S . SCHULMAN Coagulation Unit, Division of Hematology, Department of Medicine, Karolinska Hospital, Sweden To cite this article: Schulman S. Unresolved issues in anticoagulant therapy. J Thromb Haemost 2003; 1: 1464-70. # 2003 International Society on Thrombosis and Haemostasis Correspondence: Dr Sam Schulman, Coagulation Unit, Karolinska Hospital, S-171 76 Stockholm, Sweden. Tel.: þ468 51773373; fax: þ468 51775084; e-mail: sam.schulman@ks.se Summary. Large randomized clinical trials have clarified some issues of anticoagulation and have led to progress, such as outpatient treatment of acute deep vein thrombosis with lowmolecular-weight heparin. However, many uncertainties remainaand are reviewed here. When should thrombolytic therapy be used, apart from patients in shock due to pulmonary embolism? How should low-molecular-weight heparin be used in patients with extreme obesity or renal failure? The optimal duration of anticoagulation after venous thromboembolism has been the subject of many debates. With the recognition of an increasing number of risk factors for recurrence, the picture becomes increasingly complex. Lower intensity of anticoagulation with vitamin K antagonists and novel anticoagulant drugs are possible alternatives in extended secondary prophylaxis. For stroke prophylaxis in non-valvular atrial fibrillation, there is a gray zone between the groups where there is a clear indication for aspirin or for vitamin K antagonists. Anticoagulation in connection with cardioversion raises questions regarding optimal postprocedure therapy. Fine tuning of prophylaxis against thromboembolism in patients with prosthetic heart valves requires more studies of subgroups, homogenous for position and type of valve as well as presence of atrial fibrillation. The management of these patients in case of surgical procedures has not been studied properly. Secondary prophylaxis after myocardial infarction may achieve the best effect with vitamin K antagonists at an INR of 2.0-2.5 in combination with low-dose aspirin, but is it really cost-effective? Finally, many controversies exist regarding anticoagulation during pregnancy. Keywords: atrial fibrillation, myocardial infarction, valve prosthesis, venous thromboembolism Substantial progress in the treatment of venous thromboembolism (VTE) has been achieved, mainly through a large number of randomized clinical trials over the past two decades. The advances in drug development have had limited clinical implications, with low-molecular-weight heparin (LMWH) as the main exception. Major disadvantages of current therapeutic standards are the inability to eliminate existing thrombus as well as to obviate the risk of progression, the necessity of parenteral administration during the acute phase of therapy, the need for monitoring and frequent dose adjustments of oral anticoagulant therapy with vitamin K antagonists during secondary prophylaxis, the absence of oral anticoagulant therapy for the pregnant woman that is safe for the fetus, and the inherent risk of bleeding associated with any effective anticoagulant therapy. Novel anticoagulant agents may ameliorate some of these drawbacks. In addition, there are a number of unresolved issues, which have not yet been addressed appropriately but may be answered with properly designed studies. Other issues may be of such a complexity that the necessary clinical trials are not feasible to perform due to the large number of patients required (e.g. optimal duration of treatment in case of rare thrombophilic defects or combinations of defects, treatment of caval or visceral vein thrombosis) or for ethical reasons (e.g. duration of treatment after a life-threatening event). Several of these unresolved issues will be reviewed here. Initial phase of anticoagulation Treatment of pulmonary embolism The majority of patients with pulmonary embolism (PE) are probably still treated with unfractionated heparin, but it is gradually being replaced by LMWH based on the similar efficacy and safety in submassive PE [1]. In patients with massive PE and shock thrombolytic therapy appears essential [2]. For the patients with right ventricular dysfunction but stable hemodynamics, thrombolytic therapy may be a better choice than heparin to reduce in-hospital mortality and the need for additional procedures [3,4]. However, in a recent study on patients with submassive PE and pulmonary hypertension or right ventricular dysfunction, mortality was not lower in the group randomized to alteplase and heparin (3.4%) compared with those with heparin alone (2.2%) [5]. On the other hand, among patients treated with thrombolysis there were less events with escalation of therapy, but it can obviously be argued that it is better to limit this escalation of therapy to some 20% of the patients than to give all of them thrombolytic therapy. A better selection of high-risk subgroups for thrombolytic therapy is desirable for future trials, as well as health economic analyses of the two treatment regimens. Treatment of deep vein thrombosis In deep vein thrombosis (DVT) thrombolytic therapy is rarely used, since the benefit is avoidance of disabling post-thrombotic venous insufficiency rather than of a fatal outcome, and the risk of hemorrhage includes both crippling intracranial bleeding and fatal bleeding. The duration of thrombolytic therapy needs to be longer in DVT (many hours to days) than in PE (2 h), which most likely increases the risk of hemorrhage. It is of note that the intracranial and/or fatal bleeding complications have been described in patients 44-66 years old [6] or 55-96 years old [7], with an increasing incidence among the older patients on the conventional regimen [8], all of these with streptokinase. The same trend was seen among patients treated with urokinase or tissue plasminogen activator for PE [9]. Thus, it is possible that if only patients less than 40 years of age with extensive DVT were selected for thrombolytic therapy, an acceptable risk/benefit ratio would be achieved. It is also these patients, who have the longest expected survival, that should benefit the most from a restored venous circulation, but this should be studied further. Obese patients For the vast majority of these patients the acute treatment is with LMWH, preferably as outpatients. A few subgroups of patients have been excluded from or severely under-represented in the large trials with this drug, and uncertainty therefore exists regarding dosing in those situations. In obese patients the question is whether the dose should be increased linearly with the weight or 'capped' at a maximum allowable dose. Studies with dalteparin on very obese patients with VTE [10] or with tinzaparin on obese but otherwise healthy subjects [11] indicated that body mass did not have a significant influence on the response to the treatment, measured as anti-factor Xa (FXa) levels. Another study showed that the pharmacokinetics of dalteparin were better correlated to the adjusted body weight than to the total body weight [12]. Finally, in non-obese and obese subjects receiving nadroparin according to body weight, the anti-FXa activity was 1.4 times greater among the latter [13]. Whether these discrepant results depend on differences in pharmacokinetic properties between the LMWH [14] or have occurred by chance remains to be determined. Renal failure Similarly, uncertainty prevails regarding optimal dosing in patients with renal failure. In 200 elderly patients with mild renal failure and a creatinine clearance above 20mL min_1 (mean 51.2mLmin_1), the standard dose of tinzaparin -175 IU kg_1 once daily - appeared safe [15]. However, in patients with end-stage renal disease a pharmacokinetic study with tinzaparin 75 IU kg_1 demonstrated that anti-FXa-clearance was reduced by 28% compared with subjects with normal renal function [16]. In a simulation with regular therapeutic doses of enoxaparin (1 mg kg_1 twice daily or 1.5 mg kg_1 once daily), based on a single-dose pharmacokinetic study in patients with end-stage renal disease, it appeared that steady-state concentrations would remain within the therapeutic range, obviating the need for dosing adjustments in these patients [17]. Until more information is available, especially in patients with severe renal failure, it is recommended to monitor the anti-FXa activity periodically to detect possible accumulation of LMWH. Anti-FXa analysis On the other hand, there is much controversy as to the appropriateness of the anti-FXa assay and also what it represents clinically [18]. The predictive value of high anti-FXa levels for bleeding as well as low levels for occurrence or progression of thrombosis is poor, in prophylaxis as well as in treatment. Increased risk of bleeding In patients with an increased risk of bleeding it may be considered preferable to treat with LMWH, in view of the lower risk of bleeding compared with unfractionated heparin (1.3% vs. 2.1%; odds ratio 0.60 with a confidence interval of 0.39-0.93) in a meta-analysis of 14 studies [19]. However, only a single study showed a significant reduction of bleeding [20]. On the other hand, in case of a lifethreatening bleeding complication unfractionated heparin administered by continuous infusion can be discontinued immediately and is thereafter rapidly cleared from the circulation. LMWH, injected subcutaneously, will be released slowly and has a longer plasma half-life than unfractionated heparin. Furthermore, unfractionated heparin can be completely neutralized by protamine sulfate, whereas with LMWH only the antithrombin activity but not the anti-FXa activity is fully neutralized. This may be sufficient, as emonstrated in experimental models [21], but the clinical experience is very limited. It is therefore still unclear which treatment should be recommended in this group of patients. Anticoagulation for secondary prophylaxis Optimal duration of anticoagulation Initial randomized clinical trials on different lengths of treatment after venous thromboembolism failed to show any difference, mainly due to the fact that they were underpowered [22], leading to a tendency to shorten the cumbersome secondary prophylaxis with vitamin K antagonists. During the last decade several large studies have been published, and some of these have demonstrated a benefit of a longer duration of treatment [23-25], whereas others have not [26,27]. A metaanalysis by Pinede´ et al. has shown that longer duration - up to 6 months at least - is more effective than shorter duration without a significantly increased risk of bleeding [28]. A Cochrane review also supported longer duration for improved efficacy but identified a concomitant increase in the risk ofbleeding [29]. The latter was essentially due to the influence of two trials with a treatment duration of 27 months [25] and 48 months [30], respectively, in the long duration arm. For patients with a distal DVT, provoked by temporary risk factor(s), the treatment duration is not a problem, since 6 weeks is as effective as 6 months with very low recurrence rates Unresolved issues in anticoagulation therapy 1465 thereafter [31]. However, for all patients with PE or with DVT with proximal extension, or which were provoked by an unknown or permanent risk factor, the risk of recurrence is higher. Whether 3 months would be as effective as 6 months has only been evaluated in a pilot study [32] and in a trial, which was underpowered to demonstrate equality [27]. The rapid accumulation of recurrences after discontinuation in the 3-month group in another trial [25] may indicate that this is inadequate for idiopathic (unprovoked) VTE, but definite proof for or against 3 months is still lacking. Extension of anticoagulation beyond 6 months is a doubleedged sword. The rate of recurrence during the first year after discontinuation of treatment in patients with idiopathic VTE is about 10% with a duration of anticoagulation of 6, 12 or 27 months ([26] and unpublished data from [24,25]). Thus, the residual risk of developing recurrent VTE does not decreaseduring that time. In addition, the bleeding complications are starting to take their toll, at least after 2 years of treatment [29]. Hence, such a prolonged duration should be reserved for patients with a pronounced risk of recurrence. Risk factors for recurrence There are many suggestions as to how these patients should be selected: extension/severity of the thromboembolic event, the number of events, presence of certain congenital or acquired thrombophilic defects, and evidence of remaining hypercoagulation or of venous obstruction. According to a consensus, patients with a life-threatening event, including visceral or cerebral venous sinus thrombosis, in combination with any thrombophilic defect should receive anticoagulation indefinitely [33]. This is obviously based on feelings and ethical considerations rather than solid evidence. After what number of events should anticoagulation be continued indefinitely? Some do it after the second event, many reach this decision after the third, but neither alternative is evidence based. In the only study exclusively with patients suffering the second episode of VTE [30], 4 years of anticoagulation caused a trend to moremajor bleeding than 6 months of treatment, and patients in the latter group did not have significantly more recurrences than those with a single episode after the same duration of anticoagulation (in a parallel study) [24]. A second DVT in the ipsilateral leg may be very unfavorable for the venous circulation in that leg [34], and it then seems logical to give anticoagulants to protect from additional harm to those valves - but for how long? Thrombophilia Investigation of markers for thrombophilia may be of some help. The presence of congenital deficiency of antithrombin, of combined defects or of the homozygous form of FV Leiden is associated with a high risk of recurrence [35], and extension of anticoagulation is not very controversial. There is also evidence for such a strategy in patients with the antiphospholipid syndrome [25,36], supported by a lot of observational data. The impact of the heterozygous form of FV Leiden or the prothrombin G20210A polymorphism on the risk of recurrent thromboembolism seems insignificant compared with the risk incurred by having had one thromboembolic event already, and therefore extended anticoagulation is rarely recommended. Between these extremes are the congenital deficiencies of protein C and protein S as well as hyperhomocysteinemia and increased level of FVIII. Randomized trials on different lengths of secondary prophylaxis are ongoing for patients with these and some of the other thrombophilic abnormalities. With the increasing number of thrombophilic defects described, it becomes quite complex to perform adequate studies of each subgroup and to tailor the perfect treatment regimen for each individual. One possibility would be to employ a global test of hemostasis, such as the endogenous thrombin potential. The substantially simpler measurement of D-dimer had a negative predictive value of 95.6% at 3 months after withdrawal of anticoagulation [37]. It would obviously be preferable to have the support of a test before discontinuation of anticoagulation. Another possibility could be to offer continued secondary prophylaxis to patients with persistent venous obstruction on repeated ultrasonography [38,39]. However, impedance plethysmography did not prove to be of prognostic value in a similar setting [40]. Therefore, additional prospective and preferably randomized studies are desirable. Intensity of anticoagulation In VTE only one randomized clinical trial compared two intensities of anticoagulation with a vitamin K antagonist directly [41], and the lower intensity, corresponding to an INR of 2.0-2.5, was as effective as the higher intensity, and also safer - but only based on fewer minor hemorrhages. In addition, it would be important to document whether a slightly higher intensity would be favorable during the first few weeks after a thrombotic event, with a gradual redution as the activation of the coagulation calms down. Finally, it can be argued that the treatment should be aimed at a point value rather than a range, but there are no studies to support this. Alternatives for extended anticoagulation It is evidently desirable to extend the duration of anticoagulation beyond 6 months in several situations, including recurrent - at least ipsilateral - DVT, active cancer and some types of thrombophilia, but with full-dose vitamin K antagonists there is a price to pay with severe major hemorrhages after a few years of treatment [29]. A reasonable alternative would be to step down to a lower intensity after perhaps 6 months, when the activation of coagulation has abated and the thrombus has been recanalized and covered by intima. In a pilot study with vitamin K antagonist therapy aimed at an INR of 1.4-2.0 in 101 patients, albeit with few suffering from VTE, this appeared safe [42]. This regimen was recently reported as efficacious and safe for VTE in the PREVENT trial [43], and in a small study on patients with a high risk of recurrence, due to thrombophilia or other risk factors [44]. However, in the large randomized ELATE trial, comparing low intensity (INR 1.5-1.9) with regular intensity (INR 2.0-3.0) of anticoagulation in a similar population, the former regimenwasless effective [45].The annual rate of recurrent events was 1.9% and 0.6%, respectively (hazard ratio 3.3; 95% confidence interval 1.2-9.1), both of which are actually lowin comparison with the typical 10%during the first year after complete scontinuation of anticoa-gulation. Perhaps more disappointing was the complete lack of a benefit on the risk of major or minor hemorrhage: low intensity (0.96% and 3.9%peryear,respectively) vs.highintensity(0.93%and2.7%per year, respectively). On the other hand, this annual rate of major hemorrhage of 0.93% with conventional anticoagulation was exceptionally low, com-pared with the 3%_4% rate seen in other studies [25,26,30]. Other agents will possibly prove to be more suitable for extended prophylaxis. The long-acting entasaccharide and FXa inhibitor idraparinux is injected subcutaneously once a week. At a dose of 2.5 mg it gave significantly less bleeding than warfarin (P¼0.029) without any loss of efficacy in a phase II trial in patients after DVT in the PERSIST trial [46], and phase III trials will be performed during 2003. Yet another interesting alternative may be ximelagatran, an orally available prodrug of the direct and reversible thrombin inhibitor melagatran. In a placebo-controlled phase III trial (THRIVE III) 1223 patients were evaluated, and ximelagatran 24 mg twice daily for 18 months (after 6 months of conventional anticoagulation) reduced the number of recurrent events from 71 to 12 (hazard ratio 0.16; 95% CI 0.09-0.30) without any increase in the risk of major hemorrhage [47]. It may be argued that the low rates of major bleeding in both the ELATE [44] and the THRIVE III trial [47] could have been generated by natural exclusion of patients with the most pronounced bleeding tendency during the first 3-6 months of standard anticoagulation before randomization. This can be supported by the fact that in the indefinite anticoagulation group of the DURAC II study [30], four major hemorrhages occurred during the initial 3 months, two during the following 3 months and four during months 7-48 (unpublished data). The crucial test for the novel anticoagulants will therefore be the incidence of major bleeding during extended anticoagulation in unselected cohorts. Secondary prophylaxis in malignancy In a recent trial it was shown that patients with cancer and VTE may, with some advantage (regarding bleeding complications and without loss of thromboprophylactic effect), receive long-term LMWH (enoxaparin 1.5 mg kg_1 daily) instead of vitamin K antagonists [48]. The former regimen is preferable from many aspects such as absence of food or drug interactions, no need for laboratory monitoring and dose adjustments and easier management in case of invasive procedures, but the cost of the drug is much higher. A health economic analysis, taking into account all costs, would be of great value. Discontinuation of anticoagulation The question has often been raised of whether it would be more prudent to taper off the secondary prophylaxis in order to avoid the rebound phenomenon, which is easily identified with elevated laboratory markers of activation of coagulation (prothrombin fragment 1þ2, thrombin-antithrombin complex, D-dimer) but whose clinical significance is undetermined [49-51]. Anticoagulation in arterial disease Atrial fibrillation Anticoagulation with vitamin K antagonists reduces the annual risk of ischemic stroke from 4.5% to 1.4% [52], with a relative risk reduction compared with aspirin of 36% for all stroke and 46% for ischemic stroke [53]. For some subsets of patients the incidence of stroke is lower to the extent that the benefit of vitamin K antagonists disappears in comparison with aspirin. Although this information is derived from subgroup analyses, it seems safe to recommend aspirin alone for patients under 65 years of age without any concomitant risk factors. For those between 65 and 75 years with or without concomitant conditions that imply additional risk for stroke, the information becomes less clear, and individual assessments are necessary [54]. The same is true for very old patients for the reason that although the risk of ischemic stroke increases with age, it may at some point be outweighed by the risk of major hemorrhage, especially intracranial. This is certainly true for the elderly with a tendency to fall, and again we have to rely on individual assessments rather than evidence from clinical trials. Cardioversion There is agreement on patients with a duration of atrial fibrillation of more than 48 h to anticoagulate for 3 weeks before cardioversion; or else to anticoagulate, establish absence of atrial thrombi with transesophageal echocardiography and cardiovert immediately; and in either case to continue anticoagulation for 4weeks of maintained sinus rhythm [54]. Patients with atrial fibrillation of less than 48 h duration seem to have a very low risk of clinical thromboembolism (<1%) [55], and it is unclear to what extent periprocedural anticoagulation should be provided and for how long afterwards. Bioprosthetic heart valves Patients with bioprosthetic valve insertion in the mitral position have a high risk of thromboembolism and should receive anticoagulation for at least 3 months, perhaps longer in the case of a left atrial thrombus at time of surgery, and long-term in the case of atrial fibrillation or a history of systemic thromboembolism [54]. However, with the bioprosthetic valve in the aortic position in the absence of complicating risk factors, the issue of anticoagulation has not been resolved. Cerebral ischemic events occurred in 6.6% without anticoagulationand in 7.3% with heparin postoperatively and warfarin for 3 months in one trial [56], but in only 1.8% among patients with only initial heparin treatment for 2-3 weeks in another study [57]. Mechanical prosthetic heart valves The risk reduction for thromboembolic complications provided by vitamin K antagonists in comparison with anti-platelet therapy is 60_80% in these patients [58]. An INR range of 2.0-3.0 is usually used for the newer generation of mechan Unresolved issues in anticoagulation therapy 1467 ical prostheses in the aortic position in the absence of complicating risk factors; otherwise an INR of 2.5-3.5 or even slightly higher is used. The recommendations regarding intensity of anticoagulation are hampered by the fact that the study populations have been quite heterogeneous regarding valve position, type of prosthesis and presence of atrial fibrillation. Regarding the additional use of antiplatelet agents, it is unclear for what indications these should be given, on what dose of aspirin, and when combination with dipyridamole should be chosen. Management in the case of surgery The adjustment of anticoagulation with vitamin K antagonists in association with surgical procedures is frequently the subject of consultations. It is probably most critical in patients with mechanical prosthetic heart valves, but these patients have only constituted one of the subgroups in various cohort studies or case series. There is an absence of randomized clinical trials on this topic, and several questions remain: How should the treatment with vitamin K antagonists be reduced or stopped prior to surgery - gradually over a number of days or abruptly with vitamin K? Is LMWH as effective as unfractionated heparin when the valve is insufficiently protected? and is it sufficiently reversed by protamine sulfate in the case of postoperative bleeding complications? Should the vitamin K antagonist be restarted with a slightly higher dose on the first day? Myocardial infarction For secondary prevention in patients with coronary artery disease, the combination of vitamin K antagonists at an intensity of at least INR 2.0 with aspirin provides an odds reduction for death, myocardial infarction (MI) or stroke of 65% compared with aspirin alone, at the cost of a moderate increase in the risk of bleeding [59]. Combination therapy should be of interest for high-risk patients, e.g. those with an increased risk of systemic embolism, emanating from a mural thrombus, including those with transmural anterior MI, extensive left ventricle dysfunction and congestive heart failure, previous systemic embolism and/or atrial fibrillation. The WARIS II trial demonstrated that for the combination of warfarin targeted at an INR of 2.0-2.5 with aspirin 75 mg once daily in comparison with aspirin 160 mg daily alone, the number needed to treat (NNT) to avoid one case of death or thromboembolic cerebral stroke or non-fatal reinfarction per year was 80, and the number needed to harm (NNH) by a major hemorrhage was 222 [60]. The benefit-risk ratio is thus advantageous for the combination. What the health-economic outcome is remains to be determined, since combination therapy requires precise monitoring of anticoagulation clinics to keep the INR within this relatively narrow range for a good portion of the time. Pregnancy This issue could constitute an entire chapter on its own, due to the almost complete lack of randomized studies. The literature on anticoagulation during pregnancy consists to a very large extent of case series and review papers. LMWH appears as effective as unfractionated heparin in the prophylaxis of VTE [61], and probably safer with regard to osteoporotic fractures (0% vs. 6%) [61] as well as for bone mineral density during the first year after pregnancy [62]. For women with prosthetic heart valves there is more controversy, and the Sixth ACCP Consensus Conference on Antithrombotic Therapy lists three alternative regimens, all with grade 2C (the lowest) recommendations[63]. Vitamin K antagonists and calcium hemostasis Chronic use of vitamin K antagonists has been shown to reduce the serum concentration of osteocalcin and increase the urinary excretion of hydroxyproline in several animal models and in man [64]. Whether this has any significant clinical implications is unclear since studies on chronic use of vitamin K antagonists have shown both decreased bone mineral density with a single case of a fracture [65-67] and absence of such abnormalities [68,69]. 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