Anticoagulation therapy with combined low dose aspirin and warfarin following mechanical heart valve replacement

Thrombosis Research 128 (2011) e91–e94

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Thrombosis Research 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 / t h r o m r e s

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Anticoagulation therapy with combined low dose aspirin and warfarin following mechanical heart valve replacement Ming-Feng Dong a, 1, Zeng-Shan Ma a, c,⁎, 1, Sheng-Jun Ma a, Shou-Dong Chai a, Pei-Zhe Tang a, Dao-Kuo Yao b, Le-Xin Wang a, c,⁎⁎ a b c

Department of Cardiac Surgery, Liaocheng People's Hospital and Liaocheng Clinical School of Taishan Medical University, Liaocheng, Shandong, 252000, P.R. China Department of Cardiology, Beijing Friendship Hospital, Capital Medical University, Beijing, PR China School of Biomedical Sciences, Charles Sturt University, Wagga Wagga, NSW 2650, Australia

a r t i c l e

i n f o

Article history: Received 17 May 2011 Received in revised form 29 June 2011 Accepted 5 July 2011 Available online 3 August 2011 Keywords: anticoagulation aspirin hemorrhage mechanical valve replacement thromboembolic event warfarin

a b s t r a c t Introduction: This study was designed to evaluate safety and efficacy of combined low dose aspirin and warfarin therapy following mechanical heart valve replacement. Methods: A total of 1 496 patients (686 males, mean age 35 ± 8.5 years) undergoing mechanical heart valvular replacement were randomly divided into study (warfarin plus 75–100 mg aspirin) or control (warfarin only) group. International normalized ratio (INR) and prothrombin time was maintained at 1.8-2.5 and 1.5-2.0 times of the normal value, respectively. Thromboembolic events and major bleedings were registered during follow up. Results: Patients were followed up for 24 ± 9 months. The average dose of warfarin in the study and control group was 2.92 ± 0.87 mg and 2.89 ± 0.79 mg, respectively (p N 0.05). The overall thromboembolic events in study group were lower than in control group (2.1% vs. 3.6%, p = 0.044). No statistically significant differences were found in hemorrhage events (3.5% vs. 3.7%, p N 0.05) or mortality (0.3% vs 0.4%, p N 0.05) between the two groups. Conclusions: Following mechanical valve replacement, combined low dose aspirin and warfarin therapy was associated with a greater reduction in thromboembolism events than warfarin therapy alone. This combined treatment was not associated with an increase in the rate of major bleeding or mortality. Crown Copyright © 2011 Published by Elsevier Ltd. All rights reserved.

Introduction Cardiac valvular diseases, such as mitral regurgitation or aortic stenosis are common and the prevalence increases with age [1,2]. Valve replacement is the mainstay of treatment for patients with moderate to severe valvular heart disease [2]. Thromboembolic events, in particular ischemic stroke, are serious complications of valve replacement surgery [3–5]. Oral anticoagulation therapy plays an important role in thromboembolic event prevention, and warfarin is required following mechanical valve replacement [2,6–8]. A combination of warfarin and an antiplatelet agent, such as aspirin, may further reduce thrombolytic complications in patients with prosthetic heart valves. Previous trials and meta-analysis showed that in patients with a mechanical heart valve, the risk for arterial thromboembolism was lower in patients ⁎ Correspondence to: Z.-S. Ma, Department of Cardiac Surgery, Liaocheng People's Hospital, Liaocheng, Shandong Province, 252000, P. R. China. Tel.: + 86 133 46256051. ⁎⁎ Correspondence to: L. Wang, School of Biomedical Sciences, Charles Sturt University, Wagga Wagga, NSW 2678, Australia. Tel.: + 61 2 69332905; fax: + 61 2 69 332587. E-mail addresses: [email protected] (Z.-S. Ma), [email protected] (L.-X. Wang). 1 Joint first authors.

receiving combined aspirin-oral anticoagulation therapy compared with oral anticoagulation therapy alone. However, the risk for major bleeding in patients receiving aspirin-oral anticoagulation therapy was higher than in patients receiving anticoagulation therapy alone [9–12]. 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 [13]. The aim of this study was to evaluate the safety and efficacy of combined low dose aspirin and warfarin in patients with mechanical valve replacement. Patients and Methods Patient selection This study was approved by the Human Research Ethics Committee of Liaocheng People's Hospital. Informed written consent was obtained from all participants. Between January 2000 and December 2010, a total of 1 697 consecutive patients admitted for cardiac valve replacement were initially screened, and 1 496 patients were enrolled in this study. Inclusion criteria were: 1) Patients who received mechanical valve replacement; 2) No history of cerebral vascular

0049-3848/$ – see front matter. Crown Copyright © 2011 Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.thromres.2011.07.006

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disease or peripheral vascular disease. Patients who did not meet the above criteria were excluded. The reasons for the excluded patients were biovalve replacement (n = 169), a previous history of cerebral infarction (n = 21) or cerebral hematoma (n = 2) or thrombosis in lower extremities (n = 12). After surgery, the selected patients were randomised, using random drawing of numbers, into study (n = 748) and control group (n = 748). The general characteristics of the patients are shown in Table 1.

Pharmacological management Study group patients were prescribed with 75–100 mg aspirin, whereas control group was prescribed with a matching placebo after the surgery. All patients in the study and control group received warfarin, with doses titrated to international normalized ratio (INR) 1.8-2.5 and prothrombin time (PT) 1.5-2.0 times of the normal value. This therapeutic INR range was based on our own experience, and on other report that in patients of similar ethnical background to ours, INR N 2.5 was associated with an significantly increased risk of major bleeding [14]. Aspirin and warfarin were commenced within 48 hours of the surgery, when patients life signs were stabilized and chest drainage fluid volume was b50 ml. Other medications used in study and control group patients were diuretics, angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), digoxin, nitrates, amiodarone or beta blockers to improve cardiac function and to control heart rate.

Platelet function tests Whole blood was collected into standard sodium citrate tubes (3.8% w/vol), with a blood to citrate ratio of 9:1. All platelet function tests were performed within 60 min of blood sample collection. Born's aggregation method was used in this study. Turbidimetric platelet aggregation was evaluated by the increases in light transmittance in a Chrono-Log platelet aggregometer (Mascia Brunelli, Milan, Italy), after addition of adenosine diphosphatase (ADP, Mascia Brunelli, Milan, Italy), at 5 μmol/L and 10 μmol/L final concentration, or collagen (Mascia Brunelli, Milan, Italy), at 2 μg/mL final concentration, to platelet-rich plasma, as previously described [15,16]. Based on our own laboratory assessment of normal subjects, we defined the upper normal limit of light transmittance aggregometry (LTA) as the mean plus one standard deviation: greater than 50% max LTA for ADP-induced aggregation, and greater than 75% max LTA for collagen-induced aggregation. 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. Cardiac and carotid ultrasonography was performed to detect any possible thromboembolics in the cardiac and carotid arteries before and at each follow-up. Cerebral computer tomography (CT) was also performed in patients who had symptoms or signs of cerebrovascular disease. Statistics analysis

Table 1 Baseline characteristics of patients in the two groups. Variables

Study group (n = 748)

Control group (n = 748)

p

Age (years) Female (%) Etiology RHD Calcified lesions Primary aortic root lesions Others Site of valve Mitral Aortic Double valves Concomitant procedure AF ablation Tricuspid valvular plasty Type of mechanical valve Unileaflet (GK,China) Unileaflet (Medtronic) Bileaflet (ST, JUDE) Combined diseases MI PTCA CABG Hypertension Diabetes Ischemic cerebral disease Peripheral arterial disease AF NYHA class III and IV (%) Medication use Diuretics ACEI/ARBs Digoxin Nitrates Beta blockers Amiodarone

34 ± 8.3 59(7.9)

35 ± 6.3 61(8.2)

0.62 0.71

472(63.1) 251(33.6) 21(2.8) 4(0.5)

478(63.9) 249(33.3) 19(2.54) 2(0.3)

0.72 0.69 0.52 0.34

628(83.9) 321(42.9) 120(16.0)

619(82.8) 330(44.1) 118(15.8)

0.50 0.49 0.16

245(32.7) 342(45.7)

236(31.6) 340(45.5)

0.56 0.60

249(33.3) 219(29.3) 280(37.4)

258(34.5) 225(30.1) 265(35.4)

0.89 0.62 0.64

354(47.3) 122(16.3) 53(7.1) 110(14.7) 71(9.5) 41(5.5) 15(2.0) 298(39.8) 32(4.3)

345(46.1) 119(15.9) 55(7.35) 113(15.1) 69(9.22) 39(5.21) 14(1.87) 299(40.0) 34(4.6)

0.34 0.41 0.82 0.79 0.81 0.56 0.49 0.65 0.76

698(93.3) 369(49.3) 465(62.2) 121(16.2) 69(9.2) 15(2.0)

701(93.7) 372(49.7) 461(61.6) 119(15.9) 65(8.69) 17(2.27)

0.83 0.76 0.71 0.54 0.48 0.66

Data are present as mean ± SD or n (%). RHD, rheumatic heart disease; AF, atrial fibrillation; MI, myocardial infarction; PTCA, percutaneous coronary angioplasty; CABG, coronary artery bypass graft; NYHA, New York heart association; ACEI, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker.

All data are presented as mean ± SD. Continuous variables were compared with student t-test or analysis of variance (ANOVA). Categorical data were compared with Chi-Square test. P value b 0.05 was considered statistically significant. All data were analyzed by SPSS 13.0 software (SPSS, Inc, Chicago). Results General findings As shown in Table 1, the most common types of valvular disease were rheumatic heart disease (RHD) (n= 950), and calcified valvular disease (n= 500). Valvular replacements were successfully performed in all patients. At the beginning of the study, there was no statistically significant difference in age, sex, type of valvular replacements, concurrent diseases or New York Heart Association (NYHA) function classes between the two groups (Table 1). The types of cardiovascular medications used were also similar between the two groups. The mean follow up time was 24 ± 9 months (6 months to 5 years). During the follow-up period, 2 patients in study group and 3 in control group died (0.3% vs. 0.4%, p = 0.654). The cause of 2 deaths in study group was cerebral hemorrhage and leukemia, respectively. The cause of 3 deaths in control group was cerebral hemorrhage, cancer and sudden cardiac death, respectively. Anticoagulation efficacy There were no statistically significant differences in mean doses of daily warfarin between study and control group (2.92 ± 0.87 mg vs. 2.89 ± 0.79 mg, p N 0.05). There were no statistically significant differences between the two groups in the days when INR target were achieved, INR control rates, rates of INRb 1.8, rates of INR N2.5 and rates of reliable anticoagulation (p N 0.05) (Table 2).

M.-F. Dong et al. / Thrombosis Research 128 (2011) e91–e94 Table 2 Comparison of INR target achieved and control rate in the two groups.

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Table 4 Comparison of thromboembolism and hemorrhage in the two groups.

Variables

Study group (n = 748)

Control group (n = 748)

p

Variables

Study group (n = 748)

Control group (n = 748)

p

Days before INR target was achieved Optimal INR control rates (%) Rates of INR b 1.8(%) Rates of INR N 2.5(%) Rates of reliable anticoagulation (%)

4.78 ± 3.56 39.3 ± 22.9 48.8 ± 27.2 10.6 ± 20.1 33.3

5.39 ± 3.44 38.0 ± 18.3 51.7 ± 23.1 9.85 ± 15.3 36.2

0.56 0.61 0.32 0.23 0.34

Thromboembolism Valvular thrombosis Non-valvular thrombosis Hemorrhage Menorrhagia Nosebleed Bleeding gums Skin ecchymosis Cerebral hemorrhage Death

16 (2.1) 9 (1.2) 7 (0.9) 26 (3.46) 5 (0.67) 3 (0.04) 4 (0.05) 12 (1.61) 2 (0.3) 2(0.3)

27(3.6) 15 (2.0) 12(1.6) 28(3.75) 4(0.05) 2 (0.03) 3 (0.04) 14 (1.86) 5 (0.67) 3(0.4)

0.044 0.109 0.124 0.391 0.850 0.752 0.803 0.655 0.457 0.327

Data are present as mean ± SD or n (%). INR: international normalized ratio.

Data are present as n (%).

Platelet aggregation As shown in Table 3, before and 2 days following the surgery, there were no statistically significant differences in platelet aggregation rates between the two groups. However, platelet aggregation rates in study group were lower than in control group 7 days, 1 month, and 1 year after the surgery (all p b 0.05). In control group, platelet aggregation rates 7 and 30 days after the surgery were higher than those before the surgery (p b 0.05). Clinical outcomes As shown in Table 4, the overall thromboembolic events in study group were lower than in control group (2.1% vs. 3.6%, p = 0.044). No statistically significant differences were found in hemorrhagic events between the two groups. Discussion This prospective and randomized study showed 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 following mechanical valve replacement. In the present study, over 50 percent of patients in the study and control group had coronary heart disease and were treated with coronary artery bypass grafting or percutaneous coronary intervention. These patients maybe particularly benefiting from combined aspirin and warfarin treatment. Two previous trials showed that in patients with acute coronary syndrome, combined lower dose aspirin with vitamin K antagonist (INR of 2.0-3.0) reduces stroke, recurrent myocardial

Table 3 Comparison of platelet aggregation detected as ADP5μmol/L, 10 μmol/L and Collagen 2 μg/mL in the two groups. Variables

Before After 2 days 7 days 1 month 1 year

Study group(n = 748)

Control group (n = 748)

ADP 5 μmol/L

ADP 10 μmol/L

Collagen 2 μg/mL

ADP 5 μmol/L

ADP 10 μmol/L

Collagen 2 μg/mL

11.9 (2.2)

15.1 (2.2)

18.6 (2.3)

13.0 (2.0)

14.9 (1.7)

18.1 (2.1)

10.7 (2.3) 11.9⁎

14.0 (2.3) 16.7⁎

16.9 (2.2) 19.7⁎

(2.0) 11.8⁎ (2.0) 11.1 (2.4)

(1.9) 14.5⁎ (1.9) 13.7⁎ (1.7)

(2.5) 18.7⁎ (2.7) 18.4⁎ (2.3)

11.4 (2.2) 14.5† (2.3) 13.5† (2.8) 14.5† (2.0)

13.6 (2.3) 17.7† (2.1) 16.3† (2.4) 16.2† (1.9)

17.5 (2.2) 21.6† (2.3) 20.9† (2.9) 21.2† (2.3)

Data are present as mean (SD). *p b 0.05 vs. control group; †p b 0.05 vs. pre-surgery. ADP, adenosine diphosphatase.

infarction and death [17,18]. In a patient with both mechanical valve replacement and coronary stents, a combination of warfarin and dual anti-platelet therapy, such as aspirin and clopidogrel, is often required, and an increased hemorrhagic risk is expected [2]. The present study showed that the rate of major bleeding during low dose aspirin and warfarin therapy was very low, and fatal cerebral hemorrhage was less than 0.5%. However, the bleeding risk of combined warfarin and dual anti-platelet therapy in our patients require further investigation. The exception for combined aspirin and warfarin therapy is patients with a history of gastrointestinal bleeding, poorly controlled hypertension and female aged over 75 years old, as addition of aspirin in these patients may increase the risk of major bleeds [19–21]. Bleeding or hemorrhage during combined use of aspirin and warfarin were usually gastrointestinal [22], but with a reduced dose of aspirin major hemorrhage may not be a great concern. In our study, gastrointestinal bleeding was rare. The most common hemorrhage was skin ecchymosis. Fatal bleeding such as cerebral hemorrhage occurred in 0.3% of the study group and 0.67% of the control group, suggesting that addition of aspirin did not increase the risk of life threatening bleeding. Our target 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 proportion of patients with an INR less than 1.8 was 48.8% in study group and 51.7% in control group. The average daily dose of warfarin and the target INR in our study were lower than in the previous reports [9–12]. Our conservative approach may explain the low bleeding rates in both study and control group. Other studies on patients whose ethnical background were 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 [14]. The combination of low dose warfarin and aspirin in the present study yielded a modest benefit of thromboembolic event prevention, a 1.5% 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 in our patients. In conclusion, combined use of low dose aspirin and warfarin following mechanical valve replacement decreased thromboembolic events in comparison with warfarin therapy alone. Combined therapy was not associated with an increase in the risk of major bleeding. These results suggest that low dose aspirin and warfarin may be used as a safe and effective thromboemlism prevention following mechanical valve replacement.

Conflict of interest statement This study received no external funding. Authors have no conflict of interest to declare.

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