Lựa chọn các thuốc điều trị đặc hiệu tăng áp lực động mạch phổi

CHOOSING SPECIFIC THERAPEUTIC STRATEGIES IN MANAGEMENT OF PULMONARY ARTERY HYPERTENSION NGUYEN THI DUYEN VIETNAM NATIONAL HEART INSTITUTE... ENDOTHELIN ANTAGONIST THERAPY Bosebtan Trac

CHOOSING SPECIFIC THERAPEUTIC STRATEGIES IN

MANAGEMENT OF PULMONARY ARTERY HYPERTENSION

NGUYEN THI DUYEN VIETNAM NATIONAL HEART INSTITUTE

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

Specific therapy according to the clinical classification

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

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

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

Ferritin (ng/ml) 1266

Height (cm) 160 Weigjt (kg) 47 BSA (m2) 1.46

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)

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

Longer (>400 m) 6MW distance Shorter (<300 m) Minimally elevated BNP Very elevated

Minimal RV dysfunction Echocardiographic findings significant RV dysfunction Pericardial effusion,

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

Design: label

Open-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: blind

Double-No: 203 Indication:

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: blind

Double-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

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

- Have interactions with

warfarin that require careful monitoring of the INR

- Contraindicated in patients

on 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 once 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 once daily at a 100 mg dose 6MWD

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

PHOSPHODIESTERASE INHIBITORS THERAPY

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 overall

- 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

FUTURE DIRECTIONS: POTENTIAL NEW THERAPEUTIC TARGETS

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

FUTURE DIRECTIONS: POTENTIAL NEW THERAPEUTIC TARGETS

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

Sequential

High risk group

Low risk group

Combination therapy

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

Initial drug combination therapy Sequential drug combination therapy-

EARLY Bosental and

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 admininstration of pressors (Moderate-quality evidence, a STRONG recommendation)

co- 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 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

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

Recommendations for Specific pAH subsets

 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 associated liver toxicity is lower

drug-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- 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

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

 Pulmonary HTN is one of the difficult therapeutic problem in CV medicine

added many new drugs

patients and combination therapy may be used in severe , non-responsive and progressive cases

TAKE HOME MESSAGE

THANK YOU FOR YOUR ATTENTION !