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, hyperplasiaandvasoconstriction which contribute to pathogenesis of IPAH.- Drugs: Nefipidine, diltiazim, amlodipine.- Use depends on HR baseline. With relative bradycardia, Nifidipine and Amlodipine isfavorable. While with relative tachycardia, Diltiazim is favorable.- If ptn. is not responsive to CCB, defined as WHO-FC I and II with marked hemodynamicimprovement, should have addition of other PAH therapy.- Pt. who did not undergo vasoreactivity study or had a negative study should not be startedon CCB due to severe side effects such as RV failure.- SE: Hypotension, syncope, RV failure.
B)ProstanoidsMechanism: Prostacycline produced by endothelial cells is a potent vasodilator,inhibitor of platelet aggregation, cytoprotective and antiproliferative. This class drugsare synthetic prostacyclines1)Epoprostenol: - Administration: continuous inf. Pump. - Efficacy of continuous IV infusion was tested in 3 unblinded RCT’s in IPAH ptns andPAH 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 inIPAH ptns. - Abrupt discontinuation on drug infusion may lead, in some patients, to rebound PHwith 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, 2.5-5microgram/inhalation, median 30 microgram daily) were compared with placebo inhalation inPAH and CTEPH ptns, showed improved exercise capacity, symptoms, PVR and clinical events intreated ptns. - Second RCT (STEP) evaluated 60 ptns already treated with Bosentan showed improved exercisecapacity 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 exercisecapacity and symptoms.
Prostanoids cont.- Exercise improvement was predominantly observed in ptn with more compromised baselineand 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 improvedexercise capacity in ptn. with sc infusion. - A phase III RCT (TRIUMPH) of inhaled Trepostinil in ptn on Bosentan or Sildenafil, showedimproved exercise capacity. - SE: infusion site pain4)Beraprost: - RCT in Europe and another in US reported improved exercise capacity up to 3-6 months, andno 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 inPAH ptns., has a prominent role in the pathogenesis of PAH. Endothelin-1 has vasoconstrictorand 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 showedimproved exercise capacity, hemodynamics, echocardiographic and Doppler variables and time toclinical worsening.- It is improved, as a result of two RCTs to be used in WHO-FC II, PAH ptns. With Eisenmenger’sSyndrome 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 associatedwith 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 100mgdaily).- 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 CTDand 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 uncontrolledstudies.- An RCT (SUPER-1) on 278 PAH ptns. treated with 20, 40 or 80 mg TID, showed improved exercisecapacity, symptoms and hemodynamics. Also improved functional class was seen in a post hocanalysis 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% onBosentan), showed improved exercise capacity, symptoms, hemodynamics and time to clinicalworsening.
Combination TherapyA 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 wasfound to have increase exercise capacity and time to clinical worsening.• Inhaled Treprostinil in ptns. treated with Bosentan or Sildenafil improved excesicecapacity.• Epoprostenol+Sildenafil (267 PAH ptns.) has improved excecise capacity and time toclinical worsening.
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 malignantventricular arrhythmia (V. tach, flutter or fibrillation). In that series, supraventriculartachyarrhythmias occurred with an annual incidence of 2.8%.• Atrial flutter and atrial fibrillation were equally common and both arrhythmias invariably led toclinical deterioration with signs of right heart failure. Treatment of atrial flutter proved to bemore successful than treatment of atrial fibrillation.• Restoration of a stable sinus rhythm was associated with a favourable long-term survival whilepersistent atrial fibrillation was associated with a 2-year mortality of .80%.• Despite lacking prospective and controlled data, the above observations suggest thatmaintenance of a stable sinus rhythm should be considered an important treatment goal inpatients with PAH.• Prophylaxis antiarrhythmic drugs without negative inotropic effects such as Amiodarone, shouldalso be considered regardless of lacking data about its efficacy.
• The concept of BAS a treatment for IPAH is supported by the observation that Eisenmenger’ssyndrome and IPAH ptns. with a patent foramen ovale have a survival advantage over thosewithout a patent foramen ovale.• Inter-atrial right-to-left shunt decompresses the right heart chambers, and increases LV preloadand CO, improves systemic O2 transport despite arterial O2 desaturation and decreasessympathetic 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% onroom air, should not have BAS.• Before considering BAS, ptns. should be on optimal medical therapy, such as pre-conditioningwith i.v inotropic drugs.• Benefit was evident in WHO-FC IV ptns. with right heart failure refractory to medical therapy orwith severe syncopal symptoms. It may be considered in patients awaiting transplantation or ifmedical therapy is not available.• The main indication for BAS in adults is severe IPAH. Other indications are PAH associated withsurgically 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 theprognosis 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 bilateralprocedures 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.