Pulmonary
`
`Sildenafil for Pulmonary Hypertension
`
`Audrey J Lee, Teresa B Chiao, and Mildred P Tsang
`
`OBJECTIVE: To evaluate the efficacy of sildenafil for treatment of pulmonary hypertension.
`DATA SOURCES: Literature retrieval was accessed through MEDLINE (1977–March 2005), Cochrane Library, and International
`Pharmaceutical Abstracts (1977–March 2005) using the terms sildenafil and pulmonary hypertension. In addition, reference
`citations from publications identified were reviewed.
`STUDY SELECTION AND DATA EXTRACTION: All articles in English identified from the data sources were evaluated. Studies including
`>5 patients with primarily adult populations were included in the review.
`DATA SYNTHESIS: The treatment of pulmonary hypertension is challenging. Sildenafil has recently been studied as monotherapy and
`in combination with other vasodilators in the management of pulmonary hypertension. Eight hemodynamic studies and 12 clinical
`trials were reviewed (1 retrospective, 3 double-blind, 8 open-label). Sildenafil reduced pulmonary arterial hypertension and
`pulmonary vascular resistance/peripheral vascular resistance index and tended to increase cardiac output/cardiac index compared
`with baseline. Sildenafil was comparable to nitric oxide and at least as effective as iloprost or epoprostenol in terms of its pulmonary
`vasoreactivity. Combination therapy with iloprost, nitric oxide, or epoprostenol resulted in enhanced and prolonged pulmonary
`vascular effects. Clinical trials suggest that sildenafil improves exercise tolerance and New York Heart Association functional class,
`but large, randomized controlled trials are needed to confirm these findings. Overall, sildenafil was well tolerated.
`CONCLUSIONS: Overall, sildenafil is a promising and well-tolerated agent for management of pulmonary hypertension. Further well-
`designed trials are warranted to establish its place in the treatment of pulmonary hypertension.
`KEY WORDS: pulmonary hypertension, sildenafil.
`Ann Pharmacother 2005;39:869-84.
`
`Published Online, 12 Apr 2005, www.theannals.com, DOI 10.1345/aph.1E426
`ACPE UNIVERSAL PROGRAM NUMBER: 407-000-05-015-H01
`
`THIS ARTICLE IS APPROVED FOR CONTINUING EDUCATION CREDIT
`
`Pulmonary hypertension, characterized by a mean pul-
`
`monary arterial pressure (PAP) >20 mm Hg at rest, may
`result in progressive right ventricular heart failure and early
`mortality, depending on the etiology.1,2 As a result, early di-
`agnosis and prompt management are imperative to treat the
`underlying cause of pulmonary hypertension.1-4 Pulmonary
`hypertension may result from increased pulmonary blood
`flow, increased pulmonary vascular resistance, or both. Al-
`though the incidence of pulmonary hypertension of all
`causes has not been reported, the annual incidence of a rare
`form, idiopathic pulmonary hypertension (IPAH), is esti-
`mated to be 1–2 per million of the population.5
`A variety of commercially available vasodilators have
`been used as monotherapy or in combination to treat pul-
`
`Author information provided at the end of the text.
`
`monary hypertension.2,4-9 Since many of these agents are
`costly, toxic, inconvenient to administer, or partially effec-
`tive or ineffective in certain patients, other agents have been
`investigated for pulmonary hypertension.2,4,6-9 Recently,
`sildenafil, a phosphodiesterase inhibitor approved for the
`treatment of erectile dysfunction, has been investigated for
`the treatment of pulmonary hypertension in both pediatric
`and adult patients.4,6,8,10-16 The purpose of this review is to
`evaluate the efficacy and safety of sildenafil in predomi-
`nantly adult patients with pulmonary hypertension.
`
`Etiology
`
`One of the most common classes of pulmonary hyper-
`tension is pulmonary arterial hypertension (PAH), which
`can be idiopathic (IPAH) or the result of other etiologies
`such as collagen vascular disease, portal hypertension, cer-
`
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`AJ Lee et al.
`
`tain drugs/toxins (eg, fenfluramine, dexfenfluramine, am-
`phetamines, cocaine, L-tryptophan, inhaled rapseed oil), or
`vascular/cardiac shunts.5,17,18 Other major classes of pul-
`monary hypertension include pulmonary venous hyperten-
`sion, pulmonary hypertension associated with respiratory
`system diseases and/or hypoxemia (eg, chronic obstructive
`pulmonary disease (COPD), alveolar–capillary dysplasia,
`interstitial lung disease), chronic thrombotic and/or embol-
`ic diseases, and inflammatory disorders affecting the pul-
`monary vasculature (eg, sarcoidosis).
`
`Diagnosis
`
`Pulmonary hypertension is defined by the presence of a
`mean PAP >20 mm Hg at rest or >30 mm Hg with exer-
`cise.5 In particular, the definition of PAH is a mean PAP
`>25 mm Hg with a pulmonary capillary pressure <15
`mm Hg.3 Depending on the etiology of pulmonary hyper-
`tension, pulmonary vascular resistance (PVR) may be ele-
`vated, as exemplified by patients with PAH who have PVR
`>160 dynes•sec/cm–5.19 Diagnosis and determination of the
`etiology and severity of pulmonary hypertension are estab-
`lished by right cardiac catheterization.1,3,5 Doppler echocar-
`diography can also be used to provide evidence for the eti-
`ology and diagnosis of pulmonary hypertension.3 Many
`patients do not present with symptoms until their PAP ex-
`ceeds 3–5 times baseline.1 Thus, diagnosis is often delayed
`because patients may present with either no symptoms or
`nonspecific symptoms.1,3
`Severity of pulmonary hypertension is based upon the
`World Health Organization (WHO) functional classifica-
`tion, which integrates symptoms of dyspnea, fatigue, chest
`pain, or syncope with the New York Heart Association
`(NYHA) functional classification of physical activity (Table
`1).3 The most common early symptom of pulmonary hyper-
`tension is exertional dyspnea,3,5 which can be measured using
`the Borg dyspnea index (scale of 1–10; 1 = non-exertion, 10
`= maximal exertion).20 Disease progression and response to
`
`Table 1. WHO Functional Classification of
`Pulmonary Hypertensiona
`
`Class
`
`Population
`
`I
`
`II
`
`III
`
`IV
`
`no limitation in physical activity; ordinary physical activity
`does not cause dyspnea or fatigue
`slight limitation in physical activity; ordinary physical activity
`produces dyspnea, fatigue, chest pain, or near syncope; no
`symptoms at rest
`marked limitation of physical activity; less than ordinary
`physical activity produces dyspnea, fatigue, chest pain, or
`near syncope; no symptoms at rest
`unable to perform any physical activity without symptoms;
`dyspnea and/or fatigue present at rest; discomfort increased
`by any physical activity
`
`WHO = World Health Organization.
`aUses the New York Heart Association functional classification to cat-
`egorize the level of physical activity.
`
`treatment are frequently based upon NYHA/WHO function-
`al assessment and the 6-minute walk test.3
`
`Treatment
`
`Initial treatment of pulmonary hypertension should be
`directed at the underlying etiology so that it may result in
`clinical improvement or resolution.1,5,7,9 Complete remis-
`sion of pulmonary hypertension is rare, but has been ob-
`served in patients receiving appetite suppressants that were
`discontinued7 and in patients receiving certain surgical in-
`terventions (eg, thromboendarterectomy for acute pul-
`monary emboli or mitral valve surgery).4 Most patients re-
`ceive medical management to ameliorate symptoms, as
`surgical options such as lung transplants are not readily
`available and some patients are not appropriate transplant
`candidates.
`
`MEDICAL MANAGEMENT
`
`Most patients receive medical management to amelio-
`rate their symptoms.4-6,8,9 Patients can receive treatment
`with supplemental oxygen, diuretics, digoxin, and warfarin
`depending on the etiology and severity of their disease.4,5,9
`In addition, vasodilators, such as calcium-channel block-
`ers, are considered the mainstay of therapy for certain pa-
`tients with pulmonary hypertension, particularly those with
`PAH.4 Since PAH is one of the more common causes of
`pulmonary hypertension, various drug treatments targeting
`its management are discussed in greater detail.
`Recently, the American College of Chest Physicians
`(ACCP) published evidence-based clinical practice guide-
`lines for PAH (Figure 1).4 The ACCP recommends acute
`vasodilator testing for patients with PAH for evaluation of
`their response to therapy prior to administering chronic va-
`sodilator therapy. The ACCP defines a positive response to
`these vasodilators as a reduction in PAP of at least 10 mm
`Hg to ≤40 mm Hg, with an increased or unchanged cardiac
`output (CO). Others have defined a positive response as a
`mean reduction in PVR and PAP >20% with an increase in
`cardiac index (CI), but with minimal changes in mean arte-
`rial pressure and oxygen saturation.9,21 Short-acting va-
`sodilators, including intravenous epoprostenol, adenosine,
`and nitric oxide, have been used for vasodilator testing.4,22
`Nitric oxide is frequently used in research and clinical
`practice as the standard screening agent for vasoactivity
`because, in contrast to adenosine and epoprostenol, it usu-
`ally does not cause hypotension and other systemic effects.
`However, nitric oxide is rarely used as long-term treatment
`because it requires continuous nebulization due to its short
`half-life and is not approved for pulmonary hyperten-
`sion.19,22
`Table 2 describes the commercially available vasodila-
`tors in the US and selective investigational agents used for
`long-term treatment of pulmonary hypertension including
`their mechanism of action, usual dosing regimens, toxici-
`ties, advantages, and limitations.4,6,8,23,24 In prospective
`long-term trials (3 mo–5 y), these agents have demonstrat-
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`ed significant improvements or improved trends (be-
`raprost) in cardiopulmonary hemodynamic endpoints, in-
`cluding mean decreases in right atrial pressure, PVR, and
`PAP combined with mean increases in CI.25-33 In addition,
`these agents have significantly increased exercise capacity,
`decreased dyspnea, and improved NYHA or WHO func-
`tional class. To date, epoprostenol and calcium-channel
`blockers are the only agents that have increased survival,
`predominantly in patients with IPAH.4,21,29 Because of the
`many limitations of these vasodilators, other agents have
`been investigated for the management of pulmonary hy-
`pertension, including sildenafil.
`
`Sildenafil for Pulmonary Hypertension
`
`PDE-5, causing decreased hydrolytic breakdown of cGMP.
`As a result, sustained and increased cGMP concentrations
`accumulate in the pulmonary smooth muscle vasculature.
`Activation of cGMP kinase then occurs, leading to the
`opening of potassium channels, resulting in pulmonary va-
`sodilation.4,16 In support of the pharmacologic effects of
`sildenafil, data in humans have shown that nitric oxide
`plus sildenafil treatment results in synergistic increases in
`arterial cGMP levels compared with nitric oxide or silde-
`nafil monotherapy.19
`
`Clinical Trials
`
`Pharmacology of Sildenafil
`
`High concentrations of cyclic nucleotide phosphodi-
`esterase-5 (PDE-5) isoenzymes are found in the lung tis-
`sue.4 This enzyme rapidly degrades cyclic guanosine-
`monophosphate (cGMP), a secondary intracellular mes-
`senger that mediates the activity of nitric oxide (or
`endothelial-derived relaxing factor).4,34 Sildenafil inhibits
`
`In healthy volunteers, a randomized double-blind study
`demonstrated that oral sildenafil 100 mg almost complete-
`ly reversed the pulmonary arterial vasoconstriction in-
`duced by hypoxic conditions.35 A number of case reports
`have also documented the potential benefits of sildenafil in
`patients with pulmonary hypertension.11,36,37 Many of these
`cases are summarized in detail in one review.11 Short- and
`long-term studies evaluating the hemodynamic and clinical
`
`Figure 1. Therapy for PAH for Functional NYHA Class II–IV.4 A = Grade of recommendation. Level of evidence good, benefit substantial; B = Grade of recom-
`mendation. Level of evidence fair, benefit intermediate; C = Grade of recommendation. Level of evidence low, benefit intermediate.
`CCB = calcium-channel blocker; NYHA = New York Heart Association; PAH = pulmonary arterial hypertension; PDE-5 = phosphodiesterase-5.
`
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`AJ Lee et al.
`
`effects of sildenafil as monotherapy and in combination
`with other agents in ≥5 patients with pulmonary hyperten-
`sion are discussed here. Specific dosing regimens used for
`all evaluated therapies are described in Tables 3 and 4.
`
`tients with a mean age range of 18–81 years. The predom-
`inant diagnosis was IPAH in 6 of the studies,19,38,40-42,44
`whereas the remaining 2 trials had a heterogeneous patient
`population.39,43 Sildenafil was administered orally in these
`studies, with single doses ranging from 12.5 to 75 mg.
`
`SINGLE-DOSE HEMODYNAMICS
`
`Noncomparative
`
`As shown in Table 3, 8 open-label trials compared the
`hemodynamic effects of sildenafil with those of other va-
`sodilator drugs in patients with pulmonary hyperten-
`sion.19,38-44 These studies included between 5 and 60 pa-
`
`Sildenafil had decreased trends38,39 or significant de-
`creases in PAP19,40,43 and PVR or PVR index19,38,40 com-
`pared with baseline.19,38,40,43 Sildenafil also demonstrated
`significant improvements19,38,43 or trends39,40 in CO/CI com-
`
`Table 2. Comparison of Commercially Available Agents in the US and Selected Investigational Drugs
`for Pulmonary Hypertension
`
`Drug
`
`Mechanism
`of Action
`
`Calcium-channel blockersb
`nifedipine
`blocks vascular
`smooth muscle
`calcium chan-
`nels
`
`Regimen
`
`Toxicity
`
`titrate dose
`gradually as
`toleratedc
`
`edema,
`headache,
`hypoxia,
`hypotension
`
`Long-Term
`Clinical
`Studies
`
`Mortality
`IPAH Othera Benefit
`
`yes
`
`no
`
`yesd
`
`Advantages
`
`Limitations
`
`inexpensive, available
`po, regression in LVH,
`survival benefits
`
`useful in only 25–30%
`of pts. with IPAH; no
`randomized controlled
`trials; high doses may
`be required; may cause
`clinical deterioration in
`pts. with COPD or
`parenchymal lung dis-
`ease (worsening oxy-
`gen desaturation; V/Q
`mismatch)
`useful in only 25–30%
`of pts. with IPAH; no
`randomized controlled
`trials; high doses may
`be required; may cause
`clinical deterioration in
`pts. with COPD or
`parenchymal lung dis-
`ease (worsening oxy-
`gen desaturation; V/Q
`mismatch)
`
`diltiazem
`
`blocks vascular
`smooth muscle
`calcium chan-
`nels
`
`titrate dose
`gradually as
`toleratedc
`
`bradycardia,
`heart block,
`edema,
`headache,
`hypotension,
`hypoxia
`
`yes
`
`no
`
`yesc
`
`inexpensive, available
`iv and po, survival
`benefits
`
`Endothelin receptor antagonist
`inhibits the vaso- weight ≤40 kg: dose-related
`bosentan
`constricting
`62.5 mg bid
`hepatotoxicity
`action of endo- weight >40 kg: dose-related
`thelin, inhibits
`62.5 mg bid
`anemia
`proliferation of
`for 4 wk, then
`(usually
`vascular smooth 125 mg bid
`mild),
`muscle cells,
`nasopharyn-
`reverses pul-
`gitis, edema,
`monary vascular
`syncope,
`remodeling,
`flushing,
`RVH
`headache,
`teratogenic
`effects
`
`yes
`
`yes
`
`not shown available po, approved high cost;
`for pts. with NYHA
`hepatotoxic and terato-
`class II–IV PAH
`genic CYP3A4 and
`2C9 inducer, concur-
`rent use of glyburide
`and cyclosporine
`contraindicated, not
`available iv
`
`ACCP = American College of Chest Physicians; COPD = chronic obstructive pulmonary disease; IPAH = idiopathic pulmonary arterial hypertension;
`LVH = left ventricular hypertrophy; NYHA = New York Heart Association; PAH = pulmonary arterial hypotension; RVH = right ventricular hypertrophy;
`V/Q = ventilation/perfusion.
`aOther indications include pulmonary hypertension due to non-primary pulmonary hypertension, appetite suppressants, collagen vascular disease
`or connective tissue disease (eg, scleroderma), chronic thromboembolic pulmonary hypertension, congenital heart disease (left-to-right shunts).
`bCalcium-channel blockers are mainly studied in patients with IPAH. Verapamil should usually be avoided because of its negative inotropic effects. Hemo-
`dynamic effects of amlodipine and felodipine have been studied in patients with pulmonary hypertension, but no long-term clinical trials have been
`conducted.
`cBased upon the ACCP guidelines for pulmonary arterial hypertension.
`dOnly with IPAH.
`
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`pared with baseline. Ghofrani et al.43 demonstrated that silde-
`nafil produced dose-dependent changes in CI, PAP, and PVR
`index, although significant differences were not reported be-
`tween the 12.5- and 50-mg doses. Several studies39,43 report-
`ed that sildenafil decreased the ratio of pulmonary to sys-
`
`temic vascular resistance, suggesting pulmonary vascular se-
`lectivity; however, the results of one of these trials suggested
`that sildenafil may be less pulmonary selective at higher dos-
`es.43 Sildenafil had either no effect on arterial saturation or in-
`creased partial pressure of arterial oxygen.19,39,40,43
`
`Sildenafil for Pulmonary Hypertension
`
`Table 2. Comparison of Commercially Available Agents in the US and Selected Investigational Drugs for
`Pulmonary Hypertension (continued)
`
`Long-Term
`Clinical
`Studies
`
`Mortality
`IPAH Othera Benefit
`
`yes
`
`yes
`
`yes
`
`Advantages
`
`Limitations
`
`approved for pts. with high cost, short half-life
`NYHA class III–IV
`(3–5 min), requires
`PAH, sustained
`indwelling central
`survival benefits in
`venous catheter/
`pts. with IPAH with
`pump, most pts. require
`NYHA Class III, IV
`warfarin to prevent
`catheter-induced
`thrombosis, drug
`instability (requires
`storage on ice after
`preparation and
`unstable at acidic pH),
`tolerance occurs,
`rebound pulmonary
`hypertension after
`discontinuation, may
`cause oxygen de-
`saturation V/Q
`mismatch in pts. with
`lung parenchymal dis-
`ease or fibrosis
`high cost, administered
`sc via an abdominal
`wall catheter by a small
`infusion pump, rebound
`pulmonary hypertension
`after discontinuation,
`has potential for caus-
`ing oxygen desaturation
`in pts. with lung paren-
`chymal disease,e pain/
`erythema at infusion
`site
`inconvenient administra-
`tion, hemodynamic
`effects resolve within
`30–90 min after
`inhalation
`
`not shown no indwelling central
`venous iv line, no
`line-related compli-
`cations, stable at
`room temperature,
`longer half-life than
`epoprostenol (3–4 h)
`
`not shown well tolerated, no
`line-related complica-
`tions, no indwelling
`central venous line,
`longer half-life than
`epoprostenol
`(20–25 min)
`
`yes
`
`yes
`
`yes
`
`yes
`
`Drug
`
`Mechanism
`of Action
`
`Regimen
`
`Toxicity
`
`Prostaglandin analogs
`1–2 ng/kg/min
`epoprostenol acts as a non-
`iv, then 1–2
`selective vaso-
`ng/kg/min
`dilator, inhibits
`platelets, inhibits as tolerated
`smooth muscle
`or until relief
`proliferation
`of dyspnea
`(average
`2–40 ng/kg/
`min)
`
`jaw pain,
`myalgias,
`leg/feet pain,
`headache,
`flushing,
`rash, hypo-
`tension,
`arrhythmias,
`nausea,
`anorexia,
`edema, iv
`line-related
`complications
`(eg, throm-
`bosis, sepsis,
`cellulitis,
`pneumo-
`thorax,
`hemothorax)
`
`treprostinil
`
`acts as a non-
`selective vaso-
`dilator, inhibits
`platelets, inhibits
`smooth muscle
`proliferation
`
`1.25 ng/kg/min jaw pain, myal-
`sc and ↑ by
`gias, head-
`1.25 ng/kg/min ache, flushing,
`over 4 wk,
`diarrhea,
`usual minimal
`nausea/vom-
`effective dose
`iting, edema,
`13.8 ng/kg/min,
`rash, infusion
`maximum
`site reactions
`studied dose
`(eg, pain,
`40 ng/min
`erythema,
`induration)
`
`iloprost
`
`beraprost
`
`acts as a non-
`selective vaso-
`dilator, inhibits
`platelets, inhibits
`smooth muscle
`proliferation
`
`jaw pain, head-
`2.5–5 µg
`ache, cough-
`inhaled
`ing, flushing,
`over 5 min
`(jet nebulizers) syncope on
`or 15 min
`exertion (not
`(ultrasound
`associated
`nebulizers)
`with clinical
`6–9 times/day
`deterioration)
`20 µg po qid,
`jaw pain, head-
`acts as a non-
`increase by
`ache, dizzi-
`selective vaso-
`20 µg po qid
`ness, flushing,
`dilator, inhibits
`platelets, inhibits each wk if tol-
`leg pain,
`smooth muscle
`erated (max-
`nausea,
`proliferation
`imum 120 µg
`diarrhea
`qid), median
`80 µg qid
`
`yes
`
`yes
`
`not shown po formulation, no line- orphan drug, hemody-
`related complications, namic effects may
`no indwelling central
`decrease with time
`venous line, longer
`half-life than epo-
`prostenol (35–40 min)
`
`ACCP = American College of Chest Physicians; IPAH = idiopathic pulmonary arterial hypertension; NYHA = New York Heart Association; PAH = pul-
`monary arterial hypotension; V/Q = ventilation/perfusion.
`aOther indications include pulmonary hypertension due to non-primary pulmonary hypertension, appetite suppressants, collagen vascular disease
`or connective tissue disease (eg, scleroderma), chronic thromboembolic pulmonary hypertension, congenital heart disease (left-to-right shunts).
`eSimilar to epoprostenol; therefore, it may cause clinical deterioration in patients with lung parenchymal disease, although, as of March 14, 2005, this
`has not been documented in the literature.
`
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`

`other NR
`oxygen (16),
`long-term nasal
`oxygen (9)
`specified),
`vasodilators (not
`previously on
`
`E (1), oxygen (5)
`CCBs (6),
`diuretics (11),
`warfarin (9),
`
`Regimena(n)
`Treatment
`
`Therapy (n)
`
`Other
`
`III (6)
`IV (10),
`
`other [6])
`CREST [3],
`(IPF [7],
`LF (16)
`
`M (6)
`F (10)
`
`56.5
`27–79, median
`
`N = 16
`OL, R
`
`(2002)39
`Ghofrani et al.
`
`NR
`
`IPAH (9)
`
`M (2)
`F (7)
`
`N = 9
`OL, non-R28–75, mean 47
`
`(2002)38
`Lepore et al.
`
`II (1)
`III (3),
`IV (9),
`
`Class (n)
`NYHA
`
`LVD (2)
`PAH (2),
`IPAH (9),
`
`M (4)
`F (9)
`
`N = 13
`OL, non-R35–56, mean 44
`
`et al. (2002)19
`Michelakis
`
`Gender Diagnosis
`
`(n)
`
`(n)
`
`Age (y)
`
`Design
`
`Reference
`
`AJ Lee et al.
`
`Table 3.Single-Dose Hemodynamic Studies Involving Sildenafil
`
`(continued on page 875)
`
`cPercent change calculated using formula based upon absolute hemodynamic values: (baseline–treatment)/baseline ×100.
`bEstimated from figure since not reported in the text.
`aSildenafil given orally, NO and iloprost by inhalation, and epoprostenol by intravenous infusion.
`sistance; PVRI = peripheral vascular resistance index; R = randomized; S = sildenafill.
`pressure; NO = nitric oxide; NR = not reported; NYHA = New York Heart Association; OL = open-label; PAH = pulmonary arterial hypertension; PAP = pulmonary arterial pressure; PVR = peripheral vascular re-
`tasia syndrome; E = epoprostenol; I = iloprost; IPAH= idiopathic pulmonary arterial hypertension; IPF = idiopathic pulmonary fibrosis; LF = lung fibrosis; LVD = left ventricular dysfunction; MAP = mean arterial
`ADRs = adverse drug reactions; CCBs = calcium-channel blockers; CI = cardiac index; CO = cardiac output; CREST = calcinosis, the Raynaud phenomenon, esophageal dysfunction, sclerodactyly, telangiec-
`
`I (6)
`CCBs (3),
`
`II (4)
`III (5),
`IV (1),
`
`IPAH (10)
`
`M (3)
`F (7)
`
`N = 10
`OL, non-R33–59, mean
`
`46.1
`
`(2004)40
`Leuchte et al.
`
`NR
`
`S +3.56
`I +6.41
`NO +2.19
`CO
`
`S –15
`I –33.2
`NO –12.7
`PVR
`
`S –11.2
`I –17.2
`NO –13.4
`
`none
`
`NR
`
`S +9.1
`E +42.0
`NO +2.9
`CO
`S + NO +24
`S +16
`NO +16
`CI
`
`S –32b
`E –38b
`NO –21.9
`PVRI
`S + NO –30.5
`S –19.7
`NO –23.1
`PVR
`
`S –25b
`E –12b
`NO –22b
`
`S + NO –11.1
`S –3.7
`NO –9.3
`
`transient headache (1)
`
`ADRs (n)
`Sildenafil
`
`S + NO +17
`S + 17
`NO +0.2
`CI
`
`change)
`(mean %
`
`CO/CI
`
`S + NO –32
`S –27
`NO –19
`PVRI
`
`change)
`(mean %
`PVR/PVRI
`
`S + NO –13.1b
`S –13b
`NO –8b
`
`change)
`(mean %
`
`PAP
`
`30 min
`50 mg after
`initially, then
`S 50 mg
`I 15–20 µg
`NO 40 ppm
`
`S 50 mg (8)
`(8)
`<70 mmHg)
`or MAP
`headache,
`(eg, flushing,
`intolerance
`min until
`by 2 ng/kg/
`every 15 min
`E infusion ↑
`10–20 ppm
`requiring
`response
`maximum
`NO with
`
`S + NO
`S 50 mg
`NO 80 ppm
`
`S + NO
`S 75 mg
`60 ppm (1)
`(12) or
`NO 80 ppm
`
`874 I The Annals of Pharmacotherapy I 2005 May, Volume 39
`
`www.theannals.com
`
`
`
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`
`
`
`UNITED THERAPEUTICS CORP., EX1017, page 6
`UNITED THERAPEUTICS CORP. v. ACTELION PHARMACEUTICALS
`U.S. PATENT 8,268,847
`
`

`

`Sildenafil for Pulmonary Hypertension
`
`cPercent change calculated using formula based upon absolute hemodynamic values: (baseline–treatment)/baseline ×100.
`bEstimated from figure since not reported in the text.
`aSildenafil given orally, NO and iloprost by inhalation, and epoprostenol by intravenous infusion.
`vardenafil.
`arterial pressure; PVR = peripheral vascular resistance; PVRI = peripheral vascular resistance index; R = randomized; S = sildenafil; T = tadalafil; TE = chronic thromboembolic pulmonary hypertension; V =
`dactyly, telangiectasia syndrome; I = iloprost; IPAH = idiopathic pulmonary arterial hypertension; NO = nitric oxide; NR = not reported; NYHA = New York Heart Association; OL = open-label; PAP = pulmonary
`ADRs = adverse drug reactions; C = controlled; CCBs = calcium-channel blockers; CI = cardiac index; CO = cardiac output; CREST = calcinosis, the Raynaud phenomenon, esophageal dysfunction, sclero-
`
`NR
`
`T60+18.8
`T40+7.5
`T20+9.3
`V20+18.4
`V10+9.3
`S +13.2
`CI
`
`none
`
`S + I +45b
`high-dose
`S + I +35b
`low-dose
`S +13.2
`high-dose
`S +5
`low-dose
`I +22.8
`NO +7.9
`CI
`
`T60–26.7
`T40–27.1
`T20–18.6
`V20–26.3
`V10–21.6
`S –28
`PVRI
`S + I –44.2
`high-dose
`S + I –17b
`high-dose
`S + I –11.5b
`–17b
`low-dose
`high-dose S + I
`S + I –35b
`low-dose
`–11.5b
`low-dose S + I
`–24.3
`–13.5
`high-dose S
`high-dose S
`S –14.7
`low-dose S –8.5low-dose
`I –10b
`NO –7.0
`
`T60–10
`T40–18.3
`T20–12.6
`V20–12.1
`V10–14.3
`S –16.2
`
`I –27.1
`NO –14.1
`PVR
`
`drop (1)
`headache (2), nausea (1), BP
`
`I + S +22.5
`S +9.4c
`I +43.6
`CO
`
`I + S –43
`S –21.8
`I –43.8
`PVR
`
`I + S –24.7
`S –12.6
`I –16.3
`
`nausea (1)
`
`ADRs (n)
`Sildenafil
`
`–13
`E + S + NO
`E + S –8
`E + NO 0
`CO
`
`–23
`
`E + S –24
`E + NO –13
`PVR
`
`E + S + NO –12E + S + NO
`E + S –10
`E + NO –10
`
`change)
`(mean %
`
`CO/CI
`
`change)
`(mean %
`PVR/PVRI
`
`change)
`(mean %
`
`PAP
`
`T 60 mg (8)
`T 40 mg (8)
`T 20 mg (9)
`V 20 mg (9)
`V 10 mg (7)
`S 50 mg (19)
`(baseline)
`NO 20–40 ppm
`
`(high dose)
`I 2.8 µg (8)
`S 50 mg +
`(low dose)
`I 2.8 µg (7)
`S 12.5 mg +
`50 mg (8)
`high-dose S
`12.5 mg (7)
`low-dose S
`I 2.8 µg
`NO 20–40 ppm
`+ I 8.4–10.5 µg
`S 75–100 mg
`if tolerated
`30 min later
`then 50 mg
`if tolerated,
`30 min later
`then 25 mg
`S 25 mg,
`I 8.4–10.5 µg
`E + S 50 mg
`E + NO 40 ppm
`2.9 y
`average of
`min for
`25.7 ng/kg/
`E mean dose
`
`CCBs (14)
`
`II (9)
`III (35),
`IV (16),
`
`other (3)
`CREST (4),
`disease (7),
`Eisenmenger’s
`IPAH (46),
`
`M (21)
`F (39)
`
`18–81, mean 51
`
`(2004)44
`N = 60
`Ghofrani et al.OL, R
`
`I (11)
`
`NR)
`(number
`III, IV
`
`artery (1)
`monary
`left pul-
`aplasia of
`CREST (6),
`TE (13),
`IPAH (10),
`
`M (6)
`F (23)
`
`(2002)43
`Ghofrani et al. OL, R, CNR
`
`N = 30
`
`oxygen (4)
`I (4), CCBs (1),
`diuretics (3),
`warfarin (5),
`
`CCBs (1)
`diuretics (5),
`warfarin (7),
`
`III (2)
`IV (3),
`
`IPAH (5)
`
`M (1)
`F (4)
`
`56.4
`49–62, mean
`
`N = 5
`
`(2001)42
`Wilkens et al. OL
`
`II (2)
`III (6),
`
`IPAH (8)
`
`M (2)
`F (6)
`
`42.8
`32–63, mean
`
`N = 8
`OL
`
`(2004)41
`Kuhn et al.
`
`Regimena(n)
`Treatment
`
`Therapy (n)
`
`Other
`
`Class (n)
`NYHA
`
`Diagnosis
`
`(n)
`
`Gender
`
`(n)
`
`Age (y)
`
`Design
`
`Reference
`
`Table 3.Single-Dose Hemodynamic Studies Involving Sildenafil (continued)
`
`www.theannals.com
`
`The Annals of Pharmacotherapy I 2005 May, Volume 39 I 875
`
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`
`aop.sagepub.com
`
` at PENNSYLVANIA STATE UNIV on September 17, 2016
`
`UNITED THERAPEUTICS CORP., EX1017, page 7
`UNITED THERAPEUTICS CORP. v. ACTELION PHARMACEUTICALS
`U.S. PATENT 8,268,847
`
`

`

`(continued on page 877)
`
`aSildenafil given orally, iloprost by inhalation.
`ized; S = sildenafil; TE = chronic thromboembolic pulmonary hypertension.
`iopathic pulmonary arterial hypertension; NR = not reported; NYHA = New York Heart Association; OL = open-label; P = placebo; PAH = pulmonary arterial hypertension; PC = placebo-controlled; R = random-
`ADRs = adverse drug reactions; B = baseline; CCBs = calcium-channel blockers; CVD = collagen vascular disease; DB = double-blind; ES = Eisenmenger syndrome; IILD = interstitial lung disease; IPAH = id-
`
`no deaths
`but no ADRs reported;
`↓systemic arterial pressure,
`
`no deaths
`resolved after discontinuation,
`transient blurred vision (1)
`
`nifedipine
`pine; resolved after stopping
`5 pts. also receiving nifedi-
`worsening leg edema in 3 of
`
`none
`
`NR
`
`III to I (1)
`III to II (3),
`
`3 mo (4)
`improved at
`
`S 100 mg 2.5
`S 50 mg 2.4
`B 3.8
`mean
`improvement in
`no change (1)
`IV to II (2)
`IV to III (3)
`changes in class
`
`S 366
`B 312
`±1.1 mo
`(meters) after 6.5
`6-min walk test
`
`S 395
`B 283
`
`the first 4–5 days
`dosage ↑over
`S 50 mg tid,
`
`CCBs (NR)
`diuretics (NR),
`phenprocumon (12),
`
`3 mo (meters)
`6-min walk test at
`
`to 50 mg tid
`S 25 mg, titrated
`
`CCBs (4)
`diuretics (6),
`warfarin (10),
`
`NR
`
`II (5)
`III (5),
`
`TE (12)
`toxin (1)
`CVD (1),
`TE (1),
`PAH (7),
`sporadic
`
`M (7)
`F (5)
`
`NR
`
`(2003)50
`Ghofrani et al.OL, non-R
`
`N = 12
`
`M (2)
`F (8)
`
`35.4
`20–60, mean
`
`N = 10
`OL, non-R
`
`(2004)49
`Mikhail et al.
`Long-term monotherapy
`
`S 100 mg 385
`S 50 mg 377
`B 234
`(meters)
`
`6-min walk test
`
`wk, then ↑to 100
`S 50 mg bid for 4
`
`dobutamine (4)
`(10), digoxin (15),
`(15), spironolactone mg bid for 4 wk
`pine (5), furosemide
`warfarin (11), nifedi-
`
`III (3)
`IV (12),
`
`IPAH (15)
`
`M (4)
`F (11)
`
`mean 27
`range NR,
`
`N = 15
`OL, non-R
`
`et al. (2005)48
`Chockalingam
`
`death (1) in P group
`no dropouts due to ADRs,
`feet (4), constipation (3),
`numbness of hands and
`backache (3), headache (3),
`ADRs > placebo
`
`NR
`
`S 686
`P 475
`at 6 wk
`exercise time (sec)
`
`NR
`
`6 wk
`S 50 mg tid for
`
`100 mg tid
`>51kg =
`50 mg tid
`26–50 kg =
`25 mg tid
`<25 kg =
`S dose
`(no washout)
`over for 6 wk
`then cross-
`P or S for 6 wk,
`
`warfarin (6)
`
`IV (6)
`
`TE (6)
`
`M (5)
`F (1)
`
`60.5
`43–79, mean
`
`N = 6
`OL, non-R
`
`(2005)47
`Sheth et al.
`
`(NR)
`anticoagulants
`digoxin, diuretics,
`
`II (18)
`III (4),
`
`IPAH (22)
`
`M (10)
`F (12)
`
`NR
`16–55, mean
`
`N = 22
`crossover
`R, DB, PC,
`
`(2004)46
`Sastry et al.
`
`AJ Lee et al.
`
`none, deaths NR
`
`end of 2 wk (2)
`improved at the
`
`ADRs (n)
`Sildenafil
`
`Improvement
`
`Class (n)
`Functional
`in NYHA
`
`P 170
`S 266.67
`B 163.89
`(meters)
`6-min walk test
`
`S 25 mg every 8 h
`for 2 wk
`then crossover
`2-wk washout,
`then at least
`P or S for 2 wk,
`
`digoxin (2)
`diuretics (4),
`nifedipine (4),
`warfarin (9),
`
`NR (1)
`II (3),
`III (5),
`IV (1),
`
`[2])
`TE [1]; ES
`ILD [2],
`(IPAH [3],
`PAH
`
`M (4)
`F (5)
`
`32.11
`18–60, mean
`
`N = 10
`crossover
`R, DB, PC,
`
`(2003)45
`Bharani et al.
`Short-term monotherapy
`
`Tolerance
`Exercise
`
`Regimena(n)
`Treatment
`
`Therapy (n)
`
`Other
`
`Class (n)
`NYHA
`
`Diagnosis
`
`(n)
`
`Gender
`
`(n)
`
`Age (y)
`
`Design
`
`Reference
`
`Table 4.Short- and Long-Term Clinical Trials Involving Sildenafil
`
`876 I The Annals of Pharmacotherapy I 2005 May, Volume 39
`
`www.theannals.com
`
`
`
`Downloaded from at PENNSYLVANIA STATE UNIV on September 17, 2016aop.sagepub.com
`
`
`
`UNITED THERAPEUTICS CORP., EX1017, page 8
`UNITED THERAPEUTICS CORP. v. ACTELION PHARMACEUTICALS
`U.S. PATENT 8,268,847
`
`

`

`Sildenafil for Pulmonary Hypertension
`
`(continued on page 878)
`
`cAll class IV at baseline.
`bIf no fall in BP, second dose administered in 1–2 hours, then dosed 3 times daily, titrating up over 4–6 weeks based on response and adverse effects.
`aSildenafil given orally, iloprost by inhalation.
`sure; NR = not reported; NYHA = New York Heart Association; OL = open-label; PAH = pulmonary arterial hypertension; R = randomized; S = sildenafil.
`ADRs = adverse drug reactions; B = baseline; CCBs = calcium-channel blockers; CVD = collagen vascular disease; I = iloprost; IPAH = idiopathic pulmonary arterial hypertension; MAP = mean arterial pres-
`
`to drug therapy
`vision; deaths (2) unrelated
`unwanted erections, abnormal
`headache, dyspepsia,
`dizziness; no reports of
`(88–80 mmHg), but no
`asymptomatic minor ↓ in MAP
`
`death (1) in an accident
`(3); no dropouts due to ADRs;
`flushing sensation
`abdominal discomfort,
`minor headache, mild
`
`II (3)
`III (8),
`IV (1),
`I + S at 9–12 mo,
`II (2)
`III (9),
`IV (3),
`I + S at 3 mo,
`III (4)
`IV (10),
`I at B,
`
`12 mo
`I + S 349 at 9–
`I + S 338 at 6 mo
`I + S 3