Low Molecular Weight Heparin ============================ þ LMWH in the Obese: - In patients defined as obese (BMI 30-48 kg/m2), current recommendations support the use of total or actual body weight when dosing enoxaparin or other LMWHs. The literature has shown that weight-based dosing using total body weight does not alter the mean maximum plasma activity of enoxaparin in obese patients. The practice of setting a maximum dose is discouraged as it may complications. Therefore, the appropriate enoxaparin treatment regimen for the obese patient with normal renal function is 1 mg/kg Q 12 hours, using actual body weight. When using enoxaparin for prophylactic indications, the suggested fixed dosing regimens may not be sufficient. An increase of approximately 25-30% in the fixed-dose regimens may be used for this population. [UPMC Mercy Pharmacy Newsletter, 9/08] þ Renal Impairment - Unlike unfractionated heparin (UFH), enoxaparin primarily undergoes renal excretion and available studies suggest that as renal function decreases, elimination of enoxaparin will also decrease. Plasma concentration will typically increase and adverse complications such as bleeding may occur. In patients with severe renal impairment or those undergoing hemodialysis, UFH may be the preferred agent. If enoxaparin is to be used in patients with severe renal impairment, dosing adjustments are necessary and are outlined in the table below. In patients undergoing hemodialysis, the use of enoxaparin is generally discouraged, but is not an absolute contraindication. Standard and Renally Adjusted LMWH Dosing Regimens Indication Standard Regimen Severe Renal Impairment (CrCl <30mL/minute) DVT prophylaxis in medical patients 40 mg SC once daily 30 mg SC once daily Inpatient treatment of acute DVT with or without pulmonary embolism 1 mg/kg SC every 12 hours or 1.5 mg/kg SC once daily (with warfarin) 1 mg/kg SC once daily Outpatient treatment of acute DVT without pulmonary embolism 1 mg/kg SC every 12 hours (with warfarin) 1 mg/kg SC once daily Unstable angina and non-Q-wave MI 1 mg/kg SC every 12 hours (with aspirin) 1 mg/kg SC once daily Acute STEMI in patients <75 years of age [For dosing in subsequent PCI, see Dosage and Administration 30-mg single IV bolus plus a 1 mg/kg SC dose followed by 1 mg/kg SC every 12 hours (with aspirin) 30-mg single IV bolus plus a 1 mg/kg SC dose followed by 1 mg/kg SC once daily Acute STEMI in patients >75 years of age 0.75 mg/kg SC every 12 hours (no bolus) 1 mg/kg SC once daily (no bolus) CrCl = creatinine clearance; STEMI = ST-segment elevation myocardial infarction © sanofi-aventis U.S. LLC. accessed August 3, 2008. [Mercy Pharmacy Newsletter 9/08] þ Heparin Allergy: - use fondaparinux (Arixtra) - 7.5-10 mg SQ daily - OK for DVT/PE þ LMWH instead of unfractionated heparin for PE? - Low molecular weight heparin is more cost effective for deep venous thrombosis than unfractionated heparin, in both inpatient and outpatient settings [Rodger M, Bredeson C, Wells PS, Beck J, Kearns B, Huebsch LB. Cost-effectiveness of low-molecular-weight heparin and unfractionated heparin in treatment of deep vein thrombosis. Canadian Med Assoc J 1998; 159: 931-938.] + Results were pooled using the Mantel--Haenszel method and tested for statistical heterogeneity. + Costs for unfractionated heparin therapy were prospectively collected by a case-costing accounting system for 105 people with deep vein thrombosis treated in fiscal year 1995/1996. Costing for equivalent people receiving LMWH were modeled using savings in nursing time, derived from time and motion studies, monitoring costs and drug costs. + The authors created a decision tree incorporating four treatment strategies. They used incremental analysis, relating outcomes at 3 months to total costs in 1995 Can$. Uncertainty in probabilities and costs was explored using sensitivity analysis, including a worst-case analysis in which all variables most favoring unfractionated heparin were entered into the decision analysis. Cost to treat one hospital patient was Can$2993 for LMWH and Can$3048 for unfractionated heparin. Increased drug costs were offset by reduced nursing time and monitoring. Only in the worst case sensitivity analysis does the cost effectiveness of inpatient unfractionated heparin exceed inpatient LMWH. AUTHORS' CONCLUSIONS Treating deep vein thrombosis with LMWH is more cost effective than treating with unfractionated heparin in both inpatient and outpatient settings. þ LMWH and pregnancy (2/02) - Lovenox not OK for prosthetic heart valves - Especially in pregnant patients - some congenital abnormalities in those who got Lovenox, but no higher than in the general population þ Thrombolysis Interest Group of Candada's Protocol þ enoxaparin (Lovenox) - 30 mg SQ BID for prophylaxis - 1 mg/kg SQ BID for unstable angina - Letter from Company with details of research data: þ dalteparin (Fragmin) - 2500 units SQ daily is one dosage regime - dosage adjustment for dalteparin (Fragmin), due to lack of proportionately increased volume of distribution in obese patients: "We currently recommend either: 1. Dose on total body weight up to a patient weight of 90 kg. Heavier patients are dosed as if they weighed 90kg (maxm dose/day is therefore either 18000 iu or 21600 iu), or 2. Dose on weight adjusted body weight (this isn't popular with the house staff!). --Steve Duffull Dept of Clinical Pharmacology Christchurch Hospital Private Bag 4710, CHCH New Zealand Ph +64 3 364 0900 Fax +64 3 364 0902 Email: sduffull@chmeds.ac.nz A few days ago, Fabrice Czarnecki wrote: > >Low Molecular Weight Heparin is commonly used in France to treat DVT without >admission. Some people even use LWMH for "minor" pulmonary embolism. >Our cardiologists do not like LWMH as a treatment (opposed to prevention >only), because there are more bleeding complications with LWMH than with heparin SC or IV. They also say that anti-Xa activity is not a reliable test >of the LWMH concentration. Comments: My understanding is just slightly different. Although I believe that LMWH is great, and that unfractionated heparin is probably obsolete, I am guessing that the above paints a slightly misleading picture of the current European practice of phlebology. My sense of current European practice is inexact, but is based on my experiences at the past few congresses of the UIP (Union Internationale de Phlebologie) and from discussions with our European colleagues at joint international meetings of the American Venous Forum and of the North American Society of Phlebology, and from reviewing much of the French, English and German literature from the past 40 years, and from regularly reading the French journal Phlebologie, to which I subscribe. As I understand it, the European approach to DVT differs from the American in several key ways. Most importantly, it has long included the use of real gradient compression for DVT. Prospective studies have shown that gradient compression is the single most effective form of prophylaxis against the formation of new clot in perioperative patients -- even more effective than anticoagulation alone -- and most experts believe that it is equally efficacious in the prevention of clot extension in patients who already have DVT. This modality is rarely used in America. The second major difference is that many European practitioners do keep their DVT patients ambulatory -- although this remains controversial, and the only study I know of that compared the two approaches was a small one published by my friend and colleague Professor Hugo Partsch (Vienna). Ambulatory does not necessarily mean that patients are managed as outpatients. Outpatient management of DVT is sometimes done, but remains controversial. The problem, of course, is that most (maybe all) DVT embolizes. A certain fraction of patients will be seriously ill, and some will die. It is probably true that the death rate for DVT patients managed as elective inpatients and the death rate for DVT patients managed as elective outpatients are roughly the same, but it has not been proven, and it would take a really large prospective study to prove it. If you are an American physician, trained to admit all DVT's for bedrest and IV heparin, and you send home a patient with DVT and find out two days later that he/she has died from PE, you are certainly going to wonder whether you did right. Notice I am not saying that you did not do right -- only that you are bound to wonder. This is not at all a rare occurrence -- I have reviewed a number of legal cases that hinge on this kind of question. The use of fractionated heparin products is much more widespread in Europe, mainly because there are several such products available and because they have been available for a number of years. With a little experience, most clinicians prefer them because they demonstrate more reliability than does unfractionated heparin. In study after study, when patients are equally anticoagulated, fractionated heparin is associated with a slightly LOWER incidence of bleeding complications, not a higher incidence. Some practitioners anecdotally tell of seeing more bleeding complications with LMWH -- but a little investigation quickly reveals the reason: they had previously been using non-therapeutic heparin dosing regimens, old regimens that have been proven ineffective over and over in the last 20 years. Switching to an effective dosing regimen certainly does result in more bleeding complications. _______________ Re: 'minor' PE There is no such thing as 'minor' pulmonary embolism. This is a myth I am sorry to see promulgated again. In the absence of hemodynamic compromise, the likelihood of death is still high and is unrelated to the size of the prior PE as determined by V/Q, by angiography, or by subsequent autopsy. Nearly all of the risk of death is associated not with the 'sentinal embolism', but with either a progressive accumulation of pulmonary clot load over a period of days to weeks, or with a sudden single substantial episode of embolization following multiple prior 'minor' episodes. The fact that about 80% of those who die from PE don't even have the diagnosis suspected before autopsy should be enough to lay this old myth to rest in anyone's mind. Hundreds of autopsy studies involving many thousands of patients have shown unequivocally that the vast majority of those who die from PE would have their premorbid emboli classified as 'minor' based on absolutely any criteria you can suggest. _________________ Re LMWH for PE: LMWH is not rationally restricted to 'selected' patients with PE -- it is an alternative anticoagulation regimen that is believed by many experts to be more effective AND more reliable AND easier to use AND safer than unfractionated heparin, for ANY situation in which prompt effective anticoagulation is desired. Attempts to select patients for different types of heparin based on long-disproved myths using unjustified clinical guesses about the prognosis of each patient are just plain silly. The fractionated low-molecular-weight heparin that is available in the United States is enoxaparin (Lovenox). Enoxaparin is approximately 3 times more active against factor Xa than against factor IIa, in contrast to unfractionated heparin, which affects the two factors nearly equally. In other words, Lovenox generally does not prolong the APTT, even when the patient is fully anticoagulated. This does not matter, because Lovenox has a wide therapeutic window. The same dose of Lovenox (30 mg SQ BID) produces effective anticoagulation in virtually all patients with no dose adjustment and no monitoring. In contrast, fewer than 40% of patients are adequately anticoagulated within 24 hours when the APTT is followed and efforts are made to adjust anticoagulation with IV heparin. _________ Opinion: I think the day of LMWH is here. I also believe that outpatient ambulatory treatment of DVT is unproven, but probably appropriate, provided that the patient has also been placed in 30 - 40 mm Hg gradient compression hose (Waist-high or thigh-high with waist strap) and that serial ultrasound exam is being followed carefully by a reliable examiner (If it were MY leg, I would want daily ultrasound with video recording and snapshots until the thrombus is seen to regress). Some patients treated in this way will throw large emboli and will die, but on the other hand bedrest == venous stasis == the worst possible situation for thrombus progression == fresh thrombus == higher risk of large recurrent PE. End of opinion. ===== From: ============================================================ Craig F. Feied, MD, FACEP, FAAEM | Director of Informatics,