Herz © [HEART] URBAN & VOGEL 2005
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`New therapies in the treatment of pulmonary hypertension
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`Hossein Ardeschir Ghofrani, Robert Voswinckel, Frank Reichenberger, Friedrich Grimminger, Werner
`Seeger1
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`1 Medical Clinic and Outpatient Clinic II, University of Giessen Lung Center
`(UGLC), Justus Liebig University in Giessen.
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`Ghofrani HA, et al. Pulmonary hypertension – new aspects of therapy
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`Introduction
`The therapy pursuant to the guidelines for
`pulmonary arterial hypertension (PAH) was already
`discussed extensively in the contribution from
`Hoeper in this issue. In this case, pursuant to the
`guidelines means referencing approved medications
`or substances that have found their way into
`evidence-based therapy recommendations due to
`clear status in publications. The content of this
`contribution is the presentation of new therapy
`approaches, which are partially still under
`development, and that can find their way into the
`therapy guidelines in the near future or that are
`already being employed in so-called “off label use”
`due to clear evidence of efficacy. Specifically, we
`will discuss therapy with inhaled prostanoids,
`selective endothelin A receptor antagonists
`(sitaxsentan and ambrisentan) and
`phosphodiesterase-5-(PDE5-) inhibitors (especially
`sildenafil). Furthermore, combination therapies will
`be discussed as a possible future therapy standard.
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`Vasoactive therapy
`The points of attack for a vasoactive therapy are the
`potentially reversible components of vascular
`obstruction. In principle, there are two possibilities
`to expand the vessel diameter with pharmacological
`intervention:
`• Elimination of permanently increased vasotone
`by relaxing the smooth vessel musculature
`(direct effect of vasodilators);
`• Influence of the vessel structure (vascular
`remodeling) by using anti-inflammatory and
`anti-proliferative substances.
`A number of vasodilating agents have been
`clinically tested in the treatment of chronic
`pulmonary hypertension. With respect to the
`application of calcium antagonists, prostanoids and
`non-selective endothelin antagonists, we refer once
`again to the article by Hoeper in this issue. Although
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`inhaled iloprost (Ventavis®) was also discussed in
`this article, this therapy form will be briefly
`mentioned here again since it provides the
`theoretical and clinical background for explaining
`the new inhaled treprostinil therapy.
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`Inhaled iloprost
`The inhalation of aerosolized prostanoids avoids a
`large part of the disadvantages of infusion therapy
`while providing efficacy: due to the alveolar
`deposition of the active substance, pulmonary and
`intrapulmonary selective action is achieved.
`Therapy for pulmonary hypertension with repeated
`inhalations of the long-acting prostacyclin analog
`iloprost has proven its efficacy with simultaneous
`good safety in a multi-centric, randomized, placebo-
`controlled study [1]. In the group that was treated
`with iloprost, there was both a significant
`improvement in the 6-min. walk test (as a
`benchmark for stamina) and in the NYHA class
`(New York Heart Association) in comparison to the
`group treated with placebo. This study that is
`relevant for approval of the drug was already
`preceded by several, non-controlled studies in
`patients with various forms of pulmonary
`hypertension [2-4]. The phase III study was
`predominately able to confirm the earlier positive
`experiences. However, in addition to the expensive
`aerosol technology, a disadvantage of this therapy is
`the relatively short duration of action for a single
`dose (60-90 min.), which makes frequent
`inhalations necessary (six to nine times per day) and
`there is a therapeutic pause during the night.
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`Inhaled treprostinil
`Treprostinil is a long-acting prostacyclin analog,
`which offers potential benefits versus epoprostenol
`due to its long plasma half life and chemical
`stability in solution, and therefore was initially
`developed as a substitute for infusion treatment.
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`Ghofrani HA, et al. Pulmonary hypertension – new aspects of therapy
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`In order to avoid complications related to catheters,
`the treprostinil infusion is administered
`subcutaneously via a special cannula (taken from
`long-term insulin therapy). The study for this
`therapy concept that is relevant for approval of the
`drug showed efficacy in the treatment of patients
`with pulmonary arterial hypertension [5]. However,
`the downside of this form of treatment is that up to
`80% of the patients have pain at the injection site,
`which makes a long-term therapy more difficult.
`Initial trials in Giessen have shown proof of
`efficacy of inhaled treprostinil for the effective
`reduction of the pulmonary vascular resistance
`(PVR) [6]. In this first study, 17 patients with
`severe pre-capillary pulmonary hypertension were
`administered inhaled treprostinil (15
`mcg/inhalation). This led to a major reduction in
`pulmonary selective pressure and resistance with an
`overall duration of action of > 180 min. In direct
`comparison with inhaled iloprost, inhaled
`treprostinil showed a stronger pulmonary
`selectivity, so that it is possible to increase the
`dosage to up to 90 mcg (absolute inhaled dose per
`inhalation exercise) without adverse effects
`occurring [6]. Due to these unique properties
`(pronounced pulmonary selectivity and long
`duration of action after an individual inhalation), it
`is possible to reduce the number inhalations
`necessary to up to four per day; the inhalation
`period can be reduced to < 1 min. by selecting a
`suitable device. Additionally, the initial data shows
`that it is technically feasible for there to be only one
`to two breaths in an application. A multi-centric,
`placebo-controlled study shall now also study the
`efficacy of this new therapy during long-term use.
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`Sitaxsentan. The selective ETA receptor antagonist
`sitaxsentan (Thelin®) has a much higher binding
`affinity for the ETA receptor than for the ETB
`receptor. Preclinical data have already indicated a
`possible efficacy for PAH treatment. Published
`clinical phase II data show that at a comparable
`efficacy to bosentan, the incidence of liver toxicity
`in the group treated with 100 mg sitaxsentan (tablet
`taken once per day) is 0% and is 10% in the group
`treated with 300 mg [7]. In the phase III study that is
`relevant for drug approval, which is still being
`evaluated, both 50 mg and 100 mg sitaxsentan were
`used in comparison to a placebo or bosentan (125
`mg twice a day). The data that has so far only been
`published by press release indicates again that 100
`mg dose of sitaxsentan showed a trend of lower liver
`toxicity than bosentan (3% vs. 11%) while having
`comparable efficacy (improvement in walking
`distance in the 6-min. walk test by 31.4 m
`[sitaxsentan] vs. 29.5 m [bosentan]). It is currently
`not known when and for what patient cohort this
`medication will be approved. For sitaxsentan, an
`interaction with warfarin is described, which
`requires a dosage adjustment of the oral anti-
`coagulant.
`Ambrisentan. Just as with sitaxsentan, ambrisentan
`is a selective ETA antagonist [8]. A phase II study
`on this substance has already been completed,
`however, the results are currently not available in
`published form. The phase III study that is relevant
`for the drug approval is currently still recruiting
`patients and is expected to be completed at the end
`of 2005.
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`Phosphodiesterase inhibitors
`The mutual end segment in the sequence of action of
`the endogenous vasodilating mediators (e.g. NO,
`prostanoids and atrial natriuretic peptide [ANP]) is
`the intracellular release of cyclic nucleotides (cyclic
`adenosine monophosphate [cAMP], cyclic
`guanosine monophosphate [cGMP]. These so-called
`second messengers are mainly formed by an
`activation of adenylate and guanylate cyclase [9].
`The decomposition of cyclic nucleotides by
`phosphodiesterase (PDE) limits the intensity and
`duration of action of the vasodilating agonists [9,
`10]. PDEs partially show organ-specific or cell-
`specific distribution patterns [10, 11]. Thus, PDE5 is
`highly expressed in both the corpus cavernosum in
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`Selective endothelin A receptor antagonists
`The activation of endothelin A (ETA) receptors
`leads to vasoconstriction and vascular proliferation
`in the lung, while the ETB receptor binds (and
`eliminates) circulating endothelin and leads to an
`increase in the endogenous prostacyclin and
`nitrogen monoxide (NO) production. In addition, it
`is assumed that the liver toxicity described for
`bosentan is mainly related to the ETB-inhibiting
`effect. Against the backdrop of these presumably
`risky partial components of the non-selective
`endothelin receptor antagonist (ERA), selective ETA
`antagonists have made their way into clinical
`testing. There are currently experiences with two
`substances in this regard, which are discussed in
`detail below.
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`Ghofrani HA, et al. Pulmonary hypertension – new aspects of therapy
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`males and the lungs under physiological
`conditions [10]. In addition, PDEs are
`overexpressed in the case of various
`proliferative and constrictive vascular
`diseases. PDE inhibitors can interfere
`with the decomposition of cAMP or
`cGMP or both systems simultaneously,
`depending on their selectivity profile.
` Therefore, therapeutic approaches are
`seen in two respects in the context of
`these pathophysiological considerations:
`1. PDE inhibitors can inhibit the basal
`decomposition of cyclic nucleotides and
`therefore achieve vasodilating effects per
`se, and
`2. PDE inhibitors can extend the effects
`of vasodilators such as NO and
`prostanoids.
`Sildenafil. Sildenafil is a selective PDE5
`inhibitor and has been approved for
`erectile dysfunction therapy. In this
`indication, the medication has shown an
`extraordinarily good safety profile so far,
`especially without detection of a relevant
`decrease in systemic blood pressure [12].
`In patients that are treated with nitro
`preparations due to a cardiovascular disease, however, a
`combined application with sildenafil should be avoided
`in order to prevent undesired severe hypotension.
` Based on experimental preliminary results, it was
`obvious to employ PDE inhibitors for the prolongation
`and/or increase in the action of prostanoids. Two clinical
`studies have been able to impressively prove that
`sildenafil is a potent vasodilator per se, which exhibits a
`surprising pulmonary selectivity despite systemic
`application [13, 14]. In addition, a clear synergistic
`action of oral sildenafil with inhaled iloprost was able to
`be documented. A comparison of the efficacy with the
`known pulmonary selective vasodilator inhaled NO was
`performed on 30 patients with
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`severe pulmonary hypertension [14]. This showed that
`50 mg of oral sildenafil caused significantly stronger
`pulmonary vasodilation than inhaled NO (PVR
`reduction: ~25% [50 mg sildenafil] vs. ~15% [~20 ppm
`NO]; Figure 1). With respect to possible combined
`applications of PDE inhibitors and prostanoids, both
`substances in this study showed an impressive synergism
`of efficacy (>45% PVR reduction), with preserved
`pulmonary selective method of action, and therefore
`very good tolerability. Also in the case of pulmonary
`hypertension as a secondary disease of an interstitial
`lung disease, sildenafil showed an excellent action
`profile. Although patients with pulmonary fibrosis and
`pulmonary hypertension have a predisposition for
`oxygenation disorders while being administered non-
`selective vasodilators, sildenafil not only showed
`selectivity in these patients (despite oral administration)
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`Ghofrani HA, et al. Pulmonary hypertension – new aspects of therapy
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`in the sense of preferred reduction of the
`PVR, but also in the sense of
`intrapulmonary selectivity, which was
`expressed in improvement in the gas
`exchange [15] (Figure 2).
` In a recently published study, it was able
`to be documented for the first time that
`sildenafil increased performance in the case
`of hypoxia-induced pulmonary
`hypertension, which was not only
`associated with a reduction in pressure in
`the lesser circulation, but also with an
`improvement in oxygenation [16].
` In the meantime, the phase III study for
`the treatment of PAH with sildenafil that is
`relevant for drug approval has been
`completed. The results were presented in
`2004 at the ACCP (American College of
`Chest Physicians) conference in Seattle,
`WA, USA. This showed that sildenafil is
`more effective at attaining the primary
`endpoint (improvement in the 6-min. walk
`test; up to 50 m in the 80 mg group) than
`the placebo with a high degree of
`significance at all three tested doses of 20
`mg, 40 mg and 80 mg (each administered
`three times per day). Secondary parameters
`such as improvement in pulmonary
`hemodynamics and life quality parameters
`were significantly improved as well. The
`approval of the medication has been
`requested from the US and European
`authorities in the meantime.
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`Combination therapies
`Unfortunately, the clinical reality of patients
`with severe chronic pulmonary
`hypertension is often the situation that there
`is a progressive deterioration of the clinical
`condition of the patient despite chronic
`therapy with prostanoids or endothelin
`antagonists.
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`Ghofrani HA, et al. Pulmonary hypertension – new aspects of therapy
`Previously, patients in such a situation were given
`principle). The previous reticence with respect to initiating
`an atrial septostomy as a bridging measure or were
`an early medicinal therapy is surely due to the high costs
`directly given a lung transplant (with all the
`of the established medications in conjunction with the
`restrictions due to the long wait times for donor
`costly equipment needs on the one hand, and on the other
`organs and the previously unsatisfactory long-term
`due to the partially considerable therapeutic adverse
`results after transplantation). As mentioned,
`effects. In addition, with respect to a therapeutic benefit of
`sildenafil also shows an extraordinarily good action
`infused prostanoids, it is shown that only patients with a
`profile even in combination with e.g. inhaled
`far advanced stage of the disease exhibit a significant
`iloprost with preserved pulmonary selectivity
`survival benefit, while those with milder forms even show
`regardless of dosage [14]. Some experiences with
`a tendency for worse long-term results with the therapy
`respect to combined long-term application of
`[21].
` Due to the very good safety profile, the high efficacy
`sildenafil with inhaled iloprost as part of clinical
`and the relatively low costs of therapy, in the future oral
`healing attempts have shown very encouraging
`sildenafil could play an important role in the early therapy
`results with regard to patient re-compensation, who
`for latent or mild pulmonary hypertension, especially as a
`were at risk of decompensation despite ongoing
`large number of patients with functional NYHA class II
`iloprost inhalation therapy [17]. A further study on
`were able to be successfully treated with this substance in
`the combined application of sildenafil and bosentan
`the phase III study that is relevant for drug approval.
`also showed a synergy of both therapies with
`Likewise, this could be true of inhaled prostanoids with
`respect to improvement in physical stamina [18].
`further simplification of the inhalation technology.
`Larger, placebo-controlled studies are necessary in
`However, studies that answer these questions are still
`order to finally clarify the questions of 1. whether
`outstanding.
`the initiation of a multi-substance medicinal
`
`therapy for pulmonary hypertension (e.g. PDE
`Literature
`inhibitors + prostanoids or PDE inhibitors + ERA
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`or prostanoids + ERA) is superior to an individual
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`therapy, 2. whether patients that become worse
`under a monotherapy can become better by adding
`another active substance, and 3. which medication
`combination is the most effective with respect to
`efficacy and improvement in the prognosis. The
`optimization of the functional stamina of patients
`with chronic pulmonary hypertension should be at
`the center of any therapeutic endeavor, since this is
`of prognostic relevance [19, 20]. Possibly, in the
`future combinations of three or even more
`medications could be part of a standard regimen for
`the treatment of pulmonary hypertension in order to
`achieve this goal.
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`Treatment of early forms of pulmonary
`hypertension
`Currently there is no general recommendation for
`therapy with vasodilators for early forms of
`pulmonary hypertension. The rationale for the early
`use of such substances is to prevent the
`presentation of secondary chronic (irreversible)
`remodeling processes of the pulmonary vessels,
`which can form as a result of long-term
`vasoconstriction (which are still reversible in
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`Ghofrani HA, et al. Pulmonary hypertension – new aspects of therapy
`______________________________________________________________________________________
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`Correspondence address
`Dr. Hossein Ardeschir Ghofrani
`Medical Clinic II
`Klinikstrasse 36
`35392 Giessen
`Telephone (+49/641) 99-42351, fax -42359
`E-mail: ardeschir.ghofrani@innere.med.uni-giessen.de
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`I, Brooke Hampshire, declare that:
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`1.
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`i am fluent in both German and English. To the best of my knowledge and belief, the attached
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`document is a true and correct translation of an article titled Neue Therapieoptionen in der Behandlung
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`der pulmonalarteriellen Hypertonie from German to English.
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`2.
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`I hereby declare that all statements made herein of my own knowledge are true and that all
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`statements made on information and belief are believed to be true; and further that these statements
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`were made with knowledge that willful false statements and the like so made are punishable by fine or
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`imprisonment, or both, under 18 U.S.C. 1001.
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`Date: é/Qo/(QOL;
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`BROOKE HAMPSHIRE
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