European Review for Medical and Pharmacological Sciences 2011; 15: 950-959 Update on low molecular weight heparins at the beginning of third millennium. Focus on reviparin R. DEL BONO, G. MARTINI, R. VOLPI Haemostasis and Thrombosis Centre, University-Hospital Institute of “Spedali Civili di Brescia”, Brescia (Italy) Abstract. – Background: This review pro- Outline of Low Molecular Weight vides an outline of the main pharmacological Heparin Pharmacology and clinical features of low molecular weight he- parins (LMWHs) and a wider description of re- Low molecular weight heparins (LMWHs), viparin. The basic pharmacological properties of marketed first in Europe from the second half of LMWHs are compared with those of unfraction- ated heparin, showing clear advantages of the ’80, represented a new therapeutic measure, not former, mainly as for pharmacokinetic profile. only alternative and more practical, but also often Design: Consequently LMWHs are character- more effective than standard heparin in many ized by a more predictable behaviour. A key is- clinical fields1-3. sue is the lack of “bioequivalence”: LMWHs are As known, the search on LMWHs (obtained in fact distinct chemical entities, with typical by unfractionated heparin (UFH) through differ- pharmacological and clinical profile for each agent. Therefore, they are not reciprocally inter- ent chemical or enzymatic methods) has been changeable. The efficacy and safety of re- prompted by some basic observations: viparin, a second generation LMWH, has been – markedly lower activity of LMWHs on factor evaluated in many clinical trials as both throm- IIa than on factor Xa of the coagulation cas- bosis prevention and treatment. Reviparin use cade4,5; is documented in general and orthopaedic – higher risk/benefit ratio of LMWHs versus surgery. In patients undergoing abdominal UFH in animal models6,7; surgery reviparin resulted more effective and better tolerated than unfractionated heparin – strongly better clinical pharmacokinetic profile 8-13 (UFH). In total hip replacement patients, re- of LMWHs versus UFH . viparin compared favourably with enoxaparin, showing the same efficacy but better safety. In The pharmacological differences between var- patients who undergone total hip replacement, ious LMWHs are largely explained by different also the long-term, out of hospital prevention of methods of production and by varying propor- deep vein thrombosis (DVT) has been proven. Conclusions: The comparison with aceno- tions in chains of different length: short, medium 1 coumarol demonstrated that reviparin was more and long chains . effective in preventing DVT recurrences and far LMWHs, showing a mean molecular weight better tolerated than oral anticoagulant treat- of 4,000-5,000 d (range 2,000-9,000 d), are char- ment. Reviparin was also effective and well tol- acterised by a reverse anti-IIa/anti-Xa ratio and erated in immobilised patients following leg in- also by a reduced interaction with blood cells and jury with plaster casts or braces applications. plasma proteins2. This implies a more predictable Positive results were also obtained in the treat- ment of venous thromboembolism in well-de- behaviour versus UFH and a lower risk of he- 2,14-16 signed studies on large patient populations. In parin-induced thrombocytopenia . this indication reviparin compared favourably As for clinical pharmacokinetics, LMWHs ex- with iv UFH. As for the use in cardiology patient, hibit a bioavailability by subcutaneous (sc) route reviparin is at present the only approved LMWH close to 100%, a peak plasma level following sc ad- for the prevention of acute thrombotic events in ministration at 3-5 h, a predictable dose-response patients undergoing percutaneous transluminal 2-16 coronary angioplasty. profile and an elimination half-life of 3-6 h . It is easily understandable, therefore, the inter- Key Words: est stimulated among clinicians and researchers by this new class of molecules, that has been de- Low molecular weight heparin (LMWH), Reviparin, veloped in many indications as prophylactic and Review, Pharmacology, Clinical efficacy. therapeutic measures2. 950 Corresponding Author: Roberto Del Bono, MD; e-mail: [email protected] Update on low molecular weight heparins at the beginning of third millennium Role of LMWHs in Clinical Practice Differentiation of LMWHs It is definitely acquired that clinicians should Due to the various depolimerization techniques base their therapeutic decisions on the best avail- adopted to obtain different LMWHs, the resulting able medical evidence as, for example, that pro- products show molecular and structural differences vided by randomised controlled clinical trials17. and, consequently, different profiles: it is impor- A strong support is also given by Guidelines tant, therefore, to start underlying that the several worked out by the most reliable Medical Associ- LMWHS on the market are not reciprocally inter- ations as, for instance, the American College of changeable on weight basis or anti-Xa activity22-24. Chest Physicians18. In fact, it is now definitely acquired that: According to the recommendations of the 1. The various LMWHs are distinct entities; most recent international guidelines, LMWHs are 2. They exhibit typical pharmacokinetic and phar- now properly indicated in prophylaxis and thera- macodynamic features for any single agent; py of deep vein thrombosis (DVT) in the medical 3. Each drug shows a definite efficacy and safety conditions listed in Table I. profile; In each of the above mentioned conditions, the 4. The “bioequivalence” does not exist; decision of adopting a prophylaxis with LMWH 5. Therefore, LMWHs are not reciprocally inter- as well as the application protocol (doses, time of changeable1,25-28. administration, possible association with other measures, etc) will depend on the thrombotic risk The major Regulatory Authorities, particularly of each single patient and on the balance with the Food and Drug Administration (FDA) and Euro- haemorrhagic risk, as provided in detail in the pean Medicines Agency (EMEA), clearly stated Guidelines already quoted18-21. that LMWHs are distinct pharmacological In fact, specific Guidelines and different Con- agents, each showing a unique therapeutic profile sensus Conferences reported in detail the patient in different clinical conditions23. characteristics requiring routine DVT prophylax- For instance, in surgical patients at high risk of is and other categories, where special preventive venous thromboembolism (VTE), reviparin, the measure and possible precautions are needed19. most recently marketed LMWH, resulted as ef- fective as enoxaparin but with a far better safety profile29. Table I. Clinical use of LMWHs18-21. Prophylaxis Orthopaedic surgery Hip replacement Safety of LMWHs: Knee replacement Some Critical Issues Arthroscopic surgery Hip fracture In spite of the great amount of clinical studies, Elective spine surgery some aspects concerning safety and optimal use Neurosurgery of LMWHs still need deeper evaluations25. For Surgery Major general surgery instance, even if their safety at therapeutic doses Gynaecologic surgery has been evaluated in proper clinical trials, some Vascular surgery 25 Urologic surgery doubts on specific issue still remain . Laparoscopic surgery Bariatric surgery Thoracic surgery Patients at High Haemorrhagic Coronary Artery Bypass Risk/Renal Failure Graft (CABG) Traumatic conditions Trauma As in these cases the main problem is repre- Spinal injury sented by bleeding events, one relevant question Burns is if the fixed dose, not adjusted on activated par- Non surgical patients tial thromboplastin time (aPTT) values, could be Oncology patients considered safe in patients at documented haem- Intensive care patients orrhagic risk as elderly, obese, pregnant and renal Therapy failure patients25. Deep vein thrombosis (DVT) In patients with severe renal failure (creatinine Pulmonary embolism (PE) clearance < 30 ml/min), needing a therapeutic 951 R. Del Bono, G. Martini, R. Volpi dose, UFH should certainly be considered a safer It is, therefore, useful at this time an assessment option. of the benefits provided by reviparin, clearly result- All above mentioned patients are usually ex- ing from both, pharmacological and clinical data. cluded from clinical trials and the most part of data on these cases is provided by pharmacoki- netic or pharmacodynamic studies. Consequent- Pharmacological Profile ly, little information is available – unfortunately – on the possible precautions to be adopted in pa- Reviparin, a second generation LMWH, is tients with chronic real failure showing higher characterised by an interesting pharmacological blood anticoagulation, due to a reduced elimina- and clinical profile37-39. tion rate25,30. A summary of the main pharmacological A growing number of major bleeding events, properties is given in Table II. sometimes fatal, has been reported in patients In clinical practice reviparin resulted markedly with reduced renal clearance and it is clear that effective and well tolerated in many indications. the lack of dose adjustment remains one of the Clinical studies demonstrated that reviparin can unsolved issues in these cases30. maximise the antithrombotic activity minimising More exactly, it has been noticed that the ac- at the same time the haemorrhagic risk37. cumulation of anti-Xa activity is an effect of varying intensity depending on the LMWH used25. Clinical Efficacy 1-VTE Prophylaxis Risk of Spinal/Epidural Hematoma in Neuraxial Anaesthesia