International Journal of Cardiology 184 (2015) 769–771
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
Gemella morbillorum tricuspid valve endocarditis resulting in septic pulmonary emboli in a patient with intracranial hemorrhage Makrides Constantinos a,⁎, Symeonides Marios b a b
Limassol Cardiological Centre, Cyprus Limassol Internal Medicine Centre, Cyprus
a r t i c l e
i n f o
Article history: Received 13 January 2015 Accepted 24 February 2015 Available online 26 February 2015 Keywords: Endocarditis Intracerebral hemorrhage Tricuspid valve Septic emboli Pulmonary embolism
Gemella morbillorum is a catalase-negative anaerobic organism, that is a part of the normal flora of the oropharynx, genitourinary tract and gastrointestinal tract [1]. G. morbillorum causes a diverse range of infections, including brain abscesses, meningitis [2,3], arthritis [4], and endocarditis [1,5–14]. Native valves have been reported to be more commonly affected as compared to prosthetic valves while mitral and aortic valves have been affected in an almost equal number, sometimes even simultaneously. The tricuspid valve is rarely involved. We report a case of an 80 year old lady, with a history of aortic valve replacement (biological prosthesis 9 months before presentation), hypertension and diabetes mellitus, that was transferred to our center after she was found confused on the ground. The patient was reported to be experiencing fever and sharp on and off chest pain 1–2 weeks before admission. On examination the patient was confused and febrile with a temperature of 39 °C. Her heart rate was 110 bpm (sinus) while her blood pressure was 120/80 mm Hg. She had a grade II–III crescendo–decrescendo murmur on the aortic region and a grade II holosystolic murmur on the lower left sternal border. Auscultation of the lungs revealed basal rales. Her oxygen saturation while breathing room air was 90% while examination of the extremities showed no palpable cords or calf tenderness. ⁎ Corresponding author. E-mail address: [email protected] (M. Constantinos).
http://dx.doi.org/10.1016/j.ijcard.2015.02.094 0167-5273/© 2015 Elsevier Ireland Ltd. All rights reserved.
While waiting for the laboratory tests — INR levels where promptly asked as the patient was under treatment with a combination of oral anticoagulants and aspirin, an immediate CT scan of the brain was performed which revealed a 4.5 cm left parietal intracerebral hematoma with significant mass effect. Her INR levels were increased (4.2) and according to guidelines and expert opinion on the management of warfarin-associated intracerebral hemorrhage [16–22], there was immediate cessation of all anticoagulant and antiplatelet therapy and infusion of fresh frozen plasma and vitamin K was initiated. Further laboratory tests revealed leukocytosis with left shift and a significantly increased level of C-reactive protein. A transthoracic echocardiogram disclosed a highly mobile, oval shaped hyperechoic mass which measured 1.3 cm by 1.5 cm and was attached to the septal tricuspid leaflet consistent with a vegetation (Figs. 1, 2). There was no evidence of a valve ring abscess, leaflet perforation or fistula formation. On transesophageal echocardiography no other valve abnormality was demonstrated, while the biological aortic valve prosthesis was normally functioning with no evidence of vegetation. Contrast material-enhanced pulmonary CT arteriography revealed multifocal low attenuation emboli in the subsegmental left pulmonary artery as well as diffuse patchy infiltrates and multiple nodules more prominent in the lower lobes thus making the diagnosis of septic pulmonary embolism secondary to tricuspid valve endocarditis the most probable one. Three sets of blood cultures (each set contained one aerobic and anaerobic vials) were taken and empiric antibiotic therapy was initiated. On the third day of admission, all cultures grew alpha-hemolytic, catalase-negative Gram positive to Gram variable cocci arranged in clusters. G. morbillorum was subsequently identified using an API 20 STREP system (Bio Merieux) along with successful sub-culturing. Susceptibility testing of the organism was done using the disc diffusion method; the organism showed pan-sensitivity. Following the results of the susceptibility testing, initial antibiotic therapy was replaced with ceftriaxone for 6 weeks and gentamycin for 2 weeks. The patient responded well to this treatment regimen. Our patient met the modified Duke's criteria for a definite diagnosis of infective endocarditis [15]. The major criterion included endocardial involvement documented by positive echocardiographic evidence
770
M. Constantinos, S. Marios / International Journal of Cardiology 184 (2015) 769–771
Fig. 1. A highly mobile, oval shaped hyper echoic mass, attached to the septal leaflet of the tricuspid leaflet consistent with a vegetation.
of vegetations. The minor criteria were met and included fever (temperature N 38 °C), vascular phenomena (pulmonary septic emboli), and a blood culture growing persistently an organism that does not meet major criterion (G. morbillorum). Predisposing factors for G. morbillorum endocarditis include poor dental hygiene, dental manipulation, gastrointestinal procedures, inflammatory bowel disease and colon malignancies [1,14]. Steroid therapy, diabetes mellitus and hepatorenal dysfunction will also predispose to infective endocarditis with this organism. Also other intracardiac lesions, such as hypertrophic cardiomyopathy [8] and cardiac myxoma [9], can be the underlying condition for endocarditis as well as valvular lesions, like congenitally bicuspid valves. The tricuspid valve has been affected in a case of drug abuse [10], while prosthetic valves [5,11] and vascular prostheses [12] can also be affected. Almost all the cases reported with endocarditis and endovascular infection caused by G. morbillorum have been bacteriologically cured by antibiotic therapy, usually a combination of penicillin and aminoglycoside. For the penicillin-resistant or penicillin-allergic patient,
monotherapy or a combination of other antibiotics, such as vancomycin [12] or erythromycin plus rifampicin has been effective. However, cerebral mycotic aneurysm [13] or refractory cardiac failure [14] has been reported to occur. In this case, intracerebral hemorrhage could not be attributed to cerebral mycotic aneurysm, as transesophageal echocardiography revealed no right to left shunt, and no left cardiac valve involvement. Since the patient responded well to the medical treatment, as evidenced by reduced vegetation size on echocardiography and improvement in symptomatology, there was no indication for surgical management. Relative contraindication for surgical treatment was also a risk for the patient taking into consideration brain hemorrhage in addition to other risk factors. In our patient, the definitive source of infection for the organism was not found. Examination of the oropharyngeal mucosa did not show any lesions that could have acted as portals of entry for the organism. Nevertheless we should take into account as a possible etiological association the aortic valve replacement surgery performed 9 months before presentation. ICH is the most common neurological complication of OACs in the elderly [23,24]. The combination of OACs with antiplatelet therapy has recently received considerable attention [23,24]. Aspirin appears to double the risk for ICH, regardless of the dose. Predictors of anticoagulant-related intracerebral hematoma are advanced patient age, prior ischemic stroke, hypertension, and intensity of anticoagulation. Conflict of interest The authors report no relationships that could be construed as a conflict of interest. References
Fig. 2. The vegetation is classified as large, measuring 13x15 mm.
[1] R.M. Zakir, A. Al-Dehneh, L. Dabu, R. Kapila, M. Saric, Mitral bioprosthetic valve endocarditis caused by an unusual microorganism, Gemella morbillorum, in an intravenous drug user, J. Clin. Microbiol. 42 (2004) 4893–4896. [2] M.C. Liberto, G. Matera, R. Puccio, et al., An unusual case of brain abscess by Gemella morbillorum, Jpn. J. Infect. Dis. 59 (2006) 126–128.
M. Constantinos, S. Marios / International Journal of Cardiology 184 (2015) 769–771 [3] A. Lopes, R. Providencia, R.P. Pais, M.J. Frade, F. Chaddad Neto, E. Oliveira, Cerebellar abscess by Gemella morbillorum in a patient with inter-atrial communication, Arq. Neuropsiquiatr. 65 (2007) 1022–1025. [4] Y. Omran, C.A. Wood, Endovascular infection and septic arthritis caused by Gemella morbillorum, Diagn. Microbiol. Infect. Dis. 16 (1993) 131–134. [5] G. Al-Hujailan, P. Lagac -Wiens, Mechanical valve endocarditis caused by Gemella morbillorum, J. Med. Microbiol. 56 (2007) 1689–1691. [6] M. Zheng, O.T. Ng, B.W. Teo, Aortic and mitral valve endocarditis caused by Gemella morbillorum in a haemodialysis patient, Singap. Med. J. 49 (2008) e385–e387. [7] E. Farmaki, E. Roilides, E. Darilis, M. Tsivitanidou, C. Panteliadis, D. Sofianou, Gemella morbillorum endocarditis in a child, Pediatr. Infect. Dis. J. 19 (2000) 751–753. [8] J.R. Kerr, C.H. Webb, J.G. McGimpsey, N.P.S. Campbell, Infective endocarditis due to Gemella morbillorum complicating hypertrophic obstructive cardiomyopathy, Ulster Med. J. 63 (1994) 108–110. [9] T.-D. Wang, S.-C. Chang, I.-P. Chiang, K.-T. Luh, Y.-T. Lee, Infected left atrial myxoma caused by Gemella morbillorum, Scand. J. Infect. Dis. 28 (1996) 633–634. [10] E. Bell, A.C. McCartney, Gemella morbillorum endocarditis in an intravenous drug abuser, J. Infect. 25 (1992) 110–112 (9. Kerr JR, Webb CH, McGimpsey JG, Campbell NPS: Infective). [11] J. Holland, R. Wilson, N. Cumpston, Gemella morbillorum prosthetic valve endocarditis, N. Z. Med. J 27 (1996) 367. [12] M.J. Martin, D.A. Wright, A.R.R. Jones, A case of Gemella morbillorum endocarditis, Postgrad. Med. J. 71 (1995) 188. [13] M. Calopa, F. Rubio, M. Aguilar, J. Peres, Giant basilar aneurysm in the course of subacute bacterial endocarditis, Stroke 21 (1990) 1625–1627. [14] M. Lopez-Dupla, C. Creus, O. Navarro, X. Raga, Association of Gemella morbillorum endocarditis with adenomatous polyps and carcinoma of the colon: case report and review, Clin. Infect. Dis. 22 (1996) 379–380.
771
[15] J.S. Li, D.J. Sexton, N. Mick, R. Nettles, V.G. Fowler Jr., T. Ryan, T. Bashore, G.R. Corey, Proposed modifications to the Duke criteria for the diagnosis of infective endocarditis, Clin. Infect. Dis. 30 (2000) 633–638. [16] L.T. Goodnough, A. Shander, How I treat warfarin-associated coagulopathy in patients with intracerebral hemorrhage, Blood 117 (23) (2011) 6091. [17] L.B. Morgenstern, J.C. Hemphill III, C. Anderson, K. Becker, J.P. Broderick, E.S. Connolly Jr., S.M. Greenberg, J.N. Huang, R.L. MacDonald, S.R. Messé, P.H. Mitchell, M. Selim, R.J. Tamargo, Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association, Am. Heart Assoc. Stroke Counc. Counc. Cardiovasc. Nurs. Stroke 41 (9) (2010) 2108. [18] J.N. Goldstein, J. Rosand, L.H. Schwamm, Warfarin reversal in anticoagulantassociated intracerebral hemorrhage, Neurocrit. Care. 9 (2) (2008) 277. [19] V. Aiyagari, F.D. Testai, Correction of coagulopathy in warfarin associated cerebral hemorrhage, Curr. Opin. Crit. Care 15 (2) (2009) 87. [20] Bleeding during antithrombotic therapy in atrial fibrillation. Stroke Prevention in Atrial Fibrillation Investigators, Arch. Intern. Med. 156 (1996) 409–416. [21] C.S. Landefeld, L. Goldman, Major bleeding in outpatients treated with warfarin: incidence and prediction by factors known at the start of outpatient therapy, Am. J. Med. 87 (1989) 144–152. [22] K. Fredricksson, B. Norrving, L.G. Stromblad, Emergency reversal of anticoagulation after intracerebral hemorrhage, Stroke 23 (1992) 972–977. [23] A.G.G. Turpie, M. Gent, A. Laupacis, Y. Latour, J. Gunstensen, F. Basile, M. Klimek, J. Hirsh, A comparison of aspirin with placebo in patients treated with warfarin and heart valve replacement, N. Engl. J. Med. 329 (1993) 524–529. [24] S.G. Goodman, A. Langer, S.S. Durica, G.E. Raskob, P.C. Comp, R.J. Gray, J.H. Hall, P. Kelley, T.A. Hua, R.J. Lee, V. Fuster, for the Coumadin Aspirin Reinfarction Pilot Study Group, Safety and anticoagulation effect of a low-dose combination of warfarin and aspirin in clinically stable coronary artery disease, Am. J. Cardiol. 74 (1994) 657–661.
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
Gemella morbillorum tricuspid valve endocarditis resulting in septic pulmonary emboli in a patient with intracranial hemorrhage Makrides Constantinos a,⁎, Symeonides Marios b a b
Limassol Cardiological Centre, Cyprus Limassol Internal Medicine Centre, Cyprus
a r t i c l e
i n f o
Article history: Received 13 January 2015 Accepted 24 February 2015 Available online 26 February 2015 Keywords: Endocarditis Intracerebral hemorrhage Tricuspid valve Septic emboli Pulmonary embolism
Gemella morbillorum is a catalase-negative anaerobic organism, that is a part of the normal flora of the oropharynx, genitourinary tract and gastrointestinal tract [1]. G. morbillorum causes a diverse range of infections, including brain abscesses, meningitis [2,3], arthritis [4], and endocarditis [1,5–14]. Native valves have been reported to be more commonly affected as compared to prosthetic valves while mitral and aortic valves have been affected in an almost equal number, sometimes even simultaneously. The tricuspid valve is rarely involved. We report a case of an 80 year old lady, with a history of aortic valve replacement (biological prosthesis 9 months before presentation), hypertension and diabetes mellitus, that was transferred to our center after she was found confused on the ground. The patient was reported to be experiencing fever and sharp on and off chest pain 1–2 weeks before admission. On examination the patient was confused and febrile with a temperature of 39 °C. Her heart rate was 110 bpm (sinus) while her blood pressure was 120/80 mm Hg. She had a grade II–III crescendo–decrescendo murmur on the aortic region and a grade II holosystolic murmur on the lower left sternal border. Auscultation of the lungs revealed basal rales. Her oxygen saturation while breathing room air was 90% while examination of the extremities showed no palpable cords or calf tenderness. ⁎ Corresponding author. E-mail address: [email protected] (M. Constantinos).
http://dx.doi.org/10.1016/j.ijcard.2015.02.094 0167-5273/© 2015 Elsevier Ireland Ltd. All rights reserved.
While waiting for the laboratory tests — INR levels where promptly asked as the patient was under treatment with a combination of oral anticoagulants and aspirin, an immediate CT scan of the brain was performed which revealed a 4.5 cm left parietal intracerebral hematoma with significant mass effect. Her INR levels were increased (4.2) and according to guidelines and expert opinion on the management of warfarin-associated intracerebral hemorrhage [16–22], there was immediate cessation of all anticoagulant and antiplatelet therapy and infusion of fresh frozen plasma and vitamin K was initiated. Further laboratory tests revealed leukocytosis with left shift and a significantly increased level of C-reactive protein. A transthoracic echocardiogram disclosed a highly mobile, oval shaped hyperechoic mass which measured 1.3 cm by 1.5 cm and was attached to the septal tricuspid leaflet consistent with a vegetation (Figs. 1, 2). There was no evidence of a valve ring abscess, leaflet perforation or fistula formation. On transesophageal echocardiography no other valve abnormality was demonstrated, while the biological aortic valve prosthesis was normally functioning with no evidence of vegetation. Contrast material-enhanced pulmonary CT arteriography revealed multifocal low attenuation emboli in the subsegmental left pulmonary artery as well as diffuse patchy infiltrates and multiple nodules more prominent in the lower lobes thus making the diagnosis of septic pulmonary embolism secondary to tricuspid valve endocarditis the most probable one. Three sets of blood cultures (each set contained one aerobic and anaerobic vials) were taken and empiric antibiotic therapy was initiated. On the third day of admission, all cultures grew alpha-hemolytic, catalase-negative Gram positive to Gram variable cocci arranged in clusters. G. morbillorum was subsequently identified using an API 20 STREP system (Bio Merieux) along with successful sub-culturing. Susceptibility testing of the organism was done using the disc diffusion method; the organism showed pan-sensitivity. Following the results of the susceptibility testing, initial antibiotic therapy was replaced with ceftriaxone for 6 weeks and gentamycin for 2 weeks. The patient responded well to this treatment regimen. Our patient met the modified Duke's criteria for a definite diagnosis of infective endocarditis [15]. The major criterion included endocardial involvement documented by positive echocardiographic evidence
770
M. Constantinos, S. Marios / International Journal of Cardiology 184 (2015) 769–771
Fig. 1. A highly mobile, oval shaped hyper echoic mass, attached to the septal leaflet of the tricuspid leaflet consistent with a vegetation.
of vegetations. The minor criteria were met and included fever (temperature N 38 °C), vascular phenomena (pulmonary septic emboli), and a blood culture growing persistently an organism that does not meet major criterion (G. morbillorum). Predisposing factors for G. morbillorum endocarditis include poor dental hygiene, dental manipulation, gastrointestinal procedures, inflammatory bowel disease and colon malignancies [1,14]. Steroid therapy, diabetes mellitus and hepatorenal dysfunction will also predispose to infective endocarditis with this organism. Also other intracardiac lesions, such as hypertrophic cardiomyopathy [8] and cardiac myxoma [9], can be the underlying condition for endocarditis as well as valvular lesions, like congenitally bicuspid valves. The tricuspid valve has been affected in a case of drug abuse [10], while prosthetic valves [5,11] and vascular prostheses [12] can also be affected. Almost all the cases reported with endocarditis and endovascular infection caused by G. morbillorum have been bacteriologically cured by antibiotic therapy, usually a combination of penicillin and aminoglycoside. For the penicillin-resistant or penicillin-allergic patient,
monotherapy or a combination of other antibiotics, such as vancomycin [12] or erythromycin plus rifampicin has been effective. However, cerebral mycotic aneurysm [13] or refractory cardiac failure [14] has been reported to occur. In this case, intracerebral hemorrhage could not be attributed to cerebral mycotic aneurysm, as transesophageal echocardiography revealed no right to left shunt, and no left cardiac valve involvement. Since the patient responded well to the medical treatment, as evidenced by reduced vegetation size on echocardiography and improvement in symptomatology, there was no indication for surgical management. Relative contraindication for surgical treatment was also a risk for the patient taking into consideration brain hemorrhage in addition to other risk factors. In our patient, the definitive source of infection for the organism was not found. Examination of the oropharyngeal mucosa did not show any lesions that could have acted as portals of entry for the organism. Nevertheless we should take into account as a possible etiological association the aortic valve replacement surgery performed 9 months before presentation. ICH is the most common neurological complication of OACs in the elderly [23,24]. The combination of OACs with antiplatelet therapy has recently received considerable attention [23,24]. Aspirin appears to double the risk for ICH, regardless of the dose. Predictors of anticoagulant-related intracerebral hematoma are advanced patient age, prior ischemic stroke, hypertension, and intensity of anticoagulation. Conflict of interest The authors report no relationships that could be construed as a conflict of interest. References
Fig. 2. The vegetation is classified as large, measuring 13x15 mm.
[1] R.M. Zakir, A. Al-Dehneh, L. Dabu, R. Kapila, M. Saric, Mitral bioprosthetic valve endocarditis caused by an unusual microorganism, Gemella morbillorum, in an intravenous drug user, J. Clin. Microbiol. 42 (2004) 4893–4896. [2] M.C. Liberto, G. Matera, R. Puccio, et al., An unusual case of brain abscess by Gemella morbillorum, Jpn. J. Infect. Dis. 59 (2006) 126–128.
M. Constantinos, S. Marios / International Journal of Cardiology 184 (2015) 769–771 [3] A. Lopes, R. Providencia, R.P. Pais, M.J. Frade, F. Chaddad Neto, E. Oliveira, Cerebellar abscess by Gemella morbillorum in a patient with inter-atrial communication, Arq. Neuropsiquiatr. 65 (2007) 1022–1025. [4] Y. Omran, C.A. Wood, Endovascular infection and septic arthritis caused by Gemella morbillorum, Diagn. Microbiol. Infect. Dis. 16 (1993) 131–134. [5] G. Al-Hujailan, P. Lagac -Wiens, Mechanical valve endocarditis caused by Gemella morbillorum, J. Med. Microbiol. 56 (2007) 1689–1691. [6] M. Zheng, O.T. Ng, B.W. Teo, Aortic and mitral valve endocarditis caused by Gemella morbillorum in a haemodialysis patient, Singap. Med. J. 49 (2008) e385–e387. [7] E. Farmaki, E. Roilides, E. Darilis, M. Tsivitanidou, C. Panteliadis, D. Sofianou, Gemella morbillorum endocarditis in a child, Pediatr. Infect. Dis. J. 19 (2000) 751–753. [8] J.R. Kerr, C.H. Webb, J.G. McGimpsey, N.P.S. Campbell, Infective endocarditis due to Gemella morbillorum complicating hypertrophic obstructive cardiomyopathy, Ulster Med. J. 63 (1994) 108–110. [9] T.-D. Wang, S.-C. Chang, I.-P. Chiang, K.-T. Luh, Y.-T. Lee, Infected left atrial myxoma caused by Gemella morbillorum, Scand. J. Infect. Dis. 28 (1996) 633–634. [10] E. Bell, A.C. McCartney, Gemella morbillorum endocarditis in an intravenous drug abuser, J. Infect. 25 (1992) 110–112 (9. Kerr JR, Webb CH, McGimpsey JG, Campbell NPS: Infective). [11] J. Holland, R. Wilson, N. Cumpston, Gemella morbillorum prosthetic valve endocarditis, N. Z. Med. J 27 (1996) 367. [12] M.J. Martin, D.A. Wright, A.R.R. Jones, A case of Gemella morbillorum endocarditis, Postgrad. Med. J. 71 (1995) 188. [13] M. Calopa, F. Rubio, M. Aguilar, J. Peres, Giant basilar aneurysm in the course of subacute bacterial endocarditis, Stroke 21 (1990) 1625–1627. [14] M. Lopez-Dupla, C. Creus, O. Navarro, X. Raga, Association of Gemella morbillorum endocarditis with adenomatous polyps and carcinoma of the colon: case report and review, Clin. Infect. Dis. 22 (1996) 379–380.
771
[15] J.S. Li, D.J. Sexton, N. Mick, R. Nettles, V.G. Fowler Jr., T. Ryan, T. Bashore, G.R. Corey, Proposed modifications to the Duke criteria for the diagnosis of infective endocarditis, Clin. Infect. Dis. 30 (2000) 633–638. [16] L.T. Goodnough, A. Shander, How I treat warfarin-associated coagulopathy in patients with intracerebral hemorrhage, Blood 117 (23) (2011) 6091. [17] L.B. Morgenstern, J.C. Hemphill III, C. Anderson, K. Becker, J.P. Broderick, E.S. Connolly Jr., S.M. Greenberg, J.N. Huang, R.L. MacDonald, S.R. Messé, P.H. Mitchell, M. Selim, R.J. Tamargo, Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association, Am. Heart Assoc. Stroke Counc. Counc. Cardiovasc. Nurs. Stroke 41 (9) (2010) 2108. [18] J.N. Goldstein, J. Rosand, L.H. Schwamm, Warfarin reversal in anticoagulantassociated intracerebral hemorrhage, Neurocrit. Care. 9 (2) (2008) 277. [19] V. Aiyagari, F.D. Testai, Correction of coagulopathy in warfarin associated cerebral hemorrhage, Curr. Opin. Crit. Care 15 (2) (2009) 87. [20] Bleeding during antithrombotic therapy in atrial fibrillation. Stroke Prevention in Atrial Fibrillation Investigators, Arch. Intern. Med. 156 (1996) 409–416. [21] C.S. Landefeld, L. Goldman, Major bleeding in outpatients treated with warfarin: incidence and prediction by factors known at the start of outpatient therapy, Am. J. Med. 87 (1989) 144–152. [22] K. Fredricksson, B. Norrving, L.G. Stromblad, Emergency reversal of anticoagulation after intracerebral hemorrhage, Stroke 23 (1992) 972–977. [23] A.G.G. Turpie, M. Gent, A. Laupacis, Y. Latour, J. Gunstensen, F. Basile, M. Klimek, J. Hirsh, A comparison of aspirin with placebo in patients treated with warfarin and heart valve replacement, N. Engl. J. Med. 329 (1993) 524–529. [24] S.G. Goodman, A. Langer, S.S. Durica, G.E. Raskob, P.C. Comp, R.J. Gray, J.H. Hall, P. Kelley, T.A. Hua, R.J. Lee, V. Fuster, for the Coumadin Aspirin Reinfarction Pilot Study Group, Safety and anticoagulation effect of a low-dose combination of warfarin and aspirin in clinically stable coronary artery disease, Am. J. Cardiol. 74 (1994) 657–661.
