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Congestive Heart Failure. Dr Bernard Silke, MD, DSc, FRCP, Cardiovascular Physician, St. James’ Hospital, Dublin 8. Congestive Heart Failure Changing population trends. Clinical Scenario. JB is 75 and is a retired publican. First presented 12 yr ago with MI.
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Congestive Heart Failure Dr Bernard Silke, MD, DSc, FRCP, Cardiovascular Physician, St. James’ Hospital, Dublin 8.
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?
Congestive Heart FailureIncidence and age Eur Heart J 1999: 20; 421-428.
Congestive Heart FailureChanging population trends • < 5% of population • CHF in 1.5% (25-75 yr) • LV Systolic function abnormality in 1% • Clinical CHF - 1% • Suspect CHF - 1%
Congestive Heart FailureChanging population trends • MI deaths peaked 1985 Rate 215 / 100,000 • Between 1985 - 1995 mortality rates decrease by 33% (215.3 - 144.2) • Numbers of very elderly predicted to increase by 30% and 57% over next two decades
Heart FailureDefinition • 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
Heart FailureNatural history 0 100 Rest symptoms Pump Failure No symptoms No deaths Morbidity Mortality 100 0 Time from onset
Heart FailureTherapeutic goals Normal A I Stroke Volume A + V V CHF D Ventricular Filling Pressure
Heart FailureEjection Fraction • Ejection Fraction - % of EDV ejected each beat • Normal 50 - 75% • Impaired function < 40% • Symptomatic < 30% • If EDV 100 ml • Stroke volume 65 ml • CHF < 40 ml
Heart FailureTherapeutic implications • Volume overload • Diuretics • Elevated impedance • Vasodilators • Decreased contractility • Inotropes
Heart FailureClinical goals • Patient oedema free • Ambulant • Avoid hospitalisation • Optimise quality of life
Heart FailureClinical 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
Heart FailureTherapeutic groups • Diuretics Thiazide group, Loopdiuretics • Angiotensin converting enzyme inhibitors • Long-acting nitrates • Captopril, Enalapril, Lisinopril, Trandolopril • Inotropes • Digoxin
DIURETICS Thiazides 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
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
Heart Failure Diuretics : Sites of Action Tubular cell hypertrophy Ascending Limb (Loop) Sodium load to distal nephron increased Na/K/Cl Collecting Duct
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
Heart FailureACE Inhibitors • Prolong survival in early and established CHF • Improve Quality of Life • Relieve symptomatic congestion • Increase exercise tolerance • Reduce hospitalisation
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
Heart Failure Benefits of ACEI 0.8 0.7 Placebo 0.6 PROBABILITYOFDEATH p< 0.001 0.5 0.4 p< 0.002 0.3 Enalapril 0.2 0.1 0 CONSENSUS N Engl J Med 1987;316:1429 0 1 2 3 4 5 6 7 8 9 10 11 12 MONTHS
50 40 30 20 10 0 Heart Failure Benefits of ACEI p = 0.0036 Placebo n=1284 % MORTALITY Enalapril n=1285 n = 2589 CHF - NYHA II-III - EF < 35 48 0 6 12 18 24 30 36 42 SOLVD (Treatment)N Engl J M 1991;325:293 Months
Heart Failure Contemporary management with ACEI • Considerable variations in ACE prescribing • ACE Inhibitors used in 30 - 60% 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.
Enalapril Captopril Ramipril Lisinopril Trandolapril Quinapril 20 150 10 10 / 20 4 40 Heart Failure Survival benefits & dosage (mg / day) Am. Heart J. 1998:136;43.
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.
2% 4% 3% 9% • 82% Heart Failure Contemporary management with ACEI • SPICE registry • Eight countries • Hospital cases • Consecutive 9581 • Current practice • USA and Europe
Heart FailureACEI ADR profile • SPICE registry of 8485 cases • Cough (308 - 4%) • Renal sufficiency (188 - 2%) • Symptomatic hypotension (147 - 2%) • Hyperkalaemia (35) • Rash / pruritus (25) • Angioedema / analyphaxis (19)
DIGOXIN Na-K ATPase Na-Ca Exchange Na+ K+ Na+ Ca++ Ca++ Myofilaments K+ Na+ CONTRACTILITY
Heart Failure Drug Therapy : Digoxin • Positive Inotropic • S-A and A-V Nodal actions • Enhanced Automaticity
DIGOXIN EFFECT ON CHF PROGRESSION 30 Placebo n=93 DIGOXIN Withdrawal % WORSENING OF CHF 20 p = 0.001 DIGOXIN: 0.125 - 0.5 mg /d (0.7 - 2.0 ng/ml) EF < 35% Class I-III (digoxin+diuretic+ACEI) Also significantly decreased exercise time and LVEF. 10 DIGOXIN n=85 0 60 0 20 40 80 100 RADIANCE N Engl J Med 1993;329:1 Days
Heart Failure The DIG Study • CHF patients (6800) studied 1991 - 1995 • 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
50 40 30 20 10 0 OVERALL MORTALITY Placebo n=3403 % p = 0.8 DIGOXIN n=3397 0 12 24 36 48 DIG Study N. Engl. J. Med. 1997: 336; 525 Months
Heart Failure The DIG Study • Mortality similar (34.8% vs. 35.1%) • Hospitalisations reduced 22% (16 - 28) • 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
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
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 0.8 - 2.0 ng / ml
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
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 0 50 100 150 200 250 300 350 400 Days Packer et al (1996) Survival Mortality (%) CIBIS-II MERIT-HF 1.00.80.6 0 20 Placebo Bisoprolol 15 Metoprolol CR/XL 10 Placebo Risk reduction=34% Risk reduction=34% 5 p=0.0062 p<0.0001 0 0 200 400 600 800 0 3 6 9 12 15 18 21 Time after inclusion (days) Months of follow-up The MERIT-HF Study Group (1999) CIBIS-II Investigators (1999)
Heart Failure ß - blocking Therapy • Over 13 000 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)
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
CHARM Programme 3 component trials comparing candesartan to placebo in patients with symptomatic heart failure CHARMAlternative CHARM Added CHARMPreserved 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
Every 4 months until study end31 March 2003 Time 0 w 2 w 4 w 6 w 6 m Visit 1 2 3 4 5 Study designDose-titration and visit schedule Candesartan/matching placebo once daily 32 mg 16 mg 8 mg 32 mg 4 mg 16 mg 8 mg
Baseline characteristics Alternative Added PreservedOverall n=2028 n=2548 n=3023 n=7599 Mean age (years) 67 64 67 66 Women (%) 32 21 40 32 NYHA class (%) II 48 24 60 45 III 49 73 38 52 IV 3 3 2 3Mean LVEF 30 28 54 39 Medical history (%) myocardial infarction 61 56 44 53 diabetes 27 30 28 28 hypertension 50 48 64 55 atrial fibrillation 25 26 29 27
CHARM Programme 3 component trials comparing candesartan to placebo CHARMAlternative CHARM Added CHARMPreserved 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
50 406 (40.0%) Placebo 40 334 (33.0%) 30 Candesartan 20 10 HR 0.77 (95% CI 0.67-0.89), p=0.0004Adjusted HR 0.70, p<0.0001 0 0 1 2 3 3.5 years CHARM-Alternative: Primary outcome CV death or CHF hospitalisation % Number at risk Candesartan 1013 929 831 434 122 Placebo 1015 887 798 427 126
CHARM-Alternative Investigator reported CHF hospitalisations Placebo Candesartan Proportion of patients (%) Number of episodes p=0.0001 p<0.0001 Hospitalisations Patients hospitalised
CHARM-Alternative Permanent study drug discontinuations Percent of patients Placebo 25 Candesartan 21.5 19.3 20 15 10 6.1 5 3.7 2.7 1.9 0.9 0.4 0.2 0.3 0.1 0 0 AE/lab. abnorm. Hypo-tension Increased creatinine Increasedpotassium Cough Angio-edema p=0.23 p<0.0001 p<0.0001 p=0.0005 p=0.69 p=0.50
CHARM-AlternativeConclusions • 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
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
Study Overview 5010 patients18 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 Valsartan40 mg bid titrated to160 mg bid Placebo Cohn JN et al. Eur J Heart Fail. 2000;2:439-446.
Patients’ Baseline Characteristics Valsartan(n = 2511) Placebo (n = 2499) Mean age (y) 62.4 63.0 Gender, male (%) 79.9 80.0 Race (%) White 89.8 90.9 NYHA Class (%) II 62.1 61.4III 36.1 36.3IV 1.7 2.2 Ejection fraction (%) 26.6 26.9 Background therapy (%)Diuretic 85.8 85.2 Digoxin 67.1 67.6 -Blocker 34.5 35.3 ACE inhibitor 92.6 92.8 Cohn JN et al. N Engl J Med. 2001;345:1667-1675.