Primary Pulmonary Hypertension and Sildenafil

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Primary Pulmonary Hypertension andSildenafil

• Azim E. Surka
• WFUMC
• Resident Grand Rounds
• November 11, 2003

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Overview

• Background
• WHO Classification
• Epidemiology
• Pathophysiology
• Current Therapies
• Sildenafil

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Primary Pulmonary Hypertension

• Rare disorder characterized by elevated pulmonary
  arterial pressures
• First described in 1951 by Dresdale
• Presenting symptom is most commonly dyspnea
• Can also present with syncope, chest pain and
  peripheral edema

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Primary Pulmonary Hypertension

• Incidence is 1-2 cases per million in general
  population
• Mean survival was 2.8 years after diagnosis
• Although survival probably longer since the
  advent of IV epoprostenol

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Primary Pulmonary HypertensionNIH

• Defines PPH as mean pulmonary arterial pressure
  (PAP) gt 25 mmHg at rest, or gt30 mmHg with
  exertion
• Absence of heart disease, chronic thromboembolic
  disease, underlying pulmonary disorder, or other
  secondary cause

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WHO Classification

• In 1998 World Health Organization reclassified
  pulmonary hypertension
• Subdivided all Pulmonary Hypertension into 5
  groups
• Primary Pulmonary Hypertension is characterized
  as a subclass of Pulmonary Arterial Hypertension

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WHO Classification

• Pulmonary Arterial Hypertension
• Primary Pulmonary Hypertension (PPH)
• Familial
• Sporadic
• Related to
• Collagen Vascular Disease
• Congenital systemic to pulmonary shunts
• Portal Hypertension
• HIV
• Drugs/Toxins, i.e. appetite suppressants
• Persistent pulmonary hypertension of the neonate

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WHO Classification

• Pulmonary venous hypertension
• Left sided valvular or ventricular disease
• Pulmonary Hypertension associated with disorders
  of the respiratory system/ hypoxemia
• COPD, interstitial lung disease, sleep disorders

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WHO Classification

• Pulmonary hypertension due to chronic thrombotic
  and/or embolic disease
• Pulmonary emboli, and sickle cell disease
• Pulmonary Hypertension due to disorders directly
  affecting pulmonary vasculature
• Sarcoid, schistosomiasis

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Epidemiology of PPH

• Female predominance of 2 to 1
• No ethnic or geographical predisposition
• Approximately 6 of cases are familial

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Pathophysiology

• Associated with obstruction of small pulmonary
  arteries
• Microscopic characteristics
• Medial hypertrophy
• Plexiform lesions
• Thrombotic lesions
• Concentric laminar fibrosis
• Bone Morphogenetic Protein Receptor gene found in
  2000 in patients with Familial PPH
• May play role in pathophysiology

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Pathophysiology
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Current Therapies

• Calcium Channel Blockers
• Anticoagulation
• Prostacyclin
• Bosentan (endothelin antagonist)
• Lung transplantation

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Calcium Channel Blockers

• Has shown to benefit small number of people
• Nifedipine and diltiazem are the CCB of choice
• Side effects include hypotension, edema, and
  hypoxemia

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Anticoagulation

• PPH patients more likely to have thrombosis
  secondary to sluggish blood flow and sedentary
  lifestyle
• Increased levels of thromboxane have also been
  found in PPH patients
• Goal INR 2.0

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Lung Transplantation

• Only curative therapy for PPH
• Indications
• NYHA Class III or IV despite optimum medical
  therapy
• Cardiac Index less than 2L/min/m2
• Right Atrial Pressure gt 15 mmHg
• Pulmonary Arterial Pressure gt 55mmHg
• Limited by availability

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Epoprostenol (Flolan)

• Prostacyclin
• Increases exercise capacity and decrease PAP
  after 12 week period
• Improves survival at 1, 3, and 5 years
• Side Effects include hypotension, jaw pain,
  diarrhea, flushing, and nausea and vomiting
• Tachyphalaxis is common and dosages have to be
  increased

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Epoprostenol (Flolan)

• Delivered through continuous IV pump
• Infection and thrombosis can occur
• Dose Limited by hypotension
• Cost of epoprostenol and pump delivery is
  5000/month
• Iloprost
• Aerosolized prostacyclin
• Available in Europe
• Easier delivery through nebulizer
• Must be dosed 6-12 times a day

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Bosentan (Tracleer)

• Endothelin 1 and 2 antagonist
• Given Orally
• Endothelin is a potent vasoconstrictor and smooth
  muscle mitogen
• PPH patients have been shown to have greater
  endothelin 1 concentration in plasma and lungs

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Bosentan (Tracleer)

• Two Randomized controlled trials showed
  improvement in six minute walk time,
  cardiopulmonary hemodynamics, and WHO functional
  Class
• No mortality data on Bosentan

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Sildenafil (Viagra)

• A Phosphodiesterase 5 Inhibitor (PDE5)
• Currently approved for treatment of Erectile
  Dysfunction in U.S.
• Thought to work by increasing levels of cGMP, a
  vasodilator
• PDE5 is found in greater amounts the lung and
  breaks down cGMP

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Sildenafil (Viagra)
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Long Term Treatment With Oral Sildenafil in
Addition to Continuous IV Epoprostenol in
Patients with Pulmonary Arterial
HypertensionStiebellehner, et al. Chest 123,
1293-1295, 2003
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Stiebellehner, et al.

• Case Study
• Three female patients
• Ages 61, 33, 51
• Patients 1 and 2 had PPH, Patient 3 had PAH
  secondary to closure of atrial septal defect

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Stiebellehner, et al.

• All had baseline six minute walk time (6MWT) and
  cardiopulmonary hemodynamic measurements
• Primary endpoint was PAP and 6MWT after 5 months
  of therapy

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Stiebellehner, et al.Baseline Characteristics
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Stiebellehner, et al.Intervention

• Patient 1 received 50 mg of Sildenafil four times
  a day
• Patient 2 and 3 received 12.5 mg of Sildenafil
  six times a day secondary to nausea and vomiting
• All patients continued with current dose of
  epoprostenol

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Stiebellehner, et alResults
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Stiebellehner, et al.

• Conclusions
• All patients had decrease in PAP and increase in
  6MWT after 5 months of therapy
• Effects of sildenafil were additive to
  epoprostenol

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Stiebellehner, et al.

• Limitations
• Case Series
• Small sample group
• Lack of control
• No randomization

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• Effect of Inhaled Iloprost Plus Oral Sildenafil
  in Patients with PPH
• Wilkens H, et al Circulation 104 1218-1222, 2001

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Wilkens, et al

• Crossover study with iloprost and sildenafil
• 5 patients with PPH with NYHA class III or IV
• Exclusion Criteria pregnancy, hypotension, and
  secondary pulmonary hypertension
• Patients admitted to ICU and Swan-Ganz catheters
  were placed
• PAP, CO, and PVR were measured

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Wilkens, et alPatient Characteristics
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Wilkens, et alInterventions

• Patients were given iloprost, and measurements
  were taken every 15 minutes for 2 hours
• Patients were then given two 25 mg doses of
  Sildenafil 30 minutes apart, and Swan-Ganz
  measurements were taken
• Patients were given additional 50 mg of
  sildenafil if there was no response after 60 min
• Patients were then given inhaled iloprost 90
  minutes after first sildenafil

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Wilkens, et alResults

• PAP
• Iloprost
• -16.3 /-2.2 plt0.01
• Sildenafil
• -12.6 /-0.9 plt0.01
• Sildenafil Iloprost
• -24.7/-3.0 plt0.002

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Wilkens, et al
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Wilkens, et alResults

• Similar Decreases in Pulmonary Vascular
  Resistance
• Iloprost
• -43.8/- 3.9 (plt0.05)
• Sildenafil
• -21.8 /- 3.0 (plt0.05)
• Sildenafil and Iloprost
• -43.0 /- -2.7 (plt0.02)

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Wilkens, et al
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Wilkens, et al

• Conclusions
• Effects of iloprost began to wear off after 1
  hour
• Sildenafils effect on PAP and PVR was still
  evident after 90 min
• Additive effect of two agents together
• Most of effect of sildenafil was after the first
  25 mg dose

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Wilkens, et al

• Limitations
• Small sample group
• No randomization
• Open crossover study

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• Combination Therapy with Oral Sildenafil and
  Inhaled Iloprost Severe Pulmonary Hypertension
• Ghofrani, et al Annals Internal Medicine, 136
  515-522, 2002

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Ghofrani, et al

• Randomized open label trial in the ICU
• 30 Patients
• 16 patients with Pulmonary Arterial Hypertension
• 10 with PPH and 6 with CREST
• 13 with chronic thromboembolic disease
• 1 with PH secondary to aplasia of left pulmonary
  artery
• 23 women and 7 men

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Ghofrani, et al

• Inclusion Criteria
• Severe PAH i.e. PAP gt40mm Hg
• NYHA class III or IV
• Exclusion Criteria
• Pulmonary Hypertension secondary to COPD
• Pulmonary Venous Congestion
• Congenital Heart Disease
• Pregnancy
• Inflammatory Lung Disease

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Ghofrani, et al

• After Swan-Ganz catheter placement, each patient
  had a trial of inhaled nitric oxide
• PAP, PVR, CI, and SVR were measured
• Iloprost was delivered after all measurements had
  returned to baseline
• Iloprost decreased PAP, PVR, and Increased CI

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Ghofrani, et alPatient Characteristics
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Ghofrani, et al
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Ghofrani, et al
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Ghofrani, et al
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Ghofrani, et al
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Ghofrani, et al

• Conclusions
• Sildenafil lowered PAP and PVR and increased CI
  without many systemic symptoms or side effects
• Combination of drugs had more dramatic but
  transient benefit
• Improved hemodynamics of those with PPH and
  chronic thromboembolic disease

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Ghofrani, et al

• Limitations
• Small Sample Size
• Lack of placebo control
• Open trial
• Lack of long term data

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Long-Term Treatment with Oral Sildenafil is
Safe and Improves Functional Capacity and
Hemodynamics in Patients with Pulmonary Arterial
Hypertension Michelakis ED, Tymchak W, et al
Circulation 108 2066-2069
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Michelakis et al.

• Case Review
• Aimed to show long-term safety and efficacy of
  sildenafil
• 5 patients enrolled in the study
• 4 with PPH
• Primary endpoint was 6MWT and PAP at 3 months
  after initiation of the sildenafil

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Michelakis et al.

• Patients
• Four were NYHA class III and 1 was NYHA class II
• All patients were stable for past three months
  with no changes in therapy
• All were on diuretics and coumadin and patients 2
  and 4 were on calcium channel blockers as well
• Patients were excluded if they were on
  epoprostenol or NYHA class IV

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Michelakis et al.Results

• PAP decreased 25.7 /- 10 plt0.007
• Statistically significant increases in 6MWT
  plt0.001
• 3 patients who had cardiac MRI had decreases in
  size of right ventricle, increase in RV EF, and
  reverse of paradoxical septal shift

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Michelakis et al.

• Conclusions
• Sildenafil with traditional therapies reduced PAP
  and increased 6MWT after 3 months
• Limitations
• Small sample size
• Lack of placebo control
• Lack of randomization

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Cost Analysis
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Final Conclusions

• Sildenafil alone and in combination with other
  therapies has benefit for treating patients with
  PPH
• Sildenafil decreases PAP, PVR, and increases CO
  and 6MWT
• Benefits of sildenafil are its cost, ease of
  delivery, and few side effects

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Final Conclusions

• May benefit those awaiting transplantation and to
  those who have maximized their epoprostenol dose
• Need larger multi-center randomized controlled
  trials that shows long-term hemodynamic or
  mortality benefit of sildenafil before it can be
  used in routine treatment of PPH

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