3A B C D Stages in the Evolution of Heart Failure. Clinical CharacteristicsHypertensionDiabetes, Hyperchol.Family HxCardiotoxinsABHeart disease(any)AsymptomaticLV dysfunctionSystolic / DiastolicCDyspnea, FatigueReduced exerciseTolerance (current or past)DMarked symptomsat rest despitemax. therapyAHA / ACC HF guidelines 20014
4Classification of Recommendation Class I: General agreement or evidence that a therapy is beneficial►(therapy is recommended)Class II: Conflicting evidenceIIa: evidence in favor of efficacy►( therapy should be considered)IIb: evidence less well established►( therapy may be considered)Class III: Not recommended, may be harmful
5Level of evidenceLevel A: multiple randomized clinical trials or meta-analysisLevel B: single randomized trial, or non randomized studiesLevel C: Consensus opinion of experts
6Treatment Objectives Mainly decrease symptoms and prolong life But also:Decrease morbidity (hospital admissions, embolism…)Increase exercise capacity and improve quality of lifeControl neurohormonal changesRetard progression of CHFTreatment of Heart Failure.ObjectivesThe objectives of treatment of the patient with heart failure are many, but they may be summarized in two principles: decrease symptoms and prolong life. In daily practice, the first priority is symptom control and the best plan is to adjust to the individual patient’s particular circumstances over the course of therapy. Nevertheless, the rest of the listed objectives should not be forgotten, as medical therapy now has the potential for decreasing morbidity (hospital admissions, embolism, etc.), increasing exercise capacity (all of the usually prescribed drugs), improve the quality of life, control neurohormonal changes (ACE-I, beta blockers), retard progression (ACEI) and prolong life.
7Treatment of CHF All Control of risk factors Life style Treat etiologic cause / aggravating factorsDrug therapyRevascularizationICD (Implantable Cardiac Defibrillator)Ventricular resynchronization (CRT)Ventricular assist devicesHeart transplantArtificial heartNeoangiogenesis, Gene therapyAllSelected patients
8Correction of reversible causes IschaemiaValvular heart diseaseThyrotoxicosis and other high output statusShuntsArrhythmiaAtrial fibrillation, flutter,MedicationsCa channel blockers, some antiarrhythmics
9Pharmacologic Therapy DiureticsACE inhibitorsBeta BlockersARBsDigitalisSpironolactoneOtherTreatment of Heart Failure.DrugsThis is a simple and pragmatic classification of the vast numbers and types of medications in the pharmacopoeia for the treatment of heart failure.
11Adverse Effects of Diuretics. K+, Mg+ ( %) (sudden death ???)Na+Hyperuricemia ( %)Stimulation of neurohormonal activityHypotension. Pre-renal azotemia, Ototoxicity, Gastrointestinal, Metabolic Alkalosis.Skin rashes, Neutropenia, Thrombocytopenia
12Inhibitors of renin-angiotensin- aldosterone system Renin-angiotensin-aldosterone system is activated early in the course of heart failure and plays an important role in the progression of the syndrome
14ACE-I. Clinical Effects in CHF Improve symptomsReduce remodeling / progressionReduce hospitalizationImprove survivalTreatment of Heart Failure.Angiotensin Converting-Enzyme Inhibitors (ACEI): Mechanisms of actionACE-inhibitors cause arteriovenous vasodilatation. Venodilation is accompanied by reduction in PAD, PCWP, and LVEDP. Arterial vasodilatation decreases SVR and MAP and increases cardiac output, ejection fraction, and exercise tolerance. Heart rate and contractility do not change, and, thus, double product and myocardial oxygen demand are decreased. These effects are more noticeable in patients with low sodium levels, in whom there is an increased plasma renin activity. Vasodilatation is seen in various vascular territories: renal, coronary, cerebral, and musculoskeletal (increasing exercise capacity). Additionally, ACE-inhibitors cause diuretic and natriuretic effects that are a consequence of the inhibition of angiotensin II and aldosterone synthesis, as well as the increase in cardiac output and renal perfusion.It is now known that the magnitude and duration of blood pressure reduction correlates better with the activity of ACE in certain tissues (heart, vessels, kidney, adrenal, etc.) than with its plasma levels, which indicates that ACE-inhibitors act by inhibiting local tissue production of angiotensin II. Plasma levels of ACE are not good predictors of the magnitude of hemodynamic effects of ACE-inhibition.
15ACE-I Placebo Probability of Death Enalapril CONSENSUS 253 patients N Engl J Med 1987;316:1429ACE-I0.80.7Placebo0.6Probability ofDeathp< 0.0010.50.4p< 0.0020.3EnalaprilTreatment of Heart Failure.Angiotensin Converting-Enzyme Inhibitors (ACEI): SurvivalCONSENSUS. Prolonged administration of ACE-inhibitors reduces mortality in symptomatic heart failure. The first study to demonstrate this effect was CONSENSUS I. This graph shows the cumulative mortality curves of the treatment and placebo group in this randomized, double-blind trial. The study analyzed the effect of enalapril on prognosis of 253 patients with class IV heart failure, who also received digitalis, diuretics, and conventional vasodilators. At the end of 6 months of treatment, there was a clear-cut improvement in functional class, a reduction in the need for medications, and a 40% reduction in mortality (p<0.002). After 12 months the mortality reduction was 31% (p<0.001). Nonetheless, there were no differences in the incidence of sudden death between the two groups, or in the sub-group that received other conventional vasodilators. Another characteristic of this study was variability of the dose that was used for each patient (adjusted for tolerance and symptoms): mg/day. This aspect shows the importance of individualized treatment for heart failure patients.The CONSENSUS Trial Study Group. N Engl J Med 1987;316:1429.253 patientsNYHA IV0.231 %0.1123456789101112Months
16ACE-I % Mortality SOLVD (Treatment) N Engl J M 1991;325:293 Placebo 5040302010p =Placebon=1284% MortalityEnalapriln=1285Treatment of Heart FailureAngiotensin Converting-Enzyme Inhibitors (ACEI) : SurvivalSOLVD study-symptomatic heart failure. Mortality curves in patients with clinical heart failure in the SOLVD treatment study. In this study, 2589 symptomatic heart failure patients with EFs<35% (90% in functional class II – III) were randomized to receive enalapril or placebo. Mortality over a 41 month follow-up period was 39.7% in the enalapril arm and 35.2% in the placebo arm (p<0.004). The mortality reduction was chiefly mediated through less progression of heart failure; deaths due to arrhythmia were not reduced. Additionally, the enalapril group required fewer hospitalizations for heart failure.The SOLVD Investigators. N Engl J Med 1991;325:293N = 2589 CHF- NYHA II-III- EF < 35 %612182430364248Months
17ACE-I Mortality % Years SAVE 30 Placebo 20 Captopril 10 1 2 3 4 N Engl J Med 1992;327:669ACE-I30Asymptomaticventriculardysfunction post MIPlacebon=1116Mortality %20Captopriln=1115Treatment of Heart FailureAngiotensin Converting-Enzyme Inhibitors (ACEI): SurvivalSAVE (Survival and Ventricular Enlargement). Mortality curves in the SAVE study in patients with varying degrees of post-infarct ventricular dysfunction. In this study, 2231 patients with EF < 40% were randomized to receive captopril or placebo between 3 to 16 days after experiencing a transmural infarct. After 42 months, the captopril group had a significant reduction in overall mortality (-19%), number of reinfarctions (-25%), hospitalizations (-22%), and in the number of patients who developed clinical congestive heart failure. The mortality reduction appeared after 1 year of treatment.Pfeffer MA et al. Survival and Ventricular Enlargement (SAVE) Study. NEngl J Med 1992;327:669.10N = 2231days post AMIEF < 40 %mg / day² -19%p=0.0191234Years
18ACE-I AIRE Mortality % Placebo Ramipril p = 0.002 Months N = 2006 Lancet 1993;342:821ACE-IPlacebo30Mortality %20Ramipril10p = 0.002N = 2006HF after AMI612182430Months
19ACE-I Indications Symptomatic heart failure (stage C) Asymptomatic ventricular dysfunctionLVEF <35-40 % (stage B)Patients with recent or remote history of MI regardless of EF or presence of HF (stage B)Class I recommendationLevel of evidence AAHA / ACC HF guidelinesESC HF guidelines
20ACE-I. Practical Use Start with very low dose Renal function & serum K+ after 1-2 wIn the absence of fluid retention, ACE-I should be given first / In the presence of fluid retention together with diureticsDose NOT determined by symptoms. ACE-I should be up-titrated to dosages shown to be effective in clinical trials
21ACE-I. Adverse Effects Hypotension (1st dose effect) Worsening renal function, HyperkalemiaCoughAngioedemaRash, ageusia, neutropenia, …Pregnancy is a contra indicationTreatment of Heart Failure.Angiotensin Converting-Enzyme Inhibitors (ACEI) : Undesirable EffectsThese can be classified into two groups. One group includes those effects that are inherent to its mechanism of action, and therefore are common to all ACE-inhibitors. The other includes those effects that are related to the specific chemical structure of the drug. In this case, substitution of one ACE-inhibitor for another could possibly reduce the intensity of the adverse reaction (e.g. choosing an ACE-inhibitor without a sulfhydryl moiety).
22Substitute or adjunctive therapy to ACE inhibitors ? Angiotensin Receptor Blockers (ARBs) in Heart FailureSubstitute or adjunctive therapy to ACE inhibitors ?
23Potential advantages of ARBs ARBs more effective than ACE-I due to:- Better RAAS Blockade- Absence of angiotensin II escape- Placebo like side effects
24ELITE II: Endpoint Results 1.00.8All-cause mortalityProbability of Survival0.6Losartan0.4P = .16Captopril0.20.01.00.8Event-free Probability0.6Sudden death or resuscitated arrestP = .080.40.21.0The recommended treatment of HF due to left ventricular systolic dysfunction (ejection fraction, <0.35 to 0.40) ranges from monotherapy with ACEIs in patients with the mildest manifestations to the use of a combination of ACEI, digoxin, diuretic(s), and hydralazine HCl or isosorbide dinitrate for patients with severe HF.35 The efficacy of ACEIs in the treatment of HF is well established. However, some physicians do not prescribe these agents due to safety concerns surrounding the accumulation of bradykinin associated with these agents.36 Therefore, clinical studies with ARBs in HF were initiated in an effort to find out if similar efficacy was observed with better tolerability.In 1997, the results of a 48-week study in HF patients demonstrated a 46% risk reduction in mortality with losartan therapy (an ARB) compared to captopril (an ACEI).36 However, these results were analyzed with caution because mortality was a secondary endpoint of the study and the number of events in this initial trial were small.36 Therefore, a larger study, including over 3,000 patients with HF, randomized patients to losartan or captopril and evaluated death from any cause as the primary endpoint.36 After a median follow-up period of 1.5 years, no differences in all-cause mortality, sudden death or resuscitated arrest, or all-cause mortality or hospital admission were observed between the two treatment groups.36 Interestingly, losartan therapy was associated with significantly fewer discontinuations due to adverse events attributed to study drug or due to cough compared to captopril (P<.001).36 Worsening HF was reported in 25% of patients in each group and the frequency of discontinuations did not differ for worsening of HF.36Slide ReferencePitt B, Poole-Wilson PA, Segal R, et al, on behalf of the ELITE II investigators. Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: randomized trial–the Losartan Heart Failure Survival Study ELITE II. Lancet. 2000;355:0.8Event-free Probability0.6P = .180.4All-cause mortality or hospital admission0.2100200300400500600700Follow-up (days)(Reprinted with permission from Pitt B, et al. Lancet. 2000)
25Val-HeFT: Study Design and Inclusion Criteria 5010 patientsEF < 40%; NYHA II - IVReceiving background therapyACEIs (93%), diuretics (86%), digoxin (67%), beta-blockers (35%)Over 5,000 patients with chronic heart failure defined as NYHA class II (62%), III (36%), and IV (2%) with an ejection fraction of <40% and left ventricular diastolic transverse diameter (LVIDD) >2.0 cm/m2 were randomized to receive valsartan 40 mg twice daily titrated to 160 mg twice daily or placebo.38At the time of randomization, 93% of patients were receiving an ACEI, 86% a diuretic, 67% digoxin, and 35% were receiving a beta-blocker.38Slide ReferenceCohn JN, Tognoni G, for the Val-HeFT Investigators. A randomized trial of the angiotensin receptor blocker valsartan in chronic heart failure. N Engl J Med. 2001;345:Randomized toValsartan 40 mg bid titrated to 160 mg bidPlacebo(Cohn JN, et al. N Engl J Med. 2001)
26Time since randomisation (months) Effect of Valsartan on Combined Mortality and Morbidity End Point* in Overall PopulationAll-cause mortality and morbidityAll-cause mortality1.01.00.90.80.7Time since randomisation (months)p = 0.80Survival probability (%)369122118152427Valsartan0.90.8Event-free probabilityPlacebo0.7In the overall population, Val-HeFT showed a significant benefit on the primary endpoint combined morbidity and mortality, which was reduced by 13.2% (p=0.009), but a neutral effect on all-cause mortality.13% risk reduction p= 0.0090.6369121518212427Time since randomisation (months)Cohn et al. NEJM 2001;345:1667
27CHARM Program 3 component trials comparing Candesartan to placebo in patients with symptomatic heart failureCHARM AlternativeCHARM AddedCHARM Preservedn=2028LVEF £40% ACE inhibitor intolerantn=2548LVEF £40% ACE inhibitor treatedn=3025LVEF >40% ACE inhibitor treated/not treated
28CHARM Program Mortality and morbidity CV Death or CHF HospitalisationAll Cause Mortality0.77Alternativep=0.00040.85Addedp=0.0110.89Preservedp=0.1180.910.84Overallp=0.055p<0.00010.70.80.91.01.11.20.60.70.80.91.01.11.2Hazard ratioHazard ratiop heterogeneity=0.37p heterogeneity=0.43
29ARB Indications in CHF Patients intolerant to ACE-Inhibitors: (Class I recommendation in stage C)On top of ACE I and B Blockers in patients who remain symptomatic: optional (discrepancy in guidelines):Class I (ESC, CCS), IIa (HFSA), and IIb (ACC/AHA)Use of ARB instead of ACE-I is a Class IIa recommendation (reasonable, should be considered) in stage C heart failure
30Spironolactone Survival RALES Aldactone N = 1663 NYHA III-IV NEJM 1999;341:709Spironolactone1.00.90.80.70.60.5Annual MortalityAldactone 18%; Placebo 23%SurvivalAldactoneN = 1663NYHA III-IVMean follow-up 2 yMortality curves in the RALES study. (probably already shown by previous speaker). I will coment on the progressive increase in benefit and will made a comparation with the CIBIS-II results.p <monthsPlacebo61218243036
31Spironolactone. Indications Moderate-severe symptoms/advanced heart failureClass I recommendation, level of evidence BRoutine combination of ACE-I, ARB and aldosterone antagonist is not recommended (Class III)
32Spironolactone. Practical use Do not use if hyperkalemia, renal insuficienyMonitor serum K+ at “frequent intervals”Start ACE-i firstStart with 25 mg / 24h
33ß-Blockers Has been traditionally contraindicated in pts with CHF Now they are a corner stone in treatment of CHF
34ß-Adrenergic Blockers Mechanism of action Density of ß1 receptorsInhibit cardiotoxicity of catecholaminesNeurohormonal activationHRAnti-ischemicAnti-hypertensiveAnti-arrhythmicTreatment of congestive heart failure.Possible benefits of beta adrenergic blockers.
35ß-Adrenergic Blockers Clinical Effects in CHF Improve symptoms (only long term)Reduce remodeling / progressionReduce hospitalizationReduce sudden deathImprove survival
42ß-Adrenergic Blockers When to start ? Patient stableNo physical evidence of fluid retentionNo need for I.V. inotropic drugsStart ACE-I / diuretic firstStart Low, Increase SlowlyIncrease the dose every weeks
44ß-Adrenergic Blockers Adverse Effects HypotensionFluid retention / worsening heart failureFatigueBradycardia / heart blockReview treatment (+/-diuretics, other drugs)Reduce doseConsider cardiac pacingDiscontinue beta blocker only in severe cases
45Digitalis GlycosidesThe role of digitalis has declined somewhat because of safety concernRecent studies have shown that digitals does not affect mortality in CHF patients but causes significantReduction in hospitalizationReduction in symptoms of HF
46Digitalis DIG Mortality % 50 40 30 20 10 Placebo N=6800 NYHA II-III N Engl J Med 1997;336:5255040302010Mortality %Placebon=3403p = 0.8N=6800NYHA II-IIITreatment of heart failure.Digoxin: Effect on survivalThe results obtained from 3 controlled studies which included patients at low risk (The German and Austrian Xamoterol Study Group, 1988; The Captopril-Digoxin Multicenter Research Group, 1988; DiBianco et al., 1989) indicate that the mortality was similar in the group of patients with placebo. The results of the Digitalis Investigator Group-DIG study, which included 7788 patients with heart failure in sinus rhythm, functional class II-III and LVEF < 45%. The patients were treated with digoxin or placebo, in addition to conventional therapy over a mean of 37 months ( months). No differences in mortality were observed between the two treatment groups.Am Coll Cardiol 1996Digoxinn=339712243648Months
47Digitalis. Indications • Sinus rythm: When no adequate response to ACE-i + diuretics + beta-blockers• Atrial Fibrillation: to slow AV conductionDose to mg / dayNarrow therapeutic to toxic ratio !!
48Other Drugs. (only in selected patients) Inotropics: refractory HFNitrates: ischemia, angina, pulmonary congestionAntiarrhythmics: (only amiodarone) H risk arrhyth.Anticoagulants: High risk of embolism e.g Atrial Fibr.Ca channel blockers (only amlodipine): ischemia, hypertension28
50Cardiac Resynchronization Therapy for Heart Failure (CRT) Ventricular DysynchronyElectrical: Inter- or Intraventricular conduction delays typically manifested as left bundle branch blockMechanical: Regional wall motion abnormalities compromising ventricular mechanicsCardiac ResynchronizationModification of interventricular, intraventricular, and atrio-ventricular activation sequencesIntroduces “new” terms used in this slide series.Ventricular dysynchrony is defined as the effect caused by intra- and inter-ventricular conduction defects or bundle branch block. Read Dr. Tavazzi’s editorial referenced here for a summary of the three potential causes of ventricular dysynchrony.Cardiac resynchronization is defined as the therapeutic intent of atrial synchronized biventricular pacing for patients with heart failure and ventricular dysynchrony. The intent of the therapy is to resynchronize the ventricular activation sequence, and to better coordinate atrial-ventricular timing to improve pumping efficiency.Cardiac resynchronization therapy is currently indicated for the reduction of symptoms of moderate to severe heart failure (NYHA Function Class III or IV) in those patients who remain symptomatic despite stable, optimal medical therapy, and have a left ventricular ejection fraction 35% and a QRS duration 130 ms. An ICD is also available for patients with a standard ICD indication who also meet the above listed criteria.Using atrial-synchronized biventricular pacing in combination with optimal drug therapy has been shown to significantly improve a patient’s symptoms.Tavazzi L. Eur Heart J 2000;21:
51Primary and secondary outcomes in CARE-HF: 409 CRT-treated patients as compared with 404 control patientsOutcomesHazard ratio (95% CI)pAll-cause mortality0.64( )0.0019All-cause mortality/HF hospitalization0.54( )<0.0001Cleland JG. NEJM 2005; 352:
52Cardiac Resynchronization Therapy (CRT) NYHA class III or IV, LVEF < 0.35 and dyssynchrony (QRS >= 120 ms)Class I recommendation, Level A
53Intra Cardiac Defibrillator. Indications in Secondary Prevention Patients with sustained VT or SCD → ICD
54Intracardiac Defibrillator Mortality outcomes over five years in SCD-HeFT (Sudden Cardiac Death in Heart Failure Trial)ParameterICD,n=829Amiodarone, n=845Placebo, n=847All-cause mortality (%)222829Mortality risk vs placebo, HR (97.5% CI)0.77( ), p=0.0071.06( ), p=0.53—* randomized 2521 patients with NYHA class 2-3 HF and an LVEF <35%Bardy GH et al. N Engl J Med 2005; 352:
55ICD indications Primary prevention NYHA class II or III and LVEF <= 30 %With a reasonable life expectancy > 1 yearClass I recommendationHowever may be indicated even in stage B (NYHA class I) especially in ischemic aetiology
56Heart Transplant. Indications Refractory cardiogenic shockDocumented dependence on IV inotropic supportSevere symptoms of ischemia not amenable to revascularizationRecurrent symptomatic ventricular arrhythmias refractory to all therapeutic modalities
57Stages in the Evolution of Heart Failure.TreatmentTreat risk factors.ACE-I (or ARB) in appropriate pts for vascular disease or diabetesAAHA / ACC HF guidelines 2005ACE-I, ARB,-Blockers in appropriate pts.ICD in selected pts.B(Asymptomatic LV Systolic Dysfunction)C(Symptomatic LV Systolic Dysfunction)Routine: ACE-I, blockers, DiureticsIn selected pts: aldost antag, ARB, Digitalis, nitratesICD, CRTD(Refractory End-Stage HF)CRTMech. Assist deviceHeart Transplant4