optimizing heart failure management 2005 bridging the care gap
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Optimizing Heart Failure Management
2005 Bridging the CARE GAP
Optimizing Heart Failure Management
2005 Bridging the CARE GAP
CME Needs of Family Physicians re CHF
CME Needs of Family Physicians re CHF
• Early detection• Etiology• Prognosis• Diagnosis
– Physical exam– Asymptomatic LV
dysfunction
• How to use beta blockers– Which beta blocker– Better standardization of
therapy
• Rx titration – Diuretics– Beta blockers
• Post hospital interventions– Lifestyle– Patient education
• Diet• Rx• Exercise Rx
• Compliance• Multi-system disease
– Renal disease
Measuring the Impact of HFMeasuring the Impact of HF
• Currently, there are over 500,000 Canadians with HF
• Incidence 50,000 cases/year• One year mortality after diagnosis ranges between
25-40% (ICES Atlas)• 1% of Canadians over age 65 and 4% of
Canadians over 70 have CHF • The age-adjusted mortality for CHF is
106/100,000
Measuring the Impact of HFMeasuring the Impact of HF
• Median survival currently 1.7 years for males, 3.2 yrs for females
• 5-year age adjusted mortality rate of 45% based on the time period 1990-1999
• Commonest diagnosis that brings a patient to hospital for medical admission.
• Re-admission rates are 46% within 3 months of discharge and 54% within 6 months.
Heart Failure EpidemiologyHeart Failure Epidemiology
• Heart failure associated with high morbidity and mortality
• Contemporary Canadian data to quantify the burden of CHF is limited
• In 2000/01:– Total of 106,130 discharges for 85,679 CHF patients– 32.7% of discharges were readmissions – 19.9% of patients were re-hospitalized once or more during 2000– Total in-hospital mortality was 15.8%.– CHF is associated with the second highest total number of hospital
days and third highest number of patients affected.
Can J Cardiol. 2003 Mar 31;19(4):436-8.Contemporary burden of illness of congestive heart failure in Canada.
Tsuyuki RT, Shibata MC, Nilsson C, Hervas-Malo M.
Contemporary burden of illness of congestive heart failure in Canada.
Tsuyuki RT, Shibata MC, Nilsson C, Hervas-Malo M.
Contemporary burden of illness of congestive heart failure in Canada.
Tsuyuki RT, Shibata MC, Nilsson C, Hervas-Malo M.
“These figures should signal a call to action for researchers, administrators and health care providers regarding the need for more efficacious therapies, better application of already-proven therapies and patient education.”
Can J Cardiol. 2003 Mar 31;19(4):436-8.
Heart Failure is the Quintessential Disorder of Cardiovascular Aging
Heart Failure is the Quintessential Disorder of Cardiovascular Aging
• Convergence of– Age related changes in cardiovascular
structure and function
• Rising prevalence of – Hypertension– Coronary heart disease– Valvular heart disease
NORMAL
Asymptomatic LV Dysfunction
CompensatedCHF
DecompensatedCHF
No symptomsNormal exerciseNormal LV fxn
No symptomsNormal exerciseAbnormal LV fxn
No symptoms ExerciseAbnormal LV fxn
Symptoms ExerciseAbnormal LV fxn
RefractoryCHF
Symptoms not controlled with treatment
Chronic Congestive Heart FailureEvolution of Clinical Stages
Chronic Congestive Heart FailureEvolution of Clinical Stages
Ventricular Remodeling in CHFVentricular Remodeling in CHF
Jessup, NEJM 2003
Symptoms of HF Symptoms of HF
• Fatigue
• Activity decrease
• Cough (especially supine)
• Edema
• Shortness of breath
DIET Approach to the Patient With Heart Failure
• Diagnose– Etiology
– Severity (LV dysfunction)
• Initiate– Diuretic/ACE inhibitor -blocker
– Spirololactone
– Digoxin
• Educate– Diet
– Exercise
– Lifestyle
– CV Risk
• Titrate– Optimize ACE
inhibitor
– Optimize -blocker
Therapy of CHF Therapy of CHF
Clinical Approach to CHF: Consider etiologyIdentify triggersExclude ischaemiaGeneral measuresSymptomatic therapyPrognostic therapy
See Guide for HF Management Check-list
Guide for HF Management Guide for HF Management Approach Recommendations
Symptoms & Signs of HF:
Fatigue (low cardiac output), SOB, JVP, rales, S3, edema, radiologic congestion, cardiomegaly. Elevated BNP. CXR to r/o infection, interstitial lung disease & PPH
Ejection fraction (obtain echo or LV gated study)
40% = systolic dysfunction 40-55% = mixed systolic and diastolic dysfunction 55% = diastolic dysfunction - treat underlying disorder (HPT/ischaemia/pericardial constriction/restrictive CM (cardiomyopathy)/infiltrative disorders)
Consider etiology
Ischemic-CM HPT-CM Valvular HD-CM (AS/AR/MR) Metabolic: hyper/hypo thyroidism / hemochromatosis/pheochromocytoma Toxins: Alcohol/ anthracyclines/cocaine/amphetamines Viral CM Idiopathic Dilated CM Other:
Identify triggers Acute-sudden onset Ischaemia, arrhythmia, infection, pulmonary embolism, acute valvular pathology
Chronic-gradual onset Anemia, thyrotoxicosis, non-compliance, diet, Rx e.g. NSAID’s
Treatment: Correct triggers and precipitants of acute and chronic Heart Failure
General measures Low sodium diet Regular exercise/activity Treat ischemia Control hypertension
D/C smoking Treat lipid abnormalities Treat and control diabetes Identify & Rx depression
Symptomatic therapy Diuretics-titrate to euvolemic state Maintain Ideal Body Weight (dry weight = JVP normal / trace pedal edema) Furosemide 20 - 80 mg OD-BID
HCT/Zaroxolyn for refractory congestion Digoxin-for persisting symptoms in NSR (systolic dysfunction) or symptoms and rate
control in Afib. Dose: 0.125 mg – 0.25 mg (Lower dose in elderly: 0.0625 mg) Therapy to
improve prognosis
AACCEE IInnhhiibbiittoorrss--GGeenneerraall GGuuiiddeelliinnee:: SSttaarrtt llooww aanndd ttiittrraattee ttoo tthhee ttaarrggeett ddoossee uusseedd iinn tthhee cclliinniiccaall ttrriiaallss oorr tthhee MMAAXXIIMMUUMM TTOOLLEERRAATTEEDD DDOOSSEE:: CCaappttoopprriill 66..2255--1122..55 mmgg 5500 mmgg BBIIDD--TTIIDD EEnnaallaapprriill 22..55mmgg 1100mmgg BBIIDD†† RRaammiipprriill 22..55 mmgg 55mmgg BBIIDD §§ LLiissiinnoopprriill 22..55 mmgg 3300--4400 mmgg OODD
TTrraannddoollaapprriill 11 44 mmgg mmgg OODD‡‡ **QQuuiinnaapprriill 1100 mmgg 4400 mmgg OODD **CCiillaazzaapprriill 00..55 mmgg 1100 mmgg OODD **FFoossiinnoopprriill 55 mmgg 4400 mmgg OODD *Perindopril 4 mg 88 mmgg OODD **NNoo llaarrggee ssccaallee oouuttccoommee ttrriiaallss †† SSooLLVVDD//XX--SSooLLVVDD §§ AAIIRREE //AAIIRREEXX‡‡TTRRAACCEE Consider ISDN 5-40mg QID+Hydralazine 10-75mg QID for ACE-I/ARB intolerance VHeFT
CCoonnssiiddeerr AACCEE--II//AARRBB ccoommbbiinnaattiioonn iinn AACCEE--II aanndd //oorr --bblloocckkeedd ppaattiieennttss wwiitthh wwoorrsseenniinngg HHFF oorr hhoossppiittaalliizzaattiioonn
Angiotensin II receptor antagonists (ARB’s) AACCEE--IInnhhiibbiittoorrss rreemmaaiinn ffiirrsstt lliinnee tthheerraappyy AARRBB’’ss iinnddiiccaatteedd iinn AACCEE--II iinnttoolleerraanntt ppaattiieennttss ((CCHHAARRMM ccaannddeessaarrttaann 1166--3322 mmgg OODD)) ((VVaall--HHeeFFTT //VVAALLIIAANNTT vvaallssaarrttaann 116600 mmgg BBIIDD))
Beta-blockers-Add Beta-blocker* to ACE-inhibitor/diuretic/+/- digoxin in stable Class II-IV CHF/LVEF 40% (*No outcome data for other beta-blockers) Bisoprolol* 1.25 10 mg OD (CIBIS II Trial) Carvedilol* 3.125 mg BID 25 mg BID (50 mg BID if weight > 85 kg) Metoprolol* 12.5 mg BID 75 mg BID (MERIT Trial)
Caution:diabetics/renal disease/elderly/ NSAIDs & COX-2 inhibitors
Aldosterone antagonist (follow K/Cr in 3-7 days/ furosemide to avoid azotemia) Spironolactone 12.5-25 mg OD added to ACE-inhibitor/diuretic/+/- digoxin in stable
Class III-IV CHF/LVEF 35%/CR<220/K<5.0 (RALES Trial) Anti-coagulant
anti-platelet Rx ASA if CAD ( dose to ACE inhibitor interaction) Coumadin for Afib, LV thrombus, LVEF 20%, DVT or pulmonary embolism Duration of A/C therapy: Indefinite for Afib/recurring systemic TE or DVT/PE
Consider Internal Medicine/Cardiology or Heart Failure Clinic referral for initiation/titration of - blocker. Consider EPS referral for symptomatic sustained or non-sustained ventricular arrhythmia (LVEF 30-40%) or AICD: Prior MI/CAD (LVEF 30% with IVCD 0.12 sec: MADIT II) CHF: (NYHA II-III & LVEF <35% SCD-HeFT) Cardiac Resynchronization Therapy(CRT):(NYHA Class III-IV with reduced ejection fractions; LVEF < 35%; QRS duration 0.13 with IVCD or LBBB: MIRACLE / MUSTIC) or both CRT/AICD: (NYHA III-IV;QRS 0.12:COMPANION). EECP/Transplant for refractory CHF.
Symptoms & Signs of HF:Symptoms & Signs of HF:
• Fatigue (low cardiac out-put)• SOB JVP• Rales• S3• Edema• Radiologic congestion• Cardiomegaly
Obtain CXR to r/o non-cardiac causes e.g. interstitial lung disease & PPH
BNP in the Diagnosis of HFBNP in the Diagnosis of HF
The role of natriuretic peptides• ANP-atrial natriuretic peptide
– Produced in atria in response to wall stress
• BNP-brain natriuretic peptides– Produced in ventricles in response to volume and pressure
overload
• CNP-central nervous system and endothelium– Produced in response to endothelial stress
• Produced as prohormones and cleaved to active molecule (ANP/BNP)and inactive NT forms
BNP in the Diagnosis of HFBNP in the Diagnosis of HF
ANP/BNP elevated in • Heart failure
• Systemic and pulmonary hypertension
• Hypertrophic and restrictive cardiomyopathy
• Pulmonary embolism
• COPD
• Cor pulmonale
• AMI Cirrhosis
• Renal Failure
BNP in the Diagnosis of HFBNP in the Diagnosis of HF
Higher levels of BNP correlate with• higher PCW pressures
– in compensated and decompensated patients
• larger LV volumes• lower ejection fractions
– in symptomatic HF patients
• BNP study (Circ 2002;106: 416-422)
– BNP sensitivity 90% and specificity 73% for HF
BNP Diagnostic Cut Points for CHF JACC 2001;37(2):379-85.
BNP Diagnostic Cut Points for CHF JACC 2001;37(2):379-85.
BNP > 400 pg/L – acute CHF present BNP 100 pg/L – 400 pg/L• Diagnostic of CHF with
– Sensitivity 90%– Specificity 76%– Predictive accuracy 83%– R/O pulmonary embolism, LV dysfunction without
acute CHF or cor pulmonale
BNP < 100 pg/L – 98% negative predictive accuracy
Identify triggers Identify triggers
Acute-sudden onset • Ischaemia• Arrhythmia• Infection • Pulmonary
embolism• Acute valvular
pathology
Chronic-gradual onset • Anemia• Thyrotoxicosis• Non-compliance• Diet• Rx e.g. NSAID’s
Non-Invasive Evaluation of the Heart Failure Patient-Implications of LV Ejection Fraction
Non-Invasive Evaluation of the Heart Failure Patient-Implications of LV Ejection Fraction
• To know where you are going you must know where you are coming from
• Evaluate LV function clinical echo gated study
Ejection fraction (obtain echo or LV gated study)
Ejection fraction (obtain echo or LV gated study)
• LVEF 40% = systolic dysfunction• LVEF 40-55% = mixed systolic and
diastolic dysfunction• LVEF 55% = diastolic dysfunction
identify triggers – treat underlying disorder
(HPT/ischaemia/pericardial constriction/restrictive CM/infiltrative disorders)
Echocardiographic Evaluation of CHF
Echocardiographic Evaluation of CHF
• LV function (EF),chamber size,wall motion
• Segmental dysfunction-coronary disease
• MS-severity, valve area
• AS- valve gradient, valve area
• AR/MR severity
• TR- RV systolic pressure = PA pressure
• RV function
• R/O IHSS, HCM
• R/O Pericardial Disease
• R/O rare causes e.g. myxoma, infiltrative disorders- restrictive cardiomyopathy
• Diastolic function
• Hyperdynamic states
Diastolic DysfunctionDiastolic Dysfunction
• 30-50% of elderly HF patients have reserved LV systolic function
• Diastolic dysfunction may induce dyspnea on exertion
• Frank congestion usually has identifiable precipitant
Clinical Implications of LV Dysfunction in Heart FailureClinical Implications of LV Dysfunction in Heart Failure
• Calculated EF by echo unreliable in remodeled LV
• Visual estimate of EF semi-quantitative
• (CCN LV function scale)– Grade I LV EF ≥50%
– Grade 2 LVEF 35-49%
– Grade 3 LVEF 20-34%
– Grade 4 LVEF< 20%
LVEF Entry Criteria in ACE inhibitor and
-blocker Trials
– SOLVD treatment an prevention 35%
– SAVE (post MI) 40%
– U.S. Carvedilol HF Trials Program LVEF 35%
– Merit-HF LVEF 40%
– CIBIS II LVEF 40%
Consider etiologyConsider etiology
• Ischemic- Cardiomyopathy (CM) • HPT-CM • Valvular HD-CM (AS/AR/MR) • Metabolic:
/ thyroid/hemochromatosis/ pheochromocytoma • Toxins:
Anthracyclines/Etoh/cocaine/amphetamines • Viral CM • Idiopathic Dilated CM • Other:
TreatmentGeneral Measures
TreatmentGeneral Measures
General measures:• Correct triggers and
precipitants of acute and chronic HF
• Low sodium diet• Fluid restriction• Regular exercise/• Activity HR Rx
• Treat ischemia• Control hypertension• D/C Smoking• Treat lipid
abnormalities• Treat and control
diabetes• Identify & Rx
depression
Diagnostic Tests:CXR/ECG/BNP
Echo/RNA/MRI:Etiology/Severity
Additional TestsSpecific Tx
•Cath•CABG
•Valve Sx
Diastolic HF:Rx causeReferral
Systolic HF:MedicalSx/Device
Is it Heart Failure?Symptoms & Signs
Life Style + Patient EducationHF Clinics F/U
HF Management AlgorithmHF Management Algorithm
YES
YES
Primary Targets of Treatments in CHF
Primary Targets of Treatments in CHF
Jessup, NEJM 2003
Assess LV Function (echo, gated RNA)•EF < 40%-systolic dysfunction
•EF 40-55%-systolic/diastolic dysfunction
•EF >55%-diastolic dysfunction
Assess Volume Status
Signs and Symptoms of Fluid Retention
No Signs and Symptoms of Fluid Retention
Loop Diuretic+/- Thiazide
(titrate to euvolemic state)
ACE inhibitor/ARB if ACE intolerantCombination Rx if HF, hospitalization or -blocker intolerant
Spironolactone (NYHA Class III-IV CHF/EF<35%/Cr<200/K<5)
Add Digoxin for symptom control
Symptoms Prognosis & Symptoms
-blocker (NYHA II-IV)
Heart Failure Therapeutic GoalHeart Failure Therapeutic Goal
• Mild-Moderate Heart Failure
– Primary goal = Reduce mortality -blockers + ACE inhibitors
– Prevent progression to symptoms
– Prevent progressive LV dysfunction
Heart Failure Therapeutic GoalHeart Failure Therapeutic Goal
• Moderate-Severe Heart Failure
– Primary goal = Reduce symptoms
– Improve quality of life (QOL)
– Reduce hospitalizations
– Prevent sudden death
Inotropes, mitral repair, VAD, TxInotropes, mitral repair, VAD, Tx
General Rx Strategies in HFGeneral Rx Strategies in HF
Angiotensin Converting Enzyme InhibitorsAngiotensin Converting Enzyme Inhibitors
Carvedilol/ Carvedilol/ -Blockers-Blockers
Diuretics (Spironolactone)Diuretics (Spironolactone)
DigoxinDigoxin
No Added SaltNo Added Salt 2 gm Na2 gm NaActivity as ToleratedActivity as Tolerated Customized Ex TrainingCustomized Ex Training
Tailored RxTailored RxCorrect Cause:Correct Cause:ArrhythmiasArrhythmiasIschemiaIschemiaPressure LoadPressure Load
AsymptomaticAsymptomatic Mild/ModMild/Mod SevereSevere RefractoryRefractory
Modified from Warner-Stevenson, ACC HF SummitModified from Warner-Stevenson, ACC HF Summit
Symptomatic therapySymptomatic therapy
Diuretics (see How to Adjust Your Diuretic)• Titrate to euvolemic state• Maintain Ideal Body Weight
– (dry weight = JVP normal / trace pedal edema)• Furosemide 20 mg. – 80 mg OD-BID• HCT/Zaroxolyn for refractory congestionDigoxin• For persisting symptoms in NSR (systolic
dysfunction) • or symptoms and rate control in Afib.
Dose: 0.125 mg – 0.25 mg (Lower dose in elderly: 0.0625 mg)
The Effect of Digoxin on Mortality and Morbidity in Patients with Heart FailureThe Effect of Digoxin on Mortality and Morbidity in Patients with Heart Failure
1
Digitalis
Investigation Group (DIG Trial)
Sponsored by the National Heart, Lung, and Blood Instituteand Department of Veterans Affairs
Cooperative Studies Program
- a large simple, long-term trial
NEJM Volume 336:525-533 February 20, 1997 Number 8
13
Placebo
Digoxin
p = 0.80
Months
0 4 8 12 16 20 24 28 32 36 40 44 48 520
10
20
30
40
50
DIG: All Cause Deaths
Per
cent
Mor
talit
y
15
0
10
40
30
50
20
p = 0.0001
Placebo
Digoxin
Months
0 4 8 12 16 20 24 28 32 36 40 44 48 52
DIG: CHF Mortality or Related Hospitalizations
Per
cent
Eve
nt
DIG TrialDIG Trial
DIG TrialDIG Trial
16
25 -45< 25
YesNo
IHDNon-IHD
< 0.55> 0.55
I/IIIII/IV
Overall
0.25 0.5 0.75 1 1.25(Risk Ratio: Active/Control)
Benefit Harm
DIG: CHF Mortality or Related Hospitalizations
EF
Prev Dig Use
Etiology
CT Ratio
NYHA Class
20
DIG: Conclusions
• No effect on overall survival
• Reduced worsening heart
failure deaths
• Reduced worsening heart
failure hospitalizations
• Small absolute excess in
digoxin toxicity
ACE Inhibitors are the Cornerstone of Rx in CHF
ACE Inhibitors are the Cornerstone of Rx in CHF
CCS 2003 Consensus HF Update (draft)• ACE I Rx ASAP post MI
– Continue indefinitely if EF < 40% or clinical HF
– Rx for all asymptomatic patients with LVEF 35%
– Rx for all symptomatic patients with LVEF 35%
– Target dose use in clinical trials or max tolerated dose
ACE Inhibitors in CHFACE Inhibitors in CHF
Study No. Males Age EF% Class Drug F/U Mortality Reduction
% V-HeFT 642 100% 58 30 II.III HDZN/
ISDN 2.3 yrs.
11
CONCENSUS 253 70% 70 NA IV Enalapril 188 Days
27
V-HeFT II 804 100% 61 29 II,III Enalapril 2.5 yrs.
14
SOLVD Treatment
2569 80% 61 25 II,III Enalapril 41.4 mo.
16
SOLVD Prevention
4228 89% 59 28 I,II Enalapril 37.4 mo.
8
ACE Inhibitors Post MIACE Inhibitors Post MI
Trial No. Entry Criteria
Drug Initiation Period
F/U Period Effect on Mortality
SAVE 2231 EF<40% Captopril 3-16 days 2-5 years + CONCENSUS II 6090 ALL Enalapril <24 hours 1.5-6 months -
AIRE 2006 CHF Ramipril 3-10 days 6-30 months + GISSI 3 20,000 All Lisinopril < 24 hours 6 weeks + ISIS 4 60,000 All Captopril 24 hours 5 weeks +
TRACE 1749 LVD Trandolapril 3-7 days 2-4 years + Chinese study 10,000 All Captopril < 36 hours 5 weeks +
SMILE 1556 AWMI Zofenopril < 24 hours 5 weeks +
Overview of Long Term ACE Inhibitor Trials Showing Mortality Benefit
Overview of Long Term ACE Inhibitor Trials Showing Mortality Benefit
Study Number Criteria RRR % ARR % NNT Lives saved/1000
SOLVDTreatment
2569 LVEF
35%
16 4.5 22 50
SAVE 2231 LVEF
40%
19 4.2 24 45
AIRE 2006 ClinicalCHF
27 5.7 18 60
TRACE 1749 LVEF
35%
22 7.6 13 90
What’s New in Ace inhibition in HFLong Term Follow-up
What’s New in Ace inhibition in HFLong Term Follow-up
X -SOLVDX -SOLVDEffect of Enalapril on 12-Year Survival and Life Expectancy in Patients with Left Ventricular Systolic Dysfunction
X-SOLVD Investigators
Philip Jong,* Salim Yusuf,* Michel F. Rousseau,** Sylvie A. Ahn,** Shrikant I. Bangdiwala***
*Population Health Research Institute, McMaster University - Hamilton, Canada **Division of Cardiology, University of Louvain - Brussels, Belgium
***Collaborative Studies Coordinating Center, University of North Carolina - Chapel Hill, USA
SOLVDSOLVD
X-SOLVD
X-SOLVD
Mortality in SOLVD Trials
SOLVD Prevention
Years after Randomization
Mo
rta
lity
0 1 2 3 40.0
0.1
0.2
0.3
0.4
0.5
Enalapril (n=399)Placebo (n=436)
2P=0.30 at 4 years
SOLVD Treatment
Years after Randomization
Mo
rta
lity
0 1 2 3 40.0
0.1
0.2
0.3
0.4
0.5
Enalapril (n=299)Placebo (n=333)
2P=0.0072 at 4 years
Adapted from: The SOLVD Investigators. N Engl J Med 1992;327:685-691 & N Engl J Med 1991;325:293-302.
X-SOLVD
X-SOLVD
Months after Randomization
HF
Dev
elo
pm
en
t0 6 12 18 24 30 36 42 48
0
5
10
15
20
25
30
35
40 Relative Risk 0.63(95% CI 0.56-0.72)p<0.001 at 4 years
Enalapril (n=438)Placebo (n=640)
HF Development in Prevention Trial
Adapted from: The SOLVD Investigators. N Engl J Med 1992;327:685-691.
X-SOLVDX-SOLVD
X-SOLVD
X-SOLVD Cumulative 12-Year Survival
in Prevention Trial
Years after Randomization
Pro
po
rtio
n o
f S
urv
ivo
rs
0 1 2 3 4 5 6 7 8 9 10 11 120.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
In-TrialPeriod
Trial Termination
0.86
0.84
5-year
0.77
0.730.47 (n=319)
0.41 (n=297)
EnalaprilPlacebo
p=0.001 at 12 years
Adapted from Jong et al. Lancet 2003;361:1843-1848.
Number at RiskEnalapril 2111 1917 1736 1533 1348 1010 319Placebo 2117 1901 1664 1457 1252 935 297
X-SOLVD
X-SOLVD Cumulative 12-Year Survival
in Treatment Trial
Years after Randomization
Pro
po
rtio
n o
f S
urv
ivo
rs
0 1 2 3 4 5 6 7 8 9 10 11 120.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
In-TrialPeriod
Trial Termination
0.64
0.60
5-year
0.53
0.490.21 (n=153)
0.20 (n=151)
EnalaprilPlacebo
p=0.01 at 12 years
Adapted from Jong et al. Lancet 2003;361:1843-1848.
Number at Risk
Enalapril 1285 1009 785 612 454 346 153Placebo 1284 940 719 562 425 328 151
Optimal Dosing of ACE Inhibitors
Optimal Dosing of ACE Inhibitors
• General Guideline:• Start low and titrate to
the target dose used in the clinical trials or the MAXIMUM TOLERATED DOSE (ATLAS trial)
• Captopril 6.25-12.5 mg 50 mg BID-TID (SAVE)
• Enalapril 2.5 mg BID 20 mg BID (SOLVD/X)
• Ramipril 2.5 mg BID 5 mg BID (AIRE/EX)
• Lisinopril 10 mg OD 30-40 mg OD (GISSI 3)
• Trandolapril 1mg 4 mg (TRACE)
Summary – ARBs in CHFSummary – ARBs in CHFELITE II Val-HeFT VALIANT CHARM
ARB vs ACEI ARB vs placebo ( ACEI BB)
Captopril, Valsartan or Combination
ARB vs placebo ( ACEI)
# pts. 3,152 5,010 4909/4909/4885 7,601
Popula-tion
Heart failure Heart failure Post MI with
clinical or radiologic HF
Symptomatic HF Class II-III/ LV function/preserved LVF (added+alternative/preserved)
End-points
1o All-cause mortality, sudden death or resuscitated cardiac arrest: NS
1o All-cause mortality: NS
1o Combined M/M: ACEI+ARB = -13.2%
ACE intolerant: -33% all cause mortality
1o All-cause mortality: NS2o CV Death, MI, or HF:NS
Valsartan non-inferior to Captopril
1o All-cause mortality: NS
2o CV death or HF hospitalization:
•CHARM Added:
–ACEI+ARB = -15%
•CHARM Alternative:
–ARB = -30%
•CHARM Preserved: NS
Combined Morbidity/Mortality in Subgroups: Val-HeFT
Combined Morbidity/Mortality in Subgroups: Val-HeFT
No. patientsAll 5010
Demographics< 65 266065 2350Male 4007Female 1003
Etiology/Co-morbidityIHD (yes) 2865IHD (no) 2145Diabetes (yes) 1276Diabetes (no) 3734
Disease SeverityNYHA II 3095NYHA III/IV 1910EF 27 2623EF < 27 2385LVIDD < 3.57 2505LVIDD 3.57 2505
0.4 0.6 0.8 1.0 1.2 1.4
Favors valsartan Favors placebo
Cohn JN, et al: Val-HeFT NEJM December 2001
Mortality in SAVE,TRACE, AIRE, and VALIANT
Mortality in SAVE,TRACE, AIRE, and VALIANT
Hazard Ratio for Mortality
FavorsActive Drug
FavorsPlacebo
Pfeffer M et al. N Engl J Med 2003;349:1893-906
0.5 1 2
CombinedCombined
TRACETRACE
SAVESAVE
AIREAIRE
VALIANTVALIANT(imputed placebo)(imputed placebo)
Valsartan preserves 99.6% of mortality benefit of captopril,
representing a 25% RR
CHARM Programme Mortality and morbidityCHARM Programme Mortality and morbidity
0.7 0.8 0.9 1.0 1.1 1.2 0.6 0.7 0.8 0.9 1.0 1.1 1.2
All Cause Mortality CV Death or CHF Hospitalisation
Hazard ratio Hazard ratio
p heterogeneity=0.43
Alternative
Added
Preserved
Overall
p heterogeneity=0.37
p=0.0004
p=0.055
p=0.011
p=0.118
p<0.0001
0.77
0.85
0.89
0.840.91
Diovan Avapro Cozaar Atacand Micardis Teveten(valsartan) (irbesartan) (losartan) (candesartan (telmisartan) (eprosartan)
cilexetil)
Reduction in -45% -6% -35% -30% N/a N/a microalbumin-uria withstarting dose
Heart failure -27.5% N/a -8.1% -17% N/a N/a hospitaliza- (ValHeFT) (ELITE II) (CHARM) tions
CV outcome in -13.3% N/a +7% -15% N/a N/a CHF-treated (ValHeFT) (ELITE II) (CHARM) patients
Positive CV Yes N/a No Yes N/a N/a outcomes inCHF
Equivalent Yes N/a No N/a N/a N/a Efficacy to ACEipost MI
Evidence for Various ARBsEvidence for Various ARBs
-Blocker Saves Lives in Heart Failure?
-Blocker Saves Lives in Heart Failure?
––blocker is the most important progress in blocker is the most important progress in Heart Failure Rx in the last 5 yearsHeart Failure Rx in the last 5 years
Trial HF Pts N Rx RR US Carvedilol II-III 1,094 Carvedilol 0.35
Aus-NZ II 415 Carvedilol 0.74
CIBIS II EF<35% 2,647 Bisoprolol 0.66
MERIT EF<40% 3,991 Metopr-CR 0.66 COPERNICUS EF<25% 2,289 Carvedilol 0.65
Trial HF Pts N Rx RR US Carvedilol II-III 1,094 Carvedilol 0.35
Aus-NZ II 415 Carvedilol 0.74
CIBIS II EF<35% 2,647 Bisoprolol 0.66
MERIT EF<40% 3,991 Metopr-CR 0.66 COPERNICUS EF<25% 2,289 Carvedilol 0.65
HF Trials Modulating receptorsHF Trials Modulating receptors
Background Rx = ACEi + Diuretics +/- DigoxinBackground Rx = ACEi + Diuretics +/- Digoxin
Number Need to Rx in HFNumber Need to Rx in HF
TRIAL Therapy Annual Mortality-Placebo
Annual Mortality-Treatment
Absolute Risk Reduc’n
NNRx/year to Save One Life
SOLVD Enalapril vs. Plac 12.5% 11.2% 1.3% 77
MERIT Metoprolol vs. Plac 11.0% 7.2% 3.8% 26
CIBIS-2 Bisoprolol vs. Plac 13.2% 8.8% 4.4% 23
COPERNICUS
Carvedilol vs. Plac 18.5% 11.4% 7.1% 14
RALES Spiro vs. Placebo 22.5% 15.8% 6.7% 15
Lee, Liu, PackerLee, Liu, Packer
-adrenergic Blocking Agents-adrenergic Blocking Agents
• Titrate to target dose– Bisoprolol 1.25 -10 mg OD– Carvedilol 3.125 - 25 mg BID– Metoprolol 12.5 - 50 to75 mg /BID
• If unable to tolerate high dose -blocker maintain highest tolerated dose
• Continue indefinitely
Patient Selection for Successful - Blocker Initiation
Patient Selection for Successful - Blocker Initiation
• Stable symptoms
• Stable background heart failure medications
• No recent CV hospitalization
• Stable CV status (no hypotension or bradycardia)
• Euvolemic status
• Start low and titrate slowly
Patients With Heart Failure Who Should Not Be Started on -blockers
Patients With Heart Failure Who Should Not Be Started on -blockers
• General Contraindications– Bronchospastic pulmonary disease– Severe bradycardia, high degree AV block,
sick sinus syndrome
• Heart Failure Considerations– Congestive symptoms at rest (NYHA Class IV)– Patients who require intravenous therapy for HF– Unstable symptoms or recent changes in
background medications– Hospitalized patients (especially for worsening HF)
RALES TrialRALES Trial
• Spironolactone 12.5-25 mg OD added to ACE-inhibitor/diuretic/+/- digoxin in stable Class III-IV CHF/LVEF 35%/CR<220/K<5.0
• 30% RRR in death from progressive HF and sudden cardiac death
• 35% reduction in hospitalization for worsening HF
• NEJM Volume 341:709-717 Number 10
RALES CaveatsRALES Caveats
• With aldosterone antagonist follow K/Cr in 3-7 days furosemide to avoid azotemia
• Inadequate follow-up can lead to increased rates of hospitalization for hyperkalemia and associated mortality – NEJM Volume 351:543-551 Number 6
• Caution: – Diabetics– Renal disease– Elderly– NSAIDS– COX-2 inhibitors
Severity of Heart FailureModes of Death
MERIT-HF Study Group. LANCET 1999;353:2001-07.
12%12%
24%24%
64%64%
CHFCHF
OtherOther
SuddenSuddenDeathDeathn = 103n = 103
NYHA IINYHA II
26%26%
15%15%
59%59%
CHFCHF
OtherOther
SuddenSuddenDeathDeathn = 103n = 103
NYHA IIINYHA III
56%56%
11%11%
33%33%
CHFCHF
OtherOther
SuddenSuddenDeathDeath
n = 27n = 27
NYHA IVNYHA IV
Therapies Provided by Today’sDual-Chamber ICDs
Therapies Provided by Today’sDual-Chamber ICDs
Atrium & Ventricle
Bradycardia sensing
Bradycardia pacing
Atrium
AT/AF tachyarrhythmia detection
Antitachycardia pacing
Cardioversion
Ventricle VT/ VF detection
Antitachycardia pacing
Cardioversion
Defibrillation
Evaluate for Implantable DevicesConsider EPS Referral
Evaluate for Implantable DevicesConsider EPS Referral
VT:• Symptomatic sustained or non-sustained ventricular arrhythmia
(LVEF 30-40%) AICD: • Prior MI/CAD (LVEF 30% with IVCD 0.12 sec:
MADIT II) or both CRT/AICD(NYHA III-IV;QRS 0.12:COMPANION).
• CHF: (NYHA II-III & LVEF < 35% SCD-HeFT) Cardiac Resynchronization Therapy (CRT):• (NYHA Class III-IV with reduced ejection fractions; LVEF <
35%• QRS duration 0.13 with IVCD or LBBB: MIRACLE /
MUSTIC)
Sudden Cardiac Death-Heart Failure SCD-HeFT
Sudden Cardiac Death-Heart Failure SCD-HeFT
Hypothesis and Primary Endpoint • To determine, by intention-to-treat analysis, if
amiodarone or a conservatively programmed shock-only single lead ICD reduces all-cause mortality compared to placebo* in patients with either ischemic or non-ischemic NYHA Class II and III CHF and EF < 35%.
• Good background Therapy– ACE or ARB 87% -blocker 78%
Sudden Cardiac Death
SCD-HeFT Heart Failure Trial
*Double-blind for drug therapy
Bardy G et al.NEJM 2005; 352:3
Enrollment SchemeEnrollment Scheme
R
DCM + CAD and CHF
EF < 35%
NYHA Class II or III
6 minute walk, Holter
Placebo Amiodarone ICD Sudden Cardiac Death
SCD-HeFT Heart Failure Trial
Bardy G et al.NEJM 2005; 352:3
Kaplan-Meier Estimates of Death from Any Cause
Kaplan-Meier Estimates of Death from Any Cause
Bardy G et al.NEJM 2005; 352:3
Sudden Cardiac Death
SCD-HeFT Heart Failure Trial
Bardy G et al.NEJM 2005; 352:3
Kaplan-Meier Estimates of Death from Any Cause:
Kaplan-Meier Estimates of Death from Any Cause:
Sudden Cardiac Death
SCD-HeFT Heart Failure Trial
Ischemic CHF Non-Ischemic CHF
Bardy G et al. NEJM 2005; 352:3
Hazard Ratios for the Comparison of Amiodarone and ICD Therapy with Placebo
Hazard Ratios for the Comparison of Amiodarone and ICD Therapy with Placebo
Sudden Cardiac Death
SCD-HeFT Heart Failure Trial
SCD-HeFT: Primary ConclusionsSCD-HeFT: Primary Conclusions
1. In class II or III CHF patients with EF < 35% on good background drug therapy, the mortality rate for placebo-controlled patients is 7.2% per year over 5 years
2. Simple, single lead, shock-only ICDs decrease mortality by 23%
3. Amiodarone, when used as a primary preventative agent, does not improve survival
Sudden Cardiac Death
SCD-HeFT Heart Failure Trial
Bardy G et al.NEJM 2005; 352:3
Cardiac Resynchronization Therapy (CRT)
Cardiac Resynchronization Therapy (CRT)
• Atrial-biventricular stimulation
• Electrical synchronization narrower QRS
• Mechanical synchronization reverse remodeling
Resynchronization/Defibrillation for Advanced
Heart Failure Trial
Resynchronization/Defibrillation for Advanced
Heart Failure Trial
RAFTRAFT
Hypothesis:In patients with LV Dysfunction (EF 30%) and QRS duration 120 ms with moderate to severe CHF symptoms, the addition of Cardiac Resynchronization Therapy (CRT) to Implantable Cardioverter Defibrillator (ICD) and optimal medical therapy reduces the combined end point of mortality and CHF hospitalization.
RAFT - DesignRAFT - Design
• Randomized Controlled Trial: – ICD vs CRT/ICD
• Blinding – Patient, HF Care (Blinded)– Device care (Un-blinded)
• Patients randomized to a 1:1 proportion to:– ICD (Single or Dual) or– CRT/ICD
• Stratified for: Center & AF & Single/Dual ICD indication
RAFT Inclusion CriteriaRAFT Inclusion Criteria
• NYHA Class II or III• QRS duration 120 ms or Paced QRS 200 ms• LVEF 30% by MUGA or LVEF 30% and LVEDD > 60mm by
echocardiogram within 6 months of randomization• ICD indication: 1° or 2° prevention• Optimal Heart Failure Pharmacotherapy• Normal sinus rhythm or
Chronic persistent atrial tachyarrhythmia with resting ventricular Heart Rate of ≤ 60 bpm and ventricular rate ≤ 90 bpm during a 6 minute hall walk orChronic persistent atrial tachyarrhythmia with resting ventricular Heart Rate of >60 bpm and ventricular rate > 90 bpm during a 6 minute hall walk and booked for an AV junction ablation
*NYHA Class II: Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in fatigue or dyspnea** NYHA Class III: Marked limitation of physcial activity. Comfortable at rest, but less than ordinary activity causes fatigue or dyspnea.
RAFT Exclusion CriteriaRAFT Exclusion Criteria
• In-hospital patients who have an acute cardiac or noncardiac illness that requires intensive care
• Intra-venous inotropic agent 4 days prior to randomization• Expected to undergo cardiac transplantation within one year (status I)• Coronary revascularization (CABG or PCI) < 1month• Acute coronary syndrome(including MI) < 4 weeks• Patients with an existing ICD (Patients with an existing pacemaker
may be included if the patient satisfies all other inclusion/exclusion criteria)
• Uncorrected or uncorrectable primary valvular disease• Restrictive, hypertrophic or reversible form of cardiomyopathy
RAFT Exclusion criteria cont’d
RAFT Exclusion criteria cont’d
• Patients with a life expectancy of less than one year from non-cardiac cause.
• Patients included in other clinical trial that will affect the objectives of this study
• Unable or unwilling to provide informed consent
• History of noncompliance of medical therapy
• Severe primary pulmonary disease such as cor pulmonale
• Tricuspid prosthetic valve
Heart Failure Management IssuesHeart Failure Management Issues
• High Mortality
• High re-admission rates
• Poor understanding of disease
• Poor Rx adherence
• On-going symptoms
• Reduced Quality of Life
• Dose Adjustments in the Elderly
Adherence GapAdherence Gap
• Cost of medications
• Complacency-patient and physician
• Side effects
• Lack of understanding
• Infrequent monitoring intervals
• Lack of reinforcement
• Lack of feedback
Adherence StrategiesAdherence Strategies
• Patient education materials
• Medication monitoring strategies
• Pharmacy patient surveillance
• Follow-up protocols
• Role of Public Health nurses
• Patient Awareness Initiatives– Out-patient Heart Failure Education Programs
CHF Implementation TargetsCHF Implementation Targets
• Heart Failure Specialists• General Cardiologists
– Academic/Community
• Internists– Academic/Community
• Family Physicians• Hospital Nursing staff• Public Health Nurse• Residents & Housestaff• General Public
Recognition-Initial Therapy- Family MD
Community Based Awareness/Understanding
How can we amplify the impact of HF therapy?
How can we amplify the impact of HF therapy?
Dosing Optimization- Family MD & Specialist
Specialist/Cardiologist
HF Clinic
Inotropes,Devices Transplant 4º
2º & 3º
1º & 2º
Primary Care Physician
HF Awareness Program/PHN
Heart Failure NetworkHeart Failure Network
• Apically connected tertiary centres• Vertically integrated local networks• Laterally integrated at all levels• Regional centres linked to local specialist• Hubs of resources dissemination• Shared resources/minimize duplication• Common denominator is primary care
physician/patient base
Heart Failure NetworksLateral Integration
Heart Failure NetworksLateral Integration
Role of Heart Failure ClinicsRole of Heart Failure Clinics
• 4º and 3º Heart Failure Clinics– Pre-transplant work-up– Out-patient parenteral inotropic therapy– Patient education– High risk rehabilitation programs– Regional hubs- national Heart Failure Network– Co-ordinating centre-Heart Failure Network
data-base
• 2º hospital based and community based Heart Failure Clinics/Disease Management Programs– Patient identification and risk assessment
– Patient education
– Rx titration and fluid status monitoring
– Low risk and intermediate risk exercise programs
– Primary care liaison, education
– Long term follow-up
Role of Heart Failure ClinicsRole of Heart Failure Clinics
Role of Primary Care PhysicianRole of Primary Care Physician
• Patient identification• Assess etiology• Assess LV Function• Initial stabilization of
acute HF– Rx initiation and
titration (diuretics/ACE-inhibitor/digoxin)
• Optimize ACE inhibitors
• Rx -blocker if comfortable with Rx
• Patient education• Treatment integration• Long term follow-up
Role of Public Health NurseRole of Public Health Nurse
• Patient education
• Patient monitoring
• Adherence
• Follow-up
Role of the PublicRole of the Public
• Awareness
• Initiate contact
• Understanding
• Lifestyle & diet modification
• Compliance
Goals & Outcomes Goals & Outcomes
• Improve symptoms • Improve quality of life • Prevent progression of
LV dysfunction• Reduce hospitalization
and morbidity • Reduce mortality
– Progression of HF– Sudden death
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