CHF presentation

1
Update on the Management of Heart Failure
Jo E. Rodgers, Pharm.D., BCPS Clinical Assistant
Professor Division of Pharmacotherapy University
of North Carolina School of Pharmacy Clinical
Pharmacist University of North Carolina Heart
Center
2
Epidemiology

• Estimated prevalence of 4.7 million patients
  in the United States
• 400,000 new patients diagnosed and 250,000
  deaths annually
• Five-year overall survival rate lt 50
• Economic burden approximately 5.4 of total
  health care expenditure

3
Acute Decompensated Heart Failure
Incidence, Cost, Prognosis

• Most frequent reason for hospitalization in
  patients gt 65 years of age in U.S.
• Average duration of hospitalization 6 days
• Rehospitalization within 6 months high as 50
• Hospitalizations increased from 600,000 (1985) to
  900,000 (1998) in U.S.
• mean LOS 7 days
• mean charge per patient 10,000
• Greatest expenditure for HF, annual inpatient
  management, approximately 23 billion
• Average 6-12 month mortality ? 35

4
HF Population by NYHA Class
Class IV 240 K (5)
Class I No limitations of physical
activity Class II Slight limitations of physical
activity Class III Marked limitations of
physical activity Class IV Inability to carry
out physical activities without discomfort
Class II 1.68 M (35)
Class III 1.20 M (25)
Class I 1.68 M (35)
American Heart Association
5
Hospitalization Predominant Contributor to Heart
Failure Costs
38.6 Outpatient care 14.7 billion (3.4
visits/year /patient)
60.6 Hospitalization 23.1 billion
0.7 Transplants 270 million
Total 38.1 billion (5.4 of total healthcare
costs)
OConnell JB et al. J Heart Lung Transplant 1994
13S107-S112
6
Hospital Visits for Heart Failure
Initial Episode 21

• Rates of readmission
• 2 within 2 days
• 20 within 1 month
• 50 within 6 months

Repeat Visit 79
7
Hospital Readmission for Heart Failure
Diet Noncompliance 24
Rx Noncompliance 24
16 Inappropriate Rx
17 Other
19 Failure to Seek Care
HFSA Research 2000
8
Cardiomyopathy

• Dilated Cardiomyopathy
• Most common type
• Characterized by systolic dysfunction
• Moderate to severe reduction in LVEF
• Hypertrophic Cardiomyopathy
• Characterized by filling abnormalities or
  diastolic dysfunction
• Systolic function is preserved initially
• Normal or increased LVEF

9
Etiology
Diastolic Dysfunction
Systolic Dysfunction
Hypertrophic Cardiomyopathy
Dilated Cardiomyopathy
Ischemic Disease
Nonischemic Disease
Hypertension
Primary dysfunction
Ischemia
Ischemia
Valvular abnormalities
Infarction
Hypertension
Structural damage
10
Pathophysiology

• Cardiac Compensatory Adaptations
• Remodeling of myocardial cells
• Down-regulation of beta receptors
• Extracardiac Compensatory Adaptations
• Renin-angiotensin system (RAS)
• Sympathetic nervous system (SNS)

11
Pathophysiology

• Renin-angiotensin system
• Sensitive to low CO
• Stimulates vasoconstriction (increases afterload)
• Conserves sodium/water (increases preload)
• Sympathetic nervous system
• Sensitive to changes in BP
• Promotes vasoconstriction (increases afterload)
• May be directly cytotoxic to myocardial cells

12
Diagnosis

• Subjective and Objective Evaluation
• Signs and symptoms of left ventricular failure
• Signs and symptoms of right ventricular failure
• Echocardiography
• To determine etiology
• To estimate severity of dysfunction
• Radionuclide ventriculogram
• To assess severity of dysfunction

13
Functional Class
14
Advanced Heart Failure
Precipitating Factors

• Noncompliance
• diet
• medications
• Arrhythmias
• Emotional stress
• Administration of inappropriate medications

• Myocardial infarction
• Environmental factors
• Inadequate therapy
• Endocrine disorders
• thyrotoxicosis
• Pulmonary infection

15
Acute Decompensated Heart Failure
Signs and Symptoms

• Fluid Overload
• Increased weight
• Pulmonary edema
• DOE, PND, orthopnea
• rales, tachypnea, hypoxia
• Peripheral edema
• JVD/HJR
• hepatic congestion
• lower extremity edema
• Early satiety

• Low Cardiac Output
• Fatigue
• Nausea/vomiting
• Early satiety
• Decreased weight
• Elevated serum creatinine

16
BNP Concentrations Variation with
Absence/Presence HF
17
BNP ConcentrationsVariation with Degree of HF
Severity
18
Goals of Therapy
Chronic Heart Failure

• Prolong survival
• Slow disease progression
• Reduce hospitalization
• Reduce symptoms
• Improve quality of life

19
Goals of Therapy
Acute Heart Failure

• Relieve pulmonary congestion
• Decrease systemic vascular resistance
• Improve myocardial systolic function
• Improve myocardial diastolic function
• Preserve systemic perfusion pressure
• Optimize oral drug therapy

20
Case

• 55 YOF with newly diagnosed HF (LVEF 38)
• CC SOB at rest/DOE
• PMH
• long-standing uncontrolled HTN, mild asthma, OA
• EKG NSR, 95 bpm
• CXR left lower lobe infiltrate
• Labs
• Na 134 mmol/l, K 4.8 mmol/l, BUN 24 mg/dl, sCr
  1.5 mg/dl (baseline 1.2 mg/dl), WBC 21 K, pro-BNP
  4,028 pg/ml

21
Case (continued)

• Physical exam
• BP 142/93, HR 95, RR 25, SaO2 93 on 4L NC
• no JVD/HJR, S4, 1 LEE to shins
• rales throughout, mild crackles at bases
• Medications prior to admission
• HCTZ 25 mg qd, ramipril 5 mg qd, albuterol PRN,
  OTC naproxen PRN

22
Diuretics Case Discussion

• How can this hospitalization be avoided in the
  future?
• How can the diuretic regimen be optimized?

23
Non-Pharmacologic Therapy

• Diet
• Low sodium
• Low fat/cholesterol
• Maintain Fluid Balance
• Restrict Na 2-3 g/d (1g Na 2.5g NaCl)
• Daily weight measurements to assess fluid changes
• Limit intake to 3 liters per day
• Exercise
• Discourage intense isometric exercise
• Encourage mild to moderate dynamic exercise
• Eliminate modifiable risk factors
• Hypertension, smoking, diabetes, etc.

24
Diuretics
25
Diuretics HFSA Guideline Highlights

• 1999 Guideline
• No Recommendations
• 2005 Guideline
• To be announced

26
?-Adrenergic Receptor Blockers
27
Beta Blockers Case Discussion

• Does it matter which beta blocker or which dose?
• What to do with beta blocker therapy in the
  hospital?
• On beta blocker PTA? Should it be continued?
• Not on beta blocker PTA? Should it be initiated?
  When?
• Should there be any reason not to initiate beta
  blocker therapy in this patient?
• Absolute contraindications?
• Relative contraindications?
• Should one beta blocker be preferred over another
  in certain patient populations?

28
Beta Blockers Survival Studies
MERIT-HF
CIBIS-II
COPERNICUS
1.0
P.0062 (adjusted) P.00009 (nominal)
n2289
Bisoprolol
.9
Carvedilol
.8
.7
Placebo
.6
Placebo
Cumulative mortality ()
Placebo
.5
Probability of survival
Survival
Log rank P.00006
.4
n3991
.3
.2
P.00014 (unadjusted)
Metoprolol CR/XL
.1
n2647
P.0014 (adjusted)
0
Follow-up (months)
Time (Days)
Months
Lancet. 19993532001-2007.
Lancet. 19993539-13.
N Engl J Med. 20013441651-1658.
34
34
35
Mortality
29
Beta-blockers HFSA Guideline Highlights

• 1999 Guideline
• 7 Recommendations
• Routinely administered to NYHA Class II-III (LVEF
  40)
• Considered for NYHA Class I (LVEF 40)
• Insufficient evidence to recommend in NYHA Class
  IV
• 2005 Guideline
• To be announced

30
?-Adrenergic Receptor Blockers Initial Dosing
and Uptitration
31
Beta Blockers Target Doses
Target Mean Dosage Dosage Achieved
Target Study (mg) (mg/day)
(mg/day) CIBIS-II 10 mg qd 7.5
75 Lancet 1999 MERIT-HF 200 mg qd 159
80 Lancet 1999 US Carvedilol
6.25-50 mg bid 45 94 NEJM 1996
bid COPERNICUS 25 bid 37
74 NEJM 2001
32
COPERNICUS Inclusion Criteria

• Heart failure due to ischemic or non-ischemic
  cardiomyopathy
• Symptoms at rest or minimal exertion ? 2 months
• LV ejection fraction lt 25
• Receiving diuretics and ACE inhibitor ? 2 months
  ( amiodarone, digoxin)
• No or minimal evidence of fluid retention

33
COPERNICUS All-cause mortality

100
90
Carvedilol (n1156)
80
Survival
70
Placebo (n1133)
60
P0.00014
50
24
0
20
16
12
8
4
28
Months
.
34
COPERNICUS
Annual placebo mortality rate
MERIT-HF 11.0 US Carvedilol Program 11.1 CIBIS
II 13.2 BEST 16.6 COPERNICUS 18.5
35
Beta-Blockers
COMET
3,029 patients with Class III-IV heart
failure Enrolled at 317 centers in 15 European
countries

• Carvedilol
• (target dose 25 mg twice daily)
• A multiple adrenergic inhibitor
• (n 1,511)

• Metoprolol tartrate
• (target dose 50 mg twice daily)
• A beta-1 blockade agent
• (n 1,518)

• Endpoints (mean follow-up 58 months)
• Primary 1) All-cause mortality and 2)
  All-cause mortality or all-cause hospitalization
• Secondary Composite of all cause mortality or
  cardiovascular hospitalization Composite of
  cardiovascular death, non-fatal acute MI, or
  heart transplantation Worsening of heart
  failure Cardiovascular death NYHA class

Lancet 2003362713.
36
Beta Blockers COMET Trial
Carvedilol 25 mg bid target dose 42 mg/day
mean dose achieved Metoprolol 50 mg bid target
dose 85 mg/day mean dose achieved
37
Beta Blockers Case Discussion

• When to stop BB during hospitalization?
• recent initiation or uptitration responsible for
  fluid overload
• significant low BP or cardiogenic shock
• When to start BB during hospitalization?
• IMPACT-HF Trial (n363)
• admitted for worsening HF and stabilized in
  preparation for discharge
• in-hospital initiation of carvedilol -vs-
  
  post-discharge (gt 2 weeks) initiation of
  carvedilol at MD discretion
• beta blocker use at 60 days was improved (91 vs
  73, plt 0.0001)
• no significant increase in hypotension,
  bradycardia, or worsening HF
• mean LOS 5 days in both groups
• tendency toward lower event rate

Gattis et al. JACC 2004 431534-41
38
Beta-blockers HFSA Guideline Highlights
(continued)

• 1999 Guideline
• Dosing - Start low and go slow approach
• 2005 Guideline
• To be announced

39
Beta-blockers HFSA Guideline Highlights
(continued)

• 1999 Guideline
• No specific recommendation regarding special
  populations
• 2005 Guideline
• To be announced

40
Angiotensin II Receptor Blockers
41
ACE Inhibitors Mechanism of Action

VASOCONSTRICTION
VASODILITATION
ALDOSTERONE
PROSTAGLANDINS
VASOPRESSIN
SYMPATHETIC
Angiotensinogen
RENIN
BRADYKININ
Angiotensin I
ACE
Kininase II
Inhibitor
ANGIOTENSIN II
Inactive Fragments
42
ACE Inhibitors
V-HeFT II
CONSENSUS
p0.016
p0.001

?28

?31
SOLVD-T
SOLVD-P
P0.3

plt0.001

?16
?29
NEJM 19873161429. NEJM 1991325303. NEJM
1991325293. NEJM 1992327685.
43
ACE Inhibitors

• ATLAS Trial
• Target doses in previous clinical trials
• enalapril 10 mg BID, lisinopril 20 mg daily,
  captopril 50 mg TID
• Study subjects (n3,164 pts)
• NYHA class II-IV, LVEF lt 30
• Comparison
• lisinopril low 2.5-5 mg qd vs high 32.5-35 mg
  qd
• follow-up - 46 months (median)
• primary endpoint - all-cause mortality

Circulation 19991002312.
44
ACE Inhibitors
Circulation 19991002312.
45
ACE Inhibitors

• Is obtaining target dose important?
• Ramipril 5 mg po bid
• Enalapril 10 mg po bid
• Lisinopril 40 mg po qd
• Is it truly an ACE inhibitor cough?
• consider fluid, optimize diuretic dose
• Are there reasons not to consider an ARB?
• Hypotension, hyperkalemia, renal dysfunction
• Are there reasons to consider an ARB?
• Intolerable cough, angioedema (caution)
• Do target doses need to be reach prior to
  initiating beta blocker therapy?

46
Angiotensin II Receptor Blockers Mechanism of
Action

RENIN
ANGIOTENSIN I ANGIOTENSIN II
Angiotensinogen
ACE
Alternative paths
AT1 RECEPTOR BLOCKERS
RECEPTORS
AT1
AT2
Vasoconstriction
Proliferation
Vasocondilation
Anti-proliferation
47
Angiotensin II Receptor Blockers Case Discussion

• When should ARBs be used in lieu of ACEIs?
• When should ARBs be used in addition to ACEIs?

48
Angiotensin II Receptor Blockers

• Valsartan (Diovan) Val-HeFT Trial
• add on to ACEI therapy in HF (35 BB)
• valsartan 160 mg bid reduced in hospitalizations
• combo of BB/ACEI/ARB worse?
• Candesartan (Atacand) CHARM Trial
• three trials with candesartan 32 mg qd
• ALTERNATIVE - ARB safe in ACEI intolerant patient
• ADDED ACEI/ARB/BB combination safe
• PRESERVED - trend toward benefit
• Valsartan (Diovan) VALIANT Trial
• post MI with clinical/radiological sx HF
• valsartan 160 mg bid equivalent to captopril 50
  mg tid
• combo ACEI/ARB associated with additional ADEs

NEJM 2001 3451667-75 Lancet 2003
362759-66 NEJM 2003 3491893-906
49
ACE Inhibitors and ARBs HFSA Guideline

• 1999 Guideline
• 2 Recommendations
• ACEIs, rather than ARBs, are drugs of choice for
  patients with LVSD with or without symptoms of HF
• In patients who are intolerant, consider the
  combination of hydralazine/ISDN or ARB
• 2005 Guideline
• To be announced

50
Digoxin
51
Digoxin
The Digitalis Investigation Group. NEJM 1997
336525-533
52
Digoxin HFSA Guideline

• 1999 Guideline
• 2 Recommendations
• Digoxin should be considered if systolic
  dysfunction (LVEF 40), symptomatic HF (NYHAc
  II-III (A), NYHAc IV (C)), std therapy
• Digoxin should be routinely administered to the
  majority of patients at a dose of 0.125-0.25 mg
  daily
• Rationale
• RADIANCE 1.2ng/mL, DIG Trial 0.8ng/mL
• PROVED/RADIANCE retrospective, cohort analysis
  lt0.9 ng/mL

53
Digoxin

• RADIANCE PROVED Trials
• Patients stabilized on digoxin, ACE-I, and
  diuretics
• Worsening of HF, ? exercise tolerance, worsening
  NYHA class, ? QOL, ? LVEF with withdraw of
  digoxin
• DIG Trials
• Patients randomized to digoxin or placebo
• No reduction in mortality
• Significant reduction in hospitalizations

J Am Coll Cardiol 199322955. NEJM 19933291.
NEJM 1997336525.
54
DigoxinAssociation of Outcomes and Concentration
JAMA 2003 289871
55
Aldosterone Antagonists
56
Aldosterone Antagonists

ALDOSTERONE
Spironolactone
Competitive antagonist of the Aldosterone
receptor (myocardium, arterial walls, kidney)
Collagen deposition
Retention Na Retention H2O Excretion
K Excretion Mg2
Collagen deposition Fibrosis -
myocardium - vessels
Edema
Arrhythmia
57
Aldosterone Antagonists Case Discussion

• When should an aldosterone antagonist be
  considered?
• What are the relative contraindications?
• What monitoring is important?

58
RALES Trial

• Study subjects (n1,663)
• severe HF, NYHA class IV currently or w/in 6 mos
• serum potassium lt 5.0 mmol/L, serum creatinine lt
  2.5 mg/dL
• Comparison
• spironolactone 12.5-25 mg daily vs placebo
• follow-up - 24 months (mean)
• primary endpoint - all-cause mortality

NEJM 1999341709-717.
59
EPHESUS Trial
AMI, RALES, LVEF 40, Standard Therapy
Placebon3,319
Eplerenone 25-50 mg QD n3,313
Randomize 3-14 Days Post-AMI
1,012 Deaths
Primary endpoints All-cause mortality CV
mortality CV hospitalization Secondary
endpoints CV mortality CV
hospitalization All-cause mortality
all-cause
hospitalization Other endpoints New onset of
atrial fibrillation/flutter NYHA functional
class QOL
AMIacute myocardial infarction QOLquality of
life. Reproduced with permission Pitt B, et al.
Cardiovasc Drugs Ther 20011579-87.
60
EPHESUS Mortality Results
22
16
Cumulative incidence ()
Placebo Eplerenone
10
RR0.85 (95 CI, 0.75-0.96) P0.008
4
36
27
18
9
0
Months since randomization
Pitt B et al. NEJM 20033481309-1321
61
Aldosterone Antagonists

• Spironolactone (Aldactone) - RALES Trial
• recent or current NYHAc IV
• beta blocker use 10
• initial dose 25 mg qd, mean dose 27 mg/d
• Eplerenone (Inspra) - EPHESUS Trial
• post-MI LVEF lt 40 and rales
• initial dose 25 mg, mean dose 43 mg/d

Pitt B et al. NEJM 1999 341709-17, Pitt B et
al. NEJM 2003 3481309-1321
62
Aldosterone Antagonists HFSA Guideline

• 1999 Guideline
• 1 Recommendation
• Spironolactone should be considered in patients
  with severe HF due to LVSD
• 2005 Guideline
• To be announced

63
Role of the RAAS and NPS
Angiotensinogen Angiotensin I Angiotensin
II AII Receptor/Aldosterone
Pro ANP, BNP ANP BNP CNP Inactive
Metabolites
Kininogen Kinins Bradykinin Inactive Metabolit
es
Renin
Kallikrein
ACE
NEP
64
Natriuretic Peptides
Physiologic Effects

• Released in response to ventricular
  stretch/volume overload
• Used as a marker of presence/severity of
  systolic dysfunction

• RAA System
• Vasoconstriction
• Sodium retention
• Increased aldosterone release
• Increased cellular growth
• Increased sympathethic nervous system activity

• NP System
• Vasodilation
• Sodium excretion
• Decreased aldosterone release
• Decreased cellular growth
• Inhibition of sympathetic nervous system activity

65
Efficacy Trial Hemodynamic Outcomes
Abraham WT et al. J Cardiac Failure 1998437-44
66
Efficacy Trial Clinical Outcomes
p 0.017
p lt 0.001
p 0.028
p 0.271
p lt 0.001
Colucci, et al. New Engl J Med 2000 343246-53
67
Burger AJ, et al. Am Heart J 2002 144 (6)
1102-8
PRECEDENT Trial
p 0.001
p lt 0.001
68
Inotropic Therapy in ADHF

• Concerns with use
• limited evidence suggesting benefit
• small trials, not randomized or placebo
  controlled
• subjective endpoints
• growing evidence suggesting harm
• PROMISE, OPTIME, ADHERE registry and others
• Limited indications
• cardiogenic shock
• bridge to transplantation
• palliative care

69
OPTIME Trial
Milrinone (n 477)
Control (n 472)

• Adverse event 12.6 2.1
• Sustained hypotension 10.7 3.2
• Acute MI 1.5 0.4
• Atrial fibrillation (new onset) 4.6 1.5
• Death (60-day) 10.3 8.9
• Death (in-hospital) 3.8 2.3
• Rehospitalization or death 35.0 35.3
• Median cumulative hospital days 7 6
• for CV cause within 60 days of
• randomization (primary endpoint)

p 0.004 p lt 0.001
Cuffe MS et al. JAMA. 200228715411547
70
Implantable Defibrillators (MADIT II)

• Inclusion criteria
• MI gt 1 month prior
• LVEF lt 0.30
• No inducible arrhythmias
• No coronary revascularization within 3 months
• Average follow-up was 20 months

Moss AJ et al. NEJM 2002 346877-83
71
Implantable Cardiac Defibrillators
72
Mechanical Support

• Intra-aortic balloon pump (IABP)
• used as bridge to TP or myocardial ischemia
• placed into high descending thoracic aorta
• balloon counterpulsation
• inflates during diastole - ? coronary perfusion
• deflates w/ aortic valve opening - ? arterial
  impedence
• Left ventricular assist device (LVAD)
• extracorporeal vs implantable
• allows ambulation and even discharge
• operative mortality 10-15
• requires continuous anticoagulation

73
Intra-aortic balloon pump
Left ventricular assist device
74
Potential Future Agents

• Vasopressin Receptor Antagonists
• Conivaptan (V1a/V2 antagonist) Phase 2 trials
• Tolvaptan (V2 antagonist) Phase 3 trials
• ACTIV in CHF trial JAMA 2004 291 1963-1971.
• EVEREST Trial ongoing
• Calcium Sensitizers
• Levosimendan
• Calcium sensitization of contractile proteins
• Binding site in the N-terminal domain of troponin
  C
• Exerts both inotropic and vasodilatory effects
• LIDO Study - significant reduction in mortality
  at 180 days
• REVIVE and SURVIVE Trials ongoing

75
Transplantation

• Current waiting list
• candidates 88,523 (as of 6/6/05, 1035 am)
• transplants 2005 4,375 (as of 5/27/05)
• donors 2005 - 2,263 (as of 5/27/05)
• Average waiting time - greater than 6 months
• Only about one in five approved potential
  recipients receive a heart before succumbing to
  their disease
• Another large percentage of patients rejected
  from consideration because of age, concurrent
  illness, psychosocial factors

76
(No Transcript)