Prognosis of Atrial Fibrillation in Patients with Symptomatic Peripheral Arterial Disease: Data from the REduction of Atherothrombosis for Continued Health (REACH) Registry

Article Outline

• Abstract
• Introduction
• Methods
  • Database of the REACH Registry
  • Definition of AF
  • Study outcomes
  • Statistical analysis
• Results
  • Study outcomes
• Discussion
  • Incidence, prevalence and risk factors associated with AF
  • Identification of AF patients at increased risk of adverse outcome
  • Management of patients with AF
  • Limitations
• Conclusion
• Funding
• Author Access to Data
• Conflict of Interest
• Acknowledgements
• References
• Copyright

Abstract 

Background

Atrial fibrillation (AF) is a significant risk factor for cardiovascular (CV) mortality. This study aims to evaluate the prognostic implication of AF in patients with peripheral arterial disease (PAD).

Methods

The International Reduction of Atherothrombosis for Continued Health (REACH) Registry included 23,542 outpatients in Europe with established coronary artery disease, cerebrovascular disease (CVD), PAD and/or ≥3 risk factors. Of these, 3753 patients had symptomatic PAD. CV risk factors were determined at baseline. Study end point was a combination of cardiac death, non-fatal myocardial infarction (MI) and stroke (CV events) during 2 years of follow-up. Cox regression analysis adjusted for age, gender and other risk factors (i.e., congestive heart failure, coronary artery re-vascularisation, coronary artery bypass grafting (CABG), MI, hypertension, stroke, current smoking and diabetes) was used.

Results

Of 3753 PAD patients, 392 (10%) were known to have AF. Patients with AF were older and had a higher prevalence of CVD, diabetes and hypertension. Long-term CV mortality occurred in 5.6% of patients with AF and in 1.6% of those without AF (p<0.001). Multivariable analyses showed that AF was an independent predictor of late CV events (hazard ratio (HR): 1.5; 95% confidence interval (CI): 1.09–2.0).

Conclusion

AF is common in European patients with symptomatic PAD and is independently associated with a worse 2-year CV outcome.

Keywords: Atrial fibrillation, Prognosis, REACH Registry

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Introduction 

Atherothrombosis is a progressive, generalised disorder that affects large- and medium-sized arteries throughout the arterial tree, with many clinically acute or chronic manifestations.¹ In the peripheral arteries, atherothrombosis can contribute to the progression of peripheral arterial disease (PAD) producing intermittent claudication, as well as ischaemic necrosis and, potentially, loss of the limb. Occurrence of an arterial ischaemic event due to atherothrombosis implies that a similar pathological process may have already affected other arterial territories.², ³ Patients with a first ischaemic event are at high risk of developing further atherothrombotic events. The prevalence of additional risk factors, such as atrial fibrillation (AF), increases the risk of atherothrombotic events, as shown in the AF sub-study of the REACH Registry.⁴, ⁵

AF is gaining attention from the medical community as its epidemiological weight is increasing.⁶ AF is the most common cardiac arrhythmia in clinical practice, with >4.5 million affected in Europe. Most patients with AF are >65 years of age and present with many co-morbidities, in particular, hypertension (37%), heart failure (23%), coronary artery disease (18%) and diabetes (15%).⁷ The prevalence of AF is estimated to increase due to the ageing general population.⁶, ⁷ AF is a major cause of morbidity, being associated with left ventricular dysfunction, decreased exercise tolerance and quality of life⁸ as well as a twofold-increased risk in cardiac mortality.⁷ In the Copenhagen City Heart Study, a 60% increase in hospital admissions for AF, independent of changes in known risk factors, was reported during the last 10–20 years.⁹ Much of the morbidity and mortality associated with AF is attributed to the thromboembolic complications, resulting in increased risk of cardiovascular (CV) death,⁴ as well as ischaemic stroke.⁷ Goto et al. reported worse 1-year CV events in patients with atherothrombosis and AF.⁴

The aim of the analysis in this article was to evaluate the prevalence and prognostic implication of AF among European patients with symptomatic PAD, focussing on risk-factor profiles, medication use and 2-year rates of CV death, myocardial infarction (MI) and stroke in AF and non-AF patients. Data were based on the REduction of Atherothrombosis for Continued Health (REACH) Registry, which is a large-scale, prospective, international cohort of stable subjects with or at high risk of atherothrombotic complications.³, ¹⁰

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Methods 

Database of the REACH Registry 

Full details of the rationale and design of the REACH Registry have been described elsewhere.¹⁰ In brief, it is an international, prospective, observational registry designed to provide up to 24 months of clinical follow-up of >68,000 outpatients from ∼5000 sites in 44 countries; it has recently been extended to provide up to 48 months of clinical follow-up.³ Patients enrolled were ≥45 years of age with at least one of the following four criteria: documented symptomatic (1) coronary artery disease (CAD; angina, MI or angioplasty/stent/bypass), (2) cerebrovascular disease (CVD; ischaemic stroke or transient ischaemic attack (TIA)), (3) peripheral arterial disease (PAD; historical or current intermittent claudication associated with ankle–brachial index (ABI) <0.9) or (4) at least three pre-defined atherothrombotic risk factors.¹⁰ Patients already in a clinical trial, hospitalised patients or those who might have difficulty returning for a follow-up visit were excluded. Subjects were recruited consecutively, mainly by general practitioners (42%) and internists (32%).³ They were evaluated at baseline for a range of demographic, medical and laboratory characteristics, prior to being re-evaluated annually for up to 48 months post-baseline to ascertain whether they experienced any clinical events or hospitalisations. The institutional review board in each participating country approved the study design and all patients included in the analysis provided signed, informed consent. In this manuscript, we focus on the difference in AF and non-AF patients with symptomatic PAD in the European population, which included 23,542 stable outpatients.

Definition of AF 

All patients were classified based on the presence or absence of AF, at the time of enrolment.⁴ If participating physicians could not confirm whether patients had a history of AF, the patients were classified as ‘unknown’ and excluded from this analysis.

Patients with AF were also stratified using the CHADS2 risk score in which one point is assigned to patients with a history of congestive heart failure (CHF), hypertension, diabetes mellitus, age≥75 years and two points for a history of stroke or TIA.¹¹

Study outcomes 

There were two primary study outcomes. The first was a combined end point of non-fatal stroke, non-fatal MI and CV death assessed at 21±3 months from enrolment. The second was a combined end point of CV death, non-fatal stroke, non-fatal MI, vascular interventions and hospitalisations for atherothrombotic events at 2 years of follow-up. The limb outcome and individual clinical events described constituted the pre-defined secondary end points of the study. Events were not adjudicated; however, reports of ischaemic stroke and TIA had to be sourced from a neurologist or hospital to ensure a reliable diagnosis.

Statistical analysis 

Continuous variables are expressed as mean±standard deviation (SD) compared by using the Mann–Whitney–Wilcoxon test. Categorical variables are expressed as numbers and percentages and analysed using the chi-square test. A p-value of <0.01 was considered statistically significant (for Table 1, Table 2, Table 3) and no allowance for multiple hypothesis testing was made. The relationship between a history of AF and the combined end point at 2 years of follow-up was assessed with multivariate Cox regression analyses, correcting for age, gender, and risk factors (i.e., CHF, coronary artery re-vascularisation, CABG, MI, hypertension, stroke, current smoking and diabetes). Hazard Ratios (HR) are given with 95% confidence intervals (CI). A p-value of <0.05 (two-sided) was considered significant. All analyses were performed using the Statistical Analysis Software version 9 (SAS v.9; SAS Institute Inc., Cary, NC, USA).

Table 1. Baseline characteristics.

	With AF (n=392)	Without AF (n=3263)	p-value
Patient characteristics
Age, years	71.6±9.1	67.2±9.6	<0.001
Female, %	25.6	24.8	0.74
BMI (kg/m2)	27.4±4.4	27.1±4.5	0.29
Current smoker, %	18.6	29.2	<0.001
Previous history of
Smoking, %	65.0	78.2	<0.001
Stable angina, %	40.4	27.2	<0.001
Unstable angina, %	15.6	9.8	<0.001
Myocardial Infarction, %	33.2	24.9	<0.001
Coronary angioplasty/stenting, %	20.5	16.3	<0.05
Coronary artery bypass graft, %	19.6	15.5	<0.05
TIA, %	20.2	13.5	<0.001
Ischaemic stroke, %	19.0	14.1	<0.01
Diabetes, %	43.4	36.5	<0.01
Hypertension (despite therapy for minimally 3 months), %	61.0	52.0	<0.001
Hypercholesterolemia (in treatment), %	60.2	64.9	0.07
Congestive heart failure, %	43.5	11.2	<0.001
Aortic valve stenosis, %	11.2	3.5	<0.001
Asymptomatic carotid stenosis (≥70%), %	22.9	15.1	<0.01
Carotid surgery, %	7.2	6.6	0.65
Abdominal aortic aneurysm, %	8.9	6.0	<0.05
Previous history of PAD
ABI<0.9, %	89.5	90.2	0.70
Lower limb graft, %	46.4	51.0	0.09
Lower limb amputation, %	11.2	10.8	0.78
Medications
ASA, %	42.6	61.5	<0.001
Other anti-platelet agent, %	20.2	34.4	<0.001
ASA and other anti-platelet agent, %	7.9	10.8	0.08
Oral anticoagulants, %	52.3	10.1	<0.001
At least 1 anti-thrombotic agent, %	95.9	92.1	<0.01
Oral anticoagulant and ASA, %	8.4	2.5	<0.001
NSAIDs, %	13.0	7.5	<0.001
Statins, %	60.7	62.6	0.47
Calcium channel blockers, %	31.1	33.0	0.45
Beta blockers, %	48.0	38.3	<0.001
Nitrates, %	34.7	21.4	<0.001
Diuretics, %	62.8	40.1	<0.001
ACE-Inhibitors, %	73.0	60.6	<0.001

TIA=transient ischaemic attack, PAD=peripheral arterial disease, ABI=ankle brachial index, ASA=acetyl salicylic acid, NSAID=non-steroidal anti-inflammatory drug, ACE=angiotensin-converting enzyme, and BMI=Body Mass Index.

Table 2. Comparison between patients with atrial fibrillation and the use of oral anticoagulants.

	AF+Yes anticoagulants (n=222)	AF+No anticoagulants (n=205)	p-value
Patient characteristics
Age, years	72.3±8.6	71.4±9.6	0.17
Female, %	27.5	22.5	0.24
BMI (kg/m2)	27.4±4.3	27.2±4.5	0.45
Current smoker, %	12.0	27.7	<0.001
Previous history of
Smoking, %	51.4	40.5	<0.05
Stable angina, %	35.9	42.8	0.15
Unstable angina, %	19.6	13.0	0.07
Myocardial Infarction, %	32.9	34.5	0.73
Coronary angioplasty/stenting, %	21.3	19.5	0.65
Coronary artery bypass graft, %	19.9	19.5	0.92
TIA, %	20.5	19.5	0.79
Ischaemic stroke, %	22.1	15.8	0.10
Hypertension (despite therapy for minimally 3 months), %	58.1	63.4	0.26
Hypercholesterolemia (in treatment), %	56.8	60.5	0.43
Congestive heart failure, %	47.5	36.9	<0.05
Aortic valve stenosis, %	11.2	10.8	0.91
Asymptomatic carotid stenosis (≥70%), %	22.2	21.5	0.89
Carotid surgery, %	7.2	7.4	0.95
Abdominal aortic aneurysm, %	7.3	9.6	0.43
Previous history of PAD
ABI<0.9, %	89.3	89.7	0.91
Lower limb graft, %	50.0	42.4	0.12
Lower limb amputation, %	11.7	12.2	0.88
Medications
ASA, %	16.2	70.7	<0.001
Other anti-platelet agent, %	9.5	32.2	<0.001
Oral anticoagulants, %	100	0
At least 1 anti-thrombotic agent, %	100	91.2	<0.001
NSAIDs, %	9	17.1	<0.05
Statins, %	59.0	59.0	1.00
Calcium channel blockers, %	28.4	35.6	0.11
Beta blockers, %	46.8	44.4	0.61
Nitrates, %	32.0	40.5	0.07
Diuretics, %	66.2	60.0	0.18
ACE-Inhibitors, %	59.9	56.6	0.49

TIA=transient ischaemic attack, PAD=peripheral arterial disease, ABI=ankle brachial index, ASA=acetyl salicylic acid, NSAID=non-steroidal anti-inflammatory drug, and ACE=angiotensin-converting enzyme.

Table 3. Long-term clinical outcome (2-year follow-up).

	Yes AF (n=392)	No AF (n=3263)	p-Value
Cardiovascular death, %	5.6	1.6	<0.001
Non-fatal stroke, %	4.1	2.8	0.16
Non-fatal MI, %	4.6	1.8	<0.001
CV events	12.5	6.0	<0.001
CV events and hospitalisation	37.0	25.5	<0.001

MI=myocardial infarction, and Combined end point=cardiovascular (CV) events (cardiovascular death, non-fatal stroke, non-fatal MI).

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Results 

The study population consisted of 23,542 European patients with atherothrombosis. Of these, 3753 patients had symptomatic PAD. Baseline information regarding a history of AF was available from 3655 patients and represents the analysis sample. The baseline characteristics and medication use are listed in Table 1. The mean age at baseline was 67.7±9.6 years and 75.1% of the PAD patients were male. The prevalence of AF in the PAD patient group was 10.4% (n=392). Patients with AF were significantly older, more often had a history of angina pectoris, MI, ischaemic stroke, TIA, CHF, aortic valve stenosis, CVD, diabetes, hypertension and included a lower prevalence of smokers.

In general, patients with AF received more medication as compared to those without AF. Use of anti-thrombotics was high among patients with AF, with ∼96% receiving at least one anti-thrombotic agent. Significantly more patients with AF used non-steroidal anti-inflammatory drugs, beta blockers, nitrates, diuretics and angiotensin-converting enzyme (ACE) inhibitors. There were no differences between statin and calcium channel blocker use in AF vs. non-AF patients. Approximately half (52.3%) of the patients with AF were treated with oral anticoagulants and 42.6% received aspirin (Table 1). As is shown in Table 2, patients with a history of AF and no use of anticoagulant agents more often had a history of current smoking.

In addition, in the current analyses, it was calculated that patients with AF had a significantly higher CHADS2 risk score as compared to those without AF (mean CHADS2 score in AF vs. non-AF patients; 2.1±1.4 vs. 1.9±1.3, general linear model p<0.001).

Study outcomes 

As shown in Table 3, the presence of AF at baseline was associated with higher rates of 2-year adverse CV outcomes (i.e., combined CV death, MI and stroke). The all-cause (7.7%) and CV mortality (5.6%) rates of patients with AF were substantially higher than in non-AF patients (2.5% and 1.6%, respectively; p-value<0.001). In the 2 years after the baseline visit, there was a significantly higher incidence of CHF (16.8% vs. 5.1%, respectively), unstable angina (11.6% vs. 7%, respectively) and bleeding requiring hospitalisation and transfusion (2.7% vs. 1.4%, respectively) in patients with AF compared to those without AF. Worsening of claudication related to PAD was not more evident in the AF vs. non-AF patients (27.1% vs. 27.4%, p=0.89, respectively). On the other hand, during the 2-year follow-up period, patients with AF more often underwent amputations affecting the lower limb as compared to those without AF (4.8% vs. 2.1%, p<0.01, respectively). There were no differences between the two groups in combined end point and/or re-vascularisation during follow-up (patients with AF 27.1% vs. non-AF 23.7%, p=0.13, respectively).

The combined end point of CV events occurred in 49 (12.5%) patients with a previous history of AF and 196 (6.0%) patients in those without AF (Table 3). Patients with AF also had a higher incidence of the CV events and/or hospitalisation for atherothrombotic events than those without AF (37% vs. 25.5%, p-value<0.001, Table 3). As shown in Fig. 1, the presence of AF at baseline was associated with a significantly higher rate of CV events during 2 years of follow-up. In multivariable analyses, after adjusting for age, gender and risk factors, AF was an independent predictor of long-term CV events (HR: 1.48; 95% CI: 1.09–2.02; Table 4). Other risk factors that were associated with 2-year CV events were: age, diabetes, CHF, current smoking and stroke.

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• Figure 1 

  CV events (cardiovascular death, MI, and stroke) occurred in 12.5% of PAD patients with AF compared to 6.0% in those without AF (p<0.001).

Table 4. Multivariate analyses for long-term cardiovascular (CV) events, adjusting for age, gender and risk factors (diabetes, hypertension, congestive heart failure, coronary artery revascularization, CABG, stroke, current smoking and myocardial infarction).

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Discussion 

This study demonstrates that AF is a common condition in European patients with symptomatic PAD and could indicate patients with extensive atherothrombosis. Furthermore, AF is an independent predictor of late adverse outcome with a 1.5-fold increase of CV mortality in patients with PAD.

Incidence, prevalence and risk factors associated with AF 

The prevalence of AF is 0.4–1% in the general population.⁶, ¹² In the coming years, this prevalence will likely increase due to the ageing of the general population, a rising prevalence of CV disease and more frequent diagnosis of AF through use of more specific ambulatory monitoring devices.⁷ Furthermore, it has to be noticed that the prevalence of AF is an underestimation of this type of arrhythmia since a great proportion of patients are asymptomatic.⁷ The AnTicoagulation and Risk Factors In Atrial Fibrillation (ATRIA) study assembled a contemporary cohort of 17,974 patients with non-transient AF and found that AF affects one in 25 adults ≥60 years of age and nearly one in 10 adults ≥80 years.⁶ However, in patients with established atherothrombotic disease, such as PAD,¹³, ¹⁴ the prevalence and incidence of AF is likely higher,⁷, ¹⁵ as previously demonstrated in the AF sub-study of the REACH Registry.⁴ This high prevalence of AF in PAD patients is also confirmed in the current European focussed AF sub-study as we observed a prevalence of 10.4%. When comparing the baseline characteristics of the ATRIA study ⁶ and the REACH Registry population, it is evident that the current patients have more number of atherothrombotic risk factors. These data supported the concept that the prevalence of AF is higher in patients with symptomatic atherothrombosis.⁴ This process could also be vice versa, that is, due to acute thromboembolic occlusions or progression of the atherothrombotic process which enhances the obstruction of blood flow to the peripheral arteries and could cause intermittent claudication.², ¹⁶ However, it is hard to define which process precedes the other since these will often be present simultaneously. The Framingham heart study demonstrated that gender, age, diabetes, hypertension, CHF and cardiac valve disease were independent risk factors for AF.¹⁷ Previous studies have also identified non-cardiac precipitants for AF, for example, obesity,¹⁸, ¹⁹ thyrotoxicosis,²⁰, ²¹, ²² alcohol use,²⁰, ²³ severe infections²⁰, ²⁴ and pulmonary pathology.²⁰, ²¹, ²² These general and pathophysiology risk factors have also been confirmed in the current data, where PAD patients with AF were significantly older, more often had a history of angina pectoris, MI, CHF, aortic valve stenosis, CVD, diabetes and hypertension.

Identification of AF patients at increased risk of adverse outcome 

Patients with lone AF were initially thought to have a good prognosis with respect to thromboembolism and mortality, but more recent data suggest that it is associated with higher mortality.⁶, ²⁴ Our data, along with previously published AF sub-study of the REACH Registry,⁴ demonstrated that AF is an independent predictor of long-term CV events in patients with PAD. Goto et al. assessed the distribution of the CHADS2¹¹ score in patients with and at high risk of atherothrombosis and its relation to cerebrovascular outcomes.¹¹, ²⁵ They concluded that, in patients with AF, CV events, especially non-fatal stroke, and the combined end point of CV death/MI/stroke, were more frequent in the higher CHADS2 score subgroup (the rate of CV death/MI/stroke varied from 3.9% in the CHADS2 score-0 group to 12.4% in the CHADS2 score-6 group).⁴ In the current study, the calculated CHADS2 risk score was also significantly differing between the two groups, with a higher CHADS2 score in those patients with AF as compared to those without AF.

Management of patients with AF 

Managing patients with AF and the associated conditions is a major challenge. Restoration and maintenance of sinus rhythm in patients with AF is clearly an important therapeutic goal,²⁶ in combination with anti-thrombotic therapy to decrease the rate of embolic complications caused by AF. The efficacy, safety and shortcomings of current anti-thrombotic therapies for patients with AF are an ongoing discussion. Recent clinical trials comparing rhythm and rate control have suggested that effective anticoagulation and heart-rate control is not inferior to rhythm control.⁶, ²⁶ Current guidelines recommend warfarin for patients who have AF and are at risk of stroke.⁷ The combination of anti-platelet and anticoagulant therapy (triple therapy) is often used in patients with established atherothrombotic disease and AF.⁷, ²⁷ However, the Warfarin anti-platelet Vascular Evaluation (WAVE) trial randomised patients with PAD to receive oral anticoagulant (OAC) plus anti-platelet therapy or anti-platelet therapy alone and found that the combination of an OAC and anti-platelet therapy was not more effective than anti-platelet therapy alone in preventing major CV complications and was associated with an increase in life-threatening bleeding.²⁸, ²⁹ The use of combined therapy is expected to become more prominent, yet is also associated with a significantly increased bleeding risk.²⁷ The rate of major bleeding complications may be kept acceptably low even in elderly AF patients, provided there is a careful management of anticoagulation.³⁰ Our data, however, show that only 50% of PAD patients with AF received oral anticoagulants. This confirms earlier studies showing an under-treatment in AF patients.³, ⁴ In the study from REACH on patients with AF in the global population by Goto et al., the use of oral anticoagulants was low even in patients at high risk of stroke.⁴ An explanation for this low use of oral anticoagulants in the REACH population was coupled to the markedly high background use of anti-platelet agents.⁴ In the current results of the REACH data, 2-year CV outcomes confirms that patients with AF more often had bleeding requiring hospitalisation, which could be speculated to be associated with using combined therapy.

In a more recent non-inferiority trial by Connolly et al., the new, oral, direct thrombin-inhibitor dabigatran, administered at a dose of 150mg in patients with AF, was associated with lower rates of stroke and systemic embolism but similar rates of major haemorrhage as compared with warfarin.³¹ These results could likely increase the intake of these new thrombin inhibitors since these are less cumbersome than vitamin-K antagonists.³¹

Patients with PAD should receive beta blockers, statins and, most commonly, an anti-platelet agent.³²

However, as is also shown in the current study, patients with PAD are largely under-treated.

Limitations 

There are several limitations to these data. First, there are no data on the classification of AF (paroxysmal, persistent or chronic), duration of AF or use of anti-arrhythmic agents available. The specification of the AF classification could partly help explain the therapeutic regiments. Furthermore, no laboratory markers were tested at baseline, which could have helped to make more specifications in a predictive model for risk factors for AF, for example, inflammation markers and N-terminal pro-B-type natriuretic peptide. In addition, due to the exclusion of patients without an apparent or certain history of AF by participating physicians, it could well be that patients with AF and PAD have been excluded from these analyses, with the possibility of underestimating the true prevalence of AF in European PAD patients.

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Conclusion 

AF is common in European patients with symptomatic PAD and is independently associated with a worse 2-year CV outcome. Current guidelines for AF management should be observed to manage the increased risk of CV morbidity and mortality.

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Funding 

All manuscripts in the REACH Registry are prepared by independent authors who are not governed by the funding sponsors and are reviewed by an academic publications committee before submission. The funding sponsors have the opportunity to review manuscript submissions but do not have authority to change any aspect of a manuscript.

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Author Access to Data 

All authors had access to the data.

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Conflict of Interest 

U. Zeymer has received research grants and speaker honoraria from Bristol–Myers Squibb and Sanofi–Aventis.

D.L. Bhatt has received research grants (to the institution) from: AstraZeneca, Bristol–Myers Squibb, Eisai, Ethicon, Heartscape, Sanofi–Aventis and the Medicines Company. Dr. Bhatt has served as a consultant (honoraria waived or donated for past 3 years) for: Arena, Astellas, AstraZeneca, Bayer, Bristol–Myers Squibb, Cardax, Centocor, Cogentus, Daiichi-Sankyo, Eisai, Eli Lilly, GlaxoSmithKline, Johnson & Johnson, McNeil, Medtronic, Millennium, Molecular Insights, Otsuka, Paringenix, PDL, Philips, Portola, Sanofi-Aventis, Schering Plough, Scios, Takeda, The Medicines Company and Vertex.

Ph. G Steg has received research grant from Sanofi–Aventis (1999–2008), is on the Speaker's Bureau for Boehringer–Ingelheim, Bristol–Myers Squibb, GlaxoSmithKline, Menarini, Medtronic, Nycomed, Pierre Fabre, Sanofi-Aventis, Servier and the Medicines Company, is on the consulting/advisory boards for Astellas, AstraZeneca, Bayer, Boehringer–Ingelheim, Bristol–Myers Squibb, Daiichi–Sankyo, Endotis, GlaxoSmithKline, Medtronic, MSD, Nycomed, Sanofi–Aventis, Servier and the Medicines Company and is a stockholder for Aterovax.

S. Goto received honoraria from Sanofi-Aventis, Eisai, Otsuka, Daiichi–Sankyo, Shering-Plau, GSK, Novartis, Asteras, Teijin, Towa-Eiyo, Bayer, Pfizer, Banyu, Mochida, J and J, Kowa, Avot Vascular, Tanabe Mitsubishi and AstraZenneca last year. Dr. Goto received research grants from Pfizer, Sanofi–Aventis, Ono, Eisai, Otsuka, Sankyo, Daiichi, Takeda, Asteras, Kowa and AstraZeneca within 3 years.

J. Röther has received honoraria and consulting fees from Sanofi–Aventis, Bristol-Myers Squibb, Lundbeck and Boehringer–Ingelheim.

P. Cacoub has received research grants from Sanofi–Aventis, Schering Plough, Servier, Roche, Encysive and Gilead, and honoraria from Sanofi–Aventis, Schering Plough, Servier, Roche, Encysive, Gilead, AstraZeneca and Bristol–Myers Squibb.

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Acknowledgements 

The REACH Registry is sponsored by Sanofi–Aventis, Bristol–Myers Squibb and the Waksman Foundation (Tokyo, Japan). Tamara Winkel and Sanne Hoeks were partially supported by the Lijf & Leven Foundation, Rotterdam, the Netherlands. The REACH Registry is endorsed by the World Heart Federation. A complete list of REACH investigators is accessible online at www.reachregistry.org. The REACH Registry enforces a no ghost-writing policy. This manuscript was written and edited by the authors, who take full responsibility for its content. The first draft was written by Tamara A. Winkel. We thank Deborah Burrage (PhD) for her assistance with coordinating revisions and providing editorial help in preparing this manuscript including editing, checking content and language, formatting, referencing and preparing tables and figures, and Tobias Limbourg for his support with statistical analyses. The Institut für Herzinfarktforschung Ludwigshafen verified all statistical analyses.

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