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Class I: PAH
- Idiopathic vs. Familial
- Associated with connective tissue diseases, Portal HTN, and HIV
- Pulmonary HTN of newborn
- Drug and toxin induced (vasoconstrictors)
- → Fenfluramine
- → Amphetamines/Cocaine
- → Chemotherapy (etoposide, bleomycin)
- Pulmonary venoocclusive disease
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Class II: PH Associated w/Left Heart Disease
- Left ventricular dysfunction (systolic or diastolic)
- Valvular disease
- → Underlying valve disease (HF)
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Class III: PH Associated w/Respiratory Disorders
- COPD
- → Significant COPD, not early stages
- Interstitial lung disease
- Mixed restrictive and obstructive disease
- Sleep-disordered breathing
- Alveolar hypoventilation
- Chronic high altitude exposure
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Class IV: PH Associated w/Chronic Thromboembolism
- Thromboembolic obstruction
- Obstruction of distal arteries
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Class V: PH Resulting from Unclear Multifactorial Mechanisms
- Hematologic
- Systemic
- Metabolic
- Everything else
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PAH Sx
- Exertional dyspnea
- Fatigue
- Weakness
- General exertion intolerance
- Looks like HF, Kidney disease
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PAH Sx of Disease Progression
- Lower extremity edema
- Dyspnea at rest
- Exertional chest pain
- Syncope
- Abdominal distention
- Anorexia
- Profound fatigue (worse RV dysfunction /valvular regurg)
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PAH Signs
- Physical features
- Audible S2 at apex of heart
- Early systolic ejection click
- Midsystolic ejection murmur
- S4 gallop
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PAH Signs of Advanced Disease
- Diastolic murmur (worsening)
- → Pulmonary regurgitation
- → Tricuspid regurgitation
- Hepato-jugular reflux
- Pulsatile liver
- Peripheral edema
- Hypotension/cool extremities
- Diminished pulse pressure
- Cyanosis
- Digital clubbing
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Functional Classification in PH: Class I
- No Sx
- No limitation in ordinary physical activity
- Median survival: 6 years
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Functional Classification in PH: Class II
- Mild Sx
- Slight limitation during ordinary activity
- Comfortable at rest
- Median survival: 6 years
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Functional Classification in PH: Class III
- Marked limitation in activity due to Sx even during less-than-ordinary activity
- Comfortable ONLY at rest
- Median survival: 2.5 years
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Functional Classification in PH: Class IV
- Sx w/any activity, even while at rest
- Severe limitations
- Median survival: 6 months
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Diagnostic Testing
- Right heart catheterization
- → Definitive Gold Standard, invasive test
- Establishes diagnosis of PH
- Evaluates pulmonary vasoreactivity
- Guides therapy
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Vasoreactivity testing
- Identifies candidates for calcium channel blocker (CCBs) therapy
- Use short acting vasodilator during test:
- → Epoprostenol (IV)
- → Nitric oxide (Inhaled)
- → Adenosine (IV)
- Goal: reduction in mPAP of ≥ 10 mmHg to < 40 mmHg without decreasing CO
- → Positive test- can use CCBs
- Do NOT use CCBs if patient does not respond (negative test)
- Contraindications
- → Low systemic blood pressure
- → Low cardiac output (EF, cold extremities)
- → Presence of WHO FC IV symptoms (Stage III, IV)
- Adverse events: Hypotension
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Non-pharmacological Tx (Lifestyle Modifications)
- Low grade aerobic exercise: Walking
- → Improves PH functional class and peak oxygen consumption
- → Does NOT improve hemodynamic abnormalities
- → Helps day to day function
- Avoid high altitudes: Supplemental oxygen on commercial aircraft
- Sodium restricted diet
- → Less than 2400mg/day
- → Can cause right heart failure
- Immunizations
- → Influenza
- → Pneumococcal
- Avoid pregnancy
- → 30-50% maternal mortality
- → Meds increase teratogenicity
- Avoid cold and sinus medications: Vasoconstriction
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Monitoring for PH
- Right heart catheterization
- → “Gold standard” for diagnosis
- → AKA: Swan-ganz catheter or pulmonary catheter (ICU)
- Exercise capacity
- → 6-min walk test every 3-6 mos
- Functional class
- → Every 3 months
- Doppler echocardiography
- → Non-invasive determination of pulmonary pressures
- Serologic markers
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Management of all PH Groups
- Oxygen
- Anticoagulation
- Digoxin
- Diuretics
- Exercise
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Diuretics for PH
- Treat fluid retention
- Decrease hepatic congestion and peripheral edema
- Administer with CAUTION
- → Avoid decreased CO
- → If excessively decrease right and/or left preload
- → Caution in over diuressing them
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Oxygen Therapy for PH
- Continuous oxygen administration (>90%)
- Cornerstone of therapy in Group 3 PH
- → Underlying COPD
- May also benefit other PH groups to relieve hypoxemia
- → Resting
- → Exercise-induced
- → Nocturnal
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Anticoagulation for PH
- ↑ risk for intrapulmonary thrombosis and thromboembolism
- Indicated for:
- → Idiopathic PH
- → Hereditary PAH
- → Drug-induced PH
- → Group 4 PH
- Warfarin (goal INR 1.5-2.5)
- → Blood flow slows down- increases risk of thromboembolism
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Digoxin for PH
- Improves right ventricular EF
- → Increased risk digoxin toxicity
- → Require close monitoring
- Rate control: supraventricular tachycardias
- → Verapamil preferred
- → EXCEPT? LVEF <40% (negative inotropic effects worsening cardiac output)
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Endothelin-1 Pathway in PH
- Excess production of endothelins
- Vasoconstriction
- Proliferation
- Tx: Endothelin-receptor antagonists
- → Bosentan (Tracleer) PO
- → Ambrisentan (Letairis) PO
- → Macitentan (Opsumit) PO
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Nitric Oxide Pathway in PH
- Decreased production of NO
- Vasodilation
- Antiproliferation
- Tx: PDE inhibitors
- → Sildenafil (Revatio, Viagra) PO
- → Tadalafil (Adcirca, Cialis) PO
- → Vardenafil (Staxyn / Levitra)
- → Riociguat (Adempas)
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Prostacyclin Pathway in PH
- Decreased production of prostacyclins
- Vasodilation
- Antiproliferation
- Tx: Prostacyclin derrivatives
- → Epoprostenol (Flolan, Veletri) IV
- → Iloprost (Ventavis) Inhaled
- → Treprostinil
- ¤ (Remodulin, Orenitram) IV, SQ, PO
- ¤ (Tyvaso) Inhaled
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Look at
- Slide 7
- Slide 8
- Slide 25
- Slide 30
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CCB in PH
- WHO FC I to IV (positive vasodilator response)
- Dihidropyridine CCBs preferred
- → Nifedipine (long-acting) 30 mg/day initially
- → Titrate to 240 to 720 mg daily
- → Do NOT use short-acting formulation (profound drops in BP, increases mortality)
- Diltiazem may be used in patients with tachycardia
- → Diltiazem 120 mg/day initially
- → Inhibits myocardial contractility, AV conduction, and HR
- Avoid non-DHP CCBs in LV systolic dysfunction <40%
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Primary Therapy in PH
- PH Class I: Advanced PH Therapy
- PH Class II: Treat underlying HF
- PH Class III: Oxygen
- PH Class IV: Anticoagulation
- PH Class V: Treat underlying PH cause
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Bosentan (Tracleer®)
- Dual endothelin-A (ETA) and endothelin-B (ETB) receptor antagonist
- Delays clinical worsening and improves pulmonary vascular hemodynamics and exercise capacity
- Mortality improved in idiopathic PAH
- Indicated for WHO Functional class II-IV
- Dose: 62.5mg PO BID x 4 weeks, then 125mg PO BID
- Drug Interactions
- → Many DIs, need to screen for DIs
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Macitentan (Opsumit®)
- Dual endothelin-A (ETA) and endothelin-B (ETB) receptor antagonist
- One randomized trial (n=250) showed fewer patients progressed or died on therapy
- Improved exercise capacity and WHO functional class
- Studies not powered to assess mortality benefits
- Indicated for WHO Functional Class II-IV
- Dose: 10 mg PO daily
- Multiple significant drug interactions
- → Substrate of CYP3A4 and CYP2C19
- → DI screening
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Ambrisentan (Letairis®)
- Selective endothelin-A (ETA) receptor antagonist
- Improved exercise capacity, WHO functional class, quality of life, and pulmonary vascular hemodynamics
- Delays disease progression and clinical worsening
- → No mortality benefit
- Recommended for WHO Functional Class II-IV
- Dose
- → Initially 5 mg once daily
- → Increase to 10 mg once daily (if tolerated)
- May be tried in patients with prior asymptomatic liver function abnormalities on bosentan after liver enzymes return to normal (less risk of hepatotoxicity)
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Adverse Effects of ERAs
- Peripheral edema (up to 17%)
- → Manage with diuretics
- → Discontinue, if severe
- Potential serious liver injury
- → Hepatotoxicity
- → Bosentan- monitor LFTs monthly, indefinitely Q4wks
- → Ambrisentan, Macitentan (lesser risk)- LFTs baseline and PRN
- ¤ Less risk of liver toxicity
- Pregnancy category X
- → Teratogenecity
- → Decrease efficacy of oral contraceptives
- Restrictive access programs
- → Bosentan: Tracleer Access Program (TAP)
- → Ambrisentan: Letairis Education and Access Program (LEAP)
- → Macitentan: Risk Evaluation and Mitigation Strategy (REMS)
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Sildenafil (Revatio®)
- Potent and highly specific PDE-5 inhibitor
- → ↑s intracellular concentration of cGMP → vasorelaxation and antiproliferative effects on vascular smooth muscle cells
- → Relaxes pulmonary smooth muscle cells which leads to the dilation of pulmonary arteries
- Improves pulmonary hemodynamics and exercise capacity
- Mortality effects NOT adequately evaluated
- Effective in WHO Functional Class II and III (combo in IV)
- Dose 20 mg TID (higher doses used clinically)
- DI- CI w/nitrates→ Precipitous drop in BP
- ADR- vision changes→ Need to stop medication
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Tadalafil (Adcirca®)
- Improves exercise capacity, time to clinical worsening, and quality of life
- Decreased clinical worsening
- Effective in WHO functional Class II and III (combo in IV)
- Dose: 40 mg oral daily (longer ½ life)
- Adverse Effects: Headache, myalgia, and flushing
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Riociguat (Adempas)
- Indicated in patients with inoperable and persistent chronic thromboembolic PH (CTEPH, group IV PH)
- Guanylate cyclase stimulant
- → Increase sensitivity of soluble guanylate cyclase to nitric oxide (pulmonary vasodilator)
- → Directly stimulate the receptor
- Dose
- → Initial 1 mg oral TID (Max: 2.5 mg oral TID)
- → Initiate at 0.5 mg oral TID (patients intolerance to hypotensive effects)
- → May increase by 0.5 mg oral TID if SBP > 95 mm HG
- → Increase at intervals ≥ 2 weeks
- Dose adjustments
- → Concurrent strong CYP and P-gp inhibitors
- → Smokers: may titrate over max → decrease dose may be necessary in patients who stop smoking during therapy
- → Pulmonary edema: stop if pulmonary veno-occlusive disease
- Pregnancy Category X
- Prescribing and Access Restrictions- Adempas REMs program
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Prostacyclin Pathway
- Relax smooth muscle by increasing intracellular cAMP
- Inhibit platelet aggregation
- Inhibit smooth muscle proliferation
- Inhibit pulmonary vascular remodeling
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Epoprostenol (Flolan, Veletri)
- Considered first line in severe (Class IV PAH)
- Improves hemodynamic parameters, functional capacity, and survival (idiopathic PH)
- Usual starting dose: 2 ng/kg/min
- → Increase by 1 ng/kg/min every 30-60 min until dose-limiting side effects occur (every 1-2 days)
- → Increase to maximum tolerated dose
- → Deliver dose continuously through permanently implanted central venous catheter using portable infusion pump
- Patients develop tolerance keep titrating up
- ADR: Flushing, jaw pain, diarrhea, nausea, rash, headache
- → Keep titrating up until they experience jaw pain
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Treprostinil (Remodulin)
- IV (continuous infusion) or SubQ
- Improve hemodynamic parameters, symptoms, exercise capacity, and possibly survival in group 1 PAH (IV and SubQ- longer ½ life)
- Dose Range: 15-100 ng/kg/min
- → Smaller pump, like an insulin pump
- Dose Adjustment:
- → Hepatic Impairment (mild or moderate)
- → Decrease to 0.625 ng/kg/min SubQ or IV (initially)
- Half-life: 4 hours
- Advantages of IV treprostinil formulation over epoprostenol
- → Option of continuous SubQ delivery
- → Longer half-life
- → No need for refrigeration
- → Patients can be transitioned without loss of efficacy
- Can be offered as first line (over epoprostenol)
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Combination Therapy in PH
- Address the multiple pathophysiologic mechanisms
- → Improvement in hemodynamics
- → Resolution of symptoms
- → Increased exercise capacity
- Simultaneous initiation of two (or more) treatments or by the addition of a second (or third) agent
- Indications
- → signs of right-heart failure
- → 6-minute walk distance <380 m
- → persistent functional class III or IV symptoms despite active treatment
- → Inadequate response to monotherapy
- → WHO functional class IV– prostacyclin Tx
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Surgical Interventions in PH
- “When all else fails…”
- → Atrial Septostomy
- ¤ Increase systemic blood flow
- ¤ Reduces RV preload
- → Lung Transplantation
- → Heart-Lung Transplantation
- ¤ Reserved for medication non-responders
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