pulmonary%20arterial%20hypertension
PULMONARY ARTERIAL HYPERTENSION
Pulmonary arterial hypertension is a syndrome resulting from restricted flow through the pulmonary arterial circulation resulting in increased pulmonary vascular resistance and ultimately leading to right heart failure.
It is a part of the spectrum of pulmonary hypertension, which is hemodynamic and pathophysiological condition defined as an increase in mean pulmonary arterial pressure ≥25 mmHg at rest.
Typical symptoms include progressive dyspnea on exertion, palpitations, fatigue, weakness, angina, syncope and abdominal distention.

Treatment Strategy

Step I

  • Includes general care, patient education, & supportive therapy
  • Acute vasoreactivity testing should be done prior to initiation of Ca antagonist therapy

Step II

  • Includes initiation of pharmacologic therapy
    • Initial combination therapy is considered in non-vasoreactive & treatment-naive high-risk patients
    • Choice of therapy will depend on the approval status/availability of the drug, route of administration, side effect profile, patient preference & practitioner’s experience

Step III

  • Depends on the patient’s response to initial treatment; includes pharmacologic combination therapy & interventional treatments

Pharmacotherapy

Management of Patients with Positive Acute Vasoreactivity

Calcium Antagonists

  • Eg Amlodipine, Diltiazem, Nifedipine
    • Choice of agent should be based on the patient’s heart rate (HR) at baseline
    • Nifedipine & Amlodipine are preferred in those with relative bradycardia; Diltiazem is favored in those with relative tachycardia
  • Of the vasodilators studied in pulmonary arterial hypertension (PAH) patients, calcium (Ca) antagonists have been the most successful
    • Has shown hemodynamic & functional status improvements of >1 year
  • Patients with idiopathic pulmonary arterial hypertension (IPAH) & without right heart failure who demonstrate acute response to vasodilator should be considered for a trial of oral calcium (Ca) antagonist
  • If patients with PAH associated with underlying processes such as scleroderma or congenital heart disease have had positive acute vasoreactivity tests, a trial of calcium (Ca) antagonists should be attempted
  • Single agent treatment of calcium (Ca) antagonists should only continue in patients showing clinical & hemodynamic response
  • Patients with positive acute vasoreactivity & are treated with calcium (Ca) antagonists should be reassessed initially after 3-4 months of therapy with RHC then followed closely for drug safety & efficacy

Management of Patients with Negative Acute Vasoreactivity or Non-Responders to Calcium Antagonists

Endothelin Receptor Antagonists

  • Eg Ambrisentan, Bosentan, Macitentan
  • Endothelin receptor antagonism is a promising treatment approach due to increased evidence of the pathogenic role of endothelin-1 in pulmonary arterial hypertension (PAH)
    • Endothelin-1 is a potent vasoconstrictor & a smooth muscle mitogen that might contribute to increase in vascular tone & the pulmonary vascular hypertrophy associated with PAH

Ambrisentan

  • Relatively selective antagonist of the ETA receptor
  • Demonstrated efficacy on symptoms, exercise capacity (6MWT), hemodynamics, & time to clinical worsening of patients with idiopathic pulmonary arterial hypertension (IPAH) & PAH associated with connective tissue diseases & human immunodeficiency virus (HIV) infection
  • Recommended for the improvement of 6MWT results in WHO FC II-III patients who cannot tolerate combination therapy
  • Require monthly liver function test (LFT) assessment

Bosentan (Oral)

  • Should be considered in PAH patients in functional class (FC) II to III who are not candidates for or who have failed calcium (Ca) antagonists & is recommended for WHO FC II-III patients intolerant to combination therapy to delay disease progression & reduce hospital stay due to PAH-related complications
  • Studies in PAH have shown improved exercise capacity, functional class, hemodynamics, echocardiographic & Doppler variables & time to clinical worsening
  • Oral active dual ETA & ETB receptor antagonist
  • Liver function tests should be checked monthly & hematocrit checked every 3 months
  • Barrier methods of contraception are recommended over hormonal methods because it may reduce efficacy of hormonal agents & is potentially teratogenic

Macitentan

  • Should be considered for treatment of PAH patients, & for long-term therapy of PAH patients with WHO FC-II to III to delay disease progression & improve functional class
  • Modified using the same structure of Bosentan, with improvements in the efficacy & with lesser adverse effects
  • Action: Dual ETA & ETB receptor antagonist; prevents endothelin-1 from binding to ETA & ETB
  • Not recommended for female patients planning to get pregnant or is currently pregnant
  • Studies showed decreased hospitalization in PAH patients on Macitentan therapy

Guanylate Cyclase Stimulators

Riociguat

  • A soluble guanylate cyclase stimulator, an enzyme that helps regulate nitric oxide
  • Treatment option used to improve exercise capacity & hemodynamics, & delay clinical worsening in patients with WHO FC II-III

Prostacyclin Analogs

  • Eg Beraprost, Epoprostenol, Iloprost, Treprostinil
  • Prostacyclin is produced mainly by endothelial cells which can induce potent vasodilatation of all vascular beds; it also inhibits platelet aggregation & has cytoprotective & antiproliferative activities
  • Prostacyclin analogs have been included in pharmacotherapy of PAH for more than a decade
  • Treatment with IV or inhaled prostanoids should only be considered in patients with WHO FC II who are intolerant to first-line agents or those previously treated but with unsatisfactory treatment results
  • In patients with WHO FC III with evidence of rapid disease progression or poor clinical prognosis, initial therapy using a parenteral prostanoid should be considered
  • Parenteral & inhaled prostanoid should also be considered if patient remains unresponsive despite treatment with 1-2 classes of oral prostanoids

Beraprost (Oral)

  • First chemically stable & orally active prostacyclin analogue
  • Monotherapy option for patients with WHO FC III who are intolerant to first-line agents or those previously treated but with unsatisfactory treatment results
  • Increase in exercise capacity has been shown but this effect persists only up to 3-6 months of therapy with no hemodynamic benefits

Epoprostenol [Intravenous (IV)]

  • Synthetic prostacyclin that has shown symptomatic & hemodynamic improvements as well as survival in patients with idiopathic pulmonary arterial hypertension (IPAH) in WHO functional class III-IV
  • Continuous IV Epoprostenol should be considered in patients with WHO FC III with rapid disease progression or poor clinical prognosis, patients with WHO FC IV, those who remain unresponsive despite treatment with 1-2 classes of oral prostanoids, & those with PAH associated with scleroderma to improve functional status & exercise capacity
  • Treatment of choice in PAH WHO FC IV patients who are not candidates for or who have failed Ca antagonist therapy & preferred by most experts in class IV patients with unstable condition because of its proven survival improvement, worldwide experience & the rapidity of action
  • Exact mechanism of action is still unknown but has shown pulmonary vasodilator properties
  • Disadvantage of therapy is the need to administer by continuous IV infusion

Iloprost [Inhaled & Intravenous (IV)]

  • A chemically stable prostacyclin analog for IV & aerosol administration
  • Inhaled Iloprost should be considered in patients who remain symptomatic despite correct & appropriate treatment with other prostacyclin analogues or phosphodiesterase inhibitors
  • Studies have shown increase in exercise capacity & improvement of symptoms, time to disease progression, peripheral vascular resistance (PVR) & clinical events with inhaled therapy
  • Continuous IV administration appears to be as effective as Epoprostenol in a small series of patients with PAH & chronic thromboembolic pulmonary hypertension (CTEPH)
    • It is a more potent pulmonary vasodilator than acute inhaled NO
  • Approved for use in WHO functional class III & IV PAH
  • Disadvantages of inhaled therapy is the short duration of action & therefore 6-9 inhalations/day are needed

Treprostinil [Inhaled, Intravenous (IV) or Subcutaneous (SC)]

  • A stable tricyclic benzidine analogue of Epoprostenol with a half-life of about 4.5 hours
  • Administered via micro-infusion pumps & small subcutaneous catheters similar to those used for administration of insulin
  • Recently approved as an inhaled prostacyclin analogue, to be used on patients who remain symptomatic despite correct & appropriate treatment with other prostacyclin analogues or phosphodiesterase inhibitors
  • Has been shown to improve exercise capacity, hemodynamics & clinical events
    • Those who benefited the most are those who were more compromised at baseline & in subjects who could tolerate the higher dose 
  • Continuous IV and SC Treprostinil should be considered in patients with WHO FC III with rapid disease progression or poor clinical prognosis, & in patients with WHO FC IV to improve patient’s 6MWT
  • IV Treprostinil should be considered in patients who remain unresponsive despite treatment with 1-2 classes of oral phosphodiesterase inhibitor or endothelin receptor antagonist to improve exercise capacity
  • Disadvantage of therapy is pain & erythema occurring at the infusion site

Prostacyclin Receptor Agonist

Selexipag (Oral)

  • Studies have shown that Selexipag may decrease pulmonary vascular resistance & morbidity/mortality events (eg death, disease progression, need for hospitalization & surgery)
  • Mechanism of action: selective prostacyclin IP receptor agonist that in turn triggers smooth muscle vasodilation & inhibits platelet aggregation
  • Recommended for use in PAH patients with WHO-FC II & III

Phosphodiesterase Inhibitors

Sildenafil (Oral)

  • Recommended for the improvement of 6MWT results in WHO FC II-III patients who cannot tolerate combination therapy 
  • Has shown favorable effects in IPAH, PAH associated with connective tissue diseases, congenital heart disease (CHD) & CTEPH on exercise capacity, symptoms & hemodynamics in clinical studies
  • Long-term data (available only at a dose of 80 mg 8 hrly) in patients completing 1 year of treatment with Sildenafil monotherapy showed sustained improvement at 1 year in the 6-minute walk test (6MWT) 
  • Action: Orally active, potent & selective inhibitor of cGMP phosphodiesterase type-5 that exerts its pharmacological effect by increasing intracellular concentration of cGMP, inducing relaxation & antiproliferative effects on vascular smooth muscle cells

Tadalafil

  • A longer-acting selective phosphodiesterase type-5 inhibitor recommended for patients with WHO FC II-III for the improvement of 6MWT results especially those who cannot tolerate combination therapy
  • Has shown favorable results on exercise capacity, symptoms, hemodynamic & time to clinical worsening at the largest dose in the study while demonstrating durability of these effects
  • Side effect profile is similar to Sildenafil

Vardenafil

  • Currently under study for its use in the treatment of PAH
  • Previous studies conducted showed an increase in the 6MWT, improved hemodynamics, and reduced time to disease progression
  • Mechanism of action: A selective phosphodiesterase type 5 inhibitor which may stimulate vascular relaxation by increasing cGMP concentrations in smooth muscles

Combination Therapy

  • Recommended for non-vasoreactive patients not responding adequately to monotherapy, but should be instituted by expert centers only
  • Safety & efficacy of combination therapy in PAH is a subject of active investigation

Initial Combination Therapy

  • Eg Ambrisentan + Tadalafil, Bosentan + Sildenafil + Epoprostenol IV, Bosentan + Epoprostenol IV
  • Used for WHO-FC II-III after initial monotherapy has been deemed ineffective
  • IV treatments may be used in WHO-FC IV PAH patients who are unresponsive to oral formulations

Sequential Combination Therapy

  • Eg Macitentan added to Sildenafil, Riociguat added to Bosentan, inhaled Treprostinil added to Sildenafil or Bosentan, Sildenafil added to Epoprostenol or Bosentan, Ambrisentan added to Sildenafil, Iloprost added to Bosentan, Tadalafil added to Bosentan, Bosentan added to Epoprostenol, Riociguat added to Sildenafil or other phosphodiesterase inhibitor
  • Used for WHO-FC II-IV PAH patients unresponsive to initial combination oral & IV therapies
  • May improve 6MWT, WHO FC, & time to disease progression
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