Abstract
Objective
To investigate the clinical outcomes of patients who underwent cardioversion compared with those who did not have cardioverson in a large dataset of patients with recent onset non-valvular atrial fibrillation.
Design
Observational study using prospectively collected registry data (Global Anticoagulant Registry in the FIELD-AF—GARFIELD-AF).
Setting
1317 participating sites in 35 countries.
Participants
52 057 patients aged 18 years and older with newly diagnosed atrial fibrillation (up to six weeks’ duration) and at least one investigator determined stroke risk factor.
Main outcome measures
Comparisons were made between patients who received cardioversion and those who had no cardioversion at baseline, and between patients who received direct current cardioversion and those who had pharmacological cardioversion. Overlap propensity weighting with Cox proportional hazards models was used to evaluate the effect of cardioversion on clinical endpoints (all cause mortality, non-haemorrhagic stroke or systemic embolism, and major bleeding), adjusting for baseline risk and patient selection.
Results
44 201 patients were included in the analysis comparing cardioversion and no cardioversion, and of these, 6595 (14.9%) underwent cardioversion at baseline. The propensity score weighted hazard ratio for all cause mortality in the cardioversion group was 0.74 (95% confidence interval 0.63 to 0.86) from baseline to one year follow-up and 0.77 (0.64 to 0.93) from one year to two year follow-up. Of the 6595 patients who had cardioversion at baseline, 299 had a follow-up cardioversion more than 48 days after enrolment. 7175 patients were assessed in the analysis comparing type of cardioversion: 2427 (33.8%) received pharmacological cardioversion and 4748 (66.2%) had direct current cardioversion. During one year follow-up, event rates (per 100 patient years) for all cause mortality in patients who received direct current and pharmacological cardioversion were 1.36 (1.13 to 1.64) and 1.70 (1.35 to 2.14), respectively.
Conclusion
In this large dataset of patients with recent onset non-valvular atrial fibrillation, a small proportion were treated with cardioversion. Direct current cardioversion was performed twice as often as pharmacological cardioversion, and there appeared to be no major difference in outcome events for these two cardioversion modalities. For the overall cardioversion group, after adjustments for confounders, a significantly lower risk of mortality was found in patients who received early cardioversion compared with those who did not receive early cardioversion.
Study registration
ClinicalTrials.gov NCT01090362.
Introduction
After anticoagulation treatment for stroke prevention has been prescribed to appropriate patients (those with increased risk of stroke), there are two main treatment approaches for atrial fibrillation. One approach is to try and restore sinus rhythm, which can be achieved by direct current or pharmacological cardioversion. Rhythm control can potentially relieve symptoms and prevent progression of atrial fibrillation1 and left atrial remodelling.2 The other treatment option is to allow atrial fibrillation to continue but to control the ventricular rate (rate control). Several randomised controlled trials have shown that this treatment strategy is non-inferior to rhythm control when considering endpoints such as stroke rates and mortality.3 4 5 6 7 8 9 Previous studies also indicate that rates of hospital admission for rate control are lower than those for rhythm control.4 Guidelines in Europe and America support both strategies but stress the need for better knowledge about their efficacy and safety.10 11 However, the recently reported Early Treatment of Atrial Fibrillation for Stroke Prevention Trial (EAST-AFNET 4)12 showed that early rhythm control was superior to guideline mandated management, which consisted largely of rate control until or unless symptoms became refractory.
The Global Anticoagulant Registry in the FIELD-AF (GARFIELD-AF) is a worldwide prospective study of adult patients with newly diagnosed non-valvular atrial fibrillation.13 14 The registry includes information on baseline patient characteristics, rate of interventions such as cardioversions, and clinical outcomes. Only patients with first time onset of atrial fibrillation within six weeks were included, and so a high proportion might be eligible for an early rhythm control strategy. These data assess the use of cardioversion in daily clinical practice and might provide important information for clinicians treating patients with recent onset non-valvular atrial fibrillation.
In the current study, we aimed to investigate the characteristics of patients who received cardioversion treatment at baseline versus those who did not, and to assess types of cardioversion performed. We also describe the associations between cardioversion and clinical outcomes in a large dataset of patients presenting with recent onset non-valvular atrial fibrillation.
Methods
Study design
GARFIELD-AF is an international registry of adult patients with newly diagnosed non-valvular atrial fibrillation with at least one additional risk factor for stroke. Patients from 35 countries were prospectively enrolled into five consecutive cohorts of approximately 10 000 patients with intended two year follow-up. A total of 52 057 patients were enrolled. The registry excluded patients with a transient and reversible cause of atrial fibrillation and those for whom follow-up was not possible. The sites were randomly selected and when this did not generate the required number of sites in a given country, the national lead investigators were asked to recommend sites to make up the numbers (18 of 1317 sites). The sites represent different care settings in each participating country (office based practice; hospital departments including neurology, cardiology, geriatrics, internal medicine, and emergency; anticoagulation clinics; and general or family practice). Outcomes are investigator reported, but a comprehensive audit and quality control system that includes onsite audits and remote quality control measures was enacted in GARFIELD-AF.
Data collection
Data for the present analysis were extracted from the GARFIELD-AF registry in June 2019. Five independent, prospective cohorts were included from 2010 to 2016. Data were collected from electronic case report forms, which were designed by Dendrite Clinical Systems (Henley-on-Thames, UK). The coordinating centre of the GARFIELD-AF database is the Thrombosis Research Institute (London, UK). Patients were contacted at four monthly intervals by telephone or postal mail. Data were examined for completeness and accuracy by the coordinating centre. In accordance with the study protocol, 20% of all data submitted electronically were monitored against source documentation.15
Content and definitions
Comparisons were made between patients who received cardioversion and those who had no cardioversion at baseline, and between those who received direct current cardioversion and pharmacological cardioversion throughout the study. Baseline cardioversion was defined as a cardioversion that was reported at baseline or that occurred within 48 days after enrolment to allow for adequate anticoagulation treatment for at least three weeks before cardioversion. Patients who received more than one cardioversion during follow-up were evaluated according to the first type of cardioversion received. Cardioversion type was evaluated by considering cardioversions that occurred at any time during follow-up (type of cardioversion was only reported in the follow-up forms).
At the time of diagnosis, data on clinical characteristics, medical history, cardiovascular risk profile, type of atrial fibrillation, care setting specialty and treatment choice were collected. We applied the GARFIELD-AF risk calculator for measures of stroke, bleeding, and mortality risks; this represents the expected occurrence of each event within two years of enrolment.16 The CHA2DS2-VASc score (congestive heart failure, hypertension, age >75, diabetes, stroke or transient ischaemic attack, vascular disease, age >65, sex category) was also calculated for risk of stroke.17 Atrial fibrillation types were defined according to the European Society of Cardiology guidelines.11 Heart failure included patients with current congestive heart failure or a history of the condition, or those with left ventricle ejection fraction <40%. Vascular disease was defined as peripheral artery disease or coronary artery disease. During follow-up, data on the occurrence of non-haemorrhagic stroke or systemic embolism, major bleeding, and all cause mortality were obtained.
Non-haemorrhagic stroke or systemic embolism was defined as a composite of ischaemic stroke, unknown type stroke, and systemic embolism. Major bleeding was classified by investigators according to the International Society on Thrombosis and Haemostasis definition. Major bleeds, including intracranial bleeds, were defined as a combined endpoint of haemorrhagic stroke and any major bleed. Minor or non-major clinically relevant bleeds that required transfusion, that occurred in a critical site, or were fatal bleeds were reclassified as major bleeds.
Statistical analysis
Continuous baseline variables are expressed as median (interquartile range) and categorical variables as frequency and percentage. Clinical endpoints of the study were all cause mortality, non-haemorrhagic stroke or systemic embolism, and major bleeding. We describe the occurrence of a clinical outcome by using the number of events, event rate per 100 person years, and 95% confidence interval. Person year rates were estimated using a Poisson model. We only considered the first occurrence of each event.
We calculated the effect of baseline cardioversion on clinical endpoints by using a Cox proportional hazards model with a propensity method of overlap weighting to balance covariates in the population. This newly developed method of overlap propensity weighting avoids excluding patients (as with matching) and gives the most weight to propensities where equipoise exists. This method overlaps weights and optimises the efficiency of comparisons by defining the population with the most overlap in the covariates between treatment groups. This scheme eliminates the potential for outlier weights by avoiding a weight based on a ratio calculation using values bounded by 0 and 1. Therefore, when using overlap weights, many of the concerns about the assessment and the trimming of the weights are eliminated.18 We applied the same method to the comparison of cardioversion techniques.
We used the following variables in the propensity model and supplementary list 1 gives a detailed description of the variables: country and cohort enrolment, sex, age, ethnicity, type of atrial fibrillation, care setting specialty and location, heart failure, acute coronary syndromes, vascular disease, carotid occlusive disease, previous stroke, transient ischaemic attack or systemic embolism, previous bleeding, venous thromboembolism, hypertension, hypercholesterolemia, diabetes, cirrhosis, moderate to severe chronic kidney disease, dementia, hyperthyroidism, hypothyroidism, current smoking, heavy alcohol consumption, body mass index, heart rate, systolic and diastolic blood pressure at diagnosis, baseline anticoagulation, and antiplatelet use. Figures S1 and S2 give absolute standardised differences for all these variables. Figures S3 and S4 show the distribution of the propensity score for the two comparisons.
We estimated the effects of baseline cardioversion for all studied outcomes at one and two years after enrolment. Baseline cardioversions include cardioversions that occurred within 48 days from enrolment. To limit the possible immortal time bias caused by this selection, we also performed landmark analyses for the all cause mortality outcome 48 and 365 days after enrolment. These analyses were not replicated for non-fatal events because of the small number of events.
We carried out two sensitivity analyses. The first analysis included patients with a follow-up cardioversion after enrolment but within 48 days; time at risk was taken from cardioversion instead of enrolment. Secondly, we conducted a time dependent analysis; time at risk started from enrolment and we modified the baseline cardioversion status within 48 days when a cardioversion occurred. Tables S1 and S2 present the results from these analyses. Negligible differences were found compared with the main analyses.
Event occurrence by cardioversion type (pharmacological or direct current) were reported as the number of events and the event rate per 100 person years from time of follow-up cardioversion up to one year. We did not exclude patients with missing values from the study, but single imputation was applied to estimate the baseline cardioversion effect. We performed the imputation procedure assuming arbitrary missing patterns and by applying a fully conditional specification method that assumes a joint distribution for all variables. The fully conditional specification method involves two steps: the filled in phase, where a discriminant function is used for binary variables, logistic for ordinal and regression for continuous variables, filling in sequentially over the variables, one at a time; and the imputation phase. These steps are iterated to obtain final estimates. Table S3 presents the proportion of missing data. Data analysis was performed at the Thrombosis Research Institute with SAS software, version 9.4 (SAS Institute, Cary, NC, USA).
Patient and public involvement
Members of the study group have performed regular meetings with patient representatives about ongoing scientific projects and activities. There was no explicit funding for patient and public involvement and because this was a multinational study, we did not have enough resources for involvement of patient representatives in all countries that were involved in the study.
Results
The analyses comparing cardioversion or no cardioversion comprised 44 201 patients after we excluded those with unknown cardioversion information (n=1277), those with permanent or unknown type of atrial fibrillation (n=6546), and those with unavailable follow-up information (n=33; fig 1). Of the 6595 patients with a baseline cardioversion, 299 had a follow-up cardioversion that occurred more than 48 days after enrolment. In the analysis comparing type of cardioversion, 7175 patients were assessed: 2427 were treated with pharmacological cardioversion and 4748 with direct current cardioversion.
Fig 1.
Flowchart for selection of study population. GARFIELD-AF=Global Anticoagulant Registry in the FIELD-AF. *Baseline cardioversion was defined as cardioversion that was reported at baseline or that occurred within 48 days after enrolment
Baseline patient characteristics: cardioversion versus no cardioversion
Patients who received cardioversion were younger (median age 67.0 years, interquartile range 58.0-74.0) than those who did not have cardioversion (71.0, 63.0-78.0, P<0.001; table 1) and a higher proportion had a CHA2DS2-VASc score of ≤1 (21.1% v 14.4%, P<0.001). The proportion of patients with previous stroke, transient ischaemic attack, or systemic embolism in the cardioversion group was around half that reported in the non-cardioversion group (6.8% v 11.9%, P<0.001), while occurrence of previous bleeding appeared similar between the two groups (2.3% v 2.6%, P=0.13). The GARFIELD-AF risk scores of death, stroke, and major bleeding were all numerically lower in the cardioversion group.
Table 1.
Baseline characteristics by baseline cardioversion and cardioversion type. Data are numbers (percentages) unless stated otherwise
| Baseline characteristics | Baseline cardioversion | Cardioversion type | |||||
|---|---|---|---|---|---|---|---|
| No (n=37606) |
Yes (n=6595) |
P value* | Pharmacological (n=2427) | Direct current (n=4748) | P value* | ||
| Sex | |||||||
| Male | 20 689 (55.0) | 3856 (58.5) | <0.001 | 1259 (51.9) | 3057 (64.4) | <0.001 | |
| Female | 16 917 (45.0) | 2739 (41.5) | 1168 (48.1) | 1691 (35.6) | |||
| Age (years), median (IQR) | 71.0 (63.0-78.0) | 67.0 (58.0-74.0) | <0.001 | 66.0 (58.0-75.0) | 67.0 (59.0-74.0) | 0.83 | |
| Ethnicity | |||||||
| White | 22 012 (60.1) | 5024 (77.9) | <0.001 | 1857 (78.6) | 3925 (85.9) | <0.001 |
|
| Hispanic/Latino | 2450 (6.7) | 294 (4.6) | 158 (6.7) | 114 (2.5) | |||
| Asian | 11 493 (31.4) | 893 (13.9) | 288 (12.2) | 416 (9.1) | |||
| Afro-Caribbean/mixed/other | 662 (1.8) | 236 (3.7) | 59 (2.5) | 114 (2.5) | |||
| Body mass index, median (IQR) | 26.7 (23.8-30.5) | 27.9 (24.9-32.0) | <0.001 | 27.7 (24.8-32.0) | 28.7 (25.6-32.7) | <0.001 | |
| Systolic blood pressure (mm Hg), median (IQR) | 131.0 (120.0-145.0) | 130.0 (120.0-145.0) | 0.04 | 130.0 (120.0-146.0) | 132.0 (120.0-146.0) | 0.85 | |
| Diastolic blood pressure (mm Hg), median (IQR) | 80.0 (70.0-88.0) | 80.0 (70.0-90.0) | <0.001 | 80.0 (70.0-90.0) | 80.0 (74.0-90.0) | <0.001 | |
| Pulse (beats per min), median (IQR) | 83.0 (70.0-103.0) | 95.0 (74.0-122.0) | <0.001 | 92.0 (72.0-126.0) | 95.0 (77.0-120.0) | 0.62 | |
| Type of atrial fibrillation | |||||||
| Persistent | 6291 (16.7) | 1298 (19.7) | <0.001 | 294 (12.1) | 1222 (25.7) | <0.001 | |
| Paroxysmal | 12 303 (32.7) | 1680 (25.5) | 834 (34.4) | 676 (14.2) | |||
| New onset (unclassified) | 19 012 (50.6) | 3617 (54.8) | 1299 (53.5) | 2850 (60.0) | |||
| Care setting specialty at diagnosis | |||||||
| Internal medicine, neurology, geriatrics | 7779 (20.7) | 1089 (16.5) | <0.001 | 452 (18.6) | 782 (16.5) | <0.001 | |
| Cardiology | 24 831 (66.0) | 4733 (71.8) | 1692 (69.7) | 3160 (66.6) | |||
| Primary care, general practice | 4996 (13.3) | 773 (11.7) | 283 (11.7) | 806 (17.0) | |||
| Care setting location at diagnosis | |||||||
| Hospital | 22 194 (59.0) | 3989 (60.5) | <0.001 | 1506 (62.1) | 2666 (56.1) | <0.001 |
|
| Office, anticoagulation clinic, thrombosis centre | 11 458 (30.5) | 1276 (19.3) | 315 (13.0) | 1314 (27.7) | |||
| Emergency department | 3954 (10.5) | 1330 (20.2) | 606 (25.0) | 768 (16.2) | |||
| Medical history | |||||||
| Heart failure | 8117 (21.6) | 1553 (23.5) | <0.001 | 631 (26.0) | 1036 (21.8) | <0.001 | |
| Acute coronary syndromes | 3984 (10.6) | 786 (11.9) | 0.001 | 335 (13.8) | 458 (9.7) | <0.001 | |
| Vascular disease† | 9184 (24.6) | 1688 (25.7) | 0.04 | 789 (32.7) | 942 (19.9) | <0.001 | |
| Carotid occlusive disease | 1090 (2.9) | 180 (2.8) | 0.45 | 78 (3.3) | 106 (2.3) | 0.01 | |
| Venous thromboembolism | 964 (2.6) | 175 (2.7) | 0.66 | 60 (2.5) | 139 (2.9) | 0.27 | |
| Previous stroke, transient ischaemic attack, systemic embolism | 4462 (11.9) | 444 (6.8) | <0.001 | 190 (7.9) | 363 (7.7) | 0.80 | |
| Previous bleeding | 967 (2.6) | 149 (2.3) | 0.13 | 60 (2.5) | 105 (2.2) | 0.48 | |
| Hypertension | 28 687 (76.5) | 4947 (75.2) | 0.03 | 1914 (79.0) | 3507 (74.1) | <0.001 | |
| Hypercholesterolemia | 15 102 (41.5) | 2889 (45.1) | <0.001 | 1138 (48.7) | 1970 (42.8) | <0.001 | |
| Diabetes | 8485 (22.6) | 1278 (19.4) | <0.001 | 462 (19.0) | 919 (19.4) | 0.75 | |
| Cirrhosis | 223 (0.6) | 34 (0.5) | 0.45 | 14 (0.6) | 22 (0.5) | 0.53 | |
| Moderate to severe CKD | 3914 (10.8) | 557 (8.7) | <0.001 | 231 (9.8) | 393 (8.5) | 0.07 | |
| Dementia | 566 (1.5) | 46 (0.7) | <0.001 | 19 (0.8) | 17 (0.4) | 0.02 | |
| Heavy alcohol consumption | 765 (2.4) | 134 (2.4) | 0.91 | 35 (1.6) | 122 (3.3) | <0.001 | |
| Current smoker | 3785 (11.1) | 765 (12.7) | <0.001 | 292 (12.8) | 541 (12.8) | 0.10 | |
| Treatment | |||||||
| New oral anticoagulants±antiplatelets | 9825 (26.5) | 2388 (36.9) | <0.001 | 649 (27.5) | 1882 (40.2) | <0.001 | |
| Vitamin K antagonists±antiplatelets | 14 376 (38.7) | 2189 (33.9) | 710 (30.1) | 1992 (42.6) | |||
| Antiplatelets only | 8251 (22.2) | 1110 (17.2) | 671 (28.4) | 416 (8.9) | |||
| None | 4650 (12.5) | 779 (12.0) | 330 (14.0) | 390 (8.3) | |||
| CHA2DS2-VASc score, median (IQR) | 3.0 (2.0-4.0) | 3.0 (2.0-4.0) | <0.001 | 3.0 (2.0-4.0) | 3.0 (2.0-4.0) | <0.001 | |
| CHA2DS2-VASc score ≤1 | 5336 (14.4) | 1373 (21.1) | <0.001 | 418 (17.4) | 1086 (23.1) | <0.001 | |
| HAS-BLED score, median (IQR)‡ | 1.0 (1.0-2.0) | 1.0 (1.0-2.0) | <0.001 | 1.0 (1.0-2.0) | 1.0 (0.0-2.0) | <0.001 | |
| GARFIELD-AF death score, median (IQR)§ | 4.6 (2.5-8.6) | 3.9 (2.3-7.0) | <0.001 | 4.1 (2.5-7.5) | 3.7 (2.3-6.4) | <0.001 | |
| GARFIELD-AF stroke score, median (IQR)¶ | 1.6 (1.1-2.4) | 1.3 (0.9-1.9) | <0.001 | 1.4 (1.0-2.1) | 1.2 (0.9-1.8) | <0.001 | |
| GARFIELD-AF bleeding score, median (IQR)** | 1.6 (1.0-2.4) | 1.3 (0.9-2.1) | <0.001 | 1.3 (0.8-2.1) | 1.3 (0.8-2.1) | 0.02 | |
CHA2DS2-VASc=congestive heart failure, hypertension, age >75, diabetes, stroke or transient ischaemic attack, vascular disease, age >65, sex category; GARFIELD-AF=Global Anticoagulant Registry in the FIELD-AF; HAS-BLED=hypertension, abnormal renal or liver function, stroke, bleeding tendency or predisposition, labile INR, elderly (>65 years), drugs or alcohol; INR=international normalised ratio; IQR=interquartile range.
Calculated using two independent sample t tests or Wilcoxon-Mann-Whitney tests for continuous variables, as appropriate, and χ2 or Fisher exact test for categorical variables, as appropriate.
Defined as peripheral artery disease or coronary artery disease.
The risk factor labile INRs is not included in HAS-BLED score because it is not collected at baseline. As a result, maximum HAS-BLED score at baseline is 8 (not 9).
Represents expected risk of mortality within two years.
Represents expected risk of non-haemorrhagic stroke or systemic embolism within two years.
Represents expected risk of major bleeding within two years.
Table S4 presents the distribution of symptoms at atrial fibrillation diagnosis by cardioversion or no cardioversion at baseline. Patients who underwent cardioversion were more likely to be symptomatic (85.8% v 73.9%, P<0.001). Table S5 presents the adjunctive treatment results. Antiarrhythmic drugs were taken by 48% of patients in the cardioversion group and 28% in the non-cardioversion group (P<0.001). Ablation was performed in 1.7% of patients in the cardioversion group and 1.0% in the non-cardioversion group (P=0.005). Table S6 gives the baseline cardioversion distribution by country.
Baseline patient characteristics: pharmacological versus direct current cardioversion
The pharmacological cardioversion group had a higher proportion of several comorbidities, including history of heart failure (26.0% v 21.8%, P<0.001) and vascular disease (32.7% v 19.9%, P<0.001; table 1). In contrast, among patients who had pharmacological cardioversion, 6.9% had a left ventricle ejection fraction ≤40% compared with 15.4% for those who had direct current cardioversion (P<0.001). Most patients in both groups had a CHA2DS2-VASc score ≥1 (96.7% and 95.8% for pharmacological cardioversion and direct current cardioversion, respectively, P=0.08). At the beginning of the study, anticoagulation treatment was given less often to patients in the pharmacological cardioversion group than to those in the direct current cardioversion group (57.6% v 82.8%, P<0.001). The proportion of patients who were treated with pharmacological cardioversion was high in Ukraine, China, and Mexico (>70%), while few patients received this treatment in the United States, Singapore, the UK, Sweden, and Norway (<10%; table 2).
Table 2.
Distribution of cardioversion type by country
| Country | Pharmacological (row %) | Direct current (row %) |
|---|---|---|
| Ukraine (n=519) | 78.8 | 21.2 |
| China (n=97) | 77.3 | 22.7 |
| Mexico (n=48) | 72.9 | 27.1 |
| Russia (n=370) | 69.5 | 30.5 |
| United Arab Emirates (n=87) | 63.2 | 36.8 |
| Chile (n=83) | 62.6 | 37.4 |
| India (n=32) | 62.5 | 37.5 |
| Egypt (n=85) | 60.0 | 40.0 |
| Japan (n=149) | 58.4 | 41.6 |
| Argentina (n=136) | 53.7 | 46.3 |
| Hungary (n=243) | 51.8 | 48.2 |
| Italy (n=253) | 45.4 | 54.6 |
| Brazil (n=154) | 44.2 | 55.8 |
| Spain (n=312) | 41.7 | 58.3 |
| Canada (n=133) | 39.9 | 60.1 |
| France (n=287) | 33.5 | 66.5 |
| Thailand (n=25) | 32.0 | 68.0 |
| Switzerland (n=22) | 31.8 | 68.2 |
| Poland (n=584) | 30.1 | 69.9 |
| Turkey (n=107) | 26.2 | 73.8 |
| Czech Republic (n=374) | 25.9 | 74.1 |
| Austria (n=45) | 24.4 | 75.6 |
| Denmark (n=137) | 24.1 | 75.9 |
| Australia (n=214) | 19.2 | 80.8 |
| Belgium (n=670) | 16.1 | 83.9 |
| Germany (n=374) | 15.8 | 84.2 |
| South Korea (n=265) | 15.1 | 84.9 |
| South Africa (n=169) | 13.6 | 86.4 |
| Finland (n=121) | 13.2 | 86.8 |
| Netherlands (n=315) | 10.2 | 89.8 |
| United States (n=193) | 9.8 | 90.2 |
| Singapore (n=13) | 7.7 | 92.3 |
| United Kingdom (n=260) | 7.3 | 92.7 |
| Sweden (n=234) | 2.6 | 97.4 |
| Norway (n=65) | 1.5 | 98.5 |
Patient outcomes: cardioversion versus no cardioversion
The mortality event rates per 100 person years (95% confidence interval) from baseline to two year follow-up were 2.52 (2.26 to 2.81) in the cardioversion group and 3.87 (3.73 to 4.02) in the non-cardioversion group (P<0.001). After adjusting for differences in baseline risk, the propensity score weighted hazard ratio for all cause mortality in the cardioversion group was 0.74 (0.63 to 0.86, P<0.001) from baseline to one year follow-up, 0.77 (0.64 to 0.93, P=0.008) from one year to two year follow-up, and 0.75 (0.67 to 0.85, P<0.001) from baseline to two year follow-up. The weighted hazard ratio for cardioversion from baseline to two year follow up was 0.66 (0.54 to 0.82, P<0.001) for cardiovascular mortality and 0.91 (0.75 to 1.09, P=0.30) for non-cardiovascular mortality.
In the cardioversion group, the event rate for non-haemorrhagic stroke or systemic embolism during two year follow-up was 0.79 per 100 person years (0.65 to 0.96) compared with 1.03 (0.96 to 1.11) for those who did not receive this treatment (P=0.01). For major bleeds, the event rates were 0.84 (0.69 to 1.01) and 1.02 (0.95 to 1.10), respectively (P=0.05). No statistically significant beneficial effect of baseline cardioversion was observed for non-fatal outcomes after propensity score weighting. Table 3 and figure 2 depict the event rates and risk estimates for selected time periods for the two groups. Figure 3 provides adjusted cumulative survival probabilities and propensity score weighted hazard ratios for baseline cardioversions versus no cardioversion. From the analysis stratified by the presence of symptoms, no major differences in the effect of cardioversion emerged between patients who were symptomatic and those without symptoms (tables S7 and S8).
Table 3.
Event rates (per 100 person years), crude and propensity score weighted hazard ratios* by baseline cardioversion within one and two year follow-up
| Outcome, time period (days) | No baseline cardioversion | Baseline cardioversion | Crude HR (95% CI)† | Propensity score weighted HR (95% CI)† | |||
|---|---|---|---|---|---|---|---|
| Events | Rate (95% CI) | Events | Rate (95% CI) | ||||
| All cause mortality | |||||||
| 0-48 | 291 | 5.92 (5.28 to 6.65) | 40 | 4.64 (3.40 to 6.32) | 0.78 (0.56 to 1.09) | 0.83 (0.59 to 1.17) | |
| 49-365 | 1284 | 4.10 (3.88 to 4.33) | 145 | 2.60 (2.21 to 3.06) | 0.64 (0.54 to 0.75) | 0.71 (0.60 to 0.85) | |
| 366-730 | 1130 | 3.35 (3.16 to 3.56) | 131 | 2.14 (1.81 to 2.55) | 0.64 (0.53 to 0.77) | 0.77 (0.64 to 0.93) | |
| 0-365 | 1575 | 4.35 (4.14 to 4.57) | 185 | 2.87 (2.49 to 3.32) | 0.66 (0.57 to 0.77) | 0.74 (0.63 to 0.86) | |
| 0-730 | 2705 | 3.87 (3.73 to 4.02) | 316 | 2.52 (2.26 to 2.81) | 0.65 (0.58 to 0.73) | 0.75 (0.67 to 0.85) | |
| Non-haemorrhagic stroke or systemic embolism | |||||||
| 0-365 | 443 | 1.23 (1.12 to 1.35) | 61 | 0.95 (0.74 to 1.22) | 0.78 (0.59 to 1.01) | 0.92 (0.69 to 1.23) | |
| 0-730 | 716 | 1.03 (0.96 to 1.11) | 98 | 0.79 (0.65 to 0.96) | 0.76 (0.62 to 0.94) | 0.93 (0.75 to 1.17) | |
| Major bleeding | |||||||
| 0-365 | 476 | 1.32 (1.21 to 1.45) | 65 | 1.01 (0.80 to 1.29) | 0.77 (0.59 to 1.00) | 0.78 (0.59 to 1.02) | |
| 0-730 | 709 | 1.02 (0.95 to 1.10) | 104 | 0.84 (0.69 to 1.01) | 0.82 (0.67 to 1.01) | 0.85 (0.69 to 1.06) | |
HR=hazard ratio.
Obtained using an overlap weighted Cox model. Variables included in weighting scheme are as follows: country and cohort enrolment, sex, age, ethnicity, type of atrial fibrillation, care setting specialty and location, congestive heart failure, acute coronary syndromes, vascular disease, carotid occlusive disease, previous stroke, transient ischaemic attack or systemic embolism, previous bleeding, venous thromboembolism, hypertension, hypercholesterolemia, diabetes, cirrhosis, moderate to severe chronic kidney disease, dementia, hyperthyroidism, hypothyroidism, current smoking, heavy alcohol consumption, body mass index, heart rate, systolic and diastolic blood pressure at diagnosis, baseline anticoagulation, and antiplatelet use.
Reference: no baseline cardioversion.
Fig 2.
Crude and propensity score weighted hazard ratios by baseline cardioversion (reference: no baseline conversion) for selected time periods. Hazard ratios obtained by using an overlap weighted Cox model. Variables included in the weighting scheme are country and cohort enrolment, sex, age, ethnicity, type of atrial fibrillation, care setting speciality and location, congestive heart failure, acute coronary syndromes, vascular disease, carotid occlusive disease, previous stroke, transient ischaemic attack or systemic embolism, previous bleeding, venous thromboembolism, hypertension, hypercholesterolemia, diabetes, cirrhosis, moderate to severe chronic kidney disease, dementia, hyperthyroidism, hypothyroidism, current smoking, heavy alcohol consumption, body mass index, heart rate, systolic and diastolic blood pressure at diagnosis, baseline anticoagulation, and antiplatelet use
Fig 3.
Adjusted cumulative survival probabilities by baseline cardioversion and propensity score weighted hazard ratio for baseline cardioversion versus no baseline cardioversion (reference)
The analysis stratified by heart failure showed similar rates for all cause mortality in patients with and without heart failure. For non-haemorrhagic stroke or systemic embolism and major bleeding, the uncertainty around the estimates is too wide to identify any evidence of possible differences (tables S9 and S10).
Patient outcomes: pharmacological versus direct current cardioversion
Within one year of cardioversion, the mortality event rate per 100 person years was 1.70 (95% confidence interval 1.35 to 2.14) for patients treated with pharmacological cardioversion compared with 1.36 (1.13 to 1.64) among those treated with direct current cardioversion (P=0.14). The rates for non-haemorrhagic stroke or systemic embolism were 0.50 (0.33 to 0.76) and 0.47 (0.34 to 0.65), respectively (P=0.84), and for major bleeds 0.55 (0.36 to 0.82) and 0.64 (0.48 to 0.84), respectively (P=0.55; table 4). After adjusting for differences in baseline risk, the propensity score weighted hazard ratio for all cause mortality in the pharmacological cardioversion group compared with the direct current cardioversion group was 1.27 (0.89 to 1.80, P=0.18).
Table 4.
Event rates (per 100 person years) by cardioversion type from date of cardioversion up to one year
| Outcome | Pharmacological | Direct current | Crude HR (95% CI)* | Propensity score weighted HR (95% CI)* | |||
|---|---|---|---|---|---|---|---|
| Events | Rate (95% CI) | Events | Rate (95% CI) | ||||
| All cause mortality | 72 | 1.70 (1.35 to 2.14) | 110 | 1.36 (1.13 to 1.64) | 1.29 (0.96 to 1.73) | 1.27 (0.89 to 1.80) | |
| Non-haemorrhagic stroke or systemic embolism | 21 | 0.50 (0.33 to 0.76) | 38 | 0.47 (0.34 to 0.65) | 1.09 (0.64 to 1.85) | 0.89 (0.47 to 1.68) | |
| Major bleeding | 23 | 0.55 (0.36 to 0.82) | 51 | 0.64 (0.48 to 0.84) | 0.89 (0.54 to 1.45) | 1.03 (0.59 to 1.83) | |
HR=hazard ratio.
Reference: direct current.
Discussion
In this study of a large sample of patients with recent onset atrial fibrillation who were followed up for two years, a small number received cardioversion at baseline. Importantly, we found that patients treated with baseline cardioversion appeared to have a significantly lower mortality risk during follow-up after adjustment for known confounders (event rates per 100 patient years 2.52 v 3.87, weighted hazard ratio 0.75, 95% confidence interval 0.67 to 0.85, P<0.001). Our analyses show that most patients treated with cardioversion receive a direct current approach. Event rates for all cause mortality in these patients, given differences in baseline risk, appear similar to those for patients who received pharmacological cardioversion.
Of the 44 201 patients included in the analysis of cardioversion versus no cardioversion at baseline, an attempt was made to restore sinus rhythm in only 14.9%. Given that the study population consisted of patients with newly diagnosed atrial fibrillation, this number seems low. Studies suggest that recent onset atrial fibrillation responds favourably to rhythm control10 11 19 20 because a long duration of atrial fibrillation could make cardioversion less likely to succeed.21 22 23 24 Additionally, patients may experience symptom relief after rhythm control even when not obviously symptomatic before cardioversion.25 26 Therefore, international guidelines suggest a rhythm control strategy should be considered with the aim of reducing atrial fibrillation related symptoms and improving quality of life.11 However, several randomised controlled trials comparing rate control and rhythm control strategies have not found significant differences in mortality rates or other adverse outcomes, but a higher hospital rate has been reported for rhythm control.3 4 5 6 7 8 9 In the recently published EAST-AFNET 412 that included patients diagnosed one year or less before enrolment, a rhythm control strategy was associated with a lower risk of cardiovascular outcomes and a similar hospital admission rate compared with usual care among patients with early atrial fibrillation and cardiovascular conditions. Our observations support a rhythm control strategy being beneficial for patients with recent onset non-valvular atrial fibrillation.
In our dataset, direct current cardioversion was performed twice as often as pharmacological cardioversion. Previous data support the concept that direct current cardioversion has a higher success rate than pharmacological cardioversion,22 27 with quicker onset of effect, less monitoring, and fewer hospital admissions.28 29 Therefore, direct current cardioversion has emerged as the method of choice, although from a patient perspective, pharmacological cardioversion is often perceived as less frightening. Because of an increased risk of severe side effects, the options available for pharmacological cardioversion in patients with heart failure and reduced ejection fraction are limited. Amiodarone is often preferred but has a later onset of effect than other antiarrhythmic drugs.11 26 30 31 Therefore, when patients are considered for a rhythm control strategy, direct current cardioversion might be more appropriate. In our dataset, a higher proportion of patients in the direct current cardioversion group were observed to have a left ventricle ejection fraction <40%. Additionally, we believe that a driver for the difference between these groups might be that this form of cardioversion is preferred by clinicians, in accordance with current guidelines, for patients who are haemodynamically unstable.10 11 Nevertheless, the pharmacological cardioversion group had a higher proportion of patients with coronary artery disease.
Patients in GARFIELD-AF had at least one non-specified risk factor for stroke, and in our analysis of cardioversion type, we found that more than 95% in both cardioversion groups had a CHA2DS2-VASc score ≥1. However, only 57.6% of patients who received pharmacological cardioversion were treated with anticoagulants at baseline. The number was higher in the direct current cardioversion group in which 82.8% received anticoagulants. Most of our sample had an increased risk of stroke, and so it might have been more beneficial for patient outcome if a higher anticoagulation rate had been achieved. Anticoagulation treatment was registered at baseline. For some patients the choice of cardioversion could have come later and anticoagulation treatment might have been started at that point.
Considerable variations were found in choice of cardioversion modality from country to country. Patient comorbidities, treatment choice, and follow-up opportunities in the different countries might therefore have contributed to the differences observed between the two groups in the cardioversion modality analysis.
In the analysis comparing cardioversion with no cardioversion we found that fewer patients in the cardioversion group experienced a severe clinical event (all cause mortality, non-haemorrhagic stroke or systemic embolism, or major bleed) in the first year and from baseline to two year follow-up. Patients who received cardioversion had a lower risk profile at baseline. To better evaluate the effect of cardioversion, weighted hazard ratio prediction models were used. After adjusting for baseline risk, we found that there was a significant difference in mortality among the two treatment groups, within one and two years of follow-up. The lower all cause mortality rate was driven by less cardiovascular mortality. Risks of non-haemorrhagic stroke or systemic embolism, and major bleeding trended in the same direction. In two sensitivity analyses (the first with time at risk changed from time of inclusion to time of cardioversion; the second, with time at risk from time of inclusion but with baseline cardioversion status modified if cardioversion occurred), only negligible differences were found compared with the main analysis. Our study reported significantly lower rates of mortality in the cardioversion group and supports the use of rhythm control strategies over rate control strategies. Rhythm control strategies were started early after atrial fibrillation diagnosis in our study and in EAST-AFNET 4, which is in contrast to previous studies6 7 8; this might have contributed to the better outcomes reported in the rhythm control groups.
There was a trend of lower event rates in our study compared with the recently published EAST-AFNET 4. When considering baseline characteristics, we found that patients in GARFIELD-AF (in baseline cardioversion and no baseline cardioversion groups) appeared to have lower risk profiles than both study groups in EAST-AFNET 4. Additionally, EAST-AFNET 4 had a median follow-up of 5.1 years, while in GARFIELD-AF the follow-up was two years. This longer observational period subsequently leads to a study sample with more aged patients with higher risk (both studies only included patients with newly diagnosed atrial fibrillation). Therefore, a better risk profile at baseline combined with a shorter observational period are some potential causes of the lower event rates presented in our study. In contrast to EAST-AFNET, the Catheter Ablation versus Antiarrhythmic Drug Therapy for Atrial Fibrillation (CABANA) study32 reported similar mortality rates. Follow-up in the CABANA study was longer than in the present study, but baseline characteristics appeared comparable.
When we analysed patients who received pharmacological or direct current cardioversion, we found that the event rates for non-haemorrhagic stroke or systemic embolism, and major bleeding within the first year of cardioversion were similar in the two groups. After adjusting for known confounders, we found no significant difference in mortality rates. The low number of events made it difficult to obtain robust hazard ratio estimates to compare cardioversion type effects on other outcomes.
Strengths and limitations of the study
One strength of the GARFIELD-AF registry is the large study sample with patients represented from many countries, which improves generalisability to real world clinical practice. Data in the registry are observational and non-randomised, and for any comparisons the data had to be adjusted for potential confounding baseline factors. Cardioversion was not randomised and the rationale for varying treatment decisions is unknown; although robust statistical methods were used to account for differences between groups, the potential for residual confounding cannot be ruled out. Although several possible confounders were included in the propensity score weighting scheme, we were not able to account for factors such as healthier lifestyle, better surveillance, and adjunctive treatment. Other unrecognised factors might also have influenced the results and the application of falsification endpoints to check for residual confounding was not deemed feasible with the available recorded outcomes.
Information on type of cardioversion was only available from the follow-up forms and the modality is therefore not known for all cardioversions performed. Data on success and duration of a successfully restored sinus rhythm were not obtained. The precise treatment given for pharmacological cardioversion was not collected.
The decision to separate baseline cardioversions from follow-up cardioversions at 48 days was based on the requirement of previous anticoagulation treatment, and therefore this was an arbitrary choice. The analysis and the comparison between cardioversion and no cardioversion were applied to this group. Therefore, the results presented in this study might not be generalisable to patients with longer duration of atrial fibrillation. In the cardioversion type analysis, event rates were too low to calculate adjusted hazard ratios for non-fatal events. Therefore, differences in the baseline risk profile between the two groups should be taken into account when interpreting the results.
Clinical event rates were evaluated after two years in the cardioversion versus no cardioversion analysis and after one year when analysing the type of cardioversion. A longer observation time would be valuable when assessing the long-terms effects of the different interventions.
Conclusions
In this large dataset of patients with recent onset non-valvular atrial fibrillation, a small proportion were treated with cardioversion. Direct current cardioversion was performed twice as often as pharmacological cardioversion. No major difference in outcome events was observed for these two cardioversion modalities. For the overall cardioversion group, after adjusting for confounders, a significantly lower risk of mortality was found in patients who received cardioversion at baseline compared with those who did not receive this treatment at baseline.
What is already known on this topic
For decades direct comparisons of rhythm control and rate control strategies in patients with atrial fibrillation have favoured rate control
More recent results from real world observations on the effect of rhythm control versus rate control on clinical endpoints (such as strokes and mortality) in patients with new onset atrial fibrillation are inconclusive
What this study adds
A small proportion of patients were treated with cardioversion
Direct current cardioversion was performed twice as often as pharmacological cardioversion, and no major difference in outcome events was found for these two modalities
A lower risk of mortality was observed for patients with newly diagnosed atrial fibrillation who underwent early cardioversion compared with patients who did not have early cardioversion
Acknowledgments
We thank physicians, nurses, and patients contributing to the GARFIELD-AF registry. Editorial support was provided by Dr Surekha Damineni (Thrombosis Research Institute, London, UK). Programming support was provided by Madhusudana Rao (Thrombosis Research Institute). A complete list of investigators is given in the supplementary file.
Web extra.
Extra material supplied by authors
Web appendix 1: GARFIELD-AF Registry Investigators
Web appendix 2: Supplementary material
Contributors: JYLH, PJ, DAF, DA, AJC, and AKK contributed to the study design. SV and KSP analysed the data. MKP, TSH, and RC provided the interpretation of results and contributed to the drafting. All authors supervised the data analysis, provided the interpretation of results, and contributed to the drafting and critical review of the manuscript. All authors approved the final draft. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted. DA is the guarantor of this study.
Funding: This work is supported by Kantor Charitable Foundation for the Kantor-Kakkar Global Centre for Thrombosis Science. The funding source had no involvement in trial design, collection and analysis of data, or in the writing process of this paper.
Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: support from Kantor Charitable Foundation for the Kantor-Kakkar Global Centre for Thrombosis Science for the submitted work. TSH reports personal fees from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Imedic, Novartis, MSD, Sanofi, and Pfizer. JYLH reports personal fees from Bayer, BMS/Pfizer, Boehringer Ingelheim, and Daiichi-Sankyo. PJ has served as a consultant or on an advisory board for Bayer, Boehringer Ingelheim, and Novartis. RC reports research grants from Boston Scientific, Medtronic, Abbott, Pfizer, Daiichi Sankyo, Biosense Webster, Boehringer Ingelheim, Johnson and Johnson, and personal fees from Boston Scientific, Medtronic, Biosense Webster, Abbott. DA reports personal fees from Bayer, Boehringer-Ingelheim, Bristol Meier Squibb, MSD and Pfizer, and grants to the institution from Medtronic and BMS. AJC has received institutional grant funding and personal fees from Bayer, Boehringer Ingelheim, Bristol Meier Squibb, Daiichi Sankyo, and Pfizer. AKK has received grants from Bayer AG, and Sanofi, personal fees from Bayer AG, Janssen, Pfizer, Sanofi, Verseon, and Anthos Therapeutics. All other authors have reported that they have no relationships relevant to the content of this paper to disclose.
Patient consent: Obtained.
The lead author (DA) affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned have been explained.
Dissemination to participants and related patient and public communities: We plan to disseminate the results to clinical study sites. We also plan to disseminate the research results through media releases (mainly by the research institutions of the authors), and to distribute the paper to clinicians.
Provenance and peer review: Not commissioned; externally peer reviewed.
Contributor Information
Collaborators: GARFIELD-AF investigators, Jean-Pierre Bassand, Keith A A Fox, Bernard J Gersh, Samuel Z Goldhaber, Shinya Goto, Sylvia Haas, Werner Hacke, Lorenzo G Mantovani, Frank Misselwitz, Alexander G G Turpie, Martin van Eickels, Freek W A Verheugt, Hector Lucas Luciardi, Harry Gibbs, Marianne Brodmann, Frank Cools, Antonio Carlos Pereira Barretto, Stuart J Connolly, John Eikelboom, Ramon Corbalan, Zhi-Cheng Jing, Jørn Dalsgaard Nielsen, Hany Ragy, Pekka Raatikainen, Harald Darius, Matyas Keltai, Jitendra Pal Singh Sawhney, Giancarlo Agnelli, Giuseppe Ambrosio, Yukihiro Koretsune, Carlos Jerjes Sánchez Díaz, Hugo Ten Cate, Janina Stepinska, Elizaveta Panchenko, Toon Wei Lim, Barry Jacobson, Seil Oh, Xavier Viñolas, Marten Rosenqvist, Jan Steffel, Pantep Angchaisuksiri, Ali Oto, Alex Parkhomenko, Wael Al Mahmeed, Samuel Z Goldhaber, Dayi Hu, Kangning Chen, Yusheng Zhao, Huaiqin Zhang, Jiyan Chen, Shiping Cao, Daowen Wang, Yuejin Yang, Weihua Li, Hui Li, Yuehui Yin, Guizhou Tao, Ping Yang, Yingmin Chen, Shenghu He, Yong Wang, Guosheng Fu, Xin Li, Tongguo Wu, Xiaoshu Cheng, Xiaowei Yan, Ruiping Zhao, Moshui Chen, Longgen Xiong, Ping Chen, Yang Jiao, Ying Guo, Li Xue, Zhiming Yang, Praveen Jadhavm, Raghava Sarma, Govind Kulkarni, Prakash Chandwani, Rasesh Atulbhai Pothiwala, Mohanan Padinhare Purayil, Kamaldeep Chawla, Veerappa Annasaheb Kothiwale, Bagirath Raghuraman, Vinod Madan Vijan, Jitendra Sawhney, Ganapathi Bantwal, Aziz Khan, Ramdhan Meena, Manojkumar Chopada, Sunitha Abraham, Vikas Bisne, Govindan Vijayaraghavan, Debabrata Roy, Rajashekhar Durgaprasad, A G Ravi Shankar, Sunil Kumar, Dinesh Jain, Kartikeya Bhargava, Vinay Kumar, Udigala Madappa Nagamalesh, Rajeeve Kumar Rajput, Yukihiro Koretsune, Seishu Kanamori, Kenichi Yamamoto, Koichiro Kumagai, Yosuke Katsuda, Keiki Yoshida, Fumitoshi Toyota, Yuji Mizuno, Ikuo Misumi, Hiroo Noguchi, Shinichi Ando, Tetsuro Suetsugu, Masahiro Minamoto, Hiroyuki Oda, Susumu Adachi, Kei Chiba, Hiroaki Norita, Makoto Tsuruta, Takeshi Koyanagi, Kunihiko Yamamoto, Hiroshi Ando, Takayuki Higashi, Megumi Okada, Shiro Azakami, Shinichiro Komaki, Kenshi Kumeda, Takashi Murayama, Jun Matsumura, Yurika Oba, Ryuji Sonoda, Kazuo Goto, Kotaro Minoda, Yoshikuni Haraguchi, Hisakazu Suefuji, Hiroo Miyagi, Hitoshi Kato, Tsugihiro Nakamura, Tadashi Nakamura, Hidekazu Nandate, Ryuji Zaitsu, Yoshihisa Fujiura, Akira Yoshimura, Hiroyuki Numata, Jun Ogawa, Yasuyuki Kamogawa, Kinshiro Murakami, Yutaka Wakasa, Masanori Yamasawa, Hiromitsu Maekawa, Sumihisa Abe, Hajime Kihara, Satoru Tsunoda, Katsumi Saito, Hiroki Tachibana, Ichiro Oba, Takashi Kuwahata, Satoshi Higa, Masamichi Gushiken, Takuma Eto, Hidetoshi Chibana, Kazuaki Fujisawa, Yuhei Shiga, Hirokuni Sumi, Toshihisa Nagatomo, Yoshihiko Atsuchi, Toshiro Nagoshi, Kazuhisa Sanno, Fumihiro Hoshino, Naoto Yokota, Masahiro Kameko, Toshifumi Tabuchi, Munesumi Ishizawa, Yoshitake Fujiura, Daisuke Ikeda, Taku Seto, Tetsu Iwao, Norio Ishioka, Koichi Oshiro, Keizo Tsuchida, Yutaka Hatori, Motoshi Takeuchi, Hiroto Takezawa, Shinjiro Nagano, Masaaki Iwaki, Yuichiro Nakamura, Naomasa Miyamoto, Toshifumi Taguchi, Ko Ashida, Naoto Yoshizawa, Jun Agata, Seishiro Matsukawa, Osamu Arasaki, Shuji Fukuoka, Hirofumi Murakami, Kazuya Mishima, Yoshiki Hata, Ichiro Sakuma, Kotaro Obunai, Ichiro Takamura, Mitsuyuki Akutsu, Toshihide Unoki, Yoshinori Go, Makoto Ikemura, Shoji Morii, Shigeru Marusaki, Hideo Doi, Mitsuru Tanaka, Takaaki Kusumoto, Shigeo Kakinoki, Chiga Ogurusu, Kazuya Murata, Masaki Shimoyama, Masami Nakatsuka, Yutaka Kitami, Yoichi Nakamura, Hiroshi Oda, Rikimaru Oyama, Masato Ageta, Teruaki Mita, Kazuhiko Nagao, Takafumi Mito, Junichi Minami, Mitsunori Abe, Masako Fujii, Makoto Okawa, Tsuneo Fujito, Toshiya Taniguchi, Tenei Ko, Hiroshi Kubo, Mizuho Imamaki, Masahiro Akiyama, Takashi Ueda, Hironori Odakura, Masahiko Inagaki, Yoshiki Katsube, Atsuyuki Nakata, Shinobu Tomimoto, Mitsuhiro Shibuya, Masayuki Nakano, Kenichiro Ito, Masahiro Matsuta, Motoyuki Ishiguro, Taro Minagawa, Masamichi Wada, Hiroaki Mukawa, Masato Mizuguchi, Fumio Okuda, Teruaki Kimura, Kuniaki Taga, Masaaki Techigawara, Morio Igarashi, Hiroshi Watanabe, Toshihiko Seo, Shinya Hiramitsu, Hiroaki Hosokawa, Mitsumoto Hoshiai, Michitaka Hibino, Koichi Miyagawa, Hideki Horie, Nobuyoshi Sugishita, Yukio Shiga, Akira Soma, Kazuo Neya, Tetsuro Yoshida, Kunio Akahane, Sen Adachi, Chiei Takanaka, Takashi Ueda, Saori Matsui, Hirofumi Kanda, Masanori Kaneko, Shiro Nagasaka, Atsushi Taguchi, Shuta Toru, Kazuyuki Saito, Akiko Miyashita, Hiroki Sasaguri, Jin Nariyama, Taketo Hatsuno, Takash Iwase, Kazuki Sato, Kazuya Kawai, Tomobumi Kotani, Tsuyoshi Tsuji, Hirosumi Sakai, Kiyoshi Nishino, Kenichi Ikeda, Kazuo Maeda, Tomohiro Shinozuka, Takeshi Inoue, Koichi Kawakami, Hiromichi Kitazumi, Tsutomu Takagi, Mamoru Hamaoka, Jisho Kojima, Akitoshi Sasaki, Yoshihiro Tsuchiya, Tetsuo Betsuyaku, Koji Higuchi, Masaaki Honda, Koichi Hasegawa, Takao Baba, Kazuaki Mineoi, Toshihiko Koeda, Kunihiko Hirasawa, Toshihide Kumazaki, Akira Nakagomi, Eiji Otaki, Takashi Shindo, Hiroyoshi Hirayama, Chikako Sugimoto, Takashi Yamagishi, Ichiro Mizuguchi, Kazunori Sezaki, Isamu Niwa, Ken Takenaka, Osamu Iiji, Koichi Taya, Hitoshi Kitazawa, Samu Ueda, Hirokazu Kakuda, Takuya Ono, Seizo Oriso, Junya Kamata, Toshihiko Nanke, Itaru Maeda, Yoshifusa Matsuura, Hiroki Teragawa, Yasuyuki Maruyama, Kazuo Takei, Hajime Horie, Tetsutaro Kito, Hiroshi Asano, Koji Matsushita, Masaichi Nakamura, Takashi Washizuka, Tomoki Yoshida, Masato Sawano, Shinichi Arima, Hidekazu Arai, Hisanori Shinohara, Hiroyuki Takai, Nobufusa Furukawa, Akira Ota, Kentaro Yamamoto, Kenji Aoki, Taku Yamamoto, Takeaki Kasai, Shunji Suzuki, Shu Suzuki, Nitaro Shibata, Masayuki Watanabe, Yosuke Nishihata, Toru Arino, Masaki Okuyama, Tetsushi Wakiyama, Tomoko Kato, Yasuo Sasagawa, Takeshi Tana, Yoshihito Hayashi, Shinichi Hirota, Yukihiko Abe, Yoshihiro Saito, Hirohide Uchiyama, Hiroshi Takeda, Hiroshi Ono, Shuichi Tohyo, Naoto Hanazono, Seiichi Miyajima, Hisashi Shimono, Takuma Aoyama, Yasunobu Shozawa, Yawara Niijima, Osamu Murai, Osamu Murai, Hideko Inaba, Katsumasa Nomura, Masatsugu Nozoe, Kazuo Suzuki, Toshiyuki Furukawa, Toshihiko Shiraiwa, Nobuhisa Ito, Shunichi Nagai, Kiyoharu Sato, Shiro Nakahara, Yujin Shimoyama, Naoko Ohara, Teruhiko Kozuka, Hideaki Okita, Masato Endo, Tsutomu Goto, Makoto Hirose, Emiko Nagata, Noriyuki Nakanishi, Toshizumi Mori, Shuichi Seki, Katsuhiro Okamoto, Osamu Moriai, Yoko Emura, Tsuyoshi Fukuda, Haruhiko Date, Shuichi Kawakami, Sho Nagai, Yuya Ueyama, Tetsuro Fudo, Mitsuru Imaizumi, Takuo Ogawa, Shunsuke Take, Hideo Ikeda, Hiroaki Nishioka, Norihiko Sakamoto, Kiyomitsu Ikeoka, Nobuo Wakaki, Masatake Abe, Junji Doiuchi, Tetsuya Kira, Masato Tada, Ken Tsuzaki, Naoya Miura, Yasuaki Fujisawa, Wataru Furumoto, Susumu Suzuki, Akinori Fujisawa, Ryosai Nakamura, Hiroyasu Komatsu, Rei Fujiki, Shuichi Kawano, Keijiro Nishizawa, Yoji Kato, Junya Azuma, Kiyoshi Yasui, Toshio Amano, Yasuhiro Sekine, Tatsuo Honzawa, Yuichiro Koshibu, Yasuhide Sakamoto, Yukihiro Seta, Shingo Miyaguchi, Kojuro Morishita, Yasuko Samejima, Toyoshi Sasaki, Fumiko Iseki, Toshiyuki Kobayashi, Hiroshi Kano, Jaeyoung Kim, Hiroshi Yamaguchi, Yoichi Takagi, Yoko Onuki Pearce, Yasuyuki Suzuki, Takayuki Fukui, Toru Nakayama, Hideaki Kanai, Yoshiyuki Kawano, Tetsuji Ino, Hironori Miyoshi, Yasufumi Miyamoto, Masahito Shigekiyo, Shimato Ono, Yoshiyuki Kawano, Yutaka Okamoto, Satoshi Ubukata, Kojiro Kodera, Tatsuo Oriuchi, Naoki Matsumoto, Koichi Inagaki, Atsushi Iseki, Tomohiro Yoshida, Toshihiro Goda, Tsukasa Katsuki, Atsushi Sato, Etsuo Mori, Toshio Tsubokura, Hiroshi Shudo, Shunichi Fujimoto, Tomohiro Katsuya, Yoshiyuki Furukawa, Hiroshi Hosokawa, Jun Narumi, Kiichiro Yamamoto, Masaki Owari, Takuya Inakura, Takafumi Anno, Kazuyuki Shirakawa, Chi Keong Ching, Toon Wei Lim, David Foo, Kelvin Wong, Tan Yuyang, Seil Oh, Hui Nam Park, Woo-Shik Kim, HyeYoung Lee, Sung-Won Jang, Dae Hyeok Kim, Jun Kim, DongRyeol Ryu, Jaemin Shim, Dae-Kyeong Kim, Dong Ju Choi, Yong Seog Oh, Myeong-Chan Cho, Hack-Lyoung Kim, Hui-Kyung Jeon, Dong-Gu Shin, Sang Weon Park, Hoon Ki Park, Sang-Jin Han, Jung Hoon Sung, Hyung-Wook Park, Gi-Byoung Nam, Young Keun On, Hong Euy Lim, JaeJin Kwak, Tae-Joon Cha, Taek Jong Hong, Seong Hoon Park, Jung Han Yoon, Nam-Ho Kim, Kee-Sik Kim, Byung Chun Jung, Gyo-Seung Hwang, Chong-Jin Kim, Sakda Rungaramsin, Peerapat Katekangplu, Porames Khunrong, Thanita Bunyapipat, Wanwarang Wongcharoen, Pinij Kaewsuwanna, Khanchai Siriwattana, Waraporn Tiyanon, Supalerk Pattanaprichakul, Khanchit Likittanasombat, Doungrat Cholsaringkarl, Warangkana Boonyapisit, Sirichai Cheewatanakornkul, Songkwan Silaruks, Pisit Hutayanon, Seksan Chawanadelert, Pairoj Chattranukulchai, Boonsert Chatlaong, Yingsak Santanakorn, Khompiya Kanokphatcharakun, Piya Mongkolwongroj, Sasivimon Jai-Aue, Ongkarn Komson, Armagan Altun, Ali Aydinlar, Ramazan Topsakal, Zeki Ongen, Sadik Acikel, Durmus Yildiray Sahin, Ozcan Yilmaz, Mehmet Birhan Yilmaz, Hasan Pekdemir, Mesut Demir, Murat Sucu, Levent Sahiner, Ali Oto, Murat Ersanli, Ertugrul Okuyan, Dursun Aras, Florencia Rolandi, Adrian Cesar Ingaramo, Gustavo Alberto Sambadaro, Vanina Fernandez Caputi, Hector Luciardi, Sofia Graciela Berman, Pablo Dragotto, Andres Javier Kleiban, Nestor Centurion, Rodolfo Andres Ahuad Guerrero, Leonel Adalberto Di Paola, Ricardo Dario Dran, Javier Egido, Matias Jose Fosco, Victor Alfredo Sinisi, Luis Rodolfo Cartasegna, Oscar Gomez Vilamajo, Jose Luis Ramos, Sonia Sassone, Gerardo Zapata, Diego Conde, Guillermo Giacomi, Alberto Alfredo Fernandez, Mario Alberto Berli, Fabian Ferroni, Dário Celestino Sobral Filho, Jefferson Jaber, Luciana Vidal Armaganijan, Costantino Roberto Frack Costantini, André Steffens, Weimar Kunz Sebba Barroso de Souzaem, João David de Souza Neto, José Márcio Ribeiro, Marcelo Silveira Teixeira, Paulo Rossi, Leonardo Pires, Daniel Moreira, José Carlos Moura Jorge, Adalberto Menezes Lorga Filho, Luiz Bodanese, Marcelo Westerlund Montera, Carlos Henrique Del Carlo, Jamil Abdalla Saad, Fernando Augusto Alves da Costa, Renato Lopes, Gilson Roberto de Araújo, Euler Roberto Manenti, Jose Francisco Kerr Saraiva, João Carlos Ferreira Braga, Alexandre Negri, Carlos Moncada, Dalton Precoma, Fernando Roquette, Gilmar Reis, Roberto Álvaro Ramos Filho, Estêvão Lanna Figueiredo, Roberto Vieira Botelho, Cláudio Munhoz da Fontoura Tavares, Helius Carlos Finimundi, Adriano Kochi, César Cássio Broilo França, Fábio Alban, Guido Bernardo Aranha Rosito, João Batista de Moura Xavier Moraes Junior, Rogério Tadeu Tumelero, Lilia Maia, Roberto Simões de Almeida, Ney Carter do Carmo Borges, Luís Gustavo Gomes Ferreira, Ramón Corbalán, Benjamin Aleck Joseh Stockins Fernandez, Humberto Montecinos, Fernando Lanas, Martín Larico Gómez, Carlos Astudillo, Carlos Conejeros, Patricio Marin Cuevas, Alejandro Forero, Claudio Bugueño Gutiérrez, Juan Aguilar, Sergio Potthoff Cardenas, German Eggers, Cesar Houzvic, Carlos Rey, Germán Arriagada, Gustavo Charme Vilches, Jesus Jaime Illescas Diaz, Raul Leal Cantu, Maria Guadalupe Ramos Zavala, Ricardo Cabrera Jardines, Nilda Espinola Zavaleta, Enrique Lopez Rosas, Guillermo Antonio Llamas Esperón, Gerardo Pozas, Ernesto Cardona Muñoz, Norberto Matadamas Hernandez, Adolfo Leyva Rendon, Norberto Garcia Hernandez, Manuel de los Rios Ibarra, Luis Ramon Virgen Carrillo, David Lopez Villezca, Carlos Hernandez Herrera, Juan Jose Lopez Prieto, Rodolfo Gaona Rodriguez, Efrain Villeda Espinosa, David Flores Martinez, Jose Velasco Barcena, Omar Fierro Fierro, Ignacio Rodriguez Briones, Jose Luis Leiva Pons, Humberto Alvarez Lopez, Rafael Olvera Ruiz, Carlos Gerardo Cantu Brito, Eduardo Julian Jose Roberto Chuquiure Valenzuela, Roxana Reyes Sanchez, Alberto Esteban Bazzoni Ruiz, Oscar Martin Lopez Ruiz, Roberto Arriaga Nava, Jesus David Morales Cerda, Pedro Fajardo Campos, Mario Benavides Gonzalez, Marianne Brodmann, Kurt Lenz, Claus Hagn, Johannes Foechterle, Heinz Drexel, Kurt Huber, Andrea Podczeck-Schweighofer, Michael Winkler, Bruno Schneeweiss, Alfons Gegenhuber, Wilfried Lang, Sabine Eichinger-Hasenauer, Peter Kaserer, Josef Sykora, Heribert Rasch, Bernhard Strohmer, Luc Capiau, Geert Vervoort, Bart Wollaert, Frank Cools, Geert Hollanders, Jan Vercammen, Dirk Faes, Yohan Balthazar, Marc Delforge, Olivier Xhaet, Harry Striekwold, John Thoeng, Kurt Hermans, Georges Mairesse, Wim Anné, Ivan Blankoff, Michel Beutels, Stefan Verstraete, Peter Vandergoten, Philippe Purnode, Pascal Godart, Tim Boussy, Philippe Desfontaines, Alex Heyse, Joeri Voet, Axel De Wolf, Eva Zidkova, Rudolf Spacek, Vilma Machova, Ondrej Ludka, Josef Olsr, Lubos Kotik, Blazej Racz, Richard Ferkl, Jan Hubac, Ilja Kotik, Zdenek Monhart, Hana Burianova, Ondrej Jerabek, Jana Pisova, Iveta Petrova, Vratislav Dedek, Michaela Honkova, Petr Podrazil, Petr Reichert, Jindrich Spinar, Miroslav Novak, Vaclav Durdil, Katarina Plocova, Jiri Lastuvka, Jørn Nielsen, Steen Husted, Helena Dominguez, Ulrik Hintze, Søren Rasmussen, Næstved Sygehus, Arne Bremmelgaard, John Markenvard, Jan Børger, Jorgen Solgaard, Ebbe Eriksen, Thomas Løkkegaard, Michael Bruun, Jacob Mertz, Morten Schou, Helena Dominguez, Michael Olsen, Pekka Raatikainen, K E Juhani Airaksinen, Franck Paganelli, Joël Ohayon, Frédéric Casassus, Jean-Yves Le Heuzey, Michel Galinier, Yannick Gottwalles, Philippe Loiselet, Jean-Joseph Muller, Mohamed Bassel Koujan, André Marquand, Sylvain Destrac, Olivier Piot, Nicolas Delarche, Jean-Pierre Cebron, Maxime Guenoun, Dominique Guedj-Meynier, A G Lokesh, Mathieu Zuber, Pierre Amarenco, Emmanuel Ellie, James Kadouch, Pierre-Yves Fournier, Jean-Pierre Huberman, Nestor Lemaire, Gilles Rodier, Xavier Vandamme, Igor Sibon, Jean-Philippe Neau, Marie Hélène Mahagne, Antoine Mielot, Marc Bonnefoy, Jean-Baptiste Churet, Vincent Navarre, Frederic Sellem, Gilles Monniot, Jean-Paul Boyes, Bernard Doucet, Michel Martelet, Désiré Obadia, Bernard Crousillat, Joseph Mouallem, Etienne Bearez, Jean Philippe Brugnaux, Alain Fedorowsky, Pierre Nazeyrollas, Jean-Baptiste Berneau, Frédéric Chemin, Sebastien Schellong, Harald Darius, Georg Koeniger, Andreas Kopf, Uwe Gerbaulet, Bernd-Thomas Kellner, Thomas Schaefer, Jan Purr, Enno Eißfeller, Heinz-Dieter Zauzig, Peter Riegel, Christoph Axthelm, Gerd-Ulrich Heinz, Holger Menke, Andreas Pustelnik, Stefan Zutz, Wolfgang Eder, Guenter Rehling, Dirk Glatzel, Norbert Ludwig, Petra Sandow, Henning Wiswedel, Cosmas Wildenauer, Steffen Schoen, Toralf Schwarz, Adyeri Babyesiza, Maximilian Kropp, Hans-Hermann Zimny, Friedhelm Kahl, Andreas Caspar, Sabine Omankowsky, Torsten Laessig, Hermann-Josef Hartmann, Gunter Lehmann, Hans-Walter Bindig, Gunter Hergdt, Dietrich Reimer, Joachim Hauk, Holger Michel, Praxis Dres, Werner Erdle, Wilfried Dorsch, Janna Dshabrailov, Karl-Albrecht Rapp, Reinhold Vormann, Thomas Mueller, Peter Mayer, Uwe Horstmeier, Volker Eissing, Heinz Hey, Heinz Leuchtgens, Volker Lilienweiss, Heiner Mueller, Christian Schubert, Herrmann Lauer, Thomas Buchner, Gunter Brauer, Susanne Kamin, Karsten Mueller, Sylvia Baumbach, Muwafeg Abdel-Qader, Hans-Holger Ebert, Carsten Schwencke, Peter Bernhardt, Laszlo Karolyi, Britta Sievers, Wilhelm Haverkamp, Jens-Uwe Roehnisch, Andras Vertes, Gabor Szantai, Andras Matoltsy, Nikosz Kanakaridisz, Zoltan Boda, Erno Kis, Balazs Gaszner, Ferenc Juhasz, Gizella Juhasz, Sandor Kancz, Zoltan Laszlo, Zsolt May, Bela Merkely, Ebrahim Noori, Tamas Habon, Peter Polgar, Gabriella Szalai, Sandor Vangel, Andras Nagy, Gabriella Engelthaler, Judit Ferenczi, Mihaly Egyutt, Giuliana Martini, Leone Maria Cristina, Eros Tiraferri, Rita Santoro, Sophie Testa, Giovanni Di Minno, Marco Moia, Teresa Maria Caimi, Maria Tessitori, Giancarlo Agnelli, Roberto Cappelli, Daniela Poli, Roberto Quintavalla, Franco Cosmi, Raffaele Fanelli, Vincenzo Oriana, Raffaele Reggio, Roberto Santi, Leonardo Pancaldi, Raimondo De Cristofaro, Giuliana Guazzaloca, Angelo De Blasio, Jorge Salerno Uriate, Flavia Lillo, Enrico Maria Pogliani, Grzegorz Bilo, Michele Accogli, Antonio Mariani, Mauro Feola, Arturo Raisaro, Luciano Fattore, Andrea Mauric, Fabrizio Germini, Luca Tedeschi, Maria Settimi, Sergio Nicoli, Paolo Ricciarini, Antonio Argena, Paolo Ronchini, Claudio Bulla, Filippo Tradati, Massimo Volpe, Maria D’Avino, Maria Grazia Bongiorni, Silva Severi, Alessandro Capucci, Corrado Lodigiani, Enrico Salomone, Gaetano Serviddio, Claudio Tondo, Giuseppe Ambrosio, Paolo Golino, Carmine Mazzone, Saverio Iacopino, Hugo ten Cate, J H Ruiter, Andreas Lucassen, Henk Adriaansen, Maarten Bongaerts, Mathijs Pieterse, Coen van Guldener, Johannes Herrman, S H K P R Nierop, Pieter Hoogslag, Walter Hermans, B E Groenemeijer, W Terpstra, Cees Buiks, L V A Boersma, Eivind Berge, Per Anton Sirnes, Erik Gjertsen, Torstein Hole, Knut Erga, Arne Hallaråker, Gunnar Skjelvan, Anders Østrem, Beraki Ghezai, Arne Svilaas, Peter Christersson, Torbjørn Øien, Svein Høegh Henrichsen, Jan Erik Otterstad, Jan Berg-Johansen, Janina Stepinska, Andrzej Gieroba, Malgorzata Biedrzycka, Michal Ogorek, Beata Wozakowska-Kaplon, Krystyna Loboz-Grudzien, Wieslaw Supinski, Jerzy Kuzniar, Roman Zaluska, Jaroslaw Hiczkiewicz, Lucyna Swiatkowska-Byczynska, Lech Kucharski, Marcin Gruchala, Piotr Minc, Maciej Olszewski, Grzegorz Kania, Malgorzata Krzciuk, Zbigniew Lajkowski, Bozenna Ostrowska-Pomian, Jerzy Lewczuk, Elzbieta Zinka, Agnieszka Karczmarczyk, Malgorzata Chmielnicka-Pruszczynska, Iwona Wozniak-Skowerska, Grzegorz Opolski, Marek Bronisz, Marcin Ogorek, Grazyna Glanowska, Piotr Ruszkowski, Grzegorz Skonieczny, Ryszard Sciborski, Boguslaw Okopien, Piotr Kukla, Krzysztof Galbas, Krzysztof Cymerman, Jaroslaw Jurowiecki, Pawel Miekus, Waldemar Myszka, Stanislaw Mazur, Roman Lysek, Jacek Baszak, Teresa Rusicka-Piekarz, Grzegorz Raczak, Ewa Domanska, Jadwiga Nessler, Jozef Lesnik, Vera Eltishcheva, Roman Libis, Gadel Kamalov, Dmitry Belenky, Liudmila Egorova, Alexander Khokhlov, Eduard Yakupov, Dmitry Zateyshchikov, Olga Barbarash, Olga Miller, Evgeniy Mazur, Konstantin Zrazhevskiy, Tatyana Novikova, Yulia Moiseeva, Elena Polkanova, Konstantin Sobolev, Maria Rossovskaya, Yulia Shapovalova, Alla Kolesnikova, Konstantin Nikolaev, Oksana Zemlianskaia, Anna Zateyshchikova, Victor Kostenko, Sergey Popov, Maria Poltavskaya, Anton Edin, Elena Aleksandrova, Oksana Drapkina, Alexander Vishnevsky, Oleg Nagibovich, Petr Chizhov, Svetlana Rachkova, Mikhail Sergeev, Borys Kurylo, Alexey Ushakov, Xavier Vinolas, Pere Alvarez Garcia, Maria Fernanda Lopez Fernandez, Luis Tercedor Sanchez, Salvador Tranche Iparraguirre, Pere Toran Monserrat, Emilio Marquez Contreras, Jordi Isart Rafecas, Juan Motero Carrasco, Pablo Garcia Pavia, Casimiro Gomez Pajuelo, Luis Miguel Rincon Diaz, Luis Fernando Iglesias Alonso, Angel Grande Ruiz, Jordi Merce Klein, Jose Ramon Gonzalez Juanatey, Ines Monte Collado, Herminia Palacin Piquero, Carles Brotons Cuixart, Esther Fernandez Escobar, Joan Bayo i Llibre, Cecilia Corros Vicente, Manuel Vida Gutierrez, Francisco Epelde Gonzalo, Carlos Alexandre Almeida Fernandez, Encarnacion Martinez Navarro, Jordi Isart Rafecas, Juan Jose Montero Alia, Maria Barreda Gonzalez, Maria Angels Moleiro Oliva, Jose Iglesias Sanmartin, Mercedes Jimenez Gonzalez, Maria del Mar Rodriguez Alvarez, Juan Herreros Melenchon, Tomas Ripoll Vera, Manuel Jimenez Navarro, Maria Vazquez Caamano, Maria Fe Arcocha Torres, Gonzalo Marcos Gomez, Andres Iniguez Romo, Miguel Angel Prieto Diaz, Mårten Rosenqvist, Alexander Wirdby, Jan Lindén, Kerstin Henriksson, Micael Elmersson, Arnor Egilsson, Ulf Börjesson, Gunnar Svärd, Bo Liu, Anders Lindh, Lars-Bertil Olsson, Mikael Gustavsson, Lars Andersson, Lars Benson, Claes Bothin, Ali Hajimirsadeghi, Björn Martinsson, Marianne Ericsson, Åke Ohlsson, Håkan Lindvall, Peter Svensson, Katarina Thörne, Hans Händel, Pyotr Platonov, Fredrik Bernsten, Ingar Timberg, Milita Crisby, Jan-Erik Karlsson, Agneta Andersson, Lennart Malmqvist, Johan Engdahl, Jörgen Thulin, Aida Hot-Bjelak, Steen Jensen, Per Stalby, Jan Steffel, Johann Debrunner, Juerg H Beer, Dipen Shah, Iurii Rudyk, Vira Tseluyko, Oleksandr Karpenko, Svitlana Zhurba, Igor Kraiz, Oleksandr Parkhomenko, Iryna Kupnovytska, Nestor Seredyuk, Yuriy Mostovoy, Oleksiy Ushakov, Olena Koval, Igor Kovalskiy, Yevgeniya Svyshchenko, Oleg Sychov, Mykola Stanislavchuk, Andriy Yagensky, Susanna Tykhonova, Ivan Fushtey, Will Murdoch, Naresh Chauhan, Daryl Goodwin, Louise Lumley, Ramila Patel, Philip Saunders, Bennett Wong, Alex Cameron, Philip Saunders, Niranjan Patel, P Jhittay, Andrew Ross, M S Kainth, Karim Ladha, Kevin Douglas, Gill Pickavance, Joanna McDonnell, Laura Handscombe, Trevor Gooding, Helga Wagner, Colin Bradshaw, Catherine Bromham, Kevin Jones, Shoeb Suryani, Richard Coates, Bhupinder Sarai, W Willcock, S Sircar, John Cairns, A Gilliand, Roman Bilas, E Strieder, Peter Hutchinson, Anne Wakeman, Michael Stokes, Graham Kirby, Bhaskhar Vishwanathan, Nigel Bird, Paul Evans, M Clark, John Bisatt, Jennifer Litchfield, E Fisher, Tim Fooks, Richard Kelsall, Neil Paul, Elizabeth Alborough, Michael Aziz, C Ramesh, Pete Wilson, Simon Franklin, Sue Fairhead, Julian Thompson, Hasan Chowan, Gary Taylor, Dawn Tragen, Matt Parfitt, Claire Seamark, Carolyn Paul, Mark Richardson, Angus Jefferies, Helen Sharp, Hywel Jones, Claire Giles, Matthew Bramley, Philip Williams, Jehad Aldegather, Simon Wetherell, William Lumb, Phil Evans, Frances Scouller, Neil Macey, Stephen Rogers, Yvette Stipp, Richard West, Philip Pinney, Paul Wadeson, John Matthews, Preeti Pandya, Andrew Gallagher, T Railton, Emyr Davies, Jonathan McClure, Marc Jacobs, Claire Hutton, R Thompson, Bijoy Sinha, Keith Butter, Susan Barrow, Helen Little, David Russell, Ulka Choudhary, Ikram Haq, Paul Ainsworth, Claire Jones, Phil Weeks, Jane Eden, Lisa Gibbons, Janet Glencross, Alison MacLeod, K Poland, Conor Mulolland, A Warke, Paul Conn, D Burns, R Smith, R Kamath, Jonathan Webster, Ian Hodgins, Stephen Vercoe, Paul Roome, Hilary Pinnock, Jayesh Patel, Amar Ali, Nigel Hart, Richard Davies, Nigel De-Sousa, Catherine Neden, Mark Danielsen, Purnima Sharma, Sophia Galloway, Charlotte Hawkins, Raife Oliver, Martin Aylward, Mira Pattni, Gordon Irvine, Shahid Ahmad, Catherine Rothwell, Fiaz Choudhary, Sabrina Khalaque, Stephanie Short, Sharon Peters, Warwick Coulson, Neil Roberts, Amy Butler, Steven Coates, Ben Ward, Daniel Jackson, Steve Walton, Diane Shepherd, Toh Wong, Mark Boon, Melanie Deacon, David Cornelius, Sarah Davies, Ben Frankel, Nick Hargreaves, Henry Choi, Jon Sumner, Tim Myhill, Salah Estifanos, Diane Geatch, Justin Wilkinson, Richard Veale, Karen Forshaw, Rob Hirst, Kashif Zaman, Catherine Liley, Rebecca Wastling, Paul McEleny, Andre Beattie, Philip Cooke, Mike Wong, Mark Pugsley, Chaminda Dooldeniya, Greg Rogers, James Bennett, Polly Jacobs, Rajesh Muvva, Matthew Adam, Robin Fox, Nicolas Thomas, Simon Cartwright, Rory Reed, Simon Randfield, Christine A’Court, Ann Flynn, Andrew Halpin, Shoeb Suryani, Simon Dobson, Louise Lomax, Minnal Nadaph, Iain Munro, Jane Goram, Helen Stoddart, Phil Simmons, John Shewring, Emma Bowen-Simpkins, Mark Rickenbach, Polly Jacobs, Adam Blenkhorn, Bhuwanendu Singh, Penny Astridge, William van Gaal, Walter Abhayaratna, Philip Thomson, Ron Lehman, Jens Kilian, David Coulshed, Andrei Catanchin, David Colquhoun, Hosen Kiat, David Eccleston, John French, Bronte Ayres, Peter Blombery, Thanh Phan, James Rogers, David O’Donnell, Sang Cheol Bae, Harry Gibbs, Patrick Carroll, Greg Starmer, Margaret Arstall, Maurits Binnekamp, Astin Lee, John Eikelboom, Robert Luton, Milan Gupta, Amritanshu Shekhar Pandey, Stephen Cheung, Rolland Leader, Philippe Beaudry, Félix Ayala-Paredes, Joseph Berlingieri, John Heath, Germain Poirier, Miranda du Preez, Bradley Schweitzer, Reginald Nadeau, Ripple Dhillon, Tomasz Hruczkowski, Andrea Lavoie, Ratika Parkash, James Cha, Benoit Coutu, Paul MacDonald, Brian Ramjattan, Jorge Bonet, Saul Vizel, Paul Angaran, Sameh Fikry, Ahmed Mowafy, Azza Katta, Mazen Tawfik, Moustafa Nawar, Mohamed Sobhy, Seif Kamal Abou Seif, Tarek Khairy, Ahmed Abd El-Aziz, Nasser Taha, Ashraf Reda, Atef Elbahry, Mohamed Setiha, Mohamed Gamal El Din, Magdi Elkhadem, Adel El-Etreby, David Kettles, Junaid Bayat, Heidi Siebert, Adrian Horak, Ynez Kelfkens, Riaz Garda, Barry Jacobson, Thayabran Pillay, Michele Guerra, Louis van Zyl, Hendrik Theron, Andrew Murray, Rikus Louw, Deon Greyling, Pindile Mntla, Siddique Ismail, Fayzal Ahmed, Johannes Engelbrecht, Shambu Maharajh, Wessel Oosthuysen, Rehana Loghdey, Veronica Ueckermann, Wael Al Mahmeed, Abdullah Al Naeemi, Ghazi Yousef, Nooshin Bazargani, Munther AlOmairi, Rajan Maruthanayagam, Rupesh Singh, Ahmed Naguib, Mohamed Ibrahim, Amrish Agrawal, Mukesh Nathani, Ehab M Esheiba, Adel Wassef, Rajeev Gupta, Michael Cox, Scott Beach, Peter Duffy, Stephen Falkowski, Kevin Ferrick, Miguel Franco, W Michael Kutayli, Annette Quick, Niraj Sharma, Vance Wilson, Stephen Miller, Mark Alberts, Edwin Blumberg, Roddy Canosa, Ted Gutowski, Rodney Ison, Jorge Garcia, Paul Mullen, Howard Noveck, Pamela Rama, Rajneesh Reddy, Marcus Williams, Daniel Nishijima, Keith Ferdinand, Ihsan Haque, Robert Mendelson, Sridevi Pitta, Daniel Theodoro, Charles Treasure, Moustafa Moustafa, Cas Cader, Walter Pharr, Alisha Oropallo, George Platt, Jaspal Gujral, James Welker, and Firas Koura
Ethics statements
Ethical approval
All patients signed written informed consent to participate before enrolment. Approvals for the registry protocol were obtained from independent ethics committees or hospital based institutional boards. The database is being conducted according to the principles of the Declaration of Helsinki and the International Conference on Harmonisation—Good Pharmaco-epidemiological and Clinical Practice guidelines.
Data availability statement
Requests for patient level data can be made to the head of statistics at the Thrombosis Research Institute (kpieper@tri-london.ac.uk). These requests should include a protocol summary and a summary of the statistical analysis plan. The request will be reviewed by the data sharing committee for approval and next steps will be discussed with the requestor.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Web appendix 1: GARFIELD-AF Registry Investigators
Web appendix 2: Supplementary material
Data Availability Statement
Requests for patient level data can be made to the head of statistics at the Thrombosis Research Institute (kpieper@tri-london.ac.uk). These requests should include a protocol summary and a summary of the statistical analysis plan. The request will be reviewed by the data sharing committee for approval and next steps will be discussed with the requestor.