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Updates in the Treatment of Chronic Thromboembolic Pulmonary and Pulmonary Arterial Hypertension

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - International Conference of the American Thoracic Society

Philadelphia, Pennsylvania / May 17-22, 2013

Philadelphia - Currently, the gold standard for chronic thromboembolic pulmonary hypertension (CTEPH) is pulmonary endarterectomy (PEA) but when patients are deemed inoperable or when symptoms persist or recur following PEA, new medical approaches are needed. Subcutaneous prostanoids represent a potential treatment strategy as they have shown benefit in inoperable CTEPH patients. A new dual endothelin receptor antagonist has shown morbidity and mortality benefit in pulmonary arterial hypertension. Another novel oral agent that helps stimulate cyclic GMP via the guanylate cyclase pathway, promoting vasodilation independent of nitric oxide, has shown considerable benefit in inoperable and symptomatic CTEPH as well as in pulmonary arterial hypertension.

Chief Medical Editor: Dr. Léna Coïc, Montréal, Quebec

Chronic thromboembolic pulmonary hypertension (CTEPH) has emerged as one of the leading causes of severe pulmonary hypertension (PH) (Circulation 2006;113:2011-20). “CTEPH is different from pulmonary arterial hypertension (PAH),” Dr. Nick Kim, Associate Clinical Professor and Director, Pulmonary Vascular Medicine, University of California, San Diego, told delegates here. Unlike PAH which affects small vessels in the lungs, CTEPH is characterized by a component of mechanical obstruction thought to be caused by organized proximal thrombi within the pulmonary arteries that increase resistance of blood flow through the lungs. This leads to high levels of pulmonary vascular resistance (PVR) and progressive right heart failure. Ultimately, death ensues without effective treatment.

Speakers here agreed that the gold standard for the treatment of CTEPH is pulmonary endarterectomy (PEA) which is curative in the right patient. Of a large cohort of CTEPH patients (n=679), over 89% of those who underwent PEA (n=404) were still alive at 3 years compared with roughly 70% of those who did not undergo PEA (n=275) (abstract A5365). Difference in survival between the 2 groups was maintained after adjustment for age, gender, functional class and specific measures of pulmonary function.

However, not all patients respond fully to PEA and may remain symptomatic or have recurrent PH following surgical resection. Moreover, recent data from the European CTEPH registry indicate that well over one-third of patients with CTEPH are not candidates for PEA (Br J Haematol 2010;149:478-83). “To date, we have no approved pharmacological therapy for this disease,” Dr. Kim noted. “As a result, we feel there is an unmet medical need in patients who for various reasons cannot have surgery.” Those with symptomatic or recurrent PH following PEA are in a similar situation, he added.

Stimulating the sGC Pathway Independent of NO: Findings

Since PH is associated with endothelial dysfunction and subsequently impaired nitric oxide (NO) synthesis, increasing cyclic GMP to enhance vasodilation either by stimulating the production of cyclic GMP or by preventing the breakdown of cyclic GMP is a key goal in the treatment of PH.

The novel oral compound riociguat binds with soluble guanylate cyclase (sGC) to stabilize nitric oxide (NO). In directly stimulating the sGC pathway, it increases cyclic GMP independent of NO. CHEST-1 (abstract A3529) was the first randomized, double-blind placebo-controlled study designed to assess the efficacy of the novel agent in CTEPH.

A total of 261, treatment-naive patients with centrally-adjudicated, anatomically inoperable disease or those who had undergone PEA but had persistent/recurrent PH, were randomized to 8 weeks of titration of active drug, starting with 1 mg TID, followed by 8 weeks of maintenance or 16 weeks of placebo. Both primary and secondary end points were analyzed at week 16. Investigators aimed for a target dose of up to 2.5 mg TID of active drug, the primary end point being the 6 minute walk distance (6MWD) compared with baseline at 16 weeks. At 16 weeks, 90% of patients had successfully been titrated to either 2 mg or 2.5 mg TID, Dr. Kim noted.

From a baseline 6MWD of approximately 350 metres in both arms, “the treatment effect for the total population was a [placebo-corrected] gain of 46 metres,” Dr. Kim reported. Interestingly, the effect of active therapy was more robust in patients judged to be inoperable at a placebo-corrected gain of 54 meters compared with 26 meters for patients who had previously undergone PEA but had persistent or recurrent PH. Hemodynamic measures also improved in response to active therapy vs. placebo.

The novel agent was well tolerated and had a good safety profile, with comparable rates of syncope for the 2 arms. Hypotension did occur but was deemed largely mild. “This drug is not intended to replace surgery in patients who are deemed operable,” Dr. Kim emphasized. “CHEST-1 is the first study where statistically significant efficacy has been demonstrated in both the 6MWD and PVR and the significant correlation between the change in exercise capacity and change in hemodynamics underlines the efficacy of riociguat in this investigational cohort.”

Prostacyclin Analogues

Anecdotal experience had suggested that subcutaneous (SC) treprostinil, a prostacyclin analogue, may be of some benefit in CTEPH patients. To more rigorously assess this benefit, investigators carried out a randomized, double-blind, low dose treprostinil-controlled study in 54 patients with severe CTEPH, classified as non-operable by expert surgeons (CTREPH trial, abstract A3533). Mean baseline 6MWD of the cohort was 298 metres. “We did allow for pre-medication,” stated Dr. Irene Lang, Professor of Vascular Pathology, Medical University of Vienna, Austria.

Patients were assigned to high-dose SC treprostinil—target dose of 30 ng/kg/min by 12 weeks—or a placebo-like low dose of SC treprostinil 3 ng/kg/min. At week 24, change from baseline in the 6MWD, the primary outcome of the study, was 42.9 metres (non-significant at this interim analysis) compared with low-dose SC treprostinil.

Notably, per-protocol analysis indicated that change in the 6MWD at 57.4 metres over baseline was significant relative to the low-dose SC treprostinil arm (P=0.0045). Significant improvements were also noted in PVR (P=0.003) and in WHO functional class in favour of the high-dose vs. the low-dose prostanoid group (P=0.003).

“The majority of side effects were infusion-site reactions and these were similar between the high and low dose groups,” Dr. Lang noted, “and we believe that SC prostanoids in non-operable CTEPH patients is safe and efficacious and a valuable treatment option for this patient population.”

PAH Treatment

PAH occurs as a result of a variety of underlying conditions but is frequently idiopathic in nature. The PDE5 inhibitors and the endothelin-receptor antagonists (ERAs) are frequently used as first-line therapy for PAH and have approximately the same effect on hemodynamics and exercise capacity in the short-term. Whether they remain similarly effective over a longer-term follow-up was addressed by researchers in Italy.

As reported here by Mazzanti et al. a total of 200 treatment-naive PAH patients were randomized to sildenafil 20 mg TID or bosentan 125 mg BID for 4 months (abstract A3535). At the end of 4 months, 44 patients in the sildenafil group and 35 in the bosentan group did not have clinical worsening and went on to long-term follow-up. At a mean follow-up of 26 months, time to clinical failure and all-cause mortality estimates were almost identical between the 2 groups.

Macitentan is a new dual ERA with sustained receptor binding. As reported here by Dr. Richard Channick, Associate Professor of Medicine, Harvard Medical School, Boston, Massachusetts, (SERAPHIN trial, abstract G1/A3269) macitentan at both 3 and 10 mg significantly prolonged time to death due to PAH or hospitalization for PAH by 33% and 50% respectively, compared to placebo (P=0.0146 for the 3 mg and P<0.0001 for the 10 mg dose).

The same dual ERA also reduced PAH-related hospitalizations/year by 43% for the 3 mg dose and by 55% for the 10 mg dose relative to placebo (P=0.0068 and P=0.0002 for the 3 and 10 mg dose, respectively). The 10 mg dose also significantly reduced the number of PAH-related hospital days/year by approximately half compared with placebo (P=0.0416).

“This reduction in hospitalization may well impact quality of life for patients as well as cost of care for PAH,” Dr. Channick remarked.

Also presented here at the ATS was a phase III randomized, double blind study of riociguat in PAH (PATENT-1 trial, abstract A3532). It involved 443 patients who were treatment-naive or pre-treated with ERAs or prostanoids. At 12 weeks, a 6MWD increase of ≥40 metres was achieved by 49% of treatment-naive patients treated with riociguat vs. 20% of placebo-treated patients. In the ERA-pretreated arm, it was 35% vs. 28%, respectively. For patients pretreated with prostanoids it was 50% with riociguat compared with 14% on placebo.


An important proportion of patients with PH have CTEPH for whom PEA remains curative if operable. If inoperable, there is currently an unmet medical need for CTEPH patients as well as those who remain symptomatic or who have recurrent PH after PEA. Riociguat represents a novel oral agent that has hemodynamic and functional benefit in this patient population. SC prostanoids may represent an alternative strategy for the same CTEPH patient population. For patients with PAH, the PDE5 inhibitors and ERAs represent equally viable short and long-term treatment options. Macitentan and riociguat have also shown benefit in the PAH population. 

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