J Huazhong Univ Sci Technol［Med Sci］ 34(6):902-906,2014 DOI 10.1007/s11596-014-1371-4 J Huazhong Univ Sci Technol［Med Sci］ 34(6):2014
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Combined Low-dose Aspirin and Warfarin Anticoagulant Therapy of Postoperative Atrial Fibrillation Following Mechanical Heart Valve Replacement Jian-tang WANG (王建堂)1, 2, Ming-feng DONG (董铭峰)2, Guang-min SONG (宋光民)1#, Zeng-shan MA (马增山)1, Sheng-jun MA (马胜军)2 1 Department of Cardiac Surgery, Qilu Hospital, Shandong University, Jinan 250012, China 2 Department of Cardiac Surgery, Liaocheng People’s Hospital and Liaocheng Clinical School of Taishan Medical University, Liaocheng 252000, China © Huazhong University of Science and Technology and Springer-Verlag Berlin Heidelberg 2014
Summary: The safety and efficacy of combined low dose aspirin and warfarin therapy in patients with atrial fibrillation after mechanical heart valve replacement were evaluated. A total of 1016 patients (620 females, mean age of 36.8±7.7 years) admitted for cardiac valve replacement and complicated with atrial fibrillation after surgery were randomly divided into study (warfarin plus 75–100 mg aspirin) or control (warfarin only) groups. International normalized ratio (INR) and prothrombin time were maintained at 1.8–2.5 and 1.5–2.0 times the normal values, respectively. Thromboembolic events and major bleedings were registered during the follow-up period. Patients were followed up for 24±9 months. The average dose of warfarin in the study and control groups was 2.91±0.83 mg and 2.88±0.76 mg, respectively (P>0.05). The incidence of overall thromboembolic events in study group was lower than that in control group (2.16% vs. 4.35%, P=0.049). No statistically significant differences were found in hemorrhage events (3.53% vs. 3.95%, P=0.722) or mortality (0.20% vs. 0.40%, P=0.559) between the two groups. Combined low dose aspirin and warfarin therapy in the patients with atrial fibrillation following mechanical heart valve replacement significantly decreased thromboembolic events as compared with warfarin therapy alone. This combined treatment was not associated with an increase in the risk of major bleeding or mortality. Key words: anticoagulation; mechanical valve replacement; atrial fibrillation; aspirin; warfarin
Valvular heart disease combined with atrial fibrillation, especially rheumatic heart disease, is not uncommon in clinical practice. Atrial fibrillation is the most common sustained cardiac rhythm disturbance and is a major risk factor for stroke, increasing in prevalence with age, occurring in 1%–2% of the general population. Hemodynamic impairment and thromboembolic events related to atrial fibrillation result in significant morbidity, mortality and cost[1]. Atrial fibrillation predisposes to thrombus formation, especially in the left atrial appendage, with risk for subsequent thromboembolism. Therefore, atrial fibrillation is strongly associated with cardioembolic stroke. Moreover, the risk of stroke in patients with non-rheumatic chronic atrial fibrillation is increased more than five-fold over that in controls with sinus rhythm. The risk is increased by 17-fold when the etiology of atrial fibrillation is rheumatic heart disease[2]. Cardiac valve replacement is the mainstay of treatment for patients with moderate to severe valvular heart disease[3]. Thromboembolic events, in particular ischemic stroke, are serious complications of valve replacement surgery[4–6]. Therefore, oral anticoagulation therapy plays an important role in preventing thromboembolic events in patients with atrial fibrillation after
Jian-tang WANG, E-mail: [email protected] Corresponding author, E-mail: [email protected]
#
mechanical heart valve replacement. Vitamin K antagonists are the only oral anticoagulants available for valve-implanted patients[7]. Acetylsalicylic acid (aspirin) has been widely used as an agent for prevention of ischemic events, and can reduce the stroke risk by about 20%[8, 9]. According to the ACC/AHA/ESC guidelines, a lifelong anticoagulant therapy, such as aspirin or warfarin, is recommended as antithrombotic therapy after the assessment of individual risk[1, 3]. A combination of warfarin and aspirin may further reduce thrombolytic complications in these patients. Meanwhile, anticoagulation has been augmented with an antiplatelet agent, as a means of improving the efficacy of antithrombotic therapy of postoperative atrial fibrillation following cardiac valve implantation. Previous studies have shown that in patients with mechanical heart valve replacement, combined aspirin (500 mg per day) and warfarin therapy was associated with less thromboembolic events, but the risk of major bleeding complications obviously increased[10]. The purpose of this study was to further assess the safety and efficacy of combined low dose aspirin (75–100 mg per day) and warfarin therapy versus warfarin therapy alone in patients with atrial fibrillation after mechanical heart valve replacement.
J Huazhong Univ Sci Technol［Med Sci］ 34(6):2014
1 PATIENTS AND METHODS 1.1 Patient Selection This study was approved by the Human Research Ethics Committee of Liaocheng People’s Hospital (China). Informed written consent was obtained from all participants. From January 2000 to December 2013, a total of 2597 consecutive patients admitted for cardiac valve replacement were initially screened, and 1042 patients with atrial fibrillation were enrolled in this study. Inclusion criteria were as follows: (1) patients who received mechanical heart valve replacement and were complicated with atrial fibrillation after surgery; (2) no
903 history of cerebral vascular disease or peripheral vascular disease. Patients who did not meet the above criteria were excluded. The reasons for the excluded patients were sinus rhythm (n=1524), biovalve replacement (n=207), a previous history of cerebral infarction (n=26) or cerebral hematoma (n=3) or thrombosis in lower extremities (n=14). After surgery, the selected patients were randomized, using random drawing of numbers, into study group (n=521) and control group (n=521). The general characteristics of the patients are shown in table 1.
Table 1 Baseline characteristics of patients in the two groups Variables Study group (n=510) Control group (n=506) P 0.266 36.6±7.5 37.1±6.8 Age (years) Sex 0.775 195 (38.5%)/311 (61.5%) 201 (39.4%)/309 (60.6%) Male/Female Etiology 0.468 375 (74.1%) 388 (76.1%) RHD 0.415 121 (23.9%) 111 (21.8) Calcified lesions 0.840 10 (1.98%) 11 (2.2%) Others Site of valve 0.827 352 (69.6%) 358 (70.2%) Mitral 0.766 104 (20.5%) 101 (19.8%) Aortic 0.950 50 (9.9%) 51 (10.0%) Double valves Concomitant procedure 0.528 25 (4.94%) 21 (4.12%) AF ablation 0.563 225 (44.5%) 236 (46.3%) Tricuspid valvular plasty Type of mechanical valve 0.627 185 (36.6%) 179 (35.1%) Unileaflet (GK, China) 0.795 150 (29.6%) 155 (30.4%) Unileaflet (Medtronic) 0.810 171 (33.8%) 176 (34.5%) Bileaflet (ST, JUDE) Concomitant diseases 0.583 34 (6.72%) 30 (6.08%) CAD 0.456 70 (13.8%) 79 (15.5%) Hypertension 0.622 46 (9.09%) 51 (10.0%) Diabetes 0.811 28 (5.53%) 30 (5.88%) Ischemic cerebral disease 13 (2.57%) 12 (2.35%) Peripheral arterial disease 0.824 21 (4.15%) 23 (4.50%) NYHA class Ⅲ and Ⅳ 0.778 Medication use 351 (69.4%) 345 (67.6%) Digoxin 0.555 478 (94.5%) 481 (94.3%) Diuretics 0.916 248 (49.0%) 253 (49.6%) ACEI/ARBs 0.849 74 (14.6%) 72 (14.1%) Nitrates 0.818 51 (10.1%) 47 (9.22%) Beta blockers 0.641 31 (6.13%) 29 (5.69%) Amiodarone 0.766 Data are presented as ±s or n (%). RHD: rheumatic heart disease; AF: atrial fibrillation; CAD: coronary atherosclerotic heart disease; NYHA: New York heart association; ACEI: angiotensin converting enzyme inhibitor; ARB: angiotensin receptor blocker
1.2 Pharmacological Management Aspirin and warfarin were commenced within 48 h of the surgery, when patients’ life signs were stabilized and chest drainage fluid volume was 2.5 was associated with a significantly increased risk of major bleeding[10–12]. The patients in study group were prescribed with 75–100 mg aspirin daily, whereas those in control group with a matching placebo after the surgery. Other medications used in study and control groups were diuretics, angiotensin converting enzyme inhibitors
(ACEI) or angiotensin receptor blocker (ARBs), digoxin, nitrates, amiodarone or beta blockers to improve cardiac function and to control heart rate. 1.3 Outcome Evaluation All patients were followed up in our hospital clinics every 3 months after the surgery. In both groups, PT and INR were measured before the surgery and at each follow-up time point. Cardiac and carotid ultrasonography was performed to detect any possible thromboembolics in the cardiac and carotid arteries before and at each follow-up time point. Cerebral computed tomography (CT) was also performed in patients who had symptoms or signs of cerebrovascular disease. 1.4 Statistical Analysis All data are presented as ±s. Continuous variables were compared by using student t-test or analysis of
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variance (ANOVA). Categorical data were compared with Chi-Square test. P value 0.05). There were no statistically significant differences between the two groups in the days when INR target was achieved, in INR control rate, rate of INR 2.5 and rate of reliable anticoagulation (all P>0.05) (table 2). 2.3 Clinical Outcomes As shown in table 3, the incidence of overall thromboembolic events in study group was lower than that in control group (2.16% vs. 4.35%, P=0.049). No statistically significant differences were found in hemorrhagic events and mortality between the two groups.
Fig. 1 Flow chart of randomized clinical trials Table 2 Comparison of INR target achieved and control rate in the two groups Variables Study group (n=510) Control group (n=506) Days before INR target was achieved 5.15±3.46 4.76±3.54 Optimal INR control rates (%) 38.1±20.5 39.2±23.1 Rates of INR 2.5 (%) 9.92±18.2 11.0±20.5 Rates of reliable anticoagulation (%) 33.9 36.8 Data are presented as ±s or n (%). INR: international normalized ratio Table 3 Comparison of thromboembolism and hemorrhage in the two groups Variables Study group (n=510) Control group (n=506) 22 (4.35%) 11 (2.16%) Thromboembolism 13 (2.57%) 7 (1.37%) Valvular thrombosis 9 (1.78%) 4 (0.78%) Non-valvular thrombosis 20 (3.95%) 18 (3.53%) Hemorrhage 10 (1.98%) 8 (1.57%) Skin ecchyosis 2 (0.40%) 3 (0.59%) Nosebleed 5 (0.99%) 4 (0.78%) Bleeding gums 1 (0.20%) 2 (0.39%) Menorrhagia 2 (0.40%) 1 (0.20%) Cerebral hemorrhage 2 (0.40%) 1 (0.20%) Death Data are presented as n (%).
P 0.076 0.422 0.116 0.375 0.344
P 0.049 0.170 0.159 0.722 0.622 0.660 0.729 0.568 0.559 0.559
J Huazhong Univ Sci Technol［Med Sci］ 34(6):2014
3 DISCUSSION The main conclusion of this prospective and randomized study is that combined low dose aspirin and warfarin therapy was associated with less thromboembolic events than warfarin therapy alone. This study also showed that addition of a low dose aspirin to warfarin did not increase the risk of hemorrhage or mortality in patients with atrial fibrillation following mechanical heart valve replacement. In the present study, all the patients in the study and control groups had atrial fibrillation after mechanical heart valve replacement. Atrial fibrillation predisposes to thrombus formation. ACC/AHA/ESC has accordingly developed corresponding anticoagulant treatment guidelines. The thromboembolic risks are reduced by guideline-adherent antithrombotic therapy with warfarin or aspirin[1, 3, 13]. These patients may particularly benefit from combined aspirin and warfarin treatment. Warfarin is currently the most commonly used oral anticoagulant in clinical medicine. It has been the mainstay of treatment for patients with atrial fibrillation and prosthetic heart valves, markedly reducing left ventricular thrombus, as well as for prevention or treatment of stroke, deep venous thrombosis and pulmonary embolism. Randomized clinical trials have shown that warfarin is superior to either aspirin or clopidogrel for prevention of stroke in patients with atrial fibrillation, and observational data seem to have established it as the standard antithrombotic treatment in patients with mechanical valve prostheses[14, 15]. Aspirin is the most commonly used clinical antiplatelet drugs. It has mounting evidence of evidence-based medicine in the prevention and treatment of cardiovascular diseases[16–18]. Meta-analysis showed that adjusted-dose warfarin and antiplatelet agents reduce stroke by approximately 60% and by approximately 20%, respectively, in patients who have atrial fibrillation. Furthermore, adding antiplatelet therapy, such as low-dose aspirin, to oral anticoagulation decreases the risk of systemic embolism or death among patients with prosthetic heart valves or those with high risk of atrial fibrillation or prior thromboembolic events[19]. In our study, the range for INR was set at 1.8–2.5, and a relatively low dose of warfarin (average 2.9 mg/day) was used. The average daily dose of warfarin and the target INR were lower than in the previous reports[20–23]. Our conservative approach may explain the low bleeding rate in both study and control groups. Other studies on patients whose ethnical background was similar to ours also found that an INR of 1.8–2.4 was associated with the lowest rate of major bleeding or thromboembolic events[11, 12]. The combination of low dose aspirin and warfarin yielded a modest benefit of thromboembolic event prevention, a 2.19% absolute risk reduction compared with patients treated with warfarin alone. Further studies are required to ascertain whether a more robust warfarin dosing regimen will lead to further thromboembolic event reduction. Warfarin can reduce the risk for thromboembolic stroke and also halve the risk for systemic thromboembolism. However, warfarin has considerable limitations, one of which is its association with increased bleeding[15]. Additionally, warfarin has a narrow therapeutic window and an unpredictable response that requires routine
905 coagulation monitoring and frequent dose adjustment, and variable dose-response in individuals, and interact with several foods and drugs[24, 25]. Although antiplatelet therapy is widely used for prevention of ischemic events, the optimum dose of aspirin is still not known. Aspirin-dosing regimen has important implications for bleeding[18]. Previous trials and meta-analysis showed that in patients with mechanical heart valve, the risk for major bleeding was higher in patients receiving combined aspirin-oral anticoagulation therapy than in those receiving oral anticoagulation therapy alone[20–23]. The increased bleeding risk following combination therapy seems to be related to the dose of aspirin, as lower dose aspirin was associated with a reduced risk of major bleeding when used together with warfarin[26]. To lessen the risk of major hemorrhage events, the dosage of aspirin is a key factor. Randomized clinical trials have shown that the most appropriate and effective antithrombotic dose of aspirin is 50–100 mg daily, most commonly used dose is 75 mg daily[19, 26]. In our study, the study group patients were prescribed with 75–100 mg daily aspirin. The most common hemorrhage was skin ecchymosis and bleeding gum, and fatal bleeding such as cerebral hemorrhage occurred in 0.2% of the study group and 0.4% of the control group, respectively. Therefore, the present study suggested that addition of aspirin did not increase the risk of life threatening bleeding. However, the bleeding risk of combined warfarin and dual antiplatelet therapy in our patients requires further investigation. In conclusion, combined use of low dose aspirin and warfarin in the patients with mechanical heart valve replacement and atrial fibrillation decreased thromboembolic events in comparison with warfarin therapy alone. Combined therapy was not associated with an increase in the risk of major bleeding or mortality. These results suggest that low dose aspirin combined with warfarin may be used as a safe and effective thromboemlism prevention. Conflict of interest statement This study received no external funding. Authors have no conflict of interest to declare. REFERENCES 1 Fuster V, Rydén LE, Cannom DS, et al. 2011 ACCF/AHA/HRS focused updates incorporated into the ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation, 2011,123(10): e269-367 2 Petersen P. Thromboembolic complications in atrial fibrillation. Stroke, 1990,21(1):4-13 3 Bonow RO, Carabello BA, Chatterjee K, et al. ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (writing Committee to Revise the 1998 guidelines for the management of patients with valvular heart disease) developed in collaboration with the Society of Cardiovascular Anesthesiologists endorsed by the Society for Cardiovascular Angiography and Interventions and the Society of Thoracic Surgeons. J Am Coll Cardiol, 2006,48(3):e1-e148
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Hering D, Piper C, Bergemann R, et al. Thromboembolic and bleeding complications following St. Jude Medical valve replacement: results of the German experience with low-intensity anticoagulation study. Chest, 2005,127(1): 53-59 Edmunds Jr LH. Thrombotic and bleeding complications of prosthetic heart valves. Ann Thorac Surg, 1987,44(4):430450 Russo A, Grigioni F, Avierinos JF, et al. Thromboembolic complications after surgical correction of mitral regurgitation incidence, predictors, and clinical implications. J Am Coll Cardiol, 2008,51(12):1203-1211 Sun JC1, Davidson MJ, Lamy A, et al. Antithrombotic management of patients with prosthetic heart valves: current evidence and future trends. Lancet, 2009,374(9689): 565-576 Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med, 2007, 146(12):857-867 Goldstein LB, Adams R, Alberts MJ, et al. Primary prevention of ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council: cosponsored by the Atherosclerotic Peripheral Vascular Disease Interdisciplinary Working Group; Cardiovascular Nursing Council; Clinical Cardiology Council; Nutrition, Physical Activity, and Metabolism Council; and the Quality of Care and Outcomes Research Interdisciplinary Working Group: the American Academy of Neurology affirms the value of this guideline. Stroke, 2006,37(6):1583-1633 Chesebro JH, Fuster V, Elveback LR, et al. Trial of combined warfarin plus dipyridamole or aspirin therapy in prosthetic heart valve replacement: danger of aspirin compared with dipyridamole. Am J Cardiol, 1983,51(9):15371541 You JH, Chan FW, Wong RS, et al. Is INR between 2.0 and 3.0 the optimal level for Chinese patients on warfarin therapy for moderate-intensity anticoagulation? Br J Clin Pharmacol, 2005,59(5):582-587 Zhang H, Chen XJ, Zhen RL, et al. Antithrombotic effect of warfarin with different anticoagulation intensities on prognosis of old patients with paroxysmal atrial fibrillation. Chin J Geriatr Heart Brain Vessel Dis (Chinese), 2009, 11(10):758-761 Menke J, Lüthje L, Kastrup A, et al. Thromboembolism in atrial fibrillation. Am J Cardiol, 2010,105(4):502-510 Holmes DR Jr1, Kereiakes DJ, Kleiman NS, et al. Combining antiplatelet and anticoagulant therapies. J Am Coll Cardiol, 2009,54(2):95-109
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15 Bassand JP. Review of atrial fibrillation outcome trials of oral anticoagulant and antiplatelet agents. Europace, 2012,14(3):312-324 16 Hennekens CH, Dyken ML, Fuster V. Aspirin as a therapeutic agent in cardiovascular disease: a statement for healthcare professionals from the American Heart Association. Circulation, 1997,96(8):2751-2753 17 Antithrombotic Trialists’ (ATT) Collaboration, Baigent C, Blackwell L, et al. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet, 2009,373(9678):1849-1860 18 US Preventive Services Task Force. Calonger N, Petitti DB, et al. Aspirin for the prevention of cardiovascular disease: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med, 2009,150(6):396-404 19 Massel DR, Little SH. Antiplatelet and anticoagulation for patients with prosthetic heart valves. Cochrane Database Syst Rev, 2013:CD003464. doi: 10.1002/14651858.CD003464.pub2 20 Turpie AG, Gent M, Laupacis A, et al. A comparison of aspirin with placebo in patients treated with warfarin after heart-valve replacement. N Engl J Med, 1993, 329(8):524-529 21 Cappelleri JC, Fiore LD, Brophy MT, et al. Efficacy and safety of combined anticoagulant and antiplatelet therapy versus anticoagulant monotherapy after mechanical heart-valve replacement: a metaanalysis. Am Heart J, 1995,130(3 Pt 1):547-552 22 Larson RJ, Fisher ES. Should aspirin be continued in patients started on warfarin? J Gen Intern Med, 2004,19(8): 879-886 23 Dentali F, Douketis JD, Lim W, et al. Combined aspirin-oral anticoagulant therapy compared with oral anticoagulant therapy alone among patients at risk for cardiovascular disease: a meta-analysis of randomized trials. Arch Intern Med, 2007,167(2):117-124 24 Brtko M, Dusek J. Antithrombotic therapy in patients after valve surgery with special attention to the combination of anticoagulant and antiplatelet therapy. Thrombosis, 2013,55(2):e164-e169 25 Berkowitz SD. Antithrombotic therapy after prosthetic cardiac valve implantation: potential novel antithrombotic therapies. Am Heart J, 2001,142(1):7-13 26 Massel D, Little SH. Risks and benefits of adding anti-platelet therapy to warfarin among patients with prosthetic heart valves: a meta-analysis. J Am Coll Cardiol, 2001,37(2):569-578 (Received Apr. 25, 2014; revised Oct. 18, 2014)
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Combined Low-dose Aspirin and Warfarin Anticoagulant Therapy of Postoperative Atrial Fibrillation Following Mechanical Heart Valve Replacement Jian-tang WANG (王建堂)1, 2, Ming-feng DONG (董铭峰)2, Guang-min SONG (宋光民)1#, Zeng-shan MA (马增山)1, Sheng-jun MA (马胜军)2 1 Department of Cardiac Surgery, Qilu Hospital, Shandong University, Jinan 250012, China 2 Department of Cardiac Surgery, Liaocheng People’s Hospital and Liaocheng Clinical School of Taishan Medical University, Liaocheng 252000, China © Huazhong University of Science and Technology and Springer-Verlag Berlin Heidelberg 2014
Summary: The safety and efficacy of combined low dose aspirin and warfarin therapy in patients with atrial fibrillation after mechanical heart valve replacement were evaluated. A total of 1016 patients (620 females, mean age of 36.8±7.7 years) admitted for cardiac valve replacement and complicated with atrial fibrillation after surgery were randomly divided into study (warfarin plus 75–100 mg aspirin) or control (warfarin only) groups. International normalized ratio (INR) and prothrombin time were maintained at 1.8–2.5 and 1.5–2.0 times the normal values, respectively. Thromboembolic events and major bleedings were registered during the follow-up period. Patients were followed up for 24±9 months. The average dose of warfarin in the study and control groups was 2.91±0.83 mg and 2.88±0.76 mg, respectively (P>0.05). The incidence of overall thromboembolic events in study group was lower than that in control group (2.16% vs. 4.35%, P=0.049). No statistically significant differences were found in hemorrhage events (3.53% vs. 3.95%, P=0.722) or mortality (0.20% vs. 0.40%, P=0.559) between the two groups. Combined low dose aspirin and warfarin therapy in the patients with atrial fibrillation following mechanical heart valve replacement significantly decreased thromboembolic events as compared with warfarin therapy alone. This combined treatment was not associated with an increase in the risk of major bleeding or mortality. Key words: anticoagulation; mechanical valve replacement; atrial fibrillation; aspirin; warfarin
Valvular heart disease combined with atrial fibrillation, especially rheumatic heart disease, is not uncommon in clinical practice. Atrial fibrillation is the most common sustained cardiac rhythm disturbance and is a major risk factor for stroke, increasing in prevalence with age, occurring in 1%–2% of the general population. Hemodynamic impairment and thromboembolic events related to atrial fibrillation result in significant morbidity, mortality and cost[1]. Atrial fibrillation predisposes to thrombus formation, especially in the left atrial appendage, with risk for subsequent thromboembolism. Therefore, atrial fibrillation is strongly associated with cardioembolic stroke. Moreover, the risk of stroke in patients with non-rheumatic chronic atrial fibrillation is increased more than five-fold over that in controls with sinus rhythm. The risk is increased by 17-fold when the etiology of atrial fibrillation is rheumatic heart disease[2]. Cardiac valve replacement is the mainstay of treatment for patients with moderate to severe valvular heart disease[3]. Thromboembolic events, in particular ischemic stroke, are serious complications of valve replacement surgery[4–6]. Therefore, oral anticoagulation therapy plays an important role in preventing thromboembolic events in patients with atrial fibrillation after
Jian-tang WANG, E-mail: [email protected] Corresponding author, E-mail: [email protected]
#
mechanical heart valve replacement. Vitamin K antagonists are the only oral anticoagulants available for valve-implanted patients[7]. Acetylsalicylic acid (aspirin) has been widely used as an agent for prevention of ischemic events, and can reduce the stroke risk by about 20%[8, 9]. According to the ACC/AHA/ESC guidelines, a lifelong anticoagulant therapy, such as aspirin or warfarin, is recommended as antithrombotic therapy after the assessment of individual risk[1, 3]. A combination of warfarin and aspirin may further reduce thrombolytic complications in these patients. Meanwhile, anticoagulation has been augmented with an antiplatelet agent, as a means of improving the efficacy of antithrombotic therapy of postoperative atrial fibrillation following cardiac valve implantation. Previous studies have shown that in patients with mechanical heart valve replacement, combined aspirin (500 mg per day) and warfarin therapy was associated with less thromboembolic events, but the risk of major bleeding complications obviously increased[10]. The purpose of this study was to further assess the safety and efficacy of combined low dose aspirin (75–100 mg per day) and warfarin therapy versus warfarin therapy alone in patients with atrial fibrillation after mechanical heart valve replacement.
J Huazhong Univ Sci Technol［Med Sci］ 34(6):2014
1 PATIENTS AND METHODS 1.1 Patient Selection This study was approved by the Human Research Ethics Committee of Liaocheng People’s Hospital (China). Informed written consent was obtained from all participants. From January 2000 to December 2013, a total of 2597 consecutive patients admitted for cardiac valve replacement were initially screened, and 1042 patients with atrial fibrillation were enrolled in this study. Inclusion criteria were as follows: (1) patients who received mechanical heart valve replacement and were complicated with atrial fibrillation after surgery; (2) no
903 history of cerebral vascular disease or peripheral vascular disease. Patients who did not meet the above criteria were excluded. The reasons for the excluded patients were sinus rhythm (n=1524), biovalve replacement (n=207), a previous history of cerebral infarction (n=26) or cerebral hematoma (n=3) or thrombosis in lower extremities (n=14). After surgery, the selected patients were randomized, using random drawing of numbers, into study group (n=521) and control group (n=521). The general characteristics of the patients are shown in table 1.
Table 1 Baseline characteristics of patients in the two groups Variables Study group (n=510) Control group (n=506) P 0.266 36.6±7.5 37.1±6.8 Age (years) Sex 0.775 195 (38.5%)/311 (61.5%) 201 (39.4%)/309 (60.6%) Male/Female Etiology 0.468 375 (74.1%) 388 (76.1%) RHD 0.415 121 (23.9%) 111 (21.8) Calcified lesions 0.840 10 (1.98%) 11 (2.2%) Others Site of valve 0.827 352 (69.6%) 358 (70.2%) Mitral 0.766 104 (20.5%) 101 (19.8%) Aortic 0.950 50 (9.9%) 51 (10.0%) Double valves Concomitant procedure 0.528 25 (4.94%) 21 (4.12%) AF ablation 0.563 225 (44.5%) 236 (46.3%) Tricuspid valvular plasty Type of mechanical valve 0.627 185 (36.6%) 179 (35.1%) Unileaflet (GK, China) 0.795 150 (29.6%) 155 (30.4%) Unileaflet (Medtronic) 0.810 171 (33.8%) 176 (34.5%) Bileaflet (ST, JUDE) Concomitant diseases 0.583 34 (6.72%) 30 (6.08%) CAD 0.456 70 (13.8%) 79 (15.5%) Hypertension 0.622 46 (9.09%) 51 (10.0%) Diabetes 0.811 28 (5.53%) 30 (5.88%) Ischemic cerebral disease 13 (2.57%) 12 (2.35%) Peripheral arterial disease 0.824 21 (4.15%) 23 (4.50%) NYHA class Ⅲ and Ⅳ 0.778 Medication use 351 (69.4%) 345 (67.6%) Digoxin 0.555 478 (94.5%) 481 (94.3%) Diuretics 0.916 248 (49.0%) 253 (49.6%) ACEI/ARBs 0.849 74 (14.6%) 72 (14.1%) Nitrates 0.818 51 (10.1%) 47 (9.22%) Beta blockers 0.641 31 (6.13%) 29 (5.69%) Amiodarone 0.766 Data are presented as ±s or n (%). RHD: rheumatic heart disease; AF: atrial fibrillation; CAD: coronary atherosclerotic heart disease; NYHA: New York heart association; ACEI: angiotensin converting enzyme inhibitor; ARB: angiotensin receptor blocker
1.2 Pharmacological Management Aspirin and warfarin were commenced within 48 h of the surgery, when patients’ life signs were stabilized and chest drainage fluid volume was 2.5 was associated with a significantly increased risk of major bleeding[10–12]. The patients in study group were prescribed with 75–100 mg aspirin daily, whereas those in control group with a matching placebo after the surgery. Other medications used in study and control groups were diuretics, angiotensin converting enzyme inhibitors
(ACEI) or angiotensin receptor blocker (ARBs), digoxin, nitrates, amiodarone or beta blockers to improve cardiac function and to control heart rate. 1.3 Outcome Evaluation All patients were followed up in our hospital clinics every 3 months after the surgery. In both groups, PT and INR were measured before the surgery and at each follow-up time point. Cardiac and carotid ultrasonography was performed to detect any possible thromboembolics in the cardiac and carotid arteries before and at each follow-up time point. Cerebral computed tomography (CT) was also performed in patients who had symptoms or signs of cerebrovascular disease. 1.4 Statistical Analysis All data are presented as ±s. Continuous variables were compared by using student t-test or analysis of
904
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variance (ANOVA). Categorical data were compared with Chi-Square test. P value 0.05). There were no statistically significant differences between the two groups in the days when INR target was achieved, in INR control rate, rate of INR 2.5 and rate of reliable anticoagulation (all P>0.05) (table 2). 2.3 Clinical Outcomes As shown in table 3, the incidence of overall thromboembolic events in study group was lower than that in control group (2.16% vs. 4.35%, P=0.049). No statistically significant differences were found in hemorrhagic events and mortality between the two groups.
Fig. 1 Flow chart of randomized clinical trials Table 2 Comparison of INR target achieved and control rate in the two groups Variables Study group (n=510) Control group (n=506) Days before INR target was achieved 5.15±3.46 4.76±3.54 Optimal INR control rates (%) 38.1±20.5 39.2±23.1 Rates of INR 2.5 (%) 9.92±18.2 11.0±20.5 Rates of reliable anticoagulation (%) 33.9 36.8 Data are presented as ±s or n (%). INR: international normalized ratio Table 3 Comparison of thromboembolism and hemorrhage in the two groups Variables Study group (n=510) Control group (n=506) 22 (4.35%) 11 (2.16%) Thromboembolism 13 (2.57%) 7 (1.37%) Valvular thrombosis 9 (1.78%) 4 (0.78%) Non-valvular thrombosis 20 (3.95%) 18 (3.53%) Hemorrhage 10 (1.98%) 8 (1.57%) Skin ecchyosis 2 (0.40%) 3 (0.59%) Nosebleed 5 (0.99%) 4 (0.78%) Bleeding gums 1 (0.20%) 2 (0.39%) Menorrhagia 2 (0.40%) 1 (0.20%) Cerebral hemorrhage 2 (0.40%) 1 (0.20%) Death Data are presented as n (%).
P 0.076 0.422 0.116 0.375 0.344
P 0.049 0.170 0.159 0.722 0.622 0.660 0.729 0.568 0.559 0.559
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3 DISCUSSION The main conclusion of this prospective and randomized study is that combined low dose aspirin and warfarin therapy was associated with less thromboembolic events than warfarin therapy alone. This study also showed that addition of a low dose aspirin to warfarin did not increase the risk of hemorrhage or mortality in patients with atrial fibrillation following mechanical heart valve replacement. In the present study, all the patients in the study and control groups had atrial fibrillation after mechanical heart valve replacement. Atrial fibrillation predisposes to thrombus formation. ACC/AHA/ESC has accordingly developed corresponding anticoagulant treatment guidelines. The thromboembolic risks are reduced by guideline-adherent antithrombotic therapy with warfarin or aspirin[1, 3, 13]. These patients may particularly benefit from combined aspirin and warfarin treatment. Warfarin is currently the most commonly used oral anticoagulant in clinical medicine. It has been the mainstay of treatment for patients with atrial fibrillation and prosthetic heart valves, markedly reducing left ventricular thrombus, as well as for prevention or treatment of stroke, deep venous thrombosis and pulmonary embolism. Randomized clinical trials have shown that warfarin is superior to either aspirin or clopidogrel for prevention of stroke in patients with atrial fibrillation, and observational data seem to have established it as the standard antithrombotic treatment in patients with mechanical valve prostheses[14, 15]. Aspirin is the most commonly used clinical antiplatelet drugs. It has mounting evidence of evidence-based medicine in the prevention and treatment of cardiovascular diseases[16–18]. Meta-analysis showed that adjusted-dose warfarin and antiplatelet agents reduce stroke by approximately 60% and by approximately 20%, respectively, in patients who have atrial fibrillation. Furthermore, adding antiplatelet therapy, such as low-dose aspirin, to oral anticoagulation decreases the risk of systemic embolism or death among patients with prosthetic heart valves or those with high risk of atrial fibrillation or prior thromboembolic events[19]. In our study, the range for INR was set at 1.8–2.5, and a relatively low dose of warfarin (average 2.9 mg/day) was used. The average daily dose of warfarin and the target INR were lower than in the previous reports[20–23]. Our conservative approach may explain the low bleeding rate in both study and control groups. Other studies on patients whose ethnical background was similar to ours also found that an INR of 1.8–2.4 was associated with the lowest rate of major bleeding or thromboembolic events[11, 12]. The combination of low dose aspirin and warfarin yielded a modest benefit of thromboembolic event prevention, a 2.19% absolute risk reduction compared with patients treated with warfarin alone. Further studies are required to ascertain whether a more robust warfarin dosing regimen will lead to further thromboembolic event reduction. Warfarin can reduce the risk for thromboembolic stroke and also halve the risk for systemic thromboembolism. However, warfarin has considerable limitations, one of which is its association with increased bleeding[15]. Additionally, warfarin has a narrow therapeutic window and an unpredictable response that requires routine
905 coagulation monitoring and frequent dose adjustment, and variable dose-response in individuals, and interact with several foods and drugs[24, 25]. Although antiplatelet therapy is widely used for prevention of ischemic events, the optimum dose of aspirin is still not known. Aspirin-dosing regimen has important implications for bleeding[18]. Previous trials and meta-analysis showed that in patients with mechanical heart valve, the risk for major bleeding was higher in patients receiving combined aspirin-oral anticoagulation therapy than in those receiving oral anticoagulation therapy alone[20–23]. The increased bleeding risk following combination therapy seems to be related to the dose of aspirin, as lower dose aspirin was associated with a reduced risk of major bleeding when used together with warfarin[26]. To lessen the risk of major hemorrhage events, the dosage of aspirin is a key factor. Randomized clinical trials have shown that the most appropriate and effective antithrombotic dose of aspirin is 50–100 mg daily, most commonly used dose is 75 mg daily[19, 26]. In our study, the study group patients were prescribed with 75–100 mg daily aspirin. The most common hemorrhage was skin ecchymosis and bleeding gum, and fatal bleeding such as cerebral hemorrhage occurred in 0.2% of the study group and 0.4% of the control group, respectively. Therefore, the present study suggested that addition of aspirin did not increase the risk of life threatening bleeding. However, the bleeding risk of combined warfarin and dual antiplatelet therapy in our patients requires further investigation. In conclusion, combined use of low dose aspirin and warfarin in the patients with mechanical heart valve replacement and atrial fibrillation decreased thromboembolic events in comparison with warfarin therapy alone. Combined therapy was not associated with an increase in the risk of major bleeding or mortality. These results suggest that low dose aspirin combined with warfarin may be used as a safe and effective thromboemlism prevention. Conflict of interest statement This study received no external funding. Authors have no conflict of interest to declare. REFERENCES 1 Fuster V, Rydén LE, Cannom DS, et al. 2011 ACCF/AHA/HRS focused updates incorporated into the ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation, 2011,123(10): e269-367 2 Petersen P. Thromboembolic complications in atrial fibrillation. Stroke, 1990,21(1):4-13 3 Bonow RO, Carabello BA, Chatterjee K, et al. ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (writing Committee to Revise the 1998 guidelines for the management of patients with valvular heart disease) developed in collaboration with the Society of Cardiovascular Anesthesiologists endorsed by the Society for Cardiovascular Angiography and Interventions and the Society of Thoracic Surgeons. J Am Coll Cardiol, 2006,48(3):e1-e148
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15 Bassand JP. Review of atrial fibrillation outcome trials of oral anticoagulant and antiplatelet agents. Europace, 2012,14(3):312-324 16 Hennekens CH, Dyken ML, Fuster V. Aspirin as a therapeutic agent in cardiovascular disease: a statement for healthcare professionals from the American Heart Association. Circulation, 1997,96(8):2751-2753 17 Antithrombotic Trialists’ (ATT) Collaboration, Baigent C, Blackwell L, et al. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet, 2009,373(9678):1849-1860 18 US Preventive Services Task Force. Calonger N, Petitti DB, et al. Aspirin for the prevention of cardiovascular disease: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med, 2009,150(6):396-404 19 Massel DR, Little SH. Antiplatelet and anticoagulation for patients with prosthetic heart valves. Cochrane Database Syst Rev, 2013:CD003464. doi: 10.1002/14651858.CD003464.pub2 20 Turpie AG, Gent M, Laupacis A, et al. A comparison of aspirin with placebo in patients treated with warfarin after heart-valve replacement. N Engl J Med, 1993, 329(8):524-529 21 Cappelleri JC, Fiore LD, Brophy MT, et al. Efficacy and safety of combined anticoagulant and antiplatelet therapy versus anticoagulant monotherapy after mechanical heart-valve replacement: a metaanalysis. Am Heart J, 1995,130(3 Pt 1):547-552 22 Larson RJ, Fisher ES. Should aspirin be continued in patients started on warfarin? J Gen Intern Med, 2004,19(8): 879-886 23 Dentali F, Douketis JD, Lim W, et al. Combined aspirin-oral anticoagulant therapy compared with oral anticoagulant therapy alone among patients at risk for cardiovascular disease: a meta-analysis of randomized trials. Arch Intern Med, 2007,167(2):117-124 24 Brtko M, Dusek J. Antithrombotic therapy in patients after valve surgery with special attention to the combination of anticoagulant and antiplatelet therapy. Thrombosis, 2013,55(2):e164-e169 25 Berkowitz SD. Antithrombotic therapy after prosthetic cardiac valve implantation: potential novel antithrombotic therapies. Am Heart J, 2001,142(1):7-13 26 Massel D, Little SH. Risks and benefits of adding anti-platelet therapy to warfarin among patients with prosthetic heart valves: a meta-analysis. J Am Coll Cardiol, 2001,37(2):569-578 (Received Apr. 25, 2014; revised Oct. 18, 2014)
