Apixaban after hip or knee arthroplasty versus enoxaparin: efficacy and safety in key clinical subgroups.

BACKGROUND: New oral anticoagulants for thromboprophylaxis after hip or knee arthroplasty have been given as fixed-dose regimens. OBJECTIVE: To evaluate the consistency of the antithrombotic efficacy and bleeding risk of apixaban 2.5 mg twice daily compared with enoxaparin 40 mg once daily after knee or hip arthroplasty across the clinical characteristics of age, gender, body weight, body mass index (BMI) and creatinine clearance. METHODS: The pooled results of the ADVANCE-2 (knee arthroplasty) and -3 (hip arthroplasty) randomized trials were used to evaluate if treatment had a statistically significantly different effect (P < 0.10) on major venous thromboembolism (VTE) and bleeding for the characteristics of age, gender, body weight, BMI and creatinine clearance. Both univariate analysis and multivariate logistic regression were used. RESULTS: Univariate analyses identified statistically significant interactions for age and major VTE (P = 0.09); for both age (P = 0.07) and body weight (P = 0.07) and the outcome of major bleeding; and for creatinine clearance (P = 0.03) and the composite outcome of major and clinically relevant non-major bleeding. Estimates of these possible differences were not precise, with wide 95% confidence intervals (CIs) that included a zero difference for several subgroups. Multivariate logistic regression analysis did not detect a statistically significant interaction for any outcomes. CONCLUSIONS: This analysis found no convincing evidence that age, weight, gender, BMI or creatinine clearance influenced the balance of benefit to risk for apixaban compared with enoxaparin. Because only 5% of patients had a creatinine clearance between 30 and 50 mL min(-1), further data are needed in such patients.

Apixaban versus enoxaparin for thromboprophylaxis after hip or knee replacement: pooled analysis of major venous thromboembolism and bleeding in 8464 patients from the ADVANCE-2 and ADVANCE-3 trials.

In order to compare the effect of oral apixaban (a factor Xa inhibitor) with subcutaneous enoxaparin on major venous thromboembolism and major and non-major clinically relevant bleeding after total knee and hip replacement, we conducted a pooled analysis of two previously reported double-blind randomised studies involving 8464 patients. One group received apixaban 2.5 mg twice daily (plus placebo injection) starting 12 to 24 hours after operation, and the other received enoxaparin subcutaneously once daily (and placebo tablets) starting 12 hours (± 3) pre-operatively. Each regimen was continued for 12 days (± 2) after knee and 35 days (± 3) after hip arthroplasty. All outcomes were centrally adjudicated. Major venous thromboembolism occurred in 23 of 3394 (0.7%) evaluable apixaban patients and in 51 of 3394 (1.5%) evaluable enoxaparin patients (risk difference, apixaban minus enoxaparin, -0.8% (95% confidence interval (CI) -1.2 to -0.3); two-sided p = 0.001 for superiority). Major bleeding occurred in 31 of 4174 (0.7%) apixaban patients and 32 of 4167 (0.8%) enoxaparin patients (risk difference -0.02% (95% CI -0.4 to 0.4)). Combined major and clinically relevant non-major bleeding occurred in 182 (4.4%) apixaban patients and 206 (4.9%) enoxaparin patients (risk difference -0.6% (95% CI -1.5 to 0.3)). Apixaban 2.5 mg twice daily is more effective than enoxaparin 40 mg once daily without increased bleeding.

Individual patient data meta-analysis of enoxaparin vs. unfractionated heparin for venous thromboembolism prevention in medical patients.

BACKGROUND: Unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) are both recommended for venous thromboembolism (VTE) prophylaxis in hospitalized medical patients. OBJECTIVE: To perform an individual patient data meta-analysis to evaluate the relative efficacy and safety of the LMWH enoxaparin and UFH in preventing VTE in hospitalized medical patients. METHODS: Randomized clinical trials comparing subcutaneous enoxaparin (4000 IU once-daily) and UFH (5000 IU subcutaneous two- or three-times daily) for VTE prevention were identified by a systematic search. Individual patient data were obtained from each eligible trial. RESULTS: Overall, four trials were eligible, including 3600 patients randomized to receive enoxaparin (n = 1799) or UFH (n = 1801). Median patient age was 71 years, and 49.3% were female. Compared with UFH, enoxaparin was associated with risk reductions of 37% for total VTE [relative risk (RR) 0.63, 95% confidence interval (CI) 0.51-0.77] and 62% for symptomatic VTE (RR 0.38, 95% CI 0.17-0.85) at day 15. RR for total VTE in stroke and non-stroke patients was 0.59 (95% CI 0.47-0.74) and 0.87 (95% CI 0.51-1.50), respectively. Major bleeding rates were consistently low and similar between treatment groups at day 15 (RR 1.13, 95% CI 0.53-2.44). There was a trend towards reduced risk for mortality in patients receiving enoxaparin (RR 0.83, 95% CI 0.64-1.08), compared with UFH. CONCLUSIONS: Enoxaparin significantly reduces VTE in hospitalized medical patients, compared with UFH, without increasing the risk for major bleeding, and was associated with a trend towards reduced all-cause mortality.

Extended out-of-hospital low-molecular-weight heparin prophylaxis against deep venous thrombosis in patients after elective hip arthroplasty: a systematic review.

PURPOSE: Evidence-based medicine guidelines based on venographic end points recommend in-hospital prophylaxis with low-molecular-weight heparin (LMWH) in patients having elective hip surgery. Emerging data suggest that out-of-hospital use may offer additional protection; however, uncertainty remains about the risk-benefit ratio. To provide clinicians with a practical pathway for translating clinical research into practice, we systematically reviewed trials comparing extended out-of-hospital LMWH prophylaxis versus placebo. DATA SOURCES: Studies were identified by 1) searching PubMed, MEDLINE, and the Cochrane Library Database for reports published from January 1976 to May 2001; 2) reviewing references from retrieved articles; 3) scanning abstracts from conference proceedings; and 4) contacting pharmaceutical companies and investigators of the original reports. STUDY SELECTION: Randomized, controlled trials comparing extended out-of-hospital prophylaxis with LMWH versus placebo in patients having elective hip arthroplasty. DATA EXTRACTION: Two reviewers extracted data independently. Reviewers evaluated study quality by using a validated four-item instrument. DATA SYNTHESIS: Six of seven original articles met the defined inclusion criteria. The included studies were double-blind trials that used proper randomization procedures. Compared with placebo, extended out-of-hospital prophylaxis decreased the frequency of all episodes of deep venous thrombosis (placebo rate, 150 of 666 patients [22.5%]; relative risk, 0.41 [95% CI, 0.32 to 0.54; P < 0.001]), proximal venous thrombosis (placebo rate, 76 of 678 patients [11.2%]; relative risk, 0.31 [CI, 0.20 to 0.47; P < 0.001]), and symptomatic venous thromboembolism (placebo rate, 36 of 862 patients [4.2%]; relative risk, 0.36 [CI, 0.20 to 0.67; P = 0.001]). Major bleeding was rare, occurring in only one patient in the placebo group. CONCLUSIONS: Extended LMWH prophylaxis showed consistent effectiveness and safety in the trials (regardless of study variations in clinical practice and length of hospital stay) for venographic deep venous thrombosis and symptomatic venous thromboembolism. The aggregate findings support the need for extended out-of-hospital prophylaxis in patients undergoing hip arthroplasty surgery.

Orally active heparin and low-molecular-weight heparin.

The heparins, (unfractionated heparin (UFH) and low-molecular-weight heparins (LMWH)) given by subcutaneous or intravenous injection have been used extensively in the prevention and treatment of both venous and arterial thromboembolic disorders. The increasing use of the heparins, LMWHs in particular, in the out of hospital setting has stimulated interest in the development of orally absorbable antithrombotic agents that require little or no monitoring, and this includes the heparins. UFH or LMWH delivered orally has been shown to have an antithrombotic effect in animal thrombosis models although there is little change in plasma coagulation tests. The addition of a simple organic chemical N -(8-(2-hydroxybenzoyl)amino)caprylate (SNAC) to UFH markedly enhances its absorption. A phase II study in patients undergoing total hip replacement indicated that SNAC heparin in two different doses was as effective and safe as UFH given subcutaneously. A phase III clinical trial comparing two doses of SNAC heparin given orally with LMWH by subcutaneous injection for the prevention of venous thromboembolism in patients undergoing total hip replacement is currently underway.

Dalteparin sodium.

Dalteparin sodium (Fragmin, Pharmacia Corporation) is a low molecular weight heparin (LMWH) with a mean molecular weight of approximately 5000 Da. As with the other LMWHs, dalteparin sodium has certain advantages over unfractionated heparin (UFH), most important of which are improved bio-availability by sc. injection, a prolonged antithrombotic activity which is highly correlated with body weight permitting the o.d. administration of the drug. Dalteparin sodium has been subjected to a large number of well-designed randomised clinical trials for the prevention and treatment of thrombotic disorders. Based on data from the randomised clinical trials, dalteparin sodium has been approved internationally for a wide spectrum of clinical indications (e.g., prevention of thromboembolic events after surgery). Dalteparin sodium has also been studied in randomised controlled trials in the maintenance of graft patentcy following peripheral vascular surgery, in place of warfarin for the long-term treatment of patients presenting with deep vein thrombosis (DVT), in the prevention of upper extremity thrombosis in patients with indwelling portacath devices and in pregnant patients with a history of previous venous thromboembolism with or without thrombophilia. Dalteparin sodium has been compared with heparin for the prevention of thrombotic complications during haemodyalisis and haemofiltration. These studies have shown promising results but further work is required before dalteparin sodium can be recommended for these indications.

Timing of initial administration of low-molecular-weight heparin prophylaxis against deep vein thrombosis in patients following elective hip arthroplasty: a systematic review.

BACKGROUND: Perioperative and postoperative venous thrombosis are common in patients undergoing elective hip surgery. Prophylactic regimens include subcutaneous low-molecular-weight heparin 12 hours or more before or after surgery and oral anticoagulants. Recent clinical trials suggest that low-molecular-weight heparin initiated in closer proximity to surgery is more effective than the present clinical practice. We performed a systematic review of the literature to assess the efficacy and safety of low-molecular-weight heparin administered at different times in relation to surgery vs oral anticoagulant prophylaxis. METHODS: Reviewers (A.F.M. and S.M.M.) identified studies by searching MEDLINE, reviewing references from retrieved articles, scanning abstracts from conference proceedings, and contacting investigators and pharmaceutical companies. Randomized trials comparing low-molecular-weight heparin administered at different times relative to surgery with oral anticoagulants in patients undergoing elective hip arthroplasty, evaluated using contrast phlebography, were selected. Two reviewers (A.F.M. and S.M.M.) extracted data independently. RESULTS: The literature review identified 4 randomized trials meeting predefined inclusion criteria. The results indicate that low-molecular-weight heparin initiated in close proximity to surgery resulted in absolute risk reductions of 11% to 13% for deep vein thrombosis, corresponding to relative risk reductions of 43% to 55% compared with oral anticoagulants. Low-molecular-weight heparin initiated 12 hours before surgery or 12 to 24 hours postoperatively was not more effective than oral anticoagulants. Low-molecular-weight heparin initiated postoperatively in close proximity to surgery at half the usual dose was not associated with a clinically or statistically significant increase in major bleeding rates (P =.16). CONCLUSIONS: The timing of initiating low-molecular-weight heparin significantly influences antithrombotic effectiveness. The practice of delayed initiation of low-molecular-weight heparin prophylaxis results in suboptimal antithrombotic effectiveness without a substantive safety advantage.

New developments in the prevention and treatment of venous thromboembolism.

Although unfractionated heparin has been widely used for preventing and treating venous thromboembolism, low-molecular-weight heparins (LMWHs) have been extensively studied. In particular, LMWHs have been valuable in the prevention of venous thromboembolism in high-risk surgical patients, such as those undergoing total joint replacement, and in high-risk medical patients. Recent studies indicated that the extended use of LMWHs after discharge in patients undergoing total hip replacement significantly decreases the frequency of venous thrombosis compared with placebo. Furthermore, LMWHs have been shown to be as effective and safe as unfractionated heparin for the initial treatment of both deep vein thrombosis and pulmonary embolism and have extended the treatment of these conditions into the outpatient setting. New recommendations from the sixth American College of Chest Physicians Consensus Conference on Antithrombotic Therapy and the rationale for change are discussed.

Low-molecular-weight heparin prophylaxis: preoperative versus postoperative initiation in patients undergoing elective hip surgery.

Administration of low-molecular-weight heparin prophylaxis in elective hip implant patients commonly begins 12 h preoperatively in European practices to optimize effectiveness, and 12 to 24 h postoperatively in North American practices to optimize safety. A meta-analysis comparing these two treatment regimes revealed that preoperative initiation demonstrated greater efficacy and superior safety for patients (10.0% rate of total deep-vein thrombosis vs. 15.3%, P = .023). In addition to the pre/postsurgical debate, proximity of initiation of low-molecular-weight heparin in relation to surgery is an issue of critical importance. Recent studies revealed that beginning therapy immediately within 2 h preoperatively or 6 h postoperatively dramatically decreased the risk of venous thrombosis. An investigation of low-molecular-weight heparin prophylaxis initiated 2 h before elective hip surgery or approximately 6 h after surgery compared with warfarin sodium revealed that total and proximal deep-vein thrombosis rates were reduced in patients receiving low-molecular-weight heparin compared with warfarin. The frequencies of deep-vein thrombosis for patients receiving preoperative and postoperative dalteparin vs. warfarin for all deep-vein thrombosis were 36 of 337 (10.7%, P < .001) and 44 of 336 (13.1%, P < .001) vs. 81 of 338 (24.0%); and for proximal deep-vein thrombosis were 3 of 354 (0.8%, P = .035) and 3 of 358 (0.8%, P = .033) vs. 11 of 363 (3.0%). Relative risk reductions for the dalteparin groups vs. warfarin ranged from 45% to 72%. In this case, low-molecular-weight heparin administered in close proximity to surgery provided superior efficacy over warfarin. Major bleeding was significantly increased with the preoperative regimen but not the postoperative regimen.

Cost-effectiveness of currently accepted strategies for pulmonary embolism diagnosis.

Improvements in the methods of clinical trials combined with the use of objective tests to detect venous thrombosis have enhanced the clinician's ability to diagnose pulmonary embolism and venous thrombosis (venous thromboembolism). The authors updated a previous cost-effectiveness analysis of the commonly recommended strategies for pulmonary embolism diagnosis and management to reflect current clinical practice. Two criteria of effectiveness were used: correct identification of venous thromboembolism and correct identification of venous thromboembolism and correct identification of patients for whom treatment was unnecessary. The cost of each diagnostic alternative was defined as the direct cost of administering the diagnostic tests plus the treatment costs associated with a positive test result. A strategy based on the combined use ofventilation-perfusion lung scanning, serial ultrasonography, cardiorespiratory evaluation, and pulmonary angiography was the most cost-effective. This strategy also necessitated pulmonary angiography in the fewest number of patients. The safety of this strategy relates to two important biologic concepts: 1) local extension of submassive pulmonary embolism in the lung is not an important cause of morbidity or mortality in patients with adequate cardiorespiratory reserve, and 2) in most patients, proximal vein thrombi of the lower extremities are the source of recurrent pulmonary embolism.

Low-molecular-weight heparin in the treatment of venous thromboembolism.

The low-molecular-weight heparins (LMWHs) have been evaluated in the prevention and treatment of deep-vein thrombosis and pulmonary embolism. LMWHs have been found to be safe and effective in this clinical setting and have advantages over unfractionated heparin. These advantages include less serious and less frequent therapeutic complications. The favorable pharmacokinetic profile of LMWHs compared with heparin has allowed for safe, effective, and convenient treatment of patients with venous thromboembolism. Use of LMWHs ultimately results in considerable cost savings for the health care system.

Low-molecular-weight heparin prophylaxis using dalteparin in close proximity to surgery vs warfarin in hip arthroplasty patients: a double-blind, randomized comparison. The North American Fragmin Trial Investigators.

BACKGROUND: Based on the current understanding that venous thrombosis starts perioperatively, administration of just-in-time low-molecular-weight heparin immediately before or in close proximity after hip arthroplasty may be more effective than usual clinical practice. METHODS: We performed a randomized, double-blind trial comparing subcutaneous dalteparin sodium given once daily immediately before or early after surgery with the use of postoperative warfarin sodium in 1472 patients undergoing elective hip arthroplasties. The primary end point was deep vein thrombosis detected using contrast venography performed after surgery (mean, 5. 7 days) in each group. RESULTS: The frequencies of deep vein thrombosis for patients with interpretable venograms receiving preoperative and postoperative dalteparin for all deep vein thrombosis were 36 (10.7%) of 337 (P<.001) and 44 (13.1%) of 336 (P<.001), respectively, vs 81 (24.0%) of 338 for warfarin; for proximal deep vein thrombosis, 3 (0.8%) of 354 (P =.04) and 3 (0.8%) of 358 (P =.03), respectively, vs 11 (3.0%) of 363. Relative risk reductions for the dalteparin groups ranged from 45% to 72%. Symptomatic thrombi were less frequent in the preoperative dalteparin group (5/337 patients [1.5%]) vs the warfarin group (15/338 patients [4.4%]) (P =.02). Serious bleeding was similar among groups. Increased major bleeding at the surgical site was observed for patients receiving preoperative dalteparin vs warfarin (P =.01). CONCLUSIONS: A modified dalteparin regimen in close proximity to surgery resulted in substantive risk reductions for all and proximal deep vein thrombosis, compared with warfarin therapy. Such findings have not been observed with low-molecular-weight heparin therapy commenced 12 hours preoperatively or 12 to 24 hours postoperatively vs oral anticoagulants. Increased major but not serious bleeding occurred in patients receiving preoperative dalteparin. Dalteparin therapy initiated postoperatively provided superior efficacy vs warfarin without significantly increased overt bleeding.

Low-molecular-weight heparin prophylaxis using dalteparin extended out-of-hospital vs in-hospital warfarin/out-of-hospital placebo in hip arthroplasty patients: a double-blind, randomized comparison. North American Fragmin Trial Investigators.

BACKGROUND: No randomized trials have directly evaluated the need for extended out-of-hospital thromboprophylaxis for patients who have hip arthroplasty in the United States or Canada. The uncertainty as to the need for extended prophylaxis in North American patients is complicated by early hospital discharge, resulting in a short thromboprophylaxis interval. METHODS: To resolve this uncertainty, we performed a randomized double-blind trial in 569 patients who underwent hip arthroplasty comparing the use of dalteparin sodium started immediately before surgery or early after surgery and extended out-of-hospital to an overall interval of 35 days with the use of warfarin sodium in-hospital and placebo out-of-hospital. RESULTS: For patients with interpretable venograms in the preoperative, postoperative, and combined dalteparin groups, new proximal vein thrombosis out-of-hospital was observed in 1.3%, 0. 7% (P =.04), and 1.0% (P =.02) of patients, respectively, compared with 4.8% in the in-hospital warfarin/out-of-hospital placebo group. The respective overall cumulative frequencies of all deep vein thrombosis were 30 (17.2%) of 174 patients (P<.001), 38 (22.2%) of 171 (P =.003), and 68 (19.7%) of 345 (P<.001) in the dalteparin groups compared with 69 (36.7%) of 188 for the in-hospital warfarin/out-of-hospital placebo group. For proximal deep vein thrombosis, the respective frequencies were 5 (3.1%) of 162 (P =.02), 3 (2.0%) of 151 (P =.007), and 8 (2.6%) of 313 (P =.002) compared with 14 (9.2%) of 153. No major bleeding occurred during the extended prophylaxis interval. CONCLUSIONS: Extended dalteparin prophylaxis resulted in significantly lower frequencies of deep vein thrombosis compared with in-hospital warfarin therapy. Despite in-hospital thromboprophylaxis, patients having hip arthroplasty in the United States and Canada remain at moderate risk out-of-hospital. The number needed to treat provides a public health focus; only 24 to 28 patients require extended prophylaxis to prevent 1 new out-of-hospital proximal vein thrombosis. Recent studies demonstrate that asymptomatic deep vein thrombi cause the postphlebitic syndrome; thus, extended out-of-hospital prophylaxis will lessen the burden to both the patient and society.

Low-molecular-weight heparin vs heparin in the treatment of patients with pulmonary embolism. American-Canadian Thrombosis Study Group.

BACKGROUND: Pulmonary embolism (PE) occurs in 50% or more of patients with proximal deep-vein thrombosis. 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 200 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 (6.8%) of 103 patients who received intravenous heparin (95% confidence interval for the difference, 1.9%-11.7%; P = .01). Major bleeding associated with initial therapy occurred in 1 patient (1.0%) who was given low-molecular-weight heparin and in 2 patients (1.9%) given intravenous heparin (95% confidence interval for the difference, -2.4% to 4.3%). 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.

Long term outpatient prophylaxis for venous thromboembolism.

Recent reductions in the incidence of postoperative venous thromboembolism are related to the widespread use of prophylactic anticoagulants, but many uncertainties about the most effective ways to use thromboprophylaxis remain. Orthopedic patients are at high risk of thromboembolism, and the trend towards shorter hospital stays means that they may receive less than the recommended 7 to 10 days of prophylaxis. Longer periods of thromboprophylaxis may be beneficial for high risk patients. The relative rarity of symptomatic deep-vein thrombosis and pulmonary embolism means that very large patient populations are required for studies that rely on clinical endpoints, but studies using venographic endpoints have shown 30 days of prophylaxis with low molecular weight heparin (LMWH) to be more effective than 7 days. Other factors that may influence the efficacy of thromboprophylaxis include the timing of the first injection and the choice of agent.

Thrombin inhibitors as anticoagulant agents.

Hirudin and its analogues and the synthetic antithrombin agents are interesting new antithrombotic agents that have been studied in a number of well-designed randomized clinical trials and further studies are underway. These agents offer certain advantages over heparin and low-molecular-weight heparin, and at least one agent is orally bioavailable. Studies have shown that the specific thrombin inhibitors can significantly decrease the incidence of composite cardiac endpoints in acute ischemic syndromes (following thrombolysis for myocardial infarction, unstable angina, and non-Q wave myocardial infarction and coronary angioplasty), but it is disappointing that the benefits obtained during short-term treatment are not sustained in the long term. Recent data are reviewed here from clinical trials supporting the use of the specific antithrombin agents in the treatment of acute cardiac ischemic syndromes, the prevention and treatment of venous thromboembolism, and the management of heparin-induced thrombocytopenia.