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					                                                               Reference Section




                                        Medical Treatment of Pulmonar y Hyper tension in 2004

                                                                                                                                                         a report by
                                                                                                                                       Michael D McGoon

                                                                Professor of Medicine, Director, Pulmonary Hypertension Clinic, Mayo Clinic College of Medicine




  Michael D McGoon is Professor of      Pulmonary hypertension (PH) is a hemodynamic                        management strategies. Idiopathic pulmonary arterial
  Medicine and a Consultant in the
                                        condition defined by pulmonary arterial systolic                    hypertension (IPAH; also called primary pulmonary
  Division of Cardiovascular Diseases
        at the Mayo Clinic College of   pressure (PASP) above an upper limit of 35mmHg, or by               hypertension (PPH)) is a rare illness affecting all ages, but
Medicine, where he is also Director     pulmonary arterial mean pressure (PAMP) exceeding                   predominantly young to middle-aged women. A genetic
     of the Pulmonary Hypertension
                                        25mmHg at rest.1,2 Pulmonary arterial hypertension                  type of IPAH has been identified, associated with
Clinic. He has been on staff of the
         Mayo Clinic for 21 years. Dr   (PAH) is present when pre-capillary pulmonary vascular              mutations of the gene coding for the bone morphogenic
McGoon recently served as Chair of      pressure is elevated in the absence of pulmonary                    protein receptor.6,7 The low incidence of both sporadic
 the Scientific Leadership Council of
                                        capillary wedge pressure >15mmHg, such as that                      and familial IPAH (approximately one to five per million
         the Pulmonary Hypertension
Association (PHA) and is Chair-elect    associated with left ventricular dysfunction or valve               in the US) and subtle signs at early stages makes it difficult
  of the PHA Board of Trustees. He      disease, or obstruction of the pulmonary veins. PH can              to recognize. Improving physician awareness and
       attended Harvard College and
                                        be suspected on the basis of symptomatic presentation               widespread availability of non-invasive screening by
  received his MD at Johns Hopkins
      School of Medicine. He did his    (though may be present in the absence of symptoms),                 echocardiography, however, are shortening the delay to
medical residency at Johns Hopkins      physical examination and transthoracic Doppler-                     the time of diagnosis. When other types of PAH are
and Mayo Clinic, and his cardiology
                                        echocardiogram. Chest X-ray and electrocardiogram,                  considered, the prevalence increases substantially.
                  fellowship at Mayo.
                                        while important for assessment of co-existing                       Moreover, the diagnosis of PH based on
                                        conditions, may be supportive of a diagnosis of PH but              echocardiography includes patients who may have left-
                                        is not definitive in determining the presence of PH.3               sided cardiac abnormalities, hypoxemic or parenchymal
                                        Echocardiography, by assessment of the tricuspid and                lung disease, or chronic pulmonary thromboembolic
                                        pulmonary regurgitant velocities and application of the             disease. Since the management of PAH (idiopathic or in
                                        modified Bernoulli equation, estimates PASP and                     association with connective tissue disease, HIV infection,
                                        pulmonary artery diastolic pressure. Although the                   prior appetite suppressant use or other toxic exposures,
                                        estimated value correlates well with invasively measured            Eisenmenger’s syndrome, or portal hypertension) differs
                                        hemodynamics,4 individual variation and inaccuracy                  from PH due to chronic thromboembolic disease, lung
                                        requires that right heart catheterization be performed              disease, and left heart etiologies, accurate diagnostic
                                        for definitive evaluation of pulmonary hemodynamics,                distinction is essential.A general process for evaluating PH
                                        including response to vasoactive agents.                            is illustrated in Figure 1.

                                        Pulmonary hypertensive disorders have been classified               The untreated natural history of PAH is one of
                                        according to the World Health Organization (WHO)                    progressive symptoms of dyspnea and right heart failure
                                        definition of 1998 and modified by an international                 culminating in a markedly curtailed survival (mean 2.8
                                        symposium in 2003 (see Table 1).5 The schema of                     years). Medical treatment can now provide improved life
                                        classification is based on a combination of pathological            expectancy with more stable and tolerable symptoms.
                                        features, clinical constellation, hemodynamics, and                 Because of their complex nature, however, the use of

                                        1. Barst R J, McGoon M D,Torbicki A, Sitbon O, Krowka M, Olschewski H and Gaine S P          ,“Diagnosis and differenctial assessment
                                           of pulmonary arterial hypertension”, J. Am. Coll. Cardiol. (2004),43: pp. 40S–47S.
                                        2. Rubin L, “Diagnosis and management of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines”,
                                           Chest (2004), 126: pp. 7S–10S.
                                                                                 ,
                                        3. McGoon M D, Gutterman D, Steen V Barst R J, McCrory D C, Fortin T A and Loyd J E,“Screening, early detection, and diagnosis
                                           of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines”, Chest (2004), 126: pp. 14S–34S.
                                        4. Currie P J, Seward J B and Chan K-L, “Continuous wave Doppler determination of right ventricular pressure: a simultaneous
                                           Doppler-catheterization study in 127 patients”, J. Am. Coll. Cardiol. (1985), 6: pp. 750–756.
                                                                                                   ,
                                        5. Simonneau G, Galiè N, Rubin L, Langleben D, Seeger W Domenighetti G, Gibbs S, Lebrec D, Speich R, Beghetti M, Rich S and
                                           Fishman A,“Clinical classification of pulmonary hypertension”, J. Am. Coll. Cardiol. (2004), 43, Supplement 1: pp. S5–S12.
                                        6. Morse J H, “Bone morphogenetic protein receptor 2 mutations in pulmonary hypertension”, Chest (2002), 121: pp. 50S–53S.
1                                       7. Loyd J E, “Genetics and gene expression in pulmonary hypertension”, Chest (2002), 121: pp. 46S–50S.


                                                                                                                         BUSINESS BRIEFING: US CARDIOLOGY 2004
                                      Reference Section



    Figure 1: Guideline for Approaching the Differential Diagnosis of Pulmonary Hypertension 3


                          Is there a reason to suspect PAH?
                 Clinical history (symptoms, risk factors, family Hx),
                                    Exam, CXR, ECG

         No                                             Yes
                                                                                                  Rationale
                                 No
           No further                                      Is PAH likely?
           Evaluation                                                                                                     TRV to measure RVSP; RVE; RAE; RV Dysfunction;
                                                                Echo
            for PAH
                                                        Yes
                                                                                                    Yes                   Dx LV systolic, diastolic dysfunction;
                                                    Is PAH due to LH disease?
                                                              Echo                                                        valvular disease: Appropriate treatment and further
                                                                                                                          evaluation if necessary, including R&LHC
                                                        No

                                                                                                    Yes                   Dx abnormal morphology; shunt:
                                                       Is PAH due to CHD?                                                 Surgery. Medical treatment of PAH or evaluation for
                                                        Echo with contrast                                                further definition or other contributing causes,
                                                                                                                          including R&LHC if necessary
                                                        No

                                                                                                    Yes                   Dx Scleroderma, SLE, other CTD, HIV: Medical
                                                     Is PAH due to CTD, HIV?
                                                                                                                          treatment of PAH and further evaluation for
                                                            Serologies
                                                                                                                          other contributing causes, including RHC

                                                        No

                                                                                                    Yes                                                                   Yes
                                                     Is chronic PE suspected?                                             Is chronic PE confirmed and operable?
                                                             VQ scan                                                      Pulmonary angiogram

                                                        No               VQ normal

                                                                                                                          Anatomic definition (CT, MRI may provide
                                                                                                   No                     additional useful but not definitive information):
                                                                                                                          Thromboendarterectomy if appropriate or
                                                                                                                          medical treatment; clotting evaluation; a/c
                                                       Is PAH due to lung
                                                      disease or hypoxemia?
                                                     PFT’s, arterial saturation
                                                                                                  Yes                     Dx parenchymal lung disease, hypoxemia, or sleep disorder:
                                                                                                                          Medical treatment, oxygen, positive pressure breathing as
                                                                                                                          appropriate, and further evaluation for other contributing
                                                                                                                          causes, including RHC if necessary
                                                        No

                                                 What limitations are caused by                                           Document exercise capacity regardless of cause of PH:
                                                             the PAH?                                                     Establish baseline, prognosis and document
                                               Functional class; 6 minute walk test                                       progression/response to treatment with serial reassessments



                                                                                                                          Document PA pressure, PCWP (LV or LA pressure if
                                                                                                                          PCWP unobtainable or uncertain), transpulmonary
                                                                                                                          gradient, CO, PVR, MVO2 (including central venous and
                                                 What are the precise pulmonary                                           right heart O2 saturations to assess possible shunt),
                                                         hemodynamics?                                                    hepatic wedge pressures if portopulmonary
                                                              RHC                                                         hypertension suspected, response to vasodilators:
                                                                                                                          Confirm PAH, or IPAH if no other cause identified.
                                                                                                                          Discuss genetic testing and counseling of IPAH family members.
                                                                                                                          Refer to section on Therapy.


    A series of questions or considerations are addressed primarily by the diagnostic modalities listed beneath the line.The possible positive outcomes of each stage of evaluation are
    shown, with basic further steps suggested. Note that further evaluation may be advisable even if an abnormality is identified, since discovery of an abnormality does not necessarily
    imply that it is the sole or predominant cause of pulmonary hypertension. Negative outcome requires further evaluation until, by a process of diagnostic exclusion, the final diagnosis
    is IPAH.The diagnosis of pulmonary hypertension from any cause cannot be considered established unless confirmed by right heart catheterization. Although the algorithm is
    illustrated as a linear progression, clinical circumstances may dictate a different order of testing. In addition, several questions can be addressed at the time of a single test (i.e.
    Doppler echocardiogram).

    Abbreviations: a/c = anticoagulation; CHD = congenital heart disease; CO = cardiac output; CT = contrast enhanced chest computerized tomography; CTD = connective tissue
    disease; CXR = chest x-ray; Dx = diagnosis; ECG = electrocardiogram; Echo = Doppler transthoracic echocardiogram; Exam = physical examination; HIV = human immunodeficiency
    virus infection; IPAH = idiopathic pulmonary arterial hypertension; LA = left atrial; LH = left heart; LV = left ventricular; PA = pulmonary artery; PAH = pulmonary arterial
    hypertension; MRI = magnetic resonance imaging; MVO2 = mixed venous oxygen saturation; PCWP = pulmonary capillary wedge pressure; PE = pulmonary embolism; PFT’s =
    pulmonary function test including diffusing capacity; PH = pulmonary hypertension; PVR = pulmonary vascular resistance; R&LHC = right and left heart catheterization; RHC = right
    heart catheterization; RAE = right atrial enlargement; RVE = right ventricular enlargement; RVSP = right ventricular systolic pressure; SLE = systemic lupus erythematosus;TRV =
2
    tricuspid regurgitant velocity;VQ = ventilation perfusion.



                                                                                                                     BUSINESS BRIEFING: US CARDIOLOGY 2004
                                                       Medical Treatment of Pulmonar y Hyper tension in 2004

these agents has been largely focused in multidisciplinary         unstable have WHO Class IV symptoms or severe right
referral centers with dedicated PH clinics and specialized         heart failure never do well with calcium channel blockers
personnel who provide follow-up including careful                  and need not undergo vasodilator assessment. These
reassessment and modification of treatment.                        patients and vasodilator nonresponders require treatment
                                                                   with an alternative agent.
Therapeutic Strategy
                                                                   A p p r o v e d Tr e a t m e n t
Treatment is dictated by multiple factors:
                                                                   Since 1996, three drugs have been approved by the US
• severity of disease and symptoms;                                Food and Drug Administration (FDA) for use in
• specific type of PAH;                                            patients with PAH (see Table 2).
• access to and ability to use expensive, complex
  medications; and                                                 E p o p ro s t e n o l
• acute vasodilator responsiveness.
                                                                   Prostacyclin, a potent endogenous vasodilator with
Va s o d i l a t o r A s s e s s m e n t                           platelet anti-aggregatory effects, is deficient in patients
                                                                   with PAH. Randomized studies and subsequent reports
Right heart catheterization, including assessment of               have shown that epoprostenol sodium, a synthetic
response to pulmonary vasodilators, is a pivotal                   prostacyclin analog, improves exercise capacity, quality of
component of the evaluation of PH.8 Following careful              life, hemodynamics in IPAH and PAH related to
assessment of baseline hemodynamics and confirmation               scleroderma, and improved survival in patients with
of pre-capillary pulmonary hypertension, a pulmonary               IPAH.10,11 Survival of IPAH patients treated with
vasodilator (inhaled nitric oxide, or infused prostacyclin         epoprostenol therapy is 85% to 88%, 70% to 76%, and
or adenosine) is administered and the peak effect is               63% at one, two, and three years, respectively (compared
noted. Patients with PAH who acutely respond to                    with expected survival of 59%, 46%, and 35%).12,13
vasodilators (by demonstration of a decrease in PAMP               Epoprostenol treatment is complicated.The drug must be
and pulmonary vascular resistance by >20%) have                    given by continuous intravenous infusion through an
improved survival when treated with calcium channel                indwelling central line. It is unstable at room temperature,
blockers (CCB). Patients with a vasodilator response of            so the supply must be changed frequently (at least three
this magnitude who are treated with a CCB have a                   times a day) or kept cool, necessitating somewhat bulky
reported survival of up to 94% at five years (compared             ice packs surrounding an administration pump.
with 38% in those who failed to respond and were not               Epoprostenol (Flolan®; GlaxoSmithKline) is extremely
treated with a CCB).9 A decrease of PAMP by at least               expensive (up to US$100,000 or more per year in
10mmHg to less than or equal to 40mmHg, with an                    commonly used dose ranges). Finally, patients are exposed
increased or unchanged cardiac output has been adopted             to significant side-effects and risks. Common side-effects
as a criterion for portending a beneficial response to             of epoprostenol include headache, flushing, jaw pain,
CCBs.8 The likelihood of demonstrating an acute                    diarrhea, nausea, dermatitis, and painful leg discomfort.
response in IPAH is less than 10%, however, and even less          Infection of the central venous catheter may occur.
in patients with substrates such as connective tissue              Sudden interruption of the infusion may cause rebound
disease or congenital heart disease. Patients who are              severe PH and death.

                                                                                                             ,
8. Badesch D B, Abman S H, Ahearn G S, Barst R J, McCrory D C, Simonneau G and McLaughlin V “Medical therapy for
   pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines”, Chest (2004), 126: pp. 35S–62S.
9. Rich S, “Calcium channel blockers and anticoagulants in the therapy of pulmonary hypertension”, ACC Current Journal
   Review (1994), Nov/Dec: pp. 19–22.
                                ,
10. Badesch D B, Tapson V F McGoon M D, Brundage B H, Rubin L J, Wigley F M, Rich S, Barst R J and Barrett P S,
    “Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease”, Annals of
    Internal Medicine (2000), 132: pp. 425–434.
                                                                                                        ,
11. Barst R J, Rubin L J, Long W A, McGoon M D, Rich S, Badesch D B, Groves B M,Tapson V F Bourge R C, Brundage B
                                                                       ,
    H, Koerner S K, Langleben D, Keller C A, Murali S, Uretsky B F Clayton L M, Jobsis M M, Blackburn Jr. S D, Shortino D
                    ,
    and Crow J W “A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary
    pulmonary hypertension”, New England Journal of Medicine (1996), 334: pp. 296–301.
                     ,
12. McLaughlin V V Shillington A and Rich S, “Survival in primary pulmonary hypertension: the impact of epoprostenol therapy”,
    Circulation (2002), 106: pp. 1,477–1,482.
                                                 ,                      ,
13. Sitbon O, Humbert M, Nunes H, Parent F Garcia G, Herve P Rainisio M and Simonneau G, “Long-term intravenous
    epoprostenol infusion in primary pulmonary hypertension: prognostic factors and survival”, J.Am. Coll. Cardiol. (2002), 40: pp.
    780–788.                                                                                                                          3


BUSINESS BRIEFING: US CARDIOLOGY 2004
                                                        Medical Treatment of Pulmonar y Hyper tension in 2004

Despite the improvement in symptoms, longevity, and                 Table 1: Revised Clinical Classification of Pulmonary Hypertension (Venice
exercise capacity (as measured by the distance an                   2003) 5
individual can walk on level ground in six minutes) seen
in many patients, hemodynamic improvement tends to be               1. Pulmonary arterial hypertension (PAH)
relatively modest. Benefit in some, if not most, patients                1.1. Idiopathic (IPAH)
may be due to stabilization and prevention of progression                1.2. Familial (FPAH)
of the disease with its attendant right heart failure. Many              1.3. Associated with (APAH):
investigators feel that much of the benefit over time may                     1.3.1. Collagen vascular disease
result from anti-proliferative properties of the drug which                   1.3.2. Congenital systemic-to-pulmonary shunts
lead to beneficial vascular reverse remodeling. A salutary                    1.3.3. Portal hypertension
inotropic effect of the drug has also been postulated.                        1.3.4. HIV infection
                                                                              1.3.5. Drugs and toxins
Tre p ro s t i n i l                                                          1.3.6. Other (thyroid disorders, glycogen storage disease, Gaucher disease,
                                                                                     hereditary hemorrhagic telangiectasia, hemoglobinopathies,
Treprostinil (Remodulin®; United Therapeutics                                        myeloproliferative disorders, splenectomy)
Corporation) is a prostacyclin analog with a half-life of                1.4. Associated with significant venous or capillary involvement
three hours. In contradistinction to epoprostenol, it is                      1.4.1. Pulmonary veno-occlusive disease (PVOD)
stable at room temperature. Because of its stability, longer                  1.4.2. Pulmonary capillary hemangiomatosis (PCH)
half-life, and a documented equivalent hemodynamic                       1.5. Persistent pulmonary hypertension of the newborn
effect when administered subcutaneously, it avoids the use          2. Pulmonary hypertension with left heart disease
of an intravascular catheter. Instead, it is given via a tiny            2.1. Left-sided atrial or ventricular heart disease
subcutaneous catheter using a small pump that does not                   2.2. Left-sided valvular heart disease
require an ice-pack.The medication is provided in usable            3. Pulmonary hypertension associated with lung diseases and/or hypoxemia
form, rather than requiring daily mixing of active                       3.1. Chronic obstructive pulmonary disease
compound with a diluent (as epoprostenol does) by the                    3.2. Interstitial lung disease
patient. Compared with placebo, treprostinil tends to                    3.3. Sleep-disordered breathing
improve exercise capacity on six-minute-walk testing,                    3.4. Alveolar hypoventilation disorders
quality of life, and hemodynamics, but the benefits are                  3.5. Chronic exposure to high altitude
quite limited.14,15 At higher doses and among more                       3.6. Developmental abnormalities
symptomatic patients, the beneficial effects are more               4. Pulmonary hypertension due to chronic thrombotic and/or embolic disease
pronounced. Treprostinil exhibits a similar side-effect                  4.1. Thromboembolic obstruction of proximal pulmonary arteries
profile to epoprostenol, but an additional concern is the                4.2. Thromboembolic obstruction of distal pulmonary arteries
frequent occurrence of pain at the infusion site.This may                4.3. Non-thrombotic pulmonary embolism (tumor, parasites, foreign material)
limit the ability to raise doses to a level most likely to          5. Miscellaneous
produce optimal benefit.The expense of treprostinil is also            Sarcoidosis, histiocytosis X, lymphangiomatosis, compression of pulmonary vessels
similar to epoprostenol. Thus, the advantages of                       (adenopathy, tumor, fibrosing mediastinitis)
treprostinil are the absence of a central venous catheter, a
smaller infusion pump set-up, and availability of drug that        endothelin-1 (ET-1), a potent vasoconstrictor and smooth
does not require reconstitution by the patient. The                muscle mitogen, at endothelin receptor sub-types A and
feasibility and efficacy of using treprostinil intravenously       B (ETA and ETB). Its therapeutic effect is due to
to take advantage of its ease of use while avoiding site pain      reduction of vasoconstriction and pulmonary vascular
is being explored.                                                 hypertrophy caused by increased plasma levels of ET-1 in
                                                                   patients with PAH, and mediated predominantly via ETA
Bosentan                                                           receptors. As with the prostanoids above, the demon-
                                                                   strable clinical vasodilatory effect of the drug is quite
Bosentan (Tracleer®; Actelion, Inc.) is a nonselective             modest in patients with established PAH,16 but clinical
endothelin receptor antagonist, blocking the action of             studies of bosentan have demonstrated an augmented six-

                              .;                                                                    ,
14. McLaughlin V V G, S.P Barst, R J, Oudiz R, Bourge R C, Frost A, Robbins I M,Tapson V F McGoon M D, Badesch D B,
    Sigman J, et al., “Efficacy and safety of treprostinil: an epoprostenol analog for primary pulmonary hypertension”, Journal of
    Cardiovascular Pharmacology (2003), 41: pp. 293–299.
15. Simonneau G, Barst R J, Galie N, Naeije R, Rich S, Bourge R C, Keogh A, Oudiz R, Frost A, Blackburn S D, Crow J W
    and Rubin L J “Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial
    hypertension”, American Journal of Respiratory and Critical Care Medicine (2002), 165: pp. 800–804.
                                                                           ,
16. Channick R N, Simonneau G, Sitbon O, Robbins I M,Tapson V F Badesch D B, Roux S, Rainisio M, Bodin F and Rubin
    L J, “Effects of the dual endothelin-receptor anatgonist bosentan in patients with pulmonary hypertension: a randomised placebo-
    controlled study”, Lancet (2001), 358: pp. 1,119–1,123.                                                                                                 4


BUSINESS BRIEFING: US CARDIOLOGY 2004
                           Reference Section



    minute-walk distance compared with placebo and                    local pulmonary arteries vasodilate, thereby enhancing
    improved functional classification over 16 weeks,17 leading       ventilation-perfusion matching. Iloprost improves func-
    to FDA approval of the medication. Some of its benefit            tional class, exercise capacity, and pulmonary hemo-
    may be related to anti-proliferative and anti-fibrotic            dynamics in open and randomized studies, with side-
    effects that stabilize the disease process and promote            effects of flushing, headache, and cough in some
    remodeling. Side-effects associated with bosentan include         patients.18,19 The relatively short duration of action of
    dose-dependent elevation of transaminases reflecting              inhaled iloprost requires between six and nine five- to 15-
    hepatic toxicity, syncope and flushing. Drug interactions         minute inhalations daily to obtain a sustained clinical
    with glyburide and cyclosporine are recognized; bosentan          benefit. Co-administration of iloprost with other
    may interfere with the action of hormonal contraceptives.         pulmonary vasoactive agents such as sildenafil reportedly
    The medication is administered orally in pill form twice          augments and prolongs the duration of action.20–22 Iloprost
    daily and liver function tests are monitored monthly. Like        is approved in Europe for symptomatic IPAH and studies
    the prostanoids, it is extremely expensive, costing over          in the US are in the early stages. Beraprost is a stable oral
    US$30,000 annually.                                               prostacyclin analog that has been used clinically in Japan
                                                                      based predominantly on uncontrolled studies suggesting
    Other Medications                                                 improved hemodynamics and six-minute-walk
                                                                      distance.23,24 Subsequent randomized studies have yielded
    In addition to the FDA-approved agents and CCBs,                  variable results,25,26 suggesting an early modest clinical
    other agents have been and are currently being used or            benefit that markedly attenuates or vanishes during
    investigated as treatment modalities (see Table 2).               follow-up of six to 12 months. FDA approval ultimately
                                                                      was not sought.
    Other Prostanoids
                                                                      Other Endothelin Receptor Antagonists
    Iloprost is a stable prostacyclin analog available for
    intravenous, oral, and aerosolized administration. Inhaled        Sitaxsentan and ambrisentan are ETA receptor-selective
    therapy delivers drugs to ventilated alveolar units where         agents currently undergoing randomized studies. Initial

    17. Rubin L J, Badesch D B, Barst R J, Galie N, Black C M, Keogh A, Pulido T, Frost A, Roux S, Leconte I, Landzberg M and
        Simonneau G,“Bosentan therapy for pulmonary arterial hypertension”, New England Journal of Medicine (2002), 346: pp.
        896–903.
    18. Olschewski H, Simonneau G, Galie N, Higenbottam T, Naeije R, Rubin L J, Nikkho S, Speich R, Hoeper M M, Behr J,Winkler
                                ,
        J, Sitbon O, Popov W Ghofrani H A, Manes A, Kiely D G, Ewert R, Meyer A, Corris P A, Delcroix M, Gomez-Sanchez M,
        Siedentop H and Seeger W     ,“Inhaled iloprost for severe pulmonary hypertension”, New England Journal of Medicine (2002),
        347: pp. 322–329.
    19. Hoeper M M, Schwarze M, Ehlerding S,Adler-Schuermeyer A, Spiekerkoetter E, Niedermeyer J, Hamm M and Fabel H,“Long-
        term treatment of primary pulmonary hypertension with aerosolized iloprost, a prostacyclin analogue”, New England Journal of
        Medicine (2000), 342: pp. 1,866–1,870.
                                                                                                          ,
    20. Wilkens H, Guth A, Konig J, Forestier N, Cremers B, Hennen B, Bohm M and Sybrecht G W “Effect of inhaled iloprost plus
        oral sildenafil in patients with primary pulmonary hypertension”, Circulation (2001), 104: pp. 1,218–1,222.
                                  ,
    21. Ghofrani H A, Rose F Schermuly R T, Olschewski H,Wiedemann R, Kreckel A,Weissmann N, Ghofrani S, Enke B, Seeger W
                             ,
        and Grimminger F “Oral sildenafil as long-term adjunct therapy to inhaled iloprost in severe pulmonary arterial hypertension”,
        J. Am. Coll. Cardiol. (2003), 42: pp. 158–164.
                                                ,
    22. Ghofrani H A,Weidemann R, Rose F Olschewski H, Schermuly R T,Weissman N, Seeger W and Grimminger F,“Combination
        therapy with oral sildenafil and inhaled iloprost for severe pulmonary hypertension”, Annals of Internal Medicine (2002), 136:
        pp. 515–522.
    23. Okada M,Yamashita C, Okada M and Okada K,“Endothelin receptor antagonists in a beagle model of pulmonary hypertension:
        contribution to possible potential therapy?”, J. Am. Coll. Cardiol. (1995), 25: pp. 1,213–1,217.
                                                                               ,
    24. Nagaya N, Uematsu M, Okano Y, Satoh T, Kyotani S, Sakamaki F Nakanishi N, Miyatake K and Kunieda T,“Effect of orally
        acitve prostacyclin analogue on survival of outpatients with primary pulmonary hypertension”, J.Am. Coll. Cardiol. (1999), 34:
        pp. 1,188–1,192.
    25. Galie N, Humbert M,Vachiery J L,Vizza C D, Kneussl M, Manes A, Sitbon O,Torbicki A, Delcroix M, Naeije R, Hoeper
        M, Chaouat A, Morand S, Besse B and Simonneau G, “Effects of beraprost sodium, an oral prostacyclin analogue, in patients
        with pulmonary arterial hypertension: a randomized, double-blind, placebo-controlled trial”, J. Am. Coll. Cardiol. (2002), 39:
        pp. 1,496–1,502.
                                                      ,              ,
    26. Barst R, McGoon M D, McLaughlin V V Tapson V F Oudiz R, Shapiro S, Robbins I M, Channick R N, Badesch D B,
        Rayburn B K, Flinchbaugh R, Sigman J,Arneson C and Jeffs R,“Beraprost therapy for pulmonary arterial hypertension”, J.Am.
5       Coll. Cardiol. (2003), 41: pp. 2,119–2,125.


                                                                                   BUSINESS BRIEFING: US CARDIOLOGY 2004
                                                                           Medical Treatment of Pulmonar y Hyper tension in 2004

Table 2

Medications used in US                              Agents under                                        Possible future                  Adjunctive
for treatment of PAH                                investigation or                                    treatment concepts               treatment
based on FDA approval                               consideration, or                                   that may warrant                 modalitiesk
or reported experience                              available outside US                                clinical investigation
Epoprostenola                                       Sitaxsentane                                        Aspirin                          oxygen
Treprostinilb                                       Ambrisentane                                        Oral antithrombin agents         warfarin
Bosentanc                                           Sildenafilf                                         Statins                          digoxin
Calcium Channel Blockersd                           Iloprostg                                           Serotonin transport inhibitors   diuretics
                                                    Beraprosth                                          Potassium channel openers
                                                    L-argininei                                         Genetic manipulation
                                                    Nitric oxidej                                       Modifiers of angiogenesis

a: intravenous prostacyclin analog
b: subcutaneous prostacyclin analog
c: nonselective endothelin receptor antagonist
d: not FDA-approved for this purpose
e: ETA receptor selective antagonist; randomized studies in progress
f: PDE-5 inhibitor; randomized studies in progress
g: inhaled prostacyclin analog; available outside US, randomized studies planned
h: oral prostacyclin analog; available outside US, FDA approval not sought after randomized study results
i: limited studies in progress
j: limited empiric use inhaled
k: commonly used and felt to be efficacious in reducing symptoms or consequences, but no rigorous study data


Phase III study results suggest that sitaxsentan improves                                 pulmonary vasculature (PDE5) consequently have a net
exercise capacity, functional class, and pulmonary                                        effect of boosting the pulmonary vascular response to
hemodynamics at 12-week follow-up.27 Ambrisentan                                          endogenous NO. Sildenafil (Viagra®; Pfizer) is a potent
Phase II pilot studies have recently been completed and                                   and highly specific PDE5 inhibitor used for treatment of
suggested sufficient benefit28 to proceed with Phase III                                  erectile dysfunction since PDE5 is present in the corpus
international clinical investigation.                                                     cavernosum. Since PDE5 is the predominant PDE in the
                                                                                          pulmonary vascular bed, the use of sildenafil to generate
Nitric Oxide, Nitric Oxide Donors and                                                     pulmonary vasodilation is conceptually attractive.Animal
Phosphodiesterase Inhibitors                                                              studies, anecdotal reports, uncontrolled case series, and
                                                                                          small controlled trials suggest that sildenafil may have
Nitric oxide (NO) is an endogenous vasodilator                                            salutary effects in PAH, either alone or in combination
produced from L-arginine by nitric oxide synthase in                                      with other medications.21 A larger prospective
endothelial cells. NO has a pivotal function in regulating                                multicenter blinded controlled study has been completed
basal vascular resistance. In vascular smooth muscle cells,                               and the results are expected in late 2004.The possibility
it promotes conversion of GTP to cyclic GMP. Cyclic                                       that other PDE5 inhibitors, such as tardalafil (Cialis®;
GMP is a second messenger that leads to a cascade of                                      Lilly) or vardenafil (Levitra®; Bayer/GlaxoSmithKline)
events that reduces entry of calcium ions into smooth                                     may be efficacious has not been tested.
muscle cells, thereby producing vasodilation. Intracellular
cyclic GMP levels are regulated by phosphodiesterases                                     Studies have shown that inhaled NO is a vasodilator in a
that catalyze its degradation to 5’GMP. Agents that                                       variety of pulmonary hypertensive states, supporting its
inhibit the predominant phosphodiesterase (PDE) in the                                    use in pulmonary vasodilator testing29,30 and acute

                                                                                       ,                 ,
27. Barst R J, Langleben D, Frost A, Horn E M, Oudiz R, Shapiro S, McLaughlin V V Hill N,Tapson V F Robbins I M, Zwicke
    D, Duncan B, Dixon R A and Frumkin L R, “Sitaxsentan therapy for pulmonary arterial hypertension”, American Journal
    of Respiratory and Critical Care Medicine (2004), 169: pp. 441–447.
28. Rubin L, Galie N, Badesch D B, Oudiz R, Simonneau G, McGoon M D, Manes A, Keogh A, Frost A, Zwicke D and Naeije
    R, “Ambrisentan improves exercise capacity and clinical measures in pulmonary arterial hypertension (abstract)”, American
    Journal of Respiratory and Critical Care Medicine (2004), 169: p. A210.
29. Sitbon O, Brenot F, Denjean A, Bergeron A, Parent F                     ,
                                                       ,Azarian R, Herve P Raffestin B and Simmoneau G,“Inhaled nitric oxide
    as a screening vasodilator agent in primary pulmonary hypertension: a dose-response study and comparison with prostacyclin”,
    American Journal of Respiratory and Critical Care Medicine (1995), 151: pp. 384–89.
30. Krasuski R A,Warner J J,Wang A, Harrison J K,Tapson V and, Bashore T M,“Inhaled nitric oxide selectively dilates pulmonary
    vasculature in adult patients with pulmonary hypertension, irrespective of etiology”, J. Am. Coll. Cardiol. (2000); 36: p.
    2,204–2,211.                                                                                                                                       6


BUSINESS BRIEFING: US CARDIOLOGY 2004
                           Reference Section



    pulmonary hypertensive states post-operatively.31 Rare             congestion. Hypoxemia due to reduced diffusing
    patients have been treated chronically with inhaled NO             capacity, low cardiac output and low mixed venous
    therapy.32,33 Studies of L-arginine administered to                oxygen saturation, suboptimal ventilation-perfusion
    supplement the substrate for NO production are limited,            matching, and right-to-left shunting of blood through a
    but may suggest a hemodynamic benefit.34                           patent foramen ovale may necessitate the use of
                                                                       supplemental oxygen.
    Combination Therapy
                                                                       Speculative Therapy
    Combining medications with different mechanisms of
    action has not been systematically explored, but growing           Hypothetical considerations, cellular studies, and/or early
    experience suggests that empirical multidrug therapy               anecdotal reports have raised possible new avenues of
    may produce additive benefit in some patients, or allow            treatment for patients with or at risk of developing PAH
    use of doses less likely to produce adverse effects.               (see Table 2). Whether appropriately rigorous clinical
                                                                       studies are ever performed examining these approaches
    Adjunctive Therapy                                                 remains an open question.

    In general, patients with PAH are treated with warfarin            Summary
    in conservative doses aiming for an international
    normalized ratio (INR) of 2.0–2.5.The use of chronic               The spectrum of medical treatment for PAH has
    anticoagulation is predicated on the results of two                expanded in the last decade. While providing benefits
    retrospective studies that demonstrate an apparent                 including increased longevity for many patients, the
    survival benefit,35,36 possibly due to minimization of in          available therapies remain essentially palliative.
    situ small vessel thrombosis. PAH results in right                 Moreover, the options of various medications and
    ventricular pressure overload and eventual right                   investigational protocols has made treatment more
    ventricular failure. Inotropic support with digoxin is             complex rather than simpler. Because of this,
    appropriate under these circumstances, and diuretics are           management of most patients seems to be most
    frequently required to manage resulting intravascular              appropriately directed to facilities with expertise,
    volume overload, peripheral edema, ascites and hepatic             experience and involvement in clinical studies. ■

                                                      ,
    31. Fullerton D, Jones S, Jaggers J, Piedalue F Grover F and McIntyre R, “Effective control of pulmonary vascular resistance with
        inhaled nitric oxide after cardiac operation”, Journal of Thoracic and Cardiovascular Surgery (1996), 111 (4): pp. 753–764.
                                                                                                             ,
    32. Perez-Penate G, Julia-Serda G, Pulido-Duque J M, Gorriz-Gomez E and Cabrera-Navarro P “One-year continuous inhaled
        nitric oxide for primary pulmonary hypertension”, Chest (2001), 119: pp. 970–973.
                                       ,         ,
    33. Snell G I, Salamonsen R F Bergin P Esmore D S, Khan S and Williams T J, “Inhaled nitric oxide used as a bridge to heart-
        lung transplantation in a patient with end-stage pulmonary hypertension”, American Journal of Respiratory and Critical
        Care Medicine (1995), 151: pp. 1,263–1,266.
                                                                ,
    34. Nagaya N, Uematsu M, Oya H, Sato N, Sakamaki F Kyotani S, Ueno K, Nakanishi N,Yamagishi M and Miyatake K,“Short-
        term oral administration of L-arginine improves hemodynamics and exercise capacity in patients with precapillary pulmonary
        hypertension”, American Journal of Respiratory and Critical Care Medicine (2001), 163: pp. 887–891.
    35. Rich S and Brundage B H,“High-dose calcium channel-blocking therapy for primary pulmonary hypertension: evidence for long-term
        reduction in pulmonary arterial pressure and regression of right ventricular hypertrophy”, Circulation (1987), 76: pp. 135–141.
                 ,
    36. Fuster V Frye R L, Gersh B J, McGoon M D and Steele P M, “Primary pulmonary hypertension: natural history and the
        importance of thrombosis”, Circulation (1984), 70: pp. 580–587.




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