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Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USABioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
Corresponding author. Division of Pulmonary, Critical Care & Sleep Medicine, Houston Methodist Hospital, 6445 Main St Floor 22, Houston, TX, 77030, USA.
Pulmonary arterial hypertension (PAH) therapy goals are to achieve low-risk status.
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Patients on phosphodiesterase-5 inhibitors (PDE5is) may not reach therapy goals.
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Switching from PDE5is to riociguat may be beneficial to patients not at therapy goal.
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Emerging data suggest that riociguat may be a potential upfront combination drug.
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Further studies are needed to assess riociguat in upfront combination PAH treatment.
Abstract
Effective clinical decision-making in initial treatment selection and switching or escalations of therapy for pulmonary arterial hypertension (PAH) depends on multiple factors including the patient's risk profile. Data from clinical trials suggest that switching from a phosphodiesterase-5 inhibitor (PDE5i) to the soluble guanylate cyclase stimulator riociguat may provide clinical benefit in patients not reaching treatment goals. In this review, we cover the clinical evidence for riociguat combination regimens for patients with PAH and discuss their evolving role in upfront combination therapy and switching from a PDE5i as an alternative to escalating therapy. Specifically, we review current evidence which suggests or provides a hypothesis for 1) the potential use of riociguat plus endothelin receptor antagonist combinations for upfront combination therapy in patients with PAH at intermediate to high risk of 1-year mortality and 2) the benefits of switching to riociguat from a PDE5i in patients who are not achieving treatment goals with PDE5i-based dual combination therapy and at intermediate risk.
N-terminal propeptide of brain natriuretic peptide
OR
odds ratio
PAH
pulmonary arterial hypertension
PCA
prostacyclin analog
PDE5i
phosphodiesterase-5 inhibitor
PVR
pulmonary vascular resistance
ROAR
RiOciguAt UseR
SAE
serious adverse event
sGC
soluble guanylate cyclase
WHO
World Health Organization
1. Introduction
Pulmonary arterial hypertension (PAH) is a rare and relentlessly progressive disease which, if left untreated, leads to progressive right heart failure and death [
]. Currently available therapies for PAH target three physiologic pathways: the nitric oxide (NO) pathway (soluble guanylate cyclase [sGC] stimulators and phosphodiesterase-5 inhibitors [PDE5is]), the prostacyclin pathway (prostacyclin analogs [PCAs] and prostacyclin receptor agonists), and the endothelin pathway (endothelin receptor antagonists [ERAs]) [
]. The involvement of multiple signaling pathways in the pathogenesis of PAH gives a clear rationale for combination therapy targeting two or more pathways simultaneously [
Targeting the prostacyclin pathway with selexipag in patients with pulmonary arterial hypertension receiving double combination therapy: insights from the randomized controlled GRIPHON study.
]. Additionally, where previously the hope for PAH treatment was to prevent deterioration, the introduction of multiple PAH-targeted treatments has shifted expectations to clinical improvement [
]. The event-driven, randomized, double-blind, Phase III AMBITION study laid the foundation for upfront combination therapy demonstrating that among treatment-naïve patients with PAH, initial combination therapy with ambrisentan and tadalafil resulted in significantly lower risk of clinical-failure events than with either treatment alone [
]. Furthermore, a meta-analysis of 17 studies showed greater efficacy and a significant reduction in risk of clinical worsening with combination therapies compared with monotherapy [
]. Recently updated guidelines recommend upfront combination treatment to achieve a low-risk status; achievement or maintenance of an intermediate-risk profile is considered an inadequate treatment response for most patients with PAH. Initial monotherapy is only recommended in some subgroups of patients such as those with cardiopulmonary comorbidities and the elderly [
]. As a result, current standard of care practice is to use upfront combination treatment in PAH.
The recent REPLACE study demonstrated improved outcomes for patients with PAH at intermediate risk of 1-year mortality on PDE5i therapy switching to the sGC stimulator riociguat [
Switching to riociguat versus maintenance therapy with phosphodiesterase-5 inhibitors in patients with pulmonary arterial hypertension (REPLACE): a multicentre, open-label, randomised controlled trial.
], providing a rationale for its use as a potential treatment option in upfront combination with other drugs. In this review, we highlight the clinical evidence for riociguat and discuss its potential role in upfront combination therapy for the treatment of PAH.
2. Concepts for the evolving role of riociguat in combination therapy in PAH treatment
To date, use of riociguat combination therapy for PAH has generally been part of sequential combination therapy [
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).
Predictors of long-term outcomes in patients treated with riociguat for pulmonary arterial hypertension: data from the PATENT-2 open-label, randomised, long-term extension trial.
]. These studies were conducted when initial monotherapy and sequential combination therapy in patients with inadequate response to monotherapy was the recommended approach. PATENT-1 and the open-label, long-term extension (LTE) PATENT-2 included both patients who were treatment naïve (50%) and patients who were pre-treated, predominantly with ERAs (44%) but also with non-intravenous prostanoids (6%) [
]. Data from PATENT-1 demonstrated significant improvements in exercise capacity and a range of secondary endpoints with riociguat compared with placebo [
Predictors of long-term outcomes in patients treated with riociguat for pulmonary arterial hypertension: data from the PATENT-2 open-label, randomised, long-term extension trial.
] due to safety findings from the early-terminated PATENT-PLUS study, which showed no evidence of a positive benefit/risk ratio when adding riociguat to background sildenafil therapy [
] (Table 1). In particular, six (35%) patients withdrew from the PATENT-PLUS LTE as a result of drug-related AEs while receiving riociguat/sildenafil therapy, including three non-serious AEs and one serious adverse event (SAE) of arterial hypotension.
Table 1Summary of pivotal clinical trials of riociguat-based combination therapy.
Comparison of hemodynamic parameters in treatment-naïve and pre-treated patients with pulmonary arterial hypertension in the randomized phase III PATENT-1 study.
Numbers of patients varied for the individual hemodynamic parameters evaluated: riociguat + non-IV prostanoid n = 19–20, placebo + non-IV prostanoid n = 5–6.
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Nominally significant improvements in PVR, SVR, mPAP, and cardiac output with riociguat versus placebo at 12 weeks
No between-group differences in changes in standing SBP and supine or standing DBP
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No favorable effect of combination therapy on exploratory clinical parameters, including hemodynamics and exercise capacity
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Withdrawal from LTE due to study drug-related adverse events: n = 6 (35%)
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Deaths in LTE: n = 3; none considered to be related to study treatment
•
Study terminated by the sponsor
6MWD, 6-min walk distance; CI, cardiac index; DBP, diastolic blood pressure; ERA, endothelin receptor antagonist; FC, functional class; IV, intravenous; LTE, long-term extension; mPAP, mean pulmonary artery pressure; NT-proBNP, N-terminal propeptide of brain natriuretic peptide; PVR, pulmonary vascular resistance; QoL, quality of life; SBP, systolic blood pressure; SvO2, mixed venous oxygen saturation; SVR, systemic vascular resistance; WHO, World Health Organization.
a 3–6 months of ERA therapy before initiating riociguat.
b > 6 months of ERA therapy before initiating riociguat.
c Results in this small subgroup should be interpreted with caution.
d Numbers of patients varied for the individual hemodynamic parameters evaluated: riociguat + ERA n = 89–101, placebo + ERA n = 44–48.
e Numbers of patients varied for the individual hemodynamic parameters evaluated: riociguat + non-IV prostanoid n = 19–20, placebo + non-IV prostanoid n = 5–6.
Given the recent guideline recommendations for pharmacologic PAH treatment, with upfront combination therapy now standard of care, there is interest in whether riociguat combinations may be appropriate as upfront therapy.
Alternatively, switching from a PDE5i to riociguat could be considered a potential escalation strategy for patients who do not achieve sufficient response to PDE5i treatment, particularly given the differences in pharmacology between sGC stimulators and PDE5is. Riociguat and PDE5is both target the NO-sGC-cGMP pathway, but with different modes of action. While riociguat increases cyclic guanosine monophosphate (cGMP) production by directly stimulating sGC, independent of NO, and sensitizing sGC to endogenous NO by stabilizing NO-sGC binding [
Fig. 1Mode of action of riociguat and PDE5is on the NO-sGC-cGMP molecular pathway. Several pathways, including the NO-sGC-cGMP molecular pathway, play a role in the development and progression of PAH. NO, diminished in patients with PAH, is an endogenous vasodilator produced in endothelial cells which activates sGC to synthesize cGMP from GTP, promoting vasodilation and inhibiting smooth muscle proliferation, and vascular remodeling via several downstream mechanisms. Riociguat and PDE5i both act on this pathway with different mechanisms and distinct molecular targets. Riociguat, an sGC stimulator, has a dual mechanism of action. It directly stimulates sGC, independent of NO binding, causing the conversion of GTP to cGMP. In addition, riociguat enhances endogenous NO induced activation of sGC through stabilization of the NO-sGC binding. PDE5is act downstream of the NO-sGC-cGMP axis to prevent the hydrolysis and inactivation of cGMP to GMP by PDE5, increasing the downstream signaling effects of NO. As cGMP production is limited in patients with PAH due to reduced levels of endogenous NO, the efficacy of PDE5is may be limited as they can only be effective with sufficient levels of cGMP. PDE5is are also NO dependent and their activity may be reduced in the event of low endogenous NO. This may explain why some patients do not achieve treatment goals with PDE5i therapy.
]. However, a substantial proportion of patients receiving PDE5is do not reach treatment goals, even with dual combination therapy. For example, in the AMBITION study, ∼60% of patients receiving upfront tadalafil plus ambrisentan did not achieve a satisfactory clinical response after 24 weeks [
]. Furthermore, in a retrospective Italian Pulmonary Hypertension Network study of treatment-naïve patients with PAH receiving upfront PDE5i plus ERA combination, a low-risk status at 6 months was only achieved or maintained in 35–43% of patients, depending on the risk score assessed [
Switching to riociguat versus maintenance therapy with phosphodiesterase-5 inhibitors in patients with pulmonary arterial hypertension (REPLACE): a multicentre, open-label, randomised controlled trial.
] studies. RESPITE was a 24-week, open-label, single-arm pilot study in which 61 patients with an insufficient response to PDE5is with or without ERAs (World Health Organization functional class [WHO FC] III, 6-min walk distance [6MWD] 165–440 m, cardiac index <3.0 L min−1 m−2, and pulmonary vascular resistance [PVR] > 400 dyn s cm−5) and at intermediate risk were switched to riociguat [
]. Of note, most patients (82%) were receiving PDE5i plus ERA combination therapy at baseline. At Week 24, treatment with riociguat with or without an ERA significantly improved exercise capacity, WHO FC, N-terminal propeptide of brain natriuretic peptide (NT-proBNP) levels, PVR, and cardiac index compared with baseline. Additionally, in the overall study population, 27% of patients achieved the combined responder endpoint of WHO FC I/II, ≥30 m improvement in 6MWD, and freedom from clinical worsening. In terms of risk profile, the proportion of patients considered as low-risk by European Society of Cardiology (ESC)/European Respiratory Society (ERS) treatment guidelines increased from 15% at baseline to 51% at Week 24 (Table 2). Overall, 16% of patients experienced SAEs, the most common of which was right ventricular failure (n = 3; 5%); no other SAE occurred in more than one patient. No new safety signals were identified when switching from a PDE5i to riociguat.
Table 2Summary of risk status in riociguat clinical studies.
Switching to riociguat versus maintenance therapy with phosphodiesterase-5 inhibitors in patients with pulmonary arterial hypertension (REPLACE): a multicentre, open-label, randomised controlled trial.
Low risk defined as achievement of low-risk status in three or four components of the FPHN invasive risk calculator.
–
12 months
Riociguat + ambrisentan: 0
Riociguat + ambrisentan: 46†
REVEAL Lite 2.0
–
Riociguat + ambrisentan: 15
Riociguat + ambrisentan: 43
COMPERA, Comparative Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension; ERS, European Respiratory Society; ESC, European Society of Cardiology; FPHN, French Pulmonary Hypertension Network; mRRS, modified REVEAL risk score; PDE5i, phosphodiesterase type 5 inhibitor; REVEAL, Registry to Evaluate Early and Long-Term PAH Disease Management *p ≤ 0.05 vs riociguat arm; †p = 0.01 vs baseline.
a Low risk defined as achievement low-risk status in three components of the FPHN non-invasive risk calculator.
b Low risk defined as achievement of low-risk status in three or four components of the FPHN invasive risk calculator.
Based on the promising results from RESPITE, switching from a PDE5i to riociguat was assessed in the open-label, randomized, controlled REPLACE study which was the first pivotal PAH study to use clinical improvement as a primary endpoint. In REPLACE, 226 patients at intermediate risk of 1-year mortality were randomized to continue PDE5i therapy (n = 115), with or without an ERA, or switch to riociguat (n = 111) [
Switching to riociguat versus maintenance therapy with phosphodiesterase-5 inhibitors in patients with pulmonary arterial hypertension (REPLACE): a multicentre, open-label, randomised controlled trial.
]. Similar to the patient population in RESPITE, many patients in REPLACE were receiving PDE5i plus ERA combination therapy at baseline (71%). In the overall study population, clinical improvement at Week 24 (absence of clinical worsening plus at least two of: ≥10% or ≥ 30 m improvement in 6MWD, WHO FC I/II, or ≥ 30% reduction in NT-proBNP) was achieved by significantly more patients who received riociguat compared with those who remained on PDE5i (41% vs 20%; odds ratio [OR] 2.78, 95% confidence interval [CI] 1.53, 5.06; p = 0.0007; relative risk, 1.99, 95% CI 1.30, 3.06). This clinical benefit of riociguat over PDE5i was also observed in the subgroup of patients who received PDE5i plus ERA combination therapy at baseline (OR 2.21, 95% CI 1.12, 4.38). In the overall population, significant improvements versus PDE5i were observed from baseline to Week 24 in WHO FC (44% vs 23%; mean difference −0.26, 95% CI –0.42, −0.11; p = 0.0007), and clinical worsening events occurred in fewer patients in the riociguat group (1%) versus the PDE5i group (9%) (OR 0.1, 95% CI 0.01, 0.73; p = 0.0047). In exploratory analysis of three different PAH risk score calculators, a higher proportion of riociguat-treated patients compared with PDE5i-treated patients, achieved low-risk status at the end of the study (Table 2). No new safety signals were observed when switching from a PDE5i to riociguat, with similar AE rates in the two groups and a higher incidence of SAEs in the PDE5i group (17%) than the riociguat group (7%) (Table 3).
Table 3Summary of clinical trials of switching PDE5i to riociguat-based therapy.
Defined as: death, atrial septostomy, lung transplantation, non-planned PAH-related hospitalization, start of new PAH treatment (ERA, inhaled or oral prostanoid) or modification of pre-existing treatment, initiation of IV or subcutaneous prostanoids, persistent decrease of >15% from baseline or > 30% from last measurement in 6MWD, persistent worsening of WHO FC, or appearance or worsening of signs/symptoms of right heart failure not responding to optimized oral diuretic therapy.
, including two deaths (3%; not study-drug related)
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10 patients (16%) discontinued; four (7%) due to AEs
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10 patients (16%) had SAEs (two considered study-drug related: right ventricular failure and asthenia)
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10 patients (16%) had hypotension (seven symptomatic)
Switching to riociguat versus maintenance therapy with phosphodiesterase-5 inhibitors in patients with pulmonary arterial hypertension (REPLACE): a multicentre, open-label, randomised controlled trial.
Defined as absence of clinical worsening plus improvements from baseline in at least two of: ≥10% or ≥30 m improvement in 6MWD, WHO FC I/II, or ≥30% reduction in NT-proBNP.
by Week 24: riociguat 41%, PDE5i 20% (OR 2.78, 95% CI: 1.53, 5.06; p = 0.0007); benefit of riociguat in patients receiving baseline PDE5i monotherapy and combination therapy
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Improvement in 6MWD from baseline: riociguat +36 m, PDE5i +14 m; mean treatment difference +23 m
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Numeric decrease in NT-proBNP with riociguat: riociguat −88 pg/mL, PDE5i +81 pg/mL (mean treatment difference: −170 pg/mL)
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Significantly more patients had improved WHO FC with riociguat than PDE5i (44% vs 23%)
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A higher proportion of patients improved to low-risk scores with riociguat than PDE5i (REVEAL, COMPERA, and FPHN)
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Clinical worsening: riociguat, one patient (1%); PDE5i, 10 patients (9%) (OR 0.10, 95% CI: 0.01, 0.73; p = 0.0047)
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Similar AE rates in riociguat (79 patients [71%]) and PDE5i (75 patients [66%]) groups
Discontinuations due to AEs: riociguat, six patients (5%); PDE5i, one patient (1%)
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Four deaths (all in PDE5i group, three due to an AE and one during follow-up period due to worsening disease)
6MWD, 6-min walk distance; AE, adverse event; CI, cardiac index; COMPERA, Comparative Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension; ERA, endothelin receptor antagonist; ERS, European Respiratory Society; ESC, European Society of Cardiology; FC, functional class; FPHN, French Pulmonary Hypertension Network; IV, intravenous; NT-proBNP, N-terminal propeptide of brain natriuretic peptide; PAH, pulmonary artery disease; PDE5i, phosphodiesterase type 5 inhibitor; PVR, pulmonary vascular resistance; RAP, right arterial pressure; REVEAL, Registry to Evaluate Early and Long-Term PAH Disease Management; SAE, serious adverse event; SvO2, mixed venous oxygen saturation; WHO, World Health Organization.
a In patients who completed the study.
b Defined as freedom from clinical worsening, WHO FC I/II, and ≥30 m improvement in 6MWD at Week 24.
c Defined as: death, atrial septostomy, lung transplantation, non-planned PAH-related hospitalization, start of new PAH treatment (ERA, inhaled or oral prostanoid) or modification of pre-existing treatment, initiation of IV or subcutaneous prostanoids, persistent decrease of >15% from baseline or > 30% from last measurement in 6MWD, persistent worsening of WHO FC, or appearance or worsening of signs/symptoms of right heart failure not responding to optimized oral diuretic therapy.
d Defined as absence of clinical worsening plus improvements from baseline in at least two of: ≥10% or ≥30 m improvement in 6MWD, WHO FC I/II, or ≥30% reduction in NT-proBNP.
Given the results of the RESPITE and REPLACE studies, switching from a PDE5i to riociguat may benefit those patients with PAH with insufficient response to therapy and at intermediate risk of 1-year mortality, including those receiving PDE5i plus ERA combination therapy, and may serve as a strategic option for treatment escalation by optimizing the NO pathway. As a result of these data, treatment guidelines now state that switching from PDE5i to riociguat may be considered in patients with PAH at intermediate-low risk of death while receiving PDE5i plus ERA combination therapy (Class IIb recommendation) [
The demonstrated benefits of switching PDE5i for riociguat in patients not at treatment goal on PDE5i-based therapy in RESPITE and REPLACE also provide a potential rationale for using upfront riociguat in combination with ERAs. However, evidence of the efficacy and safety of upfront riociguat combination therapy for patients with PAH is limited to small clinical trials and exploratory analyses of riociguat combination data from the PATENT studies in the subgroup of patients who received early combination therapy with riociguat plus ERA (after 3–6 months of ERA treatment) [
]. In these analyses, riociguat plus an ERA combination was effective in improving exercise capacity (6MWD) versus placebo (placebo-corrected: +65 m), WHO FC, and other parameters (Table 1). Additionally, a post hoc analysis of hemodynamic parameters in PATENT-1 showed that the combination of riociguat plus an ERA improved multiple hemodynamic parameters, including PVR, mean pulmonary artery pressure (mPAP), cardiac index, and mixed venous oxygen saturation [
Comparison of hemodynamic parameters in treatment-naïve and pre-treated patients with pulmonary arterial hypertension in the randomized phase III PATENT-1 study.
Comparison of hemodynamic parameters in treatment-naïve and pre-treated patients with pulmonary arterial hypertension in the randomized phase III PATENT-1 study.
]. In a post hoc analysis of both PATENT studies, long-term early combination therapy with riociguat plus ERA was well tolerated with no new safety signals; although the proportion of pretreated patients discontinuing due to AEs (13% vs 8%) or SAEs (11% vs 6%) was slightly higher than treatment-naïve patients, pretreated patients at PATENT-1 baseline tended to be sicker compared with treatment-naïve patients [
], showing promising improvements in multiple clinical and hemodynamic parameters. In the first study, upfront therapy with riociguat plus macitentan was retrospectively evaluated in 15 consecutive patients with newly diagnosed PAH at a single US center who were at intermediate or high mortality risk (Table 4) [
]. A significant improvement from baseline was observed in exercise capacity (6MWD: +32 m, p < 0.05; +13.5%, p < 0.05) after a median of 12 months' follow-up. Significant improvements from baseline were also seen in hemodynamics and WHO FC, with seven patients (47%) improving to low risk after a median of 12 months’ treatment with riociguat plus macitentan (Table 2). Additionally, there were no new safety signals compared with either drug alone, with mild drug-related side effects occurring in five patients (33%).
Table 4Summary of clinical and retrospective studies of upfront riociguat combination therapy.
PVR improvement at 4 months: −54% (absolute change of −5.8 Wood units [95% CI: −4.0, –7.5; p < 0.001]; sustained at 12 months [change of −5.9 Wood units [95% CI: −4.3, –7.5; p < 0.001])
•
Other hemodynamic variables, WHO FC, and risk scores (French invasive and REVEAL 2.0 Lite) also improved at 12 months
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Six patients (30%) discontinued riociguat, eight (40%) discontinued ambrisentan, and five (25%) discontinued both
The UPFRONT study was a prospective, open-label, single-arm study evaluating upfront riociguat plus ambrisentan therapy in 20 newly diagnosed patients with PAH who were in WHO FC III from two centers in Canada [
]. The primary endpoint, PVR at 4 months decreased from baseline by 54%, with an absolute reduction of −5.8 Wood units (p < 0.001), with the change sustained at 12 months (Table 4). Low-risk status was achieved by >40% of patients at 12 months (Table 2). While 11/20 patients (55%) were still receiving riociguat plus ambrisentan, and a further three patients (15%) were receiving riociguat with an alternative ERA, with or without selexipag, after 12 months, the discontinuation rate was high with six (30%), eight (40%), and five (25%) patients discontinuing riociguat, ambrisentan, and both drugs, respectively. In total, six patients (30%) discontinued due to AEs. It should be noted that a substantial proportion of patients had comorbidities which may have affected the tolerability of this combination in some patients. The results from these two studies suggest that macitentan may be a better tolerated combination therapy with riociguat, a supposition that needs to be confirmed in larger, randomized studies.
Outside of clinical trials, real-world data on riociguat were provided by the EXPERT study, a prospective, international, non-interventional study following patients receiving riociguat for up to 4 years [
]. The results showed that the safety and tolerability of riociguat as combination therapy (mostly riociguat plus an ERA) in patients with PAH was broadly similar to that of monotherapy, although the overall incidence of AEs was slightly higher in patients receiving combination therapy (67–74%) compared with riociguat monotherapy (61%). Separate evaluation of patients who had started riociguat in the previous 3 months and those who had already been receiving riociguat for ≥3 months at the time of study entry showed the overall incidence of AEs was higher with combination therapy compared with monotherapy. The RiOciguAt UseR (ROAR) registry was established to generate additional real-world data on the safety and effectiveness of riociguat treatment in PAH, including upfront two- and three-drug combination regimens [
]. The registry aims to enroll 500 patients with PAH in the USA, with interim analyses scheduled when 6, 12, and 24-month data are available for 100 and 250 patients.
Overall, these data provide evidence that upfront riociguat plus ERA combination therapy is an attractive and efficacious treatment option. These smaller studies point toward efficacy of this combination along with some tolerability concerns which need to be validated in a randomized, controlled trial setting. There is currently a lack of data on riociguat dual combination therapy with PCAs or prostacyclin receptor antagonists [
Real-world experience using combination therapy with riociguat and risk assessment using REVEAL Lite 2.0 in patients with pulmonary arterial hypertension.
]. Prospective studies are necessary to determine when and how such combinations could be used. However, other dual riociguat combination approaches are being investigated, including a study evaluating the combination of treprostinil and riociguat on right ventriculo-vascular coupling and morphology in advanced PAH (ClinicalTrials.gov identifier NCT04062565).
For patients at higher risk in WHO FC III/IV with severe hemodynamic impairment, it has been suggested that targeting all three pathways underlying PAH with upfront triple combination therapy may be of benefit [
]. Indeed, a retrospective analysis of 1611 patients with PAH enrolled in the French Pulmonary Hypertension Registry showed that 5-year survival was higher with triple therapy compared with mono- or dual therapy [
]. Although data for upfront riociguat triple combinations are scarce, riociguat, macitentan, plus selexipag was evaluated in a retrospective single-center study that included data from 26 patients, of whom almost two-thirds (n = 17) were treatment naïve [
]. In a subanalysis of 11 patients from this study, mPAP, PVR, and cardiac output improved from baseline to follow-up by 29%, 66%, and 90%, respectively, over a median observation period of 293 days. Additionally, WHO FC, 6MWD, and brain natriuretic protein concentrations also improved and one patient (9%) each discontinued macitentan and riociguat. However, these effects need to be confirmed in prospective, randomized trials.
5. Expert opinion and clinical experience
Clinicians rely on treatment guidelines in conjunction with individual patient characteristics and their own clinical experience to guide initial treatment selection and escalations of therapy for patients with PAH in clinical practice. Current ESC/ERS guidelines recommend upfront PDE5i plus ERA combination therapy for most patients. Failure to achieve low-risk status should prompt escalation of therapy. As previously mentioned, in patients at intermediate-low risk of death while receiving PDE5i plus ERA combination therapy, switching from PDE5i to riociguat may also be considered [
], as discussed further below. Patient-centered factors, such as adherence, tolerability, history with other medications, and patient preference, should be taken into account when considering addition of a new drug or a treatment switch [
Delphi consensus recommendation for optimization of pulmonary hypertension therapy focusing on switching from a phosphodiesterase 5 inhibitor to riociguat.
]. For example, PDE5i and riociguat are contraindicated in patients who are treated with nitrates to relieve angina symptoms, while bosentan is contraindicated in combination with glyburide, which is used to lower blood glucose levels in patients with type 2 diabetes [
In alignment with treatment guidelines, in our practices, we no longer use initial monotherapy outside of specific patient groups, and oral dual combination therapy is our standard initial approach for patients at low to intermediate risk. In general, we escalate to triple therapy after several months in patients who are at higher risk, are progressing or not reaching treatment goals, or have progressed to WHO FC IV [
Delphi consensus recommendation for optimization of pulmonary hypertension therapy focusing on switching from a phosphodiesterase 5 inhibitor to riociguat.
The choice of specific upfront combination therapy is dependent on individual patient characteristics and preferences. Evidence from a small study suggests that upfront riociguat plus the ERA macitentan may provide evidence of effectiveness and feasibility for patients at intermediate risk, and provide another treatment option in this setting [
Delphi consensus recommendation for optimization of pulmonary hypertension therapy focusing on switching from a phosphodiesterase 5 inhibitor to riociguat.
]. Current ESC/ERS guidelines highlight that switching from PDE5i/ERA combination therapy to riociguat/ERA combination therapy may be considered as an alternative to adding a PCA in those at intermediate-low risk to reduce the risk of clinical worsening [
]. This is based on data from the RESPITE and REPLACE studies, which included large proportions of patients receiving PDE5i plus ERA combination therapy, demonstrating that in patients who are not meeting treatment goals, switching from a PDE5i to riociguat may provide clinical benefit without needing to add a third therapy [
Switching to riociguat versus maintenance therapy with phosphodiesterase-5 inhibitors in patients with pulmonary arterial hypertension (REPLACE): a multicentre, open-label, randomised controlled trial.
]. A recent Delphi consensus recommendation for optimizing PAH therapy was developed with input from 20 physicians with expertise in PAH drawn from large academic centers in the USA [
Delphi consensus recommendation for optimization of pulmonary hypertension therapy focusing on switching from a phosphodiesterase 5 inhibitor to riociguat.
]. The results of the process indicated that while multiple factors are involved in treatment regimen selection, the most important for clinicians were severity of disease and risk profile, clinical evidence of efficacy and safety, and the physician's clinical experience. Switching from PDE5i to riociguat also reached consensus in the recent Delphi consensus publication relating to a clinical scenario in which a patient on dual combination therapy who had previously been stable had progressed from low risk to an increased risk level [
Delphi consensus recommendation for optimization of pulmonary hypertension therapy focusing on switching from a phosphodiesterase 5 inhibitor to riociguat.
]. In this scenario, it was agreed that switching from PDE5i-based to riociguat-based dual combination therapy could be considered in patients who did not achieve significant benefit from a PDE5i and were at low-intermediate risk, and/or in patients experiencing limiting side effects (e.g. ocular side effects) from PDE5i treatment, or to improve adherence if it was contributing to a lack of efficacy [
Delphi consensus recommendation for optimization of pulmonary hypertension therapy focusing on switching from a phosphodiesterase 5 inhibitor to riociguat.
]. Switching may also be considered in patients with low-to-moderate risk who have not improved at 3–4 months, and those who are unwilling, or who are poor candidates, to start a new class of medication.
While switching from a PDE5i to riociguat is an alternative to adding a PCA for patients at intermediate-low risk, the ESC/ERS guidelines also state that for patients who are intermediate-high or high risk while receiving oral therapies, where the addition of intravenously or subcutaneously administered prostacyclin analogs is unfeasible, switching from a PDE5i to riociguat may be considered [
]. In the Delphi consensus, adding a new agent to initiate triple therapy was recommended in high-risk patients and those receiving dual combination therapy with progressive disease or who are not reaching their treatment goals [
Delphi consensus recommendation for optimization of pulmonary hypertension therapy focusing on switching from a phosphodiesterase 5 inhibitor to riociguat.
]. To date there are only limited data on combinations of riociguat with PCAs, and in the REPLACE study, patients who had received PCAs or prostacyclin receptor antagonists within the previous 30 days were excluded [
Switching to riociguat versus maintenance therapy with phosphodiesterase-5 inhibitors in patients with pulmonary arterial hypertension (REPLACE): a multicentre, open-label, randomised controlled trial.
The current guidelines, recommending switching from PDE5i plus ERA dual therapy to a riociguat plus ERA combination are reflective of the frequent use of PDE5i plus ERA combinations in clinical practice [
]. For sildenafil, treatment must be discontinued ≥24 h before administration of riociguat, while tadalafil must be discontinued ≥48 h before administration of riociguat. It is also recommended that patients be monitored for signs and symptoms of hypotension after switching, while patients at known risk of hypotension may benefit from initiating riociguat titration at a lower dose [
Although RESPITE and REPLACE did not evaluate switching from a PDE5i to riociguat in patients receiving triple combination therapy who required treatment escalation, the Delphi consensus publication provided some insight in this setting [
Delphi consensus recommendation for optimization of pulmonary hypertension therapy focusing on switching from a phosphodiesterase 5 inhibitor to riociguat.
]. The Delphi study considered scenarios where escalation was needed in patients receiving triple oral therapy. In this population, switching from a PDE5i to riociguat was considered for those not at goal and at low to moderate risk. Similarly, for therapy involving subcutaneous or intravenous prostacyclins, in addition to maximizing the prostacyclin use and dosage, switching from a PDE5i to riociguat was also considered. The potential clinical role of switching to riociguat from a PDE5i in patients receiving triple combination therapy should be investigated in clinical trials.
6. Conclusions
Upfront combination therapy is now the standard of care for patients with PAH. Based on the current evidence, the combination of riociguat plus an ERA is an attractive option to improve patients’ risk status. For patients who are not at their treatment goal and/or remain at intermediate risk with PDE5i-based dual combination therapy, treatment guidelines recommend that switching from PDE5i to riociguat may be considered as an alternative to adding a third agent. Further investigation evaluating additional riociguat-based dual or triple combinations for upfront and switching therapies, such as the ROAR registry, will provide valuable evidence to further aid clinical decision-making.
Funding
Development of the manuscript was funded by Bayer HealthCare Pharmaceuticals, Inc., Whippany, New Jersey, USA.
Author contributions
F.F.R., M.G.T., and S.S. were involved in the conceptualization, methodology, review and editing of the manuscript.
Declaration of competing interest
The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: F.F.R. reports grants or contracts from Bayer, Janssen PH, and Acceleron; consulting fees from United Therapeutics, Janssen PH, Bayer, and Acceleron; payments or honoraria from United Therapeutics, Janssen PH, and Bayer. The author is Principal Investigator on trials by Janssen PH, Merck, and Gossamer Bio. M.G.T. is the recipient of the Bayer PAH Accelerated Award; has participated in Advisory Boards for United Therapeutics and Bayer; and is the Principal Investigator on trials by Janssen-PH, Bayer, United Therapeutic, and Bellerophon Therapeutics. S.S. reports serving on the speaker panel for Actelion pharmaceuticals, Bayer, and United Therapeutics; and has received honoraria from these entities for consultancy and speaking engagements. Member of a data safety and monitoring board for an industry-sponsored FDA-approved study. The author is Principal Investigator or Sub Investigator on multiple clinical trials sponsored by Actelion and United Therapeutics.
Acknowledgment
Medical writing services were provided by Kristen Brown, PhD, of Adelphi Communications Ltd, Macclesfield, UK and funded by Bayer HealthCare Pharmaceuticals, Inc. (Whippany, NJ, USA), in accordance with Good Publication Practice (GPP4) guidelines.
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