- Email: [email protected]
Fatal aplastic anaemia associated with clopidogrel
RESEARCH LETTERS
Similar limitations of the historical control design apply to our study and Blunt and Burchett's.1 However, as the two intensivists, similar staffing and resources were consistent during the study period, and the historical control period, it is highly unlikely that factors such as different treatment were responsible for the documented differences in mortality risk. These differences are more likely to be the result of an overall improvement in the quality of paediatric intensive care delivered. Shortened lengths of stay may result from less mechanical ventilation and ICU-dependent therapies due to more rapidly titrated therapy where an intensivist is present for 24 hours. Blunt and Burchett's report and our data provide further evidence that the intensivist plays a major role in achieving the best possible outcome for adult and paediatric patients requiring ICU treatment. Particularly in developing countries such as Malaysia, improvement in intensive care may be achieved at lower costs by 24 h provision of trained intensivists rather than costly equipment and drugs. 1. Blunt MC, Burchett KR. Out-of-hours consultant cover and casemix adjusted mortality in intensive care. Lancet 2000; 356: 735–36. 2. Pronovost PJ, Jenckes MW, Dorman T, et al. Organizational characteristics of intensive care units related to outcomes of abdominal aortic surgery. JAMA 1999; 281: 1310–17. 3. Pollack MM, Alexander SR, Clarke N, et al. Improved outcomes from tertiary center paediatric intensive care: a statewide comparison of tertiary and non-tertiary care facilities. Crit Care Med 1991; 19: 150–59. 4. DiCarlo JV, Zaitseva TA, Khodateleva TV, et al. Comparative assessment of paediatric intensive care in Moscow, the Russian Federation: a prospective, multicenter study. Crit Care Med 1996; 24: 1403–07. 5. Rapoport J, Teres D, Lemeshow S, Gehlbach S. A method for assessing the clinical performance and cost-effectiveness of intensive care units: a multicenter inception cohort study. Crit Care Med 1994; 22: 1385–91.
Paediatric Intensive Care Unit, Department of Paediatrics, University Malaya Medical Center, 50603 Kuala Lumpur, Malaysia (A Goh MD, L Lum MD, M Abdel-Latif MD) Correspondence to: Dr Goh (e-mail: [email protected])
Fatal aplastic anaemia associated with clopidogrel Jean-Marc Trivier, Jacques Caron, Michel Mahieu, Nathalie Cambier, Christian Rose Clopidogrel, an inhibitor of platelet aggregation, was initially thought to be free of the side-effects of ticlopidine. We describe a man who developed aplastic anaemia after 5 months of treatment with clopidogrel. There were no other plausible causes. We suggest that his fatal aplastic anaemia might have been induced by clopidogrel.
Inhibitors of platelet aggregation are used to prevent cerebrovascular accidents. Aspirin and ticlopidine are indicated for secondary prevention of cerebrovascular accidents. An analogue of ticlopidine, clopidogrel, a new platelet adenosine-diphosphate-receptor antagonist, is an alternative treatment. Clopidogrel seems to be as safe as aspirin in respect to haematological adverse reactions, especially neutropenia and thrombocytopenia.1 An 88-year-old man with ischaemic cardiomyopathy underwent endarterectomy of his right carotid artery in September, 1997. He later developed symptomatic left carotid stenosis and was started on 75 mg clopidogrel per day in April, 1999. His baseline haematological values were normal at this time. Concomitant drugs at the start of the treatment were felodipine, fosinopril, furosemide,
446
rilmenidine, potassium hydrochloride, and molsidomine. All these drugs had been taken by the patient since January, 1998, with no adverse haematological consequences. On Aug 30, 1999, he was admitted to the emergency department for cardiac failure. His haemoglobin was 8·6 g/dL, erythrocyte count 2·5⫻1012/L, white-cell count (neutrophils 67%, lymphocytes 16%, 2·6⫻109/L monocytes 14%, and eosinophils 3%), and platelets 30⫻109/L. His reticulocyte count was 25⫻109/L. No new drugs had been introduced since April, 1999, except for clopidogrel. A bone-marrow aspirate showed poor cellularity without dysmyelopoeisis. A bone-marrow biopsy sample was strikingly hypocellular without fibrosis. Results of cytogenetic analysis were normal (46, XY with no structural anomaly) and a Ham test was negative. There was no evidence of autoimmune disorders and liverfunction tests were normal. Ultrasound examination did not show splenomegaly or adenopathy. We diagnosed aplastic anaemia, as defined by Gordon-Smith and Lewis.2 Clopidogrel was discontinued in August, 1999, and redblood cells were transfused when the patient’s haemoglobin fell below 8 g/dL. He received 14 red-blood cell units and was admitted to the hospital twice with infections. He died from pulmonary infection in February, 2000. Agranulocytosis and aplastic anaemia have been associated with ticlopidine.3 Clopidogrel could share this toxicity, although evidence of comparative results on safety and tolerability from the CAPRIE trial showed that thrombocytopenia and neutropenia rarely occurred (0·26 and 0·10%, respectively).1 Rates of severe thrombocytopenia (platelets <50⫻109/L) were 0·19% for clopidogrel versus 0·10% for aspirin.1 One case of aplastic anaemia was reported in a patient treated with clopidogrel. Aplastic anaemia resolved 3 months after stopping the drug. However, this patient also received a known myelotoxic drug (phenytoin) at the same time.4 To the best of our knowledge, only one case of reversible aplastic anaemia associated with clopidogrel has so far been reported to the French regulatory authorities. There have been no reports of aplastic anaemia with the other drugs concomitantly prescribed in our patient except for angiotensin-converting enzyme inhibitors (captopril and lisinopril5 but not fosinopril) and these effects were mostly associated with renal impairment. In our patient, the sudden onset of pancytopenia five months after introducing clopidogrel and the lack of any other plausible cause suggests that this drug might be responsible. Although its occurrence is rare, clinicians should be alerted to the possibility of severe bone-marrow depression with clopidogrel. 1
2
3 4 5
Harker LA, Boissel JP, Pilgrim AJ, Gent M. Comparative safety and tolerability of clopidogrel and aspirin: results from CAPRIE. Clopidogrel versus aspirin in patients at risk of ischaemic events. Drug Saf 1999; 21: 325–35. Gordon-Smith EC, Lewis SM. Aplastic anaemia and other types of bone marrow failure. In: Hoffbrand AV, Lewis SM, Tuddenham EGD, eds. Postgraduate haematology, 4th edn. Oxford: Butterworth-Heinemann, 1999: 68–90. Quinn MJ, Fitzgerald DJ. Ticlopidine and clopidogrel. Circulation 1999; 100: 1667–72. Green D. CAPRIE trial. Lancet 1997; 349: 354–55. Harrison BD, Laidlaw ST, Reilly JT. Fatal aplastic anaemia associated with lisinopril. Lancet 1995; 346: 247–48.
Unité de Pharmacovigilance (J M Trivier PhD) et Service d’OncoHématologie (M Mahieu MD, N Cambier MD, C Rose MD), CH Saint Vincent, 59020 Lille cedex, France; and Centre Régional de Pharmacovigilance (J Caron MD), CHRU, Lille cedex. Correspondence to : Dr Christian Rose (e-mail: [email protected])
THE LANCET • Vol 357 • February 10, 2001
For personal use only. Reproduce with permission from The Lancet Publishing Group.
Similar limitations of the historical control design apply to our study and Blunt and Burchett's.1 However, as the two intensivists, similar staffing and resources were consistent during the study period, and the historical control period, it is highly unlikely that factors such as different treatment were responsible for the documented differences in mortality risk. These differences are more likely to be the result of an overall improvement in the quality of paediatric intensive care delivered. Shortened lengths of stay may result from less mechanical ventilation and ICU-dependent therapies due to more rapidly titrated therapy where an intensivist is present for 24 hours. Blunt and Burchett's report and our data provide further evidence that the intensivist plays a major role in achieving the best possible outcome for adult and paediatric patients requiring ICU treatment. Particularly in developing countries such as Malaysia, improvement in intensive care may be achieved at lower costs by 24 h provision of trained intensivists rather than costly equipment and drugs. 1. Blunt MC, Burchett KR. Out-of-hours consultant cover and casemix adjusted mortality in intensive care. Lancet 2000; 356: 735–36. 2. Pronovost PJ, Jenckes MW, Dorman T, et al. Organizational characteristics of intensive care units related to outcomes of abdominal aortic surgery. JAMA 1999; 281: 1310–17. 3. Pollack MM, Alexander SR, Clarke N, et al. Improved outcomes from tertiary center paediatric intensive care: a statewide comparison of tertiary and non-tertiary care facilities. Crit Care Med 1991; 19: 150–59. 4. DiCarlo JV, Zaitseva TA, Khodateleva TV, et al. Comparative assessment of paediatric intensive care in Moscow, the Russian Federation: a prospective, multicenter study. Crit Care Med 1996; 24: 1403–07. 5. Rapoport J, Teres D, Lemeshow S, Gehlbach S. A method for assessing the clinical performance and cost-effectiveness of intensive care units: a multicenter inception cohort study. Crit Care Med 1994; 22: 1385–91.
Paediatric Intensive Care Unit, Department of Paediatrics, University Malaya Medical Center, 50603 Kuala Lumpur, Malaysia (A Goh MD, L Lum MD, M Abdel-Latif MD) Correspondence to: Dr Goh (e-mail: [email protected])
Fatal aplastic anaemia associated with clopidogrel Jean-Marc Trivier, Jacques Caron, Michel Mahieu, Nathalie Cambier, Christian Rose Clopidogrel, an inhibitor of platelet aggregation, was initially thought to be free of the side-effects of ticlopidine. We describe a man who developed aplastic anaemia after 5 months of treatment with clopidogrel. There were no other plausible causes. We suggest that his fatal aplastic anaemia might have been induced by clopidogrel.
Inhibitors of platelet aggregation are used to prevent cerebrovascular accidents. Aspirin and ticlopidine are indicated for secondary prevention of cerebrovascular accidents. An analogue of ticlopidine, clopidogrel, a new platelet adenosine-diphosphate-receptor antagonist, is an alternative treatment. Clopidogrel seems to be as safe as aspirin in respect to haematological adverse reactions, especially neutropenia and thrombocytopenia.1 An 88-year-old man with ischaemic cardiomyopathy underwent endarterectomy of his right carotid artery in September, 1997. He later developed symptomatic left carotid stenosis and was started on 75 mg clopidogrel per day in April, 1999. His baseline haematological values were normal at this time. Concomitant drugs at the start of the treatment were felodipine, fosinopril, furosemide,
446
rilmenidine, potassium hydrochloride, and molsidomine. All these drugs had been taken by the patient since January, 1998, with no adverse haematological consequences. On Aug 30, 1999, he was admitted to the emergency department for cardiac failure. His haemoglobin was 8·6 g/dL, erythrocyte count 2·5⫻1012/L, white-cell count (neutrophils 67%, lymphocytes 16%, 2·6⫻109/L monocytes 14%, and eosinophils 3%), and platelets 30⫻109/L. His reticulocyte count was 25⫻109/L. No new drugs had been introduced since April, 1999, except for clopidogrel. A bone-marrow aspirate showed poor cellularity without dysmyelopoeisis. A bone-marrow biopsy sample was strikingly hypocellular without fibrosis. Results of cytogenetic analysis were normal (46, XY with no structural anomaly) and a Ham test was negative. There was no evidence of autoimmune disorders and liverfunction tests were normal. Ultrasound examination did not show splenomegaly or adenopathy. We diagnosed aplastic anaemia, as defined by Gordon-Smith and Lewis.2 Clopidogrel was discontinued in August, 1999, and redblood cells were transfused when the patient’s haemoglobin fell below 8 g/dL. He received 14 red-blood cell units and was admitted to the hospital twice with infections. He died from pulmonary infection in February, 2000. Agranulocytosis and aplastic anaemia have been associated with ticlopidine.3 Clopidogrel could share this toxicity, although evidence of comparative results on safety and tolerability from the CAPRIE trial showed that thrombocytopenia and neutropenia rarely occurred (0·26 and 0·10%, respectively).1 Rates of severe thrombocytopenia (platelets <50⫻109/L) were 0·19% for clopidogrel versus 0·10% for aspirin.1 One case of aplastic anaemia was reported in a patient treated with clopidogrel. Aplastic anaemia resolved 3 months after stopping the drug. However, this patient also received a known myelotoxic drug (phenytoin) at the same time.4 To the best of our knowledge, only one case of reversible aplastic anaemia associated with clopidogrel has so far been reported to the French regulatory authorities. There have been no reports of aplastic anaemia with the other drugs concomitantly prescribed in our patient except for angiotensin-converting enzyme inhibitors (captopril and lisinopril5 but not fosinopril) and these effects were mostly associated with renal impairment. In our patient, the sudden onset of pancytopenia five months after introducing clopidogrel and the lack of any other plausible cause suggests that this drug might be responsible. Although its occurrence is rare, clinicians should be alerted to the possibility of severe bone-marrow depression with clopidogrel. 1
2
3 4 5
Harker LA, Boissel JP, Pilgrim AJ, Gent M. Comparative safety and tolerability of clopidogrel and aspirin: results from CAPRIE. Clopidogrel versus aspirin in patients at risk of ischaemic events. Drug Saf 1999; 21: 325–35. Gordon-Smith EC, Lewis SM. Aplastic anaemia and other types of bone marrow failure. In: Hoffbrand AV, Lewis SM, Tuddenham EGD, eds. Postgraduate haematology, 4th edn. Oxford: Butterworth-Heinemann, 1999: 68–90. Quinn MJ, Fitzgerald DJ. Ticlopidine and clopidogrel. Circulation 1999; 100: 1667–72. Green D. CAPRIE trial. Lancet 1997; 349: 354–55. Harrison BD, Laidlaw ST, Reilly JT. Fatal aplastic anaemia associated with lisinopril. Lancet 1995; 346: 247–48.
Unité de Pharmacovigilance (J M Trivier PhD) et Service d’OncoHématologie (M Mahieu MD, N Cambier MD, C Rose MD), CH Saint Vincent, 59020 Lille cedex, France; and Centre Régional de Pharmacovigilance (J Caron MD), CHRU, Lille cedex. Correspondence to : Dr Christian Rose (e-mail: [email protected])
THE LANCET • Vol 357 • February 10, 2001
For personal use only. Reproduce with permission from The Lancet Publishing Group.