CHOOS OOSING ING SPECIFIC IFIC THERAPEUTIC RAPEUTIC STRATEGIES TEGIES IN MA MANAGE NAGEMENT MENT OF F PULMON MONARY ARY ARTERY TERY HYP YPERTENSION RTENSION NGUYEN EN THI DUYEN VIE IETNAM NATI TIONA NAL HEART RT IN INSTITU ITUTE
Spec ecific ific th ther erapy apy accord ording ing to to th the e clinical nical classification ssification 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 In selected Group 4: Thromboembolic patient Group 5: Anything else e.g. sarcoid Fuso et al. Frontiers in Pharmacology | Pharmacotherapy of Respiratory Diseases , April 2011 | Volume 2 | 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. No risk of CVDs and no usage any drugs for a long time 2 months before going to meet the medical staff due to fatigue and lose appetite feeling, History dyspnea on exertion. Exertional dyspnoea, WHO-FC III. No cyanosis and clubbing, SpO2: 90% Exam 6MWT = 400m Blood pressure: 160/80 mmHg Loud S2 at cardiac base. Clear lung sound Mild hepatomegaly, mild ankle edema.
CASE - STUDY CXR Central PA dilatation Pruning of peripheral blood vessels Sinus rhythm ECG Right axis deviation Right ventricular hypertrophy T wave inversion at V2 – V5 A large secondary ASD (29mm), left to right shunt. Echo 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 Body Normal plethysmofraphy
CASE - STUDY Blood count Biochemistry Position Pressure Saturation Data Value (mmHg) oxygen RBC (T/l) 5.18 Ure (mmol/l) 7.8 (%) Height (cm) 160 Hb (g/l) 170 Creatinin (mmol/l) 100 SVC 70.9 Hct (l/l) 0.47 Protein (g/l) 75.1 Weigjt (kg) 47 IVC MCV (fL) 91.5 Albumin (g/l) 37.6 BSA (m 2 ) 1.46 SRA WBC (G/l) 8.7 SGOT (U/l) 140 Hb (g/l) 160 MRA 12/0/4 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 127/0/42 INR 1.00 lipid (mmol/l) normal Qp/Qs 0.63 MPA Immune Negative a.uric (µmol/l) 563 SVR 17.41 LPA 127/55/80 67.7 body tests PVR 24.34 RPA HbsAg Negative Troponin T (ng/ml) 0.005 Rp/Rs 0.47 LV HIV Negative Pro-BNP (pmol/l) 540 Ferritin (ng/ml) 1266 AO 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. Dependent on the drugs impacts Approval status (WHO FC). Mechanism, routine, dose, advantage, side – effects. Rapidity of oral effectiveness (PDE5i). Disease severity. Potential Interactions with other drugs (nitrates). Vaso - responsiveness. Availability. Patient preference: economic. Dependent on the physician Cost. 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
Factors for drug selection MAKE SURE PAH DIAGNOSE
MAKE SURE PAH DIAGNOSE Heart Fail Rev, published onine: 29 December 2015
PAH DETERMINANTS OF RISK Lower Risk Determinants of Risk Higher Risk Clinical evidence of No Yes RV failure Gradual Progression Rapid II, III WHO class IV Longer (>400 m) 6MW distance Shorter (<300 m) Minimally elevated BNP Very elevated Pericardial effusion, Minimal RV dysfunction Echocardiographic findings significant RV dysfunction Normal/near normal Hemodynamics High RAP, low CI RAP and CI McLaughlin VV, McGoon MD. Circulation. 2006;114:1417-1431.
Factors for drug selection Dependent on the drugs impacts Mechanism, routine, dose, advantage, side – effects. Potential Interactions with other drugs (nitrates). Approval Availability. Cost. Barst RJ, et al. J ACC 2009
THREE KEY PATHWAYS FOR PAH THERAPY Physician Referral and Consultation (800) 266-0366 Humbert M, et al. N Engl J Med. 2004; 351: 1425 - 1436
SPECIFIC DRUG PATHWAYS AND DRUGS
FDA – PPROVED MEDICINES FOR PAH
PROSTACYCLIN THERAPY Drugs Actions Study Routine Dose Positive results Disadvantage Short half-life (6mins) Design: Open- IV Symptoms, 6MWD Flushing, headache, diarrhea, label Initial : 4-8ng/kg/min Epoprostenol Permanent Exercise tolerance jaw discomfort. No: 81 Ultimate : 40- (Flolan) central venous Hemodynamics Difficult to manage follow-up Indication: 60ng/kg/min catheter Short-term survival. Expensive ($ 25.000- WHO FC III,IV 125.000/year) Initial : 2.5 µg Vasodilation Design: Double- Short half-life of <30 min If well tolerate: 5 µg Antiproliferative blind Flushing and cough If 5 µg not tolerated, 6MWD Antipatelet No: 203 Peripheral edema Iloprost Inhalation reduce to 2.5µg & Exercise tolerance Increase NO Indication: Nauseate (Ventavis) maintain. Improved dyspnea Decrease ET -1 WHO FC III,IV 6-9 inhalations daily Inotrope during walking hours. Design: Double- 6MWD blind Longer half-life (4hours) Intravenously 75 to 150 ng/kg per Improved No: 470 Site pain. Treprostini Subcutaneously min hemodynamics Indication: Headache, Dizzy (Remodulin) Inhalation Improved dyspnea WHO FC II-IV Rash Therapeutic and clinical risk management of PAH, download from http://www.dovepress.com
ENDOTHELIN ANTAGONIST THERAPY Drugs Stuty Action Routin Dose Positive results Disadvantage Bosebtan BREATHE-1 A nonselective Oral Initial dose: 62.5 mg BD for 6MWD - Half-life: 5.4h - (Tracleer) ET receptor first month Improved dyspnea - Liver toxicity - blocker, increased to 125 mg BD Delayed clinical - Teratogen - worsening - Anemia - Edema - Have interactions with Ambrisentan ARIES-1 ET-A-selective Oral once daily at a 5-mg dose, 6MWD - warfarin that require careful (Letaris) ARIES-2 endothelin 9 – 15h can be increased to 10 mg if Delayed clinical - monitoring of the INR receptor blocker the drug is well tolerated. worsening - Contraindicated in patients Improved - on cyclosporine or glyburide hemodynamics concurrently (*)Currently approved only in Sitaxsentan ETA-selective Oral once daily at a 100 mg dose. 6MWD the European Union, Canada, (*) (Thelin) endothelin and Australia receptor blocker Therapeutic and clinical risk management of PAH, download from http://www.dovepress.com
PHOSPHODIESTERASE INHIBITORS THERAPY Drugs Stuty Action Routin Dose Positive results Disadvantage SUPER-1 Selective Oral 20 mg three times daily, Well tolerated - Can have hypotension & - Double- phosphodiesterase 3.7h but dosages as high as 80 overall edema formation blind E5 inhibitor: mg three times daily No blood level - Should not be given with - No: 278 - Vasodilation have been used safely, monitoring nitrates, caution with Sildenafil Indication: - Antiproliferative and in some patients No LFT alpha blockers - (Revatio) Class II-IV abnormalitie.s - No delay in clinical 6MWD worsening end point - Improved - Headache, flushing, - dyspnea dyspepsia, epistaxis, Improved visual disturbance. long-acting selective Oral The effective dose was 5- - hemodynamics - Nasal congestion PDE5 inhibitor 18h 40 mg once daily. Tadalafil Therapeutic and clinical risk management of PAH, download from http://www.dovepress.com
FUT UTUR URE DIRE RECTIO TIONS: NS: POT OTENT NTIAL IAL NE NEW TH THERA RAPEUT PEUTIC IC TAR ARGE GETS TS NEW PERSPECTIVES FOR TREATMENT OF PH PULMONARY ARTERIAL HYPERTENSION CELLULAR PROCESSES The Journal of Heart and Lung Transplantation, Vol 35, No 6, June 2016 Newman JH. Circulation 2004;109:2947-2952
FUT UTUR URE DIRE RECTIO TIONS: NS: POTE TENTIA TIAL L NEW TH THERA RAPEUT PEUTIC IC TAR ARGE GETS TS www.nature.com/nrcardio , SEPTEMBER 2011 | VOLUME 8
Choosing a specific therapeutic strategy Dependent on the physician Experience. Literature. Clinical judgment. Barst RJ, et al. J ACC 2009
TREATMENT ALGORITHM FOR PAH Badesch D. B. et.al. Chest 2007;131:1917-1928
CHOICE OF INITIAL PAH THERAPY Baldi et al , Therapeutics and Clinical Risk Management 2014:10
BEST DRUGS FOR WHO CLASS II & III, IV PATIENTS
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