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Congestive Heart Failure

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Presentation on theme: "Congestive Heart Failure"— Presentation transcript:

1 Congestive Heart Failure
Dr Bernard Silke, MD, DSc, FRCP, Cardiovascular Physician, St. James’ Hospital, Dublin 8.

2 Congestive Heart Failure Changing population trends

3 Clinical Scenario JB is 75 and is a retired publican. First presented 12 yr ago with MI. A strong family Hx of CVS disease. Father died at age 40 with Stroke. Mother had angina. Subsequent LVF 5 yr ago with hospitalization. Echo dilated / asymmetrical contraction / dysynergy. Ejection Fraction 35%. Effort Dyspnoea What are the therapeutic options?

4 Congestive Heart Failure Incidence and age
Eur Heart J 1999: 20;

5 Congestive Heart Failure Changing population trends
< 5% of population CHF in 1.5% (25-75 yr) LV Systolic function abnormality in 1% Clinical CHF - 1% Suspect CHF - 1%

6 Congestive Heart Failure Changing population trends
MI deaths peaked 1985 Rate 215 / 100,000 Between mortality rates decrease by 33% ( ) Numbers of very elderly predicted to increase by 30% and 57% over next two decades

7 Heart Failure Definition
Heart unable to meet peripheral blood flow requirements without a rise in filling volume Contraction energy is reduced Stroke volume incompletely expelled Chamber volume increases

8 Heart Failure Natural history
100 Rest symptoms Pump Failure No symptoms No deaths Morbidity Mortality 100 Time from onset

9 Heart Failure Therapeutic goals Ventricular Filling Pressure
Normal A I Stroke Volume A + V V CHF D Ventricular Filling Pressure

10 Heart Failure Ejection Fraction
Ejection Fraction - % of EDV ejected each beat Normal % Impaired function < 40% Symptomatic < 30% If EDV 100 ml Stroke volume 65 ml CHF < 40 ml

11 Heart Failure Therapeutic implications
Volume overload Diuretics Elevated impedance Vasodilators Decreased contractility Inotropes

12 Heart Failure Clinical goals
Patient oedema free Ambulant Avoid hospitalisation Optimise quality of life

13 Heart Failure Clinical assessment
Peripheral oedema – none to minimal Paroxysmal nocturnal dyspnoea - infrequent Posture at night - < 2 pillows Dyspnoea – absent at rest, activity possible Nocturia – common and not significant

14 Heart Failure Therapeutic groups
Diuretics Thiazide group, Loop diuretics Angiotensin converting enzyme inhibitors Long-acting nitrates Captopril, Enalapril, Lisinopril, Trandolopril Inotropes Digoxin

15 DIURETICS Cortex Medulla Thiazides K-sparing Loop diuretics
Inhibit active exchange of Cl-Na in the cortical diluting segment of the ascending loop of Henle Cortex K-sparing Inhibit reabsorption of Na in the distal convoluted and collecting tubule Loop diuretics Inhibit exchange of Cl-Na-K in the thick segment of the ascending loop of Henle Medulla Loop of Henle Collecting tubule

16 Heart Failure Diuretics : Sites of Action
Distal CT (Thiazides) Na/Cl Glomerulus Amiloride Na Proximal Tubule (CAI) Ascending Limb (Loop) Spironolactone Na/K Na/K/Cl Collecting Duct

17 Heart Failure Diuretics : Sites of Action
Tubular cell hypertrophy Ascending Limb (Loop) Sodium load to distal nephron increased Na/K/Cl Collecting Duct

18 Heart Failure Diuretics : Resistance
Check compliance Check Na+ intake Low salt diet Avoid bread / processed foods Daily fluid allowance 1L Check not taking a NSAID Increased dose of a loop diuretic? Metolazone (pulse 2.5 mg) once / twice week

19 Heart Failure ACE Inhibitors
Prolong survival in early and established CHF Improve Quality of Life Relieve symptomatic congestion Increase exercise tolerance Reduce hospitalisation

20 Heart Failure Choice of ACE Inhibitor
Captopril - first generation Short duration of action Multiple dose administration (50 mg tds) Enalapril, Lisinopril - second generation Longer duration of action (once daily) Increased liklihood of hypotension Perindopril, Trandolopril - third generation Vascular selective Favourable side-effect profile Lack of first-dose effect

21 Heart Failure Benefits of ACEI
0.8 0.7 Placebo 0.6 PROBABILITY OF DEATH p< 0.001 0.5 0.4 p< 0.002 0.3 Enalapril 0.2 0.1 CONSENSUS N Engl J Med 1987;316:1429 1 2 3 4 5 6 7 8 9 10 11 12 MONTHS

22 Heart Failure Benefits of ACEI
50 40 30 20 10 p = Placebo n=1284 % MORTALITY Enalapril n=1285 n = 2589 CHF - NYHA II-III - EF < 35 48 6 12 18 24 30 36 42 SOLVD (Treatment) N Engl J M 1991;325:293 Months

23 Heart Failure Contemporary management with ACEI
Considerable variations in ACE prescribing ACE Inhibitors used in % of CHF cases Elderly less likely to be treated (21 vs 69%) Physician perceptions of contra-indication No documented contra-indications in 35% Elderly high rate of morbid events Withhold ACE more complications (p < 0.01) Am. Heart J. 1998:136;43.

24 Heart Failure Survival benefits & dosage (mg / day)
Enalapril Captopril Ramipril Lisinopril Trandolapril Quinapril 20 150 10 10 / 20 4 40 Am. Heart J. 1998:136;43.

25 Heart Failure Contemporary issues & ACEI
Pharmacodynamic response to ACEI elderly Valid concerns hypotension / renal dysfunction Reluctance to adequately dose titrate Many patients left on initiation dosage Elderly patients will tolerate ACEI and achieve target doses if titrated gradually Suboptimal Rx important due to high morbidity Am. Heart J. 1998:136;43.

26 Heart Failure Contemporary management with ACEI
82% 9% 4% 2% 3% SPICE registry Eight countries Hospital cases Consecutive 9581 Current practice USA and Europe

27 Heart Failure ACEI ADR profile
SPICE registry of 8485 cases Cough ( %) Renal sufficiency ( %) Symptomatic hypotension ( %) Hyperkalaemia (35) Rash / pruritus (25) Angioedema / analyphaxis (19)

28 DIGOXIN Na-K ATPase Na-Ca Exchange
Myofilaments Ca++ K+ Na+ CONTRACTILITY

29 Heart Failure Drug Therapy : Digoxin
Positive Inotropic S-A and A-V Nodal actions Enhanced Automaticity

30 DIGOXIN EFFECT ON CHF PROGRESSION
30 Placebo n=93 DIGOXIN Withdrawal % WORSENING OF CHF 20 DIGOXIN: mg /d ( ng/ml) EF < 35% Class I-III (digoxin+diuretic+ACEI) Also significantly decreased exercise time and LVEF. p = 0.001 10 DIGOXIN n=85 RADIANCE N Engl J Med 1993;329:1 20 40 60 80 100 Days

31 Heart Failure The DIG Study
CHF patients (6800) studied Sinus rhythm; E.F. < 45% NYHA Class III 33%; Class II < 50% Background ACEI and/or diuretic (78%) Digoxin (median 250 ug / day) vs. placebo Endpoints: mortality and hospitalisation N. Engl. J. Med. 1997: 336; 525

32 OVERALL MORTALITY % 50 40 30 20 10 Placebo n=3403 DIGOXIN n=3397 12 24
% Placebo n=3403 p = 0.8 DIGOXIN n=3397 12 24 36 48 DIG Study N. Engl. J. Med. 1997: 336; 525 Months

33 Heart Failure The DIG Study
Mortality similar (34.8% vs. 35.1%) Hospitalisations reduced 22% ( ) Benefits greatest in those at highest risk Lower E.F. ( < 25% ) Enlarged hearts NYHA Class III & IV Digoxin toxicity Ventricular fibrillation / tachycardia Supraventricular dysrhythmia Second or 3rd degree heart block N. Engl. J. Med. 1997: 336; 525

34 Heart Failure The DIG Study
No substantial change in mortality /morbidity No ethical mandate for its use May be prescribed for symptomatic relief Other drug categories have proven benefit ACEI and ß-blockers drugs N. Engl. J. Med. 1997: 336; 575

35 Heart Failure Digoxin Therapeutics
Atrial fibrillation with uncontrolled response Reduce apex rate to 100 or less. Loading 15 ug / kg in three doses over 24 hr Maintenance dose 250 to 500 ug / day Therapeutic concentration ng / ml

36 Heart Failure ß - blocking Therapy
Reduce heart rate & myocardial contractility Concern about risk of cardiac depression In CHF ß - adrenoceptors are downregulated Cardiac efficiency impaired by compensation Upregulation during ß - blocking treatment CIBIS I in 641 CHF - 20% mortality reduction

37 b blockers in heart failure –
US Carvedilol Programme Survival 1.0 0.9 0.8 0.7 0.6 0.5 Carvedilol (n=696) b blockers in heart failure – all-cause mortality Placebo (n=398) Risk reduction=65% p<0.001 50 100 150 200 250 300 350 400 Days Packer et al (1996) Survival Mortality (%) CIBIS-II 20 MERIT-HF Placebo Bisoprolol 15 Metoprolol CR/XL 10 Placebo Risk reduction=34% Risk reduction=34% 5 p<0.0001 p=0.0062 3 6 9 12 15 18 21 Time after inclusion (days) Months of follow-up CIBIS-II Investigators (1999) The MERIT-HF Study Group (1999)

38 Heart Failure ß - blocking Therapy
Over patients evaluated in placebo-controlled clinical trials Consistent improvement in cardiac function, symptoms and clinical status Decrease in all-cause mortality by 30–35% (p<0.0001) Decrease in combined risk of death and hospitalisation by 25–30% (p<0.0001)

39 Background Angiotensin II type 1 (AT1) receptor blockers (ARBs) provide a pharmacologically distinct mechanism of inhibiting the renin-angiotensin- aldosterone system ARBs offer the potential to produce further clinical improvements above and beyond ACE inhibitors as well as an alternative for those previously intolerant to an ACE inhibitor

40 CHARM Programme 3 component trials comparing candesartan
to placebo in patients with symptomatic heart failure CHARM Alternative CHARM Added CHARM Preserved n=2028 LVEF £40% ACE inhibitor intolerant n=2548 LVEF £40% ACE inhibitor treated n=3025 LVEF >40% ACE inhibitor treated/not treated Primary outcome for each trial: CV death or CHF hospitalisation Primary outcome for Overall Programme: All-cause death

41 Study design Dose-titration and visit schedule
Candesartan/ matching placebo once daily 32 mg 16 mg 8 mg 32 mg 4 mg 16 mg 8 mg Time 0 w 2 w 4 w 6 w 6 m Every 4 months until study end 31 March 2003 Visit 1 2 3 4 5

42 Baseline characteristics
Alternative Added Preserved Overall n=2028 n=2548 n=3023 n=7599 Mean age (years) Women (%) NYHA class (%) II III IV Mean LVEF Medical history (%) myocardial infarction diabetes hypertension atrial fibrillation

43 CHARM Programme 3 component trials comparing candesartan to placebo
CHARM Alternative CHARM Added CHARM Preserved n=2028 LVEF £40% ACE inhibitor intolerant n=2548 LVEF £40% ACE inhibitor treated n=3025 LVEF >40% ACE inhibitor treated/not treated Primary outcome: CV death or CHF hosp

44 CHARM-Alternative: Primary outcome CV death or CHF hospitalisation
1 2 3 years 10 20 30 40 50 Placebo Candesartan HR 0.77 (95% CI ), p= Adjusted HR 0.70, p<0.0001 3.5 406 (40.0%) 334 (33.0%) % Number at risk Candesartan Placebo

45 CHARM-Alternative Investigator reported CHF hospitalisations
Placebo Candesartan Proportion of patients (%) Number of episodes p=0.0001 p<0.0001 Patients hospitalised Hospitalisations

46 CHARM-Alternative Permanent study drug discontinuations
Percent of patients 25 Placebo 21.5 Candesartan 20 19.3 15 10 6.1 5 3.7 2.7 1.9 0.9 0.3 0.4 0.2 0.1 AE/ lab. abnorm. Hypo- tension Increased creatinine Increased potassium Cough Angio- edema p=0.23 p<0.0001 p<0.0001 p=0.0005 p=0.69 p=0.50

47 CHARM-Alternative Conclusions
Despite prior intolerance to another inhibitor of the renin-angiotensin-aldosterone system, candesartan was well tolerated In patients with symptomatic chronic heart failure and ACE-inhibitor intolerance, candesartan reduces cardiovascular mortality and morbidity

48 University of Minnesota Medical School Minneapolis, Minnesota, USA
Cardioprotective Effects of Valsartan as Seen in the Valsartan-Heart Failure Trial (Val-HeFT) Jay N. Cohn, MD Professor of Medicine University of Minnesota Medical School Minneapolis, Minnesota, USA

49 Study Overview 5010 patients 18 years; EF <40%; NYHA II-IV; LVIDd >2.9 cm/m2 Receiving background therapy ACE inhibitors (92.7%), diuretics (85.8%), digoxin (67.3%), -blockers (35.6%) Randomized to Valsartan 40 mg bid titrated to 160 mg bid Placebo Val-HeFT, a randomized, double-blind, placebo-controlled study of 5010 HF patients with NYHA class II-IV, was an international collaboration in 16 industrialized countries at 300 centers Patients continued on their standard background therapies, which included ACE inhibitors (n=4644, 92.7%), diuretics (n=4300, 85.5%), digoxin (n=3375, 67.3%), and -blockers (n=1784, 35.6%) Patients were randomized to treatment with valsartan 40 mg bid titrated to 160 mg bid or placebo The primary endpoints were combined all-cause mortality and morbidity and all-cause mortality Patients were stratified to each arm according to whether they were on a -blocker or not Study continued until 906 deaths were reported Cohn JN et al. Eur J Heart Fail. 2000;2:

50 Patients’ Baseline Characteristics
Valsartan (n = 2511) Placebo (n = 2499) Mean age (y) Gender, male (%) Race (%) White NYHA Class (%) II III IV Ejection fraction (%) Background therapy (%) Diuretic Digoxin -Blocker ACE inhibitor Patients in the valsartan and placebo group were comparable with respect to all baseline characteristics Cohn JN et al. N Engl J Med. 2001;345:

51 Primary and Secondary Efficacy Endpoints*
Combined all-cause mortality and morbidity (time to event) Hospitalization for heart failure Sudden death with resuscitation Need for intravenous inotropes/vasodilators for worsening HF All-cause mortality (time to event) Hospitalization for heart failure Signs and symptoms of heart failure NYHA functional class (change from baseline) Echocardiographic indices of left ventricular function (LVEF and LVIDd — change from baseline) Quality of life score (Minnesota Living With Heart Failure score) * For the trial to be positive, one of the primary endpoints had to reach statistical significance (P < ). Cohn JN et al. N Engl J Med. 2001;345:

52 Mortality and Morbidity Analyses

53 Primary Endpoint Analyses
Events Valsartan (n = 2511) Placebo (n = 2499) Reduction RR P Value Combined all- cause mortality and morbidity 723 (28.8%) 801 (32.1%) 13.2% 0.87 ( ) 0.009* All-cause mortality 495 (19.7%) 484 (19.4%) 1.02 ( ) 0.80 *Log-rank test. Cohn JN et al. N Engl J Med. 2001;345:

54 Primary Endpoint Sensitivity* Analyses
Events Valsartan (n = 2511) Placebo (n = 2499) Reduction RR P Value Combined all- cause mortality and morbidity 585 (23.3%) 720 (28.8%) 19.0% 0.81 ( ) 0.0003 All-cause mortality 372 (14.8%) 411 (16.4%) 7.0% 0.93 ( ) 0.342 *With censoring of events after permanent discontinuation of study medication at the time of treatment discontinuation or analysis cut-off date. Data on file, Novartis Pharma AG.

55 Effect of Valsartan on Morbidity Endpoint*
65 70 75 80 85 90 95 100 Valsartan Placebo 13.2% Risk Reduction P = 0.009 Probability of Event-Free Survival 3 6 9 12 15 18 21 24 27 30 Months *All-cause mortality, sudden death with resuscitation, hospitalization for worsening heart failure, or therapy with IV inotropes or vasodilators. Cohn JN et al. N Engl J Med. 2001;345:

56 All-Cause Mortality: Kaplan-Meier Analysis (Val-HeFT)*
1.0 Valsartan Placebo 0.9 0.8 Proportion Survived 0.7 0.6 0.5 3 6 9 12 15 18 21 24 27 30 Mention in text that there was a difference in placebo rate. Placebo death rate was only 9% as opposed to the assumption of 12% Patients were on maximally tolerated therapy Time Since Randomization (mo) Patients at Risk Months Valsartan Placebo *P value (log-rank): 0.801; hazard ratio (Cox model): Cohn JN et al. N Engl J Med. 2001;345:

57 Mortality by ACE Inhibitor/Beta Blocker Subgroups
Favors Valsartan Favors Placebo ACEI - 366 ACEI BB BB ACEI - BB - 226 ACEI - BB + 140 ACEI + BB ACEI + BB 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 Data on file, Novartis Pharma AG. Cohn JN et al. N Engl J Med. 2001;345:

58 HF-Related Hospitalizations*
65 70 75 80 85 90 95 100 Valsartan Placebo Event-Free Probability 27.5% Risk Reduction P < 3 6 9 12 15 18 21 24 27 30 Months HF = heart failure. *First hospitalization. Cohn JN et al. Circulation. 2000;102:2672b.


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