2018 CHEST指南：成人肺动脉高压的治疗

Accepted Manuscript

 Therapy for Pulmonary Arterial Hypertension in Adults 2018: Update of the CHEST Guideline and Expert Panel Report

James R. Klinger, MD, FCCP, Gregory Elliott, MD, FCCP, Deborah J. Levine, MD, FCCP, Eduardo Bossone, MD, PhD, FCCP, Laura Duvall, PharmD, BCPS, Karen Fagan, MD, Julie Frantsve-Hawley, PhD, Steven M. Kawut, MD, MS, FCCP, John J. Ryan, MD, Erika B. Rosenzweig, MD, Nneka Sederstrom, PhD, FCCP, Virginia D. Steen, MD, David B. Badesch, MD, FCCP

PII: S0012-3692(19)30002-9 DOI: https://doi.org/10.1016/j.chest.2018.11.030 Reference: CHEST 2094 To appear in: CHEST Received Date: 9 August 2018 Revised Date: 28 November 2018 Accepted Date: 29 November 2018

Please cite this article as: Klinger JR, Elliott G, Levine DJ, Bossone E, Duvall L, Fagan K, FrantsveHawley J, Kawut SM, Ryan JJ, Rosenzweig EB, Sederstrom N, Steen VD, Badesch DB, Therapy for Pulmonary Arterial Hypertension in Adults 2018: Update of the CHEST Guideline and Expert Panel Report, CHEST (2019), doi: https://doi.org/10.1016/j.chest.2018.11.030 .

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1 Therapy for Pulmonary Arterial Hypertension in Adults 2018: Update of the

## CHEST Guideline and Expert Panel Report

3 James R Klinger, MD, FCCP; Gregory Elliott, MD, FCCP; Deborah J Levine, MD, FCCP; Eduardo Bossone, 4 MD, PhD, FCCP; Laura Duvall, PharmD, BCPS; Karen Fagan, MD; Julie Frantsve-Hawley, PhD; Steven M. 5 Kawut, MD, MS, FCCP; John J Ryan, MD; Erika B. Rosenzweig, MD; Nneka Sederstrom, PhD, FCCP; 6 Virginia D Steen, MD; David B Badesch, MD, FCCP

8 Affiliations: Brown University (Dr Klinger), Providence, RI; Intermountain Healthcare and the University 9 of Utah School of Medicine (Dr Elliott ), Murray, UT; University of Texas Health Science Center at San 10 Antonio (Dr Levine), San Antonio, TX; A. Cardarelli Hospital (Dr Bossone), Naples, Italy; OhioHealth / The 11 Ohio State University (Dr Duvall); Columbus, OH; University of South Alabama (Dr Fagan); Mobile, AL; 12 CHEST (Dr Frantsve-Hawley), Glenview, IL; Perelman School of Medicine at the University of 13 Pennsylvania (Dr Kawut), Philadelphia, PA; University of Utah (Dr Ryan), Salt Lake City, UT; Columbia 14 University Medical Center (Dr Rosenzweig), New York, NY; Children’s Hospitals and Clinics of Minnesota 15 (Dr Sederstrom), Minneapolis, MN; Georgetown University Medical Center (Dr Steen), Washington, DC; 16 University of Colorado School of Medicine (Dr. Badesch), Aurora, CO

17 Conflicts of Interest: see e-Table 1

18 Funding/Support: This study was funded in total by internal funds from the American College of Chest 19 Physicians 20 Disclaimer: CHEST Guidelines are intended for general information only, are not medical advice, and do 21 not replace professional medical care and physician advice, which should always be sought for any 22 medical condition. The complete disclaimer for this guideline can be accessed at: 23 http://www.chestnet.org/Guidelines-and-Resources

24 Correspondence to: Dr. David Badesh at David.Badesch@ucdenver.edu

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31 Abstract

32 Background: Pulmonary arterial hypertension (PAH) carries a poor prognosis if not promptly diagnosed 33 and appropriately treated. The development and approval of 14 medications over the last several 34 decades has led to a rapidly evolving approach to therapy, and has necessitated periodic updating of 35 evidence-based treatment guidelines. This guideline statement, which now includes a visual algorithm to 36 enhance its clinical utility, represents the $4^{\mathrm{th}}$ iteration of the American College of Chest Physicians 37 Guideline and Expert Panel Report on Pharmacotherapy for PAH. 38 Methods : The guideline panel conducted an updated systematic review to identify studies published 39 after those included in the 2014 guideline. A systematic literature search was conducted using MEDLINE 40 via PubMed and the Cochrane Library. The quality of the body of evidence was assessed for each critical 41 or important outcome of interest using the Grading of Recommendations Assessment, Development 42 and Evaluation (GRADE) approach. Graded recommendations and ungraded consensus-based 43 statements were developed and voted on using a modified Delphi technique to achieve consensus. 44 Results : Two new recommendations on combination therapy and two ungraded consensus-based 45 statements on palliative care were developed. An evidence-based and consensus-driven treatment 46 algorithm was created to guide the clinician through an organized approach to management, and to 47 direct readers to the appropriate area of the document for more detailed information. 48 Conclusions: Therapeutic options for the patient with PAH continue to expand through basic discovery, 49 translational science, and clinical trials. Optimal use of new treatment options requires prompt 50 evaluation at an expert center, utilization of current evidence-based guidelines, and collaborative care 51 employing sound clinical judgement.

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60 Abbreviations:

61 6MWD $=$ six-minute walk distance 62 ACCP = American College of Chest Physicians 63 AHRQ = Agency for Healthcare Research and Quality 64 AMBITION $=$ Ambrisentan and Tadalafil in Patients with Pulmonary Arterial Hypertension 65 BNP = Brain natriuretic peptide 66 BP = blood pressure 67 $\mathsf{C C B}=$ calcium channel blocker 68 $\mathtt{C C C}=$ Centers of Comprehensive Care 69 CI = confidence interval 70 CO = cardiac output 71 COI = Conflict of Interest 72 COMPERA $=$ Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension 73 COPD $=$ chronic obstructive pulmonary disease 74 DART $=$ Documentation and Appraisal Review Tool 75 DVT $=$ deep vein thrombosis 76 ERA $=$ endothelin receptor antagonist 77 FC = Functional class 78 FDA $=$ Food and Drug Administration 79 GOC = Guidelines Oversight Committee 80 GRADE $=$ Grading of Recommendations, Assessment, Development and Evaluation 81 GRIPHON $=$ Prostacyclin (PGI 2 ) Receptor Agonist In Pulmonary Arterial Hypertension 82 HR = hazard ratio 83 IMT $=$ inspiratory muscle training 84 ${\mathsf{P A H}}=$ idiopathic pulmonary arterial hypertension 85 IV = intravenous therapy 86 MID $=$ Minimal Important Difference 87 mPAP = mean pulmonary artery pressure 88 NT-BNP = N-terminal pro brain natriuretic peptide 89 OR = odds ratio 90 PAH = Pulmonary Arterial Hypertension 91 PH = Pulmonary Hypertension 92 PHCC = Pulmonary Hypertension Care Centers 93 PDE5I $=$ phosphodiesterase type-5 inhibitors 94 PPH = primary pulmonary hypertension 95 PE = pulmonary embolism 96 PSC = Professional Standards Committee 97 PICO = population, intervention, comparator, outcome

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Note on Shaded Text: In this guideline, shaded text with an asterisk (shading appears in PDF only) indicates statements that are newly added or have been changed since the publication of “Pharmacologic Therapy for Pulmonary Arterial Hypertension in Adults: CHEST Guideline and Expert Panel Report” in 2014. Statements that remain unchanged since that edition are not shaded. The order of our presentation should not be interpreted as the guideline panel’s order of preference for the use of these agents.

Summary of Recommendations

Grey shading $=$ new recommendations

1. We suggest that the severity of a PAH patient’s disease be evaluated in a systematic and consistent manner, using a combination of WHO FC, exercise capacity, echocardiographic, laboratory and hemodynamic variables in order to inform therapeutic decisions (Ungraded consensus- based statement). 2. We suggest that, whenever possible, all PAH patients be evaluated promptly at a center with expertise in the diagnosis of PAH, ideally prior to the initiation of therapy (Ungraded consensusbased statement). 3. We suggest collaborative and closely coordinated care of PAH patients involving the expertise of both local physicians and those with expertise in PAH care (Ungraded consensus-based statement). Remark : Appropriate care may require the coordinated efforts of cardiologists, pulmonologists, rheumatologists, radiologists, cardiothoracic surgeons, transplant teams, primary care, and other specialists. In addition, appropriate care may involve teams of allied health professionals, including advanced practice clinicians, nurse coordinators, respiratory therapists, exercise physiologists, social workers, pharmacists, among others. Caregiver support, whether it be by family or friends remain an integral part of the care team.

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160 These teams of physicians, and allied health professionals and caregivers are important components 161 in centers with expertise in the diagnosis of PAH. 162 Remark : Further discussion of tools for evaluating disease severity and mortality risk and description of 163 centers of expertise is provided in the section entitled “Pharmacologic Therapy for PAH in Adults” 164 Treatment Naive PAH Patients Without Symptoms (WHO FC I) and Patients at Increased Risk 165 for the Development of PAH 166 4. For treatment-naive PAH patients with WHO FC I symptoms, we suggest continued monitoring for 167 the development of symptoms that would signal disease progression and warrant the initiation of 168 pharmacotherapy (Ungraded consensus-based statement). 169 Remark : Early symptoms concerning for the progression of PAH include new or worsening dyspnea on 170 exertion, fatigue, and weakness. As the disease evolves, symptoms including lower extremity edema, 171 angina or syncope could signal right heart dysfunction and or failure. Patients with PAH and FC I 172 symptoms should be closely monitored for increased symptoms. 173 174 5. We suggest that patients at increased risk for the development of PAH (table 4) be monitored for 175 the development of symptoms of PAH (Ungraded consensus-based statement). 176 6. We suggest also that contributing causes of PH (e.g. sleep apnea and systemic hypertension) in 177 patients with PAH be treated aggressively (Ungraded consensus-based statement). 178 Symptomatic Patients With PAH 179 Vasoreactivity Testing and Use of Calcium Channel Blockers (CCBs) 180 7. We suggest that patients with PAH, in the absence of contraindications, should undergo acute

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vasoreactivity testing using a short-acting agent at a center with experience in the performance and interpretation of vasoreactivity testing (Ungraded consensus-based statement). Remark : Patients at increased risk of adverse events during acute vasoreactivity testing include those with FC IV symptoms, a low systemic BP, low CO, or PVOD. Acute vasoreactivity testing may be complicated by hypotension, and the misinterpretation of results may result in the inappropriate exposure of patients to the risks of a treatment trial with CCBs without the possibility of clinical benefit. Vasoreactivity testing should be performed by individuals with appropriate training in test performance and interpretation. 8. We suggest that patients with PAH who, in the absence of right-sided heart failure or contraindications to CCB therapy, demonstrate acute vasoreactivity according to consensus definition, should be considered candidates for a trial of therapy with an oral CCB (Ungraded consensus-based statement). Remark : Careful follow up of these patients is advised. Long-acting nifedipine or diltiazem, or 1 amlodipine are suggested. Due to its potential negative inotropic effects, verapamil should be avoided. The daily doses of these drugs that have shown efficacy in IPAH are relatively high: 120–240 mg for 2 nifedipine, 240–720 mg for diltiazem and up to 20 mg for amlodipine. Patients should be followed up closely for both safety and efficacy, with an initial reassessment after 3 months of therapy. If a patient does not improve to functional class I or II, additional or alternative PAH therapy should be instituted. Remark: Even though a small percentage $(<\!5\%)$ of PAH in patients with connective tissue diseases may be vasoreactive, there are no studies to suggest that CCB have been effective. 9. We suggest that CCBs should not be used empirically to treat PAH in the absence of demonstrated acute vasoreactivity (Ungraded consensus-based statement).

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204 PAH-Specific Pharmacotherapies

205 \*10. For treatment naive PAH patients with WHO FC II and III, we suggest initial combination therapy 206 with ambrisentan and tadalafil to improve 6MWD (weak recommendation, moderate quality 207 evidence) (Figure 2) 208 209 Patients with WHO Functional Class II Symptoms 210 For treatment-naive patients with PAH with WHO FC II symptoms who are not candidates for, or who 211 have failed, CCB therapy, we advise that therapy be initiated with a combination of ambristenan and 212 tadalafil as stated in Recommendation #10. For patients who are unwilling or unable to tolerate 213 combination therapy, we advise monotherapy with a currently approved ERA, PDE5I inhibitor, or the 214 soluble guanylate cyclase stimulator riociguat as outlined in the 2014 guidelines. More specifically in 215 these patients: 216 11. We recommend ambrisentan to improve 6MWD (strong recommendation, low quality evidence ) . 217 12-13. We suggest bosentan to delay time to clinical worsening (ungraded consensus-based 218 statement) . 219 14. We suggest macitentan to delay the time to clinical worsening (ungraded consensus-based 220 statement ) . 221 15. We recommend sildenafil to improve 6MWD ( strong recommendation, low quality evidence ) . 222 16. We suggest tadalafil to improve 6MWD (ungraded consensus-based statement).

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223 17-20. We suggest riociguat to improve 6MWD (ungraded consensus-based statement ) , improve WHO 224 FC (ungraded consensus-based statement), delay the time to clinical worsening (ungraded consensus 225 based statement). 226 21. We suggest that parenteral or inhaled prostanoids not be chosen as initial therapy for treatment 227 naive PAH patients with WHO FC II symptoms or as second line agents for PAH patients with WHO FC 228 II symptoms who have not met their treatment goals (Ungraded consensus-based statement). 229 Patients with WHO FC III Symptoms 230 For treatment-naive PAH patients with WHO FC III symptoms who are not candidates for, or who have 231 failed CCB therapy, we advise that therapy be initiated with a combination of ambristenan and 232 tadalafil as stated in Recommendation #10. For patients who are unwilling or unable to tolerate 233 combination therapy, we advise monotherapy with a currently approved ERA, a PDE5I, or the soluble 234 guanylate cyclase stimulator riociguat. More specifically in these patients: 235 22. We recommend the use of bosentan to improve 6MWD (strong recommendation, moderate 236 quality evidence). 237 23-24. We suggest the use of bosentan to decrease hospitalizations related to PAH in the short-term 238 (weak recommendation, low quality evidence). 239 25. We recommend the use of ambrisentan to improve 6MWD (strong recommendation, low quality 240 evidence). 241 26-27. We suggest macitentan to improve WHO FC (ungraded consensus-based statement) and delay 242 the time to clinical worsening (ungraded consensus-based statement).

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243 28-30. We recommend the use of sildenafil to improve 6MWD (strong recommendation, low quality 244 evidence), to improve WHO FC (ungraded consensus-based statement). 245 31-34. We suggest the use of tadalafil to improve 6MWD (ungraded consensus-based statement), to 246 improve WHO FC (ungraded consensus-based statement), to delay time to clinical 247 worsening (ungraded consensus-based statement). 248 35-38. We suggest riociguat to improve 6MWD (ungraded consensus-based statement), improve WHO 249 FC (ungraded consensus-based statement), delay the time to clinical worsening (ungraded consensus 250 based statement). 251 For treatment naive PAH patients with WHO FC III symptoms who have evidence of rapid progression 252 of their disease, or other markers of a poor clinical prognosis, we advise consideration of initial 253 treatment with a parenteral prostanoid. More specifically in these patients: 254 39-41. We suggest continuous IV epoprostenol to improve FC (ungraded consensus-based statement), 255 improve 6MWD (ungraded consensus-based statement). 256 42. We suggest continuous IV treprostinil to improve 6MWD (ungraded consensus-based statement). 257 43-44. We suggest continuous subcutaneous treprostinil to improve 6MWD (ungraded consensus 258 based statement). 259 For PAH patients in WHO FC III who have evidence of progression of their disease, and/or markers of 260 poor clinical prognosis despite treatment with one or two classes of oral agents, we advise 261 consideration of the addition of a parenteral or inhaled prostanoid. More specifically in these 262 patients:

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263 45-47. We suggest IV epoprostenol to improve WHO FC ( ungraded consensus-based statement), 264 improve 6MWD (ungraded consensus-based statement). 265 48-49. We suggest IV treprostinil to improve 6MWD (ungraded consensus-based statement). 266 50. In patients with PAH who remain symptomatic on stable and appropriate doses of an ERA or a 267 PDE5I, we suggest the addition of inhaled treprostinil to improve 6MWD ( weak recommendation, low 268 quality evidence ) . 269 51-52. In patients with PAH who remain symptomatic on stable and appropriate doses of an ERA or a 270 PDE5I, we suggest the addition of inhaled iloprost to improve WHO FC ( ungraded consensus-based 271 statement ) and delay the time to clinical worsening ( ungraded consensus-based statement ). 272 273 Patients with WHO FC IV Symptoms 274 For treatment naive PAH patients in WHO FC IV, we advise initiation of therapy with a parenteral 275 prostanoid agent. More specifically in these patients: 276 53-55. We suggest continuous IV epoprostenol to improve WHO FC ( ungraded consensus-based 277 statement ) , improve 6MWD ( ungraded consensus-based statement ) . 278 56. We suggest continuous IV treprostinil to improve 6MWD ( ungraded consensus-based statement ) . 279 57-58. We suggest continuous subcutaneous treprostinil to improve 6MWD (ungraded consensus 280 based statement).

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59. For treatment naive PAH patients in WHO FC IV who are unable or do not desire to manage parenteral prostanoid therapy, we advise treatment with an inhaled prostanoid in combination with an oral PDE5I and an ERA (ungraded consensus-based statement).

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Remark : The management of PAH patients with FC IV symptoms who are unable or unwilling to use parenteral prostanoid therapy is particularly challenging because of their high risk of mortality and the lack of data on the efficacy of oral therapies in this group. Very few FC IV patients were included in trials of oral therapies making it difficult to determine how they will respond. Further studies are needed to determine the efficacy of combination oral and/or inhaled therapies in patients with advanced PAH who are unable or unwilling to tolerate parenteral prostacyclin therapy. Although these guidelines have been limited to pharmacologic therapy for PAH, there is consensus among the panel that the option of lung transplantation should be discussed with PAH patients who have advanced disease such as FC III who fail to improve on medical therapy or those in FC IV. Patients who are interested in this option should be evaluated at a transplant center experienced in transplantation for patients with PAH.

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295 PAH Patients on Established PAH-Specific Therapy:

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60. In PAH patients initiating therapy with IV epoprostenol, we suggest against the routine simultaneous initiation of bosentan (ungraded consensus-based statement).

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For WHO FC III or IV PAH patients with unacceptable clinical status despite established PAH-specific monotherapy, we advise addition of a second class of PAH therapy to improve exercise capacity. Such patients are ideally evaluated at centers with expertise in the evaluation and treatment of patients with PAH. More specifically:

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302 61. In patients with PAH who remain symptomatic on stable doses of an ERA or a PDE5I, we suggest 303 the addition of inhaled iloprost to improve 6MWD (ungraded consensus-based statement). 304 62. In patients with PAH who remain symptomatic on stable doses of an ERA or a PDE5I , we 305 recommend the addition of inhaled treprostinil to improve 6MWD ( strong recommendation, low 306 quality evidence). 307 63. In PAH patients who remain symptomatic on stable doses of established IV epoprostenol, we 308 suggest the addition of sildenafil or up titration of epoprostenol to improve 6MWD ( ungraded 309 consensus-based statement). 310 64-66. In patients with PAH who remain symptomatic on stable doses of bosentan, ambrisentan or an 311 inhaled prostanoid, we suggest the addition of the soluble guanylate cyclase stimulator riociguat to 312 improve 6MWD ( ungraded consensus-based statement), WHO FC (ungraded consensus-based 313 statement) and to delay the time to clinical worsening (ungraded consensus-based statement). 314 67-69. In patients with PAH who remain symptomatic on stable doses of a PDE5I or an inhaled 315 prostanoid we suggest macitentan to improve 6MWD (ungraded consensus-based statement), WHO 316 FC (ungraded consensus-based statement) and to delay the time to clinical worsening (ungraded 317 consensus-based statement). 318 70. For WHO FC III or IV PAH patients with unacceptable or deteriorating clinical status despite 319 established PAH-specific therapy with two classes of PAH pharmacotherapy, we suggest addition of a 320 third class of PAH therapy (ungraded consensus-based statement). 321 Remark: Such patients are ideally evaluated at centers with expertise in the evaluation and treatment of 322 patients with PAH.

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324 \*71. For stable or symptomatic PAH patients on background therapy with ambrisentan, we suggest 325 the addition of tadalafil to improve 6MWD (weak recommendation, low quality evidence) (Figure 2) 326 Palliative Care and Supportive Therapies 327 \*72. We suggest incorporating palliative care services in the management of PAH patients (ungraded 328 consensus-based statement). (Figure 3) 329 \*73. We suggest that patients with PAH participate in supervised exercise activity as part of the 330 integrated care of their disease (ungraded consensus-based statement). (Figure 3) 331 Preventive Care 332 74. In patients with PAH, we suggest maintaining current immunization against influenza and 333 pneumococcal pneumonia (ungraded consensus-based statement). 334 Specific Patient Situations 335 Pregnancy 336 75. In patients with PAH, we suggest that pregnancy be avoided (ungraded consensus-based 337 statement). 338 76. When pregnancy does occur in patients with PAH, we suggest care at a pulmonary hypertension 339 center with experience in this area, using a multidisciplinary approach including the pulmonary 340 hypertension, the high-risk obstetrical, and cardiovascular anesthesiology services (ungraded 341 consensus-based statement).

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342 Altitude and Air Travel

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77. In patients with PAH, we suggest that exposure to high altitude be avoided, and that supplemental oxygen be used as needed during altitude exposure or air travel to maintain oxygen saturations $>\pmb{91\%}$ ( ungraded consensus-based statement). Remark : Patients with borderline oxygen saturations at sea level may require 3-4 L per minute of supplemental oxygen at high altitude or while traveling on commercial aircraft, and those already using supplemental oxygen at sea level should increase their oxygen flow rate under these conditions.

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78. In patients with PAH, we suggest avoiding non-essential surgery, and when surgery is necessary we suggest care at a pulmonary hypertension center, using a multidisciplinary approach including the pulmonary hypertension team, the surgical service, and cardiovascular anesthesiology with careful monitoring and management of clinical status, oxygenation and hemodynamics postoperatively (ungraded consensus-based statement) .

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356 Introduction

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WHO Group 1 PAH (Table 1) is a progressive and fatal disorder for which there was once no effective treatment. However, during the past four decades basic discoveries and pivotal clinical trials have led to the development and regulatory approval of 14 medications (Table 7).

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As a resource for clinicians, the American College of Chest Physicians (ACCP) convened expert panelists who developed guidelines for the treatment of PAH. In 2004, the first guidelines appeared as a 3-9 supplement to CHEST. In 2007, a consensus panel updated these guidelines based on evidence

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1 published after the 2004 guideline and before September 1, 2006. In 2014, CHEST published the most recent guideline and expert panel report regarding pharmacotherapy for PAH based on evidence 10 available before November 2013. Since November 2013 investigators have published a substantial body of new evidence related to the treatment of PAH, and 2 medications received regulatory approval for the treatment of PAH. An orally active preparation of treprostinil was approved by the FDA in December 2013 and selexipag, an oral prostacyclin receptor agonist, received FDA approval in 2015. Research groups have provided data on initial treatment with combinations of PAH targeted medications as well as data on the addition of PAH medications to background therapy. These new studies and medications have altered the therapeutic landscape for patients with PAH and for the clinicians who care for them. In January 2016, the CHEST Guidelines Oversight Committee (GOC) accepted a proposal to update the 2014 guideline and expert panel report, and they organized a broadly constituted guideline and expert panel that included content experts, methodologists, an ethicist, a patient representative, and a pharmacist. The panel followed CHEST’s rigorous process for the development of the guidelines in line with the National Academies (formerly Institute of Medicine) standards. The panel sought to create a methodologically sound evidence-based document that is credible, accurate, and useful. Several of the new studies reviewed in this update employed a composite of clinical endpoints indicative of PAH disease progression as the primary outcome. The definition of clinical failure varied between studies, but included events such as death, hospitalization for PAH, clinical worsening based on a decrease in 6-minute walk distance, change in WHO Functional Class or unsatisfactory long term response. While these endpoints were not identical, they represented primary pre-specified measures, much like composite scores for recurrent DVT, DVT extension, new PE or death from PE were used as a primary endpoint for clinical trials of antithrombotic therapies in venous thromboembolism.13,14 The

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guideline committee recognized the challenges created by the similar, but different, endpoints reported in more recent PAH trials and concluded that the small number of studies using composite endpoints and the differences between the endpoints made it difficult to determine how to weigh the strength of recommendations. Instead, the guideline committee chose to use the 6-minute walk test as a clinically relevant outcome, which allowed data to be extracted from the AMBITION and GRIPHON (a clinical trial of a prostacyclin receptor agonist as monotherapy or add on therapy in patients with PAH) trials. This decision resulted in a weak recommendation with moderate quality of evidence for initial combination therapy with ambrisentan and tadalafil over initial monotherapy with either medication for treatment naïve patients with FC II or III symptoms (Recommendation 10) and insufficient evidence to make a recommendation for or against the use of selexipag. However, the committee recognizes that some clinicians and patients may place a greater value on slowing PAH disease progression than on improving functional capacity and if so, may choose to use the beneficial effect of combination therapy or selexipag on delaying time to clinical worsening as their rationale for using these treatments in the management of PAH.

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In summary, this article provides current evidence-based guidelines for the treatment of PAH, updating the recommendations that were included in the 2014 guideline and expert panel report. This document reflects CHEST’s hybrid approach of accommodating evidence-based recommendations with consensusbased statements in areas where there is insufficient evidence. All clinicians and individuals involved in the care and management of PAH patients are the target users of this guideline.

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Methods

406 Expert Panel Composition

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The qualifications of the suggested co-chairs of the guideline were reviewed and approved by CHEST’s

408 Professional Standards Committee (PSC). Panelists were nominated by the co-chairs based on their

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expertise relative to the scope of the guideline. The complete guideline panel consisted of three cochairs (DL, DB, JK), three panelists (GE, SK, NS) and panel representatives from the following organizations: Pulmonary Hypertension Association (LD, EBR), American Thoracic Society (KF), American Heart Association (JR), a representative from CHEST’s Guideline Oversight Committee (EB) and a patient representative (SR).

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414 Conflicts of Interest

415 All panel nominees were reviewed for their potential conflicts of interest (COI) by CHEST’s PSC. 416 Nominees who were found to have no substantial COIs were approved, whereas nominees with either 417 potential intellectual or financial COIs that were manageable were “approved with management.” 418 Panelists who were approved with management were prohibited from drafting and voting on 419 recommendations in which they had substantial potential COIs. Additionally, in situations where one of 420 the co-chairs had a conflict preventing engagement based on the management terms, an un-conflicted 421 co-chair led the panel discussion. 422 As with many rare diseases, pulmonary arterial hypertension (PAH) has historically lacked research 423 funding from governmental agencies due to the relatively few numbers of patients who would benefit. 424 Patient advocacy organizations’ fundraising and public awareness campaigns have until recently 425 provided the bulk of resources for scientific research related to etiology, diagnosis, and treatment of 426 PAH patients. Similarly, the number of basic science researchers and clinicians involved in the field has 427 been low, yielding a small number of subject matter experts who have been able to conduct clinical 428 trials that have resulted in 14 targeted therapies available within the past 25 years. 429 While CHEST’s conflict of interest protocol clearly limits involvement of guidelines panel members who 11 430 have potential industry and academic conflicts , the unique circumstances dictated by research in this 431 rare disease presented the option of preparing a document without the expertise of hands-on subject

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matter experts or involving those with experience and knowledge who also have shared –and gained-- their expertise with industry research programs in the effort to improve care for this patient population. As with all CHEST programs, the principals’ conflict of interest disclosures are published and available to all readers. In an attempt to provide clinicians worldwide with the best evidence analyzed by subject matter experts via its rigid methodologic process, CHEST has chosen to rely on the expertise of panel members who, although having disclosed potential conflicts, are among the small but growing number of experts in this field.

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440 Key Question Development

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Key clinical questions were developed using the PICO (Population, Intervention, Comparator, Outcome) format. This guideline is an update of the 2014 CHEST guideline, “Pharmacologic Therapy for Pulmonary 10 Arterial Hypertension in Adults.” That guideline used the Agency for Healthcare Research and Quality (AHRQ) Comparative Effectiveness Report, “Pulmonary Arterial Hypertension: Screening, Management, 12 and Treatment,” for the evidence review. The guideline specifically focused on key question 3 of that report, which states, “For patients with PAH, what are the comparative effectiveness and safety of monotherapy or combination therapy for PAH using calcium channel blockers, prostanoids, endothelin antagonists or phosphodiesterase inhibitors on intermediate term and long-term patient outcomes?” Because this current guideline is an update, the PICO was developed based on this key question and used the AHRQ methods for defining inclusion and exclusion criteria. The AHRQ methodology did not use composite endpoints due to lack of comparability in definition among studies and the assignment of equal importance to events included in the composites such as mortality, hospitalization, transplant, 12 and changes in 6MWD distance. The panel agreed with this decision and chose to maintain the exclusion of composite endpoints for these reasons and also to maintain consistency between the

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455 original and updated review. Among study outcomes, the 6MWD was one of the most frequently 456 reported in studies. The AHRQ evidence review recognized that not all change in 6MWD was clinically 457 important. They used the MID (minimally important difference) specified in PAH literature as 33 meters 12 458 to define clinically significant improvement. We maintained this definition for the review. 459 During discussion and development of the PICO, the panel decided it was important to update the 460 pharmacologic therapies by adding orally active prostacyclins and prostacyclin receptor agonists and to 461 add non-pharmacologic interventions. Therefore, the final PICO question addressed in this guideline is: 462 For adult patients with pulmonary arterial hypertension, what are the comparative effectiveness and 463 safety of 1) mono- or combination pharmacotherapies using calcium channel blockers, prostanoids, 464 endothelin antagonists, phosphodiesterase inhibitors, soluble guanylate cyclase stimulators, or orally 465 active prostacyclin derivatives and prostacyclin receptor agonists; 2) cardio-pulmonary rehabilitation; 466 3) palliative care; 4) supportive care; and 5) preventive care on intermediate-term and long-term 467 patient outcomes? (Table 2) 468 To maintain the integrity of the update process and to add the additional interventions, we decided to 469 manage the evidence review search and selection of eligible studies in 2 phases. Phase I was an update 470 of the prior review that was conducted by AHRQ and Phase II was a review of the new pharmacologic 471 and non-pharmacologic interventions. 472 Systematic Literature Search 473 A systematic literature search for individual studies for this PICO was conducted using the following 474 databases: MEDLINE via PubMed and the Cochrane Library. Searches for Phase I were updated from 475 January 2012 to July 2016. The search strategy from the AHRQ review was used with slight modification

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476 to focus on Group 1 PAH (e-Table 2). All searches were also limited to English language. Searches for 477 Phase II modified the Phase I search to retrieve the additional interventions (e-Table 2). 478 The panelists reviewed the titles and abstracts of the search results independently and in parallel to 479 identify potentially relevant articles based on the inclusion and exclusion criteria (Table 2). All 480 discrepancies were resolved by discussion. Studies deemed eligible then underwent a second round of 481 full-text screening by the same pair of panelists for final inclusion. Again, discrepancies were resolved 482 by discussion. Important data from each included study were then extracted into structured evidence 483 tables completed independently and in parallel by two abstractors. 484 Quality assessment 485 Included studies were assessed for quality and risk of bias using the following assessment tools: • 13 486 DART for systematic review • 14 487 Cochrane risk of bias tool for randomized controlled trials • 15 488 Risk of bias tool for observational intervention studies 489 Grading the Evidence and Development of Recommendations 490 GRADE Evidence Profiles were created to grade the overall quality of the body of evidence supporting 491 the outcomes for each intervention based on 5 domains: risk of bias, inconsistency, indirectness, 492 imprecision, and publication bias. The quality of the evidence for each outcome is rated as high, 16,17 493 moderate, low, or very low according to GRADE standards. 494 The panel drafted recommendations for each key clinical question that had sufficient evidence. 495 Recommendations were graded using the CHEST grading system (Table 3), based on GRADE, which is 496 composed of 2 parts: the strength of the recommendation (either strong or weak) and a rating of the

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18 overall quality of the body of evidence. In instances where there was insufficient evidence, but a recommendation was still warranted, a weak suggestion was developed and “Ungraded ConsensusBased Statement” replaced the grade. The 2014 guideline used CHEST’s previous grading system, modified GRADE. All unchanged recommendations and suggestions from that iteration of the guideline 19 have been converted to standard GRADE format for consistency with current methodology.

The 2014 guideline included multiple ungraded statements referencing use of interventions to improve cardiopulmonary hemodynamic parameters that were not supported by evidence addressing overall patterns of hemodynamic changes. The rationale used at that time was that since only evidence on a single parameters (eg, for PVR, [mPAP], CO, cardiac index, right atrial pressure) were available in some circumstances, ungraded statements were included to alert clinicians to when improvements in individual parameters have been found. However, since neither GRADE methodology, nor the CHEST approach toward consensus statements, support ungraded statements in the absence of evidence, all references to potentially improved cardiopulmonary hemodynamic outcomes were removed from this update guideline when there is lack of evidence to support such statements.

Consensus Development

All drafted recommendations and suggestions were presented to the panel in an anonymous voting survey to achieve consensus through a modified Delphi technique. Panelists were requested to indicate their level of agreement on each statement, using a 5-point Likert scale derived from the GRADE 18,20 grid. Panelists also had the option to provide open-ended feedback on each statement with suggested edits or general comments. According to CHEST policy, each statement required a $75\%$ voting participation rate and at least $80\%$ consensus agreement to be accepted. Panelists with COIs related to the individual statements were not allowed to vote (per the terms of their COI management).

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The flow chart in e-Figure 1 presents the results of the systematic search for Phase I. The updated search identified 300 potentially new studies. Of those, 106 were selected for full text review, and of 21-24 those only 4 studies met all inclusion criteria. Those 4 studies each examined different combination 21-23 24 therapies. Three of the studies earned a low risk of bias rating ; the fourth earned an unclear rating. The flow chart in e-Figure 2 presents the results of the systematic search for Phase II. The search for new interventions identified 379 citations. Of those, 30 were selected for full text review, and of those, only 25-36 25,26 12 studies met all inclusion criteria. Of these, 2 studies evaluated selexipag. One systematic 27 review, which included 2 of the primary studies we identified, evaluated exercise-based rehabilitation. 28 One study evaluated inspiratory muscle training. One systematic review and 3 primary studies 29-32 34 33 evaluated anticoagulation. One study evaluated antiplatelet therapy and one evaluated SSRIs. Both systematic reviews were well designed and executed and earned a good quality rating, although they found little or no evidence relevant to our question. All of the 10 primary studies earned an unclear risk of bias rating.

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535 Pharmacologic Therapy for PAH in Adults

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Lacking head-to-head comparisons of pharmacologic agents for the treatment of PAH, and because of their different desirable and undesirable effects for patients, we recommend that drug therapy be chosen on the basis of a methodical evaluation of disease severity, the risk for further short-term deterioration, and the preferences and values of the patient. The optimal method of evaluation has not been studied. Previous guidelines have suggested that WHO FC, echocardiographic assessment of right ventricular function, 6MWD, plasma BNP or NT-BNP level, hemodynamic measurements, and cardiopulmonary exercise testing in addition to patient symptoms and clinical findings can be useful

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37 indicators of disease severity and response to treatment. Specific parameters for each of these 2 variables have been proposed to identify patients at low, intermediate or high risk of 1-year mortality and predictive equations for survival in PAH have been developed (REVEAL, French Pulmonary 38,39 Hypertension Network predictive equation). However, none of these tools have been prospectively validated and the ability of any of these tools to identify which patients are more likely to derive benefit from a particular therapy has not been formally studied. Lacking data from such studies, we provide recommendations that are based upon the WHO FC of the patients enrolled in the clinical studies we evaluated. Please refer to the full treatment algorithm in Figure 1.

Due to the rare occurrence of PAH in the general population, most physicians, including those whose subspecialty practice includes pulmonary and cardiology, are unlikely to encounter sufficient numbers of PAH patients to gain meaningful experience with the diagnosis and management of this disease. For this reason, we suggest that newly diagnosed patients with PAH be referred to a center with experience in managing PAH, ideally before treatment is initiated. Until recently, there was no formal process for identifying centers that had expertise in managing PAH. In 2015, the Pulmonary Hypertension Association began the PH Care Centers (PHCC) initiative. This program accredits Centers of Comprehensive Care (CCC) and Regional Clinical Programs (RCP) in the United States based on their willingness to participate in the program and their ability to demonstrate proficiency in managing PAH patients. Currently there are over 50 PHA accredited centers throughout the US. Many other centers outside of the PHA accreditation program also have extensive management experience in PAH. Although differences in outcome between patients managed with or without the advice of an expert center has not been formally studied, referral to such centers is recommended by treatment guidelines from the joint task force of the European Society of Cardiology and the European Respiratory Society (reference # 2) and by the World Symposium on Pulmonary Hypertension. Considering the increased availability of centers that specialize in the management of PAH , the guideline committee agreed that

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567 patients should be offered access to these resources whenever feasible.

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Despite variability in clinicians’ approaches, the WHO FC (Table 5) provides a symptom-based means of 40 assessing disease impact on a patient’s life. Similarly, despite limitations in its use as a surrogate measure, the 6MWD provides functional information. Additionally, hemodynamic, echocardiographic, and BNP or NT-BNP provide an assessment of cardiac impairment that may be useful in guiding therapy. A combination of variables, each evaluated in a consistent manner, is recommended. All treatment decisions should be informed by patient preferences and values, goals, and assessments of healthrelated quality of life.

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Additionally, the panel acknowledges that the drugs reviewed in this guideline are expensive, and that current costs should be taken into account with other information on efficacy, safety, and the patient’s individual situation when selecting the most appropriate therapy. Furthermore, multiple drug options are provided for many of the patient conditions. In these circumstances, no comparative effectiveness data is available to suggest greater benefit of one therapy over the other. In these situations, other factors, such as patient preferences & values, cost, and insurance coverage, may guide decision-making.

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585 Newly Approved Therapies

586 Selexipag: In the first FDA phase 2 trial, 43 adult patients with symptomatic PAH (receiving stable ERA 25 587 and/or a PDE5I therapy) were randomized to receive either selexipag or placebo. Dosage was up

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titrated in 200 mg increments from 200 mg twice daily on day 1 to the maximum tolerated dose by day 35 (maximum allowed dose of 800 mg twice daily). Mean change in 6MWD from baseline to 17 weeks was reported as an increase of 24.2 meters ( $.95\%$ CI -23.7m- 72.2m) for the Selexipag group, with no change in 6MWD reported for the placebo group. In this study, mean difference between the treatment and control groups, and confidence intervals, were not reported. This study was limited by its small size and is described as a “proof of concept” study.

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Selexipag was then studied in an FDA phase 3 trial in which 1156 patients with PAH were randomly

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twice daily).

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The primary endpoint was a composite of death from any cause or a complication related to PAH up to

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the end of the treatment period (defined for each patient as 7 days after the date of the last intake of

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selexipag or placebo). There was no significant difference in PAH mortality (HR, 0.86; 95% CI 0.63-1.18,

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), death from any cause (HR, 0.97; 95% CI 0.74-1.28,

), or absence of worsening in WHO FC

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(OR, 1.16; 99% CI 0.81-1.66, p=0.28) between the two study groups. While the change in 6MWD within

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the Selexipag group was statistically significant (12m, 99% CI 1-24), it did not meet our pre-specified MID

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defined in PAH literature as 33 meters for clinically significant improvement. Due to the use of a

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composite score as a primary endpoint and the lack of a clinically relevant change in 6MWD, the

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committee concluded that there is insufficient evidence at this time to make a recommendation for or

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against the use of selexipag.

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Oral Treprostinil: Oral treprostinil is FDA-approved as monotherapy for PAH. Our updated search identified one randomized controlled trial on monotherapy by Jing et al (FREEDOM-M) which assessed 41 the efficacy and safety of monotherapy with oral treprostinil compared to placebo. Investigators found that among patients receiving oral treprostinil, 6MWD significantly improved at 8 weeks (17m; 95% CI 1-33m; p=0.0307) and 12 weeks (23m; $95\%$ CI 4-41m; p=0.0125). This study was ultimately

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611 excluded from our review because of the inclusion of pediatric patients (age 12 and older), and thus the 612 panel was unable to make a recommendation for or against the use of oral treprostinil as monotherapy. 613 There is also currently no evidence to support its use in add-on or combination therapeutic approaches, 614 as discussed in the “ Combination of Prostacyclin Therapy with ERAs and PDE5Is ” section below. 615 Combination Trials in PAH since 2014 616 Since the 2014 guidelines were published, four studies have been completed in which PAH-specific 617 therapies have been used in combination, resulting in some changes and additions to the previous 21-24 618 recommendations. 619 620 Combination Studies of Endothelin Receptor Antagonists and Phosphodiesterase Inhibitors 621 Since the 2014 guidelines, three studies have been published reported using combinations of ERAs and 622 PDE5Is in different scenarios: 623 Bosentan added to sildenafil therapy in patients with PAH McLaughlin, et al conducted a multicenter 624 prospective, double-blind, event-driven trial of symptomatic PAH patients who were on stable therapy 625 with sildenafil at > 20 mg three times daily for at least 3 months. Three hundred and thirty-four patients 626 were randomized to receive placebo or bosentan at 62.5 mg twice daily for one month followed by 125 627 mg twice daily. 22 The between group mean difference for 6MWD was found to be $+21.8\,\mathsf{m}$ ( $95\%$ CI 5.9- 628 37.8, P =0.0106) in the bosentan treated patients compared to placebo. While this increase was found 629 to be statistically significant, it was less than the minimally important difference (33m) identified in the 630 methodology section of this guideline. No differences between the two groups were identified in other 631 outcomes of interest (change in WHO FC or time to death from any cause). There is currently insufficient 632 evidence to make a recommendation for or against addition of bosentan to patients on sildenafil.

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Initial use of ambrisentan plus tadalafil in pulmonary arterial hypertension: In the AMBITION trial, Galie, et al studied combination therapy with ambrisentan (10mg daily) plus tadalafil (40mg daily) versus 21 either ambrisentan or tadalafil alone in PAH.

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A total of 610 patients were randomized 2:1:1 to receive ambrisentan (10 mg daily) plus tadalafil (40 mg daily) versus ambrisentan plus placebo versus tadalafil plus placebo, respectively. The primary outcome was the time to first event of clinical failure defined as the composite endpoint for death, hospitalization for worsening PAH (including transplant, atrial septostomy and initiation of parenteral prostanoid therapy), disease progression (defined as a $15\%$ decrease in the 6MWD combined with a FC III or IV at 2 consecutive visits separated by 14 days), or unsatisfactory long-term clinical response in patients completing at least 6 months of the trial (assessed as a decrease in 6MWD from baseline and FC III symptoms at 2 visits separated by at least 6 months).

The median change from baseline for 6MWD improved more in the combination treatment group compared to the pooled monotherapy groups (49 m versus 24 m respectively, ${\cal P}{<}0.001$ ) (e-Table 4). There was no effect on the WHO FC. The improvement in 6MWD in the treatment group suggests that initial combination treatment may be more efficacious than monotherapy in improving exercise capacity. Because there was only one study, and the clinical outcome measured demonstrated a borderline clinically significant effect on 6MWD, the panel supported a weak suggestion instead of a strong recommendation. It is important that each physician and patient work together to decide best treatment options based on each individual situation and what is in the best interest for the particular patient.

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657 Recommendation

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\*10. For treatment naive PAH patients with WHO FC II and III, we suggest initial combination therapy with ambrisentan and tadalafil to improve 6MWD (weak recommendation, moderate quality evidence)

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Randomized study of adding tadalafil to existing ambrisentan in pulmonary arterial hypertension: Zhuang, et. al. conducted a prospective, double-blinded, randomized controlled study to investigate the 24 efficacy of addition of oral tadalafil in patients receiving background ambrisentan therapy for PAH. 124 patients with symptomatic IPAH, heritable PAH, or PAH associated with connective tissue disease, anorexigen use, or repaired congenital heart disease who were treated with ambrisentan (10 mg daily) for 4 or more months received either placebo or tadalafil (40 mg daily) for 16 weeks. At 16 weeks, there was a non-significant improvement in 6MWD from baseline in the placebo group (mean change 18.3 m; 95% CI 4.3-34.8, P =n.s) and a significant improvement in the tadalafil group (mean change 54.4 m; 95% CI 30.2-80.1, P <0.05) (e-Table 3). Compared to the placebo group, the increase in the treatment group was found to be significant $\left(\mathsf{p}\!\!=\!\!0.042\right)$ ), but mean difference between the treatment group and control group, and confidence intervals, were not reported. Change in WHO FC did not differ between groups at 16 weeks. Because there was only one study, and the clinical outcome measured demonstrated a borderline clinically significant effect on 6MWD, the panel supported a weak suggestion instead of a strong recommendation. It is still important that each physician and patient work together to decide best treatment options based on each individual situation and what is in the best interest for the particular patient.

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681 \*71. For stable or symptomatic PAH patients on background therapy with ambrisentan, we suggest 682 the addition of tadalafil to improve 6MWD (weak recommendation, low quality evidence) 683 684 Combination of Prostacyclin Therapy with ERAs and PDE5Is 685 Since publication of the 2014 guidelines, oral treprostinil was approved for treatment of PAH. Two 23 686 studies examined the effect of addition of oral treprostinil to background ERAs and/or PDE5Is. . 687 Tapson, et al performed an international multi-center, double-blind, placebo controlled trial of addition 688 of oral treprostinil to PAH patients receiving background therapy with ERAs and/or PDE5Is in the 23 689 FREEDOM-C2 trial. No significant difference was shown in the primary outcome of improvement in the 690 6MWD from baseline to 16 weeks (median difference: 10m; 95% CI -2 – 22m, p=.089). 691 This study is limited by a high percentage of premature discontinuations, relatively short treatment 692 duration, relatively small size, and potential “ceiling effect” of the 6MWD in patients already receiving 693 multiple background therapies. 694 At this time, there is insufficient evidence to make a recommendation for or against addition of bid oral 695 treprostinil to patients on background therapy with ERAs and/or PDE5Is. 696 Additional Considerations for Combination Therapies in PAH 697 As discussed in the 2014 guidelines and reviewed above, the addition of therapies to existing treatments 698 or the use of multiple therapies as initial treatment remains a complicated issue. Consideration of 699 addition of new therapies to a patient already on PAH treatment requires that the clinician assess 700 whether the patient has received an adequate trial of the initial therapy to assess efficacy and clinical

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status. This assessment includes evaluation of the duration of therapy, the expected response to the therapy, the observed response to the therapy, and the patient’s severity of illness and pace of decline. Unacceptable clinical status will vary for individual patients and clinicians, but symptomatic limitation of desired physical activities usually guides these decisions. The clinician must then review the evidence available to determine which additional therapy is likely to benefit the patient the most while limiting expected adverse events. The studies reviewed here represent the increasing interest in assessing combination therapy in additive or initial strategies and provide some framework to aid the clinician in these decisions.

As identified in the 2014 Guidelines, studies adding a second PAH-specific drug to already initiated PAH specific therapy have routinely continued the initial drug. None of the studies reviewed here indicate that the patient has or has not had a therapeutic benefit of the initial treatment but instead state the patients are stable. Published reports have not indicated whether clinical benefit had been noted in response to the initial agent. Indeed, many authors cite the potential “ceiling effect” of background treatments on outcome measures as limitations to identifying a benefit of their intervention, but fail to provide enough clinical information to make that determination. We continue to lack data to inform whether such practice is appropriate or whether it would be more appropriate to discontinue an initial agent if clinical benefit had not been observed following its initiation as was done in a recently published 42 open label study for riociguat. A lack of clinical improvement or a worsening of clinical status with therapy might represent an absence of benefit or even harm from the treatment, progression of disease, or a combination of these factors. As all drugs have potential adverse effects, and PAH-specific therapies are costly, this remains an important gap in the evidence available from clinical trials and a problematic issue for clinical care. More combination studies may inform clinicians to potential additive or even synergistic effects in the future

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724 Palliative Care and Supportive Therapies

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Six studies were identified for palliative care and supportive therapies. After full-text review, no eligible studies on palliative care and PAH exist to provide direct recommendations. The studies relating to 29-32 34 supportive care measures included 4 on anticoagulation , 1 on anti-platelet therapy , and 1 on SSRI 33 additions.

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729 Palliative Care

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Palliative medicine is a well-established and growing field with clearly documented benefits to patients and outcomes. Other lung diseases such as lung cancer have shown significant improvements in outcome measurements with the addition of palliative care to standard interventions. Our search identified no eligible studies to directly evaluate the effectiveness of palliative care therapies in conjunction with standard interventions for PAH; but this lack of evidence in the literature does not negate the potential benefits palliative care offers to all patients and families for assisting in management of disease burden, pain, and symptoms of chronic or acute needs. The addition of palliative care interventions to assist in management of disease burden and symptoms can often be beneficial to improving patient quality of life.

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\*72. We suggest incorporating palliative care services in the management of PAH patients (ungraded consensus-based statement).

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743 Pulmonary Rehabilitation

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Pulmonary rehabilitation has been shown to be safe and beneficial in improving exercise capacity and quality of life in chronic lung disease (ie: chronic obstructive lung disease (COPD), lung cancer and 43-45 pulmonary fibrosis). Studies exist on many aspects related to supervised exercise based 46-49 rehabilitation in PH. International guidelines recommend integrating exercise training into the care 2 of patients with PAH. Pulmonary rehabilitation, however, was not evaluated as a therapy for PAH in the 2014 ACCP guidelines. For this iteration of the CHEST guidelines, no studies were identified in our review that directly addressed pulmonary rehabilitation in adults with PAH.

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Exercise Training

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27,35,36 Our search identified three studies that assessed exercise training in PH. Studies by Ehlken and 27 Weinstein were included in a full systematic review by Morris. To avoid double counting, we used the systematic review only. While the systematic review included other studies on pulmonary hypertension, only two small studies (totaling 36 patients combined) were specific to patients with Group 1 PAH and were of low quality (e-Table 5).

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758 Profile Inspiratory Muscle Training

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28 One small study by Saglam et al met our inclusion criteria. Twenty-nine clinically stable PAH patients were randomly assigned to inspiratory muscle training (IMT) program or to a sham protocol. After 6 weeks, a significant change in 6MWD was seen in the IMT group $426.93\pm97.76$ before and $476.43\pm$ 90.11 after; p= .001), and no significant change was seen in the control group (357.24 ± 137.17 before and 334.00 ± 121.60 after; $\mathsf{p}\!\!=\!\!.109.$ ) (e-Table 6). The difference between groups was found to be significant $(\mathsf{p}\!<\!.001)$ ), but it is unclear if this difference is due to group differences at the start of the study.

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766 \*73. We suggest that patients with PAH participate in supervised exercise activity as part of the 767 integrated care of their disease (ungraded consensus-based statement).

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769 Anticoagulation 29-32 770 Four studies were identified in our review addressing anticoagulation. The Ezedunukwe et al. 771 systematic review evaluated randomized controlled trials that addressed the effectiveness and potential 772 adverse events of anticoagulation in the management of pulmonary hypertension. No eligible studies 773 were identified in this review. Olsson et al. conducted a retrospective cohort analysis from the 774 Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA) 30 775 registry. Among patients with IPAH on any type of anticoagulant, the adjusted hazards ratio for 776 survival was found to be 0.79 (95% CI 0.66-0.94; p=0.007). For patients with the scleroderma-spectrum 777 of disease and PAH (SSc-PAH), the use of anticoagulants was associated with a trend towards worse 778 survival (HR 1.82, 95% CI 0.94-3.54; p=0.08). 779 Preston et al. also conducted a retrospective cohort analysis using data from the REVEAL registry to 31 780 assess the effect of warfarin anticoagulation on survival in IPAH and SSc-PAH. In IPAH patients, 781 warfarin use was not significantly associated with survival (adj HR 1.37, 95% CI 0.84-2.25; $\mathsf{p}\!\!=\!\!0.17$ ). 782 Likewise, in patients with SSc-PAH, warfarin use was also not significantly associated with better survival 783 (adj HR 1.60, 95% CI 0.84-3.06; p=0.15). 784 The Kang et al. study also assessed survival outcomes associated with the use of warfarin among Korean 32 785 IPAH patients. They found that among the 31 included patients, warfarin use was associated with 786 better survival outcomes (HR 0.21, 95% CI 0.045-0.976; p=0.047).

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787 These included studies could not be combined in meta-analysis as they were all relatively small, included 788 different classes of interventions and had differing subpopulations. Due to the varying outcomes and 789 uncertainty of this intervention, the panel chose not to make any recommendations at this time. 790 Antiplatelet Agents 791 One randomized controlled trial was identified that addressed the use of aspirin and simvastatin in 34 792 patients with PAH receiving background therapy. No difference was found in the primary outcome, 793 6MWD, between the aspirin and placebo group (-0.5m, 95% CI: -28.4m – 27.4m). There is currently 794 insufficient evidence to recommend for or against the use of antiplatelet therapy for PAH. 795 SSRI 796 One retrospective cohort study was identified that assessed selective serotonin reuptake inhibitor (SSRI) 33 797 use in PAH patients. Kawut et al. found that use of SSRI did not significantly improve survival 798 outcomes (HR 0.53, 95% CI 0.07-3.9; p=0.53). At this time, there is insufficient evidence to recommend 799 for or against the use of SSRIs in patients with PAH. 800 801 Additional Considerations 802 Despite the progress in medical therapy for PAH, there are still a significant number of patients 803 who do not adequately respond to–or who are unable to tolerate -maximal medical therapy. 804 For these patients, lung or heart-lung transplantation continues to be an important therapeutic 805 option that provides substantial improvements in long-term survival and quality of life.

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|806| Current guidelines from the International Society of Heart Lung Transplantation recommend| |---|---| |807|early counseling about transplant and early referral to a transplant program to minimize risks of| |808|delay of timely listing for transplantation for potential candidates. (see Table 6).| |809|Bilateral lung transplant is the most common transplant procedure for patients with PAH,| |810| however heart-lung transplantation may be required for patients with complex congenital| ||disease and other considerations.| |81２|| ||813　 Conclusions| |814|| |815| Basic discovery, translational science, and clinical trials continue to advance the treatment of patients with PAH. This document provides an evidence-based update addressing important developments in the | |816|utilization of combination therapy, and consensus-based suggestions on the integration of palliative care| |817|and exercise training (cardiopulmonary rehabilitation) into overall disease management. A treatment| |818| algorithm has been added to assist the care provider in navigating the guidelines. Dissemination and implementation efforts will follow. Importantly, we continue to suggest early referral to expert centers, | |8１9|| |820| and collaborative care employing sound clinical judgement.| | ¥821 82２ || |823| Looking to the future, we strongly encourage the translation of basic discovery into safe and effective new therapies, through the conduct of well-designed clinical trials. | |824|| |825||

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values and preferences throughout the guideline development process.

827 Author contributions: All authors contributed equally to this manuscript

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Table 1 - Comprehensive Clinical Classification of Pulmonary Hypertension

1. Pulmonary arterial hypertension

1.1 Idiopathic PAH 1.2 Heritable PAH 1.2.1 BMPR2 1.2.2 ALK-1, ENG, SMAD9, CAV1, KCNK3 1.2.3 Unknown 1.3 Drug and toxin induced 1.4 Associated with: 1.4.1 Connective tissue disease 1.4.2 HIV infection 1.4.3 Portal hypertension 1.4.4 Congenital heart diseases 1.4.5 Schistosomiasis 1’. Pulmonary veno-occlusive disease and/or pulmonary capillary haemangiomatosis 1’.1 Idiopathic 1’.2 Heritable 1’.2.1 EIF2AK4 mutation 1’.2.2 Other mutations 1’.3 Drugs, toxins and radiation induced 1’.4 Associated with: 1’.4.1 Connective tissue disease 1’.4.2 HIV infection 1”. Persistent pulmonary hypertension of the newborn (PPHN)

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2. Pulmonary hypertension due to left heart disease 2.1 Left ventricular systolic dysfunction 2.2 Left ventricular diastolic dysfunction 2.3 Valvular disease 2.4 Congenital/acquired left heart inflow/outflow tract obstruction and congenital cardiomyopathies 3. Pulmonary hypertension due to lung diseases and/or hypoxia 3.1 Chronic obstructive pulmonary disease 3.2 Interstitial lung disease 3.3 Other pulmonary diseases with mixed restrictive and obstructive pattern 3.4 Sleep-disordered breathing 3.5 Alveolar hypoventilation disorders 3.6 Chronic exposure to high altitude 3.7 Developmental lung diseases 4. Chronic thromboembolic pulmonary hypertension (CTEPH) 4.1 Chronic thromboembolic pulmonary hypertension 4.2 Other pulmonary artery obstructions 4.2.1 Angiosarcoma 4.2.2 Other intravascular tumors 4.2.3 Arteritis 4.2.4 Congenital pulmonary arteries 5. Pulmonary hypertension with unclear multifactorial mechanisms 5.1 Hematologic disorders: chronic hemolytic anemia, myeloproliferative disorders, splenectomy 5.2 Systemic disorders: sarcoidosis, pulmonary histiocytosis, lymphangioleiomyomatosis

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||5.3Metabolic disorders: glycogenstorage disease,Gaucher disease, thyroiddisorders|| |---|---|---| ||5.4 Others: tumoral|| |836||| |837||| |838| Adapted with permission from Galie 2015 and Simonneau 2013 || |839|currentlybeing sought>|| |840||| |841||| |842|Table 2- PICO Question||

|Study Characteristic||Inclusion Criteria||Exclusion Criteria| |---|---|---|---|---| |||||| || For adult patients with pulmonary arterial hypertension, what are the comparative effectiveness and safety of 1) mono- or combination pharmacotherapies using calcium channel blockers, prostanoids, endothelin antagonists, phosphodiesterase inhibitors, soluble guanylate cyclase stimulators, or selexipag; 2) cardio-pulmonary rehabilitation; 3) palliative care; 4) supportive care; and 5) preventive care on intermediate-term and long-term patient outcomes? |||| |||||| |Population|| Adult patients with Pulmonary Arterial Hypertension - Group 1 within the Pulmonary Hypertension World Health Organization (WHO) clinical classification |Children|| |||||| |Interventions|| Calcium channel blockers (amlodipine, diltiazem, nifedipine) ||| |Interventions||||| ||| Prostacyclin derivatives or related (epoprostenol, treprostinil, iloprost) ||| ||| Endothelin antagonists (bosentan, ambrisentan, macitentan) ||| |||Phosphodiesterase inhibitors (sildenafil, tadalafil)||| |||||| |||Soluble guanylate cyclase stimulator (riociguat)||| |||Selexipag||| |||Cardio-pulmonary rehabilitation||| |||Palliative care||| |||Supportive care (supplemental oxygen, diuretics,||| ||| digoxin, anticoagulants, physical therapy/ rehabilitation) Preventive Care (influenza and pneumonia ||| |||immunizations, contraception, high risk pregnancy||| ||| management, avoiding non-essential surgery and perioperative risk management) ||| ||| One pharmacotherapy vs another pharmacotherapy as monotherapy ||| |Comparators|||||

|||Monotherapy vs combination therapy, including either|| |---|---|---|---| ||| as add-on therapy or as an initial treatment regimen using combination therapy || ||||| ||| One combination therapy to another combination therapy || ||||| ||| Cardio-pulmonary rehabilitation vs pharmacotherapy Cardio-pulmonary rehabilitation plus pharmacotherapyCardio-pulmonary rehabilitation plus pharmacotherapy vs pharmacotherapy alone || ||||| ||| Palliative care vs no palliative care|| |Outcomes|| Intermediate-term outcomes (hemodynamic parameters, dyspnea, and 6-minute walk distance considering MID) | Composite endpoints | |Outcomes|| considering MID) Long-term outcomes (functional class, Qol, right-sided heart failure or right ventricular dysfunction, mortality, || |Outcomes|| heart failure or right ventricular dysfunction, mortality, PAH-related hospitalization, need for interventional || |Outcomes|| PAH-related hospitalization, need for interventional procedures) || |Study Design|| Systematic reviews (with or without, meta-analyses), RCTs, prospective and retrospective cohort studies ||

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851 Table 3 - CHEST Grading System 852

| Grade of Recommendation | Benefit vs Risk and Burdens | Methodologic Strength of Supporting Evidence |Implications| |---|---|---|---| | Strong recommendation, ||We are very confident that the|Recommendation can apply to| | recommendation, High-quality evidence | outweigh risk and burdens, or |true effect lies close to that of|| | recommendation, High-quality evidence |vice versa|the estimate of the effect.| most patients in most circumstances. Further research is very unlikely to change our confidence in the estimate of effect. | | recommendation, High-quality evidence |||| || Benefits clearly outweigh risk and burdens, or ||Recommendation can apply to| | Strong recommendation, Moderate-quality evidence ||| most patients in most circumstances. Higher quality | | Strong recommendation, Moderate-quality evidence || in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different | circumstances. Higher quality research may well have an important impact on our confidence in the estimate of effect and may change the estimate. | | Strong recommendation, Moderate-quality evidence |||| | Strong recommendation, Moderate-quality evidence |||| | Strong recommendation, || Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect. |Recommendation can apply to| | recommendation, Low-quality evidence | outweigh risk and burdens, or | Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect. |most patients in many| | recommendation, Low-quality evidence |viceversa| Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect. |circumstances. Higher quality| ||| Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect. |research is likely to have an| ||| Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect. |important impact on our| |||| effect and may well change the estimate. | | Strong recommendation, very low quality | Benefits clearly|We have very little confidence| Recommendation can apply to most patients in many | | recommendation, very low quality evidence | outweigh risk and burdens, or | in the effect estimate: The true effect is likely to be || | recommendation, very low quality evidence |||circumstances. Higher quality| | recommendation, very low quality evidence || substantially different from the estimate of effect | research is likely to have an important impact on our | | recommendation, very low quality evidence ||| confidence in the estimate of effect and may well change theeffect and may well change the estimate. | |Weak||We are very confident that the|| |||true effect lies close to that of|The best action may differ| | (conditional) recommendation, High-quality evidence | balanced with risks and burden |the estimate of the effect.| depending on circumstances or patients' or societal values. Further research is very unlikely to change our | | (conditional) recommendation, High-quality evidence ||the estimate of the effect.|| | (conditional) recommendation, High-quality evidence ||| confidence in the estimate of effect. | | (conditional) recommendation, High-quality evidence ||||

| weak (conditional) |Benefits closely|We are moderately confident|Best action may differ| |---|---|---|---| | weak (conditional) |balanced with|in the effect estimate: The true|depending on circumstances or| |recommendation,|risks and burden|effect is likely to be close to|| |||the estimate of the effect, but| patients' or societal values. Higher quality research may well have an important impact on our confidence in the estimate of effect and may | | Moderate-quality evidence || there is a possibility that it is substantially different || | Weak (conditional) || there is a possibility that it is substantially different || | (conditional) recommendation, | Uncertainty in the estimates of benefits, risks, and burden; benefits, risk | estimate is limited: The true effect may be substantially | Other alternatives may be equally reasonable. Higher quality research is likely to have an important impact on our confidence in the estimate of effect and may well change the estimate. Other alternatives may be | || and burden; benefits, risk and burden may be closely balanced ||| | Low-quality evidence || different from the estimate of the effect. || |weak||We have very little confidence|| ||| in the effect estimate: The true effect is likely to be | Other alternatives may be equally reasonable. Higher quality research is likely to have an important impact on our confidence in the estimate of effect and may well change the estimate. | || Uncertainty in the estimates of benefits, risks, and burden; benefits, risk and burden may || Other alternatives may be equally reasonable. Higher quality research is likely to have an important impact on our confidence in the estimate of effect and may well change the estimate. | | recommendation, very-low quality evidence || substantially different from the estimate of effect || | recommendation, very-low quality evidence |||| ||||| ||||| ||Ungraded Consensus-based Suggestions||| | Ungraded Consensus-Based Statement || Insufficient evidence for a graded recommendation || ||| Insufficient evidence for a graded recommendation | Future research may well have an important impact on our confidence in the estimate of effect and may change the estimate. | ||| Insufficient evidence for a graded recommendation || || expert opinion that benefits outweigh risk and burdens or vice versa ||| || expert opinion that benefits outweigh risk and burdens or vice versa ||| || expert opinion that benefits outweigh risk and burdens or vice versa |||

853 854 855

|Family history of PAH| |---| | N Known genetic mutation for PAH in patient or first degree relative BMPR2 TBXA2 KNCK3 EIF2AK4 Caveolin-1 | | 3， Limited cutaneous scleroderma or mixed connective tissue disease FVC/DLCO > 1.6 DLCO |

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859 TABLE 5 – World Health Organization Functional Classification of Patients With Pulmonary Hypertension

|Classification| |---| |Class I: Patients with PH but without resulting limitation of physical activity. Ordinary physical activity| |does not cause undue dyspnea or fatigue, chest pain, or near syncope.| |Class Il: Patients with PH resulting in slight limitation of physical activity. They are comfortable at rest.| |Ordinary physical activity causes undue dyspnea or fatigue, chest pain, or near syncope.| || |Less than ordinary activity causes undue dyspnea or fatigue, chest pain, or near syncope.| || | Class IV: Patients with PH with inability to carry out any physical activity without symptoms. These patients manifest signs of right-sided heart failure. Dyspnea and/or fatigue may even be present at rest. | |Discomfort is increased by any physical activity|

18 860 PH=pulmonary hypertension. Adapted from Rich et al.

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862 Table 6. ISHLT Recommendations: Referral for transplantation for PAH

|WHO FC Ill (with worsening symptoms despite optimal therapy)| |---| |WHOFCIVSymptoms| |Rapidlyprogressivedisease| |Use of parenteral PAH therapy regardless of symptoms or FC| | Known or suspected pulmonary veno-occlusive disease (PvoD) or pulmonary capillary hemangiomatosis （PCH） |

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Table 7. Currently Approved Medications for Treatment Of Pulmonary Arterial Hypertension

|ciass|Drug| Route of administration |Dose| |---|---|---|---| | Prostacyclin Derivatives |Epoprostenol*|intravenous infusion| 2 ng/kg/min Increase as tolerated | | Prostacyclin Derivatives |lloprost|Inhaled| 2.5 or 5.0 mcg 6-9 inhalations/day | | Prostacyclin Derivatives |Treprostinil|oral| 0.25 mg BID or 0.125 mg TID Increase 0.125 mg BID every 3 to 4 days | | Prostacyclin Derivatives |Treprostinil|Inhaled| 18 mcg - 54 mcg (3 - 9 inhalations) 4 times daily | | Prostacyclin Derivatives |Treprostinil| Subcutaneous or intravenous infusion | 1.25 ng/kg/min; increase 1.25 ng/kg/min per week based on clinical response | | Endothelin Receptor Antagonists |bosentan|oral|125 mg twice daily| | Endothelin Receptor Antagonists |ambrisentan|oral| 5 or 10 mg once daily| | Endothelin Receptor Antagonists |macitentan|oral|10 mg once daily| | Phosphodiesterase type-5 inhibitors |sildenafil| Oral Intravenous injection |20 mg every 8 hours|

||Tadalafil|Oral|40 mg once daily| |---|---|---|---| ||||| | Soluble cGMP Stimulators |riociguat|oral| 0.5 - 1.0 mg every 8 hours. (Increase 0.5 mg every 2 weeks as tolerated to maximum dose 2.5 mg) | | Prostacyclin Receptor Agonists |selexipag|oral| 200 mcg twice daily Increase as tolerated to maximum dose of 160 mcg twice daily |

865 Available in a pH neutral (Flolan ®) or highly alkaline (Veletri®) diluent. The latter provides increased 866 drug stability at room temperature.

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873 1. Badesch DB, Abman SH, Simonneau G, Rubin LJ, McLaughlin VV. Medical therapy for pulmonary 874 arterial hypertension: updated ACCP evidence-based clinical practice guidelines. Chest. 875 2007;131(6):1917-1928. 876 2. Galie N, Humbert M, Vachiery JL, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment 877 of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary 878 Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society 879 (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), 880 International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J. 2016;37(1):67-119. 881 3. Badesch DB, Abman SH, Ahearn GS, et al. Medical therapy for pulmonary arterial hypertension: 882 ACCP evidence-based clinical practice guidelines. Chest. 2004;126(1 Suppl):35S-62S. 883 4. Rubin LJ, American College of Chest P. Diagnosis and management of pulmonary arterial 884 hypertension: ACCP evidence-based clinical practice guidelines. Chest. 2004;126(1 Suppl):4S-6S. 885 5. McCrory DC, Lewis SZ. Methodology and grading for pulmonary hypertension evidence review 886 and guideline development. Chest. 2004;126(1 Suppl):11S-13S. 887 6. McGoon M, Gutterman D, Steen V, et al. Screening, early detection, and diagnosis of pulmonary 888 arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest. 2004;126(1 889 Suppl):14S-34S. 890 7. Doyle RL, McCrory D, Channick RN, Simonneau G, Conte J, American College of Chest P. Surgical 891 treatments/interventions for pulmonary arterial hypertension: ACCP evidence-based clinical 892 practice guidelines. Chest. 2004;126(1 Suppl):63S-71S. 893 8. Atwood CW, Jr., McCrory D, Garcia JG, Abman SH, Ahearn GS, American College of Chest P. 894 Pulmonary artery hypertension and sleep-disordered breathing: ACCP evidence-based clinical 895 practice guidelines. Chest. 2004;126(1 Suppl):72S-77S. 896 9. McLaughlin VV, Presberg KW, Doyle RL, et al. Prognosis of pulmonary arterial hypertension: 897 ACCP evidence-based clinical practice guidelines. Chest. 2004;126(1 Suppl):78S-92S. 898 10. Taichman DB, Ornelas J, Chung L, et al. Pharmacologic therapy for pulmonary arterial 899 hypertension in adults: CHEST guideline and expert panel report. Chest. 2014;146(2):449-475. 900 11. American College of CHEST Physicans. Conflict of Interest Policy: Guidelines and Consensus 901 Statements. file:///C:/Users/jhawley/Downloads/20180711CHESTCOIPolicy.pdf. Accessed 902 September 10, 2018. 903 12. McCrory DC, Coeytaux RR, Schmit KM, et al. AHRQ Comparative Effectiveness Reviews. 904 Pulmonary Arterial Hypertension: Screening, Management, and Treatment . Rockville (MD): 905 Agency for Healthcare Research and Quality (US); 2013. 906 13. Diekember RL, Ireland BK, Merz LR. Development of the Documentation and Appraisal Review 907 Tool for systematic reviews. World J Meta-Anal. 2015;3(3):142-150. 908 14. Higgins J, Altman D, Sterne J, (editors). Chapter 8: Assessing risk of bias in included studies. In: 909 Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions 910 Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from 911 www.cochrane-handbook.org. 2011. 912 15. Sterne JA, Hernán MA, Reeves BC, et al. ROBINS-I: a tool for assessing risk of bias in non 913 randomised studies of interventions. BMJ. 2016;355. 914 16. Andrews J, Guyatt G, Oxman AD, et al. GRADE guidelines: 14. Going from evidence to 915 recommendations: the significance and presentation of recommendations. Journal of Clinical 916 Epidemiology. 66(7):719-725. 917 17. Balshem H, Helfand M, Schünemann HJ, et al. GRADE guidelines: 3. Rating the quality of 918 evidence. Journal of Clinical Epidemiology. 64(4):401-406.

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18. Lewis SZ, Diekemper R, Ornelas J, Casey KR. Methodologies for the development of CHEST guidelines and expert panel reports. Chest. 2014;146(1):182-192. 19. Diekemper RL, Patel S, Mette SA, Ornelas J, Ouellette DR, Casey KR. Making the GRADE. Chest. 2018;153(3):756-759. 20. Jaeschke R, The GRADE Working Group. Use of GRADE grid to reach decisions on clinical practice guidelines when consensus is elusive. BMJ. 2008;337:327-330. 21. Galie N, Barbera JA, Frost AE, et al. Initial Use of Ambrisentan plus Tadalafil in Pulmonary Arterial Hypertension. The New England journal of medicine. 2015;373(9):834-844. 22. McLaughlin V, Channick RN, Ghofrani HA, et al. Bosentan added to sildenafil therapy in patients with pulmonary arterial hypertension. The European respiratory journal. 2015;46(2):405-413. 23. Tapson VF, Jing ZC, Xu KF, et al. Oral treprostinil for the treatment of pulmonary arterial hypertension in patients receiving background endothelin receptor antagonist and phosphodiesterase type 5 inhibitor therapy (the FREEDOM-C2 study): a randomized controlled trial. Chest. 2013;144(3):952-958. 24. Zhuang Y, Jiang B, Gao H, Zhao W. Randomized study of adding tadalafil to existing ambrisentan in pulmonary arterial hypertension. Hypertension research : official journal of the Japanese Society of Hypertension. 2014;37(6):507-512. 25. Simonneau G, Torbicki A, Hoeper MM, et al. Selexipag: an oral, selective prostacyclin receptor agonist for the treatment of pulmonary arterial hypertension. The European respiratory journal. 2012;40(4):874-880. 26. Sitbon O, Channick R, Chin KM, et al. Selexipag for the Treatment of Pulmonary Arterial Hypertension. The New England journal of medicine. 2015;373(26):2522-2533. 27. Morris NR, Kermeen FD, Holland AE. Exercise-based rehabilitation programmes for pulmonary hypertension. The Cochrane database of systematic reviews. 2017;1:Cd011285. 28. Saglam M, Arikan H, Vardar-Yagli N, et al. Inspiratory muscle training in pulmonary arterial hypertension. Journal of cardiopulmonary rehabilitation and prevention. 2015;35(3):198-206. 29. Ezedunukwe Ifeanyi R, Enuh H, Nfonoyim J, Enuh Collins U. Anticoagulation therapy versus placebo for pulmonary hypertension. Cochrane Database of Systematic Reviews. 2014(6). http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD010695.pub2/abstract. 30. Olsson KM, Delcroix M, Ghofrani HA, et al. Anticoagulation and survival in pulmonary arterial hypertension: results from the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA). Circulation. 2014;129(1):57-65. 31. Preston IR, Roberts KE, Miller DP, et al. Effect of Warfarin Treatment on Survival of Patients With Pulmonary Arterial Hypertension (PAH) in the Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL). Circulation. 2015;132(25):2403-2411. 32. Kang BJ, Oh Y-M, Lee S-D, Lee JS. Survival benefits of warfarin in Korean patients with idiopathic pulmonary arterial hypertension. The Korean Journal of Internal Medicine. 2015;30(6):837-845. 33. Kawut SM, Horn EM, Berekashvili KK, et al. Selective serotonin reuptake inhibitor use and outcomes in pulmonary arterial hypertension. Pulmonary pharmacology & therapeutics. 2006;19(5):370-374. 34. Kawut SM, Bagiella E, Lederer DJ, et al. Randomized clinical trial of aspirin and simvastatin for pulmonary arterial hypertension: ASA-STAT. Circulation. 2011;123(25):2985-2993. 35. Weinstein AA, Chin LM, Keyser RE, et al. Effect of aerobic exercise training on fatigue and physical activity in patients with pulmonary arterial hypertension. Respiratory medicine. 2013;107(5):778-784. 36. Ehlken N, Lichtblau M, Klose H, et al. Exercise training improves peak oxygen consumption and haemodynamics in patients with severe pulmonary arterial hypertension and inoperable chronic

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966 thrombo-embolic pulmonary hypertension: a prospective, randomized, controlled trial. Eur 967 Heart J. 2016;37(1):35-44. 968 37. McLaughlin VV, Gaine SP, Howard LS, et al. Treatment goals of pulmonary hypertension. Journal 969 of the American College of Cardiology. 2013;62(25 Suppl):D73-81. 970 38. Benza RL, Gomberg-Maitland M, Miller DP, et al. The REVEAL Registry risk score calculator in 971 patients newly diagnosed with pulmonary arterial hypertension. Chest. 2012;141(2):354-362. 972 39. Humbert M, Sitbon O, Yaici A, et al. Survival in incident and prevalent cohorts of patients with 973 pulmonary arterial hypertension. The European respiratory journal. 2010;36(3):549-555. 974 40. Rich S. A New Classification of Pulmonary Hypertension. Advances in Pulmonary Hypertension. 975 2002;1(1):3-8. 976 41. Jing ZC, Parikh K, Pulido T, et al. Efficacy and safety of oral treprostinil monotherapy for the 977 treatment of pulmonary arterial hypertension: a randomized, controlled trial. Circulation. 978 2013;127(5):624-633. 979 42. Hoeper MM, Simonneau G, Corris PA, et al. RESPITE: switching to riociguat in pulmonary arterial 980 hypertension patients with inadequate response to phosphodiesterase-5 inhibitors. The 981 European respiratory journal. 2017;50(3). 982 43. Gomes-Neto M, Silva CM, Ezequiel D, Conceicao CS, Saquetto M, Machado AS. Impact of 983 Pulmonary Rehabilitation on Exercise Tolerance and Quality of Life in Patients With Idiopathic 984 Pulmonary Fibrosis: A SYSTEMATIC REVIEW AND META-ANALYSIS. Journal of cardiopulmonary 985 rehabilitation and prevention. 2018. 986 44. Puhan MA, Gimeno-Santos E, Cates CJ, Troosters T. Pulmonary rehabilitation following 987 exacerbations of chronic obstructive pulmonary disease. The Cochrane database of systematic 988 reviews. 2016;12:Cd005305. 989 45. Shannon VR. Role of pulmonary rehabilitation in the management of patients with lung cancer. 990 Current opinion in pulmonary medicine. 2010;16(4):334-339. 991 46. Chia KS, Wong PK, Faux SG, McLachlan CS, Kotlyar E. The benefit of exercise training in 992 pulmonary hypertension: a clinical review. Internal medicine journal. 2017;47(4):361-369. 993 47. Inagaki T, Terada J, Tanabe N, et al. Home-based pulmonary rehabilitation in patients with 994 inoperable or residual chronic thromboembolic pulmonary hypertension: a preliminary study. 995 Respiratory investigation. 2014;52(6):357-364. 996 48. Zafrir B. Exercise training and rehabilitation in pulmonary arterial hypertension: rationale and 997 current data evaluation. Journal of cardiopulmonary rehabilitation and prevention. 998 2013;33(5):263-273. 999 49. Ganderton L, Jenkins S, Gain K, et al. Short term effects of exercise training on exercise capacity 1000 and quality of life in patients with pulmonary arterial hypertension: protocol for a randomised 1001 controlled trial. BMC pulmonary medicine. 2011;11:25.

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Figure2.CombinationTherapyAlgorithm

Wheremultipledrugoptions areprovided,thereisnocomparativeeffectivenessdatatosuggestgreaterbenefit of onetherapyovertheother.Inthesesituations,otherfactors,su

 \*Combinationtherapycarrieswithitcostsaswellasmultiplemedications,includingthepotentialforincreasedadverseeventsthatmaybeundesirableforsomepatients.In thesesituationspatientsareunwillingorunabletotoleratecombinationtherapyandthepanelsuggestsmonotherapy.

|Drug|Outcome|Grade| Recommendation Number | |---|---|---|---| |Ambrisentan| Improve 6MVD | strongrecommendation,low qualityevidence || |Bosentan| Delay timeto clinical worsening | ungradedconsensus-based statement |12-13| |Macitentan| Delay time to clinical worsening | ungraded consensus-based statement |14| |Sildenafil| Improve 6MD | strong recommendation,low qualityevidence |16| |Tadalafil| Improve 6MWD | ungraded consensus-based statement |16| |Riociguat| Improve 6MD | ungraded consensus-based statement |17-20| |Riociguat| ImproveWHO FC | ungraded consensus-based statement |17-20| |Riociguat| Delay time to clinical worsening | ungradedconsensus-based statement |17-20| | Parenteral orinhaled prostanoids shouldnot be chosenasinitial therapyoras second line agent |ungraded consensus-based|21||

|Drug|Outcome|Grade| Recommendation Number | |---|---|---|---| |Bosentan|Improve6MWD| strong recommendation, moderate quality evidence) || |Bosentan| Decrease hospitalizations related to PAH in the short-term | weak recommendation, lowquality evidence |23-24| |Ambrisentan|Improve6MWD| strong recommendation,low qualityevidence |26| |Macitentan|Improve WHO FC| ungraded consensus- basedstatement |26-27| |Macitentan| Delay time to clinical worsening | ungraded consensus- basedstatement |26-27| |Sildenafil|Improve6MWD| strong recommendation,low qualityevidence |28-30| |Sildenafil|Improve WHO FC| ungraded consensus- basedstatement |28-30| |Tadalafil|Improve6MWD| ungraded consensus- based statement |31-34| |Tadalafil|ImproveWHOFC| ungraded consensus- basedstatement |31-34| |Tadalafil| Delay time to clinical worsening | ungraded consensus- basedstatement |31-34| |Riociguat|Improve6MWD| ungraded consensus- basedstatement |35-38| |Riociguat|ImproveWHOFC| ungraded consensus- basedstatement |35-38| |Riociguat| Delay time to clinical worsening | ungraded consensus- basedstatement |35-38|

 Institution received grants from Actelion, AIRES, Arena, Bayer, Belleraphon, Duke University,

Therapeutics/LLC, University of Cincinatti; Dr. Badesch received monetary and non-monetary support for Advisory Boards for Acceleron, Actelion, Arena, Complexa, Gilead, Liquidia; Dr. Badesch received monetary and non-monetary support for CME Activity from Actelion and United Therapeutics, Practice Point Communications, Activity organized by Renown Institute with industry sponsor; Dr. Badesch received monetary and/or non-monetary support for Speaking Activities from Actelion, Aspen Pharmacare, Bayer, Gilead; Dr. Badesch recieved

Therapeutics/LLC, University of Cincinatti; Dr. Badesch received monetary and non-monetary support for Advisory Boards for Acceleron, Actelion, Arena, Complexa, Gilead, Liquidia; Dr. Badesch received monetary and non-monetary support for CME Activity from Actelion and United Therapeutics, Practice Point Communications, Activity organized by Renown Institute with industry sponsor; Dr. Badesch received monetary and/or non-monetary support for Speaking Activities from Actelion, Aspen Pharmacare, Bayer, Gilead; Dr. Badesch recieved

Financial COI

David Badesch, MD, FCCP

Therapeutics/LLC, University of Cincinatti; Dr. Badesch received monetary and non-monetary support for Advisory Boards for Acceleron, Actelion, Arena, Complexa, Gilead, Liquidia; Dr. Badesch received monetary and non-monetary support for CME Activity from Actelion and United Therapeutics, Practice Point Communications, Activity organized by Renown Institute with industry sponsor; Dr. Badesch received monetary and/or non-monetary support for Speaking Activities from Actelion, Aspen Pharmacare, Bayer, Gilead; Dr. Badesch recieved

Institution received grants from Actelion, AIRES, Arena, Bayer, Belleraphon, Duke University,

Institution received grants from Actelion, AIRES, Arena, Bayer, Belleraphon, Duke University,

from Actelion, Gilead,

For patients with PAH, we suggest some type of supervised exercise activity as part of the integrated care for their disease. (ungraded

Description of COI

Recommendation or Suggestions

Institution received grants from Actelion, AIRES, Arena, Bayer, Belleraphon, Duke University,

Eiger, Gilead, Ikaria/Belleraphon, INOVA Healthcare Services, Lung LLC, Reatta, United

Therapeutics/LLC, University of Cincinatti; Dr. Badesch received monetary and non-monetary support for Advisory Boards for Acceleron, Actelion, Arena, Complexa, Gilead, Liquidia; Dr. Badesch received monetary and non-monetary support for CME Activity from Actelion and United Therapeutics, Practice Point Communications, Activity organized by Renown Institute with industry sponsor; Dr. Badesch received monetary and/or non-monetary support for Speaking Activities from Actelion, Aspen Pharmacare, Bayer, Gilead; Dr. Badesch recieved

consensus-based statement)

non-monetary support for educational industry-sponsored scientific meeting, Actelion:

Johnson & Johnson stock held, transfered to spouse 11/2018.

addition of tadalafil to improve mean change in 6MWD. (weak recommendation, low quality

Eiger, Gilead, Ikaria/Belleraphon, INOVA Healthcare Services, Lung LLC, Reatta, United

For patients on background therapy with ambrisentan, we suggest considering the

non-monetary support for educational industry-sponsored scientific meeting, Actelion:

evidence)

Class II and III patients, we suggest initial

Eiger, Gilead, Ikaria/Belleraphon, INOVA Healthcare Services, Lung LLC, Reatta, United

In treatment naïve WHO Group 1 Functional

Johnson & Johnson stock held, transfered to spouse 11/2018.

non-monetary support for educational industry-sponsored scientific meeting, Actelion:

combination therapy with ambrisentan and

Johnson & Johnson stock held, transfered to spouse 11/2018.

tadalafil to improve 6MWD. (weak

recommendation, moderate quality evidence)

Eiger, Gilead, Ikaria/Belleraphon, INOVA Healthcare Services, Lung LLC, Reatta, United

Johnson & Johnson stock held, transfered to spouse 11/2018.

non-monetary support for educational industry-sponsored scientific meeting, Actelion:

(ungraded consensus-based statement).

For patients with PAH, we suggest including palliative care services among the care team

Pharmacologic Therapy for Pulmonary Arterial Hypertension

Eduardo Bossone,

Steven Kawut, MD

Dr. Kawut on Advisory Board for GlaxoSmithKline, no compensation; Received monetary support for providing expert opinion for legal activity on topics: pulmonary embolism/pulmonary hypertension; Received monetary support for CME Speaking Activities, Actelion, Bayer, Gilead; CME Speaking Activity with

Description of COI

Financial COI

compensation.

compensation.

Dr. Kawut on Advisory Board for GlaxoSmithKline, no compensation; Received monetary support for providing expert opinion for legal activity on topics: pulmonary embolism/pulmonary hypertension; Received monetary support for CME Apeaking Activities, Actelion, Bayer, Gilead; CME Speaking Activity with

compensation.

United Therapeutics, no

United Therapeutics, no

Dr. Kawut on Advisory Board for GlaxoSmithKline, no compensation; Received monetary support for providing expert opinion for legal activity on topics: pulmonary embolism/pulmonary hypertension; Received monetary support for CME Speaking Activities, Actelion, Bayer, Gilead; CME Speaking Activity with

United Therapeutics, no

Dr. Kawut on Advisory Board for GlaxoSmithKline, no compensation; Received monetary support for providing expert opinion for legal activity on topics: pulmonary embolism/pulmonary hypertension; Received monetary support for CME Speaking Activities, Actelion, Bayer, Gilead; CME Speaking Activity with

compensation.

United Therapeutics, no

||sch,MD,FCCP|||GRSnEIBOMD||stewen|| DeborabJo Levine, Financial COl ||| |---|---|---|---|---|---|---|---|---|---|---| ||nofcot|DescriptiornOfcO#|||Descriptic ofcOI|||||| ||||||||Acinalaf||| porionoingtosalaup Sqt | || antsfromActelio | nin eedgnted ||||||||| |||||edrimaluntaidatesr|||ep| | || ||ond|||||Gad MEspeaking Activt||||| ||||||Received NonT-patent|| meunBayeenttport for Dr.Kl erfrom nli || FBoan forBayer | Reata | || d grats from ectelon, AIEs Arena, ayer elerahon, uke nierstye etar |ned||||prvidinrtpinnforle||||| ||||||||| Preloednonepe monetrysupport ||| || ||||||n|||| ||||||||meeting, Bayer....|||Reata| |||||||||||| |Intreatment naveWHOGroup Funtional|||| foyMed monohar support ||||menetaratiopport||Gilead,Rea| ||||||| || |forBaer|Reata.| ||||none||Royalties UpToDate.|| meeting,Bayer. mfi |||| |||||Irom Actelen, Gilearahs|| oryBoardfor || Dr.Levine mdnvednoupp ||wthn| |||||TherapeuticsDrElliot|fromhnver Flead, |||||| ||| consultancy with Ikaria ||framia /Actelirn,hayer,rophon.|||| tmene Actelion |forBa| |

Karen Fagan, MD

Description of COI

Financial COI

Institution received grants from Actelion, Bayer, Gilead, United Therapies: Dr. Fagan

received Non-patent Royalties UpToDate.

Institution received grants from Actelion, Bayer, Gilead, United Therapies: Dr. Fagan

received Non-patent Royalties UpToDate.

Institution received grants from Actelion, Bayer, Gilead, United Therapies: Dr. Fagan

received Non-patent Royalties UpToDate.

received Non-patent Royalties UpToDate.

Institution received grants from Actelion, Bayer, Gilead, United Therapies: Dr. Fagan

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Description of COI

Greg Elliott, MD

Financial COI

Institution received grants

from Actelion, Gilead,

Intermountain Research & Medical Foundation, United Therapeutics; Dr. Elliott reveived monetary support for Medical Consultancies

Institution received grants

from, Actelion, Bayer, Ikaria/Bellerophon.

from Actelion, Gilead,

Intermountain Research & Medical Foundation, United Therapeutics; Dr. Elliott reveived monetary support for Medical Consultancies

from, Actelion, Bayer, Ikaria/Bellerophon.

Institution received grants

from Actelion, Gilead,

Intermountain Research & Medical Foundation, United Therapeutics; Dr. Elliott reveived monetary support for Medical Consultancies

from, Actelion, Bayer, Ikaria/Bellerophon.

Institution received grants

Intermountain Research & Medical Foundation, United Therapeutics; Dr. Elliott reveived monetary support for Medical Consultancies

from, Actelion, Bayer, Ikaria/Bellerophon.

Laura Duvall,

Financial COI

Description of COI

PharmD

none

none

none

none

Description of COI

MD, FCCP

Financial COI

none

none

none

none

Erika Berman-Rosenzweig, MD

Financial COI

Description of COI

Institution received grants from Actelion, Gilead, United Therapeutics; Dr. Berman- Rosenzweig received monetary support for Speaking Activity

Rosensweig received monetary

for Gilead; Dr. Berman

support for medical consultancy with Ikaria.

Institution received grants from Actelion, Gilead, United Therapeutics; Dr. Berman- Rosenzweig received monetary support for Speaking Activity

Rosensweig received monetary

for Gilead; Dr. Berman

support for medical consultancy with Ikaria.

Institution received grants from Actelion, Gilead, United Therapeutics; Dr. Berman- Rosenzweig received monetary support for Speaking Activity

Rosensweig received monetary

for Gilead; Dr. Berman

support for medical consultancy with Ikaria.

Institution received grants from Actelion, Gilead, United Therapeutics; Dr. Berman- Rosenzweig received monetary support for Speaking Activity

Rosensweig received monetary

for Gilead; Dr. Berman

support for medical consultancy with Ikaria.

ACCEPTED MANUSCRIPT

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e-Table 2. Search Strategy

|PhaseI| #1 "pulmonary arterial hypertension"[ti] OR "pulmonary artery hypertension"[ti]) OR (pah[ti] OR ipah[ti] | |---|---| ||| || #2 ("Calcium Channel Blockers"[Mesh] OR "Calcium Channel Blockers"[Pharmacological Action] OR calcium channel blockers[tiab] OR calcium channel blocker[tiab] OR nifedipine[tiab] OR diltiazem[tiab] | ||| || OR amlodipine[tiab]) OR ("prostaglandins"[MeSH Terms] OR "prostaglandins"[tiab] OR"prostaglandins"[tiab] OR "prostanoid"[tiab] OR "prostanoids"[tiab] OR "epoprostenol"[MeSH Terms] OR "epoprostenol"[tiab] OR"prostacyclin"[tiab] OR | || "treprostinil"[Supplementary Concept] OR "treprostinil"[tiab] OR "iloprost"[MeSH Terms] OR "iloprost"[tiab] OR "Receptors, | ||| || Endothelin/antagonists and inhibitors"[Mesh] OR ("endothelins"[MeSH Terms] OR "endothelins"[tiab] OR "endothelin"[tiab]) AND (antagonist[tiab] OR | || "antagonists"[tiab] OR "inhibitors"[tiab])) OR "bosentan"[Supplementary Concept] OR "bosentan"[tiab] OR "ambrisentan"[Supplementary Concept] OR | ||| ||"ambrisentan"[tiab] OR "phosphodiesterase inhibitors"[MeSH Terms] OR| || ("phosphodiesterase"[tiab] AND "inhibitors"[tiab]) OR "phosphodiesterase inhibitors"[tiab] OR "phosphodiesterase inhibitors"[Pharmacological Action] OR | ||"phosphodiesterase 5 inhibitors"[tiab] OR "phosphoric diester hydrolases"[MeSH| ||| ||("phosphodiesterase"[tiab] OR "phosphodiesterases"[tiab]) AND (inhibitor[tiab]| || OR"antagonists and inhibitors"[Subheading] OR "antagonists"[tiab] OR "inhibitors"[tiab] OR antagonist[tiab])) OR (pde5[tiab] AND (inhibitor[tiab] OR | || "inhibitors"[tiab] OR antagonist[tiab])) OR (pde5[tiab] AND (inhibitor[tiab] OR "antagonists and inhibitors"[Subheading] OR "antagonists"[tiab] OR"antagonists and inhibitors"[Subheading] OR "antagonists"[tiab] OR 'antagonist"[tiab] OR"inhibitors"[tiab] OR "inhibitors"[tiab])) OR pde5i[tiab] OR | ||| ||'sildenafil"[Supplementary Concept] OR "sildenafil"[tiab] OR| ||"tadalafi"[Supplementary Concept] OR "tadalafil"[tiab] OR "Vasodilator| ||Agents"[Mesh:noexp] OR "Vasodilator Agents "[Pharmacological| ||Actionl)| || #3 (randomized controlled trial[pt] OR controlled clinical trial[pt] OR randomized[tiab] OR randomised[tiab] OR randomization[tiab] OR | ||| || randomisation[tiab] OR placebo[tiab] OR"drug therapy"[Subheading] OR randomly[tiab] OR trial[tiab] OR groups[tiab] OR Clinical trial[pt] OR "clinical | ||| || trial"[tw] OR "clinical trials"[tw] OR "evaluation studies"[Publication Type] OR "evaluation studies as topic"[MeSH Terms] OR "evaluation study"[tw] OR | ||evaluation studies[tw] OR "intervention studies"[MeSH Terms] OR "intervention| || study"[tw] OR "intervention studies"[tw] OR "case-control studies"[MeSH Terms] OR "case-control"[tw] OR "cohort studies"[MeSH Terms] OR cohort[tw] OR | ||"longitudinal studies"[MeSH Terms] OR "longitudinal"[tw] OR longitudinally[tw] OF| ||"prospective"[tw] OR prospectively[tw] OR "retrospective studies"[MeSH Terms]|

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||Type] OR "comparative study"[tw] OR systematic[subset]| |---|---| ||OR "meta-analysis"[Publication Type] OR "meta-analysis as topic"[MeSH Terms] OR| ||"metaanalysis"[tw] OR "meta-analyses"[tw]) NOT (Editorial[ptyp] OR Letter[ptyp]| || OR Case Reports[ptyp] OR Comment[ptyp]) NOT ("animals"[MeSH Terms] NOT "humans"[MeSH Terms]) | ||#4 #1 AND #2 AND #3| ||| ||| |Phase Il| Search string for PAH| || #1 ("pulmonary arterial hypertension"[ti] OR "pulmonary artery hypertension"[ti]) OR (pah[ti] OR ipah[ti]) | ||| ||Search string for eligible studies| ||| || #2 (randomized controlled trial[pt] OR controlled clinical trial[pt] OR randomized[tiab] OR randomised[tiab] OR randomization[tiab] OR randomisation[tiab] OR placebo[tiab] OR "drug therapy"[Subheading] OR randomly[tiab] OR trial[tiab] OR groups[tiab] OR Clinical trial[pt] OR "clinical trial"[tw] OR"clinical trials"[tw] OR "evaluation studies"[Publication Type] OR "evaluation studies as topic"[MeSH Terms] OR "evaluation study"[tw] OR | ||| ||| ||evaluation studies[tw] OR "intervention studies"[MeSH Terms] OR "intervention| || study"[tw] OR "intervention studies"[tw] OR "case-control studies"[MeSH Terms] OR "case-control"[tw] OR "cohort studies"[MeSH Terms] OR cohort[tw] OR | || OR "case-control"[tw] OR "cohort studies"[MeSH Terms] OR cohort[tw] OR "longitudinal studies"[MeSH Terms] OR "longitudinal"[tw] OR longitudinally[tw] OR"longitudinal studies"[MeSH Terms] OR "longitudinal"[tw] OR longitudinally[tw] OR "prospective"[tw] OR prospectively[tw] OR "retrospective studies"[MeSH Terms] | || "prospective"[tw] OR prospectively[tw] OR "retrospective studies"[MeSH Terms] OR"retrospective"[tw] OR "follow up"[tw] OR "comparative study"[Publication | || OR"retrospective"[tw] OR "follow up"[tw] OR "comparative study"[Publication Type] OR "comparative study"[tw] OR systematic[subset] OR "meta- | ||| || "metaanalysis"[tw] OR "meta-analyses"[tw]) NOT (Editorial[ptyp] OR Letter[ptyp] OR Case Reports[ptyp] OR Comment[ptyp]) NOT ("animals"[MeSH Terms] NOT | ||| ||Search string for Phase Il interventions| ||#3 (soluble guanylate cyclase stimulator OR riociguat OR soluble guanylate cyclase| ||OR selective IP prostacyclin receptor agonist OR oral prostacyclin IP receptor| || agonist OR selexipag OR uptravi OR prostacyclin receptor agonist OR exercise training OR exercise therapy OR physical activity OR physical fitness OR pulmonary rehabilitation OR pulmonary rehab OR cardio-pulmonary rehabilitation OR cardio- | ||| ||| || supplemental oxygen OR diuretics OR digoxin OR anticoagulants OR supplemental therapy OR supportive therapy OR palliative therapy OR palliative OR palliation OR | ||| ||influenza vaccine OR influenza vaccination OR influenza immunization OR|

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||vaccination OR pneumonia immunization OR contraception OR contraceptives OR| |---|---| ||| | contraceptive methods OR pregnancy prevention OR high risk pregnancy management OR perioperative risk OR perioperative management OR surgical risk OR surgical risk assessment) || |#4#1AND#2AND #3||

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e-Figure 1. PRISMA Diagram – Phase I Search Results

 Online supplements are not copyedited prior to posting and the author(s) take full responsibility for the accuracy of all data.

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e-Figure 2. PRISMA Diagram – Phase II Search Results


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e-Table 3. GRADE Evidence Profile: Tadalafil added to existing ambrisentan

Bibliography: Zhuang 2014

|||||||| No of patients| No of patients|Effect|Quality|Importance| |---|---|---|---|---|---|---|---|---|---|---|---| | # of studies|Design|Risk of bias| Inconsistency| Indirectness|Imprecision| Publication Bias|Placebo|Tadalfil| Mean Change (95% CI or p value) ||| |Change in 6MWD; baseline ||||||||||||

1 Unclear risk of bias (note also cannot clearly determine which 6MWD, stratified or not, was the pre-specified outcome of interest) 2 Inconsistency cannot be assessed because of single study 3 imprecision due to small study size makes it difficult to determine if the lack of statistical significance is due to no real difference or underpowered study 4 Unclear risk of bias 5 Surrogate, not patient important outcomes.

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e-Table 4. GRADE Evidence Profile - Initial combination therapy with Ambrisentan and Tadalafil

Bibliography: Galie 2015 (AMBITION)

|||||||| No of patients| No of patients|Effect|Quality|Importance| |---|---|---|---|---|---|---|---|---|---|---|---| |# of studies|Design| Risk of bias| Inconsistency| Indirectness| Imprecision| Publication Bias |Pooled monotherapy|Combo|Difference|Quality|Importance| |Change in 6MWD from baseline|||||||||||| ||RCT|Not serious|Serious1|Not Serious|Not Serious|Undetected|24７|253| 23.80 (-12.25 to 64.53) vs. 48.98 (4.63 to 85.75) p |||

1 Inconsistency cannot be assessed because of single study 2 Assessment limited by only raw data available since authors did not analyze this endpoint individually in the primary data set; cannot assess whether finding of no difference due to no real difference or underpowered study. Raw, unadjusted $95\%$ CI calculated for proportions using vassarstats.net/prop2_ind.html

\* Only raw data available

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e-Table 5. GRADE Evidence Profile – Exercise based Rehabilitation

Bibliography: Morris 2017 (note: Ehlken 2016 and Weinstein 2013 were included in the Morris systematic review. According to authors they reviewed and extracted data from Chan 2013, a duplicate report of Weinstein 2013))

Note that only 2 very small studies in the Morris review were specific to Group 1 PAH

|||||||| No of patients| No of patients|Effect|Quality| Importance| |---|---|---|---|---|---|---|---|---|---|---|---| | # of studies|Design|Risk of bias| Inconsistency| Indirectness| Imprecision | Publication Bias|Placebo|Exercise| Relative Mean Difference (95%C1) |Quality| Importance| |Change in 6MWD|Change in 6MWD|Change in 6MWD|Change in 6MWD|Change in 6MWD|Change in 6MWD|Change in 6MWD|Change in 6MWD|Change in 6MWD|Change in 6MWD|Change in 6MWD|Change in 6MWD| | 2 studies in SR| Systematic Review |Serious1|Not serious|Not Serious|Serious2|Undetected|18|18|33.84 (0.95 to 66.73)|LOW||

1 Unclear risk of bias 2 Both studies were very small and range includes values that cross clinical decision threshold or may not represent clinically meaningful change.

e-Table 6. GRADE Evidence Profile – Inspiratory Muscle Training

Bibliography: Saglam 2015

|||||||| No of patients| No of patients|Effect| |---|---|---|---|---|---|---|---|---|---| |# of studies|Design |Risk of bias| Inconsistency| Indirectness| Imprecision| Publication Bias|Placebo| Inspiratory Muscle Training | Mean Before and After |

Change in 6MWD

|RCT|Serious1|Serious2|Not Serious|Serious3|Undetected|15|14| Control group 357.24 + or - 137.17 before and |VeryLow| |---|---|---|---|---|---|---|---|---|---| ||||||||| or - 137.17 before and 334.00 + or - 121.60 || ||||||||||| ||||||||| after p .109 IMT group 426.93 + or - 97.76426.93 + or - 97.76 before and 476.43 + or - 90.11 after p= .001 ||

1 Unclear risk of bias 2 Inconsistency cannot be assessed because of single study 3 Very small study; can’t determine if difference detected is related to before group differences at study start

There was a 50-m increase in the mean distance walked in the IMT group. There were no significant changes in the 6MWT distance or the percentage of predicted distance in the control group; note the groups differed in 6MWD at study start.