Role of Beta blocker in management of Acute Myocardial Infarction.

1. Beta Blocker in Acute
Myocardial Infarction
Dr. Vatsal Kayal
Senior Resident
Department of Cardiology
ABVIMS & Dr. RML Hospital

2. INTRODUCTION
• Beta-Blockers have been used extensively in the last 40 years after
AMI as part of therapy and in secondary prevention.
• Beta blocker therapy reduces infarct size and early mortality when
started early and lowers the risk of death when continued long term.
• Evidence supporting the benefit of beta blockers has been obtained
primarily from randomized trials that included predominantly
patients with STEMI.

3. Mechanism of Benefit of beta blocker in AMI
• Decreased oxygen demand - Reductions in heart rate, blood pressure,
and contractility, and the consequent relief of ischemic chest pain.
• Decreased risk of ventricular fibrillation - Experimental studies
demonstrate an increase in the ventricular fibrillation threshold &
clinical trials showing a relative risk reduction in sudden cardiac death
(30 to 47 percent).
• Decreased automaticity, increased electrophysiologic threshold for
activation, and slowing of conduction.

4. • Bradycardia prolongs diastole and thus improves coronary diastolic
perfusion and reduces after-depolarizations and triggered activity.
• Reduction in remodeling and improvement in LV hemodynamic
function (depending upon infarct size and the timing of treatment).
• Improved LV diastolic function with a less restrictive filling pattern.
• Slowing progression of coronary atherosclerosis.
• Inhibition of platelet aggregation and thromboxane synthesis.
• Reduction in reperfusion injury.

5. Goteborg
metoprolol trial
MIAMI Trial
BHAT Trial
Norwegian
Multicenre study
group
ISIS 1
TIMI II B
Study
GUSTO 1
COMMIT
trial
CAPRICORN
METOCARD
CNIC Trial
Early BAMI
CADILLAC
Trial
BEAT AMI
Trial
PRE REPERFUSION ERA THROMBOLYTIC
ERA
PCI ERA

6. Pre- Reperfusion Era
• Major data and recommendations of pre reperfusion era comes from
• Goteborg Metoprolol Trial
• MIAMI Trial
• BHAT Research Group
• Norwegian Multicentre Study Group
• ISIS 1

7. 1983

8. •The Goteborg trial - was one of the first randomized, double-
blinded trials to demonstrate the beneficial effect of BBs on
survival during the early phase of AMI.
•The protocol randomized total 1,395 patients.
•697 to placebo and 698 to metoprolol.
•15 mg iv metoprolol was initially given F/B oral metoprolol 200
mg/day for 90 days.
RESULTS
Overall Mortality-
• Metoprolol significantly reduced 3-month mortality in
the metoprolol group as a whole by 36%

9. Cumulative number of
deaths in all patients
randomly
allocated to treatment
with metoprolol and
placebo

10. Effect on Infarct Development
Index Infarction (Within 72 Hours)
• The patients who developed a definite index infarction
in the metoprolol group was 10% lower than that
in the placebo group
• Significantly lower maximum LDH I + II value compared
with the placebo group for all randomized patients.
Late Myocardial Infarction (4-90 Days)
• Metoprolol caused a 35% reduction of the development of
infarction

11. Number of patients who developed a
definite infarction
(AMI) on 4-90 days after the beginning
of treatment.
This includes patients with fatal and
nonfatal myocardial infarction.
 This study is the first to demonstrate
the beneficial effect of beta
blockade on survival during the early
phase of MI.

12. Cumulative number of
deaths in all patients
randomly allocated to
treatment with
metoprolol and
placebo during the first
3 months.
After 3 months, all
patients were given
open treatment with
metoprolol.

13. Effect on Ventricular Fibrillation
• 17 patients in the placebo group had ventricular
fibrillation, compared with 6 in the metoprolol group.
• Interestingly, the 17 patients in the placebo group
developed 41 episodes, compared with only six among
the six patients in the metoprolol group.

14. 19811981

15. BHAT Research Group - Propranolol
1982

16. • To test whether the regular administration of propranolol
hydrochloride to men and women who had experienced at
least one MI would result in a significant reduction in total
mortality during a 2-4 year period.
• During a 27-month interval, 3,837 persons between the ages
of 30 and 69 years were randomized to either propranolol or
placebo, 5-21 days after the infarction.
• The overall results show propranolol to have reduced
mortality by 26%.

17. • The results of BHAT are consistent with those of the
Norwegian Multicentre Study Group trial of timolol.
• Like timolol, propranolol is a nonselective betablocker
without intrinsic sympathomimetic activity and has been
shown to reduce total and coronary mortality in patients with
a recent MI.

19. 1985

20. • The primary objective of the MIAMI was to determine whether
short-term mortality (15 days) after AMI could be reduced by early
metoprolol intervention.
• The effect of metoprolol on mortality and morbidity after 15 days,
was compared with that of placebo in patients with definite or
suspected AMI.
• IV metoprolol (15mg) or placebo was started shortly after the
patient's arrival in hospital within 24 h of the onset of symptoms, and
then oral treatment 200 mg daily was continued for the study period
(15 days).
• Of total 5778 patients included, 2901 were allocated to placebo and
2877 to metoprolol.

21. • Metoprolol had no apparent effect in the low mortality risk group but
was associated with a 29 per cent lower mortality in the high
mortality risk group.
• The 8 risk predictors were: Age >60 years; Abnormal ECG at entry;
History of MI, Angina pectoris, congestive heart failure, HTN, DM;
chronic or acute treatment with diuretics and/or cardiac glycosides
before randomisation.
• There was no significant effect on ventricular fibrillation but the
number of episodes tended to be lower in the metoprolol treated
patients

22. ISIS 1 – IV Atenolol in Acute MI
1986

23. ISIS - 1
•It Randomized 16,027 patients with suspected acute MI to a
regimen of intravenous atenolol versus no betablocker therapy.
•Patients assigned to active treatment received an immediate
intravenous injection of 5–10 mg atenolol, followed by 100
mg/day orally for seven days.
•Vascular mortality was significantly lower in the treated group.
•Representing a 15% mortality reduction.

24. • Taken together, these data suggest that early treatment
of 200 acute MI patients with beta-blocker therapy would
lead to avoidance of one reinfarction, one cardiac arrest, and
one death during the initial 7 day period.

25. Role of Beta Blocker in Thrombolytic era
• Major data in the thrombolytic era comes from
• TIMI II B Study
• GUSTO 1 post hoc analysis
• COMMIT trial
• CAPRICON trial

26. GUSTO 1 TRIAL
1998

27. • To asses the use and effects of acute intravenous and later
oral atenolol treatment in a prospectively planned post
hoc analysis of the GUSTO-I dataset.
• They compared the 30-day mortality of patients given no atenolol,
any atenolol, any intravenous atenolol, only oral atenolol and both
intravenous and oral drug.
• Overall stroke and intracranial hemorrhage rates were lower among
patients given atenolol.

28. • The reinfarction rate was similar between patients given intravenous
atenolol vs. no intravenous atenolol and between patients given
intravenous and oral vs. oral atenolol alone.
• The use of atenolol in GUSTO-I was associated with decreased
mortality, stroke, shock and arrhythmias, but increased recurrent
ischemia and reinfarction.

29. TIMI II B Study 2003

30. • TIMI IIB compares the effect of immediate vs. delayed (6
days) metoprolol therapy among patients with ST elevation
myocardial infarction treated with rtPA (a substudy of the
TIMI II trial).
• Immediate metoprolol: 3 doses of 5 mg IV, followed by 50 mg
bid on day 1 then 100 mg bid.
• Deferred metoprolol: oral metoprolol 50 mg bid on day 6
followed by 100 mg bid thereafter

32. Interpretation :
• In appropriate post infarction patients, beta-blockers are safe
when given early after thrombolytic therapy.
• Beta-blockers are associated with decreased MI and
reinfarction in the first week
• But offer no benefit over late administration either in
improving ventricular function or reducing mortality.

33. 2005Commit trial

34.  TREATMENT: Metoprolol 15 mg iv over 15 mins, then 200 mg oral
daily vs matching placebo
 INCLUSION: Suspected acute MI (ST change or LBBB) within 24 h of
symptom onset
 EXCLUSION: Shock, systolic BP <100 mmHg, heart rate <50/min or
II/III AV block
 1 OUTCOMES: Death & death, re-MI or VF/arrest up to 4 weeks in
hospital (or prior discharge)
45852 patients were recruited with mean treatment
and follow-up: 16 days
COMMIT: Study design

35. COMMIT: Effects of METOPROLOL on
Reinfarction
Metoprolol Placebo Odds ratio & 95% CI
Metop. better Placebo better
Outcome
after Re-MI (22,927) (22,922)
Died 206 226(0.9%) (1.0%)
Survived 261 342(1.1%) (1.5%)
ALL COMBINED 467 568(2.0%) (2.5%)
18% SE 6
(2P = 0.002)
0.4 0.7 1.0 1.3 1.6 1.9

36. ß-blocker Control Odds ratio & 95% CI
ß-blocker better Control better
Trial
(33,841) (33,813)
MIAMI 85 111(3.0%) (3.8%)
ISIS-1 148 161(1.8%) (2.0%)
COMMIT 467 568(2.0%) (2.5%)
OVERALL 700 840(2.1%) (2.5%)
17% SE 5
(2P = 0.0003)
0.4 0.6 0.8 1.0 1.2 1.4 1.6
Effects of iv then oral -blocker on reinfarction
in 3 major trials of acute MI

37. COMMIT: Effects of METOPROLOL on Death
by attributed cause(s)
Metoprolol Placebo Odds ratio & 95% CI
Metop. better Placebo better
Cause(s)
(22,927) (22,922)
Arrhythmia 388 498(1.7%) (2.2%) 22% SE 6
Shock 496 384(2.2%) (1.7%) -29% SE 8
Other causes 892 916(3.9%) (4.0%) 3% SE 5
ANY DEATH 1776 1798(7.7%) (7.8%)
1% SE 3
(2P > 0.1; NS)
0.4 0.7 1.0 1.3 1.6 1.9

38. COMMIT: Effects of METOPROLOL on
Cardiogenic Shock by day of event
Metoprolol Placebo Odds ratio & 95% CI
Metop. better Placebo better
Day of event
(22,927) (22,922)
0 475 317(2.1%) (1.4%)
1 282 210(1.2%) (0.9%)
2+ 384 361(1.7%) (1.6%)
ALL 1141 888(5.0%) (3.9%)
-29% SE 5
(2P < 0.00001)
0.4 0.7 1.0 1.3 1.6 1.9

39. COMMIT: Absolute effects of
METOPROLOL on Re-MI, VF, Shock
and Death by KILLIP class
Killip
at entry
Absolute differences per 1000
Re-MI VF Shock Death
I 4 3 -7 3
II 10 11 -14 3
III -5 11 -58 -36
Any 5 5 -11 1

40. COMMIT: Conclusions
• Metoprolol (15 mg iv, then 200 mg oral daily) in acute MI did not significantly
reduce mortality in hospital
• It reduced the absolute risks of reinfarction by 5 per 1000 (P=0.001) and of VF by
5 per 1000 (P<0.001)
• But, overall, it increased the risk of cardiogenic shock by 11 per 1000 (P<0.00001),
chiefly on days 0-1
• The use of early -blocker therapy in acute MI reduces the risks of reinfarction and
ventricular fibrillation, but increases the risk of cardiogenic shock, especially
during the first day or so after admission.
• Consequently, it might generally be prudent to consider starting -blocker therapy
in hospital only when the haemodynamic condition after MI has stabilised.

43. CAPRICORN TRIAL
• To evaluate the effect of carvedilol on all cause mortality in patients
with LV Dysfunction who have recently survived an acute MI in the
modern era.
• Multicentre randomized placebo controlled, parallel group trial in
patients with LV ejection fraction <40% with or without heart failure.
• CAPRICORN is a landmark study and the only RCT that provides
evidence for the benefit of beta-blocker therapy in acute MI with LV
dysfunction in the era of reperfusion.

44. 1959 PATIENTS

48. Role of Beta Blocker in PCI Era
• Major trials for use of beta blocker in patients undergoing PCI
• CADILLAC Trial
• METOCARD CNIC Trial
• Early BAMI
• BEAT AMI Trial

49. CADILLAC Trial
2004

50. • To examine the effect of IV beta-blockers administered before
primary PCI on survival and myocardial recovery after AMI.
• It randomized 2,082 AMI patients to either stenting or balloon
angioplasty, each +/- abciximab.
• In accordance with the protocol, intravenous beta-blockers
were administered before PCI.

51. • The 30-day mortality was significantly lower in the BB + group than in
the BB – group an effect entirely limited to patients
who had not been receiving beta-blockers before admission.
• In contrast, no survival benefit with pre-procedural beta-blockers
was observed in patients receiving beta-blockers at home

52. Freedom from death
among patients
treated (BB, solid line)
& not treated (BB,
broken line)
with pre-procedural
intravenous beta-
blockers before PCI

53. METOCARD CNIC TRIAL
• The goal of the trial was to evaluate Long-Term Benefit of Early Pre-
Reperfusion Metoprolol Administration in Patients With Acute
Myocardial Infarction undergoing PCI.
• Trial recruited 270 patients with Killip class ≤II anterior STEMI
presenting early after symptom onset (<6 h) and randomized them to
pre-reperfusion IV metoprolol or control group.
• Long-term magnetic resonance imaging (MRI) was performed on 202
patients (101 per group) 6 months after STEMI. Patients had a
minimal 12-month clinical follow-up.
2013

54. LVEF on MRI 6 Months After Infarction

55. LVEF Comparison & Indication for ICD

56. MACE & HF Admission comparison

57. • In patients with anterior Killip class ≤II STEMI undergoing pPCI, early
IV metoprolol within 6 hours before reperfusion resulted in
• Higher long-term LVEF
• Reduced incidence of severe LV systolic dysfunction and ICD indications, and
• Fewer heart failure admissions.

58. EARLY BAMI
• Early Intravenous Beta-Blockers in Patients With ST-Segment Elevation
Myocardial Infarction Before Primary Percutaneous Coronary Intervention.
• 683 STEMI patients presenting <12 h from symptom onset in Killip class I to
II without atrioventricular block were randomized 1:1 to IV metoprolol (2
5-mg bolus) or matched placebo before PPCI.
• Primary endpoint was myocardial infarct size as assessed by cardiac
magnetic resonance imaging (CMR) at 30 days.
• Secondary endpoints were enzymatic infarct size and incidence of
ventricular arrhythmias. Safety endpoints included symptomatic
bradycardia, symptomatic hypotension, and cardiogenic shock.
2016

59. Comparison of Infarct size

60. Ventricular arrhythmia was
significantly reduced in
metoprolol group
No significant difference in MACE
and Cardiac Mortality

61. EARLY BAMI

62. • According to ESC 2017 guidelines based on the current available
evidence from METOCARD CNIC & EARLY BAMI Trial, early
administration of i.v. beta-blockers at the time of presentation
followed by oral beta-blockers should be considered in
haemodynamically stable patients undergoing primary PCI.

63. BEAT AMI
2016

64. • This study sought to evaluate the role of esmolol-induced tight
sympathetic control in patients with STEMI.
• The first in which continuous intravenous beta-blocker is
administrated in the very acute phase of STEMI
• Randomized, single-blind trial involving patients with STEMI and
successful PCI (Killip class I and II).
• Patients were randomly allocated to heart rate control with IV
esmolol for 24 h or placebo.
• A total of 101 patients were enrolled in the study.

65. • The primary outcome was the maximum change in troponin T
release as a prognostic surrogate marker for myocardial damage.
• There was a significant difference between patients allocated to
placebo and those who received sympathetic control with esmolol in
terms of maximum change in troponin T release.
• The levels of peak CK, CK-MB, and NT-proBNP were lower in the
esmolol group compared with placebo.

66. Time-dependent serum
concentration of
(A) troponin T,
(B) creatine kinase
(C) creatine kinase subunit MB
in patients.

67. MAJOR ONGOING TRIALS
• ABYSS TRIAL : The primary objective is to demonstrate the non-
inferiority of the interruption of ΒB therapy after an uncomplicated
MI after six months or more of follow-up compared to the
continuation of βB evaluated by the primary endpoint.
• REBOOT clinical trial will study whether long-term maintenance beta-
blockers therapy results in a clinical benefit after heart attack without
reduced left ventricular function.
• SWEEDEHEART Trial will study the long term effect of metoprolol
succinate and bisoprolol in acute MI over a period of 3 years.

68. CONCLUSION
• In the treatment of patients with myocardial infarction, b-blockers reduced
mortality in the pre-reperfusion but not in the reperfusion era, where
there was short term reduction in myocardial infarction and angina, but
increase in
 Heart failure,
 Cardiogenic shock, and
 Drug discontinuation
• Carvedilol is preferred in patients with LVSD (LVEF 40%).
• Incidence of VF is significantly reduced in all the trials.

69. • Early data from CADILLAC & METOCARD CNIC TRIAL show a
promising result of pre PCI beta blocker with reduction in infarct size
but later studies (EARLY BAMI) did not show promising results of
preprocedural Beta blockers.
• Currently recommended for 3 years in all patients and indefinitely for
patients with LVSD (LVEF <40%) but guideline authors should
reconsider the strength of recommendations for b-blockers post
myocardial infarction.
• Three large ongoing multicenter randomized trials (AβYSS, REDUCE-
SWEDEHEART, and REBOOT-CNIC) are evaluating early
discontinuation of β-blockers after an uncomplicated acute MI.

70. THANK YOU