REDUCE-AMI: Beta-blockers in MI & LVEF >=50%

REDUCE-AMI: NEJM 2024 DOI: 10.1056/NEJMoa2401479

Bottom line: In patients with myocardial infarction, LVEF >=50%, and no other indication for beta-blockers (angina, arrhythmia, heart failure), beta-blockers do not meaningfully reduce death or recurrent myocardial infarction. Additional trials that should complete in 2024 will provide additional data, including in patients with LVEF 41-49%.

Patients (n=5020 randomized)

• Setting: Sweden (95%), Estonia, NZ, 2017-2023

• Included:

  • Adults 1-7 days from MI

  • Obstructive coronary artery disease (CAD) on coronary angiography (i.e. stenosis >=50%, FFR <=0.8 or iFR <=0.89 in any segment)

  • Echo after MI showing left ventricular ejection fraction (LVEF) >=50% (i.e. preserved)

• Excluded: Any other indication for beta-blockers; any contraindication to beta-blockers.

• Baseline:

  • Age 65, 22% female

  • Median 2 days from admission to randomization

  • LVEF & coronary angiography variables not reported

  • STEMI 35%, PCI 95-96%

  • Comorbidities: Prior MI ~7%, diabetes 14%, HTN 46%, smoking ~20%

  • Medications:

    • Beta-blocker prior to admission ~11-12%

    • At discharge: ASA/P2Y12 inhibitor 95-98%, ACEI/ARB 80%, statin, 98-99%

Intervention: Beta-blocker

• Metoprolol (1st choice; target >=100 mg/d) or bisoprolol (target >=5 mg/d)

• 96% prescribed beta-blocker on discharge (2/3 metoprolol, 1/3 bisoprolol), ~91% receiving at “month 2” visit, 82% receiving at “1-year” visit

Comparator: No beta-blocker

• 10% prescribed beta-blocker on discharge

Outcomes @ median 3.5 years

Primary outcome (death from any cause or new MI): Beta-blocker 7.9%, no beta-blocker 8.3% (hazard ratio [HR] 0.96, 95% confidence interval [CI] 0.79-1.16)

• Death: 3.9% vs 4.1% (HR 0.94, 95% CI 0.71-1.24)

• MI: 4.5% vs 4.7%

• Bayesian re-analysis (using https://benjamin-andrew.shinyapps.io/bayesian_trials/): Assuming non-informative prior (ignoring outdated post-MI beta-blocker RCTs from the pre-reperfusion era), posterior probability=19% of an absolute risk reduction of >=1% absolute risk reduction (HR<=0.88) at 3.5 years

Safety

• Hospitalization for bradycardia, 2-30 AVB, hypotension, syncope, or PPM implantation: 3.4% vs 3.2% (HR 1.08, 95% CI 0.79-1.46)

• Hospitalization for asthma or COPD: 0.6% in both groups (HR 0.94, 0.46-1.89)

Internal validity

• Randomization using permuted blocks

• Allocation via web-based system

• Performance bias: Moderate crossover (18% from beta-blocker to no beta-blocker by 1 year in intervention group; ~10% to beta-blocker in comparator group) biases the results toward the null

• Detection bias: No blinding of participants or treating clinicians (open-label), but objective (death from any cause) & semi-objective outcomes (e.g. MI hospitalization) minimize risk of detection bias

• No loss to follow-up (but missing data for 8 who emigrated, 4 withdrew consent)

• Intention-to-treat analysis

Generalizability & other considerations

• Who does these results NOT apply to?

  • These results do NOT apply to patients with another valid cardiovascular indication for beta-blockers, including:

    • Angina (despite PCI/CABG, if indicated)

    • Arrhythmia (ventricular arrhythmia, atrial arrhythmia requiring rate control, congenital long QT syndrome, etc)

    • Ejection fraction <50% [especially those with heart failure]

    • HF with reduced/mildly-reduced/improved LVEF

• With that said, these results broadly apply to patients not captured within the above, which is most patients with MI seen in contemporary practice

• This is the first contemporary trial of beta-blockers post-MI (see https://nerdcat.org/studysummaries/beta-blockers-cad for our summary of this previous evidence)

  • Prior to this trial, practice was mainly driven by a 1999 meta-analysis of RCTs conducted 1966-1991; prior to widespread use of now-established treatments for ACS/MI (especially reperfusion with PCI/fibrinolytics, ASA, statins)

• Several other ongoing trials will shed further light on the role of beta-blockers in patients post-MI with LVEF >40%, including:

  • ABYSS (n=3700, France): Beta-blocker continuation vs discontinuation 6 months post-MI (excluding patients with LVEF <40%, persistent angina/ischemia, HF in last 2 y, arrhythmia)

  • BETAMI (n=2900, Norway) & DANBLOCK (n=2760, Denmark): Beta-blocker vs no beta-blocker post-MI (excluding patients with LVEF <40%, clinical heart failure, LV akinesia in >=3 segments, arrhythmia)

TRED-HF - Withdrawal of HF meds in patients with recovered (non-ischemic) dilated cardiomyopathy

Halliday BP, et al. Withdrawal of pharmacological treatment for heart failure in patients with recovered dilated cardiomyopathy (TRED-HF): an open-label, pilot, randomised trial. Lancet 2019 Jan 5;393(10166):61-73.

Bottom Line: In patients with recovered dilated cardiomyopathy (DCM), even careful withdrawal of HF medications will result in relapse of DCM (based on clinical signs, imaging or biomarkers) in approximately 4 out of 10 patients within 6 months, compared to no deterioration in this timeframe if these medications are continued.

These medications should be considered “lifelong” medications until we have tools that can reliably predict which patients can stop them without deteriorating.

Context

• In patients who initially have HF with reduced ejection fraction (HFrEF), recovery of ejection fraction >50% portends a more favorable prognosis

  • e.g. In one study, vs patients who had initial HFrEF followed by LVEF recovery to >50%, patients with non-recovered HFrEF had an increased risk of death, transplant or VAD placement (HR 3.4) & CV hospitalization (HR 1.8)

• The 2017 Canadian Cardiovascular Society (CCS) heart failure (HF) guidelines recommend consideration of monitored, sequential discontinuation of HF meds in certain subsets of patients with recovered non-ischemic cardiomyopathy

  • Including: chemotherapy-related, ETOH overuse-related, peripartum, tachycardia-related, or valvular cardiomyopathy

  • If: Asymptomatic (NYHA 1), LVEF and LV volumes normalized, trigger eliminated (e.g. ETOH abstinence, HR controlled, valve repaired/replaced)

• There is limited evidence for pharmacological treatment withdrawal in patients with HFrEF who get EF recovery

  • e.g. in an early observational study of 13 participants with DCM taking metoprolol for >2.5 years who weaned off metoprolol, 54% (7/13) experienced clinical deterioration (4 deaths & 3 patients who worsened by 1 NYHA functional class).

Design: Open-label RCT (pilot trial designed to plan larger trial)

Patients (n=51)

• Included if:

  • 16+ y/o

  • Previous dx of dilated cardiomyopathy (DCM) with LVEF 40% or lower

  • Currently:

    • NYHA functional class 1 (no current HF symptoms)

    • LVEF 50% or higher & left ventricular end diastolic volume indexed (LVEDVi) WNL (based on cardiac MRI, or 3D echo if MRI contraindicated)

    • NT-proBNP <250 ng/L

    • Treatment with 1+ of the following HF meds: Loop diuretic, ACEI, ARB, mineralocorticoid-receptor antagonist (MRA; spironolactone or eplerenone)

• Key exclusion criteria

  • Uncontrolled HTN (>160/100 mmHg in clinic)

  • Mod-severe valvular disease

  • Angina

  • Beta-blocker required for AF/flutter, VT, or SVT

  • GFR <30

  • Pregnant.

• Baseline characteristics (average of both groups unless specified)

  • Median age 55 y/o (IQR 45-64), male (67%)

  • Time since dx (4.9 y), median LVEF at dx 25%

  • Cause: Idiopathic (69%), familial (14%), trigger (excess ETOH, pregnancy, anthracycline, hyperthyroidism or myocarditis; 18%), pathogenic TTN truncation (22%)

  • Time since LVEF >50% (2 y)

  • CV symptom burden (0=none, 185=severe): 10-11

  • Quality of life using Kansas City Cardiomyopathy Questionnaire (KCCQ; 0=worst, 100=best)): 94-97

  • LVEF 60%, LVEDVi 83 mL/m^2, NT-proBNP 72 ng/L

    • Global longitudinal strain median 14% (values <16% considered abnormal)

  • Meds: ACEI/ARB (100%), beta-blocker (88%), MRA (47%), loop diuretic (12%)

Intervention & Comparator

• Intervention: Sequential discontinuation of HF meds over max 4 months, total 6 months follow-up

  • Order of drug dose reduction/discontinuation:

    • (1) Loop diuretic (reduced by 50% q2 weeks until furosemide 40 mg/d-equivalent, then D/Ced)

    • (2) MRA (reduced by 50% until equivalent to spiro 50 mg/d, then D/Ced)

    • (3) Beta-blocker (reduced by 50% until 25% target dose or lower, then D/Ced)

    • (4) ACEI/ARB (reduced by 50% until 25% target dose or lower, then D/Ced)

  • Follow-up schedule:

    • Baseline: Clinic visit, symptom & QoL questionnaire, exercise stress test, cardiac MRI, NT-proBNP

    • q4 weeks: Clinic visit & NT-proBNP

    • @ week 16: Repeat cardiac MRI

    • @ month 6: Same as baseline

• Comparator:

  • Phase 1 (randomized phase) x6 months: Continued all HF meds per baseline

    • @ baseline & month 6: Same as intervention group

    • @ weeks 8 & 16: Clinic visit, NT-proBNP

  • Phase 2: Then, non-randomized crossover to sequential discontinuation of HF meds as per intervention protocol

Results

Primary outcome: DCM relapse in 6-month randomized phase

• Defined as meeting 1+ of:

  • Clinical HF based on signs & symptoms

  • LVEF reduced by >10%, to <50%

  • LVEDVi increased by >10%, to above normal range

  • NT-proBNP doubled, to >400 ng/L

• Discontinuation group 44%, control group 0% (p=0.0001) - “number needed to harm” = 3 (rounded up from 2.3)

View fullsize

Figure 3 from TRED-HF. Kaplan-Meier curve of time to relapsed DCM comparing discontinuation versus continuation of HF meds

Secondary outcomes:

• Composite safety outcome (CV death, major adverse CV events, unplanned CV hospitalization): 0 in both groups

• (Select) differences in means between groups from baseline to month 6:

  • KCCQ: -5.1 (95% CI -9.9 to -0.4; lower with discontinuation vs continuation of HF meds)

  • LVEF -9.5% (lower with discontinuation vs continuation)

  • LVEDVi +4.7 mL/m^2 (95% CI -1.5 to +11.0, p=0.14)

  • Vitals: HR +15 bpm, BP +7/+7 mmHg

  • Inconclusive: CV symptom burden, exercise time, peak VO2, log-transformed NT-proBNP

Secondary analyses including withdrawals from phase 1 + phase 2

• DCM relapse in control group phase 2: 36%

• Overall DCM relapse rate after HF med discontinuation: 40% (26% relapse <2 months of discontinuation)

Figure 4 from TRED-HF. Venn diagram breakdown of component of primary outcome met (includes all withdrawals from randomized phase + single-arm crossover phase)

Internal validity

• Allocation bias: Low risk

  • Computer-generated random sequence, 1:1 allocation in permuted blocks, stratified by baseline NT-proBNP

  • Centralized allocation via online system

• Performance bias: Low/unclear risk

  • Patients & their clinicians aware of treatment allocation; however, the study employed a standardized protocol to wean & D/C HF meds, as well as standardized monitoring

• Detection bias

  • Low risk of bias for objective outcomes (core lab MDs reading imaging unaware of study group allocation)

  • High risk of bias for QoL outcomes (patients completed the questionnaires aware of treatment allocation)

• Attrition bias: Low risk

  • Loss to follow-up 2% (1 participant in withdrawal group left trial after 7 days)

  • Analyzed intention-to-treat population

Other Considerations

• We can’t yet predict which stable, recovered DCM patients will deteriorate with D/C of HF meds

  • In this trial, predictors of DCM relapse after withdrawal of therapy included: greater age, use of >2 meds, use of MRA, higher NT-proBNP, lower global radial strain on cardiac MRI, & possibly lower peak VO2

    • However, based on univariable analysis only (no adjusting for other variables) & small n of events

  • DCM etiology did not clearly predict risk of deterioration with therapy withdrawal. Some patients with a seemingly reversible cause of DCM (e.g. ETOH use, pregnancy) did have DCM relapse upon D/Cing HF meds. Therefore, presence of a trigger does not indicate that D/Cing HF meds after HF remission will be safe.

Beta-blockers post-MI or in stable CAD

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

 

Beta-blocker side-effects

Ko DT, et al. Beta-blocker therapy and symptoms of depression, fatigue, and sexual dysfunction. JAMA 2002;288:351-7.

Bottom line: In patients with HF, MI or HTN, beta-blockers increased the risk of fatigue (NNH 34) & sexual dysfunction (NNH 24), particularly erectile dysfunction in men.

Design

• Systematic review and meta-analysis of 15 trials (n= ~35,000) published up to 2001
• Included RCTs HF, MI or HTN with >100 patients & >6 months of follow-up

Results @ 0.5-6 years

• Fatigue: Beta-blockers 33.4% vs placebo 30.4% (NNH 34), relative risk (RR) 1.15 (1.05-1.26)
  • Absolute risk increase 1.8%/year
  • Risk greater for older beta-blockers (e.g. propranolol; RR 1.78) than new beta-blockers (e.g. atenolol, metoprolol; RR 1.06)
• Sexual dysfunction: Beta-blockers 21.6% vs placebo 17.4%, RR 1.10 (0.96-1.25)
  • Impotence in men: RR 1.22 (1.05-1.41)
• Depression: Beta-blockers 20.1% vs placebo 20.5%, relative risk RR 1.12 (0.89-1.41)
• None of the risks differed based on lipid solubility

INVEST - Verapamil- vs atenolol-based HTN treatment in CAD

Pepine CJ, et al. A calcium antagonist vs a non-calcium antagonist hypertension treatment strategy for patients with coronary artery disease. The International Verapamil-Trandolapril Study (INVEST): A randomized controlled trial. JAMA 2003;290:2805-16.

Bottom line:

• Although INVEST technically demonstrated "equivalence" of a HTN regimen based primarily on verapamil SR + trandolapril versus atenolol + hydrochlorothiazide in patients with CAD & HTN, this does not generalize to patients with (1) HF or LV dysfunction or (2) recent MI without contraindication for a beta-blocker.

• Additionally, this likely does not generalize to patients on better evidence-based thiazides (chlorthalidone or indapamide), & possibly not to other beta-blockers.

• Overall, there was no clinically relevant benefit of the verapamil-based regimen in CAD that would justify using this agent over a beta-blocker in this population.

 

Patients (n=22,576)

• Included
  • Age 50+ y
  • CAD, clinically stable, defined as any of:
    • Remote MI >3 months ago;
    • Stenosis of >50% of at least 1 coronary artery on angiography;
    • "Classic" angina
    • Ischemia on 2+ non-invasive investigations (EKG, echo, and/or nuclear imaging)
  • Hypertension (HTN)
• Exclusion
  • HF NYHA functional class IV (I-III could be enrolled)
  • Taking beta-blockers for an MI that occurred <1 year
• Typical study patient
  • Age 66 y (~33% >70 y)
  • Female 52%
  • Inclusion criteria
    • Angina 67%
    • Coronary stenosis on angiogram 39%
    • MI 32%
    • Abnormal stress test 21%
  • PMHx
    • CABG or PCI 27%
    • Stroke 5%
    • HF (NYHA I-III) 5-6%
    • Current smoker 12%
    • Dyslipidemia 56%
    • Diabetes 28%
  • BP 150/86 mm Hg
  • HR 76 bpm
  • Meds
    • Antiplatelet 57%
    • Lipid-lowering 37%
    • Hormone replacement therapy 18% of women

Interventions

• Both groups received treatment for HTN to target office-based BP <140/90 mm Hg (<130/85 mm Hg for patients with diabetes or renal dysfunction)
• I: Verapamil SR-based HTN regimen
  • Step 1: Verapamil SR 240 mg PO once daily (if HF, diabetes, or renal impairment: also add trandolapril 2 mg/d)
  • Step 2: Add trandolapril 2 mg PO daily
  • Step 3: Increase verapamil to 180 mg PO BID & trandolapril to 2 mg PO BID
  • Step 4: Add hydrochlorothiazide 25 mg PO daily
  • Steps 5+: Max doses of verapamil 480 mg/d, trandolapril 8 mg/d, hydrochlorothiazide 100 mg/d, non-beta-blocker non-study antihypertensive
  • At 2 y, 82% on verapamil SR
• C: Atenolol-based HTN regimen
  • tep 1: Atenolol 50 mg PO once daily (if HF, diabetes, or renal impairment: also add trandolapril 2 mg/d)
  • Step 2: Add hydrochlorothiazide 25 mg PO daily
  • Step 3: Increase both atenolol & hydrochlorothiazide to BID
  • Step 4: Add trandolapril 2 mg/d
  • Steps 5+: Max doses of atenolol 200 mg/d, hydrochlorothiazide 100 mg/d, trandolapril 8 mg/d, non-CCB non-study antihypertensive
  • At 2 y, 77% taking atenolol

Results @ mean 2.7 years

• Vitals @ year 2
  • BP reduction of ~19/10 mm Hg in both groups
  • Achieved BP <140/90 mm Hg: 71.7% vs 70.7%
  • Mean resting HR 73 bpm vs 69 bpm
• Primary outcome (death, non-fatal MI, non-fatal stroke): 9.9% vs 10.2%, relative risk (RR) 0.98 (0.90-1.06)
  • Death: 7.75% vs 7.9%
  • Non-fatal MI: 1.3% in both groups
  • Non-fatal stroke: 1.2% vs 1.3%
• Angina:
  • Baseline: 1.5 episodes/week in both groups
  • At 2 years: 1.3 vs 1.6 episodes/week (p=0.02)
• Adverse events:
  • Lightheadedness: 0.4% vs 0.6%
  • Symptomatic bradycardia: 0.7% vs 1.3%
  • Dyspnea: 1% vs 0.7%
  • Wheezing: 0.2% vs 0.4%
• Subgroup analyses:
  • Different effect based on whether patients had HF (possibly ~5% absolute risk reduction with beta-blockers in primary outcome) versus those who did not (no difference)
  • Otherwise, no other baseline characteristics had a significant subgroup effect

Generalizability

• Population widely representative CAD population, with key caveats:
  • First, those with an MI in the last year who were already on a beta-blocker were excluded. Thus, this trial likely selected out patients who may benefit most from beta-blockers.
  • Second, this trial included patients with clinical HF. Notably, although only 5-6% of the population, there appeared to be much worse outcomes in those receiving verapamil subgroup, which is consistent with previous concerns of HF-related mortality due to the negative inotropic effect of non-dihydropyridine CCBs like verapamil. It should therefore be avoided in this population.
  • Third, there was generally poor use of CAD secondary prevention therapies such as ASA & lipid-lowering, & uncharacteristically high use of hormone replacement therapy (55% of enrolled patients were female & 18% of them were receiving HRT despite a confirmed CAD history). This would be expected to increase the underlying risk of primary outcome events in both treatment groups.
• Multiple considerations regarding the intervention arms are required to interpret the results:
  • First, the interventions represent BP-lowering "regimens" focused on using verapamil or atenolol, rather than a true head-to-head comparison of these agents;
  • Second, although it lowers BP, atenolol seems to reduce the risk of CV events less than antihypertensive agents from other classes in patients with HTN. Similarly, hydrochlorothiazide is a weaker antihypertensive agent & generally has less evidence supporting its use than other thiazides, which have a clearer signal for benefit. This combination may have therefore been disadvantaged versus using a beta-blocker + thiazide combination with more robust supporting evidence (e.g. bisoprolol plus chlorthalidone).
  • Third, adherence to the primary drug of the regimen (verapamil & atenolol) as well as to BP goals was fairly poor, with only 75-80% in each group still taking this drug & only ~70% with BP <140/90 mm Hg at year 2.

Internal validity

• Low risk of allocation bias due to appropriate sequence generation & allocation concealment (centralized, automated Internet-based randomization with permuted blocks).
• As this trial was a "prospective, randomized, open-label, blinded-endpoint" (PROBE) trial, it is by default at high risk of performance & detection bias due to knowledge of clinicians & patients of the allocated treatment
  • The risk of performance bias was minimized with a standardized treatment algorithm for HTN & a similarly low proportion of patients (~70%) achieved their BP target. Additionally, few patients had revascularization procedures & there were similar rates of crossover between groups
  • Investigators attempted to minimize the risk of detection bias by adjudication of events by a committee unaware of treatment allocation, however, they could not eliminate this bias as well as if they would have blinded patients and clinicians to allocation to verapamil or atenolol. Given that this was a feasible option with a few minor changes to the study HTN treatment algorithm, it is not possible to give the investigators "a pass" for this.
• Low risk of attrition bias as analyses followed intention-to-treat principles, & loss-to-follow-up was low at ~2-3% in both groups
• This trial was technically designed as an equivalence trial, with an equivalence boundary for the relative risk of 0.83-1.20.