Inhaled Therapies for Pulmonary Hypertension
`
`Nicholas S Hill MD, Ioana R Preston MD, and Kari E Roberts MD
`
`Introduction
`Advantages and Disadvantages of Inhaled Therapies for Pulmonary
`Hypertension
`The Prostacyclin Pathway
`Epoprostenol
`Iloprost
`Treprostinil
`Nitric Oxide/cGMP Pathway
`Nitric Oxide
`Sildenafil
`Other Possible Inhaled Therapies for Pulmonary Hypertension
`Vasoactive Intestinal Peptide
`Rho Kinase Inhibitors
`Tyrosine Kinase Inhibitors
`Summary
`
`The inhaled route has a number of attractive features for treatment of pulmonary hypertension,
`including delivery of drug directly to the target organ, thus enhancing pulmonary specificity and
`reducing systemic adverse effects. It can also improve ventilation/perfusion matching by dilating
`vessels supplying ventilated regions, thus improving gas exchange. Furthermore, it can achieve
`higher local drug concentrations at a lower overall dose, potentially reducing drug cost. Accord-
`ingly, a number of inhaled agents have been developed to treat pulmonary hypertension. Most in
`current use are prostacyclins, including epoprostenol, which has been cleared for intravenous
`applications but is used off-label in acute care settings as a continuously nebulized medication.
`Aerosolized iloprost and treprostinil are both prostacyclins that have been cleared by the FDA to
`treat pulmonary arterial hypertension (PAH). Both require frequent administration (6 and 4 times
`daily, respectively), and both have a tendency to cause airway symptoms, including cough and
`wheeze, which can lead to intolerance. These agents cannot be used to substitute for the infused
`routes of prostacyclin because they do not permit delivery of medication at high doses. Inhaled
`nitric oxide (INO) is cleared for the treatment of primary pulmonary hypertension in newborns. It
`is also used off-label to test acute vasoreactivity in PAH during right-heart catheterization and to
`treat acute right-heart failure in hospitalized patients. In addition, some studies on long-term
`application of INO either have been recently completed with results pending or are under consid-
`eration. In the future, because of its inherent advantages in targeting the lung, the inhaled route is
`likely to be tested using a variety of small molecules that show promise as PAH therapies. Key
`words: inhaled route; aerosol therapies; pulmonary hypertension; pulmonary arterial hypertension;
`inhaled nitric oxide. [Respir Care 2015;60(6):794 –805. © 2015 Daedalus Enterprises]
`
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`INHALED THERAPIES FOR PULMONARY HYPERTENSION
`
`Introduction
`
`Rather than discuss aerosol therapies per se, we will
`address inhaled therapies for pulmonary hypertension gen-
`erally because inhaled nitric oxide (INO) is used diagnos-
`tically, has therapeutic potential in pulmonary hyperten-
`sion, and is a gas rather than an aerosol. However, aerosols
`will be the focus of our discussion because 2 have been
`cleared to treat pulmonary arterial hypertension (PAH).
`Before examining inhaled therapies for pulmonary hy-
`pertension, we will first provide an overview of pulmonary
`hypertension, which is defined as a mean pulmonary ar-
`terial pressure of ⱖ 25 mm Hg. The World Symposium on
`Pulmonary Hypertension, most recently held in Nice,
`France, in 2013,1 has classified pulmonary hypertension
`into 5 groups. Group 1 PAH requires a pulmonary artery
`wedge pressure of ⱕ 15 mm Hg and increased pulmonary
`vascular resistance (PVR), calculated as the difference be-
`tween the mean pulmonary arterial pressure and pulmo-
`nary artery wedge pressure divided by the cardiac output.
`Group 1 consists of idiopathic PAH (formerly called pri-
`mary pulmonary hypertension) and associated forms of pul-
`monary hypertension (formerly called secondary pulmonary
`hypertension). PAH may be associated with connective tissue
`disease (especially scleroderma), congenital cardiac shunts,
`portal hypertension, human immunodeficiency virus, and tox-
`ins like fenfluramine and methamphetamine.
`Group 2 is the most prevalent form of pulmonary hy-
`pertension and is related to left-heart disease (systolic,
`diastolic, or valvular). In Group 2 pulmonary hyperten-
`sion, the filling pressure of the left heart (pulmonary artery
`wedge pressure) is ⬎ 15 mm Hg. To maintain the trans-
`pulmonary pressure gradient (mean pulmonary arterial pres-
`sure ⫺ pulmonary artery wedge pressure), the mean pul-
`monary arterial pressure must rise at least concomitantly.
`In most patients, the mean pulmonary arterial pressure
`
`The authors are affiliated with the Division of Pulmonary, Critical Care
`and Sleep Medicine, Tufts Medical Center, Boston, Massachusetts.
`
`Dr Hill presented a version of this paper at the 53rd RESPIRATORY CARE
`Journal Conference, “Aerosol Drug Delivery in Respiratory Care,” held
`June 6–7, 2014, in St Petersburg, Florida.
`
`Dr Hill has disclosed relationships with Ikaria, Reata Pharmaceuticals,
`United Therapeutics, Actelion Pharmaceuticals, Bayer, Gilead Sciences,
`and the Lung Biotechnology Data and Safety Monitoring Board. Dr
`Preston has disclosed relationships with Actelion Pharmaceuticals, Bayer,
`Gilead Sciences, and United Therapeutics. Dr Roberts has disclosed rela-
`tionships with Actelion Pharmaceuticals, Bayer, and United Therapeutics.
`
`Correspondence: Nicholas S Hill MD, Division of Pulmonary, Critical
`Care and Sleep Medicine, Tufts Medical Center, Boston, MA 02111.
`E-mail: nhill@tuftsmedicalcenter.org.
`
`DOI: 10.4187/respcare.03927
`
`increases passively in proportion to the rise in the pulmo-
`nary artery wedge pressure, giving rise to post-capillary
`pulmonary hypertension. In some patients, the pulmonary
`arteries undergo remodeling and constriction, resulting in
`an elevated pre-capillary resistance, thus contributing to
`combined pre- and post-capillary pulmonary hypertension.
`In this instance, the mean pulmonary arterial pressure can
`be substantially higher than what would be expected from
`the increase in pulmonary artery wedge pressure alone.
`Group 3 is pulmonary hypertension associated with
`chronic hypoxemia or parenchymal lung disease, includ-
`ing COPD, interstitial lung disease, particularly idiopathic
`pulmonary fibrosis, and obstructive sleep apnea. Group 4
`is chronic thromboembolic pulmonary hypertension,
`caused by thromboemboli accumulating in the pulmonary
`arteries and failing to resolve. Finally, Group 5 is a mis-
`cellaneous category. Currently, sarcoidosis- and sickle cell-
`related pulmonary hypertension are in this category, along
`with a number of other unusual causes.
`Over the past 20 years, the FDA has cleared 9 therapies
`for PAH. These therapies target one of 3 main signaling
`pathways: prostacyclin, NO, and endothelin. The first clin-
`ically available drug was epoprostenol, a prostacyclin an-
`alogue. Endogenous prostacyclins are derived from ara-
`chidonic acid, which signals through the prostacyclin
`receptor, stimulating adenylate cyclase to generate cyclic
`adenosine monophosphate (cAMP). This intracellular sec-
`ond messenger mediates vasodilatation and inhibition of
`cell proliferation and has antiplatelet actions. The second
`pathway of interest is NO. NO is a potent endogenous
`vasodilator that activates guanylyl cyclase to release cyclic
`guanosine monophosphate (cGMP), which has actions sim-
`ilar to those of cAMP. Finally, endothelin receptor antag-
`onists attenuate the influence of the excess endothelin-1
`signal observed in PAH. All of the available therapies for
`pulmonary hypertension have been cleared for Group 1
`PAH, with one also approved for patients with Group 4
`chronic thromboembolic pulmonary hypertension.
`We discuss the advantages and disadvantages of the inha-
`lation route generally and then examine each of the available
`inhaled therapies individually according to their biochemical
`pathway, reviewing their pharmacology, indications, evidence
`for efficacy, practical applications, and limitations.
`
`Advantages and Disadvantages of Inhaled Therapies
`for Pulmonary Hypertension
`
`The inhaled route offers several significant advantages
`over systemic routes of drug administration (Table 1). First,
`it delivers medication directly to the diseased organ, en-
`abling higher doses locally with less systemic toxicity.
`This can minimize systemic hypotension, a common lim-
`itation in acutely ill patients, because most of the drugs are
`systemic and pulmonary vasodilators. Second, inhaled va-
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`INHALED THERAPIES FOR PULMONARY HYPERTENSION
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`Table 1. Advantages and Disadvantages of the Inhaled Route for
`Administration of Pulmonary Hypertension Medications
`
`Table 2. Advantages and Disadvantages of Nitric Oxide as an
`Inhaled Agent to Treat Pulmonary Hypertension
`
`Advantages
`
`Disadvantages
`
`Advantages
`
`Disadvantages
`
`Local delivery, potentially higher
`concentration of medication in
`the target organ
`Avoidance of systemic adverse
`effects, including systemic
`hypotension
`Delivery to ventilated areas,
`vasodilatation improves V˙ /Q˙
`and gas exchange
`Potentially lower total dose of
`medication with lower cost
`
`V˙ /Q˙ ⫽ ventilation/perfusion ratio
`
`Irritant effects on airways
`
`Odorless and colorless
`
`Limitation of medication dose due
`to airway symptoms
`
`Delivery systems can be
`cumbersome and time-
`consuming
`May be very costly
`
`Rapid-acting, full response
`usually within minutes
`
`Rapid offset, very safe
`
`Short exposure time suitable for
`busy catheterization lab
`setting
`
`No systemic adverse effects due
`to immediate inactivation by
`combining with hemoglobin
`to form methemoglobin
`
`Administration technology very
`expensive at present
`Short duration of effect necessitates
`continuous administration if used
`long-term
`Requires cumbersome portable tanks
`for out-patient use at present*
`Withdrawal syndrome consisting of
`deterioration of hemodynamics and
`gas exchange poses a potential
`impediment to long-term use
`
`sodilators are likely to improve or at least have fewer
`adverse effects on gas exchange compared with other sys-
`temic routes of administration. This is because they are
`delivered to ventilated areas, where their vasodilatory ac-
`tion can enhance blood flow to ventilated regions, enhanc-
`ing ventilation/perfusion matching. On the other hand, sys-
`temically delivered vasodilators indiscriminately dilate the
`pulmonary arterial bed, leading to blunted (or blocked)
`hypoxic vasoconstriction with enhanced blood flow to
`poorly ventilated areas, impairing gas exchange. Third, by
`delivering drug directly to the target organ, inhalation may
`permit reduction of the total medication dose, potentially
`lowering cost.
`The inhaled route also has significant disadvantages.
`Intolerance of inhaled drug administration due to sensiti-
`zation or direct irritant effects of the medications (or the
`excipients) on the airways may result in cough or even
`bronchospasm. Also, control over drug dosing is less pre-
`cise due to variability in breathing patterns and the diffi-
`culty in determining exactly how much medication reaches
`the target regions of the lung. Delivery systems may also
`be cumbersome and difficult to operate, introducing the
`potential for error and inaccurate dose administration. This,
`coupled with cost considerations, may limit practical ap-
`plication of inhaled drugs in the out-patient setting.
`
`The Prostacyclin Pathway
`
`Epoprostenol
`
`Prostacyclins, discovered in 1976 by the Nobel Prize
`winner John Vane, are derived from arachidonic acid via
`the action of prostacyclin synthase.2 Originally character-
`ized by their potent vasodilatory activity, they have since
`been shown to have antiproliferative, pro-apoptotic, and
`antithrombotic properties.3,4 The first prostacyclin cleared
`
`* More portable technology is currently in development.
`
`by the FDA for the treatment of PAH was epoprostenol in
`1995, which was administered by continuous intravenous
`infusion. In the pivotal randomized clinical trial, epopro-
`stenol improved exercise capacity as well as survival (the
`only pulmonary hypertension drug shown to do so in a
`randomized trial).5 Today, it remains a commonly pre-
`scribed agent for the treatment of advanced PAH.
`Although epoprostenol was approved for continuous in-
`travenous infusion, the intravenous formulation can be aero-
`solized and used therapeutically off-label. One of the lim-
`itations of epoprostenol (intravenous and nebulized) is its
`very short half-life (3–5 min). As a result, it requires con-
`tinuous nebulization, rendering it impracticable for long-
`term application. However, for short-term in-hospital ap-
`plications, it has advantages over the intravenous route,
`including less adverse effects on gas exchange or systemic
`blood pressure, making it attractive for treatment of pulmo-
`nary hypertensive crises or vasodilator testing. Notably, even
`though epoprostenol is very expensive when used as a long-
`term continuous infusion, for short-term acute care applica-
`tions, it is much cheaper than INO (see below).
`No large randomized trials have yet evaluated the ap-
`plication of inhaled epoprostenol in subjects with pulmo-
`nary hypertensive crises, but one small study examined its
`short-term effects on hemodynamics and gas exchange in
`a group of subjects with pulmonary hypertension follow-
`ing surgery, including cardiac procedures and lung trans-
`plantation or resection (Table 2).6 After 4 – 6 h of inhaled
`epoprostenol, the mean pulmonary arterial pressure fell
`oxy-
`/FIO2
`significantly, cardiac output rose, and the PaO2
`genation index tended to rise. Furthermore, there was less
`effect on the mean systemic arterial pressure than on the
`mean pulmonary arterial pressure, indicating pulmonary
`selectivity. Although this study suggested that inhaled
`
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`INHALED THERAPIES FOR PULMONARY HYPERTENSION
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`Iloprost
`
`Iloprost is an alternative prostacyclin that was first used
`clinically in Europe, where it is available in some coun-
`tries by inhalation as well as intravenously. It was cleared
`in the United States for inhalation in 2004. It has a longer
`half-life than epoprostenol (7– 8 min) and a half-life of
`pharmacodynamic activity of ⬃0.5 h.8 Although this ne-
`cessitates frequent treatments (at least 6 times/d), iloprost
`is approved for long-term use in out-patients.
`Iloprost was approved based on the Aerosolized Iloprost
`Randomized (AIR) Trial performed in Germany, which
`enrolled 203 subjects, roughly two thirds with idiopathic
`PAH and the remainder with chronic thromboembolic pul-
`monary hypertension.9 Subjects self-administered treat-
`ments an average of 7.8 times/d and realized a highly
`significant placebo-subtracted improvement in 6-min walk
`distance (6MWD) of 36 m (P ⫽ .004) (Fig. 2). In addition,
`the primary outcome variable (a combination of improve-
`ment in New York Heart Association [NYHA] functional
`class of at least 1 and in 6MWD of at least 10% and no
`deterioration or death) occurred in 16.8% of treated sub-
`jects and only 4.9% of controls (P ⫽ .07). In addition,
`significantly more iloprost-treated subjects improved their
`NYHA class, quality-of-life, and dyspnea scores. Of con-
`cern, subjects in the iloprost group more often had syncope
`considered serious, mainly during exertion in the morning.
`This was thought to be possibly related to the lengthy
`period without medication during sleeping hours.
`In subjects with pulmonary fibrosis and pulmonary hy-
`pertension, iloprost, in contrast to an infused prostacyclin,
`had more pulmonary specificity and was less likely to
`increase shunt fraction.10 In a group of 22 children, one
`third were intolerant of inhaled iloprost because of adverse
`airway effects, including cough and bronchospasm.11 Only
`9 subjects tolerated longer-term use, but there were favor-
`able outcomes in these, including improved functional ca-
`pacity. Some evidence supports the use of iloprost as a
`vasodilator in the acute setting. In a nonrandomized cohort
`of 22 mechanically ventilated subjects with residual pul-
`monary hypertension post-thromboendarterectomy, in-
`haled iloprost reduced PVR by 33% in half of the subjects
`compared with no change in the other half, who received
`only inhaled saline.12 Iloprost (25 ␮g) was added to nor-
`mal saline to achieve a volume of 2 mL and was admin-
`istered over 15 min by jet nebulizer via the ventilator’s
`inspiratory limb.
`Inhaled iloprost is administered using the I-neb aerosol-
`ized adaptive delivery system (Philips Respironics, Mur-
`rysville, Pennsylvania), which adapts to patient breathing
`patterns to optimize drug delivery (Fig. 3). However, it
`must be held parallel to the surface of the ground and
`requires a predictable breathing pattern, which some pa-
`tients find challenging. Furthermore, it can take up to 10 min
`
`Fig. 1. Pulmonary vascular resistance (PVR; dyn/s/cm) at baseline
`and after exposure to inhaled nitric oxide (INO; 20 ppm) for 10 min,
`inhaled epoprostenol (EPO; 50 ␮g/min) for 10 min, and the com-
`bination (Combo). * P ⬍ .05 versus baseline. From Reference 7,
`with permission.
`
`epoprostenol may be helpful in such perioperative settings,
`controlled trials are indicated to establish efficacy.
`For short-term use, inhaled epoprostenol is a less ex-
`pensive alternative to INO. To define the relative thera-
`peutic benefits of these 2 agents, we compared them in a
`randomized short-term crossover trial (Fig. 1). 7
`During 10-min exposures between 10-min washout peri-
`ods, we compared INO (20 ppm) and inhaled epoprostenol
`(50 ␮g/min) administered via a vibrating mesh nebulizer
`(Aerogen, Dublin, Ireland). Both agents reduced PVR by
`⬃20%. Interestingly, there were no significant systemic
`hemodynamic differences between the agents, and there
`was no additive effect (beneficial or detrimental) when
`delivered in combination. These data support the concept
`that inhaled epoprostenol is a suitable alternative to INO.
`For these vasodilator trials performed on awake, non-
`intubated subjects, we used a face mask with a well-sealed
`air cushion (Vital Signs, Totowa, New Jersey) and admin-
`istered the aerosol via a T-connector in a single-tube cir-
`cuit with a filter for exhaled gas to prevent epoprostenol
`aerosol from dispersing into the atmosphere. Although a
`mouthpiece might be more efficient for aerosol delivery,
`the use of sedation in the catheterization laboratory and the
`need for multiple hours or even days of administration in
`the ICU render the mouthpiece impractical for most of
`these applications. For mechanical ventilation via endotra-
`cheal tubes, we administered the aerosol via the inhalation
`limb of the ventilator circuit, downstream from the humidi-
`fier. We also placed a filter (Respirgard II, Vital Signs) in the
`exhalation tubing to prevent entry of epoprostenol into the
`exhalation circuitry of the ventilator, where it can be damag-
`ing. We changed the filter every 4 h to prevent saturation and
`increased backpressure. Our institution now uses inhaled
`epoprostenol instead of INO in postoperative patients, and we
`have seen an ⬃90% drop in respiratory therapy costs related
`to INO (personal communication, 2015, Joseph Curro RRT
`MEd, Tufts Medical Center). Additional details on inhaled
`epoprostenol administration are given in Table 3.
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`Table 3. Applications of Currently Available Inhaled Therapies for Pulmonary Hypertension
`
`Agent
`
`Indications
`
`Dose
`
`Cost
`
`Outcomes
`
`Adverse Effects
`
`Nitric oxide
`
`PPHN
`Vasoreactivity testing*
`Hypertensive crises
`Long-term use for PAH
`Epoprostenol Vasoreactivity testing*
`Hypertensive crises*
`
`Iloprost
`
`Treprostinil
`
`Group 1 PAH to improve exercise
`tolerance and symptoms, avoid
`deterioration
`Group 1 PAH to improve exercise
`ability
`
`5–40 ppm
`For 10 min
`For hours to days
`For months to years
`50 ␮g/min via mask
`For 10 min or hours
`to days
`2.5 or 5 ␮g/dose,
`6–9 times/d
`
`3–9 puffs,
`4 times/d*
`
`$100–400/h Decreased mean pulmonary
`artery pressure, PVR,
`improved O2, increased
`6MWD
`
`$36/vial
`
`Decreased mean pulmonary
`artery pressure, PVR
`
`$70,000/y
`
`$100,000/y
`
`Decreased mean pulmonary
`artery pressure, increased
`6MWD
`Increased 6MWD
`
`Possible withdrawal
`
`Possible withdrawal, cough,
`headache, jaw ache,
`nausea, diarrhea
`Cough, wheeze, headache,
`flushing, trismus, nausea,
`diarrhea, syncope
`Cough, wheeze, headache,
`throat, irritation, nausea,
`diarrhea, syncope
`
`* Off-label application.
`PPHN ⫽ persistent pulmonary hypertension of the newborn
`PAH ⫽ pulmonary arterial hypertension
`PVR ⫽ pulmonary vascular resistance
`6MWD ⫽ 6-min walk distance
`
`usually prescribed for out-patients with moderate-to-se-
`vere PAH who are not deemed to be sick enough for, are
`poor candidates for, or have declined infusion therapy. It is
`supplied by specialty pharmacies that employ specialized
`nurses to educate patients on proper application of the
`device (see Table 3).
`In summary, inhaled iloprost is effective in patients with
`idiopathic PAH in improving exercise capacity and dys-
`pnea. The inhaled route is associated with fewer adverse
`effects on gas exchange or systemic symptoms and hemo-
`dynamics compared with intravenous drug delivery. De-
`spite these benefits, application of inhaled iloprost has
`been limited due to frequent airway symptoms and the
`significant time investment required for compliance with
`recommended dose frequency and for maintenance of the
`nebulizer apparatus. Finally, given that the estimated half-
`life of action is in the range of 0.5 h even with 6 –9 times
`daily dosing, patients using it are not exposed to active
`drug most of the time.8
`
`Treprostinil
`
`Treprostinil, another prostacyclin analogue, was first
`cleared for subcutaneous use in 2002, intravenous use in
`2007, and inhalation in 2011. Compared with other com-
`mercially available prostacyclins, treprostinil has the lon-
`gest half-life (3– 4 h), which translates to a longer dosing
`interval when administered by inhalation.13 Inhaled trepro-
`stinil was cleared by the FDA in 2011 based on the results
`of the TRIUMPH I (Double Blind Placebo Controlled Clin-
`ical Investigation Into the Efficacy and Tolerability of In-
`haled Treprostinil Sodium in Patients With Severe Pulmo-
`
`Fig. 2. Iloprost effect on 6-min walk distance in the 12-week Aero-
`solized Iloprost Randomized (AIR) Trial. * P ⫽ .004. From Refer-
`ence 9, with permission.
`
`Fig. 3. A: I-neb, courtesy Philips Respironics. B: TD-100, courtesy
`United Therapeutics.
`
`(or sometimes more) to administer each dose and requires
`daily cleaning and maintenance. Many patients find this
`cumbersome and have difficulty keeping up with the rec-
`ommended 6 doses/d. The Venta nebulizer is an alterna-
`tive device used more often in Europe. Inhaled iloprost is
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`nary Arterial Hypertension) Trial, which randomized 235
`subjects into inhaled treprostinil versus placebo groups.14
`All subjects were on background monotherapy: approxi-
`mately two thirds on bosentan and one third on sildenafil.
`Overall improvement in the median 6MWD was 20 m
`(P ⫽ ⬍.001). Post hoc subgroup analyses indicated that
`the improvement was significant for subjects on back-
`ground bosentan (25 m) but not for those taking sildenafil
`(9 m), although the study was not powered adequately for
`such analysis. Secondary outcomes also showing signifi-
`cant improvements with inhaled treprostinil included N-
`terminal pro-brain natriuretic peptide and quality of life
`(Minnesota Living with Heart Failure Questionnaire scale),
`but no differences were apparent in rate of clinical wors-
`ening, dyspnea score, or NYHA functional class. Adverse
`effects encountered significantly more frequently in the
`treprostinil group included cough (54 vs 29%), headache
`(41 vs 23%), and flushing (17 vs 1%). Data for inhaled
`treprostinil are lacking for pediatric and acute care appli-
`cations.
`Treprostinil aerosol is administered via the Opti-Neb
`(Teleflex Medical, Reading, Pennsylvania), which, like the
`I-neb, requires assembly, cleaning, and maintenance (see
`Fig. 3 and Table 3). However, treprostinil is administered
`4 times/d, with up to 12 puffs each time, but less time is
`needed compared with I-neb treatments, which require
`many more steady breaths until the treatment is finished.
`Thus, acceptance of and adherence to the Opti-Neb tends
`to be better (personal observation). Like iloprost, inhaled
`treprostinil is prescribed for out-patients, usually as an
`add-on therapy via specialty pharmacies that provide spe-
`cialized nurses for teaching and technical support.
`Compared with benefits demonstrated with other ther-
`apies, inhaled treprostinil is arguably less potent, consid-
`ering that the improvement in 6MWD was less, and clin-
`ical worsening and NYHA end points were not met.14 On
`the other hand, it is important to consider that all subjects
`in the TRIUMPH I Trial were on background therapy,
`which generally reduces the increase in 6MWD compared
`with de novo therapy. Furthermore, relatively few events
`occurred in the control group, making it unlikely that the
`treatment arm could sufficiently reduce events to achieve
`a significant benefit for clinical worsening. On the other
`hand, in a small retrospective cohort (18 subjects) transi-
`tioned from infusion prostacyclins to inhaled treprostinil, a
`minority of subjects deteriorated over the ensuing 7 months,
`leading the authors to advise caution and close monitoring
`after such transitions.15 Conversely, subjects with PAH who
`were deteriorating on inhaled treprostinil were successfully
`transitioned to intravenous or subcutaneous treprostinil.16
`Given the limitations, inhaled iloprost and treprostinil
`are used less often in the PAH population compared with
`the oral or infused medications. Their best application ap-
`pears to be for patients who are already on one or 2 oral
`
`agents and have not reached improvement goals, but are
`not candidates for or have not deteriorated enough to war-
`rant infusion therapy. On the other hand, these therapies
`would be poor choices for initial therapy because of lim-
`ited efficacy and cost (⬎ $100,000/y), and they should not
`be used as substitutes for infusion therapy when needed to
`rescue unstable patients.
`
`Nitric Oxide/cGMP Pathway
`
`Nitric Oxide
`
`Nitric oxide is an endogenous vasodilator and maintains
`low basal tone in vascular beds.17 It has multiple actions,
`including antiproliferative and anti-inflammatory effects
`under physiologic conditions. However, in pathologic
`states, inducible nitric oxide synthase increases NO re-
`lease, which can have pro-inflammatory and toxic effects,
`especially when peroxynitrite is formed by the interaction
`of NO and superoxide.18 Nitric oxide is produced by a
`number of different cell types, but endothelial cells are
`important sources in the vasculature. It acts very rapidly
`and is almost immediately inactivated by combining with
`hemoglobin to form methemoglobin. Accordingly, it has
`very few systemic adverse effects, which is one of its big
`advantages (see Table 1).
`In adults, INO is used off-label in the catheterization
`laboratory to test acute pulmonary vasoreactivity, seeking
`to identify patients who may be long-term responders to
`calcium channel blocker therapy. According to current prac-
`tice standards, a positive acute vasodilator response is de-
`fined as a fall in mean pulmonary arterial pressure of at
`least 10 mm Hg to below 40 mm Hg without a reduction
`in cardiac output.19 Acute vasoreactivity also has some
`prognostic significance. Subjects who experience a ⬎ 30%
`drop in PVR have a better prognosis than non-respond-
`ers.20 INO is also used quite commonly to treat acute
`pulmonary hypertensive crises due to conditions such as
`deteriorating chronic pulmonary hypertension; acute right-
`heart failure following massive pulmonary embolism, car-
`diac surgery, and heart or lung transplantation; or after
`lung resection surgery. Although some reports have dem-
`onstrated favorable hemodynamic effects of INO (includ-
`ing decreased mean pulmonary arterial pressure and PVR
`and increased cardiac output),21 there are no data from
`adequately controlled trials to support its routine use in
`these clinical settings.
`NO has 2 main disadvantages. First, it is very expensive
`as currently formulated. Cost via currently available tech-
`nology can reach $12,000/month, which is prohibitive at
`most institutions. At institutions with a neonatology unit,
`INO is used for its only FDA-approved application, per-
`sistent pulmonary hypertension of the newborn, a rare form
`of PAH Group 1. In this context, INO use in vasodilator
`
`RESPIRATORY CARE • JUNE 2015 VOL 60 NO 6
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`799
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`Liquidia's Exhibit 1079
`Page 6
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`INHALED THERAPIES FOR PULMONARY HYPERTENSION
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`trials during right-heart catheterization in adults with PAH
`adds marginally to cost. At institutions lacking neonatol-
`ogy units, however, it is frequently cost-prohibitive, and
`intravenous or inhaled epoprostenol or older agents such
`as intravenous adenosine are used more often for vasore-
`activity testing. Second, when administration is too rapidly
`discontinued, patients may experience a withdrawal syn-
`drome, characterized by rebound pulmonary hypertension.
`In one ICU study on use of INO to treat acute pulmonary
`hypertensive crises due to a variety of etiologies, two thirds
`of the subjects encountered withdrawal, and mortality was
`⬎ 50%.22 Some evidence suggests that co-administration
`of sildenafil may be helpful in mitigating the withdrawal.23
`For in-patient applications of INO, our institution uses
`the same face mask as that used with inhaled epoprostenol
`and the INOmax DS (Ikaria, Hampton, New Jersey), which
`enables the user to quickly and accurately provide INO in
`doses ranging from 1 to 80 ppm by mixing pressurized NO
`and oxygen via adjustment of bleeder valves. For vasodi-
`lator testing and for most clinical applications, we use
`10 –20 ppm, concentrations that are generally adequate to
`bring about maximal vasodilatation.6 The INOmax also
`monitors nitrogen dioxide (NO2) concentration, a toxic
`metabolite of the reaction between NO and oxygen, to
`ensure that levels stay below safe limits. Considering that
`NO concentrations are low and the exposure is brief, we
`have not seen problems with excessive NO2 levels during
`vasoreactivity testing. For pulmonary hypertensive crises,
`we use the same range of INO concentrations as used for
`acute vasodilator testing and the same face mask. During
`use of both INO and inhaled epoprostenol, standard moni-
`toring includes a pulmonary artery catheter, although lower-
`ing pulmonary arterial pressure to a desirable level is often
`not possible, and with applications of INO for more than a
`few hours, methemoglobin levels should be checked period-
`ically.
`In older literature, there are several reports of therapeu-
`tic use of INO in out-patients with chronic pulmonary
`hypertension. These systems use pulsed nasal oxygen de-
`vices with compressed tanks containing 80 ppm NO pulsed
`for 0.1 s via one cannula and providing continuous oxygen
`via the other. Channick et al24 reported decreases in mean
`pulmonary arterial pressure (from 51 to 43 mm Hg) and
`PVR (from 790 to 620 dyn/s/cm) in subjects with idio-
`pathic PAH using this system. Preston et al25 reported their
`experience using a similar system for long-term out-pa-
`tient INO, demonstrating acute vasoresponsiveness in 7 of
`8 subjects with pulmonary hypertension related to sarcoid-
`osis and improvements in 6MWD in all 5 subjects who
`continued therapy for the subsequent 2– 4 months. Further
`research on and clinical use of long-term INO have been
`stymied by the high cost and lack of insurance coverage
`for off-label applications after FDA approval for persistent
`pulmonary hypertension of the newborn, but interest has
`
`resurged recently. We are anxiously awaiting results of a
`recently completed phase-2 trial sponsored by Ikaria on
`long-term INO in subjects with Group 1 PAH. Other man-
`ufacturers are working on technology that can deliver INO
`via compact canisters suitable for ambulatory use. GeNO
`(Cocoa, Florida) is developing a device that generates NO
`via a chemical reaction from liquid NO2 and that can
`provide INO for up to several days from a container that
`fits in a fanny pack.
`INO has an established role as a testing agent for pul-
`monary vasoreactivity, but its role as a therapeutic agent in
`either acute or chronic pulmonary hypertension remains to
`be established. It is used frequently for acute pulmonary
`hypertensive crises, but without evidence to demonstrate
`efficacy beyond acute vasodilator effects. For longer-term
`out-patient applications, it could be used as an add-