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


Therapeutics

Extended prophylaxis with idraparinux prevented recurrence of venous thromboembolism but increased risk for bleeding

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ACP J Club. 2008 Jan-Feb;148:20. doi:10.7326/ACPJC-2008-148-1-020

Related Content in the Archives
Idraparinux was noninferior to standard therapy for deep venous thrombosis but inferior for pulmonary embolism


Clinical Impact Ratings

Hematol/Thrombo: 6 stars

Pulmonology: 6 stars


Source Citation

The van Gogh Investigators. Extended prophylaxis of venous thromboembolism with idraparinux. N Engl J Med. 2007;357:1105-12. [PubMed ID: 17855671]


Abstract

Question

In patients with venous thromboembolism (VTE) who have completed 6 months of anticoagulant therapy, is idraparinux more effective than placebo in preventing recurrence in the following 6 months?

Methods

Design: Randomized placebo-controlled trial.

Allocation: Concealed.*

Blinding: Blinded (patients, clinicians, and central outcome adjudication committee).*

Follow-up period: 6 months.

Setting: 157 centers in 23 countries in North and South America, Europe, Africa, and Australia/New Zealand.

Patients: 1215 patients ≥ 18 years of age (mean age 60 y, 53% men) with symptomatic deep venous thrombosis (55% of patients) and/or pulmonary embolism (48%) who had been treated for 6 months with a vitamin K antagonist (warfarin or acenocoumarol) or idraparinux. Exclusion criteria included an indication to continue anticoagulation for the index VTE or another reason, pregnancy, creatinine clearance < 10 mL/min, severe hepatic disease, high risk for or active bleeding, and uncontrolled hypertension.

Intervention: Idraparinux, 2.5 mg subcutaneously once weekly (in patients with creatinine clearance < 30 mL/min, dose was 1.5 mg after the first injection) (n = 594), or placebo (n = 621), for 6 months.

Outcomes: Objectively confirmed symptomatic recurrent VTE, major bleeding, clinically relevant bleeding, and death from all causes.

Patient follow-up: 99.8% (intention-to-treat analysis).

Main results

Idraparinux reduced risk for recurrent VTE more than placebo (Table). Episodes of major bleeding occurred only in the idraparinux group (Table); 3 of these episodes were fatal intracranial hemorrhage. Idraparinux increased risk for clinically relevant bleeding (Table). Groups did not differ for death (Table).

Conclusion

In patients with venous thromboembolism who had completed 6 months of anticoagulant therapy, idraparinux prevented recurrence in the following 6 months but increased risk for bleeding.

*See Glossary.

Source of funding: Sanofi-Aventis.

For correspondence: Dr. H.R. Buller, Academic Medical Center, Amsterdam, The Netherlands. E-mail h.r.buller@amc.uva.nl.


Table. Idraparinux vs placebo for extended prophylaxis against recurrence of venous thromboembolism (VTE)†

Outcomes at 6 mo Idraparinux Placebo RRR (95% CI) NNT (CI)
Recurrent VTE 1.0% 3.7% 72% (33 to 89) 38 (31 to 82)
RRI (CI) NNH (CI)
Major bleeding 1.9% 0% 54
Clinically relevant bleeding‡ 4.5% 1.5% 211% (50 to 546) 33 (20 to 82)
Death 1.5% 0.6% 133% (−23 to 611) Not significant

†Abbreviations defined in Glossary. RRR, RRI, NNT, NNH, and CI calculated from data in article.
‡Includes major bleeding.


Commentary

The inferiority of the long-acting pentasaccharide factor Xa inhibitor idraparinux to standard therapy among patients with PE is intriguing, especially in contrast to its noninferiority among patients with DVT. Although recent clinical data support the efficacy of standard dosing for both DVT and PE, earlier studies suggested that a more rapid clearance of heparin necessitates a higher initial dose among patients with PE (1-3). Therefore, a pharmacokinetic difference in Xa inhibition may exist (possibly as it pertains to long-acting Xa inhibitors). Although the van Gogh Investigators reported no substantial difference in pharmacokinetics between the idraparinux and conventional therapy groups, the difference in incidence of recurrent VTE between the 2 groups originated mainly during the first 2 weeks of therapy. This finding raises the possibility of variable Xa inhibition in the acute period among patients with PE. It is worth noting that the recurrence rate in the conventional therapy group of the PE study (1.6%) was considerably lower than expected and lower than that seen in the DVT study (3.0%). Further study of idraparinux in patients with DVT and PE may explain the divergent outcomes noted in this trial.

Certain populations (e.g., patients with cancer or those for whom monitoring of international normalized ratio is difficult) would benefit from the easily administered treatment regimen that idraparinux affords. Trials have yet to show the superiority of pentasaccharides over vitamin K antagonists, as has been shown with low-molecular-weight heparins in patients with cancer. Further study is needed to better characterize the efficacy of idraparinux in the treatment of PE before it can be recommended in this population.

The potent Xa inhibition and long half-life of idraparinux, which are among the desirable characteristics of this anticoagulant, are also possible explanations for the increased bleeding observed among patients randomized to idraparinux in the extended anticoagulation trial. Bleeding during idraparinux therapy poses challenges, because no known drug antidote exists (although investigational studies are ongoing). In the meantime, treatment should include transfusion of packed red blood cells or fresh frozen plasma when clinically indicated, and use of prothrombin concentrate or recombinant factor VIIa can be considered.

An effective anticoagulant is needed that does not require dose adjustment and offers a favorable safety profile and predictable pharmacokinetics. The trials by the van Gogh Investigators provide valuable insight into the potential benefits and limitations of idraparinux. However, the coagulation cascade presents multiple opportunities to intervene. Newer anticoagulants, including rNAPc2 (which inhibits the tissue factor/activated factor VII complex), oral factor Xa inhibitors, and oral direct thrombin inhibitors, show promise.

A compelling role for idraparinux would involve use in the emergency department on diagnosis of DVT, because once-weekly dosing would facilitate discharge and follow-up in the outpatient setting. A trial of idraparinux specifically in outpatients would be welcome.

Scott C. Woller, MD
Scott M. Stevens, MD
C. Gregory Elliott, MD
Intermountain Medical Center and University of Utah School of Medicine
Salt Lake City, Utah, USA


References

1. Büller HR, Agnelli G, Hull RD, et al. Antithrombotic therapy for venous thromboembolic disease: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126:401S-28S. [PubMed ID: 15383479]

2. Hirsh J, van Aken WG, Gallus AS, et al. Heparin kinetics in venous thrombosis and pulmonary embolism. Circulation. 1976;53:691-5. [PubMed ID: 1253392]

3. Simon TL, Hyers TM, Gaston JP, Harker LA. Heparin pharmacokinetics: increased requirements in pulmonary embolism. Br J Haematol. 1978;39:111-20. [PubMed ID: 666973]