PULMONARY HYPERTENSION For Cardiologists

Transcription

1 PULMONARY HYPERTENSION For Cardiologists

2 Pulmonary Hypertension Classification

3 Pulmonary Hypertension General Definition Resting Systolic PAP Resting Diastolic PAP Resting Mean PAP > 35mmHg > 15mmHg > 25mmHg Pulmonary Arterial Hypertension PCWP, LAP, LVEDP Pulmonary Arteriolar Resistance < 15mmHg > 3 Wood Units (> 240 dyn s/cm 5 )

4 Pulmonary Hypertension Pulmonary Arterial Hypertension Pre-capillary High PVR, High TPG Pulmonary Venous Hypertension Post-capillary Normal TPG Hyperdynamic Pulmonary Hypertension Pre-capillary Normal transpulmonary resistance

5 Classification Group 1 Group 2 Group 3 Group 4 Group 5 Pulmonary Arterial Hypertension Left-Sided Heart Disease Lung disease and/or Hypoxemia Chronic thrombotic and/or embolic disease Miscellaneous: Sarcoidosis, compression of pulmonary vessels (adenopathy, tumor, fibrosing mediastinitis)

6 At-Risk Populations for PAH Populations Prevalence IPAH 1 Connective Tissue Disease 2 6 cases/million 27% (13% newly identified) Congenital Heart Disease 3 HIV infection 4 0.5% Sickle Cell Disease 5 20% to 40% Up to 50% of patients with large VSDs develop Eisenmenger syndrome, often associated with PAH Drugs/Toxins 6 Direct relationship with anorexigens (amphetamines, cocaine); L-tryptophan may also be associated with PAH 1 Humbert M et al. Am J Respir Crit Care Med. 2006;173: Wigley FM et al. Arthritis Rheum. 2005;52: Simonneau G et al. J Am Coll Cardiol. 2004;43:5S-12S. 4 Limsukon A et al. Mount Sinai J Med. 2006;73: Lin EE et al. Curr Hematol Rep. 2005;4: Rich S et al. Chest. 2000;117:

7 Classification Dana Point Clinical Classification of PH (2008) Group 1: PAH 1. Pulmonary arterial hypertension (PAH) 1.1 Idiopathic PAH ( primary pulmonary hypertension ) 1.2 Heritable BMPR ALK1, endoglin (with or without hereditary hemorrhagic telangiectasia) Unknown 1.3 Drug- and toxin-induced 1.4 Associated with Connective tissue diseases HIV infection Portal hypertension Congenital heart disease Schistosomiasis Chronic hemolytic anemia 1.5 Persistent pulmonary hypertension of the newborn 1'. Pulmonary veno-occlusive (PVOD) and /or pulmonary capillary hemangiomatosis (PCH)

8 Pulmonary Hypertension Mean survival based on etiology of pulmonary hypertension Chest. 2004;126:78S 92S.

9 Pulmonary Hypertension Disease Mechanisms

10 Risk Factors: Shear stress (HD, CHD), HIV, CTD, toxins Genetic Predisposition: BMPR2, ALK-1, 5-HTT Pulmonary Vascular Dysfunction Endothelial Cell Dysfunction: NO, PGI2, ET-1 Smooth Muscle Cell Dysfunction: Kv1.5 Inflammation and Remodeling: IL-1, IL-6, PDGF, Chemokines Pulmonary Vascular Remodeling and Disease Progression

11 Pulmonary Hypertension SMC proliferation Fibrosis Normal PA Plexiform lesion formation Adapted from Cool CD et al. Chest. 2005;128:565S-571S.

12 Pulmonary Hypertension Evaluation

13 Evaluation History Physical Examination CXR ECG PFTs Echo Overnight Oximetry VQ Scan vs. CT Scan Blood Tests Right Heart Catheterization ANA RF / Anti-CCP LFTs/HCV HIV Anticentromere SCL-70 Anti-Jo, Anti U1 RNP, ANCA BNP (pbnp), RDW, CRP APLA, LAC

14 ECHO: Evaluation Mild PH defined by a tricuspid valve velocity of m/sec, which corresponds to a tricuspid insufficiency pressure gradient (TIPG) of 31mmHg or higher (Modified Bernoulli equation pressure = 4v 2 ) More stringent criteria would be a TIPG of 45mmHg to reduce the number of falls positives.

15 Other ECHO measures of RV dysfunction TAPSE (Tricuspid annular plane systolic excursion, <1.8cm)

16 ECHO: Evaluation The greater the degree of pulmonary hypertension by catheterization, the worse the correlation between echocardiogram measurement of RVSP and catheterization measured values. D. Mukerjee, D. St. George, C. Knight, J. Davar, et al. Rheumatology; 43 (4): 461

17 Evaluation: Hemodynamics Vasoreactivity Testing: Fall in mean pulmonary artery pressure of >10mmHg, to a value <40mmHg (older criteria: 20% decrease in mpap) Increased or unchanged CO No significant decrease in BP vasoreactive fixed Agents used for testing: Epoprostenol: 1-2 ng/kg/min and increased by 2ng/kg/min every 5-10 minutes until significant fall in BP, increase in heart rate or symptoms Adenosine: 50 µg/kg/min, increase every 2 minutes until dose of µg/kg/min ino: 20ppm for 10 minutes followed by 40ppm for 10 minutes

18 Right Ventricular Adaptations After PAH-targeted therapy, RV function can deteriorate despite a reduction in PVR. Loss of RV function is associated with a poor outcome, irrespective of any changes in PVR. J Am Coll Cardiol 2011;58:2511 9

19 V/Q SCAN: Evaluation Sensitivity %, Specificity % for distinction between IPAH and CTEPH A Normal V/Q will rule out CTEPH but mismatched perfusion defects can be seen in veno-occlusive disease, pulmonary arterial sarcoma, large-vessel pulmonary arteritis, or extrinsic vascular compression.

20 PAH Determinants of Risk Lower Risk Determinants of Risk Higher Risk No Clinical evidence of RV failure Yes Gradual Progression Rapid II, III WHO class IV Longer (>400 m) 6MW distance Shorter (<300 m) Minimally elevated BNP Very elevated Minimal RV dysfunction Normal/near normal RAP and CI Echocardiographic findings Hemodynamics Pericardial effusion, significant RV dysfunction High RAP, low CI McLaughlin VV, McGoon MD. Circulation. 2006; 114:

21 Survival (%) 6MWD Predicts Survival at Initial Screening Long distance group (332 meters) Short distance group (<332 meters) Months p < (Logrank test) Miyamoto et al Am J Respir Crit Care Med 2000;161:

22 Pulmonary Hypertension Therapies

23 Treatment: Adjunctive Therapy Anticoagulants (oral) Used in ~70% of patients in recent RCTs Recommended to be used if no contraindications exist Caution with potential drug-drug interactions (DDIs) There is no difference in efficacy based on FC severity Diuretics: Used in ~50 70% of patients in recent RCTs Not studied in controlled trials (and won t be) Recommended to be used in cases of fluid retention Spirinolactone may be helpful in decreasing RV fibrosis Digoxin: Used in ~25 50% of patients in recent RCTs No evidence for its efficacy Supplemental oxygen

24 Medical Treatment of Pulmonary Hypertension N Engl J Med 2004;351:

25 Vasoactive Mediators Involved In PAH ABNORMALITIES Nitric Oxide deficiency Prostacyclin deficiency Endothelin Overexpression THERAPIES PDE-5 inhibitors/sgc Block the activity of PDE-5, restoring vasodilation through an increase in cgmp1 Prostacyclin Supplement the deficiency in PGI2, resulting in vasodilation, anti proliferation and inhibition of platelet aggregation4 ETRA s Block the binding of ET-1 to its receptors, preventing vasoconstrictor effects of ET-12 1.HumbertM, Morrell NW, Archer SL, etal. Cellular and molecular pathobiology of pulmonary arterial hypertension. JAmCollCardiol. 2004;43(supplS):13S-24S. 2.GalièN, TorbickiA, BarstR, etal. Guidelines on diagnosis and treatment of pulmonary arterial hypertension: the Task Force on Diagnosis and Treatment of Pulmonary Arterial Hypertension of the European Society of Cardiology. EurHeartJ.2004;25: HumbertM, SitbonO, Simonneau G.Treatment of pulmonary arterial hypertension. Nengl J Med. 2004;351: pahdiseasestate_v.1 25

26 ACCF/AHA Consensus PAH Treatment Algorithm

27 CCB Therapy is Effective in Only a Small Percent of PAH Patients A retrospective study of 557 patients who were tested for acute vasoreactivity: 70 (12.6%) patients responded and were put on CCB therapy Of those 70 patients, only 38 improved Therefore only 6.8% of the total number of patients benefited from long-term CCB therapy For the 32 patients who responded positively to acute vasoreactivity testing but who failed to respond to CCB therapy, the 5-year survival rate was 48% Long-term CCB responders represent <10% of ipah patients Sitbon O et al. Circulation. 2005;111:

28 Treatment: PDE5 Inhibitors PDE5 Inhibitor Dose Side effects Sildenafil (Revatio) 20mg TID to 40mg TID Minimal side effects Shorter 1/2 life Tadalafil (Adcirca) 40mg daily Less costly Longer 1/2 life Headaches Side Effects: headaches, lower blood pressure, sinus congestion, diarrhea, vision changes, myalgias, flushing

29 From: Effect of Phosphodiesterase-5 Inhibition on Exercise Capacity and Clinical Status in Heart Failure With Preserved Ejection Fraction: A Randomized Clinical Trial JAMA. 2013;309(12): doi: /jama Table 3. Primary, Secondary, and Safety End Points Placebo Sildenafil No. of Patients Variable No. of Patients Variable Primary end point Change in peak oxygen consumption at 24 wk, median (IQR), ml/kg/min ( 0.70 to 1.00) ( 1.70 to 1.11).90 Secondary end points Clinical rank score, mean a Change in 6-minute walk distance at 24 wk, median (IQR), m ( 26.0 to 45.0) ( 37.0 to 55.0).92 Change in peak oxygen consumption at 12 wk, median (IQR), ml/kg/min ( 1.10 to 0.67) ( 1.35 to 1.25).98 Change in 6-minute walk distance at 12 wk, median (IQR), m ( 14.5 to 48.0) ( 25.0 to 36.0).13 Components of clinical rank score at 24 wk Death, No. (%) b (3).25 Hospitalization for cardiovascular or renal cause, No. (%) (13) (13).89 Change in MLHFQ, median (IQR) 91 8 ( 21 to 5) 91 8 ( 19 to 0).44 Safety end points, No. (%) Adverse events (76) (80).49 Serious adverse events (16) (22).22 Abbreviations: IQR, interquartile range; MLHFQ, Minnesota Living with Heart Failure Questionnaire. a A mean value of 95 in each group is expected under the null hypothesis of no treatment effect. b Site investigator identified causes of death were sudden death (n=1), progressive cardiorenal failure (n=1), and noncardiovascular (n=1). P Value Date of download: 12/4/2014 Copyright 2014 American Medical Association. All rights reserved.

30 Sildenefil in Secondary Pulmonary Hypertension due to Systolic Dysfunction may have benefit Lewis G D et al. Circulation. 2007;116: Copyright American Heart Association, Inc. All rights reserved.

31 Soluble Guanylate Cyclase (sgc) Inhibitors Cinaciguat and Riociguat Next Class of Agents that work distally to PDE5 inhibitors. Antiproliferative, Antiplatelet, and Vasoldilatory Multiple Clinical Trials support Benefit in 6 minute walk time, NYHA Class. Benefit In CTEPH (Riociguat) Cannot be combined with PDE5 inhibitors

32 Treatment: Endothelin Antagonists Δ in 6MWD (m) Weeks mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n=144) Treatment Effect: 44 m (P<0.001) Placebo (n=69) *Data are mean ± SEM. Walk distance was somewhat greater with 250 mg BID, but the potential for increased liver injury causes this dose not to be recommended [125 mg BID (n=74) change in walk distance (m): 27±75, 250 mg BID (n=70) change in walk distance (m): 46±62]. Rubin LJ et al N Engl J Med. 2002;346:

33 Treatment: Prostacyclin Prostanoid Routes of Administration Half-life Epoprostenol (Flolan) Intravenous 6 min Treprostinil (Remodulin) Iloprost (Ventavis) Subcutaneous Intravenous Inhaled Oral Inhaled Intravenous 240 min min Beraprost Oral 60 min Side Effects: jaw pain, diarrhea, leg pain, flushing, platelet inhibition

34 Treatment: Epoprostenol N Engl J Med 1996; 334: week prospective, randomized, multicenter open trial comparing epoprostenol to conventional therapy 81 patients with severe primary pulmonary hypertension (New York Heart Association functional class III or IV). Exercise capacity improved (Net 6MWT difference: 113m) PAP mean decrease of 8%, PVR decrease by 21%. Eight deaths, all in conventional arm (p = 0.003).

35 How Effective is Monotherapy? In Clinical Trials: 1/2 to 3/4 of patients did not improve > 1 functional class 1/3 to 1/2 of patients did not achieve a 6MWD > 380 meters Long Term Response in PH: Is incomplete Is not universal

36 Interventional and Surgical Therapy Lung Transplantation ISHLT 2006 registry survival: 78% at 1 yr, 49% at 5 yr and 25% at 10 yr. IPAH: 1990 accounted for 10% of all transplants, 2004 accounted for 3.9% of all lung transplants. Options include: single lung, double lung and heart-lung. ISHLT registry suggests no survival benefit of double lung over single lung. Heart Lung reserved for congenital heart disease / Eisenmenger

37 Surgical Therapy for PH: Pulmonary Thromboemblectomy Cumulative incidence after PE is up to 3.8%. 1 PH therapy may have minimal effect on hemodynamics although may allow for some symptomatic improval. 2 UCSD Remains Highest Volume PTE Referral Center Worldwide, Performing Roughy PTE yearly. Pulmonary thromboendarterectomy is the only definitive treatment. Operative mortality with surgery can be 4.4% at experienced centers and up to 24%. (Refer to UCSD) Persistent pulmonary hypertension (PVR > 6 WU) after surgery is marker for poor outcomes. 1 N Engl J Med 350: Circulation. 2009;120(13):

38 Conclusions Pulmonary Hypertension can be divided into 5 categories. Patients with Group I PH (PAH) are potential candidates for PH-specific treatments. Catheterization is mandatory to work-up PH. Vasodilator testing should be performed during catheterization. Non-invasive testing can provide additional information. Specific treatment for PAH includes ERAs (bosentan, ambrisentan), PDE5 inhibitors (sildenafil, tadalafil) and prostacyclins (epoprostenol, treprostinil, iloprost) Patients who do not respond to therapy should be referred for lung transplantation/heart lung.