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Rapid Responses: Rapid Responses published:
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anticoagulant dilemma.
- dr.manan vasenwala (12 October 2002)
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Ischaemic Strokes are an important risk factor for cerebral haemorrhage
- Richard Fuller (14 October 2002)
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Aspirin and gastrointestinal bleeding
- Yoon K Loke, Sheena Derry (15 October 2002)
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Cancer as risk factor for bleeding during Warfarin treatment
- Mario Mandala, Marco Cremonesi, Marina Cazzaniga and Sandro Barni (15 October 2002)
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Incomplete Data Makes Review Unhelpful
- Thomas F heston (16 October 2002)
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Warfarin: Risks not always easy to evaluate
- Anthony R Cox, Sally N. Dent (26 October 2002)
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Atrial fibrillation & infective endocarditis
- JOhn Haughey (24 December 2002)
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dr.manan vasenwala, consultant-cardiologist(non-invasive) aligarh-india 202002
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there are many conditions where role of anticoagulants cannot be faulted. trouble comes in those cases where either its role is doubtful or may be hazardous if not supervised. in india majority of patients come from outlying villages to the cities for medical treatment. they cannot be relied to take anticoagulants as advised. also dietary restriction of foods containing high vitk for warfarin cannot be adhered to. clearly, it becomes a situation where the risks of antocoagulations outweigh the benefits. "improvise" is the key word. a large number of patients who cannot take either lmwh or warfarin return home taking aspirin only. a large number of patients have dilated cardiomyopathy. surprisingly, when on aspirin, the incidence of thrombo-embolism is not high as one would expect. manan |
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Richard Fuller, Specialist Registrar in geriatric and general medicine St James's University Hospital, Leeds, LS9 7TF
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Editor - The clinical review by Fitzmaurice and colleagues was a pertinent reminder of the need to carefully balance both benefits and risks when considering anticoagulation, especially in older people [1]. The authors however fail to mention the importance of cerebral ischaemia as a risk factor for cerebral haemorrhage, particularly as sustained atrial fibrillation and stroke is a common indication for oral anticoagulation of older people. The risks of haemorrhagic transformation in the first 2-4 weeks after stroke are well established, with the mechanism by which cerebral ischaemia predisposes to haemorrhage well described [2]. As a response to ischaemia, microvascular integrity is lost with accompanying early extravasation of plasma and red cells, with consequent increases in the risk of parenchymal cerebral haemorrhage. Of equal importance is the concurrent development of microhaemorrhages alongside cerebral ischaemia, seen in up to 6.4% of healthy older people on gradient-echo MRI [3]. This is closely linked with small vessel ischaemia and hypertension, via a combination of hypertensive microangiopathy and cerebral amyloid angiopathy. It has been suggested that these 'silent' microhaemorrhages may be a predictor of symptomatic intracerebral haemorrhage, suggesting a role for MR imaging prior to anticoagulation [4],[5]. It is vital that clinicians are fully aware that the very reason they are considering anticoagulation in patients (i.e. stroke and atrial fibrillation) may turn out to be one of the major risks for developing intracerebral haemorrhage. [1] Fitzmaurice DA, Blann AD & Lip GYH ABC of antithrombotic therapy - Bleeding risks of antithrombotic therapy BMJ 2002;325:828-831 [2] Del Zoppo GJ, Von Kummer R & Hamann GF Ischaemic damage of brain microvessels: inherent risks for thrombolytic treatment in stroke J Neurol Neurosurg Psychiatry 1998;65:1-9 [3] Roob G, Scmidt R, Kapeller P et al MRI evidence of past cerebral microhaemorrhages in a healthy elderly population Neurology 1999;52:991-994 [4] Greenberg SM, O'Donnell HC, Schaefer PW & Kraft E MRI detection of new haemorrhages: potential marker of progression in cerebral amyloid angiopathy Neurology 1999;53:1135-1138 [5] Tsushima Y, Tanizaki Y, Aoki J & Endo K MR detection of microhaemorrhages in neurologically healthy adults Neuroradiology 2002;44:31-36 |
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Yoon K Loke, Clinical Lecturer Dept Clinical Pharmacology, Radcliffe Infirmary. Oxford OX2 6HE, Sheena Derry
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We were very surprised to read in this narrative review that "the risk of gastrointestinal bleeding is related to dose and should not be problematic at doses of 75 mg/day given as thromboprophylaxis". This flies in the face of robust data from two meta-analyses (involving randomised controlled trials [1] and observational studies [2]) in which even low-dose prophylactic aspirin therapy was associated with a significant risk of gastrointestinal haemorrhage. Both meta-analyses also showed that dosage reduction from say 300mg/day down to 75 mg/day would have little, if any, impact on alleviating this risk of gastrointestinal haemorrhage. These findings are clearly reported in Clinical Evidence, [3] a BMJ publication, which is cited in the bibliography of this review article. Furthermore, the results of the meta-analyses are backed up by basic pharmacological studies [4] [5] which suggest that maximal inhibition of platelet enzymes is achieved at aspirin doses well below 75 mg/day. We are concerned that if doctors and patients continue to believe that using low dosages of aspirin (say 50 or 75 mg/day) effectively eliminates the risk of serious bleeding, they will not be able to make an accurate assessment of the benefit:harm trade off in aspirin prophylaxis. The misleading information in this review article creates a false sense of security, and patients who suffer serious aspirin-related gastrointestinal bleeds may justifiably feel that they have been deceived by the advice found in purportedly reputable medical journals. 1. Derry S, Loke YK. Risk of gastrointestinal haemorrhage with long term use of aspirin: meta-analysis. BMJ 2000;321:1183-7. 2. Garcia Rodriguez LA, Hernandez-Diaz S, de Abajo FJ. Association between aspirin and upper gastrointestinal complications: systematic review of epidemiologic studies. Br J Clin Pharmacol. 2001;52:563-71. 3. Cardiovascular disorders. Clinical Evidence. BMJ Publishing Group, 2002. 4. Cryer B, Feldman M. Effects of very low dose daily, long-term aspirin therapy on gastric, duodenal, and rectal prostaglandin levels and on mucosal injury in healthy humans. Gastroenterology 1999;117:17-25. 5. FitzGerald GA, Oates JA, Hawiger J, Maas RL, Roberts LJ 2nd, Lawson JA, Brash AR. Endogenous biosynthesis of prostacyclin and thromboxane and platelet function during chronic administration of aspirin in man. J Clin Invest 1983;71:676-88. |
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Mario Mandala, Clinica Assistant Ospedale Treviglio Division of Medical Oncology P.le Ospedale 1 24047 Treviglio (Bg) Italy, Marco Cremonesi, Marina Cazzaniga and Sandro Barni
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Dear Editor, We read with great interest the excellent review by Fitzmaurice et al. entitled Bleeding risks of antithrombotic therapy. Among risk factors for bleeding cancer is an important issue to consider. The estimated risk of major bleeding with warfarin therapy ranges from 0.2 to 5.2% [1,2], but there is controversy about whether patients with cancer are at increased risk of recurrences and bleeding complications during anticoagulant therapy. Several investigators have observed an increased risk of haemorrhagic and thrombotic complications in cancer patients [3, 4]. In a recent retrospective analysis of two prospective studies [5, 6], Hutten et al. [7] found that the risk for recurrence and major bleeding in cancer patients was three- to six-fold that of patients without malignancy during treatment with warfarin for VTE. These findings are consistent with the results of Gitter et al. [8], who reported that malignant disease at initiation of warfarin therapy is significantly associated with an increased risk for major bleeding and recurrent. In addition, the routine use of anticoagulant therapy during continuous infusion of 5-fluorouracil is theoretically hampered by a potential interaction between warfarin and this drug. Prolonged 5-fluorouracil half- life and increased INR were reported, probably due to interference with the synthesis of hepatic cytocrome 450 and impaired metabolism of warfarin and 5-fluorouracil (9,10). References 1. Levine M, Raskob G, Landefeld CS, Kearon C. Hemorrhagic complications of anticoagulant treatment. Chest 1998;114:511-523. 2. Krauth D, Holden A, Knapic N, et al. Safety and efficacy of long-term oral anticoagulation in cancer patients. Cancer 1987;59:983-985. 3. Moore FD, Osteen RT, Karp DD, et al. Anticoagulants, venous thromboembolism, and the cancer patient. Arch Surg 1981;116:405-407. 4. Prandoni P. Antithrombotic strategies in patients with cancer. Thromb Haemostas 1997;78:141-144. 5. Koopman MMW, Prandoni P, Piovella F, et al. Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared with subcutaneous low molecular weight heparin administered at home. N Engl J Med 1996;334:682-687. 6. The Columbus Investigators. Low molecular weight heparin in the treatment of patients with venous thromboembolism. N Engl J Med 1997;337:657-662. 7. Hutten BA, Prins MH, Gent M, Ginsberg J, Tijssen J, Buller HR. Incidence of recurrent thromboembolic and bleeding complications among patients with venous thromboembolism in relation to both malignancy and achieved international normalised ratio. J Clin Oncol 2000;18:3078-3083. 8. Gitter MJ, Jaeger TM, Petterson TM, et al. Bleeding and thromboembolism during anticoagulant therapy: A population-based study in Rochester, Minnesota. Mayo Clin Proc 1995;70:725-733. 9. An adverse interaction between warfarin and 5-fluoruracil: A case report and review of the literature. Chemotherapy 1999; 45: 392-395. 10. Scarfe MA, Israel MK. Possible drug interaction between warfarin and combination of levamisole and fluoruracil. Ann Pharmacother 1994; 28:464 -467 |
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Thomas F heston, Editor, Medjournal.com Kellogg, USA
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The authors present incomplete data on the risk of aspirin. On page 830, they state that there was a 1.8% increase in non-fatal, major bleeding events (129 versus 70) but they do not state out of how many patients overall these events occurred. Assuming this is an absolute increase, then the total number of subjects in the aspirin group is 3278 and the absolute risk is 3.9%. However, with incomplete data, my figures can only be assumptions. The authors should have stated the denominator (the total number of patients taking aspirin) as well as the numerator (the number of patients with major bleeding events) in presenting their data. For example, in the table they list the aspirin group as having 107 GI bleeds... but do not state the total number of patients taking aspirin. So what is the absolute risk? These glaring omissions by the authors indicate a misguided emphasis upon numerical statistics, and not upon clinical meaning or significance. Furthermore, they do not reference the source research article. A clinical review should be more helpful and complete. Because the authors chose to not reference the research data they presented, this review was more frustrating than helpful. I expect better from the BMJ. |
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Anthony R Cox, ADR Pharmacist West Midlands Centre for Adverse Drug Reaction Reporting, City Hospital, Dudley Road, B18 7QH., Sally N. Dent
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Fitzmaurice et al.(1) in their review of the bleeding risks of antithrombotic therapy describe warfarin as a relatively safe drug. However, warfarin toxicity is a significant cause of drug-related hospital admissions when measured by International Classification Disease (ICD-10) coding.(2) We examined the records of all patients admitted to a teaching hospital (649 beds) with an ICD-10 code related to warfarin toxicity (Y442) between 1st January 2001 and 31st December 2001. Particular attention was paid to co-medication. Reports from the hospital to the Committee on Safety of Medicines (CSM) Yellow Card scheme were also examined during this period. During the study period 18 of 25,679 emergency admissions were assigned a code related to warfarin toxicity and 5 Yellow Cards relating to suspected adverse effects of warfarin were sent to the CSM. Only one case was found by both methods. The 18 patients (67% male) identified by ICD-10 coding had an mean age of 71 (SD 6.9) and spent an average of 8.6 days in hospital. Records were unobtainable in 7 cases, including in 1 patient who died on admission. Review of the remaining 11 sets of records confirmed warfarin toxicity in 8 cases on admission (6 with haemorrhage) and in 3 cases during their hospital stay (2 with haemorrhage). Of the 8 cases with haemorrhage, 5 had an ICD code for haemorrhage. Presenting INRs ranged from 4.9 to greater than 20. All reviewed cases matched the criteria for reporting to the Yellow Card scheme. The average number of co-medications taken was 7. Seventy-three percent of patients took medication with the potential to interact with warfarin, as indicated by the 42nd edition of the British National Formulary, with an average of 1.8 (range 1-3) interacting drugs per patient. Interacting drugs included antibiotics, anti-arrhythmics, NSAIDs and H2-receptor antagonists. Both spontaneous reporting and ICD-10 coding underestimate the prevalence of warfarin toxicity. Cases unreported to the CSM could provide valuable information about interactions with drugs and risk factors for warfarin toxicity. Patients identified in this study exhibited the main factors which increase the risk of bleeding: age and the prescribing of interacting medications. In older patients with high levels of polypharmacy and a lower desire for information about warfarin therapy (3), it may be harder to judge the risks and benefits of warfarin treatment. We would therefore reinforce Fitzmaurie et al’s advice to carry out careful and continual evaluation of patients. Anthony R Cox
Sally N Dent
1. Fitzmaurice DA, Blann AD, Lip GYH. ABC of antithrombotic therapy: Bleeding risks of antithrombotic therapy BMJ 2002; 325: 828-831 2. Cox AR, Anton C, Goh CHF. et al. Adverse drug reactions in patients admitted to hospital identified by discharge ICD-10 codes and by spontaneous reports. Br J Clin Pharmacol 2001;52:337-339 3. Engova D, Duggan C, MacCallum P. Bates, I. Patients’ understanding and perceptions of treatment as determinants of adherance to warfarin treatment. Int J Pharm Pract. 2002;10 (suppl):R69 Competing financial interests: none |
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JOhn Haughey, research research
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Just a query- I have not seen much in the literature as to the risk of continuing oral anticoagulant therapy in individuals with atrial fibrillation who develop infective endocarditis/ sepsis. Could you comment? Competing interests: None declared |
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