The therapeutic approach is guided by the diagnosis of the PH type. In recent years, various new pulmonary vasodilators have been successively tested for their effects in clinical trials and launched on the market. However, these drugs are only approved for the therapy of PAH (→
group 1, Tables and ). They exert their effects using different signaling pathways, that is, the endothelin-signaling pathway
(endothelin receptor antagonists: bosenthan, ambrisentan), the prostacyclin-signaling pathway (prostacyclin analogues: iloprost, epoprostenol, and treprostinil), and the NO-signaling pathway
(phosphodiesterase-5 inhibitors: sildenafil, tadalafil). gives an overview of all approved substances [8
Table 4 Therapy of pulmonary hypertension: approved drugs (mod. ).
The most potent vasoconstrictor in the human organism is endothelin-1 [16
]. It exerts an influence on the pulmonary arteries by means of two receptors—the endothelin-A receptor and the endothelin-B receptor. There is a local difference in the distribution of the two receptors, which is modified under the influence of pulmonary hypertension. The dual endothelin receptor antagonist bosentan is approved for the treatment of PAH patients in WHO functional classes II and III. Its effectiveness was confirmed for patients with idiopathic or familial PAH and for PAH associated with connective tissue disease or congenital heart defects. In the study leading to the substance's approval, the capacity
of the patients (n
= 144, bosentan of either 125
mg or 250
= 69 placebo) improved after 16 weeks of treatment, as measured by an average improvement of 36
m in the six-minute walk distance (6MWD) [17
]. An elevation in transaminases was observed in 7-8% of patients treated with bosentan, which eventually led to a therapy interruption in approx. Three percent of all patients. For this reason, it is essential to monitor transaminases during therapy (every 4 weeks) [18
Similar regulations apply to the approval of ambrisentan, a selective endothelin-A receptor antagonist. A study examining ambrisentan administered in a dose of 5 or 10
mg compared to a placebo in patients with idiopathic PAH or PAH with systemic sclerosis observed an improvement of 31
mg) or 51
mg) in the 6 MWD [19
]. Although this drug is not associated with hepatotoxicity, the formation of peripheral edema is often observed during ambrisentan therapy.
Two phosphodiesterase-5 inhibitors, sildenafil and tadalafil, are available for the treatment of pulmonary arterial hypertension. They elevate cGMP by blocking its decomposition, thereby inhibiting calcium entry and consequently enabling pulmonary vasodilation. The formulation of its indication is similar to that of the endothelin antagonists. Meanwhile, data is now available in relation to monotherapy with sildenafil over 3 years. A survival rate of 79% was observed among patients in this study (n
= 259). After 3 years of therapy, 60% of patients showed the same or better results in relation to walk distance in the six-minute walk test and their WHO functional class [20
]. It is noteworthy that the majority of patients received a dose (3 × 80
mg) above the approved dose (3 × 20
mg). In a double-blind placebo-controlled prospective study with the approved dose (1 × 40
mg) over 16 weeks, tadalafil led to an improvement of 33
m in 6MWD. This dose also had a significant positive influence on other endpoints, for example, on the time until clinical aggravation [21
]. New drugs elevating the cGMP level through stimulation of guanylyl cyclase are currently undergoing clinical trial, and the initial results look promising.
In contrast, the prostanoids reduce calcium entry into smooth muscle cells by elevating the cAMP level. They also have an influence on endothelial cells, thrombocytes, leukocytes, and fibroblasts. Two drugs from this group are approved in Germany, that is, inhalative iloprost and long-term subcutaneous treprostinil. Their indication is limited to idiopathic pulmonary arterial hypertension for patients in WHO functional class III. It has long been known that inhaled prostanoids reach the affected organ directly (selective pulmonary vasodilation), which minimizes systemic side effects. In 2002, Olschewski and coworkers investigated daily inhalation of iloprost in a large randomized placebo-controlled multicenter study and showed a significant increase in the distance walked in six minutes, a significant improvement of hemodynamic values, an improvement in the NYHA-class, dyspnea, and quality of life [22
]. Inhalative application also offers the option of treating ventilated patients using a dedicated nebulizing system.
Long-term subcutaneous administration of treprostinil is realized using a subcutaneous catheter with a supply line and a pump. However, three quarters of patients experience pain in the injection site when receiving this treatment. The only drug that was recently approved for the treatment of IPAH in Germany is epoprostenol. In spite of the difficulties caused by its method of administration and the short half-life of epoprostenol, it is still the most frequently used prostanoid worldwide for intravenous application. A major study of 162 IPAH patients being treated with epoprostenol showed 1-, 2-, and 3-year survival rates of 88%, 77%, and 63% [23
No drugs for pulmonary vasodilation have been approved for the treatment of other forms of PH outside of group 1 (Tables and ). For thromboembolic pulmonary hypertension in particular, operative thromboendarterectomy is the treatment of choice and should always be considered. Prospective randomized studies for this indication have been unable to show any clear benefit of a specific pulmonary vasodilator treatment [24
]. Nonetheless, there are indications that some of these patients could benefit from drugs originally approved for PAH [25
Basic therapeutic measures for PH, especially in the case of stress or partial respiratory insufficiency, are oxygen supplementation and, if signs of right-sided heart failure are detected, diuretic therapy. It is also advisable to administer anticoagulants to patients with idiopathic, familial, or thromboembolic pulmonary hypertension [8