Use of low-molecular-weight heparins and new anticoagulants in elderly patients with renal impairment

Elderly people with renal impairment are at high risk for venous thromboembolism (VTE) and acute coronary syndromes (ACS); however, they are also at increased risk for bleeding complications. Evidence-based data for the management of anticoagulation in elderly patients with severe renal impairment, in particular, are limited. These patients are frequently excluded from randomized clinical trials evaluating anticoagulants, confounding clinical decision making. Low-molecular-weight heparins (LMWHs), such as enoxaparin sodium and dalteparin sodium, provide a predictable anticoagulant effect across almost all patient populations; however, because they are primarily eliminated through the kidneys, elderly patients with moderate or severe renal impairment are potentially at risk for LMWH accumulation. Clinical evidence suggests that treatment with full-dose enoxaparin sodium could increase the risk for bleeding in elderly patients with severe renal impairment; however, this risk is ameliorated with approved dose adjustments. Dalteparin sodium has been evaluated in small studies within this population but no strategy for reduced dosing has been developed. There are limited clinical data on the use of fondaparinux sodium and, in particular, the new anticoagulants, such as dabigatran etexilate and rivaroxaban, in elderly patients with renal impairment. Evidence suggests that the clearance of fondaparinux sodium is mildly reduced in elderly patients, and more substantially reduced in patients with severe renal impairment; a dose reduction has recently been approved in Europe. Age and renal function appear to affect the exposure of dabigatran etexilate. A dose reduction is recommended in the elderly and in those with moderate renal function, but dabigatran etexilate is contraindicated in severe renal impairment. Rivaroxaban has been associated with increased exposure and pharmacodynamic effects in the elderly and those with renal impairment; at present there is no facility for dose reduction. Monitoring anticoagulant activity may help improve the safety profile of anticoagulants in elderly patients with renal impairment, particularly when approved dose reductions are unavailable. However, unlike the LMWHs, clinical surveillance of the new anticoagulants is challenging. In conclusion, extra care should be taken when anticoagulants are administered to elderly patients with renal impairment. Additional data are needed, particularly for the new anticoagulants, in order to guide the prevention and treatment of VTE and ACS, and to ensure the optimal safety profile in older patients with renal impairment.     

Review article: the safety of anticoagulants and antiplatelet agents in patients with cirrhosis

Patients with cirrhosis were long thought to be coagulopathic. However, this paradigm has changed in recent years and currently, cirrhosis is recognised as a prothrombotic state. Due to the increasing incidence of cirrhosis from nonalcoholic steatohepatitis which is closely associated with cardiac disease, patients with cirrhosis increasingly require therapy with anticoagulants and antiplatelet agents. However, their potential for causing catastrophic and life-threatening bleeding in patients with cirrhosis leads to hesitancy about their use in patients with cirrhosis. Overall, traditional anticoagulation is safe for all Child-Pugh classes while newer direct oral anticoagulants (DOACs) are mostly safe in Child-Pugh class A/B and contraindicated in severe hepatic impairment. For different indications, published data to date suggest that anticoagulation is overall safe for patients with cirrhosis who have venous thromboembolism, atrial fibrillation and portal vein thrombosis, and does not increase the risk of variceal bleeding. Moreover, DOACs appear to have similar safety profiles as traditional anticoagulants. Finally, most studies suggest that antiplatelet agents are also safe to use in patients with cirrhosis although they are mostly contraindicated in severe hepatic impairment. For both anticoagulants and antiplatelet agents, severe thrombocytopaenia presents a relative contraindication to their use. More prospective trials and large cohort studies are needed to advance our understanding of the safety and nuances of DOACs and antiplatelet agents in patients with advanced cirrhosis.     

Use of newer anticoagulants in patients with chronic kidney disease.

PURPOSE: The current indications, dosing, and practical considerations for use of newer anticoagulants in patients with various degrees of renal impairment who do not require dialysis are reviewed. SUMMARY: Kidney function should generally be evaluated in all patients commencing anticoagulant therapy. As in the general population, hospitalized patients with impaired renal function most often have impairment that is mild to moderate in severity. Drug dosing in patients with chronic kidney disease may require that adjustment be made to the usual loading or maintenance dose of a drug. Newer anticoagulants with labeling approved by the Food and Drug Administration for venous thromboembolism (VTE) prophylaxis, treatment, or both include the low-molecular-weight heparins (LMWHs) and the factor Xa inhibitor fondaparinux. Some LMWHs are also indicated for the management of patients with acute coronary syndrome (ACS). All of the newer anticoagulants currently available for the management of VTE and ACS have approved labeling for use in patients with mild-to-moderate renal impairment. Currently available LMWHs, factor Xa inhibitors, and direct thrombin inhibitors (excluding argatroban) are eliminated primarily by the kidneys, so dosing in patients with severe renal impairment may require cautious dosage reduction or increased monitoring for bleeding and thromboembolic complications or both. Unfractionated heparin is the preferred anticoagulant for use in most of these patients. CONCLUSION: Newer anticoagulants should be used with caution in patients with mild-to-moderate renal impairment. Unfractionated heparin remains the preferred anticoagulant in most patients with severe renal impairment even though its use is associated with increased bleeding in this population. Dosing of newer anticoagulants, except argatroban, requires cautious dosage reduction and increased monitoring for complications.     

A new approach with anticoagulant development: tailoring anticoagulant therapy with dabigatran etexilate according to patient risk

INTRODUCTION: Although vulnerable patients, including the elderly and those with renal impairment or low body weight, are at greater risk of bleeding and/or venous thromboembolism following total hip or total knee replacement, there have been few clinical studies to determine the optimal dose of anticoagulants for this group. AREAS COVERED: For this paper the authors searched the literature for data on efficacy and bleeding rates with low-molecular-weight heparins and fondaparinux in routine clinical practice; and on the effects of standard or reduced dosing with these anticoagulants or with the oral direct thrombin inhibitor dabigatran etexilate in vulnerable patient groups. EXPERT OPINION: Tailoring anticoagulation therapy according to the risk of individual patients is the best way to optimize the benefit/risk of thrombosis and bleeding, and is recommended on treatment guidelines. Specific recommendations for dose reduction have been made for fondaparinux in renal impairment. The availability of two approved doses of dabigatran etexilate for thromboprophylaxis following orthopedic surgery allows the dose to be tailored to the individual patient's characteristics, based on the age and renal function of the patient, as recommended by the European Medicines Agency, in order to maintain efficacy while decreasing bleeding risk.     

Insights from the dabigatran versus warfarin in patients with atrial fibrillation (RE-LY) trial

Oral anticoagulants such as warfarin have been used widely for the treatment of venous thromboembolism and stroke prevention in atrial fibrillation (AF) patients. Warfarin has significant limitations and also requires frequent monitoring. Thus, there is an unmet need, with the quest for alternative oral anticoagulants with stable pharmacokinetics and pharmacodynamics that do not need monitoring. The paper under evaluation provides us with up-to-date information on the safety and efficacy of a new oral anticoagulant, dabigatran, compared with warfarin for stroke prevention in AF patients.     

New frontiers with bemiparin: use in special populations

Special populations are rarely included in conventional clinical trials and subsequently there is a lack of guidance on the appropriate treatment regimens to use. This paper reviews data on the use of bemiparin in such populations, including the elderly, those with renal impairment, pregnant women and children. Pharmacokinetic data from elderly patients suggest that bemiparin is also safe in this patient population. There was no evidence of the accumulation of bemiparin after repeated prophylactic doses. At therapeutic doses, there was no significant difference in pharmacokinetic profile between groups. There is no need for dose adjustment of bemiparin in the elderly, either during prophylaxis or during treatment. Data from another pharmacokinetic study showed that bemiparin at prophylactic doses is safe in patients with mild to moderate renal impairment. In general, no dose adjustment was required in patients with mild to moderate renal impairment when bemiparin is used as therapy or prophylaxis. To date, bemiparin has not been tested in patients with severe renal impairment; therefore, conclusions on the safety of bemiparin in patients with severe renal failure cannot be drawn at present. Although there are no published data on the use of bemiparin in pregnant women, promising anecdotal data are beginning to emerge. Current guidelines recommend low molecular weight heparins (LMWH) for the treatment of venous thromboembolism (VTE) in pregnant women, with treatment maintained at therapeutic doses throughout pregnancy. Anticoagulation should continue for 6 weeks or more post-partum and should be maintained for 3 months or more after diagnosis of the VTE event. Monitoring of pregnant women receiving LMWH is not necessary, except in those at high risk. A case report describing the treatment of a neonate with renal vein thrombosis showed that 2 months' treatment with bemiparin followed by 10 months' prophylaxis was effective and safe. These data suggest that bemiparin may play a role in the treatment of VTE in paediatric patients.     

Anticoagulant Use in Patients with Chronic Renal Impairment

Patients with renal failure have an increased risk of both thrombotic and bleeding complications. A number of antithrombotic drugs undergo renal clearance. Therefore, estimation of renal function is necessary when prescribing these drugs to patients with renal dysfunction. Pharmacokinetic and clinical data in patients with chronic renal impairment are limited for several anticoagulants, and adequate administration information is often absent. Dose adjustment of anticoagulants may be indicated when the creatinine clearance falls below 30 mL/min. Unfractionated heparin, argatroban, and vitamin K antagonists generally do not require dose adjustment with renal dysfunction. However, smaller doses of warfarin may be required to achieve a particular target international normalized ratio. Close monitoring of anticoagulation is recommended when argatroban or high doses of unfractionated heparin are administered in patients with severe chronic renal impairment. Low-molecular weight heparins, danaparoid sodium, hirudins, and bivalirudin all undergo renal clearance. Lower doses and closer anticoagulation monitoring may be advisable when these agents are used in patients with chronic renal failure. We recommend that fondaparinux sodium and ximelagatran (not yet licensed) be avoided in the presence of severe renal impairment and be used with caution in patients with moderate renal dysfunction. While acknowledging the lack of pharmacokinetic data, this review provides specific recommendations for the use of anticoagulants in patients with chronic renal impairment.     

A new approach with anticoagulant development: tailoring anticoagulant therapy with dabigatran etexilate according to patient risk

Introduction: Although vulnerable patients, including the elderly and those with renal impairment or low body weight, are at greater risk of bleeding and/or venous thromboembolism following total hip or total knee replacement, there have been few clinical studies to determine the optimal dose of anticoagulants for this group.

Areas covered: For this paper the authors searched the literature for data on efficacy and bleeding rates with low-molecular-weight heparins and fondaparinux in routine clinical practice; and on the effects of standard or reduced dosing with these anticoagulants or with the oral direct thrombin inhibitor dabigatran etexilate in vulnerable patient groups.

Expert opinion: Tailoring anticoagulation therapy according to the risk of individual patients is the best way to optimize the benefit/risk of thrombosis and bleeding, and is recommended on treatment guidelines. Specific recommendations for dose reduction have been made for fondaparinux in renal impairment. The availability of two approved doses of dabigatran etexilate for thromboprophylaxis following orthopedic surgery allows the dose to be tailored to the individual patient's characteristics, based on the age and renal function of the patient, as recommended by the European Medicines Agency, in order to maintain efficacy while decreasing bleeding risk.     

Novel oral anticoagulants: clinical pharmacology, indications and practical considerations

Background

Novel oral anticoagulants are approved in several indications: rivaroxaban, apixaban, and dabigatran for the prevention of venous thromboembolism after elective hip or knee replacement surgery, and edoxaban for hip or knee replacement surgery and hip fracture surgery (in Japan only); rivaroxaban for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE; and rivaroxaban, apixaban, and dabigatran for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation. These agents overcome some limitations of traditional anticoagulants, are suggested to have no requirement for routine coagulation monitoring, and are administered orally. Rivaroxaban, apixaban, and dabigatran have different pharmacological characteristics, and guidance is needed on optimum doses and dosing intervals and the effects of renal or hepatic impairment, age, food, and other drugs. Dabigatran has stricter prescribing advice than rivaroxaban or apixaban for patients with moderate-to-severe renal impairment. All three drugs have restrictions on use in patients with hepatic impairment. Apixaban requires twice-daily dosing in all indications, whereas rivaroxaban and dabigatran are dosed once- or twice-daily depending on indication. Although head-to-head comparisons are lacking, the novel oral anticoagulants may show favorable cost–benefit relations compared with traditional vitamin K antagonists or no therapy.

Aim

This review summarizes the pharmacology of rivaroxaban, apixaban, edoxaban, and dabigatran, and the indications for which they are approved. Issues regarding the optimization of the use of these anticoagulants for the management of thromboembolic disorders will also be discussed.     

Pharmacokinetics, safety, and tolerability of solifenacin in patients with renal insufficiency

To evaluate the pharmacokinetics, safety, and tolerability of solifenacin in patients with mild, moderate, or severe renal disease, eighteen patients with renal disease and six healthy volunteers received a single oral dose of solifenacin (10 mg). Pharmacokinetic parameters were assessed from blood samples drawn over a 360-h period. Safety and tolerability were also evaluated. Total mean +/- S.D. exposure (ng . h/mL) to solifenacin in healthy individuals (1190 +/- 403) was increased in patients with renal disease (mild: 1784 +/- 792, moderate: 1559 +/- 555, severe: 2530 +/- 700), and elimination half-life (mean +/- S.D. [h]) was prolonged (healthy: 68.2 +/- 27.2, mild: 89.1 +/- 34.5, moderate: 90.6 +/- 27.3, severe: 111 +/- 38.3). A significant correlation was found between creatinine clearance and pharmacokinetic parameters for exposure and apparent oral clearance. No deaths or serious adverse events occurred during the study. Solifenacin 10 mg was well tolerated in patients with renal disease. Solifenacin displays a higher exposure and a prolonged half-life in patients with renal impairment, especially severe. Therefore, while no special cautions are necessary for patients with mild/moderate renal impairment, patients with severe renal impairment should receive no more than 5 mg solifenacin once daily.     

The pharmacogenetics of coumarin therapy

Vitamin K antagonists (coumarins) are widely-used oral anticoagulants for the prevention of venous thromboembolism and strokes. Wide inter-individual variation in dose response and frequent bleeds characterize the initiation of coumarin therapy. Over the past 10 years both genetic and nongenetic determinants of coumarin dose response have been identified. A comprehensive pharmacogenetics approach to warfarin therapy has the potential to improve the safety and efficiency of warfarin initiation.     

Life-threatening hemorrhage after dalteparin therapy in a patient with impaired renal function

Dalteparin and other low-molecular-weight heparins are frequently used for the treatment of deep vein thrombosis and for other indications. Unlike unfractionated heparin (UFH), dalteparin is mainly cleared through the kidney; therefore, it can accumulate in patients with impaired renal function, increasing the risk of hemorrhage. An 84-year-old woman with chronic renal failure was hospitalized because of stenosis of a femorofibular bypass in her right leg. Peripheral transluminal angioplasty was performed successfully. Later the same day, Doppler sonography revealed deep vein thrombosis of the left lower leg. Treatment with dalteparin was started. The patient was discharged home 3 days later, with dalteparin to be continued at home. One day later, the patient was rehospitalized because of a pronounced hematoma on her flank. Her hemoglobin level had dropped to 5.5 g/dl. Treatment with dalteparin was stopped, and protamine 2500 U and two transfusions of packed red blood cells were administered. Treatment with UFH and oral anticoagulants were started because of a persistent risk for venous thrombosis. Thereafter, the patient's hemoglobin level remained stable, and no further bleeding episodes occurred. As long as systematic studies of the efficacy and safety of dalteparin in patients with severe renal impairment are lacking, dalteparin should be avoided or used only with close monitoring of antifactor Xa activity in these patients. As an alternative, UFH can be used because monitoring of UFH is well established and easier than it is with dalteparin. Renal impairment does not notably influence the short elimination half-life of UFH, which unlike that of dalteparin or other low-molecular-weight heparins allows for rapid dosage adjustments to prevent hemorrhage.     

Current options in the prevention of thromboembolic disease

Significant advances in the pharmacological prophylaxis of venous thromboembolism have occurred since warfarin and unfractionated heparin were introduced for this indication nearly 60 years ago. Despite these advances, coumarin derivatives such as warfarin remain the only orally active anticoagulants available for prophylaxis in venous thromboembolism. Although administered orally, coumarin derivatives are not convenient to use, because they have narrow therapeutic indexes and require routine coagulation monitoring and dose adjustment. This is inconvenient for patients and physicians and costly for the healthcare system. Low-molecular-weight heparins, which are administered in fixed or weight-adjusted doses and do not require monitoring, are widely used for the prevention of venous thromboembolism in patients in both the hospital and the outpatient setting. However, these drugs must be given subcutaneously, which can be difficult for outpatients and resource-intensive for in-hospital use. Likewise, fondaparinux, the synthetic pentasaccharide, must be administered subcutaneously. Consequently, there remains a need for new orally active anticoagulants that can be given in fixed doses and do not have a narrow therapeutic index, so that coagulation monitoring is unnecessary. Because such agents would be more convenient for patients and physicians, they would probably expand the use of prophylaxis in venous thromboembolism in those at risk, and would simplify treatment of patients with established venous thromboembolism.     

Prevention of venous thromboembolism following orthopaedic surgery: clinical potential of direct thrombin inhibitors

Patients undergoing total hip or total knee replacement are at high risk of venous thromboembolism (VTE), and are therefore considered to be populations well suited for the evaluation and dose optimisation of new anticoagulants. Deep vein thrombosis may lead to life-threatening pulmonary embolism, disabling morbidity in the form of the post-thrombotic syndrome, and risk of recurrent thrombotic events. There is increasing evidence that anticoagulant treatment for the prevention of VTE should be extended from 1 to at least 4 weeks after surgery. Anticoagulation with vitamin K antagonists (such as warfarin), low molecular weight heparin or unfractionated heparin effectively lowers the risk of VTE, but these anticoagulants have limitations such as the need for coagulation monitoring and subsequent dose adjustment (vitamin K antagonists), difficulty of continuing prophylaxis out of hospital because of the requirement for parenteral administration, and risk of heparin-induced thrombocytopenia. The development of new anticoagulants has been pursued with the aim of finding more effective, safer and/or more convenient therapies.Thrombin is a central regulator in the coagulation and inflammation process and several direct thrombin inhibitors (DTIs) with distinct pharmacological profiles, as well as pharmacological differences from the conventional anticoagulants, are currently in clinical use for certain indications or are under development. Clinical experience with parenterally administered DTIs has accumulated since the mid 1990s, although only desirudin (a recombinant hirudin) is currently approved for use in patients undergoing orthopaedic surgery. Two oral DTIs, ximelagatran and dabigatran etexilate, are in clinical development. Dabigatran etexilate has recently been evaluated in phase II clinical trials in patients undergoing total hip replacement. Several large phase III trials have now demonstrated the efficacy and safety of ximelagatran in the prevention of VTE following total hip or knee replacement. Ximelagatran can be used with an oral fixed dose without the need for coagulation monitoring or dose adjustment. Hence, it offers significant potential to facilitate the management of anticoagulation in or out of hospital.     

Initial and long-term treatment of deep venous thrombosis: recent clinical trials and their impact on patient management

Introduction: Deep venous thrombosis (DVT) is common and associated with significant morbidity and mortality if not diagnosed early and managed effectively. Specific conditions including advanced age, obesity and renal impairment need to be considered when implementing anticoagulation treatment to ensure optimal therapeutic efficacy and safety.

Areas covered: This review summarizes the current treatment of acute DVT according to the 2012 American College of Physicians Evidence-based Clinical Practice Guidelines. Recent and ongoing clinical trials on acute DVT treatment are highlighted. The authors also provide suggestion for the treatment of DVT in patients with advanced age, obesity and renal impairment.

Expert opinion: New oral anticoagulants (NOACs) have the potential as an alternative to warfarin for DVT treatment. Elastic compressive stockings and catheter-directed thrombolysis should be considered for symptomatic relief and the prevention of post-thrombotic syndrome, respectively. ASA has emerged as a treatment option for selected patients with unprovoked DVT and pulmonary embolism (PE) with a low-to-intermediate risk for disease recurrence or who are unsuitable for long-term oral anticoagulant therapy due to practical or safety reasons. Additional trials are needed in special patient populations, including the elderly, obese and those with renal impairment and cancer-associated DVT, to assess the efficacy and safety of anticoagulants especially the NOACs for DVT treatment.     

Benefit-risk assessment of telithromycin in the treatment of community-acquired pneumonia.

The purpose of this review is to assess the benefits and risks associated with the use of the ketolide antibacterial telithromycin, currently licensed for the treatment of adults with mild to moderate community-acquired pneumonia (CAP). Telithromycin is active against both the major (Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis) and atypical/intracellular (Chlamydophila pneumoniae, Legionella pneumophila and Mycoplasma pneumoniae) CAP pathogens. It is associated with a low potential to select for resistance and has maintained its in vitro activity against isolates of respiratory pathogens in countries where it has been in clinical use for several years. In randomized clinical trials, telithromycin has demonstrated efficacy comparable to the established antibacterial classes (macrolides, fluoroquinolones and beta-lactams) in the treatment of CAP.The safety profile of telithromycin is broadly similar to that of other antibacterials used to treat CAP. The most common adverse events are gastrointestinal adverse effects and headache; these are generally mild to moderate in severity and reversible. Telithromycin appears to be well tolerated by adult patients in all age groups, including those with co-morbid conditions. In common with other antibacterials, telithromycin has the potential to affect the corrected QT interval; the concomitant use of cisapride or pimozide with telithromycin is contraindicated, while telithromycin should be avoided in patients receiving Class IA or Class III antiarrhythmic drugs. Visual disturbances (usually transient) have occurred in a small proportion of patients treated with telithromycin; it is recommended that activities such as driving are minimized during treatment. Telithromycin is contraindicated in patients with myasthenia gravis. Hepatic dysfunction may occur in some patients taking telithromycin; rare cases of acute hepatic failure and severe liver injury, including deaths, have been reported. As telithromycin is an inhibitor of the cytochrome P450 (CYP) 3A4 system, coadministration of telithromycin with drugs metabolized by this pathway may require dose adjustments (e.g. with benzodiazepines) or a temporary hiatus in the use of the coadministered drug (e.g. HMG-CoA reductase inhibitors) metabolized by CYP3A4. Telithromycin may potentiate the effects of oral anticoagulants; careful monitoring is recommended in patients receiving telithromycin and oral anticoagulants simultaneously.Although serious and sometimes fatal events have occurred in patients receiving telithromycin therapy, current data indicate that telithromycin offers an acceptable benefit risk ratio in the treatment of mild to moderate CAP.     

Melagatran and ximelagatran: new drug. No real simplification of anticoagulant therapy

(1) The reference drug for prophylaxis against venous thromboembolism after hip or knee replacement surgery is a low-molecular-weight heparin (LMWH), given subcutaneously for 1 to 5 weeks. Vitamin K antagonists, including warfarin, have similar risk-benefit balances. (2) Subcutaneous melagatran and its oral metabolic precursor ximelagatran have recently been granted marketing authorisation in France for use as prophylaxis after hip or knee replacement surgery. Melagatran, unlike LMWH, is a specific thrombin inhibitor. (3) There are four randomised double-blind trials in more than 9000 patients comparing these agents with a LMWH (enoxaparin in three trials, dalteparin in one). Melagatran was given subcutaneously for one or two days before being replaced with ximelagatran (as soon as oral feeding was possible) for 6 to 9 days. These trials showed no advantage of melagatran-ximelagatran in terms of clinical endpoints such as symptomatic deep venous thrombosis, pulmonary embolism, and death from all causes. (4) Three randomised double-blind trials have compared ximelagatran with warfarin in more than 5000 patients. Treatment lasted 7 to 12 days. Ximelagatran was no better than warfarin when assessed using clinical endpoints. (5) In these trials melagatran-ximelagatran did not increase the risk of bleeding compared with LMWH or warfarin. (6) Melagatran-ximelagatran can cause an increase in serum transaminase activity, and is contraindicated if pretreatment serum transaminase activity is more than twice the upper limit of normal. (7) Trials versus warfarin showed a higher risk of myocardial infarction in patients taking ximelagatran (0.7% versus 0.16%). (8) There are few data on the patient subgroups most likely to receive melagatran-ximelagatran, namely patients over 75, underweight and overweight patients, and patients with renal failure. (9) There is currently no clotting test that allows the melagatran-ximelagatran dose regimen to be adjusted in patients who have an increased risk of adverse effects due to overdosing. There is no available antidote if overdose occurs. (10) Erythromycin increases melagatran bioavailability, thereby increasing the bleeding risk. Melagatran and ximelagatran must not be combined with other anticoagulants, thrombolytic agents or antiplatelet drugs because of a increased bleeding risk. (11) In practice, low-molecular-weight heparin remains the reference prophylactic treatment for venous thromboembolism after hip or knee replacement surgery.     

The pharmacokinetics of pioglitazone in patients with impaired renal function

AIMS: To evaluate the effect of renal impairment on the pharmacokinetics and safety of pioglitazone and its metabolites M-III and M-IV with impaired renal function and normal renal function. METHODS: In a phase-I, open-label, parallel-group study, six healthy subjects with normal renal function (creatinine clearance> 80 ml min-1), nine patients with moderate renal impairment (creatinine clearance 30-60 ml min-1) and 12 patients with severe renal impairment (creatinine clearance < 30 ml min-1) received single and multiple oral doses of pioglitazone 45 mg. The serum pharmacokinetic profiles of pioglitazone and its metabolites M-III and M-IV were assessed for the first and last dose administered (day 1 and day 12, respectively). RESULTS: Pharmacokinetic data revealed no significant accumulation of pioglitazone or its metabolites M-III and M-IV in patients with renal impairment. There was no significant difference in the pharmacokinetic profile of pioglitazone in subjects with normal and with moderately impaired renal function. After single oral doses, mean area under the concentration-time curve (AUC) values were decreased in patients with severe renal impairment compared with healthy subjects with normal renal function for pioglitazone (13 476 vs 17 387, P = 0.371; -23%; confidence interval (CI) -57, 38), M-III metabolite (13 394 vs 15 071, P = 0.841; -11%; CI -74, 194) and M-IV metabolite (27 991 vs 49 856, P = 0.006; -44%; CI -62, -17). After repeated oral doses of pioglitazone, mean AUC values (microg.h l-1) were decreased in patients with severe renal impairment compared with healthy subjects with normal renal function for pioglitazone (8744 vs 14,565, P = 0.004; -40%; CI -57, -16), M-III (3991 vs 7,289, P = 0.0009; -45%; CI -60, -25) and M-IV (21 080 vs 25 706, P = 0.181; -18%; CI 39, 10). The tolerability and safety profile of pioglitazone was comparable between groups. CONCLUSIONS: Pioglitazone was well tolerated in patients with varying degrees of renal impairment. Although mean serum concentrations of pioglitazone and its metabolites are increased in patients with severe renal impairment, adjustment of starting and maintenance doses in these patients is probably unwarranted.     

肿瘤相关性血栓栓塞症的研究进展

恶性肿瘤是静脉血栓栓塞症（VTE）的高危因素之一。随着肿瘤患者的数量增加,静脉血栓栓塞的发病率也呈上升趋势。因为血栓形成的病理生理是多因素的,迄今为止没有一种适合所有预防和治疗的药物。大多数的临床指南推荐低分子量肝素（LMWHs）用于癌症患者住院期间VTE的预防和治疗,不推荐对门诊癌症患者进行常规血栓预防。在安全性和有效性得到充分的证实之前,不推荐对恶性肿瘤静脉血栓的患者使用新型口服抗凝药。这篇综述系统阐述了肿瘤合并VTE的流行病学、风险评估、预防和治疗以及新型抗凝药的研究状况。     

Tinzaparin in the treatment of venous thromboembolism

Low molecular weight heparin (LMWH) has been widely used for the initial treatment of patients presenting with venous thromboembolism. The LMWH, tinzaparin, has been shown in randomised clinical trials to be as effective and safe as unfractionated heparin for the initial treatment of venous thromboembolism and in clinical trials, it has been used in place of warfarin for the long-term treatment of deep vein thrombosis. Tinzaparin can safely be given to patients with significant renal impairment (creatinine clearance of ≥ 20 ml/min) and the dose of tinzaparin does not need to be altered in patients with a body mass index of > 25.