Anticoagulation for three versus six months in patients with deep vein thrombosis or pulmonary embolism, or both: randomised trial.

OBJECTIVE: To determine the optimum duration of oral anticoagulant therapy after an episode of deep vein thrombosis or pulmonary embolism, or both. DESIGN: Multicentre, prospective, randomised study with follow-up for one year. SETTING: 46 hospitals in United Kingdom. PARTICIPANTS: Patients aged > or =18 with deep vein thrombosis or pulmonary embolism, or both. INTERVENTIONS: Three (n=369) or six months (n=380) of anticoagulation with heparin for five days accompanied and followed by warfarin, with a target international normalised ratio of 2.0-3.5. MAIN OUTCOME MEASURES: Death from deep vein thrombosis or pulmonary embolism; failure to resolve, extension, recurrence of during treatment; recurrence after treatment; and major haemorrhage during treatment. RESULTS: In the patients allocated to three months' treatment two died from deep vein thrombosis or pulmonary embolism during or after treatment, compared with three in the six month group. During treatment deep vein thrombosis or pulmonary embolism failed to resolve, extended, or recurred in six patients in the three month group without fatal consequences, compared with 10 in the six month group. After treatment there were 23 non-fatal recurrences in the three month group and 16 in the six month group. Fatal and non-fatal deep vein thrombosis or pulmonary embolism during treatment, and after treatment thus occurred in 31(8%) of those who had received three months' anticoagulation compared with 29 (8%) of those who had received six months' (P=0.80, 95% confidence interval for difference -3.1% to 4.7%). There were no fatal haemorrhages during treatment but there were eight major haemorrhages in those treated for six months and none in those treated for three months (P=0.008, -3.5% to -0.7%). Thus 31 (8%) of the patients receiving three months' anticoagulation experienced adverse outcomes as a result of deep vein thrombosis or pulmonary embolism or its treatment compared with 35 (9%) of those receiving six months' (P=0.79, -4.9% to 3.2%). CONCLUSION: For patients in the UK with deep vein thrombosis or pulmonary embolism and no known risk factors for recurrence, there seems to be little, if any, advantage in increasing the duration of anticoagulation from three to six months. Any possible advantage would be small and would need to be judged against the increased risk of haemorrhage associated with the longer duration of treatment with warfarin. TRIAL REGISTRATION: Clinical Trials NCT00365950 [ClinicalTrials.gov].

Colchicine induced rhabdomyolysis.

A case of colchicine induced rhabdomyolysis is reported. A 73 year old man with ischaemic heart disease, atrial fibrillation, chronic congestive cardiac failure, and chronic gout presented with diffuse muscle pain. He had been taking an increased dose of colchicine (1.5 mg daily) for an exacerbation of gout for six weeks before the presentation. Investigations confirmed the diagnosis of rhabdomyolysis and discontinuation of colchicine resulted in resolution of clinical and biochemical features of rhabdomyolysis. Although neuromuscular adverse effects of colchicine are well recognised, rhabdomyolysis is rare and this is only the fourth reported case of colchicine induced rhabdomyolysis in the literature.

The effect of repeated-dose activated charcoal on the pharmacokinetics of sodium valproate in healthy volunteers.

AIMS: We investigated the effects of repeated-dose charcoal administered several hours after sodium valproate on the pharmacokinetics of a single dose of the drug in healthy volunteers. METHODS: The pharmacokinetics of sodium valproate were studied in seven healthy volunteers after administration of a syrup (300 mg) on two occasions, one of which was followed by administration of repeated doses of oral charcoal starting 4 h after the drug up to 32 h (total dose 80 g). RESULTS: Valproate was rapidly absorbed with maximum concentrations 1 h after administration. The area under the plasma concentration-time curve to 48 h (AUC (0.48 h)) was 408 +/- 114.5 (s.d.) mg l-1 h in the control phase and 398 +/- 108.6 mg l-1 h after charcoal and the t1/2 elimination was 20 +/- 6.8 h in the control phase, and 22 +/- 9.2 h after charcoal (NS). CONCLUSIONS: Repeated-dose activated charcoal does not appear to enhance the rate of elimination of sodium valproate after therapeutic doses of the drug and any beneficial effect of charcoal in overdose may be to prevent absorption of valproate still present in the gut.

The pharmacology of oral anticoagulants: implications for therapy.

All oral anticoagulants act by producing a functional deficiency of vitamin K, thereby impairing the normal synthesis of factors II, VII, IX and X. All, except dicumarol, are well absorbed after oral administration. They are highly protein bound and are mainly metabolized in the liver. A number of factors such as altered absorption, distribution, elimination, genetic factors, aging, vitamin K excess or deficiency, alterations in the level of vitamin K-dependent coagulation factors and drug interactions may affect response to oral anticoagulants. Adverse effects include hemorrhage, skin necrosis and teratogenicity. Phenindione can also cause serious hypersensitivity reactions. Five oral anticoagulants are available in Europe, although warfarin, phenprocoumon and nicoumalone (acenocumarol) are the most commonly used agents. The choice of oral anticoagulant is often influenced by previous experience and familiarity, but in a survey of 22 clinical pharmacologists in 12 countries of Europe, warfarin (57%) or phenprocoumon (24%) were the agents recommended most often in clinical practice.

Effective reversal of warfarin-induced excessive anticoagulation with low dose vitamin K1.

Reversal of the anticoagulant effect of warfarin in patients with no active haemorrhage can be achieved by administration of intravenous vitamin K1. Currently recommended doses of intravenous vitamin K1, for this purpose often result in subsequent difficulties in anticoagulation. We observed the response to low dose intravenous vitamin K1 in patients requiring reversal of anticoagulant therapy. Ten consecutive patients received 1 mg and 21 further patients received 0.5 mg of intravenous vitamin K1. In 50% of the patients who received 1 mg of vitamin K1 the INR (International Normalised Ratio) fell below 2 at 24 h whereas in patients who received 0.5 mg the INR fell below 5.5 in all subjects after 24 h and in none did it fall below 2.0. No patient had any thrombotic or haemorrhagic complications and no difficulty was encountered in re-establishing anticoagulant control after 24 h. We recommend 0.5 mg of vitamin K1 as an effective and convenient method of predictable and fine control of oral anticoagulant therapy.

Hypernatraemia in an adult in-patient population.

We report a retrospective study of hypernatraemia (serum sodium concentration greater than 150 mmol/l) in an adult in-patient population of a health district during one year. The incidence was 0.3% with at least 60% of cases developing after hospital admission, mainly in elderly patients. Dehydration appeared to be the major cause, with the use of diuretics, depressed conscious level or febrile illness implicated in a majority. Most patients had more than one contributory factor and iatrogenic causes were common. Associated illnesses were often severe and the in-hospital mortality was high (54%) regardless of age. Hypernatraemia in hospitalized patients should be largely avoidable and there is a need for greater awareness of the importance of active maintenance of hydration in susceptible patients.

Optimising the dose of oral anticoagulants.

Oral anticoagulants, although valuable, can be dangerous if their use is not carefully monitored. Variability in response to warfarin due to a variety of factors means that initial dose is difficult to predict. The fixed dose regime for initiation of anticoagulant therapy (10 mg daily for three days) results in excessive anticoagulation in one third of patients. A flexible loading dose regime on the other hand, allows smooth initiation and it can also be used to predict maintenance dose. Warfarin therapy can be commenced along with heparin and it is probably unnecessary to continue the latter for more than five days in patients who are adequately anticoagulated with the former. Rational prediction of warfarin maintenance dose is difficult because of a variety of pharmacokinetic and pharmacodynamic factors. Several methods have been described and of these, a feed-back method that uses Bayesian technique is considered to be the most accurate. There is no evidence that computer-assisted methods of dosage prediction are better than empirical or semi-empirical methods. However, for most situations, clinical conditions requiring anticoagulant therapy, maintenance of an International Normalised Ratio (INR) of 2-3 is sufficient but for recurrent deep vein thromboses, recurrent pulmonary emboli, mechanical prosthetic valves and arterial disease including myocardial infarction an INR of 3-4.5 is recommended. Estimation of plasma warfarin and plasma warfarin clearance are valuable in determining the cause of abnormal responsiveness. Low doses of vitamin K, can be used to reverse over-anticoagulation without the risk of producing under-anticoagulation in patients who require long term treatment. Fresh frozen plasma or prothrombin complex may be necessary in patients who are bleeding.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical presentation and investigation of patients proceeding to isotope lung scanning for suspected pulmonary embolism.

The presenting features of 250 consecutive patients who underwent a ventilation/perfusion lung scan for suspected pulmonary embolus (PE) were analysed. Ninety-six patients had lung scans highly suggestive of PE, with one or more unmatched segmental perfusion defects (scan positive), 86 had low probability scans (scan negative) and 68 an indeterminate scan. Scan positive patients were more likely to have a PaO2 of less than 10.7 kPa, an elevated P(A-a)O2 and an abnormal chest X-ray compared with scan negative patients but these measurements were of poor specificity. Furthermore, scan-positive patients had a higher incidence of lung disease. Localized chest wall tenderness was more common in scan-positive patients, occurring in 9% of patients, but there were no other significant differences in individual symptoms, signs or electrocardiographic findings between scan-positive and scan-negative patients. The diagnosis of PE should not be made on clinical grounds alone and all patients suspected of having a PE should at least undergo isotope lung scanning.

Anticentromere antibody positive CREST syndrome associated with polyarthritis, renal impairment and mixed cryoglobulinaemia.

We describe a 63-year-old female who developed the CREST syndrome within two years. Even though she was anticentromere antibody positive, her illness followed a very aggressive course and was associated with severe polyarthritis, renal impairment, hypocomplementaemia and mixed cryoglobulinaemia.

Clinical pharmacokinetic considerations in the control of oral anticoagulant therapy.

Aspects of the pharmacokinetics of warfarin that are clinically relevant are reviewed here. Since warfarin is normally completely absorbed, resistance to treatment due to impaired absorption is unusual, even in severe short bowel syndrome. Warfarin is highly albumin-bound; thus, hypoalbuminaemic states result in an increased free fraction of the drug and a decreased half-life but, as might be expected, there is no evidence of altered response at steady-state. Warfarin is completely metabolised by the liver to hydroxy-warfarins and warfarin alcohols, and although the latter have some biological activity they do not contribute significantly to the drug effect. No information is available concerning the metabolism of warfarin in chronic liver disease, but there is evidence of increased sensitivity due to impaired vitamin K-dependent clotting factor synthesis. Impaired renal function does not appear to alter the effect of warfarin. Lowered response to the drug may be secondary to poor compliance, kinetic resistance or pharmacodynamic resistance. These factors can be identified using algorithms based on population values for plasma warfarin concentrations and clearances at steady-state. The pharmacokinetics and pharmacodynamics of warfarin indicate that several days' overlap with heparin on initiation of warfarin, and gradual (rather than sudden) discontinuation of warfarin, might theoretically be necessary. However, those studies which have been performed have indicated that a long overlap and gradual discontinuation are not associated with greater safety or efficacy of the drug. Because of the long elimination half-life of warfarin and the short elimination half-life of vitamin K, many days' treatment with phytomenadione may be required after warfarin overdose. The elimination half-life and therefore the duration of therapy may be reduced by regular oral cholestyramine, although the means by which the latter enhances warfarin elimination is still unknown.

Carotid sinus hypersensitivity and complete heart block in Reiter's syndrome.

We describe a 42-year-old man with Reiter's syndrome who developed complete heart block only 5 weeks after the onset of his illness. He was also noted to have carotid sinus hypersensitivity and evidence of sinoatrial disease. There were no clinical signs or echocardiographic findings to suggest involvement of the aortic root or aortic valve. His arrhythmias were treated successfully with a physiological pacemaker. The combination of sinoatrial and atrioventricular node disease suggests that the inflammatory process in Reiter's syndrome can produce widespread involvement of the conducting system.