Side effects. The most common side effect of bosentan is hepatic aminotransferase elevation (9% of patients), usually occurring within 16 weeks (90%). All elevations have resolved upon drug withdrawal (97% within 8 weeks). The FDA mandates monthly monitoring of aminotransferase for bosentan. Furthermore, bosentan is teratogenic39 and absolutely contraindicated in pregnancy. There may be significant fluid retention. Sitaxsentan and ambrisentan have similar side effects and their eventual clinical use is expected to require similar monitoring.
Phosphodiesterase-5 inhibitors: Sildenafil, vardenafil, tadalafil
Phosphodiesterases (PDEs) are a group of isoenzymes widely distributed in various organs. PDE5 is found in the corpus cavernosum, pulmonary vasculature, muscle, and platelets.
Use for PAH off-label. Sildenafil, vardenafil, and tadalafil are cyclic guanosine monophosphate-specific PDE5 inhibitors with potent, selective pulmonary vasodilatory and antiplatelet effects. Sildenafil and vardenafil have relatively short half-lives (4–6 hours). Tadalafil has a longer half-life (17.5 hours) with potential for once-daily administration. All these compounds are only available orally. The FDA has approved these for erectile dysfunction only, but they have been used off-label.
A phase III study of sildenafil in PAH has been completed, but has not been published. One randomized study has shown clinical efficacy.40 Small series have also shown clinical improvement.41,42
Due to their short half-lives, sildenafil and vardenafil require multidose regimens, with potential for noncompliance leading to rebound pulmonary vasoconstriction. Retinopathy at high dose, from inhibition of PDE6, remains a concern for sildenafil.43 Priapism has not been reported in the PAH population so far, but may be a relevant consideration in sickle cell anemia.
Lung transplantation
Lung transplantation should be considered if functional class II is not achieved despite optimal medical therapy.44 Improved medical therapy has decreased the need for this surgical option, lengthened the time to transplantation, or even eliminated the requirement altogether.45 The 5-year survival of patients on epoprostenol is comparable with, or better than, that with lung transplant.46 Patient selection and early referral for transplantation are crucial to success in this process. Published international guidelines help guide this process.47 In general, PAH patients in WHO functional class II, III, or IV should be medically treated. Concurrently, referral for transplantation should be considered, even before there are signs that functional class I or II cannot be achieved. This is because transplant evaluation is a fairly lengthy process and it is not unusual for patients to die while on the long waiting list. If medical therapy is successful, the patient can be inactivated. In case medical therapy begins to fail subsequently, listing can be reactivated.
Lung transplantation remains the surgical treatment of choice for refractory PAH. Heart-lung transplants tend to be reserved for patients with structural cardiac abnormalities. Single lung transplantation has the advantages of less complex surgery and more efficient use of harvested organs to benefit more patients, thereby leading to shorter waiting periods. However, most transplant centers in the US prefer double lung transplantation, mainly because there is greater pulmonary reserve should the patient sustain rejection or infection.48
The operative mortality range is between 16% to 29%.48 The 1-year survival rate after lung transplantation (single as well as double) is approximately 70% to 75%, 2-year survival is 50% to 60%, and 5-year survival is 40% to 45%.49 The International Society of Heart and Lung Transplantation database shows that overall survival for both single and double lung transplantation is nearly equal up to 3 years postsurgery. After that, there is a significant survival advantage for double lung transplant.50 Although several studies have documented a significant improvement in the quality of life after transplantation for PH, cost-effectiveness has not yet been addressed.
Balloon atrial septostomy
Balloon atrial septostomy reduces strain on the right ventricle and improves cardiac output. Its use is limited by systemic hypoxemia caused by the right-to-left shunt and perioperative morbidity. It may be used as a bridge procedure while awaiting lung transplantation.51 Functional improvement has been demonstrated in a small series.52 Patient selection, improvement in hemodynamics, and clinical outcomes vary from center to center.53,54 It is likely that patient selection, technique, and experience influence the outcome considerably. This procedure should only be performed in experienced centers on carefully selected patients.
Combination therapy increasingly used
There are no prospective data on combination therapy for PAH. Whether combination therapy has an additive, synergistic, or even antagonistic effect is uncertain. However, there is pathophysiologic rationale for this approach, especially in therapeutic failure following monotherapy. Addition of sildenafil to epoprostenol reduces PA pressure and PVR without hypotension or desaturation.42 When iloprost failed as monotherapy for 14 patients with PAH, addition of sildenafil reversed clinical deterioration, increased functional capacity, and yielded favorable hemodynamics at 3 months, with sustained efficacy up to 12 months.55 There are no data showing whether sildenafil will have synergistic benefits with bosentan. Despite lack of evidence, combination therapy has been used increasingly in clinical practice.