CHOOS OOSING ING SPECIFIC IFIC THERAPEUTIC RAPEUTIC STRATEGIES - - PowerPoint PPT Presentation

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

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 Group 5: Anything else e.g. sarcoid

In selected patient

Fuso et al. Frontiers in Pharmacology | Pharmacotherapy of Respiratory Diseases , April 2011 | Volume 2 | Article 21

Spec ecific ific th ther erapy apy accord

• rding

ing to to th the e clinical nical classification ssification

Specific drugs for which patient?

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 2 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 Central PA dilatation Pruning of peripheral blood vessels ECG Sinus rhythm Right axis deviation Right ventricular hypertrophy T wave inversion at V2 – V5 Echo 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 Body plethysmofraphy Normal

CASE - STUDY

Blood count Biochemistry RBC (T/l) 5.18 Ure (mmol/l) 7.8 Hb (g/l) 170 Creatinin (mmol/l) 100 Hct (l/l) 0.47 Protein (g/l) 75.1 MCV (fL) 91.5 Albumin (g/l) 37.6 WBC (G/l) 8.7 SGOT (U/l) 140 NEUT% 44.2 SGPT (U/l) 108 PLT (G/l) 214 Bil total (µmol/l) 20.4 PTs 12.4 Bil indirect (µmol/l) 9.1 INR 1.00 lipid (mmol/l) normal Immune body tests Negative a.uric (µmol/l) 563 HbsAg Negative Troponin T (ng/ml) 0.005 HIV Negative Pro-BNP (pmol/l) 540 Ferritin (ng/ml) 1266

Data Value Height (cm) 160 Weigjt (kg) 47 BSA (m2) 1.46 Hb (g/l) 160 Ht (%) 52 Qp 3.02 Qs 4.77 Qp/Qs 0.63 SVR 17.41 PVR 24.34 Rp/Rs 0.47 Position Pressure (mmHg) Saturation

• xygen

(%) SVC 70.9 IVC SRA MRA 12/0/4 IRA ORV RV 127/0/42 MPA LPA 127/55/80 67.7 RPA LV AO 149/56/87 90

CASE STUDY

Diagnose: PAH associated with ASD - hypertension

How to choose a specific therapectic strategy in treatmentfor this patient ?

CASE - STUDY

Factors for drug selection

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

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.

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

Heart Fail Rev, published onine: 29 December 2015

MAKE SURE PAH DIAGNOSE

Lower Risk Determinants of Risk Higher Risk No Clinical evidence of RV failure Yes Gradual Progression Rapid II, III WHO class IV Longer (>400 m) 6MW distance Shorter (<300 m) Minimally elevated BNP Very elevated Minimal RV dysfunction Echocardiographic findings Pericardial effusion, significant RV dysfunction Normal/near normal RAP and CI Hemodynamics High RAP, low CI

McLaughlin VV, McGoon MD. Circulation. 2006;114:1417-1431.

PAH DETERMINANTS OF RISK

Factors for drug selection

Barst RJ, et al. J ACC 2009

Dependent on the drugs impacts

Mechanism, routine, dose, advantage, side – effects. Potential Interactions with other drugs (nitrates). Approval Availability. Cost.

Physician Referral and Consultation (800) 266-0366

THREE KEY PATHWAYS FOR PAH THERAPY

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 Epoprostenol (Flolan) Vasodilation Antiproliferative Antipatelet Increase NO Decrease ET -1 Inotrope Design: Open- label No: 81 Indication: WHO FC III,IV IV Permanent central venous catheter Initial : 4-8ng/kg/min Ultimate : 40- 60ng/kg/min Symptoms, 6MWD Exercise tolerance Hemodynamics Short-term survival. Short half-life (6mins) Flushing, headache, diarrhea, jaw discomfort. Difficult to manage follow-up Expensive ($ 25.000- 125.000/year) Iloprost (Ventavis) Design: Double- blind No: 203 Indication: WHO FC III,IV Inhalation Initial : 2.5 µg If well tolerate: 5 µg If 5 µg not tolerated, reduce to 2.5µg & maintain. 6-9 inhalations daily during walking hours. 6MWD Exercise tolerance Improved dyspnea Short half-life of <30 min Flushing and cough Peripheral edema Nauseate Design: Double- blind No: 470 Indication: WHO FC II-IV Intravenously Subcutaneously Inhalation 75 to 150 ng/kg per min 6MWD Improved hemodynamics Improved dyspnea Longer half-life (4hours) Site pain. Headache, Dizzy Rash Treprostini (Remodulin)

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 (Tracleer) BREATHE-1 A nonselective ET receptor blocker, Oral Initial dose: 62.5 mg BD for first month increased to 125 mg BD

• 6MWD
• Improved dyspnea
• Delayed clinical

worsening

• Half-life: 5.4h
• Liver toxicity
• Teratogen
• Anemia
• Edema
• Have interactions with

warfarin that require careful monitoring of the INR

• Contraindicated in patients
• n cyclosporine or glyburide

concurrently (*)Currently approved only in the European Union, Canada, and Australia Ambrisentan (Letaris) ARIES-1 ARIES-2 ET-A-selective endothelin receptor blocker Oral 9 – 15h

• nce daily at a 5-mg dose,

can be increased to 10 mg if the drug is well tolerated.

• 6MWD
• Delayed clinical

worsening

• Improved

hemodynamics Sitaxsentan (*) (Thelin) ETA-selective endothelin receptor blocker Oral

• nce daily at a 100 mg dose.

6MWD

Therapeutic and clinical risk management of PAH, download from http://www.dovepress.com

PHOSPHODIESTERASE INHIBITORS THERAPY

Drugs Stuty Action Routin Dose Positive results Disadvantage Sildenafil (Revatio) SUPER-1 Double- blind No: 278 Indication: Class II-IV Selective phosphodiesterase E5 inhibitor:

• Vasodilation
• Antiproliferative

Oral 3.7h 20 mg three times daily, but dosages as high as 80 mg three times daily have been used safely, and in some patients

• Well tolerated
• verall
• No blood level

monitoring

• No LFT

abnormalitie.s

• 6MWD
• Improved

dyspnea

• Improved

hemodynamics

• Can have hypotension &

edema formation

• Should not be given with

nitrates, caution with alpha blockers

• No delay in clinical

worsening end point

• Headache, flushing,

dyspepsia, epistaxis, visual disturbance.

• Nasal congestion

Tadalafil long-acting selective PDE5 inhibitor Oral 18h The effective dose was 5- 40 mg once daily.

Therapeutic and clinical risk management of PAH, download from http://www.dovepress.com

NEW PERSPECTIVES FOR TREATMENT OF PH FUT UTUR URE DIRE RECTIO TIONS: NS: POT OTENT NTIAL IAL NE NEW TH THERA RAPEUT PEUTIC IC TAR ARGE GETS TS

The Journal of Heart and Lung Transplantation, Vol 35, No 6, June 2016

PULMONARY ARTERIAL HYPERTENSION CELLULAR PROCESSES

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

Barst RJ, et al. J ACC 2009

Dependent on the physician Experience. Literature. Clinical judgment.

Badesch D. B. et.al. Chest 2007;131:1917-1928

TREATMENT ALGORITHM FOR PAH

CHOICE OF INITIAL PAH THERAPY

Baldi et al , Therapeutics and Clinical Risk Management 2014:10

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 3 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

Concurrent

+ +

Drug 1 Drug 2 Drug 2 Drug 1

Sequential

High risk group

Low risk group

Combination therapy

Recom commen mendati dations ns for

• r efficacy

ficacy of drug ug co combinati mbination

• n ther

herapy apy-2015 2015 ESC/ERS ERS

Init Initia ial l drug g combin binat atio ion thera rapy py Sequential drug combination therapy-

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 TRIUMPH- 1 Bosentan + Inhaled Treprostinil RCT 235 + 20 m

Overview of Combination Therapy Trials Combination Therapy: Ongoing or Recently Completed



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 co- admininstration 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

Recommendations for efficacy of drug combination therapy in acute PAH - 2015 ESC/ERS

Pulmonary arterial hypertension: Bridging the gap between efficacy, quality of life, and cost-effectiveness

DOSING & COST OF PAH TREATMENT OPTIONS

 Physical exam – JVP, murmurs, edema, ascites, liver enlargement, hypotension  Functional – history (WHO or NYHA functional classification, 6 minute walk, exercise test  Labs - BNP, renal and hepatic function  Echocardiography – RV function, pericardial effusion  Right heart catheterization – RAP, CI

EVALUATION OF RESPONSE TO THERAPY

PARADIGM SHIFT IN PAH MANAGEMENT

 Like HF, cancer, etc- the mantra is :

• Treat quickly
• Hit hard
• 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

PRINCIPLES OF OF PAH TREATMENT

PRINCIPLES OF DRUG MANAGEMENT

 Patients should undergo cardiac catheterization before initiating therapy.  Obtain baseline assessments of the disease to know whether treatments are effective.  Test Vasoreactivity.  Reactive patients should be treated with calcium channel blockers.  Nonreactive patients should be offered other therapies.  Reassess at 8 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 Recommendation Class/Level Pediatric PAH 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 PAH - CHD Bosentan is recommended in WHO-FC III patients with Eisenmenger syndrome I/B 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 Recommendation Class/Leve l PAH- CTD 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- PoPH PAH associated with portal hypertension should be referred to centres with expertise in managing both conditions I/C

• 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 drug-

associated liver toxicity is lower.

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 Recommendation Class/Level PAH- HIV 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

• 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 in-

hibitors is not recommended because of possible interactions due to the same meta bolic pathway PAH- CTEPH

• 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 I/B

• 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
• r 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 Steinmủller and Ardeschir Ghofrani



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.

TAKE HOME MESSAGE

THANK YOU FOR YOUR ATTENTION !