Running Head: Statins in Preventing
Postoperative Atrial Fibrillation
Abbreviations: AF, atrial
fibrillation; RCTs, randomized controlled trials; MOOSE, Meta-analysis of
Observational Studies in Epidemiology group; CABG, coronary artery bypass graft;
CRP, C-reactive protein; WBC, white blood cells; ACE-I, angiotension converting
enzyme inhibitors.
Corresponding Address: Zhinong Wang, Room 204, NO.24 Building, Changhai Hospital, 168# Changhai Road, Shanghai 200433, China.
Background :
Postoperative occurrence of AF has been associated with less favorable outcomes
in patients undergoing cardiac surgery and may result in increased postoperative
morbidity and mortality.
Objectives : A
focused clinical question was designed and a Meta-analysis of published studies
was performed to identify the effect of preoperative use of statins on the
occurrence of AF after cardiac surgery.
Methods : Using the Medline
database, the Cochrane clinical trials database and online clinical trial databases,
we reviewed all RCTs and observational studies examining the effect of statins on
AF occurrence following cardiac surgery. We searched for literature published before
April 2009 and earlier.
Results : This analysis
identified 6 studies (observational studies) which examined the effect of preoperative
use of statins on AF occurrence following cardiac surgery, involving 10165
patients. Contradictory to most of previous studies, the overall outcomes suggested
that the statins group did not have a significant decrease in AF occurrence
following cardiac surgery comparing to control group (P = 0.19).
Conclusions : The
preoperative medication of statins showed no significant decrease in AF
occurrence following cardiac surgery in this Meta-analysis result. More
prospective studies and researches are needed to explore and demonstrate the accurate
mechanism and effect of statins on postoperative AF.
Keywords : Statins;
Atrial Fibrillation; Cardiac Surgery; Postoperative; Meta-analysis
AF is one of the most common complications following
cardiac surgery, which has important clinical and economic implications. Patients undergoing cardiac operations are more
likely to develop AF during their postoperative period with the incidence ranging
from 25% to 50% [1].
Moreover, recent studies have shown that postoperative AF is associated with
increased morbidity and prolonged hospitalization, which requires additional
medical and nursing time, even intensive care unit stay [2][3].
The preoperative medication of amiodarone
and β-Blocker are thought to be useful to prevent postoperative AF, though
recently in an increasing number of studies, they showed no effect on AF
occurrence following cardiac comparatively [4][4].
Although the exact cause and mechanism of AF following cardiac surgery have not
been testified, inflammatory component of this postoperative arrhythmia has
been verified by several articles [6][7]. Statin
drugs, which have both antioxidant and antiinflammatory properties, have showed
efficacy in attenuating postoperative AF and may constitute a potential
preventive approach [8][10] for postoperative
arrhythmia. But there are several studies which showed different outcomes in
the prophylactic use of statins [11][13].
Whether statins would maintain efficacy in preventing AF following cardiac
surgery has not been verified [14].
Therefore, we conducted a Meta-analysis over
the evidence obtained from observational studies to evaluate the effect of
statins on AF occurrence following cardiac surgery, which we think can provide
useful clinical evidence for the prophylactic medication of cardiac surgery to
decrease the complications.
We
performed this analysis according to the guidelines of the MOOSE [15].
Inclusion
criteria: Studies were considered eligible for this review if they met
the following criteria: (1) the study must have observational study design.
Patients
included were assigned into statins group and control group, (2) the study
should describe the basic characteristics of patients involved in the study ,
and (3) evaluate the postoperative effect of statins on AF occurrence.
Search
strategies: Published and unpublished studies from 1990-2009
without language restriction were included. The databases of MEDLINE, EMBASE
and the Cochrane Controlled Trials Register were searched. The following
keywords: “atrial fibrillation” “statins” “cardiac surgery” “effect”
“outcome” were used to help find the articles. Titles and abstracts as well as
the reference lists of all of the identified reports were also independently
examined. The whole searching process was examined by two reviewers
independently (YW and WW). Discussion was
launched or consensus with the third reviewer (XY) was taken when disagreement occurs
Quality assessment: According
to the checklist of the Dutch Cochrane Centre which was proposed by MOOSE, we assessed
several key points of study quality of the included studies. The factors
involved in assessment include: (1) whether there is clear definition of
outcomes, (2) whether independent assessment of outcome is performed, (3) whether
the author carries out a follow-up in a certain period of time, (4) whether
there is elective loss during follow-up, and (5) whether important prognostic
factors are identified for each study. The result is showed in Table 1.
Table 1: The quality assessment showed that all the included articles had clear definition of study population, definition of outcomes, and assessment of outcome and identified prognostic factors. But 4 of them were lack of follow-up and none of them mentioned the selective loss during follow-up.
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Statistical analysis: The
data extraction was performed using a well-designed data extraction form to
determine eligibility for inclusion and extract data. The data elements include:
(1) publication details: first author’s name, and publication year, (2)
characteristics of the studied population: sample size, age, gender, and operation
performed, and (3) end-point evaluation: AF occurrence during the same period
of time for each group. All studies were conducted using Review Manager Version
4.2 (Revman, The Cochrane Collaboration). If significant heterogeneity was
tested a random-effects model was used, otherwise, with a fixed-effects model [16][21]. All
the statistical strategies were performed by the professional statistical reviewer
independently (LY). Disagreements were resolved by consensus with a second
reviewer (XY).
2.1
Articles
Fourteen
records were identified by the primary literature search. However, finally 6
studies were included in this analysis, the other 8 studies were excluded
because they were either laboratory studies, review articles, or irrelevant to
the current analysis. There were altogether 10165
patients included, with the publication year ranging from 2006 to 2009.The characteristics
of each study are depicted in Table 2.
Table 2: The baseline characteristics of each article were showed above, including author, publication year, groups, sample size, age, and gender.
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In
the 6 included articles, 4 of which favored that preoperative statins use may
be protective against AF after cardiac surgery, especially in CABG. Marín13
demonstrated that this protective effect was possibly due to alterations in the
extracellular matrix and remodeling by statins. Also, in another report[22], preoperative statins use was associated with a 42%
reduction in risk of AF development after CABG surgery, and patients undergoing
elective revascularization may benefit from a preventive statins approach. In
favor of this result, Kourliouros’s research[45] suggested
that higher-dose statins had the greater preventative effect, whereas low-dose
statins did not influence postoperative AF. Lertsburapa and his colleagues[14] also
got the same result that higher-dose statins seemed to more protective than the
low-dose statins. But the other two articles refused to support this idea. In a
total of 2096 patients study, Virani[12] found that
preoperative statins therapy was not associated with decreased incidence of
postoperative AF in patients undergoing cardiac surgery (OR = 1.13). Furthermore,
in the study reported by Miceli[36] they even demonstrated
that based on the similar baseline characteristics preoperative statins was
associated with a significantly higher incidence of postoperative atrial
fibrillation compared with no statins treatment in patients undergoing CABG.
2.2
Effect of statins on the AF occurrence following cardiac surgery
Of all the 6 studies, there were totally
10165 patients included, with 5483 patients in the statins group and 4682 for
the control. Using the software of Review Manager Version 4.2 it was found that
there was significant heterogeneity within the 6 articles (P = 0.0002),
so random-effects model was used. Compared with the control group, the result
showed that the statins group did not have a significant decrease in the AF occurrence
following cardiac surgery. The overall statistical result is that the OR was
0.85 units (95% confidence interval 0.66 to 1.09), and the z-score for overall
effect was 1.30(P = 0.19). [Figure1]
Figure 1: Meta-analysis result of the included 6 articles on AF occurrence following cardiac surgery. Compared with the control group, the statins group did not have a significant decrease in AF occurrence. The overall odds ratio (OR) was 0.85 units (95% confidence interval 0.66 to 1.09), and the z-score for overall effect was 1.30(P = 0.19).
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Postoperative AF following cardiac surgery remains
a problem, especially in CABG which is associated with an increasing hospital
stay. Furthermore, it may result in hypotension, congestive heart failure and stroke,
the risk of thromboembolic complications also increases in patients with AF
after cardiac surgery [1][13][32].
But the mechanisms underlying remains unknown and are thought to be
multifactorial. Recently there are reports which demonstrate the role of
inflammation in the initiation of AF, especially in postoperative AF following
cardiac surgery [7],[23][25].
The association between CRP and AF in non-postoperative patients has been
reported by many studies, which aroused new exploration into the mechanism of
AF. These reports suggested that levels of CRP are higher in patients with AF
and are significantly associated with unsuccessful cardioversion to sinus
rhythm [26][27]. In a recent study, Manuel
L and his colleagues demonstrate that a rise in the WBC count immediately after
surgery has been recognized and attributed to inflammatory reaction in
postoperative AF patients and they also suggested that preoperative leukocytosis
was a significant predictor of AF independent of CRP [27].
Though preoperative medication of β-blocker
and amiodarone are thought to be effective to prevent postoperative AF, recent
studies challenged this idea [28][29] Statins,
a type of lipid-lowering agents, which is also known for its effect of attenuation
of inflammation, shows great effect in prevention AF following cardiac surgery
by some previous reports. It used to be considered as lipid-lowering agents but
more studies demonstrate a pleiotropic effect rather than lipid-lowering [30]. The anti-inflammatory
property of statins has been suggested as one of the mechanisms by which they
exhibit their protective role in parthenogenesis and possibly in the
development of AF [30]. And the anti-inflammatory role of statins
as a regulatory mechanism for AF has been used preoperatively to reduce the
occurrence of AF following cardiac surgery, which showed great efficacy [31][33]. This
beneficial effect of statins on AF has been described in different reports. Two
recent studies observed a significant reduction in AF risk following cardiac
surgery on patients with preoperative statins use. In a study published by
Patti and his colleagues, a randomized 200 patients with preoperative
atorvastatin use starting 7 days before operation showed a significant decrease
in postoperative AF than placebo [34]. But there are studies
by other researchers which argued that preoperative statins therapy is not
associated with a decrease in the incidence of postoperative AF in patients [12][35][36]. So the exact
efficacy of statins in preventing AF occurrence following cardiac surgery needs
more studies to be verified. And we searched related articles to give a
Meta-analysis and to provide clinical evidence for the prophylaxis of AF in
cardiac surgery.
Our study is a Meta-analysis, we searched
published studies related to the effect of statins on the occurrence of AF following
cardiac surgery to conduct this analysis. In the 14 studies, 6 met our criteria
and are included in this analysis. Finally we include a total of 10165
patients, 5483 of which had used statins preoperatively and showed no
significant decrease in the occurrence of AF compared to the control group, which
is contradictory to most previous studies’ demonstration that statins could
decrease the postoperative AF occurrence greatly. In a recent Meta-analysis
conducted by Saso and his team [46], they reviewed the same
purpose with mixed RCTs and retrospective reports, by which they got the result
that statins administration results in a reduction in the incidence of AF in
patients who undergo cardiac surgery. Since there are a number of factors
causing AF in patients undergoing cardiac surgery, including the age, weight, history
of hypertension, obesity, use of β-Blocker and ACE-I, diabetes, coronary
diseases and others, which may have important impact on the AF occurrence after
surgery [37][40]. In our study, the two
groups were reasonably balanced in the preoperative baseline characters, but
their effect was thought to be inevitable. More prospective studies and
researches are needed to explore and demonstrate the exact effect of statins on
postoperative AF occurrence.
In
a recent study, Dimitrios and his colleagues found that therapy with statins in
patients with coronary artery disease and AF was associated with an increase in
collagen degradation and cholesterol lowering [30]. And
previous studies have also shown that atrial fibrosis with collagen deposition
is the underlying substrate in AF, Kumagai also reported that a decreased
fibrosis was found in all atrial regions in the atorvastatin group compared
with the control group in a prospective study [6][41][42]. This evidence may imply that the
anti-remodeling effect of statins may play an important role in preventing the
occurrence of AF following cardiac surgery in some cases. In some cases whose
AF occurrence did not decreased more than the control group, a decreased
fibrosis was also found. In other reports the most researches found the
decreased AF occurrence after electrical cardioversion by the use of statins,
and most studies are observational designed. Until now the indication and
mechanism are still not well known exactly, so further research is need to be
done [43][44]. The contradictory result of
our analysis is absolutely a support for the further research.
Our study adds to the prevention effect of
statins on AF occurrence following cardiac surgery. However, some potential
limitations may be apparent. Firstly, because of the lack of prospective
published studies, the analysis based on 6 observational articles, which
definitely would affect the final outcomes. Secondly, our included studies are
not enough and it requires more related studies, which may be subjected to the
potential biases of such studies. Thirdly, in converting non-normally
distributed statistics to normally distributed statistics, there may be a cause
of bias in this analysis. But in conclusion, our studies may be useful for clinical
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