Abstract
Pulmonary arterial hypertension is a chronic, progressive disease of the pulmonary vasculature resulting in poor outcomes if left untreated. The management of group 1 pulmonary arterial hypertension has included the use of prostanoids, phosphodiesterase-5 inhibitors, and endothelin receptor antagonists targeting the prostacyclin, endothelin-1, and nitric oxide pathways. Three new medications have been approved by the US Food and Drug Administration over the past couple of years. Macitentan is the newest endothelin receptor antagonist, riociguat is a soluble guanylate cyclase stimulator, and treprostinil diolamine is the first oral prostanoid. This review will focus on the key trials leading to their approval, special considerations for each medication, and their potential place in therapy. The use of combination therapy as initial therapy in pulmonary arterial hypertension will also be discussed.
Introduction
Pulmonary arterial hypertension (PAH) is a chronic debilitating disease of the pulmonary vasculature which results in poor outcomes, such as right ventricular failure and death, without medical management [Voelkel et al. 2006]. For many years there have been only a handful of medications used in the treatment of PAH. The calcium channel blockers are utilized in patients with acute vasoreactivity and have shown benefits in survival, although not US Food and Drug Administration (FDA) approved for this indication [Rich et al. 1987, 1992; Woodmansey et al. 1996; Sitbon et al. 2005; Taichman et al. 2014]. Oxygen, diuretics, warfarin, and digoxin are adjuvant therapies [Badesch et al. 2004, 2007; McLaughlin et al. 2009]. For several years the only FDA-approved agents for the medical management of PAH included the prostacyclin analogues or prostanoids, phosphodiesterase 5 (PDE-5) inhibitors, and endothelin receptor antagonists (ERAs). These medications target prostacyclin, endothelin (ET)-1, and nitric oxide (NO) pathways which have been identified in the pathogenesis of PAH [Humbert et al. 2004]. Prostacyclins promote vasodilation via cyclic adenosine monophosphate and also have both antiproliferative and anticoagulative benefit. ET-1 is a potent vasoconstrictor that is both produced and secreted by vascular endothelium; therefore, blockade of the endothelin surface receptors on vascular smooth muscle reverses vasoconstriction. These medications have been shown to improve survival, symptoms, and quality of life [Savarese et al. 2013]. Many of these medications have complex administration regimens and considerations, along with significant adverse effects and monitoring requirements.
The most recent CHEST guidelines recommend that for treatment-naïve patients with World Health Organization (WHO) functional class (FC) II and III symptoms, monotherapy is recommended with an ERA, PDE-5, or soluble guanylate cyclase stimulator (sGC) [Taichman et al. 2014]. For WHO FC IV treatment-naïve patients, monotherapy with a parenteral prostanoid is recommended [Taichman et al. 2014].
Several new medications, some with novel mechanisms, have been developed and have recently come to market. The new medications that will be discussed in this review include macitentan, riociguat, and oral treprostinil (Table 1). Key trials that led to FDA approval, important considerations for each medication, and their potential place in therapy will be discussed (Table 2). Additionally, the results from studies using upfront combination therapy will be reviewed.
Newly approved PAH medications.
ERA, endothelin receptor antagonist; PAH, pulmonary arterial hypertension; sGC, soluble guanylate cyclase.
Recent PAH trials.
6MWD, 6 min walk distance; AE, adverse events; AMBITION, A Study of First-Line Ambrisentan and Tadalafil Combination Therapy in Subjects with Pulmonary Arterial Hypertension; CHEST-1, 2, CTEPH sGC Trial 1, 2; COMPASS-2, Effects of Combination of Bosentan and Sildenafil versus Sildenafil Monotherapy on Morbidity and Mortality in Symptomatic Patients with Pulmonary Arterial Hypertension; FC, functional class; mITT, modified intention to treat; NT-proBNP, N-terminal pro brain natriuretic peptide; PVR, pulmonary vascular resistance; PATENT-1, 2, Pulmonary Arterial Hypertension sGC-Stimulator Trial 1, 2; QOL, quality of life; SAE, serious adverse event; SERAPHIN, Study with an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcome; WHO, World Health Organization.
Macitentan
Macitentan is the newest ERA which was developed with enhanced tissue penetration as ET-1 is 80% paracrine along with enhanced affinity for ET receptors and the longest duration of blockade [Iglarz et al. 2008].
The Study with an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcome (SERAPHIN) was a multicenter, double-blind, placebo-controlled, randomized long-term efficacy trial completed involving patients with WHO FC II, III, or IV treated with macitentan alone or in combination therapy with PDE-5 inhibitors or oral/inhaled prostanoids. SERAPHIN was the first event-driven study which evaluated morbidity and mortality in patients with PAH. Inclusion criteria were patients with PAH 12 years and older with right heart catheter confirmation, a minimum 6 min walk distance (6MWD) of 50 m, and WHO FC II, III, or IV. Patients were allowed to be on stable doses of concomitant therapy (PDE-5 inhibitors, oral or inhaled prostanoids, calcium channel blockers, or L-arginine) for 3 months prior to randomization. Background therapy with another ERA or infusion prostanoid was an exclusion criterion at enrollment. A total of 742 patients with group 1 PAH, divided into three groups of approximately 250 patients each, received either macitentan 3 mg daily, 10 mg daily, or placebo for an average of 2 years. Two-thirds of all patients (66.8%) were receiving a PDE-5 inhibitor (61.4%) or oral or inhaled prostanoid (5.4%) for a minimum of 3 months before inclusion. Laboratory data, WHO FC, and 6MWD were performed at screening/randomization, months 3 and 6, then every 6 months to the end of treatment. The composite primary endpoint of this trial was time to first PAH-related event, including worsening of PAH, infusion prostanoid initiation, lung transplantation, atrial septostomy, or death. Secondary endpoints included the change in 6MWD from baseline to month 6, the percentage of patients with an improvement in WHO FC at month 6, death due to PAH or hospitalization for PAH up to the end of treatment, and death from any cause up to the end of treatment and up to the end of the study. Follow-up hemodynamics were measured in a subgroup. It was found that macitentan was effective in delaying disease progression and significantly reduced morbidity and mortality [Pulido et al. 2013]. Macitentan was shown to delay disease progression, including death, initiation of infusion prostanoid therapy, or clinical worsening (decreased 6MWD, worsened PAH symptoms, and need for additional PAH treatment), and decrease hospitalizations [Pulido et al. 2013]. Interestingly, the impact on 6MWD was modest at best. The authors concluded that differences in the rates of PAH worsening were the main driving force for treatment effect of the primary endpoint [Pulido et al. 2013]. The composite secondary outcome of PAH-related death or hospitalization was driven by lower rates of hospitalization in the macitentan groups compared with the placebo group [Pulido et al. 2013]. The SERAPHIN trial was one of the first to demonstrate reductions in a hard endpoint such as hospitalization. In addition, the clinical events were adjudicated. The burden of hospitalization in group 1 PAH is substantial; therefore, therapy that reduces PAH-related hospitalization may potentially improve survival [Burger et al. 2014].
A dose-ranging study was completed and determined that maximum effects occurred at 10 mg [Sidharta et al. 2013]. Peak plasma concentration occurs approximately 8 h after administration with a plasma half life of approximately 16 h [Sidharta et al. 2013]. Macitentan is metabolized into an active metabolite, ACT-132577, which has a half life of approximately 48 h [Iglarz et al. 2008; Sidharta et al. 2013]. The FDA-approved dose is 10 mg daily for patients with PAH WHO group 1 to delay disease progression.
Common side effects of macitentan in SERAPHIN include the following in descending order of frequency: anemia (placebo-subtracted rate 10%), nasopharyngitis, bronchitis, headache, influenza, and urinary tract infection [Pulido et al. 2013]. Class effect of ERA adverse events include nasal congestion, flushing, abnormal hepatic function, anemia, peripheral edema, and teratogenicity (requiring dual contraceptive methods). Macitentan does not interact with the bile salt export pump or organic anion transport protein, both of which are thought to be involved in the hepatotoxicity observed with bosentan [Sidharta et al. 2013]. Mandatory routine monitoring of liver function tests in patients taking macitentan is not required as is the case with bosentan. Liver function tests should be ordered at baseline then as clinically indicated. Daily weights should be monitored since fluid retention is relatively common (approximately 15–20%) with ERA therapy. The ERAs are pregnancy category X; therefore, a black box warning exists regarding harm to a developing fetus. Women are required to be enrolled with the Opsumit Risk Evaluation and Mitigation Strategy (REMS) and be counseled regarding the importance of highly reliable contraception to obtain the medication. It is recommended that concomitant use of strong cytochrome P450 3A4 (CYP3A4) inducers or inhibitors is avoided since macitentan is metabolized by the CYP3A4 pathway.
The Fifth World Symposium on Pulmonary Hypertension (5th WSPH) and CHEST guidelines provide similar recommendations concerning when to use macitentan [Galie et al. 2013; Taichman et al. 2014]. The 5th WSPH updated treatment algorithm recommends macitentan for patients with WHO FC II/II (class I recommendation) and WHO FC IV (class IIa recommendation) [Galie et al. 2013]. The CHEST guidelines recommend the use of ERAs for patients with WHO FC II/III/IV [Taichman et al. 2014]. Specifically for WHO FC II, macitentan delays time to clinical worsening (grade CB, i.e. consensus based) and for WHO FC III, macitentan improves WHO FC (grade CB) and delays the time to clinical worsening (grade CB). For patients with WHO FC IV who are treatment naïve and are unable or do not desire to manage parenteral prostanoid therapy, inhaled prostanoid in combination with an ERA is recommended. In patients with PAH who remain symptomatic on stable doses of a PDE-5 inhibitor or an inhaled prostanoid, macitentan is recommended to improve 6MWD (grade CB), WHO FC (grade CB) and to delay the time to clinical worsening (Grade CB).
Riociguat
Riociguat is a sGC stimulator that produces vasodilation. The mechanism of action includes sensitizing sGC to endogenous NO by stabilizing NO-sGC binding, thereby acting in synergy with NO. The theoretical advantage over PDE-5 inhibition is that the direct stimulation of sGC occurs independently of NO availability [Grimminger et al. 2009; Stasch et al. 2011]. Riociguat is the first sGC stimulator approved by the FDA (October 2013) to treat adults with PAH and group 4 chronic thromboembolic pulmonary hypertension (CTEPH). The latter indication is the first medication approved for group 4 CTEPH but it is important to note that the primary treatment for CTEPH is surgical, that is, a pulmonary thromboendarterectomy. The FDA-approved use in CTEPH is specific to inoperable disease or patients with persistent or recurrent CTEPH despite thromboendarterectomy.
The Pulmonary Arterial Hypertension sGC-Stimulator Trial 1 (PATENT-1) was a multicenter, randomized, placebo-controlled trial evaluating the safety and effectiveness of riociguat to treat group 1 PAH. The study involved 443 participants who were treatment naïve (50% of patients) or those already receiving treatment with ERAs (44% of patients, primarily bosentan) or nonintravenous prostanoids (6% of patients, primarily inhaled iloprost) who were randomly assigned to take either riociguat or placebo. Three cohorts were compared: placebo (126 patients), riociguat at individually adjusted doses up to 2.5 mg three times daily (254 patients), and riociguat at individually adjusted doses with a maximum dose of 1.5 mg three times daily (63 patients). After 12 weeks of treatment, riociguat-treated patients showed improvement in 6MWD by an average of 36 m more compared with the placebo group [Ghofrani et al. 2013b]. Riociguat was also shown to reduce the secondary endpoints of pulmonary vascular resistance (PVR), brain natriuretic peptide (NT-proBNP) levels, WHO FC, Borg dyspnea score, and clinical worsening [Ghofrani et al. 2013b].
The CTEPH sGC Trial 1 (CHEST-1) was a multicenter, randomized, double-blind, placebo-controlled trial involving 261 patients with inoperable group 4 CTEPH or persistent or recurrent pulmonary hypertension after pulmonary thromboendarterectomy. Notable inclusion criteria were a 6MWD of 150–450 m, PVR greater than 300 dyn s cm−5, and a mean pulmonary artery pressure of at least 25 mm Hg. Patients receiving an ERA, prostanoid, PDE-5 inhibitor, or NO donor within 3 months before study initiation were excluded. The patients were assigned to receive either riociguat (173 patients received riociguat 0.5–2.5 mg three times daily) or placebo (88 patients). Three-quarters (77%) of the patients in the riociguat group were taking the maximal dose at the end of 16 weeks. At the end of the 4-month study, riociguat-treated patients had a 39 m mean increase in 6MWD compared with the placebo group whose 6MWD decreased by 6 m. Riociguat-treated patients also had improvements in the secondary endpoints of NT-proBNP level and WHO FC [Ghofrani et al. 2013a].
PATENT-2 is a long-term extension trial which included 396 patients (98%) from PATENT-1. At 1 year, mean 6MWD increased by 51 ± 74 m compared with the PATENT-1 study baseline. Additionally, 94% of patients had an improved or stable WHO FC and 97% survival at 1 year [Rubin et al. 2015]. At 2 years, mean 6MWD increased by 47 m compared with the PATENT-1 study baseline and 91% of patients had an improved or stable WHO FC and 93% survival at 2 years [Rubin et al. 2014].
Two-year data from the CHEST-2 study involving 237 (98%) patients completing CHEST-1 also found an increase in 6MWD in the riociguat group by 50 m compared with baseline, improved or stable on WHO FC in 97% of CTEPH patients, and 93% survival in the riociguat group [Simonneau et al. 2014].
Peak plasma concentrations occur 1.5 h post administration with a half life of approximately 12 h in patients with PAH. Bioavailability is approximately 94%, but reduced with concomitant use of antacids (must separate by at least 1 h). Doses greater than 2.5 mg three times a day may be required in patients who smoke and subsequent dose reductions may be required when patients stop smoking. Omeprazole does not seem to reduce bioavailability. Metabolism is via hepatic cytochromes with both urinary and fecal excretion. The most serious adverse effect of riociguat is systemic hypotension. If the systemic blood pressure drops on treatment then the dose must be reduced by 0.5 mg. In addition, concomitant use of PDE-5 inhibitors and nitrates are prohibited due to the risk of hypotension. Other common side effects of riociguat in descending order of frequency include headache, dizziness, dyspepsia, peripheral edema, nausea, diarrhea, and vomiting [Ghofrani et al. 2013ab]. Due to riociguat’s teratogenic effects (category X), all female patients must be enrolled in the Adempas REMS program, comply with pregnancy testing requirements, and be counseled regarding the importance of highly reliable contraception in order to receive the medication.
The FDA-approved dose of riociguat is 2.5 mg three times daily in adult patients with PAH (WHO group 1) to improve exercise capacity, improve WHO FC and to delay clinical worsening. The 5th WSPH updated treatment algorithm recommends riociguat for patients with WHO FC II/III (class I recommendation) and for WHO FC IV (class IIa recommendation) [Galie et al. 2013]. The CHEST guidelines recommend the use of riociguat for patients with WHO FC II/III/IV. Specifically for WHO FC II/III, riociguat is recommended to improve 6MWD (grade CB), improve WHO FC (grade CB), delay the time to clinical worsening (grade CB), and improve cardiopulmonary hemodynamics. For patients with WHO FC III/IV PAH with unacceptable clinical status despite established PAH-specific monotherapy, riociguat can be added to stable doses of bosentan, ambrisentan, or an inhaled prostanoid to improve 6MWD (grade CB), WHO FC (grade CB), and cardiopulmonary hemodynamics, and to delay the time to clinical worsening (grade CB) [Taichman et al. 2014].
Riociguat is the first PAH-specific medication to be approved for WHO group 4 CTEPH. As previously noted, it is imperative to limit the use to the approved indications within this group 4 spectrum as patients eligible for pulmonary thromboendarterectomy should be referred to specialty centers for surgical treatment. Specifically, riociguat is FDA approved for patients with inoperable disease or that which is persistent or recurrent after pulmonary thromboendarterectomy to improve exercise capacity and WHO FC.
Oral treprostinil
Parenteral and inhaled formulations of prostanoids are effective for the management of PAH, but require many special administration considerations and are complicated for patients to manage.
Treprostinil diolamine is the first FDA-approved oral prostanoid. All of the prostanoids previously approved were for either inhaled or continuous infusion administration; therefore, oral treprostinil offers a heretofore unavailable option for patients with PAH. The mechanism of action is class specific to the prostanoids and includes vasodilation of the pulmonary and systemic arterial vascular beds, inhibition of platelet aggregation, and suppression of smooth muscle cell proliferation.
A multicenter, double-blind, placebo-controlled trial called FREEDOM-C was completed to determine the safety and efficacy of oral treprostinil for the treatment of PAH [Tapson et al. 2012]. The study included 350 patients who were stable on an ERA (30%), PDE-5 inhibitor (25%), or both (45%). Patients in the oral treprostinil arm received 1 mg twice daily initially with subsequent dose increases in 1 mg increments. Patients for whom all doses were available received oral treprostinil 0.5 mg twice daily with dose increases of 0.5 mg every 3 days to a maximum of 16 mg twice daily over the 16 weeks based on side effects and symptoms. At 16 weeks, the median difference in 6MWD from baseline in the oral treprostinil group was 11 m compared with 4.8 m in the placebo group which was not statistically significant. However, there were statistically significant differences in dyspnea fatigue index score and combined 6MWD and Borg dyspnea score when comparing oral treprostinil with placebo. The authors observed a statistically significant difference at week 12, but it was not a prespecified time endpoint. They also concluded that one factor which may have led to the nonsignificant results at week 16 was the rate of therapy discontinuation (14%) due to adverse effects at the higher doses of oral treprostinil [Tapson et al. 2012]
The FREEDOM-M study was a randomized, placebo-controlled trial that evaluated the safety and efficacy of oral treprostinil as initial monotherapy treatment for PAH in 349 patients [Jing et al. 2013]. Patients were excluded if they received an ERA, PDE-5 inhibitor, or prostacyclin therapy within 30 days of study inclusion or if they had evidence of significant left-sided heart disease or parenchymal disease. A total of 233 patients were in the oral treprostinil intention to treat (ITT) group and 116 in the placebo group. At the beginning of the study, randomized patients received oral treprostinil 1 mg twice daily. Once the FREEDOM-C results were published, the protocol was modified to dose escalations that would improve tolerance. The initial dose was lowered to 0.5 mg twice daily and later the starting dose was further decreased to 0.25 mg twice daily. Doses were subsequently increased by 0.25–0.5 mg twice daily every 3 days to a maximum dose of 12 mg twice daily. The modified ITT (mITT) group included 228 patients randomized to receive 0.25 mg twice daily. In the mITT group, there was a 23 m statistically significant difference between the treatment and placebo groups. In addition, there was a significant improvement in the combined 6MWD/Borg dyspnea score at week 12. There were no significant differences in Borg dyspnea index, clinical worsening, and symptoms of PAH. [Jing et al. 2013]
A multicenter, double-blind, placebo-controlled study called FREEDOM-C2 was completed to compare oral treprostinil with placebo when used with background therapy [Tapson et al. 2013]. This study was very similar to the FREEDOM-C trial, but used lower doses of oral treprostinil to improve tolerance. A total of 310 patients were stratified based on their background therapy of either an ERA (17%), PDE-5 inhibitor (43%), or both (40%) and were on the background medication for at least 90 days with a stable dose of these medications 30 days prior to baseline and throughout the study. The oral treprostinil group included 157 patients who received 0.25 mg twice daily with a dose increase of 0.25–0.5 mg every 3 days if clinically indicated versus 153 in the placebo group. All primary (6MWD) and secondary endpoints (WHO FC, Borg dyspnea score, dyspnea fatigue index, signs and symptoms of PAH, and clinical worsening) were not statistically significant. The most common adverse effects in the oral treprostinil group included headache, diarrhea, nausea, flushing, and jaw pain [Tapson et al. 2013].
Oral treprostinil is FDA approved for the treatment of PAH (WHO group 1) to improve exercise capacity beginning with 0.25 mg twice daily or 0.125 mg three times daily and titrating by 0.25 or 0.5 mg twice daily or 0.125 mg three times daily, not more than every 3–4 days as tolerated with a maximum dose based on tolerability. Peak plasma concentrations occur in 4–6 h after oral administration [White et al. 2013]. Abrupt discontinuation of the medication should be avoided. If a planned short-term discontinuation occurs, then the patient should be converted to subcutaneous or intravenous equivalent prostanoid. The parenteral dose would be one-fifth of the total daily dose of oral treprostinil. The dose of oral treprostinil should be reduced by 0.5–1 mg per day when discontinuing the medication.
The most common adverse effects in descending order of frequency as reported in the package insert are headache, nausea, diarrhea, flushing, jaw pain, extremity pain, hypokalemia, and abdominal discomfort. The current guidelines and recommendations for the 5th WSPH and the CHEST guidelines do not address the role of oral treprostinil. Results from the FREEDOM-M trial suggest oral treprostinil can be used as initial monotherapy for patients with class II or III symptoms [Jing et al. 2013]
Combination therapy
As described above, the SERAPHIN trial was the first long-term trial involving PAH and found that macitentan in combination with background therapy with a PDE-5 inhibitor or prostanoid resulted in positive outcomes. PATENT-1 involving riociguat included 50% of patients with background therapy with ERA or nonintravenous prostanoid. The PAH guidelines have generally suggested a stepwise approach to adding medications to the PAH treatment regimen. Additional data have been forthcoming since the publication of the current guidelines. One pilot study of triple therapy and also the results from two large, prospective combination trials have been released and presented at national society meetings.
The pilot study was conducted to assess the efficacy and safety of a triple combination therapy regimen in adult patients with newly diagnosed severe PAH FC III/IV. Upfront triple combination therapy included intravenous epoprostenol, bosentan, and sildenafil. Data were collected retrospectively from a prospective registry. A total of 19 patients were included in the study, after 4 months of triple therapy and at final evaluation (approximately 32 months), 18 patients had significant improvements in 6MWD and hemodynamics. After a mean follow up of 41 months, all patients on the triple combination regimen were still alive [Sitbon et al. 2014].
Two large combination studies were recently concluded but differed in study design, one with sequentially added therapy and one involved frontline combination treatment. The former was entitled ‘Effects of Combination of Bosentan and Sildenafil versus Sildenafil Monotherapy on Morbidity and Mortality in symptomatic Patients with Pulmonary arterial Hypertension’ or COMPASS-2. The trial was a prospective, randomized, double-blind, placebo-controlled, event-driven study to evaluate the time to first morbidity or mortality event when adding bosentan to patients with symptomatic PAH already receiving sildenafil. Patients were on a stable dose of sildenafil of at least 20 mg three times daily for at least 12 weeks and were randomized to receive bosentan 125 mg twice daily or placebo. It was one of the first trials to evaluate morbidity and mortality rather than relying on 6MWD as the primary endpoint. Results did not demonstrate a mortality risk reduction with the addition of bosentan compared with placebo, perhaps due to the length of the trial required to capture sufficient clinical events and a high subject withdrawal rate. In an exploratory analysis, the addition of bosentan to sildenafil showed an improvement of 21.8 m in 6MWD at week 16. Over a median 2-year double-blind treatment exposure to either placebo or bosentan added to sildenafil, the observed rate of elevated hepatic transaminases more than three times the upper limit of normal was 6% and 22% respectively [McLaughlin et al. 2014]. More definitive conclusions should be reserved until such time that the results of the COMPASS-2 trial are published in peer-reviewed format.
The frontline combination trial was entitled ‘A Study of First-Line Ambrisentan and Tadalafil Combination Therapy in Subjects with Pulmonary Arterial Hypertension’ or AMBITION. It was a randomized, double-blind study to compare the safety and efficacy of ambrisentan and tadalafil use in combination versus monotherapy as first-line agents. The study involved 500 patients with WHO FC II and III PAH who were randomized to receive the combination of ambrisentan and tadalafil (n = 253) or monotherapy with ambrisentan (n = 126) or tadalafil (n = 121) (titrated from 5 to 10 mg once daily and from 20 to 40 mg once daily for ambrisentan and tadalafil respectively). The treatment effect observed with the primary endpoint was mainly driven by a reduction in hospitalizations. Significant outcomes include time to first hospitalizations, change from baseline of NT-proBNP, percentage of patients with satisfactory clinical response at 24 weeks, and median change from baseline to week 24 in 6MWD. The clinical benefit of frontline combination therapy was observed regardless of age and irrespective of WHO FC. Both safety and tolerability profiles seem acceptable [Galie, 2014].
The results from the SERAPHIN, PATENT-1, and AMBITION studies suggest that combination therapy may be a reasonable consideration for initial or early treatment of patients with WHO group 1 PAH FC III. Current guidelines recommend a stepwise approach in the management of PAH. Since the most recent guidelines were published prior to the publication of many of the above studies, it is expected that the guidelines will require modification to address the availability of the newer agents as well as recommendations on the use of initial combination therapy for patients with FC III.
Footnotes
Funding
The authors received no funding from writing this manuscript.
Conflict of interest statement
The authors declare no conflict related to writing this article.