Table of Contents

Introduction
Epidemiology
Pathophysiology
Standard Therapies
Conclusions

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Introduction

Primary Pulmonary Hypertension (PPH) is a rare disorder that is characterized by elevated pulmonary arterial pressures of unclear etiology.  It was first described in 1951, and the first documented case was in 1954 in a mother and a son with elevated pulmonary arterial pressures.   The National Institute of Health defines primary pulmonary hypertension as a resting pulmonary artery pressure of more than 25 mmHg at rest, or greater than 30mmHg with exercise and the exclusion of left sided cardiac valvular disease, myocardial disease, congenital heart disease, and any relevant respiratory, connective tissue, or chronic thromboembolic disease.¹   

More recently in 1998, the World Health Organization (WHO) subdivided pulmonary hypertension into five categories:  pulmonary arterial hypertension, pulmonary venous hypertension secondary to left sided heart disease, pulmonary hypertension associated with respiratory disorders, pulmonary hypertension secondary to chronic thromboembolic disease, and pulmonary hypertension secondary to disorders directly affecting the pulmonary vasculature, such as schistosomiasis (see table to left).  Primary pulmonary hypertension is defined as pulmonary arterial hypertension of unknown or familial cause²; however because of the similar pulmonary pathophysiology of all the pulmonary arterial hypertension disorders, many of the treatments are the same.

Traditional treatments for PPH included calcium channel blockers, anticoagulation, and oxygen therapy to minimize hypoxia.  Eventually most patients will require lung or heart/lung transplantation, but unfortunately this is limited by availability.      More recently newer vasodilators such as epoprostenal and bosentan have been shown to be effective in lowering pulmonary arterial pressures, improving quality of life, and increasing the time needed to transplantation.

 

Epidemiology

PPH is a rare disorder with a frequency of 1-2 cases per million people, with a female to male predominance of 2 to 1.  Prognosis is grim with median survival of 2.8 years after time of diagnosis, although with the advent of new vasodilators such as epoprostenol and bosentan and new surgical techniques in the last decade, prognosis has improved.³There is no ethnic or geographical predisposition.  Approximately 6 % of the cases of PPH are familial, with an incomplete penetrance.  Other risk factors for Pulmonary Arterial Hypertension (PAH) include cocaine use, appetite suppressants, HIV infection, collagen vascular diseases and cirrhosis with portal hypertension.²

 

 

Pathophysiology

Primary Pulmonary Hypertension is pulmonary hypertension of unknown or familial etiology. PPH is associated with obstruction of the small pulmonary arteries.  Medial hypertrophy, concentric laminar intimal fibrosis, thrombotic lesions, and plexiform lesions are characteristic of PPH.    These microscopic features do give us insight into treatment of PPH, but not into diagnosis.  In 2000, the Bone Morphogenetic Protein Receptor (BMPR2) gene was discovered when studying patients with familial PPH.⁴  It is hypothesized that abnormal signaling from this gene gives way to endothelial cell proliferation.  However, the relationship is still not clear, given that only 50% of those with familial PPH have a mutation in this gene.  As the diagram shows, prostacyclin, endothelin and nitric oxide are also thought to play a role in the pathogenesis of PPH and will be discussed with their respective therapies.

 

Standard Therapies

Calcium Channel Blockers

Calcium channel blocker (CCB) therapy is a vasodilator therapy that has been shown to be of benefit for a small number patients (25- 30%) with PPH who respond to acute vasodilator therapy i.e. prostacyclin, or inhaled nitric oxide.  Nifedipine and diltiazem are the CCB of choice; however, the dose is usually higher then what is used to treat hypertension.  Side effects include hypotension, edema, and hypoxemia, which limit the use of these drugs.   Calcium channel blockers are being used less often since the introduction of newer therapies, such as prostacyclin and its analogues and endothelin antagonists.

 

 

 

 

 

 

 

 

 

 

 

 

PPH predisposes patients to thrombosis in the pulmonary arteries secondary to sluggish blood flow and sedentary lifestyle.  Additionally, increased levels of thromboxane have also been found in patients with PPH, which may favor formation of thromboemboli.  It is, therefore, recommended that patients with PPH be on warfarin therapy with a goal INR of 2.¹

 

Lung Transplantation

Transplantation is the only curative therapy for PPH.  Indications for transplantation are NYHA class III or IV despite optimum medical therapy, cardiac index less than 2 L/min/m², right atrial pressure greater than 15 mm Hg, and mean pulmonary arterial pressure greater than 55 mmHg.  The major side effects are obliterative bronchiolitis or chronic rejection.²

 

Epoprostenol

Epoprostenol (Flolan) is prostacyclin.  Prostacyclin has been shown to cause vasodilation and decrease in platelet aggregation in patients with PPH.  When epoprostenol in addition to conventional therapy was compared to conventional therapy alone, it was shown to be superior in increasing exercise capacity and improving hemodynamics after a 12 week period.⁵ Epoprostenol has also been shown to improve survival at 1, 3, and 5 years.⁶ Major side effects include hypotension, jaw pain, diarrhea, flushing, nausea and vomiting.  Tachyphalaxis is common and dosages have to be increased throughout the duration therapy.  Epoprostenol must be delivered intravenously with a continuous delivery pump, which causes complications of infection and thrombosis secondary to the complex delivery system.  Dosage is usually limited by systemic hypotension.  Epoprostenol is often used as a bridge to transplantation. Aerosolized prostacyclin (iloprost) is currently available in Europe, but not in the United States.   Because it is an inhaled nebulizer it is easier to take; but, its disadvantages are that it’s short half life make it necessary to dose it 6-12 times a day.  The cost of epoprostenal is $5000.00-$6000.00/mo which includes the cost of the catheter and pump delivery system.

 

Bosentan

Bozeman (Tracleer) is an oral endothelin receptor antagonist.  Endothelin 1 is a potent vasoconstrictor and smooth muscle mitogen, and may contribute to increasing pulmonary vascular tone and hypertrophy. Patients with pulmonary hypertension have been shown to have higher concentration of endothelin 1 in their plasma and lungs.  Bosentan blocks both endothelin 1 and 2.  Two randomized controlled trials comparing bosentan to placebo showed an increase in six minute walk time, improvement in cardiopulmonary hemodynamics, and greater improvement in WHO functional class.^{7, 8} The only major side effect in both studies was a greater incidence of increased liver function tests in the bosentan group.  There are currently no studies comparing bosentan to epoprostenal; however, bosentan does provide the benefit of being oral as opposed to IV.  There is no mortality data on Bosentan.  The cost of bosentan is approx $600.00-$800.00/month.

 

Sildenafil

Sildenafil (Viagra) is starting to be used to treat PPH and PAH secondary to connective tissue diseases.  It is a phosphodiesterase 5 (PDE5) inhibitor, and leads to relaxation of the smooth muscle.  It is currently approved in the United States for erectile dysfunction.  Phosphodiesterases are a family of enzymes that break down cyclic adenosine monophosphate (cyclic AMP) and cyclic guanosine monophosphate (cyclic GMP).   The phosphodiesterase 5 inhibitor sildenafil is thought to work by increasing availability of cyclic GMP, a potent vasodilator in the lung.  Cyclic GMP works through the nitric oxide pathway of vasodilation.  PDE5 is found in greater numbers in the lung as opposed to other tissues.  Because of this predominance, it is hoped that sildenifil may cause dilation of the pulmonary arteries, thereby decreasing pulmonary arterial pressures with little effects on systemic blood pressure.

 

Stiebellehner, et al.  Long-term Treatment with Oral Sildenafil in Addition to Continuous IV Epoprostenol in Patients with Pulmonary Arterial Hypertension, Chest 123: 1293-1295, 2003. 

 

In this case review, three patients with PAH who were already receiving epoprostenol were started on the sildenafil.  The ages of the patients were 61, 33, and 51 years old and all were female.  Patients 1 and 2 had PPH and patient 3 had PAH secondary to closure of atrial septal defect.  The epoprostenol dose was not changed in the three months preceding the trial.    Patients had their baseline six-minute walk test (6MWT) and cardiopulmonary hemodynamic parameters (pulmonary arterial pressure, cardiac output, and pulmonary vascular resistance) measured at initiation of therapy (table 1).

 

 

 

 

Patient 1 was kept on 50 mg of sildenafil four times a day without any side effects.  Patients 2 and 3 could not tolerate the higher dose secondary to nausea and vomiting and had a maximum dose of 12.5 mg six times a day.   All three patients were continued on their current doses of epoprostenol. The results are listed in table 1.  Patient 1, 2 and 3 had a -14.3%, -41.4%, and -21.8% decrease in PAP respectively, and a 34.4%, 6.36%, and 28.5% increase in their six minute walk time

Variables	PAP, mm Hg		Cardiac Output, L/min	PVR, dyne · s · cm-5	Mean Arterial BP, mm Hg	SaO2, %	SvO2, %	6MWT Distance, m
Patient 1
Baseline		49	4.8	536	73	89	75	305
Treatment		42	7.1	280	68	90	73	410
Patient 2
Baseline		70	4.8	1,128	76	93	60	550
Treatment		41	Not done	Not done	72	95	59	585
Patient 3
Baseline		55	2.2	1,464	75	91	52	245
Treatment		43	3.5	664	72	94	57	315

Table 1

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

As the table shows, all patients had an increase in the SMWT and a decrease in their pulmonary artery pressures after five months when compared to their numbers at initiation.  These results that sildenafil might be of benefit when added to epoprostenol in patients with refractory PPH are encouraging.  Also promising is that the drug was still effective after 5 months.  Sildenafil might also be useful in increasing the time to transplantation in patients who have maximized their prostacyclin therapy.  However, the limitations of the study were that it is a case review with a small sample group, which limits its clinical application and power.

 

Wilkens, et al.  Effect of Inhaled Iloprost plus Oral Sildenafil in Patients with PPH, Circulation 104: 1218-1222, 2001.

 

 

 

Iloprost is a prostacyclin analogue that has been aerosolized, and is inhaled via nebulizer.  Its advantage over epoprostenol is that it does not require continuous IV access.  Its disadvantages are that it has a short half-life; and the effects wear off in 30-60 minutes after nebulization.  Usually, 6-12 inhalations are required daily.  In this prospective crossover study sildenafil was added to iloprost to see if there is prolongation of the effects.

 

 

 

 

 

 

 

 

 

 

 

 

 

Patient	Age, y	Sex	Duration of PPH, y	Weight, kg	Height, cm	Mean PAP, mm Hg	PVR, Dyne · s · cm-5	CVP, mm Hg	NYHA Class	Treatment
1	59	Female	2.5	69	155	68	1447	20	IV	Inhaled iloprost, warfarin, furosemide, spironolactone, LTOT
2	60	Female	4	54	158	62	1982	12	IV	Inhaled iloprost, warfarin, furosemide, LTOT
3	52	Female	2	73	159	58	1338	8	III	Inhaled iloprost, warfarin, amlodipine, LTOT
4	49	Female	15	53	162	52	1526	13	IV	Inhaled iloprost, warfarin, furosemide, spironolactone, LTOT
5	62	Male	1.5	70	170	49	820	3	III	Warfarin
LTOT indicates long-term oxygen treatment.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Table 2
 

 

 

 

 

 

 

 

 

 

 

 

This study included five patients with PPH, in New York Heart Association Class III or IV. Exclusion criteria were pregnancy, hypotension, secondary pulmonary hypotension, or any other significant disease.  As table 2 shows, four of the five patients were being treated with iloprost before the study.  Patients were admitted to the ICU and Swan Ganz catheters were placed.  Baseline hemodynamic (PAP, CO, PVR) measurements were taken after a 30 minute equilibrium period. (Table 2)

 

 

 

 

 

 

Figure 1

After patients had received aerosolized iloprost, measurements were taken at fifteen minute intervals for 2 hours.    Patients were then given two 25 mg doses of sildenafil 30 minutes apart.  Measurements were again taken every 15 minutes.  Patients were given another 50 mg of sildenafil if there was no response after 60 minutes.  Patients were given a second dose of iloprost 90 minutes after the first sildenafil dose.

Table 3

After inhalation of iloprost, patients had a decrease in their mean PAP -16.3% +/- 2.2% (p<0.01) and PVR -43.8% +/- 3.9% (p<0.05), with a return to baseline after 120 minutes.   Sildenafil alone produced similar results with a reduction in PAP of -12.6+/- 0.9% (p<0.01) and in PVR of 21.8% +/- 3.0% (p<0.03). Interestingly most of the effect of the sildenafil was seen after the first 25 mg dose.  The combination of sildenafil and iloprost produced the most dramatic results with a decrease in PAP –24.7+/-3.0% (p<0.002) and PVR of - 43.0 +/- 2.7% (p<0.02) 15 minutes after the inhalation, and remained decreased at the end of the 120 minute period, PAP -15% (see table 3 and figure 1).

 

This small open trial once again showed the benefits of sildenafil; however, the study is limited by its small size, lack of randomization, and lack of long term follow up.  The patients with sildenafil alone seem to have a longer effect of the medication with or without the iloprost, but the two agents together seemed to cause a more dramatic, but transient, decrease in PAP.  An increase in cardiac output was also seen, without an increase in heart rate, but the differences were not statistically significant.   Of interest, as well, was the observation that most of the benefit from sildenafil occurred after the first 25 mg dose and that additional doses did not significantly decrease PAP.  In conclusion, while interesting and encouraging, this trial lacks the size, randomization, and placebo control group to change clinical management of PPH.

 

Ghofrani et al. Combination Therapy with Oral Sildenafil and Inhaled Iloprost for Severe Pulmonary Hypertension, Ann Intern Med 136: 515-522, 2002. 

 

In this randomized, open trial, the effectiveness of sildenafil alone and in combination with iloprost was studied.  The study design was a randomized open label trial in the intensive care unit.  The patient population consisted of 30 patients (23 women, 7 men) with pulmonary hypertension.  Sixteen patients had pulmonary arterial hypertension (PAH), 13 had chronic thromboembolic pulmonary hypertension, and 1 had pulmonary hypertension secondary to aplasia of the left pulmonary artery.  Of the 16 patients with PAH, 10 had PPH and 6 had calcinosis, Raynaud’s, esophageal dysfunction, sclerodactyly, and telangiectasia (CREST syndrome). 

 

Inclusion criteria for the study included severe pulmonary hypertension with PAP> 40mm Hg, and classification as NYHA class III or IV.  Patients were excluded if they had pulmonary hypertension secondary to COPD, pulmonary venous congestion, congenital heart disease, inflammatory lung disease, pregnancy, or previous treatment with phosphodiesterase inhibitors.     

Table 4

 

Each patient had a vasodilation trial with inhaled nitric oxide after Swan-Ganz catheter placement.  Pulmonary arterial pressure (PAP), cardiac index (CI), pulmonary vascular resistance (PVR), and systemic vascular resistance (SVR) were measured at baseline and after nitric oxide.  After all measurements had returned to baseline, inhaled iloprost was delivered via nebulizer and measurements were again taken from the Swan-Ganz catheter.  As expected the iloprost reduced PAP by -11%, PVR by -27.1% (22.2% to 32.1%), and increased Cardiac Index by 22.8% (17.6% to 27.9%).   The 30 patients were then randomized into 4 groups: 12.5mg of sildenafil alone, 12.5 mg sildenafil plus iloprost, 50 mg sildenafil alone, and 50 mg sildenafil plus iloprost.  The baseline characteristics of the patients in each group are shown in table 4.  A second iloprost dose was given 1 hour after sildenafil was administered.  Pulmonary artery pressure, pulmonary vasculature resistance, systemic vascular resistance, and cardiac index measurements were taken for up to 3 hours at 30 min intervals.

Sildenafil at both 12.5 mg and 50 mg doses decreased pulmonary artery pressure by -8.5% (p<0.05, +/-6.6%) and -13.5% (p<0.05, +/-10.3%) respectively.  Pulmonary vascular resistance also decreased by -14.7% (p<0.001, +/-8.1%) with 12.5mg of sildenafil and by -24.3% (p<0.001, +/-7.6%) with the 50 mg dose.  Cardiac index also increased by 13.2% (p<0.01, +/-8.9%) with the 50 mg sildenafil dose, but was not statistically significant with the 12.5 mg dose.  The combination of 50 mg sildenafil and iloprost showed decreases in pulmonary vascular resistance of -44.2% (p<0.05, +/-5.4%) and pulmonary arterial pressure by -17.5% (p<0.001).  The pulmonary arterial pressure was decreased 11.5% (p<0.05) with the 12.5 mg sildenafil dose and iloprost (figure 2 & 3).

 

Figure 2

Figure 3

 

The study was limited by sample size and lack of long term observations; however, it is encouraging from the standpoint that sildenafil did lower both pulmonary arterial pressures and pulmonary vascular resistance, and increase cardiac index especially at higher doses, without any major side effects.  Sildenafil in combination with iloprost appear to provide greater decreases in PAP and PVR, than either therapy alone; however, it does not appear that sildenafil prolongs the therapeutic effect of iloprost.  Interestingly, sildenafil and iloprost improved pulmonary hemodynamics in patients with primary pulmonary hypertension, as well as those with chronic thromboembolic disease.   

 

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

               

This case review aimed to show the long-term safety and efficacy of sildenafil.  Five patients (3 males, 2 females) were included in this study, four with PPH and one with Eisenmenger’s syndrome.  Four patients were NYHA class III and one was NYHA class II.  Patients on epoprostenol and NYHA IV were excluded from the trial.  All patients had been stable for three months, with no changes in their medications and were on traditional agents including diuretics, calcium channel blockers, and coumadin.

Figure 4

 

 

 

 

Patients had right heart catherization and 6-minute walk at baseline and 3 months after initiation of therapy.  Three patients had cardiac MRI at baseline and at three months. The results are in figure 4.   PAP decreased 25.7% or 18 mm Hg after three months of sildenafil.  Statistically significant increases in six-minute walk time were also seen in all patients with improvement ranging from 50 to 100m.    Interesting also were the findings on the 3 patients who underwent Cardiac MRI.  All had decreases in the size of the right ventricles, increases in the RV ejection fraction, and reversal of the paradoxical septal shift. 

The limitations of this study are the lack of placebo control and randomization, as well as its small sample size.  Sildenafil was added to traditional therapies in this study, as opposed to a prostacyclin analogue, as it had in previous studies.  The effectiveness of sildenafil in lowering pulmonary artery pressure and increasing the six-minute walk time after three months of therapy shows the possible potential for sildenafil in the clinical setting, but larger studies are needed. 

Conclusions

After extensive review of the literature it appears that sildenafil alone and in combination with prostacyclins has benefit for treating patients with primary pulmonary hypertension.  It has been shown to decrease pulmonary artery pressure and increase 6-minute walk time, but most of the studies have been open trials or case reviews with small focused groups. Stiebellehner et al and Michelakis et al showed the benefit of sildenafil on PAP and 6MWT after five and three months of the drug, respectively.  However, both studies were case reviews with three and five patients respectively, which limit its clinical application.  Ghrofani et al did show decreases in PAP and PVR in larger sample group (n=30) but lacked long term data.  A larger multi-center randomized controlled trial that shows hemodynamic or mortality benefit of sildenafil alone or in combination with other therapies would be helpful. The cost of four times a day sildenafil is approximately $3600.00/year or $300 a month, which is less expensive than both epoprostenol and bosentan. However, epoprostenol and bosentan have both been shown to have benefit in treating PPH in well designed randomized control trials and are approved for treating PPH.  Epoprostenol has also been shown to reduce mortality in patients with PPH.  Sildenafil has many benefits over bosentan and epoprostenol including its relative few side effects, cost, and easy oral delivery.  In conclusion, sildenafil may be of benefit for PPH, but the data is preliminary.  Despite this fact, sildenafil may have benefit in treating refractory patients who have maximized their dose of epoprostenol or are intolerant of other vasodilator therapy and are awaiting lung transplantation.

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References

 

1.  Rubin LJ.  Primary Pulmonary Hypertension.  New England Journal of Medicine 336: 111-117, 1997.

2.  Runo JR, Loyd JE.  Primary Pulmonary Hypertension. Lancet 361:1533-44, 2003.

3.   Rich S, Dantzker DR, et al.  Primary Pulmonary Hypertension: a national prospective study.  Ann Internal Medicine 107: 216-223, 1987.

4.    Rudarakanchana N, Trembeth RC, Morrell NW.  New Insights into the Pathogenesis and Treatment of Primary Pulmonary Hypertension.  Thorax 56: 888-890, 2001.  \

5.    Barst RJ, Rubin LJ, et al.  A Comparison of Continuous Intravenous Epoprostenol with Conventional Therapy for Primary Pulmonary Hypertension.  New England Journal of Medicine 334: 296-301,               1996. 

6.    Barst RJ, Rubin LJ, et al.  Survival in Primary Pulmonary Hypertension with Long-Term Continuous Intravenous Prostacyclin.  Annals of Internal Medicine 121: 409-415, 1994.

7.    Rubin LJ, Badesch DB, et al.  Bosentan Therapy for Pulmonary Arterial Hypertension. New England Journal of Medicine 346: 896-903, 2002.

8.   Channick RN, Simonneau G, et al.  Effects of the Dual Endothelin-Receptor Antagonist Bosentan in Patients with Pulmonary Hypertension: a Randomized placebo-controlled study.  Lancet 358: 1119-1123, 2001.

9.     Stiebellehner L, et al. Long-Term treatment With Oral Sildenafil in Addition to Continuous IV

 Epoprostenol in patients with Pulmonary Arterial Hypertension.  Chest 123: 1293-1295, 2003.

10.   Wilkens H, et al.  Effect of Inhaled Iloprost plus Oral Sildenafil in Patients with Primary Pulmonary

 Hypertension.  Circulation 104: 1218-1222, 2001.

11.   Ghofrani HA, Wiedemann R, et al.  Combination Therapy with Oral Sildenafil and Inhaled Iloprost for Sever Pulmonary Hypertension.  Ann Intern Med 136: 515-522, 2002. 

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

 

 

 

 

 

 

 

 

 

 

 

 

 

Sildenafil

And

Primary Pulmonary Hypertension

Azim E. Surka

WFUBMC

Resident Grand Rounds

November 11, 2003