AUGUSTUS - Antithrombotic regimens including apixaban vs warfarin, & aspirin vs placebo, in patients with AFib plus PCI &/or ACS

Reference: Lopes RD, et al. Antithrombotic therapy after acute coronary syndrome or PCI in atrial fibrillation. NEJM 2019.

Bottom line: In patients with atrial fibrillation who either undergo PCI and/or have ACS, in combination with a P2Y12 inhibitor (almost always clopidogrel):

  • Apixaban reduces the risk of major or clinically-relevant non-major bleeding (NNT=24), hospitalizations (NNT=27), & stroke (NNT=84) compared to warfarin at 6 months;

  • Aspirin (beyond the first week) increases the risk major or clinically-relevant non-major bleeding (NNH=15), without a clear effect on hospitalization/death or ischemic events compared to placebo at 6 months;

  • Therefore, an antithrombotic regimen of apixaban + clopidogrel (without aspirin) should be routinely considered in these patients. Warfarin should be limited to patients for whom a DOAC is contraindicated, intolerable or unaffordable; & aspirin beyond the first week should be limited to patients with very high risk of stent thrombosis/recurrent coronary events.

Patients (n=4614 from 33 countries)

  • Included if (all of the following):

    • Age 18+ years

    • Known AF (paroxysmal, persistent or permanent) with planned long-term oral anticoagulation

    • Recent (<14 days) ACS &/or PCI with plan for 6+ months of P2Y12 inhibitor

  • Key exclusion criteria:

    • Other indication for anticoagulation (prosthetic valve, VTE, mitral stenosis, etc)

    • History of intracranial hemorrhage, ongoing bleeding or coagulopathy

    • Recent/planned CABG

    • “Severe” renal insufficiency

  • Average baseline characteristics:

    • Age 71 years, male (71%), white (92%)

    • Qualifying event: ACS+PCI (37%), medically-managed ACS (24%), elective PCI (39%)

      • ~6.6 days from ACS/PCI to randomization

    • CHA2DS2-VASc ~4, HAS-BLED ~3

    • Prior stroke/TIA/thromboembolism (14%), HF (43%), HTN (88%), diabetes (36%)

    • SCr >133 (8%)

    • Previous oral anticoagulant (49%)

Interventions x6 months

  • 2x2 factorial design: Patients were simultaneously randomized to apixaban vs warfarin & aspirin vs placebo within 14 days of ACS &/or PCI, so total of 4 different intervention groups.

  • Management prior to randomization: At the discretion of treating physicians according to local standard of care (likely that all at least received DAPT +/- anticoagulation leading up to randomization, though not recorded/reported)

  • Anticoagulation: Apixaban vs warfarin

    • Apixaban arm: 5 mg PO BID

      • Reduced to 2.5 mg PO BID if 2 of the following: Age >80 years, wt <60 kg, SCr >133 umol/L

      • Discontinued study regimen prematurely: 13%

    • Warfarin to target INR 2.0-3.0

      • Median time in therapeutic range (TTR)=59%; INR<2.0 23% of the time, INR>3.0 3% of the time

      • Discontinued study regimen prematurely: 14%

  • Antiplatelet: Aspirin 81 mg PO daily vs matching placebo

    • Discontinued study drug prematurely: 15-17%

  • All: P2Y12 inhibitor left at the discretion of the treating clinicians (clopidogrel 93%, prasugrel 1%, ticagrelor 6%)

  • After 6 months, anticoagulation & antiplatelets were managed according to local standard of care (i.e. not standardized for the trial)

Results @ 6 months

  • Primary outcome: Major or clinically-relevant non-major bleeding, ISTH definition

  • Key secondary outcomes: Composite of death or hospitalization; composite of death or ischemic events (stroke, MI, definite/probable stent thrombosis, or urgent revascularization).

Outcomes at 6 months of apixaban versus warfarin in combination with P2Y12 inhibitor +/- aspirin

Outcomes at 6 months of aspirin versus placebo in combination with P2Y12 inhibitor + apixaban or warfarin

Risk of bias

  • Low risk of: Allocation bias (allocation concealed via interactive voice-response system), attrition bias (low [0.3%] loss to follow-up & analyzed by intention-to-treat), outcome reporting bias (all outcomes of interest defined & reported).

  • Variable risk of performance/detection bias:

    • Apixaban vs warfarin comparison was open-label (i.e. patients & clinicians aware of treatment assignment):

      • All outcomes were adjudicated by a blinded clinical endpoint committee, therefore providing some protection against (but not eliminating) detection bias.

    • Aspirin vs placebo comparison was blinded (patients, clinicians, outcome adjudicators unaware of treatment assignment): Low risk of performance & detection bias.

BRIDGE - Peri-procedure bridging of anticoagulation of AF patients on warfarin

Douketis JD, et al. Perioperative bridging anticoagulation in patients with atrial fibrillation. NEJM 2015;373:823-33.

Bottom line: In patients with AF & CHADS2 score <4 requiring interruption of warfarin, bridging with parenteral anticoagulation increases major bleeding (NNH 53 from bridging) without reducing thromboembolic events.

Patients (n=1884)

  • Randomized 1884, analyzed 1813

  • Included

    • Atrial fibrillation or flutter (paroxysmal or permanent) confirmed by EKG or pacemaker interrogation

    • Non-valvular or valvular AF both eligible

    • CHADS2 score 1 or higher

    • Receiving warfarin for 3+ months with INR 2.0-3.0

    • Undergoing elective invasive procedure felt to require interruption of warfarin

  • Excluded

    • Mechanical heart valve

    • Recent stroke, systemic embolism or TIA (in past 12 weeks) or major bleeding (in past 6 weeks)

    • CrCl <30 mL/min

    • Platelets <100

    • Planned cardiac, brain or spine surgery

  • Baseline characteristics

    • Age 72 y, male (73%), white (91%)

    • CHADS2 score

      • Mean score 2.3

      • 1 (23%), 2 (40%), 3 (24%), 4 (10%), 5 (3%), 6 (<1%)

      • HF/LV dysfunction ~33%

      • HTN 87%

      • Diabetes 41%

      • Prior stroke 8%

      • Prior TIA 8%

      • MI 15%

    • Undergoing procedure classified as having low bleeding risk 89%

    • Labs: INR 2.4, CrCl 88 mL/min

    • Concomitant ASA ~35%

Intervention & comparator

  • I: No bridging

    • Warfarin stopped 5 days before the procedure & restarted evening of surgery or POD 1, without bridging

  • C: Anticoagulant bridging

    • Warfarin stopped 5 days before the procedure & restarted POD0 evening or POD 1

    • Pre-op bridging: Dalteparin 100 units/kg subcut BID started 3 days before the procedure, last dose AM day before procedure (~24h before)

    • Post-op bridging: Dalteparin restarted 12-24h after low-bleeding-risk procedure & 48-72h after high-bleeding-risk procedure; continued x5-10 days until INR 2 or higher once

  • Adherence in both groups was ~86% pre-op & 96% post-op

Results @ day 30-37

  • Not bridging was non-inferior to bridging for the primary efficacy outcome (arterial thromboembolism; a composite of ischemic/hemorrhagic stroke, TIA, systemic embolism)

    • Intention-to-treat (ITT) population: No bridging 04.%, bridging 0.3% (difference 0.1%, 95% confidence interval [95%CI] -0.6% to +0.8%)

      • Stroke: 0.2% vs 0.3%

    • Per-protocol population: 0.3% vs 0.4% (difference 0.0%; 95% CI -0.7% to +0.7%)

  • Not bridging reduced the risk of major bleeding (ITT population): 1.3% vs 3.2% (NNT 53)

    • Minor bleeding: 12.0% vs 20.9% (NNT 12)

  • No difference in all-cause mortality: 0.5% vs 0.4%

Internal validity

  • Low risk of allocation, performance & detection bias

    • Interactive voice-response system

    • Dalteparin & matching placebo in identical vials

    • Blinded adjudication of all outcomes

  • Possible attrition bias due to moderate loss-to-follow-up (3.8%), which is higher than the rate of primary outcome events

  • Non-inferiority trial

    • Non-inferiority margin set as an absolute difference of 1.0% for arterial thromboembolism (wide);

    • Assumed ~1.0% absolute risk of arterial thromboembolism in both groups (actual event rate <1/2 expected);

    • Analysis of both ITT & per-protocol populations, which were nearly identical.

AVERROES - Apixaban versus ASA in patients with AF not suitable for warfarin

Connolly SJ, et al. Apixaban in patients with atrial fibrillation. N Engl J Med 2011;364:806-17.

Bottom line:

  • In patients with non-valvular AF, apixaban is more effective at reducing stroke risk than ASA (relative risk reduction 55%; NNT ~46/year), with a small increase in minor bleeding (NNH 84/year) but no significant increase in major bleeding;

  • This favorable benefit/risk profile of apixaban over ASA was present even in patients with a CHADS2 score of 0-1.

Patients

  • Included:
    • 50+ y/o
    • AF (documented within 6 months before enrolment or by 12-lead EKG)
    • At least 1 stroke risk factor (any CHADS2 criteria or PAD):
      • HF (NYHA class 2-4 symptoms or LVEF 35% or less), HTN, Age 75+, diabetes (on treatment), prior stroke/TIA, or documented PAD
    • Not receiving a warfarin because previously demonstrated to be "unsuitable" or expected to be unsuitable
  • Excluded:
    • Additional indication for anticoagulation other than AF
    • Serious bleeding within 6 months
    • High risk of bleeding (eg active peptic ulcer, plt <100, Hb <100 g/L, stroke within 10 days, blood dyscrasias)
    • Serum creatinine >221 umol/L or CrCl <25 mL/min
  • Baseline characteristics:
    • Age 70, male 59%
    • AF type: Paroxysmal (27%), persistent (21%), permanent (52%)
    • CHADS2 mean 2 (0 or 1 in 36%)
    • Stroke risk factors: Clinical HF (40%), LVEF <35% (5%), HTN (86%), diabetes (20%), prior stroke/TIA (14%)
    • Most common reason warfarin was "unsuitable" (multiple reasons in 51%):
      • Unable to measure INR frequently enough 43%
      • Patient refused to take warfarin 38% (the only reason in 15%)
      • CHADS2=1 so warfarin not recommended by physician 21%
      • Unable to keep INR therapeutic 17%
      • Unsure if patient can adhere to instructions to take warfarin 16%

Intervention & control

  • Intervention: Apixaban 5 mg PO BID
    • Decreased to 2.5 mg BID if 2/3 of: Age 80+ y, wt <60 kg, SCr >132 umol/L (occurred in 6%)
  • Control: ASA 81-324 mg/d (64% on 81 mg/d)

Results @ mean 1.1 years

  • Efficacy
    • Primary outcome (any stroke or systemic embolism): Apixaban 1.8% versus ASA 4.0%, hazard ratio (HR) 0.45 (0.32-0.62), NNT=46
    • Death from any cause: 4.0% vs 5.0%, HR 0.79 (0.62-1.02)
    • CV hospitalization: 13.1% vs 16.3%, HR 0.79 (0.69-0.91), NNT=32
  • Safety
    • Major bleed (overt bleed with Hb decrease 20+ g/L over 24h, transfusion 2+ units of RBCs, or bleeding at a critical site [e.g. brain, eyes, pericardium, retroperitoneum): 1.6% vs 1.4%, HR 1.13 (0.74-1.75)
      • Intracranial: 0.4% vs 0.5%, HR 0.85 (0.38-1.90)
      • Extracranial: 1.2% vs 1.0%, HR 1.23 (0.74-2.05)
    • Minor bleed: 6.7% vs 5.5%, HR 1.24 (1.00-1.53), NNH=84
    • Serious adverse events: 22% vs 27%, NNT=20
  • Subgroup analysis by baseline CHADS2 score demonstrated consistent relative risk reductions with apixaban over ASA regardless of score, with higher-risk patients deriving greater ABSOLUTE reductions in stroke (NNT=143/year for CHADS2=0 to 1, NNT=23/year for CHADS2=3+)

Generalizability

  • Representative sample of elderly patients with AF & a wide spectrum of stroke risk who had a difficult time maintaining INRs in the therapeutic range, going to the lab for INR monitoring, or who were expected not to do well with warfarin based on clinical judgement. Results were similar regardless of the reason for being unsuitable for warfarin.

Internal validity

  • Low risk of allocation, performance, detection, attrition, selective reporting bias
    • Central, computerized, automated randomization
    • Double-dummy blinding
    • Blinded outcome adjudication
    • No patients lost to follow-up
    • All relevant & important outcomes reported
  • Trial stopped early after 1st interim analysis for efficacy based on 104 events between groups

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

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%

Consequences of inadequate direct oral anticoagulant (DOAC) dosing

Yao X, et al. Non-vitamin K antagonist oral anticoagulant dosing in patients with atrial fibrillation and renal dysfunction. J Am Coll Cardiol 2017;69:2779-90.

Bottom line:

  • Many patients with non-valvular AF receiving a DOAC receive inappropriate doses.

  • In patients with an indication to reduced the DOAC dose, "overdosing" (using regular doses) is associated with a 2-fold higher risk of major bleeding vs using appropriate reduced doses.

  • In patients taking apixaban without an indication to reduce the dose, "underdosing" (using reduced doses) apixaban is associated with a ~5-fold increased risk of stroke/systemic embolism.

 

Design summary

  • Cohort study using administrative claims database & linked lab data
  • Included: US patients enrolled with Medicare Advantage with non-valvular AF treated with apixaban, dabigatran or rivaroxaban between Oct 2010-Sept 2015 who had serum creatinine results available within 1 year
  • Excluded: Valvular heart disease, other indication for DOAC, eGFR <15 (calculated using CKD-EPI)
  • Account for bias & confounding: Propensity score matching to balance baseline characteristics, statistical adjustment with Cox proportional hazards regression, numerous sensitivity analyses (such as changing criteria for apixaban dose reduction to age >80 + SCr >132 umol/L, dabigatran dose reduction criteria to eGFR <50), different matching criteria, subgroup analyses based on baseline criteria & individual DOACs, analysis of ICH as individual outcome, & analysis of 'falsification outcomes')
    • Note on the point of evaluating falsification outcomes: Falsification outcomes are outcomes that should not be associated with the presence/absence of an exposure. This is used to identify residual confounding after matching & statistical adjustment (i.e. if there's an association with an outcome that the exposure shouldn't affect, it implies residual confounding).

Results for PICO 1: Normal renal function (no need for DOAC dose reduction), n=13,392

  • Overall, 16.5% of patients underdosed
  • Increased risk of stroke/systemic embolism with reduced dose ("underdosed") vs normal dose of apixaban
    •  2.6% vs 0.5% per year, hazard ratio (HR) 4.87 (1.30-18.26)
  • No statistically significant difference in stroke/systemic embolism with reduced vs normal doses of dabigatran or rivaroxaban, though confidence intervals are very wide
  • No statistically significant difference in major bleeding with reduced vs normal doses of any DOAC

PICO 2: Renal impairment (indication for DOAC dose reduction), n=1,473

  • Overall, 48.5% of patients were overdosed
  • Definition of indication for dose reduction: Apixaban (SCr >132 umol/L), dabigatran (eGFR <30), rivaroxaban (eGFR <50)
  • Increased risk of major bleeding with normal ("overdosing") vs reduced dose of any DOAC
    • 11.3% vs 5.1% per year, HR 2.19 (1.07-4.46)
  • No difference of stroke/systemic embolism with normal vs reduced dose of any DOAC
    • 2.32% vs 1.85%, HR 1.66 (0.40-6.88)

Caveats

  • Due to a limited sample size & low outcome event rates, many analyses were underpowered, particularly when evaluating DOACs individually.
  • Due to limitations with available data, study definitions for criteria to reduce DOAC dose were not entirely consistent with drug label (e.g. weight for apixaban)
  • The analyses only partially accounted for known drug interactions (e.g. amiodarone, digoxin), & could not account for unknown or novel drug interactions (e.g. P-glycoprotein interaction between dabigatran & simvastatin).