2014 肺动脉高压治疗流程-中国英文版

INITIALTHERAPYWITHPAHAPPROVEDDRUGS

YELLoW:Morbidity andmortality asprimary end-point inrandomized controlledstudy orreduction in all causemortality(prospectivelydefined) \*LevelofevidenceisbasedontheWHO-FCofthemajorityofthepatientsofthestudies. +Approved only: by the FDA (macitentan, riociguat, treprostinil inhaled); in New Zealand (iloprost i.v); in JapanandS.Korea(beraprost). +PositiveopinionforapprovaloftheCHMPofEMA

|Recommendation|Evidence*|WHO-FC|WHO-FC|WHO-FC| |---|---|---|---|---| ||AorB| Ambrisentan Bosentan Macitentan++ Riociguatt Sildenafil Tadalafil | Ambrisentan Bosentan Epoprostenol i.v. lloprostinhaled Macitentan++ Riociguatt Sildenafil Tadalafil Treprostinil s.c.,inhaled+ |Epoprostenol i.v.| |ma||| loprosti.v.t Treprostinil i.v. | Ambrisentan,Bosentan lloprost inhaled and i.vt Macitentan++ Riociguat+ SildenafilTadalafil Treprostinil s.c., i.v., Inhaled | ||||Beraprostt|| ||||Initial CombinationTherapy|Initial Combination Therapy| | CONSIDERELIGIBILTY INADEQUATECLINICAL FORLUNG RESPONSE TRANSPLANTATION Sequential combination therapy (I-A) ERAS INADEQUATECLINICAL Referral for RESPONSE LUNG TRANSPLANTATION on MAXIMAL THERAPY Prostanoids PDE-5ior (I-C) SGCS BAS (lla-C) |||||

Figure 1 Evidence-Based Treatment Algorithm

APAH ¼ associated pulmonary arterial hypertension; BAS ¼ balloon atrial septostomy; CCB ¼ calcium channel blockers; ERA $=$ endothelin receptor antagonist; sGCS ¼ soluble guanylate cyclase stimulators; IPAH $=$ idiopathic pulmonary arterial hypertension; i.v. $=$ intravenous; PDE-5i $=$ phosphodiesterase type-5 inhibitor; s.c. $=$ subcutaneous; WHO-FC ¼ World Health Organization functional class.

in 2 large RCTs (ARIES [Ambrisentan in pulmonary arterial hypertension, Randomized, double-blind, placebocontrolled, multicentre, Ef fi cacy Study]-1 and -2), which have demonstrated ef fi cacy on symptoms, exercise capacity,

hemodynamics, and time to clinical worsening of patients with idiopathic PAH and PAH associated with connective tissue disease and human immunode fi ciency virus infection (24) . Ambrisentan has been approved for the treatment of

|Table 3||||||| |---|---|---|---|---|---|---| |Drug(s) Tested|Study|Background|Primary Endpoint|Outcome(SecondaryEndpoint)|Duration (weeks)|No.of Patients| |Ambrisentan|ARIES-1|¥20|6MWD|TTCW (NS)||202| ||ARIES-2|¥7O|6MWD|TTCW|42|19:２| |Bosentan|Study-351|NO|6MWD|TTCW||③2| ||BREATHE-1|¥70|6MWD|TTCW|16|213| ||BREATHE-2*|¥70|PVR||12|33| ||EARLY|NoSildenafil(16%)|PVR,6MWD|TTCW||185| ||BREATHE-5||SaO2,PVR||42|54| |Macitentant|SERAPHIN|No,PDE5i or Inhal iloprost|TTCWW|Safety|100|742|

\*Bosentan þ epoprostenol versus placebo þ epoprostenol. y Approved by the FDA for PAH patients and has obtained at the time of printing the positive opinion of the Committee for Medicinal Products for Human Use of the the EMA for this indication. 6M ¼ 6-min walk distance; inhal $=$ inhalation; $\tt N S=$ not statistically signi fi cant; PDE5i $=$ phosphodiesterase type-5 inhibitors; PVR ¼ pulmonary vascular resistance; $\mathsf{S a O}_{2}=$ fi nger oxygen saturation; TTCW ¼ $=$ time to clinical worsening.

WHO-FC II and III patients. The incidence of abnormal liver function tests range from $0.8\%$ to $3\%$ . No tendency for development of abnormal liver function tests was observed in patients who had previously demonstrated abnormalities while on other ERA, and monthly liver function assessment is not mandated in the United States (25) . An increased incidence of peripheral edema has been reported with ambrisentan use. Ambrisentan is approved for PAH patients.

BOSENTAN. Bosentanisanoralactivedualendothelin-Aand-B receptor antagonist and the fi rst molecule of its class to be synthesized. Bosentan has been evaluated in PAH (idiopathic, associated with connective tissue disease and Eisenmenger ’ s syndrome) in 5 RCTs (Study-351, BREATHE [Bosentan Randomised trial of Endothelin Antagonist THErapy]-1, BREATHE-2, BREATHE-5, and EARLY [Endothelin Antagonist tRial in mildLY symptomatic pulmonary arterial hypertension patients]), which showed improvement in exercise capacity, functional class, hemodynamics, echocardiographic and Doppler variables, and time to clinical worsening (26 – 30) . Increases in hepatic aminotransferases occurred in approximately $10\%$ of the subjects but were found to be dose-dependent and reversible after dose reduction or discontinuation. For these reasons, liver function testing should be performed monthly in patients receiving bosentan. Bosentan is approved for PAH patients.

MACITENTAN. The dual ERA macitentan was developed by modifying the structure of bosentan to increase ef fi cacy and safety. Macitentan is characterized by sustained receptor binding and enhanced tissue penetration. In the eventdriven SERAPHIN (Study with an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcome) study (31) , 742 PAH patients were treated with 3 or $10\;\mathrm{\mb{~meg}}$ macitentan as compared with placebo for an average of 100 weeks. The primary endpoint was the time from the initiation of treatment to the fi rst occurrence of a composite endpoint of death, atrial septostomy, lung transplantation, initiation of treatment with intravenous or subcutaneous prostanoids, or worsening of PAH. Macitentan signi fi cantly reduced this composite endpoint of morbidity and mortality among patients with PAH and also increased exercise capacity. Bene fi ts were shown both for patients who had not received treatment previously and for those receiving background therapy for PAH. While no liver toxicity was shown, reduction in blood hemoglobin ${\leq}8\ \mathrm{g/d1}$ was observed in $4.3\%$ of patients receiving $10\;\mathrm{\mb{~meg}}$ of macitentan. Macitentan is approved by the U.S. Food and Drug Administration (FDA) for PAH patients and has obtained at the time of printing the positive opinion of the Committee for Medicinal Products for Human Use of the European Medicines Agency (EMA) for this indication.

| Table 4| Characteristics of Randomized Controlled Trials With Pulmonary Arterial Hypertension Drugs Interfering With the Nitric Oxide Pathway (See Text for References) |||||| |---|---|---|---|---|---|---| |Drug(s) Tested|Study|Background|Primary Endpoint|Outcome(Secondary Endpoint)|Duration(weeks)|No. of Patients| ||||Soluble Guanylate Cyclase Stimulators|||| |Riociguat*|PATENT|No bosentan or prostanoids| 6MWD Phosphodiesterase Type-5 Inhibitors |TTCW|42|443| |Sildenafil|SUPER-1|NO|6MWD|TTCW (NS)|12|277| ||Sastry|NO||||| ||Singh|NO|6MWD|||20| ||PACES|Epoprostenol|6MWD|TTCW|16|264| ||Iversen|Bosentan|6MWD|||20| |Tadalafil|PHIRST|No or bosentan (54%)|6MWD|TTCW|16|405| |Vardenafilt|EVALUATION|NO|6MWD|TTCW|12|66|

\*Approved by the FDA for PAH and CTEPH patients and is currently undergoing the regulatory approval process by the EMA for both indications. y Not approved for pulmonary arterial hypertension. Table 3 .

|Table 5| Characteristics of Randomized Controlled Trials With Pulmonary Arterial Hypertension Drugs Interfering With the Platelet-Derived Growth Factor Pathway (See Text for References) ||||||| |---|---|---|---|---|---|---|---| | Drug(s) Tested |Study|||(Secondary Endpoint)| Duration (weeks) | No.of Patients || |Tyrosinekinaseinhibitor imatinib*||| Background Bosentan and/or sildenafil and/or prostanoids |Primary Endpoint||24|¥59| ||| Phase 2 IMPRES ||6MWD (NS)|||| |||| Bosentanand/orsildenafiland/or prostanoids |6MWD|TTCW (NS)|24|202|

\*Not approved for pulmonary arterial hypertension. Abbreviations as in Table 3 .

Nitric oxide pathway. Impairment of NO synthesis and signaling through the NO – soluble guanylate cyclase (sGC) – cyclic guanosine monophosphate (cGMP) pathway is involved in the pathogenesis of pulmonary hypertension.

Soluble guanylate cyclase stimulators. While PDE-5is, such as sildena fi l, tadala fi l, and vardena fi l, enhance the NO – cGMP pathway, slowing cGMP degradation, sGC stimulators enhance cGMP production and are potentially effective also in conditions in which endogenous NO is depleted (32) . Pre-clinical studies with sGC stimulators have shown antiproliferative and antiremodeling properties in various animal models.

RIOCIGUAT. Riociguat has a dual mode of action, acting in synergy with endogenous NO and also directly stimulating sGC independent of NO availability. An RCT (PATENT [Pulmonary Arterial Hypertension Soluble Guanylate Cyclase – Stimulator Trial]-1) (33) in 443 PAH patients ( $44\%$ and $6\%$ on background therapy with ERA or prostanoids, respectively) treated with riociguat up to $2.5\ \mathrm{mg}\,3$ times daily has shown favorable results on exercise capacity, hemodynamics, WHO-FC, and time to clinical worsening. The increase in exercise capacity was also demonstrated in patients on background therapy. The most

common serious adverse event in the placebo group and the $2.5~\mathrm{mg}$ group was syncope ( $(4\%$ and $1\%$ , respectively). The combination of riociguat and PDE-5i is contraindicated due to hypotension and other relevant side effects detected in the open-label phase of the PATENT-plus study (34) . Riociguat is approved by the FDA for PAH and chronic thromboembolic pulmonary hypertension (CTEPH) patients and is currently undergoing the regulatory approval process by the EMA for both indications. PDE-5is. Inhibition of the cyclic guanosine monophosphate degrading enzyme PDE-5 results in vasodilation through the NO/cGMP pathway at sites expressing this enzyme. Because the pulmonary vasculature contains substantial amounts of PDE-5 the potential clinical bene fi t of PDE-5ì has been investigated in PAH. In addition, PDE-5i exerts antiproliferative effects (35,36) . All 3 PDE5is approved for the treatment of erectile dysfunction, sildena fi l, tadala fi l, and vardena fi l cause signi fi cant pulmonary vasodilation with maximum effects observed after 60, 75 to 90, and 40 to 45 min, respectively (37) .

SILDENAFIL. Sildena fi l is an orally active, potent, and selective PDE-5i. Five RCTs in PAH patients treated with sildena fi l have con fi rmed favorable results on exercise

|Characteristics of Randomized Controlled Trials With Pulmonary Arterial Hypertension Drugs Interfering With the||||||| |---|---|---|---|---|---|---| |Drug(s) Tested|Study|Background| Primary Endpoint | Outcome (Secondary Endpoint) | Duration (weeks) | No.of Patients | ||||Prostanoids|||| |Beraprost|ALPHABET|20|6MWD|||¥130| ||Barst|20|CW(NS)||¥52|116| |Epoprostenol|Rubin|2O|6MWD|||23| ||Barst|20|6MWD|Survival||¥81| ||Badesch|¥20|6MWD|||111| |lloprost|AIR|20|6MWD and FC|||| ||STEP|Bosentan|6MWD|TTCW|| 203 67 | ||COMBI|Bosentan|6MWD (NS)|||40| |Treprostinil|SC-Simonneau|¥2O|6MWD||12|470| ||Inhal TRIUMPH|Bosentan or Sildenafil|6MWD|||235| ||PO-Freedom M|¥2O|6MWD||16|| ||PO-Freedom C1|Bosentan and/or sildenafil|6MWD (NS)||16| 185 354 | ||PO-Freedom C2|Bosentan and/or sildenafil|6MWD(NS)||16|310| ||Prostacyclin IP-receptor Agonists|||||| |Selexipag*|Phase2|Bosentan and/or sildenafil|PVR|6MWD(NS)||43|

\*Not approved for pulmonary artery hypertension. CW ¼ clinical worsening; $\tt F C=$ Functional Class; inhal $=$ inhalation; $\mathtt{P O}=$ oral; $\mathtt{s c}=$ subcutaneous; other abbreviations as in Table 3 .

|Table 7| Survival After Lung Transplantation in Patients With Pulmonary Arterial Hypertension ||| |---|---|---|---| ||1year|5years|10years| |Pittsburgh (Toyoda et al., 2008 [74])|86|75|66| |Paris (Fadel et al., 2010 [75])||62|4③| |Toronto (de Perrot et al., 2012 [76])||60|45| | Vienna (Klepetko, unpublished data,2011) ||||

capacity, symptoms, and/or hemodynamics (38 – 41) . The PACES (Pulmonary Arterial hypertension Combination study of Epoprostenol and Sildena fi l) trial addressing the effects of adding sildena fi l to epoprostenol showed improvements after 12 weeks in 6MWD and time to clinical worsening. Of note, 7 deaths occurred in this trial, all in the placebo group (42) . The approved dose of sildena fi l is $20\:\mathrm{mg}$ three times daily. Most side effects of sildena fi l are mild to moderate and mainly related to vasodilation (headache, fl ushing, epistaxis). On the basis of pharmacokinetic data an intravenous formulation of sildena fi l (43) has been approved by the FDA and EMA as a bridge for PAH patients on long-term oral treatment who are temporarily unable to ingest tablets. Sildena fi l is approved for PAH patients.

TADALAFIL. Tadala fi l is a once daily dispensed, selective PDE-5i. An RCT (PHIRST [Pulmonary arterial Hypertension and ReSponse to Tadala fi l] trial) in 406 PAH patients $53\%$ on background bosentan therapy) treated with tadala fi l 2.5, 10, 20, or $40~\mathrm{mg}$ once daily has shown favorable results on exercise capacity, symptoms, hemodynamics, and time to clinical worsening at the highest dose (44) . The side effect pro fi le was similar to that of sildena fi l. Tadala fi l is approved for PAH patients.

VARDENAFIL. Vardena fi l is a twice daily dispensed PDE-5i. An RCT (EVALUATION [Ef fi cacy and Safety of Vardena fi l in the Treatment of Pulmonary Arterial Hypertension]) in 66 treatment naive PAH patients treated with vardena fi l 5 mg twice daily has shown favorable results on exercise capacity, hemodynamics, and time to clinical worsening (45) . The side effect pro fi le was similar to that of sildena fi l. Vardena fi l is currently not approved for PAH patients.

Platelet-derived growth factor pathway. Proliferation of endothelial cells and vascular smooth muscle cells with narrowing or occlusion of the vessel lumen is a histopathological hallmark of the distal pulmonary arteries in PAH patients. Evidence from animal models and human disease suggest that platelet-derived growth factor and c-KIT signaling are important in vascular smooth muscle cell proliferation and hyperplasia.

Tyrosine kinase inhibitors. IMATINIB. Imatinib is an antiproliferative agent developed to target the Bcr-Abl tyrosine kinase in patients with chronic myeloid leukemia. In addition, the inhibitory effects of imatinib on plateletderived growth factor receptors and c-KIT suggest that it

may be ef fi cacious in PAH. Two RCTs on PAH patients treated with imatinib (all of them on background therapy with at least 2 PAH-approved drugs) have shown positive results on exercise capacity and hemodynamics (data possibly in fl uenced by the drop-out rate in the treated group), but failed to show favorable effects on time to clinical worsening (46,47) . In addition, an increased incidence of subdural hematoma was observed in PAH patients treated with both imatinib and oral anticoagulants. Regulatory consideration of imatinib for the PAH indication has recently been halted. Prostacyclin pathway. Prostacyclin is produced predominantly by endothelial cells and induces potent vasodilation of all vascular beds and in addition is an inhibitor of platelet aggregation and it also appears to have both cytoprotective and antiproliferative activities (48) . Dysregulation of the prostacyclin metabolic pathways has been shown in patients with PAH as assessed by reduction of prostacyclin synthase expression in the pulmonary arteries and of urinary metabolites of prostacyclin (49,50) .

Prostanoids. The clinical use of prostacyclin in patients with PAH has been extended by the synthesis of stable analogues.

BERAPROST. Beraprost is the fi rst chemically stable and orally active prostacyclin analogue. The RCT ALPHABET (Arterial Pulmonary Hypertension And Beraprost European Trial) (51) in Europe and a second study in the United States (52) with this compound have shown an improvement in exercise capacity, which unfortunately persists only up to 3 to 6 months. There were no hemodynamic bene fi ts. The most frequent adverse events were headache, fl ushing, jaw pain, and diarrhea. Beraprost is approved for PAH in Japan and South Korea.

EPOPROSTENOL. Epoprostenol (synthetic prostacyclin) has a short half-life (3 to 5 min) and is stable at room temperature for only 8 h requiring cooling, continuous administration by means of an infusion pump and a permanent tunneled catheter. The ef fi cacy of continuous intravenous (IV) administration of epoprostenol has been tested in 3 unblinded RCTs in patients with idiopathic PAH (53,54) and in those with PAH associated with the scleroderma spectrum of diseases (55) . Epoprostenol improves symptoms, exercise capacity, and hemodynamics in both clinical conditions, and is the only treatment shown to reduce mortality in idiopathic PAH in a randomized study (54) . The meta-analysis for total mortality of the 3 epoprostenol RCTs (53 – 55) performed with the Mantel – Haenszel and the Peto fi xed-effect methods showed a relative risk (RR) reduction o $70\%$ $\left(\mathrm{z}=2.35\right.$ , ${\tt p}=0.019$ , heterogeneity $\mathtt{p}=0.182)$ and 68% (z $\mathrm{(z=2.52}$ ¼ ${\tt p}=0.012$ , heterogeneity $\mathrm{~p~}=\ 0.153)$ ), respectively ( Fig. 2 ). Serious adverse events related to the delivery system include pump malfunction, local site infection, catheter obstruction, and sepsis. Intravenous epoprostenol is approved for PAH patients. A thermostable formulation of epoprostenol is approved in the United States, Canada, Japan and in most of the European

countries and does not require cooling packs to maintain stability beyond 8 to $12\mathrm{~h~}$ .

ILOPROST. Iloprost is a chemically stable prostacyclin analogue available for intravenous, oral, and inhaled administration. Inhaled iloprost has been evaluated in 1 RCT (AIR [Aerosolized Iloprost Randomized] study) in which daily repetitive iloprost inhalations (6 to 9 times, 2.5 to 5 m g/inhalation, median $30~\upmu\mathrm{g}$ daily) were compared with placebo inhalation in patients with PAH and CTEPH (56) . The study showed an increase in exercise capacity and improvement in symptoms, pulmonary vascular resistance (PVR) and clinical events in enrolled patients. Two additional RCTs (STEP [Safety and pilot ef fi cacy Trial of inhaled iloprost in combination with bosentan for Evaluation in Pulmonary arterial hypertension] and COMBI [COMbination therapy of Bosentan and aerosolized Iloprost in idiopathic pulmonary arterial hypertension]) of patients already treated with bosentan have shown con fl icting results of the addition of inhaled iloprost (57,58) . Overall, inhaled iloprost was well tolerated with fl ushing and jaw pain being the most frequent side effects. Continuous IV administration of iloprost appears to be as effective as epoprostenol in a small uncontrolled series of patients with PAH and CTEPH (59) . Inhaled iloprost is approved for PAH. The IV formulation is approved for PAH in New Zealand.

TREPROSTINIL. Treprostinil is a tricyclic benzidine analogue of epoprostenol, with suf fi cient chemical stability to be administered at ambient temperature. These characteristics allow administration of the compound by the IV as well as the subcutaneous and oral route. The subcutaneous administration of treprostinil can be accomplished by a microinfusion pump and a small subcutaneous catheter. The effects of treprostinil in PAH were studied in an RCT and showed improvements in exercise capacity, hemodynamics, and symptoms (60) . Infusion site pain was the most common adverse effect of treprostinil, leading to discontinuation of the treatment in $8\%$ of cases on active drug and limiting dose increase in an additional proportion of patients (60) . An RCT was performed with intravenous treprostinil in PAH patients (TRUST [Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial Compared Continuous IV Treprostinil to Placebo in PAH Patients]) but the enrollment of this trial was closed after 45 $(36\%)$ of the planned 126 patients had been randomized because of safety considerations (61) . The data generated from 31 $(25\%)$ survivors after the randomized phase (23 active and 8 placebo) are not considered reliable and the study is not included in Table 6 .

An RCT (TRIUMPH [inhaled TReprostInil sodiUM in Patients with severe Pulmonary arterial Hypertension]) with inhaled treprostinil in PAH patients on background

 Meta-Analysis of Published Randomized Controlled Studies (Identi fi ed by First Author and Year of Publication) With Epoprostenol in Pulmonary Arterial Hypertension by Mantel – Haenszel and Peto Methods

Figure 2

The analysis included 215 patients in 3 trials. The fi gure shows the cumulative relative risk (RR) estimate of death in active treatment groups when compared with control groups. An overall reduction of the risk of mortality of $70\%$ ${\mathfrak{p}}=0.019$ ) and $68\%$ $\circ=0.012$ ) is shown with Mantel – Haenszel and Peto methods, respectively. ${\mathsf{C}}{\mathsf{I}}=$ con fi dence interval; OR ¼ odds ratio.

therapy with either bosentan or sildena fi l showed improvements in 6MWD by 20 m at peak dose, N-terminal pro – B-type natriuretic peptide (NT-proBNP) and quality-of-life measures (62) .

Oral treprostinil has been evaluated in 2 RCTs in PAH patients on background therapy with bosentan and/or sildena fi l (FREEDOM [Multicenter, Double-101 Blind, Randomized, Placebo-Controlled Study of the Ef fi cacy and Safety of Oral treprostinil Sustained Release Tablets in Subjects With Pulmonary Arterial Hypertension] C1 and C2) and in both the primary endpoint 6MWD did not reach statistical signi fi cance (63,64) . An additional RCT in PAH naive patients showed improvement in 6MWD by $26~\mathrm{m}$ at peak dose (65) . Subcutaneous treprostinil is approved for PAH. Intravenous treprostinil is approved in the United States and European Union in patients with PAH who cannot tolerate the subcutaneous administration (based on bioequivalence). Inhaled treprostinil is approved for PAH in the United States. Oral treprostinil is currently not approved for PAH.

Prostacyclin IP-receptor agonists. SELEXIPAG. Selexipag is an orally available, selective prostacyclin IP receptor agonist. Although selexipag and its metabolite have modes of action similar to that of endogenous prostacyclin (IP receptor agonism), they are chemically distinct from prostacyclin with a different pharmacology. In a pilot RCT in PAH patients (receiving stable ERA and/or a PDE-5i therapy) selexipag reduced PVR after 17 weeks (66) . A large event-driven phase 3 RCT (GRIPHON [Prostocyclin (PGI2) Receptor Agonist in Pulmonary Arterial Hypertension] trial) is currently ongoing. Selexipag is currently not approved for PAH.

Clinical Response, Combination Therapy, and Interventional Procedures

After initial therapy, the next steps are based on the clinical response, which is usually reassessed at 3 to 6 months after treatment start.

The clinical response is based on the evaluation of different parameters including WHO-FC, exercise capacity, cardiac index, right atrial pressure, NT-proBNP plasma levels, echocardiographic parameters, and perceived need for additional/change of therapy. The exact de fi nition of clinical response is addressed in another paper of this supplement and is beyond the scope of this paper.

If the clinical response is considered not adequate, combination therapy is considered.

Combination therapy. Combination therapy d using 2 or more classes of drugs simultaneously d has been used successfully in the treatment of systemic hypertension and heart failure. It is also an attractive option for the management of PAH, because 3 separate signaling pathways are known to be involved in the disease: the prostacyclin pathway, the endothelin pathway, and the NO pathway.

In Tables 3 to 6 , 13 $(43\%)$ of the RCTs performed in PAH patients included at least 1 subgroup treated with

combination therapy. The experience with combination therapy is therefore growing and a recent meta-analysis on 6 RCTs with combination therapy including 858 patients has been published (67) : compared with the control group, combination therapy reduced the risk of clinical worsening (RR: 0.48; $95\%$ con fi dence interval: 0.26 to $\mathrm{~p~}=$ 0.023), increased the 6MWD signi fi cantly by 22 m, and reduced mean pulmonary arterial pressure, right atrial pressure, and PVR. The incidence of serious adverse events was similar in the 2 groups (RR: 1.17; $95\%$ con fi dence interval: 0.40 to 3.42; $\mathsf{p}=0.77\$ ). The reduction on all-cause mortality was not statistically signi fi cant. However, the incidence of mortality in RCTs with PAH medications is relatively low and to achieve statistical signi fi cance a sample size of several thousands of patients may be required (67) .

The patterns to apply combination therapy may be sequential or initial (upfront).

Sequential combination therapy is the most widely utilized strategy both in RCTs (12 of 13 of the RCTs with combination therapy) ( Tables 3 to 6 ) and in clinical practice: From monotherapy there is addition of a second and then third drug in cases of inadequate clinical results or in cases of deterioration. A structured prospective program to evaluate the adequacy of clinical results is the so-called “ goal-oriented therapy, ” a treatment strategy that uses known prognostic indicators as treatment targets. The therapy is considered adequate only if the targets are met. The key difference between goal-oriented therapy and nonstructured approaches is that patients who are stabilized, or even those who improve slightly, can still receive additional therapy if treatment goals are not met. The goaloriented treatment strategy has been endorsed by recent PAH guidelines proposing different targets including WHO-FC I or II and the near normalization of resting cardiac index and/or of NT-proBNP plasma levels (4) . A recent study has con fi rmed a better prognosis in patients achieving these goals as compared with the patients who did not (68) . Sequential combination therapy has been allocated a grade of recommendation I and level of evidence A in PAH patients with inadequate clinical response to initial monotherapy.

The rationale for initial or upfront combination therapy is based on the known mortality of PAH that is reminiscent of many malignancies and the fact that malignancies and critical medical illnesses (heart failure, malignant hypertension) are not treated with a stepwise approach to therapy but rather with pre-emptive combination therapy. The experience on RCTs with initial combination therapy is limited to the small BREATHE-2 study, which failed to demonstrate any signi fi cant difference between patients treated initially with the combination epoprostenol and bosentan as compared with epoprostenol alone (28) . In a more recent experience, 23 treatment naive PAH patients were treated with the initial combination of epoprostenol and bosentan and compared with a matched historical control group treated with epoprostenol (69) . The study

showed a statistically signi fi cantly greater decrease in PVR in the initial combination therapy group but this hemodynamic bene fi t did not translate into a statistically signi fi cant difference in survival, or in transplant-free survival. A multicenter, multinational blinded placebo controlled trial (AMBITION [A Randomized, Multicenter Study of FirstLine Ambrisentan and Tadala fi l Combination Therapy in Subjects with Pulmonary Arterial Hypertension]) comparing fi rst line monotherapy with tadala fi l, monotherapy with ambrisentan and combination therapy with tadala fi l and ambrisentan in de novo WHO-FC II and III PAH patients was underway at the time of this publication to address the ef fi cacy to safety ratio of initial combination therapy. Initial combination therapy has been allocated a grade of recommendation IIb and level of evidence C in WHO-FC IV PAH patients in case of nonavailability of IV prostanoids. Interventional procedures. LUNG TRANSPLANTATION. The advent of disease targeted therapy for severe PAH has reduced and delayed patients referral for lung transplant programs (70) . The long-term outcomes of medically treated patients remain uncertain and transplantation should continue to be an important option for those who fail on such therapy and remain in WHO-FC III or IV (71,72) . Delayed referral in combination with the length of the waiting time, due to the shortage of organ donors, may increase the mortality on the waiting list and clinical severity at the time of transplantation.

The overall 5-year survival following transplantation for PAH was considered to be $45\%$ to $50\%$ with evidence of continued good quality of life (73) . More recent data show that survival is increased to $52\%$ to $75\%$ at 5 years and to $45\%$ to $66\%$ at 10 years ( Table 7 ) (74 – 76) .

Considering together the previous information, it seems reasonable to consider eligibility for lung transplantation after an inadequate clinical response to the initial monotherapy and to refer the patient soon after the inadequate clinical response is con fi rmed on maximal combination therapy ( Fig. 1 ).

Also the etiology of PAH may help the decision making because the prognosis varies according to the underlying condition. In fact, PAH associated with connective tissue disease has a worse prognosis than idiopathic PAH even when treated with prostanoids, while patients with PAH associated with congenital heart disease have a better survival. The worst prognosis is seen in patients with pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis because of the lack of effective medical treatments and these patients should be listed for transplantation at diagnosis.

Both heart-lung and double-lung transplantation have been performed for PAH, although the threshold for unrecoverable right ventricle systolic dysfunction and/or left ventricle diastolic dysfunction is unknown. Currently the vast majority of patients worldwide receive bilateral lungs as evidenced by the International Society for Heart and Lung Transplantation Registry fi gures (77) . Patients with

Eisenmenger ’ s syndrome due to simple shunts have been treated by isolated lung-transplantation and repair of the cardiac defect or by heart-lung transplantation (73) .

While registry data initially supported a survival bene fi t of heart-lung transplantation for patients with pulmonary hypertension associated with a ventricular septal defects (78) experience with isolated bilateral lung transplantation has grown and more recent data supports a role for this approach combined with repair of the defect (79) .

Recent reports indicate that venoarterial extracorporeal membrane oxygenation may be employed in awake endstage PH patients for bridging to lung transplantation (80) .

BALLOON ATRIAL SEPTOSTOMY. The creation of an interatrial right-to-left shunt can decompress the right heart chambers, and increase left ventricle pre-load and cardiac output (81,82) . In addition, this improves systemic $\mathrm{O}_{2}$ transport despite arterial $\mathrm{O}_{2}$ desaturation (81) and decreases sympathetic hyperactivity. The recommended technique is graded balloon dilation atrial septostomy, which produces equivalent improvements in hemodynamics and symptoms but reduced risk compared with the original blade technique. Other techniques are considered experimental (83) .

A careful pre-procedure risk assessment ensures reduced mortality. Balloon atrial septostomy (BAS) should be avoided in end-stage patients presenting with a baseline mean right atrial pressure of ${>}20\ \mathrm{mm\Hg}$ and $\mathrm{O}_{2}$ saturation at rest of ${<}85\%$ on room air. Patients should be on optimal medical therapy, which may include preconditioning with IV inotropic drugs, prior to considering BAS. Published reports suggest a bene fi t in patients who are in WHO-FC IV with right heart failure refractory to medical therapy or with severe syncopal symptoms (81,82) . It may also be considered in patients awaiting transplantation or when medical therapy is not available. Studies show improvements in cardiac index and decreases in right atrial pressure with improvement in 6MWD (81,82) . The impact of BAS on long-term survival has not been established in RCTs (81,82) . BAS should be regarded as a palliative or bridging procedure to be performed only by centers with experience in the method (70) .

Treatment algorithm principles and description.

PRINCIPLES.

The treatment algorithm for PAH patients is shown in Figure 1 . The de fi nitions of the grades of recommendation and the levels of evidence are reported in Tables 1 and 2 . The different treatments have been evaluated by RCTs mainly in idiopathic PAH, heritable PAH, PAH due to anorexigen drugs, and in PAH associated with connective tissue disease or with congenital heart disease (surgically corrected or not). The grades of recommendation and levels of evidence for the other associated PAH conditions may be lower. However, the treatment algorithm is applicable to associated PAH conditions without substantial changes.

PAH is a rare disease and regulatory agencies may require only 1 RCT with pre-speci fi ed characteristics (e.g., size, duration, endpoint, level of statistical signi fi cance) to grant the approval for the use. For these reasons approved drugs with level of evidence A (more than 1 RCT or meta-analysis) and approved drugs with Level of Evidence: B (1 RCT) have been grouped together. The treatment algorithm does not apply to patients in other clinical groups, and in particular not to patients with PH associated with left heart disease (group 2) or with lung diseases (group 3). Only the compounds of fi cially approved for PAH or under regulatory approval process in at least 1 country are included. Single compounds are listed by alphabetical order according with the pharmacological name. As head-to-head comparisons among different compounds are not available, no evidence-based fi rstline treatment can be proposed. In this case the choice of the drug may depend on a variety of factors including the approval status, the labeling, the route of administration, the side effect pro fi le, patients preferences, physician experience, and the cost. A 4-level hierarchy for endpoints in RCT has been proposed by experts according to level of evidence regarding ef fi cacy (84,85) : Level 1 is a true clinical ef fi cacy measure; Level 2 is a validated surrogate (for a speci fi c disease setting and class of interventions); Level 3 is a nonvalidated surrogate, yet 1 established to be reasonably likely to predict clinical bene fi t (for a speci fi c disease setting and class of interventions); and Level 4 is a correlate that is a measure of biological activity but that has not been established to be so at a higher level. All-cause death and morbidity and mortality endpoints for PAH have been included in Level 1 (84) whereas 6MWD is not considered a validated surrogate in PAH (86) and it may be included either at Level 3 or 4. According to this hierarchy, drugs with morbidity and mortality as primary endpoint in RCTs or drugs with demonstrated reduction in all-cause mortality (prospectively de fi ned) have been highlighted.

DESCRIPTION.

The suggested initial approach after the diagnosis of PAH is the adoption of the general measures, the initiation of the supportive therapy, and referral to an expert center. Acute vasoreactivity testing should be performed in all patients with PAH (group 1), although patients with idiopathic PAH, heritable PAH, and PAH associated with anorexigen use are the most likely to exhibit an acute positive response and to bene fi t from high-dose CCB therapy. Vasoreactive patients should be treated with high and optimally tolerated doses of CCBs;

adequate response should be con fi rmed after 3 to 4 months of treatment. Nonresponders to acute vasoreactivity testing who are in WHO-FC II should be treated with an oral compound. Nonresponders to acute vasoreactivity testing, or responders who remain in (or progress to) WHO-FC III, should be considered candidates for treatment with any of the approved PAH drugs. As head-to-head comparisons among different compounds are not available, no evidence-based fi rstline treatment can be proposed (see previous) for either WHO-FC II or III patients. Continuous IV epoprostenol is recommended as fi rstline therapy for WHO-FC IV PAH patients because of the survival bene fi t in this subset. In absence of IV epoprostenol all other compounds may be utilized. Although ambrisentan, bosentan, and sildena fi l are approved in WHO-FC IV patients in the United States, only a small number of these patients were included in the RCTs of these agents. Accordingly, most experts consider these treatments as a second line in severely ill patients. In WHO-FC IV patients initial combination therapy may also be considered. In case of inadequate clinical response, sequential combination therapy should be considered. Combination therapy can either include an ERA plus a PDE-5i or a prostanoid plus an ERA or a prostanoid plus a PDE-5i. Upon regulatory approval the sGC stimulator riociguat can be considered as a potential alternative to PDE-5i in the different types of double combinations. The combination of riociguat and PDE-5is is contraindicated. In case of inadequate clinical response with double combination therapy, triple combination therapy should be attempted. It seems reasonable to consider eligibility for lung transplantation after an inadequate clinical response to the initial monotherapy and to refer the patient for lung transplantation soon after the inadequate clinical response is con fi rmed on maximal combination therapy. Balloon atrial septostomy should be regarded as a palliative or bridging procedure in patients deteriorating despite maximal medical therapy.

Reprint requests and correspondence: Dr. Nazzareno Galiè, University of Bologna, Institute of Cardiology, via Massarenti 9, 40138-Bologna, Italy. E-mail: nazzareno.galie@unibo.it .

REFERENCES

1. McLaughlin VV, Rich S. Pulmonary hypertension d advances in medical and surgical interventions. J Heart Lung Transplant 1998;17:739 – 43.

2. Galie N, Seeger W, Naeije R, Simonneau G, Rubin L. Comparative analysis of clinical trials and evidence-based treatment algorithm in pulmonary arterial hypertension. J Am Coll Cardiol 2004;43:S81 – 8. 3. Barst R, Gibbs J, Ghofrani A, et al. Updated evidence-based treatment algorithm in pulmonary arterial hypertension. J Am Coll Cardiol 2009; 54:S78 – 84. 4. Galiè N, Hoeper M, Humbert M, et al. Guidelines on diagnosis and treatment of pulmonary hypertension: the Task Force on Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology and of the European Respiratory Society. Eur Heart J 2009; 30:2493 – 537. 5. Galie N, Manes A, Negro L, Palazzini M, Bacchi Reggiani ML, Branzi A. A meta-analysis of randomized controlled trials in pulmonary arterial hypertension. Eur Heart J 2009;30:394 – 403. 6. Bai Y, Sun L, Hu S, Wei Y. Combination therapy in pulmonary arterial hypertension: a meta-analysis. Cardiology 2011;120:157 – 65. 7. Jais X, Olsson KM, Barbera JA, et al. Pregnancy outcomes in pulmonary arterial hypertension in the modern management era. Eur Respir J 2012;40:881 – 5. 8. Mereles D, Ehlken N, Kreuscher S, et al. Exercise and respiratory training improve exercise capacity and quality of life in patients with severe chronic pulmonary hypertension. Circulation 2006;114:1482 – 9. 9. de Man FS, Handoko ML, Groepenhoff H, et al. Effects of exercise training in patients with idiopathic pulmonary arterial hypertension. Eur Respir J 2009;34:669 – 75. 10. Grunig E, Ehlken N, Ghofrani A, et al. Effect of exercise and respiratory training on clinical progression and survival in patients with severe chronic pulmonary hypertension. Respiration 2011;81:394 – 401. 11. Grunig E, Maier F, Ehlken N, et al. Exercise training in pulmonary arterial hypertension associated with connective tissue diseases. Arthritis Res Ther 2012;14:R148. 12. Grunig E, Lichtblau M, Ehlken N, et al. Safety and ef fi cacy of exercise training in various forms of pulmonary hypertension. Eur Respir J 2012;40:84 – 92. 13. Becker-Grunig T, Klose H, Ehlken N, et al. Ef fi cacy of exercise training in pulmonary arterial hypertension associated with congenital heart disease. Int J Cardiol 2013;168:375 – 81. 14. Weinstein AA, Chin LMK, Keyser RE, et al. Effect of aerobic exercise training on fatigue and physical activity in patients with pulmonary arterial hypertension. Respir Med 2013;107:778 – 84. 15. Chan L, Chin LM, Kennedy M, et al. Bene fi ts of intensive treadmill exercise training on cardiorespiratory function and quality of life in patients with pulmonary hypertension. Chest 2013;143:333 – 43. 16. Thiemann DR, Coresh J, Oetgen WJ, Powe NR. The association between hospital volume and survival after acute myocardial infarction in elderly patients. N Engl J Med 1999;340:1640 – 8. 17. Delcroix M, Naeije R. Optimising the management of pulmonary arterial hypertension patients: emergency treatments. Eur Respir Rev 2010;19:204 – 11. 18. Delcroix M, Adir Y, Andreassen AK, et al. Care organization for pulmonary arterial hypertension in developed countries: a survey. J Heart Lung Transplant 2012;31 4 Suppl:s81 – 2. 19. Jing ZC, Jiang X, Han ZY, et al. Iloprost for pulmonary vasodilator testing in idiopathic pulmonary arterial hypertension. Eur Respir J 2009;33:1354 – 60. 20. Giaid A, Yanagisawa M, Langleben D, et al. Expression of endothelin1 in the lungs of patients with pulmonary hypertension. N Engl J Med 1993;328:1732 – 9. 21. Stewart DJ, Levy RD, Cernacek P, Langleben D. Increased plasma endothelin-1 in pulmonary hypertension: marker or mediator of disease? Ann Intern Med 1991;114:464 – 9. 22. Galie N, Manes A, Branzi A. The endothelin system in pulmonary arterial hypertension. Cardiovasc Res 2004;61:227 – 37. 23. Galie N, Badesch BD, Oudiz R, et al. Ambrisentan therapy for pulmonary arterial hypertension. J Am Coll Cardiol 2005;46: 529 – 35. 24. Galie N, Olschewski H, Oudiz RJ, et al. Ambrisentan for the treatment of pulmonary arterial hypertension. Results of the Ambrisentan in Pulmonary Arterial Hypertension, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Ef fi cacy (ARIES) study 1 and 2. Circulation 2008;117:3010 – 9. 25. McGoon M, Frost A, Oudiz R, et al. Ambrisentan therapy in patients with pulmonary arterial hypertension who discontinued bosentan or sitaxsentan due to liver function test abnormalities. Chest 2009;135: 122 – 9. 26. Channick RN, Simonneau G, Sitbon O, et al. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study. Lancet 2001; 358:1119 – 23. 27. Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002;346:896 – 903. 28. Humbert M, Barst RJ, Robbins IM, et al. Combination of bosentan with epoprostenol in pulmonary arterial hypertension: BREATHE-2. Eur Respir J 2004;24:353 – 9. 29. Galiè N, Rubin LJ, Hoeper M, et al. Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (EARLY study): a double-blind, randomised controlled trial. Lancet 2008;371: 2093 – 100. 30. Galie N, Beghetti M, Gatzoulis MA, et al. Bosentan therapy in patients with Eisenmenger syndrome: a multicenter, double-blind, randomized, placebo-controlled study. Circulation 2006;114:48 – 54. 31. Pulido T, Adzerikho I, Channick RN, et al. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med 2013; 369:809 – 18. 32. Giaid A, Saleh D. Reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. N Engl J Med 1995;333:214 – 21. 33. Ghofrani HA, Galie N, Grimminger F, et al. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med 2013;369: 330 – 40. 34. Galie N, Neuser D, Muller, Scalise AV, Grunig E. A placebocontrolled, double-blind phase II interaction study to evaluate blood pressure following addition of riociguat to patients with symptomatic pulmonary arterial hypertension (PAH) receiving sildena fi l (PATENT PLUS). Am J Resp Crit Care Med 2013;187:A3530. 35. Wharton J, Strange JW, Moller GMO, et al. Antiproliferative effects of phosphodiesterase ype 5 inhibition in human pulmonary artery cells. Am J Respir Crit Care Med 2005;172:105 – 13. 36. Tantini B, Manes A, Fiumana E, et al. Antiproliferative effect of sildena fi l on human pulmonary artery smooth muscle cells. Basic Res Cardiol 2005;100:131 – 8. 37. Ghofrani HA, Voswinckel R, Reichenberger F, et al. Differences in hemodynamic and oxygenation responses to three different phosphodiesterase-5 inhibitors in patients with pulmonary arterial hypertension: a randomized prospective study. J Am Coll Cardiol 2004; 44:1488 – 96. 38. Galie N, Ghofrani HA, Torbicki A, et al. Sildena fi l citrate therapy for pulmonary arterial hypertension. N Engl J Med 2005;353: 2148 – 57. 39. Sastry BKS, Narasimhan C, Reddy NK, Raju BS. Clinical ef fi cacy of sildena fi l in primary pulmonary hypertension: a randomized, placebocontrolled, double-blind, crossover study. J Am Coll Cardiol 2004; 43:1149 – 53. 40. Iversen K, Jensen AS, Jensen TV, Vejlstrup NG, Søndergaard L. Combination therapy with bosentan and sildena fi l in Eisenmenger syndrome: a randomized, placebo-controlled, double-blinded trial. Eur Heart J 2010;31:1124 – 31. 41. Singh T, Rohit M, Grover A, Malhotra S, Vijayvergiya R. A randomized, placebo-controlled, double-blind, crossover study to evaluate the ef fi cacy of oral sildena fi l therapy in severe pulmonary artery hypertension. Am Heart J 2006;151:851.e1 – 5. 42. Simonneau G, Rubin L, Galie N, et al. Addition of sildena fi l to longterm intravenous epoprostenol therapy in patients with pulmonary arterial hypertension. Ann Intern Med 2008;149:521 – 30. 43. Vachiery JL, Huez S, Gillies H, et al. Safety, tolerability and pharmacokinetics of an intravenous bolus of sildena fi l in patients with pulmonary arterial hypertension. Br J Clin Pharmacol 2011;71: 289 – 92. 44. Galie N, Brundage BH, Ghofrani HA, et al. Tadala fi l therapy for pulmonary arterial hypertension. Circulation 2009;119:2894 – 903. 45. Jing ZC, Yu ZX, Shen JY, et al. Vardena fi l in pulmonary arterial hypertension: a randomized, double-blind, placebo-controlled study. Am J Respir Crit Care Med 2011;183:1723 – 9. 46. Ghofrani HA, Morrell NW, Hoeper MM, et al. Imatinib in pulmonary arterial hypertension patients with inadequate response to established therapy. Am J Respir Crit Care Med 2010;182:1171 – 7.

47. Hoeper MM, Barst RJ, Bourge RC, et al. Imatinib mesylate as add-on therapy for pulmonary arterial hypertension: results of the randomized IMPRES study. Circulation 2013;127:1128 – 38. 48. Jones DA, Benjamin CW, Linseman DA. Activation of thromboxane and prostacyclin receptors elicits opposing effects on vascular smooth muscle cell growth and mitogen-activated protein kinase signaling cascades. Mol Pharmacol 1995;48:890 – 6. 49. Christman BW, McPherson CD, Newman JH, et al. An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary hypertension. N Engl J Med 1992;327:70 – 5. 50. Galie N, Manes A, Branzi A. Prostanoids for pulmonary arterial hypertension. Am J Respir Med 2003;2:123 – 37. 51. Galie N, Humbert M, Vachiery JL, et al. Effects of beraprost sodium, an oral prostacyclin analogue, in patients with pulmonary arterial hypertension: a randomised, double-blind placebo-controlled trial. J Am Coll Cardiol 2002;39:1496 – 502. 52. Barst RJ, McGoon M, Mc Laughlin VV, et al. Beraprost therapy for pulmonary arterial hypertension. J Am Coll Cardiol 2003;41:2125. 53. Rubin LJ, Mendoza J, Hood M, et al. Treatment of primary pulmonary hypertension with continuous intravenous prostacyclin (epoprostenol). Results of a randomized trial. Ann Intern Med 1990; 112:485 – 91. 54. Barst RJ, Rubin LJ, Long WA, et al., Primary Pulmonary Hypertension Study Group. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med 1996;334:296 – 302. 55. Badesch DB, Tapson VF, McGoon MD, et al. Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease. A randomized, controlled trial. Ann Intern Med 2000;132:425 – 34. 56. Olschewski H, Simonneau G, Galie N, et al. Inhaled iloprost in severe pulmonary hypertension. N Engl J Med 2002;347:322 – 9. 57. McLaughlin VV, Oudiz RJ, Frost A, et al. Randomized study of adding inhaled iloprost to existing bosentan in pulmonary arterial hypertension. Am J Respir Crit Care Med 2006;174:1257 – 63. 58. Hoeper M, Leuchte H, Halank M, et al. Combining inhaled iloprost with bosentan in patients with idiopathic pulmonary arterial hypertension. Eur Respir J 2006;4:691 – 4. 59. Higenbottam T, Butt AY, McMahon A, Westerbeck R, Sharples L. Long-term intravenous prostaglandin (epoprostenol or iloprost) for treatment of severe pulmonary hypertension. Heart 1998;80:151 – 5. 60. Simonneau G, Barst RJ, Galie N, et al. Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertension. A double-blind, randomized, placebo-controlled trial. Am J Respir Crit Care Med 2002;165: 800 – 4. 61. Hiremath J, Thanikachalam S, Parikh K, et al. Exercise improvement and plasma biomarker changes with intravenous treprostinil therapy for pulmonary arterial hypertension: a placebo-controlled trial. J Heart Lung Transplant 2010;29:137 – 49. 62. McLaughlin V, Rubin L, Benza RL, et al. Addition of inhaled treprostinil to oral therapy for pulmonary arterial hypertension: a randomized controlled clinical trial. J Am Coll Cardiol 2010;55: 1915 – 22. 63. Tapson VF, Torres F, Kermeen F, et al. 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. Chest 2012;142:1383 – 90. 64. Tapson VF, Jing ZC, Xu KF, et al. 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-C2 Study): a randomized controlled trial. Chest 2013;142:1363 – 4. 65. Jing ZC, Parikh K, Pulido T, et al. Ef fi cacy and safety of oral treprostinil monotherapy for the treatment of pulmonary arterial hypertension: a randomized, controlled trial. Circulation 2013;127:624 – 33. 66. Simonneau G, Torbicki A, Hoeper MM, et al. Selexipag, an oral, selective IP receptor agonist for the treatment of pulmonary arterial hypertension. Eur Respir J 2012;40:874 – 80. 67. Galie N, Palazzini M, Manes A. Pulmonary arterial hypertension: from the kingdom of the near-dead to multiple clinical trial meta-analyses. Eur Heart J 2010;31:2080 – 6. 68. Nickel N, Golpon H, Greer M, et al. The prognostic impact of followup assessments in patients with idiopathic pulmonary arterial hypertension. Eur Respir J 2012;39:589 – 96. 69. Kemp K, Savale L, O ’ Callaghan DS, et al. Usefulness of fi rst-line combination therapy with epoprostenol and bosentan in pulmonary arterial hypertension: An observational study. J Heart Lung Transplant 2012;31:150 – 8. 70. Keogh A, Benza RL, Corris P, et al. Interventional and surgical modalities of treatment in pulmonary arterial hypertension. J Am Coll Cardiol 2009;54:S67 – 77. 71. Sitbon O, Humbert M, Nunes H, et al. Long-term intravenous epoprostenol infusion in primary pulmonary hypertension: prognostic factors and survival. J Am Coll Cardiol 2002;40:780 – 8. 72. McLaughlin VV, Shillington A, Rich S. Survival in primary pulmonary hypertension: the impact of epoprostenol therapy. Circulation 2002; 106:1477 – 82. 73. Trulock EP, Edwards LB, Taylor DO, et al. Registry of the International Society for Heart and Lung Transplantation: twenty-third of fi - cial adult lung and heart lung transplantation report d 2006. J Heart Lung Transplant 2006;25:880 – 92. 74. Toyoda Y, Thacker J, Santos R, et al. Long-term outcome of lung and heart-lung transplantation for idiopathic pulmonary arterial hypertension. Ann Thorac Surg 2008;86:1116 – 22. 75. Fadel E, Mercier O, Mussot S, et al. Long-term outcome of doublelung and heart-lung transplantation for pulmonary hypertension: a comparative retrospective study of 219 patients. Eur J Cardiothorac Surg 2010;38:277 – 84. 76. de Perrot M, Granton JT, McRae K, et al. Outcome of patients with pulmonary arterial hypertension referred for lung transplantation: a 14- year single-center experience. J Thorac Cardiovasc Surg 2012;143: 910 – 8. 77. Christie JD, Edwards LB, Kucheryavaya AY, et al. The Registry of the International Society for Heart and Lung Transplantation: 29th of fi cial adult lung and heart-lung transplant report d 2012. J Heart Lung Transplant 2012;31:1073 – 86. 78. Waddell TK, Bennett L, Kennedy R, Todd TR, Keshavjee SH. Heartlung or lung transplantation for Eisenmenger syndrome. J Heart Lung Transplant 2002;21:731 – 7. 79. Choong CK, Sweet SC, Guthrie TJ, et al. Repair of congenital heart lesions combined with lung transplantation for the treatment of severe pulmonary hypertension: a 13-year experience. J Thorac Cardiovasc Surg 2005;129:661 – 9. 80. Fuehner T, Kuehn C, Hadem J, et al. Extracorporeal membrane oxygenation in awake patients as bridge to lung transplantation. Am J Respir Crit Care Med 2012;185:763 – 8. 81. Sandoval J, Gaspar J, Pulido T, et al. Graded balloon dilation atrial septostomy in severe primary pulmonary hypertension. A therapeutic alternative for patients nonresponsive to vasodilator treatment. J Am Coll Cardiol 1998;32:297 – 304. 82. Kurzyna M, Dabrowski M, Bielecki D, et al. Atrial septostomy in treatment of end-stage right heart failure in patients with pulmonary hypertension. Chest 2007;131:977 – 83. 83. Althoff TF, Knebel F, Panda A, et al. Long-term follow-up of a fenestrated Amplatzer atrial septal occluder in pulmonary arterial hypertension. Chest 2008;133:283 – 5. 84. Fleming TR, Powers JH. Biomarkers and surrogate endpoints in clinical trials. Statist Med 2012;31:2973 – 84. 85. Fleming TR. Surrogate endpoints and FDA accelerated approval process. Health Affairs 2005;24:67 – 78. 86. Savarese G, Paolillo S, Costanzo P, et al. Do changes of 6-minute walk distance predict clinical events in patients with pulmonary arterial hypertension?: A meta-analysis of 22 randomized trials. J Am Coll Key Words: endothelin receptor antagonists - guanylate cyclase stimulators - hypertension, pulmonary - lung transplantation - phosphodiesterase type-5 inhibitors - prostanoids - pulmonary.

相关指南

• 2024+中国专家共识：成人烧伤患者静脉血栓栓塞的预防诊断和管理（英文版） · 心血管内科 2024
• 小腿肌肉静脉血栓形成规范化诊疗与护理中国专家共识 · 心血管内科
• 2025 下肢深静脉血栓形成介入治疗护理实践指南 · 心血管内科 2025
• 老年人静脉血栓栓塞症防治中国专家共识2023 · 心血管内科 2023
• 围手术期静脉血栓栓塞症防治策略与药学监护专家共识 · 心血管内科
• （2025.V3）NCCN临床实践指南：癌症相关性静脉血栓栓塞性疾病 · 心血管内科 2025
• 战创伤后静脉血栓栓塞性疾病防治及康复专家共识（2025版） · 心血管内科 2025
• 2024 国际共识声明：静脉血栓栓塞的预防和管理 · 心血管内科 2024