TO THE EISENMENGER COMPLEX PATIENT: HOW DO WE OPTIMIZE CARE Maria Concepcion C. Sison, MD, FPPS, FPCC Pediatric Cardiologist

Eisenmenger Complex Victor Eisenmenger (1897): 32 yo/male with cyanosis and dyspnea since infancy, was active until 3 years before death; succumbed to hemoptysis Autopsy: large malaligned VSD, marked RVH Paul Wood (1951): described pathophysiology of Eisenmenger syndrome as PULMONARY HYPERTENSION with REVERSED SHUNT

EISENMENGER Complex/Syndrome/Physiology: DEFINITION Pulmonary vascular obstructive disease induced by uncorrected significant left-to-right shunt (any large congenital cardiac defect) causing a balanced or predominantly right to left shunt

Eisenmenger Complex/Syndrome: DEFINITION Hemodynamically: – Elevation of PVR to 12 (10) Wood units – Pulmonary-to-systemic resistance ratio 1.0 – No significant respone so vasoreactivity testing EISENMENGER SYNDROME =INOPERABILITY =PROGRESSIVE HEART FAILURE = INEVITABLE PREMATURE DEATH

Eisenmenger Complex/Syndrome: PROGNOSIS LONG SYMPTOM FREE PERIOD USUALLY SYMPTOMATIC AROUND 30 years old USUALLY DIE BETWEEN years old Actuarial survival rate: – 80% at 10 years – 77% at 15 years – 42% at 25 years Kaemmerer H et al. The Adult Patient with Eisenmenger Syndrome: A Medical Update After Dana Point Part I: Epidemiology, Clinical Aspects and Diagnostic Options. Current Cardiology Review 2010;6:

LIGHT IN THE TUNNEL: OPTIMIZING CARE OF THE EISENMENGER PATIENT

OUTLINE 1.Definition of Eisenmenger Complex (EC) 2.Pathophysiology relevant to management 3.Problems and complications of EC 4.Therapeutic Objectives 5.Choose Optimal Therapy- efficacy, safety a.Standard or Conventional Therapy b.Advanced or New Therapy 6.Other Issues/General Measures/Supportive Treatment

PATHOPHYSIOLOGY Beghetti M and Galie N. J Am Coll Cardiol 2009;53:

PATHOPHYSIOLOGY VASOACTIVE MEDIATORS PAH-CHD Endothelin-1 and endothelin receptors A and B Angiotensin II and angiotensin receptors Vascular endothelial growth factor and the flk1/tdr receptor SIGNALING PATHWAYS PAH-CHD Calcium-dependent K+ channels Increased phosphodiesterase 5 activity Decreased nitric oxide synthase activity Angiopoietin 1 Tenascin Diminished function of BMPR1A, BMPR2 Landberg MJ. Clin Ches Med 2007;28:

PROBLEMS AND COMPLICATIONS 1. Dyspnea on exertion, easy fatigability, shortness of breath, tiredness 2.Edema and fluid retention 3.Palpitations/Cardiac arrhythmia 4. Syncopal episodes 5.Erythrocytosis – increased blood viscosity and intravascular sludging – CVA, Renal insufficiency, pulmonary thromboembolism

PROBLEMS AND COMPLICATIONS: MULTISYSTEM DISORDER 5.Fluid retention and elevated systemic venous pressure may alter hepatic function 7.Hyperuricemia and gout 8.Bleeding tendencies/Coagulation disorders – hemoptysis 9.Sudden death

THERAPEUTIC OBJECTIVES: 1.TO IMPROVE QUALITY OF LIFE 2.TO IMPROVE, IF NOT RELIEVE, SYMPTOMS 3.TO DECREASE, IF NOT PREVENT, MORBIDITY/COMPLICATIONS 4.TO OPTIMIZE FUNCTIONAL/ EXERCISE CAPACITY 5.TO IMPROVE HEMODYNAMICS (decrease PAP, increase oxygenation) 6.TO DELAY DETERIORATION, AND PROLONG SURVIVAL, IF POSSIBLE

STANDARD/CONVENTIONAL THERAPY DIGOXIN – supportive treatment DIURETICS- supportive treatment ANTIARRHYTHYMICS- when appropriate ANTICOAGULANTS- controversial O2 THERAPY- controversial IRON SUPPLEMENTATION- general measure

ANTICOAGULATION EFFICACY: – Prevalence of pulmonary artery thrombosis in ES ~ 20% – Shown to reduce morbidity and mortality in patients with IPAH SAFETY: – Thrombus formation and bleeding coexist in patients with ES. – Risk of Fatal and life threatening and bleeding complication particularly significant hemoptysis Oechslin E et al. Current Cardiology Review 2010;6: Beghetti M and Galie N. J Am Coll Cardiol 2009;53:

ANTICOAGULATION May be CONSIDERED as supportive treatment in patients with PA THROMBOSIS in the ABSENCE of significant hemoptysis Oechslin E et al. Current Cardiology Review 2010;6:

OXYGEN THERAPY EFFICACY: In PAH: extrapolated from RCTs in COPD patients Subjective benefit in patients with intense hypoxemia, dyspnea at rest and loss of vital capacity RISK and SIDE EFFECTS: desiccation of nasal mucosa, epistaxis, sleep disturbance No impact of nocturnal oxygen therapy on exercise capacity, natural history and survival of the patients within a follow up period of 2 years. Can be considered in cases in which it produces a consistent increase in O2 saturation and reduces symptoms Oechslin E et al. Current Cardiology Review 2010;6:

IRON SUPPLEMENTATION BASIS: – Erythrocytosis – Hyperviscosity syndrome occurs at lower Hb level in the presence of iron deficiency anemia – Iron deficiency may cause headache, reduced exercise tolearnce, restless leg syndrome CONTROVERSY: – No studies on the role of iron store repletion in lowering the occurrence of other organ system damage or thrombosis – In vitro study: iron deficiency has no impact on blood viscosity Iron deficiency must be avoided in ES! Oechslin E et al. Current Cardiology Review 2010;6:

Conventional Pharmacologic Treatment Conventional pharmacological treatment, including digitalis, diuretics, antiarrhythmics, anticoagulants, iron supplementation, and oxygen therapy, may be used empirically, BUT does not seem to alter survival rate

NEWER/ADVANCED/ TARGETED THERAPIES For stable patients: noli-me-tangere is still an option due to delicate balance of many variables INDICATED IN PATIENTS WITH REDUCED EXERCISE TOLERANCE, INCREASING CYANOSIS, OR INCREASING SIGNS OF HEART FAILURE – WHO FC III-IV Siegrun M et al. The Adult Patient with Eisenmenger Syndrome: A Medical Update After Dana Point Part II: Medical Treatment-Study Results. Current Cardiology Review 2010;6:

ADVANCED/NEWER THERAPY Beghetti M and Galie N. J Am Coll Cardiol 2009;53:

ADVANCED/NEWER THERAPY: PULMONARY VASODILATORS ENDOTHELIN-1 RECEPTOR ANTAGONISTS (BOSENTAN) PHOSPHODIESTERASE-5 INHIBITORS (SILDENAFIL)- PROSTACYCLIN and PROSTACYCLIN ANALOGS (EPOPROSTENOL) TO SOME EXTENT, DEMONSTRATED IMPROVEMENT IN EXERCISE CAPACITY, QUALITY OF LIFE, AND HEMODYNAMICS Siegrun M et al. The Adult Patient with Eisenmenger Syndrome: A Medical Update After Dana Point Part II: Medical Treatment-Study Results. Current Cardiology Review 2010;6:

ET-1 ANTAGONIST: BOSENTAN BOSENTAN: BREATHE-5 – First RCT Eisenmenger patients, 16 weeks – Significant improvement in hemodynamics and exercise capacity (6 MWD) without compromising oxygen saturations Approved for use in PAH both in adults in children Maintained up to 40 wks (open-label) – Initial persistent improvement, decline after 1 year, reduction to baseline after 2 years (natural progression vs tachyphylaxis)

PDE-5 Inhibitors- Sildenafil SUPER-1: large prospective multicenter blinded and controlled:IPAH: improved EC (6 MW test), FC, HD In ES: case reports, series, observational studies, few RCT placebo: Safe and improved symptoms, FC, Exercise Capacity (6MWD, Ex duration, pulmonary HD) Tadalafil- observational study (ES)- benefits in O2 sat and mean FC

PROSTACYCLIN ANALOG:EPOPROSTENOL LIMITED DATA ON EFFICACY AND SAFETY IN ES Case series: improved O2 and 6 MWD, FC IPAH – RCT: improved exercise capacity, QOL, hemodynamics Side effects IV Administration: CVA, infection TREPROSTNIL (SC, IV)- IPAH, CTD, CHD – benefits on EC, HD, clinical events – Side effects: high frequency of injection site pain Iloprost (inhalation)- IPAH Beraprost- no crucial role

OPTIMIZING CARE IN ES OTHER GENERAL MEASURES AND SUPPORTIVE TREATMENT

PHLEBOTOMY Phlebotomy with isovolumic replacement should be considered in the presence of moderate to severe symptoms of hyperviscosity Prophylactic phlebotomy plays no role in patient management Causes iron deficiency anemia, reduces exercise tolerance

HYPERVISCOSITY SYMPTOMS

HYPERURICEMIA/GOUT Asymptomatic, secondary hyperuricemia is no indication for routine therapy to lower uric acid level because it does not have any serious impact on renal function TREAT: Acute Gouty Arthritis

ISCHEMIC EVENTS: REDUCING RISKS Avoidance and treatment of volume depletion; Iron supplementation in patients with iron deficiency or those undergoing repeated phlebotomies; Use of air filters in all intravenous lines. Oechslin E et al. Current Cardiology Review 2010;6:

FACTORS THAT MAY AGGRAVATE PAH IN EISENMENGER SYNDROME PREGNANCY Dehydration or acute vasodilation (eg, sauna, hot tub) Increased fluid volume Worsened renal or hepatic function Chronic environmental hypoxia Increased left-sided filling pressure Left ventricular diastolic dysfunction Obstructive congenital lesion Myocardial restriction Systemic hypertension with increased left ventricular afterload Erythrocytosis and increased blood viscosity; anemia Hypercoagulability: thrombosis

OTHER GENERAL MEASURES Infective Endocarditis PROPHYLAXIS Pregnancy and Contraception – ES is an absolute contraindication to Pregnancy – Maternal mortality= 30-60% – Spontaneous abortion=40% – Premature delivery 50% – IUGR 30% of infants – Perinatal infant mortality 8-28%

Transplantation Heart/Lung Transplantation or Lung Transplantation with repair of CHD Option for patients with poor prognosis and poor quality of life

SURVIVAL BENEFITS RETROSPECTIVE STUDY (systematic cohort), EISENMENGER PATIENTS RECEIVING ADVANCED THERAPY (Bosentan, Sildenafil, Epoprostenol) showed LOWER RISK OF DEATH 52 PATIENTS DIED, ONLY 2 WHILE ON AT CLINICAL DIFFERENCES STATISICALLY CORRECTED – Those on AT had more advanced disease Dimopoulos K et al. Improved Survival Among Patients With Eisenmenger Syndrome Receiving Advanced Therapy For Pulmonary Arterial Hypertension. Circulation. 2010;121:20-25

Management algorithm for PAH in CHD Kaemmerer H et al. The Adult Patient with Eisenmenger Syndrome: A Medical Update After Dana Point Part I: Epidemiology, Clinical Aspects and Diagnostic Options. Current Cardiology Review 2010;6:

Teach us to number our days aright, that we may gain a heart of wisdom Psalm 90:12

MAJOR REFERENCES: Kaemmerer H et al. The Adult Patient with Eisenmenger Syndrome: A Medical Update After Dana Point Part I: Epidemiology, Clinical Aspects and Diagnostic Options. Current Cardiology Review 2010;6: Siegrun M et al. The Adult Patient with Eisenmenger Syndrome: A Medical Update After Dana Point Part II: Medical Treatment-Study Results. Current Cardiology Review 2010;6: Oechslin E et al. The Adult Patient with Eisenmenger Syndrome: A Medical Update After Dana Point Part III. Specific Management and Surgical Aspects. Current Cardiology Review 2010;6: Dimopoulos K et al. Improved Survival Among Patients With Eisenmenger Syndrome Receiving Advanced Therapy For Pulmonary Arterial Hypertension. Circulation. 2010;121:20-25 Landberg MJ. Congenital Heart Disease Associated Pulmonary Arterial Hypertension. Clin Ches Med 2007;28: Beghetti M and Galie N. Eisenmenger Syndrome: A Clinical Perspective in a New Therapeutic Era of Pulmonary Arterial Hypertension. J Am Coll Cardiol 2009;53: