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Primary Pulmonary Hypertension and Sildenafil . Azim E. Surka WFUMC Resident Grand Rounds November 11, 2003. Overview:. Background WHO Classification Epidemiology Pathophysiology Current Therapies Sildenafil. Primary Pulmonary Hypertension.

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primary pulmonary hypertension and sildenafil

Primary Pulmonary Hypertension andSildenafil

Azim E. Surka


Resident Grand Rounds

November 11, 2003

  • Background
  • WHO Classification
  • Epidemiology
  • Pathophysiology
  • Current Therapies
  • Sildenafil
primary pulmonary hypertension
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
primary pulmonary hypertension4
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
primary pulmonary hypertension nih
Primary Pulmonary HypertensionNIH
  • Defines PPH as mean pulmonary arterial pressure (PAP) > 25 mmHg at rest, or >30 mmHg with exertion
  • Absence of heart disease, chronic thromboembolic disease, underlying pulmonary disorder, or other secondary cause
who classification
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
who classification7
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
who classification8
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
who classification9
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
epidemiology of pph
Epidemiology of PPH
  • Female predominance of 2 to 1
  • No ethnic or geographical predisposition
  • Approximately 6% of cases are familial
  • 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
current therapies
Current Therapies
  • Calcium Channel Blockers
  • Anticoagulation
  • Prostacyclin
  • Bosentan (endothelin antagonist)
  • Lung transplantation
calcium channel blockers
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
  • 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
lung transplantation
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 > 15 mmHg
    • Pulmonary Arterial Pressure > 55mmHg
  • Limited by availability
epoprostenol flolan
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
epoprostenol flolan18
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
bosentan tracleer
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
bosentan tracleer20
Bosentan (Tracleer)
  • Two Randomized controlled trials showed improvement in six minute walk time, cardiopulmonary hemodynamics, and WHO functional Class
  • No mortality data on Bosentan
sildenafil viagra
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

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

stiebellehner et al
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
stiebellehner et al25
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
stiebellehner et al intervention
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
stiebellehner et al29
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
stiebellehner et al30
Stiebellehner, et al.
  • Limitations:
    • Case Series
    • Small sample group
    • Lack of control
    • No randomization
Effect of Inhaled Iloprost Plus Oral Sildenafil in Patients with PPH

Wilkens H, et al Circulation 104: 1218-1222, 2001

wilkens et al
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
wilkens et al interventions
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
wilkens et al results
Wilkens, et alResults
  • PAP
    • Iloprost
      • -16.3% +/-2.2% p<0.01
    • Sildenafil
      • -12.6% +/-0.9% p<0.01
    • Sildenafil +Iloprost
      • -24.7%+/-3.0% p<0.002
wilkens et al results37
Wilkens, et alResults
  • Similar Decreases in Pulmonary Vascular Resistance
    • Iloprost
      • -43.8%+/- 3.9% (p<0.05)
    • Sildenafil
      • -21.8% +/- 3.0% (p<0.05)
    • Sildenafil and Iloprost
      • -43.0% +/- -2.7% (p<0.02)
wilkens et al39
Wilkens, et al
  • Conclusions:
    • Effects of iloprost began to wear off after 1 hour
    • Sildenafil’s 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
wilkens et al40
Wilkens, et al
  • Limitations:
    • Small sample group
    • No randomization
    • Open crossover study
Combination Therapy with Oral Sildenafil and Inhaled Iloprost Severe Pulmonary Hypertension

Ghofrani, et al Annals Internal Medicine, 136: 515-522, 2002

ghofrani et al
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
ghofrani et al43
Ghofrani, et al
  • Inclusion Criteria:
    • Severe PAH i.e. PAP >40mm Hg
    • NYHA class III or IV
  • Exclusion Criteria:
    • Pulmonary Hypertension secondary to COPD
    • Pulmonary Venous Congestion
    • Congenital Heart Disease
    • Pregnancy
    • Inflammatory Lung Disease
ghofrani et al44
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
ghofrani et al50
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
ghofrani et al51
Ghofrani, et al
  • Limitations:
    • Small Sample Size
    • Lack of placebo control
    • Open trial
    • Lack of long term data

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

michelakis et al
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
michelakis et al54
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
michelakis et al results
Michelakis et al.Results:
  • PAP decreased 25.7% +/- 10%p<0.007
  • Statistically significant increases in 6MWT p<0.001
  • 3 patients who had cardiac MRI had decreases in size of right ventricle, increase in RV EF, and reverse of paradoxical septal shift
michelakis et al56
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
final conclusions
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
final conclusions59
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