The role of biomarkers in the diagnosis of cardiac dysfunction and heart failure in the elderly: time for a paradigm shift? Dr. Bert Vaes

Case: George, 84 years old George, 84 years, married, living at home

Case: George - Background: Ex-smoker (40 package years till 1992) COPD stage II-III Osteoarthritis with a knee prosthesis (2003) Hypercholesterolemia Peripheral arterial disease with ilio-femoral bypass surgery (1992) - Medication Clopidogrel, ramipril 5mg, simvastatin, paracetamol, inhaled CS and β mimetics - Symptoms Dyspnea and fatigue when marching up a stairs, nocturnal dyspnea, loss of appetite - Clinical ex Fine bilateral crepitations on lung auscultation, systolic cardiac murmur (intensity 2/6) - Lab results Haemoglobin 12.4mg/dL, creat 1.1mg/dL (MDRD 63mL/min)

Are the patient’s symptoms caused by heart failure? The research question Are the patient’s symptoms caused by heart failure? “The very essence of cardiovascular medicine is the recognition of early heart failure” Sir Thomas Lewis, 1933

Definition of heart failure ESC Heart Failure guidelines 2005 ESC Heart Failure guidelines 2008

HFrEF versus HFpEF? Difference between systolic and diastolic dysfunction (HFPEF)  two separate syndromes? Based on functional, structural and molecular biological arguments  single syndrome? 2 phenotypes at the end of the spectrum

HFrEF versus HFpEF? ESC guidelines 2012

Heart failure staging

Problems in the very elderly High burden of multimorbidity 2. Polypharmacy  BELFRAIL: 85% one or more cardiac (possibly symptom reducing) medication

Problems in the very elderly Cardinal symptoms of HF are very prevalent in subjects aged 80 and older1 4. Low specificity of signs and symptoms in elderly patients2 5. No accurate signs and symptoms for cardiac dysfunction or HF in the elderly, especially for detection of the early stages3 1Vaes et al. Int J Cardiol 2012;155:134-143, 2Fonseca et al. Eur J Heart Fail 2004;6:795-802, 3Morgan et al. BMJ 1999;318:368-372

NPR-C/ endopeptidase / renal Natriuretic peptides: the ‘ultimate’ biochemical test for heart failure? Differences between BNP and NT-proBNP BNP NT-proBNP Half-life 20’ 120’ Clearance NPR-C/ endopeptidase / renal Renal +++ Increase with age + +++ Stability 4-24h >72h Variability (significant changes) +++ (>130%) ++ (>90%) Also explain NP are not just used as a diagnostic test, but are also used as prognostic markers, therapeutic agents and indicators to guide treatment of patients with heart failure. Wu et al. Eur J Heart Fail 2004;6:355-8

Natriuretic peptides: a marker of pancardiac disease in old age  marker of pancardiac disease1 Cardiovascular continuum of Braunwald and Dzau2 1Struthers A et al. Eur Heart J 2007;28:1678-82, 2Dzau E, Braunwald E. Am Heart J 1991;121:1244-63.

BELFRAIL study Vaes B et al. BMC Geriatr. 2010; 10:39.

Prevalence of cardiac dysfunction 1Int J Card 2012;155:134-143, 2JAMA 2003;289:194-202, 3Heart 2006;92:1259-64, 4Lancet 2006;368:1005-11.

Prevalence of cardiac dysfunction In the Western World 1-2% of the adult population >70j  >10%! BELFRAIL study (≥80j) - According to GP  30% chronic HF - Cardiac dysfunction  19.3% °LVEF≤50% °severe diastolic dysfunction °valvular heart disease - 55% had symptoms of heart failure - 85% received cardiovascular medication °49% diuretics °42% B-blockers °42% ACE-I of sartans

The added value of NP What is the diagnostic value of background variables, anamnesis and clinical examination 2. What is the added value of natriuretic peptides for the diagnosis of heart failure / severe cardiac dysfunction

The added value of NP The clinical model Table 3. The diagnostic accuracy of anamnesis and clinical examination for severe CD or new-onset heart failure BELFRAIL1 Oudejans et al2 Kelder et al3 n 567 206 721 Mean age (±SD) 85 ± 4 82 ± 6 71 ± 12 Women (n,%) 358 (63) 144 (70) 466 (65) Reference standard Severe CD New-onset HF C statistic clinical model (95% CI) 0.79 (0.74 – 0.85) 0.75 (0.69 – 0.82) 0.83 1Am J Cardiol 2013;111:1198-208, 2Eur J Heart Fail 2011;13:518-527, 3Circulation 2011;124;2865-2873

The added value of NP The clinical + model Subjects without CAF or PM Table 7. The diagnostic accuracy of anamnesis and clinical examination for severe CD or new-onset heart failure BELFRAIL1 Oudejans et al2 Kelder et al3 n 567 206 721 Mean age (±SD) 85 ± 4 82 ± 6 71 ± 12 Women (n,%) 358 (63) 144 (70) 466 (65) Reference standard Severe CD New-onset HF C statistic clinical model (95% CI) 0.79 (0.74 – 0.85) 0.75 (0.69 – 0.82) 0.83 C statistic clinical + NP 0.81 (0.75 – 0.87) 0.92 (0.88 – 0.95) 0.86 C statistic clinical +ECG 0.80 (0.74 – 0.85) 0.79 (0.73 – 0.85) 0.84 1Am J Cardiol 2013;111:1198-208, 2Eur J Heart Fail 2011;13:518-527, 3Circulation 2011;124;2865-2873

Case evaluation ESC guidelines 2012

Case evaluation Oudejans et al. Eur J Heart Fail 2011;13:518-527 Kelder et al. Circulation 2011;124;2865-2873

Case evaluation: George NT-proBNP  1612pg/mL ESC guidelines: echocardiography is needed Oudejans  56 points  echocardiography Kelder  92 points  HF> 80% likelihood Echocardiography: dilated left ventricle, LVEF 20%, mitral regurgitation 2/4 and diastolic relaxation disturbance

Case: Maria 88 years old

Case: Maria Background: Osteoarthritis with bilateral knee prosthesis (1999, 2001) Hypertension and diabetes type II Chronic renal insufficiency Colon cancer (surgery and chemo) 1995 Chronic atrial fibrillation - Medication Ace-I, β blocker, diuretics, coumarine, insuline, paracetamol - Symptoms Severe fatigue and oedema LE, no dyspnea - Clinical ex Oedema LE, obese, HJR+, systolic cardiac murmur (3/6), BP 170/70mmHg, HR 82/min - Lab results Haemoglobin 10.6mg/dL, creat 1.9mg/dL (MDRD 25mL/min)

Case evaluation: Maria NT-proBNP = 1514pg/mL ESC  Echocardiography is needed Oudejans  echocardiography Kelder  Heart failure > 80% likelihood Echocardiography: LVEF 62%, left atrium dilated, moderate aortic stenosis

Conclusions A high prevalence of cardiac dysfunction High diagnostic accuracy of history, anamnesis and clinical examination Natriuretic peptides  disease specific markers, despite ↑ burden of multimorbidity  markers of pancardiac disease  Impact of confounders on test performance (CAVE renal function, atrial fibrillation)  “rule-out” test and “rule-in” test  could be used as a prognostic marker in the very old

No limits, just edges (Jackson Pollock)