Pulmonary Aterial Hypertension Flashcards
Cardiac Anatomy
Normally pressures higher on left side of heart, goes all throughout body; right side just goes to lungs, lower pressure
PAH we’re focused on pulmonary artery –> have elevated pressures in this vessel and the right side of the heart not equipped to pump high pressures
Pulmonary Hypertension
- Pulmonary hypertension is higher than normal blood pressure in the arteries that carry blood away from the heart into the lungs
- Pulmonary Hypertension (PH)
– Mean pulmonary artery pressure (MPAP) ≥ 20 mmHg at rest
– More common - Pulmonary Arterial Hypertension(PAH)
– Progressive disease involving endothelial lung dysfunction –> elevated pulmonary
arterial pressure and pulmonary vascular resistance
– Rare
WHO Classification
Group 1: pulmonary arterial hypertension
causes:
- Unknown (idiopathic) - more common in adults
- Genetic
- Drug and toxin exposure
- Disease associated with PAH: CHD, HIV, connective tissue disorders
treatment:
Medications specifically for treatment of PAH
CCB in responders
Lung transplantation
Hemodynamic definitions
PH: mean pulmonary artery pressure: > 20mmHg
PAH: mean pulmonary artery pressure: > 20mmHg; pulmonary artery wedge pressure: </= 15mmHg; pulmonary vascular resistance: > 2 wood units
Hemodynamic Definitions
- Pulmonary arterial wedge pressure
– Estimates left atrial pressure
– Normal = 4-12 mmHg
– Elevated numbers signal LV failure or mitral stenosis - Pulmonary vascular resistance
– Calculated using formula based on mPAP and PAWP
PAH Epidemiology (Group 1)
- Rare
– 2-7.6 cases per million adults/year
– prevalence 10-26 per one million adults - Variable age @ diagnosis
– Mean 50 ± 14 years
– 4 x more common in women - Underrecognized
– Median 1.1 years to diagnostic right heart catheterization (gold standard for diagnosing)
– 1 in 5 symptomatic > 2 years before diagnosis - Prognosis is poor but improving
- Approx 15% mortality within 1 year * Median survival 6 years
Negative predictors: - Advanced functional class
- Poor exercise capacity
- High right atrial pressure
- Right ventricular dysfunction
- Low cardiac output
Signs & Symptoms
27% reported fatigue
15% reported fainting or light-headedness
22% reported chest pain
86% reported shortness of breath
13% reported palpitations
21% reported edema
frequently misdiagnosed as asthma
Diagnosis
echocardiogram: Useful for evaluating potential causes, RV function, estimating PAP and PVR (ultrasound of heart)
right heart catheterization: Confirms diagnosis and estimates severity; Assess response to pulmonary vasodilators before starting therapy (AVT); acute vasoreactivity test to see if candidates for CCBS
exercise testing: Distance walked in 6 minutes
biomarkers: BNP and NTproBNP
PH Centers
- If PH suspected, guidelines suggest early evaluation at PH Center
- Accreditation for adult and pediatric programs through Pulmonary Hypertension Association
- Access to specialty physicians, allied health, diagnostics, active research program
- Approx. 9 pediatric centers nationwide (Riley = closest)
- IN Adult Centers: St. Vincent, IU Health
Effects of PAH
- Right side of heart has difficulty pumping against high pulmonary pressures
- Leads to right ventricular failure
PAH Disease Progression
Vascular injury: endothelial dysfunction - decrease nitric oxide synthase, decrease prostacyclin production, increase thromboxane production, increase endothelin 1 production
where the drugs act; want to try to slow this vascular injury process
WHO Functional Classes
class 1: Symptom-free when physically active or resting (at risk, don’t receive tx)
class II: Slight limitation of physical activity – ordinary activity may cause symptoms; Comfortable at rest
class III: Marked limitation in physical activity – less than ordinary activity causes symptoms; Comfortable at rest
class IV: Significant symptoms with activity; Symptoms at rest
worse functional class, your mortality is worse
Risk Assessment in PAH
- Stratification in European guidelines based on low (<3%), intermediate-low (2-7%), intermediate-high (9-19%), or high (>20%) risk of 1-year mortality
– Registry data suggest risk model helps predict mortality
– Use additional criteria as needed (age, renal function, comorbidities, etc) - US guidelines focus on WHO functional class, but clinician discretion will shape treatment
Treatment of PAH
- Goals of therapy
– Alleviate symptoms
– Improve quality of life
– Prevent or delay disease progression
– Reduce hospitalization
– Improve survival
Pharmacotherapy
- Calcium channel blockers (CCB)
- Direct pulmonary vasodilator (inhaled nitric oxide - iNO)
- Phosphodiesterase 5 (PDE-5) inhibitors
- Endothelin receptor antagonists (ERAs)
- Prostacyclins (oral, inhaled, parenteral)
- Soluble guanylate cyclase (sGC) stimulator (riociguat)
Things to Remember
- Head-to-head comparisons of therapies still emerging
- Different drugs have different safety profiles/ADRs
- Consider patient values/preferences/goals
- Cost/insurance
rare disease state makes it harder to study
Guideline Recommendation: AVT
acute vasoreactivity testing –> positive responder –> CCB
acute vasoreactivity testing –> negative responder, RV failure, or CCB contraindication –> do not use CCB
Acute Vasoreactivity Test (AVT)
- Done in cath lab during initial hemodynamic evaluation
- Acute response to pulmonary-specific vasodilators predicts response to
calcium channel blockers - Agents used include – Inhaled nitric oxide – IV epoprostenol
- Positive test = drop in mPAP > 10 mmHg w/PAP less than 40 mmHg w/stable-improved cardiac output
Calcium Channel Blockers
- Only 5-8% of patients are responders; long-term response is rare
- Consider CCBs in positive responders without right-sided failure or other
contraindication to CCB; do not use w/out positive AVT - Recommended drugs
– Long-acting nifedipine 120-240 mg daily – Long-acting diltiazem 240-720 mg daily – Amlodipine 20 mg daily - NO verapamil due to negative inotropic effects
- If patients do not improve to functional class I or II after CCB initiation,
start additional or alternative PAH therapy
Guideline Recommendation: WHO FC I
treatment naive PAH patients w/ WHO FC I –> continued monitoring for disease progression –> determine when to start therapy
* PAH FC I patients do not necessarily require immediate drug therapy; consider CCB if responder
* Monitor closely and consider initiation if worsening symptoms (dyspnea on exertion, fatigue, weakness) or concern for disease progression
Guideline Recommendation: WHO FC II
treatment naive PAH with WHO FC II –> tolerate combo therapy –> yes: combo treatment –> ambrisentan + tadalafil
treatment naive PAH with WHO FC II –> tolerate combo therapy –> no: monotherapy –> ERA, riociguat, or PDE-5 inhibitor
* PAH FC II patients who fail/are not candidates for CCBs should receive targeted PAH therapy
* Combination therapy may increase costs and risk of ADRs – Some patients may prefer to start with monotherapy
– May have comorbidities that require caution
Guideline Recommendation: WHO FC III
treatment naive PAH with WHO FC III w/o rapid progression or poor prognosis –> tolerate combo therapy? –> yes: combo therapy –> ambrisentan + tadalafil
treatment naive PAH with WHO FC III w/o rapid progression or poor prognosis –> tolerate combo therapy? –> no: monotherapy –> ERA, riociguat, or PDE-5 inhibitor
Therapeutic Pathways
nitric oxide pathway
endothelin pathway
prostacyclin pathway
Nitric Oxide Pathway
- PDE-5 Inhibitors: sildenafil, tadalafil
- Soluble Guanylate Cyclase Stimulator: riociguat
Endothelin Pathway
Endothelin Receptor Antagonists
* Bosentan
* Ambrisentan
* Macitentan
Prostacyclin Pathway
- Prostacyclins: epoprostenol (IV), iloprost (inh), treprostinil (IV, SQ, inh, oral)
- IP prostacyclin receptor agonist: selexipag
Phosphodiesterase Inhibitors
- PDE-5 inhibition
– Decreases conversion of cGMP to GMP
– Increased levels of cGMP –> pulmonary vasodilation - Sildenafil and tadalafil: Improved 6MWD, functional capacity
- May be used as monotherapy or in combination with other classes
- Considered first line in many cases – FC II, FC III without rapid progression
- May require specialty pharmacy (cost)
PDE-5 Inhibitors
MOA: block PDE-5 –> increase cGMP –> muscle relaxation, vasodilation
sildenafil: TID
tadalafil: daily
avoid use with riociguat or nitrates (hypotension); substrate: CYP3A4
ADRs: Flushing, headache, dyspepsia, visual disturbances (blue-tinged vision), priapism, tinnitus/hearing loss, sudden vision loss, hypotension
IV sildenafil
- Available but rarely used
- Restricted for patients who are strictly NPO
- Dosing differs from oral
- $$$
- Must be given as slow infusion to avoid hypotension
Endothelin Receptor Antagonists
- ET receptors on vascular smooth muscle mediate vasoconstriction
– Overexpression of ET-1 in PH patients, correlates with remodeling
– Blocking ET –> vasodilation - Option in Class II-IV
– Tadalafil + ambrisentan combo first line for Class II and Class III without rapid progression - Improve 6MWD, pro-BNP, delay time to clinical worsening, optimize hemodynamics
Receptor Subtypes: A vs B
- ETA receptors
– Located on pulmonary smooth muscle walls
– Promote vasoconstriction, proliferation, and inflammation - ETB receptors
– Receptors on endothelium: Promote vasodilation, stimulate NO and
– Receptors on muscle cells of vascular walls: Cause vasoconstriction and cell proliferation - In PAH, expression of ETB receptors is upregulated in the media of blood vessels (vasoconstriction)
- Ambrisentan = selective for ETA (may cause worse edema) and bosentan/macitentan = mixed
- Unclear how selectivity impacts clinical outcomes
Endothelin Receptor Antagonists Medications
MOA: Block endothelin receptors on vascular smooth muscle –> reduced vasoconstriction/cell proliferation
bosentan: BID; interactions with CYP2C9/3A4; most toxic, highest risk of hepatic dysfunction
ambrisentan: daily; interaction with CYP3A4
macitentan: daily; interaction with CYP3A4
all highly protein bound
ERA Adverse Events
peripheral edema, LFT abnormalities, anemia (tx discontinuation/transfusion not typically necessary)
bosentan black box warning: embryo-fetal toxicity, hepatotoxicity
ambrisentan + macitentan black box warning: embryo-fetal toxicity
REMS program for bosentan: reproductive harm and hepatoxicity
REMS program for ambrisentan + macitentan: reproductive harm
avoid use in hepatic impairment, do not initiate if LFT > 3x ULN
ERA Required Monitoring
pregnancy test monthly
LFTS (except ambrisentan)
hemoglobin
Clinical Effects of ERAs
- Improve
– exercise capacity (6MWD)
– functional capacity
– hemodynamic parameters
– time to clinical worsening
– WHO FC - Note: Improvement not likely seen for 8-10 weeks
Soluble Guanylate Cyclase Stimulator
- Riociguat (Adempas®) is currently only drug in class
- May be used as alternative to PDE-5i
– Cannot be used in combination with tadalafil or sildenafil due to risk of hypotension - Demonstrate antiproliferative and antiremodeling activity in animal models
- Improves exercise capacity, WHO FC, and time to clinical worsening
AMBITION
- 500 treatment-naïve patients with FC II or III PAH
- Randomized 2:1:1
– 10 mg ambrisentan daily + 40 mg tadalafil daily
– 10 mg ambrisentan + placebo
– 40 mg tadalafil + placebo - Primary composite endpoint : Death, hospitalization for PAH (including lung transplant or parenteral prostanoids), disease progression, or unsatisfactory clinical response (assessed by FC/6MWD)
AMBITION results
- In combination group, peripheral edema, headache, nasal congestion, dizziness and anemia were more common than either monotherapy group
- Rates of hypotension were similar
- Rate of discontinuation and serious ADRs were similar across all groups
reason why ambrisentan + tadalafil are 1st line; longer time of being event free
TRITON
- Evaluating triple vs dual therapy in newly diagnosed treatment naïve PAH group 1 patients
- N = 247
- Randomized 1:1 to macitentan + tadalafil + selexipag vs placebo
- Primary = 26-week change in PVR – Triple therapy = 54% decrease
– Dual therapy = 52% decrease
– 95% CI: 0.86-1.07, p = 0.42
no difference b/w these 2 groups
Guideline Recommendation: WHO FC III
WHO FC III WITH rapid progression or poor prognosis –> Candidate for parenteral prostanoids? –> yes –> SC treprostinil, IV treprostinil, IV epoprostenol
WHO FC III WITH rapid progression or poor prognosis –> Candidate for parenteral prostanoids? –> no –> Consider inhaled or oral prostanoid (likely in combo w/ERA + PDE- 5i)
Guideline Recommendation: WHO FC IV
WHO FC IV –> Candidate for parenteral prostanoids? –> yes –> SC treprostinil, IV treprostinil, IV epoprostenol
WHO FC IV –> Candidate for parenteral prostanoids? –> no –> Inhaled prostanoid + ERA + PDE-5i
Prostacyclins
- Prostacyclins stimulate the cAMP pathway to increase pulmonary vasodilation
- Parenteral prostacyclins = standard for severe PH with RV failure
– subQ treprostinil is becoming most common - Available in parenteral (IV + subQ), oral and inhaled formulations
- Reserved for WHO Class III and IV patients
– Class II or low-risk Class III: optimize oral therapy
– Parenteral: first-line if Class IV or rapidly progressing Class III - Improve symptoms, 6MWD, hemodynamics, mortality?
- May be used in combination with ERA plus PDE-5 or riociguat
- Do not use oral, inhaled and parenteral concurrently
Prostacyclins Medication
MOA: Induce vasodilation in all vascular beds, inhibits platelet aggregation, cytoprotective and antiproliferative effect
ADRs: Headache, jaw pain, limb pain, flushing/skin rash, diarrhea, nausea/vomiting, thrombocytopenia (more in epoprostenol) hypotension
Oral: diarrhea, anemia
Inhaled: cough, throat irritation
IV: line infections, erythema
subQ: site pain, infusion site rxns
Prostacyclins: Oral
- Option for patients w/ indication for prostacyclin who refuse or cannot manage parenteral therapy
treprostinil - BID; if more than 2 doses missed, must re-titrate
selexipag - titrate to max tolerated dose (max dose = 1600 mcg BID); therapy interruption more than 3 days requires re-titration; contraindicated with CYP2C8 inhibitors
Prostacyclins: Inhaled
- Option for patients w/ indication for prostacyclin who refuse or cannot manage parenteral therapy
iloprost - daily; requires up to 9 doses daily
treprostinil - QID
Treprostinil inhaled
- Tyvaso more common due to less frequent dosing
- New device can be charged (vs always plugged in)
- Assembling device is complicated and done once every day
- Treatments throughout the day are 2-3 minutes
Prostacyclin: Treprostinil IV/SQ
- Treprostinil (Remodulin®) 1-3 ng/kg/min IV or subQ (continuous), titrated as tolerated, max dose varies
– t1⁄2: 4 hours
– Start in hospital and titrate Q8-12 hours to ~20 ng/kg/min then weekly at home by ~2 ng/kg/min increments up to goal dose (usually 50-80 ng/kg/min) - IV infusion requires stable access, do not co-infuse with anything else; risk of line infection with continuous IV
- SQ/IV dosing is the same
Prostacyclin: SubQ vs IV Treprostinil
- IV is reserved for patients who cannot tolerate subQ
- SubQ avoids risk of central lines (including associated infections)
- May have infusion-site reactions with subQ (may treat with antihistamines, topical agents)
– Some patients do not tolerate and must be converted to IV - SubQ administration typically utilizes undiluted drug; IV must be prepared with diluent into cassettes
- SubQ pums are smaller and more portable
Prostacyclin: Epoprostenol IV
- Epoprostenol 1-3 ng/kg/min IV (continuous), titrated as t1⁄2: 3- 5 minutes
– Must always have back-up cassette prepared
– Abrupt D/C may precipitate PH crisis - Flolan®: non-thermostable product
- Veletri®: thermostable product
- Startinhospital,titratetoeffect
- Requires permanent, stable IV access (no subQ)
- Incompatible with everything – DO NOT co-administer any other fluids - could cause profound hypertension
– Inadvertent bolus can lead to CV collapse and death - Used less often than treprostinil
PGI2 Analogs: Key Information
- Prostacyclin therapy requires significant education before initiation
- $$$$
- Patients should have their own pumps and supplies
- Interview patient; may need to call specialty pharmacy to confirm – Drug concentration
– Diluent (if IV)
– Dosing weight
– Infusion rate
– Infusion dose
– Last syringe/cassette change
Prostacyclin Medication Errors
- Electronic survey of health providers at pulmonary hypertension centers (n = 95)
– 68% reported serious or potentially serious errors
– 29% reported serious adverse events
– 9 deaths reported - Common reported errors:
– Flushing of line(33%)
– Calculation or concentration error(31%)
– Programming error(25%)
– Pump turned off(25%)
– Inappropriate change in weight(3%)
Guideline Recommendation: Disease Progression
- Expert consultation likely needed
- For patients who do not respond to initial therapy (monotherapy
or combination), consider adding on a second or third class
– Ex: Add on ERA if on PDE-5i, or add inhaled prostacyclin if already on ERA and PDE-5i - For FC III and FC IV patients with inadequate response to maximal pharmacotherapy, consider lung transplantation
Pharmacotherapy
- Guidelines provide algorithm but based largely on expert opinion
– Incorporate patient specific factors and preferences when
appropriate
– Evaluation of disease severity, medication costs, patient preference
– Compliance can be challenging and have clinical consequences
*Therapeutic escalation, rebound symptoms, clinical worsening, hospitalization, death
Adjunct Therapy
- Treat underlying/contributing conditions like hypertension/sleep apnea
- Anticoagulation
– May consider anticoagulation or antiplatelet therapy depending on
cardiac function
*Warfarin: INR goal 1.5-2.5 - don’t do if on prostacyclin
*Aspirin 81 mg daily - Diuretics to maintain euvolemia
Supportive Therapy
- Immunizations
– Influenza
– Pneumococcal
– SARS-CoV-2 - new RSV immunizations
- Supplemental oxygen (pulmonary vasodilation)
- Iron supplementation if deficiency
- Avoid air travel/high altitudes if possible (altitude may effect ability to keep O2 saturations up)
– May need supplemental O2 to keep saturations >91% - Consider pulmonary rehabilitation/supervised exercise program
- Avoid non-essential surgical intervention
- Palliative care consultation
Pregnancy Considerations
- Avoid pregnancy
– Estrogen-containing contraceptives may increase VTE risk
– Bosentan can decrease efficacy
– ERAs (bosentan, ambrisentan, macitentan) and riociguat category X
*REMS programs for distribution
*Specialty pharmacies and provider enrollment
*Monthly pregnancy tests
*“Highly reliable” contraception required - If pregnancy occurs, should be cared for at PAH center
ERAs contraindicated
