Successful use of intravenous treprostinil as a bridge to pulmonary thromboendarterectomy

Abstract

Chronic thromboembolic pulmonary hypertension (CTEPH) involves non-resolving thromboemboli in the pulmonary arteries. Treatment for CTEPH includes lifelong anticoagulation and determination of patients who have disease which is operable versus inoperable. Pulmonary arterial hypertension (PAH) targeted therapies are oftentimes used as a bridge to pulmonary thromboendarterectomy (PTE), though riociguat is the only Food and Drug Administration (FDA)-approved therapy for CTEPH. There is a paucity of data regarding the efficacy of other PAH therapies, particularly as a bridge to PTE. Here, we present a case report of severe CTEPH related to ventriculoatrial shunt in which intravenous treprostinil was used as a bridge to PTE.

Background

Chronic thromboembolic pulmonary hypertension (CTEPH) involves non-resolving thromboemboli in the pulmonary arteries. Pulmonary hypertension (PH) is multifactorial and related to obstruction of pulmonary arteries by chronic thrombi as well as accompanying vascular changes in pulmonary arteries and microvasculature that leads to increased pulmonary vascular resistance (PVR).¹ There are many factors that lead to an increased risk of CTEPH, and one such cause is ventriculoatrial (VA) shunts placed for the treatment of hydrocephalus. VA shunts have been demonstrated to increase the risk for developing CTEPH.^2–4 Two studies showed that 2.8% and 6% of patients with CTEPH, respectively, had a VA shunt.^{2 4} In the latter study, this corresponded to an OR of 13.

Treatment for CTEPH includes lifelong anticoagulation and determination of patients who have disease which is operable versus inoperable. If operable and risk/benefit ratio is deemed favourable, pulmonary thromboendarterectomy (PTE) should be strongly considered and considered early as it may be curative. However, thrombotic lesions not easily accessible surgically, multiple and severe patient comorbidities, and PH which is out of proportion to the degree of chronic thromboemboli can be prohibitive. For patients who are not operative candidates, other options include balloon pulmonary angioplasty and targeted PH therapy.

PH-targeted medical therapy is commonly used for both bridging therapy to PTE and in patients with non-surgical disease. However, only riociguat is Food and Drug Administration (FDA) approved for patients with CTEPH, as it has shown both functional and haemodynamic benefits in the placebo-controlled, randomised controlled trial (RCT), Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase Stimulator Trial-1 (CHEST-1).^{5 6} Phosphodiesterase 5 (PDE-5) inhibitors have not been consistently shown to improve exercise capacity and PVR,^{7 8} and were found by a recent Cochrane Review to not have clear benefit in CTEPH based on the available evidence.⁹ Endothelin receptor antagonists bosentan and macitentan have been studied in the RCTs BENEFiT and Merit-1, respectively.^{10 11} Both were shown to significantly decrease PVR compared with controls. CTEPH is the only RCT that has studied subcutaneous treprostinil in patients with CTEPH, and demonstrated improvement in 6 minute walk distance (6MWD), WHO functional class and some haemodynamic variables.¹² Several other retrospective cohort studies, prospective studies and case series using prostacyclins have shown improvement in functional parameters, haemodynamic parameters or both.^13–23 Limitations of most studies for all classes of targeted pulmonary arterial hypertension (PAH) therapy include small study sizes, a high number of included patients with inoperable disease, and most with a combined study population of patients with PAH and patients with CTEPH. There are even less data on operable patients and bridging therapy. Preoperative management during the bridging period is important because preoperative PVR has been shown to be a predictor of postoperative mortality both short and long term.²⁴

Here, we present a unique case of a patient with CTEPH related to a VA shunt with progressively worsening symptoms and right heart failure who was bridged to successful PTE using intravenous treprostinil.

Case presentation

A 47-year-old woman with CTEPH presented to the hospital with worsening dyspnoea and cough. She had a complex medical history that included spina bifida and congenital hydrocephalus with VA shunt placement in infancy. The VA shunt had been removed and replaced with a ventriculoperitoneal shunt 1 year prior to presentation after an episode of hydrocephalus. The procedure was complicated by a fractured catheter with a retained intravascular catheter fragment which was unable to be removed.

Two years prior, she was diagnosed with severe CTEPH, functional class III–IV, and had been on riociguat since that time (figure 1). She initially had a positive response with improvement in exercise tolerance and decrease in pulmonary arterial pressures (PAP) with treatment; however, in recent months had two admissions for decompensated right heart failure and worsening dyspnoea.

Figure 1.

V/Q scan image demonstrating multiple mismatched perfusion defects.

In the emergency department, systolic blood pressure was 84/35, heart rate 120 and oxygen requirement was 6 L/min by nasal cannula. On physical examination, she appeared uncomfortable and tachypneic, breath sounds were clear, extremities were warm and 2+ pitting oedema to the knee was present. Labs were notable for lactic acid 3.2, white cell count 12.7 x10⁹/L and elevated creatinine from her baseline. Urinalysis showed positive nitrites and occasional white blood cells.

She was admitted to the medical intensive care unit (ICU) with shock requiring initiation of vasopressors. Urine culture grew vancomycin resistant enterococcus, and blood cultures later grew pseudomonas aeruginosa. Her echocardiogram showed normal left ventricular function, a dilated right ventricle with preserved systolic function and estimated pulmonary artery systolic pressures (PASP) 80 mm Hg. Despite treatment with intravenous antibiotics for urinary tract infection and bacteraemia, the patient had a protracted ICU course due to inability to wean off vasopressors. After a month of admission, she had completed antibiotics and blood cultures had cleared, but she remained hypotensive. Due to concern for worsening PH contributing to persistent hypotension, intravenous treprostinil was initiated and slowly up titrated. Discussions with a PTE-capable centre were in progress, and it was hoped that intravenous vasodilator therapy could help improve her refractory combined septic and cardiogenic shock and stabilise her to safely have PTE. After starting intravenous treprostinil, hypotension gradually improved, diuresis was more successful, and a subsequent echocardiogram 1.5 months and 2.5 months after initiation of treprostinil, respectively, showed decreased estimated PASP 63 mm Hg and 50 mm Hg.

She was discharged to inpatient rehab but was readmitted 1 month later for recurrent pseudomonas bacteraemia with persistently positive cultures despite antibiotics. She had an extensive work up for the source of infection. Urine culture was negative, chest CT showed no evidence of pneumonia, and echocardiogram showed no vegetations. A PET CT demonstrated increased uptake in the region of a retained portion of VA shunt catheter located in the right brachiocephalic vein, and this was ultimately determined to be the source of bacteraemia. After discussion with multiple consulting services, it was determined that a partial sternotomy would be required for removal of the VA shunt fragment. Her case was discussed with the surgical team at the nearest PTE-capable centre, and it was determined she was stable enough to undergo PTE with concurrent catheter removal. She had been deemed a good PTE surgical candidate due to the presence of central and progressive disease.

On transfer to PTE-capable centre, preoperative right heart catheterisation showed PAP 76/29 mm Hg (see online supplemental file 1). Right ventricular function was moderately decreased on preoperative echocardiogram with moderate to severe tricuspid regurgitation. She underwent uncomplicated catheter removal and PTE (figures 2 and 3).

Figure 2.

Thrombi removed during pulmonary thromboendarterectomy.

Figure 3.

Shunt catheter fragment removed during pulmonary thromboendarterectomy.

Outcome and follow-up

Postoperative right heart catheterisation showed significant improvement in pulmonary artery (PA) pressure. The tricuspid valve was repaired with trivial regurgitation postoperatively. She was no longer on any targeted medical therapies for PH, had no oxygen requirement and was eventually discharged home. Right heart catheterisation 1 year later showed PAP 40/18 with mean PAP 28. She has had no hospital admissions since her PTE and has remained off pulmonary vasodilators.

Discussion

CTEPH is a class of PH with many diverse phenotypes. This case highlights three noteworthy scenarios related to CTEPH. First, this patient likely developed CTEPH related to the long-term presence of her VA shunt catheter. While previous studies showed a minority of patients with CTEPH had a VA shunt (2.8%–6%),^{2 4} this was one of the strongest risk factors for the development of CTEPH. This association is likely underrecognised, and a higher index of suspicion for CTEPH should be present in this patient population.

Next, this patient was successfully bridged to PTE using intravenous treprostinil. While there are several studies demonstrating significant benefit in both haemodynamic values and functional metrics such as 6MWD with treprostinil, they have been limited by their small study sizes, single centre and most with lack of RCT study designs. These studies were conducted in patients who had either inoperable disease or residual PH after PTE. This case report contributes to the existing literature suggesting that prostanoids may have a role in patients with CTEPH, both in inoperable disease and possibly as a bridge to PTE. Significant clinical improvement was seen in this patient as demonstrated by decrease in PAP and survival to PTE. Change in PVR and 6WMD with treprostinil were not able to be determined for this patient in the immediate postoperative setting. This highlights the need for further literature in this area, as riociguat remains the only FDA-approved medication for CTEPH.

Finally, while treprostinil was effective for this patient, her course was complicated by persistent gram-negative bacteraemia. Multiple prior studies have shown an increased rate of bloodstream infections, primarily with gram-negative organisms, in patients receiving intravenous treprostinil.^25–27 One prospective study of 1146 patients from 2006 to 2009 receiving intravenous prostanoids showed a 3.08-fold increase in all bloodstream infections and 6.86-fold increase in gram-negative bloodstream infections, with intravenous treprostinil when compared with intravenous epoprostenol.²⁷ While the reason for this increased rate of infection is not known with certainty, it has been proposed to be related to the pH of the diluent used in intravenous treprostinil.^{28 29} Differences in product storage and anti-inflammatory effects have also been proposed.²⁷ While the retained shunt catheter fragment likely provided a nidus for infection that contributed to the inability to clear cultures despite antibiotics, intravenous treprostinil could be a predisposing factor for development gram-negative infection. Her persistent bacteraemia greatly increased the patient’s length of stay and complicated her hospital course. Benefits of continuing intravenous remodulin significantly outweighed the risks in this patient and therefore parenteral prostacyclin therapy was continued.

Learning points.

• Treprostinil may have a role in patients with chronic thromboembolic pulmonary hypertension (CTEPH), both for inoperable disease and as a bridge to pulmonary thromboendarterectomy.

• A high index of suspicion for CTEPH should be maintained in patients with ventriculoatrial shunts.

• Gram-negative bacteraemia may complicate therapy with intravenous treprostinil.