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Regional Lack of Consistency in the Management of Atrial Fibrillation (from the RECORD-AF Trial)
Accepted Manuscript Regional Lack of Consistency in the Management of Atrial Fibrillation (From the RecordAF Trial) Yousef H. Darrat, MD, Jignesh Shah, MD, MPH, Claude-Samy Elayi, MD, Gustavo X. Morales, MD, Lisa Naditch-Brûlé, MD, Sandrine Brette, Christine Taniou, Peter R. Kowey, MD, Peter J. Schwartz, MD PII:
S0002-9149(16)31567-3
DOI:
10.1016/j.amjcard.2016.09.009
Reference:
AJC 22149
To appear in:
The American Journal of Cardiology
Received Date: 6 June 2016 Revised Date:
2 September 2016
Accepted Date: 6 September 2016
Please cite this article as: Darrat YH, Shah J, Elayi C-S, Morales GX, Naditch-Brûlé L, Brette S, Taniou C, Kowey PR, Schwartz PJ, Regional Lack of Consistency in the Management of Atrial Fibrillation (From the RecordAF Trial), The American Journal of Cardiology (2016), doi: 10.1016/j.amjcard.2016.09.009. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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ACCEPTED MANUSCRIPT Regional Lack of Consistency in the Management of Atrial Fibrillation (From the RecordAF Trial)
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Yousef H Darrat, MD (a), Jignesh Shah, MD, MPH (b), Claude-Samy Elayi, MD (a), Gustavo X Morales, MD (a), Lisa Naditch-Brûlé,MD (c), Sandrine Brette (d), Christine Taniou (e), Peter R Kowey, MD* (f), Peter J Schwartz, MD* (g). Affiliations:
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(a) University of Kentucky, Lexington, KY, USA (b) Boulder Heart, Longmont, CO, USA (c) Sanofi, Paris, France (d) Lincoln, Boulogne-Billancourt, France (e) Experis IT, Nanterre, 92723, France, (f) The Lankenau Institute for Medical Research, Wynnewood, PA, USA and Jefferson Medical College, Philadelphia, PA. (g) Center for Cardiac Arrhythmias of Genetic Origin—IRCCS Instituto Auxologico Italiano, Milan, Italy
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* Senior author. Disclosures: RecordAF study was funded by Sanofi. Peter Kowey: ad hoc consultant for Sanofi.
Correspondence: Yousef H Darrat, MD
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Running head: Global variations in atrial fibrillation management
Division of Cardiovascular Medicine
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University of Kentucky
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326 C.T. Wethington Bldg.
900 South Limestone Street Lexington, KY 40536-0200 Phone: (859) 3236036 Fax: (859) 323-6475 [email protected]
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ACCEPTED MANUSCRIPT Abstract American and European society guidelines for atrial fibrillation (AF) management mostly agree on the utilization of rate and rhythm control strategies as well as the indications for oral
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anticoagulant (OAC) use. However, the level of adherence to guidelines in clinical practice may vary by region. In this study, data analysis from RECORDAF, an international registry in patients with newly diagnosed AF of less than 1 year, shows that differences in practice exist between three regions, namely Western Europe (WE), Eastern Europe (EE) and North
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America (NA). Data analysed included major cardiovascular outcomes at 12 months, choice
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of rhythm versus rate control strategy and the use of OAC according to CHADS2 score between regions as well as the cost incurred according to management strategy. In conclusion, there is preference for rhythm control strategy in Europe compared to NA without a significant impact on major cardiovascular outcomes, there is significant discrepancy in the use of OAC in EE compared to the 2 other regions and rate control was
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found to be more costly in all regions.
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Key words: atrial fibrillation; cost; anticoagulation
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This analysis evaluates regional variations in AF management (rhythm versus rate control strategy at the inclusion in the study), choice of rhythm control treatment at time of inclusion, use of appropriate thromboembolism prophylaxis based on CHADS2 score for stroke risk
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assessment and major cardiovascular outcomes at 12 months in three regions assessed, namely NA, WE and EE. In addition, the three geographic regions were combined to compare clinical outcomes and the cost of AF management at one year between rate and
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rhythm control strategies.
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Methods
RECORD-AF was a prospective, observational survey of patients recently diagnosed with AF followed in 21 countries from May 2007 to April 2009. The number of patients in Asia (8.9% of the study population) and South America (7.5% of the study population) were small compared to the NA and Europe and are excluded from the current analysis. The study
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centers were randomly selected from an extensive list of office- or hospital-based cardiologists in each participating country. The physicians were randomly selected in ratios
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reflecting the cardiology practice in each country. The study protocol was approved by Ethics Committee at the local participating center. The study included consecutive patients 18 years
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of age and more with either a history of AF diagnosed within 1 year or with AF discovered at the inclusion visit. AF was diagnosed by either standard electrocardiogram or by Holter monitor recording. Patients had to be eligible for a pharmacological treatment of AF by either rate control or rhythm control agents and had to sign a written informed consent. Patients were excluded from the study if AF was due to transient cause such as thyrotoxicosis, alcohol intoxication, acute phase of myocardial infarction, pericarditis, myocarditis, electrocution, pulmonary embolism or other pulmonary disease, electrolytic disorder or metabolic disorder. Patients with post cardiac surgery AF (less than 3 months) as
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ACCEPTED MANUSCRIPT well as those with permanent AF were excluded from the study. Patients with a pacemaker or implantable cardioverter defibrillator, or those scheduled for pulmonary vein isolation, atrioventricular node/His bundle ablation, or pacemaker implantation were excluded from the study. Finally, patients with life expectancy of less than 1 year due to a severe disease,
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pregnant or breastfeeding women, mentally disabled, unable to attend for follow-up visits, or included in an AF related clinical trial in the previous 3 months were also excluded. Enrollment in the study started in April 2007. Data were collected at baseline (visit 1) and
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during routine follow-up visits at 6 ± 2 months (visit 2) and 12 ± 3 months (visit 3). During the 12 months from recruitment to end of study, treatment including the choice of
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medication, dosage and titration was conducted at the physician’s discretion. The study instrument recorded various parameters during these visits such as: heart rhythm, heart rate, interim cardiovascular event such as cardiovascular death, stroke, transient ischemic attack (TIA) leading to hospitalization, myocardial infarction (MI), hospitalization for anti- or pro-
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arrhythmic events, and ablative procedures. Warfarin use was collected and represents oral anticoagulant (OAC) use at that time since novel anticoagulants were not available. OAC prescription was recorded at baseline visit in all patients (including new onset AF) as well as
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during follow up visits in the study.
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Data were summarized as mean and standard deviation for continuous variables and as count and percentages for qualitative variables. Baseline characteristics and therapeutic strategy at inclusion were described according to the regions. For each region, a description of specific treatments in the rhythm control strategy is presented. The antithrombotic treatments are described according to region and CHADS2 score at baseline. The outcomes over the 12-month period of evaluation are described for each region and according to the therapeutic strategy at inclusion. Comparisons between subgroups were made using χ2 test or analysis of variance as appropriate. A logistic regression adjusted on CHADS2 score at
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ACCEPTED MANUSCRIPT baseline was performed to compare death, stroke and MI between regions.All data necessary for an economic analysis are present in the RECORD AF database. These include resource use for all patients, such as hospitalization and pharmacologic therapy, patients’ occupation and days missed from work. Hospitalizations include details of therapy, such as
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cardioversion or ablation procedures, clinical outcomes such as strokes, MI and death. Each hospitalization was assigned a diagnosis related group (DRG), which was used for costing purposes. United States (US) unit costs were applied to all patients assuming absence of
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differences among the three regions. Redbook average wholesale price (AWP) was used to cost medications.
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Medication costs, hospitalization costs based on DRG classification, outpatient and inpatient procedures at baseline and follow-up were performed using CPT4 or ICD9 codes. These costs were then applied to individual RECORD AF patients and summed to obtain a total cost per patient. All costs are expressed in 2007 US dollars and applied to all patients in
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the registry. The Consumer Price Index was used to inflate costs obtained from prior years to 2007 US dollars. Total cost was composed of five sub-costs: hospitalization costs, AF
costs.
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Results
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medications costs, non AF medications costs, procedures costs, adverse events (bleeding)
A total of 4690 patients from NA (n = 955), WE (n = 2285) and EE (n = 1450) were
included in this study. There was a 7.2% loss of follow up at 12 months in the Record AF study. The only country from NA was the US. Mexico was determined as part of South America in the RecordAF study defintions. Countries included in the study from WE were Austria, Denmark, France, Germany, Greece, Italy, Portugal, Spain, Sweden, United Kingdom, whereas Russia, Belarus, Hungary, Poland represented countries in EE region. Table 1 shows the baseline characteristics and demographics of the populations according to
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ACCEPTED MANUSCRIPT region. There were significant differences among the three regions with regard to the type of AF at inclusion particularly persistent atrial fibrillation was more frequently seen in Europe compared to NA, while “Lone” AF was significantly lower in EE There was also a significant difference in comorbidities among patients with AF in the 3 regions. However,
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there was no difference in the incidence of stroke among the three regions. Comparison of treatment strategy revealed a significant preference for rate control strategy among physicians in the NA compared to those in the other two regions. There was more use of
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Vaughan Williams Class I agents (table 2) in Europe compared to NA and a preference for Class III antiarrhythmic drugs over Class I in all three regions.
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There were also significant differences in the use of aspirin and OAC between regions (table 3). Overall, there was underutilization of OAC in patients with a CHADS2 score of 2 or higher in the three regions. The use of OAC in EE was significantly lower compared to the other regions. Surprisingly, over half of patients (54.7%) in EE with a
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CHADS2 score of 2 or more used aspirin. On the other hand, there is a higher use of OAC in NA and WE compared to EE in patients with a low CHADS2 score. Despite the discrepancy in AF management and baseline characteristics, there was no
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significant difference in major adverse events of death, MI or stroke among the three regions
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over the 12-month period of evaluation after adjustment for CHADS2 score NA vs EE (OR: 0.98, 95% CI 0.60 to 1.59) and WE vs EE OR: 0.88, 95% CI 0.58 to 1.32). However, Pooled data from NA and Europe showed higher mortality, stroke and MI in the rate control group but more hospitalization for arrhythmia in the rhythm control group. Interestingly, rate control strategy was found to be more expensive than rhythm control in the three regions combined (table 4). Discussion
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ACCEPTED MANUSCRIPT The present analysis of data from RECORDAF discloses three main findings. There is a greater tendency to use rhythm control strategy among recently diagnosed (of less than 1 year) AF patients in Europe compared to NA, without a significant impact on major cardiovascular outcomes at 12 months. There is a significant discrepancy in the use of OAC
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according to CHADS2 score between EE and the other regions with underutilization of its use in that region for intermediate and high risk patients. Finally, although a greater number of patients were admitted for arrhythmia management in the rhythm control group, total costs
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were higher for rate control in all three regions.
Our data demonstrate a higher prevalence of heart failure, hypertension, coronary
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artery disease and renal failure among AF patients evaluated in EE compared to WE and NA. Furthermore, patients with lone AF constituted a much lower percentage of patients seen in these centers in EE compared to the other 2 regions. This may reflect a bias in referral patterns to cardiovascular centers with a higher threshold for referral in EE based on
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available resources at that time and their optimal utilization in the respective regions. This may be due to the lower ratio of cardiologists to patients in EE compared to that in WE and the US (1, 2).
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Although this study has shown geographical variations in the choice of management
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strategy, several randomized trials (3-7) have concluded that there were no significant differences between rate and rhythm control with respect to clinical outcomes. Based on those findings, current guidelines (8, 9) as well as the AHA/ACC/ESC 2006 (10) guidelines, contemporaneous with the period of time RECORDAF was conducted, agreed that there is no preference for either as a definitive treatment strategy. Analysis of pooled data in this study from the 3 regions showed that there is higher death, stroke and MI in the rate control group. Our previous report of RECORDAF data showed that the difference is mainly explained by co-morbidity rather than the treatment strategy (11). However, it is noteworthy
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ACCEPTED MANUSCRIPT that there was higher incidence of rhythm management related hospitalization among patients treated with rhythm control. This likely reflects the need for repeated cardioversion and antiarrhythmic therapy adjustment consistent with the findings of previous studies (7). Interestingly our analysis has shown that rhythm control, although associated with more
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hospitalizations, carries a lower overall cost compared to rate control.
The impact of OAC in preventing strokes in intermediate and high-risk patients with AF is well established. The data has been refined further and it is well accepted that patients
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with risk factors leading to CHADS2 score of ≥ 2 need to be prescribed OAC to prevent stroke. However, it has been demonstrated that there is a gross underutilization of OAC even
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among patients considered ideal for utility of these agents (12, 13). The results of RECORDAF also suggest that there is a considerable underutilization of OAC in all three regions particularly in EE. Our data shows a wide variation in the use of OAC between EE and the other regions according to CHADS2 score but there are no differences in the
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incidence of stroke or TIA between the 3 regions.
RECORDAF is a registry and hence carries the limitations inherent to observation registries, such as the lack of randomization and variation in management strategy based on
In addition, variation in the management strategy provides a natural
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world” situation.
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physician preference. However, registries can assess the impact of these strategies in a “real
experiment to assess the difference in the outcomes. Another limitation is the short duration of follow-up in this registry. The number of patients with major cardiovascular events during the study follow-up was also relatively small. This limits conclusions regarding these events although the results regarding hospitalization continue to be valid and applicable. Furthermore, the study captures a different era of AF management during which catheter ablation was less used, although new guidelines (8, 9) have not significantly changed with regard to choice of rate versus rhythm control strategy.
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1.
Block P, Weber H, Kearney P, Cardiology Section of the UEMS. Manpower in cardiology II in western and central Europe (1999–2000). Eur Heart J 2003;24:299310. Rodgers GP, Conti JB, Feinstein JA, Griffin BP, Kennett JD, Shah S, Walsh MN,
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2.
Williams ES, Williams JL. ACC 2009 survey results and recommendations: Addressing the cardiology workforce crisis A report of the ACC board of trustees
3.
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workforce task force. J Am Coll Cardiol 2009;54:1195-1208.
The AFFIRM Investigators. Survival in patients presenting with atrial fibrillation: the
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Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study. N Engl J Med 2002;347:1825–1833. 4.
Van Gelder IC, Hagens VE, Bosker HA, Kingma JH, Kamp O, Kingma T, Said SA, Darmanata JI, Timmermans AJ, Tijssen JG, Crijns HJ; Rate Control versus Electrical
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Cardioversion for Persistent Atrial Fibrillation Study Group. A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation. N Engl J Med 2002;347:1834-1840.
Hohnloser SH, Kuck KH, Lilienthal J. Rhythm or rate control in atrial fibrillation--
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5.
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Pharmacological Intervention in Atrial Fibrillation (PIAF): a randomised trial. Lancet 2000;356:1789-1794.
6.
Carlsson J, Miketic S, Windeler J, Cuneo A, Haun S, Micus S, Walter S, Tebbe U; STAF Investigators. Randomized trial of rate-control versus rhythm-control in persistent atrial fibrillation: the Strategies of Treatment of Atrial Fibrillation (STAF) study. J Am Coll Cardiol 2003;41:1690-1696.
7.
Opolski G, Torbicki A, Kosior DA, Szulc M, Wozakowska-Kaplon B, Kolodziej P, Achremczyk P; Investigators of the Polish How to Treat Chronic Atrial Fibrillation
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ACCEPTED MANUSCRIPT Study. Rate control vs rhythm control in patients with nonvalvular persistent atrial fibrillation: the results of the Polish How to Treat Chronic Atrial Fibrillation (HOT CAFE) Study. Chest 2004;126:476-486. 8.
January CT, Wann LS, Alpert JS, Calkins H, Cigarroa JE, Cleveland JC Jr, Conti JB,
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Ellinor PT, Ezekowitz MD, Field ME, Murray KT, Sacco RL, Stevenson WG, Tchou PJ, Tracy CM, Yancy CW; ACC/AHA Task Force Members. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary:
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a report of the American College of Cardiology/American Heart Association Task
2014;130:2071-2104. 9.
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Force on practice guidelines and the Heart Rhythm Society. Circulation
Camm AJ(1), Lip GY, De Caterina R, Savelieva I, Atar D, Hohnloser SH, Hindricks, G, Kirchhof P; ESC Committee for Practice Guidelines (CPG). 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010
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ESC Guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association. Eur Heart J 2012; 33:271947.
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European Heart Rhythm Association; Heart Rhythm Society, Fuster V, Rydén LE, Cannom DS, Crijns HJ, Curtis AB, Ellenbogen KA, Halperin JL, Le Heuzey JY, Kay
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10.
GN, Lowe JE, Olsson SB, Prystowsky EN, Tamargo JL, Wann S, Smith SC Jr, Jacobs AK, Adams CD, Anderson JL, Antman EM, Hunt SA, Nishimura R, Ornato JP, Page RL, Riegel B, Priori SG, Blanc JJ, Budaj A, Camm AJ, Dean V, Deckers JW, Despres C, Dickstein K, Lekakis J, McGregor K, Metra M, Morais J, Osterspey A, Zamorano JL; American College of Cardiology; American Heart Association Task Force on Practice Guidelines; European Society of Cardiology Committee for Practice Guidelines; Writing Committee to Revise the 2001 Guidelines for the
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ACCEPTED MANUSCRIPT Management of Patients With Atrial Fibrillation. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation--executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice
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Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation). J Am Coll Cardiol 2006;48:854-906. 11.
Camm AJ, Breithardt G, Crijns H, Dorian P, Kowey P, Le Heuzey JY, Merioua I,
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Pedrazzini L, Prystowsky EN, Schwartz PJ, Torp-Pedersen C, Weintraub W. Real-life observations of clinical outcomes with rhythm- and rate-control therapies for atrial
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fibrillation RECORDAF (Registry on Cardiac Rhythm Disorders Assessing the Control of Atrial Fibrillation). J Am Coll Cardiol 2011;58:493-501. 12.
Reynolds MR, Shah J, Essebag V, Olshansky B, Friedman PA, Hadjis T, Lemery R, Bahnson TD, Cannom DS, Josephson ME, Zimetbaum P. Patterns and predictors of
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warfarin use in patients with new-onset atrial fibrillation from the FRACTAL Registry. Am J Cardiol 2006;97:538-543. Alan S. Go, MD; Elaine M. Hylek, MD, MPH; Yuchiao Chang, PhD; Kathleen A.
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Phillips; Lori E. Henault, MPH; Angela M. Capra, MA; Nancy G. Jensvold, MPH; Joe V. Selby, MD, MPH; Daniel E. Singer, MD. Anticoagulation Therapy for Stroke
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13.
Prevention in Atrial Fibrillation How Well Do Randomized Trials Translate Into Clinical Practice? JAMA 2003;290:2685-2692.
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Table 1: Baseline characteristics and choice of strategy at inclusion by region. Western Europe (N=2285)
Eastern Europe (N=1450)
p-value
67.4 ±10.7 950 (41.6%) 81.6 ±23.1
61.8 ±11.1 629 (43.4%) 76.7 ±17.6
<0.001a 0.48b <0.001a
440 (46.1%)
1498 (65.7%)
608 (42.0%)
<0.001b
900 (94.2%)
1813 (79.3%)
1325 (91.4%)
<0.001b
23 (2.4%) 632 (67.3%) 284 (30.2%) 158 (16.7%)
140 (6.2%) 1026 (45.5%) 1088 (48.3%) 205 (9.1%)
35 (2.4%) 751 (51.8%) 664 (45.8%) 254 (18.3%)
<0.001b <0.001b <0.001b <0.001b
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1773 (77.7%) 536 (23.5%) 1446 (63.3%) 345 (15.1%) 312 (14.1%)
1327 (91.5%) 126 (8.7%) 1193 (82.3%) 190 (13.1%) 328 (27.2%)
<0.001b <0.001b <0.001b <0.001b <0.001b
79 (3.5%)
27 (1.9%)
<0.001b
74 (5.1%) 90 (6.3%) 11 (0.8%) 739 (51.0%) 638 (44.0%) 101 (7.0%) 191 (13.4%)
0.99b 0.04b 0.23b <0.001b <0.001b <0.001b <0.001b
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49 (5.2%)
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735 (77.3%) 174 (18.3%) 669 (70.2%) 187 (19.6%) 216 (23.1%)
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68.9±12.5 413 (43.2%) 72.6 ±15.7
50 (5.3%) 85 (9.0%) 14 (1.5%) 140 (14.7%) 114 (12.0%) 22 (2.3%) 247 (26.3%)
118 (5.2%) 175 (7.7%) 22 (1.0%) 370 (16.2%) 300 (13.1%) 69 (3.0%) 419 (18.5%)
59 (6.2%) 530 (55.7%) 172 (18.2%) 317 (33.5%) 458 (48.4%)
82 (3.6%) 872 (38.2%) 536 (23.7%) 863 (38.2%) 860 (38.1%)
138 (9.7%) 676 (46.7%) 148 (10.3%) 474 (32.9%) 817 (56.8%)
<0.001b <0.001b <0.001 b 0.002 b <0.001 b
569 (59.6%)
914 (40.0%)
512 (35.3%)
<0.001 b
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Age in years † Gender (female) Resting HR (bpm)† Baseline AF (ECG) Diagnosis in previous year First AF diagnosis Paroxysmal AF Persistent AF Non-AF arrhythmia Symptomatic AF Lone AF Hypertension* Diabetes Mellitus Coronary artery disease Transient ischemic attack Stroke TIA or Stroke TIA and Stroke Heart Failure Class I-II Class III-IV Valvular heart disease Renal disease Dyslipidemia** CHADS2 score 0 CHADS2 score 1 CHADS2 score ≥ 2 Rate control
North America (N=955)
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Variable
† Mean±standard deviation, aUsing ANOVA (type 3) with factors: Region of World. b
comparing frequency distribution based on Chi-square test .
* Blood pressure >140/90 mmmHg. ** Low-density lipoprotein >155 mg/dl and high-density lipoprotein < 40 mg/dl in men and < 48 mg/dl in women. Records with missing values for factors or response were excluded from statistical analyses
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Table 2: Choice of rhythm control strategy at inclusion based on region. p-value
Western Europe (N=1371) 271 (19.8%)
Eastern Europe (N=938) 150 (16%)
<0.001†
167 (43.3%)
560 (40.8%)
378 (40.3%)
0.6 †
Ablation
1 (0.3%)
11 (0.8%)
9 (1.0%)
0.42 †
Other ***
171 (44.3%)
529 (38.6%)
401 (42.8%)
0.04†
Class III**
* Vaughan Williams Class I agents ** Vaughan Williams Class III agents
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Class I*
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North America (N=386) 47 (12.2%)
*** Others include electrical or pharmacological cardioversion, surgical AF treatment and pacemaker implantation.
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† Comparing frequency distribution based on Chi-square test.
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Table 3: Antithrombotic treatment according to region and CHADS2 Score at baseline. North America (N=955)
Western Europe (N=2285)
Eastern Europe (N=1450)
P-value
75 (50.0%)
<0.0001a
3 (2.0%)
0.3063a
47 (31.8%)
0.0019a
33 (22.3%)
0.2351a
CHADS2 Score: 0 147 (27.4%)
3 (1.7%)
20 (3.7%)
OAC (alone or with antiplatelet agents)
87 (50.6%)
244 (45.5%)
None
36 (20.9%)
143 (26.7%)
123 (38.8%)
233 (27.0%)
275 (58.0%)
<0.0001a
11 (3.5%)
53 (6.1%)
18 (3.8%)
0.0669a
190 (59.9%)
520 (60.3%)
166 (35.0%)
<0.0001a
50 (15.8%)
110 (12.7%)
42 (8.9%)
0.0114a
166 (36.2%)
201 (23.4%)
447 (54.7%)
<0.0001a
35 (7.6%)
74 (8.6%)
25 (3.1%)
<0.0001a
309 (67.5%)
601 (69.9%)
342 (41.9%)
<0.0001a
54 (11.8%)
70 (8.1%)
66 (8.1%)
0.0495a
Other antiplatelets agents (alone or with ASA)
ASA (alone or with antiplatelet agents) Other antiplatelets agents (alone or with ASA) OAC (alone or with antiplatelet agents) None
CHADS2 Score: ≥2 ASA (alone or with antiplatelet agents)
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Other antiplatelets agents (alone or with ASA)
a
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OAC (alone or with antiplatelet agents) None
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CHADS2 Score: 1
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63 (36.6%)
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ASA (alone or with antiplatelet agents)
comparing frequency distribution based on Chi-square test . Records with missing values for factors or response were excluded from statistical analyses.
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ASA: Aspirin, OAC: Oral anticoagulant
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ACCEPTED MANUSCRIPT Table 4: Clinical outcomes and mean cost at 12 months in North America and Europe based on rhythm or rate control strategy selected at time of inclusion. Rhythm control 50 (1.9%)
Rate control 75 (3.8%)
P- value <0.001†
Hospitalization for arrhythmia
298 (11.1%)
143 (7.2%)
<0.001†
Hospitalization for ablation
15 (0.6%)
14 (0.7%)
Hospitalization for other CV event
172 (6.4%)
168 (8.4%)
Mean Cost (SD) *
4089.3 (6104)
4581.8 (8320)
† Comparing frequency distribution based on Chi-square test.
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0.53†
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Death, stroke, MI
0.01†
0.02
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* Cost was composed of five sub-costs: hospitalization costs, AF medications costs, non AF medications costs, procedures costs and adverse events (bleeding) costs.
S0002-9149(16)31567-3
DOI:
10.1016/j.amjcard.2016.09.009
Reference:
AJC 22149
To appear in:
The American Journal of Cardiology
Received Date: 6 June 2016 Revised Date:
2 September 2016
Accepted Date: 6 September 2016
Please cite this article as: Darrat YH, Shah J, Elayi C-S, Morales GX, Naditch-Brûlé L, Brette S, Taniou C, Kowey PR, Schwartz PJ, Regional Lack of Consistency in the Management of Atrial Fibrillation (From the RecordAF Trial), The American Journal of Cardiology (2016), doi: 10.1016/j.amjcard.2016.09.009. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1
ACCEPTED MANUSCRIPT Regional Lack of Consistency in the Management of Atrial Fibrillation (From the RecordAF Trial)
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Yousef H Darrat, MD (a), Jignesh Shah, MD, MPH (b), Claude-Samy Elayi, MD (a), Gustavo X Morales, MD (a), Lisa Naditch-Brûlé,MD (c), Sandrine Brette (d), Christine Taniou (e), Peter R Kowey, MD* (f), Peter J Schwartz, MD* (g). Affiliations:
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(a) University of Kentucky, Lexington, KY, USA (b) Boulder Heart, Longmont, CO, USA (c) Sanofi, Paris, France (d) Lincoln, Boulogne-Billancourt, France (e) Experis IT, Nanterre, 92723, France, (f) The Lankenau Institute for Medical Research, Wynnewood, PA, USA and Jefferson Medical College, Philadelphia, PA. (g) Center for Cardiac Arrhythmias of Genetic Origin—IRCCS Instituto Auxologico Italiano, Milan, Italy
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* Senior author. Disclosures: RecordAF study was funded by Sanofi. Peter Kowey: ad hoc consultant for Sanofi.
Correspondence: Yousef H Darrat, MD
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Running head: Global variations in atrial fibrillation management
Division of Cardiovascular Medicine
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University of Kentucky
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326 C.T. Wethington Bldg.
900 South Limestone Street Lexington, KY 40536-0200 Phone: (859) 3236036 Fax: (859) 323-6475 [email protected]
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ACCEPTED MANUSCRIPT Abstract American and European society guidelines for atrial fibrillation (AF) management mostly agree on the utilization of rate and rhythm control strategies as well as the indications for oral
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anticoagulant (OAC) use. However, the level of adherence to guidelines in clinical practice may vary by region. In this study, data analysis from RECORDAF, an international registry in patients with newly diagnosed AF of less than 1 year, shows that differences in practice exist between three regions, namely Western Europe (WE), Eastern Europe (EE) and North
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America (NA). Data analysed included major cardiovascular outcomes at 12 months, choice
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of rhythm versus rate control strategy and the use of OAC according to CHADS2 score between regions as well as the cost incurred according to management strategy. In conclusion, there is preference for rhythm control strategy in Europe compared to NA without a significant impact on major cardiovascular outcomes, there is significant discrepancy in the use of OAC in EE compared to the 2 other regions and rate control was
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found to be more costly in all regions.
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Key words: atrial fibrillation; cost; anticoagulation
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This analysis evaluates regional variations in AF management (rhythm versus rate control strategy at the inclusion in the study), choice of rhythm control treatment at time of inclusion, use of appropriate thromboembolism prophylaxis based on CHADS2 score for stroke risk
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assessment and major cardiovascular outcomes at 12 months in three regions assessed, namely NA, WE and EE. In addition, the three geographic regions were combined to compare clinical outcomes and the cost of AF management at one year between rate and
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rhythm control strategies.
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Methods
RECORD-AF was a prospective, observational survey of patients recently diagnosed with AF followed in 21 countries from May 2007 to April 2009. The number of patients in Asia (8.9% of the study population) and South America (7.5% of the study population) were small compared to the NA and Europe and are excluded from the current analysis. The study
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centers were randomly selected from an extensive list of office- or hospital-based cardiologists in each participating country. The physicians were randomly selected in ratios
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reflecting the cardiology practice in each country. The study protocol was approved by Ethics Committee at the local participating center. The study included consecutive patients 18 years
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of age and more with either a history of AF diagnosed within 1 year or with AF discovered at the inclusion visit. AF was diagnosed by either standard electrocardiogram or by Holter monitor recording. Patients had to be eligible for a pharmacological treatment of AF by either rate control or rhythm control agents and had to sign a written informed consent. Patients were excluded from the study if AF was due to transient cause such as thyrotoxicosis, alcohol intoxication, acute phase of myocardial infarction, pericarditis, myocarditis, electrocution, pulmonary embolism or other pulmonary disease, electrolytic disorder or metabolic disorder. Patients with post cardiac surgery AF (less than 3 months) as
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ACCEPTED MANUSCRIPT well as those with permanent AF were excluded from the study. Patients with a pacemaker or implantable cardioverter defibrillator, or those scheduled for pulmonary vein isolation, atrioventricular node/His bundle ablation, or pacemaker implantation were excluded from the study. Finally, patients with life expectancy of less than 1 year due to a severe disease,
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pregnant or breastfeeding women, mentally disabled, unable to attend for follow-up visits, or included in an AF related clinical trial in the previous 3 months were also excluded. Enrollment in the study started in April 2007. Data were collected at baseline (visit 1) and
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during routine follow-up visits at 6 ± 2 months (visit 2) and 12 ± 3 months (visit 3). During the 12 months from recruitment to end of study, treatment including the choice of
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medication, dosage and titration was conducted at the physician’s discretion. The study instrument recorded various parameters during these visits such as: heart rhythm, heart rate, interim cardiovascular event such as cardiovascular death, stroke, transient ischemic attack (TIA) leading to hospitalization, myocardial infarction (MI), hospitalization for anti- or pro-
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arrhythmic events, and ablative procedures. Warfarin use was collected and represents oral anticoagulant (OAC) use at that time since novel anticoagulants were not available. OAC prescription was recorded at baseline visit in all patients (including new onset AF) as well as
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during follow up visits in the study.
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Data were summarized as mean and standard deviation for continuous variables and as count and percentages for qualitative variables. Baseline characteristics and therapeutic strategy at inclusion were described according to the regions. For each region, a description of specific treatments in the rhythm control strategy is presented. The antithrombotic treatments are described according to region and CHADS2 score at baseline. The outcomes over the 12-month period of evaluation are described for each region and according to the therapeutic strategy at inclusion. Comparisons between subgroups were made using χ2 test or analysis of variance as appropriate. A logistic regression adjusted on CHADS2 score at
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ACCEPTED MANUSCRIPT baseline was performed to compare death, stroke and MI between regions.All data necessary for an economic analysis are present in the RECORD AF database. These include resource use for all patients, such as hospitalization and pharmacologic therapy, patients’ occupation and days missed from work. Hospitalizations include details of therapy, such as
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cardioversion or ablation procedures, clinical outcomes such as strokes, MI and death. Each hospitalization was assigned a diagnosis related group (DRG), which was used for costing purposes. United States (US) unit costs were applied to all patients assuming absence of
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differences among the three regions. Redbook average wholesale price (AWP) was used to cost medications.
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Medication costs, hospitalization costs based on DRG classification, outpatient and inpatient procedures at baseline and follow-up were performed using CPT4 or ICD9 codes. These costs were then applied to individual RECORD AF patients and summed to obtain a total cost per patient. All costs are expressed in 2007 US dollars and applied to all patients in
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the registry. The Consumer Price Index was used to inflate costs obtained from prior years to 2007 US dollars. Total cost was composed of five sub-costs: hospitalization costs, AF
costs.
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Results
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medications costs, non AF medications costs, procedures costs, adverse events (bleeding)
A total of 4690 patients from NA (n = 955), WE (n = 2285) and EE (n = 1450) were
included in this study. There was a 7.2% loss of follow up at 12 months in the Record AF study. The only country from NA was the US. Mexico was determined as part of South America in the RecordAF study defintions. Countries included in the study from WE were Austria, Denmark, France, Germany, Greece, Italy, Portugal, Spain, Sweden, United Kingdom, whereas Russia, Belarus, Hungary, Poland represented countries in EE region. Table 1 shows the baseline characteristics and demographics of the populations according to
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ACCEPTED MANUSCRIPT region. There were significant differences among the three regions with regard to the type of AF at inclusion particularly persistent atrial fibrillation was more frequently seen in Europe compared to NA, while “Lone” AF was significantly lower in EE There was also a significant difference in comorbidities among patients with AF in the 3 regions. However,
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there was no difference in the incidence of stroke among the three regions. Comparison of treatment strategy revealed a significant preference for rate control strategy among physicians in the NA compared to those in the other two regions. There was more use of
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Vaughan Williams Class I agents (table 2) in Europe compared to NA and a preference for Class III antiarrhythmic drugs over Class I in all three regions.
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There were also significant differences in the use of aspirin and OAC between regions (table 3). Overall, there was underutilization of OAC in patients with a CHADS2 score of 2 or higher in the three regions. The use of OAC in EE was significantly lower compared to the other regions. Surprisingly, over half of patients (54.7%) in EE with a
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CHADS2 score of 2 or more used aspirin. On the other hand, there is a higher use of OAC in NA and WE compared to EE in patients with a low CHADS2 score. Despite the discrepancy in AF management and baseline characteristics, there was no
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significant difference in major adverse events of death, MI or stroke among the three regions
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over the 12-month period of evaluation after adjustment for CHADS2 score NA vs EE (OR: 0.98, 95% CI 0.60 to 1.59) and WE vs EE OR: 0.88, 95% CI 0.58 to 1.32). However, Pooled data from NA and Europe showed higher mortality, stroke and MI in the rate control group but more hospitalization for arrhythmia in the rhythm control group. Interestingly, rate control strategy was found to be more expensive than rhythm control in the three regions combined (table 4). Discussion
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ACCEPTED MANUSCRIPT The present analysis of data from RECORDAF discloses three main findings. There is a greater tendency to use rhythm control strategy among recently diagnosed (of less than 1 year) AF patients in Europe compared to NA, without a significant impact on major cardiovascular outcomes at 12 months. There is a significant discrepancy in the use of OAC
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according to CHADS2 score between EE and the other regions with underutilization of its use in that region for intermediate and high risk patients. Finally, although a greater number of patients were admitted for arrhythmia management in the rhythm control group, total costs
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were higher for rate control in all three regions.
Our data demonstrate a higher prevalence of heart failure, hypertension, coronary
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artery disease and renal failure among AF patients evaluated in EE compared to WE and NA. Furthermore, patients with lone AF constituted a much lower percentage of patients seen in these centers in EE compared to the other 2 regions. This may reflect a bias in referral patterns to cardiovascular centers with a higher threshold for referral in EE based on
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available resources at that time and their optimal utilization in the respective regions. This may be due to the lower ratio of cardiologists to patients in EE compared to that in WE and the US (1, 2).
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Although this study has shown geographical variations in the choice of management
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strategy, several randomized trials (3-7) have concluded that there were no significant differences between rate and rhythm control with respect to clinical outcomes. Based on those findings, current guidelines (8, 9) as well as the AHA/ACC/ESC 2006 (10) guidelines, contemporaneous with the period of time RECORDAF was conducted, agreed that there is no preference for either as a definitive treatment strategy. Analysis of pooled data in this study from the 3 regions showed that there is higher death, stroke and MI in the rate control group. Our previous report of RECORDAF data showed that the difference is mainly explained by co-morbidity rather than the treatment strategy (11). However, it is noteworthy
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ACCEPTED MANUSCRIPT that there was higher incidence of rhythm management related hospitalization among patients treated with rhythm control. This likely reflects the need for repeated cardioversion and antiarrhythmic therapy adjustment consistent with the findings of previous studies (7). Interestingly our analysis has shown that rhythm control, although associated with more
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hospitalizations, carries a lower overall cost compared to rate control.
The impact of OAC in preventing strokes in intermediate and high-risk patients with AF is well established. The data has been refined further and it is well accepted that patients
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with risk factors leading to CHADS2 score of ≥ 2 need to be prescribed OAC to prevent stroke. However, it has been demonstrated that there is a gross underutilization of OAC even
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among patients considered ideal for utility of these agents (12, 13). The results of RECORDAF also suggest that there is a considerable underutilization of OAC in all three regions particularly in EE. Our data shows a wide variation in the use of OAC between EE and the other regions according to CHADS2 score but there are no differences in the
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incidence of stroke or TIA between the 3 regions.
RECORDAF is a registry and hence carries the limitations inherent to observation registries, such as the lack of randomization and variation in management strategy based on
In addition, variation in the management strategy provides a natural
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world” situation.
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physician preference. However, registries can assess the impact of these strategies in a “real
experiment to assess the difference in the outcomes. Another limitation is the short duration of follow-up in this registry. The number of patients with major cardiovascular events during the study follow-up was also relatively small. This limits conclusions regarding these events although the results regarding hospitalization continue to be valid and applicable. Furthermore, the study captures a different era of AF management during which catheter ablation was less used, although new guidelines (8, 9) have not significantly changed with regard to choice of rate versus rhythm control strategy.
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1.
Block P, Weber H, Kearney P, Cardiology Section of the UEMS. Manpower in cardiology II in western and central Europe (1999–2000). Eur Heart J 2003;24:299310. Rodgers GP, Conti JB, Feinstein JA, Griffin BP, Kennett JD, Shah S, Walsh MN,
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2.
Williams ES, Williams JL. ACC 2009 survey results and recommendations: Addressing the cardiology workforce crisis A report of the ACC board of trustees
3.
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workforce task force. J Am Coll Cardiol 2009;54:1195-1208.
The AFFIRM Investigators. Survival in patients presenting with atrial fibrillation: the
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Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study. N Engl J Med 2002;347:1825–1833. 4.
Van Gelder IC, Hagens VE, Bosker HA, Kingma JH, Kamp O, Kingma T, Said SA, Darmanata JI, Timmermans AJ, Tijssen JG, Crijns HJ; Rate Control versus Electrical
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Cardioversion for Persistent Atrial Fibrillation Study Group. A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation. N Engl J Med 2002;347:1834-1840.
Hohnloser SH, Kuck KH, Lilienthal J. Rhythm or rate control in atrial fibrillation--
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5.
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Pharmacological Intervention in Atrial Fibrillation (PIAF): a randomised trial. Lancet 2000;356:1789-1794.
6.
Carlsson J, Miketic S, Windeler J, Cuneo A, Haun S, Micus S, Walter S, Tebbe U; STAF Investigators. Randomized trial of rate-control versus rhythm-control in persistent atrial fibrillation: the Strategies of Treatment of Atrial Fibrillation (STAF) study. J Am Coll Cardiol 2003;41:1690-1696.
7.
Opolski G, Torbicki A, Kosior DA, Szulc M, Wozakowska-Kaplon B, Kolodziej P, Achremczyk P; Investigators of the Polish How to Treat Chronic Atrial Fibrillation
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ACCEPTED MANUSCRIPT Study. Rate control vs rhythm control in patients with nonvalvular persistent atrial fibrillation: the results of the Polish How to Treat Chronic Atrial Fibrillation (HOT CAFE) Study. Chest 2004;126:476-486. 8.
January CT, Wann LS, Alpert JS, Calkins H, Cigarroa JE, Cleveland JC Jr, Conti JB,
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Ellinor PT, Ezekowitz MD, Field ME, Murray KT, Sacco RL, Stevenson WG, Tchou PJ, Tracy CM, Yancy CW; ACC/AHA Task Force Members. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary:
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a report of the American College of Cardiology/American Heart Association Task
2014;130:2071-2104. 9.
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Force on practice guidelines and the Heart Rhythm Society. Circulation
Camm AJ(1), Lip GY, De Caterina R, Savelieva I, Atar D, Hohnloser SH, Hindricks, G, Kirchhof P; ESC Committee for Practice Guidelines (CPG). 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010
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ESC Guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association. Eur Heart J 2012; 33:271947.
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European Heart Rhythm Association; Heart Rhythm Society, Fuster V, Rydén LE, Cannom DS, Crijns HJ, Curtis AB, Ellenbogen KA, Halperin JL, Le Heuzey JY, Kay
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10.
GN, Lowe JE, Olsson SB, Prystowsky EN, Tamargo JL, Wann S, Smith SC Jr, Jacobs AK, Adams CD, Anderson JL, Antman EM, Hunt SA, Nishimura R, Ornato JP, Page RL, Riegel B, Priori SG, Blanc JJ, Budaj A, Camm AJ, Dean V, Deckers JW, Despres C, Dickstein K, Lekakis J, McGregor K, Metra M, Morais J, Osterspey A, Zamorano JL; American College of Cardiology; American Heart Association Task Force on Practice Guidelines; European Society of Cardiology Committee for Practice Guidelines; Writing Committee to Revise the 2001 Guidelines for the
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ACCEPTED MANUSCRIPT Management of Patients With Atrial Fibrillation. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation--executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice
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Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation). J Am Coll Cardiol 2006;48:854-906. 11.
Camm AJ, Breithardt G, Crijns H, Dorian P, Kowey P, Le Heuzey JY, Merioua I,
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Pedrazzini L, Prystowsky EN, Schwartz PJ, Torp-Pedersen C, Weintraub W. Real-life observations of clinical outcomes with rhythm- and rate-control therapies for atrial
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fibrillation RECORDAF (Registry on Cardiac Rhythm Disorders Assessing the Control of Atrial Fibrillation). J Am Coll Cardiol 2011;58:493-501. 12.
Reynolds MR, Shah J, Essebag V, Olshansky B, Friedman PA, Hadjis T, Lemery R, Bahnson TD, Cannom DS, Josephson ME, Zimetbaum P. Patterns and predictors of
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warfarin use in patients with new-onset atrial fibrillation from the FRACTAL Registry. Am J Cardiol 2006;97:538-543. Alan S. Go, MD; Elaine M. Hylek, MD, MPH; Yuchiao Chang, PhD; Kathleen A.
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Phillips; Lori E. Henault, MPH; Angela M. Capra, MA; Nancy G. Jensvold, MPH; Joe V. Selby, MD, MPH; Daniel E. Singer, MD. Anticoagulation Therapy for Stroke
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13.
Prevention in Atrial Fibrillation How Well Do Randomized Trials Translate Into Clinical Practice? JAMA 2003;290:2685-2692.
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Table 1: Baseline characteristics and choice of strategy at inclusion by region. Western Europe (N=2285)
Eastern Europe (N=1450)
p-value
67.4 ±10.7 950 (41.6%) 81.6 ±23.1
61.8 ±11.1 629 (43.4%) 76.7 ±17.6
<0.001a 0.48b <0.001a
440 (46.1%)
1498 (65.7%)
608 (42.0%)
<0.001b
900 (94.2%)
1813 (79.3%)
1325 (91.4%)
<0.001b
23 (2.4%) 632 (67.3%) 284 (30.2%) 158 (16.7%)
140 (6.2%) 1026 (45.5%) 1088 (48.3%) 205 (9.1%)
35 (2.4%) 751 (51.8%) 664 (45.8%) 254 (18.3%)
<0.001b <0.001b <0.001b <0.001b
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1773 (77.7%) 536 (23.5%) 1446 (63.3%) 345 (15.1%) 312 (14.1%)
1327 (91.5%) 126 (8.7%) 1193 (82.3%) 190 (13.1%) 328 (27.2%)
<0.001b <0.001b <0.001b <0.001b <0.001b
79 (3.5%)
27 (1.9%)
<0.001b
74 (5.1%) 90 (6.3%) 11 (0.8%) 739 (51.0%) 638 (44.0%) 101 (7.0%) 191 (13.4%)
0.99b 0.04b 0.23b <0.001b <0.001b <0.001b <0.001b
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49 (5.2%)
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735 (77.3%) 174 (18.3%) 669 (70.2%) 187 (19.6%) 216 (23.1%)
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68.9±12.5 413 (43.2%) 72.6 ±15.7
50 (5.3%) 85 (9.0%) 14 (1.5%) 140 (14.7%) 114 (12.0%) 22 (2.3%) 247 (26.3%)
118 (5.2%) 175 (7.7%) 22 (1.0%) 370 (16.2%) 300 (13.1%) 69 (3.0%) 419 (18.5%)
59 (6.2%) 530 (55.7%) 172 (18.2%) 317 (33.5%) 458 (48.4%)
82 (3.6%) 872 (38.2%) 536 (23.7%) 863 (38.2%) 860 (38.1%)
138 (9.7%) 676 (46.7%) 148 (10.3%) 474 (32.9%) 817 (56.8%)
<0.001b <0.001b <0.001 b 0.002 b <0.001 b
569 (59.6%)
914 (40.0%)
512 (35.3%)
<0.001 b
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Age in years † Gender (female) Resting HR (bpm)† Baseline AF (ECG) Diagnosis in previous year First AF diagnosis Paroxysmal AF Persistent AF Non-AF arrhythmia Symptomatic AF Lone AF Hypertension* Diabetes Mellitus Coronary artery disease Transient ischemic attack Stroke TIA or Stroke TIA and Stroke Heart Failure Class I-II Class III-IV Valvular heart disease Renal disease Dyslipidemia** CHADS2 score 0 CHADS2 score 1 CHADS2 score ≥ 2 Rate control
North America (N=955)
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Variable
† Mean±standard deviation, aUsing ANOVA (type 3) with factors: Region of World. b
comparing frequency distribution based on Chi-square test .
* Blood pressure >140/90 mmmHg. ** Low-density lipoprotein >155 mg/dl and high-density lipoprotein < 40 mg/dl in men and < 48 mg/dl in women. Records with missing values for factors or response were excluded from statistical analyses
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Table 2: Choice of rhythm control strategy at inclusion based on region. p-value
Western Europe (N=1371) 271 (19.8%)
Eastern Europe (N=938) 150 (16%)
<0.001†
167 (43.3%)
560 (40.8%)
378 (40.3%)
0.6 †
Ablation
1 (0.3%)
11 (0.8%)
9 (1.0%)
0.42 †
Other ***
171 (44.3%)
529 (38.6%)
401 (42.8%)
0.04†
Class III**
* Vaughan Williams Class I agents ** Vaughan Williams Class III agents
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Class I*
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North America (N=386) 47 (12.2%)
*** Others include electrical or pharmacological cardioversion, surgical AF treatment and pacemaker implantation.
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† Comparing frequency distribution based on Chi-square test.
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Table 3: Antithrombotic treatment according to region and CHADS2 Score at baseline. North America (N=955)
Western Europe (N=2285)
Eastern Europe (N=1450)
P-value
75 (50.0%)
<0.0001a
3 (2.0%)
0.3063a
47 (31.8%)
0.0019a
33 (22.3%)
0.2351a
CHADS2 Score: 0 147 (27.4%)
3 (1.7%)
20 (3.7%)
OAC (alone or with antiplatelet agents)
87 (50.6%)
244 (45.5%)
None
36 (20.9%)
143 (26.7%)
123 (38.8%)
233 (27.0%)
275 (58.0%)
<0.0001a
11 (3.5%)
53 (6.1%)
18 (3.8%)
0.0669a
190 (59.9%)
520 (60.3%)
166 (35.0%)
<0.0001a
50 (15.8%)
110 (12.7%)
42 (8.9%)
0.0114a
166 (36.2%)
201 (23.4%)
447 (54.7%)
<0.0001a
35 (7.6%)
74 (8.6%)
25 (3.1%)
<0.0001a
309 (67.5%)
601 (69.9%)
342 (41.9%)
<0.0001a
54 (11.8%)
70 (8.1%)
66 (8.1%)
0.0495a
Other antiplatelets agents (alone or with ASA)
ASA (alone or with antiplatelet agents) Other antiplatelets agents (alone or with ASA) OAC (alone or with antiplatelet agents) None
CHADS2 Score: ≥2 ASA (alone or with antiplatelet agents)
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Other antiplatelets agents (alone or with ASA)
a
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OAC (alone or with antiplatelet agents) None
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CHADS2 Score: 1
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63 (36.6%)
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ASA (alone or with antiplatelet agents)
comparing frequency distribution based on Chi-square test . Records with missing values for factors or response were excluded from statistical analyses.
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ASA: Aspirin, OAC: Oral anticoagulant
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Rate control 75 (3.8%)
P- value <0.001†
Hospitalization for arrhythmia
298 (11.1%)
143 (7.2%)
<0.001†
Hospitalization for ablation
15 (0.6%)
14 (0.7%)
Hospitalization for other CV event
172 (6.4%)
168 (8.4%)
Mean Cost (SD) *
4089.3 (6104)
4581.8 (8320)
† Comparing frequency distribution based on Chi-square test.
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0.53†
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Death, stroke, MI
0.01†
0.02
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* Cost was composed of five sub-costs: hospitalization costs, AF medications costs, non AF medications costs, procedures costs and adverse events (bleeding) costs.