IJCA-18064; No of Pages 3 International Journal of Cardiology xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
Enterococcus faecalis bacteremia and mitral valve endocarditis under dabigatran for stroke prevention Claudia Stöllberger ⁎,1, Elisabeth Bonner 1, Josef Finsterer 1 Krankenanstalt Rudolfstiftung, Juchgasse 25, A-1030 Wien, Austria
a r t i c l e
i n f o
Article history: Received 23 January 2014 Accepted 13 April 2014 Available online xxxx Keywords: Endocarditis Sepsis Spondylodiscitis Dabigatran Atrial fibrillation
Dabigatran is an oral thrombin inhibitor which has been approved for the prevention of stroke or embolism in atrial fibrillation (AF)patients as an alternative to vitamin-K-antagonists (VKAs), based on the results of the RE-LY trial [1]. Dabigatran has been introduced into clinical practice although drug- and food-interactions are largely unknown and an antidote is not available [2]. It has not been investigated if dabigatran-treated patients are more prone to infections and sepsis than VKA-treated patients. We report the fatal course of a patient with Enterococcus faecalis bacteremia, endocarditis, and renal failure 10 weeks after initiation of dabigatran. A 74-year old Caucasian HIV-negative female was admitted because of increasing weakness and vomiting since several weeks, epigastric pain since one week and diarrhea since two days. She had a history of AF since 30 years, arterial hypertension since 20 years, and osteoporosis and lumbar pain since 10 years. Mitral insufficiency was known since 10 years and she had refused cardiac surgery. Six months prior to the actual admission, she had been hospitalized for more than 4 months because of Staphylococcus aureus bacteremia. Antibiotic therapy with flucloxacillin and fosfomycin was started and changed to fucidine and ciprofloxacin because of severe diarrhea. Spondylodiscitis L5/S1 was suspected from magnetic resonance imaging.
⁎ Corresponding author at: Steingasse 31/18, A-1030 Wien, Austria. Tel.: +43 676 403 11 87; fax: +43 1 71165 2209. E-mail address: [email protected] (C. Stöllberger). 1 This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.
Transthoracic echocardiography showed moderate mitral regurgitation due to a prolapsing posterior leaflet. The course was complicated by acute renal failure, recurrent Klebsiella urinary tract infections, Clostridium difficile enteritis, and heart failure. Since monitoring of VKA therapy was estimated as too cumbersome, dabigatran was started 10 weeks before the actual admission. At hospital-discharge, five weeks before the actual admission, the serum creatinine was 1.1 mg/dl and the creatinine clearance (calculated using the Cockcroft–Gault formula) 39 ml/min. The medication was: pantoprazole 40 mg/d, nebivolol 2.5 mg/d, mirtazapine 15 mg/d, spironolactone 100 mg/d, sertraline 50 mg/d, torasemide 5 mg/d, pancreatin 25,000 IU/d, dabigatran 220 mg/d and amiodarone 200 mg/d. Although laboratory control of renal function after four weeks was recommended, it was not carried out since the patient was too weak to leave her apartment. She was not seen by her general practitioner and her family controlled that she took the prescribed tablets. Clinical examination showed a 160 cm, 55 kg (BMI 21.5) dehydrated female. Blood-pressure was 80/60 mm Hg. A holosystolic murmur over the left ventricular apex was found. The epigastrium was painful to palpation. ECG showed AF with a ventricular rate of 112/min and right bundle branch block. Laboratory findings are listed in Table 1. Because of vomiting, she had skipped the morning-medication on the admission day, thus she had taken the last tablets 24 h prior to admission. Despite intravenous fluids, blood-pressure did not increase and she was transferred to the intensive care unit after 14 h on day 2. Because of melena and hematemesis intravenous pantoprazole 8 mg/h was started. Transthoracic echocardiography showed a normally sized left ventricle with good systolic function. Both mitral leaflets were thickened, the anterior leaflet showed a structure suggestive of vegetation, the posterior leaflet showed a prolapse, and Doppler sonography showed severe mitral regurgitation. Despite intravenous fluids, dopamine and vasopressin, she remained hypotensive, and norepinephrine and dobutamine were added. Continuous citrate-hemodiafiltration was started on day 2 because of anuria and led to a decrease in serum creatinine levels and a slight increase in the coagulation parameters as listed in Table 1. Despite these measures she became confused, serum lactate increased and she was intubated and mechanically ventilated on day 3. In all three blood cultures, taken at admission, grew E. faecalis. Meropenem 2 g every 8 h was started. She developed swelling and suffusions on the right thigh. Her condition deteriorated continuously and she died 65 h after admission. At autopsy macroscopic inspection showed ulceropolypous vegetations of mitral leaflets, bilateral pyelonephritic abscesses, generalized atherosclerosis and blood within the stomach, the duodenum and the
http://dx.doi.org/10.1016/j.ijcard.2014.04.163 0167-5273/© 2014 Elsevier Ireland. Ltd
Please cite this article as: Stöllberger C, et al, Enterococcus faecalis bacteremia and mitral valve endocarditis under dabigatran for stroke prevention, Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.04.163
2
C. Stöllberger et al. / International Journal of Cardiology xxx (2014) xxx–xxx
Table 1 Results of blood tests. Time of blood sampling parameter (reference)
Day 1 17:20
Day 2 09:35
Day 2 17:52
Day 3 05:52
Day 3 11:47
Day 3 17:44
Day 3 22:01
Day 4 07:10
BUN mg/dl (9–20) Creatinine mg/dl (b1.1) Creat. Clear. ml/min (N90)b CRP mg/dl (b0.6) Hemoglobin g/dl (14–17) Thrombocytes/nl (150–450) INR PT % (70–130) c aPTT sec (b33) d TT sec (14–21)e Fibrinogen mg/dl (150–450) Lactate mmol/l (0.5–2.2) pH (7.2–7.41)
64 2.30 22 14.17 13.4 237 3.0 15 88 NMa NMa 3.0 7.28
62 1.97 26 8.65 11.5 191 NMa NM 100 N120 NMa 1.4 7.26
NMa NMa NMa NMa 10.9 186 NMa 15 82 N120 355 1.3 7.41
32 0.95 53 10.18 10.8 188 2.0 24 66 N120 340 2.9 7.34
NMa NMa NMa NMa 10.0 155 1.8 21 73 229 309 9.7 7.22
NMa NMa NMa NMa 10.4 148 1.8 74 74 212 344 6.0 7.3
9 0.56 90 NMa 9.8 149 1.9 16 73 186 302 8.7 7.27
7 0.49 103 8.90 9.2 123 2.4 8 88 N120 249 18.0 7.26
a b c d e
NM = Not measured. Creat. Clear = Creatinine clearance according to the Cockcroft-Gault formula. PT = prothrombin time. aPTT = activated partial thromboplastin time. TT = thrombin time.
coecum but no evidence for any malignancy within the gastrointestinal tract. The bleeding sources were multiple erosions of the gastric mucosa. The spleen was enlarged. No signs of inflammation were detected in the lumbar vertebrae. Candida albicans, Bacteroides fragilis and Enterococcus faecium grew on the mitral valve vegetations, and C. albicans and E. faecium on the swabs from the renal abscesses. Histological investigation of the subcutaneous tissue of the right thigh showed edema and siderophages. Histological investigation of the mitral leaflets showed that the vegetations were attached to sclerosed valves with basal granulation tissue. The following aspects of the disease course should be emphasized: Although serum concentration of dabigatran was not measured, the laboratory findings indicate dabigatran overdose: The activated partial thromboplastin time and thrombin time were prolonged and did not normalize (Table 1). Dabigatran overdose might be due to renal failure as well as co-medication with amiodarone which is known to affect the p-glycoprotein transport system and thus the bioavailability of dabigatran [3,4]. Additionally sepsis due to E. faecalis bacteremia might have contributed to the coagulation abnormality. In case of dabigatran overdose, haemodialysis is recommended to accelerate plasma clearance. That recommendation is supported by data from an open-label study in 6 clinically stable male patients with end-stage renal disease on maintenance haemodialysis, who received 50 mg dabigatran etexilate at the start of a 4-hour dialysis session. In that study, haemodialysis removed 62–68% of the dabigatran concentration [4]. Use of intermittent and continuous renal replacement therapy has been reported in the treatment of dabigatran-associated bleeding cases with mixed results. In our patient, the primary indication for hemofiltration was not reversal of dabigatran-induced bleeding but renal failure with anuria. The case illustrates how rapidly renal function deteriorates due to diuretics, hypovolemia and dehydration: Whereas at the time when dabigatran was started, the serum creatinine was 1.1 mg/dl and the creatinine clearance 39 ml/min, it deteriorated within 10 weeks to a level at which dabigatran would be contraindicated (b30 ml/min). The advantage that no laboratory control is necessary during dabigatrantherapy might turn into a disadvantage under “real life” conditions. Our patient was neither seen by any physician nor did she undergo any laboratory testing. On the contrary, patients treated by VKA are at least seen by their physicians when they come for INR measurement. Since lesions like decubital ulcers, skin lesions or indwelling device were absent, the most probable entry site for the E. faecalis bacteremia might be either the previous spondylodiscitis or the urinary tract. Whether endocarditis developed as a complication of spondylodiscitis or only terminally is uncertain, however, histological findings were
indicative for a long-lasting inflammatory process on the mitral leaflets. Contamination during autopsy was probably the cause for the growth of the microorganisms detected at post-mortem swabs. Thrombin plays a role in infection, sepsis, immune response, angiogenesis, tumor growth and endothelial function [5]. Thrombin modulates inflammation and coagulation in endotoxin-mediated shock and Pseudomonas aeruginosa sepsis in animal experiments [6]. Whereas there are indications from animal experiments that dabigatran might prevent S. aureus sepsis, the situation with Enterococci appears to be different [7,8]. Unfortunately, there are no data about the effects of long-term thrombin inhibition by dabigatran on the immune response in humans. Furthermore, dabigatran is not only a thrombininhibitor but also an inhibitor of the detoxification oxidoreductase ribosyldihydronicotinamide dehydrogenase (NQO2) [9]. NQO2 plays a role in the regulation of immune response and autoimmunity [10]. Thus it remains speculative whether dabigatran might have contributed to the fatal outcome of bacteremia in our patient. Since dabigatran is a medication that should be given lifelong to atrial fibrillation patients at risk for thromboembolism, an increase in the knowledge of this potential side effect is relevant. As a first step we suggest to publish the occurrence and type of infections in participants of the RE-LY trial and to compare the incidence between dabigatran- and warfarintreated patients. Dabigatran-treated patients deserve diligent monitoring of renal function. In patients with questionable adherence, efforts are needed to educate the patient and their caregivers about the importance of monitoring renal function under a therapy with dabigatran. There is a need to investigate the influence of long-term thrombin-inhibition on rate and severity of infections.
References [1] Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139–51. [2] Stöllberger C, Finsterer J. Contra: “new oral anticoagulants should not be used as 1st choice for secondary stroke prevention in atrial fibrillation”. Thromb Haemost 2013;110:496–500. [3] Blech S, Ebner T, Ludwig-Schwellinger E, Stangier J, Roth W. The metabolism and disposition of the oral direct thrombin inhibitor, dabigatran, in humans. Drug Metab Dispos 2008;36:386–99. [4] Stangier J, Rathgen K, Stähle H, Mazur D. Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: an open-label, parallel-group, single-centre study. Clin Pharmacokinet 2010;49:259–68. [5] Davie EW, Kulman JD. An overview of the structure and function of thrombin. Semin Thromb Hemost 2006;32(Suppl. 1):3–15. [6] Kalle M, Papareddy P, Kasetty G, et al. Host defense peptides of thrombin modulate inflammation and coagulation in endotoxin-mediated shock and Pseudomonas aeruginosa sepsis. PLoS One 2012;7:e51313.
Please cite this article as: Stöllberger C, et al, Enterococcus faecalis bacteremia and mitral valve endocarditis under dabigatran for stroke prevention, Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.04.163
C. Stöllberger et al. / International Journal of Cardiology xxx (2014) xxx–xxx [7] McAdow M, Kim HK, Dedent AC, Hendrickx AP, Schneewind O, Missiakas DM. Preventing Staphylococcus aureus sepsis through the inhibition of its agglutination in blood. PLoS Pathog 2011;7:e1002307. [8] Ravindranath TM, Goto M, Iqbal O, et al. Plasma thrombin activatable fibrinolysis inhibitor and tissue factor pathway inhibitor changes following sepsis. Clin Appl Thromb Hemost 2007;13:362–8.
3
[9] Michaelis S, Marais A, Schrey AK, et al. Dabigatran and dabigatran ethyl ester: potent inhibitors of ribosyldihydronicotinamide dehydrogenase (NQO2). J Med Chem 2012;55:3934–44. [10] Iskander K, Li J, Han S, Zheng B, Jaiswal AK. NQO1 and NQO2 regulation of humoral immunity and autoimmunity. J Biol Chem 2006;281:30917–24.
Please cite this article as: Stöllberger C, et al, Enterococcus faecalis bacteremia and mitral valve endocarditis under dabigatran for stroke prevention, Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.04.163
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
Enterococcus faecalis bacteremia and mitral valve endocarditis under dabigatran for stroke prevention Claudia Stöllberger ⁎,1, Elisabeth Bonner 1, Josef Finsterer 1 Krankenanstalt Rudolfstiftung, Juchgasse 25, A-1030 Wien, Austria
a r t i c l e
i n f o
Article history: Received 23 January 2014 Accepted 13 April 2014 Available online xxxx Keywords: Endocarditis Sepsis Spondylodiscitis Dabigatran Atrial fibrillation
Dabigatran is an oral thrombin inhibitor which has been approved for the prevention of stroke or embolism in atrial fibrillation (AF)patients as an alternative to vitamin-K-antagonists (VKAs), based on the results of the RE-LY trial [1]. Dabigatran has been introduced into clinical practice although drug- and food-interactions are largely unknown and an antidote is not available [2]. It has not been investigated if dabigatran-treated patients are more prone to infections and sepsis than VKA-treated patients. We report the fatal course of a patient with Enterococcus faecalis bacteremia, endocarditis, and renal failure 10 weeks after initiation of dabigatran. A 74-year old Caucasian HIV-negative female was admitted because of increasing weakness and vomiting since several weeks, epigastric pain since one week and diarrhea since two days. She had a history of AF since 30 years, arterial hypertension since 20 years, and osteoporosis and lumbar pain since 10 years. Mitral insufficiency was known since 10 years and she had refused cardiac surgery. Six months prior to the actual admission, she had been hospitalized for more than 4 months because of Staphylococcus aureus bacteremia. Antibiotic therapy with flucloxacillin and fosfomycin was started and changed to fucidine and ciprofloxacin because of severe diarrhea. Spondylodiscitis L5/S1 was suspected from magnetic resonance imaging.
⁎ Corresponding author at: Steingasse 31/18, A-1030 Wien, Austria. Tel.: +43 676 403 11 87; fax: +43 1 71165 2209. E-mail address: [email protected] (C. Stöllberger). 1 This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.
Transthoracic echocardiography showed moderate mitral regurgitation due to a prolapsing posterior leaflet. The course was complicated by acute renal failure, recurrent Klebsiella urinary tract infections, Clostridium difficile enteritis, and heart failure. Since monitoring of VKA therapy was estimated as too cumbersome, dabigatran was started 10 weeks before the actual admission. At hospital-discharge, five weeks before the actual admission, the serum creatinine was 1.1 mg/dl and the creatinine clearance (calculated using the Cockcroft–Gault formula) 39 ml/min. The medication was: pantoprazole 40 mg/d, nebivolol 2.5 mg/d, mirtazapine 15 mg/d, spironolactone 100 mg/d, sertraline 50 mg/d, torasemide 5 mg/d, pancreatin 25,000 IU/d, dabigatran 220 mg/d and amiodarone 200 mg/d. Although laboratory control of renal function after four weeks was recommended, it was not carried out since the patient was too weak to leave her apartment. She was not seen by her general practitioner and her family controlled that she took the prescribed tablets. Clinical examination showed a 160 cm, 55 kg (BMI 21.5) dehydrated female. Blood-pressure was 80/60 mm Hg. A holosystolic murmur over the left ventricular apex was found. The epigastrium was painful to palpation. ECG showed AF with a ventricular rate of 112/min and right bundle branch block. Laboratory findings are listed in Table 1. Because of vomiting, she had skipped the morning-medication on the admission day, thus she had taken the last tablets 24 h prior to admission. Despite intravenous fluids, blood-pressure did not increase and she was transferred to the intensive care unit after 14 h on day 2. Because of melena and hematemesis intravenous pantoprazole 8 mg/h was started. Transthoracic echocardiography showed a normally sized left ventricle with good systolic function. Both mitral leaflets were thickened, the anterior leaflet showed a structure suggestive of vegetation, the posterior leaflet showed a prolapse, and Doppler sonography showed severe mitral regurgitation. Despite intravenous fluids, dopamine and vasopressin, she remained hypotensive, and norepinephrine and dobutamine were added. Continuous citrate-hemodiafiltration was started on day 2 because of anuria and led to a decrease in serum creatinine levels and a slight increase in the coagulation parameters as listed in Table 1. Despite these measures she became confused, serum lactate increased and she was intubated and mechanically ventilated on day 3. In all three blood cultures, taken at admission, grew E. faecalis. Meropenem 2 g every 8 h was started. She developed swelling and suffusions on the right thigh. Her condition deteriorated continuously and she died 65 h after admission. At autopsy macroscopic inspection showed ulceropolypous vegetations of mitral leaflets, bilateral pyelonephritic abscesses, generalized atherosclerosis and blood within the stomach, the duodenum and the
http://dx.doi.org/10.1016/j.ijcard.2014.04.163 0167-5273/© 2014 Elsevier Ireland. Ltd
Please cite this article as: Stöllberger C, et al, Enterococcus faecalis bacteremia and mitral valve endocarditis under dabigatran for stroke prevention, Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.04.163
2
C. Stöllberger et al. / International Journal of Cardiology xxx (2014) xxx–xxx
Table 1 Results of blood tests. Time of blood sampling parameter (reference)
Day 1 17:20
Day 2 09:35
Day 2 17:52
Day 3 05:52
Day 3 11:47
Day 3 17:44
Day 3 22:01
Day 4 07:10
BUN mg/dl (9–20) Creatinine mg/dl (b1.1) Creat. Clear. ml/min (N90)b CRP mg/dl (b0.6) Hemoglobin g/dl (14–17) Thrombocytes/nl (150–450) INR PT % (70–130) c aPTT sec (b33) d TT sec (14–21)e Fibrinogen mg/dl (150–450) Lactate mmol/l (0.5–2.2) pH (7.2–7.41)
64 2.30 22 14.17 13.4 237 3.0 15 88 NMa NMa 3.0 7.28
62 1.97 26 8.65 11.5 191 NMa NM 100 N120 NMa 1.4 7.26
NMa NMa NMa NMa 10.9 186 NMa 15 82 N120 355 1.3 7.41
32 0.95 53 10.18 10.8 188 2.0 24 66 N120 340 2.9 7.34
NMa NMa NMa NMa 10.0 155 1.8 21 73 229 309 9.7 7.22
NMa NMa NMa NMa 10.4 148 1.8 74 74 212 344 6.0 7.3
9 0.56 90 NMa 9.8 149 1.9 16 73 186 302 8.7 7.27
7 0.49 103 8.90 9.2 123 2.4 8 88 N120 249 18.0 7.26
a b c d e
NM = Not measured. Creat. Clear = Creatinine clearance according to the Cockcroft-Gault formula. PT = prothrombin time. aPTT = activated partial thromboplastin time. TT = thrombin time.
coecum but no evidence for any malignancy within the gastrointestinal tract. The bleeding sources were multiple erosions of the gastric mucosa. The spleen was enlarged. No signs of inflammation were detected in the lumbar vertebrae. Candida albicans, Bacteroides fragilis and Enterococcus faecium grew on the mitral valve vegetations, and C. albicans and E. faecium on the swabs from the renal abscesses. Histological investigation of the subcutaneous tissue of the right thigh showed edema and siderophages. Histological investigation of the mitral leaflets showed that the vegetations were attached to sclerosed valves with basal granulation tissue. The following aspects of the disease course should be emphasized: Although serum concentration of dabigatran was not measured, the laboratory findings indicate dabigatran overdose: The activated partial thromboplastin time and thrombin time were prolonged and did not normalize (Table 1). Dabigatran overdose might be due to renal failure as well as co-medication with amiodarone which is known to affect the p-glycoprotein transport system and thus the bioavailability of dabigatran [3,4]. Additionally sepsis due to E. faecalis bacteremia might have contributed to the coagulation abnormality. In case of dabigatran overdose, haemodialysis is recommended to accelerate plasma clearance. That recommendation is supported by data from an open-label study in 6 clinically stable male patients with end-stage renal disease on maintenance haemodialysis, who received 50 mg dabigatran etexilate at the start of a 4-hour dialysis session. In that study, haemodialysis removed 62–68% of the dabigatran concentration [4]. Use of intermittent and continuous renal replacement therapy has been reported in the treatment of dabigatran-associated bleeding cases with mixed results. In our patient, the primary indication for hemofiltration was not reversal of dabigatran-induced bleeding but renal failure with anuria. The case illustrates how rapidly renal function deteriorates due to diuretics, hypovolemia and dehydration: Whereas at the time when dabigatran was started, the serum creatinine was 1.1 mg/dl and the creatinine clearance 39 ml/min, it deteriorated within 10 weeks to a level at which dabigatran would be contraindicated (b30 ml/min). The advantage that no laboratory control is necessary during dabigatrantherapy might turn into a disadvantage under “real life” conditions. Our patient was neither seen by any physician nor did she undergo any laboratory testing. On the contrary, patients treated by VKA are at least seen by their physicians when they come for INR measurement. Since lesions like decubital ulcers, skin lesions or indwelling device were absent, the most probable entry site for the E. faecalis bacteremia might be either the previous spondylodiscitis or the urinary tract. Whether endocarditis developed as a complication of spondylodiscitis or only terminally is uncertain, however, histological findings were
indicative for a long-lasting inflammatory process on the mitral leaflets. Contamination during autopsy was probably the cause for the growth of the microorganisms detected at post-mortem swabs. Thrombin plays a role in infection, sepsis, immune response, angiogenesis, tumor growth and endothelial function [5]. Thrombin modulates inflammation and coagulation in endotoxin-mediated shock and Pseudomonas aeruginosa sepsis in animal experiments [6]. Whereas there are indications from animal experiments that dabigatran might prevent S. aureus sepsis, the situation with Enterococci appears to be different [7,8]. Unfortunately, there are no data about the effects of long-term thrombin inhibition by dabigatran on the immune response in humans. Furthermore, dabigatran is not only a thrombininhibitor but also an inhibitor of the detoxification oxidoreductase ribosyldihydronicotinamide dehydrogenase (NQO2) [9]. NQO2 plays a role in the regulation of immune response and autoimmunity [10]. Thus it remains speculative whether dabigatran might have contributed to the fatal outcome of bacteremia in our patient. Since dabigatran is a medication that should be given lifelong to atrial fibrillation patients at risk for thromboembolism, an increase in the knowledge of this potential side effect is relevant. As a first step we suggest to publish the occurrence and type of infections in participants of the RE-LY trial and to compare the incidence between dabigatran- and warfarintreated patients. Dabigatran-treated patients deserve diligent monitoring of renal function. In patients with questionable adherence, efforts are needed to educate the patient and their caregivers about the importance of monitoring renal function under a therapy with dabigatran. There is a need to investigate the influence of long-term thrombin-inhibition on rate and severity of infections.
References [1] Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139–51. [2] Stöllberger C, Finsterer J. Contra: “new oral anticoagulants should not be used as 1st choice for secondary stroke prevention in atrial fibrillation”. Thromb Haemost 2013;110:496–500. [3] Blech S, Ebner T, Ludwig-Schwellinger E, Stangier J, Roth W. The metabolism and disposition of the oral direct thrombin inhibitor, dabigatran, in humans. Drug Metab Dispos 2008;36:386–99. [4] Stangier J, Rathgen K, Stähle H, Mazur D. Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: an open-label, parallel-group, single-centre study. Clin Pharmacokinet 2010;49:259–68. [5] Davie EW, Kulman JD. An overview of the structure and function of thrombin. Semin Thromb Hemost 2006;32(Suppl. 1):3–15. [6] Kalle M, Papareddy P, Kasetty G, et al. Host defense peptides of thrombin modulate inflammation and coagulation in endotoxin-mediated shock and Pseudomonas aeruginosa sepsis. PLoS One 2012;7:e51313.
Please cite this article as: Stöllberger C, et al, Enterococcus faecalis bacteremia and mitral valve endocarditis under dabigatran for stroke prevention, Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.04.163
C. Stöllberger et al. / International Journal of Cardiology xxx (2014) xxx–xxx [7] McAdow M, Kim HK, Dedent AC, Hendrickx AP, Schneewind O, Missiakas DM. Preventing Staphylococcus aureus sepsis through the inhibition of its agglutination in blood. PLoS Pathog 2011;7:e1002307. [8] Ravindranath TM, Goto M, Iqbal O, et al. Plasma thrombin activatable fibrinolysis inhibitor and tissue factor pathway inhibitor changes following sepsis. Clin Appl Thromb Hemost 2007;13:362–8.
3
[9] Michaelis S, Marais A, Schrey AK, et al. Dabigatran and dabigatran ethyl ester: potent inhibitors of ribosyldihydronicotinamide dehydrogenase (NQO2). J Med Chem 2012;55:3934–44. [10] Iskander K, Li J, Han S, Zheng B, Jaiswal AK. NQO1 and NQO2 regulation of humoral immunity and autoimmunity. J Biol Chem 2006;281:30917–24.
Please cite this article as: Stöllberger C, et al, Enterococcus faecalis bacteremia and mitral valve endocarditis under dabigatran for stroke prevention, Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.04.163
