Management of thromboembolism in the outpatient setting

Management of Thromboembolism Outpatient Setting

in the

G. Agnelli, R. Rossi, and M.G. Santacuria Low-molecular-weight heparins (LMWHs) are suitable for self-administration at home, because they have a predictable anticoagulant effect following subcutaneous injection and do not require laboratory monitoring. Clinical trials evaluating the safety and efficacy of LMWHs in the outpatient setting for the prevention of deep vein thrombosis (DVT) after orthopedic surgery and for the treatment of established DVT are reviewed. Extended LMWH prophylaxis reduces the incidence of venographically detected DVT by approximately 50%. Medical practice relies heavily on clinical diagnosis of DVT, for which both sensitivity and specificity are poor. It is uncertain how the results of research trials on DVT prevention based on venography relate to ordinary practice. In the treatment of established DVT, there was no significant difference between outpatient management with LMWH and inpatient treatment with unfractionated heparin (UFH). However, outpatient management offered a considerable reduction in resource usage, with associated cost savings. Semin Hematol37(suppl5):23-26. Copyright 0 2000 by W.B. Saunders Company.

I

N RECENT YEARS, a reduction in the length of hospital stays after elective surgical procedures has been observed. A total hip replacement in the United States now involves a 3-day hospital stay. One possible consequence of a short-term hospital stay is that complications, such as venous thromboembolism (VTE), may appear after patient discharge. Prophylaxis of VTE in orthopedic surgery patients during hospitalization is routine. The availability of low-molecular-weight heparins (LMWHs), which can be self-administered and do not require activated partial thromboplastin time (aPTT) monitoring, increases the feasibility of continued prophylaxis after discharge. However, before routinely extending prophylaxis in all orthopedic surgery patients, it is important to ascertain whether benefits are associatedwith this practice. The availability of LMWHs also allows the possibility of treating established deep vein thrombosis (DVT) on an outpatient basis. Treatment of DVT consists of anticoagulation with intravenous unfractionated heparin (UFH) or a once- or twice-daily dose of LMWH administered by subcutaneous injection for 5 to 6 days, and oral warfarin starting on day 1 or 2 and continued for at least 3 months. Such a regimen provides effective reduction in the incidence of recurrent VTE, with a low risk of bleeding. Safety and efficacy are at least equivalent when intravenous UFH is substituted by Seminars

in Hematology,

Vol37,

LMWH in the hospital setting, raising the question of whether DVT can be effectively treated without hospital admission.8 Should such an approach be validated, it offers the potential for considerable cost savings and reduction of patient discomfort.

Postdischarge

Prophylaxis

Even without formal studies such as that undertaken by Scurr, every clinician will recall surgical patients who, following their initial discharge from hospital, were later readmitted with DVT.l3 While in practice only symptomatic DVT are diagnosed and treated, data from venography-controlled clinical trials show that many more surgical patients have asymptomatic DVT. Four clinical trials on DVT prophylaxis after orthopedic surgery, all of which included mandatory venography at 3 to 4 weeks after discharge, found that postdischarge prophylaxis with LMWH reduced the incidence of From the Department of Internal Medicine, Institute of Internal and Vascular Medicine, University of Pwugia, Perugia, Italy. Address reprint requests to G. Agnelli, MD, Istituto di Medicina Interna e Medicina Vascolare, Vniuersit~ degli Studi, Via Enrico dal Pozzo, 06123 Perugia, Italy. Copyright 0 2000 by W.B. Saunders Company 0037-1963/00/3703-5007$10.00/0 doi:10.10S3/shm.2000.8428

No 3, Suppt 5 (July),

2000:

pp 23-26

23

24

Table

Agnelli, Rossi, and Santamaria

1. Results of Four Venographically on Extended Study

Planes et alI1 Bergqvist et al* Dahl et al3 Lassen et al7

Prophylaxis

Placebo 19% 39% 26% 12%

Controlled of DVT

Studies

LMWH

P

7% 18% 12% 4%

Value

.018 < .OOl .017

VTE with respect to in-hospital prophylaxis (Table 1).2J,7J1 In the first study, 179 consecutive patients undergoing total hip replacement and in-hospital prophylaxis with enoxaparin (ClexaneB/ LovenoxB, Aventis, Strasbourg, France), 40 mg once daily, were enrolled.ll All patients underwent venography at discharge: those with negative venography were randomized to receive enoxaparin 40 mg once daily or placebo until day 2 1. At the end of the treatment period or at occurrence of symptoms, a second venography was performed. The incidence of DVT was 7.1% in enoxaparin-treated patients compared with 19.3% in controls (P = .OlS>. A secondstudy with a slightly different protocol included 233 patients, who all received prophylaxis with enoxaparin 40 mg once daily during hospital admission following hip replacement surgery.2 Patients were randomized to continue enoxaparin or placebo injection after discharge, for up to 1 month. Patients were not screened for DVT before discharge; therefore, it is likely that the study population included somepatients with venographically detectable DVT. Venography at the end of the treatment period detected a 39% incidence of DVT in the controls compared with 18% in the enoxaparin group (P < .OOl). The incidence of proximal DVT was also significantly reduced (from 24% to 7%; P -=c .OOl) by continued enoxaparin. Similar results were obtained in a study comparing dalteparin (Fragmin, Pharmacia & Upjohn, Stockholm, Sweden) with placebo in the same setting.3 All patients received dalteparin, 5000 IU once daily, dextran, and graduated compression stockings during their hospital stay. At day 6 after surgery, patients with negative venography, chest x-ray, and lung scanning were randomized to withdraw prophylaxis and receive placebo or to continue prophylaxis for 4 weeks. A second venography, lung

scan, and chest x-ray were performed on day 3 5. The incidence of DVT was 25.8% in the placebo group and 11.8% in the dalteparin group (P = .017). In a similar clinical trial, Lassen et al randomized patients undergoing elective total hip arthroplasty to receive dalteparin or placebo at hospital discharge.’ As in the study of Bergqvist et al, no mandatory venography was performed bfefore randomization. At day 35, venography was done: the incidence of DVT was 12% in the placebo group and 4% in the dalteparin group. In a large review of 13 studies of more than 4,000 patients undergoing major orthopedic surgery, predischarge venography found a DVT incidence of greater than 30%.12 Only a small proportion of patients with positive venography developed clinically overt DVT in these studies. It should be noted that of 2,361 patients with negative venography at discharge, none of whom received prophylaxis after discharge, only 1.3% experienced clinically overt thromboembolic events during follow-up. It is therefore difficult to predict which individual patients require postdischarge prophylaxis, even on the basis of a clear venography result at discharge.

Treatment

of Established

DVT

A number of trials evaluated subcutaneous LMWHs in the treatment of DVT in hospitalized patients, and a recently updated metaanalysis of the results showed that LMWH is at least equivalent to intravenous UFH in this indication (Table 2).5 Three major srudies evaluated the use of LMWH on an outpatient basis.6,9,i” Levine et al randomized patients to the LMWH enoxaparin (1 mg/kg twice daily) who were in hospital at the time of enrollment and discharged early; patients presenting as outpatients were managed entirely att home. 9 There was no significant difference between the two treatment groups with respect to recurrent VTE or incidence of bleeding, and there was a nonsignificant trend towards lower mortality in the group receiving enoxaparin. However, the time spent in hospital was markedly reduced by enoxaparin treat-

Thrombmabolismin Outpatients

Table

2. Updated

Meta-analysis

Event Recurrent

Comparing

UFH

VTE

Major bleeding (fixed-effects Major bleeding (random-effects Death

of Studies

5.4% (97/1,792)

1.9% model) model)

Abbreviations: ARR, average Data from Gould et a1.s

(35/1,853) 1.9% (35/1,853) 6.8% (122/1,792) relative

ratio;

LMWHs

1.1%

Cl)

OR (95%

Cl)

0.85 (0.63-1.14)

0.61(-0.04-1.26)

0.57 (0.33-0.99)

(-0.09-1.41)

1.65 (0.36-2.94)

interval;

of DVT

0.88 (-0.48-2.24)

0.66

(20/1,821) 5.0% (88/1,774)

ment (mean, 1.1 + 2.9 days) compared with UFH (mean, 6.5 t 3.4 days). Of 247 patients randomized to enoxaparin, 120 were managed entirely as outpatients. Koopman et al, using a similar protocol, evaluated the efficacy of nadroparin.6 Again, there was no significant difference between the LMWH and UFH groups with respect to recurrent VTE,, mortality, or major bleeding. The mean hospital stay was reduced by 67% in patients treated with LMWH (2.7 days v 8.1 days). After initial instruction, 85% of patients randomized to nadroparin were able to administer injections without professional help. The Columbus study was a multicenter, open trial that evaluated the efficacy and safety of subcutaneous reviparin (Clivarine, Knoll AG, Ludwigshafen, Germany) compared with intravenous UFH in the treatment of VTE.l* Patients assigned to reviparin might be treated on an outpatient basis.The incidence of recurrent VTE was 5.3% in the reviparin group and 4.9% in the UFH group. The absolute difference of 0.4% met the predefined criteria for equivalence between the two treatment regimens. There was no significant difference between the two groups with respect to the incidence of bleeding. The mean hospital stay was 3 days shorter in the LMWH group. Of 510 reviparin patients, 100 were treated without hos.pital admission, and 56 were discharged within the first 3 days of hospital stay. An open, nonrandomized study on treatment of DVT with dalteparin encouraged outpatient treatment whenever possible, achieving it for at leastpart of the study period in 80% of patients.lO In addition to confirming the feasibility of out of hospital treatment, this study calculated the cost of treatment and compared it with average costsof

and UFH for the Treatment ARR (95%

4.6% (82/1,774) 1.1% (20/1,821)

Cl, confidence

LMWHs

25

0.71(0.40-1.27) 0.71(0.53-0.94)

OR, odds ratio.

inpatient UFH treatment at two of the participating hospitals. Compared with inpatient treatment, costs were reduced by 34.5%, and the authors calculated that a further reduction of 11.5 % could be achieved if all patients discharged during LMWH treatment had their hospital stay reduced to lessthan 24 hours.

Discussion Despite absolute differences in the results, the four studies of extended prophylaxis hold two consistent messages. First, the incidence of DVT is high in patients who receive no prophylaxis after discharge from hospital, and second, extended prophylaxis with LMWH for 3 to 4 weeks after discharge reduces the risk of late thrombosis by about 50%. The protocol requirements of clinical trials impose some limitations on the interpretation of these data. It is not possible to extrapolate these results to all patients: in the majority of clinical trials patients with a positive venography at discharge were excluded, while in clinical practice venography is not routinely performed after orthopedic surgery. Bergqvist et al and Lassenet al did not perform venography at discharge: as in clinical practice, asymptomatic venographically detectable DVTs were not diagnosed. This aspect may have influenced the absolute incidence of DVT in these two studies, but has not changed their results: extended prophylaxis is more effective than in-hospital prophylaxis and postdischarge placebo to prevent venographically detected DVT at 3 to 4 weeks. In all four studies, the incidence of clinically overt thromboembolic events in both groups was significantly lower than rate of venographi-

26

Agnelli, Rossi, and Santamuvia

tally detected DVT. The low number of clinically overt events is consistent with the metaanalysis of Ricotta et al. I2 Venography is highly unusual outside the clinical trial situation, and is used only on an individual basis. Future trials should use alternative methods to measure end points that are more practical than venography and can be applied to clinical practice. Compression ultrasonography failed to diagnose asymptomatic DVT and did not offer any utility as a screening pr0cedure.l Serum D-dimer less than 500 ng/mL has a high negative predictive value for DVT in nonsurgical patients, but a suitable cut-off level has yet to be identified for surgical patients.* The practical advantage of LMWH over UFH also can be exploited during the treatment of DVT. The aforementioned studies established that outpatient treatment of DVT is feasible, with no reduction in safety or efficacy compared with intravenous UFH, but with a substantial reduction in the use of resources. Essential requirements for home-treatment of DVT are an objective diagnosis and a careful assessmentof risk of bleeding. Based on clinical judgment, patient management should include an assessmentof risk factors for VTE, including occult cancer and thrombophilia.

Conclusions The studies reported here indicate that the role of LMWHs in the prophylaxis and treatment of DVT could be extended. Prolonged prophylaxis with LMWHs significantly reduces the incidence of venographically detected post-discharge DVT in orthopedic patients, although these results may not be directly applicable to routine clinical practice. For patients who do develop DVT, outpatient treatment based on self-administered subcutaneous LMWHs and oral warfarin is practical and offers cost savings to health care providers.

2. Bergqvist D, Benoni G, Bjorgell 0, et al: Lowmolecular-weight heparin (enoxaparin) as prophylaxis against venous thromboembolism after total hip replacement. N Engl J Med 335:696-700, 1996 G, Asp&n T, et al: Prolonged 3. Dahl OE, Andreassen thromboprophylaxis following hip replacement surgery-Results of a double-blind, prospective, randomised, placebo-controlled study with dalteparin (FragminTM). Thromb Haemost 77:26-31, 1997 4. Goldhaber SZ, Simons GR, Elliott CG, et al: Quantitative plasma D-dimer levels among patients undergoing pulmonary angiography for suspected pulmonary embolism. JAMA 270:2819-2822, 1993 5. Gould ME;, Dembitzer AD, Doyle RL, et al: Lowmolecular weight heparins compared with unfractionated heparin for treatment of acute deep venous thrombosis. Ann Intern Med 130:800-809, 1999 6. Koopman IM, Prandoni P, Piovella F, et al: Treatment of venous thrombosis with i.v. unfractionated heparin administered in the hospital as compared with subcutaneous low molecular weight heparin administered at home. N Engl J Med 334:682-687, 1996 7. Lassen MR, Berris 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 Haemost 73:11.04, 1995 (abstr) 8. Lensing AWA, Prins MH, Davidsson BL, et al: Treatment of deep venous thrombosis with low molecular weight heparins. A meta-analysis. Arch Intern Med 155:601-607, 1995 of 9. Levine M, Gent M, Hirsh J, et al: A comparison low molecular weight heparin administered primarily at home with unfractionated heparin administered in hospital for proximal deep-vein thrombosis. N Engl J Med 334:677-681, 1996 P, Holmstrom M: Use of low molecular 10. Lindmarker weight heparin (dalteparin), once daily, for the treatment of deep vein thrombosis. A feasibility and health economic study in an outpatient setting. J Intern Med 240:395-401, 1996 11.

12

References 1. Anderson DR, Gross M, Robinson KS, et al: Ultrasonographic screening for deep vein thrombosis following arthroplasty fails to reduce posthospital thromboembolic complications: The Postarthroplasty Screening Study (PASS). Chest 114:119S122s, 1998 (suppl 2)

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Planes AN, Vochelle N, Darmon J-Y, et al: Risk of deep venous thrombosis after hospital discharge in patients undergoing total hip replacement. Doubleblind randomised comparison of enoxaparin versus placebo. Lancet 348:224-228, 1996 Ricotta S, Iorio A, Parise P, et al: Post discharge clinically overt venous thromboembolism in orthopaedic patients with negative venography-An overview analysis. Thromb Haemost 76:887-892, 1996 Scurr JH: How long after surgery does the risk of thromboembolism persist? Arch Stand Surg 556:2224, 1990 The COLUMBUS heparin in the thromboembolism.

Investigators: Low-molecular-weight treatment of patients with venous N Engl J Med 337:657-662, 1997