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.

Pulmonary%20arterial%20hypertension Treatment

Treatment Strategy

Step I

  • Includes general care, patient education, and 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 and 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 and practitioner’s experience

Step III

  • Depends on the patient’s response to initial treatment; includes pharmacologic combination therapy and 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 and 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 and functional status improvements of >1 year
  • Patients with idiopathic pulmonary arterial hypertension (IPAH) and without right heart failure who demonstrate acute response to vasodilator should be considered for a trial of oral 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 Ca antagonists should be attempted
  • Single agent treatment of Ca antagonists should only continue in patients showing clinical and hemodynamic response
  • Patients with positive acute vasoreactivity and are treated with Ca antagonists should be reassessed initially after 3-4 months of therapy with RHC then followed closely for drug safety and efficacy

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

Initial Management

  • Considered as residual agents for:
    • IPAH patients >75 years old and with multiple risk factors for left heart disease
    • Non-vasoreactive patients with WHO-FC I-II and remain stable on monotherapy
    • Patients with PAH associated with HIV, portal hypertension, or uncorrected heart disease
    • PAH patients with high suspicion for pulmonary veno-occlusive disease or pulmonary capillary hemangiomatosis
    • Patients with contraindications to combination therapy or unavailability of combination therapy

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 PAH
    • Endothelin-1 is a potent vasoconstrictor and a smooth muscle mitogen that might contribute to increase in vascular tone and the pulmonary vascular hypertrophy associated with PAH

Ambrisentan

  • Relatively selective antagonist of the ETA receptor
  • Demonstrated efficacy on symptoms, exercise capacity (6MWT), hemodynamics, and time to clinical worsening of patients with IPAH and PAH associated with connective tissue diseases and human immunodeficiency virus (HIV) infection
  • Recommended for the improvement of 6MWT results in WHO FC II-III patients who cannot tolerate combination therapy
  • Increased incidence of peripheral edema has been reported with Ambrisentan use
  • 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 Ca antagonists and is recommended for WHO FC II-III patients intolerant to combination therapy to delay disease progression, improve 6MWT and reduce hospital stay due to PAH-related complications
  • Studies in PAH have shown improved exercise capacity, functional class, hemodynamics, echocardiographic and Doppler variables and time to clinical worsening
  • Oral active dual ETA and ETB receptor antagonist
  • Liver function tests should be checked monthly and hematocrit checked every 3 months
  • Barrier methods of contraception are recommended over hormonal methods because it may reduce efficacy of hormonal agents and is potentially teratogenic

Macitentan

  • Dual ETA and ETB receptor antagonist; prevents endothelin-1 from binding to ETA and ETB 
  • Should be considered for treatment of PAH patients, and for long-term therapy of PAH patients with WHO FC-II to III to delay disease progression and improve functional class
  • May be used as additional treatment agent for PAH patients with WHO-FC III-IV who remain symptomatic despite optimal doses of phosphodiesterase-5 inhibitor (PDE5i) or inhaled prostacyclin analogs to improve functional class, 6MWT and delay time to clinical worsening 
  • Modified using the same structure of Bosentan, with improvements in the efficacy and with lesser adverse effects
  • Studies showed increased exercise capacity, slower disease progression, and 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 and hemodynamics, and delay clinical worsening in patients with WHO FC II-III
  • May be used as additional treatment agent for PAH patients with WHO-FC III-IV who remain symptomatic despite optimal doses of Ambrisentan, Bosentan or inhaled prostacyclin analogs to improve functional class, 6MWT and delay time to clinical worsening
  • Indicated for therapy of symptomatic inoperable or recurrent CTEPH patients

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 and has cytoprotective and 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 and inhaled prostanoid should also be considered if patient remains unresponsive despite treatment with 1-2 classes of oral prostanoids

Beraprost (Oral)

  • First chemically stable and 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 and hemodynamic improvements as well as survival in patients with 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, and those with PAH associated with scleroderma to improve functional status and exercise capacity
  • Treatment of choice in PAH WHO FC IV patients who are not candidates for or who have failed Ca antagonist therapy and preferred by most experts in class IV patients with unstable condition because of its proven survival improvement, worldwide experience and 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 and IV]

  • A chemically stable prostacyclin analog for IV, oral and aerosol administration
  • Inhaled Iloprost should be considered in patients who remain symptomatic despite correct and appropriate treatment with other prostacyclin analogues or PDE5i
    • May be used as an additional treatment agent for PAH patients with WHO-FC III who remain symptomatic on stable and optimal doses of ERA or PDE5i to delay time to clinical worsening
    • May be used as an additional treatment agent for PAH patients with WHO-FC III-IV who remain symptomatic on stable and optimal doses of ERA or PDE5i to delay time to improve exercise capacity
  • Studies have shown increase in exercise capacity and improvement of symptoms, time to disease progression, peripheral vascular resistance (PVR) and clinical events with inhaled therapy
  • Continuous IV administration appears to be as effective as Epoprostenol in a small series of patients with PAH and chronic thromboembolic pulmonary hypertension (CTEPH)
    • It is a more potent pulmonary vasodilator than acute inhaled NO
  • Approved for use in WHO functional class III and IV PAH
  • Disadvantages of inhaled therapy is the short duration of action and therefore 6-9 inhalations/day are needed

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

  • A stable tricyclic benzidine analogue of Epoprostenol with a half-life of about 4.5 hours
  • Administered via micro-infusion pumps ang 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 and appropriate treatment with other prostacyclin analogues or PDE5i
    • Recommended as an additional treatment agent for PAH patients with WHO-FC III-IV who remain symptomatic on stable and optimal doses of ERA or PDE5i to improve 6MWT
  • Has been shown to improve exercise capacity, hemodynamics and clinical events
    • Those who benefited the most are those who were more compromised at baseline and 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, and 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 PDE5i or ERA to improve exercise capacity
  • Oral preparation is US FDA-approved for PAH monotherapy
    • Has been shown to improve exercise capacity in treatment-naive PAH patients with WHO-FC II or III
  • Disadvantage of therapy is pain and erythema occurring at the infusion site

Prostacyclin Receptor Agonist

Selexipag (Oral)

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

Phosphodiesterase-5 Inhibitors (PDE5i)

Sildenafil (Oral)

  • Orally active, potent and selective inhibitor of cGMP phosphodiesterase type-5 that exerts its pharmacological effect by increasing intracellular concentration of cGMP, inducing relaxation and antiproliferative effects on vascular smooth muscle cells 
  • Recommended for the improvement of 6MWT results and improve functional class in WHO FC II-III patients who cannot tolerate combination therapy 
  • May be used as additional treatment agent for PAH patients with WHO-FC IV who remain symptomatic despite optimal doses of Epoprostenol IV to improve 6MWT 
  • Has shown favorable effects in IPAH, PAH associated with connective tissue diseases, congenital heart disease (CHD) and CTEPH on exercise capacity, symptoms and hemodynamics in clinical studies
  • Long-term data (available only at a dose of 80 mg 8 hourly) in patients completing 1 year of treatment with Sildenafil monotherapy showed sustained improvement at 1 year in the 6MWT 

Tadalafil

  • A longer-acting selective phosphodiesterase type-5 inhibitor recommended for patients with WHO FC II-III for the improvement of 6MWT results, improve functional class and delay time to clinical worsening especially those who cannot tolerate combination therapy
  • Has shown favorable results on exercise capacity, symptoms, hemodynamic and 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

  • A selective phosphodiesterase type 5 inhibitor which may stimulate vascular relaxation by increasing cGMP concentrations in smooth muscles 
  • 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
  • Side effect profile is similar to Sildenafil

Combination Therapy

  • Recommended for non-vasoreactive patients not responding adequately to monotherapy, but should be instituted by expert centers only
  • Safety and 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
  • Recommended for non-vasoreactive patients with WHO-FC II-III
  • IV treatments may be used in WHO-FC IV PAH patients who are unresponsive to oral formulations
  • Ambrisentan/Tadalafil combination is recommended for treatment-naive WHO-FC II-III PAH patients to improve 6MWT results and those who are unresponsive or with contraindications to Ca antagonist therapy
    • AMBITION trial showed that Ambrisentan/Tadalafil combination therapy improved exercise capacity and decreased hospitalizations in treatment-naive PAH patients with WHO-FC II-III
  • Macitentan/Sildenafil combination therapy has been shown to improve exercise capacity and WHO functional class in the SERAPHIN trial
  • Macitentan/Tadalafil combination therapy has been shown to significantly improve exercise capacity, cardiopulmonary hemodynamics and functional capacity in treatment-naive PAH patients in the OPTIMA study

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, Tadalafil added to Ambrisentan, 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 and IV therapies
  • May improve 6MWT, WHO FC, and time to disease progression
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