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Reprint requests: Manreet K. Kanwar, MD, Cardiovascular Institute at Allegheny General Hospital, 320 East North Avenue, 16th Floor South Tower, Pittsburgh, PA 15212. Telephone: 412-359-4760. Fax: 412-359-6544
Significant developments have occurred in the field of pulmonary hypertension (PH) in the past 2 years, especially in terms of treatment options available. These include: approval of new drugs; evidence for use of initial combination therapies in pulmonary arterial hypertension; approved drugs for use in chronic thromboembolic disease not amenable to, or persistent after surgical thromboendarterectomy; and ongoing clinical trials in PH related to left heart disease and hypoxia. The field continues to evolve and address the challenges in treatment of this multifaceted disease with the aim to provide novel solutions and meet the needs of a growing population with PH. This has led to an extensive body of literature, ranging from case series to prospective, multicenter clinical trials, which will enhance the future of patient outcomes in PH. This contemporary review highlights the key articles in treatment updates for PH for the years 2013 to 2015.
Pulmonary hypertension (PH) is a complex disorder involving multiple clinical conditions, including intrinsic pulmonary vascular disease, left heart disease and lung disorders, causing hypoxia, which is usually associated with a poor prognosis.
ACCF/AHA 2009 expert consensus document on pulmonary hypertension a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association.
During the Fifth World Symposium held in 2013, several modifications were made to the previous clinical classification, especially in the nomenclature of the Group I sub-category of pulmonary arterial hypertension (PAH).
There has been a recent surge in available therapeutic options as well as investigational trials for the treatment of PH, with 3 drugs (macitentan, riociguat and treprostinil diolamine) being approved for PAH in the last 18 months.
However, all trials using PAH-approved therapies have failed to demonstrate a benefit in the context of heart failure, which is the most common etiology of PH. In this article, we review the literature from last 2 years and provide an update on the management of PH.
Updates in PAH: World Health Organization Group I
PAH is characterized by pulmonary vascular remodeling leading to right ventricular failure and, without treatment, ultimately death.
Predicting survival in pulmonary arterial hypertension: insights from the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL).
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).
Currently approved therapies for PAH target the 3 main pathways implicated in the pathogenesis of pulmonary vascular remodeling: prostacyclin (epoprostenol, treprostinil and iloprost); endothelin (bosentan, ambrisentan and macitentan); the nitric oxide pathway (sildenafil, tadalafil and riociguat) (Figure 1).
Although some of these drugs have resulted in delay in clinical worsening noted in PAH patients, their impact on reducing premature death due to PAH continues to be limited.
Figure 1The 3 major pathogenetic pathways targeted by current therapies in pulmonary arterial hypertension. Reproduced with permission from Humbert et al.
Treprostinil diolamine is an oral, salt form of treprostinil that was recently approved as monotherapy in PAH patients, based on findings from the FREEDOM M trial.
During this randomized, placebo-controlled, Phase III study, oral treprostinil improved 6-minute walk distance (6MWD) by 23 meters at 12 weeks in 349 treatment-naive PAH patients (95% confidence interval 4 to 41 m, p = 0.0125). However, there was no improvement in functional class or time to clinical worsening.
The common side effects of oral treprostinil in the clinical trials were nausea, diarrhea, headache and jaw pain. It is better tolerated when started at a lower, divided dose (usually 0.125 mg or 0.25 mg) and increased very gradually every 3 or 4 days. Because it is metabolized predominantly in the liver by CP2YC8 enzyme, it is contraindicated in patients with severe hepatic impairment (Child–Pugh Stage 3).
Both the parent drug and its metabolite have a high affinity for the IP receptor compared with other protanoid receptors. This selectivity allows for minimal side effects (nausea, vomiting, diarrhea and jaw pain), better tolerability and successful dose escalation. In a Phase II, placebo-controlled trial, selexipag decreased pulmonary vascular resistance (PVR) by 30% after 17 weeks of treatment in PAH patients stable on background therapy.
It was well tolerated with no death or unexpected serious adverse events in this trial. Subsequently, the long-term effect of selexipag was evaluated in the recently completed, event-driven GRIPHON trial, which was a multicenter, double-blind, placebo-controlled trial of 1,156 patients who were randomized in a 1:1 fashion to selexipag or placebo.
The primary end-point was a composite of death, lung transplantation, atrial septostomy, hospitalization for worsening PAH or worsening PAH. Selexipag was started at 200 μg twice daily and gradually up-titrated to a maximum of 1,600 μg twice daily, as tolerated. It was well tolerated and prostacyclin side effects were less frequent (>3% vs placebo). It reduced the risk of primary end-point by 40% compared with placebo (hazard ratio [HR] = 0.60; 99% confidence interval [CI] 0.46 to 0.78; p < 0.0001). The drug is currently under review by the United States Food and Drug Administration (FDA) and the European Medical Agency (EMA).
Endothelin pathway
Macitentan
Macitentan is an oral, non-selective dual-endothelin receptor (A and B) antagonist recently approved for the treatment of PAH. The drug was evaluated in a long-term randomized, double-blind, placebo-controlled, multicenter trial (SERAPHIN).
This was the first event-driven trial assessing long-term morbidity and mortality as the primary end-point in PAH. In this trial, 750 patients were randomized in a 1:1:1 fashion to placebo, macitentan 3 mg/day and macitentan 10 mg/day, respectively. The primary end-point was similar to the GRIPHON study and the median treatment duration was 32 months. Macitentan 3 mg/day and 10 mg/day reduced the risk of primary end-point, primarily driven by reduction in PAH worsening, by 30% (HR = 0.70; 97.5% CI 0.52 to 0.96; p = 0.01) and 45% (HR = 0.55; 97.5% CI 0.39 to 0.76; p < 0.001), respectively. There was no difference in all-cause mortality or mortality related to PAH between the treatment groups. The common side effects were headache, nasopharyngitis and anemia. With a more sustained receptor blockade and tissue penetration when compared with bosentan, its advantages include once-daily dosing, less drug–drug interaction (sildenafil and cyclosporine), and absence of association with increased incidence of liver function test abnormalities and edema.
Nitric oxide pathway
Riociguat
Riociguat stimulates the nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) pathway independent of endogenous NO, leading to increased levels of cGMP and vasodilation.
The safety and efficacy of riociguat in PAH was assessed in the PATENT-1 trial, an international, multicenter, randomized, placebo-controlled clinical trial.
A total of 443 patients with PAH, both treatment-naive and on background therapy, were randomized to either placebo, riociguat titrated to 1.5 mg 3 times daily or riociguat titrated to 2.5 mg 3 times daily. The latter dose increased 6MWD by 36 meters at 12 weeks (95% CI 20 to 52 weeks; p < 0.001). There were also improvements in PVR, N-terminal pro–brain natriuretic peptide (NT-pro-BNP), functional class and time to clinical worsening at 12 weeks compared with placebo. The beneficial effects were consistent, regardless of underlying functional class and background PAH therapy. The improvement in 6MWD was sustained at 24 weeks in the long-term extension study (PATENT 2).
Riociguat is teratogenic and therefore contraindicated in pregnancy. Finally, it should not be used together with a phosphodiesterase type 5 (PDE5) inhibitor due to increased incidence of hypotension. The combination of riociguat and sildenafil led to discontinuation of the drug and death in the blinded, randomized extension study in PAH patients (PATENT-PLUS).
When patients have an inadequate clinical response or deterioration in clinical status with monotherapy, a second agent targeting a different pathway is added. Although evidence for improvement in long-term clinical outcomes with sequential combination therapy in PAH is limited, current guidelines endorse this approach with a Level IA recommendation.
Oral treprostinil for the treatment of pulmonary arterial hypertension in patients on background endothelin receptor antagonist and/or phosphodiesterase type 5 inhibitor therapy (the FREEDOM-C study): a randomized controlled trial.
Of the total 742 patients in the SERAPHIN trial, 61% were on PDE5 inhibitor (PDE5-I) therapy and 6% were on oral or inhaled prostacyclin background therapy.
Compared with placebo, macitentan 10 mg/day delayed the time to composite clinical end-point in the subgroup of patients on background medical therapy (HR = 0.62; 95% CI 0.43 to 0.89; p = 0.009), but there was no difference between macitentan 3 mg/day and placebo (HR = 0.83; 95% CI 0.34 to 0.85; p = 0.27). In addition, in the subgroup of patients on background therapy, macitentan 10 mg increased 6MWD by at 6 months (vs placebo, 26 meters; 95% CI 4.5 to 47.3; p = 0.007) and there was a trend toward improvement in 6MWD with the macitentan 3-mg dose (vs placebo, +17.9 meters; 95% CI –5.0 to 40.8; p = 0.08). In the GRIPHON trial, selexipag delayed time to composite end-point of mortality and mortality, even in patients who were on background PAH therapies.
In this randomized, double-blind, placebo-controlled clinical trial, 334 patients with PAH who were symptomatic on sildenafil for >3 months were randomized in a 1:1 fashion to either bosentan or placebo. In contrast to the subgroup analysis from the SERAPHIN trial, sequential combination therapy with sildenafil and bosentan was not superior to sildenafil monotherapy in delaying the time to first event of all-cause mortality; hospitalization for worsening PAH; or intravenous prostanoids initiation, atrial septostomy or transplant (HR = 0.83; 95% CI 0.58 to 1.19; p = 0.2508). However, on exploratory secondary analysis, bosentan and sildenafil combination therapy improved 6MWD at 16 weeks. A greater number of patients in the sildenafil and bosentan combination group had an adverse event leading to premature discontinuation from the study (24.5% vs 12.6% with sildenafil monotherapy) and also had significant liver function tests abnormalities (21.8% vs 6.4% with sildenafil monotherapy).
In the FREEDOM C trial, oral treprostinil did not improve 6MWD at 16 weeks when added to background therapy with an endothelin-receptor antagonist (ERA) or PDE5-I.
Oral treprostinil for the treatment of pulmonary arterial hypertension in patients on background endothelin receptor antagonist and/or phosphodiesterase type 5 inhibitor therapy (the FREEDOM-C study): a randomized controlled trial.
Oral treprostinil for the treatment of pulmonary arterial hypertension in patients receiving background endothelin receptor antagonist and phosphodiesterase type 5 inhibitor therapy (the FREEDOM-C2 study): a randomized controlled trial.
despite using lower dose tablets, oral treprostinil showed no improvement in 6MWD at 16 weeks as an add-on therapy in patients who were on background therapy with an ERA or PDE5-I.
Initial double combination therapy
Data are emerging for initial combination therapy at the time of treatment initiation with drugs targeting more than one pathogenic pathway involved in PAH. In the BREATHE-2 trial, upfront combination therapy with bosentan and epoprostenol was not superior to epoprostenol monotherapy in improving functional capacity and hemodynamics at 12 weeks.
However, the study was likely underpowered, with only 30 patients recruited.
The AMBITION trial is the first strategic trial ever performed in PAH comparing initial combination therapy to monotherapy in newly diagnosed patients. It is an event-driven, multicenter, randomized, double-blind clinical trial that included 500 treatment-naive PAH patients with Functional Class II or III symptoms.
Patients were randomized in a 2:1:1 fashion to a combination of ambrisentan and tadalafil, ambrisentan monotherapy or tadalafil monotherapy, respectively. The primary end-point was time to clinical failure, which is a composite of death, lung transplantation, hospitalization for PAH worsening, worsening PAH and persistent worsening after 6 months. Initial combination therapy with ambrisentan and tadalafil was associated with a 50% lower risk (HR = 0.50; 95% CI 0.35 to 0.72; p < 0.01) of primary end-point when compared with pooled results from the ambrisentan and tadalafil monotherapy groups. The combination therapy was also superior when compared with either monotherapy group individually. Of note, similar to other recent, event-driven, long-term clinical trials in PAH (SERAPHIN and GRIPHON), the difference in the primary end-point was driven mainly by the delay in time to first hospitalization and there was no difference in mortality between the treatment arms.
More importantly, initial combination therapy was not associated with an increase in adverse events.
Initial triple combination therapy
The French network of PAH investigators reported their initial experience with upfront triple combination therapy targeting all 3 pathways implicated in the pathogenesis of PAH. They retrospectively reviewed 19 patients with severe hemodynamic compromise (cardiac index <2 liters/min/m2 and PVR >20 Wood units) who were initiated on bosentan, sildenafil and intravenous epoprostenol therapy simultaneously at the time of initial treatment.
Of the 19 patients, 18 had a significant improvement in 6MWD (463 ± 94 vs 227 ± 171 meters) and hemodynamics (cardiac index: 3.5 ± 0.7 vs 1.7 ± 0.4 liters/min/m2; PVR: 7.1 ± 3.3 vs 21.5 ± 7.8 Wood units) at 4 months compared with baseline, and these beneficial effects were sustained to final follow-up evaluation at 32 ± 10 months. One patient underwent heart–lung transplantation at 3 months. More importantly, the 1-, 2- and 3-year survival rates were 100%, significantly higher than that predicted by the French equation.
Although these results are encouraging, the findings from this single-center, retrospective analysis and need further validation in well-designed, prospective clinical trials before widespread application can be recommended.
Novel pathways and potential therapies in PAH
In addition to the traditional pathways in PAH, emerging pre-clinical data suggest several additional pathways being involved in the pathogenesis of PAH, presenting potential new therapies for treatment (Table 2).
Effect of pulmonary hypertension on clinical outcomes in advanced heart failure: analysis of the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) database.
World Health Organization Pulmonary Hypertension Group 2: Pulmonary hypertension due to left heart disease in the adult—a summary statement from the Pulmonary Hypertension Council of the International Society for Heart and Lung Transplantation.
PDE5 inhibition with sildenafil improves left ventricular diastolic function, cardiac geometry, and clinical status in patients with stable systolic heart failure: results of a 1-year, prospective, randomized, placebo-controlled study.
Effects of sildenafil on invasive haemodynamics and exercise capacity in heart failure patients with preserved ejection fraction and pulmonary hypertension: a randomized controlled trial.
Long-term effects of qdarusentan on left-ventricular remodelling and clinical outcomes in the EndothelinA Receptor Antagonist Trial in Heart Failure (EARTH): randomised, double-blind, placebo-controlled trial.
RITZ-5: randomized intravenous TeZosentan (an endothelin-A/B antagonist) for the treatment of pulmonary edema: a prospective, multicenter, double-blind, placebo-controlled study.
Do results of the ENABLE (Endothelin Antagonist Bosentan for Lowering Cardiac Events in Heart Failure) study spell the end for non-selective endothelin antagonism in heart failure?.
Riociguat for patients with pulmonary hypertension caused by systolic left ventricular dysfunction: a phase IIb double-blind, randomized, placebo-controlled, dose-ranging hemodynamic study.
Acute hemodynamic effects of riociguat in patients with pulmonary hypertension associated with diastolic heart failure (DILATE-1): a randomized, double-blind, placebo-controlled, single-dose study.
Of these various novel therapies, drugs targeting inflammation, growth factors, right ventricular metabolism and neurohormonal activation have made significant progress (currently in Phase II and III clinical trials) and appear promising for the near future.
Table 2Novel Pathways and Potential Therapies for Pulmonary Arterial Hypertension
A Randomized, Double-Blind, Placebo-Controlled, Phase II Multicenter Trial of a Monoclonal Antibody to CD20 (Rituximab) for the Treatment of Systemic Sclerosis-Associated Pulmonary Arterial Hypertension (SSc-PAH). Clinicaltrialsgov; NCT01086540.
The inhibition of pyruvate dehydrogenase kinase improves impaired cardiac function and electrical remodeling in two models of right ventricular hypertrophy: resuscitating the hibernating right ventricle.
Aldosterone inactivates the endothelin-B receptor via a cysteinyl thiol redox switch to decrease pulmonary endothelial nitric oxide levels and modulate pulmonary arterial hypertension.
Effect of pulmonary hypertension on clinical outcomes in advanced heart failure: analysis of the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) database.
Unfortunately, the pathophysiology of PH-LHD remains poorly understood, which results in a relative paucity of successful, targeted treatment strategies. Although small, single-center trials have shown improvements in exercise capacity and hemodynamic parameters, the results of randomized trials have been largely unsatisfactory. There are no Class I recommendations for targeted pulmonary vascular remodeling as treatment options for patients with PHLHD.
World Health Organization Pulmonary Hypertension Group 2: Pulmonary hypertension due to left heart disease in the adult—a summary statement from the Pulmonary Hypertension Council of the International Society for Heart and Lung Transplantation.
PDE5-Is have the potential to decrease LV after-load and improve diastolic function, thereby improving PH hemodynamics and functional capacity in PH-LHD patients.
PDE5 inhibition with sildenafil improves left ventricular diastolic function, cardiac geometry, and clinical status in patients with stable systolic heart failure: results of a 1-year, prospective, randomized, placebo-controlled study.
However, treatment with sildenafil for 12 weeks did not reduce pulmonary artery pressure (PAP) and invasive hemodynamic or clinical parameters in 52 diastolic HF patients with predominantly isolated post-capillary PH.
Effects of sildenafil on invasive haemodynamics and exercise capacity in heart failure patients with preserved ejection fraction and pulmonary hypertension: a randomized controlled trial.
A multicenter clinical trial evaluating sildenafil vs placebo in patients with PH due to systolic HF is currently enrolling patients (SilHF trial, NCT01616381).
The hemodynamic alterations from earlier use of ERAs and prostanoids failed to translate into clinical benefit in multiple randomized, controlled trials.
Long-term effects of qdarusentan on left-ventricular remodelling and clinical outcomes in the EndothelinA Receptor Antagonist Trial in Heart Failure (EARTH): randomised, double-blind, placebo-controlled trial.
RITZ-5: randomized intravenous TeZosentan (an endothelin-A/B antagonist) for the treatment of pulmonary edema: a prospective, multicenter, double-blind, placebo-controlled study.
Do results of the ENABLE (Endothelin Antagonist Bosentan for Lowering Cardiac Events in Heart Failure) study spell the end for non-selective endothelin antagonism in heart failure?.
It should be noted that most of these studies did not stratify patients with LHD for the presence of PH or require optimization of volume status as criteria for inclusion. Therefore, they should not be totally eliminated as potential agents until they have been studied in appropriate clinical trials in PH-LHD. Recently, a trial with a non-selective ERA, bosentan, was completed in patients with diastolic HF and secondary PH (BADDHY trial, NCT00820352). A pilot Phase II study with macitentan (MELODY-1 trial, NCT02070991) has recently completed enrollment of patients with PH with HF and ejection fraction >35%.
Riociguat, although well tolerated, did not show a change in mean PAP after 16 weeks of use in a multicenter, randomized, placebo-controlled trial in patients with PH related to systolic HF.
Riociguat for patients with pulmonary hypertension caused by systolic left ventricular dysfunction: a phase IIb double-blind, randomized, placebo-controlled, dose-ranging hemodynamic study.
Acute hemodynamic effects of riociguat in patients with pulmonary hypertension associated with diastolic heart failure (DILATE-1): a randomized, double-blind, placebo-controlled, single-dose study.
The Phase IIb trial studying the safety and efficacy of another soluble guanylate cyclase inhibitor, vericiguat, in both systolic (SOCRATES–REDUCED trial, NCT01951625) and diastolic HF (SOCRATES–PRESERVED trial, NCT01951638) recently concluded patient enrollment.
WHO Group 3: PH due to lung disease and/or hypoxia
Management of patients with PH associated with lung disease, including chronic obstructive pulmonary disease (COPD), sleep-disordered breathing and idiopathic pulmonary fibrosis (IPF), focuses on treatment of the underlying lung disease as per guidelines.
However, none of the current management guidelines of lung diseases focus on the vascular component of the disease, except for long-term oxygen treatment. Systemic PAH-approved therapies have the potential of worsening gas exchange in patients with lung disease due to differential interference in hypoxia-mediated vasoconstriction. As a result, inhaled agents (iloprost, treprostinil or nitric oxide) may be advantageous.
The non-selective ERA bosentan was well tolerated but failed to improve the end-point of time to clinical worsening in a Phase III trial in IPF patients.
Findings regarding its use in patients with IPF-associated PH in a Phase IV trial (B-PHIT trial, NCT00637065) are not yet available. However, the selective ERA, ambrisentan, is contraindicated in IPF, given its increased rate of disease progression and hospitalization, as shown in the ARTEMIS-IPF study.
A recent case series demonstrated sustained hemodynamic improvements in patients with interstitial lung disease (ILD)–PH after treatment with PDE5-I (sildenafil or tadalafil) in 10 patients.
Riociguat was well tolerated and showed efficacy in lowering PVR and increasing cardiac output and 6MWD in patients with diffuse parenchymal lung disease, but it failed to meet the primary end-point of reduction in PAP.
For example, use of bosentan in COPD patients with PH not only caused deterioration in gas exchange, but also failed to improve exercise capacity or quality of life in a small, randomized, controlled trial.
There have been no long-term clinical trials on use of prostanoids in PH–COPD. Both sildenafil and tadalafil have been reported to improve hemodynamics, but they have failed to improve exercise tolerance or quality of life in COPD patients with moderate to severe PH.
WHO Group 4: Chronic thromboembolic pulmonary hypertension (CTEPH)
CTEPH is considered potentially curable with pulmonary thromboendarterectomy (PTE) surgery, which can be performed in select patients with low peri-operative mortality at experienced centers. However, not all CTEPH patients are considered operable and up to one third have persistent or recurrent CTEPH after the procedure.
There has been increasing focus on use of PAH-specific therapies in CTEPH patients, especially those considered inoperable with persistent PH post-operatively.
Bosentan for treatment of inoperable chronic thromboembolic pulmonary hypertension: BENEFiT (Bosentan Effects in iNopErable Forms of chronIc Thromboembolic pulmonary hypertension), a randomized, placebo-controlled trial.
A retrospective analysis of CTEPH patients referred for PTE at the University of California, San Diego from 2005 to 2007 addressed hemodynamic and clinical outcomes for patients undergoing PTE on PAH-specific therapy (bosentan, sildenafil or epoprostenol and combination therapy; n = 111) in a comparison with therapy-naive patients (n = 244). There was minimal benefit of treatment with PHT on pre-PTE mean PAP, but its use was associated with a significant delay in time to referral for PTE.
CHEST-1 randomized 261 patients with inoperable or persistent post-operative PH to riociguat vs placebo and showed improvement in 6MWD (46 meters from baseline; p < 0.0001), PVR (31% reduction in therapy; p < 0.001), NT-pro-BNP and New York Heart Association (NYHA) functional class.
The drug was well tolerated by the majority of patients. Compared with the baseline established by the CHEST-1 trial, after 1 year of CHEST-2, 6MWD improved by 54 ± 62 meters in the inoperable subgroup and 44 ± 64 m in the persistent/recurrent subgroup. Riociguat was approved for use in both PAH and CTEPH by the FDA in October 2013 and by the EMA in March 2014.
A multicenter, randomized, double-blind, placebo-controlled trial is currently enrolling patients to study the safety and efficacy of macitentan (MERIT-1, NCT02021292) in patients with inoperable CTEPH.
Balloon pulmonary angioplasty (BPA)
Initially introduced in the 1980s, BPA as therapy for inoperable CTEPH has gained recent traction with single-center studies reporting hemodynamic improvement as well as improved safety and efficacy.
Although less invasive than PTE, BPA requires multiple procedures and has been associated with risks related to vascular access, intravenous contrast and cumulative radiation exposure. Patient selection for this procedure should occur in conjunction with consideration of approved medical therapy and in collaboration with established CTEPH centers.
Conclusions
PH is a complex, multidisciplinary disease, which continues to be associated with high morbidity and mortality. Recent advances have led to increased recognition of newer treatment pathways and better understanding of the pathophysiology of pulmonary vascular dynamics and their interplay with RV function. Although these strategies have resulted in delayed clinical worsening in PAH patients, their impact on reduction in mortality continues to be limited. This is in part due to the limited efficacy of available drugs and the fact that long-term trials used the time to first event as the primary end-points, although death is never the first event in PAH. Based on the emerging data, we believe that combination therapy (whether initial or sequential) is becoming the standard of care in treatment of PAH. Initial oral combination therapy will likely replace oral monotherapy in the management of low- to intermediate-risk PAH patients in the near future. Although oral drugs targeting the prostacyclin pathway are now available, they are limited in efficacy. Therefore, for high-risk patients, parenteral prostacyclin will likely remain the treatment of choice for now until more data become available. Results from ongoing investigational trials will likely continue to advance the field of available therapies in the future.
Disclosure statement
M.K.K. has received a speaker’s fee from Bayer Pharma. J.L.V. received consultancy and speaker’s fees from Actelion Pharmaceuticals and GlaxoSmithKline, and speaker’s fees from Bayer Pharma and travel grants from Bayer Pharma and United Therapeutics.
The remaining authors have no conflicts of interest to disclose.
References
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ACCF/AHA 2009 expert consensus document on pulmonary hypertension a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association.
Predicting survival in pulmonary arterial hypertension: insights from the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL).
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).
Oral treprostinil for the treatment of pulmonary arterial hypertension in patients on background endothelin receptor antagonist and/or phosphodiesterase type 5 inhibitor therapy (the FREEDOM-C study): a randomized controlled trial.
Oral treprostinil for the treatment of pulmonary arterial hypertension in patients receiving background endothelin receptor antagonist and phosphodiesterase type 5 inhibitor therapy (the FREEDOM-C2 study): a randomized controlled trial.
Effect of pulmonary hypertension on clinical outcomes in advanced heart failure: analysis of the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) database.
World Health Organization Pulmonary Hypertension Group 2: Pulmonary hypertension due to left heart disease in the adult—a summary statement from the Pulmonary Hypertension Council of the International Society for Heart and Lung Transplantation.
PDE5 inhibition with sildenafil improves left ventricular diastolic function, cardiac geometry, and clinical status in patients with stable systolic heart failure: results of a 1-year, prospective, randomized, placebo-controlled study.
Effects of sildenafil on invasive haemodynamics and exercise capacity in heart failure patients with preserved ejection fraction and pulmonary hypertension: a randomized controlled trial.
Long-term effects of qdarusentan on left-ventricular remodelling and clinical outcomes in the EndothelinA Receptor Antagonist Trial in Heart Failure (EARTH): randomised, double-blind, placebo-controlled trial.
RITZ-5: randomized intravenous TeZosentan (an endothelin-A/B antagonist) for the treatment of pulmonary edema: a prospective, multicenter, double-blind, placebo-controlled study.
Do results of the ENABLE (Endothelin Antagonist Bosentan for Lowering Cardiac Events in Heart Failure) study spell the end for non-selective endothelin antagonism in heart failure?.
Riociguat for patients with pulmonary hypertension caused by systolic left ventricular dysfunction: a phase IIb double-blind, randomized, placebo-controlled, dose-ranging hemodynamic study.
Acute hemodynamic effects of riociguat in patients with pulmonary hypertension associated with diastolic heart failure (DILATE-1): a randomized, double-blind, placebo-controlled, single-dose study.
Bosentan for treatment of inoperable chronic thromboembolic pulmonary hypertension: BENEFiT (Bosentan Effects in iNopErable Forms of chronIc Thromboembolic pulmonary hypertension), a randomized, placebo-controlled trial.
A Randomized, Double-Blind, Placebo-Controlled, Phase II Multicenter Trial of a Monoclonal Antibody to CD20 (Rituximab) for the Treatment of Systemic Sclerosis-Associated Pulmonary Arterial Hypertension (SSc-PAH). Clinicaltrialsgov; NCT01086540.
The inhibition of pyruvate dehydrogenase kinase improves impaired cardiac function and electrical remodeling in two models of right ventricular hypertrophy: resuscitating the hibernating right ventricle.
Aldosterone inactivates the endothelin-B receptor via a cysteinyl thiol redox switch to decrease pulmonary endothelial nitric oxide levels and modulate pulmonary arterial hypertension.
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