C o m b i n a t i o n Th e r a p y i n Pulmonary Ar t er ial Hypertension Meredith E. Pugh, MD, MSCI, Anna R. Hemnes, MD, Ivan M. Robbins, MD* KEYWORDS Pulmonary arterial hypertension Combination therapy Endothelin receptor antagonists Prostacyclin Phosphodiesterase-5 inhibitors Treatment
KEY POINTS Multiple open-label, small, and often single-center studies describing results with combination therapy in pulmonary arterial hypertension (PAH) have been published. The results of these studies are mixed, although most suggest a benefit without significant toxicity. Several multicenter, randomized, placebo-controlled studies have also been performed, also with mixed results, although the largest of these studies, TRIUMPH-1 and PACES, showed significant improvement in exercise capacity, and the latter in hemodynamics and survival, although with the caveat that the dose of sildenafil used was higher than that approved for use. Regardless of the mixed results of published studies, combination therapy is used in a sizable proportion of patients with PAH and will likely be used in even greater numbers of patients as more drugs for PAH are approved. Other than the BREATHE-2 study, randomized trials have not raised issues of safety with combination therapy. The IMPRES study reported a large number of subdural hematomas in patients receiving imatinib, but this appears more likely to be related to the drug itself rather than combination therapy. Both of these studies enrolled very sick patients with more severe hemodynamic impairment, suggesting that this may be an important factor with regard to the severe adverse events seen. Several large, long-term studies with a variety of medications should provide more robust data in the near future, especially with regard to oral therapy combinations and upfront versus add-on combination therapy.
oxide, and prostacyclin pathways) have been evaluated, and have shown benefit in the treatment of PAH. Currently approved therapies for the treatment of PAH in the United States include endothelin receptor antagonists (ambrisentan [Letairis], bosentan [Tracleer]), phosphodiesterase-5 (PDE5)
Conflicts of Interest: M.E. Pugh has received consulting fees from Gilead and funding from the NIH; A.R. Hemnes has served as a consultant for United Therapeutics, Actelion, and Pfizer, and has received grants from the NIH, United Therapeutics, and Pfizer; I.M. Robbins has received consulting fees from United Therapeutics, Gilead, and Actelion for attending advisory board meetings, and has received grants from the NIH. Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University, T1218 Medical Center North, 1161 21st Avenue South, Nashville, TN 37232, USA * Corresponding author. E-mail address: [email protected] Clin Chest Med 34 (2013) 841–855 http://dx.doi.org/10.1016/j.ccm.2013.08.007 0272-5231/13/$ – see front matter Ó 2013 Elsevier Inc. All rights reserved.
chestmed.theclinics.com
Despite the availability of multiple agents for the treatment of pulmonary arterial hypertension (PAH), PAH remains a progressive disease with unacceptably high morbidity and mortality. Although the complete pathobiology of PAH is not known, therapies targeting 3 pathways (endothelin, nitric
842
Pugh et al inhibitors (sildenafil [Revatio], tadalafil [Adcirca]), and prostacyclin derivatives (epoprostenol [Flolan, Veletri], iloprost [Ventavis], treprostinil [Remodulin, Tyvaso]).1,2 These agents improve PAH symptoms, exercise capacity, and hemodynamic outcomes over the short term,3–9 and are available as oral agents (ambrisentan, bosentan, tadalafil, sildenafil), inhaled therapies (iloprost, treprostinil), subcutaneous infusions (treprostinil), and intravenous infusions (epoprostenol, treprostinil). Even with use of these diverse agents, many patients on PAH monotherapy continue to worsen, develop right heart failure, and, too often, die of the disease. Targeting more than 1 pathway with combination therapy to improve outcome, similar to the way in which other chronic disorders such as congestive heart failure and cancer are treated, is a natural extension of the treatment algorithm of PAH.2,10 There are data to support a synergistic interaction with PAH-approved medications; this has been demonstrated with the combination of a PDE5 inhibitor and a prostaglandin in animals, and in acute studies in humans with pulmonary hypertension (PH).11–14 Although not providing a basis for all combinations, the synergistic effect that was demonstrated acutely provided support and impetus for combining agents in the treatment of PAH. Combinations include concomitant use of endothelin receptor antagonists (ERAs) and PDE5 inhibitors (PDE5-Is), prostanoids and ERAs or PDE5-Is, and all 3 classes of agents (prostanoids 1 ERA 1 PDE5-I). In addition, 2 recent studies have evaluated the addition of the tyrosine kinase inhibitor, imatinib (Gleevec) to the regimen of patients treated with approved PAH therapy. Use of combination therapy in clinical practice is widespread, but although it is a logical next step in the treatment of PAH, there are presently few data to support the benefit of this approach. Numerous small, open-label studies or case series have been published with varying results, and even the results of randomized clinical trials of combination therapy in PAH have not consistently supported this approach. In addition, the results of randomized studies of certain combinations, in particular combination oral therapy, are not yet available. Most studies have evaluated the benefit of sequential add-on therapy, and only a few published studies have evaluated initial treatment with combination therapy. Data from the REVEAL registry show a high prevalence of the use of combination therapy for PAH, with the majority of patients on PAH treatment receiving multiple agents at registry enrollment.15 Combination therapy is recommended in consensus guidelines for patients who are not responding to initial monotherapy.10 Which combination of agents is most beneficial is not known, and
whether combination therapy is best initiated as sequential (or add-on) therapy or as first-line combination therapy is also uncertain at present. Although combination therapy seems to be well tolerated in many patients in clinical practice, the question of when to consider this strategy remains largely unanswered. Several ongoing multicenter studies should provide more robust results in the near future that will help guide treatment decisions. This review examines the current evidence regarding combination therapy in PAH, and discusses which patients may benefit from this strategy.
PROSTACYCLIN ANALOGUES D ENDOTHELIN RECEPTOR ANTAGONISTS Small or Nonrandomized Trials and Case Series Several uncontrolled studies report a beneficial effect of additive therapy with ERAs and prostacyclin analogues. In a study of 20 idiopathic PAH (IPAH) patients who had evidence for declining clinical status on nonparenteral prostanoid therapy, either inhaled iloprost or oral beraprost (the latter not approved in the United States), Hoeper and colleagues16 showed that the addition of bosentan lead to significant improvement in 6-minute walk distance (6MWD) after 3 months of follow-up (346 106 m baseline vs 404 101 m, P
KEY POINTS Multiple open-label, small, and often single-center studies describing results with combination therapy in pulmonary arterial hypertension (PAH) have been published. The results of these studies are mixed, although most suggest a benefit without significant toxicity. Several multicenter, randomized, placebo-controlled studies have also been performed, also with mixed results, although the largest of these studies, TRIUMPH-1 and PACES, showed significant improvement in exercise capacity, and the latter in hemodynamics and survival, although with the caveat that the dose of sildenafil used was higher than that approved for use. Regardless of the mixed results of published studies, combination therapy is used in a sizable proportion of patients with PAH and will likely be used in even greater numbers of patients as more drugs for PAH are approved. Other than the BREATHE-2 study, randomized trials have not raised issues of safety with combination therapy. The IMPRES study reported a large number of subdural hematomas in patients receiving imatinib, but this appears more likely to be related to the drug itself rather than combination therapy. Both of these studies enrolled very sick patients with more severe hemodynamic impairment, suggesting that this may be an important factor with regard to the severe adverse events seen. Several large, long-term studies with a variety of medications should provide more robust data in the near future, especially with regard to oral therapy combinations and upfront versus add-on combination therapy.
oxide, and prostacyclin pathways) have been evaluated, and have shown benefit in the treatment of PAH. Currently approved therapies for the treatment of PAH in the United States include endothelin receptor antagonists (ambrisentan [Letairis], bosentan [Tracleer]), phosphodiesterase-5 (PDE5)
Conflicts of Interest: M.E. Pugh has received consulting fees from Gilead and funding from the NIH; A.R. Hemnes has served as a consultant for United Therapeutics, Actelion, and Pfizer, and has received grants from the NIH, United Therapeutics, and Pfizer; I.M. Robbins has received consulting fees from United Therapeutics, Gilead, and Actelion for attending advisory board meetings, and has received grants from the NIH. Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University, T1218 Medical Center North, 1161 21st Avenue South, Nashville, TN 37232, USA * Corresponding author. E-mail address: [email protected] Clin Chest Med 34 (2013) 841–855 http://dx.doi.org/10.1016/j.ccm.2013.08.007 0272-5231/13/$ – see front matter Ó 2013 Elsevier Inc. All rights reserved.
chestmed.theclinics.com
Despite the availability of multiple agents for the treatment of pulmonary arterial hypertension (PAH), PAH remains a progressive disease with unacceptably high morbidity and mortality. Although the complete pathobiology of PAH is not known, therapies targeting 3 pathways (endothelin, nitric
842
Pugh et al inhibitors (sildenafil [Revatio], tadalafil [Adcirca]), and prostacyclin derivatives (epoprostenol [Flolan, Veletri], iloprost [Ventavis], treprostinil [Remodulin, Tyvaso]).1,2 These agents improve PAH symptoms, exercise capacity, and hemodynamic outcomes over the short term,3–9 and are available as oral agents (ambrisentan, bosentan, tadalafil, sildenafil), inhaled therapies (iloprost, treprostinil), subcutaneous infusions (treprostinil), and intravenous infusions (epoprostenol, treprostinil). Even with use of these diverse agents, many patients on PAH monotherapy continue to worsen, develop right heart failure, and, too often, die of the disease. Targeting more than 1 pathway with combination therapy to improve outcome, similar to the way in which other chronic disorders such as congestive heart failure and cancer are treated, is a natural extension of the treatment algorithm of PAH.2,10 There are data to support a synergistic interaction with PAH-approved medications; this has been demonstrated with the combination of a PDE5 inhibitor and a prostaglandin in animals, and in acute studies in humans with pulmonary hypertension (PH).11–14 Although not providing a basis for all combinations, the synergistic effect that was demonstrated acutely provided support and impetus for combining agents in the treatment of PAH. Combinations include concomitant use of endothelin receptor antagonists (ERAs) and PDE5 inhibitors (PDE5-Is), prostanoids and ERAs or PDE5-Is, and all 3 classes of agents (prostanoids 1 ERA 1 PDE5-I). In addition, 2 recent studies have evaluated the addition of the tyrosine kinase inhibitor, imatinib (Gleevec) to the regimen of patients treated with approved PAH therapy. Use of combination therapy in clinical practice is widespread, but although it is a logical next step in the treatment of PAH, there are presently few data to support the benefit of this approach. Numerous small, open-label studies or case series have been published with varying results, and even the results of randomized clinical trials of combination therapy in PAH have not consistently supported this approach. In addition, the results of randomized studies of certain combinations, in particular combination oral therapy, are not yet available. Most studies have evaluated the benefit of sequential add-on therapy, and only a few published studies have evaluated initial treatment with combination therapy. Data from the REVEAL registry show a high prevalence of the use of combination therapy for PAH, with the majority of patients on PAH treatment receiving multiple agents at registry enrollment.15 Combination therapy is recommended in consensus guidelines for patients who are not responding to initial monotherapy.10 Which combination of agents is most beneficial is not known, and
whether combination therapy is best initiated as sequential (or add-on) therapy or as first-line combination therapy is also uncertain at present. Although combination therapy seems to be well tolerated in many patients in clinical practice, the question of when to consider this strategy remains largely unanswered. Several ongoing multicenter studies should provide more robust results in the near future that will help guide treatment decisions. This review examines the current evidence regarding combination therapy in PAH, and discusses which patients may benefit from this strategy.
PROSTACYCLIN ANALOGUES D ENDOTHELIN RECEPTOR ANTAGONISTS Small or Nonrandomized Trials and Case Series Several uncontrolled studies report a beneficial effect of additive therapy with ERAs and prostacyclin analogues. In a study of 20 idiopathic PAH (IPAH) patients who had evidence for declining clinical status on nonparenteral prostanoid therapy, either inhaled iloprost or oral beraprost (the latter not approved in the United States), Hoeper and colleagues16 showed that the addition of bosentan lead to significant improvement in 6-minute walk distance (6MWD) after 3 months of follow-up (346 106 m baseline vs 404 101 m, P
