AFIRE - Antithrombotics for AF + stable CAD

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Yasuda S, et al. Antithrombotic therapy for atrial fibrillation with stable coronary disease. NEJM 2019;381:1103-13.

Bottom Line:

  • Among Japanese patients with AF warranting OAC & stable CAD, using OAC monotherapy reduced the risk of dying (3% fewer) & having a major bleed (2% fewer) without increasing thrombotic risk compared with OAC plus an antiplatelet at 2 years.

  • These results are likely generalizable to non-Japanese patients & to other DOACs using approved doses.

Participants (n=2246 randomized, n=2215 analyzed)

  • Setting: Japan, enrolled 2015-2017

  • Included

    • Age >20 y

    • AF with CHADS2 score 1-6

    • Stable CAD (prior PCI or CABG >1 y ago, coronary stenosis 50%+ on angiography)

  • Key exclusion

    • Prior stent thrombosis

    • Active tumor

    • Poorly-controlled HTN

  • Baseline

    • Age 74 y, female 21%

    • AF: Paroxysmal 53%, persistent 15%, permanent 32%

    • CHADS2=2, CHA2DS2-VASc=4, HASBLED=2 (medians)

    • Previous stroke 15%, MI 35%, PCI 71% (drug-eluting stent 65-70%, mostly everolimus-eluting)

    • Current smoker 13%, diabetes 42%

    • CrCl <50 mL/min 34%

Intervention: Oral anticoagulant (OAC) monotherapy

  • Rivaroxaban 15 mg/d if CrCl 50+ (standard dose in Japan)

    • If CrCl 15-49: 10 mg/d (equivalent to 15 mg/d in non-Japanese)

    • 3.5% used antiplatelet

Control: OAC + antiplatelet

  • Rivaroxaban (as above) + antiplatelet (ASA or P2Y12 inhibitor at clinician’s discretion)

  • Antiplatelet used: ASA 70%, P2Y12 inhibitor 27%, other 2%, none <1%

Outcomes @ median 24 months

  • Primary outcome (death, stroke, systemic embolism, MI, unstable angina requiring PCI/CABG):

    • OAC 8.0% vs OAC+antiplatelet 10.9% (ARR 2.9%, NNT 35)

    • Hazard ratio (HR) 0.72 (95% confidence interval 0.55-0.95)

  • Death: 3.7% vs 6.6% (HR 0.55, 0.38-0.81; ARR 2.9%, NNT 35)

  • Ischemic stroke: 1.9% vs 2.5%

  • MI: 1.2% vs 0.7%

  • Major bleed (ISTH definition): 3.2% vs 5.2% (HR 0.59, 0.39-0.89; ARR 2%, NNT 50)

    • Hemorrhagic stroke: 0.4% vs 1.2% (HR 0.30, 0.10-0.92)

Internal Validity: Low risk of bias overall

  • Allocation bias: Low risk

    • Randomization using computer-generated minimization algorithm

    • Allocation concealed via web-based response system

  • Performance bias: Unclear risk

    • Open-label (patients & clinicians aware of allocated intervention)

    • Potential for crossover, differential management of antithrombotics & other cardiovascular risk factor modification

  • Detection bias: Low risk

    • Difference in outcomes driven by mortality; hard outcome with little opportunity to “game”

    • Outcomes assessed by blinded adjudication committee

  • Attrition bias: Low risk

    • Analyzed modified intention-to-treat (mITT) population & per-protocol (for non-inferiority)

    • Loss-to-follow-up: OAC monotherapy 2.5%, OAC+antiplatelet 1.8%

  • Other biases: Low risk

    • Stopped early for safety (higher risk of death in comparator group)

Other Considerations

  • Non-inferiority trial

    • Non-inferiority margin HR<1.46

    • Non-inferiority (and superiority) of OAC monotherapy met in both mITT & per-protocol analyses

  • Lower dose of rivaroxaban than used in North America

    • The approved “full dose” of rivaroxaban for stroke prophylaxis in AF in Japan is 15 mg/d (rather than 20 mg/d outside Asia) based on the J-ROCKET AF trial, as well as supporting pharmacokinetic-pharmacodynamic data

    • The 20 mg/d dose should be used among non-Asians. It is unclear what dose we should use in non-Japanese Asians & South Asians.

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

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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

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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

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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

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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%