PAH Management

By: Walid Alkeridy

Goals Of Therapy

• In stable ptns.: - Prevent disease progression. - Patient education - Lifestyle changes (weight, smoking, traveling, pregnancy)

• In unstable ptns.: - Stabilize the right-sided heart function - Symptomatic relief - Increase functional capacity - Hemodynamic improvement ( ↓or↔ preload, ↓RV afterload, support RV contractility.

• Treatment modalities: - Pharmacological - Non-pharmacological - Surgical

Pharmacological

Supportive therapy:

• Oxygen: O2 administration reduce the pulmonary vascular resistance (PVR) in

patients with PAH. However, long term therapy is controversial. Consider

ambulatory O2 during exercise to prevent desaturation.

• Diuretics: indicated for Cor pulmonale, to manage ascites and volume over load in

CHF 2ry to PAH.

• Digoxin: indicated for atrial tachyarrhythmias and to some extent improve cardiac

out put.

• Oral anticoagulants: prevalence of vascular thrombotic events is higher in patients

with IPAH. Indicated based on weighing risk of bleeding Vs. benefit.

Specific Therapy

A)CCB:

Mechanism: Decrease smooth muscle cell hypertrophy, hyperplasia andvasoconstriction which contribute to pathogenesis of IPAH.

- Drugs: Nefipidine, diltiazim, amlodipine.

- Use depends on HR baseline. With relative bradycardia, Nifidipine and Amlodipine is favorable. While with relative tachycardia, Diltiazim is favorable.

- If ptn. is not responsive to CCB, defined as WHO-FC I and II with marked hemodynamic improvement, should have addition of other PAH therapy.

- Pt. who did not undergo vasoreactivity study or had a negative study should not be started on CCB due to severe side effects such as RV failure.

- SE: Hypotension, syncope, RV failure.

B)Prostanoids

Mechanism: Prostacycline produced by endothelial cells is a potent vasodilator, inhibitor of platelet aggregation, cytoprotective and antiproliferative. This class drugs are synthetic prostacyclines

1)Epoprostenol: - Administration: continuous inf. Pump. - Efficacy of continuous IV infusion was tested in 3 unblinded RCT’s in IPAH ptns and PAH associated with scleroderma ptns., showed improved excersice capacity, symptoms, and hemodynamics in both groups of ptns. - A randomised study showed that it is the only treatment seen to improve survival in IPAH ptns. - Abrupt discontinuation on drug infusion may lead, in some patients, to rebound PH with symptomatic deterioration and possibly death.

Prostanoids Cont.

2)Iloprost: - Administration: IV, oral, Inhilation. - One RCT (AIR) evaluated inhaled therapy in which daily repetitive inhalation (6-9 times, 2.5-5 microgram/inhalation, median 30 microgram daily) were compared with placebo inhalation in PAH and CTEPH ptns, showed improved exercise capacity, symptoms, PVR and clinical events in treated ptns. - Second RCT (STEP) evaluated 60 ptns already treated with Bosentan showed improved exercise capacity with addition of inhaled Iloprost compared with placebo. - SE: flushing, jaw pain.

3)Trepostinil: - Analogue of epoprostenol - Administration: IV, SC - Was studied in the largest worldwide RCT preformed in PAH, showed improved exercise capacity and symptoms.

Prostanoids cont.

- Exercise improvement was predominantly observed in ptn with more compromised baseline and who tolerated the upper quarter dose (more than 13.8 ng/kg/min) - Another long-term, open-label study in IPAH or CTEPH ptns, showed sustained improved exercise capacity in ptn. with sc infusion. - A phase III RCT (TRIUMPH) of inhaled Trepostinil in ptn on Bosentan or Sildenafil, showed improved exercise capacity. - SE: infusion site pain

4)Beraprost: - RCT in Europe and another in US reported improved exercise capacity up to 3-6 months, and no hemodynamic effect. - SE: headache, flushing, jaw pain and diarrhea.

C)Endothelial Receptor Antagonist (ERA):

Mechanism: Activation of the endothelial system in both plasma and lung tissue in PAH ptns., has a prominent role in the pathogenesis of PAH. Endothelin-1 has vasoconstrictor and mitogenic effects by binding to two receptors isoforms in the vascular smooth muscle cell, Endothelin-A and Endothelin-B receptors.

1)Bosentan: - Oral active Endothelin-A and Endothelin-B receptor antagonist.- Was studied in 5 RCTs (PILOT, BREATHE-1, BREATHE-2, BREATHE-5, and EARLY) that showed improved exercise capacity, hemodynamics, echocardiographic and Doppler variables and time to clinical worsening.- It is improved, as a result of two RCTs to be used in WHO-FC II, PAH ptns. With Eisenmenger’s Syndrome or with congenital systemic –to-pulmonary shunts.- Durable effects in IPAH ptns., was shown by long-term observational study.- Dose-dependant and reversible increase in hepatic aminotransferases seen in 10% of ptns., Monthly hepatic enzymes test is required.- SE: reduction of hemoglobin level and spermatogenesis were also observed.

ERA cont.

2)Sitaxentan: - Oral active Endothelin-A receptor antagonist.- Was studied in two RCTs (STRIDE 1 and 2) on WHO-FC II and III PAH, IPAH and PAH associated with CTDs ot CHD ptns, that showed improved exercise capacity and hemodynamics.- Durable effects reported in 1-year open-label observational study.- Monthly liver function test is required (observed 3-5% of ptns. On the approved does of 100mg daily).- Interaction with Warfrin causes increased INR (Warfrin dose should be decreased).

3)Ambrisentan: - Endothelin-A receptor Antagonist.- Was evaluated in a pilot study and two RCTs (ARIES 1 and 2), shown improved exercise capacity, symptoms, hemodynamics and time to clinical worsening in PAH and IPAH associated with CTD and HIV infection ptns.- Approved for WHO-FC II and III PAH ptns.- Durability of at least 1 year, observed in open-label continuation study.- SE: increased peripheral odema, abnormal liver function (seen in 3% of small group ptns.)

D)Phosphodiesterase Type-5 inhibitors

Mechanism: Inhibition of cGMP-degrading enzyme phosphodiesterase type-5 through NO/cGMP pathway. Also has antiproliferative effects.

1)Sildenafil: - Orally active, potent inhibitor.- Favorable effects in IPAH, PAH associated with CTD,CHD,CTEPH, was shown in uncontrolled studies.- An RCT (SUPER-1) on 278 PAH ptns. treated with 20, 40 or 80 mg TID, showed improved exercise capacity, symptoms and hemodynamics. Also improved functional class was seen in a post hoc analysis of 89 PAH associated with CTD ptns. at 12 week compared with placebo.- SE: headache, flushing, epistaxis.

2)Tadalafil:- An RCT (PHIRST) on 406 PAH ptns. treated with 5, 10, 20 or 40 mg OD (approx. 50% on Bosentan), showed improved exercise capacity, symptoms, hemodynamics and time to clinical worsening.

Combination Therapy

A Few RCTs that studied combination therapy for PAH showed:

• Epoprostenol+Bosentan has better hemodynamic effect than Epoprostenol alone.

• Inhaled Iloprost+Bosentan 12 week efficacy and safety was addressed and was found to have increase exercise capacity and time to clinical worsening.

• Inhaled Treprostinil in ptns. treated with Bosentan or Sildenafil improved excesice capacity.

• Epoprostenol+Sildenafil (267 PAH ptns.) has improved excecise capacity and time to

clinical worsening.

Drug Interactions

Arrythmias Therapy

• In 132 PAH ptns. who witnessed cardiac arrests, ventricular fibrillation was observed in only 8% of the cases.

• In 231 PAH or CTEPH ptns. followed over a 6-year period, there was no reporting of malignant ventricular arrhythmia (V. tach, flutter or fibrillation). In that series, supraventricular tachyarrhythmias occurred with an annual incidence of 2.8%.

• Atrial flutter and atrial fibrillation were equally common and both arrhythmias invariably led to clinical deterioration with signs of right heart failure. Treatment of atrial flutter proved to be more successful than treatment of atrial fibrillation.

• Restoration of a stable sinus rhythm was associated with a favourable long-term survival while persistent atrial fibrillation was associated with a 2-year mortality of .80%.

• Despite lacking prospective and controlled data, the above observations suggest that maintenance of a stable sinus rhythm should be considered an important treatment goal in patients with PAH.

• Prophylaxis antiarrhythmic drugs without negative inotropic effects such as Amiodarone,

should also be considered regardless of lacking data about its efficacy.

Surgical Therapy :

A) Balloon Atrial Septostomy (BAS)

• The concept of BAS a treatment for IPAH is supported by the observation that Eisenmenger’s syndrome and IPAH ptns. with a patent foramen ovale have a survival advantage over those without a patent foramen ovale.

• Inter-atrial right-to-left shunt decompresses the right heart chambers, and increases LV preload and CO, improves systemic O2 transport despite arterial O2 desaturation and decreases sympathetic hyperactivity.

• A careful pre-procedure risk assessment ensures reduced mortality.

• Endstage ptns. with a baseline mean RAP of 20 mmHg and O2 saturation at rest of ,80% on room air, should not have BAS.

• Before considering BAS, ptns. should be on optimal medical therapy, such as pre-conditioning with i.v inotropic drugs.

• Benefit was evident in WHO-FC IV ptns. with right heart failure refractory to medical therapy or with severe syncopal symptoms. It may be considered in patients awaiting transplantation or if medical therapy is not available.

• The main indication for BAS in adults is severe IPAH. Other indications are PAH associated with surgically corrected CHD, CTD, distal CTEPH, PVOD, and pulmonary capillary haemangiomatosis.

• Evidence shows improvements in CI, exercise capacity and decreases in right atrial pressure .

• Long-term survival has not been established in RCTs.

B) Lung Transplant

• Studies showed up to 25% of IPAH ptns. may fail to improve on disease-specific therapy and the prognosis of patients who remain in WHO-FC III or IV is poor.

• Prognosis of PAH depends on the aetiology, and PAHassociated with CTD has a worse prognosis than IPAH even whentreated with prostanoids. But PAH associated withCHD ptns. have better survival.

• The worst prognosis is seen in PVOD and pulmonary capillary haemangiomatosis ptns. due tothe lack of effective medical treatments. Those ptns. shouldbe listed for transplantation at diagnosis.

• After double-lung transplantation, RV afterloadis immediately reduced, RV systolicand LV diastolic functions do not improve immediately. Similar survival in both single and bilateral procedures as observed.

• Although patients with Eisenmenger’s syndrome due to simpleshunts have been treated by isolated lung transplantation and repairof the cardiac defect,174 patients with ventricular septal defects mayhave a better outcome with heart–lung transplantation.175The overall 5-year survival following transplantation for PAH is45–50%, with evidence of continued good quality of life.

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