Primary and secondary prevention with new oral anticoagulant drugs for stroke prevention in atrial fibrillation: indirect comparison analysis

BMJ 2012; 345 doi: (Published 5 November 2012)
Cite this as: BMJ 2012;345:e7097

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Parra’s comment that the primary prevention subgroup would be more variable between subgroups is incorrect. Our indirect comparison analysis was focused on the secondary prevention population, to minimize inter-trial heterogeneity and allow more homogenous populations for comparisons. The analysis in the primary prevention cohort was very much a secondary aim.

In trials of stroke prevention in atrial fibrillation, the principal efficacy endpoint is ‘stroke and systemic embolism’ (upon which the trial is powered) whilst the principal safety endpoint is usually ‘major bleeding’. The main observations from indirect comparisons should initially focus on these principal efficacy/safety endpoints. Other endpoints (even in the randomized trials) are secondary endpoints, and whilst our paper shows the indirect comparisons for most quoted endpoints (both primary and secondary), these should not be over-interpreted.

The bottom line is that the novel oral anticoagulants are a major advance in the provision of thromboprophylaxis in atrial fibrillation[1], and the latest European guidelines strongly advocates a clinical practice shift towards initial identification of ‘truly low risk’ patients who do not need any antithrombotic therapy, so all others with ≥1 risk factors can be offered effective stroke prevention, which is oral anticoagulation[2]. Aspirin is ineffective for stroke prevention in atrial fibrillation, and the risks of major bleeding are not significantly different between aspirin and warfarin, especially in the elderly[2].

‘Truly low risk’ patients are defined as those ‘age<65 and lone AF, or a CHA2DS2-VASc score=0’. The older CHADS2 score has many limitations[3,4], and is inadequate for identification of ‘low risk’, given that real life patients with CHADS2=0 can have a stroke risk that ranges from 0.8% to 3.2%/year, whilst a CHADS2=1 can have a stroke risk ranging from 1.9% to 8.2%/year[5]. Thus, anticoagulation decisions based on CHADS2 of 0-1 could expose many atrial fibrillation patients to devastating strokes.


1. Potpara TS, Lip GY, Apostolakis S. New anticoagulant treatments to protect against stroke in atrial fibrillation. Heart. 2012;98:1341-1347
2. Camm AJ, Lip GY, De Caterina R, Savelieva I, Atar D, Hohnloser SH, Hindricks G, Kirchhof P. 2012 focused update of the esc guidelines for the management of atrial fibrillation: An update of the 2010 esc guidelines for the management of atrial fibrillation--developed with the special contribution of the european heart rhythm association. Europace. 2012;14:1385-1413
3. Keogh C, Wallace E, Dillon C, Dimitrov BD, Fahey T. Validation of the chads2 clinical prediction rule to predict ischaemic stroke. A systematic review and meta-analysis. Thromb Haemost. 2011;106:528-538
4. Karthikeyan G, Eikelboom JW. The chads2 score for stroke risk stratification in atrial fibrillation--friend or foe? Thromb Haemost. 2010;104:45-48
5. Olesen JB, Torp-Pedersen C, Hansen ML, Lip GY. The value of the cha2ds2-vasc score for refining stroke risk stratification in patients with atrial fibrillation with a chads2 score 0-1: A nationwide cohort study. Thromb Haemost. 2012;107:1172-1179

Competing interests: None declared

Gregory YH Lip, Professor of Cardiovascular Medicine

Lars Hvilsted Rasmussen, Torben Bjerregaard Larsen, Tina Graungaard, Flemming Skjøth

University of Birmingham, City Hospita, Birmingham B18 7QH

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New anticoagulants are becoming available as alternatives to warfarin and the results of multi centre trials show varying degrees of benefit over warfarin. However the degree of benefit may not be as high for the new drugs in the UK where higher levels of anticoagulant control have been achieved than the in the international trials which show 55% – 64% time in therapeutic range (TTR) whereas 69% is the mean in one benchmarking exercise.
This involved 235,944 patients, 80% of the patients are in the UK and the median TTR was 71. The clinical and cost effectiveness of this and comparable soft ware was previously reported. ‘ The cost-effectiveness of computer-assisted anticoagulant dosage: results from the European Action on Anticoagulation (EAA) multicentre study. J Thromb Haemost. 2009 Sep;7(9):1482-90. Epub 2009 Jun 8’.

The higher levels of TTR in routine clinical practice as demonstrated should be taken into account when considering the possible benefits of novel anticoagulants in comparison to warfarin.

Competing interests: None declared

Eric J Watts, Hon. Consulting Haematologist

Basildon Hospital, 11 Parkway, Brentwood , Essex, CM15 8LH

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To the Editor,

I have read with interests the indirect comparison analysis by Rasmussen et al. I believe that the conclusion about primary prevention can not be drawn from the analysis.

Although the authors discuss the limitations and clearly state that these results are hypothesis generating, in the ‘What this study adds section’ we read: “for primary prevention, the three drugs showed some differences in relation to efficacy and bleeding”.

First: If there is important heterogeneity between the populations of the trials and the reason for focus on the secondary prevention subgroups is to allowing more homogeneity, the logic consequence is that the complementary subgroups (primary prevention) are even more heterogeneous than the whole trial populations. Comparisons between those subgroups are seriously biased.

Second: If 57 tests have been performed in each subgroup, the probability that some of them show statistical significance only by chance is quite high.

Competing interests: None declared

Javier Garjon Parra, Primary Care Pharmacist

Servicio Navarro de Salud-Osasunbidea, Plaza de la Paz s/n. 31002 Pamplona (Spain)

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I read with interest the recent article entitled ‘Primary and secondary prevention with new oral anticoagulant drugs for stroke prevention in atrial fibrillation: indirect comparison analysis’ by Rasmussen LH et al.

The incidence and prevalence of atrial fibrillation are quickly increasing, mainly due to the ageing of the population.[1] It is associated with an increased risk of stroke and therefore, the mainstays of treatment to date have been antiplatelet agents and vitamin K antagonists, depending on a risk stratification score such as the CHADS2 score. Warfarin, the most commonly used vitamin K antagonist brings with it many difficulties including multiple drug interactions, the need for frequent monitoring and variable pharmacokinetics. This has led to the search for newer, ‘more convenient’ to use agents. The oral direct thrombin inhibitor (dabigatran etexilate) and the oral factor Xa inhibitors (rivaroxa¬ban and apixaban) discussed in the article were meant to fulfil this role as they have been found to be safe and effective in reducing stroke risk in patients with atrial fibrillation compared with war¬farin. However they bring about their own problems which must be taken into account prior to their use.

A recent article by Lamori et al [2] outlined the health burden carried by patients with atrial fibrillation - 44.9% of the 1297 patients studied had scores of 1-2 and 20.5% had scores of 3 or higher on the Charlson Comorbidity Index. While this score was developed to give an estimate of 10 year survival for a patient, its use here demonstrates that when treating patients with atrial fibrillation, many factors must be taken into account when choosing the correct agent.

Commonly available laboratory tests in the form of the Prothrombin time (PT) and its derived measure the international normalized ratio (INR) are used not only to ensure that warfarin is therapeutic but also to monitor reversal in the emergency setting. But in the case of the new anticoagulants, while routine coagulation tests are altered, their alterations poorly reflect the circulating concentrations as determined by functional approaches. [3] The ecarin clotting time (ECT) and thrombin time (TT) are both sensitive to dabigatran etexilate but the standard TT is oversensitive. Thus, the main contenders for routine use appear to be either the ECT or a modified (e.g., ‘diluted’) TT. [4] Unfortunately, these are not yet routinely available in the clinical setting. Barrett YC et al reported that while the PT was affected by Xa inhibitor use, that anti-Xa activity was the better indicator of plasma concentrations. [5]

There are clear protocols in place for reversal of warfarin [6] and in addition to this there is a wealth of clinical experience in the management of warfarin related complications. This is not the case with the new oral anticoagulants and herein, lies the danger. There is some evidence that the Xa inhibitors can be reversed with prothrombin complex concentrate but this reversibility is not seen with direct thrombin inhibitors. [7]

While there is no doubt that the new oral anticoagulant drugs will play a role in primary and secondary prevention for stroke prevention in atrial fibrillation, mechanisms must be put in place to ensure that both those prescribing them and those who deal with their complications are well informed with regard to limitations in terms of monitoring and reversal.

1. Le Heuzey JY. Antithrombotic treatment of atrial fibrillation: New insights. Thromb Res. 2012 Oct;130 Suppl 1:S59-60.

2. Lamori JC, Mody SH, Gross HJ, Dacosta Dibonaventura M, Patel AA, Schein JR, Nelson WW. Burden of comorbidities among patients with atrial fibrillation. Ther Adv Cardiovasc Dis. 2012 Oct 22. [Epub ahead of print]
3.Freyburger G, Macouillard G, Labrouche S, Sztark F Coagulation parameters in patients receiving dabigatran etexilate or rivoroxiban Two observational studies in patients undergoing total hip or total knee replacement. Thrombosis Research 2011 May; 127(5): 457-465.
4. Favaloro EJ, Lippi G. The new oral anticoagulants and the future of haemostasis laboratory testing. Biochemia Medica 2012;22(3):329-41.
5. Barrett YC, Wang Z, Frost C, Shenker A. Clinical laboratory measurement of direct factor Xa inhibitors: Anti-Xa assay is preferable to prothrombin time assay Thromb Haemost. 2010 Dec;104(6):1263-71.
6. Warfarin reversal Hanley JP. J Clin Pathol. 2004 November; 57(11): 1132–1139.
7. Reversal of Rivaroxaban and Dabigatran by Prothrombin Complex Concentrate A Randomized, Placebo-Controlled, Crossover Study in Healthy Subjects. Eerenberg ES, Kamphuisen PW, Sijpkens MK, Meijers JC, Buller HR, Levi M. Circulation. 2011; 124: 1573-1579

Competing interests: None declared

Maeve P Crowley, Haematology Specialist Registrar

Cork University Hospital, Wilton, Cork, Ireland

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