treatment pulmonary hypertension

8/18/2019 treatment pulmonary hypertension

1/14www.thelancet.com/respiratory Vol 4 April 2016 323

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Lancet Respir Med 2016;

4: 323–36

Published Online

March 11, 2016

http://dx.doi.org/10.1016/

S2213-2600(15)00542-1

See Editorial page 241

See Review page 306

See Online for podcast interview

with Marius Hoeper

Department of Respiratory

Medicine, Hannover Medical

School and German Centre forLung Research, Hannover,

Germany (Prof M M Hoeper MD);

Department of Internal

Medicine, University of

Michigan Health System,

Ann Arbor, MI, USA

(Prof V V McLaughlin MD);

Section of Pulmonary Medicine,

King Faisal Specialist Hospital

and Research Center, Riyadh,

Saudi Arabia (A M Al Dalaan MD);

Division of Cardiology,

Department of Medicine, Kyorin

University School of Medicine,

Tokyo, Japan (Prof T Satoh MD);

Department of Experimental,

Diagnostic and SpecialtyMedicine (DIMES), University of

Bologna, Bologna, Italy

(Prof N Galiè MD)

Treatment of pulmonary hypertension

Marius M Hoeper, Vallerie V McLaughlin, Abdullah M Al Dalaan, Toru Satoh, Nazzareno Galiè

The most common forms of pulmonary hypertension are pulmonary arterial hypertension, chronic thromboembolicpulmonary hypertension, and pulmonary hypertension due to left-sided heart and lung disease. The treatment ofpulmonary arterial hypertension has advanced substantially over the past 20 years. Five different classes of drugs arenow available—ie, endothelin receptor antagonists, phosphodiesterase-5 inhibitors, soluble guanylate cyclasestimulators, prostacyclin analogues, and prostacyclin receptor agonists. Long-term studies have provided evidencethat various combinations of these compounds improve the progression-free survival of patients with pulmonaryarterial hypertension. For patients with chronic thromboembolic pulmonary hypertension, surgical pulmonaryendarterectomy is the treatment of choice. For patients who are inoperable and have chronic thromboembolicpulmonary hypertension, riociguat, a stimulator of soluble guanylate cyclase, has proven effi cacious. Additionally,interventional approaches could become a treatment option for these patients. For patients with pulmonaryhypertension due to left-sided heart disease or lung disease, the use of pulmonary vasodilator treatment has not been

proven to be safe and effective.

IntroductionPulmonary hypertension, defined by a mean pulmonaryartery pressure of 25 mm Hg or more at rest, 1 is acommon disorder frequently associated with variousdiseases, predominantly left-sided heart disease and lungdisease. The term pulmonary arterial hypertension isused to describe a rare subtype of pulmonaryhypertension characterised by an angioproliferativevasculopathy affecting mainly the small pulmonaryarteries, which results in progressive pulmonary vascularremodelling, increased pulmonary vascular resistance

and, eventually, right-sided heart failure.

2,3

Haemodynamically, pulmonary hypertension isclassified as precapillary or postcapillary on the basis ofleft-sided cardiac filling pressure—ie, the pulmonaryartery wedge pressure (PAWP) or, in the absence ofmitral stenosis, the left ventricular end-diastolic pressure.In precapillary pulmonary hypertension, the left-sidedcardiac filling pressure is normal—ie, 15 mm Hg or less.In postcapillary pulmonary hypertension, left-sidedcardiac filling pressures are elevated (>15 mm Hg). Somepatients with postcapillary pulmonary hypertension havean additional precapillary component as indicated by adiastolic pressure gradient (the difference between thediastolic pulmonary artery pressure and the PAWP) of

7 mm Hg and more or an increased pulmonary vascularresistance (>3 Wood units or >240 dyn s cm−⁵).4

From a pathophysiological, clinical, and therapeuticperspective, pulmonary hypertension is divided into fivegroups: pulmonary arterial hypertension; pulmonaryhypertension due to left-sided heart disease; pulmonaryhypertension due to lung disease or hypoxia; chronicthromboembolic pulmonary hypertension; andpulmonary hypertension with unclear multifactorialmechanisms.5–7 The epidemiology of these pulmonaryhypertension groups is reviewed in another Review.8

Over the past 20 years, substantial therapeutic progresshas been made for pulmonary arterial hypertension andchronic thromboembolic pulmonary hypertension,although no established treatments are available for most

of the other forms of pulmonary hypertension.9–12 ThisReview summarises the present knowledge on themanagement of the most common forms of pulmonaryhypertension with a particular focus on long-term trialsin the field of pulmonary arterial hypertension and therecent guidelines for the diagnosis and treatment ofpulmonary hypertension, published jointly by theEuropean Society of Cardiology (ESC) and the EuropeanRespiratory Society (ERS).6,7

Group 1—pulmonary arterial hypertension

Pulmonary arterial hypertension consists of idiopathic,drug-associated, and heritable forms, and pulmonaryarterial hypertension associated with connective tissue

Key messages

• The most common forms of pulmonary hypertension are pulmonary arterial

hypertension, chronic thromboembolic pulmonary hypertension, and pulmonary

hypertension due to left-sided heart disease and lung disease.

• Five different classes of drugs are available to treat pulmonary arterial hypertension—

ie, endothelin receptor antagonists, phosphodiesterase-5 inhibitors, soluble guanylate

cyclase stimulators, prostacyclin analogues, and prostacyclin receptor agonists.

• The SERAPHIN trial has shown improved progression-free survival with the

endothelin receptor antagonist, macitentan, in patients with pulmonary arterial

hypertension, irrespective of whether they were treatment naive or pretreated with a

phosphodiesterase-5 inhibitor.

• The AMBITION study has shown improved progression-free survival in patients with

pulmonary arterial hypertension receiving initial combination therapy with

ambrisentan, an endothelin receptor antagonist, and tadalafil, a phosphodiesterase-5

inhibitor, compared with monotherapy with these compounds.

• For patients with chronic thromboembolic pulmonary hypertension, surgical

pulmonary endarterectomy is the preferred treatment.

• For patients with chronic thromboembolic pulmonary hypertension who are

inoperable, new treatment options include balloon pulmonary angioplasty and

treatment with riociguat, a stimulator of the soluble guanylate cyclase.

• Existing evidence is not suffi cient to establish whether pulmonary vasodilators are

safe and effective in patients (or subsets of patients) with pulmonary hypertension

due to left-sided heart disease or lung disease.

http://crossmark.crossref.org/dialog/?doi=10.1016/S2213-2600(15)00542-1&domain=pdf


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Correspondence to:

Prof Marius M Hoeper,

Department of Respiratory

Medicine, Hannover Medical

School, 30623 Hannover,

Germany

hoeper.marius@mh-hannover.

de

disease, HIV infection, portal hypertension, congenital

heart disease, and schistosomiasis.

5

All of these entitiesshare common haemodynamic features with precapillarypulmonary hypertension, often accompanied by a lowcardiac output, and a high pulmonary vascular resistance.The histological hallmark of pulmonary arterialhypertension is obliteration of small pulmonary arteriescaused by proliferating endothelial cells and pulmonaryvascular smooth muscle cells.2 As a consequence, thepulmonary vascular resistance rises, putting incrementalstrain on the right ventricle.3 Left untreated, pulmonaryarterial hypertension is a progressive disease and right-sided heart failure is the most frequent cause of death inthese patients. In the US National Institutes of Healthregistry, which enrolled patients between 1981 and 1985

before effective treatments became available, the mediansurvival was 2·8 years after diagnosis.13 This registryincluded patients with what at that time was calledprimary pulmonary hypertension, which today would beclassified predominantly as idiopathic pulmonary arterialhypertension. In patients with pulmonary arterialhypertension associated with connective tissue diseaseand pulmonary arterial hypertension associated withportal hypertension, survival is even worse, whereaspatients with pulmonary arterial hypertension associatedwith congenital heart disease tend to have a better long-term survival.14,15

Treatment is similar for all forms of pulmonary arterialhypertension, albeit almost all randomised controlledtrials have included predominantly patients withidiopathic pulmonary arterial hypertension or pulmonaryarterial hypertension associated with connective tissuedisease. Generally, the main results of these trials havebeen confirmed by smaller trials and case series ofpatients with other forms of pulmonary arterialhypertension.16,17

General measures and supportive treatments forpatients with pulmonary arterial hypertensionGeneral measures such as immunisation againstinfluenza and pneumococcal infection, psychosocialsupport, and supervised exercise training are

recommended for patients with pulmonary arterialhypertension.6,7 Supportive measures include homeoxygen treatment when the partial pressure of oxygen inthe arterial blood is consistently less than 60 mm Hg orwhen oxygen saturation deteriorates substantially duringexercise or sleep. Iron deficiency or anaemia, if present,should be corrected.18 Diuretics are administered asneeded. The choice of agents is empirical because nostudies have compared the use of various diureticstrategies in patients with pulmonary arterialhypertension. The same is true for the use ofmineralocorticoid receptor antagonists, such asspironolactone or eplerenone. Anticoagulation has beenadvocated for pulmonary arterial hypertension, mainlybecause of histological findings showing in situ

thrombosis in the affected pulmonary vessels and

because of observational data suggesting improvedsurvival in patients with idiopathic pulmonary arterialhypertension receiving anticoagulation.19–21 However,clear evidence is missing and the 2015 ESC/ERSpulmonary hypertension guidelines state thatanticoagulation might be considered in patients withidiopathic pulmonary arterial hypertension but not inother forms of pulmonary arterial hypertension, in whichthe risk–benefit ratio seems to be unfavourable.6,7,22

Vasoreactivity testing and high-dose calcium channelblocker treatmentMost patients with pulmonary arterial hypertensionexhibit little acute haemodynamic response to pulmonary

vasodilators, such as inhaled nitric oxide. However, about5–10% of these patients show distinct pulmonaryvasoreactivity with normalisation or near normalisationof their pulmonary haemodynamics during acutevasodilator challenge.23 These so-called responders canhave a remarkable response to high-dose calciumchannel blocker treatment with sustained improvementor even normalisation of haemodynamics and anexcellent long-term outcome.23 Such long-termresponders are reported almost exclusively in patientswith idiopathic pulmonary arterial hypertension andpredominantly in young females. Patients with otherforms of pulmonary arterial hypertension almost neverexperience long-term improvement with calciumchannel blocker treatment, even if these patients seem tobe responders during acute vasoreactivity testing.24 Hence, the present ESC/ERS guidelines recommendpulmonary vasoreactivity testing only in patients withidiopathic pulmonary arterial hypertension (includingheritable and drug-associated forms) but not in otherforms of pulmonary arterial hypertension, or pulmonaryhypertension.6,7

Targeted therapiesSeveral drugs are currently approved for the treatmentof pulmonary arterial hypertension: the endothelinreceptor antagonists ambrisentan, bosentan, and

macitentan; the phosphodiesterase-5 inhibitorssildenafil and tadalafil; the soluble guanylate cyclasestimulator riociguat; the prostacyclin analoguesberaprost (in Japan and South Korea only), epoprostenol,iloprost, and treprostinil; and the prostacyclin receptoragonist selexipag. With the exception of macitentan andselexipag, all available drugs for treatment of pulmonaryarterial hypertension have been approved on the basisof short-term trials of 12–24 weeks duration, which havefocused mainly on exercise capacity as assessed bychange in 6 min walk distance. The main characteristicsand key findings of these trials are listed in table 1. Some, but not all, of these studies showed a delay in thetime to clinical worsening, a composite endpoint that included different variables (such as a decline in exercise


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capacity, admission to hospital for pulmonary arterialhypertension, the need for additional pulmonary arterialhypertension treatment, or a combination of outcomes).

Long-term trialsLong-term, event-driven trials entered the specialty ofpulmonary arterial hypertension only recently. In the last

3 years two such trials, COMPASS-241 and AMBITION,42 explored treatment strategies with already approveddrugs and another two, SERAPHIN43 and GRIPHON,44 assessed new compounds (table 2).

COMPASS-2 investigated the hypothesis that bosentanadded to sildenafil in stable patients with pulmonaryarterial hypertension would improve long-term outcome.41

Number of

participants

Study

duration

Primary endpoint(s)* Functional

classimproved

TTCW

improved

Main adverse events

BREATHE-1 (bosentan vs placebo; all patientstreatment naive)25

213 12 weeks 6MWD +35 m with 125 mg of bosentan

twice daily (p


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The primary endpoint was the time to the first morbidity

or mortality event (defined as all-cause mortality,admission to hospital for worsening of pulmonary arterialhypertension, initiation of intravenous prostacyclintreatment, atrial septostomy, lung transplantation, orclinical worsening). Secondary endpoints includedchange in 6 min walk distance and change in functionalclass of the disease at week 16, change in N-terminalfragment of probrain natriuretic peptide (NT-proBNP)over time, and all-cause mortality.

Over 6 years, the study enrolled 334 patients,predominantly with idiopathic pulmonary arterialhypertension (64%) or pulmonary arterial hypertensionassociated with connective tissue disease (26%), who wererandomised to placebo (n=175) or bosentan (n=159). The

study did not meet its primary endpoint. A clinicalworsening event occurred in 90 (51%) patients randomisedto placebo and in 68 (43%) of the patients randomised tobosentan (hazard ratio [HR] 0·83; 95% CI 0·58–1·19;p=0·251). The 6 min walk distance at week 16 improved by21·8 m in the bosentan group compared with the placebogroup (p=0·011). NT-proBNP concentrations improved aswell. However, no improvement was noted in functionalclass (HR 0·98; 95% CI 0·60–1·61; p=1·00) and in all-cause mortality at the end of the study (HR 0·855; 95% CI0·544–1·344, p=0·497). Potential reasons for the negativeresults of COMPASS-2 include insuffi cient powerand a high number of premature discontinuations.41 Additionally, bosentan decreases sildenafil plasmaconcentrations by 60% to 70%,45,46 which might rendersildenafil less effi cacious.

The AMBITION study explored a new treatment

strategy: initial combination treatment with theendothelin receptor antagonist ambrisentan and thephosphodiesterase-5 inhibitor tadalafil versus mono-therapy with these compounds.42 The primary endpointwas the time from randomisation to the first clinicalfailure event, which was a composite of death; admissionto hospital for worsening of pulmonary arterialhypertension; disease progression; or unsatisfactory long-term response, indicating that the patient was infunctional class III or IV after at least 6 months oftreatment. Secondary endpoints included the changefrom baseline to week 24 in 6 min walk distance,functional class, and NT-proBNP concentrations.

The primary analysis set comprised 500 patients with

treatment naive pulmonary arterial hypertension whowere randomly assigned to combination treatment(n=253), or monotherapy with either ambrisentan (n=126)or tadalafil (n=121). The primary endpoint was significantlyreduced in the combination treatment group versus thepooled monotherapy groups (HR 0·50; 95% CI 0·35–0·72;p


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nasal congestion, peripheral oedema, and anaemia.

Treatment discontinuations due to adverse eventsoccurred in 12% of the patients receiving combinationtreatment, which was similar to ambrisentan (11%) andtadalafil monotherapy (12%).

SERAPHIN assessed the long-term safety and effi cacyof macitentan, a new endothelin receptor antagonist, inpatients with pulmonary arterial hypertension.43 Theprimary endpoint was the time to the first morbidity ormortality event, which included all-cause mortality, atrialseptostomy, lung transplantation, initiation of parenteralprostacyclin treatment, or pulmonary arterialhypertension worsening as defined by a reduction in6 min walk distance of at least 15% from baseline,worsening in functional class, and need for additional

pulmonary arterial hypertension treatments. Secondaryoutcome measurements included the change in 6 minwalk distance and the proportion of patients with animproved functional class, both at 6 months of treatment.

The study enrolled 742 patients who were randomlyassigned to placebo (n=250), macitentan at 3 mg oncedaily (n=250), and macitentan at 10 mg once daily(n=242). At inclusion, 36% of the patients were treatmentnaive, whereas 64% were receiving background treatmentwith other pulmonary arterial hypertension drugs, most(61%) with a phosphodiesterase-5 inhibitor. Both dosesof macitentan were reported to be effective, butmacitentan at a daily dose of 10 mg had more pronouncedeffects on the primary endpoint than macitentan had at adaily dose of 3 mg, particularly in patients receivingbackground treatment. This finding was the main reasonwhy only the 10 mg dose has been approved for thetreatment of pulmonary arterial hypertension. Thehazard ratio for the 10 mg dose compared with placebowas 0·55 (98% CI 0·39–0·76, p


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Patients are classified as low, intermediate, or high risk

based on several variables (table 3).

6,7

The main treatmentobjective is reaching and maintaining a low risk profile.For patients presenting at low or intermediate risk, initialmonotherapy is still deemed to be an option, andendothelin receptor antagonists and phosphodiesterase-5-inhibitors seem to have similar short-term and long-term effi cacy.42,51 Initial combination therapy, in particularwith an endothelin receptor antagonist and aphosphodiesterase-5 inhibitor, is a viable alternative.Based on the results of AMBITION, initial combinationtreatment with ambrisentan and tadalafil received ahigher level of evidence and a higher grade ofrecommendation than other possible combinations ofendothelin receptor antagonists and phosphodiesterase-5

inhibitors.6,7 SERAPHIN and GRIPHON suggested thatpatients with pulmonary arterial hypertension who wereat low or intermediate risk had a better long-termoutcome when macitentan or selexipag, respectively,were added to background treatments.43,44 Taken together,AMBITION, SERAPHIN, and GRIPHON provide astrong rationale for using initial or early combinationregimens in these patients. The evidence is particularlyrobust for the combination of endothelin receptorantagonists and phosphodiesterase-5 inhibitors.

The therapeutic role for riociguat in pulmonary arterialhypertension is less clear. Long-term data from controlledtrials are not available, and riociguat must not becombined with phosphodiesterase-5 inhibitors becauseof the risk of hypotension and adverse events.32 TheRESPITE study (NCT02007629) is evaluating whetherpatients with pulmonary arterial hypertension with aninsuffi cient clinical response to phosphodiesterase-5

inhibitors benefit from switching to riociguat. Results

are expected in mid-2016.Inhaled and oral prostacyclin analogues have notshown consistent improvements in exercise capacity andclinical outcomes, especially when added to otherbackground treatments (table 1), so these analogues havean ancillary role in the management of pulmonaryarterial hypertension.52,53

For high-risk patients, monotherapy is no longerdeemed to be appropriate and the present guidelines6,7 strongly recommend the use of initial double or triplecombination treatment including an intravenousprostacyclin analogue, although the evidence for thisapproach is based on uncontrolled case series.54–56 The useof intravenous prostacyclin analogues is deemed to be

mandatory in high-risk patients, as this is the onlytreatment that has been shown to improve survival inpatients with severe disease.33 For patients who aredeteriorating despite optimised medical treatment, lungtransplantation is a viable treatment option and potentiallyeligible patients should be referred early to a transplantcentre.57 The figure shows the present treatment algorithmfor patients with pulmonary arterial hypertension.

Group 2—pulmonary hypertension due toleft-sided heart diseasePulmonary hypertension due to left-sided heart disease isarguably the most common type of pulmonaryhypertension and consists of three main groups—pulmonary hypertension due to left ventricular systolicdysfunction, pulmonary hypertension due to leftventricular diastolic dysfunction, and pulmonaryhypertension due to valvular disease.4 Pulmonary

Low risk (10%)

Clinical signs of right-sided heart failure Absent Absent Present

Progression of symptoms No Slow Rapid

Syncope No Occasional syncope* Repeated syncope†

WHO functional class I and II III IV

6MWD >440 m 165–440 m 15 mL/min/kg (>65%

predicted); VE/VCO slope


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hypertension is common in all of these disorders, and is

associated with aggravated clinical symptoms and a pooroutcome. In patients with left-sided heart disease,pulmonary hypertension presents either as isolatedpostcapillary pulmonary hypertension or as postcapillarypulmonary hypertension with a precapillary component.Postcapillary pulmonary hypertension with a precapillarycomponent has been associated with particularly poorsurvival and might be an important treatment target.58,59 However, there is little evidence to suggest that the drugsused for pulmonary arterial hypertension are safe andeffective in patients with left-sided heart disease, with orwithout pulmonary hypertension.

The FIRST study60 investigated the effects of intravenousepoprostenol compared with standard treatment in

471 patients with severe congestive heart failure and a leftventricular ejection fraction of less than 25%, a cardiacindex of 2·2 L/min/m2 or less, and a pulmonary arterywedge pressure of 15 mm Hg or more. Dose titration ofepoprostenol in the catheter room resulted in a significantincrease in cardiac index from 1·8 to 2·6 L/min/m² and adecrease in the wedge pressure from 25 mm Hg to 20 mmHg. Still, no improvement was noted in walk distance andthe trial was terminated early because of a trend towardsdecreased survival in patients treated with epoprostenol.

Several endothelin receptor antagonists have beeninvestigated as treatments for left-sided heart failure butnone of them were reported to be effi cacious.61–64 Side-effects were common, in particular fluid retention. Sofar, only one randomised controlled trial specificallyaddressed the safety and effi cacy of an endothelinreceptor antagonist, bosentan, in patients with heartfailure (left ventricular ejection fraction 40 mm Hg).65 The primary endpoint was the change inthe systolic pulmonary artery pressure after 20 weeks oftreatment. The study enrolled 94 patients who wererandomly assigned to bosentan (n=60) or placebo (n=34).At the end of the study, no differences were reportedbetween both treatment groups in systolic pulmonaryartery pressure (p=0·24) or in other echocardiographic

variables. More patients in the bosentan group hadserious adverse events, mainly weight gain and oedema,and 20 patients prematurely discontinued the study drugcompared with three patients in the placebo group.

Phosphodiesterase-5 inhibitors, especially sildenafil,have also been assessed in patients with left-sided heartdisease, with and without pulmonary hypertension. Tomany researchers, these drugs are of particular interestin these patients because the drugs not only reduce thepulmonary vascular resistance but might also improveleft ventricular systolic and diastolic function.66–71 However, data from randomised controlled trials72–74 aresparse and have yielded conflicting results.

In a double-blind, single centre study, Guazzi and co-workers72 randomly assigned 44 patients with heart

failure with preserved ejection fraction and pulmonaryhypertension, most of them postcapillary with aprecapillary component, to sildenafil at a dose of 50 mg

given three times daily (n=22) or placebo (n=22). After12 months of treatment, haemodynamics wereunchanged in the placebo group. In the sildenafil group,mean pulmonary artery pressure decreased from39 mm Hg to 21 mm Hg, right atrial pressure decreasedfrom 23 mm Hg to 9 mm Hg, PAWP decreased from22 mm Hg to 18 mm Hg, and pulmonary vascularresistance decreased from 3·9 Wood units to 1·0 Woodunits (all p


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In the RELAX trial,73 216 patients with heart failure and

preserved ejection fraction were randomly assigned toplacebo (n=103) or sildenafil (n=113) at a daily dose of20 mg for 12 weeks followed by 60 mg daily for 12 weeks.These patients did not undergo right heart catheterisationand did not necessarily have pulmonary hypertension.After 24 weeks of treatment, no changes were noted inpeak oxygen consumption, 6 min walk distance, orquality of life.73 The numbers of patients who had adverseor serious adverse events were similar in both groups.Three deaths were noted in the sildenafil group ascompared with none in the placebo group.

Hoendermis and co-workers74 published the results of asingle-centre, randomised, double-blind study withsildenafil in 52 patients with pulmonary hypertension

due to heart failure with preserved ejection fraction. Mostof these patients had isolated postcapillary pulmonaryhypertension without a precapillary component. Thesildenafil dose was gradually titrated to 60 mg given threetimes per day. After 12 weeks of treatment, sildenafil hadno beneficial effects compared with placebo on meanpulmonary artery pressure, cardiac output, and peakoxygen uptake.74

Two randomised controlled trials with riociguat havebeen done in patients with left heart disease andpulmonary hypertension.75,76 The LEPHT study75 enrolledpatients with pulmonary hypertension due to leftventricular systolic dysfunction. The primary outcomewas the change at week 16 in the mean pulmonary arterypressure. Overall, 201 patients with a left ventricularejection fraction of 40% or less and a mean pulmonaryartery pressure of 25 mm Hg or more were randomlyassigned to various target doses of riociguat (0·5 mg,1·0 mg, or 2·0 mg three time per day) or placebo. Theprimary endpoint was not met, but treatment withriociguat at a dose of 2·0 mg three times a day increasedcardiac output and stroke volume and decreasedpulmonary and systemic vascular resistances.75 Thehaemodynamic effects achieved with lower dosages ofriociguat did not reach statistical significance. After16 weeks of treatment, none of the riociguat dosesstudied had led to significant improvements in 6 min

walking distance, functional class, or NT-proBNP. Themost frequently reported adverse events associated withriociguat were nausea, diarrhoea, headache, dizziness,and hypotension. Three deaths were reported in theriociguat group as compared with none in the placebogroup.

The DILATE-1 study76 assessed the acute haemodynamiceffects of riociguat given as a single dose of 0·5 mg,1·0 mg, or 2·0 mg compared with placebo in patientswith pulmonary hypertension due to heart failure withpreserved ejection fraction. Measurements took placeover 6 h after study drug administration. In this setting,riociguat had no significant effect on the meanpulmonary artery pressure but improved stroke volume(p=0.04) and cardiac index (p=0.03).

Two randomised controlled, phase 2 studies have been

implemented with vericiguat, another stimulator of thesoluble guanylate cyclase, one in patients with leftventricular systolic dysfunction (SOKRATES-REDUCED;NCT01951625)77 and one in patients with left ventriculardiastolic dysfunction (SOKRATES-PRESERVED;NCT01951638). SOKRATES-REDUCED was mainly adose-finding study that enrolled 456 patients with heartfailure and reduced ejection fraction. The patients wererandomly assigned to placebo or vericiguat at targetdoses of 1·25 mg, 2·5 mg, 5 mg, or 10 mg per day. 77 Theprimary endpoint was the change from baseline toweek 12 in serum NT-proBNP in the pooled three highestdose vericiguat groups. This endpoint was not met. Anexploratory secondary analysis suggested that higher

doses of vericiguat were associated with greaterreductions in NT-proBNP, improved left ventricularejection fraction, and numerically, but not statisticallysignificant, lower rates of admission to hospital. A larger,phase 3 study will be needed to establish whethervericiguat has beneficial long-term effects in patientswith heart failure and reduced ejection fraction. Resultsof SOKRATES-PRESERVED are expected by mid-2016.

Existing trials with pulmonary vasodilators in patientswith heart failure with preserved ejection fraction haveyielded conflicting results. The main lesson from theFIRST study was that improved haemodynamics do notnecessarily translate into improved symptoms orimproved outcomes,60 raising the question whetherhaemodynamics are appropriate endpoints for proof-of-concept studies in this patient population. In fact, theseresults are reminiscent of the experiences withphosphodiesterase-3 inhibitors in patients with left heartfailure that also showed short-term improvements inhaemodynamics but detrimental long-term effects onsurvival.78

The endothelin receptor antagonists studied so far inpatients with left heart disease have also not yieldedclinical benefits, but have been associated with a high rateof side-effects, especially fluid retention.63,65 However,most of these compounds have been studied in non-selected cohorts of patients with left heart disease and not

explicitly in patients with left heart disease and combinedprecapillary and postcapillary pulmonary hypertensionidentified by right heart catheterisation. Such patients areenrolled into the MELODY-1 study, a phase 2 trialassessing the safety and effi cacy of macitentan(NCT02070991). The results are expected in 2016.

Phosphodiesterase-5 inhibitors and riociguat still holdpromise for the treatment of pulmonary arterialhypertension, but long-term event-driven trials in wellcharacterised cohorts are needed to establish if and whenthese drugs are beneficial in patients with left heartdisease.

At present, the use of drugs approved for pulmonaryarterial hypertension is not recommended for patientswith pulmonary hypertension due to left heart disease.


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Patients with combined precapillary and postcapillary

pulmonary hypertension should be referred to expertcentres for individual treatment decisions.6,7

Group 3—pulmonary hypertension due to lungdiseaseAfter left heart disease, lung diseases are the secondmost common cause of pulmonary hypertension,particularly chronic obstructive pulmonary disease(COPD) and interstitial lung disease. Patients withadvanced disease stages are more often affected, butpulmonary hypertension might also develop in patientswith mild lung function abnormalities and no tightcorrelation exists between impairment in lung functionand severity of pulmonary hypertension. In COPD as

well as in Interstitial lung disease, the development ofpulmonary hypertension is associated with worseningsymptoms, impaired gas exchange, and poor survival.79–81 Hence, a rationale to use drugs targeting pulmonaryhypertension exists in this patient population but, as inleft-sided heart disease, no compelling evidence isavailable that such treatments are safe and effective inpatients with pulmonary hypertension due to lungdisease.

Pulmonary vasodilators in patients with COPDStolz and co-workers82 randomly assigned 30 patientswith severe COPD to bosentan or placebo. These patientsdid not have pulmonary hypertension at rest, but theauthors reasoned that they were prone to pulmonaryhypertension on exercise, which was the rationale tostudy bosentan. After 12 weeks, no improvements werereported in 6 min walking distance, maximum oxygenuptake, and systolic pulmonary artery pressure estimatedby echocardiography, while arterial oxygen pressuredropped and quality of life deteriorated.82 Similar findingswere reported in a randomised crossover trial withsildenafil in patients with COPD and emphysema, butwithout pulmonary hypertension.83 Several short-termtrials with sildenafil in patients with COPD showedimproved haemodynamics but worsened oxygenationand no effects on exercise capacity.83–86

A randomised placebo-controlled trial assessed the useof tadalafil in patients with COPD and suspectedpulmonary hypertension based on a systolic pulmonaryartery pressure >30 mm Hg, as estimated byechocardiography.87 The primary endpoint was thechange in 6 min walk distance after 12 weeks of therapy.A total of 120 patients were randomised to receivetadalafil at a dose of 10 mg once daily (n=60) or placebo(n=60). The primary endpoint was not met as thechanges in 6 min walk distance at week 12 were virtuallyidentical in both groups (placebo-corrected change in6 min walk distance 0·5 m; 95% CI –11·6 to 12·5,p=0·937). Several echocardiographic variables suggestedimprovements in pulmonary artery pressure and rightventricular function, but changes in NT-proBNP levels

did not differ between the two groups. The most

common side-effects related to tadalafil were headacheand dyspepsia. Peripheral oxygen saturations did notchange with tadalafil treatment.

Pulmonary vasodilators in patients with interstitiallung diseaseAt least five randomised controlled trials have assessedthe effects of endothelin receptor antagonists in patientswith interstitial lung disease, three with bosentan, andone each with ambrisentan and macitentan.88–92 Thesestudies were targeting pulmonary fibrosis, not pulmonaryhypertension, but none of them reported positive effects.The studies using bosentan and macitentan did not showan effect on outcome, whereas the ARTEMIS-IPF trial

was terminated early because of an increased rate ofdisease progression, admissions to hospital forrespiratory reasons, and deaths in patients receivingambrisentan.91

A randomised controlled trial specifically addressed theuse of bosentan in patients with pulmonary hypertensiondue to interstitial lung disease.93 In this study, patientswith interstitial lung disease and a catheter-baseddiagnosis of pulmonary hypertension were randomlyassigned 2:1 to bosentan or placebo. The primaryoutcome measure was the change in the pulmonaryvascular resistance index after 16 weeks of treatment.The study enrolled 60 patients (40 to bosentan, and 20 toplacebo) but only 39 were available for a repeat rightheart catheterisation (25 in the bosentan group and 14 inthe placebo group). The study reported no significanteffects of bosentan on pulmonary haemodynamics,symptoms, functional class, or deaths.

The STEP-IPF study94 addressed the use of sildenafil inpatients with advanced idiopathic pulmonary fibrosisand a low diffusion capacity (less than 35% of thepredicted value). This cutoff value was chosen to enrichthe study with patients having a higher likelihood ofconcomitant pulmonary hypertension, but right-sidedheart catheterisations were not part of the protocol.A total of 180 patients were randomly assigned tosildenafil at a dose of 20 mg administered three times

daily (n=89) or placebo (n=91). The primary endpoint wasthe proportion of patients with 20% or greaterimprovement in 6 min walk distance after 12 weeks oftreatment. This endpoint was met in 10% of the patientsin the sildenafil group and in 7% of the patients in theplacebo group (p=0·39). Statistically significantimprovements were modest in arterial oxygen saturation,diffusion capacity, Borg dyspnoea index, and quality-of-life scores. Adverse events and serious adverse eventswere similar in both groups.

A small, non-controlled phase 2A study of riociguat in22 patients with pulmonary hypertension due tointerstitial lung disease has been completed.95 This studyshowed an increase in cardiac output along withdecreases in pulmonary and systemic vascular resistance


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after 12 weeks of treatment. Arterial oxygen tension

deteriorated whereas 6 min walk distance increased by25 m. During the first 12 months of therapy, 13 of22 patients discontinued the study drug, most because ofadverse events. A larger phase 2B trial (RISE-IIP;NCT02138825) is assessing the effects of riociguat on6 min walk distance and other outcome measures inpatients with pulmonary hypertension due to interstitiallung disease. Results are expected in 2017.

None of the trials that have been done so far withpulmonary vasodilators in patients with lung diseasehave shown convincing evidence suggesting effi cacy.However, all of the trials had various limitationsincluding sample size, duration, selection of endpoints,and absence of invasive haemodynamics.

During the 5th World Symposium on Pulmonary

Hypertension, held in 2013 in Nice, France, a workinggroup proposed criteria for severe pulmonaryhypertension in patients with chronic lung disease.Severe pulmonary hypertension was defined by a meanpulmonary artery pressure of 35 mm Hg or more, or amean pulmonary artery pressure of 25 mm Hg or more,together with a cardiac index below 2·0 L/min/m² atrest.79 This definition was not based on any evidence buton the notion that such severe forms of pulmonaryhypertension are rarely encountered in patients withlung disease and that this extent of pulmonaryhypertension would be expected to cause circulatoryrestriction contributing to impaired exercise capacity. Sofar, no randomised controlled trials have assessed the

Phase Intervention Comments

Pulmonary arterial hypertension

ARROW (N CT0 2234141) 2 Sa fe ty, effi cacy, and dose finding of GS- 4997, an ASK1 inhibitor; pr imaryendpoint is change in PVR from baseline to week 24

Estimated completion date isAugust, 2016

LA RIAT (NCT0 20 36970 ) 2A Dose-find ing study with bardoxolone methyl, a compound with anti-inflammatory and antiproliferative properties, in patients with pulmonary

arterial hypertension or group III and V pulmonary hypertension; primaryendpoint is change in 6MWD from baseline to week 16

Estimated study completion date isDecember, 2016

FK-506, TransformPAH

(NCT01647945)

2A Dose finding study assessing the safety and effi cacy of tacrolimus in

patients with pulmonary arterial hypertension

Results have been published101

RESPITE (NCT02007629) 3B Open label study addressing safety and effi cacy of riociguat in patients

with an insuffi cient clinical response to phosphodiesterase-5 inhibitors;primary endpoint is change in 6MWD from baseline to week 24

Estimated completion date is June,

2016

TRITON (NCT02558231) 3B E ffi cacy and sa fe ty of initial tr ipl e combination treatment withmacitentan, tadalafil, and selexipag vs double combination treatmentwith macitentan and tadalafil; primary endpoint is change in PVR from

baseline to week 26

Planned study start is January,2016; planned completion date isDecember, 2018

APD811 (NCT0227 9160 ) 2 Sa fe ty and effi cacy of A PD811, a n oral prosta gland in I₂ re ceptor agonist ;

primary endpoint is change in PVR from baseline to week 22

Estimated primary completion

date is August, 2016

FREEDOM-ev (NCT01560624) 3B Safety and effi cacy of oral treprostinil in patients receiving backgroundmonotherapy with an ERA or a phosphodiesterase-5 inhibitors; primary

endpoints are change in 6MWD from baseline to week 24 and time toclinical worsening during long-term follow-up

Estimated study completion date isAugust, 2016

INOvation (NCT not available) 3 Safety and effi cacy of inhaled nitric oxide; primary endpoint is change in6MWD from baseline to week 18

Enrolment expected to start in2016

Pulmonary hypertension due to left-sided heart disease

MELODY-1 (NCT02070991) 2 Safety and effi cacy of macitentan in patients with pulmonary

hypertension due to left heart failure with preserved ejection fraction;

primary outcome measure is safety—ie, the incidence of fluid retention orworsening in functional class

Completion date is February, 2016

(awaiting completed data)

SOCRATES-PRESERVED(NCT01951638)

2 Safety and effi cacy of vericiguat in patients with pulmonary hypertensiondue to heart failure with preserved ejection fraction; primary outcome

measures are changes in serum NT-proBNP and left atrial volume

Results expected by May, 2016

Pulmonary hypertension due to lung disease

RISE -I IP (N CT0 2138825) 2 Sa fe ty and effi cacy of r iocigu at in pat ients with id iop athic interst it ialpneumonias and pulmonary hyperternsion; primary endpoint is change in6MWD from baseline to week 26

Estimated primary completiondate is January, 2017

Chronic thromboembolic pulmonary hypertension

MERIT- 1 (NCT0 20 21292) 2 24 wee k, placeb o- controll ed stud y with ma cite ntan in patients with

inoperable chronic thromboembolic pulmonary hypertension; primaryendpoint is change in PVR at week 16

Estimated study completion date is

June, 2016

ASK1=apoptosis signal-regulating kinase-1. ERA=endothelin receptor antagonist. PVR=pulmonary vascular resistance.

Table : Selected recently published or ongoing clinical trials in pulmonary hypertension


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effects of pulmonary vasodilators in patients with lung

disease fulfilling these criteria.

Group 4—chronic thromboembolic pulmonaryhypertensionChronic thromboembolic pulmonary hypertension hasbeen reviewed recently in this journal.96 Hence, thetreatment of chronic thromboembolic pulmonaryhypertension is summarised only briefly here and readersare referred to the previous article for detailed information.

Surgical pulmonary endarterectomy is the preferredtreatment option for patients with chronic thromboembolicpulmonary hypertension.10,97 For patients who are notcandidates for surgery, interventional balloon pulmonaryangioplasty is an emerging treatment option.98,99 Riociguat

is the only drug approved for patients with inoperablechronic thromboembolic pulmonary hypertension orresidual postoperative disease.100 Other classes of drugsmight be used with a lower grade of recommendation.6,7

Group 5—pulmonary hypertension with unclearmultifactorial mechanismsGroup 5 contains various and heterogeneous forms ofpulmonary hypertension, most of which have not beenstudied in randomised controlled trials. Hence, specifictreatment recommendations cannot be made and thesepatients should be referred to expert centres forindividual treatment decisions.

Future developmentsMost of the present clinical studies in groups 2–5 usecompounds that have already been shown to be effective inthe treatment of pulmonary arterial hypertension,although clinical trials in pulmonary arterial hypertensionfocus on combination treatments and on drugs thatreverse pulmonary vascular remodelling (table 4). Onesuch approach has already been tested with imatinib, aninhibitor of various receptor tyrosine kinases. In patientswith pulmonary arterial hypertension, imatinib improvedhaemodynamics, NT-proBNP, and 6 min walking distance,but not disease progression and survival.102,103 This finding,together with safety concerns, which included an increased

risk of subdural haematoma, led to a stop of the clinicaldevelopment programme.104 Nevertheless, effi cacy wassuggested in some patients, and case reports have shownthat disease remission might be possible with long-termimatinib treatment.105 Hence, tyrosine kinase inhibitorsremain targets of future research.

In addition to medical treatments, an interventionalapproach involving pulmonary artery denervation isbeing researched for various forms of pulmonaryhypertension.106,107 The available data do not yet allowprediction of the future role of this strategy.

ConclusionsIn pulmonary arterial hypertension, substantialtherapeutic progress has been made over the past

20 years. Five classes of drugs (ie, endothelin receptorantagonists, phosphodiesterase-5 inhibitors, soluble

guanylate cyclase stimulators, prostacyclin analoguesand prostacyclin receptor agonists) have been approvedto treat this condition. All of these compounds areeffective as monotherapies, but recent studies haveprovided compelling evidence that initial or earlycombination regimens improve the progression-freesurvival of patients with pulmonary arterial hypertension.

Various treatment options are also available forchronic thromboembolic pulmonary hypertension, withpulmonary endarterectomy remaining the preferredtreatment. For inoperable patients, riociguat was the firstdrug to be approved for patients with inoperable chronicthromboembolic pulmonary hypertension or persistentor recurrent pulmonary hypertension af ter pulmonaryendarterectomy, and balloon pulmonary angioplastymight become a new treatment option.

Whether patients or some subgroups of patients withpulmonary hypertension due to left heart disease or lungdisease benefit from pulmonary vasodilator treatment isstill unclear. The clinical trials completed so far have notyielded conclusive results. Randomised controlled, long-term studies in patients presenting with clinicallysignificant pulmonary hypertension are needed to definethe role of pulmonary vasodilators in these patientpopulations.

Contributors

MMH conceived the idea of this Review and was responsible for its

overall content. VVM, AMA, TS, and NG assisted with writing, editing,and created part of the tables.

Declaration of interests

AMA reports funding for a pulmonary hypertension registry at KingFaisal Specialist Hospital from Actelion, outside of this Review. NG andMMH received personal fees from Actelion, Bayer, GSK, and Pfizer.VVM received grants and personal fees from Actelion, Bayer, Gilead,Ikaria, and United Therapeutics, and grants from Novartis. TS receivedpersonal fees from Actelion. This Review is independent of anyinfluence from pharmaceutical companies and has been written by theauthors without any third-party support.

References1 Hoeper MM, Bogaard HJ, Condliffe R, et al. Definitions and

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2 Tuder RM, Archer SL, Dorfmüller P, et al. Relevant issues in thepathology and pathobiology of pulmonary hypertension. J Am Coll Cardiol 2013; 62 (suppl): D4–12.

Search strategy and selection criteria

We identified references for this Review through searches of

PubMed from 1970 to September, 2015, by using the terms

“pulmonary hypertension”, “pulmonary arterial hypertension”,

and “treatment”. MMH reviewed all abstracts of the identified

publications and selected articles of interest for this Review.

These articles and relevant references cited in those articles were

reviewed. Particular attention was given to randomised

controlled trials. Studies on paediatric patient populations were

not considered. Only articles published in English were included.


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