Estimation of clinical and economic effects of prophylaxis against venous thromboembolism in medical patients, including the effect of targeting patients at high-risk.

BACKGROUND: The clinical and economic effects of medical thromboprophylaxis (MT) using low molecular weight heparin in Australia are unknown. AIM: To estimate the effects of MT in Australia. METHODS: A decision tree model of MT was populated with national data for medical admissions. The Prevention of Recurrent Venous Thromboembolism (PREVENT) trial was chosen as the primary data source because its design uniquely avoided bias caused by treatment of sub-clinical events. Clinical efficacy and costs were estimated compared with no prophylaxis, assuming full compliance and according to three definitions of eligibility. Effectiveness was estimated as thrombotic events saved, mortality from bleeding or pulmonary embolus (PE), cost and $/year of life saved. Model outputs were subjected to sensitivity analysis. RESULTS: MT decreased thrombotic events, and the numbers avoided increased as eligibility broadened (deep vein thrombosis (DVT): 2597, 2771 and 3232 at restricted, intermediate and broad eligibility; PE: 454, 484 and 565 respectively). The annual cost of no prophylaxis was $88.7 m. Costs were reduced at most restricted eligibility (-$7.9 m), but increased by $3.0 and $32.1 m at broader eligibility. PE deaths declined, but this was offset by deaths from haemorrhage, causing a net increase (158, 299 and 672 respectively). Estimates were sensitive to the incidence of venous thromboembolic event (VTE), case-fatality rates for PE and bleeds and the relative risk reduction for PE with prophylaxis. CONCLUSIONS: Under PREVENT trial conditions, MT avoids up to 3200 DVT and 565 PE events annually, but may increase mortality.

Cerebral abscess following adenotonsillectomy: a rare complication.

In the present paper, we report an extremely rare case of a 4-year-old girl who developed a frontal lobe intracerebral abscess following adenotonsillectomy. This was diagnosed by computerised tomography at scan 21 days post-tonsillectomy when she presented with bilateral sixth nerve palsies. We believe that intracranial complications should be considered in any patient who present with headache or vomiting following tonsil surgery, especially if the patient has a spiking pyrexia.

Selection of medical patients for prophylaxis of venous thromboembolism based on analysis of the benefit-hazard ratio.

BACKGROUND: Medical patients may benefit from anticoagulant prophylaxis of venous thromboembolism (VTE), but assessment of thrombotic risk is complex. I describe a method for estimating the minimum thrombotic risk required to ensure that a reasonable benefit-hazard ratio is maintained. METHODS: An equation was derived relating baseline VTE risk and a minimum acceptable benefit-hazard ratio (R), defined as 'pulmonary embolus (PE) alone', 'PE or symptomatic proximal deep venous thrombosis (DVT)', or 'PE or any symptomatic DVT' prevented per major bleeding. The equation was used to estimate the relative risk (RR) of thromboembolism required for net benefit (main outcome measure). The PREVENT study was the primary data source, backed by data from two meta-analyses. RESULTS: For R ranging from 3 to 10, the RR required for net beneficial prophylaxis was 6.5-21.6 (PE alone); 3.0-9.9 (PE or symptomatic proximal DVT); and 2.3-7.6 (PE or any symptomatic DVT), respectively. These RR are possible only in the presence of risk factors of high weighting. Sensitivity analysis showed that the findings were robust to changes in baseline assumptions related to thrombosis and bleeding rates. CONCLUSION: A method for risk assessment for medical thromboprophylaxis has been developed. The results suggest that only a minority of medical patients with high RR should receive prophylaxis.

Relationship between sample size and the definition of equivalence in non-inferiority drug studies.

Statistical testing of clinical trial data leads to acceptance of a hypothesis if a test of the opposite (null) hypothesis (H0) fails to reach a critical probability value. The usual aim is to demonstrate that a new treatment is superior to a comparator, whence H0 is that the two treatments are the same. By contrast, in studies designed to show that a new treatment is equivalent to an existing therapy, the same principle is satisfied by an amended null hypothesis, that the treatments differ by more than a defined amount. This reversal entails subtle but important logical and practical problems which affect particularly the calculation of sample size. The choice of the limits used to define equivalence is critical to the calculation of sample size in a manner not previously discussed, and in the interpretation of data in relation to the probability of Type I and Type II errors. Investigators, regulatory bodies and institutional ethics committees must ensure that the range of values chosen to indicate equivalence is clinically appropriate and be aware of the effect of this decision on possible errors in accepting or rejecting H0.

Is the Australian HREC system unsustainable?

The Australian HREC system is now highly centralised and subject to national guidelines in an attempt to assure consistency of decision-making and of ethical standards. The penalty has been greatly increased paperwork and reporting requirements which many committees feel burdensome. In addition, many Committees may be under-resourced. However, I argue that though it is timely to reassess the current directions it is an exaggeration to claim that the system is in danger of collapse.

A review of Clinical Terms Version 3 (Read Codes) for speech and language record keeping.

There may be bugs, there may be viruses, but computers are here to stay. Access to computers may vary greatly from 'seen one once' to daily usage. However, with an increasing dependence on electronic records, even the most remote therapist will ultimately be faced with computerization. To make this process as painless as possible some commonality in approach is logical. A common vocabulary, for instance, would ensure that dysphasia in Cape Town is the same as dysphasia in Dundee. This is great in theory but is Clinical Terms Version 3 (Read Codes) (CTV3) sufficient to encode records in clinical practice? It is to this end that the Speech and Language Therapy Department at Burton Hospital took part in a multidisciplinary project with the NHS Centre for Coding and Classification (NHS CCC). (NHS CCC became the NHS Information Authority, Coding and Classification on 1 April 1999.) Their CTV3 offers a standardized clinical terminology. An audit of patient case-notes found that 78% of the terms used by therapists were available in CTV3. Although there are many issues raised concerning electronic patient records, CTV3 presented as a potential vocabulary for recording patient information in this acute setting.

The role of Ca2+ stores in the muscarinic inhibition of the K+ current IK(SO) in neonatal rat cerebellar granule cells.

Cerebellar granule neurons (CGNs) possess a standing outward potassium current (IK(SO)) which shares many similarities with current through the two-pore domain potassium channel TASK-1 and which is inhibited following activation of muscarinic acetylcholine receptors. The action of muscarine on IK(SO) was unaffected by the M2 receptor antagonist methoctramine (100 nM) but was blocked by the M3 antagonist zamifenacin, which, at a concentration of 100 nM, shifted the muscarine concentration-response curve to the right by around 50-fold. Surprisingly, M3 receptor activation rarely produced a detectable increase in [Ca2+]i unless preceded by depolarization of the cells with 25 mM K+. Experiments with thapsigargin and ionomycin suggested that the endoplasmic reticulum Ca2+ stores in CGNs were depleted at rest. In contrast, cerebellar glial cells in the same fields of cells possessed substantial endoplasmic reticulum Ca2+ stores at rest. Pretreatment of the cells with BAPTA AM, thapsigargin or the phospholipase C (PLC) inhibitor U-73122 all blocked the muscarine-induced Ca2+ signal but had little or no effect on muscarinic inhibition of IK(SO). Raising [Ca2+]i directly with ionomycin caused a small but significant inhibition of IK(SO). It is concluded that muscarine acts on M3 muscarinic acetylcholine receptors both to inhibit IK(SO) and to mobilize Ca2+ from intracellular stores in CGNs. While the mobilization of Ca2+ occurs through activation of PLC, this does not seem to be the primary mechanism underlying muscarinic inhibition of IK(SO).

Implications of pulse pressure as a predictor of cardiac risk in patients with hypertension.

Previously we demonstrated that pulse pressure is a strong risk factor for coronary events in male hypertensive subjects in the MRC Mild Hypertension Trial, whereas stroke is best predicted by mean blood pressure. In this study, we have assessed the implications of this finding in the treatment of mild essential hypertension. We examined the relationship between diastolic blood pressure and both coronary disease risk and stroke when these events were predicted by the above blood pressure measures using an empirical linear model and multivariate logistic regression models that contained data from the MRC trial. Under these circumstances, the predicted stroke risk increased progressively with increasing values of diastolic blood pressure, but in both empirical and formal statistical models, the predicted risk of a coronary event exhibited a J-shaped relationship with diastolic blood pressure. These results suggest that if coronary event risk in mild essential hypertension is predicted by pulse pressure then it may increase at low values of diastolic blood pressure, in contrast to stroke risk, which declines continuously as diastolic blood pressure falls within the physiological range. This raises the possibility that different sequelae of hypertension are best predicted by different measures of blood pressure and that the effect of treatment on stroke and coronary events in some circumstances may be discordant.

A functional role for the two-pore domain potassium channel TASK-1 in cerebellar granule neurons.

Cerebellar granule neurons (CGNs) are one of the most populous cells in the mammalian brain. They express an outwardly rectifying potassium current, termed a "standing-outward" K(+) current, or IK(SO), which does not inactivate. It is active at the resting potential of CGNs, and blocking IK(SO) leads to cell depolarization. IK(SO) is blocked by Ba(2+) ions and is regulated by activation of muscarinic M(3) receptors, but it is insensitive to the classical broad-spectrum potassium channel blocking drugs 4-aminopyridine and tetraethylammonium ions. The molecular nature of this important current has yet to be established, but in this study, we provide strong evidence to suggest that IK(SO) is the functional correlate of the recently identified two-pore domain potassium channel TASK-1. We show that IK(SO) has no threshold for activation by voltage and that it is blocked by small extracellular acidifications. Both of these are properties that are diagnostic of TASK-1 channels. In addition, we show that TASK-1 currents expressed in Xenopus oocytes are inhibited after activation of endogenous M(3) muscarinic receptors. Finally, we demonstrate that mRNA for TASK-1 is found in CGNs and that TASK-1 protein is expressed in CGN membranes. This description of a functional two-pore domain potassium channel in the mammalian central nervous system indicates its physiological importance in controlling cell excitability and how agents that modify its activity, such as agonists at G protein-coupled receptors and hydrogen ions, can profoundly alter both the neuron's resting potential and its excitability.

Inhibition of neuronal KV potassium currents by the antidepressant drug, fluoxetine.

1. The effect of the antidepressant drug, fluoxetine on neuronal delayed rectifier (KV) potassium (K) currents was investigated using perforated-patch whole-cell electrophysiological recording methods. 2. Fluoxetine was an effective inhibitor of KV currents in cerebellar granule neurons (CGNs) and also inhibited recombinant KV1.1 channels expressed in Chinese hamster ovary (CHO) cells. 3. Fluoxetine had an IC50 of 11 microM in CGNs but was slightly less potent on KV1.1 channels (IC50=55 microM). Interestingly, fluoxetine was a much more potent inhibitor of KV1.1 expressed in mammalian cells than has been found previously for the same homomeric channel expressed in Xenopus oocytes. 4. At concentrations that produced around 50% block, the shape of the KV currents in the presence of fluoxetine was simply scaled down when compared to control currents. 5. The effect of fluoxetine on KV currents in CGNs was neither voltage-dependent nor dependent on the channels being in their open state. Both of these observations suggest that fluoxetine does not act as a simple open channel blocking agent. 6. It is concluded that block of KV currents in mammalian neurons can occur at therapeutic levels of fluoxetine. This could lead to an increase in neuronal excitability and this effect may contribute to the therapeutic antidepressant action of fluoxetine.

Pulse pressure as a risk factor for cardiovascular events in the MRC Mild Hypertension Trial.

OBJECTIVES: The aim of this study was to determine whether pulse pressure is a risk factor for coronary artery disease using data from the MRC trial of treatment of mild hypertension, and whether the effect of anti-hypertensive drug therapy on pulse pressure may be a determinant of outcome in treated patients. METHODS: Logistic regression and Cox regression analyses were used to compare systolic and diastolic blood pressure, pulse pressure and mean blood pressure as predictors of coronary events and stroke in the MRC Mild Hypertension Trial. The effects of anti-hypertensive drug treatment with bendrofluazide and propranolol on pulse pressure were assessed using 1-year follow-up data. Event rates in the placebo-treated group and responses to anti-hypertensive treatment were measured in quartiles of age-adjusted entry pulse pressure. A 'four-corners' analysis was performed, with subjects divided into the upper and lower halves of the distributions of systolic and diastolic blood pressure at entry. RESULTS: Pulse pressure was a stronger predictor of coronary events than systolic, diastolic or mean blood pressure in males by logistic regression. Pulse pressure was similar to systolic pressure as a coronary event predictor on Cox regression. Stroke was predicted most strongly by mean blood pressure. Fatal and non-fatal coronary event rates increased progressively in ascending quartiles of age-adjusted pulse pressure, but there was also a strong correlation with systolic blood pressure. The values of partial logistic regression coefficients in models containing both systolic and diastolic blood pressure also supported a role for pulse pressure in predicting coronary events and for mean blood pressure in predicting stroke. Coronary risk, but not stroke, was inversely related to diastolic blood pressure in the four-corners analysis. In a Cox model, regressions of coronary event probability on systolic blood pressure at entry were significantly and inversely related to diastolic blood pressure categorized in quartiles. Bendrofluazide but not propranolol decreased pulse pressure significantly and was associated with a reduction in cardiovascular events overall, but no definite relationship between the effect of drugs on pulse pressure and specific responses to treatment was seen. CONCLUSION: Pulse pressure is a strong risk factor for coronary events in untreated hypertensive male subjects in the MRC Mild Hypertension Trial, whereas stroke is best predicted by mean blood pressure. Bendrofluazide and propranolol have different effects on pulse pressure which may be related to their relative efficacy in the treatment of hypertension, but this possibility requires further study in more suitable populations.

Impaired endothelium-dependent and independent dilatation of forearm resistance arteries in men with diet-treated non-insulin-dependent diabetes: role of dyslipidaemia.

1. We measured endothelium-dependent and independent dilatation of forearm resistance arteries in 29 men with diet-treated non-insulin-dependent diabetes mellitus and 18 age- and sex-matched control subjects. None of the diabetic patients had hypercholesterolaemia, overt hypertension or microproteinuria. 2. We examined endogenous and exogenous nitric oxide-mediated vasodilatation by measuring forearm blood flow with venous occlusive plethysmography after administration of acetylcholine (7.5 and 15 micrograms/min) and sodium nitroprusside (3 and 10 micrograms/min), respectively, into the brachial artery. NG-monomethyl-L-arginine was also infused to study the inhibition of basal and stimulated release of nitric oxide. 3. The vasodilatory response to acetylcholine, expressed as area under curve, was significantly decreased in the diabetic patients compared with the control subjects (P = 0.019). NG-monomethyl-L-arginine significantly reduced basal (P < 0.001) and acetylcholine-stimulated blood flow (P < 0.02) in both groups. The vasodilatory response (also expressed as area under curve) to sodium nitroprusside was significantly less (P = 0.044) in the diabetic patients than in the control subjects. 4. In the diabetic patients, impaired vasodilatory responses to acetylcholine were significantly correlated with higher serum triacylglycerols (P = 0.048) and lower high-density lipoprotein-cholesterol concentrations (P = 0.007); the association with high-density lipoprotein was independent of age, glycated haemoglobin and blood pressure. Sodium nitroprusside responses were not correlated with lipid and lipoprotein concentrations. 5. We conclude that there is impaired endothelial and smooth muscle cell function in men with diet-treated non-insulin-dependent diabetes mellitus uncomplicated by overt hypertension or microproteinuria. Endothelial dysfunction may be related to diabetic dyslipidaemia and associated metabolic disturbances.

Measurement of blood pressure may be affected by an interaction between subject and observer based on gender.

Retrospective studies have suggested that blood pressure (BP) may be affected by a covert gender interaction between patient and observer, which is most marked for female patients and male observers. Such an effect could be one of the determinants of the "white coat' response. We have assessed this interaction in a prospective study in 56 hospital outpatients (31 males, 25 females) in whom supine and erect BP and heart rate were measured by two male and two female subjects, and by an automatic sphygmomanometer when no persons were present. Supine systolic BP (SBP) was related to age, and fell progressively over three measurements. Absolute BP was less in females but the fall on repeated measurement was significantly greater than in males. When absolute BP was analysed by patient and observer sex, no significant interaction was present. BP measured by automatic sphygmomanometry was less than the value obtained clinically. Absolute BP showed no significant interaction with observer and patient sex, but the difference between machine and age-adjusted clinical measurements for SBP was significantly greater in female patients when BP was measured by male observers. However, this effect dissipated on repeated measurement. These data suggest that a transient gender interaction can contribute to the white-coat effect, especially in female patients when BP is measured by a male observer.