Idiopathic pulmonary arterial hypertension

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

Treatment goals include the following: improvement to WHO functional class I or II, improvement in the 6-minute walk distance (6MWD) to 380-440 metres, normal or near normal right ventricular (RV) size and function on echocardiography, a peak oxygen uptake of >15 mL/kg/minute during cardiopulmonary exercise testing, normal B-type natriuretic peptide (BNP) levels, and normalisation of RV function as assessed by haemodynamics obtained by right heart catheterisation (right atrial pressure <8 mmHg and cardiac index >2.5 L/minute/m²).[55]

Due to the complexities that these patients pose, it is strongly recommended that they are referred to a centre with expertise in the treatment of pulmonary arterial hypertension (PAH). Treatment options available include general supportive therapy, pulmonary artery hypertension-specific therapy (calcium-channel blockers, prostanoids, endothelin receptor antagonists, phosphodiesterase-5 [PDE5] inhibitors, a selective prostacyclin IP receptor agonist [selexipag], a soluble guanylate cyclase stimulator [riociguat], or an activin signalling inhibitor [sotatercept]), and lung transplantation as appropriate.[3][35][56]

Supportive therapy

General supportive therapy is indicated for most patients.[3][35][56]

Supervised exercise training: recommended for those on PAH medical therapy who are in a stable clinical condition.[3][57][58][59] [ ] Heavy physical exertion and isometric exercise should be avoided.[60] There is a lack of evidence for a direct impact of exercise training on survival and outcome in pulmonary hypertension. However, there are studies showing a beneficial effect on prognostically important parameters. The European Respiratory Society has identified a strong need to establish specialised rehabilitation programmes for patients with PAH to enhance access to this treatment intervention, which appears to be effective, cost-efficient and safe.[58]
Psychosocial support: should be considered, including advanced care planning with referral to specialist palliative care services at the right time.[3]
Vaccinations: patients should be offered influenza, Streptococcus pneumoniae, and coronavirus disease 2019 (COVID-19) vaccinations at a minimum.[3]
Diuretics: recommended in patients with fluid retention and signs of right ventricular failure.[3][61][62]
Supplemental oxygen: given in hypoxaemia.[4]
Supplemental iron: correction of iron status in case of iron deficiency.[3]
Anticoagulation: not generally recommended in patients with PAH but should be considered on a case-by-case basis.[3]
Pregnancy: patients with IPAH should avoid pregnancy, and women of child-bearing age should be counselled about the risks associated with becoming pregnant.[3][35] Those who present during pregnancy, or who become pregnant, should be treated by a multidisciplinary team experienced in managing pulmonary hypertension in pregnancy. Some of the drugs used to treat IPAH may cause fetal harm and may not be recommended in pregnancy; consult your local drug information source for more information.

Acute vasoreactivity testing

In some patients, vasoconstriction largely predominates over vascular remodeling phenomena. In this situation, calcium channel blockers can provide real clinical benefit.[4] These patients are identified by acute vasoreactivity testing (with inhaled nitric oxide, inhaled iloprost, or intravenous epoprostenol), which should generally be performed in all IPAH patients. Patients who are responsive should be treated with optimally tolerated doses of calcium-channel blockers. It is estimated that <10% of patients with IPAH are responders.[63] Vasoreactivity testing is contraindicated in patients with WHO functional class IV symptoms and low cardiac index. Vasoreactivity testing is generally not recommended for pulmonary hypertension that is caused by underlying diseases.

Positive response:

A positive response is defined as a fall in mean pulmonary artery pressure by ≥10 mmHg to reach an absolute value ≤40 mmHg, with an increased or unchanged cardiac output.[3][60] About 12% of IPAH patients may have a positive response and should be started on calcium-channel blocker therapy.[3][47]
A satisfactory response to calcium-channel blocker therapy is defined as being in WHO functional class I or II with near-normal haemodynamics after several months of therapy.[3][47] Close monitoring is mandatory, and patients should have a full re-assessment at 3-6 months.[3]
Patients with a sustained satisfactory response should continue calcium-channel blocker therapy, with further re-assessment every 6-12 months.[3]
Patients without a sustained satisfactory response require additional therapy and should be treated the same as those with a negative response to acute vasoreactivity testing. Continuation of calcium-channel blocker (combined with additional therapy) may need to be considered in some patients because of clinical deterioration with calcium-channel blocker withdrawal attempts.[3]
Calcium-channel blockers predominantly used in PAH are nifedipine, diltiazem, felodipine, and amlodipine.[3] Choice of drug is based on baseline heart rate (HR): if HR <100 beats/minute - nifedipine, felodipine, amlodipine; if HR >100 beats/minute - diltiazem.

Non-responders to vasoreactivity testing and patients without sustained response to calcium-channel blockers, or those in whom calcium-channel blockers are contraindicated, should be started on another PAH-specific therapy. All currently approved drugs target the vasoconstriction-vasodilation balance of endothelial dysfunction and vascular smooth muscle cell proliferation observed in PAH.[4] Targeted treatment options include the following.

Prostanoids: prostanoids have been shown to improve the distance walked in 6 minutes, functional class, and haemodynamics, and to avoid clinical worsening.[3][64] [ ] Epoprostenol is administered via continuous intravenous infusion (requiring an infusion pump and a permanent central venous catheter, with associated risks of central venous catheter bloodstream infections). In one prospective, randomised, multi-centre trial, continuous intravenous infusion of epoprostenol improved symptoms, haemodynamics, and survival in patients with severe IPAH.[65] Other prostanoids include treprostinil, which can be administered subcutaneously or intravenously. [ ] Subcutaneous administration of treprostinil avoids the risks associated with chronic indwelling central venous catheters, and in one double-blind, placebo-controlled multi-centre trial was shown to improve exercise capacity, symptoms, and haemodynamics in patients with PAH.[66]

Endothelin receptor antagonists: endothelin-1 binds to endothelin A and B receptors and is a potent vasoconstrictor and smooth-muscle mitogen whose system is activated in IPAH.[3] One Cochrane review found that for people with WHO functional class II and III PAH, endothelin receptor antagonists probably increase exercise capacity, improve WHO functional class, prevent WHO functional class deterioration, and improve haemodynamics.[67] [ ] Bosentan, an oral antagonist of both endothelin A and B receptors, has shown improvements in the 6MWD, functional class, haemodynamics, and time to clinical worsening. Liver function tests should be checked every month and haematocrit every 3 months. Bosentan is teratogenic in animals and may lessen the effectiveness of hormonal contraception. It may cause testicular atrophy and male infertility.[60] Ambrisentan, a selective endothelin A receptor antagonist, improves exercise capacity, symptoms, and haemodynamics and carries a low risk of liver toxicity.[68][69] Macitentan is a novel dual endothelin receptor antagonist found to delay a composite endpoint of morbidity and mortality (driven by worsening PAH symptoms) in one long-term event-driven placebo-controlled clinical trial.[70]

PDE5 inhibitors: these agents augment the pulmonary vascular response to nitric oxide (NO).[71] Tadalafil has been shown to improve the 6MWD and to be associated with less clinical worsening and improved quality of life.[72] [ ] Sildenafil has been shown to improve exercise capacity, functional class, and haemodynamics in patients with PAH, and may reduce clinical worsening.[73][74]
Soluble guanylate cyclase stimulators: also augment the NO pathway, but they do so by directly stimulating the enzyme that synthesises cyclic guanosine monophosphate (cGMP), the second messenger and downstream effector of NO. Riociguat, the only drug available in this class to date, improved 6MWD, pulmonary vascular resistance, N-terminal pro-B-type natriuretic peptide, WHO functional class, and time to clinical worsening in one 12-week, double-blind, multi-centre randomised trial.[75]
Selective prostacyclin IP receptor agonists: selexipag, the only drug available in this class, reduced the risk of a composite of death or complications related to PAH in both pre-treated patients and patients naive to therapy. Lower rates of disease progression and hospitalisation accounted for the majority of the risk reduction.[76]
Activin signalling inhibitor: sotatercept is a recombinant fusion protein composed of the extracellular domain of the human activin receptor type IIA linked to the FC domain of human IgG1, which acts as a ligand trap by binding activins and GDFs, thus restoring the balance between pro-proliferative and anti-proliferative bone morphogenetic protein (BMP) pathways.[77] Sotatercept is approved in the US for the treatment of adults with PAH to increase exercise capacity, improve WHO functional class, and reduce the risk of clinical worsening events. It is also approved in Europe for this indication. In one phase 2 trial, treatment with sotatercept resulted in a reduction in pulmonary vascular resistance in patients receiving background therapy for PAH, compared with placebo.[78] In the multi-centre, double-blind, phase 3 STELLAR trial, in patients with PAH (WHO functional class II or III) on stable background therapy, adding sotatercept significantly improved exercise capacity (as assessed by the 6-minute walk test), compared with placebo.[79]

Risk stratification as a basis for treatment decisions

For treatment decisions, a rational approach should be used to classify patients into risk groups based on the combination of several clinical features, including haemodynamics, WHO functional class, 6MWD, and BNP or N-terminal pro-BNP (NT-proBNP).[3][56] In general, the goal of therapy is to shift patients to, or maintain patients in, a low-risk category. Significant clinical judgement and experience is needed to make these decisions.

For patients without cardiopulmonary comorbidities, the European Society of Cardiology (ESC)/European Respiratory Society (ERS) guidelines recommend a three-strata model for risk assessment at the time of diagnosis, using categories of low, intermediate, and high risk of mortality at 1 year to assess survival and guide management.[3][54][Figure caption and citation for the preceding image starts]: Comprehensive risk assessment in pulmonary arterial hypertension (three-strata model)European Heart Journal. 2022 Oct 7;43(38):3618-731; used with permission [Citation ends]. com.bmj.content.model.Caption@1ed6a5a4 Patients initially assessed as at low or intermediate risk of mortality who are unresponsive to acute vasoreactivity testing, or who cannot take calcium-channel blockers, should preferably be started on combination therapy with an endothelin receptor antagonist plus a PDE5 inhibitor.[3] ESC/ERS guidelines recommend initial oral combination therapy with tadalafil plus either ambrisentan or macitentan.[3] Combinations of other endothelin receptor antagonists and PDE5 inhibitors may also be considered.

One multi-centre, randomised, double-blind, phase 3 study showed a lower risk of clinical failure with upfront combination therapy with ambrisentan plus tadalafil compared with each monotherapy alone.[80] In this study, upfront combination therapy with ambrisentan plus tadalafil delayed clinical worsening in PAH, particularly hospitalisations. Another multi-centre, randomised, double-blind, phase 3b study demonstrated substantial improvements in haemodynamics and exercise capacity with initial combination therapy (macitentan and tadalafil) and that there was no benefit of triple therapy (macitentan, tadalafil, and selexipag) compared with the double therapy.[81]

Patients initially assessed as being at high risk of mortality who are unresponsive to acute vasoreactivity testing, or who cannot take calcium-channel blockers, should be considered for combination therapy with an endothelin receptor antagonist plus a PDE5 inhibitor plus a parenteral prostanoid (intravenous epoprostenol or intravenous/subcutaneous treprostinil).[3] Upfront triple therapy is associated with clinical and haemodynamic improvement and reduces right ventricular remodelling.[82][83][84]

During monitoring and follow-up after initial therapy (every 3-6 months according to patient needs), the ESC/ERS guidelines recommend using a four-strata model, which uses categories of low, intermediate-low, intermediate-high, and high risk to guide treatment decisions.[3][Figure caption and citation for the preceding image starts]: Variables used to calculate the simplified four-strata risk-assessment toolEuropean Heart Journal. 2022 Oct 7;43(38):3618-731; used with permission [Citation ends]. com.bmj.content.model.Caption@64da69c9 Patients assessed to be at low risk should continue their initial therapy.[3] Switching from intravenous or subcutaneous therapy to oral therapy in patients who achieve a low risk status can be considered on a case-by-case basis.

Addition of selexipag to the initial combination of an endothelin receptor antagonist plus a PDE5 inhibitor should be considered for patients assessed to be at intermediate-low risk. Alternatively, switching from the PDE5 inhibitor to riociguat may also be considered.[85] A PDE5 inhibitor and riociguat should not be used in combination, because this leads to a higher risk of systemic hypotension.[86]

Addition of a prostanoid should be considered for patients assessed to be at intermediate-high or high risk while on an initial combination of an endothelin receptor antagonist plus a PDE5 inhibitor.[86] Referral for lung transplantation evaluation should also be considered.

Patients with cardiopulmonary comorbidities

Evidence for treatment of patients with cardiopulmonary comorbidities is lacking. The ESC/ERS guidelines recommend that initial monotherapy with an endothelin receptor antagonist or a PDE5 inhibitor may be considered, with additional treatment options considered on an individual basis for those at intermediate or high risk of death at follow-up.[3]

Treatment-resistant patients

Patients refractory to all medical therapy should be evaluated for lung transplantation.[3]

The availability of effective medical therapy has reduced the need for lung transplantation. However, transplantation remains an important option for patients in whom medical therapy has failed and who remain in WHO functional class III or IV. Referral for lung transplant evaluation is recommended when patients present with an inadequate response to optimised combination therapy and have an intermediate-high or high risk of death.[3] Double lung transplantation is most commonly performed. Heart-lung transplantation should be considered in patients with additional cardiac conditions.[3] When to list a patient for lung transplantation is a difficult decision, further complicated by the unpredictable waiting list and the shortage of donor organs.[3]

Balloon atrial septostomy (BAS) produces right-to-left shunting that decompresses the right atrium and right ventricle, increases systemic cardiac output, and decreases systemic arterial oxygen saturation. The latter is offset by the increase in output leading to an increase in systemic oxygen transport.[3] BAS is used as a palliative option or bridge to lung transplantation in patients who are deteriorating despite maximal medical therapy; as it is a complex and high-risk procedure it is rarely performed and only considered in experienced centres.[3][56]

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