Postdischarge prophylaxis for venous thromboembolism among high-risk surgery patients

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1 Postdischarge prophylaxis for venous thromboembolism among high-risk surgery patients Giancarlo Agnelli Abstract: The role of pharmacological prophylaxis against venous thromboembolism in highrisk surgical patients is straightforward during hospitalization but controversial after hospital discharge. Clinical trials based upon venography-detected deep vein thrombosis (DVT), yield high DVT rates which may not be clinically relevant, since most cases are asymptomatic. On the other hand, clinical surveys based upon clinically overt venous thromboembolism yield low DVT rates that underestimate the problem. If postdischarge prophylaxis is used, oral anticoagulants may be more cost-effective than low-molecular-weight heparins. However, optimal strategies for venous thromboembolism prophylaxis after hospital discharge will not be definitively provided until large studies are performed with sufficient power to detect clinically relevant endpoints such as symptomatic DVT or pulmonary embolism. Key words: deep vein thrombosis; heparin; low-molecular-weight heparins; pulmonary embolism; venography; venous thromboembolism Introduction Venous thromboembolism is the most common cause of preventable in-hospital postoperative morbidity and mortality. 1 The incidence of postoperative deep vein thrombosis (DVT) can be reduced with pharmacological prophylaxis. 2,3 The large majority of clinical studies on the incidence of postoperative DVT and the efficacy of pharmacological prophylaxis have surveyed patients until hospital discharge. Therefore, the incidence of DVT developed after hospital discharge and the optimal duration of pharmacological prophylaxis for its prevention is still unknown. 4 Optimal duration of pharmacological prophylaxis A number of reports have implied a high incidence of DVT presenting after hospital discharge, thus generating debate on the optimal duration of pharmacological prophylaxis for venous thromboembolism The controversy began in 1959 when Sevitt and Gallagher reported that fatal pulmonary embolism might occur 30 days or more after surgery for hip fracture. 5 Thereafter, two studies from Clarke-Pearson et al reported conflicting results. 6,7 In a retrospective trial, the prevalence of postdischarge isotopic DVT was as high as 45%, while it was only 3% in a subsequent prospective study. The interest in postdischarge venous thromboembolism increased steeply after the report by Scurr et al in which 13 out of 57 patients undergoing major nonorthopaedic surgery developed isotopic DVT confirmed by Istituto di Medicina Interna e Vascolare, Università di Perugia, Perugia, Italy Address for correspondence: Giancarlo Agnelli, Istituto di Medicina Interna e Medicina Vascolare, Università di Perugia, Via Enrico Dal Pozzo, Perugia, Italy. venography during the 6-week follow-up period. 8 Most of these delayed events were recorded in the first 10 days following discharge. Thereafter, Hoek et al followed up 200 hip replacement patients with negative venography at discharge; three patients developed DVT confirmed by venography and one died of pulmonary embolism confirmed by autopsy. 9 Eriksson followed up 66 hip surgery patients free of isotopic DVT at discharge for 2 months and found that one patient developed clinical evidence of thromboembolism. 10 In general surgery patients, the rate of postoperative pulmonary embolism increased by 30% when the events occurring within 30 days of hospital discharge were considered. 11 Support for continuing prophylaxis after discharge comes from a non-randomized study carried out by Amstutz et al in 3000 patients who were not tested for venous thromboembolism at discharge. 12 One-third of the patients were treated with warfarin for 3 weeks after discharge, while the remaining patients received no prophylaxis according to the preference of the investigators. Five episodes of pulmonary embolism (PE) (0.3%) were observed in patients receiving no prophylaxis after discharge compared with no episodes in patients receiving oral anticoagulants. Three additional studies contributed to the controversial issue of the optimal duration of DVT prophylaxis Prophylaxis of venous thromboembolism after hospital discharge may be problematic and risky. Indeed, continuing heparin prophylaxis on an outpatient basis presents some limitations. Heparin injection is rather impractical because it requires monitoring the platelet count in order to detect promptly the occurrence of heparin-induced thrombocytopenia, whose incidence has been correlated with the duration of heparin administration. 16 Warfarin and low-molecularweight heparins (LMWHs) might be reasonable alternatives to heparin, but their value remains to be established. The majority of patients with postoperative DVT are asymptomatic and non-invasive diagnostic methods for identifying asymptomatic DVT are not sensitive. 17 There- Arnold X(98)VM215MP

2 52 G Agnelli Table 1 Deep vein thrombosis (DVT) at venography 3 weeks after discharge. Placebo Enoxaparin p-value Patients (no.) Overall DVT 17 (19.3%) 6 (7.1%) Proximal DVT 7 (7.9%) 5 (5.9%) Distal DVT 10 (11.4%) 1 (1.2%) Data from ref. 18. Table 2 Deep vein thrombosis (DVT) at venography 3 weeks after discharge. Placebo Enoxaparin p-value Patients (no.) Overall DVT 43 (37%) 21 (18%) Proximal DVT 28 (24%) 8 (7%) Distal DVT 15 (13%) 13 (11%) Data from ref. 19. fore, it is not clear whether late presenting postoperative DVT actually develop or simply become symptomatic after hospital discharge. Venography is the only accurate diagnostic method in patients with asymptomatic DVT. When reviewing the literature on the incidence of postdischarge venous thromboembolism, different figures are obtained and different conclusions could be drawn with respect to clinical trials that used venography or clinically overt thromboembolic events as endpoint measurements. For this reason, the data from these two types of trials should be considered separately. Clinical trials based on venographydetected DVT Three studies in elective hip surgery with venography to assess DVT have been published recently (Tables 1 3). Planes et al carried out a single-centre, randomized, doubleblind trial aimed at assessing the risk of postdischarge venous thromboembolism and the efficacy of postdischarge prophylaxis. 18 At hospital discharge, days after surgery, 179 consecutive hip replacement patients with negative venography, were randomly assigned to subcutaneous enoxaparin, 40 mg once a day, or placebo for 21 days. Venography was repeated at the end of 21 days treatment or earlier in 173 patients. There were no deaths or symptomatic pulmonary embolism. The rate of DVT was significantly lower in the enoxaparin group than in the placebo group (7.1% versus 19.3%, p = 0.018). Proximal DVT was Table 3 Deep vein thrombosis (DVT) at venography 3 weeks after discharge. Placebo Dalteparin p-value Patients (no.) Overall DVT 23 (26%) 11 (12%) Data from ref. 20. observed in 5.9% of the patients in the enoxaparin group and in 7.9% of the patients in the placebo group (p = 0.6). Three minor bleeds occurred in the enoxaparin group and one in the placebo group; none required treatment withdrawal. The authors concluded that in patients who have undergone elective hip replacement with negative venography at hospital discharge, the risk of late-occurring DVT screened by venography is high if they do not receive further antithrombotic prophylaxis. Continued prophylaxis with enoxaparin was shown to be effective and safe in reducing venography-screened DVT. Bergqvist et al investigated in major orthopaedic surgery whether 1 month of enoxaparin is more effective than enoxaparin given only during hospitalization. 19 Two hundred sixty-two patients undergoing hip replacement received enoxaparin during their 10-day hospital stays. The patients were then randomly assigned to receive enoxaparin or placebo according to a double-blind design. Enoxaparin or placebo was continued until the total treatment period, in hospital plus following discharge, was 1 month. Venography, performed days after discharge, was adequate in 116 patients in the placebo group and in 117 in the enoxaparin group. DVT was identified in 43 patients in the placebo group and in 21 patients in the enoxaparin group (37% and 18%, respectively, p 0.001). Proximal DVT was found in 24% and 7% of the placebo and enoxaparin patients, respectively, p Two patients had pulmonary embolism before venography was performed. The origin of the thrombi remained undetermined. Six patients in the enoxaparin group and one patient in the placebo group had haematomas at the injection sites. No patients died or had major complications. Thus, there were significantly fewer venous thromboembolic events in patients undergoing elective hip replacement when prophylaxis with enoxaparin was given for a total of 1 month, rather than only during the hospitalization, without excessive bleeding. Dahl et al carried out a double-blind, randomized study in 308 patients to investigate whether prophylaxis with dalteparin should be prolonged beyond the hospital stay. 20 All patients received initial prophylaxis with dalteparin, dextran and compression stockings. On day 7, patients with negative venography were randomized to receive dalteparin 5000 IU once daily or placebo, for 4 weeks. All patients underwent bilateral venography, perfusion-ventilation lung scan and chest X-ray on days 7 and 35. The overall prevalence of DVT on day 7 was 15.9%. On day 35, the prevalence of DVT from day 7 to day 35 was 25.8% in the placebo group and 11.8% in the dalteparin-treated group (p = 0.017). The incidence of symptomatic pulmonary embolism from day 7 to day 35 was 2.8% in the placebo group compared with no case in the dalteparin group. Pulmonary embolism was fatal in one case. No patients experienced serious complications related to dalteparin or placebo. The authors concluded that prolonged thromboprophylaxis with dalteparin for 35 days significantly reduces the prevalence of DVT and should be recommended for 5 weeks after hip replacement surgery. Clinical surveys based on clinically overt thromboembolic events Agnelli et al performed a prospective survey to assess the prevalence of clinically overt thromboembolic events in hip

3 Postdischarge prophylaxis for venous thromboembolism 53 surgery patients with a negative venography discharged from the hospital without further pharmacological prophylaxis. 21 The authors followed up 213 patients with negative venography at discharge (105 elective hip replacement and 108 hip fracture patients). One hundred and eighty-six patients (87.3%) were re-examined as outpatients 1 2 months after discharge. Five patients reported symptoms of DVT but the diagnosis was not confirmed by objective testing. The remaining 27 patients (12.7%) were followed up through their family doctor or by telephone call; in these patients the follow-up period ranged from 60 days to 2 years. Twenty-two of the 27 patients were alive and reported no signs or symptoms of venous thromboembolism. Three patients (1.4%) died for reasons not correlated with venous thromboembolism. Two patients could not be traced due to geographical inaccessibility; they were alive after 1 year according to the records of their health care district. The results of this study indicate that in hip surgery patients with negative venography the prevalence of clinically overt thromboembolic events after hospital discharge ranges from 0 to 2.2% (95% CI). These figures, when confirmed in larger studies, suggest that it is conceivable that the majority of late presenting postoperative DVT actually develop during the hospital stay and become symptomatic after hospital discharge. Ricotta et al performed an overview analysis to evaluate the incidence of late occurring clinically overt venous thromboembolism in major orthopaedic surgery patients discharged with negative venography and without further pharmacological prophylaxis. 22 The authors selected studies published from 1974 to 1995 on the prophylaxis of venous thromboembolism after major orthopaedic surgery that fulfilled the following criteria: (1) pharmacological prophylaxis during the hospital stay; (2) bilateral venography before discharge; (3) interruption of pharmacological prophylaxis at discharge in patients with negative venography; and (4) postdischarge follow-up of the patients for at least 4 weeks. Out of 31 identified studies, 13 fulfilled the overview criteria (Table 4). The total number of evaluated patients was Adequate venography was obtained in 3469 patients (84.1%). In the 2361 patients with negative venography (68.1%), 30 episodes of symptomatic venous thromboembolism (including six cases of pulmonary embolism) after hospital discharge were reported, with a cumulative incidence of 1.27% (95% CI ) (Table 5). This overview showed a low incidence of clinically overt venous thromboembolism at follow-up in major orthopaedic surgery patients discharged with negative venography. On the basis of these results, extending the duration of pharmacological prophylaxis in these patients may not be justified. Pharmacoeconomic studies Sarasin et al evaluated the net clinical benefit and the economic burden of prophylactic anticoagulation after hospital discharge following general surgery and orthopaedic surgery. 36,37 These authors performed a cost-effectiveness analysis, based on data from the literature, assessing the risk of developing symptomatic venous thromboembolism beyond the hospital stay, the risk of major bleeding and the efficacy of treatment. In general surgery (gastrointestinal, gynaecologic, urologic or vascular surgery), two strategies were compared: (1) prolonged self-administered prophylactic low-dose LMWHs during 4 weeks after discharge from the hospital; and (2) anticoagulant therapy with heparin started immediately after the first clinically overt venous thromboembolism. The number of venous thromboembolic events prevented, the number of major bleeding events induced and the average direct costs were considered as the main outcome measures. Prophylactic LMWHs turned out to be effective. Depending on the rate of venous thromboembolic events ( % per week), this strategy prevented venous thromboembolisms for a hypothetical cohort of patients, more than the number of anticoagulationrelated complications, estimated to be 10 cases. Its marginal costs, however, exceeded US$2.5 million for patients. As the weekly rate of venous thromboembolism Table 4 In-hospital incidence of deep vein thrombosis (DVT) in the studies included in the analysis. In-hospital incidence of DVT Patients with adequate Patients with positive Author and ref. Patients (no.) venographies venography (%) 95% CI Harris, Eriksson, Bergqvist, Hoek, Leclerc, GHAT, Agnelli, Hull, Fauno, Cohen, Spiro, Trowbridge, Agnelli, Totals Data from ref. 22. The incidence and 95% CI were recalculated for each study, and for the pooled studies patients were as described in the text.

4 54 G Agnelli Table 5 Postdischarge incidence of venous thromboembolism in patients discharged from hospital with a negative venography. The incidence and 95% CI were recalculated for each study. Patients with DVT Follow-up incidence of DVT Follow-up Deaths Patients negative during incidence during Author and ref. (no.) venography follow-up (%) 95% CI of PE follow-up Harris, Eriksson, Bergqvist, a 8 b Hoek, Leclerc, b GHAT, Agnelli, b Hull, Fauno, Cohen, Spiro, Trowbridge, Agnelli, Totals a Minor PE detected autopsy in a patient who died of myocardial infarction on the eighteenth postoperative day. b Not PE related. Data from ref. 22. increased, prophylactic LMWHs became more cost-effective, with a marginal cost-effectiveness ratio per venous thromboembolism prevented ranging from US$ (rate of venous thromboembolism, 0.06% per week) to US$ (rate of venous thromboembolism, 0.18% per week). The authors concluded that, although prolonged prophylactic anticoagulation after hospital discharge for general surgery is effective in preventing venous thromboembolism, its marginal costs are too high to recommend its indiscriminate use. A decision analysis model was used to determine the clinical and economic effects of different strategies in patients undergoing total hip replacement. 24 The following interventions were analyzed: (1) stopping prophylactic antithrombotic therapy after the in-hospital perioperative period (7 14 days); (2) extending prophylactic antithrombotic therapy with oral anticoagulants for up to 6 weeks or 3 months; and (3) screening for DVT at the time of hospital discharge by compression ultrasonography or venography. The risk of developing DVT recurrence and pulmonary embolism, the risk of major bleeding side-effects and the cost associated with each strategy were measured for a hypothetical cohort of patients. Data were obtained from the published literature and from the hospital costs where the analysis was performed. Compared with stopping prophylaxis at the time of hospital discharge, a 6-week course of prophylactic oral anticoagulant therapy would reduce the number of cases of recurrent DVT from 1172 to 493 and the number of symptomatic pulmonary embolisms from 234 to 99, and would be less costly. This gain would be achieved at the cost of 29 major bleedings if the bleeding risk is low (0.2 per month) and 71 if the bleeding risk is moderate (0.5 per month). Compared with stopping prophylaxis at discharge, ultrasound screening would reduce symptomatic pulmonary embolisms from 234 to 142, induce only 13 major bleeding episodes, and be cost-effective, with marginal costs per additional pulmonary embolism averted ranging from US$3000 to US$7000, depending on ultrasound sensitivity. Venography screening would be the most effective strategy; however, compared with ultrasound, its marginal costs per additional pulmonary embolism averted would exceed US$ Venography versus clinically overt events: accuracy versus clinical relevance Venography was compared with clinically overt events in clinical trials on postdischarge prophylaxis for venous thromboembolism. When used to measure the endpoint DVT in studies on prophylaxis of venous thromboembolism, venography has a number of advantages. It is a relatively well-defined technique, which is relatively easy to perform in study centres familiar with the conduct of clinical trials on prophylaxis of venous thromboembolism. In addition, venography is more sensitive than non-invasive techniques such as plethysmography and real-time B-mode ultrasonography for the diagnosis of asymptomatic DVT. However, venography has important shortcomings when used in studies on prophylaxis of venous thromboembolism. A single venography can only measure the rate of DVT at the moment when this diagnostic procedure is performed and not the total rate in the postoperative period. Furthermore, the clinical relevance of venography-detected DVT, that is asymptomatic in most of the cases, is unknown. On the other hand, clinically overt events are obviously clinically relevant but present some limitations as the endpoint of long-term follow-up studies. Indeed, clinically overt events have a low rate, are characterized by an unpredictable timing and their diagnosis is rather non-specific. Studies on postdischarge prophylaxis showed a high incidence of venography-detected DVT and a low incidence of

5 Postdischarge prophylaxis for venous thromboembolism 55 clinically overt events. This contrast between symptomatic and venography DVT makes it difficult to judge the riskbenefit and cost-benefit of prophylaxis of venous thromboembolism, particularly if prolonged after discharge. In addition, these contrasting results make crucial the choice of endpoints in assessing the efficacy of postdischarge prophylaxis for venous thromboembolism. In the past, emphasis has been placed on diagnostic accuracy. This approach invariably favoured venography as the only accurate diagnostic test. However, additional criteria should be considered, namely, clinical relevance. Actually, although venography is the diagnostic gold standard, its value for assessing clinical benefit is unknown. The role of screening patients before discharge is still undefined. Venography cannot be performed in every patient, while the role of real-time B-mode ultrasonography remains unclear. Recently, Robinson et al confirmed the low rate of clinically overt thromboembolic events in orthopaedic patients discharged without further prophylaxis, regardless of the results of ultrasonography at discharge. 38 In conclusion, the analysis of benefit versus risk of postdischarge prophylaxis for venous thromboembolism should be based on large studies that have the power to detect clinically relevant endpoints as symptomatic DVT and pulmonary embolism. Indeed, large clinical endpoint trials with strict rules for outcome detection are needed before setting the guidelines for the optimal duration of postoperative pharmacological prophylaxis. References 1 Salzman EW, Hirsh J. The epidemiology, pathogenesis and natural history of venous thrombosis. In: Colman RW, Hirsh J, Marder VJ, Salzman EW eds. Haemostasis and thrombosis. Basic principles and clinical practice. Philadelphia, PA: JB Lippincott Company, 1994: Collins R, Scrimigeour A, Yusuf S, Peto R. 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