Pharmacological treatment prior to pulmonary endarterectomy

Pulmonary endarterectomy is the guideline recommended therapy for chronic thromboembolic pulmonary artery hypertension (CTEPH). The use of vasodilator-targeted medical therapy in patients with CTEPH is only recommended for inoperable patients, or those with residual pulmonary hypertension (PH) post-endarterectomy.

Riociguat was evaluated within the CHEST-1 trail and is currently the only licenced drug treatment for patients with CTEPH; importantly, the trial excluded operable patients by an experienced clinical adjudication committee. Hence, the licence is only for inoperable patients or those with residual/recurrent post-surgery [1]. The BENEFIT trail evaluating the use of bosentan showed a haemodynamic effect with a significant reduction in pulmonary vascular resistance (PVR) but failed to show clinically relevant improvements in exercise capacity [2]. There was no prerandomization adjudication of potentially operable patients in this earlier trial that predated the CHEST-1 trial above. However, a more recent phase 2 trials with macitentan did demonstrate reduction in PVR and improvement in 6-min walk distance [3].

However, a retrospective study from a large experienced pulmonary endarterectomy centre demonstrated that medically treated patients had a longer referral pathway before pulmonary endarterectomy, but no overall benefit [4]. In addition, the International CTEPH registry failed to demonstrate any benefit of medical treatment prior to surgery and such treatment was associated with higher mortality [5].

The treatment of CTEPH patients prior to surgery is controversial and up to now not supported by clinical trial evidence. A multicentre randomized controlled trial with Riociguat (The Bridging trial ClinicalTrials.gov Identifier: NCT03273257) was unfortunately abandoned in 2020 because of delayed recruitment and the COVID-19 pandemic. However, many centres are treating patients with targeted pulmonary vasodilator therapy prior to surgery based on direct feedback and clinical experience.

Hence, this small retrospective propensity matched series does bring some further evidence into the field of medical treatment of operable CTEPH patients [6]. However, importantly, there was no difference in 30-day mortality or late survival between bosentan-treated patients and controls without pre-treatment. Those treated with bosentan who had a PVR of >10 Wood units appeared to benefit from a greater reduction in PVR post-surgery that just reached statistical significance. It is also important to realize that this was a small selected retrospective series and there was no attempt to reassess PVR in the bosetan group before surgery, so the actual impact of the drug therapy alone is not known.

Thus, the unlicenced use of pulmonary vasodilator drugs in patients with operable CTEPH continues despite little research evidence to support it. However, individual patients with very high PVR do appear to benefit and all surgical centres have experience of some patients improving with clinically significant reduction in PVR prior to surgery. If physicians continue to commence vasodilator drugs at the time of investigation and before referral for consideration of surgery, the prospect of a RCT to answer the question remains minimal.

Conflict of interest: David P. Jenkins reports cardiac index (CI) for bridging study funded by Bayer and an adjudication committee member of SELECT and Maciteph trials. The other reports no conflict of interest.

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