Jean-Yves Darmon

A COMPARISON OF ENOXAPARIN WITH PLACEBO FOR THE PREVENTION OF VENOUS THROMBOEMBOLISM IN ACUTELY ILL MEDICAL PATIENTS

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.

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.

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)

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

SummaryAlthough 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). En-oxaparin 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

SummaryThe 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. During the course of several clinical studies, nicorandil was associated with antihypertensive, antidiabetic, hypolipemic, or other antianginal agents; these combinations did not increase the incidence of adverse events or study withdrawals. In all long-term clinical studies using doses up to 80 mg/day, nicorandil has had a favorable cardiovascular safety profile. There were no meaningful changes in heart rate and blood pressure, and ECG at rest and during exercise did not show rhythm or conduction disorders or QT- and ST-segment modification. Up to now, there has been no evidence that nicorandil exerts a negative inotropic effect. The nicorandil safety profile was not different in patients aged over 65 years (33%). Finally, nicorandil did not affect the usual laboratory parameters, including blood potassium and glucose levels, and the blood lipid profile. Therefore, nicorandil, alone or in combination, appears to be a safe, active antianginal agent for the long-term treatment of a wide range of patients with chronic stable angina.

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

Venous thromboembolism is much more frequent in pregnant women than in nonpregnant women of similar age, and it remains a major cause of maternal morbidity and mortality. Low-molecular-weight heparins such as enoxaparin are more bioavailable and have longer half-lives than unfractionated heparin, and they produce more predictable responses. For these reasons they have become the standard for preventing and treating venous thromboembolism in nonpregnant individuals. There also is a convenience factor, because these heparins may be self-administered at home for long periods. The risks of thrombocytopenia and osteoporosis may be less than with unfractionated heparin. This retrospective study enrolled 604 enoxaparin-treated women with 624 pregnancies, seen at 55 perinatal centers in France in the years 1988-1997. The agent was used prophylactically in 92% of cases and to treat acute venous thromboembolism in 8%. Previous thromboembolism was recorded in 30% of women, and known thrombophilia, in 15%. Treatment began in the first, second, and third trimesters in 8%, 25%, and 67% of women, respectively. Nearly one third of deliveries were within 24 hours of the last injection. A mean daily dose of 97 mg (1 mg/kg twice daily) was delivered for a mean time of 84 ½ days. There were eight documented venous thrombolic episodes (1.3%), five before delivery and three afterward. None of these women were known to be thrombophilic when entering the study. Adverse events were recorded in 38% of women. Eleven of 72 hemorrhages were viewed as serious; five of these women had placental abruption, and three, placenta previa. None of 32 bleeds occurring at delivery were considered to be serious. The incidence of maternal thrombocytopenia was 1.6%; neither of the two serious cases seemed related to enoxaparin. No other adverse events could be related to enoxaparin. The rate of preterm gestation was 28% and of stillbirth, 1.1%. No stillbirth was ascribed to enoxaparin administration. Serious hemorrhage occurred in 1.4% of newborn infants, including five intraventricular bleeds and a total of nine intracranial hemorrhages, all in premature infants. Major congenital abnormalities occurred in 2.5% of infants. These findings signify that enoxaparin is well tolerated by pregnant women. In this review, adverse events could be accounted for by the study groups high-risk profile.