Drugs for Pulmonary Arterial Hypertension: A Systematic Review of the Clinical-Effectiveness of Combination Therapy
From CADTH Technology Overviews, Volume 1, Issue 1, e0105. March 2010
[Adapted from Pohar R, Clark M, Spry C. Drugs for Pulmonary Arterial Hypertension: A Systematic Review of the Clinical Effectiveness of Combination Therapy. (Health Technology Inquiry Service). (Health Technology Inquiry Service). Ottawa: Canadian Agency for Drugs and Technologies in Health; 2009.]
Pulmonary hypertension (PH) is a life-threatening, progressive condition with a poor prognosis when left unmanaged.1 It is characterized by increased pulmonary arterial pressure and secondary right ventricular failure.1 There are five different classifications of PH, one of which is pulmonary arterial hypertension (PAH), where the disease is primarily localized to the small pulmonary arteries.1,2 It is defined as a mean pulmonary artery pressure ≥ 25 mm Hg with a pulmonary capillary wedge pressure ≤ 15 mm Hg, as measured by cardiac catheterization at rest.1 PAH can occur with a variety of underlying medical conditions such as collagen vascular disease or HIV or drug exposures (e.g., anorexiants such as fenfluramine and dexfenfluramine), but it can also occur in the absence of such comorbid medical conditions (known as “idiopathic PAH” or IPAH).1,3 There are four functional New York Heart Association or World Health Organization classes of PAH based on the severity of symptoms ranging from class I to class IV, with class IV being the most severe.42 The cause of PAH is not completely understood, but it is thought to include both genetic and environmental factors.
Treatment options in PAH have increased over the past two decades, with regulatory approval of newer drugs and greater experience with combinations of existing drugs.3 Calcium channel blockers (long-acting nifedipine or diltiazem, or amlodipine), prostacyclin derivatives (epoprostenol, treprostinil, iloprost), endothelin receptor antagonists (bosentan, sitaxsentan, and ambrisentan), and phosphodiesterase-5 inhibitors (sildenafil) are all used in the management of the disease. In IPAH, calcium channel blockers cause vasodilation, which can lower pulmonary arterial pressure, but are effective in less than 10% of patients.2 Thus, other treatment options are often required.
Individuals with PAH may underproduce prostacyclin, an eicosanoid that promotes vasodilation and inhibits vascular proliferation and platelet aggregation.5 In PAH, prostacyclin derivatives reduce right and left ventricular afterload and increase cardiac output and stroke volume.6 Epoprostenol is administered by continuous intravenous infusion through a central venous catheter using an ambulatory infusion pump.6 The initial dose is 2 ng/kg/minute, which can be increased until dose-limiting pharmacological effects result or a tolerance limit to the drug is established.6 Treprostinil is administered by continuous subcutaneous infusion through a self-inserted subcutaneous catheter using an infusion pump at an initial rate of 1.25 ng/kg/minute.7 The infusion rate can be increased up to 2.5 ng/kg/minute.7 It can also be administered intravenously. Iloprost (not currently available in Canada, but available in the United States) is administered by inhalation six to nine times daily.2
Individuals with PAH have increased circulating levels of endothelin-1, a potent vasoconstrictor.2 Endothelin receptor antagonists block the action of endothelin-1, which results in decreased pulmonary and systemic vascular resistance and increased cardiac output.8 Bosentan is administered orally at a dosage of 62.5 mg twice daily for four weeks and then increased to the recommended maintenance dosage of 125 mg twice daily,8 whereas sitaxsentan is administered orally at a dosage of 100 mg daily.9 Ambrisentan is initiated at 5 mg orally once daily, which may be increased to 10 mg once daily.10
In patients with PAH, phosphodiesterase-5 inhibitors increase cGMP (cyclic guanosine monophosphate) within pulmonary vascular smooth muscle cells resulting in relaxation, which leads to vasodilation of the pulmonary vascular bed.11 Sildenafil is a phosphodiesterase-5 inhibitor approved for use in PAH in Canada, and is administered orally at a dosage of 20 mg three times daily.11
The availability of newer treatment options for PAH impacts how the disease can be optimally managed.3 If a combination of drugs is considered, it is important that rational combinations of therapies are used so that the clinical benefit to the patient can be maximized. The report reviews the evidence of clinical effectiveness and guidelines for the use of combination of drugs in PAH, which could potentially help in decision-making at the level of the health care system. As well, the potential for expanded use of these medications is considered, because this issue is important to consider in the context of a publicly funded health care system.
The objective of the report is to answer the following research questions:
- What is the clinical effectiveness of combination therapy of drugs for IPAH compared with monotherapy?
- What are the guidelines for the use of drugs for IPAH?
- What is the potential for expanded use of drugs for IPAH?
Published literature was obtained by cross-searching BIOSIS Previews, Embase, and MEDLINE on the OVID search system between January 2003 and December 2008. Parallel searches were performed on PubMed and The Cochrane Library (Issue 4, 2008) databases. Websites of regulatory agencies and health technology assessment and related agencies were also searched, as were specialized databases, such as those of the University of York Centre for Reviews and Dissemination (CRD). These searches were supplemented by handsearching the bibliographies of selected papers.
Two individuals screened and selected articles for inclusion in the report.
There were four randomized controlled trials (RCTs) and two guidelines identified. No relevant meta-analyses, systematic reviews, or health technology assessment reports were identified.
One RCT12 assessed the effect of adding oral sildenafil to long-term intravenous epoprostenol in 267 patients with PAH. After 16 weeks, the adjusted mean change in the six-minute walk distance was 29.8 m for the sildenafil group and 1.0 m for the placebo group, a treatment difference of 28.8 m (95% CI 13.9 to 43.8 m; P < 0.001) after adjusting for baseline walking distance and etiology using analysis of variance models. In patients with IPAH, the difference between groups was 33.9 m in favour of the sildenafil group (P value not reported). Sildenafil also had a beneficial effect on hemodynamic measurements and health-related quality of life.
Another RCT13 assessed the effect of adding inhaled iloprost to stable monotherapy with bosentan in 67 patients with PAH. After 12 weeks, the mean increase in post-inhalation six-minute walk distance from baseline was 30 m in the iloprost group and 4 m in the placebo group, a mean difference of 26 m (P = 0.051). The mean increase in pre-inhalation six-minute walk distance from baseline was 29 m in the iloprost group and 11 m in the placebo group, a mean difference of 19 m (P = 0.14). In 34% of iloprost-treated patients, the New York Heart Association class improved compared with 6% of patients in the placebo group (P = 0.002). Time to clinical worsening and post-inhalation hemodynamics also favoured the iloprost group.
A third RCT14 assessed the efficacy and safety of combination bosentan and epoprostenol in 33 patients with severe PAH relative to epoprostenol alone. All patients were started on epoprostenol and then randomized to bosentan or placebo. After 12 weeks, neither the differences between groups in hemodynamics were statistically significant, nor were differences in six-minute walk distance, dyspnea-fatigue rating, or change in New York Heart Association functional class. The authors concluded that the combination of bosentan and epoprostenol may be a therapeutic option for the treatment of patients with severe PAH.
One additional RCT15 evaluating bosentan in mildly symptomatic patients also assessed the effect of combination therapy with bosentan and sildenafil. However, the results of the combination therapy were better described in abstract form.16 From this study, it was concluded that in mildly symptomatic PAH patients treated with sildenafil, add-on bosentan therapy improved hemodynamics and delayed clinical worsening, consistent with the effects seen in patients not receiving concomitant sildenafil.
The guidelines identified included recommendations about combination therapy in PAH and tended to be cautious with respect to combination therapy for PAH until more evidence is available.3,17
Four RCTs were identified that assessed combination therapy, but no meta-analyses or health technology assessment reports were identified. Generally speaking, the identified RCTs tended to be short in duration, which impeded the ability to explore important long-term outcomes such as health-related quality of life and mortality. It should be noted, however, that PAH is a relatively rare disease, which may impede the ability to recruit a sufficient number of patients to evaluate such outcomes over the longer term. As well, although studies were identified that assessed combination therapy with a prostacyclin derivative and a phosphodiesterase-5 inhibitor, a prostacyclin derivative and an endothelin receptor antagonist, and a phosphodiesterase-5 inhibitor and an endothelin receptor antagonist, it is not clear if the results of such studies would be generalizable to other drugs in the same class or whether they would be specific to the particular drugs studied. In addition, it is not clear whether the observed differences in outcomes between combination and monotherapy would be considered clinically important. Finally, most studies included only patients with more severe disease (Class III or IV PAH). Thus, it is not known if similar results would be expected in less severe disease. That said, the identified guidelines recommend combination therapy only in patients with Class III or IV PAH.3
Treatment guidelines for IPAH reserved combination therapy for more severe cases that fail to respond to monotherapy. As well, it is recommended that combination therapy take place under the supervision of experienced PAH-specialty practitioners or within the context of clinical trials. The guidelines tend to be cautious with respect to combination therapy for IPAH until more evidence is available.3,17 From the limited number of published RCTs, it appears that there may be some additional benefit from certain combinations of drugs in PAH, but these studies have been relatively short in duration and two of the studies included only small numbers of patients and patients with PAH of different etiologies (i.e., some patients had IPAH, whereas others had PAH associated with other conditions).12-14 There are a number of RCTs of various combinations of drugs underway that may help to clarify the clinical benefit of this treatment approach. Until these studies are completed, evidence to make broad policy decisions about combination therapy in PAH may be insufficient. Decisions to fund combination therapy may be best considered on a case-by-case basis until further evidence is available. When additional evidence from the clinical trials currently underway becomes available, there could be some potential for expanded use of combination therapy if results are positive.
- Hopkins W, Rubin LJ. Treatment of pulmonary hypertension. 2008 [cited 2008 Dec 16]. In: UpToDate [Internet]. Version 16.3. Waltham (MA): UpToDate; c2005- . Available from: www.uptodate.com Subscription required.
- Chin KM, Rubin LJ. Pulmonary arterial hypertension. J Am Coll Cardiol. 2008 Apr 22;51(16):1527-38.
- Badesch DB, Abman SH, Simonneau G, Rubin LJ, McLaughlin VV. Medical therapy for pulmonary arterial hypertension - updated ACCP evidence-based clinical practice guidelines. Chest [Internet]. 2007 [cited 2008 Dec 16];131(6):1917-28. Available from: http://www.chestjournal.org/cgi/reprint/131/6/1917
- Galie N, Torbicki A, Barst R, Dartevelle P, Haworth S, Higenbottam T, et al. Guidelines on diagnosis and treatment of pulmonary arterial hypertension. The Task Force on Diagnosis and Treatment of Pulmonary Arterial Hypertension of the European Society of Cardiology. Eur Heart J. 2004 Dec;25(24):2243-78.
- Lunze K, Gilbert N, Mebus S, Miera O, Fehske W, Uhlemann F, et al. First experience with an oral combination therapy using bosentan and sildenafil for pulmonary arterial hypertension. Eur J Clin Invest. 2006 Sep;36(Suppl 3):32-8.
- e-CPS [Internet]. Ottawa: Canadian Pharmacists Association; 2008. Flolan© for injection. [cited 2008 Dec 16]. Available from: https://www.e-therapeutics.ca/ Subscription required.
- Treprostinil: drug information. 2008 [cited 2008 Dec 16]. In: UpToDate [Internet]. Version 16.3. Waltham (MA): UpToDate; c2005- . Available from: www.uptodate.com Subscription required.
- e-CPS [Internet]. Ottawa: Canadian Pharmacists Association; 2008. Tracleer©. [cited 2008 Dec 16]. Available from: https://www.e-therapeutics.ca/ Subscription required.
- Sitaxsentan: drug information. 2008 [cited 2008 Dec 16]. In: UpToDate [Internet]. Version 16.3. Waltham (MA): UpToDate; 2005- . Available from: www.uptodate.com Subscription required.
- Ambrisentan: drug information. 2008 [cited 2008 Dec 16]. In: UpToDate [Internet]. Version 16.3. Waltam (MA): UpToDate; 2005- . Available from: www.uptodate.com Subscription required.
- e-CPS [Internet]. Ottawa: Canadian Pharamacists Association; 2006. Revatio™. [cited 2006 Dec 16]. Available from: https://www.e-therapeutics.ca/ Subscription required.
- Simonneau G, Rubin LJ, Galie N, Barst RJ, Fleming TR, Frost AE, et al. Addition of sildenafil to long-term intravenous epoprostenol therapy in patients with pulmonary arterial hypertension: a randomized trial. Ann Intern Med. 2008 Oct 21;149(8):521-30.
- McLaughlin VV, Oudiz RJ, Frost A, Tapson VF, Murali S, Channick RN, et al. Randomized study of adding inhaled iloprost to existing bosentan in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2006 Dec 1;174(11):1257-63.
- Humbert M, Barst RJ, Robbins IM, Channick RN, Galie N, Boonstra A, et al. Combination of bosentan with epoprostenol in pulmonary arterial hypertension: BREATHE-2. Eur Respir J [Internet]. 2004 Sep [cited 2008 Dec 16];24(3):353-9. Available from: http://www.erj.ersjournals.com/cgi/reprint/24/3/353
- Galie N, Rubin LJ, Hoeper MM, Jansa P, Al-Hiti H, Meyer GMB, et al. Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (EARLY study): a double-blind, randomised controlled trial. Lancet. 2008;371(9630):2093-100.
- Rubin LJ, Simonneau G, Hoeper MM, Jansa P, Kusic-Pajic A, Galie N. Bosentan improves hemodynamics in patients receiving background sildenafil treatment: results from early, a randomized, double-blind, placebo-controlled study in patients with mildly symptomatic pulmonary arterial hypertension [abstract]. Chest [Internet]. 2007 [cited 2009 Jan 20];132(4 Suppl S):487S. Available from: http://meeting.chestjournal.org/cgi/reprint/132/4/487
- Gibbs JSR. Consensus statement on the management of pulmonary hypertension in clinical practice in the UK and Ireland. Thorax. 2008;63(Suppl 2):ii1-ii41.