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Three Part Question

In [patients diagnosed with non-ST elevation acute coronary syndrome] is [enoxaparin more effective than dalteparin] in [reducing morbidity and mortality]

Clinical Scenario

You start a new job at Manchester Royal Infirmary and find yourself as the RMO. You are referred a gentleman with cardiac chest pain, being treated as an acute coronary syndrome (non-ST elevation). You are surprised to find that he is being given fragmin (dalteparin), as clexane (enoxaparin) is used in every other hospital you have ever worked. Your colleagues also tell you that have used clexane much more in the past, but are not bothered by which LMWH they use. You think you are probably over-reacting, but you wonder whether the patients of central Manchester are getting a raw deal by not being given clexane.

Search Strategy

OVID Medline 1966 - 2006 March Week 2
OVID Embase 1980 - 2006 Week 10
PUBMED Medline 1966 - 2006 March Week 2
OVID Medline and Embase:
{exp Angina Pectoris/ OR exp Coronary Disease/ OR exp Myocardial Ischemia/ OR exp Myocardial Infarction/ OR exp Angina, Unstable/ OR exp Coronary Thrombosis/ OR acute coronary syndrome.mp. OR MI.mp. OR (myocard$ ADJ ischaem$).mp. OR (myocard$ ADJ ischem$).mp. OR (myocard$ ADJ infarct$).mp. OR AMI.mp. OR heart attack.mp.} AND {exp fragmin/ OR fragmin.mp. OR exp dalteparin/ OR dalteparin.mp. OR exp clexane/ or clexane.mp. or exp enoxaparin/ or enoxaparin.mp.}
PUBMED medline:
{comparison of dalteparin AND enoxaparin} AND {unstable angina OR NSTEMI}

Search Outcome

OVID search identified 1585 papers, of which 2 were deemed relevant. PUBMED search identified 135 papers, of which 3 were relevant. In total, 5 papers were appraised.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Hodl, R et al. March 2002 Austria	Patients with unstable angina or NSTEMI assigned either enoxaparin (n=30) or dalteparin (n=31)	Prospective randomized controlled trial	Markers of thrombin generation (a surrogate marker for anti-thrombotic efficacy)	No significant differences detected between enoxaparin and dalteparin	Small numbers of patients studied Wide interquartile range in the parameters measured No short or long term measurement of actual clinical outcomes (e.g death, MI, recurrent angina)
			Markers of plasmin activation (a surrogate marker for anti-thrombotic efficacy)	No significant differences detected between enoxaparin and dalteparin
			Change in von Willebrand factor (a marker that correlates with poor clinical outcome) at 4 and 66 hours after initiation of treatment	No significant differences detected between enoxaparin and dalteparin
Ozdemir, M et al. September 2002 Turkey	142 patients with unstable angina or non Q wave MI randomly assigned enoxaparin or dalteparin. 69 patients in enoxaparin group, 73 patients in dalteparin group. Baseline characteristics of patients in the two groups were similar.	Prospective randomised controlled trial	Death within 5 days	No deaths in either group	Small patient group in a single centre No long term follow up of patients (end-points after only 5 days)
			Myocardial infarction within 5 days	MI occurred in two patients in dalteparin group, none in enoxaparin group
			Angina recurrence within 5 days	Angina recurrence seen in 11 patients in dalteparin group and 11 patients in enoxaparin group
			Time to occurrence of first event (death, MI, angina)	Dalteparin group: 37.6 +/- 23.4 hours. Enoxaparin group: 82.3 +/-33.2 hours. P value=0.007.
			Major bleeding	1 patient in enoxaparin group, none in dalteparin group
			Minor bleeding	Occurred in 21 patients in dalteparin group, 17 patients in enoxaparin group (P>0.05)
Montalescot, G et al. April 2003 France	141 patients with unstable angina or NSTEMI randomized to treatment for 48 to 120 hours with enoxaparin (n=46), dalteparin (n=48) or unfractionated heparin (UFH) (n=47)	Prospective randomised controlled trial	Plasma levels of Von Willebrand factor (vWF) (increased levels shown to be associated with a worse outcome)	Enoxaparin and dalteparin reduced the release of vWF into the plasma compared with UFH	Small number of patients despite multicentre trial. No long term follow up (e.g. 6 month follow up)
			Platelet levels of glycoprotein Ib/IX complexes (decreased levels shown to be associated with a worse outcome)	Enoxaparin increased glycoprotein levels more than dalteparin or UFH
			1 month adverse outcome (death, MI or recurrent ischaemia)	Adverse outcome incidence: 13% with enoxaparin, 19% with dalteparin, 28% with UFH
Katsouras, C et al. September 2005 Greece	438 pateints with non-ST elevation acute coronary syndrome randomized to receive either enoxaparin (n=220) or tinzaparin (n=218)	Prospective randomized controlled trial	Triple end point of death, MI or recurrent angina at 7days, 30 days and 6 months	7 day and 30 day end point incidence significantly lower with enoxaparin than tinzaparin. 6 month incidence of end points 25.5% with enoxaparin and 44.0% with tinzaparin (p<0.001)	Compared enoxaparin to tinzaparin (not licensed for use in UK for ACS). No direct comparison of enoxaparin to dalteparin
			Secondary composite end point of death or MI at 6 months	Incidence 2.7% with enoxaparin and 6.9 % with tinzaparin (p=0.046).
			Need for revascularization at 6 months	23.2% with enoxaparin and 37.2% with tinzaparin (p=0.002)
Sullivan, S September 2005 unknown	Patients with non-ST elevation acute coronary syndrome randomized to receive either enoxaparin or fondaparinux (a newer type of LMWH)	Report on OASIS 5 Study (a PRCT presented at European society of cardiology annual conference)	9 day incidence of death, MI or ischaemia	No difference between enoxaparin and fondaparinux	No access to exact figures (e.g. numbers involved, p values) No direct comparison between enoxaparin and dalteparin
			Incidence of bleeding episodes	Significantly lower with fondaparinux compared to enoxaparin
			6 month mortality rate	Lower with fondaparinux than with enoxaparin

Comment(s)

The advent of low molecular weight heparins (LMWHs) was heralded by numerous trials comparing them to unfractionated heparin (UFH). These trials showed LMWHs to be at least as efficacious, if not more, than UFH. In view of their simplicity of use, this has made LMWHs an attractive option in the treatment of non-ST elevation acute coronary syndromes (NSTEACS). Although there have been many trials comparing LMWHs in the treatment of venous thromboembolic disease, there has been little comparison made between these in the treatment of NSTEACS. The papers appraised above were found after an extensive literature search. Currently in the UK there are two LMWHs licensed for use in NSTEACS: enoxaparin (clexane) and dalteparin (fragmin). 3 of the papers described make a direct comparison between enoxaparin and dalteparin. In two of these cases (bearing in mind the waeknesses of the studies) there is clear evidence that enoxaparin is associated with a better outcome than dalteparin. The other two papers do not make a direct comparison between enoxaparin and dalteparin, but instead compare enoxaparin to other LMWHs. Their importance lies in the fact that they show that the benefit of LMWHs in NSTEACS is NOT a class effect. Different compounds have different outcomes.

Clinical Bottom Line

The evidence available suggests that there is a difference between low molecular weight heparins in the treatment of non-ST elevation ACS. Enoxaparin is associated with a better outcome than dalteparin, but may be superseded in the future by newer compounds which are safer such as fondaparinux.

References

1. Hodl R, Huber K, Kraxner W, Nikfardjam M, Schumacher M, Fruhwald FM, Zorn G, Wonisch M, Klein W. Comparison of effects of dalteparin and enoxaparin on hemostatic parameters and von Willebrand factor in patients with unstable angina pectoris or non-ST-segment elevation acute myocardial infarctio American Journal of Cardiology 2002 Mar 1;89(5):589-92
2. Ozdemir M, Erdem G, Turkoglu S, Cemri M, Timurkaynak T, Boyaci B, Ridvan Y, Cengel A, Dortlemez O, Dortlemez H. Head-to-head comparison of two different low-molecular-weight heparins in acute coronary syndrome: a single center experience. Japanese Heart Journal 2002 Sep;43(5):433-42
3. Montalescot G, Bal-dit-Sollier C, Chibedi D, Collet JP, Soulat T, Dalby M, Choussat R, Cohen A, Slama M, Steg PG, Dubois-Rande JL, Metzger JP, Tarragano F, Guermonprez JL, Drouet L; ARMADA Investigato Comparison of effects on markers of blood cell activation of enoxaparin, dalteparin, and unfractionated heparin in patients with unstable angina pectoris or non-ST-segment elevation acute myocardial i American Journal of Cardiology 2003 Apr 15;91(8):925-30
4. Katsouras, Christos MD; Michalis, Lampros K. MD, MRCP, FESC; Papamichael, Nikos MD; Adamides, Kostas PhD; Naka, Katerina K. MD, PhD; Nikas, Dimitris MD; Goudevenos, John A. MD, FACC; Sideris, Dimitris Enoxaparin versus tinzaparin in non-ST-segment elevation acute coronary syndromes: Results of the enoxaparin versus tinzaparin (EVET) trial at 6 months American Heart Journal 150(3):385-391, September 2005
5. Sullivan, S Fondaparinux has the edge over enoxaparin in ACS Inpharma Weekly (1505):11-12, September 17, 2005