Pulmonary Arterial Hypertension

1
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)

2
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 patients life and overall well-
• being.
• Determine functional status of patient
• Determine treatment modality appropriate for
  patient (support system, tolerance of PAH, mental
  capacity, etc)

3
Presenting symptoms in PAH
Common Initial Symptoms (N187) Patients ()
Dyspnea 60
Fatigue 19
Syncope or near syncope 13
Chest pain 7
Palpitations 5
Leg edema 3
4
Vascular Pressure in Systemic and Pulmonary
Circulations (mm Hg)
Pulmonary Circulation
Systemic Circulation
120/80, mean 90
25/10, mean 15
Arteries
Arteries
Right Atrium Mean gt6
Left Atrium Mean 5
Lung
Body
SVR 17.6 PVR 1.8
Right Ventricle 25/5
Left Ventricle 120/5
Veins
Veins
5
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)

6
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

7
ETA Receptor Pathway ETB Receptor Pathway
8
The Common Denominator of PAH Pulmonary
Vasculopathy
9
The Hemodynamic Working Definition of Pulmonary
Arterial Hypertension

• Systolic pulmonary arterial pressure 35 to 40 mm
  Hg
• Mean pulmonary arterial pressure25 mm Hg
• PWP, LAP, LVEDP lt15 mm Hg
• Pulmonary vascular resistance gt3U
• PCWPpulmonary capillary wedge pressure LAPleft
  arterial pressure LVEDPleft ventricular
  end-diastolic pressure.

10
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

11
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

12
Optional Tests in PAH diagnosis

• Sleep study
• Pulmonary angiography
• Exercise physiology study
• Evaluation for coronary artery disease
• Transesophageal echocardiography for valvular
  heart disease, shunt

13
PAH May Occur at All Ages Distribution of
Patients by Age

• More frequent in women than men-2.5 to 1

Males
Females
Frequency ()
18-20
21-30
31-40
41-50
51-60
61-70
gt70
Age (y)
14
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

15
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)

16
Pulmonary Arterial HypertensionGoals of Therapy

• Improve exercise capacity with decrease in
  symptoms
• Improve functional class
• Prevent clinical worsening
• Improve survival
• Improve hemodynamics

17
Conventional Therapy

• Anticoagulation (coumadin, warfarin)
• Diuretics (lasix, aldactone, zaroxolyn)
• Calcium Channel Blockers (cardizem, procardia,
  norvasc), only if gt20 decrease to lt40 mmHg with
  vasodilator challenge
• Oxygen therapy

18
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

19
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

20
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

21
Clinical Therapies Available

• 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

22
Flolan

• 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

23
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

24
Flolan protocol

• 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

25
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

26
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

27
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 lt 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.

28
The Common Denominator of PAH Pulmonary
Vasculopathy
29
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

30
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)

31
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.

32
Remodulin Protocol

• 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.

33
Iloprost (Ventavis)

• 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

34
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

35
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

36
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.
37
Ventavis protocol

• 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 patients
  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.
• 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.

38
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

39
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.

40
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
  lt 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

41
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)

42
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
  time-released capsule with twice daily dosing
  (UT-15C)
• Tadalafil (Cialis) - phosphodiesterase inhibitor
  with once daily dosing

43
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.

44
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

45
Comparison of Medical Treatments
Cost (annual) Route Frequency Ease of Use Side effects Long- term Data
Epoprostenol 100,000 IV Continuous Yes
Bosentan Ambrisentan 48,000 Oral BID QD Yes No
Treprostinil gt150,000 SQ, IV Continuous Yes
Iloprost 70-80,000 Inhaled 6-9X per day No
Sildenafil 15,000 Oral TID Yes