Current issues of ACP Journal Club are published in Annals of Internal Medicine


Therapeutics

Ximelagatran prevented secondary venous thromboembolism

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ACP J Club. 2004 Jul-Aug;141:9. doi:10.7326/ACPJC-2004-141-1-009

Related Content in this Issue
• Companion Abstract and Commentary: Ximelagatran reduced venous thromboembolism more than warfarin after total knee replacement


Clinical Impact Ratings

GIM/FP/GP: 5 stars

Hematol/Thrombo: 7 stars


Source Citation

Schulman S, Wåhlander K, Lundström T, Clason SB, Eriksson H. Secondary prevention of venous thromboembolism with the oral direct thrombin inhibitor ximelagatran. N Engl J Med. 2003;349:1713-21. [PubMed ID: 14585939]


Abstract

Question

What is the long-term efficacy and safety of ximelagatran after 6 months of standard anticoagulant therapy for secondary prevention of venous thromboembolism (VTE)?

Design

Randomized (allocation concealed*),blinded (clinicians, patients, {data collectors, outcome assessors, and data analysts}†),* placebo-controlled trial with 18-month follow-up (Thrombin Inhibitor in Venous Thromboembolism [THRIVE III]).

Setting

142 centers in 18 countries.

Patients

1233 patients who were ≥ 18 years of age with symptomatic, objectively confirmed deep venous thrombosis (DVT) or pulmonary embolism (PE) and had received anticoagulant therapy for 6 months with no recurrent VTE event. Exclusion criteria were indication for continuous anticoagulant therapy, hemoglobin level < 9.0 g/dL, platelet count < 90 000/mm3, pregnancy, lactation, expected survival < 18 months, renal impairment, clinically important liver disease, or persistent elevation of the aminotransferase level > 3 times the upper limit of normal. 1223 patients (99%) (mean age 57 y, 53% men) were included in the intention-to-treat analysis.

Intervention

Patients were allocated to twice-daily ximelagatran, 24 mg (n = 612), or placebo (n = 611) for 18 months. All patients discontinued anticoagulant therapy but did not begin study treatment until the international normalized ratio (INR) was < 1.5.

Main outcome measures

VTE (recurrent DVT and PE), major and minor bleeding, and all-cause mortality.

Main results

Analysis was by intention to treat. Fewer patients who received ximelagatran had recurrent VTE events than did patients who received placebo (Table). Groups did not differ for major or minor bleeding or for all-cause mortality (Table).

Conclusion

In patients with deep venous thrombosis or pulmonary embolism receiving standard anticoagulant therapy for 6 months, ximelagatran reduced recurrent venous thromboembolism and did not increase bleeding.

*See Glossary.

†Information provided by author.

Source of funding: AstraZeneca Research and Development.

For correspondence: Dr. S. Schulman, Karolinska Hospital, Stockholm, Sweden. E-mail sam.schulman@ks.se.


Table. Ximelagatran vs placebo for secondary prevention of venous thromboembolism (VTE) at 18 months‡

Outcomes Ximelagatran Placebo RRR (95% CI) NNT (CI)
VTE 2.8% 12.6% 83% (69 to 90) 10 (9 to 12)
All-cause mortality 1.1% 1.4% 17% (−143 to 72) Not significant
Major bleeding 1.1% 1.3% 16% (−65 to 273) Not significant
RRI (CI) NNH
Major and minor bleeding 23.9% 21.0% 16% (−6 to 44) Not significant

‡Abbreviations defined in Glossary; RRR, RRI, NNT, NNH, and CI calculated from data in article using estimates from hazards ratios in article.


Commentary

The trial by Francis and colleagues shows the superiority of 36 mg twice daily of ximelagatran over warfarin, both started after surgery, for prevention of VTE after total knee replacement surgery. However, as the greater efficacy came entirely from a decreased incidence of isolated (largely asymptomatic) calf-vein thrombosis, the interpretation of these results deserves comment.

In most studies comparing low-molecular-weight heparins (LMWHs), which have a rapid onset of action, and oral anticoagulants, which require 2 to 4 days to render an anticoagulant effect, the latter category of drugs has been less effective. Because both the study and the comparator drugs were started at the same time after surgery, I wonder whether the superiority of ximelagatran simply reflects the different onset of action of the 2 drugs. All that oral anticoagulants can do in this setting is prevent thrombus from growing. Indeed, both in this trial and in virtually all those assessing LMWHs, the incidence of proximal-vein thrombosis and that of PE, when taken together, did not differ between patients receiving oral anticoagulants and those receiving heparin.

Despite this consideration, warfarin is problematic for VTE prophylaxis because of the need for laboratory monitoring and potential drug interactions, and LMWHs are the standard of care for prevention of VTE after orthopedic surgery. Although ximelagatran was shown to be more effective than enoxaparin in the EXPRESS study (1), it has not been compared with fondaparinux, a synthetic anti-Xa inhibitor that is more effective than enoxaparin for VTE prophylaxis after orthopedic surgery. The ultimate comparison of efficacy in the prevention of VTE after orthopedic surgery may be a head-to-head comparison between ximelagatran and fondaparinux.

The optimal long-term treatment of patients who present with unprovoked (or idiopathic) VTE is controversial. 15% to 30% of patients with idiopathic VTE will have recurrent VTE in the first year after 3 to 6 months of anticoagulation. Prolonging the duration of anticoagulation beyond 3 to 6 months may delay recurrences while exposing patients to the hemorrhagic risk associated with extended anticoagulation. The possibility that a lower-intensity warfarin regimen (INR 1.5 to 1.9) would allow safer anticoagulation without compromising efficacy (2) was trumped by the results of another study that showed that conventional-intensity anticoagulation (INR 2.0 to 3.0) has better efficacy than a lower-intensity regimen (3). The results of the trial by Schulman and colleagues show that long-term ximelagatran therapy, administered orally in a fixed dose and without laboratory monitoring, is effective for preventing recurrent VTE in patients who received 6 months of conventional anticoagulant therapy and is not associated with an increased hemorrhagic risk.

However, the extent to which ximelagatran prevented recurrent VTE was not different from that of oral anticoagulants in the many trials that addressed their benefit. Furthermore, the apparent lack of hemorrhagic potential may have been because of the unusually high rate of bleeding in patients who received placebo. Finally, in about 6% of patients, aminotransferase levels increased to > 3 times the upper limit of normal. Additional research is required to identify the optimal strategy of long-term anticoagulation in patients with idiopathic VTE. There is the potential that disease recurrence can be predicted on an individual basis after 3 to 6 months of conventional therapy if venous ultrasonography shows persistent abnormalities or D-dimer levels are elevated (4, 5).

Paolo Prandoni, MD
University of Padua
Padua, Italy


References

1. Eriksson BI, Agnelli G, Cohen AT, et al. The direct thrombin inhibitor melagatran followed by oral ximelagatran compared with enoxaparin for the prevention of venous thromboembolism after total hip or knee replacement: the EXPRESS study. J Thromb Haemost. 2003;1:2490-6 [PubMed ID: 14675083]

2. Ridker PM, Goldhaber SZ, Danielson E, et al. Long-term, low-intensity warfarin therapy for the prevention of recurrent venous thromboembolism. N Engl J Med. 2003;348:1425-34. [PubMed ID: 12601075]

3. Kearon C, Ginsberg JS, Kovacs MJ, et al. Comparison of low-intensity warfarin therapy with conventional-intensity warfarin therapy for long-term prevention of recurrent venous thromboembolism. N Engl J Med. 2003;349:631-9. [PubMed ID: 12917299]

4. Prandoni P, Lensing AW, Prins MH, et al. Residual venous thrombosis as a predictive factor of recurrent venous thromboembolism. Ann Intern Med. 2002;137:955-60. [PubMed ID: 12484710]

5. Palareti G, Legnani C, Cosmi B, et al. Predictive value of D-dimer test for recurrent venous thromboembolism after anticoagulation withdrawal in subjects with a previous idiopathic event and in carriers of congenital thrombophilia. Circulation. 2003;108:313-8. [PubMed ID: 12847064]