AMPLIFY-EXT

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Agnelli G, et al. "Apixaban for extended treatment of venous thromboembolism". The New England Journal of Medicine. 2013. 368(8):699-708.
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Clinical Question

In patients with VTE who have completed 6-12 months of anticoagulation, does long-term apixaban treatment reduce recurrent VTE or all-cause mortality?

Bottom Line

In patients with VTE who have completed 6-12 months of anticoagulation, long-term apixaban treatment reduces recurrent VTE or all-cause mortality without increasing rates of major bleeding.

Major Points

The rate of VTE recurrence is up to 11% in the first year alone,[1] prompting investigators to study continued low-dose anticoagulation or antiplatelet agents in the secondary prevention of VTE. ASPIRE and WARFASA (both 2012) demonstrated that aspirin reduces VTE recurrence by 32%, while AMPLIFY-EXT studied apixaban, a factor Xa inhibitor.

AMPLIFY-EXT (an extension of the 2013 AMPLIFY trial) randomized 2,482 patients with VTE who have completed 6-12 months of anticoagulation to apixaban 2.5 mg bid, apixaban 5 mg bid, or matching placebo. Compared to placebo, the low and high doses of apixaban were associated with 63% and 67% reductions in the primary endpoint of recurrent VTE or all-cause mortality. Neither dose of apixaban increased the rate of major bleeding.

Guidelines

ACCP Antithrombotic Therapy for VTE Disease (2016, adapted): [2]

  • In patients with DVT of the leg or PE and no cancer, as long-term (first 3 months) anticoagulant therapy, dabigatran, rivaroxaban, apixaban, or edoxaban are recommended over vitamin K antagonist (VKA) therapy (all Grade 2B)
  • In patients with DVT of the leg or PE and cancer (“cancer-associated thrombosis”), as long-term (first 3 months) anticoagulant therapy, LMWH is recommended over other agents (Grade 2C)
  • In patients with DVT of the leg or PE who receive extended therapy, recommend no need to change the choice of anticoagulant after the first 3 months (Grade 2C)
  • In patients who have recurrent VTE on VKA therapy (in the therapeutic range) or on dabigatran, rivaroxaban, apixaban, or edoxaban (and are believed to be compliant), recommend switching to treatment with LMWH at least temporarily (Grade 2C).
  • In patients with an unprovoked DVT of the leg (isolated distal or proximal) or PE, we recommend treatment with anticoagulation for at least 3 months over treatment of a shorter duration (Grade 1B), and we recommend treatment with anticoagulation for 3 months over treatment of a longer, time-limited period (eg, 6, 12, or 24 months) (Grade 1B).
  • In patients with a first VTE that is an unprovoked proximal DVT of the leg or PE and who have a (i) low or moderate bleeding risk (see text), we suggest extended anticoagulant therapy (no scheduled stop date) over 3 months of therapy (Grade 2B), and a (ii) high bleeding risk (see text), we recommend 3 months of anticoagulant therapy over extended therapy (no scheduled stop date) (Grade 1B).
  • In patients with a second unprovoked VTE and who have a (i) low bleeding risk (see text), we recommend extended anticoagulant therapy (no scheduled stop date) over 3 months (Grade 1B); (ii) moderate bleeding risk (see text), we suggest extended anticoagulant therapy over 3 months of therapy (Grade 2B); or (iii) high bleeding risk (see text), we suggest 3 months of anticoagulant therapy over extended therapy (no scheduled stop date) (Grade 2B).
  • In patients with DVT of the leg or PE and active cancer (“cancer-associated thrombosis”) and who (i) do not have a high bleeding risk, we recommend extended anticoagulant therapy (no scheduled stop date) over 3 months of therapy (Grade 1B), and (ii) have a high bleeding risk, we suggest extended anticoagulant therapy (no scheduled stop date) over 3 months of therapy (Grade 2B).
  • In patients with an unprovoked proximal DVT or PE who are stopping anticoagulant therapy and do not have a contraindication to aspirin, we suggest aspirin over no aspirin to prevent recurrent VTE (Grade 2B).

ESC Guidelines on the diagnosis and management of acute pulmonary embolism (2014, adapted):[3]

  • For patients with PE secondary to a transient (reversible) risk factor, oral anticoagulation is recommended for 3 months (class I, level B).
  • For patients with unprovoked PE, oral anticoagulation is recommended for at least 3 months (class I, level A).
  • Extended oral anticoagulation should be considered for patients with a first episode of unprovoked PE and low bleeding risk (class IIa, level B).
  • Anticoagulation treatment of indefinite duration is recommended for patients with a second episode of unprovoked PE (class I, level B).
  • Alternatives to a VKA for patients who need extended anticoagulation (class IIa, level B):
    • Rivaroxaban 20 mg daily
    • Dabigatran 150 mg BID (or 110 mg BID for patients ≥80 years of age or taking concomitant verapimil)
    • Apixaban 2.5 mg BID
  • In patients who receive extended anticoagulation, the risk-benefit ratio of continuing such treatment should be reassessed at regular intervals (class I, level C).
  • In patients who refuse to take or are unable to tolerate any form of oral anticoagulants, aspirin may be considered for extended secondary VTE prophylaxis (class IIb, level B).
  • For patients with PE and cancer, LMWH should be considered for the first 3-6 months (class IIa, level B).
  • For patients with PE and cancer, extended anticoagulation should be considered for an indefinite period or until the cancer is cured (class IIa, level C).

Design

  • Multicenter, prospective, randomized, double-blind, placebo-controlled trial
  • N=2,482
    • Apixaban 2.5mg (n=840)
    • Apixaban 5mg (n=813)
    • Placebo (n=829)
  • Setting: 328 centers in 28 countries
  • Enrollment: 2008-2011
  • Follow-up: 1 year
  • Analysis: Intention-to-treat
  • Primary clinical outcome: Recurrent VTE or all-cause mortality
  • Primary safety outcome: Major bleeding

Population

Inclusion Criteria

  • ≥18 years with objective confirmation of VTE (DVT or PE)
  • Treated for 6-12 months with apixaban, enoxaparin, or warfarin
  • No symptomatic recurrence while on initial AC therapy
  • Clinical equipoise for continuation or cessation of AC therapy

Exclusion Criteria

  • Contraindication to continued anticoagulation
  • Requirement for continued anticoagulation
  • Dual antiplatelet therapy
  • Aspirin >165 mg PO daily
  • Hgb <9 mg/dL
  • Platelets <100,000/mm3
  • Creatinine clearance < 25 mL/min
  • ALT or AST >2x ULN
  • Bilirubin > 1.5x ULN

Baseline Characteristics

From the apixaban 2.5 mg group.

  • Mean age: 57 years
  • Male: 58%
  • Weight: 86kg
  • CrCl:
    • ≤30 mL/min: 0.1%
    • >30-≤50 mL/min: 5.6%
    • >50-≤80 mL/min: 20.7%
    • >80 mL/min: 70.8%
  • VTE type: DVT 64.8%, PE 35.2%, provoked 93.2%
    • ≥1 risk factor: 6.7%
      • Cancer: 1.8%
      • Immobilization: 2.3%
      • Previous VTE: 11.8%
      • Prothrombotic genotype: 3.8%
  • Antiplatelet agents: 14.3%
  • Duration of prior anticoagulation:
    • <6 months: 0.2%
    • 6-12 months: 98.6%
    • >12 months: 1.2%

Interventions

  • Randomization to twice daily apixaban 2.5 mg, apixaban 5 mg, or placebo with stratification by DVT/PE and participation in AMPLIFY trial within ~7 days of completion of AC
  • For those on warfarin, therapy was not started until the INR was ≤2

Outcomes

Results presented as apixaban 2.5 mg vs. apixaban 5 mg vs. placebo. P values were not presented for most outcomes in the article. The different doses of apixaban did not differ for the following outcomes.

Primary Outcomes

Recurrent VTE or all-cause mortality
3.8% vs. 4.2% vs. 11.6%
Apixaban 2.5 mg vs. placebo: RR 0.33; 95% CI 0.22-0.48; NNT=13
Apixaban 5 mg vs. placebo: RR 0.36; 95% CI 0.25-0.53; NNT=14
Major bleeding
Defined as overt bleeding with drop in hgb ≥2 g/dL, requiring transfusion of ≥2 units pRBC, bleeding in a "critical site," or bleeding mortality.
0.2% vs. 0.1% vs. 0.5%
Apixaban 2.5 mg vs. placebo: RR 0.49; 95% CI 0.09-2.64
Apixaban 5 mg vs. placebo: RR 0.25; 95% CI 0.03-2.24

Secondary Outcomes

Recurrent VTE or VTE mortality
1.7% vs. 1.7% vs. 8.8%
Apixaban 2.5 mg vs. placebo: RR 0.19; 95% CI 0.11-0.33; NNT=15
Apixaban 5 mg vs. placebo: RR 0.20; 95% CI 0.11-0.34; NNT=15
Non-VTE CV mortality, MI, or CVA
0.5% vs. 0.6% vs 1.3%
Apixaban 2.5 mg vs. placebo: RR 0.36; 95% CI 0.11-1.12
Apixaban 5 mg vs. placebo: RR 0.47; 95% CI 0.16-1.33
Recurrent VTE, VTE mortality, MI, CVA, CV mortality
2.1% vs. 2.3% vs. 10.0%
Apixaban 2.5 mg vs. placebo: RR 0.21; 95% CI 0.13-0.35
Apixaban 5 mg vs. placebo: RR 0.23; 95% CI 0.14-0.38
Clinically-relevant non-major bleeding
3.0% vs. 4.2% vs. 2.3%
Apixaban 2.5 mg vs. placebo: RR 1.29; 95% CI 0.72-2.33
Apixaban 5 mg vs. placebo: RR 1.82; 95% CI 1.05-3.18; NNH=53
Major or clinically-relevant non-major bleeding
3.2% vs. 4.3% vs. 2.7%
Apixaban 2.5 mg vs. placebo: RR 1.20; 95% CI 0.69-2.10
Apixaban 5 mg vs. placebo: RR 1.62; 95% CI 0.96-2.73
VTE, VTE mortality, MI, CVA, CV mortality, or major bleeding
2.4% vs. 2.5% vs. 10.4%
Apixaban 2.5 mg vs. placebo: RR 0.23; 95% CI 0.14-0.37; NNT=13
Apixaban 5 mg vs. placebo: RR 0.24; 95% CI 0.15-0.38; NNT=13

Criticisms

The authors identify that few participants were older than 75 years, had weight below 60 kg, or had moderate to severe renal impairment

Funding

Bristol-Myers Squibb and Pfizer

Further Reading

  1. Prandoni P, et al. "The risk of recurrent venous thromboembolism after discontinuing anticoagulation in patients with acute proximal deep vein thrombosis or pulmonary embolism. A prospective cohort study in 1,626 patients." Haematologica (2007):92:199-205.
  2. Kearon C et al. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest 2016. 149:315-52.
  3. Konstantinides SV, et al. 2014 ESC guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J. 2014 Nov 14;35(43):3033-69.