Need For Laboratory Monitoring Research Articles

Laboratory monitoring of low‐molecular‐weight heparin therapy

I have been invited to comment on the recent debate in theJournal of Thrombosis and Haemostasisabout the need for laboratory monitoring of low‐molecular‐weight heparin (LMWH) therapy [1,2]. Bounameux and De Moerloose summarized the rationale for laboratory monitoring of LMWH therapy, identified limitations of laboratory assays that are used for that purpose, and concluded that available evidence does not support laboratory monitoring of LMWH [2]. They acknowledge that treatment with fixed‐dose weight‐based LMWH may not be suitable in certain situations such as pregnancy, very light or heavy individuals, in newborns and in those with renal impairment, and they concede that dose adjustment in response to laboratory monitoring of heparin activity may be indicated in these relatively uncommon circumstances.

Tinzaparin sodium: a review of its pharmacology and clinical use in the prophylaxis and treatment of thromboembolic disease.

Tinzaparin sodium (tinzaparin; innohep) is a low molecular weight heparin (LMWH) formed by the enzymatic degradation of porcine unfractionated heparin (UFH). In clinical trials, once-daily subcutaneous (SC) tinzaparin was effective and generally well tolerated in the prophylaxis and treatment of thromboembolic disease. SC tinzaparin 75 anti-Xa IU/kg/day showed similar thromboprophylactic efficacy to adjusted-dosage oral warfarin in patients undergoing total hip arthroplasty; in patients undergoing knee replacement, the incidence of deep vein thrombosis (DVT) was significantly lower with tinzaparin. The drug had similar efficacy to equivalent-dosage SC enoxaparin sodium in orthopaedic surgery. In patients undergoing general surgery, SC tinzaparin 3500 anti-Xa IU/day was of equivalent thromboprophylactic efficacy to SC UFH 5000IU twice daily. Encouraging preliminary results have been obtained with tinzaparin in the prevention of DVT in patients with complete motor paralysis. In the initial treatment of acute proximal DVT and pulmonary embolism, SC tinzaparin 175 anti-Xa IU/kg/day was at least as effective as adjusted-dosage intravenous (IV) UFH. In the outpatient treatment of venous thromboembolism, tinzaparin has demonstrated similar efficacy to dalteparin sodium (dalteparin) and warfarin. Tinzaparin was effective in preventing clotting in haemodialysis circuits; the anticoagulant efficacy of tinzaparin in patients undergoing haemodialysis was similar to that of SC dalteparin and similar to or less than (although in this case the tinzaparin dose was too low for sufficient anticoagulant efficacy) that of IV UFH. Advantages of tinzaparin over UFH and warfarin include ease of administration and lack of need for laboratory monitoring. Tinzaparin is more cost effective than UFH in the treatment of established thromboembolic disease, and home-based treatment with tinzaparin may offer greater cost benefits than hospital-based therapy. Tinzaparin is well tolerated, including in elderly patients and those with renal impairment receiving long-term treatment. Incidences of major bleeding complications were low and reports of heparin-induced thrombocytopenia were infrequent in clinical studies. In conclusion, tinzaparin is a valuable LMWH in the prophylaxis and management of thromboembolic disease.

Treat DVT with low molecular weight heparin.

Each year, deep vein thrombosis (DVT) affects two million Americans, and pulmonary embolism (PE) affects 600,000. Traditional treatment requires hospitalization to receive continuous intravenous unfractionated heparin (UFH), which has substantial pharmacokinetic limitations. Low molecular weight heparins have overcome many of these limitations, resulting in a predictable anticoagulant response without the need for laboratory monitoring or dosage adjustment.

Oxcarbazepine, topiramate, zonisamide, and levetiracetam: Potential use in neuropathic pain

Background: Oxcarbazepine, topiramate, zonisamide, and levetiracetam are the antiepileptic drugs (AEDs) most recently approved by the US Food and Drug Administration. Based on the experience with carbamazepine, gabapentin, and lamotrigine, these newer AEDs are being investigated for the management of neuropathic pain. Objective: This article reviews preclinical and clinical data on the efficacy and tolerability of these 4 AEDs in the management of neuropathic pain, as well as the pharmacokinetics, drug-interaction potential, adverse effects, and dosing of these agents, with an emphasis on their use in older individuals. Methods: Relevant studies were identified through a MEDLINE search of the Englidh-language literature published between 1986 and May 2003, a review of the reference lists of identified articles, and abstracts from the annual meetings of the American Academy of Neurology (1986–2002) and the 2003 Annual Meeting of the American Pain Society. Search terms were oxcarbazepine, topiramate, zonisamide, and levetiracetam. Results: Oxcarbazepine and topiramate have been effective in animal models of neuropathic pain. Thirty-four publications on the efficacy and tolerability of the 4 agents were identified (25 case reports/case series, 6 randomized parallel-group studies, and 3 randomized crossover studies). The 9 randomized studies were restricted to oxcarbazepine and topiramate, and 23 (68%) publications were available in abstract form only. These preliminary data suggest that the 4 newer AEDs may be useful in a wide variety of neuropathic pain syndromes; however, additional data, including full-length peer-reviewed reports, are necessary before their true analgesic potential in neuropathic pain can be determined. All 4 agents have pharmacodynamic interactions with other psychotherapeutic drugs, potentiating adverse central nervous system events such as sedation. With the exception of levetiracetam, these drugs also have pharmacokinetic interactions with other drugs, although to a somewhat lesser extent than carbamazepine. These agents have some unique adverse effects not frequently monitored by clinicians, such as hyponatremia, nephrolithiasis, acute myopia with secondary angle-closure glaucoma, and weight loss. Conclusions: Based on preliminary data, oxcarbazepine, topiramate, zonisamide, and levetiracetam may be useful in the treatment of a wide variety of neuropathic pain syndromes, although full publication of the results of controlled trials is awaited. These agents are associated with specific adverse effects not commonly monitored by clinicians. Of the 4, levetiracetam appears to be easiest to use (ie, no need for dose adjustment in organ dysfunction, no need for laboratory monitoring) and best tolerated, and has not been associated with the unique toxicities seen with oxcarbazepine, topiramate, and zonisamide. The ultimate role of these agents in the therapeutic armamentarium against pain requires further research and experience. In the interim, these 4 agents should be used to treat neuropathic pain in the elderly only when carbamazepine, gabapentin, or lamotrigine cannot be used or when the response to the aforementioned agents is suboptimal.

Orally active direct thrombin inhibitors.

Anticoagulants are widely used for the prevention and treatment of venous and arterial thrombosis. Current treatment strategies often employ a combination of parenteral and oral agents because the only available orally active anticoagulants, vitamin K antagonists, have a delayed onset of action. Furthermore, vitamin K antagonists have a narrow therapeutic window that necessitates careful anticoagulation monitoring, and dosing is problematic because of multiple food and drug interactions. These limitations highlight the need for oral anticoagulants that produce a more predictable anticoagulant response than vitamin K antagonists, thereby obviating the need for laboratory monitoring. Ximelagatran has the potential to meet this need. A prodrug of melagatran, an agent that targets thrombin, ximelagatran exhibits many of the characteristics of an ideal anticoagulant. This article (1). reviews the limitations of vitamin K antagonists, (2). lists the characteristics of an ideal anticoagulant, (3). rationalizes thrombin as a target for new anticoagulants, (4). reviews the preclinical and clinical data with ximelagatran, and (5). provides clinical perspective as to the future of ximelagatran and other orally active anticoagulants currently under development.

Biochemistry and clinical pharmacology of new anticoagulant agents

New anticoagulants have been designed using advances in the biotechnology and the biochemistry of the clotting factors. They are classified according to their target or their mechanism of action (AT-dependent or AT-independent). Antithrombotic activity after oral administration is another important property. This abstract is restricted to the synthetic pentasaccharide and the ximelagatran/melagatran. Fondaparinux (Arixtra) is a chemically synthesized methoxy derivative of the natural pentasaccharide (MW=1728 Da). Fondaparinux has nearly complete bioavailabity after subcutaneous injection. The elimination half-life is about 17 hours. Fondaparinux is cleared from the kidneys. In contrast to heparin, fondaparinux does not interact with plasma proteins other than antithrombin and it does not cross-react in vitro with heparin induced thrombocytopenia antibodies. Fondaparinux inhibits specifically FXa, although some other targets are suspected (FIXa and FVIIa). Endogenous levels of AT are the rate limiting factor for its anti-Xa activity. Fondaparinux, in contrast to direct FXa inhibitors (i.e. DX-9065a) inhibits free FXa but not the FXa bound to prothrombinase, and it does not prolong PT and aPTT. Fondaparinux inhibits thrombin generation in human plasma. We have shown that the inhibition of thrombin generation by fondaparinux is inversely correlated with thromboplastin concentration. This original observation may explain the absence of any effect of fondaparinux on PT. Melagatran dipeptide (MW=430 Da) is a specific, reversible direct thrombin inhibitor. It inhibits free and clot bound thrombin. Its half-life is 1.7-2.5 hours after i.v. or s.c. administration. Ximelagatran (Exantas), is a pro-drug with a hydroxyamidino instead of amidino-group and an esterified carboxyl-group. It is the first clinically used direct orally acting thrombin inhibitor. Ximelagatran after intestinal absorption is metabolized to melagatran. Melagatran is not metabolized and is cleared through the kidney. Among the specific FXa inhibitors the synthetic pentasaccharide (Fondaparinux-Arixtra) has been approved by FDA and several European health organizations for the prophylaxis of VTE in major orthopedic surgery. No specific antidote has been described for the new antithrombotics. Encouraging results have been obtained from our group on the possible use of rFVIIa (Novoseven). The general opinion is that there is no need for laboratory monitoring of the new antithrombotic agents. Conclusion. The research for safer and more effective anticoagulants has been successful by targeting specific steps in coagulation. These single-targeted agents are challenging multi-targeted drugs (heparins and vitamin-K antagonists). Other drugs including orally active FXa direct inhibitors will probably enrich the armentarium of antithrombotic drugs.

Heparin pentasaccharide.

Fondaparinux (a synthetic heparin analogue) (Sanofi-Synthelabo; Paris, France and Organon Research; Oss, The Netherlands) is the subject of intense recent clinical evaluation for the prevention and treatment of venous and arterial thromboembolism. The drug replicates the sulphated antithrombin-binding pentasaccharide sequence in heparin and induces potent and specific antithrombin-mediated anti-Xa activity with excellent bioavailability and a long circulating half-life of 18 hours that makes it ideal for once-daily subcutaneous dosing. Its very short chain length ensures this heparin pentasaccharide (PS) is devoid of anti-factor IIa activity. No need for laboratory monitoring is anticipated. Fondaparinux does not cross-react ex vivo with the anti-platelet antibodies responsible for heparin-induced thrombocytopenia. Fondaparinux was evaluated in four large, randomized, placebo-controlled, double-blind phase III trials of deep vein thrombosis prevention after major joint surgery where the PS given after surgery was compared with a low molecular weight heparin (LMWH). LMWH was started before surgery in two comparisons and soon after surgery in the others. The trials shared the same blindly adjudicated efficacy and safety endpoints: efficacy was measured by recording subclinical deep vein thrombosis detected by screening with bilateral venography, plus clinically suspected and confirmed symptomatic thrombosis and embolism; safety was indicated by the rate of major bleeding. Bleeding was considered major if it caused death or reoperation, affected an internal organ, or was overt and associated with a bleeding index of 2 or more. By comparison with LMWH, 2.5 mg/d of the PS beginning 4 to 8 hours after wound closure reduced venous thromboembolism rates by 56% and 26% after elective hip replacement, 63% after knee replacement, and 62% after hip fracture surgery. In three studies and overall, the effect was statistically very significant and included similarly reduced rates of proximal deep vein thrombosis. In absolute terms, the DVT rates with PS are the lowest yet seen after major joint surgery. Trends toward more major bleeding with PS in three studies were statistically significant in one trial. PS did not increase risks from reoperation, internal bleeding, or death because of bleeding, because between-group differences were caused entirely by an excess of patients with a raised bleeding index. Post hoc analysis suggests this excess can be explained by too-early postoperative drug administration and may be avoided without loss of efficacy by giving the first PS injection 6 to 8 hours after surgery. Results of phase III treatment trials for DVT/PE will soon be available, but studies in coronary artery disease are less advanced.

Treatment of symptomatic venous thromboembolism: improving outcomes.

Antithrombotic therapy with unfractionated heparin (UFH) and warfarin for the treatment of deep venous thrombosis (DVT) and pulmonary embolism (PE) became widely accepted in the early 1960s. Subsequent clinical trials have focused on the importance of early intravenous UFH in the treatment of venous thromboembolic events, the method of heparin administration, the importance of rapid anticoagulation to prevent recurrent venous thromboembolism (VTE), and the optimal duration of UFH administration. Low-molecular-weight heparin (LMWH) represents a significant advance over UFH therapy for VTE. Developed in the late 1980s, LMWH has become an excellent alternative to UFH because it offers superior efficacy and safety, improved pharmacokinetics, longer half-life, and once- or twice-daily subcutaneous administration without the need for laboratory monitoring. Fondaparinux is the first of a new class of antithrombotic agents that targets factor Xa. Based on studies of the heparin binding site of antithrombin, this novel pentasaccharide has superior pharmacokinetics and bioavailability when compared with LMWH and can be administered once daily. Studies in patients undergoing major orthopedic surgery and in those with proximal DVT indicate that the efficacy and safety of fondaparinux may represent an improvement over those of LMWH.

Fixed minidose versus-adjusted low-dose warfarin after total joint arthroplasty: A randomized prospective study

Widespread use of adjusted low-dose warfarin has been limited by the inconvenience of outpatient laboratory monitoring and the perceived risk of bleeding complications. We sought to determine if the dose of warfarin could be lowered safely even further, eliminating the need for laboratory monitoring and lowering the complication rate. Two hundred forty-five Patients undergoing primary total joint arthroplasty (n = 245) were randomized prospectively to adjusted low-dose warfarin (international normalized ratio [INR], 1.4-1.8) or fixed minidose warfarin (2 mg daily, regardless of INR) before hospital discharge. Prophylaxis continued for 6 weeks, with twice-weekly laboratory monitoring. Patients were followed for bleeding, thromboembolic events, and minor reported complications of warfarin therapy. With the numbers available, the rates of thromboembolic and bleeding events were not significantly different using equivalence analysis. Of patients in the fixed group, 8% had INRs >3.1, necessitating a decrease in dosage to 1 mg. Although such a fixed-dose protocol may simplify outpatient prophylaxis, intermittent monitoring still would be required because a subset of patients achieve a moderate level of anticoagulation and would be at risk for bleeding complications.

Fondaparinux sodium: a selective inhibitor of factor Xa.

The pharmacology and mechanism of action of fondaparinux sodium are described. Fondaparinux sodium is the first agent of a new class of anticoagulants that selectively target factor Xa. It has a linear, dose-dependent pharmacokinetic profile, which provides a highly predictable response. It is 100% bioavailable, has a rapid onset of action, and has a half-life of 14 to 16 hours, allowing for sustained antithrombotic activity over a 24-hour period. The drug does not affect prothrombin time or activated partial thromboplastin time, nor does it affect platelet function or aggregation. Studies in patients with confirmed heparin-induced thrombocytopenia demonstrate that the drug is not associated with in vitro cross-reactivity to heparin antibodies. Fondaparinux sodium appears to meet the criteria for an ideal antithrombotic agent: equal or better effectiveness than currently available agents, a low bleeding risk, no need for laboratory monitoring, and once-daily administration.

Low-Molecular-Weight Heparins: Are They Interchangeable?

Unfractionated heparin (UFH) has been used as an antithrombotic agent in the treatment of various clinical entities for over 60 years. Low-molecular-weight heparin (LMWH) com- pounds have gradually replaced UFH for these indications as they have several advantages, including subcutaneous administration and the lack of need for laboratory monitoring. Ever since their introduction, there has been discussion about whether LMWH compounds differ in their efficacy and safety. The best answer is given by direct comparison of two or more preparations; however, such trials are very scarce. Comparison using classical meta-analysis is limited as only a small number of trials with the respective low-molecular-weight heparin compounds are available. The objective of the present analysis has been to use a novel way of plotting the odds ratios of the different studies to compare the efficacy and safety of different LMWH compounds in the initial treatment of patients with venous thromboembolism. Classical meta-analysis revealed reductions in safety and efficacy of 30–40% in favour of LMWHs. Contrasting the log odds ratios of efficacy and safety indicated that there is no conclusive evidence that LMWHs have intrinsic different safety and efficacy profiles.

Heparin and Low-Molecular-Weight Heparin Mechanisms of Action, Pharmacokinetics, Dosing, Monitoring, Efficacy, and Safety

Abbreviations: ACT 5 activated clotting time; APTT 5 activated partial thromboplastin time; AT 5 antithrombin; AT-III 5 antithrombin III; CI 5 confidence interval; DVT 5 deep vein thrombosis; GP 5 glycoprotein; HIT 5 heparininduced thrombocytopenia; INR 5 international normalized ratio; LMWH 5 low-molecular-weight heparin; MI 5 myocardial infarction; NQMI 5 non-Q-wave myocardial infarction; OR 5 odds ratio; PE 5 pulmonary embolism; PF4 5 platelet factor 4; PTCA 5 percutaneous coronary angioplasty; RR 5 relative risk; sc 5 subcutaneous; tPA 5 tissue plasminogen activator; UA 5 unstable angina; UFH 5 unfractionated heparin (CHEST 2001; 119:64S‐94S) H eparin and its derivative, low-molecular-weight heparin (LMWH), are the anticoagulants of choice when a rapid anticoagulant effect is required, because their onset of action is immediate when administered by IV injection. Both types of heparins are administered in lower doses for primary prophylaxis than for treatment of venous thrombosis or acute myocardial ischemia. Heparin has pharmacokinetic limitations 1 not shared by LMWHs. Based on these pharmacokinetic limitations, heparin therapy is usually restricted to the hospital setting, where its effect can be monitored and its dosage adjusted frequently. In contrast, LMWH preparations can be administered in either the in-hospital or out-of-hospital setting because they can be administered subcutaneously (sc) without the need for laboratory monitoring. When longterm anticoagulant therapy is indicated, heparin or LMWH administration is usually followed by treatment with oral anticoagulants. However, long-term out-of-hospital treatment with heparin or LMWH is used when anticoagulant therapy is indicated in pregnancy and in patients who develop recurrent venous thromboembolism while treated with appropriate doses of oral anticoagulants. Since our report in 1998 (Supplement to CHEST, Vol. 114, iss 5), a number of LMWH preparations have been approved for use for the treatment of venous thrombosis and for the treatment of unstable angina (UA). Clinical Indications Heparin is effective and indicated for the prevention of venous thromboembolism; for the treatment of venous thrombosis and pulmonary embolism (PE); for the early treatment of patients with UA and acute myocardial infarction (MI); for patients who undergo cardiac surgery using cardiac bypass, vascular surgery, and coronary angioplasty; in patients with coronary stents; and in selected patients with disseminated intravascular coagulation. LMWHs are effective and indicated for the prevention of venous thromboembolism, for the treatment of venous thrombosis, for the treatment of acute PE, and for the early treatment of patients with UA. The levels of evidence and grading of recommendations for the clinical use of heparin and LMWHs are discussed in the chapters that consider the evidence supporting antithrombotic therapy with these agents for the various clinical indications. This chapter will review the mechanisms of action of heparin and LMWHs, their pharmacokinetics, anticoagulant effects, side effects, and laboratory monitoring. The clinical uses of heparin and LMWHs and the results of clinical trials will also be discussed, although more details appear in other chapters.

Clinical utilization of the international normalized ratio (INR).

The prothrombin time (PT) is one of the most important laboratory tests to determine the functionality of the blood coagulation system. It is used in patient care to diagnose diseases of coagulation, assess the risk of bleeding in patients undergoing operative procedures, monitor patients being treated with oral anticoagulant (coumadin) therapy, and evaluate liver function. The PT is performed by measuring the clotting time of platelet-poor plasma after the addition of calcium and thromboplastin, a combination of tissue factor and phospholipid. Intra- and interlaboratory variation in the PT was a significant problem for clinical laboratories in the past, when crude extracts of rabbit brain or human placenta were the only source of thromboplastin. The international normalized ratio (INR), developed by the World Health Organization in the early 1980s, is designed to eliminate problems in oral anticoagulant therapy caused by variability in the sensitivity of different commercial sources and different lots of thromboplastin to blood coagulation factor VII. The INR is used worldwide by most laboratories performing oral anticoagulation monitoring, and is routinely incorporated into dosage planning for patients receiving warfarin. Although the recent availability of sensitive PT reagents prepared from recombinant human tissue factor (rHTF) and synthetic phospholipids eliminated many of the earlier problems associated with the use of crude thromboplastin preparations, local instrument variability in the INR still remains a problem. Presently, the use of plasma calibrants seems the best solution to this problem. Standardizing the point-of-care instruments for INR monitoring is another dilemma faced by the industry. Ultimately, new generations of anticoagulant drugs may eliminate the need for laboratory monitoring of anticoagulant therapy.

Intrahepatic hemorrhage after use of low-molecular-weight heparin for total hip arthroplasty

Low-molecular-weight heparin (LMWH) has become a popular agent for prophylaxis against deep vein thrombosis and thromboembolic disease after total joint arthroplasty. LMWH allows for consistent dosing in postoperative patients without the need for laboratory monitoring. Hemorrhage is an uncommon but documented adverse reaction when using LMWH; however, intrahepatic hemorrhage has not been previously reported in conjunction with LMWH therapy. We report the case of a woman who suffered intrahepatic hemorrhage presenting with acute abdominal pain and vomiting after the use of enoxaparin for total hip arthroplasty.

Low-molecular Weight Heparins in Venous and Arterial Thrombotic Disease

Since the introduction of low-molecular-weight heparins (LMWHs) in the early 1980's, the use of these compounds has been extensively investigated as a substitute for unfractionated heparin (UFH) in patients with venous and arterial thrombotic diseases. LMWHs have several advantages as compared to UFH, such as the subcutaneous route of administration, the predictable anticoagulant response and the lack of the need for laboratory monitoring. The present systematic review evaluates randomised clinical trials which investigated the efficacy and safety of LMWH in the acute treatment of venous thromboembolism, myocardial infarction, unstable coronary syndromes and ischemic stroke. A computerised and manual search was performed to identify all relevant clinical trials. All randomised studies, with an a priori defined study population, clinical outcome measurement and adequate follow-up, were reviewed by two independent assessors. Whenever possible a common effect estimate of the included studies was calculated. Thirteen studies in approximately 4000 patients with acute venous thromboembolism revealed an odds ratio for the 3-month recurrent thromboembolism rate and major bleeding complications during exposure of 0.77 (C.I. 0.57-1.04) and 0.61 (C.I. 0.39-0.95), respectively, in favour of LMWH as compared to UFH. In patients with acute myocardial infarction, one study suggested a reduction in the incidence of reinfarction and cardiac death in LMWH recipients compared to UFH, while a placebo-controlled study revealed no beneficial effect of LMWH on these outcomes. In six studies including over 7000 patients with acute unstable coronary syndromes, there was an odds ratio for recurrent angina, myocardial infarction, urgent revascularisation and major bleedings of 0.88 (C.I. 0.76-1.01), 0.84 (C.I. 0.69-1.01), 0.83 (C.I. 0.70-0.99), 1.09 (C.I. 0.70-1.70), respectively, in favour of LMWH compared to UFH. The three studies comparing LMWH treatment with placebo in approximately 1000 patients with acute ischemic stroke revealed an odds ratio for the 10-day recurrent stroke, death or disability after 3 months and major bleeding complications of 0.68 (C.I. 0.41-1.13), 0.94 (C.I. 0.78-1.15), 2.92 (C.I. 1.88-4.55), respectively. Fixed-dose subcutaneous LMWH appears to be a safe and effective alternative for dose-adjusted intravenous heparin in the treatment of patients with acute venous thrombotic disease as well as in patients with acute unstable coronary syndromes. The effectiveness of LMWH in patients with acute myocardial infarction remains unclear. There seems to be no beneficial effect of LMWH treatment as compared to placebo in patients with acute ischemic stroke, while the risk of major bleeding was clearly increased.

Low-Molecular-Weight Heparin for the Out-of-Hospital Treatment of Venous Thrombosis: Rationale and Clinical Results

LMWH preparations have been proven to be safe and effective in the outpatient management of acute DVT. Although LMWHs are more expensive than unfractionated heparin, the lack of need for laboratory monitoring of LMWHs and their potential for outpatient treatment more than offset the drug-related cost difference and result in a net cost savings in favor of LMWHs. LMWHs have undergone limited investigation for the secondary prevention of venous thromboembolism after an initial inpatient course of unfractionated heparin. To date, LMWHs have been given in prophylactic doses in these trials. In this setting, the LMWHs are associated with a similar risk for bleeding as fixed, intermediate-dose unfractionated heparin in patients with a high risk for bleeding. In patients with no increase in bleeding risk, fixed prophylactic-dose LMWH appears to be associated with both a lower risk for bleeding than warfarin (target INR of 2.0 to 3.0) and an increased risk for recurrence, although these findings need to be confir...

Low-molecular-weight heparin for the out-of-hospital treatment of venous thrombosis: rationale and clinical results.

LMWH preparations have been proven to be safe and effective in the outpatient management of acute DVT. Although LMWHs are more expensive than unfractionated heparin, the lack of need for laboratory monitoring of LMWHs and their potential for outpatient treatment more than offset the drug-related cost difference and result in a net cost savings in favor of LMWHs. LMWHs have undergone limited investigation for the secondary prevention of venous thromboembolism after an initial inpatient course of unfractionated haparin. To date, LMWHs have been given in prophylactic doses in these trials. In this setting, the LMWHs are associated with a similar risk for bleeding as fixed, intermediate-dose unfractionated heparin in patients with a high risk for bleeding. In patients with no increase in bleeding risk, fixed prophylactic-dose LMWH appears to be associated with both a lower risk for bleeding than warfarin (target INR of 2.0 to 3.0) and an increased risk for recurrence, although these findings need to be confirmed in larger trials.

Prevention of recurrences after deep venous thrombosis: role of low-molecular-weight heparins.

The management of deep venous thrombosis (DVT) requires an initial treatment with unfractionated (UF) or low-molecular-weight (LMW) heparin followed by oral anticoagulants (OA) for at least 3 months. OA therapy, however, requires laboratory monitoring and is associated with a definite bleeding risk. Therefore, alternative treatments such as UF or LMW heparin have been evaluated. In a study by Monreal et al in patients with DVT and contraindications to OA, dalteparin (5000 anti-Xa U b.i.d.) was equivalent to UF heparin (10,000 IU b.i.d.) and was associated with fewer vertebral fractures. In a study by Pini et al, Enoxaparin (4000 anti-Xa U once daily) was evaluated against OA and showed similar efficacy with fewer bleeding complications in the 3-month treatment period. A number of studies have recently shown that the risk for late thrombotic recurrences for patients developing postoperative DVT or associated with other transient risk factors is much lower than in patients with idiopathic DVT or associated with a persistent risk factor, suggesting that for the formers, 4 to 6 weeks of OA therapy may be sufficient. LMW heparins appear to be a promising alternative therapy for these patients, because in the first month of OA administration the risk for bleeding is higher and the need of laboratory monitoring more stringent. This should be evaluated in appropriate clinical trials.

Utility of intravascular stents for ostial renal artery stenoses

In view of the potential of low-molecular-weight heparins (LMWH) to simplify initial therapy and allow outpatient treatment of proximal deep-vein thrombosis, we undertook a randomised comparison of fixed-dose subcutaneous LMWH with adjusted-dose intravenous standard heparin in the initial treatment of this disorder. Our main objectives were to compare the efficacy of these regimens for 6 months of follow-up and to assess the risk of clinically important bleeding. Of 170 consecutive symptomatic patients with venographically proven proximal deep-venous thrombosis, 85 received standard heparin (to achieve an activated partial thromboplastin time of 1·5 to 2·0 times the pretreatment value) and 85 LMWH (adjusted only for body weight) for 10 days. Oral coumarin was started on day 7 and continued for at least 3 months. The frequency of recurrent venous thromboembolism diagnosed objectively did not differ significantly between the standard-heparin and LMWH groups (12 [14%] vs 6 [7%]; difference 7% [95% confidence interval -3% to 15%]; p=0·13). Clinically important bleeding was infrequent in both groups (3·5% for standard heparin vs 1·1% for LMWH; p>0·2). We conclude that fixed-dose subcutaneous LMWH is at least as effective and safe as intravenous adjusted-dose heparin in the initial treatment of symptomatic proximal-vein thrombosis. Since there is no need for laboratory monitoring with the LMWH regimen, patients with venous thrombosis can be treated at home.

Low Molecular Weight Heparin for the Out-of-Hospital Treatment of Venous Thrombosis: Rationale and Clinical Results

LMWH preparations have been proven to be safe and effective in the out-patient management of acute DVT. Although LMWHs are more expensive than unfractionated heparin, the lack of need for laboratory monitoring of LMWHs and their potential for out-patient treatment more than offsets the drug related cost difference and results in a net cost savings in favour of LMWH. LMWHs have undergone limited investigation for the secondary prevention of venous thromboembolism after an initial in-patient course of unfractionated heparin. To data, LMWHs have been given in prophylactic doses in these trials. In this setting, the LMWHs are associated with a similar risk of bleeding as fixed, intermediate dose unfractionated heparin in patients with a high risk of bleeding. In patients with no increase in bleeding risk, fixed prophylactic dose LMWH appears to be associated with both a lower risk of bleeding than warfarin (target INR of 2.0 to 3.0) and an increased risk of recurrence, although these findings need to be confirmed in larger trials.