State-of-the-Art Paper
Updated Treatment Algorithm of Pulmonary Arterial Hypertension

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The demands on a pulmonary arterial hypertension (PAH) treatment algorithm are multiple and in some ways conflicting. The treatment algorithm usually includes different types of recommendations with varying degrees of scientific evidence. In addition, the algorithm is required to be comprehensive but not too complex, informative yet simple and straightforward. The type of information in the treatment algorithm are heterogeneous including clinical, hemodynamic, medical, interventional, pharmacological and regulatory recommendations. Stakeholders (or users) including physicians from various specialties and with variable expertise in PAH, nurses, patients and patients’ associations, healthcare providers, regulatory agencies and industry are often interested in the PAH treatment algorithm for different reasons. These are the considerable challenges faced when proposing appropriate updates to the current evidence-based treatment algorithm.The current treatment algorithm may be divided into 3 main areas: 1) general measures, supportive therapy, referral strategy, acute vasoreactivity testing and chronic treatment with calcium channel blockers; 2) initial therapy with approved PAH drugs; and 3) clinical response to the initial therapy, combination therapy, balloon atrial septostomy, and lung transplantation. All three sections will be revisited highlighting information newly available in the past 5 years and proposing updates where appropriate. The European Society of Cardiology grades of recommendation and levels of evidence will be adopted to rank the proposed treatments.

Key Words

endothelin receptor antagonists
guanylate cyclase stimulators
hypertension, pulmonary
lung transplantation
phosphodiesterase type-5 inhibitors
prostanoids
pulmonary

Abbreviations and Acronyms

APAH
associated pulmonary arterial hypertension
BAS
balloon atrial septostomy
CCB
calcium channel blocker
ERA
endothelin receptor antagonist
PAH
pulmonary arterial hypertension
PVR
pulmonary vascular resistance
RCT
randomized controlled trials
6MWD
6-min walk distance
WHO-FC
World Health Organization Functional Class

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Dr. Galiè has served on the advisory boards of and received paid lectures from Eli Lilly, Actelion, Pfizer, Bayer-Schering, GlaxoSmithKline, and Novartis; has been paid lectures for Eli Lilly and Company, Pfizer, Bayer-Schering, and GlaxoSmithKline; and received institutional grant support from Actelion, Pfizer, Bayer-Schering, GlaxoSmithKline, and Novartis. Dr. Corris has received grant support from Bayer and Actelion; and honoraria for speaking and chairing meetings for Actelion, Bayer, Pfizer, and GlaxoSmithKline. Dr. Frost has received clinical research grants from Gilead, Actelion, Pfizer, GlaxoSmithKline, InterMune, Eli Lilly, United Therapeutics, AIRES, Novartis, Bayer, and IKARIA; has received honoraria for speakers’ bureau presentations from Actelion, Gilead, United Therapeutics, Bayer, and Pfizer; has served on the steering committee for AIRES, AMBITION (Gilead, GlaxoSmithKline, Eli Lilly); has served on the advisory boards for Bayer, Gilead, and Actelion; has served on the steering committee for AIRES, IKARIA, Gilead/GlaxoSmithKline, and United Therapeutics/Lung LLC; and has served as a committee member for Entelligence and REVEAL funded by Actelion. Dr. Girgis has served on the speakers’ bureau for Bayer; and is a consultant for Gilead. Dr. Granton has received support for investigator-led research from Actelion, Bayer, GlaxoSmithKline, Lilly, United Therapeutics, Ikaria, and Pfizer; has received honoraria directed to his institution for consultant work from Actelion, Eli Lilly, GlaxoSmithKline, Ikaria, and Bayer; his institution has received support for their foundation from Actelion, Bayer, and Lilly; and has received unrestricted support for investigator-led research from Actelion and Pfizer/CIHR grant (Canadian Institute for Health Research). Dr. Jing has served as a consultant, member of scientific advisory boards, and investigator and speaker in trials for Actelion, Bayer Schering, Pfizer, GlaxoSmithKline, and United Therapeutics. Dr. McGoon has received grant support directed at his institution for investigator-led research from Medtronic and Gilead; has participated in speaking activities for Actelion and Gilead (funded conferences, not speakers' bureaus); has served as a consultant to Pharma and Actelion; has served as the chair of the REVEAL Registry; on the data adjudication committees for Gilead; and on the advisory committee for Lung LLC and GlaxoSmithKline. Dr. McLaughlin has served on the speakers’ bureau for Gilead and United Therapeutics; has served as a consultant or member of the advisory board/steering committee for Actelion, Bayer, Gilead, United Therapeutics; and has received institutional grant/research support from Actelion, Bayer, Lkana, and Novartis. Dr. Preston has received research grants from Actelion, Bayer, Gilead, United Therapeutics, Novartis, GeNO, and AIRES; and has served as a consultant for Actelion, Bayer, Gilead, and United Therapeutics. Dr. Rubin has a relationship with United Therapeutics, Bayer, GeNO, NHLBI, FDA, Actelion, Lung LLC, Gilead, Reata Pharmaceuticals, Arena Pharmaceuticals, and AIRES. Dr. Sandoval has received honoraria and lecture fees from Bayer Schering. Dr. Seeger has received speaker fees from Pfizer and Bayer HealthCare; and is a consultant for Bayer Pharma AG. Dr. Keogh has served as a clinical trialist for Actelion, Aires, Bayer, GlaxoSmithKline, Pfizer, Novartis, Arena, and United Therapeutics; has served on the advisory board for Actelion, Bayer, and GlaxoSmithKline; and has served on the speakers’ bureau for Actelion, Bayer, and GlaxoSmithKline. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.