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CHF presentation

VIEWS: 56 PAGES: 76

									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
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 < 50%
   Economic burden approximately 5.4% of total
    health care expenditure
Acute Decompensated Heart Failure
                            Incidence, Cost, Prognosis
   Most frequent reason for hospitalization in patients
    > 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%
      HF Population by NYHA Class
            Class IV                 Class I
             240 K        Class II
Class III                            No limitations of physical
             (5%)         1.68 M     activity
1.20 M                               Class II
                          (35%)
 (25%)                               Slight limitations of physical
                                     activity
                                     Class III
                                     Marked limitations of physical
                                     activity
                                     Class IV
                                     Inability to carry out physical
                                     activities without discomfort
                       Class I
                       1.68 M
                       (35%)         American Heart Association
      Hospitalization: Predominant
      Contributor to Heart Failure Costs
                                                          38.6%
     60.6%                                            Outpatient care
  Hospitalization                                      $14.7 billion
   $23.1 billion                                      (3.4 visits/year
                                                         /patient)


                                                  0.7%
                                               Transplants
Total = $38.1 billion
(5.4% of total healthcare costs)
                                               $270 million

                 O’Connell JB et al. J Heart Lung Transplant 1994; 13:S107-S112
Hospital Visits for Heart Failure

                    Initial Episode 21%




                             Rates of readmission
                             • 2% within 2 days
 Repeat Visit 79%            • 20% within 1 month
                             • 50% within 6 months
   Hospital Readmission for Heart Failure


 Diet Noncompliance                     Rx Noncompliance
      24%                                      24%




      16%                                    17%
Inappropriate Rx            19%              Other
                      Failure to Seek
                           Care
                                           HFSA Research 2000
Cardiomyopathy
   Dilated Cardiomyopathy
     Mostcommon 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
     Etiology
       Systolic Dysfunction             Diastolic Dysfunction

            Dilated                           Hypertrophic
        Cardiomyopathy                       Cardiomyopathy

Ischemic Disease    Nonischemic Disease
 Ischemia            Primary dysfunction       Hypertension
                    Valvular abnormalities     Ischemia
 Infarction
                     Hypertension
                     Structural damage
Pathophysiology
   Cardiac Compensatory Adaptations
     Remodeling of myocardial cells
     Down-regulation of beta receptors

   Extracardiac Compensatory Adaptations
     Renin-angiotensinsystem (RAS)
     Sympathetic nervous system (SNS)
Pathophysiology
   Renin-angiotensin system
     Sensitiveto low CO
     Stimulates vasoconstriction (increases afterload)
     Conserves sodium/water (increases preload)
   Sympathetic nervous system
     Sensitiveto changes in BP
     Promotes vasoconstriction (increases afterload)
     May be directly cytotoxic to myocardial cells
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
Functional Class

Class I     No limitation of physical activity.

Class II    Slight limitation of physical activity.

Class III   Marked limitation of physical
            activity.
Class IV    Unable to carry on any physical
            activity without discomfort.
Advanced Heart Failure
                               Precipitating Factors

   Noncompliance          Myocardial infarction
      diet                Environmental factors
      medications         Inadequate therapy
   Arrhythmias            Endocrine disorders
   Emotional stress          thyrotoxicosis
   Administration of      Pulmonary infection
    inappropriate
    medications
Acute Decompensated Heart Failure
 Signs and Symptoms

 Fluid Overload            Low Cardiac Output
 Increased weight          Fatigue
 Pulmonary edema           Nausea/vomiting
   DOE, PND, orthopnea     Early satiety
   rales, tachypnea,       Decreased weight
   hypoxia                 Elevated serum
 Peripheral edema            creatinine
   JVD/HJR
   hepatic congestion
   lower extremity edema
 Early satiety
BNP Concentrations
Variation with Absence/Presence HF

                          1400                P < 0.001
                                                            1076 ± 138
  Concentration (pg/ml)   1200
                          1000
      Mean BNP




                           800
                           600
                           400
                                             141 ± 31
                           200
                                 38 ± 4
                             0
                                 No CHF    LV Dysfunction      CHF
                                 (n=139)       (n=14)         (n=97)
BNP Concentrations
Variation with Degree of HF Severity


                             2500                          2013 ± 266
 BNP Concentration (pg/ml)



                             2000

                             1500
                                               791 ± 165
                             1000

                              500
                                    186 ± 22
                                0
                                      Mild     Moderate      Severe
                                     (n=27)     (n=34)       (n=36)
Goals of Therapy
                               Chronic Heart Failure
   Prolong survival
   Slow disease progression
   Reduce hospitalization
   Reduce symptoms
   Improve quality of life
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
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
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
Diuretics
    Case Discussion

   How can this hospitalization be avoided in the future?
   How can the diuretic regimen be optimized?
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
     Discourageintense isometric exercise
     Encourage mild to moderate dynamic exercise
   Eliminate modifiable risk factors
     Hypertension,   smoking, diabetes, etc.
Diuretics
Diuretics
HFSA Guideline Highlights
1999 Guideline
• No Recommendations
2005 Guideline
• To be announced
  -Adrenergic
Receptor Blockers
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?
                                            Beta Blockers
                                                Survival Studies
                                           MERIT-HF                                                               CIBIS-II                                        COPERNICUS
                           20                                                                                                                        100
Cumulative mortality (%)




                                    P=.0062 (adjusted)                                            1.0                        Bisoprolol                                                n=2289




                                                                        Probability of survival
                                    P=.00009 (nominal)                                             .9                                                    90                   Carvedilol
                           15                                                                      .8
                                                                                                   .7




                                                                                                                                            % Survival
                                                                                                                                 Placebo                 80
                                                                                                   .6
                                      Placebo                                                                                                                      Placebo
                           10                                                                      .5
                                                                                                   .4        Log rank P=.00006                           70
                                                            n=3991                                 .3
                           5                                                                       .2                                                    60
                                                 Metoprolol CR/XL                                  .1                                                             P=.00014 (unadjusted)
                                                                                                            n=2647                                                P=.0014 (adjusted)
                                                                                                    0                                                    50
                           0
                                      Follow-up (months)                                                0         200      400       600   800                0     4   8   12   16   20   24   28
                                0      3    6     9   12   15     18   21                                            Time (Days)                                            Months
                                    Lancet. 1999;353:2001-2007.                                             Lancet. 1999;353:9-13.                        N Engl J Med. 2001;344:1651-1658.




Mortality:                                                 34%                                                             34%                                              35%
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
-Adrenergic Receptor Blockers
Initial Dosing and Uptitration

                    Carvedilol         Metoprolol CR/XL
                    (Coreg)             (Toprol XL)
Initial Dose      3.125 mg bid         NYHAc II 25 mg qd
                                      NYHAc III 12.5 mg qd
Up-titration   6.25 mg, 12.5 mg bid    50 mg, 100 mg qd

Target Dose     <85 kg 25 mg bid           150 mg qd
                >85 kg 50 mg bid
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
COPERNICUS
Inclusion Criteria
   Heart failure due to ischemic or non-ischemic
    cardiomyopathy
   Symptoms at rest or minimal exertion  2 months
   LV ejection fraction < 25%
   Receiving diuretics and ACE inhibitor  2 months
    (± amiodarone, ± digoxin)
   No or minimal evidence of fluid retention
COPERNICUS
All-cause mortality
             100


              90
                                                       Carvedilol
                                                        (n=1156)
              80
% Survival
              70
                                            Placebo
                                            (n=1133)
              60
                       P=0.00014
              50
                   0      4        8   12     16       20   24     28
                                       Months
                                                   .
COPERNICUS

                         Annual placebo
                          mortality rate
 MERIT-HF                    11.0%

 US Carvedilol Program       11.1%

 CIBIS II                    13.2%

 BEST                        16.6%

 COPERNICUS                  18.5%
     Beta-Blockers
                                    COMET
              3,029 patients with Class III-IV heart failure
                  Enrolled at 317 centers in 15 European countries

           Carvedilol                                  Metoprolol tartrate
(target dose 25 mg twice daily)                  (target dose 50 mg twice daily)
 A multiple adrenergic inhibitor                    A beta-1 blockade agent
           (n = 1,511)                                      (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 2003;362:7–13.
Beta Blockers
COMET Trial
Endpoint           Carvedilol     Metoprolol        HR         P
                    (n=1511)       (n=1518)

# Deaths            512 (34%)      600 (40%)       0.83     0.0017

Annual                 8.3%          10.0%
Mortality
Mortality/             74%            76%          0.94     0.1222
Hospitalization

  Carvedilol – 25 mg bid target dose – 42 mg/day mean dose achieved
  Metoprolol – 50 mg bid target dose – 85 mg/day mean dose achieved
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 (n=363)
           admitted for worsening HF and stabilized in preparation for
            discharge
           in-hospital initiation of carvedilol -vs-
            post-discharge (> 2 weeks) initiation of carvedilol at MD discretion
           beta blocker use at 60 days was improved (91% vs 73%, p< 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; 43:1534-41
Beta-blockers
HFSA Guideline Highlights (continued)
1999 Guideline
   Dosing - “Start low and go slow” approach
2005 Guideline
   To be announced
Beta-blockers
HFSA Guideline Highlights (continued)
1999 Guideline
   No specific recommendation regarding “special populations”
2005 Guideline
   To be announced
Angiotensin II Receptor Blockers
   ACE Inhibitors
    Mechanism of Action
VASOCONSTRICTION                      VASODILITATION
  ALDOSTERONE                         PROSTAGLANDINS
     VASOPRESSIN
       SYMPATHETIC
        Angiotensinogen

                        RENIN
        Angiotensin I
                                        BRADYKININ

      ACE                 Inhibitor      Kininase II

ANGIOTENSIN II                          Inactive Fragments
                   ACE Inhibitors
                                                   V-HeFT II                                                                                                                   CONSENSUS
              60
                                   enalapril             p=0.016                                                                                                                          p=0.001
              50                                                                             47
                                   hydralazine-isosorbide
                                   dinitrate
                                                                                       42                                                                0.7
                                                                                                                                                                                                                                *




                                                                                                                       Cumulative Probability of Death
              40                                                                                                                                                        Placebo
                                                   28%
                                                                            36
% Mortality




                                                                                                                                                         0.6
                                                                       31                                                                                               Enalapril
                                                                                                                                                         0.5
              30
                                                   *        25
                                                                                                                                                         0.4
              20                                    18
                                                                                                                                                                                                                       31%
                                       13                                                                                                                0.3
                              9
              10                                                                                                                                         0.2
                                                                                                                                                         0.1
              0
                              1 Year               2 Years             3 Years         4 Years                                                            0
                                                                                                                                                               0    1      2        3     4   5     6    7    8   9       10    11   12
                                                                                                                                                                                                  Months

                                                   SOLVD-T                                                                                                                     SOLVD-P
                              70                                                                                                   50
                                            Placebo              P=0.3                                                             45                                                   p<0.001
                              60
                              50
                                            Enalapril                                        *                                     40
                                                                                                                                                                   Placebo
                                                                                                                                                                   Enalapril
                                                                                                                                                                                                                      *
                                                                                                                                   35
                   Events %




                                                                                                            % Events
                              40                                                                                                   30
                                                                                      16%                                         25
                              30
                                                                                                                                   20                                                                         29%
                              20                                                                                                   15
                                                                                                                                   10
                              10
                                                                                                                                    5
                              0                                                                                                     0
                                   0           6       12        18     24       30    36         42   48                                                0         6        12        18    24     30        36   42           48
                                                                      Months                                                                                                        Months of Follow-up



               NEJM 1987;316:1429. NEJM 1991;325:303. NEJM 1991;325:293. NEJM 1992;327:685.
ACE Inhibitors
   ATLAS Trial
     Target  doses in previous clinical trials
        enalapril 10 mg BID, lisinopril 20 mg daily,
         captopril 50 mg TID
     Study subjects (n=3,164 pts)
        NYHA class II-IV, LVEF < 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 1999;100:2312.
  ACE Inhibitors
Outcome                Low-Dose High-Dose      RRR      P value
                        (n=1596) (n=1568)
Mortality                44.9%    42.5%         8%       0.128
CV mortality             40.2%    37.2%        10%       0.073
Mortality/hosp          83.8%     79.7%        12%       0.002
Mortality/HF hosp       74.1%     71.1%         8%       0.036
Mortality/CV hosp       60.4%     55.1%        15%      <0.001
CV mortality/CV hosp    72.7%     69.4%         9%       0.027
MI/USA hosp             14.0%     13.2%         8%       0.374



                                            Circulation 1999;100:2312.
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?
    Angiotensin II Receptor Blockers
     Mechanism of Action
                     RENIN

Angiotensinogen              ANGIOTENSIN I
                                               ACE
 Alternative paths           ANGIOTENSIN II
   AT1
RECEPTOR
BLOCKERS
                    AT1      RECEPTORS           AT2


 Vasoconstriction    Proliferation   Vasocondilation   Anti-proliferation
Angiotensin II Receptor Blockers
Case Discussion
   When should ARBs be used in lieu of ACEIs?
   When should ARBs be used in addition to ACEIs?
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; 345:1667-75      Lancet 2003; 362:759-66   NEJM 2003; 349:1893-906
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
Digoxin
Digoxin

           Digoxin   Placebo               RRR        P value
          (n=3397) (n=3403)
Cause of Death
All         34.8%     35.1%                 NS          0.80
CV          29.9%     29.5%                 NS          0.78
Prog HF     11.6%     13.2%                12%          0.06
Reason for Hospitalization
All         64.3%     67.1%                 8%        0.006
CV          49.9%     54.4%                13%        <0.001
Prog HF     26.8%     34.7%                28%        <0.001


       The Digitalis Investigation Group. NEJM 1997; 336:525-533
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 <0.9 ng/mL
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 1993;22:955. NEJM 1993;329:1. NEJM 1997;336:525.
Digoxin
Association of Outcomes and Concentration




                                   JAMA 2003; 289:871
Aldosterone Antagonists
       Aldosterone Antagonists
                                       ALDOSTERONE
Spironolactone
Competitive antagonist of the
Aldosterone receptor
(myocardium, arterial walls, kidney)


Retention Na+                                  Collagen
                                Edema
Retention H2O                                  deposition
             Collagen
             deposition                        Fibrosis
Excretion K+            Arrhythmia              - myocardium
Excretion Mg2+                                  - vessels
Aldosterone Antagonists
    Case Discussion
   When should an aldosterone antagonist be
    considered?
   What are the relative contraindications?
   What monitoring is important?
RALES Trial
   Study subjects (n=1,663)
       severe HF, NYHA class IV currently or w/in 6 mos
       serum potassium < 5.0 mmol/L, serum creatinine < 2.5 mg/dL
   Comparison
       spironolactone 12.5-25 mg daily vs placebo
       follow-up - 24 months (mean)
       primary endpoint - all-cause mortality

                   Placebo      Diuretic    RRR        P value
                   (n=841)      (n=822)
Mortality             46%         35%       30%        <0.001
CV Mortality          37%         27%       31%        <0.001
 - Prog HF            22%         16%       36%        <0.001
 - SCD                13%         10%       29%         0.02


                                                     NEJM 1999;341:709-717.
      EPHESUS Trial
                   AMI, RALES, LVEF 40%, Standard Therapy

       Eplerenone                Randomize 3-14 Days                   Placebo
      25-50 mg QD                     Post-AMI
                                                                       n=3,319
        n=3,313                     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
AMI=acute myocardial infarction; QOL=quality of life.
Reproduced with permission: Pitt B, et al. Cardiovasc Drugs Ther 2001;15:79-87.
EPHESUS
Mortality Results
Cumulative incidence (%)   22




                           16




                           10                                           Placebo
                                                                        Eplerenone

                                               RR=0.85 (95% CI, 0.75-0.96)
                            4                  P=0.008


                                0   9          18          27           36
                                    Months since randomization

                                               Pitt B et al. NEJM 2003;348:1309-1321
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 < 40% and rales
     initial dose 25 mg, mean dose 43 mg/d




Pitt B et al. NEJM 1999; 341:709-17, Pitt B et al. NEJM 2003; 348:1309-1321
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
        Role of the RAAS and NPS
   Angiotensinogen                               Pro ANP, BNP
                                 Kininogen
Renin               Kallikrein
                                                        ANP
                                   Kinins
        Angiotensin I                                   BNP
                                 Bradykinin
                                                        CNP
                        ACE                    NEP
                                  Inactive
     Angiotensin II
                                 Metabolites
                                                      Inactive
                                                     Metabolites

AII Receptor/Aldosterone
Natriuretic Peptides
Physiologic Effects
 Released in response to ventricular stretch/volume overload
 Used as a marker of presence/severity of systolic dysfunction

RAA System                      NP System
   Vasoconstriction               Vasodilation
   Sodium retention               Sodium excretion
   Increased aldosterone          Decreased aldosterone
    release                         release
   Increased cellular growth      Decreased cellular growth
   Increased sympathethic         Inhibition of sympathetic
    nervous system activity         nervous system activity
Efficacy Trial Hemodynamic Outcomes
Change from baseline (%)
                           60
                                      Placebo (n = 4)
                           40         Nesiritide (n = 10)                +

                           20

                            0
                                                                            * p <0.01 vs baseline
                           -20                                              + p<0.05 vs baseline
                                                                            # p < 0.05 vs placebo
                           -40                 *                +
                                                      *#
                           -60   HR       RAP       PCWP     SVR       CI         SVI

                                               Abraham WT et al. J Cardiac Failure 1998;4:37-44
       Efficacy Trial Clinical Outcomes
             Appetite
                                                      p = 0.017
              Fatigue
                                                                  p < 0.001
              Edema                           p = 0.028

Peripheral Circulation
                                          p = 0.271
                                                                                   p < 0.001
            Dyspnea

                         0    10        20        30          40              50          60
                                         Percent Improved

           Placebo (n = 42)   Nesiritide 0.015 (n = 43)     Nesiritide 0.030 (n = 42)


                              Colucci, et al. New Engl J Med 2000; 343:246-53
PRECEDENT Trial
                                                Dobutamine (n = 83)

                                                Nesiritide 0.015 mcg/kg/min (n = 84)

                        p = 0.001               Nesritide 0.030 mcg/kg/min (n = 79)

                  80
                  60
                                    p < 0.001
                  40
 Change from
                  20
  Baseline in
                    0
Events/24 hours
                  -20                           p < 0.001
                  -40
                  -60
                        Couplets    Triplets    V-Tach


                            Burger AJ, et al. Am Heart J 2002; 144 (6): 1102-8
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
OPTIME Trial
                              Milrinone       Control
                              (n = 477)      (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 < 0.001            Cuffe MS et al. JAMA. 2002;287:1541–1547
Implantable Defibrillators (MADIT II)
   Inclusion criteria
       MI > 1 month prior
       LVEF < 0.30
       No inducible arrhythmias
       No coronary revascularization within 3 months
   Average follow-up was 20 months

                            Defibrillator     Conventional
                              Group             Therapy
                             (n = 742)          (n = 490)
      Mortality                14.2%               19.8%
      p = 0.016


                                    Moss AJ et al. NEJM 2002; 346:877-83
Implantable Cardiac Defibrillators
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
Intra-aortic balloon pump   Left ventricular assist device
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
Transplantation
   Current waiting list
     candidates  – 88,523 (as of 6/6/05, 10:35 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

								
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