Management of pulmonary artery hypertension

1. MANAGEMENT OF PULMONARY
ARTERY HYPERTENSION
DR ADITYA NAG
DR GOVIND SINGH

2. GOALS OF THERAPY
• In Stable patients:
• Prevent disease progression
• Patient education
• Lifestyle changes (weight, smoking, traveling, pregnancy)
• In Unstable patients:
• Stabilize the right-sided heart function
• Symptomatic relief
• Increase functional capacity
• Hemodynamic improvement ( ↓or↔ preload, ↓RV afterload, support
RV contractility)

3. TREATMENT MODALITIES
• Pharmacological
• Non pharmacological
• Surgical

4. PHARMACOLOGICAL
• Supportive therapy:
• Oxygen: Reduces the pulmonary vascular resistance
• Diuretics: indicated for Cor pulmonale, to manage ascites and volume over
load in CHF 2ndary to PAH
• Digoxin: indicated for atrial tachyarrhythmias and to some extent improve
cardiac output.
• Oral anticoagulants: prevalence of vascular thrombotic events
• Avoidance of altitude

6. SPECIFIC THERAPY
• Prostanoids:
• Prostacyclin is a powerful vasodilator (both pulmonary and systemic) as
well as an inhibitor of smooth muscle proliferation and platelet
aggregation
• Several synthetic prostacyclin analogs are currently available:
formulations administered by continuous intravenous infusion
(epoprostenol and treprostinil), subcutaneous infusion (treprostinil),
and via inhalation (treprostinil and iloprost)

7. • Long-term follow-up studies have shown sustained benefits, including
improved functional class and improved survival. Five-year survival of
greater than 60% has been seen
• However chronic use of epoprostenol is complex requires an
indwelling central venous catheter, continuous-infusion pump, and
daily preparation of the medication. In addition, there are numerous
side effects including jaw claudication, leg and foot pain, diarrhea,
rash, and weight loss occasionally with ascites.

8. • Epoprostenol
• Administration: continuous inf. Pump.
• Intravenous epoprostenol is typically initiated in the hospital setting at 1 to 2
ng/kg/min and titrated up slowly over a few days to approximately 4 to 6 ng/kg/min
• Patients showed improved excersice capacity, symptoms, and hemodynamics
• Abrupt discontinuation on drug infusion may lead, in some patients, to rebound PH
with symptomatic deterioration and possibly death.
• Approved for WHO Class 3 and 4 PAH

9. • Iloprost:
• Approved by the FDA as an inhaled formulation in 2004
• Inhaled iloprost is delivered via ultrasonic nebulizer at a starting dose of 2.5
µg delivered six to nine times daily and increased to 5 µg six to nine times
daily if well-tolerated
• Administration: IV, oral, Inhalation
• showed improved exercise capacity, symptoms, PVR and clinical events in
treated ptns.

10. • Trepostinil:
• Administration: IV, SC, Oral
• Dose similar to Epoprostenol
• Was studied in the largest worldwide RCT preformed in PAH, showed
improved exercise capacity and symptoms.
• Approved for WHO Class 3 and 4 PAH
• Oral approved for WHO Class 1 PAH
• Main advantage of less frequent administration than other prostacyclins

11. Cont by Dr Govind Singh

12. Endothelial Receptor Antagonists:
• Endothelin-1 (ET-1) is secreted by endothelial cells & promotes
vasoconstriction and modulates the proliferation of vascular smooth muscle
and endothelial cells. ET-1 is overexpressed in the vasculature of patients with
various forms of PAH
• Endothelin receptor antagonist (ERA); prevents binding of endothelin
(ET)-1 to both ET-A and ET-B receptors with high affinity to ET
receptors in pulmonary arterial smooth muscle cells
• Three ERA’s have been approved Bosentan, Ambrisentan, Macitentan
• Contraindicated in pregnant females

13. • Bosentan:
• Received FDA approval in 2001
• Bosentan therapy is initiated at 62.5 mg orally twice daily and, if liver function
remains normal, increased after 1 month to 125 mg twice daily.
• Liver function must be monitored monthly as significant elevations may occur
• Side effects: peripheral edema, anemia, and nasal congestion.
• Bosentan is contraindicated with either cyclosporine or glyburide

14. • Ambrisentan:
• Ambrisentan is a relatively ETA-selective antagonist
• 5 and 10 mg daily of ambrisentan for 12 weeks resulted in placebo-corrected
improvements in 6-minute walk distance of 31 and 51 m, respectively, in one
trial, and 32 and 59 m with 2.5 and 5 mg treatments, respectively, in the other
trial
• Approved for WHO-FC II and III PAH ptns.

15. • Macitentan
• In October 2013, oral macitentan received its first global approval in the US
for the treatment of pulmonary arterial hypertension (PAH)
• 10 mg OD dose in PAH
• Approved for use in WHO 1 and 4 PAH patients

16. PHOSPHODIESTERASE TYPE-5 INHIBITORS
• There is relative deficiency of NO-mediated vasodilation and modulation of
cell growth in patients with PAH
• NO acts through the second messenger cGMP, which is metabolized in the
lung predominantly by phosphodiesterase 5.
• PDE-5 inhibitors work by inhibition of cGMP-degrading enzyme
phosphodiesterase type-5 through NO/cGMP pathway. Also has
antiproliferative effects.

17. • In a double-blind, randomized placebo-controlled trial of 267 patients
predominantly with IPAH but also some with congenital heart or collagen
vascular disease, sildenafil administered orally at 20, 40, or 80 mg three
times daily improved hemodynamics, exercise capacity, and functional class
• Common side effects of phosphodiesterase type 5 inhibitors when used to
treat PAH are headache, flushing, diarrhea, epistaxis, and myalgias.

18. • Sildenafil:
• Orally active, potent inhibitor.
• Favorable effects in IPAH, PAH associated with CTD,CHD,CTEPH, was shown in
uncontrolled studies
• U.S. FDA and European Medicines Association approved dosage is 20 mg
three times daily

19. • Tadalafil:
• Tadalafil (Adcirca) was approved in 2009 based on the PHIRST trial
• Tadalafil 40 mg led to improvement in exercise capacity, quality of life,
hemodynamics, and time to clinical worsening
• 40 mg once daily is the recommended dosage

20. SOLUBLE GUANYLYL CYCLASE INHIBITOR
• Stimulates soluble guanylate cyclase (sGC), an enzyme in the
cardiopulmonary system and the receptor for nitric oxide (NO)
• NO binds to sGC and catalyzes synthesis of cGMP, which in turn activates
protein kinase G regulation of cytosolic calcium ion concentration; this
cascade changes actin-myosin contractility resulting in vasodilation
• Elicits a dual mode of action; sensitizes sGC to endogenous NO by
stabilizing the NO-sGC binding, and directly stimulates sGC via a different
binding site, independently of NO

21. • Riociguat:
• Approved in Patients with symptomatic PAH -idiopathic, familial, or associated with
connective-tissue disease, congenital heart disease, portal hypertension with liver
cirrhosis, or anorexigen or amphetamine use
• Dosage – 0.5mg to 2.5mg TID
• Side Effects: Headache, Hypotension, Indigestion, Diarrhea, Dizziness, Anemia
• Improvement in the primary end point, change in 6MWD versus placebo at 12 weeks
(PATENT) or 16 weeks (CHEST), and to improvement in a number of secondary end
points including PVR, NT-BNP level, and WHO functional class

22. COMBINATION THERAPY
• Epoprostenol+Bosentan
• 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
excessive capacity.
• Epoprostenol+Sildenafil (267 PAH ptns.) has improved exercise capacity and time
to clinical worsening
• Macitentan + Tadalafil is being studied

23. SURGICAL THERAPY
• Balloon Atrial Septostomy:
• 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.
• Lung Transplantation:
• The worst prognosis is seen in PVOD and pulmonary capillary
haemangiomatosis ptns. should be listed for transplantation at diagnosis.