Orthopedics

The Post-Discharge Prophylactic Management of the Orthopedic Patient With Low-Molecular-Weight Heparin: Enoxaparin

Paul E Nilsson, MD, PhD; David Bergqvist, MD, PhD; Göran Benoni, MD; Ola Björgell, MD; Hans Fredin, MD, PhD; Urban Hedlund, MD; Sylvain Nicolas; Göran Nylander, MD, PhD

Abstract

This prospective, double-blind trial was performed to determine whether 4 weeks' prophylaxis with enoxaparin after total hip replacement (THR) is more effective in protecting against deep vein thrombosis (DVT) than prophylaxis during hospitalization. Two hundred sixty-two patients undergoing THR were given enoxaparin 40 mg once daily during hospitalization (9 ± 2 days) before being randomized at discharge to continue enoxaparin (N=131) or receive placebo (N=131) for a total of 1 month (30 ± 4 days). According to intention-to-treat analysis, 43 DVT and 2 pulmonary emboli (PE) occurred in the placebo group (34.4%) versus 21 DVT and no PE in the enoxaparin group (P<0.001). The reduction in proximal DVT was also significant (21.4 vs 6.1%; P<0.001). No major bleeding complications developed. Prophylaxis with enoxaparin for one month significantly reduces venous thromboembolic disease in patients undergoing THR compared to conventional prophylaxis during hospitalization.

Abstract

This prospective, double-blind trial was performed to determine whether 4 weeks' prophylaxis with enoxaparin after total hip replacement (THR) is more effective in protecting against deep vein thrombosis (DVT) than prophylaxis during hospitalization. Two hundred sixty-two patients undergoing THR were given enoxaparin 40 mg once daily during hospitalization (9 ± 2 days) before being randomized at discharge to continue enoxaparin (N=131) or receive placebo (N=131) for a total of 1 month (30 ± 4 days). According to intention-to-treat analysis, 43 DVT and 2 pulmonary emboli (PE) occurred in the placebo group (34.4%) versus 21 DVT and no PE in the enoxaparin group (P<0.001). The reduction in proximal DVT was also significant (21.4 vs 6.1%; P<0.001). No major bleeding complications developed. Prophylaxis with enoxaparin for one month significantly reduces venous thromboembolic disease in patients undergoing THR compared to conventional prophylaxis during hospitalization.

Various methods of prophylactic anticoagulation are used during the hospital period following total hip replacement (THR) surgery.1"3 At present, the best option to prevent deep vein thrombosis (DVT) after THR is low-molecularweight heparin (LMWH).1 -3^ The usual practice is to restrict administration of LMWH to the period of hospitalization. Recent studies, however, have reported a significant risk of DVT during the earliest weeks or months after discharge from hospital.71' The European Consensus Statement in 1991 concerning prevention of venous thromboembolic disease (VTED) stated that this risk needs to be assessed in prospective trials and that the efficacy of continued prophylaxis beyond hospitalization deserves investigation.12

Against this background, several European studies were instituted to address these concerns and the results of four of these trials are now available.13" 16 One of these studies was performed to determine whether post-discharge prophylaxis for DVT after THR was more effective than prophylaxis during hospitalization.13 An abbreviated summary of this study is reported here together with a discussion of its results in the context of current data on thromboembolic prophylaxis in the post-discharge period.

MATERIALS AND METHODS

The study was conducted at a single center in Sweden and had a prospective, randomized, double-blind design. A total of 262 patients undergoing primary elective hip arthroplasty were included. Surgical data are given in Table 1. The median age was 70 (range 44-87) years and 57% of the patients were female. During the hospitalization period all patients received thrombosis prophylaxis with enoxaparin (Clexane®; Lovenox®, Rhône-Poulenc Rorer, Collegeville, Pa) administered once daily by the subcutaneous route at a dose of 40 mg. The first injection was given 12 hours before surgery. At the end of the hospital stay (9 ± 2 days), all patients were randomized to one of two post-discharge, double-blind treatment groups: a placebo group (N=I 3 1 ) and an enoxaparin group (N=Bl) in which patients continued to receive enoxaparin 40 mg once daily. The duration of postdischarge prophylaxis was 3 weeks, resulting in a total treatment duration of 30 ± 4 days. No screening for DVT was performed at discharge. At the end of the post-discharge period, every patient underwent bilateral phlebography. This procedure was performed earlier if there were clinical signs of thrombosis. The trial medication (enoxaparin or placebo) was administered by special project nurses who visited the patients every day in their homes, thereby guaranteeing 100% compliance.

Surgery was performed via a lateral approach with the patient in supine position with or without osteotomy. Distal and proximal thrombosis, pulmonary embolism (PE), death, and changes in laboratory parameters were recorded. The analysis was made on an intentionto-treat basis.

RESULTS

Of 262 intention-to-treat patients, 12 clinically symptomatic events were noted during the post-discharge period (Table 2). Eight patients developed DVT (20 ± 6 days after surgery) and two PE (day 17 and 18, respectively, after surgery) in the placebo group compared with two patients who developed DVT (day 14 and 16, respectively after surgery) in the enoxaparin group.

Bilateral ascending phlebography performed 4 weeks after surgery identified an additional 35 asymptomatic cases of DVT in the placebo group and 19 in the enoxaparin group (Table 3). Therefore, there were a total of 43 patients with DVT and two with PE in the placebo group compared with 21 patients with DVT but none with PE in the enoxaparin group. This is a statistically significant difference (P<0.001). The number and distribution of cases of proximal and distal DVT are given in Table 3. The majority of the DVT episodes in the placebo group were proximal. Some cases of DVT in the enoxaparin group were proximal, but the majority were small distal thromboses. The reduction in the number of proximal DVT in the enoxaparin group was significant (P<0.001).

There were no deaths during the prophylactic period or during 3 months of follow-up. During the post-discharge period, six injection-site hematomas were observed in the enoxaparin group versus one in the placebo group. This difference was not statistically significant. Thrombocytopenia, defined as a platelet count below 100 X 10 p 9 /L, and severe thrombocytosis were not observed in either group. Ninety-five percent of the patients were operated on in epidural anesthesia and received enoxaparin 12 hours before surgery. No complication was seen with this combination.

Table

TABLE 1Patient surgical data

TABLE 1

Patient surgical data

Table

TABLE 2Analysis of symptomatic VTED during the randomization period (21 ± 2 days)

TABLE 2

Analysis of symptomatic VTED during the randomization period (21 ± 2 days)

Table

TABLE 3Thromboprophylactic effect of post-discharge treatment with enoxaparin according to intention-to-treat analysis

TABLE 3

Thromboprophylactic effect of post-discharge treatment with enoxaparin according to intention-to-treat analysis

DISCUSSION

In this study, enoxaparin was used as routine thrombosis prevention for all patients during the hospitalization period. Subsequently, half of the patients received an additional 3 weeks of prophylaxis with enoxaparin and the other half of the patients received placebo. This mode of prophylaxis was well tolerated and there were no problems that could be attributed to the administration of enoxaparin. Some reports claim that LMWH should not be combined with epidural or spinal anesthesia; however, 95% of the patients in this study received enoxaparin 1 2 hours before surgery was performed during epidural/spinal anesthesia, and no complication was noted. This finding is in agreement with those of other studies.17,18 Thrombocytopenia is a well-known complication of heparin treatment.'9 There were no cases of thrombocytopenia with enoxaparin in this trial and this observation is consistent with that of another trial.16 Furthermore, only mild thrombocytosis occurred in the present study.

Table

TABLE 4Percentage (%) of patients in different subpopulations with VTED

TABLE 4

Percentage (%) of patients in different subpopulations with VTED

The main finding of the present study was that prolonged prophylaxis produced a 50% relative reduction in VTED and 75% reduction in the frequency of proximal DVT. This difference in number of thromboembolic complications was also reflected in the need for thrombosis treatment. Irrespective of symptomatology, 21 of the 45 patients with VTED in the placebo group needed ^hospitalization for a total duration of 269 days. The corresponding figures for the enoxaparin group were 11 patients requiring 99 days hospitalization.

Is prolonged prophylaxis cost effective? In order to answer this question, formal comprehensive health economic analyses must be performed; however, brief calculations may reveal a trend towards cost savings. The cost per day for treatment of confirmed VTED in the United States in 1993 was US$460, excluding diagnostic tests.20 If these figures are applied to all 262 intentionto-treat patients in our study, the savings ascribed to the difference in hospitalization for treatment of VTED is approximately US$600 per patient receiving enoxaparin after discharge. Calculation of cost savings based solely on the cost of treating symptomatic DVT may be clinically more relevant. There were eight episodes of symptomatic DVT and two episodes of PE in the placebo group compared with two cases of symptomatic DVT in the enoxaparin group. The total cost for treatment of DVT and PE in Sweden in 1993 has been estimated to be US$1160 and US$9713, respectively (US$1 = SEK6.70).21 Based on these assumptions, the savings per patient that can be attributed to this difference in post-discharge prophylactic treatment is estimated to US$120. These informal calculations indicate that the financial savings at least partially compensate for the increased cost of the prolonged prophylaxis. Compared to the huge cost for THR in Sweden (US$10,000), the cost for 3 additional weeks of prophylaxis with enoxaparin (US$120) seems justified.

What is the optimum duration of prolonged prophylaxis? Some authors have empirically suggested up to 3 months' prolonged prophylaxis after THR.11 Others have claimed that there is insufficient evidence to recommend thromboprophylaxis after discharge from hospital.22 In the present study, the majority of the clinically symptomatic thromboembolic events were prevented by 1 month's prophylaxis, which, therefore, may be enough. However, there were still some non-responders, ie, patients who had asymptomatic DVT at bilateral phlebography 1 month after THR despite receiving prophylaxis during this time. The prophylaxis had, therefore, not prevented the development of asymptomatic DVT in those patients. It is unclear whether those cases of asymptomatic DVT were prevented from developing into symptomatic episodes. Most cases of DVT in the enoxaparin group were distal and small muscle vein thrombosis, of which several were treated with only elastic compression stockings and/or antiphlogistic agents and without the need for rehospitalization. Two of the eight patients with proximal thrombosis in the enoxaparin group had small valve cusp thrombosis. Thus, although several of the DVT cases occurring during 1 month's enoxaparin treatment were probably of little clinical significance, about 5% of the patients still had a remaining proximal DVT. This sub-group of non-responders has to be further investigated to disclose possible underlying risk factors, such as coagulation disorders. The risk of developing new DVT after 1 month also has to be further investigated.

Which THR patients have a higher risk of developing VTED? Table 4 displays subgroups of at-risk patients included in the study. There was an over-representation of females with asymptomatic DVT according to bilateral phlebography performed 1 month after surgery in both the placebo and the enoxaparin groups. This female predisposition to develop DVT is known from other studies in non-surgical patients. There was little difference in the number of male and female patients who developed symptomatic VTED (Table 2). Patients who underwent simultaneous bilateral surgery also seem to have an extremely high risk of developing DVT. If one does not want to treat every patient undergoing THR with prolonged prophylaxis, at least those patients who have undergone bilateral surgery and probably all female patients would benefit from such treatment.

Could the beneficial results of this study be reproduced in a routine clinical setting? Special project nurses visited the patients in their homes during the post-discharge period to ensure 100% compliance with injection of the trial medication. Would the compliance be as high if the injections had been administered by the patients themselves or their relatives? The clinical impression seems to be that most patients, at least in Sweden, if well motivated, are able to perform subcutaneous self-injections without difficulty. If not, there will be a point at which the economic benefits will be lost.

The clinical significance of asymptomatic DVT diagnosed phlebographically after THR remains a point of contention among orthopedic surgeons. One study22 reported a low incidence of VTED in patients followed for 6 months after hospital discharge. The authors concluded that a significant discrepancy exists between the high prevalence of DVT observed in clinical trials using phlebography and symptomatic VTED occurrence. Based on their findings, they claimed that insufficient evidence for extending thromboprophylaxis after discharge from hospital exists; however, in the current study, as in similar published studies14"16, the incidence of symptomatic disease was substantially higher among the patients whose thromboprophylaxis was discontinued at the time of hospital discharge.

CONCLUSION

In this study, 4 weeks' prophylaxis with the LMWH, enoxaparin, substantially reduced the incidence of venous thromboembolic events in the post-discharge period, particularly the number of proximal thromboses. Furthermore, the safety of 4 weeks' enoxaparin therapy was equal to that of the placebotreated controls.

REFERENCES

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2. Paiement GD, Schutzer SF, Wessinger SJ, et al. Influence of prophylaxis on proximal venous thrombus formation after total hip arthroplasty. / Arthroplasty. 1992;7:471-475.

3. Mohr DN, Silverstein MD, Murtaugh PA, et al. Prophylactic agents for venous thrombosis in elective hip surgery. Arch Intern Med. 1993; 153:2221-2228.

4. Bergqvist D. Review of clinical trials of low molecular weight heparins. Eur J Surg. 1992; 158:67-78.

5. Leizorovicz A, Haugh MC, Chapuis F-R, et al. Low molecular weight heparin in prevention of perioperative thrombosis. BMJ. 1992; 305:913-920.

6. Planes A, Vochelle N, Mazs F, et al. Prevention of postoperative venous thrombosis: A randomised trial comparing unfractioned heparin with low molecular weight heparin in patients undergoing total hip replacement. Thromb Haemostas. 1988;60:407-410.

7. Scurr JH, Coleridge-Smith PD, Hasty JH. Deep venous thrombosis: a continuing problem. BMJ. 1988;297:28.

8. Trowbridge A, Boese CK, Woodruff B, et al. Incidence of posthospitalization proximal deep venous thrombosis after total hip replacement arthroplasty. Clin Orthopaed. 1994; 299: 203-208.

9. Bergqvist D, Lindblad B. A 30-year survey of pulmonary embolism verified at autopsy: an analysis of 1274 surgical patients. Br J Surg. 1985;72:105-108.

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11. Tremarne JD, Choroszy CH, Menking SA. Deep vein thrombosis in total hip arthroplasty patients. J Vase Technol. 1992; 16:23-27.

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13. Bergqvist D, Benoni G, Björgell O, et al. Low molecular weight heparin (enoxaparin) for prophylaxis against venous thromboembolism following total hip replacement. N Engl J Med. 1996; 335:696-700.

14. Dahl S, Andreassen G, Müller C, et al. The effect of prolonged thromboprophylaxis with dalteparin on the frequency of deep vein thrombosis (DVT) and pulmonary embolism (PE) 35 days after hip replacement surgery (HRS). Thromb Haemost. 1 995; 7 1 : 1 094.

15. Planes A, Vochelle N, Darmon J, et al. Persistence of the risk of deep venous thrombosis after hospital discharge in patients undergoing total hip replacement: double-blind randomised comparison of enoxaparin versus placebo, Lancet. 1996; 348:224-228.

16. Lassen MR, Borris LC on behalf of the Danish Prolonged Prophylaxis Study Group. Prolonged thromboprophylaxis with low molecular weight heparin (Fragmin®) after elective total hip arthroplasty - a placebo-controlled study. Thromb Haemostas. 1995; 73:1 104(A-781).

17. Haas S, Flosbach CW. Prevention of postoperative thromboembolism in general surgery with enoxaparin: preliminary findings. Acta Chir Scand. 1990; Suppl 556:96-102.

18. Bergqvist D, Lindblad B, Mätzsch T. Low molecular weight heparin for thromboprophylaxis and epidural/spinal anaesthesia - is there a risk. Review article. Acta Anaesth Scand. 1992: 36:605-609.

19. Schmitt BP, Adelman B. Heparin-associated thrombocytopenia: a critical review and pooled analysis. Am J Med Sci. 1993; 305(4): 208-215.

20. Menzin J, Colditz GA, Regan MM, et al. Cost-effectiveness of enoxaparin versus low-dose warfarin in the prevention of deep vein thrombosis after total hip replacement surgery. Arch Intern Med. 1995; 155:757-764.

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22. Warwick D, Williams MH, Bannister GC. Death and thromboembolic disease after total hip replacement. A series of 162 cases with no routine chemical prophylaxis. J Bone Joint Surg. 1995; 77-B:6-10.

TABLE 1

Patient surgical data

TABLE 2

Analysis of symptomatic VTED during the randomization period (21 ± 2 days)

TABLE 3

Thromboprophylactic effect of post-discharge treatment with enoxaparin according to intention-to-treat analysis

TABLE 4

Percentage (%) of patients in different subpopulations with VTED

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