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`This article is part of a certified activity. The complete activity is available at:
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`www.medscape.org
`
`Supported by
`an independent
`educational grant from
`Therapeutic Options for the Treatment of Pulmonary Hypertension
`Nicholas Hill, MD
`
`Posted: 9/8/2005
`
`Treatment Options for Pulmonary Hypertension
`
`Pulmonary hypertension refers to an abnormal elevation of pulmonary artery (PA) pressure (mean PA pressure > 25 mm Hg at
`rest and 30 mm Hg with exercise) and can be caused by or associated with a wide variety of conditions. According to the most
`recent classification of pulmonary hypertension developed in Venice in 2003.(11 pulmonary hypertension can be attributed to:
`
`The therapy of pulmonary hypertension depends on the identification of underlying contributing factors. PAH, which can be
`idiopathic (formerly referred to as primary pulmonary hypertension) or related to connective tissue disease (usually
`scleroderma), portal hypertension, HIV disease, ingestion of certain drugs or toxins, or congenital heart disease, had no specific
`therapy until recently. However, the past decade has seen remarkable progress, and these heretofore devastating and usually
`lethal forms of pulmonary hypertension now often respond to one form of therapy or another, leading to improved functional
`capacity and even survival. The following will consider the major pharmac~therapies now available for PAH and suggest a
`framework for therapeutic decision-making.
`
`General Approach
`
`Some therapies have long been available to treat pulmonary hypertension and are still of value. Fluid retention is common, and
`adequate diuresis frequently brings about substantial symptomatic improvement. Oxygen supplementation should be provided
`to hypoxemic patients, either at rest or with exertion or during sleep. Digoxin is often administered for supraventricular
`arrhythmias or right ventricular dilatation. Based on uncontrolled trials, warfarin anticoagulation is routinely administered to
`patients with moderate to severe PAH, usually aiming for an INR between 1.5 and 2.5. Phlebotomy has been recommended
`when the hematocrit exceeds 56, particularly in patients with congenital heart disease. Calcium channel blockers, sometimes in
`high doses, were considered the most effective pharmacotherapies for pulmonary hypertension prior to the advent of newer
`specific therapies.121 Responders to calcium channel blockers, who usually manifest substantial acute vasoreactivily, have an
`excellent prognosis. Unfortunately, they constitute only 5% lo 10% of PAH patients. With the exception of anticoagulation and
`calcium channel blocker therapy in responders, these therapies should be considered mainly palliative, and although they can
`be quit e useful for ameliorating symptoms, they do not significantly affect the natural history of the disease.
`
`Newer and more effective pharmacotherapies for PAH are now available, starting with prostacyclins in 1996 and, more recently,
`endothelin receptor antagonists and phosphodiesterase 5 inhibitors. Randomized controlled trials have demonstrated significant
`benefits for these therapies, but they all have limitations and must be used judiciously. Relative merits of the different therapies,
`suggested applications, possible combinations, and newer therapies are discussed below.
`
`Prostacyclins
`
`Epoprosteno l. Discovered in 1976 by the Nobel Prize-winning team led by John Vane, prostacyclin is a potent vasodilator
`prostaglandin that is synthesized and released by vascular endothelium and participates in the maintenance of low vascular
`tone.l31 Possessing antiproliferative and platelet antiaggregatory effects as well, the enzyme that synthesizes it, prostacyclin
`synthase, has been reported to be reduced in patients with idiopathic PAhl.141 The therapeutic administration of prostacyclin
`(epoprostenol) as a continuous intravenous infusion to patients with idiopathic PAH was first reported during the 1980s,l51 and a
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`pivotal randomized, controlled trial on patients with idiopathic PAH was reported in 1996.161 En rolling 81 patients. this trial
`demonstrated a significant improvement in 6-minute walk distance, the major outcome variable, as well as in pulmonary
`hemodynamics, oxygenation, and survival. Based on these findings, the US Food and Drug Administration (FDA} approved
`epoprostenol as a continuous Intravenous therapy for patients with class Ill or IV idiopathic PAH. Subsequent studies have
`demonstrated a substantially improved survival of idiopathic PAH patients treated with intravenous epoprostenol compared with
`historical controls.£71 In addition, a subsequent randomized controlled trial showed efficacy in improving exercise capacity and
`hemodynamics in patients with PAH related to scleroderma,l81 although survival was not significantly improved. Other smaller
`uncont rolled studies suggest that epoprostenol is effective in the treatment of PAH related to congenital heart disease, HIV, and
`portopulmonary hypertension. These favorable effects of epoprostenol in patients with various forms of PAH are better
`substantiated than with any other pulmonary hypertension therapy, and it is still considered the therapy of first choice for patients
`in the New York Heart Association class IV and the last resort when other therapies have failed.
`
`Despite its demonstrated efficacy, intravenous epoprostenol is far from an ideal therapy. It requires daily mixing and must be
`kept in a cold pack to avoid degradation at room temperature. The infusion pump and cold pack can be carried in a fanny pack,
`but are cumbersome for many patients. In addition, the need for a permanent transcutaneous intravenous catheter poses risks
`for line infection and sepsis (estimated to occur in 0.14 patients/year), and sudden occlusion of the catheter can precipitate
`hemodynamic collapse because of the several minute half-life of the drug. The cost of the drug and administration system are
`also substantial, amounting to $100,000 to $250,000 annually.
`
`Treprostinil. The shortcomings of intravenous epoprostenol have stimulated the search for alternative therapies. Treprostinil, a
`prostacyclin analog with a half-life of several hours, was approved by the FDA for subcutaneous administration in 2002. Stable
`at room temperature, it requires no cold packs and can be administered using a continuous infusion pump that approximates the
`size of a pager. The drug was shown to be safe and effective in a pivotal trial that demonstrated an average improvement in 6-
`minute walk distance of 16 meters, approximately a third that reported for epoprostenor.191 However, an analysis of the dose
`response to the drug indicated that many patients in the pivotal trial were underdosed because of reluctance to increase the
`infusion rate in the face of infusion site pain. Patients treated with 14 or more ng/kg/minute had improvements in 6-minute walk
`distance averaging 36 meters, whereas patients treated with less than 10 ng/kg/minute had virtually no improvement. Follow-up
`studies demonstrate improvements in 6-minute walk distance that are comparable to those achieved by epoprostenol as higher
`doses are reached. Because of its subcutaneous route of administration, mo need for mixing, and the highly portable pump
`system, subcutaneous treprostinil has substantial safety and convenience advantages over intravenous epoprostenol.
`Unfortunately, many patients encounter pain at the infusion site, and a significant minority of patients finds the drug intolerable.
`Various topical formulations and narcotics bring some alleviation, but this pain has limited the appeal of this form of therapy.
`
`In late 2004, the FDA approved intravenous treprostinil to treat class II to IV PAH. A lthough this therapy shares with
`epoprostenol the risks of continuous intravenous administration, it is more· convenient because it requires no daily mixing and
`safer because sudden interruption of the infusion is less threatening with the drug's longer half-life. Dosing of intravenous
`treprostinil has not been definitively established, but most investigators recommend doubling the doses ordinarily used during
`epoprostenol infusions.1101 An inhaled form of treprostinil is currently under investigation, and preliminary reports suggest that
`the hemodynamic effect is sustained for more than 2 hours after only a few inhalations.1111
`
`lloprost. lloprost, another prostacyclin analog with a half-life between those of epoprostenol and treprostinil, has been available
`in Germany for several years, but received FDA approval only during 2004. A randomized controlled trial in patients with PAH or
`chronic thromboembolic pulmonary hypertension showed a significant improvement in the 6-minute walk distance,l121 but 5% of
`patients experienced syncope, presumably because they exerted excessively after the drug effect had waned. Tlhe duration of
`hemodynamic effect averages approximately 90 minutes after inhalation, and the drug requires 6 to 9 nebulizer treatments per
`24 hours, each treatment requiring up to 10 to 20 minutes. Although the inhaled route has obvious safety advantages over the
`intravenous route and avoids the pain of subcutaneous administration, many patients find the frequency of treatments
`cumbersome.
`
`Oral Beraprost. Beraprost, another prostacyclin analog with a longer half-life than epoprostenol, is suitable for oral
`administration. Uncontrolled trials in Japan. where the drug is currently av.ailable. have suggested beneficial actions in patients
`with pulmonary hypertension related to congenital heart disease as well as in chronic thromboembolic pulmonary hypertension.
`1131 Although a 3-month randomized controlled trial in Europe showed a significant improvement in 6-minute walk distance, a
`subsequent 12-month randomized controlled trial in the United States failed to show sustained benefit, even though there was
`significant improvement in the 6-minute walk distance at the 3- and 6-month time points.1141 For this reason, the FDA will not
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`approve oral prostacyclin therapy in the United States at the present time. However, other oral therapies (treprostinil) are under
`investigation, and further work will be needed to determine whether the lack of the sustained effect for beraprost might be
`related to insufficient dose escalation or another remediable problem.
`
`Endothelin Receptor Antagonists
`
`The endothelins are a family of vasoactive peptides synthesized and released by endothelial cells. The main vasoactive
`endothelin, endothelin 1 (ET-1 ), a 22 amino acid peptide, has higher plasma levels in patients with idiopathic PAH and PAH
`related to connective tissue disease than in normal controls.!151 Two endothelin receptors have been identified; the A-receptor
`that is found mainly on the surface of smooth muscle cells and participates in the mediation of vasoconstriction, and the 8 -
`receptor, found mainly on the surface of endothelial cells. The B-receptor mediates not only vasoconstriction, but also
`vasodilation via release of prostacyclin and nitric oxide, and it serves as a clearance receptor for endothelin as wen.!161 A
`number of endothelin receptor blockers have been developed to treat PAH that vary in their specificity for receptor blockade.
`Althou.gh theoretical arguments based on experimental animal evidence can be mounted to support either nonspecific or
`specific A-receptor blockade as the preferred mode of therapy, there is no convincing evidence from clinical trials to support any
`one approach.
`
`Nonselective Endothelin Receptor Blockade. Presently, only one endothelin receptor antagonist has received FDA approval
`for clinical use in the United States -- the oral nonselective blocker, bosentan. This drug was studied in an earlier randomized
`controlled trial that demonstrated not only a significant improvement in 6-nninute walk distance, but also improvements in
`pulmonary hemodynamics.l17J A subsequent 16-week pivotal randomized controlled trial (BREATHE-1) confirmed the
`improvement in 6-minute walk distance (44 nneters greater compared with placebo) and also showed significant improvements
`in New York Heart Association functional class and quality-of-life scores, as well as a significant decrease in the rate of clinical
`worsening.1181 Since its FDA approval in 2001 , bosentan has been the most widely prescribed specific pulmonary hypertension
`therapy. Subsequent long-term follow-up studies demonstrate a 2-year survival of 89% in patients begun on bosentan, with 70%
`remaining on monotherapyJ19J
`
`The drug is usually well tolerated, but can exacerbate fluid retention and may not bring about clinical improvements for as long
`as 2 to 3 months after initiation. For this reason, even though the drug was approved for therapy of both class Ill and class IV
`patients with idiopathic PAH or PAH related to connective tissue disease, routine monotherapy for class IV patients is
`inadvisable. Also, the drug causes greater than a 3-fold elevation in liver transaminases in approximately 10% of patients, and
`liver function tests must be monitored monthly for the duration of therapy. The recommendation is to start at 62.5 mg twice daily
`for a month and then advance to 125 mg twice daily if liver function tests are acceptable.
`
`Specific A-receptor Blockers. Two specific A-receptor blockers are currently under investigation for the therapy of PAH. The
`first, sitaxsentan, is approximately 6000-fold more specific for the A than B receptor and has a longer half-life that permits once(cid:173)
`daily oral administration. Tested in a 12-week randomized controlled trial (STRIDE-1 ))20J it failed to show a statistically
`significant benefit in the major outcome variable, maximal oxygen uptake at the 100 mg per day dose, but it did show significant
`improvements in the 6-minute walk distance, pulmonary hemodynamics, and New York Heart Association classification.
`Because of the failure to show significant benefit in the major end point, further trials have been performed including STRIDE-2,
`in which daily doses of 50 mg and 100 mg were compared with placebo and open-label bosentan at 125 mg twice daily. A
`preliminary report!211 shows that 100-mg daily dose of sitaxsentan improves 6-minute walk distance and New York Heart
`Association class compared with placebo and comparably to bosentan, but the 50-mg daily dose failed to show significant
`benefit. Liver toxicity tended to be less at the 100-mg dose of sitaxsentan compared with bosentan 125 mg twice daily (3% vs
`11%), !but the difference was not statistically significant. Sitaxsentan offers the advantages of once daily administ ration and
`possibly less liver toxicity than bosentan, but efficacy appears to be comparable. It is currently under consideration for approval
`by the FDA.
`
`Ambrisentan, another endlothelin receptor antagonist that is 18 times more specific for the A than B receptor, is currently
`undergoing investigation. Like sitaxsentan, it is a once-a-day oral therapy, and preliminary findings suggest that it poses a low
`risk of liver toxicity.
`
`Phosphodiesterase 5 Inhibitors
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`Cyclic guanosine monophosphate (GMP) is an intracellular second messenger that has vasodilator and antiproliferative actions.
`Phosphodiesterase-5 metabolizes cyclic GMP, decreasing intracellular levels, and limiting vasodilator effects.
`Phosphodiesterase-5 inhibitors slow the metabolism of cyclic GMP, intens.ifying the vasodilator actions, and several have been
`approved for the treatment of erectile dysfunction. Presently, only one phosphodiesterase inhibitor, sildenafil, has been tested in
`PAH and was recently approved by the FDA 'for the therapy of PAH patients at a dose of 20 nng 3 times daily. A pivotal
`randomized controlled trial of sildenafil (SUPER-1) (thus far only presented in oral abstract form) showed statistically significant
`improvements in 6-minute walk distance (45-50 meters), pulmonary hemodynamics, and New York Heart Association class over
`12 weeks. There was no significant delay in the time to clinical worsening, unlike bosentan, but the drug was well tolerated.
`Headache and epistaxis were the only side effects encountered more often than with placebo. Favorable effects are often seen
`within days of drug initiation. A trial to test the efficacy of a longer-acting phosphodiesterase-5 inhibitor, tadalafil, is just being
`started. This would presumably allow once-daily or even less frequent administration.
`
`New Potential Therapies
`
`A number of other therapeutic approaches to PAH are being tested or contemplated ( ). Most block mediators or signaling
`pathways known to be involved in PAH pathogenesis. The thromboxane A-2 antagonist, terbogrel, was studied in a randomized
`controlled trial that was stopped prematurely when many patients in the treatment arm experienced leg pain.l221 Stalins are
`under consideration as a pulmonary hypertension therapy because they possess anti-innammatory and antiproliferative actions
`and have been effective in rodent models of PAH.1231 A small clinical trial is currently under way, but preliminary findings are not
`yet available. Estrogens have been shown to blunt pulmonary hypertension in some animal nnodels,1241 and a phase 1 clinical
`investigation is currently underway. Serotonin potentiates smooth muscle ·cell proliferation in some animal models, and gene
`mutations of the serotonin transporter have been associated with pulmonary hypertension in chronic obstructive pulmonary
`disease patients. Accordingly, serotonin receptor inhibitors are being considered as pulmonary hypertension therapies. Gene
`therapy approaches are also under consideration, such as transfection with the nitric oxide or prostacyclin synthase genes, but
`suitable long-acting vectors have not yet been developed.
`
`Table. lnvestigational Ag,ents Under Consideration as PAH Therapies
`
`Thromboxane receptor antagonists
`
`Stalins (HMG coreductase inhibitors)
`
`K+ channel openers
`
`NO donors
`
`Estrogens
`
`Rho kinase inhibitors
`
`Angiogenesis factors
`
`Gene therapy
`NOS, K+ channel openers
`
`Combination Therapy
`
`The success of treating malignancies and congestive heart failure with combination therapies has generated enthusiasm and
`optimism for combination therapy in PAH. The concept of combining agents with fundamentally different mechanisms of action is
`attractive; however, few clinical data are available to substantiate the theoretical benefits of combination therapy in PAH. In an
`uncontrolled study, Ghofrani and colleaguesl251 demonstrated that the addition of sildenafil in patients who deteriorated while on
`iloprost therapy alone restored clinical stability, associated with improvements in 6-minute walk distance.
`
`The combination of prostanoids and endothelin receptor antagonists also appears promising. In the randomized controlled
`BREATHE-2 trial, bosentan combined with intravenous epoprostenol showed trends toward improved pulmonary hemodynamics
`compared with epoprostenol with placebo, but the study was underpowered to achieve statistical significance. A series of 16
`patients with PAH on prostanoid therapy showed improvement in 6-minute walk distance and functional class after bosentan
`was added,1261 but results from randomized trials are needed. Preliminary results were recently released on the STEP-2 trial that
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`randomly added inhaled iloprost vs placebo in patients already receiving bosentan therapy. A significant improvement in 6-
`minute walk distance was attributable to the addition of iloprost when administered an average of 6 times daily.127J Few data are
`available on the combination of endothelin receptor antagonists and sildenafil, but a recent case series described improvement
`in functional status(:> 100-m improvement in 6-minute walk distance) after sildenafil was added in 9 patients deteriorating after a
`year on bosentan monotherapy.1281
`
`Even in the absence of supportive data, however, many patients in clinical practice have been empirically placed on combination
`therapy when the initial agent either fails to bring about the desired improvement. or deterioration occurs after an initial favorable
`response. Some patients, anecdotally, are being treated with all 3 FDA approved PAH therapies, along with statins and
`traditional therapies. However, this is very expensive, and we cannot be certain, in the absence of data, that these combinations
`are beneficial. A number of randomized controlled trials are being initiated that should provide answers to many ,of the questions
`surrounding combination therapy over the next several years.
`
`Surgical Therapeutic Options
`
`Lung and heart/lung transplantation as well as atrial septostomy have been available for years to treat severe PAH. With the
`advent of effective pharmacotherapy, however, the need for these interventions has diminished, but they are still considerations
`for patients who fail to respond favorably and remain in class Ill or IV after at least several months of optimal pharmacotherapy.
`When contemplating lung transplantation, it should be considered that different transplant centers have great variability in
`waiting times, ranging from several weeks to several years.
`
`Summary and Conclusions
`
`Although we have long had a variety of palliative treatments for pulmonary hypertension that should not be forgotten, in recent
`years, 3 new pharmacotherapeutic categories have been added to our therapeutic regimen for PAH: the prostacyclins,
`endothelin receptor antagonists, and phosphodiesterase-5 inhibitors. Eaclh year, new agents are being added to each of these
`new categories, and newer therapeutic avenues are being investigated or contemplated. This burgeoning of therapies has
`added to the complexity of therapeutic decision-making. Recent guidelinesl291 may help, but provide no recommendations on
`recently approved agents such as inhaled iloprost and sildenafil. Currently, there is no convincing evidence to support treating
`NYHA class I patients. Most clinicians use an oral therapy to initiate therapy for class II or Ill patients, but whether to begin with
`sildenafil or bosentan is currently a matter of debate. A prostacyclin infusion, either intravenous epoprostenol or intravenous or
`subcutaneous treprostinil, is usually initiated for class IV patients. However, many questions remain unanswered, such as
`whether some patients should be initiated on combination therapy, what to do when patients fail to respond adequately to initial
`therapy, and when to use inhaled therapies. Because of the complexity of managing PAH patients, referral to centers
`specializing in pulmonary hypertension is recommended, partly to give them the opportunity to participate in clinical trials.
`
`References
`
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`Abstract
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`pulmonary arterial hypertension. J Am Coll Cardiol. 2003;42:158-164. Abstract
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`
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