Risk-benefit assessment of anticoagulant therapy

Thromboembolic disease is a common medical condition which, if untreated, carries a significant risk of morbidity and mortality. Treatment with anticoagulant therapy, while clearly beneficial, may expose patients to potentially serious side effects. A thoughtful risk-benefit assessment is therefore crucial before initiating therapy. Thromboembolic disease involves syndromes of both the venous and arterial circulation, and its pathogenesis is best understood by considering the elements of Virchow's Triad. This model defines the risk factors for venous thromboembolism and allows us to classify surgical and medical patients into low, moderate and high risk groups. Similar analysis allows risk assessment for patients prone to cardiogenic embolism resulting from nonvalvular atrial fibrillation, ischaemic heart disease, rheumatic heart disease and valvular prostheses. All anticoagulant therapy is prophylactic. Primary prophylaxis involves instituting anticoagulant therapy in patients at risk, before thromboembolism occurs, while secondary prophylaxis involves treating patients with established disease. The 2 major anticoagulants, heparin and warfarin, differ in their mechanism of action, mode of administration and methods of monitoring. Either may be used as primary or secondary prophylaxis. Heparin, because it acts immediately, is the drug of choice for the short term treatment of thromboembolic disease. Warfarin is the drug of choice for long term oral maintenance therapy. The principal complication of heparin therapy is haemorrhage, although thrombocytopenia and osteoporosis may also occur; the complications of warfarin include haemorrhage and skin necrosis. The risks of complications vary with the underlying thromboembolic disease. After the benefits of treatment are weighed against the risks of complications, recommendations for therapy can be established. The use of anticoagulants in pregnancy is especially complex. Here heparin is probably the preferred agent since, unlike warfarin, it does not cross the placenta and is nonteratogenic.     

Secondary prevention of stroke in patients with nonvalvular atrial fibrillation: optimal intensity of anticoagulation

Nonvalvular atrial fibrillation (NVAF) is frequently seen in elderly people and has become a main cause of cardioembolic stroke. The efficacy of anticoagulation for primary prevention of stroke or transient ischaemic attacks (TIAs) in patients with NVAF has been established by prospective, randomised and controlled trials. Warfarin decreased the frequency of all strokes by 68% and the rate of the combined outcome of stroke, systemic embolism or death by 48%. Anticoagulation with warfarin using international normalised ratios (INRs) ranging from 2.0 to 3.0 is recommended for patients with NVAF, who have any of the risk factors identified by the Atrial Fibrillation Investigators (AFI) [previous stroke or TIA, history of hypertension, diabetes mellitus, advanced age (> or = 65 years old), congestive heart failure and coronary artery disease], the American College of Chest Physicians (ACCP) [increased age (> 75 years old), prior stroke, hypertension and heart failure], or the Stroke Prevention in Atrial Fibrillation (SPAF) investigators [women > 75 years old, prior stroke, systolic blood pressure > 160mm Hg, recent heart failure, and fractional shortening < 25% on echocardiography]. For the secondary prevention of stroke, the efficacy of adjusted-dose warfarin therapy has been demonstrated by 2 major randomised trials. SPAF III (INR 2.0 to 3.0) demonstrated a lower incidence of ischaemic stroke or systemic embolism (3.4 %/year) compared with low fixed-dose warfarin plus aspirin (acetylsalicylic acid) [11.9%]. The European Atrial Fibrillation Trial [EAFT] (INR 2.5 to 4.0) showed a lower incidence of all stroke (4.0 %/year) with adjusted-dose warfarin compared with placebo (12.0 %/year). The incidence of major bleeding in the adjusted-dose warfarin group in SPAF III and EAFT was 2.4 and 2.8 %/year, respectively. EAFT incidence rates for the occurrence of a first ischaemic or haemorrhagic complication analysed by INR range indicated that the rate was lowest at INRs of 2.0 to 2.9, and higher with INRs of 3.0 to 3.9. Therefore, the optimal intensity of anticoagulation for prevention of recurrent stroke seems to be an INR of between 2.0 and 3.0, as for primary prevention. Retrospective and prospective studies from Japan reported that in the elderly, haemorrhagic complications occur frequently with INRs above 2.6 and major ischaemic events cannot be prevented at INRs below 1.6. Therefore, an INR target between 1.6 and 2.6 may be an alternative for secondary prevention of stroke in elderly patients with NVAF who have a potential risk of bleeding, to avoid both major ischaemic and haemorrhagic events. Antiplatelets may be administered in patients who are unable to manage taking warfarin properly or who have a high risk of falling and subsequently sustaining a head injury, although the efficacy of antiplatelets for secondary prevention of stroke in NVAF has not yet been established.     

Resuming anticoagulant therapy after intracerebral bleeding

The clinical benefit of resuming anticoagulant treatment after an anticoagulants-associated intracranial hemorrhage (ICH) is debated. No randomized trial has been conducted on this particular clinical issue. The risk of ICH recurrence from resuming anticoagulant therapy is expected to be higher after index lobar than deep ICH and in patients with not amendable risk factors for ICH. Retrospective studies have recently shown improved survival with resumption of treatment after index anticoagulants-associated ICH. Based on these evidences and on the risk for thromboembolic events without anticoagulant treatment, resumption of anticoagulation should be considered in all patients with mechanical heart valve prosthesis and in those with amendable risk factors for anticoagulants-associated ICH. Resumption with direct oral anticoagulants appears a reasonable option for non-valvular atrial fibrillation (NVAF) patients at moderate to high thromboembolic risk after deep ICH and for selected NVAF patients at high thromboembolic risk after lobar ICH. For VTE patients at high risk for recurrence, resumption of anticoagulation or insertion of vena cava filter should be tailored on the estimated risk for ICH recurrence.     

Patient Self-Monitoring of Oral Anticoagulant Therapy

Coumarin derivatives are widely used oral anticoagulants for patients with chronic atrial fibrillation, venous thromboembolism, valvular heart disease, myocardial infarction or a mechanical prosthetic heart valve. Because of the narrow therapeutic window associated with coumarins and the potential for drug interactions, frequent monitoring of anticoagulation is required to maintain the International Normalized Ratio (INR) between 2.0 to 3.5 for most clinical indications. Monitoring of oral anticoagulant therapy is placing a considerable burden on healthcare providers because many patients require life-long treatment with coumarins, and because of an increasing number of elderly patients with conditions that are treated with coumarins. A novel approach that might, in part, address this healthcare need is patient self-monitoring of anticoagulation with a portable coagulometer. Several cohort studies and randomized controlled trials have found that anticoagulation self-monitoring is as good as, or better than, conventional monitoring in a specialized anticoagulation clinic or by a general practitioner. The advantages of anticoagulation self-monitoring include reduced patient inconvenience relating to anticoagulation clinic visits and laboratory monitoring of warfarin therapy, and fewer INR levels outside the therapeutic INR range if INR measurements are preformed more frequently with anticoagulation self-monitoring. Thus, anticoagulation self-monitoring has the potential to reduce the incidence of thromboembolic and bleeding episodes in patients who are receiving long term oral anticoagulant therapy. The potential drawbacks of anticoagulation self-monitoring include the costs of the portable coagulometer. Additionally, self-monitoring is limited to patients who have the cognitive and physical capabilities to perform the technique required for the portable coagulometer.     

Anticoagulant therapy in very old patients

Older patients are less likely than younger patients to receive anticoagulation and are more likely to be underanticoagulated. Although the use of warfarin in the elderly has been increasing, fewer than half of eligible patients take warfarin. Evidence suggests that stroke recurrence in patients on oral anticoagulation is mainly ischemic, and hemorrhagic complications that derive from oral anticoagulation would be related to overdosing. Several risk factors for developing hemorrhagic complications have been described, and clinical criteria have been designed to help clinicians in decision-making concerning the start of anticoagulation treatment. Finally, given the promising results of recent studies on new anticoagulant drugs, it is possible that vitamin K antagonists will be replaced in the coming years.     

Stroke prevention in atrial fibrillation: putting the guidelines into practice

Atrial fibrillation confers a 5-fold increase in risk of stroke. A number of drugs aimed at reducing this risk have been tested in randomized controlled trials. These include antiplatelet agents (singly and in combination); anticoagulants, including vitamin K antagonists and direct thrombin inhibitors; and anticoagulants with antiplatelet agents. Guidelines recommend that the choice of therapy should be determined by an assessment of underlying risk of stroke, with antiplatelet agents being indicated for people at low risk of stroke and anticoagulants for those at higher risk. The treatment decision is complicated by considerations of haemorrhage risk, with factors that increase risk of stroke also associated with increased risk of haemorrhage. Evidence from recent studies confirms that patients at high risk of stroke should be treated with anticoagulants, including elderly patients, provided that good international normalized ratio (INR) control can be maintained. Newer agents may enable a higher proportion of patients at high risk of stroke to be treated with anticoagulants than is currently the case. Decision making about people at moderate risk of stroke is less clear cut, and a choice of either an antiplatelet agent or an anticoagulant can be justified. For people at low risk of stroke, anticoagulation is not indicated.     

Stroke risk reduction outweighed bleeding risk increase from vitamin K antagonist treatment among nonvalvular atrial fibrillation patients with high stroke risk and low bleeding risk

Objective: Warfarin is widely used for stroke prevention in patients with nonvalvular atrial fibrillation (NVAF). We compared the rates of stroke and major bleeding in NVAF patients with a high stroke risk and low bleeding risk profile during warfarin treated (W+) and warfarin untreated (W?) periods.

Method: Insurance claims from six commercial, Medicaid or Medicare databases were analyzed from 2000 to 2014. NVAF patients treated with warfarin, with a CHADS₂/CHA₂DS₂-VASc score ≥2, and an ATRIA score ≤3 at baseline were identified. Incidence rate ratios (IRRs) of stroke and major bleeding were calculated for W?+?versus W? episodes of person-time, as well as for first 30 days versus beyond 30 days of W?+?episodes.

Results: Among 316,145 patients, anticoagulant prophylaxis with warfarin significantly reduced stroke risk, with IRRs ranging from 0.48 (95% CI: 0.46–0.51) to 0.80 (95% CI: 0.70–0.91), and increased major bleeding risk, with IRRs ranging from 1.13 (95% CI: 1.10–1.15) to 1.95 (95% CI: 1.10–3.45). Stroke and major bleeding rates were higher during the first 30 days of W?+?than beyond.

Conclusion: In NVAF patients at high risk for stroke and low risk for bleeding, our data confirm the effectiveness of anticoagulation for stroke prevention. The decrease in stroke risk of anticoagulation may outweigh the risk of major bleeding events, particularly among elderly patients. Potential risks of warfarin during initiation warrant attention, especially among patients who stop and start therapy repeatedly.     

中国非瓣膜性心房颤动患者华法林使用不足的相关因素分析

目的:评估中国首发缺血性卒中或短暂性脑缺血发作(TIA)的已知非瓣膜性心房颤动(NVAF)患者华法林的使用情况及使用不足的相关因素。方法:从中国国家卒中登记数据库(CNSR)中连续筛选首发缺血性卒中或TIA的NVAF患者,筛选已知心房颤动和新发心房颤动患者,评估华法林在适合抗凝治疗的已知心房颤动患者中的使用比例。采用多变量logistic回归模型评估华法林使用不足的相关因素。结果:在筛选出的11 080例首发缺血性卒中或TIA患者中,有996例(9.7%)患者存在NVAF且无抗凝治疗禁忌症,其中有592例既往已知存在心房颤动。在这些患者中,只有96例(16.2%)发病前服用了华法林,496例(83.8%)发病前未服用华法林。在服用华法林的患者中,只有1例患者入院时的国际标准化比值(INR)在治疗范围(2.0～3.0)内。依据CHADS2卒中风险评分,在卒中发生前的低危心房颤动患者中,有近20.2%的患者服用了华法林,而在中危及高危患者中,华法林的服用比例分别只有15.2%和16.4%。年老的和既往存在冠心病病史的患者服用华法林的可能性较小,而发病前服用抗血小板药物的患者更有可能服用华法林。结论:CNSR中首发缺血性卒中或TIA的NVAF患者中,适宜抗凝治疗的患者存在严重的华法林使用不足,即使接受抗凝治疗,达标率也极低。如果发病前给予合适的抗凝治疗并监测,许多由心房颤动导致的卒中和TIA就可避免。     

Dietary implications for patients receiving long-term oral anticoagulation therapy for treatment and prevention of thromboembolic disease

Introduction: The effectiveness of oral anticoagulation therapy with warfarin (a vitamin K antagonist) in the treatment of thromboembolic disease, including stroke prophylaxis in patients with atrial fibrillation is well recognised. However, warfarin has a narrow therapeutic window and an unpredictable anticoagulation response, which make it difficult to achieve and maintain optimal anticoagulation. Various dietary factors, including sudden changes in eating patterns, can significantly alter anticoagulation control, thereby potentially exposing patients to the risk of bleeding or thromboembolic complications. Dietary vitamin K intake is a particularly important factor, given the mechanism of action of warfarin.

Areas covered: In this article, we cover the sources of vitamin K and their potential effect of dietary vitamin K on anticoagulation response to warfarin. We also discuss the results of studies on the effect of vitamin K supplementation on anticoagulation stability.

Expert commentary: A stable dietary vitamin K, promoted by daily oral vitamin K supplementation, can improve anticoagulation stability in patients on warfarin therapy. There is experimental evidence in animals that dietary vitamin K affects anticoagulation response to the direct thrombin inhibitor, ximelagatran. Whether dietary vitamin K affects anticoagulation response to the currently licensed direct oral anticoagulants (DOACs) in man remains to be investigated.     

Haemorrhagic complications of vitamin k antagonists in the elderly: risk factors and management

In patients >75 years of age, the two main indications for oral anticoagulant therapy with vitamin K antagonists (VKAs) are treatment of venous thromboembolic disease and prevention of systemic embolism in patients with nonvalvular atrial fibrillation. In both indications, a target International Normalized Ratio of 2.5 (range 2.0-3.0) is recommended. Bleeding is the adverse effect feared by physicians that most limits the use of VKAs in older frail patients. In this paper, we discuss (i) the risk of VKA-related bleeding with advancing age; (ii) the severity of bleeding complications and particularly the risk of intracranial haemorrhage in older patients; (iii) the risk factors for bleeding related to patient characteristics; and (iv) the risk factors or determinants for bleeding related to treatment variables (warfarin induction and maintenance administration, instability of anticoagulation, poor compliance and patient's education level, and concomitant use of drugs). Avoiding over-anticoagulation and/or reducing periods of overdosing in the course of oral anticoagulant treatment with tailored monitoring may help to minimise the risk of bleeding in older patients.     

华法林与阿司匹林用于老年阵发性房颤患者抗凝治疗临床对比研究

目的对比华法林与阿司匹林用于老年阵发性房颤（NVAF）患者抗凝治疗临床效果。方法总结在我院治疗的NVAF患者46例资料,按照患者用药种类不同进行分组：选择华法林进行治疗的23例资料为治疗一组,选择阿司匹林进行治疗的23例资料为治疗二组,治疗后按照文中统计指标进行统计,最后统计学方法比较组间疗效差异性。结果治疗一组患者有1例（4.3%）发生脑栓塞,有2例患者（8.7%）有出血现象,数据结果与治疗二组无统计学差异（P〉0.05）。结论华法林与阿司匹林用于NVAF患者抗凝治疗临床疗效无统计学差异性,但阿司匹林用药更加安全、方便且具有价格优势。     

房颤合并肝硬化患者的口服抗凝药物选择及抗栓策略研究

目的 探讨房颤合并肝硬化患者临床治疗中口服抗凝药物的选择及安全性。方法 在1例房颤合并乙型肝炎肝硬化患者房间隔修补术后抗栓方案的制定中,通过查阅指南和文献,总结、分析房颤合并肝硬化患者口服抗凝药物的疗效及安全性评价现状。结果 通过综合评估患者情况,停用华法林,予达比加群酯110 mg,bid,联合氯吡格雷75 mg,qd抗栓6个月,之后达比加群酯110 mg,bid长期抗凝治疗。结论 房颤合并肝硬化患者抗栓治疗,应充分评估血栓及出血风险,制定个体化的抗栓策略。房颤合并Child-Pugh A级肝硬化,新型口服抗凝药均可使用;合并Child-Pugh C级肝硬化,口服抗凝剂均不建议使用;合并Child-Pugh B级肝硬化,出血风险高的患者长期抗凝治疗中可选用小剂量达比加群酯。     

A rapid evidence assessment of bleed-related healthcare resource utilization in publications reporting the use of direct oral anticoagulants for non-valvular atrial fibrillation

Objective: Non-valvular atrial fibrillation (NVAF), a common cardiac arrhythmia, is associated with high morbidity and carries a substantial economic burden. Historically, vitamin K antagonists (VKAs; e.g. warfarin) have been used for therapy of NVAF, but recently several direct oral anticoagulants (DOACs) have been approved for prevention of stroke in patients with NVAF. This review summarizes the real-world evidence (RWE) for healthcare resource utilization (HRU) in patients receiving oral anticoagulants (VKAs and/or DOACs) for therapy of NVAF.

Methods: A PRISMA-compliant literature search assessed Medline^® and Embase^® databases from 1 January 2011 to 4 May 2017, and the National Health Service Economic Evaluation Database from 1 January 2011 to 31 December 2015. Publications were included if they reported observational data from real-world use of one or more anticoagulant therapies. Outcomes of interest included hospitalizations, length of stay (LOS), mortality and costs.

Results: Twenty-eight publications were included. Apixaban and dabigatran were associated with fewer bleed-related hospitalizations than warfarin. Bleed-related LOS were generally longer for warfarin than for DOACs. Bleed-related treatment costs were lower for patients receiving apixaban or receiving dabigatran than patients receiving rivaroxaban or receiving warfarin. Bleed-related mortality in patients receiving oral anticoagulation for treatment of NVAF were low across all DOACs and warfarin.

Conclusions: The limited available evidence for HRU burden among patients receiving oral anticoagulation for NVAF suggests that DOACs (particularly apixaban and dabigatran) offer some degree of benefit in terms of HRU outcomes, compared with warfarin. Further work is required to understand HRU outcomes in patients receiving DOACs.     

华法林抗凝治疗质量评价及影响因素分析

目的：对华法林抗凝治疗质量的评价和影响因素进行分析,为进一步加强对华法林的管理而提供数据支持。方法：收集符合纳入标准的85例服用华法林患者的相关临床资料,计算每位患者抗凝治疗范围内时间百分比[the percentage time in therapeutic International Norrnalised Ratio （INR） range,TTR]评价抗凝控制质量,并对可能影响TTR的因素进行分析。结果：85例患者的TTR为（50.45±28.52）%,抗凝质量较好（TTR ≥ 60%）的患者仅占40%。对可能影响TTR的因素进行单因素回归分析,结果显示年龄、是否同服抗血小板药物、住院期间是否有抗凝临床药师驻科,差异具有显著性（P<0.05）;其他因素如是否进行华法林基因检测,是否合并高血压、糖尿病、肝/肾功能不全、脑梗塞、外周血管疾病,是否合用胺碘酮、中药汤剂等,差异无显著性。结论：本研究显示年龄、是否同服抗血小板药物、住院期间是否有抗凝临床药师驻科是影响华法林抗凝控制质量的相关因素,鉴于本研究60%的患者抗凝质量不佳,需要进一步加强华法林的抗凝管理。     

Individualisation of oral anticoagulant therapy.

The hepatic synthesis of vitamin K dependent coagulation factors is modified by oral anticoagulant drugs, resulting in the release of functionally deficient coagulation factors into the circulation and consequently anticoagulation. Since their introduction into clinical medicine over 30 years ago, both clinical and scientific evidence has demonstrated the value of oral anticoagulants in the treatment and prophylaxis of venous thrombosis. In the treatment of arterial disease, however, both the indications for and usefulness of oral anticoagulants remain very much in doubt despite their widespread use in the 1950s and 1960s and in numerous clinical trials. The initiation and continuation of oral anticoagulant therapy is a co-operative venture involving the patient, the clinician and the laboratory. The clinician must have a thorough knowledge of the indications for and contraindications to the use of these drugs, and regular, accurate laboratory control is essential if haemorrhage, the major side effect, is to be avoided or reduced to a minimum. The patient must bear the responsibility for regular clinic attendance, abstinence from proprietary medications, and must immediately seek medical advice if any sign of haemorrhage occurs.     

Aspirin and heparin in acute ischaemic stroke in older patients.

Over four-fifths of all strokes are due to thrombotic or embolic occlusion of cerebral arteries. There is a strong rationale for considering antithrombotic therapy for the treatment of patients with acute ischaemic stroke. Antiplatelet therapy with 150 to 300 mg of aspirin (acetylsalicylic acid) started within the first 48 hours of an ischaemic stroke improves patient outcome in the short and long term, with a low risk of adverse effects. Anticoagulants such as heparin may reduce the risk of developing deep venous thrombosis and pulmonary embolism in patients with stroke, but randomised controlled trials have demonstrated a significant and dose-dependent risk of intracranial haemorrhage. The routine use of parenteral anticoagulants, including unfractionated heparin, low-molecular-weight heparins and heparinoids in the acute phase of ischaemic stroke is not associated with any net short or long term benefit. Aspirin is, therefore, the antithrombotic drug of choice in the treatment of acute ischaemic stroke.     

Guidelines for stroke prevention in patients with atrial fibrillation

Atrial fibrillation (AF) is a major independent risk factor for stroke. AF is most commonly associated with nonvalvular cardiovascular disease and is especially frequent among the elderly. The annual risk for stroke in patients with AF is approximately 5% with a wide range depending on the presence of additional risk factors. For patients who cannot successfully be converted and maintained in normal sinus rhythm (NSR), antithrombotic therapy is an effective method for preventing stroke. The 2 drugs which are indicated for stroke prophylaxis in patients with AF are warfarin and aspirin. For primary prevention, warfarin reduces the risk of stroke approximately 68%. Aspirin therapy is less effective, resulting in a 20 to 30% risk reduction. Combination therapy with aspirin and low intensity warfarin adjusted to an International Normalised Ratio (INR) of 1.2 to 1.5 has not been shown to be superior to standard intensity warfarin with a target INR of 2.0 to 3.0. In patients with AF and a prior history of stroke or transient ischaemic attack (TIA), the absolute risk reduction with warfarin is even greater because of the high risk of stroke in this population. In contrast, aspirin has not been shown to significantly reduce the risk of stroke in patients with AF when used for secondary prevention. When appropriately managed, warfarin is associated with a low risk of major bleeding. In controlled trials of highly selected patients, the annual rate of intracranial haemorrhage (ICH) with warfarin was approximately 0.3%. Studies have shown that specialty anticoagulation clinics can achieve similar low rates of major bleeding. However, these results cannot be extrapolated to the general population. Factors which have been identified as predictors of bleeding include advanced age, number of medications and most importantly, the intensity of anticoagulation. INR values above 4.0 have been associated with an increased risk of major bleeding while values below 2.0 have been associated with thrombosis. Slow careful dosage titration, regular laboratory monitoring and patient education can substantially reduce the risk of complications. In patients with AF, antithrombotic therapy has been shown to be cost effective. For high risk patients, warfarin is the most cost-effective therapy, provided the risks for bleeding are minimised. In contrast, aspirin is the most cost-effective agent for low risk patients. Current practice guidelines for stroke prophylaxis recommend warfarin (target INR 2.5: range 2.0 to 3.0) for AF patients at high risk for stroke including those over 75 years of age or younger patients with additional risk factors. Aspirin should be reserved for low risk patients or those unable to take warfarin. Although these recommendations are strongly supported by the clinical trial evidence, studies show that many patients are not receiving appropriate antithrombotic therapy. In particular, warfarin is underutilised in high risk elderly patients. Additional studies are needed to identify barriers that prevent implementation of the clinical trial findings into clinical practice.     

Management of venous thromboembolism in the elderly

In this review the authors discuss the use of oral and parenteral anticoagulants for the prevention and treatment of venous thromboembolism (VTE) in the elderly. The use of anticoagulant agents in VTE prophylaxis and treatment in the elderly is complicated by an increase with age in the presence of multiple risk factors and co-morbidities that may increase the risk of both VTE and bleeding. Age itself is identified as an independent risk factor for thromboembolism. VTE is underdiagnosed in the elderly population, and routine prophylaxis frequently falls short of the levels required according to level of risk. Although appropriate anticoagulation of at-risk patients offers a means of reducing the significant VTE burden in this population, concerns have been raised over the use of anticoagulants in a patient group in whom multiple risk factors are common. Bleeding in the elderly can be exacerbated by reduced renal clearance and hypersensitivity to oral anticoagulants that may lead to over-anticoagulation. Although bleeding due to anticoagulant therapy is a serious issue in the elderly, it is often overemphasized, given the therapeutic value otherwise observed in treating this patient group. Warfarin is still used in VTE prophylaxis after orthopaedic surgery and for long-term VTE treatment. Unfractionated and low-molecular-weight heparins (LMWHs) have been shown to be safe and effective in the prophylaxis of VTE, and are now being shown to be as effective as warfarin in the initial and long-term treatment of VTE. LMWHs confer the advantage over unfractionated heparin of subcutaneous once-daily administration with no requirement for laboratory monitoring of their anticoagulant effect, which allows for the convenience of outpatient therapy. New anticoagulants that may be of potential benefit in this patient population include fondaparinux sodium, but clinical experience of this drug in the elderly remains limited.     

Optimum use of anticoagulants in pregnancy

Pregnant women pose special problems when deciding upon optimal anticoagulant therapy. Heparin does not cross the placenta and is probably safe for the fetus. Long term heparin therapy is occasionally associated with maternal haemorrhage and rarely with symptomatic osteoporosis. Coumarin derivatives, however, cross the placenta and are potentially teratogenic, particularly in the first trimester. Neonatal infant haemorrhage is a possibility if warfarin is administered to the pregnant mother near term. For the prevention and treatment of venous thromboembolism, heparin is the anticoagulant of choice since its safety and efficacy are well established. For the prevention of systemic embolism associated with prosthetic heart valves or valvular heart disease, the efficacy of heparin has not been established. Nevertheless, 12-hourly subcutaneous heparin in doses to prolong a mid-interval activated partial thromboplastin time (aPTT) to 1.5 times control is likely to be effective and safe. An alternative is to use heparin for the first trimester, change to warfarin until the middle of the third trimester, then to restart heparin until term. However, before warfarin is used in pregnant patients, the risks should be carefully explained to the patient to help avoid medicolegal problems. Warfarin can be safely used postpartum by the breast-feeding mother.