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Drug combo improves RV contractility in scleroderma-PAH

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Comment by Jason Lazar, MD, FCCP

Dr. Jason Lazar

Dual therapy is standard therapy for PAH but not for secondary pulmonary hypertension. Dual oral therapy represents a novel approach for treatment, and very few studies have demonstrated any drug to benefit secondary pulmonary hypertension.



A combination of ambrisentan (Letairis) and tadalafil (Cialis) improves regional and global right ventricular contractility in patients with scleroderma-associated pulmonary arterial hypertension, according to an open-label investigation of 23 patients.

The project was a follow-up to a previous report showing that the upfront combination – tadalafil 40 mg and ambrisentan 10 mg oral once daily – improved hemodynamics, right ventricular (RV) structure and function, and functional status in treatment-naive patients after 36 weeks and “may represent a very effective therapy for this patient population” (Am J Respir Crit Care Med. 2015 Nov 1;192(9):1102-10).

Dr. Valentina Mercurio

Survival in scleroderma pulmonary artery hypertension (PAH) depends mostly on RV function, so investigators in the follow-up study wanted to take a closer look at how the combination affected the heart. They reviewed conventional echocardiograph imaging and RV strain analyses for the 23 of the 24 patients in the original trial for which it was available (Am J Respir Crit Care Med. 2017 Jun 29. doi: 10.1164/rccm.201704-0789LE).

At baseline, the subjects had normal left ventricular (LV) size and function, with borderline left atrial enlargement and mild LV diastolic dysfunction. Their right heart chambers were significantly dilated, with RV hypertrophy. Conventional RV function parameters – tricuspid annular systolic plane excursion (TAPSE) and fractional area change (FAC) – were impaired. RV systolic pressure (RVSP) was severely elevated. There was also a marked reduction of global RV longitudinal systolic strain (RVLSS), compared with normal values mainly because of a reduction in midventricular and apical RVLSS, with relative hyperkinesis of basal RVLSS

After 36 weeks of treatment, right heart chamber sizes were significantly reduced. There was also a decrease in RV free wall thickness, which coincided with a significant reduction in RV mass on cardiac MRI. TAPSE, FAC, and global RVLSS improved significantly, and RVSP decreased significantly. LV end-diastolic and end-systolic diameters and volumes increased significantly.

The changes “may represent transition from maladaptive RV remodeling ... to a more physiological and adaptive RV remodeling;” however, “the effects of treatment should be interpreted with caution, as this was an open-label study without a placebo or a single-drug control group,” said investigators led by Valentina Mercurio, MD, a postdoc fellow at Johns Hopkins University, Baltimore.

“It is conceivable that a heterogeneous RVLSS pattern exists in [scleroderma] patients with longitudinal hyperkinetic basal segment as the predominant vector of contraction early in the disease course. As PAH develops, the ability of the basal segment to compensate decreases, and RV failure ensues, suggesting a ‘two-hit’ hypothesis, in which a preexisting RV contractile dysfunction may predispose to further RV impairment when a second insult (PAH development) occurs,” they said.

Subjects were about 60 years old on average, and most were women. The majority shifted from World Health Organization PAH functional class 3 to 2 during the original trial. Mean 6 minute walk tests increased from 341 m to 401 m.

Gilead and United Therapeutics provided the ambrisentan and tadalafil. Dr. Mercurio reported funding from both companies and Merck. The original study was sponsored by United Therapeutics.

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