Combination Therapy in the Treatment of Pulmonary Arterial Hypertension
Combination Therapy in the Treatment of Pulmonary Arterial Hypertension
As a result of the multimechanistic pathology of pulmonary arterial hypertension (PAH), combination therapy is emerging as a potential treatment option. Recent guidelines from the American College of Chest Physicians and expert consensus from the American College of Cardiology Foundation and American Heart Association do not definitively support or disapprove of combination pharmacotherapy for the treatment of PAH. Published trials have investigated different combinations including endothelin receptor antagonists with prostanoids, prostanoids with phosphodiesterase inhibitors, and phosphodiesterase inhibitors with endothelin receptor antagonists. Pertinent trials on combination pharmacotherapy for PAH were identified through a MEDLINE search of literature from 1967–2009 in addition to a manual search of references from the articles retrieved. Search results identified 12 trials that evaluated combination therapy for PAH; some included an add-on agent for patients who failed treatment with monotherapy and others were placebo controlled. Even with the published data, the overall consensus is unclear. Well-designed, larger trials with validated end points are needed to further identify when to initiate combination therapy for the treatment of PAH. Meanwhile, perhaps the most appropriate situation for using combination pharmacotherapy may be in the setting of a lack of clinical improvement or deterioration.
Pulmonary arterial hypertension (PAH) is a progressive, debilitating disorder that may occur either in the setting of a variety of underlying medical conditions (e.g., human immunodeficiency virus infection) or as a disease that uniquely affects the pulmonary circulation. This disorder affects approximately 200,000 people worldwide. Pulmonary arterial hypertension is defined as mean pulmonary artery pressure (mPAP) greater than 25 mm Hg with a pulmonary capillary wedge pressure, left atrial pressure, or left ventricular end-diastolic pressure of 15 mm Hg or less, and a pulmonary vascular resistance (PVR) greater than 3 Wood units as measured by cardiac catheterization. A patient's level of activity and severity of PAH symptoms can be categorized by using the New York Heart Association (NYHA) functional classification or the World Health Organization (WHO) functional classification, which is an adaptation of the NYHA classification. Class I indicates no limitation of usual physical activity; class II, mild limitation of physical activity; class III, marked limitation; and class IV, inability to perform any physical activity and symptomatic at rest with the possible presence of signs of right ventricular failure (Table 1). Patients with PAH often complain of dyspnea, fatigue, or exercise intolerance. As the disease progresses, dyspnea and fatigue may be present at rest. This devastating and progressive disease leads to right ventricular dysfunction and may ultimately cause right-sided heart failure and death. The prognosis of patients with PAH is poor, with the mortality rate estimated to be 42% at 5 years.
The pathophysiology of PAH is poorly understood but involves both genetic and environmental factors that ultimately alter vascular structure and function. The pathologic mechanisms of PAH include endothelial dysfunction in the pulmonary microvasculature. This leads to impaired production of the endogenous vasodilator nitric oxide and prostacyclin, along with an overexpression of the specific vasoconstrictors endothelin (ET)-1 and thromboxane. Current treatment for PAH includes calcium channel blockers, prostacyclin analogs, endothelin receptor antagonists (ERAs), and phosphodiesterase (PDE) inhibitors. These classes of drugs work by counteracting vascular changes caused by PAH and have been used as monotherapy and, more recently, in combination therapy for the treatment of PAH.
Current guidelines and expert consensus recommend an acute vasodilator test for all patients with idiopathic PAH. Clinicians could also consider testing patients with nonidiopathic PAH. Patients with a positive response (defined as a decrease of ≥ 10 mm Hg in mPAP to an absolute mPAP of ≤ 40 mm Hg) would be candidates for long-term calcium channel blocker therapy. Unfortunately, calcium channel blockers provide less than optimal therapy in patients with nonidiopathic PAH. In patients who fail the acute vasoreactivity test or do not achieve sustained response to calcium channel blocker therapy, prostanoids, PDE inhibitors, or ERAs are potential therapeutic options (Table 2). Despite recent advances and major improvements in the drugs available for treating PAH, no current treatment is curative. Treatment goals in patients with PAH include improvement in symptoms (e.g., dyspnea), enhancement of functional capacity, and improvements in exercise endurance as measured by tests such as the 6-minute walk distance and the cardiopulmonary exercise test.
The multifactorial processes involved with the pathophysiology of PAH make combination therapy an attractive, theoretical treatment option. The role of combination therapy has been explored, and trials have been conducted that evaluated different classes of drugs used concomitantly for PAH. To our knowledge, a comprehensive review of available clinical trials focusing on combination therapy has not been published. Therefore, in this review, we examine the safety and efficacy of combination therapies in patients with PAH (adult WHO group 1; Table 3) based on published literature. Pertinent trials were identified through a MEDLINE search of the literature from 1967–2009, in addition to a manual search of references from the articles retrieved. Search terms were pulmonary arterial hypertension, endothelin receptor antagonist, prostanoids, phosphodiesterase inhibitor, pulmonary hypertension, epoprostenol, treprostinil, iloprost, bosentan, ambrisentan, sildenafil, and tadalafil.
Abstract and Introduction
Abstract
As a result of the multimechanistic pathology of pulmonary arterial hypertension (PAH), combination therapy is emerging as a potential treatment option. Recent guidelines from the American College of Chest Physicians and expert consensus from the American College of Cardiology Foundation and American Heart Association do not definitively support or disapprove of combination pharmacotherapy for the treatment of PAH. Published trials have investigated different combinations including endothelin receptor antagonists with prostanoids, prostanoids with phosphodiesterase inhibitors, and phosphodiesterase inhibitors with endothelin receptor antagonists. Pertinent trials on combination pharmacotherapy for PAH were identified through a MEDLINE search of literature from 1967–2009 in addition to a manual search of references from the articles retrieved. Search results identified 12 trials that evaluated combination therapy for PAH; some included an add-on agent for patients who failed treatment with monotherapy and others were placebo controlled. Even with the published data, the overall consensus is unclear. Well-designed, larger trials with validated end points are needed to further identify when to initiate combination therapy for the treatment of PAH. Meanwhile, perhaps the most appropriate situation for using combination pharmacotherapy may be in the setting of a lack of clinical improvement or deterioration.
Introduction
Pulmonary arterial hypertension (PAH) is a progressive, debilitating disorder that may occur either in the setting of a variety of underlying medical conditions (e.g., human immunodeficiency virus infection) or as a disease that uniquely affects the pulmonary circulation. This disorder affects approximately 200,000 people worldwide. Pulmonary arterial hypertension is defined as mean pulmonary artery pressure (mPAP) greater than 25 mm Hg with a pulmonary capillary wedge pressure, left atrial pressure, or left ventricular end-diastolic pressure of 15 mm Hg or less, and a pulmonary vascular resistance (PVR) greater than 3 Wood units as measured by cardiac catheterization. A patient's level of activity and severity of PAH symptoms can be categorized by using the New York Heart Association (NYHA) functional classification or the World Health Organization (WHO) functional classification, which is an adaptation of the NYHA classification. Class I indicates no limitation of usual physical activity; class II, mild limitation of physical activity; class III, marked limitation; and class IV, inability to perform any physical activity and symptomatic at rest with the possible presence of signs of right ventricular failure (Table 1). Patients with PAH often complain of dyspnea, fatigue, or exercise intolerance. As the disease progresses, dyspnea and fatigue may be present at rest. This devastating and progressive disease leads to right ventricular dysfunction and may ultimately cause right-sided heart failure and death. The prognosis of patients with PAH is poor, with the mortality rate estimated to be 42% at 5 years.
The pathophysiology of PAH is poorly understood but involves both genetic and environmental factors that ultimately alter vascular structure and function. The pathologic mechanisms of PAH include endothelial dysfunction in the pulmonary microvasculature. This leads to impaired production of the endogenous vasodilator nitric oxide and prostacyclin, along with an overexpression of the specific vasoconstrictors endothelin (ET)-1 and thromboxane. Current treatment for PAH includes calcium channel blockers, prostacyclin analogs, endothelin receptor antagonists (ERAs), and phosphodiesterase (PDE) inhibitors. These classes of drugs work by counteracting vascular changes caused by PAH and have been used as monotherapy and, more recently, in combination therapy for the treatment of PAH.
Current guidelines and expert consensus recommend an acute vasodilator test for all patients with idiopathic PAH. Clinicians could also consider testing patients with nonidiopathic PAH. Patients with a positive response (defined as a decrease of ≥ 10 mm Hg in mPAP to an absolute mPAP of ≤ 40 mm Hg) would be candidates for long-term calcium channel blocker therapy. Unfortunately, calcium channel blockers provide less than optimal therapy in patients with nonidiopathic PAH. In patients who fail the acute vasoreactivity test or do not achieve sustained response to calcium channel blocker therapy, prostanoids, PDE inhibitors, or ERAs are potential therapeutic options (Table 2). Despite recent advances and major improvements in the drugs available for treating PAH, no current treatment is curative. Treatment goals in patients with PAH include improvement in symptoms (e.g., dyspnea), enhancement of functional capacity, and improvements in exercise endurance as measured by tests such as the 6-minute walk distance and the cardiopulmonary exercise test.
The multifactorial processes involved with the pathophysiology of PAH make combination therapy an attractive, theoretical treatment option. The role of combination therapy has been explored, and trials have been conducted that evaluated different classes of drugs used concomitantly for PAH. To our knowledge, a comprehensive review of available clinical trials focusing on combination therapy has not been published. Therefore, in this review, we examine the safety and efficacy of combination therapies in patients with PAH (adult WHO group 1; Table 3) based on published literature. Pertinent trials were identified through a MEDLINE search of the literature from 1967–2009, in addition to a manual search of references from the articles retrieved. Search terms were pulmonary arterial hypertension, endothelin receptor antagonist, prostanoids, phosphodiesterase inhibitor, pulmonary hypertension, epoprostenol, treprostinil, iloprost, bosentan, ambrisentan, sildenafil, and tadalafil.