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CHOOSING SPECIFIC THERAPEUTIC STRATEGIES IN MANAGEMENT OF PULMONARY ARTERY HYPERTENSION NGUYEN THI DUYEN VIETNAM NATIONAL HEART INSTITUTE Specific therapy according to the clinical classification Specific drugs for which patient? Group 1: Primary vessel problem (pulmonary arterial hypertension, PAH) Group 2: Problems with left heart & valves Group 3: Problems with lungs/hypoxia Group 4: Thromboembolic In selected patient Group 5: Anything else e.g sarcoid Fuso et al Frontiers in Pharmacology | Pharmacotherapy of Respiratory Diseases , April 2011 | Volume | Article 21 IMPACTS OF SPECIFIC THERAPY The comparision of survive of PAH patients before (NIH) and after (French and REVEAL) specific therapy Reduce morbidity and mortality Reduce pulmonary artery pressure Reduce pulmonary vascular resistance Improve RV function Improve CI BEFORE RV failure becomes irreversible Maintain adequate preload Maintain SVR Avoid acidosis, hypercapnia, hypothermia, hypoxia CASE - STUDY Name A 53 yrs male patient History No risk of CVDs and no usage any drugs for a long time months before going to meet the medical staff due to fatigue and lose appetite feeling, dyspnea on exertion Exam Exertional dyspnoea, WHO-FC III No cyanosis and clubbing, SpO2: 90% 6MWT = 400m Blood pressure: 160/80 mmHg Loud S2 at cardiac base Clear lung sound Mild hepatomegaly, mild ankle edema CASE - STUDY CXR ECG Echo Body plethysmofraphy Central PA dilatation Pruning of peripheral blood vessels Sinus rhythm Right axis deviation Right ventricular hypertrophy T wave inversion at V2 – V5 A large secondary ASD (29mm), left to right shunt Septal intraventricular reverse movement LVEDD: 36mm, EF (4C-simpson): 46%, E/A > 1, E/e’ >10 RV: 36mm, PV: 49mm, TAPSE: 24mm, systolic PAP: 90mmHg Normal CASE - STUDY Blood count Biochemistry Data Value Position RBC (T/l) 5.18 Ure (mmol/l) 7.8 Hb (g/l) 170 Creatinin (mmol/l) 100 Height (cm) 160 SVC Hct (l/l) 0.47 Protein (g/l) 75.1 Weigjt (kg) 47 IVC MCV (fL) 91.5 Albumin (g/l) 37.6 BSA (m2) 1.46 SRA WBC (G/l) 8.7 SGOT (U/l) 140 Hb (g/l) 160 MRA NEUT% 44.2 SGPT (U/l) 108 Ht (%) 52 IRA PLT (G/l) 214 Bil total (µmol/l) 20.4 Qp 3.02 ORV PTs 12.4 Bil indirect (µmol/l) 9.1 Qs 4.77 RV INR 1.00 lipid (mmol/l) normal Qp/Qs 0.63 MPA Immune body tests Negative a.uric (µmol/l) 563 SVR 17.41 LPA HbsAg Negative Troponin T (ng/ml) 0.005 PVR 24.34 RPA HIV Negative Pro-BNP (pmol/l) 540 Rp/Rs 0.47 LV Ferritin (ng/ml) 1266 AO Pressure (mmHg) Saturation oxygen (%) 70.9 12/0/4 127/0/42 127/55/80 67.7 149/56/87 90 CASE - STUDY CASE STUDY Diagnose: PAH associated with ASD - hypertension How to choose a specific therapectic strategy in treatmentfor this patient ? Factors for drug selection Dependent on the patient  Make sure PAH diagnose  Approval status (WHO FC)  Disease severity  Vaso - responsiveness  Patient preference: economic Dependent on the drugs impacts Mechanism, routine, dose, advantage, side – effects Rapidity of oral effectiveness (PDE5i) Potential Interactions with other drugs (nitrates) Availability Cost Dependent on the physician Experience Literature Clinical judgment Barst RJ, et al J ACC 2009 Assess the patient’ elements Dependent on the patient  Make sure PAH diagnose  Approval status (WHO FC)  Disease severity  Vaso - responsiveness  Patient preference: economic Barst RJ, et al J ACC 2009 BEST DRUGS FOR WHO CLASS II & III, IV PATIENTS Combination therapy  Benefit  Increased efficacy  Decrease side effects by use of smaller doses  Simplicity by shifting from IV to oral therapy  The drug groups had been combined as add on therapy in many clinical trials with good results though sometimes conflicting  The role of combinations though stressed on in the guidelines for severe cases need further more data to confirm its benefit Limitations:  Lack of survival benefit  Cost of therapy  Treatment failure  Drug interactions  Toxicity and side effects Combination therapy Concurrent Drug High risk group + Drug Sequential Drug + Drug Low risk group Recommendations for efficacy of drug combination therapy-2015 ESC/ERS Initial drug combination therapy Sequential drug combination therapy- Overview of Combination Therapy Trials Combination Therapy: Ongoing or Recently Completed EARLY Bosental and Sildenafil RCT 29 + 19 m STEP Iloprost inhalation and Bosentan RCT 67 + 26 m COMBI Iloprost/Beraprost and Bosentan RCT 40 NS BREATHE -2 Bosentan and IV Epoprostenol RCT 33 NS PACES Sildenafil and IV Epoprostenol RCT 267 + 26 m TRIUMPH1 Bosentan + Inhaled Treprostinil RCT 235 + 20 m Recommendations for efficacy of drug combination therapy in acute PAH - 2015 ESC/ERS  Low-dose dobutamine (up to 10 μg/kg/min) improves RV function and may be useful in patients with pulmonary vascular dysfunction, although it may reduce SVR (Low-moderate-quality evidence, a WEAK recommendation)  Dopamine may increase tachyarrhythmias and is not recommended in the setting of cardiogenic shock (STRONG recommendation based on high-quality evidence level)  PDE III inhibitors improve RV performance and reduce PVR in patients with acute pulmonary vascular dysfunction, although systemic hypotension is common, usually requiring coadmininstration of pressors (Moderate-quality evidence, a STRONG recommendation)  Inhaled milrinone may be useful to minimize systemic hypotension and V/Q mismatch in pulmonary vascular dysfunction (Based on low-quality evidence, a WEAK recommendation)  Levosimendan may be considered for short-term improvements in RV performance in patients with biventricular heart failure (low-quality evidence, a WEAK recommendation) Price LC et al Critical Care 2010, 14:R169 doi:10.1186/cc9264 DOSING & COST OF PAH TREATMENT OPTIONS Pulmonary arterial hypertension: Bridging the gap between efficacy, quality of life, and cost-effectiveness EVALUATION OF RESPONSE TO THERAPY  Physical exam – JVP, murmurs, edema, ascites, liver enlargement, hypotension  Functional – history (WHO or NYHA functional classification, minute walk, exercise test  Labs - BNP, renal and hepatic function  Echocardiography – RV function, pericardial effusion  Right heart catheterization – RAP, CI PRINCIPLES OF PAH TREATMENT PARADIGM SHIFT IN PAH MANAGEMENT PRINCIPLES OF DRUG MANAGEMENT  Patients should undergo cardiac catheterization before initiating therapy  Like HF, cancer, etc- the mantra is :  Treat quickly  Obtain baseline assessments of the disease to know whether treatments are effective  Hit hard  Test Vasoreactivity  Use upfront combos rather than wait & rescue- even in relatively stable patients for better long term outcomes  Larger RCT’s of triple upfront therapy needed  Reactive patients should be treated with calcium channel blockers  Nonreactive patients should be offered other therapies  Reassess at weeks; patients who don’t respond are unlikely to respond with longer exposure  Ineffective treatments should be substituted rather than new added  Patients who fail all treatments should be considered for lung transplantation  Only the addition of sildenafil to epoprostenol has been shown to be efficacious Pulmonary Hypertension and its management Recommendations for Specific pAH subsets PAH subsets Pediatric PAH Recommendation Class/Level A PAH-specific therapeutic algorithm is recommended in paediatric PH patientsd, similar to that used in adults I/C Combination therapy should be considered in paediatric PH patients IIa/C Bosentan is recommended in WHO-FC III patients with Eisenmenger I/B syndrome PAH - CHD Other ERAs, PDE-5is and prostanoids should be considered in patients with Eisenmenger syndrome IIa/C The use of CCBs is not recommended in patients with Eisenmenger syndrome III/C 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension , European Heart Journal (2016) 37, 67–119 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension , European Heart Journal (2016) 37, 67–119 Recommendations for Specific pAH subsets PAH subsets PAH- CTD Recommendation Class/Leve l In patients with PAH associated with CTD, the same treatment algorithm as for patients with IPAH is recommended I/C  Treatment of patients with CTD and PAH should follow the same treatment algorithm as in IPAH  Subgroup analysis of patients with SSc enrolled in the RCTs per- formed with bosentan, macitentan, sildenafil, riociguat and subcuta- neous treprostinil have shown favourable effects  Continuous i.v epoprostenol therapy was shown to improve ex- ercise capacity, symptoms and haemodynamics in a 3-month RCT in SSc-PAH.222  Treprostinil, an analogue of epoprostenol suitable for continuous subcutaneous administration, has modest effects on symptoms and hemodynamics in PAH PAH associated with portal hypertension should be referred to centres with expertise in managing both conditions PAH- PoPH • • • Anecdotal reports suggest that ERAs, PDE-5is, sGC stimulators and prostacyclin analogues may be used in this patient population This includes potentially hepatotoxic drugs such as bosentan, but it should be noted that this compound tends to accumulate in patients with severely impaired liver function (i.e Child – Pugh class B and C) Newer ERAs (ambrisentan, maxcitentan) have a theoretical advantage over bosentan, as the risk of drugassociated liver toxicity is lower 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension , European Heart Journal (2016) 37, 67–119 I/C Recommendations for Specific pAH subsets PAH subsets Recommendation Class/Level In patients with PAH associated with HIV infection, the same treatment algorithm used for patients with PAH should be considered, taking into consideration co-morbidities and drug– drug interactions IIIa/C • • • PAH- HIV • • • PAH- CTEPH Non-responders to acute vasodilator challenge and thus should not receive CCBs Experiences with prostacyclin in HIV-associated pulmonary hyperten- sion are based on smaller, uncontrolled trials Iloprost- treated patients showed a significant improvement in exercise capacity, as measured by a six-minute walk test, as well as in NYHA classification The major side effect of this therapy is an elevation of liver enzymes The use of bosentan in patients suffering from HCV/HIV co-infection has to be considered carefully Sildenafil (RevatioTM) was the first phosphodiesterase-5 inhibitor to be approved for the therapy of pulmonary hypertension by the FDA last year, and at the beginning of this year by the EMEA in Europe RevatioTM is also approved for use in HIV-associated pulmonary hypertension, although combination with protease inhibitors is not recommended because of possible interactions due to the same meta bolic pathway • Riociguat is recommended in symptomatic patients who have been classified as having persistent/recurrent CTEPH after surgical treatment or inoperable CTEPH by a CTEPH team including at least one experienced PEA surgeon • • The dual endothelin antagonist bosentan decreased in PVR and an increase in the 6MWD was not met However, an oral sGC stimulator, riociguat, was administered to 261 of 446 screened patients with non-operable CTEPH or persistent/recurrent PH after PEA for 16 weeks and led to a mean increase of 39 m in the 6MWD and to a least squares mean differrence of 246 dyn.cm.s25 in PVR; the time to clinical worsening remained unchanged HIV-associated Pulmonary Hypertension Georg Friese, Mirko Steinmüller and Ardeschir Ghofrani I/B TAKE HOME MESSAGE  Pulmonary HTN is one of the difficult therapeutic problem in CV medicine  The recent understanding of the complicated pathophysiology of the disease has added many new drugs  Choosing specific therapeutic strategy depends on drugs, patient and physican  Shift to the FDA approved drugs ( prostenoid, ERA, NO pathway active) in early patients and combination therapy may be used in severe , non-responsive and progressive cases  Benefits from therapy need more than 6MWD THANK YOU FOR YOUR ATTENTION !