3 Pulmonary Hypertension Pulmonary hypertension is defined as an increase in mean pulmonary artery pressure ≧ 25 mmHg at restPulmonary hypertension is a hemodynamic and pathophysiological state that can be found in multiple clinical condition
4 Pulmonary Arterial Hypertension Diagnostic Classification • 1.1Idiopathic PAH• 1.2 Heritable• 1.3 Drugs and toxin related• 1.4 Associated with (APAH)1.4.1 Connective tissue diseases1.4.2 HIV1.4.3 Portal hypertension1.4.4 Congenital heart diseases1.4.5 Schistosomiasis1.4.6 Chronic haemolytic anaemia• 1.5 Persist PH of the newborn1’ Pulmonary veno-occlusive disease3. PH with Lung Diseases/Hypoxemia• 3.1 COPD• 3.2 Interstitial lung diseases3.3 mixed restrictive and obstructive pattern• 3.4 Sleep-disordered breathing3.5 Alveolar hypoventilation disorders3.6 Chronic exposure to high altitude• 3.7 Developmental abnormalities4. Chronic thromboembolicPH• TE obstruction of proximal PA• TE obstruction of distal PA• Non thrombotic P embolism5. PH with unclear and /ormultifactorial mechanisms2. PH with left heart disease• 2.1 Systolic dysfunction• 2.2 Diastolic dysfunction2.3 Valvular diseaseDana Point 2008
5 Pulmonary Arterial Hypertension Pulmonary hypertensionElevated pressure in the pulmonary vascular bed, without specify the location of the pathologyPulmonary arterial hypertensionElevated pressure in the pulmonary vascular bed, specially ascribed to pathology in the pulmonary arterial tree.
6 Definition of PAH by WHO Mean PAP > 25mmHg at restPAWP < 15 mmHg
7 What do we face ?RareMiss diagnosisRapid progressPoor prognosis
8 Really rare ? Or Under diagnosis? 4/8/2017Really rare ? Or Under diagnosis?
9 4/8/2017Prevalence of PAHThis is the title slide for Session 4: Pulmonary arterial hypertension (PAH): what challenges do we face?
10 PAH is a rare disease: Prevalence of PAH 4/8/2017PAH is a rare disease: Prevalence of PAHFrance:15 cases/millionEngland and Wales:Severe PAH: 30–50 cases/millionEstimated prevalence of 120,000 pts with PAH in the USA, EU, Canada and Japan.- US 50,000 to 100,000- 15,000 to 25,000 diagnosed and treatedEstimated 260,000 pts hospitalized/year with all cause PH in USA (medicare database)Key message: PAH is a rare orphan disease, although the prevalence varies, being substantially higher in at-risk groups.References1. Humbert M, Sitbon O, Chaouat A, et al. Pulmonary arterial hypertension in France: results from a national registry. Am J Resp Crit Care Med 2006; 173: 1023–30.2. Peacock AJ. Treatment of pulmonary hypertension. BMJ 2003; 326: 835–6.3. Sitbon O, Lascoux-Combe C, Delfrissy JF, et al. Prevalence of HIV-related pulmonary arterial hypertension in the current antiretroviral therapy era. Am J Respir Crit Care Med 2008; 177: 108–113.4. Lin EE, Rodgers GP, Gladwin MT. Hemolytic anemia-associated pulmonary hypertension in sickle cell disease. Curr Hematol Rep 2005; 4: 117–25.5. McGoon M, Gutterman D, Steen V, et al. Screening, early detection, and diagnosis of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest 2004; 126(1 Suppl): 14S–34S.Humbert, et al. Am J Resp Crit Care Med 2006; 173: 1023–30Peacock. BMJ 2003; 326: 835–6Link J. Chest 2011; 139:Gomberg-Maitland M. Chest 2011;139:
11 Prevalence of PAH in Associated Conditions Systemic sclerosis7-12 %HIV infection%Portal hypertension2-6 %Congenital heart diseaseper million in those with congenital systemic-to-pulmonary shunts → % affected by Eisenmenger syndromeSchistosomiasis4.6 % in those with hepatosplenic diseaseChronic hemolytic anemiaHighly variable; currently being studiedThe prevalence of PAH in associated conditions varies dramatically. Patients with systemic sclerosis have an estimated prevalence of 7-12%. Those with HIV infection have an estimated prevalence of less than 0.5%. The prevalence is 2-6% for patients with portal hypertension. PAH is prevalent in per million of patients with congenital systemic to pulmonary shunts. Furthermore, 25-50% go on to be affected by Eisenmenger syndrome. Just less than 5% of patients with hepatosplenic disease develop PAH. Patients with chronic hemolytic anemia are at an increased risk of developing PAH; however, the prevalence rates are highly variable and are being actively studied.Simonneau, et al. J Am Coll Cardiol. 2009;54(1):S43-54.
12 Pathogenesis of Pulmonary Arterial NORMALREVERSIBLE DISEASEIRREVERSIBLE DISEASEPathogenesis of Pulmonary ArterialHypertension4/8/2017
15 PAH: a rapidly evolving disease 4/8/2017PAH: a rapidly evolving diseaseIPreclinical /no symptomsIISymptomatic /stableIIIProgression /decliningRV functionPulm. pressureLevelCardiac outputTherapeutic windowKey message: PAH is a rapidly evolving disease especially in the later stages (WHO Functional Class III).YearsMonthsTime
16 Severity of Pulmonary Hypertension Degree of diseaseMildModerateSevereMean PAP (mmHg)>55
17 NYHA/WHO classification of functional status DescriptionIPatients with pulmonary hypertension in whom there is no limitation of usual physical activity: ordinary physical activity does not cause increased dyspnoea, fatigue, chest pain or pre-syncopeIIPatients with pulmonary hypertension who have mild limitation of physical activity. There is no discomfort at rest but normal physical activity causes increased dyspnoea, fatigue, chest pain or pre-syncopeIIIPatients with pulmonary hypertension who have a marked limitation of physical activity. There is no discomfort at rest but less than ordinary activity causes increased dyspnoea, fatigue, chest pain or pre-syncopeIVPatients with pulmonary hypertension who are unable to perform any physical activity and who may have signs of right ventricular failure at rest. Dyspnoea and/or fatigue may be present at rest and symptoms are increased by almost any physical activityBarst RJ et al. J Am Coll Cardiol ; 43 (12 Suppl S): 40S–47S
18 4/8/2017PAH progresses rapidly if left untreated ... even in mildly symptomatic diseaseEarly diagnosis of PAH and early intervention improves survival prospects10075WHO class I – II (n = 30)Survival (%)5025Key message: Early diagnosis of PAH is important along with early intervention to improve survival prospects.ReferenceBrenot F. Primary pulmonary hypertension. Case series from France. Chest 1994; 105:33S–36S.WHO class III – IV (n = 75)1224364860728496MonthsBrenot F. Chest 1994; 105: 33S–36S18
19 Prognosis of Pulmonary Hypertension Survival years
21 PAH is still often diagnosed late: French National Registry 2002–2003 4/8/2017PAH is still often diagnosed late: French National Registry 2002–2003n = 67480%70%63%60%50%40%30%24%20%12%Key message: Since diagnosis of PAH is difficult, it is still often diagnosed late (predominantly at the stage of Functional Classes II and III).ReferenceHumbert M, Sitbon O, Chaouat A, et al. Pulmonary arterial hypertension in France: resultsfrom a national registry. Am J Resp Crit Care Med 2006; 173: 1023–30.10%1%0%Class IClass IIClass IIIClass IVHumbert M, et al. Am J Resp Crit Care Med 2006; 173: 1023–302121
22 Symptoms Symptoms may include: Dyspnea ● Fatigue Syncope ● Edema Dizziness ● Chest PainNon-specific nature of complaint can lead to:MisdiagnosisDelayed diagnosis ( It takes an average of 3 years from first symptoms to diagnosis )
23 Why is missed?Young patient with non specific symptom with “normal” CXR and EKGLack of practical therapy in the earlier era lead to therapeutic nihilismCo-mobid condition have similar symptoms
27 Diagnosis of PAH: a four-stage process 1. Suspicion of pulmonary hypertension2. Detection of pulmonary hypertension3. Pulmonary hypertension class identification4. Pulmonary arterial hypertension evaluationSymptoms and physical examinationScreening proceduresIncidental findingsElectrocardiogramChest radiographTransthoracic Doppler echocardiographyPulmonary function tests and arterial blood gasesVentilation/perfusion lung scanHigh-resolution CTSpiral CTPulmonary angiographyType (blood tests and immunology, HIV test, abdominal ultrasound)Exercise capacity (6MWD, peak oxygen consumption)Haemodynamics (right- heart catheterisation)Diagnosis 4 stageOn of exclusion until final confirmation via r heart cathWill inform whether idepathic or 2ary to other diease e.g. CTD, HIV2nd stage – treatment evolution opportunity inc early dx & early referral3rd stage – spirometry excludes other lung disease i.e. PAH secondary to COPD4th stage via PWP / PVR confirms right sided, artrerial bedGaliè N et al Eur Heart J 2004; 25: 2243–2278
28 Case 2006/03/1121 y/o femaleDyspnea and fatigue for about several monthsVisited LMD for help but in vainCondition get worse and worse----
39 PAH Therapy: Life style considerations Sodium restrictionAbstinence from smokingAvoid high altitude<4,000 feet above sea levelAvoid physical exertion in setting of pre- or frank syncopeAvoid pregnancyImmunization for illnesses (Influenza and pneumococcal vaccination)
42 Goals of TherapyAlleviate symptoms, improve exercise capacity and quality of lifeImprove cardiopulmonary hemodynamics and prevent right heart failureDelay time to clinical worseningReduce morbidity and mortality
43 PAH: Traditional Therapy PharmacologicCalcium channel blockerSupplemental O2Anticoagulation (INR≈ 2-3)Diuretics (excessive preload)DigoxinIV inotropes (low dose dobutamine,dopamine 1-2 mcg/kg/min)}Rx for RVfailure
45 Anticoagulation Studies only show benefit in iPAH patients Other PAH groups not as clearAim for INRBenefit thought to beReduction of in-situ thrombosisReduction DVT risk in low CO status
46 Oxygen Formal assessment of nocturnal and exertion oxygen levels Minimal added insult of hypoxic vasocontrictionAim to keep oxygen saturation > 90%Often impossible in large right to left shunt patients
48 FDA-Approved Agents for the Treatment of PAH Prostacyclin analogs (PA)EpoprostenolIloprostTreprostinilEndothelin-receptor antagonists (ERA)BosentanAmbrisentanPhosphodiesterase-5 inhibitors (PDE-I)SildenafilTadalafil
50 Endothelin is increased in IPAH and PAH associated with other Diseases Congenital Heart DiseaseIPAHSclerodermaP<0.001P<0.055P<0.001101048836Delta ET-LI (PV-RV) (pg/ml)IrET-1 (pg/ml)Concentration of ET-1(pg/ml)24621This slide is not designed to compare between trials. What these 3 studies show is that ET is key in each of these patient PAH populations.Stewart et al. demonstrated that in 27 patients with PAH, immunoreactive endothelin-1, measured by a specific radioimmunoassay, was significantly higher (3.5 +/- 2.5 pg/mL), than in normal subjects (1.45 +/ pg/mL), (p<0.001).Vancheeswara et al. demonstrated that serum levels of ET are significantly increased in patients with SSC compared with healthy controls (p<0.05). Furthermore, localized cutaneous (lC) SSc patients with PAH had significantly higher levels of ET than comparable patients with no PAH (p=0.025)Yoshibayasi et al. demonstrated significantly increased plasma ET concentrations in patients with CHD’s and PAH (n=18) compared to those without PAH (n=27); (p<0.001). The bar graph above depicts increments of plasma ET-like immunoreactivity concentrations sampled from right ventricle (RV) to pulmonary vein (PV).4Non-PPHPPHLcSSc Non-PAHLcSSc PAHNon-PHPHStewart et al., Ann Inter Med, Vancheeswaran et al., J. Rheum, Yoshibayashi et al., Circulation, 1991
51 Endothelin is a Key Pathogenic Mediator* ProliferationVascular Smooth MuscleFibroblastsVasoconstrictionDirect Or Via Facilitation Of OtherVasoconstrictor Systems (ReninAngiotensin System, Sympathetic)ETHypertrophyCardiac/VascularInflammation Vascular PermeabilityNeutrophil / Mast Cell ActivationPromotes Cellular Adhesion Cytokine ProductionFibrosisFibroblast Proliferation Extracellular Matrix Proteins Collagenase ProductionET is a mediator of diverse effects including vasoconstriction, vascular hypertrophy, fibrosis, and inflammation. These effects are deleterious and are thought to play a key role in PAH pathogenesis. ET is therefore thought to be a key pathogenic mediator in PAH.Details not included on slide:ET stimulates production of the following cytokines - IL-1b, IL-6, IL-8, TNFa, TGFb;promotion of cellular adhesion relates to increased neutrophil adhesion to endothelium and induction of expression of adhesion molecules.*Based on observations reported from in-vitro, in-vivo, or animal models. The clinical significance in humans is unknown.Clozel. Ann Med
52 Bosentan for PAHEndothelin receptor antagonist (ETA/ETB non selective)Indication – WHO group I - functional class II, III, IVDosage – 62.5 mg oral twice daily for 4 weeks then 125 mg oral twice dailyBosentan is an endothelin receptor antagonist indicated for the treatment of PAH, functional class II, III, and IV. The initial dosage of bosentan is 62.5 mg oral twice daily for 4 weeks. Patients are then titrated to 125 mg oral twice daily.
53 Bosentan for PAH: BREATHE Clinical Trial Change in 6-MWD (from Baseline to Week 16)-40-2020406080Bosentan (N = 144)Change from Baseline (meters)P =Placebo (N = 69)The BREATHE clinical trial was conducted by Rubin and colleagues. The trial was a double-blind, placebo-controlled, 16-week study in patients with PAH. Patients who received bosentan were titrated from 62.5 mg twice daily to 125 mg or 250 mg twice daily at week 4. A significant improvement in exercise capacity (6-MWD) was noted in patients treated with bosentan (N = 144) compared to patients treated with placebo (N = 69). The investigators also reported that bosentan was well tolerated in patients.BaselineWeek 4Week 8Week 1662.5 mg bid125 or 250 mg bid BosentanRubin, et al. N Engl J Med. 2002;346:
54 Long-term outcomes on bosentan 96%89%86%10090Bosentan80706069%Cumulative Survival (%)5057%Predicted (NIH)4048%3085% and 70% were on bosentan monotherapyat 12 and 24 mos, respectively20LO: She has the slide as hidden, so I did NOT edit or make any changes.1061218243036Time (Months）1691671631531132316Patients at riskEvent rate/year (exponential): 5.5%McLaughlin VV et al. Eur Respir J. 2005;25:54
55 Bosentan for PAH: EARLY Clinical Trial Study designRandomized, double-blind, placebo-controlled, six-month studyPatientsN = 177Mildly-symptomatic PAH (WHO group II)Study resultsPrimary study endpointsDecreased PVR (P < )No significant change in 6-MWD (P = 0.076)Secondary study endpointsDelayed time to clinical worsening (P = 0.018; 70% reduction in risk)SafetyConsistent with previous studiesPVR is expressed as the geometric means of the % of baseline at month 6. The geometric mean is used as the clinical interest focuses in a fold change from baseline. In other words, patients who change from 300 to 100 or from 450 to 150 have a 3-fold reduction, which is considered the same in the statistical analysis, regardless of having an absolute change of 200 and 300. This allows to account for baseline heterogeneity.After 6 months of treatment, mean PVR had decreased from baseline in the bosentan group to 83% and increased in the placebo group to 107%.Values at Month 6 expressed as a percent of baseline values showed a significant 22.6% reduction in PVR in the bosentan group compared with placebo.Imputation rules:Missing values for either PVR at Month 6 were replaced by carrying forward the last available post-baseline value in the treatment period unless one of the following applied:If the patient died during the treatment period or experienced a treatment-emergent adverse event that led to permanent discontinuation and resulted in death, the worst value (the worst between the absolute change and maximum value for PVR) was used to replace the missing value.If the patient was alive but otherwise experienced clinical worsening during the treatment period, the worst between the absolute change and maximum value for PVR was used to replace the missing value.Actual imputation:For three patients in each treatment group, missing values were substituted with worst values.Galie, et al. Lancet (9630):Valerio et al. Vasc Health Risk Manag. 2009;5:5555
56 Bosentan for PAH: EARLY Clinical Trial Change in PVR (from Baseline to Week 24)Decrease in PVR:Surrogate marker for delaying disease progressionP <% of Baseline PVR at Week 24 (geometric means)Treatment effect =- 22.6%Galie, et al. Lancet (9630):Valerio et al. Vasc Health Risk Manag. 2009;5:
57 Bosentan for PAH: EARLY Clinical Trial Change in 6-MWD (from Baseline to Week 24)25201511.2Placebo (N= 91)10P = 0.076Bosentan (N= 86)5Change in 6-MWD (meters)512weeks24weeksIn this slide, change in 6-MWD from baseline to week 24 is plotted. Patients treated with bosentan had a significant improvement in exercise capacity compared to patients taking placebo. The 6-MWD increased by 11.2 meters (on average) in the bosentan group and decreased by 7.9 meters (on average) in the placebo group. The average treatment effect was an improvement of 19.1 meters.10- 7.915Treatment effect =meters20Galie, et al. Lancet (9630):Valerio et al. Vasc Health Risk Manag. 2009;5:57
58 Bosentan for PAH: EARLY Clinical Trial Slide Template4/8/2017 5:05 AMTime to Clinical Worsening (from Baseline to Week 32)100P < 0.0280Placebo60BosentanEvent-Free Patients (%)4020A significant delay in the time to clinical worsening was observed with bosentan compared with placebo, which could be discerned before 16 weeks of treatment.The hazard ratio was 0.227, indicating that, overall, treatment with bosentan was likely to reduce the rate of clinical worsening by 77% of that experienced by placebo-treated patients.The date of clinical worsening was defined as the earliest among the date of death, the date of hospitalization due to PAH complications, and the date of symptomatic progression of PAH.The proportions of patients without clinical worsening were estimated at Weeks 4, 8, 12, 16, 20, 24, and 28 and at the last observed value (longest period of observation before a censoring or an event denoting clinical worsening) using the Kaplan-Meier method and displayed with 95% confidence intervals. Patients without clinical worsening were censored at the end of double-blind treatment plus 1 day. For some patients (recruited in early stage of study and following original protocol, which did not fix the treatment period to 6-months) double-blind treatment period lasted up to 32 weeks.48121620242832weeksPatients at risk (N)92908986848318779939287858483278015Galie, et al. Lancet (9630):Valerio et al. Vasc Health Risk Manag. 2009;5:5858
59 NTUH data Respiratory Medicine 2007 Bosentan have benefit effects on functional status, exercise capacity, right heart function and pulmonary function.Respiratory Medicine 2007
60 Ambrisentan for PAH Endothelin receptor antagonist (ETA selective) Indication – WHO group I - functional class II, IIIDosage – 5 mg and 10 mg oral daily60
61 Ambrisentan for PAH Change in 6-MWD (from Baseline to Week 12) ARIES 1 5060N = 202N = 19210 mg:+43.6 m5 mg:+49.4 m40255 mg:+22.8 m2.5 mg+22.2 m20Change from Baseline (meters)Ambrisentan in PAH: ARIES-1 and ARIES-2ARIES-1 and ARIES-2 were concurrent, double-blind, placebo-controlled studies of ambrisentan, a selective ETA receptor antagonist.The primary endpoint for each study was the change in 6-minute walk distance from baseline to week 12.The 6-minute walk distance increased in all ambrisentan groups; mean placebo-corrected treatment effects were 31 meters (p = 0.008) and 51 meters (p < 0.001) in ARIES-1 for 5mg and 10mg ambrisentan, and 32 meters (p = 0.022) and 59 meters (p < 0.001) in ARIES-2 for 2.5mg and 5mg ambrisentan.Improvements in time to clinical worsening (ARIES-2), World Health Organization functional class (ARIES-1), Short Form-36 score (ARIES-2), Borg dyspnea score (both studies), and B-type natriuretic peptide (both studies) were observed.These are the studies than led to FDA approval of ambrisentan.Placebo:-7.8 mPlacebo:-10.1 m-20-254812 weeks4812 weeksPlacebo-adjusted change at week 12:Ambrisentan 5 mg = 31 m; 10 mg = 51 mPlacebo-adjusted change at week 12:Ambrisentan 2.5 mg = 32 m; 5 mg = 59 mGalie, et al. Circulation. 2008;117:6161
62 Endothelin Receptor Antagonists Comparison of Agents BosentanAmbrisentanUse in pregnancyPregnancy category X (non-hormonal birth control method required)LFT elevationMonthly LFT monitoring required; ≥ 3x ULN in ~ 11% patients (pooled data from 16-week studies)≥ 3x ULN in 0.8% patients in 12-week studies, 2.8% patients in 1-year studiesPeripheral edema1.7% patients (placebo-adjusted; fluid retention/edema)6% patients (placebo-adjusted)Additional adverse eventsRespiratory tract infections, headache, fainting, flushing, low blood pressure, sinusitis, joint pain, irregular heartbeatNasal congestion, sinusitis, flushing, palpitations, nasopharyngitis, abdominal pain, constipationThis table compares the endothelin receptor antagonists, bosentan and ambrisentan. Both agents are pregnancy category X. Monthly LFT monitoring is required for both agents. However, the incidence of LFT elevation differs between the two medications. A greater than three times the upper level of normal increase in LFT has been reported in nearly 11% of bosentan-treated patients and 0.8% or 2.8% of ambrisentan-treated patients. The incidence of peripheral edema is approximately 1.7% for bosentan and 6% for ambrisentan. Adverse events reported during bosentan therapy include respiratory tract infections, headache, fainting, flushing, low blood pressure, sinusitis, joint pain, and irregular heartbeat. Adverse events reported during ambrisentan therapy include nasal congestion, sinusitis, flushing, palpitations, nasopharyngitis, abdominal pain, and constipation.Source: FDA-approved product labeling for individual agents.
63 Endothelin Receptor Antagonists Comparison of Drug-Drug Interactions BosentanAmbrisentanRitonavirRifampinCyclosporine AHormonal contraceptivesSildenafilTadalafil1GlyburideSimvastatin (+ other CYP3A-metabolized statins)CYP2C9 inhibitors (fluconazole, amiodarone)CYP3A inhibitors (ketoconazole, itraconazole, amprenavir, erythromycin, fluconazole, diltiazem)TacrolimusPhenytoin2Warfarin2Hormonal contraceptives3Omeprazole4Ketoconazole2,4This table compares the drug-drug interactions for bosentan and ambrisentan. Common to both medications are drug interactions with: ritonavir, rifampin, cyclosporine A, hormonal contraceptives, and ketoconazole.Source: FDA-approved product labeling for individual agents. 1) Barst, et al. J Am Coll Cardiol. 2009;54:S ) Galie, et al. Eur Heart J. 2009;30: ) Spence, et al. ATS. San Diego, CA. May 15-20, ) Harrison, et al. ATS. San Diego, CA. May 15-20, 2009.
66 Nitric Oxide/ PDE-5 Inhibitors Increase cGMP PDE-5 located in pulmonary circulationPDE-5 responsible for cGMP hydrolysis in the lungcGMP appears to regulate pulmonary vascular tone and growthPDE-5 inhibitor raises cGMP levelsNitric oxideL-ArgininecGMPLowersPApressureeNOSPDE-5IPDE-5What is the rationale for sildenafil or other PDE5 inhibitors?PDE5 is located PDE-5 located in pulmonary circulationPDE-5 is responsible for cGMP hydrolysis in the lungcGMP appears to regulate pulmonary vascular tone and growthPDE-5 inhibitor raises cGMP levelsGMPWharton J et al. Am J Respir Crit Care Med. 2005;172:
70 Phosphodiesterase-5 Inhibitors Comparison of Drug-Drug Interactions SildenafilTadalafilNitratesAlpha blockersAmlodipineRitonavirBosentan1HMG CoA reductase inhibitors1Phenytoin1Erythromycin1Ketoconazole1Cimetidine1Rifampin1Phenobarbital1Carbamazepine1Antihypertensive agentsKetoconazoleRifampinThis table compares the drug-drug interactions associated with sildenafil and tadalafil. Common to both medications are interactions with nitrates, alpha blockers, ketoconazole, ritonavir, rifampin, and bosentan.Source: FDA-approved product labeling for individual agents. 1) Galie, et al. Eur Heart J. 2009;30:
72 Smooth Muscle Cell relaxation Inhibits SMC proliferation ProstacyclinsPGI2SMCIPGScATPAdenylate cyclasecAMPAt the smooth muscle cell, PGI2 binds to the IP receptor. With the help of adenylate cyclase, cATP is converted to cAMP leading to smooth muscle cell relaxation, inhibition of smooth muscle cell proliferation, less clotting, and may alter apopotosis.Smooth Muscle Cell relaxationInhibits SMC proliferation? ApoptosisAnti-thrombotic
73 Prostenoid AnalogueInhalational Iloprost (Ventavis®) Approved for WHO Class III, IV patients with PAHProperties:Selective pulmonary vasodilatorVasodilatory potency similar to PGI2Exerts preferential vasodilation in well- ventilated lung regionsLonger duration of vasodilation than PGI2 (30-90 vs 15 min)
74 Ventavis® (iloprost) Inhalation Solution: Dosage and Administration Indicated for inhalation via the Prodose® AAD® system only2.5 mcg initial doseincrease to 5 mcg if 2.5 mcg dose is toleratedmaintain at maximum tolerable dose (2.5 mcg or 5 mcg)6-9 inhalations daily during waking hours; 8-10 minutes eachProstacyclin may soon be available in an inhaled formulation to eliminate the inconvenience and associated side effects of IV or SQ dosing. Inhaled iloprost is currently seeking approval at the FDA for the treatment of PAH in patients with NYHA class III or IV symptoms and is presently available in Europe. The dosing for inhaled iloprost (Trade name Ventavis) is via the breath-actuated nebulizer (ProDose®) in six to nine daily doses during the waking hours. The benefits seen with epoprostenol but limited by its dose route and regimen would be possibly extended to patients in this more convenient formulation.THIS MAY NEED TWEAKING!!!
75 Iloprost for PAH Composite Primary Endpoint at Week 12 Responders (% Patients)N = 203A study by Olschewski and colleagues measured the response to iloprost in 203 patients with PAH. After 12 weeks, the composite primary endpoint was significantly poorer in placebo-treated patients compared to iloprost-treated patients. The composite primary endpoint combined change in exercise capacity, functional class, and clinical deterioration.Olschewski, et al. N Engl J Med. 2002;347:322-9.
76 FLOLAN ® (epoprostenol): Synthetic prostenoid Sodium epoprostenol (Flolan)--short-lived relatively locally acting vasodilator, t1/2 3-5 minutes.Most potent effect -- cardiac output in patients with PAHResting heart rate, mean right atrial pressure, and a marked improvement in survival.Abrupt cessation can be fatalContraindicated in veno-occlusive disease
77 Epoprostenol for PAH Prostacyclin analog Indication – WHO group I - functional class III, IVAdministration – continuous IV infusion via central venous catheterDosage – ng/kg/minStorage – must keep medication cold with ice packs (stable for 8 hours at room temp)CADD pumpCentral lineEpoprostenol has a short half-life (3–5 minutes) and a rapid onset of action, reaching plasma steady-state concentrations within 15 minutes. It is stable at room temperature for only 8 hours after dissolved in buffer. Direct vasodilatation and inhibition of platelet aggregation are two major actions of epoprostenol.77
78 Epoprostenol vs. Conventional Therapy for IPAH Patient Survival Epoprostenol (N = 41)10080604020P = 0.003Conventional therapy (N = 40)Patient Survival (%)LO: This slide to replace her slide 8. Content is the same.NOTE: Only PAH clinical study to demonstrate a patient survival benefitEpoprostenol vs. Conventional Therapy in IPAH: SurvivalEpoprostenol therapy added to conventional therapy resulted in improvements in symptoms, hemodynamics and survival.Eight patients died in the 12 week study period, and all were on conventional therapy only (p = 0.003).Performance of the six-minute walk at baseline was an independent predictor of survival (p < 0.05). However, survival remained significantly improved in the epoprostenol group after adjustment for that variable (p < 0.002).Survival also remained significantly improved in the epoprostenol group (p < 0.001) after adjustment for the changes in stroke volume and in systemic vascular resistance in response to the short-term infusion of epoprostenol (the only significant differences between the groups).24681210WeeksBarst, et al. N Engl J Med. 1996;334:78
79 Subcutaneous Treprostinil (Remodulin ) SQ administrationLonger half-life than epoprostenolPre-mixedStable at room temperature
80 Treprostinil SC for PAH Change in 6-MWD (from Baseline to Week 12) 51015202530354036.1P = 0.0320Change from Baseline (meters)3.31.4Subcutaneous Treprostinil in PAH: 6MWD Change vs Dose (week 12)This 12 week, double-blind, placebo-controlled multicenter trial in 470 patients with PAH by Simonneau evaluated the improvement in exercise capacity associated with SQ infusions of treprostinil.6MW scores improved with treprostinil therapy, and was unchanged with placebo. The between treatment group difference in median six-minute walking distance was 16 meters (p = 0.006).The most common adverse events were: infusion site pain, infusion site reactions, infusion site bleeding/bruising, headache, diarrhea, nausea, rash, and jaw pain.The most benefit is at the highest doses, so if subcutaneous treprostinil is to be used, the dose should be aggressively titrated.< 5.0ng/kg/minng/kg/min8.2 – 13.8 ng/kg/min> ng/kg/minSimonneau, et al. Am J Respir Crit Care Med. 2002;165:800-4.80
81 Administration of Treprostinil Subcutaneous AdministrationContinuous infusion using ambulatory pump designed for SC infusionsSelf-inserted SC catheterStore at room temperatureChange medication every 48 hours (half-life > 4 hours)LimitationsRequires capable patientPossible pain (~ 85% of patients), erythema, and induration at infusion siteMixed results with treatments for pain (ice or heat, capsaicin, lidocaine patches, collagenase, NSAIDs, gabapentin, pregabalin, transdermal gels, low-dose narcotics)Mini-MedCADDms3LO: Reworked her slide 16, basically same content.Infusion site reaction81
83 Route of Administration Comparison of AgentsAgentRoute of AdministrationAdverse EventsEpoprostenolContinuous IV infusionHeadache, jaw pain, flushing, nausea, diarrhea, skin rash, musculoskeletal painIloprostInhalationHeadache, cough, flushing, jaw painTreprostinil» Subcutaneous» IV» Inhalation*» Pain and erythema at injection site, headache, nausea, diarrhea, rash» Headache, jaw pain, flushing, nausea, diarrhea, skin rash, musculoskeletal pain» Cough, headache, flushing, throat irritation, nauseaBosentanOralHepatotoxicity (LFT elevation ≥ 3x ULN ~ 11%), peripheral edema, anemiaAmbrisentanHepatotoxicity (LFT elevation ≥ 3x ULN ~ 2.8%), peripheral edemaSildenafilHeadache, flushing, dyspepsia, epistaxisTadalafilHeadache, dyspepsia, back pain, myalgia, flushingThe table compares the individual agents in terms of route of administration used and adverse events reported. Epoprostenol is administered via continuous IV infusion. Iloprost is administered via inhalation (ultrasonic nebulizer). Treprostinil can be delivered subcutaneously, intravenously, or through inhalation. Adverse events common to these three agents include headache, jaw pain, and flushing. Injection site reactions are also possible for epoprostenol and treprostinil IV. Bosentan and ambrisentan are both administered orally. Bosentan has a greater incidence of LFT elevation compared to ambrisentan. Peripheral edema has been reported with both medications. Sildenafil and tadalafil are both administered orally. Headache, flushing, and dyspepsia have been reported with both agents.Adapted from McLaughlin, et al. J Am Coll Cardiol. 2009;53: *Benza, et al. ATS. San Diego, CA. May 15-20, 2009.
92 But………. The patient suffered from progressive dyspnea since 2010/06 Syncope (+)Screening cardiac echoEstimated PAP > 200 mmHgAdmitted to ICU on 2010/07/02
93 Critical PAH PatientCardiac arrest occurs frequently in critically ill patients with severe PAH.Survival 90 days post-cardiac arrest was only 6 percent.
94 PH and RV Failure: The Downward Spiral RVEDPHYPOTENSIONAdaptation of Price lC et al. Crit Care. 2010;14:R169
95 Management Principles Optimal volume status: avoid filling if RV volume overload, diuretics if necessaryAugment COReduce PVR :a) use pulmonary vasodilatorsb)treat reversible factors that may increase PVRMaintain adequate systemic pressure: Keep PVR well below SVR; use pressors if necessary
96 Course of hospitalization ICUMilrinone infusionDiuretics for symptomBosentan 125mg bid poIloprost 5 mg q4h inhalationSildenafil 25mg tid poSymptom improved graduallyShift iloprost to prn useDischarge on 2010/07/13Bosentan 125mg bid + Sildenafil 25 mg tid + iloprost 5mg inhalation prn
97 Adaptation of Price lC et al. Crit Care. 2010;14:R169 Mechanical DevicesDevicesindicationCommentsRV-assist devicesUsed in primary RV dysfunction and have been used with coexisting PHPulsatile devices may cause pulmonary microcirculatory damage in PH . A pumpless "lung assist" device has been used in patients bridging to transplant.Extracorporeal membrane oxygenationUsed in severe PH as a bridge to lung transplant and after endarterectomy or massive PE.Intraaortic balloon counterpulsationUsed for RV failure after CPB and transplantationImproves CO by augmenting left coronary flow rather than by direct RV effectsAdaptation of Price lC et al. Crit Care. 2010;14:R16997
98 Case 55 y/o male Progressive dyspnea, leg edema and hypotension Pulmonary hypertension was notedTransfer to CCU under the impression of PAH with right heart failure complicated with shock and multiple organ failure
100 Goal-Directed Therapy Diagnosis of PAHvasoreactivity test negativeBaseline exam and 3-6 monthly re-evaluation to assess treatment goals(Clinically stable, functional class II, 6-MWD > 400 meters, RAP/CI normal)Treatment goals NOT metTreatment goals metStart ERA or PDE-IContinue treatmentAdd ERA or PDE-IContinue treatmentLO: Editing and other changes to slide. This is similar to a slide we had in the source deck. I merged the two slides. She adapted information from the Hoeper article, so I noted that in the citation.Parenteral PA and/or enrollment in clinical trialsContinue treatmentUrgent lung transplantationAdapted from: Hoeper, et al. Eur Respir J. 2005;26:
101 Improved Patient Survival With Goal-Directed Therapy 1.0Treatment group( )0.8Historical control group( )0.6Cumulative Patient SurvivalExpected survival0.4P = Treatment Vs. historicalP < Treatment Vs. expected0.261218243036MonthsPatients at risk (N)8967836469476138463143233720Treatment groupHistorical control groupHoeper, et al. Eur Respir J. 2005;26:
102 Combination therapy: frequently utilised strategy in PAH treatment 2017/4/8Combination therapy: frequently utilised strategy in PAH treatmentBackground therapy only (8%)Triple combination (9%)Monotherapy (47%):13% bosentan\ambrisenten13% sildenafil8% epoprostenol2% sitaxentan4% calcium channel blockerDual combination (36%):Key message: Because of the challenges in PAH, combination therapy is frequently and increasingly being used to treat the disease.8% bosentan and sildenafil3% bosentan and epoprostenol3% bosentan and iloprost8% epoprostenol and sildenafil2% sildenafil and iloprostReferenceMcGoon MD, Barst RJ, Doyle RL, et al. Reveal registry: treatment history and treatment at baseline. Chest 2007; 132: 631S (Abstract).Patients with PAHn=1226McGoon, et al. Chest 2007; 132: 631S
104 Bosentan + Sildenafil Patients Dosing Results P Mathai et al. 45 B 125 mg bid + S mg tid6 MWD + 46 mNYHA improved in 5 of 130.05NSHoper et al.9B 125 mg bid +S 25-50mg tid6MWD +115 mVO2 max +3.4 ml/min/kg<0.0070.006European4996Bosentan vs bosentan+sildenafilSafety reports were similarEarly trial29S + Bvs S + PlaceboLower PVR 20.4%6MWD +17M<0.050.855
105 Bosentan + Prostacyclin CombinationPatientsResultpHoper et alBosentan+iloprost/beraprost206 MWD +45 M<0.05Channick et al.Bosentan+treprostinil ih116MWD +67MPAP-10%PVR-26%0.010.0410.052Benza RL et al.SC remodulin + Bosentan196 MWDBrog dyspneaPAP0.0010.02<0.001BREATH-2Bosentan + Epo33PVR: 36 % vs 23 %NSSTEPBosentan+ iloprost676MWDDelayed TCW0.0510.022
106 Prostacyclin+ PDE inhibitors CombinationPatientsResultpGhofrani et alIloprost+sildenafil146 MWD +90 M0.002Goberg-Matiland M et al.Treprostinil sc + sildenafilTET time +42%0.049Ruiz MJ et al.Prostanoids+ sildenafil206 MWD+79m (1 year)MWD +105m (2years)NYHA improved<0.005Simonneau G et al.Epo+sildenafil2676MWD+26M TCW delay0.00880.012
107 CASE 338 y/o maleIPAH was diagnosed at 2008/8Bosentan used since 2008/8/19Add Iloprost since 2010/4/16
108 6 minute walk test 2008/08/19 Bosentan 2010/4/16 Iloprost 375m 378m
115 NCKUH Team MembersPAH- specific Cardiologist (PAH clinic, 24 hr on call)Special nurse (24 hr on call)RadiologistPharmacistDieticianCritical care team (24 hr on call)ECMO team (24 hr on call)Lung transplant teamLab
116 Core member trainingWhole membertrainingMultiple centereducation program