Use of beta blockers in patients with non-ACS CAD

MOA

Current AHA guidelines

Class IIb (Weak benefit Benefit may outweigh or be equal to risk)1. b-Blockers may be considered as chronic
therapy for all other patients with coronary or other vascular disease. (Level of Evidence: C  recommendation
based on expert opinion and panel consensus )

Beta-1 : Activation causes increase in HR, Contractility, and AV conduction

Beta-2: In heart cause vasodilation (not as much I heart)

Beta-3: Adipose tissue; thought ot mediate catecholamine induced thermogenesis which may decrease contractility

How are they beneficial? Reduction in Myocardial oxygen demand which is determined by HR, Contractility, Left
ventricular wall stress (each is decreased by beta blockade)

Increase cardiac coronary perfusion due to prolonged perfusion during diastole

Beta blockers only help patients survive in certain subgroups with stable coronary artery disease  systolic heart
failure and MI

No prospective trials done:

JACC 2014
JAMA 2012

In the international REACH registry of patients with established cardiovascular disease patients were enrolled in
2003 and 2004 and followed prospectively for up to four years. The primary outcome was a composite of
cardiovascular death, nonfatal myocardial infarction (MI), or nonfatal stroke. Propensity score matching identified
3599 pairs of patients (with known coronary artery disease but without prior MI) who were or were not taking beta
blocker. Aspirin use was 70 percent and statin use 75 percent. After a median follow-up of 44 months, there was no
difference in the primary outcome (12.9 versus 13.6 percent, respectively; hazard ratio [HR] 0.92, 95% CI 0.79-
1.08).

JACC 2016

OBJECTIVES This study sought to examine predictors, trends, and outcomes associated withβ-blocker
prescriptions at discharge in patients with stable angina without prior history of myocardial infarction (MI)
or systolic heart failure (HF) undergoing elective percutaneous coronary intervention (PCI).
BACKGROUND The benefits ofβ-blockers in patients with MI and/or systolic HF are well established.
However, whetherβ-blockers affect outcomes in patients with stable angina, especially after PCI, remains
uncertain.
METHODS We included patients with stable angina without prior history of MI, left ventricular systolic
dysfunction (left ventricular ejection fraction <40%) or systolic HF undergoing elective PCI between
January 2005 and March 2013 from the hospitals enrolled in the National Cardiovascular Data Registry
(NCDR) CathPCI registry. These patients were retrospectively analyzed for predictors and trends ofβ-
blocker prescriptions at discharge. All-cause mortality (primary endpoint), revascularization, or
hospitalization related to MI, HF, or stroke at 30-day and 3-year follow-up were analyzed among
patients ≥65 years of age.
RESULTSA total of 755,215 patients from 1,443 sites were studied, and 71.4% population of our cohort
was discharged onβ-blockers. At 3-year follow-up among patients ≥65 years of age with CMS data linkage
(16.3% of the studied population), there was no difference in adjusted mortality rate (14.0% vs. 13.3%;
adjusted hazard ratio [HR]: 1.00; 95% confidence interval [CI]: 0.96 to 1.03; p = 0.84), MI (4.2% vs. 3.9%;
adjusted HR: 1.00; 95% CI: 0.93 to 1.07; p = 0.92), stroke (2.3% vs. 2.0%; adjusted HR: 1.08; 95% CI:
0.98 to 1.18; p = 0.14) or revascularization (18.2% vs. 17.8%; adjusted HR: 0.97; 95% CI: 0.94 to 1.01; p =
0.10) withβ-blocker prescription. However, discharge onβ-blockers was associated with more HF
readmissions at 3-year follow-up (8.0% vs. 6.1%; adjusted HR: 1.18; 95% CI: 1.12 to 1.25; p <0.001).
Results at 30-day follow-up were broadly consistent as well. During the period between 2005 and 2013,
there was a gradual increase in prescription ofβ-blockers at the index discharge in our cohort (p <0.001).
CONCLUSIONSAmong patients ≥65 years of age with history of stable angina without prior MI, systolic
HF or left ventricular ejection fraction <40% undergoing elective PCI,β-blocker use at discharge was not
associated with any reduction in cardiovascular morbidity or mortality at 30-day and at 3-year follow-up.
Over time,β-blockers use at discharge in this population has continued to increase.
 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

o Double-blind RCT of 45,852 patients with suspected MI (87% with STEMI, mean 10h
fromsymptom 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