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PULMONARY EMBOLISM: Natalya Thorevska, Yaw Amoateng-Adjepong, Ramin Sabahi, Irina Schiopescu, Anan Salloum, Visvanathan Muralidharan, and Constantine A. Manthous Anticoagulation in Hospitalized Patients With Renal Insufficiency: A Comparison of Bleeding Rates With Unfractionated Heparin vs Enoxaparin Chest 2004; 125: 856-863 [Abstract] [Full text] [PDF]

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Low Molecular Weight Heparins have different pharmacologic and clinical profiles

Walter S. Calderon-Gerstein, Andreux Chernne, MD, Ruchita Patel, MD, Jose Martinez, MD, and Rawand Khader, MD.   (12 April 2004)

Low Molecular Weight Heparins have different pharmacologic and clinical profiles 12 April 2004
Walter S. Calderon-Gerstein, Internal Medicine Resident Metropolitan Hospital - New York Medical College, Andreux Chernne, MD, Ruchita Patel, MD, Jose Martinez, MD, and Rawand Khader, MD. Send letter to journal: Re: Low Molecular Weight Heparins have different pharmacologic and clinical profiles waltercalder27{at}yahoo.com Walter S. Calderon-Gerstein, et al.	N. Thorevska et al (1) have recently shown that the risk of major bleeding with the use of enoxaparin at therapeutic doses is not higher than when unfractionated heparin (UFH) is used. In theory, the utilization of enoxaparin was expected to increase the number of cases of minor and serious bleeding, due to the almost exclusive renal metabolism of this drug (2). In fact, all low molecular weight heparins have extensive renal metabolism and their elimination is prolonged in patients with impaired renal function.(3)Tinzaparin clearance (measured through Anti-Xa activity) is 28 % lower in patients with end-stage renal disease (ESRD) relative to healthy volunteers who received it intravenously (DuPont Pharmaceuticals Co, study DMP 702-918);other clinical trials for the treatment of deep venous thrombosis (DVT) and pulmonary embolism showed a 24% decrease for subcutaneous tinzaparin (Innohep) (4). When nadroparine (Fraxiparine) was used in patients with a creatinine clearance ranging from 10 to 20 ml/min, the half-life of elimination of the antifactor Xa activity was significantly prolonged. (5). The clearance of ardeparin (Normiflo) was reduced by approximately 25% to 50% in patients with moderate and severe renal failure, but bleeding rates did not correlate with creatinine clearance (Prod Info Normiflo(R), 2000). Similar results have been reported after the use of dalteparin (Fragmin), parnaparin (Fluxum) and enoxaparin (Clexane). There are not enough data about the use of certoparin (Alphaparin) in renal failure. On the other hand, reviparin (Clivarine) showed little reduction in elimination of anti-Xa activity in patients with renal failure, compared to healthy subjects (6), but more studies are needed to determine its safety at therapeutic doses. V. Farooq et al (7).have detailed recently serious adverse events in patients using LMWHs. In a retrospective study, they reported ten patients who experienced severe bleeding on LMWH (6 patients on enoxaparin, 3 on tinzaparin, and one on dalteparin therapy). Three of them had fatal outcomes, one patient had retroperitoneal bleeding, other hemorrhagic pericardial effusion, and another, intracranial hemorrhage. Notwithstanding, seven patients were using clopidogrel or aspirin simultaneously, alone or in combination, and all patients were using fixed -doses not adjusted for creatinine clearance. The concern about the possibility of serious bleeding is, therefore, justified. But, as it has been shown in the case of tinzaparin (8), the monitoring of anti-Xa activity in patients with mild and moderate renal failure, has allowed to identify patients with elevated values of this marker, leading to a dose reduction of 20 % of the drug, with good results, avoiding bleeding episodes. Unfortunately, a similar approach was not done in Thorevska’s et al. article because it was a retrospective study. According to current information, it is not standard of care to use LMWHs in patients with severe renal failure without monitoring of anti-Xa levels. Unfortunately, the determination of anti-Xa is not readily available in all medical centers. Considering that UFH use demands frequent monitoring, it poses similar bleeding risks in patients with renal failure, affecting also platelet aggregation, and there have been numerous reports of hyperkalemia associated to its utilization, LMWHs appear as suitable alternatives for use in patients with unstable angina, non-ST-elevation MI (NSTEMI) or DVT with chronic kidney disease (CKD). A decision is to be made about the use of LMWH or UFH, as it is estimated that the number of patients with CKD in the United States borders eleven million, and there are, currently, approximately 350,000 patients with end-stage renal disease (ESRD). This population, the majority of which is older than sixty years, are, at the same time, more prone to thromboembolic events, requiring frequent therapeutic and prophylactic anticoagulation. We should not forget that LMWHs have different pharmacologic and clinical profiles, hence, new and independent studies are required to establish the efficacy and safety of the individual LMWHs for each indication in patients with CKD. One of the objectives of further studies must be the determination of dose adjustments according to the creatinine clearance of this patients, in order to avoid major bleeding episodes, and minimize the need to measure anti-Xa levels. References 1.Thorevska N, Amoateng-Adjepong Y, Sabahi R, Schiopescu I, Salloum A, Muralidharan V, Manthous CA. Anticoagulation in hospitalized patients with renal insufficiency: a comparison of bleeding rates with unfractionated heparin vs enoxaparin. Chest. 2004 Mar;125(3):856-63. 2. Cadroy Y, J Pourrat, MF Baladre, S Saivin, G Houin, JL Montastruc, I Vernier and B Boneu, Delayed elimination of enoxaparin in patients with chronic renal insufficiency. Thromb Res 63 3 (1991), pp. 385–390 3. Reddan D, Szczech LA, O'Shea S, Califf RM. Anticoagulation in acute cardiac care in patients with chronic kidney disease. Am Heart J. 2003 Apr;145(4):586-94 4. Hainer JW, Sherrard DJ, Swan SK, Barrett JS, Assaid CA, Fossler MJ, Cox DS, Williams RM, Pittenger AL, Stephenson CA, Hua TA. Intravenous and subcutaneous weight-based dosing of the low molecular weight heparin tinzaparin (Innohep) in end-stage renal disease patients undergoing chronic hemodialysis. Am J Kidney Dis. 2002 Sep;40(3):531-8. 5. Goudable C, Saivin S, Houin G, Sie P, Boneu B, Tonthat H, Suc JM.Pharmacokinetics of a low molecular weight heparin (Fraxiparine) in various stages of chronic renal failure. Nephron. 1991;59(4):543-5. 6. Baumelou A, Singlas E, Petitclerc T, Desmichels D, Jacobs C, Soria J: Pharmacokinetics of a low molecular weight heparin (reviparine) in hemodialyzed patients. Nephron 68:202-206, 1994 7. Farooq V, Hegarty J, Chandrasekar T, Lamerton EH, Mitra S, Houghton JB, Kalra PA, Waldek S, O'Donoghue DJ, Wood GN. Serious adverse incidents with the usage of low molecular weight heparins in patients with chronic kidney disease.Am J Kidney Dis. 2004 Mar;43(3):531-7. 8. Pautas E., Gouin I, Bellout O, Andreux JP, and V Siguret. Safety profile of tinzaparine administered once daily at a standard curative dose in two hundred very elderly patients.Drug Safety 2002; 25 (10):725-733.