Heparin, enoxaparin & fondaparinux in ACS

NSTE-ACS

Heparin: Systematic review of 6 RCTs (3 were double-blind) published 1988-1995

• P: NSTE-ACS patients treated with ASA (n=1353)
• I: Heparin bolus + infusion x2-7 days
• C: Placebo/no treatment
• O:
  • Death/MI: Heparin 7.9%, control 10.4% (NNT 40), OR 0.67 (0.45-0.99)
  • Recurrent angina: OR 0.94 (0.58-1.54)
  • Revascularization: OR 1.25 (0.76-2.06)
  • Major bleed: OR 1.88 (0.60-5.87)

Enoxaparin (A to Z, ESSENCE, SYNERGY, TIMI 11B)

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Fondaparinux: OASIS 5 - Double-blind non-inferiority RCT

• P: NSTE-ACS (n=20,078)
  • Clopidogrel given to 2/3
• I: Fondaparinux 2.5 mg  once daily up to 8 days or until discharge
• C: Enoxaparin 1 mg/kg q12h (if CrCl <30: 1 mg/kg q24h) x2-8 days or until "clinically stable"
• O @ day 9:
  • Primary outcome (death/MI/refractory ischemia): Fondaparinux 5.8%, enoxaparin 5.7%, HR 1.01 (0.90-1.13)
    • Death: 1.8% vs 1.9%
    • MI: 2.6% vs 2.7%
    • Refractory ischemia: 1.9% for both
  • Major bleed: 2.2% vs 4.1% (NNT 53), HR 0.52 (0.44-0.61)
• O @ 180 days:
  • Primary outcome: 12.3% vs 13.2% (NNT 112), HR 0.93 (0.86-1.00)
    • Death: 5.8% vs 6.5%
  • Major bleed: 4.3% vs 5.8%, HR 0.72 (0.64-0.82)
• Benefit & safety preserved in 1/3 of patients who underwent PCI during initial ACS hospitalization (in fondaparinux group, heparin given during PCI)

 

STEMI

Enoxaparin: (ASSENT 3, EXTRACT TIMI 25)

• ASSENT 3
  • P: STEMI undergoing fibrinolysis with TNK (n6095)
  • I: Enoxaparin 30 mg IV bolus, then 1 mg/kg subcutaneously q12h continued for max 7 days
  • C: Heparin bolus, then infusion for at least 48h (also 3rd group given abciximab & no anticoagulant)
  • O @ 30 days:
    • Primary outcome (death, in-hospital re-infarction or refractory ischemia): Enoxaparin 11.4%, heparin 15.4% (NNT 25)
      • Death: 5.4% vs 6.0% (p=0.25)
      • Re-infarction: 2.7% vs 4.2%
      • Refractory ischemia: 4.6% vs 6.5%
    • ICH: 0.9% in both groups
    • Major bleed, non-ICH: 3.0% vs 2.2% (NNH 125)
• EXTRACT TIMI 25
  • P: STEMI undergoing fibrinolysis (n=20,506)
  • I: Enoxaparin 30 mg IV bolus, then 1 mg/kg subcutaneously q12h continued for max 8 days or until discharge
    • If >75 y/o: No bolus, 0.75 mg/kg q12h
    • If CrCl <30 mL/min: 1 mg/kg q24h
  • C: Heparin infusion to aPTT 1.5-2.0x above normal, given for at least 48h
  • O @ 30 days:
    • Primary outcome (death/MI): Enoxaparin 9.9%, heparin 12.0% (NNT 48), RR 0.83 (0.77-0.90)
      • Death: 6.9% vs 7.5%
      • MI: 3.0% vs 4.5%
    • Urgent revascularization: 2.1% vs 2.8%
    • Major bleed: 2.1% vs 1.4% (NNH 143), RR 1.53 (1.23-1.89)

Fondaparinux: OASIS 6 - Double-blind RCT

• P: STEMI (n=12,092)
• I: Fondaparinux 2.5 mg daily (first dose IV if lytic/PCI) for up to 8 days or until discharge
• C: Stratified by indication for placebo
  • No indication for heparin: Placebo
  • Indication for heparin (fibrin-specific thrombolytic or scheduled for 1o PCI): Heparin x1-2 days
• O @ 30 days (only presenting data for those with indication for heparin)
  • Primary outcome (death/MI): Fondaparinux 8.3%, heparin 8.7%, HR 0.96 (0.81-1.13)
  • Major bleed: Fondaparinux 2.1%, heparin 2.3%, HR 0.93 (0.67-1.30)

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

 

ARTE - Dual versus single antiplatelet therapy after TAVI

Aspirin versus aspirin plus clopidogrel as antithrombotic treatment following transcatheter aortic valve replacement with a balloon-expandable valve: The ARTE (Aspirin Versus Aspirin + Clopidogrel Following Transcatheter Aortic Valve Implantation) randomized clinical trial. JACC: Cardiovascular Intervention 2017 [online]

Bottom line: In patients undergoing TAVI with no other indication for anticoagulation or DAPT, 3 months of DAPT increases the risk of major/life-threatening bleeding (number needed to harm 14) versus ASA alone without any apparent benefit.

 

Patients (n=222)

• Included patients who underwent TAVI (aka TAVR) with Edwards SAPIEN XT or SAPIEN 3 valve (balloon-expandable valve)
• Excluded patients requiring chronic anticoagulation or dual antiplatelet therapy (DAPT) for other indication, or those who had a major bleed within 3 months before TAVI or any history of intracranial hemorrhage
• Baseline characteristics
  • Age 79 y
  • Male 58%
  • Indexed AVA 0.4 cm2/m2
  • LVEF 55%
  • Procedural characteristics
    • Femoral approach ~70%
    • SAPIEN XT ~92%, SAPIEN 3 8%
    • Post-TAVI indexed AVA 0.95-1.0 cm2/m2
    • New-onset AF 11%

Interventions

• I: DAPT - clopidogrel (300 mg/d load <1 day before/after TAVI, then 75 mg/d) x90 days
• C: ASA monotherapy
• In both groups, ASA started >24h before TAVI & continued for 6+ months
• PPI use not reported (though authors report that all patients with GI bleed were receiving a PPI prior to the event)

Results @ 90 days

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• Types of major/life-threatening bleeds in DAPT group (all occurred in first 30 days): GI bleed (5), peri-operative or access-site bleed (annular rupture, femoral hematoma; 7)

Generalizability

• This trial represents elderly patients undergoing TAVI with moderate-high risk of peri-operative mortality
  • Although the results of this trial do not apply to those requiring anticoagulation, we would expect an even greater increase in serious bleeds when adding DAPT to an oral anticoagulant
• These results with the SAPIEN valves are also likely generalizable to self-expanding valves (Medtronic's CoreValve line)

Internal validity

• Unclear risk of allocation bias (allocation concealment not adequately described)
• High risk of performance & detection bias (no blinding to treatment)
• Stopped prematurely due to slow enrolment + loss of funding

Other studies

• Results from our systematic review of 4 small studies (2 RCTs & 2 cohorts) were consistent with the ARTE trial; DAPT increased the risk of bleeding events without significantly reducing stroke or other ischemic events
• Notably, none of the studies - alone or in combination - have sufficient power to evaluate the efficacy of DAPT in this setting, though it is likely that the severity and magnitude of harm from bleeds related to DAPT likely exceeds any possible benefit in this patient population
• Therefore, the existing evidence does not support routine use of DAPT in patients undergoing TAVI

GAUSS-3 - Evolocumab vs ezetimibe in true muscle-related statin intolerance

Efficacy and tolerability of evolocumab vs ezetimibe in patients with muscle-related statin intolerance: The GAUSS-3 randomized clinical trial. JAMA 2016;315:1580-90

Bottom line:

• ~43% of patients with perceived statin-related muscle symptoms had intolerance reproducible with a N-of-1 trial;

• In those with muscle-related statin intolerance reproducible with a N-of-1 trial, evolocumab & ezetimibe were similarly tolerated;

• LDL-C reductions with these agents were consistent with those from other trials with LDL-C reductions of 50-55% for evolocumab & 15-20% for ezetimibe.

Patients (Phase A n=491, Phase B n=218)

• Included
  • Adults unable to tolerate atorvastatin 10 mg/d & any other statin (any dose) or 3+ statins
  • Baseline LDL-C
    • >2.6 mmol/L + CAD
    • >3.3 mmol/L + 2 CV risk factors
    • >4.1 mmol/L + 1 CV risk factor
    • >4.9 mmol/L (at least possible familial hypercholesterolemia [FH])
• Baseline characteristics (of Phase B patients)
  • Age 59 y
  • Male 51%
  • CV hx: CAD 31%, cerebrovascular disease/PAD 20%
  • Hx of intolerance to at least 3 statins 82%
  • Worst muscle-related adverse effects: Myalgias 80%, myositis 14%, rhabdomyolysis 6%
  • Mean LDL-C 5.7 mmol/L

Interventions

• Phase A (confirming statin-related muscle symptoms)
  • I: Atorvastatin 20 mg/d x10 weeks
  • C: Matching placebo x10 weeks
  • Note: Preceded by 4-week washout without any lipid-lowering therapy
• Phase B (comparison of non-statin lipid-lowering monotherapy for those with reproducible statin-related muscle symptoms in Phase A)
  • I: Evolocumab 420 mg subcutaneously q1 month (+ ezetimibe placebo)
  • C: Ezetimibe 10 mg daily (+ evolocumab placebo)

Results

Phase A: Muscle symptoms with

• Atorvastatin but not placebo (truly statin-related muscle symptoms) 43%
• Placebo but not atorvastatin: 27%
• Both atorvastatin & placebo 10%
• Neither 18%

Phase B

• Total muscle-related events: Evolocumab 20.7%, ezetimibe 28.8%, p=0.23
  • Myalgia: 13.8% vs 21.9%
  • Elevated CK: 2.8% vs 1.4%
• LDL-C reduction
  • Evolocumab lowered by ~53% (-2.7 mmol/L) from baseline
  • Ezetimibe lowered by 17% (-0.8 mmol/L) from baseline
  • ~37% (1.9 mmol/L) difference between groups
  • Maximal LDL-C reduction achieved at ~4 weeks & maintained during 6-month follow-up

Considerations (generalizability, internal validity, etc)

• Low risk of bias (allocation, performance, detection, attrition) in both phases due to computer-generated randomization sequence with allocation concealed by centralized allocation and blinding of patients and outcome assessors using matching placebos
• Phase A of this trial is generalizable to our patients who have a history of perceived intolerance to numerous statins
  • The Phase A results indicate that many of these patients can tolerate a statin with rechallenge, particularly if bias is minimized by way of a N-of-1 double-blind trial design. However, up to 43% of these patients have true statin-related myalgia that is reproducible with a N-of-1 trial;
  • Given the high cost of PCSK9 inhibitors, this raises the question of whether it would be cost-effective to perform N-of-1 trials in patients with history of statin intolerance if it allowed us to get 53% of them back onto a statin rather than a more expensive (and in the case of ezetimibe monotherapy at least, inferior) lipid-lowering therapy?
• Generalizability of Phase B is limited by the fact that most of us cannot perform N-of-1 trials routinely. Consistent with clinical practice however, it does indicate that some of these of these patients will go on to report muscle symptoms while receiving an alternate lipid-lowering agent and even discontinue these agents. Since Phase B of this trial did not have a placebo group, this cannot show that either of these drugs were truly responsible for the muscle symptoms.

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