Highlights
- •Treatments for PAH approved in EU are not disease-modifying therapies.
- •Compared to placebo treatments for PAH as a whole reduce mortality.
- •No specific drug or class of medicines but prostanoids proved effective in itself.
- •Combinations provide no longer survival than monotherapies.
- •Drug approvals in spite of poor evidence can harm patient and hamper further R&D.
Abstract
Background
Pulmonary arterial hypertension (PAH) is a life-threatening rare disease. Between
2001 and 2016 the European Medicines Agency (EMA) approved nine drugs to treat PAH.
Considering the poor prognosis of patients with PAH it would be useful to understand
whether the approved therapies can change the natural history of the disease. We assessed
the therapeutic value and the quality of the evidence on medicines that have been
authorized by the EMA in the 2000s.
Methods
Information about drug approval was obtained from the EMA website and the European
Public Assessment Reports. MedLine, Embase, and Cochrane databases were systematically
searched for published randomized clinical trials and meta-analyses of the selected
drugs and their combinations.
Results
At the time of approval no medicine had been proved to reduce mortality or slow the
progression of the disease or to improve patients' quality of life. Recent meta-analyses
concluded that, compared to placebo, active treatments reduced mortality but there
was no conclusion on any preferred therapeutic option. Approvals of monotherapies
in the absence of best evidence of their efficacy, have prompted the search for better
efficacy of their combinations. Three meta-analyses found no advantage in survival
from combinations as opposed to monotherapies.
Conclusions
This model case confirms previous analyses that marketing authorizations granted in
spite of low evidence of therapeutic efficacy not only expose patients to treatments
with unknown benefit-risk profiles but also hamper post-marketing research aimed at
filling the information gap.
Keywords
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References
- Pulmonary arterial hypertension (PAH).(Date last updated January 2018. Date last accessed March 2018)
- 2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension: the joint 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: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT).Eur. Heart J. 2016; 37: 67-119
- Pulmonary hypertension: diagnosis and management.BMJ. 2013; 346f2028
- Pulmonary arterial hypertension.(Date last updated January 2015. Date last accessed March 2018)
- Combination therapy versus monotherapy for pulmonary arterial hypertension: a meta-analysis.Lancet Respir. Med. 2016; 4: 291-305
- European Medicines Agency.(Date last updated March 2018 Date last accessed March 2018)
- Ambrisentan, European public assessment report.(Date last updated April 2008. Date last accessed March 2018)
- Bosentan, European public assessment report.(Date last updated October 2005. Date last accessed March 2018)
- Riociguat, European public assessment report.(Date last updated April 2014. Date last accessed March 2018)
- Iloprost, European public assessment report.(Date last updated October 2005. Date last accessed March 2018)
- Macitentan, European public assessment report.(Date last updated February 2014. Date last accessed March 2018)
- Sildenafil, European public assessment report.(Date last updated October 2006. Date last accessed March 2018)
- Selexipag, European public assessment report.(Date last updated May 2016. Date last accessed March 2018)
- Sitaxentan, European public assessment report.(Date last updated April 2007. Date last accessed March 2018)
- Ambrisentan for the treatment of pulmonary arterial hypertension: results of the ambrisentan in pulmonary arterial hypertension, randomized, double-blind, placebo-controlled, multicenter, efficacy (ARIES) study 1 and 2.Circulation. 2008; 117: 3010-3019
- Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study.Lancet. 2001; 358: 1119-1123
- Inhaled iloprost for severe pulmonary hypertension.N. Engl. J. Med. 2002; 347: 322-329
- Macitentan and morbidity and mortality in pulmonary arterial hypertension.N. Engl. J. Med. 2013; 369: 809-818
- Low-dose nitric oxide therapy for persistent pulmonary hypertension of the newborn. Clinical inhaled nitric oxide research group.N. Engl. J. Med. 2000; 342: 469-474
- Riociguat for the treatment of pulmonary arterial hypertension.N. Engl. J. Med. 2013; 369: 330-340
- Selexipag for the treatment of pulmonary arterial hypertension.N. Engl. J. Med. 2015; 373: 2522-2533
- Sildenafil citrate therapy for pulmonary arterial hypertension.N. Engl. J. Med. 2005; 353: 2148-2157
- Tadalafil therapy for pulmonary arterial hypertension.Circulation. 2009; 119: 2894-2903
- Tadalafil, European public assessment report.(Date last updated October 2008. Date last accessed March 2018)
- Survival in patients with primary pulmonary hypertension. Results from a national prospective registry.Ann. Intern. Med. 1991; 115: 343-349
- The evolving classification of pulmonary hypertension.Arch. Pathol. Lab. Med. 2017; 141: 696-703
- Pharmacotherapy in pulmonary arterial hypertension: a systematic review and meta-analysis.Respir. Res. 2010; 11: 12
- Assessment of pulmonary artery pressure by echocardiography —a comprehensive review.IJC Heart Vascul. 2016; 12: 45-51
- Characterization of brain natriuretic peptide in long-term follow-up of pulmonary arterial hypertension.Chest. 2005 Oct; 128: 2368-2374
- A meta-analysis of randomized controlled trials in pulmonary arterial hypertension.Eur. Heart J. 2009; 30: 394-403
- How can we regulate medicines better?.BMJ. 2007; 335: 803-805
- Efficacy and safety of pulmonary arterial hypertension-specific therapy in pulmonary arterial hypertension: a meta-analysis of randomized controlled trials.Chest. 2016; 150: 353-366
- A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension.N. Engl. J. Med. 1996 Feb 1; 334: 296-301
- WMA Declaration of Helsinki – Ethical principles for medical research involving human subjects. 64th WMA General Assembly F, Brazil, October 2013.(Available at:) (Date last updated March 2017. Date last accessed March 2018)
- Combination therapy for pulmonary arterial hypertension: a systematic review and meta-analysis.Can. J. Cardiol. 2016; 32: 1520-1530
- Initial use of Ambrisentan plus Tadalafil in pulmonary arterial hypertension.N. Engl. J. Med. 2015; 373: 834-844
- The Efficacy and Safety of Initial Triple Versus Initial Dual Oral Combination Therapy in Patients With Newly Diagnosed Pulmonary Arterial Hypertension (TRITON).(last access May 2018)
- Pulmonary arterial hypertension: epidemiology and registries.J. Am. Coll. Cardiol. 2013; 62: D51-D59
- Five-year outcomes of patients enrolled in the REVEAL registry.Chest. 2015; 148: 1043-1054
- The Giessen pulmonary hypertension registry: survival in pulmonary hypertension subgroups.J Heart Lung Transplant. 2017; 36: 957-967
- The REVEAL registry risk score calculator in patients newly diagnosed with pulmonary arterial hypertension.Chest. 2012; 141: 354-362
- Update on the European respiratory review.Eur. Respir. J. 2010; 36: 993-994
- Survival in patients with idiopathic, familial, and anorexigen-associated pulmonary arterial hypertension in the modern management era.Circulation. 2010; 122: 156-163
- Approvals of drugs with uncertain benefit-risk profiles in Europe.Eur. J. Intern. Med. 2015; 26: 572-584
- Letting post-marketing bridge the evidence gap: the case of orphan drugs.BMJ. 2016; 353: i2978
Article info
Publication history
Published online: May 25, 2018
Accepted:
May 17,
2018
Received in revised form:
May 14,
2018
Received:
March 6,
2018
Identification
Copyright
© 2018 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
