Pulmonary Hypertension A-Z

Transcription

1 Pulmonary Hypertension A-Z Lana Melendres-Groves UNM Pulmonary Hypertension Program Director Assistant Professor of Medicine Pulmonary/Critical Care Division 9/17/16

2 Disclosures Advisory board member Actelion Pharm, Bayer Pharm. Speaker for Actelion Pharm, Gilead Pharm, and Bayer Pharm on PH disease state.

3 Objectives Define Pulmonary Hypertension (PH) and Pulmonary Arterial Hypertension (PAH) Discuss Appropriate Diagnosis and Classification System of PH Describe the pathophysiology/pathobiology of PAH Discuss detection and diagnosis of PH and PAH Discuss PAH specific medical therapies

4 Pulmonary Hypertension PH refers to the presence of abnormally high pulmonary vascular pressure

5 Pulmonary Arterial Hypertension PAH is a syndrome resulting from restricted blood flow in the pulmonary arterial circulation resulting in increased pulmonary vascular resistance leading to right ventricular strain and ultimately right heart failure and death.

6 WHO Classification System for PH Group 1: Pulmonary Arterial Hypertension (PAH) Group 2: PH due to left heart disease Group 3: PH due to lung disease and/or hypoxia Group 4: Chronic thromboembolic pulmonary hypertension Group 5: PH with unclear multifactorial mechanisms

7 Clinical Classification of Pulmonary Hypertension (NICE, 2013) 1. Pulmonary arterial hypertension (PAH) 1.1 Idiopathic PAH (IPAH) 1.2 Heritable PAH 1.3 Drug- and toxin-induced PAH 1.4 Associated PAH Connective tissue disease HIV infection Portal hypertension Congenital heart disease Schistosomiasis 1. Pulmonary veno-occlusive disease (PVOD) and/or pulmonary capillary hemagiomatosis (PGH) 1. Persistent pulmonary hypertension of the newborn (PPHN) 2. PH due to left heart disease 2.1 LV systolic dysfunction 2.2 LV diastolic dysfunction 2.3 Valvular disease 2.4 Congenital/acquired left heart inflow/outflow tract obstruction and congenital cardiomyopathies 3. PH due to lung disease and/or hypoxia 3.1 COPD 3.2 Interstitial lung disease 3.3 Other pulmonary disease with mixed restrictive and obstructive pattern 3.4 Sleep-disordered breathing 3.5 Alveolar hypoventilation disorders 3.6 Chronic exposure to high altitude 4. Chronic thromboembolic hypertension (CTEPH) 5. PH with unclear multifactorial mechanisms 5.1 Hematologic disorders 5.2 Systemic disorders 5.3 Metabolic disorders 5.4 Others Simonneau G, et al. J AmColl Cardiol. 2013;62(25, suppl D);D34-D41

8 Hemodynamic Classification of PH (mean PAP >25 mm Hg) Post-capillary PH VC RA RV PA PV PC LA LV Ao Mixed PH Pre-capillary PH High-flow PH (O2 sat run) Diagram courtesy of Teresa De Marco, MD, UCSF

9 Hemodynamic Classification of PH (mean PAP >25 mm Hg) Post-capillary PH PCWP>15 mm Hg; PVR normal VC RA RV PA PV PC LA LV Ao PVP LAP LVEDP Diagram courtesy of Teresa De Marco, MD

10 Hemodynamic Classification of PH (mean PAP >25 mm Hg) Post-capillary PH PCWP>15 mm Hg; PVR normal MR VC RA RV PA PV PC Diagram courtesy of Teresa De Marco, MD PVP LA LAP LV LVEDP Myocardial Disease Dilated CMP-ischemic/non-ischemic Hypertrophic CMP Restrictive/infiltrative CMP Obesity related CMP Pericardial disease Ao Systemic HTN AoV disease

11 Hemodynamic Classification of PH (mean PAP >25 mm Hg) Post-capillary PH PCWP>15 mm Hg; PVR normal VC RA RV PA PV PC PVP LA LV Ao PV Compression Diagram courtesy of Teresa De Marco, MD

12 Hemodynamic Classification of PH (mean PAP >25 mm Hg) PAH Lung diseases +/- hypoxemia CTEPH { VC RA RV PA PV PC { LA LV Ao Pre-capillary PH PCWP <15 mm Hg; PVR >3 woods units Diagram courtesy of Teresa De Marco, MD

13 The Impact of a PH Diagnosis WHO Group 1 PAH Based on a sample of 194 patients followed between 1981 and 1986, median survival was estimated at 2.8 years (IPAH) WHO Group 2 Left-heart related In a study of 379 patients referred to a single center between 1992 and 1998, patients with Group 2 PH had 7x higher mortality than left-sided heart failure alone WHO Group 3 Lung/hypoxia 5-year related survival rate in study of 84 COPD patients was 36% in those with PH vs 62% in those without PH In a study of 79 IPF patients, the 6.5- year survival rate was 40% when PH was present vs 70% in patients with IPF alone WHO Group 4 CTEPH Mean survival 6.8 years without surgical treatment in a study of 48 Japanese patients

14 Question 1 A 72 year old man with a history of coronary artery disease, hypertension, and hyperlipidemia presents to his cardiologist for routine follow-up. He indicates that he has not been as faithful with his diuretics over the past several weeks because it makes him have to use the bathroom too often. He also has had some worsening chest pressure with exertion. His cardiologist obtains an echocardiogram which shows an enlarged right ventricle and a pulmonary artery systolic pressure of 65mmHg. He has a moderately enlarged right and left atrium. The patient is sent for a right and left heart catheterization which shows:

15 Question 1 A mean pulmonary artery pressure (PAP) of 40mmHg, pulmonary capillary wedge pressure (PCWP) of 28mmHg, and a pulmonary vascular resistance of 2.7 woods units. Coronaries show non-obstructive disease. What is the best treatment for our patient? A. Improve compliance with his diuretic therapy B. Start him on a calcium channel blocker C. Begin a phosphodiesterase type-5 inhibitor D. Refer him to cardiothoracic surgery for evaluation E. Refer him to hospice

16 Question 1 A mean pulmonary artery pressure (PAP) of 40mmHg, pulmonary capillary wedge pressure (PCWP) of 28mmHg, and a pulmonary vascular resistance of 2.7 woods units. Coronaries show non-obstructive disease. What is the best treatment for our patient? A. Improve compliance with his diuretic therapy B. Start him on a calcium channel blocker C. Begin a phosphodiesterase type-5 inhibitor D. Refer him to cardiothoracic surgery for evaluation E. Refer him to hospice

17 Answer: A A. Improved compliance with his diuretic therapy The patient has evidence of elevated left heart pressures with a wedge pressure of 28mmHg. He hasn t been using his diuretics as prescribed and as such is in decompensated heart failure. He would be classified into WHO group 2 pulmonary hypertension (as are 80% of patients with pulmonary hypertension) owing to left heart dysfunction. He will need optimization of his fluid status. He has no increased pulmonary vascular resistance to indicate pulmonary vascular disease.

18 Rationale for Incorrect Answers A calcium channel blocker would be indicated in a patient with pulmonary arterial hypertension (WHO group 1) who are vasoresponsive on right heart catheterization. This patient is not WHO group 1. A PDE5I are indicated in WHO group 1 not for WHO group 2. He has no evidence of obstructive coronary disease and is just decompensated no surgical intervention would be useful at this point. Referral to hospice would be inappropriate at this time

19 Pulmonary Arterial Hypertension A further look into WHO Group 1

20 Epidemiology of PAH PAH is a progress fatal disease with an incidence of 2 new cases per million people each year 1 Prevalence is approximately cases per million people based on the French 2 and REVEAL 1 registries Primarily female predominance (78% in REVEAL) 1 Mean age at diagnosis 47 years 1 1. Frost AE, et al. Chest. 2011;139(1): ; 2. Humbert M et al. Am J Respir Crit Care Med 2006; 173:

21 Distribution of PAH Subtypes French Registry (n=674) IPAH 39.2% FPAH 3.9% CTD 15.3% CHD 11.3% Portal htn 10.4% Drugs and toxins 9.5% HIV 6.2% REVEAL (n=2525) IPAH 46.2% APAH 50.7% CTD/CVD 49.9% CHD 19.5% Drugs and toxins 10.5% Portal htn 10.6% Other 5.5% HIV 4.0% FPAH 2.7% Other 0.4%

22 Prevalence of PAH in Connective Tissue Diseases SLE MCTD Systemic lupus erythematosis (SLE): 0.5% to 17% Mixed Connective tissue disease (MCTD): up to 25% Systemic Sclerosis Systemic Sclerosis: 8% to 27%

23 PAH Associated with Drugs and Toxins Definite - Aminorex - Fenfluramine - Dexfenfluramine - Toxic rapeseed oil - Benfluorex - SSRIs Likely - Amphetamines - L-tryptophan - Methamphetamines - Dasatinib Possible - Cocaine - Phenylpropanolamine - St. John s Wort - Chemotherapeutic agents - Interferon alpha and beta - Amphetamine-like drugs Unlikely - Oral contraceptives - Estrogen - Cigarette smoking

24 Portal Hypertension Prevalence of PAH in portal htn ranges from 2% to 6% Risk of developing PAH increases with duration of portal hypertension Liver disease is most common cause of portal hypertension, but it can be secondary to nonhepatic causes Presence of portopulmonary hypertension may exclude the patient from transplant

25 Question 2 A 38 year old comes to see you in your office because she notes severe and increasing shortness of breath. She denies wheezing. Notably, she weighs 250 pounds and is 5 2 tall. She denies smoking, alcohol ingestion, or illicit drug abuse. She delivered her first child 1 year ago. She has taken diet pills on and off throughout her life and started again after her delivery to lose the weight she gained during her pregnancy. She sleeps through the night and does not have daytime somnolence. Her room air saturation is 98%. Her screening spirometry is normal and chest radiograph shows small lung volumes but otherwise normal.

26 Question 2 The most likely diagnosis is: A. Sleep apnea B. Idiopathic pulmonary fibrosis C. Pulmonary arterial hypertension D. Asthma E. Hypothyroidism

27 Question 2 The most likely diagnosis is: A. Sleep apnea B. Idiopathic pulmonary fibrosis C. Pulmonary arterial hypertension D. Asthma E. Hypothyroidism

28 Answer: C C. Pulmonary arterial hypertension This patient has PAH due to her ingestion of appetite suppressants. She is obese, but does not have symptoms of sleep apnea (no daytime somnolence or problems with sleeping). The patient has a normal room air oxygen saturation and her screening spirometry documents normal volumes, so idiopathic pulmonary fibrosis is not a likely diagnosis. Asthma is unlikely since the patient does not wheeze, and she has normal screening spirometry. Finally, although weight gain can be a sign of hypothyroidism, there are no other indicators of hypothyroidism.

29 Pathogenesis of PAH: Aberrant Pathways

30 Loss of Biological Balance in PAH Vasodilation Apoptosis Vasodilation Apoptosis Vasoconstriction Proliferation Vasoconstriction Proliferation

31 Time to Diagnosis After Symptom Onset months 27 months 33 months Months NIH Registry 2003 French Registry Major PH Registries 2012 REVEAL Registry Humbert M, et al. Am J Respir Crit Care Med 2006; 173: ; Badesch DB, et al. Chest 2010; 137: ; Rich S. Ann Intern Med 1987;107:

32 No further evaluation for PAH Is there a reason to suspect PAH Clinical history (symptoms, risk factors, family Hs.), Exam, CXR, ECG no no yes Is PAH likely? Echo yes Is PAH due to LH disease? Echo no Is PAH due to CHD? Echo with contrast no Is PAH due to CTD, HIV? Serologies Rationale yes yes yes PAH: Detection & Diagnosis TRV to measure RVSP; RVE; RAE; RV Dysfunction: Dx LV systolic, diastolic dysfunction; valvular disease: Appropriate treatment and further evaluation if necessary, including R&LHC Dx abnormal morphology; shunt: Surgery. Medical treatment of PAH or evaluation for further definition or other contributing causes, including R&LHC if necessary Dx Scleroderma, SLE, other CTD, HIV: Medical treatment of PAH and further evaluation for other contributing causes, including RHC no Is chronic PE suspected? VQ scan Screening, Early Detection, and Diagnosis of PAH: ACCP Evidence-Based Clinical Practice Guidelines McGoon et al. Chest 2004;126:14S-34S

33 PAH: Detection and Diagnosis Continued Is chronic PE suspected? VQ scan no VQ normal yes Is chronic PE confirmed and operable? Pulmonary angiogram yes Is PAH due to lung disease or hypoxemia? PFTs, arterial saturation no What limitations are caused by the PAH? Functional class; 6-minute walk test What are the precise pulmonary hemodynamics? RHC McGoon et al. Chest 2004;126:14S-34S no yes Anatomic definition (CT, MRI may provide additional useful but not definitive information): Thromboendarterectomy if appropriate or medical treatment; clotting evaluation; a/c Dx parenchymal lung disease, hypoxemia, or sleep disorder: Medical treatment, oxygen, positive pressure breathing as appropriate, and further evaluation for other contributing causes, including RHC if necessary Document exercise capacity regardless of cause of PH: Establish baseline, prognosis and document progression/ response to treatment with serial reassessments Document PA and RA pressures, PCWP (LV or LA pressure if PCWP unobtainable or uncertain), transpulmonary gradient CO, PVR, SvO 2, response to vasodilators: Confirm PAH, or IPAH if no other cause identified Discuss genetic testing and counseling of IPAH

34 Right Heart Catheterization: Diagnostic Gold Standard Hemodynamics: RAP, mpap, PCWP, CO/CI, PVR Saturations: Rule out shunts Angiography: Vessel properties CTEPH Vasodilator response

35 Survival After Diagnosis Estimated Median Survival (Years) Years 3.9 Years 5.5 Years 7 Years 1980s 1990s 2000s 2010s D'Alonzo GE, et al. Ann Intern Med. 1991:115: ; Thenappan T, et al. Eur Respir J. 2010;35: ; Humbert M, et al. Eur Respir J. 2010;36: ; Benza RL, et al. Chest. 2012;142:

36 Importance of Accurate Diagnosis RePHerral study: Multicenter, descriptive, cross-sectional study Consisting of 140 patients Performed to determine: accuracy of PH diagnoses in patients referred to PH centers frequency of PAH-specific medication use despite an uncertain or incorrect diagnosis. Results indicated that 33% of patients diagnosed with PAH upon referral had an incorrect diagnosis. 42% did not have a confirmatory heart catheterization at the time of referral Deano RC, et al. JAMA Intern Med 2013; 173:

37 Functional Assessment Functional assessment is key to appropriate therapeutic approach WHO functional class (WHO I-IV) The RePHerral study indicated that at the time of referral, more than half of all 140 patients had functional class III and IV disease (62%) REVEAL registry showed a mortality of 50% at 2 years for class IV patients Deano RC, et al. JAMA Intern Med 2013; 173:

38 Treatment Recommendations Despite ongoing updated therapeutic guidelines (most recently from 2015 in ESC/ERS), there is still a substantial problem with inappropriate prescribing of PAH therapies. 57% of the RePHerral study patients who had been prescribed PAH-specific medications prior to referral, showed treatment guidelines had not been adhered to Galiè N, et al. Eur Heart J. 2016; 37:67-119; Galiè N, er al. Eur Respir J., 2015; 46:

39 Treatment Recommendations These guidelines can be difficult to interpret in terms of specific therapeutic approaches; however, even those guidelines which are clear tend to not be upheld Epoprostenol IV/SQ is the only Grade 1A recommendation, functional class IV patients REVEAL registry showed that at time of death for class IV patients, 42% had still not received appropriate therapy Increasing evidence for sequential and dual upfront combination therapy

40 PAH Specific Therapies

41 Introduction of PAH Therapies Conventional therapy Prostanoids introduced ERAs introduced PDE-5is introduced sgc introduced Oral prostanoid analog Continued exploration of new treatment strategies

42 Therapies The only groups that have been approved for the specialized medications for pulmonary hypertension are WHO Group 1 (PAH) and Group 4 (CTEPH) The WHO Group 2, 3, and 5 require treatment of the underlying condition or optimization of that condition

43 FDA Approved PAH Therapies Prostanoid/Prostanoid Analogs Epoprostenol (flolan/veletri) Treprostinil (IV/SQ/Inhaled) Inhaled Iloprost (Ventavis) Oral treprostinil (Orenitram) Selexipag (Uptravi) PDE-5 Inhibitors Sildenafil (Revatio) Tadalafil (Adcirca) ERA s Bosentan (Trecleer) Ambrisentan (Letairs) Macitentan (Opsumit) Soluable Guanylate Cyclase Stimulator Riociguat (Adempas) (Only medication currently approved for the use in CTEPH)

44 Prostanoids Prostacyclin (PGI2)- member of the eicosanoids family, inhibits platelet activation and effective vasodilator. Prostacyclin released by healthy endothelial cells. Deficiency in PAH patients Several routes of administration: IV/parenteral, SQ, Inhaled, oral

45 IV Prostanoids Epoprostenol- Flolan and Veletri Half-life approximately 2-5min Treprostinil- Remodulin Half-life several hours Both administered in ng/kg/min Dosing never changes even if weight does, start weight remains the same throughout duration of therapy.

46 Single Lumen Hickman Catheter Never stop infusion Never draw labs from line Never flush

47 Oral Prostacyclins Treprostinil (Orinetram) Antiplatelet and vasodilatory actions, including pulmonary vasodilation Selexipag (Uptravi) Most recently approved in January 2016 Not a substitute for parenteral therapy Prostacyclin analog

48 Endothelin Receptor Antagonist Endothelian-1 (ET-1) levels are increased in PAH and found in the precapillary pulmonary microvasculature which is the site of the increased vascular resistance in PAH. Bosentan (Tracleer) to 125mg BID Monitor for liver toxicity Ambrisentan (Letairis)- 5-10mg daily Macitentan (Opsumit)- 10mg daily

49 Phosphodiestrase-5 Inhibitors PDE5 Inhibitor- blocks the degradative action of phosphodiesterdase type 5 on cyclic GMP in smooth muscle cells resulting in vasodilation of the vessels. Sildenafil (Revatio) mg TID Tadalafil (Adcirca) mg daily

50 Guanylate Cyclase Stimulator Riociguat (Adempas) has a dual mode of action Synergist with endogenous nitric oxide Directly stimulating guanylate cyclase independent of NO availability FDA approved for both use in PAH as well as inoperable or residual CTEPH

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54 Ongoing Management Standard of care is for PAH patients to be established with a PH Care Center Multidisciplinary approach to care PHA initiative to standardized care through CCC and RCC Patients on advance therapies to be seen every 3 months if not more frequently Ongoing escalation of care, more evidence coming out showing the importance of combination therapies upfront.

55 Discussion PH is an umbrella term that encompasses a multitude of disease processes. Simply a hemodynamic definition The pathobiology for PAH is the same no matter the underlying etiology: 3 pathways Classification of PH includes 5 WHO groups PH is screened with an echo and diagnosed with RHC Management is multifactorial and requires a multidisciplinary approach to care.

56 Questions?