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`
`
`Review
`
`
`
`Medical therapeutics for
`pulmonary arterial hypertension:
`from basic science and clinical trial
`
`design to evidence-based medicine
`
`Roxana Sufica and-Michael Peon?
`
`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-controtled trials with agents known to target specific
`abnormalities present in pulmonary arterial hypertension have been completed. Most
`commonly, therapeutic efficacy wasjudged by the ability of the drug under study to
`improve exercise capacity and to decrease the rate or 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 thera peutictargets. 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.
`
`ExperrReM Cardiovasr. 77mm 3(2), 347—360 [2005)
`
`Definition it classification
`arterial
`
`(PAH)
`Pulmonary
`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 (IPAl—l; formerly primary pule
`monary hypertension),
`familial PAH, PAH
`associated with collagen vascular disease, cone
`'genital systemic-to—pulmonary shunts, portal
`hypertension, HIV infection, drug and toxins,
`and other conditions (thyroid disorders. giye
`cogen storage disease, Gaucher disease, here-
`ditary hemorrhagic telangiectasia. hemoglob—
`inopathies, myeloproliferative disorders and
`splenectomy), PAH associated with significant
`venous or capiilary 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 [2L Survival is primarily determined
`by the levei of the right—ventricular dysfunc—
`tion and the most common cause of death is
`
`righteventricular 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 pathoV
`logic
`characteristics,
`clinical presentation,
`diagnostic modalities
`and
`therapeutic
`options. In PAH, the small pulmonary artere
`ies are occluded by a combination of active
`vasoconstriction,
`1'1”er
`thrombosis
`and.
`
`most importantly, vascular proliferation and
`remodeling. PAH treatment is directed at all
`of these processes (FIGURE 1).
`
`10.686114779072323“
`
`© 2005 Future Drugs Ltd
`
`ISSN unsure
`
`34']
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`

`Sulica & Poon
`
`
`
`
`
`output. This response is present in less
`than 10% of PAH patients, mainly lPAH
`and PAH associated with anorexigen
`use 15]. 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. lndiscrirninate
`use of orai calcium channel blockers in
`
`patients with PAH is strongly discouraged '
`to acid precipitation of hypotension
`and heart failure with potentially fatal
`consequences.
`
`Oral anticoaguia tion
`Although no randomized. doubleeblind,
`trials
`of
`anti—
`placebo—controlled
`coagulation were performed in patients
`with PAH, two retrospective studies and
`one prospective report in patients with
`lPAH and PAH associated with anorexia
`
`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 longuterm anticoagulant therapy,
`with a goal of keeping the international
`normalized ratio between 1.8 and 2.5.
`
`recommen-
`Some experts extend this
`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).
`
`Specific pulmonary arterial
`hypertension treatment
`Basic pathogenesis ofpuimonary
`Figure 1. Treatment of putmonary arterial hypertension.
`arterial hypertension
`Vascular wall remodeling and proliferation
`are the hallmarks of pulmonary arterial obstruction in PAH [B].
`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 [943k There is an over
`expression and/or activation of vasoconstricting, mitogenic and
`prothrombotic factors [endothelin {ETLL thromboxane and
`serotonin), while prostacyclin, NO and heparinelike sub
`stances, which promote vasodiiatation 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).
`
`Conventional treatment
`Oral calcium channel blockers
`
`Active vasoconstriction is detectable at right—heart cathetcrization
`during acute vasoreactivity testing. Patients who manifest acute
`vasoreactivity may have a good longiterm response to oral calf
`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 intrae
`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
`
`
`,
`
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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
`continuous
`prostaglandin
`lg,
`subcutaneous ' treprostinil
`(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 berapro'st, siidenafil, 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
`
`trials. At least nine more
`than ten completed major clinical
`randomized, controlled trials are planned or ongoing. TABLES 1—4
`summarize
`the
`findings of
`the major
`clinical
`trials
`in
`PAH [14735]. Sildenafil. a phosphodiesterase-5 inhibitor with
`pulmonary vasodilatory action, has also been evaluated in a
`3—month double blind, placebo-controlled, multicenter, rande
`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 daiiy). The primary end point
`was the change from baseline in the 57min walk test [6MWT)
`distance. There was a significant improvement in the exercise
`capacity as measured by the BMWT, 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 scleroe
`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 5ryear 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
`3rmonth, 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 l—, 3— and
`5uyear survival rates of 85, 63 and 55%, respectively [1920].
`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 clinicaltrials with intravenous epoprostenol in patients with PAH.
`Trial
`:1 PAH WHO Route Duration Dose of
`Control“ Primary
`Treatment effect
`class
`(months) active drug
`and point
`(%)
`achieved
`(nglkglmin)
`
`ii
`iii
`iv
`
`
`Rubin
`{1990)
`
`Barst
`[1996)
`
`24 iPAH
`
`9 65 26 iv.
`
`Bi EPAH
`
`75 25 iv.
`
`2
`
`3
`
`MIA
`
`9.2
`
`Conv.
`therapy
`
`Conv.
`therapy
`
`Hfdyn
`
`Hldyn
`
`SMWT H/dyn WHO Symptoms QOL
`{in}
`class
`+45
`Better NlA
`(mean)
`
`Better
`
`N/A
`
`Survival
`
`No
`change
`
`+47
`(mean)
`
`Better Better Better
`-
`
`Better Better
`
`
`
`Ref.
`
`[14]
`
`[15}
`
`[16]
`
`3
`
`11.2
`
`BMWT
`
`Better Better Better
`
`N/A
`
`No
`'ig’l
`Conv.
`Badesch ill SPAH 5 78 17 Iv.
`Change
`(median)
`therapy
`[2000)
`'Nooe of these studies were mambo-controlled for ethical reasons: Patients in the active group received intravenous epoprostenol in addition to conventional therapy. while the controi
`group was represented by patients renewing conventional therapy alone
`BMWT: 6-miri waik test; Coov; Conventional: llloyn: licniodyrianiics: lF‘AH: Idiopathic pulriionary allUIIHl hypertension; iv: intravenous: NM: Not applicable; PAH: Pulmonary arterial
`hypertension; (JUL: Quality oi lire, SPAH Scieroderma pulmonary arterial hypertension: WHO: World Heaith Organization.
`
`mvwiuture-di‘ugsicotn
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`

`Sulica & Poon
`
`
`
`
`
`
`Table 2. Other clinical trials with intravenous epoprostenoi in patients with PAH.‘
`Trial
`Comments
`Findings
`Effect on survival
`
`improved long—term survival in IPAH patients treated with epoprostenol compared
`with historic controls
`
`Ref.
`
`[17.18]
`
`Long-term outcome (Befieyear
`followup] and predictors of
`response to therapy
`
`Baseline hemodynamics and right~veritricular function predict response to therapy.
`Patients who improve at 3e12-month followup have better longuterm prognosis.
`Patients with scleroderma PAH haveivvorse ionguterm prognosis. even if treated
`with intravenous epoprostenol. Treated patients had better survival compared with
`historic controls or to expected survival derived from the NEH equation
`
`119-21]
`
`insights into mechanism
`of action
`
`With epoprostenol. longeterm decrease in PVR is more pronounced
`compared with the acute response. suggesting an effect on pulmonary
`vascular remodeling
`
`
`
`Barst 1994
`
`Shapiro 1997
`
`Retrospective
`reviews:
`
`McLaughlin (2002)
`Sitbon {2002)
`Kuhn (2003)
`
`McLaughlin (1998)
`
`
`
`
`
`122]
`
`[231
`
`[24-281
`
`Rich 1999
`
`Dose adjustment
`
`Intravenous epoprostenol rate should be adjusted to avoid deleterious
`hyperdynamic cardiovascular effects
`
`Use of intravenous
`epoprostenol in other forms
`of PAH
`
`Herriodynamic and symptomatic improvement with intravenous epoprostenol in
`patients with other forms of PAH
`
`
`
`
`
`
`
`Case series:
`McLaughlin 1999
`Robbins 2000
`Horn 2000
`Krowka i999
`
`Rosenzweig 1999
`JPAH‘ 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 clinicai 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 actr
`ing through a N0~dependent pathway (such as sildenafil, a
`phosphodiesterase inhibitor} have different intracellular signal
`transduction pathways with potential synergistic effect. A
`smali 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 [401. In retrospective studies of patients on chronic E2130"
`prostenol or treprostinil, the addition of bosentan was safe and
`increased vasodilatory efficacy, which allowed for prostacyclin
`dose reduction or even discontinuation I41743l- 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 [44747]. 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 clinicai 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 lifeethreat'ening side effects,
`such as line—related sepsis and thrombosis or rebound pulmonary
`hypertension and acute right heart failure from inadvertent dise
`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 epopt‘ostenol
`to other
`therapeutic alternatives. such as subcutaneous treprostinil and
`oral bosentan [4148,49]. In addition, a current multicenter trial is
`evaiuating the safety of transitioning PAH patients from intra~
`venous epoprostenol
`to subcutaneous treprostinil. At
`the
`present time, however, the authors caution against indiscrimir
`nate discontinuation and substitution of intravenous epopros“
`tenol with other available drugs. There is no guarantee that, in
`the case of ciinical deterioration, reinstitution of previous there
`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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`and inhalatory routes of administration
`were recently investigated. Treprostinil has
`a
`longer half-life compared with cpoe
`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 treprose
`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 denavo
`therapy [50]. Intravenous treprostinil was
`associated with an improvement in exere
`cise
`performance
`and hemodynamics,
`with added advantages of safety and cone
`venicnce i501. It has recently received FDA
`approvai 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 sympe
`tomatic
`and
`functional
`benefit
`in
`chronic use in a small number of PAH
`patients [51].
`
`Pulmonary arterial hypertension
`
`
`
`9g stedfsuspectedis ee
`
`
`
`Figure 2. PAH management. Investigations used to characterize the disease process.
`‘Strongly consider eariy referral to spectalized centers.
`iRight heart catheterization IS requtrecl to confirm the diagnosts of PAH. Vasoreactivity testing by
`inexperienced operators may place patients at unduly increased risk.
`
`éType and extent of work-up varies on incliwclual basis. but all patients With suspected PAH diagnosis
`
`should undergo a battery of essential tests. which include ecnocardiography. chest radiography.
`
`ventiiatloneperfusion scan, HIV testing and screening for connective tissue disease. and pulmonary
`
`function test with oximetry.
`
`I'lPri‘or to institution of therapy. it is essential to evaluate functional parameters with prognostic
`
`significance. such as exercise capaoty and right-ventricular function.
`_
`
`MRI; Magnetic resonance imaging: PAH: Puimonary arterial hypertension; WHO: World
`
`Health Organization.
`
`
`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 iikely to arise. Head—terhead
`comparison trials are the most meaning-
`ful and accurate method of detecting effi-
`cacy and safety differences among various
`PAI—I 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 (ETlst
`subtype) and smooth muscle cells (ETBZ subtype)
`[52]. ET
`binding to receptors located on the vascular smooth muscle
`cell
`(ETA and ETBZ]
`induces vasoconstriction and smooth
`muscle—cell proliferation {53,54}. The relative contribution of
`ETA and ETHZ receptors to the ETemediated vasoconstriction
`depends on the species, experimental conditions and vascular
`bed studied. ETBI 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
`
`approved for clinical use, and the selective ETA receptor
`antagonists, sitaxsentan and ambriscntan. Theoretically, selece
`tive blockade of the ETA receptors may be more advantageous
`compared with nonselective ETA/ETB antagonism, by presere
`ving ETBrmediated vasodilatation and ET clearance. How~
`ever,
`in isolated pulmonary arteries and in animal models,
`combined ETA/ETB receptor blockade was superior to selecv
`tive ETA antagonism in reducing vasoconstriction and in
`improving right-ventricular hypertrophy and animal survival,
`respectively [5557}.
`In randomized clinical
`trials in patients
`with PAH, all three ET receptor antagonists improved exer~
`cise capacity, hemodynamics, symptoms and WHO func—
`tional class [337736], It is impossible to accurateiy compare their
`relative efficacy on the basis of the available trials, because the
`PAH patient populations and trial designs were different.
`However, conducting largeescale headwto—head comparison
`studies would require more refined methodology and increased
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`

`Sulica & Poon
`
`
` Table 3. Major clinical trials with newer prostanoids.
`Triai
`Drug/
`n
`PAH (%)
`WHO class (%)
`Duration Controi
`Primary
`Dose
`route
`active/piacebo
`active/placebo
`(months)
`end point
`
`
`
`Simmoneau SQ
`(2002)
`treprostinil
`
`470 iPAl-l: 58/58
`(3102: 17/21
`Cl—lDzi 25/22
`
`Olschewski
`{2002)
`AIR
`
`inhaled
`iloprost
`
`203 lPAH: 505/50
`C102: 129/215
`Anorex.: 4/49
`CTEPH: 327/235
`
`Gaiie
`(2002)
`ALPHABET
`
`Oral
`beraprost
`
`130 IPAH: 53.9/431
`CTDZ: 7.7/123
`CHDZ: 13.8/23/1
`Portal HTN: 185/138
`HIV: 6.2/7.7
`
`it
`' m
`/V
`
`
`11/12
`
`82/81
`
`8/7
`
`3
`
`Placebo
`
`SMWT
`
`9.3 ng/kg/rnin
`(mean)
`
`594/518 406/422 3
`
`Placebo
`
`Combined
`clinical
`_
`end point
`
`30 pg/day
`(median)
`6—9 inhal./day
`
`471/508 523/492
`
`3
`
`Piacebo
`
`EMWT
`
`80 pg
`fouretimes daily
`
`Barst
`(2003)
`
`Oral
`boraprost
`
`116
`
`IPAH: 18/70
`0102: 10/11
`CHDZ: 12/20
`
`55/50
`
`45/50
`
`12
`
`Placebo
`
`Disease
`progressron‘
`
`120 pg
`four—times daiiy
`
`‘Combined clinical end pornt was met if there was an improvement in the WHO class by at Eeast one unit and in the fiMWl distance by at least 10% compared with baseline
`in the absence of clinical deterioration or death.
`iDisease progression was represented by death. transplantation. epoprostenol rescue or more than 25% decrease in the peak V02. Beraprost-treated patients exhibited less
`disease progression at 6 months, but no such effect was evident at shorter or longer duration of toiiow—up. The 6MW1 distance improved at 3— and 6-month follow-up, but
`there were no further treatment effects noted at '37 and lzrmonth intervals.
`fiireatrnent effect on the SMWl distance is the difference between active and placebo groups.
`lClinicalworsening, variously defined in studies, includes clinical events consistent with PAH progression. such as death. (need for) transplantation, hospital admission/or
`right heart failure. or need for additional PAH therapy.
`fiMWl‘ 6-min walk test; AER: Aerosolized lloprost Randomized study; ALPHABET: ArteriaL Pulmonary Hypertension And Beraprosl, CHDz: Congenital heart disease; Clllz: Connective
`tissue disease; CTEPH. Chronic thromboembolic pulmonary hypertension; H/dyn: Hemodynamics: HTN: l-lypertensron; 00L: Quality oflife.‘ WHO; World Heaith 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]
`H). 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 and 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 difficule
`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, doserranging, active treatment extensions for long
`term data collection. Specific mechanisms to protect patients
`in case of clinicai 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 clinicai effect
`[321, and it may be
`inadequate for trials enrolling patients with less advanced diSr
`ease or evaluating combination therapies.
`The most commonly used primary end point in recent PAH
`clinical trials was the SMWT 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
`hemodynarnics, symptoms (Borg score), general ciinical status
`(cg, 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 epoprostenoi) and quality of life measures were
`employed as secondary and points. The 6MWT is reliable, easy
`to administer and clinicaliy meaningful, since it correlates with-
`prognosis and CPET parameters in IPAH {58,59}. The SMWT 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 portopulmonat‘y hypertension.
`
`352
`
`EXMJ‘IHC‘I’. Card/mew. Titer: 3(2). (2005)
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`

`
`Table 3. Major clinical trials with newer prostanoids (cont).
`
`Treatment effect
`
`Comments
`
`Ref.
`
`Pulmonary arterial hypertension
`
`6MWT
`(m)
`-I 16
`(median)
`
`+364
`{median}
`
`+25}
`(mean)
`
`Peak V02 H/clyn
`
`WA
`
`Better
`
`Clinical
`worsening
`No effect
`
`Survival Symptoms WHO
`class
`NlA
`
`Better
`
`No
`effect
`
`00l-
`
`Better
`
`Treatment effect was dependent on
`the baseline BMWT distance and the
`dose achieved
`
`NlA
`
`Better
`
`Better
`
`No
`effect
`
`Better
`
`Better
`
`Better
`
`Absolute change in the mean BMWT
`distance was larger in the lPAH group
`
`NlA
`
`No effect No effect
`
`No
`effect
`
`Better
`
`No
`change
`
`NlA
`
`Subgroup analysis showed greater
`BMWT improvement in lPAH
`
`+31
`(median)‘
`
`Trend to No effect Better
`increase
`
`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
`5 months only
`
`[29]
`
`£30]
`
`|3ll
`
`[32]
`
`”Combined cllnlcal end point was met Ifthere was an improvement in the WHO class by at least one unit and in the EMWT distance by at least 10% compared with baseline
`ln the absence of clinical deterioration or death.
`
`TDlsease progresslon was represented by death. transplantation epoprostenol rescue or more than 25% decrease in the peak V02. Beraprost-treated patients exhibited less
`disease progression at 6 months. but no such effect was evident at shorter or longer duration of followeup The BMWl distance improved at 3- and 6-month follow-up. but
`there were no further treatment effects noted at Sr and ermonth intervals
`§Treatment effect on the BMW? distance is the dlfference between active and placebo groups.
`lCrlnlcal Wflrseningi 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.
`SMWT: 5-min walk test; AIR: Aerosolized lloprost Randomized study; ALPHABET: Arterial Pulmonary Hypertenslon And BeraprosT, CHDz: Congenitai heart disease: CTDZ: Connective
`tissue disease, CTEPH. Chronic thromboembolic pulmonary hypertension; Hidyn: Hemodynamics, lilN- l-lypertension: 00L: Quality of life; WHO. World Health Organization.
`
`Compared with the GMWT. CPET parameters may provide
`more objective and detailed evaluation of the functionai
`capacity and the state of the pulmonary circulation in
`PAH [Boeazt
`In one triat with beraprost and another with
`Sitaxsentan, the SMWT distance and peak oxygen consumpr
`tion were used in parallel
`as study and points
`l32,35].
`Although a treatment effect was detected by improvement in
`the GMWT 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 BMWT dis—
`tance [63]. Use of follow—up right heart catheterization to
`document the treatment effect, although objective and accur
`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 clinir
`cal and point in trials evaluating patients in WHO/NYHA
`Classes Ill 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 wcli 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 and point from the perspective of
`both patients and regulatory agencies. To date, most PAH
`studies analyzed measures of general health status, such as
`Short—form Health Survey 36 and Nottingham Health Profile,
`rather than quality of life.
`
`Five-year View
`Based on a more advanced and ever improving understanding
`of the pathogenesis of PAH, the next 5 years are likely to bring
`dramatic changes in the management of PAH. New classes of
`drugs are likely to be developed as a result of recent advances in
`the molecular and cellular pathobiology of PAH. Larger proV
`portions of patients with less advanced disease will be enrolled
`in clinical trials. Trial design will continue toevolve in an effort
`to gain further insights into the clinical management'of PAH.
`
`inclusion of patients with WHO Class ll in large-scale
`Clinical trials
`
`Treatment of less advanced disease may halt and even reverse
`the pathologic process early in its development, which may
`translate into improved outcome.
`intravenous epoprostenol,
`oral. bosentan and inhaled iloprost
`trials did not
`include
`patients with less severe, WHO/NYHA Class H disease. A few
`recent trials, investigating newer agents such as subcutaneous
`
`www.ful.ure-drugs.com
`
`353
`
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`

`
`
`Channlclr
`(2001]
`
`Oral
`bosentan
`
`Rubin
`(2002)
`BREATHEJ
`
`Oral
`bosentan
`
`Barst
`(2003)
`SlRIDE-1
`
`Oral
`sitaxsentan
`
`25 mg bid.
`250 mg bid.
`
`00 mg on.
`300 mg q.d.
`
`
`
`Rubin
`(2004)
`
`' mg po q.d.
`Oral
`ambrisentan 2.5 mg po Cid.
`5 mg po go.
`