Inhaled prostanoid therapy for pulmonary arterial hypertension – a promise unfulfilled?

Keywords::

• pumonary arterial hypertension
• prostacyclin
• inhaled prostacyclin
• pulmonary hypertension

Pulmonary arterial hypertension (PAH) is an incurable, progressive disease resulting from narrowing of the precapillary vasculature, ultimately leading to right ventricular failure and death. PAH-specific vasodilators have drastically altered the trajectory of this once fatal disease, improving walk distance and hemodynamics, reducing clinical worsening and enhancing quality of life. Although current treatments are aimed at restoring the balance of endogenous vasoactive agents by enhancing the beneficial effects of nitric oxide (NO) and prostacyclin and blunting the deleterious effects of endothelin, only continuous infusion prostacyclin therapy has demonstrated improved survival in randomized clinical trials [1]. Although highly efficacious, continuous infusion therapy remains cumbersome, requiring a portable pump, and either a central venous catheter for intravenous delivery or a smaller catheter for subcutaneous delivery.

Inhaled prostacyclin therapies possess several potential advantages over continuous infusion and nonprostacyclin approved PAH therapies:

• drug delivery directly to the pulmonary vasculature, bypassing the systemic circulation, thereby minimizing problematic systemic side effects

• reduction of ventilation/perfusion mismatch and hypoxemia via drug delivery only to alveoli actively participating in gas exchange

• delivery of highly potent prostanoids, without the need for catheters, pumps, or central venous lines

Even beyond these reasons, it just seems so logical to consider inhaled therapies for medical conditions that primarily affect the lungs. The reality of inhaled vasodilator therapy has been much more complicated and, though efficacious, many of these unique advantages demonstrated in smaller studies have failed to translate into clinically meaningful benefits.

The current review is thorough and insightful, and the authors adroitly navigate the inhaled prostanoid literature, highlighting the strengths and weakness of inhaled pulmonary arterial vasodilators [2]. While inhaled therapies improve walk distance, we agree with the authors that efficacy of inhaled prostacyclin does not parallel that of intravenous or subcutaneous delivery [3,4]. One wonders, should we be surprised that inhaled prostacyclins have not been more effective?

The use of inhaled therapies for conditions beyond those affecting the lung parenchyma, such as asthma, chronic obstructive pulmonary disease or pneumonia, has been disappointing. Inhaled insulin, highly anticipated and introduced with great fanfare, gained USapproval in 2006. Plagued by a cumbersome delivery system, high cost and the need for continued background subcutaneous insulin therapy, the drug failed to gain widespread acceptance form physicians or third-party insurance payers and was abandoned in 2008 [5].

While inhaled prostacyclins remain available, their role in the treatment algorithm of PAH remains highly variable and practitioner dependent.

The authors discuss in detail differences between iloprost and inhaled treprostinil, emphasizing delivery systems, dosing intervals and significant variances between the pivotal studies that gained drug approval. In our opinion, the undeniable advantage of inhaled treprostnil stems from its q.i.d. dosing and shorter inhalation times, which compare favorably to the 6 – 9-times dosing schedule and longer treatment times required for iloprost. However, even q.i.d. dosing is quite cumbersome, and both therapies require equally motivated and knowledgeable patients with an adequate support system. In addition, despite significant differences between the drug delivery systems, both units require significant effort from the patient in cleaning, maintenance and setup.

In the absence of head-to-head studies, additional comparisons and inferences between the two inhaled therapies become challenging because of differences in the pivotal clinical trials involving background therapy, primary and secondary outcomes and inclusion criteria. As an example, iloprost improved functional class in the AIR (Aerosolized Iloprost Randomized) study, a finding not observed with treprostinil in TRIUMPH (TReprostinil Sodium Inhalation Used in the Management of Pulmonary Arterial Hypertension), though this may have reflected the presence of background vasodilator therapy and patient selection [6,7]. Additionally, inhaled treprostinil improved walk distance when used as combination therapy with either bosentan or sildenafil in TRIUMPH, and iloprost was associated with a trend towards improved walk distance when used as combination therapy with bosentan in STEP (Safety and pilot efficacy Trial in combination with bosentan for evaluation of Pulmonary arterial Hypertension), although this finding did not meet criteria for significance [8]. Are these meaningful differences to the treating physician or the patient, or just findings related to studies being done at different timelines in PAH therapy?

How does one choose between iloprost and inhaled treprostinil? Recommendations are difficult to provide in the absence of well-designed clinical trials. As a general rule, in suitable candidates, we would recommend practitioners gain experience with both inhaled therapies. We typically make decisions based upon the individual patient's side-effect profile and perceived compliance. For those patients who have significant headaches or cough, we might be more inclined to initiate iloprost, and for those who strongly prefer q.i.d. dosing, we would lean towards inhaled treprostinil. We are familiar with the iloprost–treprostinil switch study by Bourge et al., demonstrating improved biomarkers and patient satisfaction on inhaled treprostinil, and believe that, while highly provocative and interesting, we cannot draw meaningful conclusions regarding comparative drug efficacy in this open label, nonrandomized study [9].

Can the global healthcare system handle the incremental cost of inhaled prostacyclin therapy? Physicians in all medical specialties are coming under increasing scrutiny regarding the costs of diagnostic tests, therapeutic procedures and drugs. While actual drug costs are difficult to obtain, figures cited in recently published guidelines report annual costs of sildenafil, bosentan and iloprost at of $12 – 761, $55 – 890 and $92 – 146, respectively [10]. The annual cost of continuous infusion therapy is highly variable owing to the drug dose and patient weight, but for a 70-kg patient the cost was estimated at $33 – 153 for epoprostenol and $97 – 615 for treprostinil [10]. The British National Health Service (NHS), one of the most cost-conscientious global healthcare organizations, has questioned the cost–benefit ratio of all prostacyclin therapy [11]. Although there is a strict ordering system for some costly therapies, such as implantable cardio-defibrillators (ICDs), the PAH arena has so far been spared such oversight, most likely as a result of low disease prevalence. However, as costs rise and overall funding allocated for healthcare becomes scarce, third-party scrutiny may become inevitable. The use of avastin for breast cancer has come under tremendous scrutiny owing to questionable benefits and clinical trial end points, and we wonder if improvement in short-term improvements in 6-min walk distance will continue to serve as a primary end point for drug approval in PAH.

Oral prostacyclin analogues are now under investigation in Phase III clinical trials. An efficacious oral prostacyclin with a manageable dosing schedule, side-effect profile and reasonable cost may drastically change the market for inhaled prostacyclins.

Author recommendations

The optimal candidate for inhaled therapy continues to evolve as newer drugs are developed and additional literature is published on safety and efficacy of combination pharmacotherapy. Although published guidelines suggest a role for inhaled prostacyclins as initial therapy in a patient with WHO functional class II – III symptoms [10], and the AIR study demonstrated significant symptomatic benefit in treatment-naive patients with inhaled iloprost [6], we believe such a patient is best initiated on an oral drug, either a phosphodiesterace type 5 (PDE-5) inhibitor or an endothelin receptor antagonist (ERA). A patient who remains symptomatic, or exhibits high-risk features for clinical progression, is a good candidate for inhaled therapy. This patient may not be a candidate for dual oral therapy, owing to side effects or drug contraindications, and may not be sufficiently ill or motivated to justify initiation of continuous infusion prostacyclin therapy. Also, although iloprost has been approved for WHO functional class IV patients, we agree with the authors that this highly symptomatic cohort is best treated with continuous infusion prostacyclins.

In general, we feel that inhaled therapy is most ideally suited for patients with functional class III symptoms on oral background therapy, and consideration can be given to those with functional class II symptoms with high-risk features for clinical progression. The current literature does not support use of ‘triple therapy’, involving dual oral agents and inhaled drug from different classes, and we discourage this practice. It bears emphasis that there are no randomized, clinical trial data to guide such important therapeutic decisions, which are based primarily upon expert opinion and individual experiences.

Declaration of interest

G Ramani is a consultant for United Therapeutics (the manufacturer of inhaled treprostinil).