Skip to main content
main-content

01.12.2016 | Research | Ausgabe 1/2016 Open Access

Thrombosis Journal 1/2016

Edoxaban versus enoxaparin for the prevention of venous thromboembolism after total knee or hip arthroplasty: pooled analysis of coagulation biomarkers and primary efficacy and safety endpoints from two phase 3 trials

Zeitschrift:
Thrombosis Journal > Ausgabe 1/2016
Autoren:
Yohko Kawai, Takeshi Fuji, Satoru Fujita, Tetsuya Kimura, Kei Ibusuki, Kenji Abe, Shintaro Tachibana
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​s12959-016-0121-1) contains supplementary material, which is available to authorized users.
Abbreviations
AE
Adverse event
CRNM
Clinically relevant nonmajor
DOAC
Direct oral anticoagulant
DVT
Deep vein thrombosis
F1+2
Prothrombin fragments 1 + 2
FXa
Factor Xa
LMWH
Low-molecular-weight heparin
PE
Pulmonary embolism
SD
Standard deviation
SFMC
Soluble fibrin monomer complex
THA
Total hip arthroplasty
TKA
Total knee arthroplasty
VTE
Venous thromboembolism

Background

Patients undergoing orthopedic surgery such as total knee arthroplasty (TKA) or total hip arthroplasty (THA) are at high risk for venous thromboembolism (VTE) [ 1, 2]. Anticoagulation therapy and/or mechanical prophylaxis, including compression stockings or intermittent pneumatic compression, are recommended for prevention of VTE after orthopedic surgery [ 1, 2]. In Japan, edoxaban [ 3], a direct oral anticoagulant (DOAC) selective inhibitor of activated factor Xa (FXa), and enoxaparin [ 4], an injectable low-molecular-weight heparin (LMWH), are both indicated for prophylaxis of deep vein thrombosis (DVT) following TKA, THA, or hip fracture surgery. The approval of edoxaban for the primary prevention of VTE after lower limb orthopedic surgery was based on evidence collected during three phase 3 studies evaluating the safety and efficacy of edoxaban compared with enoxaparin for prevention of VTE in Japanese or Taiwanese patients following TKA [ 5], THA [ 6], and hip fracture surgery [ 7]. In these studies, edoxaban demonstrated significantly reduced or comparable rates of VTE and similar rates of bleeding events relative to enoxaparin.
This report presents a post hoc pooled analysis of coagulation biomarkers in the TKA/THA studies as well as pooled results of the primary efficacy (VTE) and safety (bleeding events) endpoints. Coagulation biomarkers include D-dimer, prothrombin fragments 1 + 2 (F 1+2), and soluble fibrin monomer complex (SFMC). D-dimer, which has a high negative predictive value for VTE, is formed upon cleavage of cross-linked fibrin polymers by plasmin [ 810]. F 1+2 is a marker of thrombin generation and represents coagulation activity [ 11]. Fibrin monomers result from cleavage of fibrinogen by thrombin [ 8]. Soluble fibrin in plasma is also a marker of coagulation activity and is seen to increase rapidly during and after hip replacement surgery [ 12]. Assessment of coagulation biomarkers can provide information on the effect of anticoagulants in relation to dose and clinical response.

Methods

Detailed descriptions of the methodology of these trials are available in the primary publications (STARS E-3 [ 5] and STARS J-V [ 6]). The trial designs for patients undergoing TKA (STARS E-3; NCT01181102) or THA (STARS J-V; NCT01181167) were similar. In the randomized, double-blind, double-dummy, multicenter trials, patients received oral edoxaban 30 mg or edoxaban placebo once daily within 6 to 24 h after surgery, and subcutaneous enoxaparin 2000 IU (equivalent to 20 mg) or enoxaparin placebo twice daily within 24 to 36 h after surgery, each for 11 to 14 days. Enoxaparin 20 mg is the usual recommended dose for adults in Japan due to the lower body weight of Japanese patients [ 13]; standard of care is administration of enoxaparin 24 to 36 h postsurgery.
Concomitant use of anticoagulants, antiplatelet agents, thrombolytic agents, or other agents that affect thrombus formation was not allowed from the day of surgery until 24 h after the final dose of study drug, unless treatment of deep vein thrombosis or pulmonary embolism (PE) was required. Mechanical prophylaxis (eg, elastic stockings or intermittent pneumatic compression therapy of the foot sole or lower leg and thigh) was permitted from the day of surgery to venography. Venography of the operated lower limb in the TKA trial STARS E-3 and of both lower limbs in the THA trial STARS J-V was performed within 24 h of the last dose of study drug or within 96 h in exceptional cases such as difficulty establishing an intravenous line.
The studies were performed in accordance with the provisions of the Declaration of Helsinki, Guidelines for Good Clinical Practice, and other related regulations. The protocols were approved by institutional review boards at each study center, and written informed consent was obtained from all patients prior to randomization.

Patients

Men and women 20 to <85 years of age undergoing unilateral TKA or THA (both excluding revision arthroplasty) were included. Presurgical exclusion criteria included risk for bleeding, risk for thromboembolism, previous TKA, weight <40 kg, severe renal impairment (creatinine clearance <30 mL/min) [ 14], evidence of hepatic dysfunction (serum aspartate aminotransferase or serum alanine aminotransferase levels ≥2 times the upper limit of normal or total bilirubin ≥1.5 times the upper limit of normal), previous treatment with edoxaban, and current antithrombotic therapy for another complication. Postsurgical exclusion criteria included abnormal bleeding from the puncture site during spinal anesthesia, need for repeat surgery before the start of study treatment, abnormal or excessive bleeding experienced during surgery, and inability to take oral medication.

Assessments

Thromboembolic events included asymptomatic or symptomatic DVT—confirmed by venography at the end of study treatment—and symptomatic and diagnosed PE. Additional imaging techniques used to confirm suspected DVT or PE included ultrasonography, computerized tomography scanning, pulmonary scintigraphy, or pulmonary arteriography.
Major bleeding was defined as fatal bleeding; clinically overt bleeding accompanied by a decrease in hemoglobin of >2 g/dL or requiring transfusion with >800 mL of blood; retroperitoneal, intracranial, intraocular, or intrathecal bleeding; or bleeding requiring repeat surgery. Clinically relevant nonmajor (CRNM) bleeding was defined as bleeding that did not meet the criteria for major bleeding, but was characterized by hematoma ≥5 cm in diameter, epistaxis or gingival bleeding in the absence of external factors lasting ≥5 min, gastrointestinal bleeding, gross hematuria persistent after 24 h of onset, or any other bleeding deemed clinically significant by the investigator. Minor bleeding was any bleeding event that was not considered a major or CRNM bleeding event. Thromboembolic events were assessed by the blinded Thromboembolic Event Assessment Committee and bleeding events by the Bleeding Event Assessment Committee.
Blood sampling was performed at presurgical evaluation, pretreatment (postsurgery), predose on day 7, predose on completion of treatment, and at a follow-up examination 25 to 35 days after the last dose of study drug. All biomarker assessments for D-dimer, F 1+2, and SFMC were performed and measured at a central laboratory (SRL Inc., Tokyo, Japan). D-dimer was measured by a latex agglutination assay using the LATECLE D-dimer test kit (Kainos Laboratories, Inc., Tokyo, Japan; upper limit of detection, 1.0 μg/mL); data were expressed as D-dimer units. Assessment of F 1+2 was performed via ELISA (Fibinostika, Organon Teknika BV, The Netherlands; normal detection range 69–229 pmol/L) [ 15] and assessment of SFMC was performed via a latex immunoturbidimetric assay (upper limit of detection, 6.1 μg/mL) [ 16].
Treatment compliance was assessed by clinical interview with patients and by remaining drugs collected.

Statistical analysis

The primary efficacy endpoint—the proportion of patients who experienced at least 1 thromboembolic event from the start of treatment to venography—was assessed in the full analysis set of patients, those who received ≥1 dose of study drug and who underwent interpretable venography. Baseline data and safety results were analyzed in the safety set—patients who received ≥1 dose of study drug and had safety data collected after the start of treatment. Biomarker results were analyzed in the pharmacodynamic set—patients who received ≥1 dose of study drug, had no protocol violations, had compliance rates of ≥80%, and had ≥1 biomarker measurement (Fig.  1).
The number of VTE events and number of bleeding events across the 2 trials were added. The Farrington-Manning method [ 17] was used to derive the difference in VTE incidence. The SCORE method [ 18] was used to calculate 95% confidence intervals (CIs) for both VTE and bleeding events. For analysis of coagulation biomarkers, summary statistics were calculated by group and time.
Paired comparisons between groups were performed using chi squared or Wilcoxon rank sum testing with a significance level set to 5%. All statistical tests were conducted as 2-sided tests.

Results

Patients

There were no significant differences in baseline characteristics between the combined treatment groups from the 2 trials (Table  1). Overall, patients were predominantly women (83%) of a mean age of 68 years. The primary disease was most frequently osteoarthritis (88%). A total of 1326 patients were enrolled; this analysis included 657 patients who received edoxaban 30 mg once daily and 650 patients who received enoxaparin 20 mg twice daily. Patient disposition was similar between the 2 trials (Fig.  1).
Table 1
Patient demographics and baseline characteristics
Variable
Edoxaban
30 mg QD
N = 657
Enoxaparin
20 mg BID
N = 650
P value
Female, n (%)
552 (84.0)
527 (81.1)
0.161 a
Age, years, mean (min–max)
68.3 (36–84)
68.1 (24–84)
0.760 b
Body weight, kg, mean (min–max)
58.7 (40–124)
58.8 (40–98)
0.848 b
Creatinine clearance, mL/min, mean (min–max)
82.1 (30.6–242.9)
81.7 (31.0–209.7)
0.804 b
Primary disease, n (%)
 Osteoarthritis
582 (88.6)
563 (86.6)
0.270 c
 Rheumatoid arthritis
42 (6.4)
46 (7.1)
 Other
35 (5.0)
41 (6.3)
BID twice daily, QD once daily
aChi square test
bt test
cWilcoxon test

Primary efficacy endpoint

The composite of asymptomatic DVT and symptomatic DVT or PE occurred in 28 of 554 patients who received edoxaban (5.1%) and 58 of 543 patients who received enoxaparin (10.7%), P <0.001 (Fig.  2). Thromboembolic events were primarily asymptomatic DVT.

Biomarkers

Plasma levels of the coagulation biomarker D-dimer are shown in Fig.  3a and Table  2. Mean D-dimer concentrations substantially increased after surgery but before treatment. After treatment, mean D-dimer levels (standard deviation [SD]) decreased significantly more in the edoxaban-treated than the enoxaparin-treated patients, respectively, both on day 7 (4.4 [2.1] vs 5.5 [2.6] μg/mL) and at the end of treatment (days 11–14) (5.4 [2.5] vs 6.2 [3.1] μg/mL), P <0.0001 for both. Median values and ranges are provided in Additional file 1: Table S1.
Table 2
Mean plasma concentrations of coagulation biomarkers at various time points after total knee or total hip arthroplasty
 
Preoperation
Pretreatment
Day 7 a
End of treatment (days 11–14) a
n
Mean (SD)
n
Mean (SD)
n
Mean (SD)
n
Mean (SD)
D-dimer (μg/mL)
Edoxaban
535
0.73 (0.82)
535
9.42 (12.56)
532
4.43 b (2.08)
528
5.37 b (2.52)
Enoxaparin
527
0.78 (0.96)
527
10.92 (16.23)
480
5.53 (2.56)
472
6.23 (3.12)
F 1+2 (pmol/L)
Edoxaban
535
273.9 (150.6)
535
479.7 (741.8)
532
362.8 b (164.2)
528
292.1 b (167.6)
Enoxaparin
527
277.8 (160.9)
527
633.2 (3234.9)
480
463.3 (185.6)
472
379.6 (174.4)
SFMC (μg/mL)
Edoxaban
535
5.62 (17.86)
535
32.25 (40.47)
532
5.71 b (9.76)
528
6.15 b (10.72)
Enoxaparin
527
4.81 (8.42)
527
34.72 (45.62)
480
6.82 (13.99)
472
7.23 (11.78)
F 1+2 thrombin fragments 1 + 2, SD standard deviation, SFMC soluble fibrin monomer complex
aPredose
b P vs enoxaparin <0.0001 (Wilcoxon test)
Mean F 1+2 concentrations increased after surgery and decreased following treatment with edoxaban or enoxaparin. The observed decrease in F 1+2 following edoxaban treatment was larger relative to the decrease observed with enoxaparin treatment (Fig.  3b and Table  2). The mean F 1+2 concentrations (SD) in edoxaban-treated and enoxaparin-treated patients, respectively, on day 7 of treatment were 363 (164) vs 463 (186) pmol/L and at the end of treatment were 292 (168) vs 380 (174) pmol/L, P <0.0001 for both. Median values and ranges are provided in Additional file 1: Table S1.
Mean SFMC concentrations rose after surgery and showed a larger decrease following edoxaban treatment relative to enoxaparin treatment (Fig.  3c and Table  2). The mean SFMC concentrations (SD) in edoxaban and enoxaparin patients, respectively, on day 7 were 5.7 (9.8) vs 6.8 (14.0) μg/mL and at the end of treatment were 6.2 (10.7) vs 7.2 (11.8), P <0.0001 for both. Median values and ranges are provided in Additional file 1: Table S1.
Assessment of plasma concentrations of biomarkers was performed in patients stratified by the presence or absence of VTE and the presence or absence of major or CRNM bleeding. Values followed a similar trend for patients with and without VTE and for edoxaban and enoxaparin treatment for D-dimer and F 1+2 (Table  3). Values for SFMC were similar between edoxaban and enoxaparin treatments and were numerically elevated for patients with VTE relative to those who did not have VTE. Values for D-dimer, F 1+2, and SFMC followed a similar trend for patients with and without CRNM and for treatment with edoxaban and enoxaparin (Table  4).
Table 3
Mean plasma concentrations of coagulation biomarkers at various time points after total knee or total hip arthroplasty in patients with and without VTE
 
Preoperation
Pretreatment
Day 7 a
End of treatment (days 11–14) a
n
Mean (SD)
n
Mean (SD)
n
Mean (SD)
n
Mean (SD)
Patients without VTE
 D-dimer (μg/mL)
Edoxaban
526
0.73 (0.84)
526
9.33 (12.54)
521
4.40 (2.09)
511
5.35 (2.49)
Enoxaparin
485
0.77 (0.94)
485
10.28 (14.82)
443
5.38 (2.32)
430
6.00 (2.96)
 F 1+2 (pmol/L)
Edoxaban
526
273.6 (150.3)
526
478.6 (748.6)
521
361.5 (164.6)
511
293.5 (169.3)
Enoxaparin
485
273.9 (139.3)
485
614.6 (3357.3)
443
457.9 (183.8)
430
372.6 (166.6)
 SFMC (μg/mL)
Edoxaban
526
5.38 (17.34)
526
31.21 (39.32)
521
5.55 (9.04)
511
6.31 (11.22)
Enoxaparin
485
4.33 (6.04)
485
31.87 (43.53)
443
6.22 (11.68)
430
6.94 (10.80)
Patients with VTE
 D-dimer (μg/mL)
Edoxaban
28
0.75 (0.86)
28
8.40 (9.17)
24
4.56 (1.52)
23
5.46 (2.88)
Enoxaparin
58
0.90 (0.97)
58
16.96 (24.17)
47
7.06 (3.86)
49
8.41 (3.78)
 F 1+2 (pmol/L)
Edoxaban
28
258.4 (117.4)
28
483.3 (220.5)
24
352.9 (128.3)
23
248.7 (86.31)
Enoxaparin
58
309.8 (273.2)
58
824.8 (959.3)
47
531.2 (213.6)
49
444.5 (222.0)
 SFMC (μg/mL)
Edoxaban
28
8.90 (21.23)
28
52.19 (48.89)
24
8.10 (18.70)
23
4.77 (2.38)
Enoxaparin
58
8.36 (18.17)
58
63.67 (56.12)
47
12.31 (26.32)
49
9.85 (17.73)
F 1+2 thrombin fragments 1 + 2, SD standard deviation, SFMC soluble fibrin monomer complex, VTE venous thromboembolism
aPredose
Table 4
Mean plasma concentrations of coagulation biomarkers at various time points after total knee or total hip arthroplasty in patients with and without major or clinically relevant nonmajor bleeding
 
Preoperation
Pretreatment
Day 7 a
End of treatment (days 11–14) a
n
Mean (SD)
n
Mean (SD)
n
Mean (SD)
n
Mean (SD)
Patients without major or CRNM bleeding
 D-dimer (μg/mL)
Edoxaban
627
0.75 (0.99)
627
9.75 (12.95)
597
4.43 (2.07)
578
5.38 (2.49)
Enoxaparin
626
0.78 (0.92)
626
10.72 (15.39)
552
5.47 (2.53)
517
6.15 (3.00)
 F 1+2 (pmol/L)
Edoxaban
627
275.4 (148.0)
627
484.7 (736.0)
597
361.1 (162.2)
578
291.7 (163.2)
Enoxaparin
626
276.4 (153.3)
626
617.3 (2975.3)
552
463.4 (192.4)
517
378.2 (171.4)
 SFMC (μg/mL)
Edoxaban
627
5.72 (17.49)
627
32.69 (40.46)
597
5.66 (9.50)
578
6.30 (11.18)
Enoxaparin
626
4.80 (8.14)
626
34.71 (45.40)
552
6.88 (13.49)
517
7.12 (11.43)
Patients with major or CRNM bleeding
 D-dimer (μg/mL)
Edoxaban
30
0.52 (0.27)
30
8.73 (11.84)
15
4.53 (1.70)
9
6.29 (3.52)
Enoxaparin
24
0.89 (1.29)
24
8.95 (9.28)
14
5.24 (1.86)
10
8.40 (6.20)
 F 1+2 (pmol/L)
Edoxaban
30
264.5 (108.3)
30
440.3 (430.4)
15
371.5 (141.5)
9
325.0 (140.9)
Enoxaparin
24
265.8 (113.4)
24
526.2 (714.4)
14
470.3 (143.3)
10
449.0 (120.6)
 SFMC (μg/mL)
Edoxaban
30
3.41 (1.82)
30
30.28 (44.24)
15
4.03 (1.06)
9
6.42 (3.20)
Enoxaparin
24
5.05 (4.38)
24
26.66 (32.86)
14
4.08 (1.49)
10
7.84 (4.31)
CNRM clinically relevant nonmajor, F 1+2 thrombin fragments 1 + 2, SD standard deviation, SFMC soluble fibrin monomer complex
aPredose

Safety

There were no significant differences in the incidence of bleeding events during the trial between groups treated with edoxaban or enoxaparin (Fig.  4). Combined major and CRNM bleeding events occurred in 4.6% of edoxaban-treated and 3.7% of enoxaparin-treated patients ( P = 0.427). The incidence of adverse events (AEs) was slightly lower in the edoxaban group (66%) than the enoxaparin group (75%). There were no differences in the frequency of serious AEs between the treatment groups [ 5, 6].

Discussion

The risk of VTE increases after knee or hip arthroplasty [ 1, 2]. As shown in this pooled analysis of two phase 3 trials 11 to 14 days after surgery for TKA or THA, the incidence of VTE was significantly lower in patients administered once-daily oral edoxaban 30 mg (5.1%) than in those receiving twice-daily subcutaneous enoxaparin 20 mg (10.7%), P <0.001. Coagulation biomarkers D-dimer, F 1+2, and SFMC each increased immediately after surgery. Over the course of 11 to 14 days, levels of the coagulation biomarkers were significantly lower after treatment with the DOAC edoxaban relative to the LMWH enoxaparin. In contrast, the frequency of bleeding events in the pooled results did not significantly differ.
Doses and timing used in this study are consistent with the Japanese standard of care for enoxaparin. Japanese patients typically have a lower body weight relative to their Western counterparts. Although the dose of enoxaparin used was low (2000 IU, twice daily), this is the recommended dose specific to Japan for prevention of VTE [ 4]. Prophylactic, subcutaneous enoxaparin doses of 40 mg once daily or 30 mg twice daily in males weighing >57 kg are associated with increased enoxaparin exposure and increased bleeding risk. Administration of LMWH 2 to 4 h postoperatively has been associated with higher rates of major bleeding relative to administration at 12 to 48 h postoperatively [ 19]. The Japanese standard of care calls for initiation of enoxaparin 24 to 36 h following surgery.
The results of STARS E-3 (TKA) [ 5] and STARS J-V (THA) [ 6] followed the same pattern as the pooled results reported here, with an incidence of VTE after surgery of 7.4 and 2.4% for edoxaban and 13.9 and 6.9% for enoxaparin in the 2 trials, respectively, and no significant differences in bleeding events. In a phase 2, dose-finding study in Japan, mean levels of D-dimer and F 1+2 increased after TKA and remained above baseline for 11 to 14 days in placebo-treated patients, whereas treatment with edoxaban after surgery significantly reduced levels of the coagulation biomarkers in a dose-dependent manner [ 20]. In a retrospective study of patients undergoing TKA in Japan, patients treated with edoxaban 15 mg once daily showed significant reductions in D-dimer relative to enoxaparin 20 mg twice daily or fondaparinux 1.5 mg once daily over a 2-week period following surgery [ 21].
Edoxaban directly and selectively inhibits FXa, which is part of both the intrinsic and extrinsic coagulation pathways that lead to generation of thrombin and clot formation [ 22, 23]. One molecule of FXa can catalyze the formation of approximately 1000 thrombin molecules [ 23]. In contrast, LMWHs target FXa indirectly and affect multiple targets in the coagulation pathway [ 23]. The direct and selective targeting of FXa by edoxaban may account for the significantly greater reduction in coagulation biomarkers, which translates to reduced rates of VTE.
Limitations of this analysis include that it is post hoc and that it combines data from 2 different studies. However, the studies were very similar in anticoagulant treatment regimens and patient characteristics. In addition, for the coagulation biomarker results, pooling of results was required to obtain sufficient data to perform statistical comparisons between treatments. It also should be noted that edoxaban is approved only in Japan for VTE prophylaxis and is not approved for this indication in Europe or the United States.

Conclusions

In conclusion, the biomarker results for the pooled analysis of the TKA and THA trials may suggest stronger anticoagulant activity with once-daily oral edoxaban 30 mg than twice-daily, subcutaneous enoxaparin 20 mg following lower limb orthopedic surgery, although the initial timing of edoxaban or enoxaparin administration differed. The 2 treatments were associated with similar rates of bleeding events.

Acknowledgements

Daiichi Sankyo, the study sponsor, was involved in the design of the study and the collection and analysis of the data. Medical writing and editorial support was provided by Elizabeth Rosenberg, PhD; and Terri Schochet, PhD; of AlphaBioCom, LLC (King of Prussia, PA).

Funding

This study was sponsored by Daiichi Sankyo Co., Ltd. (Tokyo, Japan).

Availability of data and materials

The datasets generated during and/or analysed during the current study are not publicly available due to concerns regarding preserving the privacy of individual study participants, but are available from the corresponding author upon reasonable request.

Authors’ contributions

YK, TF, SF, TK, KI, and ST were involved in the concept and design of the study, interpretation of the data, critical revising of the manuscript, and provided final approval to submit the manuscript for publication. KA was involved in analysis of the data, critical review of the mansucript, and provided final approval to submit the manuscript for publication.

Competing interests

YK has been a consultant for Daiichi Sankyo and Toyama Chemical. TF has been a consultant for Daiichi Sankyo, Bayer, Astellas, GlaxoSmithKline, Kaken, and Ono Pharmaceutical Company; served on the speakers’ bureau for Daiichi Sankyo; and received royalties from Century Medical and Showa Ikakogyo. SF has been a consultant for Daiichi Sankyo, Astellas, and GlaxoSmithKline. ST has been a consultant for Daiichi Sankyo and GlaxoSmithKline. TK, KI, and KA are employees of Daiichi Sankyo Co., Ltd.

Consent for publication

Not applicable.

Ethics approval and consent to participate

The studies were performed in accordance with the provisions of the Declaration of Helsinki, Guidelines for Good Clinical Practice, and other related regulations. The protocols were approved by institutional review boards at each study center, and written informed consent was obtained from all patients prior to randomization.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://​creativecommons.​org/​licenses/​by/​4.​0/​), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://​creativecommons.​org/​publicdomain/​zero/​1.​0/​) applies to the data made available in this article, unless otherwise stated.
Zusatzmaterial
Literatur
Über diesen Artikel

Weitere Artikel der Ausgabe 1/2016

Thrombosis Journal 1/2016 Zur Ausgabe

Neu im Fachgebiet Innere Medizin

Mail Icon II Newsletter

Bestellen Sie unseren kostenlosen Newsletter Update Innere Medizin und bleiben Sie gut informiert – ganz bequem per eMail.

© Springer Medizin 

Bildnachweise