- Email: [email protected]
Antiphospholipid syndrome and anticoagulation quality: a clinical challenge
Atherosclerosis 244 (2016) 48e50
Contents lists available at ScienceDirect
Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis
Antiphospholipid syndrome and anticoagulation quality: a clinical challenge Daniele Pastori a, 1, Sandro Parrotto a, 1, Tommasa Vicario a, Mirella Saliola a, Ivano Mezzaroma b, Francesco Violi a, 2, Pasquale Pignatelli a, *, 2 a b
I Clinica Medica, Department of Internal Medicine and Medical Specialties, “Sapienza” University of Rome, Rome, Italy Department of Clinical Medicine, “Sapienza” University of Rome, Rome, Italy
a r t i c l e i n f o
a b s t r a c t
Article history: Received 25 July 2015 Received in revised form 22 October 2015 Accepted 26 October 2015 Available online 30 October 2015
Background and aims: Antiphospholipid Syndrome (APS) is often complicated by ischemic vascular events. Vitamin K Antagonists (VKAs) reduce the risk of recurrent thrombosis. Quality of VKAs treatment, as assessed by the Time in Therapeutic Range (TTR), has never been investigated in APS patients. Methods: We performed a prospective observational study including 30 APS and 30 Atrial Fibrillation (AF) patients balanced by age and gender. All patients were treated with VKAs (INR target 2.5), and TTR was calculated. Results: Median TTR of APS was 53.5% vs. 68% of AF patients (p ¼ 0.001). A multivariable linear regression analysis confirmed that the presence of APS (vs. AF) was independently associated with a worse TTR (B: 14.067, 95% Confidence Interval 25.868/2.266, p ¼ 0.020). The weekly dosage of VKAs was significantly higher in APS than AF patients. Conclusions: APS patients disclose a lower quality of anticoagulation compared to those with AF, requiring higher doses of VKAs. The efficacy of non-vitamin K oral anticoagulants in this high-risk patients should be tested. © 2015 Elsevier Ireland Ltd. All rights reserved.
Keywords: Warfarin Time in therapeutic range Antiphospholipid syndrome
1. Introduction Antiphospholipid Syndrome (APS) is an autoimmune disorder characterized by ischemic vascular events both in arterial and venous compartment [1] Venous thromboembolism (VTE) and cerebral ischemia represent the most frequent complications of APS. Patients positive for anti-phospholipid antibodies have a low risk to develop thrombotic events (<1%/year), but after a first episode of venous thromboembolism, or after the interruption of anticoagulation the risk dramatically increases by 10e67% [2]. Patients with APS are usually treated with Vitamin K Antagonists (VKAs), which reduces the risk of recurrent venous and arterial thrombosis [3]. Thus, for all APS patients with a previous thrombotic event, current guidelines from the American College of Chest
* Corresponding author. I Clinica Medica, Viale del Policlinico 155, Rome 00161, Italy. E-mail address: [email protected] (P. Pignatelli). 1 Equal contribution. 2 Joint senior authors. http://dx.doi.org/10.1016/j.atherosclerosis.2015.10.105 0021-9150/© 2015 Elsevier Ireland Ltd. All rights reserved.
Physicians [3] recommend VKAs to a moderate intensity INR range (2.0e3.0) [4,5]. Nevertheless, the rate of thrombotic complications remains high despite current treatments [6]. Beyond the level of intensity of INR control, one important aspect for the management and the efficacy of anticoagulation with VKAs, concerns the quality of therapy. The Time in Therapeutic Range (TTR) represents an established marker of the quality of oral anticoagulation [7]. Thus, TTR has been inversely correlated with thromboembolism and mortality [8]. For instance, in patients with atrial fibrillation (AF) on treatment with VKAs, the ischemic risk dramatically raises for TTR <60% [8,9]. Due to the relevance of anticoagulation quality for thrombotic prevention and the lack of information on TTR in APS patients, we wondered if APS patients are comparable or different to AF patients in terms of achieving adequate TTR. Thus, aim of the study was to analyse the TTR in a population affected by APS on treatment with VKAs, in comparison to AF patients. 2. Methods We performed a prospective observational study including 30
D. Pastori et al. / Atherosclerosis 244 (2016) 48e50
consecutive patients with APS who referred to our centre for monitoring and management of antithrombotic therapies of the Department of Internal Medicine and Medical Specialties of Sapienza-University of Rome. The mean TTR of APS patients was compared with that of 30 non-valvular AF patients, balanced by age and gender, with the same INR therapeutic range (2.0e3.0). The diagnosis of APS [10] and AF [11] were made according to international definitions. All patients with APS had an arterial or venous ischemic event before starting VKAs. AF patients were stratified according to the CHA2DS2-VASc Score before starting oral anticoagulation. The quality of the anticoagulation of the last six months of treatment with VKAs was assessed by the TTR, determined according to the method described by Rosendaal [12]. For each patient, the mean weekly dosage of VKAs was calculated (mg/week). Exclusion criteria and definition of cardiovascular risk factors is reported in the online Supplementary file. 2.1. Statistical analysis Categorical variables were reported as counts (percentage); continuous variables were expressed as mean ± standard deviation or median and interquartile range (IQR), as appropriate. Independence of categorical variables was tested with the c2 test. Student unpaired t test and ManneWhitney U test were used to compare means and medians. Multivariable linear regression analysis was performed including all factors potentially affecting TTR including: age, gender, presence of APS (vs. AF), arterial hypertension, diabetes, heart failure, history of stroke, serum creatinine, use of corticosteroids/immunosuppressive drugs and amiodarone. Only p values < 0.05 were considered as statistically significant (SPSS-18.0, SPSS Inc.). The study was conducted according to the principles embodied in the Declaration of Helsinki and was approved by local ethical board of Sapienza University of Rome. 3. Results Baseline characteristics of patients are listed in Table 1. No significant differences were found between the two groups for cardiovascular risk factors and renal function. APS was associated with systemic lupus erythematosus (SLE) in six patients and with systemic sclerosis (SS) in one.
49
In addition to VKAs, 16 APS patients were treated with corticosteroids, 2 with micofenolate mofetil, 4 with hydroxychloroquine, 1 with azathioprine; 5 patients received a concomitant antiplatelet treatment. In APS patients, thrombotic events were VTE in 19, ischemic stroke/TIA in 9 and arterial thrombosis in 2. Median CHA2DS2-VASc Score was 2.0 [1.0e3.0]. Among APS patients, 16 received warfarin and 14 acenocumarol; 19 AF patients were treated with warfarin and 11 with acenocumarol. Mean follow-up of the whole cohort was 42.7 ± 20.7 months. The follow-up was similar between the two groups: 40.5 ± 19.3 for AF vs. 45.1 ± 22.1 months for APS patients (p ¼ 0.397). The mean weekly dosage of warfarin and acenocumarol was significantly higher in APS patients than AF (Table 1). Median TTR was 53.5% [IQR 39.0e66.7] for APS patients and 68.0% [IQR 62.5e78.2] for AF patients (p ¼ 0.001). Patients with APS had 30.0% [IQR 19.0e43.2] of their time below the TTR, compared to 14.0% [IQR 9.7e27.0] of AF patients (p ¼ 0.002). Analysis of the time outside the TTR revealed that, for patients with APS, the time below TTR, exceeded that above the TTR (Table 1, p ¼ 0.001). Patients with associated SLE/SS disclosed similar TTR when compared with those who suffered from APS alone (57.5% [35.2e63.2] vs. 53.0% [40.0e68.2] p ¼ 0.938). A multivariable linear regression analysis confirmed that the presence of APS (vs. AF) was independently associated with a worse TTR (B: 14.067, 95%CI 25.868/2.266, p ¼ 0.020), after adjustment for potential confounders. See Table 1 on supplementary data for complete results. 4. Discussion Our study shows that patients with APS have a low-quality therapy with VKAs (TTR <60%), spending an important proportion of time below the therapeutic range. Second, we found that APS patients need a significant higher weekly dosage of warfarin to maintain adequate INR values compared to patients affected by AF. The most consolidate evidence on the benefits provided by a good-quality oral anticoagulant treatment derived from large prospective studies which included patients affected by non-valvular AF. These studies clearly indicated that a TTR >60% is needed to reduce the rate of ischemic complication, with the most benefit for a TTR >70% [8]. We found that APS patients have a median TTR of 53%, far less
Table 1 Baseline characteristics.
Age (years) Women (%) History of stroke/TIA (%) Arterial Hypertension (%) Diabetes (%) Heart failure (%) ACE inhibitors/ARBs (%) Beta blockers (%) Amiodarone (%) Creatinine (mg/dl) Anti-cardiolipin antibodies Anti-beta 2 glycoprotein I antibodies Lupus anticoagulant % of time in therapeutic range % of time below therapeutic range % of time above therapeutic range Warfarin dosage (mg/week) Acenocumarol (mg/week) a
Data expressed as median and interquartile range.
APS (N ¼ 30)
AF (N ¼ 30)
P
52.9 ± 15.1 66.7 33.3 58.6 3.4 10.3 44.8 24.1 3.6 1.0 ± 0.4 19/30 10/30 20/30 53.5 [39.0e66.7]a 30.0 [19.0e43.2]a 13.5 [3.5e25.7]a (n ¼ 16) 42.2 ± 22.8 (n ¼ 14) 26.6 ± 10.7
55.1 ± 12.8 46.7 13.3 53.3 3.3 23.3 53.3 46.7 33.3 0.9 ± 0.2 e e e 68.0 [62.5e78.2]a 14.0 [9.7e27.0]a 10.0 [0.0e19.5]a (n ¼ 19) 25.7 ± 11.3 (n ¼ 11) 16.5 ± 7.3
0.538 0.192 0.125 0.795 0.981 0.299 0.606 0.103 0.006 0.486
0.001 0.002 0.231 0.009 0.014
50
D. Pastori et al. / Atherosclerosis 244 (2016) 48e50
from that would confer a benefit in term of reduction of thrombotic complications. In particular, analysis of time spent outside the therapeutic range showed that APS patients spent most of the time below the recommended INR range. Thus, APS patients receive inadequate protection, remaining potentially exposed to a high risk of recurrent ischemic events, with a frequent need of additional therapy with a low molecular weight heparin [13]. This result was observed despite a larger amount of weekly dosage of VKAs was given in APS compared to AF patients. This finding is in keeping with previous data reporting a degree of warfarin resistance in patients with APS and thrombotic events [14]. Thus, in a retrospective analysis, Authors found that patients with primary antiphospholipid syndrome, despite being on good anticoagulation, had a greater consumption of warfarin compared to patients with inherited thrombophilia (43.9 ± 20 vs. 34.1 ± 15 mg/week, p ¼ 0.02), similar to that observed in the present study. Nevertheless, an explanation for this “resistance” of APS to VKAs is difficult to be deduced. However, this finding might explain the high risk of recurrent thrombotic events [15] of APS when compared to other populations at high risk of thrombosis, such as those with thrombophilia [16]. The main limitation of the study is represented by the small sample size; moreover, all patients were recruited from a single centre. In conclusion, the low-quality anticoagulation, together with the “resistance” of APS to VKAs, suggests the need of exploring the potential efficacy and safety of the Non-Vitamin K Oral Anticoagulants (NOACs) for APS patients. In fact, NOACs showed to be effective compared to warfarin regardless of the quality of TTR [17e19]. Thus, randomized interventional clinical trials using NOACs in APS patients are needed. Competing interests None declared. Funding None. Acknowledgements None. Appendix A. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.atherosclerosis.2015.10.105.
References [1] B. Giannakopoulos, S.A. Krilis, The pathogenesis of the antiphospholipid syndrome, N. Engl. J. Med. 368 (2013) 1033e1044. [2] W. Lim, M.A. Crowther, J.W. Eikelboom, Management of antiphospholipid antibody syndrome: a systematic review, JAMA J. Am. Med. Assoc. 295 (2006) 1050e1057. [3] A. Holbrook, S. Schulman, D.M. Witt, et al., Evidence-based management of anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines, Chest 141 (2012) e152See184S. [4] G. Finazzi, R. Marchioli, V. Brancaccio, et al., A randomized clinical trial of high-intensity warfarin vs. conventional antithrombotic therapy for the prevention of recurrent thrombosis in patients with the antiphospholipid syndrome (WAPS), J. Thromb. Haemost. JTH 3 (2005) 848e853. [5] M.A. Crowther, J.S. Ginsberg, J. Julian, et al., A comparison of two intensities of warfarin for the prevention of recurrent thrombosis in patients with the antiphospholipid antibody syndrome, N. Engl. J. Med. 349 (2003) 1133e1138. [6] R. Cervera, R. Serrano, G.J. Pons-Estel, et al., Morbidity and mortality in the antiphospholipid syndrome during a 10-year period: a multicentre prospective study of 1000 patients, Ann. Rheum. Dis. 74 (6) (2015 Jun) 1011e1018. [7] E.M. Hylek, Vitamin K antagonists and time in the therapeutic range: implications, challenges, and strategies for improvement, J. Thromb. Thrombolysis 35 (2013) 333e335. [8] H.D. White, M. Gruber, J. Feyzi, et al., Comparison of outcomes among patients randomized to warfarin therapy according to anticoagulant control: results from SPORTIF III and V, Arch. Intern. Med. 167 (2007) 239e245. [9] D. Pastori, P. Pignatelli, M. Saliola, et al., Inadequate anticoagulation by vitamin K antagonists is associated with major adverse cardiovascular events in patients with atrial fibrillation, Int. J. Cardiol. 201 (2015) 513e516. [10] S. Miyakis, M.D. Lockshin, T. Atsumi, et al., International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS), J. Thromb. Haemost. JTH 4 (2006) 295e306. [11] C.T. January, L.S. Wann, J.S. Alpert, 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, Circulation 130 (2014) e199e267. [12] F.R. Rosendaal, S.C. Cannegieter, F.J. van der Meer, et al., A method to determine the optimal intensity of oral anticoagulant therapy, Thromb. Haemost. 69 (1993) 236e239. [13] M.M. Ciccone, F. Cortese, F. Corbo, et al., Bemiparin, an effective and safe low molecular weight heparin: a review, Vasc. Pharmacol. 62 (2014) 32e37. [14] P.R. Ames, M. Margaglione, A. Ciampa, et al., Increased warfarin consumption and residual fibrin turnover in thrombotic patients with primary antiphospholipid syndrome, Thromb. Res. 127 (2011) 595e599. [15] M.A. Khamashta, M.J. Cuadrado, F. Mujic, et al., The management of thrombosis in the antiphospholipid-antibody syndrome, N. Engl. J. Med. 332 (1995) 993e997. [16] G. Kenet, L.K. Lutkhoff, M. Albisetti, et al., Impact of thrombophilia on risk of arterial ischemic stroke or cerebral sinovenous thrombosis in neonates and children: a systematic review and meta-analysis of observational studies, Circulation 121 (2010) 1838e1847. [17] L. Wallentin, S. Yusuf, M.D. Ezekowitz, et al., Efficacy and safety of dabigatran compared with warfarin at different levels of international normalised ratio control for stroke prevention in atrial fibrillation: an analysis of the RE-LY trial, Lancet 376 (2010) 975e983. [18] L. Wallentin, R.D. Lopes, M. Hanna, et al., Efficacy and safety of apixaban compared with warfarin at different levels of predicted international normalized ratio control for stroke prevention in atrial fibrillation, Circulation 127 (2013) 2166e2176. [19] J.P. Piccini, A.S. Hellkamp, Y. Lokhnygina, et al., Relationship between time in therapeutic range and comparative treatment effect of rivaroxaban and warfarin: results from the ROCKET AF trial, J. Am. Heart Assoc. 3 (2014) e000521.
Contents lists available at ScienceDirect
Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis
Antiphospholipid syndrome and anticoagulation quality: a clinical challenge Daniele Pastori a, 1, Sandro Parrotto a, 1, Tommasa Vicario a, Mirella Saliola a, Ivano Mezzaroma b, Francesco Violi a, 2, Pasquale Pignatelli a, *, 2 a b
I Clinica Medica, Department of Internal Medicine and Medical Specialties, “Sapienza” University of Rome, Rome, Italy Department of Clinical Medicine, “Sapienza” University of Rome, Rome, Italy
a r t i c l e i n f o
a b s t r a c t
Article history: Received 25 July 2015 Received in revised form 22 October 2015 Accepted 26 October 2015 Available online 30 October 2015
Background and aims: Antiphospholipid Syndrome (APS) is often complicated by ischemic vascular events. Vitamin K Antagonists (VKAs) reduce the risk of recurrent thrombosis. Quality of VKAs treatment, as assessed by the Time in Therapeutic Range (TTR), has never been investigated in APS patients. Methods: We performed a prospective observational study including 30 APS and 30 Atrial Fibrillation (AF) patients balanced by age and gender. All patients were treated with VKAs (INR target 2.5), and TTR was calculated. Results: Median TTR of APS was 53.5% vs. 68% of AF patients (p ¼ 0.001). A multivariable linear regression analysis confirmed that the presence of APS (vs. AF) was independently associated with a worse TTR (B: 14.067, 95% Confidence Interval 25.868/2.266, p ¼ 0.020). The weekly dosage of VKAs was significantly higher in APS than AF patients. Conclusions: APS patients disclose a lower quality of anticoagulation compared to those with AF, requiring higher doses of VKAs. The efficacy of non-vitamin K oral anticoagulants in this high-risk patients should be tested. © 2015 Elsevier Ireland Ltd. All rights reserved.
Keywords: Warfarin Time in therapeutic range Antiphospholipid syndrome
1. Introduction Antiphospholipid Syndrome (APS) is an autoimmune disorder characterized by ischemic vascular events both in arterial and venous compartment [1] Venous thromboembolism (VTE) and cerebral ischemia represent the most frequent complications of APS. Patients positive for anti-phospholipid antibodies have a low risk to develop thrombotic events (<1%/year), but after a first episode of venous thromboembolism, or after the interruption of anticoagulation the risk dramatically increases by 10e67% [2]. Patients with APS are usually treated with Vitamin K Antagonists (VKAs), which reduces the risk of recurrent venous and arterial thrombosis [3]. Thus, for all APS patients with a previous thrombotic event, current guidelines from the American College of Chest
* Corresponding author. I Clinica Medica, Viale del Policlinico 155, Rome 00161, Italy. E-mail address: [email protected] (P. Pignatelli). 1 Equal contribution. 2 Joint senior authors. http://dx.doi.org/10.1016/j.atherosclerosis.2015.10.105 0021-9150/© 2015 Elsevier Ireland Ltd. All rights reserved.
Physicians [3] recommend VKAs to a moderate intensity INR range (2.0e3.0) [4,5]. Nevertheless, the rate of thrombotic complications remains high despite current treatments [6]. Beyond the level of intensity of INR control, one important aspect for the management and the efficacy of anticoagulation with VKAs, concerns the quality of therapy. The Time in Therapeutic Range (TTR) represents an established marker of the quality of oral anticoagulation [7]. Thus, TTR has been inversely correlated with thromboembolism and mortality [8]. For instance, in patients with atrial fibrillation (AF) on treatment with VKAs, the ischemic risk dramatically raises for TTR <60% [8,9]. Due to the relevance of anticoagulation quality for thrombotic prevention and the lack of information on TTR in APS patients, we wondered if APS patients are comparable or different to AF patients in terms of achieving adequate TTR. Thus, aim of the study was to analyse the TTR in a population affected by APS on treatment with VKAs, in comparison to AF patients. 2. Methods We performed a prospective observational study including 30
D. Pastori et al. / Atherosclerosis 244 (2016) 48e50
consecutive patients with APS who referred to our centre for monitoring and management of antithrombotic therapies of the Department of Internal Medicine and Medical Specialties of Sapienza-University of Rome. The mean TTR of APS patients was compared with that of 30 non-valvular AF patients, balanced by age and gender, with the same INR therapeutic range (2.0e3.0). The diagnosis of APS [10] and AF [11] were made according to international definitions. All patients with APS had an arterial or venous ischemic event before starting VKAs. AF patients were stratified according to the CHA2DS2-VASc Score before starting oral anticoagulation. The quality of the anticoagulation of the last six months of treatment with VKAs was assessed by the TTR, determined according to the method described by Rosendaal [12]. For each patient, the mean weekly dosage of VKAs was calculated (mg/week). Exclusion criteria and definition of cardiovascular risk factors is reported in the online Supplementary file. 2.1. Statistical analysis Categorical variables were reported as counts (percentage); continuous variables were expressed as mean ± standard deviation or median and interquartile range (IQR), as appropriate. Independence of categorical variables was tested with the c2 test. Student unpaired t test and ManneWhitney U test were used to compare means and medians. Multivariable linear regression analysis was performed including all factors potentially affecting TTR including: age, gender, presence of APS (vs. AF), arterial hypertension, diabetes, heart failure, history of stroke, serum creatinine, use of corticosteroids/immunosuppressive drugs and amiodarone. Only p values < 0.05 were considered as statistically significant (SPSS-18.0, SPSS Inc.). The study was conducted according to the principles embodied in the Declaration of Helsinki and was approved by local ethical board of Sapienza University of Rome. 3. Results Baseline characteristics of patients are listed in Table 1. No significant differences were found between the two groups for cardiovascular risk factors and renal function. APS was associated with systemic lupus erythematosus (SLE) in six patients and with systemic sclerosis (SS) in one.
49
In addition to VKAs, 16 APS patients were treated with corticosteroids, 2 with micofenolate mofetil, 4 with hydroxychloroquine, 1 with azathioprine; 5 patients received a concomitant antiplatelet treatment. In APS patients, thrombotic events were VTE in 19, ischemic stroke/TIA in 9 and arterial thrombosis in 2. Median CHA2DS2-VASc Score was 2.0 [1.0e3.0]. Among APS patients, 16 received warfarin and 14 acenocumarol; 19 AF patients were treated with warfarin and 11 with acenocumarol. Mean follow-up of the whole cohort was 42.7 ± 20.7 months. The follow-up was similar between the two groups: 40.5 ± 19.3 for AF vs. 45.1 ± 22.1 months for APS patients (p ¼ 0.397). The mean weekly dosage of warfarin and acenocumarol was significantly higher in APS patients than AF (Table 1). Median TTR was 53.5% [IQR 39.0e66.7] for APS patients and 68.0% [IQR 62.5e78.2] for AF patients (p ¼ 0.001). Patients with APS had 30.0% [IQR 19.0e43.2] of their time below the TTR, compared to 14.0% [IQR 9.7e27.0] of AF patients (p ¼ 0.002). Analysis of the time outside the TTR revealed that, for patients with APS, the time below TTR, exceeded that above the TTR (Table 1, p ¼ 0.001). Patients with associated SLE/SS disclosed similar TTR when compared with those who suffered from APS alone (57.5% [35.2e63.2] vs. 53.0% [40.0e68.2] p ¼ 0.938). A multivariable linear regression analysis confirmed that the presence of APS (vs. AF) was independently associated with a worse TTR (B: 14.067, 95%CI 25.868/2.266, p ¼ 0.020), after adjustment for potential confounders. See Table 1 on supplementary data for complete results. 4. Discussion Our study shows that patients with APS have a low-quality therapy with VKAs (TTR <60%), spending an important proportion of time below the therapeutic range. Second, we found that APS patients need a significant higher weekly dosage of warfarin to maintain adequate INR values compared to patients affected by AF. The most consolidate evidence on the benefits provided by a good-quality oral anticoagulant treatment derived from large prospective studies which included patients affected by non-valvular AF. These studies clearly indicated that a TTR >60% is needed to reduce the rate of ischemic complication, with the most benefit for a TTR >70% [8]. We found that APS patients have a median TTR of 53%, far less
Table 1 Baseline characteristics.
Age (years) Women (%) History of stroke/TIA (%) Arterial Hypertension (%) Diabetes (%) Heart failure (%) ACE inhibitors/ARBs (%) Beta blockers (%) Amiodarone (%) Creatinine (mg/dl) Anti-cardiolipin antibodies Anti-beta 2 glycoprotein I antibodies Lupus anticoagulant % of time in therapeutic range % of time below therapeutic range % of time above therapeutic range Warfarin dosage (mg/week) Acenocumarol (mg/week) a
Data expressed as median and interquartile range.
APS (N ¼ 30)
AF (N ¼ 30)
P
52.9 ± 15.1 66.7 33.3 58.6 3.4 10.3 44.8 24.1 3.6 1.0 ± 0.4 19/30 10/30 20/30 53.5 [39.0e66.7]a 30.0 [19.0e43.2]a 13.5 [3.5e25.7]a (n ¼ 16) 42.2 ± 22.8 (n ¼ 14) 26.6 ± 10.7
55.1 ± 12.8 46.7 13.3 53.3 3.3 23.3 53.3 46.7 33.3 0.9 ± 0.2 e e e 68.0 [62.5e78.2]a 14.0 [9.7e27.0]a 10.0 [0.0e19.5]a (n ¼ 19) 25.7 ± 11.3 (n ¼ 11) 16.5 ± 7.3
0.538 0.192 0.125 0.795 0.981 0.299 0.606 0.103 0.006 0.486
0.001 0.002 0.231 0.009 0.014
50
D. Pastori et al. / Atherosclerosis 244 (2016) 48e50
from that would confer a benefit in term of reduction of thrombotic complications. In particular, analysis of time spent outside the therapeutic range showed that APS patients spent most of the time below the recommended INR range. Thus, APS patients receive inadequate protection, remaining potentially exposed to a high risk of recurrent ischemic events, with a frequent need of additional therapy with a low molecular weight heparin [13]. This result was observed despite a larger amount of weekly dosage of VKAs was given in APS compared to AF patients. This finding is in keeping with previous data reporting a degree of warfarin resistance in patients with APS and thrombotic events [14]. Thus, in a retrospective analysis, Authors found that patients with primary antiphospholipid syndrome, despite being on good anticoagulation, had a greater consumption of warfarin compared to patients with inherited thrombophilia (43.9 ± 20 vs. 34.1 ± 15 mg/week, p ¼ 0.02), similar to that observed in the present study. Nevertheless, an explanation for this “resistance” of APS to VKAs is difficult to be deduced. However, this finding might explain the high risk of recurrent thrombotic events [15] of APS when compared to other populations at high risk of thrombosis, such as those with thrombophilia [16]. The main limitation of the study is represented by the small sample size; moreover, all patients were recruited from a single centre. In conclusion, the low-quality anticoagulation, together with the “resistance” of APS to VKAs, suggests the need of exploring the potential efficacy and safety of the Non-Vitamin K Oral Anticoagulants (NOACs) for APS patients. In fact, NOACs showed to be effective compared to warfarin regardless of the quality of TTR [17e19]. Thus, randomized interventional clinical trials using NOACs in APS patients are needed. Competing interests None declared. Funding None. Acknowledgements None. Appendix A. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.atherosclerosis.2015.10.105.
References [1] B. Giannakopoulos, S.A. Krilis, The pathogenesis of the antiphospholipid syndrome, N. Engl. J. Med. 368 (2013) 1033e1044. [2] W. Lim, M.A. Crowther, J.W. Eikelboom, Management of antiphospholipid antibody syndrome: a systematic review, JAMA J. Am. Med. Assoc. 295 (2006) 1050e1057. [3] A. Holbrook, S. Schulman, D.M. Witt, et al., Evidence-based management of anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines, Chest 141 (2012) e152See184S. [4] G. Finazzi, R. Marchioli, V. Brancaccio, et al., A randomized clinical trial of high-intensity warfarin vs. conventional antithrombotic therapy for the prevention of recurrent thrombosis in patients with the antiphospholipid syndrome (WAPS), J. Thromb. Haemost. JTH 3 (2005) 848e853. [5] M.A. Crowther, J.S. Ginsberg, J. Julian, et al., A comparison of two intensities of warfarin for the prevention of recurrent thrombosis in patients with the antiphospholipid antibody syndrome, N. Engl. J. Med. 349 (2003) 1133e1138. [6] R. Cervera, R. Serrano, G.J. Pons-Estel, et al., Morbidity and mortality in the antiphospholipid syndrome during a 10-year period: a multicentre prospective study of 1000 patients, Ann. Rheum. Dis. 74 (6) (2015 Jun) 1011e1018. [7] E.M. Hylek, Vitamin K antagonists and time in the therapeutic range: implications, challenges, and strategies for improvement, J. Thromb. Thrombolysis 35 (2013) 333e335. [8] H.D. White, M. Gruber, J. Feyzi, et al., Comparison of outcomes among patients randomized to warfarin therapy according to anticoagulant control: results from SPORTIF III and V, Arch. Intern. Med. 167 (2007) 239e245. [9] D. Pastori, P. Pignatelli, M. Saliola, et al., Inadequate anticoagulation by vitamin K antagonists is associated with major adverse cardiovascular events in patients with atrial fibrillation, Int. J. Cardiol. 201 (2015) 513e516. [10] S. Miyakis, M.D. Lockshin, T. Atsumi, et al., International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS), J. Thromb. Haemost. JTH 4 (2006) 295e306. [11] C.T. January, L.S. Wann, J.S. Alpert, 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, Circulation 130 (2014) e199e267. [12] F.R. Rosendaal, S.C. Cannegieter, F.J. van der Meer, et al., A method to determine the optimal intensity of oral anticoagulant therapy, Thromb. Haemost. 69 (1993) 236e239. [13] M.M. Ciccone, F. Cortese, F. Corbo, et al., Bemiparin, an effective and safe low molecular weight heparin: a review, Vasc. Pharmacol. 62 (2014) 32e37. [14] P.R. Ames, M. Margaglione, A. Ciampa, et al., Increased warfarin consumption and residual fibrin turnover in thrombotic patients with primary antiphospholipid syndrome, Thromb. Res. 127 (2011) 595e599. [15] M.A. Khamashta, M.J. Cuadrado, F. Mujic, et al., The management of thrombosis in the antiphospholipid-antibody syndrome, N. Engl. J. Med. 332 (1995) 993e997. [16] G. Kenet, L.K. Lutkhoff, M. Albisetti, et al., Impact of thrombophilia on risk of arterial ischemic stroke or cerebral sinovenous thrombosis in neonates and children: a systematic review and meta-analysis of observational studies, Circulation 121 (2010) 1838e1847. [17] L. Wallentin, S. Yusuf, M.D. Ezekowitz, et al., Efficacy and safety of dabigatran compared with warfarin at different levels of international normalised ratio control for stroke prevention in atrial fibrillation: an analysis of the RE-LY trial, Lancet 376 (2010) 975e983. [18] L. Wallentin, R.D. Lopes, M. Hanna, et al., Efficacy and safety of apixaban compared with warfarin at different levels of predicted international normalized ratio control for stroke prevention in atrial fibrillation, Circulation 127 (2013) 2166e2176. [19] J.P. Piccini, A.S. Hellkamp, Y. Lokhnygina, et al., Relationship between time in therapeutic range and comparative treatment effect of rivaroxaban and warfarin: results from the ROCKET AF trial, J. Am. Heart Assoc. 3 (2014) e000521.