TO THE EISENMENGER COMPLEX PATIENT: HOW DO WE OPTIMIZE CARE

TO THE EISENMENGER COMPLEX PATIENT: HOW DO

WE OPTIMIZE CARE

Maria Concepcion C. Sison, MD, FPPS, FPCCPediatric 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: DEFINITIONHemodynamically:– 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 30-35 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;6:343-355

“LIGHT IN THE TUNNEL: OPTIMIZING CARE OF THE EISENMENGER

PATIENT”

OUTLINE1. Definition of Eisenmenger Complex (EC)2. Pathophysiology relevant to management3. Problems and complications of EC4. Therapeutic Objectives5. Choose Optimal Therapy- efficacy, safety

a. “Standard or Conventional” Therapyb. “Advanced or New” Therapy

6. Other Issues/General Measures/Supportive Treatment

PATHOPHYSIOLOGY

Beghetti M and Galie N. J Am Coll Cardiol 2009;53:733-740

PATHOPHYSIOLOGYVASOACTIVE MEDIATORS PAH-CHDEndothelin-1 and endothelin receptors A and BAngiotensin II and angiotensin receptorsVascular endothelial growth factor and the flk1/tdr receptor

SIGNALING PATHWAYS PAH-CHDCalcium-dependent K+ channelsIncreased phosphodiesterase 5 activityDecreased nitric oxide synthase activityAngiopoietin 1TenascinDiminished function of BMPR1A, BMPR2

Landberg MJ. Clin Ches Med 2007;28:243-253

PROBLEMS AND COMPLICATIONS

1. Dyspnea on exertion, easy fatigability, shortness of breath, tiredness

2. Edema and fluid retention3. Palpitations/Cardiac arrhythmia4. Syncopal episodes5. 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 gout8. Bleeding tendencies/Coagulation disorders– hemoptysis

9. Sudden death

THERAPEUTIC OBJECTIVES:

1. TO IMPROVE QUALITY OF LIFE2. TO IMPROVE, IF NOT RELIEVE, SYMPTOMS3. TO DECREASE, IF NOT PREVENT,

MORBIDITY/COMPLICATIONS4. TO OPTIMIZE FUNCTIONAL/ EXERCISE CAPACITY5. TO IMPROVE HEMODYNAMICS (decrease PAP,

increase oxygenation)6. TO DELAY DETERIORATION, AND PROLONG

SURVIVAL, IF POSSIBLE

STANDARD/CONVENTIONAL THERAPY

DIGOXIN – supportive treatmentDIURETICS- supportive treatmentANTIARRHYTHYMICS- when appropriateANTICOAGULANTS- controversialO2 THERAPY- controversialIRON SUPPLEMENTATION- general measure

ANTICOAGULATIONEFFICACY: – Prevalence of pulmonary artery thrombosis in ES ~

20%– Shown to reduce morbidity and mortality in

patients with IPAHSAFETY:– 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;6:363-372Beghetti M and Galie N. J Am Coll Cardiol 2009;53:733-740

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;6:363-372

OXYGEN THERAPYEFFICACY:• 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;6:363-372

IRON SUPPLEMENTATIONBASIS:

– 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;6:363-372

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;6:356-362

ADVANCED/NEWER THERAPY

Beghetti M and Galie N. J Am Coll Cardiol 2009;53:733-740

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;6:356-362

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;6:363-372

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;6:343-355

“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;6:343-355

• 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;6:356-362

• 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;6:363-372

• 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;28:243-253

• Beghetti M and Galie N. Eisenmenger Syndrome: A Clinical Perspective in a New Therapeutic Era of Pulmonary Arterial Hypertension. J Am Coll Cardiol 2009;53:733-740