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APACHE-AF

Apixaban versus Antiplatelet drugs or no antithrombotic drugs after anticoagulation-associated intracerebral haemorrhage in patients with atrial fibrillation

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Year of Publication: 2021

Authors: Schreuder FHBM, van Nieuwenhuizen KM, Hofmeijer J, ..., Klijn CJM; APACHE-AF Trial Investigators

Journal: The Lancet Neurology

Citation: Lancet Neurol 2021;20(11):907-916

Link: https://doi.org/10.1016/S1474-4422(21)00298-2

Clinical Question

In patients with atrial fibrillation who survive anticoagulation-associated intracerebral hemorrhage, what are the rates of non-fatal stroke or vascular death when treated with apixaban compared to avoiding anticoagulation?

Bottom Line

Patients with AF who had anticoagulation-associated ICH have a very high annual risk of non-fatal stroke or vascular death (~12%) regardless of whether they receive apixaban or avoid anticoagulation. This phase 2 trial was underpowered to detect a treatment difference and underscores the need for larger trials.

Major Points

  • Phase 2 trial designed to inform sample size for a larger phase 3 trial
  • Specifically enrolled patients who had ICH WHILE ON anticoagulation (anticoagulation-associated ICH)
  • No significant difference in primary composite outcome between groups (HR 1.05)
  • Very high annual event rates in both groups (~12%) highlight the severity of this clinical situation
  • Numerically more recurrent ICH with apixaban (8% vs 2%) but not statistically significant
  • Similar rates of ischemic stroke in both groups (12% vs 12%)
  • 21% crossover rate in avoid group (11/51 crossed to anticoagulation)
  • Trial underpowered; authors estimate 5744 participants per group needed for definitive trial

Design

Study Type: Randomized, open-label, phase 2 trial with masked endpoint assessment (PROBE design)

Randomization: 1

Blinding: Open-label for participants and treating physicians; outcome adjudicators masked to treatment allocation and antithrombotic drug use

Enrollment Period: January 2015 to July 2020

Follow-up Duration: Median 1.9 years (IQR 1.0-3.1); minimum 6 months

Centers: 16

Countries: Netherlands

Sample Size: 101

Analysis: Intention-to-treat; Cox proportional hazards regression adjusted for age and ICH location (minimization variables); on-treatment analysis as secondary

Inclusion Criteria

  • Adults ≥18 years
  • Spontaneous ICH (including isolated intraventricular hemorrhage) in previous 7-90 days
  • ICH occurred during treatment with anticoagulation (VKA, DOAC, or therapeutic-dose heparin/LMWH)
  • Documented paroxysmal or non-paroxysmal non-valvular atrial fibrillation
  • CHA₂DS₂-VASc score ≥2
  • Modified Rankin Scale ≤4
  • Clinical equipoise regarding optimal treatment

Exclusion Criteria

  • Conditions other than AF requiring long-term anticoagulation (e.g., mechanical heart valve)
  • Other serious bleeding events besides ICH in previous 6 months
  • High risk of bleeding
  • Ischemic stroke in previous 7 days
  • Active alcohol or drug misuse
  • Life expectancy <1 year
  • Severe renal insufficiency
  • Liver test abnormalities
  • Women with childbearing potential, pregnant, or breastfeeding

Arms

FieldApixabanControl
InterventionApixaban 5 mg twice daily orally; reduced dose 2.5 mg twice daily if CrCl ≤30 mL/min OR if 2 of 3 criteria present: age ≥80, weight ≤60 kg, serum creatinine ≥133 µmol/LNo anticoagulation; oral antiplatelet therapy permitted at treating physician discretion (51% received antiplatelet: ASA 80mg, carbasalate calcium 100mg, clopidogrel 75mg, or dipyridamole combinations)
DurationOngoing treatment with follow-up minimum 6 monthsOngoing with follow-up minimum 6 months

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
Composite of non-fatal stroke (ischemic stroke, ICH, or SAH) or vascular death, whichever came firstPrimary12 (24%); Annual event rate 11.9% (95% CI 6.2-20.8)13 (26%); Annual event rate 12.6% (95% CI 6.7-21.5)1.050.90
Recurrent Intracerebral HemorrhageSecondary1 (2%)4 (8%)4.080.21
All Major Haemorrhagic EventsSecondary3 (6%)6 (12%)2.110.29
Ischemic StrokeSecondary6 (12%)6 (12%)0.960.94
All Major Occlusive Events (ischemic stroke, MI, PE, systemic embolism)Secondary11 (22%)6 (12%)0.460.13
Myocardial InfarctionSecondary2 (4%)0 (0%)
Pulmonary EmbolismSecondary4 (8%)0 (0%)
Vascular DeathSecondary7 (14%)5 (10%)
All-cause DeathSecondary11 (22%)9 (18%)
All Major Vascular Events (MI, stroke, or vascular death - ATT definition)Secondary13 (25%)13 (26%)0.930.85
Serious Adverse Events (non-outcome)Adverse29 (57%)29 (58%)
Major Extracranial HemorrhageAdverse2 (4%)2 (4%)
Clinically Relevant Non-major BleedingAdverse0 (0%)1 (2%)

Subgroup Analysis

Prespecified exploratory subgroup analyses showed no evidence of heterogeneity for the primary outcome based on: ICH location (lobar vs non-lobar), age (<75 vs ≥75), sex, time since ICH (<7 weeks vs ≥7 weeks), CHA₂DS₂-VASc score, intention for antiplatelet in comparator group, or CT small vessel disease score.

Criticisms

  • Small sample size (n=101) - phase 2 trial underpowered to detect treatment differences
  • Wide 95% confidence intervals preclude definitive conclusions
  • Open-label design may introduce reporting, observation, and detection bias
  • High crossover rate: 21% (11/51) in avoid group crossed over to anticoagulation
  • 9 participants in apixaban group did not start or discontinued treatment
  • Blood pressure control during follow-up was suboptimal
  • Nearly all participants (99%) were White - limited generalizability to other ethnicities
  • Small median ICH volume (5-7 mL) suggests selection of patients who recovered well
  • Single country (Netherlands) enrollment only

Funding

Dutch Heart Foundation (grant 2012T077)

Based on: APACHE-AF (The Lancet Neurology, 2021)

Authors: Schreuder FHBM, van Nieuwenhuizen KM, Hofmeijer J, ..., Klijn CJM; APACHE-AF Trial Investigators

Citation: Lancet Neurol 2021;20(11):907-916

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