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Durham, NC - The SYNERGY and A to Z trials, both showing enoxaparin to be "noninferior" to unfractionated heparin in ACS patients but with increased bleeding complications, have been published together in the July 7, 2004 issue of the Journal of the American Medical Association. Also appearing in the same issue is a meta-analysis of these two trials and four other studies of enoxaparin vs unfractionated heparin in ACS, which does suggest a significant benefit of enoxaparin.
In an accompanying editorial, Drs Pranab Das and David Moliterno (University of Kentucky, Lexington) say that these two new trials and the meta-analysis provide "something for everyone," with plenty of material for opposing viewpoints and interpretations.1
While the mass of new data still does not clarify if one antithrombin is definitely better than the other, the major recommendation to emerge appears to be that changing antithrombin agents in the midst of an episode of ACS may be hazardous.
The A to Z trial was first reported at the 2003 American College of Cardiology (ACC) meeting, and the SYNERGY trial and some details of the meta-analysis were presented at the 2004 ACC meeting earlier this year.
While previous studies have shown an advantage for enoxaparin over heparin, these were mainly conducted before the routine use of GP IIb/IIIa blockers and early revascularization in these patients. The A to Z and SYNERGY trials were therefore conducted to find out whether the benefits of enoxaparin are maintained in the modern-day treatment of ACS.
A to Z
The A to Z trial, led by Dr Michael Blazing (Duke University, Durham, NC), randomized almost 4000 patients to enoxaparin or unfractionated heparin on a background of tirofiban and aspirin.2 The primary end point (death, MI, or refractory ischemia at seven days) showed a trend toward a benefit with enoxaparin, but this was not significant.
Primary end point in the A to Z study|
Primary end point |
Enoxaparin |
Heparin |
Hazard ratio |
95% CI |
|
Death, MI, refractory ischemia (%) | 8.4 | 9.4 | 0.88 | 0.71-1.08 |
Bleeding was slightly increased with enoxaparin. Using a worst-case approach that combined two independent bleeding evaluations, use of enoxaparin was associated with one additional TIMI major bleeding episode for each 200 patients treated. The A to Z authors say that "the clinical relevance of this finding is low and is further diminished by the absence of any associated increase in transfusion rates."
Bleeding results in A to Z|
Bleeding |
Enoxaparin |
Heparin |
p |
|
Any TIMI grade bleeding (%) | 3.0 | 2.2 | 0.13 |
|
TIMI major bleeding (%) | 0.9 | 0.4 | 0.05 |
They conclude, "Because it is easier to use and modestly reduces recurrent ischemic events without an increase in the need for blood products, enoxaparin compares favorably with unfractionated heparin in patients with non-ST-segment elevation ACS who are receiving tirofiban and aspirin."
SYNERGY
The SYNERGY trial, led by Dr Kenneth Mahaffey (Duke University, Durham, NC), randomized more than 10000 high-risk patients with ACS undergoing an early invasive strategy to receive enoxaparin or unfractionated heparin.3 The primary end point of death/MI at 30 days was similar between the two groups, but there was more bleeding with enoxaparin.
Primary end point in the SYNERGY trial|
Primary End point |
Enoxaparin |
Heparin |
Hazard ratio |
95% CI |
|
Death/MI (%) | 14 | 14.5 | 0.96 | 0.86-1.06 |
Bleeding results in SYNERGY
|
Bleeding |
Enoxaparin |
Heparin |
p |
|
TIMI major bleeding (%) | 9.1 | 7.6 | 0.008 |
|
GUSTO severe bleeding (%) | 2.7 | 2.2 | 0.08 |
|
Transfusions (%) | 17.0 | 16.0 | 0.16 |
Since many patients in the SYNERGY trial received an antithrombin agent before randomization to enoxaparin or heparin, the investigators performed an analysis including just those patients who received no prerandomization antithrombin therapy. This showed that the hazard ratio for 30-day death/MI with enoxaparin decreased from 0.96 in the overall analysis to 0.83, but the odds ratio for TIMI major bleeding with enoxaparin increased from 1.17 to 1.45.
Adding another complication, 800 patients in SYNERGY were switched to an open-label antithrombin after randomization, and this group had a markedly higher rate of adverse events, with the 30-day death/MI rate increasing by one third (13.9% to 18.5%) and the percentage of patients receiving blood transfusions more than doubling (15.2% to 31.5%).
The SYNERGY authors conclude: "Enoxaparin is a safe and effective alternative to unfractionated heparin, and the advantages of convenience should be balanced with the modest excess of major bleeding." They add, "Changing antithrombin agents in the midst of an episode of ACS may be hazardous, with an increase in bleeding and less clinical benefit."
Meta-analysis suggests enoxaparin superior?
In the meta-analysis, Dr John Peterson (Duke University, Durham, NC) and several of the SYNERGY and A to Z leading investigators combined data from A to Z, SYNERGY, and four older trials (ESSENCE, TIMI 11B, ACUTE II, and INTERACT) comparing enoxaparin and unfractionated heparin in a total of 22000 ACS patients.4
This showed a significant reduction in the 30-day composite of death or MI with enoxaparin in the overall trial populations, which is more impressive in patients who received no prerandomization antithrombin therapy. There was no difference in major bleeding or transfusion rate.
Death/MI at 30 days in meta-analysis|
Death / MI |
Enoxaparin |
Heparin |
Hazard Ratio |
95% CI |
|
All patients (%) | 10.1 | 11 | 0.91 | 0.83-0.99 |
|
Patients who did not receive prerandomization antithrombin therapy (%) | 8.0 | 9.4 | 0.81 | 0.70-0.94 |
|
Major bleeding |
Enoxaparin |
Heparin |
Hazard Ratio |
95% CI |
|
All patients (%) | 4.7 | 4.5 | 1.04 | 0.89-1.30 |
|
Patients who did not receive prerandomization antithrombin therapy (%) | 3.8 | 3.4 | 1.15 | 0.86-1.55 |
The authors conclude, "The substantial and consistent treatment benefit in patients who had not received prior antithrombin therapy indicates that enoxaparin maybe superior to unfractionated heparin as a first-line agent in ACS."
Results can be used to justify either treatment
However, in their editorial, Das and Moliterno point out, "Had A to Z or SYNERGY shown enoxaparin to be superior to unfractionated heparin, as some had expected and many had hoped, commentators would be giving accolades instead of point-counterpoint perspectives. Likewise, a meta-analysis including older and smaller studies would not be needed to defend the benefits of enoxaparin."
They report that from SYNERGY, the numbers needed to treat with enoxaparin to prevent an occurrence of death or MI at 30 days and to produce a TIMI major bleeding event are 184 and 68, respectively and add that these latest results can be used to justify the use of either enoxaparin or unfractionated heparin.
"Proponents of enoxaparin now have more evidence that this drug is a reasonable alternative to unfractionated heparin even when combined with contemporary strategies," but "for those preferring unfractionated heparin, these studies suggest that enoxaparin provides less benefit than previously observed, perhaps due to a shortened interval of ischemic risk between hospital admission and coronary revascularization. The residual value of enoxaparin may be additionally offset by bleeding in the era of progressively higher-risk patients, polypharmacy anticoagulation, and arteriotomy closure devices during invasive cardiac procedures."
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Fractionating heparins and their clinical trial data--something for everyone.2004 Jul 7; 292(1):101-3
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Safety and efficacy of enoxaparin vs unfractionated heparin in patients with non-ST-segment elevation acute coronary syndromes who receive tirofiban and aspirin: a randomized controlled trial.2004 Jul 7; 292(1):55-64
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Enoxaparin vs unfractionated heparin in high-risk patients with non-ST-segment elevation acute coronary syndromes managed with an intended early invasive strategy: primary results of the SYNERGY randomized trial.2004 Jul 7; 292(1):45-54
-
Efficacy and bleeding complications among patients randomized to enoxaparin or unfractionated heparin for antithrombin therapy in non-ST-Segment elevation acute coronary syndromes: a systematic overview.2004 Jul 7; 292(1):89-96
