Written by: Terese Whipple, MD (NUEM PGY-3) Edited by: Andrew Ketterer, MD (NUEM Alum ‘17) Expert commentary by: Michael Macias (NUEM Alum ‘17)
The Case
A 64 year old female with history of diabetes and hypertension is brought to your emergency department (ED) by EMS for “acid reflux.” She has new T wave inversions in leads II, III, and aVF with a troponin of 0.12. The patient is given aspirin, nitroglycerine, and ticagrelor, but before signing your heparin drip order, you ask yourself:
Would enoxaparin (LMWH) be a better option?
The Recommendation:
The AHA and ACC guidelines state, “In patients with NSTE-ACS, anticoagulation, in addition to antiplatelet therapy, is recommended for all patients irrespective of initial treatment strategy. Treatment options include:
Enoxaparin: 1 mg/kg subcutaneous every 12 hours, continued for the duration of hospitalization or until PCI is performed. An initial IV loading dose is 30 mg (Level of evidence A)
Unfractionated heparin (UFH) IV: initial loading dose 60 IU/kg (max 4000 IU) plus 12 IU/kg/h (max 1000 IU/h) adjusted per activated PTT in according to specific hospital protocol (Level of evidence B)”[2]
Bivalirudin/Fondaparinux- These are other options outside the scope of this post
The Evidence:
So why is the evidence for enoxaparin Level A and UFH level B? Multiple randomized controlled trials have examined this issue:
The ESSENCE (Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events) trial was the first major RCT to demonstrate the efficacy of enoxaparin over UFH. Although it was conducted in the late 90s, before GIIb/IIIa inhibitors or early invasive intervention were commonplace, it demonstrated a statistically significant decrease in the risk of death, MI, or recurrent angina in those randomized to treatment with enoxaparin (16.6%) v. UFH (19.8%) (p=.019). Incidence of major bleeding was similar in both groups.
TIMI-II: Enoxaparin was found to be superior with no increase in hemorrhage. Outcomes measured were death, MI, and urgent revascularization at 8 and 43 days, respectively, for enoxaparin (12.4%, 17.3%) and UFH (14.5%, 19.7%) (P=.048).
SYNERGY: In patients undergoing early PCI, enoxaparin was not inferior to UFH in the treatment of NSTEMI. However, enoxaparin was associated with more major bleeding (3.7% v 2.5%, p=.028). Both bleeding and efficacy were potentially confounded by crossover from LMWH before randomization to UFH upon randomization and vice versa … more below.
A to Z: Studied the efficacy and safety of enoxaparin and tirofiban compared w/ UFH and tirofiban. Incidence of death, MI, refractory ischemia with enoxaparin (8.4%) v. UFH (9.4%) were similar with similar bleeding incidences. Enoxaparin was found to be not inferior to UFH.
A systematic review conducted in 2004 of approximately 22,000 patients extending across the evolution of ACS treatment from conservative management to early PCI, demonstrated that enoxaparin is more effective than UFH in preventing MI and death.
It may seem that as treatment of NSTEMI has evolved to include antiplatelet therapy and early invasive intervention, the superiority of enoxaparin has been negated. However, both the SYNERGY and A to Z trials were potentially confounded by the fact that a majority of patients received pre-randomization therapy. A subgroup analysis performed on those patients who received only enoxaparin in the SYNERGY trial and no pre-treatment anticoagulation demonstrated the superiority once again of enoxaparin over UFH in regards to the combined outcome of death and MI (13.3% vs. 15.9% , p= 0.004). The bleeding risk also seemed to be increased by pre-randomization therapy. The subgroup analysis showed no significant difference in major bleeding between UFH and enoxaparin when the patients received enoxaparin only (OR 1.04, CI 0.83-1.3).
If changing anticoagulation potentially increases bleeding risk, what about those destined for PCI?
The practices and procedures involved in PCI are beyond the scope of emergency medical practice, however the medications that we choose in the ED have downstream effects on patient care. Therefore, if we chose to use enoxaparin in the ED, we need to make sure that it won’t interfere with the ability of the patient to undergo PCI, and that it won’t increase their risk of adverse outcomes. Fortunately, this has been evaluated in controlled trials:
STEEPLE (Safety and Efficacy of Enoxaparin in PCI patients, an international randomized evaluation). This trial examined the safety and efficacy of IV bolus (0.5 mg/kg or 0.75 mg/kg) of LMWH at time of PCI.[7]
Bleeding: Incidence of non-CABG-related bleeding complications in first 48 hours - 5.9% with 0.5 mg/kg enoxaparin (p=0.01 vs. UFH), 6.5% with 0.75 mg/kg enoxaparin (p= 0.051 vs. UFH), and 8.5% with UFH.
Conclusion: IV bolus 0.5 mg/kg enoxaparin associated with reduced rates of bleeding, 0.75 mg/kg associated with similar bleeding risk to UFH. For the combined end point of bleeding and ischemic events, both doses of LMWH were non-inferior to UFH.
1-year mortality rates were comparable between patients receiving enoxaparin and UFH (2.3% for 0.5 mg/kg, 2.2% for 0.75 mg/kg, 1.9% for UFH)
CRUSADE (Can rapid risk stratification of unstable angina patients suppress adverse outcomes with early implementation of ACC/AHA guidelines). This trial studied the efficacy and safety of LMWH compared with UFH in high risk NSTEMI patients also receiving early GPIIb/IIIa inhibitor therapy.
In patients who underwent PCI within 48 hours the ORs for risk of death and reinfarction were similar for LMWH compared to UFH (OR 0.93, CI 0.67-1.31).
In patients who underwent PCI >48 hours into hospitalization, LMWH therapy was associated with reduced rates of death or reinfarction (OR 0.57, 95% CI = 0.44-0.73) and transfusion (OR 0.66, 95% CI = 0.52-0.84).
Conclusion: Early invasive management with LMWH and GP IIb/IIIa inhibitor in NSTEMI is safe and doesn’t result in increased bleeding complications. In fact, it actually improves outcomes for those who don’t undergo PCI within 48 hours. 9
Take Home Points:
Enoxaparin has been proven to be at least non-inferior and likely even superior to UFH when it comes to reducing the risk of death and MI in the setting of NSTEMI.
Bleeding risk with enoxaparin compared to UFH appears to be equal (with the exception of the Synergy trial).
Enoxaparin is safe and efficacious for use during PCI.
Dialogue should occur between ED providers and interventional cardiologists to ensure their comfort with enoxaparin use and to prevent bleeding complications. If everyone is on board with using enoxaparin, it will likely get your patient anticoagulated more expediently than they otherwise would while waiting for pharmacy to mix up your heparin drip.
Expert Commentary
Dr. Whipple, thank you for an excellent review of the literature supporting the use of lower molecular weight heparin (LMWH) for Non-ST-Elevation Myocardial Infarction (NSTEMI). There are two important points to discuss here before we even talk about LMWH, specifically: (1) What is the evidence behind good ole unfractionated heparin (UFH) in patients with NSTEMI? (2) Based on the evidence for UFH, is there a subgroup of patients who are likely to benefit more than others?
What is the evidence behind good ole unfractionated heparin (UFH) in patients with NSTEMI?
If you look at the AHA/ACC guidelines, UFH is listed as a Class I recommendation. Like any recommendations in guidelines, it is always important to look back at the data behind it. Specifically with respect to UFH, this data is weak but unfortunately is the best we have. Many of studies supporting the use of UFH in NSTEMI involved patients with “unstable angina” in the era before modern laboratory diagnostics (most studies used creatinine kinase), dual anti-platelet therapy (DAPT), GpII/IIIa inhibitors, early invasive strategies, and revascularization [10]. This is a very different population than NSTEMI patients today. In general, these studies did find a strong trend in reduction of composite endpoints (mainly recurrent angina, death or MI) however this was only during hospitalization (short term endpoints) and this is the main crux of the AHA/ACC guideline recommendations. Further in the guidelines favor, the Cochrane review also concluded that UFH in NSTEMI reduces the rate of MI with a relative risk of 0.4 (0.25-0.63) [11]. However what both the guidelines and Cochrane review failed to consider is the benefits of UFH to our patients at a later time point. Deeper analysis of the Cochrane review reveals that the majority of their data points came from the FRISC study, which used only a six-day end point for their outcomes. A meta-analysis performed by Oler in 1996, took into account a time period beyond the UFH treatment duration (2-12 weeks) and found no significant difference in outcomes:
“Because the anticoagulant effects of heparin are brief, any benefit of therapy is unlikely to last beyond the duration of treatment. Consistent with this theory, we found no reduction in the risk of MI or death between 2 and 12 weeks following randomization in patients with unstable angina who received heparin and aspirin compared to those who received aspirin alone. This result underscores that heparin is a short-acting, temporizing therapy, and not an intervention that alters underlying atherosclerotic disease. - Oler et al. 1996”
Not only do the studies that the guidelines base their data off fail to consider more later end points, they also include a different patient population, in a different era of acute coronary syndrome management. Since heparin has now become the standard of care for management of NSTEMI, no further placebo- controlled trials of heparin will ever exist.
Based on the evidence for UFH, is there a subgroup of patients who are likely to benefit more than others?
Based on the discussion above, there isn’t strong evidence to support UFH use in all comers with NSTEMI however based on its mechanism of action, it is likely to benefit those with high risk NSTEMI (TIMI Risk Score), or those who will undergo coronary intervention or revascularization. Intuitively this makes sense and jives with the evidence in the AHA/ACC guidelines. Patients who are placed on UFH and bridged to PCI/revascularization will benefit from the theoretical plaque stabilization. Those who are observed without any intervention will not, as once heparin is discontinued, their ongoing plaque burden and coronary anatomy will be unchanged, placing them at risk for a “rebound” event.
In the emergency department we are burdened with making decisions with minimal initial information and only a few hours of observation. That being said, making a confident decision about which NSTEMI patients will need PCI/revascularization (and therefore will benefit from UFH) may prove very difficult. Therefore it may be more prudent to consider when certain situations make intervention less likely. These situations may include:
Patients without ACS symptoms but with elevated troponin:
Renal disease
hypotension
Sepsis
Toxic ingestion
Significant metabolic derangement
Anemia
Heart failure (without suspicion for ischemic etiology)
Supraventricular tachycardia (SVT)
Other presentations where troponin elevation is suspected to be related to a supply/demand issue
Patients with atypical history and high bleeding risk
The best course of action in these situations is to discuss the utility of UFH with the consulting cardiologist or admitting hospitalist about what is right for your patient based on the risk and benefits of anticoagulation, as well as your clinical suspicion for true acute coronary syndrome.
UFH or LMWH?
Now that we have a better understanding of the utility of UFH in NSTEMI, the use of LMWH becomes more clear. The same considerations just discussed should be similarly applied to the use of LMWH. As your literature review demonstrates, LMWH appears to be as good (if not better) than UFH with a similar bleeding risk profile. It is also easier to administer, requires less monitoring and has a lower risk of accidental supra-therapeutic anticoagulation. While it seems that it may be an obvious decision to switch to LMWH, remember that there is always a significant time lag between evidence and its incorporation into clinical practice. Therefore as you mentioned in your take home points, clear communication with other services is key. Before you go rogue giving LMWH to all your NSTEMI patients, I recommend having a evidence based discussion with your cardiologists and hospitalists to ensure everyone is on the same page.
Michael Macias, MD
NUEM Alumus 2017
University of California, San Diego
How To Cite This Post
[Peer-Reviewed, Web Publication] Whipple T, Ketterer A. (2019, March 18). Lovenox in NSTEMI [NUEM Blog. Expert Commentary by Macias M]. Retrieved from http://www.nuemblog.com/blog/lovenox-NSTEMI
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Blazing MA, et al. Safety and efficacy of enoxaparin v unfractionated heparin in patients with no-ST-segment elevation acute coronary syndromes who receive tirofiban and aspirin: a randomized controlled trial. JAMA. 2004; 292: 55-64.
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