Indirect comparison meta-analysis of two enoxaparin regimens in patients undergoing major orthopaedic surgery. Impact on the interpretation of thromboprophylactic effects of new anticoagulant drugs.

Two enoxaparin dosage regimens are used as comparators to evaluate new anticoagulants for thromboprophylaxis in patients undergoing major orthopaedic surgery, but so far no satisfactory direct comparison between them has been published. Our objective was to compare the efficacy and safety of enoxaparin 3,000 anti-Xa IU twice daily and enoxaparin 4,000 anti-Xa IU once daily in this clinical setting by indirect comparison meta-analysis, using Bucher's method. We selected randomised controlled trials comparing another anticoagulant, placebo (or no treatment) with either enoxaparin regimen for venous thromboembolism prophylaxis after hip or knee replacement or hip fracture surgery, provided that the second regimen was assessed elsewhere versus the same comparator. Two authors independently evaluated study eligibility, extracted the data, and assessed the risk of bias. The primary efficacy outcome was the incidence of venous thomboembolism. The main safety outcome was the incidence of major bleeding. Overall, 44 randomised comparisons in 56,423 patients were selected, 35 being double-blind (54,117 patients). Compared with enoxaparin 4,000 anti-Xa IU once daily, enoxaparin 3,000 anti-Xa IU twice daily was associated with a reduced risk of venous thromboembolism (relative risk [RR]: 0.53, 95% confidence interval [CI]: 0.40 to 0.69), but an increased risk of major bleeding (RR: 2.01, 95% CI: 1.23 to 3.29). In conclusion, when interpreting the benefit-risk ratio of new anticoagulant drugs versus enoxaparin for thromboprophylaxis after major orthopaedic surgery, the apparently greater efficacy but higher bleeding risk of the twice-daily 3,000 anti-Xa IU enoxaparin regimen compared to the once-daily 4,000 anti-Xa IU regimen should be taken into account.

Meta-analysis of low molecular weight heparin in the prevention of venous thromboembolism in general surgery.

BACKGROUND: Low molecular weight heparins (LMWHs) have become routine thromboprophylaxis in general surgery. However, their actual clinical effect, its magnitude relative to that of unfractionated heparin (UFH), and the optimal dose are still debated. METHODS: A meta-analysis was performed of all available randomized trials in general surgery comparing LMWH with placebo or no treatment, or with UFH. RESULTS: Comparison versus placebo or no treatment confirmed that the significant reduction in asymptomatic deep vein thrombosis (DVT) obtained with LMWH (n = 513; relative risk (RR) 0.28 (95 per cent confidence interval 0.14-0.54)) was associated with a significant reduction in clinical pulmonary embolism (n = 5456; RR 0.25 (0.08-0.79)) and clinical venous thromboembolism (VTE) (n = 4890; RR 0.29 (0.11-0.73)), and a trend towards a reduction in overall mortality rate. Comparison versus UFH showed a trend in favour of LMWH, with a significant reduction in clinical VTE (P = 0.049), a trend also found for cancer surgery. LMWH at doses below 3400 anti-Xa units seemed to be as effective as, and safer than, UFH, while higher doses yielded slightly superior efficacy but increased haemorrhagic risk, including that of major haemorrhage. CONCLUSION: Asymptomatic DVT may be regarded as a reliable surrogate endpoint for clinical outcome in studies investigating thromboprophylaxis in general surgery. LMWH seems to be as effective and safe as UFH. Determination of the optimal dose regimen of LMWH for this indication requires further investigation.

Venous thromboembolism during pregnancy: a retrospective study of enoxaparin safety in 624 pregnancies.

OBJECTIVE: To assess the maternal, fetal and neonatal safety of enoxaparin in pregnant women who require antithrombotic therapy. DESIGN: Retrospective analysis of case notes of women who received enoxaparin during pregnancy, irrespective of dose, duration and reason for treatment. SETTING: Fifty-five French perinatal centres. SAMPLE: Data from 624 pregnancies in 604 women between 1988 and 1997. The incidence of previous thromboembolism was 29.8%, known thrombophilia 15.2%. METHODS: Indication, regimen of enoxaparin and outcome measures were reported for each pregnancy. Information was obtained from case records, validated by research staff and analysed by an independent scientific committee. MAIN OUTCOME MEASURES: Incidence, seriousness and causality of maternal, fetal and neonatal adverse events, pregnancy outcome, and incidence of venous thromboembolism. RESULTS: Enoxaparin was administered for treatment of an acute episode in 49 cases and for thromboprophylaxis in 574 cases. Serious maternal haemorrhage occurred in 11 cases during pregnancy (1.8%), one being reasonably related to enoxaparin, and in nine cases at delivery (1.4%), all unrelated to enoxaparin. Maternal thrombocytopenia was reported in 10 cases (1.6%). two being serious but unrelated to enoxaparin. Eight pregnancies ended in stillbirth (1.1%). Among the 693 live births, 17 major congenital abnormalities (2.5%) and 10 serious neonatal haemorrhages (1.4%) were reported. None of the fetal or neonatal adverse events was related to enoxaparin. Eight venous thromboembolic events (1.3%) were reported. CONCLUSIONS: The incidence of adverse events reported could be explained by the high risk profile of the study population. Overall, this retrospective study suggests enoxaparin is well tolerated during pregnancy.

Treatment of heart failure with celiprolol, a cardioselective beta blocker with beta-2 agonist vasodilatory properties. The CELICARD Group.

Treatment with beta blockers results in improvement in functional status, and reduces mortality in patients with heart failure. A number of differences in the results noted could be due to additional properties of the specific beta blockers studied: absence of cardioselectivity, and existence of a vasodilator effect and of an associated antioxidant effect. We studied the effects of celiprolol, a cardioselective beta blocker with a stimulant effect on beta2 receptors. One hundred thirty-two patients presenting with chronic heart failure of various etiologies, with an ejection fraction of <40% and New York Heart Association cardiac functional status grades II and III were included in a randomized, double-blind, placebo-controlled study. The maximum dose of celiprolol (100 mg) was attained after 1 month. The study lasted 1 year. The primary evaluation criterion was functional class as evaluated using the Goldman questionnaire. There was no difference in efficacy between the 2 treatment groups in terms of functional class (p = 0.56). With regard to the secondary evaluation criteria, an improvement in DiBianco functional score was seen with celiprolol (p = 0.03), as well as a significant reduction in heart rate (p = 0.01). Ejection fraction increased in both groups (p = 0.15). There was no difference regarding improvement in left ventricular volume as determined at echocardiography or in exercise capacity. The safety profile of celiprolol was excellent. There was no difference in terms of cardiovascular mortality (2 receiving celiprolol vs 4 placebo), onset of arrhythmias (2 receiving celiprolol vs 3 placebo), worsening of heart failure (26 receiving celiprolol vs 23 placebo), or noncardiovascular adverse events (9 receiving celiprolol vs 14 placebo). The absence of a significant efficacy of celiprolol, a beta blocker with vasodilator properties, but exerting stimulation of beta2 receptors, suggests an unfavorable role of this latter property in heart failure. However, the safety profile of celiprolol was excellent. This beta blocker may consequently be used for its other indications, hypertension and angina, in patients presenting with altered cardiac function.

A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. Prophylaxis in Medical Patients with Enoxaparin Study Group.

BACKGROUND: The efficacy and safety of thromboprophylaxis in patients with acute medical illnesses who may be at risk for venous thromboembolism have not been determined in adequately designed trials. METHODS: In a double-blind study, we randomly assigned 1102 hospitalized patients older than 40 years to receive 40 mg of enoxaparin, 20 mg of enoxaparin, or placebo subcutaneously once daily for 6 to 14 days. Most patients were not in an intensive care unit. The primary outcome was venous thromboembolism between days 1 and 14, defined as deep-vein thrombosis detected by bilateral venography (or duplex ultrasonography) between days 6 and 14 (or earlier if clinically indicated) or documented pulmonary embolism. The duration of follow-up was three months. RESULTS: The primary outcome could be assessed in 866 patients. The incidence of venous thromboembolism was significantly lower in the group that received 40 mg of enoxaparin (5.5 percent [16 of 291 patients]) than in the group that received placebo (14.9 percent [43 of 288 patients]) (relative risk, 0.37; 97.6 percent confidence interval, 0.22 to 0.63; P< 0.001). The benefit observed with 40 mg of enoxaparin was maintained at three months. There was no significant difference in the incidence of venous thromboembolism between the group that received 20 mg of enoxaparin (43 of 287 patients [15.0 percent]) and the placebo group. The incidence of adverse effects did not differ significantly between the placebo group and either enoxaparin group. By day 110, 50 patients had died in the placebo group (13.9 percent), 51 had died in the 20-mg group (14.7 percent), and 41 had died in the 40-mg group (11.4 percent); the differences were not significant. CONCLUSIONS: Prophylactic treatment with 40 mg of enoxaparin subcutaneously per day safely and effectively reduces the risk of venous thromboembolism in patients with acute medical illnesses.

Risk of deep-venous thrombosis after hospital discharge in patients having undergone total hip replacement: double-blind randomised comparison of enoxaparin versus placebo.

BACKGROUND: The risk of deep-vein thrombosis (DVT) and pulmonary embolism after total hip replacement (THR) surgery may persist after hospital discharge, but the extent of the risk is not known. We carried out a single-centre, prospective, randomised, double-blind trial with the aims of quantifying this risk and assessing the efficacy of continued prophylactic treatment. METHODS: At hospital discharge 13-15 days after surgery, we recruited 179 consecutive THR patients who had no DVT visible on bilateral ascending venography of the legs. The patients were randomly assigned subcutaneous enoxaparin (40 mg, once daily; n = 90) or placebo (n = 89) for 21 (19-23) days. The primary endpoint was the occurrence of DVT or pulmonary embolism. Venography was repeated at the end of 21 days' treatment or earlier if necessary. FINDINGS: There were no deaths and no symptomatic pulmonary embolisms during the study or follow-up periods. Of 173 patients with evaluable venograms, intention-to-treat analysis of efficacy showed that the rate of DVT at day 21 after discharge was significantly lower in the enoxaparin group than in the placebo group (6 [7.1%] vs 17 [19.3%], p = 0.018). Distal DVT was detected in one (1.2%) patient in the enoxaparin group and in ten (11.4%) patients in the placebo group (p = 0.006). Proximal DVT was observed in five (5.9%) patients in the enoxaparin group and in seven (7.9%) patients in the placebo group (p = 0.592). A perprotocol analysis of efficacy in 155 patients confirmed these findings. Safety was good; three minor bleeding episodes occurred in the enoxaparin group and one in the placebo group, but none of these episodes necessitated withdrawal from the study. INTERPRETATION: In patients who have undergone THR surgery, are without venogram-proven DVT at hospital discharge, and do not receive antithrombotic prophylaxis after discharge, the risk of late-occurring DVT remains high at least until day 35 after surgery. Continued prophylaxis with enoxaparin is effective and safe in reducing this risk.

Efficacy and safety of postdischarge administration of enoxaparin in the prevention of deep venous thrombosis after total hip replacement. A prospective randomised double-blind placebo-controlled trial.

Although venous thromboembolism has occasionally been reported after hospital discharge in patients who have undergone total hip replacement (THR), this risk has not been fully quantified and the usefulness of a prophylactic treatment has not been evaluated. We conducted a single-centre prospective randomised double-blind clinical trial in 2 parallel groups of patients who had undergone THR and were free of deep venous thrombosis (DVT) at discharge, as assessed by bilateral ascending venography. During hospitalisation, all patients received a low molecular weight heparin, enoxaparin (enoxaparin sodium), as a prophylactic treatment for venous thromboembolism. Just before hospital discharge (15 +/- 1 days from surgery) 179 consecutive patients were randomly assigned to receive subcutaneous enoxaparin 40mg (n = 90) or placebo (n = 89) once daily for 21 +/- 2 days. The primary efficacy outcome was defined as the occurrence of DVT and/or documented pulmonary embolism (PE). DVT was assessed by ascending bilateral venography performed 21 +/- 2 days after randomisation or earlier if necessary. Secondary efficacy outcomes were the occurrence of proximal and distal DVT. Safety outcomes were defined as the occurrence of major and minor haemorrhage, other adverse events and changes in laboratory parameters. All patients underwent a 3-month follow-up. There were no deaths or cases of clinical PE during the study and the follow-up periods. In 173 patients with evaluable venograms, analysis of efficacy on an intention-to-treat basis showed that the incidence of DVT at day 21 was significantly lower in the enoxaparin group (6 of 85; 7.1%) than in the placebo group (17 of 88; 19.3%; p = 0.018), a risk reduction of 63%. Distal DVT was less frequent in the enoxaparin group than in the placebo group (1.2 vs 11.4%; p = 0.006) but there was no significant difference between groups in the incidence of proximal DVT. A 'per-protocol' analysis of efficacy in 155 patients confirmed the results for total and distal DVT, but also showed a trend in efficacy in favour of enoxaparin with regard to the incidence of proximal DVT (p = 0.064). Enoxaparin was safe in comparison with placebo: only 2 minor bleedings occurred in the enoxaparin group and there was no difference in the incidence of other adverse events between the 2 groups. In patients undergoing THR, the risk of late-occurring DVT remained high during the 21 days after hospital discharge in the placebo group. Prophylactic treatment with enoxaparin reduced the risk and was well tolerated in this context.

Nicorandil safety in the long-term treatment of coronary heart disease.

The results of an open prospective study that evaluated the long-term clinical safety of nicorandil are presented. This study included 199 patients with severe chronic stable angina treated over a 1-year period. The most often reported adverse event was headache, which was responsible for most of the study withdrawals due to clinical intolerance (9.6%). When using a progressive titration scheme, this incidence was substantially reduced to 2.7%. As with other less frequent adverse events (dizziness, gastrointestinal disorders), headaches were reported as being mild to moderate in severity, were experienced during the first days of treatment, and, if treatment was maintained, usually resolved within a few days. The incidence of adverse events was not modified when nicorandil was given in combination with a beta-blocker, a calcium antagonist, or both agents. Cardiovascular safety was satisfactory and laboratory parameters were not altered. At the end of the study, 70% of patients were maintained on nicorandil. These results are in agreement with those reported from the nicorandil safety database, which gathered 1152 patients treated by nicorandil, including those of the present study. In comparative studies of nicorandil versus beta-blockers, calcium antagonists, or nitrates, the overall incidence of adverse events was no different between the two treatment groups, although the safety profile differed according to the drug category.(ABSTRACT TRUNCATED AT 250 WORDS)

Oxidative stress in patients with unstable angina.

The aim of this study was to determine whether oxidative stress occurs in unstable angina. Thirty patients with unstable angina class B (Braunwald classification) were prospectively studied. Control groups consisted of 23 patients presenting with stable angina and of 21 age-matched healthy volunteers. Upon admission and every 8 h for 24 h, blood samples were drawn for the determination of plasma malondialdehyde (MDA) levels, Se-glutathione peroxidase (GPX) activity, erythrocyte reduced glutathione (GSH) concentrations, erythrocyte GPX and superoxide dismutase (SOD) activities. Coronary angiograms were performed within 4 days of admission in 26 out of the 30 patients included in the study. Nine of these 30 patients were subsequently identified as presenting a non-Q wave myocardial infarction and were separately examined. On admission, only plasma MDA levels and erythrocyte GSH concentrations differed among groups. Plasma MDA levels of patients presenting with unstable angina (P < 0.01) and acute myocardial infarction (P < 0.05) were higher than those of patients with stable angina and of normal volunteers, whereas there was no difference in these parameters between unstable angina and non-Q wave myocardial infarction groups. Erythrocyte GSH concentration was lower in all patient groups as compared to normal subjects. ANOVA for repeated measures showed no difference between admission and subsequent levels for all parameters. Finally, no difference was observed for any of the parameters when anti-ischaemic or anti-aggregant treatment before admission, or the number of affected vessels on coronary angiograms, were considered. We conclude that an oxidative stress can be evidenced in patients with unstable angina or acute myocardial infarction.

[Necrotizing fasciitis, caused by Neisseria meningitidis, simultaneously involving an arm and a leg]. / Fasciite nécrosante à Neisseria meningitidis atteignant simultanément le bras et la jambe.

INTRODUCTION: Necrotizing fasciitis is usually due to Streptococcus species but can be caused by a variety of organisms, among which Neisseria species are distinctly rare, as only four cases have been reported in the literature. CASE REPORT: We report the first case of Neisseria meningitidis necrotizing fasciitis in a non-immunocompromised man, with a possibly predisposing effect of non-steroidal anti-inflammatory drugs. Neisseria meningitidis group C was isolated from subcutaneous and bullae aspirates. The involvement of two distant sites strongly suggests hematogenous dissemination of the microorganism. Four previous cases of fasciitis caused by Neisseria species are reviewed. CONCLUSION: Although Streptococcus group A is the main cause of apparently primary necrotizing fasciitis, Neisseria meningitidis must be considered a possible etiologic agent of this severe soft tissue infection.

Evaluation of risk factors for laryngeal edema after tracheal extubation in adults and its prevention by dexamethasone. A placebo-controlled, double-blind, multicenter study.

Because laryngeal edema (LE) after tracheal extubation is likely to result from an exudative response, corticosteroids often are given routinely as a preventive treatment. No adequate controlled study supports this strategy, however. A prospective, randomized, placebo-controlled, double-blind, multicenter trial that included 700 consecutive patients requiring tracheal intubation and mechanical ventilation was conducted to determine risk factors for LE occurrence after tracheal extubation in adults and to evaluate the efficacy of corticosteroids in its prevention. One hour before extubation, patients were given either an intravenous bolus of 8 mg dexamethasone or a placebo. Patients were divided into two groups: 1) those in whom short-duration intubation (SDI, less than 36 h) was administered; and 2) those in whom long-duration intubation (LDI, more than 36 h) was administered. Minor LE was diagnosed when either stridor or laryngeal dyspnea, or both, occurred; major LE was diagnosed when reintubation due to LE was required, with LE evidenced during direct laryngoscopy. The overall incidence of LE was 4.2% and varied among the six participating centers from 2.3 to 6.9% (not significant). In only seven patients (1%), all with LDI, was tracheal reintubation required for LE. Laryngeal edema occurred more frequently after LDI than after SDI (7.2 vs. 0.9%; P less than 0.001). It also was more frequent in female than in male patients (20/284 vs. 8/379; P less than 0.05), irrespective of intubation duration and treatment. There was no association between LE and either difficulty/route of intubation or admission diagnosis.(ABSTRACT TRUNCATED AT 250 WORDS)

[Diagnosis of severe pulmonary embolism by transesophageal echocardiography]. / Diagnostic d'embolie pulmonaire grave par échocardiographie transoesophagienne.

A 56-year-old woman was admitted to the Emergency Department for profuse diarrhoea, associated with hypokaliemia and dehydration. A subclavian venous catheter was inserted after she had a cardiac arrest. Six days later, the subclavian and innominate veins were thrombosed. Prophylactic low molecular weight heparin was then replaced by sodium heparinate. The patient's platelet count decreased to 65 G.1-1. It was nevertheless decided to remove her villous tumour. After the operation, the patient became shocked, with worsening thrombocytopaenia (15 G.1-1). She was unresponsive to fluid replacement. Transoesophageal echocardiography (TEE) was carried out, as pulmonary arterial catheterization was considered too dangerous. A "white" thromboembolus was discovered in the right pulmonary artery. Embolectomy was successfully performed without extracorporeal circulation. Flow was completely restored in the main pulmonary artery, but only partially in the right branch. Oral anticoagulation was started postoperatively. It is concluded that TEE might be a very helpful technique to promptly diagnose acute pulmonary embolism; moreover, it could be an alternative to pulmonary angiography, especially in patients in a poor state.

Involvement of ANF in the acute antidiuresis during PEEP ventilation.

To investigate the potential role of natriuretic factor (ANF) on changes on renal excretory function in response to increased intrathoracic pressure, seven patients were studied during three successive 60-min periods of 1) mechanical ventilation (MV) and zero end-expiratory pressure (ZEEP), 2) MV with 12 cmH2O positive end-expiratory pressure (PEEP), and 3) MV with the same level of PEEP while lower-body positive pressure (LBPP) was applied to restore venous return and increase central blood volume without fluid loading. Hemodynamics, renal excretory function parameters, and plasma immunoreactive atrial natriuretic factor (irANF) levels were recorded at the end of each period. Compared with ZEEP, PEEP induced a significant reduction of diuresis (from 134 +/- 17 to 59 +/- 13 ml/h, P less than 0.01) and natriuresis (from 8.37 +/- 3.5 to 3.83 +/- 2 mmol/h, P less than 0.01), whereas plasma irANF fell from 520 +/- 292 to 155 +/- 40 pg/ml (P less than 0.01) and transmural right atrial pressure decreased from 3.9 +/- 0.5 to 2.4 +/- 0.3 mmHg (P less than 0.01). Opposite changes were observed during application of LBPP, which restored diuresis and plasma irANF to near control ZEEP values, despite continuation of PEEP. Changes in renal excretory function parameters thus paralleled changes in right atrial pressure and plasma irANF. We suggest that changes in plasma irANF in response to hemodynamic variations induced by changes in intrathoracic pressure may contribute to alterations of renal excretory function during PEEP.