Oral anticoagulants for prevention of stroke in atrial fibrillation: systematic review, network meta-analysis, and cost effectiveness analysis

Dear Editors,

ARISTOTLE was a large, randomised controlled Phase 3 trial comparing the direct-acting oral anticoagulant, apixaban, with warfarin in >18,000 patients with atrial fibrillation (Lopes et al 2010). The results showed that apixaban was superior to warfarin in preventing stroke or systemic embolism, caused less bleeding and resulted in lower mortality (Granger et al 2011).

Since publication of the primary manuscript (Granger et al 2011) over 30 secondary manuscripts have been published on the ARISTOTLE study (PubMed search, 18 Mar 2019). Data from the full data set of ARISTOTLE have also been included in 22 meta-analyses (Garmendia et al 2019).

However, the FDA has identified that ARISTOTLE included some falsified data (Seife 2015) and this is an important consideration for subsequent research that relies on these data.

A subsequent analysis conducted recently by Garmendia et al (2019) concluded that among the 22 meta-analyses that included ARISTOTLE data, exclusion of these data would change the results in almost half of cases (10/22; 46%) and the conclusions would change for 21 of the 99 analyses conducted (32%). Of the 32 affected estimates 31 (97%) no longer favoured apixaban for the prevention of serious medical issues, and 1 (3%) favoured the control.

One of these meta-analyses, published in 2017 (Lopez-Lopez et al 2017), was carried out to evaluate the comparative clinical effectiveness and cost-effectiveness of different oral anticoagulants using a network meta-analysis (NMA) in a UK setting. The analysis included 23 studies of >93,000 patients; amongst these, ARISTOTLE was the largest, and thus in a fixed effect network meta-analyses, ARISTOTLE will receive the most weight. Based on the results, the authors concluded that ‘Despite a similar mechanism of action, apixaban at the right dose appears to maximise efficacy and safety among the DOACs, with favourable cost effectiveness.’ Additionally, the authors concluded that apixaban 5mg twice daily was ranked highest for most outcomes. In light of the falsified data reported in ARTISTOTLE, the results of this analysis could have the potential to mislead policy makers, commissioners and treating physicians.

The network geometry in the Lopez-Lopez NMA provides some insights into the central importance of the ARISOTLE study for estimates of the relative clinical effectiveness for apixaban. For example, with regard to the primary outcome of Stroke and Systemic embolism, apixaban 5mg is connected to the network via a direct treatment comparison with warfarin INR 2-3. If ARISTOTLE were removed from the network, indirect treatment comparisons between apixaban 5mg and all other interventions would be informed by a direct treatment comparison between apixaban 5mg and warfarin INR 2-3 which, in the absence of ARISTOTLE, is obtained from a small Phase 2 three-arm trial (n=222, Ogawa et al 2011) in a Japanese patient population with few events (#events=3); and thus, uncertainty in the point estimate for apixaban relative to all other interventions is likely to increase, potentially impacting on the ranking of treatment outcomes. If the falsified data in ARISTOTLE systematically leads to an under or over reporting of the observed effects in ARISTOTLE, then the relative effects of apixaban could also change.

We encourage Lopez-Lopez et al. to acknowledge the data falsification reports associated with the ARISTOTLE trial and suggest caution with respect to interpreting NMA outcomes that rely heavily on the results of this study. In the absence of appropriate caution, policy and treatment decisions may be made that are not supported by the evidence.

References
1. Garmendia CA, Nassar Gorra L, Rodriguez AL, et al. Evaluation of the Inclusion of Studies Identified by the FDA as Having Falsified Data in the Results of Meta-analyses: The Example of the Apixaban Trials. JAMA Intern Med. 2019 Mar 4. doi: 10.1001/jamainternmed.2018.7661. [Epub ahead of print]
2. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011 Sep 15;365(11):981-92.
3. Lopes RD, Alexander JH, Al-Khatib SM, et al. Apixaban for reduction in stroke and other ThromboemboLic events in atrial fibrillation (ARISTOTLE) trial: design and rationale. Am Heart J. 2010 Mar;159(3):331-9.
4. López-López JA, Sterne JAC, Thom HHZ, et al. Oral anticoagulants for prevention of stroke in atrial fibrillation: systematic review, network meta-analysis, and cost effectiveness analysis. BMJ. 2017 Nov 28;359:j5058. doi: 10.1136/bmj.j5058.
5. Ogawa S, Shinohara Y, and Kanmuri K. Safety and Efficacy of the Oral Direct Factor Xa Inhibitor Apixaban in Japanese Patients With Non-Valvular Atrial Fibrillation – The ARISTOTLE-J Study. Circ J 2011; 75: 1852–1859.
6. Seife C. Research misconduct identified by the US Food and Drug Administration: out of sight, out of mind, out of the peer-reviewed literature. JAMA Intern Med. 2015 Apr;175(4):567-77.