Pulmonary Arterial Hypertension
• Idiopathic (IPAH) and familial (FPAH)
• Associated with (APAH):
– Collagen vascular disease – Drugs/Toxins
– Portal hypertension
– HIV Infection
– Congenital systemic to pulmonary shunts
– Other (glycogen storage disease, HHT, etc.)
• Significant venous or capillary involvement:
-Pulmonary veno-oclussive disease (PVOD)
-Pulmonary capillary hemangiomatosis (PCH)
Goals of Patient Evaluation
• Determine presence of PAH
• Determine cause of PAH (primary or secondary)
*IPAH is diagnosis of exclusion
• Determine severity of PAH
*Impact on patient’s life and overall wellbeing.
• Determine functional status of patient
• Determine treatment modality appropriate for
patient (support system, tolerance of PAH,
mental capacity, etc)
Presenting symptoms in PAH
Common Initial Symptoms
(N=187)
Patients (%)
Dyspnea
60
Fatigue
19
Syncope or near syncope
13
Chest pain
7
Palpitations
5
Leg edema
3
Vascular Pressure in Systemic and
Pulmonary Circulations (mm Hg)
Systemic
Circulation
120/80, mean 90
25/10, mean 15
Arteries
Arteries
Right
Atrium
Mean >6
Left
Atrium
Mean 5
Pulmonary
Circulation
Body
SVR= 17.6
Veins
Right
Ventricle
25/5
Left
Ventricle
120/5
PVR=
1.8
Veins
Role of ET-1 and Its Receptors
Are Important in PAH
ET-1 is elevated in PAH:
Correlates to disease severity
• Regulated by ETA and ETB receptors
– ETA: vasoconstriction, cell proliferation
– ETB: vasodilation, antiproliferation (increased
NO and PGI² production)
Pulmonary circulation
• Low resistance, high compliance vascular
bed
• Only organ to receive entire cardiac output
(CO)
• Changes in CO as well as pleural/alveolar
pressure affect pulmonary blood flow
• Different reactions compared to the
systemic circulation-hypoxia
• Normally in a state of mild vasodilation
ETA Receptor Pathway
ETB Receptor Pathway
The Common Denominator of
PAH: Pulmonary Vasculopathy
Intimal thickening due to
endothelial proliferation
Medial thickening and
muscularization
Plexiform
lesions
The Hemodynamic “Working”
Definition of Pulmonary Arterial
Hypertension
• Systolic pulmonary arterial pressure 35 to
40 mm Hg
• Mean pulmonary arterial pressure
≥25 mm Hg
• PWP, LAP, LVEDP <15 mm Hg
• Pulmonary vascular resistance >3U
PCWP=pulmonary capillary wedge pressure; LAP=left arterial pressure; LVEDP=left
ventricular end-diastolic pressure.
Diagnostic Classification of
Pulmonary Hypertension (PH)*
• Group 1. Pulmonary arterial hypertension
• Group 2. Pulmonary venous hypertension
• Group 3. PH associated with disorders of
the respiratory system and/or hypoxemia
• Group 4. PH due to chronic
thromboembolic disease
• Group 5. Miscellaneous
3rd world symposium on pulmonary arterial hypertension, JACC 2004
Normal Hemodynamics
I. Normal parameters
• Cardiac output = 5-6l/m for men
• Normal pressures for different cardiovascular
compartments:
• RA 0-5mmHg
• RV syst 25mmHg; diast 0-5mmHg
• PA syst 25mmHg; diast 10mmHg
• PCWP 10mmHg
• LA 10mmHg
• LVsyst 120mmHg diast 10mmHg
• Aorta syst 120mmHg diast 80mmHg
Optional Tests in PAH diagnosis
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Sleep study
Pulmonary angiography
Exercise physiology study
Evaluation for coronary artery disease
Transesophageal echocardiography for
valvular heart disease, shunt
PAH May Occur at All Ages:
Distribution of Patients by Age
More frequent in women than men-2.5 to 1
30
Males
Females
25
20
Frequency
(%)
15
10
5
0
18-20
21-30
31-40
41-50 51-60
Age (y)
61-70
>70
NYHA/ WHO Functional Class in
assessment of PAH
• Class I: Minimal symptoms, no activity
limitation
• Class II: Dyspnea or fatigue with ordinary
activity
• Class III: Comfortable at rest only;
dyspnea, fatigue, chest pain or near
syncope with minimal activity
• Class IV: Dyspnea and/or fatigue at rest
and/or signs of right heart failure
Determining Therapy
• Based on severity of illness:
• 6 minute walks are extremely important to determine
functional limitations, response to therapy.
-patient symptomology is paramount, if syncopal or s/sx
of heart failure, regardless of current hemodynamics,
use FLOLAN, unless no social support, patient mentally
impaired or refuses this therapy. (Current philosophy
among PH specialists is that it is better to treat with the
best therapy available, then back down to less invasive
therapy)
-Hemodynamic parameters (RAP, PAP Mean, COP, CI,
PVR, PA O2 sat) secondary
-Exercise tolerance (NYHA Functional class)
Pulmonary Arterial Hypertension:
Goals of Therapy
• Improve exercise capacity with decrease
in symptoms
• Improve functional class
• Prevent clinical worsening
• Improve survival
• Improve hemodynamics
Conventional Therapy
• Anticoagulation (coumadin, warfarin)
• Diuretics (lasix, aldactone, zaroxolyn)
• Calcium Channel Blockers (cardizem,
procardia, norvasc), only if >20% decrease
to <40 mmHg with vasodilator challenge
• Oxygen therapy
Basic Treatment: Anticoagulation
• Recommended for patients with IPAH
– benefit not shown in other groups with PAH
• Studies only in IPAH patients:
– benefit demonstrated 3 studies
– neither randomized, 2 retrospective
• No evidence for effect on disease
• Not likely to affect symptoms
• Suggested INR 1.5-2.5, unless CTEPH: 2.5-3.5
• Catheter prophylaxis INR 1.5-2.2
Basic Treatment : Diuretics
• Reduce peripheral edema, intravascular volume,
and central venous pressure
• Combination of loop diuretic (furosemide (lasix),
Bumetanide (bumex), torsemide (demadex)
/spironolactone (aldactone),/ metolazone may
be beneficial
• IV diuretics in refractory cases
• Can significantly improve symptoms and
function
• Titrate to keep patient edema free or until
BUN/Cr elevate
• Low BP is not a contraindication to diuretics
Calcium Channel Blockers (CCBs)
• Largest prospective study1:
– 64 pts w/IPAH Rx with CCB, followed for up to 5 yrs
– ave. dose: nifedipine - 172  41mg,
diltiazem - 720  208 mg
– 17 pts (26%) responded to Rx with 39% in mPAP and 53% in
PVR
• Recent retrospective study of 557 pts w/IPAH showed
only 6.8% long-term response with CCBs1, lower in
other PAH groups (secondary)
• If patient is a responder, but does not tolerate one type
of CCB, may do well with another type of CCB
2. Rich et al, NEJM, 1992
1. Sitbon et al, Circulation, 2005
Clinical Therapies Available
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Flolan® (epoprostenol) continuous infusion
Tracleer® (bosentan)
Remodulin® (treprostinil) – SQ and IV
Ventavis® (iloprost)
Revatio® (sildenafil)
Letairis® (ambrisentan)
Atrial Septostomy
Lung Transplantation
Pulmonary Thromboendarterectomy (UCSD, Vanderbilt,
Cleveland Clinic)
• Septal Defect Closure Devices
Flolan
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Approved for functional class III-IV
Given via continuous infusion with mechanical pump
Short half life of 3 to 6 minutes
Must be kept cold for maximum effectiveness
Requires implanted central venous catheter
Must do daily sterile mixing of the medication
Needs nursing support for up-titration, medication related
problems or catheter issues
• Requires intensive education prior to and during initiation
of therapy
• Must have insurance approval prior to elective initiation
• Consider referral for lung transplantation if no significant
improvement with therapy
CADD 1 Legacy Pump
• Easy to read and
understand display. Easy
to operate with sufficient
training.
• Battery Powered
• Portable, weighs about 7
pounds with full cassette
and ice packs.
• Not waterproof
• Pump sensitive to
extreme temperatures
Flolan protocol
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Provide PH flolan patient/family education booklet for review/possible
questions. If patient agreeable, proceed.
Send referral form to Accredo Therapeutics, must receive approval prior to
initiation of therapy (clinical records, procedure results, CCB statement,
sleep study, if any, medical necessity for flolan, etc)
Once patient approved, order start kit for flolan therapy (pumps x 2, pouch,
ice packs, batteries, educational material)
Schedule pre-hospital teaching (1-2 days) with Accredo nurse clinical
specialist
Schedule patient admission and reserve telemetry bed
Schedule Hickman catheter placement or PICC if emergent start or unsure
therapy will be effective. No port-a-caths for flolan.
Coordinate with pharmacy for dispensing of flolan, diluent, medication
cassettes and tubing for entire patient hospitalization
Once patient admitted, begin intensive patient education (approx 4 hours
per day). Provide practice supplies for patient and family once nurse time
completed. Encourage them to PRACTICE, PRACTICE, PRACTICE mixing
Document progress, flolan increases, side effects, arrhythmias, increase
activity to assess effects of flolan
Arrange Home Health RN for 3 to 4 days after discharge from hospital
f/u in clinic with PH specialist in one month, CM will schedule
Call nurse case manager weekly for flolan increases, side effects, issues
Flolan Patient Education
• Flolan
-mix and administration of medication cassettes (back-up daily)
-anticipated dose increase schedule – daily while hospitalized then
once or twice weekly after discharge to home based on side effects
-programming of CADD 1 Legacy pumps
-Hickman catheter care and maintenance including dressing
changes and monitoring for infection
-Emergency management/EMS letter
• 2 Gm sodium diet restriction/2000 cc fluid restriction
• Coumadin management and drug interactions
• Quick reference for managing flolan
• Cold and Flu season management
• Patient f/u schedule: clinic evaluation at 1 month, echo and CXR at
4 months, cath at 1 year.
• Managing other co-morbid illnesses – PCP involvement
Bosentan (Tracleer)
• Oral, non-selective ET-1 receptor antagonist
• Bosentan (2 doses) vs. placebo evaluated in a
multicenter center (Breathe-1) study
• 213 PAH patients evaluated over 16 weeks:
-70% IPAH, 30% CTD
-90% class III, 10% class IV
• Primary endpoint: change in 6 min walk distance
- showed an increase in exercise tolerance with
walk distance increase of 30 to 40 meters.
Rubin et al NEJM, 2002
Use of bosentan
• Approved for treatment of Functional Class III and IV
PAH
• Initiate at 62.5 mg bid x 4 wks, then increase to 125 mg
bid. For patients < 40 kg body weight, start at 31.25 mg.
• Need to follow monthly LFTs (generally observe increase
in first few months of use, but may occur years later)
• Dose reduction necessary for significant elevations in
liver enzymes (3 to 5 times above normal)
• Teratogenic (causes birth defects) in animals, need to
check beta-HCG (pregnancy test) at BL and q monthly
• Can cause transient anemia (10 point drop in
hematocrit), so need to monitor CBC every 3 months.
The Common Denominator of PAH:
Pulmonary Vasculopathy
Intimal thickening due to
endothelial proliferation
Medial thickening and
muscularization
Plexiform lesions
Treprostinil (Remodulin)
• Longer acting prostacyclin analogue, given sq or
IV by continuous infusion - half-life 4 hours
• SQ Continuously infused via a CADD MS 3
pump; IV via CADD 1 Legacy or Chrono 5
• Evaluated SQ in a 12 week multi-center,
placebo-controlled study of 471 patients with
PAH1:
-IPAH, CTD and CHD
-NYHA class II-IV (81% class III)
• Primary endpoint: change in six-minute walk
distance-walk test improved 34 meters at 4th
quarter interval
1. Simonneau et al. AJRCCM, 2002
Treprostinil - Summary
• Approved for treatment of Functional
Class II, III and IV PAH (SQ and IV)
• At higher doses, there may be more
significant benefits. Many times patients
require two to three times as much
treprostinil as flolan.
• Majority of patients experience pain or
discomfort at the infusion site with SQ
therapy (8% D/C rate during the study)
CADD MS 3
Ambulatory Infusion Pump
• Drug and Pump for SQ use shown
below-IV Drug is the same, pump
is the CADD 1 Legacy or Chrono 5
Pump.
Remodulin Protocol
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Discuss therapy with patient and distribute patient education material
If patient agreeable, submit remodulin referral to Accredo, Curascript, or
Caremark.
• Once approval obtained, order start kit from distributor to be shipped to
clinical specialist for pre-initiation patient education. Remind patient to bring
start kit with them to hospital on day of initiation.
• Arrange date for pre-initiation teaching.
• For SQ Remodulin, reserve clinic room and schedule nurse clinic visit
-Patient education: drug, use of reservoir, programming of pump, battery
change, site rotation, managing side effects, reordering of supplies.
Discuss weekly increases as tolerated.
-f/u in clinic at 3 month intervals, echo at 6 months, cath at one year.
• For IV remodulin, reserve telemetry bed for patient admission and schedule
Hickman catheter placement.
-follow flolan protocol with regard to patient education.
-HH nurse for 2 to 3 visits after discharge from hospital for ongoing patient
education.
- f/u in clinic at 1 month, then 3 month intervals with echo at 6 months, cath
at 1 year.
**Consider additional therapy if no significant benefit at 3 months or disease
progression.
Iloprost (Ventavis)
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Prostacyclin analogue with half-life of ~45-60 min
Can be given by inhalation (or intravenously)
Evaluated in randomized, multi-center (AIR) study1
203 patients: 72% w/IPAH, 28% w/CTEPH
Functional class III (59%), class IV (41%)
Combined primary endpoint:
– 10% increase in 6 min walk distance after inhalation
– improvement in functional class
– No clinical deterioration or death
1.Olschewski et al. NEJM, 2002
Adaptive Aerosol Delivery (AAD®)
• Analyzes pressure changes relevant to flow of first 3 breaths
• Delivers aerosol during first phase of inspiration
• Continually monitors and adapts to individual changes in
breathing pattern
Ventavis-Summary
• Iloprost approved for treatment of class III
and IV PAH patients
• Well tolerated by most patients
• Less invasive than other prostacyclin
therapies
• Requires 6-9 inhalations/D, 7 to 15 min/Trt
• No benefit in patients with CETPH
• Will be used mainly in combination with
oral therapy in USA
Ventavis I-neb
Only the I-neb and Pro-dose have been proven to deliver safe and accurate
dosing of Ventavis. While the Pro-dose system requires availability of electricity,
with the I-neb, a patient can get up to 40 treatments with a single charge, giving
them freedom and flexibility. CoTherix is looking into alternatives for medication
delivery, including changes to the existing I-neb, as well as the possibility of a
powdered form of Iloprost.
Ventavis protocol
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Discuss therapy with patient and distribute patient education material
If patient agreeable, submit referral form to Accredo or Curascript for Ventavis
along with required documentation (same as with flolan)
Once patient approved for therapy, arrange pre-initiation education with community
clinical specialist.
Schedule patient for nurse clinic visit (requires approximately 4 hours)
Reinforce patient education done at patient’s home:
- Drug actions, side effects, management of side effects, s/sx to report to case manager or
PH specialist, placement of medication in and cleaning of nebulizers, reordering of
supplies, and calling distributor for nebulizer issues.
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Take baseline VS, O2 sats
Patient completes 1st treatment of 2.5 mcg by inhalation
VS and O2 sats repeated at 30 and 60 minutes, along with review of side effects.
Wait an additional hour (treatments are 2 hours apart), then take baseline VS for
2nd inhalation
Patient completes 2nd treatment of 5 mcg by inhalation
VS and O2 sats repeated at 30 and 60 minutes, as well as review of side effects.
Patient to perform 6 minute walk test after 2nd treatment to assess exercise
tolerance and presence of side effects.
f/u in clinic every 3 months, echo at 6 months, cath at one year.
Consider additional therapy if no significant benefit at 3 months or progression of
disease.
Sildenafil
• Multi-center, randomized, double blind, placebo
controlled, 12 week trial (SUPER)
• 280 patients enrolled, four treatment arms:
– placebo
– sildenafil at 20, 40 and 80 mg TID
• 63% IPAH, 37% CTD, 7% CHD
• 39% class II, 58% class III, 3% class IV
• Primary endpoint: change in six-min walk
distance
Sildenafil (Revatio)
• Sildenafil demonstrated significant improvement vs.
placebo respect to:
– 6MWD with all doses
– Hemodynamic parameters
– Functional class
• Acceptable safety profile
• FDA approved for functional class II, III and IV
• Available at local pharmacies and specialty pharmacies.
May need to obtain prior-authorization due to expense of
therapy, approximately $1200/month.
• Initiated at home with 10-20 mg po TID, may need to
increase to 50 mg po TID, while obtaining insurance
approval can be difficult.
• f/u in clinic at 3 months, echo at 6 months, cath at 1 year
• Consider additional therapy if no significant benefit at 3
months.
Ambrisentan (Letairis®)
• Oral endothelin-A selective blocking agent
• Approved for treatment of Functional Class II and III PAH
• Initiate at 5 mg daily x 4 wks, then increase to 10 mg
daily long-term as tolerated. For patients < 40 kg body
weight, start at 2.5 mg.
• Need to follow monthly LFTs (lower incidence of
elevations in LFTs noted in clinical trial than with
Tracleer)
• Dose reduction necessary for significant elevations in
liver enzymes (3 to 5 times above normal)
• Teratogenic (causes birth defects) in animals, need to
check beta-HCG (pregnancy test) at BL and q monthly
• Can cause transient anemia (10 point drop in
hematocrit), so need to monitor CBC every 3 months.
• Monitor closely for increased occurrence of edema
Combination Therapy
• Increasingly being used to treat PAH due to
disease complexity (3 pathways: nitric oxide
pathway, prostacyclin pathway, and endothelin
pathway
• Combinations:
-Epoprostenol and bosentan (study completed)
-Bosentan and iloprost (study completed)
-Epoprostenol and sildenafil (on-going)
-Treprostinil and bosentan (on-going)
-Bosentan and tadalafil (on-going)
-Bosentan and sildenafil (on-going)
Investigational Medications
• Sitaxsentan - endothelin A receptor antagonist,
dosed once daily (definite interaction with
coumadin)
• Inhaled treprostinil - Administration of
treprostinil medication performed by inhalation
(6 to 12 puffs) with the OPTINEB™ ultrasonic
nebulizer four times daily in combination with
Tracleer or Revatio at stable dose
• Oral treprostinil - oral remodulin in timereleased capsule with twice daily dosing (UT15C)
• Tadalafil (Cialis) - phosphodiesterase inhibitor
with once daily dosing
Investigational Medications (cont):
• Pulmolar-potent inhibitor of vascular smooth
muscle and endothelial cell proliferation,
markedly reduced vascular remodeling and right
ventricular hypertrophy, and reduction of
pulmonary hypertension and inflammatory cell
infiltration in lung tissues: 2-methoxyestradiol
(2ME), an endogenous non-estrogenic
metabolite of estradiol.
• Gleevec-used now to treat leukemia; The
substance conveys its potent anti-proliferative
effect by selectively suppressing the tyrosine
kinase pathway. In cancer, tissue proliferation is
uncontrolled and leads to the spreading of the
tumor. In pulmonary hypertension, also,
uncontrolled growth of the vascular wall is the
underlying mechanism of the disease.
Investigational Medications (cont):
• Biomarin: Nitric Oxide Precursor (may be
a good indicator of survival long-term
• (Rho kinase inhibitors: Protein Kinase
Inhibitors-Hydroxyfasudil)
• REVEAL - Registry to EValuate Early And
Long-term PAH disease management =
National PAH Disease Registry launched
in 2006
Comparison of Medical Treatments
Cost $
(annual)
Route
Frequency
Epoprostenol
~100,000
IV
Continuous
+
+++
Yes
Bosentan
Ambrisentan
~48,000
Oral
BID
QD
+++
+
Yes
No
Treprostinil
>150,000
SQ, IV
Continuous
++
+++
Yes
Iloprost
70-80,000
Inhaled
6-9X per
day
++
++
No
Sildenafil
~15,000
Oral
TID
+++
+
Yes
Ease
Side
of Use effects
Longterm
Data