American Heart Journal
Volume 146, Issue 2 , Pages 191-193, August 2003

Low molecular weight heparins for acute coronary syndrome: tackling the issues head-on

  • Elliott M. Antman, MD

      Affiliations

    • Samuel A. Levine Cardiac Unit, Brigham and Women’s Hospital, and Harvard Medical School, Boston, Mass, USA
    • Corresponding Author InformationReprint requests: Elliott M. Antman, MD, Director, Samuel A. Levine Cardiac Unit, Brigham and Women’s Hospital, 75 Francis St, Boston, MA, USA 02115.

Article Outline

 

Clinicians are faced with a startling array of options for treating patients with an acute coronary syndrome. In view of the heterogeneous nature of patients and their risk of clinical events, this is good news. However, one consequence of such a rich armamentarium of treatment choices is uncertainty about their relative strengths and weakness. For some clinicians, the role of new therapeutic options as compared with older ones is unclear and leads to indecision and a reluctance to move away from the prior “gold standard,” thus producing a delay in translating the results of randomized trials into clinical practice. Other clinicians might be willing to accept the findings of a randomized trial that studied a drug in a particular class, but have reservations about the ability to generalize the findings to other drugs in the same broad class of compounds that have not been subjected to a randomized trial. When several drugs in the same broad class have been studied but the magnitude of the reported treatment effect varies, considerable discussion frequently ensues about differences in trial design, the profile of patients studied, and biochemical differences among the drugs. These issues are particularly well illustrated in the reports of trials comparing a low molecular weight heparin (LMWH) with unfractionated heparin (UFH) in patients with unstable angina/non ST-segment myocardial infarction (UA/NSTEMI).1

The use of intravenous unfractionated heparin (UFH) for the acute management of UA/NSTEMI was introduced in 1982.2 Subsequently, the benefits of adding UFH to aspirin compared with aspirin alone were considered sufficiently compelling that authoritative bodies recommended the combination. This recommendation was widely adopted in clinical practice. Remarkably, the evidence base for the benefit of adding UFH to aspirin consists only of 6 randomized trials that collectively enrolled 1353 patients and showed a relative risk for death/non-fatal myocardial infarction (MI) of 0.67 (0.44–1.02) that favors the combination as compared with aspirin alone (13 fewer events in the combination group).3

LMWHs as a class offer the theoretical advantages over UFH of a higher anti Xa:IIa ratio, a stable and reliable level of anticoagulation without the need for hematologic monitoring, and simpler administration via the subcutaneous route.1 Several trials have compared a LMWH with UFH in patients with UA/NSTEMI. Analyzing studies of multiple drugs within a class can be complex. A meta-analysis was published that showed a trend favoring LMWH for reducing death/MI during short-term follow-up, although the confidence intervals overlapped unity, and the authors concluded there was no evidence of superiority of a LMWH over UFH.4 At the early point analyzed, only 276 events occurred in 12,171 patients, and there was <60% power to demonstrate even a 20% reduction in events with LMWH.1 Because LMWH preparations vary in average molecular weight, antiXa:antiIIa ratio, ionic nature, release profile of tissue factor pathway inhibitor, and a number of other properties, it can be argued that no pooling should take place. With a composite end point of death/MI/recurrent ischemia plus or minus urgent revascularization at 6 to 14 days, trials of enoxaparin show it to be superior to UFH, a result that was not observed in trials of dalteparin or nadroparin.5

In addition to pharmacologic differences among the various LMWHs in the trials aforementioned, distinctions in trial design should be considered. The enrollment window after the qualifying event was 24 hours for the Efficacy Safety Subcutaneous Enoxaparin in Non-Q-wave Coronary Events (ESSENCE) and Thrombolysis in Myocardial Infarction (TIMI) 11B trials, 48 hours in the Fraxiparine in Ischemic Syndrome (FRAXIS) trial, and 72 hours in the Fragmin in Unstable Coronary Artery Disease (FRIC) trial.6 It is possible that the enrollment of patients who were at lower risk in the FRIC and FRAXIS trials, combined with the use of LMWHs with a lower antiXa:antiIIa ratio, biased those trials to a null effect. The American College of Cardiology/American Heart Association Guidelines for Management of Patients with UA/NSTEMI distinguish enoxaparin from the other LMWHs and state that it is preferable to UFH in the absence of renal failure and in patients in whom coronary artery bypass graft surgery is not planned within the next 24 hours (class IIa, level of evidence A).5

What clinicians need most at this point is a head-to-head comparison of LMWHs. Despite the desire for randomized trial data in our evidence-based era, it is relatively rare for us to see head-to-head comparisons of new drug choices. Dr Michalis and the Enoxaparin Versus Tinzaparin in Non-ST-segment Elevation Acute Coronary Syndromes (EVET) trial investigators are to be congratulated for their report in this issue of the American Heart Journal on a direct comparison of the 2 LMWHs, enoxaparin and tinzaparin.7 This open-label trial enrolled 436 patients who had at least 10 minutes of ischemic discomfort at rest within the prior 24 hours and electrocardiographic evidence of ischemia. Enoxaparin (1 mg/kg [100 IU/kg] every 12 hours) was superior to tinzaparin (175 IU/kg once daily) in preventing the composite end point of death/MI/recurrent angina at 7 days (12.3% in the enoxaparin group vs 21.1% in the tinzaparin group; P = .015). The enoxaparin group also had a significantly lower composite event rate at 30 days and was associated with a significantly lower rate of revascularization by day 30 (16.4% vs 26.1%; P = .019). The rates of major hemorrhage were comparable in the 2 treatment groups.

Although the EVET trial is helpful in settling the question of whether clinically important differences exist among LMWHs, it does not completely resolve the issue. As acknowledged by the authors, the differences in the composite event rates at 7 and 30 days were driven almost entirely by differences in recurrent angina—the “softest” component of the composite end point and the one most susceptible to bias in an open-label trial. The dose of tinzaparin, selected via experience in treating deep vein thrombosis and acute pulmonary embolism, may not have been optimal in patients with an arterial thrombotic disorder. A dose of 175 IU/kg of tinzaparin produces antiXa levels of about 0.87 IU/mL 6 hours later, but by 12 hours, the antiXa level falls to between 0.25 and 0.50 IU/mL.8 The twice daily regimen of 100 IU/kg of enoxaparin keeps the antiXa level between 0.5 and 1.0 IU/mL throughout the 24-hour period.9 It is possible that the tinzaparin group may have had subtherapeutic antiXa levels toward the end of the dosing interval. Because the antiXa:antiIIa ratio is 3.8:1 for enoxaparin and is 2.8:1for tinzaparin, it can be argued that the anticoagulant actions of the 2 study drugs in EVET may not have been comparable.

Where do we stand at this point? One can state that, when viewed as a class, LMWHs are unequivocally superior to placebo and at least as effective as UFH. They are certainly more convenient. When the subtleties of pharmacology and trial design are considered (as they should be), the available data indicate that enoxaparin is superior to UFH in the management of UA/NSTEMI, producing an approximate 20% reduction in death/MI that is evident within 48 hours and becomes statistically significant by 8 days and having a treatment effect that is maintained through 43 days.6 There is no incremental gain from administering enoxaparin for 1 additional month in the outpatient setting.10 Follow-up at 1 year shows that patients treated with enoxaparin maintain a lower rate of events, thus demonstrating that the treatment benefit of enoxaparin is durable for the long term.11 The Fragmin and Fast Revascularisation During Instability in Coronary Artery Disease (FRISC) II study suggests that for those clinical settings in which an early invasive strategy is not possible, treatment with dalteparin is helpful as a bridge to implementation of an invasive strategy.12 Dalteparin was not shown to be superior to UFH in patients treated with an early invasive strategy. In contrast, patients treated with enoxaparin have lower event rates than patients treated with UFH, whether treated with an invasive strategy or a conservative medical approach.13

As suggested by the EVET investigators and by investigators in India, the data to this point do not support the belief that all LMWHs provide the same benefit.7, 14 The therapeutic interchange advocated by pharmacy departments as a cost-saving measure is not consistent with evidence-based care and cannot be condoned. More trials like EVET are needed, but investigators must be certain that equitherapeutic doses of LMWHs are being compared. Additional information on the use of enoxaparin in the setting of percutaneous coronary intervention supported by glycoprotein IIb/IIIa inhibitors will be forthcoming from the Superior Yield of the New Strategy of Enoxaparin, Revascularization, and Glycoprotein IIb/IIIa Inhibitors (SYNERGY) trial.15 The Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment-Thrombolysis in Myocardial Infarction (ExTRACT-TIMI) 25 trial will help to establish the role of enoxaparin in patients with STEMI who are treated with fibrinolytics.

The EVET investigators made it clear that their trial was exploratory and did not have a pre-specified hypothesis. Recruitment of patients ended when the investigators ran out of resources. We must advocate strongly for adequately powered head-to-head comparison trials of new therapeutic options to refine our clinical decision-making. Because individual pharmaceutical sponsors often find such trials unacceptably risky, creative funding approaches are urgently needed.

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References 

  1. Antman EM. The search for replacements for unfractionated heparin. Circulation. 2001;103:2310–2314
  2. Telford AM, Wilson C. Trial of heparin versus atenolol in prevention of myocardial infarction in intermediate coronary syndrome. Lancet. 1981;1:1225–1228
  3. Oler A, Whooley MA, Oler J, Grady D, et al.  Adding heparin to aspirin reduces the incidence of myocardial infarction and death in patients with unstable angina (a meta-analysis). JAMA. 1996;276:811–815
  4. Eikelboom JW, Anand SS, Malmberg K, et al.  Unfractionated heparin and low-molecular-weight heparin in acute coronary syndrome without ST elevation (a meta-analysis). Lancet. 2000;355:1936–1942
  5. Braunwald E, Antman EM, Beasley JW, et al.  ACC/AHA guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction–2002 (summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Unstable Angina)). Circulation. 2002;106:1893–1900
  6. Antman EM, Cohen M, Radley D, et al.  Assessment of the treatment effect of enoxaparin for unstable angina/non-Q-wave myocardial infarction. TIMI 11B-ESSENCE meta-analysis. Circulation. 1999;100:1602–1608
  7. Michalis LK, Katsouras CS, Papamichael N, et al.  Enoxaparin versus tinzaparin in non-ST-segment elevation acute coronary syndromes (the EVET trial). Am Heart J. 2003;146:304
  8. Barrett JS, Hainer JW, Kornhauser DM, et al.  Anticoagulant pharmacodynamics of tinzaparin following 175 iu/kg subcutaneous administration to healthy volunteers. Thromb Res. 2001;101:243–254
  9. The Thrombolysis in Myocardial Infarction (TIMI) 11A Trial Investigators. Dose-ranging trial of enoxaparin for unstable angina (results of TIMI 11A). J Am Coll Cardiol. 1997;29:1474–1482
  10. Antman EM, McCabe CH, Gurfinkel EP, et al.  Enoxaparin prevents death and cardiac ischemic events in unstable angina/non-Q-wave myocardial infarction (results of the thrombolysis in myocardial infarction (TIMI) 11B trial). Circulation. 1999;100:1593–1601
  11. Antman EM, Cohen M, McCabe C, et al.  Enoxaparin is superior to unfractionated heparin for preventing clinical events at 1-year follow-up of TIMI 11B and ESSENCE. Eur Heart J. 2002;23:308–314
  12. Fragmin and Fast Revascularisation During Instability in Coronary Artery Disease Investigators. Invasive compared with non-invasive treatment in unstable coronary-artery disease (FRISC II prospective randomised multicentre study). Lancet. 1999;354:708–715
  13. Fox KA, Antman EM, Cohen M, et al.  Comparison of enoxaparin versus unfractionated heparin in patients with unstable angina pectoris/non-ST-segment elevation acute myocardial infarction having subsequent percutaneous coronary intervention. Am J Cardiol. 2002;90:477–482
  14. Malhotra S, Karan RS, Bhargava VK, et al.  A meta-analysis of controlled clinical trials comparing low-molecular-weight heparins with unfractionated heparin in unstable angina. Indian Heart J. 2001;53:197–202
  15. The SYNERGY trial: study design and rationale. Am Heart J 2002;143:952–60

PII: S0002-8703(03)00180-7

doi:10.1016/S0002-8703(03)00180-7

American Heart Journal
Volume 146, Issue 2 , Pages 191-193, August 2003

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