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(Aust Prescr 2001;24:107-9)

Letters, which may not necessarily be published in full, should be restricted to not more than 250 words. When relevant, comment on the letter is sought from the author. Due to production schedules, it is normally not possible to publish letters received in response to material appearing in a particular issue earlier than the second or third subsequent issue.

Prevention of deep vein thrombosis

Editor, â⚬â↚¬Å- I refer to G. Weiszâ⚬➢ recent letter â⚬ƹÅ-Economy class syndromeâ⚬➢ (Aust Prescr 2001;24:52). My understanding is that a recent meta-analysis demonstrated no value in the use of aspirin for venous thromboembolism as prophylaxis and treatment, and a reported 3% chance of some degree of gastrointestinal bleeding. It would seem that the use of this drug is best left to the management of arterial problems. Recommendation as a therapy for prevention of deep vein thrombosis is not supported by the Australian Medicines Handbook (â⚬ƹÅ-Aspirin is probably ineffective in the prevention of venous thromboembolismâ⚬➢), and in view of the incidence of adverse effects I would not advise its use for this purpose.

I would be interested to learn of any studies which support the view that there is a place for aspirin in this setting, or indeed in any situation with a recognised risk of venous thrombosis.

Ashley Collard
General Practitioner
Fairlight, NSW

Agnes Vitry, Senior Editor, Australian Medicines Handbook, comments:

A recent editorial in the Medical Journal of Australia concluded that the evidence on the risk of venous thromboembolism associated with air travel was, as yet, missing.1 Most of the evidence comes from case series and two conflicting prospective case-control studies.2,3 Given the current uncertainty about possible increased risk, it seems common sense and harmless to give the usual advice about regular foot exercises, generous fluid intake and avoiding excessive alcohol. A recent randomised trial showed that compression stockings may prevent symptomless deep venous thrombosis but may cause superficial thrombophlebitis in varicose veins.4

The second edition of the Australian Medicines Handbook did not recommend the use of aspirin for prevention of venous thromboembolism on the basis of a meta-analysis, which suggested aspirin provided relatively little protection for postoperative patients compared to heparins or oral anticoagulants.5 A recent large trial showed that aspirin (160 mg daily, started before surgery and continued for five weeks) slightly reduced the risk of pulmonary embolism and deep venous thrombosis, but not the overall mortality in patients with hip fracture.6 Results of this trial are difficult to interpret, as only some of the patients received additional prophylaxis with heparin or low molecular weight heparins, and also as aspirin has not been directly compared with these first-line treatments.

Low-dose aspirin may be used in addition to first-line treatments in patients with hip fracture at low risk of bleeding. At present, low-dose aspirin cannot be recommended for the prevention of venous thromboembolism in other situations.

References

1. Gallus AS, Baker RI. Economy class syndrome. Med J Aust 2001;174:264-5.
2. Ferrari E, Chevallier T, Chapelier A, Baudouy M. Travel as a risk factor for venous thromboembolic disease: a case-control study. Chest 1999;115:440-4.
3. Kraaijenhagen RA, Haverkamp D, Koopman MM, Prandoni P,
Piovella F, Buller HR. Travel and risk of venous thrombosis. Lancet 2000;356:1492-3.
4. Scurr JH, Machin SJ, Bailey-King S, Mackie IJ, McDonald S, Smith PD. Frequency and prevention of symptomless deep-vein thrombosis in long-haul flights: a randomised trial. Lancet 2001;357:1485-9.
5. Collaborative overview of randomised trials of antiplatelet therapy â⚬â↚¬Å- III: Reduction in venous thrombosis and pulmonary embolism by antiplatelet prophylaxis among surgical and medical patients. Antiplatelet Trialistsâ⚬➢ Collaboration. Br Med J 1994;308:235-46.
6. Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) trial. Lancet 2000;355:1295-302.

Medications which may lower seizure threshold

Editor, â⚬â↚¬Å- I would like to offer another explanation for the apparent â⚬ƹÅ-seizure activityâ⚬➢ reported by Dr Loadsman (Aust Prescr 2001;24:51â⚬â↚¬Å-2) when pethidine and tramadol were used concurrently. Both these drugs have serotonin reuptake inhibitor activity and have been implicated in serotonin toxicity when combined with other serotonergic drugs.

Co-administration of pethidine and tramadol could certainly result in a pharmacodynamic interaction, leading to signs and symptoms of excess serotonin in the central nervous system such as â⚬ƹÅ-twitching and anxietyâ⚬➢. These as well as the neuromuscular features, myoclonic spasms, tremor, clonus, hyperreflexia and hypertonia are included in Sternbachâ⚬➢s diagnostic criteria for â⚬ƹÅ-serotonin syndromeâ⚬➢ and can easily be mistaken for â⚬ƹÅ-seizure activityâ⚬➢. Physicians should be alert to the possibility of serotonin toxicity when pethidine is given to patients who have recently taken, or are still taking, serotonergic drugs (such as selective serotonin reuptake inhibitors and monoamine oxidase inhibitors). Concurrent use of pethidine and tramadol should be undertaken with caution or avoided when possible, because of the risk of serotonin toxicity.

Stephanie Pepper
Drug Information Pharmacist
Hunter Drug Information Service
Newcastle Mater Misericordiae Hospital
Waratah, NSW

Oxaliplatin

Editor, – The new drug comment (Aust Prescr 2001;24:73–4) does not reflect the Australian trial experience with oxaliplatin. At the American Society of Clinical Oncology meeting in San Francisco we reported a phase II trial of oxaliplatin in conjunction with 5-fluorouracil and folinic acid in 40 patients with previously untreated advanced or metastatic colorectal cancer.1 There was a low rate of severe (grade 3/4) toxicities and these included neuropathy (grade 3–17%), diarrhoea (grade 3–11%), mucositis (grade 3–4%) and neutropenia (grade 3/4–34%). Nausea and vomiting were not a major problem with the use of simple antiemetics. In addition the tumour response rate was 56% (95% CI 38–72%), which is very high for these conditions.

The comment that ‘like other platinum-based drugs, oxaliplatin is very toxic’ is therefore inaccurate, as is the following suggestion that ‘most patients will have vomiting, diarrhoea, anaemia and altered liver function tests’. These comments cannot have been written by anyone who has ever used this compound.

Stephen Clarke
Senior Staff Specialist
Department of Medical Oncology
Royal Prince Alfred Hospital
Sydney

Reference

1. Goldstein D, Michael M, Mitchell P, Smith J, Clarke S. Improving patient convenience: a modification schedule of FOLFOX (oxalipatin combined with 5FU) with high activity and tolerability in untreated metastatic colorectal cancer (CRC). Proceedings of the Annual Meeting of the American Society of Clinical Oncology; 2001 May 12-15; San Francisco. Report No. 578.

Editorial comment
The Executive Editorial Board prepared the new drug comment before oxaliplatin was marketed in Australia. Prior to marketing there is obviously little information available about the use of any new drug in Australia. To ensure readers are presented with a balanced view of a new drug the Executive Editorial Board considers data from a variety of sources including information provided by the manufacturer. While the Executive Editorial Board is interested in the results of Dr Clarke’s phase II study they do not negate the new drug comment.

The comment was based on the pivotal clinical trials which used different regimens from the phase II study. In these trials symptoms of neuropathy developed in 85–95% of patients. Anaemia occurred in more than 80% of patients and neutropenia and thrombocytopenia were very common. The comment that most patients will have vomiting and diarrhoea is also consistent with the manufacturer’s product information.

In Dr Clarke’s trial 83% of the patients required a dose reduction and toxicity resulted in 25% ceasing treatment. While the frequency of severe adverse effects may be low from an oncology perspective, it is important that patients decide what is acceptable to them. The Executive Editorial Board hopes that the favourable response rate seen in the trial will lead to improved survival for the patients.