120 CHAPTER 7 of standard dose NOAC treatment over VKA treatment was mainly driven by the results in patients who are VKA naive. Moreover, an interaction of ageing on safety outcomes was observed: every 10-year increase in age led to a 10.2% increase in the HR for major bleeding for standard dose NOAC treatment (P-interaction 0.02) and every 10-year increase in age led to a 17.6% increase in the HR for major bleeding for reduced dose NOAC treatment (P-interaction 0.01). In addition to these results of the COMBINE-AF study, the ROCKET-AF trial and the ARISTOTLE trial both found a statistically significant interaction for the effect of polypharmacy on major bleeding with a waning (and in some analyses a reversed) advantage of NOACs over VKAs on this safety outcome when using more drugs.22,23 Last, in the ENGAGE AF-TIMI 48 trial edoxaban was associated with a significant lower rate of bleeding compared with warfarin, at different levels of frailty, except in those at the most severe end of the frailty spectrum. Here, the HR for major bleeding no longer reached statistical significance; the HR for edoxaban 30 mg was 0.74 (95% CI 0.36–1.52) and the HR for edoxaban 60 mg was 0.60 (95% CI 0.29–1.26).24 Hence, given that at the end of the trial tails from the pivotal NOAC trials a waning (and in some analyses a reversed) advantage of NOACs over VKAs in the oldest and most comorbid trial participants had already been observed, our findings of an increased risk of major or clinically relevant non-major bleeding associated with switching VKA treatment to a NOAC compared to continuing with a VKA in a trial with patients who are even older and more frail may be less unexpected than a priori foreseen. In addition to this trial evidence, observational studies looked at the effect of ageing and frailty in real-world patients with AF treated with a VKA or a NOAC. With respect to ageing, findings from these observational studies are largely in line with the abovedescribed trial evidence. For instance, a systematic review in 444,281 included older patients with AF found that the HR for haemorrhagic stroke was lower in older patients treated with a NOAC compared with a VKA: HR 0.61 (95% CI 0.48–0.79).25 Similar to what we observed in our trial, the HR for gastrointestinal bleeding was higher in NOAC recipients compared with patients who received INR guided VKA treatment: HR 1.46 (95% CI 1.30–1.65). However, it is important to note that observational studies exploring the effect of frailty are more scarce and also more difficult to perform given that, in the context of frailty, residual confounding bias remains problematic.26 For full appreciation, a number of topics need to be discussed. First, our population included patients who were tolerant to VKA treatment. Switching from a treatment that most patients tolerate to a newer drug (NOAC) could have resulted in a higher tendency to report bleeding complications in the arm that switched. Previous reports, using both aggregated or pooled individual patient data from the pivotal NOAC trials, also revealed that the efficacy and safety differences favoured NOACs over warfarin most strongly in patients with AF that were VKA naive.2,21 However, including patients that currently use INR guided VKA treatment was the clinically relevant population for
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