The basics often aren’t exciting, but it’s important to get them right. DVT prophylaxis is a good example of this. Most critically ill patients will receive DVT prophylaxis at some point during their ICU stay (that’s 5 million patients per year in the United States alone). Thus, even minor tweaks in the optimal treatment for DVT prophylaxis could improve outcomes for tens of thousands of patients.
Enoxaparin 40 mg daily was popularized for DVT prophylaxis based on multi-center RCTs showing equivalence or superiority to subcutaneous unfractionated heparin among patients who weren’t critically ill.1,2 Unfortunately, research largely stalled at that point. There was little impetus for a huge RCT comparing different doses of enoxaparin among critically ill patients (a study which would be costly rather than flashy). So 40 mg enoxaparin daily became entrenched as a standard treatment in many medical ICUs. However, available evidence suggests that this is a poor strategy.
Why 40 mg enoxaparin daily isn’t a good dosing strategy
Problem #1) Fixed dosing enoxaparin ignores variation in weight.
Enoxaparin drug levels are well known to vary in an inverse fashion related to the patient’s total body weight. Thus, for therapeutic anticoagulation, enoxaparin is dosed based on weight (e.g., 1 mg/kg sq. twice daily). This is pharmacology 101. So it makes no sense to give the same 40-mg dose to a 55-kg patient and to a 110-kg patient.
Retrospective studies have found that increased weight is a predictor of sub-therapeutic enoxaparin levels, which further correlates with the occurrence of DVT. Increased risk of suboptimal dosing may occur even in patients with weights only slightly above average (e.g., ~90 kg).3
The optimal dose in morbid obesity remains controversial. Particularly among surgical ICU patients, there seems to some convergence towards using a weight-based dose of 0.5 mg/kg enoxaparin twice daily (more on this below). This implies that 40 mg enoxaparin once daily is wholly inadequate for most above-average weight patients.
Problem #2) 40 mg enoxaparin will often fail to achieve therapeutic peak levels, even in patients of average weight.
The efficacy of prophylactic enoxaparin is estimated by measuring a peak anti-Xa level four hours after a dose. The target level for prophylaxis is currently regarded to be ~0.2-0.5 IU/ml, although there is disagreement about the exact value.
Critically ill patients may be less sensitive to enoxaparin for various reasons:
- Systemic inflammation and tissue edema may increase the volume of distribution.
- Reduced levels of anti-thrombin III are commonly seen (enoxaparin works indirectly via enhancement of anti-thrombin III activity, so anti-thrombin III deficiency causes enoxaparin resistance).
- Shocked patients might have impaired absorption via a subcutaneous route.
- An increase in acute-phase reactant proteins may bind enoxaparin, reducing the effective dose.4
For example, Priglinger et al showed that 40 mg enoxaparin achieved considerably higher levels among ward patients than among ICU patients:5
Published series show a shocking amount of disagreement regarding enoxaparin’s efficacy among critically ill patients (even if morbidly obese patients are excluded). Most studies show that 40 mg enoxaparin usually achieves only sub-therapeutic peak anti-Xa levels.6–9 Other studies show that 40 mg enoxaparin routinely achieves adequate peak levels.10,11 The difference between these studies is likely different populations of patients with varying illness severity (e.g., series of patients with low anti-Xa levels often also have sicker patients with lower anti-thrombin III levels as well).4,6 Regardless, one thing is clear – it’s not fair to assume that 40 mg enoxaparin will achieve a therapeutic peak anti-Xa level in a critically ill patient.
Problem #3) 40 mg enoxaparin daily will commonly yield unmeasurably low trough levels.
Enoxaparin has a half-life of about 4.5 hours. Consequently, enoxaparin is generally prescribed twice daily for therapeutic anticoagulation (i.e., the familiar regimen of 1 mg/kg sq. twice daily).
Giving enoxaparin once daily for prophylaxis will commonly leave patients with undetectably low trough drug levels (above figure, top left panel).12–14 This should come as little surprise – 24 hours is over five half-lives of enoxaparin, plenty of time for the drug to wear off. Undetectable trough levels are most common in patients with normal or augmented renal clearance.10
It stands to reason that anticoagulating the patient half the time isn’t a fabulous strategy for DVT prophylaxis. Several studies have indeed correlated low trough drug levels with a higher incidence of DVT.15–17 One before/after study found that implementing a dose-adjustment protocol based on targeting trough levels of 0.1-0.2 anti-Xa units/ml correlated with a decrease in venous thromboembolism rates.18
There’s no irrefutable evidence that trough levels matter. The highest quality evidence might be the comparison of 40 mg enoxaparin daily versus 2.5 mg fondaparinux daily for DVT prophylaxis following orthopedic surgery. Two multi-center RCTs show that fondaparinux works considerably better than enoxaparin.19,20 Why? Both drugs are very similar (both are oligosaccharides which augment the function of antithrombin-III on factor Xa). The major difference is that fondaparinux has a much longer half-life than enoxaparin (~20 hours for fondaparinux vs. ~4.5 hours for enoxaparin). So fondaparinux provides DVT prophylaxis around the clock, whereas enoxaparin works only part-time.
So, where should we go from here?
Unfortunately, there remains an absence of RCT-level evidence regarding the optimal dose of enoxaparin in critically ill patients. Synthesizing available data may suggest the following:
Possible solution #1) Consider an initial enoxaparin regimen of roughly 0.5 mg/kg sq. twice daily
There seems to be some convergence in the recent literature that twice-daily, weight-based enoxaparin is probably the best approach. Studies vary somewhat regarding the exact dosing. Most utilize 0.5 mg/kg sq twice daily.3,21–25 One suggested 0.4 mg/kg twice daily and another used 0.6 mg/kg twice daily.26,27 Other studies have used a similar approach of twice-daily weight-based enoxaparin employing several dosing tiers defined by body weight or body mass index.28,29
Dosing enoxaparin based on weight simply makes pharmacological sense. Weight-based dosing was first engineered for patients with morbid obesity, because using a fixed dose is most clearly ridiculous for these patients. However, optimizing dose based on weight makes sense for patients within a lower weight range as well.
Giving 0.5 mg/kg enoxaparin twice daily seems like a high dose at first, but this actually makes a lot of sense. Compared to therapeutic anticoagulation, this is essentially a 50% dose reduction in order to achieve a 50% lower therapeutic target (table below). Simple arithmetic.
Dosing enoxaparin twice daily is probably the only way to reliably achieve adequate trough levels. Studies which have measured and targeted trough levels were able to achieve trough levels only with a twice-daily dosing regimen.6,18 In everyday clinical practice, measuring trough levels probably isn’t feasible. However, a strategy of twice-daily enoxaparin with adequate peak levels is likely to achieve adequate trough levels as well.
Possible solution #2) More frequent monitoring of peak anti-Xa levels
We take it for granted that patients on a heparin infusion will receive frequent monitoring of anti-Xa level, whereas patients treated with enoxaparin will receive no monitoring. This paradigm may require revision. Numerous studies among critically ill patients have shown that even with weight-based enoxaparin protocols, the peak Xa level is often suboptimal and requires individualized dose adjustment.
This evidence suggests that we might consider checking anti-Xa levels more often. We often check a host of laboratory studies that virtually never affect management (e.g., liver function tests). In comparison, checking an anti-Xa level is reasonably likely to directly affect patient management. The laboratory assay costs about $40,18 which is minimal compared to the cost of an iatrogenic DVT or PE (several thousand dollars). Precisely which patients require monitoring of anti-Xa levels isn’t clear, but this could be more useful in patients with more extreme variations in weight, renal dysfunction, or very high illness severity.
DVT prophylaxis for critically ill COVID-19 patients
The optimal dosing of anticoagulation in severely ill patients with COVID-19 is controversial. If a decision is made to use prophylactic dosing, a recently published expert guideline recommends using higher than traditional doses:30
The recommendation to use 0.5 mg/kg enoxaparin twice daily in this guideline is wholly consistent with the larger evidence basis regarding critically ill patients. Thus, this might not truly represent an “increased dose” of enoxaparin – it might simply be the appropriate dose for critically ill patients.
Limitations to this post
This post isn’t intended to render firm recommendations, but rather to foster discussion. Some limitations deserve highlighting.
First, the post relies on pharmacokinetic studies which are based on targeting specific anti-Xa levels. However, this involves numerous limitations. There isn’t uniform agreement about precisely what the target anti-Xa levels should be for DVT prophylaxis. Consequently, there is no guarantee that achieving specific anti-Xa levels translates into clinical benefit. Ideally, RCTs should be performed to validate the clinical utility of targeting specific anti-Xa targets (but, sadly, such RCTs are lacking despite decades of uncertainty, and unlikely to materialize anytime soon).
Second, studies validating the use of 0.5 mg/kg enoxaparin BID were performed in surgical and trauma ICUs, rather than medical ICUs. This dose hasn’t been validated among medical ICU patients. However, medical patients are generally undergoing fewer hemostatic challenges (i.e., fewer surgeries), so it might be speculated that this regimen could be safer among medical patients.
Third, this discussion focuses on patients with normal weight or obesity. Far less information is available about underweight patients (a much less common scenario in the United States). One study did find a linear correlation between weight and anti-Xa level, suggesting that weight-based dosing might be reasonable in this situation as well (figure below).31 However, there is very little data here, so caution and anti-Xa monitoring are advisable.
Finally, all of these studies excluded patients with renal dysfunction (typically defined as GFR < 30 ml/min). As such, this discussion doesn’t apply to patients with renal failure.
- There is no Level-I evidence regarding the optimal dose of enoxaparin for DVT prophylaxis among critically ill patients. Critical illness increases both the risk of venous thromboembolic disease and resistance to enoxaparin, so these patients may require a more aggressive anticoagulation strategy.
- The practice of giving patients 40 mg enoxaparin daily is based more on convenience than on evidence. Nearly every study which has evaluated drug levels resulting from this strategy among critically ill patients has found substantial problems with it.
- Recent studies seem to be converging on a strategy of twice-daily, weight-based enoxaparin (~0.5 mg/kg sq. BID). Given variability in pharmacokinetics between patients, therapeutic drug monitoring may help optimize the dose (especially among patients with unusual weight, renal dysfunction, or extreme illness severity).
- It’s common for ICU patients to develop thromboembolic disease despite receiving DVT prophylaxis. Rather than patients’ failing to respond to DVT prophylaxis, it’s possible that we’re failing to optimize their dose.
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