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Atrial flutter and thromboembolic risk: a systematic review
  1. Henrik Vadmann1,2,
  2. Peter Brønnum Nielsen1,2,
  3. Søren Pihlkjær Hjortshøj1,
  4. Sam Riahi1,
  5. Lars Hvilsted Rasmussen2,
  6. Gregory Y H Lip2,3,
  7. Torben Bjerregaard Larsen1,2
  1. 1Department of Cardiology, Atrial Fibrillation Study group, Aalborg University Hospital, Aalborg, Denmark
  2. 2Aalborg Thrombosis Research Unit, Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
  3. 3University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Birmingham, UK
  1. Correspondence to Professor Torben Bjerregaard Larsen, Department of Cardiology, Cardiovascular Research Centre, Aalborg University Hospital, Aalborg, Denmark. Forskningens Hus, Soendre Skovvej 15, Aalborg DK-9000, Denmark; tobl{at}rn.dk

Abstract

Atrial flutter confers a thromboembolic risk, but contrary to atrial fibrillation the relationship has only been addressed in few studies. This study performs an up to date systematic review of the literature to investigate the association between atrial flutter and thromboembolic events. Articles were found by MEDLINE, EMBASE search and a manual search of references list in included articles. International guidelines, meta-analyses, reviews, case reports, studies reporting thromboembolic events in relation to ablation, or cardioversion procedures, echocardiography, and observational studies were found eligible in this review. A total of 52 articles were included in this review. During cardioversion, thromboembolic event rates varied from 0% to 6% with a follow-up from 1 week to 6 years. Echocardiographic studies reported prevalence of thrombus material from 0% to 38% and a prevalence of spontaneous echo contrast (SEC) from 21% to 28%. One ablation study in non-anticoagulated patients reported thromboembolic events at 13.9%. Observational studies reported an overall elevated stroke risk (risk ratio 1.4, 95% CI 1.35 to 1.46) and mortality risk (HR 1.9, 95% CI 1.2 to 3.1) with long time follow-up compared with a control group in both studies. Given the limitations and heterogeneity of the data, a meta-analysis was not a part of this systematic review. Notwithstanding the limitations of observational studies and indirect data from echocardiographic studies, this systematic review confirms that clinical thromboembolic events, left atrial thrombus and SEC are highly prevalent in atrial flutter.

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Introduction

Atrial flutter confers a thromboembolic (TE) risk, but contrary to atrial fibrillation (AF) the relationship has only been addressed in few studies.1 ,2 The TE risk solely associated with atrial flutter can be difficult to determine as atrial flutter and AF often coexist,3 additionally there is probably a common pathophysiological interrelationship between the two arrhythmias.4

No separate guidelines for the management of patients with atrial flutter exist, but in the 2012 European guideline for AF, it is stated that ‘Antithrombotic therapy is recommended for patients with atrial flutter as for those with AF. (Level of evidence C)’.5 However, there are no large randomised controlled trials (RCT) specifically addressing the TE risk associated with atrial flutter, and most data derive from case reports as well as echocardiographic and cohort studies. To our knowledge, only one systematic review from 19986 and one meta-analysis from 20047 have summarised the limited studies on atrial flutter and TE risk.

The systematic review by Berger and Schweitzer6 studied the timing of TE events after cardioversion and reviewed data from 32 studies, including patients with atrial flutter as well as AF. They found an overall TE risk at 2% and the interval between TE event and cardioversion ranged from <1 to 18 days with 98% occurring within 10 days from cardioversion. The meta-analysis by Ghali et al7 included 13 studies and found an elevated risk of TE ranging from 0% to 7.3% in patients with atrial flutter undergoing cardioversion. Given that the last systematic reviews were performed a decade ago, our objective was to perform an up to date systematic review of the literature to investigate the association between atrial flutter and TE events.

Methods

This review is conducted in accordance with the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines8 using the population, intervention, control, outcomes and study design (PICOS) search criteria.

We searched MEDLINE and EMBASE for studies published until October 2014. We performed both structured and unstructured searches. We included MeSH terms as ‘atrial flutter’ and ‘stroke’ to identify original research papers. We also performed a search specifically to identify published international guidelines by the American College of Cardiology (ACC), American Heart Association (AHA) and European Society of Cardiology (ESC). The searches were restricted to human subjects and English language.

Assessment of study eligibility and data collection

All titles and abstracts identified by the searches were screened for inclusion, and reference lists of included studies were hand-searched for additional eligible articles. Studies obviously irrelevant determined on the basis of title and abstract were excluded. Eligibility of the remaining studies was assessed on the basis of the PICOS components, and all set inclusion criteria had to be satisfied to warrant inclusion. Inclusion criteria were restricted to, population with atrial flutter aged >18 years and a clear differentiation between atrial flutter and AF, and reported either echocardiographic findings or TE events. We included observational, case report, interventional studies but excluded editorials and letters to the editor, conference abstracts and book chapters. The following information from each study was extracted: author, year of publication, study design, sample size, distribution of patients with atrial flutter and AF, type (if any) of anticoagulant treatment, length of follow-up, results of transthoracic echocardiography (TTE) and transoesophageal echocardiography (TEE), comorbidities and TE events. International guidelines were also included to get a comprehensive review.

Quality assessment

As no eligibility criteria on study design were made, quality assessment was undertaken using context-specific methodological aspects.9 This includes assessment of the following five parameters for each included study: (1) anticoagulant treatment, defined as vitamin K antagonist treatment before inclusion and at follow-up, as this affects the outcome of TE events. (2) Definition and stratification of AF and atrial flutter at baseline establish the basis for this review, and included studies were evaluated by the definition and length of the arrhythmia. (3) Results from echocardiographic studies were assessed by the reporting of TTE and TEE examination and clear definition of thrombus material and spontaneous echo contrast (SEC). (4) Risk of stroke in terms of cardiovascular comorbidity for atrial flutter patients was stratified in accordance with parameters in the CHA2DS2-VASc (congestive heart failure, hypertension, age >75 years, diabetes mellitus, stroke, vascular disease, age 65–75 years, and female sex) score.10 (5) TE events were assessed by the reporting of neurological symptoms and radiology examination.

Given the limitations and heterogeneity of the data, we did not perform a meta-analysis as part of the present systematic review. Indeed, the clinical and methodological diversities (reporting of outcomes, inclusion and exclusion criteria, interventions, study designs) among the included studies, the risk of deriving false summaries was regarded too high. A meta-analysis could ascertain inaccurate meta-analysed results. However, to assess the directions of associations, we provided a forest plot of outcomes for the subgroup of publications applying an observational design.

Results

Our search strategy identified 298 articles. An initial screening of titles and abstracts excluded 242 articles that did not meet the inclusion criteria. Additional 14 eligible articles were found by searching the reference list of included articles. By examining full articles, additionally 18 articles were excluded, mainly due to lack of discrimination between atrial flutter and AF. The systematic review comprises 52 studies (figure 1).

Figure 1

Flowchart explaining the articles selection process.

Study characteristics

The 52 articles included were divided as follows: international guidelines, meta-analyses, reviews, case reports, studies reporting TE events in relation to ablation, or cardioversion procedures, echocardiography, and observational studies. The publication period spans from 1964 to 2014. We identified both prospective and retrospective studies but no RCTs. The reported endpoints, follow-up and inclusion periods, amount of patients with AF and the use of anticoagulant treatment varied greatly among the studies (tables 15).

Table 1

Population characteristics

Table 2

Risk of bias

Table 3

Observational studies

Table 4

Echocardiography studies

Table 5

Cardioversion studies

Observational studies

We found six published observational studies22 ,35 ,39 ,40–42 comprising a study population of 715 741 patients of whom 17 804 (2.48%) patients had atrial flutter (table 3). The follow-up period varied from 1 month to 30 years. The reported stroke risk varies from risk ratio (RR) 1.4 (95% CI 1.35 to 1.46), HR 2.6 (95% CI 1.2 to 5.3) to non-significant HR 1.9 (95% CI 0.85 to 4.4) when comparing non-hypertensive atrial flutter patients with patients with AF. The mortality risk was non-significant during follow-up <13 months, but became significant with follow-up >13 months, with a HR 1.9 (95% CI 1.2 to 3.1) compared with a healthy control group.

The largest study by Biblo et al39 reported a greater stroke risk compared with controls (RR 1.4, 95% CI 1.35 to 1.46,), but less than in patients with AF. Vidaillet et al40 reported an overall increased risk of death in patients with atrial flutter compared with a matched control group during the entire follow-up (mean 3.6±2.3 years; HR 1.7, 95% CI 1.2 to 2.6), however, the all-cause mortality was similar in atrial flutter and patients with AF during longer follow-up.

Halligan et al41 reported a higher incidence of ischaemic stroke or transient ischaemic attack (TIA) in patients with atrial flutter compared with patients with AF (HR 2.6, 95% CI 1.2 to 5.3). When non-hypertensive patients with atrial flutter or AF were compared, the rate of stroke or TIA did not differ (HR 1.9, 95% CI 0.85 to 4.4). Scheuermeyer et al22 reported an annual mortality rate of 2.5% in patients with atrial flutter. Figure 2 summarises the directions of associations related to the outcomes of stroke and death across the observational studies.

Figure 2

Forest plot of associations between atrial flutter and stroke and/or all-cause mortality.

Echocardiographic studies

We found 15 published studies reporting echocardiographic findings in patients with atrial flutter (table 4).20 ,25–38 Black et al25 published their results of TEE-guided cardioversion in non-anticoagulated patients with atrial flutter and AF. The remaining studies reported a prevalence of thrombus material from 0% to 38% and a prevalence of SEC from 21% to 28%. Two studies26 ,33 reported a prevalence of SEC of 50% and 94%, respectively, but included patients with both atrial flutter and AF, and the prevalence of atrial flutter per se was uncertain.

The majority of these studies only reported the echocardiography findings, despite patients being referred for a cardioversion procedure, nevertheless the reported TE events varies from 0 to 13 (0%–6.8%). Seidl et al31 reported the highest number of TE events (5%), but did not discriminate between atrial flutter and AF.

Cardioversion studies

Electrical cardioversion (direct-current cardioversion (DCC)) of atrial flutter was first reported in 1962 by Lown et al43 and until 1969, several case reports were subsequently published (table 5). The observed overall TE risk rate ranged from 0% to 4.3%. Generally, the publications did not discriminate between AF and atrial flutter and are therefore deemed out of scope for this particular study.

We found no publications from 1969 to 1992 addressing this issue. In 1992, Arnold et al15 published a retrospective study of 428 patients referred for a cardioversion procedure, in which 122 patients had lone atrial flutter and 90 (74%) of these patients did not receive anticoagulant treatment; no TE events occurred in the follow-up period of 2–6 weeks.

Until 2011, additional eight studies were published:16–23 five retrospective and three prospective studies. There were a total of 3952 patients of which 1767 had lone atrial flutter. The use and reporting of anticoagulant treatment were generally poor and inconsistent, and the TE rates varied from 0% to 6% with a follow-up from 1 week to 6 years. All TE events occurred in insufficient or non-anticoagulated patients. The highest incidence of TE events occurred 1–2 days post cardioversion. In 2014, a small study published data on patients who underwent successful cardioversion procedure treated with novel oral anticoagulants and found no TE events in the follow-up.24

Ablation studies

In 1997, Wood et al44 published a retrospective study of 86 patients treated with radiofrequency ablation of atrial flutter with a mean follow-up period of 4.5 years. There were 12 (13.9%) TE events and none of these patients received anticoagulant treatment at the time of the event. In eight patients of 12 TE events, atrial flutter was the only known arrhythmia. Hypertension was the only significant independent predictor of TE risk with an overall risk at 7% over a mean follow-up period of 4.5 years. Seara et al45 found that the occurrence of AF after atrial flutter ablation was high. The incidence rate of stroke was similar to that of the general population (0.6 per 100 person-years), but nearly double in patients developing AF after atrial flutter ablation (1.1 per 100 person-years). Dewland et al46 found an incidence rate of stroke at 17.9 per 1000 person-years in a general atrial flutter population with a decreased incidence rate of stroke to 13.1 per 1000 person-years after a atrial flutter ablation procedure.

Case reports

Two case reports were included in this review. Mehta and Baruch47 described three patients with TE events after DCC. Two patients received anticoagulant treatment and all three patients had a TEE with no signs of intracardiac thrombi, but one patient had SEC. Liaudet et al48 described a 72-year-old man, with atrial flutter of 3 months duration, without anticoagulant treatment, developing a TE event after cardioversion.

Discussion

In this systematic review, we provide estimates of the TE risks associated with atrial flutter. Notwithstanding the limitations of observational and indirect data from echocardiographic studies, this systematic review confirms that clinical TE, left atrial thrombus and SEC are highly prevalent in atrial flutter. A clear increase in TE risk is evident with this arrhythmia; however, due to large heterogeneity it is not possible to make an exact estimate of this risk (tables 1 and 2).

The risk of stroke and TE associated with atrial flutter is unlikely to be homogeneous and is dependent upon the presence of additional stroke risk factors.10 These risk factors predispose to the development of atrial flutter, and in addition, contribute to TE risk. It is well known that patients with atrial flutter frequently have AF and it has also been proposed that atrial flutter and AF are dependent on each other.4

In 2001, ACC/AHA/ESC published the first international guidelines on the management of AF49 where the management of atrial flutter was briefly described. The guidelines state that antithrombotic therapy for patients with atrial flutter, in general, should be as for those with AF. This recommendation was based on echocardiographic studies showing that the emptying of the left atrial appendage is decreased during atrial flutter compared with sinus rhythm, but higher than in AF. In addition, there is a transient mechanical dysfunction (stunning) of the left atrium and left atrial appendage after successful ablation or DCC of atrial flutter.50 ,51 The guidelines acknowledge that RCTs of antithrombotic therapy in the treatment of atrial flutter were lacking, but emphasised that in case–control series the risk for TE is 1%–5%. The guidelines state that the risk of thromboembolism for patients with chronic atrial flutter is generally estimated higher than for patients with sinus rhythm, but less than for those with persistent or permanent AF.49 In 2003, the ACC/AHA/ESC guidelines for the management of patients with supraventricular arrhythmias was published,3 emphasising that the knowledge about the TE risk associated with atrial flutter was limited, being based upon observational and echocardiographic studies and recommended that anticoagulant treatments in patients with AF should be extended to those with atrial flutter. In subsequent ACC/AHA/ESC guidelines from 2006,52 2008,53 2010,2 ,54 201155 and 2013,1 the recommendation ‘Antithrombotic therapy is recommended for patients with atrial flutter as for those with AF’ with a level of evidence C is maintained.

There were five studies reporting TEE finding and TE events.20 ,30 ,31 ,35 ,36 Three studies found no relationship between SEC and TE events. Irani et al30 found 11 patients with positive SEC and one patient suffered an undefined cerebrovascular accident 4 days after TEE and start of anticoagulant treatment. Seidl et al31 performed TEE examination in 44 patients with a prior TE event or expected higher risk of TE. They found SEC in seven patients; however, it is not reported if these patients underwent cardioversion or ablation or whether there were a TE event in this group. However, as the relationship between SEC and TE events are debateable, these data could not identify a clear consistency between these.

In 1998, Berger and Schweitzer6 published a review of articles published between 1966 and 1997, included 32 studies with 4621 patients who underwent cardioversion for atrial flutter and AF: 92 (2%) patients had a TE event after cardioversion but the results do not discriminate between the underlying arrhythmias. Moreyra et al56 also reviewed the risk of TE events related to cardioversion from pooled results in seven TEE-guided trials compared with 18 historical controlled trials with ‘blind’ cardioversion in both anticoagulant and non-anticoagulant patients, with atrial flutter being present in 10.6% in the TEE studies and 9% in control studies. The results were not clearly stratified for atrial flutter and AF and the reported TE events rate were 1.34% (TEE group), 0.33% (control group anticoagulant) and 2% (control group non-anticoagulant). However in the study by Bertaglia et al,19 there were no TE events after cardioversion of patients with atrial flutter, despite that 56% had hypertension and 30% ischaemic heart disease and thereby a minimum CHA2DS2-VASc above one. Additionally, Clementy et al57 demonstrated an improve survival rate independent of coexisting AF when undergoing atrial flutter ablation. However, the use of anticoagulation was not well balanced between control and cases (55% vs 74%), and the patient population in general had a high risk of stroke as reflected by a CHA2DS2-VASc score above three in both groups. In 2005, Ghali et al7 published a systematic review and meta-analysis on atrial flutter and the risk of TE. They included 13 studies investigating the risk of TE in relation to cardioversion and four studies reporting the long-term TE risks of atrial flutter. They concluded that the reported risk of thromboembolism around the time of cardioversion for atrial flutter varied by study, and that study-level clinical factors contributed to the variability in reported event rates. Nonetheless, Ghali et al7 suggested that the risk of thromboembolism was indeed elevated as compared with patients in sinus rhythm.

Limitations

It is possible that our inclusion criteria excluding foreign language papers could have led to some selection bias. There was marked heterogeneity and low-quality data highlighting the differences in the endpoints employed, differing follow-up periods, clinical and methodological differences and other confounding factors, which should be taken into consideration when interpreting the findings. Due to the close relationship between atrial flutter and AF, the presence of AF may be underestimated in the included studies, and furthermore it was not possible to determine the type of atrial flutter (typical, atypical, etc). Additionally, it cannot be ruled out that some of the available data from atrial flutter populations do not include patients with silent AF. The inclusion of patients with rheumatic heart disease may overestimate the TE risk, as patients with rheumatic heart disease per se carry a higher TE risk. Lastly, the ‘true’ TE risk may be underestimated because the included studies mainly focused on stroke and/or TIA and did not report on systemic embolism.

Conclusions

Notwithstanding the limitations of observational studies and indirect data from echocardiographic studies, this systematic review suggests that clinical TE, left atrial thrombus and SEC are prevalent in atrial flutter. There seems to be a trend of an increase TE risk with this arrhythmia, and extrapolating from trials with AF, thromboprophylaxis should strongly be considered in the presence of one or more additional stroke risk factors.

References

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Footnotes

  • GYHL and TBL are joint senior authors.

  • Contributors All authors have contributed with the planning, conduct and reporting of the work described in the article.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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