Apixaban Dosing to Optimize Protection From Thrombosis - ADOPT

Nov 13, 2011
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Author/Summarized by Author:
Dharam J. Kumbhani, MD, SM, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
Bristol-Myers Squibb and Pfizer
Date Presented:
01/01/2011
Date Published:
01/01/2011
Date Updated:
11/13/2011
Original Posted Date:
11/13/2011
References

Description:

It is unclear if extended venous thromboembolism (VTE) prophylaxis is beneficial in acutely ill patients. The current trial sought to study the safety and efficacy of extended use of apixaban as compared with short-term use of enoxaparin in these patients.

Hypothesis:

  • Apixaban for 30 days would be superior to in-hospital treatment with enoxaparin in patients with acute medical illness for VTE prophlaxis.
  • Apixaban would be noninferior to enoxaparin for the duration of parenteral treatment.
  • Apixaban would be superior to enoxaparin for the duration of parenteral treatment.

    These three hypotheses would be sequentially tested.

Study Design

  • Placebo Controlled
  • Randomized
  • Blinded
  • Parallel

Patient Populations:

  • Hospitalized with congestive heart failure or acute respiratory failure
  • Infection, acute rheumatic disorder, or inflammatory bowel disease, plus at least one of the following VTE risk factors:
    • Age ≥75 years, prior VTE, BMI ≥30, estrogen therapy
    • Mobility restricted to walking in room

      Duration of follow-up: 90 days
      Mean patient age: 66.8 years
      Percentage female: 51%
      NYHA class: II (7%), III (26%), IV (12%)

Exclusions:

  • Confirmed VTE
  • Requires anticoagulation
  • Dual antiplatelet therapy, or aspirin ≥165 mg/day
  • Hemoglobin <9 g/dl, platelet count ≤100,000/cm3
  • Creatinine clearance ≤30 ml/min
  • Alanine aminotransferase ≥2x upper limit of normal or direct/total bilirubin >1.5 mg/dl
  • Active or high risk of bleeding
  • Active liver disease
  • Allergy to enoxaparin or heparin
  • VTE prophylaxis within 14 days
  • Planned or scheduled invasive procedures during treatment period

Primary Endpoints:

  • Composite of total VTE/VTE-related death
    • Fatal PE or sudden death where PE cannot be excluded as a cause
    • Nonfatal PE
    • Symptomatic DVT
    • Asymptomatic proximal DVT (ultrasound)

  • Major bleeding

Secondary Endpoints:

  • Total VTE/VTE-related death during the parenteral period
  • Symptomatic DVT/nonfatal PE at 60 days
  • All-cause mortality at 30 days
  • All-cause mortality at 90 days
  • Clinically relevant nonmajor bleeding

Drug/Procedures Used:

Patients admitted with an acute medical illness were randomized in a double-dummy fashion to either 2.5 mg oral apixaban or 40 mg subcutaneous enoxaparin for the duration of hospitalization (minimum of 6 days).

Concomitant Medications:

Estrogen hormone therapy (1%)

Principal Findings:

A total of 6,528 patients were enrolled at 302 centers in 35 countries, 3,255 to apixaban and 3,273 to enoxaparin. Baseline characteristics were similar between the two arms. The mean duration of exposure to apixaban was 24.9 days, and to enoxaparin was 7.3 days. About 44% of the patients were obese (body mass index [BMI] ≥30%). The underlying medical conditions were congestive heart failure (39%), active cancer (3%), acute infectious diseases without septic shock (22%), and acute respiratory insufficiency (37%). About 4% of patients had a history of prior VTE, and 6% had a remote history of cancer. About 27% of patients were severely restricted (confined to bed or chair at the bedside).

The primary efficacy endpoint of total VTE/VTE-related death was similar between the apixaban and enoxaparin arms (2.71% vs. 3.05%, hazard ratio [HR] 0.87, 95% confidence interval [CI] 0.62-1.23, p = 0.44). Similarly, the secondary endpoints of total VTE/VTE-related death during the parenteral-treatment period (1.73% vs. 1.61%), total VTE/VTE-related death in the post-parenteral period (0.92% vs. 1.55%), and post-parenteral symptomatic VTE/VTE-related death (0.25% vs. 0.56%) were similar between the two arms. All individual endpoints such as pulmonary embolism (PE) and deep-vein thrombosis (DVT) were also similar between the two arms.

Major bleeding, as defined by the trial investigators, was significantly higher in the apixaban arm (0.47% vs. 0.19%, HR 2.58, 95% CI 1.02-7.24, p = 0.04). The combination of major and clinically relevant nonmajor bleeding was elevated, but not statistically significant (2.67% vs. 2.08%, p = 0.12). The increase in bleeding was driven mainly by a decrease in hemoglobin ≥2 g/dl over a 24-hour period; rates of intracranial bleeding were similar. Bleeding rates were higher with apixaban both during the parenteral and post-parenteral periods.

Interpretation:

The results of this trial indicate that extended duration of VTE prophylaxis with oral apixaban is not superior to in-hospital subcutaneous enoxaparin in patients admitted with acute medical illness and is associated with an increased risk of bleeding. This trial required a day-10 ultrasound, which may have picked up incidental DVTs, and thus biased the results toward the null.

The recently presented MAGELLAN trial had a similar study design, wherein outcomes were compared between rivaroxaban (for 35 ± 4 days) and enoxaparin (for 10 ± 4 days). In that trial, rivaroxaban was noninferior to enoxaparin for reduction in VTE-related outcomes at 10 days, and superior at 35 days, mainly due to a reduction in asymptomatic DVTs. This trial had also noted an increased risk of bleeding with rivaroxaban as compared with enoxaparin.

Both apixaban and rivaroxaban are oral anti-Xa agents, and have been studied for thromboprophylaxis in postoperative patients and stroke prevention in patients with AF. Further studies will need to identify if there are high-risk acutely ill patients who would benefit with the use of these agents for VTE prophylaxis, without concomitantly increasing their risk of bleeding.

References:

Goldhaber SZ, Leizorovicz A, Kakkar AK, et al., on behalf of the ADOPT Trial Investigators. Apixaban versus enoxaparin for thromboprophylaxis in medically ill patients. N Engl J Med 2011;Nov 13:[Epub ahead of print].

Presented by Dr. Samuel Goldhaber at the American Heart Association Scientific Sessions, Orlando, FL, November 13, 2011.

Keywords: Shock, Septic, Stroke, Neoplasms, Morpholines, Inflammatory Bowel Diseases, Pulmonary Embolism, Venous Thromboembolism, Respiratory Insufficiency, Pyrazoles, Walking, Hemoglobins, Body Mass Index, Enoxaparin, Estrogens, Heart Failure, Venous Thrombosis, Pyridones


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