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.