Medical Therapy for Pulmonary Arterial Hypertension

Abstract

David B. Badesch, MD, FCCP; Steve H. Abman, MD; Gregory S. Ahearn, MD; Robyn J. Barst, MD; Douglas C. McCrory, MD, MHSc; Gerald Simonneau, MD; and Vallerie V. McLaughlin, MD, FCCP Pulmonary arterial hypertension (PAH) is often difficult to diagnose and challenging to treat. Untreated, it is characterized by a progressive increase in pulmonary vascular resistance leading to right ventricular failure and death. The past decade has seen remarkable improvements in therapy, driven largely by the conduct of randomized controlled trials. Still, the selection of most appropriate therapy is complex, and requires familiarity with the disease process, evidence from treatment trials, complicated drug delivery systems, dosing regimens, side effects, and complications. This chapter will provide evidence-based treatment recommendations for physicians involved in the care of these complex patients. Due to the complexity of the diagnostic evaluation required, and the treatment options available, it is strongly recommended that consideration be given to referral of patients with PAH to a specialized center. (CHEST 2004; 126:35S-62S)Key words: anticoagulation; arginine; beraprost; bosentan; calcium-channel blockers; endothelin; endothelin receptor antagonist; epoprostenol; idiopathic pulmonary arterial hypertension; iloprost; medical therapy; oxygen; primary pulmonary hypertension; prostacyclin; pulmonary arterial hypertension; pulmonary hypertension; secondary pulmonary hypertension; sildenafil; therapy; treatment; treprostinil; vasoreactivity; warfarin Abbreviations: cAMP ϭ cyclic adenosine monphosphate; CART ϭ combination antiretroviral therapy; CCB ϭ calcium-channel blocker; cGMP ϭ cyclic guanosine 3Ј-5Ј monophosphate; CI ϭ confidence interval; CO ϭ cardiac output; CTEPH ϭ chronic thromboembolic pulmonary hypertension; FDA ϭ Food and Drug Administration; INR ϭ international normalized ratio; IPAH ϭ idiopathic pulmonary arterial hypertension; mPAP ϭ mean pulmonary arterial pressure; NYHA ϭ New York Heart Association; NO ϭ nitric oxide; NOS ϭ nitric oxide synthase; PAH ϭ pulmonary arterial hypertension; PAP ϭ pulmonary arterial pressure; PH ϭ pulmonary hypertension; PPH ϭ primary pulmonary hypertension; PPHN ϭ persistant pulmonary hypertension of the newborn; PVR ϭ pulmonary vascular resistance; RCT ϭ randomized controlled clinical trial H istorically, medical treatment of pulmonary arterial hypertension (PAH) has been difficult. Idiopathic PAH (IPAH), formerly known as primary pulmonary hypertension (PPH), carried a very poor prognosis (median survival of approximately 2.8 years from the date of diagnosis) through the mid-1980s. Since then, a number of therapeutic options have been developed, with varying degrees of evidence to support their use. This chapter will review the current treatment of PAH, objectively detailing the evidence available to support each form of therapy. Some widely used therapies for PAH are generally accepted as being important and efficacious, although not supported by randomized controlled clini...

Oral sildenafil citrate lacks genotoxicity and cytotoxicity in a primate model: Callithrix jacchus

“…However, the literature suggests the possibility of developing systemic hypotension as a result of vasodilatation induced by SC. 2,8 Shekerdemian et al 39 report that in piglets being treated with inhaled nitric oxide, intravenous SC (0.5 mg/kg) lowered the systemic BP and the systemic vascular resistance leading to profound arterial hypoxemia. This could be a particular characteristic of that species, as it is well known that some compounds can be species specific.…”

“…By inhibiting PDE-5, GMPc levels can be elevated and this leads to pulmonary vasodilatation. [6][7][8][9][10] Based on PDE-5 activity in the pulmonary vasculature, some experimental studies have described that SC diminishes the pulmonary vascular resistance. [11][12] Also case reports suggest that children and adults with pulmonary arterial hypertension have been treated successfully with oral SC.…”

The value of tools to assess pulmonary arterial hypertension

“…A positive acute response was, until recently, defined as a reduction of both P pa and PVR of at least 20% relative to baseline values [21]. However, recent consensus defines a favourable response as a fall in P pa o10 mmHg to a P pa f40 mmHg, with an unchanged or increased CO [22]. Using this criterion, only ,10% of patients with idiopathic PAH will be regarded as acute responders.…”

Safety Recommendations for Administering Intravenous Prostacyclins in the Hospital

“…1 When PAH is diagnosed early in the course of the disease, initial treatment usually consists of oral therapy, including phosphodiesterase type 5 inhibitors and endothelin receptor antagonists.2 Intravenous epoprostenol sodium (Flolan), epoprostenol for injection (Veletri), and treprostinil (Remodulin) are intravenous prostacyclins given as continuous infusions in the most advanced cases of PAH.1 Prostacyclins are potent vasodilators, inhibit platelet activation, and have antiproliferative effects on smooth muscle and intimal cells. Intravenous prostacyclins are expensive and require a comprehensive insurance approval process.…”

“…1 When PAH is diagnosed early in the course of the disease, initial treatment usually consists of oral therapy, including phosphodiesterase type 5 inhibitors and endothelin receptor antagonists.…”