PRESCRIBING IN PRACTICE ■ P ulmonary hypertension refers to increased pressure in the pulmonary arterial circulation. The pulmonary circulation has to accommodate the entire cardiac output in each cardiac cycle, and evolution has adapted to this by making it a low-pressure high-flow system. However, pathology can affect both the arterial and venous components of this system. Pulmonary venous hypertension mainly refers to diseases that result in elevated venous pressure and occurs mainly from mitral valve and left-sided heart disease; these will not be discussed in this article. As a result of greater understanding of the molecular and cellular pathways involved in the pathobiology of pulmonary arterial hypertension (PAH), novel and exciting treatments have become available to treat this condition. These new drugs represent a huge step forward in the treatment of this universally fatal disease in that they allow improvement in quality of life and survival; however, they do not as yet offer a cure. Definition PAH is defined by consensus as a mean pulmonary artery pressure of above 25mmHg in the setting of a normal or reduced cardiac output, with a normal pulmonary capillary wedge pressure (PCWP) and elevated pulmonary vascular resistance (PVR). The normal PCWP is required to exclude the presence of significant left heart disease and pulmonary venous hypertension. As a result, the diagnosis of pulmonary hypertension requires invasive right-heart catheterisation. Classification Pulmonary hypertension is an umbrella term that refers simply to elevated pressure in the pulmonary vasculature. There are a wide variety of causes of this and the 2008 WHO conference in Dana Point attempted to clarify and organise these into a more defined classification (see Figure 2). 1 This article will focus on PAH (group 1).

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Guidelines summarize and evaluate all available evidence on a particular issue at the time of the writing process, with the aim of assisting health professionals in selecting the best management strategies for an individual patient with a given condition, taking into account the impact on outcome, as well as the risk–benefit ratio of particular diagnostic or therapeutic means. Guidelines and recommendations should help health professionals to make decisions in their daily practice. However, the final decisions concerning an individual patient must be made by the responsible health professional(s) in consultation with the patient and caregiver as appropriate.

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BACKGROUNDData on the effect of initial combination therapy with ambrisentan and tadalafil on long-term outcomes in patients with pulmonary arterial hypertension are scarce. METHODSIn this event-driven, double-blind study, we randomly assigned, in a 2:1:1 ratio, participants with World Health Organization functional class II or III symptoms of pulmonary arterial hypertension who had not previously received treatment to receive initial combination therapy with 10 mg of ambrisentan plus 40 mg of tadalafil (combination-therapy group), 10 mg of ambrisentan plus placebo (ambrisentanmonotherapy group), or 40 mg of tadalafil plus placebo (tadalafil-monotherapy group), all administered once daily. The primary end point in a time-to-event analysis was the first event of clinical failure, which was defined as the first occurrence of a composite of death, hospitalization for worsening pulmonary arterial hypertension, disease progression, or unsatisfactory long-term clinical response. RESULTSThe primary analysis included 500 participants; 253 were assigned to the combination-therapy group, 126 to the ambrisentan-monotherapy group, and 121 to the tadalafil-monotherapy group. A primary end-point event occurred in 18%, 34%, and 28% of the participants in these groups, respectively, and in 31% of the pooledmonotherapy group (the two monotherapy groups combined). The hazard ratio for the primary end point in the combination-therapy group versus the pooled-monotherapy group was 0.50 (95% confidence interval [CI], 0.35 to 0.72; P<0.001). At week 24, the combination-therapy group had greater reductions from baseline in N-terminal pro-brain natriuretic peptide levels than did the pooled-monotherapy group (mean change, −67.2% vs. −50.4%; P<0.001), as well as a higher percentage of patients with a satisfactory clinical response (39% vs. 29%; odds ratio, 1.56 [95% CI, 1.05 to 2.32]; P = 0.03) and a greater improvement in the 6-minute walk distance (median change from baseline, 48.98 m vs. 23.80 m; P<0.001). The adverse events that occurred more frequently in the combination-therapy group than in either monotherapy group included peripheral edema, headache, nasal congestion, and anemia. CONCLUSIONSAmong participants with pulmonary arterial hypertension who had not received previous treatment, initial combination therapy with ambrisentan and tadalafil resulted in a significantly lower risk of clinical-failure events than the risk with ambrisentan or tadalafil monotherapy. (Funded by Gilead Sciences and GlaxoSmithKline; AMBITION ClinicalTrials.gov number, NCT01178073.)

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