Critical Concept in Advanced Blocker Treatment


1
Critical Concept in Advanced ß-Blocker Treatment

• Shahriar Dadkhah MD.MBA.FACP.FACC
• Director Section of Cardiology Research
  SFH SCH
  
• Assistant Professor of Medicine
• University of Illinois
• And
• Midwestern University (CCOM)

2
Myocardial Infarction (MI)The Scope of the
Problem

• An estimated 1.1 million Americans will have a
  new or recurrent MI this year and over 40 will
  die from it
  
• Approximately 40 of MIs are accompanied by LV
  dysfunction with or without clinical HF
  
• Approximately 22 of male and 46 of female
  victims will be disabled with HF within 6 years
  

3
Worldwide Mortality Rates for Ischemic Heart
Disease (MI Angina)
450
Before Correction After Correction
400
350
300
250
IHD Death Rate per 100000 Population
200
150
100
50
0
Japan
(Age-standardized mortality rate for men and
women aged 30 about 1990) Adjustment made for a
ny miscoding of disease.
Murray CJL et al. Lancet. 199734912691276.
4
Hospitalizations in the USDue to Acute Coronary
Syndromes
Acute Coronary Syndromes
1.5 Million Hospital Admissions
Unstable Angina
Myocardial Infarction(Q-wave and NonQ-wave)
750000 Admissions
750000 Admissions
Cairns J et al. Can J Cardiol. 199612(12)127912
92.
5
Acute Coronary Syndromes Risk of Mortality
Cumulative 6-Month Mortality
25
(N 21761)
20
15
Death (100/Pts/Month)
Acute MI Unstable Angina Stable Angina
10
5
0
0
1
2
3
4
5
6
Months After Hospital Admission
Theroux P et al. Circulation. 19989711951206.
6
Acute Coronary SyndromesCurrent Medical
Management of Unstable Angina and NonQ-Wave MI

• Acute Therapy
• Oxygen bed rest ECG monitoring
• Antiplatelet Therapy
• Heparin / LMWH / Hirudin
• Nitroglycerin
• Beta Blockers
• Maintenance Therapy
• Antiplatelet Therapy
• Beta Blockers

7
Mortality Reduction With PharmacologicInterventio
ns in MI patients

• Thrombolysis 25 reduction in mortality
• Aspirin 23 reduction in mortality
• ACE inhibition 23 reduction in mortality
• ß-blockade (n24000)
• - 23 reduction in all-cause mortality
• - 30 reduction in risk of sudden death
• - 26 reduction in nonfatal reinfarction

8
Benefits of -Blockade in Hypertension

• In a meta-analysis of 18 randomized long-term
  placebo-controlled hypertension trials
  (N18883) use of -blockade to decrease BP
  
• Risk of stroke by 29
• Risk of CHD by 7
• Risk of CHF by 42

This meta-analysis was performed using MEDLINE
studies published from 1980 to 1985. Patients in
study trials were followed up for an average of 5
years. Drugs studied included propranolol
atenolol metoprolol and pindolol.
Nonsignificant. Psaty BM et al. JAMA. 1997277
739745.
9
Underutilization of ß-blockade Post-MI

• Cooperative Cardiovascular Project
• 201752 patients post-MI
• Only 34 received a ß-blocker
• High-risk patients less likely to be treated

10
TIMI II trial

• Patients with persisting ST-segment elevation
  who were randomized to receive early metoprolol
  in addition to intravenous alteplase experienced
  a 49 lower incidence of subsequent nonfatal
  reinfarction (P0.02) and a 27 lower incidence
  of recurrent ischemia (P0.005) compared to
  patients randomized to receive metoprolol only
  orally beginning 6 days after the acute event.

11
Carvedilol

• Nonselective ß-adrenergic blocking agent with a
  a-blocking activity
  
• Undergoes substantial oxidative metabolism the
  metabolism and pharmacokinetics of carvedilol may
  be affected by induction or inhibition of
  cytochrome P450 enzymes
• Due to the a-receptor blocking activity of
  carvedilol blood pressure is lowered more in the
  standing than in the supine position and
  symptoms of postural hypotension (1.8)
  including rare instances of syncope

12
Carvedilol

• Little effect on plasma catecholamines plasma
  aldosterone or electrolyte levels but it does
  significantly reduce plasma renin activity when
  given for at least 4 weeks. It also increases
  level of atrial natriuretic peptide

13
CAPRICORN CArvedilol Post-infaRct
survIvalCOntRol in LV dysfunctioN

• Rationale
• ß-Blocker trials in acute myocardial infarction
  were conducted mostly during the 1970s/1980s
  
• - No thrombolysis or primary angioplasty
• - Much less use of aspirin
• - No ACE inhibitors
• Patients with heart failure were usually
  excluded
  
• - Left ventricular function was not assessed
• - Study populations were mostly lower risk

14
Objective/Design

• To evaluate the effect of carvedilol on clinical
  outcome in patients with LV dysfuction following
  an acute myocardial infarction (MI) treated in
  the modern era
• Multicenter randomized placebo-controlled
  parallel-group trial in patients with LV ejection
  fraction 40 with or without heart failure
  
• CAPRICORN involved 163 investigators in 17
  countries (Europe Isreal North America
  Australia New Zealand)

15
Inclusion Criteria

• Confirmed acute myocardial infarction within 3-21
  days (mean 10 d)
  
• LV ejection fraction 40
• All appropriate treatments for MI including
  aspirin thrombolysis and percutaneous
  interventions
  
• Receiving an ACE inhibitor for 48 hours
• Patients were usually hospitalized but may have
  been recently discharged

16
All-Cause Mortality
17
CAPRICORN Summary

• In patients with LV dysfunction following an
  acute MI carvedilol treatment was associated
  with
  
• -23 lower risk of all-cause mortality
• -8 lower risk of mortality or CV
  hospitalizations
  
• -26 lower risk of sudden death
• -14 lower risk of HF hospitalization
• -41 lower risk of nonfatal myocardial
  infarction
  
• -29 lower risk of mortality plus MI
• Carvedilol was well tolerated and target doses
  for treatment were reached in the majority of
  patients

18
CAPRICORN Conclusions

• Carvedilol markedly reduced major coronary
  events
  
• -All other end points were also less frequent on
  carvedilol
  
• The number needed to treat for 1 year to prevent
  1 death is 43
  
• -Identical but additional to ACE inhibitors in
  AMI
  
• CAPRICORN bridges the gap between CCU and CHF

19
Hospitalization and Heart Failure

• Major public health problem
• Most frequent cause of hospitalization in
  patients older than 65 years
  
• Fourth leading cause of adult hospitalization in
  US
  
• DRG 127 (heart failure)
• Primary diagnosis 1000000 hospitalizations/yr
• Secondary diagnosis 2000000 hospitalizations/yr
  
• Associated with high readmission rates

20
CHF Patient Population by NYHA Class
Class I No limitations of physical activity Clas
s II Slight limitations of physical activity Cla
ss III Marked limitations of physical activity C
lass IV Inability to carry out physical activitie
s without discomfort
Class III 1.20 M (25)
Class IV 240 K (5)
Class II 1.68 M (35)
Class I 1.68 M (35)
Source American Heart Association
21
Classification of HF Comparison Between ACC/AHA
HF Stage and NYHA Functional Class
ACC/AHA HF Stage1
NYHA Functional Class2
A At high risk for heart failure but
without structural heart disease or symptoms of
heart failure (eg patients with hypertension or
coronary artery disease)
None
B Structural heart disease but without symptoms
of heart failure
I Asymptomatic
C Structural heart disease with prior or current
symptoms of heart failure
II Symptomatic with moderate exertion
III Symptomatic with minimal exertion
IV Symptomatic at rest
D Refractory heart failure requiring specialized
interventions
Carvedilol is indicated for use in patients with
mild to severe chronic HF and in patients with
HTN. 1Hunt SA et al. J Am Coll Cardiol. 2001382
1012113. 2New York Heart Association/Little Bro
wn and Company 1964. Adapted from Farrell MH et
al. JAMA. 2002287890897.
22
New Approach to the Classification of Heart
Failure
Carvedilol is indicated for use in patients with
mild to severe chronic HF and in patients with
HTN. Hunt SA et al. J Am Coll Cardiol. 20013821
012113.
23
Two SystemsTwo Therapies
Angiotensin II (Renin-Angiotensin System RAS)
Norepinephrine (Sympathetic Nervous System SNS
)
ACE Inhibition
-Blockade
Disease Progression
Steering Committee and Membership of the Advisory
Council to Improve Outcomes Nationwide in Heart
Failure. Am J Cardiol. 199983(Suppl 2A)1A38A.
24
Morbidity and Mortality Risk Remains High in HF
Patients on ACE Inhibitors Alone

• Despite the benefits of ACE inhibitors
• Mortality by 2025 (P
• Death plus hospitalization by 3035
  (P
  
• patients still require aggressive therapy
  because as many as
  
• 50 will die within 5 years2
• 30 may be rehospitalized for CHF within 3
  months3
  
• The cost of hospitalization for HF is twice that
  for all forms of cancer4

1Garg R Yusuf S. JAMA. 199527314501456 2AHA.
2001 Heart and Stroke Statistical Update. 2000
3Young JB Mills RM. Clinical Management of Heart
Failure. Caddo Okla Professional
Communications Inc. 200124 4Steering Committee
and Membership of the Advisory Council to Improve
Outcomes Nationwide in Heart Failure. Am J
Cardiol. 199983(Suppl 2A)1A39A.
25
Effects of Adding -Blockers or Angiotensin
Receptor Blockers vs Increasing ACE Inhibitor
Dose in HF
Symptoms Morbidity Mortality Increase dose No
10-15 NS of ACE inhibitor1 effect Add angiot
ensin 10-15 No receptor blocker2 effec
t Add -blockade3 20-35 35
Not recommended for patients receiving ACE I.
1Packer M et al. Circulation. 199910023122318.
2Cohn JN et al. N Engl J Med. 200134516671675.
3Lechat P et al. Circulation. 19989811841191.
26
The Ratio of 2- and 1-Adrenergic Receptors in
the Damaged Heart
In the damaged heart the ratio of receptors
shifts increasing the relative proportion of
2- and 1-receptors




Adapted from Bristow MR. J Am Coll Cardiol.
199322(4 Suppl A)61A71A.
27
Norepinephrine Exerts Negative Effects Through
1- 2- and 1-Receptors
Injury to the heart (eg MI HTN DM)
Levels of norepinephrine
Negative cardiac effects
Negative renal effects
Negative vascular effects
1
b1
b1
b2
1
1
Cardiac injury Hypertrophy Arrhythmias
Activation of RAS
Sodium retention
Vasoconstriction
Disease progression
28
Selectivity of -Blocking Agents
MI HTN DM Insulin Resistance
Sympathetic Activation
1 receptors
2 receptors
1 receptors
1 selectiveblockade
non-selectiveblockade
1 2 1blockade
Cardiotoxicity
29
Effect of -Blockade on Outcomes in Heart Failure
Target HF Dosage Study Drug Severity (mg
/day) Outcome US Carvedilol1 carvedilol mi
ld/ 6.25 to 25 48 disease progression
moderate bid (P.001) CIBIS-II2 bisoprolol
moderate/ 10 qd 34 mortality
severe (Pld/ 200 qd 34 mortality succinate moderate
(P.0062) COPERNICUS4 carvedilol severe
25 bid 35 mortality (P.0014)
50 mg bid if 85 kg. Disease progression was d
efined as HF death or hospitalization or the need
for sustained increase in medications for HF.
1Colucci WS et al. Circulation.
19969428002806. 2CIBIS II Investigators and Co
mmittees. Lancet. 1999353913.
3MERIT-HF Study Group. Lancet. 199935320012007.
4Packer M et al. N Engl J Med. 20013441651165
8.
HF NOT AN APPROVED INDICATION
30
Beta-blockers in Class IV Heart Failure
1Packer M. N Engl J Med 1996 2MERIT-HF Study
Group Lancet 1999 3CIBIS-II Investigators La
ncet 1999 4Domanski M. presentation at ACC 2000
31
Carvedilol Prospective Randomized
Cumulative Survival Trial
(COPERNICUS)
32
COPERNICUS
Study Design
2289 patients with symptoms of heart failure
at rest or minimal exertion with a LV ejection
fraction inhibitor ( digitalis). Diuretics were optimiz
ed to achieve euvolemia. No need for intensive
care and no treatment with IV inotropic or IV
vasodilator therapy within 4 days.
Patients were randomized to placebo or
carvedilol (11) target dose 25 mg BID to up
to 29 months.
33
COPERNICUS
Protocol-Specified Endpoints
Primary Endpoint All-cause mortality Secondar
y Endpoints All-cause mortality or CHF hospit
alization All-cause mortality or cardiovascula
r hospitalization All-cause mortality or hospi
talization for any reason Patient global asses
sment Other Prespecified Analyses Health care
resource utilization Safety
34
COPERNICUS
Hazard
Log-rank

Placebo
Carvedilol
Ratio
P-Value
Death or hospitalization for any reason
507/1133
425/1156
0.76
0.00004
(0.670.87)
Death or hospitalization for CV reason
395/1133
314/1156
0.73
0.00002
(0.630.84)
Death or hospitalization for heart failure
357/1133
271/1156
0.69
0.000004
(0.590.81)
35
COPERNICUS
Death Hospitalization
Death Hospitalization
for Heart Failure
for Any Reason
Men
Women
Age North/South America
Other continents
LV ejection fraction Ischemic
Nonischemic
No recent hospitalization
Recent hospitalization
All patients
0.25
0.5
0.75
1
1.25
0.25
0.5
0.75
1
1.25

Hazard Ratios
36
COPERNICUS Additional observations

• The patients enrolled in COPERNICUS had the most
  advanced heart failure of any large-scale trial
  of beta-blockade.
  
• The effects of COPERNICUS were consistent across
  all subgroups of patients.
  
• The number of patients who stopped the study
  medications permanently was higher in the placebo
  group.

US Carvedilol Program (Packer M N Engl J Med
1996) MERIT-HF (MERIT-HF Study Group Lancet
1999) CIBIS-II (CIBIS-II Investigators Lancet
1999) BEST (Domanski M presentation at ACC 2000)
37
COPERNICUS
Safety
Placebo
Carvedilol
P
Any adverse 75.4 75.7 0.860
effect Any serious 45.5 39.0
0.002 adverse effect Any non-fatal
38.0 33.3 0.018 serious adverse effect
38
COPERNICUS
Adverse Events More Common on Carvedilol
Placebo
Carvedilol
Bradycardia 3.2
11.8 Dizziness 16.8
24.1 Headache
3.0 4.8 Hypotension
8.7 15.1
Presyncope 2.9
4.8
39
COPERNICUS
Adverse Events More Common on Placebo
Placebo
Carvedilol
Heart failure 33.6
28.1 Cardiogenic shock 1.7
0.4 Atrial fibrillation
4.3 2.2
Supraventricular tachycardia 1.0
0.2 Ventricular tachycardia 3.9 1.
6 Ventricular fibrillation 2.1 1.0
Sudden death 6.1 3.9
40
COPERNICUS
In patients with severe chronic heart failure
carvedilol reduced Risk of death Combined r
isk of death or hospitalization
Frequency of hospitalizations
Risk of repeated hospitalizations
Number of days in the hospital for any reason
Average duration of each admission
Utilization of treatments and procedures for
heart failure
41
COPERNICUS
In patients with severe chronic heart failure
carvedilol Was associated with improved patient
overall sense of well-being. Was well tolerate
d. Was associated with a lower risk of a serio
us adverse event particularly one related to the
progression of heart failure. Was associated wi
th fewer patients requiring withdrawal of
treatment for an adverse event or for another
reason.
42
Carvidilol Or Metoprolol European TrialCOMET
43
COMET
44
COMET

• Annual mortality rate was reduced from 10 in the
  metoprolol group to 8.3 in the carvedilol
  group prolong median survival by 1.4 year

45
COMET

• COMET used an immediate-released formulation of
  metoprolol tartatewhich is different from the
  formulation used in the main clinical trial
  showing benefits of metprolol in heart failure
  (MERIT HF) which evaluated a controlled-release
  formulation of metoprololo succinate.

46
COMET

• It is thus reasonable to conclude that carvedilol
  is the preferred beta blocker for the treatment
  of chronic heart failure

47
2004 ACC/AHA STEMI GuidelinesOral Therapy With
-Blockers
Level of Recommendation and Evidence
Procedure/Treatment SHOULD be performed/administ
ered Recommendation that procedure or treatment
is useful/effective Sufficient evidence from mu
ltiple randomized trials or meta-analyses
PCIpercutaneous coronary intervention
STEMIST-elevation myocardial infarction.
Antman TJ et al. Circulation. 2004110588636.
48
2005 ACC/AHA HF Guidelines -Blocker Use in
Post-MI LVD Patients Without Symptoms of HF
Hunt SA et al. Circulation. 200511218251852.
49
LIFE LIFE is a Sexually Transmitted Disease wit
h a 100 Mortality
50
If you always dowhat youve always doneyoull
always getwhat you always got
51
You are as good as Your Arteries
52
THE END
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