REVEAL: Anacetrapib in ASCVD

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The HPS3/TIMI55-REVEAL Collaborative Group. Effects of anacetrapib in patients with atherosclerotic vascular disease. N Engl J Med 2017;377:1217-27.

Bottom line: In patients with ASCVD & a risk of coronary events ~3%/year, anacetrapib reduced the risk of major coronary events (NNT 100 over 4.1 years, or NNT 410/year).

Anacetrapib's CV benefit is proportional to its LDL-C reduction, & may be unrelated to its effect on HDL-C.

Context

  • Lower HDL-C concentrations are associated with greater risk of CV disease; however, no trial has yet to show benefit of increasing HDL-C with pharmacological therapy;
  • Mechanism: Cholesteryl ester transfer protein (CETP) transfer triglycerides & cholesteryl esters between LDL or VLDL to HDL. Inhibiting CETP results in greater HDL-C serum concentrations & lower LDL-C & non-HDL-C serum concentrations;
  • Previous trials of CETP inhibitors have all failed to demonstrate clinical benefit, & some even caused harm:
    • ILLUMINATE: RCT of 15,067 patients at high risk of ASCVD. Torcetrapib increased the risk of CV events versus placebo over 550 days (6.2% vs 5.0% [NNH 84); hazard ratio [HR] 1.25, 1.09-1.44), as well as death (1.2% vs 0.8% [NNH 250], HR 1.58, 1.14-2.19);
    • dal-OUTCOMES: RCT of 15,871 patients with recent ACS. Dalcetrapib did not reduce the risk of CV events versus placebo over 31 months (8.3% vs 8.0%; HR 1.04, 0.93-1.16);
    • ACCELERATE: RCT of 12,092 patients with ASCVD stopped early for futility. Evacetrapib did not reduce CV events versus placebo over 26 months (12.9% vs 12.8%; HR 1.01, 0.91-1.11).
  • In October 2017, the maker of anacetrapib announced that it would not seek market approval, essentially ensuring that no CETP inhibitor would reach clinical use.

Patients (n=30,449)

  • Inclusion
    • Age >50 years
    • Hx of ASCVD (MI, cerebrovascular aatherosclerotic disease, PAD, or diabetes with symptomatic CAD)
  • Exclusion
    • ACS or stroke <3 months ago
    • Planned CABG/PCI
    • "Clinically significant liver, kidney, inflammatory muscle, or other disease"
    • Current tx with a fibrate, niacin, "or any drug contraindicated with anacetrapib or atorvastatin"
    • Previous statin-related adverse reaction
    • Known poor adherence to clinic visits or medications
  • Baseline characteristics
    • Age 67 y
    • Male 88%
    • PMHx
      • ASCVD: CAD 88%, cerebrovascular disease 22%, PAD 8%
      • Diabetes 37%
      • HF 6%
    • BP 131/78 mm Hg
    • HDL-C 1.0 mmol/L
    • LDL-C 1.6 mmol/L
    • Non-HDL-C 2.4 mmol/L

Interventions

  • Intervention: Anacetrapib 100 mg once daily
  • Control: Matching placebo
  • Co-intervention for all: Atorvastatin to reduce LDL-C <2.0 mmol/L

Results @ median 4.1 years

  • Effect on lipids (difference vs placebo) @ year 2:
    • HDL-C: +104% (+1.1 mmol/L)
    • LDL-C, non-HDL-C, ApoB: -18% (LDL-C -0.3 mmol/L)
    • Lp(a) -25%
  • Effect on BP: +0.7/0.3 mm Hg with anacetrapib vs placebo
  • Note 1: The reduction in major coronary events only became apparent after day 3; additionally, the relative risk reduction (RRR) increased over time (e.g. from 2% at year 1 up to 17% after year 4)
  • Note 2: Annualized NNT for major coronary events: ~410/year

Safety

  • Serious adverse events: Anacetrapib 58.4%, placebo 58.5%
  • Non-serious adverse events: Anacetrapib 5.4%, placebo 5.4%
  • eGFR <60 mL/min: Anacetrapib 11.5%, placebo 10.6%, p=0.04 (NNH 112)

Generalizability & other considerations

  • Key characteristics of included patients
    • Moderate risk for a population with existing ASCVD (risk of major vascular event ~3.5%/year & major coronary event ~3%/year) in control group)
    • Excellent LDL-C control (mean ~1.6 mmol/L), & low baseline HDL-C (mean ~1.0 mmol/L)
  • It's unclear if the coronary event reduction with anacetrapib resulted from the HDL-C increase or LDL-C reduction. However, the benefits in REVEAL are consistent with what would be expected based on the LDL-C reduction:

Internal validity: Low risk of bias

  • Allocation: Randomization by minimization, allocation concealed
  • Performance & detection: Patients, clinicians blinded, matching placebo
  • Attrition: Loss-to-follow-up 0.1%, intention-to-treat analysis
  • Selective outcome reporting: Reporting of all clinical outcomes of interest for both efficacy & safety

RE-DUAL PCI - Dabigatran-based dual antithrombotic regimen in patients with AF after PCI

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Cannon CP, et al. Dual antithrombotic therapy with dabigatran after PCI in atrial fibrillation. NEJM 2017

Bottom line:

  • RE-DUAL PCI provides further evidence supporting dual therapy with an oral anticoagulant + P2Y12 inhibitor in patients with AF post-PCI instead of triple therapy.

  • Dual therapy with dabigatran 150 mg BID reduced clinically relevant bleeds (NNT 19) as well as major bleeds (NNT 36-56 depending on definition), & was non-inferior in terms of thromboembolic events over approximately 1 year.

  • Dual therapy with dabigatran 110 mg BID showed a possible increase in death, MI & definite stent thrombosis, & was potentially inferior for the composite efficacy outcome. Despite reducing major & clinically-relevant bleeds, this regimen can't be recommended due to inadequate evidence of efficacy in this setting.

    • Notably, the PIONEER trial did not assess for non-inferiority of rivaroxaban-based dual therapy regimens to triple therapy, but if it had, it would not have met the non-inferiority criteria from RE-DUAL PCI. However, the PIONEER results did not show the concerning numerical trends seen here with dabigatran 110 mg BID.

Patients (n=2725)

  • Included

    • Non-valvular AFib (paroxysmal, persistent or permanent)

    • PCI (bare-metal or drug-eluting stent) within 120h for stable CAD or ACS

  • Exclusion

    • Bioprosthetic or mechanical heart valve

    • CrCl <30 mL/min

    • "Other major coexisting conditions"

  • Baseline characteristics

    • ~72 y

    • Female ~24%

    • AF characteristics

      • Paroxysmal (~50%), persistent (~17%), permanent (33%)

      • CHA2DS2-VASc score ~4, HAS-BLED score ~3

      • Previous stroke 10%

    • PCI characteristics

      • Previous: MI ~25%, PCI ~33%, CABG ~10%

      • Indication for PCI: ACS (~50%), stable angina/+ stress test (44%), other (~6%)

      • Drug eluting stent 85%

Interventions

  • Intervention1: Dabigatran 150 mg BID + clopidogrel/ticagrelor

    • Note: Elderly outside the US not eligible for this group due to dabigatran labeling

  • Intervention2: Dabigatran 110 mg BID + clopidogrel/ticagrelor

  • Control ("triple therapy"): Warfarin (INR 2-3) + clopidogrel/ticagrelor + low-dose ASA

    • ASA D/Ced after 1 month with bare-metal stent or 3 months with drug-eluting stent

    • Time in therapeutic INR: 64%

  • In all groups

    • P2Y12 inhibitor was continued for at least 12 months

    • P2Y12 inhibitor chosen: Clopidogrel 88%, ticagrelor 12%

    • Mean duration of trial anticoagulant: 12.3 months

Results @ mean 14 months

Dabigatran 150 mg BID vs triple therapy (control group excludes elderly outside US not eligible for higher dabigatran dose)

  • Primary outcome (major or clinically relevant non-major bleed, ISTH definition):

    • Dabi150 20.2%, control 25.7%, NNT 19

    • HR 0.72 (0.58-0.88), p<0.001 for non-inferiority

  • Major bleed:

    • ISTH definition: Dabi150 5.6%, control 8.4%, HR 0.64 (0.43-0.94), NNT 36

    • TIMI definition: Dabi150 2.1%, control 3.9%, HR 0.51 (0.28-0.93), NNT 56

    • Intracranial hemorrhage: Dabi150 0.1%, control 1.0%, p=0.047

  • Composite efficacy outcome (death, MI, stroke, or systemic embolism, or unplanned PCI/CABG): Dabi150 11.8%, control 12.8%, HR 0.89 (0.67-1.19)

Dabigatran 110 mg BID vs triple therapy

  • Primary outcome:

    • Dabi110 15.4%, control 26.9%, NNT 9

    • HR 0.52 (0.42-0.63), p<0.001 for non-inferiority

  • Major bleed:

    • ISTH definition: Dabi110 5.0%, control 9.2%, HR 0.52 (0.37-0.74), NNT 24

    • TIMI definition: Dabi110 1.4%, control 3.8%, HR 0.37 (0.20-0.68), NNT 42

    • Intracranial hemorrhage: Dabi110 0.3%, control 1.0%, p=0.06

  • Composite efficacy outcome: Dabi110 15.2%, control 13.4%, HR 1.13 (0.90-1.43) - did not meet non-inferiority criteria

    • Thromboembolic events or death: Dabi110 11.0%, control 8.5%, HR 1.30 (0.98-1.73)

      • Death Dabi110 5.6%, control 4.9%

      • MI: Dabi110 4.5%, control 3.0%

      • Definite stent thrombosis: Dabi110 1.5%, control 0.8%

Considerations

  • Low to unclear risk of bias

    • Unclear randomization & allocation concealment (not adequately reported)

    • Open-label design - low risk of performance bias, but high risk of detection bias for softer outcomes (ie clinically significant non-major bleeds)

    • Low risk of attrition bias (ITT analysis that included all randomized patients regardless of receipt of study intervention; 0.2% lost to follow-up, <4% withdrew consent with no vital status available at end of study)

  • Non-inferiority trial

    • Non-inferiority margin 1.38 for HR upper end of 95% confidence interval for both efficacy & safety outcomes

    • Primary analysis using ITT population with sensitivity on-treatment analysis

    • Dual therapy with dabi150 met non-inferiority for both bleeding & thromboembolic outcomes, but dabi110 only met non-inferiority criteria for bleeding

  • Excellent generalizability due to broad eligibility criteria & enrolment of a representative, relatively elderly population

  • Unadjusted bleed rates from a subgroup analysis by choice of P2Y12 inhibitor (clopidogrel vs ticagrelor) suggest that risk of bleeding increases gradually with number of antithrombotic agents as well as potency of the inhibitor, e.g. ISTH major bleed over mean 14 months from Figure 2:

    • Clopidogrel + dabigatran: ~5%

    • Clopidogrel + ASA + warfarin OR ticagrelor + dabigatran: ~8%

    • Ticagrelor + ASA + warfarin: ~16.5%

CANTOS - Canakinumab for patients with previous MI

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Ridker PM, et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. NEJM 2017

Bottom line:

  • In patients with prior MI & hsCRP >2 mg/L, canakinumab reduced the risk of non-fatal coronary events (NNT ~160/year), but increased the risk of fatal infections (NNH ~1000/year).

  • Due to unresolved issues of cost & feasibility of use of this therapy, CANTOS has limited direct applicability to real-world practice, but serves as a proof of concept for anti-inflammatory therapy to reduce the risk of ASCVD.

 

Patients (n=10,061 after 17,482 were screened)

  • Included
    • Hx of MI
    • High-sensitivity CRP 2 mg/L or higher
  • Exclusion
    • Hx of chronic/recurrent infection
    • Previous CA
    • Known/suspected immunocompromised
    • Hx/high risk of TB or HIV-related disease
    • Ongoing use of other systemic anti-inflammatory tx
  • Baseline characteristics
    • 61 y
    • Female 26%
    • STEMI 54%, NSTEMI 34%, unknown 12%
    • Previous PCI 66%, CABG 14%
    • HF 22%
    • CV risk factors: Smoker 23%, HTN ~80%, diabetes ~40%
    • Labs
      • Median hsCRP 4.2 mg/L
      • LDL-C 2.1 mmol/L
    • Meds
      • ACEI/ARB ~80%
      • Anti-ischemic therapy 92%
      • Statin ~90%

Interventions

  • Interventions: Canakinumab 50 mg, 150 mg or 300 mg subcutaneously q3 months
    • 300 mg dose group: 300 mg q2 weeks x2 doses, then q3 months
  • Control: Matching placebo
     

Results @ median 3.7 years

Labs

  • hsCRP reduction: 50 mg (26%), 150 mg (37%), 300 mg (41%)
  • LDL, HDL: No effect

Efficacy

  • Primary outcome (CV death, MI or stroke):
    • Canakinumab 150 mg: 14.0% over follow-up (incidence rate: 3.86 per 100 patient-years)
    • Placebo: 16.0% over follow-up (incidence rate: 4.50 per 100 patient-years)
    • HR 0.85 (0.74-0.98), NNT 50 (NNT ~160/y)
  • Secondary efficacy outcome (primary + unstable angina hospitalization leading to unplanned revascularization):
    • Canakinumab 150 mg: 4.29 per 100 patient-years
    • Placebo: 5.13 per 100 patient-years
    • HR 0.83 (0.73-0.95)
  • Death: Canakinumab 150 mg 2.73/100 pt-y, placebo 2.97/100 pt-y, HR 0.92 (0.78-1.09)
  • MI: Canakinumab 150 mg 1.90/100 pt-y, placebo 2.43/100 pt-y, HR 0.76 (0.62-0.92)
  • Stroke: HR 0.98 (0.71-1.35)
  • Revascularization: Canakinumab 150 2.49/100 pt-y, placebo 3.61/100 pt-y, HR 0.68 (0.58-0.81)
  • Note: For brevity, I only include the efficacy data for the 150-mg dose here (50 mg generally ineffective/less effective, & 300 mg similar to 150 mg)

Safety/tolerance

  • Discontinued study drug: Canakinumab 18.7%, placebo 18.1%
  • Serious adverse events: Canakinumab 11.8/100 pt-y, placebo 12/100 pt-y, p=0.79
  • Serious adverse event from infection: Canakinumab 3.1/100 pt-y, placebo 2.9/100 pt-y, p=0.14
  • Fatal infection or sepsis: Canakinumab 0.3/1000 pt-y, placebo 0.2/100 pt-y, p=0.02

Considerations

  • Low risk of bias
    • Central, computerized randomization (allocation concealed)
    • Participants, clinicians & investigators blinded
    • 0.3% lost to follow-up
  • Generalizability
    • Eligibility criteria for this trial are broad (any prior MI + hsCRP >2 mg/L) & primarily excluded patients at high risk of adverse effects of immunosuppressive therapy, though enrolled patients had a relatively high risk of ASCVD (~4%/year in the placebo group)
  • Currently, canakinumab is approved under the organ drug status for rare diseases, & is priced at $200,000/year (US price in USD)

COMPASS - ASA + rivaroxaban (or riva alone) vs ASA alone in stable CVD

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Eikelboom JW, et al. Rivaroxaban with or without aspirin in stable cardiovascular disease. NEJM 2017

Note: This was a factorial trial; the other intervention under study - pantoprazole vs placebo - will be reported later in a separate report.

Bottom line:

  • In patients with stable CAD/PAD, addition of rivaroxaban 2.5 mg PO BID to low-dose ASA resulted in a reduction in cardiovascular events, primarily driven by all-cause mortality & stroke (NNT ~144 each), and an increase in major & minor bleed (NNH 84 & 28, respectively) over an average duration of 1.9 years;

    • In patients with PAD, rivaroxaban + ASA also reduces the risk of major adverse limb events (NNT 100).

  • Monotherapy with rivaroxaban 5 mg PO BID did not reduce events compared to ASA monotherapy, but increased major & minor bleeds (NNH 112 & 39).

Patients (n=27,402)

  • Included either CAD or PAD:
    • CAD (MI within 20 years, multivessel CAD with symptoms or history of angina, multivessel PCI, multivessel CABG), plus
      • Age >65 y
      • Atherosclerosis in at least 2 vascular beds
      • At least 2 more risk factors (current smoking, diabetes, eGFR <60, non-lacunar stroke >1 month earlier)
    • PAD (with either claudication, previous revasc [including carotid], or amputation)
  • Exclusion
    • High bleeding risk
    • Recent stroke, or previous hemorrhagic or lacunar stroke
    • Severe HF
    • eGFR <15
    • Use of DAPT, anticoagulation, or other antithrombotic therapy
  • Baseline characteristics
    • Age 68 y
    • Female 22%
    • CV history
      • Previous MI 62% (mean 7.1 years ago)
      • CAD 90% (multivessel 62%; enrolled within 2 weeks of CABG ~5%)
      • PAD 27%
    • Risk factors: Tobacco use 21%, HTN 75%, diabetes 38%
    • eGFR: <30 (<1%), 30-59 (22%), 60+ (77%)
    • Meds: ACEI/ARB ~70%, BB 70%, lipid-lowering ~90%

Interventions

  • Intervention1: Enteric-coated ASA 100 mg/d + rivaroxaban 2.5 mg PO BID
  • Intervention2: Rivaroxaban 5 mg PO BID
  • Control: Enteric-coated ASA 100 mg/d

Results @ mean 1.9 years (max 3.92 years)

Subgroup analyses published in separate papers:

  • CAD (91% of study population, n=24,824)
    • Of the 69% with prior MI, timing: <1 y (5%), 1-5 y (29%), >5 y (34%)
    • 4-5% received DAPT during trial follow-up, & most in rivaroxaban groups D/Ced rivaroxaban
    • Efficacy & safety results virtually identical to full trial
    • Additional analyses:
      • Post-hoc defined coronary event composite (MI, coronary death, sudden death, resuscitated cardiac arrest, or unstable angina): ASA+riva vs ASA HR 0.83 (0.81-0.98)
      • Stent thrombosis: ASA+riva vs ASA HR 1.08 (0.72-1.61)
      • Coronary revascularization: ASA+riva vs ASA HR 0.95 (0.84-1.07)
      • Post-hoc landmark analysis suggests that efficacy HR consistent between years 1, 2 & >2, whereas bleeding risk is front-loaded & decreases after year 1
      • Further subgroups suggest that relative risk reduction similar across most subgroups, including those with vs without prior PCI, optimal use of 2o CV prevention vs not, & different risk categories. Notably, however, significant p-value for interaction suggesting no/less benefit in patients with history of CABG.
  • PAD or carotid disease (27% of study population, n=7470)
    • Efficacy & safety results virtually identical to full trial
    • Additional analyses:
      • Prespecified limb outcomes - Major adverse limb event or major amputation: ASA+riva 1% vs ASA 2%: HR 0.54 (0.35-0.82)
      • Composite of 1o outcome + limb outcome: ASA+riva 6% vs ASA 9% (NNT 34), HR 0.69 (0.56-0.85)
  • Modified ISTH definition of major bleed included standard ISTH major bleed components (fatal bleed, symptomatic bleed into a critical organ, bleeding into a surgical site requiring re-operation) plus bleeding that led to hospitalization (including ED visits without overnight stay)

Considerations

  • Risk of bias
    • Low for allocation, performance, detection, attrition bias
      • Computer-generated randomization (reported in Lancet substudies)
      • Allocation concealed by using central web-based randomization (reported in Lancet substudies)
      • Blinding of all participants, clinicians & investigators
      • 0.2% lost to follow-up, ~16% discontinued study drug before last follow-up (but continued follow-up)
      • ITT analysis
    • Trial stopped early after 1st interim analysis for efficacy of ASA + rivaroxaban
    • Run-in phase (active ASA & placebo rivaroxaban BID) to ensure patient able to adhere to trial regimen (~8% excluded after run-in)
  • Generalizability
    • This trial applies to patients with previous MI or clear history of angina/ischemia/coronary revascularization + angiographically-proven CAD, or with PAD
      • Unclear how these results may translate to use of higher doses of rivaroxaban once daily (i.e. rivaroxaban 15-20 mg once daily as used in AF +/- PCI)

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