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High-quality but outdated evidence (with likely overestimated benefit) from RCTs, corroborated by contemporary observational studies, supports the use of beta-blockers in patients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

 

TOPIC - Continuing ticagrelor/prasugrel vs switching to clopidogrel 1 month after ACS

Benefit of switching dual antiplatelet therapy after acute coronary syndrome: The TOPIC (timing of platelet inhibition after acute coronary syndrome) randomized study. Eur Heart J 2017 [online]

Bottom line: In patients with ACS who underwent PCI & tolerated prasugrel/ticagrelor x1 month, discontinuing prasugrel/ticagrelor & switching to a pill that combines ASA+clopidogrel reduced the risk of mainly minor bleeding over the subsequent 11 months.

TOPIC was underpowered to evaluate ischemic events, & is inadequate to inform practice or change routine care. Based on results from PLATO, employing this strategy would result in an increased risk of death/MI/stroke, particularly during the crossover period between stopping ticagrelor & waiting for clopidogrel to achieve its full antiplatelet effect (up to 7 days).

Patients (n=645)

• Included: 
  • Adults with ACS, & PCI within 3 days of ACS admission initially treated with prasugrel/ticagrelor
  • No major adverse event in 1st month (including ischemia or bleed)
• Key exclusion: Major bleed (BARC criteria) in last year, long-term use of anticoagulation
• Baseline characteristics
  • Age ~60 y
  • Male ~83%
  • ACS type: STEMI ~40%, NSTE-ACS 60%
  • Previous CAD 30%
  • CV risk factors: Smoker ~45%, HTN ~50%, T2DM ~25%
  • Meds
    • P2Y12 inhibitor: Prasugrel ~55%, ticagrelor ~45%
    • ACE inhibitor or ARB ~75%
    • Beta-blocker ~70%
    • Statin ~95%
    • PPI 100%

Interventions

ASA 75 mg/d + ticagrelor/prasugrel (clinician selection) x1 month, then randomized to:

• I ("switch"): Switch to clopidogrel 75 mg/d + ASA 75 mg/d (combined in 1 pill) x11 months (total 1 year on DAPT)
  • The published report does not specify what strategy was used to perform the switch to clopidogrel. This is critical as clopidogrel 75 mg/d takes 5-7 days to achieve its full antiplatelet effect
  • 86% still receiving at 1 year (~6% switched back to ticagrelor/prasugrel, ~6% on ASA only, <1% on no antiplatelet)
• C ("continue"): Continue ticagrelor/prasugrel + ASA 75 mg/d (not combined into 1 pill) x11 months (total 1 year on same P2Y12 inhibitor)
  • 75% still receiving at 1 year (~17% switched to clopidogrel, ~7% on ASA only, <1% on no antiplatelet)

Results @ 1 year

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• BARC bleeding definitions

 

Generalizability

• P: This trial applies to ACS patients who tolerated ticagrelor/prasugrel for 1 month without issue, including recurrent coronary event or clinically-important bleeding
• I/C:
  • The "switch" intervention was actually 2 distinct interventions:
    1. Consolidation of multiple pill administrations into a single tablet
       • For initial ticagrelor users, simplified from 3 tabs/day to 1
       • For initial prasugrel users, simplified from 2 tabs/day to 1
    2. Switch to lower-potency antiplatelet agent (clopidogrel)
    • Reduced bleeding rates in this trial are a combined result of decreased antiplatelet potency, as well as more consistent adherence due to decreased pill burden and simplification of administration regimen. This also reduces any apparent benefit on ischemic outcomes with the prasugrel/ticagrelor continuation, since non-adherence dulls their efficacy
  • Use of either prasugrel or ticagrelor in the control group complicates this further, as these agents have different efficacy/safety profiles (ticagrelor generally considered more efficacious + safer), & administration methods (ticagrelor is dosed BID)

Internal validity

• Use of inappropriate composite primary outcome
  • Includes biologically disparate events (both ischemic/efficacy & bleeding/safety events)
  • Largely driven by the least "clinically important" outcome (bleeding requiring medical evaluation)
  • Inadequate power to evaluate more important components (CV/overall death, stroke, revascularization), & cannot rule in/out a difference nor determine consistency between different components
• Enrolment occurred in a single center in France 2014-2016
  • Single-center trials systematically overestimate benefits compared to multi-center trials, likely related issues in minimizing typical bias domains (allocation, performance & detection)
• Unclear risk of allocation bias
  • Allocation concealed by sequentially-numbered sealed envelopes: Application of this strategy varies, and is prone to manipulation
• High risk of performance and detection bias
  • Patients, caretakers and clinicians not blinded to study intervention
  • "Switch" intervention simpler, easier to adhere to
  • Adjudicated by physician unaware of allocated intervention, though reporting of events to adjudicators may have been biased (particularly the subjective BARC 2 bleeds)
• Low risk of attrition bias (intention-to-treat analysis with 2% loss-to-follow-up at 1 year)
• Potential selective outcome reporting
  • Reporting of coronary events limited to those "requiring unplanned hospitalization for urgent coronary revascularization," but investigators did not report ACS events not requiring revascularization

GEMINI-ACS-1: Rivaroxaban vs ASA added to P2Y12 inhibitor following ACS

Ohman EM, et al. Clinically significant bleeding with low-dose rivaroxaban versus aspirin, in addition to P2Y12 inhibition, in acute coronary syndromes (GEMINI-ACS-1): A double-blind, multicentre, randomised trial. Lancet 2017 (epub ahead of print)

Bottom-line:

• In patients with ACS, low-dose rivaroxaban produces a similar or greater risk of clinically-significant or major bleed compared to ASA (potential NNH 100), with unclear effect on efficacy outcomes.

• Although this trial is insufficient to change practice, it provides preliminary evidence that will guide further trials refining antithrombotic regimens in various ACS subpopulations.

 

Context

• The ATLAS trial demonstrated that adding low-dose rivaroxaban to clopidogrel-based DAPT reduces CV events and death following PCI, offset by an increase in major bleeds
• The PIONEER trial and other studies have investigated various anticoagulation-based regimens in patients with AF who undergo PCI

Patients (n=3037)

• Included:
  • Age > 18 years
  • ACS (unstable angina, NSTEMI or STEMI)
  • If age <55 years, at least 1 of the following:
    • Diabetes
    • Previous MI
  • If unstable angina, at least 1 of the following:
    • TIMI score 4+
    • Ischemic changes on EKG
    • Revascularization for this event
• Key exclusion criteria:
  • Hx of bleeding, ICH or GI bleed within past year
  • CrCl <20 mL/min
  • Need for full-dose anticoagulation
• Typical study patient
  • Age 62 years
  • Male 75%
  • ACS type: unstable angina 11%, NSTEMI 40%, STEMI 49%
  • Procedure for ACS: Cath 94%, PCI 87% (DES 67%, BMS 33%), CABG <1%
  • Randomized median 5.5 days after ACS
  • Previous MI 22%
  • Previous PCI/CABG 20%/4%
  • PAD 5%
  • CV risk factors
    • Smoker 33%
    • HTN 73%
    • Dyslipidemia 56%
    • Diabetes 30%
  • Meds
    • ACEI/ARB 63%
    • Beta-blocker 64%
    • Statins 69%

Interventions

• I: Rivaroxaban 2.5 mg PO BID for a minimum 180 days
• C: ASA 100 mg PO daily for a minimum 180 days
• Median duration of study drug 9.6 months
• Co-interventions:
  • Clopidogrel 75 mg daily (44%) or ticagrelor 90 mg BID (56%) based on investigator preference (i.e. choice of P2Y12 inhibitor not randomized)
    • Prematurely discontinued in 4%

Results @ median 10.7 months

• Primary outcome (TIMI non-CABG clinically significant bleeding): 5% in both groups, hazard ratio (HR) 1.09 (0.80-1.50)
• Results vary based on bleeding definition
  • ISTH major bleeding: Rivaroxaban 2% versus ASA 1% (NNH 100), HR 1.83 (1.01-3.31)
  • BARC 3a or higher: 1% in both groups, HR 1.70 (0.85-3.37)
  • GUSTO life-threatening or severe: <1% in both groups, HR 1.50 (0.25-8.95)
  • TIMI major bleeding: 1% in both groups, HR 1.25 (0.49-3.17)
• Efficacy outcomes
  • Death: Rivaroxaban 1%, ASA 1.5%, HR 0.95 (0.53-1.71)
  • CV death, MI, stroke or definite stent thrombosis: 5% in both groups, HR 1.06 (0.77-1.46)
  • Any stent thrombosis: 1% in both groups, HR 1.06 (0.54-2.11)

Internal validity

• Low risk of bias (including allocation, performance, detection, attrition and reporting biases)
  • Computer-generated randomization
  • Centralized, electronic allocation (allocation concealment)
  • Blinding using identical placebos
  • <0.5% (1 patient) lost to follow-up

Generalizability & applicability

• Excluded patients with an indication for full-dose anticoagulation (e.g. AF, LV thrombus, VTE)
• Rivaroxaban dose is dose found to be efficacious in ACS in ATLAS trial, but only 25% of dose demonstrated to have efficacy in AF & VTE
• Majority used ticagrelor as P2Y12 inhibitor
• Phase 2 trial:
  • Not powered to compare low-dose rivaroxaban to ASA for: Death, major bleed, and efficacy (including MI, stroke or stent thrombosis)
  • Not formally designed as a non-inferiority trial, but primary analysis met wide pre-defined non-inferiority margin (HR <2.0)

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

ARBs vs ACEIs patients post-MI or at high risk of CVD

Dickstein K, et al. Effects of losartan and captopril on mortality and morbidity in high-risk patients after acute myocardial infarction: the OPTIMAAL randomised trial. Lancet 2002;360:752-60.

The ONTARGET Investigators. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008;358:1547-59.

VALIANT: Pfeffer MA, et al. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med 2003;349:1893-906.

Bottom line:

• In patients post-MI or at high risk of CVD, telmisartan & valsartan generally prevent CV events as well as ACE inhibitors with similar safety;

• The combination of ACEI+ARB is no better than monotherapy & increases the risk of adverse events (e.g. hypotension, hyperkalemia & renal impairment);

• Losartan is inferior to captopril for prevention of CV events.

 

Patients

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Interventions

• OPTIMAAL: ARB vs ACEI
  • ARB: Losartan started at 12.5 mg PO daily; increased to target 50 mg PO daily
    • 83% achieved target dose
  • ACEI: Captopril started at 12.5 mg PO TID; increased to target 50 mg PO TID
    • 81% achieved target dose
• ONTARGET: ARB, ACEI or combination of both
  • ARB: Telmisartan started at 20 mg PO daily; increased to target 80 mg PO daily
    • 87% achieved target dose
  • ACEI: Ramipril started at 2.5 mg PO daily; increased to target 10 mg PO daily (HOPE dose)
    • 82% achieved target dose
• VALIANT: ARB, ACEI or combination of both
  • ARB: Valsartan started at 20 mg PO BID; increased to target 160 mg PO BID
  • ACEI: Captopril started at 6.25 mg PO TID; increased to target 50 mg PO TID
  • 56% in each monotherapy group achieved target dose, 47% in combination group achieved target doses

Results @ 2-4.7 years

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Generalizability & internal validity

• Design of these trials essentially identical to the original 'ACEI vs placebo' trials that they mimic
  • I.e. high-quality allocation-concealed double-blind RCTs
• All 3 trials are non-inferiority trials with fair non-inferiority margins and analyses
  • Note: OPTIMAAL is the only of the 3 that does not demonstrate of the ARB (losartan) & in fact points towards significant inferiority to an ACEI
• As with the 'ACEI vs placebo' RCTs, results of these trials apply to patients that are post-MI, especially those with clinical HF & LV dysfunction, and those at high risk of CVD