ADVANCES IN PULMONARY HTN TREATMENT

Advances in management of pulmonary hypertension

Speaker – Dr. Rajeev sharma

Preceptor – Dr. Sandeep singh

Dr. S ramakrishnan

Points of Discussion

Introduction

Approach to patient

Management of PAH

Recent advances

Summary

Pulmonary circulation

Distensible, low pressure

Normal PAP: 24/9 mmHg

MPAP: 15 mmHg

PVR: 50-150 dyn.s/cm5

PCWP : <15 mm Hg

PAH is defined as MPAP > 25 mm Hg at rest

Natural HistoryNIH registry of IPAH patients from 1981-1985 showed a median

survival of 2.8 years

Recently report suggest 3-year survival < 60% despite current

therapy - need for more option Circulation. 2010;122:156-163

Chest. 2004;126:78S–92S.

Classification

2.4 Congenital/acquired left heart inflow/outflow tract obstruction andcongenital cardiomyopathies

Approach to patient

Diagnostic algorithm

Suspicion of PAH

History, clinical examination, chest X- ray, electrocardiogram


TTE (with bubble contrast)

PAH : diagnosis, severity, clue to the cause


RHC - Confirmation of diagnosis

Vasodilator response


V/Q Scan Pulmonary angiographyMulti-detector CTCoagulation profile

Chronic pulmonary embolism


Pulmonary function tests

Arterial blood gas analysis

Overnight polysomnography

Gas exchange

Ventilatory function


CTD work up : ANA/RF/ANCA/ anti

DNA Topoisomerase antibody,

HIV ELISA

LFT,TFT ,serum ACE level

Scleroderma, SLE

HIV

PP Hypertension

Approach to treatment

1. General measures

2. Primary therapy

3. Supportive therapy

4. Advanced therapy

Treatment ConsiderationsNo Cure with drugs

Goals are

To decrease PVR & Pressure

Reduce symptoms

Increase patient activity & longevity

General measures

Physical activity

Encouraged to be active within symptom limits

Study has shown the value of a training programme in

improving exercise performance

Mereles D et al Circulation 2006;114:1482–1489.

Pregnany & contraception

30–50% mortality in patients with PAH

Barrier contraceptive methods are safe but unpredictable

effect

Progesterone-only preparations are effective approaches to

contraception

Bosentan may reduce the efficacy of OCP

IUCD- vasovagal reaction - poorly tolerated

Primary therapy

Anticoagulation Thromboendarterectomy

Oxygen therapy

Treat underlying Heart disease

No effective therapy Advanced therapy used

1

4

2

3

Supportive therapy

Oxygen

Main therapy for Group 3 PAH

Maintain SPo2 > 90 %

NOTT trial compared continuous (19 hours/ day) to nocturnal

(12 hours/ day) oxygen administration

Three-year mortality rate was lower with continuous oxygen

than nocturnal oxygen (22 versus 42 percent)

Ann Intern Med 1980 ;93;391

NOTT Trial

Diuretics

Symptom benefit

Decrease RV filling pressure & wall stress

Arrhythmia risk & may decrease CO

Digoxin No long term studies

Used in patients with Rt Heart failure & low CO state

PAH with atrial arrhythmias

Anticoagulation

Rationale

High prevalence of thrombotic lesions in IPAH

Thrombin leads to disease progression

Survival advantage with warfarin

Chest. 1997;112:714 –21Circulation. 1984;70:580 –7.

Anticoagulation

COMPERA Registry

Prospective registry

To assess role of OAC in various forms of PAH

1283 patients ( n=738 (58%) received OAC )

800 patients are of IPAH ( including 34 patients with heritable

& drug-associated PAH )

Target INR was 2-3Circulation 2014

Anticoagulation

COMPERA registry

Anticoagulation used in 66% of IPAH and in 43% of other forms

of PAH

OAC in IPAH was associated with significantly better 3-year-

survival (p=0.006)

The survival difference at 3 years remained statistically

significant(p=0.017)

OAC not associated with a survival benefit in other forms of PAH

Anticoagulation

Recommended in

IPAH

Heritable PAH

Anorexigen associated PAH

CTEPH

Advanced therapy

CCB Prostanoid

ERB PDE 5 I

CCB

Oldest class of drugs

Only in patients with definite vasoreactivity

A retrospective analysis of 557 patients with IPAH showed that only 13%

of patients had vasoreactivity, of these only 50% benefitted from CCB

Circulation. 2005 Jun 14;111(23):3105-3111. Epub 2005 Jun 6.

Drug Starting Dose Usual Dose Maximum Daily Dose

Amlodipine 2.5mg OD 20 mg OD 20-30 mgNifedipine 30 mg BD(SR) 120-240 mg per

day240 mg

Diltiazem 60 mg TDS 240-720 mg per day

920 mg

PDE-5 Inhibitor

Sildenafil

Tadalafil

Verdanafil

Vasodilation

Antiproliferative action

Headache,flushing,epistaxis

impaired colour vision

PDE-5 Inhibitor

PHIRST- Tadalafil

RCT on 405 patients of PAH showed favorable effects on

hemodynamics & exercise capacity at largest doses(40 mg OD)

Significantly improved 6 MWD at 16 week both in treatment

naïve and on baseline bosentan therapy group

Circulation 2009;119:2894–2903.

ERADrug Route Dose Advantage Disadvant

Bosentan oral 62.5-125 mg BD

•6MWT

•NYHA

•Heamod Elevation OT/PT

Ambrisentan oral 5-10 mg OD -DO-

Sitaxentan Withdrawn due to fatal hepatic failure

Prostanoids

Drug Route Dose Advantage Disadvantage

Epoprostenol IV (infusion) •25-40

ng/kg/min

•6 MWT•NYHA class• Survival

•Long term IV access•Rebound•Jaw pain

Iloprost Inhaled • 9-10 doses/day

-Do- •Frequent dosing

Riociguat Soluble GC stimulator

Dual action

In RCT( n-443 ) – PATENT 1 Trial - Riociguat significantly

improved exercise capacity (Both in naïve and baseline B or E)

FDA Approved for Class II-IV

Dose – 2.5 mg TDS

Riociguat

Vardenafil More potent PDE 5 Inhibitor

Evaluation study

RCT – 70 patient

Dose - 5 mg Bid for 12 week

Improved 6MWD , hemodyanamics

Improved clinical outcomes

Not Approved

Macitentan

Sustained receptor binding and enhanced tissue penetration

In RCT ( SERAPHIN)- 742 pt ( 1:1:1 - P : M3: M10 )

64 % on baseline PDE-5 I or prostanoid

Reduced morbidity and mortality

Well tolerated

FDA Approved for Class II-IV with

Dose – 10 mg

Oral Treprostinil

Freedom –M trial

RCT - 349 patient (Treprostinil - 233 , placebo - 116) not on ERA or

PDE -5 I

At 12 week 6MWD improved significantly (P=0.0125)

Improves exercise capacity in patient not receiving other treatment

Based on this trial oral Treprostinil was approved in dec 2013

Circulation 2013;127:624-633.

Selexipag

Selective prostacyclin receptor agonist

Chemically distinct from prostacyclin

Oral

Long acting - Twice daily dosing & less fluctua

Selexipag

GRIPHON trialRCT to assess safety and efficacy of selexipag

N – 1156 ( placebo (n=582) or selexipag (n=574)

Selexipag reduced risk of M/M event vs placebo (p<0.0001)by 40%

Effect was observed irrespective of background treatment

The most frequent adverse events were headache, diarrhea, nausea,

jaw pain

JACC 2015

Imatinib mesylate

Rationale : PAH

Vasoconstriction + Remodeling

PDGF and c-KIT Proliferation of VSMC

Imatinib

Impres study

24-week RCT ( n – 202 )

PVR > 800 and on ≥ 2 drugs

Primary outcome - change in 6MWD

Dose – 200 - 400 mg / day

Impres study

Impres study

Placebo-corrected effect on 6MWD - 32m (P=0.002)

PVR decreased by 379 dynes·sec ( P<0.001)

Functional class, TTCW and mortality did not differ

Effect maintained in the extension study

Adverse events and discontinuation more

Subdural hematoma more ( 2+6 ) - imatinib and

anticoagulation

Impres study

Study suggest imatinib improves exercise capacity and

hemodynamics in patients with

Advanced PAH who remain symptomatic on at least

2 drugs of the currently available 3 drug classes

Combination TherapyUse of more than 1 class of drugs

Now recommended

Multiple combinations effective and well tolerated

Patient should be reassessed every 3–6 months and addition of

new therapy considered when goals have not met

Sequential Combination Therapy

Well studied

Class 1 A recommendation

SERAPHIN

PATENT

GRIPHON

PHIRST

COMPASS 1 COMPASS 2 COMPASS 3

Pt on B > 12 week

Single oral S dose of 25mg

Sig decrease in PVR & MPAP

Pt on S for > 12 week

Placebo / B

No effect on mortality

Improved 6MWD and NT-pro BNP

More LFT abnor ( B >P)

Naïve pt

B till 16 week / B 0r B + S ( based on achievement of 6 MWD of 380 m at 16 week )

Showed that B+S result in more achievement of predefined 6MWD ( 31 % at 28 week c/f B alone 16 % at 16 week )

Well tolerated

J Am Coll Cardiol. 2013

Chest. 2010J Clin Pharma 2009

Upfront Combination Therapy

Commencing > 1 therapies in treatment naive patients

Less data

WHO functional class III/IV -- IIb-C

BREATHE-2 AMBITION

• 33 patient

• B + E / E + P in 2:1 manner

• Trend toward improvement but

no sig difference in Hemody or

clinical

• Less s/e of Epo in combination

group

• RCT – 500 patients

• 253 A+ T , 247 A or T

• Combination therapy superior

to monotherapy

• Less hospitalization

• improved 6 MWD

•

Eur Respir J 2004 Euro Resp J 2014

Triple Upfront Combination

• E + B + S in severe PAH ( class III/IV)

• A prospective analysis of 19 patients of idiopathic or heritable

PAH

• Significant improvements in haemodynamics, func class and

6MWD

• 3-year survival rate of 100%( Expected- 49% )

• Achievement of WHO functional class I or II in all

Eur Respir J 2014; 43: 1691–1697

Balloon atrial septostomy

Indications

Patients with persistent RHF or recurrent syncope despite

medical therapy

Bridge to transplant

Palliation

RationaleImproved CO

RV decompression

Reduced sympathetic activity

Improved o2 transport ( despite fall in spo2)

Most favorable results patient with RAP 10-20mmHg

BAS

2.Mean RAP

3. Size of BAS

4.LA pressure

5.LV Function

BAS

Graded dilatation

End-points

LV EDP reaches 18mmHg

SpO2 80% or 10% from baseline

16mm dilatation is achieved

After BAS opening comm

only closes

Stent fe

nestrat

ion technique o

r

Fenestrat

ed device

Stent fenestration technique

Control degree of shunt & Maintain patency

Free of thrombotic complications ( c/f Fenestrated ASO )

Mounted on balloon catheter that is constricted by loop

Full balloon inflation result in diabolo-shaped stent

Diabolo Fenestrated Stent Technique

Stent Across the Atrial Septum

ASO With Self-Made Fenestration

BASBAS at early stage of disease (mean RAP of 9 ± 5 mm Hg and syncope

rather than overt RHF ) may offer a survival advantage

Timing of BAS should be before

RAP ≥20 mm Hg

LV EDP >18 mm Hg

PVRI >55 U/m2

Baseline SPO2 <90%

Eur Respir J 2011;38:1343–8

Pott shunt

Rationale

Decompression

Blood is shunted into the dAo, which avoids exposing the

brain and myocardium to desaturated blood

Reliable shunting than ASD

Pott shunt

In a series of 8 children of IPAH

NYHA IV with repeated syncope or signs RHF

Six of 8 patients survived and remained well ( func class 1 /2 ) at a

mean follow-up of 63 months

Improved 6MWD & BNP levels

Ann Thorac Surg 2012;94:817–24

TPS Percutaneous Pott shunt in a series of 4 adults ( total 7

critically ill )

Brockenbrough needle and the "stiff" end of a 0.014-inch wire

used to puncture the dAo and LPA.

After balloon dilation, an iCAST 7 × 22-mm covered stent

Two patient died

Remaining 2 did well over 4 month follow up

J Heart Lung Transplant 2013;32:381–7

TPS

TPSIn 3 patients with IPAH and severe PH having small PDA

PDA allowed easy insertion of covered stent

After a mean follow-up of 14 ± 9 months, all 3 patients

showed improved functional capacity and improved RV

function

No major complications or deaths

Circ Cardiovasc Interv 2013

TPSThe optimal timing – Not clear

Should be reserved for patients in whom BAS or lung

transplantation is contraindicated

Balloon pulmonary angioplasty

PEA in CTEPH is contraindicated in the presence of

Severe underlying lung disease

Lesions located in distally

BPA improves pulmonary blood flow distribution and

increases pulmonary vascular capacitance, decreasing RV

afterload


Feinstein et al. - BPA in 18 patients with CTEPH

Gradually dilated using balloons - sized to be 75% to 100% of

vessel diameter

Improved in NYHA class, 6MWD and mean PAP

Repeat angiography demonstrated that all previously treated

vessels remained patent at 1 to 40 months after initial BPA

Circulation 2001;103:10–3.


Kataoka et al. BPA in 29 patients with CTEPH

Significant improvements in hemodynamic parameters,

functional capacity and BNP levels at 6 months

Circ Cardiovasc Interv 2012;5:756–62


Mizoguchi et al. performed BPA in 68 inoperable CTEPH.

All patients showed significant improvements in PAP, BNP

levels, and functional exercise capacity

66 patients were alive at 2.2 ± 1.4 years

Follow-up at 1 year confirmed improved angiographic appearance

of the pulmonary arteries Circ Cardiovasc Interv 2012;5:748–55


Balloon pulmonary angioplastyReperfusion pulmonary injury can be a fatal complication

Limit dilation to no more than 2 vessels per sitting

IVUS & OCT to ensure that the maximal size is not >90% of

the original size of the vessel diameter

In candidates found to be unsuitable for PEA, BPA can be

considered an alternative

Pulmonary artery denervation

Rationale

Increased β1-adrenoreceptor RNA expression on pulmonary blood

vessels

Increased sympathetic activity demonstrated by higher MSNA

Post-BAS, MSNA levels decrease compared with controls

Baroreceptors near bifurcation of the MPA and are involved in

facilitating a neural reflex

PADN-1 Study

PADN-1 Study

Patient -21 ( 13 - PADN )

PADN at bifurcation of MPA and at ostial RPA & LPA

Significant improvement of

Mean PAP (p<0.01)

6 MWT ( p < 0.006)

Tei index (p < 0.001)

PADN

PADN

EPC BM derived

Involved in endothelial homeostasis & angiogenesis

Junhui et al. Found decreased EPCs in IPAH

Act through paracrine mechanism

EPC

EPC

RCT comparing effects of early EPC transplantation plus

conventional therapy with those of conventional therapy alone

in 31 patients with IPAH

EPC significantly improved exercise tolerance and pulmonary

haemodynamics J Am Coll Cardiol 2007; 49:1566–1571

EPC

A pilot study showed that EPC transplantation was associated

with significant improvements in exercise capacity, NYHA

class and pulmonary haemodynamics in children with IPAH

Pediatr Transplant 2008; 12: 650–655

Hemoptysis remains a major cause of morbidity in

patients of PAH ( sp. ES )

AIIMS data – 41 patients of ES studied

24 had no hemoptysis and 17 patients had hemoptysis

Mean age of the patients was 23.7 ± 7.9 years with a

range from 13 – 50 years

Bronchial artery embolization

Bronchial artery embolization

Highly successful in acute termination of hemoptysis

Polyvinyl alcohol particles of 250–500 microns size

Complications- rare and include

Non-target embolization

Subintimal dissection

Arterial perforation

Bronchial artery embolization In study of 21 patient BAE procedure was successful in 96% patients

14 in BAE therapy group and 7 in the conservative group

28-day mortality was 14% in the BAE group and 28.5% in the

conservatively managed group (p= 0.57)

Recurrence rate 43% Int J Clin Pract Suppl. 2012

PAH mangement

PAH mangement

PAH mangement

Older

• Sildenafil

• Tadalafil

• Bosentan

• Ambrisentan

• Epoprostenol

Newer

• Riociguat

• Vardenafil

• Macitentan

• Oral

Treprostinil

• Selexipag

• Imatinib

Intervention

• BAS with

stenting

• BPA

• TPS

• PADN

• EPC

Combination therapy – sequential/ upfront

Thank you

Health & Medicine

ADVANCES IN PULMONARY HTN TREATMENT