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Communications to the Editor |

Dose Capping Enoxaparin Is Unjustified and Denies Patients With Acute Coronary Syndromes a Potentially Effective Treatment FREE TO VIEW

Sarah A. Spinler, PharmD, FCCP; Paul Dobesh, PharmD, FCCP, BCPS
Author and Funding Information

Affiliations: University of the Sciences in Philadelphia, Philadelphia, PA,  University of Nebraska Medical Center College of Pharmacy, Omaha, NE,  University of Manitoba, Winnipeg, MB,  McMaster University, Hamilton, ON, Canada

Correspondence to: Sarah A. Spinler, PharmD, FCCP, Associate Professor of Clinical Pharmacy, Philadelphia College of Pharmacy, University of the Sciences in Philadelphia, 600 S Forty-Third St, Philadelphia, PA 19104; e-mail: s.spinle@usip.edu



Chest. 2005;127(6):2288-2290. doi:10.1378/chest.127.6.2288
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Published online

To the Editor:

We read with interest the article from Macie et al (May 2004)1 highlighting the importance of adhering to the correct dosing of enoxaparin for the prevention of ischemic events in patients with unstable angina or non–ST-segment elevation myocardial infarction. The article adds to the current controversy over dosing practices for enoxaparin in obese patients, while discussing the risk factors for increased bleeding. We would like to add the following points:

The optimal dose of enoxaparin for treatment of acute coronary syndromes (ACS) is 1 mg/kg, and this dose should be adhered to—ie, no more and no less.2There is evidence that when the dose is adjusted down unnecessarily, survival and efficacy is reduced, thus emphasizing the importance of a correct dosing regimen.3

There is evidence that the 100-mg capped dose used in this study is unnecessary, both in terms of the pharmacokinetics of enoxaparin in obese volunteers and its safety and efficacy in ACS patients.46 In fact, there is no evidence to suggest the need to modify the currently recommended dose of enoxaparin for treatment of venous thromboembolism and ACS in obese patients. The 100-mg capped dose applicable in Canada goes against all known data, arising from a demand from the Canadian Health Authority that is supported by neither clinical trial data nor the recommendation of the manufacturer. We can only speculate as to the rationale behind this labeling requirement. When the effect of low-molecular-weight heparin (LMWH) in protecting against new cardiac events in unstable coronary artery disease (CAD) was looked at, the Fragmin During Instability in Coronary Artery Disease study group7capped the dosage of dalteparin at 10,000 IU and dalteparin was the first LMWH licensed in Canada for ACS. However, because different LMWHs have different pharmacologic profiles and recommended doses, the results obtained with one LMWH preparation should not be extrapolated to another.8It is interesting to note that the subsequent Fragmin in Unstable Coronary Artery Disease Study trial had no mention of a capped dose and used a patient-weight range > 150 kg.9

It was stated in the article by Macie et al1 that previous randomized controlled trials (RCTs) have limitations in addressing practical issues that may impact on bleeding risk in the real-world population, because of the exclusion of patients weighing > 100 kg. First, the prespecified definition of obesity should use body mass index (BMI), because body weight alone is not always an accurate reflection of obesity. For example, the heaviest weight recorded in the Thrombolysis in Myocardial Infarction (TIMI) 11B10and Efficacy and Safety of Subcutaneous Enoxaparin in NonQ-Wave Coronary Events (ESSENCE)11 databases for a nonobese patient is 110 kg. Second, it is untrue that other studies have not researched patients weighing > 100 kg: in the meta-analysis of the TIMI 11B and ESSENCE trials comparing the safety and efficacy of a weight-adjusted dose of enoxaparin and unfractionated heparin (UFH) in obese patients (n = 7,081), approximately 26% of patients in the trial were obese (defined as BMI ≥ 30), thereby providing a large sample size for comparison.6 The maximum weight of patients treated with enoxaparin in this meta-analysis was 158.6 kg. Of these patients, 540 patients weighed > 100 kg (n = 275 UFH, n = 265 enoxaparin). Statistical analysis on this subgroup showed no significant difference between the UFH and enoxaparin groups in either the double or triple end points (incidence of death and myocardial infarction and/or urgent revascularization). Meanwhile, the maximum weight of patients in the Superior Yield of the New strategy of Enoxaparin, Revascularization and Glycoprotein IIb/IIIa inhibitors (SYNERGY) trial,12which evaluated the effect of enoxaparin and UFH on death and myocardial infarction in high-risk patients presenting with non–ST-segment elevation ACS (n = 10,027), was 175 kg in the UFH group and 196 kg in the enoxaparin group, while the interquartile range was 70 to 91 kg for both groups—the highest weights for any ACS trial to date. There were no inclusion/exclusion criteria related to weight, and dosing was 1 mg/kg for all patients. Recent preliminary results from the SYNERGY trial have shown no evidence of differing efficacy or safety between 1 mg/kg weight-adjusted enoxaparin and UFH in the obese subgroup (K.W. Mahaffey, MD; personal communication; September 24, 2004). To our knowledge, there has only been one clinical trial13 of enoxaparin in patients with ACS where there was a weight cutoff at 110 kg. Third, the studies referenced for this statement are a pharmacodynamic study of tinzaparin and a pharmacokinetic study on the effect of weight and LMWH in the treatment of venous thromboembolism (ie, no ACS patients).

In the study by Macie et al,1 the authors report that increased length of treatment was related to bleeding; one should question whether incorrect dosing also impacted on bleeding and whether this was tested in the bleeding risk model. For instance, what was the incidence of major bleeding in the 17 patients who received a dose > 1 mg/kg? It is also important to note that the major bleeding definition used by Macie et al1 was less stringent than that used in TIMI 11B and ESSENCE—with the definition in the study by Macie et al1 including a hemoglobin drop of 20 g/L in place of 30 g/L. It is therefore difficult to compare bleeding rates, because one could expect rates to be higher in the study by Macie et al1 compared with the RCTs.

When “any bleeding episode” is recorded as a safety end point, subcutaneous administration in obese patients is expected to cause a higher incidence of ecchymosis and hematoma (at the injection site) compared with IV administration. In a real-world setting—an analysis of 13,231 ACS patients in the Global Registry of Acute Coronary Events (GRACE)—major bleeding rates have been reported to be 2.1% in patients receiving a LMWH (of which 80.1% received enoxaparin) vs 4.9% in those receiving UFH.14

With regard to the reported risk factors that increase bleeding risk with enoxaparin, advance age and renal insufficiency have also been reported in GRACE15 to be independent predictors of bleeding, ie, independent of LMWH use. Dose adjustment of the standard of 1 mg/kg qd dose of enoxaparin is recommended by the manufacturer in patients with severe renal impairment (creatinine clearance < 30 mL/min), because enoxaparin is renally cleared (according to the prescribing information of the manufacturer). However, there is no clinical evidence to support dose adjustment in patients with mild and moderate renal impairment.

The lack of comparator drug in the study by Macie et al1 means that any potential bias due to study design, and factors associated with increased bleeding, would also apply to another anticoagulant therapy, such as UFH. Furthermore, in terms of classifying patients with renal impairment, there were probably more patients with severe impairment than the number noted (3%), because impairment was defined as < 25 mL/min creatinine clearance as opposed to the < 30 mL/min level widely recognized and used as an appropriate cutoff point.

Important predictors of bleeding, such as cardiac catheterization and coronary artery bypass surgery, were not evaluated in the study by Macie et al.1 Since > 50% of patients go on to undergo a coronary procedure, it questions the real-world validity of this investigation. Patients in SYNERGY who received consistent enoxaparin therapy (patients who started on a certain therapy and stayed on that original therapy throughout the trial) and underwent early percutaneous coronary intervention had numerically less major bleeding than patients receiving UFH (1.3% of patients had Global Utilization of Streptokinase and Tissue Plasminogen Activator to Open Occluded Coronary Arteries trial bleeding compared with 1.7% using UFH).16

There is also a disconnect between patient care observed in this study and our practice experience: low-risk patients with ACS who do not require transfer for revascularization are not hospitalized for 10 days in our practice (as was average in the study). It appears from the results of the study by Macie et al1 that enoxaparin treatment at 1 mg/kg was not evaluated for safety (ie, increased bleeding risk with increased dose). In addition, the authors did not evaluate whether or not patients who received > 100 mg per dose had higher rates of bleeding. Therefore, we cannot concur with the authors’ recommendations that the dose of enoxaparin should be capped at 100 mg. We see no evidence to suggest the validity of a dose-capping regimen for enoxaparin in obese patients at risk of major bleeding, patients who could potentially be denied an effective treatment therapy.

Macie, C, Forbes, L, Foster, GA, et al (2004) Dosing practices and risk factors for bleeding in patients receiving enoxaparin for the treatment of an acute coronary syndrome.Chest125,1616-1621. [CrossRef] [PubMed]
 
The Thrombolysis in Myocardial Infarction (TIMI) 11A Trial Investigators. Dose-ranging trial of enoxaparin for unstable angina: results of TIMI 11A.J Am Coll Cardiol1997;29,1474-1482. [CrossRef] [PubMed]
 
Montalescot, G, Collet, JP, Tanguy, ML, et al Anti-Xa activity relates to survival and efficacy in unselected acute coronary syndrome patients treated with enoxaparin.Circulation2004;110,392-398. [CrossRef] [PubMed]
 
Becker, RC, Spencer, FA, Bruno, R, et al Excess body weight does not adversely influence either bioavailability or anticoagulant activity of enoxaparin administered subcutaneously in acute coronary syndromes [abstract].Circulation2000;102(Suppl 2),II427-II428
 
Sanderink, GJ, Le Liboux, A, Jariwala, N, et al The pharmacokinetics and pharmacodynamics of enoxaparin in obese volunteers.Clin Pharmacol Ther2002;72,308-318. [CrossRef] [PubMed]
 
Spinler, SA, Inverso, SM, Cohen, M, et al ESSENCE and TIMI 11B Investigators. Safety and efficacy of unfractionated heparin versus enoxaparin in patients who are obese and patients with severe renal impairment: analysis from the ESSENCE and TIMI 11B studies.Am Heart J2003;146,33-41. [CrossRef] [PubMed]
 
Fragmin During Instability in Coronary Artery Disease (FRISC) Study Group. Low-molecular-weight heparin during instability in coronary artery disease.Lancet1996;347,561-568. [PubMed]
 
Nightingale, SL From the Food and Drug Administration. JAMA. 1993;;270 ,.:1672. [PubMed]
 
Klein, W, Buchwald, A, Hillis, SE, et al Comparison of low-molecular-weight heparin with unfractionated heparin acutely and with placebo for 6 weeks in the management of unstable coronary heart disease.Fragmin in Unstable Coronary Artery Disease Study (FRIC). Circulation1997;96,61-68
 
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.Circulation1999;100,1593-1601. [CrossRef] [PubMed]
 
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 Med1997;337,447-452. [CrossRef] [PubMed]
 
Ferguson, JJ, Califf, RM, Antman, EM, et al SYNERGY Trial Investigators. 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.JAMA2004;292,45-54. [CrossRef] [PubMed]
 
Michalis, LK, Katsouras, CS, Papamichael, N, et al Enoxaparin versus tinzaparin in non-ST-segment elevation acute coronary syndromes: the EVET trial.Am Heart J2003;146,304-310. [CrossRef] [PubMed]
 
Klein, W, Kraxner, W, Hodl, R, et al GRACE Investigators. Patterns of use of heparins in ACS: correlates and hospital outcomes; the Global Registry of Acute Coronary Events (GRACE).Thromb Haemost2003;90,519-527. [PubMed]
 
Moscucci, M, Fox, KA, Cannon, CP, et al Predictors of major bleeding in acute coronary syndromes: the Global Registry of Acute Coronary Events (GRACE).Eur Heart J2003;24,1815-1823. [CrossRef] [PubMed]
 
Cohen, M, Mahaffey, KW, White, HD, et al Enoxaparin 0.3 mg/kg intravenous supplement for patients transitioning to percutaneous coronary intervention: Results from SYNERGY [abstract].Am J Cardiol2004;85,38E-39E
 
To the Editor:

We thank Drs. Spinler and Dobesh for their letter, and agree that the management of patients with an acute coronary syndrome (ACS) who weigh > 100 kg and receive enoxaparin, 1 mg/kg bid, is clinically relevant, as approximately 16% of adults in North America are obese (body mass index > 30 kg/m2), many of whom weigh > 100 kg.12 Such patients were underrepresented in the Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events (ESSENCE) and Thrombolysis In Myocardial Infarction (TIMI) 11B trials of enoxaparin in patients with an ACS, as only 7.6% of the study population (540 of 7,081 patients) weighed > 100 kg.34 More recent data, published after our study was completed, suggest that weight-based dosing of enoxaparin, without a maximum (or capped) dose of 100 mg bid, is effective and safe.5

Drs. Spinler and Dobesh state that the capping of enoxaparin observed in our study was unnecessary. In retrospect, we agree. However, this was the practice at our institution during the period of study (from 2000 to 2001), and was consistent with the manufacturer’s guidelines at that time for the use of enoxaparin in patients with an ACS.6

Drs. Spinler and Dobesh question whether incorrect enoxaparin dosing had an effect on bleeding. Despite one in five patients in our study receiving an enoxaparin dose that was > 10% or < 10% of the recommended 1 mg/kg dose, major bleeding did not occur in any of the 17 patients who received a dose > 1 mg/kg. Consequently, enoxaparin dose was not included as a variable in the logistic regression model that assessed determinants of bleeding. The authors also state that our criteria for major bleeding were more liberal than those used in the ESSENCE and TIMI 11B trials, which may have accounted for the higher rate of bleeding in our study (4%) than that observed in the clinical trials (1 to 2%). All patients who had major bleeding had a decrease in hemoglobin > 30 g/L, which would qualify as a major bleed, irrespective of the criteria used. Indeed, there are no accepted standard criteria for major bleeding.7 Furthermore, we never stated the intent to formally compare rates of bleeding across studies.

Drs. Spinler and Dobesh question the lack of a comparator anticoagulant strategy. The prespecified objectives of our study were to assess dosing practices in patients with an ACS who received enoxaparin, not to compare treatment practices with different anticoagulants. The authors also question our use of a creatinine clearance cut-off of < 25 mL/min in our description of the study population. However, this cut-off was used only to describe patients, whereas in the regression analyses, creatinine clearance was a continuous variable when assessed as a predictor of bleeding. Furthermore, the creatinine clearance cut-off of < 30 mL/min, which the authors claim is widely recognized to adjust low-molecular-weight heparin (LMWH) dosing, has never been validated as the cut-point at which LMWH dosing should be adjusted because of concerns of excessive anticoagulation due to impaired renal clearance of LMWH.8

Drs. Spinler and Dobesh question why cardiac catheterization or bypass surgery were not included as predictors of bleeding. As stated in our article, our institution does not support cardiac catheterization; therefore, these procedures could not have been assessed as predictors of bleeding. The authors also state there is a “disconnect” between patient care in our study and that from their experience, questioning why our patients who did not require revascularization were hospitalized, on average, for 10 days. The intent of our study was not to evaluate reasons for length of hospital stay, which we presume would have been related to comorbid conditions, social issues, or lengthy waiting times for cardiac catheterization.

Although Drs. Spinler and Dobesh state that we did not assess the safety of weight-based dosing of enoxaparin (1 mg/kg bid), this was not a prespecified study objective. Furthermore, we did not evaluate bleeding in patients weighing > 100 kg for reasons stated previously. Finally, contrary to the statement of Drs. Spinler and Dobesh, we did not provide any “recommendations” regarding enoxaparin dose capping in patients weighing > 100 kg. What we can all agree on is that using enoxaparin and other LMWHs with a weight-based dosing, irrespective of patient weight, appears effective and safe.5,910

References
Flegal, KM, Carroll, MD, Ogden, CL, et al Prevalence and trends in obesity among US adults, 1999–2000.JAMA2002;288,1772-1723. [CrossRef] [PubMed]
 
Katzmarzyk, PT The Canadian obesity epidemic, 1985–1998.Can Med Assoc J2002;166,1039-1040
 
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.Circulation1999;100,1593-1601. [CrossRef] [PubMed]
 
Cohen, M, Demers, C, Gurfinkel, EP, et al A comparison of low-molecular-weight heparin with unfractionated heparin for unstable coronary artery disease.N Engl J Med1997;337,447-452. [CrossRef] [PubMed]
 
Ferguson, JJ, Califf, RM, Antman, EM, et al SYNERGY Trial Investigators. Enoxaparin vs unfractionated heparin in high-risk patients with non-ST elevation acute coronary syndromes managed with an intended early invasive strategy: primary results of the SYNERGY randomized trial.JAMA2004;292,45-54. [CrossRef] [PubMed]
 
 Compendium of pharmaceuticals and specialties: the Canadian drug reference for health professionals. 2002; ,.:920 -922 Canadian Pharmacists Association. Ottawa, Canada:.
 
Linkins, L, Choi, P, Douketis, JD What is the clinical impact of bleeding in patients with venous thromboembolism who are receiving oral anticoagulant therapy? An assessment of case-fatality and risk of major bleeding.Ann Intern Med2003;139,893-900. [PubMed]
 
Nagge, J, Crowther, M, Hirsh, J Is impaired renal function a contraindication to the use of low molecular weight heparin?Arch Intern Med2002;162,2605-2609. [CrossRef] [PubMed]
 
Hainer, JW, Barrett, JS, Assaid, CA, et al Dosing in heavy-weight/obese patients with the LMWH, tinzaparin: a pharmacodynamic study.Thromb Haemost2003;87,817-823
 
Wilson, SJ, Wilbur, K, Burton, E, et al Effect of patient weight on the anticoagulant response to adjust therapeutic dosage of low-molecular-weight heparin for the treatment of venous thromboembolism.Haemostasis2001;31,42-48. [PubMed]
 

Figures

Tables

References

Macie, C, Forbes, L, Foster, GA, et al (2004) Dosing practices and risk factors for bleeding in patients receiving enoxaparin for the treatment of an acute coronary syndrome.Chest125,1616-1621. [CrossRef] [PubMed]
 
The Thrombolysis in Myocardial Infarction (TIMI) 11A Trial Investigators. Dose-ranging trial of enoxaparin for unstable angina: results of TIMI 11A.J Am Coll Cardiol1997;29,1474-1482. [CrossRef] [PubMed]
 
Montalescot, G, Collet, JP, Tanguy, ML, et al Anti-Xa activity relates to survival and efficacy in unselected acute coronary syndrome patients treated with enoxaparin.Circulation2004;110,392-398. [CrossRef] [PubMed]
 
Becker, RC, Spencer, FA, Bruno, R, et al Excess body weight does not adversely influence either bioavailability or anticoagulant activity of enoxaparin administered subcutaneously in acute coronary syndromes [abstract].Circulation2000;102(Suppl 2),II427-II428
 
Sanderink, GJ, Le Liboux, A, Jariwala, N, et al The pharmacokinetics and pharmacodynamics of enoxaparin in obese volunteers.Clin Pharmacol Ther2002;72,308-318. [CrossRef] [PubMed]
 
Spinler, SA, Inverso, SM, Cohen, M, et al ESSENCE and TIMI 11B Investigators. Safety and efficacy of unfractionated heparin versus enoxaparin in patients who are obese and patients with severe renal impairment: analysis from the ESSENCE and TIMI 11B studies.Am Heart J2003;146,33-41. [CrossRef] [PubMed]
 
Fragmin During Instability in Coronary Artery Disease (FRISC) Study Group. Low-molecular-weight heparin during instability in coronary artery disease.Lancet1996;347,561-568. [PubMed]
 
Nightingale, SL From the Food and Drug Administration. JAMA. 1993;;270 ,.:1672. [PubMed]
 
Klein, W, Buchwald, A, Hillis, SE, et al Comparison of low-molecular-weight heparin with unfractionated heparin acutely and with placebo for 6 weeks in the management of unstable coronary heart disease.Fragmin in Unstable Coronary Artery Disease Study (FRIC). Circulation1997;96,61-68
 
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.Circulation1999;100,1593-1601. [CrossRef] [PubMed]
 
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 Med1997;337,447-452. [CrossRef] [PubMed]
 
Ferguson, JJ, Califf, RM, Antman, EM, et al SYNERGY Trial Investigators. 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.JAMA2004;292,45-54. [CrossRef] [PubMed]
 
Michalis, LK, Katsouras, CS, Papamichael, N, et al Enoxaparin versus tinzaparin in non-ST-segment elevation acute coronary syndromes: the EVET trial.Am Heart J2003;146,304-310. [CrossRef] [PubMed]
 
Klein, W, Kraxner, W, Hodl, R, et al GRACE Investigators. Patterns of use of heparins in ACS: correlates and hospital outcomes; the Global Registry of Acute Coronary Events (GRACE).Thromb Haemost2003;90,519-527. [PubMed]
 
Moscucci, M, Fox, KA, Cannon, CP, et al Predictors of major bleeding in acute coronary syndromes: the Global Registry of Acute Coronary Events (GRACE).Eur Heart J2003;24,1815-1823. [CrossRef] [PubMed]
 
Cohen, M, Mahaffey, KW, White, HD, et al Enoxaparin 0.3 mg/kg intravenous supplement for patients transitioning to percutaneous coronary intervention: Results from SYNERGY [abstract].Am J Cardiol2004;85,38E-39E
 
Flegal, KM, Carroll, MD, Ogden, CL, et al Prevalence and trends in obesity among US adults, 1999–2000.JAMA2002;288,1772-1723. [CrossRef] [PubMed]
 
Katzmarzyk, PT The Canadian obesity epidemic, 1985–1998.Can Med Assoc J2002;166,1039-1040
 
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.Circulation1999;100,1593-1601. [CrossRef] [PubMed]
 
Cohen, M, Demers, C, Gurfinkel, EP, et al A comparison of low-molecular-weight heparin with unfractionated heparin for unstable coronary artery disease.N Engl J Med1997;337,447-452. [CrossRef] [PubMed]
 
Ferguson, JJ, Califf, RM, Antman, EM, et al SYNERGY Trial Investigators. Enoxaparin vs unfractionated heparin in high-risk patients with non-ST elevation acute coronary syndromes managed with an intended early invasive strategy: primary results of the SYNERGY randomized trial.JAMA2004;292,45-54. [CrossRef] [PubMed]
 
 Compendium of pharmaceuticals and specialties: the Canadian drug reference for health professionals. 2002; ,.:920 -922 Canadian Pharmacists Association. Ottawa, Canada:.
 
Linkins, L, Choi, P, Douketis, JD What is the clinical impact of bleeding in patients with venous thromboembolism who are receiving oral anticoagulant therapy? An assessment of case-fatality and risk of major bleeding.Ann Intern Med2003;139,893-900. [PubMed]
 
Nagge, J, Crowther, M, Hirsh, J Is impaired renal function a contraindication to the use of low molecular weight heparin?Arch Intern Med2002;162,2605-2609. [CrossRef] [PubMed]
 
Hainer, JW, Barrett, JS, Assaid, CA, et al Dosing in heavy-weight/obese patients with the LMWH, tinzaparin: a pharmacodynamic study.Thromb Haemost2003;87,817-823
 
Wilson, SJ, Wilbur, K, Burton, E, et al Effect of patient weight on the anticoagulant response to adjust therapeutic dosage of low-molecular-weight heparin for the treatment of venous thromboembolism.Haemostasis2001;31,42-48. [PubMed]
 
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