SECTION IX. Authors Name Authors Name

SECTION IX THIS RIGHT IS HEART AN EXAMPLE AND PULMONARY OF A SECTION TITLE CIRCULATION Authors Name Authors Name 667

Chapter 81 Combination Therapy in Pulmonary Hypertension: Current Status MOHAN BHARGAVA ABINAV JAIN PRACHAL BHARGAVA INTRODUCTION The term pulmonary hypertension (PH) refers to the presence of high pulmonary vascular pressure and can be the result of various underlying disorders. Pulmonary arterial hypertension (PAH) is defined as an increase in mean pulmonary arterial pressure (mpap) of 25 mm Hg or greater at rest as assessed by right heart catheterization. The lung has a double arterial blood supply from the pulmonary and the bronchial arteries as well as dual drainage into venous system by the pulmonary and the azygous veins. The pulmonary arteries are either elastic ( 500 microns) or muscular (100 500 microns). Arterioles are precapillaries smaller than 100 microns in diameter. Pulmonary artery divides down with appropriate generation bronchus down to the respiratory bronchiole. Bronchial circulation is a physiologic right to left shunt and provides nutrition to the airways. In PAH, the pathologic lesions involve mainly the muscular arteries and the veins are classically unaffected. In pulmonary veno-occlusive disease (PVOD), the septal veins and preseptal veins are involved and exhibit occlusive fibrotic lesion, venous muscularization, pulmonary oedema, alveolar haemorrhage, lymphatic dilatation and inflammatory infiltrates. In PH caused by left-sided heart diseases there is involvement of pulmonary veins, pulmonary capillaries, interstitium, lymphatics and muscular arteries. In PH caused by lung diseases there is medial hypertrophy and intimal obstructive proliferation of distal pulmonary arteries. In chronic thromboembolic pulmonary hypertension (CTEPH), there is involvement of the elastic pulmonary arteries. Pulmonary vasoconstriction has been regarded as an early component of the PH process and excessive vasoconstriction has been related to abnormal function or expression of potassium channels and to endothelial dysfunction. Pulmonary vasoconstriction and associated remodelling of the vascular walls are thought to be involved in the initiation of PAH which if left untreated can lead to heart failure and death. Endothelial dysfunction has been attributed to impaired production of vasodilators such as nitric oxide and prostacyclin along with overexpression of vasoconstrictors such as endothelin 1. The endothelin pathway is a key mediator of pulmonary vascular remodelling through the induction of smooth muscle cell and fibroblast proliferation and vasoconstriction. Activation of endothelin receptor type B also mediates vasodilation via the nitric oxide and prostacyclin pathways as shown in Fig. 81-1. Activation of the nitric oxide signalling pathway leads to vasodilation and inhibits cell proliferation; phosphodiesterase type-5 (PDE-5) inhibitors augment this pathway by disrupting the catalysis of cyclic gaunine monophosphate (cgmp) to GMP. Finally, the PGI2 pathway has an established role in increasing vasodilation and inhibiting vascular smooth muscle cell proliferation and migration 1. There are other mediators with role in PH such as angiopoetins, serotonin, bone morphogenetic proteins (BMPs) and growth factors like PDGF, FGF, EGF and TGF-B. There is also a growing literature on the role of cytokines and chemokines in pulmonary vascular remodelling. In patients with PAH, lower levels of endogenous PGI2 and nitric oxide, and elevated levels of endothelin have been observed. Because of these 669

670 SECTION IX Right Heart and Pulmonary Circulation Endothelin pathway Nitric oxide pathway Prostacyclin pathway Pro-endothelin-1 L-arginine Arachidonic acid Endothelin-1 (Vasoconstriction and proliferation) Endothelin receptor A Endothelin receptor B Nitric oxide (Vasodilatation and antiproliferation) Exogenous NO Prostacyclin (Vasodilatation and antiproliferation) IP receptor Selective ETA receptor antagonists Dual ET receptor antagonists cgc stimulators PDE-5 inhibitors PGI 2 analogues Non-prostanoid IP receptor agonists cgc PDE5 camp GTP cgmp GMP Figure 81-1. Various pathways leading to pulmonary vascular remodelling and also the therapeutic targets in PAH (ET, endothelin; ETA, endothelin type A; IP, prostaglandin I2; NO, nitric oxide; PAH, pulmonary arterial hypertension; PDE-5, phosphodiesterase type-5; sgc, soluble guanylate cyclase). Reproduced with permission from: Humbert, M., Lau, E. M. T., Montani, D., Jais, X., Sitbon, O., & Simonneau, G. (2014). Advances in therapeutic interventions for patients with pulmonary arterial hypertension. Circulation, 130, 2189 2208. observations and the potential interaction between these pathways, the combined use of drugs that target the different pathways is an attractive therapeutic option that could increase the effect of targeting one pathway alone and, as a result, may improve treatment outcomes. HAEMODYNAMICS Pulmonary circulation is characterized by high flow, low pressure and low resistance. Normal mpap at rest is 14 3 mm Hg independent of sex and ethnicity. PH can be precapillary if pulmonary arterial wedge pressure (PAWP) is 15 mm Hg

Chapter 81 Combination Therapy in Pulmonary Hypertension: Current Status 671 TABLE 81-1 EUROPEAN SOCIETY OF CARDIOLOGY AND THE EUROPEAN RESPIRATORY SOCIETY RECOMMENDATIONS FOR HAEMODYNAMIC DEFINITIONS OF PULMONARY HYPERTENSION 2 Definition Characteristics Clinical Group(s) PH PAPm 25 mm Hg All Precapillary PH PAPm 25 mm Hg PAWP 15 mm Hg 1. Pulmonary arterial hypertension 2. PH due to lung diseases 3. Chronic thromboembolic PH 4. PH with unclear and/or multifactorial mechanisms Postcapillary PH PAPm 25 mm Hg 1. PH due to left heart disease Isolated postcapillary PH PAWP 15 mm Hg 2. PH with unclear and/or multifactorial mechanisms Combined postcapillary and precapillary PH Diastolic pressure gradient 7 mm Hg and/or PVR 3 Wood unit Diastolic pressure gradient 7 mm Hg and/or PVR 3 Wood unit Note: CO, cardiac output; DPG, diastolic pressure gradient (diastolic PAP mean PAWP); mpap, mean pulmonary arterial pressure; PAWP, pulmonary arterial wedge pressure; PH, pulmonary hypertension; PVR, pulmonary vascular resistance; WU, Wood units. and postcapillary if PAWP is 15 mm Hg as shown in Table 81-1 (see ref 2). Some may have mixed picture with increased mpap and PAWP with transpulmonary gradient (mpap PAWP) 12 mm Hg. Normal pulmonary vascular bed offers less than 10% of the resistance to flow than does the systemic bed. PVR (mpap PAWP)/CO TPR mpap/co Units for PVR are dyne s/cm 5 or Wood unit (mm Hg/L/min). Normal calculated PVR in adults is 67 23 dyne s/ cm 5 or 1 Wood unit. Clinical classification of PH is as shown in Table 81-2 (see refs 2,3). EPIDEMIOLOGY PAH is uncommon, with an incidence of 2.4 7.6 patients per million and a prevalence of 15 50 patients per million population 4. This disease is still associated with considerable morbidity, the short-term mortality remains poor if left untreated and discontinuing treatment results in clinical worsening. Moreover, these therapies are administered long term and are expensive. Consequently, the impact of PH on health care systems worldwide is significant 5. DIAGNOSIS Diagnostic modalities are Electrocardiogram Chest radiograph Pulmonary function tests and arterial blood gases Echocardiography Ventilation/perfusion lung scan High-resolution computed tomography, contrast-enhanced computed tomography and pulmonary angiography Blood tests and immunology Abdominal ultrasound scan Right heart catheterization and vasoreactivity Genetic testing Echocardiographic evaluation and risk assessment of PAH are as seen in Tables 81-3 and 81-4 (see ref 2). Prognostic evaluation and risk assessment in PAH are shown in Table 81-5 (see ref 2). THERAPY IN PH The treatment process of PAH patients cannot be considered as a mere prescription of drugs, but is characterized by a complex strategy that includes the initial evaluation of severity and the subsequent response to treatment. The current treatment strategy for PAH patients can be divided into three main steps: (1) The initial approach includes general measures ( Table 81-6 ) (physical activity and supervised rehabilitation, pregnancy, birth control and postmenopausal hormonal therapy, elective surgery, infection prevention, psychosocial support, adherence to treatments, genetic counselling and travel), supportive therapy ( Table 81-7 ) (oral anticoagulants, diuretics, O 2, digoxin), referral to

672 SECTION IX Right Heart and Pulmonary Circulation TABLE 81-2 UPDATED CLINICAL CLASSIFICATION OF PULMONARY HYPERTENSION AS APPROVED DURING THE 5TH WORLD SYMPOSIUM IN PULMONARY HYPERTENSION 2, 3 1. Pulmonary Arterial Hypertension 1.1 Idiopathic 1.2 Heritable 1.2.1 BMPR2 mutation 1.2.2 Other mutations 1.3 Drugs and other toxins induced 1.4 Associated with: 1.4.1 Connective tissue diseases 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 Haemangiomatous 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 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 2.5 Congenital/acquired pulmonary veins stenosis 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 and Other Pulmonary Artery Obstructions 4.1 Chronic thromboembolic pulmonary hypertension 4.2 Other pulmonary artery obstructions 4.2.1 Angiosarcoma 4.2.2 Other intravascular tumours 4.2.3 Arteritis 4.2.4 Congenital pulmonary arteries stenoses 4.2.5 Parasites (hydatidosis) 5. Pulmonary Hypertension with Unclear and/or Multifactorial Mechanisms 5.1 Haematological disorders: chronic haemolytic anaemia, myeloproliferative disorders, splenectomy 5.2 Systemic disorders: sarcoidosis, pulmonary histiocytosis, lymphangioleiomyomatosis, neurofibromatosis 5.3 Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders 5.4 Others: pulmonary tumoural thrombothic microangiopathy, fibrosing mediastinitis, chronic renal failure (with/ without dialysis), segmental pulmonary hypertension TABLE 81-3 ECHOCARDIOGRAPHIC PROBABILITY OF PULMONARY HYPERTENSION IN SYMPTOMATIC PATIENTS WITH A SUSPICION OF PULMONARY HYPERTENSION 2 Peak Tricuspid Regurgitation Velocity (m/s) Presence of Other Echo PH Signs Echocardiographic Probability of Pulmonary Hypertension 2.8 or not measurable No Low 2.8 or not measurable Yes Intermediate 2.9 3.4 No 2.9 3.4 Yes High 3.4 Not required expert centres and acute vasoreactivity testing for the indication of chronic calcium channel blocker (CCB) therapy 2. (2) The second step includes initial therapy with high-dose CCB in vasoreactive patients or drugs approved for PAH in nonvasoreactive patients according to the prognostic risk of the patient and the grade of recommendation and level of evidence for each individual compound or combination of compounds ( Table 81-8 ) 2. (3) The third part is related to the response to the initial treatment strategy; in the case of an inadequate response, the role of combinations of approved drugs and lung transplantation are proposed. Combination therapy may be applied sequentially or initially (upfront). Sequential combination therapy is the most widely utilized strategy both in RCTs and in clinical

Chapter 81 Combination Therapy in Pulmonary Hypertension: Current Status 673 TABLE 81-4 ECHOCARDIOGRAPHIC SIGNS SUGGESTING PULMONARY HYPERTENSION USED TO ASSESS THE PROBABILITY OF PULMONARY HYPERTENSION IN ADDITION TO TRICUSPID REGURGITATION VELOCITY MEASUREMENT IN TABLE 81-3 (see Ref 2) A: The Ventricles B: Pulmonary Artery Right ventricle/ left ventricle basal diameter ratio 1.0 Flattening of the interventricular septum (left ventricular eccentricity index 1.1 in systole and/or diastole) Right ventricular outflow Doppler acceleration time 105 ms and/ or midsystolic notching Early diastolic pulmonary regurgitation velocity 2.2 m/s PA diameter 25 mm C: Inferior Vena Cava and Right Atrium Inferior cava diameter 21 mm with decreased inspiratory collapse ( 50% with a sniff or 20% with quiet inspiration Right atrial area (end-systole) 18 cm 2 TABLE 81-5 EUROPEAN SOCIETY OF CARDIOLOGY AND THE EUROPEAN RESPIRATORY SOCIETY RECOMMENDATIONS FOR RISK ASSESSMENT IN PULMONARY ARTERIAL HYPERTENSION 2 Determinants of Prognosis (Estimated 1-Year Mortality) Low Risk, 5% Intermediate Risk, 5% 10% High Risk, 10% Clinical signs of right heart Absent Absent Present failure Progression of symptoms No Slow rapid Rapid Syncope No Occasional syncope Recurrent syncope WHO functional class I, II III IV 6MWD 440 m 165 440 m 165 m Cardiopulmonary exercise testing Peak VO 2 15 ml/min/ kg ( 65% predicted) VE/VCO 2 slope 36 Peak VO 2 11 15 ml/min/kg (35% 65% predicted) VE/VCO 2 slope 36 44.9 Peak VO 2 11 ml/min/ kg ( 35% predicted) VE/VCO 2 slope 45 NT-proBNP levels BNP 50 ng/l BNP 50 300 ng/l BNP 300 ng/l Imaging (echocardiography, CMR imaging) Haemodynamics NT-proBNP 300 ng/l RA area 18 cm 2 No pericardial effusion RAP 8 mm Hg CI 2.5 L/min/m 2 SvO 2 65% NT-proBNP 300 1400 ng/l RA area 18 26 cm 2 No or minimal, pericardial effusion RAP, 8 14 mm Hg CI, 2.0 2.4 L/min/m 2 SvO 2, 60% 65% NT-proBNP 1400 ng/l RA area 26 cm 2 Pericardial effusion RAP 14 mm Hg CI 2.0 L/min/m 2 SvO 2 60% Note: 6MWD, 6-min walking distance; BNP, brain natriuretic peptide; CI, cardiac index; CMR, cardiac magnetic resonance; NT-proBNP, N-terminal pro-brain natriuretic peptide; RA, right atrium; RAP, right atrial pressure; SvO 2, mixed venous oxygen saturation; VE/VCO 2, ventilatory equivalents for carbon dioxide; VO 2, oxygen consumption; WHO, World Health Organization. TABLE 81-6 EUROPEAN SOCIETY OF CARDIOLOGY AND THE EUROPEAN RESPIRATORY SOCIETY RECOMMENDATIONS FOR GENERAL MEASURES 2 Recommendations Class Level It is recommended that PAH patients avoid pregnancy I C Immunization of PAH patients against influenza and pneumococcal infection is recommended I C Psychosocial support is recommended in PAH patients I C Supervised exercise training should be considered in physically deconditioned PAH patients under IIa B medical therapy In-flight O 2 administration should be considered for patients in WHO FC III and IV and those with IIa C arterial blood O 2 pressure consistently 8 kpa (60 mm Hg) In elective surgery, epidural rather than general anaesthesia should be preferred whenever possible IIa C Excessive physical activity that leads to distressing symptoms is not recommended in PAH patients III C

674 SECTION IX Right Heart and Pulmonary Circulation TABLE 81-7 EUROPEAN SOCIETY OF CARDIOLOGY AND THE EUROPEAN RESPIRATORY SOCIETY RECOMMENDATIONS FOR SUPPORTIVE THERAPY 2 Recommendations Class Level Diuretic treatment is recommended in PAH patients with signs of RV failure and fluid retention I C Continuous long-term O 2 therapy is recommended in PAH patients when arterial blood O 2 pressure I C is consistently 8 kpa (60 mm Hg) Oral anticoagulant treatment may be considered in patients with IPAH, HPAH and PAH due to use IIb C of anorexigens Correction of anaemia and/or iron status may be considered in PAH patients IIb C The use of angiotensin-converting enzyme inhibitors, angiotensin-2 receptor antagonists, betablockers and ivabradine is not recommended in patients with PAH unless required by comorbidities (i.e. high blood pressure, coronary artery disease or left heart failure) III C TABLE 81-8 EUROPEAN SOCIETY OF CARDIOLOGY AND THE EUROPEAN RESPIRATORY SOCIETY RECOMMENDATIONS FOR CALCIUM CHANNEL BLOCKER THERAPY IN PATIENTS WHO RESPOND TO THE ACUTE VASOREACTIVITY TEST 2 Recommendations Class Level High doses of CCBs are recommended in patients with IPAH, HPAH and DPAH who are responders to acute vasoreactivity testing Close follow-up with complete reassessment after 3 4 months of therapy (including RHC) is recommended in patients with IPAH, HPAH and DPAH treated by high doses of CCBs Continuation of high doses of CCBs is recommended in patients with IPAH, HPAH and DPAH in WHO FC I or II with marked haemodynamic improvement (near normalization) Initiation of specific PAH therapy is recommended in patients in WHO FC III or IV or those without marked haemodynamic improvement (near normalization) after high doses of CCBs High doses of CCBs are not indicated in patients without a vasoreactivity study or nonresponders unless standard doses are prescribed for other indications (e.g. Raynaud phenomenon) I I I I III C C C C C practice: from monotherapy there is an addition of a second and then a third drug in cases of inadequate clinical results or in cases of deterioration. PAH-targeted therapy is considered in symptomatic patients who are not vasoreactive or who are vasoreactive but display a suboptimal response to treatment with CCBs. The current PAH treatment algorithm, as updated following the 5th World Symposium on Pulmonary Hypertension, recommends targeting at least one of the three main disease pathways. The endothelin pathway is targeted by endothelin receptor antagonists (ERAs) such as bosentan, ambrisentan or macitentan. The nitric oxide pathway is targeted through PDE-5 inhibitors that include sildenafil and tadalafil, and a soluble guanylate cyclase stimulator, riociguat. The prostacyclin pathway include epoprostenol, iloprost, treprostinil and beraprost. Until 2001, epoprostenol was the only drug available to treat PAH, and then primarily as a bridge to transplantation 6. Since then, the development of new PAH-specific medications has grown apace. Today, there are nine medications approved in Europe for treatment of PAH, six of which are oral, with others in development. With the advent of new medications, evidence-based guidelines have evolved to reflect the rapidly changing treatment environment 2. Observations that patients with an inadequate clinical response to initial single-agent therapy had a much worse prognosis soon led to recommendations to add a second and potentially a third drug to the PAH-specific regimen to improve clinical and functional parameters and long-term outcomes 7, 8. Therapies for PH developed over the last two decades and directed towards the endothelin, nitric oxide and prostacyclin pathways, and have imparted significant clinical benefit, improving exercise capacity and symptoms. Nevertheless, their impact on the underlying pathophysiology, in particular the remodelling process, is uncertain and they are not curative 9. SEQUENTIAL DRUG COMBINATION THERAPY Initial short-term RCTs on sequential combination therapy gave conflicting results in patients with PAH ( Table 81-9 ).

Chapter 81 Combination Therapy in Pulmonary Hypertension: Current Status 675 TABLE 81-9 SUMMARY OF RANDOMIZED CONTROLLED TRIALS OF SEQUENTIAL COMBINATION THERAPY IN PULMONARY ARTERIAL HYPERTENSION Drug Tested Aetiology Inhaled iloprost (STEP) Inhaled iloprost (COMBI) Inhaled treprostinil (TRIUMPH-1) Oral treprostinil (FREEDOM-C) Oral treprostinil (FREEDOM-C2) Background Therapy (%) IPAH, APAH Bosentan IPAH Monotherapy Arm No. of Subjects Duration End Points Comment Ref Primary Secondary No 67 12 weeks 6MWD TTCW, PVR, FC, Borg score Bosentan No 40 12 weeks 6MWD TTCW, FC, peak VO2, QoL IPAH, APAH Bosentan (70%) or Sildenafil (30%) IPAH, APAH ERA (30%) or PDE-5i (25%) or both (45%) IPAH, APAH ERA (17%) or PDE-5i (43%) or both (40%) No No No Primary end point did not meet defined statistical significance (P 0.051). Improvement in TTCW, FC, and haemodynamics All primary and secondary end points were not met. Trial was stopped early after interim analysis revealed low likelihood of reaching primary end point 350 16 weeks 6MWD TTCW, Borg score 310 16 weeks 6MWD TTCW, FC, NTproBNP, QoL Tadalafil (PHIRST) IPAH, APAH Bosentan Yes 216 (405) a 16 weeks 6MWD Sildenafil (PACES) IPAH, APAH Epoprosteno Riociguat (PATENT-1) IPAH, APAH ERA (13%) or prostanoid (87%) Macitentan (SERAPHIN) IPAH, APAH PDE-5i (92%) or nonparenteral, prostanoid (8%) TTCW, PVR, QoL No 267 16 weeks 6MWD TTCW, PVR, QoL Yes 222 (443) a 12 weeks 6MWD Yes 471 (742) a Median exposure 115 weeks Composite end point (mortality and morbidity) TTCW, FC, PVR, NTproBNP, QoL 6MWD, FC, QoL 235 12 weeks 6MWD TTCW, FC, QoL Primary end point met. However, no difference in TTCW but QoL improved in treprostinil group Primary end point not met. No difference in TTCW Primary end point not met. No significant differences in all secondary end points Primary end point was met for entire study cohort, but subgroup on background therapy did not demonstrate improvement in 6MWD or FC Primary end point met together with delayed TTCW, improvement in haemodynamics and QoL Primary end point met and efficacy also demonstrated in pre-specified subgroup on background therapy. Improved TTCW, FC, and PVR Primary end point met and efficacy also demonstrated in pre-specified subgroup on background therapy. Liver function abnormalities not significantly different in treatment groups 10 11 12 13 14 15 16 17 18 6MWD, 6-min walk distance; APAH, associated pulmonary arterial hypertension; ERA, endothelin receptor antagonist; FC, functional class; IPAH, idiopathic pulmonary arterial hypertension; NT-proBNP, N-terminal pro-brain natriuretic peptide; PAH, pulmonary arterial hypertension; PDE-5i, phosphodiesterase type-5 inhibitor; PVR, pulmonary vascular resistance; QoL, quality of life; RCT, randomized controlled trial; TTCW, time to clinical worsening. a Trial total. Reproduced with permission from: Humbert, M., Lau, E. M. T., Montani, D., Jais, X., Sitbon, O., Simonneau, G. (2014). Advances in therapeutic interventions for patients with pulmonary arterial hypertension. Circulation, 130, 2189 2208.

676 SECTION IX Right Heart and Pulmonary Circulation A meta-analysis of monotherapy compared with combination therapy in six RCTs (ranging from 12 to 16 weeks in duration) did not show a beneficial effect of sequential combination therapy on either a combined clinical worsening or survival end point, although a modest improvement in exercise capacity was observed 19. This finding was echoed by a systematic review and meta-analysis of 28 RCTs 20. A separate metaanalysis of seven clinical trials indicated combination therapy was associated with beneficial effects in both exercise capacity and disease worsening, but no improvement was reported in survival compared to monotherapy 21. However, other recent results have shown beneficial effects of combination therapy versus monotherapy alone. The 12-week PATENT-1 study showed that riociguat improved 6-min walking distance (6MWD) compared to placebo in patients receiving riociguat in addition to ERAs or prostanoids 17. The COMPASS-2 trial was a long-term study of the use of bosentan in addition to background sildenafil. While the study did not meet its primary end point of reducing time to first morbidity or mortality event, an exploratory analysis indicated that bosentan in addition to sildenafil led to an improvement in 6MWD at week 16 (see ref 22). A subgroup analysis from the SERAPHIN study (n 317; median treatment duration 2.2 years) showed that the addition of macitentan significantly reduced the risk of a composite morbidity/mortality event by 38% ( P.009) in patients on stable background therapies for PAH; a PDE-5 inhibitor (predominantly sildenafil) was used in 96% of these patients 18. Dardi et al. assessed the impact of sequential combination therapy of bosentan and sildenafil on both short-term responses and long-term outcomes in a real-world setting. Double combination therapy significantly improved clinical and haemodynamic parameters, independent of aetiology or the order of drug administration. Significant improvements in functional class were observed in patients with idiopathic/heritable PAH. The 1-, 3- and 5-year overall survival estimates were 91%, 69% and 59%, respectively. Patients with PAH associated with connective tissue disease had significantly poorer survival rates compared to other aetiologies ( P.003) 8. INITIALLY (UPFRONT) COMBINATION THERAPY Ambrisentan and Tadalafil in Patients with Pulmonary Arterial Hypertension (AMBITION) trial, the first randomized controlled trial of initial combination dual therapy, showed a highly significant reduction in the risk of clinical failure for patients on first-line dual therapy, as compared with patients on monotherapy. The study did not, however, include haemodynamic indices as outcome measures 23. Kemp et al. analysed efficacy and safety of upfront epoprostenol and bosentan combination therapy in consecutive patients with idiopathic, heritable or anorexigen-associated PAH and compared outcomes with matched controls treated by epoprostenol monotherapy. They took functional class III and IV patients and measured 6MWD, mean pulmonary artery pressure, cardiac index and pulmonary vascular resistance (PVR). After 4 months, 6MWD and PVR significantly improved and these improvements were maintained long term. Overall survival estimates were 100%, 94%, 94% and 74%, and transplant-free survival estimates were 96%, 85%, 77% and 60% at 1, 2 and 3 years, respectively. Compared with matched controls started on epoprostenol monotherapy, there was a trend to an improvement in overall survival ( P.07) 24. The experience with combination therapy is increasing and a recent meta-analysis on six RCTs with combination therapy including 858 patients has been published; compared with the control group, combination therapy reduced the risk of clinical worsening (relative risk [RR] 0.48 [95% confidence interval (CI): 0.26, 0.91], P.023), increased the 6MWD significantly by 22 m and reduced mean PAP, Right atrial pressure (RAP) and PVR. The incidence of serious adverse events was similar in the two groups (RR, 1.17 [95% CI: 0.40, 3.42], P.77). The reduction in all-cause mortality was not statistically significant. However, the incidence of mortality in RCTs with PAH medications is relatively low and to achieve statistical significance a sample size of several thousand patients may be required 25. Sitbon et al. performed a retrospective analysis of initial dual drug therapy in patients with PAH. They had 97 patients who were initiated on firstline dual oral combination therapy consisting of an ERA (bosentan or ambrisentan) and a PDE-5 inhibitor (sildenafil or tadalafil). Within these regimens, therapies were given concomitantly, starting with two drugs on day 1. Dosing was as follows: bosentan 62.5 mg twice daily, increasing to 125 mg twice daily after 4 weeks; ambrisentan 5 mg once daily, increasing to 10 mg once daily if needed (in cases of insufficient clinical

Chapter 81 Combination Therapy in Pulmonary Hypertension: Current Status 677 and/or haemodynamic response at the first followup visit) and there were no tolerability issues; sildenafil 20 mg three times daily, increasing to 40 mg three times daily if needed (in cases of insufficient clinical and/or haemodynamic response at the first follow-up visit); or tadalafil 20 mg once daily with uptitration to 40 mg once daily after 3 7 days, according to tolerability. In addition to PAH-specific therapy, if needed, patients also received standard supportive therapy that included oral anticoagulants, diuretics and oxygen. Assessments included NYHA FC, 6MWD and pulmonary haemodynamics (assessed by RHC). Combination therapy (pooled analysis) was associated with significant improvements in functional class, exercise capacity and dyspnoea. Significantly fewer patients had evidence of right heart failure (suggesting a reduction in clinical worsening), while levels of brain natriuretic peptide (BNP) were significantly reduced. These improvements were accompanied by significant improvements in 6MWD and haemodynamic parameters, including reductions from baseline in PVR. Over a median (IQR) observational follow-up period of 30 (20 43) months, 75 (82%) patients were still alive 26. Hassoun et al. found that upfront combination therapy with ambrisentan and tadalafil significantly improved haemodynamics, RV structure and function, and functional status in treatmentnaive patients with SSc-PAH and represents a very effective therapy for this patient population 27. UPFRONT TRIPLE COMBINATION THERAPY A pilot observational study of upfront triple combination therapy with epoprostenol, bosentan and sildenafil in patients with severe PAH who present in NYHA FC III/IV together with severe haemodynamic impairment was recently reported. Severe haemodynamic impairment was defined as either a cardiac index 2.0 L/min/m 2 or mean right atrial pressure 20 mm Hg or PVR 1000 dyne s/cm 5. At a median follow-up of 39 months, 18 of 19 patients had sustained clinical improvement and remained in NYHA FC I/II. 6MWD increased dramatically from 227 to 514 m ( P.01) and PVR declined from 1718 to 492 dyne s/cm 5 ( P.01). Despite the observational nature of this study, it provides preliminary proof of concept for the adoption of an aggressive upfront combination strategy in patients who have very severe PAH for whom prognosis has traditionally been extremely poor 28. The current treatment algorithm indicating the addition of a second treatment in addition to background therapy may be considered when an inadequate clinical response or deterioration is observed with monotherapy in patients in the World Health Organization (WHO) functional class III/IV. Since the 4th World Symposium on Pulmonary Hypertension recommendations in 2008, the level of evidence for sequential combination therapy has been upgraded to I-A in the 5th World Symposium on Pulmonary Hypertension recommendations in 2013 ( Table 81-10 ) 2, 7. By contrast, evidence to support upfront combination therapy remains largely based on expert consensus and/or small studies, retrospective studies and registries. The 5th World Symposium on Pulmonary Hypertension has graded the evidence of initial combination therapy in the WHO functional class III/IV as IIb C ( Table 81-11 ) 2, 7. The 2015 ESC/ERS guidelines for the diagnosis and treatment of PH gave the initial combination of ambrisentan and tadalafil a class Ib recommendation in WHO class III patients based on the results of the AMBITION trial 23. CONCLUSION In conclusion, treatment for PH has evolved over decades to include drugs targeting three different pathways. Different modalities of treatment include monotherapy and combination drug therapy in addition to general measures and supportive treatment. Evidence-based medicine has found good results for combination therapy over monotherapy which may be sequential or upfront combination therapy. Since the 4th World Symposium on Pulmonary Hypertension recommendations in 2008, the level of evidence for sequential combination therapy has been upgraded to I-A in the 5th World Symposium on Pulmonary Hypertension recommendations in 2013. Combination of ambrisentan and tadalafil has been given a I-B recommendation after the results of the AMBITION trial. A trial on upfront triple combination therapy has also been published recently which also had good results providing hope for patients with severe PAH for whom the prognosis was traditionally poor 28. Despite the results of this trial, patient s quality of life and long-term prognosis remain suboptimal for many of them. Future research is thus required to identify the choice of treatment strategy between initial upfront versus rapid sequential combination and dual versus triple combination therapy as well as novel drugs in combination with traditional vasodilators.

678 SECTION IX Right Heart and Pulmonary Circulation TABLE 81-10 EUROPEAN SOCIETY OF CARDIOLOGY AND THE EUROPEAN RESPIRATORY SOCIETY RECOMMENDATIONS FOR EFFICACY OF SEQUENTIAL DRUG COMBINATION THERAPY FOR PULMONARY ARTERIAL HYPERTENSION (GROUP 1) ACCORDING TO WORLD HEALTH ORGANIZATION FUNCTIONAL CLASS 2 Measure/Treatment Class Level WHO FC II WHO FC III WHO FC IV Macitentan added to sildenafil I B I B IIa C Riociguat added to bosentan I B I B IIa C Selexipage added to ERA and/or PDE-5i I B I B IIa C Sildenafil added to epoprostenol I B IIa B Treprostinil inhaled added to sildenafil or IIa B IIa B IIa C bosentan Iloprost inhaled added to bosentan IIb B IIb B IIb C Tadalafil added to bosentan IIa C IIa C IIa C Ambrisentan added to sildenafil IIb C IIb C IIb C Bosentan added to epoprostenol IIb C IIb C Bosentan added to sildenafil IIb C IIb C IIb C Sildenafil added to bosentan IIb C IIb C IIb C Other double combinations IIb C IIb C IIb C Other triple combinations IIb C IIb C IIb C Riociguat added to sildenafil or other PDE-5i III B III B III B Note: ERA, endothelin receptor antagonist; PDE-5i, phosphodiesterase type-5 inhibitor; WHO FC, World Health Organization functional class. TABLE 81-11 EUROPEAN SOCIETY OF CARDIOLOGY AND THE EUROPEAN RESPIRATORY SOCIETY RECOMMENDATIONS FOR EFFICACY OF INITIAL DRUG COMBINATION THERAPY FOR PULMONARY ARTERIAL HYPERTENSION (GROUP 1) ACCORDING TO WORLD HEALTH ORGANIZATION FUNCTIONAL CLASS 2 Measure/Treatment Class Level WHO FC II WHO FC III WHO FC IV Ambrisentan tadalafil I B I B IIb C Other ERA PDE-5i IIa C IIa C IIb C Bosentan sildenafil IV epoprostenol - IIa C IIa C Bosentan IV epoprostenol - IIa C IIa C Other ERA PDE-5i IV epoprostenol IIb C IIb C Other ERA PDE-5i other IV prostacyclin analogues IIb C IIb C Note: ERA, endothelin receptor antagonist; IV, intravenous; PDE-5i, phosphodiesterase type-5 inhibitor; WHO FC, World Health Organization functional class. REFERENCES 1. Sitbon, O., & Morrell, N. ( 2012 ). Pathways in pulmonary arterial hypertension: The future is here. European respiratory Review, 21, 321 327. 2. Galiè, N., Humbert, M., Vachiery, J. L., Gibbs, S., Lang, I., Torbicki, A., et al. ( 2016 ). 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. European Heart Journal, 37, 67 119. 3. Simonneau, S., Gatzoulis, M. A., Adatia, I., Celermajer, D., Denton, C., Ghofrani, A., et al. ( 2013 ). Updated clinical classification of pulmonary hypertension. Journal of the American College of Cardiology, 62, D34 41. 4. Peacock, A. J., Murphy, N. F., McMurray, J. V., Caballero, L., & Stewart, S. ( 2007 ). An epidemiological study of pulmonary arterial hypertension. European Respiratory Journal, 30, 104 109. 5. Benza, R. L., Miller, D. P., Gomberg-Maitland, M., Frantz, R. P., Foreman, A. J., Coffey, C. S., et al. ( 2010 ). Predicting survival in pulmonary arterial hypertension: Insights from the registry to evaluate early and long-term pulmonary arterial hypertension disease management (REVEAL). Circulation, 122, 164 172. 6. Rich S. ( 1995 ). Medical treatment of primary pulmonary hypertension: A bridge to transplantation? American Journal of Cardiology, 75, 63A 66A.

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