TREATMENT OF THROMBOSIS
Deep venous thrombosis
The causes of deep vein thrombosis are multifactorial and result from an abnormality of 1 or all the components of Virchow's triad, alteration in flow pattern in the vessel, damage to the vessel wall, or a hypercoagulable state of circulating blood in the vessel. DVT can be asymptomatic and remain undetected clinically or it can manifest as local tenderness or impaired drainage of blood distal to the obstruction. Apart from producing local symptoms deep venous thrombi can embolize and give rise to a pulmonary embolus. The more proximal to the heart the deep venous thrombosis, the higher the incidence of pulmonary embolism.
In patients with established deep venous thrombosis, the role of anticoagulation is to prevent clot propagation and prevent new clot formation. Standard treatment for patients with symptomatic venous thromboembolism is hospital admission and administration of unfractionated heparin intravenously for 5 to 10 days followed by oral anticoagulation for at least 3 months.60,61 In a selected group of inpatients with DVT daily subcutaneous LMWH (CY 216 Fraxiparine, Sanofi, New York, NY) was equally effective and safe compared with standard unfractionated heparin.62,63
LMWH has also been studied in the prevention of DVT in patients at high risk of developing DVT and was found to be as effective in this population.2,29,64 With encouraging efficacy and safety results from earlier trials, LMWH was evaluated in the treatment of patients with deep venous thrombosis. Though several trials and metaanalyses have demonstrated the safety and efficacy of LMWH in treating patients with deep venous thrombosis, skepticism has prevented widespread incorporation into clinical practice primarily because these studies excluded patients with symptomatic PE and those with a history of recurrent DVT.65
A large study was recently reported addressing the issue of using LMWH in treating patients with DVT or associated PE.66 Several additional randomized trials evaluating LMWH and unfractionated heparin in the treatment of venous thromboembolism were published in the last 2 decades.62,63,67,68 Two recent metaanalyses69,70 summarized the results of these studies with particular focus on defining the safety and efficacy of LMWH compared with that of unfractionated heparin in treating patients with thromboembolism.
In the metaanalysis by Lensing and colleagues69 data was pooled from ten randomized trials evaluating safety and efficacy of LMWH with that of unfractionated heparin. The size of venous thrombosis was evaluated by ultrasound or by venogram at the time of enrollment and at followup. There was a statistically significant reduction (18%-73%) in the development of recurrent thromboembolic complications in patients treated with LMWH. Only 3.1% of patients in the LMWH group developed thromboembolic complications compared with 6.6% in the unfractionated heparin group, with a relative risk reduction of 61% in favor of LMWH.
Bleeding remains an important complication in patients receiving anticoagulation therapy. In this setting, bleeding is either from the anticoagulation itself or from an underlying potentiating cause such as recent surgery or fracture. When analyzed for major bleeding complications, data from a pooled analysis of patients treated for DVT revealed that LMWH treated patients had a 0.9% incidence of major bleeding compared with 3.2% of unfractionated heparin treated patients. This represents a statistically significant decrease in relative risk of 68% in favor of LMWH.69
The pooled followup data also demonstrated a difference in mortality between the 2 groups. The combined result revealed a mortality rate of 3.9% in the LMWH group versus 7.1% in the unfractionated heparin group with a relative risk reduction in favor of LMWH by 47% (95% CI, range 10% to 69% p [gt] 0.047). However, no survival benefit can be attributed to LMWH in treating DVT based on this metaanalysis because the 2 groups had disproportionate numbers of patients with severe or critical illnesses such as cancer.
Regression of thrombus is of undefined clinical significance in the treatment of deep venous thrombosis. On the other hand, clot extension is suggested to be a risk factor for development of PE.71 Pooled data of the followup evaluation of clot size showed clot regression in 63% of patients in the LMWH group compared with 52% in the unfractionated heparin group. It is important to note that there was also a group of patients whose clot size increased in size in spite of anticoagulation. The clot size increased in 6% of patients in the LMWH group compared with 12% in unfractionated heparin group.
One-thousand-twenty-one patients with DVT or PE were enrolled in a prospective, randomized study evaluating 2 different heparins in the initial management of venous thromboembolism.66 Five-hundred-ten patients received fixed doses of LMWH (Reviparin) administered subcutaneously twice daily and 511 patients received standard intravenous unfractionated heparin titrated to keep the aPTT at 1.5 to 2 times the pretreatment level. All patients were started on oral anticoagulation on day 1 and study drug was discontinued once the international normalized ratio (INR) reached 2 to 3. The principal endpoints evaluated at 12 weeks of follow-up were recurrent deep venous thrombosis, PE, or major bleed.
One-third of all patients enrolled had PE at entry into the study. The incidence of recurrent DVT/PE in the LMWH group was 5.3% compared with 4.9% in the unfractionated heparin group. Major bleeding occurred in 3.1% of patients in the LMWH group compared with 2.3% in unfractionated heparin group. An additional observation is made of the higher incidence of recurrent DVT in the group of patients enrolled in the study with PE, (8 of 271) 2.9%, compared with (36 of 750) 4.8% of patients with DVT at the time of enrollment. The aforementioned study dispels doubts about the efficacy of LMWH in the treatment of hospitalized patients with established DVT or PE.66
Symptomatic DVT traditionally necessitates that patients be admitted to the hospital and treated with intravenous heparin, adjusting the dose to a therapeutic level of 1 to 2 times pretreatment level of aPTT. LMWHs, with their novel properties of long halflife, ease of administration, predictable antifactor Xa activity, and minimal need for monitoring can be regarded as emerging agents of choice in the treatment of DVT on an outpatient basis. Annually in North America, 250,000 patients require hospitalization for the treatment of deep venous thrombosis. A large portion of these patients may be candidates for home treatment with LMWH, which would strongly influence the economy of treating patients with deep venous thrombosis. Two studies explored this avenue and shed light on the new options. In the first study by Levine and associates67, 500 patients with proximal DVT were randomized to receive either standard intravenous unfractionated heparin or subcutaneous LMWH (Enoxaparin) at 1 mg/kg body weight primarily administered on an outpatient basis. Care was exercised to start treatment with LMWH in the outpatient setting or to discharge patients to home as soon as possible after admission. All patients were started on oral anticoagulant, and study medication was discontinued once the INR reached 2 to 3. During a 3-month followup, 13 of 247 patients (5.3%) receiving LMWH and 17 of 23 patients (6.7%) receiving unfractionated heparin had recurrent deep venous thrombosis. There was no statistically significant difference in the incidence of major bleeding between groups.
In the LMWH group, mean length of hospitalization was 1.1 days compared with 6.5 days in the unfractionated heparin group. Among 247 LMWH treated patients, 120 were never admitted to the hospital. Of the 2,230 patients with acute DVT screened for enrollment into the study, only 739 (33%) met the criteria. The reasons for excluding two-thirds of the patients were related to underlying conditions which required hospitalization, risk for noncompliance, or evidence of concurrent pulmonary embolism.
In a second study by Koopman and colleagues,68 400 patients with acute DVT were randomized to receive standard intravenous unfractionated heparin or fixed dose subcutaneous LMWH (Nadroparin). Treatment groups consisted of 198 and 202 patients, respectively. This group of investigators also looked at the quality of life in their primary evaluation along with incidence of recurrent DVT and major bleeding. Seventeen of 198 patients (8.6%) in the unfractionated heparin group and 14 of 202 (6.9%) in the LMWH group developed recurrent deep venous thrombosis. Major bleeding occurred in 2% of patients in the unfractionated heparin and 0.5% of patients in the LMWH group. Among the patients in the LMWH group, 36% were never admitted to the hospital and 40% were discharged early. On the score of quality of life, both groups showed improvement, but on 2 fronts, physical activity and social functioning, there was a statistically significant difference in favor of LMWH compared with unfractionated heparin group.
The above 2 studies shed light on new options for the treatment of DVT and invite development of criteria to identify groups of patients that can be safely treated as outpatients with LMWH. Care must be taken in generalizing these results because a large number of patients, nearly two-thirds, were considered not eligible for enrollment because of reasons commonly associated with patients with DVT risk, eg, stroke, cancer, infection, history of prior thromboembolic events and concurrent DVT, and pulmonary embolism. Further evaluation of LMWH in the outpatient treatment of DVT is warranted.
Pulmonary embolism
Though thromboembolism has long been considered and studied as a single entity, PE warrants individual attention because of its high morbidity and mortality. Thrombolytic agents and surgical interventions are used in up to 12% of patients with PE.72 The majority of studies evaluating LMWH in the treatment of thromboembolic diseases either excluded patients with PE during enrollment or represented it in very small numbers. However, with expanding indications and more and more data on safety and efficacy, LMWHs are being more intensely studied in the treatment of pulmonary embolism.
In a recent study reporting the use of LMWH (Reviparin) in the treatment of thromboembolism, 26% of patients had a documented pulmonary embolism. In the subgroup analysis of these patients with PE randomized to receive either unfractionated heparin or LMWH, the outcomes measures were encouraging. The incidence of recurrent thromboembolism was 5.3% and 4.9% in the unfractionated heparin and LMWH groups, respectively. The incidence of major bleeding was 3.1% and 2.3% in unfractionated heparin and LMWH groups, respectively.66
The first controlled study evaluating LMWH in the treatment of submassive PE was designed to determine a safe dose of LMWH (Fraxiparine). Three doses of LMWH were evaluated in comparison with standard unfractionated heparin. Of the 101 patients enrolled, 72% completed the study and the remainder dropped out secondary to bleeding complications in the 2 high-dose LMWH groups. Results from the low-dose LMWH group, which used 400 antifactor Xa units/kg/day,73 supported the safety and efficacy of LMWH in treating nonmassive pulmonary embolism. Using the lower dose as suggested from the above study Meyer and coworkers74 reproduced the safety and efficacy of LMWH (Fragmin) in treating patients with submassive PE in a small open-randomized study that enrolled 60 patients.
A larger study recently reported the use of LMWH in patients with symptomatic pulmonary embolism. Simonneau and colleagues72 enrolled 612 patients with objectively documented PE and randomized 308 patients to receive intravenous unfractionated heparin titrated to keep aPTT at 2 to 3 times pretreatment level and 304 patients to receive fixed dose LMWH (Tinzaprin, Novo) 175 antifactor Xa/kg subcutaneously once daily. All patients were started on oral anticoagulation between the first and third days and study medication was discontinued once the INR reached 2.0 to 3.0. This study was well designed in terms of selection criteria, endpoint definition, and followup. Primary endpoints were analyzed at day 8 and at day 90. At day 8, 2 of 308 patients (0.64%) in the unfractionated heparin group and 3 of 304 patients (1%) in the LMWH group had recurrent thromboembolic complications. This difference was not significant. The same endpoint evaluated at day 90 revealed an incidence of recurrent thrombosis of 1.9% in the unfractionated heparin group and 1.6% in the LMWH group. Major bleeding was observed in 1.6% of the unfractionated heparin group and 1% of the LMWH group on day 8 and 2.6% and 2% on day 90, respectively. Overall mortality at 3 months was 7.1% and 5.9% in the unfractionated heparin and LMWH groups, respectively. However, deaths related directly to PE or bleeding were 5 of 308 patients (1.6%) in the unfractionated heparin group and 4 of 304 patients (1.3%) in the LMWH group. The authors noted that their selection criteria may have excluded some patients at high risk for death, recurrence, or major bleeding. Nonetheless the authors concluded that LMWH can be safely used to treat patients with acute PE after screening for those with hemodynamic instability or those who would need thrombolytic agents or surgical intervention.
The simplicity and convenience of administering LMWH has the potential to shift treatment of PE from the inpatient to the outpatient setting. This shift could substantially reduce the cost of treating pulmonary embolism.
SPECIAL CONSIDERATIONS
Pediatric patients
In children with thromboembolic complications, treatment with unfractionated heparin is the current standard of care.75-77 This therapy is fraught with many problems in the pediatric population. Unfractionated heparin is metabolized more quickly in infants than in adults,78 and children often experience delays in achieving therapeutic aPTT and experience higher incidences of recurrent thromboembolic disease (18%) and postphlebitic syndrome (18%) than adults.77,79 In addition, children may be more sensitive to the pain associated with repeat blood drawing to monitor anticoagulation. LMWH may be a better alternative in pediatric patients because of its ease of administration and lack of laboratory monitoring requirements.
Massicotte and associates78 studied the dosing requirements and effectiveness of LMWH in 25 children, 9 of whom were less than 2 months old. All had documented DVT and 9 had thrombosis involving the intracranial venous system. LMWH (Enoxaparin) was used in patients at high risk for bleeding from unfractionated heparin or with a documented bleed from unfractionated heparin. The LMWH was administered subcutaneously at a dose of 1 mg/kg body weight twice a day. The antifactor Xa activity was tested in vitro and was similar in children and adults.78 A therapeutic level of antifactor Xa activity (0.5-1.0 micro units/mL) was achieved at 4 hours in all but 7 children (28%), 6 of whom were less than 2 months old. Dose escalation was necessary to achieve a therapeutic level in this group. Median duration of LMWH therapy was 14 days. There were no episodes of new thromboembolic events at day 14. Two patients with a history of GI bleeding experienced bleeding complications and required blood transfusion without any further complications or changes in therapy.
This study demonstrated the increased dose requirements of children, and the authors reported that the cost of using LMWH was 30% lower than were the costs of using unfractionated heparin. This study brought to the foreground the need for further randomized trials comparing LMWH with unfractionated heparin in pediatric patients.
Cancer patients with indwelling catheters
Patients with cancer pose a special risk for development of DVT because of the thrombogenic profile of their plasma associated with the underlying cancer. Those who have a high platelet count simultaneously are at very high risk of developing deep venous thrombosis. Management of these patients is further complicated by the frequent requirement of indwelling or central venous catheters for the infusion of chemotherapy or total parenteral nutrition. These factors lead to a high incidence of catheter-related deep venous thrombosis, which develops in up to 40% of patients with underlying cancer.80
Monreal and colleagues81 prospectively studied the role of LMWH in preventing DVT in cancer patients with a Port-a-Cath device placed surgically in the subclavian vein. Twenty-nine patients were randomized to receive either 2,500 IU of subcutaneous dalteparin (Fragmin) daily, or no prophylaxis. Venograms were performed to evaluate development of DVT at day 90 or sooner if symptoms of DVT developed. The study was terminated sooner than planned because of the high number of DVT in patients not given low molecular weight heparin. One of 16 (6%) in the group receiving LMWH versus 8 of 13 (62%) in the group receiving no prophylaxis developed deep venous thrombosis. The author concluded that LMWH is effective in preventing DVT in cancer patients with indwelling catheters. In addition, the LMWH was safe in these patients. Further evaluation of LMWH in comparison with standard unfractionated heparin is needed.
Unstable angina
The principle behind using unfractionated heparin in patients with angina is the same as in patients with deep venous thrombosis; that is, to prevent further clot propagation and prevent further myocardial ischemia. Unfractionated heparin and aspirin are mainstays in the treatment of patients with unstable angina.
Few studies have evaluated the efficacy of LMWH in patients with unstable angina. In 1 study, LMWH (CY 216 Nadroparin) was compared with placebo and at day 6, patients taking the LMWH had lower mortality and lower incidence of myocardial infarction.82 The efficacy of LMWH and unfractionated heparin in reducing death, myocardial infarction, and recurrent angina was demonstrated to be equal in 1 study. However, in another study, LMWH (Enoxaparin) had superior survival, benefit, and myocardial protection by 17% when compared to unfractionated heparin.52 The risk of major bleeding was comparable in both groups, 6.5% in the group treated with LMWH versus 7% in the group treated with unfractionated heparin. The incidence of bleeding complications was greater when the dose of LMWH (CY 216 Nadroparin) exceeded 100 antifactor Xa units/kg.54
Acute ischemic stroke
Ischemic stroke accounts for more than 83% of all acute strokes.83 Though there are established guidelines for the prevention of stroke,84 management of acute ischemic stroke is still evolving. The role of unfractionated heparin and aspirin in the management of acute stroke remains controversial.85 Because of their novel characteristics, LMWHs are being evaluated in the setting of acute ischemic stroke. A LMWH (Nadroparin) was tested in an open, randomized trial of patients with acute ischemic stroke and was found to be well tolerated and safe.86
A larger prospective randomized blinded placebo-controlled study reported by Kay and colleagues85 evaluated the safety and efficacy of 2 different doses of LMWH in patients with ischemic stroke. The primary endpoints were death or dependency at 6 months. Of the 308 patients studied, 102 received LMWH (Nadroparin) at a dose of 4,100 antifactor Xa, subcutaneously twice a day, 101 received LMWH (Nadroparin) at a dose of 4,100 antifactor Xa subcutaneously once a day and 105 patients received placebo. Nine percent of patients developed hemorrhagic stroke by day 10; only 1 was symptomatic. There was no statistical difference among the 3 groups. At 6 months, 45% of patients in the high dose group, 52% in the low dose group, and 65% in the placebo group died or became dependent. Outcomes were statistically significant in favor of high dose LMWH compared with placebo. The authors concluded that LMWH reduced death and dependency at 6 months after ischemic stroke with no increase in the risk of hemorrhagic transformation. Further controlled trials comparing LMWH to unfractionated heparin, aspirin, and other antiplatelet agents are warranted. However, this data suggests that LMWH is an alternative to unfractionated heparin in the management of ischemic stroke.
LIMITATIONS
Clinical limitations of the LMWHs. The LMWHs have been shown to have equal or better efficacy than unfractionated heparin in several of the clinical indications discussed above. Animal models and clinical trials have also demonstrated equal or less tendency toward bleeding with LMWH than with unfractionated heparin. Excitement over these results and the possibility of treating patients at home for conditions that once required hospitalization are mounting. However, there are precautions and limitations to the utility of LMWH that must be considered to ensure their safety and efficacy.
Osteoporosis. Prolonged use of unfractionated heparin is associated with a risk for osteoporosis. This risk increases with the duration of unfractionated heparin therapy and is usually evident after 1 month of therapy.87 LMWHs are associated with a lower risk for osteoporosis. In 2 small studies, risks for osteoporosis with unfractionated heparin and LMWH were 17.6% and 2.6%, respectively. Though significantly lower, the risk for osteoporosis and subsequent fractures must be considered in patients treated for long periods of time.
Immune-mediated unfractionated heparin-induced thrombocytopenia (HIT). There are 2 types of unfractionated heparin-induced thrombocytopenia. The first is a mild, transient effect that occurs within the first 1 to 2 days of therapy. About 10% of all patients receiving intravenous unfractionated heparin experience this form of HIT.88,89 The second is a delayed, more severe form of thrombocytopenia that usually develops after 5 or more days of unfractionated heparin therapy. This form of HIT is mediated by IgG antibodies specific for heparin/platelet factor 4 complexes and occurs in up to 5% of patients independent of the dose or route of unfractionated heparin administration.90 After bleeding, thrombocytopenia is the most common adverse effect of unfractionated heparin therapy and unfractionated heparin induced thrombocytopenia is the most common of the drug-induced thrombocytopenias. LMWH has also induced thrombocytopenia, though at a lower incidence.91,92 LMWH may be used in place of standard unfractionated heparin to reduce the risk for developing HIT, but it is contraindicated in patients with documented immune mediated HIT because it crossreacts with existing unfractionated heparin antibodies in a majority of patients.
Alternatively, a direct thrombin inhibitor such as hirudin, bivalirudin, or argatroban may be used, but these agents are not readily available in the US at this time. The low molecular weight heparinoid, Danaproid (Orgaran/Organon, West Orange, NJ), is associated with a 10% or lower incidence of crossreactivity and is an available alternative to unfractionated heparin in this population.
Protamine sulfate neutralizes the antithrombotic activity of unfractionated heparin and is the standard antidote for unfractionated heparin reversal. However, protamine only partially reverses antifactor Xa activity.93 Because LMWHs produce the majority of their anticoagulant effect via factor Xa inhibition, the effectiveness of protamine in neutralizing LMWH is limited. Severe bleeding complications related to LMWH may require administration of fresh frozen plasma.
Use in patients with spinal or epidural anesthesia. Many general and orthopaedic surgery patients receiving thromboprophylaxis will undergo spinal or epidural anesthesia. The risk of spinal or epidural hematoma is inherent to the use of such catheters. However, this risk is increased by concomitant administration of drugs that affect platelet function and coagulation, including LMWH.
In a review by Bergqvist and coworkers94, concomitant use of LMWH and spinal or epidural anesthesia was identified in 9,013 patients. The majority of the studies reviewed were not designed to analyze the effect of anesthesia type on the incidence of adverse events. However, these authors note that neurologic complications are of such severity that their occurrence would have been reported. They concluded that neurologic complications after epidural or spinal anesthesia in patients receiving LMWH are extremely rare and presumed safe.
In December of 1997, the Food and Drug Administration issued a public health advisory related to reports of epidural or spinal hematomas with the concurrent use of LMWH and spinal or epidural anesthesia. This advisory was prompted by more than 30 spontaneous reports of development of spinal or epidural hematomas in patients receiving this combination. The advisory notes that the voluntary nature of the reports from a population of unknown size precludes determination of the true incidence of this complication. Practitioners were warned that patients receiving LMWH when spinal or epidural anesthesia is used are at increased risk of developing a hematoma that could lead to longterm or permanent paralysis. The use of LMWH in patients treated with epidural or spinal catheters requires frequent monitoring of neurologic function and should only be done after a careful evaluation of the risks and benefits.
Interchangeability of products. Each LMWH has a unique pharmacologic and pharmacokinetic profile (Table 1). Because of differences in molecular weight, halflife, and anti-Xa activity, any generalization of results obtained with a specific LMWH must be done cautiously. One study did compare 2 different LMWHs (Enoxaparin and Reviparin) based on their anti-Xa activity and found them to be equally effective in preventing DVT.7 Additional studies that directly compare the individual agents with each other are needed before further comment can be made on the interchangeability of LMWHs. Specific product literature and manufacturer recommendations should be consulted when prescribing these agents.
Other complications. In vitro and animal data and the anticoagulant profile of the LMWHs suggest that these agents are less likely than unfractionated heparin to produce bleeding complications. Several clinical trials, however, found no statistically significant difference in the incidence of major bleeding between these 2 agents.95 When analyzed for minor bleeding and wound hematoma LMWH (Logiparin) demonstrated a lower incidence of overall bleeding complications. In 1207 patients undergoing total hip replacement surgery, LMWH was compared with warfarin. In this study, there was a trend toward higher bleeding in the LMWH treated patients (1.2% versus 2.8%).15 Because LMWH is administered subcutaneously, local infusion site reactions are common. Pain, hematoma, and erythema have been reported. Other adverse effects include fever, pain, nausea, ecchymosis, hypochromic anemia, edema, and confusion.
ECONOMIC CONSIDERATIONS
The introduction of a new treatment modality should be reviewed not only in terms of its safety and efficacy, but also in terms of its relative cost. The safety and efficacy of LMWH in various clinical settings is well described in the literature. These data can be used to understand the potential economic ramifications of LMWH use. When evaluating the cost of therapy, one must consider drug acquisition costs as well as related direct costs. In addition, the clinical outcomes are significant influences on economic evaluation. A true economic evaluation is beyond the scope of this discussion, but the following points should be noted.
For DVT prophylaxis, direct costs include the cost of medication, laboratory monitoring charges, and the cost to diagnose and treat complications of therapy. When considering LMWH and unfractionated heparin for DVT prophylaxis, the drug cost for LMWH is 10 to 20 times that of unfractionated heparin. Given in fixed subcutaneous doses, unfractionated heparin does not require anticoagulant monitoring, so the laboratory charges can be considered equal for the 2 therapies. To justify the added drug cost, there must be a compensatory decrease in the cost to diagnose and treat complications. Depending on the clinical indication, LMWH has been shown to have equal or fewer complications. Ideally, each institution would conduct this analysis using internal data complication rates. However, literature reports can be used more conveniently. For those indications where complications are known to occur less often in LMWH-treated patients (eg, total knee replacement) LMWH is the cost-effective alternative. Where the complication rates are equivalent or where controversy exists regarding complication rates, cost effectiveness of LMWH cannot be concluded. Where LMWH is as effective as adjusted dose unfractionated heparin or warfarin, such as prophylaxis in total hip replacement surgery, laboratory monitoring costs associated with unfractionated heparin and warfarin tend to compensate for the lower drug costs of these agents. Though not proved in controlled economic evaluations, LMWH may be cost effective in these instances.
The greatest potential for economic advantage of LMWHs lies in the outpatient treatment of DVT and pulmonary embolism. The safety and efficacy of this alternative have been demonstrated to be equivalent to intravenous heparin. Avoidance of hospital admission and monitoring costs associated with adjusted dose intravenous unfractionated heparin substantially exceed the cost of subcutaneous LMWH given on an outpatient basis. The magnitude of this cost advantage is institution specific but can be as high as thousands of dollars per patient.
SUMMARY
Thromboembolic complications are associated with significant morbidity and mortality in postoperative patients. For many years, unfractionated heparin has been used successfully in primary and secondary prophylaxis of these complications. In recent times, however, the usefulness of LMWHs has caught the attention of clinicians because of improved bioavailability, predictable anticoagulation, ease of administration, and the lack of need for monitoring anticoagulation. In clinical situations, LMWHs have been tested and proved to be safe and equipotent or superior when compared with unfractionated heparin or warfarin (Table 5). It is clear from clinical trials that LMWHs are superior in primary prophylaxis of DVT in orthopaedic surgical procedures, treatment of unstable angina, and in patients with multiple traumas. LMWHs were also tested and found to be an acceptable alternative to unfractionated heparin in both the primary prophylaxis of DVT in high risk general surgical procedures and in the treatment of patients with DVT and pulmonary embolism. However, the role of LMWHs in ischemic heart diseases, valvular heart diseases, postcoronary angioplasty, and vascular surgery remains to be proved. The major impact of LMWHs would be in allowing clinicians to treat PE and DVT in an outpatient setting, which would directly impact medical economics.
LMWHs are associated with similar complications as unfractionated heparin is, but the complications occur less frequently. Currently, the main limitation in using LMWHs in place of unfractionated heparin or warfarin is its cost. However, taking into account the cost incurred by hospitalization and longterm monitoring of anticoagulation in patients treated with unfractionated heparin, certain trials have proved the cost of LMWHs to be the same or less than the cost of unfractionated heparin overall. We envision that LMWHs will be widely used in the future and will bring welcomed change in the treatment of thromboembolic diseases.
Table 5. Therapeutic Uses of Low Molecular Weight Heparins Marketed in the US
| Enoxaparin (Lovenox6) | Dalteparin (Fragmin6) | Ardeparin (Normiflo6) | ||||
| Therapeutic use | Dose | Efficacy rating | Dose | Efficacy rating | Dose | Efficacy rating |
| Prevention of restenosis following percutaneous transluminal angioplasty | 40 mg 1x/d | Unproved | — | — | — | — |
| Coronary artery bypass surgery | 20 mg x 1 then 70 mg & 60 min | Probable | — | — | — | — |
| Catheter related thrombosis | 1 mg/kg | Probable | 2,500 U 1x/d | Probable | — | — |
| Prophylaxis in TKR | 30 mg* 2x/d | Proved superior | — | — | 50 U/kg Q12 hours* | Proved equivalent |
| Prophylaxis in THR | 30 mg* | Proved equivalent | 5,000 U 1[times]/d | Proved equivalent | 40-50 U/kg Q12 | Proved equivalent |
| Prophylaxis in high risk abdominal surgery | 40 mg* | Proved equivalent | 2,500-5,000 U* 1x/d |
Proved equivalent | — | — |
| Prophylaxis in general surgery | 20-40 1x/d | Proved equivalent | — | — | — | — |
| Prophylaxis in gynecology surgery | 20-40 mg | Probable | — | — | — | — |
| Trauma | 30 mg 2x/d | Proved superior | — | — | — | — |
| Deep venous thrombosis treatment | 1 mg/kg or 1.5 mg/kg 1x/d | Proved equally effective | 120 U/kg 2x/d | Proved equivalent | — | — |
| Post myocardial infarction | 40 mg 1[times]/d | Probable | 300 U/kg/d | Unproved | — | — |
| Pulmonary embolism treatment | 1 mg/kg | Proved equivalent | — | — | — | — |
| Femoropopliteal reconstruction | 75 Units/kg/2x/d | Probable | — | Unproved | — | — |
| Unstable angina and non-Q wave myocardial infarction | 1 mg/kg* plus aspirin | Proved equivalent | — | — | — | — |
| Disseminated intravascular coagulation | — | — | 75 U/kg/day | Probable | — | — |
| Stroke | — | — | 2,500 U 2x/d or 55-65 U/kg 1x/d | Unproved | — | — |
| Unstable coronary artery disease | — | — | 10,000 U [times] 2 wks then 5,000 U | Unproved | — | — |
| Hemodialysis | — | — | 500 U | Proved equivalent | — | — |
| *FDA Proven superior, improved safety/efficacy demonstrated in controlled trials; Proven equivalent, safety and efficacy comparable to unfractionated heparin in randomized controlled trials; Probable, favorable data from case reports or uncontrolled trials; TKH, Unproven, demonstrated inferior efficacy in controlled trials or proven equivalent to placebo. |
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