Eptifibatide and tirofiban: new preparations. Limited benefit

(1) Two antiplatelet drugs, eptifibatide and tirofiban, are licensed for the prevention of early myocardial infarction in patients with unstable angina or non Q-wave myocardial infarction. (2) These drugs appear to have a mechanism similar to that of abciximab. Abciximab reduced the incidence of myocardial infarction during the month following administration to patients with unstable angina who were scheduled for a percutaneous coronary procedure. (3) The clinical assessment files on eptifibatide and tirofiban are both centred on a large double-blind, placebo-controlled trial. (4) In patients with unstable angina or non Q-wave myocardial infarction, the PURSUIT trial, involving 10,948 patients, showed a lower incidence, at one month, of a combined end point (death or non fatal myocardial infarction) in patients on the eptifibatide + heparin + aspirin combination than in patients on the heparin + aspirin + placebo combination. A retrospective subgroup analysis raised the hypothesis that eptifibatide would be most beneficial in patients who had had coronary interventions. (5) In patients with unstable angina or non Q-wave myocardial infarction, the patients with unstable angina or non Q-wave myocardial infarction, the PRISM-PLUS trial, involving 1,915 patients, showed a reduction in the risk of myocardial infarction at 7 days in patients on the tirofiban + heparin + aspirin combination compared with those on the heparin +aspirin combination. Here too a retrospective subgroup analysis suggested that tirofiban would be most beneficial in patients who had had coronary intervention. (6) On the whole, these three antiplatelet drugs appear to benefit the same type of patient at high risk of myocardial infarction, but abciximab has been more thoroughly assessed than eptifibatide and tirofiban. Neither eptifibatide nor tirofiban (which were developed simultaneously) has been directly compared with abciximab. The value of antiplatelet drugs in patients treated with a low-molecular-weight heparin + aspirin combination is unknown. (7) These antiplatelet drugs carry a risk of haemorrhage and thrombocytopenia. On treatment cessation, coagulation function appears to normalise slightly more rapidly with eptifibatide (approximately 6 hours) and tirofiban (approximately 8 hours) than with abciximab (approximately 12 hours).     

Antiplatelet drugs in cardiovascular prevention: coronary events: acute phase and secondary prevention

(1) Aspirin reduces acute-phase mortality after myocardial infarction, and also reduces the risk of myocardial infarction and death in patients with unstable angina. Aspirin reduces the risk of myocardial infarction in patients with stable angina and after unstable angina, and the risk of relapse after myocardial infarction. It reduces the risk of complications during coronary angioplasty, and the risk of venous coronary bypass graft occlusion after coronary surgery. (2) The best risk-benefit ratio with aspirin is achieved at a daily dose of 75-350 mg; 160 mg/day is the best-validated dose in the acute phase of myocardial infarction. (3) Aspirin must be combined with a thrombolytic agent in patients with myocardial infarction, and with heparin in patients with unstable angina. During coronary stenting the aspirin + clopidogrel combination may have a better risk-benefit ratio than the aspirin + ticlopidine combination. (4) Clopidogrel can be used when aspirin is contraindicated or poorly tolerated. (5) Oral anticoagulants seem a better option than aspirin after complicated myocardial infarction.     

Tenecteplase: new preparation. Another thrombolytic agent for myocardial infarction: a slightly simpler treatment

(1) Alteplase is the standard thrombolytic agent for treating patients under 75 years with myocardial infarction if they are seen within 6 hours. It is given as an intravenous infusion over 90 minutes in combination with aspirin and unfractionated or low-molecular-weight heparin. (2) Tenecteplase has been authorized for use in myocardial infarction as an intravenous bolus over 5 to 10 seconds. (3) The evaluation file on tenecteplase contains data from three dose-finding studies and one double-blind trial against alteplase in nearly 17 000 patients. The trial found no difference in mortality between the two treatments (6% at 30 days). Nor was there any substantial difference in serious adverse events (stroke, intracranial haemorrhage or heart failure). (4) Major haemorrhage was slightly less frequent in patients given tenecteplase, but there was no difference between groups in the incidence of intracranial haemorrhage or stroke. (5) A comparative trial suffering from a number of biases suggests that combined treatment with tenecteplase + enoxaparin has a similar risk-benefit ratio to combined treatment with tenecteplase + unfractionated heparin. The combination of tenecteplase and enoxaparin makes treatment simpler, which could be particularly useful prior to hospital admission. A smaller trial of alteplase + enoxaparin against alteplase + unfractionated heparin gave similar findings. (6) In practice, tenecteplase has the advantage of a more convenient administration; a very large trial strongly suggests that its effects are almost identical to those of alteplase.     

Dalteparin: new indication. Prophylaxis in medical patients: no advance

(1) Heparin prophylaxis for medical inpatients who are confined to bed is controversial, because there are no reliable comparative data. Prophylaxis only seems justified for some patients at high risk of pulmonary embolism who have no risk factors for bleeding. (2) The licence of dalteparin, a low-molecular-weight heparin (LMWH), has been extended in France to cover prophylaxis of deep venous thrombosis in patients confined to bed for heart failure, acute respiratory failure, acute infections or acute rheumatological conditions who have at least one other risk factor for venous thromboembolism. (3) Evaluation data in this setting include a placebo-controlled trial but no trials versus unfractionated heparin or enoxaparin (another LMWH already available for this use). (4) The PREVENT trial included 3681 patients matching the characteristics described in the licence. They were randomised to receive (double-blind) daily subcutaneous injections of dalteparin (5000 IU) or placebo for 14 days. There was no difference between the groups in the following outcomes: death, pulmonary embolism and venous thrombosis (incidence below 1% in the placebo group). The results based on an endpoint combining clinical outcomes and phlebographic abnormalities favoured dalteparin. (5) Few data are available on the adverse events occurring in this trial. In other clinical situations, dalteparin has the same adverse effects as other LMWH (thrombocytopenia, hyperkalemia, etc.). (6) In practice, for medical inpatients who are confined to bed, where the thromboembolic risk is low, dalteparin offers no tangible advantages over unfractionated heparin or enoxaparin. The optimal dose for preventing symptomatic thromboembolism and minimising the bleeding risk is unknown.     

A comparison of enoxaparin with unfractionated heparins in patients with coronary heart disease in an emergency department in rural South Indian tertiary care teaching hospital

Aim:Antithrombotic therapy with heparin plus antiplatelets reduces the rate of ischemic events in patients with coronary heart disease. Low molecular weight heparin has a more predictable anticoagulant effect than standard unfractionated heparin, is easier to administer, does not require monitoring and is associated with less ADRs. The purpose of the present study was to evaluate and compare the clinical and cost outcomes of Enoxaparin with a standard unfractionated heparin in patients with coronary heart disease.Results:Compared to unfractionated heparin group of patients, the average prothrombin time was significantly higher (P < 0.0001) whereas hypokalemia was significantly lower (P < 0.02) in enoxaparin group of patients. Even though recurrence of angina and ADRs such as bleeding, nausea, headache and sudden cough occurred less frequently in the enoxaparin group of patients compared to unfractionated heparin group of patients, the differences were not significant.Conclusions:Antithrombotic therapy with enoxaparin plus aspirin was safer and more effective than unfractionated heparin plus aspirin, in reducing the incidence of ischemic events in patients with unstable angina or myocardial infarction in the early phase.KEY WORDS: Anticoagulant, coronary heart disease, enoxaparin, safety, and efficacy, unfractionated heparin     

Antithrombotic agents for acute coronary syndromes

Current evidence suggests a central role for antithrombotic agents such as unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) in the management of acute coronary syndromes (ACS). In patients with acute myocardial infarction, several studies have shown that LMWHs may represent an effective alternative to UFH as an adjunct to thrombolytic therapy and are not associated with an increased risk of major bleeding. In patients with unstable angina or non-ST-segment elevation myocardial infarction, trials have shown that the LMWH enoxaparin significantly reduces the risk of cardiovascular events, compared with UFH, while other trials have shown that the combination of enoxaparin and a glycoprotein IIb/IIIa antagonist is not associated with an excess risk of bleeding. However, LMWHs are significantly more expensive that UFH. Recently, newer antithrombotic agents such as fondaparinux and bivalirudin have shown equivalent efficacy to the heparins with less bleeding and appear clinically attractive. This review examines the current evidence for the efficacy and safety of antithrombotic agents in ACS.     

A comparative study of dalteparin and unfractionated heparin in patients with unstable angina pectoris

Objective:

To compare the efficacy and safety profile of dalteparin, a low-molecular-weight heparin with a standard unfractionated heparin in patients with unstable angina pectoris.

Materials and Methods:

This was a 6-month, prospective, parallel, randomized and open-labeled study. Patients of angina pectoris were randomized to receive either unfractionated heparin or dalteparin for 5 days. They were followed for 21 days during three visits on 1^st, 5^th and 21^st days. A series of resting electrocardiogram were undertaken in all patients on each visit.

Results:

The frequency of the combined clinical outcome of death, myocardial infarction and recurrence of angina was similar during 21 days of follow-up with either dalteparin or intravenous unfractionated heparin. In patients who received dalteparin 2.43% patients developed minor bleeding in the form of epistaxis and 2.5% patients who received unfractionated heparin developed minor bleeding in the form of macroscopic hematuria.

Conclusion:

Dalteparin is as effective and safe as unfractionated heparin in the treatment of unstable angina. Dalteparin does not require routine laboratory monitoring as with unfractionated heparin.KEY WORDS: Anticoagulant, bleeding, low-molecular-weight heparin, unstable angina     

Low molecular weight heparin in unstable coronary artery disease

Since the recognition that any thrombosis overlying a ruptured atherosclerotic plaque is a central component of the pathogenesis of unstable coronary artery disease (CAD), a number of antithrombotic treatment strategies have been investigated in randomised clinical trials. Aspirin reduces the occurrence of symptomatic and silent ischaemia, myocardial infarction (MI) and death in patients with unstable CAD, both in the acute phase and during continued long-term treatment and is now considered routine therapy. The addition of unfractionated heparin infusion further reduces cardiac events during the treatment period, but is not associated with any sustained benefits during long-term follow-up. Low molecular weight heparins (LMWHs) are completely absorbed by the sc. route. A predictable anticoagulant effect is maintained by sc. injections every 12 - 24 h without laboratory monitoring. The FRISC trial demonstrated that, in conjunction with aspirin, the LMWH dalteparin reduced death and MI by more than 50% in the acute phase. Four similar trials have directly compared LMWH with unfractionated heparin and demonstrated at least the same efficacy in the acute phase, treated between three and eight days. The LMWH enoxaparin was more effective at reducing death or MI than unfractionated heparin infusion during the three days of treatment, an effect which lasted up to 12 months. Prolonged out-patient treatment beyond the acute phase has been evaluated in four trials. It was demonstrated, in two of these trials, that continuing twice-daily injections of dalteparin further reduced the risk of death, MI and need for revascularisation at least during the initial six weeks of treatment. This effect was confined, however, to patients with signs of myocardial damage, i.e., elevation of troponin, at admission. During prolonged out-patient treatment, there is an increased risk of severe bleeding due to the combination of LMWH with aspirin. Based on successful results, the LMWHs, having the convenience of treatment and the option for continuation in an out-patient setting, should replace unfractionated heparin as the routine treatment in unstable CAD. If an early invasive procedure is considered, the LMWH therapy should be continued until the intervention as a 'bridge-to-revascularisation'. New antiplatelet agents are also emerging as additional useful tools for treating these patients, thus it is urgent to evaluate the comibination of these new therapies with the LMWHs.     

Low molecular weight heparin in unstable coronary artery disease

Since the recognition that any thrombosis overlying a ruptured atherosclerotic plaque is a central component of the pathogenesis of unstable coronary artery disease (CAD), a number of antithrombotic treatment strategies have been investigated in randomised clinical trials. Aspirin reduces the occurrence of symptomatic and silent ischaemia, myocardial infarction (MI) and death in patients with unstable CAD, both in the acute phase and during continued long-term treatment and is now considered routine therapy. The addition of unfractionated heparin infusion further reduces cardiac events during the treatment period, but is not associated with any sustained benefits during long-term follow-up. Low molecular weight heparins (LMWHs) are completely absorbed by the sc. route. A predictable anticoagulant effect is maintained by sc. injections every 12 - 24 h without laboratory monitoring. The FRISC trial demonstrated that, in conjunction with aspirin, the LMWH dalteparin reduced death and MI by more than 50% in the acute phase. Four similar trials have directly compared LMWH with unfractionated heparin and demonstrated at least the same efficacy in the acute phase, treated between three and eight days. The LMWH enoxaparin was more effective at reducing death or MI than unfractionated heparin infusion during the three days of treatment, an effect which lasted up to 12 months. Prolonged out-patient treatment beyond the acute phase has been evaluated in four trials. It was demonstrated, in two of these trials, that continuing twice-daily injections of dalteparin further reduced the risk of death, MI and need for revascularisation at least during the initial six weeks of treatment. This effect was confined, however, to patients with signs of myocardial damage, i.e., elevation of troponin, at admission. During prolonged out-patient treatment, there is an increased risk of severe bleeding due to the combination of LMWH with aspirin. Based on successful results, the LMWHs, having the convenience of treatment and the option for continuation in an out-patient setting, should replace unfractionated heparin as the routine treatment in unstable CAD. If an early invasive procedure is considered, the LMWH therapy should be continued until the intervention as a ‘bridge-to-revascularisation’. New antiplatelet agents are also emerging as additional useful tools for treating these patients, thus it is urgent to evaluate the comibination of these new therapies with the LMWHs.     

A randomized trial to compare the efficacy, safety, cost and platelet aggregation effects of enoxaparin and unfractionated heparin (the ESCAPEU trial)

OBJECTIVE: To compare the efficacy, safety, cost and effects on platelet aggregation of unfractionated heparin and low-molecular weight heparin in unstable angina patients. PATIENTS AND METHODS: Ninety-three patients with unstable angina were randomized to receive either unfractionated heparin (UFH) or enoxaparin in an open design clinical trial with blinded end point evaluation. The effects of the heparins on platelet aggregation were also compared. RESULTS: The composite end point of myocardial infarction, cardiac death, recurrent angina and need for intervention was observed in 62% of patients treated with UFH and in 37% of patients treated with enoxaparin (RR 1.7, 95% CI 0.75 to 3.71, p = 0.04). There was no difference in the frequency or severity of adverse events. A cost-effectiveness analysis showed both the heparins to be similar. Platelet aggregation was inhibited to a greater extent by UFH when compared to enoxaparin. CONCLUSIONS: Enoxaparin appears to be superior in efficacy to UFH and similar to UFH in safety. No difference in costs was detected in this study. The greater inhibition of platelet aggregation observed in the case of UFH compared to enoxaparin indicates that there may be more bleeding complications with UFH.     

Combination of low molecular weight heparins with antiplatelet agents in non-ST elevation acute coronary syndromes: an update

This article reviews the use of low molecular weight heparin (LMWH) and antiplatelet agents in the treatment of unstable angina and non-ST segment elevation myocardial infarction (NSTEMI), which together account for 1 million hospitalisations annually in the US alone. Mortality and recurrent myocardial infarction (MI) in these conditions is currently approximately 8 to 16% at 1 month, and there is a need to optimise treatment further. Since their introduction, LMWHs have been shown to be successful and well tolerated in the treatment of unstable angina and NSTEMI, but differences have been seen in their efficacy compared with the parent compound, unfractionated heparin (UFH). A meta-analysis of all LMWHs, grouped, versus UFH showed equivalent efficacy and safety. The LMWHs dalteparin sodium and nadroparin calcium have independently been shown to be as effective as UFH. However, enoxaparin sodium has been shown to have greater clinical efficacy than UFH in patients with unstable angina (UA)/NSTEMI. One area of new research is patients with UA/NSTEMI who later undergo percutaneous coronary interventions (PCI), and early data suggest enoxaparin can be safely used as an anticoagulant instead of UFH in these patients. There is a wealth of data for glycoprotein (GP) IIb/IIIa receptor antagonists (abciximab, eptifibatide, lamifiban, and tirofiban), although some are conflicting. Recent meta-analyses suggest that some benefit is conferred by using these compounds, particularly in patients who undergo PCI. Recent trials have focussed on combining GP IIb/IIIa antagonists with LMWH, and although data is still scant, the ACUTE (Anti-thrombotic Combination Using Tirofiban and Enoxaparin) and ACUTE II studies indicate the safety and potential clinical benefit of combining enoxaparin with tirofiban in patients with UA/NSTEMI not undergoing PCI, compared with UFH and tirofiban. The NICE (National Investigators Collaborating on Enoxaparin) 4 study collected data on the combination of enoxaparin and abciximab in patients undergoing PCI, and both safety and efficacy data compared well with historical data collected on the use of UFH with abciximab. The more recent NICE 3 study extended this finding to the combination of enoxaparin with abciximab, tirofiban or eptifibatide. The safety of two doses of dalteparin and abciximab had also been investigated, with the higher dose the efficacious, and also with safety, in patients undergoing PCI. In addition, a GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries in Acute Coronary Syndromes) IV substudy found that dalteparin had equivalent safety to UFH when co-administered with abciximab in patients not undergoing PCI. The NICE 3 and 4 trials were not randomised comparisons, and as such there results must be interpreted with caution. Recently, the CRUISE (Coronary Revascularisation Utilizing Integrelin [eptifibatide] and Single-bolus Enoxaparin) and INTERACT (Integrelin and Enoxaparin randomised assessment of Acute Coronary Syndromes Treatment) studies have provided evidence for both the safety and efficacy of enoxaparin combined with eptifibatide in non-ST elevation patients with acute coronary syndromes. A further study (SYNERGY [Superior Yield of the New strategy of Enoxaparin, Revascularization and GlYcoprotein IIb/IIIa inhibitors]) will investigate the efficacy of the combination of enoxaparin with abciximab versus that of UFH and abciximab in a large cohort of 8000 patients. The use of GP IIb/IIIa agents and LMWH in patients with UA/STEMI has led to their use in those with ST-elevation MI, and studies indicate LMWH is efficacious and can be used safely as an adjunct to thrombolysis. New studies will investigate the use of these agents in patients with STEMI not undergoing thrombolysis and we await the results of these studies.     

Enoxaparin: a pharmacoeconomic review of its use in the prevention and treatment of venous thromboembolism and in acute coronary syndromes

The pharmacoeconomics of the low molecular weight heparin (LMWH) enoxaparin in the prophylaxis and treatment of venous thromboembolism have mostly been investigated in cost-effectiveness studies that estimated direct costs associated with treatment, using decision analyses and clinical outcome data from randomised controlled trials. These studies have shown enoxaparin to be cost effective compared with unfractionated heparin (UFH) and warfarin in short-term thromboprophylaxis for hospital inpatients undergoing orthopaedic surgery and in thromboprophylaxis following trauma. Outpatient treatment of acute proximal deep vein thrombosis with enoxaparin has also been shown to be cost effective compared with inpatient treatment using UFH. In general surgery, however, it remains to be determined whether enoxaparin is a cost-effective alternative to UFH. The cost effectiveness of enoxaparin compared with UFH in the treatment of unstable angina and non-Q-wave myocardial infarction has also been investigated in several countries using clinical outcomes data from the Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-wave Coronary Events (ESSENCE) randomised trial. ESSENCE demonstrated that enoxaparin was superior to UFH in terms of tolerability and efficacy, and cost saving at both 30-day and 1-year follow-ups. An increasing number of studies indicate enoxaparin to be of economic benefit when used for prevention and treatment of venous thromboembolism and treatment of acute coronary symdromes.     

Comparison of cost, effectiveness, and safety of injectable anticoagulants used for thromboprophylaxis after orthopedic surgery.

PURPOSE: The cost, effectiveness, and safety of injectable anticoagulants used for thromboprophylaxis after orthopedic surgery were compared. METHODS: This retrospective, observational, cross-sectional, cohort analysis of inpatient billing data was conducted from the institutional perspective. Patients who received dalteparin, enoxaparin, fondaparinux, or unfractionated heparin after orthopedic surgery were included in the analysis. The primary outcome measure was the mean aggregated cost per patient treated with each injectable anticoagulant. Secondary outcomes included the percentages of patients in each treatment group who had a venous thromboembolism (VTE) or major bleeding episode. RESULTS: Mean total adjusted costs were significantly lower for fondaparinux ($18,019) compared with other anticoagulants, with unfractionated heparin being the most costly ($20,835). Relative adjusted cost differences were 1.4% (p = 0.0127), 1.8% ( p = 0.0105), and 14.6% (p < 0.0001) higher for enoxaparin, dalteparin, and unfractionated heparin, respectively, compared with fondaparinux. Significantly fewer fondaparinux-treated patients had a VTE event compared with the other treatment groups. The use of dalteparin was associated with fewer major bleeding events, and no significant differences in the rate of major bleeding events were observed among groups treated with fondaparinux, enoxaparin, or unfractionated heparin. CONCLUSION: A retrospective analysis of inpatient billing data showed that, among orthopedic surgery patients, fondaparinux was associated with lower institutional cost and a lower frequency of VTE than were dalteparin, enoxaparin, and unfractionated heparin. Dalteparin was associated with a lower rate of major bleeding events than was fondaparinux, but there were no significant differences in such events among fondaparinux, enoxaparin, and unfractionated heparin.     

Clinical use of enoxaparin in the management of non-ST segment elevation acute coronary syndromes

Enoxaparin (Lovenox; Roule-Poulenc Rorer, Inc.), a low molecular weight heparin (LMWH), is commonly used in the management of non-ST-segment elevation acute coronary syndromes (NSTE ACS) based on clinical trial outcomes. It is one of a group of glycosaminoglycan compounds that accelerate the inactivation of factor Xa by inducing a conformational change in antithrombin. In contrast to unfractionated heparin (UFH), LMWH have greater bioavailability, a more predictable anticoagulant response, longer half-life and a higher proportion of anti-factor Xa to anti-factor IIa activity. As a consequence, laboratory monitoring of the anticoagulant effect is typically unnecessary. Antithrombin therapy with LMWH or UFH has the highest-level recommendation (IA) in the 2002 professional guidelines for the management of unstable angina and non-ST-elevation myocardial infarction, where enoxaparin has a IIA recommendation over UFH unless early coronary artery bypass surgery is planned. In a recent systematic overview of > 20,000 patients with NSTE ACS from six clinical trials, including conservative and invasively managed patients, enoxaparin provided a statistically significant reduction in 30-day death or nonfatal myocardial infarction (MI) compared with UFH with no significant excess in transfusions, or major bleeding. These data support the role of enoxaparin as an anti-coagulant in patients with NSTE ACS.     

Enoxaparin: an update of its clinical use in the management of acute coronary syndromes

Enoxaparin (enoxaparin sodium) is a low molecular weight heparin (LMWH) indicated for use in the treatment of ischaemic complications of unstable angina and non-Q wave myocardial infarction (MI). Unfractionated heparin (UFH) has for many years represented the standard in anticoagulant therapy for patients with acute coronary syndromes; however, recent studies suggest that enoxaparin is also a viable option for anticoagulant therapy in these patients. The ESSENCE (Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q wave Coronary Events) and the TIMI 11B (Thrombolysis in Myocardial Infarction) studies reported that twice daily enoxaparin was significantly more effective than a continuous infusion of UFH in reducing the composite triple endpoint of death, MI, or recurrent angina or urgent revascularisation. Follow-up of both patient populations showed continued benefit associated with enoxaparin. Enoxaparin has been compared with tinzaparin in the treatment of unstable coronary artery disease using a nonblind study design. There was no difference between treatment groups in the therapeutic endpoints. Three nonblind studies have also compared the effects of enoxaparin and UFH in patients receiving thrombolytic therapy following acute MI. The HART II (Heparin and Aspirin Reperfusion Therapy), the ASSENT 3 (Assessment of the Safety and Efficacy of a New Thrombolytic Regimen) and the ENTIRE-TIMI 23 (Enoxaparin and Tenecteplase with or without glycoprotein IIb/IIIa Inhibitor as Reperfusion strategy in ST Elevation MI - Thrombolysis in Myocardial Infarction) studies have revealed that enoxaparin in combination with alteplase or tenecteplase is at least equivalent (HART II and ENTIRE-TIMI 23), and possibly superior (ASSENT 3) to UFH. Enoxaparin is administered as a twice-daily subcutaneous injection. In contrast, UFH is administered as an intravenous infusion which requires routine monitoring of the activated partial thromboplastin time to ensure adequate levels of anticoagulation are maintained. During the acute phase of the the ESSENCE and TIMI 11B studies, the incidence of major bleeding was similar in patients receiving enoxaparin to that in patients receiving UFH. In contrast, the rates of minor bleeding were higher in patients receiving enoxaparin than in those receiving UFH throughout these studies. Conclusions: Data from the ESSENCE, TIMI 11B and ASSENT 3 studies have prompted calls for those LMWHs which have been shown to be superior to UFH, to be considered as first choice treatment for anticoagulation in unstable coronary syndromes. To date, these suggestions are not reflected in current guidelines which consider UFH and LMWHs equally. Irrespective, the clinical data reported in this review support the use of enoxaparin in the treatment of acute coronary syndromes. These data suggest that enoxaparin shows certain clinical and practical advantages over standard treatment with UFH and represents an important development in the treatment of acute coronary syndromes.     

Clinical use of enoxaparin in the management of non-ST segment elevation acute coronary syndromes

Enoxaparin (Lovenox^®; Roule-Poulenc Rorer, Inc.), a low molecular weight heparin (LMWH), is commonly used in the management of non-ST-segment elevation acute coronary syndromes (NSTE ACS) based on clinical trial outcomes. It is one of a group of glycosaminoglycan compounds that accelerate the inactivation of factor Xa by inducing a conformational change in antithrombin. In contrast to unfractionated heparin (UFH), LMWH have greater bioavailability, a more predictable anticoagulant response, longer half-life and a higher proportion of anti-factor Xa to anti-factor IIa activity. As a consequence, laboratory monitoring of the anticoagulant effect is typically unnecessary. Antithrombin therapy with LMWH or UFH has the highest-level recommendation (IA) in the 2002 professional guidelines for the management of unstable angina and non-ST-elevation myocardial infarction, where enoxaparin has a IIA recommendation over UFH unless early coronary artery bypass surgery is planned. In a recent systematic overview of > 20,000 patients with NSTE ACS from six clinical trials, including conservative and invasively managed patients, enoxaparin provided a statistically significant reduction in 30-day death or nonfatal myocardial infarction (MI) compared with UFH with no significant excess in transfusions, or major bleeding. These data support the role of enoxaparin as an anti-coagulant in patients with NSTE ACS.     

Enoxaparin. A review of its pharmacology and clinical applications in the prevention and treatment of thromboembolic disorders.

Enoxaparin (PK 10169) belongs to the group of low molecular weight heparins which have a greater bioavailability and longer half-life than unfractionated heparin, permitting less frequent subcutaneous administration. In well controlled trials in surgical patients at high risk of deep venous thrombosis (DVT), enoxaparin has demonstrated prophylactic efficacy against venographically confirmed DVT at least equal to that observed with unfractionated heparin. Efficacy has also been demonstrated in patients at moderate risk and in limited investigations using 125I-fibrinogen scanning in nonsurgical patients at risk of DVT; in addition, enoxaparin appears to provide effective treatment of established DVT. In clinical studies, enoxaparin has also prevented coagulation of extracorporeal circulation, maintaining the patency of the circuit in patients undergoing haemodialysis. Thus, enoxaparin represents an effective alternative in the prophylaxis and treatment of thrombosis, with the convenience of less frequent administration than unfractionated heparin and the possible advantage of a lesser propensity for bleeding complications.     

低分子肝素钙联合阿司匹林治疗不稳定型心绞痛的随机对照研究

目的探究在不稳定型心绞痛患者中应用阿司匹林联合低分子肝素钙的效应。方法将37例不稳定型心绞痛患者采取双盲随机的方法分为治疗组、对照组,对照组给予阿司匹林、普通常规治疗和安慰剂治疗2周,治疗组给予阿司匹林、普通常规治疗和低分子肝素钙治疗1周,后等同对照组方案治疗1周。结果治疗组总有效率为75%,较对照组优;治疗组的心肌梗死发生率较对照组低,不良反应发生率为5%,C-反应蛋白、血小板数量的降低幅度较对照组大,差异均有统计学意义(P<0.05)。结论在不稳定型心绞痛患者治疗中给予阿司匹林联合低分子肝素钙有效率较高,心肌梗死的发生率较低。     

Factor Xa inactivation in acute coronary syndrome

The increasing incidence of patients who develop acute coronary syndrome (ACS) stresses the importance of effective initial treatment to reduce morbidity and mortality. The recommended initial therapeutic regimen for patients with ACS includes both anticoagulants and antiplatelet agents to prevent excessive coronary thrombosis, stroke, and further coronary events. Most commonly, unfractionated heparin (UFH) is used for initial antithrombotic treatment of ACS, despite limited published evidence regarding effectiveness and safety (bleeding complications). Therefore, this treatment regimen is primarily based upon expert opinion rather than evidence-based medicine. Studies addressing the dilemma of effectiveness and increased risk of bleeding when using UFH and low molecular weight heparin (LMWH) in patients with ACS showed superior clinical outcome in patients treated with LMWH. Nevertheless, the concurrent increased risk of bleeding while using anticoagulants is a severe problem and negatively impacts upon clinical outcome. Furthermore, non-hemorrhagic side effects of heparin such as heparin-induced thrombocytopenia (HIT), and skin reactions at the site of subcutaneous injection are reduced but not abolished by replacing UFH with LMWH. The limitations of UFH and LWMH as outlined above provided the impetus for the development of a pentasaccharide, called fondaparinux, which inhibits factor Xa selectively. Fondaparinux has been shown to be as effective as enoxaparin in the prevention of thrombosis in patients undergoing orthopedic surgery and showed similar results compared to enoxaparin or UFH in patients with deep-vein-thrombosis or pulmonary embolism. Recently, a large clinical study addressed the dilemma of the effectiveness and adverse effects of anticoagulation in ACS by comparing fondaparinux and LMWH such as enoxaparin in patients with unstable angina or non ST-segment elevation myocardial infarction (NSTEMI).     

Fondaparinux Sodium

Fondaparinux sodium (Arixtra) is a synthetic, sulfated pentasaccharide, selective factor Xa inhibitor that is indicated in Europe for preventing thrombus formation in patients with acute coronary syndromes (ACS; the focus of this review), including those with ST-segment elevation myocardial infarction (STEMI), non-STEMI (NSTEMI), or unstable angina.The large (n = 20,078), well designed OASIS-5 trial showed that subcutaneous fondaparinux 2.5 mg/day for 12,000) OASIS-6 trial. There were no differences in the incidence of major bleeding between these groups, resulting in a benefit : risk balance favoring fondaparinux. The specificity and selectivity of fondaparinux, combined with its long half-life and 100% bioavailability, allows once-daily anticoagulation without the need for monitoring activated clotting time. Subcutaneous fondaparinux was noninferior to enoxaparin treatment in patients with unstable angina or NSTEMI, and was more effective than usual care in those with STEMI. Fondaparinux has a favorable tolerability profile, particularly with regard to the risk of major bleeding, and limited data suggest that it is more cost effective than enoxaparin in the short term. Thus, overall, clinical evidence suggests that fondaparinux has a valuable place in the treatment of patients with ACS.