Current Therapeutic Approaches to Pulmonary Arterial Hypertension

INTRODUCTION

Pulmonary hypertension (PH) is a hemodynamicand pathophysiological condition defined as anincrease in mean pulmonary arterial pressure(PAP) ≥25 mmHg at rest as assessed by right heartcatheterization (RHC).¹

PH is heterogeneous from the pathophysiologicalpoint of view and the diversity is also reflected in thehemodynamic classification (Table 1).²

The different hemodynamic forms of PH canbe found in multiple clinical conditions whichhave been classified in 6 main groups and at least26 subgroups (Table 2). Each main clinical groupshows specific pathologic changes in the lung distalarteries, capillaries and small veins. If we combinethe hemodynamic and clinical heterogeneity weunderstand the importance of an accurate diagnosisin the individual patient, which is crucial for theprognostic assessment and the treatment strategy.In addition, the concomitant presence of differenthemodynamic and clinical mechanisms cannot beexcluded in individual patients.

The presence of PH as defined above is alwaysan ominous prognostic sign even if the severity maydiffer according to hemodynamic changes and theunderlying clinical condition.

The therapeutic approach also is markedlydifferent according to the clinical groups and thesymptomatic and hemodynamic severity.

The classifications are described in an initialcommon paragraph while the treatment strategies ofthe four more frequent clinical groups are discussedindividually.

DEFINITIONS AND CLASSIFICATIONS

Hemodynamic Classification

PH has been defined as an increase in mean PAP ≥25 mmHg at rest as assessed by RHC.^3,4 Recent re-evaluation of available data have shown that thenormal mean PAP at rest is 14 (3) mmHg with anupper limit of normal of approximately 20 mmHg.^5,6 The significance of mean PAP between 21 and 24 mmHg is unclear. Patients presenting with PAP inthis range need further evaluation in epidemiologicalstudies. The definition of PH on exercise as a meanPAP >30 mmHg as assessed by RHC is not supportedby published data; healthy individuals can reachmuch higher values.^5,7 Thus no viable definition forPH on exercise as assessed by RHC can be providedat the present time.

An additional very important haemodynamicparameter which characterizes the definitions ofPH is pulmonary wedge pressure (PWP). In fact,according to various combinations of values ofPWP, pulmonary vascular resistance (PVR) andcardiac output (CO), different hemodynamic typesof PH are shown in Table 1. Pre-capillary PH (PHwith normal PWP) is found in the clinical groups 1,3, 4, and 5 while post-capillary PH (PH with elevatedPWP) is found in the clinical group 2 (Table 2).⁸ Thedistinction between pre-capillary and post-capillaryPH is extremely important because the treatmentstrategy may differ markedly between the twohemodynamic conditions; therapies effective in thepre-capillary form may be detrimental in the post-capillary type and vice versa.

Clinical Classification

The more updated clinical classification of PH ispresented in Table 2.⁹ Clinical conditions with PHare classified into six groups according to similarpathological, pathophysiological and therapeuticcharacteristics: pulmonary arterial hypertension(PAH - group 1), pulmonary veno-occlusive disease(group 1'), PH due to left heart disease - group 2,PH due to lung diseases (group 3), chronicthromboembolic PH (CTEPH, group 4) and PHwith unclear and/or multifactorial mechanisms(group 5). Despite possible comparable elevations of PAP and PVR in the different clinical groups, theunderlying mechanisms, the diagnostic approachesand the prognostic and therapeutic implicationsare completely different. The features of each mainclinical group are discussed in the specific sections, with particular attention to PAH - group 1, inwhich PH represents the leading pathophysiologicalfeature.

It is important to avoid the typical confusionbetween PH and PAH. In fact, while PH is a hemodynamic condition (Table 1), PAH is a clinical condition characterised by the presence ofprecapillary PH (Table 1) in the absence of othercauses of precapillary PH such as PH due to lungdiseases, CTEPH or other rare diseases (Table 2).PAH includes different forms that share a similarclinical picture and virtually identical pathologicalchanges of the lung microcirculation (Table 2).

Comparative epidemiological data on theprevalence of the different groups of PH arenot available. In a survey performed in anechocardiography laboratory,¹⁰ the prevalence ofPH (defined as a PA systolic pressure >40 mmHg)among 4,579 patients was 10.5%. Among the 483cases with PH 78.7% had left heart disease (Group 2), 9.7% had lung diseases and hypoxaemia (Group 3), 4.2% had PAH (Group 1), 0.6% had CTEPH(Group 4) and in 6.8% it was not possible to definea diagnosis.

PULMONARY ARTERIAL HYPERTENSION

PAH (Table 2) represents the type of PH in whichthe most important advances in the understandingand treatment have been achieved in the past decade.It is also the group in which PH is the "core" of theclinical problems and may be treated by specificdrug therapy.

Pathobiology and Pathophysiology

PAH comprises apparently heterogeneousconditions (Table 2) that share comparable clinicaland hemodynamic pictures and virtually identicalpathological changes of the lung microcirculation.Pathological lesions affect the distal pulmonaryarteries (<500 µm) in particular. They arecharacterized by medial hypertrophy, intimalproliferative and fibrotic changes (concentric,eccentric), adventitial thickening with moderateperi-vascular inflammatory infiltrates, complexlesions (plexiform, dilated lesions) and thromboticlesions. Pulmonary veins are classically unaffected.Additional pathological changes include dilatationof the proximal elastic pulmonary arteriesand of the bronchial arteries (likely due to acompensatory mechanism intended to providesupplementary blood flow to hypoperfused lungparenchyma areas). The exact processes thatinitiate the pathological changes seen in PAH arestill unknown, even if it is recognized that PAHhas a multifactorial pathobiology that involves various biochemical pathways and cell types. Theincrease in PVR is related to different mechanisms,including vasoconstriction, proliferative andobstructive remodeling of the pulmonary vessel wall,inflammation and thrombosis. The PVR increaseleads to right ventricular (RV) overload, hypertrophyand dilatation and eventually to RV failure anddeath. The importance of the progression of RVfailure on the outcome of idiopatic PAH (IPAH)patients is confirmed by the prognostic impact ofright atrial pressure, cardiac index (CI) and PAP,⁴ the 3 main parameters of RV pump function. Thedepression of myocardial contractility seems to beone of the primary events in the progression of heartfailure in a chronically overloaded RV. Changes inthe adrenergic pathways of RV myocytes leadingto reduced contractility have been shown in IPAHpatients.¹¹ Afterload mismatch remains the leadingdeterminant of heart failure in patients with PAH andCTEPH because its removal, as follows successfulpulmonary endarterectomy or lung transplantation,¹² leads almost invariably to sustained recovery ofRV function. The hemodynamic changes and theprognosis of patients with PAH are related to thecomplex pathophysiological interactions between therate of progression (or regression) of the obstructivechanges in the pulmonary microcirculation and theresponse of the overloaded RV, which may also beinfluenced by genetic determinants.¹³

Initial Treatment Approach

The suggested initial approach after the diagnosisof PAH is the adoption of the general measures,initiation of supportive therapy and referral to anexpert centre for vasoreactivity testing. Generalmeasures are recommendations on generalactivities of daily living including physical activity,birth control and pregnancy, travel, psychosocialsupport, infection prevention, and elective surgery.Supportive therapies include oral anticoagulants,diuretics, oxygen, digoxin, and other inotropicdrugs. These treatments are recommended evenif no formal randomised controlled trials (RCTs)have been performed in PAH. Supportive therapiesare largely used in PAH patients, as demonstratedby the baseline treatment of PAH patients includedin the RCTs testing the efficacy of modern targetedtreatments.¹⁴ Calcium channel blockers agents(CCBs) are included in this chapter because theyrepresent the first class of drugs developed for thetreatment of a minority of patients with PAH,those responders to the acute vasoreactivity test.In these cases, the clear favourable response of thelong-term treatment with high doses of CCBs hasdiscouraged the performance of RCTs for ethicalreasons.

General Measures

Patients with PAH require sensible advice aboutgeneral activities of daily living and need to adaptto the uncertainty associated with a serious chroniclife-threatening disease. The diagnosis usuallyconfers a degree of social isolation.¹⁵ Encouragingpatients and their family members to join patientsupport groups can have positive effects on coping,confidence and outlook.

Physical Activity and Supervised Rehabilitation

Patients should be encouraged to be active withinsymptom limits. Mild breathlessness is acceptablebut patients should avoid exertion that leads to severebreathlessness, exertional dizziness, or chest pain.Patients should therefore avoid excessive physicalactivity that leads to distressing symptoms but whenphysically deconditioned may undertake supervisedexercise rehabilitation.¹⁶ There is growing evidencesupporting loss of peripheral muscle mass in patientswith advanced PAH and this may be corrected by adefined rehabilitation program.

Pregnancy and Birth Control

Pregnancy is associated with a 30%-50% mortalityin patients with PAH¹⁷ and as a consequencePAH is a contra-indication to pregnancy.¹ Barriercontraceptive methods are safe for the patientbut with an unpredictable effect. Progesterone-only preparations such as medroxyprogesteroneacetate and etonogestrel are effective approachesto contraception and avoid potential issues ofestrogens such as those included in the mini-pill.¹⁸ It should be remembered that the endothelin receptorantagonist (ERA) bosentan may reduce the efficacyof oral contraceptive agents. The Mirena coil is alsoeffective.¹⁸ A combination of 2 methods may also beutilized. The patient who becomes pregnant shouldbe informed of the high risk of pregnancy andtermination of pregnancy discussed. Those patientswho choose to continue pregnancy should be treatedwith disease targeted therapies, planned electivedelivery and effective close collaboration betweenobstetricians and the PAH team.^19,20

Travel/Altitude

Air travels are considered to be of potentialharm for patients with underlying pulmonaryhypertension because of the generalized pulmonaryvasoconstriction at O₂ concentration <21%.²¹ Theknown physiological effects of hypoxia suggest thatin-flight O₂ administration should be consideredfor patients in World Health Organization (WHO) functional class III and IV and those with arterialblood O₂ pressure consistently less than 8 kPa (60mmHg). Similarly, such patients should avoid goingto altitudes above 1500 to 2000 metres withoutsupplemental O₂. Patients should be advised totravel with written information about their PAHand be advised how to contact local PH clinicsin close proximity to where they are travelling.Prolonged air travel is considered a risk factor fordeep venous thrombosis and for PAH patients whoare not treated with oral anticoagulants and havepotential additional risk factors such as WHOfunctional class III and IV or obesity, preventivemeasures (low-molecular-weight heparin, legexercises) on long-haul flights over 5000 km maybe considered.

Psychosocial Support

Many PAH patients develop anxiety anddepression leading to impairment in quality of life.Timely referral to a psychiatrist or psychologistshould be made when appropriate. Patient supportgroups may also play an important role in thisarea and patients should be advised to join suchgroups.

Infection Prevention

Patients with PAH are susceptible to developingpneumonia, which is the cause of death in 7% ofcases.²² Whilst there are no controlled trials, it isrecommended to vaccinate against influenza andpneumococcal pneumonia.

Elective Surgery

Elective surgery is expected to have an increasedrisk in patients with PAH. It is not clear as to whichform of anaesthesia is preferable but epidural isprobably better tolerated than general anaesthesia.Patients usually maintained on oral therapy mayrequire temporary conversion to intravenous ornebulised treatment until they are able to bothswallow and absorb drugs taken orally.

Hemoglobin Level

PAH patients are highly sensitive to reductionof hemoglobin levels. Any kind of anaemia evenof milder degrees should be corrected. On theother hand, especially patients with long-standinghypoxemia like those with right-to-left shunts tendto develop erythrocytosis with elevated levels ofhematocrit. In these circumstances, venesectionsare indicated only if hematocrit is above 65% andhyperviscosity symptoms are present.²³

Concomitant medications

Currently 3 classes of drugs are approved in PAH(ERA, phosphodiesterase type-5 inhibitors, andprostanoids) and care is needed to avoid interactionsbetween them and with any other drug.¹ Even ifnon-steroid anti-inflammatory drugs seem not tobe associated to PAH in a case-control study,²⁴ theiruse may further reduce glomerular filtration ratein patients with low cardiac output and pre-renalazotaemia. Anorexigens that have been linked tothe development of PAH are no longer availableon the market. The effects of the new generationserotonin-related compounds (eg, antidepressants)are unknown but no clear relationships with PAHhave yet been demonstrated. The efficacy of currenttreatments for chronic "biventricular" heart failurelike ACE-inhibitors and beta-blockers has not beentested in patients with PAH. In addition, the useof these compounds may favour hypotension andprogression of right heart failure in PAH patientsdue to vasodilatation and negative inotropiceffects.

Supportive Treatments

Oral Anticoagulants

There is a high prevalence of vascular thromboticlesions at post mortem in patients with IPAH.^25,26 Abnormalities in coagulation and fibrinolyticpathways have also been reported, and muralthrombi have been shown in central elasticpulmonary arteries of patients with IPAH²⁶ and Eisenmenger's syndrome patients.^23,27

All the above factors together with the non-specific increased risk for venous thromboembolism,including heart failure and immobility, may representthe rationale for oral anticoagulation in PAH.

Evidence in favor of oral anticoagulation isconfined to patients with IPAH, heritable PAH andPAH due to anorexigens; it is generally retrospectiveand based on single centre experience.^25,28,29 In recent clinical trials, oral anticoagulant treatmentwas present at inclusion in a fraction of patientsranging from 50% to 80%.³⁰ The potential benefits oforal anticoagulation should be weighed against therisks in patients with other forms of PAH, especiallywhen there is an increased risk of bleeding such asPAH associated with Eisenmenger's syndrome andhemoptysis, connective tissue diseases and gastrointestinal tract abnormalities (predisposing tobleeding), portal hypertension (severe oesophagealvarices, coagulation abnormalities, low plateletcount) and HIV infection (low platelet count,poor compliance). Generally, patients with PAHreceiving therapy with long-term intravenous prostaglandins are anticoagulated in the absenceof contra-indications, due in part to the additionalrisk of catheter-associated thrombosis. Adviceregarding the target international normalized ratioin patients with IPAH varies from 1.5 to 2.5 in mostcentres of North America to 2.0 to 3.0 in Europeancentres.

Diuretics

Decompensated right heart failure leads to fluidretention, raised central venous pressure, hepaticcongestion, peripheral oedema, and ascites (inadvanced cases).³¹ Clinical experience shows clearsymptomatic benefit in fluid overloaded patientstreated with this therapy. The appropriate diureticdose is strictly individual and theoretically shouldbe the lowest dose that maintains an optimal fluidbalance and minimizes symptoms of congestion.Proper fluid balance can be facilitated by acontrolled salt and water intake. Intravenousadministration of diuretics is temporarilypreferred in cases of fluid retention to overcomethe reduced oral bioavailability. Loop diureticsare generally used and furosemide oral doses mayvary from 20-25 mg/day up to 500 mg/day.³² The addition of aldosterone antagonists should also be considered.

Oxygen

The oxygen content of arterial blood andoxygen delivery to tissues are generally notreduced unless the PaO₂ falls <60 mmHg.33 Mostpatients with lung diseases are hypoxemic becauseof altered ventilation-perfusion matching.³⁴ In contrast, most patients with PAH (except thosewith associated congenital heart disease) presentwith only mild degrees of arterial hypoxemia atrest. No consistent data are currently availableon the effect of long-term O₂ treatment in patientswith PAH. Guidance may be empirically basedon the guidelines of parenchymal lung diseases:when arterial blood O₂ pressure is consistentlyless than 8 kPa (60 mmHg) patients are advisedto take O₂ to achieve arterial blood O₂ pressure >8 kPa.³⁵ Ambulatory O₂ may be considered inpatients when there is evidence of symptomaticbenefit and correctable desaturation on exercise.There is little rationale to treat with long-termoxygen therapy patients with hypoxaemiapredominantly due to right-to-left shunt througha patent foramen ovale, atrial or ventricular septaldefects or patent ductus arteriosus. In these casesa consistent increase of oxygen saturation andsymptomatic improvement on oxygen therapyshould be demonstrated.

Inotropic Drugs

The effects of adrenergic inotropic drugs on thefailing right ventricle have received little attention byinvestigators. Data on humans are available mostlyfor the prevalent beta 2-adrenergic receptor agonistisoproterenol³⁶ that was administered to IPAHpatients for its supposed effects of vasodilatationon pulmonary circulation.^37,38 Dobutamine³⁶ is aprevalent beta 1-adrenergic receptor agonist thatexerts inotropic and vasodilator effects comparableto isoproterenol but has a less pronouncedchronotropic activity. Dopamine³⁶ is a beta-, alpha-and dopaminergic-receptor agonist and its profileof action may present some advantages over theprevalent beta-receptor agonist drugs. In fact, thealpha-adrenergic activity helps to preserve theblood pressure levels and even to increase them.The absence of systemic hypotensive effects togetherwith the renal blood flow increase suggest the use ofdopamine alone or in combination with dobutamineas the inotropic strategy of choice in PAH patients.

Although digoxin has been shown to improvecardiac output acutely in IPAH, its efficacy isunknown when administered chronically.³⁹ It may be given to slow ventricular rate in patients withPAH who develop atrial tachyarrhythmias.

Acute Vasoreactivity Test and Long-TermTreatment With Calcium-Channel Blockers(CCBs)

A minority of patients with PAH (in particularidiopathic PAH) respond with a meaningfulreduction of pulmonary artery pressure associatedto a reduction of pulmonary vascular resistance onacute vasoreactivity tests. In these cases, a favourableeffect of long-term treatment with high doses ofCCBs, in particular with nifedipine and diltiazem,has been demonstrated.^28,40

In PAH, vasoreactivity testing should beperformed at the time of diagnostic right heartcatheterization to identify patients who may benefitfrom long-term therapy with CCBs.^28,41 Acute vasodilator challenge should only be performedwith short-acting, safe and easy to administer drugswith no or limited systemic effects. Currently theagent most used in acute testing is nitric oxide⁴¹; based on previous experience^28,42,43 intravenous epoprostenol or intravenous adenosine mayalso be used as an alternative (but with a risk ofsystemic vasodilator effects). Inhaled iloprost andoral sildenafil may be associated with significantvasodilator effects. Their role in the predictionof response to CCB therapy has not yet beendemonstrated. Due to the risk of potentiallylife-threatening complications, the use of CCB given orally or intravenously as an acute test isdiscouraged. A positive acute response is definedas a reduction of mean PAP ≥10 mmHg to reachan absolute value of mean PAP ≤40 mmHg withan increased or unchanged CO.⁴¹ Only about 10%of patients with IPAH will meet these criteria.Positive acute responders are most likely to showa sustained response to long-term treatment withhigh doses of CCB and they are the only patientsthat can safely be treated with this type of therapy.About half of IPAH positive acute responders arealso positive long-term responders to CCBs⁴¹ andonly in these cases is the continuation of CCB asa single treatment warranted. The usefulness ofacute vasoreactivity tests and long-term treatmentwith CCBs in patients with other PAH types, suchas heritable PAH, connective tissues diseases,and HIV infection is less clear than in IPAH.Acute vasoreactivity studies to identify patientswith a long-term favourable response to CCB isnot recommended in patients with pulmonaryhypertension associated with left heart disease,lung diseases, CTEPH, and PH due to multiplemechanisms..

The CCBs that have been predominantly usedin reported studies are nifedipine, diltiazem andamlodipine, with particular emphasis on the first 2.^28,41 The daily doses of these drugs that have shown efficacy in IPAH are relatively high, 120-240 mg for nifedipine, 240-720 mg for diltiazem,and up to 20 mg for amlodipine. It is advisableto start with a low dose, eg, 30 mg of slow releasenifedipine twice a day or 60 mg of diltiazem 3times a day or 2.5 mg of amlodipine once a dayand increase cautiously and progressively to themaximum tolerated dose. Limiting factors fordose increase are usually systemic hypotensionand lower limb peripheral oedema. Patientswith IPAH who meet the criteria for a positivevasodilator response and are treated with CCBshould be followed closely for both safety andefficacy with an initial reassessment after 3-4months of therapy including RHC.

If the patient does not show an adequate response(defined as being in WHO functional class I or IIand with a marked hemodynamic improvement),additional PAH therapy should be instituted.Patients who have not undergone a vasoreactivitystudy or those with a negative study should notbe started on CCBs because of potential severeside-effects (eg, hypotension, syncope, and RVfailure).

Vasodilator responsiveness does not appear topredict a favourable long-term response to CCBtherapy in patients with PAH in the setting ofconnective tissue diseases, and high dose CCB areoften not well tolerated in such patients.⁴⁴

No clear data support the use of CCBs inpatients with Eisenmenger's syndrome and theempirical use of CCB is dangerous and should beavoided.

Specific Drug Therapies

Specific therapies include those targeting thepathobiological abnormalities of PAH such asprostanoids, ERA and phosphodyesterase type-5inhibitors.

Prostanoids

Prostacyclin is produced predominantly byendothelial cells and induces potent vasodilatationof all vascular beds studied. This compound isthe most potent endogenous inhibitor of plateletaggregation and also appears to have bothcytoprotective and antiproliferative activities.⁴⁵ Dysregulation of the prostacyclin metabolicpathways has been shown in patients with PAHas assessed by reduction of prostacyclin synthaseexpression in the pulmonary arteries and ofprostacyclin urinary metabolites.⁴⁶

Epoprostenol (synthetic prostacyclin) isavailable as a stable freeze-dried preparationthat needs to be dissolved to allow intravenousinfusion. Epoprostenol has a short half-life (3-5min) and is stable at room temperature for only8 h; this explains why it must be administeredcontinuously by means of infusion pumps andpermanent tunnellized catheters. The efficacyof continuous intravenous administration ofepoprostenol has been tested in three unblindedRCTs in patients with IPAH^47,48 and in those withPAH associated with the scleroderma spectrumof diseases.⁴⁹ Epoprostenol improves symptoms,exercise capacity and hemodynamics in bothclinical conditions, and is the only treatment shownto improve survival in IPAH in a randomizedstudy. Long-term treatment with epoprostenol isinitiated at a dose of 2-4 ng/kg/min, with dosesincreasing at a rate limited by adverse effects(flushing, headache, diarrhea, leg pain). Optimaldose varies between individual patients, rangingfrom 20 to 40 ng/kg/min.^50,51 Serious adverse events related to the delivery system includepump malfunction, local site infection, catheterobstruction and sepsis. Abrupt interruption ofthe epoprostenol infusion should be avoided asthis may, in some patients, lead to a reboundworsening of their PH with symptomaticdeterioration and even death.

Treprostinil is a tricyclic benzidine analogue ofepoprostenol, with sufficient chemical stabilityto be administered at ambient temperature. These characteristics allow administration ofthe compound by the intravenous as well asthe subcutaneous route. The subcutaneousadministration of treprostinil can be accomplishedby micro-infusion pumps and small subcutaneouscatheters. The effects of treprostinil in PAH werestudied in the largest worldwide randomizedcontrolled trial performed in this condition,and showed improvements in exercise capacity,hemodynamics and symptoms.⁵² The greatestexercise improvement was observed in patientswho were more compromised at baseline andin subjects who could tolerate upper quartiledoses (>13.8 ng/kg/min). Infusion site pain wasthe most common adverse effect of treprostinil,leading to discontinuation of the treatment in 8%of cases on active drug and limiting dose increasein an additional proportion of patients. Amongthe 15% of patients who continued to receivesubcutaneous treprostinil alone, survival appearsto be improved.⁵³

In another long-term, open-label study, sustainedimprovement in exercise capacity and symptomswith subcutaneous treprostinil was reportedin patients with IPAH or CTEPH, with a meanfollow-up of 26 months.⁵⁴ Treprostinil has beenrecently approved in the USA for intravenoususe in patients with PAH: the effects appear to becomparable with those of epoprostenol but at adose 2 to 3 times higher. It is more convenient forthe patient because the reservoir can be changedevery 48 hours as compared to 12 hours withepoprostenol. A phase III randomised controlledtrial of inhaled treprostinil was recently completedand preliminary data show improvements inexercise capacity. Oral treprostinil is currentlybeing evaluated in RCT and in PAH Iloprost is achemically stable prostacyclin analogue availablefor intravenous, oral and aerosol administration.Inhaled therapy for PAH is an attractive conceptthat has the theoretical advantage of being selectivefor the pulmonary circulation. Inhaled iloprosthas been evaluated in one RCT in which dailyrepetitive iloprost inhalations (6 to 9 times, 2.5-5 µg/inhalation, median 30 µg daily) were comparedwith placebo inhalation in patients with PAHand CTEPH.⁵⁵ The study showed an increase inexercise capacity and improvement in symptoms,PVR and clinical events in enrolled patients. Asecond RCT on 60 patients already treated withbosentan increased in exercise capacity in thesubjects randomized to the addition of inhalediloprost, compared with placebo. Overall,inhaled iloprost was well tolerated. Continuousintravenous administration of iloprost appears tobe as effective as epoprostenol in a small series ofpatients with PAH and CTEPH.⁵⁶

Endothelin Receptor Antagonists

Activation of the endothelin (ET)-1 system hasbeen demonstrated in both plasma and lung tissuesof PAH patients.⁵⁷ Although it is not clear if theincreases in ET-1 plasma levels are a cause or aconsequence of PH,⁵⁸ studies on tissue ET systemexpression support a prominent role for ET-1 in thepathogenesis of PAH.⁵⁹

Bosentan is an oral active dual ET_A and ET_Breceptor antagonist and was the first molecule of thisclass of drugs to be synthesized. Bosentan has beenevaluated in PAH in five RCTs that have shownimprovement in exercise capacity, functional class,haemodynamics, echocardiographic and Dopplervariables, and time to clinical worsening.^60-64 Two randomised controlled trials have enrolledexclusively patients with WHO/New York HeartAssociation (NYHA) functional class II⁶³ or patients with Eisenmenger Syndrome.⁶⁴ Long-term observational studies have demonstrated thedurability of the effect of bosentan over time.⁹ Increases in hepatic aminotransferases occurredin 10% of the subjects but were found to be dosedependent and reversible after dose reduction ordiscontinuation. For these reasons liver functiontests should be performed at least monthly inpatients receiving bosentan.

Sitaxsentan, a selective orally active ET_A receptor antagonist, has been assessed in 2 RCTsin patients with WHO/NYHA class II/III PAH.^65,66 Aetiology included IPAH and PAH associatedwith connective tissue diseases or congenital heartdiseases. The studies demonstrated improvementsin exercise capacity and hemodynamics. A one-year,open-label observational study demonstrated thedurability of the effects of sitaxsentan over time.⁶⁷ Incidence of abnormal liver function tests, whichreversed in all cases, was 3%-5% for the approveddose of 100 mg (monthly monitoring is required).Interaction with warfarin requires the reduction ofthe anticoagulant dose by about 80% to stabilizethe international normalized ratio.

Ambrisentan, a non-sulfonamide, propanoicacid-class, ERA that is selective for the ET_A receptor, has been in evaluated in a pilot study⁶⁸ and in 2 large RCT that demonstrated efficacyon symptoms, exercise capacity, hemodynamicsand time to clinical worsening.⁶⁹ The open-label continuation study has demonstrated thedurability of the effects of ambrisentan for at leastone year.⁶⁹ Ambrisentan has been approved forthe treatment of WHO/NYHA functional class IIpatients. The current approved is 5 mg once daily(OD), which can be increased to 10 mg OD if thedrug is tolerated with the initial dose. Incidenceof abnormal liver function tests ranges from 0.8% to 3%. However even in patients treated withambrisentan, liver function tests are required atleast monthly. Caution is suggested for the co-administration of ambrisentan with ketoconazoleand cyclosporine.

Phosphodiesterase Type-5 Inhibitors

Sildenafil is an orally active, potent and selectiveinhibitor of phosphodiesterase type-5 that exerts itspharmacological effect by increasing the intracellularconcentration of cGMP. A number of uncontrolledstudies have reported favourable effects of sildenafilin IPAH, PAH associated to connective tissuediseases and to congenital heart diseases, and inCTEPH.^70-72 A pivotal RCT in 278 PAH patientstreated with sildenafil 20, 40, or 80 mg 3 times daily(TID) has confirmed favourable results on exercisecapacity, symptoms and hemodynamics.⁷³ Althoughthe approved dose is 20 mg TID, the durability ofeffect up to one year has been demonstrated onlywith the dose of 80 mg TID. In clinical practice,up-titration beyond 20 mg TID. (mainly 40 to 80mg TID) is frequently needed. Most side effects ofsildenafil were mild to moderate and mainly relatedto vasodilation.

Tadalafil is an OD dosing, selectivephosphodyesterase-5 (PDE-5) inhibitor, currentlyapproved for the treatment of erectile dysfunction.A pivotal RCT on 406 PAH patients treatedwith tadalafil 5, 10, 20, or 40 mg OD has shownfavourable results on exercise capacity, symptoms,hemodynamics and time to clinical worsening forthe largest dose.⁷⁴ Side effects profile was similar tosildenafil.

Combination Therapy

Combination therapy is the simultaneous use ofmore than one PAH-targeted class of drugs, eg,ERA, PDE-5 inhibitors, prostanoids, and novelsubstances. Although long-term safety and efficacyhave not yet been amply explored, numerous caseseries have suggested that various drug combinationsappear to be safe and effective. Different randomisedcontrolled studies have shown the efficacy of thecombination of bosentan and epoprostenol,⁶² of the addition of inhaled iloprost to patients onbackground therapy with bosentan,⁷⁵ of bosentan inpatients on background therapy with sildenafil,⁶³ of sildenafil in patients on background treatment withepoprostenol,⁷⁶ of inhaled treprostinil in patientswith background treatment with either bosentan orsildenafil and of tadalafil in patients on backgroundtreatment with bosentan.⁷⁴ Additional trials withnovel compounds are on going. There are many openquestions regarding combination therapy, including the optimal combination and timing. Candidatesto combination therapy are patients whose statusis defined as stable but unsatisfactory or unstableand deteriorating.¹ Given the complexities relatedto combination therapy, it is recommended thatcandidates be referred to expert centers.

Interventional Procedures

Balloon Atrial Septostomy

The role of balloon atrial septostomy in thetreatment of patients with PAH is uncertain becauseits efficacy has been reported only in small seriesand case reports.⁷⁷ In addition to symptomatic andhemodynamic improvement, increased survivalcompared with historical control groups has beenshown. In most circumstances, this interventionhas been performed in severely ill patients as apalliative bridge to lung transplantation, whichmay explain a procedure mortality rate of 5%-15%. In expert centers this procedure is nowperformed in cases of failure of available medicaltreatments.

Lung transplantation

Lung and heart-lung transplantation in PAHhas been assessed only in prospective uncontrolledseries, since formal RCTs are considered unethicalin the absence of alternative treatment options.⁷⁷ The 3-year and 5-year survival after lung and heart-lung transplantation is approximately 55% and45%, respectively.⁷⁸ Both single and bilateral lungtransplantation have been performed for IPAH andthese operations have been combined with repairof cardiac defects in Eisenmenger's syndrome.Recipient survival rates have been similar aftersingle and bilateral lung transplantation and afterheart-lung transplantation for PAH. However,many transplant centres currently prefer to performbilateral lung transplantation. Lung and heart-lungtransplantation are indicated in PAH patients withadvanced WHO/NYHA class III and class IVsymptoms that are refractory to available medicaltreatments. The appropriate timing of listing fortransplantation is complicated by the unpredictablewaiting period and the donor organ shortage.

Clinical Response to Treatment

The treatment algorithm includes the concept ofadequacy of response to initial treatment. Adequateclinical response is defined as the achievement ofa stable and satisfactory clinical status, includingabsence of clinical signs of RV failure,⁵¹ stable WHOfunctional class I or II without syncope, a 6-minute walk distance >500 meters^51,79, a peak VO₂ >15 mL/min/kg,^80,81 normal or near-normal BNP/NT-proBNP plasma levels,^82,83 no pericardial effusion,⁸⁴ tricuspid annular plane systolic excursion >2 cm,⁸⁵ right atrial pressure <8 mmHg, and a CI >2.5 L/min/m².^{4,50,51,79,86}

Inadequate clinical response to treatment forpatients initially in WHO functional class II or III isconsidered a clinical status defined as stable and notsatisfactory: some of the limits described above fora stable and satisfactory condition are not fulfilled,and the patient and treating physician consider thestatus, although stable, to be less than desirable.

Alternatively, a clinical state defined as unstableand deteriorating is also an inadequate clinicalresponse: the patient is characterized by evidenceof progression of RV failure symptoms and signs,worsening WHO functional class, ie, from II to IIIor III to IV, a 6-min walk distance <300 meters,^51,79 a peak VO₂ <12 mL/min/kg,80 rising BNP/NT-proBNPplasma levels,^82,83 evidence of pericardial effusion,⁸⁴ tricuspid annular plane systolic excursion <1.5 cm,⁸⁵ right atrial pressure >15 mmHg and rising, and aCI that is <2 L/min/m² and falling.^{4,50,51,79,86} Clinical warning signs include increasing oedema and/orthe need to escalate diuretic therapy, new onset orincreasing frequency/severity of angina (which canbe a sign of deteriorating RV function), and theonset or increasing frequency of syncope which isoften a grim prognostic sign and requires immediateattention as it heralds low output heart failure.Supraventricular arrhythmias may be seen in thiscondition and contribute to clinical deterioration.

Finally, inadequate clinical response for patientswho were initially in WHO functional class IV isconsidered the absence of a rapid improvement toWHO functional class III or better.

Treatment Algorithm

The treatment algorithm for PAH patients(Figure) is not appropriate for patients in otherclinical groups and in particular for patients inPH associated with left heart diseases or withparenchymal lung diseases.

Figure 1. Evidence-based treatment algorithm for pulmonary arterial hypertension patients. APAH indicates associated pulmonary arterial hypertension; BAS, balloon atrial septostomy; CCB, calcium channel blockers; ERA, endothelin receptorantagonists; FC, functional class; IPAH, idiopathic pulmonary arterial hypertension; PDE-5 I: phosphodyesterase-5 inhibitors; WHO/NYHA, World HealthOrganization/New York Heart Organization.^aTo maintain O₂ at 92%.^bUnder regulatory review. ^cIIa-C for WHO-FC II.

General measures and supportive therapy need tobe initiated after PAH diagnosis.

Due to the complexity of the additional evaluationand the treatment options available, it is stronglyrecommended that patients with PAH be referred toa specialized center.

Acute vasoreactivity testing should be performedand high-dose CCBs therapy performed asappropriate.

Non-responders to acute vasoreactivity testingwho are in WHO/NYHA functional class II shouldbe treated with an ERA or a PDE-5 inhibitor.

Non responders to acute vasoreactivity testing,or responders who remain in (or progress to) WHOfunctional class III should be considered candidatesfor treatment either an ERA, a PDE-5 inhibitor ora prostanoid. As head-to-head comparisons amongdifferent compounds are not available, no evidence-based first-line treatments can be proposed. In thiscase, the choice of therapy depends on a varietyof factors, including the approval status, route ofadministration, the side effect profile, patient'spreferences and physician's experience. Some settingsstill use first-line intravenous epoprostenol in WHOfunctional class III patients, due to its demonstratedsurvival benefits.

Continuous intravenous epoprostenol may beconsidered as first-line therapy for WHO functionalclass IV PAH patients because of the demonstratedsurvival benefit in this subset. Intravenous andsubcutaneous treprostinil have also been approvedfor the treatment of WHO functional class IVpatients in the USA. Although no randomisedcontrolled trials have been performed with theintravenous delivery of iloprost, this PGI2 analoguehas been approved in New Zealand. Both ERA andPDE-5 inhibitors are considered as a second linefor severely ill patients. In WHO functional classIV patients, initial combination therapy may beconsidered.

In case of inadequate clinical response,sequential combination therapy can be considered.Combination therapy may include a prostanoid plus an endothelin receptor antagonist, anendothelin receptor antagonist plus a PDE-5inhibitor, a prostanoid plus a PDE-5 inhibitor.Appropriate protocols for timing and dosing to limitpossible side effects of the combination have yet tobe defined.

Balloon atrial septostomy and/or lungtransplantation are indicated for PAH withinadequate clinical response despite optimalmedical therapy or where medical treatments areunavailable. These procedures should be performedonly in experienced centers.

PULMONARY HYPERTENSION DUE TO LEFTHEART DISEASE

PH carries a poor prognosis for patientswith chronic heart failure.⁸⁷ The mechanismsresponsible for the increase in PAP are multipleand include the passive backward transmissionof the elevated pressure (post-capillary passivePH, Table 1). In these cases the transpulmonarypressure gradient (TPG = mean PAP minus meanPWP) and PVR are within the normal range.In other circumstances the elevation of PAP isgreater than that of PWP (increased TPG) and an increase in PVR is also observed (postcapillaryreactive or "out of proportion" PH, Table 1).The elevation of PVR is due to an increase inpulmonary arteries vasomotor tone and/or tofixed structural obstructive remodelling of thepulmonary artery resistance vessels⁸⁸: the former component of reactive PH is reversible underacute pharmacological testing while the latter,characterized by medial hypertrophy and intimalproliferation of the pulmonary arteriole, does notrespond to the acute challenge.⁸

Which factors lead to reactive (out of proportion)PH and why some patients develop the acutelyreversible vasoconstrictive or fixed obstructivecomponents or both is poorly understood.Pathophysiological mechanisms may includevasoconstrictive reflexes arising from stretchreceptors localized in the left atrium and pulmonaryveins, and endothelial dysfunction of pulmonaryarteries that may favour vasoconstriction andproliferation of vessel wall cells. The prevalence ofPH in patients with chronic heart failure increaseswith the progression of functional class impairment.Up to 60% of patients with severe left ventricularsystolic dysfunction and up to 70% of patients withisolated left ventricular diastolic dysfunction maypresent with PH.⁸⁹ In left-sided valvular diseases,the prevalence of PH increases with the severity ofthe defect and of the symptoms. PH can be foundin virtually all patients with severe symptomaticmitral valve disease and up to 65% of those withsymptomatic aortic stenosis.^6,8,90 Currently, there is no specific therapy for PH due to left heartdiseases. A number of drugs (including diuretics,nitrates, hydralazine, angiotensin convertingenzyme inhibitors, beta-adrenoceptors blockers,nesiritide, and inotropic agents) or interventions(left ventricular assist device implantation,valvular surgery, resynchronization therapy andheart transplantation) may lower PAP more orless rapidly through a drop in left-sided fillingpressures.⁸ Therefore, management of PH due toleft heart disease should be aimed at the optimaltreatment of the underlying disease. No heartfailure drugs are contra-indicated because ofPH.⁹¹

Few studies have examined the role of drugscurrently recommended in PAH. The use ofinhaled nitric oxide has been shown to reducePAP but also to increase PWP, increasing thelikelihood of lung oedema.⁹² RCTs evaluatingthe effects of chronic use of epoprostenol⁹³ and bosentan^94,95 in advanced heart failure have beenterminated early due to an increased rate of eventsin the investigational drug treated group comparedwith conventional therapy. A small study recentlysuggested that sildenafil may improve exercise capacity and quality of life in patients with PHdue to left heart disease.⁹⁶ The history of medicaltherapy for heart failure is full of examples wheredrugs had positive effects on surrogate endpointsbut eventually turned out to be detrimental, suchas the phosphodiesterase type-3 inhibitors. Thus,the use of PAH-specific drugs is not recommendeduntil robust data from long-term studies areavailable, in particular in "out of proportion" PHassociated with left heart disease.

PULMONARY HYPERTENSION DUE TO LUNGDISEASE

PH is a poor prognostic factor in eitherchronic obstructive pulmonary disease (COPD)or interstitial lung diseases. The pathobiologicaland pathophysiological mechanisms involvedin this setting are multiple and include hypoxicvasoconstriction, mechanical stress of hyperinflatedlungs, loss of capillaries, inflammation andtoxic effects of cigarette smoke. There arealso data supporting an endothelium-derivedvasoconstrictor-vasodilator imbalance. Basedon published series, the incidence of significantPH in COPD patients with at least one previoushospitalization for exacerbation of respiratoryfailure is 20%. In advanced COPD, PH is highlyprevalent (>50%),^97,98 although generably of mildseverity. In interstitial lung disease, the prevalenceof PH is 32%-39%.⁹⁹ The combination of lungfibrosis with emphysema is associated with a higherprevalence of PH.¹⁰⁰ Currently there is no specifictherapy for PH associated with COPD or interstitiallung diseases. Long-term O₂ administration hasbeen shown to partially reduce the progression ofPH in COPD. Nevertheless, with this treatmentPAP rarely returns to normal values and thestructural abnormalities of pulmonary vesselsremain unaltered.³⁵ In interstitial lung diseases, therole of long-term O₂ therapy on PH progressionis less clear. Treatment with conventionalvasodilators is not recommended because theymay impair gas exchange due to the inhibition ofhypoxic pulmonary vasoconstriction^101,102 and their lack of efficacy after long-term use.^103,104 Published experience with specific PAH drug therapy is scarceand consists of the assessment of acute effects^105,106 and uncontrolled studies in small series.^107-111

The treatment of choice for patients with COPDor interstitial lung diseases and associated PH whoare hypoxemic is long-term O₂ therapy. Patientswith "out of proportion" PH due to lung diseases(characterized by dyspnoea insufficiently explainedby lung mechanical disturbances and mean PAP≥40-45 mmHg) should be referred to expert centresand enrolled in clinical trials targeting PAH specific drug therapy. The use of targeted PAH therapy inpatients with COPD or interstitial lung diseasesand mean PAP<40 mmHg is currently discouragedbecause there are no systematic data regarding itssafety or efficacy.

CHRONIC THROMBOEMBOLIC PULMONARYHYPERTENSION

Non-resolution of acute embolic masses whichlater undergo fibrosis leading to mechanical obstruction of pulmonary arteries is the mostimportant pathobiological process in CTEPH.The obstructive lesions observed in the distalpulmonary arteries of non-obstructed areas(virtually identical to those observed in PAH)may be related to a variety of factors, such asshear stress, pressure, inflammation, and therelease of cytokines and vasculotrophic mediators.Although more recent papers suggest that theprevalence of CTEPH is up to 3.8% in survivorsof acute pulmonary embolism,¹¹² most experts believe that the true incidence of CTEPH afteracute pulmonary embolism is 0.5%-2%. CTEPHcan be found in patients without any previousclinical episode of acute pulmonary embolism ordeep venous thrombosis (up to 50% in differentseries).¹¹³

Patients with CTEPH should receive life longanticoagulation, usually with vitamin K antagonistsadjusted to a target international normalized ratiobetween 2.0 and 3.0. Despite anticoagulation,CTEPH patients without additional treatments havea poor prognosis.

Therapeutic decisions concerning patients withCTEPH should be made at an expert centre basedupon interdisciplinary discussion among internists,radiologists and expert surgeons. Pulmonaryendarterectomy is the treatment of choice forpatients with CTEPH, as it is a potentially curative option. As a rule, a patient should not be consideredinoperable until the case has been reviewed by anexperienced surgeon.

The general medical intensive treatment ofadvanced WHO functional class III or class IVCTEPH patients does not differ substantiallyfrom treatment of PAH. An urgent pulmonaryendarterectomy should be planned as soon asreasonable hemodynamic conditions have beenrestored.

Specific PAH drug therapy may play a role inselected CTEPH patients, mainly for three differentscenarios: a) patients are not considered candidatesfor surgery; b) preoperative treatment is deemedappropriate to improve hemodynamics; and c) patients present with symptomatic residual/recurrent PH after pulmonary endarterectomysurgery.

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Correspondence: Prof N. Galiè,
Institute of Cardiology. University of Bologna,Via Massarenti 9. 40138-Bologna. Italy
E-mail: [e-mail]