Pharmacological Treatment for Chronic Heart Failure Dr Elaine Chau HK Sanatorium & Hospital, Hong Kong 3 August 2014 1
ACC/AHA 2005 guideline update for Diagnosis & management of CHF in the Adult -SA Hunt et al 2
Guidelines (ESC) - heart failure 3
Diagnostic flow-chart 4
Treatment for chronic symptomatic systolic heart failure (NYHA II-IV) 5
Diuretics relieve dyspnoea and oedema aim to use minimum dose necessary to restore and maintain euvolaemia( dry weight ) combination diuretic therapy sometimes needed to achieve this goal in patients with severe HF, renal dysfunction or both loop diuretics produce a more intense and shorter diuresis than thiazides (more gentle and prolonged diuresis) 6
Doses of diuretics commonly used to treat HF 7
Treatment for symptomatic (NYHA II-IV) systolic heart failure Class of recommendation: I Level of evidence: A ACEI (or ARBif ACEI not tolerated) for all patients with EF <40% to reduce risk of HF hospitalization and premature death Beta-blocker for all patients with EF <40% to reduce risk of HF hospitalization and premature death MRA persisting symptoms despite ACEI/ARB + BB EF <35% 8
Treatment for symptomatic (NYHA II-IV) systolic heart failure ACEI and BBshould be started as soon as HF is diagnosed ACEI modest effect on LV remodelling BB substan al improvement in EF ACEI CONSENSUS (enalapril) SOLVD (enalapril) ATLAS (lisinopril) SAVE (captorpil) AIRE (ramipril) TRACE (trandolapril) BB CIBIS-II (bisoprolol) COPERNICUS (carvedilol) MERIT-HF (metoprolol CR/XL) BEST (bucindolol) COMET (carvedilol) 9
Treatment for symptomatic (NYHA II-IV) systolic heart failure MRAs RALES(spironolactone) EMPHASIS(eplerenone) can cause hyperkalaemiaand worsening RFT, especially in the elderly serial monitoring of electrolytes and RFT is mandatory 10
Treatment for chronic symptomatic systolic heart failure (NYHA II-IV) 11
Inverse linear relation between RHR and life expectancy in mammals and humans Cook, S. et al. Eur Heart J 2006 27:2387-2393; doi:10.1093/eurheartj/ehl259 12
Resting heart rate and risk of mortality in general population n=5713 men; 23-year follow-up; ETT 4.0 3.5 Non-sudden death from myocardial infarction; P=0.02 Sudden death from myocardial infarction; P<0.001 24 3.0 2.5 2.0 1.5 1.0 33 11 14 9 21 13 27 23 34 0.5 0.0 <60 60-64 65-69 70-75 >75 Resting heart rate (bpm) Jouv en et al. N Engl J Med. 2005;352:1951-1958. 13
A high resting heart rate as an independent predictor of mortality in CAD patients n=24 913; 14.1-year follow-up 1.0 Adjusted survival curves for overall mortality 1.0 Adjusted survival curves for cardiovascular mortality Cumulative survival 0.9 0.8 0.7 0.6 0.5 =<62 63-70 71-76 77-82 =>83 bpm 0 5 10 15 20 Years after enrolment Diaz A, et al. Eur Heart J. 2005;26:867-874. P<0.0001 0.9 0.8 0.7 0.6 0.5 P<0.0001 0 5 10 15 20 Years after enrolment 14
The sinus node I f current is a key determinant of heart rate Sinus node currents Sinus node mv 0 500 ms -50 pa -50 50 I f I K Sinus node channels -50 I CaL I CaT -50 Ca channel T- type f-channel -50 I NaCa Ca channel L- type K channel Robinson RB, DiFrancesco D. Fundamental and Clinical Cardiology; NY; Marcel Decker; 2001:151-170. 15
Selective I f current inhibition leads to pure heart rate reduction Na + Na + K + RR 0 mv Pure heart rate reduction -40 mv -70 mv Reduces the diastolic depolarization slope Adapted from: Thollon C, et al. Br J Pharmacol. 1994;112:37-42. DiFrancesco A, et al. Drugs. 2004;64:1757-1765. 16
10 917 participants with Documented coronary artery disease and left ventricular dysfunction Sinus rhythm and resting heart rate 60 bpm
Effect of ivabradine on hospitalization for fatal/nonfatal MI Angina (n = 1507) Angina and HR >70 bpm (n = 712) Event rate (%) Event rate (%) 15 HR = 0.58 P=0.021 15 HR = 0.27 P=0.002 10 Placebo 10 Placebo 5 0 42% Ivabradine 0 0.5 1 1.5 2 Years 5 0 73% Ivabradine 0 0.5 1 1.5 2 Years Fox K, et al. Eur Heart J.2009; 30:2337-2345.
Systolic Heart Failure treatment with the I f inhibitor IvabradineTrial A 3-year randomized double-blind placebo controlled international multicentre phase III study 19
CV death or hospitalization for HF (%) Ivabradineimproves outcomes (CV death or hospitalization for HF) in patients with chronic systolic HF 40 30 HR = 0.82 p<0.0001 Placebo - 18% 20 Ivabradine 10 NNT for 1 year = 26 0 0 6 12 18 24 30 Months Swedberg K, et al. Lancet 2010;376: 875-885. 20
Main results Heart rate lowering with ivabradine led to significant reduction in the primary composite endpoint of cardiovascular mortality or hospitalization for worsening heart failure by 18% (p<0.0001) This beneficial effect was mainly driven by a favourable effect on heart failure death (RRR 26%) and on hospital admission for heart failure (RRR 26%) Treatment with ivabradine was safe and well tolerated Swedberg K, et al. Lancet. 2010;376:875-885. 21
Treatment for symptomatic (NYHA II-IV) systolic heart failure Ivabradine for patients in sinus rhythm EF <35% HR >70/min to reduce risk of HF hospitalization despite maximum tolerated doses of ACEI+BB+MRA Class of recommendation: IIa Level of evidence: B despite ACEI+MRA but unable to tolerate BB Class of recommendation: IIa Level of evidence: C 22
Treatment for chronic symptomatic systolic heart failure (NYHA II-IV) 23
Treatment for chronic symptomatic systolic heart failure (NYHA II-IV) 24
Disease-modifying drugs in heart failure 25
Treatments with less certain benefits in HF Digoxin for patients in sinus rhythm EF <45% HR >70/min to reduce risk of HF hospitalization despite ACEI+MRA but unable to tolerate BB Class of recommendation: IIb Level of evidence: B persisting symptoms despite ACEI+MRA+BB Class of recommendation: IIb Level of evidence: B 26
Treatments with less certain benefits in HF Hydrallazine& IsosorbideDinitrate(H-ISDN) as alternative to ACEI or ARB (if neither is tolerated) to reduce risk of HF hospitalization & premature death EF <45% and dilated LV (or EF <35%) despite BB+MRA Class of recommendation: IIb Level of evidence: B persisting symptoms despite ACEI+MRA+BB Class of recommendation: IIb Level of evidence: B 27
Treatments with less certain benefits in HF N-3 PUFA (polyunsaturated fatty acids) to reduce risk of CV hospitalization & death treated with ACEI+MRA+BB Class of recommendation: IIb Level of evidence: B Based on GISSI-HF trial (randomized, double blind, placebo controlled trial): 6975 patients with symptomatic CHF (NYHA II-IV) relative risk of death reduced by 14% In absolute terms, 56 patients needed to be treated for 3.9 years to avoid one death 28
Treatments that may cause harm in heart failure 29
For control ventricular rate in HF and AF 30
For control ventricular rate in HF and AF 31
For rhythm control in HF and AF 32
Assessment of stroke risk in patients with AF 33
Assessment of bleeding risk in patients with AF 34
Prevention of thromboembolism in symptomatic HF and paroxysmal/persistent/permanet AF 35
Management of ventricular arrhythmias in HF 36
Txof stable angina in symptomatic HF and LV systolic dysfunction 37
Txof stable angina in symptomatic HF and LV systolic dysfunction 38
Txof stable angina in symptomatic HF and LV systolic dysfunction 39
Treatment of hypertension in symptomatic HF and LV systolic dysfunction 40