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Arrhythmias and sudden death
Original article
Importance of persistent elevation of cardiac biomarkers in atrial fibrillation: a RE-LY substudy
  1. Ziad Hijazi1,
  2. Jonas Oldgren1,
  3. Ulrika Andersson2,
  4. Stuart J Connolly3,
  5. Michael D Ezekowitz4,
  6. Stefan H Hohnloser5,
  7. Paul A Reilly6,
  8. Agneta Siegbahn7,
  9. Salim Yusuf3,
  10. Lars Wallentin1
  1. 1Department of Cardiology, Uppsala Clinical Research Center and Department of Medical Sciences, Uppsala University, Uppsala, Sweden
  2. 2Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden
  3. 3Population Health Research Institute, Hamilton, Canada
  4. 4Thomas Jefferson Medical College and the Heart Center, Wynnewood, Pennsylvania, USA
  5. 5Department of Cardiology, J. W. Goethe University, Frankfurt, Germany
  6. 6Boehringer Ingelheim Pharmaceuticals, Ridgefield, USA
  7. 7Department of Medical Sciences, Uppsala Clinical Research Center, Clinical Chemistry, Uppsala University, Uppsala, Sweden
  1. Correspondence to Dr Ziad Hijazi, Uppsala Clinical Research Center, Dag Hammarskjölds väg 14B, 1st floor, SE- 752 37 Uppsala, Sweden; Ziad.hijazi{at}ucr.uu.se

Abstract

Objectives To evaluate the prognostic importance of transient or persistent elevations of cardiac troponin-I (cTnI) and N-terminal-B-type natriuretic peptide (NT-proBNP) in atrial fibrillation (AF).

Methods Plasma samples were obtained at randomisation and after 3 months in 2514 patients with AF in the RE-LY trial; median follow-up was 2.0 years. Patients were grouped based on levels at the two time points according to detectable cTnI levels (≥0.01 µg/L) or NT-proBNP levels above median (≥778 ng/L). These groups were related to occurrence of stroke or cardiovascular events evaluated with Cox models adjusting for established risk factors.

Results The proportion of patients with detectable cTnI levels at both time points was 48.5%, at one time point 28.5% and at neither time point 21.0%. Patients with detectable cTnI at both time points had substantially higher rates of stroke compared with those with transient elevations and those with no elevation at either time point (p<0.005, effect of cTnI). Persistent elevation of either or both cardiac biomarkers at baseline and 3 months was associated with a higher risk for cardiovascular events and mortality (p<0.0001). Prognostic prediction improved most with the use of repeated measurements of both cardiac biomarkers simultaneously (p<0.05) and achieved C-statistic 0.644 for stroke compared with 0.611 for CHADS2-score.

Conclusions Persistent elevation of troponin and NT-proBNP indicates a worse prognosis than transient elevations or no elevations of either marker. Prognostication of stroke, death and thromboembolic events is improved by the use of repeated determinations of cardiac biomarkers.

Trial registration number: http://www.clinicaltrials.gov, NCT00262600

https://doi.org/10.1136/heartjnl-2013-304872

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    Introduction

    Atrial fibrillation (AF) is associated with a fivefold increase in the rate of ischaemic stroke and doubled total mortality.1 ,2 Risk prediction in AF is commonly based on clinical schemes, for example, the CHADS2 or CHA2DS2VASC risk scores.3 Cardiac biomarkers, such as cardiac troponin and B-type natriuretic peptide (BNP), have recently been proposed to significantly enhance the information regarding risk and prognosis in patients with AF.4–8 Further, serial measurement of troponin and BNP has been shown to provide added prognostic information in several patient populations such as acute coronary syndromes, stable coronary artery disease, in acute and chronic heart failure, and in apparently healthy community dwelling adults.9–15 The concept of using serial measurement of cardiac biomarkers in relation to the risk for future cardiovascular events in patients with AF has not been established.

    The Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial included 18 113 AF patients and demonstrated the superiority of dabigatran versus warfarin for prevention of stroke or systemic embolism.16 Our aims in this prospectively designed RE-LY biomarker substudy were to describe the levels of cardiac biomarkers over time in patients with AF and to investigate whether serial samples provide additional prognostic information.

    Methods

    Study population and trial design

    The trial design, patient characteristics and outcomes of the RE-LY study have been published previously.16 ,17 In brief, RE-LY was a prospective, multicentre, randomised trial comparing two blinded doses of dabigatran with open-label warfarin for a minimum of 12 months in 18 113 patients. Inclusion criteria were documented AF and at least one risk factor for stroke. The primary efficacy outcome in the study was fatal and non-fatal stroke (ischaemic, haemorrhagic or unspecified) or systemic embolism, and the secondary outcomes were total mortality, vascular mortality, non-vascular mortality and a composite thromboembolic outcome (ischaemic stroke/systemic embolism/myocardial infarction/pulmonary embolism/vascular mortality (excluding hemorrhagic death)). Median follow-up was 2.0 years in the substudy. Events were classified by two independent adjudicators.

    Blood sampling

    Venous blood was drawn at randomisation, before initiation of study treatment and after 3 months treatment, using a 21/22 needle into vacutainer tubes containing EDTA. The blood was centrifuged within 30 min at 2000 G for 10 min, thereafter immediately frozen at −20°C or colder. Aliquots were stored at −70°C to allow batch analysis.

    Laboratory methods

    All plasma samples were centrally analysed in Uppsala Clinical Research Center (UCR) laboratory, Sweden. Troponin I was analysed with the Access AccuTnI assay (Beckman Coulter). The lower limit of detection with this assay is 0.006 µg/L with 0.014 µg/L as the lowest concentration measurable with a coefficient of variation of <10% and 0.04 µg/L as the 99th centile URL regardless of age.4 ,10 With present instrument calibration, all troponin I concentrations below 0.010 µg/L are reported as <0.010 µg/L and considered non-detectable; levels ≥0.010 as detectable.

    NT-proBNP was analysed using the Elecsys, Roche Diagnostics. The analytical range extends from 20 to 35 000 ng/L according to the manufacturer. The upper reference level (97.5th centile) in men and woman aged 66–76 years is 269 and 391 ng/L, respectively.18

    Statistical analysis

    Demographics and baseline characteristics were summarised for the troponin I and NT-proBNP level groups using frequencies for categorical variables, and median and 25th and 75th quartiles for continuous variables. Due to low numbers of patients in the CHADS2 scores, 0, 4, 5 and 6 patients were grouped in CHADS2-classes of 0–1, 2 and ≥3. For tests of differences among groups, the χ2 test was used for categorical variables and Kruskal–Wallis test was used for continuous variables. Multivariable analysis of the impact of demographic variables on the outcome of detectable cTnI or high NT-proBNP at 3 months was performed using logistic regression. Model-adjusted ORs were calculated for comparison of magnitude of effect of the demographic variables on the outcomes. The models included, in addition to the demographic variables, screening biomarker value and randomised treatment as independent variables.

    The risk of event is reported as percentage per year, which was calculated by dividing the total number of patients with events by the total number of patient-years of follow-up. Cumulative hazard plots were used to illustrate the timing of events. The relations between levels of troponin I and NT-proBNP groups and events were investigated using Cox proportional-hazards regression. For the stroke or systemic embolism outcome, the model was adjusted for study treatment, creatinine clearance class and the CHA2DS2VASc variables (congestive heart failure, hypertension, age, diabetes, prior stroke/systemic embolism/TIA, prior myocardial infarction/peripheral artery disease/coronary artery disease and gender). Smoking status and systolic blood pressure were, based on the Framingham risk factors, added to the adjusted Cox model for the vascular death and composite outcomes. Patients with events before the month 3 sample dates were excluded from analysis: 6 patients in regards to stroke or systemic embolism outcomes and 13 patients regarding the composite thromboembolic outcome.

    The increased discriminative values of month 3 measurement of troponin I and NT-proBNP were investigated by estimating the difference in C statistics generalised for survival data19 after adding the month 3 value to a model with screening value and randomised treatment and also the continuous (category-free) net reclassification improvement index (NRI) for survival data as described by Pencina et al.20 In these analyses, the continuous measures were used (natural logarithm). Troponin I was analysed using a binary variable indicating undetectable values and a continuous variable taking the values of the detectable concentrations. We performed likelihood ratio tests to evaluate whether the global model fit improved after the addition of the month 3 measurements of the biomarkers.

    A p value less than 0.05 from two-sided tests was considered to indicate statistical significance. Since the analyses were exploratory, the p values were not adjusted for multiple comparisons. The statistical software package SAS, V.9.3 for Windows (SAS institute, Cary, North Carolina, USA) was used for all analyses.

    Results

    A total of 2514 patients were included in the serial biomarkers substudy. Patients were grouped according to cardiac biomarker levels. cTnI group 1 had non-detectable (<0.01 µg/L) cTnI at randomisation and at 3 months follow-up (n=576), group 2 had transient cTnI elevation (detectable (≥0.01 µg/L) cTnI at randomisation or at 3 months (n=715) and group 3 had detectable cTnI at both time points (n=1210). Concerning NT-proBNP, a threshold value was based on median levels (778 ng/L) measured from 6189 patients in the RE-LY study with available samples at randomisation.4 NT-proBNP group 1 had NT-proBNP levels lower than median (NT-proBNP <778 ng/L) at both randomisation and at 3 months follow-up (n=1053), group 2 had transient NT-proBNP levels higher than median (NT-proBNP≥778 ng/L) at randomisation or at 3 months (n=459) and group 3 had NT-proBNP levels higher than median at both time points (n=996). Further, in a third step, patients were also grouped in regards to combined troponin I and NT-proBNP levels at the two time points; group 1 with non-detectable cTnI at both time points and NT-proBNP lower than median at both time points (n=311), group 2 consisted of patients with one sample of either cTnI or NT-proBNP above the threshold value at one time point (n=1605) and group 3 with detectable levels of cTnI at both time points and NT-proBNP higher than median at both time points (n=591).

    Baseline characteristics

    Patient characteristics are summarised in table 1. At randomisation, detectable cTnI (≥0.010 µg/L) were found in 1455 (58.2%) patients. At 3 months follow-up, detectable cTnI were found in a total of 1683 (67.3%) patients. The proportion of patients with detectable cTnI levels at both time points was 48.5%, at one time point 28.5% and at neither time point 21.0%. Median NT-proBNP level at randomisation was 788 ng/L (25th and 75th centile values of 397 and 1379 ng/L). At 3 months follow-up, median NT-proBNP level was 744 ng/L (348 and 1275 ng/L). Several patient characteristics were significantly associated with cTnI and NT-proBNP groups.

    View this table:
    Table 1

    Baseline characteristics according to troponin I and NT-proBNP serial measurement group

    Multivariable logistic regression for analysis of association of demographic variables with detectable levels of cTnI at follow-up displayed male gender (OR 95% CI 1.42 (1.15 to 1.74)), renal impairment (GFR<50 mL/min) (OR 1.74 (1.28–2.37)), coronary artery disease (OR 1.42 (1.12–1.80)) and hypertension (OR 1.32 (1.03–1.69)) as the most influential variables. For NT-proBNP, renal impairment (GFR<50 mL/min) (OR 2.64 (1.88–3.72)), AF type (permanent vs paroxysmal) (OR 2.49 (1.82–3.41)) and AF rhythm at screening (OR 1.69 (1.22–2.35)) were the most influential variables.

    Serial changes of cardiac biomarkers in relation to outcomes

    During follow-up, median 2.0 years, there were 64 events of stroke or systemic embolism. For cTnI groups, the yearly event rate was 0.67%, 0.77% and 1.96% for groups 1, 2 and 3, respectively (table 2). In multivariable Cox analysis, relation of cTnI groups to outcome was significant (p=0.0045) with HRs of 1.08 and 2.64 for groups 2 and 3, respectively, using group 1 (non-detectable troponin at both time points) as reference. Based on NT-proBNP groups, stroke or systemic embolism rates ranged from 0.55% to 1.87% (p=0.0464, effect of NT-proBNP group) (table 2). Combining cTnI and NT-proBNP resulted in an improved risk stratification compared with each marker alone with yearly event rates ranging from 0.47% to 2.45% (p=0.0046) (figure 1A, table 2).

    View this table:
    Table 2

    Cox proportional hazards model with troponin I and NT-proBNP groups in relation to outcomes

    Figure 1
    Figure 1

    (A–B) Cumulative hazard rates for study endpoints according to combined cardiac biomarkers levels. Cumulative hazard rates for stroke or systemic embolism (A), vascular death (B), composite thromboembolic outcome consisting of ischaemic stroke, systemic embolism, myocardial infarction, pulmonary embolism and vascular death (excluding haemorrhagic death) (C). Combined cardiac biomarkers: group 1 non-detectable cTnI at both time points and NT-proBNP lower than median at both time points (n=311), group 2 one sample of either cTnI or NT-proBNP above the threshold value at one time point (n=1605) and group 3 detectable levels of cTnI at both time points and NT-proBNP higher than median at both time points (n=591).

    A total of 108 events of vascular mortality occurred. For cTnI groups, the yearly event rate ranged from 0.50% to 3.70% for groups 1 and 3, respectively (table 2). In multivariable Cox analysis, the relation of cTnI groups to outcome was significant (p<0.0001) with HRs of 2.39 and 6.10 for groups 2 and 3, respectively, using group 1 as reference. Based on NT-proBNP groups, vascular mortality rates ranged from 0.72% to 3.83% with significantly increased HRs in adjusted Cox analysis (p<0.0001) (table 2). Combining cTnI and NT-proBNP resulted in an improved risk stratification compared with each marker alone with yearly event rates ranging from 0.47% to 5.41% (p<0.0001) (figure 1B, table 2).

    There were 168 events of the composite thromboembolic outcome (ischaemic stroke, systemic embolism, pulmonary embolism, myocardial infarction and vascular death excluding haemorrhagic death). For cTnI groups, the yearly event rate ranged from 1.26% to 5.35% for groups 1 and 3, respectively (table 2). In multivariable Cox analysis, relation of cTnI groups to outcomes remained significant (p<0.0001) with HRs of 1.75 and 3.66 for groups 2 and 3, respectively, using group 1 as reference. Based on NT-proBNP groups, the yearly event rates ranged from 1.73% to 5.63% with significantly increased HRs in adjusted Cox analysis (p<0.0001) (table 2). Combining cTnI and NT-proBNP resulted in an improved risk stratification compared with each marker alone with yearly event rates ranging from 1.09% to 7.67% (p<0.0001) (table 2).

    For all the above outcomes, there were no significant interactions between troponin I or NT- proBNP groups and effects of study treatment with warfarin or dabigatran 110 mg or 150 mg.

    Analyses of the biomarkers in continuous log form yielded significant associations to all outcomes (p<0.05 for all). Regression dilution may be one factor explaining the better result when adding the month 3 value. Correcting the HR of one SD change in baseline (log) NT-proBNP using the correlation coefficient between baseline and month 3 value resulted in 5% higher HR for stroke, 18% for cardiac death and 13% higher for the composite thromboembolic outcome. This analysis was not performed for cTnI due to the distribution with a large amount of non-detectable levels.

    Prognostic discrimination using serial measurements of cardiac biomarkers

    The clinically used CHADS2 risk model was used to assess C-statistic in this RE-LY substudy cohort and an area under the curve of 0.611, 0.581 and 0.581 was achieved for stroke/systemic embolism, vascular death and the composite thromboembolic outcome, respectively. The CHA2DS2-VASc model yielded C-statistics of 0.622, 0.610 and 0.602 for the respective outcomes. Based on serial measurements of combined cardiac biomarkers, C-statistics of 0.644, 0.765 and 0.717 was achieved for the stroke/systemic embolism, vascular death and the composite thromboembolic outcomes yielding significant improvements as compared with information from screening measurements solely (table 3).

    View this table:
    Table 3

    Prognostic discrimination of serial measurements of cardiac biomarkers

    Category-free NRI analysis based on addition of combined cardiac biomarkers at 3 months to screening measurements resulted in significant improvements for stroke or systemic embolism, vascular death and the composite thromboembolic outcome with NRI ranging up to 40.1%, 37.4% and 34.3%, respectively. The improvement was mainly among patients with events.

    Clinical risk stratification based on serial measurements

    Annual rates of stroke or systemic embolism, vascular death and the composite thromboembolic outcome in relation to simultaneous use of the serial cardiac biomarkers and the clinically used CHADS2 score are illustrated in figure 2A–C. As expected, there was a trend of increased annual rates for all outcomes with rising CHADS2 score. However, the risk increase was even more pronounced based on rising levels of serial cardiac biomarkers. In patients considered low-to-intermediate risk for stroke or systemic embolism according to CHADS2 classification (0–1), there was a 5.5-fold increase in annual rates when comparing patients with low levels of cardiac biomarkers at both time points (0.36%) with patients having high levels at both time points (2.06%) (figure 2A). Similar patterns were also seen concerning vascular death and the composite thromboembolic outcome (figure 2B–C).

    Figure 2
    Figure 2

    (A–C) Study endpoint in relation to combined cardiac biomarker levels and CHADS2 score. Stroke or systemic embolism (A) and vascular death (B) and composite thromboembolic outcome consisting of ischaemic stroke, systemic embolism, myocardial infarction, pulmonary embolism and vascular death (excluding haemorrhagic death) (C) in relation to cardiac biomarker levels and CHADS2 score. Combined cardiac biomarkers: group 1 non-detectable cTnI at both time points and NT-proBNP lower than median at both time points (n=311), group 2 one sample of either cTnI or NT-proBNP above the threshold value at one time point (n=1605) and group 3 detectable levels of cTnI at both time points and NT-proBNP higher than median at both time points (n=591).

    Discussion

    The current results from this RE-LY biomarker substudy show that persistent elevations of troponin I or NT-proBNP were common and seen in respectively 49% and 40% of patients with AF. Persistent elevation of cardiac biomarker levels in an AF population was strongly related to factors such as AF type, AF rhythm, renal function and male gender. Persistent elevation of troponin or NT-proBNP indicated a worse prognosis than transient elevations or no elevations of either marker. Simultaneous elevation of both markers increased the prognostic discrimination further. The information from repeated biomarker determinations had an incremental value for the prognostication of the risk of stroke, vascular death and all thromboembolic events when added to the conventional CHADS2 score.

    Recent publications have displayed the important effect of cardiac biomarkers for adverse outcomes in stable AF cohorts.4–8 So far there is no information concerning if the levels of these biomarkers remain constant or change over time in patients with AF. Neither is it known if the risk associated with elevated cardiac markers remains constant or vary with the eventual variability of biomarker levels. In this RE-LY biomarker substudy, levels of cardiac biomarkers were analysed at randomisation and at 3 months and related to outcomes during follow-up, median 2.0 years. The present results are in accordance with previous studies in which serial measurement of cardiac biomarkers has demonstrated to be powerful prognostic markers of mortality and morbidity in several patient populations such as acute coronary syndromes, stable coronary artery disease, in acute and chronic heart failure and in apparently healthy community-dwelling adults.9–15 Our findings in the present RE-LY substudy therefore extend these observations to a novel population by displaying the prognostic importance of serial measurements of cardiac biomarkers in patients with AF.

    Persistent elevations of cTnI levels were primarily associated with male gender, coronary artery disease, renal impairment and hypertension indicating an association with myocardial ischaemia and cardiovascular dysfunction. Sustained elevations of NT-proBNP were associated with renal impairment, AF type and AF rhythm. In a clinical setting, some of these factors might be possible to modify by pharmacological and/or interventional treatments. The regression dilution correction suggests that the true elevation in risk is underestimated with a single measure of the cardiac biomarkers. Identification of individuals at risk based on transient or persistent elevations might therefore be useful for instituting specific treatment to lower the risk of future cardiovascular events. This cardiac biomarker approach might therefore be a new innovative way to tailor the individual treatment in patients with AF. Such a strategy has recently been suggested in patients with chronic heart failure as those randomised to NT-proBNP-level-guided treatment had improved outcomes compared with standard care.21 ,22

    The precise mechanism of elevated cardiac biomarkers in patients with AF is not known. It has been hypothesised that there might be alternative explanations in AF populations, as contrary to the mechanism in acute coronary syndromes for cardiac troponin, and heart failure for NT-proBNP. Among these are increased ventricular rate that might lead to oxygen demand/mismatch and myocardial ischaemia, volume and pressure overload and changes in microvascular blood flow and, in particular regarding NT-proBNP, an association to atrial dysfunction and the arrhythmia per se.3 ,23–27 Myocyte dysfunction or damage resulting in elevated levels of troponin or NT-proBNP may to various degrees be linked to underlying processes of atrial inflammation and fibrosis, a well-described entity in AF pathology, and contributory to a hypercoagulable state that might add to the risk of thromboembolism and thereby provide a plausible mechanism for the relation of cardiac biomarker levels and thromboembolic events, as shown in the present study.26 ,28 ,29

    There are several limitations of this study. The findings concern an AF population with at least one risk factor for stroke. In order to extend and apply the results to patients with AF without any clinical stroke risk factors, further studies in other AF populations are warranted. Furthermore, the study design, with all study participants receiving oral anticoagulants, does not allow final conclusions concerning cardiac biomarkers as a decision support tool for improved selections of patients with AF for oral anticoagulation, although it would be reasonable to assume worse outcomes without fully anticoagulated patients. This influences event rates and power in the analysis, which however display plausible trends, consistent with findings in non-AF population, and may form the basis for replication in other studies. The mechanisms behind the release and origin of NT-proBNP in patients with AF without congestive heart failure need further clarification as well as the exact mechanisms behind troponin elevations and their relations to events such as stroke in AF.

    Conclusion

    Repeated measurements of cardiac troponin and natriuretic peptides in AF patients provide significantly improved risk assessment and prognostic information concerning stroke or systemic embolism, cardiovascular events and vascular death. Persistent elevation of cardiac biomarkers indicates a worse prognosis than transient elevations or no elevations of either marker. The use of serial measurements of cardiac biomarkers may provide novel strategies for risk identification and potential treatment tailoring in AF populations.

    Key messages

    • What is already known on this subject?

    • Cardiac biomarkers, such as cardiac troponin and natriuretic peptides, have recently been proposed to significantly enhance the information regarding risk and prognosis in patients with atrial fibrillation.

    • What this study adds?

    • The present study for the first time describes the levels of cardiac biomarkers over time in patients with atrial fibrillation and investigates if repeated measurements provide additional prognostic information.

    • How might this impact on clinical practice?

    • The results show that persistent elevation of troponin and NT-proBNP confers a worse prognosis than transient elevations or no elevations of either marker. Prognostication of stroke, death and thromboembolic events is improved by the use of repeated determinations of cardiac biomarkers.

    • This might improve clinical practice by better identification of individuals at risk and potentially be useful for instituting specific treatment to lower the risk of future cardiovascular events.

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    Footnotes

    • Contributors All coauthors contributed to conception and design, revising the manuscript critically for important intellectual content and final approval of the version to be submitted.

    • Funding The RE-LY trial was funded by Boehringer Ingelheim Pharmaceuticals.

    • Competing interests All authors have completed and submitted the ICMJE form for disclosure of potential conflicts of interest. ZH reports receiving lecture fees and an institutional research grant from Boehringer-Ingelheim. JO reports receiving consulting and lecture fees, and grant support from Boehringer Ingelheim, and consultant and lecture fees from Bayer and Bristol-Myers Squibb. UA reports no conflicts of interest. SJC reports receiving consulting fees, lecture fees and grant support from Boehringer Ingelheim. MDE reports receiving consulting fees, lecture fees and grant support from Boehringer Ingelheim and Aryx Therapeutics; consulting fees from Sanofi-Aventis; and lecture fees and grant support from Portola Pharmaceuticals. SHH reports receiving consulting fees and lecture fees from Boehringer Ingelheim, St Jude Medical and Sanofi Aventis, and lecture fees from Cardiome. PAR is an employee of Boehringer Ingelheim. AS reports consulting fees, lecture fees and grant support from Boehringer Ingelheim, lecture fees and grants from Eli Lilly and grant support from AstraZeneca. SY reports receiving consulting fees, lecture fees and grant support from Boehringer Ingelheim; and consulting fees from AstraZeneca, Bristol-Myers Squibb and Sanofi-Aventis. LW reports receiving consulting and lecture fees, honoraria and research grants from Boehringer Ingelheim; research grants from AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline and Schering-Plough; honoraria from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline and Schering-Plough; consultant fees from Athera Biotechnologies, AstraZeneca, Eli Lilly, GlaxoSmithKline and Regado Biotechnologies; lecture fees from AstraZeneca and Eli Lilly.

    • Ethics approval Health Authorities in all participating countries.

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

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