PAH module 3: the treatment of pulmonary hypertension

Medical therapy in the treatment of pulmonary arterial hypertension

Physicians are advised to consult the latest SPC (summary of product characteristics) for all medications

Calcium channel blockers

At the time of the diagnostic cardiac catheterisation, vasoreactivity testing is carried out to identify those patients who might benefit from long-term calcium channel blockers (CCBs). Less than 10% of patients with IPAH are positive acute responders (ESC 2015 guidelines), and only about half of these patients demonstrate long-term improvement with CCBs.⁸

The usefulness of vasoreactivity testing (see the chapter on Investigation of PH) is less clear in other subclasses of pulmonary arterial hypertension. CCBs must not be given to patients who have not undergone vasoreactivity testing or to those with a negative test response. In these patients, the deleterious effect on myocardial function in the absence of reduced pulmonary vascular resistance may cause clinical deterioration or death. The prognosis of long-term responders who are optimally managed with CCBs is very good.

The most commonly used CCBs are nifedipine, diltiazem and amlodipine.^8,9,10 The choice is based on the patient’s heart rate, nifedipine and amlodipine being used for those with a relatively slow heart rate and diltiazem in those with a faster heart rate. The drugs are started at low doses and titrated up to the maximum tolerated dose (systemic hypotension and peripheral oedema are the usual limiting factors). Efficacy has been shown for this group of agents at high doses—120-240mg nifedipine per day, 240-720mg diltiazem per day and up to 20mg per day for amlodipine.

These patients require particularly close follow-up and are normally recatheterised after achieving a maximum tolerated dose of the CCB. If the patient does not improve to WHO-FC I or II and have normal or near normal haemodynamics, then he or she is classed as a non-responder and additional disease-targeted therapy is commenced according to the algorithm. Pulmonary hypertension can break through CCB treatment at any time during follow-up; and care must be taken to ensure that these patients are continuing to respond to CCBs. The below table summarises the recommendations for calcium channel blocker therapy in patients who are respond to the acute vasoreactivity test.

Learning point

• Calcium channel blockers may have a role in “vasoreactor positive” patients with pulmonary arterial hypertension

Prostacyclin analogues and Prostacyclin receptor agonists

Prostacyclin, produced predominantly by endothelial cells, is a potent vasodilator and inhibitor of platelet aggregation, with cytoprotective and antiproliferative effects. Patients with PAH have reduced expression of prostacyclin synthase in the pulmonary arteries. The four prostacyclin analogues in current clinical use are epoprostenol, iloprost, treprostinil and beraprost. Selexipag is a prostacyclin receptor agonist and has similar modes of actions to that of endogenous prostacylin, but is chemically distinct. A brief outline of the agents in this class, and the trial and observational evidence for each, is shown in table 2.

The general side effects for the drugs interfering with the prostacyclin pathway are headache, flushing, jaw pain, diarrhoea, nausea and myalgia. Side effects often worsen with dose increases but then rapidly subside.

Epoprostenol

Epoprostenol is a synthetic prostacylin, has a short life and is administed intravenously, requiring a permanent tunnelled catheter. It has an important role in patients who are deteriorating rapidly in FC III and in patients who are WHO FC IV. Intravenous epoprostenol improves symptoms, functional class, exercise capacity and haemodynamics in IPAH, and is the only treatment shown to improve survival in a randomized study¹¹ Observational studies have also confirmed long-term benefits of epoprostenol in IPAH, as well as APAH conditions and non-operable CTEPH.

The starting dose is commonly 1–2 ng/kg/min; this dose is up-titrated during the first few days of treatment according to symptoms, side effects and efficacy. Further dose increases during long-term follow-up can be made according to the patient’s response to treatment, and there is no upper dose limit. Most adults are typically treated in the range of 20–40 ng/kg/min.

The patient and their carer are trained and must be competent to manage the delivery system before discharge from hospital. There is a risk of delivery system malfunction, and patients should know how to troubleshoot this. Patients should be provided with a spare pump in case of malfunction. Infection and sepsis may be life-threatening. Abrupt interruption of the infusion may lead to a potentially fatal rebound pulmonary hypertension. Clearly, this drug needs to be initiated and monitored by those with special expertise in the treatment of pulmonary hypertension.

Iloprost

Iloprost is a prostacyclin analogue and is available IV, orally or via aerosol; though most commonly via aerosol, 6 to 9 times a day. The patient goes without treatment while they are asleep.

Compared with inhaled placebo, inhaled iloprost increases exercise capacity and improves symptoms, PVR and clinical events in patients wtih PAH and CTEPH.An RCT combining bosentan with ilopost showed an increase in exercise capacity. The most frequent side effects are flushing and jaw pain.

Treprostinil

Treprostinil may be administered subcutaneously,intravenously or by aerosol.

Treprostinil is usually given subcutaneously with a microinfusion pump and subcutaneous catheter. It improves exercise capacity, symptoms and haemodynamics. Subcutaneous infusion overcomes some of the difficulties and complications of intravenous infusion. It frequently causes infusion site pain by activation of prostacyclin pain receptors. Patients need assistance in managing infusion site pain from a healthcare professional experienced in using treprostinil. If the pain becomes intolerable then it may be appropriate to consider an intravenous infusion.

Intravenous treprostinil has been approved in the US for PAH patients who cannot tolerate subcutaneous infusion. Treprostinil has a half-life of about two hours and its infusion pump needs less frequent changes of the drug than epoprostenol.

One RCT in patients taking inhaled treprostinil on a background of bosentan or sildenafil demonstrated improvements in 6MWD, NT-proBNP and quality of life measures.¹⁹ Oral trepostinal has been studied in two RCTs on background therapy and in both trials, there was no statistically significant improvement.

Beraprost

Beraprost is not currently available in Europe. It is administered orally. Two randomised controlled trials have shown only short-term improvement in exercise capacity without haemodynamic benefit.^20,21

Selexipag

Selexipag is an oral, selective prostacyclin IP receptor agonist. Selexipag alone or in comination with ERAs and/or PDE-5i has been shown to reduce PVR and a composite morbidity and mortality endpoint by 39%.

Learning points

• Most of the PDE5-inhibitors are delivered via infusion and can be challenging to use
• Intravenous Epoprostenol is the gold standard first line therapy for patients in WHO FC IV