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Warfarin may reduce risk of ischemic stroke by preventing atrial fibrillation for patients with heart failure and sinus rhythm
International Journal of Cardiology 164 (2013) 245–254
Contents lists available at SciVerse ScienceDirect
International Journal of Cardiology j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / i j c a r d
Letter to the Editor
Warfarin may reduce risk of ischemic stroke by preventing atrial fibrillation for patients with heart failure and sinus rhythm Gen-Min Lin a,⁎, Yi-Hwei Li b, Lamin .E.S. Jaiteh c, Chih-Lu Han d a
Department of Medicine, Hualien Armed Forces General Hospital, Hualien, Taiwan Department of Public Health, Tzu-Chi University, Hualien, Taiwan Department of Royal Victoria Teaching Hospital, Banjul, Gambia d Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan b c
a r t i c l e
i n f o
Article history: Received 20 June 2012 Accepted 24 June 2012 Available online 12 July 2012 Keywords: Warfarin Aspirin Atrial fibrillation Heart failure
To the Editor: As compared with the general population, patients with reduced ejection fraction who are in sinus rhythm are observed with a higher risk for ischemic stroke. This relationship is caused by left ventricular stasis, a systemic hypercoagulable state, and endocardial dysfunction in a situation of impaired left ventricular systolic function [1,2]. Therefore, the issue whether antithrombotic agents especially aspirin or warfarin could successfully prevent stroke for patients with heart failure and sinus rhythm has been tested in a series of clinical trials. The former two trials (the Warfarin/Aspirin Study in Heart Failure (WASH) trial in 2004 and the Heart Failure Long-Term Antithrombotic Study (HELAS) trial in 2006) had too small sample size to detect a significant difference in ischemic stroke rate between patients receiving warfarin and those receiving aspirin [3,4]. Until recently, the following two largest trials, the Warfarin and Antiplatelet Therapy in Chronic Heart Failure (WATCH) trial in 2009 and the Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) in 2012 demonstrated that warfarin could reduce risk of ischemic stroke among heart failure patients in sinus rhythm [5,6]. In these two trials, warfarin was observed with a protective trend to reduce risk of stroke by preventing the development of atrial fibrillation (AF) in addition to the anticoagulation effect. In the WATCH trial, the incidence of paroxysmal AF was marginally higher in the aspirin group ⁎ Corresponding author at: Hualien Armed Forces General Hospital. No. 163, Jiali Rd., Xincheng Township, Hualien County 97144, Hualien, Taiwan. Tel.: + 886 3 826 0601. E-mail address: [email protected] (G.-M. Lin).
than in the warfarin group if patients who discontinued drug therapy during the study period were taken into account (13.2% for aspirin vs 9.6% for warfarin, respectively; P=0.08) [7]. Similarly, in the WARCEF trial, the incidence of AF/atrial flutter/supraventricular tachycardia was significantly higher in the aspirin group than that in the warfarin group at the end of the study (4.8% for aspirin vs. 3.1% for warfarin, respectively; P=0.032). Atrial fibrillation is one of the most encountered cardiac arrhythmia in patients with systolic heart failure and warfarin can reduce risk of ischemic stroke mainly by its anticoagulation effect. However, as we know, warfarin has never been found to show an anti-arrhythmic effect clinically and pharmacologically. On the basis of current knowledge, warfarin may prevent AF via the anti-inflammation effect [8]. As compared to aspirin, warfarin may lower plasma interleukin-6 which is a potent inflammatory marker to predict the occurrence of AF [9]. Since the AF was not the primary end point in each trial, this association should be further adjusted by some baseline variables such as the measurement of left atrium dimension by echocardiography and the presence of severe cardiac valve disease that has higher risk to AF. In conclusion, the following study should be conducted and focus on the incidence of AF for patients with systolic heart failure and sinus rhythm. Meanwhile, a long-term electrocardiographic record has to be performed to distinguish the effect of different antithrombotic agents on AF. Conflict of interest The authors declare no conflict of interests and no financial support from any institutes. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology.
References [1] Eikelboom JW, Connolly SJ. Warfarin in heart failure. N Engl J Med 2012;366:1936–8. [2] Freudenberger RS, Schumaecker MM, Homma S. What is the appropriate approach to prevention of thromboembolism in heart failure? Thromb Haemost 2010;103:489–95. [3] Cleland JG, Findlay I, Jafri S, et al. The Warfarin/Aspirin Study in Heart failure (WASH): a randomized trial comparing antithrombotic strategies for patients with heart failure. Am Heart J 2004;148:157–64.
246
Letters to the Editor
[4] Cokkinos DV, Haralabopoulos GC, Kostis JB, Toutouzas PK. Efficacy of antithrombotic therapy in chronic heart failure: the HELAS study. Eur J Heart Fail 2006;8:428–32. [5] Massie BM, Collins JF, Ammon SE, 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;119:1616–24. [6] Homma S, Thompson JLP, Pullicino PM, et al. Warfarin and aspirin in patients with heart failure and sinus rhythm. N Engl J Med 2012;366:1859–69. [7] Kan LP, Chu KM, Lin GM. Letter by Kan et al regarding Article, “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;120:e164. [8] Kater AP, Peppelenbosch MP, Brandjes DP, Lumbantobing M. Dichotomal effect of the coumadin derivative warfarin on inflammatory signal transduction. Clin Diagn Lab Immunol 2002;9:1396–7. [9] Marcus GM, Whooley MA, Glidden DV, Pawlikowska L, Zaroff JG, Olgin JE. Interleukin-6 and atrial fibrillation in patients with coronary artery disease: data from the Heart and Soul Study. Am Heart J 2008;155:303–9.
0167-5273/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijcard.2012.06.080
Endocrine associations with health-related quality of life in coronary artery disease patients Robertas Bunevicius a,1, Margarita Staniute a,⁎,1, Vilte Gintauskiene a,1, Juste Buneviciute b,1, Charles B. Nemeroff c,1, Julija Brozaitiene a,1 a b c
Behavioral Medicine Institute, Lithuanian University of Health Sciences, Palanga, Lithuania School of Medicine, St. George's University, St. George, Grenada Department of Psychiatry and Behavioral Sciences at the University of Miami, Leonard M. Miller School of Medicine, FL, USA
a r t i c l e
i n f o
Article history: Received 19 June 2012 Accepted 24 June 2012 Available online 18 July 2012 Keywords: Thyroid hormones Cortisol Health-related quality of life Coronary artery disease
The most significant distress syndrome affecting health-related quality of life (HRQoL) in coronary artery disease (CAD) patients is depression. Endocrine alterations associated with CAD may in part underlie the development of depression in these patients. Depressed myocardial infarction (MI) patients have lower concentrations of thyroid hormone triiodothyronine (T3) compared to non-depressed patients [1]. Low T3 concentrations in CAD patients are associated with worse clinical outcomes [2], with worse cardiac functioning [3] and with more severe fatigue [4]. Relationships between cortisol secretion and depression symptoms severity have been reported in psychiatric as well as in cardiac patients. In patients with CAD, depression is associated with elevated cortisol concentrations [5]. Indeed, hypercortisolemia may be a mediating factor between depression and increased risk for cardiovascular morbidity and mortality [6]. Recently it was reported that chronic stress, as assessed by increased hair cortisol concentration 3 months prior to the event, may be a contributing factor for acute MI [7]. On the other hand, low cortisol concentrations after acute MI are associated with higher early mortality [8]. Despite this considerable evidence that adrenal and thyroid axis activity is associated with morbidity and clinical outcomes in patients
⁎ Corresponding author at: Vyduno str. 4, LT-00135 Palanga, Lithuania. Tel.: + 370 61567921; fax: + 370 46030014. E-mail address: [email protected] (M. Staniute). 1 This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.
with CAD, to the best of our knowledge, there are no available studies evaluating the effects of endocrine function on HRQoL in CAD patients. A total of 172 consecutive CAD patients (121 men and 51 women) admitted to the Cardiovascular Rehabilitation Clinic at the Behavioral Medicine Institute of the Lithuanian University of Health Sciences in Palanga, Lithuania were invited to participate in the study. Patients were included in the study if they were treated as inpatients for a recent acute cardiac event (MI or angina pectoris), had no history of thyroid or adrenal disease, had no cognitive disorientation or communicative disabilities, had no other severe medical diseases, and spoke Lithuanian fluently. Patients were excluded from the study if they were taking thyroid medications, amiodarone or antidepressants (n = 14), had increased TSH (N3.7 μg/mL) concentrations indicating hypothyroidism (n = 6) or decreased TSH (b0.5 μg/mL) concentrations indicating hyperthyroidism (n = 4), had high concentrations of auto-antibodies against thyroid peroxidase (TPO-Abs ≥60 U/mL) indicating autoimmune thyroid disease (n = 11) and had coronary artery bypass grafting (n = 15). Therefore 122 CAD patients (93 men and 29 women; mean age 56 years) were enrolled in the study. The study protocol was approved by the Regional Committee of Biomedical Ethics at the Lithuanian University of Health Sciences in Kaunas, Lithuania, and written informed consent was obtained from all patients participating in the study. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology [9]. Demographic and clinical characteristics were obtained during the initial interview and from the medical documentation. The 36item Short Form Medical Outcome Questionnaire (SF-36) was completed by the patients to determine the HRQoL [10]. The Hospital Anxiety and Depression scale (HADS) was completed by the patients to determine the presence and severity of anxiety and depression symptoms. Blood samples for thyroid axis hormones and morning cortisol (cortisol AM) assessments were obtained from an antecubital vein at about 8 AM before breakfast after overnight fasting; for afternoon cortisol (cortisol PM) assessments were obtained at 3 PM. Blood was centrifuged and serum was deeply frozen. The samples from all patients for each assay were analyzed in a single batch. Serum concentrations of free T3, free thyroxine (T4), thyroid stimulating hormone (TSH) and cortisol were measured by radioimmunoassay.
Contents lists available at SciVerse ScienceDirect
International Journal of Cardiology j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / i j c a r d
Letter to the Editor
Warfarin may reduce risk of ischemic stroke by preventing atrial fibrillation for patients with heart failure and sinus rhythm Gen-Min Lin a,⁎, Yi-Hwei Li b, Lamin .E.S. Jaiteh c, Chih-Lu Han d a
Department of Medicine, Hualien Armed Forces General Hospital, Hualien, Taiwan Department of Public Health, Tzu-Chi University, Hualien, Taiwan Department of Royal Victoria Teaching Hospital, Banjul, Gambia d Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan b c
a r t i c l e
i n f o
Article history: Received 20 June 2012 Accepted 24 June 2012 Available online 12 July 2012 Keywords: Warfarin Aspirin Atrial fibrillation Heart failure
To the Editor: As compared with the general population, patients with reduced ejection fraction who are in sinus rhythm are observed with a higher risk for ischemic stroke. This relationship is caused by left ventricular stasis, a systemic hypercoagulable state, and endocardial dysfunction in a situation of impaired left ventricular systolic function [1,2]. Therefore, the issue whether antithrombotic agents especially aspirin or warfarin could successfully prevent stroke for patients with heart failure and sinus rhythm has been tested in a series of clinical trials. The former two trials (the Warfarin/Aspirin Study in Heart Failure (WASH) trial in 2004 and the Heart Failure Long-Term Antithrombotic Study (HELAS) trial in 2006) had too small sample size to detect a significant difference in ischemic stroke rate between patients receiving warfarin and those receiving aspirin [3,4]. Until recently, the following two largest trials, the Warfarin and Antiplatelet Therapy in Chronic Heart Failure (WATCH) trial in 2009 and the Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) in 2012 demonstrated that warfarin could reduce risk of ischemic stroke among heart failure patients in sinus rhythm [5,6]. In these two trials, warfarin was observed with a protective trend to reduce risk of stroke by preventing the development of atrial fibrillation (AF) in addition to the anticoagulation effect. In the WATCH trial, the incidence of paroxysmal AF was marginally higher in the aspirin group ⁎ Corresponding author at: Hualien Armed Forces General Hospital. No. 163, Jiali Rd., Xincheng Township, Hualien County 97144, Hualien, Taiwan. Tel.: + 886 3 826 0601. E-mail address: [email protected] (G.-M. Lin).
than in the warfarin group if patients who discontinued drug therapy during the study period were taken into account (13.2% for aspirin vs 9.6% for warfarin, respectively; P=0.08) [7]. Similarly, in the WARCEF trial, the incidence of AF/atrial flutter/supraventricular tachycardia was significantly higher in the aspirin group than that in the warfarin group at the end of the study (4.8% for aspirin vs. 3.1% for warfarin, respectively; P=0.032). Atrial fibrillation is one of the most encountered cardiac arrhythmia in patients with systolic heart failure and warfarin can reduce risk of ischemic stroke mainly by its anticoagulation effect. However, as we know, warfarin has never been found to show an anti-arrhythmic effect clinically and pharmacologically. On the basis of current knowledge, warfarin may prevent AF via the anti-inflammation effect [8]. As compared to aspirin, warfarin may lower plasma interleukin-6 which is a potent inflammatory marker to predict the occurrence of AF [9]. Since the AF was not the primary end point in each trial, this association should be further adjusted by some baseline variables such as the measurement of left atrium dimension by echocardiography and the presence of severe cardiac valve disease that has higher risk to AF. In conclusion, the following study should be conducted and focus on the incidence of AF for patients with systolic heart failure and sinus rhythm. Meanwhile, a long-term electrocardiographic record has to be performed to distinguish the effect of different antithrombotic agents on AF. Conflict of interest The authors declare no conflict of interests and no financial support from any institutes. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology.
References [1] Eikelboom JW, Connolly SJ. Warfarin in heart failure. N Engl J Med 2012;366:1936–8. [2] Freudenberger RS, Schumaecker MM, Homma S. What is the appropriate approach to prevention of thromboembolism in heart failure? Thromb Haemost 2010;103:489–95. [3] Cleland JG, Findlay I, Jafri S, et al. The Warfarin/Aspirin Study in Heart failure (WASH): a randomized trial comparing antithrombotic strategies for patients with heart failure. Am Heart J 2004;148:157–64.
246
Letters to the Editor
[4] Cokkinos DV, Haralabopoulos GC, Kostis JB, Toutouzas PK. Efficacy of antithrombotic therapy in chronic heart failure: the HELAS study. Eur J Heart Fail 2006;8:428–32. [5] Massie BM, Collins JF, Ammon SE, 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;119:1616–24. [6] Homma S, Thompson JLP, Pullicino PM, et al. Warfarin and aspirin in patients with heart failure and sinus rhythm. N Engl J Med 2012;366:1859–69. [7] Kan LP, Chu KM, Lin GM. Letter by Kan et al regarding Article, “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;120:e164. [8] Kater AP, Peppelenbosch MP, Brandjes DP, Lumbantobing M. Dichotomal effect of the coumadin derivative warfarin on inflammatory signal transduction. Clin Diagn Lab Immunol 2002;9:1396–7. [9] Marcus GM, Whooley MA, Glidden DV, Pawlikowska L, Zaroff JG, Olgin JE. Interleukin-6 and atrial fibrillation in patients with coronary artery disease: data from the Heart and Soul Study. Am Heart J 2008;155:303–9.
0167-5273/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijcard.2012.06.080
Endocrine associations with health-related quality of life in coronary artery disease patients Robertas Bunevicius a,1, Margarita Staniute a,⁎,1, Vilte Gintauskiene a,1, Juste Buneviciute b,1, Charles B. Nemeroff c,1, Julija Brozaitiene a,1 a b c
Behavioral Medicine Institute, Lithuanian University of Health Sciences, Palanga, Lithuania School of Medicine, St. George's University, St. George, Grenada Department of Psychiatry and Behavioral Sciences at the University of Miami, Leonard M. Miller School of Medicine, FL, USA
a r t i c l e
i n f o
Article history: Received 19 June 2012 Accepted 24 June 2012 Available online 18 July 2012 Keywords: Thyroid hormones Cortisol Health-related quality of life Coronary artery disease
The most significant distress syndrome affecting health-related quality of life (HRQoL) in coronary artery disease (CAD) patients is depression. Endocrine alterations associated with CAD may in part underlie the development of depression in these patients. Depressed myocardial infarction (MI) patients have lower concentrations of thyroid hormone triiodothyronine (T3) compared to non-depressed patients [1]. Low T3 concentrations in CAD patients are associated with worse clinical outcomes [2], with worse cardiac functioning [3] and with more severe fatigue [4]. Relationships between cortisol secretion and depression symptoms severity have been reported in psychiatric as well as in cardiac patients. In patients with CAD, depression is associated with elevated cortisol concentrations [5]. Indeed, hypercortisolemia may be a mediating factor between depression and increased risk for cardiovascular morbidity and mortality [6]. Recently it was reported that chronic stress, as assessed by increased hair cortisol concentration 3 months prior to the event, may be a contributing factor for acute MI [7]. On the other hand, low cortisol concentrations after acute MI are associated with higher early mortality [8]. Despite this considerable evidence that adrenal and thyroid axis activity is associated with morbidity and clinical outcomes in patients
⁎ Corresponding author at: Vyduno str. 4, LT-00135 Palanga, Lithuania. Tel.: + 370 61567921; fax: + 370 46030014. E-mail address: [email protected] (M. Staniute). 1 This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.
with CAD, to the best of our knowledge, there are no available studies evaluating the effects of endocrine function on HRQoL in CAD patients. A total of 172 consecutive CAD patients (121 men and 51 women) admitted to the Cardiovascular Rehabilitation Clinic at the Behavioral Medicine Institute of the Lithuanian University of Health Sciences in Palanga, Lithuania were invited to participate in the study. Patients were included in the study if they were treated as inpatients for a recent acute cardiac event (MI or angina pectoris), had no history of thyroid or adrenal disease, had no cognitive disorientation or communicative disabilities, had no other severe medical diseases, and spoke Lithuanian fluently. Patients were excluded from the study if they were taking thyroid medications, amiodarone or antidepressants (n = 14), had increased TSH (N3.7 μg/mL) concentrations indicating hypothyroidism (n = 6) or decreased TSH (b0.5 μg/mL) concentrations indicating hyperthyroidism (n = 4), had high concentrations of auto-antibodies against thyroid peroxidase (TPO-Abs ≥60 U/mL) indicating autoimmune thyroid disease (n = 11) and had coronary artery bypass grafting (n = 15). Therefore 122 CAD patients (93 men and 29 women; mean age 56 years) were enrolled in the study. The study protocol was approved by the Regional Committee of Biomedical Ethics at the Lithuanian University of Health Sciences in Kaunas, Lithuania, and written informed consent was obtained from all patients participating in the study. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology [9]. Demographic and clinical characteristics were obtained during the initial interview and from the medical documentation. The 36item Short Form Medical Outcome Questionnaire (SF-36) was completed by the patients to determine the HRQoL [10]. The Hospital Anxiety and Depression scale (HADS) was completed by the patients to determine the presence and severity of anxiety and depression symptoms. Blood samples for thyroid axis hormones and morning cortisol (cortisol AM) assessments were obtained from an antecubital vein at about 8 AM before breakfast after overnight fasting; for afternoon cortisol (cortisol PM) assessments were obtained at 3 PM. Blood was centrifuged and serum was deeply frozen. The samples from all patients for each assay were analyzed in a single batch. Serum concentrations of free T3, free thyroxine (T4), thyroid stimulating hormone (TSH) and cortisol were measured by radioimmunoassay.