BETA BLOCKERS IN ST ELEVATION MYOCARDIAL INFARCTIONDr Vivek Baliga Internal MedicineManaging Partner, Baliga Diagnostics Pvt. Ltd®

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

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.

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Promethanol, withdrawn due to formation of thymic tumors in mice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

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

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

TYPES OF BETA BLOCKERS Non Cardioselective – Acebutolol, Propranolol Partially Cardioselective – Atenolol,

Metoprolol Highly Cardioselective – Nebivolol, Bisoprolol

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%

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.

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%.

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-infarction1. 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.

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

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.

COMMIT/CCS-2 STUDY

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).

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.

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.

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.

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.

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.

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’

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).

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).

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).

Results contrary to METOCARD CNIC trial

EARLY BAMI - CONCLUSIONS

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

POST STEMI ROLE Well established for oral β blockers CAPRICORN – Carvedilol in post MI patients

with LVSD

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.

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

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

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

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.