The NewsPAHper

Over the past two decades, there has been a significant shift in the epidemiology of PAH and contemporary registries have shown a marked increase in the age of PAH patients 1. The United Kingdom and Ireland Registry showed that the median age of idiopathic PAH patients at diagnosis increased from 45 years between 2001-2003 to 52 years between 2007-2009 2. The Pulmonary Hypertension Society of Australia and New Zealand (PHSANZ) Registry mirrored these findings, with an average age of 57 years for those diagnosed since 2012 3. It remains unclear whether the ageing PAH population is a manifestation of improved case-finding in the older population due to greater community awareness or an intrinsic change in the biology of the disease. Because of increasing age, PAH patients often have medical co-morbidities which make management more challenging. In the PHSANZ Registry, common co-morbidities included obesity (34.1%), systemic hypertension (30.5%), diabetes mellitus (19.5%), and coronary artery disease (16.4%) 3. Importantly, these co-morbidities increase the likelihood of patients having left heart dysfunction, where pulmonary vasodilator therapies may not be helpful or even harmful 4.

A recent post-hoc analysis of the Ambrisentan and Tadalafil in Patients with Pulmonary Arterial Hypertension (AMBITION) study provided important data on the use of initial combination therapy in PAH patients with cardiovascular risk factors 5. The AMBITION study was a landmark study which showed initial combination therapy with ambrisentan and tadalafil was associated with a lower risk of clinical-failure events compared to monotherapy with ambrisentan or tadalafil alone 6. The AMBITION study resulted in the current PAH guidelines giving a strong recommendation for the initial use of combination therapy in newly diagnosed PAH patients 7. However, the above results were based on the primary analysis set (PAS), which excluded patients with 3 or more risk factors for left heart disease (obesity, systemic hypertension, diabetes mellitus and coronary artery disease). Patients with high normal pulmonary artery wedge pressure and mild pulmonary vascular resistance elevation were also excluded from the PAS (Table 1). The rationale for excluding these patients from the PAS was to avoid contamination of the main results with patients who may have occult left heart disease. It is important to note the patients excluded from the PAS (termed ex-PAS population) fulfilled the traditional haemodynamic definition of PAH, but had a "left heart disease flavour" on the basis of their co-morbidities and/or haemodynamics. This ex-PAS group is of immense interest to the pulmonary hypertension physician since they make up a significant proportion of the patients encountered in the clinic. Indeed, an analysis of the PHSANZ Registry found that about one third of idiopathic PAH patients fulfil criteria for ex-PAS (unpublished data, PHSANZ Registry).

Figure 1 - Summary of the effect of initial combination therapy compared with pooled monotherapy in PAS and Ex-PAS patients

Compared to monotherapy, combination therapy in the ex-PAS group was associated with a 30% reduction (HR 0.70, 95%CI [0.35-1.37]) in risk of clinical failure event versus 50% (HR0.50 95%CI [0.35-0.72]) in the PAS group. In terms of exercise capacity at 24 weeks, the ex-PAS group exhibited average changes in 6-minute walk distance of 19.6m for the combination therapy group and 11.4m in monotherapy. In contrast, PAS patients had larger increases in 6-min walk distances (49m in combination group and 23.8m in monotherapy group). An important aspect is the tolerability of aggressive pulmonary vasodilator use in the ex-PAS population. In this regard, rates of permanent study drug withdrawal because of adverse events were 14% in PAS versus 33% in ex-PAS for patients receiving initial combination therapy, but the incidence of peripheral oedema in those receiving combination therapy was similar in both groups (41% and 45% in the ex-PAS and PAS populations, respectively).

Although potential gains were less and severe adverse events more common in the ex-PAS group, does this mean that targeted therapy should not be used in patients with multiple risk factors for left heart disease who fulfil clinical and haemodynamic criteria for PAH? Certainly not, since cardiovascular co-morbidities are very common and may not necessarily imply the presence of left ventricular dysfunction. One must first recognise that differentiating PAH (Group 1) from PH due to left heart disease (Group 2) can be difficult, even in experienced physicians. Therefore, patients should be assessed in an expert PAH centre. Invasive haemodynamics must be interpreted in the context of clinical and echocardiographic findings, as well as fluid status of the patient at the time of right heart catheterisation. Over-diuresis may artificially lower the pulmonary artery wedge pressure, whilst a fluid challenge can be employed to unmask occult left heart disease 8. Accordingly, a "start slow, go slow" approach should be considered in this population if there is clinical uncertainty regarding occult left heart disease. Patients can be started on monotherapy, with escalation to combination if monotherapy therapy is well tolerated and treatment goals are not met at follow-up*.