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Sana M. Al-Khatib, Laine Thomas, Lars Wallentin, Renato D. Lopes, Bernard Gersh, David Garcia, Justin Ezekowitz, Marco Alings, Hongqui Yang, John H. Alexander, Gregory Flaker, Michael Hanna, Christopher B. Granger, Outcomes of apixaban vs. warfarin by type and duration of atrial fibrillation: results from the ARISTOTLE trial, European Heart Journal, Volume 34, Issue 31, 14 August 2013, Pages 2464–2471, https://doi.org/10.1093/eurheartj/eht135
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Abstract
It is uncertain whether the benefit from apixaban varies by type and duration of atrial fibrillation (AF).
A total of 18 201 patients with AF [2786 (15.3%) with paroxysmal and 15 412 (84.7%) with persistent or permanent] were randomized to apixaban or warfarin. In this pre-specified secondary analysis, we compared outcomes and treatment effect of apixaban vs. warfarin by AF type and duration. The primary efficacy endpoint was a composite of ischaemic or haemorrhagic stroke or systemic embolism. The secondary efficacy endpoint was all-cause mortality. There was a consistent reduction in stroke or systemic embolism (P for interaction = 0.71), all-cause mortality (P for interaction = 0.75), and major bleeding (P for interaction = 0.50) with apixaban compared with warfarin for both AF types. Apixaban was superior to warfarin in all studied endpoints, regardless of AF duration at study entry (P for all interactions >0.13). The rate of stroke or systemic embolism was significantly higher in patients with persistent or permanent AF than patients with paroxysmal AF (1.52 vs. 0.98%; P = 0.003, adjusted P = 0.015). There was also a trend towards higher mortality in patients with persistent or permanent AF (3.90 vs. 2.81%; P = 0.0002, adjusted P = 0.066).
The risks of stroke, mortality, and major bleeding were lower with apixaban than warfarin regardless of AF type and duration. Although the risk of stroke or systemic embolism was lower in paroxysmal than persistent or permanent AF, apixaban is an attractive alternative to warfarin in patients with AF and at least one other risk factor for stroke, regardless of the type or duration of AF.
Comments
Our study shows that patients with paroxysmal atrial fibrillation (AF) have lower event rates than those with persistent or permanent AF.(1) The differences between the 2 groups are striking for both mortality and stroke and barely non-significant for bleeding. The consistency across multiple endpoints suggests that this is not a chance finding, but a reflection of generally better health state. Although there is uncertainty about how much lower the risks of stroke or systemic embolism, mortality and particularly bleeding are among patients with paroxysmal versus permanent AF, we do not find the confidence intervals in Table 2 to be unusually wide. It is not clear how this should impact assessment of benefit vs. risk of oral anticoagulation since these patients have lower risk of stroke or systemic embolism (less to gain) and lower risk of bleeding (less to lose). However, our focus in the paper is to compare treatments (apixaban vs. warfarin) directly in the populations of interest. The results in Figure 1 show no evidence of heterogeneity in the treatment effect when comparing patients with paroxysmal AF with patients with persistent or permanent AF. This is a different issue from "confounding", whereby some causal effect of interest is obscured by unmeasured factors. In the paper, we do not attempt to isolate a causal mechanism; therefore, the term "confounding" is out of context. In the noted example of aspirin, the point estimates with wide confidence intervals fell on both sides of the unity line; however, in our paper, all the point estimates and confidence intervals favor apixaban.(2) We agree that it is not helpful to fixate on the point estimate within the smaller subgroups; however, various ways to address the question, including interaction tests, send a similar message in favor of apixaban vs. warfarin for reduction of both stroke or systemic embolism and bleeding. Therefore, we agree that confidence intervals are important to illustrate uncertainty around a point estimate, and we recommend readers interpret our results with the standard caution applied to any subgroup analysis, but the overall trial results provide the best estimate for major subgroups and in this case that is reassuring for important benefits on stroke and bleeding with apixaban.
References: 1) Al-Khatib S., Thomas L., Wallentin L et al. Outcomes of apixaban vs warfarin by type and duration of atrial fibrillation:results from the ARISTOTLE trial Eur Heart J 2013;34:2461-2471. 2) Hart RG., Benavente O., McBride R., Pearce LA. Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: A meta-analysis. Ann Intren Med 1999;131:492-501
Conflict of Interest:
All authors' interests are disclosed in the original manuscript.
Inspection if the confidence intervals in Fig 1(Outcomes by type of atrial fibrillation and study treatment)shows that, in spite of the assertion that "there was [also] a trend towards a lower risk of major bleeding in the paroxysmal AF group...", and the assertion that "the risk of stroke or systemic embolism was still significantly lower for paroxysmal AF than for persistent or permanent AF"(1), the confidence intervals for both outcomes were much wider for paroxysmal AF than for persistent of permanent AF(1). This outcome might signify that, for patients with paroxysmal AF characterised by high arrhythmia burden(2), the benefit vs risk profile might be higher than for those with low arrhythmia burden. Attention to confidence intervals is a useful strategy for raising the index of suspicion for the confounding effect of subgroups , as was the case in revealing the impact of the Stroke Prevention in Atrial Fibrillation Study(which used an aspirin dose of 325 mg/day) on the wide confidence intervals(2% to 38%) which generated the widely quoted 22% reduction in stroke incidence attributed to the use of a wide range of aspirin doses in thromboprophylaxis of nonvalvular atrial fibrillation(3). The consequences of ignoring the wide confidence intervals in that study were pivotal in generating what some of us consider to be a highly prevalent and misplaced belief in the thromboprophylactic benefit of a wide range of aspirin doses in NVAF. There is a risk of repeating that "genre" of errors of judgement if we do not take heed of the confounding effect of arrhythmia burden when thromboprophylaxis generates an outcome associated with wide confidence intervals in paroxysmal AF References
(1) Al-Khatib S., Thomas L., Wallentin L et al Outcomes of apixaban vs warfarin by type and duration of atrial fibrillation:results from the ARISTOTLE trial Eur Heart J 2013;34:2461-2471
((2)Capucci A., Santini M., Padeletti L et al Monitored atrial fibrillation duration predicts arterial embolic events in patients suffering from bradycardia and atrial fibrillation implanted with antitachycardia pacemakers J Amer Coll Cardiol 2005;46:1913-1920
((3) Hart RG., Benavente O., McBride R., Pearce |LA Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: A meta-analysis Ann Intren Med 1999;131:492-501
Conflict of Interest:
None declared