Therapy goals are an improvement in symptoms, quality of life and survival. Changes in functional capacity (6-minute walk test, ergometry, etc.) and haemodynamics are used to assess therapeutic success. In principle, PH patients should always be managed by specialist centres.
In general, patients affected by this condition should avoid physical exertion since this may lead to dramatic increases in pulmonary vascular pressure. Efficient infection prophylaxis and aggressive treatment of infections should also be ensured. Since 50% of all pregnancies in PH women have a fatal outcome, strict contraception is recommended.
1. Oral anticoagulation
Blood clots in the small resistance vessels of the lung are a common phenomenon in PH. On the basis of one prospective and two retrospective trials, oral anticoagulation is recommended for all patients with iPAH. The European Society of Cardiology (ESC) recommends an INR of between 1.5 and 2.5 as the target value. Few data are available regarding anticoagulation in associated forms of PAH. The international expert consensus is that anticoagulation is recommended for these patients only at an advanced stage of the disease (e.g. patients receiving continuous i.v. therapy). For patients with CTEPH, oral anticoagulation with a target INR of 2.5–3.5 is indicated in order to prevent any further thrombotic event.
Diuretics are used to treat right heart failure, which may result in ascites and peripheral oedema at an advanced stage of the disease. Calcium-sparing diuretics are preferred because of their aldosterone-antagonising action and are given once daily. However no clinical trials are available in this patient population so that the selection of substance class and dosage is left to the experience of the physician treating the patient.
The majority of patients with PAH has only mild arterial hypoxaemia. Patients with a patent foramen ovale may develop considerable hypoxaemia. Although no consistent trial data are currently available, the ESC recommends oxygen therapy for all patients.
4. Digitalis and dobutamine
It has been demonstrated that short-term intravenous administration of digoxin in cases of iPAH causes a slight improvement in cardiac output and a significant reduction in circulating norepinephrine . However, since no data are available proving the effect of long-term treatment with positive inotropic agents, the use of these substances is left to the doctor treating the patient.
5. Specific vasodilators
A number of specific vasodilators are currently available for the treatment of PAH. The substances listed are recommended by international professional associations on the basis of positive trial results.
5.1. Calcium channel antagonists. The use of calcium channel blockers is only justified in cases of genuine haemodynamic responders with idiopathic PAH. The success of the treatment must be documented consistently. If patients who are described by definition as “acute responders” do not achieve functional stages I or II under calcium channel blocker therapy, an alternative or additional PAH treatment should be considered. The substances used in trials are nifedipine (120–240 mg/day) or diltiazem (240–720 mg/day). Arterial hypotension and oedema of the legs are particular limiting factors for this treatment.
5.2. Beta-blockers. According to the recommendation of the Guidelines, beta-blockers are contraindicated in PH because of their negative inotropic action. Recent data contradict this dogma: the favourable effect of beta-blockers has in fact been illustrated in an animal model .
5.3. Synthetic prostacyclin and prostacyclin analogues. Prostanoids have a vasodilatory, anti-proliferative, anti-inflammatory and anticoagulant action. The current treatment algorithm provides for prostanoids only once patients have reached NYHA stages III and IV and for patients with right ventricular decompensation. This recommendation is arbitrary and tends to correspond more to patient desires than to evidence-based medicine. No trial exists that proves that what is known as a “goal-oriented” approach is better than a “hit-hard-and-early” strategy. In practice, the former results in significant time losses .
5.3.1. Epoprostenol (Flolan®, Dynovas®) is given intravenously. It is given on an outpatient basis using a portable infusion pump linked to a permanent central venous catheter (Hickman line) because of its short half-life (3 to 5 minutes). The dose may be altered according to requirement and tolerability, with one limiting factor here being the development of side effects, such as gastrointestinal symptoms, headache, jaw pain, diarrhoea, flush, nausea, joint pain or hypotension. The conventional starting dose under inpatient conditions is 2 ng/kg/min, gradually increased as a function of the PAH symptoms and the side effects. Most experts believe that the optimum dose for chronic treatment is 25-40 ng/kg/min, with customised adjustment being undertaken.
5.3.2. Treprostinil (Remodulin®) is given subcutaneously. The action is just as good as that of its benzidine analogue epoprostenol, but with treprostinil it is pain at the injection site that is the main limiting factor. Subcutaneous treprostinil has been authorised since 2002 for functional classes NYHA II, III and IV. The TRIUMPH trial was able to demonstrate the efficacy of inhaled treprostinil , while oral pharmaceutical forms were unable to demonstrate any benefit for patients with PAH in trials that have not yet been published.
5.3.3. Inhaled iloprost (Ventavis®) is well established in trials but almost exclusively used as a supplementary therapy in practice. One reason for this might be the fact that, because of its short half-life, iloprost has to be taken every 90 minutes. It has been authorised since 2004 for functional classes NYHA III and IV. Improvements in terms of performance efficiency, NYHA class and haemodynamics have been observed in randomised trials .
5.3.4. Selexipag is the first selective, orally administered prostacyclin receptor agonist. This class of substances is unique and new. A placebo-controlled double-blind trial was able to demonstrate a statistically significant reduction in pulmonary vascular resistance (PVR – as primary endpoint of the trial) after 17 weeks. With a reduction of 30% in PVR, this primary endpoint was therefore achieved with a high level of statistical significance.
5.4. Endothelin receptor antagonists (ERA). Endothelin (ET) is a strong vasoconstrictor which is created in increased amounts in PH patients and leads to vasoconstriction and remodelling. Endothelin also stimulates the proliferation of smooth muscle cells in the pulmonary blood vessels. Two endothelin receptors are known (ET-A and ET-B), blockade of which results in vasodilation without reflex tachycardia and in improvement of endothelial function. Endothelin-1 plasma levels correlate with the severity and prognosis of the disease.
5.4.1 Bosentan (Tracleer®) is a “dual ERA”, i.e. it blocks both endothelin A and B receptors. Trials have shown that bosentan improves physical capacity, haemodynamics and possibly also the survival of patients with PH. However, 6% of patients developed a reversible increase in liver enzyme levels, so that monthly monitoring of transaminases is recommended. An improvement in haemodynamics and functional capacity was also achieved in patients with Eisenmenger syndrome (BREATHE 5 trial) . The initial data from an open-label trial in HIV patients show a clinical improvement with bosentan  and preliminary data for patients with CTEPH also provide evidence of improvement with bosentan .
5.4.2 Ambrisentan (Volibris®). Ambrisentan also selectively inhibits the endothelin A receptor. The ARIES trial demonstrated the efficacy of ambrisentan with an improvement in 6-minute walk distance and with a longer “time to clinical worsening” . Ambrisentan has been authorised for PAH patients in NYHA functional classes II and III since June 2007.
5.5. Phosphodiesterase (PDE-)inhibitors.
5.5.1. Sildenafil (Revatio®) is a PDE5 inhibitor that was developed for the treatment of erectile dysfunction (Viagra®). By increasing the intracellular concentration of cyclic GMP (cGMP), it reduces the tone of smooth vascular musculature. Clinical trials demonstrated improved performance capacity and haemodynamics during treatment . Sildenafil has been authorised for the treatment of PAH in Austria since February 2006.
5.5.2. Tadalafil (Adcirca®) is also a PDE5 inhibitor developed, like sildenafil, for the treatment of erectile dysfunction (Cialis®). Its advantage over sildenafil is the longer half-life requiring tablets to be taken only once daily (in comparison with the three times daily dosage of sildenafil) and the absence of interaction with ERAs.
5.5.3. Stimulators of soluble guanylate cyclase. The prototype of this new group of drugs is riociguat, which is currently being tested in randomised trials. A Phase 2 trial demonstrated improvements in 6MWD .
5.6. Combined therapies. In cases of lack of response or clinical deterioration with a single treatment, combined therapies are being increasingly publicised that take advantage of the various pathobiological mechanisms of the treatments available. However, care must be taken to avoid drug-drug interactions. For example, interactions have been reported between sildenafil and bosentan (increase in bosentan plasma levels and decrease in sildenafil plasma levels), although the clinical relevance of these observations is not yet clear. The ERAs bosentan and sitaxentan and the PDE5 inhibitor sildenafil act in particular on various CYP enzymes, whereas this is not the case with prostanoids and the ERA ambrisentan. Combination trials currently in progress should create greater clarity regarding the risks and benefits of different combinations of PAH-specific therapies.
5.7. Start of treatment. Since the World Symposium on Pulmonary Hypertension at Dana Point in 2008, targeted therapy is recommended even for patients who are at an early stage of the disease. The basis of this recommendation is findings from three randomised, placebo-controlled trials, in which patients in NYHA stages II and III were included. Early therapy with bosentan, ambrisentan and/or sildenafil was found to be of benefit to these patients. In Europe, the endothelin receptor antagonists bosentan and ambrisentan are the only substances authorised for the treatment of Stage II PAH  [38, 39].
5.8. Treatment of “non-PAH pulmonary hypertension” (non – PAH PH). The post-capillary form, i.e. pulmonary hypertension linked to increased left ventricular filling pressure, is the most common form of PH (post-capillary PH). It includes all the diseases that lead to an increased left ventricular end-diastolic pressure (LVEDP), i.e. reduced systolic function, diastolic dysfunction and valvular disease. The aim here is to cure or treat the underlying disease. But a specific therapy may be indicated in very rare cases if the underlying disease is being optimally treated, the PCWP is normal or minimally increased, pulmonary vascular resistance is significantly increased and an improvement of the clinical condition of the patient appears possible with a PAH-specific therapy. This form of PH is described as “out of proportion PH”, in other words greater than would be assumed from the raised left ventricular filling pressure or the lung disease. However, caution should be exercised before generally treating these patients with PAH-specific therapy until clinical trials have proved a benefit for these patients. Potential side effects of PAH-specific treatment for these patients are fluid retention, pulmonary oedema and a ventilation/perfusion mismatch .
1. Atrial septostomy
The creation of this right-left shunt is indicated in cases of right heart failure and syncope despite maximum conservative therapy. The aim is to reduce the right ventricular end-diastolic pressure. This procedure may also be used as a bridging measure before other forms of treatment.
2. Pulmonary thrombendarterectomy (PEA)
PEA is the treatment of choice for patients with CTEPH. In this operation, the blood clot and some of the vascular media are dissected out of the pulmonary vessel. The indication is based on functional restriction, haemodynamics and location of the blood clots (more central or more peripheral). Whether thromboembolic lesions can be reached depends very much on the experience of the surgical team. In the ideal case, thrombotic material can be removed even from subsegmental vascular sections. The prerequisite for PEA is oral anticoagulation for at least 3 months. Perioperative mortality is reported as between 5 and 24% depending on the centre. With a 5-year survival rate of 75–80%, PEA is clearly superior to drug therapy and also to lung transplant and should therefore be undertaken in all patients who meet the criteria for surgery.
3. Lung transplant
If the condition of a patient does not improve despite the maximum drug therapy, lung transplant constitutes a further option. The 5-year survival rate for this procedure is about 45%.
Because of the complexity of both the disease and the treatment, patients with PAH should be very closely monitored. For patients in the early stages of the disease, being given oral therapy, six-monthly check-ups are recommended. Patients at an advanced stage of the disease, particularly those receiving parenteral or combined therapy, should be observed in specialist centres at three-monthly intervals.
Correspondence: Prof. Dr. Irene Lang, Klinische Abteilung für Kardiologie, Universitätsklinik für Innere Medizin II, Medizinische Universität Wien, Währinger Gürtel 18–20, 1090 Wien, Austria, e-mail: firstname.lastname@example.org
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