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


Therapeutics

Idraparinux was noninferior to standard therapy for deep venous thrombosis but inferior for pulmonary embolism

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ACP J Club. 2008 Jan-Feb;148:19. doi:10.7326/ACPJC-2008-148-1-019

Related Content in the Archives
Extended prophylaxis with idraparinux prevented recurrence of venous thromboembolism but increased risk for bleeding


Clinical Impact Ratings

Emergency Med: 6 stars

Hematol/Thrombo: 6 stars

Pulmonology: 6 stars


Source Citation

The van Gogh Investigators. Idraparinux versus standard therapy for venous thromboembolic disease. N Engl J Med. 2007;357:1094-104. [PubMed ID: 17855670]


Abstract

Question

In patients with deep venous thrombosis (DVT) or pulmonary embolism (PE), is idraparinux as effective as standard therapy (heparin followed by a vitamin K antagonist) in preventing recurrence of venous thromboembolism (VTE)?

Methods

Design: 2 randomized, controlled, noninferiority trials.

Allocation: Concealed.*

Blinding: Blinded (central outcome adjudication committee).*

Follow-up period: 3 and 6 months.

Setting: 318 centers in 25 countries in North and South America, Europe, Africa, and Australia/New Zealand.

Patients: Patients ≥ 18 years of age with acute symptomatic DVT (n = 2904, mean age 58 y, 54% men) or PE (n = 2215, mean age 62 y, 52% women). Exclusion criteria included receipt of heparin for > 36 hours; need for thrombolysis, embolectomy, or a vena cava filter; another indication for a vitamin K antagonist; pregnancy; creatinine clearance < 10 mL/min; 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 = 1452 in the DVT study and 1095 in the PE study), or standard therapy (tinzaparin, enoxaparin, or intravenous heparin followed by warfarin or acenocoumarol, with monitoring and dose adjustment as required) (n = 1452 in the DVT study and 1120 in the PE study). Treatment duration was either 3 months (22% of patients in the DVT study and 9% in the PE study) or 6 months, based on the physician's assessment of recurrence risk.

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

Patient follow-up: 99% (intention-to-treat analysis).

Main results

Risk for recurrent VTE at 3 months was higher with idraparinux than with standard therapy in the PE study, but groups did not differ in the DVT study (Table). Similar results were seen at 6 months in patients treated for the longer period (Table). In both studies, idraparinux had less risk for bleeding than standard therapy at 3 months (Table), but groups did not differ at 6 months. Idraparinux increased risk for death from all causes in the PE study (including 12 vs 5 cases of fatal PE) but not in the DVT study (4 vs 3 cases of fatal PE) (Table).

Conclusion

For prevention of recurrent venous thromboembolism, idraparinux was noninferior to standard therapy in patients with deep venous thrombosis but was inferior to standard therapy in patients with pulmonary embolism.

*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 standard therapy (heparin followed by a vitamin K antagonist) to prevent recurrence of venous thromboembolism (VTE) in patients with deep venous thrombosis (DVT) or pulmonary embolism (PE)†

Outcomes Follow-up Study Idraparinux Standard therapy Odds ratio (95% CI) NNH (CI)
Recurrent VTE 3 mo DVT 2.9% 3.0% 1.0 (0.6 to 1.5)‡ Not significant
PE 3.4% 1.6% 2.1 (1.2 to 3.8) 57 (24 to 304)
RRI (CI)
6 mo§ DVT 3.7% 3.7% 1% (−34 to 53) Not significant
PE 4.0% 2.0% 107% (22 to 248) 47 (21 to 231)
Death 3 mo DVT 2.3% 2.0% 14% (−30 to 86) Not significant
PE 5.1% 2.9% 79% (17 to 173) 45 (26 to 157)
RRR (CI) NNT (CI)
Clinically relevant bleeding 3 mo DVT 4.5% 7.0% 36% (13 to 52) 41 (24 to 126)
PE 5.8% 8.2% 30% (5 to 49) 41 (22 to 295)

†Abbreviations defined in Glossary. RRR, RRI, NNH, NNT, and CI calculated from data in article.
‡Criterion for noninferiority was met because the upper limit of the CI was < 2.
§Analysis includes only the 78% of patients in the DVT study and the 91% of patients in the PE study who received treatment for 6 mo.


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]