Pulmonary hypertension

Transcription

1 Pulmonary hypertension Pulmonary hypertension (PH) is a severe, progressive, life-changing and life-threatening disorder of the heart and lungs in which the blood pressure in the pulmonary arteries is above normal and which can lead to heart failure and death. 1,2 People with PH develop a markedly decreased exercise capacity and have a reduced quality of life. 3 Research suggests that nitric oxide (NO) deficiency, accompanied by endothelial dysfunction, lies at the heart of the problem of PH and is linked to disease progression and death. 4,5 There are five types of PH; each can affect the patient in a different way and every patient may have a different etiology and manifestation of PH. 3,6,7 Currently available pharmacological treatments are only approved to treat one of the five types of PH, pulmonary arterial hypertension (PAH), and all current treatments have significant limitations. 8 Prevalence of PH PH can affect people of all ages, including children, though the average age at diagnosis is 50 years. PH can occur alone or as a comorbidity with other underlying diseases. There are no definitive figures for the prevalence of all forms of PH but it is thought that there are several hundred thousand patients globally diagnosed with PH. 9,10 Symptoms and diagnosis Early PH is often asymptomatic and, by the time symptoms appear, disease progression is usually well advanced and not entirely reversible. 11 The most common symptoms of PH include shortness of breath, fatigue, dizziness and fainting, all of which are worsened by exertion. 12,13 As the symptoms of PH are non-specific, diagnosis can be delayed by as much as two years. 3,7,14 Early diagnosis and accurate identification of the PH types is essential as a delay in treatment initiation of even a few months can have a negative impact on survival. 3,11 Continuous treatment monitoring by a PH specialist is vital to ensure that patients are receiving optimal care for their particular type and stage of disease. 3 While echocardiogram, electrocardiogram, exercise testing (e.g. six-minute walk test), ventilation/perfusion lung scan 1

2 (VQ scan) and other tests are helpful in diagnosing the disease, a definitive diagnosis of PH requires inserting a special pressure-sensing catheter into the right side of the heart (right heart catheterization). 3 For the best chance of success, patients need to be treated at a PH specialist center. 3,15 Chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension (PAH) According to the clinical classification of PH (Dana Point), there are five different types of PH based on different underlying causes. The five types are: pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension (CTEPH), pulmonary hypertension owing to left heart disease (e.g. PH-LVD), pulmonary hypertension owing to lung diseases and/or hypoxemia (e.g. PH-COPD or PH-ILD) and pulmonary hypertension with unclear multifactorial mechanisms (miscellaneous PH). 3 PAH PAH, one of the five types of PH, is a progressive and life-threatening disease in which the blood pressure in the pulmonary arteries is significantly increased and which can lead to heart failure and death. PAH is characterized by morphological changes to the endothelium of the arteries of the lungs causing remodeling of the tissue, vasoconstriction and thrombosis-in-situ causing the blood pressure in the pulmonary arteries to be significantly increased. As a result of these changes, the blood vessels in the lungs constrict, making it more difficult for the heart to pump blood through to the lungs. 1,2 PAH is a rare disease and affects an estimated people per million globally. 1,8,14 It is more prevalent in younger women than men. 16 In most cases, PAH has no known cause, though it can sometimes be inherited. 3,16 Despite the availability and advantages of several approved PAH therapies, the prognosis for patients remains poor and new treatment options are needed. Mortality of patients remains high and is still 15% at one year; 32% at three years after diagnosis. 8,16 In addition, the majority of patients with PAH are not at treatment goal (> 50% remain in WHO functional class III). 17 PAH patients should be reassessed regularly at PH centers for modification of therapy taking into consideration the principles of goal-orientated therapy. 3,15 2

3 CTEPH CTEPH is a progressive and life-threatening disease and a type of PH in which it is believed that thromboembolic occlusion (organized blood clots) of pulmonary vessels gradually lead to an increased blood pressure in the pulmonary arteries, resulting in an overload of the right heart. 3,6 CTEPH may evolve after prior episodes of pulmonary embolism but the pathogenesis is not yet completely understood. 6 CTEPH is comparable in terms of population size to PAH, though there are fewer diagnoses made so far. 10 The standard and potentially curative treatment for CTEPH is pulmonary endarterectomy (PEA), a surgical procedure in which the blood vessels of the lungs are cleared of clot and scar material. 6 However CTEPH is inoperable in an estimated 20 to 40% of patients and up to 35% of patients who survive PEA have persistent or recurrent PH following surgery. 18,19,20 While European Society of Cardiology (ESC) guidelines recommend that CTEPH patients are assessed for PEA by an experienced surgeon, it is estimated that globally only one in four patients receives a surgical assessment. 3,10 All PH patients with suspected CTEPH should be referred to a CTEPH expert center for diagnosis, operability assessment and appropriate treatment. 3,21 The definitive tool to confirm diagnosis of CTEPH is a test called a ventilation/perfusion lung scan (VQ scan). 3,6,21 To date, no approved pharmacological therapy exists for CTEPH and, as a result, there is an urgent unmet medical need for patients who are unable to undergo surgery or who have persistent or recurrent PH after surgery. 8,18 New approaches to the treatment of CTEPH and PAH Although the prognosis for patients with PH has improved in recent years, there is still a high unmet need for more efficient therapies. Riociguat is an investigational, oral treatment being developed by Bayer to target a key molecular mechanism underlying pulmonary hypertension (PH). Riociguat is the first and only drug that has consistently demonstrated robust clinical efficacy in two separate PH indications (CTEPH and PAH). 22,23 Riociguat is a soluble guanylate cyclase (sgc) stimulator, the first member of a novel class of compounds. sgc is an enzyme found in the cardiopulmonary system and the receptor for nitric oxide (NO). When NO binds to sgc, the enzyme enhances synthesis of the signaling 3

4 molecule cyclic guanosine monophosphate (cgmp). cgmp plays an important role in regulating vascular tone, proliferation, fibrosis, and inflammation. PH is associated with endothelial dysfunction, impaired synthesis of NO and insufficient stimulation of sgc. 24 Riociguat has a unique mode of action: it sensitizes sgc to endogenous NO by stabilizing the NO-sGC binding. Riociguat also directly stimulates sgc via a different binding site, independently of NO. Riociguat, as a stimulator of sgc, addresses NO deficiency by restoring the NO-sGC-cGMP pathway, leading to increased generation of cgmp. With its novel mode of action, riociguat has the potential to overcome a number of limitations of currently approved PAH therapies, including NO dependence, and is the first drug which has shown clinical benefits in CTEPH, where no pharmacologic treatment is approved. References 1 Rosenkranz, S. Pulmonary hypertension: current diagnosis and treatment. Clin Res Cardiol 2007;96: Macchia, A et al. A meta-analysis of trials of pulmonary hypertension: A clinical condition looking for drugs and research methodology. Am Heart J 2007;153: Galiè, N et al. Guidelines for the diagnosis and treatment of pulmonary hypertension: The Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J 2009;30: Kielstein, JT et al. Asymmetric dimethylarginine in idiopathic pulmonary hypertension. Arterioscler Thromb Vasc Biol 2005;25: Skoro-Sajer, N et al. Asymmetric dimethylarginine is increased in chronic thromboembolic pulmonary hypertension. Am J Respir Crit Care Med 2007;176: Ali, JM et al. Chronic thromboembolic pulmonary hypertension: An underdiagnosed entity? Hosp Pract 2012;40: Armstrong, I et al. The trajectory to diagnosis with pulmonary arterial hypertension: a qualitative study. BMJ Open 2012; 2:e Girgis, RE. Emerging drugs for pulmonary hypertension. Expert Opin Emerg Drugs 2010; 15: PHA UK website. Available from: Last accessed May Bayer HealthCare. Data on File 11 Vachiery, J-L et al. How to detect disease progression in pulmonary arterial hypertension. Eur Respir Rev 2012; 21:

5 12 McKenna, S et al. The Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR): A measure of health-related quality of life and quality of life for patients with pulmonary hypertension. Qual Life Res 2006;15: PHA UK website. Available from: Last accessed: May Peacock, JA. Treatment of pulmonary hypertension. BMJ 2003; 326: Ghofrani, HA et al. Treatment of pulmonary arterial hypertension (PAH): updated recommendations of the Cologne Consensus Conference Int J Cardiol 2011;154(Suppl 1):S20 S33 16 Peacock, AJ et al. An epidemiological study of pulmonary arterial hypertension. Eur Respir J 2007;30: Badesch, DB et al. Pulmonary arterial hypertension. Baseline characteristics from the REVEAL registry. Chest 2010; 137: Mayer, E. Surgical and post-operative treatment of chronic thromboembolic pulmonary hypertension. Eur Respir Rev 2010;19: Condliffe, R et al. Improved outcomes in medically and surgically treated chronic thromboembolic pulmonary hypertension. Am J Respir Crit Care Med 2008;177: Freed, DH et al. Survival after pulmonary thromboendarterectomy: effect of residual pulmonary hypertension. J Thorac Cardiovasc Surg 2011;141: Wilkens, H et al. Chronic thromboembolic pulmonary hypertension (CTEPH): updated recommendations of the Cologne Consensus Conference Int J Cardiol 2011; 154(Suppl.): S54 S60 22 Ghofrani, HA. et al. Riociguat for the Treatment of Chronic Thromboembolic Pulmonary Hypertension. N Engl J Med 2013;369: Ghofrani, HA. et al. Riociguat for the Treatment of Pulmonary Arterial Hypertension. N Engl J Med 2013;369: Ghofrani, HA et al. Riociguat for pulmonary hypertension. Future Cardiol 2010;6: Grimminger, F et al. First acute haemodynamic study of soluble guanylate cyclase stimulator riociguat in pulmonary hypertension. Eur Respir J 2009;33: