clinical trial design will continue to evolve in an
`attempt to enable inclusion of patients with less advanced disease and evaluation of
`treatment combinations or comparisons of the currently approved drugs.
`
`Expert Rev. Cardiovasc. Ther. 3(2), 347–360 (2005)
`
`Definition & classification
`(PAH)
`Pulmonary
`arterial hypertension
`encompasses a heterogeneous group of dis-
`orders characterized by increased pulmonary
`artery pressure (PAP) and pulmonary vascular
`resistance (PVR). PAH classification includes
`idiopathic PAH (IPAH; formerly primary pul-
`monary hypertension), familial PAH, PAH
`associated with collagen vascular disease, con-
`genital systemic-to-pulmonary shunts, portal
`hypertension, HIV infection, drug and toxins,
`and other conditions (thyroid disorders, gly-
`cogen storage disease, Gaucher disease, here-
`ditary hemorrhagic telangiectasia, hemoglob-
`inopathies, myeloproliferative disorders and
`splenectomy), PAH associated with significant
`venous or capillary involvement and persistent
`pulmonary hypertension of the newborn [1].
`
`Without intervention, PAH has a progressive
`course and poor prognosis. Estimated median
`survival of untreated IPAH patients
`is
`2.8 years [2]. Survival is primarily determined
`by the level of the right-ventricular dysfunc-
`tion and the most common cause of death is
`right-ventricular failure. Appropriate therapy
`may alter the natural course of the disease,
`but does not offer a definitive cure. To a cer-
`tain degree, all forms of PAH share patho-
`logic characteristics, clinical presentation,
`diagnostic modalities
`and
`therapeutic
`options. In PAH, the small pulmonary arter-
`ies are occluded by a combination of active
`in situ
`vasoconstriction,
`thrombosis and,
`most importantly, vascular proliferation and
`remodeling. PAH treatment is directed at all
`of these processes (FIGURE 1).
`
`CONTENTS
`Definition & classification
`Conventional treatment
`Specific pulmonary arterial
`hypertension treatment
`Expert opinion
`Five-year view
`Key issues
`References
`Affiliations
`
`†Author for correspondence
`Mount Sinai School of Medicine,
`Director of Cardiology, Cabrini
`Medical Center, New York,
`NY 10003, USA
`Tel.: +1 212 995 6865
`Fax: +1 212 979 3474
`mpoon@cabrininy.org
`
`KEYWORDS:
`ambrisentan, bosentan,
`epoprostenol, exercise capacity,
`hemodynamics, iloprost,
`pulmonary arterial hypertension,
`sildenafil, sitaxsentan, treprostinil
`
`www.future-drugs.com
`
`10.1586/14779072.3.2.347
`
`© 2005 Future Drugs Ltd
`
`ISSN 1477-9072
`
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`Sulica & Poon
`
`In situ thrombosis
`
`Vascular endothelium
`(cid:127) Endothelial dysfunction
`(cid:127) Endothelial proliferation
`
`Prostacyclin replacement:
`epoprostenol, treprostinil,
`iloprost and beraprost
`
`Anticoagulation:
`warfarin
`
`Endothelin receptor
`antagonists: bosentan,
`sitaxsentan and
`ambrisentan
`
`Prostacyclin ↓
`
`Endothelin-1 ↑
`
`Nitric oxide ↓
`
`Nitric oxide replacement
`enhancers or
`donors: sildenafil
`
`Calcium channel blockers
`
`output. This response is present in less
`than 10% of PAH patients, mainly IPAH
`and PAH associated with anorexigen
`use [5]. Initiation of oral calcium channel-
`blocker therapy is restricted to patients
`who manifest acute vasoreactivity and
`requires frequent monitoring to document
`long-term clinical efficacy. Indiscriminate
`use of oral calcium channel blockers in
`patients with PAH is strongly discouraged
`to avoid precipitation of hypotension
`and heart failure with potentially fatal
`consequences.
`
`Oral anticoagulation
`Although no randomized, double-blind,
`placebo-controlled
`trials
`of
`anti-
`coagulation were performed in patients
`with PAH, two retrospective studies and
`one prospective report in patients with
`IPAH and PAH associated with anorexi-
`gen drug use have suggested improved
`outcome in patients receiving long-term
`warfarin therapy [3,6,7]. In the absence of
`contraindications, IPAH patients should
`receive long-term anticoagulant therapy,
`with a goal of keeping the international
`normalized ratio between 1.8 and 2.5.
`Some experts extend this recommen-
`dation to other forms of PAH, although
`this is controversial, particularly in cases
`with an increased risk of bleeding, such as
`PAH patients with scleroderma (erosive
`esophagitis), portopulmonary hyper-
`tension (gastrointestinal bleed) or congenital
`heart disease (hemoptysis).
`
`Vascular smooth muscle cells
`(cid:127) Vasoconstriction
`(cid:127) Proliferation
`(cid:127) Dysfunction of voltage-dependent K +
` channels and Ca++ channels
`
`Figure 1. Treatment of pulmonary arterial hypertension.
`
`Conventional treatment
`Oral calcium channel blockers
`Active vasoconstriction is detectable at right-heart catheterization
`during acute vasoreactivity testing. Patients who manifest acute
`vasoreactivity may have a good long-term response to oral cal-
`cium channel-blocker therapy [3]. Therefore, testing for acute
`vasoreactivity is recommended during initial evaluation in all
`patients with PAH [4]. During right heart catheterization,
`patients are administered short acting vasodilators such as
`inhaled nitric oxide (NO), intravenous epoprostenol or intra-
`venous adenosine. Acute vasoreactivity is present if, after vaso-
`dilator challenge, the mean PAP decreases by at least 10 mmHg
`and to less than 40 mmHg, with preserved or increased cardiac
`
`Specific pulmonary arterial
`hypertension treatment
`Basic pathogenesis of pulmonary
`arterial hypertension
`Vascular wall remodeling and proliferation
`are the hallmarks of pulmonary arterial obstruction in PAH [8].
`Central to the pathogenesis of vascular remodeling is the dys-
`function of the pulmonary vascular endothelium with an
`imbalance between endothelial mediators with opposing
`actions on the pulmonary vasculature [9–13]. There is an over-
`expression and/or activation of vasoconstricting, mitogenic and
`prothrombotic factors (endothelin [ET]-1, thromboxane and
`serotonin), while prostacyclin, NO and heparin-like sub-
`stances, which promote vasodilatation and have antiprolifera-
`tive and antithrombotic properties, are decreased. Specific PAH
`treatment entails either replacing deficient vasodilator factors or
`inhibiting mediators that induce vasoconstriction and vascular
`proliferation (FIGURE 1).
`
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`Pulmonary arterial hypertension
`
`Specific pulmonary arterial hypertension therapeutic agents
`Recent developments in the management of PAH focus on the
`introduction of new drugs with different intracellular mecha-
`nisms of action and the use of alternative routes of administra-
`tion. In the USA, the agents approved by the US Food and
`Drug Administration (FDA) for the specific treatment of PAH
`are continuous intravenous epoprostenol (prostacyclin and
`subcutaneous
`treprostinil
`I2), continuous
`prostaglandin
`(prostacyclin analog) and oral bosentan (ET receptor antago-
`nist). Agents approved by the European Agency for the Evalua-
`tion of Medicinal Products are intravenous epoprostenol, oral
`bosentan and inhaled iloprost (prostacyclin analog). Other oral
`drugs recently investigated or currently studied in clinical trials
`include beraprost, sildenafil, sitaxsentan and ambrisentan.
`
`Expert opinion
`Evidence-based management
`During the past 5 years, more than 2500 patients with PAH
`have been studied in a randomized, controlled fashion in more
`than ten completed major clinical trials. At least nine more
`randomized, controlled trials are planned or ongoing. TABLES 1–4
`summarize the findings of the major clinical trials
`in
`PAH [14–36]. Sildenafil, a phosphodiesterase-5 inhibitor with
`pulmonary vasodilatory action, has also been evaluated in a
`3-month double blind, placebo-controlled, multicenter, rand-
`omized trial in patients with PAH (63% IPAH, 30% PAH
`associated with connective tissue disease and 6% PAH associ-
`ated with surgically corrected congenital heart disease) [37]. This
`trial included 278 patients with PAH in World Health Organi-
`zation (WHO) functional Classes II to IV (39% Class II, 58%
`Class III and 3% Class IV) and evaluated three sildenafil doses
`(20, 40 and 80 mg three-times daily). The primary end point
`was the change from baseline in the 6-min walk test (6MWT)
`distance. There was a significant improvement in the exercise
`capacity as measured by the 6MWT, in hemodynamics and in
`WHO class for all three doses studied [37].
`
`Multiple new findings in PAH pathobiology, genetics,
`diagnosis and therapy were assessed during the Third World
`Symposium on Pulmonary Arterial Hypertension (Venice,
`2003) and proceedings of this meeting were published in a sup-
`plement
`to
`the Journal of
`the American College of
`Cardiology [38]. In addition, the American College of Chest
`Physicians has recently published evidence-based guidelines for
`PAH diagnosis and management [39]. Therapeutic choices in
`PAH depend on the etiopathogenic particularities of the disease
`and the severity of the functional impairment (FIGURE 2). A new
`treatment algorithm has been devised based on data from pub-
`lished randomized, controlled trials (FIGURE 3). This algorithm is
`mainly restricted to patients in WHO functional Classes III
`and IV and patients with IPAH and PAH due to the sclero-
`derma spectrum of disease, who represented the majority of
`studied patients. Extrapolation of current recommendations to
`other PAH patient populations requires caution.
`In the face of substantial achievements in the therapeutic
`armamentarium, PAH remains a disease with particularly
`poor prognosis, even among treated patients. Untreated
`IPAH patients from the National Institutes of Health regis-
`try had 1-, 3- and 5-year survival rates of 68, 48 and 34%,
`respectively [2]. Intravenous epoprostenol is the only PAH-
`specific therapy that has been shown to improve survival in a
`3-month, randomized, controlled trial in IPAH [15], while
`newer drugs have been shown to reduce clinical deterio-
`ration during the same time interval [29–31]. IPAH is more
`responsive to treatment compared with other forms of PAH
`[21,31,34] and intravenous epoprostenol is still considered the
`most efficacious therapy available. Retrospective studies of
`IPAH patients treated with
`intravenous epoprostenol,
`demonstrated improved long-term outcome with 1-, 3- and
`5-year survival rates of 85, 63 and 55%, respectively [19,20].
`Response to available therapy is not universally favorable
`and there is no cure for PAH. Therefore, there is a continual
`need for discovery of novel therapeutic strategies.
`
`Table 1. Major randomized controlled clinical trials with intravenous epoprostenol in patients with PAH.
`Control* Primary
`Treatment effect
`Trial
`n PAH WHO
`Route Duration
`Dose of
`end point
`class
`(months)
`active drug
`(%)
`achieved
`(ng/kg/min)
`
`II
`
`III
`
`IV
`
`Rubin
`(1990)
`
`Barst
`(1996)
`
`Badesch
`(2000)
`
`24 IPAH 9 65 26 Iv.
`
`81 IPAH
`
`75 25 Iv.
`
`111 SPAH 5 78 17 Iv.
`
`2
`
`3
`
`3
`
`N/A
`
`9.2
`
`11.2
`
`Conv.
`therapy
`
`Conv.
`therapy
`
`Conv.
`therapy
`
`H/dyn
`
`H/dyn
`
`6MWT
`
`6MWT
`(m)
`+45
`(mean)
`
`+47
`(mean)
`
`+94
`(median)
`
`H/dyn WHO
`class
`Better N/A
`
`Symptoms QOL
`
`Survival
`
`Better
`
`N/A
`
`No
`change
`
`Better Better Better
`
`Better Better
`
`Better Better Better
`
`N/A
`
`No
`Change
`
`Ref.
`
`[14]
`
`[15]
`
`[16]
`
`*None of these studies were placebo-controlled for ethical reasons; patients in the active group received intravenous epoprostenol in addition to conventional therapy, while the control
`group was represented by patients receiving conventional therapy alone.
`6MWT: 6-min walk test; Conv.: Conventional; H/dyn: Hemodynamics; IPAH: Idiopathic pulmonary arterial hypertension; Iv.: Intravenous; N/A: Not applicable; PAH: Pulmonary arterial
`hypertension; QOL: Quality of life; SPAH: Scleroderma pulmonary arterial hypertension; WHO: World Health Organization.
`
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`Sulica & Poon
`
`Table 2. Other clinical trials with intravenous epoprostenol in patients with PAH.
`Trial
`Findings
`Comments
`Barst 1994
`Effect on survival
`Improved long-term survival in IPAH patients treated with epoprostenol compared
`Shapiro 1997
`with historic controls
`
`Retrospective
`reviews:
`McLaughlin (2002)
`Sitbon (2002)
`Kuhn (2003)
`
`McLaughlin (1998)
`
`Long-term outcome (3–5-year
`follow-up) and predictors of
`response to therapy
`
`Baseline hemodynamics and right-ventricular function predict response to therapy.
`Patients who improve at 3–12-month follow-up have better long-term prognosis.
`Patients with scleroderma PAH have worse long-term prognosis, even if treated
`with intravenous epoprostenol. Treated patients had better survival compared with
`historic controls or to expected survival derived from the NIH equation
`
`Insights into mechanism
`of action
`
`With epoprostenol, long-term decrease in PVR is more pronounced
`compared with the acute response, suggesting an effect on pulmonary
`vascular remodeling
`
`Rich 1999
`
`Dose adjustment
`
`Intravenous epoprostenol rate should be adjusted to avoid deleterious
`hyperdynamic cardiovascular effects
`
`Ref.
`[17,18]
`
`[19–21]
`
`[22]
`
`[23]
`
`Use of intravenous
`epoprostenol in other forms
`of PAH
`
`Hemodynamic and symptomatic improvement with intravenous epoprostenol in
`patients with other forms of PAH
`
`[24–28]
`
`Case series:
`McLaughlin 1999
`Robbins 2000
`Horn 2000
`Krowka 1999
`Rosenzweig 1999
`
`IPAH: Idiopathic pulmonary hypertension; NIH: National Institutes of Health; PAH: Pulmonary arterial hypertension; PVR: Pulmonary vascular resistance.
`
`Alternative approaches to therapy with currently
`available drugs
`Several therapeutic strategies aimed at improving the control of
`the disease or the risk–benefit ratio of the treatment were
`employed in small clinical trials and retrospective series.
`
`Combination therapy
`Since multiple and complex pathogenetic mechanisms are
`implicated in the development and progression of pulmonary
`hypertension, various combinations of drugs with already
`proven benefit may represent alternative therapeutic strategies
`in PAH. Prostacyclins, ET receptor antagonists and drugs act-
`ing through a NO-dependent pathway (such as sildenafil, a
`phosphodiesterase inhibitor) have different intracellular signal
`transduction pathways with potential synergistic effect. A
`small multicenter clinical trial on the combined use of epo-
`prostenol and bosentan, initiated simultaneously, suggested
`that bosentan may provide a small additional hemodynamic
`benefit to severe PAH patients who require epoprostenol treat-
`ment [40]. In retrospective studies of patients on chronic epo-
`prostenol or treprostinil, the addition of bosentan was safe and
`increased vasodilatory efficacy, which allowed for prostacyclin
`dose reduction or even discontinuation [41–43]. Small series
`have demonstrated acute and chronic benefit from combined
`use of various prostacyclins (intravenous epoprostenol, subcu-
`taneous
`treprostinil
`and
`inhaled
`iloprost)
`and oral
`sildenafil [44–47]. A multicenter trial investigating the effect of
`combined oral sildenafil and intravenous epoprostenol is cur-
`rently ongoing. The possibility of unexpected interactions
`between these drugs and the absence of efficacy and safety data
`in large clinical trials preclude recommendation of routine use
`of combination PAH therapy.
`
`Transition from intravenous epoprostenol to oral bosentan or
`subcutaneous treprostinil
`Continuous intravenous epoprostenol administration, although
`known to improve exercise capacity, symptoms, hemodynamics
`and right-ventricular function in severe PAH and to offer survival
`benefit in IPAH patients, requires a complicated delivery system.
`It may be associated with potentially life-threatening side effects,
`such as line-related sepsis and thrombosis or rebound pulmonary
`hypertension and acute right heart failure from inadvertent dis-
`continuation. Newer PAH drugs have also been shown to have
`beneficial effects on exercise capacity, symptoms, hemodynamics
`and clinical events in patients with severe PAH. Small published
`series from centers with extensive experience in PAH manage-
`ment have demonstrated the feasibility and safety of transition-
`ing selected patients from intravenous epoprostenol to other
`therapeutic alternatives, such as subcutaneous treprostinil and
`oral bosentan [43,48,49]. In addition, a current multicenter trial is
`evaluating the safety of transitioning PAH patients from intra-
`venous epoprostenol to subcutaneous treprostinil. At the
`present time, however, the authors caution against indiscrimi-
`nate discontinuation and substitution of intravenous epopros-
`tenol with other available drugs. There is no guarantee that, in
`the case of clinical deterioration, reinstitution of previous ther-
`apy will reverse disease progression, which may have fatal con-
`sequences. Larger clinical investigations are warranted to estab-
`lish enrollment criteria and transitioning methods to assure
`both the efficacy and safety of such an approach.
`
`Use of alternative methods of delivery
`The main difficulty with subcutaneous treprostinil therapy
`is the development of pain and reactions at the infusion
`site [29]. To avoid this side effect of treprostinil, intravenous
`
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`Pulmonary arterial hypertension
`
`PAH diagnosis
`Suggested/suspected/screening*
`
`Diagnosis confirmation and
`determination of severity
`(cid:127) Right heart catheterization ‡
`(cid:127) Vasoreactivity testing
`
`Determination of the
`diagnostic class§
`(cid:127) Echocardiography
`(cid:127) Electrocardiography
`(cid:127) Pulmonary function test
`(cid:127) HIV test
`(cid:127) Ventilation–perfusion scan
`(cid:127) Chest imaging tests
`(cid:127) Connective tissue-disease
` screening
`(cid:127) Pulmonary angiogram
`(cid:127) Cardiac MRI
`
`Evaluation of the
`functional impairment¶
`(cid:127) WHO class
`(cid:127) Echocardiography
`(cid:127) Right-heart
` catheterization
`(cid:127) 6 min walk test
`(cid:127) Cardiopulmonary
` exercise test
`(cid:127) Cardiac MRI
`
`Treatment
`
`Follow-up
`Transplant referral
`
`and inhalatory routes of administration
`were recently investigated. Treprostinil has
`a longer half-life compared with epo-
`prostenol, which decreases the risk of
`rebound pulmonary hypertension and
`right heart failure in the case of abrupt dis-
`continuation. In comparison to intrave-
`nous epoprostenol, intravenous trepros-
`tinil administration alleviates the need for
`a large infusion pump, drug reconstitution
`and the use of ice packs. Continuous
`intravenous treprostinil administration has
`been evaluated for safety and efficacy in a
`multicenter trial, both as transition from
`intravenous epoprostenol and as de novo
`therapy [50]. Intravenous treprostinil was
`associated with an improvement in exer-
`cise performance and hemodynamics,
`with added advantages of safety and con-
`venience [50]. It has recently received FDA
`approval for this route of administration.
`In a recent report from Germany,
`inhaled treprostinil demonstrated sub-
`stantial pulmonary vasodilatory efficacy
`in acute administration, as well as symp-
`tomatic and
`functional benefit
`in
`chronic use in a small number of PAH
`patients [51].
`
`Head-to-head comparisons between
`currently available drugs
`With the advent of multiple therapeutic
`options for PAH patients, questions of
`relative efficacy, safety and therapy of
`choice are likely to arise. Head-to-head
`comparison trials are the most meaning-
`ful and accurate method of detecting effi-
`cacy and safety differences among various
`PAH treatments with already proven benefit. Experimental
`data from tissue culture and animal studies are not necessarily
`predictive of human response, and data from individual clini-
`cal trials cannot be directly compared. An example is repre-
`sented by ET receptor antagonists. There are two types of ET
`receptors: ETA receptors, located in the vascular smooth mus-
`cle cells, and ETB receptors, found on both endothelial (ETB1
`subtype) and smooth muscle cells (ETB2 subtype) [52]. ET
`binding to receptors located on the vascular smooth muscle
`cell (ETA and ETB2) induces vasoconstriction and smooth
`muscle-cell proliferation [53,54]. The relative contribution of
`ETA and ETB2 receptors to the ET-mediated vasoconstriction
`depends on the species, experimental conditions and vascular
`bed studied. ETB1 receptors mediate vasodilatation and are
`responsible for ET clearance from the circulation [55]. Three
`ET receptor antagonists were recently evaluated in PAH trials:
`bosentan, a mixed ETA/ETB receptor antagonist already
`
`Figure 2. PAH management. Investigations used to characterize the disease process.
`*Strongly consider early referral to specialized centers.
`‡Right heart catheterization is required to confirm the diagnosis of PAH. Vasoreactivity testing by
`inexperienced operators may place patients at unduly increased risk.
`§Type and extent of work-up varies on individual basis, but all patients with suspected PAH diagnosis
`should undergo a battery of essential tests, which include echocardiography, chest radiography,
`ventilation-perfusion scan, HIV testing and screening for connective tissue disease, and pulmonary
`function test with oximetry.
`¶Prior to institution of therapy, it is essential to evaluate functional parameters with prognostic
`significance, such as exercise capacity and right-ventricular function.
`MRI: Magnetic resonance imaging; PAH: Pulmonary arterial hypertension; WHO: World
`Health Organization.
`
`approved for clinical use, and the selective ETA receptor
`antagonists, sitaxsentan and ambrisentan. Theoretically, selec-
`tive blockade of the ETA receptors may be more advantageous
`compared with nonselective ETA/ETB antagonism, by preser-
`ving ETB1-mediated vasodilatation and ET clearance. How-
`ever, in isolated pulmonary arteries and in animal models,
`combined ETA/ETB receptor blockade was superior to selec-
`tive ETA antagonism in reducing vasoconstriction and in
`improving right-ventricular hypertrophy and animal survival,
`respectively [56,57]. In randomized clinical trials in patients
`with PAH, all three ET receptor antagonists improved exer-
`cise capacity, hemodynamics, symptoms and WHO func-
`tional class [33–36]. It is impossible to accurately compare their
`relative efficacy on the basis of the available trials, because the
`PAH patient populations and trial designs were different.
`However, conducting large-scale head-to-head comparison
`studies would require more refined methodology and increased
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`Sulica & Poon
`
`Table 3. Major clinical trials with newer prostanoids.
`Trial
`Drug/
`n
`PAH (%)
`WHO class (%)
`route
`active/placebo
`active/placebo
`
`Duration
`(months)
`
`Control
`
`Primary
`end point
`
`Dose
`
`Simmoneau
`(2002)
`
`SQ
`treprostinil
`
`Olschewski
`(2002)
`AIR
`
`Inhaled
`iloprost
`
`Galie
`(2002)
`ALPHABET
`
`Oral
`beraprost
`
`470 IPAH: 58/58
`CTDz: 17/21
`CHDz: 25/22
`
`203 IPAH: 50.5/50
`CTDz: 12.9/21.6
`Anorex.: 4/4.9
`CTEPH: 32.7/23.5
`
`130 IPAH: 53.9/43.1
`CTDz: 7.7/12.3
`CHDz: 13.8/23/1
`Portal HTN: 18.5/13.8
`HIV: 6.2/7.7
`
`Barst
`(2003)
`
`Oral
`beraprost
`
`116 IPAH: 78/70
`CTDz: 10/11
`CHDz: 12/20
`
`II
`
`III
`
`IV
`
`11/12
`
`82/81
`
`8/7
`
`3
`
`Placebo
`
`6MWT
`
`9.3 ng/kg/min
`(mean)
`
`59.4/57.8 40.6/42.2 3
`
`Placebo
`
`Combined
`clinical
`end point*
`
`30 µg/day
`(median)
`6–9 inhal./day
`
`47.7/50.8 52.3/49.2
`
`3
`
`Placebo
`
`6MWT
`
`80 µg
`four-times daily
`
`55/50
`
`45/50
`
`12
`
`Placebo
`
`Disease
`progression*
`
`120 µg
`four-times daily
`
`*Combined clinical end point was met if there was an improvement in the WHO class by at least one unit and in the 6MWT distance by at least 10% compared with baseline
`in the absence of clinical deterioration or death.
`‡Disease progression was represented by death, transplantation, epoprostenol rescue or more than 25% decrease in the peak VO2. Beraprost-treated patients exhibited less
`disease progression at 6 months, but no such effect was evident at shorter or longer duration of follow-up. The 6MWT distance improved at 3- and 6-month follow-up, but
`there were no further treatment effects noted at 9- and 12-month intervals.
`§Treatment effect on the 6MWT distance is the difference between active and placebo groups.
`¶Clinical worsening, variously defined in studies, includes clinical events consistent with PAH progression, such as death, (need for) transplantation, hospital admission for
`right heart failure, or need for additional PAH therapy.
`6MWT: 6-min walk test; AIR: Aerosolized Iloprost Randomized study; ALPHABET: ArteriaL Pulmonary Hypertension And BeraprosT; CHDz: Congenital heart disease; CTDz: Connective
`tissue disease; CTEPH: Chronic thromboembolic pulmonary hypertension; H/dyn: Hemodynamics; HTN: Hypertension; QOL: Quality of life; WHO: World Health Organization.
`
`cost. Such a study is expected to involve a longer duration,
`larger number of patients and more elaborate and sensitive end
`points to detect significant differences between groups. With
`the exception of an ongoing trial on the use of sitaxsentan in
`PAH (i.e., Sitaxsentan To Relieve ImpaireD Exercise [STRIDE]
`II), which has a bosentan comparison arm, the authors are not
`aware of any other direct comparison trials being conducted.
`
`Particularities associated with clinical trial design in pulmonary
`arterial hypertension
`Current design of therapeutic trials in PAH is challenged by
`ethical and logistic dilemmas, particularly with respect to the
`study design and the choice of appropriate end points. The
`scientific community and regulatory agencies require perform-
`ance in randomized, controlled trials of investigational PAH
`drugs as definitive proof of efficacy and safety. Ethical difficul-
`ties may arise from enrolling patients in double-blind, pla-
`cebo-controlled, randomized studies in the face of available
`therapeutic options known to improve outcome. Most of the
`recently completed randomized trials were blinded and pla-
`cebo-controlled for 3 to 4 months, followed by open-label or
`blinded, dose-ranging, active treatment extensions for long-
`term data collection. Specific mechanisms to protect patients
`in case of clinical worsening were incorporated, such as
`
`switching to open-label active treatment or using rescue therapy
`with already approved drugs. The relatively short duration of
`the placebo-controlled period, however, may not detect possi-
`ble attenuation of the clinical effect [32], and it may be
`inadequate for trials enrolling patients with less advanced dis-
`ease or evaluating combination therapies.
`The most commonly used primary end point in recent PAH
`clinical trials was the 6MWT distance as a measure of the exer-
`cise capacity. Peak oxygen consumption during formal cardio-
`pulmonary exercise test (CPET), WHO/New York Heart Asso-
`ciation (NYHA) functional class or measures of disease
`progression were also used as primary end points. Resting
`hemodynamics, symptoms (Borg score), general clinical status
`(e.g., dyspnea-fatigue rating), WHO/NYHA class, the time to
`clinical worsening (a composite of death, transplant, hospital
`admission for right heart failure or need for rescue therapy with
`intravenous epoprostenol) and quality of life measures were
`employed as secondary end points. The 6MWT is reliable, easy
`to administer and clinically meaningful, since it correlates with
`prognosis and CPET parameters in IPAH [58,59]. The 6MWT is
`validated for studies in PAH patients with moderate and severe
`disease. However, it may be insensitive in patients with less
`advanced disease and to date it is not validated in patients with
`certain forms of PAH, such as portopulmonary hypertension.
`
`352
`
`Expert Rev. Cardiovasc. Ther. 3(2), (2005)
`
`Liquidia's Exhibit 1104
`Page 6
`
`

`

`Table 3. Major clinical trials with newer prostanoids (cont.).
`Treatment effect
`
`Comments
`
`Ref.
`
`Pulmonary arterial hypertension
`
`6MWT
`(m)
`+16
`(median)
`
`+36.4
`(median)
`
`+25.1
`(mean)
`
`Peak VO2 H/dyn
`
`N/A
`
`Better
`
`Clinical
`worsening
`No effect
`
`Survival Symptoms WHO
`class
`N/A
`
`Better
`
`No
`effect
`
`QOL
`
`Better
`
`N/A
`
`Better
`
`Better
`
`No
`effect
`
`Better
`
`Better
`
`Better
`
`Treatment effect was dependent on
`the baseline 6MWT distance and the
`dose achieved
`
`Absolute change in the mean 6MWT
`distance was larger in the IPAH group
`
`N/A
`
`No effect No effect
`
`No
`effect
`
`Better
`
`No
`change
`
`N/A
`
`Subgroup analysis showed greater
`6MWT improvement in IPAH
`
`+31
`(median)*
`
`Trend to
`increase
`
`No effect Better
`
`No
`effect
`
`No effect
`
`No effect No
`effect
`
`The study was prematurely terminated
`to accelerate data review. Less disease
`progression in the treated group at
`6 months only
`
`[29]
`
`[30]
`
`[31]
`
`[32]
`
`*Combined clinical end point was met if there was an improvement in the WHO class by at least one unit and in the 6MWT distance by at least 10% compared with baseline
`in the absence of clinical deterioration or death.
`‡Disease progression was represented by death, transplantation, epoprostenol rescue or more than 25% decrease in the peak VO2. Beraprost-treated patients exhibited less
`disease progression at 6 months, but no such effect was evident at shorter or longer duration of follow-up. The 6MWT distance improved at 3- and 6-month follow-up, but
`there were no further treatment effects noted at 9- and 12-month intervals.
`§Treatment effect on the 6MWT distance is the difference between active and placebo groups.
`¶Clinical worsening, variously defined in studies, includes clinical events consistent with PAH progression, such as death, (need for) transplantation, hospital admission for
`right heart failure, or need for additional PAH therapy.
`6MWT: 6-min walk test; AIR: Aerosolized Iloprost Randomized study; ALPHABET: ArteriaL Pulmonary Hypertension And BeraprosT; CHDz: Congenital heart disease; CTDz: Connective
`tissue disease; CTEPH: Chronic thromboembolic pulmonary hypertension; H/dyn: Hemodynamics; HTN: Hypertension; QOL: Quality of life; WHO: World Health Organization.
`
`Compared with the 6MWT, CPET parameters may provide
`more objective and detailed evaluation of the functional
`capacity and the state of the pulmonary circulation in
`PAH [60–62]. In one trial with beraprost and another with
`sitaxsentan, the 6MWT distance and peak oxygen consump-
`tion were used in parallel as study end points [32,35].
`Although a treatment effect was detected by improvement in
`the 6MWT distance, there were no consistent significant
`changes in peak oxygen consumption. Such a difference in
`findings is most likely due to variable interpretation of the
`CPET results at different centers, unpredictable degree of
`technical skill and failure to weight-adjust the 6MWT dis-
`tance [63]. Use of follow-up right heart catheterization to
`document the treatment effect, although objective and accu-
`rate, may impact on the safety of study participants and
`increase the cost of investigation. Time to clinical worsening
`as a measure of severe complications has been a useful clini-
`cal end point in trials evaluating patients in WHO/NYHA
`Classes III and IV. It may be less sensitive in combination
`and direct comparison trials and even unethical in patients
`with less advanced disease. WHO/NYHA classification corre-
`lates well with disease severity and prognosis in IPAH, but it is
`a self-reported measure, subjected to interpersonal variability
`and observer bias. The impact of therapy on quality of life
`
`measures is an important end point from the perspective of
`both