Beta blockers have a variety of different uses in the management of ischemic heart disease. This presentation by Dr Vivek Baliga, Internal Medicine Physician talks about the role in ST elevation MI.

1. BETA BLOCKERS IN ST ELEVATION
MYOCARDIAL INFARCTION
Dr Vivek Baliga
Internal Medicine
Managing Partner, Baliga Diagnostics Pvt. Ltd®

2. A SHORT STORY
 Introduction
 How it all began
 It’s use in heart disease – Protective effects
 Pre-thrombolytic era
 Thrombolytic era
 PCI era
 Guidelines

3. INTRODUCTION
 In acute MI, β blocker therapy can reduce the risk
of death when started early. This evidence is seen
in STEMI
 In NSTEMI, there are no randomised trials that
have addressed this issue (evidence is from meta-
analysis and registry data)
 Here, we will discuss the role of β blockers in
STEMI.

4. HOW IT ALL BEGAN
 1st beta blocker discovered –
Promethanol, withdrawn due to
formation of thymic tumors in mice
 Nobel Prize winner 1988 for
discovery of beta blocker
Propranolol in 1962
 Started research after his father fell
ill
 Discovery was based on Ahlquist’s
theory on α and β receptors
Dr James Black
1924 - 2010

5. PROTECTIVE EFFECTS OF BETA BLOCKERS
 ↓ HR and contractility
 ↓ VO2
 ↓ apoptosis signalling
 Anti-ischemic and anti-
arrhythmic effects - ↓ VF
 Anti-inflammatory
 Increase synthesis of
myocardial proteins
 Shift from FFA to glucose
metabolism
 Peripheral antioxidant effect
 Reduce catecholamine
release

6. PROTECTIVE EFFECTS OF BETA BLOCKERS IN
ISCHEMIA
 Reduce the myocardial oxygen demand via
 negative inotropic action
 reduction of heart rate
 blood pressure decrease
 Increase coronary blood flow via
 increase in diastolic perfusion time by reducing heart
rate
 augmentation of collateral blood flow and
 redistribution of blood flow to ischemic areas
 Alter the myocardial substrate utilization
 Decrease the microvascular damage
 Stabilize the cell and lysosomal membranes

7. TYPES OF BETA BLOCKERS
 Non Cardioselective – Acebutolol, Propranolol
 Partially Cardioselective – Atenolol, Metoprolol
 Highly Cardioselective – Nebivolol, Bisoprolol

8. ROLE IN STEMI: PRE – THROMBOLYTIC ERA
 Goteborg trial - One of the first randomized,
double-blinded trials to demonstrate the beneficial
effect of β blockers on survival during the early
phase of AMI.
 Randomized 1,395 patients to metoprolol vs.
Placebo. Intravenous metoprolol was initially given
followed by oral metoprolol.
 Patients treated within 12 hours of onset of
ischemic pain
 Lower LDH levels
 16% decrease in index infarctions
 90 day mortality decreased by 36%

9. ROLE IN STEMI: PRE – THROMBOLYTIC ERA
 MIAMI trial (Metoprolol in acute myocardial
infarction)
 Randomized 5,778 patients to IV metoprolol or
placebo within 24h of symptom onset, followed by
oral treatment for 15 days.
 Significant decrease in development of definite
infarction and reduction in tachyarrythmias with
metoprolol, especially when treated within 7 hours
of symptom onset.
 No statistical difference in mortality.

10. ROLE IN STEMI: PRE – THROMBOLYTIC ERA
 Many trials done in the pre-thrombolytic era have all
shown inconclusive results
 Timolol - Sederholm , et al: Reduction of infarct size with
the early use of timolol in acute myocardial infarction. N
Engl J Med 1984; 310: pp. 9-15
 Propranolol - Peter T., Heng M.K., Singh B.N., et al:
Failure of high doses of propranolol to reduce
experimental myocardial ischemic damage. Circulation
1978; 57: pp. 534-540
 Yusuf S., Sleight P., Rossi P., et al: Reduction in infarct
size, arrhythmias and chest pain by early intravenous
beta blockade in suspected acute myocardial infarction.
Circulation 1983; 67: pp. I32-I41
PRE-THROMOBOLYTIC ERA
EVIDENCE FROM ALL TRIALS AVAILABLE
SHOWS OVERALL MORTALITY REDUCTION
BETWEEN 10 – 25%.

11. ROLE IN STEMI: THROMBOLYTIC ERA
 TIMI – IIB1
 Assessed the effects of immediate versus deferred β
blockers therapy in patients receiving i.v rTPA.
 Immediate beta-blockade produced no improvement in
LVEF, nor reduced mortality (in both invasive and non-
invasive treatment arms) at hospital discharge.
 However, reduced re-infarction rate and recurrent chest
pain noted
 Gusto I Post Hoc analysis2
 Oral atenolol conferred a 5-fold lower mortality risk
 Associated with decreased stroke, shock and
arrhythmias
 Increased recurrent ischemia and re-infarction
1. Roberts R, Rogers WJ, Mueller HS, et al. Immediate versus deferred beta-blockade following thrombolytic therapy in patients with acute myocardial infarction.
Results of the Thrombolysis in Myocardial Infarction [TIMI] II-B Study. Circulation. 1991;83(2):422–37.
2. Pfisterer M, Cox JL, Granger CB, et al. Atenolol use and clinical outcomes after thrombolysis for acute myocardial infarction: the GUSTO-I experience. Global
Utilization of Streptokinase and TPA [alteplase] for Occluded Coronary Arteries. J Am Coll Cardiol. 1998;32(3):634–40.

12. ROLE IN STEMI: THROMBOLYTIC ERA
 2004 STEMI guidelines (AHA/ACC) recommended
the use of early iv β blockers in those undergoing
fibrinolytic treatment
 Doubt was raised from a review of the GUSTO – I
trial (atenolol)
 2007 issued new guidelines, took into account the
COMMIT study of metoprolol

13. COMMIT STUDY
 45852 patients randomised to receive metoprolol (up to
3 doses of 5 mg IV each in the first 15 minutes, followed
by 200 mg orally daily) Vs matching placebo
 Fifteen minutes after the IV doses, a 50-mg tablet of
metoprolol or placebo was administered orally and
repeated every 6 hours during Days 0 to 1 of
hospitalization.
 From Day 2 onward, 200 mg of controlled-release
metoprolol or placebo was administered orally daily until
discharge up to a period of 4 weeks
 Primary end points included death, re-infarction,
ventricular fibrillation (arrhythmias) and shock.
Doll, Richard. "Early intravenous then oral metoprolol in 45 852 patients with acute
myocardial infarction: randomised placebo-controlled trial." Lancet 366 (2005): 1622-32.

14. COMMIT/CCS-2 STUDY

15. COMMIT/CCS-2 STUDY
 Conclusions
 Metoprolol (15 mg IV, then 200 mg oral daily) in acute
MI patients did not significantly reduce in-hospital
mortality.
 It reduced the absolute risks of re-infarction by 5 per
1000 (P = .001) and of VF by 5 per 1000 (P < .001) from
Day 2.
 Overall, metoprolol increased the risk of cardiogenic
shock by 11 per 1000 (P < .00001), chiefly during the
first day of hospitalization.
 In acute MI, it may be better to start beta-blocker
therapy when the patient is stable (and then continue
long-term therapy).

16. SO WHAT DID THE AHA RECOMMEND?
 Administer iv β blockers on Day 0 -1 if –
 There is hypertension
 Sinus tachycardia or AF (provided bedside echo shows
normal LV function)
 Avoid early oral β blockers if –
 Signs of heart failure +
 Increased risk of Cardiogenic Shock
 Relative contraindications are present
 1st degree AV block (or any other block)
 Active asthma
 If early contraindications are present, then re-
evaluate suitability after 24 hours.

17. SO WHAT DID THE AHA RECOMMEND?
 From Day 2, benefit is seen on re-infarction and VF
reduction rate
 Start with Metoprolol 50 mg 6 hourly (can go up to
200 mg/day)
 Long term use strongly recommended
Antman, Elliott M., et al. "2007 focused update of the ACC/AHA 2004 guidelines for the management of
patients with ST-elevation myocardial infarction." Journal of the American College of Cardiology 51.2
(2008): 210-247.

18. ROLE IN STEMI – PCI ERA
 METOCARD CNIC Trial
 Enrolled Killip II or less with anterior ST elevation
 Received Metoprolol Tartrate Vs placebo within 24
hours
 Three doses of 5 mg given iv 2 minutes apart, oral given
12 – 24 hrs later
 Infarct size assessed through MRI 5 – 7 days after
STEMI
 Patients on pre-existing beta blocker therapy were
excluded.
Ibanez, Borja, et al. "Effect of early metoprolol on infarct size in ST-segment elevation myocardial infarction patients undergoing primary PCI: the
METOCARD-CNIC Trial." Circulation (2013): CIRCULATIONAHA-113.

19. METOCARD CNIC TRIAL
Ibanez, Borja, et al. "Effect of early metoprolol on infarct size in ST-segment elevation myocardial infarction patients undergoing primary PCI: the
METOCARD-CNIC Trial." Circulation (2013): CIRCULATIONAHA-113.

20. METOCARD CNIC TRIAL
Ibanez, Borja, et al. "Effect of early metoprolol on infarct size in ST-segment elevation myocardial infarction patients undergoing primary PCI: the
METOCARD-CNIC Trial." Circulation (2013): CIRCULATIONAHA-113.

21. METOCARD CNIC TRIAL – CONCLUSIONS
 Pre – PCI iv β blockers reduce infarct size (by
~20%)
 Lesser infarct size means better LV function post
MI/PCI
 However, it only studied anterior infarcts, not others
 The authors say –
‘although important and encouraging, the results of
the METOCARD-CNIC trial are probably not strong
enough to warrant a change in the clinical practice
of the use of β-blockade in patients with STEMI’

22. ROLE IN STEMI – PCI ERA
 Early BAMI
 First double blind randomised control trial assessing
early iv β blocker therapy before PPCI
 Used CMR to assess infarct size
 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.
Roolvink, Vincent, et al. "Early Administration of intravenous Beta blockers in patients with ST-elevation myocardial infarction
before primary PCI." Journal of the American College of Cardiology (2016).

23. EARLY BAMI - RESULTS
Roolvink, Vincent, et al. "Early Administration of intravenous Beta blockers in patients with ST-elevation myocardial infarction
before primary PCI." Journal of the American College of Cardiology (2016).

24. EARLY BAMI - RESULTS
Roolvink, Vincent, et al. "Early Administration of intravenous Beta blockers in patients with ST-elevation myocardial infarction
before primary PCI." Journal of the American College of Cardiology (2016).

25.  Results contrary to METOCARD CNIC trial
EARLY BAMI - CONCLUSIONS

26. POST PCI ROLE
 BEAT AMI Trial
 Single blinded
 Enrolled only patients within 6 hours of symptom onset
who had Killip class I or II STEMI
 Randomly allocated to receive heart rate control with IV
esmolol for 24 hours (target of 60 bpm) or placebo.
 Result
 Lesser troponin rise
 Lesser CK rise
 Lesser NT pro-BNP rise
 Infarct size not assessed with CMR

27. POST STEMI ROLE
 Well established for oral β blockers
 CAPRICORN – Carvedilol in post MI patients with
LVSD

28. CHOICE OF BETA BLOCKER
 Use a cardioselective one – either metoprolol
(preferred) or atenolol
 Start low, go slow
 If ongoing ischemia before PPCI, some groups
recommend iv metoprolol, atenolol or esmolol.
 Watch for bradycardia or hypotension
 If hypertension present, better to use iv NTG
instead to reduce BP.

29. LONG TERM THERAPY – HOW LONG?
 The optimal duration of treatment is not very clear.
 Evidence supports total duration of treatment of 3
years; not much for longer than that
 When stopping, taper the dose
 REACH registry data showed no difference in
benefit between beta blocker and no beta blocker
groups at 2 years.
 Maybe better for those with higher risk of LVSD and
chronic kidney disease
 In high risk patients, longer duration of treatment is
acceptable

30. LONG TERM THERAPY – HOW MUCH
 Clinical trials suggest doses of 200 mg/day of
metoprolol
 Not practical, not used in clinical practice
 Best policy – Start Low, Go Slow
 Better to use longer acting preparation

31. TARGETS
 Recommendation
 Heart Rate < 70 bpm
 SBP > 90 mmHg
 Avoid if
 SBP low / shock
 Severe bronchospasm
 Bradycardia / heart block
 Acute heart failure
 Can be given in
 Controlled COPD – mortality benefit seen
 Controlled heart failure – carvedilol
 Peripheral vascular disease

32. CLOSING REMARKS
 The role of ‘very early’ β blockers in managing
STEMI is not clearly defined.
 However, its role in preventing arrhythmias post MI
is established.
 Careful assessment of patients must be before
starting β blockers – follow AHA guidelines
 Start β blockers within 24 hours if patient stable and
no contraindication present
 Beta blockers after STEMI reduce overall mortality,
non fatal MI and SCD
 As always, we need more data.