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.

ASA vs rivaroxaban for extension of VTE prophylaxis after hip/knee arthroplasty

Anderson DR, et al. Aspirin or rivaroxaban for VTE prophylaxis after hip or knee arthroplasty. NEJM 2018;378:699-707.

Bottom line: In patients who underwent elective hip or knee replacement with rivaroxaban 10 mg/d up until POD #5, switching to ASA 81 mg/d on POD #6 is no worse than continuing rivaroxaban 10 mg/d for preventing VTE, with similar rates of bleeding. 

Patients (n=3427)

  • Setting: 15 Canadian university-affiliated hospitals from Jan 2013 to April 2016
  • Included: Elective unilateral hip (THA) or knee arthroplasty (TKA), primary or revision
  • Excluded:
    • Hip or lower limb fracture in previous 3 months
    • Metastatic cancer
    • Did NOT exclude patients who received ASA pre-op (they could continue open-label ASA <100 mg/d in addition to blinded study drug)
  • Baseline characteristics:
    • Age 63 y
    • Male 48%
    • Joint operated: Hip (53%), knee (47%)
    • VTE risk factors: Prior VTE 2-3%, previous surgery ~3%, cancer 2-3%, smoker ~9%
    • BMI 31
    • Post-op mechanical compression: IPCs (50%), graduated stockings (42%), both (8%)
    • Hospital LOS 3.5 days
    • Peri-op tranexamic acid 54.5%
    • Pre-op ASA 25%

Intervention & control

  • All patients received rivaroxaban 10 mg once daily on POD #0 (starting >6h after wound closure) or POD #1, & was continued until POD #5
  • Intervention: Switched to ASA 81 mg daily on POD #6
  • Control: Continued Rivaroxaban 10 mg once daily
  • Duration of study drug in both groups:
    • Hips x30 days (total 35 days of VTE prophylaxis)
    • Knees x9 days (total 14 days of VTE prophylaxis) 

Results @ 90 days

  • Primary efficacy outcome (symptomatic DVT or PE): ASA 0.6% vs rivaroxaban 0.7%
    • Absolute risk difference -0.06% (upper end of 95% confidence interval [CI]: +0.55%), p<0.001 for non-inferiority
  • Mortality: 0.06% (1 death from PE) vs 0%
  • Primary safety outcome (major or clinically-relevant non-major bleed): 1.3% vs 1.0%
    • All consisted of overt bleeding at the surgical site; most occurred between POD #6-16
  • Major bleed: 0.5% vs 0.3%

Generalizability (external validity)

  • Widely applicable to patients who underwent elective THA/TKA (whether they received DOAC or LMWH from POD #0-5)

Risk of bias: Low (high internal validity)

  • Low risk of allocation, performance, detection or attrition bias
    • Random sequence generation: using permuted-block design, stratified by THA or TKA, centre, & use of open-label ASA
    • Allocation concealment: patients & personnel (central pharmacy staff aware)
    • Blinding of patients & personnel: ASA & rivaroxaban administered in identical-appearing opaque gelatin capsules
    • Blinding of outcome assessors: Independent adjudication committee unaware of treatment allocation
    • ITT analysis
    • 1 patient lost to follow-up of VTE, but vital status known (alive @ 90 days)
  • Non-inferiority trial design
    • Non-inferiority margin set at <1.0% absolute risk difference justified based on survey of Canadian thromboembolism specialists & orthopedic surgeons (reference not provided)
    • ITT analysis used for primary analysis; on-treatment analysis consistent with ITT analysis:
      • Primary outcome: 0.4% vs 0.4%
      • Bleeding: 0.9% vs 0.75%
    • No safety advantage for ASA demonstrated in this trial, however, non-inferiority design is justifiable based on substantially-lower cost of ASA (<$5 for 1 month) compared to rivaroxaban ($3/day for 10 mg-tab).

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

ATLAS - Rivaroxaban in patients with a recent ACS

ATLAS ACS 2-TIMI 51: Mega JL, et al. Rivaroxaban in patients with a recent acute coronary syndrome. NEJM 2012;366:9-19.

Bottom line:

  • Over ~13 months of follow-up, the addition of rivaroxaban 2.5 mg BID to ASA+clopidogrel/ticlopidine reduced the risk of CV events, mainly driven by fatal events, which led to lower all-cause mortality (NNT 63) in patients post-ACS. Adding rivaroxaban also reduced stent thrombosis (NNT 143). This came at the cost of a greater risk of major bleeds (NNH 84), including intracranial hemorrhages (NNH 500).

  • Adding rivaroxaban 5 mg BID did not reduce mortality, & further increased the risk of major bleeds.

  • It remains unclear which of the following regimens would have the best balance between efficacy & safety: Ticagrelor-based DAPT, clopidogrel-based DAPT + low-dose rivaroxaban, or ticagrelor-based DAPT + low-dose rivaroxaban.

Patients (n=15,526)

  • Included
    • ACS (within 7 days of admission, after revascularization if planned)
    • Plus either
      • Age >55 y
      • Previous MI
      • Diabetes
    • Excluded
      • Previous intracranial hemorrhage
      • Clinically-significant GI bleed within 12 months
      • CrCl <30 mL/min
      • Hb <100 g/L
      • Platelet count <90
  • Baseline characteristics
    • Age 61.5 y (9.6% 75 y or greater)
    • Female 25%
    • STEMI (~50%), NSTEMI (~25%), UA (~25%)
    • Previous MI 27%
    • CV risk factors: HTN ~67%, diabetes ~32%, dyslipidemia ~50% 
    • CrCl 86 mL/min
    • Meds
      • ASA 99%, P2Y12 inhibitor ~93%
      • ACEI/ARB ~40%
      • Beta-blocker ~66%
      • Statin ~15%

Interventions

  • Intervention1: Rivaroxaban 2.5 mg BID
  • Intervention2: Rivaroxaban 5 mg BID
  • Control: Placebo
  • All groups: ASA + clopidogrel or ticlopidine

Results @ 13.1 months

Considerations

  • Low risk of bias (allocation, performance, detection & attrition)
    • Allocation concealed by central computer/phone allocation
    • Participants, clinicians & investigators blinded to study drug
    • Modified ITT & full ITT analysis
    • 0.3% lost to follow-up, though ~28% in all groups discontinued study drug before end of study
  • Generalizability
    • Patients represented a group of post-ACS patients at very high risk of recurrent ASCVD with very low use of proven secondary prevention therapies
    • Additionally, this trial was performed before approval of more potent P2Y12 inhibitors (prasugrel & ticagrelor), so background DAPT included ASA + clopidogrel/ticlopidine (how many specifically received clopidogrel not reported)
    • Based on the preliminary results from ATLAS ACS-TIMI 46 (see below), the investigators selected 2.5 and 5 mg BID doses of rivaroxaban for this trial; this is pharmacokinetically rational given the 5-13h half-life of rivaroxaban (apixaban & dabigatran have similar half-lives and are generally dosed BID), however, it is a very different regimen than that used for AF/VTE. As a result, it's unclear if this regimen preserves the efficacy of rivaroxaban for these other conditions.

Summary of ATLAS ACS-TIMI 46

  • Dose-ranging study with identical enrolment criteria as ATLAS ACS 2-TIMI 51