Fractionating heparins and their clinical trial data--something for everyone.

HEPARIN, A GLYCOSAMINOGLYCAN OF VARYING POLYsaccharide units and molecular weights, has been shown to reduce ischemic events beyond that of aspirin alone in the setting of an acute coronary syndrome (ACS). This benefit translated into a class I indication for unfractionated heparin in the 2000 American College of Cardiology/American Heart Association (ACC/ AHA) treatment guidelines for non–ST-segment elevation ACS. Unfractionated heparin has several known limitations, however, including a narrow therapeutic window, poorly predictable kinetics, platelet activation, and inability to inhibit clot-bound thrombin. In comparison, enoxaparin, a low-molecular-weight heparin (LMWH), has a higher anti-factor Xa–anti-factor IIa ratio, thereby reducing some of these limitations. For intermediate and longer-term administration as part of medical therapy, enoxaparin has been considered particularly convenient and cost minimizing because it can be given subcutaneously twice daily without the need for routine monitoring. Based on several LMWH studies, including 2 with enoxaparin (ESSENCE and TIMI-11B) showing a moderate benefit over unfractionated heparin, LMWH and unfractionated heparin have shared the class I indication as alternatives to one another. An accumulation of experience and weight of evidence prompted an update to the prior ACC/AHA guidelines within 2 years. The current (2002) guidelines moved the level of evidence for unfractionated heparin and LMWH to the highest rank (level A), and enoxaparin was made possibly preferable (class IIa) to unfractionated heparin. Even with this update and upgrade, more key questions emerged for enoxaparin since simultaneous advancements in the treatment of patients with ACS demonstrated the benefits of platelet glycoprotein (Gp) IIb/IIIa inhibitors and an early invasive strategy in reducing ischemic events. While observational and small open-label studies suggested that the combination of enoxaparin and Gp IIb/IIIa inhibitors with or without an early invasive strategy was not associated with increased bleeding risks when compared with historical controls, data from large-scale randomized clinical trials were lacking. With this in mind, and appreciating interventional cardiologists’ concerns regarding the inability to rapidly monitor or fully reverse the anticoagulant effects of enoxaparin, the ACC/ AHA guidelines suggested an alternative approach: the use of LWMH prior to invasive procedures (ie, “upstream”) with a switch to unfractionated heparin for procedural anticoagulation while withholding the dose of enoxaparin prior to the procedure. Soon thereafter, and to assess the contemporary safety and efficacy of enoxaparin relative to unfractionated heparin (or more specifically whether the benefits of upstream enoxaparin over unfractionated heparin would be affected by concomitant Gp IIb/IIIa inhibitors or an early invasive strategy), the “A phase” of the A to Z and SYNERGY trials were forged. The results of these trials, presented in this issue of JAMA, advance the current understanding and potential future role of enoxaparin in the management of non–ST-segment elevation ACS. From the A phase of the A to Z trial, Blazing and colleagues report the outcome of nearly 4000 patients randomized to receive enoxaparin or unfractionated heparin therapy superimposed on a background of tirofiban and aspirin. They report that the primary end point (a 7-day composite of death, myocardial infarction [MI], or refractory ischemia) occurred in 8.4% of patients assigned to receive enoxaparin vs 9.4% assigned to receive unfractionated heparin (hazard ratio [HR], 0.88; 95% confidence interval [CI], 0.71-1.08). The authors conclude that enoxaparin is an effective, noninferior alternative to unfractionated heparin for treatment of ACS. In the SYNERGY trial, Mahaffey and colleagues bridged upstream and inpatient anticoagulation therapy by randomizing more than 10000 high-risk patients with ACS undergoing an early invasive strategy to receive enoxaparin or unfractionated heparin. They found that the primary end point (a 30-day composite of death or MI) occurred in 14.0% of patients assigned to receive enoxaparin vs 14.5% assigned to receive unfractionated heparin (HR, 0.96; 95% CI, 0.86-1.06). The authors also conclude that enoxaparin was not superior but was noninferior to unfractionated heparin.