Figures
Abstract
Aim
Heart failure (HF) increases the risk of thromboembolic events (TE). Study in a Caucasian population has shown that the CHA2DS2-VASc score predicts TE among HF patients without atrial fibrillation. We sought to assess the usefulness of the CHA2DS2-VASc score in predicting TE in an Asian population and refine the scoring system to improve its predictability of TE among HF patients in sinus rhythm.
Methods
A total of 1,202 consecutive patients who were admitted to our institution for new-onset HF from 2005 to 2012 and without atrial fibrillation or anticoagulation were retrospectively reviewed.
Results
The mean age was 77.6 ± 12.2 years and 51.7% were female. After 36.2 ± 30.1 months, 113 (9.4%) developed TE. The annual incidence was 0.54%, 1.54%, 2.98% and 5.04% per year in those who had a CHA2DS2-VASc score of 1, 2–3, 4–5 and ≥6, respectively. In multivariate analysis, age ≥75 years [Hazard ratio (HR) 2.59, 95% confidence interval (CI) 1.23–5.46, p = 0.012), chronic ischemic heart disease (HR 1.54, 95% CI 1.02–2.31, p = 0.040) and chronic kidney disease (HR 1.66, 95% CI 1.09–2.53, p = 0.018) independently predicted TE. Incorporation of chronic ischemic heart disease and chronic kidney disease into the CHA2DS2-VASc score significantly increased the area under the Receiver Operating Curve from 0.57 (95% CI 0.54–0.59) to 0.61 (95% CI 0.55–0.66; p = 0.022).
Citation: Hai J-J, Chan P-H, Chan Y-H, Fong C-H-Y, Huang D, Li W-H, et al. (2016) Prediction of Thromboembolic Events in Heart Failure Patients in Sinus Rhythm: The Hong Kong Heart Failure Registry. PLoS ONE 11(12): e0169095. https://doi.org/10.1371/journal.pone.0169095
Editor: Nanette H. Bishopric, University of Miami School of Medicine, UNITED STATES
Received: August 29, 2016; Accepted: December 11, 2016; Published: December 30, 2016
Copyright: © 2016 Hai et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the paper and its Supporting Information files.
Funding: The authors received no specific funding for this work.
Competing interests: The authors have declared that no competing interests exist.
Abbreviations: AF, atrial fibrillation; CI, confidence interval; eGFR, estimated glomerular filtration rate; HR, hazard ratio; HF, heart failure; HFPEF, heart failure with preserved ejection fraction; LVEF, left ventricular ejection fraction; ROC, Receiver-Operating Characteristics; TE, thromboembolic events; WARCEF, Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction
Introduction
Heart failure (HF) is an emerging epidemic that affects 26 million people worldwide.[1] Although the condition is well-known for its poor prognosis due to pump failure and/or sudden death, significant morbidity and mortality also results from an increased risk of thromboembolism.[2–5] In fact, HF is the second most common cause of cardioembolic stroke after atrial fibrillation (AF).[6] Left ventricular dysfunction is associated with intra-cardiac stasis, endocardial and endothelial dysfunction, and a hypercoagulable state, all of which promote thrombus formation and subsequent embolization.[2, 7–9] In stark contrast to AF, in which long-term anticoagulation is shown to substantially reduce the risk of thromboembolic events (TE), randomized controlled trials in HF patients in sinus rhythm have failed to demonstrate a net clinical benefit of oral anticoagulation over antiplatelet agents or placebo.[10–13] In the largest Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction Trial (WARCEF) that involved 2,305 HF patients in sinus rhythm, warfarin conferred a reduction in ischemic stroke by 48% compared with aspirin that was offset by an increase in major hemorrhage.[13] Nonetheless this may also suggest that there exists a high-risk subset of HF patients in sinus rhythm who may derive a net clinical benefit from oral anticoagulation therapy.
The CHA2DS2-VASc score is a risk stratification tool to predict TE among patients with non-valvular AF.[14–18] This simple clinical prediction rule has been well validated in different populations and is recommended by current guidelines for the stratification of patients with AF for antithrombotic therapy.[15–20] Recently, the CHA2DS2-VASc score has also been shown in a Danish registry to predict TE among HF patients in sinus rhythm.[4, 21] Nevertheless this has not been evaluated in other populations. Furthermore, since the CHA2DS2-VASc score is based on studies in AF populations[14], clinical parameters not included in the CHA2DS2-VASc score may have incremental value for the prediction of TE among HF patients in sinus rhythm. We therefore performed this study to 1) determine independent clinical predictors of TE among HF patients in sinus rhythm; 2) assess the usefulness of the CHA2DS2-VASc score in predicting TE in Asian HF patients; 3) assess the value of incorporating independent clinical predictors into the CHA2DS2-VASc score to predict TE in HF patients in sinus rhythm.
Materials and Methods
Study design
This was a retrospective observational study based on the Hong Kong Heart Failure Registry. The study protocol was approved by the local Institutional Review Board. Details of the registry have been described in a previous study.[22] In summary, patients at Queen Mary Hospital, Hong Kong who were diagnosed with new-onset HF based on the Framingham Heart Study criteria from January 2005 to April 2012, were identified via the computerized clinical management system.[23] Demographic data, cardiovascular risk factors, clinical presentation, echocardiographic findings and laboratory test results on admission were recorded and clinical outcomes were followed. Patients who were younger than 18 years of age, had incomplete follow-up data, or were prescribed anticoagulation were excluded. Prior myocardial infarction was defined as a myocardial infarction that occurred during or prior to the index hospitalization. Chronic ischemic heart disease was defined as either a significant coronary artery stenosis diagnosed by angiography or myocardial ischemia diagnosed by stress testing in those without prior myocardial infarction. Chronic kidney disease was defined as an estimated glomular filtration rate (eGFR) <60 ml/min/1.73m2 by the Modification of Diet in Renal Disease formula.[24] HF with preserved ejection fraction (HFPEF) was defined as HF with left ventricular ejection fraction (LVEF) ≥40%.[25] The CHA2DS2-VASc score of each patient at diagnosis of HF was calculated (C: congestive heart failure [1 point]; H: hypertension [1 point]; A2: age 65–74 years [1 point] and age ≥75 years [2 points]; D: diabetes mellitus [1 point]; S: prior stroke or transient ischemic attack [2 points]; V: vascular disease, defined as prior myocardial infarction or peripheral vascular disease [1 point]; and Sc: sex category = female [1 point]).[14]. The primary outcome was TE and included ischemic stroke, transient ischemic attack and peripheral thromboembolism. All diagnoses were adjudicated by two cardiologists in accordance with the updated consensus statements and guidelines.[24, 26–30]
Statistical analysis
Continuous variables are expressed as mean ± standard deviation, and categorical variables are presented in frequency tables. Statistical comparison of continuous variables was performed using Student’s t test, and catagorical variables with Fisher’s exact test or Chi-square test. Kaplan-Meier survival analysis with the log-rank test was used to compare TE-free survival of different patient groups. Hazard ratio (HR) and 95% confidence interval (CI) of clinical variables to predict primary outcome among HF patients in sinus rhythm were determined by a multivariate Cox regression model using a p value <0.1 for inclusion. The prognostic performance of prediction models of TE was assessed using c-statistics and compared using the DeLong test. Internal validation of the final prediction model was evaluated by bootstrapping 1,000 random samples. The optimism was estimated by comparing the final model performance on each bootstrapped sample to that of the original data. The corrected area under the Receiver-Operating Characteristics (ROC) curve was computed by subtracting the optimism from the original area under the ROC curve. A 2-tailed p value <0.05 was considered statistically significant. Calculations were performed using SPSS software (version 21.0) and R package (version 3.3.1).
Results and Discussion
Patient selection, exclusion and clinical outcomes are summarized in Fig 1. From January 2005 to April 2012, 1,940 patients were admitted to our hospital for new-onset HF. After excluding 164 patients (8.5%) who were prescribed warfarin, the final analysis included 1,776 patients. The mean age of the cohort was 78.7 ± 11.7 years and 965 (54.3%) were female. Of the 858 patients (48.3%) who had a technically adequate echocardiogram during the admission, the mean LVEF was 47.0 ± 16.0% and 59.3% of patients had a LVEF ≥40%, i.e., HFPEF.
SR–sinus rhythm.
Clinical characteristics and outcomes of patients with and without AF
A total of 574 patients (32.3%) had prior or concomitant AF, and the remaining 1,202 were in sinus rhythm (67.7%). Table A in S1 File summarizes their clinical characteristics. After a mean follow-up of 36.2 ± 30.1 months, 190 patients with new-onset HF developed TE, of whom 169 had an ischemic stroke and 21 a transient ischemic attack. The annual incidence of TE in our cohort was 3.55% per year (95% CI: 3.41–3.69). Of the 190 TE, 77 developed in those with AF and 113 in patients in sinus rhythm. The annual incidence of TE among HF patients with AF and in sinus rhythm was 5.23% per year (95% CI 4.88–5.62) and 2.91% per year (95% CI 2.79–3.05), respectively. Fig A in S1 File depicts the Kaplan-Meier survival analysis comparing TE-free survival of HF patients with AF and those in sinus rhythm.
Predictors of TE among HF patients in sinus rhythm
Among HF patients in sinus rhythm, those who developed TE were more likely to have hypertension (82.3% vs. 72.5%, p = 0.025), chronic ischemic heart disease (40.7% vs. 24.0%, p<0.001) and chronic kidney disease (69.0% vs. 55.7%, p = 0.024. Table 1). They also had a higher CHA2DS2-VASc score (4.89 ± 1.40 vs. 4.52 ± 1.54, p = 0.014) and were more likely to be prescribed aspirin (54.9% vs. 43.5%, p = 0.022. Table 1). In univariate analyses, increasing age (age 65–74 years: HR 2.41, 95% CI1.07–5.41, p = 0.033; age ≥75 years: HR 3.10, 95% CI 1.50–6.43, p = 0.002), hypertension (HR 1.88, 95% CI 1.16–3.06, p = 0.010), diabetes mellitus (HR 1.46, 95% CI 1.01–2.11, p = 0.045), chronic ischemic heart disease (HR 1.95, 95% CI 1.34–2.83) and chronic kidney disease (HR 2.15, 95% CI 1.44–3.21, p<0.001) were associated with an increased risk of TE (Table 2). In multivariate analysis, increasing age (age ≥75 years: HR 2.59, 95% CI 1.23–5.46, p = 0.012), chronic ischemic heart disease (HR 1.54, 95% CI 1.02–2.31, p = 0.040) and chronic kidney disease (HR 1.66, 95% CI 1.09–2.53, p = 0.018) remained independently associated with TE (Table 2). Importantly, the use of aspirin, clopidogrel, and anti-HF medications such as betablockers, renal-angiotensin-aldosterone inhibitors and mineralocorticoid receptor antagonists was not associated with a reduced risk of TE in HF patients in sinus rhythm (Table 2).
The CHA2DS2-VASc score and TE among HF patients in sinus rhythm
Kaplan-Meier survival analysis showed that the TE-free survival of HF patients in sinus rhythm reduced with increasing CHA2DS2-VASc score (log-rank p<0.001. Fig 2A). As shown in Fig 2B, the annual incidence of TE increased with an increasing CHA2DS2-VASc score. Specifically, for patients who had a CHA2DS2-VASc score of 1, i.e. no other risk factor other than HF alone, the annual incidence of TE was 0.54% per year (95% CI 0.45–0.67). For those who had a CHA2DS2-VASc score of 2–3, the annual incidence of TE was 1.54% per year (95% CI 1.41–1.70). Nevertheless for patients who had a CHA2DS2-VASc score of 4–5 and ≥6, the annual incidence of TE was as high as 2.98% (95% CI 2.81–3.18) and 5.04% (95% CI 4.59–5.60) per year, respectively. The area under the ROC curve for the CHA2DS2-VASc score to predict TE was 0.57 (95% CI 0.54–0.59. Fig 3).
(A) Kaplan-Meier curves for thromboembolic event-free survival. Log-rank: 19.714. P<0.001. (B) Annual incidence of thromboembolic events. CHA2DS2-VASc = 1: 0.54% per year (95% CI 0.45–0.67); CHA2DS2-VASc = 2–3: 1.54% per year (95% CI 1.41–1.70); CHA2DS2-VASc = 4–5: 2.98% per year (95% CI 2.81–3.18); CHA2DS2-VASc ≥6: 5.04% per year (95% CI 4.59–5.60).
The area under the curve for the CHA2DS2-VASc score was 0.57 (95% CI 0.54–0.59) and that for the CHA2DS2-VASc-HK2 score was 0.61 (95% CI 0.58–0.63). A significant improvement in the area under the curve was noticed after incorporation of chronic ischemic heart disease and chronic kidney disease into the CHA2DS2-VASc score (p = 0.022).
Modification of the CHA2DS2-VASc score to improve prediction of TE among HF patients in sinus rhythm
Based on the additional independent predictors of TE identified in the multivariate cox regression analysis, we developed the CHA2DS2-VASc-HK2 by incorporating 1) chronic ischemic heart disease, and 2) chronic kidney disease into CHA2DS2-VASc score as follows: C: congestive heart failure [1 point]; H: hypertension [1 point]; A2: age 65–74 years [1 point] and age ≥75 years [2 points]; D: diabetes mellitus [1 point]; S: prior stroke or transient ischemic attack [2 points]; V: peripheral vascular disease and aortic disease [1 point]; and Sc: sex category = female [1 point]; H: ischemic heart disease, including myocardial infarction or chronic ischemic heart disease [1 point]; K: chronic kidney disease [2 points]. In general, the TE-free survival of HF patients in sinus rhythm also reduced with an increasing CHA2DS2-VASc-HK2 score (log-rank p<0.001. Fig 4A). In particular, patients with a CHA2DS2-VASc-HK2 score of 1–3 had good TE-free survival, patients with a CHA2DS2-VASc-HK2 score of 4–7 had intermediate TE-free survival, and those with a CHA2DS2-VASc-HK2 score ≥8 had the worst TE-free survival. The annual incidence of TE was 0.86% (95% CI 0.78–0.96), 2.76% (95% CI 2.61–2.92) and 5.50% (95% CI 4.99–6.12) per year for patients who had a CHA2DS2-VASc-HK2 score of 1–3, 4–7 and ≥8, respectively (Fig 4B). The area under the ROC curve for the CHA2DS2-VASc-HK2 score to predict TE was superior to that of the CHA2DS2-VASc score [0.61 (95% CI 0.55–0.66) vs. 0.57 (95% CI 0.54–0.59), p = 0.022. Fig 3]. When assessed by Cox regression analysis, a CHA2DS2-VASc-HK2 score of 4–7 was associated with a 3-fold increase in risk of TE and a CHA2DS2-VASc-HK2 score ≥8 was associated with a 6-fold increase in the risk of TE among HF patients in sinus rhythm (Table 3).
(A) Kaplan-Meier curves for thromboembolic event-free survival. Log-rank: 25.896. P<0.001. (B) Annual incidence of thromboembolic events. CHA2DS2-VASc-HK2 = 1–3: 0.86% per year (95% CI 0.78–0.96); CHA2DS2-VASc-HK2 = 4–7: 2.76% per year (95% CI 2.61–2.92); CHA2DS2-VASc-HK2 ≥8: 5.50% per year (95% CI 4.99–6.12).
Internal validation of the CHA2DS2-VASc-HK2 score
Internal validation of the final prediction model was performed as described. Cox regression analyses of 1000 bootstrapped samples resulted in the same independent predictors of TE (Table B in S1 File). The optimism-corrected area under the ROC curve was 0.61 (95% CI 0.55–0.66). We further compared the ability of the CHA2DS2-VASc-HK2 in predicting TE among patients with HFREF and HFPEF using z-test. The area under the ROC curve for the CHA2DS2-VASc-HK2 to predict TE in patients with HFREF and HFREF were not significantly different [0.63 (95% CI 0.52–0.73) and 0.70 (95% CI 0.60–0.80), respectively, (p = 0.368)].
Discussion
In this study, we confirmed that the risk of TE increases with an increasing CHA2DS2-VASc score in Asian HF patients in sinus rhythm. We also established that chronic ischemic heart disease and chronic kidney disease are independent predictors of TE among HF patients in sinus rhythm, incorporation of which into the CHA2DS2-VASc score modestly improves its predictive value.
Observational studies and post-hoc analyses from HF trials have shown that HF patients in sinus rhythm are at high risk of TE.[2–5] In our study, although the risk of TE was lower among HF patients in sinus rhythm than those with AF, the annual incidence was 2.91% per year, markedly higher than the reported incidence of 1.45 per 1000 persons per year in the general population.[31] Nevertheless, the risk of TE is not the same among all HF patients in sinus rhythm. Prior studies of a Danish registry have shown that the risk of TE increases with an increasing CHA2DS2-VASc score.[4, 21] We found a similar difference in the annual incidence of TE among HF patients with different CHA2DS2-VASc score. More importantly, both our study and the Danish study showed that a CHA2DS2-VASc score of 1 was associated with only modestly increased risk of TE.[21] Even in those who had a CHA2DS2-VASc score of 2–3, the annual incidence of TE was still less than 2% per year. In these patients, the benefit of anticoagulation may not outweigh the risk of the therapy. This may partially explain the negative results from previous randomized controlled trials that tested the benefit of anticoagulation therapy among HF patients in sinus rhythm.[10–13] Future randomized study is needed to properly assess the value of anticoagulation therapy among the high-risk subgroup of HF patients.
In this study, chronic ischemic heart disease and chronic kidney disease were independent predictors of TE. By incorporating these parameters into the CHA2DS2-VASc score, we modestly increased its predictive value from 0.57 (95% CI 0.54–0.59) to 0.61 (95% CI 0.55–0.66; p = 0.022). Furthermore, the new CHA2DS2-VASc-HK2 score was able to stratify HF patients in sinus rhythm into low (annual incidence of TE <2% per year), intermediate (annual incidence of TE 2–5% per year) or high (annual incidence of TE >5% per year) thromboembolic risk. Nevertheless, the relatively low area under the ROC curve implies that there remain significant missing variables in the new scoring system. In a pooled analysis of two clinical trials largely consisting of patients with chronic HFREF, Abdul-Rahim and colleagues have shown that age, previous stroke, New York Heart Association class, diabetes mellitus treated with insulin and body mass index predicted stroke in HF patients without AF.[5] We did not include New York Heart Association class or body mass index in our analysis, as both parameters are dynamic and particularly inaccurate in patients with new-onset HF.[5] Furthermore, we did not find prescription of insulin predictive of TE, in contrast to the findings by Abdul-Rhaim et al.[5] This is not surprising, as prescription of insulin in real-life situation can be affected by many factors. Other than secondary oral drug failure and chronic renal failure, availability of new oral hypoglycemic agents, perceived risk of tight diabetic control, acceptability and practicability of insulin injection, all affect one’s decision on prescribing insulin to a patient.
More recently, Abdul-Rahim et al. have published another study comprising patients from two clinical trials of chronic HFPEF.[32] They have found that patients with HFREF and HFPEF share similar risk factors for stroke.[32] In addition, they have shown that the risk model derived from the HFREF cohort predicts stroke in patients with HFPEF with comparable c-index.[5, 32] Similarly, our study did not find any significant differences in the ability of the CHA2DS2-VASc-HK2 score in predicting TE among patients with HFREF and HFPEF. These findings suggest that although the risk factors for HFREF and HFPEF are different, the risk factors for TE in HF remain similar. Furthermore, post-hoc analyses of previous clinical trials have not consistently shown that LVEF is a risk factor for TE in patients with HF.[33–35] In addition, the study by Abdul-Rahim et al. has not shown that LVEF predicts TE in HF patients.[5] It is likely that other factors leading to the common pathophysiologic pathway of inflammation, hypercoagulability, endocardial and endothelial dysfunction play a more important role in TE among HF patients than intracardiac stasis associated with LV systolic dysfunction per se.[2, 7–9]
Although both the CHA2DS2-VASc score and the CHA2DS2-VASc-HK2 score demonstrated limited predictive ability of TE as shown in the ROC analyses, both scoring systems involve simple calculation by summing up objective clinical risk factors, which improves their applicability as a risk stratification tool. External validation of the CHA2DS2-VASc-HK2 score is required to assess the robustness of this scoring system in predicting TE among HF patients in sinus rhythm.
A major strength of this study is that complete records for all patients were available, such that all baseline and outcome variables were adjudicated. In addition, patients in our study were followed up for a considerably long period of time. However, our study also has limitations. First, not all patients in our study had an echocardiogram performed on admission. As a result, our study might be underpowered to evaluate the effect of LVEF on TE. Nevertheless, our finding that LVEF was not predictive of TE is echoed by the result of another study comprising patients of clinical trials.[5] Second, although the incidence of TE was much higher in the HF than the general population, the actual number of events in each of the HFREF and HFPEF group was small due to small sample size, which precluded detailed subgroup analyses. However, previous study by Abdul-Rahim et al. has shown that the risk factors for stroke in HFREF and HFPEF are similar. Furthermore, we did not find any significant differences in the ability of the CHA2DS2-VASc-HK2 score in predicting TE among patients with HFREF and HFPEF. Third, patients were not systemically followed up for the development of AF. It is possible that some patients had undiagnosed paroxysmal AF prior to the development of TE. Forth, it is usually not possible to delineate the actual mechanism of ischemic cerebrovascular events.[36] As a result, the exact proportion of cardioembolic stroke versus ruptured atherosclerotic plaque remains undetermined.
Conclusions
HF, even without AF, is associated with a high incidence of TE. The CHA2DS2-VASc score is useful in stratifying thromboembolic risk among this group of patients. Incorporation of chronic ischemic heart disease and chronic kidney disease into the scoring system confers a modest but significant improvement in the ability to predict TE among HF patients in sinus rhythm.
Supporting Information
S1 File.
Table A. Baseline characteristics of heart failure patients with and without atrial fibrillation. Table B. Internal validation based on 1000 bootstrapped samples. A) Multivariate predictors of thromboembolic events in 1,000 bootstrapped samples. B) Prediction of thromboembolic events in 1,000 bootstrapped samples using the CHA2DS2-VASc-HK2 score. Fig A. Kaplan-Meier survival analysis of thromboembolic event-free survival among heart failure patients with and without atrial fibrillation. Log-rank: 9.085. P = 0.003.
https://doi.org/10.1371/journal.pone.0169095.s001
(PDF)
Author Contributions
- Conceptualization: JJH PHC CPL HFT CWS.
- Data curation: JJH DH WHL LXY.
- Formal analysis: JJH PHC YHC CHYF CPL HFT CWS.
- Investigation: JJH DH WHL LXY CWS.
- Methodology: JJH PHC YHC CHYF CPL HFT CWS.
- Project administration: CWS.
- Resources: JJH DH WHL LXY CWS.
- Software: JJH YHC CHYF.
- Supervision: CPL HFT CWS.
- Validation: JJH PHC YHC CHYF CWS.
- Visualization: JJH PHC CPL HFT CWS.
- Writing – original draft: JJH PHC.
- Writing – review & editing: JJH PHC CPL HFT CWS.
References
- 1. Braunwald E. Shattuck lecture—cardiovascular medicine at the turn of the millennium: triumphs, concerns, and opportunities. The New England journal of medicine. 1997;337(19):1360–9. pmid:9358131
- 2. Lip GY, Ponikowski P, Andreotti F, Anker SD, Filippatos G, Homma S, et al. Thrombo-embolism and antithrombotic therapy for heart failure in sinus rhythm. A joint consensus document from the ESC Heart Failure Association and the ESC Working Group on Thrombosis. European journal of heart failure. 2012;14(7):681–95. pmid:22611046
- 3. Lip GY, Rasmussen LH, Skjoth F, Overvad K, Larsen TB. Stroke and mortality in patients with incident heart failure: the Diet, Cancer and Health (DCH) cohort study. BMJ open. 2012;2(4). PubMed Central PMCID: PMCPMC4400696.
- 4. Melgaard L, Gorst-Rasmussen A, Lane DA, Rasmussen LH, Larsen TB, Lip GY. Assessment of the CHA2DS2-VASc Score in Predicting Ischemic Stroke, Thromboembolism, and Death in Patients With Heart Failure With and Without Atrial Fibrillation. Jama. 2015:1–9.
- 5. Abdul-Rahim AH, Perez AC, Fulton RL, Jhund PS, Latini R, Tognoni G, et al. Risk of Stroke in Chronic Heart Failure Patients Without Atrial Fibrillation: Analysis of the Controlled Rosuvastatin in Multinational Trial Heart Failure (CORONA) and the Gruppo Italiano per lo Studio della Sopravvivenza nell'Insufficienza Cardiaca-Heart Failure (GISSI-HF) Trials. Circulation. 2015;131(17):1486–94; discussion 94. pmid:25810334
- 6. Pullicino P, Homma S. Stroke in heart failure: atrial fibrillation revisited? J Stroke Cerebrovasc Dis. 2010;19(1):1–2. pmid:20123219
- 7. Lip GY, Gibbs CR. Does heart failure confer a hypercoagulable state? Virchow's triad revisited. Journal of the American College of Cardiology. 1999;33(5):1424–6. pmid:10193748
- 8. de Peuter OR, Kok WE, Torp-Pedersen C, Buller HR, Kamphuisen PW. Systolic heart failure: a prothrombotic state. Semin Thromb Hemost. 2009;35(5):497–504. pmid:19739040
- 9. Jug B, Vene N, Salobir BG, Sebestjen M, Sabovic M, Keber I. Procoagulant state in heart failure with preserved left ventricular ejection fraction. Int Heart J. 2009;50(5):591–600. pmid:19809208
- 10. Cleland JG, Findlay I, Jafri S, Sutton G, Falk R, Bulpitt C, et al. The Warfarin/Aspirin Study in Heart failure (WASH): a randomized trial comparing antithrombotic strategies for patients with heart failure. American heart journal. 2004;148(1):157–64. pmid:15215806
- 11. Cokkinos DV, Haralabopoulos GC, Kostis JB, Toutouzas PK, investigators H. Efficacy of antithrombotic therapy in chronic heart failure: the HELAS study. European journal of heart failure. 2006;8(4):428–32. pmid:16737850
- 12. Massie BM, Collins JF, Ammon SE, Armstrong PW, Cleland JG, Ezekowitz M, et al. Randomized trial of warfarin, aspirin, and clopidogrel in patients with chronic heart failure: the Warfarin and Antiplatelet Therapy in Chronic Heart Failure (WATCH) trial. Circulation. 2009;119(12):1616–24. pmid:19289640
- 13. Homma S, Thompson JL, Pullicino PM, Levin B, Freudenberger RS, Teerlink JR, et al. Warfarin and aspirin in patients with heart failure and sinus rhythm. The New England journal of medicine. 2012;366(20):1859–69. PubMed Central PMCID: PMCPMC3723382. pmid:22551105
- 14. Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the euro heart survey on atrial fibrillation. Chest. 2010;137(2):263–72. pmid:19762550
- 15. Olesen JB, Lip GY, Hansen ML, Hansen PR, Tolstrup JS, Lindhardsen J, et al. Validation of risk stratification schemes for predicting stroke and thromboembolism in patients with atrial fibrillation: nationwide cohort study. BMJ. 2011;342:d124. PubMed Central PMCID: PMCPMC3031123. pmid:21282258
- 16. Boriani G, Botto GL, Padeletti L, Santini M, Capucci A, Gulizia M, et al. Improving stroke risk stratification using the CHADS2 and CHA2DS2-VASc risk scores in patients with paroxysmal atrial fibrillation by continuous arrhythmia burden monitoring. Stroke. 2011;42(6):1768–70. pmid:21493904
- 17. Friberg L, Rosenqvist M, Lip GY. Evaluation of risk stratification schemes for ischaemic stroke and bleeding in 182 678 patients with atrial fibrillation: the Swedish Atrial Fibrillation cohort study. European heart journal. 2012;33(12):1500–10. pmid:22246443
- 18. Guo Y, Apostolakis S, Blann AD, Wang H, Zhao X, Zhang Y, et al. Validation of contemporary stroke and bleeding risk stratification scores in non-anticoagulated Chinese patients with atrial fibrillation. International journal of cardiology. 2013;168(2):904–9. pmid:23167998
- 19. January CT, Wann LS, Alpert JS, Calkins H, Cigarroa JE, Cleveland JC Jr., et al. 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol. 2014;64(21):e1–e76. pmid:24685669
- 20. Camm AJ, Lip GY, De Caterina R, Savelieva I, Atar D, Hohnloser SH, et al. 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association. Eur Heart J. 2012;33(21):2719–47. pmid:22922413
- 21. Wolsk E, Lamberts M, Hansen ML, Blanche P, Kober L, Torp-Pedersen C, et al. Thromboembolic risk stratification of patients hospitalized with heart failure in sinus rhythm: a nationwide cohort study. European journal of heart failure. 2015;17(8):828–36. pmid:26136386
- 22. Hai JJ, Chan PH, Huang D, Ho MH, Ho CW, Cheung E, et al. Clinical Characteristics, Management, and Outcomes of Hospitalized Heart Failure in a Chinese Population-The Hong Kong Heart Failure Registry. Journal of cardiac failure. 2016.
- 23. Siu CW, Yeung CY, Lau CP, Kung AW, Tse HF. Incidence, clinical characteristics and outcome of congestive heart failure as the initial presentation in patients with primary hyperthyroidism. Heart. 2007;93(4):483–7. PubMed Central PMCID: PMCPMC1861478. pmid:17005710
- 24. Ito H, Oshikiri K, Mifune M, Abe M, Antoku S, Takeuchi Y, et al. The usefulness of the revised classification for chronic kidney disease by the KDIGO for determining the frequency of diabetic micro- and macroangiopathies in Japanese patients with type 2 diabetes mellitus. J Diabetes Complications. 2012;26(4):286–90. pmid:22621778
- 25. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr., Drazner MH, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Journal of the American College of Cardiology. 2013;62(16):e147–239. pmid:23747642
- 26. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr., et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. Jama. 2003;289(19):2560–72. pmid:12748199
- 27. American Diabetes A. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2010;33 Suppl 1:S62–9. PubMed Central PMCID: PMC2797383.
- 28. European Stroke O, Tendera M, Aboyans V, Bartelink ML, Baumgartner I, Clement D, et al. ESC Guidelines on the diagnosis and treatment of peripheral artery diseases: Document covering atherosclerotic disease of extracranial carotid and vertebral, mesenteric, renal, upper and lower extremity arteries: the Task Force on the Diagnosis and Treatment of Peripheral Artery Diseases of the European Society of Cardiology (ESC). European heart journal. 2011;32(22):2851–906. pmid:21873417
- 29. Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, White HD, et al. Third universal definition of myocardial infarction. Journal of the American College of Cardiology. 2012;60(16):1581–98. pmid:22958960
- 30. Kernan WN, Ovbiagele B, Black HR, Bravata DM, Chimowitz MI, Ezekowitz MD, et al. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2014;45(7):2160–236. pmid:24788967
- 31. Witt BJ, Gami AS, Ballman KV, Brown RD Jr., Meverden RA, Jacobsen SJ, et al. The incidence of ischemic stroke in chronic heart failure: a meta-analysis. Journal of cardiac failure. 2007;13(6):489–96. pmid:17675064
- 32. Abdul-Rahim AH, Perez A, Maclsaac RL, Jhund PS, Carson PE, Komajda M, et al. Risk of Stroke in Chronic Heart Failure Patients With Preserved Ejection Fraction, but Without Atrial Fibrillation: Analysis of the CHARM-Preserved and I-Preserve Trials. European heart journal. 2016. Epub Nov 13.
- 33. Loh E, Sutton MS, Wun CC, Rouleau JL, Flaker GC, Gottlieb SS, et al. Ventricular dysfunction and the risk of stroke after myocardial infarction. The New England journal of medicine. 1997;336(4):251–7. pmid:8995087
- 34. Solomon SD, Wang D, Finn P, Skali H, Zornoff L, McMurray JJ, et al. Effect of candesartan on cause-specific mortality in heart failure patients: the Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity (CHARM) program. Circulation. 2004;110(15):2180–3. pmid:15466644
- 35. Freudenberger RS, Hellkamp AS, Halperin JL, Poole J, Anderson J, Johnson G, et al. Risk of thromboembolism in heart failure: an analysis from the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT). Circulation. 2007;115(20):2637–41. pmid:17485579
- 36. Uchiyama S. The concept of acute cerebrovascular syndrome. Front Neurol Neurosci. 2014;33:11–8. pmid:24157553