European Journal of Heart Failure (2015) 17, 828–836 doi:10.1002/ejhf.309

Thromboembolic risk stratification of patients hospitalized with heart failure in sinus rhythm: a nationwide cohort study Emil Wolsk1*, Morten Lamberts1, Morten L. Hansen1, Paul Blanche2, Lars Køber3, Christian Torp-Pedersen4, Gregory Y. H. Lip5,†, and Gunnar Gislason1,6,† 1 Department

of Cardiology, Gentofte Hospital, University of Copenhagen, Gentofte, Denmark; 2 Department of Biostatistics, University of Copenhagen, Copenhagen, Denmark; Heart Centre, Department of Cardiology, Rigshospitalet, Copenhagen, Denmark; 4 Institute of Health, Science and Technology, Aalborg University, Aalborg, Denmark; 5 University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Birmingham, UK; and 6 The National Institute of Public Health, University of Southern Denmark, Odense, Denmark 3 The

Received 7 January 2015; revised 25 February 2015; accepted 20 May 2015 ; online publish-ahead-of-print 2 July 2015

Aims

Patients with heart failure in sinus rhythm are at an increased risk of thromboembolic complications. So far, validated risk stratification tools are lacking for such patients, which makes the decision to initiate anti-thrombotic treatment difficult. ..................................................................................................................................................................... Methods We included 136 545 patients admitted with heart failure in sinus rhythm from national registries from 1999 to 2012. and results Patients receiving oral anticoagulants were omitted from the study. First, we investigated if the CHA2 DS2 -VASc score could identify heart failure patients in sinus rhythm with high rates of thromboembolic complications. Second, we investigated if any single CHA2 DS2 -VASc risk factor carried a greater prognostic value with regard to thromboembolism. The risk of thromboembolism increased more than ninefold (hazard ratio 9.2, 95% confidence interval 6.8–12.5) in patients with all CHA2 DS2 -VASc risk factors compared with those with heart failure alone. The incidence rates of thromboembolism were clinically significant, averaging 6.0 (95% confidence interval 5.98–6.02) events per 100 patient years during the first year following diagnosis. Risk factors such as diabetes, age, vascular disease, and especially previous thromboembolism, conferred an independent risk of future thromboembolism. ..................................................................................................................................................................... Conclusion The CHA2 DS2 -VASc risk stratification scheme was able to provide prognostic information on future thromboembolic events in patients with heart failure in sinus rhythm. The CHA2 DS2 -VASc scale could be easily implemented as an aid to clinicians in risk stratifying heart failure patients in sinus rhythm, for thromboembolism.

.......................................................................................................... Stroke • Heart failure • CHA2 DS2 -VASc

Sinus rhythm •

Introduction Patients with heart failure in sinus rhythm are at an increased risk of thromboembolic complications but data reporting the incidence of thromboembolic rates in patients with heart failure vary greatly with different study designs and populations.1 Many older studies have also failed to divide heart failure patients with

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Keywords

Cerebral infarction •

Thromboembolism •

concomitant atrial fibrillation/flutter (AF) from those patients in sinus rhythm.2 – 4 Recognizing that heart failure patients in sinus rhythm are at an increased risk of stroke and thromboembolic complications, recent controlled studies have randomized patients to either antiplatelet therapy or anticoagulation with a vitamin K antagonist (VKA).5 – 7 Although there was a lower incidence of stroke and

*Corresponding author: Department of Cardiology, Post 635, Copenhagen University, Hospital Gentofte, Kildegårdsvej 28, Hellerup 2900, Denmark. Tel: +45 39773977; Fax: +45 39751803; E-mail: [email protected] † Joint senior authors.

© 2015 The Authors European Journal of Heart Failure © 2015 European Society of Cardiology

thromboembolism using VKA, the benefit was offset by an increase in episodes of bleeding. Guidelines from Heart Failure Society of America and a consensus statement from the European Society of Cardiology (ESC) both address the issue.1,8 Both suggest that VKA treatment for heart failure patients in sinus rhythm should be based on an individual risk assessment and instituted only if the thromboembolic risk outweighs the excess risk of bleeding with VKA treatment. The 2012 ESC guidelines for heart failure do not recommend routine oral anticoagulation for heart failure patients in sinus rhythm.9 To date, adequate strategies for thromboembolic risk stratification in heart failure are lacking, which may increase both the risk of thromboembolism and bleeding. In AF, contemporary guidelines use the well-validated CHA2 DS2 -VASc [Congestive heart failure, Hypertension, Age (≥75 years), Diabetes, Stroke, Vascular disease, intermediate Age (65–74 years), Sex category] score for stroke risk stratification.10 – 13 Many of the CHA2 DS2 -VASc risk factors have previously been associated with stroke in heart failure patients in sinus rhythm.14,15 and recent studies have demonstrated that the CHA2 DS2 -VASc score is also predictive of stroke and thromboembolism in non-AF populations, although not in a heart failure population per se.16,17 Indeed, the CHA2 DS2 -VASc score has not been previously validated in a large population of heart failure patients in sinus rhythm without known AF. In the present study, we investigated the issue of risk stratification in the heart failure patient population by using the CHA2 DS2 -VASc score, applied to a retrospective ‘real-world’ cohort of more than 136 000 patients. First, we investigated if the CHA2 DS2 -VASc score could identify heart failure patients in sinus rhythm with high rates of thromboembolic complications. Second, we investigated if any single CHA2 DS2 -VASc risk factor carried a greater prognostic value with regard to thromboembolism, defined as either peripheral artery embolism, transient cerebral ischemia, or stroke.

Methods In Denmark, each resident is at birth or immigration provided with a unique and permanent civil registration number that allows linkage between administrative registers at the individual level. Since 1978 all hospitalizations have been registered in the Danish National Patient Registry.18 Each hospitalization is, at discharge, coded with one primary, and if appropriate, one or more secondary diagnoses, classified according to the International Classification of Diseases (ICD), until 1994 the 8th revision (ICD-8) and thereafter the 10th revision (ICD-10). The National Causes of Death Register and the Civil Registration System contain data on date of death, as well as data on the cause of death. The Danish Register of Medicinal Product Statistics keeps records of all dispensed prescriptions from Danish pharmacies since 1995.19 The registry contains information on date and quantity dispensed and each drug is classified according to the international Anatomical Therapeutical Chemical (ATC) classification.

Population Patients discharged alive with first time heart failure (ICD-10 codes I110, I42, I50, J819; ICD-8 codes 425, 4270–4271) between 1999

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and 2012 were included at the date of discharge. The diagnosis of heart failure had previously been validated with a specificity of 99% and positive predictive value of 81%.20 Patients with known atrial fibrillation and/or flutter (I48, 4274) at inclusion were excluded from our intended cohort; also excluded were patients who claimed a prescription for VKA or any non-VKA oral anti-coagulants (NOACs, previously referred to as new or novel OACs)21 up to 6 months before the first admission for heart failure. Only patients aged 18 years or older at the time of diagnosis of heart failure were included.

Thromboembolic risk stratification For each patient, their CHA2 DS2 -VASc score was calculated using nationwide registries. All patients scored at least one point because of their heart failure condition. One additional point was given for hypertension, age 65–74 years, diabetes, vascular disease, and female sex, whereas previous stroke (thromboembolism) and age above 74 years each gave two points. A maximum of nine points was obtainable. The score has been shown to accurately predict thromboembolic risk in an AF population.22 Details on ATC and ICD codes used to classify patients with co-morbidity are listed in the Supplementary material online.

Statistics The unadjusted risk of thromboembolism is presented as incidence rates per 100 patient years [95% confidence intervals (CI)], unless otherwise stated. Three models were used to examine stroke risk: (i) cumulative incidences of thromboembolism with death as a competing risk, and patients were categorized into their respective CHA2 DS2 -VASc class upon their first hospitalization for heart failure; (ii) incidence rates were obtained by extracting all thromboembolic events within the follow-up period and adjusting for the time at risk for the population; and (iii) yearly incidence rates were obtained by extracting all thromboembolic events in each given year in our heart failure population, and adjusting for the time at risk. If a thromboembolic event occurred within 7 days of a previous thromboembolic event it was censored, to minimize the risk of a single event being classified more than once. At each consecutive year in the analysis, all patients with a new diagnosis of AF and similarly all patients who had claimed a prescription for VKA or a NOAC were also censored (a proxy for AF). At each year all patients were reclassified according to their CHA2 DS2 -VASc risk factors at the time. The Cox proportional hazard regression model was used to predict the hazard ratio of CHA2 DS2 -VASc classes, with CHA2 DS2 -VASc class 1 as the reference group. We used the area under the time-dependent receiver operating characteristic (ROC) Curve [AUC(t)] to quantify how the CHA2 DS2 -VASc discriminates patients that experience thromboembolism within t = 1, 3, 5 and 10 years from others.23 SAS version 9.2 (SAS Institute, Cary, NC, USA) and R version 3.1.1, timeROC version 0.2 (Vienna, Austria) were used for statistical analyses. A two-sided P-value of 75 years - 51.5% Hypertension - 47.8% Age 65-74 years - 23.4% Vascular disease - 32.3%

Figure 1 Overview of the study population. Flowchart showing the heart failure cohort included.

Results Of the 176 029 heart failure patients identified, and following exclusion of 39 484 patients because of AF or OAC use, a total of 136 545 patients (78%) were included with a mean follow up of 3.6 ± 3.4 years (Figure 1). Of patients included, 47% were female and the average age was 73.3 ± 13.7 years. Table 1 lists the baseline characteristics of the study population. Of 13 017 thromboembolic events registered, 78.8% were caused by ischaemic stroke, 14.7% by transient cerebral ischemia, and 6.5% by peripheral artery embolism. Figure 2 depicts the cumulative incidence of thromboembolic events in heart failure patients according to their CHA2 DS2 -VASc score at the time of their heart failure diagnosis, while Table 2 lists incidence rates per 100 patient years. There was an increase in the rate of thromboembolism with increasing CHA2 DS2 -VASc score, ranging from 1.1 to 12.8 events per 100 patient years. Table 3 lists the annual event rates of thromboembolic events in each CHA2 DS2 -VASc class, in relation to time-interval since diagnosis. In each year all patients were reclassified according to their CHA2 DS2 -VASc risk factors at the time. The risk of thromboembolism was highest in the first year following hospitalization with heart failure. Table 4 lists the incidence rates of thromboembolic events for heart failure patients with one additional CHA2 DS2 -VASc risk factor (excluding previous thromboembolism and age >75 years) assessed at the time of their heart failure diagnosis totalling a CHA2 DS2 -VASc score of 2. Thus, among those with a CHA2 DS2 -VASc score of 2, patients aged 65–74 years, followed by those with diabetes mellitus or with vascular disease had the highest incidences of thromboembolism. The cumulative incidences are illustrated in the Supplementary material online. Figure 3 shows the 12 combinations of risk factors equalling a CHA2 DS2 -VASc score of 3 assessed at the time of their heart failure diagnosis. Patients who had a previous thromboembolism (‘TE’)

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had a significantly worse prognosis than all other combinations of risk factors. To explore the effect of previous thromboembolism on future events, we looked at patients with or without previous thromboembolism as a risk factor, as visualized in Figure 4. The incidence rates of CHA2 DS2 -VASc groups with equal numerical value with or without previous thromboembolism (±TE) as a risk factor, are listed in the Supplementary material online.

Predictive ability of CHA2 DS2 -VASc Using C-statistics, the ability of CHA2 DS2 -VASc to predict thromboembolism during the follow-up period at years 1, 3, 5, and 10 was 62.6% (95% CI 61.8–63.3), 61.5% (95% CI 60.9–62.1), 60.4% (95% CI 59.9–60.9), and 57.6% (95% CI 57.1–58.1), respectively. As expected, it was more difficult to predict the long-term risk of thromboembolism than the short-term risk, based on the value of the CHA2 DS2 -VASc score. The ROC curves are displayed in the Supplementary material online. Table 2 shows that compared to patients with heart failure and no additional CHA2 DS2 -VASc risk factors (CHA2 DS2 -VASc = 1, n = 7325), hazard ratios also increased with increasing CHA2 DS2 -VASc scores. There were no clinical significant differences in outcomes between patients if they had ischaemic heart disease or not (data not shown).

Discussion In this nationwide study on thromboembolic risk in patients with heart failure, our principal findings are: first, thromboembolic risk clearly increased with an increasing CHA2 DS2 -VASc score, in a similar fashion to that reported in patients with AF (the rates are higher than have been reported previously); and second, among heart failure patients with one additional risk factor, those with previous thromboembolism, high age, diabetes mellitus, or vascular disease, confers the highest risks. Our aim was to assess if the CHA2 DS2 -VASc risk stratification tool could aid in predicting risk of thromboembolic complications in real-life patients with heart failure. Thromboembolic risk clearly increased with an increasing CHA2 DS2 -VASc score, but with slightly lower rates compared with patients with AF.22 Regardless of changing risk factor burden and incident AF over time, the CHA2 DS2 -VASc classification was still able to risk stratify heart failure patients after adjustments for these risk factors. Although there was an overall decrease in the rate of thromboembolism over time, the CHA2 DS2 -VASc scoring system was still able to stratify patients within a given year after inclusion. As previously reported, the pattern of early excess of thromboembolism in heart failure patients following the initial post-hospitalization period,24,25 was also seen in the present study. Thus, CHA2 DS2 -VASc may be a valuable tool to assess thromboembolic risk in patients with a first-time hospitalization for heart failure. This was further substantiated by C-statistics, with values indicating a fair discriminatory value of CHA2 DS2 -VASc. An earlier registry study of AF patients not using VKA reported incidence rates of thromboembolism during the first year of © 2015 The Authors European Journal of Heart Failure © 2015 European Society of Cardiology

© 2015 The Authors European Journal of Heart Failure © 2015 European Society of Cardiology

136 545 47 73.3 ± 13.7 47.8 13.1 14.4 32.3 42.3 8.5 4.7 38.1 44.8 17.9 54.0 13.5 24.9 39.0 9.4 13.7 7325 0 52.1 ± 10.7 0 0 0 0 13.5 6.0 3.2 29.3 35.5 13.0 35.1 6.0 13.9 18.2 2.0 9.0

17 631 29 58.0 ± 11.0 30.0 3.8 0 11.2 25.3 7.8 3.4 40.2 47.3 19.2 45.6 9.6 23.0 29.4 5.9 12.3 27 985 28 69.9 ± 12.2 38.6 8.1 1.4 22.7 36.3 9.5 4.2 37.7 45.4 17.6 51.1 11.0 26.6 37.0 9.1 13.3

35 906 56 77.9 ± 10.5 42.0 11.0 4.3 28.7 39.2 9.0 4.4 33.7 40.8 16.8 56.2 12.7 22.4 38.8 8.1 14.9

26 490 62 80.2 ± 8.6 70.7 16.9 16.1 44.8 51.3 8.4 5.3 42.3 48.9 20.2 60.1 17.7 26.4 45.4 11.1 15.4

13 424 68 81.1 ± 7.9 67.7 26.7 48.5 60.9 62.7 8.0 6.1 41.3 46.1 18.0 60.0 17.5 30.4 48.2 14.9 12.8

AIIRB, angiotensin II receptor blocker; ARB, aldosterone receptor blocker; ASA, acetylsalicylate acid; CCB, calcium channel blocker; IHD, ischaemic heart disease; TE, thromboembolism. All numerical values listed are means ± SEM, except age, which is given as mean ± SD. All medications are based on claimed prescriptions within 3 months after their heart failure diagnosis.

n Females (%) Age Hypertension (%) Diabetes (%) Previous TE (%) Vascular disease (%) IHD (%) Cancer (%) Renal failure (%) Beta-blockers (%) ACEi/AIIRB (%) ARB (%) Loop diuretic (%) CCB (%) Statin (%) ASA (%) Clopidogrel (%) Digoxin (%)

5736 68 81.9 ± 7.0 76.3 33.3 85.7 64.1 62.5 7.5 7.3 41.2 46.4 17.7 59.7 19.7 28.8 49.1 15.1 12.5

1820 84 82.5 ± 6.0 92.3 43.7 100 86.7 78.5 6.9 8.5 45.6 50.8 18.7 60.0 24.3 33.5 50.4 19.0 11.2

228 100 83.0 ± 5.3 100 100 100 100 84.7 7.0 7.9 54.8 57.9 24.1 68.0 24.6 39.9 57.5 25.4 9.7

CHA2 DS2 -VASc class ..................................................................................................................................................................................................... All 1 2 3 4 5 6 7 8 9 ...................................................................................................................................................................................................................

Table 1 Baseline characteristics of the heart failure population

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Figure 2 Thromboembolism in heart failure (HF) patients according to CHA2 DS2 -VASc classification. Cumulative incidences of thromboembolism during the entire follow-up period. Each graph represents different CHA2 DS2 -VASc groups 1–9. The incidence rates are listed in Table 2.

Table 2 Incidence of thromboembolism according to CHA2 DS2 -VASc score CHA2 DS2 -VASc n Thromboembolic events Incidence rates Hazard ratios ........................................................................................................................................... 1 2 3 4 5 6 7 8 9

7325 17 631 27 985 35 906 26 490 13 424 5736 1820 228

406 1104 2156 3326 2964 1795 908 313 45

1.1 (1.1–1.1) 1.3 (1.3–1.3) 2.1 (2.1–2.1) 3.0 (3.0–3.1) 4.1 (4.0–4.1) 5.8 (5.7–5.9) 8.2 (7.9–8.5) 9.7 (9.2–10.3) 12.8 (12.4–13.3)

1.0 1.2 (1.1–1.3) 1.8 (1.6–2.0) 2.6 (2.3–2.9) 3.4 (3.0–3.8) 4.6 (4.1–5.1) 6.3 (5.6–7.0) 7.3 (6.3–8.4) 9.2 (6.8–12.5)

follow-up of 2.0 and 3.7 (per 100 patient years) in patients having a CHA2 DS2 -VASc score of 1 or 2, respectively.22 These incidence rates are similar to other reported registry data.26 The AF patients with a CHA2 DS2 -VASc score of 1 may be prescribed an OAC, whereas a CHA2 DS2 -VASc score of 2 or more holds a class 1A indication for OAC, unless their bleeding risk is too high. In our data, the rate of thromboembolism was 2.9 per 100 patient years with a CHA2 DS2 -VASc score of both 1 and 2 in the first year of follow-up. This would be a sufficiently high event rate to justify thromboprophylaxis (with respect to any excess bleeding risk) in an AF population. Whether thromboprophylaxis would provide a net benefit for our population, especially with the availability of NOACs that offer efficacy, safety, and convenience compared with VKA,27 – 29 is unknown. Indeed, NOACs show greater efficacy in reducing stroke with rates of major bleeding (and intracranial bleeding) similar to those of aspirin.30

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Incidence of thromboembolism per 100 patient years (95% confidence interval) after heart failure diagnosis according CHA2 DS2 -VASc class.

Earlier randomized trials have addressed the question of whether VKA is of benefit to heart failure patients in sinus rhythm. Although the WARCEF (the Warfarin and Aspirin in Reduced Cardiac Ejection Fraction) trial did find a small but significant reduction in stroke with VKA treatment vs. aspirin, the benefit was offset by more bleeds.7 . The stroke rate in patients receiving aspirin (1.36 per 100 patient years) was comparable to our patients with CHA2 DS2 -VASc score of 2 (1.3 thromboembolic events per 100 patients years, Table 2), despite the WARCEF population having many CHA2 DS2 -VASc risk factors present. It was not possible to extract how many patients suffered from multiple risk factors in these trials. There seems to be a lower incidence of thromboembolic complications in the randomized controlled trials investigating OAC to heart failure patients compared with our and other real-world findings, which could indicate a bias in patient selection towards a healthier population.5,7,26 Hence, © 2015 The Authors European Journal of Heart Failure © 2015 European Society of Cardiology

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Incidence rates per 100 patient years (95% confidence interval) during each time interval after first-time hospitalization for heart failure according to CHA2 DS2 -VASc class. Patients listed did not have atrial fibrillation (AF) or take vitamin-K antagonist (VKA) or non-VKA oral anti-coagulants (NOACs). Patients were stratified into their respective CHA2 DS2 -VASc class yearly; n equals all patients included in the annual analyses.

22.7 (20.8–25.0) 8.9 (8.5–9.3) 11.1 (10.7–11.7) 8.7 (8.2–9.2) 4.9 (4.5–5.3) 16.9 (16.4–17.5) 9.2 (9.0–9.4) 6.6 (6.5–6.7) 6.6 (6.5–6.7) 7.4 (7.2–7.6) 14.9 (14.6–15.1) 9.8 (9.7–9.9) 7.6 (7.6–7.7) 7.7 (7.6–7.8) 7.3 (7.2–7.4) 10.8 (10.7–10.9) 5.4 (5.3–5.4) 5.4 (5.4–5.5) 4.5 (4.5–4.6) 5.5 (5.5–5.6) 7.4 (7.4–7.5) 3.8 (3.8–3.8) 3.7 (3.7–3.7) 3.3 (3.3–3.3) 3.5 (3.4–3.5) 5.6 (5.6–5.7) 2.7 (2.7–2.7) 2.4 (2.4–2.4) 2.2 (2.2–2.2) 2.6 (2.6–2.6) 4.0 (4.0–4.1) 1.7 (1.7–1.7) 1.8 (1.8–1.8) 1.7 (1.7–1.7) 1.6 (1.6–1.6) 2.9 (2.9–3.0) 0.8 (0.8–0.8) 1.2 (1.1–1.2) 0.6 (0.6–0.6) 0.9 (0.9–0.9) 2.9 (2.9–2.9) 0.6 (0.6–0.6) 0.8 (0.8–0.8) 0.4 (0.4–0.4) 0.6 (0.6–0.6) 136 545/6302 72 713/2056 57 763/1587 45 958/1132 36 507/988 0–1 years 1–2 years 2–3 years 3–4 years 4–5 years

................................................................................................................................................................. 1 2 3 4 5 6 7 8 9 .........................................................................................................................................................................................

CHA2 DS2 -VASc class

n/Thromboembolic events Time interval

Table 3 Incidence of thromboembolism, in relation to time interval since first-time hospitalization for heart failure

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Table 4 The thromboembolic risk of heart failure and one additional risk factor Risk factors

N

Thromboembolic Incidence events rates ................................................................ Age 65–74 years Diabetes mellitus Vascular disease Hypertension Female

4575 673 1975 5286 5122

361 57 138 323 225

2.1 (2.0–2.2) 2.0 (1.9–2.1) 1.4 (1.4–1.5) 1.2 (1.1–1.2) 0.8 (0.8–0.8)

Incidence of thromboembolism per 100 patient years (95% confidence intervals) after first hospitalization because of heart failure according to CHA2 DS2 -VASc class 2.

the potential benefit of VKA or other antithrombotic treatment may have been low compared with the inherent risk of bleeding with VKA treatment in the randomized trials. Conversely, patients included in the WARCEF and WASH (Warfarin/Aspirin Study in Heart failure)5,31 trial had left ventricular ejection fraction (LVEF) ≤35%, whereas our cohort most likely also included patients with LVEF above 35%. Importantly, in contrast to most trials,5 – 7 our study also examines thromboembolic risk from time of first time hospitalization for heart failure. Studies have suggested that risk of stroke substantially increases following hospitalization owing to heart failure.24,25 Thus, risk stratification and evaluation of the potential indication of antithrombotic therapy may be warranted at diagnosis (or first-time hospitalization for heart failure) and our data clearly reflects this initial increased hazard. Although our data suggests that the CHA2 DS2 -VASc score is helpful in risk-stratifying patients with heart failure, our analyses also revealed that the prognostic weight of the individual risk factors were different. Most notably, in keeping with a previous analysis, previous thromboembolism appeared to be a very strong predictor of future thromboembolism.24 . Even when comparing patient groups with similar CHA2 DS2 -VASc values, having previous thromboembolism in your risk profile, significantly increased the risk of future thromboembolism. This trend is well-recognized in patients with AF,22 reiterating that previous thromboembolism is a prognostic risk factor for future thromboembolism. In contrast, being female did not add any excess risk compared with being male when simply comparing these groups without any adjustment for age or other confounding variables. What are the clinical implications? Our data show that many heart failure patients with multiple risk factors display thromboembolic rates well above 2–3%, where especially previous thromboembolism is a strong predictor of future thromboembolic complications. Our data also show that the rates are much higher during the first year following the diagnosis of heart failure, which should be noted when assessing whether a patient is candidate for OAC treatment. The ESC consensus paper states that the better risk profile of NOACs compared with VKA may actually reduce this threshold to 0.9%, before OAC is favourable.1 In this context, future clinical studies with OAC for the most ‘high risk’ thromboembolic prone patients with heart failure are warranted.

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Figure 3 Thromboembolism in heart failure patients with previous thromboembolism or other risk factors. Cumulative incidences of thromboembolism during the entire follow-up period in patients with heart failure (HF). Patient included all had a CHA2DS2-VASc score of 3. Apart from prior TE, the 11 other combinations of co-morbidity equalling a CHA2 DS2 -VASc score of 3, are not depicted on the graph owing to space constraints.

Limitations Patients included in this study were coded as having heart failure in the registry but data on the systolic and diastolic function of the heart was not present in the registry. This diagnosis has previously been validated with a sensitivity of 29%, a specificity of 99%, and a positive predictive value of 81%.20 This implies that patients without heart failure were likely present in our cohort. Although many of our patients had thromboembolic risk rates surpassing those that warrant OAC treatment, it is not known

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Figure 4 The prognostic significance of previous thromboembolism on future events. Cumulative incidence of thromboembolism during the entire follow-up period in patients with heart failure (HF) and a CHA2 DS2 -VASc score of 3–7. Patients were stratified into two subgroups depending on whether they had experienced a previous thromboembolic event (±TE). The incidence rates are listed in Table 5.

whether these patients would benefit from the treatment. The WARCEF and WATCH trials did not find an overall benefit in their primary efficacy endpoint (which included all-cause mortality), when bleeding episodes were taken into account. This could be because different populations studied compared with ours, and mortality in heart failure patients can have non-thromboembolic causes. Another important limitation is that the 0.9% threshold is based on data from AF patients treated with dabigatran, a population unlike the one in the present study.32 We sought to exclude patients with AF using diagnostic codes and VKA and © 2015 The Authors European Journal of Heart Failure © 2015 European Society of Cardiology

NOAC as proxy markers of unregistered AF; despite this, patients with AF may still be present in our cohort but may be either asymptomatic, undetected, or erroneously not coded.

Conclusion The thromboembolic risk in patients hospitalized with heart failure in sinus rhythm was associated with CHA2 DS2 -VASc risk factors. Importantly, the CHA2 DS2 -VASc risk stratification scheme was able to provide prognostic information about future thromboembolic events. Finally, we found that the thromboembolic complications in this real-world population of heart failure patients in sinus rhythm are much higher than previously reported in randomized trials. We suggest that the CHA2 DS2 -VASc scale could be easily implemented as an aid to clinicians in risk-stratifying heart failure patients in sinus rhythm, for thromboembolism.

Supplementary Information Additional Supporting Information may be found in the online version of this article: Figure S1. The time dependent ROC curves. Figure S2. Thromboembolism in heart failure (HF) patients with one additional risk factor. Text S1. Identification of patients with co-morbidity. Table S1. Incidence rates according to CHA2 DS2 -VASc classes with and without TCI in the composite endpoint of thromboembolism. Table S2. Hazard ratios according to CHA2 DS2 -VASc classes with and without TCI in the composite endpoint of thromboembolism. Table S3. Patients at risk at selected times from 1st. hospitalization for heart failure. Table S4. Previous thromboembolism as a risk factor for future thromboembolic events.

Funding No funding was received for this study. Conflict of interest: Y.H.L. has served as a consultant for Bayer, Astellas, Merck, AstraZeneca, Sanofi, BMS/Pfizer, Biotronik, Portola, and Boehringer Ingelheim and has been on the speakers bureau for Bayer, BMS/Pfizer, Boehringer Ingelheim, and Sanofi-Aventis. C.T-P. reports personal fees and other from Cardiome, personal fees and other fees from Merck, personal fees and other fees from Sanofi, personal fees and other fees from Daiichi, and other fees from BMS. L.K. reports payment of department for participation in clinical trials (Novartis and Bayer); All other authors declare no conflict of interest.

References 1. Lip GYH, Piotrponikowski P, Andreotti F, Anker SD, Filippatos G, Homma S, Morais J, Pullicino P, Rasmussen LH, Marín F, Lane DA, Heart Failure Association (EHFA) of the European Society of Cardiology (ESC) and the ESC Working Group on Thrombosis. Thromboembolism and antithrombotic therapy for heart failure in sinus rhythm: an executive summary of a joint consensus document from the ESC Heart Failure Association and the ESC Working Group on Thrombosis. Thromb Haemost 2012;108:1009–1022.

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© 2015 The Authors European Journal of Heart Failure © 2015 European Society of Cardiology

Thromboembolic risk stratification of patients hospitalized with heart failure in sinus rhythm: a nationwide cohort study.

Patients with heart failure in sinus rhythm are at an increased risk of thromboembolic complications. So far, validated risk stratification tools are ...
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