Apixaban (trade name Eliquis) has been approved since July 2014 for acute treatment of adults with deep vein thrombosis or pulmonary embolism. In addition, the drug can be used for low-dose long-term treatment to prevent recurrent thrombosis or pulmonary embolism. The German Institute for Quality and Efficiency in Health Care (IQWiG) examined in a dossier assessment whether in these cases the drug offers patients an added benefit over the appropriate comparator therapies.
According to the findings, considerable added benefit of apixaban is proven for the initial treatment of patients with a body mass index (BMI) of over 28 kg/m². In contrast, an added benefit versus the appropriate comparator therapy is neither proven for initial treatment of patients with lower BMI, nor for long-term prevention - irrespective of the BMI.
Third dossier assessment because of new therapeutic indication
Apixaban is an anticoagulant, a type of drug that prevents blood-clotting. After the dossier assessments on apixaban in hip replacement (2012) and atrial fibrillation (2013), and following another expansion of approval, the Institute now investigated which advantages and disadvantages the drug has in comparison with the appropriate comparator therapy in the therapeutic indications "deep vein thrombosis" and "pulmonary embolism". In vein thrombosis, a blood clot blocks a vein, usually in the lower leg or thigh. A blood clot that travels to the lungs, however, can cause life-threatening pulmonary embolism.
The Federal Joint Committee (G-BA) posed two research questions and accordingly specified two appropriate comparator therapies: As initial treatment, apixaban (10 mg twice daily for 7 days, then 5 mg twice daily) was to be compared with a vitamin K antagonist, which, until it unfolds its full effect, was to be supplemented with a heparin in the beginning of the treatment. As long-term prevention, i.e. to prevent recurrent deep vein thrombosis or pulmonary embolism, low-dose apixaban (2.5 mg twice daily) was to be compared with a vitamin K Antagonist.
Only one study on one research question
The dossier submitted by the drug manufacturer contained no data on the second research question, however. Hence the added benefit of apixaban in long-term prevention is not proven. For the first research question, initial treatment after occurrence of pulmonary embolism or deep vein thrombosis, the manufacturer presented data from a single randomized controlled trial: In the AMPLIFY study, apixaban was administered for six months. In the comparator arm, enoxaparin was used as low molecular weight heparin, and warfarin as vitamin K antagonist.
Effect modifier BMI
For some patient-relevant outcomes, there was no proof of an advantage or disadvantage of apixaban versus the comparator therapy: In mortality and treatment discontinuations due to adverse events, there were no statistically significant differences between the study arms. Health-related quality of life was not investigated in the study.
For the outcome "symptomatic non-fatal deep vein thrombosis", the data suggested effect modification by the characteristic "BMI": Whereas there is a hint of an added benefit of apixaban in patients with a BMI of over 28 kg/m², an added benefit of the drug is not proven in patients with lower BMI. The BMI also modified the effect in the outcome "symptomatic non-fatal pulmonary embolism": In patients with a BMI of up to 28 kg/m², there is an indication of lesser benefit of apixaban in comparison with enoxaparin and warfarin; in a BMI of 28 kg/m² or higher, there is no difference.
Fewer bleeding events
Irrespective of the BMI, treatment with apixaban had advantages with respect to two side effect outcomes: In major bleeding, there was an indication of lesser harm. In the clinically relevant non-major bleeding events, the results were considered to be so robust that even proof of lesser harm from apixaban than from enoxaparin and warfarin could be derived although there was only one study.
Overall, in the initial treatment of deep vein thrombosis and pulmonary embolism, considerable added benefit of apixaban versus the appropriate comparator therapy is therefore proven for patients with a BMI of over 28 kg/m². For the initial treatment of patients with a BMI of up to 28 kg/m², in contrast, an added benefit is not proven. For long-term prevention, an added benefit of apixaban is also not proven.
G-BA decides on the extent of added benefit
The dossier assessment is part of the overall procedure for early benefit assessments according to the Act on the Reform of the Market for Medicinal Products (AMNOG) supervised by the G-BA. After publication of the manufacturer's dossier and IQWiG's assessment, the G-BA conducts a commenting procedure, which may provide further information and result in a change to the benefit assessment. The G-BA then decides on the extent of the added benefit, thus completing the early benefit assessment.
An overview of the results of IQWiG's benefit assessment is given by a German-language executive summary. In addition, the website » http://www.
The G-BA website contains both general English-language information on benefit assessment pursuant to §35a Social Code Book V and specific German-language information on the assessment of apixaban. More English-language information will be available soon (Sections 2.1 to 2.6 of the dossier assessment as well as subsequently published health information on » http://www.
If you would like to be informed when these documents are available, please send an e-mail to » firstname.lastname@example.org.