Go hard. By the time you see PAH, it’s already bad

Cardiologists and respiratory physicians agree – there is no such thing as mild pulmonary arterial hypertension (PAH).

Speaking at CSANZ 2018, Professor David Celemejer, from the University of Sydney and the Royal Prince Alfred Hospital, said resting pulmonary hypertension was a very late feature of pulmonary vascular disease.

“Pulmonary vascular disease preempts pulmonary hypertension so there is no such thing as mild PAH. It’s already bad.”

Respiratory physician Dr Gregory Keir, from Brisbane’s Princess Alexandra Hospital, agreed it was a very important message for clinicians.

“By the time resting pulmonary pressures are elevated, you’ve got advanced disease. By the time you see these patients, even with haemodynamically mild disease, they have lost a lot of that pulmonary microcirculation and you need to treat aggressively to try and retrieve that if you can.”

Dr Keir said the AMBITION trial, comparing ambrisentan and tadalfil alone or in combination versus placebo, was one of the pivotal studies in PAH.

“This was probably one of the first really good quality studies that proved that combination therapy, particularly when used early, was of benefit to the patients.”

“So using drugs from two different classes targeting two different pathways just seems like common sense … but it had been surprisingly difficult to prove that this approach worked.”

The study found patients on an upfront combination therapy were half as likely to have a bad outcome as those on monotherapy (HR=0.5).

He said another landmark study in PAH was selexipag versus placebo, in which about 80% of participants were already on background therapy.

“And that’s kind of how things are going. I would be very reluctant to randomise any of my patients to a placebo arm of a study without an escape clause these days, given that we have got effective therapies available.”

The study found the risk of the primary composite end point of death or a complication related to PAH was significantly lower with selexipag than placebo.

“We don’t yet have this drug available to us in Australia but Actelion are pushing hard to get it listed on the PBS,” he said.

A subsequent meta-analysis confirmed that combination therapy was associated with a significant reduction in clinical worsening compared with monotherapy.

“Certainly that is the way that therapy in PAH is moving these days – using combination therapy early to try and reverse or unravel that vascular remodeling that we see.”

“That all sounds terrific from a theoretical point of view but unfortunately in the real world, the PBS will only fund one drug.”

“We are lucky in the last couple of years that most PAH pharma companies do have compassionate access programs so that if you prescribe their particular endothelin receptor antagonist, they will fund either sildenafil or tadalafil as add-on therapy.”

“And the other limiting factor is the PBS will only fund therapy for functional class III or IV so these are people who are very, very impaired and in some ways the horse has bolted by the time their symptoms get to that stage.”

He said there was an increasing role for stratifying patients to ensure high-risk patients were being appropriately treated.

Dr Keir said in his own clinical practice he used combination therapy for almost everyone – typically starting them on macitentan or ambrisentan and checking for any adverse effects before adding in a PDE5 inhibitor.

He added that IV prostacyclin therapy was probably one of the best and most potent anti-PAH drugs available but underused both in Australia and globally.

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