Pulmonary Arterial Hypertension

Transcription

1 A Medicines Management Review of Treprostinil Sodium (Remodulin ) in Pulmonary Arterial Hypertension Patrick Wong Senior Staff Writer, Touch Briefings Reviewed by Professor Jean-Luc Vachiery, Head, Pulmonary Vascular Diseases and Heart Failure Clinic, Department of Cardiology, CUB-Hôpital Erasme, Brussels Executive Summary Infusions of prostacyclin or its analogues are part of the treatment strategy for moderate to severe pulmonary arterial hypertension. Treprostinil is a stable prostacyclin analogue with a half-life of over four hours that can be administered either by inhalation or by an intravenous (IV) or subcutaneous (SC) infusion. During the pivotal trial for SC treprostinil, the incidence of infusion-site pain led to dose reductions or limitations in uptitration, resulting in underdosing of treprostinil. As a result, improvements in functional ability at 12 weeks with treprostinil were modest. However, the mean dose achieved was far short of the target dose, and an analysis of the dose quartiles revealed that patients receiving >13ng/kg/min had comparable improvement to those receiving other therapies. Moreover, current knowledge suggests that pain associated with treprostinil is not directly related to the dose. Long-term experience has led to improved and more rapid upward dose titration of treprostinil, resulting in better pain management and better outcomes. Long-term survival in patients remaining on treprostinil therapy appears similar to that achieved with the current gold standard, epoprostenol. An IV formulation of treprostinil has recently been approved in the US, Canada, Switzerland, Israel and much of South America. IV infusion of treprostinil offers an alternative for patients who are intolerant to SC delivery or to first-line prostacyclin therapy. Increasingly, published evidence suggests that with good patient preparation and support, treprostinil delivered subcutaneously or intravenously is an effective prostanoid to improve PAH outcome. Disclosure: No sources of funding were used to assist in the preparation of this review. United Therapeutics provided a non-binding review of this article. Introduction to Pulmonary Arterial Hypertension Pulmonary hypertension (PH) is a haemodynamic and pathophysiological condition defined as an increase in mean pulmonary arterial pressure (PAP) 25mmHg at rest, as assessed by right heart catheterisation. PH covers a heterogeneous group of clinical conditions and is classified (according to the most recent classification system defined during the fourth World Symposium on PH held in 2008 in Dana Point, CA, US) into five clinical groups with specific characteristics (see Table 1). 1 Pulmonary arterial hypertension (PAH; group 1 in the Dana Point classification) is a rare and devastating clinical condition characterised by the presence of pre-capillary PH and is caused by functional and structural changes in the pulmonary vasculature, leading to a progressive increase in pulmonary vascular resistance (PVr), right ventricular failure and, eventually, death. 2 4 PAH can be idiopathic (IPAH), heritable (HPAH) or associated with a number of risk factors or conditions, such as connective tissue disease or congenital heart disease (associated PAH [APAH]). 1 PAH has a prevalence of cases per million population and an annual incidence of two to seven cases per million population. 5,6 There is an equal prevalence between the sexes in childhood, although in adulthood more women are affected by PAH than men (female:male ratio 1.7:1). 7 IPAH and HPAH are most prevalent between 20 and 40 years of age. 8,9 Dyspnoea and fatigue are the leading manifestations of PAH. Therefore, patients are characterised according to the severity of symptoms according to the World Health organization (WHo) functional classification (adapted from the New York Heart Association [NYHA] classification). It distinguishes four levels, based on severity of symptoms (fatigue, dyspnoea) and signs of right heart failure according to the degree of ordinary physical activities that patients can carry out without impairment (see Table 2) Such assessment provides useful information on the current level of physical function, correlates to prognosis and can help guide decisions on therapy. Patients with PAH can experience a progressive worsening of physical capabilities, which is reflected in an increase in WHo functional class. These problems can become so severe that quality of life (QoL) is profoundly affected. 13,14 The pathogenesis of PAH is characterised by abnormal vascular remodelling involving the proliferation and migration of vascular smooth muscle, endothelial cells and fibroblasts. This vascular remodelling, along with additional factors such as inflammation and in situ thrombus formation, are the likely mechanisms that lead to vessel narrowing, followed by a progressive increase in PVr and the clinical manifestations of PAH. endothelial cells are the major source of mediators of pulmonary vascular tone, and endothelial dysfunction is thought to play a major role in driving the cellular and molecular pathology of PAH. 15 PH is associated with increased levels of vasoconstrictors, such as endothelin and serotonin, 19 together with a reduction in vasodilators or their pathways, such as nitric oxide signalling 20 and prostacyclin synthesis and secretion. 21 Studies have also shown that patients with PH exhibit a deficiency of the neuropeptide vasodilator vasoactive intestinal polypeptide (VIP) in their 2 T o U C H B r I e f I N g S

2 A Medicines Management Review of Treprostinil Sodium (Remodulin ) in PAH lungs. 22 These pathways are therefore rational therapeutic targets for PAH. Although there is no cure for PAH, targeted therapies have been shown to improve a variety of clinically relevant end-points, including survival, functional class, exercise capacity, haemodynamic variables and QoL measures. Current Treatment Options for Pulmonary Arterial Hypertension There are now several disease-targeted therapies available for patients with PAH. These include: prostacyclin (epoprostenol; [flolan ]) and the prostacyclin analogues treprostinil (remodulin ), iloprost (Ventavis ) and beraprost (Berasil ); the endothelial receptor antagonists bosentan (Tracleer ), sitaxentan (Thelin ) and ambrisentan (Volibris ); and the phosphodiesterase type-5 (PDe-5) inhibitors sildenafil (revatio ) and tadalafil (Adcirca ). Prostacyclins endogenous prostacyclin is a potent vasodilator and inhibitor of platelet aggregation and has additional cytoprotective and antiproliferative activities. 23 Patients with PAH have been shown to have decreased levels of prostacyclin synthase in pulmonary arteries 24 as well as a deficiency of prostacyclin and an excess of thromboxane. 21 Prostacyclin therapy is part of the therapeutic management of moderate to severe PAH. 25 Epoprostenol epoprostenol (synthetic prostacyclin) was the first exogenous prostacyclin therapeutic to demonstrate clinical utility in PAH. epoprostenol has a half-life of less than six minutes, resulting in the need for continuous delivery through a permanent catheter into a large central vein. 26 Continuous long-term treatment with epoprostenol was shown to improve exercise capacity, haemodynamics and survival in patients with various forms of PH. 27,28 The safety and efficacy of intravenous (IV) epoprostenol were established in three pivotal open-label, randomised trials. 27,29,30 A study of 23 patients with primary PH, many of whom had advanced right heart failure, who were randomised to receive epoprostenol or conventional therapy for eight weeks showed significant improvements from baseline in cardiopulmonary haemodynamics with epoprostenol compared with conventional therapy. In addition, a greater mean six-minute walk distance (6MWD) was achieved with epoprostenol over conventional therapy (132 and 87m, respectively) 29 and, importantly, a long-term extension of this study was the first to show a survival benefit in PAH patients receiving long-term continuous IV prostacyclin. 31 The second and third studies randomised 81 patients with severe IPAH 27 and 111 patients with moderate to severe PH associated with scleroderma spectrum of disease 30 to receive, respectively, epoprostenol with conventional therapy or conventional therapy alone. After 12 weeks of treatment, epoprostenol therapy led to significant improvements in 6MWD compared with conventional therapy alone in both studies. epoprostenol also conferred improvements in QoL, cardiopulmonary haemodynamic properties, WHo functional class, Borg dyspnoea score and dyspnoea fatigue ratings. Although epoprostenol is an effective therapy for PAH, the IV delivery system gives rise to a number of complications. These complications range in severity from local exit-site infection, which can be easily treated with antibiotics, to life-threatening bloodstream sepsis. Table 1: Updated Clinical Classification of Pulmonary Hypertension 1 Pulmonary arterial hypertension (PAH) 1.1 Idiopathic PAH 1.2 Heritable 1.2.1* BMPr * ALK1, endoglin (with or without hereditary haemorrhagic telangiectasia) 1.2.3* Unknown 1.3 Drug- and toxin-induced 1.4 Associated with: Connective tissue diseases HIV infection Portal hypertension Congenital heart diseases 1.4.5* Schistosomiasis 1.4.6* Chronic hemolytic anaemia 1.5 Persistent pulmonary hypertension of the newborn 1 Pulmonary veno-occlusive disease (PVoD) and/or pulmonary capillary haemangiomatosis (PCH) 2 Pulmonary hypertension owing to left heart disease 2.1 Systolic dysfunction 2.2 Diastolic dysfunction 2.3 Valvular disease 3. Pulmonary hypertension owing to lung diseases and/or hypoxia 3.1 Chronic obstructive pulmonary disease 3.2 Interstitial lung disease 3.3 other pulmonary diseases with mixed restrictive and obstructive pattern 3.4 Sleep-disordered breathing 3.5 Alveolar hypoventilation disorders 3.6 Chronic exposure to high altitude 3.7 Developmental abnormalities 4 Chronic thromboembolic pulmonary hypertension (CTEPH) 5 Pulmonary hypertension with unclear multifactorial mechanisms 5.1 Haematological disorders: myeloproliferative disorders, splenectomy 5.2 Systemic disorders: sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatosis, neurofibromatosis, vasculitis 5.3 Metabolic disorders: glycogen storage disease, gaucher disease, thyroid disorders 5.4 others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure on dialysis From the Fourth World Symposium on Pulmonary Hypertension. ALK1 = activin receptor-like kinase type 1; BMPR2 = bone morphogenetic protein receptor type 2. Source: Simonneau et al., Table 2: NYHA/WHO Classification of Functional Status of Patients with Pulmonary Hypertension I II III IV Patients have cardiac disease but without the resulting limitations of physical activity. ordinary physical activity does not cause undue fatigue, palpitation, dyspnoea or anginal pain. Patients have cardiac disease resulting in slight limitation of physical activity. They are comfortable at rest. ordinary physical activity results in fatigue, palpitation, dyspnoea or anginal pain. Patients have cardiac disease resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary physical activity causes fatigue, palpitation, dyspnoe, or anginal pain. Patients have cardiac disease resulting in inability to carry out any physical activity without discomfort. Symptoms of cardiac insufficiency or of the anginal syndrome may be present even at rest. If any physical activity is undertaken, discomfort is increased. NYHA = New York Heart Association; WHO = World Health Organization. Source: Barst et al., e U r o P e A N C A r D I o L o g Y 3

3 furthermore, interruptions to the delivery of epoprostenol can be life-threatening due to rebound pulmonary hypertensive crisis. In addition, common pharmacological side effects of epoprostenol therapy include flushing, headache, jaw pain with the first bite of food, diarrhoea, nausea, blotchy erythematous rash and muscular aches and pains (predominantly involving the legs and feet). 30 epoprostenol is approved for the treatment of IPAH and/or PAH connective tissue disease (CTD) in some european countries and is also approved for the treatment of PAH in the US. Prostacyclin Analogues There are two prostacyclin analogues available in europe and the US that have a longer half-life than epoprostenol and are stable at room temperature. The longer half-lives of treprostinil (four hours) and iloprost (20 25 minutes) allow alternative routes of administration to be used for these drugs. for example, treprostinil can be delivered intravenously, via subcutaneous (SC) infusion or by inhalation. In addition, research is ongoing to develop an oral formulation. Details of treprostinil efficacy are described in more detail in the section on remodulin Treprostinil Sodium Solution for Infusion later in this article. Iloprost is most commonly used as an inhaled therapy. 3 Through inhalation, it is possible to vasodilate the pulmonary vessels by means of alveolar deposition due to the proximity of the intra-acinar pulmonary arteries to the alveolar surfaces. Clinically, the pulmonary selectivity of iloprost may provide the opportunity to administer a prostanoid to patients who are prone to decreases in systemic arterial pressure, for example in portopulmonary hypertension and emergency situations. 32 However, the benefit of such an approach in these indications has not been demonstrated in randomised controlled trials (rcts). An open-label study in 24 patients with IPAH found that daily inhalations of iloprost resulted in significant improvements in exercise capacity and haemodynamics from baseline following three months of treatment. These improvements were sustained for approximately 12 months, at which point significant improvements in cardiac output from baseline were also noted. 33 In a subsequent multicentre, double-blind study, 203 patients with IPAH, PAH-CTD and distal forms of chronic thromboembolic PH (CTePH) were randomised to receive either inhaled iloprost or placebo with conventional therapy. 34 The primary composite end-point consisted of a 10% increase in 6MWD 30 minutes after drug inhalation and improvement of one WHo functional class in the absence of clinical deterioration or death over the course of the 12-week study; this end-point was met by significantly more patients in the iloprost group than in the placebo group (16.8 versus 4.9%; p=0.007). After 12 weeks, the iloprost group experienced significant improvements in cardiopulmonary outcomes compared with baseline (p<0.001), while patients receiving placebo showed significant worsening in the same parameters (p<0.05). Common side effects of iloprost treatment included flushing, headache and jaw pain; coughing during inhalation often resolved by itself. The principal disadvantage of inhaled iloprost is the fact that the haemodynamic effects plateau within minutes, and six to nine inhalations per day are needed to achieve satisfactory clinical results. 26 it is not currently approved for the treatment of PAH via this route in europe or the US. Endothelin Receptor Antagonists The endothelin (et) system, particularly et-1 and the et A and et B receptors, has been implicated in the pathogenesis of PAH. et receptor antagonism therefore represents a rational approach to the treatment of PAH. Three orally active et receptor antagonists are currently approved for the treatment of PAH: bosentan (Tracleer), sitaxentan (Thelin) and ambrisentan (Volibris). Bosentan and sitaxsentan are sulphonamide analogues, whereas ambrisentan is a propanoic acid derivative. Currently available clinical data do not permit any definitive conclusions to be drawn regarding the relative superiority of these three et receptor antagonists, although the clinically important differences between them relate to safety and side effects. Bosentan, a non-selective et A and et B receptor inhibitor, was the first et receptor antagonist to be approved in the US and the eu and is indicated for the treatment of PAH patients in WHo functional class III (eu) or III/IV (US and Canada). Bosentan received approval for use as a monotherapy in PAH based on efficacy data published from two randomised, double-blind, multicentre, placebo-controlled trials. 35,36 Bosentan improved 6MWD, haemodynamic variables, WHo functional class status and time to clinical worsening in PAH patients. overall, bosentan was well tolerated in this patient population and the number and nature of adverse events were similar in the bosentan and placebo groups in both trials. However, hepatotoxic side effects were noted with bosentan treatment during phase III evaluation. These toxicities were found to be dose-dependent, occurring more frequently at doses of 250mg twice daily than 125mg twice daily; for this reason the latter dose of bosentan is approved for the treatment of PAH. As a consequence of these hepatic toxicities, monthly liver function tests are necessary for patients receiving bosentan. Trials investigating bosentan as a combination therapy with other drugs available for the treatment of PAH have yielded mixed results, and further studies are ongoing. 37 Bosentan was found to significantly decrease the plasma concentration of sildenafil in a study evaluating the co-administration of these agents in PAH, and such a pharmacokinetic interaction could undermine any potential benefits of combining these two drugs. 38 Sitaxentan is a selective et A antagonist that is approved for the treatment of PAH patients in WHo functional class III in the eu and class II and III in Canada and Australia; sitaxentan is not currently approved in the US. Sitaxentan has been shown to improve exercise capacity, functional class and cardiopulmonary haemodynamics in two multicentre, randomised, placebo-controlled clinical trials 39,40 and in one open-label pilot study 41 of PAH patients. Liver function abnormalities have been noted with sitaxentan, although the incidence of elevated transaminase levels appears to be lower than that observed with bosentan and, overall, sitaxentan was considered safe and tolerable. The dosage judged to have the greatest risk benefit ratio during clinical evaluation was 100mg once daily, and only this dose has been approved for PAH to date. Sitaxentan inhibits warfarin metabolism via inhibition of CYP2C9, requiring mandatory dose reductions for patients receiving this anticoagulant therapy. 39 Inhaled iloprost is approved for the treatment of class III PAH in europe and the US. Iloprost can be delivered intravenously, although Ambrisentan is less selective for et A than sitaxentan. This agent is approved in the US and eu for the treatment of PAH patients in 4 e U r o P e A N C A r D I o L o g Y

4 A Medicines Management Review of Treprostinil Sodium (Remodulin ) in PAH Figure 1: European Society of Cardiology/European Respiratory Society Pulmonary Arterial Hypertension Treatment Algorithm Avoid pregnancy (I C) Influenza and pneumococcal immunisation (I C) Supervised rehabilitation (IIa B) Psycho-social support (IIa C) Avoid excessive physical activity (III C) General measures and supportive therapy Expert referral (I C) Acute vasoreactivity test (I C for IPAH) (IIb C for APAH) Diuretics (I C) Oxygen* (I C) Oral anticoagulants: IPAH, heritable PAH and PAH due to anorexigens (IIa C); APAH (IIb C). Digoxin (IIb C) Vasoreactive Non-vasoreactive WHO FC I III CCB (I C) Initial therapy Recommendationevidence WHO FC II WHO FC III WHO FC IV Sustained response (WHO FC I II) I-A Ambrisentan; bosentan; sildenafil Ambrisentan; bosentan; sitaxentan; sidenafil; epoprostenol IV; iloprost inhaled Epoprostenol IV I-B Tadalafil Tadalafil; treprostinil SC; inhaled Yes No IIa-C Sitaxentan Iloprost IV; teprostinil Ambrisentan; bosentan; sitaxentan; sidenafil; tadalafil; iloprost inhaled, IV; treprostinil SC, IV, inhaled; initial combination therapy Continue CCB IIb-B Beraprost Inaedquate clinical response Inaedquate clinical response Sequential combination therapy (IIa B) ERA + + Prostanoids + PDE-5I BAS (I C) and/or lung transplantation (I C) *To maintain arterial blood oxygen pressure >8kPa (60mmHg); Under regulatory review in the EU; IIa c for WHO FC II. APAH = pulmonary arterial hypertension associated with risk factors or conditions; BAS = balloon atrial septostomy; CCB = calcium channel blocker; ERA = endothelium-receptor antagonist; IPAH = idiopathic pulmonary arterial hypertension; IV = intravenous; PAH = pulmonary arterial hypertension; PDE-5I = phosphodiesterase type 5 inhibitor; SC = subcutaneous; WHO FC = World Health Organization functional class. Source: Galie et al., WHo functional class II/III and is the first PAH therapeutic indicated for functional class II patients in europe. results from two randomised, double-blind, placebo-controlled trials demonstrated that treatment with ambrisentan improved exercise capacity, delayed clinical worsening and could improve one-year survival rates in patients with PAH. 42 Ambrisentan also demonstrated a favourable safety profile, and liver toxicity in ambrisentan-treated patients appeared to be less common than in bosentan-treated patients, although long-term safety evaluation of ambrisentan (and sitaxentan) is necessary before definitive conclusions can be drawn regarding this important safety issue. A significant advantage of ambrisentan is the lack of any apparently clinically important drug interactions with warfarin or sildenafil, both of which are frequently used by patients being treated for PAH. 43 Phosphodiesterase Inhibitors Phosphodiesterase inhibitors prevent the breakdown of cyclic guanosine monophosphate (cgmp) by phosphodiesterase, leading to an increase in cgmp levels, which induces relaxation and exerts antiproliferative effects on vascular smooth-muscle cells. 44,45 Sildenafil is an orally active, potent and selective inhibitor of phosphodiesterase type 5 (PDe5) and has been shown to be effective in improving 6MWD, haemodynamic variables and WHo functional class status. 46 Side effects include flushing, dyspepsia and diarrhoea. Sildenafil was approved in the eu for the treatment of functional class III PAH in october A second PDe5 inhibitor, tadalafil, is approved in the US and eu for the treatment of PAH. Tadalafil showed strong and durable efficacy, e U r o P e A N C A r D I o L o g Y 5

5 Figure 2: American College of Cardiology Foundation/ American Heart Association Pulmonary Arterial Hypertension Treatment Algorithm Anticoagulation ± diuretics ± oxygen ± digoxin Oral CCB Sustained response Yes Continue CCB No Positive ERAs or PDE-5Is (oral), epoprostenol or treprostinil (IV), iloprost (inhaled), treprostinil (SC) Reassess: consider combination therapy Investigational protocols Acute vasoreactivity testing* Negative Lower risk Higher risk Epoprostenol or treprostinil (IV), iloprost (inhaled), ERAs or PDE-5Is (oral), treprostinil (SC) Atrial septostomy, lung transplant** *Acute vasodilator testing should be performed in all idiopathic pulmonary arterial hypertension (IPAH) patients who may be potential candidates for long-term therapy with calcium-channel blockers (CCBs). Patients with PAH due to conditions other than IPAH have a very low rate of long-term responsiveness to oral CCBs, and the value of acute vasodilator testing in such patients needs to be individualized. IPAH patients in whom CCB therapy would not be considered, such as those with right heart failure or hemodynamic instability, should not undergo acute vasodilator testing. CCBs are indicated only for patients who have a positive acute vasodilator response, and such patients need to be followed closely both for safety and efficacy. For patients who did not have a positive acute vasodilator testing and are considered lower risk based on clinical assessment (see Table 3), oral therapy with an endothelium-receptor antagonist (ERA) or phosphodiesterase type 5 inhibitor (PDE-5I) would be the first line of therapy recommended. If an oral regimen is not appropriate, the other treatments would need to be considered based on the patient s profile and the side effects and risks of each therapy. For patients who are considered high-risk based on clinical assessment (see Table 3), continuous treatment with intravenous (IV) prostacyclin (epoprostenol or treprostinil) would be the first line of therapy recommended. If a patient is not a candidate for continuous IV treatment, the other therapies would have to be considered based on the patient s profile and the side effects and risk of each treatment. **Timing for lung transplantation and/or atrial septostomy is challenging and is reserved for patients who progress despite optimal medical treatment. SC = subcutaneous. Source: McLaughlin et al., Table 3. Determinants of Pulmonary Arterial Hypertension* Prognosis Determinants of Risk Lower Risk Higher Risk (good prognosis) (poor prognosis) Clinical evidence of No Yes rv failure Symptom progression gradual rapid WHo functional class II, III IV 6MWD >400m <300m CPeT Peak Vo 2 Peak Vo 2 >10.4ml/kg/min <10.4 ml/kg/min echocardiography Minimal rv Pericardial effusion, dysfunction significant rv enlargement/dysfunction, right atrial enlargement Haemodynamics rap <10mmHg, rap >20mmHg, CI >2.5l/min/m 2 CI <2.0l/min/m 2 BNP Minimally elevated Significantly elevated *Most data available pertains to idiopathic pulmonary arterial hypertension (IPAH). 6MWD = six-minute walk distance; BNP = brain natriuretic peptide; CI = cardiac index; CPET = cardiopulmonary exercise testing; peak VO2 = average peak oxygen uptake during exercise; RAP = right atrial pressure; RV = right ventricular; WHO = World Health Organization. Source: McLaughlin et al., safety and tolerability in the treatment of PAH in a 16-week doubleblind, placebo-controlled phase III study. Tadalafil 40mg improved 6MWD and haemodynamic variables compared with placebo and delayed the time to clinical worsening. Changes in WHo functional class and Borg dyspnoea score did not differ significantly from those seen with placebo. 47 Common side effects included headache, muscle pain, flushing, nasopharyngitis, respiratory tract infection, pain, upset stomach and nasal congestion. Current Guidelines for Pulmonary Arterial Hypertension Joint guidelines from the european Society of Cardiology (esc) and the european respiratory Society (ers) were published in late 2009 (see Figure 1). All patients should benefit from conventional/supportive measures according to the aetiology of PAH. It is recommended to refer patients to expert centres to test vasoreactivity and management. only patients presenting an acute response under short-acting vasodilators (IV epoprostenol, IV adenosine or inhaled nitrous oxide) performed under right heart catheterisation may receive high doses of calcium channel blockers (CCBs). Patients in WHo functional class III who do not have a positive vasoreactivity test result or who fail to show a long-term response to CCBs should be considered for treatment with targeted therapy that includes an oral et receptor antagonist (e.g. bosentan, sitaxentan or ambrisentan), a PDe5 inhibitor (e.g. sildenafil or tadalafil) or a prostanoid (e.g. SC, IV or inhaled treprostinil, IV epoprostenol or inhaled or IV iloprost). The highest level of evidence and the strongest level of recommendation favours the use of oral therapies with et receptor antagonists or PDe5 inhibitors and, in some cases, IV epoprostenol. for patients with functional class IV PAH, the highest grade of recommendation is reserved for IV epoprostenol, but it is noted that other targeted therapies may be used in this population. Sequential combination therapy may be considered in patients who deteriorate or fail to improve with first-line treatments. 3 In the UK and Ireland, patients with PAH are treated in designated national PH centres. In 2001, the British Cardiovascular Society (BCS) guidelines and Medical Practice Committee published their recommendations on the management of PH in clinical practice, which were approved by the British Thoracic Society (BTS) and the British Society of rheumatology (BSr). 48 In 2008, the committee published a consensus statement intended to complement the PAH guidelines, with specific emphasis on UK and Irish practice. 4 guidelines for the management of PAH in the US were first published by the American College of Chest Physicians (ACCP) in These were updated in 2007 to take into account subsequent clinical trials and the development of new therapies since 2004, 2 and were updated once more in 2009 by the Task force led by the American College of Cardiology foundation (ACCf) and the American Heart Association (AHA) (see Figure 2 and Table 3). 49 Remodulin Treprostinil Sodium Solution for Infusion Treprostinil is a tricyclic benzidene prostanoid that has broadly the same pharmacological actions as epoprostenol in the treatment of PAH. These include direct vasodilation of pulmonary and systemic arterial vascular beds and inhibition of platelet aggregation. Treprostinil infusion therapy reduces pressure in the pulmonary vascular system and increases the cardiac index. 6 e U r o P e A N C A r D I o L o g Y

6 A Medicines Management Review of Treprostinil Sodium (Remodulin ) in PAH Table 4: Geographical Registration Status for Treprostinil Country First Approval Date Indication Comments Argentina May 2005 Subcutaneous and intravenous infusion for NYHA Class II IV PAH Australia May 2004 Subcutaneous infusion for NYHA Class II V PAH Canada october 2002 Subcutaneous and intravenous infusion for NYHA Class II IV PAH Intravenous formulation approved october 2005 Chile January 2006 Subcutaneous infusion for NYHA Class II V PAH ecuador November 2006 Subcutaneous infusion for NYHA Class II IV PAH europe february 2005 Subcutaneous infusion for NYHA Class III PPH france was the reference Member State; approval has been gained in 23 eu contries but not in the UK, Ireland and Spain Israel october 2002 Subcutaneous and intravenous infusion for PAH Intravenous formulation approved December 2005 Mexico November 2006 Subcutaneous infusion for NYHA Class II V PAH Peru November 2005 Subcutaneous and intravenous infusion for NYHA Class II IV PAH Switzerland November 2004 Subcutaneous and intravenous infusion for NYHA Class III IV PAH Intravenous formulation approved June 2007 Taiwan December 2002 Subcutaneous infusion for PAH US May 2002 Subcutaneous and intravenous infusion for NYHA Class II IV PAH Intravenous formulation approved November 2004; also indicated for patients who require transition from flolan to reduce the rate of clinical deterioration NYHA = New York Heart Assocation; PAH = pulmonary arterial hypertension; PPH = primary pulmonary hypertension. Treprostinil can be administered as a continuous SC infusion. When drawn undiluted into a syringe for SC delivery, treprostinil is chemically and microbiologically stable at 37 C for up to 72 hours. 50 Treprostinil can also be administered as a continuous IV infusion via a central catheter. When diluted for IV use, it is chemically and microbiologically stable at 37 C for up to 48 hours. 50 This enables infusion pumps to be filled with a pre-mixed solution changed only at hour intervals, compared with 12 or 24 hours with epoprostenol, which is presented as a powder that must be reconstituted and kept stable with cold packs. As a result, the IV line needs to be disconnected less frequently with treprostinil than with epoprostenol. Despite the concomitant risk of sepsis from IV administration, recent techniques involving the use of closed hubs on the central venous catheter have suggested that these risks can be minimised. 51 As treprostinil is more stable than epoprostenol in vivo, with an elimination half-life of 4.5 hours, 52 interruption in supply carries less risk of rapid and life-threatening rebound of PH. In clinical trials, treprostinil-treated patients had a lower risk of syncopal events than has been observed for iloprost 34,53 or epoprostenol. 27,30 Licensed Indications SC delivery of treprostinil was approved in 2005 under the Mutual recognition Procedure. It is licensed in france, the reference state, and approved in 23 member countries of the european eu, but not in the UK, Ireland and Spain, for the treatment of primary PAH in patients with WHo class III symptoms to diminish symptoms associated with exercise. Geographical Registration Status Treprostinil was approved by the US food and Drug Administration (fda) in 2002 for use in WHo functional class II IV patients with PAH, and the IV route was included in A specific indication as an alternative to IV epoprostenol was confirmed following a placebocontrolled randomised trial switching patients from IV epoprostenol to SC treprostinil. 54 Treprostinil has also received approval for the treatment of PAH by the SC route in Australia and Taiwan, and by both SC and IV routes in Israel, Canada, Switzerland, Argentina, Peru and Mexico (see Table 4). Dosage In europe, the Summary of Product Characteristics (SPC) guidance suggests that the infusion rate of treprostinil be initiated at 1.25ng/kg/min; if this initial dose cannot be tolerated because of systemic effects, the infusion rate should be reduced to 0.625ng/kg/min. Published experience since the pivotal trial has demonstrated that, since infusion-site pain is largely unrelated to dose, a more rapid uptitration is both safe and effective. 55 The goal of chronic dose adjustments is to establish a dose at which PAH symptoms are improved while minimising any excessive pharmacological effects of treprostinil (e.g. headache, nausea, emesis, restlessness, anxiety or infusion-site pain or reaction). Clinical Efficacy in Pulmonary Arterial Hypertension IV epoprostenol has been considered the gold standard treatment for WHo functional class III IV PAH patients. 2,56 Long-term reviews 39,57 have established that treprostinil may be comparable to epoprostenol when delivered subcutaneously, and a number of researchers have published data to demonstrate that transitions from IV epoprostenol to either SC or IV treprostinil can take place. 54,58,59 The longer elimination half-life of treprostinil brings added benefits, reducing the risk of rebound pulmonary hypertension in the event of a short interruption in therapy and increasing the freedom of the patient. Subcutaneous Treprostinil following animal studies to evaluate the safety and efficacy of treprostinil, 60,61 a number of clinical trials have demonstrated the efficacy of treprostinil in the treatment of PAH. Based on the promising results of an acute phase I trial and a pilot placebo-controlled, randomised phase II trial, 62 SC treprostinil was evaluated in two identical placebocontrolled, randomised phase III studies (P01:04 and P01:05). 53 The eightweek multicentre, double-blind, placebo-controlled phase II study (P01:03) assessed the efficacy of treprostinil plus conventional therapy versus placebo plus conventional therapy (e.g. diuretics, anticoagulants, digoxin and oxygen) and demonstrated the efficacy of treprostinil in the medium term for WHo class III IV IPAH patients. Improvements with treprostinil therapy included improved 6MWD by a mean of 38.6±18.6m among treprostinil patients compared with a decrease of 5.8±27.5m in those receiving placebo (p=0.299), with a slight improvement in Borg e U r o P e A N C A r D I o L o g Y 7

7 Figure 3: Mean Change in Six-minute Walk Distance Mean change from baseline (metres) ± (n=45) Analysis by trepostinil dose quartile. Source: Simonneau et al., ±9 5.0 to <8.2 (n=45) +20±9 8.2 to <13.8 (n=45) +36.1±10 (ng/kg/min) >13.8 (n=3) dyspnoea score and a decrease in PVr index of 4.8 Wood units/m Treprostinil was initiated at a dose of ng/kg/min and initially adjusted in increments of ng/kg/min every 24 hours based on response to therapy and side effects, to a maximum dose of 20ng/kg/min. Many patients experienced pain at the injection site, which was thought at that time to be dose-related, so the doses were kept lower than is believed to be optimal for significant improvements in exercise capacity and haemodynamic parameters. Simonneau et al. suggested that the relatively low doses of treprostinil administered in this trial were suboptimal, despite the improvements in the 6MWD and haemodynamic parameters, 53 whereas a later study also demonstrated that site pain is unrelated to dosage. 57 results from two identical 12-week multicentre, double-blind, placebo-controlled phase III randomised trials in a total of 470 patients (eight to 75 years of age) with PAH with a wide variety of aetiologies showed similar results and were combined as a single large trial (P01:04/05). 53 These data further demonstrated the efficacy of SC treprostinil in terms of improved exercise capacity, reduced dyspnoea and improved haemodynamic parameters. Due to concerns regarding injection-site pain, the doses of treprostinil were again suboptimal, with a mean final dose of only 9.3±0.4ng/kg/min in the treprostinil group. The difference in median 6MWD between the treprostinil and placebo groups at week 12 was 16m (p=0.006), with the greatest improvements seen in severely ill patients and those who could tolerate the highest doses. Analysis by quartile (see Figure 3) revealed that patients receiving doses above 14ng/kg/min showed the greatest improvement over 37m in 6MWD. A small eight-week rct (P01:13) evaluated patients receiving IV epoprostenol randomised to switch (in a gradual fashion over a number of days) to either placebo or SC treprostinil. In this study, rubenfire et al. demonstrated that SC treprostinil effectively prevented clinical deterioration and maintained functional status in patients transitioned from epoprostenol therapy. These results suggest that, in the population studied, SC treprostinil provides similar efficacy to IV epoprostenol in the treatment of PAH. 54 Vachiery et al. reported similar findings with regard to the safety and feasibility of transitioning from epoprostenol to SC treprostinil in patients having difficulties with IV therapy. 59 Long-term and Sub-population Efficacy Two retrospective analyses 39,57 observed that SC treprostinil therapy is associated with sustained improvements in exercise capacity and potential survival benefits. Lang et al. conducted a retrospective study of 122 PH patients treated with SC treprostinil from three european hospitals (including some patients following on from the original pivotal trial). of the 122 patients, 99 patients with PAH and 23 patients with inoperable CTePH in functional class II IV were followed up for a mean of 26.2±17.2 months and assessed for long-term efficacy using the 6MWD, Borg dyspnoea score and WHo functional class status at baseline and at one-, two- and three-year time-points. Local pain at the SC site accounted for only 5% of treatment interruptions. Survival rates were 88.6 and 70.6% at one year and three years, respectively. These SC treprostinil survival rates compared favourably to the survival rates observed in patients treated with IV epoprostenol. 28 event-free survival rates defined as survival without hospitalisation for clinical worsening, transition to IV epoprostenol or the need for combination therapy or atrial septostomy were 83.2 and 69%, respectively. 57 The efficacy of SC treprostinil has also been evaluated in severe inoperable CTePH. In an open-label, uncontrolled study, 19 patients with severe, inoperable CTePH were enrolled and assessed for the long-term efficacy of SC treprostinil treatment. Treprostinil-treated patients demonstrated significant improvements in 6MWD (over 100m), WHo functional class (3.2 down to 2.1 on average), B-type brain natriuretic peptide plasma levels, cardiac output and PVr measurements after 19±6.3 months. 63 Intravenous Treprostinil The chemical stability of treprostinil at room temperature, due to it having up to 48 hours of microbial stability in the delivery system, a long half-life and easy drug preparation, has resulted in additional clinical interest in treprostinil as an alternative IV prostacyclin therapy for PAH. Continuous IV infusion of treprostinil is an alternative that is particularly suitable for patients who are unable to tolerate SC therapy, for example due to injection-site pain. The bioequivalence of IV and SC treprostinil dosed at 10ng/kg/min infused for 72 hours in terms of onset and time to steady state has been demonstrated in 51 healthy volunteers in a cross-over study (see Figure 4). 52 The pharmacokinetic bioequivalence in treprostinil plasma levels correlated with the infused dose equally for SC and IV delivery up to doses of 125ng/kg/min in active patients under treatment (see Figure 5). 64 A small 12-week prospective, multicentre, uncontrolled, openlabel trial also showed that long-term IV treprostinil is well tolerated and appears to be effective for the treatment of patients with PAH. 65 A 12-week multicentre, placebo-controlled study in WHo functional class III IV patients with IPAH, collagen vascular disease or HIVassociated PAH conducted in India was prematurely interrupted in response to safety concerns related with increased rates of catheter infection in both groups. An analysis performed in the 44 patients enrolled in the trial (out of 126 planned) suggests that IV treprostinil improves 6MWD, Borg dyspnoea score and WHo functional class. 66 The average doses of treprostinil achieved in these studies were 41 and 72ng/kg/min, respectively. Transitioning from Epoprostenol The safety and efficacy of chronic use of IV treprostinil was first evaluated in 31 stable patients transitioned from IV epoprostenol to IV treprostinil. After 12 weeks of therapy with IV treprostinil, mean 6MWD, Naughton-Balke treadmill test time, WHo functional class and Borg dyspnoea score were maintained at the same levels as on IV epoprostenol. The transition was managed through a staged increase 8 e U r o P e A N C A r D I o L o g Y

8 A Medicines Management Review of Treprostinil Sodium (Remodulin ) in PAH in the IV infusion of treprostinil, while IV epoprostenol was concomitantly reduced. However, the dosage levels for treprostinil were seen to be twice those of IV epoprostenol before transition. 58 A more rapid switch from IV epoprostenol to IV treprostinil appears to be well tolerated and effective. Patients were transferred from IV epoprostenol to IV treprostinil by a direct switch of the medication reservoir. The dose of treprostinil was adjusted throughout the study to achieve a two-fold increase of treprostinil compared with the baseline epoprostenol dose. Baseline clinical status was maintained over 12 weeks with no serious adverse events. All 12 patients reported fewer prostacyclin-related side effects with treprostinil and remained on treprostinil after study completion. 67 This observation supports the hypothesis that the decrease in cardiac index observed in the first trial 58 may be explained by a less prominent systemic effect of treprostinil compared with epoprostenol. In both of these IV switch studies, the patients had been stable on epoprostenol therapy for many years prior to the transition. Two publications detail the transition from IV epopostenol to SC treprostinil. The first, by Vachiery et al. in 2002, 59 demonstrated successful transition at equal doses of drug with no serious adverse side effects or deterioration in clinical status. The second, a randomised, placebo-controlled phase IV trial designed by the fda as part of the US approval conditions for SC therapy, required the transition from IV epoprostenol to SC treprostinil or placebo under controlled conditions. Twenty-two patients were enrolled and completed the study. Seven of eight patients (93%) withdrawn to placebo had clinical deterioration and were returned promptly to epoprostenol, while only one out of 14 patients (14%) withdrawn to SC treprostinil had clinical deterioration. It was noted that this one patient was unblinded after a syncopal event, but declined to return to epoprostenol therapy and finished the study receiving SC treprostinil. 54 Combination Therapies with Treprostinil Treprostinil in combination with oral PAH therapies seems to be well tolerated and appears to contribute to improvements in 6MWD, Borg dyspnoea score and PAH symptoms in patients who remain symptomatic on PDe5 inhibitors and/or endothelin receptor antagonists. 68,69 A retrospective, single-centre, open-label study also assessed the efficacy of long-term, subcutaneously administered treprostinil-based therapy alone or in combination with bosentan. Benza et al. concluded from the 38 patients included in the study that long-term treatment with SC treprostinil improved functional parameters and haemodynamics in patients with moderate to severe PAH and that the addition of oral bosentan to the treprostinil-based therapy was well tolerated and was associated with further clinical improvements. 70 Safety and Tolerability The clinical trials P01:04 and P01:05 form the basis of the main safety and tolerability evaluations for SC treprostinil (see Table 5). Long-term treprostinil treatment has a very similar adverse event profile to chronic IV epoprostenol therapy, with adverse events including headaches, diarrhoea, flushing, jaw pains and foot pains. Despite an elimination half-life of 4.5 hours for treprostinil, the distribution halflife is about 40 minutes; therefore, patients taken off SC treprostinil may become symptomatic in under an hour, although even longer periods of interruption of SC treprostinil therapy have not resulted in adverse events. 71 Figure 4: Mean Plasma Concentration of Treprostinil Following Intravenous and Subcutaneous Infusion Concentration (ng/ml) Hour Linear plot. IV = intravenous; SC = subcutaneous. Source: Laliberte et al., IV Figure 5: Treprostinil Plasma Level versus Treprostinil Sodium Dose for Subcutaneous and Intravenous Routes Concentration (ng/ml) 18,000 16,000 14,000 12,000 10,000 8,000 6,000 4,000 2, Treprostinil sodium dose (ng/kg/min) n=47. IV = intravenous; SC = subcutaneous. Source: McSwain et al., IV The main adverse event associated with SC treprostinil treatment is infusion-site pain, which has hampered dose titrations and resulted in discontinuations in trials of SC treprostinil. Infusion-site pain has not been shown to be dose-independent. Topical ointments or hot/cold packs appear to help, and pain at the infusion site decreases over time when patients maintain the infusion site for more than a week. 71 In the pivotal trial of SC treprostinil, the protocol required infusion-site changes at the time of the syringe changes approximately every three days. Skoro-Sajer et al. demonstrated that visual analogue scale pain scores reduced after the first few days, which led to the rationale for keeping the same site in place for at least two to three weeks, rather than changing every time the syringe is changed. 55 An additional safety and tolerability issue with intravenously infused prostanoids is the risk of infection of IV catheters. Switching patients from IV epoprostenol to SC treprostinil will SC SC e U r o P e A N C A r D I o L o g Y 9

9 Table 5: Selected Treprostinil Clinical Trials Study Phase Treatment Arm Patients (n) Mean Change Mean Change Change in Functional Class from Baseline: in 6MWD±SE in BDS±SE Improved Worse No Change Study P01.01 I Tre IV vs epo IV 14 Nr Nr Nr Nr Nr (McLaughlin, ) Tre IV: 5ng/kg/min increased to max. 30ng/kg/min epo IV: 2 ng/kg/min increased until MTD achieved Study P01.02 I Tre IV vs Tre SC 25 Nr Nr Nr Nr Nr (McLaughlin, ) Tre IV: 10ng/kg/min for 75 mins Tre SC: 5, 10, 20ng/kg/min for 150 mins Study P01.03 II Tre SC vs PLA SC ±17 vs 0.0±0.39 vs (McLaughlin, ) Tre SC ng/kg/min -6± ±0.83 Nr Nr Nr increased to max. 20ng/kg/min Study P01:04/P01:05 III Tre SC vs PLA SC ±16.5 vs 0.00±0.3 vs 17.2% 2.9% 76.1% (Simonneau, ) Tre SC: 1.25ng/kg/min Tre: ± ±0.83 at start, titrated upwards PLA: 236 Max. allowable at week 12 = 22.5ng/kg/min Study P01:13 IV Tre SC vs PLA ±40.1 vs +0.61±0. 60 vs Nr Nr Nr (rubenfire, ) epo IV was withdrawn and the Tre: ± ±0.94 dose of SC Tre or SC PLA was PLA: 8 increased as clinically required 6MWD = six-minute walk distance; BDS = Borg dyspnoea scale; EPO = erythropoietin; IV = intravenous; MTD = maximum tolerated dose; NR = not recorded; PLA = placebo; SC = subcutaneous; SE = standard error; TRE = treprostinil. enable maintenance of the patient s PAH while they recover from infections. Switching from epoprostenol to treprostinil also allows patients to benefit from the greater convenience of treprostinil therapy due to its longer half-life. 54 In 2007 the US Centers for Disease Control and Prevention (CDC) reported on the incidence of bloodstream infections associated with both IV treprostinil and epoprostenol, noting that the rate of gramnegative infections appeared higher with treprostinil and that further research needed to be conducted. It has since been demonstrated that taking steps to ensure moisture is kept away from the central venous line is of paramount importance, and the use of closed hub connectors and protective waterproof film coverings, as well as teaching patients good aseptic techniques, 51 have had a dramatic effect on reducing infections to near zero over an 18-month period in one of the centres that acted as a reference centre for the infections investigated in the earlier CDC report. 72 Patient Quality of Life Benefits Patient QoL declines steadily with worsening WHo functional class. In the pivotal 12-week double-blind, placebo-controlled trial in 470 patients with PAH (either primary or associated with connective tissue disease or congenital systemic-to-pulmonary shunts), continuous SC infusion of treprostinil was associated with a significant improvement in the physical dimension score of the Minnesota Living with Heart failure Questionnaire 73 at week 12 (p=0.0064), with a trend towards improvement in the global dimension score (p=0.17) compared with the placebo group. 53 Preliminary data presented in abstract form from an ongoing eightweek single-centre study of treatment satisfaction of PAH patients who switched from epoprostenol to IV treprostinil suggest a favourable impact on patient QoL, as well as time saved on therapyrelated preparation, as early as eight weeks following transition, although this needs to be confirmed by further studies. 74 Health Economic Benefits and Budget Impact To date, there have been a number of studies assessing the costeffectiveness of treatments for PAH Two cost-minimisation analyses, based in US and Canadian settings, found that use of SC treprostinil in place of IV epoprostenol would produce considerable cost savings per patient year, although it should be noted that geographical pricing differences need to be considered, making direct comparisons with european costs difficult. 77,78 Disease-targeted therapies for PAH are typically costly and have high cost-effectiveness ratios in comparison with treatments for more common diseases, such as cancer. The low prevalence of IPAH and fpah (one to two cases per million population) 79,80 means that therapies licensed for PAH are ultra-orphan drugs. This means that new treatments available only for these extremely rare conditions are almost invariably expensive. The majority of members of the National Institute for Health and Clinical excellence (NICe) Citizens Council felt that the National Health Service (NHS) should consider paying more for treatments for rare diseases, 81 and a NICe statement suggests that the appropriate threshold incremental cost-effectiveness ratio for ultra-orphan drugs may be as high as 200, ,000 per quality-adjusted life-year gained. 82 Sepsis via catheter infection is a known risk factor associated with IV epoprostenol and treprostinil treatments, and can significantly increase the cost of treating PAH patients, particularly if patients suffer repeated infections. The relative cost of infections has been estimated to be between US$22,100 and US$63,496 per case from five US studies. 78,83 86 A Canadian study estimated the cost to be CA$16,228, 77 whereas the cost of sepsis in the UK has been estimated to be between 2,247 and 12,706 per case, based on inflated prices. 85 SC delivery avoids this risk of bloodstream infection. 10 e U r o P e A N C A r D I o L o g Y