Medical Treatment of Pulmonary Arterial Hypertension

Sandeep Sahay, MD; Marc Humbert, MD, PhD; Olivier Sitbon, MD, PhD


Semin Respir Crit Care Med. 2017;38(5):686-700. 

In This Article

Abstract and Introduction


Pulmonary arterial hypertension (PAH) is a progressive and life-threatening disease leading to right ventricular failure and death if left untreated. Over the past two decades, progress in the understanding of pathophysiological mechanisms of the disease has led to the development of medications targeting the three major pathways of endothelial dysfunction: prostanoids, endothelin-receptor antagonists, and phosphodiesterase type-5 inhibitors. Efficacy of PAH-targeted medications has been demonstrated in monotherapy through randomized clinical trials leading to their regulatory approval. However, despite the growing numbers of available PAH-targeted medications, many patients with PAH continue to deteriorate and the disease ultimately remains fatal. The availability of multiple classes of drugs targeting different pathophysiological pathways provides strong biological rationale for the use of combination therapy in PAH. Evidence to support this strategy is growing, and many studies have demonstrated that combination therapy, administered as either a sequential or an initial regimen, can improve long-term outcomes in PAH. Treatment strategy for PAH has thereby changed significantly over the past decade, combination therapy becoming progressively the gold standard of care in patients with PAH. This is underscored by the current European Society of Cardiology/European Respiratory Society guidelines, in which combination therapy now plays a central part in the treatment algorithm.


Pulmonary hypertension (PH) is a progressive and morbid disease. Current World Health Organization (WHO) classification of patients with PH categorizes pulmonary arterial hypertension (PAH) into group 1 disease, and these patients have distinct diagnostic and treatment recommendations.[1–3] If left untreated, PAH leads to right heart failure and death.[1,2] Early efforts evaluating the prognosis of PAH suggested a median survival after diagnosis of 2.8 years.[4] The pathobiology of PAH is complex and involves many pathways such as endothelial cell dysfunction, smooth muscle cell proliferation, vascular inflammation and immune dysregulation, metabolic and mitochondrial abnormalities, excessive growth factor stimulation, ion channel defects, as well as germline mutations.[5] These complex pathways converge to produce excessive vasoconstriction and a pro-proliferative phenotype of pulmonary vascular cells. Thus, currently approved PAH therapies target three key molecular pathways that are implicated in the control of pulmonary vasomotor tone and vascular cell proliferation:[6,7] prostacyclin (prostaglandin I2 [PGI2]), endothelin-1 (ET-1), and nitric oxide (NO) pathways (Figure 1). The better knowledge of pathophysiology and the development of novel treatments over the past two decades have improved the survival of patients with PAH.[8] With the establishment of effective therapies for PAH, research has been started focusing on how to customize treatment to individualized patients. Identifying phenotypes of the disease and understanding different patterns of pathophysiologic derangements will be critical in advancing the treatment of PAH.[9,10] Treatment of PAH is not just prescribing medications, rather it is a complex strategy aimed at improving symptoms, quality of life, and survival of the patient. At present, there are more than 10 medications available for the treatment of PAH that have been approved by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA). Choosing the best therapy for the patient is dependent on a variety of factors and a detailed risk assessment must be done at the time of initial evaluation. That is why an early referral to a dedicated expert center must be considered when facing a patient with suspected PAH.[1,2] The main role of expert centers is to receive all patients with suspected PH, undertake diagnostic assessment, and manage appropriate patients with PAH-targeted therapies.[1,2] In the United States, expert centers are designated as PH comprehensive care centers.[11] In Europe, there is an attempt to create a rare disease network dedicated to PH. In some countries, such as France and the United Kingdom, such a network already exists and almost all patients with PAH are followed up in these care networks.[12,13]

Figure 1.

Schematic representation of the three different pathways of endothelial dysfunction that are targeted in the treatment of PAH.6,7 cAMP, cyclic adenosine monophosphate; cGMP, cyclic guanosine monophosphate; PAH, pulmonary arterial hypertension.