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Pulmonary Arterial Hypertension in Rural Communities: Early Diagnosis and Intervention to Improve Outcomes

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Pulmonary Arterial Hypertension in Rural Communities: Early Diagnosis and Intervention to Improve Outcomes

Learning Objectives
-Identify the signs, symptoms, and risk factors associated with PAH to facilitate timely referral of patients to specialized pulmonary hypertension centers for early diagnosis and treatment
-Explain the WHO PH Groups and functional status classifications for PAH and their impact on treatment selection
-Outline the diagnostic tests that may be used to identify patients with PAH
-Identify the indications and contraindications for currently available therapies used in the treatment of patients with PAH
-Describe the role of PCPs in managing PAH patients

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Pulmonary Arterial Hypertension in Rural Communities: Early Diagnosis and Intervention to Improve Outcomes

  1. 1. Pulmonary Arterial Hypertension in Rural Communities: Early Diagnosis and Intervention to Improve Outcomes
  2. 2. • Jointly sponsored by Postgraduate Institute for Medicine and Horizon CME • Postgraduate Institute for Medicine designates this activity for – A maximum of 1 AMA PRA Category 1 Credits™ for physicians • This activity was supported by an independent educational grant from Actelion • Disclosures and conflicts of interest for content development faculty, speakers, and independent clinical reviewers are listed in your handouts Activity Overview
  3. 3. • Identify the signs, symptoms, and risk factors associated with PAH to facilitate timely referral of patients to specialized pulmonary hypertension centers for early diagnosis and treatment • Explain the WHO PH Groups and functional status classifications for PAH and their impact on treatment selection • Outline the diagnostic tests that may be used to identify patients with PAH • Identify the indications and contraindications for currently available therapies used in the treatment of patients with PAH • Describe the role of PCPs in managing PAH patients Objectives
  4. 4. What do you do? • 54 year old female with fatigue, dizziness and shortness of breath x 2-3 years, progressed over the last year • She climbs stairs slowly, trouble walking up grades, pedal edema more than a year • Scleroderma diagnosed 7 years ago • Echo shows normal LV function, RV pressure estimated at 80 mmHg; RV dilated, hypofunctional Case Report
  5. 5. mPAP ≥25 mmHg mPAP = mean pulmonary artery pressure; PAWP = pulmonary artery wedge pressure; PVR = pulmonary vascular resistance. Hoeper MM, et al. J Am Coll Cardiol. 2013;62(25 Suppl):D42-50. PAH definition: • mPAP ≥25 mmHg • PAWP ≤15 mmHg • PVR >3 Wood Units •  PAP associated with adverse changes: – in the pulmonary vasculature (vasculopathy), and – at the level of the right ventricle (hypertrophy) • Absence of lung disease, left-sided heart disease Pulmonary Hypertension Pulmonary Hypertension (PAH)
  6. 6. Left-sided heart disease Lung disease/hypoxia Types of Pulmonary Hypertension
  7. 7. Left-sided heart disease Lung disease/hypoxia Types of Pulmonary Hypertension Thromboembolic disease
  8. 8. Left-sided heart disease Lung disease/hypoxia Thromboembolic disease IPAH and APAH Types of Pulmonary Hypertension IPAH = idiopathic pulmonary artery hypertension; APAH = associated pulmonary artery hypertension.
  9. 9. 5th World Symposium on Pulmonary Hypertension Nice, France February 27-March 1, 2013 2013 Updated Clinical Classification of Pulmonary Hypertension (PH)
  10. 10. PH: Diagnostic Classification 1. Pulmonary arterial hypertension (PAH) 1.1. Idiopathic PAH (IPAH) 1.2. Heritable 1.2.1. BMPR2 1.2.2. ALK1, ENG, SMAD9, CAV1, KCNK3 1.2.3. Unknown 1.3. Drug- and toxin-induced 1.4. Associated with 1.4.1. Connective tissue diseases (CTD) 1.4.2. HIV infection 1.4.3. Portal hypertension 1.4.4. Congenital heart diseases 1.4.5. Schistosomiasis 1’ Pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis 1’’ Persistent PH of the newborn 2. PH due to left heart disease 2.1. Left ventricular systolic dysfunction 2.2. Left ventricular diastolic dysfunction 2.3. Valvular disease 2.4. Congenital/acquired left heart inflow/ outflow tract obstruction and congenital cardiomyopathies 3. PH due to lung diseases and/or hypoxemia 3.1. Chronic obstructive pulmonary disease 3.2. Interstitial lung disease 3.3. Other pulmonary diseases with mixed restrictive and obstructive pattern 3.4. Sleep-disordered breathing 3.5. Alveolar hypoventilation disorders 3.6. Chronic exposure to high altitude 3.7. Developmental lung diseases 4. Chronic thromboembolic PH 5. PH with unclear multifactorial mechanisms 5.1. Hematologic disorders: chronic hemolytic anemia, myeloproliferative disorders splenectomy 5.2. Systemic disorders: sarcoidosis, pulmonary histiocytosis: lymphangioleiomyomatosis 5.3. Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders 5.4. Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure, segmental PH Simonneau G, et al. J Am Coll Cardiol. 2013;62(25 Suppl):D34-41.
  11. 11. • Incidence: 1-2 cases per million per year (“epidemic” in the 1990’s) • Female: Male = >3:1 range 2:1 to 9:1) • Average age: 32 years • Symptoms: (~2 years from onset to diagnosis) – dyspnea (60%), – weakness (19%), – recurrent syncope (13%). Idiopathic PAH McGoon MD, et al. J Am Coll Cardiol. 2013;62(25 Suppl):D51-9. Hoeper MM, et al. J Am Coll Cardiol. 2013;62(25 Suppl):D42-50.
  12. 12. • Family history of PAH • Congenital heart disease • Connective tissue diseases (i.e., SSC, SLE) • Drugs and toxins (i.e., aminorex, methamphetamines, fenfluramine) • Human immunodeficiency virus (HIV) • Portal hypertension Risk Factors for PAH SSc = systemic sclerosis; SLE = systemic lupus erythematosus. Morrell NW. F1000 Biol Rep. 2010;2. pii:22. McLaughlin VV, et al. J Am Coll Cardiol. 2009;53(17):1573-1619. Humbert M, Souza R, Simonneau G (eds): Pulmonary Vascular Disorders. Prog Respir Res. Basel, Karger, 2012, vol 41, pp 76-84. Simonneau G, et al. J Am Coll Cardiol. 2013;62(25 Suppl):D34-41.
  13. 13. *Untreated patients; IPAH = idiopathic pulmonary arterial hypertension; NYHA = New York Heart Association. D'Alonzo GE, et al. Ann Intern Med. 1991;115(5):343-9. IPAH Survival According to NYHA Functional Class (NIH Registry – 1980’s Data) NYHA Class Median Survival* I and II 58.6 months III 31.5 months IV 6 months
  14. 14. RHF = right heart failure. Galiè N, et al. Eur Heart J. 2009;30(20):2493-537. WHO Functional Classification of PAH Class Definition I Pts without limitation of physical activity. Ordinary physical activity does not cause undue dyspnoea or fatigue, chest pain, or near syncope. II Pts with slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity causes undue dyspnoea or fatigue, chest pain, or near syncope. III Pts with marked limitation of physical activity. They are comfortable at rest. Less than ordinary activity causes undue dyspnoea or fatigue, chest pain, or near syncope. IV Pts with inability to carry out any physical activity without symptoms. They manifest signs of RHF. Dyspnoea and/or fatigue may even be present at rest. Discomfort is increased by any physical activity.
  15. 15. PH: Diagnostic Classification 1. Pulmonary arterial hypertension (PAH) 1.1. Idiopathic PAH (IPAH) 1.2. Heritable 1.2.1. BMPR2 1.2.2. ALK1, ENG, SMAD9, CAV1, KCNK3 1.2.3. Unknown 1.3. Drug- and toxin-induced 1.4. Associated with 1.4.1. Connective tissue diseases (CTD) 1.4.2. HIV infection 1.4.3. Portal hypertension 1.4.4. Congenital heart diseases 1.4.5. Schistosomiasis 1’ Pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis 1’’ Persistent PH of the newborn 2. PH due to left heart disease 2.1. Left ventricular systolic dysfunction 2.2. Left ventricular diastolic dysfunction 2.3. Valvular disease 2.4. Congenital/acquired left heart inflow/ outflow tract obstruction and congenital cardiomyopathies 3. PH due to lung diseases and/or hypoxemia 3.1. Chronic obstructive pulmonary disease 3.2. Interstitial lung disease 3.3. Other pulmonary diseases with mixed restrictive and obstructive pattern 3.4. Sleep-disordered breathing 3.5. Alveolar hypoventilation disorders 3.6. Chronic exposure to high altitude 3.7. Developmental lung diseases 4. Chronic thromboembolic PH 5. PH with unclear multifactorial mechanisms 5.1. Hematologic disorders: chronic hemolytic anemia, myeloproliferative disorders splenectomy 5.2. Systemic disorders: sarcoidosis, pulmonary histiocytosis: lymphangioleiomyomatosis 5.3. Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders 5.4. Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure, segmental PH Simonneau G, et al. J Am Coll Cardiol. 2013;62(25 Suppl):D34-41. Largest group of associated PAH conditions
  16. 16. Survival Curves of Scleroderma PAH Patients Based on Organ Involvement Condliffe R, et al. Am J Respir Crit Care Med. 2009;179(2):151-7
  17. 17. ATP = adenosine triphosphate; RV = right ventricle. Courtesy of Oudiz RJ. ‘Vasculopathy’ • Leads to reduced blood flow through the lungs • Decreased cardiac output—‘Fixed Stenosis’ • Decreased oxygen to the tissues • Decreased ATP production • Fatigue RV failure—end-stages of PAH PAH Vascular Remodeling
  18. 18. Pathogenesis of PAH HIV = human immunodeficency virus; BMPR2 = bone morphogenetic protein receptor II gene. Gaine S. JAMA. 2000;284(24):3160-8. 1. Risk Factors and Associated Conditions Collagen Vascular Disease Congenital Heart Disease Portal Hypertension HIV Infection Drugs and Toxins Pregnancy Susceptibility Abnormal BMPR2 Gene Other Genetic Factors Normal Reversible Disease Irreversible Disease 2. Vascular Injury Endothelial Dysfunction ↓ Nitric Oxide Synthase ↓ Prostacyclin Production ↑ Thromboxane Production ↑ Endothelin 1 Production Vascular Smooth Muscle Dysfunction Impaired Voltage-Gated Potassium Channel (Kv1.5) 3. Disease Progression Loss of Response to Short-Acting Vasodilator Trial
  19. 19. CO = cardiac output; LV = left ventricle; PBF = pulmonary blood flow. Courtesy of Oudiz RJ. • Patients die of right heart failure. • Volume overload does not cause “CHF” • Volume overload does cause RV overload/ischemia and decreased blood flow (CO) delivered to the lungs (and thus to the LV and to the tissues) PAH Progression Consequences of PAH ↑ PVR ↑ RV afterload ↓ RV ejection (CO) & ↓ PBF RV hypertrophy & dilation Death
  20. 20. Is There a Reason to Suspect PAH? CXR = chest x ray; ECG = electrocardiogram. McGoon M, et al. Chest. 2004;126:14S-34S. • Clinical History – Symptoms, risk factors, family history, exam, CXR, ECG… • Non-specific Symptoms – Dyspnea – 60% of IPAH (NIH Registry) – Fatigue, weakness (reflects impaired O2 transport) – Chest pain, syncope – 40% of IPAH • Symptoms of Related Conditions – CHF, Sleep apnea, arthralgias, arthritis, rash – Liver disease, Appetite suppressant exposure, Deep venous thrombosis or pulmonary embolism, HIV risk factors, Underlying lung disease • Non-specific nature of complaint can lead to: – Confusion with other conditions – Delayed diagnosis
  21. 21. Is There a Reason to Suspect PAH? CXR = chest x ray; ECG = electrocardiogram; BMPR-II = bone morphogenetic protein receptor type II. McGoon M, et al. Chest. 2004;126:14S-34S. • Clinical History – Symptoms, risk factors, family history, exam, CXR, ECG… • Non-specific Symptoms – Dyspnea – 60% of IPAH (NIH Registry) – Fatigue, weakness (reflects impaired O2 transport) – Chest pain, syncope – 40% of IPAH • Symptoms of Related Conditions – CHF, Sleep apnea, arthralgias, arthritis, rash – Liver disease, Appetite suppressant exposure, Deep venous thrombosis or pulmonary embolism, HIV risk factors, Underlying lung disease • Family History: defective BMPR-II gene – 25% of “IPAH”
  22. 22. Is There a Reason to Suspect PAH? McGoon M, et al. Chest. 2004;126:14S-34S. Findings on Physical Examination – Loud pulmonic valve closure (P2) – Right-sided fourth heart sound – Graham-Steele murmur – Jugular venous distention – Right ventricular heave – Peripheral edema, ascites
  23. 23. Bogaard HJ, et al. Chest. 2009;135:794-804. Key Finding in PAH: Right Ventricular Dysfunction A Normal B IPAH RV LV RV LV
  24. 24. Increased Index of Suspicion is a Must • Unexplained dyspnea • Autoimmune disease • History of drug exposure (diet pills, amphetamines) • Family history of PH or PH-like illness Diagnostic Algorithm How Is PAH Diagnosed? McGoon M, et al. Chest. 2004;126:14S-34S.
  25. 25. DLco = diffusing capacity for carbon monoxide. Hoeper MM, et al. J Am Coll Cardiol. 2013;62(25 Suppl):D42-50. NICE PAH Diagnostic Algorithm Echocardiography compatible with PH? Consider most common causes of PH (i.e., left heart disease, lung disease) PH unlikely History, signs, risk factors, ECG, X-ray, PFT incl. DLCO, consider BGA, HR-CT Consider other causes or recheck Diagnosis or heart disease or lung disease confirmed? No signs of severe PH/RV dysfunction Signs of severe PH/RV dysfunction V/Q scintigraphy Unmatched perfusion defects? Treat underlying disease Refer to PH expert center NO YESYES NOYES Symptoms, signs, history suggestive of PAH
  26. 26. Dilated, hypofunctional RV Small, flattened LV Courtesy of Oudiz RJ. Echocardiography in Evaluation of PH
  27. 27. LHD = left-sided heart disease; CHD = coronary heart disease. • Echocardiography is often the 1st window into the discovery of PH • Echo can help diagnose LHD and CHD, and can characterize PH severity • Echo has several limitations: – PH by ECHO does not necessarily = PAH, it is much more likely to be Group 2 or 3 PH – Even with PAH confirmed, beware of the accuracy of your measurements Echocardiography: Points to Remember
  28. 28. DLco = diffusing capacity for carbon monoxide. Hoeper MM, et al. J Am Coll Cardiol. 2013;62(25 Suppl):D42-50. NICE PAH Diagnostic Algorithm REFER! Consider referral to card/pulm specialists Consider most common causes of PH (i.e., left heart disease, lung disease) PH unlikely History, signs, risk factors, ECG, X-ray, PFT incl. DLCO, consider BGA, HR-CT, Polysomnogram Consider other causes or recheck Diagnosis or heart disease or lung disease confirmed? No signs of severe PH/RV dysfunction Signs of severe PH/RV dysfunction V/Q scintigraphy Unmatched perfusion defects? Treat underlying disease Refer to PH expert center NO YESYES NOYES Echocardiography compatible with PH?
  29. 29. Deano RC, et al. JAMA Intern Med. 2013;173(10):887-93. N=141 patients referred over a 10-month period for PH evaluation. 39% of patients initiated on PAH-specific meds prior to referral did not have Group I PAH. Post Referral Diagnosis Group 1 Group 2 Group 3 No PH Unk. Pre- Referral Diagnosis Group 1 41 (73%) 3 (5%) 4 (7%) 7 (12%) 1 (18%) Group 2 0 8 (61%) 1 (8%) 4 (31%) 0 Group 3 4 (17%) 4 (17%) 13 (56%) 2 (9%) 0 Unk. 12 (29%) 13 (31%) 1 (2%) 14 (33%) 2 (5%) The Multicenter RePHerral Study: Referral of Patients with PH Diagnoses to Tertiary PH Centers Incorrect Pre-Referral DiagnosisCorrect Pre-Referral Diagnosis
  30. 30. • “Of the 98 patients who received a definitive diagnosis before referral, 32 (33%) received a misdiagnosis” • “Patients referred to PH centers for diagnosis and treatment are often referred late (with functional class III or IV disease), receive misdiagnoses, and are inappropriately prescribed medications.” RePHerral Study: Findings Deano RC, et al. JAMA Intern Med. 2013;173(10):887-93.
  31. 31. • “High-volume specialized centers have recurrently shown to obtain the best outcomes for patients in different areas of medicine while maintaining greatest patient satisfaction, lowest complication rates, shortest length of hospital stay and best value for healthcare payers.” • It is recommended that PAH patients be referred to expert centers after diagnosis Updated Treatment Algorithm of PAH Referral Centers Galiè N, et al. J Am Coll Cardiol. 2013;62(25 Suppl):D60-72.
  32. 32. Select Criteria for Accredited PH Care Centers http://www.phassociation.org/PHCareCenters/MedicalProfessionals/CenterCriteria. Accessed Oct. 10, 2014. The purpose of the PHA-Accredited Pulmonary Hypertension Care Centers (PHCC) initiative is to establish a program of accredited centers with expertise in PH that aspires to improve overall quality of care and ultimately improve outcomes of patients with PH, particularly PAH, a rare and life-threatening group of disease.
  33. 33. REFER! DLco = diffusing capacity for carbon monoxide. Hoeper MM, et al. J Am Coll Cardiol. 2013;62(25 Suppl):D42-50. NICE PAH Diagnostic Algorithm Echocardiography compatible with PH? Consider most common causes of PH (i.e., left heart disease, lung disease) PH unlikely History, signs, risk factors, ECG, X-ray, PFT incl. DLCO, consider BGA, HR-CT Consider other causes or recheck Diagnosis or heart disease or lung disease confirmed? No signs of severe PH/RV dysfunction Signs of severe PH/RV dysfunction V/Q scintigraphy Unmatched perfusion defects? Treat underlying disease Refer to PH expert center NO YESYES NOYES
  34. 34. NICE PAH Diagnostic Algorithm Hoeper MM, et al. J Am Coll Cardiol. 2013;62(25 Suppl):D42-50. V/Q scintigraphy Unmatched perfusion defects? CTEPH likely CT angiography, RHC plus PA (PEA expert center) RHC PAPm ≥25 mmHg, PAWP ≤15 mmHg, PVR >3 WU PAH likely Specific diagnostic tests Consider other causes PVOD PCH Other (group 57) Idiopathic or Heritable PAH Family history; consider genetic studies (expert centers only) CTD CHD Drugs Toxins Porto- Pulmonary HIV Schisto- somiasis Group 1 PAH YES NO YES NO
  35. 35. V/Q Scan in PH – A Required Screen for CTEPH • CT angiography – Good for acute PE; insensitive for CTEPH • V/Q Scan – Sensitive, less specific  follow-up abnormal test with pulmonary angiography – Consider referral to specialty PH/CTEPH center – In PAH, perfusion images can show mottling; no segmental mismatches should be seen PE = pulmonary embolism; V/Q = ventilation perfusion. McLaughlin VV, et al. J. Am. Coll. Cardiol. 2009;53(17):1573-1619
  36. 36. PFTs in PH- A Required Screen for ILD • Use in combination with history/physical, radiography • % predicted FVC/ % predicted DLco ratio >1.6 or an unexplained decrease in DLco suggests PAH PFTs = pulmonary function test; ILD = interstitial lung disease; FVC = forced vital capacity; DLco = diffusing capacity for carbon monoxide. McLaughlin VV, et al. J Am Coll Cardiol. 20098;53(17):1573-1619.
  37. 37. Cardiac Catheterization The Gold-Standard for PAH Diagnosis McLaughlin VV, et al. J Am Coll Cardiol. 20098;53(17):1573-1619.
  38. 38. • Mean RAP (normal < 6 mmHg) • PAP (normal < 28/12 mmHg) • Mean PAP (normal < 20 mmHg) – PH definition > 25 mmHg • PCWP (normal < 12 mmHg) – PAH allows PCWP < 15 mmHg • Cardiac Output (normal 2.5 - 4.0 l/min/m2) Key Measurements of RHC RHC = right heart catheterization. McLaughlin VV, et al. J Am Coll Cardiol. 20098;53(17):1573-1619.
  39. 39. PH Clinical Follow-up: Routine Measures a. Intervals should to be adjusted to individual patients needs; b. Usually one of the two exercise tests is performed; c. Is recommended; d. Should be performed. RHC = right heart catheterization. Galie N, et al. Eur Heart J. 2009;30:2493-2537. At Baseline (prior to Therapy) Every 3-6 Monthsa 3-4 Months after Initiation or Changes in Therapy In Case of Clinical Worsening Clinical Assessment WHO-FC ECG ✔ ✔ ✔ ✔ 6MWTb ✔ ✔ ✔ ✔ Cardio-Pulmonary Exercise Testingb ✔ ✔ ✔ BNP/NT-proBNP ✔ ✔ ✔ ✔ Echocardiography ✔ ✔ ✔ RHC ✔c ✔d ✔d
  40. 40. Humbert M, et al. Eur Respir Rev Off J Eur Respir Soc. 2012;21(126):306–312. Holliman K. Amercian Coll Physicians ACP Internist. 2013. • An initial suspicion for PH is important for early recognition and intervention. • A thorough workup for common causes of PH is required. • Right heart catheterization is mandatory for making the correct diagnosis. • The management of PH depends on the etiology (Group I, II, III, IV, V). Diagnostic Algorithm for PH Key Points
  41. 41. • Treatment failure is based on a set of goals, rather than a change in one or more measures: – No decrease in 6MW (>380?) – Get to NYHA/WHO FC I or II – Keep the patient out of the hospital – Etc… • “...studies focusing on outcomes have shown that no single test can reliably serve as a long-term prognostic marker and that composite treatment goals are more predictive of long-term outcome.” Treatment Goals in PAH McLaughlin VV, et al. J Am Coll Cardiol. 2013;62(25 Suppl):D73-81.
  42. 42. • Diuretics • Oxygen • Warfarin* • Exercise training PAH Treatment: General Measures and Supportive Therapy *Idiopathic pulmonary artery hypertension only.
  43. 43. • Vasoreactivity is defined as a • Decrease in mPAP of >10 mmHg • To a mPAP of <40 mmHg • With a normal CO in response to IV epoprostenol, IV adenosine or inhaled NO • Calcium Channel Blockers (CCBs) should only be used in “vasoreactive” PAH patients • Clinical response to CCB response must be carefully followed of patients PAH Treatment: Acute Vasoreactivity Testing CCB = calcium channel blocker; CO = cardiac output; RAP = right atrial pressure. McLaughlin VV, et al. J Am Coll Cardiol. 20098;53(17):1573-619. Galiè N, et al. J Am Coll Cardiol. 2013;62(25 Suppl):D60-72. ESC/ERS/ISHLT, Galiè N, et al. Eur Respir J. 2009;34(6):1219-63. DO NOT USE CCBs unless patient is proven to have an acute vasodilator response in at catheterization AND the CO is preserved, with normal RAP. Risks for inappropriate use include syncope, shock, and possibly death
  44. 44. Endothelin pathway Nitric oxide pathway Prostacyclin pathway Humbert M, et al. N Engl J Med. 2004;351:1425-36. 3 Key Signaling Pathways in PAH
  45. 45. 2000 2002 2004 2006 2008 2010 Oral tadalafil and inhaled treprostinil • Epoprostenol approved for APAH • SQ treprostinil and oral bosentan for IPAH & APAH Approval Date 2012 2014 IPAH = idiopathic pulmonary artery hypertension; APAH = associated pulmonary artery hypertension. http://emedicine.medscape.com/article/301450-treatment#aw2aab6b6b4. Accessed October 22, 2014. FDA-Approved Therapies The Evolution of PAH Therapies IV treprostinil & inhaled iloprost Oral sildenafil Oral ambrisentan Oral riociguat and macitentan Oral treprostinil
  46. 46. PAH Specific Agents: Prostacyclin Analogues HA = headache; D = diarrhea; N = nausea; V = vomiting; ER = extended release; PE = pulmonary embolism; Sx = symptoms. AC = anticoagulant. http://emedicine.medscape.com/article/301450-medication#3. Accessed December 21, 2014. http://www.pdr.net/browse-by-drug-name. Accessed December 21, 1014. Epoprostenol Iloprost Treprostinil Route IV Inhalation IV, SQ, inhalation, PO Indication WHO Group I PAH WHO Group I PAH WHO Group I PAH Contraindications CHF or pulmonary edema during initial dose titration None Severe hepatic impairment for ER tablets Side effects Flushing, HA, jaw pain, D, N, V, rash, thrombocytopenia Flushing, cough, hypotension, N, HA, bronchospasm Flushing, headache, nausea, diarrhea, jaw pain, rash Comments AC should be initiated to decrease PE or systemic embolism risk (not guideline based) Hemoptysis has been reported with iloprost use Abrupt withdrawal may worsen PAH Sx, can occur with other agents in this class as well
  47. 47. PAH Specific Agents: Endothelin Antagonists IPF = idopathic pulmonary fibrosis; ALT = alanine transaminase; AST = aspartate transaminase; Hgb = hemoglobin. http://emedicine.medscape.com/article/301450-medication#3. Accessed December 21, 2014. http://www.pdr.net/browse-by-drug-name. Accessed December 21, 1014. Bosentan Ambrisentan Macitentan Route PO PO PO Indication WHO Group I PAH WHO Group I PAH WHO Group I PAH Contraindications Pregnancy Category X Pregnancy Category X, WHO Group 3 PH, IPF Pregnancy Category X Side effects Increased ALT/AST, HA, Nasal congestion, edema, decreased Hgb Increased ALT/AST, edema, HA, nasal congestion, dyspnea, decreased Hgb Increased ALT/AST, nasal congestion, HA, anemia, bronchitis Comments Serum liver enzymes at baseline & then monthly, monthly pregnancy tests Pregnancy test at baseline & then monthly Pregnancy test at baseline & then monthly
  48. 48. PAH Specific Agents: PDE-5 Inhibitors and sGC Stimulators PDE-5 = phosphodiesterase type 5; sGC = soluble guanylate cyclase; NO = nitric oxide. http://emedicine.medscape.com/article/301450-medication#3. Accessed December 21, 2014. http://www.pdr.net/browse-by-drug-name. Accessed December 21, 1014. Sildenafil Tadalafil Riociguat Route PO PO PO Indication WHO Group I PAH WHO Group I PAH WHO Group I PAH, WHO Group 4 PH Contraindications Organic nitrates in any form Organic nitrates in any form Pregnancy Category X Side effects HA, flushing, epistaxis, dyspepsia, insomnia, erythema, diarrhea HA, myalgia, flushing, respiratory tract infection, dyspepsia, nasal congestion HA, dyspepsia and gastritis, dizziness, N, D, V, hypotension Comments Vaso-occlusive crisis (PAH secondary to sickle-cell anemia) CYP3A4 inhibitors may increase drug levels Monthly pregnancy tests and 1 month after discontinuation
  49. 49. Clinical Value of PAH Specific Agents • Prostacyclin analogues, endothelin antagonists, PDE-5 inhibitors, and sGC stimulators – Improve symptoms and exercise capacity – Delay clinical worsening of PAH sGC = soluble guanylate cyclase. McLaughlin VV, et al. J Am Coll Cardiol. 2009;53:1573-1619. Khaybullina D, et al. P T. 2014;39(11):749-58.
  50. 50. Galiè N, et al. Eur Heart J. 2009;30:394-403. Survival with PAH Drugs: Meta Analysis Study ID RR (95% CI) % Weight Rubin et al 0.36 (0.04, 3.00) 5.21 Barst et al 0.06 (0.00, 0.96) 2.92 Badesh et al 0.79 (0.22, 2.77) 17.59 Langleben et al 1.66 (0.07, 39.30) 2.32 Simmoneau et al 2002 0.92 (0.38, 2.21) 29.81 Galiè et al 1.00 (0.06, 15.65) 3.07 Olschewski et al 0.25 (0.03, 2.22) 4.91 Rubin et al 0.24 (0.02, 2.60) 4.08 Barst et al 0.47 (0.04, 5.01) 4.12 Sastry et al 0.39 (0.02, 8.73) 2.42 Barst et al 1.54 (0.06, 37.19) 2.29 Galiè et al 1.01 (0.11, 9.55) 4.60 Galiè et al 0.41 (0.11, 1.49) 13.77 Galiè et al 0.99 (0.06, 15.58) 3.05 Simonneau et al 2008 0.07 (0.00, 1.15) 2.85 Channick et al (Excluded) 0.00 Singh et al (Excluded) 0.00 Galiè et al (Excluded) 0.00 Barst et al (Excluded) 0.00 McLaughlin et al (Excluded) 0.00 Hooper et al (Excluded) 0.00 Overall 0.57 (0.35, 0.93) 100.00 0.01 0.1 0 10 100 Favors Controls Favors Treatments
  51. 51. • Treatment choice may be based on: – Disease severity – Patient preference – Patient feasibility – Clinical trial availability – PAH type? Treatment Approach to PAH
  52. 52. 6-MWD = 6 minute walk distance; PaCO2 = partial pressure of carbon dioxide. McLaughlin VV, et al. J Am Coll Cardiol. 2009;53:1573-1619. PAH Determinants of Patient Risk ACCF/AHA Expert Consensus Low Risk Determinants of Risk High Risk No Clinical evidence of RV failure Yes Gradual Disease progression Rapid II, III WHO functional class IV Longer (>400 meters) 6-MWD Shorter (<300 meters) Peak VO2 >10.4 mL/kg/min Cardiopulmonary exercise testing Peak VO2 <10.4 mL/kg/min Minimally ↑ and stable BNP/NT-proBNP Significantly ↑ PaCO2 >34 mm Hg Blood gasses PaCO2 <30 mm Hg Minimal RV dysfunction ECHO findings MRI Pericardial effusion, RV dysfunction, RA enlargement RAP <10 mm Hg; Cl >2.5 L/min/m2 Hemodynamics RAP >20 mm Hg; Cl <2 L/min/m2
  53. 53. • The relative efficacy of prostacyclins vs ERAs vs PDE-5 inhibitors is poorly described (no head-to- head studies) • Cost considerations have usually taken a back seat in PAH treatment (already changing with generics) • The optimal strategy for initial use is not clear, ie, which drug(s) to use first, when and how to combine, up-front therapy, etc. • There is limited evidence for the use of PAH drugs in patients with multifactorial causes of PH PAH Drugs: Unresolved Issues
  54. 54. • Atrial septostomy • Lung transplantation • Exercise training PAH Non-Medical Treatments:
  55. 55. Christie JD, et al. J Heart Lung Transplant. 2012;31(10):1073-86. 29th Adult Lung Transplant Report – 2012 Half-Life Alpha-1 6.2 Years CF 7.5 Years COPD 5.3 Years IPF 4.4 Years PAH 5.0 Years Sarcoidosis 5.3 Years Alpha-1 (N=2,490) CF (N=5,608) PAH (N=1,308) Sarcoidosis (N=849) IPF (N=7,540) COPD (N=11,948) High Initial Mortality Overall Survival 0 20 80 Survival(%) 100 0 2 4 40 10 60 Years 8 11 14 70 90 30 50 61 3 7 9 135 1210
  56. 56. Christie JD, et al. J Heart Lung Transplant. 2012;31(10):1073-86. 29th Adult Lung Transplant Report – 2012 0 20 80 Survival(%) 100 0 2 4 40 10 60 Years 8 11 14 70 90 30 50 6 Alpha-1 (N=1,860) CF (N=4,217) 1 3 7 9 135 1210 PAH (N=831) Sarcoidosis (N=573) IPF (N=5,079) COPD (N=8,969) Half-Life Alpha-1 8.6 Years CF 10.4 Years COPD 6.8 Years IPF 6.8 Years PAH 10.0 Years Sarcoidosis 8.4 Years All comparisons are statistically significant at 0.05 except Alpha-1 vs Sarcoidosis, CF vs PAH and COPD vs IPF “1-Year” Survivors All made it to 1 year f/u PAH
  57. 57. Mereles D, et al. Circulation. 2006;114(14):1482-9. PAH Rehab in Europe: Exercise and Respiratory Training on 6MW -80 20 170 Changein6-MinuteWalking Distance(m) 220 0 3 15 70 -30 120 Weeks 0 3 15 Secondary Training Group (N=10)Primary Training Group (N=15) Control Group (N=15)
  58. 58. • Low level graded aerobic exercise, such as walking, as tolerated is recommended • Intensive exercise training in one study of 30 stable patients on disease-targeted medical therapy showed improvements in 6MW test, quality of life, functional class, and peak oxygen consumption over 15 weeks • Patients should avoid heavy physical exertion or isometric exercise (straining against a fixed resistance) as this may evoke exertional syncope 2009 ACCF/AHA PH Guidelines General Measures McLaughlin VV, et al. J Am Coll Cardiol. 2009;53(17):1573-619.
  59. 59. • Exercise within symptom limits is recommended • Mild breathlessness is acceptable but exertion that leads to severe breathlessness, exertional dizziness, or chest pain should be avoided • But when physically deconditioned, patients may undertake supervised exercise rehabilitation • More data are required before appropriate recommendations can be made regarding exercise rehabilitation ESC/ERS PH Guidelines Physical Activity and Supervised Rehabilitation ESC/ERS/ISHLT, Galiè N, et al. Eur Respir J. 2009;34(6):1219-63.
  60. 60. PAH Treatment Goals Summary • Traditional surrogate endpoints used in PAH trials have been informative for PAH drug development and approval • Short-term surrogate endpoints may be less informative than longer-term, harder endpoints in predicting outcome • A therapeutic approach using a composite of clinical, laboratory, and functional measures for monitoring progress/worsening of PAH patients is recommended
  61. 61. Role of PCPs in Screening and Diagnosis of PAH Patients Recognize possible PAH in the patient presenting with unexplained dyspnea on exertion Initiate appropriate screening evaluation • Chest X-ray, PFT, ECG, VQ scan, oximetry Facilitate appropriate referral to specialty center • Contact a specialist in pulmonary hypertension • Obtain appropriate referrals and approvals from the patient’s insurer • Provide the patient’s records to the specialty center PCPs = primary care providers. Rubin LJ, Badesch DB. Ann Intern Med. 2005;143:282-292.
  62. 62. Unexplained dyspnea on exertion with evidence of PH on echocardiography Evidence of moderate to severe PAH • Estimated pulmonary arterial systolic pressure 45 mm Hg on echocardiogram • Symptoms consistent with NYHA functional class II • Near-syncope or syncope Absence of substantial left-sided cardiac disease or parenchymal lung disease Clinical or echocardiographic evidence of right ventricular dysfunction • Lower-extremity edema • Ascites • Right ventricular enlargement or systolic dysfunction on echocardiogram Consider Referral to PH Specialty Center… NYHA = New York Heart Association. Rubin LJ, Badesch DB. Ann Intern Med. 2005;143:282-292.
  63. 63. • High-risk patients • Patients with NYHA/WHO class IV symptoms • NYHA/WHO class III patients with worsening or not responding to initial treatment • Patients with concomitant/comorbid conditions that complicate treatment • Patients with pulmonary hypertension of unclear etiology • Lack of clinical experience in providing initial or long-term management of patients with pulmonary hypertension Consider Referral to PH Specialty Center…
  64. 64. Role of PCPs in the Co-Management of PAH Patients Provide regular follow-up in the patient’s local community • Assess volume status, vital signs, and oxygenation • Monitor laboratory test results, including serum electrolyte levels, renal function, and results of liver function tests • Manage low-dose anticoagulation with warfarin, if indicated • Maintain close communication with PH referral center • Manage co-morbidities such as renal dysfunction, sleep issues, endocrinopathies, and anemia • Survey for catheter-related blood stream infections Provide emergency care in the patient’s local community Rubin LJ, Badesch DB. Ann Intern Med. 2005;143:282-292.
  65. 65. • Timely referral and diagnosis of PAH is essential for optimal outcomes • Proper classification of PH is essential before considering treatment; the management is dependent on the etiology • >10 treatments for PAH targeting 3 molecular pathways are available in oral, inhaled, and parenteral form • The evidence base is limited for informing us on the optimal treatment strategy of PAH; combining PAH drugs / knowing what to use first is only recently better understood; how to handle co-morbidities and the importance of modulating pulmonary hemodynamics is still challenging • PCPs play an important role in early identification, referral, and co-management of PAH patients Conclusions

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