This systematic review, comprising more than fifty thousand patients enrolled in 3 randomised clinical trials, is to our knowledge the first systematic attempt to assess separately the efficacy of the NOAC in preventing thromboembolic events (nonhemorrhagic stroke and SEE) and major prohemorrhagic effects (ICB) [14
] in NVAF. The data indicate that the NOAC have a generally similar efficacy than warfarin in the prevention of nonhemorrhagic stroke and SEE. This efficacy endpoint, which does not include hemorrhagic stroke, differs from the main outcome chosen for pivotal trials with NOAC in NVAF, which has been a net clinical endpoint including all strokes (ischemic, hemorrhagic, or undefined/unknown type) and SEE [22
]. Our results are not inconsistent with the primary efficacy analyses of the respective studies but clearly suggest that, in the overall population, the weight of the effect tends to rely on the reduction of ICB, rather than on the antithromboembolic effect.
Two relevant meta-analyses of the NOAC in NVAF have been recently published [56
]. These meta-analyses showed an overall clinical benefit of the NOAC versus warfarin in NVAF, which is consistent with the results of our meta-analysis regarding the net clinical endpoint of all strokes and SEE. With respect to the assessment of efficacy, there are some methodological differences between our meta-analysis and those conducted by Dentali et al. [56
] and Miller et al. [57
]. We analysed the composite of ischemic/undefined strokes and SEE, while the other meta-analyses only included ischemic strokes [56
] or ischemic/undefined strokes [57
]. Notwithstanding, the meta-analysis by Dentali et al. showed a similar efficacy of the NOAC and warfarin in preventing ischemic stroke (RR = 0.92; CI 0.81 to 1.04) [56
], which is consistent with the similar efficacy in preventing nonhaemorrhagic stroke and SEE found in our meta-analysis. On the other hand, the meta-analysis by Miller et al. [57
] included the dabigatran 150
mg BID dose but excluded the dabigatran 110
BID dose, as the meta-analysis was conducted from a US perspective and the dabigatran 110
BID dose is not currently approved in the US for use in NVAF. This issue could result in an overestimation of the efficacy of the NOAC versus warfarin in preventing ischemic/undefined strokes in their meta-analysis (RR = 0.87; CI 0.77 to 0.99) [57
]. On the contrary, we included both dabigatran doses (150
BID and 110
BID), because both are already approved in Europe and many other regions for use in NVAF. The long-term extension of the RE-LY study has shown no differences in efficacy between the high and low dabigatran dose in the long term [58
], which further supports our decision of including both dabigatran doses in the meta-analysis.
To the best of our knowledge, our systematic review is the first one that analyses specific subgroups and gives absolute risks estimates, thus providing a clear picture about the absolute benefit in efficacy or safety that may be expected with the NOAC in the heterogeneous population of patients with AF.
Although this review shows that the overall net clinical benefit of the NOAC versus warfarin is favourable, the magnitude of such benefit may be however influenced by a number of factors, as suggested by subgroup analyses. In RE-LY and ARISTOTLE, superiority in the composite of all strokes and SEE was mainly gained at expenses of events that occurred in non-European countries (e.g., South America, Asia, and Africa), while all the NOAC were consistently not superior to warfarin in Europe. In the ROCKET study, with a higher proportion of European patients, these differences were not apparent. It is hard to believe that geography itself influences treatment effect, but it may influence the way patients are managed in clinical practice [59
]. Potential interaction factors accounting for geographic differences may comprise the quality of oral anticoagulation and control of associated risk factors for thrombosis (e.g., hypertension, diabetes, and heart failure). The benefit of oral anticoagulation is largely dependent on the quality of INR control achieved by centers and countries as measured by TTR [61
]. The use of center-based TTRs as a proxy for individual-level INR control is a matter of controversy, but it may be considered a reasonable approach in clinical trials comparing the NOAC and warfarin in AF [28
]. Individual-level comparisons between the NOAC and warfarin would increase the relevance of the results to decision-making, but these comparisons are very difficult to conduct given that there were no comparable INRs in the treatment arms with the NOAC. While the understanding of the determinants of individual TTR remains incomplete, it is clear that the providers of care, and the systems within which they work, have a profound effect on the quality of anticoagulation [63
]. Beyond statistical significance, subgroup analyses suggest that the net benefit of the NOAC seems better than that of warfarin in situations in which quality of oral anticoagulation is poor, given that thromboembolic complications, major bleeding, and mortality may be decreased, as well as in patients with prior stroke or transient ischemic attack, particularly if they have concomitant predictive factors for developing ICB (e.g., leukoaraiosis) [64
], given that the absolute risk reduction in ICB may be significant.
Switching between anticoagulants may be sometimes clinically indicated and have deleterious consequences if not properly planned. In ROCKET-AF and ARISTOTLE, an excess in (mainly ischemic) strokes occurred in the rivaroxaban and apixaban arms upon discontinuation at the end of the trial. This resumption of events was probably related to inadequate control of anticoagulation, but induction of a hypercoagulable state by long-term treatment with the NOAC has not been ruled out [51
The present systematic review has limitations. The main efficacy outcome in our study (nonhemorrhagic stroke and SEE) was a part of the main net clinical outcome (all strokes and SEE) in individual studies. In addition, the main safety outcome in our study (ICB) was a secondary safety endpoint in individual studies. On the other hand, we conducted subgroup analyses, which have well-known limitations [65
]. Testing multiple subgroups, even though prespecified, creates the possibility of false-positive findings. However, when subgroups are described in the protocol of the original trials along with a stated hypothesis, these secondary analyses may be used to illustrate applicability across patient subgroups [65
]. RE-LY, ROCKET-AF, and ARISTOTLE trials included a heterogeneous population (), and in such a situation, subgroup analyses are reasonable. In addition, most subgroups included a significant number of patients (e.g., 14,527 had prior stroke/TIA and 21,695 were recruited in European centers; ) thus having sufficient statistical power to detect clinically meaningful differences between treatments.
At the time of translating the results from these clinical trials into practise, some additional considerations are necessary. On the one hand, thrombotic and haemorrhagic events in the real-world anticoagulated AF population are higher than those reported in clinical trials [67
], probably due to the strict selection of population and close followup applied in clinical trials. In particular, patients aged 75 years or older were underrepresented in clinical trials (range: 31% to 43% of patients) compared with real-world AF cohorts (range: 47% to 64% of patients) [69
]. This issue may have important implications in bleeding risk, as renal function declines with age and all NOAC undergo renal elimination to a greater or lesser extent. Postmarketing reports of serious bleedings have frequently involved patients generally not qualified for the NOAC (i.e., severe renal insufficiency) [70
]. This finding, accompanied by the current unavailability of specific antidotes, emphasizes the need for their appropriate use according to product labelling in order to minimise bleeding risk [8
Finally, there is a need for strategies that could optimize anticoagulation quality and improve clinical outcomes in AF [71
]. Beyond the use of NOAC in selected patients, these strategies may include systems facilitating algorithm-based warfarin dosing in the anticoagulation clinics [72
], as well as the use of home-monitoring and self-management of anticoagulation with VKA in suitable candidates [73