LA CONSULTA SEMANAL

CONSULTA

1: Eur Heart J 2002 Aug;23(16):1282

Improved reperfusion and clinical outcome with enoxaparin as an adjunct to streptokinase thrombolysis in acute myocardial infarction. The AMI-SK study.

Simoons M, Krzeminska-Pakula M, Alonso A, Goodman S, Kali A, Loos U, Gosset F,

Louer V, Bigonzi F.

Thorax Centre, Erasmus University Medical Center, Rotterdam, The Netherlands

Aims To establish whether the addition of enoxaparin (a low-molecular-weight heparin) to streptokinase therapy improves early and sustained coronary patency and clinical outcome in patients with evolving myocardial infarction.Methods and Results A total of 496 patients with acute myocardial infarction treated with streptokinase were randomized to an intravenous bolus (30mg) and subcutaneous injections (1mg.kg(-1), twice daily) of enoxaparin (n=253), or placebo (n=243) for 3-8 days. The median duration of treatment in both groups was 5 days. ST-segment resolution at 90min and 180min measured by electrocardiogram was improved in patients receiving enoxaparin. Complete, partial and no ST-segment resolution at 180min was observed in 36%, 44% and 19% in the enoxaparin group vs 25%, 44% and 31% in the placebo group, respectively (P=0.004). Assessment of the primary end-point revealed improved TIMI-3 flow with enoxaparin vs placebo (70% vs 58%, P=0.01). Combined TIMI-2 and -3 flow was also improved (88% vs 72%, P=0.001), as was TIMI frame count (P=0.003). The triple clinical end-point of death, reinfarction and recurrent angina at 30 days was reduced with enoxaparin (13% vs 21%, P=0.03).ConclusionStreptokinase in combination with enoxaparin is associated with better ST-segment resolution and better angiographic patency at days 5-10, suggesting more effective reperfusion. This was associated with a significant reduction in clinical events, indicating less reocclusion.

2: Drugs 2002;62(9):1407-30

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

Ibbotson T, Goa KL.

Adis International Limited, Auckland, New Zealand. demail@adis.co.nz

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.

Publication Types:

Review

3: Curr Opin Cardiol 2001 Nov;16(6):384-9

The role of low-molecular-weight heparin in the management of acute coronary syndromes.

Cohen M.

Division of Cardiology, MCP-Hahnemann School of Medicine, Philadelphia, Pennsylvania 19102-1192, USA. marc.cohen@tenethealth.com

Optimized medical treatment for the non-ST segment elevation acute coronary syndromes (NSTE ACS) should consist of a combined antithrombotic/anti-anginal regimen. Standard antithrombotic treatment is currently unfractionated heparin and aspirin, and in high-risk patients glycoprotein IIb/IIIa inhibitors. However, low-molecular-weight heparins (LMWHs) have practical and clinical advantages over UFH and can be considered an effective alternative in the medical treatment of ACS and in patients proceeding to surgical interventions. Benefits include a more predictable and stable therapeutic response, no need for coagulation monitoring and a reduced incidence heparin-induced thrombocytopenia. In this context, the LMWH enoxaparin has demonstrated sustained clinical and economic benefits compared with UFH, with no increase in major bleeding complications. In addition, recently published studies indicate that LMWHs can improve reperfusion of the arteries and reduce reocclusion when used as adjunctive anticoagulant therapy in patients with ST segment elevation (STE) ACS undergoing thrombolysis with fibrin-specific agents or streptokinase.

Publication Types:

Review

4: Lancet 2001 Aug 25;358(9282):605-13

Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT-3 randomised trial in acute myocardial infarction.

The Assessment of the Safety and Efficacy of a New Thrombolytic Regimen (ASSENT)-3 Investigators.

BACKGROUND: Current fibrinolytic therapies fail to achieve optimum reperfusion in many patients. Low-molecular-weight heparins and platelet glycoprotein IIb/IIIa inhibitors have shown the potential to improve pharmacological reperfusion therapy. We did a randomised, open-label trial to compare the efficacy and safety of tenecteplase plus enoxaparin or abciximab, with that of tenecteplase plus weight-adjusted unfractionated heparin in patients with acute myocardial infarction. METHODS: 6095 patients with acute myocardial infarction of less than 6 h were randomly assigned one of three regimens: full-dose tenecteplase and enoxaparin for a maximum of 7 days (enoxaparin group; n=2040), half-dose tenecteplase with weight-adjusted low-dose unfractionated heparin and a 12-h infusion of abciximab (abciximab group; n=2017), or full-dose tenecteplase with weight-adjusted unfractionated heparin for 48 h (unfractionated heparin group; n=2038). The primary endpoints were the composites of 30-day mortality, in-hospital reinfarction, or in-hospital refractory ischaemia (efficacy endpoint), and the above endpoint plus in-hospital intracranial haemorrhage or in-hospital major bleeding complications (efficacy plus safety endpoint). Analysis was by intention to treat. FINDINGS: There were significantly fewer efficacy endpoints in the enoxaparin and abciximab groups than in the unfractionated heparin group: 233/2037 (11.4%) versus 315/2038 (15.4%; relative risk 0.74 [95% CI 0.63-0.87], p=0.0002) for enoxaparin, and 223/2017 (11.1%) versus 315/2038 (15.4%; 0.72 [0.61-0.84], p<0.0001) for abciximab. The same was true for the efficacy plus safety endpoint: 280/2037 (13.7%) versus 347/2036 (17.0%; 0.81 [0.70-0.93], p=0.0037) for enoxaparin, and 287/2016 (14.2%) versus 347/2036 (17.0%; 0.84 [0.72-0.96], p=0.01416) for abciximab. INTERPRETATION: The tenecteplase plus enoxaparin or abciximab regimens studied here reduce the frequency of ischaemic complications of an acute myocardial infarction. In light of its ease of administration, tenecteplase plus enoxaparin seems to be an attractive alternative reperfusion regimen that warrants further study.

Publication Types:

Clinical Trial

5: Circulation 2001 Aug 7;104(6):648-52

Randomized comparison of enoxaparin, a low-molecular-weight heparin, with unfractionated heparin adjunctive to recombinant tissue plasminogen activator thrombolysis and aspirin: second trial of Heparin and Aspirin Reperfusion Therapy (HART II).

Ross AM, Molhoek P, Lundergan C, Knudtson M, Draoui Y, Regalado L, Le Louer V, Bigonzi F, Schwartz W, de Jong E, Coyne K; HART II Investigators.

Cardiovascular Research Institute, Institute of Medicine, George Washington University, Washington, DC, USA. allanmross@aol.com

BACKGROUND: Adjunctive unfractionated heparin (UFH) during thrombolytic therapy for acute myocardial infarction (AMI) promotes the speed and magnitude of coronary artery recanalization and reduces reocclusion. Low-molecular-weight heparins offer practical and potential pharmacological advantages over UFH in multiple applications but have not been systematically studied as adjuncts to fibrinolysis in AMI. METHODS AND RESULTS: Four hundred patients undergoing reperfusion therapy with an accelerated recombinant tissue plasminogen activator regimen and aspirin for AMI were randomly assigned to receive adjunctive therapy for at least 3 days with either enoxaparin or UFH. The study was designed to show noninferiority of enoxaparin versus UFH with regard to infarct-related artery patency. Ninety minutes after starting therapy, patency rates (thrombolysis in myocardial infarction [TIMI] flow grade 2 or 3) were 80.1% and 75.1% in the enoxaparin and UFH groups, respectively. Reocclusion at 5 to 7 days from TIMI grade 2 or 3 to TIMI 0 or 1 flow and TIMI grade 3 to TIMI 0 or 1 flow, respectively, occurred in 5.9% and 3.1% of the enoxaparin group versus 9.8% and 9.1% in the UFH group. Adverse events occurred with similar frequency in both treatment groups. CONCLUSIONS: Enoxaparin was at least as effective as UFH as an adjunct to thrombolysis, with a trend toward higher recanalization rates and less reocclusion at 5 to 7 days.

Publication Types:

Clinical Trial

6: Thromb Res 2001 May 1;102(3):261-71

Superiority of enoxaparin over heparin in combination with a GPIIb/IIIa receptor antagonist during coronary thrombolysis in dogs.

Rebello SS, Kasiewski CJ, Bentley RG, Morgan SR, Chu V, Bostwick JS, Klein SI, Perrone MH, Leadley RJ.

Cardiovascular Biology, Aventis Pharmaceuticals, 19426, Collegeville, PA, USA. sam.rebello@aventis.com

It is known that a low-molecular-weight heparin (LMWH) is more effective than unfractionated heparin in unstable angina/non-Q-wave myocardial infarction (UA/NQMI) and the platelet GPIIb/IIIa receptors play an important role in acute myocardial infarction (AMI). Therefore, enoxaparin might have a similar advantage over heparin when used with a GPIIb/IIIa antagonist (RPR109891) in coronary thrombolysis. After induction of coronary thrombosis in anesthetized dogs, infusion of saline, enoxaparin, heparin, RPR109891, enoxaparin+RPR109891, or heparin+RPR109891 was initiated followed 15 min later by recombinant tissue plasminogen activator (rt-PA). The incidence of reperfusion in the enoxaparin+RPR109891- and the heparin+RPR109891-treated groups was similar, but time to reperfusion tended to be shorter for enoxaparin versus heparin. Only 43% of the vessels reoccluded in the enoxaparin+RPR109891 group, compared to 100% vessels in the heparin+RPR109891 group. Enoxaparin+RPR109891 maintained flow for a significantly longer time compared to saline, enoxaparin, heparin, and heparin+RPR109891. Enoxaparin+RPR109891 and heparin+RPR109891 increased the template bleeding time by 2- and 3-fold and activated partial thromboplastin time (APTT) by 1.3- and 3-fold, respectively. These data suggest that enoxaparin is more effective and potentially safer than heparin when combined with a GPIIb/IIIa receptor antagonist during rt-PA-induced coronary thrombolysis.

7: J Invasive Cardiol 2000 Dec;12 Suppl D:16D-8D

Concomitant use of eptifibatide and enoxaparin in the medical management of a patient with a non-ST segment elevation acute coronary syndrome and in-stent restenosis.

Nahlawi M, Benzuly K, Fintel D.

Northwestern University School of Medicine, Coronary Care Unit, Wesley Suite 726, 250 East Superior Street, Chicago, IL 60611, USA.

8: J Thromb Thrombolysis 2000 Dec;10(3):241-6

The TETAMI trial: the safety and efficacy of subcutaneous enoxaparin versus intravenous unfractionated heparin and of tirofiban versus placebo in the treatment of acute myocardial infarction for patients not thrombolyzed: methods and design.

Cohen M, Maritz F, Gensini GF, Danchin N, Timerman A, Huber K, Gurfinkel EP, White H, Fox KA, Vittori L, Le-Louer V, Bigonzi F.

Hahnemann University Hospital, Philadelphia, Pennsylvania 19102-1192, USA. marc.cohen@tenethealth.com

Patients with acute myocardial infarction (AMI) who do not receive early reperfusion therapy are at high risk of reinfarction or death, and the efficacy and safety of antithrombotic therapy in this group of patients has not been evaluated. Enoxaparin is a low-molecular-weight heparin (LMWH) that has previously been shown to reduce the incidence of ischemic events in patients with unstable angina or non-Q-wave MI. The principal aims of the TETAMI study are to investigate the efficacy and safety of treatment with enoxaparin or tirofiban (a glycoprotein IIb/IIIa receptor antagonist) alone or in combination for 2 to 8 days in patients with AMI who are not eligible for early reperfusion therapy. In this 2 by 2 factorial design study approximately 900 patients will be randomly assigned, in a blinded manner, to one of four treatments: enoxaparin alone, enoxaparin plus tirofiban, unfractionated heparin (UFH), or UFH plus tirofiban, with appropriate matched placebos. The primary end point is the composite of death, recurrent AMI, and recurrent angina, analyzed at 30 days after AMI. The design and methods of the TETAMI study are described in this article.

Publication Types:

Clinical Trial

9: Arch Mal Coeur Vaiss 2000 Jan;93(1 Spec No):77-81

The best of thrombosis and thromboembolic disease in 1999

Ferrari E.

Service de cardiologie, Hopital Pasteur, Nice.

1999 has been a good year in the field of innovation in thrombosis. In coronary syndrome without ST elevation: low molecular weight heparin has been confirmed to be more effective than non-fractionated heparin (enoxaparin) and to improve the prognosis of non-revascularised patients (dalteparin) after the hospital phase; hirudin has been shown to be more effective in terms of incidence of myocardial infarction and recurrence of angina than non-fractionated heparin without a higher incidence of bleeding complications; the anti-GP IIb-IIIa (abciximab) has confirmed all its advantages at 6 months and 1 year after a coronary event. The association of heparin and aspirin, which has been the mainstay of antithrombotic treatment of acute coronary syndromes without ST elevation, will soon be improved upon at the beginning of the third millennium. In myocardial infarction, medical thrombolysis has probably reached a turning point in its history. The association of half doses of rt-Pa and anti-GP IIb-IIIa has been shown to be more effective in obtaining good reflow than the thrombolytic agent alone at conventional doses. These results were obtained without any increase in bleeding complication. The same anti-GP IIb-IIIa also improve mechanical revascularisation by optimising reperfusion after the 24th hour. This benefit is rapidly transformed into reduced left ventricular dysfunction. Pulmonary embolism remains a critical illness as the ICOPER registry reports a 3 year mortality of nearly 16%. This emphasises the importance of early diagnosis which is usually possible without resorting to invasive procedures and by modulating all the results of paraclinical investigations with respect to the pretest clinical probability.

Publication Types:

Review

10: J La State Med Soc 1999 May;151(5):272-7

Advances in the pathogenesis and treatment of acute coronary syndromes.

Thompson CA, Danzell JD, Hanley HG.

Department of Internal Medicine, Louisiana State University School of Medicine, Shreveport, USA.

The clinical entities of unstable angina, non-Q wave myocardial infarction, and Q wave myocardial infarction share the same pathogenesis and, because of this, are linked under the heading of acute coronary syndromes. Prompt reperfusion in the early phase of acute ST segment elevation myocardial infarction, with thrombolysis or percutaneous transluminal coronary angioplasty, now has an established place in the treatment of this condition. However, thrombolysis has been disappointing and may be harmful in the treatment of unstable angina and non-Q wave myocardial infarction. While traditional therapy with morphine, oxygen, nitrates, aspirin, heparin, and beta blockers may be indicated in the treatment of all types of acute coronary syndromes, recent studies have led to advances in the treatment of unstable angina/non-Q wave myocardial infarction patients. In these patients, enoxaparin (a low molecular weight heparin) and the platelet glycoprotein IIb/IIIa receptor antagonists may be particularly effective.

Publication Types:

Review