Publication Bias
For the primary outcomes, there were no potential publication biases by inspecting the funnel plots (Supplementary Figure XⅣ ). For the secondary outcomes, there were no publication biases inspected by the funnel plots (Supplementary FigureXⅤ ).
Effects of NOACs versus VKAsin AF patients with and without polypharmacy
We synthesized the results of the included 3 post-hoc RCTs [9, 10, 28] and 8 retrospective [15, 23-27, 29, 30] studies that reported the effects of NOACs versus VKAs in AF patients with and without polypharmacy. As shown in Table 3 , all primary and secondary outcomes of NOACs and VKAs had comparably similar rates between AF patients with and without polypharmacy (all P>0.05;Supplementary Figure Ⅶ-ⅩⅢ ). There were also no publication biases inspected by the funnel plots for all primary and secondary outcomes (Supplementary Figure XⅥ- ⅩⅦ ).
Discussion
The main findings of our meta-analysis can be summarized as follows: 1) There were no differences in the rates of SSE between polypharmacy and no-polypharmacy AF patients, while moderate and severe polypharmacy was associated with an increased risk of all-cause death and major bleeding compared with no-polypharmacy AF patients. 2) For the primary outcomes, NOACs were associated with a significant reduction in SSE but with no significant difference in the risk of major bleeding compared with VKAs in AF patients with moderate polypharmacy and severe polypharmacy. 3) For the secondary outcomes, NOACs were associated with a reduction in any bleeding but with no significant difference in the risk of ischemic stroke, all-cause death, and gastrointestinal bleeding compared with VKAs in AF patients with moderate polypharmacy and severe polypharmacy. Compared with VKAs, the risk of intracranial hemorrhage was reduced in patients with moderate polypharmacy but not in patients with severe polypharmacy in NOACs users. 4) Similar rates of primary and secondary outcomes (NOACs versus warfarin) were observed between AF patients with and without polypharmacy.
Polypharmacy is common in the elderly population who is often accompanied by AF [1, 2]. Although polypharmacy has been shown to be associated with adverse clinical outcomes, the evidence for an association between polypharmacy and adverse outcomes in AF patients receiving maintenance oral anticoagulants is sparse and mixed. The meta-analysis by Harskamp et al [16] enrolled two high-quality post-hoc analyses of RCTs showed that the frequencies of bleeding events and mortality, but not of SSE, were increased with the increasing number of concomitant drugs. Our study yielded the same results after including more high-quality retrospective studies and post-hoc analyses of RCTs, which was more statistically significant. Of note, this increased risk of adverse outcomes should be placed in the context of the association between comorbidities present at baseline. Since subjects with severe polypharmacy are older and sicker, often with multiple comorbidities and frailty, the observed associations between polypharmacy, bleeding events, and all-cause death need to be tightly controlled for potential confounding factors. Since most of the included articles were extensively adjusted for covariates, our conclusions show an increased risk of adverse outcomes with greater confidence. However, Focks et al [9] focused only on the number of concomitant medications as a marker of comorbidities or frailty and poor outcomes, without extensive adjustment for baseline levels. The inclusion of data from this study partly explains the high heterogeneity of our pooled results.
Regardless, our results show that polypharmacy is associated with poor clinical outcomes in AF patients receiving oral anticoagulant maintenance therapy, suggesting that clinicians should minimize the risk of bleeding during the treatment of such patients, including during discontinued concomitant antiplatelet therapy as appropriate.
Before the advent of NOACs, VKAs had been the first choice for anticoagulation in AF patients. As research progresses, 4 landmark RCTs confirm that NOACs are superior to warfarin in the AF population [4-7]. The current guidelines only recommend the use of NOACs as first-line anticoagulants in general population AF patients, but specifically for those patients with polypharmacy, their safety and efficacy remain to be verified. Our results show that NOACs are non-inferior to VKAs in AF patients with polypharmacy and are even superior to VKAs in some efficacy and safety outcomes, such as SSE and any bleeding. The intuitive effect of polypharmacy is an increase in drug-drug interactions, which may lead to a decrease in the efficacy of given drugs or an increase in the level of toxicity. While NOACs can target a single coagulation factor such as factor Xa and factor IIa, the anticoagulant effect is independent of antithrombin, has a rapid onset of oral administration, and has less interaction with food and drugs [31]. This property of NOACs gives them an advantage in a polypharmacy population with an increased risk of drug interactions.
Existing evidence suggests that NOACs may interact pharmacokinetically with strong Cytochrome P450 (CYP3A4) and P-glycoprotein (P-gp) inhibitor or inducer, thereby affecting their absorption, distribution, or clearance levels [32]. Even though many of the drugs used in AF patients are P-gp or CYP3A4 inhibitors (e.g., verapamil, amiodarone, and rifampicin), guidelines recommend avoiding or very cautiously combining NOACs with them [33]. Unfortunately, our study did not focus on this issue, but related studies have shown that the advantages of NOACs in terms of efficacy or safety are not affected in patients using the above-mentioned combined inhibitors [10, 16].
Another effect of polypharmacy is a decrease in drug adherence. A systematic review by Claxton et al. [34]showed that drug adherence decreased with increasing frequency of dosing, with adherence of 79% for once-daily medication and only 51% for four-times-daily medication. This result may be due to a patient’s loss of trust in medical care or drug intolerance. In any case, decreased drug adherence in patients with AF is associated with an increased risk of thromboembolic and bleeding events. There has been no consensus on whether NOAC or warfarin drug adherence is higher. There is a view that warfarin requires frequent monitoring and dose adjustment, which has been shown to be associated with higher adherence [35]. Other studies have shown that NOACs (especially rivaroxaban and dabigatran) have higher adherence in AF patients [26, 28, 36]. The latter may partly explain the demonstrated advantages of NOACs over VKAs in terms of efficacy and safety. Unfortunately, many relevant retrospective studies based on claims databases, because frequent dose changes of warfarin make assessment difficult, did not further assess adherence to both oral anticoagulants.