Friday, October 19, 2018

Anterior STEMI and multiform PVCs with Narrow Coupling Interval. When to give beta blockers in acute MI?

A middle-aged male had 45 minutes of chest discomfort and drove to the ED.  He has a history of hyperlipidemia. No previous MI.  

His initial BP was 152/102, pulse 76.

Here is his triage ECG:
Obvious anterolateral STEMI.  Notice there are already well formed Q-waves.  Q waves form in 1/2 of anterior MI within the first hour (Raitt et al.)

The cath lab was activated, aspirin and ticagrelor and a heparin bolus were given, and another ECG was recorded while waiting for the cath team to arrive in off hours:
There are now multiform PVCs.  

There are 4 PVCs in the 10 seconds recorded in lead II.  But they are not all captured for every lead on the printed pdf 12-lead.

On the McKesson system, however, one can scroll through all 10 seconds of each lead.  I have done so below in order to show the PVCs in all leads, including leads V1-V3:
Now one can see easily that the PVCs (complexes 3 and 4 in leads V1-V3) are of a right bundle pattern.  This means they originate in the LV.  Notice that there is concordant ST elevation (STE in the same direction as the R'-wave).  This makes the STEMI even more obvious.

Notice also that there is a very short coupling interval
The first PVC occurs 320 ms after the initiation of the normal QRS, and it almost occurs directly on the T-wave.
So this is almost an R on T.

Here I magnify that area:
The second beat here, which is the first PVC, is almost on the T-wave

The K was 3.4 mEq/L.  Lactate 4.8 (this suggests some shock, but did not correlate with the rest of the clincical picture).  K was given.

The interventionalist was concerned about the multiform PVCs with short coupling interval

The defibrillation pads were placed, and the interventionalist asked that metoprolol 5 mg IV be given prior to cath.  It was given, and the PVCs stopped.

The first troponin I was less than 0.010 ng/mL (below the level of detection).  (Remember this the next time someone tells you that it cannot be an MI because the troponin is negative; 50% of STEMI have an initial troponin less than the 99% URL, and many below the level of detection.)

An LAD occlusion proximal to a large 2nd diagonal was found and opened and stented.

The peak troponin was 75 ng/mL.

He received oral metoprolol after cath.

Contrast Echo done after cath:
Moderately reduced left ventricular systolic function. The estimated ejection fraction is 36%.
Regional wall motion abnormality-distal septum anterior and apex.

24 hours ECG:
QS-waves (significant myocardial loss of septum and anterior wall)
There is still quite a bit of ST elevation and tall T-waves, suggesting some degree of "No-Reflow" (downstream plugging of small vessels with platelet-fibrin aggregates causing persistent ischemia)

At about 47 hours, he had a run of Ventricular Tachycardia.  (Any VT beyond 48 hours in a patient without persistent or recurrent ischemia, there is consideration of an ICD.  This patient barely met the cutoff)

However, no Reflow, with persistent ischemia, may explain the borderline late VT.

48 hours
Terminal T-wave inversion suggests some possible additional reperfusion.  

72 hours
Not much change

PVCs and risk of VT

It may be that multiform PVCs, especially PVCs with a short coupling interval, put the patient at high risk of VT/VF, but as far as I can tell, it is not definitely proven in the literature (see a couple references below).  PVCs of any coupling interval do increase the risk of VT/VF, as all VT/VF is initiated by a PVC.  But it hasn't been proven, as far as I can tell, that suppressing them increases or decreases risk.

In the CAST trial (cardiac arrhythmia suppression trial) of patients with previous, but not acute, MI and low ejection fraction and PVCs, patients whose PVCs were suppressed in a trial period of Type 1 antidysrhythmic (encainide, flecainide, or moricizine) were randomized to a type 1 vs. placebo.  Results: those who received the anti-dysrhythmic had a higher risk of sudden arrhythmic death.

So type I antidysrhythmics are dangerous for this population (again, not the acute MI population).

PVCs and coupling intervals
This study suggests that short coupling intervals do increase the risk for Monomorphic ventricular tachycardias.   VT can usually be witnessed to be initiated by PVCs.

This study which was much smaller, from 1974, contradicts that:

So what can we do to decrease the risk of VT/VF in this patient?  

Beta Blockers 
--class II antidysrhythmic in the Vaughan Williams classification)
--I won't be discussing class I (e.g. lidocaine, Ib) or III (e.g. amiodarone) antidysrhythmics here.

Beta blockers decrease the incidence of ventricular fibrillation, and are overall beneficial for a stable subgroup of anterior STEMI who will undergo PCI (see details below), but for a less stable subgroup, they increase the risk of cardiogenic shock.  Until 2005, early (ED) beta blockers were mandated for patients with acute MI.  But all the data in their support had come from the pre-reperfusion era.  Then the COMMIT trial of patients with STEMI receiving thrombolytics (2005, described in detail below) showed they lead to a decreased incidence of v fib, but increased incidence of cardiogenic shock, and overall no difference in mortality.  Interestingly, the decrease in ventricular fibrillation by giving early beta blockers was a decrease in v fib after day 1.  Later trials of subgroups with a lower risk of cardiogenic shock who are undergoing PCI showed modest probable benefit of early beta blockade without the adverse effects.

Bottom Line:  If there are no contraindications (no heart failure, SBP at least 120, no tachycardia, no AV block), metoprolol 5mg IV x 3, with oral metoprolol given later if tolerated, seems to convey benefit prior to PCI in anterior MI.  

Anterior MI patients treated with PCI (not fibrinolytics) without contraindications to beta blockers, who are anticipated to undergo PCI within 6 hours of onset, who have a BP greater than 120 systolic, appear to benefit from 3 5 mg doses of IV metoprolol given prior to PCI.  All patients without contraindications benefit from oral metoprolol after PCI.

Our patient above fits this.

The best strategy may be to give esmolol bolus and drip which is a very short acting beta blocker that can be turned off at the first sign of cardiogenic shock.  

Finally, there is little evidence that beta blockers are more important in patients with ventricular dysrhythmias, including frequent PVCs and short coupling intervals, but at least there is some face validity to this idea and randomized trials seem to show benefit without showing harm in this subgroup who are not at high risk of cardiogenic shock. 

5 key references

1.  Recommendations of the European Society of Cardiology 2017 guidelines for STEMI.

7.3.1 Early intravenous beta-blocker administration
Based on the current available evidence, 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.
In patients undergoing fibrinolysis, early i.v. beta-blocker treatment reduces the incidence of acute malignant ventricular arrhythmias, although there is no clear evidence of long-term clinical benefit.344–346
In patients undergoing primary PCI, the Effect of Early Metoprolol in Cardioprotection During an Acute Myocardial Infarction by Ibanez et al. (METOCARD-CNIC) trial (n = 270) (and this long term followup by Pizarro et al., see description below) showed that the very early administration of i.v. metoprolol (15 mg) at the time of diagnosis in patients with anterior STEMI, no signs of heart failure, and SBP at least 120 mmHg was associated with a reduction in infarct size measured by CMR at 5–7 days (25.6 g vs. 32.0 g; P = 0.012), and higher LVEF at 6 months CMR (48.7% vs. 45.0%; P = 0.018) compared with control treatment.347,348 All patients without contraindications received oral metoprolol within 24 h. The incidence of MACE (composite of death, admission as a result of heart failure, reinfarction, or malignant ventricular arrhythmias) at 2 years was 10.8% vs. 18.3% in the i.v. metoprolol and control arms (P = 0.065).348 Metoprolol treatment was associated with a significant reduction in the incidence and extent of MVO.349   Roolvink et al. The Early Intravenous Beta-Blockers in Patients With ST-Segment Elevation Myocardial Infarction Before Primary Percutaneous Coronary Intervention (EARLY-BAMI) trial randomized 683 patients with STEMI within 12 h of onset to i.v. metoprolol (5 mg at recruitment and an additional 5 mg immediately before PCI) or placebo.350 All patients without contraindications received oral metoprolol within 12 h. Early i.v. metoprolol administration did not show any benefit in reducing CMR-based infarct size, the trial primary endpoint, available only in 342 patients (55%), or the level of cardiac biomarker release. Early i.v. metoprolol was associated with a borderline reduction of malignant ventricular arrhythmias (3.6% vs. 6.9%; P = 0.050). Patients treated with i.v. metoprolol showed no increased risk of haemodynamic instability, atrioventricular (AV) block, or MACE at 30 days. Post hoc analyses from primary PCI trials testing other hypotheses have suggested that early i.v. beta-blocker administration might be associated with a clinical benefit, but a selection bias cannot be excluded even after correction for imbalances in baseline characteristics.351,352 Based on the current available evidence, 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.

7.3.2 Mid- and long-term beta-blocker treatment

Based on the current evidence, routine administration of beta-blockers in all post-STEMI patients should be considered as discussed in detail in the heart failure guidelines;6 beta-blockers are recommended in patients with reduced systolic LV function (LVEF less than or equal to 40%), in the absence of contraindications such as acute heart failure, haemodynamic instability, or higher degree AV block. Agents and doses of proven efficacy should be administered.357–361 As no study has properly addressed beta-blocker duration to date, no recommendation in this respect can be made. Regarding the timing of initiation of oral beta-blocker treatment in patients not receiving early i.v. beta-blockade, a retrospective registry analysis on 5259 patients suggested that early (i.e. less than 24 h) beta-blocker administration conveyed a survival benefit compared with a delayed one.362 
Therefore, in haemodynamically stable patients, oral beta-blocker initiation should be considered within the first 24 h.

Ventricular Dysrhythmias

Also from the ESC guidelines on Ventricular dysrhythmias (there is no comment on short coupling intervals)
Ventricular premature beats are very frequent on the first day of the acute phase and complex arrhythmias (multiform complexes, short runs, or the R-on-T phenomenon) are common. Their value as predictors of VF is questionable and no specific therapy is required. Sustained VT or VF outside the early phase (usually 48 h after STEMI onset) not triggered by recurrent ischaemia has a poor prognostic implication, and evaluation for ICD implantation for secondary prevention of sudden cardiac death is recommended according to current guidelines.3 Primary prevention of sudden cardiac death with the ICD within 40 days after MI in the absence of VT/VF is generally not indicated.3 
Ventricular Tachycardia after 48 hours:
In this large study, the occurrence of ventricular dysrhythmias after 48 hours portended a worse prognosis.

Thus, the ESC guidelines say:

"Sustained VT or VF outside the early phase (usually 48 h after STEMI onset) not triggered by recurrent ischaemia has a poor prognostic implication, and evaluation for ICD implantation for secondary prevention of sudden cardiac death is recommended according to current guidelines.  Their reference is the 2006 ACC/AHA guidelines for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death.   

2. COMMIT Trial

The COMMIT trial randomized 45,000 STEMI patients who were not at high risk of adverse events from beta blockade  (systolic blood pressure below 100 mm Hg), heart rate below 50 bpm, heart block, or cardiogenic shock) to 15 mg IV metoprolol in 3 q 5 minutes doses, followed by 50 mg po, then 200 mg sustained release starting on day 2.  Mortality at 4 weeks was the same in both groups.  The metoprolol group had less arrhythmic death (all of that difference was beyond day 1 however) but more cardiogenic shock, especially in high risk groups (23·1 per 1000 for those 70 years or older at entry; 23·3 per 1000 for systolic blood pressure below 120 mm Hg; 34·6 per 1000 for those presenting with heart rate of more than 110 bpm; and 56·9 (14·4) per 1000 for those in Killip class III).

This suggests that in any patient at significantly increased risk for cardiogenic shock, that beta blockers should be avoided.  One should be very wary of anyone with anterior MI, especially with tachycardia (indicating decreased stroke volume) or with poor LV function on point of care cardiac ultrasound.  It is better to have ventricular fibrillation (which can be defibrillated) than cardiogenic shock.

Important paragraphs from the COMMIT trial (quotes):

When the attributed causes of death were considered separately (table 3), however, allocation to metoprolol was associated with a highly significant 22% (11–32) proportional reduction in death attributed to arrhythmia (388 [1·7%] metoprolol vs 498 [2·2%] placebo; p=0·0002) and, by contrast, with a highly significant 29% (13–47) proportional increase in death attributed to cardiogenic shock (496 [2·2%] vs 384 [1·7%]; p=0·0002). On average in the whole study population, the absolute reduction in arrhythmia-related deaths and the absolute increase in shock-related deaths were of similar magnitude. No apparent difference was noted between the two treatment groups in the other attributed causes of death, either individually or in aggregate (890 [3·9%] vs 915 [4·0%]; p=0·55).

The first intravenous injection of 5 mg metoprolol or matching placebo was to be given immediately over about 2–3 min. About 2–3 min later, if the heart rate was above 50 bpm and systolic blood pressure above 90 mm Hg, the second ampoule was to be injected; and similarly for the third ampoule (otherwise part or all of the second and third intravenous treatment could be avoided). 15 min after these intravenous doses, a 50 mg metoprolol or placebo tablet was to be given, and repeated every 6 h during days 0–1. From day 2 onwards, a 200 mg controlled-release metoprolol or placebo tablet was to be given once daily for up to 4 weeks (or, if earlier, until hospital discharge or death), unless some definite contraindication was thought to have arisen.

Reductions in the risks of reinfarction and of ventricular fibrillation with metoprolol seemed to emerge more gradually, with no significant difference between the treatment groups during days 0–1 (reinfarction: 0·9% metoprolol vs 1·0% placebo; ventricular fibrillation: 1·3% vs 1·5%), but with significant benefit during days 2 onwards (reinfarction: 1·1% vs 1·5%; ventricular fibrillation: 1·3% vs 1·6%; each p0·01).

The probability of developing shock was much higher in some types of control patients than in others, the absolute excess risks of shock with metoprolol allocation were particularly large in certain baseline categories: for example, 23·1 (SE 4·7) per 1000 for those aged 70 years or older at entry; 23·3 (4·0) per 1000 for those presenting with systolic blood pressure below 120 mm Hg; 34·6 (11·5) per 1000 for those presenting with heart rate of more than 110 bpm; and 56·9 (14·4) per 1000 for those in Killip class III (table 6).

For the combined efficacy and safety outcome, allocation to metoprolol was associated with a marked increased risk in high-risk patients and with a tendency for a risk reduction in low-risk patients. In particular, there was an absolute increase of 43·7 (SE 13·0) such events per 1000 patients in the high shock risk group compared with an absolute increase of only 2·3 (6·2) per 1000 in the medium-risk group and a decrease of 5·1 (2·8) per 1000 in the low shock risk group (trend p0·0001).

3.  Ibanez et al. Early Metoprolol in STEMI patients undergoing PCI.


This study showed benefit of early IV metoprolol, 15 mg, in the below patients.  A second report showed that the benefit was sustained at 12 months.  

Inclusion criteria were patient age 18 to 80 years, Killip class less than or equal to II,  anterior STEMI undergoing PCI, and anticipated symptom onset-to-reperfusion time ≤6 h.

Exclusion criteria were systolic blood pressure persistently less than 120, PR interval greater than 240 ms, or any 2nd or 3rd degree AV block, or heart rate persistently less than 60, or active BB treatment. 

TreatmentPatients randomized to intravenous metoprolol received up to three 5-mg boluses of metoprolol tartrate 2 minutes apart (no placebo).  All patients except those who developed contraindications received oral metoprolol tartrate during hospitalization. The first oral dose was scheduled for 12 to 24 hours after infarction, in line with clinical guidelines.

Malignant Ventricular dysrhythmias occurred in 5 of 140 given metoprolol and 10 of 130 given placebo (P = NS)

This is the main outcome, and it was pre-specified: Mean±SD infarct size by magnetic resonance imaging was smaller after intravenous metoprolol compared with control (25.6±15.3 versus 32.0±22.2 g; adjusted difference, −6.52; 95% confidence interval, −11.39 to −1.78; P=0.012).

The composite of death, malignant ventricular arrhythmia, cardiogenic shock, atrioventricular block, and reinfarction at 24 hours in the intravenous metoprolol and control groups was 7.1% and 12.3%, respectively (P=0.21).

Results of the long term outcome: At a median follow-up of 2 years, occurrence of the pre-specified composite of death, heart failure admission, reinfarction, and malignant arrhythmias was 10.8% in the IV metoprolol group versus 18.3% in the control group, adjusted hazard ratio (HR): 0.55; 95% CI: 0.26 to 1.04; p = 0.065. Heart failure admission was significantly lower in the IV metoprolol group (HR: 0.32; 95% CI: 0.015 to 0.95; p = 0.046)

Conclusion of first report: In patients with anterior Killip class II or less ST-segment–elevation myocardial infarction undergoing primary percutaneous coronary intervention, early intravenous metoprolol before reperfusion reduced infarct size and increased left ventricular ejection fraction with no excess of adverse events during the first 24 hours after STEMI.

Conclusion of 2nd report: In patients with anterior Killip class ≤II STEMI undergoing pPCI, early IV metoprolol before reperfusion resulted in higher long-term LVEF, reduced incidence of severe LV systolic dysfunction and ICD indications, and fewer heart failure admissions.

Interesting Discussion:

"The results of the Clopidogrel and Metoprolol in Myocardial Infarction Trial (COMMIT) trial are the main reason why clinical practice guidelines do not emphasize early intravenous β-blocker initiation in STEMI. In this trial, STEMI patients undergoing thrombolysis were randomized to early intravenous followed by oral metoprolol or matching placebo. The COMMIT trial did not report data on infarct size but showed significantly reduced rates of reinfarction and ventricular fibrillation in response to early intravenous metoprolol; however, this benefit came at the cost of excess cardiogenic shock, resulting in a net neutral effect on mortality. Although patients in COMMIT presented late (mean time from symptom onset to thrombolysis, 10.3 hours), mortality was lower in Killip class I and II patients receiving intravenous metoprolol. Conversely, total mortality was increased by intravenous metoprolol in Killip class III patients. In addition, metoprolol increased mortality in patients with systolic blood pressure less than 120 mmHg was increased by intravenous metoprolol in Killip class III patients. In addition, metoprolol increased mortality in patients with systolic blood pressure less than 120 mmHg. These results reinforce the contraindications for intravenous β-blocker therapy in patients with overt heart failure, and these patients have been systematically excluded from other β-blocker trials. In contrast to the COMMIT trial, we randomized patients presenting early (within 6 hours of STEMI onset), used PCI as the reperfusion strategy, and excluded patients with Killip class III or greater at first medical contact. In METOCARD-CNIC, the number of patients who progressed to Killip class grade III to IV during admission was similar in both treatment groups (7.9% for intravenous metoprolol versus 6.9% for control). Patients with Killip class III to IV STEMI potentially have larger infarctions. Given that we excluded these types of patients (for safety reasons), we might have underestimated infarct size in our population and potentially diluted the benefits of this cardioprotective strategy.

4. Pizzaro et al.  Long-Term Benefit of Early Pre-Reperfusion Metoprolol Administration in Patients With Acute Myocardial Infarction  

This study was a long term followup of the Ibanez study.

In patients with anterior Killip class II STEMI undergoing pPCI, early IV metoprolol before reperfusion resulted in higher long-term LVEF, reduced incidence of severe LV systolic dysfunction and ICD indications, and fewer heart failure admissions.

5. Roolvink V et al.  Early Intravenous Beta Blockers in Patients with STEMI Before PCI.    2016 Jun 14;67(23):2705-2715. doi: 10.1016/j.jacc.2016.03.522. Epub 2016 Apr 3.  


In a nonrestricted STEMI population, early intravenous metoprolol before PPCI was not associated with a reduction in infarct size. Metoprolol reduced the incidence of malignant arrhythmias in the acute phase and was not associated with an increase in adverse events. 

Comment by KEN GRAUER, MD (10/19/2018):
Important discussion by Dr. Smith regarding which patients with acute MI might benefit from ß-blockers. I limit my comments here to a few selected fine points about ECG interpretation of the 2nd tracing shown in this case (Figure-1).
Figure-1: The 2nd ECG shown in this case (See text).
QUESTIONS about Figure-1:
  • What are beats #1, 5 and 9?
  • Is there an underlying sinus rhythm? How certain are you of your answer?
  • In the long lead II rhythm strip at the bottom of the tracing — Look at the amount of ST depression in beats #1,2; 5,6; 9-14. Do some beats show more ST depression than others?
ANSWERS: I preface my comments by emphasizing that clinical management in this case is unchanged by the fine points in ECG interpretation that I bring up here. That said, these fine points sharpen our attention to detail, which serves to enhance our ECG interpretation skills.
  • In Figure-2 — I’ve labeled the long lead II rhythm strip with RED arrows that indicate sinus P waves that we can be certain about. Note that the PR interval preceding beats #1, and is too short to conduct. Therefore, these 3 beats with similar QRS morphology as sinus-conducted beats, must be junctional escape beats — which is appropriate, since each of these 3 beats is preceded by a longer R-R interval than is seen anywhere else on the tracing.
  • As per Dr. Smith — beats #3 & 4; and #7 & 8 represent multiform ventricular couplets.
  • NOTE: The reason we KNOW the RED arrows preceding beats #1,5,9 indicate sinus P waves is revealed by attention to simultaneously-recorded leads. That is, there should be no doubt that the 6 RED arrows in leads V1,V2,V3 all indicate sinus P waves. This confirms there must also be a sinus P wave with a short PR interval deforming the onset of the QRS complex of beat #9 in the long lead II rhythm strip — and by extension, also deforming the onset of the QRS complex of beats #1 and #5.
  • We are admittedly less certain that the PURPLE and BLUE arrows in Figure-2 indicate sinus P waves. It is logical that that they would represent underlying continuous sinus activity — given that we do see 10 definite sinus P waves ( = the RED arrows in the long lead II rhythm strip) occurring at a similar P-P interval — and because the PURPLE arrows in leads II and III for beat #3 overlie a notch that appears to be right on time for an underlying sinus rhythm. But we admittedly cannot be certain — and we can’t rule out the possibility that one or both of the PVCs in each group conducted retrograde ...
  • PEARL: The KEY to interpreting many complex arrhythmias lies with identifying underlying sinus activity. Even though we cannot be certain about all atrial activity in this tracing — this case does illustrate this principle that we use for seeking out atrial activity. And, application of this principle does confirm that beats #1, 5 and 9 in Figure-2 are junctional escape beats.
Figure-2: Addition of arrows to the 2nd ECG in this case, suggesting atrial activity (See text).
  • ANSWER to Final Question: The amount of ST depression in the long lead II rhythm strip is more for the 3 junctional escape beats (ie, beats #1,5,9) — than it is for each of the sinus-conducted beats (ie, beats #2,6 and 10-14). Whether this is due to a slightly longer preceding R-R interval (ie, reduced perfusion) or some additional J-point depression (ie, superimposed by the T of the P wave from the short PR interval) is uncertain — but recognizing this finding is part of optimally honing your skills.


  1. Because you mentioned that he was given ticagrelor i wanted to ask you about it if you can.

    In our EMS service we administer patintes with STEMI aspirin, heparin and ticagrelor.

    Some cath units argue with us that prehospital ticagrelor is benefitial to our patients, and may potentially delay a CABG if needed.

    What is your opinion?

    1. Yes, always a P2Y12 inhibitor for STEMI going to the cath lab. Not so for NonSTEMI. The patient may need CABG, but overall mortality better if early ticagrelor.

  2. What about other indications for betablockers in MI?
    Are betablockers indicated in type 2 MI with high blood pressure?

    1. Yes, beta blockers for any MI that is low risk for cardiogenic shock and does not have other contraindications

  3. Dr. Grauer,
    Thank you for the details. Just one question: Do you use TP segment or PQ junction to measure STD in this case?

  4. @ Anonymous — Excellent question you ask! I used the TP segment here, as I believe there is PR segment depression. As per My Comment (at the bottom of Dr. Smith's last blog post — ) — one could use either the PR segment OR the TP (or some combination of both), depending on particulars of the tracing — :)


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