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A Tale of Two Heparins: Use of unfractionated versus low-molecular-weight heparin in patients presen

Case Presentation:

A 59 year old male with PMH of type 2 DM, HTN, HLD, former smoker, prior TIA, prostate cancer, and severe asthma presented to the ED with acute onset of chest pain and dizziness six hours ago. Pain was non-radiating and non-pleuritic. He also was experiencing diaphoresis, nausea, shortness of breath, palpitations, dizziness, and blurriness of vision.

Initial Troponin: 0.16, Three-hour Troponin: 0.13

ECG:

Patient was diagnosed with an NSTEMI and started on dual antiplatelet therapy when the question arose for the decision to use heparin or LMWH for his anticoagulation.

Clinical Question:

Should patient’s presenting with an NSTEMI be given unfractionated heparin (UFH) or enoxaparin for anticoagulation?

Summary of Evidence:

Evidence for the efficacy of heparins (UFH and LMWH)

  • American College of Cardiology/American Heart Association strongly recommends anticoagulation in patients presenting with Non- ST elevation ACS.Class 1 recommendation for anticoagulation in addition to antiplatelet therapy irrespective of initial treatment strategy. Options include enoxaparin, bivalirudin, fondaparinux, and UFH, with only enoxaparin receiving a level of evidence A. (1)

  • A 2014 Cochrane Review of eight studies with a total of 3118 participants found that there was no overall mortality benefit between groups treated with heparin versus placebo (risk ratio (RR) = 0.84, 95% confidence interval (CI) 0.36 to 1.98). (2)

  • However, this same review found that there was evidence that the use of heparins reduced the incidence of recurrent myocardial infarction in patients with NSTEMI or unstable angina (RR = 0.40, 95% CI 0.25 to 0.63, number needed to benefit = 33). (2)

  • Of note, the evidence assessed in this review was considered to be low quality according to the GRADE approach and therefore must be interpreted with caution.

Comparative effectiveness of enoxaparin vs. heparin

  • For patients managed conservatively (revascularization not intended) the following evidence shows the benefits of enoxaparin versus unfractionated heparin:

  • The ESSENCE trial enrolled 3171 patients treated with aspirin presenting with either unstable angina or NSTEMI who were then randomized to receive either enoxaparin or UFH, with therapy given for a minimum of 48 hours to a maximum of 8 days. Primary endpoints evaluated were death, recurrent nonfatal MI, or recurrent angina at 14 days. (3)

  • At 14 days, enoxaparin therapy was found to have a significantly lower rate of the combined triple endpoint compared to UFH (16.6 percent vs. 19.8 percent, P=0.019), an effect that was maintained at 30 days (19.8 percent vs. 23.3 percent, P=0.016). (3) This combined triple endpoint was later found to be maintained at one year for patients on enoxaparin (32.0% vs. 35.7%, p = 0.022). (4)

  • There was also a significant reduction in the need for revascularization procedures at 30 days for patients receiving enoxaparin (27.1 percent vs. 32.2 percent, P=0.001). (3)

  • When looking at rates of bleeding, the 30-day incidence of major bleeding complications was also lower in the enoxaparin group compared to that of the UFH group (6.5% versus 7.0%) although bleeding risk overall was higher in the enoxaparin group (18.4 percent vs. 14.2 percent, P=0.001) due to local ecchymosis at the injection site. (3)

  • The benefit of enoxaparin was again seen in the TIMI 11B trial of 3910 aspirin-treated patients for whom revascularization was not intended randomized to treatment with UFH versus enoxaparin. (5)

  • At 8 days, the incidence of the primary end point (death, MI, or urgent revascularization) was significantly lower among patients treated with enoxaparin (12.4% versus 14.5%, OR 0.83; 95% CI 0.69 to 1.00; P=0. 048). (5)

  • When considering bleeding complications, there was no difference in the rate of major hemorrhage between the two treatment groups during the first 72 hours, although during the outpatient phase, major hemorrhage events occurred in 2.9% of patients on Enoxaparin versus 1.5% of patients on placebo (UFH group given placebo in outpatient phase). (5)

  • The Phase A of the A to Z trial analyzed 3987 patients presenting with NSTEMI or unstable angina who were randomized to either enoxaparin or UFH. The primary endpoints of this study were death, MI, or refractory ischemia. Although no significant difference was found in all patients (8.4 versus 9.4 percent in the enoxaparin and UFH groups respectively; hazard ratio 0.88; 95% CI 0.71-1.08), in the subgroup treated with conservative therapy (i.e., not treated with immediate revascularization), there was a significant reduction in the primary end point with enoxaparin (7.7 versus 10.6 %). (6)

  • Rates for any TIMI (Thrombolysis in Myocardial Infarction classification system) grade bleeding were low (3.0% for enoxaparin and 2.2% for unfractionated heparin; P =.13). (6)

The Role for Unfractionated Heparin

For patients being managed invasively (with angiography and possible revascularization within 48 hours), the following evidence addresses the role of UFH versus enoxaparin.

  • The SYNERGY Trial randomly assigned 10,027 patients with an NSTEMI to open label enoxaparin or UFH, in the setting of 92% of those patients undergoing coronary angiography, 47% undergoing PCI, and 19% undergoing surgical revascularization. Although there was no significant difference in the primary endpoint of death, endpoint there was a significant increase in in-hospital major bleeding with enoxaparin (9.1 versus 7.6 percent for UFH). (7)

  • At many hospitals, UFH still remains popular, a practice which is thought to be due to its efficacy in combination with low cost, short half-life and easy reversibility with protamine. (8)

  • There are also some patient populations in which the use of enoxaparin is disadvantageous. One such patient population are individuals with renal insufficiency, as enoxaparin is cleared through the kidneys. For individuals with CrCl of < 30 ml/min, dose reduction or use of unfractionated heparin is indicated.

  • Other contraindications to the use of enoxaparin include known hypersensitivity to enoxaparin, heparin, pork products, or any component of the formulation, a history of immune mediated heparin-induced thrombocytopenia (HIT) in the past 100 days, and active major bleeding

Recommendations:

  1. Despite lack of evidence for mortality benefit, strong recommendation persists for the use of anticoagulation for patients presenting with NSTEMI

  2. When evaluating for primary endpoints of death, recurrent MI, and refractory ischemia, enoxaparin should be considered as the anticoagulant of choice compared to UFH[JJ1]

  3. Special consideration should be given to patients managed with invasive approach, a history of bleeding conditions, and cost and institutional practice regarding the decision for enoxaparin vs. UFH

References:

  1. Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014; 130:2354.

  2. Andrade-Castellanos CA, Colunga-Lozano LE, Delgado-Figueroa N, Magee K. Heparin versus placebo for non-ST elevation acute coronary syndromes. Cochrane Database of Systematic Reviews 2014, Issue 6. Art. No.: CD003462.DOI: 10.1002/14651858.CD003462.pub3.

  3. Cohen M, Demers C, Gurfinkel EP, et al. A comparison of low-molecular-weight heparin with unfractionated heparin for unstable coronary artery disease. Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events Study Group. N Engl J Med 1997; 337:447.

  4. Goodman SG, Cohen M, Bigonzi F, et al. Randomized trial of low molecular weight heparin (enoxaparin) versus unfractionated heparin for unstable coronary artery disease: one-year results of the ESSENCE Study. Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q Wave Coronary Events. J Am Coll Cardiol 2000; 36:693.

  5. 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.

  6. Blazing MA, de Lemos JA, White HD, et al. 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. JAMA 2004; 292:55.

  7. Ferguson JJ, Califf RM, Antman EM, et al. 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. JAMA 2004; 292:45.

  8. Silvain J, Beygui F, Barthelemy O et al. Efficacy and safety of enoxaparin versus unfractionated heparin during percutaneous coronary intervention: systematic review and meta-analysis. BMJ. 2012;344:e553. doi: 10.1136/bmj.e553.

 

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