Subjects were then crossed over to the alternate therapy and followed for a further 12 weeks 36 dialyses. Infusion was discontinued 1 h prior to cessation of HD. Activated coagulation times were monitored hourly using an Actester Trimed to maintain times around s early in the HD session and s later in the session. Anticoagulation was monitored by visual inspection of the arterial bubble trap every 30—60 min.
The Clexane dose was titrated if indicated clinically see below. The cost per treatment was calculated for each therapy by including the cost of the drug and disposable items. The calculations thus included the average cost of dialyser, blood lines, heparin syringes, and normal saline priming solutions but excluded nursing time.
Costs of disposable items Actester tubes, syringes, and needles for activated coagulation times were included in cost per treatment using heparin. The cost of adverse events included the cost of syringes, drugs e.
The latter was based on the standard daily cost of a hospital bed in our facility. This assessment was carried out after the blood had been returned to the patient by flushing the dialyser and lines with normal saline.
Episodes of adverse events such as haemorrhage or thrombosis either during or between dialyses were also noted. The Clexane dose was reduced by 0. Fasting standard lipid profiles were determined pre-dialysis at baseline week 0 and at the end of each arm of the study.
Total cholesterol TC , high-density lipoprotein cholesterol HDL , and triglyceride concentrations Trigs were measured on a high-throughput autoanalyser Hitachi using reagents supplied by Boehringer Mannheim Germany. Paired data was compared using the paired t-test.
Non-parametric data was compared using Mann—Whitney rank sum test. The significance of proportions was assessed by the z-test. The study was designed as a prospective, randomized, cross-over study, with patients randomly assigned to receive either unfractionated heparin or Clexane as the first mode of treatment. However, as no difference was noted between the two sections of the study for any of the parameters measured, data for each phase was pooled.
Five subjects did not finish the study: three received renal transplants, one changed to CAPD, and one required hospitalization for amputation of a leg because of arterial occlusive disease. The appearance of significant clots grades 4—10 in both lines and dialysers was infrequent, with no difference using either type of heparin.
Clexane use was accompanied by a significantly higher frequency of minor haemorrhage between dialyses 7. During the course of the Clexane arm of the study, prolonged or recurrent blood oozing from needle puncture sites between dialyses in a few patients suggested that the dose recommended by the manufacturer might have been excessive for some patients.
Consequently the Clexane dose was reviewed during the trial, and the dose reduced in those affected patients. The mean dose in our patients at the end of the study was 0. One patient experienced significant extracorporeal clotting, and eventually required a dose of 1.
Ninety per cent of patients were anticoagulated with 0. The frequency of minor clotting grades 2—4 was unchanged, but the frequency of clear dialysers grade 1 fell slightly A measure of haemostasis at the puncture sites was obtained by recording vascular access clotting times at the end of haemodialysis with a stop-watch.
There was no significant difference in clotting times for either anticoagulation modality Table 3. Three patients received packed-cell transfusions while on Clexane compared to two during the heparin arm. Data was available for 20 patients.
There was no difference between the groups 1. No changes in serum lipids were observed with either anticoagulant Table 4. The median cost of adverse events arising from Clexane anticoagulation was slightly higher than with heparin 1. While the benefits of LMW heparin over standard, unfractionated heparin in the treatment and prophylaxis of venous thromboembolism are well established, the relative merits of LMW heparin for haemodialysis coagulation are less clear.
The ease of administration of LMW heparin single bolus pre-dialysis and lack of laboratory monitoring would seem clear advantages. However, early in the course of the Clexane arm of the study, we observed an increased frequency of minor interdialytic haemorrhage none requiring clinical intervention. This problem may not become apparent until after several 4—8 dialyses.
Moderate and severe haemorrhagic events, however, were rare in both heparin groups; moreover, there was no difference in the frequency of haemorrhage or thrombosis between the groups. If the initial phase of minor bleeding between dialyses is discounted, our observations are in line with earlier studies comparing Fragmin [ 19 ], Braun [ 20 ], and Fraxiparin [ 21 ] with unfractionated heparin.
While the study was not specifically a dose-finding study, we began with the manufacturer's recommended dose for Clexane. The bleeding tendency between dialyses led to a re-examination of patients' doses, and downward dose adjustment in several patients.
Two earlier studies have similarly used lower doses than recommended by the manufacturer. In an extended trial involving consecutive haemodialyses in 35 HD patients, other researchers used enoxaparin 0. However, the frequency of minor bleeding was still significantly higher with enoxaparin than with unfractionated heparin 4.
The primary purpose of anticoagulation during haemodialysis is of course the prevention of thrombosis in the extracorporeal circuit, and in this respect Clexane was more effective than unfractionated heparin.
This accords with previous studies of enoxaparin. Vukusich et al. In our study, dose titration had very little overall effect on clotting frequencies associated with Clexane use. This suggested that blood flow through the dialysers, and hence solute clearances, were not significantly affected by the choice of anticoagulant.
In addition to its anticoagulation properties, unfractionated heparin is known to release lipoprotein lipase from its active site at the capillary endothelial surface. Preliminary studies with LMWH suggested beneficial effects on the lipid metabolism of haemodialysis patients, but this has not been supported by later, larger studies, at least in the short term [ 11 , 18 ].
The cross-sectional, multicentre study of Kronenberg et al. Only 18 of these patients were treated with enoxaparin. A smaller study of 36 patients using three LMWH preparations including enoxaparin for 6 months, found no effects on cholesterol or triglyceride concentrations [ 16 ]. However, the longer-term study of Spaia et al. Of note is that the lipid parameters returned to baseline in the 10 patients switched back to unfractionated heparin for 6 months.
In the latter two studies mentioned above [ 16 , 24 ] enoxaparin was given both as an initial bolus and as a continuous infusion during the HD session. It is therefore possible that differences in the mode of administration may have a bearing on differences found between studies, a point raised by Kronenberg et al.
In our study, enoxaparin was administered as a bolus dose prior to haemodialysis, and we observed no beneficial effects on lipids over 12 weeks.
Two important points in relation to our lipid findings should be noted. First, care was taken not to alter any of the patients' lipid-lowering therapies or diet. Secondly, although apo E isotyping was not undertaken in this study, any possible heterogeneity effect was negated by treating all patients with both types of heparin.
In conclusion, Clexane should be considered as an effective, safe and convenient alternative to conventional heparin anticoagulation in haemodialysis patients.
However, with more widespread usage the price of Clexane is likely to reduce and the small extra cost is counterbalanced by the convenience of administration. This is approximately We are indebted to Srs J.
Boys, C. Kelly, J. Best, and N. Activated partial thromboplastin times APTTs for the study patients during initial treatment according to treatment group and test sequence. Black boxes indicate patients receiving low-molecular-weight heparin; gray boxes, patients receiving intravenous heparin; top and bottom of each box, upper and lower quantities, respectively, of the values for the sample; circles, medians; and bars above and below each box, maximal and minimal values, respectively, in the sample or, if there are extreme data points, to limits based on the interquartile range, defined as the distance from the lower quartile to the upper quartile.
Outliers beyond these limits are plotted separately. The first 3 tests reflect the results of the 4 to 6 daily tests obtained on the first day; thereafter the tests were performed daily. Chromogenic Xa assay findings for the study patients during initial treatment according to treatment group and test sequence. The first 3 tests reflect results of the 4 to 6 daily tests obtained on the first day; thereafter the tests were performed daily. Arch Intern Med.
Low-molecular-weight heparin treatment is effective and safe in patients with deep vein thrombosis and may also be so in patients with PE. Recent rigorous clinical trials have established objective criteria for determining a high probability of PE by perfusion lung scanning. Objective To compare low-molecular-weight heparin with intravenous heparin for the treatment of patients with objectively documented PE and underlying proximal deep vein thrombosis.
Methods In a multicenter, double-blind, randomized trial, we compared fixed-dose subcutaneous low-molecular-weight heparin tinzaparin sodium given once daily with dose-adjusted intravenous heparin given by continuous infusion using objective documentation of clinical outcomes. Pulmonary embolism at study entry was documented by the presence of high-probability lung scan findings. Results Of patients with high-probability lung scan findings at study entry, none of the 97 who received low-molecular-weight heparin had new episodes of venous thromboembolism compared with 7 6.
Major bleeding associated with initial therapy occurred in 1 patient 1. Conclusions Low-molecular-weight heparin administered once daily subcutaneously was no less effective and probably more effective than use of dose-adjusted intravenous unfractionated heparin for preventing recurrent venous thromboembolism in patients with PE and associated proximal deep vein thrombosis.
Our findings extend the use of low-molecular-weight heparin without anticoagulant monitoring to patients with submassive PE. Pulmonary embolism commonly occurs in patients presenting to the hospital.
Use of accurate objective tests to detect venous thromboembolism VTE 6 - 8 , 11 - 18 has led to randomized trials 19 - 28 of treatment for venous thrombosis. These trials have shown that the initial heparin treatment intensity must be sufficient to prevent recurrent VTE.
Low-molecular-weight heparin fractions have a mean molecular weight of to d by comparison, conventional heparin has a mean molecular weight of 12, to 16, d. Anticoagulant monitoring of certain low-molecular-weight heparin fractions is unnecessary because of a predictable anticoagulant response when administered subcutaneously in weight-based doses. We conducted a double-blind, randomized trial comparing low-molecular-weight heparin tinzaparin sodium with intravenous heparin treatment in patients with objectively documented proximal DVT.
Recent rigorous clinical trials 18 , 53 - 55 have established objective criteria for determining a high probability of PE by perfusion lung scanning. Almost half This finding and the randomized trial design allowed us to compare low-molecular-weight heparin vs unfractionated heparin treatment in patients with objectively documented PE and proximal DVT. Our objective was to determine whether low-molecular-weight heparin administered subcutaneously once daily without anticoagulant monitoring is effective and safe in such patients.
The American-Canadian Thrombosis Study 45 was a multicenter, randomized, double-blind clinical trial comparing unfractionated continuous intravenous heparin therapy with once-daily subcutaneous low-molecular-weight heparin therapy in patients with acute proximal DVT.
The protocol mandated objective testing for PE in all patients at study entry. Fifteen centers in the United States and Canada participated in the trial. The protocol was approved by the institutional review board at each center. Consecutive eligible patients aged 18 years and older with proximal DVT thrombosis of the popliteal or more proximal veins of the legs documented by venography were enrolled in the study.
Eligible patients were excluded if they received treatment with warfarin sodium, low-molecular-weight heparin, or heparinoids within 7 days before study entry; if they received treatment with therapeutic subcutaneous heparin within the preceding 12 hours; were receiving intravenous heparin; or if they declined to give written informed consent. A randomized, computer-derived treatment schedule was used to assign patients to receive intravenous heparin or subcutaneous low-molecular-weight heparin.
Within each stratum, the randomization schedule was balanced in blocks of 4. In each patient, anticoagulant drug therapy was started as soon as possible after proximal DVT had been documented objectively, by ascending contrast venography 8 , 11 or by impedance plethysmography 6 , 7 , 12 or B-mode imaging using venous compression. Patients in the intravenous heparin group received an initial bolus dose of US Pharmocopeia units of heparin followed by continuous intravenous infusion of heparin.
The initial dose was 40, U every 24 hours for patients without the designated risk factors for bleeding and 29, U every 24 hours for those with 1 or more designated risk factors. The doses were chosen to minimize the risk of insufficient heparin treatment during the first 24 hours of therapy 22 , 28 - 32 and to avoid high initial doses of heparin in patients with designated risk factors for bleeding.
The dose of intravenous heparin was adjusted according to the results of laboratory monitoring using the activated partial thromboplastin time APTT. Thereafter, the APTT was measured once daily; if the result was subtherapeutic, the test was repeated every 4 hours until the therapeutic range was regained.
Patients receiving low-molecular-weight heparin were given a fixed dose of International Factor Xa Inhibitory Units per kilogram of body weight subcutaneously once every 24 hours. This regimen was chosen because results of pharmacokinetic studies in normal subjects demonstrated that it produced a sustained anticoagulant response anti-factor Xa activity throughout the hour dosing period and did not produce a substantial accumulation of the anticoagulant effect when given for 5 to 6 days.
All patients received long-term therapy with warfarin sodium for at least 3 months. The initial dose was 10 mg given on the second day of initial therapy, which was then adjusted to maintain the international normalized ratio between 2. Treatment with intravenous heparin or subcutaneous low-molecular-weight heparin was discontinued on the sixth day provided that the international normalized ratio was 2.
The study used a double-blind design. Patients who were randomly assigned to receive intravenous heparin also received a subcutaneous placebo injection once every 24 hours. Patients assigned to receive subcutaneous low-molecular-weight heparin also received an intravenous placebo bolus and a continuous intravenous infusion of placebo throughout initial therapy.
To maintain double-blinding, APTTs were reported only to a member of the health care team not involved in assessing the patient's outcome. The APTT was not recorded on the patient's medical chart during the study or reported to any other member of the health care team. Adjustments in the rate of intravenous infusion of heparin or placebo were made by an unblinded physician according to dosing schedules established before the trial began.
Use of drugs containing aspirin was prohibited during the study. Use of sulfinpyrazone, dipyridamole, and indomethacin was strongly discouraged. All patients were examined daily during initial therapy; symptoms or signs of recurrent DVT, PE, or bleeding were sought. Perfusion lung scanning was performed in all patients within 48 hours of study entry.
The diagnosis of PE on study entry was established according to published criteria for perfusion lung scanning. Patients with suspected recurrent PE underwent objective testing as described immediately above.
Those with suspected recurrent venous thrombosis underwent impedance plethysmography and venography; the diagnostic criteria are described elsewhere. Bleeding was classified as major or minor according to criteria described elsewhere.
Data on the outcome measures of effectiveness recurrent VTE , safety bleeding complications , and patient deaths were interpreted by a central adjudicating committee. Adjudication was made by 2 committee members not involved in the patient's care; disputes were resolved independently by a third. Objective test results were interpreted independently and without the interpreter's knowledge of the patient's other results, clinical findings, or treatment group. Ninety-five percent confidence limits for the true incidences of recurrent VTE and bleeding complications were calculated from the binomial distribution.
Confidence intervals for the difference between the 2 treatment groups in the incidence of recurrent VTE and bleeding complications were calculated using the normal approximation to the binomial distribution. The log-rank test was used to assess differences in the cumulative incidence of death and recurrent VTE. Of consecutive patients with proximal DVT enrolled in the study, Of these patients, Lung scanning was not feasible in 13 3.
High-probability perfusion lung scan findings were present in The treatment groups were comparable at entry except for age; there were more elderly patients in the low-molecular-weight heparin group Table 1. To assess the possible effect of this age imbalance, multiple logistic regression was used; no significant effect of age was found. All patients were followed up during initial therapy and during 3 months of long-term therapy; none were lost to follow-up. Frequencies of recurrent VTE are shown in Table 2.
All patients presented with overt signs and symptoms of VTE. Of 7 patients in the intravenous heparin group with new episodes of VTE, 4 had new episodes of PE all identified by new high-probability lung scan findings.
Recurrent venous thrombosis was documented by venography in 1 patient and by impedance plethysmography in the remaining 2. The APTT during initial heparin treatment was in the therapeutic range in 6 of 7 patients. During long-term follow-up, subtherapeutic prothrombin times were noted before or at the time of the recurrent thromboembolic event in only 2 of 7 patients who were receiving intravenous heparin. There were no episodes of recurrent VTE during initial treatment or long-term follow-up of patients receiving low-molecular-weight heparin.
The frequency of bleeding complications during or immediately after initial treatment is shown in Table 2. Although conducting immunogenicity testing for this product can be an extensive and time-consuming process for a manufacturer, all manufacturers of generic enoxaparin are expected to do this as part of the application process.
These studies evaluated impurities using physiochemical and biological assays. Were the heparin contamination issues in taken into account for FDA approval of enoxaparin? In early , there was a severe medication crisis in the U. There were reported deaths in the United States following administration of heparin between January 1, , and May 31, , of which were reported to the FDA in Because enoxaparin is made from standard heparin, it is important to ensure that the enoxaparin products have not been contaminated, and that the manufacturing processes for heparin and enoxaparin will meet rigorous production standards to avoid future contamination.
FDA used these inspections to assess whether heparin production facilities have adequate controls to prevent contamination or other quality defects. Inspections conducted by FDA revealed some suppliers of heparin material for the U.
Have inspections of all facilities involved in the importing or exporting of product to the U. FDA inspects both domestic and foreign manufacturing facilities to assess compliance with current good manufacturing practice CGMP.
The CGMP requirements for drugs include requirements for the methods, facilities, and controls used in manufacturing, processing, and packing of a drug.
CGMP requirements help to assure the identity, strength, quality, and purity of drugs. The approval process for generic drug marketing applications, including those for generic enoxaparin, includes a review of the manufacturer's compliance with CGMP. FDA investigators determine whether the firm has the necessary facilities, methods, and controls to manufacture the drugs. Decisions regarding compliance with CGMP regulations are based upon inspection of the facilities, sample analyses, and compliance history of the company.
Manufacturers are held to the same standards by FDA to assure the identity, strength, quality, and purity of drugs. Is generic enoxaparin the first product approved in the U. In addition to enoxaparin which is made from heparin derived from pig intestines , other products made from animal sources have been approved as generic products under the Federal Food, Drug, and Cosmetic Act FFDCA , the same law that governs chemically-manufactured drugs. For example, FDA has approved generic versions of standard heparin for many years.
Although FDA regularly takes note of the actions of other national or international regulatory authorities, those actions do not constrain our decision-making. Different regulatory authorities, such as the European Medicines Agency EMA , have different standards and procedures for the review and approval of drugs and biological products. The EMA has set guidelines for LMWH products such as enoxaparin that only require the products to contain a similar as opposed to the same active ingredient to that contained in another already marketed LMWH product.
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