AMPLIFY

From Wiki Journal Club
Jump to: navigation, search
Agnelli G, et al. "Oral apixaban for the treatment of acute venous thromboembolism". The New England Journal of Medicine. 2013. 369(9):799-808.
PubMedFull textPDF

Clinical Question

Among patients with acute VTE, is apixaban non-inferior to conventional therapy with LMWH and vitamin K antagonists for symptomatic VTE recurrence, VTE mortality, or rates of bleeding?

Bottom Line

Apixaban is noninferior to LMWH and vitamin K antagonist-based therapy for VTE recurrence and VTE mortality. Apixiban therapy has a greater reduction in rates of bleeding.

Major Points

The conventional treatment of VTE includes a heparin derivative (eg, UFH or LMWH) usually followed by a vitamin K antagonist (VKA; eg, warfarin). The new oral anticoagulants have promise as an alternative regimen for treatment of VTE as they do not require injections or frequent laboratory monitoring. RE-COVER (2009; dabigatran), EINSTEIN-DVT (2010; rivaroxaban),[1], EINSTEIN-PE (2012; rivaroxaban), and Hokusai-VTE (2013; edoxaban)[2] demonstrated noninferiority to standard therapy with an acceptable bleeding profile. The efficacy of apixaban, a factor Xa inhibitor like rivaroxaban, had not yet been demonstrated in a large trial.

The 2013 Apixaban for the Initial Management of Pulmonary Embolism and Deep-Vein Thrombosis as First-Line Therapy (AMPLIFY) trial randomized 5,395 adults with an acute proximal DVT (65%) or PE (35%) to apixaban or conventional therapy. At six months, apixaban was noninferior to conventional therapy in terms of recurrent symptomatic VTE or VTE death (P<0.001 for noninferiority). Apixaban was associated with less major bleeding compared to conventional therapy (0.6% vs. 1.8%; P<0.001 for superiority; NNT 100) and the composite outcome of major bleeding or clinically-relevant non-major bleeding (4.3% vs. 9.7%; P<0.001 for superiority; NNT 19).

Apixaban was FDA approved for the treatment of acute VTE in August 2014.[3] This was based in part on the results of AMPLIFY. The FDA also granted approval for apixaban after acute VTE treatment, to prevent recurrent VTE. This was based on the results of the follow-up AMPLIFY-EXT (2013). AMPLIFY-EXT compared ongoing apixaban to placebo after acute VTE treatment, and demonstrated that apixaban reduces the rate of recurrent VTE without increasing the rates of major bleeding.

Guidelines

CHEST Antithrombotic Therapy for VTE Disease (2016, adapted): [4]

  • In patients with proximal DVT or pulmonary embolism (PE), recommended long-term (3 months) anticoagulant therapy over no such therapy (Grade 1B).
    • For patients with DVT of the leg or PE and no cancer who are not treated with dabigatran, rivaroxaban, apixaban, or edoxaban, VKA therapy is recommended over low-molecular weight heparin (LMWH) (Grade 2C)
  • 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).

ESC Guidelines on the diagnosis and management of acute pulmonary embolism (2014, adapted):[5]

  • LMWH or fondaparinux is the recommended form of acute phase parenteral anticoagulation for most patients (class I, level A).
  • In parallel to parenteral anticoagulation, treatment with a VKA is recommended, targeting an INR of 2-3 (class I, level B).
  • As an alternative to the combination of parenteral anticoagulation with a VKA, one of the following methods of anticoagulation are recommended (class I, level B):
    • Rivaroxaban 15 mg BID for 3 weeks, then 20 mg daily
    • Apixaban 10 mg BID for 7 days, then 5 mg twice daily
    • Dabigatran 150 mg BID (with dose adjustments for some patients)
    • Edoxaban (after acute phase parenteral anticoagulation)
  • New oral anticoagulants are not recommended in patients with severe renal impairment (class III, level A).

Design

  • Prospective, randomized, double-blind trial
  • N=5,395
    • Apixaban (n=2,691)
    • Conventional therapy (n=2,704)
  • Setting: 358 centers in 28 countries
  • Enrolment: 2008-2012
  • Follow-up: 6 months
  • Analysis: Intention-to-treat
  • Primary outcomes:
    • Recurrent symptomatic VTE or VTE mortality
    • Major bleeding
    • Major bleeding or clinically-relevant non-major bleeding

Population

Inclusion Criteria

  • Age ≥18 years with symptomatic VTE, either DVT proximal to popliteal vein or PE with or without any DVT
  • Confirmation of VTE on imaging
  • Unprovoked or provoked with a low risk of recurrence

Exclusion Criteria

  • Women of childbearing age without appropriate contraception unless otherwise unable to become pregnant
  • Pregnancy or breastfeeding
  • <6 months of anticoagulation as the plan of care
  • Thrombecomy, IVC filter, or fibrinolytic for this event
  • Bleeding or high risk for bleeding
  • Cancer requiring >6 months of LMWH therapy
  • Contraindications to LMWH or warfarin (including HIT or allergic reaction)
  • Other long-term anticoagulation requirement because of mechanical valve, AF, or a. flutter unless AF is thought to be a consequence of the acute VTE
  • "Clinically significant" liver disease
  • Life expectancy <6 months
  • Bacterial endocarditis
  • Uncontrolled HTN
  • Platelets <100,000/mm3, hgb <9 g/dL, creatinine >2.5 mg/dL, CrCl <25 mL/min, ALT or AST >2x ULN, T. bili >1.5x ULN unless Gilbert's or similar syndrome
  • Treatment with a potent inhibitor of CYP3A4
  • LMWH treatment for >2 doses if daily, >3 doses if q12h, or >36 hours of UFH infusion
  • >2 doses of oral VKA therapy
  • Prior treatment with apixaban in a clinical trial
  • Requiring ASA >165 mg/day or dual antiplatelet therapy
  • Any other study medication in the prior 30 days
  • Any other disease or situation that "would preclude compliance"

Baseline Characteristics

From the apixaban group.

  • Demographics: Age 57.2 years, male 58.3%
  • Baseline health data: weight 84.6 kg,
  • CrCl:
    • ≤30 mL/min: 0.5%
    • >30-50 mL/min: 6.0%
    • >50-80 mL/min: 20.4%
    • >80 mL/min: 64.0%
  • Qualifying event: DVT 65.0%, PE 25.2%, both 9.4%
    • Clinical impression: Provoked 10.1%, unprovoked 89.8%
    • Risk factors: Prior VTE 17.2%, history of thrombophilia 2.8%, cancer 2.5%
    • DVT diagnostic modality: US 99.0%, ascending contrast venography 1.1%, CT 0.1%
      • Most proximal extension of DVT: Popleal vein 24.4%, femoral vein 32.6%, common femoral or iliac 43.1%
    • PE diagnostic modality: CT 87.1%, V/Q scan 11.7%, pulmonary angiography 2.3%
      • Extent of PE: limited 8.5%, intermediate 42.2%, extensive 38.4%
  • Time from symptom onset until randomizwo ation: 5.0 days
  • Treatment with LMWH, heparin, or fondaparinux before randomization:
    • None: 13.3%
    • ≤12 hours: 13.8%
    • >12-24 hours: 41.5%
    • >24-36 hours: 21.8%
    • >36-48 hours: 8.6%
    • >48 hours: 0.8%

Interventions

  • Randomization to a group:
    • Apixaban - Apixaban 10 mg PO bid for 7 days then 5 mg po BID along with placebo LMWH and warfarin (a sham INR result was given to simulate routine adjustments)
    • Conventional therapy - Enoxaparin 1 mg/kg q12h for ≥5 days then warfarin adjusted to an INR of 2-3
  • Both groups treated for 6 months

Outcomes

Presented as apixaban vs. conventional therapy. RR means relative risk. Statistics only given when provided by authors.

Primary Outcome

Recurrent symptomatic VTE or VTE mortality
2.3% vs. 2.7% (RR 0.84; 95% HR 0.60-1.18; P<0.001 for non-inferiority)
Major bleeding

Defined as hgb drop ≥2 g/dL, requiring ≥2 units pRBC transfusion, bleeding in a critical site, or contributing to death.

0.6% vs. 1.8% (RR 0.31; 95% CI 0.17-0.55; P<0.001 for superiority; NNT 100)
Major bleeding or clinically-relevant non-major bleeding

Clinically-relevant non-major bleeding defined as overt bleeding not meeting criteria for major bleeding but associated with a medical intervention, contact with a physician, interruption of a study drug, or pain or impairment in carrying out ADLs.

4.3% vs. 9.7% (RR 0.44; 95% CI 0.36-0.55; P<0.001 for superiority; NNT 19)

Secondary Outcomes

All-cause mortality
1.5% vs. 1.9% (RR 0.79; 95% CI 0.53-1.19)
PE or "PE not ruled out": 0.4% vs. 0.6%
CV: 0.1% vs. 0.3%
Bleeding: 0.1% vs. 0.1%
Cancer: 0.5% vs. 0.5%
Infection: 0.3% vs. 0.3%
Other: <0.1% vs. 0.2%
VTE or CV mortality
2.3% vs. 2.9% (RR 0.80; 95% CI 0.57-1.11; P=0.18)
VTE or all-cause mortality
3.2% vs. 3.9% (RR 0.82; 95% 0.61-1.08; P=0.16)
VTE, VTE mortality, or major bleeding
2.8% vs. 4.5% (RR 0.62; 95% CI 0.47-0.83; P=0.001 for superiority; NNT 59)

Additional Analyses

Duration of enoxaparin bridge in conventional treatment group
6.5 days
Time that INR was in therapeutic range in conventional treatment group
61%
Therapy adherence in apixaban group
>80% in 96% of patients

Adverse Events

Any during treatment
67.1% vs. 71.5%
Serious: 15.6% vs. 15.2%
Any bleeding: 15.5% vs. 25.8%
Resulting in discontinuation of intervention: 6.1% vs. 7.4%

Criticisms

  • Unclear if these outcomes would remain unchanged in patients with cancer, underweight, or creatinine clearance <50 mL/min
  • No analysis based upon geographic location

Funding

Pfizer and Bristol-Myers Squibb, manufacturers of Eliquis, the brand name of apixaban.

Further Reading

  1. Bauersachs R, et al. "Oral rivaroxaban for symptomatic venous thromboembolism." The New England Journal of Medicine. 2010;363(26):2499-2510.
  2. HR, et al. "Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism." The New England Journal of Medicine. 2013;369(10):1406-1415.
  3. FDA Supplement Approval. August 21, 2014.
  4. Kearon C, et al. "Antithrombotic therapy for VTE Disease: Chest Guideline and Expert Panel Report." Chest. 2016;149(2):315-352.
  5. 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.