Beta-blockers post-MI or in stable CAD

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Summary:

High-quality but outdated evidence (with likely overestimated benefit) from RCTs, corroborated by contemporary observational studies, supports the use of beta-blockers in patients post-MI without HF or LV dysfunction to reduce the risk of death;

  • Acutely post-MI, beta-blockers reduce deaths due to arrhythmias & re-infarction. In the long-term where patients with normal LV function & low risk of ventricular arrhythmias, the main mechanism for mortality reduction of beta-blockers would be by reducing re-infarctions;
  • Much uncertainty remains due to the indirectness of old evidence and high risk of bias of newer observational studies; only a contemporary, adequately-powered RCT of patients without HFrEF post-MI will provide clarity.

The evidence for post-MI beta-blocker use (in those without HF or LV dysfunction) is limited to an average of 3 years, after which the benefit of continued use is unclear;

  • After 3 years, clinicians should re-assess the benefit/risk of continuing beta-blockers based on presence/control of angina, arrhythmias and risk factors for re-infarction, as well as tolerability and patient willingness to continue taking the beta-blocker.

Beta-blockers do not appear to reduce CV events in patients with uncomplicated stable CAD (no prior MI, LV dysfunction or HFrEF), so they should only be used in the presence of a compelling indication (such as angina, for which a calcium-channel blocker could also be used as first-line therapy).

 

Current guideline recommendations

Acute coronary syndrome (ACS; AHA 2013 STEMI guidelines, AHA 2014 NSTE-ACS guidelines, AHA 2011 secondary prevention guidelines)

  • Start an oral beta-blocker on the first day of no contraindications (STEMI Class I recommendation, Level of evidence B; NSTE-ACS I, A)
  • Use a beta-blocker in all patients with prior-MI & EF 40% or less unless contraindicated" (I, A)
  • Continue during & after hospitalization in all patients with STEMI and with no contraindications" (I, B); also reasonable to continue in patients with NSTE-ACS with normal LV function" (IIa, C)
  • Continued for 3 years after an ACS in all patients with normal LV function (I, A)
    • It is also reasonable to continue beyond (I, B)

For stable coronary artery disease (CAD)/ischemic heart disease (IHD; CCS 2014 stable IHD guidelines)

  • Use a beta-blocker in all patients with stable IHD & LV dysfunction (strong recommendation, high-quality evidence) or prior MI (conditional recommendation, moderate-quality evidence)
  • Use either a beta-blocker or calcium-channel blocker for stable angina if none of the above (conditional recommendation, moderate-quality evidence)
  • Consider a beta-blocker for all other patients with coronary or other vascular disease" (AHA 2011 secondary prevention guidelines; IIb, C)

The focus of this article will be patients with CAD without HF/LV dysfunction. We have covered beta-blocker use for post-MI LV dysfunction & HFrEF elsewhere.

 

Early/short-term use during ACS

  • COMMIT provides the best-available evidence in a contemporary population
    • Double-blind RCT of 45,852 patients with suspected MI (87% with STEMI, mean 10h from symptom onset) with no planned PCI
    • Randomized to metoprolol (5 mg IV x3 over 15 min, then 200 mg/d until discharge or up to 4 weeks) or placebo
    • There was no difference in the co-primary outcomes
      • Death, re-MI, VF, or other arrest) in hospital: Metoprolol 9.4%, placebo 9.9% (odds ratio [OR] 0.96, 0.90-1.01)
      • Death: Metoprolol 7.7%, placebo 7.8% (OR 0.99, 0.92-1.05)
    • Increased risk of cardiogenic shock (metoprolol 5.0% vs placebo 3.9%, NNH 91, OR 1.30), but
    • Decreased risk of re-MI (2.0% vs 2.5%, NNT 200, OR 0.82) & VF (2.5% vs 3.0%, NNT 200, OR 0.83)

 

Should beta-blockers be used post-MI in patients with normal LV function?

  • A 1999 systematic review with meta-analysis remains the best-available evidence on this topic
    • Major caveats:
      • Included trials were published between 1966-1991, which precedes widespread use of many ACS therapies, including PCI & statins (most of the trials also preceded use of fibrinolytics, ASA)
      • Patients were not systematically assessed for HF or LV dysfunction, so it is unclear how many of these patients had normal LV function
      • Maximum average follow-up of 3 years
    • Over 2 years, use of a beta-blocker decreased the risk of death (NNT 42, OR 0.77, 0.69-0.85)
  • A newer systematic review, which attempted to determine the efficacy of statins in the modern era, had numerous issues limiting clinical utility:
    • Arbitrarily classified trials as being in the "reperfusion era" if >50% of patients underwent revascularization with PCI/CABG, reperfusion with a fibrinolytic, or received ASA+statin
    • Results of the "reperfusion era" analysis dominated by COMMIT, which was a trial of short-term metoprolol use
    • There were no "reperfusion era" trials with beta-blocker duration >1 year
  • Observational studies show conflicting results on beta-blocker use after MI
    • A 2017 cohort of 179,810 patients with MI found a reduction in 1-year mortality in unadjusted comparisons (4.9% versus 11.2% without beta-blockers), but not in adjusted analyses using propensity score matching or instrumental variables
      • Notably, 95% of participants in this study received a beta-blocker on discharge, leading to very high risk of selection bias
    • A 2015 systematic review of 10 cohort studies with 40,973 patients who underwent PCI for MI found a reduction in death with beta-blocker use (relative risk (RR) 0.58, 0.48-0.79)
      • The relative risk reduction was numerically greater for those with reduced EF (RR 0.60, 0.36-1.00) compared to those with EF >40% (RR 0.79, 0.59-1.07)
    • A 2015 cohort study (that did not exclude patients with HFrEF or LV dysfunction) not included in the above review  found that beta-blocker use after an MI reduced the relative risk of death (HR ~0.6) at a median 2.1 years 
    • Notably, a 2012 cohort study using the REACH registry that initially led to questioning the utility of beta-blockers post-MI was underpowered to identify a clinically meaningful difference

 

How long should beta-blockers be continued post-MI?

  • Average duration of beta-blocker use in the 1999 systematic review was 2-3 years
  • A 2016 cohort study of 2679 patients with MI without HF or LV dysfunction demonstrated a reduction in the risk of death at 30 days (hazard ratio (HR) 0.46, 0.26-0.82)
    • This study was underpowered to identify a clinically-important difference in death at 1 year (HR 0.77, 0.46-1.30) or 5 years (HR 1.19, 0.65-2.18)
  • There is no evidence that discontinuing beta-blockers after a certain duration post-MI is safe or beneficial

 

What about patients with stable CAD (without prior MI, or HFrEF/LV dysfunction)?

  • A 2016 systematic review with meta-analysis of cohort studies that included 17,397 patients with angiographically-proven CAD without MI or LV dysfunction found no difference in all-cause death (OR 0.91, 0.79-1.04) at 3-5.4 years
  • A 2014 cohort study of 26,793 patients with newly-diagnosed CAD found that that the effect of beta-blockers on the risk of death/MI differed on MI history (p=0.005 for interaction)
    • Prior MI: HR 0.87 (0.82-0.93)
    • PCI or CABG but no prior MI: HR 1.03 (0.93-1.13)
  • INVEST trial (see previous nerdcat summary): A beta-blocker-based regimen was not superior to a verapamil-based regimen over 2.7 years in patients with CAD+HTN without prior MI