Critical Concept in Advanced Blocker Treatment

1
Critical Concept in Advanced ß-Blocker
Treatment

• S.Dadkhah MD.MBA.FACP.FACC
• Director Section of Cardiology Research
• Co-Director Chest Pain Center
• Saint Francis Hospital, Evanston , IL
• Assistant Professor of Medicine
• University of Illinois

2
Myocardial Infarction (MI)The Scope of the
Problem

• Approximately 40 of MIs are accompanied by LV
  dysfunction with or without clinical HF
• An estimated 1.1 million Americans will have a
  new or recurrent MI this year, and over 40 will
  die from it
• 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 100,000 Population
200
150
100
50
0
Japan
(Age-standardized mortality rate for men and
women aged gt30, about 1990) Adjustment made for
any 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)
750,000 Admissions
750,000 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 21,761)
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 Pharmacologic
Interventions in MI patients

• Thrombolysis 25 reduction in mortality
• Aspirin 23 reduction in mortality
• ACE inhibition 23 reduction in mortality
• ß-blockade (ngt24,000)
• - 23 reduction in all-cause mortality
• - 30 reduction in risk of sudden death
• - 26 reduction in nonfatal reinfarction

8
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.

9
Benefits of ?-Blockade in Hypertension

• In a meta-analysis of 18 randomized, long-term
  placebo-controlled hypertension trials
  (N18,883), 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. Nonsignifican
t. Psaty BM et al. JAMA. 1997277739745.
10
Underutilization of ß-blockade Post-MI

• Cooperative Cardiovascular Project
• 201,752 patients post-MI
• Only 34 received a ß-blocker
• High-risk patients less likely to be treated

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 1,000,000 hospitalizations/yr
• Secondary diagnosis 2,000,000 hospitalizations/yr
• Associated with high readmission rates

20
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.
20013821012113. 2New York Heart
Association/Little Brown and Company,
1964. Adapted from Farrell MH et al. JAMA.
2002287890897.
21
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.
22
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.
23
Morbidity and Mortality Risk Remains High in HF
Patients on ACE Inhibitors Alone

• Despite the benefits of ACE inhibitors
• Mortality ? by 2025 (Plt.001)
• Death plus hospitalization ? by 3035 (Plt.001)1
• 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.
24
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
angiotensin ? ? 10-15 No receptor
blocker2 effect 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.
25
Effect of ?-Blockade on Outcomes in Heart Failure
Target HF Dosage Study Drug Severity
(mg/day) Outcome US Carvedilol1 carvedilol
mild/ 6.25 to 25 ?48 disease
progression moderate bid (P.001) CIBIS-II2
bisoprolol moderate/ 10 qd ?34
mortality severe (Plt.0001) MERIT-HF3
metoprolol mild/ 200 qd ?34 mortality
succinate moderate (P.0062) COPERNICUS4
carvedilol severe 25 bid ?35
mortality (P.0014)
50 mg bid if gt85 kg. Disease progression was
defined 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
Committees. Lancet. 1999353913. 3MERIT-HF
Study Group. Lancet. 199935320012007. 4Packer
M et al. N Engl J Med. 200134416511658.
HF NOT AN APPROVED INDICATION
26
Beta-blockers in Class IV Heart Failure
1Packer M., N Engl J Med 1996, 2MERIT-HF Study
Group, Lancet 1999, 3CIBIS-II Investigators,
Lancet 1999, 4Domanski M., presentation at ACC
2000
27
Carvedilol Prospective Randomized Cumulative
Survival Trial (COPERNICUS)
28
COPERNICUS
Study Design
2289 patients with symptoms of heart failure at
rest or minimal exertion with a LV ejection
fraction lt 25,despite diuretics and an ACE
inhibitor ( digitalis). Diuretics were
optimized 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.
29
COPERNICUS
Protocol-Specified Endpoints
Primary Endpoint All-cause mortality Secondary
Endpoints All-cause mortality or CHF
hospitalization All-cause mortality or
cardiovascular hospitalization All-cause
mortality or hospitalization for any
reason Patient global assessment Other
Prespecified Analyses Health care resource
utilization Safety
30
COPERNICUS
Hazard
Log-rank

Placebo
Carvedilol
Ratio
P-Value
Death or hospitalization for any reason
507/1133
425/1156
0.76
0.00004
(0.67,0.87)
Death or hospitalization for CV reason
395/1133
314/1156
0.73
0.00002
(0.63,0.84)
Death or hospitalization for heart failure
357/1133
271/1156
0.69
0.000004
(0.59,0.81)
31
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)
32
COPERNICUS
In patients with severe chronic heart failure,
carvedilol reduced Risk of death Combined
risk 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
33
COPERNICUS
In patients with severe chronic heart failure,
carvedilol Was associated with improved patient
overall sense of well-being. Was well
tolerated. Was associated with a lower risk of
a serious adverse event, particularly one related
to the progression of heart failure. Was
associated with fewer patients requiring
withdrawal of treatment for an adverse event or
for another reason.
34
Carvidilol Or Metoprolol European Trial

• COMET

35
COMET

• Objectives
• To compare the effects on mortality and morbidity
  of Coreg and metoprolol tartrate in patients with
  chronic HF
• Design
• Randomized, double-blind, parallel-group,
  multicenter study of gt3,000 patients followed for
  a mean of approximately 5 years (58 months)
• Entry Criteria
• NYHA Class II, III, or IV with LVEF ?35 due to
  ischemic or nonischemic causes, receiving
  conventional therapy for stable chronic HF with
  at least 1 CV hospitalization within the previous
  2 years

Poole-Wilson PA et al. Lancet. 20033627-13.
36
COMET Sudden Death and MI
Fatal or Nonfatal MI
Sudden Death

• Risk Reduction
• ? 19
• (3, 32)
• P.0216

20
15

• Risk Reduction
• ? 30
• (1, 50)
• P.04

15
10
Mortality ()
Event ()
10
5
5
Fatal or nonfatal MI rates metoprolol 5.2
Coreg 3.8
Sudden death rates metoprolol 17.3 Coreg 14.4
0
0
0
1
2
3
4
5
0
1
2
3
4
5
Time (years)
Time (years)
Metoprolol Tartrate (n1,518)
Noncardiovascular death Coreg 5 metoprolol
tartrate 4, RR ?8 (95 CI, ?50 to 23,
P.66).1,2 Other cardiovascular death Coreg
1.3 metoprolol tartrate 1.7, RR 29 (95 CI,
?29 to 61, P.26).2
1Poole-Wilson PA et al. Lancet. 20033627-13.
2Data on file. GlaxoSmithKline. Remme W. J Am
Coll Cardiol. 200443205A.
37
COMET Stroke Death
5
4
Risk Reduction ? 67 (38, 82) P.0006
3
2
Mortality ()
1
Stroke death rates metoprolol tartrate 2.5
Coreg .9
0
0
1
2
3
4
5
Time After Entry to Trial (years)
Metoprolol Tartrate (n1,518)
Coreg (n1,511)
Noncardiovascular death Coreg 5 metoprolol
tartrate 4, RR ?8 (95 CI, ?50 to 23,
P.66).1,2 Other cardiovascular death Coreg
1.3 metoprolol tartrate 1.7, RR 29 (95 CI,
?29 to 61, P.26).2
1Poole-Wilson, PA et al. Lancet. 20033627-13.
2Data on file. GlaxoSmithKline. Remme W. J Am
Coll Cardiol. 200443205A.
38
COMET All-Cause Mortality
Metoprolol Tartrate

• Risk Reduction
• ? 17
• (7, 26)
• P.0017

40
Coreg
30
20
Extrapolation from the survival curves suggested
that Coreg extended median survival by 1.4
years... as compared with metoprolol
tartrate....
Mortality ()
10
Mortality rates metoprolol 40 Coreg 34.
0
1
2
3
4
5
0
Number at Risk
Time (years)
1,105
933
352
1,518
1,234
Metoprolol Tartrate
1,359
1,155
1,002
383
1,511
1,259
1,366
Coreg
95 CI, .5 to 2.3. Estimated median Coreg8.0
years (95 CI, 7.3 to 8.7) metoprolol
tartrate6.6 years (95 CI, 6.1 to 7.1). The
combined endpoint of mortality or all-cause
hospital admission (rates 74 on Coreg, 76 on
metoprolol), RR 6 (95 CI, -2 to 14, P.12),
and mortality (rates Coreg 34, metoprolol 40)
were co-primary endpoints.
Metoprolol mean dose 85 mg QD Coreg mean dose
42 mg QD.
Poole-Wilson PA et al. Lancet. 20033627-13.
39
GEMINI Glycemic Effects in Diabetes
MellitusCarvedIlolMetoprolol Tartrate
ComparisoN in HypertensIves
40
Inclusion Criteria

• History of Stage 1 or Stage 2 HTN treated with an
  ACE inhibitor or ARB, and
• Concomitant controlled type 2 diabetes
• Baseline HbA1c 6.5-8.5, and
• C-peptide gt.6 ng/mL

ACEangiotensin-converting enzyme
ARBangiotensin II receptor blocker.
Bakris, et al. JAMA. 20042922227-2236.
41
Study Design

• Randomized, double-blind, parallel-group,
  multicenter, US trial
• BP target values defined by ADA/NKF Guidelines
  and updated in 2001
• Randomized agents were titrated to achieve BP
  targets based on Prescribing Information (PDR)
• Coreg 6.25, 12.5, 25 mg BID
• Metoprolol tartrate 50, 100, 200 mg BID
• Blinded therapy was maintained for five
  additional months following titration to target BP

DBPdiastolic blood pressure SBPsystolic blood
pressure.
Metoprolol tartrate is marketed in the US as
Lopressor and is a registered trademark of
Novartis Pharmaceuticals Corporation. Bakris, et
al. JAMA. 20042922227-2236.
42
Primary and Secondary Analyses

• Primary Analysis
• The difference in HbA1c change from baseline
  between the Coreg and metoprolol tartrate groups
  using a modified intention-to-treat analysis
• Secondary Analyses Prespecified Endpoints
• Metabolic
• HbA1c change from baseline (within groups)
• Insulin resistance by HOMA
• Withdrawals for worsening glycemic control
• Lipids
• Cardiovascular
• BP
• Albumincreatinine ratio
• MAU

HOMAhomeostasis model assessment.
Bakris, et al. JAMA. 20042922227-2236.
43
Patients Achieving BP lt130/80 mm Hg
80
68
67
70
60
310/454
427/636
50
310/454
427/636
Patients ()
40
30
20
10
0
Metoprolol Tartrate
Coreg
Post-hoc analysis. Bakris, et al. JAMA.
20042922227-2236.
44
Hemoglobin A1c
7.4
Plt.0001
Treatment Difference Coreg vs Metoprolol ?.13 (?
.22, ?.04) P.004
7.3
P.65
Mean HbA1c ()
7.2
7.1
Baseline Month 5
Baseline Month 5
Coreg (n454)
Metoprolol Tartrate (n657)
1,111 patients (90) were evaluable for efficacy,
having both a valid baseline and at least one
on-therapy HbA1c assessment. Bakris, et al. JAMA.
20042922227-2236.
45
HbA1c Increases of 0.5 or 1.0
P.002
Coreg
Metoprolol Tartrate
199/657
Plt.001
99/454
Patients ()
93/657
32/454
Increase ?0.5
Increase ?1.0
Post-hoc analysis. Bakris, et al. JAMA.
20042922227-2236.
46
Development of MAU in Previously Normoalbuminuric
Participants
Odds ratio, .53 95 CI (.30, .93)P.03
16
11.1
12
Patients ()
8
6.6
4
0
Coreg (n302)
Metoprolol Tartrate (n431)
79 of patients did not have MAU (defined as
albumincreatinine ratio 30-300mg/g) at
screening.
Bakris, et al. JAMA. 20042922227-2236.
47
Total Cholesterol
Plt.001
P.5
Treatment Difference Coreg vs Metoprolol ?2.9 (?4
.6, ?1.15) P.001
mg/dL
Baseline Month 5
Baseline Month 5
Coreg (n433)
Metoprolol Tartrate (n625)
Bakris, et al. JAMA. 20042922227-2236. Data on
file. GlaxoSmithKline.
48
Conclusions

• GEMINI is the first large-scale randomized trial
  to evaluate the addition of ?-blockade to ACE
  inhibition to achieve the recommended BP target
  of lt130/80 mm Hg for patients with type 2
  diabetes
• Similar BP levels were achieved with a mean total
  daily dose of 35 mg Coreg or 256 mg metoprolol
  tartrate on top of treatment with ACEI/ARB
• In these high cardiovascular risk patients,
  Coreg
• Achieved BP goal while maintaining glycemic
  control
• Improved insulin resistance
• Improved MAU as measured by ACR
• Reduced progression to MAU

49
Indications for Coreg (carvedilol)
Essential Hypertension Coreg is indicated for the
management of essential hypertension. It can be
used alone or in combination with other
antihypertensive agents, especially thiazide-type
diuretics (see PRECAUTIONS, Drug
Interactions). Left Ventricular Dysfunction
Following Myocardial Infarction Coreg is
indicated to reduce cardiovascular mortality in
clinically stable patients who have survived the
acute phase of a myocardial infarctionand have a
left ventricular ejection fraction of ?40 (with
or without symptomatic heart failure). Congestive
Heart Failure Coreg is indicated for the
treatment of mild to severe heart failure of
ischemic or cardiomyopathic origin, usually in
addition to diuretics, ACE inhibitor, and
digitalis, to increase survival and, also, to
reduce the risk of hospitalization.
Coreg is a registered trademark of
GlaxoSmithKline. Prescribing Information for
Coreg. GlaxoSmithKline, Research Triangle Park,
NC, October 2003. Please see accompanying full
Prescribing Information for Coreg.
50
2004 ACC/AHA Guidelines for MITherapy With
?-Blockers

• Class Indications
• I Oral ?-blockers should be administered
  promptly to those patients without a
  contraindication irrespective of concomitant
  fibrinolytic therapy or performance of primary
  PCI (Level of Evidence A)
• I Patients without contraindications to
  ?-blockers who did not receive them within the
  first 24 hours after STEMI should have them
  started in the early convalescent phase (Level of
  Evidence A)
• IIa It is reasonable to administer IV ?-blockers
  promptly to STEMI patients without
  contraindications especially if a tachyarrhythmia
  or hypertension is present (Level of Evidence B)

There is overwhelming evidence for the benefits
of early ?-blockade in patients with STEMI and
without contraindications to their use. Benefits
have been demonstrated for patients with and
without concomitant fibrinolytic therapy, both
early and late after STEMI.
STEMIST-elevation myocardial infarction. Antman
TJ et al. Circulation. 2004110588-636.
51
2001 ACC/AHA Guidelines for HF ?-Blockade in
Both Ischemic and Nonischemic Stage B HF (ALVD)

• Class I Indication
• ?-blockade in patients with a recent myocardial
  infarction regardless of ejection fraction (Level
  of Evidence A)
• ?-blockade in patients with a reduced ejection
  fraction, whether or not they have experienced a
  myocardial infarction (Level of Evidence B)

ALVDasymptomatic left ventricular
dysfunction. Hunt SA et al. J Am Coll Cardiol
2001382101-2113.
52
If you always doWhat youve always doneyoull
always getwhat you always got