Treatment of PAH consists of general and specific measures. General measures include oxygen, diuretics, and restriction of physical activity, etc. Specific measures include medications that are mainly targeted for PAH.
Intravenous epoprostenol was introduced in 1995. Since then significant advances in the treatment of PAH have been made in the last 15 years, with eight new medical therapies having been approved. These agents target the prostacyclin pathway, nitric oxide pathway and the endothelin pathway . In addition, combination trials have clearly demonstrated synergistic benefit by targeting two or three pathways.
The three major pathways involved in regulation of vasomotor tone in the pulmonary vasculature
Nitric oxide treatment is very cumbersome and its only possible role is in the management of pulmonary hypertension in neonatal ICU and occasionally in adult ICU. Even though anecdotal reports of improvement in oxygenation have been reported in ARDS patients, outcome measures such as mortality have not been shown to be favorably affected by nitric oxide treatment.
Calcium channel blockers
High-dose calcium channel blockers have been shown by uncontrolled studies to prolong survival in patients with pulmonary arterial hypertension.[42
] About 10% of patients with PAH belong to this group. Interestingly, patients with BMPR2 receptor mutation do not respond to calcium channel blockers. Signaling through BMPR2 and other similar receptors plays an important role in intimal and smooth cell proliferation and has no role in maintenance of vasomotor tone. Patient who may benefit from calcium channel blocker therapy can be identified by performing an acute vasodilator response test using inhaled nitric oxide, intravenous prostacyclin or adenosine during right heart catheterization.[43
] The magnitude of the short-term response to vasodilator that predicts long-term response to calcium channel blockers is not well defined.[43
] It is widely accepted that 20% reduction in mean pulmonary arterial pressure and or pulmonary vascular resistance is essential to undertake therapy with calcium channel blockers. In a large retrospective study of 557 patients with pulmonary arterial hypertension, less than 7% of patients responded to calcium channel blockers. Those patients who had a significant vasodilator response had a long-term response to calcium channel blockers. Long-term therapy with calcium channel blockers is not recommended when there is no acute vasodilator response.[44
The role of warfarin in the treatment of pulmonary arterial hypertension is not well defined. However, a large number of patients dying with PAH postmortem studies have shown a high incidence of thrombosis.[44
] Warfarin has been evaluated in two studies, one retrospective and one prospective. The authors had recommended keeping the INR between 1.5 and 2. Even though there are no double blind placebo controlled trials warfain is recommended by both AHA and ACP in functional class III and IV patients with idiopathic pulmonary hypertension.
Prostacyclin, the main product of arachidonic acid in the vascular endothelium causes relaxation of smooth muscle by stimulating the production of cyclic AMP and also results in inhibition of growth of smooth muscle cells.[45
] Intravenous prostacyclin was first introduced in the treatment of primary pulmonary arterial hypertension in the early 1980s. Forty-four Cohort analysis of patients receiving intravenous prostacyclin has shown benefits in NYHA class III and IV with regard to survival.[46
In addition to idiopathic pulmonary arterial hypertension, epoprostenol has been successfully used in the treatment of pulmonary hypertension resulting from left to right shunt, portal hypertension and HIV infection.[48
The normal dose of epoprostenol is 21 ng/kg/min. The dose can be increased up to 32 ng/kg/ min after a year. Epoprostenol has a definite role in the treatment of primary and other forms of pulmonary hypertension. However, it is expensive and very cumbersome to use. Administration of this medication requires a central line and a pump. Central line infection is a serious side effect. Other side effects include flushing, headache, jaw pain, leg pain, nausea, and diarrhea. Care should be taken when using this medication in venoocclusive disease and pulmonary capillary hemangiomatosis. Severe pulmonary edema has been reported with use of epoprostenol in these conditions. The reason for this is because of increased perfusion in the presence of vascular obstruction downstream.[52
Treprostinil is a stable prostacyclin that can be administered either subcutaneously or intravenously. The usual dose is 0.625–40 ng/kg/min.[54
] When switching from epoprostenol the starting dose of treprostinil is usually 10% of the dose of epoprostenol the patient was receiving at the time of switch. Side effects are the same as that of epoprostenol.
Treprostinil can also be given as an inhalation usually in the form of a nebulizer. The usual dose is 18 mcg (three breaths) four times a day. The dosage is usually increased to 54 mcg (nine breaths) four times a day in a few weeks. Common side effects of inhaled treprostinil include epistaxis, hemoptysis, hypotension, and syncope in addition to other side effects that are common to epoprostenol.
Beraprost sodium is a prostacyclin analog that has been approved in Japan. Clinical trials have shown improvement in 6-min walk test but not in the hemodynamics. The dose that has been used in Japan is 18 mcg four times a day.[56
Iloprost is a stable prostacyclin analog that can be given as an inhaled medication. The optimal particle size is 0.5–3 mcg to ensure alveolar deposition. The usual dose of iloprost is 2.5–5 mcg by nebulizer q.2–4 h.[58
Endothelin receptor antagonist
Bosentan is a nonselective endothelial receptor antagonist. Endothelin A receptor stimulation results in vasoconstriction and smooth muscle proliferation. Endothelin B receptor stimulation results in endothelin clearance and induction of nitric oxide and prostacyclin by endothelial cells. Sitaxsentan and ambrisentan are selective ETA receptor antagonists. Bosentan is metabolized by the liver and an increase in transaminases has been noted during treatment with this medication. Hence, it is mandatory to perform periodic liver function tests in patients taking bosentan. The usual dose of bosentan is 62.5 mg twice a day and this can be increased to 125 mg twice a day.
Two randomized double-blind placebo-controlled trials have evaluated bosentan in patients with pulmonary arterial hypertension. In a pilot study,[61
] 33 patients with PAH In functional class III or IV were randomized to receive either placebo or bosentan. Patients in the bosentan arm received 62.5 mg of the medication twice daily. After 4 weeks the dose was increased to 125 mg twice daily for at least 12 weeks. Significant improvement in 6 min walk test and hemodynamics were noted in the bosentan group. Subsequently, a large study consisting of 213 patients in functional class III and IV we randomized to receive either placebo or bosentan. After 4 weeks the treatment group was divided into two groups, one receiving 125 mg twice a day and the other 250 mg twice a day for at least 12 weeks.[62
] In addition to the improvement in 6 min walk test and hemodynamics, improvement in the time to clinical worsening such as death, lung transplantation, and hospitalization was noted. No dose response effect with respect to the drugs efficacy could be ascertained.
Sitaxsentan has 7000-fold higher activity for ETA receptors than ETB receptors. The dose of oral Sitaxsentan is 100 mg daily. Hepatotoxicity has been noted as with bosentan.[63
Ambrisentan is another ETA receptor blocker and is given in a dose of 5 mg daily. This can be increased to 10 mg daily. Again acute hepatitis has been described with the use of this medication.
Sildenafil is a phosphodiesterase 5 (PDE-5) inhibitor that increases the levels of cyclic GMP in smooth muscle cells and causes vasodilatation. It was initially used in angina pectoris and later for erectile dysfunction. The normal dosage in pulmonary arterial hypertension is 20 mg three times a day. Doses as high as 200 mg per day have been used. However, higher doses have not been found to be anymore effective. Common side effects include flushing, epistaxis, and visual disturbances. More serious reactions such as sudden blindness, myocardial infarction, stroke and sudden cardiac death secondary to ventricular arrhythmias, subarachnoid hemorrhage and retinal hemorrhages have been recognized. Tadalafil is a long acting phosphodiesterase 5 inhibitor, which can be given once a day at a dose of 40 mg.
The major landmark trial involving sildenafil was the sildenafil use in pulmonary arterial hypertension (SUPER) study. Two hundred seventy eight patients in functional class II–IV were randomized to three different doses of sildenafil namely 20, 40, or 80 mg three times daily or to placebo. The study extended for 12 weeks and based on the favorable results FDA approved 20 mg three times daily of sildenafil in the treatment of pulmonary arterial hypertension.[66
] PHIRST Trial studied the efficacy and safety of long acting phosphodiesterase-type five inhibitor (PDE 5-I) tadalafil. Patients with PAH were either treatment naïve or were already receiving bosentan. The study extended over a period of 16 weeks and the doses of tadalafil used in the study were 2.5, 10, 20, and 40 mg. Based on the favorable response FDA approved 40 mg once a day of tadalafil.[67
Combination therapy to target more than one or two pathways involved in the vasomotor tone of pulmonary vessels is appealing. Combination therapy has already been born out in the treatment of systemic hypertension. Even though it is appealing it is not entirely clear at this time whether combination therapy is more effective than monotherapy and if it alters the natural course of the disease in pulmonary arterial hypertension.
Combination therapies can be either concomitant therapy or add on therapy. To date all published trials have been done with add-on therapy.
Prostanoids and ETA receptor antagonist
In the recent multicenter placebo-controlled safety and pilot efficacy trial ((STEP) in combination with Bosentan for the evaluation in pulmonary arterial hypertension) iloprost was added to bosentan in patients with dyspnea (NYHA 3 or 4). Improvement in post inhalation hemodynamics and lengthening of time to clinical worsening were noted. Based on this trial, FDA approved iloprost as an add-on therapy in patients receiving bosentan.[68
Prostanoids and PDE 5 inhibitors
Among many trials looking at combination of prostacyclin and PDE 5 inhibitors, the most noteworthy is pulmonary arterial hypertension combination study of epoprostenol and sildenafil (PACES). Improvement in symptoms of shortness of breath and increasing 6 min walk test were noted.[69
Endothelin receptor antagonist and PDE 5 inhibitors
The benefits of combination treatment with Endothelin receptor antagonist (ERAs) and PDE-5 inhibitors came from EARLY (endothelin antagonist trial in mildly symptomatic PAH patients) trial, COMPASS-1 (hemodynamic effects of a single dose of sildenafil in symptomatic patients on bosentan treatment for PAH).[70
There is a potential interaction between bosentan and sildenafil as both are metabolized through CYP3A4. Bosentan levels may go up and increase side effects of Bosentan such as postural hypotension. Sildenafil levels have also been shown to fall with the combination treatment but these do not seem to affect the management of pulmonary hypertension as the dose of sildenafil can always be adjusted.
The major debate regarding combination treatment is whether a second medication should be used as an add-on medication or whether it should be started concomitantly from the start. There are advantages and disadvantages to each of these. In the add-on modality, the patient should be followed up very closely and a second medication added when there is failure of improvement based on 6-min walk test, hemodynamics and cardiac MRI. If a similarity can be drawn between cancer treatments and PAH, it can very easily be conceived that combination treatment has an edge over add on treatment.[72
] The major disadvantages with combination treatment are cost and risks.
Any discussion of pulmonary arterial hypertension will be incomplete without mentioning the role of lung transplantation. Both single and double lung transplantation have been carried out for a select group of patients with pulmonary arterial hypertension when targeted vasodilator therapy does not produce any improvement, and patients continue to remain in functional class III and IV. Decrease in pulmonary vascular resistance occurs within the first 24–48 h and improvement in right ventricular hemodynamics takes anywhere from a few days to a few weeks after lung transplantation. Heart lung transplantation is mostly reserved for children with Eisenmenger syndrome or in adults with severe right ventricular dysfunction. The benefits of lung transplantation have to be carefully weighed against the known complications of lung transplantation namely long-term immunosuppression and graft rejection. Atrial septostomy is not used any more since the advent of epoprostenol. It is reserved in exceptional cases with deteriorating cardiac index and increasing pulmonary vascular resistance despite epoprostenol.
A step wise algorithm in the management of PAH is illustrated in .
Treatment algorithm for pulmonary arterial hypertension
Newer therapies in PAH
Newer agents show a great promise in the treatment of PAH. All the available medications for PAH have some effect on the proliferation of mesenchymal cells namely smooth muscle cells but have no effect on the proliferation of endothelial cells which appears to be the major disturbance in the pathogenesis of PAH.[73
Newer agents such as cicletanine and riociguat provide much superior effect in comparison with the available agents for PAH. Tyrosine kinase inhibitors may address the neoplastic aspects of PAH and cell based gene therapy to reseed the vascular compartment with normal apoptosis sensitive endothelial cells are certainly in the horizon.[74
] Both cyclic guanosine mono phosphate (GMP) and cyclic adenosine mono phosphate (AMP) promote vasodilatation and inhibit smooth muscle proliferation by joining with protein kinase G.[75
] The mode of action of the newer drugs is well illustrated in . In PAH, NO synthase activity is reduced and as a result nitric oxide driven cyclic GMP production via Guanylate Cyclase is also reduced.[76
] PDE 5 levels may be increased in PAH and the available PDE 5 inhibitors increase the levels of cyclic GMP. Riociguat enhances the effect of soluble GC and hence increase cyclic GMP.[77
] Riociguat has no major side effects except dizziness, urgency micurition, urinary retention, and nasal stuffiness. There is a minor interaction with warfarin and prothrombin levels need to be watched closely in the beginning. Cicletanine has been used as an antihypertensive agent in Europe for the last few years. A phase II trial using 150 mg twice a day or 300 mg daily is currently underway.[78
Nitric oxide pathway and the site of action of the new medications cicletanine and riociguat
PAH can be considered a localized form of neoplasia. There is overexpression of certain growth factors such as platelet-derived growth factor and their receptors in PAH. Activation of these receptors increases tyrosine kinase activity. Well-known chemotherapeutic agents such as imatinib and sorafenib act by attaching themselves to these receptors and decreasing the activity of tyrosine kinase. After satisfactory preliminary results, phase 3 trials (IMPRESS) have been launched using imatinib. Imatinib is being currently used for myelogenous leukemia and gastrointestinal stromal tumors. Sorafenib is a broad-spectrum tyrosine kinase inhibitor, which has been used in the treatment of advanced renal cancer and hepatocellular carcinoma.[79
Reseeding the lung bed
Whenever there is an injury to the endothelial cells, endothelial progenitor cells (EPCs) originate in the bone marrow and reach the affected areas. It is likely that the initial injury results in widespread endothelial apoptosis and subsequent emergence of apoptosis resistant endothelial cells. Normal EPCs might limit this process by replacing the apoptosis resistant cells. It is entirely possible that EPCs in PAH patients may not work “normally.” Increased levels of bone marrow derived proliferative precursor cells by constantly invading the endothelial vascular bed contribute to excess cell burden in the pulmonary vasculature.[81
With the development of techniques to isolate cultured EPCs, cell therapy for pulmonary arterial hypertension may become a reality. Lungs microvasculature by acting as sieve will trap the exogenous endothelial cells and altering the internal milieu will restore the normal pulmonary vascular physiology. In animal models transfection of EPCs with eNOS has been shown to increase the levels of NO and provide additional benefit.[82
EPC therapy has now entered human trials. A randomized study looked at the effects of intravenous autologous EPCs in patients with PAH who were receiving conventional therapy. Significant improvement in 6 minute walk test and hemodynamics were noted 12 weeks after a single bolus of autologous EPCs.[83
A comprehensive discussion on the management of pulmonary hypertension associated with various connective tissue disease and interstitial lung disease is beyond the scope of this paper. However, it is important to mention the management of pulmonary hypertension in COPD and sleep apnea patients. There is clearly a group of patients in COPD who have significantly higher pulmonary pressure not commensurate with the severity of their disease. These patients need to be treated as aggressively as patients with Idiopathic pulmonary hypertension. In clinical practice it is often very difficult to initiate treatment for pulmonary hypertension based on Echocardiography in a patient with COPD or Interstitial Lung disease. Even after ruling out various other causes of pulmonary hypertension there is currently not enough data to warrant the treatment with specific agents such as sildenafil or Bosentan even though anecdotal case reports of success have been reported. It is generally believed that the pulmonary pressure elevation in sleep apnea patients is minimal and this usually settles down after initiation of Continuous Positive Airway Pressure (CPAP) treatment for these patients. The general rule of thumb in the management of these patients is that when expected improvement is not seen in these patients the physician should be aware of the possibility of the existence of an unrelated pulmonary hypertension and initiate treatment for the same. Even though there is a wealth of information on this topic there is no clear consensus on this issue.
Pulmonary arterial hypertension, until a few years ago was considered a rapidly progressive disorder, ultimately resulting in death. There has been a significant paradigm shift in the treatment of PAH with anticancer medications such as imatinib and sorafenib and more recently with transfusion of autologous EPCs transfected with eNOS to radically replace the pulmonary vascular bed with “normal endothelial cells.” We definitely have entered into an exciting new era in this field with a number of these new medications already being available to treat this condition and the distinct prospect of novel therapies such as tyrosine kinase inhibitors and autologous EPCs.