Accepted Manuscript Net clinical benefit of non-vitamin K antagonist oral anticoagulants versus warfarin in phase III atrial fibrillation trials Giulia Renda, MD, PhD, Marta di Nicola, PhD, Raffaele De Caterina, MD, PhD PII:
S0002-9343(15)00356-3
DOI:
10.1016/j.amjmed.2015.03.034
Reference:
AJM 12961
To appear in:
The American Journal of Medicine
Received Date: 10 March 2015 Revised Date:
18 March 2015
Accepted Date: 19 March 2015
Please cite this article as: Renda G, di Nicola M, De Caterina R, Net clinical benefit of non-vitamin K antagonist oral anticoagulants versus warfarin in phase III atrial fibrillation trials, The American Journal of Medicine (2015), doi: 10.1016/j.amjmed.2015.03.034. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Renda G. et al., Net clinical benefit of NOACs vs warfarin, page 1
ACCEPTED MANUSCRIPT
Net clinical benefit of non-vitamin K antagonist oral anticoagulants versus warfarin in phase III atrial fibrillation trials Running head: Net clinical benefit of NOACs vs warfarin Giulia Renda1, MD, PhD, Marta di Nicola2, PhD, and Raffaele De Caterina1-3, MD, PhD Institute of Cardiology, Department of Neurosciences, Imaging and Clinical Sciences, 2Laboratory of Biostatistics, Department of Experimental and Clinical Sciences – Center of Excellence on Aging, “G. d’Annunzio” University, Chieti; 3“G. Monasterio” Foundation, Pisa, Italy
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Word count 3626 (excluding: abstract, tables, references, legends)
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1
Raffaele De Caterina, MD, PhD Institute of Cardiology “G. d’Annunzio” University – Chieti C/o Ospedale SS. Annunziata
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Via dei Vestini - 66013 Chieti, Italy
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Correspondence (reprints will not be available from the authors):
Tel. +39-0871-41512 - FAX: +39-0871-402817 - E-mail: [email protected] Funding related to the manuscript: None
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Conflicts of interest: Giulia Renda declares consultant and speaker fees from Boehringer-Ingelheim, Daiichi-Sankyo and Bayer. Marta Di Nicola declares no relationship with industry. Raffaele De Caterina received consultant and speaker fees from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Daiichi Sankyo, Novartis and Merck; and research grants from Boehringer-Ingelheim. Authorship responsibility: All authors had access to the data and had a role in writing the manuscript: - Giulia Renda designed the research, acquired the data, drafted the manuscript - Marta Di Nicola designed the research, acquired the data, performed statistical analysis - Raffaele De Caterina conceived and designed the research, and made critical revision of the manuscript for key intellectual content Keywords: atrial fibrillation; oral anticoagulants; thromboembolic risk; hemorrhagic risk; net clinical benefit.
Renda G. et al., Net clinical benefit of NOACs vs warfarin, page 2
ACCEPTED MANUSCRIPT ABSTRACT
Aims: The evaluation of the “net clinical benefit” allows an integrated assessment of both the antiischemic and the pro-hemorrhagic effects of non-vitamin K antagonist oral anticoagulants (NOACs)
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compared with warfarin, and—in the absence of direct comparisons—may inform clinical decisions. We estimated the net clinical benefit of NOACs vs warfarin across the 4 phase III clinical trials performed in atrial fibrillation.
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Methods and Results: We considered various composites of the main ischemic and hemorrhagic
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events, estimating the rate ratio (RR) of all treatment groups vs warfarin for each composite outcome. Since however the clinical relevance of the various ischemic or hemorrhagic events is not identical, we then attributed to each of them a weight, according to its impact on death, as derived from previous studies. We thus evaluated a weighed net clinical benefit of each NOAC compared with warfarin in the 4 trials.
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The composite outcome of ischemic+hemorrhagic stroke was reduced by dabigatran 150 mg and apixaban. The composite of disabling stroke+life-threatening bleeding was reduced by all NOACs. The composite of ischemic stroke+systemic embolism+myocardial infarction+hemorrhagic
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stroke+major bleeding was reduced by apixaban and edoxaban at both doses. By attributing weights
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to these events according to their impact on mortality, all NOACs featured a favorable net clinical benefit compared with warfarin, albeit to a quantitatively different extent. Conclusions: The choice of the proper antithrombotic treatment in atrial fibrillation has to consider the net clinical benefit of each drug.All NOACs however have a better compounded efficacy/safety profile than warfarin in patients with atrial fibrillation.
Keywords: atrial fibrillation; oral anticoagulants; thromboembolic risk; hemorrhagic risk; net clinical benefit.
Renda G. et al., Net clinical benefit of NOACs vs warfarin, page 3
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Clinical relevance - Highlights • We evaluated the net clinical benefit for various NOACs in phase III clinical trials
to their prognostic impact on mortality
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comparing them to warfarin, by weighing non-fatal efficacy and safety outcomes according
• NOACs have been associated with variable efficacy and safety relative to VKAs, but all have a better and strikingly similar compounded net clinical benefit in patients with atrial
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fibrillation.
Renda G. et al., Net clinical benefit of NOACs vs warfarin, page 4
ACCEPTED MANUSCRIPT INTRODUCTION
Non-vitamin K antagonists oral anticoagulants (NOACs) 1, including the direct thrombin inhibitor dabigatran etexilate and the direct Factor Xa inhibitors rivaroxaban, apixaban and edoxaban, have
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emerged as an alternative to vitamin K antagonists (VKAs) for thromboembolic prevention in patients with non-valvular atrial fibrillation. These agents have all been compared with warfarin, the most commonly used VKA, in major phase III clinical trials2-5. Individually taken, they are all non-
.
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7
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inferior to warfarin as to safety and efficacy and all significantly reduced intracranial hemorrhage 6,
All anticoagulants affect hemostatic function, and therefore their benefit must be balanced against risks. In patients with atrial fibrillation, the possible favorable change (reduction) of ischemic stroke, systemic embolism and myocardial infarction has to be balanced against an increased risk in hemorrhagic events, including the ominous intracranial bleeding. Indeed, current guidelines for the
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management of antithrombotic therapy in atrial fibrillation recommend both thromboembolic and hemorrhagic risk stratification
8, 9
. However the clinical relevance of outcome events—either
averted or caused—is not equivalent, because such events differ in severity, may differently cause
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disabilities, and may differently impact mortality. As an example, a hemorrhagic stroke induced by
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an anticoagulant is more likely to cause disability and death than an ischemic stroke averted. A previous analysis 10 from the ACTIVE-W trial, a large trial examining the effect of clopidogrel plus aspirin vs VKAs for the prevention of thromboembolism in atrial fibrillation
11
, suggested the
possibility and the importance of weighing the severity of events differentially occurring with different antithrombotic treatments using their variable prognostic effect on mortality as a way to adjust for the different severity nonfatal event. The modern concept of “weighed net clinical benefit” has been therefore introduced to evaluate the overall comparative benefits of different antithrombotic treatments, integrating information on anti-ischemic and pro-hemorrhagic effects.
Renda G. et al., Net clinical benefit of NOACs vs warfarin, page 5
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On this basis, we assessed the net clinical benefit of various dose regimens of NOACs as compared with warfarin in the 4 warfarin-controlled trials so far performed in non-valvular atrial fibrillation. Such analyses—in the absence of direct comparisons of the different NOACs—may inform choices
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of drugs and drug regimens in the individual patient.
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METHODS
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Overall strategy for the analysis
In the current report we estimated the net clinical benefit of all NOACs compared with warfarin in phase III clinical trials in non-valvular atrial fibrillation, namely the RE-LY, ROCKET AF, ARISTOTLE an ENGAGE AF-TIMI 48 studies
2-5
. For the RE-LY trial we used the latest
to the primary publication 2-5.
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published data update 12, containing several primary efficacy and safety outcome events in addition
We first used the simple algebraic summation of ischemic and hemorrhagic events, alone or with
and the RE-LY
14
cohorts to gather a reliable estimate of the weighed net clinical benefit,
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13
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added either cardiovascular or total mortality. We then used the approach applied in the ACTIVE A
calculating the NNT in each arm of warfarin comparison of the 4 major warfarin-controlled phase III trials of NOACs in atrial fibrillation, as detailed below.
Renda G. et al., Net clinical benefit of NOACs vs warfarin, page 6
ACCEPTED MANUSCRIPT Evaluation of composite outcomes
We first considered unweighed different composites of main events: 1) ischemic stroke and hemorrhagic stroke; 2) disabling stroke and life-threatening bleeding; 3) ischemic stroke, systemic
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embolism, myocardial infarction, hemorrhagic stroke, and adjusted major bleeding (defined as major bleeding minus hemorrhagic stroke; see below). As a second analysis, each of these composites of events was also combined with cardiovascular mortality and all-cause mortality. The
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definition of each event was done according to what reported in the original description of the trial
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design and rationale 15-18.
The frequency of ischemic stroke and “unknown” or “uncertain” stroke was reported jointly in all trials with the exception of the ROCKET-AF, where “unknown” stroke was reported separately 5; therefore, to uniform the data, we added the frequency of unknown strokes to that of ischemic stroke throughout the collection of original data.
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On the other hand, the frequency of disabling stroke was reported separately only in the ROCKET AF trial 5, while in the other trials reports included the frequency of disabling plus fatal stroke together
2-4
. Since we conducted the unweighed analysis both alone and combined with
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cardiovascular mortality or all-cause mortality, we included only disabling strokes in the analysis
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(without fatal strokes), in order to avoid counting the same fatal events twice. Therefore, to obtain the frequency of disabling stroke in each such trial, we subtracted the frequency of fatal stroke from the composite of disabling plus fatal stroke. Since the frequency of fatal stroke was not reported in the original RE-LY trial report 2, this was acquired from the Advisory Committee Briefing Document of dabigatran published by U.S. Food and Drug Administration (FDA) 19. In order to avert the multiple counting of the same events in the analysis, we defined “adjusted major bleeding” as the number of major bleeding minus the number of hemorrhagic stroke.
Renda G. et al., Net clinical benefit of NOACs vs warfarin, page 7
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Concerning life-threatening bleeding, such definition was given in the RE-LY ENGAGE AF-TIMI 48
3, 18
2, 16
and the
trials, but not in the other 2 trials; thus, for the ARISTOTLE4, 17 and
ROCKET-AF 5, 15 trials we used data reported under the heading of “GUSTO severe bleeding” and “critical bleeding” respectively, because these coincided with life-threatening bleeding in terms of
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clinical relevance. To determine the frequency of an event not explicitly reported in a trial, we calculated this as the event rate divided by the median duration of the follow-up for each treatment arm of the trial.
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For each of the 3 composite outcomes, alone and combined with cardiovascular mortality or all-
of all treatment groups vs warfarin.
20
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cause mortality, we estimated the rate ratio (RR) and the relative confidence intervals (95% CI)
Calculation of the weighed net clinical benefit
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We evaluated the weighed net clinical benefit of each NOAC compared with warfarin in the four trials, considering ischemic stroke, systemic embolism, myocardial infarction, hemorrhagic stroke and adjusted major bleeding as a composite event. We evaluated the crude incidence rate (IR) per
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100 patient-years of each weighed event for patients receiving a NOAC (one or two doses) and for
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those receiving warfarin. The net clinical benefit was defined as the weighed sum of those IR in the warfarin groups minus the weighed sum of events in the NOAC groups:
Net clinical benefit = [IRischemic stroke_warfarin + w1IRsystemic embolism_warfarin + w2IRmyocardial infarction_warfarin + w3IRhemorrhagic embolism_NOAC +
stroke_warfarin
+ w4IRadjusted
major bleeding_warfarin]
– [IRischemic
stroke_NOAC
+ w1IRsystemic
w2IRmyocardial infarction_NOAC + w3IRhemorrhagic stroke_NOAC + w4IRadjusted major bleeding_NOAC],
Renda G. et al., Net clinical benefit of NOACs vs warfarin, page 8
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where w1, w2, w3, and w4 are the weights associated with systemic embolism, myocardial infarction, hemorrhagic stroke, and adjusted major bleeding, respectively. Since we did not known the mortality associated with each event considered during the four trials, we could not calculate the weights of these events in the specific trial populations. Therefore, we assumed that the impact of
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each event on mortality is similar in the four trial populations, and used the weights calculated in a recent analysis of net clinical benefit evaluating the combined data from the ACTIVE and RE-LY trial databases
21
. Weights were therefore 0.61 for systemic embolism, 0.89 for myocardial
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infarction, 3.23 for hemorrhagic stroke, and 0.63 for adjusted major bleeding (this latter, in practice:
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major extracranial bleeding). These weights were expressed in terms of ischemic stroke equivalents prevented per 100 persons year, using ischemic stroke as the reference event for each event (weight = 1).
Finally, we estimated the number of patients needed to treat (NNT) to prevent all grouped events included in the net clinical benefit calculation per year. The NNT was thus calculated as 1/ net
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clinical benefit for all NOACs.
All analyses were performed with the open-source statistical R software (version 3.0.0; The R Foundation for Statistical Computing) 22.
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To assess the effect of weight variations on the stability of the results, we also conducted a
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sensitivity analysis with increased and decreased weights by 25% and 50% of their original values.
RESULTS
The study design and baseline characteristics of patients enrolled in the trials considered are shown in Table 1.
Renda G. et al., Net clinical benefit of NOACs vs warfarin, page 9
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Composite outcomes
We first analyzed the composite outcomes of main thrombotic and bleeding events in terms of RR
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of all treatment arms vs warfarin. When considering the composite of ischemic stroke + hemorrhagic stroke, we found that dabigatran 150 and apixaban significantly reduced this composite outcome (Table 2), and such reduction was evident also when the composite included
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cardiovascular mortality or all-cause mortality (OS Table 1). Rivaroxaban and edoxaban 60
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reduced only the composite outcome of ischemic stroke + hemorrhagic stroke + cardiovascular /allcause mortality (Table 2 and OS Table 1). Dabigatran 110 and edoxaban 30 had no effect on this composite (Table 2 and OS Table 1).
The composite outcome of disabling stroke + life-threatening bleeding, alone or combined with cardiovascular or all-cause mortality, was reduced by all NOACs (Table 2 and OS Table 1).
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The overall composite outcome of ischemic stroke + systemic embolism + myocardial infarction + hemorrhagic stroke + adjusted major bleeding was reduced by apixaban and edoxaban at both doses (Table 2 and Figure 1). The same composite, in combination with cardiovascular mortality and all-
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cause mortality, was reduced also by apixaban, by edoxaban at both doses, and by dabigatran 150
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(OS Table 1 and OS Figure 1).
Weighed net clinical benefit
We evaluated the weighed net clinical benefit of the 4 NOACs compared with warfarin by a weighed estimate of a composite of ischemic stroke + systemic embolism + myocardial infarction + hemorrhagic stroke + adjusted major bleeding. Crude IR per 100 patient-years of each weighed
Renda G. et al., Net clinical benefit of NOACs vs warfarin, page 10
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event for all treatment groups is reported in Table 3. All NOACs featured a directionally favorable net clinical benefit compared with warfarin in terms of reduction of ischemic stroke equivalents and the related NNT to prevent all grouped events included in net clinical benefit per year, with some quantitative differences between the NOACs (Figure 2).
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Sensitivity analysis using weights increased and decreased by 25% and 50% compared with those considered for the main analysis produced similar results, showing the same favorable profile of
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NOACs compared with warfarin (OS Table 2).
DISCUSSION
This analysis shows that all NOACs in non-valvular atrial fibrillation feature a favorable net clinical
comparison.
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benefit compared with warfarin, with some quantitative differences among them in the warfarin
The efficacy of antithrombotic drugs in avoiding ischemic events in various settings—including atrial fibrillation —can be partially or totally offset by the risk of adverse hemorrhagic events they
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confer, due to their impact on hemostasis. Therefore, the evaluation of the overall benefit of oral
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anticoagulants in the treatment of patients with atrial fibrillation needs to consider both the sides of the coin. There is however no unanimous definition of what exactly should be a net clinical benefit in atrial fibrillation trials with anticoagulation, and how to estimate it. A composite of ischemic and bleeding events has been often used as measure of net clinical benefit in phase III clinical trials comparing NOACs with warfarin. However, the exercise of adding up the number of ischemic and hemorrhagic events obtaining an overall outcome is not accurate, and can actually be misleading, due to the different clinical impact of different events in terms of mortality, disability, and costs. On this basis, attempts to “weigh” the relevance of each event have been conducted.
Renda G. et al., Net clinical benefit of NOACs vs warfarin, page 11
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A first quantitative, empirically based description of the weighed net clinical benefit of warfarin treatment for patients with atrial fibrillation was derived from the large ATRIA cohort: here net clinical benefit was defined as the annual rate of ischemic strokes and systemic embolism prevented by warfarin minus intracranial hemorrhages attributable to warfarin multiplied by an arbitrary
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weight of 1.5 23. This weight was chosen by giving a rough quantitative estimate to the observations that the outcome of an intracranial hemorrhage is generally worse than that of an ischemic stroke, with the weighing factor of 1.5 reflecting the impact on mortality of an intracranial hemorrhage
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while receiving warfarin versus experiencing an ischemic stroke while not receiving warfarin. A
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similar model has been more recently proposed to quantify the balance between the risk of ischemic stroke and the risk of intracranial hemorrhage with the use of NOACs (dabigatran, rivaroxaban and apixaban) from a Danish National Patient Registry on patients with atrial fibrillation, considering 1.5 the weight of an intracranial hemorrhage compared with an ischemic stroke, here assigned the normalized weight of 1 24.
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In an alternative approach, since ischemic stroke is a common primary endpoint of efficacy for antithrombotic treatments in atrial fibrillation, a weighed net clinical benefit has been expressed in units of ischemic stroke equivalents prevented, as the reference weight for each event, and made
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equal to 1. This approach was first used for patients enrolled in the ACTIVE-A trial
13
, who, as an
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entry criterion, were unsuitable for VKAs. The net clinical benefit of dual antiplatelet therapy in the ACTIVE A trial participants was defined as the weighed event incidence with dual antiplatelet therapy subtracted from the sum of weighed event incidence on control treatment, expressed as ischemic stroke equivalents prevented per 100 patient-years
14
. Based on the same model, a more
recent report explored the net clinical benefit of each dose of dabigatran and warfarin in the RE-LY trial 21. We have here applied the same criteria to assess and compare the net clinical benefit of all 4 NOACs so far tested in atrial fibrillation.
Renda G. et al., Net clinical benefit of NOACs vs warfarin, page 12
ACCEPTED MANUSCRIPT Composite outcomes
At a first analysis, we chose the main ischemic and hemorrhagic events evaluated in the 4 clinical trials designed to compare the efficacy and safety of NOACs vs warfarin, and we grouped these
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events in various composite outcomes: a composite of ischemic stroke + hemorrhagic stroke; a composite of disabling stroke + life-threatening bleeding; and an overall composite outcome of ischemic stroke + hemorrhagic stroke + myocardial infarction + systemic embolism + adjusted
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major bleeding. Cardiovascular mortality and all-cause mortality were also combined to all
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composite outcomes in a secondary analysis. This latter combinations of non-fatal events with cardiovascular mortality or total mortality (presented in the OS Table) is to be considered exploratory, as it may include non-mutually exclusive events. We calculated the RR of NOACs vs warfarin for each composite outcome.
these composite outcomes.
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Our findings indicate that apixaban always features a better efficacy than warfarin in reducing all
Dabigatran 150 in this analysis features a better efficacy than warfarin in reducing all the composite outcomes with the exception of the most comprehensive one of ischemic stroke, systemic
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embolism, myocardial infarction, hemorrhagic stroke, and adjusted major bleeding, probably
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because this regimen was associated, in the RE-LY trial, with a slightly higher number of myocardial infarctions and an equivalent number of major bleeding compared with warfarin. However, when combined with cardiovascular or all-cause mortality, the overall composite outcome was also reduced by dabigatran 150. Dabigatran 110 features better efficacy than warfarin only for the composite of disabling stroke + life-threatening bleeding, both alone and combined with cardiovascular or all-cause mortality, probably due to the good performance of this drug regimen on bleeding. However, it does not show
Renda G. et al., Net clinical benefit of NOACs vs warfarin, page 13
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advantages in reductions of the other outcomes, possibly due to the higher number of the combination of ischemic strokes and myocardial infarctions vs warfarin. Edoxaban 60 features better than warfarin in efficacy in reducing most of the outcomes, with the exception of the composite of ischemic + hemorrhagic strokes, probably driven by the similar
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number of ischemic strokes vs warfarin observed in the ENGAGE AF-TIMI48 trial, despite a reduction in hemorrhagic strokes. However, when combined with cardiovascular or all-cause mortality the ischemic stroke + hemorrhagic stroke outcome is also reduced by edoxaban 60.
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The lower dose regimen edoxaban 30 is also disadvantaged compared with warfarin in the
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composite of ischemic stroke + hemorrhagic stroke. Here again, however, when this composite is combined with cardiovascular and all-cause mortality, edoxaban 30 also performs better than warfarin. The other composite outcomes are all reduced by edoxaban 30, mainly in virtue of the lower risk of hemorrhagic events of this treatment compared with warfarin. Rivaroxaban features better efficacy than warfarin for the composite of disabling stroke + life-
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threatening bleeding, alone and combined with cardiovascular and all-cause mortality. On the other hand, rivaroxaban does not appear to be superior to warfarin in preventing the outcome of ischemic stroke + hemorrhagic stroke, probably due to the similar number of ischemic strokes observed in
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the ROCKET AF trial in the rivaroxaban and in the warfarin arms, but appears to perform better
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than warfarin when this outcome is combined with cardiovascular and all-cause mortality. Analyzing the overall composite outcome, rivaroxaban appears not to be better than warfarin, possibly because of the similar number of ischemic strokes and major bleeds, unless such an overall outcome is combined with all-cause mortality, favorably affected by rivaroxaban. Overall, our results broadly agree with those of the phase III clinical trials comparing NOACs with warfarin, where, ad exception of ROCKET AF trial, composite outcomes of ischemic and bleeding events have been often used as measure of net clinical benefit 2-4.
Renda G. et al., Net clinical benefit of NOACs vs warfarin, page 14
ACCEPTED MANUSCRIPT Weighed net clinical benefit
In the model of weighed net clinical benefit we present here, all NOACs appear to be associated with a significantly lower rate of the composite event of ischemic stroke equivalents—and a lower
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NNT—compared with warfarin. This means that all NOACs appear to be better than warfarin when we consider the overall balance between ischemic and hemorrhagic events and “correct” the impact of these events for subsequent mortality. The weighed analysis allows all NOACs to perform better
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than warfarin in terms of efficacy/safety balance probably because the estimated weight of a
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hemorrhagic stroke is about 3 times higher than the weight of ischemic stroke, and a substantial part of the advantage of NOACs vs warfarin relates to the prevention of intracranial hemorrhage. Since we could not calculate the weights of each event considered in the specific trial populations, we chose the weights from a recent analysis of net clinical benefit using the combined data from the ACTIVE A and the RE-LY trial databases
21
, in which all patients were treated either with an
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anticoagulant or with antiplatelet drugs. We specifically chose the weights estimated for anticoagulated patients, as this is the estimate more pertinent to the populations here examined. The weighing factor of 1.5 used for intracranial hemorrhage in ATRIA cohort
23
, reflecting the higher
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impact on mortality of an intracranial hemorrhage while receiving warfarin vs experiencing an
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ischemic stroke while not receiving warfarin, is not appropriate to the populations of all trials here analyzed, all receiving anticoagulation. However, since the selection of weights could affect analysis results, as recently discussed 25, we also performed a sensitivity analysis, by using weights increased and decreased by 25% and 50% compared with the main analysis. These analyses yielded similar results, confirming the robustness of our findings. Our analysis does not provide a statistical comparison of the various treatment arms in the different studies, which would be in any case problematic because of the different populations studied. However, some differences among NOACs cannot go unnoticed. Across the 4 trials here analyzed,
Renda G. et al., Net clinical benefit of NOACs vs warfarin, page 15
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apixaban apparently confers the highest risk reduction (the lowest NNT) for preventing the composite weighed outcome of ischemic stroke + systemic embolism + myocardial infarction + hemorrhagic stroke + adjusted major bleeding. Closest to apixaban is edoxaban 30, then followed by edoxaban 60, dabigatran 150, and finally dabigatran 110 and rivaroxaban. This goes qualitatively
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in the same direction as the results of the previous unweighed analyses, but achieves formal statistical significances for all NOACs at variance from the unweighed analysis. It is interesting to notice that the weighed net clinical benefit analysis yields edoxaban 30 (and not edoxaban 60) as
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the next most favorable composite evaluation after apixaban, which would revert the impression of edoxaban 30 as an unfavorable choice compared with warfarin if restricting the analysis to efficacy
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endpoints only 3, 18, highlighting the higher level of integrated information here obtained with such analyses.
Finally, the practical message from this analysis is that the choice of the antithrombotic drug in atrial fibrillation has to integrate the efficacy of each drug in terms of prevention of
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thromboembolic events and safety in terms of hemorrhagic complications, considering that bleeding
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Study limitations
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may also have an important impact on survival.
For our analysis, we have used only published data from the 4 phase III trials comparing NOACs with warfarin for the prevention of thromboembolism in non-valvular atrial fibrillation. We had no access to undisclosed information, thus this is not a patient-level analysis, but an analysis based on published data. We argue however that different approaches are not likely to change the main conclusions of our study. We arbitrarily chose some composites of ischemic and hemorrhagic events, which are however the most relevant ones in such trials. However, not all events were reported similarly across the 4 trials:
Renda G. et al., Net clinical benefit of NOACs vs warfarin, page 16
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in such cases, as described in Methods, we indirectly determined the number of events not overtly reported in the trials, and then calculated the event rates according to the median follow-up of each trial. Furthermore, since the definition of life-threatening bleeding was available only in the RE-LY and
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ENGAGE AF-TIMI 48 trials, we considered the most similar definitions for the two other trials, which were GUSTO severe bleeding for ARISTOTLE and critical bleeding for ROCKET-AF. Minor differences among the events included under each heading would not in any case
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substantially affect outcomes, robustness, and final messages of our analysis.
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Finally, for the determination of net clinical benefit, we could not directly calculate the weights of events in the specific trial populations, not knowing the rates of subsequent death associated with the event considered. Therefore, we used the weights from a recent analysis of net clinical benefit of the two doses of dabigatran in the RE-LY trial
21
, assuming that the impact of each event on
mortality were comparable in the 4 trial populations. This may affect the estimates, although most
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CONCLUSIONS
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likely not to any substantial extent.
The assessment of a weighed net clinical benefit according to the impact of ischemic and hemorrhagic events on subsequent mortality indicates that all NOACs have a better compounded efficacy/safety profile than warfarin in patients with atrial fibrillation. Among NOACs, apixaban and edoxaban 30 mg seem to confer the lowest risk of a composite outcome including ischemic stroke + systemic embolism + myocardial infarction + hemorrhagic stroke + adjusted major bleeding.
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ACKNOWLEDGMENTS
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None.
1.
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De Caterina R, Husted S, Wallentin L, Andreotti F, Arnesen H, Bachmann F, Baigent C, Huber K, Jespersen J, Kristensen SD, Lip GY, Morais J, Rasmussen LH, Siegbahn A, Verheugt FW, Weitz JI. New oral anticoagulants in atrial fibrillation and acute coronary syndromes: ESC Working Group on Thrombosis-Task Force on Anticoagulants in Heart Disease position paper. J Am Coll Cardiol
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randomised trials. Lancet 2014;383:955-62.
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safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of
Bax JJ, Baumgartner H, Ceconi C, Dean V, Deaton C, Fagard R, Funck-Brentano C, Hasdai D, Hoes A, Knuuti J, Kolh P, McDonagh T, Moulin C, Popescu BA, Reiner Z, Sechtem U, Sirnes PA, Tendera M, Torbicki A, Vahanian A, Windecker S, Vardas P, Al-Attar N, Alfieri O, Angelini A, Blomstrom-Lundqvist C, Colonna P, De Sutter J, Ernst S, Goette A, Gorenek B, Hatala R,
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Heidbuchel H, Heldal M, Kristensen SD, Le Heuzey JY, Mavrakis H, Mont L, Filardi PP, Ponikowski P, Prendergast B, Rutten FH, Schotten U, Van Gelder IC, Verheugt FW. 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC
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De Caterina R, Connolly SJ, Pogue J, Chrolavicius S, Budaj A, Morais J, Renda G, Yusuf S. Mortality predictors and effects of antithrombotic therapies in atrial fibrillation: insights from ACTIVE-W. Eur Heart J 2010;31:2133-40.
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ACCEPTED MANUSCRIPT 11.
Connolly S, Pogue J, Hart R, Pfeffer M, Hohnloser S, Chrolavicius S, Yusuf S. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Lancet 2006;367:1903-12. Connolly SJ, Ezekowitz MD, Yusuf S, Reilly PA, Wallentin L. Newly identified events in the RELY trial. N Engl J Med 2010;363:1875-6.
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clopidogrel added to aspirin in patients with atrial fibrillation. N Engl J Med 2009;360:2066-78. Connolly SJ, Eikelboom JW, Ng J, Hirsh J, Yusuf S, Pogue J, de Caterina R, Hohnloser S, Hart RG.
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Net clinical benefit of adding clopidogrel to aspirin therapy in patients with atrial fibrillation for whom vitamin K antagonists are unsuitable. Ann Intern Med 2011;155:579-86. 15.
Rivaroxaban-once daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation: rationale and design of the ROCKET AF study. Am Heart J 2010;159:340-7 e1.
Ezekowitz MD, Connolly S, Parekh A, Reilly PA, Varrone J, Wang S, Oldgren J, Themeles E,
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Wallentin L, Yusuf S. Rationale and design of RE-LY: randomized evaluation of long-term anticoagulant therapy, warfarin, compared with dabigatran. Am Heart J 2009;157:805-10, 10 e1-2. Lopes RD, Alexander JH, Al-Khatib SM, Ansell J, Diaz R, Easton JD, Gersh BJ, Granger CB,
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Hanna M, Horowitz J, Hylek EM, McMurray JJ, Verheugt FW, Wallentin L. Apixaban for reduction
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in stroke and other ThromboemboLic events in atrial fibrillation (ARISTOTLE) trial: design and rationale. Am Heart J 2010;159:331-9. 18.
Ruff CT, Giugliano RP, Antman EM, Crugnale SE, Bocanegra T, Mercuri M, Hanyok J, Patel I, Shi M, Salazar D, McCabe CH, Braunwald E. Evaluation of the novel factor Xa inhibitor edoxaban compared with warfarin in patients with atrial fibrillation: design and rationale for the Effective aNticoaGulation with factor xA next GEneration in Atrial Fibrillation-Thrombolysis In Myocardial Infarction study 48 (ENGAGE AF-TIMI 48). Am Heart J 2010;160:635-41.
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Boehringer Ingelheim Dabigatran Briefing Document: FDA 27 Aug 2010.
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ACCEPTED MANUSCRIPT 20.
Rothman K. Epidemiology: An Introduction. 2nd ed. Oxford: Oxford University press; 2012.
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Eikelboom JW, Connolly SJ, Hart RG, Wallentin L, Reilly P, Oldgren J, Yang S, Yusuf S. Balancing the benefits and risks of 2 doses of dabigatran compared with warfarin in atrial fibrillation. J Am Coll Cardiol 2013;62:900-8. R Development Core Team. R: A Language and Environment for Statistical Computing 2011.
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Singer DE, Chang Y, Fang MC, Borowsky LH, Pomernacki NK, Udaltsova N, Go AS. The net
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clinical benefit of warfarin anticoagulation in atrial fibrillation. Ann Intern Med 2009;151:297-305. Banerjee A, Lane DA, Torp-Pedersen C, Lip GY. Net clinical benefit of new oral anticoagulants
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(dabigatran, rivaroxaban, apixaban) versus no treatment in a 'real world' atrial fibrillation population:
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25.
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a modelling analysis based on a nationwide cohort study. Thromb Haemost 2012;107:584-9.
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ACCEPTED MANUSCRIPT LEGENDS TO FIGURES
Figure 1. Rate ratio (RR) and 95% confidence intervals (CI) of all treatment arms in the phase III
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trials comparing a NOAC with warfarin for the overall composite outcome including unweighed ischemic stroke + systemic embolism + myocardial infarction + hemorrhagic stroke + adjusted major bleeding (major bleeding minus hemorrhagic stroke).
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Figure 2. Net clinical benefit and 95% confidence intervals (CI) of all treatment arms of NOACs vs warfarin tested in phase III clinical trials for the weighed composite outcome of ischemic stroke +
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systemic embolism + myocardial infarction + hemorrhagic stroke + adjusted major bleeding (major bleeding minus hemorrhagic stroke). Net clinical benefit is expressed as ischemic stroke equivalents prevented per 100 person-years using ischemic stroke as the reference event (weight = 1). NNT= number needed to treat to prevent all grouped events included in the net clinical benefit evaluation,
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per year of treatment.
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Table 1. Study design and baseline patient characteristics in the trials examined in the present analysis
INR 2.0-3.0 150 mg BID 110 mg BID
6022 6076 6015
ROCKET-AF (3)
dose-adjusted warfarin rivaroxaban
INR 2.0-3.0 20 mg (or 15 mg*) OD
7090 7131
ARISTOTLE (4)
dose-adjusted warfarin apixaban
INR 2.0-3.0 5 mg (or 2.5 mg§) BID
ENGAGE AF-TIMI48 (5) dose-adjusted warfarin edoxaban 60 edoxaban 30
INR 2.0-3.0 60 mg (or 30 mg#) OD 30 mg (or 15 mg#) OD
Mean age (years)
2
9081 9120
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7036 7035 7034
Male gender (%)
Mean CHADS2
Median TTR (%)
71.6 71.5 71.4
63.3 63.2 64.3
2.1 2.2 2.1
67 n.a. n.a.
1.9
71.2 71.2
60.3 60.3
3.46 3.48
58 n.a.
1.8
64.5 69.1
65 64.4
2.1 2.1
66 n.a.
2.8
72 72 72
62.5 62.1 61.2
2.8 2.8 2.8
68 n.a. n.a.
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dose-adjusted warfarin dabigatran 150 dabigatran 110
RE-LY (2)
Median follow-up (years)
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Number of patients
Treatment arm
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Dose
Trial name
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*15 mg OD with CrCl 30-49 mL/min. §2.5 mg BID with ≥2 of the following criteria: age 80 years, body weight
S0002-9343(15)00356-3
DOI:
10.1016/j.amjmed.2015.03.034
Reference:
AJM 12961
To appear in:
The American Journal of Medicine
Received Date: 10 March 2015 Revised Date:
18 March 2015
Accepted Date: 19 March 2015
Please cite this article as: Renda G, di Nicola M, De Caterina R, Net clinical benefit of non-vitamin K antagonist oral anticoagulants versus warfarin in phase III atrial fibrillation trials, The American Journal of Medicine (2015), doi: 10.1016/j.amjmed.2015.03.034. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Renda G. et al., Net clinical benefit of NOACs vs warfarin, page 1
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Net clinical benefit of non-vitamin K antagonist oral anticoagulants versus warfarin in phase III atrial fibrillation trials Running head: Net clinical benefit of NOACs vs warfarin Giulia Renda1, MD, PhD, Marta di Nicola2, PhD, and Raffaele De Caterina1-3, MD, PhD Institute of Cardiology, Department of Neurosciences, Imaging and Clinical Sciences, 2Laboratory of Biostatistics, Department of Experimental and Clinical Sciences – Center of Excellence on Aging, “G. d’Annunzio” University, Chieti; 3“G. Monasterio” Foundation, Pisa, Italy
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Word count 3626 (excluding: abstract, tables, references, legends)
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1
Raffaele De Caterina, MD, PhD Institute of Cardiology “G. d’Annunzio” University – Chieti C/o Ospedale SS. Annunziata
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Via dei Vestini - 66013 Chieti, Italy
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Correspondence (reprints will not be available from the authors):
Tel. +39-0871-41512 - FAX: +39-0871-402817 - E-mail: [email protected] Funding related to the manuscript: None
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Conflicts of interest: Giulia Renda declares consultant and speaker fees from Boehringer-Ingelheim, Daiichi-Sankyo and Bayer. Marta Di Nicola declares no relationship with industry. Raffaele De Caterina received consultant and speaker fees from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Daiichi Sankyo, Novartis and Merck; and research grants from Boehringer-Ingelheim. Authorship responsibility: All authors had access to the data and had a role in writing the manuscript: - Giulia Renda designed the research, acquired the data, drafted the manuscript - Marta Di Nicola designed the research, acquired the data, performed statistical analysis - Raffaele De Caterina conceived and designed the research, and made critical revision of the manuscript for key intellectual content Keywords: atrial fibrillation; oral anticoagulants; thromboembolic risk; hemorrhagic risk; net clinical benefit.
Renda G. et al., Net clinical benefit of NOACs vs warfarin, page 2
ACCEPTED MANUSCRIPT ABSTRACT
Aims: The evaluation of the “net clinical benefit” allows an integrated assessment of both the antiischemic and the pro-hemorrhagic effects of non-vitamin K antagonist oral anticoagulants (NOACs)
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compared with warfarin, and—in the absence of direct comparisons—may inform clinical decisions. We estimated the net clinical benefit of NOACs vs warfarin across the 4 phase III clinical trials performed in atrial fibrillation.
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Methods and Results: We considered various composites of the main ischemic and hemorrhagic
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events, estimating the rate ratio (RR) of all treatment groups vs warfarin for each composite outcome. Since however the clinical relevance of the various ischemic or hemorrhagic events is not identical, we then attributed to each of them a weight, according to its impact on death, as derived from previous studies. We thus evaluated a weighed net clinical benefit of each NOAC compared with warfarin in the 4 trials.
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The composite outcome of ischemic+hemorrhagic stroke was reduced by dabigatran 150 mg and apixaban. The composite of disabling stroke+life-threatening bleeding was reduced by all NOACs. The composite of ischemic stroke+systemic embolism+myocardial infarction+hemorrhagic
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stroke+major bleeding was reduced by apixaban and edoxaban at both doses. By attributing weights
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to these events according to their impact on mortality, all NOACs featured a favorable net clinical benefit compared with warfarin, albeit to a quantitatively different extent. Conclusions: The choice of the proper antithrombotic treatment in atrial fibrillation has to consider the net clinical benefit of each drug.All NOACs however have a better compounded efficacy/safety profile than warfarin in patients with atrial fibrillation.
Keywords: atrial fibrillation; oral anticoagulants; thromboembolic risk; hemorrhagic risk; net clinical benefit.
Renda G. et al., Net clinical benefit of NOACs vs warfarin, page 3
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Clinical relevance - Highlights • We evaluated the net clinical benefit for various NOACs in phase III clinical trials
to their prognostic impact on mortality
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comparing them to warfarin, by weighing non-fatal efficacy and safety outcomes according
• NOACs have been associated with variable efficacy and safety relative to VKAs, but all have a better and strikingly similar compounded net clinical benefit in patients with atrial
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fibrillation.
Renda G. et al., Net clinical benefit of NOACs vs warfarin, page 4
ACCEPTED MANUSCRIPT INTRODUCTION
Non-vitamin K antagonists oral anticoagulants (NOACs) 1, including the direct thrombin inhibitor dabigatran etexilate and the direct Factor Xa inhibitors rivaroxaban, apixaban and edoxaban, have
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emerged as an alternative to vitamin K antagonists (VKAs) for thromboembolic prevention in patients with non-valvular atrial fibrillation. These agents have all been compared with warfarin, the most commonly used VKA, in major phase III clinical trials2-5. Individually taken, they are all non-
.
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7
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inferior to warfarin as to safety and efficacy and all significantly reduced intracranial hemorrhage 6,
All anticoagulants affect hemostatic function, and therefore their benefit must be balanced against risks. In patients with atrial fibrillation, the possible favorable change (reduction) of ischemic stroke, systemic embolism and myocardial infarction has to be balanced against an increased risk in hemorrhagic events, including the ominous intracranial bleeding. Indeed, current guidelines for the
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management of antithrombotic therapy in atrial fibrillation recommend both thromboembolic and hemorrhagic risk stratification
8, 9
. However the clinical relevance of outcome events—either
averted or caused—is not equivalent, because such events differ in severity, may differently cause
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disabilities, and may differently impact mortality. As an example, a hemorrhagic stroke induced by
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an anticoagulant is more likely to cause disability and death than an ischemic stroke averted. A previous analysis 10 from the ACTIVE-W trial, a large trial examining the effect of clopidogrel plus aspirin vs VKAs for the prevention of thromboembolism in atrial fibrillation
11
, suggested the
possibility and the importance of weighing the severity of events differentially occurring with different antithrombotic treatments using their variable prognostic effect on mortality as a way to adjust for the different severity nonfatal event. The modern concept of “weighed net clinical benefit” has been therefore introduced to evaluate the overall comparative benefits of different antithrombotic treatments, integrating information on anti-ischemic and pro-hemorrhagic effects.
Renda G. et al., Net clinical benefit of NOACs vs warfarin, page 5
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On this basis, we assessed the net clinical benefit of various dose regimens of NOACs as compared with warfarin in the 4 warfarin-controlled trials so far performed in non-valvular atrial fibrillation. Such analyses—in the absence of direct comparisons of the different NOACs—may inform choices
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of drugs and drug regimens in the individual patient.
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METHODS
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Overall strategy for the analysis
In the current report we estimated the net clinical benefit of all NOACs compared with warfarin in phase III clinical trials in non-valvular atrial fibrillation, namely the RE-LY, ROCKET AF, ARISTOTLE an ENGAGE AF-TIMI 48 studies
2-5
. For the RE-LY trial we used the latest
to the primary publication 2-5.
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published data update 12, containing several primary efficacy and safety outcome events in addition
We first used the simple algebraic summation of ischemic and hemorrhagic events, alone or with
and the RE-LY
14
cohorts to gather a reliable estimate of the weighed net clinical benefit,
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13
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added either cardiovascular or total mortality. We then used the approach applied in the ACTIVE A
calculating the NNT in each arm of warfarin comparison of the 4 major warfarin-controlled phase III trials of NOACs in atrial fibrillation, as detailed below.
Renda G. et al., Net clinical benefit of NOACs vs warfarin, page 6
ACCEPTED MANUSCRIPT Evaluation of composite outcomes
We first considered unweighed different composites of main events: 1) ischemic stroke and hemorrhagic stroke; 2) disabling stroke and life-threatening bleeding; 3) ischemic stroke, systemic
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embolism, myocardial infarction, hemorrhagic stroke, and adjusted major bleeding (defined as major bleeding minus hemorrhagic stroke; see below). As a second analysis, each of these composites of events was also combined with cardiovascular mortality and all-cause mortality. The
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definition of each event was done according to what reported in the original description of the trial
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design and rationale 15-18.
The frequency of ischemic stroke and “unknown” or “uncertain” stroke was reported jointly in all trials with the exception of the ROCKET-AF, where “unknown” stroke was reported separately 5; therefore, to uniform the data, we added the frequency of unknown strokes to that of ischemic stroke throughout the collection of original data.
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On the other hand, the frequency of disabling stroke was reported separately only in the ROCKET AF trial 5, while in the other trials reports included the frequency of disabling plus fatal stroke together
2-4
. Since we conducted the unweighed analysis both alone and combined with
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cardiovascular mortality or all-cause mortality, we included only disabling strokes in the analysis
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(without fatal strokes), in order to avoid counting the same fatal events twice. Therefore, to obtain the frequency of disabling stroke in each such trial, we subtracted the frequency of fatal stroke from the composite of disabling plus fatal stroke. Since the frequency of fatal stroke was not reported in the original RE-LY trial report 2, this was acquired from the Advisory Committee Briefing Document of dabigatran published by U.S. Food and Drug Administration (FDA) 19. In order to avert the multiple counting of the same events in the analysis, we defined “adjusted major bleeding” as the number of major bleeding minus the number of hemorrhagic stroke.
Renda G. et al., Net clinical benefit of NOACs vs warfarin, page 7
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Concerning life-threatening bleeding, such definition was given in the RE-LY ENGAGE AF-TIMI 48
3, 18
2, 16
and the
trials, but not in the other 2 trials; thus, for the ARISTOTLE4, 17 and
ROCKET-AF 5, 15 trials we used data reported under the heading of “GUSTO severe bleeding” and “critical bleeding” respectively, because these coincided with life-threatening bleeding in terms of
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clinical relevance. To determine the frequency of an event not explicitly reported in a trial, we calculated this as the event rate divided by the median duration of the follow-up for each treatment arm of the trial.
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For each of the 3 composite outcomes, alone and combined with cardiovascular mortality or all-
of all treatment groups vs warfarin.
20
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cause mortality, we estimated the rate ratio (RR) and the relative confidence intervals (95% CI)
Calculation of the weighed net clinical benefit
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We evaluated the weighed net clinical benefit of each NOAC compared with warfarin in the four trials, considering ischemic stroke, systemic embolism, myocardial infarction, hemorrhagic stroke and adjusted major bleeding as a composite event. We evaluated the crude incidence rate (IR) per
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100 patient-years of each weighed event for patients receiving a NOAC (one or two doses) and for
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those receiving warfarin. The net clinical benefit was defined as the weighed sum of those IR in the warfarin groups minus the weighed sum of events in the NOAC groups:
Net clinical benefit = [IRischemic stroke_warfarin + w1IRsystemic embolism_warfarin + w2IRmyocardial infarction_warfarin + w3IRhemorrhagic embolism_NOAC +
stroke_warfarin
+ w4IRadjusted
major bleeding_warfarin]
– [IRischemic
stroke_NOAC
+ w1IRsystemic
w2IRmyocardial infarction_NOAC + w3IRhemorrhagic stroke_NOAC + w4IRadjusted major bleeding_NOAC],
Renda G. et al., Net clinical benefit of NOACs vs warfarin, page 8
ACCEPTED MANUSCRIPT
where w1, w2, w3, and w4 are the weights associated with systemic embolism, myocardial infarction, hemorrhagic stroke, and adjusted major bleeding, respectively. Since we did not known the mortality associated with each event considered during the four trials, we could not calculate the weights of these events in the specific trial populations. Therefore, we assumed that the impact of
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each event on mortality is similar in the four trial populations, and used the weights calculated in a recent analysis of net clinical benefit evaluating the combined data from the ACTIVE and RE-LY trial databases
21
. Weights were therefore 0.61 for systemic embolism, 0.89 for myocardial
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infarction, 3.23 for hemorrhagic stroke, and 0.63 for adjusted major bleeding (this latter, in practice:
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major extracranial bleeding). These weights were expressed in terms of ischemic stroke equivalents prevented per 100 persons year, using ischemic stroke as the reference event for each event (weight = 1).
Finally, we estimated the number of patients needed to treat (NNT) to prevent all grouped events included in the net clinical benefit calculation per year. The NNT was thus calculated as 1/ net
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clinical benefit for all NOACs.
All analyses were performed with the open-source statistical R software (version 3.0.0; The R Foundation for Statistical Computing) 22.
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To assess the effect of weight variations on the stability of the results, we also conducted a
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sensitivity analysis with increased and decreased weights by 25% and 50% of their original values.
RESULTS
The study design and baseline characteristics of patients enrolled in the trials considered are shown in Table 1.
Renda G. et al., Net clinical benefit of NOACs vs warfarin, page 9
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Composite outcomes
We first analyzed the composite outcomes of main thrombotic and bleeding events in terms of RR
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of all treatment arms vs warfarin. When considering the composite of ischemic stroke + hemorrhagic stroke, we found that dabigatran 150 and apixaban significantly reduced this composite outcome (Table 2), and such reduction was evident also when the composite included
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cardiovascular mortality or all-cause mortality (OS Table 1). Rivaroxaban and edoxaban 60
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reduced only the composite outcome of ischemic stroke + hemorrhagic stroke + cardiovascular /allcause mortality (Table 2 and OS Table 1). Dabigatran 110 and edoxaban 30 had no effect on this composite (Table 2 and OS Table 1).
The composite outcome of disabling stroke + life-threatening bleeding, alone or combined with cardiovascular or all-cause mortality, was reduced by all NOACs (Table 2 and OS Table 1).
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The overall composite outcome of ischemic stroke + systemic embolism + myocardial infarction + hemorrhagic stroke + adjusted major bleeding was reduced by apixaban and edoxaban at both doses (Table 2 and Figure 1). The same composite, in combination with cardiovascular mortality and all-
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cause mortality, was reduced also by apixaban, by edoxaban at both doses, and by dabigatran 150
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(OS Table 1 and OS Figure 1).
Weighed net clinical benefit
We evaluated the weighed net clinical benefit of the 4 NOACs compared with warfarin by a weighed estimate of a composite of ischemic stroke + systemic embolism + myocardial infarction + hemorrhagic stroke + adjusted major bleeding. Crude IR per 100 patient-years of each weighed
Renda G. et al., Net clinical benefit of NOACs vs warfarin, page 10
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event for all treatment groups is reported in Table 3. All NOACs featured a directionally favorable net clinical benefit compared with warfarin in terms of reduction of ischemic stroke equivalents and the related NNT to prevent all grouped events included in net clinical benefit per year, with some quantitative differences between the NOACs (Figure 2).
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Sensitivity analysis using weights increased and decreased by 25% and 50% compared with those considered for the main analysis produced similar results, showing the same favorable profile of
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NOACs compared with warfarin (OS Table 2).
DISCUSSION
This analysis shows that all NOACs in non-valvular atrial fibrillation feature a favorable net clinical
comparison.
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benefit compared with warfarin, with some quantitative differences among them in the warfarin
The efficacy of antithrombotic drugs in avoiding ischemic events in various settings—including atrial fibrillation —can be partially or totally offset by the risk of adverse hemorrhagic events they
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confer, due to their impact on hemostasis. Therefore, the evaluation of the overall benefit of oral
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anticoagulants in the treatment of patients with atrial fibrillation needs to consider both the sides of the coin. There is however no unanimous definition of what exactly should be a net clinical benefit in atrial fibrillation trials with anticoagulation, and how to estimate it. A composite of ischemic and bleeding events has been often used as measure of net clinical benefit in phase III clinical trials comparing NOACs with warfarin. However, the exercise of adding up the number of ischemic and hemorrhagic events obtaining an overall outcome is not accurate, and can actually be misleading, due to the different clinical impact of different events in terms of mortality, disability, and costs. On this basis, attempts to “weigh” the relevance of each event have been conducted.
Renda G. et al., Net clinical benefit of NOACs vs warfarin, page 11
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A first quantitative, empirically based description of the weighed net clinical benefit of warfarin treatment for patients with atrial fibrillation was derived from the large ATRIA cohort: here net clinical benefit was defined as the annual rate of ischemic strokes and systemic embolism prevented by warfarin minus intracranial hemorrhages attributable to warfarin multiplied by an arbitrary
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weight of 1.5 23. This weight was chosen by giving a rough quantitative estimate to the observations that the outcome of an intracranial hemorrhage is generally worse than that of an ischemic stroke, with the weighing factor of 1.5 reflecting the impact on mortality of an intracranial hemorrhage
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while receiving warfarin versus experiencing an ischemic stroke while not receiving warfarin. A
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similar model has been more recently proposed to quantify the balance between the risk of ischemic stroke and the risk of intracranial hemorrhage with the use of NOACs (dabigatran, rivaroxaban and apixaban) from a Danish National Patient Registry on patients with atrial fibrillation, considering 1.5 the weight of an intracranial hemorrhage compared with an ischemic stroke, here assigned the normalized weight of 1 24.
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In an alternative approach, since ischemic stroke is a common primary endpoint of efficacy for antithrombotic treatments in atrial fibrillation, a weighed net clinical benefit has been expressed in units of ischemic stroke equivalents prevented, as the reference weight for each event, and made
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equal to 1. This approach was first used for patients enrolled in the ACTIVE-A trial
13
, who, as an
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entry criterion, were unsuitable for VKAs. The net clinical benefit of dual antiplatelet therapy in the ACTIVE A trial participants was defined as the weighed event incidence with dual antiplatelet therapy subtracted from the sum of weighed event incidence on control treatment, expressed as ischemic stroke equivalents prevented per 100 patient-years
14
. Based on the same model, a more
recent report explored the net clinical benefit of each dose of dabigatran and warfarin in the RE-LY trial 21. We have here applied the same criteria to assess and compare the net clinical benefit of all 4 NOACs so far tested in atrial fibrillation.
Renda G. et al., Net clinical benefit of NOACs vs warfarin, page 12
ACCEPTED MANUSCRIPT Composite outcomes
At a first analysis, we chose the main ischemic and hemorrhagic events evaluated in the 4 clinical trials designed to compare the efficacy and safety of NOACs vs warfarin, and we grouped these
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events in various composite outcomes: a composite of ischemic stroke + hemorrhagic stroke; a composite of disabling stroke + life-threatening bleeding; and an overall composite outcome of ischemic stroke + hemorrhagic stroke + myocardial infarction + systemic embolism + adjusted
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major bleeding. Cardiovascular mortality and all-cause mortality were also combined to all
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composite outcomes in a secondary analysis. This latter combinations of non-fatal events with cardiovascular mortality or total mortality (presented in the OS Table) is to be considered exploratory, as it may include non-mutually exclusive events. We calculated the RR of NOACs vs warfarin for each composite outcome.
these composite outcomes.
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Our findings indicate that apixaban always features a better efficacy than warfarin in reducing all
Dabigatran 150 in this analysis features a better efficacy than warfarin in reducing all the composite outcomes with the exception of the most comprehensive one of ischemic stroke, systemic
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embolism, myocardial infarction, hemorrhagic stroke, and adjusted major bleeding, probably
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because this regimen was associated, in the RE-LY trial, with a slightly higher number of myocardial infarctions and an equivalent number of major bleeding compared with warfarin. However, when combined with cardiovascular or all-cause mortality, the overall composite outcome was also reduced by dabigatran 150. Dabigatran 110 features better efficacy than warfarin only for the composite of disabling stroke + life-threatening bleeding, both alone and combined with cardiovascular or all-cause mortality, probably due to the good performance of this drug regimen on bleeding. However, it does not show
Renda G. et al., Net clinical benefit of NOACs vs warfarin, page 13
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advantages in reductions of the other outcomes, possibly due to the higher number of the combination of ischemic strokes and myocardial infarctions vs warfarin. Edoxaban 60 features better than warfarin in efficacy in reducing most of the outcomes, with the exception of the composite of ischemic + hemorrhagic strokes, probably driven by the similar
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number of ischemic strokes vs warfarin observed in the ENGAGE AF-TIMI48 trial, despite a reduction in hemorrhagic strokes. However, when combined with cardiovascular or all-cause mortality the ischemic stroke + hemorrhagic stroke outcome is also reduced by edoxaban 60.
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The lower dose regimen edoxaban 30 is also disadvantaged compared with warfarin in the
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composite of ischemic stroke + hemorrhagic stroke. Here again, however, when this composite is combined with cardiovascular and all-cause mortality, edoxaban 30 also performs better than warfarin. The other composite outcomes are all reduced by edoxaban 30, mainly in virtue of the lower risk of hemorrhagic events of this treatment compared with warfarin. Rivaroxaban features better efficacy than warfarin for the composite of disabling stroke + life-
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threatening bleeding, alone and combined with cardiovascular and all-cause mortality. On the other hand, rivaroxaban does not appear to be superior to warfarin in preventing the outcome of ischemic stroke + hemorrhagic stroke, probably due to the similar number of ischemic strokes observed in
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the ROCKET AF trial in the rivaroxaban and in the warfarin arms, but appears to perform better
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than warfarin when this outcome is combined with cardiovascular and all-cause mortality. Analyzing the overall composite outcome, rivaroxaban appears not to be better than warfarin, possibly because of the similar number of ischemic strokes and major bleeds, unless such an overall outcome is combined with all-cause mortality, favorably affected by rivaroxaban. Overall, our results broadly agree with those of the phase III clinical trials comparing NOACs with warfarin, where, ad exception of ROCKET AF trial, composite outcomes of ischemic and bleeding events have been often used as measure of net clinical benefit 2-4.
Renda G. et al., Net clinical benefit of NOACs vs warfarin, page 14
ACCEPTED MANUSCRIPT Weighed net clinical benefit
In the model of weighed net clinical benefit we present here, all NOACs appear to be associated with a significantly lower rate of the composite event of ischemic stroke equivalents—and a lower
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NNT—compared with warfarin. This means that all NOACs appear to be better than warfarin when we consider the overall balance between ischemic and hemorrhagic events and “correct” the impact of these events for subsequent mortality. The weighed analysis allows all NOACs to perform better
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than warfarin in terms of efficacy/safety balance probably because the estimated weight of a
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hemorrhagic stroke is about 3 times higher than the weight of ischemic stroke, and a substantial part of the advantage of NOACs vs warfarin relates to the prevention of intracranial hemorrhage. Since we could not calculate the weights of each event considered in the specific trial populations, we chose the weights from a recent analysis of net clinical benefit using the combined data from the ACTIVE A and the RE-LY trial databases
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, in which all patients were treated either with an
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anticoagulant or with antiplatelet drugs. We specifically chose the weights estimated for anticoagulated patients, as this is the estimate more pertinent to the populations here examined. The weighing factor of 1.5 used for intracranial hemorrhage in ATRIA cohort
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, reflecting the higher
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impact on mortality of an intracranial hemorrhage while receiving warfarin vs experiencing an
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ischemic stroke while not receiving warfarin, is not appropriate to the populations of all trials here analyzed, all receiving anticoagulation. However, since the selection of weights could affect analysis results, as recently discussed 25, we also performed a sensitivity analysis, by using weights increased and decreased by 25% and 50% compared with the main analysis. These analyses yielded similar results, confirming the robustness of our findings. Our analysis does not provide a statistical comparison of the various treatment arms in the different studies, which would be in any case problematic because of the different populations studied. However, some differences among NOACs cannot go unnoticed. Across the 4 trials here analyzed,
Renda G. et al., Net clinical benefit of NOACs vs warfarin, page 15
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apixaban apparently confers the highest risk reduction (the lowest NNT) for preventing the composite weighed outcome of ischemic stroke + systemic embolism + myocardial infarction + hemorrhagic stroke + adjusted major bleeding. Closest to apixaban is edoxaban 30, then followed by edoxaban 60, dabigatran 150, and finally dabigatran 110 and rivaroxaban. This goes qualitatively
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in the same direction as the results of the previous unweighed analyses, but achieves formal statistical significances for all NOACs at variance from the unweighed analysis. It is interesting to notice that the weighed net clinical benefit analysis yields edoxaban 30 (and not edoxaban 60) as
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the next most favorable composite evaluation after apixaban, which would revert the impression of edoxaban 30 as an unfavorable choice compared with warfarin if restricting the analysis to efficacy
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endpoints only 3, 18, highlighting the higher level of integrated information here obtained with such analyses.
Finally, the practical message from this analysis is that the choice of the antithrombotic drug in atrial fibrillation has to integrate the efficacy of each drug in terms of prevention of
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thromboembolic events and safety in terms of hemorrhagic complications, considering that bleeding
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Study limitations
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may also have an important impact on survival.
For our analysis, we have used only published data from the 4 phase III trials comparing NOACs with warfarin for the prevention of thromboembolism in non-valvular atrial fibrillation. We had no access to undisclosed information, thus this is not a patient-level analysis, but an analysis based on published data. We argue however that different approaches are not likely to change the main conclusions of our study. We arbitrarily chose some composites of ischemic and hemorrhagic events, which are however the most relevant ones in such trials. However, not all events were reported similarly across the 4 trials:
Renda G. et al., Net clinical benefit of NOACs vs warfarin, page 16
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in such cases, as described in Methods, we indirectly determined the number of events not overtly reported in the trials, and then calculated the event rates according to the median follow-up of each trial. Furthermore, since the definition of life-threatening bleeding was available only in the RE-LY and
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ENGAGE AF-TIMI 48 trials, we considered the most similar definitions for the two other trials, which were GUSTO severe bleeding for ARISTOTLE and critical bleeding for ROCKET-AF. Minor differences among the events included under each heading would not in any case
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substantially affect outcomes, robustness, and final messages of our analysis.
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Finally, for the determination of net clinical benefit, we could not directly calculate the weights of events in the specific trial populations, not knowing the rates of subsequent death associated with the event considered. Therefore, we used the weights from a recent analysis of net clinical benefit of the two doses of dabigatran in the RE-LY trial
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, assuming that the impact of each event on
mortality were comparable in the 4 trial populations. This may affect the estimates, although most
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CONCLUSIONS
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likely not to any substantial extent.
The assessment of a weighed net clinical benefit according to the impact of ischemic and hemorrhagic events on subsequent mortality indicates that all NOACs have a better compounded efficacy/safety profile than warfarin in patients with atrial fibrillation. Among NOACs, apixaban and edoxaban 30 mg seem to confer the lowest risk of a composite outcome including ischemic stroke + systemic embolism + myocardial infarction + hemorrhagic stroke + adjusted major bleeding.
Renda G. et al., Net clinical benefit of NOACs vs warfarin, page 17
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ACKNOWLEDGMENTS
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None.
1.
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ACCEPTED MANUSCRIPT LEGENDS TO FIGURES
Figure 1. Rate ratio (RR) and 95% confidence intervals (CI) of all treatment arms in the phase III
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trials comparing a NOAC with warfarin for the overall composite outcome including unweighed ischemic stroke + systemic embolism + myocardial infarction + hemorrhagic stroke + adjusted major bleeding (major bleeding minus hemorrhagic stroke).
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Figure 2. Net clinical benefit and 95% confidence intervals (CI) of all treatment arms of NOACs vs warfarin tested in phase III clinical trials for the weighed composite outcome of ischemic stroke +
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systemic embolism + myocardial infarction + hemorrhagic stroke + adjusted major bleeding (major bleeding minus hemorrhagic stroke). Net clinical benefit is expressed as ischemic stroke equivalents prevented per 100 person-years using ischemic stroke as the reference event (weight = 1). NNT= number needed to treat to prevent all grouped events included in the net clinical benefit evaluation,
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per year of treatment.
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Table 1. Study design and baseline patient characteristics in the trials examined in the present analysis
INR 2.0-3.0 150 mg BID 110 mg BID
6022 6076 6015
ROCKET-AF (3)
dose-adjusted warfarin rivaroxaban
INR 2.0-3.0 20 mg (or 15 mg*) OD
7090 7131
ARISTOTLE (4)
dose-adjusted warfarin apixaban
INR 2.0-3.0 5 mg (or 2.5 mg§) BID
ENGAGE AF-TIMI48 (5) dose-adjusted warfarin edoxaban 60 edoxaban 30
INR 2.0-3.0 60 mg (or 30 mg#) OD 30 mg (or 15 mg#) OD
Mean age (years)
2
9081 9120
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7036 7035 7034
Male gender (%)
Mean CHADS2
Median TTR (%)
71.6 71.5 71.4
63.3 63.2 64.3
2.1 2.2 2.1
67 n.a. n.a.
1.9
71.2 71.2
60.3 60.3
3.46 3.48
58 n.a.
1.8
64.5 69.1
65 64.4
2.1 2.1
66 n.a.
2.8
72 72 72
62.5 62.1 61.2
2.8 2.8 2.8
68 n.a. n.a.
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dose-adjusted warfarin dabigatran 150 dabigatran 110
RE-LY (2)
Median follow-up (years)
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Number of patients
Treatment arm
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Dose
Trial name
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*15 mg OD with CrCl 30-49 mL/min. §2.5 mg BID with ≥2 of the following criteria: age 80 years, body weight
