ࡱ> svnopqr bjbj 6,v v 4h'l  $y(((().te0q{s{s{s{s{s{s{zs{Q!1))!1!1s{g$((P~>>>!1((q{>!1q{>>jsy(0qdy2u2]{~0 u&;dyy\!1!1>!1!1!1!1!1s{s{>!1!1!1 !1!1!1!1!1!1!1!1!1!1!1!1!1v : Pharmacologic Management of Pulmonary Arterial Hypertension December 2008 VHA Pharmacy Benefits Management Services and the Medical Advisory Panel The following recommendations are based on current medical evidence and expert opinion from clinicians. The content of the document is dynamic and will be revised as new clinical data becomes available. The purpose of this document is to assist practitioners in clinical decision-making, to standardize and improve the quality of patient care, and to promote cost-effective drug prescribing. The clinician should utilize this guidance and interpret it in the clinical context of individual patient situations. I. SUMMARY Pulmonary arterial hypertension (PAH) is a serious, often progressive disease with no cure. Significant advances have been made in available treatment options that have been shown to improve exercise and functional capacity, hemodynamic indices, and possibly prolong survival. When PAH is suspected, a definitive diagnosis must be made prior to initiation of therapy. A comprehensive work-up including non-invasive and invasive testing is necessary to establish a cause, determine severity and prognosis, and guide therapy. General or adjunctive therapy for PAH includes the use of diuretics, supplemental oxygen, anticoagulation, and/or digoxin. Currently available pharmacologic treatments aimed at PAH include calcium channel antagonists (sustained-release nifedipine or diltiazem, amlodipine), prostanoids (epoprostenol, treprostinil, iloprost), endothelin receptor antagonists [ERAs] (bosentan, ambrisentan), and phosphodiesterase-5 (PDE-5) inhibitors (sildenafil). Calcium channel antagonists are used for their vasodilator properties. Potential PAH responders are identified by a positive acute vasoreactivity test performed during right heart catheterization, defined as a decrease in mean pulmonary artery pressure (mPAP) of at least 10 mmHg to a mPAP of d"40 mm Hg in the presence of an unchanged or increased cardiac output. Although only a small proportion of patients display acute vasoreactivity (12.6%), and fewer are considered long term responders (6.8%), those patients who have a sustained improvement on calcium channel antagonist therapy to World Health Organization (WHO) functional class I or II have been shown to have improved survival. Epoprostenol, the first approved prostanoid, is indicated for the treatment of idiopathic PAH (IPAH) and PAH associated with scleroderma and functional class III or IV symptoms not adequately responsive to conventional therapy. Epoprostenol has been shown to improve exercise and functional capacity and hemodynamics, and may improve survival in IPAH. Administered by continuous intravenous (IV) infusion due to its short half-life, epoprostenol therapy is complex and requires considerable responsibility on the part of the patient and providers. Serious complications related to drug delivery include infection from the indwelling catheter and rebound pulmonary hypertension, syncope and sudden death if therapy is interrupted. Treprostinil is a prostacyclin analog indicated for patients with PAH and functional class II, III, or IV symptoms to diminish symptoms with exercise. Treprostinil therapy has been associated with modest improvements in exercise capacity in randomized clinical trials. Subgroup analysis and additional uncontrolled studies suggest that treprostinil may be most effective in patients with more advanced symptoms and at higher doses. With a longer half-life than epoprostenol, interruptions in therapy are not expected to cause serious rebound pulmonary hypertension. Administration of treprostinil by continuous subcutaneous (SC) infusion is likely to be associated with injection site reactions including pain and erythema, as reported by 85% of patients in clinical trials and leading to discontinuation of therapy in 18%. Alternatively, treprostinil may be administered by continuous IV infusion. Iloprost is a prostacyclin analog indicated for the treatment of PAH (WHO Group 1) in patients with functional class III or IV symptoms. Evidence on the magnitude of benefit with iloprost therapy is not consistent, but as a whole suggests that disease stabilization may occur with treatment, with marginal improvement in exercise capacity and functional class. Administered by inhalation, iloprost is not associated with the risks and complexity of continuous injectable infusions. However, due to its short half-life, 6-9 iloprost inhalations per day while awake are required. The first ERA approved in the US, bosentan is an oral agent indicated in patients with PAH (WHO Group 1) and functional class III or IV symptoms. Bosentan has been shown to improve exercise capacity and delay clinical worsening; longer term evaluations suggest a survival benefit compared to historical controls and similar to that observed with epoprostenol. According to the recently published EARLY trial, bosentan may be effective in the treatment of PAH patients with milder symptoms (functional class II). ERAs as a class are associated with hepatotoxicity and teratogenicity, requiring monthly monitoring of liver function tests (LFTs), pregnancy tests, and the use of effective contraception. Due to significant drug interactions with glyburide and cyclosporine, concomitant use with bosentan is contraindicated. Ambrisentan is the most recently approved oral ERA and is indicated in patients with PAH (WHO Group 1) and functional class II or III symptoms. Ambrisentan has been shown to improve exercise capacity and may delay clinical worsening. Potential for hepatotoxicity and teratogenicity necessitate monthly monitoring of LFTs and pregnancy tests as well as the use of effective contraception. Open label data suggest that ambrisentan is tolerated in patients who previously discontinued ERA therapy due to elevated LFTs. Sildenafil, a PDE-5 inhibitor, is indicated for the treatment of patients with PAH (WHO Group 1) to improve exercise ability; the majority of patients in randomized studies had functional class II or III symptoms. Therapy with sildenafil has been shown to improve exercise capacity and is generally well tolerated, with a favorable side effect profile. No clinically meaningful improvements in exercise capacity as measured by 6-minute walk distance (6MWD) were observed with escalating sildenafil doses in the SUPER trial. The role of combination therapy in PAH has not been clearly defined and efficacy and safety not established, although several trials are underway. Treatment of non-WHO Group 1 pulmonary hypertension (PH) is generally directed at the underlying disease. The use of the above agents for these diseases is neither approved by the FDA nor sufficiently supported by evidence from controlled clinical trials. The treatment of PAH continues to evolve, with many additional studies currently underway that aim to expand treatment options and further define optimal treatment strategies. II. INTRODUCTION PAH is a serious and often progressive disease defined hemodynamically as a mPAP >25 mmHg at rest or >30 mmHg with exercise in the setting of a normal left ventricular end diastolic pressure (LVEDP) or pulmonary capillary wedge pressure (PCWP) of d"15 mmHg, measured by right heart catheterization. The disease is frequently diagnosed in the third and fourth decades of life and occurs more frequently in women. Symptoms include dyspnea, exercise intolerance, fatigue, chest pain, palpitations, and syncope. Chronic and progressive elevations in pulmonary vascular resistance (PVR) may lead to right ventricular failure and death. Untreated, the estimated median survival from time of diagnosis is 2.8 years. Although there is no known cure, recent meaningful advances have been made in the availability of pharmacologic therapies. The treatment of PAH continues to evolve, with many additional studies currently underway that aim to expand treatment options and further define optimal treatment strategies. Pharmaceutical agents such as calcium channel antagonists, prostanoids, ERAs, and PDE5 inhibitors may improve hemodynamic parameters and exercise capacity, delay clinical worsening, and possibly prolong survival. The primary purpose of this document is to review the available evidence and provide guidance for the use of these agents for the treatment of PAH in the VA population. III. BACKGROUND PAH is thought to evolve in susceptible patients due to an insult of the pulmonary vasculature which may involve inflammation, toxins, and/or hypoxia. The result is an imbalance of vasoconstriction, smooth-muscle and endothelial hyperproliferation, and in situ thrombus formation in the pulmonary vessels, eventually leading to right ventricular failure and death. As a result of advances in the understanding of the disease, the clinical classification was revised at the Third World Conference on Pulmonary Hypertension in Venice in 2003. Based on common pathological and clinical features, the broad disease heading of pulmonary hypertension was divided into 5 groups. (See Table 1) WHO Group 1 encompasses the realm of PAH, including IPAH and familial PAH (FPAH) (both of which replace the term primary pulmonary hypertension [PPH]), and PAH associated with connective tissue disease (CTD), HIV, and portal hypertension. WHO Groups 2, 3, 4, and 5 include secondary causes, such as left heart disease, parenchymal lung disease, and chronic thromboembolic disease. For the purpose of this document, the term PAH refers to WHO Group 1 disease, and the term PH refers to non-WHO group 1 disease. Pharmacologic treatments have mainly been evaluated in IPAH and PAH associated with CTD; extrapolation to other populations should be done cautiously. Primary treatment of non-WHO Group 1 PH is aimed at treatment of the underlying disease and is not the focus of this document. When PAH is suspected, relatively non-invasive testing (e.g., electrocardiogram, Doppler echocardiography, chest x-ray, pulmonary function testing, auto-immune-collagen vascular disorder assessment, HIV testing, ventilation-perfusion scan, liver function studies, evaluation of sleep disordered breathing) are performed to identify an underlying cause or associated disease. Ultimately, right heart catheterization is required to confirm the diagnosis of PAH, determine disease severity and help guide therapy. NOTEREF _Ref196713580 \h \* MERGEFORMAT 1 Factors shown to be associated with poor prognosis include advanced functional class, low exercise capacity as measured by 6MWD, elevated mean right atrial pressure (mRAP), elevated mean pulmonary artery pressure (mPAP), decreased cardiac index, and lack of improvement in functional status with epoprostenol therapy. NOTEREF _Ref196715836 \h \* MERGEFORMAT 3, Three biochemical pathways have thus far been targeted in an effort to control or even reverse PAH: 1) the endothelin (ET) pathway (ERAs); 2) the nitric oxide pathway (exogenous nitric oxide [NO], PDE-5 inhibitors); and 3) the prostacyclin pathway (prostacyclin derivatives). Future study may be aimed at additional targets including genetic mutations (e.g., bone morphogenetic protein receptor-2 [BMPR-2] gene). Calcium channel antagonists may also be effective in a small subset of patients who show a vasodilatory response to these agents during right heart catheterization. Goals of therapy of PAH include improving or maintaining function, exercise capacity and hemodynamic measures, delaying clinical worsening and death. Endpoints that have been evaluated in clinical trials include: Exercise capacity gold standard is 6MWD Functional class New York Heart Association (NYHA) functional class for heart failure, which has been adapted by WHO for pulmonary hypertension (see Table 2) Hemodynamic measures includes mPAP, RAP, cardiac index (CI), PVR Biochemical measures (e.g., brain natriuretic peptide [BNP]) Dyspnea and/or quality of life (QOL) indices Delay in clinical worsening Survival primarily from extended, observational evaluation The approach to treatment should include consideration of the evidence for efficacy and safety of therapy, benefits vs. risks of pharmacologic options, and patient-specific factors. Pharmacologic treatments for PAH are generally costly and may be associated with serious side effects. They may require frequent monitoring and thus represent a significant commitment on the part of the patient. The American College of Chest Physicians (ACCP) published evidence-based clinical practice guidelines on the diagnosis and management of PAH first in 2004 and updated its recommendations in 2007., Although the ACCP treatment algorithm is primarily directed by the patients functional class, the consideration of other clinical prognostic indicators as determinants of high or low risk of disease progression have also been proposed to guide therapy. Table 1. WHO Clinical Classification of Pulmonary Hypertension (Revised Venice 2003) NOTEREF _Ref196666232 \h \* MERGEFORMAT 5 GroupClassification1Pulmonary arterial hypertension (PAH) Idiopathic (IPAH) Familial (FPAH) Associated (APAH) Collagen vascular disease Congenital systemic-to-pulmonary shunts Portal hypertension HIV infection Drugs and toxins Other Associated with significant venous or capillary involvement Pulmonary veno-occlusive disease Pulmonary capillary hemangiomatosis Persistent pulmonary hypertension of the newborn2Pulmonary hypertension due to left heart disease Left-sided atrial or ventricular heart disease Left-sided valvular heart disease3Pulmonary hypertension associated with lung diseases and/or hypoxemia Chronic obstructive pulmonary disease (COPD) Interstitial lung disease Sleep disordered breathing Alveolar hypoventilatory disorders Long-term exposure to high-altitude Developmental abnormalities 4Pulmonary hypertension due to chronic thrombotic or embolic disease (CTEPH) Thromboembolic obstruction of proximal or distal pulmonary arteries Non-thrombotic pulmonary embolism (tumor, parasites, foreign material) 5Miscellaneous Sarcoidosis, histiocytosis X, lymphangiomatosis, compression of pulmonary vessels  Adapted from J Am Coll Cardiol. 2004;43:10S with permission from Elsevier Table 2. WHO Functional Assessment Classification ClassDescriptionINo limitation in physical activityIISlight limitations in physical activity; ordinary physical activity produces dyspnea, fatigue, chest pain, or near-syncopeIIIMarked limitation of physical activity; less than ordinary physical activity produces dyspnea, fatigue, chest pain, or near-syncopeIVUnable to perform any physical activity without symptoms; dyspnea and/or fatigue present at rest IV. PHARMACOLOGIC TREATMENT General Therapy NOTEREF _Ref217196831 \h  \* MERGEFORMAT 7,, General or adjunctive therapy of PAH includes the use of diuretics, supplemental oxygen, warfarin, and/or digoxin. Since hypoxemia is a potent pulmonary vasoconstrictor, supplemental oxygen is generally recommended to maintain oxygen saturations >90% at all times. Diuretics and dietary salt/fluid restriction are indicated in patients with evidence of right heart failure (i.e., peripheral edema). Although not extensively studied specifically in the PAH population, digoxin therapy may be considered in patients with right ventricular failure and/or atrial dysrrhythmias. Patients with IPAH have been found to have in situ microscopic thrombosis and are thought to be at increased risk for pulmonary embolism with right ventricular failure and venous stasis. There appears to be a survival benefit in patients with IPAH anticoagulated with warfarin, although the evidence is limited to findings from observational study. Warfarin should generally be considered in patients with IPAH, weighing the benefits and risks of therapy; however, the benefits of anticoagulation in the non-IPAH population have not been extensively studied at this time. The optimal International Normalized Ratio (INR) has not been definitively determined, but recommendations fall between 1.5 and 3. The role of exercise training in the management of pulmonary hypertension has yet to be determined, although preliminary results are promising. Calcium Channel Antagonists Calcium channel antagonists have been used for their vasodilator properties in the treatment of IPAH since the 1980s. Acute vasoreactivity testing during heart catheterization identifies a small subset of patients who may respond to long-term calcium channel antagonist therapy. A consensus definition of a favorable response to acute vasoreactivity testing is a decrease in mPAP of at least 10 mmHg to a mPAP of d"40 mmHg, in the presence of an unchanged or increased cardiac output (CO). NOTEREF _Ref217208719 \h  \* MERGEFORMAT 8 In uncontrolled studies, these patients have been shown to exhibit sustained improvements in hemodynamics and functional status and prolonged survival., In a retrospective analysis of 557 patients with IPAH, 12.6% (70 patients) responded acutely to vasodilator testing and were started on calcium channel antagonists. NOTEREF _Ref217206132 \h  \* MERGEFORMAT 13 Fifty-four percent (38 patients) of the acute responders, or 6.8% of the study population, were considered long-term responders to calcium channel antagonists (defined as WHO functional class I or II and sustained hemodynamic improvement without additional PAH therapies at one year). Of the long term responders, 37/38 were alive and in WHO class I/II at 7 4.1 years compared to the calcium channel antagonist non-responders who had a 5 year survival rate of 48%. Long term responders had less severe disease at baseline and displayed a more pronounced drop in mPAP during the initial vasodilator testing. In an observational study of 64 patients with IPAH followed for 5 years, 26% of the population were considered responders to an acute vasoreactivity challenge and were treated with high-dose calcium antagonists (diltiazem mean daily dose: 720 mg 208 mg, nifedipine mean daily dose: 172 mg 41 mg). NOTEREF _Ref217208837 \h  \* MERGEFORMAT 14 The 5-year survival rate was 94% for responders on continued calcium-channel antagonist therapy and 55% for non-responders. Calcium channel antagonists should be reserved for IPAH responders without right heart failure. Their effects in non-IPAH patients have not been studied. ACCP Guidelines recommend treatment with long-acting diltiazem, nifedipine, or amlodipine. NOTEREF _Ref196722565 \h \* MERGEFORMAT 7 Verapamil is not recommended due to its negative inotropic effects. Baseline heart rate may be used to guide choice of agent (i.e., nifedipine may be preferred in setting of lower heart rate); amlodipine is generally considered an alternative when diltiazem or nifedipine is not tolerated. Doses are titrated upward slowly. Calcium channel antagonists may cause hypotension, hypoxemia due to worsening of ventilation-perfusion mismatch, and may depress myocardial contractility. Patients should be monitored closely for safety and efficacy. If a patient does not improve to WHO class I or II after three months of therapy, additional or alternative PAH therapy is recommended. NOTEREF _Ref196722565 \h \* MERGEFORMAT 7 Table 3. PAH-Specific Treatments,,,,, Generic NameTrade NameManufacturerFormulationMOAFDA IndicationAmbrisentanLetairis"!Gilead SciencesOral Endothelin antagonistWHO Group 1 with class II/III symptomsBosentan Tracleer"!ActelionOralEndothelin antagonistPAH WHO Group 1 with WHO class III/IV symptomsEpoprostenolFlolanGilead SciencesIV infusionProstanoidIPAH and PAH associated with scleroderma with NYHA class III/IV symptomsIloprostVentavisCoTherixInhalationProstanoidWHO Group 1 with class III/IV symptomsSildenafilRevatioPfizerOralPhosphodiesterase InhibitorWHO Group 1TreprostenilRemodulinUnited TherapeuticsSC or IV infusionProstanoidPAH NYHA class II/III/IV symptoms Prostanoids Prostaglandin I2 (prostacyclin), a metabolite of arachidonic acid found in the vascular endothelium, is a potent vasodilator of both the pulmonary and systemic circulations and inhibits smooth muscle cell growth and platelet aggregation., There is evidence that a relative deficiency in prostacyclin may contribute to the pathogenesis of PAH., Currently, there are three prostanoids available in the US, epoprostenol, treprostinil, and iloprost. They differ in their pharmacokinetics and routes of administration. Epoprostenol Approved in 1995, epoprostenol was the first prostacyclin agent available and is indicated in patients with IPAH or PAH associated with scleroderma that have NYHA class III/IV symptoms and have not adequately responded to conventional therapy. NOTEREF _Ref196576658 \h  \* MERGEFORMAT 17 Epoprostenol is administered by a continuous IV infusion through a central venous catheter. Therapy is generally initiated at a dose of 1-2 ng/kg/min and is increased in increments of 1-2 ng/kg/min as tolerated. Average doses from clinical trials were approximately 9-11 ng/kg/min at 12 weeks, but maintenance doses vary widely between patients and tend to increase over time. Due to the safety concerns with central venous catheterization and readily observable side effects of the drug, clinical trials with epoprostenol have been conducted in an open-label format. In a prospective, randomized, multicenter trial, the efficacy and safety of epoprostenol plus conventional therapy (anticoagulants, diuretics, oral vasodilators, digoxin, oxygen) was compared to conventional therapy alone in 81 patients with IPAH and NYHA class III/IV symptoms for 12 weeks. The primary endpoint of the trial, the median change from baseline 6MWD, was significantly improved in the epoprostenol group (an increase of 31m from a 316m baseline) compared to conventional treatment alone (a decrease of 29m from a baseline of 272m). All patients in the epoprostenol group were alive at 12 weeks, compared to 8 deaths in the control group (p <0.05). Secondary endpoints including NYHA functional class, quality of life scores, and hemodynamic measures (mPAP, CI, PVR) were significantly improved with epoprostenol. In an earlier trial of 24 patients and 8 weeks duration, epoprostenol treatment was also associated with hemodynamic and symptomatic responses, although a statistically significant difference compared to conventional therapy was not detected. The effects of epoprostenol in patients with scleroderma-associated PAH was studied in an open-label, prospective, randomized, multicenter study of 111 patients for 12 weeks. Patients had NYHA class III or IV symptoms and were randomized to receive conventional therapy alone or conventional therapy plus epoprostenol. Epoprostenol therapy was associated with significant improvements in the primary endpoint of median change from baseline of 6MWD (an increase of 46m from a baseline of 272m, compared to a decline of 48m from a baseline of 240m). Changes in functional class and hemodynamic measures were also more favorable in the epoprostenol group. No difference was observed in survival, with 4 deaths in the epoprostenol treated patients vs. 5 deaths in conventional therapy patients, although the trial was not powered to detect a significant difference. The authors concluded that epoprostenol therapy is effective in patients with pulmonary hypertension associated with the scleroderma spectrum of disease. The long term impact of epoprostenol therapy in 162 consecutive patients with IPAH or FPAH and in functional class III or IV was reported by McLaughlin and colleagues.  With a mean follow-up of 36.3 months, observed survival with epoprostenol treatment at 1, 2, and 3 years was 87.8%, 76.3%, and 62.8% respectively, which was significantly higher than that predicted by historical data (58.9%, 46.3%, and 35.4%). Baseline predictors of survival included exercise tolerance, functional class, right atrial pressure, and acute vasodilator response. After 1 year follow-up, functional class and improvement in exercise tolerance, cardiac index, and mPAP were indicators for survival. Similarly, Sitbon et al. evaluated the long term effects and prognostic indicators of survival in 178 patients with IPAH and symptoms of NYHA class III or IV over a mean follow-up of 28 months. Overall survival rates at 1, 2, 3, and 5 years were 85%, 70%, 63%, and 55% respectively. Factors influencing survival were severity of disease at baseline and response to therapy at 3 months. Use of historical control groups in these studies served to minimize the limitation of the non-randomized design and to avoid the ethical concerns of using concurrent controls in a severe disease with a poor prognosis. Due to its short half-life (<6 min) and basic pH, epoprostenol must be administered by a continuous IV infusion with an infusion pump via a central venous catheter. Any interruption in drug delivery may result in rebound pulmonary hypertension and death. Other complications of drug delivery reported include infection, cellulitis, sepsis, thrombosis, and inadvertent bolus or dose reduction. An additional consideration of epoprostenol administration is its limited stability at room temperature, necessitating the use of cold pouches during use. Common adverse events (AEs) reported in clinical trials, many of which are related to vasodilation, included headache, hypotension, diarrhea, flushing, nausea, vomiting, jaw pain, chest pain, dizziness, myalgia, and nervousness. Epoprostenol is contraindicated in patients with congestive heart failure due to left ventricular systolic dysfunction and should not be used chronically in patients who develop pulmonary edema during dose initiation. NOTEREF _Ref196576658 \h  \* MERGEFORMAT 17 Additive hypotensive effects may occur when epoprostenol is co-administered with other agents that lower blood pressure. Although patients in clinical trials were maintained on anticoagulants, the potential for increased risk of bleeding exists due to the antiplatelet effects of epoprostenol. Digoxin clearance is reduced by 15%, which is not likely to be clinically significant in most patients, but digoxin levels should be monitored with treatment initiation. Because of the above complexities and risks, only clinicians experienced in the diagnosis and treatment of PAH should manage epoprostenol treatment. Treprostinil First approved for continuous SC administration, treprostinil subsequently received an FDA indication for IV administration in patients with PAH and NYHA Class II-IV symptoms to diminish symptoms with exercise. NOTEREF _Ref196576716 \h  \* MERGEFORMAT 20 Treprostinil is also indicated to decrease the rate of clinical deterioration in patients requiring transition from epoprostenol. The preferred route of administration of treprostinil is SC, although IV administration is an alternative in those patients who do not tolerate SC infusions because of site reactions. Bioequivalence of the IV and SC routes was demonstrated in a randomized, crossover pharmacokinetics study in 51 healthy subjects. Treprostinil is initiated at a dose of 1.25 ng/kg/min (IV or SC) and titrated weekly depending on clinical response. Similar to epoprostenol, individual dose requirements vary widely. The average dose in the largest clinical trial was 9.3 ng/kg/min after 12 weeks; however, much higher doses have been observed in subsequent evaluations. The efficacy and safety of SC administration of treprostinil was evaluated in a combined analysis of two large, double-blind, randomized, placebo-controlled, international 12-week studies enrolling 470 patients with IPAH or PAH associated with CTD or congenital systemic-to-pulmonary shunts and NYHA class II, III, or IV symptoms. NOTEREF _Ref217269133 \h  \* MERGEFORMAT 31 Patients were randomized to receive treprostinil or placebo. All also received conventional therapy (oral vasodilators, anticoagulants, diuretics, and digoxin), which was optimized prior to enrollment. The majority of patients had class III symptoms (approximately 80%) and IPAH (58%). At week 12, there was a modest but statistically significant improvement in the primary endpoint of median change in 6MWD with treprostinil (an increase of 10m from a baseline of 326m in the treprostinil group and no change from a baseline of 327m in the placebo group). Statistical improvements were also reported for dyspnea, physical quality of life, and hemodynamics (RAP, mPAP, CI, PVR) with treprostinil but not global quality of life. The number of deaths, transplantations, and discontinuation due to disease worsening were similar between groups (13 in treprostinil vs. 16 in placebo). The modest improvement in 6MWD observed with treprostinil was hypothesized as due to the inclusion of less compromised patients and the use of lower doses, as limited by infusion site pain. Upon further analysis, patients receiving higher treatment doses and those who had worse symptoms at baseline showed a greater response to treatment. Results from a small, open-label, uncontrolled evaluation of IV treprostinil also suggested that the formulation was effective in improving exercise capacity in PAH and WHO class III or IV symptoms. Adverse events were similar to that seen with SC treprostinil except for the lack of infusion site reactions. Barst et al. reported on the long term outcomes with SC treprostinil in 860 patients with PAH for up to 4 years. In the whole patient population, survival was 87%, 78%, 71%, and 68% over 1, 2, 3, and 4 years. Survival in the IPAH sub-population was significantly higher than predicted by historical data. The authors state that safety in the long term was similar to that reported in 12-week studies with no unexpected adverse events. As with epoprostenol, only clinicians experienced in the diagnosis and treatment of PAH should manage treprostinil treatment due to the complexity of therapy. With a longer half-life of approximately 4 hours, brief interruptions in treprostinil therapy are not likely to result in adverse consequences of rebound pulmonary hypertension as observed with epoprostenol, although abrupt withdrawal should be avoided. Treprostinil is stable at room temperature, allowing for administration without the use of cold packs. One of the major treatment limiting adverse events of SC administration of treprostinil is injection site reaction, reported by 85% of patients in clinical trials, which led to discontinuation in 18% of patients. Erythema and pain can be severe; treatments with topical and oral analgesics, hot and cold compresses, and anti-inflammatory drugs have been variably effective. IV administration of treprostinil carries the risk of infection and thrombosis due to an indwelling catheter. Other adverse effects include diarrhea, jaw pain, vasodilatation, and nausea. Due to the vasodilating and anti-platelet properties of treprostinil, additive effects may occur when patients receive anti-hypertensive agents or anticoagulants, respectively. Treprostinil is metabolized by the liver, with small amounts of unchanged drug along with metabolites excreted in the urine; caution should be used in administration to patients with renal or severe hepatic impairment. Initial dose reduction is recommended in patients with mild-to-moderate hepatic impairment. Iloprost Approved in 2004, iloprost is a synthetic prostacyclin analogue indicated for the treatment of PAH (WHO Group 1) in patients with functional class III or IV symptoms. NOTEREF _Ref196576761 \h  \* MERGEFORMAT 18 Iloprost is administered as an oral inhalation given via a specialized nebulizer at a dose of 2.5-5 mcg taken 6 to 9 times per day during waking hours (no more than once every 2 hours). The AIR trial was a prospective, randomized, double-blind, placebo-controlled, multicenter study of 12 weeks duration that evaluated the efficacy and safety of inhaled iloprost in 203 patients with IPAH, PAH associated with scleroderma or anorexients, or chronic thromboembolic pulmonary hypertension (CTEPH), all with NYHA functional class III or IV symptoms. Iloprost was dosed at 2.5 mcg per treatment, increased to 5 mcg if tolerated, 6-9 times per day while awake (e"2 hrs apart). Ninety-one percent of the patients were maintained on 5 mcg, and the mean frequency of inhalations per day was 7.5. For the combined primary endpoint of an increase of e"10% in 6MWD, improvement of NYHA functional class, and absence of clinical deterioration, iloprost treatment was associated with a significant improvement vs. placebo, with 17% and 5% of patients meeting the endpoint, respectively. Subgroup analysis revealed a lack of benefit in the CTEPH population. Although a trend favored the iloprost group, the difference in patients achieving e"10% improvement in 6MWD alone was not statistically superior to placebo (38% vs. 26% respectively). There was a significant absolute change in 6MWD with iloprost (placebo-corrected change of 36m; baseline 6MWD of 332m in iloprost group and 315m in placebo group). NYHA functional class, dyspnea, and QOL scores were improved with iloprost. Hemodynamic measures were primarily unchanged from baseline in the iloprost group when evaluated pre-iloprost dose but were significantly improved from baseline post-dose (PAP, CO, PVR), whereas hemodynamics in the placebo group generally worsened, suggesting stabilization of hemodynamic variables with iloprost treatment. Long term effects of iloprost therapy were evaluated in a prospective uncontrolled trial of 76 patients with IPAH and NYHA class II or III symptoms given a constant dose of 100 mcg/day of inhaled iloprost (in 6 divided doses) for a median period of 383 days. At 12 months, 32/76 patients remained on iloprost therapy; reasons for discontinuation included death, transplant, switch to IV or combination therapy. Overall survival rates at 3 months, 1, 2, 3, 4, and 5 years was 93%, 79%, 70%, 59%, 59%, and 49%. Limitations of this study include the lack of comparator group and uncontrolled design; nevertheless, the authors conclude that because only a minority of patients appeared to sustain a clinical benefit, the role of inhaled iloprost as monotherapy may be limited. In contrast, Hoeper and colleagues observed a sustained benefit in a one-year follow-up uncontrolled study of 24 patients with IPAH and functional class III or IV symptoms. Patients received 100-150 mcg/day of iloprost and maintained the significantly improved 6MWD observed at 3 months (increase of 75m) and maintained at 12 months. Similarly, improvements in hemodynamic measures (mPAP, CO, PVR) were sustained for 12 months. Because of its short half life of 30 minutes, iloprost must be administered several (6-9) times per day and is given via a specialized nebulizer. Adverse effects reported in clinical trials included flushing, headache, cough, influenza-like syndrome, nausea, jaw pain, hypotension, and syncope. Like other prostanoids, iloprost may potentiate the effect of hypotensive agents and anticoagulants. Iloprost inhalation has not been evaluated in patients with renal or hepatic impairment; however, increased exposure (area under the concentration curve) without an increase in half life was noted when IV or oral iloprost was administered to these populations. Endothelin Receptor Antagonists ET-1 is a direct vasoconstrictor and stimulates smooth muscle cell proliferation. It also acts as a co-mitogen, induces fibrosis, and has pro-inflammatory effects. Abnormally high levels of ET-1 have been detected in patients with PAH. The effects of ET are mediated through ETA and ETB receptor subtypes. ETA activation results in vasoconstriction and smooth-muscle cell proliferation, while ETB activation induces vasodilation and mediates ET clearance. Currently, two oral ERAs are available in the US. Bosentan, the first agent approved, is a dual (ETA and ETB) ERA. Ambrisentan has high selectivity for ETA and thus offers the potential to favor vasodilation. However, the clinical significance of ETA selectivity has yet to be determined. Although there are differences between the agents, ERAs as a class share similar precautions for use that require close monitoring. ERAs are associated with hepatotoxicity, primarily observed as elevations of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) and occasionally accompanied by elevated bilirubin. Liver function test (LFT) abnormalities appear to be dose related, may occur at any time during treatment, and are generally asymptomatic. Should LFT abnormalities occur, management may include dose reduction, temporary or permanent discontinuation of therapy, and closer monitoring, as outlined in the prescribing information for each agent. Contraindicated in women who are or may become pregnant, ERAs are known to be teratogenic and belong to the FDA Pregnancy Category X. In women of childbearing potential, pregnancy must be ruled out prior to initiation of therapy and prevented with reliable forms of contraception during treatment. An ERA class effect as well as a clinical manifestation of PAH, peripheral edema and fluid retention requiring intervention have been reported. Because of decreases in hemoglobin and hematocrit that may occur with ERA therapy, baseline and periodic monitoring is required. Because of the risks of hepatotoxicity and teratogenic effects, ambrisentan and bosentan carry black box warnings in the prescribing information and are available only through restricted access programs. Monthly monitoring of LFTs and pregnancy tests (if appropriate) are required. A Cochrane review was conducted to evaluate the efficacy of ERAs in PAH. Last updated in 2006, the review included 5 RCTs: 2 compared bosentan vs. placebo; 1 compared bosentan plus epoprostenol vs. epoprostenol alone; 1 compared bosentan vs. sildenafil; and 1 compared sitaxsentan (selective ERA not approved in the US) vs. placebo. ERAs were associated with significant improvements in exercise capacity as measured by 6MWD (pooled treatment effect of 37m [95% CI 22.4 51.8m]), functional class, Borg dyspnea score, and hemodynamic parameters vs. placebo. Although a trend of increased incidence of hepatotoxicity with ERAs was observed, it was not statistically significant. No improvement in mortality with ERA therapy was shown, although the studies were of limited duration (12-16 weeks). This review was published prior to the availability of data from the ambrisentan trials, and the potential influence of the combination of epoprostenol and bosentan on the results is unknown. Bosentan Bosentan, the first ERA approved in the US, is an oral agent currently indicated in patients with PAH (WHO Group 1) and WHO functional class III or IV symptoms. With the recent results of the EARLY trial, it is expected that the manufacturer will seek approval for an expanded indication for patients with functional class II symptoms. NOTEREF _Ref196576793 \h  \* MERGEFORMAT 16 The recommended dose of bosentan is 62.5 mg orally twice daily for 4 weeks and then increased to 125 mg orally twice daily. Higher doses are not recommended, as the additional benefit does not outweigh the increased risk of hepatotoxicity. Channick and colleagues reported on the results of Study 351, a randomized, double-blind, placebo-controlled, multi-center trial of 12 weeks duration evaluating the efficacy of bosentan 125 mg twice daily in 32 patients with PAH and WHO class III symptoms. Regarding the primary endpoint, bosentan was associated with a significant mean increase from baseline in 6MWD vs. placebo (an increase of 70m 56 from a baseline of 360m compared to a decrease of 6m 121 from a baseline of 355m). No clinical worsening events were observed in bosentan group vs. 3 events in placebo group. Although no improvement in Borg dyspnea index (BDI) was noted, significant improvements in WHO functional class and hemodynamic measures (PVR, mPAP, PCWP, mRAP) were reported in bosentan-treated patients vs. placebo. The authors concluded that ET plays an important role in PAH and that bosentan may be a therapeutic option in this disease. In the BREATHE-1 trial, the efficacy and safety of bosentan was evaluated in 213 patients with PAH who were randomized in a double-blinded manner to receive 125 mg or 250 mg of bosentan orally twice daily or placebo for 16 weeks. , NOTEREF _Ref196576793 \h 16 Approximately 90% of patients had WHO class III symptoms, with the remainder in WHO class IV. For the primary endpoint of mean change from baseline in 6MWD vs. placebo, distance was significantly increased with bosentan treatment (increase of 27m 75 from a baseline of 326 m in 125 mg group; increase of 46m 62 from a baseline of 333m in 250 mg group; and decrease of 8m 96 from a baseline of 344m in placebo group). BDI was also improved, and a favorable trend in WHO functional class change was noted with bosentan therapy. Although improvements in 6MWD were more pronounced in the higher dose bosentan group, the difference between the bosentan 125 mg and 250 mg groups was not statistically significant. Because blinded treatment continued until the last enrolled patient completed 16 weeks of treatment, up to 28 weeks of follow-up data was available. Time to clinical worsening was significantly improved with bosentan treatment, with 6% vs. 20% of patients experiencing an event in bosentan and placebo groups, respectively, at 28 weeks. No differences were noted between bosentan groups, and improvements were evident at 16 weeks. In the recently published EARLY trial, which was a double-blind, placebo-controlled, multicenter study of 26 weeks duration, the efficacy and safety of bosentan dosed at 125 mg twice daily was evaluated in 185 PAH patients with functional class II symptoms. The majority of patients had IPAH (60%), while the remainder of patients had PAH associated with congenital heart disease, CTD, or HIV. Approximately 15% of patients in each group were on concomitant sildenafil therapy; other PAH specific treatments were not permitted. For the first co-primary endpoint of change in PVR, bosentan was associated with a statistically significant improvement at 26 weeks: mean reduction of 16.8% (95% CI: -6.3% to -26.2%) from baseline with bosentan vs. mean increase of 7.5% (95% CI: -2.4% to +18.4%) from baseline with placebo. Even though a favorable trend was observed with bosentan treatment for the second co-primary endpoint of change in 6MWD, the treatment effect of bosentan failed to reach statistical significance (increase of 11.2m from a baseline of 438m, compared to decline of 7.9 m from a baseline of 431m for placebo). There was a significant delay in clinical worsening and a reduced number of clinical worsening events with bosentan treatment (3% bosentan vs. 14% placebo patients experienced a clinical worsening event). In addition, significant WHO functional class improvements were observed with bosentan treatment vs. placebo. Two longer-term evaluations of data from open-label extensions of the placebo-controlled trials have been published. McLaughlin and colleagues reported that at a mean follow-up of 24 months, first-line therapy with bosentan (followed by additional therapy if needed) was associated with 1 and 2 year Kaplan-Meier survival estimates of 96% and 89% respectively, with the majority of patient remaining on bosentan monotherapy. In contrast, National Institutes of Health (NIH) survival estimates based on 1980s data are 69% and 57% at 1 and 2 years. In a report by Sitbon et al., bosentan therapy was not associated with worse outcomes than a historical control cohort of epoprostenol patients, which is known to positively affect survival. Limitations of these investigations include the retrospective, uncontrolled design. The most common AEs reported in clinical trials with bosentan included headache, nasopharyngitis, flushing, and lower limb edema. In clinical trials, aminotransferase elevations of >3x the upper limit of normal (ULN) occurred in 11% of bosentan treated patients vs. 2% of placebo and were dose dependent. The teratogenic risks of bosentan require the use of reliable contraception in women of childbearing potential. Due to the potential for decreased effectiveness when co-administered with bosentan, hormonal contraceptives should not be used as the sole form of contraception during therapy. Fluid retention requiring intervention has been reported post-marketing with bosentan, especially within the first weeks of initiation of therapy, requiring close monitoring of fluid status. Hemoglobin should be checked at one month, three months, and periodically thereafter, as decreased levels have been associated with bosentan treatment. Bosentan is metabolized by and is an inducer of CYP3A4 and CYP2C9, which may result in significant drug interactions. Concurrent administration with cyclosporine or glyburide is contraindicated. Of note, concomitant administration of sildenafil and bosentan resulted in a 63% decrease in sildenafil concentrations and 50% increase in bosentan concentrations, however the clinical relevance of this interaction is unknown. Because of the risks of hepatotoxicity and teratogenicity, bosentan is only available through a restricted access program TAP (Tracleer Access Program). Ambrisentan Ambrisentan was approved by the FDA as an orphan drug in 2007 and is indicated for the treatment of PAH (WHO Group 1) in patients with WHO functional class II or III symptoms to improve exercise capacity and delay clinical worsening. NOTEREF _Ref196576814 \h  \* MERGEFORMAT 15 The recommended starting dose of ambrisentan is 5 mg given orally once daily, which can be titrated up to 10 mg once daily if tolerated. The safety and efficacy of ambrisentan was evaluated in two similarly designed, phase-3, placebo-controlled trials of 12 weeks duration, ARIES-1 and ARIES-2. , Approximately two-thirds of the patients had IPAH, and the majority of the non-IPAH population had PAH associated with CTD. Most patients (93%) had WHO class II or III symptoms. In ARIES-1, 201 patients were randomized to receive 5 or 10 mg of ambrisentan orally once daily or placebo. Both treatment groups were associated with significant improvements in the primary endpoint of change from baseline in 6MWD at 12 weeks compared to placebo: increase of 22.8m 83 from a baseline of 340m (5mg); increase of 43.6m 65.9 from a baseline of 341m (10mg); and decline of 7.8m 78.9 from a baseline of 342m (placebo). A favorable but nonsignificant trend in clinical worsening was noted with ambrisentan treatment (6/134 patients in ambrisentan group vs. 6/67 patients in the placebo group experienced clinical worsening, with an ARR of 4.5%; NNT=22). Statistically significant improvements were demonstrated in the combined ambrisentan group vs. placebo in WHO functional class and BDI, but no difference was observed in the SF 36 Health Survey physical function scale. In ARIES-2, 192 patients were randomized to receive 2.5 or 5 mg of ambrisentan orally once daily or placebo. Significant improvements in 6MWD at 12 weeks were shown in both ambrisentan treatment groups compared to placebo: increase of 22.2m 82.7 from a baseline of 347m (2.5 mg); increase of 49.4m 75.4 from a baseline of 355m (5 mg); and decline of 10.1m 93.8 from a baseline of 343m (placebo). Significant delay in time to clinical worsening (TTCW) was observed at week 12 in the combined ambrisentan group vs. placebo (6/127 vs. 14/65 patients experienced clinical worsening respectively; ARR 17%; NNT 6). Significant improvements were noted with ambrisentan treatment vs. placebo in the SF 36 Health Survey and BDI, and a favorable but nonsignificant trend was observed in WHO functional class. Preliminary unpublished information from supportive, non-comparative, long-term extension trials suggests that the efficacy and safety of ambrisentan is maintained. NOTEREF _Ref195885810 \h  \* MERGEFORMAT 45 Ambrisentan was generally well tolerated in clinical trials. The most common AEs reported were mild to moderate in nature and included peripheral edema, nasal congestion, sinusitis, flushing, palpitations, and gastrointestinal effects. Because of the teratogenic risks of ambrisentan, the use of two reliable forms of contraception (unless patient has had tubal sterilization or IUD insertion) is required. Aminotransferase elevations of >3x ULN occurred in 0.8% of patients in 12-week trials. Including data from open-label long term studies of up to one year, the incidence of aminotransferase elevations >3x ULN with ambrisentan was 2.8%. Results from AMB-222, an open-label study of 36 patients, suggest that ambrisentan is tolerated in patients who had required discontinuation of previous ERA therapy due to LFT elevations. Peripheral edema and fluid retention have occurred with increased frequency in ambrisentan vs. placebo patients as well as in elderly vs. younger patients in clinical trials. Because of the potential for decreased hemoglobin levels, baseline, one month, and then periodic monitoring is required. Post marketing reports of fluid retention requiring intervention within weeks of starting ambrisentan have been received, warranting close monitoring of fluid status. No clinically relevant drug interactions have been observed when ambrisentan is co-administered with warfarin or sildenafil. Additional drug interaction studies are lacking. Due to the metabolism of ambrisentan, caution should be used when the drug is administered with the following: strong inhibitors of cytochrome P450 [CYP] 3A4 (e.g., ketoconazole), CYP2C19 (e.g., omeprazole), or of the transporters P-glycoprotein (e.g., cyclosporine) and Organic Anion Transport Protein [OATP] (e.g., cyclosporine, rifampin), as well as inducers of CYP3A or CYP2C19 (e.g., rifampin). Because of the risks of hepatotoxicity and teratogenic effects, ambrisentan is only available through a restricted distribution program, LEAP (Letairis Education and Access Program). Monthly monitoring of LFTs and pregnancy tests (if appropriate) is required. Phosphodiesterase Inhibitors Nitric oxide (NO), produced in endothelial cells, causes vasodilation through the production of cyclic guanosine 3-5 monophosphate (cGMP) in the vascular smooth muscle. NOTEREF _Ref195884285 \h  \* MERGEFORMAT 37 Overexpressed in the lungs of patients with PAH, phosphodiesterase type-5 (PDE5) is responsible for the breakdown of cGMP. Inhibitors of PDE5 increase levels of cGMP in the smooth muscle cells of the pulmonary vasculature, resulting in vasodilation. Sildenafil In 2005, sildenafil was approved by the FDA for the treatment of PAH (WHO Group 1) to improve exercise ability. NOTEREF _Ref196811905 \h  \* MERGEFORMAT 19 The formulation approved for the treatment of PAH (Revatio) differs from that approved for the treatment of erectile dysfunction (Viagra) in tablet strength only. The FDA approved dose of sildenafil for the treatment of PAH is 20 mg orally three times daily. Several doses of sildenafil have been studied in a number of clinical trials ranging from 12.5 mg to 100 mg up to three times daily. Sastry and colleagues reported on a double-blind, placebo-controlled, cross-over study enrolling 22 patients with PPH and WHO functional class II or III symptoms who were randomized to receive weight-based sildenafil therapy (d"25 kg received 25 mg three times daily; 26-50 kg received 50 mg three times daily; e"51 kg received 100 mg three times daily) or placebo for 6 weeks each. The majority of patients had WHO class II symptoms. Exercise time improved with sildenafil treatment in both groups. In patients who received sildenafil first, exercise time increased significantly from 451.6 189.6 to 698.1 272.9 seconds at 6 weeks, whereas in patients who received placebo first, exercise time increased from 475 168 to 686 224 seconds following 6 weeks of sildenafil treatment. CI was also improved as measured by echocardiography. Limitations include the small sample size, absence of a washout period, short duration, and non-invasive techniques to measure hemodynamics. In a double-blind, head-to-head study of 16 weeks duration, the effects of sildenafil and bosentan on right ventricular (RV) mass were compared in 26 patients with IPAH or PAH associated with CTD with WHO class III symptoms. The authors hypothesized that because RV hypertrophy is a response to increased PAP, a decrease in RV mass would be expected as a result of a sustained reduction in mPAP. Patients were randomized to receive either 50 mg sildenafil twice daily for 4 weeks, increased to 50 mg three times daily or 62.5 mg bosentan twice daily for 4 weeks, increased to 125 mg twice daily. For the primary endpoint of change in RV mass, there was no significant difference between groups. A statistically significant reduction in RV mass from baseline was observed with sildenafil treatment (-8.1g) but not bosentan treatment. When analyzed by intention to treat analysis, no difference between treatment groups was observed in the mean 6MWD, although both groups showed significant increases from baseline (increase of 75m from a baseline of 290m with sildenafil and increase of 59m from a baseline of 305 m with bosentan). Analysis of those patients who completed the protocol revealed a statistically significant difference in favor of sildenafil regarding mean increase in 6MWD. There was one death in the sildenafil group as well as one admission for palpitations. In the bosentan group, there were three admissions; two for fluid retention and one for hemoptysis. No patients withdrew from treatment due to AEs. Limitations of this study include its small sample size and use of the endpoint of RV mass, which has not been evaluated in other clinical trials. The SUPER trial was a double-blind, placebo-controlled, multi-center study that randomized 278 patients with PAH to one of four treatment arms: sildenafil 20 mg, 40 mg, or 80 mg given three times daily or placebo for 12 weeks.  Patients had IPAH or PAH associated with CTD or repaired congenital systemic-to-pulmonary shunts. Most patients had WHO functional class II or III symptoms. Baseline 6MWD were as follows: 347m in 20mg group, 345m in 40 mg group, 339m in 80 mg group. Based on intention-to-treat analysis, sildenafil treatment was associated with a significant improvement in the primary endpoint of mean change from baseline in 6MWD. Placebo-corrected improvements were similar between groups: 45m, 46m, and 50m in the 20 mg, 40 mg, and 80 mg groups, respectively. Although significant improvements in hemodynamic measurements (mPAP, CI, PVR) and WHO functional class were demonstrated with sildenafil treatment, no statistically significant difference in clinical worsening or BDI was found. In a long-term extension of the SUPER trial, patients were treated with 80 mg of sildenafil three times daily and followed for 12 months. Of the approximately 86% of patients who remained on sildenafil monotherapy, the 6MWD remained similar to that seen at 12 weeks. Ninety-four percent of patients in the extension trial were alive at 12 months. NOTEREF _Ref196811905 \h  \* MERGEFORMAT 19 The lack of dose-response relationship with increasing doses of sildenafil in the SUPER trial resulted in the FDA approval of the 20 mg three times daily dose. Sildenafil was generally well tolerated in clinical trials. Most adverse events were mild to moderate in nature and included headache, flushing, dyspepsia, insomnia, epistaxis, and visual disturbances. Sildenafil potentiates the hypotensive effects of other agents, and is contraindicated for use with organic nitrates. Caution should be exercised when co-administering sildenafil with alpha blockers, as additive hypotensive effects may occur. Post-marketing reports with sildenafil include rare cases of non-arteritic anterior ischemic optic neuropathy (NAION) and cases of sudden decrease or loss of hearing. Because sildenafil is metabolized by CYP3A4 (major) and CYP2C9, inhibitors or inducers of these enzymes would be expected to result in increased or decreased levels of sildenafil respectively. Patients with severe renal impairment displayed a doubling of sildenafil concentrations. Combination Therapy Combining drugs with different mechanisms of action as a strategy for the treatment of PAH is gaining interest; however, few randomized controlled trials evaluating the safety and efficacy of combination therapy have been published to date. Several trials are underway that aim to clarify the role of combination therapy in PAH. In the STEP study, 67 patients with PAH on bosentan were randomized in a double-blind manner to receive iloprost or placebo for a duration of 12 weeks. Compared to bosentan monotherapy, combination therapy was associated with a significant improvement in functional class and time to clinical worsening and an improvement in 6MWD that approached statistical significance (increase of 30m from a baseline of 331m with combination therapy, compared to a decline of 4m from a baseline of 340m with monotherapy; p=0.051). In contrast, a randomized, non-blinded evaluation of 40 patients with IPAH was terminated prematurely due to predicted failure to demonstrate a favorable effect with the addition of iloprost to bosentan. The BREATHE-2 study, which evaluated the combination of epoprostenol plus bosentan to epoprostenol alone in 33 patients with severe PAH in a randomized, double-blinded design, failed to demonstrate a significant improvement when bosentan was added to epoprostenol therapy. In the largest randomized, placebo-controlled, combination therapy trial to date, the PACES trial evaluated the addition of sildenafil in 267 PAH patients stabilized on epoprostenol. The addition of sildenafil was associated with a significant improvement in 6MWD (increase of 30m from a mean baseline of 349m with combination therapy vs. increase of 1m from a mean baseline of 342 m with monotherapy), hemodynamic parameters, and a delay in clinical worsening compared to epoprostenol monotherapy at 16 weeks. An increased number of adverse events, mostly mild to moderate in severity, were reported with sildenafil combination therapy. The remainder of the published information evaluating combination PAH therapy at this time is limited to uncontrolled observational studies and case series of small numbers of patients, which are summarized in Appendix 4.,,,,,,, Reports were excluded if they evaluated a drug or dosage form not available in the U.S. or a population not applicable to the veteran population (e.g., pediatrics). Of the reports located, combinations studied include: prostanoid + sildenafil; bosentan + sildenafil; prostanoid + sildenafil + bosentan. Combination therapy was mainly initiated at the point of clinical deterioration or when patients did not meet treatment goals, which were pre-defined in each study, although definitions differed between studies. In several of the studies, improvements in exercise capacity and functional class with combination therapy were observed. Reported adverse events were primarily known and expected side effects of each drug, although new LFT elevations were reported in some patients after sildenafil was added to bosentan therapy. Although further study is needed to determine the clinical implications, a pharmacokinetics study in 55 healthy volunteers revealed a mutual interaction between bosentan and sildenafil that resulted in a 63% increase in bosentan and 50% decrease in sildenafil plasma concentrations after 16 days of therapy. NOTEREF _Ref208623835 \h  \* MERGEFORMAT 44 In summary, evidence from randomized controlled trials is currently too limited to fully evaluate the efficacy and safety of combination therapy for PAH. Several ongoing trials will hopefully help to clarify the role of combination therapy. For additional information about ongoing trials, visit www.clinical trials.gov. Non-WHO Group 1 Pulmonary Hypertension A detailed review of the treatment of WHO Groups 2, 3, 4, and 5 are beyond the scope of this document. Primary therapy of non-WHO Group 1 PH is aimed at the underlying disease. No PAH-specific treatment available in the US (epoprostenol, iloprost, treprostinil, ambrisentan, bosentan, sildenafil) is currently FDA approved for the treatment of non-WHO Group 1 PH, and further study is needed to clarify the role of these agents in these forms of PH. The following summary is limited to information from randomized controlled trials evaluating the off-label use of PAH specific drugs and dosage forms available in the US. WHO Group 2 PH: left heart disease The use of epoprostenol for the treatment of patients with severe congestive heart failure (HF) was shown to be detrimental in the FIRST trial, a randomized controlled study of 471 patients that was terminated early due to an increased mortality rate observed in the treatment group. In addition, no benefit of epoprostenol was demonstrated in 6MWD or quality of life measures. Similarly, bosentan failed to show benefit and was associated with an increased incidence of adverse events in 94 patients with systolic heart failure and secondary PH in a randomized controlled trial of 20 weeks duration. Although PH occurs frequently in patients with left heart disease, therapy with prostacyclins or ERAs has not been shown to be favorable. With a lack of benefit and potential for harm as demonstrated by the evidence currently available, prostanoids and ERAs should generally not be used for treatment of PH due to left heart disease. In contrast, sildenafil was associated with improved exercise capacity as measured by oxygen uptake and 6MWD in a small, randomized, controlled pilot study of 12 weeks duration (n=34). Although preliminary results are promising, the use of sildenafil in the treatment of PH associated with left heart disease cannot be recommended until these results are confirmed in further study. WHO Group 3 PH: parenchymal lung disease and/or hypoxemia Therapy of PH due to parenchymal lung disease is aimed at correction of hypoxemia with supplemental oxygen where hypoxemia is present. PAH specific therapy (e.g., ERAs, prostacyclins) may potentially worsen ventilation/perfusion mismatch and should be used with caution in this population. Preliminary information suggests that the ability of an agent to preferentially lower pulmonary vascular resistance without decreasing systemic arterial pressure and worsening hypoxemia may be specific to the medication and formulation; inhaled iloprost and oral sildenafil appear to preferentially affect pulmonary vasculatures whereas IV epoprostenol appears non-selective., In an unpublished randomized controlled trial, the safety and efficacy of iloprost was evaluated in 51 patients with idiopathic pulmonary fibrosis and PH over a duration of 12 weeks. Although no unexpected safety issues were identified, treatment with iloprost was not more effective than placebo, as measured by 6MWD, functional class, and dyspnea scores. In the BUILD-1 trial, the effects of bosentan were evaluated in 158 patients with idiopathic pulmonary fibrosis (IPF) for 12 months. Although favorable trends were noted, changes in 6MWD, time to death or disease progression, pulmonary function tests, and dyspnea scores between bosentan and placebo groups failed to reach statistical significance. Twelve percent of bosentan patients discontinued treatment due to elevated LFTs. Randomized controlled trials evaluating clinical endpoints are needed to clarify the role of prostacyclins, ERAs, and PDE-5 inhibitors in the treatment of WHO Group 3 PH. WHO Group 4 PH: chronic thromboembolic pulmonary hypertension (CTEPH) Primary therapy for CTEPH is anticoagulation and potentially surgical intervention (thromboendarterectomy). Although several uncontrolled studies are available that have observed the effects of PAH specific therapy (e.g., ERAs, prostacyclins, PDE-5 inhibitors) in patients with inoperable or unresponsive CTEPH, randomized controlled evaluation is limited. In the only published, double-blind, placebo-controlled trial located to date, the effects of sildenafil in 19 consecutive patients with chronic, inoperable CTEPH were evaluated against placebo over 12 weeks. Although the study did not find a statistically significant change in 6MWD vs. placebo, significant improvements were noted in WHO functional class and PVR, and sildenafil appeared well tolerated. The patient population from the AIR trial (iloprost vs. placebo) included 33% of iloprost-treated patients with CTEPH. NOTEREF _Ref196529575 \h  \* MERGEFORMAT 34 Evidence of benefit in this population was insufficient according to subgroup analysis. NOTEREF _Ref196529575 \h  \* MERGEFORMAT 34, NOTEREF _Ref208633662 \h 69 The role of PAH specific therapy in the treatment of inoperable or unresponsive CTEPH needs to be confirmed with additional randomized controlled trials evaluating clinical endpoints. WHO Group 5 PH: PH due to inflammation, mechanical obstruction, extrinsic compression This group of PH is uncommon, and primary therapy is aimed at the underlying cause. Preliminary case reports have been published describing the use of PAH specific therapy in advanced sarcoidosis, but evidence from randomized controlled trials is lacking. Table 4. PAH Specific Treatments Dosing, Monitoring, and Costs (as of 5/08) PAH TreatmentDose FormMOAUsual DoseEstimated Annual Costs(Dose)MonitoringDrug Interactions Safety/Adverse EventsAmbrisentanOralERA5 mg/day, may be titrated up to 10 mg/day$23,749 (5mg or 10mg/day)Baseline and monthly LFTs, pregnancy test; H/H; monitor for fluid retentionLimited info; substrate of CYP3A4, 2C19, P-glycoproteinCommon: peripheral edema, nasal congestion, flushing, palpitations Serious: hepatotoxicity, teratogenicity (FDA Category X), decreases in H/H, fluid retention BosentanOralERA62.5 mg BID x4 wks, then 125 mg BID$24,168 (62.5mg BID) $24,349 (125mg BID)Baseline and monthly LFTs, pregnancy test; H/H; monitor for fluid retentionCI with glyburide, cyclosporine; substrate/inducer of CYP3A4, 2C9;Common: headache, nasopharyngitis, flushing, and lower limb edema Serious: hepatotoxicity, teratogenicity (FDA Category X), decreases in H/H, fluid retentionEpoprostenolIV infusionProstanoidInitiated at 2 ng/kg/min, titrated up; mean dose 9-11 ng/kg/min (varies widely); increases over time expected$44,322 (~9.2 ng/kg/min)aBP, cath site, pump maintenanceMay potentiate anticoagulants, antihypertensivesCommon: jaw pain, diarrhea, flushing, headaches, nausea, and vomiting Serious: drug delivery issues including infection, cellulitis, sepsis, thrombosis, inadvertent bolus or dose reduction; increased output cardiac failureIloprostInhalationProstanoid2.5 mcg, increased to 5 mcg if tolerated, given 6-9x/day while awake (e"2h apart)$70,343  $94,564 (6-9x /day)BP, syncopeMay potentiate anticoagulants, antihypertensivesCommon: flushing, headache, cough, influenza-like syndrome, nausea, jaw pain Serious: hypotension, syncope SildenafilOralPDE-5 Inhibitor20 mg TID$7,249 (20mg TID) $3,719b (25mg TID)BP, vision, hearing CI with nitrates; additive BP lowering with alpha-blockers; substrate of CYP3A4, 2C9Common: headache, flushing, dyspepsia, insomnia, and epistaxis, and visual disturbancesTreprostinilSC or IV infusionProstanoidInitiated at 1.25 ng/kg/min, titrated up; mean dose 9.3 ng/kg/min (varies widely); increases over time expected$35,150 (~9.3 ng/kg/min)cBP, cath site, pump maintenanceMay potentiate anticoagulants, antihypertensivesCommon: infusion site reaction, diarrhea, jaw pain, vasodilatation, and nausea Serious: infusion site reaction*Estimates include drug costs and special pharmacy costs when necessary. Per Diem specialty pharmacy costs were estimated to include supplies and clinical support for epoprostenol, iloprost, and treprostinil. Actual per diem costs may vary depending on services needed, specialty pharmacy used, etc. Additional costs to consider include laboratory monitoring (ambrisentan, bosentan).a70kg patient at a concentration of 10,000 ng/ml, 3.8 ml/hr; 24 hr infusion requires 2x 0.5 mg vials and 2x 50ml diluent bUsing tab of 50 mg strength (Viagra) c70kg patient at a concentration of 1mg/ml, 0.937ml/day (20ml vial lasts ~21 days) CI=contraindicated; H/H=hemoglobin/hematocrit; V. RECOMMENDATIONS: Recommendations are based on evidence from randomized, controlled clinical trials when available, the evidence-based ACCP Chest Guidelines, NOTEREF _Ref217447381 \h  \* MERGEFORMAT 6, NOTEREF _Ref217208719 \h  \* MERGEFORMAT 8 and supportive data from uncontrolled, observational trials and expert opinion when needed. PAH is a serious and often progressive disease. Much of the pharmacologic treatment available today may require close monitoring and patient/provider responsibility. Therapy may be associated with significant adverse effects and be costly. Patients should be under the care of clinicians experienced in the treatment of PAH (i.e., cardiology and/or pulmonology) and closely involved with management of patients with PAH. (Grade III A) Monitoring for response to therapy and disease progression is imperative and must occur on a regular basis. Response to therapy should be assessed by functional class status, exercise capacity (6MWD), and right ventricular function (with echocardiography or right heart catheterization). (Grade III A) General/Adjunctive Therapy Patients should be treated with diuretics in the presence of symptoms of right heart failure and supplemental oxygen in the presence of hypoxemia to maintain saturations >90%. (Grade III A) Digoxin may be considered in patients with right ventricular failure and/or atrial arrhythmias. (Grade III C). Anticoagulation with warfarin should be considered in patients with IPAH. (Grade II-3 B). The optimal therapeutic INR range has not been definitively determined but should fall between 1.5 and 3. Anticoagulation may be considered in patients with non-IPAH after weighing potential benefits and risks of therapy. (Grade III C) Calcium Channel Antagonist Therapy Patients with IPAH should undergo vasoreactivity testing. (Grade III A) Consider vasoreactivity testing in patients with associated PAH (i.e., with CTD). (Grade III C) A trial of oral calcium channel antagonist should be considered in patients with IPAH without right heart failure who have a positive acute vasoreactivity response as defined as a fall in mPAP of e"10 mmHg to a mPAP of d"40 mmHg, in the presence of an unchanged or increased cardiac output. (Grade II-3 B) In patients with associated PAH (i.e., with CTD) without right heart failure, a trial of an oral calcium channel antagonist may be considered in the setting of a positive acute vasodilator challenge. (Grade III C) Calcium channel antagonists should not be used in patients in the absence of a demonstrated positive acute vasodilator response. (Grade III A) Response to calcium channel antagonist therapy should be reassessed in three months. If a patient does not improve to WHO functional class I or II, additional or alternative PAH therapy is recommended. (Grade III B) First-line treatment with calcium channel antagonists will generally apply to IPAH patients with mild-to-moderate disease (i.e., WHO functional class I or II) due to the low proportion of responders and poor prognosis with advanced disease. PAH-Specific Therapy According to Functional Class and Risk In addition to WHO functional class, consideration of other clinical prognostic indicators may influence choice of therapy. According to McLaughlin and colleagues, those patients considered at higher risk of rapid disease progression and/or death should be considered for injectable prostanoid therapy, whereas those patients with lower risk would be candidates for oral therapy. NOTEREF _Ref196726568 \h  \* MERGEFORMAT 9 Indicators of high risk include low 6MWD, high RAP, low CI, advanced WHO functional class (IV), and rapidly progressive disease. In general, clinical trials evaluating PAH treatment have not included a sufficient number of elderly patients to determine if they have a different response. Caution should be exercised in initiating therapy in the geriatric population; careful monitoring and slow titration of doses should be considered. Functional Class II Treatment in this patient population has not been extensively studied, and the optimal strategy has not yet been determined. It is unknown whether the use of more aggressive agents (i.e., prostanoids) in patients with mildly symptomatic but progressive disease is superior to using less potent agents that may be more appealing to patients due to side effect profiles, ease of administration, monitoring requirements, and cost. ACCP Guidelines recommend sildenafil as Grade A and treprostinil as Grade B. Subsequent to the release of the ACCP Guidelines, ambrisentan received FDA approval, and the EARLY trial evaluating bosentan in mildly symptomatic PAH was published. Sildenafil treatment should be considered, and may be considered first-line due to its favorable side effect profile, ease of administration, and cost. (Grade I A) Ambrisentan therapy should be considered. (Grade I A) Bosentan therapy may be considered. (Grade I B) Although treprostinil (IV or SC) carries an FDA indication for patients in functional class II, due to the side effect profile, administration complexity, and cost, it is rarely recommended in these patients. (Grade I C) Functional Class III ACCP Guidelines recommend as first-line therapy for patients with functional class III symptoms sildenafil, bosentan, epoprostenol, iloprost, and treprostinil. All agents carry a Grade A recommendation with the exception of treprostinil, which carries a Grade B and C recommendation for SC and IV administration respectively. Since the guidelines have been published, ambrisentan has received FDA approval. Choice of agent should be based on the evidence, patient-specific factors and preference. Differences in side effect profiles, ease of administration, monitoring requirements, and cost should all be considered. In patients with early stage III disease, many clinicians will opt for oral therapies, whereas patients with more advanced disease or higher risk patients may be candidates for prostanoid therapy. In no order of preference, ambrisentan, bosentan, or sildenafil should be considered. (Grade I A) Factors that may influence treatment choice include: 1) general potential for drug interactions; 2) a more favorable side effect profile and less monitoring requirements with sildenafil; 2) a survival benefit suggested with bosentan; 3) tolerance of ambrisentan in patients with LFT elevations on bosentan. IV epoprostenol therapy may be considered. Although epoprostenol administration is complex and carries significant risks, improvements in exercise capacity, functional status, and survival have been demonstrated. (Grade I A) Inhaled iloprost may be considered. Iloprost has been shown in some studies to be effective in improving exercise and/or functional capacity, although the evidence is not consistent. As a whole, the evidence suggests that iloprost may stabilize disease progression. Inhaled iloprost is not associated with the added risks and complexity of injectable prostanoids. (Grade I A) Treprostinil SC or IV may be considered as an alternative to epoprostenol or iloprost. With the longer half life, treprostinil is less likely to cause rebound pulmonary hypertension than epoprostenol upon interruptions in therapy. Administered SC, treprostinil is associated with a high rate of injection site reactions but not the risks of an indwelling central venous catheter. In the largest randomized controlled trial, only a modest improvement in exercise capacity was demonstrated with treprostinil. Subgroup analysis and additional open-label or uncontrolled studies suggest efficacy, especially in patients with more advanced symptoms. (Grade I B) Functional Class IV Due to the quality of evidence and the net risk/benefit profile, the ACCP guidelines encourage the use of IV epoprostenol as the treatment of choice of patients with more advanced disease and in functional class IV. Bosentan, sildenafil, iloprost, and treprostinil are FDA approved for functional class IV, and may be considered in patients who are not able to manage or refuse IV epoprostenol. Epoprostenol is the treatment of choice in patients with advanced disease. (Grade I A) Bosentan, iloprost, sildenafil, and treprostinil are alternatives to epoprostenol when patients cannot or refuse to administer epoprostenol IV. (Grade I B for bosentan and iloprost, Grade C for sildenafil and treprostinil). Combination Therapy Evidence from randomized controlled trials is currently too limited to fully evaluate the efficacy and safety of combination therapy for PAH, although several trials are currently ongoing. In the 2007 ACCP Guidelines PAH treatment algorithm, combination therapy prior to atrioseptostomy and/or lung transplantation for those patients in WHO functional class III or IV who have not improved or are deteriorating on monotherapy is included as a possible consideration. At this time, combination therapy may be considered on a case-by-case basis and enrollment into a clinical trial is strongly encouraged. Non-WHO Group 1 PH Primary therapy for the treatment of WHO Groups 2, 3, 4, and 5 are generally directed at the underlying disease. No PAH specific agent is approved by the FDA for the treatment of non-WHO Group 1 PH, and current evidence from randomized controlled trials is insufficient to recommend their use. Further, detrimental effects and lack of benefit have been associated with the use of some agents in certain clinical settings (see above section on non-WHO Group 1 PH). If treatment with a PAH specific agent is considered after failure of primary therapy (or therapy is deemed not appropriate for patient), enrollment into a clinical trial is encouraged. Table 5. Quality of Evidence US Preventative Services Task Force IAt least one properly done RCTII-1Well designed controlled trial without randomizationII-2Well designed cohort or case-control analytic studyII-3Multiple time series, dramatic results of uncontrolled experimentIIIOpinion of respected authorities, case reports, expert committees Table 6. Grade of Recommendation US Preventative Services Task Force AA strong recommendation that the intervention is always indicated and acceptableBA recommendation that the intervention may be useful/effectiveCA recommendation that the intervention may be consideredDA recommendation that a procedure may be considered not useful/effective, or may be harmfulIInsufficient evidence to recommend for or against the clinician will use their clinical judgment US Preventative Services Task Force Ratings: Strength of Recommendations and Quality of Evidence. Guide to Clinical Preventative Services, Third Edition: Periodic Updates, 2000-2003. Agency for Healthcare Research and Quality, Rockville, MD. HYPERLINK "http://www.ahrq.gov/clinic/3rduspstf/ratings.htm"http://www.ahrq.gov/clinic/3rduspstf/ratings.htm. VI. METHODS Literature searches were conducted up to October 2008 via an electronic database (PubMed/Medline, Ovid) utilizing the following terms: pulmonary hypertension, pulmonary arterial hypertension, ambrisentan, bosentan, epoprostenol, iloprost, sildenafil, treprostinil, valvular heart disease, heart failure, chronic obstructive pulmonary disease, interstitial lung disease, pulmonary fibrosis, sleep apnea, sleep disordered breathing, chronic thromboembolic pulmonary hypertension, sarcoidosis. Searches were limited to English and human. Clinical trials included were limited to randomized controlled trials evaluating outcomes, and excluding phase II, pilot, and dose-ranging studies whenever possible or where otherwise noted. Studies evaluating populations not relevant to the VA population were also excluded. Cochrane Systematic Reviews was searched for relevant reviews and meta-analyses. Manufacturers were contacted for supportive information. REFERENCES Contact: Lisa Longo, Pharm.D., BCPS Appendix 1. Major trials with FDA approved prostanoids: epoprostenol, treprostinil, and iloprost. *significant vs. placebo; AEs=adverse effects; BDI=Borg dyspnea index; CI=cardiac index; CT=conventional therapy (anticoagulants, oral vasodilators, diuretics, digoxin, oxygen); CTD=connective tissue disease; CTEPH=chronic thromboembolic pulmonary hypertension; CO=cross-over; DB=double-blind; EPO=epoprostenol; FC=functional class; ILO=iloprost; MC=multicenter; mPAP=mean pulmonary artery pressure; mRAP=mean right atrial pressure; NR=number randomized; NS=nonsignificant; OL=open label; P=prospective; PC=placebo-controlled; PCWP=pulmonary capillary wedge pressure; PVR=pulmonary vascular resistance; QOL=quality of life; R=randomized; RAP=right atrial pressure; TRE=treprostinil TrialDesignPatient PopulationNRInterventionBaseline 6MWDDuration ResultsBarst NOTEREF _Ref196231474 \h \* MERGEFORMAT 25 1996 P, R, MC, OLIPAH NYHA FC III/IV81EPO + CT CT EPO=316m CT=272m (mean)12 wksEfficacy Primary Endpoint: 6MWD: +31m* (EPO+CT); -29 (CT) Improvements in QOL, NYHA FC, hemodynamics (mPAP, CI PVR) Safety Common AEs: jaw pain, diarrhea, flushing, headaches, nausea, vomiting Serious AEs: drug delivery complications  sepsis, thrombotic event Survival at 12 wks: 0* deaths in EPO vs. 8 deaths in CTBadesch NOTEREF _Ref196233156 \h \* MERGEFORMAT 27 2000P, R, MC, OLPAH due to scleroderma spectrum of disease, NYHA FC III/IV111EPO + CT CTEPO=272m CT=240m (median)12 wksEfficacy Primary Endpoint: 6MWD: +46m* (EPO+CT); -48 (CT) Improvements in hemodynamics (mPAP, PVR, RAP, CI, mixed venous O2 sat), NYHA FC with EPO+CT Safety Common AEs: jaw pain, anorexia, nausea, diarrhea AEs related to drug delivery system: sepsis, hemorrhage, cellulitis, pneumothorax Survival at 12 wks: 4 deaths in EPO vs. 5 deaths in CTSimonneau NOTEREF _Ref217269133 \h  \* MERGEFORMAT 31 2002P, R, DB, PC, MCIPAH, PAH associated with CTD or congenital systemic-to-pulmonary shunts, NYHA FC II/III/IV470TRE SQ + CT Placebo + CTTRE=326m Placebo=327m (mean)12 wksEfficacy Primary Endpoint: 6MWD: +10m* (TRE+CT); 0 change (CT) Improvements in dyspnea, physical QOL, and hemodynamics (RAP, mPAP, CI, PVR) Safety Common AEs: infusion site pain, headache, diarrhea, nausea, rash, jaw pain, dizziness Serious AEs: infusion site pain, GI bleed Death, transplant, or discontinuation due to worsening: 13 TRE; 16 placebo (NS)Olschewski (AIR) NOTEREF _Ref196529575 \h \* MERGEFORMAT 34 2002P, R, DB, PC, MCIPAH, PAH associated with scleroderma, anorexients, and CTEPH with NYHA FC III/IV203ILO 2.5 or 5mcg 6-9x/day placeboILO=332m Placebo=315m (mean)12 wksEfficacy Combined Primary Endpoint (e"10% !6MWD, improvement in NYHA FC, no deterioration): 16.8%* ILO vs. 4.9% placebo Improvements in FC, dyspnea and QOL Safety Common AEs: jaw pain, flushing, syncope, cough, headache, nausea Survival at 12 wks Appendix 2. Major Clinical Trials for FDA approved ERAs: bosentan and ambrisentan TrialDesignPatient PopulationNRInterventionBaseline 6MWDDuration ResultsChannick NOTEREF _Ref195628444 \h \* MERGEFORMAT 39 (Study 351) 2001R, DB, PC, MCPAH, WHO FC III32BOS 62.5mg BID x4 wks, then 125 mg BID PlaceboBOS=360m Placebo=355m (mean)12 wksEfficacy Primary Endpoint: 6MWD: +70m* (BOS); -6m (placebo) Improvements in hemodynamics (PVR, mPAP, PCWP, mRAP), WHO functional class, TTCW Safety AEs transient, similar incidence between groups LFT elevations: 2 BOS patients; transient and asymptomaticRubin NOTEREF _Ref195689291 \h  \* MERGEFORMAT 40 (BREATHE-1) 2002R, DB, PC, MCPAH, WHO FC III/IV (mainly WHO FC III)213BOS 125mg BID BOS 250mg BID Placebo (BOS groups started at 62.5mg BID x4wks)BOS 125=326m BOS 250=333m Placebo=344m16 wksEfficacy Primary Endpoint: 6MWD: +27m* (125mg); +46m* (250mg); -8m (placebo) Clinical worsening: 6%* BOS vs. 20% placebo at 28 wks Improvements in BDI Safety Common AEs: headache, syncope, flushing, abnormal hepatic function LFT elevations >8x ULN: 3%/7%/0 (125mg/250mg/placebo) Galiel NOTEREF _Ref208647902 \h  \* MERGEFORMAT 41 (EARLY) 2008R, DB, PC, MCWHO Group 1 PAH, FC II185BOS 125mg BID (initiated at 62.5 mg BID x4wks) PlaceboBOS 125=438m Placebo=431m24 wksEfficacy Primary Endpoints: % of baseline PVR: 83.2%* (44mmHg) BOS vs. 107.5% (56 mmHg) placebo; 6MWD: +11.2m BOS vs. -7.9m placebo (NS) Clinical worsening: 3%* BOS vs. 14% placebo at 24 wks Safety Common AEs: nasopharyngitis, abnormal LFT, edema LFT elevations: 13% BOS vs. 2% placebo (all reversible)Galie NOTEREF _Ref195885810 \h \* MERGEFORMAT 45, NOTEREF _Ref217459219 \h  \* MERGEFORMAT 46 (ARIES-1) 2008R, DB, PC, MCWHO Group 1 PAH, mainly WHO FC II/III201AMB 5mg/day AMB 10mg/day PlaceboAMB 5=340m AMB 10=341m Placebo=342m (mean)12 wksEfficacy Primary Endpoint: 6MWD: +22.8m* (5mg); +43.6m* (10mg); -7.8m (placebo) Clinical worsening: 4.5% AMB vs. 9% placebo at 12 wks (NS) Improvements in WHO FC, BDI Safety Common AEs: peripheral edema, headache, nasal congestion LFT elevations >3x ULN: 0/0/3% (5mg/10mg/placebo)Galie NOTEREF _Ref195885810 \h \* MERGEFORMAT 45, NOTEREF _Ref217459219 \h  \* MERGEFORMAT 46 (ARIES-2) 2008 R, DB, PC, MCWHO Group 1 PAH, mainly WHO FC II/III192AMB 2.5mg/day AMB 5mg/day PlaceboAMB 2.5=347m AMB 5=355m Placebo=343m (mean)12 wksEfficacy Primary Endpoint: 6MWD: +22.2m* (2.5mg); +49.4m* (5mg); -10.1m (placebo) Clinical worsening: 4.7%* AMB vs. 21.5% placebo at 12 wks Improvements in BDI, SF 36 Safety Common AEs: headache, palpitations, flushing, insomnia, dyspnea, abdominal pain, nasal congestion LFT elevations >3x ULN: 0/0/1.5% (2.5mg/5mg/placebo)*significant vs. placebo; AEs=adverse effects; AMB=ambrisentan; BDI=Borg dyspnea index; BOS=bosentan; DB=double-blind; FC=functional class; H/H=hemoglobin/hematocrit; MC=multicenter; mPAP=mean pulmonary artery pressure; mRAP=mean right atrial pressure; NR=number randomized; NS=nonsignificant; PC=placebo-controlled; PCWP=pulmonary capillary wedge pressure; PVR=pulmonary vascular resistance; R=randomized; TTCW=time to clinical worsening; ULN=upper limit of normal Appendix 3. Major Trials with FDA approved PDE-5 Inhibitors: sildenafil *significant vs. placebo; AEs=adverse effects; BDI=Borg dyspnea index; BOS=bosentan; CTD=connective tissue disease; CO=cross-over; DB=double-blind; FC=functional class; ITT=intention to treat; LV=left ventricular; MC=multicenter; mPAP=mean pulmonary artery pressure; mRAP=mean right atrial pressure; NR=number randomized; NR=not reported; NS=nonsignificant; PC=placebo-controlled; PCWP=pulmonary capillary wedge pressure; PVR=pulmonary vascular resistance; QOL=quality of life; R=randomized; RAP=right atrial pressure; RV=right ventricular; SIL=sildenafil; TTCW=time to clinical worsening; ULN=upper limit of normal TrialDesignPatient PopulationNRInterventionBaseline 6MWDDuration ResultsSastry NOTEREF _Ref195966739 \h \* MERGEFORMAT 49 2004R, DB, PC, COPPH, WHO FC II/III symptoms (mainly WHO FC II)22SIL 25mg TID (d"25 kg) SIL 50mg TID (26-50 kg) SIL 100mg TID (e"50 kg)n/a6 wksEfficacy Primary Endpoint: Treadmill exercise time: 686.8 sec* SIL vs. 475 sec placebo Improvements in hemodynamics Safety Well tolerated; mild AEs included backache, headache, insomniaGaliel NOTEREF _Ref195966794 \h \* MERGEFORMAT 51 (SUPER) 2005R, DB, PC, MCPAH IPAH, or associated with CTD, repaired shunt mainly WHO FC II/III 278SIL 20mg TID SIL 40mg TID SIL 80mg TIDSIL 20=347m SIL 40=345m SIL 80=339m Placebo=344m (mean)12 wksEfficacy Primary Endpoint: 6MWD placebo-corrected: +45m* (20mg); +46m* (40mg); +50m* (80mg) Significant improvements in WHO FC, hemodynamics (mPAP, PVR, CI) BDI, clinical worsening, RAP - NS Safety Common AEs: headache, flushing, dyspepsia, epistaxis, insomnia Serious AEs: LV dysfunction, postural hypotensionWilkins NOTEREF _Ref196016532 \h \* MERGEFORMAT 50 (SERAPH) 2005R, DBPAH IPAH or associated with CTD, WHO FC III26SIL 50 BID x4 wks, then 50mg TID BOS 62.5mg BID x4wks, then 125 mg BID SIL=290m BOS=305m (mean)16 wksEfficacy Primary Endpoint: RV mass: SIL reduced RV mass -8.8g* vs. baseline; no difference between SIL/BOS 6MWD: significant improvements from baseline in both groups; no difference between groups on ITT analysis  SIL +75m; BOS +59m No change in BDI or QOL scores on ITT analysis Safety Common AEs: NR SIL-one death; one admission for palpitations; BOS-2 hospital visits for fluid retention; 1 hospital visit for hemoptysis; no withdrawals due to AE Appendix 4. Summary of Combination Studies for PAH StudyPopulationNRIntervention/Outcome MeasuresResultsConclusions/CommentsRCTsSimonneau NOTEREF _Ref217288930 \h  \* MERGEFORMAT 55 (PACES) 2008 R, DB, PC, MC Duration: 16 wksa) PAH (IPAH or APAH) b) Mainly FC II, III c) Stabilized on epoprostenol d) Mean baseline 6MWD = 349m (EPO+SIL); 342m (EPO)267EPO + SIL vs. EPO Primary Endpoint: 6MWD Other Endpoints: hemodynamics, clinical worsening, BDI, QOL measures6MWD from baseline: +30m SIL+EPO; +1m EPO (p<0.05) Clinical worsening: 8 pts (EPO+SIL) vs. 24 pts (EPO) (p<0.05) Other endpoints: hemodynamics, QOL measures improved with SIL+EPO Safety: increased number of AEs in SIL+EPO group including headache, dyspepsia, pain in extremity, nausea; more patients in EPO group discontinued due to AE or reported a serious AE; deaths 7 EPO vs. 0 SIL+EPO (none deemed related to treatment) Statistically significant improvements in 6MWD, clinical worsening, hemodynamics, QOL measures with SIL+EPO vs. EPO No benefit of SIL+EPO in 6MWD in patients with baseline 6MWD <325m Imbalance of missing data between groups could have influenced results SIL+EPO combo associated with increased number of AEs, mostly mild-moderate in nature Dose of SIL 80mg TID usedMcLaughlin NOTEREF _Ref196821658 \h  \* MERGEFORMAT 52 (STEP) 2006 R, DB, PC, MC Duration: 12 wksa) PAH (IPAH or APAH) b) Mainly FC III c) Stable on BOS monotherapy d) Mean baseline 6MWD = 335m67BOS + ILO vs. BOS Endpoints: 6MWD, NYHA FC, hemodynamics, clinical worsening6MWD from baseline: +30m BOS + ILO; +4m BOS (NS) NYHA FC: improvement in 34% BOS + ILO vs. 6% BOS (p<0.05) Clinical worsening: 0 BOS + ILO vs. 15% BOS (p<0.05) Safety: AEs consistent with prostanoid/ERA profile; no unexpected concerns identifiedStatistically significant improvements in functional class and clinical worsening with BOS + ILO compared to BOS monotherapy; improvements in exercise capacity (6MWD) approached statistical significance BOS + ILO appeared well tolerated and safeHoeper NOTEREF _Ref208648122 \h  \* MERGEFORMAT 53 (COMBI) 2006 R, OL, MCa) IPAH b) FC III c) stable on BOS monotherapy d) mean baseline 6MWD = 297m (BOS); 309m (BOS+ILO)40BOS + ILO vs. BOS Primary Endpoint: 6MWD Secondary Endpoints: FC, oxygen uptake, QOL, clinical worsening6MWD from baseline: +1m (BOS) vs. -9m (BOS+ILO); NS Clinical worsening: 4 patients (BOS) vs. 3 pts (BOS+ILO); NS Safety: pneumonia, intractable coughing, diarrhea, headache flushingTrial terminated early due to lack of beneficial effect in interim analysis No beneficial effects of addition of ILO observed in primary or secondary endpoints 3 patients in ILO with significant deterioration affected ILO group resultsHumbart NOTEREF _Ref208288948 \h  \* MERGEFORMAT 54 (BREATHE-2) 2004 R, DB, PC, MC Duration: 16 wksa) PAH (IPAH or APAH) b) Severe: FC III or IV c) Scheduled to start EPO (baseline 6MWD not stated)33EPO + BOS vs. EPO Primary Endpoint: TPR Other Endpoints: FC, 6MWDHemodynamic parameters: improvements in both groups; non-significant trend favoring combination 6MWD, NYHA FC: no significant differences between groups Safety: increased number of reported serious AEs in EPO + BOS vs. EPO groupNo statistically significant differences in efficacy endpoints between groups, although significant within-group improvements from baseline were noted in both groups Higher number of serious AEs in EPO + BOS group (3 deaths due to disease progression and 1 withdrawal due to elevated LFTs) vs. BOS (one withdrawal due to elevated LFTs)Non-RCTsBenza NOTEREF _Ref208648159 \h  \* MERGEFORMAT 56 2008 Retrospective, OL Duration: mean follow-up of 485 days for BOS + TRE comboa) IPAH (n=16), APAH (n=20), WHO Group IV (n=2) b) Mainly FC III/IV c) Baseline TRE therapy; BOS added if patient remained in FCIII or IV, or if experiencing AE from TRE in FC II requiring a dose reduction d) Baseline (therapy nave) 6MWD of patients who required TRE + BOS (n=19) = 307m; Pre-BOS 6MWD = 333m38Baseline TRE; BOS added if patients remained in FC III or IV or were in FC II with AE to TRE requiring dose reduction Endpoints: 6MWD, hemodynamicsSummary for BOS + TRE combo (n=19): Reason for Addition of BOS: remain in FC III after 1 yr of TRE monotherapy (n=12); AE on TRE requiring dose reductions (n=7) 6MWD: +67m from baseline (p <0.05); +26m pre-BOS (NS) Hemodynamics: significant improvements in PAP, RAP; no difference in CO, PVR Safety: no deaths; decreases in hemoglobin, LFTs; other AEs not reported Study not designed to compare TRE to TRE + BOS Data collected per routine clinical practice Observational data suggests TRE + BOS well tolerated; maintenance of 6MWDMathai NOTEREF _Ref208648173 \h  \* MERGEFORMAT 57 2007 Retrospective, uncontrolled Duration: 3 mos analysis (longer observation period)a) IPAH (n=13) and PAH-SSD (n=12) b) Mainly WHO FC III/IV c) Clinical deterioration on BOS monotherapy d) Baseline 6MWD at time of SIL addition: 294m (IPAH) and 233m (PAH-SSD)25Baseline BOS; SIL added upon clinical deterioration (25-100 mg TID) Endpoints: 6MWD, FC6MWD: +46m in IPAH group (p <0.05); no change in PAH-SSD group at 3 mos after addition of SIL FC: 5/13 IPAH patients and 2/12 PAH-SSD patients improved by e"1 FC (SS not stated) Safety: 4 patients discontinued due to AEs: dyspepsia, intractable headaches, LFT abnormalities after SIL addition; 4 PAH-SSD patients died due to progressive heart failure; 1 IPAH died due to GI bleed (time of deaths not stated)Most patients initially improved on BOS monotherapy followed by clinical deterioration IPAH patients improved on combination therapy, while PAH-SSD patients did not After ~4 mos of combination therapy, 5/12 PAH-SSD and 1/13 IPAH patients required addition of prostanoid for deterioration. LFT abnormalities observed after SIL added to BOS may be related to the drug interaction between the agents that results in elevated BOS concentrations and reduced SIL concentrationsRuiz NOTEREF _Ref208648184 \h  \* MERGEFORMAT 58 2006 Uncontrolled, observational Duration: 2 yrsa) PAH (IPAH or PAH associated with toxic oil syndrome or HIV) b) Mainly FC III c) Deterioration on prostanoid therapy (ILO, EPO, or TRE) d) Mean baseline 6MWD: 350m20Baseline prostanoid; SIL (50mg TID) added when patients met 2 pre-defined criteria for clinical deterioration Endpoints: FC, 6MWD, signs and symptoms of right heart failure6MWD from baseline: +79m at 1 yr; +105m at 2 yrs (p <0.05) FC: 11/20 improved e"1 FC at 1 yr; maintained at 2 yrs (p <0.05) Signs and symptoms of right heart failure: echo measures improved; symptoms reported by 55% of patients at baseline; 16% at 1 yr; none at 2 yrs (SS not stated) Safety: headache (requiring SIL dose reduction); no serious AEs or withdrawals due to AE; 2 deaths (1-due to EPO interruption; 1-due to progressive respiratory failure)Follow-up: 20/20 followed for 1 yr; 15/20 followed for 2 yrs Patient population with severe and progressive PAH deteriorating on prostanoids Patients received a mean of 19 mos of prostanoid therapy prior to addition of SIL Combination therapy appeared well toleratedHoeper NOTEREF _Ref208648215 \h  \* MERGEFORMAT 59 2005 Uncontrolled, observational Duration: 3 yrsa) PAH (mainly IPAH) b) FC III or IV c) Mean baseline 6MWD = 308m d) treatment per algorithm123Treatment algorithm with pre-defined goals. If not met on 2 consecutive visits, patients moved on to next step: a) BOS (1st line) b) add SIL c) add inhaled ILO d) change to IV ILO 3) urgent transplantation Endpoint: survivalDeaths: 17/123 (13.8%) died during observational period Probability of survival: 98%, 83.1%, and 79.9% at 1, 2, and 3 yrs; significantly better than historical controls (89.8%, 75.2%, 63.1% at 1, 2, and 3 yrs) Treatment progression: Initiated IV ILO: 5/123 (2 died; 3 improved to BOS + SIL) Initiated BOS monotherapy: 118/123 Progressed to 2-drug regimen: 51/118 Progressed to 3-drug regimen: 19/118 Progressed to IV ILO: 5/118 Progressed to lung transplantation: 1/118 Safety: elevated LFTs with BOS, heartburn with SIL; no additive or unexpected AE observedGoal-oriented therapy with oral/combo medications associated with higher survival rates compared to historical controls Therapy with historical controls limited to inhaled or IV prostanoids (oral agents not yet available) Combination therapy appeared well tolerated Unknown whether combo therapy superior to monotherapy or whether alternative combo may be superiorGomberg-Maitland  NOTEREF _Ref208648232 \h  \* MERGEFORMAT 60 2005 Open-label, pilot study Duration: 12 wksa) PAH b) WHO FC II and III c) Baseline TRE d) Baseline treadmill time: 465 sec9Baseline TRE; SIL added (50 mg TID) Primary Endpoint:  in treadmill exercise time Other Endpoints: FC, dyspnea fatigue score in treadmill exercise time: +191 sec (p<0.05) FC: NS trend of improvement Dyspnea score: significant improvement (p <0.05) Safety: 1 patient withdrew due to AE of chest pain and dyspnea; other AEs reported include headache, flushing, jaw pain; 2 patients died (1-EPO infusion interruption; 1-progressive respiratory insufficiency) Type of PAH not reported 6MWD not reported Hoeper NOTEREF _Ref208648254 \h  \* MERGEFORMAT 61 2004 Uncontrolled, observational case series Duration: 9 mos median follow-upa) IPAH b) FC III or IV c) Failed treatment goals on BOS monotherapy (n=8) or BOS + ILO (n=1) d) Mean baseline 6MWD at time of SIL addition = 277m 9Baseline BOS (or BOS + ILO in 1 patient); SIL added when patients did not meet defined goals of exercise capacity. Endpoints: 6MWD, exercise testing6MWD: +115m (p <0.05) 3 mos after addition of SIL; effects maintained (median follow-up 9 mos) Exercise testing: peak oxygen uptake significantly improved at 3 mos with addition of SIL (data available for 6/9 patients) Safety: headache, flushing, heartburn reported; no deaths or serious AEsPatients followed were those with rapidly progressive disease who all had transient improvement with BOS followed by deterioration ~1 yr following BOS initiation One patient was on BOS + ILO at baseline with addition of SILGhofrani NOTEREF _Ref208648283 \h  \* MERGEFORMAT 62 2003 Uncontrolled, observational Duration: 9-12 mosa) IPAH or PAH associated with collagen vascular disease b) FC III or IV c) Failed monotherapy with ILO d) Mean baseline 6MWD at time of SIL addition = 256m14Baseline ILO; SIL added when patients met 2 of 3 defined criteria for clinical worsening Endpoints: 6MWD, hemodynamics, FC6MWD: +93m at 9 mos (p <0.05) 9 mos after addition of SIL (effects seen at 3 mos and maintained) Hemodynamics: PVR significantly improved at 3 mos after addition of SIL; CI, mPAP improved (SS not stated) FC: improvements (mainly from FC IV to FC III) noted at 3 mos and maintained at 9 mos (SS not stated) Safety: 2 deaths due to pneumonia; no serious AEsAll patients initially improved on ILO and deteriorated in a mean of 18 mos before SIL was added Stiebellehner NOTEREF _Ref208648303 \h  \* MERGEFORMAT 63 2003 Uncontrolled, observational case series Duration: 5 mosa) Pt #1: IPAH; baseline ILO + IV EPO, 6MWD = 305m b) Pt #2: IPAH; baseline IV EPO + ILO, 6MWD = 550m c) Pt #3: PAH after atrial septal defect repair; baseline IV EPO, 6MWD = 245m d) Clinical deterioration on prostanoid therapy3Baseline prostanoid; SIL added (75-200 mg/day) on clinical deterioration Endpoints: hemodynamics, 6MWDPt #1: 6MWD +105m; mPAP -14%; CI +48% Pt #2: 6MWD +35m; mPAP -41%; CI n/a Pt #3: 6MWD +70m; mPAP -22%; CI +59% Safety: nausea and headache reported by one patientNote: excluded studies that evaluated drugs or dosage forms not available in US, those with non-clinical endpoints (i.e., pharmacokinetics), and those evaluating single-doses of drug. AEs=adverse events; BOS=bosentan; CI=cardiac index; CO=cardiac output; EPO=epoprostenol; ERA=endothelin receptor antagonist; FC=functional class; GI=gastrointestinal; ILO=iloprost; LFTs=liver function tests; mPAP=mean pulmonary arterial pressure; NS=non-significant; PVR=pulmonary vascular resistance; RAP=right atrial pressure; RCT=randomized, controlled trial; SIL=sildenafil; SS=statistically significant; SSD=scleroderma spectrum of disease; TPR=total pulmonary resistance; TRE=treprostinil Appendix 5. Comparative efficacy endpoints from major trials of FDA approved prostanoids, ERAs, and PDE5-inhibitors DrugTrialDurationBaseline 6MWD% Change from baselineDefinition of Clinical Worsening% Reduction in Clinical Worsening EventsNNTEPOBarst12 wksEPO = 316m CT = 272mEPO = +9.8%* CT = -10.7%n/an/an/aEPOBadesch (scleroderma)12 wksEPO = 272m CT= 240mEPO = +16.9%* CT = -20%n/an/an/aTRESimonneau12 wksTRE = 326m Placebo = 327mTRE = +3%* Placebo = no changeDeath, transplantation or clinical deterioration (not defined)1.2% (NS)83ILOOlschewski12 wksILO = 332m Placebo = 315mInfo not given; Absolute difference in 6MWD of 36.4m between groups*Death, systolic BP <85 mm Hg; worsening right ventricular failure, rapidly progressing cardiogenic, hepatic, or renal failure, decrease of e"30% 6MWD, decline in measures of hemodynamic function6.9%15AMBARIES-112 wksAMB 5 = 340m AMB 10 = 341m Placebo = 342mAMB 5 = +6.8%* AMB 10 = +12.8%* Placebo = -2.3%Death, lung transplantation, hospitalization for PAH, atrial septostomy, study withdrawal because of addition of other PAH meds, early escape (patients who met 2 of the following criteria: 1) increase in WHO functional class; 2) >20% decrease in 6MWD; 3) worsening right ventricular failure; 4) progressing hepatic or renal failure; 5) systolic BP <85 mm Hg4.5% (NS)22AMBARIES-212 wksAMB 2.5 = 347m AMB 5 = 355m Placebo = 343mAMB 2.5 = +6.4%* AMB 5 = +13.9%* Placebo = -2.9%Same as ARIES-116.8%6BOSChannick12 wksBOS 125 = 360m Placebo = 355mBOS 125 = +19.4%* Placebo = -1.7%Right heart failure or aggravated PH27% 4BOSBREATHE-116 wksBOS 125 = 326m BOS 250 = 333m Placebo = 344mBOS 125 = +8.3%* BOS 250 = +16.2%* Placebo = -2.3%Combined endpoint of death, lung transplantation, hospitalization, or discontinuation of study med due to worsening of PAH, a need for EPO, atrial septostomy14%7BOSEARLY24 wksBOS 125 = 438m Placebo = 431mBOS 125 = +2.6% (NS) Placebo = -1.8%Appearance of worsening of RHF; decrease in e"10% from baseline in 2 6MWD done e"2 wks apart; or decrease of e"5% from baseline in 2 6MWD e"2 wks apart11%9SILSUPER12 wksSIL 20 = 347m SIL 40 = 345m SIL 80 = 339m Placebo = 344mSIL 20 = 13%* SIL 40 = 13.3%* SIL 80 = 14.7%* (Placebo corrected)Death, transplantation, hospitalization for PAH, initiation of additional PAH meds5.2% (NS)19SIL vs. BOSSERAPH16 wksSIL = 290m BOS = 305mSIL = +25.9% BOS = +19.3%n/an/an/a*significant vs. placebo (or conventional treatment; AMB=ambrisentan; BOS=bosentan; EPO=epoprostenol; ILO=iloprost; NNT=number needed to treat; NS=not significant; SIL=sildenafil; TRE=treprostinil     Pharmacologic Management of PAH December 2008Updated version may be found at vaww.pbm.va.gov PAGE 20 Pharmacologic Management of PAH . McGoon M, Gutterman, Steen V, et al. Screening, early detection, and diagnosis of pulmonary arterial hypertension. Chest. 2004;126:14S-34S . Rich S, Dantzker DR, Ayres SM, et al. Primary pulmonary hypertension. A national prospective study. Ann Intern Med. 1987. Aug;107(2):216-23. . DAlonzo GE, Barst RJ, Ayres SM, et al. Survival in patients with primary pulmonary hypertension. Ann Intern Med. 1991;115:343-49. . Gaine &/<?IJk  - . ;ujuju\uNuAujuhjhSCJOJQJh4hS5CJOJQJhSh x5CJOJQJh->5CJOJQJhS5CJOJQJhSCJOJQJhgdWh hgdW6CJ]aJh hgdWOJQJhgdWCJOJQJh hgdWCJOJQJh5NhgdWCJOJQJaJhgdWCJOJQJaJh'CJOJQJaJhgdWCJOJQJaJhhgdWCJOJQJaJ<J . r||ooooo $ & F@&a$gd-> $@&a$gdSgdgdWgdgdW#(($d&d-D@&M NPgdgdW"(($d&d-DM NPgdgdW#(($d&d-D@&M NPgdgdW =RWXqrQquv,1289JKV& mn:; 'puv ďhKhS5CJOJQJhIhSCJOJQJh|hSCJOJQJh12hSCJOJQJh=d5CJOJQJh!|hSCJOJQJhnhSCJOJQJhS5CJOJQJh->5CJOJQJ8n;v "$#$$$$$$$++++++++d1e1 $^a$gdgdW $a$gdgdW $@&a$gdgdW $ & F@&a$gd-> 1!5CJOJQJhJ^CJOJQJhgdWCJOJQJhSCJOJQJhphSCJOJQJh'hS5CJOJQJhhSCJOJQJhl'5CJOJQJhKhSCJOJQJhKhS5CJOJQJh<hSCJOJQJhrJ5CJOJQJh=d5CJOJQJhS5CJOJQJh"RhSCJOJQJ$4%8%l&n&P'R'(())P)*-*Z*f*j*****6+R+S+l+++++++-- --C-\-{f{[h15CJOJQJ(jh1qhgdW0J5CJOJQJUh1qhgdW5CJOJQJhJ^CJOJQJhgdWCJOJQJh*5CJOJQJhl'5CJOJQJhgdWhz5CJOJQJh)}5CJOJQJhFS(5CJOJQJ"jhgdW0J5CJOJQJUh->5CJOJQJhgdW5CJOJQJ#\-a-- .;.<.>.I.L.O.p..."/9/U////0!030@0J0M033Q3U3d3e3333333鳥ޏ|xm|]|hY9hY95CJH*OJQJjhgdWUhgdWjhgdWUh m5CJOJQJha5CJOJQJh15CJOJQJhgdWhz5CJOJQJh->5CJOJQJh}hgdW5CJOJQJ"jhgdW0J5CJOJQJUhFS(5CJOJQJhgdW5CJOJQJhvV5CJOJQJ$3444444455555553565=5e5}55555566H7I7K7L7ɵեՕzqzqzhqzqzqzqbz\zOhp'EhgdWB*CJph h mCJ hiCJhgdWhTCJhR<hgdWCJ hgdWCJ(jh mhgdW0J5CJOJQJUh mhgdW5CJH*OJQJhY9hY95CJH*OJQJ&j}h mhgdW5OJQJUh mhgdW5OJQJ jh mhgdW5OJQJUh=d5CJOJQJh mhgdW5CJOJQJe15L7#8M8809m99999K=L==== $IfgdgdW$0^`0a$gdgdW $a$gdgdW $ & F a$gdgdW $^a$gdgdW^gdgdW $^a$gd mL777889'9)9*909m9::D<E<F<G<H<S<W<f<s<}<<<< ===#=(=G=H=M=[=~~~s~s~eh hgdW5CJOJQJhyf5CJOJQJhg5CJOJQJ"jhgdW0J5CJOJQJUh/0J5CJOJQJ"jh/0J5CJOJQJUh/5CJOJQJhzhgdW5CJOJQJh5CJOJQJhFS(5CJOJQJh| 85CJOJQJhgdW5CJOJQJ"[=r============r?s?u??????!@3@?@AAATAAAAAFBGBHBݾ嫜xk[kk[kkhnhgdW5CJOJQJaJhgdW5CJOJQJaJhJr5CJOJQJaJh24hgdW5CJOJQJaJ h24hgdWh24hgdWCJOJQJaJ$h hgdW5B*CJOJQJphfhY9hY95CJH*OJQJjhgdWUhgdWjhgdWUh hgdW5CJOJQJhbMhgdWCJOJQJ"===>#>3>i^P11$ & F 8$If^`a$gdgdW$$Ifa$gdgdW $IfgdgdWkdw$$Ifl0v   t0S644 lapyt$3>E>_>>>>>>>?A?r? $ & F A$If^`a$gdgdW$ & F AAL$If^A`La$gdgdW$ & F 8$If^`a$gdgdW r?s?u????|nT:$ & F$If^`a$gdn$ & F$If^`a$gdgdW$$Ifa$gdgdW $IfgdgdWxkdR$$Ifl0v  t0S644 la???@@m@@@@@|nTTTTT$ & F$If^`a$gdgdW$$Ifa$gdgdW $IfgdgdWxkd$$Ifl0v  t0S644 la@AA AUAAAmbT::$ & F$If^`a$gdgdW$$Ifa$gdgdW $IfgdgdWxkd$$Ifl0v  t0S644 la$ & F$If^`a$gdnAAAAGB|n\$ $Ifa$gdgdW$$Ifa$gdgdW $IfgdgdWxkd$$Ifl0v  t0S644 laGBHBBBBBB}}ncc $IfgdgdW$@&`a$gdgdW $a$gdgdWxkd$$Ifl0v  t0S644 laHBIBBBBBBBBBBBBBCrC}C~CCDDDDlDmDpDrDDɻyrbrbUbrbUbrbrKhSCJOJQJhn5CJOJQJaJh24hgdW5CJOJQJaJ h24hgdWh24hgdWCJOJQJaJ!hJBhgdWB*CJOJQJphf(jh5KjhgdW0J5CJOJQJUhbMhgdWCJOJQJh5KjhgdW5CJOJQJhgdWCJOJQJhgdW56CJOJQJaJ"h^hgdW56CJOJQJaJhgdW5CJOJQJBBBBg\N$$Ifa$gdgdW $IfgdgdWkd:$$Ifl0v"  t0 644 lapyt$BCC~Cvh$$Ifa$gdgdW $IfgdgdW}kd$$Ifl0v" t0 644 laytn~CCCDvh$$Ifa$gdgdW $IfgdgdW}kd$$Ifl0v" t0 644 laytnDD DlDvh$$Ifa$gdgdW $IfgdgdW}kdb$$Ifl0v" t0 644 laytnlDmDnDpDDDDDkJlJmJwllwlwZZw$0^`0a$gdgdW $@&a$gdgdW $a$gdgdW}kd$$Ifl0v" t0 644 laytn DDDDDDDDDDDDDDDDDGE«Ҟґr`RG7GhX\hgdW5CJ OJQJaJ hgdW5CJOJQJhX\hgdW5CJOJQJ"jht0J5CJOJQJUht5CJH*OJQJ"jhG0J5CJOJQJUhG5CJH*OJQJhY95CJH*OJQJ-jhnhn5CJH*OJQJUhnhn5CJH*OJQJ'jhnhn5CJH*OJQJUhDD2hgdW>*CJOJQJhgdW>*CJOJQJGEHEEEfFFGvHwHHHHH IIUIIiJlJmJnJJJKKLLLL"Mӽ鯥錁vbRho0ho05CJH*OJQJ'jho0ho05CJH*OJQJUh<5CJOJQJho05CJOJQJhyf5CJOJQJhDD2hgdW>*CJOJQJhgdWCJOJQJhJhgdW5CJOJQJh %5CJOJQJh/5CJOJQJh/5CJOJQJhTD5CJOJQJhgdW5CJOJQJhxg_5CJOJQJmJJJBNCN}Q~QVSWS]W_WWWWWWWW$$Ifa$gdgdW$@&`a$gdgdW $^a$gdgdW$0^`0a$gdgdW $^a$gdo0 $a$gdgdW $@&a$gdgdW"M$MDMFMHMJMNMPM|MMM>N?N@NANNNOǺǯk[kG7h(h(5CJH*OJQJ'jh(h(5CJH*OJQJUhyfhyf5CJH*OJQJ(jhyfhyf0J5CJOJQJUhgdWhz5CJOJQJh(5CJOJQJhgdW5CJOJQJhyf5CJOJQJho05CJOJQJhY95CJH*OJQJ'jho0ho05CJH*OJQJUho05CJH*OJQJ-j ho0ho05CJH*OJQJUOOOOOOOPoQ|Q}Q~QQQRRRRRRRRSSSǺǯu^QFhrJ5CJOJQJho05CJH*OJQJ-j ho0ho05CJH*OJQJUho0ho05CJH*OJQJ'jho0ho05CJH*OJQJUho05CJOJQJhL5CJOJQJhgdW5CJOJQJhY95CJH*OJQJ'jh(h(5CJH*OJQJUh(5CJH*OJQJ-j h(h(5CJH*OJQJUSSST TT1T3TBTMTNTxTyTzT{T|T}T~T'W(WRWSWTWUWVW\W]W_WfWW۷ۯwm_h\:jhgdW5CJOJQJhgdWCJOJQJhR^hgdW5CJOJQJj hgdWUhY9hY95CJH*OJQJj hgdWUhgdWjhgdWUhrJ5CJOJQJh"N5CJOJQJhgdWhz5CJOJQJhgdW5CJOJQJh15CJOJQJhVhgdW5CJOJQJWWWWWWWWWWWWWWWXXYYKZLZZZZZZ[[[][i[j[y[z[\\\\W\X\ŵŵŵŵŵŵūwwb(jh{ >hgdW0J5CJOJQJUh"N5CJOJQJhLhgdW5CJH*OJQJhgdW5CJOJQJhDD2hgdW>*CJOJQJhgdWCJOJQJh24hgdW5CJOJQJaJ h24hgdWh24hgdWCJOJQJaJh\:jhgdW5CJH*OJQJ(jh\:jhgdW0J5CJOJQJU%WWWX4X@XlXX$$Ifa$gdgdWFf XXXXXY;----$$Ifa$gdgdWkd$$Iflֈ?q _E'7{4  t0$644 laY,YYYYY-kd$$Iflֈ?q _E'7{4 t0$644 la$$Ifa$gdgdWYYYZKZLZ-kd$$Iflֈ?q _E'7{4 t0$644 la$$Ifa$gdgdWLZUZ_ZhZsZ~ZZ$$Ifa$gdgdWZZZZZZ;----$$Ifa$gdgdWkd$$Iflֈ?q _E'7{4 t0$644 laZZZZZ[-kd$$Iflֈ?q _E'7{4 t0$644 la$$Ifa$gdgdW[[-[8[Z[[[-kdo$$Iflֈ?q _E'7{4 t0$644 la$$Ifa$gdgdW[[\[][i[u]v]]'`(`eeii-n.ntu u:y;y$0@&^`0a$gdgdW $@&a$gdgdW$0^`0a$gdgdW$@&`a$gdgdW $a$gdgdWX\Y\Z\\\\\-].]t]u]w]]^^x^y^^^оЦИuaQ:-jIh Dh D5CJH*OJQJUh Dh D5CJH*OJQJ'jh Dh D5CJH*OJQJUho05CJOJQJh\:jhgdW6CJOJQJhgdWCJOJQJhLhgdW5CJOJQJh"N5CJOJQJhgdW5CJH*OJQJ"jhgdW0J5CJOJQJUhgdW5CJOJQJ(jh{ >hgdW0J5CJOJQJUh{ >hgdW5CJH*OJQJ^^^^^ b bbbc c!cvcccceeYeZeeef g g#g)g*gAgCgDgEgFgagxiiiiiYk]kǵǪǪǑǃǵǪǵǪǑǑǑǪshh}_5CJOJQJhShgdW0J5CJOJQJhgdWhz5CJOJQJhmQ5CJOJQJhKhgdW5CJOJQJhN5CJOJQJ"jhgdW0J5CJOJQJUhgdW5CJOJQJhY95CJH*OJQJ'jh Dh D5CJH*OJQJUh D5CJH*OJQJ(]kkkllmmmm^pnpqprppp=qrr1r2rBrCrErFrHrtttum`ShY95CJH*OJQJh|` 5CJH*OJQJ-jh|` h|` 5CJH*OJQJUh|` h|` 5CJH*OJQJ'jh|` h|` 5CJH*OJQJUh|` 5CJOJQJhN5CJOJQJhmQ5CJOJQJhgdWhWd5CJOJQJ"jhgdW0J5CJOJQJUh}_5CJOJQJhgdW5CJOJQJuuu u!u-uAuuuvvv v"v#vCvDvwwx$xxί{n`NChj5CJOJQJ"jhgdW0J5CJOJQJUhWdhgdW5CJOJQJhY95CJH*OJQJh*<5CJH*OJQJ-jCh*<h*<5CJH*OJQJUh*<h*<5CJH*OJQJ'jh*<h*<5CJH*OJQJUh=d5CJOJQJhgdW5CJOJQJh\:jhgdW6CJOJQJhgdWCJOJQJh)hgdW5CJOJQJxx:y;y)z3zzzzzzzzzzzX{Y{{{S|V|f|||||||| }m~㹩xmbTmTbTmThKhgdW5CJOJQJh'o5CJOJQJhw5CJOJQJhY95CJH*OJQJh*<5CJH*OJQJ-jh*<h*<5CJH*OJQJUh*<h*<5CJH*OJQJ'jh*<h*<5CJH*OJQJUh*<5CJOJQJh95CJOJQJhgdW5CJOJQJ"jh*<0J5CJOJQJUm~y~}KLM01ɃΈTUo擉{p\Lh-[h-[5CJH*OJQJ'jh-[h-[5CJH*OJQJUhk]{5CJOJQJh\:jhgdW6CJOJQJhgdWCJOJQJhfhhgdW5CJOJQJhFS(5CJOJQJ"jh-[0J5CJOJQJUh15CJOJQJ"jhgdW0J5CJOJQJUh95CJOJQJhgdW5CJOJQJhgdWhWd5CJOJQJwxBCNOprdeH 0^`0gdgdW $^a$gdgdW$0^`0a$gdgdW $a$gdgdW $@&a$gdgdW$0@&^`0a$gdgdWopCrwxB`b/3OǺǯ|ncXMXh5CJOJQJh<5CJOJQJhKO5CJOJQJhKhgdW5CJOJQJhLT75CJOJQJ"jhgdW0J5CJOJQJUh15CJOJQJh-[5CJOJQJhgdW5CJOJQJhY95CJH*OJQJ'jh-[h-[5CJH*OJQJUh-[5CJH*OJQJ-j=h-[h-[5CJH*OJQJUƚԚٚMNPopqruÛě>?ĝܝݝ6<=ŻӔuuuuiuuu`uhgdWhWdCJjhgdW0JCJUhR<hgdWCJH* h]vCJhR<hgdWCJ hgdWCJhOnhgdW5CJOJQJhgdW>*CJOJQJhDD2hgdW>*CJOJQJhgdWCJOJQJhVhgdW5CJOJQJhgdW5CJOJQJhwk5CJOJQJh| 85CJOJQJhu 5CJOJQJ%=bcƟȟɟJSTЩѩөԩɫʫ(XZ[_Ь$+O~~x~~x~~~~ hCJ hCJ hY9CJH* hdlCJH*"jhdlhdlCJH*UhdlhdlCJH*jhdlhdlCJH*UhKhgdWCJ hgdW5CJhXMdhgdW56CJ hXMdCJjhgdW0JCJU huCCJhR<hgdWCJ hgdWCJ+HSȪiؼVW}VWmn$0^`0a$gdgdW $^a$gdgdW ^gdXMd^gdgdW 0^`0gdgdW0^`0gdXMdOPQRSmnoqr=lpİư+6ַ145MO̽ӶӰzttntntn hpcCJ ho0CJjhKhgdW0JCJU hFVCJ h]vCJhKhgdWCJ hsCJ hCJ hCJ hgdWCJ hY9CJH*j7hCJH*U hCJH*jhCJH*Uhj hgdWCJH*jhgdW0JCJUh.EhgdW0JCJ+ODEU]^klwM/0ʿwj\\hpzRhgdW5CJOJQJhY95CJH*OJQJhJt5CJH*OJQJ-jhJthJt5CJH*OJQJUhJthJt5CJH*OJQJ'jhJthJt5CJH*OJQJUhgdW5CJOJQJh*CJOJQJhDD2hgdW>*CJOJQJhgdWCJOJQJh|As5CJOJQJhv5CJOJQJhgdW5CJOJQJde,-z{$0^`0a$gdgdW $^a$gdgdW $@&a$gdgdW $a$gdgdW,45OP`acd tx{xk`N```N"jhgdW0J5CJOJQJUh"\5CJOJQJhY95CJH*OJQJh"\5CJH*OJQJ-j+h"\h"\5CJH*OJQJUh"\h"\5CJH*OJQJ'jh"\h"\5CJH*OJQJUhKhgdW5CJOJQJhgdW5CJOJQJh\:jhgdW6CJOJQJhgdWCJOJQJhB@hgdW5CJOJQJ16jHIJC\FКsfYOhgdWCJOJQJhY95CJH*OJQJh 5CJH*OJQJ-jh h 5CJH*OJQJUh h 5CJH*OJQJ'jh h 5CJH*OJQJU"jhgdW0J5CJOJQJUhg6hgdW0J5CJOJQJhKhgdW5CJOJQJhj"5CJOJQJhgdW5CJOJQJh 5CJOJQJ-txdvMOyOPefgbcden|~ͭͭ㢔آtآiiiihj"5CJOJQJ"jhgdW0J5CJOJQJUhKh5CJOJQJhh5CJOJQJh5CJOJQJh~$5CJOJQJ(jhKhgdW0J5CJOJQJUh 5CJOJQJhgdW5CJOJQJhKhgdW5CJOJQJhKhgdW>*CJOJQJ&NOijz{}~,3kqrƶƶƶƶƶƶ}peeeXhKhgdWCJOJQJhgdW5CJOJQJhY95CJH*OJQJ-j%hKhgdW5CJH*OJQJU'jhKhgdW5CJH*OJQJUhKhgdW5CJOJQJhKhgdW5CJH*OJQJ(jhKhgdW0J5CJOJQJUhalhgdW5CJH*OJQJ(jhalhgdW0J5CJOJQJU dfZ [  Tblp$$Ifa$gdgdWgdgdW $^a$gdgdW$0^`0a$gdgdWg78<l`bh k     I J   [ l    6x㾍Ӏuuc"jhVc0J5CJOJQJUh%-5CJOJQJhB56CJOJQJhKhgdW5CJH*OJQJh=d5CJOJQJhgdW5CJOJQJhB5CJOJQJ(jhKhgdW0J5CJOJQJUhKhgdW56CJOJQJhKhgdW5CJOJQJhKhgdW>*CJOJQJ&34DEGH«ґ}mVm}}mE!jh%-5CJH*OJQJU-jhKhgdW5CJH*OJQJUhKhgdW5CJH*OJQJ'jhKhgdW5CJH*OJQJUhY95CJH*OJQJh%-5CJH*OJQJ-jh%-h%-5CJH*OJQJUh%-h%-5CJH*OJQJ'jh%-h%-5CJH*OJQJUhKhgdW5CJOJQJh%-5CJOJQJT{ LMvjvcSFSvSFSvScSFhgdW5CJOJQJaJh24hgdW5CJOJQJaJ h24hgdWhgdWCJOJQJaJh24hgdWCJOJQJaJhgdWhgdW5CJOJQJh"[hgdW5CJOJQJhKhgdW56CJOJQJhKhgdW5CJOJQJh%-5CJH*OJQJhY95CJH*OJQJ!jh%-5CJH*OJQJU'jh%-5CJH*OJQJUp{ &rLFf$$Ifa$gdgdWLMkdz $$IflִLIp] 4%=Q t0    44 laMV[_;~$$Ifa$gdgdW ;A~nv *Vxz &0178D ,-\f}~ƿƿ՝ՎhgdW5CJH*OJQJaJhKhgdW5CJOJQJaJ"h24hgdW5CJH*OJQJaJ h24hgdWh24hgdWCJOJQJaJhgdW5CJOJQJaJhr5CJOJQJaJh24hgdW5CJOJQJaJ6kd!$$IflִLIp] 4%=Q t0    44 lanv $$Ifa$gdgdW kd"$$IflִLIp] 4%=Q t0    44 laVz $$Ifa$gdgdW kd#$$IflִLIp] 4%=Q t0    44 la1DY$$Ifa$gdgdW kd$$$IflִLIp] 4%=Q t0    44 la'2 \}$$Ifa$gdgdW }~kd%$$IflִLIp] 4%=Q t0    44 la~    x z {     '!(!)!*!+!>!ʷxaXOC4h+hgdW5B*CJphhgdW5B*CJphhKhgdWCJh'hgdWCJ,hm"hgdW5B*CJOJQJ^JaJph hKhgdWCJOJQJ^JaJhgdWCJH*OJQJ^JaJ hJNhgdWCJOJQJ^JaJhgdWCJOJQJ^JaJ%hJNhgdWB*CJOJQJaJph(hJNhgdWB*CJH*OJQJaJphhf,B*CJOJQJaJphhgdWB*CJOJQJaJph~z   (!*!>!?!""A$q%%H'I'((( h@&^hgdgdW & F 8@&^gdgdW @&`gdgdW $@&^a$gdgdW0@&^`0gdgdW@&gdgdW $a$gdgdWgdgdW>!!!!!!!!!!!""'"(")"*""@$A$$%% %p%ӽⱞymbUbJbJbh5CJOJQJh,hgdWCJOJQJhgdW5CJOJQJhB*CJH*ph+ji'hhB*CJH*UphhhB*CJH*ph%jhhB*CJH*UphhB*CJH*ph+j&hhB*CJH*UphhhB*CJH*ph%jhhB*CJH*UphhgdWB*CJphp%q%x%%%$'D'~''(((((J**++.....//z0{00ѬѣѬۉ~jZh[h[5CJH*OJQJ'jh[h[5CJH*OJQJUh5r5CJOJQJh1hgdW5CJOJQJ hgdWCJ h[CJh'hgdWCJh[B*CJph h+hgdW5B*CJ aJ phhB*CJphhgdWB*CJphhgdW5B*CJphh=<hgdW5B*CJphhgdWCJOJQJ((`)g,,-..b2d2x2555(677R:;<I>@ & F gdgdW 0^`0gdgdW $^a$gdgdW^gdgdW & F ^gdgdW ^gdgdW0000000+1-1b2c2d2x2~33557777Ƿǧ~qe~[~N~e?~hfhgdW6B*CJphhUhgdWB*CJphh[B*CJphhgdW6B*CJphhfhgdWB*CJphhgdWB*CJphhgdW5CJOJQJ hgdWCJh1hgdW5CJOJQJh[hgdW5CJH*OJQJh[h[5CJH*OJQJ'jh[h[5CJH*OJQJUh[5CJH*OJQJ-j'h[h[5CJH*OJQJU77;;@@@BBwCxCCCDD,F-F@FHHHHI3I4InIoIIIII7J8J9JJJJJ봫ununununun_unh0>hgdW5B*CJph h24hgdWh24hgdWB*CJphhgdW5B*CJphhAKB*CJphhKhgdWB*CJph hS;CJhKhgdWCJhKhgdW5B*CJphh xhgdWB*CJphhhgdW6B*CJphhgdW6B*CJphhgdWB*CJphhS;B*CJph%@@BBCC-F@FHII3I $IfgdgdW@&gdgdW & F gdgdW 0^`0gdgdW^gdgdW 3I4I9InI|| $IfgdgdWxkdc($$Ifl0&! t0644 lanIoItII|| $IfgdgdWxkd($$Ifl0&! t0644 laIIII|| $IfgdgdWxkd})$$Ifl0&! t0644 laIII7J|| $IfgdgdWxkd *$$Ifl0&! t0644 la7J8J9JJJJxmm $IfgdgdW@&gdgdWgdgdWxkd*$$Ifl0&! t0644 laJJJK|| $IfgdgdWxkd$+$$Ifl0&! t0644 laJKKQKRKKKLLLyLL M MGMHMxMyMzM{M|MMMMMMOEQGQHQRQSQTQxQij̮{nbUhxhxB*CJph *hgdWB*CJph *h@ohgdWB*phh@ohgdW5hZoCJaJh}hZohn hZohZoh}hgdW5h}hZo5 h}5h;>hgdW0JCJaJhgdWjhgdWUhgdWCJaJh;>hgdWCJaJhgdW5B*CJph h24hgdWh24hgdWB*CJph!KKKQK|| $IfgdgdWxkd+$$Ifl0&! t0644 laQKRKTKK|| $IfgdgdWxkd>,$$Ifl0&! t0644 laKKKL|| $IfgdgdWxkd,$$Ifl0&! t0644 laLLL{M|MMGQHQSQTQyQ{{{n{{X$d&dNPgdx 0^`0gdngdgdWgdgdWxkdX-$$Ifl0&! t0644 la xQyQQQQNRRRSSTTTTTTTTTUUUŹع{t_TtFTjw2hKhgdWUjhKhgdWU(hKhgdW5B*CJOJQJaJph hKhgdWhKhgdWCJH*OJQJaJhKhgdWCJOJQJaJh,dhgdWCJOJQJaJhKhgdWCJH*OJQJaJhgdWCJOJQJaJ%hlJghgdWB*CJOJQJaJphhgdWB*CJOJQJaJphhgdWB*CJphhxhgdWB*CJphyQQTTTTTTTTTTTUUU,UBUEUNURUSU$$&#$/Ifa$gdgdWFf/$&#$/IfgdgdW@&gdgdW^gdgdWgdgdWUUUUUUUKUMUrUVVV:X;XBXCXmXnXoXqXrXsXwXƯ}nnggYG"hB=5B*CJOJQJaJphj6hKhgdWU hKhgdWhKhgdWCJOJQJaJh~5CJOJQJaJhKhgdW5CJOJQJaJ(hKhgdW5B*CJOJQJaJph,hB=hB=5B*CJOJQJ^JaJph&hB=5B*CJOJQJ^JaJphhgdWjhKhgdWU+hY9hY95B*CJH*OJQJaJphSU\UdUkUrU{UjVVVxWX:X;XsXxXXXX$&#$/Ifgd~Ff4'$ & F 8L$&#$/If^`La$gdgdW$$&#$/Ifa$gdgdW$&#$/IfgdgdWwXxXXXXXXXXX[[D\E\F\G\P\Q\k\l\۲۲ۥ۞nX::j9h~h~5B*CJH*OJQJUaJph+h~h~5B*CJH*OJQJaJph4jh~h~5B*CJH*OJQJUaJph(hKhgdW5B*CJOJQJaJph hKhgdWhgdW5CJOJQJaJhKhgdWCJOJQJaJhB=5CJOJQJaJh~5CJOJQJaJhKhgdW5CJOJQJaJ(hB=hB=5B*CJOJQJaJphXXXXXXXXNZ[[v[\F\G\\\\$&#$/Ifgd~Ff7'$ & F 8L$&#$/If^`La$gdgdW$&#$/IfgdgdW$$&#$/Ifa$gdgdWl\|\}\\\\\\\\4]^:^@^n^ ____ ` `\`]`^`n`ѻѨqdqUHqHqUqUqUqUA hKhgdWhw5CJOJQJaJhKhgdWCJOJQJaJhB=5CJOJQJaJhKhgdW5CJOJQJaJ(hB=hB=5B*CJOJQJaJph"hB=5B*CJOJQJaJph%hgdW5B*CJH*OJQJaJph+h~h~5B*CJH*OJQJaJph4jh~h~5B*CJH*OJQJUaJph%h~5B*CJH*OJQJaJph\\\]]]&]-]4]=]p^ ___ `]`^````Ff?;'$ & F 8L$&#$/If^`La$gdgdW$$&#$/Ifa$gdgdW$&#$/IfgdgdWn`o`````````Pab>b@bBbbc(c8cc|m|`Q?|2m|hgdW5CJOJQJaJ#hKhgdW5CJOJQJ^JaJh>5CJOJQJ^JaJh>5CJOJQJaJhKhgdWCJOJQJaJhKhgdW5CJOJQJaJ(hKhgdW5B*CJOJQJaJph"hB=5B*CJOJQJaJph+hKhgdW5B*CJH*OJQJaJph+hY9hY95B*CJH*OJQJaJphj*=hKhgdWU hKhgdWjhKhgdWU`a a$a,a5aBaIaPaZab*c8ccccccGd@&gdgdWFf>'$ & F 8L$&#$/If^`La$gdgdW$$&#$/Ifa$gdgdW$&#$/IfgdgdWccd.d6dFdGdhdjddddddddddddddddrcVVIVhgdW5CJOJQJaJh85CJOJQJaJhY95CJH*OJQJaJ1jMEhKhgdW5CJH*OJQJUaJ"hKhgdW5CJH*OJQJaJ+jhKhgdW5CJH*OJQJUaJhKhgdW5CJOJQJaJhKhgdWCJH*OJQJaJhKhgdWCJOJQJaJh>B*CJphhKhgdWB*CJph hKhgdWGdMdTdgdjdwddddddddd e e4eh{^ 5CJH*OJQJaJ.jPh>h{^ CJH*OJQJUaJh>h{^ CJH*OJQJaJ(jh>h{^ CJH*OJQJUaJh{^ 5CJOJQJaJ hKhgdWhKhgdW5CJOJQJaJ%hKhgdWB*CJOJQJaJph(hKhgdW5B*CJOJQJaJph"hgdW5B*CJOJQJaJph(hKhgdW5B*CJOJQJaJph%hKhgdWB*CJOJQJaJphpppJpLplpnprptpvpppqqrrrrrr#sڲ||tgQ?"h>h{^ 5CJH*OJQJaJ+jh>h{^ 5CJH*OJQJUaJh{^ 5CJOJQJaJhKh{^ 5hKh{^ CJOJQJaJ(h>h{^ 5B*CJOJQJaJph"h{^ 5B*CJOJQJaJphhKh{^ 5CJOJQJaJ.jPh>h{^ CJH*OJQJUaJ(jh>h{^ CJH*OJQJUaJh>h{^ CJH*OJQJaJppppqq6qFq\qtqqqqq(rcrrrrr'$ & F 8L$&#$/If^`La$gd{^ $&#$/Ifgd{^ $$&#$/Ifa$gd{^ rrZsdsisjsxsssssssssssstt'$ & F 8L$&#$/If^`La$gd{^ $$&#$/Ifa$gd{^ $&#$/Ifgd{^ Ff/R#s$s%s's(s)s*sDsEsUsVsXsYsZsdsisjsst>uLuv v>v?v@vооооНk[L[L[L[LE hKh{^ hKh{^ CJOJQJaJhKh{^ 5CJOJQJaJ(hKh{^ 5B*CJOJQJaJphfh>h{^ 5CJOJQJaJh{^ 5CJOJQJaJh{^ CJaJ1jTh>h{^ 5CJH*OJQJUaJ"h>h{^ 5CJH*OJQJaJ+jh>h{^ 5CJH*OJQJUaJ1jTh>h{^ 5CJH*OJQJUaJtu>uNu v?v@vxxxxx`xzzzzzzz@&gdgdWgdgdW^gdgdWFfEV$$&#$/Ifa$gd{^ '$ & F 8L$&#$/If^`La$gd{^ @vWvZvxvv>w?wxGxHx`xzxxxx6yyyyy)z>zgz}zzzzzzzz-{.{4{5{_{Ⱦȫ񡗊ncjhKhgdWU(hKhgdW5B*CJOJQJaJph hKhgdWhKhT,ZB*CJphhT,ZB*CJphhgdWB*CJph%hKhgdWB*CJOJQJaJphh.B*CJphhKhgdWB*CJphhKhgdWCJH*OJQJaJhgdWCJOJQJaJhKhgdWCJOJQJaJ#zzzzzzzzz{{{-{.{e{j{x{{{{|@|n|v|$$&#$/Ifa$gdgdWFfZ$&#$/IfgdgdWgdgdW_{`{a{c{d{e{i{j{||j}z}}}~~~~.~/~0~2~3~4~5~:~;~ȸ}hVh}HhVhVjK`hKhgdWU"h{^ 5B*CJOJQJaJph(hKhgdW5B*CJOJQJaJph hKhgdWhKhgdWCJOJQJaJhKhgdW5CJOJQJaJ(h.h.5B*CJOJQJaJphh.h.5CJOJQJaJhgdWCJaJ+hY9hY95B*CJH*OJQJaJphjhKhgdWUj\hKhgdWUv|||2}l}z}}}4~<~A~O~~~~~~~~~Ffc^'$ & F 8L$&#$/If^`La$gdgdW$$&#$/Ifa$gdgdW$&#$/IfgdgdW;~<~@~A~~~2Tƀv67>?ijkǷ|u`UuGUjchKhgdWUjhKhgdWU(hKhgdW5B*CJOJQJaJph hKhgdWhgdW5CJOJQJaJ"hKhgdW5>*CJOJQJaJhKhgdWCJOJQJaJh=l5CJOJQJaJhKhgdW5CJOJQJaJ(hKh{^ 5B*CJOJQJaJph"h{^ 5B*CJOJQJaJph"hgdW5B*CJOJQJaJph~~~~~ 2v67ox}Ffa'$ & F 8L$&#$/If^`La$gdgdW$$&#$/Ifa$gdgdW$&#$/IfgdgdWkmnopvwx|}X*+ɷɷqdqqq]NAhKhgdWB*CJphhKhgdW5B*CJph hKhgdWh=l5CJOJQJaJhKhgdWCJOJQJaJhKhgdW5CJOJQJaJ(hKh=l5B*CJOJQJaJph"hgdW5B*CJOJQJaJph"h=l5B*CJOJQJaJph(hKhgdW5B*CJOJQJaJphjhKhgdWU+hY9hY95B*CJH*OJQJaJphՂւ&Ȅʅ+gdgdWFfye'$ & F 8L$&#$/If^`La$gdgdW$&#$/IfgdgdW$$&#$/Ifa$gdgdW&.CDIJKLMNO͇Ffql$If^gdgdW $IfgdgdWFfh$$Ifa$gdgdWILMNOXYstƈîyj^Oj?j?h=lhgdW>*CJOJQJaJh=lh=lCJOJQJaJhgdWCJOJQJaJh=lhgdWCJOJQJaJh=lCJH*OJQJaJ.jnh=lh=lCJH*OJQJUaJh=lh=lCJH*OJQJaJ(jh=lh=lCJH*OJQJUaJh=lCJOJQJaJhKhgdWCJOJQJaJhKhgdW5CJOJQJaJ"hKhgdW5CJH*OJQJaJfnĈƈP_WˋUŌ & FL$If^`LgdgdW$$Ifa$gdgdW $IfgdgdWP|.\^_gUVŌƌЌь Ź|o``ThgdWCJOJQJaJhKhgdWCJOJQJaJhY9CJH*OJQJaJ.j6phKhgdWCJH*OJQJUaJhKhgdWCJH*OJQJaJ(jhKhgdWCJH*OJQJUaJh;#CJOJQJaJhKhgdW5CJOJQJaJh=lCJOJQJaJh=lhgdW5CJOJQJaJh=lhgdWCJOJQJaJŌƌkd o$$IflֈF f'L5p t0544 lap<yt=lƌ .DUrf̎D/% & FL$If^`LgdgdW$$Ifa$gdgdW $IfgdgdW  f̎܎Dj$&,-GHXY[\]dejk8’,~⭝xl`lhgdWCJOJQJaJh;#CJOJQJaJhY9CJH*OJQJaJ.jqhKhgdWCJH*OJQJUaJhKhgdWCJH*OJQJaJ(jhKhgdWCJH*OJQJUaJhKhgdW5CJOJQJaJhKhgdW>*CJOJQJaJhKhgdWCJOJQJaJhKh;#CJOJQJaJ%%&]ejk://// $IfgdgdWkdp$$IflֈF f'L5p t0544 laku}בڑ~Q & FL$If^`LgdgdW$$Ifa$gdgdW $IfgdgdW~%&()*56;<ו.Dv$|Zejkpq˻˖~o__˻hKhgdW>*CJOJQJaJhKh;#CJOJQJaJhgdWCJOJQJaJh;#CJOJQJaJhY9CJH*OJQJaJ.jrhKhgdWCJH*OJQJUaJhKhgdWCJH*OJQJaJ(jhKhgdWCJH*OJQJUaJhKhgdWCJOJQJaJhKhgdW5CJOJQJaJ#*6;<://// $IfgdgdWkdr$$IflֈF f'L5p t0544 la<J\rĕ֕וD| [ & FL$If^`LgdgdW$$Ifa$gdgdW $IfgdgdW[\ef:// $IfgdgdWkd{s$$IflֈF f'L5p t0544 lafghijk$8š),›d34Ffu $IfgdgdW$$Ifa$gdgdWdk۝ܝöçp`````Hö.j\yhKhgdWCJH*OJQJUaJhKhgdW5CJOJQJaJhKhgdW>*CJOJQJaJhKh;#CJOJQJaJhgdWCJOJQJaJh;#CJOJQJaJhKhgdWCJOJQJaJhY9CJH*OJQJaJ(jhKhgdWCJH*OJQJUaJhKhgdWCJH*OJQJaJ.jwhKhgdWCJH*OJQJUaJ4c۝ & FL$If^`LgdgdW۝ܝ5://// $IfgdgdWkdux$$IflֈF f'L5p t0544 ladmʠhzstxyhbR[ĵܥܕܕܕܕm`ĵܥܕܕܕܕhY9CJH*OJQJaJ.jzhKhgdWCJH*OJQJUaJhKhgdWCJH*OJQJaJhKhgdW5CJOJQJaJhKhgdW>*CJOJQJaJhKh;#CJOJQJaJhgdWCJOJQJaJh;#CJOJQJaJhKhgdWCJOJQJaJ(jhKhgdWCJH*OJQJUaJ%56lӞcdyh@s & FL$If^`LgdgdW$$Ifa$gdgdW $IfgdgdWstˤ://// $IfgdgdWkdy$$IflֈF f'L5p t0544 laˤܤ,fhbR:ݩ  & FL$If^`LgdgdW$$Ifa$gdgdW $IfgdgdW[  +,<=?@AFGbcdPR `ars̼̗|p|`̼hKhgdW>*CJOJQJaJhgdWCJOJQJaJhKh;#CJOJQJaJh;#CJOJQJaJhY9CJH*OJQJaJ.j$|hKhgdWCJH*OJQJUaJhKhgdWCJH*OJQJaJ(jhKhgdWCJH*OJQJUaJhKhgdW5CJOJQJaJhKhgdWCJOJQJaJ!  AFGc://// $IfgdgdWkd={$$IflֈF f'L5p t0544 lacduҪ֪GYdw߬)Ol$$Ifa$gdgdW $IfgdgdWkѮ` & FL$If^`LgdgdW`a://// $IfgdgdWkd|$$IflֈF f'L5p t0544 laR)2'(./Iöçpp`````hKhgdW5CJOJQJaJhKhgdW>*CJOJQJaJhKh;#CJOJQJaJhgdWCJOJQJaJh;#CJOJQJaJhKhgdWCJOJQJaJhY9CJH*OJQJaJ(jhKhgdWCJH*OJQJUaJhKhgdWCJH*OJQJaJ.j}hKhgdWCJH*OJQJUaJ¯ԯۯJNR)&' & FL$If^`LgdgdW$$Ifa$gdgdW $IfgdgdW'(_d://// $IfgdgdWkd~$$IflֈF f'L5p t0544 laIJZ[]^_cdrʵ>QĶ  #O6Föç|llllTöç|l.jPhKhgdWCJH*OJQJUaJhKhgdW5CJOJQJaJhKhgdW>*CJOJQJaJhKh6UNCJOJQJaJh6UNCJOJQJaJhKhgdWCJOJQJaJhY9CJH*OJQJaJ(jhKhgdWCJH*OJQJUaJhKhgdWCJH*OJQJaJ.j~hKhgdWCJH*OJQJUaJ dzpr> & FL$If^`LgdgdW$$Ifa$gdgdW $IfgdgdW $@A://// $IfgdgdWkdi$$IflֈF f'L5p t0544 laAUNO6ԻQ & FL$If^`LgdgdW$$Ifa$gdgdW $IfgdgdWFԻ޻QZ !#$%)*+ܾ '0]^̼̗p`hKhgdW>*CJOJQJaJhKh6UNCJOJQJaJhgdWCJOJQJaJh6UNCJOJQJaJhY9CJH*OJQJaJ.jhKhgdWCJH*OJQJUaJhKhgdWCJH*OJQJaJ(jhKhgdWCJH*OJQJUaJhKhgdW5CJOJQJaJhKhgdWCJOJQJaJ %*+S://// $IfgdgdWkd̀$$IflֈF f'L5p t0544 laSTe˽JLܾ'\]$$Ifa$gdgdW $IfgdgdW]^  :3333gdgdWkd1$$IflֈF f'L5p t0544 la^ Z]^abefg[\()1¸̖tdtdtdttdtdtdtttttthgdWB*CJOJQJaJph%hKhgdWB*CJOJQJaJphhKhgdWCJOJQJaJ(hKhgdW5B*CJOJQJaJphhKhT,ZB*CJphhT,ZB*CJphhgdWB*CJphhKhgdWB*CJphh;#CJOJQJaJhgdWCJOJQJaJh.4hgdWCJOJQJaJ%    $$Ifa$gdgdWgdgdW%,7ANZ^bf $IfgdgdWFf$$Ifa$gdgdWfgkd$$Iflִ2 %,/v t0/    44 lagk$$Ifa$gdgdW $IfgdgdW kd$$Iflִ2 %,/v t0/    44 laNX[$$Ifa$gdgdW $IfgdgdW [\kd$$Iflִ2 %,/v t0/    44 la\`kr}|$$Ifa$gdgdW $IfgdgdW kdϊ$$Iflִ2 %,/v t0/    44 la&Hh%($$Ifa$gdgdW $IfgdgdW ()kd$$Iflִ2 %,/v t0/    44 la)-5<KXgx$$Ifa$gdgdW $IfgdgdW kd$$Iflִ2 %,/v t0/    44 la*./02$$Ifa$gdgdW $IfgdgdW 123LM46~ ݺͪwoghgdWOJQJhnOJQJh/hgdW6CJhgdWhgdW5CJ\hsbjhsbUhFVhgdW56B*CJphhT,ZB*CJOJQJaJph%hlhgdWB*CJOJQJaJphhgdWB*CJOJQJaJphhK6hgdWCJOJQJaJ%hK6hgdWB*CJOJQJaJph$23kd$$Iflִ2 %,/v t0/    44 la37AHWfuFJL$$Ifa$gdgdW $IfgdgdW LMkd3$$Iflִ2 %,/v t0/    44 laMQW^m|(04$$Ifa$gdgdW $IfgdgdW 46kdL$$Iflִ2 %,/v t0/    44 la6>JXt'z$$Ifa$gdgdW $IfgdgdWkde$$Iflִ2 %,/v t0/    44 la$$Ifa$gdgdW $IfgdgdW kd~$$Iflִ2 %,/v t0/    44 la|gdgdWakd$$IflFs& 6    44 la$$Ifa$gdgdW$IfgdgdW#ckd$$IflF&S t06    44 la $$Ifa$$If!"&'(GHKLMOǺǫwk[wNhgdW5CJOJQJaJh_hgdW5CJOJQJaJhgdWCJOJQJaJ/jh_hgdW0J5CJH*OJQJUaJhsb hgdWCJhgdW6CJ]hgdW5CJ\hx0JOJQJmHnHuhShgdW0JOJQJ!jhShgdW0JOJQJUhgdW6OJQJ]hShgdW6OJQJ]hgdWhShgdWOJQJ#$%&'(Htrpjj\$$Ifa$gdgdW$Ifkd$$IflF&S t06    44 laHIJKLj8\\vvd$h^h`a$gdS;h^h`gdgdW$h^h`a$gdgdWgdgdWakdG$$IflF!y# 3 6    44 la jkm\8\9\\\,]-]/]]]]l^m^o^^^^^ǼǼtitǼǼQDhgdW5CJOJQJaJ/jh_hgdW0J5CJH*OJQJUaJhS;hS;CJaJhS;hgdWCJaJ$jhS;hgdW0JCJH*UaJhS;hgdW5CJOJQJaJ/jhS;hgdW0J5CJH*OJQJUaJUh_hgdWCJaJhgdWCJaJ$jh_hgdW0JCJH*UaJh_hgdW5CJOJQJaJhrJ5CJOJQJaJS. Pulmonary Hypertension. JAMA. 2000; 284(24):3160-68. . Simonneau G, Nazzareno G, Rubin LJ, et al. Clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2004;43:5S-12S. . McLaughlin VV, Presberg KW, Doyle RL, et al. Prognosis of pulmonary hypertension. Chest. 2004;126:78S-92S. . ACCP Evidence-based clinical practice guidelines: diagnosis and management of pulmonary hypertension. Chest. 2004;126(1 Suppl):1S-92S. . Badesch DB, Abman SH, Simonneau G, et al. Medical therapy for pulmonary arterial hypertension: updated ACCP evidence-based clinical practice guidelines. Chest. 2007;131:1917-28. . McLaughlin VV, McGoon MD. Pulmonary arterial hypertension. Circulation. 2006;114:1417-31. . Rubin LJ. Diagnosis and management of pulmonary arterial hypertension: ACCP Evidence-based clinical practice guidelines. Chest. 2004;126(1 Suppl):7S-10S. . Johnson SR, Mehta S, Granton JT. Anticoagulation in pulmonary arterial hypertension: a qualitative systematic review. Eur Resp J. 2006;28:999-1004. . Mereles D, Ehlken N, Kreuscher S, et al. Exercise and respiratory training improve exercise capacity and quality of life in patients with severe chronic pulmonary hypertension. Circulation. 2006;114:1482-89. . Sitbon O, Humbert M, Jais X, et al. Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension. Circulation. 2005;111:3105-11. . Rich S, Kaufmann E, Levy PS. The effect of high doses of calcium channel blockers on survival in primary pulmonary hypertension. N Engl J Med. 1992;327(2):76-81. . Letairis"! Product Information. Gilead Sciences, Foster City CA. February 2008. . Tracleer Product Information. Actelion Pharmaceuticals. South San Francisco CA. February 2007 . Flolan Product Information. GlaxoSmithKline, Research Triangle Park NC. January 2008. . Ventavis Product Information. CoTherix, Inc. South San Francisco CA. January 2006. . Revatio Product Information. Pfizer Inc. New York NY. December 2007. . Remodulin Product Information. United Therapeutics, Research Triangle Park, NC. February 2008. . Humbart M, Sitbon O, Simonneau G. Treatment of pulmonary arterial hypertension. N Engl J Med. 2004;351:1425-36. . Badesch DB, Abman SH, Ahearn GS, et al. Medical therapy for pulmonary arterial hypertension. Chest. 2004;126(1 Suppl):35S-62S. . Christman BW, McPherson CD, Newman JH et al. An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary hypertension. N Engl J Med. 1992;327:70-75. . Tuder RM, Cool CD, Geraci MW, et al. Prostacyclin synthase expression is decreased in lungs from patients with severe pulmonary hypertension. Am J Resp Crit Care Med. 1999;159:1925-32. . Barst RJ, Rubin LJ, Long WA, et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med. 1996;334:296-301. . Rubin LJ, Mendoza J, Hood M, et al. Treatment of primary pulmonary hypertension with continuous intravenous prostacyclin (epoprostenol). Ann Intern Med. 1990;112:485-91. . Badesch DB, Tapson VF, McGoon MD, et al. Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease. Ann Intern Med. 2000;132(6):425-34. . McLaughlin VV, Shillington A, Rich S. Survival in pulmonary hypertension. The impact of epoprostenol therapy. Circulation. 2002;106:1477-82. . Sitbon O, Humbert M, Nunes H, et al. Long-term intravenous epoprostenol infusion in primary pulmonary hypertension. J Am Coll Cardiol. 2002;40:780-8. . Laliberte K, Arneson C, Jeffs R, et al. Pharmacokinetics and steady state bioequivalence of treprostinil sodium (Remodulin) administered by the intravenous and subcutaneous route to normal volunteers. J Cardiovasc. Pharmacol. 2004;44:209-14. . Simonneau G, Barst RJ, Galie N, et al. Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertension. Am J Respir Crit Care Med. 2002;165:800-4. . Tapson VF, Gomberg-Maitland M, McLaughlin VV, et al. Safety and efficacy of IV treprostinil for pulmonary arterial hypertension. Chest. 2006;129:683-88. . Barst RJ, Galie N, Naeije R, et al. Long-term outcome in pulmonary arterial hypertension patients treated with subcutaneous treprostinil. Eur Respir J. 2006;28:1073-5. . Olschewski H, Simonneau G, Galie N, et al. Inhaled iloprost for severe pulmonary hypertension. N Engl J Med. 2002;347:322-9. . Opitz CF, Wensel R, Winkler J, et al. Clinical efficacy and survival with first-line inhaled iloprost therapy in patients with idiopathic pulmonary arterial hypertension. Eur Heart J. 2005;26:1895-1902. . Hoeper MM, Schwarze M, Ehlerding S, et al. Long-term treatment of primary pulmonary hypertension with aerosolized iloprost, a prostacyclin analogue. N Engl J Med. 2000;342:1866-70. . McLaughlin VV, McGoon MD. Pulmonary arterial hypertension. Circulation. 2006;114:1417-31. . Liu C, Chen J. Endothelin receptor antagonists for pulmonary arterial hypertension. Cochrane Database of Systematic Reviews. 2006;Issue 3. Art. No.: CD004434. DOI: 10.1002/14651858.CD004434.pub3. . Channick RN, Simonneau G, Sitbon O, et al. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomized placebo-controlled study. Lancet. 2001;358:1119-23. . Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. (BREATHE-1). N Engl J Med. 2002;346: 896-903. . Galie N, Rubin LJ, Hoeper MM. Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (EARLY study): a double-blind, randomized controlled trial. Lancet. 2008;371:2093-2100. . McLaughlin VV, Sitbon O, Badesch DB, et al. Survival with first-line bosentan in patients with primary pulmonary hypertension. Eur Respir J. 2005;25:244-9. . Sitbon O, McLaughlin VV, Badesch DB, et al. Survival in patients with class III idiopathic pulmonary hypertension treated with first line oral bosentan compared with an historical cohort of patients started on intravenous epoprostenol. Thorax. 2005;60: 1025-30. . Burgess G, Hoogkamer H, Collings L, et al. Mutual pharmacokinetic interactions between steady-state bosentan and sildenafil. Eur J Clin Pharmacol. 2008;64(1):43-50 . Letairis"! Product Dossier. Gilead Sciences, Foster City CA. August 2007. . Galie N, Olschewski H, Oudiz RJ, et al. Ambrisentan for the treatment of pulmonary arterial hypertension. Circulation. 2008;117:(23):3010-9. Epub 2008 May 27. . McGoon MD, Frost AE, Oudiz RJ, et al. Ambrisentan therapy in patients with pulmonary arterial hypertension who discontinued bosentan or sitaxsentan due to liver function test abnormalities. Chest. 2008; published online DOI 10.1378/chest.08-1028. . Badesch DB, Abman SH, Ahearn GS, et al. Medical therapy for pulmonary arterial hypertension. CHEST. 2004;126:35S-62S. . Sastry BKS, Narasimhan DM, Reddy NK, et al. Clinical efficacy of sildenafil in primary pulmonary hypertension. J Am Coll Cardiol. 2004;43:1149-53. . Wilkins MR, Paul GA, Strange JW, et al. Sildenafil versus endothelin receptor antagonist for pulmonary hypertension (SERAPH) study. Am J Resp Crit Care Med. 2005;171:1292-97. . Galie N, Ghofrani HA, Torbicki A, et al. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med. 2005;353:2148-57. . McLaughlin VV, Oudiz RJ, Frost A, et al. Randomized study of adding inhaled iloprost to existing bosentan in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2006;174:1257-63. . Hoeper MM, Leuchte H, Halank M, et al. Combining inhaled iloprost with bosentan in patients with idiopathic pulmonary hypertension. Eur Respir J. 2006;28:691-94. . Humbart M, Barst RJ, Robbins IM, et al. Combination of bosentan with epoprostenol in pulmonary arterial hypertension. BREATHE-2. Eur Respir J. 2004;24:353-9. . Simonneau G, Rubin LJ, Galie N, et al. Addition of sildenafil to long-term intravenous epoprostenol therapy in patients with pulmonary arterial hypertension. Ann Intern Med. 2008;149:521-30. . Benza RL, Rayburn BK, Tallaj JA, et al. Treprostinil-based therapy in the treatment of moderate-to-severe pulmonary arterial hypertension. Long-term efficacy and combination with bosentan. CHEST. 2008;134:139-45. . Mathai SC, Girgis RE, Fisher MR et al. Addition of sildenafil to bosentan monotherapy in pulmonary arterial hypertension. Eur Respir J. 2007;29(3):469-75. . Ruiz MJ, Escribano P, Delgado JF, et al. Efficacy of sildenafil as a rescue therapy for patients with severe pulmonary arterial hypertension and given long-term treatment with prostanoids. J Heart Lung Transplant. 2006;25:1353-7. . Hoeper MM, Markevych I, Spiekerkoetter E, et al. Goal-oriented treatment and combination therapy for pulmonary arterial hypertension. Eur Respir J. 2005;26:858-63. . Gomberg-Maitland M, McLaughlin V, Gulati M, et al. Efficacy and safety of sildenafil added to treprostinil in pulmonary hypertension. Am J Cardiol. 2005;96:1334-6. . Hoeper MM, Faulenbach C, Golpon H, et al. Combination therapy with bosentan and sildenafil in idiopathic pulmonary arterial hypertension. Eur Respir J. 2004;24:1007-1010. . Ghofrani HA, Rose F, Schermuly RT, et al. Oral sildenafil as long-term adjunct therapy to inhaled iloprost in severe pulmonary arterial hypertension. J Am Coll Cardiol. 2003; 42:158-64. . Stiebellehner L, Petkov V, Vonbank K, et al. Long-term treatment with oral sildenafil in addition to continuous IV epoprostenol in patients with pulmonary hypertension. Chest. 2003;123(4):1293-95. . Califf RM, Kirkwood FA, McKenna WJ, et al. A randomized controlled trial of epoprostenol therapy for severe congestive heart failure: the Flolan international randomized survival trial (FIRST). Am Heart J. 1997;134:44-54. . Kaluski E, Cotter G, Leitman M, et al. Clinical and hemodynamic effects of bosentan dose optimization in symptomatic heart failure patients with severe systolic dysfunction associated with secondary pulmonary hypertension a multi-center randomized study. Cardiology. 2008;109:273-280. . Hopkins W and Rubin LJ. Treatment of pulmonary hypertension. UpToDate. Version 16.2: May 2008. . Olschewski H, Ghofrani HA, Walmrath D, et al. Inhaled prostacyclin and iloprost in severe pulmonary hypertension secondary to lung fibrosis. Am J Respir Crit Care Med. 1999;160:600-7. . Ghofrani HA, Wiedemann R, Rose F, et al. Sildenafil for treatment of lung fibrosis and pulmonary hypertension: a randomized controlled trial. Lancet. 2002;360:895-900. . \,]]l^^g__`ua4bbc(ddd+ee ffg\h i$h^h`a$gdgdWh^h`gdgdW hh^h`gdS;h^h`gdS;^*_J_g_h_j___````uavaxa4b6b@bbbbbccc(d)d+dĹuuumuZRGZRGZRh_hgdWCJaJhgdWCJaJ$jh_hgdW0JCJH*UaJhrJCJaJhS;hgdWCJaJ$jhS;hgdW0JCJH*UaJhS;htCJaJhS;CJaJ$jhS;ht0JCJH*UaJhS;hGCJaJhS;hS;CJaJ$jhS;hG0JCJH*UaJhS;5CJOJQJaJh_hgdW5CJOJQJaJ+ddddddd+e,e.eeee f!f#ffffg%gggg\h]h_h i i iiiiTjUjWjjjjkkkllllPmh> hgdWCJaJ$jh> hgdW0JCJH*UaJh> h> CJaJh> h*<CJaJh> CJaJ$jh> h*<0JCJH*UaJhrJCJaJhgdWCJaJ$jh_hgdW0JCJH*UaJh_hgdWCJaJ. iiTjjklPmm{nIop^p%qqr\ssuuvwx h^h`gdgdW hh^h`gd> h^h`gd> h^h`gdgdWPmQmSmmm{n|n~nIoJoLoppp^p_pap%q&q(q6qqqq rrrrr\s]s_ssss tuuuuuvvvvwwwwwxǼh_hgdW0J'CJaJhrJCJaJh_hgdWCJaJhgdWCJaJ$jh_hgdW0JCJH*UaJh> hgdWCJaJ$jh> hgdW0JCJH*UaJh> h-[CJaJh> CJaJ$jh> h-[0JCJH*UaJ2xxxpyqysyzz zwzzzzzD{E{G{||||||H}I}K} ~ ~ ~~~~ijlefh"#%̄̈́τQRT  ]^ڽ$jhT1hgdW0JCJH*UaJUhrJCJaJh_hgdWCJaJhgdWCJaJ$jh_hgdW0JCJH*UaJFxpyzzD{||H} ~~ie"̄Q ]  hh^h`gdT1h^h`gdgdWh^h`gdgdWVentavis Formulary Dossier. Actelion Pharmaceuticals, South San Francisco, CA. January 2008 . King TE, Behr J, Brown K, et al. BUILD-1: a randomized placebo-controlled trial of bosentan in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2008;177:75-81. . Suntharalingam J, Treacy CM, Doughty NJ, et al. Long-term use of sildenafil in inoperable chronic thromboembolic pulmonary hypertension. Chest. 2008;134(2):229-36. ^   ǿhFVhgdW56B*CJphhsbhT1hxCJaJhxCJaJhVcCJaJhT1hVcCJaJhT1CJaJ$jhT1hVc0JCJH*UaJhT1hgdWCJaJ gdgdW hh^h`gdT16&P:pgdWBP/ =!"#$%] 9 0&P:pgdWBP/ =!"#$%] =&P1+0:pgdWBP= /!"#$%] }DyK _Ref196713580}DyK _Ref196715836}DyK _Ref196666232$$If!vh55,#v#v,:V l  t0S655/ apyt$$$If!vh55,#v#v,:V l t0S655/ a$$If!vh55,#v#v,:V l t0S655a$$If!vh55,#v#v,:V l t0S655a$$If!vh55,#v#v,:V l t0S655a$$If!vh55,#v#v,:V l t0S655a$$If!vh5u5/#vu#v/:V l  t0 655/ apyt$$$If!vh5u5/#vu#v/:V l t0 655/ aytn$$If!vh5u5/#vu#v/:V l t0 655aytn$$If!vh5u5/#vu#v/:V l t0 655aytn$$If!vh5u5/#vu#v/:V l t0 655aytn}DyK _Ref217196831}DyK _Ref217208719}DyK _Ref217206132}DyK _Ref217208837}DyK _Ref196722565}DyK _Ref196722565y$$If!vh5525575{54 #v#v2#v#v7#v{#v4 :V l  t<0$65575{54 / ap<yt$kd $$Iflֈ?q _E'7{4   t<0$644 lap<yt$$$If!vh5525575{54 #v#v2#v#v7#v{#v4 :V l t0$65575{54 / a$$If!vh5525575{54 #v#v2#v#v7#v{#v4 :V l t0$65575{54 a$$If!vh5525575{54 #v#v2#v#v7#v{#v4 :V l t0$65575{54 a$$If!vh5525575{54 #v#v2#v#v7#v{#v4 :V l t0$65575{54 a$$If!vh5525575{54 #v#v2#v#v7#v{#v4 :V l t0$65575{54 a$$If!vh5525575{54 #v#v2#v#v7#v{#v4 :V l t0$65575{54 a}DyK _Ref196576658}DyK _Ref196576658}DyK _Ref196576716}DyK _Ref217269133}DyK _Ref196576761}DyK _Ref196576793}DyK _Ref196576793}DyK _Ref196576814}DyK _Ref195885810}DyK _Ref195884285}DyK _Ref196811905}DyK _Ref196811905}DyK _Ref208623835}DyK _Ref196529575}DyK _Ref196529575}DyK _Ref208633662$$If!vh55q5'55E555 #v#vq#v'#v#vE#v#v#v :V l  tP055=5555Q55apPyt$kd$$IflִLIp] 4%=Q  tP0    44 lapPyt$$$If!vh55q5'55E555 #v#vq#v'#v#vE#v#v#v :V l t055=5555Q55a$$If!vh55q5'55E555 #v#vq#v'#v#vE#v#v#v :V l t055=5555Q55a$$If!vh55q5'55E555 #v#vq#v'#v#vE#v#v#v :V l t055=5555Q55a$$If!vh55q5'55E555 #v#vq#v'#v#vE#v#v#v :V l t055=5555Q55a$$If!vh55q5'55E555 #v#vq#v'#v#vE#v#v#v :V l t055=5555Q55a$$If!vh55q5'55E555 #v#vq#v'#v#vE#v#v#v :V l t055=5555Q55a}DyK _Ref217447381}DyK _Ref217208719}DyK _Ref196726568$$If!vh55!#v#v!:V l t0655!$$If!vh55!#v#v!:V l t0655!$$If!vh55!#v#v!:V l t0655!$$If!vh55!#v#v!:V l t0655!$$If!vh55!#v#v!:V l t0655!$$If!vh55!#v#v!:V l t0655!$$If!vh55!#v#v!:V l t0655!$$If!vh55!#v#v!:V l t0655!$$If!vh55!#v#v!:V l t0655!$$If!vh55!#v#v!:V l t0655!$$If!vh5[5C5555G5!5#v[#vC#v#v#v#vG#v!#v:V l  t 6P0655@5)55K5535pPyt$kd-$$Iflִ2 & 3@)K3  t 6P06    44 lapPyt$}DyK _Ref196231474'$$If!vh5[5C5555G5!5#v[#vC#v#v#v#vG#v!#v:V l t 60655@5)55K5535kd2$$Iflִ2 & 3@)K3 t 606    44 la}DyK _Ref196233156'$$If!vh5[5C5555G5!5#v[#vC#v#v#v#vG#v!#v:V l t 60655@5)55K5535kd6$$Iflִ2 & 3@)K3 t 606    44 la}DyK _Ref217269133'$$If!vh5[5C5555G5!5#v[#vC#v#v#v#vG#v!#v:V l t 60655@5)55K5535kd:$$Iflִ2 & 3@)K3 t 606    44 la}DyK _Ref196529575'$$If!vh5[5C5555G5!5#v[#vC#v#v#v#vG#v!#v:V l t 60655@5)55K5535kd=$$Iflִ2 & 3@)K3 t 606    44 la$$If!vh55D555 555#v#vD#v#v#v #v#v#v:V l  t 6P06555755L555pPyt$kd@$$IflִntH< 37L  t 6P06    44 lapPyt$}DyK _Ref195628444'$$If!vh55D555 555#v#vD#v#v#v #v#v#v:V l t 606555755L555kdE$$IflִntH< 37L t 606    44 la}DyK _Ref195689291'$$If!vh55D555 555#v#vD#v#v#v #v#v#v:V l t 606555755L555kd[I$$IflִntH< 37L t 606    44 la}DyK _Ref208647902+$$If!vh55D555 555#v#vD#v#v#v #v#v#v:V l t 606555755L555kdL$$IflִntH< 37L t 606    44 la}DyK _Ref195885810}DyK _Ref217459219+$$If!vh55D555 555#v#vD#v#v#v #v#v#v:V l t 606555755L555kdQ$$IflִntH< 37L t 606    44 la}DyK _Ref195885810}DyK _Ref217459219+$$If!vh55D555 555#v#vD#v#v#v #v#v#v:V l t 606555755L555kdU$$IflִntH< 37L t 606    44 la$$If!vh55C555*5x5)5#v#vC#v#v#v*#vx#v)#v:V l  t 6P0555755W5535pPyt$kd4X$$Iflִnq< 37W3  t 6P0    44 lapPyt$}DyK _Ref195966739$$$If!vh55C555*5x5)5#v#vC#v#v#v*#vx#v)#v:V l t 60555755W5535kd=]$$Iflִnq< 37W3 t 60    44 la}DyK _Ref195966794$$$If!vh55C555*5x5)5#v#vC#v#v#v*#vx#v)#v:V l t 60555755W5535kd`$$Iflִnq< 37W3 t 60    44 la}DyK _Ref196016532$$$If!vh55C555*5x5)5#v#vC#v#v#v*#vx#v)#v:V l t 60555755W5535kdSd$$Iflִnq< 37W3 t 60    44 lax$$If!vh55p5555 #v#vp#v#v#v#v :V l  t<0555p5555 p<yt$kdag$$IflֈF f'L5p  t<0544 lap<yt$x$$If!vh55p5555 #v#vp#v#v#v#v :V l  t<0555p5555 p<yt$kdj$$IflֈF f'L5p  t<0544 lap<yt$}DyK _Ref217288930*$$If!vh55p5555 #v#vp#v#v#v#v :V l t0555p5555 p<yt=l}DyK _Ref196821658$$If!vh55p5555 #v#vp#v#v#v#v :V l t0555p5555 }DyK _Ref208648122$$If!vh55p5555 #v#vp#v#v#v#v :V l t0555p5555 }DyK _Ref208288948$$If!vh55p5555 #v#vp#v#v#v#v :V l t0555p5555 x$$If!vh55p5555 #v#vp#v#v#v#v :V l  t<0555p5555 p<yt$kdbt$$IflֈF f'L5p  t<0544 lap<yt$}DyK _Ref208648159$$If!vh55p5555 #v#vp#v#v#v#v :V l t0555p5555 }DyK _Ref208648173$$If!vh55p5555 #v#vp#v#v#v#v :V l t0555p5555 }DyK _Ref208648184$$If!vh55p5555 #v#vp#v#v#v#v :V l t0555p5555 }DyK _Ref208648215$$If!vh55p5555 #v#vp#v#v#v#v :V l t0555p5555 }DyK _Ref208648232$$If!vh55p5555 #v#vp#v#v#v#v :V l t0555p5555 }DyK _Ref208648254$$If!vh55p5555 #v#vp#v#v#v#v :V l t0555p5555 }DyK _Ref208648283$$If!vh55p5555 #v#vp#v#v#v#v :V l t0555p5555 }DyK _Ref208648303$$If!vh55p5555 #v#vp#v#v#v#v :V l t0555p5555 $$If!vh55555555v#v#v#v#v#v#v#v#vv:V l  tP0/,55555555vpPyt$kd$$Iflִ2 %,/v  tP0/    44 lapPyt$$$If!vh55555555v#v#v#v#v#v#v#v#vv:V l t0/,55555555v$$If!vh55555555v#v#v#v#v#v#v#v#vv:V l t0/,55555555v$$If!vh55555555v#v#v#v#v#v#v#v#vv:V l t0/,55555555v$$If!vh55555555v#v#v#v#v#v#v#v#vv:V l t0/,55555555v$$If!vh55555555v#v#v#v#v#v#v#v#vv:V l t0/,55555555v$$If!vh55555555v#v#v#v#v#v#v#v#vv:V l t0/,55555555v$$If!vh55555555v#v#v#v#v#v#v#v#vv:V l t0/,55555555v$$If!vh55555555v#v#v#v#v#v#v#v#vv:V l t0/,55555555v$$If!vh55555555v#v#v#v#v#v#v#v#vv:V l t0/,55555555v$$If!vh55555555v#v#v#v#v#v#v#v#vv:V l t0/,55555555v$$If!vh55555555v#v#v#v#v#v#v#v#vv:V l t0/,55555555vh$$If!vh5l5s5 #vl#vs#v :V l65 55$$If!vh5;5,5!#v;#v,#v!:V l t065S55$$If!vh5;5,5!#v;#v,#v!:V l t065S55h$$If!vh5!55#v!#v#v:V l65 55^) 666666666vvvvvvvvv66666686666666666666666666666666666666666666666666666666hH6666666666666666666666666666666666666666666666666666666666666666662 0@P`p2( 0@P`p 0@P`p 0@P`p 0@P`p 0@P`p 0@P`p8XV~_HmH nH sH tH @`@ LLNormalxCJ_HmH sH tH BB LL Heading 1$@&5>*OJQJLL LL Heading 2$x@&5CJOJQJ88 LL Heading 3$@&5@@ LL Heading 4$@& 6B*phLRL LL Heading 7$<@&5CJOJQJ88 LL Heading 8$@&5DA`D Default Paragraph FontRi@R 0 Table Normal4 l4a (k ( 0No List >>@> LLTitlea$5B*OJQJphDJ@D $LLSubtitlea$5B*OJQJph:B: LL Body Text CJOJQJ:": LL Footnote TextCJ6U@16 LL Hyperlink >*B*ph4@B4 &LL0Header !8R8 LLTable B*CJph>6b> LL List Bullet 2  Fx@ @r@ LLFooter ! CJOJQJ.)@. LL Page NumberHH cL Balloon TextCJOJQJ^JaJ6Q6 LL TableFootnoteD"D LLCaption $x5CJOJQJ\nn Table Grid7:V0x8+@8 a}c Endnote TextCJ>*@> a}cEndnote ReferenceH*@&@ [Footnote ReferenceH*B'B QxComment ReferenceCJaJ88 Qx Comment Text!CJ@j@ QxComment Subject"5\RY2R e Document Map#M CJOJQJ^JJAJ " Subtitle Char5B*CJOJQJph.XQ. %Emphasis6]2a2 z0 Header CharCJOq c{ti@ @u]0Revision(CJ_HmH sH tH PK![Content_Types].xmlj0Eжr(΢Iw},-j4 wP-t#bΙ{UTU^hd}㨫)*1P' ^W0)T9<l#$yi};~@(Hu* Dנz/0ǰ $ X3aZ,D0j~3߶b~i>3\`?/[G\!-Rk.sԻ..a濭?PK!֧6 _rels/.relsj0 }Q%v/C/}(h"O = C?hv=Ʌ%[xp{۵_Pѣ<1H0ORBdJE4b$q_6LR7`0̞O,En7Lib/SeеPK!kytheme/theme/themeManager.xml M @}w7c(EbˮCAǠҟ7՛K Y, e.|,H,lxɴIsQ}#Ր ֵ+!,^$j=GW)E+& 8PK!Ptheme/theme/theme1.xmlYOo6w toc'vuر-MniP@I}úama[إ4:lЯGRX^6؊>$ !)O^rC$y@/yH*񄴽)޵߻UDb`}"qۋJחX^)I`nEp)liV[]1M<OP6r=zgbIguSebORD۫qu gZo~ٺlAplxpT0+[}`jzAV2Fi@qv֬5\|ʜ̭NleXdsjcs7f W+Ն7`g ȘJj|h(KD- dXiJ؇(x$( :;˹! I_TS 1?E??ZBΪmU/?~xY'y5g&΋/ɋ>GMGeD3Vq%'#q$8K)fw9:ĵ x}rxwr:\TZaG*y8IjbRc|XŻǿI u3KGnD1NIBs RuK>V.EL+M2#'fi ~V vl{u8zH *:(W☕ ~JTe\O*tHGHY}KNP*ݾ˦TѼ9/#A7qZ$*c?qUnwN%Oi4 =3ڗP 1Pm \\9Mؓ2aD];Yt\[x]}Wr|]g- eW )6-rCSj id DЇAΜIqbJ#x꺃 6k#ASh&ʌt(Q%p%m&]caSl=X\P1Mh9MVdDAaVB[݈fJíP|8 քAV^f Hn- "d>znNJ ة>b&2vKyϼD:,AGm\nziÙ.uχYC6OMf3or$5NHT[XF64T,ќM0E)`#5XY`פ;%1U٥m;R>QD DcpU'&LE/pm%]8firS4d 7y\`JnίI R3U~7+׸#m qBiDi*L69mY&iHE=(K&N!V.KeLDĕ{D vEꦚdeNƟe(MN9ߜR6&3(a/DUz<{ˊYȳV)9Z[4^n5!J?Q3eBoCM m<.vpIYfZY_p[=al-Y}Nc͙ŋ4vfavl'SA8|*u{-ߟ0%M07%<ҍPK! ѐ'theme/theme/_rels/themeManager.xml.relsM 0wooӺ&݈Э5 6?$Q ,.aic21h:qm@RN;d`o7gK(M&$R(.1r'JЊT8V"AȻHu}|$b{P8g/]QAsم(#L[PK-![Content_Types].xmlPK-!֧6 +_rels/.relsPK-!kytheme/theme/themeManager.xmlPK-!Ptheme/theme/theme1.xmlPK-! ѐ' theme/theme/_rels/themeManager.xml.relsPK] Gx"#t*11278@:B:BBKKKKKKOOPPZUhXY]_/k;ls~t~G@ά}km~`i "$4b'jdv~"{, u K A qa( 4 XWQa] e!=""#k$%%}&E''(I))g*+r+,,,==  8 s 11 $\-3L7[=HBDGE"MOSWX\^]kuxm~o=OO~>!p%07JxQUwXl\n`cdhmp#s@v_{;~k ~[IF^1^+dPmx^ "#$%'()-79:<=EJLNPRTVY[\_acegjlorwz~e1=3>r??@AGBBB~CDlDmJWXYYLZZZ[[[HpLM}~(@3InIII7JJKQKKLyQSUX\`Gdiehlprtzv|~Ōƌ%k<[f4۝5sˤ c`'AS] fg[\()23LM46#H\ ix     !&*+,./01234568;>?@ABCDFGHIKMOQSUWXZ]^`bdfhikmnpqstuvxy{|}())D*p*r*3@3B3:<:>:ABBYCCCGFGIGHHHKKKQQQdeeeAimipimnn|||!=@o25f <?EGIuwX9996AbAeA C7C:C"ENEQE}GGGJ?JBJKKK+NWNZN&PRPUPWPPPERqRtRvRRRYYY [5[8[P]|]]```e4e7eh>hAhjk k:nfninrrrwwwS|||q1]`HHHHHHHHHHHHHHHHHHHHHH4HH4HHHHXHHHHHHH4HHHHHHHHH4H4H4H4H4H4H4H4H4H4H4sz}!\(# AA@H  0(   0(  B S  ?. _Ref196713580 _Ref196714190 _Ref196715836 _Ref196666232 _Ref217447381 _Ref196722565 _Ref217196831 _Ref217208719 _Ref196726568 _Ref217206132 _Ref217208837 _Ref196576814 _Ref196576793 _Ref196576658 _Ref196576761 _Ref196811905 _Ref196576716 _Ref196231474 _Ref196233156 _Ref217269133 _Ref196529575 _Ref195884285 _Ref195628444 _Ref195689291 _Ref208647902 _Ref208623835 _Ref195885810 _Ref217459219 _Ref195966739 _Ref196016532 _Ref195886057 _Ref195966794 _Ref196821658 _Ref208648122 _Ref208288948 _Ref217288923 _Ref217288930 _Ref208648159 _Ref208648173 _Ref208648184 _Ref208648215 _Ref208648232 _Ref208648254 _Ref208648283 _Ref208648303 _Ref208633662G#t*1112BBKKKKKKZUY;l~@}km`i "$  !"#$%&'()*+,-H#u*1112BBKKKKKK[UY?ABݛޛ1222777788A:B:AABBKKKKUkqkl+l9K V^      ~[^"$#$x%%11R3U35&5669W9====AACCEE|G}G3H:HRHVH]IhIJJVPWPPPQQuRvRRR7S;SdVoVYY[[[["^&^_`Ő668899;<>?ABݛޛSTZ_goҜӜ`u}ѝݝ<BK!',0[dޟ45AFOР֠۠ߠ{=INWƣ2\xyԤ *Vuv$,ۦDW^Fƨ٨r?C̪ѪڪmtDQR\ah3;íɭέ֭zůͯׯk~ɰʰְ۰@hmsjqv˳ҳ׳{u|9S 22:ox-6enԻۻXYcv}6>ѽ y=DJZ &P !*ABfgp9A3333333333333333333333333333333333333333333333333333333333333333333333333333333333333333333333333333333333333333333333333333333333333333333333333333333333333333333333333333333333333333()D*s*3C3:?:ABYCCGJGHHKKQQAiqimn||"Ao6f @==6AfA C;C}GGJCJKL+N[NYY [9[P]]e8ehBhj k:njnrrwwS||q1a5668899;<>?ABglvvޛ}}eeѠՠ\]_ʣˣIIm?ۭ#55ϹϹ1**]  J-j!\Y6=L%zj`=nSj5^cFd.)*x7.fybr. 2:V"!}3>Db?NY*Qԫ 8jSXa?TQX%e#!FYގ#oDAZA`&y9h\ @rfcNx3~q ^`OJQJo(-h^`OJQJo(hHh^`OJQJ^Jo(hHohp^p`OJQJo(hHh@ ^@ `OJQJo(hHh^`OJQJ^Jo(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJQJ^Jo(hHohP^P`OJQJo(hH 88^8`OJQJo(^`OJQJ^Jo(o pp^p`OJQJo( @ @ ^@ `OJQJo(^`OJQJ^Jo(o ^`OJQJo( ^`OJQJo(^`OJQJ^Jo(o PP^P`OJQJo(h^`OJQJo(hHh^`OJQJ^Jo(hHohp^p`OJQJo(hHh@ ^@ `OJQJo(hHh^`OJQJ^Jo(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJQJ^Jo(hHohP^P`OJQJo(hHh^`OJQJo(hHh^`OJQJ^Jo(hHohp^p`OJQJo(hHh@ ^@ `OJQJo(hHh^`OJQJ^Jo(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJQJ^Jo(hHohP^P`OJQJo(hH 88^8`OJQJo(^`OJQJ^Jo(o pp^p`OJQJo( @ @ ^@ `OJQJo(^`OJQJ^Jo(o ^`OJQJo( ^`OJQJo(^`OJQJ^Jo(o PP^P`OJQJo(88^8`CJOJQJaJo(^`OJQJ^Jo(o pp^p`OJQJo( @ @ ^@ `OJQJo(^`OJQJ^Jo(o ^`OJQJo( ^`OJQJo(^`OJQJ^Jo(o PP^P`OJQJo( ^`OJQJo(^`OJQJ^Jo(o pp^p`OJQJo( @ @ ^@ `OJQJo(^`OJQJ^Jo(o ^`OJQJo( ^`OJQJo(^`OJQJ^Jo(o PP^P`OJQJo(^`CJOJQJo(^`CJOJQJ^Jo(o pp^p`OJQJo( @ @ ^@ `OJQJo(^`OJQJ^Jo(o ^`OJQJo( ^`OJQJo(^`OJQJ^Jo(o PP^P`OJQJo( ^`OJQJo(^`OJQJ^Jo(o pp^p`OJQJo( @ @ ^@ `OJQJo(^`OJQJ^Jo(o ^`OJQJo( ^`OJQJo(^`OJQJ^Jo(o PP^P`OJQJo(h^`OJQJo(hHh^`OJQJ^Jo(hHohp^p`OJQJo(hHh@ ^@ `OJQJo(hHh^`OJQJ^Jo(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJQJ^Jo(hHohP^P`OJQJo(hHpp^p`CJOJQJo(pp^p`OJQJ^Jo(o @ @ ^@ `OJQJo( ^`OJQJo(^`OJQJ^Jo(o ^`OJQJo( ^`OJQJo(PP^P`OJQJ^Jo(o   ^ `OJQJo(808^8`0o(.^`.pLp^p`L.@ @ ^@ `.^`.L^`L.^`.^`.PLP^P`L.h^`OJQJo(hHhv^v`OJQJ^Jo(hHohF ^F `OJQJo(hHh ^ `OJQJo(hHh^`OJQJ^Jo(hHoh^`OJQJo(hHh^`OJQJo(hHhV^V`OJQJ^Jo(hHoh&^&`OJQJo(hHh88^8`OJQJo(hH^`OJQJ^Jo(o pp^p`OJQJo( @ @ ^@ `OJQJo(^`OJQJ^Jo(o ^`OJQJo( ^`OJQJo(^`OJQJ^Jo(o PP^P`OJQJo( 88^8`OJQJo(^`OJQJ^Jo(o pp^p`OJQJo( @ @ ^@ `OJQJo(^`OJQJ^Jo(o ^`OJQJo( ^`OJQJo(^`OJQJ^Jo(o PP^P`OJQJo( ^`OJQJo(^`OJQJ^Jo(o p^p`OJQJo( @ ^@ `OJQJo(^`OJQJ^Jo(o ^`OJQJo( ^`OJQJo(^`OJQJ^Jo(o P^P`OJQJo(>^`OJPJQJ^Jo(q@ @ ^@ `OJQJ^Jo(o ^`OJQJo( ^`OJQJo(^`OJQJ^Jo(o ^`OJQJo( PP^P`OJQJo(  ^ `OJQJ^Jo(o ^`OJQJo( ^`OJQJo(pp^p`OJQJ^Jo(o @ @ ^@ `OJQJo( ^`OJQJo(^`OJQJ^Jo(o ^`OJQJo( ^`OJQJo(PP^P`OJQJ^Jo(o   ^ `OJQJo(h^`OJQJo(hHhp^p`OJQJ^Jo(hHoh@ ^@ `OJQJo(hHh^`OJQJo(hHh^`OJQJ^Jo(hHoh^`OJQJo(hHh^`OJQJo(hHhP^P`OJQJ^Jo(hHoh ^ `OJQJo(hHh^`OJQJo(hHhp^p`OJQJ^Jo(hHoh@ ^@ `OJQJo(hHh^`OJQJo(hHh^`OJQJ^Jo(hHoh^`OJQJo(hHh^`OJQJo(hHhP^P`OJQJ^Jo(hHoh ^ `OJQJo(hHh^`OJQJo(hHh^`OJQJ^Jo(hHohp^p`OJQJo(hHh@ ^@ `OJQJo(hHh^`OJQJ^Jo(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJQJ^Jo(hHohP^P`OJQJo(hH^7..)*!}3>b?N ?TQXzjA`nSoDAZ#!FY@ry9hx3~*Q. 2!Y6**] jS         cM                          cM        $Q                 ,                          ,        D                          cM                         cM                                    m/vV>  S {^ |` [J^pTtrxj1>bj";# %l'c'FS(d( . ./1T1LT7Y7| 8Y9S; <B=Jc=->uC DTDKmEyF6UNOmQFVgdW[{YT,Z/Z-["\xg_h_HyasbVc=dXMdyfgyiwk=laldlrlnJr|AsJtk]{ }NAKXUo0Zow$G'ogine]v.8QR(s%-i *<5rQ>KO<)} u 1(5w\9B'~/51qs}#rJ1_?~$y?a*SXo0f,pc}_"NLv68@LrrrArBNLNMNNNNNNNN NNABCDFGiHiIJKLMMOMPMQMSMTZ[\]8^8_8a8befhiklCtCuCyCzCCCC99X@XX$@X&XP@XLX@XXX@XX@XX$@XX@XX8@X*XX@XVX@XZX@X^X@XbX@XfX@XjX@XnXpX@XtX@X|X@XX@XX @XX@XX @XX(@XX0@XXD@XXP@XXd@XXl@XXx@XX@XX@X@XbX@XvX@X0@UnknownG* Times New Roman5Symbol3. * ArialA. Arial Narrow5. *aTahoma;Wingdings?= * Courier NewA BCambria Math"1hCцVjҦ̆_=]_=]%n4ddd 2qHP  ?cL2!xxVISN 22 Drug Monograph TemplatestaffLisad                 Oh+'0|p   , 8 DPX`hstaffNormalLisa3Microsoft Office Word@Ik@l1a@bQ;@4n_=]_=]՜.+,D՜.+,P  hp  VHASDCd  VISN 22 Drug Monograph Template Title 8@ _PID_HLINKSA T1http://www.ahrq.gov/clinic/3rduspstf/ratings.htm  !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]ghijklmtuxyRoot Entry FпwData 1TablevWordDocument SummaryInformation( DocumentSummaryInformation8fMsoDataStore`Ny0qdyTDRUSWELTLW==2`Ny0qdyItem  PropertiesUCompObj y    F'Microsoft Office Word 97-2003 Document MSWordDocWord.Document.89qOh+'0|p   , 8 DPX`hstaffNormalLisa3Microsoft Office Word@Ik@l1a@bQ;@4n_=]